WO2006012683A1 - Chemical processes and compounds derived therefrom - Google Patents

Chemical processes and compounds derived therefrom Download PDF

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Publication number
WO2006012683A1
WO2006012683A1 PCT/AU2005/001145 AU2005001145W WO2006012683A1 WO 2006012683 A1 WO2006012683 A1 WO 2006012683A1 AU 2005001145 W AU2005001145 W AU 2005001145W WO 2006012683 A1 WO2006012683 A1 WO 2006012683A1
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optionally substituted
mmol
process according
cyclohexenone
group
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PCT/AU2005/001145
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French (fr)
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Janet Lesley Scott
Anthony Edward Rosamilia
Christopher Roy Strauss
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Monash University
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Priority claimed from AU2004904308A external-priority patent/AU2004904308A0/en
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Publication of WO2006012683A1 publication Critical patent/WO2006012683A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C07C211/48—N-alkylated amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
    • C07C211/55—Diphenylamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to N-substituted anilines and derivatives thereof and in particular to chemical processes for the preparation of N-substituted anilines and derivatives thereof.
  • EP 1258473 Al discloses that particular derivatives of 2- (2-amino-phenylmethyl)benzoic acids can bind to, and exhibit antagonistic activity on, the PGE 2 receptor.
  • Such compounds are postulated to be useful in preventing and/or treating bone diseases such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bond formation, cancer (e.g. cancer formation, cancer proliferation, cancer metastasis to organs and to bones, hypercalcemia accompanied by cancer metastasis to bones, etc.) and systemic granuloma, immunological diseases (e.g.
  • amyotropic lateral sclerosis ALS
  • multiple sclerosis multiple sclerosis
  • Sjoegren's syndrome systemic lupus erythematosus
  • AIDS amyotropic lateral sclerosis
  • allergy conjunctivitis, rhinitis, contact dermatitis, psoriasis, etc.
  • atopy atpoic dermatitis etc.
  • asthma pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease, pulmonary injury, hepatopathy, acute hepatopathy, neophritis, renal failure, myocardiac ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease and multiple organ failure, as well as for diseases associated with sleep failure or platelet aggregation.
  • JP 10072434 discloses the preparation of 2,4-substituted anilines and their use as herbicides
  • JP 60025968 discloses the use
  • the present invention provides a process for preparing N-substituted anilines comprising reacting the following components:
  • the present invention provides a process for preparing N-substituted
  • anilines comprising reacting an enamine of formula (I)
  • n represents an integer from 0 to 4.
  • R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
  • R 1 and R 2 independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R 1 and R 2 together may form an optionally substituted heterocyclyl group;
  • the present invention provides a process for preparing N-substituted anilines comprising reacting a compound of formula (II):
  • n represents an integer from O to 4.
  • R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and R 3 represents an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound;
  • N-substituted aniline refers generally to compounds having an optionally substituted benzene ring bearing at least one N-protected amine moiety. This includes traditional anilines as well as, for instance, compounds in which two of the substituents on the phenyl together form a further saturated or unsaturated ring, for example a cyclohexene or cyclohexane ring.
  • the substituted amine moiety may also be bonded to a benzene ring which is part of a polycyclic ring system, for instance, a steroid A ring as in the estrogen class of steroids.
  • Such compounds are also referred to herein as N-substituted anilines. It will become evident that in the process of the present invention the cyclohexenone component forms the optionally substituted benzene ring (or phenyl) moiety and the amine component forms the N-substituted amine moiety.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, acyloxy, alkyl, alkoxy, amino, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aminoacyl, thio, thioacyl, oxythioacyl, oxythioacyloxy, thioacyloxy, sulfinyl, sulfonyl, sulfinylamino, sulfonylamino, oxysulfinylamino, oxysulfonylamino, aminothioacyl, thioacylamino, amino sulfinyl, aminosulfonyl, alkaryl, alkaryloxy, aryl, aryloxy, carboxyl, acylamino, acylamino, acylamino, amino sulf
  • an optionally substituted alkylene group could be represented by a group such as -CH 2 CH 2 OCH 2 -, -CH 2 CH 2 NH-CH 2 -, -CH 2 NHCH 2 -, and the like.
  • optionally substituted is also taken to mean that the group may or may not be protected by a protecting group. Accordingly, when any one of the substituent groups bears a reactive moiety, such as a reactive carbonyl or amino, such moieties may be first protected to prevent them from reacting under the conditions of the present invention.
  • Suitable protecting groups are known and examples thereof are described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wutts (1999) 3 rd edition, John Wiley and Sons, Inc.
  • “Saturated carbocyclic ring compound” refers to cyclic alkyl groups, including mono- or polycyclic alkyl compounds such as cyclopropane, cyclobutane, cyclopentane, cycloctane and the like.
  • Unsaturated carbocyclic ring compound refers to mono- or polycyclic rings having at least 1 carbon to carbon double bond.
  • unsaturated carbocyclic ring compounds include aromatic rings, for instance aryl rings such as benzene, napthalene, anthracene, and the like, and also includes non-aromatic rings, for instance cycloalkenyl rings such as cyclohexene, cyclopentene and the like.
  • saturated heterocyclic ring compound refers to mono- or polycyclic alkyl groups wherein one or more of the carbon atoms which make up the ring has been replaced with a heteroatom or heterogroup.
  • heteroatoms include N, S, O, Se (or mixtures of such heteroatoms).
  • heterogroups include NR' where R' can be hydrogen, alkyl, aryl, sulfonyl, acyl and so on.
  • saturated heterocyclic ring compounds include piperidine, pyrrolidine, morpholine and the like, together with N- substituted derivatives thereof.
  • Unsaturated heterocyclic ring compound refers to mono- or polycyclic rings having at least 1 double bond and at least one heteroatom or heterogroup.
  • preferred heteroatoms include N, S, O 5 Se or P.
  • heterogroups include NR where R' can be hydrogen, alkyl, aryl, sulfonyl, acyl and the like.
  • Unsaturated heterocyclic ring compounds include aromatic heteroaryl groups such as pyridine, pyrimidine, pyrrole, furan, thiophene, and the like, and also includes non-aromatic and pseudo-aromatic rings such as dihydropyran and the like.
  • non-enolisable when used in relation to a formyl group or an aldehyde, means that there is no acidic proton ⁇ to the carbonyl group which would allow the formyl group to enolise.
  • non-enolisable formyl groups would be a formyl group which is attached directly to a ring carbon atom of an aromatic or heteroaromatic ring, or a formyl group which is attached directly to a ring heteroatom of a heteroaromatic or heterocyclic ring.
  • Another example is where the formyl group is remotely attached to an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound via a linking group such that there are no acidic protons ⁇ to the carbonyl group which would allow the formyl group to enolise.
  • a linking group such that there are no acidic protons ⁇ to the carbonyl group which would allow the formyl group to enolise.
  • An example of such a compound is cinnamaldehyde.
  • formyl also encompasses reactive derivatives of the CHO moiety.
  • Such groups may include acyclic and cyclic acetals, cyanohydrins, iminium salts, imines, aminals, amino alcohols, amino ethers, thioacyl groups, ylidenemalonitriles (eg, ArCH(CN) 2 ), as well as ⁇ -hydroxy aldehydes formed from mixed aldol reactions.
  • Alkyl refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, w-propyl, /so-propyl, r ⁇ -butyl, iso- butyl, «-hexyl, and the like.
  • Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • Arylene refers to a divalent aryl group wherein the aryl group is as described above.
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as described above.
  • Alkaryl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
  • Alkaryloxy refers to the group alkylaryl-O- wherein the alkylaryl group is as described above. Such alkaryloxy groups are exemplified by benzyloxy and the like.
  • Alkoxy refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, w ⁇ -propoxy, «-butoxy, tert-butoxy, sec- butoxy, 77-pentoxy, «-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkenyloxy refers to the group alkenyl-O- wherein the alkenyl group is as described above.
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds.
  • alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH) and the like.
  • Alkynyloxy refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
  • Alkynylene refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C ⁇ C-), propynylene (-CH 2 -C ⁇ C-) , and the like.
  • Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyacyl refers to groups alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl- OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Aminoacyl refers to the group -C(0)NR'R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Acylamino refers to the group -NRC(O)R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyloxy refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Aminoacyloxy refers to the groups -OC(O)NR'-alkyl, -OC(O)NR'-aryl, -OC(O)NR'- heteroaryl, and -OC(O)NR'-heterocyclyl where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxyacylamino refers to the groups -NR'C(O)O-alkyl, -NR'C(O)O-aryl, -NR'C(0)0- heteroaryl, and NR'C(O)O-heterocyclyl where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Acylimino refers to the groups -C(NR')-R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyliminoxy refers to the groups -0-C(NR')-R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Oxy acylimino refers to the groups -C(NR')-0R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • Cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms.
  • Examples of cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3- enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen.
  • heterocyclyl and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]
  • Heteroarylene refers to a divalent heteroaryl group wherein the aryl group is as described above.
  • Heterocyclylene refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.
  • Thio refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Thioacyl refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxythioacyl refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxythioacyloxy refers to groups HO-C(S)-O-, alkylO-C(S)-O- 5 cycloalkylO-C(S)-O-, arylO-C(S)-O-, heteroarylO-C(S)-O-, and heterocyclylO-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Thioacyloxy refers to groups H-C(S)-O-, alkyl-C(S)-O-, cycloalkyl-C(S)-O-, aryl- C(S)-O-, heteroaryl-C(S)-O-, and heterocyclyl-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Sulfinyl refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S (O)-, aryl-S(O)-, heteroaryl-S (O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Sulfonyl refers to groups H-S(O) 2 -, alkyl-S(O) 2 -, cycloalkyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, and heterocyclyl-S(O) 2 -, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Sulfmylamino refers to groups H-S(O)-NR'-, alkyl-S(O)-NR'-, cycloalkyl-S (O)-NR'-, aryl-S(O)-NR'-, heteroaryl-S(O)-NR'-, and heterocyclyl-S(O)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Sulfonylamino refers to groups H-S(O) 2 -NR'-, alkyl-S(O) 2 -NR'-, cycloalkyl-S(O) 2 - NR'-, aryl-S(O) 2 -NR'-, heteroaryl-S(O) 2 -NR'-, and heterocyclyl-S (O) 2 -NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxysulfmylamino refers to groups HO-S(O)-NR'-, alkylO-S (O)-NR'-, cycloalkylO- S(O)-NR'-, arylO-S(O)-NR'-, heteroarylO-S(O)-NR'-, and heterocyclylO-S (O)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxysulfonylamino refers to groups HO-S(O) 2 -NR'-, alkylO-S(O) 2 -NR'- 5 cycloalkylO-S (O) 2 -NR'-, arylO-S(O) 2 -NR'-, heteroarylO-S(O) 2 -NR'-, and heterocyclylO-S(O) 2 -NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminothioacyl refers to groups R'R'N-C(S)-, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Thioacylamino refers to groups H-C(S)-NR'-, alkyl-C(S)-NR'-, cycloalkyl-C(S)- NR'-, aryl-C(S)-NR'-, heteroaryl-C(S)-NR'-, and heterocyclyl-C(S)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminosulfinyl refers to groups R'R'N-S(O)-, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl., and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminosulfonyl refers to groups R'R'N-S(O) 2 -, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • the optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound is selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, having at least one formyl group or reactive derivative thereof attached directly to a ring atom thereof.
  • the optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound is selected from an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl having one, two or three formyl groups or reactive derivatives thereof attached directly to a ring atom thereof.
  • the ring compound is selected from an optionally substituted aryl or optionally substituted heteroaryl having one, two or three formyl groups or reactive derivatives thereof attached directly to a ring atom thereof.
  • the ring compound is selected from an aryl or heteroaryl having one or two formyl groups or reactive derivatives thereof attached directly to a ring atom thereof.
  • the ring atom is a ring carbon atom.
  • Preferred aryl groups as ring compounds include phenyl, napthyl, anthracenyl, pyrenyl, indenyl, and phenanthrenyl.
  • Preferred heteroaryl groups as ring compounds include pyridyl, furanyl, indolyl, indazolyl, benzotriazolyl, quinolinyl, acridinyl and benzofuranyl.
  • the "optional substituent" is additional to the non-enolisable formyl group(s) or reactive derivative(s) thereof.
  • alkyl group preferably methyl and ethyl
  • substituted alkyl group preferably 1-hydroxyethyl, 1-thioethyl, methoxyiminomethyl, ethoxyiminomethyl, l-(hydroxyimino)ethyl, l-(hydroxyimino)propyl, 1- hydrazinoethyl, 1-hydrazinopropyl, hydroxyiminomethyl, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitromethyl, 1-nitromethyl, and 2-nitroethyl;
  • acyl group preferably acetyl, propanoyl, benzoyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl or cyano);
  • alkoxy group preferably methoxy and ethoxy
  • oxyacyl group preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl;
  • acyloxy group preferably acetoxy and propioxy
  • substituted alkaryl group preferably 1-hydroxybenzyl, and 1-thiobenzyl
  • sulfmyl group preferably methylsulfinyl, ethylsulfinyl, benzene sulfinyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxysulfmyl, ethoxysulfinyl; sulfonyl group, preferably methylsulfonyl, ethylsulfonyl, benzenesulfonyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxycarbo, trifluoromethane;
  • oxyacylamino group preferably methoxycarbonylamido, and ethoxycarbonyl amido
  • oxythioacyl group preferably methoxythiocarbonyl and ethoxythiocarbonyl
  • thioacyloxy group preferably thionoacetoxy and thionopropionoxy
  • sulphinylamino group preferably methylsulfinylamino, ethylsulfinylamino, and benzenesulfmylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
  • sulphonylamino group preferably methylsulfonylamino, ethylsulfonylamino and benzene sulfonylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
  • oxysulfinylamino group preferably methoxysulfinylamino and ethoxysulfinylamino
  • oxysulfonylamino group preferably methoxysulfonylamino and ethoxysulfonylamino
  • alkenyl group preferably, 1-propenyl, vinyl, nitrovinyl, cyano vinyl, or trifluorovinyl and styryl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
  • alkynyl group preferably 1-propynyl, ethynyl or trimethylsilylethynyl.
  • substituent groups for a particular ring compound may include pentafluoroethyl, trifluoromethoxy, difluoromethoxy, thioformamido, triflurormethanethio, aminothioacyl, aminosulfonyl, trifluoroethenyl, nitro, cyano, halogen, amino, carboxyl, hydroxyl, hydrogen and aminoacyl.
  • suitable optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compounds having one or two non-enolisable formyl groups include benzaldehyde, o- and p-anisaldehyde, 4-hydroxybenzaldehyde, 4-carboxybenzaldehyde, pyridine-4-carboxaldehyde, pyridine-2-carboxaldehyde and 4-methylbenzaldehyde, isophthalaldehyde, furfural, 4-nitrobenzaldehyde, 2,2'-(propane-l,3- diylbis(oxy))dibenzaldehyde, and cinnamaldehyde.
  • the process of the present invention is amenable to the preparation of N-substituted anilines by solid phase synthetic techniques.
  • the ring compound bears a divalent linker group as a substituent to enable attachment to a polymer support.
  • Divalent linker group is taken to mean a divalent group capable of forming a stable bridge between the N-substituted aniline of the present invention and a polymer support resin.
  • divalent linker groups include optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted heterocyclylene, optionally substituted alkylenearylene, optionally substituted alkylenearylenealkylene, optionally substituted alkyleneheteroarylenealkylene, optionally substituted alkyleneheterocyclylenealkylene, and the like.
  • polymer supports include Merrifield resin, Wang resin, and so on.
  • the present invention can include an optionally substituted cyclohexenone as a reactant.
  • cyclohexenone refers to any cyclohexenone isomer and includes substituted cyclohexenones possessing an additional double bond which is exocyclic such as a mono arylidene cyclohexenone.
  • the cyclohexenone is an optionally substituted 2- or 3 -cyclohexenone, and most preferably an optionally substituted 2-cyclohexenone.
  • Suitable substituents are those which do not adversely effect or interfere with the formation of N-substituted anilines by the process of the present invention.
  • substituents include optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, thioalkyl, thioaryl, optionally substituted alkoxy, acyl, F, Cl, NO 2 , and includes cyclohexenones which are ring fused. Any substituent, if present, may be bonded to the cyclohexenone ring at either the 2 or 6 positions and additionally at one or more of the 3, 4 or 5 positions. In one embodiment the reactant is 2-cyclohexenone which has been substituted at the 3 and/or 4 and/or 5 positions, and more preferably at the 3 or 5 positions.
  • substituents are independently selected from optionally substituted aryl, optionally substituted alkyl, optionally substituted aryl, thioalkyl, thioaryl, optionally substituted alkoxy, acyl, F, Cl, NO 2 or may together represent a ring fused group such as an optionally substituted cycloalkenyl, or optionally substituted cycloalkyl group.
  • preferred cyclohexenones include 2-cyclohexenone, 3-methylcyclohex-2- enone, 3-(4-methylphenyl)cyclohex-2-enone and 5-methylcyclohex-2-enone. More preferably the reactant component is 2-cyclohexenone itself.
  • Suitable secondary and primary amines which can be used as reactant components in the present process are nucleophilic primary or secondary amines or reactive derivatives thereof in which the chosen N-substituents do not adversely effect or interfere with the amines ability to act as a nucleophile.
  • Preferred primary and secondary amines include compounds of the formula NHR 1 R 2 , where one of R 1 or R 2 represent hydrogen and the other an optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted cycloalkenyl or R 1 and R 2 independently represent optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl, or R 1 and R 2 together form an optionally substituted heterocyclyl group.
  • R 1 is hydrogen and R 2 represents optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or RWd R 2 independently represent optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or together form an optionally substituted heterocyclyl group.
  • R 1 is hydrogen and R 2 an optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or R 1 and R 2 are the same and represent an optionally substituted alkyl where the optional substituent is selected from alkyl, alkoxy or together represent a heterocyclyl group.
  • Suitable amines include benzylamine, n-hexylamine, aniline, 2- aminomethylpyridine, methyl aminoacetate, 3-indole-2-ethylamine (tryptamine), morpholine, ⁇ -methylbenzylamine, and di-»-butylamine, bis(2-methoxyethyl)amine, N 5 N- dibenzylamine, 2-phenylethylamine, 1,3 propylene amine, as well as amino acids, including esters or salts thereof such as O-methylglycine hydrochloride and glycine methyl ester.
  • amine derivatives which are able to react under the conditions of the present process.
  • reactive derivatives include ammonium salts (ie R 1 R 2 NH 2 + X " ) for example hydrochloride salts, or carbamic acids or ammonium carbamate salts (ie R 1 R 2 NCOOH 5 R 1 R 2 NH 2 + R 1 R 2 NCOO " ), where R 1 and R 2 groups are as defined above.
  • process of the present invention may include the use of additional components such as catalysts, solvents, etc.
  • Components (i), (ii) and (iii) may be reacted in single amounts or the process may involve the addition of further amounts of components (i), (ii) and/or (iii). Furthermore the process may be conducted with the use of more than one type of component (i), (ii) or (iii). For instance, in relation to this latter embodiment, the process may involve the initial reaction of components (ii) and (iii) to prepare a Michael adduct of an optionally substituted cyclohexenone. The process may then proceed by reacting this Michael adduct with component (i) and a further portion of component (iii), of the same type or of a different type.
  • N-substituted anilines by the process of the present invention preferably entails reacting together a primary or secondary amine or reactive derivative thereof, an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof, and an optionally substituted cyclohexenone for a time and under conditions sufficient to afford N-substituted aniline.
  • the reaction between the components may be conducted in a stepwise/linear fashion or in a one pot procedure.
  • the reaction of the components is facilitated in a single reaction vessel, and may involve the addition of all the components to the reaction vessel simultaneously, or the addition of any two of the three specified components to the reaction vessel such that they react to form an intermediate, in situ, and then reacting the intermediate with a third component in the same vessel.
  • the process may involve the initial reaction of the amine and ring compound components prior to the addition of the cyclohexenone to the reaction vessel.
  • the process may involve the initial reaction of the cyclohexenone and ring compound components prior to the addition of the amine to the same reaction vessel.
  • reaction yields are maximised while at the same time minimising waste solvents, as well as reaction and work up reagents and materials.
  • the process of the present invention can be performed in a stepwise or linear approach if so desired.
  • two of the components are reacted initially to form an intermediate compound which is then reacted with the third component.
  • the intermediate is separated from the initial reaction mixture and optionally purified prior to being reacted with the third component.
  • the process of the present invention is carried out in one pot.
  • the reaction may be facilitated by the addition of an acid and/or base catalyst.
  • the reaction is carried out in the presence of a base catalyst, and more preferably an acid and base catalyst mixture.
  • the reaction may be conducted without the addition of a catalyst.
  • Suitable acid catalysts include benzoic acid, p-toluene sulphonic acid (PTSA), camphor sulfonic acid, acetic acid, proponic acid or other organic acids, as well as resin bound acids such as PTSA amberlyst resin, and -CO 2 H amberlyst resin, and mineral acids for instance hydrochloric acid (as well as hydrochloride salts), nitric acid and so on.
