EP1511565A2 - Catalyst and process for the cyanation of aldehydes - Google Patents

Catalyst and process for the cyanation of aldehydes

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Publication number
EP1511565A2
EP1511565A2 EP03730328A EP03730328A EP1511565A2 EP 1511565 A2 EP1511565 A2 EP 1511565A2 EP 03730328 A EP03730328 A EP 03730328A EP 03730328 A EP03730328 A EP 03730328A EP 1511565 A2 EP1511565 A2 EP 1511565A2
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European Patent Office
Prior art keywords
optionally substituted
catalyst
groups
ring
aldehyde
Prior art date
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EP03730328A
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German (de)
French (fr)
Inventor
Michael North
Yuri Belokon
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Kings College London
AN Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences INEOS RAS
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Kings College London
AN Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences INEOS RAS
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Publication of EP1511565A2 publication Critical patent/EP1511565A2/en
Ceased legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/2243—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
    • B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B01J2531/0252—Salen ligands or analogues, e.g. derived from ethylenediamine and salicylaldehyde
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/50—Complexes comprising metals of Group V (VA or VB) as the central metal
    • B01J2531/56—Vanadium

Definitions

  • This invention relates to a catalyst, a process for the preparation of said catalyst and a process for the cyanation of aldehydes, particularly to the asymmetric cyanation of aldehydes, including the synthesis of chiral cyanohydrins and derivatives thereof, such as chiral O-acyl cyanohydrins.
  • the synthesis of chiral intermediates such as chiral cyanohydrins and derivatives is an important process for use in the manufacture of fine chemicals, agrochemicals and pharmaceuticals.
  • Enantiomerically pure cyanohydrins and derivatives are known to be versatile intermediates for the synthesis of a wide range of commercially important compounds.
  • chiral cyanohydrins and derivatives are intermediates for the synthesis of: ⁇ -hydroxy-acids, ⁇ -amino alcohols, and 1 ,2-diols.
  • chiral cyanohydrins are themselves components of highly successful pyrethroid insecticides.
  • PCT/GB01/03455 discloses a new process for the cyanation of aldehydes, and is particularly directed at the asymmetric cyanation of aldehydes.
  • the asymmetric cyanation of aldehydes is a highly useful synthetic procedure for the synthesis of chiral cyanohydrins and derivatives thereof, such as chiral O-acyl cyanohydrins. There is therefore a need for new catalysts for use in asymmetric cyanation of aldehydes.
  • R 1 and R 2 are independently hydrogen, halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or comprise part of a fused ring;
  • R 3 and R 4 are independently halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R 3 & R 4 optionally being linked in such a way as to form an optionally substituted ring(s);
  • Y is a neutral ligand
  • X is an anion
  • Hydrocarbyl groups which may be represented by R _1-4 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups
  • Alkyl groups which may be represented by R 1"4 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings.
  • alkyl groups which may be represented by R 1"4 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl, cyclohexyl and adamantyl groups.
  • Alkenyl groups which may be represented by R 1"4 include C 2-20 , and preferably C 2-6 alkenyl groups. One or more carbon - carbon double bonds may be present.
  • the alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.
  • Aryl groups which may be represented by R 1"4 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • aryl groups which may be represented by R 1"4 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
  • Perhalogenated hydrocarbyl groups which may be represented by R 1"4 include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups.
  • Examples of perhalogenated alkyl groups which may be represented by R 1"4 include -CF 3 and -C 2 F 5 .
  • Heterocyclic groups which may be represented by R 1"4 include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • the heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P.
  • Examples of heterocyclic groups which may be represented by R 1"4 include pyridyl, pyrimidyl, pyrrolyl, thienyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
  • R 3 & R 4 are linked in such a way as to form an optionally substituted ring(s), the largest ring commonly comprises from 5 to 7 ring atoms.
  • R 1"4 is a substituted hydrocarbyl, heterocyclic group, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, acyl, ester, carbonate, amide, sulphonyl or sulphonamido group, or R 3 & R 4 are linked in such a way as to form a substituted ring(s) the substituent(s) should be such so as not to adversely affect the reaction.
  • Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined above for R 1"4 .
  • One or more substituents may be present.
  • Neutral ligands which may be represented by Y include water, C 1-4 alcohols, C 1-4 thiols, C ⁇ -8 ethers, C 1-8 thioethers, C* ⁇ -8 primary, secondary or tertiary amines, and aromatic amines for example pyridine.
  • a preferred basic ligand represented by Y is water.
  • Anions which may be represented by X include, halide, sulphate, alkylsulphate, perchlorate, PF 6 " , acetate, tosylate and triflate.
  • R 1 or R 2 are independently alkyl groups, preferably methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl and cyclohexyl groups.
  • R 1 and R 2 are independently 2-propyl, butyl, 2-butyl, t-butyl, t- pentyl and cyclohexyl groups. Most preferably R 1 and R 2 are independently t-butyl, t-pentyl and cyclohexyl groups.
  • R 3 and R 4 are independently halogen, cyano, nitro, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted di- hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R 3 & R 4 optionally being linked in such a way as to form an optionally substituted ring(s) More preferably R 3 and R 4 are independently alkyl or aryl groups, or R 3 & R 4 are linked in such a way as to form an optionally substituted ring comprising from 5 to 7 ring atoms, the ring atoms being carbon atoms.
