Manganese catalyzed ester hydrogenation
阅读说明：本技术 锰催化的酯氢化 (Manganese catalyzed ester hydrogenation ) 是由 马格努斯·魏德格林 马修·李·克拉克 于 2019-01-08 设计创作，主要内容包括：本发明涉及催化氢化领域,并且更特别地涉及将酯氢化为醇的锰催化的氢化方法。有利地,在酯是手性的情况下,氢化以高的或完全的立体化学完整性进行。(The present invention relates to the field of catalytic hydrogenation and more particularly to a manganese catalyzed hydrogenation process for hydrogenating esters to alcohols. Advantageously, in the case of chiral esters, the hydrogenation is carried out with high or complete stereochemical integrity.)
1. a process comprising hydrogenating an ester in the presence of (I) a base, (ii) hydrogen, and (iii) a catalyst, wherein the conjugate acid of the base has a pKa of 6.4 to 14, the catalyst comprising a charged or neutral complex of formula (I):
wherein:
mn is a manganese atom or a manganese ion in oxidation states (I) to (VII);
R1and R2Each independently is C1-20A hydrocarbyl or heterocyclyl moiety, optionally substituted one or more times with substituents selected from the group consisting of: halogen, aliphatic C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido;
-Fc-represents ferrocene (bis (η)5-cyclopentadienyl) iron) moiety which is covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties and which may be further substituted one or more times in either cyclopentadienyl ring optionally by substituents selected from the group consisting of: halogen, aliphatic C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido;
-Z-is of the formula- (CH)2)1-6An alkylene linking group of (a) whereinOne or more hydrogen atoms in the alkylene group may be independently substituted with an alkyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, or mercapto substituent;
-Nxis a nitrogen containing amino, imino or heteroaryl moiety; and is
L1-L3Form one, two or three ligands, wherein L1-L3Each independently represents a monodentate neutral or anionic ligand; or L1-L3Represents a monodentate neutral or anionic ligand and L1-L3Together represent a bidentate neutral or anionic ligand; or L1-L3Together represent a tridentate neutral or anionic ligand,
wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counter-ions to balance the charge of the complex.
2. The method of claim 1, wherein the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, calcium hydroxide, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, and tertiary amines.
3. The method of claim 1 or claim 2, wherein the conjugate acid of the base has a pKa of 10.3 to 14.
4. The method of claim 3, wherein the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, and calcium hydroxide.
5. The method of claim 4, wherein the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate and cesium carbonate.
6. The process according to any one of claims 1 to 5, wherein Mn is a manganese ion in oxidation state (I) or (II).
7. The method of claim 6, wherein the manganese ion is in oxidation state (I).
8. The method of any one of claims 1 to 7, wherein R1And R2Each independently is optionally substituted C1-10A hydrocarbyl or monocyclic heteroaryl moiety.
9. The method of claim 8, wherein R1And R2Each independently is optionally substituted C5-10A cycloalkyl, monocyclic aryl or monocyclic heteroaryl moiety.
10. The method of claim 9, wherein R1And R2Each independently is an optionally substituted phenyl, furyl or cyclohexyl moiety.
11. The method of any one of claims 1 to 10, wherein R1And R2Independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c1-6Alkyl radical, C1-6Alkoxy, halo and trihalomethyl.
12. The method of claim 11, wherein R1And R2Independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c1-6Alkyl and C1-6An alkoxy group.
13. The method of any one of claims 1 to 12, wherein R1And R2Are the same.
14. The method of claim 13, wherein R1And R2Both of which are 4-methoxy-3,5-dimethylphenyl, phenyl, 4-methoxy-3, 5-di-tert-butylphenyl, 3, 5-dimethylphenyl, 3, 5-di (tert-butyl) phenyl, furyl or cyclohexyl.
15. A process according to any one of claims 1 to 14, wherein one or more carbon atoms of any one cyclopentadienyl ring of the ferrocene moiety, other than the point of attachment of the ferrocene to the remainder of the complex of formula (I), is independently optionally halogenated or C1-6Alkyl substituents.
16. A process according to any one of claims 1 to 14, wherein the cyclopentadienyl ring of the ferrocene moiety is not substituted except through the point of attachment of the ferrocene to the remainder of the complex of formula (I).
17. The method of any one of claims 1 to 16, wherein-Z-has the formula- (CH)2)-、-(CHR3) -or- (CH)2)2-, wherein R3Is an alkyl, aryl, heteroaryl, hydroxyl, nitro, amino, alkoxy, alkylthio or mercapto substituent.
18. The method of claim 17, wherein-Z-has the formula- (CH)2)-、-(CHR3) -or- (CH)2)2-, wherein R3Is C1-6Alkyl substituents or optionally substituted by C1-6Alkyl and/or phenyl substituted one or more times by halo.
19. The method of claim 17, wherein-Z-has the formula- (CH)2)-、-(CHR3) -or- (CH)2)2-, wherein R3Is methyl or optionally substituted by C1-6Alkyl and/or phenyl substituted one or more times by halo.
20. The method of any one of claims 1 to 19, wherein-Z-is unsubstituted.
21. The method of claim 20, wherein-Z-has the formula- (CH)2) -or- (CH)2)2-。
22. The method of claim 21, wherein-Z-has the formula- (CH)2)-。
23. The method of any one of claims 1 to 7, wherein R of the complex1R2P-Fc-CH (Me) -NH-is 1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino]-2- [1- (HN) ethyl]Ferrocene; 1- [1- (HN) ethyl]-2- (diphenylphosphino) ferrocene; 1- [ bis (4-methoxy-3, 5-di-tert-butylphenyl) phosphino group]-2- [1- (HN) ethyl]Ferrocene; 1- (Difuranylphosphino) -2- [1- (HN) ethyl]Ferrocene; 1- [ bis [3, 5-bis (trifluoromethyl) phenyl]Phosphine group]-2- [1- (HN) ethyl]Ferrocene or 1- (dicyclohexylphosphino) -2- [1- (HN) ethyl]Ferrocene.
24. The method of claim 23, wherein R of the complex1R2P-Fc-CH (Me) -NH-is (S) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino]-2- [ (R) -1- (HN) ethyl]Ferrocene, (R) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino]-2- [ (S) -1- (HN) ethyl]Ferrocene or mixtures thereof; (S) -1- [ (R) -1- (HN) ethyl]-2- (diphenylphosphino) ferrocene, (R) -1- [ (S) -1- (HN) ethyl]-2- (diphenylphosphino) ferrocene or a mixture thereof; (S) -1- [ bis (4-methoxy-3, 5-di-tert-butylphenyl) phosphino]-2- [ (R) -1- (HN) ethyl]Ferrocene, (R) -1- [ bis (4-methoxy-3, 5-di-tert-butylphenyl) phosphino]-2- [ (S) -1- (HN) ethyl]Ferrocene or mixtures thereof; (S) -1- (Difuranylphosphino) -2- [ (R) -1- (HN) ethyl]Ferrocene, (R) -1- (difurylphosphino) -2- [ (S) -1- (HN) ethyl]Ferrocene or mixtures thereof; (S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl]Phosphine group]-2- [ (R) -1- (HN) ethyl]Ferrocene, (R) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl group]Phosphine group]-2- [ (S) -1- (HN) ethyl]Ferrocene or mixtures thereof; or (S) -1- (dicyclohexylphosphino) -2- [ (R) -1- (HN) ethyl]Ferrocene, (R) -1- (dicyclohexylphosphino) -2- [ (S) -1- (HN) ethyl]Ferrocene or mixtures thereof.
25. The method of any one of claims 1 to 24, wherein-NxIs a heterocyclyl ring, optionally substituted one or more times with one or more substituents independently selected from the group consisting of: amino, halo, C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido.
26. The method of claim 25, wherein said heterocyclyl ring is optionally substituted one or more times with one or more substituents independently selected from the group consisting of: amino, halo, C1-6Alkyl groups and aryl groups.
27. The method of claim 25 or claim 26, wherein the heterocyclyl ring is a pyridyl, indolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, quinoxalinyl, pyridazinyl, triazolyl, triazinyl, imidazolidinyl, or oxadiazolyl ring.
28. The method of claim 27, wherein the heterocyclyl ring is a pyridyl, indolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, quinoxalinyl, pyridazinyl, or triazolyl ring.
29. The method of claim 28, wherein said heterocyclyl ring is a monocyclic heteroaryl ring.
30. The method of claim 29, wherein-NxIs pyridine optionally substituted one or more times by amino substituentsA pyridyl ring.
31. The method of claim 30, wherein the amino substituent is substituted with two cs1-6Tertiary amino substituted with alkyl substituents.
32. The method of claim 31, wherein the two cs1-6The alkyl substituents are the same and are selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.
33. The method of claim 30, wherein-NxIs a pyridyl or 4-dimethylaminopyridyl ring substituted with Z at the carbon atom adjacent to the ring nitrogen atom of the pyridyl ring.
34. The method of claim 33, wherein-NxIs 2-pyridyl or 4-dimethylaminopyridin-2-yl.
35. The method of any one of claims 1 to 34, wherein the one, two or three ligands L1-L3Each selected from the group consisting of: (i) a neutral ligand selected from the group consisting of: carbon monoxide, nitric oxide, amines, ethers, thioethers, sulfoxides, nitriles (RCN), isocyanides (RNC), phosphorus-containing ligands based on phosphorus (III) or phosphorus (V), and water; and (ii) an anionic ligand selected from the group consisting of: halide ions, alkoxide ions, anions of carboxylic, sulfonic and phosphoric acids, amido ligands, thiolate ions, phosphide ions, cyanide, thiocyanate, isothiocyanate, and enolate ions.
36. The method of claim 35, wherein L1-L3Three ligands selected from neutral monodentate ligands are constituted.
37. According to claim 36The method of (a), wherein L1-L3Are identical.
38. The method of claim 37, wherein L1-L3Each of which is carbon monoxide.
39. The process of any one of claims 1 to 38, wherein, when the catalyst comprises one or more additional counter ions selected from the group consisting of: halide ion, tetraarylborate, SbF6 -、SbCl6 -、AsF6 -、BF4 -、PF6 -、ClO4 -And CF3SO3 -。
40. The method of claim 39, wherein the additional counter ion is selected from the group consisting of: halide ion, SbF6 -、SbCl6 -、AsF6 -、BF4 -、PF6 -、ClO4 -、CF3SO3 -、[B{3，5-(CF3)2C6H3}4]-、[B{3，5-(CH3)2C6H3}4]-、[B(C6F5)4]-And [ B (C)6H5)4]-。
41. The method of claim 40, wherein the complex has a single positive charge and the catalyst further comprises a halide or tetraarylborate counter anion.
