Benzoin condensation crossed

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 " ... 

Highly selective cross-coupling benzoin condensations have been achieved via the use of enzymatic methods. ... 

Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. Arthur Lapworth (1872—1941) was bom in Scotland. He was one of the great figures in the development of the modem view of the mechanism of organic reactions. Lapworth investigated the Benzoin condensation at the Chemical Department, The Goldsmiths Institute, New Cross, UK. 

P. Dtinkelmann, D. Kolter-Jung, A. Nitsche, A. S. Demir, P. Siegert, B. Lingen, M. Baumann, M. Pohl, M. Muller, Development of a donor-acceptor concept for enzymatic cross-coupling reactions of aldehydes, the first asymmetric cross-benzoin condensation. f Am. Chem. Soc. 2002, 124, 12084-12085. 

Starting from the findings of the racemic cross-benzoin condensation [66], and assuming that aldehydes not accepted as donor substrates might still be suitable acceptor substrates, and vice versa, a mixed enzyme-substrate screening was performed in order to identify a biocatalytic system for the asymmetric cross-carboligation of aromatic aldehydes. For this purpose the reactions of 2-chloro-(40a), 2-methoxy- (40b) and 2-methylbenzaldehyde (40c), respectively, were studied with different enzymes in combination with benzaldehyde (Scheme 2.2.7.23) [67]. The three ortho-substituted benzaldehyde derivatives 40a-40c were... 

The selective donor-acceptor concept can be transferred to other ThDP-dependent enzymes. For example, enantiopure mixed benzoins were obtained when 2-chlorobenzaldehyde reacted with a variety of selective donor aldehydes in the presence of BAL [67]. By performing various cross-benzoin condensation reactions with this enzyme, not only new selective donors but also additional aldehydes reacting selectively as acceptors, such as 2-iodobenzaldehyde or 2,6-difluorobenzaldehyde, could be identified. Again all the mixed benzoins generated exhibited an R-configuration and were obtained with high to excellent enantiomeric excesses [69]. 

The selectivity is caused not only by the electronic properties of the substrates which are dependent on the nature of their substituents, as is the case in the chemical cross-benzoin condensation. Rather, steric demands of the aldehyde substituents and interactions of these with the active site of the biocatalyst, which (obviously) is different for each enzyme used, are also of significance. 

In order to develop a general method, the present authors began investigations on the use of simple aldehyde ketones as substrates for the carbene-catalyzed crossed intramolecular benzoin condensation. Synchronously to the studies of... 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

The precatalyst 20 led to excellent results in the enantioselective intramolecular crossed benzoin condensation of the aldehyde ketones 24, as shown in Scheme 9.6. The quaternary stereocenter of the acyloins 25 was created with good to very good yields and excellent ee-values. (For experimental details see Chapter 14.20.1). The precatalyst 19 proved to be even more active, and the yields were consistently excellent, albeit accompanied by lower ee-values (63-84%). 

The substrates of the enantioselective intramolecular crossed benzoin condensation were varied to widen the scope of the reaction. Promising results were... 

Enders D, Kallfass U (2002) An efficient nucleophilic carbene catalyst for the asymmetric benzoin condensation. Angew Chem Int Ed 41 1743-1745 Enders D, Niemeier O (2004) Thiazol-2-ylidene catalysis in intramolecular crossed aldehyde-ketone benzoin reactions. Synlett 2004 2111-2114 Enders D, Niemeier O, Balensiefer T (2006) Asymmetric intramolecular crossed-benzoin reactions by N-heterocyclic carbene catalysis. Angew Chem Int Ed 45 1463-1467... 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

Pyridazine 3-carbaldehyde can be prepared from 3-hydroxymethylpy-ridazine by oxidation with selenium dioxide (82BSB153). Its 2-oxide was obtained similarly (78JMC1333). Contrary to aromatic aldehydes, py-ridazine-4-carbaldehydes behave differently under the reaction conditions typical for benzoin condensation or cyanhydrin formation. In the first case, a crossed Cannizzaro reaction takes place and, with an equivalent amount of hydrocyanic acid, compound 80 is obtained. This is transformed with acetic anhydride into a mixture of E- and Z-isomers of 81. On attempted chromatographic separation, the mixture is converted into methyl 4-pyridazinecarboxylate (78JHC637). 

In the laboratory of K. Suzuki, a cataiytic crossed aidehyde-ketone benzoin condensation was developed and applied to the synthesis of stereochemically defined functionalized preanthraquinones. ... 

Duenkelmann, P., Kolter-Jung, D., Nitsche, A., Demir, A. S., Siegert, P., Lingen, B., Baumann, M., Pohl, M., Mueller, M. Development of a Donor-Acceptor Concept for Enzymatic Cross-Coupling Reactions of Aldehydes The First Asymmetric Cross-Benzoin Condensation. J. 

Acetylation, chlorination, reduction (aldehyde - alcohol), Benzoin condensation, Wittig-, (jrignard-, Aldol reaction, Suzuki-Miyaura cross-coupling, directed ortho-metalation [91]. 

From two conjugated carbonyl compounds the cross-benzoin condensation initiated by a chiral azolecarbene (199) sets up a sequence of oxy-Cope rearrangement, aldol reaction and decarboxylation/ ... 

PhCH2) catalyze the benzoin condensation. The methyl derivative (303 R = Me) readily cleaves to yield the nucleophilic carbene (304), which has been trapped by reaction with carbon disulphide to yield the cross-conjugated 1,3-dipole (305) the latter in turn adds dimethyl acetylenedicarboxylate to form the dithiole (306).286... 

Leznoff et al. described the use of polymer supports for the mono-protection of symmetrical dialdehydes, describing oxime formation, H img-reaction, crossed aldol-condensation, benzoin-condensation and Grignard- reaction on solid support. 

Melchione s team reported the asymmetric catalysis of Diels-Alder reactions of IQDs (Scheme 11, equation 1) [69, 70], In addition to other nitro-substituted arylethenes, methyleneindolinones were employed as dienophiles. A limited selection of the compounds synthesized is shown in Scheme 11 (30-32). The third compound (32) is the result of a final cross-benzoin condensation. Chen and colleagues effected an asymmetric Diels-Alder reaction of IQDs (33) generated under mild acidic conditions from 2-methyl-3-indolemethanols and a,p-unsaturated aldehydes (equation 2) [71], Three representative indoles that were prepared in this fashion are 34 to 36. The IQD 33 is presumed to be in equilibrium with the 3-vinylindolenium species. A wide range of substituted trani-cinnamalde-hydes was successfully employed. Although other acids (HOAc, TFA, PhCO H, silica gel) effected the reaction, Montmorillonite KIO clay was superior in terms of yield, enantioselectivity, and diastereoselectivity. 

A review of the asymmetric Stetter and asymmetric benzoin reactions focuses mainly on two classes of highly successful catalysts NHCs and metallophosphites. A new NHC, pyrido[l,2-a]-2-ethyl[l,2,4]triazol-3-ylidene (99), is a powerful catalyst of benzoin condensation in the presence of potassium f-butoxide. A DFT study of the mechanism suggests that the f-butanol solvent is explicitly involved. o-Phthalaldehyde chalcones (100) undergo intramolecular aldehyde-ketone crossed-benzoin condensation to naphthalenone tertiary alcohols (101) in yields up to 94%, in 20 min, using NHC catalysis. ... 

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