  • R 3 and R 4 are independently alkyl or aryl groups, the alkyl or aryl groups are methyl or phenyl groups. More preferably when R 3 & R 4 are linked in such a way as to form an optionally substituted ring, the ring comprises 6 ring atoms and the ring atoms are preferably carbon atoms.
  • R 3 & R 4 are linked in such a way as to form an un-substituted ring comprising 6 ring atoms and the ring atoms are carbon atoms.
  • Preferred catalysts are those in which R 1 and R 2 are independently 2-butyl, t-butyl, t-pentyl and cyclohexyl groups, and R 3 and R 4 are independently methyl or phenyl groups, or R 3 & R 4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms.
  • More preferred catalysts are those in which R 1 and R 2 are independently 2-butyl, t- butyl, t-pentyl and cyclohexyl groups, and R 3 and R 4 are independently methyl or phenyl groups, or R 3 & R 4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms
  • catalysts are those in which R 1 and R 2 are independently 2-butyl, t- butyl, and t-pentyl groups, and R 3 & R 4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms
  • Catalysts according to the present invention have been found to be useful in processes for the cyanation of aldehydes.
  • the chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention.
  • Aldehydes which can be employed in the process of the present invention have the chemical formula R 5 -CHO, wherein R 5 is a substituted or unsubstituted hydrocarbyl group, including perhalogenated hydrocarbyl groups.
  • Hydrocarbyl groups which may be represented by R 5 include alkyl, alkenyl, aryl and heterocyclic groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
  • Alkyl groups which may be represented by R 5 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R 5 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
  • Alkenyl groups which may be represented by R 5 include C 2-20 , and preferably C 2-6 alkenyl groups. One or more carbon - carbon double bonds may be present.
  • the alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.
  • Aryl groups which may be represented by R 5 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • aryl groups which may be represented by R 5 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
  • Perhalogenated hydrocarbyl groups which may be represented by R 5 include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups.
  • Examples of perhalogenated alkyl groups which may be represented by R 5 include -CF 3 and -C 2 F 5 .
  • Heterocyclic groups which may be represented by R 5 include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings.
  • the heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P.
  • Examples of heterocyclic groups which may be represented by R 5 include pyridyl, pyrimidyl, pyrrolyl, thienyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
  • R 5 is a substituted hydrocarbyl or heterocyclic group
  • the substituent(s) should be such so as not to adversely affect the reaction.
  • Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R 5 above.
  • One or more substituents may be present.
  • the cyanide source is an inorganic cyanide, preferably a metal cyanide or an in situ source of inorganic cyanide such as acetone cyanohydrin.
  • Particularly preferred cyanide sources comprise alkali metal and alkaline earth metal cyanides, for example, lithium, sodium, potassium, rubidium, caesium, magnesium and calcium cyanides.
  • the most preferred cyanide source is potassium cyanide.
  • the reaction between the aldehyde and the cyanide source occurs in the presence of a substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group.
  • substrates are compounds having the general formula Q-Y, wherein Q represents an organic acid radical, and Y represents a non- halogen leaving group.
  • the leaving group, Y is a leaving group the conjugate acid of which has a pKa of greater than about -2, such as greater than 3, and often less than 12.
  • leaving groups include alkyl and aryl sulphonates, such as mesylate and tosylate; carbonates; especially alkyl carbonates; carboxylates, especially alkyl carboxylates; and groups of formula -NR x R y , wherein R x and R y together with the nitrogen atom form an unsaturated heterocyclic ring which may comprise one or more additional heteroatoms, especially nitrogen, particularly imidazole or benzimidazole rings.
  • alkyl and aryl sulphonates such as mesylate and tosylate
  • carbonates especially alkyl carbonates
  • carboxylates especially alkyl carboxylates
  • groups of formula -NR x R y wherein R x and R y together with the nitrogen atom form an unsaturated heterocyclic ring which may comprise one or more additional heteroatoms, especially nitrogen, particularly imidazole or benzimidazole rings.
  • X represents O, S, N-R or NOR wherein R represents H or a substituted or unsubstituted hydrocarbyl group as defined for R 5 above;
  • the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group is a carboxylic acid anhydride or an anhydride of a carbonic acid.
  • Carboxylic anhydrides include mixed anhydrides and are often the anhydrides of C 1-8 alkyl or aryl carboxylic acids, such as acetic anhydride and trifluoroacetic anhydride.
  • Carbonic acid anhydrides include di-tert-butyldicarbonate, (tBuOCOOCOOtBu), N,N'-disuccinyldicarbonate, N,N'-dimaleimyldicarbonate, N-(tert- butyl-oxycarbonyloxy) maleimide or succinimide, and N-(benzyloxycarbonyloxy) maleimide or succinimide.
  • the process according to the present invention is commonly carried out in the presence of a solvent.
  • Preferred solvents are polar, aprotic solvents, including halocarbons, for example dichloromethane, chloroform and 1 ,2-dichloroethane; nitriles, for example acetonitrile; ketones, for example acetone and methylethylketone; ethers, for example diethylether and tetrahydrofuran; and amides, for example dimethylformamide, dimethylacetamide and N-methylpyrolidinone.