  • PTSA p-toluene sulphonic acid
  • camphor sulfonic acid camphor sulfonic acid
  • acetic acid acetic acid
  • resin bound acids such as PTSA amberlyst resin, and -CO 2 H amberlyst resin
  • mineral acids for instance hydrochloric acid (as well as hydrochloride salts), nitric acid and so on.
  • hydrochloric acid as well as hydrochloride salts
  • Suitable base catalysts include non-nucleophilic amines for instance any trialkylamine such as triethylamine, H ⁇ nigs base, N,N-dimethylbenzylamine as well as bases such as DABCO or DBU.
  • the preferred base is DABCO.
  • a base is added in the case where the amine component is introduced as an ammonium salt derived from a reaction with an acid such as the hydrochloride salt. Accordingly, where only a base catalyst is to be added in the present process it is preferably added in an equivalent mole amount with respect to the amine component (component (i ⁇ )).
  • the reaction is preferably performed in the presence of an acid and base catalyst mixture.
  • the acid catalyst may be selected from those mentioned above.
  • a preferred acid and base mixture is a combination of benzoic acid and DABCO.
  • the catalyst mixture is added to the reactant mixture in an equivalent mole amount or in a slight excess in relation to the amount of component (i).
  • 0.5- 0.55 mole equivalent of each component (acid and base), in respect of component (i) is added to the reactant mixture.
  • the acid catalyst is present in the mixture in an equivalent mole amount or slight excess in relation to the amount of the base catalyst, for instance in a baseiacid mole ratio of 1 : 1.1.
  • Suitable solvents include aprotic solvents for instance solvents which are able to form an azeotrope with water.
  • Suitable solvents include benzene, toluene, xylene, chloroform and the like.
  • the reaction may take place at the boiling point of the particular solvent.
  • the reaction may be carried out under reflux, and preferably at temperatures above 5O 0 C. More preferably the reaction is carried out at a temperature from 60 to 13O 0 C.
  • the primary and secondary amine is reacted in excess relative to the ring compound.
  • at least 2 mole equivalents of the amine may be present in the reaction mixture.
  • the primary or secondary amine (component (Ui)) is added in an amount of between 1.1-2.4 mole equivalents relative to the ring compound (component (i)).
  • the reaction may be conducted by simply stirring the reactants at the reaction temperature in an open vessel
  • the reaction may be conducted under conditions or by using equipment which facilitates the removal of water in order to drive the reaction to completion.
  • Such conditions may include the addition of dehydrating agents like calcium sulphate, magnesium sulphate, molecular sieves and the like.
  • the reaction is carried out with water removal by azeotrope and phase separation for example with the use of a Dean-Stark apparatus. It will be appreciated that the reaction can also be performed in closed reaction vessels under inert conditions (for example under a nitrogen or argon atmosphere).
  • reaction conditions are such that the amine and ring compounds are added first, in order to form a reactive imine.
  • the reaction vessel is initially charged with the amine and ring compound components and the cyclohexenone is then added very slowly (drop-wise or in portions).
  • the cyclohexenone addition is performed at a rate such that it is consumed (reacted) almost immediately upon addition to the reaction mixture.
  • the cyclohexenone may be added neat or as a solution.
  • the cyclohexenone is added as a solution of the reaction solvent.
  • Reaction times for the one pot process vary from about 30 minutes to 50 hours, depending on a number of factors including the reaction temperature, reactivity of reactants, etc.
  • the reaction progress can be monitored using conventional techniques including thin layer chromatography, gas chromatography, HPLC, NMR and IR spectroscopy.
  • the first step may involve reaction between the amine and cyclohexenone to afford a mixture of two enamines, having the enamine double bond lying in either the 1,2- or the 1,6-position in conjugation with the cyclohexenone double bond.
  • These positional isomers have the potential for tautomeric equilibria. It is believed that attack of the aldehyde from either the 2 or 6 position can be controlled with appropriate substitution on either the cyclohexenone or amine. For instance when bulky amines are reacted with 2-cyclohexenone attack at the 2- position is less favoured than that from the 6-position.
  • the amine also may have a role in the condensation between the enamine and the ring compound aldehyde, through the initial formation of an iminium salt of the latter.
  • attack of the enamine would involve a Mannich reaction followed by elimination of the amine rather than an aldol condensation.
  • the final product is predicted to be obtained by two eliminations and an isoaromatisation that occurs in situ.
  • the elimination steps involve the loss of at least one amine.
  • the second compound eliminated could be either another amine molecule or water.
  • An advantage of the present process is that it allows for anilines to be prepared with a variety of substituent groups.
  • the structural diversity can come from varying substituents on either the ring compound component or the cyclohexenone or by using variously substituted amines. Further structural diversity may be achieved in a process wherein the ring compound component bears more than one non-enolisable formyl group or reactive derivative thereof. In such an instance, the present process may afford multiple N- substituted anilines linked by methylene groups. Accordingly, it would be appreciated that the present process would lend itself well to combinatorial approaches to libraries of N- substituted anilines for high throughput screening in, for instance, drug discovery programs.
  • the process of the present invention can be performed starting from an enamine which can in turn be prepared from a reaction involving, for instance, the amine component with the cyclohexenone.
  • suitable enamines can be reacted with the ring compound component of the present invention to prepare N-substituted anilines.
  • another aspect of the present invention provides a process for preparing N- substituted anilines comprising reacting an enamine of formula (I)
  • n represents an integer from 0 to 4.
  • R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
  • R 1 and R 2 independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R 1 and R 2 together may form an optionally substituted heterocyclyl group;
  • an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof for a time and under conditions sufficient to form said N-substituted anilines.
  • the enamine of formula (I) may preferably be prepared by initially reacting an optionally substituted cyclohexenone with an amine. Depending upon the substitution patterns on the reactant components the reaction may proceed by direct attack of the carbonyl and enamine formation, or the initial reaction of the amine to the cyclohexenone double bond to form a Michael adduct. A further reaction with a second amount of the same or different amine may afford a 1,3-diamine substituted enamine, which can eliminate one of the amine groups to form the enamine of formula (I). Accordingly, formation of the enamine in this manner may be achieved in a linear fashion or as a one pot procedure.
  • the enamine could be prepared by reacting the amine with an equivalent of the cyclohexenone.
  • the Michael adduct could be first prepared, isolated and optionally purified before being reacted with a further amount of the same or different amine and eliminated.
  • the reaction conditions for such processes would follow those known in the art to be suitable for Michael reactions.
  • the conversion of the resultant enamine to the desired N-substituted anilines may be performed under the reaction conditions discussed above for the one pot procedure.
  • 2-hydroxymethyl-cyclohexenone which may be prepared from reacting an optionally substituted cyclohexenone with a ring compound component.
  • Other methods for preparing 2- hydroxymethyl-cyclohexenones would be recognised by the skilled person. For instance, such compounds may be prepared under standard Baylis-Hillman conditions (US 3743669,
  • the reaction of 2- hydroxymethyl-cyclohexenones with the amine component of the present invention may be an alternative route to N-substituted anilines.
  • the present invention also provides a process for preparing N-substituted anilines comprising reacting a compound of formula (II):
  • n represents an integer from 0 to 4;
  • R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
  • R represents an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound
  • the preferred protocol for the preparation of compounds of formula (II) involves the reaction of the ring compound component and cyclohexenone under Baylis-Hillman conditions.
  • the preferred method involves reacting the ring compound component and cyclohexenone under solventless conditions under an inert atmosphere.
  • the reaction is catalysed by adding a suitable base, for instance, DBU or DABCO.
  • a suitable base for instance, DBU or DABCO.
  • the reaction progress can be monitored by thin layer chromatography, gas chromatography, HPLC, NMR or IR spectroscopy.
  • the crude product can be isolated and purified by standard work up procedures.
  • the crude product can be dissolved in a suitable organic solvent which is immiscible with water (for instance, ether) and neutralised by the addition of an aqueous acid solution like 2M HCl.
  • a suitable organic solvent which is immiscible with water (for instance, ether) and neutralised by the addition of an aqueous acid solution like 2M HCl.
  • the organic layer is then collected, dried and reduced in vacuo.
  • the crude product may also be further purified by column chromatography or recrystallised or subjected to the next step in the reaction process, that is, reacted with the amine. This subsequent reaction to the desired N- substituted anilines may be performed under the reaction conditions discussed above for the one pot procedure.
  • the N-substituted anilines prepared by the aforementioned processes can be subjected to further reaction steps without separation from the crude reaction mixture, or may be separated using conventional techniques, including filtration and/or followed by chromatographic separation techniques typically on silica gel.
  • the compounds prepared by the present process are separated from the reaction mixture.
  • the residue from the reaction can be subjected to standard work up procedures. An example of this may include cooling and neutralising the reaction mixture with a suitable base or acid, such as, a saturated NaHCO 3 solution or a dilute HCl solution.
  • the residue may then be extracted into an organic solvent, washed with water, separated, dried and concentrated in vacuo.
  • the recovered residue may be purified by column chromatography or through recrystallisation with a suitable solvent or solvent mixture.
  • purification steps could be used to separate the structural isomers in the case where the present process provides mixtures of two isomers.
  • the purification step could be used to separate the 2-isomer from the 3-isomer in a reaction mixture where both isomers are formed.
  • the substituted anilines prepared from the present process may also be subjected to a deprotection step in order to afford the unsubstituted anilines.
  • Methods for deprotecting amines are known and examples thereof are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M. Wutts (1999) 3 rd edition, Johns Wiley and Son, Inc.
  • the anilines so produced may be subjected to further chemistry including functional group interconversion, reprotection, etc, including alkylation of the nitrogen atom, Friedel-Crafts acylation/alkylation of the aniline ring, formaldehyde coupling and so on.
  • Aniline derivatives which possess heteroarylmethyl or arylmethyl substituents at the ortho or para positions may be useful in preventing and/or treating a range of medical conditions, and in particular, conditions associated with nematode, fungal, protozoan, bacterial or yeast infections. These compounds may also be useful in treating proliferative diseases such as cancer. Accordingly, the present invention also relates to those compounds which have been prepared by the process described herein as well as the novel compounds described in the following examples which illustrate the present process.
  • 2-Cyclohexenone (0.968 niL, 10.0 mmol) was added to a volumetric flask made up to 10 mL with toluene.
  • the reaction mixture was cooled to room temperature.
  • White crystals (0.98 g) had formed and were filtered.
  • the cyrstals were identified by N.M.R. as benzylammonium benzoate.
  • 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture.
  • 2.5 h after that another portion 2-cyclohexenone (0.193 mL, 2.00 mmol) was added to the reaction mixture.
  • 2.5 h after that another portion 2-cyclohexenone (0.290 mL, 3.00 mmol) was added to the reaction mixture.
  • 1.5 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture.
  • 1 h after that another portion 2- cyclohexenone (0.193 mL, 2,00 mmol) was added to the reaction mixture and left to react for another 8 h.
  • a total of 2-cyclohexenone (1.255 mL, 13.0 mmol) was added and left to react over a 36 h period.
  • FT-IR (KBr) 3446 sb, 2966 w, 2938 w, 2884 w, 2816 w, 1676 s, 1610 s, 1518 m, 1492 m, 1450 m, 1422 w, 1384 w, 1320 w, 1288 m, 1256 w, 1218 w, 1181 w, 1113 s, 932 w, 702 m.
  • Microanalysis Found C 72.92 %, 6.36 %, 4.75 %, Requires C 72.71 % H 6.44 %, N 4.71 %.
  • Solution A was prepared by dissolving 5-methylcyclohex-2-enone (0.366 g, 3.14 mmol) in toluene to produce 5 mL of solution.
  • Samples The samples were supplied as weighed powders or oils. Stock solutions were prepared in MeOH or 20% (v/v) DMSO in MeOH depending on the solubility of the sample (Table 1). ARMST003 & ARMST021 required subsampling into larger vials to allow preparation of stock solutions. Aliquots of the stock solutions were diluted 1/2 with MeOH then serially diluted 1/2 with MeOH to give 12 concentrations. Aliquots (20 ul) at each concentration were transferred to bioassay plates. For CyTOX and TriTOX the bioassay plates were evaporated to dryness before use, for the remaining assays only the MeOH was evaporated. The highest concentration tested in each assay varied from 125 to 500 ug/ml, depending on the concentration of the stock solution prepared, except in MycoTOX and EuTOX where the highest concentrations tested varied from 250 to 1000 ug/ml.
  • Bioassays The samples were tested in a range of whole organism screens as indicated in Table 2 the results of which are shown in Table 3. Table 1: Preparation of stock solutions
  • Titre 2(n-1) where n is the number of the well containing the lowest concentration where an inhibitory effect was observed - for NemaTOX where 99% of larvae were affected, A titre of 0 indicated that no inhibition was noted at the highest concentration tested.

Abstract

The present invention relates to N-substituted anilines and derivatives thereof and in particular to chemical processes for the preparation of N-substituted anilines and derivatives thereof.

Description

CHEMICAL PROCESSES AND COMPOUNDS DERIVED THEREFROM
Field of the Invention
The present invention relates to N-substituted anilines and derivatives thereof and in particular to chemical processes for the preparation of N-substituted anilines and derivatives thereof.
Background of the Invention
Aniline derivatives which possess arylmethyl substituents at the ortho or 2-position are commercially important for many applications ranging from pharmaceuticals to additives in the petrochemical industry. For instance, US 4,411,805 states that certain N5TNP5N"- trisubstituted derivatives' of bis-(/?-aminobenzyi)anilines may have potential application as antioxidants for protecting petroleum products, such as lubricating oils, from oxidative degradation.
EP 1258473 Al (ONO Pharmaceuticals Co., Ltd) discloses that particular derivatives of 2- (2-amino-phenylmethyl)benzoic acids can bind to, and exhibit antagonistic activity on, the PGE2 receptor. Such compounds are postulated to be useful in preventing and/or treating bone diseases such as osteoporosis, rheumatoid arthritis, osteoarthritis, abnormal bond formation, cancer (e.g. cancer formation, cancer proliferation, cancer metastasis to organs and to bones, hypercalcemia accompanied by cancer metastasis to bones, etc.) and systemic granuloma, immunological diseases (e.g. amyotropic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, systemic lupus erythematosus, AIDS), allergy (conjunctivitis, rhinitis, contact dermatitis, psoriasis, etc.), atopy (atpoic dermatitis etc.), asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease, pulmonary injury, hepatopathy, acute hepatopathy, neophritis, renal failure, myocardiac ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease and multiple organ failure, as well as for diseases associated with sleep failure or platelet aggregation. JP 10072434 discloses the preparation of 2,4-substituted anilines and their use as herbicides, while JP 60025968 discloses the use of anilines as fungicides.
US 4,194,049 discloses the use of 2-(phenylmethyl)anilines in the preparation of 2-[[2- methyl- 1 - [2-benzoyl(or benzyl)phenyl] - 1 H-imidazol-5 -yl] methyl] - 1 H-isoindole- 1 ,3-(2H)- diones as intravenous compositions for use in preoperative anaesthesia, or as sedatives, anxiolytics, muscle relaxants and anticonvulsants.
Despite the range of potential applications, few members of this class of compound, or derivatives thereof, have been reported in the literature. The known published routes to 2- or 4-(aryl or heteroaryl)methylene N-substituted anilines usually commence from the parent aniline and typically involve a coupling reaction between formaldehyde and the aniline. Such routes generally involve multiple steps and typically proceed in variable yield, with poor atom economy and provide limited scope for structural diversity.
In contrast the development of "green chemistry" involves reactions which are high yielding and are highly convergent, proceed with high atom economy, and can be conducted in environmentally friendly solvents or solventless processes, which do not produce large quantities of toxic waste. Accordingly, in developing a new chemical process it would be desirable to introduce any of the aforementioned "green" aspects. It is also desirable to develop new methods for the synthesis of N-substituted anilines.
Summary of Invention
The present invention provides a process for preparing N-substituted anilines comprising reacting the following components:
(i) optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof; (ii) optionally substituted cyclohexenone; and
(iii) primary or secondary amine or a reactive derivative thereof, for a time and under conditions sufficient to form said N-substituted anilines.
In a further aspect the present invention provides a process for preparing N-substituted
Figure imgf000004_0001
anilines comprising reacting an enamine of formula (I)
or a tautomer thereof, wherein n represents an integer from 0 to 4;
R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
R1 and R2 independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R1 and R2 together may form an optionally substituted heterocyclyl group;
with an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof for a time and under conditions sufficient to form said N-substituted anilines. In still a further aspect the present invention provides a process for preparing N-substituted anilines comprising reacting a compound of formula (II):
Figure imgf000005_0001
or a tautomer thereof,
wherein n represents an integer from O to 4;
R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and R3 represents an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound;
with a primary or secondary amine or reactive derivative thereof, for a time and under conditions sufficient to form said N-substituted anilines.
Description of the Invention
As used herein the term "N-substituted aniline" refers generally to compounds having an optionally substituted benzene ring bearing at least one N-protected amine moiety. This includes traditional anilines as well as, for instance, compounds in which two of the substituents on the phenyl together form a further saturated or unsaturated ring, for example a cyclohexene or cyclohexane ring. The substituted amine moiety may also be bonded to a benzene ring which is part of a polycyclic ring system, for instance, a steroid A ring as in the estrogen class of steroids. Such compounds are also referred to herein as N-substituted anilines. It will become evident that in the process of the present invention the cyclohexenone component forms the optionally substituted benzene ring (or phenyl) moiety and the amine component forms the N-substituted amine moiety.
■ In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, acyloxy, alkyl, alkoxy, amino, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aminoacyl, thio, thioacyl, oxythioacyl, oxythioacyloxy, thioacyloxy, sulfinyl, sulfonyl, sulfinylamino, sulfonylamino, oxysulfinylamino, oxysulfonylamino, aminothioacyl, thioacylamino, amino sulfinyl, aminosulfonyl, alkaryl, alkaryloxy, aryl, aryloxy, carboxyl, acylamino, acylimino, acyliminoxy, oxyacylimino, cycloalkyl, cycloalkenyl, halogen, cyano, halogen, nitro, sulphate, phosphate, phosphine, heteroaryl, heterocyclyl, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifiuoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, as well as non-nucleophilic mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric non-nucleophilic di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like, and may also include a bond to a polymeric support material, (ie. substituted onto a resin). In the case of divalent groups, the term "optionally substituted" also indicates that one or more saturated carbon atoms may be substituted for a heteroatom or heterogroup, such as O, S, NH and the like. For example an optionally substituted alkylene group could be represented by a group such as -CH2CH2OCH2-, -CH2CH2NH-CH2-, -CH2NHCH2-, and the like.
The term optionally substituted is also taken to mean that the group may or may not be protected by a protecting group. Accordingly, when any one of the substituent groups bears a reactive moiety, such as a reactive carbonyl or amino, such moieties may be first protected to prevent them from reacting under the conditions of the present invention. Suitable protecting groups are known and examples thereof are described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wutts (1999) 3rd edition, John Wiley and Sons, Inc.
"Saturated carbocyclic ring compound" refers to cyclic alkyl groups, including mono- or polycyclic alkyl compounds such as cyclopropane, cyclobutane, cyclopentane, cycloctane and the like.
"Unsaturated carbocyclic ring compound" refers to mono- or polycyclic rings having at least 1 carbon to carbon double bond. Examples of unsaturated carbocyclic ring compounds include aromatic rings, for instance aryl rings such as benzene, napthalene, anthracene, and the like, and also includes non-aromatic rings, for instance cycloalkenyl rings such as cyclohexene, cyclopentene and the like.
"Saturated heterocyclic ring compound" refers to mono- or polycyclic alkyl groups wherein one or more of the carbon atoms which make up the ring has been replaced with a heteroatom or heterogroup. Examples of heteroatoms include N, S, O, Se (or mixtures of such heteroatoms). Examples of heterogroups include NR' where R' can be hydrogen, alkyl, aryl, sulfonyl, acyl and so on. Accordingly, examples of saturated heterocyclic ring compounds include piperidine, pyrrolidine, morpholine and the like, together with N- substituted derivatives thereof.
"Unsaturated heterocyclic ring compound" refers to mono- or polycyclic rings having at least 1 double bond and at least one heteroatom or heterogroup. Examples of preferred heteroatoms include N, S, O5 Se or P. Examples of heterogroups include NR where R' can be hydrogen, alkyl, aryl, sulfonyl, acyl and the like. Unsaturated heterocyclic ring compounds include aromatic heteroaryl groups such as pyridine, pyrimidine, pyrrole, furan, thiophene, and the like, and also includes non-aromatic and pseudo-aromatic rings such as dihydropyran and the like.
In this specification the term "non-enolisable" when used in relation to a formyl group or an aldehyde, means that there is no acidic proton α to the carbonyl group which would allow the formyl group to enolise. Examples of non-enolisable formyl groups would be a formyl group which is attached directly to a ring carbon atom of an aromatic or heteroaromatic ring, or a formyl group which is attached directly to a ring heteroatom of a heteroaromatic or heterocyclic ring. Another example is where the formyl group is remotely attached to an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound via a linking group such that there are no acidic protons α to the carbonyl group which would allow the formyl group to enolise. An example of such a compound is cinnamaldehyde.