42. The method of claim 41, wherein the counter anion is bromide ion or [ B {3, 5- (CF)3)2C6H3}4]-。
43. The process of any one of claims 1 to 5, wherein the catalyst has one of the following formulae:
or a mixture thereof;
or a mixture thereof;
or a mixture thereof;
or a mixture thereof;
or a mixture thereof;
or a mixture thereof.
44. The process of any one of claims 1 to 5, wherein the catalyst has one of the following formulae:
or a mixture thereof;
or a mixture thereof;
or a mixture thereof.
45. The method of claim 43 or claim 44, wherein the mixture is a racemic mixture.
46. The method of any one of claims 1 to 45, wherein the ester is photoactive.
47. The method of claim 46, wherein the ester comprises a stereocenter adjacent to a carbonyl of the ester.
48. The method of claim 46, wherein the ester is sclareolide having the formula
49. A process according to any one of claims 46 to 48 wherein the enantiomeric excess of the photoactive ester is maintained or reduced by hydrogenation to no more than 10%.
50. A process for the preparation of ambrox, the process comprising hydrogenating sclareolide by a process as defined in claim 48 or claim 49, followed by cyclization of the resulting diol (ambroxol), thereby providing ambrox.
Technical Field
The present invention relates to the field of catalytic hydrogenation, and more particularly to a manganese catalyzed process for the hydrogenation of esters to alcohols. Advantageously, in the case of chiral esters, the hydrogenation is carried out with a high or complete stereochemical integrity.
Statement regarding prior disclosure of conjunctive inventors
M B Widegren, G J Harkness, AM Z Slawin, D B cores, and M L Clarke (angle. chem. iht. ed., 56, 5825-one 5828(2017)) describe the use of hydrogenation catalysts based on manganese complexes of chiral P, N ligands in the hydrogenation of esters and enantioselective hydrogenation of prochiral ketones.
Background
The reduction of carbonyl-containing compounds to alcohols (e.g., ketones and esters to alcohols) is a fundamental transformation of organic chemistry and is an integral part of the synthesis of many industrial products, including fragrances, pharmaceuticals, and fine chemicals. Conventional methods of ester reduction involve reaction of the ester with usually at least two equivalents of a metal or semi-metal hydride. Examples of hydride sources include lithium aluminum hydride, diisobutylaluminum hydride, and in some cases sodium borohydride. Such agents are inherently unsafe, have low atomic economics, and are high cost.
The use of molecular hydrogen to catalyze the hydrogenation of esters is an attractive alternative, providing potential cost savings and environmental advantages, for example, by achieving at least the potential of a 100% atom economy. However, although the development of ruthenium catalysts for the reduction of ketones to alcohols (particularly in the case of stereochemical control) (earned the nobel prize in 2001) is a mature technology, the catalytic hydrogenation of esters is more challenging due to the relatively lower polarity of the ester carbonyl compared to the ketone and aldehyde carbonyl.
Typical heterogeneous hydrogenation precatalysts include Raney nickel (Raney nickel) and copper chromite, which require harsh reaction conditions. In contrast, S Werkmeister et al (org. process res. dev., 18, 289-302(2014)) reviews the use of homogeneous catalysis, which is generally believed to allow the use of lower reaction temperatures and hydrogen pressures, resulting in higher selectivities.
In homogeneously catalyzed ester hydrogenations, ruthenium complexes are often used as precatalysts, which are stabilized by a variety of ligands. For example, ruthenium catalysts have been reported in patent publications WO 2006/106484 a1 and WO 2006/106484 a1 (both Firmenich SA) and WO2013/171302 a1(Givaudan SA) for catalyzing the reduction of esters to their corresponding alcohols, each of which discloses the use of catalytic amounts of sodium or potassium methoxide for catalyst reformation. Indeed, most of the literature relating to the catalytic hydrogenation of esters teaches the use of strong alkoxide bases (such as these) to activate the precatalyst to a sensitive metal hydride which facilitates the reduction.
There have been some reports on the synthesis and use of catalysts in which additional steps have been carried out to prepare metal hydrides so that subsequent hydrogenation can be carried out without the use of strong alkoxide bases. An example of such a strategy is described by J Zhang et al (angelw. chem. iht. ed., 118, 1131-. In this regard, it has been reported that, under relatively mild neutral conditions, the ruthenium hydride complex is an effective ester hydrogenation catalyst, wherein no additives are required.
M Ito et al (J.Am.chem.Soc., 133, 4240-4242(2011)) describe the use of less than and less than stoichiometric amounts of potassium t-butoxide bases in the hydrogenation of chiral esters having stereocenters using ruthenium containing catalysts. In particular, the authors believe that this may lead to reversible deprotonation in substrates with relatively acidic C-H bonds, which may lead to racemization of chiral non-racemic substrates with a tertiary stereocenter at the α -carbon atom. Such epimerization of the stereocenter is described as allowing enantioselective hydrogenation by dynamic kinetic resolution.
Kuryama et al (adv. synth. cat., 352, 92-96(2010)) reported how to use a reported high activity ruthenium catalyst (RuCl)2(Aminobisphosphine)2) In view of the earlier reports of catalytic hydrogenation of ketones without addition of bases, RuH (η) was used (η)1-BH4) (bisphosphine) (diamine) and RuH (η)1-BH4) (Aminobisphosphine)2Complexes of RuCl treated with 25 equivalents of sodium borohydride2Conversion of (bisphosphine) (diamine) to the corresponding RuH (η)1-BH4) (bisphosphine) (diamine). The complex is then used at a relatively high catalyst loading (such as 1 mol%).
Subsequently, some of the same authors reported an alternative chemical process for the hydrogenation of (R) -methyl lactate using a specific ruthenium catalyst (w.kuriyama et al (org.process res.devel., 16, 166-171(2012))) to provide (R) -1, 2-propanediol with high optical purity. In this publication, the process again involves the use of a strong base (sodium methoxide). In order to avoid a drastic loss of optical purity, which occurs when the reaction is carried out at 80 ℃, temperatures of 30 ℃ and 40 ℃ are reported.
Similar to the 2010 publication by W.Kuriyama et al (vide supra), S Werkmeister et al (Angew.chem.int.Ed., 53, 8722-8726(2014)) describe preactivated FeH (η) comprising pincer-type PNP ligands1-BH4) The complexes are useful for reducing achiral esters to their corresponding alcohols. Such activated complexes, like the corresponding ruthenium complexes, often involve the use of excess hydride reagent during synthesis.
Other metals that have been described in connection with the catalytic hydrogenation of esters include the third row transition metals iridium and osmium. Dspayuk et al (j.am. chem. soc., 137, 3743-3746(2015)) describe the use of specific osmium catalysts in the hydrogenation of unsaturated esters in conjunction with various bases. The reaction is described as exhibiting chemoselectivity (i.e., towards the ester functionality relative to the carbon-carbon double bond present in the ester being hydrogenated).
X Yang et al (chem. sci., 8, 1811-one 1814(2017)) reported that an iridium hydride complex comprising a tridentate spiropyridine-aminophosphine ligand in combination with potassium or sodium tert-butoxide is used for the asymmetric hydrogenation of racemic α -substituted lactones to chiral diols. Similar to the chemical process described by M Ito et al (see above), the asymmetry of hydrogenation is due to dynamic kinetic resolution in view of the racemic starting material. The authors report that the use of potassium hydroxide, sodium hydroxide or potassium carbonate results in low yields, as opposed to reactions involving the use of potassium or sodium tert-butoxide.
As mentioned above, MB Widegren et al (vide supra) describe the use of hydrogenation catalysts based on manganese complexes of chiral P, N ligands for the hydrogenation of esters and the enantioselective hydrogenation of prochiral ketones. Although the use of potassium phosphate and potassium carbonate in connection with the reduction of ketones is described, all reported examples of ester hydrogenation involve the use of potassium tert-butoxide as base.
S.elangovan et al (angelw. chem.iht. ed., 55, 15364-15368(2016)) reported that manganese complexes stabilized by pincer-type PNP ligands in combination with catalytic amounts of potassium tert-butoxide are used for the hydrogenation of achiral esters to their corresponding alcohols.
Van Putten et al (angelw. chem. int. ed., 56, 7531-7534(2017)) reported non-clamp manganese complexes stabilized by PN ligands. Again, the hydrogenation reported is carried out in the presence of catalytic amounts of potassium tert-butoxide. Other bases tested gave much poorer conversion or no conversion.
Ruthenium, iridium and osmium are rare, expensive and potentially toxic metals, and therefore, it will generally be preferable to use catalysts based on earth-rich, cheaper and more environmentally friendly metals such as iron or manganese. However, as just described, such catalysts require pre-activation to effect ester hydrogenation without the use of a base, where such catalysts are typically less active, less stable and more complex to prepare, or (as is customary in the art) used in combination with extremely strong bases (typically with metal alkoxides such as potassium t-butoxide, which is expensive and incompatible with certain substrates). However, since the carbon atom of the carbonyl group in the ester is less electrophilic, it is not easy to develop a new catalyst for the hydrogenation of esters (as opposed to ketones).
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.
Summary of The Invention
Surprisingly, we have found that the use of the specific manganese-based catalysts described herein allows the hydrogenation of esters to be achieved at a variety of temperatures and in a variety of solvents, but without the need to use extremely strong bases (particularly metal alkoxides such as sodium methoxide, sodium tert-butoxide and sodium potassium tert-butoxide) in conjunction with other catalysts, particularly but by no means limited to those based on ruthenium. Furthermore, the surprising ability to avoid the use of strong bases in these hydrogenations means that an optically active substrate susceptible to racemization via deprotonation of a relatively acidic C-H bond (e.g. alpha to the carbonyl moiety) can undergo hydrogenation of the ester functionality therein at least with less disruption to optical purity than the corresponding reaction in which strong bases have been used hitherto. Accordingly, the present invention is useful in the art.
