Cross-benzoin products

The benzoin reaction typically consists of the homocoupling of two aldehydes, which results in the formation of inherently dimeric compounds, therefore limiting the synthetic utility. The aoss-benzoin reaction has the potential to produce four products, two homocoupled adducts and two cross-benzoin products. Several strategies have been employed to develop a selective cross-benzoin reaction, including the use of donor-acceptor aldehydes, acyl silanes, acyl imines, as well as intramolecular reactions. 

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

An alternative strategy to access cross-benzoin products is to tether the two reactive parmers. This approach has the disadvantages inherent to intramolecular reactions, but it provides access to products produced by the coupling of aldehydes with ketones, hi... 

In 2010, the Enders group reported asymmetric cross-benzoin reactions of aldehydes with ketones by using a novel chiral triazolium NHC catalyst precursor with a sterically demanding silyl protecting group. Under the optimized conditions, several heteroaromatic aldehydes reacted smoothly with aromatic trifluoroketones (2.0 equiv.) providing cross-benzoin products in up to 96% yield and 85% ee, and the enantioselectivity was improved to 99% ee by further crystallization. Through direct observation of the reaction by NMR and racemization experiments, the authors showed that the product is formed under kinetic control (Scheme 7.6). 

Two related modifications have been developed to provide cross-benzoin products not accessible under classical benzoin condensation conditions. In the first approach, one aldehyde partner is converted to a cyanohydrin derivative which serves as the stoichiometric equivalent of intermediate 3a on the catalytic cycle of the cyanide-catalyzed benzoin condensation. A number of cyanohydrin derivatives can be used, with the most popular being the O-silyl cyanohydrin 14, first reported by Hiinig and Wehner. In a subsequent step, the cyanohydrin derivative is treated with stoichiometric base followed by the second aldehyde to give the silylated cross-benzoin product 16 in high yield. 

Chiral metallophosphites were found to be effective catalysts of the acylsilane/aldehyde cross-benzoin condensation in work reported by Johnson and co-workers. The TADDOL-derived catalyst 21 is very effective for the preparation of aryl-aryl cross benzoin products, with yields from 65-87% and enantiomeric purities from 81-91% ee. The more difficult aryl-alkyl, and alkyl-aryl cross-benzoin products can also be generated, with yields from 72-88% and enantiomeric purities from 41-73% ee. 

The chemo- and enantioselective cross-couphng of two different aldehydes via a benzoin reaction remains a significant challenge. Four different benzoin products can be formed (two homo- and two cross-benzoin products), each as two possible enantiomers. The challenge is compounded by the commonly observed reversibility of the reaction. 

Mennen and Miller reported the macrocyclization of dialdehydes to obtain the cross-benzoin products in low yields but high chemoselectivity using an N-QFs triazolium precatalyst (Scheme 18.2) [25]. The chemoselective formation of 28 was... 

Yang and coworkers reported chemoselective cross-benzoin reactions between o-unsubstituted benzaldehydes and an excess (10 equiv.) of acetaldehyde (Scheme 18.4) [27]. Either cross-benzoin product 37 or 38 could be obtained selectively by employing a thiazoUum or triazolium salt, respectively. The chemoselective... 

Connon, Zeitler, and coworkers showed a-ketoesters to be competent reaction partners when using N-C Fs triazolium salt 17 [31]. Even aliphatic a-ketoesters could serve as substrates while avoiding possible competing aldol pathways. The enantioselective version of the reaction proved challenging, and cross-benzoin product 44 could be obtained in only moderate yield and enantioselectivity (Scheme 18.6). Intermolecular formal cross-benzoin reactions using pyruvate as an aldehyde equivalent were also shown to be possible, using a thiamine-dependent enzyme, with broad substrate scope [32]. 

Attempted intermolecular cross-benzoin reactions typically generate a thermodynamically controlled mixture of products [50], although several groups including Enders [51], Suzuki [52] and You [53] have utilised catalysts 116-118 for the intramolecular crossed benzoin of keto-aldehydes (Scheme 12.22). 

