By the Dakin-West reaction

A-Acyl AAs, when transformed into a-acylaminoketones by the Dakin-West reaction, react with arylhydrazines, arylsulfonylhydrazines, or some primary amines to give the corresponding ketimines which undergo cyclodehydration with POCI3/PCI5 or TPP (Scheme 21) (78LA1916). 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

The decarboxylative acylation of a-aminophenylacetic acid in refluxing acetic anhydride alone gives about 20% yield of 2,5-dimethyl-4-phenyloxazole and a similar amount of uncyclized a-acetamido-a-phenylacetone.66 2-Vinyl- and 2-isopropenyl-4,5-dimethyloxazoles have been prepared in good yields by the Dakin-West reaction of JV-acryloyl-and JV-methacryloyl-a-alanine, respectively, followed by cyclization of the oxoamides in PPA at 140°C for 4 hours,66 67... 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

When an a-amino acid is treated with an anhydride in the presence of pyridine, the carboxyl group is replaced by an acyl group and the NH2 becomes acylated. This is called the Dakin-West reaction The mechanism involves formation of an oxazolone. The reaction sometimes takes place on carboxylic acids even when an amino group is not present. A number of N-substituted amino acids, RCH-(NHR )COOH, give the corresponding N-alkylated products. 

All three isomerizations discussed above seem to occur by analogous mechanistic pathways similar to the mechanism formulated for the Dakin-West reaction [82]. Deacylation of the starting material H by catalyst G affords, in a fast and reversible step (Scheme 13.47, step I), an acylpyridinium/enolate ion-pair I. From this ion pair, enantioselective C-acylation proceeds in the rate-determining and irreversible second step, furnishing the C-acylated product J (Scheme 13.47, step II). 

Another way to form a-aminoketones from a-amino acids is via the Dakin-West reaction, in which amino acids are treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ( )-phenylalanine with the appropriate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with potassium cyanate gave 5-alkyl-4-benzyl-l,3-dihydroimidazol-2-ones 1273 (Scheme 322) <2002JHC375>. 

An improved method for the preparation of a series of oxazole-containing dual PPARa/y agonists was reported by A.G. Godfrey et al. The synthesis utilized the Dakin-West reaction which allowed the introduction of a phenyl ketone moiety. This ketone was subsequently converted to the corresponding oxazole using POCI3/DMF. 

Stegiich, W., Hoefle, G. Mechanism of the Dakin-West reaction. II. Acylation of D2-oxazolin-5-ones by carboxylic anhydrides/pyridine. Chem. Ber. 1971,104, 3644-3652. 

It is also superior to pyridine as a catalyst for C-acylation, for example in the Dakin-West reaction.3 This reaction is the conversion of a-amino acids into a-acylamino ketones by reaction with acid anhydrides catalyzed by a base (usually... 

Anhydro-5-hydroxyoxazolium hydroxides are attacked by electrophiles at position 4 cf. 229). If this position is free, substitution ensues, as in the dimerization reaction of Scheme 21. Other examples are uncatalyzed acylations (equation 55) and diazo coupling (equation 56). The key step in the Dakin-West reaction, i.e. the formation of a-acetamido ketones from a-amino acids and acetic anhydride in the presence of pyridine, is acetylation of an intermediate betaine (230 Scheme 23). 

A suggested mechanism, which is related to the Dakin-West reaction, is shown in Scheme 4.5. Evidence in support of this mechanism is seen with the isolation of 64 and 65 with bulky R groups, the latter structure of which was supported by X-ray crystallography (Fig. 4.19). 

This group also employed the Dakin-West reaction to prepare a series of amino alcohols (not shown) by reduction of the trifluoromethyl ketones 85, resulting from treatment of Walkoxycarbonylamino acids 84 with TFAA (Fig. 4.27). 

The Dakin-West reaction, which dates from 1928, is the conversion of an a-amino acid (4) to an N-acetyl-a-amino ketone (5) with acetic anhydride/pyridine (Scheme 3). Although some alternatives have been proposed, the generally accepted mechanism involves an azlactone as an intermediate. This mechanism has now been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with density functional theory (DFT) calculations. The first two steps are the conversion of the a-amino acid (6) to the A-acetylated derivative (7) and then to the A-acetyl mixed anhydride (8), which cyclizes to the oxazolone (9) (the azlactone) (Scheme 4). Deprotonation of (9) by pyridine yields resonance-stabilized l,3-oxazol-5-olate (10),... 

Under Dakin-West reaction conditions (trifluoroacetic anhydride-MeCN/80 °C/5 h), At-methoxycarbonylproline (128 R = Me) yielded Af-methoxycarbonyl-4-trifluoro-acetyl-2,3-dihydropyrrole (129 R = Me) and none of the expected Dakin-West product, the trifluoromethyl ketone (127). A possible mechanism proposed by the authors involves initial formation of a mesoionic l,3-oxazolium-5-olate (130 R = Me), but the pathway to the iV-methoxycarbonyl-2,3-dihydropyrrole (131 R = Me) and thence the final product (129 R = Me) was unexplained. ... 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

A synthetic route via the Dakin-West acylation reaction followed by a hydrolysis step was first reported for the preparation of p-acylamino a-oxo esters from acylamino acidsJ10l This method was later modified and adapted for the synthesis of peptide a-oxo esters, a-oxo acids, and a-oxoamides (Scheme 2).[1A5111... 

Dakin-West reaction.1 This reaction involves conversion of an a-amino acid to an a-acetylaminoalkyl methyl ketone by reaction with an acid anhydride and a base at 25-135°. When catalyzed by DMAP, the reaction takes place at room... 

Several reactions are occurring in this step that have been elucidated by others (1). First, an a-ketoester is the initial condensation product of an N-acyl-aminoacid and an alkyl oxalyl chloride via a Dakin-West reaction. Second, at reflux temperatures isomeric enol esters are formed that directly condense with hydrazine to form a triazinone intermediate followed by the second ring closure. Other purines have been prepared in an analogous reaction pathway (2). 

The synthesis of ketomethylene pseudopeptide analogues was accomplished by L. Cheng et al., and their biological activity as thrombin inhibitors was tested. These analogues were prepared through a modified Dakin-West reaction under mild conditions and in almost quantitative yield. The required anhydride was prepared from monomethyl succinate, and a large excess of it was mixed with the tripeptide substrate in pyridine in addition to triethylamine and catalytic amounts of DMAP. The reaction mixture was heated for one hour at 40-50 °C. 

The conversion of o -amino acids into a-amino ketones by means of acid anhydrides (Dakin-West reaction) also proceeds faster in the presence of DMAP (eq 7). 

A Dakin-West reaction on plant scale is demonstrated by elaboration of a modified procedure avoiding uncontrolled release of carbon dioxide. It seems to be generally accepted that the mechanism involves dehydrative formation of an azlactone (oxazolinone), which is then C-acylated (in equilibria with G-acylation), undergoes ring-opening hydrolysis, and then decarboxylates to form the acylamino ketone. Pyrimidine ring formation is achieved in a simple one-pot reaction, which is followed by a simple isomerization. Laboratory experiments had made clear that the mechanism... 

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