阅读说明：本技术 异构化反应 (Isomerization reaction ) 是由 L·绍丹 J·奎恩特恩 于 2020-03-17 设计创作，主要内容包括：本发明涉及有机合成领域,更具体而言,涉及一种β-三取代的C-3-C-(70)羰基化合物的β位的异构化。(The invention relates to the field of organic synthesis, in particular to beta-trisubstituted C 3 ‑C 70 Isomerization of the beta position of the carbonyl compound.)

1. C for beta-trisubstitution₃-C₇₀A process for the isomerization of a carbonyl compound to alter the conformation of the trisubstituted β -position, characterized in that the process is carried out in the presence of a photo-redox catalyst, a hydrogen atom transfer donor, an amine and light.

2. The method of claim 1, wherein the trisubstituted β -position of the carbonyl compound is part of a ring.

3. The process according to claim 1, characterized in that the carbonyl compounds of the invention are of formula (I) in the form of any one of its stereoisomers or a mixture thereof:

and wherein R¹And R²Simultaneously or independently represent a hydrogen atom or an optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); r³And R⁴Simultaneously or independently represent optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); or R¹And R³Taken together represent optionally substituted C_2-15Alkanediyl or alkenediyl of (a); or/and R²And R⁴Taken together represent optionally substituted C_2-13Alkanediyl or alkenediyl of (a); or/and R³And R⁴Taken together represent optionally substituted C_2-9Alkanediyl or alkenediyl of (a); provided that at least R¹And R³Or R²And R⁴Are combined together.

4. Process according to any one of claims 1 to 2, characterized in that the carbonyl compound is of formula (III) in any one of its stereoisomeric forms:

wherein q is an integer from 1 to 13; r⁹Represents optionally substituted C_1-11An alkyl group; each R⁷Independently of one another, represents a hydrogen atom or an optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); r⁸The radicals representing a hydrogen atom or being optionally substitutedC_1-9An alkyl group; or when R is⁸And R⁹When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when R⁸And R⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when R⁹And R⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when two R are⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when three R are⁷When taken together, represents optionally substituted C_4-9An alkanetriyl group.

5. Process according to any one of the preceding claims, characterized in that the carbonyl compound is of formula (IV) in any one of its stereoisomeric forms:

wherein q and p are independently of each other an integer from 1 to 3; r is an integer of 0 to 10, each R⁷Represents a hydrogen atom or optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); r¹⁰The radicals represent substituents of a saturated ring and are, independently of one another, optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); or when R is⁷And R¹⁰When the radicals are taken together, represent C_2-11Alkanediyl, and/or when two R are⁷When the radicals are taken together represent optionally substituted C_2-11Alkanediyl, and/or when three R are⁷When the radicals are taken together represent optionally substituted C_4-11Alkanetriyl, and/or when two R are¹⁰When the radicals are taken together represent optionally substituted C_2-11Alkanediyl, and/or when three R are¹⁰When the radicals are taken together represent optionally substituted C_4-11An alkanetriyl group.

6. Process according to any one of the preceding claims, characterized in that the carbonyl compound is of formula (V) in any one of its stereoisomeric forms:

wherein s is an integer of 0 to 8, and each R⁷And R¹⁰Have the same meaning as defined in claim 5.

7. Process according to any one of the preceding claims, characterized in that R⁷The radicals may, independently of one another, represent a hydrogen atom or a methyl or propyl group.

8. Process according to any one of the preceding claims, characterized in that R¹⁰The radicals may, independently of one another, represent methyl or ethyl.

9. The method according to any of the preceding claims, characterized in that the photo-redox catalyst is a metal complex photo-redox catalyst, a metal-free photo-redox catalyst or an organic dye.

10. The process according to any of the preceding claims, characterized in that the metal complex photo-redox catalyst is an iridium, copper or ruthenium based complex.

11. The process according to any of the preceding claims, characterized in that the photo-redox catalyst is of formula (VI):

[M(L)(L’)(L”)]Z_n (VI)

wherein M is iridium or ruthenium, L, L 'and L' are each independently of the other optionally substituted by 1 to 6 hydroxy groups, C_1-4Alkyl radical, C_1-32,2' -bipyridine or 2-phenylpyridine substituted with an alkoxy group, a halogen atom, or a halogenated or perhalogenated hydrocarbon; z represents noncoordinationAn anion, n is 0 or 1 when M is iridium and n is 2 when M is ruthenium.

12. The method according to any one of the preceding claims, characterized in that the hydrogen atom transfer donor is a thiol compound, preferably an aromatic thiol, preferably benzenethiol or 2,4, 6-triisopropylbenzenethiol.

13. The process according to any of the preceding claims, characterized in that the amine is a secondary amine.

Technical Field

The invention relates to the field of organic synthesis, in particular to beta-trisubstituted C₃-C₇₀Isomerization of the beta position of the carbonyl compound.

Background

Approaches to obtaining compounds with specific stereochemistry are highly sought. One of the processes leading to the obtaining of stereoisomerically enriched compounds is hydrogenation. However, the hydrogenation processes available to obtain trans-substituted cycloalkane or cycloalkanone compounds are very limited. In particular, although trans-decalones (decalones) compounds represent a highly desirable backbone, since they can be used as perfuming ingredients or as starting materials for the construction of compounds with more complex backbones, trans-decalones compounds are mainly obtained by reduction of the corresponding ketenes using Birch conditions. However, it is difficult to implement the conditions on a large scale for safety and environmental reasons. Even though a method of trans-selectively reducing cyclohexene to benefit thermodynamic products using cobalt and manganese catalysts has recently been reported by Journal of American Chemical society 2014,1300, the method still requires the preparation of a reducing agent, which may be difficult to handle under large scale conditions.