It will be appreciated that the term formyl also encompasses reactive derivatives of the CHO moiety. This includes known formyl derivatives which are able to react (for instance are able to undergo condensation or nucleophilic substitution by acting as electrophiles) under the conditions of the present process. Such groups may include acyclic and cyclic acetals, cyanohydrins, iminium salts, imines, aminals, amino alcohols, amino ethers, thioacyl groups, ylidenemalonitriles (eg, ArCH(CN)2), as well as β-hydroxy aldehydes formed from mixed aldol reactions.
"Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, w-propyl, /so-propyl, rø-butyl, iso- butyl, «-hexyl, and the like.
"Alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like. "Arylene" refers to a divalent aryl group wherein the aryl group is as described above.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as described above.
"Alkaryl" refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
"Alkaryloxy" refers to the group alkylaryl-O- wherein the alkylaryl group is as described above. Such alkaryloxy groups are exemplified by benzyloxy and the like.
"Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, wσ-propoxy, «-butoxy, tert-butoxy, sec- butoxy, 77-pentoxy, «-hexoxy, 1,2-dimethylbutoxy, and the like.
" Alkenyl" refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds. Examples include ethenyl (-CH=CH2), «-propenyl (-CH2CH=CH2), foo-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like.
"Alkenyloxy" refers to the group alkenyl-O- wherein the alkenyl group is as described above.
"Alkenylene" refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethenylene (-CH=CH-), and the propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-), and the like.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds. Examples of alkynyl groups include ethynyl (-C≡ CH), propargyl (-CH2C≡ CH) and the like.
"Alkynyloxy" refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
"Alkynylene" refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C≡ C-), propynylene (-CH2-C≡ C-) , and the like.
"Acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxyacyl" refers to groups alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl- OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Aminoacyl" refers to the group -C(0)NR'R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Acylamino" refers to the group -NRC(O)R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Acyloxy" refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Aminoacyloxy" refers to the groups -OC(O)NR'-alkyl, -OC(O)NR'-aryl, -OC(O)NR'- heteroaryl, and -OC(O)NR'-heterocyclyl where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Oxyacylamino" refers to the groups -NR'C(O)O-alkyl, -NR'C(O)O-aryl, -NR'C(0)0- heteroaryl, and NR'C(O)O-heterocyclyl where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Acylimino" refers to the groups -C(NR')-R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Acyliminoxy" refers to the groups -0-C(NR')-R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Oxy acylimino" refers to the groups -C(NR')-0R' where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
"Cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms. Examples of cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3- enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"Heteroaryl" refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
"Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen.
Examples of heterocyclyl and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
"Heteroarylene" refers to a divalent heteroaryl group wherein the aryl group is as described above.
"Heterocyclylene" refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above. "Thio" refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Thioacyl" refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxythioacyl" refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxythioacyloxy" refers to groups HO-C(S)-O-, alkylO-C(S)-O-5 cycloalkylO-C(S)-O-, arylO-C(S)-O-, heteroarylO-C(S)-O-, and heterocyclylO-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Thioacyloxy" refers to groups H-C(S)-O-, alkyl-C(S)-O-, cycloalkyl-C(S)-O-, aryl- C(S)-O-, heteroaryl-C(S)-O-, and heterocyclyl-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Sulfinyl" refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S (O)-, aryl-S(O)-, heteroaryl-S (O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Sulfonyl" refers to groups H-S(O)2-, alkyl-S(O)2-, cycloalkyl-S(O)2-, aryl-S(O)2-, heteroaryl-S(O)2-, and heterocyclyl-S(O)2-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Sulfmylamino" refers to groups H-S(O)-NR'-, alkyl-S(O)-NR'-, cycloalkyl-S (O)-NR'-, aryl-S(O)-NR'-, heteroaryl-S(O)-NR'-, and heterocyclyl-S(O)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Sulfonylamino" refers to groups H-S(O)2-NR'-, alkyl-S(O)2-NR'-, cycloalkyl-S(O)2- NR'-, aryl-S(O)2-NR'-, heteroaryl-S(O)2-NR'-, and heterocyclyl-S (O)2-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Oxysulfmylamino" refers to groups HO-S(O)-NR'-, alkylO-S (O)-NR'-, cycloalkylO- S(O)-NR'-, arylO-S(O)-NR'-, heteroarylO-S(O)-NR'-, and heterocyclylO-S (O)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Oxysulfonylamino" refers to groups HO-S(O)2-NR'-, alkylO-S(O)2-NR'-5 cycloalkylO-S (O)2-NR'-, arylO-S(O)2-NR'-, heteroarylO-S(O)2-NR'-, and heterocyclylO-S(O)2-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminothioacyl" refers to groups R'R'N-C(S)-, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Thioacylamino" refers to groups H-C(S)-NR'-, alkyl-C(S)-NR'-, cycloalkyl-C(S)- NR'-, aryl-C(S)-NR'-, heteroaryl-C(S)-NR'-, and heterocyclyl-C(S)-NR'-, where R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Aminosulfinyl" refers to groups R'R'N-S(O)-, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl., and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminosulfonyl" refers to groups R'R'N-S(O)2-, where each R' is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
Preferably, the optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound is selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, having at least one formyl group or reactive derivative thereof attached directly to a ring atom thereof.
More preferably the optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound is selected from an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl having one, two or three formyl groups or reactive derivatives thereof attached directly to a ring atom thereof. Even more preferably the ring compound is selected from an optionally substituted aryl or optionally substituted heteroaryl having one, two or three formyl groups or reactive derivatives thereof attached directly to a ring atom thereof. Most preferably the ring compound is selected from an aryl or heteroaryl having one or two formyl groups or reactive derivatives thereof attached directly to a ring atom thereof. Most preferably the ring atom is a ring carbon atom.
Preferred aryl groups as ring compounds include phenyl, napthyl, anthracenyl, pyrenyl, indenyl, and phenanthrenyl. Preferred heteroaryl groups as ring compounds include pyridyl, furanyl, indolyl, indazolyl, benzotriazolyl, quinolinyl, acridinyl and benzofuranyl. In relation to the aforementioned ring compounds it will be understood that the "optional substituent" is additional to the non-enolisable formyl group(s) or reactive derivative(s) thereof.
In some embodiments the ring compounds include one or more of the following substituents:
alkyl group, preferably methyl and ethyl;
substituted alkyl group, preferably 1-hydroxyethyl, 1-thioethyl, methoxyiminomethyl, ethoxyiminomethyl, l-(hydroxyimino)ethyl, l-(hydroxyimino)propyl, 1- hydrazinoethyl, 1-hydrazinopropyl, hydroxyiminomethyl, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitromethyl, 1-nitromethyl, and 2-nitroethyl;
acyl group, preferably acetyl, propanoyl, benzoyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl or cyano);
alkoxy group, preferably methoxy and ethoxy;
oxyacyl group, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl;
acyloxy group, preferably acetoxy and propioxy;
substituted alkaryl group, preferably 1-hydroxybenzyl, and 1-thiobenzyl;
sulfmyl group, preferably methylsulfinyl, ethylsulfinyl, benzene sulfinyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxysulfmyl, ethoxysulfinyl; sulfonyl group, preferably methylsulfonyl, ethylsulfonyl, benzenesulfonyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxycarbo, trifluoromethane;
oxyacylamino group, preferably methoxycarbonylamido, and ethoxycarbonyl amido;
oxythioacyl group, preferably methoxythiocarbonyl and ethoxythiocarbonyl;
thioacyloxy group, preferably thionoacetoxy and thionopropionoxy;
sulphinylamino group, preferably methylsulfinylamino, ethylsulfinylamino, and benzenesulfmylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
sulphonylamino group, preferably methylsulfonylamino, ethylsulfonylamino and benzene sulfonylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
oxysulfinylamino group, preferably methoxysulfinylamino and ethoxysulfinylamino;
oxysulfonylamino group, preferably methoxysulfonylamino and ethoxysulfonylamino;
optionally substituted alkenyl group, preferably, 1-propenyl, vinyl, nitrovinyl, cyano vinyl, or trifluorovinyl and styryl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
alkynyl group, preferably 1-propynyl, ethynyl or trimethylsilylethynyl.
In other embodiments substituent groups for a particular ring compound may include pentafluoroethyl, trifluoromethoxy, difluoromethoxy, thioformamido, triflurormethanethio, aminothioacyl, aminosulfonyl, trifluoroethenyl, nitro, cyano, halogen, amino, carboxyl, hydroxyl, hydrogen and aminoacyl.
Specific examples of suitable optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compounds having one or two non-enolisable formyl groups include benzaldehyde, o- and p-anisaldehyde, 4-hydroxybenzaldehyde, 4-carboxybenzaldehyde, pyridine-4-carboxaldehyde, pyridine-2-carboxaldehyde and 4-methylbenzaldehyde, isophthalaldehyde, furfural, 4-nitrobenzaldehyde, 2,2'-(propane-l,3- diylbis(oxy))dibenzaldehyde, and cinnamaldehyde.
It will become apparent that the process of the present invention is amenable to the preparation of N-substituted anilines by solid phase synthetic techniques. For this purpose it is preferred that the ring compound bears a divalent linker group as a substituent to enable attachment to a polymer support.
"Divalent linker group" is taken to mean a divalent group capable of forming a stable bridge between the N-substituted aniline of the present invention and a polymer support resin. Examples of divalent linker groups include optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted heterocyclylene, optionally substituted alkylenearylene, optionally substituted alkylenearylenealkylene, optionally substituted alkyleneheteroarylenealkylene, optionally substituted alkyleneheterocyclylenealkylene, and the like. Examples of polymer supports include Merrifield resin, Wang resin, and so on.
The present invention can include an optionally substituted cyclohexenone as a reactant. The term "cyclohexenone" as used in the present invention refers to any cyclohexenone isomer and includes substituted cyclohexenones possessing an additional double bond which is exocyclic such as a mono arylidene cyclohexenone. Preferably, however, the cyclohexenone is an optionally substituted 2- or 3 -cyclohexenone, and most preferably an optionally substituted 2-cyclohexenone. Suitable substituents are those which do not adversely effect or interfere with the formation of N-substituted anilines by the process of the present invention. Examples of potentially suitable substituents include optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, thioalkyl, thioaryl, optionally substituted alkoxy, acyl, F, Cl, NO2, and includes cyclohexenones which are ring fused. Any substituent, if present, may be bonded to the cyclohexenone ring at either the 2 or 6 positions and additionally at one or more of the 3, 4 or 5 positions. In one embodiment the reactant is 2-cyclohexenone which has been substituted at the 3 and/or 4 and/or 5 positions, and more preferably at the 3 or 5 positions. Preferably these substituents are independently selected from optionally substituted aryl, optionally substituted alkyl, optionally substituted aryl, thioalkyl, thioaryl, optionally substituted alkoxy, acyl, F, Cl, NO2 or may together represent a ring fused group such as an optionally substituted cycloalkenyl, or optionally substituted cycloalkyl group. Examples of preferred cyclohexenones include 2-cyclohexenone, 3-methylcyclohex-2- enone, 3-(4-methylphenyl)cyclohex-2-enone and 5-methylcyclohex-2-enone. More preferably the reactant component is 2-cyclohexenone itself.
Suitable secondary and primary amines which can be used as reactant components in the present process are nucleophilic primary or secondary amines or reactive derivatives thereof in which the chosen N-substituents do not adversely effect or interfere with the amines ability to act as a nucleophile.
Preferred primary and secondary amines include compounds of the formula NHR1R2, where one of R1 or R2 represent hydrogen and the other an optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted cycloalkenyl or R1 and R2 independently represent optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl, or R1 and R2 together form an optionally substituted heterocyclyl group. More preferably R1 is hydrogen and R2 represents optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or RWd R2 independently represent optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or together form an optionally substituted heterocyclyl group. Most preferably, R1 is hydrogen and R2 an optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or R1 and R2 are the same and represent an optionally substituted alkyl where the optional substituent is selected from alkyl, alkoxy or together represent a heterocyclyl group.
Specific examples of suitable amines include benzylamine, n-hexylamine, aniline, 2- aminomethylpyridine, methyl aminoacetate, 3-indole-2-ethylamine (tryptamine), morpholine, α-methylbenzylamine, and di-»-butylamine, bis(2-methoxyethyl)amine, N5N- dibenzylamine, 2-phenylethylamine, 1,3 propylene amine, as well as amino acids, including esters or salts thereof such as O-methylglycine hydrochloride and glycine methyl ester.
Accordingly, also preferred are amine derivatives which are able to react under the conditions of the present process. Such reactive derivatives include ammonium salts (ie R1R2NH2 +X") for example hydrochloride salts, or carbamic acids or ammonium carbamate salts (ie R1R2NCOOH5 R1R2NH2 +R1R2NCOO"), where R1 and R2 groups are as defined above.
It will be appreciated that the process of the present invention may include the use of additional components such as catalysts, solvents, etc.
Components (i), (ii) and (iii) may be reacted in single amounts or the process may involve the addition of further amounts of components (i), (ii) and/or (iii). Furthermore the process may be conducted with the use of more than one type of component (i), (ii) or (iii). For instance, in relation to this latter embodiment, the process may involve the initial reaction of components (ii) and (iii) to prepare a Michael adduct of an optionally substituted cyclohexenone. The process may then proceed by reacting this Michael adduct with component (i) and a further portion of component (iii), of the same type or of a different type.
The preparation of N-substituted anilines by the process of the present invention preferably entails reacting together a primary or secondary amine or reactive derivative thereof, an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof, and an optionally substituted cyclohexenone for a time and under conditions sufficient to afford N-substituted aniline.
The reaction between the components may be conducted in a stepwise/linear fashion or in a one pot procedure.
In the one pot approach the reaction of the components is facilitated in a single reaction vessel, and may involve the addition of all the components to the reaction vessel simultaneously, or the addition of any two of the three specified components to the reaction vessel such that they react to form an intermediate, in situ, and then reacting the intermediate with a third component in the same vessel. For instance the process may involve the initial reaction of the amine and ring compound components prior to the addition of the cyclohexenone to the reaction vessel. Alternatively, the process may involve the initial reaction of the cyclohexenone and ring compound components prior to the addition of the amine to the same reaction vessel. Accordingly, in the one pot approach the desired N-substituted anilines are built up in a flexible, convergent manner wherein more than one type of reaction may be occurring in the reaction vessel at any one time. The advantage of such a process is that it alleviates the need to isolate and purify any intermediate compound. In this regard reaction yields are maximised while at the same time minimising waste solvents, as well as reaction and work up reagents and materials.
The process of the present invention can be performed in a stepwise or linear approach if so desired. In the stepwise or linear approach, two of the components are reacted initially to form an intermediate compound which is then reacted with the third component. In this stepwise or linear procedure the intermediate is separated from the initial reaction mixture and optionally purified prior to being reacted with the third component.
Preferably the process of the present invention is carried out in one pot.
In the preferred embodiment which utilises the one pot approach the reaction may be facilitated by the addition of an acid and/or base catalyst. Preferably the reaction is carried out in the presence of a base catalyst, and more preferably an acid and base catalyst mixture. Alternatively, the reaction may be conducted without the addition of a catalyst.
Suitable acid catalysts include benzoic acid, p-toluene sulphonic acid (PTSA), camphor sulfonic acid, acetic acid, proponic acid or other organic acids, as well as resin bound acids such as PTSA amberlyst resin, and -CO2H amberlyst resin, and mineral acids for instance hydrochloric acid (as well as hydrochloride salts), nitric acid and so on. Preferably, where only an acid catalyst is to be added in the present process it is added in an equivalent mole amount with respect to the ring compound (component (i)).
Suitable base catalysts include non-nucleophilic amines for instance any trialkylamine such as triethylamine, Hϋnigs base, N,N-dimethylbenzylamine as well as bases such as DABCO or DBU. The preferred base is DABCO. Preferably a base is added in the case where the amine component is introduced as an ammonium salt derived from a reaction with an acid such as the hydrochloride salt. Accordingly, where only a base catalyst is to be added in the present process it is preferably added in an equivalent mole amount with respect to the amine component (component (iϋ)).
As stated above, the reaction is preferably performed in the presence of an acid and base catalyst mixture. In this instance the acid catalyst may be selected from those mentioned above. A preferred acid and base mixture is a combination of benzoic acid and DABCO. Preferably the catalyst mixture is added to the reactant mixture in an equivalent mole amount or in a slight excess in relation to the amount of component (i). Preferably, 0.5- 0.55 mole equivalent of each component (acid and base), in respect of component (i), is added to the reactant mixture. In relation to the relative amounts of acid/base in the catalytic mixture it is preferred that the acid catalyst is present in the mixture in an equivalent mole amount or slight excess in relation to the amount of the base catalyst, for instance in a baseiacid mole ratio of 1 : 1.1.
The process is preferably carried out in a solvent. Suitable solvents include aprotic solvents for instance solvents which are able to form an azeotrope with water. Suitable solvents include benzene, toluene, xylene, chloroform and the like. The reaction may take place at the boiling point of the particular solvent. For example, the reaction may be carried out under reflux, and preferably at temperatures above 5O0C. More preferably the reaction is carried out at a temperature from 60 to 13O0C.
Preferably the primary and secondary amine is reacted in excess relative to the ring compound. For instance, at least 2 mole equivalents of the amine may be present in the reaction mixture. Preferably, where the process involves the use of an acid and base catalyst mixture the primary or secondary amine (component (Ui)) is added in an amount of between 1.1-2.4 mole equivalents relative to the ring compound (component (i)).
In the preferred one pot embodiment the reaction may be conducted by simply stirring the reactants at the reaction temperature in an open vessel The reaction may be conducted under conditions or by using equipment which facilitates the removal of water in order to drive the reaction to completion. Such conditions may include the addition of dehydrating agents like calcium sulphate, magnesium sulphate, molecular sieves and the like. More preferably, the reaction is carried out with water removal by azeotrope and phase separation for example with the use of a Dean-Stark apparatus. It will be appreciated that the reaction can also be performed in closed reaction vessels under inert conditions (for example under a nitrogen or argon atmosphere).
In another preferred embodiment of the above one-pot process, the reaction conditions are such that the amine and ring compounds are added first, in order to form a reactive imine.
More preferably the reaction vessel is initially charged with the amine and ring compound components and the cyclohexenone is then added very slowly (drop-wise or in portions). Preferably the cyclohexenone addition is performed at a rate such that it is consumed (reacted) almost immediately upon addition to the reaction mixture. In this embodiment the cyclohexenone may be added neat or as a solution. Preferably the cyclohexenone is added as a solution of the reaction solvent.
Reaction times for the one pot process vary from about 30 minutes to 50 hours, depending on a number of factors including the reaction temperature, reactivity of reactants, etc. The reaction progress can be monitored using conventional techniques including thin layer chromatography, gas chromatography, HPLC, NMR and IR spectroscopy.
Without wishing to be bound by theory, investigations into the one pot process suggest the presence of multiple competing processes. It is postulated that the first step may involve reaction between the amine and cyclohexenone to afford a mixture of two enamines, having the enamine double bond lying in either the 1,2- or the 1,6-position in conjugation with the cyclohexenone double bond. These positional isomers have the potential for tautomeric equilibria. It is believed that attack of the aldehyde from either the 2 or 6 position can be controlled with appropriate substitution on either the cyclohexenone or amine. For instance when bulky amines are reacted with 2-cyclohexenone attack at the 2- position is less favoured than that from the 6-position. With less bulky amines, attack is predicted to occur preferentially from the 2-position. This implies that it may be possible for a second amine to react under Michael conditions to form sterically constrained enamines (Michael adducts), which can direct the regiospecficity of the reaction. It is postulated however that, even if so formed, such adducts are likely to eliminate an amine molecule, and accordingly may serve as a precursor to the aforementioned enamine. Accordingly, in selecting appropriately substituted amines and cyclohexenones, the present process may provide a selective route to either 2- or 4-(ring substituted)methylene N- substituted anilines.
Furthermore, the amine also may have a role in the condensation between the enamine and the ring compound aldehyde, through the initial formation of an iminium salt of the latter. In that event, attack of the enamine would involve a Mannich reaction followed by elimination of the amine rather than an aldol condensation. The final product is predicted to be obtained by two eliminations and an isoaromatisation that occurs in situ. Depending upon the mechanism, the elimination steps involve the loss of at least one amine. The second compound eliminated could be either another amine molecule or water. Thus, the present invention provides a convenient one-pot, highly convergent, multi-component reaction process to afford N-substituted anilines.
An advantage of the present process is that it allows for anilines to be prepared with a variety of substituent groups. The structural diversity can come from varying substituents on either the ring compound component or the cyclohexenone or by using variously substituted amines. Further structural diversity may be achieved in a process wherein the ring compound component bears more than one non-enolisable formyl group or reactive derivative thereof. In such an instance, the present process may afford multiple N- substituted anilines linked by methylene groups. Accordingly, it would be appreciated that the present process would lend itself well to combinatorial approaches to libraries of N- substituted anilines for high throughput screening in, for instance, drug discovery programs.
