Methodologies in Amine Synthesis

5 Chapter 5Scheme 5.1 General equation for the reductive amination of an aldehyde or a ...Scheme 5.2 Reductive amination of 2‐methyl‐6‐ethyl‐aniline and methoxyaceton...Scheme 5.3 Reductive amination of the ketone function to produce the chiral ...Scheme 5.4 Chiral bisphosphine‐thiourea ligand (ZhaoPhos ligand).Scheme 5.5 Intramolecular asymmetric reductive amination using [Ir(COD)Cl] 2/...Scheme 5.6 Synthesis of ( S )‐rivastigmine from meta ‐hydroxyacetophenone and d...Scheme 5.7 Asymmetric reductive amination under dynamic kinetic resolution c...Scheme 5.8 Reductive amination of alkyl aryl ketones catalyzed by [Ru(OAc) 2]...Scheme 5.9 The Knölker iron catalyst and the TRIP Brønsted acid.Scheme 5.10 Asymmetric reductive amination of 2‐methyl cyclopentanone and cy...Scheme 5.11 Asymmetric hydroamination of an unactivated alkene with a second...Scheme 5.12 Enantioselective hydroamination of 1‐octene with 1‐ tert ‐butylimi...Scheme 5.13 Proposed mechanism for the asymmetric hydroamination of ( R )‐3‐pe...Scheme 5.14 (a) Enantioselective hydroamination of styrene catalyzed by the ...Scheme 5.15 Iridium‐catalyzed hydroamination of norbornene by 4‐bromoaniline...Scheme 5.16 Intramolecular hydroaminomethylation of 5‐hex‐1‐ene amines catal...Scheme 5.17 Asymmetric intramolecular hydroamination of 2,2,5‐triphenylpent‐...Scheme 5.18 Stereoselective synthesis of 2,5‐substituted pyrrolidines from c...Scheme 5.19 Synthesis of the enantiopure α‐arylpyrrolid...Scheme 5.20 Chiral aziridine synthesis catalyzed by a Cu–H/( S )‐DTBM‐SegPhos ...Scheme 5.21 Hydroaminoalkylation of a secondary amine through C=C bond forma...Scheme 5.22 Synthesis of the tantalum catalyst precursor in the hydroaminoal...Scheme 5.23 Main steps of the catalytic cycle calculated by DFT, showing the...Scheme 5.24 Intermolecular coupling of N ‐methylaniline with...Scheme 5.25 Hydroaminomethylation reaction of olefins: synthesis of amines....Scheme 5.26 Rh‐catalyzed hydroaminomethylation of styrene using L1–L4 ...Scheme 5.27 Energy values for the hydrogenation of E ‐ and Z ‐enamines.Scheme 5.28 Dynamic kinetic reductive amination of aldehydes developed by Li...Scheme 5.29 Rh‐ and organocatalyzed asymmetric hydroaminomethylation of styr...Scheme 5.30 Improved system in the metal and organocatalyzed asymmetric HAM ...Scheme 5.31 Rh‐catalyzed asymmetric interrupted hydroaminomethylation of sty...Scheme 5.32 Rh‐catalyzed asymmetric hydroaminomethylation of...Scheme 5.33 Rhodium species observed in the Rh‐catalyzed asymmetric hydroami...Scheme 5.34 Asymmetric photoredox β‐amination of α,...