Therefore, there is a need to develop a safer, cleaner method to obtain such compounds.

The present invention allows for the modification of C at beta-trisubstitution by carrying out an isomerization reaction₃-C₇₀The configuration of the beta position of the carbonyl compound provides a solution to the above problems. To the best of our knowledge, there is no report in the prior art on the isomerization process disclosed in the present invention.

Disclosure of Invention

The present invention relates to a novel process which allows the formation of the most thermodynamic products by isomerization conditions. The process allows to avoid birch reduction conditions or unusual catalysts.

Accordingly, a first object of the present invention is a C for beta-trisubstitution₃-C₇₀A process for the isomerization of a carbonyl compound to alter the conformation of the trisubstituted β -position, characterized in that the process is carried out in the presence of a photo-redox catalyst, a hydrogen atom transfer donor, an amine and light.

Detailed Description

It has now been found that the stereochemical isomerisation of the beta position of a carbonyl compound can be achieved in combination with enamine formation, a photoredox catalyst and a hydrogen atom donor.

The object of the present invention is a C for beta-trisubstitution₃-C₇₀Process for the isomerisation of a carbonyl compound to alter the configuration of the (modify) trisubstituted beta position, characterised in that the process is carried out in the presence of a photo-redox catalyst, a hydrogen atom transfer donor, an amine and light.

To cleanFor the sake of clarity, by the expression "beta-trisubstituted C₃-C₇₀Isomerization of carbonyl compounds to alter the conformation of the trisubstituted beta position "or similar terms, is meant to have its normal meaning in the art. That is, the configuration of the carbon in the beta position of the carbonyl function will be altered and the process of the invention allows for an increase in the amount of one enantiomer or diastereomer. The process of the invention is a process for enriching the amount of one enantiomer or diastereomer. In other words, the configuration of the carbon in the β position of the carbonyl function can be switched between racemic and R, between racemic and S, between S and R or between R and S; i.e. the isomerization is an epimerization. According to another particular embodiment, the configuration of the carbon in position β to the carbonyl function can be switched between R and "50: 50 mixture of R and S" or between S and "50: 50 mixture of R and S"; preferably between 50: 50 of R and S. I.e. the isomerization is a racemization. The process of the invention allows obtaining the most thermodynamically stable enantiomer or diastereomer. In particular, the isomerization is an epimerization; i.e. beta-trisubstituted C₃-C₇₀Carbonyl compounds have two or more chiral centers and only change the configuration at the beta position.

By "configuration" is meant the normal meaning in the art. I.e. the spatial arrangement of the stereogenic (stereogenic) centers. This configuration may be absolute or relative.

For the sake of clarity, by the expression "enantiomers or diastereomers" or similar terms, it is meant the normal meaning understood by a person skilled in the art, i.e. a carbonyl compound may have several stereocenters, and each of said stereocenters may have two different stereochemistry (e.g. R or S). The carbonyl compounds may even be in the form of pure enantiomers, or in the form of mixtures of enantiomers or diastereomers. The carbonyl compound may be in racemic or non-racemic (scalemic) form. The process of the invention allows to obtain the carbonyl compound in non-racemic form starting from the racemic or non-racemic form (epimerization). Alternatively, the process of the invention allows to obtain the carbonyl compound in racemic form starting from a non-racemic form of the carbonyl compound (racemization).

For the sake of clarity, by the term "photo-redox catalyst" is meant the normal meaning in the art, i.e. a catalyst that absorbs light by activating an organic substrate by a single electron transfer process to accelerate a chemical reaction.

For the sake of clarity, by the expression "hydrogen atom transfer donor" it is meant the normal meaning of the art, i.e. a compound capable of providing hydrogen radicals. Hydrogen atom transfer is also known as HAT.

For the sake of clarity, by the term "carbonyl compound" is meant the normal meaning of the art, i.e. a compound having ketone or aldehyde functionality.

According to any of the above embodiments, the trisubstituted β -position of the carbonyl compound is part of a ring.

According to any of the above embodiments, the carbonyl compounds of the invention are of formula (I) in the form of any one of its stereoisomers or a mixture thereof:

and wherein R¹And R²Simultaneously or independently represent a hydrogen atom or an optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); r³And R⁴Simultaneously or independently represent optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); or R¹And R³Taken together represent optionally substituted C_2-15Alkanediyl or alkenediyl of (a); or/and R²And R⁴Taken together represent optionally substituted C_2-13Alkanediyl or alkenediyl of (a); or/and R³And R⁴Taken together represent optionally substituted C_2-9Alkanediyl or alkenediyl of (a); provided that at least R¹And R³Or R²And R⁴Are combined together.

For the sake of clarity, by the expression "any one of its stereoisomers or mixtures thereof" or similar, it is meant the normal meaning understood by a person skilled in the art, i.e. that the compounds of formula (I) may be pure enantiomers or diastereomers. In other words, the compound of formula (I) may have several stereocenters, and each of the stereocenters may have two different stereochemistries (e.g., R or S). The compounds of formula (I) may even be in the form of pure enantiomers or in the form of mixtures of enantiomers or diastereomers. The compounds of formula (I) may be in racemic or non-racemic form. Thus, the compound of formula (I) may be one stereoisomer, or in the form of a composition of matter comprising or consisting of various stereoisomers.