Suzuki and co-workers reported the intramolecular cross-benzoin reaction utilizing thiazolium pre-catalyst 35 to obtain products such as 37 and 38 (Eq. 3) [49],... 

The authors describe a control experiment in which CTOss-benzoin product 245 was subjected to standard reaction conditions with achiral triazolium pre-catalyst 191 yielding retro-benzoin products, as well as cyclopentene product 247 Eq. 24. This result additionally demonstrates the reversibility of the benzoin reaction. When trimethylsilyl-protected 245 is treated under the same reaction conditions with ethanol as a nucleophile, ketoester 248 is formed along with retro silyl-benzoin and Stetter products. This result provides enough evidence that the cross-benzoin/oxy-Cope mechanism cannot be dismissed. 

DMSO), a reaction temperature of 37 °C, and a residence time of 90 min, achieved by recirculating the reaction mixture through the PASSflow reactor at a flow rate of 1.0 ml min-1, the authors were able to attain 99.5% conversion of 116 to (R)-benzoin 159, determined by off-line GC analysis. Increasing the reactant concentration from 5.5 x 10 2 to 0.2 M, resulted in a reduction in benzoin 159 production of 5.9%, with longer reaction times required to attain high conversions with further increases in reactant concentration (typically 9h for 1.0 M 116). The authors subsequently demonstrated the cross-benzoin reaction between acetaldehyde... 

Recently, there has heen some work dealing with the cross-henzoin condensation to afford nonsymmetrical products chemoselectively. In this case, the Breslow intermediate has to he formed predominantly with only one of the aldehydes and react selectively with the other one. Kuhl and Glorius have succeeded in this area developing a selective hydro gmiethylation of aldehydes.With a different approach, it is also possible to use hindered ortho-substituted aldehydes to inhibit the retro-benzoin reaction and the attack of the As an extension, the cross-benzoin reaction has been... 

Compared with the aldehyde-ketone cross-benzoin reaction, intermolecular aldehyde-aldehyde coupling reactions are much more challenging, as the addition of the second aldehyde means the number of possible products is quadrupled. 

The Bode group documented a remarkable annulation reaction of 3-alkyl or 3-aryl enals with chalcone-derived imines which allows direct access to cyclopentyl-fused p-lactams with four contiguous stereocenters in an operationally simple process/ A pronounced effect of the catalytic base on the diastereoselectivity was discovered. Using 3-alkyl enals as the substrates, DBU performed as the most optimized base to afford products in up to 94% yield, >10 1 dr, and 99% ee. When cinnamaldehyde derivatives were used, it was necessary to choose DMAP as the catalytic base in order to ensure the formation of desired products in a diastereoselective manner (up to 80% yield, >20 1 dr, >99% ee). Supported by the stereochemical outcome, a tandem, or possibly concerted, crossed-benzoin/oxy-Cope reaction as the key bond-forming step was rationalized (Scheme 7.57). 

In 2005, Enders et al. reported the first enantioselective intramolecular crossed-benzoin reaction catalysed by novel chiral bicyclic D1 or tetracyclic El triazolium carbenes. A number of benzoin products 4 with a quaternary carbon stereocentre were obtained in high yields with good to high enan-tioselectivities (Scheme 20.4). ... 

Intramolecular Cross-Benzoin Reaction. In 2003, Suzuki and coworkers [21] reported the intramolecular cross-benzoin reaction utilizing thiazolium precatalyst 8 to gain the corresponding products 7 in good yields (Scheme 7.6). 

