Ni-Catalyzed Iterative Alkyl Transfer from Nitrogen Enabled by the In Situ Methylation of Tertiary Amines

Abstract

Current methods to achieve transition-metal-catalyzed alkyl carbon–nitrogen (C–N) bond cleavage require the preformation of ammonium, pyridinium, or sulfonamide derivatives from the corresponding alkyl amines. These activated substrates permit C–N bond cleavage, and their resultant intermediates can be intercepted to affect carbon–carbon bond-forming transforms. Here, we report the combination of in situ amine methylation and Ni-catalyzed benzalkyl C–N bond cleavage under reductive conditions. This method permits iterative alkyl group transfer from tertiary amines and demonstrates a deaminative strategy for the construction of Csp3–Csp3 bonds. We demonstrate PO­(OMe)3 (trimethylphosphate) to be a Ni-compatible methylation reagent for the in situ conversion of trialkyl amines into tetraalkylammonium salts. Single, double, and triple benzalkyl group transfers can all be achieved from the appropriately substituted tertiary amines. Transformations developed herein proceed via recurring events: the in situ methylation of tertiary amines by PO­(OMe)3, Ni-catalyzed C–N bond cleavage, and concurrent Csp3–Csp3 bond formation.

An amine template strategy to construct successive C–C bonds: synthesis of benzo[h]quinolines by a deaminative ring contraction cascade

“…We recently developed an amine methylation and C-N bond cleavage strategy to enable iterative benzalkyl group transfer from tertiary amines for the synthesis of 1,2-diarylethanes (Scheme 2). 30 In this reaction, PO(OMe) 3 chemoselectively methylates the tertiary amine in the presence of low valent Ni complexes. In situ formed ammoniums undergo benzalkyl group transfer as exemplified by the conversion of dibenzylmethylamine 10 into 1,2-diphenylethane 11.…”

“…The efficiency of PO(OMe) 3 cannot be replaced by MeI (entry 4) and attempts to generate MeI in situ by the addition of iodide (entry 5) were ineffective. 30,41 In anticipation of facilitating deprotonation events common to [1,2]-Stevens rearrangement and Hofmann elimination reactions, we evaluated additive sodium dimethylphosphate (entry 6). [3][4][5][6][7] Unfortunately, this and related additives had no detectable benefit.…”

“…[3][4][5][6][7] Unfortunately, this and related additives had no detectable benefit. We show seven substituted benzo[h]quinolines (29)(30)(31)(32)(33)(34)(35) are accessible following the developed build; cyclize; deaminate strategy. Substitution is tolerated at all examined posi-tions.…”

“…However, the lower observed yield for C7-methyl 33, may be the result of impeded methylation and ring contraction events due to proximal steric crowding. Despite the low to moderate yields obtained for these benzo[h]quinolines (29)(30)(31)(32)(33)(34)(35), their purifications are simple. 42 The corresponding 2,2′-dimethylbiaryl products (confer 28) are not observed.…”

Synthesis of Dibenzyls by Nickel-Catalyzed Homocoupling of Benzyl Alcohols

“…C NMR (100 MHz, CDCl 3 ):  = 157.7, 131.0, 129.9, 127.1, 120.4, 110.3, 55.4, 30.6. IR (neat): 2963, 2933, 1599, 1493, 1465, 1245, 1180, 1096, 1047, 1031, 753 cm -1 .1,2-Bis(3-methoxyphenyl)ethane (2d, known)23 Yield: 32.0 mg (66%); white solid; mp: 47-49 °C.1 H NMR (400 MHz, CDCl 3 ):  = 7.20 (t, J = 7.7 Hz, 2 H), 6.79 (d, J = 7.5 Hz, 2 H), 6.77-6.72 (m, 4 H), 3.78 (s, 6 H), 2.89 (s, 4 H) 13. C NMR (100 MHz, CDCl 3 ):  = 159.7, 143.5, 129.4, 121.0, 114.3, 111.4, 55.2, 38.0.…”