As mentioned previously it may be possible to conduct the present process in a linear fashion where two of the components are initially reacted to form an isolatable intermediate compound and then reacting this intermediate compound with the third component to afford N-substituted anilines.
For example, based upon the aforementioned mechanistic proposal the process of the present invention can be performed starting from an enamine which can in turn be prepared from a reaction involving, for instance, the amine component with the cyclohexenone. The skilled person would recognise other preparative protocols to produce such enamines. Accordingly, suitable enamines can be reacted with the ring compound component of the present invention to prepare N-substituted anilines. As such, another aspect of the present invention provides a process for preparing N- substituted anilines comprising reacting an enamine of formula (I)
Figure imgf000026_0001
or a tautomer thereof, wherein n represents an integer from 0 to 4;
R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
R1 and R2 independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R1 and R2 together may form an optionally substituted heterocyclyl group;
with an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof for a time and under conditions sufficient to form said N-substituted anilines.
The enamine of formula (I) may preferably be prepared by initially reacting an optionally substituted cyclohexenone with an amine. Depending upon the substitution patterns on the reactant components the reaction may proceed by direct attack of the carbonyl and enamine formation, or the initial reaction of the amine to the cyclohexenone double bond to form a Michael adduct. A further reaction with a second amount of the same or different amine may afford a 1,3-diamine substituted enamine, which can eliminate one of the amine groups to form the enamine of formula (I). Accordingly, formation of the enamine in this manner may be achieved in a linear fashion or as a one pot procedure. For instance, the enamine could be prepared by reacting the amine with an equivalent of the cyclohexenone. Alternatively, the Michael adduct could be first prepared, isolated and optionally purified before being reacted with a further amount of the same or different amine and eliminated. The reaction conditions for such processes would follow those known in the art to be suitable for Michael reactions. Furthermore, the conversion of the resultant enamine to the desired N-substituted anilines may be performed under the reaction conditions discussed above for the one pot procedure.
An alternative to the above linear strategy is to start from a 2-hydroxymethyl- cyclohexenone which may be prepared from reacting an optionally substituted cyclohexenone with a ring compound component. Other methods for preparing 2- hydroxymethyl-cyclohexenones would be recognised by the skilled person. For instance, such compounds may be prepared under standard Baylis-Hillman conditions (US 3743669,
Drewes, S.E., Roos G.H.P; Tetrahedron, 1988, 44, 4653-4670). The reaction of 2- hydroxymethyl-cyclohexenones with the amine component of the present invention may be an alternative route to N-substituted anilines.
Accordingly, the present invention also provides a process for preparing N-substituted anilines comprising reacting a compound of formula (II):
Figure imgf000027_0001
or a tautomer thereof,
wherein n represents an integer from 0 to 4; R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
R represents an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound;
with a primary or secondary amine or reactive derivative thereof, for a time and under conditions sufficient to form said N-substituted anilines.
The preferred protocol for the preparation of compounds of formula (II) involves the reaction of the ring compound component and cyclohexenone under Baylis-Hillman conditions. The preferred method involves reacting the ring compound component and cyclohexenone under solventless conditions under an inert atmosphere. Preferably the reaction is catalysed by adding a suitable base, for instance, DBU or DABCO. The reaction progress can be monitored by thin layer chromatography, gas chromatography, HPLC, NMR or IR spectroscopy. The crude product can be isolated and purified by standard work up procedures. For instance, the crude product can be dissolved in a suitable organic solvent which is immiscible with water (for instance, ether) and neutralised by the addition of an aqueous acid solution like 2M HCl. The organic layer is then collected, dried and reduced in vacuo. The crude product may also be further purified by column chromatography or recrystallised or subjected to the next step in the reaction process, that is, reacted with the amine. This subsequent reaction to the desired N- substituted anilines may be performed under the reaction conditions discussed above for the one pot procedure. The N-substituted anilines prepared by the aforementioned processes can be subjected to further reaction steps without separation from the crude reaction mixture, or may be separated using conventional techniques, including filtration and/or followed by chromatographic separation techniques typically on silica gel. Preferably however the compounds prepared by the present process are separated from the reaction mixture. For example, the residue from the reaction can be subjected to standard work up procedures. An example of this may include cooling and neutralising the reaction mixture with a suitable base or acid, such as, a saturated NaHCO3 solution or a dilute HCl solution. The residue may then be extracted into an organic solvent, washed with water, separated, dried and concentrated in vacuo.
The recovered residue may be purified by column chromatography or through recrystallisation with a suitable solvent or solvent mixture. For instance, such purification steps could be used to separate the structural isomers in the case where the present process provides mixtures of two isomers. For example the purification step could be used to separate the 2-isomer from the 3-isomer in a reaction mixture where both isomers are formed.
It would be appreciated that conducting the process of the present invention under solid phase conditions can significantly reduce the operational problems often associated with solution phase organic synthesis. For example, simple filtration of a solid supported substituted aniline at the end of the reaction would obviate the need for the aforementioned detailed work up procedures.
The substituted anilines prepared from the present process may also be subjected to a deprotection step in order to afford the unsubstituted anilines. Methods for deprotecting amines are known and examples thereof are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M. Wutts (1999) 3rd edition, Johns Wiley and Son, Inc. The anilines so produced may be subjected to further chemistry including functional group interconversion, reprotection, etc, including alkylation of the nitrogen atom, Friedel-Crafts acylation/alkylation of the aniline ring, formaldehyde coupling and so on.
Aniline derivatives which possess heteroarylmethyl or arylmethyl substituents at the ortho or para positions may be useful in preventing and/or treating a range of medical conditions, and in particular, conditions associated with nematode, fungal, protozoan, bacterial or yeast infections. These compounds may also be useful in treating proliferative diseases such as cancer. Accordingly, the present invention also relates to those compounds which have been prepared by the process described herein as well as the novel compounds described in the following examples which illustrate the present process.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The invention will now be described with reference to the following examples which are intended only for the purpose of illustrating certain embodiments of the invention and are not to be taken as limiting the generality of the invention previously described.
Examples SYNTHESIS
1. One pot reactions with added acid catalysts
a) Synthesis of iV-(2-benzylphenyl) morpholine and iV-(4-benzylphenyl) morpholine
i) Preparation of stock solution of 2-cyclohexenone (Solution A) 2-Cyclohexenone (0.968 mL, 10.0 mmol) was added to a volumetric flask made up to 10 mL with toluene.
ii) Amine reaction. To a round bottom flask equipped with a magnetic stirrer bar, dean-stark apparatus (10 mL trap volume) and condenser was added benzaldehyde (0.508 mL, 5.0 mmol), morpholine (1.74 mL, 20.0 mmol), benzoic acid (0.61 g, 5.0 mmol) and toluene (20 mL). The solution was stirred and refluxed for 20 min, after which a portion of solution A (1.25 mL, 1.25 mmol 2-cyclohexenone) was added to the reaction mixture. 1 h later another portion of solution A (1.25 mL, 1.25 mmol 2-cyclohexenone) was added to the reaction mixture. 1 h after that another portion of solution A (1.25 mL, 1.25 mmol 2-cyclohexenone) was added to the reaction mixture. 1 h after that another portion of solution A (1.25 mL, 1.25 mmol 2- cyclohexenone) was added to the reaction mixture and left to react for another 1% h.
The reaction mixture was then cooled down to room temperature and washed with sat. NaHCO3 (aq) solution (2 x 20 mL). The aqueous layer was washed with toluene (2 x 20 mL). The organic layers were combined and dried using MgSO4, filtered and the solvent removed in vacuo yielding a crude oil (1.81 g). The oil was then subjected to column chromatography eluting with a 1.5 : 8.5 EtOAc / Hexane mixture. Two products were recovered; JV-(2-benzylphenyl) morpholine (RF 0.38, 0.67 g, 52 %) which was crystallised for analysis from hexane (m.p. 62 - 64 °C); Η-n.m.r. (CDCl3): δ 2.82 (t, J = 4.6 Hz, 4H, N-CH2-), 3.77 (t, J= 4.6 Hz, 4H, 0-CH2-), 4.08 (s, 2H, Ar-CH2), 7.27 - 7.01 (m, 9H, ArH), I3C-n.m.r. δ 36.98 (Ar-CH2-), 2 x 53.25 (N-CH2-), 2 x 67.63 (0-CH2-), 120.83, 124.54, 125,98, 127.43, 128.45, 129.09, 131.26 (ArCH), 136.88, 141.83, 151.56 (ArC); FT-IR: (KBr) 2959 m, 2855 m, 2828 m, 1599 m, 1493 s, 1450 s, 1374 w, 1298 w, 1255 m, 1225 s, 1111 s, 1066 w, 1039 w, 942 s, 919 m, 848 w; (ESI+, MeOH): 254.2, 100 % (M + H+), 255.1, 19 % (M + 1 + H+). Microanalysis: Found C 80.59 %, H 7.60 %, N 5.49 %, Requires C 80.60 % H 7.56 %, N 5.53 %.
iV-(4-benzyIphenyI) morpholine (RF 0.28, 0..20 g, 16 %) which was crystallised for analysis from hexane (m.p. 52 - 54 0C); 1H-n.m.r. (CDCl3): δ 3.09 (t, J= 4.8 Hz, 4H, N- CH2-), 3.83 (t, J = 4.8 Hz, 4H3 0-CH2-), 3.90 (s, 2H, Ar-CH2-), 6.83 (d, J = 8.7 Hz, 2H, ArH), 7.36 - 7.05 (m, 8H, ArH); 13C-n.m.r. δ 41.15 (Ar-CH2-), 2 x 49.73 (N-CH2-), 2 x 67.10 (0-CH2-), 116.05, 126.09, 128.56, 128.98, 129.79 (ArCH); 132.88, 141.76, 149.75 (ArC). FT-IR: (KBr) 2957 w, 2901 w, 2863 w, 2808 w, 1615 m, 1513 s, 1489 w, 1448 m, 1522 w, 1299 w, 1262 m, 1239 s, 1118 s, 1067 w, 1053 w, 1030 w, 923 s, 835 w, 793 w; (ESI+, MeOH): 254.2, 100 % (M + H+), 255.2, 19 % (M + 1 + H+); Microanalysis: Found C 80.59 %, H 7.52 %, N 5.47 % Requires C 80.60 % H 7.56 %, N 5.53 %.
b) Synthesis of N-(4-benzyIphenyI)bis(2-methoxyethyl)amine
i) Preparation of stock solution of 2-cyclohexenone (Solution A)
2-Cyclohexenone (0.968 mL, 10.0 mmol) was added to a volumetric flask made up to 10 niL with toluene.
ii) Amine reaction
To a round bottom flask equipped with a magnetic stirrer bar, dean-stark apparatus (10 mL trap volume) and condenser was added benzaldehyde (0.508 mL, 5.0 mmol), bis(2- methoxyethyl)amine (2.92 mL, 20.0 mmol), solution A (1.00 mL, 1.0 mmol 2- cyclohexenone) and benzoic acid (0.61 g, 5.0 mmol) and toluene (25 mL). The solution was stirred and refluxed for 2 h, after which a portion of solution A (1.00 mL, 1.0 mmol 2- cyclohexenone) was added to the reaction mixture. 2 h later another portion of solution A (1.00 mL, 1.0 mmol 2-cyclohexenone) was added to the reaction mixture. 2 h after that another portion of solution A (1.00 mL, 1.0 mmol 2-cyclohexenone) was added to the reaction mixture. 2 h after that another portion of solution A (1.00 mL, 1.0 mmol 2- cyclohexenone) was added to the reaction mixture. 1 h after that another portion of solution A (2.00 mL, 2.0 mmol 2-cyclohexenone) was added to the reaction mixture. H h after that another portion of solution A (1.00 mL, 1.0 mmol 2-cyclohexenone) was added to the reaction mixture and left to react for another 5 h. In summary, a total of solution A (8.0 mL, 8.0 mmol) was added and left to react over a 25 h period. The reaction mixture was then cooled down to room temperature and washed with sat. NaHCO3 (aq) solution (2 x 20 mL). The aqueous layer was washed with toluene (2 x 20 mL). The organic layers were combined and dried using MgSO4, filtered and the solvent removed in vacuo yielding a crude oil (2.22 g). The oil was then subjected to column chromatography eluting with a 1.5 : 8.5 EtOAc / Hexane mixture to yield the 7V-(4- benzylphenyl) bis(2-methoxyethyl)amine (0.73 g, 49 %) as an oil.
c) Synthesis of N-[2-(4-methylbenzyl)phenyl]-n~hexylamine
With a Dean-Stark apparatus for water removal (10 mL trap volume) a solution of n- hexylamine (1.323 mL, 10.0 mmol), p-tolualdehyde (0.591 mL, 5.0 mmol), 2- cyclohexenone (0.968 mL, 10.0 mmol) and p-toluenesulfonic acid (0.192 g, 1.0 mmol) in 25 mL toluene was refluxed. The reaction was left to reflux for 26 h. The reaction mixture was cooled, washed with with sat. NaHCO3 (aq) (2 x 25 mL) was dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using ethyl acetate / hexane (1:4) afforded N-[2-(4- methylbenzyl)phenyl]-n-hexylamine (0.51 g, 36 %) as a clear oil. 13C-n.m.r. (100 MHz, CDCl3): δ 14.20 (CH2-CH3); 21.18 (Ar-CH3); 22.77, 26.81, 29.39, 31.78 (Alkyl -CH2-); 38.14 (Ar-CH2-Ar); 43.91 (N-CH2); 110.67, 116.87, 127.93, 2 x 128.55, 2 x 129.53, 130.75 (ArCH); 124.90, 136.05, 136.57, 146.73 (ArC).
2. One pot reactions without added catalysts
a) Synthesis of JV-(2-benzylphenyl) morpholine and iV-(4-benzylphenyl) morpholine
Under Dean-Stark conditions (10 mL trap volume), a solution of morpholine (2.24 mL, 25.8 mmol) and 2-cyclohexenone (1.00 mL, 10.3 mmol) in toluene (30 mL) was refluxed for 4 h, after which the water level in the dean-stark had stabilised. Benzaldehyde (1.05 mL, 10.3 mmol) was added and stirring was continued for 17 h. The solvent and volatile reagents were removed in vacuo to yield 3.36 g crude material. A portion of the crude material (2.32 g) was dissolved in ether (10 mL) and washed with water (10 mL). The ether layer was collected and the water layer washed with ether (2 x 10 mL). The ethereal fractions were collected then dried with anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to yield an oil (1.73 g). The oil was chromato graphed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford a 4 : 1 mixture of N-(2-benzylphenyl) morpholine (RF 0.38, 0.67 g, 34 %) and benzaldehyde (RF 0.38, 0.06 g) andiV-(4-benzylphenyl) morpholine (RF 0.28, 0.11 g, 6 %) as an oil.
b) Synthesis of N-(2-(4-methoxybenzyl)phenyl) morpholine and N-(4-(4- methoxybenzyl)phenyl) morpholine
Under Dean-Stark conditions (10 mL trap volume), a solution of morpholine (3.049 mL, 35.0 mmol), anisaldehyde (1.217 mL, 10 mmol) and 2-cyclohexenone (0.968 mL, 10.0 mmol) in toluene (40 mL) was refluxed for 48 h. A portion of the reaction mixture was taken and the solvent removed in vacuo. An N.M.R of this reaction mixture showed presence of the dimorpholino 4-methoxybenzyl aminal.
To the main solution was added 2-cyclohexenone (0.968 mL, 10.0 mmol) and the solution was refluxed for a further 48 h. The solvent and volatile reagents were removed in vacuo to yield a crude brown oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford crystals (m.p. 64 - 65 0C) of iV-(2-(4- methoxybenzyl)phenyl) morpholine (RF 0.21, 0.82 g, 31 %) and crystals (73 - 74 0C) of N-
(4-(4-(methoxybenzyl)phenyl) morpholine (RF 0.13, 1.34 g, 50 %). iV-(2-(4- methoxybenzyl)phenyl) morpholine; Η-n.m.r. (CDCl3): δ 2.82 (t, J = 4.6 Hz, 4H, N-
CH2-), 3.74 (s, 3H5 0-CH3), 3.78 (t, J= 4.6 Hz, 4H, 0-CH2-), 4.01 (s, 2H, Ar-CH2), 6.79
(t, J = 8.7 Hz, 2H, ArH), 7.24 - 6.97 (m, 6H5 ArH); 13C-n.m.r. δ 36.00 (Ar-CH2-), 2 x
53.23 (N-CH2-),2 x 55.33 (0-CH3),2 x 67.61 (0-CH2-), 114.06, 120.66, 124.45, 127,28,
129.96, 131.10 (ArCH), 133.82, 137.19, 151.46, 157.99 (ArC); FT-IR: (KBr) 2966 m, 2907 m, 2833 m, 1611 m, 1582 w, 1509 s, 1491 m, 1458 m, 1444 m, 1302 w, 1263 m,
1246 s, 1218 m, 1176 m, 1113 s, 1026 s, 931 s, 917 m, 842 m, 804 m, 772 s; (ESI+, MeOH): 284, 100 % (M + H+), 285, 19 % (M + 1 + H+). Microanalysis: Found C 76.6 %, H 7.5 %, N 4.9 %, Requires C 76.3 % H 7.5 %, N 4.9 %.
iV-(4-(4-(methoxybenzyl)phenyI) morpholine; 1H-n.m.r. (CDCl3): δ 3.10 (t, J = 4.8 Hz, 4H, N-CH2-), 3.76 (s, 3H), 3.83 (t, J= 4.8 Hz, 4H, 0-CH2-), 3.84 (s, 2H, Ar-CH2-), 7.21 -
6.73 (m,8H,ArH); 13C-n.m.r.δ40.32(Ar-CH2-),2 x49.88 (N-CH2-),2x 55.43 (0-CH3),
2 x 67.17 (0-CH2-), 114.05, 116.12, 129.71, 129.93 (ArCH), 132.88, 141.76, 149.75
(ArC);FT-IR: (KBr)2956m,2898w,2836w, 1609in, 1584w, 1509 s, 1459m, 1445 w,
1383w, 1332w, 1304m, 1263s, 1238s, 1187m, 1174s, 1120s, 1068m, 1053m, 1033 s, 928s,908w,854m,813s,802s,757w;(ESI+,MeOH):284, 100%(M+H+),285, 19%
(M+ 1 +H+).Microanalysis: FoundC 76.5 %,H7.5 %,N 5.0%,Requires C 76.3 %H
7.5%,N4.9%.
c) Synthesis of N-(4-benzylphenyl)bis(2-methoxyethyl)amine
Under Dean-Stark conditions (10 mL trap volume), a solution of bis(2- methoxyethyl)amine (5.906 mL, 40.0 mmol) and benzaldehyde (1.02 mL, 10.0 mmol) in toluene (40 mL) was refluxed for 2.5 h, after this time no water was produced. 2- cyclohexenone (1.93 mL, 20.0 mmol) was then added to the solution and further refluxed for 3 I h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford iV-(4- benzylphenyl) bis(2-methoxyethyl)amine (Rp 1.64, g, 55 %) as an oil, 1H-n.m.r. (300 MHz, CDCl3): δ 3.33 (s, 6H, -OMe), 3.51 (s, 8H, 0-CH2-CH2-N), 3.86 (s, 2H, Ar-CH2-), 6.64 (d, J= 8.8 Hz, 2H, ArCH), 7.02 (d, J= 8.8 Hz, 2H, ArCH), 7.28 - 7.12 (m, 5H, ArCH); 13C- n.m.r. (75 MHz, CDCl3) δ 41.05 (Ar-CH2-), 2 x 51.23 (N-CH2-), 2 x 59.11 (0-CH3), 2 x 70.38 (0-CH2), 2 x 112.19, 125.96, 2 x 128.51, 2 x 129.99, 2 x 129.91 (ArCH), 128.90, 142.22, 146.43 (ArC). d) Synthesis of 4-{4-[i\yV-bis(2-methoxyethyl)amino]benzyl}benzoic acid
Under Dean-Stark conditions (10 mL trap volume), a solution of bis(2- methoxyethyl)amine (5.906 mL, 40.0 mmol) and 4-carboxybenzaldehyde (1.50 g, 10.0 mmol) in toluene (40 mL) was refluxed for 1.5 h, after this time no water was produced. 2- Cyclohexenone (1.93 mL, 20.0 mmol) was then added to the solution and further refluxed for 9 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was triturated with ethyl acetate and the resultant precipitate filtered. The solvent was then removed en vacuo from the filtrate and the resulting oil was chromato graphed on silica gel, eluting with ethyl acetate to afford 4-{4-[N,iV-bis(2-methoxyethyl)amino]benzyl}benzoic acid bis(2-(Rp 0.55, 1.77, g, 52 % has some impurities) as an oil; 1H-n.m.r. (300 MHz, CDCl3): δ 3.34 (s, 6H, -OMe), 3.52 (s, 8H, 0-CH2-CH2-N), 3.90 (s, 2H, Ar-CH2-), 6.65 (d, J= 8.3 Hz, 2H, ArCH), 7.01 (d, J= 8.4 Hz, 2H, ArCH), 7.27 (d, J= 8.8 Hz, 2H, ArCH), 8.00 (d, J= 8.8 Hz, 2H, ArCH); 13C n.m.r. (75 MHz, CDCl3): δ 41.11 (Ar-CH2-), 2 x 51.14 (N-CH2-), 2 x 59.10 (0-CH3), 2 x 70.31 (0-CH2-), 2 x 112.24, 2 x 129.05, 2 x 129.95, 2 x 130.47 (ArCH), 127.35, 127.67, 146.63, 148.54 (ArC), 171.31 (CO2H).
e) Synthesis of JV-(2-benzylphenyl) benzylamine
Under Dean-Stark conditions (10 mL trap volume), a solution of benzylamine (3.277 mL, 30.0 mmol) benzaldehyde (1.02 mL, 10.0 mmol) in toluene (40 mL) was refluxed for 2 h, after this time the water, in the trap, had leveled off. 2-Cyclohexenone (1.93 mL, 20.0 mmol) was then added to the solution and further refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford N-Q.- benzylphenyl) benzylamine (1.42, g, 55 %) as an oil; 1H-n.m.r. and 13C-n.m.r. matched authentic sample. f) Alternate synthesis of iV-(2-benzylphenyl) benzylamine
i) Preparation of stock solution of 2-cy clohexenone (Solution A)
2-Cyclohexenone (0.968 niL, 10.0 mmol) was added to a volumetric flask made up to 10 mL with toluene.
ii) Amine reaction.