Thus viewed from a first aspect the invention provides a process comprising hydrogenating an ester in the presence of (I) a base, the conjugate acid of which base has a pKa of from 6.4 to 14, (ii) hydrogen and (iii) a catalyst comprising a charged or neutral complex of formula (I):
wherein:
mn is a manganese atom or a manganese ion in oxidation states (I) to (VII);
R1and R2Each independently is C1-20A hydrocarbyl or heterocyclyl moiety, optionally substituted one or more times with substituents selected from the group consisting of: halogen, aliphatic C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido;
-Fc-represents ferrocene (bis (η)5-cyclopentadienyl) iron) moiety, which is covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and which may optionally be interrupted in either cyclopentadienyl ring by substituents selected from the group consisting ofOne-step substitution or more times: halogen, aliphatic C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido;
-Z-is of the formula- (CH)2)1-6-an alkylene linking group of (a), wherein one or more hydrogen atoms in the alkylene can be independently substituted with an alkyl, aryl, heteroaryl, hydroxyl, nitro, amino, alkoxy, alkylthio, or mercapto substituent;
-Nxis a nitrogen containing amino, imino or heteroaryl moiety; and is
L1-L3Form one, two or three ligands, wherein L1-L3Each independently represents a monodentate neutral or anionic ligand; or L1-L3Represents a monodentate neutral or anionic ligand and L1-L3Together represent a bidentate neutral or anionic ligand; or L1-L3Together represent a tridentate neutral or anionic ligand,
wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counter-ions to balance the charge of the complex.
Further aspects and embodiments of the invention will be apparent from the following detailed discussion of the invention.
Detailed Description
Throughout this specification the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The term "about" (particularly with respect to a given amount) is intended to encompass a deviation of ± 5%. For example, both 0.95 and 105 are intended to fall within the indicated range of about 1 to about 100.
According to the process of the present invention, a particular catalyst is used to catalyze the hydrogenation of esters in the presence of a weak base. The expression "for catalyzing" in this context means that the catalyst is used for using molecular hydrogen (H)2) The hydrogenation reaction is promoted in a less than stoichiometric amount (relative to the ester substrate being hydrogenated), i.e., the catalyst is present in an amount less than 1 molar equivalent (100 mol%) relative to the ester.
The expression "for catalyzing" does not require that the catalyst in contact with the ester is the actual catalytic species, but simply that the catalyst be used to promote the hydrogenation reaction. Thus, the catalyst defined in connection with the practice of the present invention may be a so-called precatalyst, which may be converted to the actual catalytic species during the course of the hydrogenation reaction.
The catalyst which can be used in combination with the process of the present invention can be prepared, for example, by mixing, in the same reaction vessel in which the hydrogenation of the present invention is carried out, a manganese salt and another ligand or ligands suitable for forming a catalyst comprising a complex of formula (I). This is an example of an in situ preparation method. Alternatively, the catalyst may be prepared ex situ by first forming an isolatable complex (which may optionally be isolated) and then used as the catalyst in the process of the invention. Thus, such ex situ prepared catalysts may be considered to be well-defined, the term well-defined herein referring to a compound that has been isolated (as that term is commonly used in the art) so as to be readily characterized (i.e., defined) and analyzed (e.g., to determine its structure and purity). In contrast, a catalyst that is not specifically defined is a catalyst that is prepared without separation from the medium (e.g., reaction medium) in which the catalyst is prepared (e.g., an in situ prepared catalyst).
Typical sub-stoichiometric amounts of catalyst that may be used according to the invention will range from about 0.001 to about 10 mol%, for example from about 0.01 to about 5 mol%, usually from about 0.05 to about 2 mol%, relative to the molar amount of ester substrate. It will be appreciated that a greater amount of catalyst will generally accelerate (i.e., promote to a greater extent) the hydrogenation reaction and thus the hydrogenation reaction can be routinely optimized by the normal ability of the skilled artisan by adjusting the amount of catalyst used (as well as other characteristics of the hydrogenation reaction described herein, such as the concentration of ester in the reaction medium).
In connection with the present invention, the following definitions apply unless a specific context clearly suggests to the contrary, and such definitions are to be considered as confirming the general understanding of the person skilled in the art. Without explicitly defining the meaning of a particular functional group as used herein, such terms are intended to be understood by those of ordinary skill in the art, as generally evidenced by publications of the organic chemistry department of the international union of applied chemistry, entitled "Global of class names of organic compounds and reactive intermediates based on Structure" (Pure & applied. chem., 67(8/9), 1307-.
C1-20The hydrocarbon group means an aliphatic or aromatic group containing a hydrogen atom and 1 to 20 carbon atoms. In the case of aliphatic, the hydrocarbyl group may be straight or branched chain, and/or contain one or more sites of unsaturation (e.g., one or more carbon-carbon double or triple bonds). E.g. C1-6The hydrocarbyl moiety may be C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or C3-6A cycloalkyl moiety. Alternatively or additionally, the hydrocarbyl moiety may be cyclic, or a portion of its structure may be cyclic. For example, cyclohexylmethyl and cyclohexenylmethyl are aliphatic C7Two examples of hydrocarbyl groups.
Typically (but not necessarily), the hydrocarbyl moiety described herein is saturated and aliphatic, i.e., it is linear and/or branched, cyclic, or contains one or more cyclic moieties within a linear or branched structure.
Heterocyclyl means a monovalent group formally formed by abstraction of a hydrogen atom from any ring atom of a heterocyclic compound (which may be heteroaromatic). Typically, the heterocyclyl moieties herein are based on mono-, bi-or tricyclic heterocycles, typically monocyclic heterocycles.
"halide" means fluoride, chloride, bromide or iodide, typically chloride, bromide or iodide. Similarly halo represents fluoro, chloro, bromo or iodo, typically chloro, bromo or iodo.
Typically (but not necessarily), trihalomethyl represents trifluoromethyl.
Aryl represents a monovalent group formally formed by abstraction of one hydrogen atom from an aromatic moiety (used synonymously herein with the term arene, to denote a mono-or polycyclic aromatic hydrocarbon). Similarly, heteroaryl represents a monovalent group formally formed by abstraction of one hydrogen atom from a heteroaromatic moiety (used synonymously herein with the term heteroarene, used to refer to mono-or polycyclic heteroaromatic hydrocarbons).
Unless the context specifically indicates to the contrary, aryl is typically a monocyclic group (e.g., phenyl), but the term aryl also includes bicyclic aryl (such as naphthyl) and tricyclic aryl (such as phenanthryl and anthracyl). References to aromatic herein are to be interpreted analogously, i.e. in the absence of an explicit indication to the contrary, to mean a monocyclic aromatic group.
As known to those skilled in the art, heteroaromatic moieties are formally derived from aromatic moieties by substitution of one or more (usually one or two) heteroatoms (typically O, N or S) to replace one or more carbon atoms along with any hydrogen atoms to which they are attached. Exemplary heteroaromatic moieties include pyridine, furan, pyrrole, and pyrimidine. Further examples of heteroaromatic rings include pyridazine (wherein two nitrogen atoms are adjacent in an aromatic 6-membered ring); pyrazines (wherein the two nitrogens are in the 1, 4-positions in a 6-membered aromatic ring); pyrimidines (in which two nitrogen atoms are in the 1, 3-positions in a 6-membered aromatic ring); or 1, 3, 5-triazines (in which three nitrogen atoms are in the 1, 3, 5-positions in a 6-membered aromatic ring).
Unless the context specifically indicates to the contrary, heteroaryl is typically a monocyclic group (e.g., pyridyl), but the term heteroaryl also includes bicyclic heteroaryl (e.g., such as indolyl). References herein to a heteroaromatic group should be interpreted analogously, i.e. in the absence of an explicit indication to the contrary, to mean a monocyclic heteroaromatic group.
Amino herein means the formula-N (R)4)2Wherein each R4 independently represents hydrogen or C1-6Alkyl or heteroaryl, or two R4The moieties together forming an alkylene (alkylene dirad)ical, also known as alkanediyl), which formally originates from an alkane from which two hydrogen atoms have been extracted, typically from terminal carbon atoms, thereby forming a ring together with the nitrogen atom of the amine. At R4Other than hydrogen (including two of R)4Those embodiments where the moieties together form an alkylene group), one or more of its carbon atoms may be optionally substituted one or more times with one or more substituents independently selected from the group consisting of: halo, C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, amino, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido and sulfonamido, more typically the optional substituents are selected from the group consisting of: halo, C1-6Hydrocarbyl, trihalomethyl, aryl and heteroaryl.
Typically, except where-NxIs amino, amino in this context denotes-N (R)4)2Wherein each R is4Independently represent hydrogen or C1-6A hydrocarbyl group. In general, except for-NxIn the case of amino, amino represents-NH2Or simple monoalkyl-or dialkylamino moieties (e.g. dialkylamino moiety dimethylamino (-N (CH))3)2))。
Reference herein to amino groups should also be understood to include within its scope quaternized or protonated derivatives of amines obtained from compounds comprising such amino groups. Examples of the latter are understood to be salts, such as hydrochloride salts.
The alkoxy (synonymous with alkyloxy) and alkylthio moieties each have the formula-OR5and-SR5Wherein R is5Is a saturated aliphatic hydrocarbon radical, typically C1-6Alkyl or C3-6Cycloalkyl optionally substituted with one or more substituents selected from the group consisting of: halo, aryl and heteroaryl.
Carboxylate, sulfonate and phosphate are herein respectively meant to be functional groups-CO2 -、-SO3 -and-PO4 2-They may be in their protonated form.
Formyl means a group of formula-C (H) O.
An ester means a functional group comprising a-OC (═ O) -moiety.
Acyl means a group of the formula-C (O) R5Wherein R is5As previously defined. Similarly, thioacyl represents the formula-C (O) R5Of R, again wherein R5As previously defined.
Urea is herein meant to be of the formula-NHCOR5Or formula-CONHR5Wherein R is5As previously defined. Similarly, sulfonamido represents the formula-NHSO2R5Or formula-SO2NHR5Wherein R is5As previously defined.
Where the ligand is monodentate, it is capable of coordinating through one donor site (i.e., coordinating to the manganese center). Where the ligand is bidentate, it is capable of coordinating through two discrete donor sites.
The catalyst used according to the invention is characterized by comprising a complex of formula (I) as described herein. The nature of the complex is discussed in detail below.
Although, without wishing to be bound by theory, the catalytic species that constitutes the starting point for the catalytic hydrogenation reaction may be one that contains manganese ions in the oxidation state (I), it is well known in the art of transition metal catalysis that the initial precatalyst may exhibit transition metal centers in various oxidation states. These may be converted to catalytically active species during the course of the reaction being catalysed by appropriate oxidation or reduction of the transition metal (here manganese) atoms or ions, i.e. by any necessary oxidation or reduction of the manganese centres. Suitable oxidation or reduction of the manganese atom or ion can be achieved, for example, using a suitable reducing or oxidizing agent or reactive ligand.