6 Chapter 6Scheme 6.1 Hajos–Parrish–Eder–Sauer–Wiechert reactions for the synthesis of ...Scheme 6.2 Alkylation of a substituted indanone 6 catalyzed by Cinchona alka...Scheme 6.3 Retrosynthetic approach for the synthesis of telcagepant.Scheme 6.4 Optimized organocatalytic asymmetric addition of nitromethane to ...Scheme 6.5 Retrosynthetic plan to obtain MK‐8613, by using asymmetric organo...Scheme 6.6 Enantioselective malonate addition to nitrostyrene 18 promoted by...Scheme 6.7 Retrosynthetic approach to funapide encompassing the organocataly...Scheme 6.8 Optimized enantioselective aldol reaction between 21 and formalde...Scheme 6.9 Retrosynthetic analysis of letermovir encompassing the key organo...Scheme 6.10 First‐generation enantioselective aza‐Michael cyclization based ...Scheme 6.11 Second‐generation enantioselective aza‐Michael cyclization based...Scheme 6.12 Possible transition states for the aza‐Michael reaction with H‐b...Scheme 6.13 Retrosynthetic approach for the synthesis of censavudine.Scheme 6.14 Synthesis of enantiopure pyranones 38 via a dynamic kinetic acyl...Scheme 6.15 Trapping of the furanose form 37′ with benzoic anhydride u...Scheme 6.16 Regio‐ and stereoselective (at P) introduction of the phosphoram...Scheme 6.17 Stereoselective phosphoramidate formation in uprifosbuvir synthe...Scheme 6.18 Pfizer manufacturing route to pregabalin encompassing an early‐s...Scheme 6.19 Retrosynthetic disconnections of the γ‐amino acid pregabalin.Scheme 6.20 Desymmetrization of glutaric anhydride 53 promoted by quinine 58Scheme 6.21 Synthesis of pregabalin and ent ‐pregabalin by catalytic desymmet...Scheme 6.22 Enantioselective conjugate addition of cyanide to alkylidene mal...Scheme 6.23 Enantioselective addition of nitromethane to 74 catalyzed by ent Scheme 6.24 Synthesis of pregabalin on kilogram scale via enantioselective c...Scheme 6.25 Enantioselective additions of acetaldehyde to nitroalkene 56 und...Scheme 6.26 One‐pot synthesis of pregabalin by a “Michaelase” enantioselecti...Scheme 6.27 Simplified reaction pathway, intermediates, and transition state...Scheme 6.28 Addition of malonates to nitroalkene 56. Selected bifunctional c...Scheme 6.29 Downstream routes to pregabalin from catalytic product 87.Scheme 6.30 Typical preparation of nitroalkene 56 vs. flow chemistry approac...Scheme 6.31 Three‐component approach to 87 by the multisite hybrid catalyst Scheme 6.32 Enantioselective additions of Meldrum's acid to nitroalkene 56 c...Scheme 6.33 Telaprevir and synthetic approaches to its bicyclic amino acid c...Scheme 6.34 Synthesis of N ‐benzyl telaprevir core 111 based on quinidine 103Scheme 6.35 Retrosynthetic approaches to the telaprevir core 98: desymmetriz...Scheme 6.36 Enantioselective approach to telaprevir core 98 by chiral masked...Scheme 6.37 PTC in enantioselective conjugate additions of benzophenone glyc...Scheme 6.38 PTC addition of benzophenone glycinate imine 122 with binaphthyl...Scheme 6.39 PTC addition of benzophenone imine glycinate 122 to 114 catalyze...Scheme 6.40 Alternative glycinate imine substrates 133 and 136 applied to th...Scheme 6.41 Aminocatalytic additions of 2‐amidomalonates 138 and 139 to cycl...Scheme 6.42 Aminocatalytic addition of ethyl nitroacetate 142 to cyclopent‐1...Scheme 6.43 Aminocatalytic conjugate additions of nitromethane to cyclopent‐...Scheme 6.44 Conversion of the γ‐nitroaldehyde 145 to the...Scheme 6.45 Conversion of the γ‐nitroaldehyde adduct 145 to the...Scheme 6.46 5‐(Trifluoromethyl)‐2‐isoxazoline veterinary drugs.Scheme 6.47 Nissan Chemical Industry approach to the 5‐(trifluoromethyl)‐2‐i...Scheme 6.48 Enantioselective preparation of 5‐(trifluoromethyl)‐2‐isoxazolin...Scheme 6.49 Proposed reaction pathway and transition‐state model A with a ci...Scheme 6.50 Application of the PTC 5‐(trifluoromethyl)‐2‐isoxazoline formati...Scheme 6.51 Application of the PTC isoxazoline forming reaction to azetidine...Scheme 6.52 Large‐scale examples of the utilization of catalyst 172 in ( S )‐a...Scheme 6.53 PTC enantioselective reaction with Syngenta's candidates: select...Scheme 6.54 Dimeric quininium catalysts 186, 187 in the diastereoselective i...

7 Chapter 7Scheme 7.1 Biocatalytic strategies for chiral amine synthesis. Opine dehydro...Scheme 7.2 Evolution of the substrate scope of the monoamine oxidase from As ...Scheme 7.3 Enzymatic cascades involving MAO‐N variants for the preparation o...Scheme 7.4 Chemoenzymatic cascades involving MAO‐N variants for the preparat...Scheme 7.5 CHAO variants in the biocatalytic deracemization of THQs.Scheme 7.6 6‐HDNO wild‐type (black) and D350L/E352D (blue) cyclic amine subs...Scheme 7.7 Difference between reactions catalyzed by AADH and AmDH.Scheme 7.8 Selected substrate scope of the original AmDH variants developed ...Scheme 7.9 Examples of preparative scale reactions using natural AmDH.Scheme 7.10 Longer chain ketones accepted by the pocket‐expanded AmDH descri...Scheme 7.11 Scale‐up reductive amination of 2‐phenoxypropanone. CFE, cell‐fr...Scheme 7.12 Preparative scale biosynthesis of benzylic amines.Scheme 7.13 AmDH synthesis of intermediate for ethambutol.Scheme 7.14 Biocatalytic hydrogen borrowing cascade for chiral amine synthes...Scheme 7.15 Sequential dihydroxylation/hydrogen borrowing amino‐hydroxylatio...Scheme 7.16 Imine reductases in biosynthesis.Scheme 7.17 Enantioselective reduction of 2‐methylpyrroline.Scheme 7.18 Further Mitsukura IRED transformations.Scheme 7.19 IREDs in biocatalytic cascade synthesis.Scheme 7.20 IREDs in chemoenzymatic synthesis.Scheme 7.21 IRED‐catalyzed reductive amination reactions.Scheme 7.22 Applications of reductive aminases in amine alkylation cascades....Scheme 7.23 Reductive aminase‐catalyzed step in the synthesis of GSK2879552....Scheme 7.24 P411‐catalyzed intramolecular C–H amination.Scheme 7.25 Applications of engineered cytochrome P411 biocatalysts for chir...