Under Dean-Stark conditions (10 mL trap volume), a solution of benzylamine (2.180 mL, 20.0 mmol), benzaldehyde (0.508 mL, 5.0 mmol) and solution A (1.25 mL, 1.25 mmol 2- cyclohexenone) in toluene (25 mL) was refluxed.
Throughout the course of the reaction more portions of solution A were added. 20 min later another portion of solution A (1.25 mL, 1.25 mmol 2-cyclohexenone) was added to the reaction mixture. 20 min later another portion of solution A (1.25 mL, 1.25 mmol 2- cyclohexenone) was added to the reaction mixture. 20 min later another portion of solution A (1.25 mL, 1.25 mmol 2-cyclohexenone) was added to the reaction mixture. 2 h later another portion of solution A (2.50 mL, 2.50 mmol 2-cyclohexenone) was added to the reaction mixture, and left to react for another 11 h. In summary, a total of solution A (7.5 mL, 7.5 mmol 2-cyclohexenone) was added and left to react over a 14 h period.
The reaction mixture was cooled to room temperature. White crystals (0.98 g) had formed and were filtered. The cyrstals were identified by N.M.R. as benzylammonium benzoate.
The solvent and volatile reagents from the filtrate were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford iV-(2-benzylphenyl) benzylamine (0.61 g, 45 %) as an oil. 1H-n.m.r and 13C-n.m.r matched authentic sample. g) Synthesis of [2-(4-Methylbenzyl)-phenyl]-(l-phenyl-ethyl)amine
Under Dean-Stark conditions (10 mL trap volume), a solution of (R)-α-methylbenzylamine (3.869 mL, 30.0 mmol), /?-tolualdehyde (1.179 mL, 10.0 mmol) and 2-cyclohexenone (1.93 mL, 20.0 mmol) in toluene (40 mL) was refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford [2-(4- Methyl-benzyl)-ρhenyl]-(l-phenyl-ethyl)amine (0.38, g, 13 %) as an oil; Η-n.m.r. (400 MHz, CDCl3): δ 1.45 (dd, J = 6.7, 0.8 Hz, 3H, CH3); 2.48 (s, 3H5 ArCH3); 4.06 (s, 2H, ArCH2); 4.54 (q, J= 6.6 Hz, IH, CH-N); 6.52 (d, J= 8.1 Hz, IH, ArH); 6.79 (t, J= 7.4 Hz, IH, ArH); 7.14 (t, J= 7.7 Hz, IH, ArH); 7.22 -7.19 (m, 3H, ArH); 7.27 (s, 4H, ArH); 7.31 - 7.29 (m, IH, ArH); 7.37 - 7.33 (m, 2H, ArH). 13C-n.m.r. (100 MHz, CDCl3): δ 21.22 (CH3); 25.17 (CH3); 38.46 (Ar-CH2); 53.22 (N-CH); 112.08, 117.03, 125.87 x 2, 126.84, 127.80, 128.63 x 2, 128.72 x 2, 129.55 x 2, 130.71 (ArCH); 124.87, 136.16, 145.36, 145.40 (ArC).
h) Synthesis of iV-[2-(lH-indol-3-yl)ethyl]-2-(4-methylbenzyl)aiiiline.
Under Dean-Stark conditions (10 mL trap volume), a solution tryptamine (2.40 g, 15.0 mmol), p-tolualdehyde (0.590 mL, 5.0 mmol) and 2-cyclohexenone (0.965 mL, 10.0 mmol) in toluene (40 mL) was refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford N-(2- (4-methylbenzyl)phenyl)-tryptamine (0.43, g, 23 %) as an oil; Η-n.m.r. and 13C-n.m.r. matched authentic sample. i) Synthesis of Benzyl- [2-(4-methylbenzyl)-phenyl] amine
To a round bottom flask equipped with a magnetic stirrer bar, dean-stark apparatus (10 mL trap volume) and condenser was added /?-tolualdehyde (0.590 mL, 5.0 mmol), benzylamine (1.635 mL, 15.0 mmol) and toluene (25 mL). The solution was stirred and refluxed for 1.5 h, after which 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture.
Throughout the course of the reaction more portions of 2-cyclohexenone were added. I1A h later another portion of 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. VA h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 12% h after that another portion 2-cyclohexenone
(0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2.5 h after that another portion
2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2.5 h after that another portion 2-cyclohexenone (0.193 mL, 2.00 mmol) was added to the reaction mixture. 2.5 h after that another portion 2-cyclohexenone (0.290 mL, 3.00 mmol) was added to the reaction mixture. 1.5 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 1 h after that another portion 2- cyclohexenone (0.193 mL, 2,00 mmol) was added to the reaction mixture and left to react for another 8 h. In summary, a total of 2-cyclohexenone (1.255 mL, 13.0 mmol) was added and left to react over a 36 h period.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 hexane : ethyl acetate to afford Benzyl-[2-(4-methyl-benzyl)-ρhenyl]-amine (0.860, g, 60 %) as an oil; Η-n.m.r. and 13C- n.m.r. matched authentic sample. j) Synthesis of N-phenyl-2-(4-methylbenzyl)aniline
Under Dean-Stark conditions (10 mL trap volume), a solution aniline (1.37 g, 15.0 mmol), /?-tolualdehyde (0.590 mL, 5.0 mmol) and 2-cyclohexenone (0.965 mL, 10.0 mmol) in toluene (25 mL) was refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 9.5 : 0.5 hexane : diethyl ether to afford N- phenyl-2-(4-methylbenzyl)aniline(0.15 g, 11 %) as an oil; 1H-n.m.r. and 13C-n.m.r. matched authentic sample.
k) Synthesis of benzyl-[5-methyl-2-(4-methyl-benzyl)-phenyl]amine
Under Dean-Stark conditions (10 mL trap volume), a solution £>-tolualdehyde (0.590 mL, 5.0 mmol), benzylamine (1.635 mL, 15.0 mmol) and 3-methylcyclohex-2-enone (0.277 mL, 2.0 mmol) in toluene (25 mL) was refluxed.
Throughout the course of the reaction more portions of 3-methylcyclohex-2-enone were added. 2 h later another portion of 3-methylcyclohex-2-enone (0.277 mL, 2.0 mmol) was added to the reaction mixture. 2 h after that another portion 3-methylcyclohex-2-enone (0.277 mL, 2.00 mmol) was added to the reaction mixture. 2 h after that another portion 3- methylcyclohex-2-enone (0.415 mL, 3.00 mmol) was added to the reaction mixture. 2 h after that another portion 3-methylcyclohex-2-enone (0.139 mL, 1.00 mmol) was added to the reaction mixture and left to react for another 2 h. In summary, a total of 3- methylcyclohex-2-enone (1.13 mL, 10.0 mmol) was added and left to react over a 14 h period.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with a 1.5 : 8.5 EtOAc / Hexane mixture to afford benzyl-[5-methyl-2-(4-methyl-benzyl)-phenyl]-amine (0.25 g, 17 %) as an oil; tø-n.m.r.
(400 MHz, CDCl3): δ 2.25 (s,3H, -CH3), 2.89 (s,3H, -CH3), 3.79 (s,2H, Ar-CH2-Ar), 4.19 (s.2H, Ar-CH2-Ar)5 6.44 (s,lH, ArH), 6.52 (d, J= 7.5 Hz5 IH5 ArH)5 6.93 (d, J = 7.5 Hz5 IH, ArH)5 7.28 - 6.96 (m, 9H5 ArH); 13C-n.m.r. (100 MHz5 CDCl3): δ 21.18, 21.76 (- CH3), 37.69 (Ar-CH2-Ar)5 48.24 (N-CH2-Ar)5 111.88, 118.1O5 127.16, 2 x 127.45, 2 x 128.60, 2 x 128.6I5 2 x 129.48, 130.65 (ArCH), 122.29, 135.94, 136.68, 137.54, 139.61, 146.08 (ArC).
1) Synthesis of dibutyl (2-benzylphenyl)amine
To a round bottom flask equipped with a magnetic stirrer bar, dean-stark apparatus (10 mL trap volume) and condenser was added benzaldehyde (0.508 mL, 5.0 mmol), dibutylamine (3.369 mL, 20.0 mmol) and toluene (25 mL). The solution was stirred and refluxed for 25 min, after which 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture.
Throughout the course of the reaction more portions of 2-cyclohexenone were added. 2 h later another portion of 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2.5 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. I2A h after that another portion 2-cyclohexenone (0.290 mL, 3.00 mmol) was added to the reaction mixture. 14 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 3.5 h after that another portion 2-cyclohexenone (0.193 mL, 2.00 mmol) was added to the reaction mixture and left to react for another 2Vz h. In summary, a total of 2- cyclohexenone (0.965 mL, 10.0 mmol) was added and left to react over a 28 h period.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was distilled using a kugelrohr distillation apparatus to afford dibutyl (2-benzylphenyl)amine (0.44, g, 30 %) as an oil; 1H-n.m.r. (400 MHz, CDCl3): δ 0.93 (t, J = 7.3 Hz5 6H5 -CH2- CH3), 1.37 - 1.26 (m, 4H5 -CH2-CH3), 1.57 - 1.50 (m, 4H, N-CH2-CH2-), 3.21 (t, J = 7.6 Hz, 4H, N-CH2-CH2-), 3.86 (s, 2H, Ar-CH2-Ar), 6.57 (d, J= 8.8 Hz5 2H5 ArH), 7.00 (d, J = 8.6 Hz, 2H, ArH), 7.29 - 7.09 (m, 5H, ArH); 13C-n.m.r. (100 MHz, CDCl3): δ 2 x 14.20 (-CH2-CH3), 2 x 20.60 (-CH2-CH3), 2 x 29.72 (N-CH2-CH2-), 41.13 (Ar-CH2-Ar), 2 x 51.92 (N-CH2-CH2-), 2 x 112.20, 125.92, 2 x 128.50, 2 x 129.06, 2 x 129.81 (ArCH), 127.91, 142.43, 146.91 (ArC).
m) Synthesis of bis(2-methoxy ethyl [4-(4-pyridyl)phenyl] amine
Under Dean-Stark conditions (10 niL trap volume), a solution bis(2-methoxyethyl)amine (5.906 niL, 40.0 mmol), 4-pyridinecarboxyaldehyde (0.955 mL, 10.0 mmol) and 2- cyclohexenone (1.936 mL, 20.0 mmol) in toluene (40 mL) was refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was cliromatographed on silica gel, eluting with EtOAc to afford bis(2-methoxyethyl [4-(4- pyridyl)phenyl]amine (1.79 g, 60 %) as an oil; 1H-n.m.r. (400 MHz, CDCl3): δ 3.44 (s, 6H, 0-CH3), 3.53 (s, 8H, N-CH2-CH2-O), 3.84 (s, 2H, Ar-CH2-Ar), 6.66 (d5 J = 8.9 Hz, 2H, ArH), 7.00 (d, J = 8.9 Hz, 2H, ArH), 7.10 (d, J = 6.0 Hz, 2H, ArH), 8.46 (d, J = 6.0 Hz, 2H, ArH).
n) Synthesis of 4,4'-[l,3-phenylene-bis(methylene)]bis[N,N-bis(2- methoxy ethyl)] aniline
Under Dean-Stark conditions (10 mL trap volume), a solution bis(2-methoxyethyl)amine (5.906 mL, 40.0 mmol), isophthalaldehyde (0.671 g, 5.0 mmol) and 2-cyclohexenone (1.936 mL, 20.0 mmol) in toluene (40 mL) was refluxed for 27 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with a 2 : 3 EtOAc / Hexane mixture to afford the desired product (0.355 g, 14 %) as an oil; 1H-n.m.r. (400 MHz, CDCl3): δ 3.33 (s, 12 H, O- CH3), 3.51 (s, 16 H, N-CH3-CH3-O)5 3.81 (s, 4H, Ar-CH3-Ar), 6.62 (d, J = 8.8 Hz, 4H, ArH), 7.07 - 6.93 (m, 2H, ArH), 7.00 (d, J= 8.9 Hz, 4H, ArH), 7.24 - 7.12 (m, 2H, ArH); 13C-n.m.r. (100 MHz, CDCl3): δ 2 x 40.97 (Ar-CH2-Ar), 4 x 51.19 (N-CH2-), 4 x 59.08 (0-CH3), 4 x 70.35 (0-CH2-), 4 x 112.60, 2 x 126.51, 128.49, 129.57, 4 x 129.85 (ArCH), 2 x 1129.03, 2 x 142.10, 2 x 146.34 (ArC).
o) Synthesis of 1,3- Bis(2-benzylaminobenzyl)benzene
Under Dean-Stark conditions (10 niL trap volume), a solution benzylamine (3.277 niL, 30.0 mmol), isophthalaldehyde (0.671 g, 5.0 mmol) and 2-cyclohexenone (2.895 mL, 30.0 mmol) in toluene (40 mL) was refluxed for 24 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with a 1.5 : 8.5 EtOAc / Hexane mixture to afford the desired product (0.35 g, 15 %) as an oil; 1H-n.m.r. and 13C-n.m.r. matched authentic sample.
p) Synthesis of iV-(4-(2-methoxybenzyl)phenyl) morpholine and iV-(2-(2- methoxybenzyl)phenyl) morpholine
Under Dean-Stark conditions (10 mL trap volume), a solution morpholine (3.48 mL, 40.0 mmol), 2-methoxybenzaldehyde (1.36 g, 10.0 mmol) and 2-cyclohexenone (1.93 mL, 20.0 mmol) in toluene (40 mL) was refluxed for 47 h.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with 8.5 : 1.5 \ hexane : ethyl acetate to afford crystals (m.p. 68 - 70 °C) of iV-(2-(2-methoxybenzyl)ρhenyl) morpholine (0.52 g, 19 %) and crystals (m.p. 64 - 65 °C) of N-(4-(2-methoxybenzyi)phenyl) morpholine (0.47 g, 18 %). iV-(2-(2-methoxybenzyl)phenyI) morpholine; 1H-n.m.r. (300 MHz5 CDCl3): δ 2.86 (t, J= 4.6 Hz, 4H, N-CH2), 3.77 (t, J= 4.6 Hz5 4H, 0-CH2), 3.80 (s, 3H5 0-CH3), 4.07 (s, 2H5 Ar-CH2-Ar), 6.82 (td, J= 7.3, 1.2 Hz, IH, ArH)5 6.85 (d, J= 8.2 Hz, IH5 ArH), 7.02 - 6.96 (td, 2H5 ArH)5 7.06 (dd5 J = 7.6, 1.8 Hz5 IH5 ArH), 7.11 (dd, J = 7.9, 1.3 Hz, IH5 ArH)5 7.15 (dd5 J = 7.5, 1.8 Hz5 IH, ArH), 7.20 (td, J = 6.7, 1.9 Hz5 IH5 ArH); 13C-n.m.r. (50 MHz5 CDCl3): δ 30.51 (Ar-CH2-Ar), 2 x 53.12 (N-CH2), 2 x 55.48 (0-CH3), 2 x 67.64 (O- CH2), 110.38, 120.38, 120.55, 124.24, 127.06, 127.23, 130.31, 131.02 (ArCH), 130.13, 136.51, 151.59, 157.64 (ArC); Microanalysis: Found C 76.24 %, H 7.56 %, N 4.97% O 11.23% Requires C 76.29%H 7.47%N 4.94%O 11.29%.
iV-(4-(2-methoxybenzyl)phenyl) morpholine 'H-n.m.r. (300 MHz, CDCl3): δ 3.11 (t, J = 4.8 Hz, 4H, N-CH2-), 3.81 (s, 3H, 0-CH3), 3.84 (t5 J = 4.8 Hz, 4H, 0-CH2-), 3.90 (s, 2H, Ar-CH2-Ar), 6.83 (d, J= 8.6 Hz, 2H, ArH), 6.88 - 6.85 (m, 2H, ArH)5 7.04 (dd, J = 7.6, 1.7 Hz, IH, ArH), 7.12 (d, J= 8.7 Hz, 2H, ArH), 7.18 (td, J= 7.8, 1.7 Hz, IH, ArH); 13C- n.m.r. (50 MHz, CDCl3): δ 35.09 (Ar-CH2-Ar), 2 x 49.95 (N-CH2), 2 x 55.56 (0-CH3), 2 x 67.19 (0-CH2), 110.66, 2 x 116.05, 120.68, 127.42, 2 x 129.87, 130.39 (ArCH), 2 x 132.86, 149.67, 157.57 (ArC).
q) Synthesis of benzyl-(4-benzyl-4'-methylbiphenyl)-3-amine
Under Dean-Stark conditions (10 rnL trap volume), a solution benzaldehyde (0.508 niL, 5.0 mmol), benzylamine (1.635 mL, 15.0 mmol) and 3-(4-methylphenyl)cyclohex-2-enone (0.215 g, 1.15 mmol) in toluene (20 mL) was refluxed.
Throughout the course of the reaction more portions of 3-(4-methylphenyl)cyclohex-2- enone were added. 1.5 h later another portion of 3-(4-methylphenyl)cyclohex-2-enone
(0.215 g, 1.15 mmol) was added to the reaction mixture. 1.5 h after that another portion 3-
(4-methylphenyl)cyclohex-2-enone (0.215 g, 1.15 mmol) was added to the reaction mixture. 1.5 h after that another 3-(4-methylphenyl)cyclohex-2-enone (0.215 g, 1.15 mmol) was added to the reaction mixture. 3.5 h after that another 3-(4- methylphenyl)cyclohex-2-enone (0.215 g, 1.15 mmol) was added to the reaction mixture and left to react for another 12 h. In summary, a total of 3-(4-methylphenyl)cyclohex-2- enone (1.075 g, 5.77 mmol) was added and left to react over a 20 h period.