Two examples of the use of manganese (II) precatalysts are described by V Vasilenko et al (Angew. chem. int. Ed., 56, 8393-8397(2017)) in the hydroboration of ketones and by X Ma et al (ACS Omega, 2, 4688-4692(2017)) in the hydrosilylation of aryl ketones, where manganese is present in the oxidation state (II), unlike the active catalytic species.
Further, it is well known that manganese (0) species such as Mn2(CO)10Undergoes oxidation to become the desired Mn species. In fact, Nguyen et al reported such oxidation using amino ligands to produce a reduction catalyst (ACS Catal., 7, 2022-.
Although it is not necessary to use a higher oxidation state Mn precursor, it is well known to reduce manganese in a higher oxidation state (e.g., in terms of an oxidizing agent) to Mn (ii). Even simple alkoxides can reduce higher valent metal salts to the desired lower valent species, see JH Dochery et al (Nature Chemistry, 9, 595-600 (2017)). Thus, using an appropriate reducing agent, it is contemplated that manganese-containing compounds of oxidation state > (II) can be used with the present invention.
Thus, the complex of formula (I) may comprise a manganese atom or a manganese ion in oxidation states (I) to (VII), typically a manganese ion, usually a manganese ion in oxidation state (I) or (II), and very often a manganese ion in oxidation state (I).
Although according to the invention we have found that manganese (I) pentacarbonyl bromide (I) (Mn (CO))5Br) is convenient, but it should be understood that other are commercially available (e.g., manganese (0) carbonyl (Mn)2(CO)10) Or readily available manganese compounds may also be used to prepare the complexes used in the process of the invention.
As is evident from the structure of the complex of formula (I), R1And R2Is of the formula R in a complex of the formula (I)1(R2)PFcC(CH3)N(H)ZNxA phosphine moiety in the tridentate ligand of (a). As will be appreciated by those skilled in the art, substituents R at such ligands (especially at such phosphino moieties)1And R2) generally present the possibility of significant variation. Routine variations of these (e.g., through steric bulk changes around and/or electronic effects on the phosphorus atoms of such phosphino moieties) allow one to optimize these ligands comprising these catalysts and complexes for any given reaction.
For example, R1And R2The ligand may be aliphatic or aromatic (or heteroaromatic) with possibly significant substitution without destroying the function of the catalyst comprising such moieties as a hydrogenation catalyst role. In addition, there are a wide variety of commercially available or otherwise readily available phosphorus-containing reagents from which R-containing compounds can be prepared1And a ligand containing R2The ligand of (1). Still further, it has been demonstrated in the art that a variety of related ligands can be prepared and include these, including the formula R as defined in formula (I) herein1(R2)PFcC(CH3)N(H)ZNxFerrocene-based PNN tridentate ligands) may be used in catalytic hydrogenation reactions. For example, H Nie et al (Tetrahedron: asymmetry, 24, 1567-.
When constructing diphenylphosphino-substituted ferrocenes, Nie et al describe the preparation of compounds of formula R via the internal pairing of the complex of formula (I) as defined herein1(R2)PFcC(CH3)N(H)ZNxCorresponds to-C (CH) in the tridentate ligand of3) Selective lithiation of the ortho position of the substituents of the N-fragment followed by treatment with various chlorodiarylphosphines introduces a diphenylphosphino moiety. In view of the large number of analogous electrophilic chlorophosphines available to the skilled artisan, preparation of compounds having other substituents on the phosphorus atom (e.g., optionally substituted aliphatic, heteroaryl and other aryl radicals R1And R2Moieties) are those that are already within their conventional capabilities, for example to yield dialkylphosphino-containing ligands, such as diethylphosphino-and di-t-butylphosphino-.
As described in detail in the experimental section below, we synthesized formula R by reaction between N, N-dimethyl-1-ethylamino-substituted ferrocene and 2-picolylamine (2-aminomethylpyridine) in the presence of acetic anhydride1(R2)PFcC(CH3)N(H)ZNxOf (2), wherein ZNxIs a 2-pyridylmethyl group. By 1-ethylamino-abstraction in the presence of sodium borohydrideThe reaction between substituted ferrocenes and 4-dimethylamino-2-formylpyridine, we have also synthesized the formula R1(R2)PFcC(CH3)N(H)ZNxOf (2), wherein ZNxIs 4-dimethylaminopyridin-2-ylmethyl. Furthermore, as an example to illustrate the availability of the complex of formula (I), we noted that by substituting different commercially available ferrocenes to (S) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino]-2- [ (R) -1- (DMA) ethyl]Ferrocene or ((R) -1- [ (S) -1- (dimethylamino) ethyl)]-2- (diphenylphosphino) ferrocene) (their use is described herein), the commercial availability of alternatively substituted ferrocenes (sold by Solvias Ag (Switzerland) under the trade name PFA) being such that formula R1(R2)PFcC(CH3)N(H)ZNxAlternative R of (1)1-and R2The synthesis of the substituted ligands becomes simple.
In particular, the following ferrocenes are commercially available from Solvias (wherein DMA represents dimethylamino):
(S) -1- [ (R) -1- (DMA) ethyl ] -2- (diphenylphosphino) ferrocene;
(R) -1- [ (S) -1- (DMA) ethyl ] -2- (diphenylphosphino) ferrocene;
(R) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino ] -2- [ (S) -1- (DMA) ethyl ] ferrocene;
(S) -1- (difurylphosphino) -2- [ (R) -1- (DMA) ethyl ] ferrocene;
(R) -1- (difurylphosphino) -2- [ (S) -1- (DMA) ethyl ] ferrocene;
(S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] -2- [ (R) -1- (DMA) ethyl ] ferrocene;
(R) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] -2- [ (S) -1- (DMA) ethyl ] ferrocene;
(S) -1- (dicyclohexylphosphino) -2- [ (R) -1- (DMA) ethyl ] ferrocene; and
(R) -1- (dicyclohexylphosphino) -2- [ (S) -1- (DMA) ethyl ] ferrocene.
These may be used to provide a complex for use according to the invention, wherein R of the complex of formula (I)1R2P-Fc-CH(Me)-the NH-moiety is:
(S) -1- [ (R) -1- (HN) ethyl ] -2- (diphenylphosphino) ferrocene;
(R) -1- [ (S) -1- (HN) ethyl ] -2- (diphenylphosphino) ferrocene;
(S) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino ] -2- [ (R) -1- (HN) ethyl ] ferrocene;
(R) -1- [ bis (4-methoxy-3, 5-dimethylphenyl) phosphino ] -2- [ (S) -1- (HN) ethyl ] ferrocene;
(S) -1- (difurylphosphino) -2- [ (R) -1- (HN) ethyl ] ferrocene;
(R) -1- (difurylphosphino) -2- [ (S) -1- (HN) ethyl ] ferrocene;
(S) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] -2- [ (R) -1- (HN) ethyl ] ferrocene;
(R) -1- [ bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino ] -2- [ (S) -1- (HN) ethyl ] ferrocene;
(S) -1- (dicyclohexylphosphino) -2- [ (R) -1- (HN) ethyl ] ferrocene; or
(R) -1- (dicyclohexylphosphino) -2- [ (S) -1- (HN) ethyl ] ferrocene,
i.e., wherein R is a formula as described herein1(R2)PFc-CH(Me)-N(H)ZNxThe tridentate ligand of (c), the Dimethylamino (DMA) moiety is replaced with an NH moiety.
Although the invention is exemplified herein by the use of a chiral catalyst, this is because the catalyst is commercially available in a non-racemic form. Because the hydrogenation described herein does not produce new stereocenters (as opposed to hydrogenation of prochiral ketone substrates), there are neither disadvantages nor advantages to using mixtures of enantiomers of chiral ligands in the preparation of complexes of formula (I).
Albeit over a large range of R1And R2Both are synthetically obtainable and the hydrogenations according to the invention are useful, but according to a particular embodiment of the invention, R1And R2Each independently is optionally substituted C1-10A hydrocarbyl or monocyclic heteroaryl moiety. For example, and as already noted, R1And R2The moiety may be a dialkylphosphino moiety, such as diethylphosphino or di-t-butylphosphino.
According to a more particular embodiment, R1And R2Each independently is optionally substituted C5-10A cycloalkyl, monocyclic aryl or monocyclic heteroaryl moiety, for example an optionally substituted phenyl, furyl or cyclohexyl moiety. Phenyl, furyl or cyclohexyl moieties, especially phenyl moieties, and for R1And R2Other possibilities of (C)1-20Each of the hydrocarbon group or the heterocyclic group may be independently unsubstituted or substituted with one or more substituents selected from the group consisting of: c1-6Alkyl radical, C1-6Alkoxy, halo and trihalomethyl. According to still more particular embodiments, where there is substitution, this is typically by one or more C1-6Alkyl and/or C1-6Alkoxy substituents.
According to a particular embodiment, R may be independently configured1And R2Is 4-methoxy-3, 5-dimethylphenyl, phenyl, 3, 5-dimethylphenyl, 4-methoxy-3, 5-di-tert-butylphenyl, 3, 5-di (tert-butyl) phenyl, furyl or cyclohexyl. According to these and other Rs1And R2Moiety, R1And R2Both will typically (but not necessarily) be the same part.
Similar to various R1And R2Partly by the flexibility obtained by synthesis, the skilled person can obtain complexes of formula (I) comprising various Fc moieties, wherein the relevant reagents are either commercially available (see above for reagents commercially available from Solvias) or incorporated within the complexes of formula (I) using methods well known to the skilled person. In this regard, TDAppleton et al (J. organomet. chem., 279(1-2), 5-21(1985)) describe the ready functionality of the cyclopentadienyl ring of ferrocene.
According to a particular embodiment of the invention, one or more carbon atoms of any of the cyclopentadienyl rings of the ferrocene moiety Fc may be substituted by one or more halo and/or C1-6Alkyl substituents, except for the Fc portion at one of its cyclopentadienyl ringsIn addition to the inherent substitution at those carbon atoms attached to the remainder of the complex of formula (I). However, according to a still more particular embodiment of the invention, none of the cyclopentadienyl rings of the Fc portion in formula (I) is substituted (i.e. except for the intrinsic substitution through the point of attachment of ferrocene to the remainder of the complex of formula (I)).