  • halocarbons for example dichloromethane, chloroform and 1 ,2-dichloroethane
  • nitriles for example acetonitrile
  • ketones for example acetone and methylethylketone
  • ethers for example diethylether and tetrahydrofuran
  • amides for example dimethylformamide, dimethylacetamide and N-methylpyrolidinone.
  • the process of the present invention is carried out in the presence of an additive which accelerates the rate of reaction.
  • additives are inorganic bases such as Na 2 CO 3 , K 2 CO 3 or CaCO 3 or comprise a nucleophilic heteroatom, and often have pKa of greater than 10, for example in the range from 15-35, such as from 15-25.
  • preferred additives include organic bases, such as pyridine, 2,6-lutidine and imidazole; alcohols, such as C ⁇ -6 alcohols, especially tertiary alcohols such as t-butanol; and water.
  • the reaction mixture will be heterogeneous. In such circumstances, it is therefore desirable to employ efficient agitation of the reaction mixture.
  • Agitation means known in the art for example mechanical stirrers and ultrasonic agitators, selected appropriately according to the scale of reaction can be employed as desired.
  • the process of the present invention is often carried out a temperature of from about -40°C to about 40°C. Lower temperatures may be employed if desired, although they are not believed to be advantageous. Commonly, the reaction is carried out a temperature of from -25°C to ambient temperature, such as 15-25°C.
  • the use of the catalysts of the first aspect of the present invention in these processes may facilitate the reactions being carried out at temperatures which are higher than those which can be employed with other catalysts (particularly Ti(lV) catalysts) and still exhibit a high degree of enantio-selectivity.
  • the product of the cyanation reaction in the presence of the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group can then be reacted, for example by hydrolysis, to form a cyanohydrin.
  • the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group has the general formula Q-Y, the process can be represented by the sequence:
  • the process according to the present invention is particularly suited to the enantioslective cyanation of aldehydes. It has been found that particularly effective enantioselective cyanation of aldehydes can be achieved by employing an order of addition in which a mixture of chiral catalyst, cyanide source, solvent and aldehyde are prepared, preferably an additive as described above is added to this mixture. The temperature of this mixture is then adjusted to the desired reaction temperature if necessary, and the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is added. This approach has been found to be especially suited when the additive comprises lutidine, t-butanol or water and the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is a carboxylic anhydride.
  • Certain embodiments of the present invention comprise the use of a heterogeneous mixture of an alkali metal cyanide, or alkaline earth metal cyanide (or other inexpensive cyanide sources such as acetone cyanohydrin), an additive (which may be a base e.g. pyridine; or water) and acetic anhydride (or other carboxylic acid anhydrides) to generate a cyanating agent for aldehydes.
  • an additive which may be a base e.g. pyridine; or water
  • acetic anhydride or other carboxylic acid anhydrides
  • R 8 alkyl, aryl, aralkyl, and may contain halogen, oxygen, nitrogen, or sulfur atoms within the group.
  • R 9 alkyl, aryl, aralkyl, and may contain halogen, oxygen, nitrogen, or sulfur atoms within the group.
  • M alkali metal or alkaline earth metal.
  • This invention allows the synthesis of chiral cyanohydrin derivatives derived from a wide variety of aldehydes.
  • the products can be transformed into other chiral compounds by standard chemistry using either of the acyl or nitrile functional groups.
  • a process for the cyanation of an aldehyde group which comprises reacting the aldehyde with: i) an alkali metal cyanide; and ii) a carboxylic anhydride; in the presence of a catalyst of formula (3a) or (3b).
  • the chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention.
  • a process for the preparation of an O-acyl cyanohydrin which comprises reacting an aldehyde with potassium cyanide and a carboxylic anhydride in the presence of a catalyst of formula (3a) or (3b).
  • the chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention.
  • the chiral transition metal catalyst and a metal cyanide can be added as mixture.
  • a mixture is believed to be a novel composition of matter, and accordingly forms another aspect of the present invention.
  • Preferred transition metal catalysts and metal cyanides are as described above with respect to the first aspect of the present invention.
  • Catalysts according to the present invention may be prepared by reaction of a suitable compound of vanadium with a ligand in the presence of oxygen. Typically vanadyl sulphate hydrate is reacted with a salen ligand in solvent in the presence of oxygen.
  • Optical rotations were recorded on an Optical Activity Ltd. Polar 2001 or a Perkin-Elmer 241 polarimeter, and are reported along with the solvent and concentration in g/100 mL.
  • Elemental analyses were performed on a Carlo Erba Model 1106 or Model 1108 analyser.
  • Chiral GC was carried out on a DP-TFA- ⁇ -CD, fused silica capillary column (32m x 0.2 mm) using helium as the carrier gas.
  • Dichloromethane was distilled over CaH 2 .
  • Acetic anhydride was distilled from the commercial product (99%).
  • Commercial potassium cyanide (98%) was thoroughly powdered and stored in vacuo over P 2 O 5 .
  • Aliphatic and aromatic aldehydes were purified by usual methods.
  • Chiral ligands were prepared by refluxing 1 ,2-cyclohexyldiamines (R,R and S,S) with 2,4- di-fer.-butyl salicylaldehyde.
