Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings

Definitions

• the present invention relates to chiral disulfonimides and their salts and metal complexes and their use as catalysts.
• Japanese patents 2005-132815, 2005-132816 and 2005-134365 disclose the enantiomerically pure preparation of this acid, its use as a reagent for racemate resolution and its application as an NMR shift reagent.
• List et al. used this acid as a chiral Bronsted acid catalyst in Adv. Synth. Catal. 2008, 350, 962-966 and Chem. Asian. J. 2008, 3, 430-437, but without enantioselectivity.
• Ishihara et al. used the 1, 1'-binaphthalene-2,2'-disulfonic acid in combination with substituted pyridines in J. Am. Chem. Soc. 2008, 130, 16858-16860 as chiral Bronsted acid-base organocatalysts.
• the unknown cyclic disulfonimide of 1, 1'-binaphthalene-2,2'-disulfonic acid, its substituted derivatives and the substituted derivatives of 1, 1'-binaphthalene-2,2'-disulfonic acid is classified as a strong Bronsted acid.
• the conjugated bases of disulfonic acids and disulfonimides are also suitable as chiral anions in enantioselective counteranion-mediated catalysis and Lewis acid catalysis. It is an object of the present invention to provide chiral disulfonimides and a simple process for the preparation of chiral disulfonimides and their use in catalysis.
• the present invention accordingly chiral disulfonimides having the general formulas I to III
• Compound of the formula II and E and F of the compound of the formula III is a chiral radical or E and F together form a chiral backbone
• G is H 1 C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, group aryl, Ai ⁇ I- (C 1 -C 6 ) -alkyl, Hetero-O-O-alkyl, heteroaryl, or SiR 14 R 15 R 16 Br, Cl, I, F, where R 14 , R 15 , R 16 is C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C C 2 -C 6 -alkynyl, aryl, aryl- (C 1 -C 6 ) -alkyl, HeIeTO- (C 1 -C 6 ) -alkyl, heteroaryl, which may optionally be substituted,
• X is C, Si, O, N or S and n is 0, 1, 2, 3, 4, 5 or 6, where n is> 1 only when X is C, and their organic salts, metal salts and metal complexes.
• R a and R b or both are chiral radicals, as for the radicals A, B, C 1 D, E and F or they together form a so-called chiral backbone and G is H, C r C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, aryl, AryKCrCeJ-alkyl, hetero-O-alkyl, heteroaryl, or SiR 14 R 15 R 16 Br, Cl, I, F where R 14, R 15, R 16 is C r C 6 alkyl, C 2 -C 6 kenyl- -alkyl or C 2 -C 6 alkynyl, aryl, aryl (C 1 -C 6 ) -alkyl, HeIeTO- (C 1 -C 6 ) - alkyl, heteroaryl, which may optionally be substituted.
• BINOL (1-3, 21 +22) and VAPOL (4) and in the spiro compound (19) form the radicals E and F together a chiral backbone.
• the chirality results in the BINOL and VAPOL derived compounds and the spiro compounds on axial chirality.
• rotatability about the axis of the aryl (E) -aryl (F) bond (X) is limited.
• Both aryles are not chiral by themselves, because they are connected by an axis that limits their free rotation, they form a chiral axis. This results in a chiral backbone for the disulfonimides.
• the compound of the formula Z or the compounds of the formulas I, II and III can also have a helical, chiral or planar backbone, such as, for example, compound 24.
• Chiral sulfonimides in the context of the present invention means that one of the enantiomers is in excess, i. enriched or the reaction product is in enantiomerically pure form. If the compounds of the invention are obtained as reaction products racemic or scalemic mixture, the enantiomers can be separated by methods well known in the art, for example via a separation by chiral preparative HPLC or via the reaction of the compounds with chiral agents and the subsequent separation the diastereomers. The separation of the enantiomers may also be carried out if the excess enantiomer is to be further enriched, i. the ee value should be increased.