It should be understood that by "… R¹And R³Taken together represent C_2-15A linear, branched or cyclic alkanediyl group, or/and R²And R⁴Taken together represent C_2-15A linear, branched or cyclic alkanediyl group, or/and R³And R⁴Taken together … "or the like, the groups may form a (poly) cycloalkyl group. In other words, the compound (I) may be monocyclic or bicyclic, for example at R¹And R³And R³And R⁴When taken together, the compounds of formula (II) contain a bicyclic group such as decalin (decalin), i.e. R¹、R³And R⁴Taken together, represent an alkanetriyl group.

According to a particular embodiment of the invention, the carbonyl compound is of formula (II) in the form of any one of its stereoisomers or a mixture thereof:

wherein n is an integer of 1 to 11, m is an integer of 0 to 6, R¹Represents a hydrogen atom or optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); r⁶Represents optionally substituted C_1-11Alkyl or C_2-11Alkenyl or alkynyl of (a); r⁵Radical generationC which is a substituent of an unsaturated ring and which is optionally substituted independently of one another_1-4Alkyl or C_2-4And/or when two R are present⁵When the radicals are taken together represent optionally substituted C_2-5An alkanediyl group.

According to any of the above embodiments, n may be an integer from 1 to 5. In particular, n may be 1, 2 or 3. Even more particularly, n may be 2.

According to any of the above embodiments, m may be an integer from 0 to 4. In particular, m may be 0, 1, 2 or 3.

According to any of the above embodiments, R¹May be a hydrogen atom or C_1-6Alkyl or C_2-6Alkenyl or alkynyl groups of (a). In particular, R¹May be a hydrogen atom or C_1-6An alkyl group. Even more particularly, R¹May be a hydrogen atom or C_1-4An alkyl group. Even more particularly, R¹It may be a hydrogen atom or a methyl, ethyl or isopropyl group. Even more particularly, R¹May be a hydrogen atom.

According to any of the above embodiments, R⁵The radicals being C_1-3Alkyl or C_2-3Alkenyl or alkynyl groups of (a). In particular, R⁵The radicals being C_1-3An alkyl group. In particular, R⁵The radical represents methyl or ethyl. In particular, R⁵The radical represents a methyl group.

According to any of the above embodiments, R⁶The group represents optionally substituted C_1-6Alkyl or C_2-6Alkenyl or alkynyl groups of (a). In particular, R⁶The radicals being C_1-4An alkyl group. Even more particularly, R⁶The radical represents methyl or ethyl.

According to a particular embodiment of the invention, the carbonyl compound is a cycloalkanone compound. In particular, the carbonyl compound is of formula (III) in any one of its stereoisomeric forms:

whereinq is an integer from 1 to 13; r⁹Represents optionally substituted C_1-11An alkyl group; each R⁷Independently of one another, represents a hydrogen atom or an optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); r⁸The radical represents a hydrogen atom or an optionally substituted C_1-9An alkyl group; or when R is⁸And R⁹When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when R⁸And R⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when R⁹And R⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when two R are⁷When the radicals are taken together represent optionally substituted C_2-9Alkanediyl, and/or when three R are⁷When taken together, represents optionally substituted C_4-9An alkanetriyl group.

According to any one of the above embodiments, R⁸The radical may represent a hydrogen atom or an optionally substituted C_1-6An alkyl group. In particular, R⁸The radical may represent a hydrogen atom or an optionally substituted C_1-3An alkyl group. Even more particularly, R⁸The radical may represent a hydrogen atom or a methyl or ethyl radical.

According to any one of the above embodiments, R⁹The radicals may represent optionally substituted C_1-6An alkyl group. In particular, R⁹The radicals may represent optionally substituted C_1-3An alkyl group. Even more particularly, R⁹The radical may represent a methyl or ethyl radical.

According to any one of the above embodiments, when R⁸And R⁹The radicals, when taken together, may represent optionally substituted C_3-6An alkanediyl group.

According to any one of the above embodiments, the process of the present invention allows to convert a cis or racemic bicyclic carbonyl compound into a trans bicyclic carbonyl compound, or vice versa, as shown below:

without being bound by theory, the process of the invention allows to obtain the most thermodynamically stable compound, which may be a cis or trans bicyclic carbonyl compound.

Cis-bicyclic carbonyl compounds or racemic bicyclic carbonyl compounds or trans-bicyclic carbonyl compounds represent the relative configuration at the ring junction.

According to any one of the above embodiments, the carbonyl compound is of formula (IV) in any one of its stereoisomeric forms:

wherein q and p are independently of each other an integer from 1 to 3; r is an integer of 0 to 10, each R⁷Represents a hydrogen atom or optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); r¹⁰The radicals represent substituents of a saturated ring and are, independently of one another, optionally substituted C_1-4Alkyl or C_2-4Alkenyl or alkynyl of (a); or when R is⁷And R¹⁰When the radicals are taken together, represent C_2-11Alkanediyl, and/or when two R are⁷When the radicals are taken together represent optionally substituted C_2-11Alkanediyl, and/or when three R are⁷When the radicals are taken together represent optionally substituted C_4-11Alkanetriyl, and/or when two R are¹⁰When the radicals are taken together represent optionally substituted C_2-11Alkanediyl, and/or when three R are¹⁰When the radicals are taken together represent optionally substituted C_4-11An alkanetriyl group.