  • reaction mixture was vigorously stirred for 10 hours at the same temperature. Solid salts were then filtered and washed thoroughly with dichloromethane. To remove the catalyst the reaction mixture was filtered through a pad of silica (10 mm x 50 mm) eluting with dichloromethane. The solvent was evaporated.//? vacuo, and the resulting light green residue fractionated in vacuo giving the benzaldehyde cyanohydrin acetate. B.p. 95-97°C (0.2 mm); yield 7.5 g (87.2%); ee (S), 90.3%.

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Abstract

A vanadium catalyst and a process for cyanating an aldehyde are provided. The vanadium catalyst comprises a Vanadium(V) salen complex. The process comprises reacting the aldehyde with: i) a cyanide source which does not comprise a Si-CN bond or a C-(C=O)-CN moiety; and ii) a substrate susceptible to nucleophilic attack not comprising a halogen leaving group; in the presence of a chiral vanadium catalyst. The cyanide source is preferably an alkali metal cyanide and the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is a carboxylic anhydride.

Description

CATALYST AND PROCESS FOR THE CYANATION OF ALDEHYDES
This invention relates to a catalyst, a process for the preparation of said catalyst and a process for the cyanation of aldehydes, particularly to the asymmetric cyanation of aldehydes, including the synthesis of chiral cyanohydrins and derivatives thereof, such as chiral O-acyl cyanohydrins. The synthesis of chiral intermediates such as chiral cyanohydrins and derivatives is an important process for use in the manufacture of fine chemicals, agrochemicals and pharmaceuticals. Enantiomerically pure cyanohydrins and derivatives are known to be versatile intermediates for the synthesis of a wide range of commercially important compounds. For example chiral cyanohydrins and derivatives are intermediates for the synthesis of: α-hydroxy-acids, α-amino alcohols, and 1 ,2-diols. In addition, chiral cyanohydrins are themselves components of highly successful pyrethroid insecticides.
There are a number of synthetic routes available for the asymmetric synthesis of cyanohydrins and derivatives, virtually all of which involve the use of a chiral catalyst to induce the asymmetric addition of a cyanide source to a prochiral aldehyde or ketone. The available catalysts include enzymes, cyclic peptides and transition metal complexes. However, all of these methods suffer from one or more significant disadvantages which have negated their commercial exploitation. Many of the methods employ highly toxic and hazardous HCN, require very low (ca. -80°C) reaction temperatures, and/or give products with low to moderate enantiomeric excesses. Processes for the asymmetric synthesis cyanohydrins and derivatives are disclosed by M. North, Synlett, 1993, 807-20; F.Effenberger, Angew. Chem. Int. Ed. Engl.
1994, 33, 1555; M. North, Comprehensive Organic Functional Group Transformations ed. Katritzky, A.R.; Meth-Cohn, O.; Rees, C.W.; Pattenden, G.; Pergamon Press, Oxford,
1995, vol. 3, chapter 18; Y.Belokon' et al, Tetrahedron Asymmetry, 1996, 7, 851-5; Y.Belokon' et al, J.Chem. Soc, Perkin Trans. 1, 1997, 1293-5; Y.N.Belokon' et al,
Izvestiya Akademii Nauk. Seriya Khimicheskaya, 1997, 2040: translated as Russian Chem. Bull., 1997, 46, 1936-8; V.I.Tararov et al, Chem. Commun., 1998, 387-8; Y.N.Belokon' et al, J. Am. Chem. Soc, 1999, 121, 3968-73; V.I.Tararov et al, Russ. Chem. Bull., 1999, 48, 1128-30; Y.N.Belokon' et al, Tetrahedron Lett., 1999, 40, 8147-50; Y.N.Belokon' et al, Eur. J. Org. Chem., 2000, 2655-61 ; Y.N.Belokon', M.North, and T.Parsons; Org. Lett., 2000, 2, 1617-9.
J. Am. Chem. Soc, 1999, 121, 3968-73 discloses the use of catalysts 1 and 2 having the formulae given below (with R1 and R2 = tert-butyl) (Scheme 1 ). wherein each R1 and R2 independently is H, alkyl, aryl, aralkyl, alkoxy, aryloxy, halogen, nitro, halo-alkyl, amino (including with alkyl or aryl substituents on the nitrogen atom), or amido.
PCT/GB01/03455 discloses a new process for the cyanation of aldehydes, and is particularly directed at the asymmetric cyanation of aldehydes.
The asymmetric cyanation of aldehydes is a highly useful synthetic procedure for the synthesis of chiral cyanohydrins and derivatives thereof, such as chiral O-acyl cyanohydrins. There is therefore a need for new catalysts for use in asymmetric cyanation of aldehydes.
According to a first aspect of the present invention, there is provided a catalyst of formula (3a) or (3b):
(3a) (3b)
wherein,
R1 and R2 are independently hydrogen, halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or comprise part of a fused ring;
R3 and R4 are independently halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R3 & R4 optionally being linked in such a way as to form an optionally substituted ring(s);
Y is a neutral ligand; and
X is an anion.
Hydrocarbyl groups which may be represented by R _1-4 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups
Alkyl groups which may be represented by R1"4 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R1"4 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl, cyclohexyl and adamantyl groups.
