Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction
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For journal reviews see:
For book chapter reviews see:
Spindler F., 2004, Enantioselective reduction of CN bonds and enamines with hydrogen, in: Transition Metals for Organic Synthesis, 113
Blacker J., 2004, Scaleup Studies in Asymmetric Transfer Hydrogenation, in: Asymmetric Catalysis on Industrial Scale: Challenges, Approaches, and Solutions, 201
2007, The Handbook of Homogeneous Hydrogenation, 1
Nugent T. C., 2008, Chiral Amine Synthesis‐Strategies, Examples, and Limitations, in: Process Chemistry in the Pharmaceutical Industry, Vol 2, Challenges in an Ever‐Changing Climate, 137
Rueping M., 2008, New Developments in Enantioselective Brønsted Acid Catalysis: Chiral Ion Pair Catalysis and Beyond, in: Organocatalysis, 207
Claver C., 2008, Imine Hydrogenation, in: Modern Reduction Methods, 237
Wills M., 2008, Imino Reductions by Transfer Hydrogenation, in: Modern Reduction Methods, 271
For recent reviews and manuscripts on the subject of carbanion addition to imine derivatives see: refs.[1k l r]and
Patman R. L., 2008, Aldrichimica Acta, 41, 95
For examples of chiral nitrogen atoms see:
Amino acid synthesis is a specialized field unto itself is well developed has been extensively reviewed and is therefore not discussed here for examples of reviews and some recent manuscripts see: ref.[1p]and
Blacker J., 2007, Spec. Chem. Mag., 24
For some recent reviews discussing amino acid synthesisviaenamides see: refs.[1p 2c 15a]and
Knowles W. S., 1968, J. Chem. Soc. Chem. Commun., 1445
The ligands used for examiningN‐acetylenamides are also useful in general for dehydroamino acid and ester and itaconic acid reductions.
Savarin C., 2008, An Efficient and Scalable Process for the Preparation of a Potent MC4 Receptor Agonist, in: Process Chemistry in the Pharmaceutical Industry, Challenges in an Ever‐Changing Climate
For representative examples see:
transfer hydrogenation process:J.Martin L. A.Campbell (Avecia Limited Great Britain) U.S. Patent 6 696 608 2004.
An exception has just been published by Zhang where R1=Me R2=H and R3=aryl this research is discussed in Section 2.12 and a generic substrate example can be found in Figure 21.
For example see:
This may be changing even as this text is being written for example the very recent and elegant industrial example of a Pd‐mediated coupling of an enol tosylate with a primary amide to form an enamide drug precursor see ref.[30]
For example see:
For example see page 1268 of ref.[1p]
Examples of trisubstituted α‐aryl‐β‐aryl‐N‐acetylenamides or tetrasubstituted α‐aryl‐β‐aryl‐β′‐arylenamides were absent from the reviewed manuscripts. For similar substrates see Q.‐L. Zhou’s recent successes with trisubstituted α‐aryl‐β‐aryl‐N‐pyrrolidinylenamines in Section 2.13 and Figure 22.
For some examples see:
For example see:
For ameta‐CO2Me example see ref.[28d]
For an excellent discussion of the problematic nature of a nitrile substituent see ref.[30]
For example see page 943 of ref.[15b]or page 309 of ref.[21c]
The dates of submission are separated by 3 months see:
Claver C., 2000, Chem. Commun., 961
Submitted April 11 2002 see ref.[34a]
Berg M. van den, Adv. Synth. Catal. 2002, 344, 1003
Submitted August 12 2002 see ref.[21c]
Submitted August 20 2002 see: ref.[45]
No simple name acronym or shorthand was explicitly stated by the publishing author who used or synthesized the indicated ligand. The name or acronym indicated here was assigned in an effort to ease reader recognition without always looking back at the Figures while simultaneously providing structural information and was always done in a way to try and preserve the authors comments when and where possible.
Borghese A., 2008, Process Research and Development of LY414197, a 5HT2B Antagonist, in: Process Chemistry in the Pharmaceutical Industry, Challenges in an Ever‐Changing Climate
Allwein and McWilliams reported on oneorthocontaining fluoro substrate:p‐Br‐o‐F‐phenylenamide 98%ee 89% isolated yield. They employed anN‐trifluoroacetylenamide (see Section 2.10).[22b]Theeefor this substrate is not suprising based on Burk’s very similar result for thep‐F‐o‐F‐phenylenamide (98%ee) using essentially identical reaction conditions and the same catalyst.[22d]Several Josiphos ligands (Figure 20) were also examined but provided significantly lowerees.
For Zheng’s successes with trisubstituted enamides using polymer bound ligands see Section 2.14 Immobilized Catalysts forN‐Acetylenamide Reduction.
Some researchers refer to phosphepines as phosphanes.
The final step of the enamide strategy is an amide hydrolysis or hydrazinolysis see Section 2.1.
See Table 2 entries 11 and 12 of ref.[80]
Zhang showed progress with anN‐carbamoyl‐protected enamide for the synthesis of Zoloft see Table 2 entry 5 of ref.[81]Zoloft (Figure 1 of this manuscript) and a racemic precursor (Figure 16 of this manuscript) of Zhang’s were highlighted earlier in this review. He also examined anN‐tosylenamide.
The conversion and isolated yields are included here because researchers in the enamide reduction field do not provide isolated yield data but instead percent conversion data. The reactions are stated as quantitative but as these industrial chemists demonstrate this is not always the case.