• Suitable chiral radicals are any chiral radicals. If the other radical is not chiral, the radicals A or B, C or D and E or F are any organic radical which may be saturated or unsaturated, linear, cyclic or heterocyclic, aromatic and / or heteroaromatic. Examples of compounds of formula 1, 11 and III are shown below:
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 may be the same or different and independently of one another H, OH 1 F, Cl , Br, I, CN 1 NO 2 , NO, SO 2 , SO 3 H, NH 2 , PH 3 , COOH,
• R 13 is H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, aryl-, aryl- (C 1 -C 6 ) -alkyl,
• C 1 -C 6 -alkyl C 2 -C 6 -alkynyl or C 2 -C 6 -alkynyl, aryl, aryl- (C 1 -C 6 ) -alkyl, hetero- (C 1 -C 6 ) -alkyl, Heteroaryl, which may be substituted, is, as well as their organic salts, metal salts and metal complexes.
• Another object of the present invention are chiral disulfonimides derived from H8-BIN0L having the general formula V.
• R 1 " , R 2 ' , R 3' , R 3" , R 4 ' , R 4 " , R 5' , R 5" , R 6 ' , R 6 " , R 7' , R r , R 8 ' , R 8 " , R 9 ' , R 9' , R 10 ' R 10" , R 11' , and R 12 ' may be the same or different and independently of one another H, OH 1 F, Cl, Br, I, CN, NO 2, NO, SO 2, SO 3 H, NH 2, PH 3, COOH, SO 3 X, COOY, wherein X and Y is Na or K, a -C 2 o alkyl, C 2 -C 20 - Alkenyl or Cz-Cjo-alkynyl, group aryl, aryl (Ci-C 6 ) alkyl, heteroCd-Cy ⁇ J-alkyl, heteroaryl, which may be substituted, if necessary
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 , R 1 ' , R 2' , R 3 ' , R 3 " , R 4' , R 4" , R 5 ' , R 5 " , R 6' , R 6" , R 7 ' , R 7 " , R 8' , R 8" , R 9 ' , R 9 " , R 10 ' , R 10" , R 11' and R 12 ' and R 13 are as defined above, wherein the enantiomers in a ratio of 98: 2 to 100: 0, that is present in enatiomerenreiner form.
• C r C 2 o-alkyl may be unbranched (linear) or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19 or 20 carbon atoms.
• Alkyl is preferably C 1 -C 6 -alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, as well as pentyl, 1-, 2- or 3-methylpropyl, 1, 1, 1, 1, 2 or 2,2 dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2 , 3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl.
• Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene or hexylene, but also branched alkylene.
• Alkylene is preferably vinyl.
• Halogen is F, Cl, Br or I.
• Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy.
• C 3 -C 8 heterocycloalkyl having one or more heteroatoms selected from N, O and S is preferably 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2 -, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro 1-, 2-, 3-, -A- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, 2- or -4-imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1 -, -3
• Aryl is preferably phenyl, naphthyl or diphenyl.
• Arylalkyl is preferably benzyl.
• Heteroaryl having one or more heteroatoms selected from N, O and S is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5- Imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazole-1, -4- or -5-yl, 1, 2,4-triazole-1, 3 or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or 5-yl, 1, 2,4-oxadiazole -3- or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,
• R 1 or R 12 or R 1 ' or R 12' is not hydrogen and is selected from phenyl, 2,4,6-triisopropyl-phenyl, mesityl, 9-phenanthryl, 9-Anthracenyl, ferrocenyl, N- (perfluorophenyl) acetamide, N- (4-chlorophenyl) acetamide, N- (naphthalen-1-yl) acetamide, N-benzhydrylacetamide, N- (2,6-diisopropylphenyl) acetamide, 1- Anthracenyl, corannulene, porphyrin, 1-naphthyl, 2-naphthyl, 4-biphenyl, 3,5- (trifluoromethyl) -phenyl, 2,6-dimethyl-phenyl, tert-butyl, tris-mesityl-silyl, tri
• the compounds according to the invention can be converted into organic salts, metal salts or metal complexes in a manner known per se to those skilled in the art.
• the disulfonimides are reacted with a corresponding metal salt, for example with the carbonate of the corresponding metal.
• Scheme 1 General examples of metal salts or metal complexes of disulfonimides IV and disulfonimides V.
• any metals or organic cations such as tertiary ammonium ions may be M.
• the compounds are shown in Scheme 1 as salts, the exact structure with metals is not known, they may also have the structure of metal complexes. It is therefore used in the context of the present invention, the formulation metal salts or metal complexes.
• the metal compounds are not limited to specific metal compounds or complexes.