Alkenyl groups which may be represented by R1"4 include C2-20, and preferably C2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.
Aryl groups which may be represented by R1"4 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R1"4 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
Perhalogenated hydrocarbyl groups which may be represented by R1"4 include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R1"4 include -CF3 and -C2F5.
Heterocyclic groups which may be represented by R1"4 include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R1"4 include pyridyl, pyrimidyl, pyrrolyl, thienyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
When R3 & R4 are linked in such a way as to form an optionally substituted ring(s), the largest ring commonly comprises from 5 to 7 ring atoms.
When R1"4 is a substituted hydrocarbyl, heterocyclic group, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, acyl, ester, carbonate, amide, sulphonyl or sulphonamido group, or R3 & R4 are linked in such a way as to form a substituted ring(s) the substituent(s) should be such so as not to adversely affect the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined above for R1"4. One or more substituents may be present. Neutral ligands which may be represented by Y include water, C1-4 alcohols, C1-4 thiols, Cι-8 ethers, C1-8 thioethers, C*ι-8 primary, secondary or tertiary amines, and aromatic amines for example pyridine. A preferred basic ligand represented by Y is water.
Anions which may be represented by X include, halide, sulphate, alkylsulphate, perchlorate, PF6 " , acetate, tosylate and triflate. Preferably, R1 or R2 are independently alkyl groups, preferably methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl and cyclohexyl groups.
More preferably R1 and R2 are independently 2-propyl, butyl, 2-butyl, t-butyl, t- pentyl and cyclohexyl groups. Most preferably R1 and R2 are independently t-butyl, t-pentyl and cyclohexyl groups.
Preferably R3 and R4 are independently halogen, cyano, nitro, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted di- hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R3 & R4 optionally being linked in such a way as to form an optionally substituted ring(s) More preferably R3 and R4 are independently alkyl or aryl groups, or R3 & R4 are linked in such a way as to form an optionally substituted ring comprising from 5 to 7 ring atoms, the ring atoms being carbon atoms.
More preferably when R3 and R4 are independently alkyl or aryl groups, the alkyl or aryl groups are methyl or phenyl groups. More preferably when R3 & R4 are linked in such a way as to form an optionally substituted ring, the ring comprises 6 ring atoms and the ring atoms are preferably carbon atoms.
Most preferably R3 & R4 are linked in such a way as to form an un-substituted ring comprising 6 ring atoms and the ring atoms are carbon atoms. Preferred catalysts are those in which R1 and R2 are independently 2-butyl, t-butyl, t-pentyl and cyclohexyl groups, and R3 and R4 are independently methyl or phenyl groups, or R3 & R4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms.
More preferred catalysts are those in which R1 and R2 are independently 2-butyl, t- butyl, t-pentyl and cyclohexyl groups, and R3 and R4 are independently methyl or phenyl groups, or R3 & R4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms
Most preferred catalysts are those in which R1 and R2 are independently 2-butyl, t- butyl, and t-pentyl groups, and R3 & R4 are linked in such a way as to form an optionally substituted ring comprising 6 ring atoms, the ring atoms being carbon atoms
Catalysts according to the present invention have been found to be useful in processes for the cyanation of aldehydes.
According to a second aspect of the present invention there is provided a process for cyanating an aldehyde which comprises reacting the aldehyde with: i) a cyanide source which does not comprise a Si-CN bond or a C-(C=O)-CN moiety; and ii) a substrate susceptible to nucleophilic attack not comprising a halogen leaving group; in the presence of a chiral catalyst of formula (3a) or (3b).
The chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention. Aldehydes which can be employed in the process of the present invention have the chemical formula R5-CHO, wherein R5 is a substituted or unsubstituted hydrocarbyl group, including perhalogenated hydrocarbyl groups. Hydrocarbyl groups which may be represented by R5 include alkyl, alkenyl, aryl and heterocyclic groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
Alkyl groups which may be represented by R5 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprise up to 10 branched chain carbon atoms, preferably up to 4 branched chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R5 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.
Alkenyl groups which may be represented by R5 include C2-20, and preferably C2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups.
Aryl groups which may be represented by R5 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R5 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
Perhalogenated hydrocarbyl groups which may be represented by R5 include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R5 include -CF3 and -C2F5.
Heterocyclic groups which may be represented by R5 include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R5 include pyridyl, pyrimidyl, pyrrolyl, thienyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.
When R5 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R5 above. One or more substituents may be present. Cyanide sources not comprising a Si-CN bond or a C-(C=O)-CN moiety which can be employed in the process of the present invention include dicyanogen; ammonium cyanide salts, particularly quaternary ammonium salts such as tetraalkyl, preferably tetra C1-6alkyl-, ammonium salts; sulfonyl cyanides, for example tosyl cyanide and mesyl cyanide; and organic cyanides having the formula R6-O-CO-CN, where R6 is H or a substituted or unsubstituted hydrocarbyl group as described above, commonly a C1-6 alkyl group. In many embodiments, the cyanide source is an inorganic cyanide, preferably a metal cyanide or an in situ source of inorganic cyanide such as acetone cyanohydrin. Particularly preferred cyanide sources comprise alkali metal and alkaline earth metal cyanides, for example, lithium, sodium, potassium, rubidium, caesium, magnesium and calcium cyanides. The most preferred cyanide source is potassium cyanide.
