In this work, cross silyl benzoin addition reactions between acylsilanes (1) and aldehydes (2) catalyzed by metal cyanides are described. Unsymmetrical aryl-, heteroaryl-, and alkyl-substituted benzoin adducts can be generated in moderate to excellent yields with complete regiocontrol using potassium cyanide and a phase transfer catalyst. From a screen of transition metal cyanide complexes, lanthanum tricyanide was identified as an improved second-generation catalyst for the cross silyl benzoin reaction. A study of the influence of water on the KCN-catalyzed cross silyl benzoin addition revealed more practical reaction conditions using unpurified solvent under ambient conditions. A sequential silyl benzoin addition/cyanation/O-acylation reaction that resulted in two new C-C bonds was achieved in excellent yield. The mechanism of cross silyl benzoin addition is proposed in detail and is supported by crossover studies and a number of unambiguous experiments designed to ascertain the reversibility of key steps. No productive chemistry arises from cyanation of the more electrophilic aldehyde component. Formation of the carbon-carbon bond is shown to be the last irreversible step in the reaction.

Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday.Trisubstituted allylic alcohols [1,2] are ubiquitous in natural products and are readily converted into diverse chiral building blocks by enantioselective epoxidation, [2a,b] cyclopropanation, [2a,c] hydrogenation, [2a,d] and allylic substitution. [2a,e] Among methods for the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols, alkyne hydrometalation or carbometalation mediated by stoichiometric organometallic reagents has found broad use. [3][4][5][6][7] For example, in seminal studies by Corey et al. (1967), [4c] the regio-and stereoselective hydroalumination of propargyl alcohols was used to construct vinyl iodides, which were converted into trisubstituted allylic alcohols upon exposure to lithium dialkyl cuprates. Similarly, alkyne hydromagnesiation and carbomagnesiation with Grignard reagents delivered trisubstituted allylic alcohols regio-and stereoselectively. [6,7] Although alkyne functionalization through hydrometalation and carbometalation remains at the forefront of research, [3][4][5][6][7] the development of equivalent transformations that avoid stoichiometric metal reagents is clearly desirable. Conversely, whereas related nickel-catalyzed alkyne-carbonyl reductive couplings can be highly regioselective, such processes require terminal reductants that are metallic, pyrophoric, or highly mass intensive (e.g. ZnR 2 , BEt 3 , HSiR 3 ; Scheme 1), [8][9][10] although nickel-catalyzed alcoholmediated alkyne-enone couplings were recently disclosed. [11] Hence, the discovery of alkyne-carbonyl (or alkyneimine) reductive couplings under hydrogenation conditions is significant. [12,13] More recently, an alkyne-carbonyl reductive coupling by ruthenium-catalyzed transfer hydrogenation was developed; however, regioselectivity in such processes remains largely unexplored. [14,15] Herein, we report the regio-and stereoselective synthesis of trisubstituted primary allylic alcohols from alkynes in the absence of stoichiometric metallic reagents. In this reaction, paraformaldehyde is used as a C 1 feedstock and, more remarkably, as a reductant under conditions of transfer hydrogenation with nickel and ruthenium catalysts, which exhibit complementary regioselectivity (Scheme 2).In response to the lack of efficient methods for diene hydroformylation, [16] we recently developed a process for diene hydrohydroxymethylation under the conditions of ruthenium-catalyzed transfer hydrogenation using paraformaldehyde as a C1 feedstock; [17] paraformaldehyde was itself prepared from synthesis gas (via methanol). As the development of efficient catalysts for alkyne hydroformylation remains an unmet challenge, [18] we undertook the current investigation into alkyne-paraformaldehyde reductive coupling. Initial studies focused on the reductive coupling of 1-phenylpropyne (1 a) with paraformaldehyde. We explored the nickel-catalyzed reductive coupling of 1 a with paraformaldehyde in the absence of a reducing agent. [8][9][10] Re...

From a screen of (cyanide)metal complexes, an improved catalyst for the cross silyl benzoin addition was discovered. Several M(CN)(3) complexes (M = Ce, Er, Sm, Y, Yb, La) were evaluated and lanthanum tricyanide was identified as the optimal catalyst. The catalyst, prepared in situ from LaCl(3), effects the selective coupling of aryl and alkyl acylsilanes with aryl, heteroaryl, alpha,beta-unsaturated, and aliphatic aldehydes. The reactions occur at ambient temperature in less than 5 min to provide, depending on the workup, alpha-hydroxy or alpha-silyloxy ketones in 48-93% isolated yield.

No abstract

The conjugate addition of dialkylzinc reagents to allyl fumarates with subsequent Ireland-Claisen rearrangement has been accomplished yielding substituted unsymmetrical succinic acid derivatives. This one-pot reaction creates two new carbon-carbon bonds at contiguous stereogenic centers. The reaction proceeds for several alkylzinc reagents and substituted allyl fumarates. The products contain distinguishable functional handles for further manipulation.The conjugate addition of nonstabilized organometallic nucleophiles to α,β-unsaturated carbonyls is a staple of organic synthesis, but the fumarate and maleate electrophile subclass in this reaction family has received scant attention relative to simple enones and enoates. The comparative lack of research activity is surprising since maleic and fumaric acid derivatives represent cheap progenitors to functionalized succinic acids. Notable advances in this area have been reported. Ibuka and co-workers disclosed organocopper(I)-Lewis acid additions to fumarate esters that afforded good yields of the addition products; however, olefin reduction was a competing reaction pathway. 1 Hayashi and co-workers have reported enantioselective rhodium-catalyzed 1,4-additions of arylboronic acids to fumarates and maleates.2 While these examples provide useful conjugate adducts, a nonobvious feature of the reported additions is that the carbonyls in the products are still functionally equivalent and therefore challenging to distinguish. In this paper, we describe the conjugate addition of dialkylzinc reagents to diallyl fumarates with subsequent Ireland-Claisen rearrangement to give unsymmetrical succinate products. A defining characteristic of the title reaction is chemodifferentiation of the two carbonyls that can be exploited in further selective manipulations. 4 We envisioned that by using an allyl fumarate as the conjugate acceptor with an organometallic nucleophile, the metal enolate or derived silyl ketene acetal generated in situ would undergo a subsequent ester enolate Claisen rearrangement (Scheme 2). 5 In accord with precedent, the use of a chlorotrialkylsilane was projected to both accelerate the conjugate addition and generate the requisite silyl ketene acetal. 6,7