• Suitable metal compounds are derived from Li, Na, K, Rb, Cs, Be, Mg 1 Ca, Sr, Ba Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, W, Re, Os, Ir 1 Pt, Au, Al, Pb, La, Sm, Eu, Yb. as well as ammonia)
• a preferred production process of the present invention is a process for the preparation of substituted disulfonimides having general formula I or II, ie those containing chiral BINOL and H8 BINOL backbone:
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 1 ' , R 2' , R 3 ' , R 3 " R 4" , R 4 " , R 5 ' , R 5" , R 6' , R 6 " , R 7 ' , R 7" , R 8' , R 8 " , R 9 ' , R 9” , R 10 ' , R 10 " , R 11' and R 12 ' and R 13 are as defined above, wherein
• R 17 and R 18 may be the same or different and represent a dC ⁇ alkyl group to form an O-aryl thiocarbamate having the general formula XIII and XIV, respectively.
• R 1 , R 12 B (OH) 2 , B (alkyl) 2 , B (oalkyl) in a process step G) known to the person skilled in the art.
• halides and ditriflates with the general formula XX or XXI or the boronates with the general formula XXII or XXIII serve as starting materials for the well-known to those skilled coupling reactions as process step H) to the imides having the formula IV or V.
• reaction step A the dihydroxy compound of the formula IV or V is reacted with a thiocarbamoyl chloride of the formula XU in the presence of a hydride in a solvent at elevated temperature.
• Suitable solvents are any organic solvents that do not adversely affect the reaction.
• Reaction step B is preferably carried out in a suitable solvent or solvent-free by heating the O-aryl thiocarbamate obtained in step A.
• the resulting S-arylthiocarbamate of the formula XV or XVI is converted in the next process step C into a sulfonic acid having the formula XVII or XVIII.
• This process step is preferably carried out in the presence of an oxidizing agent such as H 2 O 2 and an acid and / or an organic peracid.
• the S-arylthiocarbamate of the formula XV or XVI can be converted directly into the acid halides of the formula XIX or XX in a process step (D1) known to the person skilled in the art. Ring closure with ammonia gives the disulfonimide IV or V.
• D1 a process step known to the person skilled in the art.
• Ring closure with ammonia gives the disulfonimide IV or V.
• a general description for the preparation of the disuifonimides is given in the Experimental Part.
• the Disulfonimides IVa or Va are converted into the halides or ditriflates having the general formula XX or XXI or the boronates having the general formula XXII or XXIII according to a process step which is well known to the person skilled in the art. These serve as starting substances for coupling reactions to give the imides of the formula IV or V.
• the disulfonimides MII according to the invention and their organic salts, metal salts and metal complexes are particularly suitable as strong, chiral Bronsted acid catalysts or chiral Lewis acid catalysts for a variety of reactions, in particular for the activation of ketones, aldehydes and alkenes.
• a particularly good catalytic activity are compounds in which R 13 is H, F, Cl, Br, I or SiR 14 R 15 R 16 , wherein R 14 , R 15 , R 16 is C r C 6 alkyl, C 2 C 6 alkenyl or C 2 -C 6 alkynyl.
• R 13 particularly preferably represents SiR 14 R 15 R 16 or I.
• Reactions such as aldol reactions, vinylogous aldol reactions, Mukaiyama-aldol reactions, vinylogous Mukaiyama-aldol reactions Mukaiyama-Michael reactions, Michael additions, Mannich are among the reactions in which the compounds of the invention can be used as catalysts Reactions, TMSCN additions to aldehydes and ketones, esterifications, etherifications, pinacol rearrangements, acetalizations and related reactions, cycloadditions, hydroaminations, hydroalkoxylation, hydration reactions, olefin activations in general, Friedel-Crafts reactions, epoxide openings, Ritter reactions, nucleophilic substitutions of Alcohols, asymmetric ring holes, asymmetric reductions, transfer hydrogenations, alkyne additions, allylations, epoxidations, olefin metathesis, isomerizations, iminium catalysis, and enamine catalysis
• Another object of the present invention is the use of the compounds of the formulas I to III as NMR shift reagents and as reagents for racemate resolution.
• Disulfonimide VIIa (0.41 mg, 0.5 mol%) and benzaldehyde (10 ⁇ l, 0.1 mmol) are initially charged in 0.5 ml of toluene or pentane at room temperature.