The reaction between the aldehyde and the cyanide source occurs in the presence of a substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group. Examples of such substrates are compounds having the general formula Q-Y, wherein Q represents an organic acid radical, and Y represents a non- halogen leaving group. In many embodiments, the leaving group, Y, is a leaving group the conjugate acid of which has a pKa of greater than about -2, such as greater than 3, and often less than 12. Examples of leaving groups include alkyl and aryl sulphonates, such as mesylate and tosylate; carbonates; especially alkyl carbonates; carboxylates, especially alkyl carboxylates; and groups of formula -NRxRy, wherein Rx and Ry together with the nitrogen atom form an unsaturated heterocyclic ring which may comprise one or more additional heteroatoms, especially nitrogen, particularly imidazole or benzimidazole rings. Organic acid radicals which may be represented by Q include groups of formulae R-(C=O)-, R-(C=S)-, RO-(C=O)-, RN-(C=O)-, RO-(C=S)-, RN-(C=S)-, RS-(C=O)-, RS- (C=S)-, R-(P=O)(OR)-, R-SO2- and R-SO-, wherein R represents a substituted or unsubstituted hydrocarbyl group as defined for R5 above.
In many embodiments, the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group has the general formula R7-(C=X)-A-Z, wherein R7 represents an organic radical, such as a substituted or unsubstituted hydrocarbyl group as described above or a hydrocarbyloxy group wherein the hydrocarbyl moiety is as described above; X represents O, S, N-R or NOR wherein R represents H or a substituted or unsubstituted hydrocarbyl group as defined for R5 above; A represents a chalcogen, preferably O or S and Z represents a group of formula (C=O)-R7 or (C=S)-R7 wherein R7 is as described above; or -A-Z represents a group of formula -NRxRy as described above. Preferably, X and A each represent O, and Z is a group of formula (C=O)-R7.
Commonly, the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group is a carboxylic acid anhydride or an anhydride of a carbonic acid. Carboxylic anhydrides include mixed anhydrides and are often the anhydrides of C1-8 alkyl or aryl carboxylic acids, such as acetic anhydride and trifluoroacetic anhydride. Carbonic acid anhydrides include di-tert-butyldicarbonate, (tBuOCOOCOOtBu), N,N'-disuccinyldicarbonate, N,N'-dimaleimyldicarbonate, N-(tert- butyl-oxycarbonyloxy) maleimide or succinimide, and N-(benzyloxycarbonyloxy) maleimide or succinimide. The process according to the present invention is commonly carried out in the presence of a solvent. Preferred solvents are polar, aprotic solvents, including halocarbons, for example dichloromethane, chloroform and 1 ,2-dichloroethane; nitriles, for example acetonitrile; ketones, for example acetone and methylethylketone; ethers, for example diethylether and tetrahydrofuran; and amides, for example dimethylformamide, dimethylacetamide and N-methylpyrolidinone.
Advantageously, the process of the present invention is carried out in the presence of an additive which accelerates the rate of reaction. Commonly these additives are inorganic bases such as Na2CO3, K2CO3 or CaCO3 or comprise a nucleophilic heteroatom, and often have pKa of greater than 10, for example in the range from 15-35, such as from 15-25. Examples of preferred additives include organic bases, such as pyridine, 2,6-lutidine and imidazole; alcohols, such as Cι-6 alcohols, especially tertiary alcohols such as t-butanol; and water.
It will be recognised that when the cyanide source is a metal cyanide, the reaction mixture will be heterogeneous. In such circumstances, it is therefore desirable to employ efficient agitation of the reaction mixture. Agitation means known in the art, for example mechanical stirrers and ultrasonic agitators, selected appropriately according to the scale of reaction can be employed as desired.
The process of the present invention is often carried out a temperature of from about -40°C to about 40°C. Lower temperatures may be employed if desired, although they are not believed to be advantageous. Commonly, the reaction is carried out a temperature of from -25°C to ambient temperature, such as 15-25°C.
Advantageously, the use of the catalysts of the first aspect of the present invention in these processes may facilitate the reactions being carried out at temperatures which are higher than those which can be employed with other catalysts (particularly Ti(lV) catalysts) and still exhibit a high degree of enantio-selectivity.
The product of the cyanation reaction in the presence of the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group can then be reacted, for example by hydrolysis, to form a cyanohydrin. When the substrate susceptible to nucleophilic attack which does not comprise a halogen leaving group has the general formula Q-Y, the process can be represented by the sequence:
The process according to the present invention is particularly suited to the enantioslective cyanation of aldehydes. It has been found that particularly effective enantioselective cyanation of aldehydes can be achieved by employing an order of addition in which a mixture of chiral catalyst, cyanide source, solvent and aldehyde are prepared, preferably an additive as described above is added to this mixture. The temperature of this mixture is then adjusted to the desired reaction temperature if necessary, and the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is added. This approach has been found to be especially suited when the additive comprises lutidine, t-butanol or water and the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is a carboxylic anhydride.