The solvent and volatile reagents were removed in vacuo to yield a crude oil. The oil was chromatographed on silica gel, eluting with a 2 : 8 EtOAc / Hexane mixture to afford benzyl-(4-benzyl-4'-methylbiρhenyl)-3-amine (1.21 g, 66 %) as a colourless solid (m.p. 99 - 100°C): J. (400 MHz, CDCl3): 62.37 (s, 3H, -CH3), 3.94 (s, 3H, Ar-CH2-Ar, NH)5 4.31 (s, 2H, N-CH2-Ar)5 6.83 (d, J= 1.7 Hz5 IH5 ArH), 6.93 (dd5 J= 7.6, 1.8 Hz, IH5 ArH)5 7.14 - 7.10 (m, 3H, ArH)5 7.32 - 7.18 (m, 1OH, ArH); 7.42 (d, J = 5.1 Hz5 2H5 ArH); 13C-n.m.r. (100 MHz5 CDCl3): δ 21.3 (-CH3), 38.2 (Ar-CH2-Ar)5 48.4 (N-CH2-Ar); 109.9, 116.2, 126.7, 2 x 127.1, 127.3, 2 x 127.6, 4 x 128.8, 2 x 128.9, 2 x 129.5, 131.1 (ArCH); 123.9, 136.9, 139.2, 2 x 139.5, 141.1, 146.4 (ArC). FT-IR: (KBr) 3399 w, 3030 w, 2914 w, 2862 w, 1608 m, 1579 m, 1561 s, 1529 w, 1504 s, 1492 m, 1474 m, 1451 m, 1426 m, 1396 m, 1312 m, 1246 m5 1176 w, 1139 w, 1074 W5 1029 w, 935 w, 910 w, 858 w, 820 s, 792 s, 759 s, 739 s, 700 s; (ESI+, MeOH): 364, 100 % (M + H+), 365, 39 % (M + 1 + H+); Microanalysis: Found C 89.2 % H 7.0 %, N 3.9%. Requires C 89.2 %, H 6.9 %, N 3.9 %.
r) Synthesis of 4-(2-morpholinobenzyl)benzoic acid
With water removal by a Dean and Stark apparatus (10 niL trap volume), a solution of morpholine (3.48 mL, 40.0 mmol), />-carboxybenzaldehyde (1.50 g, 10 mmol) and 2- cyclohexenone (1.93 mL, 20.0 mmol) in PhMe (40 mL) was held at reflux for 8 h. At the end of this time all volatile materials were removed in vacuo to yield an orange oil. The oil was subjected to column chromatography with straight ether to afford 4-(2- morpholinobenzyl)benzoic acid (RF 0.32, 0.74 g, 25 %) as a white solid (m.p. 177 - 181 °C). 1H-n.m.r. matched authentic sample.
s) Synthesis of -Y-(4-(4-hydroxybenzyl)phenyl)morpholine
With water removal by a Dean and Stark apparatus (10 mL trap volume), a solution of morpholine (3.48 mL, 40.0 mmol), p-hydroxybenzaldehyde (1.22 g, 10 mmol) and 2- cyclohexenone (1.93 mL, 20.0 mmol) in toluene (40 mL) was held at reflux for 18 h. All volatile materials were removed in vacuo to yield an orange oil. The oil was subjected to column chromatography with diethyl ether to afford N-(4-(4- hydroxybenzyl)phenyl)morpholine ( 0.70 g, 26 %) as a white solid (m.p. 165 - 166 0C). 1H-ILmX (200 MHz5 CDCl3): δ 3.13 (t, J= 4.8 Hz, 4H, N-CH2); 3.85 (s, 3H, OCH3); 3.87 (t, J= 4.7 Hz, 0-CH2); 4.72 (s, 2H, Ar-CH2-Ar); 6.74 (d, J= 8.6 Hz, 2H, Ar); 6.87 (d, J = 8.2 Hz, 2H, Ar); 7.02 - 7.11 (m, 4H, Ar). 13C-n.m.r. (75 MHz, CDCl3): δ 40.33 (Ar-CH2- Ar); 2 x 50.03 (N-CH2); 2 x 67.09 (0-CH2); 2 x 115. 47, 2 x 116.31, 2 xl29.80, 2 x 130.16(ArCH); 154.03 (ArC). (MS-ESI+, MeOH): 270.3, 100 % (M + H+), 271.4, 20 % (M + 1 + H+).
3. One pot reactions with added base catalysts
a) Synthesis of 0-methyl-iV-(2-(4-inethylbenzyl)phenyl) glycine
To a round bottom flask equipped with a magnetic stirrer bar, dean-stark apparatus (10 mL trap volume) and condenser was added tolualdehyde (0.590 mL, 5.0 mmol), O- methylglycine hydrochloride (1.88 mL, 15.0 mmol), triethylamine (2.3 mL, 16.5 mmol) and toluene (25 mL). The solution was stirred and refluxed for 0.5 h, after which 2- cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture.
Throughout the course of the reaction more portions of 2-cyclohexenone were added. 2 h later another portion of 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 12 h after that another portion 2-cyclohexenone (0.0965 mL, 1.00 mmol) was added to the reaction mixture. 2 h after that another portion 2- cyclohexenone (0.193 mL, 2.00 mmol) was added to the reaction mixture and left to react for another 2 h. In summary, a total of 2-cyclohexenone (0.579 mL, 13.0 mmol) was added and left to react over a 20 h period.
The reaction mixture was then cooled down to room temperature and washed with sat. NaHCO3 (aq) solution (2 x 20 mL). The aqueous layer was washed with toluene (2 x 20 mL). The organic layers were combined and dried using MgSO4, filtered and the solvent removed in vacuo yielding a crude oil. The oil was then subjected to column chromatography eluting with a 1.5 : 8.5 EtOAc / Hexane mixture to afford O-methyl-iV-(2- (4-methylbenzyl)phenyl) glycine (0.53g, 39 %) as an oil; 1H-n.m.r. (400 MHz, CDCl3): δ 2.30 (s, 3H5 Ar-CH3), 3.72 (s, 3H, 0-CH3), 3.85 (s, 2H), 3.87 (s, 2H) (Ar-CH2-Ar5 N-CH2- C=O), 6.47 (dd, J= 8.0, 0.9 Hz, IH, ArH), 6.74 (td, J= 7.4, 1.1 Hz, IH, ArH)5 7.27 - 7.04 (m, 6H, ArH); 13C-n.m.r. (75 MHz, CDCl3): δ 21.19 (Ar-CH3), 37.74 (Ar-CH2-Ar), 45.89 (N-CH2-), 52.29 (0-CH3), 110.79, 118.12, 127.89, 2 x 128.72, 2 x 129.47, 130.78 (ArCH), 125.81, 136.01, 136.16, 145.11 (ArC).
b) Synthesis of iV-(2-benzylphenyl) benzylamine
With water removal by Dean and Stark apparatus (10 mL trap volume), a solution of benzylamine (1.637 mL, 15.0 mmol), PhCHO (0.508 mL, 5.0 mmol) and DABCO (0.561 g, 5 mmol) in PhMe (30 mL) was held at reflux. Portions (0.24 mL) of 2-cyclohexenone were added after 15 min , 1 h 45 min, 3 h 15 min and 4 h 45 min. After 7 h, a double portion (0.48 mL) was added and the mixture was allowed to react for another 13 h, before cooling to room temperature and washing with distilled water (2 x 20 mL). The organic layer was collected and dried (MgSO4), filtered and the solvent evaporated in vacuo to yield a crude oil. Column chromatography with EtOAc / hexane (1 :9) mixture afforded JV- benzyl-2-benzylaniline (RF 0.36, 1.37 g, 87 %) as a colorless solid (m.p. 50 - 520C) which crystallized from Et2O. 1H-n.m.r. (300 MHz, CDCl3): δ 3.88 (s, 2H, -CH2-), 4.21 (s, 2H, - CH2-), 6.60 (d, J= 8.0 Hz, IH, ArCH), 6.70 (dt, J= 7.4, 1.1 Hz5 IH5 ArCH), 7.25 - 7.04 (m, 12H, ArCH); (75 MHz, CDCl3): δ 38.5 (Ar-CH2-), 48.2 (Ar-CH2-), 111.1, 117.4, 126.6, 127.2, 2 x 127.4, 128.0, 2 x 128.7, 4 x 128.8, 130.8 (ArCH), 124.8, 139.5, 139.6, 146.1 (ArC). FT-IR: (KBr) 3435 w, 3062 w, 3027 m, 2903 w, 2844 w, 1603 s, 1585 s, 1512 s, 1494 s, 1452 s, 1314 m, 1269 m, 1256 m, 1118 w, 1074 w, 1028 m, 748 s, 728 s, 697 s; (ESI+, MeOH): 274, 100 % (M + H+), 275, 20 % (M + 1 + H+); Microanalysis: Found C 87.8 %, H 7.1 %, N 5.1 % Requires C 87.9 % H 7.0 %, N 5.1 %.
c) Synthesis of 4-(2-morpholinobenzyl)benzoic acid
With water removal by a Dean and Stark apparatus (10 mL trap volume), a solution of morpholine (0.523 mL, 6.0 mmol), p-carboxybenzaldehyde (0.751 g, 5.0 mmol), DABCO
(0.280 g, 2.5 mmol) and 2-cyclohexenone (0.484 mL, 5.0 mmol) in PhMe (25 mL) was held at reflux for 16 h. At the end of this time all volatile materials were removed in vacuo to yield an orange oil/solid mixture.
The residue was absorbed onto silica gel and a column was run with straight ether affording the 4-(2-morpholinobenzyl)benzoic acid (RF 0.32, 0.221 g, 15 %) as a white solid (179 - 181 0C). 1H-n.m.r. (400 MHz, CD3OD): δ 2.82 (t, J= 4.2 Hz, 4H5 N-CH2); 3.76 (t, J = 4.2 Hz3 4H, 0-CH2); 4.18 (s, 2H5 Ar-CH2-Ar); 7.10 (tdd, J = 6.8, 1.6, 0.9 Hz5 IH, ArH); 7.63 (ddd, J= 7.6, 1.0, 0.5 Hz, IH, ArH); 7.24 (d, J= 7.5 Hz, IH5 ArH); 7.26 (dt, J = 7.6, 0.9, IH5 ArH); 7.80 (d, J= 8.0, 2H, ArH); 7.93 (d, J= 7.8, 2H5 ArH). FT-IR: (KBr) 3446 sb, 2966 w, 2938 w, 2884 w, 2816 w, 1676 s, 1610 s, 1518 m, 1492 m, 1450 m, 1422 w, 1384 w, 1320 w, 1288 m, 1256 w, 1218 w, 1181 w, 1113 s, 932 w, 702 m. Microanalysis: Found C 72.92 %, 6.36 %, 4.75 %, Requires C 72.71 % H 6.44 %, N 4.71 %.
d) Synthesis of N-[2-(benzyl)phenyl]gIycine methylester
With water removal by a Dean and Stark apparatus (10 mL trap volume), a solution of glycine methylester (0.753 g, 6.0 mmol), benzaldehyde (0.508 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and 2-cyclohexenone (0.484 mL, 5.0 mmol) in PhMe (20 mL) was held at reflux for 7 h. At the end of this time a precipitate had formed. The reaction was cooled room temperature and the solid filtered off. The volatile materials were removed from the filtrate in vacuo to yield an orange oil (1.13 g).
The oil was subjected to column chromatography with an 2:8 ether/hexane mix to afford iV-[2-(benzyl)phenyl]glycine methylester (RF 0.34, 0.12 g, 15 %) as a pale yellow solid
(m.p. 92 - 93 0C). 1H-n.m.r. (300 MHz, CDCl3): δ 3.72 (s, 3H5 0-CH3); 3.86 (s, 2H, -CH2-
); 4.02 (s, 2H5 -CH2-); 6.71 (d, J= 7.4, 1.1, IH, Ar); 6.85 ( app td, J= 7.4, 1.1 Hz5 IH5 Ar);
7.10 (dd, J = 7.5, 1.6 Hz, Ar); 7.19 - 7.22 (m, 6H, Ar). 13C-n.m.r. (100 MHz, CDCl3): δ
38.21 (Ar-CH2-); 45.92 (N-CH2); 52.36 (0-CH3); 110.87, 118.20, 126.60, 128.04, 2 x 128.83, 2 x 128.90, 130.92 (ArCH); 125.60, 139.35, 145.16 (ArC); 171.67 (C=O). (ESI+, MeOH): 256.1, 100 % (M + H+), 257.1, 18 % (M + 1 + H+). Microanalysis: Found C 75.44 %, H 6.72 %, N 5.47 %, Requires C 75.27 % H 6.71 %, N 5.49 %.
e) Synthesis of N-(2-benzylphenyl)-n-hexylamine
With a Dean-Stark apparatus for water removal (10 mL trap volume) a solution of n- hexylamine (0.1.98 mL, 15.0 mmol), benzaldehyde (0.508 mL, 5.0 mmol) and DABCO (0.561 g, 5.0 mmol) in 25 mL toluene was refluxed. After 10 min of refluxing, 2- cyclohexenone (0.242 mL, 2.5 mmol) was added. After another 90 min of refluxing another portion of 2-cyclohexenone (0.242 mL, 2.5 mmol) was added. After another 60 min of refluxing another portion of 2-cyclohexenone (0.242 mL, 2.5 mmol) was added. After another 16 h of refluxing another portion of 2-cyclohexenone (0.242 mL, 2.5 mmol) was added refluxed for another 5 h. In total, 2-cyclohexenone (0.968 mL, 10.0 mmol) was reacted 23.5 h.
The reaction mixture was cooled, washed with distilled water (2 x 25 mL). The organic layer was dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using ethyl acetate / hexane (1:19) afforded N-(2- benzylphenyl)-n-hexylamine (0.82 g, 61 %) as a clear oil. 13C-n.m.r. (75 MHz, CDCl3): δ 14.21 (-CH3); 22.75, 26.80, 29.40, 31.77 (Alkyl -CH2-); 38.53 (Ar-CH2-Ar); 43.96 (N- CH2); 110.75, 116.96, 126.58, 128.03, 2 x 128.67, 2 x 128.84, 130.82 (ArCH); 124.65, 139.72, 146.67 (ArC). (ESI+, MeOH): 268.3, 100 % (M + H+), 269.4, 20 % (M + 1 + H+).
4. One pot reactions with added acid and base catalysts
a) Synthesis of Benzyl-[2-(4-methylbenzyl)-phenyI]-amine
To a round bottomed flask equipped with a magnetic stirrer bar, Dean and Stark apparatus
(10 mL trap volume) and condenser, were added /?-tolualdehyde (0.59 mL, 5.0 mmol), benzylamine (0.66 mL, 6.0 mmol), DABCO (0.28 g, 2.5 mmol), PhCOOH (0.34 g, 2.5 mmol) and PhMe (25 mL). The solution was stirred at reflux for 30 min, after which time 2-cyclohexenone (0.48 mL, 5.0 mmol) followed by another portion (0.24 niL, 2.5 mmol) after 2 h. After a further 1.5 h at reflux, the reaction mixture was cooled to room temperature, washed with sat. NaHCO3 (aq) (2 x 25 mL) and then distilled water (1 x 25 mL). The organic layer was separated and dried (MgSO4), filtered and the solvent evaporated in vacuo to yield a crude oil. Silica gel column chromatography using Et2O / hexane (1:4) afforded N-benzyl-2-(4-methylbenzyl)aniline (RF 0.54, 1.44 g, 70 %) which crystallized as a white solid (m.p. 63 - 65°C) from Et2O. Η-njni (400 MHz, CDCl3): δ 2.35 (s, 3H, -CH3), 3.89 (s, 2H, Ar-CH2-Ar), 3.94 (s, IH, NH), 4.26 (s, 2H, N-CH2-Ar), 6.64 (d, J= 7.7 Hz, IH, ArH), 6.75 (td5 J = 7.4, 1.1 Hz, IH, ArH), 7.32 - 7.02 (m, HH, ArH); 13C-n.m.r. (100 MHz, CDCl3): δ 21.2 (-CH3), 38.1 (Ar-CH2-Ar), 48.2 (N-CH2-Ar), 111.1, 117.4, 127.2, 2 x 127.4, 127.9, 4 x 128.6, 2 x 129.5, 130.7 (ArCH), 125.1, 136.0, 136.4, 139.5, 146.1 (ArC). FT-IR: (KBr) 3432 w, 3026, 2922 w, 2863 w, 1603 s, 1565 s, 1511 s, 1451 s, 1314 m, 1266 m, 1121 w, 1051 w, 1028 w, 913 w, 804 w, 746.5 s, 697 m; (ESI+, MeOH): 288.3, 100 % (M + H+), 289.3, 21 % (M + 1 + H+); Microanalysis: Found C 87.7 %, H 7.3 %, N 5.0 % Requires C 87.8 % H 7.4 %, N 4.9 %.
b) Synthesis of 1,3- Bis(2-benzylaminobenzyl)benzene
With water removal by Dean and Stark apparatus (10 mL trap volume), a solution of isophthalaldehyde (0.34 g, 2.5 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g,
2.75 mmol) in PhMe (25 mL) was stirred at reflux. After 15 min, benzylamine (0.66 mL,
6.0 mmol) and 2-cyclohexenone (0.48 mL, 5.0 mmol) were added, followed by further aliquots of 2-cyclohexenone after. 1 h (0.48 mL, 5.0 mmol) and 2 h (0.12 mL, 1.25 mmol).
After a further 1.25 h at reflux, the reaction mixture was cooled to room temperature and washed with sat. NaHCO3 (aq) (2 x 25 mL) followed by distilled water (1 x 25 mL). The organic layer was collected and dried with MgSO4, filtered and the solvent removed in vacuo to yield a crude oil. Silica gel column chromatography eluting with Et2O / hexane
(1:1) afforded l,3-bis(2-benzylaminobenzyl)benzene (0.76 g, 65 %) which crystallized as a white solid (m.p. 95 - 97 °C) from hexane and Et2O. 1H-n.m.r. (400 MHz, CDCl3): δ 3.79 (s, 4H, Ar-CH2-Ar), 4.14 (s, 4H, N-CH2-Ar), 6.56 (dd, J =8.1, 0.9 Hz, 2H, ArH)5 6.66 (td,
J=7.4, 1.1 Hz, 2H, ArH), 7.23 - 6.97 (m, 18H, ArH); 13C-n.m.r. (100 MHz, CDCl3): δ 2 x 38.3 (Ar-CH2-Ar), 2 x 48.1 (N-CH2-Ar), 2 x 111.0, 2 x 117.4, 2 x 126.8, 2 x 127.2, 4 xl27.3, 2 x 127.9, 4 x 128.6, 129.1, 129.2, 2 x 130.6 (ArCH)5 2 x 124.8, 2 x 139.5, 2 xl39.9, 2 x 146.1 (ArC). FT-IR: (KBr) 3427 w, 3395 w, 3029 w, 2900 w, 2829 w, 1604 m, 1584 m, 1508 s, 1452 m, 1444 m, 1324 w, 1279 w, 1249 w, 1123 w, 1046 w, 1026 w, 751 s, 738 s, 699 s; (ESI+, MeOH): 470, 100 % (M + H+), 471, 42 % (M + 1 + H+); Microanalysis: Found C 86.9 %, H 7.0 %, N 6.0 % Requires C 87.1 % H 6.9 %, N 6.0 %.
c) Synthesis of Λ^[2-(lJΪ-indol-3-yl)ethyl]-2-(4-methylbenzyl)anilme
With water removal by Dean and Stark apparatus (10 niL trap volume), a solution of tryptamine (0.80 g, 6.0 mmol), />-tolualdehyde (0.59 mL, 5.0 mniol), 2-cyclohexenone (0.48 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.336 g, 2.75 mmol) in PhMe (25 mL) was heated at reflux for 1 h 25 min. The solvent was evaporated in vacuo and the residue dissolved in CH2Cl2. The solution was washed with sat. NaHCO3 (aq) (2 x 25 mL) then with distilled water (1 x 25 mL). The organic layer was collected and dried with MgSO4, filtered and the solvent evaporated in vacuo to give a crude oil. Silica gel column chromatography using Et2O / hexane (1:4) afforded iV-[2-(lH-indol-3-yl)ethyl]-2-(4-methylbenzyl)aniline (1.12 g, 66 %) as a white solid (m.p. 63 - 65 0C). 1H-n.m.r. (200 MHz, CDCl3): δ 2.26 (s, 3H, CH3), 2.93 (t, J= 6.7 Hz, 2H, NH-CH2-CH2-), 3.36 (t, J= 6.8 Hz, 2H, NH-CH2-CH2-), 3.63 (s, IH, NH), 3.66 (s, 2H, Ar-CH2-Ar), 6.71 - 6.64 (m, 3H, ArH), 7.26 - 6.85 (m, 12 H, ArH), 7.52 (d, J= 7.52, IH, ArH), 7.62 (s, IH, NH); 13C-n.m.r. (50 MHz, CDCl3): δ 21.2 (CH3), 25.2 (CH3), 38.5 (Ar-CH2), 53.2 (N-CH), 112.1, 117.0, 125.9 x 2, 126.8, 127.8, 128.6 x 2, 128.7 x 2, 129.6 x 2, 130.7 (ArCH), 124.9, 136.2, 145.4 x 2 (ArC). FT-IR: (KBr) 3352 w, 3338 w, 3241 W5 3211 w, 3179 w, 3046 w, 3018 w, 2949 w, 2914 w, 2848 w, 1604 m, 1585 m, 1499 s, 1458 s, 1444 m, 1432 m, 1356 w, 1336 w, 1292 w, 1249 m, 1235 m, 1198 w, 1100 w, 1082 w, 1047 w, 1022 w, 1008 w, 969 w, 918 w, 801 m, 742 s, 712 w; (ESI+, MeOH): 341, 100 % (M + H+), 342, 26 % (M + 1 + H+); Microanalysis: Found C 84.4 %, H 7.3 %, N 8.0 % Requires C 84.7 % H 7.1 %, N 8.2 %. d) Synthesis of ΛyV-dibenzyl-4-benzylaniline
With water removal by Dean and Stark apparatus (10 mL trap volume), a solution of PhCHO (0.51 mL, 5.0 mmol), dibenzylamine (1.39 mL, 7.0 mmol), 2-cyclohexenone (0.48 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g, 2.75 mmol) in PhMe (25 mL) was heated with stirring at reflux. 2-Cyclohexenone (0.24 mL, 2.5 mmol) was added portionwise after 2h, 4h and 5.5 h, after which time, the reaction was left for another 2.5 h. The reaction mixture was washed with sat. NaHCO3 (aq) (2 x 25 mL) then with distilled water (1 x 25 mL). The organic layer was collected, dried with MgSO4, filtered and the solvent removed in vacuo to yield an oil, which was subjected to column chromatography on Silica gel with Et2O / hexane (1 :4) as eluant. λyV-dibenzyl-4-benzylaniline (1.17 g, 64 %) was obtained as a colorless, highly crystalline solid (m.p. 105 - 107°C). 1H-n.m.r. (300 MHz, CDCl3): δ 3.85 (s, 2H, Ar-CH2-Ar); 4.61 (s, 4H, Ar-CH2-N); 6.66 (d, J= 8.8 Hz, 2H, ArH); 6.97 (d, J = 8.8 Hz, 2H, ArH); 7.13 - 7.33 (m, 15H, ArH); I3C-n.m.r. (100 MHz, CDCl3): δ 41.2 (Ar-CH2-Ar), 2 x 54.6 (N-CH2-Ar); 2 x 112.9, 2 x 126.0, 4 x 126.9, 2 x 127.0, 2 x 128.5, 4 x 128.8, 129.1, 2 x 129.8 (ArCH); 129.8, 2 x 139.0, 142.1, 147.8 (ArC). FT-IR: (KBr) 3059 w, 3026 w, 2912 w, 2862 w, 1611 s, 1522 s , 1492 s, 1450 m, 1401 s, 1361 m, 1231 s, 1073 w, 1025 w, 957 m, 790 m, 764 m, 736 s, 700 s; (ESI+, MeOH): 364, 100 % (M + H+), 365, 29 % (M + 1 + H+); Microanalysis: Found C 89.4 % H 7.0 %, N 3.9 %. Requires C 89.2 %, H 6.9 %, N 3.9 %.