According to any of the above embodiments, q may be 1 or 2. In particular, q may be 2.

According to any of the above embodiments, p may be 1 or 2.

According to any of the above embodiments, r may be an integer from 0 to 6. In particular, r may be an integer from 0 to 4. Even more particularly, r can be 0, 1, 2, or 3. Even more particularly, r can be 0, 1, or 2.

According to any of the above embodiments, R⁷The radicals may independently of one another represent a hydrogen atom or an optionally substituted C_1-3Alkyl or C_2-3Alkenyl or alkynyl groups of (a). Even more particularly, R⁷May represent a hydrogen atom or a methyl, tert-butyl, propyl or ethyl group. In particular, R⁷The radicals may, independently of one another, represent a hydrogen atom, a methyl group or a propyl group. Even more particularly, up to four R⁷The group may represent a methyl group. Even more particularly, one R⁷The radicals may represent a hydrogen atom, a methyl or propyl radical, and the other radicals R⁷The group may represent a hydrogen atom.

According to any of the above embodiments, R¹⁰The radicals may represent, independently of one another, optionally substituted C_1-3Alkyl or C_2-3Alkenyl or alkynyl groups of (a). Even more particularly, R¹⁰The radicals may, independently of one another, represent methyl, tert-butyl or ethyl. Even more particularly, R¹⁰The radicals may, independently of one another, represent methyl or ethyl. Even more particularly, R, when considered alone¹⁰The radicals may, independently of one another, represent methyl.

In particular, the carbonyl compound is a decalone (decalone) derivative. The process of the present invention is a process for converting a cis-or racemic-decalone derivative to a trans-decalone derivative.

In particular, the carbonyl compound is of formula (V) in any one of its stereoisomeric forms:

wherein s is an integer of 0 to 8, and eachR⁷And R¹⁰Have the same meanings as described above.

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰The optional substituents of (A) are 1 to 2 hydroxy groups, C_1-3Alkyl radical, C_1-3Alkoxy, RCOO or ROCO groups, in which R independently of one another are a hydrogen atom or C_1-4An alkyl group.

According to any of the above embodiments, s may be an integer from 0 to 6. In particular, s may be an integer from 0 to 4. Even more particularly, s may be 0, 1, 2 or 3.

Non-limiting examples of suitable carbonyl compounds can include 2,2,3, 6-tetramethylcyclohexane-1-carbaldehyde, 4a, 8-dimethyloctahydronaphthalen-2 (1H) -one, octahydronaphthalen-2 (1H) -one, 7-ethyloctahydronaphthalen-2 (1H) -one, 6- (tert-butyl) -3-methyloctahydronaphthalen-2 (1H) -one, 7,8, 8-trimethyloctahydronaphthalen-2 (1H) -one, 8, 8-dimethyloctahydronaphthalen-2 (1H) -one, 4 a-methyloctahydronaphthalen-2 (1H) -one, 7 a-propyloctahydro-5H-inden-5-one, 3-methylcyclohex-1-one or 5, 5-Dimethyloctahydronaphthalen-2 (1H) -one.

According to any of the above embodiments, the photo-redox catalyst may be a metal complex photo-redox catalyst, a metal-free photo-redox catalyst or an organic dye.

The metal complex photoredox catalyst may be an iridium, copper or ruthenium based complex. In particular, the metal complex photo-redox catalyst may be of formula (VI):

[M(L)(L’)(L”)]Z_n (VI)

wherein M is iridium or ruthenium, L, L 'and L' are each independently of the other optionally substituted by 1 to 6 hydroxy groups, C_1-4Alkyl radical, C_1-32,2' -bipyridine or 2-phenylpyridine substituted with an alkoxy group, a halogen atom, or a halogenated or perhalogenated hydrocarbon; z represents a non-coordinating anion, n is 0 or 1 when M is iridium and n is 2 when M is ruthenium.

"halogenated or perhalogenated hydrocarbon" means a hydrocarbon group substituted with halogen atoms, e.g. CF₃Or CClH₂。

According toAny of the above embodiments; l, L 'and L' may be, independently of one another, optionally substituted by 1 to 4 hydroxyl groups, C_1-4Alkyl radical, C_1-3Alkoxy, halogen atoms or halogenated or perhalogenated hydrocarbon substituted 2,2' -bipyridine or 2-phenylpyridine. In particular L, L 'and L "may be 2,2' -bipyridine or 2-phenylpyridine, optionally substituted with 1 to 4 methyl, methoxy, trifluoromethyl or tert-butyl or fluorine atoms. The appropriate amount of L is preferably selected from the group consisting of, non-limiting examples of L ' and L ' may include 2,2' -bipyridine, 2-phenylpyridine, 4,4' -dimethoxy-2, 2' -bipyridine, 4,4' -di-tert-butyl-2, 2' -bipyridine, 2- (2, 4-difluorophenyl) -5-methoxypyridine, 2- (4-fluorophenyl) -5-methoxypyridine, 5-methyl-2- (p-tolyl) pyridine, 2- (4-fluorophenyl) -5-methylpyridine, 2- (p-tolyl) -5- (trifluoromethyl) pyridine, 2- (4-fluorophenyl) -5- (trifluoromethyl) pyridine or 2- (2, 4-difluorophenyl) -5- (trifluoromethyl) pyridine.