• Tert-Butyl (1-methoxyvinyloxy) dimethylsilane or tert-butyl (1-isopropoxyvinyloxy) dimethylsilane (0.11 mmol) is added dropwise and the mixture is stirred at room temperature for 1-2 hours. Thereafter, the solvent is removed under reduced pressure, and 0.05 mmol of Ph 3 PH is added as an internal standard for an NMR measurement for yield determination.
• Disulfonimide VIa (2:05 mg, 5 mol%) and the corresponding aldehyde (0.05 mmol, 1 eq) is introduced at 0.25 ml Et 2 O at -78 0 C.
• Disulfonimide VIa (2:05 mg, 5 mol%) and the corresponding aldehyde (0.05 mmol, 1 eq) is introduced at 0.25 ml Et 2 O at -78 0 C.
• Is added dropwise trimethyl (2-methylallyl) silane (0.065 mmol, 1.3 eq) and stir for 12-16 hours at -78 0 C.
• the solution is dried over Na 2 SO 4 . Thereafter, the solvent is removed under reduced pressure, and 0.05 mmol of Ph 3 PH is added as an internal standard for an NMR measurement for yield determination.
• Disulfonimide VIa (2:05 mg, 5 mol%) and the corresponding aldehyde (0.05 mmol, 1 eq) is introduced at 0.25 ml Et 2 O at -78 0 C.
• the solvent is removed under reduced pressure to 0.05 mmol Ph 3 PH added as an internal standard for NMR measurement for yield determination.
• Disulfonimide VIa (2:05 mg, 5 mol%) and the corresponding aldehyde (0.05 mmol, 1 eq) is introduced at 0.25 ml Et 2 O at -25 0 C.
• Priority TMSCN (0.15 mmol, 3 eq) and stir at -78 0 C. Then it is quenched with 10% TFA solution in dichloromethane at -25 0 C.
• the solvent is removed under reduced pressure to 0.05 mmol Ph 3 PH as added internal standard for an NMR measurement for yield determination.
• the O-arylthiocarbamate is heated to 250 0 C under argon for 80-90 min. Purification by column chromatography (SiO 4 , ethyl acetate / hexane) provides the desired S-aryl thiocarbamate.
• Acetic acid or formic acid (10 times the volume of 30% H 2 O 2 ) is initially charged at 0 ° C. or room temperature and 30% strength H 2 O 2 (30 eq) is added dropwise. After stirring for 1 h at RT, the S-arylthiocarbamate, dissolved in acetic acid, THF or dichloromethane ( ⁇ faches volume of 30% H 2 O 2 ) was added. After stirring at room temperature for 1- 72 h, the solution is concentrated or the solution is filtered through silica gel and then absorbed. Column chromatography (SiO 4 , dichloromethane / methanol) gives the salt of the desired acid. This is converted to the desired acid by washing with 2-6M HCl or by ion exchange chromatography.
• the corresponding disulfonic acid is initially charged in thionyl chloride under argon. After addition of a catalytic amount of DMF is heated to reflux for 1-4 h. Removing the thionyl chloride under vacuum and purified by trituration with diethyl ether or by column chromatography (SiO 4, hexane / ethyl acetate).
• the corresponding disulfonic acid chloride is dissolved in THF.
• Ammonia (5-30eq) in methanol in portions or via syringe pump at -10 0 C up to 60 0 C and stirred for 6- 120 h at this temperature.
• the salt of the disulfonimide is obtained by purification by means of column chromatography (SiO 4 , hexane / ethyl acetate). This is converted to the desired disulfonimide by washing with 2-6M HCl or by ion exchange chromatography.
• the diiodide is reacted with the corresponding boronic acid (2-20eq) and 1-40 mol% Pd (PPh3) 4 under argon in a degassed mixture of 2M Na 2 CO 3 aq (2-30 eq) and DME for 1-72h at 50 Heated to -150 ° C. After cooling the mixture is diluted with water. It is extracted with ethyl acetate, the organic phases are dried over Na 2 SO 4 and concentrated. Column chromatography (SiO 4 , dichloromethane / methanol) provides the salt of the desired disulfonimides IV and V, respectively. This salt is converted to the desired acid by washing with 2-6M HCl or by ion exchange chromatography.
• Scheme 15 Illustrated disulfonimides with a chiral BINOL backbone.

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