Obtaining the ch (me) moiety adjacent to the Fc moiety within the complex of formula (I) is readily available to the skilled artisan, as the commercial availability as Ugi's amine (N, N-dimethyl-1-ferrocenylethylamine) is known in the art, available as either enantiomer.
By selecting the appropriate chlorophosphine, N, N-dimethyl-1-ferrocenylethylamine described herein can be reacted using, for example, HNie et al (vide supra) to obtain the corresponding 2-phosphino derivative (which may incorporate R as described herein)1And R2Portion). The N, N-dimethylamino moiety of the resulting 2-phosphino derivative may then be converted to the corresponding unsubstituted amino moiety, followed by the appropriate N-containing moietyxAldehyde (wherein N isxAs defined herein) to achieve reductive amination, as also described by H Nie et al (vide supra) and described herein to give formula R as described herein1(R2)PFc-CH(Me)-NH-Z-NxThe ligand of (1).
Alternatively, unsubstituted amino moieties may be reacted with formula N, as described hereinx-Z-NH2By reaction of an amine of (b), wherein NxAnd Z is as defined herein to give the formula R1(R2)PFc-CH(Me)-NH-Z-NxThe ligand of (1). It should be understood that formula Nx-Z-NH2Will give the formula R1(R2)PFc-CH(Me)-NH-Z-NxOf the ligand-Z-NxA change in termination. More specifically, the formula R is extensive1(R2) PFc-CH (Me) -LG (wherein LG is a leaving group, such as acetate or NMe2) Are available to the skilled person. These can then be converted to formula R by the methods described herein1(R2)PFc-CH(Me)-NH-Z-NxThe ligand of (1). Thus, the formula R is obtained1(R2)PFc-CH(Me)-NH-Z-NxThe ligand of (a) is readily within the normal abilities of the skilled person.
Still further, reference is made to HU Blaser et al (Topics in Catalysis, 19(1), 3-16(2002)), which provides further teaching to the skilled person, particularly with respect to formula R1(R2)PFc-CH(Me)-NH-Z-NxCH (Me) -NH-Z-N of the ligand(s)xPartial variation), additional means and strategies for incorporating ferrocene (a structurally different series of substituents) can be understood.
In the complex of formula (I) — Z-is of formula- (CH2)1-6The alkylene linking group of (a), wherein one or more hydrogen atoms in the alkylene can be independently substituted with an alkyl, aryl, heteroaryl, hydroxyl, nitro, amino, alkoxy, alkylthio, or mercapto substituent. Such a change in the linking group can be obtained, for example, by reacting a compound of formula R as described above1(R2) PFc-CH (Me) -LG (e.g. wherein LG ═ NMe2) And different ones having a Z group (except for methylene (-CH) as present in 2-picolylamine2-) to the reaction mixture. (similarly, it will be understood that different N's are obtainedxThe radicals may additionally (in addition to changing the Z radical) or alternatively be prepared by reacting a compound of the formula R1(R2) PFc-CH (Me) -LG with different compounds having NxPrimary amine reaction of groups (other than the 2-pyridyl group present in 2-picolylamine).
An alternative strategy for altering the-Z-group in the complex of formula (I) can be understood by: reference is made to C-J Hou and X-P Hu (org. Lett., 18, 5592-1(R2)PFc-CH(Me)-NH-Z-NxWherein the-Z-moiety may be a substituted methylene linking group (e.g. via 1- (2-pyridyl) ethyl methanesulfonate with a ligand of formula R1(R2)PFc-CH(Me)-NH2Reaction of the compound of (a) to provide a methyl-substituted methylene linking group-Z-); or reacting various 2-acylpyridines with the formula R1(R2)PFc-CH(Me)-NH2Followed by hydrogenation of the resulting Schiff base (thereby providing a series ofA substituted methylene linking group-Z-, wherein the substituent corresponds to the R group of a 2-acylpyridine in the formula 2-PyC (═ O) R). (similarly, it will be appreciated that an N different from 2-pyridyl is obtainedxThe radicals may additionally (i.e. in addition to changing the Z radical) or alternatively be prepared by reacting a compound of formula R1(R2)PFc-CH(Me)-NH2With 1- (2-pyridyl) ethyl methanesulfonate and derivatives having an N other than 2-pyridylx2-acylpyridine reaction of the group.
According to a particular embodiment of the invention, -Z-has the formula- (CH2) -, - (CHR)3) -or- (CH)2)2-, wherein R3Is an alkyl, aryl, heteroaryl, hydroxyl, nitro, amino, alkoxy, alkylthio or mercapto substituent. According to a particular embodiment of the invention, -Z-has the formula- (CH)2)-、-(CHR3) -or- (CH)2)2-, wherein R3Is C1-6Alkyl substituents or optionally substituted by C1-6Alkyl and/or phenyl substituted one or more times by halo. According to other embodiments, -Z-has the formula- (CH)2)-、-(CHR3) -or- (CH)2)2-, wherein R3Is methyl or optionally substituted by C1-6Alkyl and/or phenyl substituted one or more times by halo.
Typically (but not necessarily in the context of the available discussion of substituted alkylene linking groups of formula-Z-) — Z-is unsubstituted. For example, -Z-may have the formula- (CH)2) -or- (CH)2)2-, usually- (CH)2)-。
In which the formula R can be varied has already been described above1(R2)PFc-CH(Me)-NH-Z-NxN in the ligand of (1)xIn part, in various ways. In addition, however, it is noted that W Wu et al (org. Lett., 18, 2938-1(R2)PFc-CH(Me)-NH2With various substituted chloromethyl oxazoles, for constructing such ligands of another strategy, in which-Z-is methylene and NxIs a substituted oxazolyl group. It will be readily appreciated that-Z-and NxAre all made ofMay vary according to such synthetic strategies.
In light of the discussion herein, it is understood that for the nitrogen atom containing moiety of the complex of formula (I) NxThere is no particular limitation. However, N according to particular embodiments of the present inventionxIs in a heterocyclyl ring, said heterocyclyl ring being optionally substituted one or more times with one or more substituents independently selected from the group consisting of: amino, halo, C1-6Hydrocarbyl, trihalomethyl, aryl, heteroaryl, hydroxy, nitro, alkoxy, alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, ureido, and sulfonamido.
According to some embodiments, comprising NxThe heterocyclyl ring of (a) is optionally substituted one or more times with one or more substituents independently selected from the group consisting of: amino, halo, C1-6Alkyl groups and aryl groups. According to these and other embodiments of the present invention, N is includedxThe heterocyclyl ring of (a) is a pyridyl, indolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, quinoxalinyl, pyridazinyl, triazolyl, triazinyl, imidazolidinyl, or oxadiazolyl ring, for example a pyridyl, indolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, quinoxalinyl, pyridazinyl, or triazolyl ring; and/or a monocyclic heteroaryl ring. According to a particular embodiment, comprising NxThe heterocyclyl ring of (a) is an optionally substituted pyridinyl ring, for example a pyridinyl ring optionally substituted one or more times by an amino substituent, which is substituted by Z at the carbon atom adjacent to the nitrogen atom of the pyridinyl ring. The amino substituent is usually substituted by two C1-6Tertiary amino substituted with alkyl substituents. Typically, two C1-6The alkyl substituents are the same and are selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. According to a still more particular embodiment of the present invention,-Nxis 4-dimethylaminopyridin-2-yl or 2-pyridyl.
And formula R1(R2)PFc-CH(Me)-NH-Z-NxIn the same way as the tridentate ligand, in the complexes of the formula (I), the complexes additionally comprise a ligand L1-L3. Depending on whether one of them is a bidentate or tridentate ligand, these ligands may constitute one, two or three ligands: l is1-L3Each of which may independently represent a monodentate neutral or anionic ligand; l is1-L3May represent a monodentate neutral or anionic ligand and L1-L3Together represent a bidentate neutral or anionic ligand; or L1-L3Together may represent a tridentate neutral or anionic ligand.
L1-L3The nature of the ligand is not particularly important to the present invention: any suitable neutral or anionic ligand may be used, which may be monodentate, bidentate or tridentate, typically monodentate or bidentate. Ligand L1-L3May for example be selected from the group consisting of: (i) a neutral ligand selected from the group consisting of: carbon monoxide, nitrogen monoxide, amines, ethers, thioethers, sulfoxides, nitriles (e.g., acetonitrile), isocyanides (e.g., methyl isocyanide), phosphorus-containing ligands based on phosphorus (III) or phosphorus (V), and water; and (ii) an anionic ligand selected from the group consisting of: halide ions, alkoxide ions, anions of carboxylic, sulfonic and phosphoric acids, amido ligands, thiolate ions, phosphide ions, cyanide, thiocyanate, isothiocyanate, and enolate ions (e.g., acetylacetonate). At L1-L3Together represent a tridentate ligand, this is usually, but not necessarily, neutral. An example of a neutral tridentate ligand is diglyme.
According to a particular embodiment of the invention, L1-L3Three ligands selected from neutral monodentate ligands are constituted. According to these and other embodiments, L1-L3May be identical. For example, L1-L3Three carbon monoxide ligands can be constituted.
In the case where the complex of formula (I) is charged, the catalyst comprises one or more additional counter-ions to balance the charge of the complex, i.e. from a manganese centre Mn and one or more ligands L1-L3And R1(R2)PFc-CH(Me)-NH-Z-NxResulting charge of the formed complex. With one or more ligands L1-L3Likewise, the nature of any such additional counter ions is not particularly important to the working of the present invention. Where these counterions are present, they may for example be selected from the group consisting of: halide, tetraarylborate, SbF6 -、SbCl6 -、AsF6 -、BF4 -、PF6 -、ClO4 -And CF3SO3 -Optionally wherein the tetraarylborate ligand is selected from the group consisting of: [ B {3, 5- (CF)3)2C6H3}4]-、[B{3，5-(CH3)2C6H3}4]-、[B(C6F5)4]-And [ B (C)6H5)4]-For example, wherein the tetraarylborate ligand is [ B {3, 5- (CF)3)2C6H3}4]-Known as tetrakis (3, 5-bis (trifluoromethyl) phenyl) Borate (BARF)).
According to a particular embodiment of the invention, the complex has a single positive charge (e.g. a manganese centre and one or more ligands L)1-L3The resulting manganese center is a manganese ion in oxidation state (I), the ligands are three neutral monodentate ligands, e.g., three carbon monoxide ligands), and the catalyst further comprises one halide or tetraarylborate counter anion. According to yet more particular embodiments of such catalysts, the counter anion is bromide or BARF.
