Enantioselective Catalytic α-Alkylation of Aldehydes via an S_N1 Pathway

Abstract

Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of α-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, S N 1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structureactivity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.The anion-binding properties of urea and thiourea derivatives have been exploited recently in enantioselective catalytic reactions involving heteroatom-stabilized carbocations, such as N-acyliminium and oxocarbenium ions. 1,2 Experimental and computational data point to a consistent mechanistic framework wherein the H-bond donor catalysts promote these reactions by anion-abstraction from a neutral organic precursor to generate the more reactive cationic electrophile (Scheme 1). 1b We reasoned that, with the appropriate catalyst and nucleophilic partner, this mode of electrophile activation might also be applicable to catalysis of S N 1 pathways via formation and reactions of carbocations that are not heteroatom-stabilized. 3 Herein we report the successful application of this activation mode to formation of benzhydryl cations in the context of an asymmetric α-alkylation of α-branched aldehydes.The α-alkylation of 2-phenylpropionaldehyde (6a) with bromodiphenylmethane (benzhydryl bromide, 7a) was chosen as a model reaction (Table 1). Classical studies with benzhydryl derivatives have helped to establish much of the conceptual foundations of carbocation reactivity, 4 and these compounds have been especially useful for characterizing the nature and stereochemical properties of ion pairs. 5 The α-alkylation of aldehydes was deemed particularly worthy of investigation because of the high value of chiral aldehydes bearing α-quaternary stereocenters as synthetic intermediates, 6 and the inherent challenges associated with asymmetric catalysis of this type of transformation. 7 A broad screen of potential catalysts in the alkylation of 2-phenylpropionaldehyde with bromodiphenylmethane led to the discovery that primary aminothiourea derivatives were unique in inducing good reactivity and enantioselectivity (Table 1). 8 This class of catalysts has been applied

Asymmetric Ion‐Pairing Catalysis

“…A primary aminothiourea was found to catalyze the enantioselective α-alkylation of α-branched aldehydes with symmetrical diarylbromomethanes (Scheme 35). [123] Several experiments were performed to elucidate the mechanism of this reaction. A normal secondary kinetic isotope effect was observed for the benzhydryl proton, indicating that the electrophilic carbon undergoes rehybridization from sp 3 to sp 2 in the rate-determining transition state.…”

“…Combined with recent advances with bromide- [123] and fluoride-binding systems [124] (vide infra), there is clearly broad potential in asymmetric ion-pairing catalysis using halide counterions.…”

Organocatalytic asymmetric Michael addition of 1-acetylcyclohexene and 1-acetylcyclopentene to nitroolefins

“…Next, we prepared the 9-amino-6'-hydroxy-epi-cinchonidine catalyst VIII, however the enantioselectivity was modest. So, we decided to carry out further 15 reactions with catalyst VII. 20 63 3 2-nitrobenzoic acid 30 64 4 2-bromobenzoic acid 35 64 5 2-methoxybenzoic acid 20 77 6 camphorsulfonic acid <10 nd 7 propionic acid <10 nd a Isolated yield after silica gel column chromatography.…”

“…To expand the scope on the enone side, we screened 1acetylcyclopentene (1b) and 1-acetylcyclobutene (1c) with different nitroolefins (entries [11][12][13][14][15]. The yields of the products with 1-acetylcyclopentene are found to be similar to 1-10 acetylcyclohexene (1a); and the enantioselectivities obtained are good (entries [11][12][13][14].…”

A novel iridium/acid co-catalyzed transfer hydrogenative C(sp3)–H bond alkylation to access functionalized N-heteroaromatics

“…During the past decade, extensive efforts have been directed toward the search for alternative approaches to achieve the related goals. Representative examples mainly involve: (i) The -alkylation of ketones through the reaction of enolates 1 or Stork enamines 2 with carbon electrophiles such as alkyl halides, (ii) directing group-assisted C(sp 3 )-H insertion into olefins 3 , (iii) C-H bond activation followed by the coupling with alkyl halides, 4 (iv) reductive alkylation 5 including hydrogen-borrowing reactions 6 , (v) nucleophilic substitution 7 (vi) acceptorless dehydrogenative coupling (ADC) strategy employed for the reaction of N-heterocycles and reactive carbonyl electrophiles, 8 (vii) cross-dehydrogenative coupling reactions, 9 (viii) carbene insertion into C(sp 3 )-H bonds, 10 (ix)…”