Cyclohexylcarbonitriles: Diastereoselective Arylations with TMPZnCl·LiCl

Abstract

Deprotonating substituted cyclohexanecarbonitriles with TMPZnCl·LiCl affords zincated nitriles that diastereoselectively couple with aryl bromides in the presence of catalytic Pd(OAc)(2) and S-Phos. Steric and electronic effects influence the diastereoselectivity; 4-t-butyl-, 4-TBSO-, and 2-Me-cyclohexanecarbonitriles exert virtually complete diastereocontrol whereas modest diastereoselectivity is observed with 4-i-Pr-, 4-Me-, and 3-Me-cyclohexanecarbonitriles. The unusual diastereoselectivity trends should prove useful for synthesizing substituted cyclohexanecarbonitrile-containing pharmaceuticals.

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

“…Control over the nitrile configuration during α-arylation of cyclohexanecarbonitriles led to an efficient palladium-catalyzed coupling with an unusual diastereoselectivity preference . Various conformationally constrained cyclohexanecarbonitriles 78 preferentially afford α-arylcyclohexanecarbonitriles 81 with the small nitrile in an axial orientation but with diastereomeric ratios that do not directly correlate with the steric demand of the anchoring substituent.…”

“…The amidocuprate is thought to complex the nitrile π bond ( 91 ), positioning the basic amide nitrogen adjacent to the γ-proton for deprotonation. Trapping lithiated delocalized nitrile 92 with electrophiles regioselectively affords α-alkylated quaternary nitriles 93 . Arylations with 2-chloropyridine or 4-iodobenzonitrile afford the corresponding α-arylated nitriles.…”

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

“…However, in the presence of stabilizing groups such as nitriles, esters, or amides deprotometalations using TMPZnCl⋅LiCl may take place . Thus, various benzylic nitriles 11 a , b , alkylic nitriles 11 c – f , an ester 11 g and an amide ( 11 h ) were deprotonated at the most acidic position (p K a =10.8–28.3), producing alkylzinc organometallics 12 a – h in 50–85 % yield (Figure ).…”

Diastereoselective Syntheses of (3R*,4R*)- and (3R*,4S*)-4-Aryl-3-methyl-4-piperidinemethanol and Fluoro Analogues

“…18−20 The applicability of this method to cyclohexanecarbonitriles has recently been addressed, but the use of the starting nitrile in excess (nitrile/aryl halide ratio of 1.5 to 2/1) reduces the attractiveness of the reported procedure in the present work. 20 Although underexploited to date, an improved procedure for direct S N Ar arylation of the potassium salts of secondary nitriles with aryl fluorides has been described by Caron and co-workers. 17 The potassium salts of nitrile derivatives of tropinone were shown to react with fluoroarenes from a less hindered α-equatorial direction.…”

“…The route envisaged for the preparation of hydroxymethylpiperidine 11b involved 4-cyano-3-methylpiperidine 24 as the key intermediate (Scheme ). Indeed, the α-arylation of a secondary aliphatic nitriles with aryl halides provides a valuable entry to tertiary benzylic nitriles, which are precursors of hydroxymethyl derivatives. − Single-step transformation of piperidinone 13 to the nitrile intermediate 24 was carried out using tosylmethyl isocyanide and t -BuOK in DME in 64% yield, giving mixture of diastereoisomers 24a and 24b in a 70/30 ratio. Structural identification of the major isomer 24a was achieved through a combination of NMR spectroscopic analyses (COSY, HSQC, and NOE) from a pure fraction isolated by chromatography .…”