According to any one of the above embodiments; z represents ClO₄ ^-，R’SO₃ ^-Wherein R' is a chlorine or fluorine atom or C₁-C₈Fluoroalkyl or fluoroaryl, BF₄ ^-，PF₆ ^-，SbCl₆ ^-，SbF₆ ^-Or BR'₄ ^-Wherein R' is optionally substituted with one to five groups such as halogen atom or methyl or CF₃A phenyl group substituted with a group. In particular, Z may be BF₄ ^-，PF₆ ^-，ClO₄ ^-，C₆F₅SO₃ ^-，BPh₄ ^-，CF₃SO₃ ^-Or B [3,5- (CF)₃)₂C₆H₄]₄ ^-Even more particularly PF₆ ^-。

According to a particular embodiment, non-limiting examples of suitable photo-redox catalysts may include eosin Y, fluorescein, 2,4,5, 6-tetrakis (9H-carbazol-9-yl) isophthalonitrile (corresponding to 4CzIPN), rose bengal (rose bengal), 10- (3, 5-dimethoxyphenyl) -9-mesitylene (mesityl) -1,3,6, 8-tetramethoxyacridin-10-iumTetrafluoroborate (corresponding to Mes-Acr-4), tris [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-N1, N1']Ruthenium hexafluorophosphate^(II)(corresponding to Ru (bpy)₃(PF₆)₂) Tris [ 2-phenylpyrido-C²,N]Iridium (III)^(III)(corresponding to Ir (ppy)₃) [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-N1, N1']Bis [ 2-pyridyl-N]phenyl-C]Iridium hexafluorophosphate^(III)(corresponding to Ir (ppy)₂(dtbbpy)PF₆) [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-N1, N1']Bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl-N]phenyl-C]Iridium hexafluorophosphate^(III)(corresponds to Ir (dF (CF)₃)ppy)₂(dtbbpy)PF₆) [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-. kappa.N 1,. kappa.N 1']Bis [3, 5-difluoro-2- [5- (methyl) -2-pyridinyl-. kappa.N]Phenyl-kappa C]Iridium hexafluorophosphate^(III)(corresponding to Ir (dF (Me) ppy)₂(dtbbpy)PF₆) [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-. kappa.N 1,. kappa.N 1']Bis [3, 5-difluoro-2- [ 2-pyridinyl-. kappa.N]Phenyl-kappa C]Iridium hexafluorophosphate^(III)(corresponding to Ir (dFppy)₂(dtbbpy)PF₆) Or [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-. kappa.N 1,. kappa.N 1']Bis [ 3-fluoro-5-trifluoromethyl-2- [5- (trifluoromethyl) -2-pyridinyl-. kappa.N]Phenyl-kappa C]Iridium hexafluorophosphate^(III)(corresponds to Ir (FCF)₃(CF₃)ppy)₂(dtbbpy)PF₆),. In particular, the photoredox catalyst may be [4,4' -bis (1, 1-dimethylethyl) -2,2' -bipyridine-N1, N1']Bis [ 2-pyridyl-N]phenyl-C]Iridium hexafluorophosphate^(III)(corresponding to Ir (ppy)₂(dtbbpy)PF₆) Or 2,4,5, 6-tetrakis (9H-carbazol-9-yl) isophthalonitrile (corresponding to 4 CzIPN).

According to any of the above embodiments, the photo-redox catalyst may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As non-limiting examples, values of concentration of the photo-redox catalyst may be cited from about 0.001 mol% to about 10 mol% relative to the amount of carbonyl compound, in particular from about 0.005 mol% to about 5 mol% relative to the amount of carbonyl compound, even more preferably from about 0.01 mol% to about 1 mol% relative to the amount of carbonyl compound. As will be appreciated by those skilled in the art, the optimum concentration of catalyst will depend on the nature of the latter, on the nature of the carbonyl compound, hydrogen atom transfer donor and/or secondary amine, on the reaction temperature and on the desired reaction time.

According to any of the above embodiments, the hydrogen atom transfer donor may be any hydrogen atom transfer donor used in radical chemistry, such as a metal hydride, e.g. a tin, silicon, sulfur, selenium, boron or phosphorus derivative or an organic compound, e.g. malononitrile or a cyclohexadiene derivative, e.g. cyclohexa-1, 4-diene or γ -terpinene.

According to a particular embodiment, the hydrogen atom transfer donor is a sulphur derivative, such as a thiol (thio) compound, in particular an aromatic thiol. In particular, the hydrogen atom transfer donor is a thiophenol derivative of the formula:

wherein each R^aIndependently of one another, represents a hydrogen atom, a halogen atom, C_1-2Straight chain alkyl radical, C_3-4A straight or branched chain alkyl group, optionally substituted by 1 to 5 halogen atoms and/or C_1-4Phenyl substituted by alkyl or alkoxy, or by C_1-4Alkyl or aryl trisubstituted silyl groups. In particular, the thiophenol derivative may be selected from the group consisting of: benzenethiol, 2,4, 6-trimethylbenzenethiol, 2,4, 6-triisopropylbenzenethiol, 2, 6-dimethylbenzenethiol, 2, 6-di-tert-butyl-4-methylphenbenzenethiol, 2, 6-diisopropylbenzenethiol, 2,4, 6-tri-tert-butylphenbenzenethiol, 4-tert-butylmercaptan and 4-fluorobenzenethiol. In particular, the thiophenol derivative may be selected from the group consisting of: benzenethiol, 2,4, 6-trimethylbenzenethiol, 2,4, 6-triisopropylbenzenethiol, 2, 6-dimethylbenzenethiol, 2,4, 6-tri-tert-butylphenbenzenethiol, 4-tert-butylmercaptan and 4-fluorobenzenethiol. In particular, the thiophenol derivative may be selected from the group consisting of: benzenethiol, 2, 6-dimethylbenzenethiol, 2,4, 6-trimethylbenzenethiol, 2, 6-di-tert-butyl-4-methylphenenethiol, 2, 6-diisopropylbenzenethiol, 2,4, 6-triiso-benzenethiolPropylbenzenethiol and 2,4, 6-tri-tert-butylbenzenethiol. Even more particularly, the thiophenol derivative may be thiophenol or 2,4, 6-triisopropylthiophenol. Even more particularly, the thiophenol derivative may be thiophenol.

According to any of the above embodiments, thiophenol may be added to the reaction medium of the process of the present invention in a wide range of concentrations. As a non-limiting example, a thiophenol concentration value may be cited of from about 0.5 mol% to about 50 mol% relative to the amount of carbonyl compound, in particular from about 1 mol% to about 30 mol% relative to the amount of carbonyl compound, even more preferably from about 5 mol% to about 25 mol% relative to the amount of carbonyl compound. As known to those skilled in the art, the optimum concentration of thiophenol will depend on the nature of the latter, on the nature of the aldehyde, olefin, photoredox catalyst and/or secondary amine, on the reaction temperature and on the desired reaction time.

According to any of the above embodiments, the amine is a primary or secondary amine. In particular, the amine is a secondary amine.

The term "primary or secondary amine" is the normal meaning in the art, i.e., for a primary amine, the nitrogen atom is substituted with two hydrogen atoms and one group other than a hydrogen atom, and for a secondary amine, the nitrogen atom is substituted with one hydrogen atom and two groups other than a hydrogen atom.

The secondary amine may be a cyclic or acyclic amine optionally substituted with 1 to 3 halogen atoms or acid or ester groups. The secondary amine may be in the form of an ammonium salt. In particular, the secondary amine may be selected from the group consisting of: pyrrolidine, piperidine, azepane (azepane), 2- (bis (3, 5-bis (trifluoromethyl) phenyl) ((trimethylsilyl) oxy) methyl) pyrrolidine, 2,2, 2-trifluoro-N-methylethyl-1-amine, 2,2, 2-trifluoro-N-methylethyl-1-ammonium chloride, 2,2, 2-trifluoro-N-ethylethane-1-amine, 2,2, 2-trifluoro-N-ethylethane-1-ammonium chloride, bis (2-chloroethyl) amine, bis (2-chloroethyl) ammonium chloride, dimethylamine and dimethylammonium chloride. In particular, the secondary amine may be selected from the group consisting of: pyrrolidine, piperidine, azepane, 2- (bis (3, 5-bis (trifluoromethyl) phenyl) ((trimethylsilyl) oxy) methyl) pyrrolidine, 2,2, 2-trifluoro-N-methylethane-1-amine, 2,2, 2-trifluoro-N-methylethane-1-ammonium chloride, bis (2-chloroethyl) amine, bis (2-chloroethyl) ammonium chloride, dimethylamine and dimethylammonium chloride. Even more particularly, the secondary amine may be pyrrolidine, piperidine, azepane. Even more particularly, the secondary amine can be pyrrolidine or azepane.

According to any of the above embodiments, the secondary amine may be added to the reaction medium of the process of the present invention in a wide range of concentrations. By way of non-limiting example, secondary amine concentration values of from about 0.5 mol% to about 20 mol% relative to the amount of aldehyde, preferably from about 5 mol% to about 15 mol% relative to the amount of aldehyde, may be enumerated. As known to those skilled in the art, the optimum concentration of secondary amine will depend on the nature of the latter, on the nature of the aldehyde, olefin, photo-redox catalyst and/or hydrogen atom transfer donor, on the reaction temperature and on the desired reaction time.

According to any of the above embodiments, the light may have a wavelength in the range of 250nm and 800 nm. In particular, the light may be UV visible light. The light may be generated by an LED lamp or LED strip.

The reaction may be carried out in the presence or absence of a solvent. Any solvent stream of this reaction type can be used for the purposes of the present invention when a solvent is required or used for practical reasons. Solvents with high dielectric constants are preferred. Non-limiting examples of solvents include DMSO, DMPU, DMF, DMA, NMP, acetonitrile, DME, methyltetrahydrofuran, or mixtures thereof. The choice of solvent depends on the nature of the substrate and/or the catalyst and the person skilled in the art is able to select the most suitable solvent in each case in order to optimize the reaction.

The process of the present invention may be carried out at a temperature in the range of 0 ℃ to 50 ℃, more specifically at room temperature. I.e. at about 25 c. Of course, the person skilled in the art will also be able to select the preferred temperature depending on the melting and boiling points of the starting and final products and the desired reaction or conversion time.

The process of the present invention may be carried out under batch or continuous conditions.

Examples

The invention will now be described in more detail by the following examples, wherein the abbreviations have the usual meaning in the art and the temperatures are indicated in degrees Celsius (. degree. C.). NMR spectroscopic data were measured using 400 or 500MHz machines¹H and¹³c in CDCl₃Chemical shifts δ are reported in ppm relative to TMS and coupling constants J are reported in Hz (unless otherwise stated).