It will be appreciated that the complex of formula (I) exhibits chirality not only due to the stereocenter adjacent to the Fc moiety, which has the methyl group depicted in the compound of formula (I), but also due to the planar chirality resulting from the 1, 2-linkage from one of the two cyclopentadienyl rings of the Fc moiety to the remainder of the complex of formula (I). However, as already mentioned, since the hydrogenation of the ester function does not form stereocenters, it is understood that the present invention can be operated using catalysts comprising mixtures of any of the stereoisomers (e.g. enantiomers or diastereomers) of the complexes of formula (I) (e.g. racemic mixtures of enantiomeric complexes and catalysts comprising these).
For example, according to a particular embodiment of the invention, the catalyst is one of the following formulae:
whereintBu is tert-butyl.
However, the catalyst may equally be a mixture of each enantiomeric pair, for example a racemic mixture, or a mixture of other catalysts comprising a complex of formula (I).
Typically, the catalyst is one of the following formulae:
as mentioned above, the catalyst useful in the present invention can be prepared, for example, by: in the same reaction vessel in which the hydrogenation according to the invention is carried out, a suitable manganese salt is mixed, which may or may not comprise one or more ligands L1-L3And further ligands, e.g. of the formula R1(R2)PFc-CH(Me)-NH-Z-NxAre suitable for forming catalysts comprising complexes of formula (I). Alternatively, the optionally well-defined catalyst may be prepared ex situ, as briefly described above. The preparation of such catalysts is well within the ability of those of ordinary skill in the art, using the guidance herein, including reference to experimental sections and prior art as known to those of skill in the art, including those cited herein.
One skilled in the art will readily appreciate that the recognized methods of immobilizing the catalysts of formula (I) herein can be used to produce heterogeneous catalysts, if desired, for example by absorption onto a suitable solid support or reaction with such a support to form a covalently bound ligand or catalyst.
A characteristic feature of the process of the invention relates to the use of a base wherein the conjugate acid of the base has a pKa of 6.3 to 14. For the avoidance of doubt, these pKa values relate to the reaction In water at 25 ℃ in which BH+Indicating the conjugate acids of the bases involved, e.g. CRC Handbook of Chemistry and Physics, 91 st edition, 2010, dissociation constants of organic acids and bases and of inorganic acids and bases (CRC Handbook of Chemistry and Physics, 91)stedition, 2010, Dissociation Constants of Organic Acids and Bases, and Dissociation Constants of Organic Acids and Bases), and references cited therein. Thus, for example, the base used is potassium bicarbonate (KHCO)3) In the case where the conjugate acid is carbonic acid (H)2CO3) (ii) a For example, the base used is potassium carbonate (K)2CO3) In the case where the conjugate acid is bicarbonate (HCO)3 -). For further avoidance of doubt, the pKa of water at 25 ℃ is defined herein as 14.0, as is commonly recognized in the art. Thus, for exampleThe conjugate acid of both sodium hydroxide and potassium hydroxide (i.e., water) has a pKa of 14.0.
In some texts, the pKa of water is indicated as 15.74, which is higher than that of methanol (15.50) because the detailed explanation by TPSilverstein et al (j.chem.educ., 94(6), 690-695(2017)) is incorrect.
However, for the avoidance of any doubt, the present invention does not include any metal alkoxides used as bases in the process according to the invention, such as sodium methoxide, potassium tert-butoxide, etc. Thus viewed from a second aspect the invention provides a process which comprises hydrogenating an ester in the presence of (I) a base other than a metal alkoxide, (ii) hydrogen and (iii) a catalyst comprising a charged or neutral complex of formula (I) as defined in the first aspect of the invention and elsewhere herein.
According to some embodiments of the invention (i.e. according to both the first and second aspects thereof), the base is selected from the group consisting of: carbonates, phosphates, hydroxides or bicarbonates of lithium, beryllium, sodium, magnesium, potassium, calcium or cesium (i.e. one of the four salts of the six metals) or mixtures thereof, for example selected from the group consisting of: carbonates, phosphates, hydroxides or bicarbonates of lithium, sodium, magnesium, potassium, calcium or cesium, or mixtures thereof. According to a more specific embodiment of the invention (i.e. according to both the first and second aspects), the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, calcium hydroxide, potassium bicarbonate, sodium bicarbonate, and lithium bicarbonate.
According to a particular embodiment of the invention (i.e. ] again according to both the first and second aspects), the conjugate acid of the base has a pKa of from 10.3 to 14. Such pKa does not include, for example, bicarbonate.
While we have found that the use of metal bicarbonates tends to provide less effective hydrogenation conversion than when using, for example, metal carbonates, phosphates or hydroxides, we have demonstrated that hydrogenation can still be achieved using such bases, and the skilled person will recognize that a wide range of conversions can be improved by routine modification of the reaction scheme (e.g. by increasing the concentration of such bases, catalyst loading, hydrogen pressure, temperature, reaction duration or any combination of these modifications).
According to other more particular embodiments of the invention (again according to both the first and second aspects), the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, and calcium hydroxide, for example, selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate and cesium carbonate.
According to other embodiments of the first and second aspects of the invention, the base used according to these hydrogenation processes may be a tertiary amine, typically of formula N (C)1-6Alkyl radical)3Examples of tertiary amines that can be used include triethylamine, N-dimethylamine, and N, N-diisopropylethylamine (also known as H ü nig's base).
Viewed from a third aspect the invention provides a process which comprises hydrogenating an ester in the presence of (i) a base which is a carbonate, phosphate, hydroxide or bicarbonate of lithium, beryllium, sodium, magnesium, potassium, calcium or caesium or a tertiary amine, for example of formula N (C) as defined above, (ii) hydrogen and (iii) a catalyst1-6Alkyl radical)3Comprising a charged or neutral complex of formula (I) as defined in relation to the first aspect of the invention and elsewhere herein.
According to a particular embodiment of the third aspect of the invention, the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, calcium hydroxide, potassium bicarbonate, sodium bicarbonate, and lithium bicarbonate, for example wherein the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, and calcium hydroxide, and according to a particular embodiment, wherein the base is selected from the group consisting of: potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate and cesium carbonate.
As is typical for hydrogenation reactions, the process of the invention is carried out under pressure in the presence of hydrogen. Typically, the reaction is carried out at a pressure in the range of from about 1 bar (100kPa) to about 100 bar (10,000kPa), for example from about 20 bar (2,000kPa) to about 80 bar (8,000kPa), although higher or lower pressures may sometimes be suitable.
The reaction may be carried out in any convenient solvent that may be suitable for the reaction substrate (i.e., the ester). In certain embodiments, it may be convenient to carry out the hydrogenation in the absence of a solvent. Any solvent commonly used in organic chemistry can potentially be used. However, solvents containing ketone or ester functional groups, respectively, such as acetone or ethyl acetate are preferably avoided.
Typical solvents for use in the present invention include: simple alcohols, such as C1-10Hydrocarbon alcohols, usually saturated aliphatic C2-8Alcohols such as ethanol, isopropanol, and tert-butanol; polyhydric alcohols such as ethylene glycol, propylene glycol, 1, 2-propanediol, and glycerin; ethers such as Tetrahydrofuran (THF), 1, 4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether; aliphatic and aromatic hydrocarbon solvents, e.g. C5-12Alkanes, benzene, toluene and xylenes as well as halogenated (typically chlorinated) hydrocarbon solvents, such as dichloromethane and chlorobenzene, or mixtures thereof, in particular mixtures of an alcohol (for example ethanol or isopropanol) and a hydrocarbon solvent, such as hexane, xylene (i.e. isomeric mixtures) or toluene. According to a particular embodiment, methanol is not used as solvent in the present invention.
Conveniently, however, the hydrogenation reaction of the present invention may typically be carried out only at C1-10In hydrocarbon alcohols (i.e., where the only solvent is the alcohol, or there is minimal contamination (e.g., less than 10 vol%, more typically less than 5 vol%) by other liquids (e.g., water)), particularly in ethanol or isopropanol. Thus, according to some embodiments of the invention, the solvent used for the reaction is isopropanol. According to other embodiments, the solvent is ethanol.
It will be appreciated that the precise conditions for any given hydrogenation reaction may vary within the routine abilities of one of ordinary skill in the art. Thus, the concentration of catalyst and the hydrogen pressure may typically vary within the ranges already discussed. Operating temperatures that may be used typically vary from about-20 ℃ to about 200 ℃, usually from about 20 ℃ to about 120 ℃, for example from about 50 ℃ to about 110 ℃; and the duration of the reaction may vary from about 5 minutes to about 36 hours, for example from about 1 hour to about 24 hours or from about 2 hours to about 18 hours.
Suitable amounts of base that can be used can likewise be determined by the skilled person. One of the advantages of the present invention is that the cost of many bases is significantly lower than the cost of metal alkoxides. Another advantage is that the sensitivity of the bases described herein to water is greatly reduced. Thus, the problems with using larger amounts of base associated with the present invention are less compared to metal alkoxides. Examples of suitable amounts of base to use relative to the ester reactant can vary from about 0.1 mol% to about 1000 mol%, such as from about 1 mol% to about 100 mol%, such as from about 5 to about 50 mol%. However, it may sometimes be convenient or advantageous to use larger amounts of base (e.g. up to 2000 mol% or more). Combinations of more than one base may also be used.
As noted above, the present invention is premised in part on the ability to perform ester hydrogenation at a variety of temperatures and in a variety of solvents, but in doing so, without the use of extremely strong bases. Therefore, the ester which can be used as a substrate for hydrogenation reaction according to the present invention is not particularly limited. Typically, however, the ester functionality is attached to one or more hydrocarbyl moieties (for the avoidance of doubt, esters which may be hydrogenated in accordance with the scope of the invention include cyclic esters (i.e. lactones)) optionally comprising amino or halo functionality. According to a particular embodiment, the hydrocarbyl moieties to which the ester functional groups are attached do not comprise unsaturated aliphatic moieties, but they may comprise aromatic or heteroaromatic moieties in addition to one or more saturated aliphatic moieties.
A particular advantage of avoiding strong bases in the hydrogenation reaction according to the invention is the ability to hydrogenate photoactive substrates, such as those which are susceptible to racemization by deprotonation of a relatively acidic C-H bond (e.g.alpha to the carbonyl moiety), with at least less disruption to optical purity than corresponding reactions which have hitherto used strong bases.