Certain embodiments of the present invention comprise the use of a heterogeneous mixture of an alkali metal cyanide, or alkaline earth metal cyanide (or other inexpensive cyanide sources such as acetone cyanohydrin), an additive (which may be a base e.g. pyridine; or water) and acetic anhydride (or other carboxylic acid anhydrides) to generate a cyanating agent for aldehydes. This can be carried out in situ with catalyst 1 (and related catalysts) and an aldehyde to generate chiral O-acyl cyanohydrins (conditions as illustrated in Scheme 2). This methodology uses only inexpensive reagents, and produces cyanohydrin derivatives which are not sensitive to moisture and do not spontaneously racemize.
Scheme 2
R8 = alkyl, aryl, aralkyl, and may contain halogen, oxygen, nitrogen, or sulfur atoms within the group. R9 = alkyl, aryl, aralkyl, and may contain halogen, oxygen, nitrogen, or sulfur atoms within the group. M = alkali metal or alkaline earth metal.
Preferably, potassium cyanide is used as the cyanide source, acetic anhydride as the anhydride, 2,6-lutidine as the additive and catalyst 3 (or the corresponding enantiomer derived from (R,R-cyclohexane-1 ,2-diamine) with R1 and R2 = JBu is used as the catalyst.
This invention allows the synthesis of chiral cyanohydrin derivatives derived from a wide variety of aldehydes. The products can be transformed into other chiral compounds by standard chemistry using either of the acyl or nitrile functional groups.
According to one preferred aspect of the present invention there is provided a process for the cyanation of an aldehyde group which comprises reacting the aldehyde with: i) an alkali metal cyanide; and ii) a carboxylic anhydride; in the presence of a catalyst of formula (3a) or (3b).
The chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention. According to another preferred aspect of the present invention there is provided a process for the preparation of an O-acyl cyanohydrin which comprises reacting an aldehyde with potassium cyanide and a carboxylic anhydride in the presence of a catalyst of formula (3a) or (3b).
The chiral catalyst of formula (3a) or (3b) is as described above in connection with the first aspect of the present invention.
In the preferred aspects, further preferences are as described above with respect to the first aspect of the present invention.
In certain embodiments, the chiral transition metal catalyst and a metal cyanide can be added as mixture. Such a mixture is believed to be a novel composition of matter, and accordingly forms another aspect of the present invention. Preferred transition metal catalysts and metal cyanides are as described above with respect to the first aspect of the present invention.
Catalysts according to the present invention may be prepared by reaction of a suitable compound of vanadium with a ligand in the presence of oxygen. Typically vanadyl sulphate hydrate is reacted with a salen ligand in solvent in the presence of oxygen.
The invention is illustrated, without limitation, by the following examples.
General methods
1H NMR spectra were recorded at 250 MHz on a Bruker AM250 spectrometer, and at 400
MHz on a Bruker AMX-400 spectrometer (at 293 K, CDCI3 or CD2CI2). Spectra were internally referenced either to TMS or to the residual solvent peak, and peaks are reported in ppm downfield of TMS. Infrared spectra of solutions were measured with a Nicolet Magna-750 Fourier-transform spectrometer with a resolution of 2 cm"1. The spectra were recorded using a 0.06 mm KBr cell. Solvent spectra were subtracted from solution spectra using the OMNIC Nicolet program.
Optical rotations were recorded on an Optical Activity Ltd. Polar 2001 or a Perkin-Elmer 241 polarimeter, and are reported along with the solvent and concentration in g/100 mL.
Elemental analyses were performed on a Carlo Erba Model 1106 or Model 1108 analyser.
Chiral GC was carried out on a DP-TFA-γ-CD, fused silica capillary column (32m x 0.2 mm) using helium as the carrier gas. Dichloromethane was distilled over CaH2. Acetic anhydride was distilled from the commercial product (99%). Commercial potassium cyanide (98%) was thoroughly powdered and stored in vacuo over P2O5. Aliphatic and aromatic aldehydes were purified by usual methods.
Chiral ligands were prepared by refluxing 1 ,2-cyclohexyldiamines (R,R and S,S) with 2,4- di-fer.-butyl salicylaldehyde.
Example 1 - Synthesis of vanadium(V)salen complexes Solutions of (1R,2R)-Λ/,Λ/'-bis(3,5-di-tert-butylsalicyliden)-1 ,2-cyclohexanediamine
(1.0 g, 1.8 mmol) in THF (20 mL) and vanadyl sulphate hydrate (0.55 g, 2.0 mmol) in hot ethanol (32 ml) were mixed and stirred under reflux for 2 h in air, then the solvent was removed in vacuo. The residue was dissolved in dichloromethane and put atop a SiO2 filled column. Elution first with dichloromethane, then with EtOAc : methanol (2:1) gave a catalyst of formula 3b wherein R1=R = tBu, R3&R4= -(CH2) - (0.6 g, 53%) as a dark-green crystalline solid. It can be additionally recrystallized from benzene-CH2CI2. [α]^2 -914.29 (c=0.01 , CHCI3); vmax (KBr, cm"1): 1618 ( KCH=N); 1250 ( I HSO4); 965 ( JV=0); δH (CDCI3): 0.83 (3H, t), 1.33 (18H, s), 1.49 (18H, s), 1.7-2.2 (8H, m), 3.41 (2H, q), 3.81 (1H, m), 4.26 (1 H, m), 7.49 (1H, s), 7.52 (1 H, s), 7.68 (1 H, s), 7.73 (1 H, s), 8.53 (1 H, s), 8.73 (1H, s).