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

The cross-benzoin reaction between two different aldehydes typically produces a statistical mixture of products, although in some cases a single thermodynamic product predominates. A number of approaches have been developed to circumvent the limitations of the cross-benzoin reaction. In one approach, a thiamine diphosphate-dependent enzyme is used to promote a selective cross-benzoin reaction, often with high levels of asymmetric induction. In other approaches, one aldehyde coupling partner is replaced with a selective acyl donor. Cyanohydrin derivatives have proven to be ideal preformed acyl donors, and their use constitutes a stepwise benzoin condensation that is stoichiometric in cyanide. The discovery that acylsilanes can serve as cyanohydrin precursors has led to the development of a highly selective cyanide-catalyzed cross-benzoin condensation. By employing a chiral metallophosphite catalyst instead of potassium cyanide, good to excellent levels of asymmetric induction are possible. 

The cross-benzoin condensation often results in the production of mixtures of products, although a small number of specific aldehyde pairs have been identified to participate in selective cross-benzoin condensations. Eor example, the reaction of 3-ethoxy-4-methoxybenzaldehyde (11) and 2-chlorobenzaldehyde (12) in 1 1 stoichiometry provides 2 -chloro-3-ethoxy-4-methoxybenzoin 13 in high yield. These selective reactions are generally believed to be under thermodynamic control, with the predominant product containing the electron-rich aryl ring adjacent to the ketone. Investigations... 

The enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BFD) have also been shown to catalyze enantioselective cross-benzoin reactions. Aryl-aryl as well as aryl-alkyl products are produced in high yield and enantiomeric purity. In the case of aryl-aryl products, the success of the reaction depends on the empirical identification of suitable donor/acceptor pairs. Aldehydes containing or/Ao-substituents were found to be ideal acceptors in BAL and BFD-catalyzed cross-benzoin reactions. The preparation of (/ )-l-(4-bromophenyl)-2-(2-chlorophenyl)-2-hydroxyethanone (25) from 4-bromobenzaldehyde (23) and 2-chlorobenzaldehyde (24) highlights the high conversion and selectivity possible in this transformation. As with rac-benzoin, rac-l-(4-bromo-phenyl)-2-(2-chlorophenyl)-2-hydroxyethanone is easily resolved by BAL to give the (5)-enantiomer with high enantiomeric purity. 

Furthermore, N-silyl oxyketene imines derived from protected cyanohydrins were found to serve as acyl anion equivalents in a similar reaction manifold, enabling the efficient preparation of cross-benzoin and glycolate-aldol products in an almost stereochemically pure form (Scheme 7.11) [18]. 

In 2011, Connon, Zeitler, and coworkers reported detailed studies on intermolecular cross-benzoin reactions using triazoUum and thiazoUum salts [26]. These systematic studies clearly showed the intricate interplay of various factors influencing the outcome of cross-benzoin reactions. In line with the results of Miller and coworkers, the use of o-substituted benzaldehydes resulted in selective formation of benzylic alcohol products using either triazolium or thiazolium salts. When using o-unsubstituted benzaldehydes, the same chemoselectivity could be achieved with an a-branched aliphatic aldehyde and an N-QFs triazolium catalyst. Crossover experiments showed the reaction to be under kinetic control in many cases. When using chiral catalyst 31, good chemo- and enantioselectivity was achieved in the reaction between o-trifluoromethylbenzaldehyde (30) and propanal (29) (Scheme 18.3). 

The enantioselective intramolecular cross-coupUng of aldehydes and ketones to access cyclic a-hydroxy ketones has also been demonstrated. Issues of chemoselectivity are largely avoided in these cases, and the benzoin reaction can be achieved in a highly efficient and enantioselective manner (up to 93% yield and 99% ee) [28]. The usefulness of the intramolecular cross-benzoin reaction was elegantly illustrated in two separate cydizations for the synthesis of seragakinone A, an antifungal and antibacterial natural product [29]. 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

In a cross-coupling benzoin condensation of two different aldehydes, usually a mixture of products is obtained, with the ratio being determined by the relative stabilities of the four possible coupling products under thermodynamic control. If, however, an acyl silane, e.g. 5, is used as the donor component, the a-silyloxy-ketone 6 is obtained as a single product " ... 

---