Example 1

Isomerization of (4aRS,8RS,8aRS) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one to (4aRS,8RS,8aSR) - 4a, 8-Dimethyloctahydronaphthalen-2 (1H) -ones

To (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC in a Schlenk flask (schlenk) under argon]To a solution of iridium (III) hexafluorophosphate (4mg, 0.004mmol) in DMPU (0.5mL) were added rac- (4aR,8R) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one (7.22g, 38.9mmol, cis/trans ratio 53/47), pyrrolidine (0.14g, 1.92mmol) and benzenethiol (0.42g, 3.85 mmol). The mixture was stirred at room temperature and irradiated under a blue light bar for 24 hours to yield the desired highly isomerized decalones (cis/trans ratio 13/87). The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was over anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. Ball-to-ball distillation gave the desired rac- (4aR,8R) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one (6.45g, 35.77mmol, cis/trans ratio 13/87, yield 92%).

¹H NMR(500MHz,CDCl₃):0.81(d,J＝6.5Hz,3H),0.89-0.98(m,1H),1.04(s,3H),1.08-1.10(m,2H),1.35-1.73(m,7H),2.00(t,J＝15.0Hz,1H),2.26-2.33(m,1H),2.43-2.51(m,2H).

¹³C NMR(125MHz,CDCl₃):212.2(C),50.8(CH),41.5(CH2),41.0(CH2),40.6(CH2),38.1(CH2),35.7(CH2),33.3(C),32.4(CH),21.4(CH2),19.7(CH3),16.0(CH3).

Example 2

Reacting (4aRS,6RS,8aRS) -6-ethyl octahydronaphthalen-2 (1H) -one with isopropylThe structure is (4aRS,6RS,8aSR) -6-ethyl Octahydronaphthalen-2 (1H) -ones

To (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC]To a solution of iridium (III) hexafluorophosphate (11mg, 0.01mmol) in DMPU (1mL) were added rac- (4aR,6R,8aR) -6-ethyldecalin-2-one (3.57g, 19.82mmol, cis/trans ratio 86/14), pyrrolidine (76mg, 1.07mmol) and 2,4, 6-triisopropylbenzenethiol (481mg, 2.03 mmol). The mixture was stirred at room temperature and irradiated under blue light (Kessil Lamp) for 8 hours to yield highly isomerized decalones (cis/trans ratio 2/98). The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was over anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. Column chromatography on silica gel (heptane/EtOAc 95/5 aS eluent) and ball-to-ball distillation gave the desired rac- (4aR,6R,8aS) -6-ethyldecalin-2-one (2.50g, 12.89mmol, cis/trans ratio 2/98, yield 65%).

¹H NMR(500MHz,CDCl₃):0.62-0.70(m,1H),0.84-0.93(m,1H),0.89(t,J＝7.4Hz,3H),1.08-1.17(m,1H),1.21-1.45(m,6H),1.65-1.72(m,1H),1.74-1.82(m,2H),1.93-1.98(m,1H),2.05(t,J＝13.3Hz,1H),2.26-2.41(m,3H).

¹³C NMR(125MHz,CDCl₃):211.9(C),48.5(CH2),43.4(CH),41.5(CH2),41.4(CH),39.3(CH),39.0(CH2),34.1(CH2),33.6(CH2),31.9(CH2),29.8(CH2),11.5(CH3).

Example 3

Isomerization of (4aRS,8aSR) -octahydronaphthalen-2 (1H) -one to (4aRS,8aRS) -octahydronaphthalen-2 (1H) -one

To a solution of (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC ] iridium (III) hexafluorophosphate (4.7mg, 0.005mmol) in DMPU (2mL) was added octahydronaphthalen-2 (1H) -one (76.6mg, 0.50mmol, cis/trans ratio 79/21), pyrrolidine (7.1mg, 0.10mmol) and benzenethiol (11mg, 0.10 mmol). The mixture was stirred at room temperature and irradiated under a blue light bar for 24 hours to give highly isomerized octahydronaphthalen-2 (1H) -one to a cis/trans ratio of 4/96.

¹³C NMR(90MHz,CDCl₃):211.3(C),48.7(CH2),43.5(CH),41.8(CH),41.6(CH2),34.3(CH2),33.7(CH2),32.8(CH2),26.2(CH2),25.7(CH2).

Example 4

Isomerization of (4aSR,8aRS) -5, 5-dimethyloctahydronaphthalen-2 (1H) -one to (4aSR,8aSR) -5, 5-dimethyl Octahydronaphthalen-2 (1H) -ones

To (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC under argon]To a solution of iridium (III) hexafluorophosphate (7.8mg, 0.008mmol) in DMPU (5mL) were added rac- (4aR,8aS) -5, 5-dimethyldecalin-2-one (4.0g, 22.2mmol, cis/trans ratio 97/3), pyrrolidine (0.16g, 2.2mmol) and 2,4, 6-triisopropylbenzenethiol (0.52g, 2.2 mmol). The mixture was stirred at room temperature and irradiated in a Merck photoreactor for 24 hours under blue light to yield highly isomerized decalones (cis/trans ratio 7/93). The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was over anhydrous MgSO₄Dried, filtered and concentrated under reduced pressure. Column chromatography on silica gel (eluent heptane/MTBE 98/2) gave the desired rac- (4aR,6R,8aS) -6-ethyldecalin-2-one (2.14g, 11.9mmol, cis/trans ratio 1/99, yield 53%).