Thus, according to a particular embodiment of the invention, the ester is photoactive. According to a more particular embodiment, the ester comprises a stereogenic center adjacent to its carbonyl group. When hydrogenating a photoactive ester according to the present invention, the enantiomeric excess in the photoactive ester undergoing hydrogenation is typically maintained or reduced by hydrogenation to no more than about 10% (i.e., Δ e.e. 0 or less than about 10%), for example no more than about 5%. Advantageously, we have found that Δ e.e. according to the invention is typically < 0%.
According to a particular embodiment of the invention, the hydrogenated ester is the lactone sclareolide (sclareolide) which is commercially available (e.g. from Sigma-Aldrich) and has the formula:
the CAS # of sclareolide is [564-20-5], and is known under a number of names, including (+) -ambroxolide (norambrienolide), (3aR) - (+) -sclareolide, (R) - (+) -sclareolide, (3aR, 5aS, 9bR) -decahydro-3 a, 6, 6, 9 a-tetramethyl-naphtho [2, 1-b ] furan-2 (1H) -one, 3a, 4, 5, 5a α, 6, 7, 8, 9, 9a, 9b α -decahydro-3 a β, 6, 6, 9a β -tetramethyl-naphtho [2, 1-b ] furan-2 (1H) -one and [3aR- (3a α, 5a β, 9a α, 9b β) ] -decahydro-3 a, 6, 6, 9 a-tetramethyl-naphtho [2, 1-b ] furan-2 (1H) -one.
Sclareolide can be used for the synthesis of ambroxide (ambroxide) by: the esters are hydrogenated to form the corresponding diols (known as synonyms, including ambrotol), and then dehydrated to form ambroxol ethers:
it is highly appreciated as an inductive fixative in perfumes. Thus, the use of the hydrogenation of the invention in conjunction with the preparation of ambrox represents a fourth aspect of the invention. This fourth aspect provides a process for preparing ambroxol, the process comprising hydrogenating sclareolide according to any one of the first to third aspects of the invention, followed by cyclization of the resulting glycol (ambroxol), thereby providing ambroxol.
The skilled person is clearly aware of methods for converting ambergris glycol into ambergris ether. In particular, WO2017/068401 a1 (universal Michoacana De San Nicol a s De Hidalgo)) describes a method for the synthesis of ambergris ether from an extract of the plant agratina Jocotepecana, wherein a number of suitable methods for the conversion of ambergris glycol into ambergris ether are described, within the application itself and with reference to the above US patent nos. 5, 463, 089 (first inventor DHR Barton), published US patent application No. US 2010/0248316 a 567 (first inventor LH Steenkamp), published spanish patent application No. ES 2044780 (universal gradada), published spanish patent application No. ES 2195777 (universal gradada), EP 0209 a1(Fritzsche Dodge & olott et al), published european patent application No. WO 7328 a2 (EP 2383, awk # EP 2383, EP 54 a) and published japanese patent application No. 5, No. 5,463,, U.S. patent nos. 59274, 134 (first inventor K Bruns) and SI Mart i ienz-Guido et al (ACS sustamable chem. eng, 2(10), 2380-. Any of these known methods can be used to cyclize ambroxol to provide ambroxol.
Each of the patent and non-patent references cited herein is incorporated by reference in its entirety as if each were set forth in its entirety herein.
The following non-limiting examples more fully illustrate embodiments of the invention.
General Experimental procedures
The preparation of the solution for the catalytic reaction is carried out under an argon or nitrogen atmosphere. All glassware was oven dried or flame dried and cooled under vacuum prior to use. The solvent is degassed by bubbling argon or nitrogen through the solvent for at least 1 hour before use or by freeze-thaw thawing (freeze-pumped-thawed) before use. Unless otherwise indicated, all precursor chemicals were purchased from Sigma-Aldrich, Acros, Alfa Aesar, Strem or TCI and used as received (except for further degassing as described above). Room or ambient temperature means a temperature range of 15-25 ℃. Heating of the reaction mixture was performed by an oil bath or a Drysyn heat block. Unless otherwise indicated, the temperatures reported are oil bath or heating block temperatures, not internal temperatures, and were measured using a contact thermometer (PT-1000). Vacuum means using a heidolph laborota 4001 rotary evaporator or using a high vacuum line. Analytical Thin Layer Chromatography (TLC) was performed on precoated plastic plates (Kieselgel 60F254 silica gel). TLC visualization was performed using a UV lamp (254nm) or using 1% aqueous potassium permanganate. Flash silica gel chromatography was performed using Kieselgel 60 silica gel.
Bruker Avance 300(300MHz for1H, 75MHz for13C, 121MHz for31P, and 282MHz for19F)、Bruker Avance II 400(400MHz1H，100MHz13C，161MHz31P, and 376MHz for19F) Or Bruker Ultrashield 500(500 MHz)1H，125MHz13C，201MHz31P and 470MHz for19F) To carry out1H、13C、31P、19F MR. NMR analysis was performed at room temperature in deuteration. Chemical shifts are expressed in parts per million (ppm). The coupling constant J is expressed in Hz. Multiplicity is expressed as: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). The abbreviation "br" is used to indicate broad peak shape.
The IR spectra were recorded on a Shimadzu IRaffinity-1 using a Pike Attenuated Total Reflectance (ATR) accessory. Peaks are reported as weak (w), medium (m) or strong(s). The abbreviation "br" indicates a broad peak shape, and "sh" indicates a sharp peak shape. All units are expressed in cm-1.
Mass spectra (m/z) data were obtained by electrospray ionization (ESI) or Electron Impact (EI) at the san andersus University (University of St Andrews) mass spectrometry facility (using Micromass LCT spectrometer or Micromass GCT spectrometer) or at the EPRSC national mass spectrometry service center (Swansea) (using Orbitrap nano-ESI, Finnigan MAT 900XLT or Finnigan MAT 95 XP). Values are reported in daltons as mass to charge ratios. Optical rotation was measured on a Perkin Elmer 341 polarimeter using a 1ml sample cell, using a 1dm optical path at room temperature, using sodium D-line, and using the appropriate solvent reported along with the concentration (c ═ g/100 ml). HPLC analysis has been determined using Galaxie workstation PC software operating Varianprostar.
(Sc，Rp) Synthesis of (E) -N-2-picolyl-1- (2-diphenylphosphino) ferrocenylethylamine (1)
To a readily available (Sc, Rp) -N, N-dimethyl-1- [2- (diphenylphosphino) ferrocenyl]Ethylamine (209mg, 0.47mmol) [8 ]]Degassed acetic anhydride (152. mu.L, 1.59mmol) was added. The reaction mixture was heated to 90 ℃ and the solution finally became homogeneous. The mixture was kept at the reaction temperature until TLC analysis (EtOAc: heptane, 20: 80, Et)3N deactivation) showed full conversion (typically 2-3 hours). The solution was cooled to room temperature and isopropanol (551 μ L) was added. To this solution degassed 2-picolylamine (985 μ L, 9.55mmol) in isopropanol (276 μ L) was added and the reaction mixture was heated at 60 ℃ to 70 ℃ under an argon atmosphere for 5 days until TLC analysis (EtOAc: heptane, 20: 80, Et)3N deactivation) indicates the reaction is complete. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (EtOAc: hexane, 50: 50, Et)3N deactivated silica gel) to give an orange oil which was crystallized in hexane to give the product as orange crystals (106.4mg, 0.211mmol, 45%).
1H-NMR(CDCl3)：8.31(1H，d，J 4.9，NC(pyridine)H)，7.59-7.48(2H，m，CArH)，7.43-7.26(5H，m，CArH)，7.26-7.21(2H，m，CArH)，7.18-7.11(3H，m，CArH)，7.03-6.94(1H，m，NC(pyridine)HC(pyridine)H)，6.55(1H，d，J 7.8，NHCH)，4.55(1H，br s，C5H3)，4.32(1H，t，J 2.5，C5H3)，4.26-4.17(1H，m，NHCH)，4.02(5H，s，C5H5)，3.83(1H，s，C5H3)，3.64(2H，d，J 2.1，CArCH2NH) and 1.57(3H, d, J6.0, CHCH)3)；
13C-{1H}-NMR(CDCl3)：159.7(s，NC(pyridine)CH2)，148.7(s，NC(pyridine))，140.0(d，J 10.04，CAr，PPh2)，137.2(d，J 9.12，CAr，PPh2)，136.1(s，C(pyridine))，135.0(d，J 20.96，2x CArH，PPh2)，132.6(d，J 18.88，2x CArH，PPh2)，129.1(s，C(pyridine))，128.3(d，J 6.31，2xCArH，PPh2)，128.1(d，J 6.31，2x CArH，PPh2)，128.0(s，C(pyridine))，121.6(s，CArH，PPh2)，121.4(s，CArH，PPh2)，97.5(d，J 25.52，C，RC5H3)，75.1(d，J 8.11，C，C5H3P)，71.3(d，J 4.0，CH，C5H3)，69.7(s，C5H5)，69.5(d，J 4.0，CH，C5H3)，69.2(s，CH，C5H3)，52.1(s，HNCH2) 51.3(d, J7.4, NCH) and 19.5(s, CHCH)3)；
31P{1H}-NMR(CDCl3)：-25.1(PPh2).
MS：(ES+)527.13((M+Na)+33%), 397.08 ((M-picolinamine, 100%);
IR(KBr)：vmax/cm-1(KBr)3736(w)，3438(m)，3050(m)，2925(m)，1588(m)，1568(m)，1494(m)，1476(s)，1454(s)，1374(m)，1310(w)，1239(m)，1170(m)，1139(m)，1107(s)，1042(m)，1025(m)，996(m)，823(m)，780(m)，746(s)，702(s)cm-1
[αD 20]: +285.2(c 0.25, chloroform).
