Highly Diastereoselective Synthesis of α‐Difluoromethyl Amines from N‐tert‐Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone

Abstract

The first highly efficient and stereoselective difluoromethylation of structurally diverse N-tert-butylsulfinyl ketimines has been achieved with an in situ generated PhSO(2)CF(2)(-) anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α-difluoromethyl tertiary carbinamines, including α-difluoromethyl allylic amines and α-difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition state may be involved in the reaction.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…On the one hand (A), α-chloro N-tert-butanesulfinyl imines have been reported to provide the corresponding aziridines upon reaction with organomagnesium [11a,27] and organocerium [28] reagents, as well as with KCF 2 SO 2 Ph. [29] On the other hand (B), aza-Darzens-type condensations between carbenoid reagents and N-tert-butanesulfinyl imines have been disclosed with a rather large array of carbanions. These include: lithiated halomethylphosphonates like 14, [30] zincated propargylic and allylic bromides 15 [31] and 16, [32] a lithiated (chloroethyl)oxazoline, [33] lithiated bromoesters such as 17, [34] lithiated halomethanes 18 and 19, [35] the sodium anions of bromoform, [36] chloroform [14] and halo methylsulfones (i.e.…”

Asymmetric Synthesis of Less Accessible α‐Tertiary Amines from Alkynyl Z‐Ketimines

“…[1] Among these,n onproteinogenic a,a-dialkyl-a-amino acids, for instance,have attracted considerable interest in medicinal chemistry and peptide science due to their unique properties. [4][5][6][7][8][9][10][11][12][13][14][15][16] Accessing chiral a-tertiary amines with multiple alkyl substituents in an optically pure form is not trivial;h owever, some methods utilizing 3,3-sigmatropic rearrangement, [5] 1,2rearrangement, [6] asymmetric alkylation [7,8] or asymmetric 1,2-addition [9] have been developed for the asymmetric synthesis of these compounds. Conventionally, tetrasubstituted carbon centers of a-tertiary amines are constructed through various carbon-carbon bond or carbon-nitrogen bond forming reactions (Scheme 1).…”

“…[9][10][11][12][13][14][15][16] Ah igh level of enantiofacial discrimination at the ketimine by utilizing ac hiral catalyst or achiral auxiliary is crucial for asymmetric synthesis of a-tertiary amines.The geometry of the N-substituent of the ketimine has adramatic effect on the enantioselectivity. [9][10][11][12][13][14][15][16] Ah igh level of enantiofacial discrimination at the ketimine by utilizing ac hiral catalyst or achiral auxiliary is crucial for asymmetric synthesis of a-tertiary amines.The geometry of the N-substituent of the ketimine has adramatic effect on the enantioselectivity.…”

“…[11,12,17] The E/Z ratio of the ketimine is dependent on the difference in size between the ketimine substituents.D ue to rapid E/Z isomerization, as ignificant size difference between the two substituents on the imine carbon is required to render one geometric isomer more favorable. [9][10][11][12][13][14][15][16] On the other hand, ak etimine with two similar alkyl groups exists as an inseparable mixture of nearly equal amounts of E and Z-ketimines and inevitably yields the addition product in low stereoselectivity even when using the reliable chiral auxiliary-based methods (Scheme 2a). [9][10][11][12][13][14][15][16] On the other hand, ak etimine with two similar alkyl groups exists as an inseparable mixture of nearly equal amounts of E and Z-ketimines and inevitably yields the addition product in low stereoselectivity even when using the reliable chiral auxiliary-based methods (Scheme 2a).…”

Nonsteroidal Androgen Receptor Ligands: Versatile Syntheses and Biological Data

“…In particular, an alkylation reaction with pfluorophenyl methyl sulfone occurs in good yield (78%) and with 76% diastereomeric excess, which was evaluated by NMR analysis of the crude material. 17 During the purification step, only one diastereoisomer could be isolated. For in vitro experiments, we selected LNCaP and LNCaP-AR human PCa cell lines, considering them the most representative for our preliminary studies.…”