¹H NMR(400MHz,CDCl₃):0.81(s,3H),0.98(s,3H),1.00-1.70(m,9H),2.02(t,J＝13Hz,1H),2.07-2.12(m,1H),2.25-2.43(m,3H).

¹³C NMR(100MHz,CDCl₃):211.7(C),50.2(CH),49.1(CH2),42.0(CH2),41.8(CH2),38.5(CH),35.3(CH2),33.1(C),30.6(CH3),26.9(CH2),21.8(CH2),19.9(CH3).

Example 5

The isomerization of (4aRS,8RS,8aRS) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one to (4aRS, 8RS,8aSR) -4a, 8-dimethyl octahydronaphthalen-2 (1H) -one

The isomerization was carried out as described in example 1.

Table 1: isomerization Using various amines

Item(s)	Amines as pesticides	Cis/trans
			1	Azepanes as pharmaceutical agents	12/88
2	Piperidine derivatives	32/68
			3	Pyrrolidine as a therapeutic agent	12/88
4	-	53/47

Example 6

(4aRS,8RS,8aRS) -4a, 8-dimethyloctahydronaphthalene-2 using various inorganic photoredox catalysts (1H) Isomerization of ketones to (4aRS,8RS,8aSR) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one

The isomerization was carried out as described in example 1.

Table 2: isomerization using various inorganic photoredox catalysts

Example 7

(4aRS,8RS,8aRS) -4a, 8-dimethyloctahydronaphthalene-2 using various organic photoredox catalysts (1H) Isomerization of ketones to (4aRS,8RS,8aSR) -4a, 8-dimethyloctahydronaphthalen-2 (1H) -one

The isomerization was carried out as described in example 1.

Table 3: isomerization using various organic photoredox catalysts

Example 8

Isomerization of (4aRS) -8, 8-dimethyloctahydronaphthalen-2 (1H) -one to (4aRS,8aRS) -8, 8-dimethyloctahydro Naphthalen-2 (1H) -ones

To a solution of (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC ] iridium (III) hexafluorophosphate (2.5mg, 0.003mmol) in DMPU (1mL) was added (4aR) -8, 8-dimethyloctahydronaphthalen-2 (1H) -one (901.5mg, 5mmol, cis/trans ratio 19/81), pyrrolidine (17.8mg, 0.25mmol) and benzenethiol (55.1mg, 0.5 mmol). The mixture was stirred at room temperature and irradiated with a Kessil Blue lamp for 24 hours. The crude reaction mixture was diluted with water and extracted with MTBE. The organic layer was dried over anhydrous magnesium sulfate and concentrated with a rotary evaporator. The crude product was distilled to give (4aRS,8aRS) -8, 8-dimethyloctahydronaphthalen-2 (1H) -one to cis/trans ratio 2/98(840mg, 4.66mmol, yield 93%).

¹³C NMR(125MHz,CDCl₃):213.0(C),51.8(CH),42.1(CH2),41.5(CH2),41.3(CH2),36.2(CH),34.2(CH2),33.6(CH2),33.4(C),29.9(CH3),21.6(CH2),19.6(CH3).

Example 9

Isomerization of (7aSR) -7 a-propyloctahydro-5H-inden-5-one to (3aRS,7aSR) -7 a-propaneoctahydro-5H-indene- 5-ketones

To a solution of (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC ] iridium (III) hexafluorophosphate (3.7mg, 0.004mmol) in DMPU (1mL) was added (7aS) -7 a-propyloctahydro-5H-inden-5-one (1.00g, 5.55mmol, cis/trans ratio 56/44), pyrrolidine (32mg, 0.45mmol) and thiophenol (73mg, 0.66 mmol). The mixture was stirred at room temperature and irradiated with a Kessil Blue lamp for 24 hours. The crude reaction mixture was diluted with water and extracted with MTBE. The organic layer was dried over anhydrous magnesium sulfate and concentrated with a rotary evaporator. The crude product was distilled to give (3aRS,7aSR) -7 a-propyloctahydro-5H-inden-5-one to cis/trans ratio 99/1(800mg, 4.44mmol, yield 80%).

¹³C NMR(125MHz,CDCl₃):214(C),45.5(CH),42.7(C),42.3(CH2),41.9(CH2),37.1(CH2),36.5(CH2),32.6(CH2),30.4(CH2),22.4(CH2),18.0(CH2),15.0(CH3).

Example 10

Racemization of (R) -3-methylcyclohex-1-ones to 3-methylcyclohex-1-ones

In a glass vial, pyrrolidine (18.9mg, 0.26mmol), benzenethiol (57.8mg, 0.52mmol), (R) -3-methylcyclohexan-1-one (562.4mg, 5.01mmol, ee > 99%) and a solution of (4,4 '-di-tert-butyl-2, 2' -bipyridine) bis [2- (2-pyridyl-kN) phenyl-kC ] iridium (III) hexafluorophosphate (2.4mg, 0.003mmol) in DMPU (1mL) were combined. The mixture was stirred at room temperature and irradiated with a Kessil Blue lamp for 24 hours. GC analysis using a chiral column (Mega Dex DET Beta) showed that racemic 3-methylcyclohex-1-one was obtained.