(1) Alternative Synthesis of
An alternative synthesis of (1) based on the previously disclosed procedure (H Nie et al (see above)) may also be used and is described in detail below:
synthesis of (Sc, Rp) -1- (2-diphenylphosphino) ferrocenylethylamine (1-Int)
To (Sc, Rp) -N, N-dimethyl-1- (2-diphenylphosphino) ferrocenylethylamine (2.42g, 5.48mmol, 1.0 eq) in a round bottom flask was added acetic anhydride (10mL) and the mixture was heated to 100 ℃ and held for 2 hours. After cooling to ambient temperature, the excess acetic anhydride was removed in vacuo. To the residue was added a methanol/THF (1: 1) mixture (48mL) and aqueous ammonium hydroxide (10 mL). The resulting biphasic mixture was heated to 60 ℃ under an argon atmosphere and held for 3 hours, then cooled back to ambient temperature. The volatiles were removed in vacuo and the residue was extracted with dichloromethane (3 × 20 mL). The solutions were combined, dried over magnesium sulfate, filtered through a cannula equipped with a filter, and concentrated. The product (Sc, Rp) -1- (2-diphenylphosphino) ferrocenylethylamine was purified by chromatography on silica gel, which was deactivated with triethylamine using an n-hexane/ethyl acetate gradient (4/1 to 2/1) to give the intermediate as an orange solid (1.6g, 3.87mmol, 70% yield).
1H-NMR(CDCl3)：7.58-7.54(2H，m，CArH)，7.41(3H，m，CArH)，7.26(5H，m，CArH)，4.46(1H，br s，C5H3)，4.30(1H，m，C5H3)，4.25-4.21(1H，m，NHCH)，4.04(5H，s，C5H5)，3.79(1H，s，C5H3)，1.46(3H，d，J＝7.2Hz，CHCH3)，1.45(2H，s，-NH 2)
13C{1H}-NMR(CDCl3)：140.0(d，JPC＝9.7Hz，Ar-C)，137.11(d，JPC＝10.0Hz，Ar-C)，134.90(d，JPC＝20.3Hz，Ar-Cipso-P)，132.76(d，JPC＝17.1Hz，Ar-C)，129.12(Ar-C)，128.38(Ar-C)，128.33(Ar-C)，128.17(Ar-C)，128.11(Ar-C)，100.35(d，JPC＝24.4Hz，Fc-Cipso-P)，74.7(d，JPC＝8.3Hz，Fc-C)，71.24(Fc-C)，69.56(Fc-C)，69.0(Fc-C)，68.22(Fc-C)，45.30(d，JPC＝8.6Hz，Fc-C)，26.93(Fc-CH(CH3)-N)，22.84(Fc-CH(CH3)-N)，
31P{1H}-NMR(CDCl3)：-24.5ppm
MS: for [ C ]24H25FeNP]+Calculated (ES +): 414.1069, respectively; found 414.1063. In agreement with previously published data (G Sheldrick, Acta crystalloger, sect.c., 71, 3-8 (2015)).
In a round bottom flask, (Sc, Rp) -1- (2-diphenylphosphino) ferrocenylethylamine (1.06g, 2.56mmol, 1.0 eq.) was dissolved in degassed anhydrous methanol (15mL) at ambient temperature. Pyridine-2-carbaldehyde (0.30mL, 3.08mmol, 1.2 equivalents) was added to the flask and the mixture was stirred at ambient temperature for 16 hours, after which time the imine precipitated out. Sodium borohydride (194mg, 5.13mmol, 2.0 equiv.) was added to the mixture and the resulting clear solution was stirred at 40 ℃ for 1.5 hours, then cooled to ambient temperature and concentrated to dryness. The crude was dissolved in dichloromethane (20mL) and washed with saturated aqueous sodium bicarbonate (15 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined solution was dried over magnesium sulfate, filtered through a cannula equipped with a filter, and concentrated. The product was purified by silica gel chromatography (silica gel deactivated with triethylamine) using a gradient of n-hexane/ethyl acetate (5/1 to 1/1 to 0/1) to give 1 as an orange yellow solid (0.94g, 1.86mmol, 73% yield). The analytical data were found to be the same as those reported above for compound (1) using other synthetic routes.
Manganese complex (S)C，RP) Synthesis of (E) -2
N-2-picolyl (Sc, Rp) -1- (-2-diphenylphosphino) ferrocenylethylamine (280mg, 0.56mmol, 1.2 equiv.) was added to manganese (I) pentacarbonyl bromide (128mg, 0.47mmol, 1.0 equiv.) in a round bottom flask at ambient temperature. Degassed toluene (10mL) was added and the mixture was mixedThe contents were heated to reflux and the temperature was held for 16 hours. The mixture was cooled to ambient temperature and concentrated to dryness. The crude was dissolved in dichloromethane, filtered to remove insoluble material, and the product was precipitated by addition of n-hexane, collected by filtration, and washed with n-hexane to give the desired product as an orange powder (203mg, 0.28mmol, 60% yield). The product was found to be contaminated with trace amounts of paramagnetic species, giving a broad NMR peak. It was found that it was difficult to remove residual solvents (toluene and n-hexane) even after prolonged drying times at > 70 ℃ under high vacuum (< 0.3 mmHg). The solubility in most deuterated solvents was found to be extremely limited, showing a greater amount of more soluble impurities than actually present.1H-1H COSY and1H-13c-attribution of HSQC auxiliary peaks.
1H-NMR (128 scans, acetone-d6): 8.50(1H, br s, Py-H), 8.02(2H, m, Py-H), 7.79-7.28(4H, m, Ar-H), 7.25-7.15 (residual toluene), 6.97(4H, app d, Ar-H), 6.77(3H, app.d., Ar-H), 5.57(1H, br s, Fc-C)H(CH3)-N)，4.97(1H，br s，Fc-H)，4.80(1H，br s，Fc-H)，4.58(1H，brs，Fc-H)，4.48(1H，br s，NH)，4.30(1H，m，Fc-H Py-CH 2-N)，3.85(5H，br s，Fc-H)，3.72(1H，m，Py-CH 2-N), 2.33 (residual toluene) 1.78(3H, br s, Fc-CH (C)H 3) -N), 1.52 (residual hexane), 1.29 (N-hexane)
13C{1H } -NMR (1024 scans, acetone-d)6)：159.97(Ar-C)，152.70(Ar-C)，140.30(Ar-C)，140.03(Ar-C)，137.05(Ar-C)，136.12(Ar-C)，136.29(Ar-C)，134.42(d，JPC＝，10.3Hz，Ar-Cipso-P)，130.37(Ar-C)，130.29(Ar-C)，127.95(Ar-C)，127.87(Ar-C)，127.50(d，JPC＝10.3Hz，Ar-Cipso-P)，124.46(Ar-C)，120.22(Ar-C)，92.25(d，JPC＝22.2Hz，Fc-Cipso-P)，72.4(Fc-C)，71.30(Fc-C)，70.64(Fc-C)，70.32(Fc-C)，65.30(Py-CH2-N)，56.60(Fc-CH(CH3)-N)，54.52(DCM)，48.65(Fc-CH(CH3)-N)，20.33 (toluene), 14.81 (n-hexane), no CO was observed.
31P-NMR (128 scans, acetone-d)6)：90.1(br s)ppm
IR(ATR)：3199.91(w)，3053.3(w)，2358.9(m)，2341.6(m)，1921.0(s)，1842.0(s)，1712.8(m)，1481.3(m)，1433.1(m)，1361.7(w)，1232.5(w)，1220.9(w)，1163.1(w)，1093.6(m)，1051.2(w)，999.1(w)，829.4(w)，758.02(m)cm-1
HRMS: (ESI positive ion): expectation of [ C33H29FeMnN2O3P]+: 643.0640, found: 643.0634
CHN: for [ C ]33H29BrFeMnN2O3P]Calculated values: c: 54.80%, H: 4.04%, N: 3.87 percent; measured value: c, 54.73%; h, 4.05%; n, 3.94%
Manganese complex 2 with bromide counter-ion can be converted to the corresponding BARF and iodide salts by reaction with Na [ BARF ] sodium iodide, respectively.
The compound (2) was used as a catalyst in the subsequent hydrogenation examples.
Table 1 below summarizes the results of the following hydrogenation reactions (described below):
TABLE 1
a) 10 mol% base for all experiments
Examples of hydrogenations
Example 1: (S) -2- (6-methoxynaphthalen-2-yl) propan-1-ol
(S) -naproxen ethyl ester (500mg, 1.94mmol, 1 eq, 99.8% ee) and 1-methylnaphthalene (. about.50. mu.L, internal standard), manganese catalyst (14mg, 0.019mmol, 0.01 eq) and potassium carbonate (27mg, 0.19mmol, 0.1 eq) were added to a glass insert containing a stir bar, andthe insert was placed in an autoclave equipped with a vacuum/gas inlet and a charging hole. The vessel was sealed and evacuated and refilled with argon. This step was repeated twice. Degassed isopropanol (6.3mL) was added through the charging hole and the autoclave was pressurized with hydrogen (50 bar) and vented to atmosphere. This step was repeated twice. The pressure was set to 50 bar using hydrogen and the autoclave was sealed and placed in a preheated oil bath (50 ℃) and the stirring was set to 1200rpm and placed for 16 hours. After the reaction, the vessel was cooled to ambient temperature and vented to atmosphere by1The reaction was analyzed by H-NMR and conversion was estimated using an internal standard (1-methylnaphthalene). The reaction mixture was evaporated to dryness and the crude product was purified by column chromatography using 100% hexane followed by hexane/ethyl acetate (1/1) to give (S) -2- (6-methoxynaphthalen-2-yl) propan-1-ol as a white solid (450mg, 90%).
1H-NMR(CDCl3)：7.74(2H，t，J＝8.9Hz，Ar-H)，7.64(1H，s，Ar-H)，7.37(1H，d，J＝7.7Hz，Ar-H)，7.16(2H，m，Ar-H)，3.94(3H，s，-OCH3)，3.80(2H，d，J＝7.1Hz，-CH 2OH)，3.12(1H，m，CH(CH3)-)，1.38(3H，d，J＝7.2Hz，-CH 3)
13C-{1H}-NMR(CDCl3)：157.23(C Ar-OCH3)，138.63(C Ar)，133.55(C Ar)，129.11(C Ar)，129.03(C Ar)，127.24(C Ar)，126.27(C Ar)，125.93(C Ar)，118.93(C Ar)，105.58(C Ar)，68.66(-OCH3)，55.33(-CH2OH)，42.39(ArCH(CH3))，17.66(-CH3)
[αD 20]：-19.1(c.1.00，CHCl3)
Chiral analysis was performed using a Chiralcel OD-H column with n-hexane/isopropanol (96/4) mobile phase (flow rate 1.0 mL/min); t is tR(S-enantiomer, predominant): 17.0 min; t is tR(R-enantiomer, minor): 18.4min, e.e.98%.
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