Imidazole enolate acylation

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

Acyl imidazoles take part in a silyl acyloin reaction to give the corresponding silyl enol ethers in moderate yields. A possible mechanism is outlined in Scheme 2092. The silyl enol ethers could be hydrolysed to acyl silanes by treatment with acid. 

Assisted by Lewis acid the acyl imidazole 266 can be cleaved to provide the expected carboxylic acid 267. With fluoride in the presence of a Michael acceptor the intermediate enolate can be trapped. A subsequent intramolecular Claisen condensation... 

Imidazole-containing compounds have been utilized as reagents for various synthetic transformations. A convenient access to substituted allyl enol carbonates was established through the reaction of ketone enolates with the complex of allyl l//-imidazole-l-carboxylates 74 and boron trifluoride etherate <07JOC9372>. Relatively mild and highly efficient Cul-catalyzed /V-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of ligands 75 and cesium carbonate <07JOC2737>. a, -Unsaturated 2-acyl imidazoles 76 are an alternative and practical class of dienophiles for the DNA-based catalytic asymmetric Diels-Alder reaction in... 

Regiochemical synthesis of 1-substituted imidazole-4-carboxylates can be achieved by treatment of a (Z)-)3-dimethylamino-of-isocyanoacrylate with an alkyl or acyl halide (see Section 2.1.1 and Scheme 2.1.8), by cyclization of 3-alkylamino-2-aminopropanoic acids with triethyl orthoformate followed by dehydrogenation of the initially formed imidazoline (see Section 3.1.1 and Scheme 3.1.2), by condensation of 3-arylamino-2-nitro-2-enones with ortho esters in the presence of reducing agents (see Section 3.1.1 and Scheme 3.1.4), by reaction of an alkyl A -cyanoalkylimidate with a primary amine (see Section 3.2 and Scheme 3.2.1), the poor-yielding acid-catalysed cyclization of a 2-azabutadiene with a primary amine (see Section 3.2 and Scheme 3.2.3), the cyclocondensation of an isothiourea with the enolate form of ethyl isocyanoacetate (see Section 4.2 and Scheme 4.2.5), and from the interaction of of-aminonitrile, primary tunine and triethyl orthoformate (see Chapter 5, Scheme 5.1.5, and Tables 5.1.1 and 5.1.2). 

Acylainino-4-acylimidazoles have been made from 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl reagents (see Section 2.2.1 and Scheme 2.2.5). 4(5)-Acylimidazoles can be derived from 4-acylaininoisoxazoles (see Section 6.1.2 and Scheme 6.1.3). (See also the discussion in Section 2.2.1 on 4-acylimidazole synthesis.) 5-Acyl-l-arylimidazoles can be made from or-oxoketene-SJV-acetals and nitrosoaromatics (see Section 3.2 and Scheme 3.2.5), and 4-acyl-imidazoles by nitration of 1,3-dicarbonyl compounds in their enolic forms, reduction to iV-alkenylformamides and subsequent cyclization (see Section 3.2 and Scheme 3.2.4). Examples have also been isolated from reactions of 2-oximino-l,2,3-tricarbonyls and amines (see Section 4.1 and Scheme 4.1.7), from compounds such as 3-chloro-4,4-dimethoxy-2-butanone and 3,4-disubstituted 3-buten-2-ones (see Section 4.3 and Scheme 4.3.5), and by ultraviolet irradiation of 1-alkenyltetrazoles which bear an acyl group conjugated with the exocyclic double bond (see Section 6.1.2.3). 

Now the seven-membered ring must be built up. Here an azole-based reagent, CDI, carbonyl di-imidazole proves invaluable. Reaction with 232 gives the acylimidazole 233 and this acylates the potassium enolate of nitromethane in good yield to give 234 and hence, by reduction, the diamine 235. The /V-benzyl group can now be removed and the synthesis of the seven-membered ring is completed with the one-carbon electrophile HC(OEt)3. 

It has been pointed out that the triiiate ion increases the electrophilic character of W-acyl quaternary salts of imidazoles and accelerates its coupling reaction to silyl enol ethers. 78 Jn f ct, in the absence of this Lewis acid, the yield of the coupling product diminishes (eq 118). Thiazoles, benzothiazoles, and benzoimida-zoles react in a similar manner. 9... 

There is no simple, commonly accepted method for the preparation of imidazoles, but rather many different approaches. One approach, somewhat related to chemistry seen in previous chapters, involves the reaction of an a-hydroxy-ketone such as 121 with formamide, 122. The -NH2 unit of forma-mide attacks the carbonyl (acyl addition), and loss of water (elimination) gives an enol that tautomerizes to the ketone. (Keto-enol tautomerism was first discussed in Chapter 10, Section 10.4.5.) A second molecule of formamide reacts with this ketone via acyl addition to give a product, which loses water. An intramolecular attack of the nitrogen atom from this product to one -CHO rmit on the carbonyl of the other CHO unit, followed by loss of water under the reaction conditions, gives imidazole, 123. 

Although malonate derivatives were described previously, one example is included here to demonstrate their use as a carboxyl enolate. Reaction of 4.87 with carbonyl diimidazole (CDI, see chapter two, section 2.4) gave the acyl imidazole (a very highly activated acyl derivative), which reacted with the magnesium enolate of... 

The acid moiety of an amino acid can be activated for acyl substitution rather than converted to an aldehyde for acyl addition. Boc-alanine was converted to an acyl imidazole by reaction with carbonyl diimidazole (CDI see chapter two, section 2.4), and then condensed with the magnesium enolate of the mono ethyl ester of malonic acid to give keto-ester 5.9. Subsequent catalytic hydrogenation of the ketone moiety gave ethyl 3-hydroxy-5-(N-Boc amino)penlanoate, 5.10 Once the o... 

Potassium enolates derived from acylfulvalenes were trapped with TBDMSCl but not TMSCl or diphenylmethylsilyl chloride. Interestingly, TBDMSCl was found to be compatible with CpK anion at —78 °C. TBDMS enol ethers have also been used as /3-acyl anion equivalents. The TBDMS-silyl enol ethers of diketones (eq 7) and /3-keto esters (eq 8) may be prepared by mixing them with TBDMSCl in THF with imidazole. Alcohols may be protected under acidic conditions as their TBDMS ethers by treatment with /3-silyl enol ethers in polar sovents. 

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