Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in a Regioselective Aniline Synthesis

Abstract

Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (k(H/D) 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.

Reaction Mechanism of Vinamidinium Salts and Cyanoacetamide Derivatives

“…Starting material (E)-N-(3-(dimethylamino)-2-phenylallylidene)-N-methylmethanaminium perchlorate (1) was prepared according to the reported procedure. 16 HRMS data were acquired using ESI-TOF detection. The melting point was measured on a WRS-2A melting point apparatus and is uncorrected.…”

One-pot and metal-free synthesis of 3-arylated-4-nitrophenols via polyfunctionalized cyclohexanones from β-nitrostyrenes

“…The derivatives of 4-nitrophenol are widely used in various applications. In particular, 3-arylated-4nitrophenols have attracted much attention from a biological viewpoint [1][2][3][4][5][6][7][8][9][10][11]; however, they cannot be synthesized by the direct modification of 4-nitrophenol because the ortho-directing hydroxy and the meta-directing nitro group hinder the electrophilic modification at the 3-position. Generally, the aryl group is introduced by a Suzuki-Miyaura cross-coupling reaction [4,5], for which 3-bromo-4-nitrophenol must be prepared by the nitration of 3-bromophenol [6,7].…”

“…Although the hydroxylation of 3-arylated-1-fluoro-4-nitrobenzene has also been reported as a related strategy, multistep reactions are necessary for preparing the precursor [ 10 ]. The condensation of benzyl methyl ketone with a nitrovinamidinium salt also affords 3-arylated-4-nitrophenols; however, 3-arylated- N , N -dimethyl-4-nitroanilines are competitively formed in this reaction [ 11 ]. Hence, there is an urgent demand for the development of a facile method toward the preparation of 3-arylated-4-nitrophenols.…”

Strong overcrowding in dimethyl 2-(dimethylamino)terephthalate

“…In one case (refcode CUNJEA; Swisher et al, 1984) the pattern of deformations is very similar to the present one. In the other (refcode ISOGOM; Davies et al, 2004), the pattern is different. In fact, the N atom has a trigonal planar geometry, with the plane twisted with respect to the benzene ring (by about 20 ); a higher twist of the carbonyl group is observed and the carbonyl C atom is essentially coplanar with the ring.…”