e) Synthesis of iV-Phenyl-2-(4-methylbenzyI)anilme
With water removal by Dean and Stark apparatus (10 mL trap volume), a solution of aniline (0.55 mL, 6.0 mmol), /?-tolualdehyde (0.59 mL, 5.0 mmol), 2-cyclohexenone (0.48 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g, 2.75 mmol) in PhMe (25 mL) was stirred at reflux. 2-Cyclohexenone was added in two equal portions (each 0.48 mL, 5.0 mmol) after 2 h and 4.5 h. After a further 2.5 h, the reaction was cooled and the mixture washed with sat. NaHCO3 (aq) (2 x 25 mL) then with distilled water (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo yielding a crude oil. Silica gel column chromatography using Et2O / hexane (1:4) afforded N-phenyl-2-(4-methylbenzyl)aniline (0.91 g, 67 %) as a clear oil. 1H-n.m.r. (400 MHz5 CDCl3): δ 2.46 (s, 3H, -CH3), 4.06 (s, 2H5 Ar-CH2-Ar)5 5.47 (s,lH, NH)5 6.95 (dd, J= 8.6, 1.0 Hz5 2H5 ArH)5 6.99 (dd5 J= 7.2, 0.9 Hz5 IH5 ArH)5 7.11 (td, J= 7.4, 1.2 Hz5 IH5 ArH)5 7.20 (d, J= 8.1 Hz5 2H5 ArH)5 7.24 (d, J= 8.0 Hz, 2H5 ArH)5 7.35 - 7.26 (m, 4H5 ArH)5 7.41 (dd5 J = 8.0, 0.9 Hz5 IH5 ArH); 13C-n.m.r. (100 MHz5 CDCl3): δ 21.2 (Ar-CH3), 38.1 (Ar-CH2-Ar)5 2 x 117.4, 119.8, 120.5, 122.3, 127.6, 2 x 128.6, 2 x 129.4, 2 x 129.7, 131.4 (ArCH), 131.5, 136.1, 136.6, 141.6, 144.2 (ArC). FT-IR: (KBr) 3404 m, 3046 m, 3022 m5 2919 w, 1593 s, 1581 s, 1514 s, 1502 s, 1477 s, 1458 s, 1419 m, 1302 s, 1248 m, 1175 w, 1155 w, 1103 w, 1078 w, 1045 w, 1028 w, 917 w, 881 w, 828 w, 794 m, 752 s, 694 s; (ESI+, MeOH): 274, 100 %; Microanalysis: Found C 87.9 % H 7.0 % N 5.0 % Requires C 87.9 % H 7.0 %, N 5.1 %.
f) Synthesis of iV-Benzyl-2-furfurylaniline
With a Dean and Stark apparatus for water removal (10 niL trap volume), a solution of furfural (0.41 niL, 5.0 mmol), benzylamine (0.66 mL, 6.0 mmol), 2-cyclohexenone (0.48 niL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g, 2.75 mmol) in PhMe (25 mL) was stirred at reflux for 2 h. The reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 x 25 mL) and with distilled water (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using Et2O / hexane (1:9) afforded N-benzyl-2-furfurylaniline (1.00 g, 76 %) as a clear oil. 1H-U-UiJ. (400 MHz, CDCl3): δ 3.89 (s, 2H, -CH2-), 4.19 (b s5 IH5 NH)5 4.31 (s, 2H, -CH2- ), 5.99 (d, J= 3.2 Hz, IH5 ArH)5 6.27 (dd, J= 3.1, 1.9 Hz5 IH, ArH), 6.63 (d, J= 7.9 Hz, IH, ArH), 6.70 (td, J= 7.4, 0.8 Hz, IH, ArH)5 7.08 (dd5 J= 7.4, 1.2, ArH), 7.12 (td, J = 7.7, 1.5, ArH), 7.32 - 7.15 (m, 6H, ArH). 13C nmr (100 MHz, CDCl3): δ 31.3, 48.3 (-CH2- ), 106.6, 110.6, 111.4, 117.7, 127.3, 2 x 127.6, 128.4, 2 x 128.8, 130.5, 141.7 (ArCH)5 122.6, 139.5, 146.2, 153.5 (ArC); FT-IR: (KBr) 3435 w, 3064 W5 3029 W5 2895 W5 2846 w, 1604 s5 1586 s, 1508 s, 1452 S5 1322 m, 1261 m, 1162 m, 1144 m, 1072 m, 1052 w, 1009 m, 936 w, 884 w, 806 w, 747 s, 729 s, 697 s; (ESI+, MeOH): Found: 264.1385 Requires: 264.1388 Microanalysis: Found C 82.3 % H 6.3 % N 5.4 % Requires C 82.1 % H 6.5 %,
N 5.3 %.
g) Synthesis of iV-(2-phenyIethyI)-2-(4-nitrobenzyl)aniIine
With Dean and Stark apparatus fitted (10 niL trap volume), a solution of 4- nitrobenzaldehyde (0.76 g, 5.0 mmol), 2-phenylethylamine (0.75 mL, 6.0 mmol), 2- cyclohexenone (0.48 mL, 5.0 mmol). DABCO (0.28 g, 2.5 mmol) and PhCOOH (.34 g g, 2.75 mmol) in toluene (25 mL) was stirred and refluxed. After 3 h, 2-cyclohexenone was added to the reaction and was left to react for another 1.5 h.
The reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 x 25 mL) and with distilled water (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chromatography using Et2O / hexane (1 :9) afforded N-(2-phenylethyl)-2-(4- nitrobenzyl)aniline (1.41 g, 85 %) as an orange oil 2H-n.m.r. (400 MHz, CDCl3): δ 2.85 (t, J = 6.6 Hz5 2H, -CH2-); 3.36 (t, J = 6.7 Hz, 2H, -CH2-); 3.83 (s, 2H, Ar-CH2-Ar); 6.77 - 6.73 (m, 2H5 ArH); 7.02 (dd, J = 7.7, 1.6 Hz, IH, ArH); 7.06 (dd, J = 7.9, 1.6 Hz, 2H, ArH); 7.13 (d, J = 8.9 Hz, 2H, ArH); 7.14 - 7.25 (m, 4H5 ArH); 8.01 (d, J = 8.8 Hz, 2H, ArH). 13C-n.m.r. (50 MHz, CDCl3): δ 35.2, 38.0 (-CH2-CH2-); 44.6 (Ar-CH2-Ar); 111.5, 117.8, 2 x 124.0, 126.7, 2 x 128.7, 2 x 128.8, 2 x 129.2, 131.0 (ArCH); 123.2, 138.9, 146.0, 146.7, 147.4 (ArC); FT-IR: (KBr) 3422 w, 3064 w, 3026 w, 2924 w, 2850 w, 1603 s, 1585 s, 1513 s, 1464 s, 1454 s, 1348 s, 1316 s, 1263 m, 1179 m, 1110 m, 108I w5 1051 w, 1015 w, 922 w, 858 S5 834 m, 754 s, 734 s, 701 s. (ESI+, MeOH): 333, 100 % (M + H+), 334, 24 % (M + 1 + H+); Microanalysis: Found C 75.9 % H 6.0 % N 8.5 % Requires C 75.9 %, H 6.1 %, N 8.4 %.
h) Synthesis of iV-(4-(2-methoxybenzyl)phenyl) morpholine and iV-(2-(2- methoxybenzyl)phenyl) morpholine
With water removal by Dean and Stark apparatus (10 mL trap volume), a solution of morpholine (0.61 mL, 7.0 mmol), 2-methoxybenzaldehyde (0.68 g, 5.0 mmol) and 2- cyclohexenone (0.48 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g, 2.75 mmol) in PhMe (25 mL) was refluxed for 2.5 h.
The reaction mixture was cooled to room temperature and washed with sat. NaHCθ3 (aq) (2 x 25 mL), then with distilled water (1 x 25 mL). The organic layer was collected and dried with MgSO4, filtered and the solvent removed in vacuo to yield a crude oil. The oil was subjected to column chromatography on Silica gel with Et2O / hexane (7:3). Two products were recovered:
N- [2-(2-methoxybenzyl')phenyll morpholine : (0.38 g, 27 %) white crystals (m.p. 68 - 70 0C). Η-n.m.r. and 13C-n.m.r. match authentic sample. jV-[4-(2-methoxybenzyl)phenyllmorpholine: (0.21 g, 15 %) white crystals (m.p. 63 - 64 °C). 1H-n.m.r. and 13C-n.m.r. matched authentic sample.
i) Synthesis of l,3-Bis{2-[2-(lJWndol-3-yl)ethylamino]benzyl}benzene
A solution of tryptamine (0.961 g, 6.0 mmol), 2-cyclohexenone (0242 mL, 2.5 mmol), isophthaladehyde (0.335 g, 2.5 mmol), DABCO (0.280 g, 2.5 mmol) and benzoic acid (0.336 g, 2.75 mmol) in toluene (25 mL) was refluxed. 30 min later another portion of 2- cyclohexenone (0.242 mL, 2.5 mmol) was added. Ih after the last addition of 2- cyclohexenone, another portion was added (0.242 mL, 2.5 mmol). The reaction mixture was refluxed for another 40 min. In total, 2-cyclohexenone (0.724 mL, 7.5 mmol) was reacted over 2 h 10 min.
The solvent was removed in vacuo and the residue redissolved in dichloromethane (25 mL). The solution was washed with sat. NaHCO3 (aq) (2 x 25 mL) then with brine (1 x 25 mL). The organic layer was collected and dried with MgSO4, filtered and the solvent evaporated in vacuo to give a crude oil. Silica gel column chromatography using Et2O / hexane (3:7) afforded l,3-Bis{2-[2-(lH-indol-3-yl)ethylamino]benzyl}benzene (0.71 g, 49 %) as a white solid. 1H-n.m.r. (400 MHz, CDCl3): δ 2.97 (t, J= 6.3 Hz, 4H, N-CH2-CH2-); 3.39 (t, J= 6.4 Hz, 4H, N-CH2-CH2-); 3.56 (s, 4H, Ar-CH2-Ar); 6.53 (d, J= 1.8 Hz, 2H, Ar); 7.52 (d, J = 7.9 Hz, 2H, Ar); 6.72 - 6.77 (m, 6H, Ar); 6.84 (t, J = 7.6 Hz, IH, Ar); 7.02 (d, J= 7.4 Hz, 2H, Ar); 7.06 (t, J= 7.4 Hz, 2H, Ar); 7.13 - 7.25 (m, 7H, Ar); 7.77 (bs, 2H, NH). 13C-n.m.r. (75 MHz, CDCl3): δ 24.98 (N-CH2-CH2); 38.05 (Ar-CH2-Ar); 43.85 (N-CH2-CH2); 2 x 111.31, 2 x 111.43, 2 x 117.37, 2 x 118.85, 2 x 119.50, 2 x 122.31, 2 x 126.40, 2 x 128.18, 128.62, 128.89, 2 x 130.92 (ArCH); 2 x 113.00, 2 x 125.08, 2 x 127.44, 2 x 136.57, 2 x 139.57, 2 x 146.52 (ArC).
j) Synthesis of i\yV-bis(2-furfuιylphenyI)propyIene-l,3-diamine
With a Dean and Stark apparatus for water removal (10 mL trap volume), a solution of furfural (0.828 mL, 10.0 mmol), 1,3-propylene diamine (0.466 mL, 5.5 mmol), 2- cyclohexenone (0.968 mL, 10.0 mmol), DABCO (0.560 g, 5.0 mmol) and PhCOOH (0.672 g, 5.5 mmol) in PhMe (25 mL) was stirred at reflux for 30 min.
The reaction mixture was cooled, washed with sat. NaHCθ3 (aq) (2 x 25 mL) and with distilled water (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using Et2O / hexane (3:7) afforded Λr^V-bis(2-furfurylphenyl)-propylene-l,3-diamine as an oil (0.549 g, 28 %) as a orange oil. 1H-n.m.r. (400 MHz, CDCl3): δ 1.89 (app quint, J= 6.7 Hz5 2H, CH2-CH2-CH2); 3.17 (t, J= 6.1 Hz, 4H, N-CH2); 3.85 (s, 4H, Ar-CH2); 5.97 (ddd, J= 3.1, 1.9, 1.0 Hz, 2H, Ar); 6.23 (dd, J = 3.2,1.9 Hz, 2H, Ar); 6.66 (d, J = 7.8 Hz, 2H, Ar); 6.72 (t, J= 7.4, 1.1 Hz, 2H, Ar); 7.08 (dd, J= IA, 1.3 Hz, 2H, Ar); 7.17 (app td, J = 7.7, 1.6 Hz, 2H, Ar); 7.26 (dd, J = 1.9, 0.9 Hz, 2H, Ar). 13C-n.m.r. (50 MHz, CDCl3): δ 29.00 (-CH2-CH2-CH2); 31.30 (Ar-CH2); 2 x 41.63 (N-CH2); 2 x 106.44, 2 x 110.58, 2 x 111.00, 2 x 117.49, 2 x 128.32, 2 x 130.51, 2 x 141.71 (ArCH); 2 x 122.56, 2 x 146.32, 2 x 153.56 (ArC).
k) Synthesis of (Zs)-iV-benzyI-2-cinnamyl-aniline
A solution of benzylamine (0.655 mL, 6.0 mmol), cinnamaldehyde (0.629 g, 5.0 mmol) and 2-cyclohexenone (0.484 mL, 5.0 mmol), DABCO (0.28 g, 2.5 mmol) and PhCOOH (0.34 g, 2.75 mmol) in PhMe (15 mL) was refluxed for 1.5 h. After which time an additional portion of 2-cyclohexenone (0.121 mL, 1.25 mmol) was added and the solution was refluxed for an additional 1 h. The reaction mixture was cooled to room temperature and washed with sat. NaHCO3 (aq) (2 x 25 mL), then with distilled water (1 x 25 mL). The organic layer was collected and dried with MgSO4, filtered and the solvent removed in vacuo to yield a crude oil. The oil was subjected to column chromatography on Silica gel with Et2O / hexane (1:19) affording (£)-N-benzyl-2-cmnamyl-aniline (0.75 g, 50 %) as a white solid. 1H-n.m.r. (300 MHz, CDCl3): δ 3.47 (d, J = 5.8 Hz, 2H, C=CH-CH2); 4.33 (s, 2H, N-CH2-Ar); 6.31 (dt, J = 15.8, 6.1 Hz5 IH5 C=CH-CH2); 6.42 (d, J= 16.2 Hz, IH, CH=CH-CH2); 6.69 (d, J= 7.8 Hz5 IH5 Ar); 6.75 (t, J = 7.4 Hz5 IH5 Ar); 7.13 (d, J = 7.8 Hz5 2H5 Ar); 7.17 - 7.30 (m, 10H5 Ar).
1) Synthesis of (jE)-iV^V-dibenzyl-4-benzyl-3-styryl-aniline and iV,2V-dibenzyl-3- methyl-4-benzylaniline
1:1 benzaldehyde:cvclohexenone. With a Dean-Stark apparatus for water removal (10 mL trap volume), a solution of benzaldehyde (0.508 mL, 5.0 mmol), JV^V-dibenzylamine (1.436 mL, 7.0 mmol), 3- methylcyclohex-2-enone (0.284 mL, 2.5 mmol), DABCO (0.280 g, 2.5 mmol) and PhCOOH (0.336 g, 2.75 mmol) in PhMe (25 mL) was stirred at reflux for 80 min. After this time another portion of 3-methylcyclohex-2-enone (0.284 mL, 2.5 mmol) was added and the reaction refluxed for another 2 h.
The reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 x 25 mL) and with distilled water (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using Et2O / hexane (1:19) afforded (jE)-iV5JV-dibenzyl-4-benzyl-3-styryl-aniline (0.44 g, 19 % based on cyclohexenone) as a clear solid and iV5Λ/-dibenzyl-3-methyl-4-benzylaniline (0.087 g, 4.5 % based on cyclohexenone). Both 1H-n.m.r. spectra of the products matched authentic samples.
4:3 benzaldehyde: cyclohexenone With a Dean-Stark apparatus for water removal (10 mL trap volume), a solution of benzaldehyde (1.016 mL, 10.0 mmol), iV,7V-dibenzylamine (1.436 mL, 7.0 mmol), 3- methylcyclohex-2-enone (0.284 niL, 2.5 mmol), DABCO (0.280 g, 2.5 mmol) and PhCOOH (0.336 g5 2.75 mmol) in PhMe (25 niL) was stirred at reflux for 1.5 h. After this time another portion of 3-methylcyclohex-2-enone (0.284 mL, 2.5 mmol) was added and the reaction refluxed for another 2 h. After this time another portion of 3-methylcyclohex- 2-enone (0.284 mL, 2.5 mmol) was added and the reaction refluxed for another 12 h.
The reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 x 25 mL) and with brine (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using Et2O / hexane (1:99) afforded both (£)-N,N-dibenzyl-4-benzyl-3-styryl-aniline (0.82 g, 35 % based on aldehyde) as a clear solid and JV,N-dibenzyl-3-methyl-4-benzylaniline (0.46 g, 24 % based on aldehyde, 17 % based on amine) as a clear solid.
r£)-iV,iV-dibenzyl-4-benzyl-3-styryl-aniline: 1H-n.m.r. (300 MHz5 CDCl3): δ 3.98 (s, 2H, Ar-CH2-Ar); 4.62 (s,4H, N-CH2); 6.63 (dd, J= 8.0, 3.2 Hz, IH, Ar); 6.64 (d, J= 16.2 Hz, IH, CH=CH-Ar); 6.92 (d, J = 8.5 Hz, IH, Ar); 7.01 (d, J = 2.8 Hz, IH, Ar); 7.06 - 7.32 (m, 2OH, Ar + IH, CH=CH-Ar).
JVJV-dibenzyl-3-methyl-4-benzylaniline: Η-n.m.r. (300 MHz, CDCl3): δ 2.13 (s, 3H, - CH3); 3.86 (s, 2H, Ar-CH2-Ar); 4.60 (s, 4H, N-CH2); 6.52 (dd, J = 8.3, 2.9 Hz, IH, Ar); 6.60 (d, J= 2.7 Hz, IH, Ar); 6.87 (d, J= 8.4 Hz, IH, Ar); 7.11 - 7.36 (m, 15H, Ar).
m) Synthesis of iV-(2-benzyl-5-methylphenyl)morpholine and JV-(4~benzyl-3- methylphenyl)morpholine
Preparation of Solution A
Solution A was prepared by dissolving 5-methylcyclohex-2-enone (0.366 g, 3.14 mmol) in toluene to produce 5 mL of solution.
Amine reaction With a Dean-Stark apparatus for water removal (10 mL trap volume), a solution of benzaldehyde (0.320 mL, 3.14 mmol), morpholine (0.383 mL, 4.4 mmol), DABCO (0.176 g, 1.57 mmol), benzoic acid (0.221 g, 1.727 mmol) and solution A (2 niL, 1.256 mmol of 5-methylcyclohex-2-enone) in PhMe (20 mL) was stirred at reflux for 1 h. After which time another portion of solution A (1.0 mL, 0.628 mmol) was added and the reaction refluxed for another 2 h 20 min. After this time another portion of solution A (1.0 mL, 0.628 mmol) and the reaction refluxed for another 1 h. After this time another portion of solution A (1.0 mL, 0.628 mmol) was added and refluxed for 10 h. In summary a total of 5-methylcyclohex-2-enone (0.346 g, 3.14 mmol) was reacted for a period of 14 h 20 min. After this time the reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 x 25 mL) and with brine (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield an oil. Silica gel column chomatogaphy using Et2O / hexane (3:7) afforded both N-(2-benzyl-5-methylphenyl)morpholine (0.426 g, 51 %) as a white solid and N-(4-benzyl-3-methylphenyl)morpholine (0.122 g, 14 %) as a white solid.