Example 2 - Synthesis of vanadium(V)salen complexes
By the method of Example 1 , (1S,2S)-Λ/,/V'-bis(3,5-di--ert-butylsalicyliden)-1 ,2- cyclohexanediamine gave a catalyst of formula 3a wherein R1=R2= tBu, R3&R4= -(CH2)4-.
Example 3 - Cyanation of benzaldehyde promoted by V(V)-catalyst.
To a stirred mixture of KCN (12.37 g, 190 mmol), t-BuOH (3.7 g, 4.8 mL, 50 mmol), and benzaldehyde (5.21 g, 5 mL, 47.5 mmol) in dichloromethane (50 mL), H2O (0.5 mL, 31 mmol) was added. The reaction mixture was then cooled to -42°C (CH3CN/CO2) and the catalyst (0.35 g, 0.475 mmol of the catalyst prepared in Example 2) in dichloromethane (20 mL) was added, followed by acetic anhydride (11.41 g, 10.55 mL, 190 mmol) in one portion. The reaction mixture was vigorously stirred for 10 hours at the same temperature. Solid salts were then filtered and washed thoroughly with dichloromethane. To remove the catalyst the reaction mixture was filtered through a pad of silica (10 mm x 50 mm) eluting with dichloromethane. The solvent was evaporated.//? vacuo, and the resulting light green residue fractionated in vacuo giving the benzaldehyde cyanohydrin acetate. B.p. 95-97°C (0.2 mm); yield 7.5 g (87.2%); ee (S), 90.3%.

Claims

A catalyst of formula (3a) or (3b):
wherein,
R1 and R2 are independently hydrogen, halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or comprise part of a fused ring; R3 and R4 are independently halogen, cyano, nitro, hydroxy, amino, thiol, an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl, an optionally substituted heterocyclyl, an optionally substituted hydrocarbyloxy, an optionally substituted mono or di-hydrocarbylamino, an optionally substituted hydrocarbylthio, an optionally substituted acyl, an optionally substituted ester, an optionally substituted carbonate, an optionally substituted amide, or an optionally substituted sulphonyl or sulphonamido group, or R3 & R4 optionally being linked in such a way as to form an optionally substituted ring(s); Y is a neutral ligand; and X is an anion.
2. A catalyst according to Claim 1 wherein R1 or R2 are independently alkyl groups, preferably methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl, t-pentyl and cyclohexyl groups.
3. A catalyst according to Claim 1 or 2 wherein R3 and R4 are independently alkyl or aryl groups, or R3 & R4 are linked in such a way as to form an optionally substituted ring comprising from 5 to 7 ring atoms, the ring atoms being carbon atoms.
4. A catalyst according to Claim 3 wherein R3 and R4 are independently methyl or phenyl groups.
5. A catalyst according to Claim 3 wherein R3 & R4 are linked in such a way as to form an un-substituted ring comprising 6 ring atoms and the ring atoms are carbon atoms.
6. A catalyst according to any one of Claims 1 to 5 wherein Y is water, a C1-4 alcohol, a C1-4 thiol, a C1-8 ether, a C1-8 thioether, a C1-8 primary, secondary or tertiary amine, or an aromatic amines.
7. A catalyst according to any one of Claims 1 to 6 wherein X is halide, sulphate, alkylsulphate, perchlorate, PF6 " , acetate, tosylate or triflate.
8. A process for cyanating an aldehyde which comprises reacting the aldehyde with: i) a cyanide source which does not comprise a Si-CN bond or a C-(C=O)-CN moiety; and ii) a substrate susceptible to nucleophilic attack not comprising a halogen leaving group; in the presence of a chiral catalyst as claimed in any one of Claims 1 to 7.
9. A process according to Claim 8 in which the cyanide source is an alkali metal cyanide, preferably potassium cyanide.
10. A process according to Claim 8 or 9 in which the substrate susceptible to nucleophilic attack not comprising a halogen leaving group is a carboxylic anhydride or carbonic acid anhydride.
11. A process according to any one of Claims 8, 9 or 10, wherein the process is carried out in the presence of an additive having a pKa of greater than 10.
12. A process according to Claim 11 wherein the additive is selected from pyridirie, 2,6-lutidine, imadazole, t-butanol and water.
13. A process according to any one of Claims 8, 9, 10, 11 or 12 wherein the process is carried out in a polar, aprotic solvent.
14. A process for the cyanation of an aldehyde group which comprises reacting the aldehyde with: i) an alkali metal cyanide; and ii) a carboxylic anhydride; in the presence of a catalyst as claimed in any one of Claims 1 to 7.
15. A process for the preparation of an O-acyl cyanohydrin which comprises reacting an aldehyde with potassium cyanide and a carboxylic anhydride in the presence of a catalyst as claimed in any one of Claims 1 to 7.
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JP2005526608A (en) 2005-09-08
GB0212017D0 (en) 2002-07-03
AU2003241010A1 (en) 2003-12-12
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