Enamine esters

A process for the preparation of functionalized pyridines from diacetylene and the ethyl ester of /3-aminocrotonic acid and acetylacetonimine (72ZOR1328 75DIS) has been described. Owing to the lower nucleophilicity of nitrogen in the initial enamine esters and enamine ketone, the reaction with diacetylene occurs in the presence of sodium metal (80°C, dioxane, 3 h, yield of up to 20%). 

By adhering to these conditions, Kaupp and coworkers performed a remarkable one-pot synthesis of highly substituted pyrroles [21]. When primary or secondary enamine esters 10-58 were ground with trans- 1,2-dibenzoylethene 10-59 in a ball-mill, the pyrroles 10-60 were obtained in quantitative yield (Scheme 10.15). In contrast, when in solution the yields were much lower and the reaction also required higher reaction temperatures. 

Bicyclic dienic products recently synthesized by this method (Scheme 36) are lactams 144a and b (07T8267) and enamine ester 145 (09CEJ4565). The precursor of the latter substance originates from a four-component synthesis followed by y-allylation. The alternative y-propargylation and subsequent ring-closing enyne metathesis performed under an ethene atmosphere lead to the 8-vinyl derivative of product 145. 

Sitagliptin through Diastereoselective Hydrogenation of an Enamine. The PCA Enamine-Ester Route... 

However, this approach required additional functional group manipulation steps since the chiral P-amino ester intermediate had to be hydrolyzed and activated to be converted to the desired amide. These steps could potentially be dirni-nated by introducing the triazole fragment much earlier in the synthesis and then introducing the chiral center on an enamine-amide instead of an enamine-ester (Route B on Scheme 5.8). 

With the (S)-PGA enamine-amide route, sitagliptin was prepared in 65% overall yield from 2,4,5-trifluorophenylacetic acid (9) in 4 chemical steps [18]. Two addi-honal crystallization steps are required for enanhomeric purity upgrade and final salt formation. The (S)-PGA enamine-amide hydrogenahon approach eliminated the ester hydrolysis and amide formation steps of the (S)-PGA enamine-ester route by incorporating the newly developed Meldrum s acid chemistry, which enabled direct amidahon with triazole 3. 

The preparation of an enamine ester from thiopyrrolidone is a key step in a total synthesis [447] of (t)-isoretronecanol (2). 

Alkylation of thiopyrrolidone with ethyl bromoacetate preparation of an enamine ester... 

Whatever the explanation for the stereocontrol, these processes are quite useful synthetically, enabling one to prepare nearly pure erythro or threo diastereomers in high yield. A number of groups have shown that by using a chiral auxiliary in the enamine, ester or amide unit, products of very high enantiomeric excess can be obtained.69... 

Deuterium isotope effects on 13C and 15N nuclear shielding in enaminones, enamine esters and nitroenamines which often exist in solution as a mixture of E (1) and Z (2) isomers have been recently investigated1. When labelled with deuterium E and Z isotopomers are obtained. 

It has also been demonstrated that ketimines may participate in reactions with nitrostyrenes providing fused pyrroles, as shown by the preparation of the system 311. The series of events leading to this outcome were suggested to involve a Michael-type addition of the enamine tautomer of the substrate 312 to the olefin, followed by annulation with concomitant elimination of the nitro functionality (Equation 92) <1999TL4177>. In addition, solid-state reactions of enamine esters or ketones with ( )-l,2-dibenzoylethene induced by milling gave excellent yields of pyrroles <1999AGE2896>. 

A third procedure for building aza-steroidal systems proceeds by intramolecular cyclization of enamine esters derived from jS-tetralones and appropriately substituted pyrrolidines. This reaction is illustrated in the synthesis of the 14-aza-steroid (162) by reaction of the j -tetralone (160) with a 3-substituted pyrrolidine ester. 

Fig. 2.14 Rh-catalyzed enamine reductions in the absence of an N-acyl group (a) enamine ester substrate, (b) enamine amide substrate.

Others. When applying these under appropriately designed conditions (0.3 mol% catalyst, 50 °C, 5-6 bar H2) the direct hydrogenation of enamine esters and enamine amides has been successfully conducted in excellent yields and optical purities without the need for the addition of an acyl group (see Fig. 2.14) [73]. 

Reaction of RCN (R = Ph, 4-MeC6H4) with MeCOOR (R = Et, CHMe2, CMej) in diethyl ether-toluene containing Et2NMgBr gave 18-36% of enamine esters H2NCR= CHCOOR ... 

The additions of the anion of ethyl glutaconate ester (23) on cations 3a and 15 were found to form entirely the extended enamine ester tautomers 24 and 25 of the initially formed imidazolidine and perhydropyrimidine derivatives (88T6187). 

The anion from (70.5) attacks the nitrile group and a 4-aminopyridine ring is formed in this example, the product is related to the antibacterial agent nalidixic acid. 5-Phenyl esters are useful in regioselectively directing a Dieckmann condensation of the diesters (70.6) to carbacephems. Dieckmann reactions usually requite heating but the enaminic ester (70.7) undergoes cyclization without external heat. 

Reaction of the enamine-ester 513 with guanidine in boiling ethanol afforded the quinazolone 517. Hydrogenation of which gave the dihydro derivative 518 (92JHC1375) (Scheme 111). 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

The need for acylation of the nitrogen has been circumvented by use of the JosiPhos family of ligands. The trifluoromethyl ligand (24a) gives high enantioselectivities with the enamine ester, while the phenyl analogue (24b) is better for the amide substrates (Scheme 9.25). ... 

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