N-f2-benzyl-5-methylphenyl)morpholine: Η-n.m.r. (300 MHz, CDCl3): δ 2.32 (s, 3H, CH3); 2.83 (t, J = 4.6 Hz, 4H5 , N-CH2); 3.78 (t, J = 4.6 Hz, 4H, 0-CH2); 4.04 (s, 2H, Ar- CH2-Ar); 6.87 (dd, J = 7.7, 1.0 Hz, IH, Ar); 6.94 (s, IH5 Ar); 7.01 (d, J = 7.7 Hz, 7.12 - 7.27 (m. 5H, Ar).
iV-f4-benzyl-3-methylphenyl)morpholine: Η-n.m.r. (300 MHz, CDCl3): δ 2.34 (s, 3H, CH3); 3.12 (t, J = 4.8 Hz5 4H5 N-CH2); 3.84 (t, J = 4.8 Hz, 4H5 0-CH2); 3.91 (s,2H, Ar- CH2-Ar); 6.70 (dd, J = 8.2, 2.6 Hz, IH5 Ar); 6.74 (d, J = 2.5 Hz, IH, Ar); 7.00 (d, J = 8.2 Hz5 IH, Ar); 7.08 - 7.27 (m, 5H5 Ar).
n) Synthesis of 2,2'-(2,2'-(propane-l,3-diylbis(oxy))bis(2,l- phenylene))bis(methylene)-bis(N-benzyIbenzenamine)
With a Dean and Stark apparatus for water removal (10 mL trap volume), a solution of
2,2'-(propane-l,3-diylbis(oxy))dibenzaldehyde (0.711 mL, 2.5 mmol), 2-cyclohexenone (0.484 mL, 5.0 mmol), benzylamine (0.600 mL, 5.5 mmol), DABCO (0.28 g, 2.5 mmol) and benzoic acid (0.336 g, 2.75 mmol) in toluene (25 mL) was stirred at reflux for Ih 15 min. Another portion of 2-cyclohexenone (0.484 mL, 5.0 mmol) was added and refluxed for another 4.5 h.
The reaction mixture was cooled, washed with sat. NaHCO3 (aq) (2 * 25 mL) and brine (1 x 25 mL). The organic layer was collected and dried using MgSO4, filtered and the solvent removed in vacuo to yield a crude oil (2.32 g) containing the title compound with reasonable purity. 13C-n.m.r. (100 MHz, CDCl3): δ 31.49 (-CH2-CH2-CH2-); 38.32 (Ar- CH2-Ar); 48.27 (N-CH2-Ar); 64.82 (0-CH2-); 2 x 110.68, 2 x 111.49, 2 x 117.21, 2 x 121.16, 2 x 127.22, 6 x 127.68, 2 x 127.75, 4 x 129.24, 2 x 130.23, 2 x 130.67 (ArCH); 2 x 125.12, 2 x 127.80, 2 x 139.70, 2 x 146.10, 2 x 156.19 2 (ArC).
5. Stepwise reaction
a) Synthesis of N-(2-benzylphenyl)benzylamine
i) Preparation 2-(Hydroxy-phenyl-methyl)-cyelohex-2-enone
The title compound was prepared in accordance with protocol of V.K. Aggarwal; A. Mereu, Chem. Comm., 1999, 22, 2311-2312 wherein a neat mixture of benzaldehyde (0.500 mL, 4.92 mmol), 2-cyclohexenone (0.474 mL, 4.92 mmol) and DBU (0.736 mL, 4.92 mmol) was stirred for 0.5 h under nitrogen. The crude product was then dissolved in ether (30 mL) and washed with 2M HCl (aq) (2 x 2OmL). The organic layer was collected, dried with MgSO4, filtered and the solvent removed in vacuo to yield a crude material (0.86 g).
The crude material was chromatography using a silica column eluting with a 2:1 hexane / ethyl acetate mixture to afford 2-(Hydroxy-phenyl-methyl)-cyclohex-2- enone (0.33 g, 33%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.99 (app p, J = 6.4 HZ, 2H, -CH2-CH2-CH2-); 2.38 (app q, J= 5.4 Hz, 2H5 -C=CH-CH2-); 2.45 (dd, J = 7.6, 5.8 Hz, 2H, C=O-CH2-); 3.46 (s (b), IH, -OH); 5.55 (s, IH, Ar-
CH(OH)); 6.73 (t, J = 4.2 Hz, C=CH-CH2-); 7.47 - 7.15 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3): 22.57, 25.82, 38.57 (-CH2-CH2-CH2-); 72.10 (Ar-CH-OH); 2 x 126.56, 127.56, 2 x 128.35, 147.49 (ArCH); 141.17, 141.94 (ArC); 200.38 (C=O).
ii) Preparation of N-(2-benzylphenyl)benzylamine Under Dean-Stark conditions (10 mL trap volume), a solution of 2-(Hydroxy- phenyl-methyl)-cyclohex-2-enone (0.33 mL, 1.64 mmol) and benzylamine (0.359 mL, 3.28 mmol) in toluene (25 mL) was refluxed for 12 h. The solvent and volatile reagents were removed in vacuo to yield a crude oil. It was determined that the JV- (2-benzylphenyl) benzylamine was present in the crude, using 13C and 1H NMR.
BIOLOGICAL DATA
PROTOCOL
Samples: The samples were supplied as weighed powders or oils. Stock solutions were prepared in MeOH or 20% (v/v) DMSO in MeOH depending on the solubility of the sample (Table 1). ARMST003 & ARMST021 required subsampling into larger vials to allow preparation of stock solutions. Aliquots of the stock solutions were diluted 1/2 with MeOH then serially diluted 1/2 with MeOH to give 12 concentrations. Aliquots (20 ul) at each concentration were transferred to bioassay plates. For CyTOX and TriTOX the bioassay plates were evaporated to dryness before use, for the remaining assays only the MeOH was evaporated. The highest concentration tested in each assay varied from 125 to 500 ug/ml, depending on the concentration of the stock solution prepared, except in MycoTOX and EuTOX where the highest concentrations tested varied from 250 to 1000 ug/ml.
Bioassays: The samples were tested in a range of whole organism screens as indicated in Table 2 the results of which are shown in Table 3. Table 1: Preparation of stock solutions
Sample Description Weight Solvent Total vol Stock soln Highest (mg) (ml) (mg/ml) cone (ug/mIW
ARMSTOOl cream crystals 4.5 MeOH 0.450 10 500
ARMST002 cream powder 4.6 MeOH 0.460 10 500
ARMST003 cream crystals 3.1* 20%DMSO# 1.232 2.5 125
ARMST004 cream crystals 6.2 MeOH 0.620 10 500
ARMST005 clear crystals 6.0 MeOH 0.600 10 500
ARMST006 yellow oil 6.8 MeOH 0.680 10 500
ARMST007 clear crystals 8.7 MeOH 0.870 10 500
ARMST008 yellow oil 8.0 MeOH 0.800 10 500
ARMST009 yellow crystals 11.4 MeOH 1.140 10 500
ARMSTOlO white needles 9.0 MeOH 0.900 10 500
ARMSTOI l yellow powder 11.8 MeOH 1.180 10 500
ARMST012 clear crystals 5.5 20%DMSO 0.688 8.0 400
ARMST013 white crystals 12.7 MeOH 1.270 10 500
ARMST014 cream powder 15.6 MeOH 1.560 10 500
ARMSTO 15 clear oil 10.1 MeOH 1.010 10 500
ARMSTO 16 white crystals 8.6 MeOH 0.860 10 500
ARMSTO 17 white crystals 10.5 20%DMSO 1.313 8.0 400
ARMSTO 18 cream crystals 12.2 MeOH 1.220 10 500
ARMSTO 19 cream crystals 11.5 MeOH 1.150 10 500
ARMST020 d. yellow oil 6.5 20%DMSO 0.813 8.0 400
ARMST021 d. yellow oil - 3.6* 20%DMSO 0.360 10 500 not flowing
ARMST022 white crystals 9.2 20%DMSO 1.533 6.0 300
ARMST023 d. yellow oil 16.7 MeOH 1.670 10 500
ARMST024 yellow crystals 10.2 20%DMSO 1.275 8.0 400
* Sub-sample weight
# 20% (v/v) DMSO in MeOH f Highest concentration tested in all assays except EuTOX & MycoTOX, in EuTOX & MycoTOX the highest concentration was twice the indicated value. Table 2: Screens and test organisms
Screen Target Test organism Strain Abbrev.
NemaTOX Nematodes Haemonchus McMaster Hc contortus
MycoTOX Fungi - filamentous Septoria nodurum MST-FP956 Sn
CyTOX Mammalian tumour Murine cell line NS-I Cy
TriTOX Protozoans Giardia sp. - Gi
ProTOX Bacteria Bacillus subtilis ATCC-6633 Bs
EuTOX Yeasts Candida albicans ATCC-10231 Ca
Table 3: Activity of the samples in NemaTOX, ProTOX, EuTOX, CyTOX,
TriTOX and MycoTOX
NemaTOX Pro(Bs) Eu(Ca) CyTOX Tri (Gi) Myco(Sn)
Sample Titre* LD9/ Titre LD99 Titre Titre LD99 Titre LD99 Titre LD99
ARMSTOOl 0 1 500 0 2 250 0 0
ARMST002 16 31 2 250 0 1 500 0 32 31
ARMST003 0 2 63 0 0 0 0
ARMST004 0 1 500 0 1 500 0 0
ARMST005 0 2 250 0 4 130 4 130 0
ARMST006 0 1 500 0 2 250 0 0
ARMST007 0 0 0 4 130 0 0
ARMST008 0 0 0 2 250 0 0
ARMST009 16 31 0 0 4 130 0 0
ARMSTOlO 8 63 0 0 8 63 0 256 3.9
ARMSTO 11 0 4 125 0 2 250 0 1 1000
ARMST012 0 0 0 0 0 16 50
ARMST013 0 0 0 2 250 0 0
ARMST014 0 0 0 8 63 2 250 0
ARMST015 16 31 0 0 2 250 0 0
ARMSTO 16 0 0 0 2 250 0 0
ARMST017 0 0 0 0 0 0
ARMSTO 18 0 0 0 16 31 0 0
ARMSTO 19 1 500 0 0 0 0 0
ARMST020 4 200 0 0 2 200 0 1 800 ARMST021 4 130 0 0 32 16 0 1000
ARMST022 0 0 0 0 0
ARMST023 0 0 0 4 130 0
ARMST024 4 100 0 0 1 400 0
* Titre=2(n-1) where n is the number of the well containing the lowest concentration where an inhibitory effect was observed - for NemaTOX where 99% of larvae were affected, A titre of 0 indicated that no inhibition was noted at the highest concentration tested.
# LD99 (ug/ml)
ARMSTOOl
ARMST002
ARMST003
ARMST004
Figure imgf000064_0001
ARMST005
Figure imgf000064_0002
ARMST006
Figure imgf000065_0001
ARMST007
Figure imgf000065_0002
ARMST008
Figure imgf000065_0003
ARMST009
Figure imgf000065_0004
ARMSTOlO
ARMSTOI l
Figure imgf000065_0005
ARMST012
Figure imgf000065_0006
ARMSTO 13
ARMSTO 14
Figure imgf000066_0001
ARMSTO 15
ARMSTO 16
Figure imgf000066_0002
ARMST017
Figure imgf000066_0003
ARMSTO 18
Figure imgf000066_0004
ARMSTO 19
Figure imgf000067_0001
ARMST020
Figure imgf000067_0002
ARMST021
Figure imgf000067_0003
ARMST022
Figure imgf000067_0004
ARMST023
Figure imgf000067_0005
ARMST024
Figure imgf000067_0006
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A process for preparing N-substituted anilines comprising reacting the following components: (i) optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof;
(ii) optionally substituted cyclohexenone; and (iii) primary or secondary amine or a reactive derivative thereof, for a time and under conditions sufficient to form said N-substituted anilines.
2. A process according to claim 1, where components (i), (ii) and (iii) are reacted together in a single reaction vessel.
3. A process according to claim 2 wherein components (i), (ii) and (iii) are added to the reaction vessel simultaneously.
4. A process according to any one of claims 1 to 3 conducted in the presence of an acid and base catalyst mixture.
5. A process according to claim 4 wherein the acid catalyst is selected from the group consisting of benzoic acid, p-toluene sulphonic acid (PTSA), camphor sulfonic acid, acetic acid, proponic acid, PTSA amberlyst resin, -CO2H amberlyst resin, hydrochloric acid and nitric acid.
6. A process according to claim 4 wherein the base catalyst is DABCO.
7. A process according to any one of claims 4 to 6 wherein 0.5-0.55 mole equivalent of each of the acid and base is present in the reaction mixture in respect of component (i).
8. A process according to any one of claims 4 to 7 wherein the acid catalyst in the acid and base catalyst mixture is present in the reaction mixture in an equivalent mole amount or slight excess in respect of the base catalyst.
9. A process according to any one of claims 1 to 8 performed in the presence of a solvent.
10. A process according to claim 9 which is performed at the boiling point of the solvent.
11. A process according to any one of claims 1 to 10 conducted using equipment which facilitates the removal of water.
12. A process according to any one of claims 1 to 11 wherein component (iii) is reacted in excess relative to component (i).
13. A process according to claim 4 wherein 1.1-2.4 mole equivalents of component (iii) are reacted relative to component (i).
14. A process according to any one of claims 1 to 13 conducted using solid phase synthetic techniques.
15. A process according to any one of claims 1 to 14 wherein component (i) has one, two or three non-enolisable formyl groups or reactive derivatives thereof attached directly to a ring atom thereof.
16. A process according to claim 15 wherein component (i) is selected from an aryl or heteroaryl having one or two formyl groups or reactive derivatives thereof attached directly to a ring atom thereof.
17. A process according to claim 15 or 16 wherein the ring atom is a ring carbon atom.
18. A process according to claim 15 wherein component (i) is reacted in the form of a reactive derivative of a formyl group which is selected from the group consisting of an acyclic acetal, a cyclic acetal, a cyanohydrin, an iminium salt, an imine, an aminal, an amino alcohol, an amino ether, a thioacyl, a ylidenemalonitrile, and a hydroxy aldehyde.
19. A process according to any one of claims 1 to 14 wherein component (i) is selected from the group consisting of benzaldehyde, o- and p-anisaldehyde, 4- hydroxybenzaldehyde, 4-carboxybenzaldehyde, pyridine-4-carboxaldehyde, pyridine-2- carboxaldehyde, 4-methylbenzaldehyde, isophthalaldehyde, furfural, 4-nitrobenzaldehyde, 2,2'-(propane-l,3-diylbis(oxy))dibenzaldehyde, and cinnamaldehyde.
20. A process according to claim 14 wherein component (i) bears a divalent linker group as a substituent to enable attachment to a polymer support.
21. A process according to any one of claims 1 to 14 wherein component (ii) is an optionally substituted 2- or 3-cyclohexenone.
22. A process according to claim 20 wherein component (ii) is an optionally substituted 2-cyclohexenone .
23. A process according to claim 22 wherein the 2-cyclohexenone is substituted at the 3 or 5 positions.
24. A process according to any one of claims 21 to 23 wherein component (ii) is a substituted cyclohexenone wherein the substituent does not adversely affect or interfere with the formation of N-substituted anilines and is selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, thioalkyl, thioaryl, optionally substituted alkoxy, acyl, F, Cl, NO2, and cyclohexenones which are ring fused.
25. A process according to claim 21 wherein component (ii) is 2-cyclohexenone.
26. A process according to claim 4 wherein component (iii) is reacted in the form of an ammonium salt.
27. A process according to any one of claims 1 to 17 wherein component (iii) is represented by the formula NHR1R2, where one of R1 or R2 represent hydrogen and the other an optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, and optionally substituted cycloalkenyl or R1 and R2 independently represent optionally substituted alkyl, optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl or optionally substituted cycloalkenyl, or R1 and R2 together form an optionally substituted heterocyclyl group.
28. A process according to claim 27 wherein R1 is hydrogen and R2 an optionally substituted alkaryl, optionally substituted alkenyl, optionally substituted cycloalkyl or optionally substituted aryl, or R1 and R2 are the same and represent an optionally substituted alkyl where the optional substituent is selected from alkyl, alkoxy or together represent a heterocyclyl group.
29. A process according to any one of claims 1 to 14 wherein component (iii) is selected from the group consisting of benzylamine, aniline, n-hexylamine, 2- aminomethylpyridine, methyl aminoacetate, 3-indole-2-ethylamine, . morpholine, α- methylbenzylamine, di-ft-butylamine, bis(2-methoxyethyl)amine, N,N-dibenzylamine, 2- phenylethylamine, 1,3 propylene amine and amino acids and salts or esters thereof.
30. A process for preparing N- substituted anilines comprising reacting an enamine of formula (I)
Figure imgf000073_0001
or a tautomer thereof, wherein n represents an integer from 0 to 4;
R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl., or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
R1 and R2 independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or R1 and R2 together may form an optionally substituted heterocyclyl group;
with an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound having at least one non-enolisable formyl group or reactive derivative thereof for a time and under conditions sufficient to form said N-substituted anilines.
31. A process for preparing N-substituted anilines comprising reacting a compound of formula (II):
Figure imgf000073_0002
or a tautomer thereof, wherein n represents an integer from 0 to 4;
R at each occurrence independently represents optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkaryl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkaryloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, acylamino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or where any two R together represents an optionally substituted cycloalkenyl or optionally substituted cycloalkyl group; and
R3 represents an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring compound;
with a primary or secondary amine or reactive derivative thereof, for a time and under conditions sufficient to form said N-substituted anilines.
32. A N-substituted aniline obtained by a process according to any one of claims 1 to 31.
33. A compound selected from the group consisting of: iV-(2-benzylphenyl)morphorine; iV-(2-(4-methoxybenzyl)phenyl)morpholine;
N-(4-benzylphenyl)morpholine; iV-(4-benzylphenyl)bis(2-methoxyethyl)amine; iV-(4-(4-(methoxybenzyl)phenyl)morρholine;
N-(2-benzylphenyl)benzylamine;
[2-(4-methylbenzyl)-phenyl]-(l-phenyl-ethyl)amine; iV-(4-benzylphenyl)bis(2-methoxyelthyl)amine;
4-{4-[iV:>Λr-bis(2-methoxyethyl)amino]benzyl}benzoic acid; JV-[2-(lH-indol-3-yl)ethyl]-2-(4-methylbenzyl)aniline;
Benzyl-[2-(4-methylbenzyl)-phenyl]amine; Benzyl-[5-methyl-2-(4-methyl-benzyl)-phenyl]amine;
N-phenyl-2-(4-methylbenzyl)aniline;
Dibutyl(2-benzylphenyl)amine;
Bis(2-methoxyethyl[4-(4-pyridyl)phenyl]amine; 4,4'-[l,3-phenylene-bis(methylene)]bis[ΛyV-bis(2-methoxyethyl)]aniline; iV-(4-(2-methoxybenzyl)phenyl)morpholine;
JV-(2-(2-methoxybenzyl)phenyl)morpholine;
Benzyl-(4-berizyl-4'-methylbiphenyl)-3-arnine;
4-(2-morpholinobenzyl)benzoic acid; N-(4-(4-hydroxybenzyl)phenyl)morpholine;
O-methyl-iV-(2-(4-methylbenzyl)phenyl)glycine; iV-(2-benzylphenyl)benzylamme;
JV-[2-(benzyl)phenyl] glycine methyl ester;
1 ,3 -Bis(2-benzylaminobenzyl)benzene; λyV-dibenzyl-4-benzylaniline;
N-Benzyl-2-furfurylaniline; iV-(2-phenylethyl)-2-(4-nitrobenzyl)aniline; l,3-Bis{2-[2-(lH-indol-3-yl)ethylamino]benzyl}benzene;
N,N -bis(2-furfαrylphenyl)propylene- 1 ,3-diamine; (E)-iV-benzyl-2-cinnamyl-amline;
(E)-iVrN-dibenzyl-4-benzyl-3-styryl-aniline; i\y^-dibenzyl-3-methyl-4-benzylaniline; iV-(2-benzyl-5-methylphenyl)morpholine;
JV-(4-benzyl-3 -methylphenyl)moφholine ; iV-[2-(4-methylbenzylphenyl]-n-hexylamine;
2,2'-(2,2'-(propane-l,3-diylbis(oxy))bis(2,l-phenylene))bis(methylene)-bis(N- benzylbenzeneamine);
7V-(2-benzylphenyl)-n-hexylamine; salts and isomers thereof.
PCT/AU2005/001145 2004-08-02 2005-08-02 Chemical processes and compounds derived therefrom WO2006012683A1 (en)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [online] XP002997188, Database accession no. 40032-55-1 *
HORNING E.C. AND HORNING M.G.: "Aromatization studies. V. Synthesis of Alkylanilines from Alkylcyclohexenones", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 69, 1947, pages 1907 - 1908 *
KOLIS S.P. ET AL: "Dearomatization of Anilines by Coordination to Pentaammineosmium (II)", ORGANOMETALLICS, vol. 15, 1996, pages 245 - 259 *
ROSAMILIA A.E. ET AL: "Preparation of 2- and 4-Arylmethyl N-substituted and N,N-Disubstituted Anilines via a "Green", Multicomponent Reaction", ORGANIC LETTERS, vol. 7, no. 8, 2005, pages 1525 - 1528 *

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