The use of pinacolone (tert‐butyl methyl ketone) and 1‐adamantyl methyl ketone is acceptable because they contain an α‐quaternary carbon ketones lacking a quaternary carbon bound to the carbonyl carbon had not been previously demonstrated.
See ref.[30]and citations given therein.
For an industrial example indicating the need to control residual rhodiumviatreatment with carbon see page 87 of ref.[30]
For literature pertaining to the origins and definition of reductive amination see:
Emerson W. S, 1948, Org. React., 4, 174
Moore M. L., 1949, Org. React., 5, 301
2001, March’s Advanced Organic Chemistry, 1187
Similarly direct asymmetric reductive amination is discouraged and should be replaced by the shorter and more accurate phrase asymmetric reductive amination or enantioselective reductive amination.
See for example:
The reader is referred to the following citations to better appreciate the role of iodine:
Spindler F., 1999, Enantiomer, 4, 557
method for the production of amines by reductive amination of carbonyl compounds under transfer hydrogenation conditions see:A.Börner U.Dingerdissen R.Kadyrov T. H.Riermeier V.Tararov (Degussa AG Germany) U.S. Patent 2004267051 2004.
Method for producing amines by homogeneously catalyzed reductive amination of carbonyl compounds see:T.Riermeier K.‐J.Haack U.Dingerdissen A.Boerner V.Tararov R.Kadyrov (Degussa AG Germany) U.S. Patent 6 884 887 2005.
Note: the aryl alkyl ketones required the addition of 5 mol% TRIP in addition to the noted catalysts.
We were unable to locate the number of equivalents used in the text of the manuscript or its supporting information.
We were unable to locate the wt% of 4 Å molecular sieves used in the text of the manuscript or its supporting information.
process for the preparation of (S S)‐cis‐2‐benzhydryl‐3‐benzylaminoquinuclidine:T. C.Nugent R.Seemayer (Pfizer Products Inc. and DSM Pharmaceuticals Inc.) Patent Appl. WO2004035575 2004.
The method was used as a trade secret within Catalytica/Pfizer since 1998 see citation 19 in ref.[132a]
For recent publications by Bhattacharyya see:
Kumpaty H. J., 2005, Synthesis, 2205
7‐alpha‐Aminosteroid derivatives or pharmaceutically acceptable salts thereof preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient see:H. S.Kim N. J.Cho S. N.Khan (South Korea) Patent Appl. WO 038965 A1 2008.
For an example of another chiral ketone reductively aminated with Ti(O‐i‐Pr)4or Al(O‐i‐Pr)3with hydride reagents see:A process which is useful for converting the carbonyl function in position 4′’ of the cladinose unit of an aza‐macrolide into an amine derivative:J.Dhainaut P.Leon F.Lhermitte G.Oddon (Merial France) U.S. Patent 6 562 953 2003.
No reaction times were reported.
The outlined reductive amination protocols with (R)‐ or (S)‐PEA and prochiral alkyl alkyl′ and aryl alkyl ketones (acyclic or cyclic) allow higher yields and shorter reaction times than the previously practiced two‐step strategyviaisolated (R)‐ or (S)‐phenylethyl ketimines for example compare with:
To enable racemic primary amine formation (not shown) the ketone (structure shown in Scheme 14) was reductively aminated with NH4OAc/NaBH3CN over 15 h at 60 °C providing the racemic amine in 52% yield.
Spindler F., 2007, Enantioselective Hydrogenation of CN Functions and Enamines, in: The Handbook of Homogeneous Hydrogenation, 1193
Blaser H.‐U., 2004, The Chiral Switch of Metolachlor: The Development of a large‐Scale Enantioselective Catalytic Process, in: Asymmetric Catalysis on Industrial Scale, Challenges, Approaches and Solutions, 55
See ref.[151]specifically page 1211.
Reetz M. T., 2008, Ernst Schering Foundation Symposium Proceedings 2007–2, Organocatalysis
Aldrich pricing 2009 5 gram costs 180 Euro July2009.
The modified NaBH4was prepared under the inert conditions of 0 °C with fine grain NaBH4(0.75 mmol) in CH3Cl (5 mL) EtOH (0.75 mmol) tetrahydrofurfuryl alcohol (10.3 mmol) after 3 h of stirring.
Wang Y.‐Q., 2006, Synlett, 8, 1189
Aniline its substituted derivatives andN‐alkylated forms are well known to be genotoxic see:
Braish T. F., 2008, Emerging Trends in Process Chemistry, in: Process Chemistry in the Pharmaceutical Industry, Challenges in an Ever‐Changing Climate, 13
Federsel H.‐J., 2008, To Overcome the Hurdles: Coping with the Synthesis of Robalzotan, a Complex Chroman Antidepressant, in: Process Chemistry in the Pharmaceutical Industry, Challenges in an Ever‐Changing Climate, 111
Sugiura M., 2003, Synlett, 11, 1749
Cozzi P. G., 2003, Synlett, 6
We were unable to locate (in the manuscript or its supporting information) information regarding catalyst loading reaction time and yield for the reuse of the polymeric catalyst.
‐Lin‐Wu P., 1995, Synthesis, 435
Nishikori H., 2003, Synlett, 561
they also examined phenyl methyl N‐Ns‐imines (Ns=p‐nitrobenzenesulfonyl) but the reaction provided low yield (35%) with mediocreee(72%).
No catalyst loading was provided.
Personal communication from Dr. Tamim Braish Senior Director Chemical R&D Pfizer Groton Connecticut USA.