Benzoin reactions cyclization

In concurrent and independent work, Suzuki and Enders found that tethered keto-aldehydes undergo highly enantioselective cross-benzoin reactions using tria-zolium based catalysts [50, 51], The scope includes various aromatic aldehydes with alkyl and aryl ketones (Table 4). Additionally, aliphatic substrate 39a is cyclized in excellent enantioselectivity, albeit in 44% yield. 

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. 

The synthesis of 3-H-oxazol-2-ones was described by Nam et al. [69]. The substituted benzoin 89 was formed from the coupling of 3,4,5-trimethoxy-benzaldehyde 18 with 3-nitro-4-methoxybenzaldehyde, Scheme 22. Reaction with PMB-isocyanate and subsequent cyclization gave the protected oxazolone derivative 90. The PMB group was removed by reflux in TFA and reduction of the nitro-group was performed using Zn to give the combretoxazolone-aniline 91. 

Isoflavanones.1 A synthesis of these products from a poly hydroxy desoxy-benzoin such as 2 involves conversion of the nonhydrogen-bonded hydroxyl group to the protected ether by reaction with 1 and K2C03 in acetone at 25°. Further reaction with 1 at 60-70° gives an a-hydroxymethyl ketone 3 in 85-95% yield. This product cyclizes to the isoflavanone 4 in the presence of Na2C03. The final step involves deprotection of the ethoxymethyl group to give 5 (92-94% yield). 

The catalytic enantioselective crossed aldehyde-ketone benzoin cyclization has been reported.145 The reactions have been performed in the presence of Rovis aminoindanol- derived chiral triazolium salts (37) as catalysts with excellent enantioselectivities (up to 99% ee) (Scheme 19). 

With respect to the application of asymmetric carbene catalysis as a tool for enantioselective synthesis, the last decade s major success is based on substantial improvements in catalyst development. Early reports dealt with implementing chirality in thiazolium scaffolds (Sheehan and Hunneman 1966 Sheehan and Hara 1974 Dvorak and Rawal 1998), but their catalytic performance suffered from either low yields or low ee-values. In this regard, the investigation of triazole heterocycles as an alternative core structure (Enders et al. 1995) has played a crucial role to provide heterazolium precatalysts improving both asymmetric benzoin and Stetter reactions. An intramolecular Stetter reaction yielding chromanones upon cyclization of salicylaldehyde-derived substrates is commonly used as a benchmark reaction to compare catalyst efficiency (Scheme 1 Ciganek 1995 Enders et al. 1996 Kerr et al. 2002 Kerr and Rovis 2004). 

Reaction of benzoin-a-oxime with sodium hydride in propan-2-ol produces 1,5-dianion which is further cyclized into 1,5,6-dioxazocine ring system with 1,3-dibromopropane (Equation 29 <2004S837>). 

Methylquinazolin-4(3//)-one was obtained in over 62% yield by reacting the phosphorane (25) with sodium hydride in methyl cyanide. The phos-phorane was readily formed from anthranilamide and prop-2-ynyltriphenyl-phosphonium bromide. When anthranilamide was fused with benzoin and a trace of acid at 150°C, it gave 2-phenylquinazolin-4(3H)-one together with o-iV-(a-benzoyl benzyl)aminobenzamide. The latter was cyclized, with ethyl orthoformate, to l-(a-benzoylbenzyl)quinazolin-4-one. If anthranilamide and benzoin were boiled in benzene with azeotropic removal of water, then the Schiff base (26) was formed. This gave 2-phenylquinazolin-4(3Jf/)-one and benzoic acid on heating alone at 150°C or with ethyl orthoformate. The mechanism of this reaction is not clear unless a retro-benzoin condensation and oxidation are occurring. 

The cyclodehydration of readily available Af-phenacyl-A( -acylhydrazines (177) and related compounds, continues to provide a versatile entry to the 1,3,4-oxadiazine ring-system. Cyclodehydration, which usually yields the 4//-derivatives (178) can be effected with polyphosphoric acid and acetic acid at 140°C <83MI 6i7-0l>, or, as in the case of the benzoin iV-acyl hydrazones (179 X = OH), in good yields (75-80%) with polyphosphoric acid at 160°C <85IJC(B)979>. The 5,6-diphenyl-4//-1,3,4-oxadiazines (180) resulting from this latter reaction are also available, but in lesser yields (50-60%), by condensation of desyl halides (179 X = Cl or Br) with an acylhydrazide (RCONHNHj) followed by cyclization in hot ethanolic potassium hydroxide. 

It is traditionally prepared by esterification of benzoin 58 with subsequent cyclization of the ketoester 60 with the nitrogen-donating cyclization agent ammonium acetate (Scheme 25.9). The fact that production of oxaprozin requires elevated temperatures for several hours makes its synthesis attractive for use in our investigations using microwaves to decrease the reaction time and increase the overall yield. 

The two general procedures for cyclization of the keto ester 60 to 57 require heating with ammonium acetate (8 eq) in acetic acid or ammonium acetate (2 eq) in a mixture of acetic acid and formic acid for several (2 to 6) hours. Optimization of the reaction parameters (time, temperature, and ratio of the reaction components) afforded an 86% yield (HPLC) of oxaprozin when 63 was heated, with 8 eq of CH3COONH4 in acetic acid, at 150°C for 10 min. The overall isolated yield of oxaprozin 57 from benzoin 58 under microwave irradiation was 76% (versus 72% ) at significantly accelerated reaction speeds (15 min versus 10 h ). 

Diarylquinoxalines are similarly prepared by reaction of o-phenylenediamine with benzils. The required benzils have been prepared traditionally by oxidation of the corresponding benzoins, which in turn have been prepared by treatment of the appropriate aldehydes with potassium cyanide. In a more recent procedure, benzils have been obtained in good yield by oxidation of para-substituted diphenyloxazoles with bromine in acetic acid. The oxazoles themselves are readily prepared by cyclization of the benzoin acetate with urea (Scheme 3). ... 

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