Preparation of indolizine derivatives via aza-Baylis-Hillman intermediates
Scheme 31. Intramolecular deacetylation to indolizine ester 90
Scheme 31. Intramolecular deacetylation to indolizine ester 90.
The reaction conditions drive the resulting deacetylated ester 90 to saponification which results in the formation of the indolizine-2-carboxylic acid 138. In cases where both deacetylation and saponification occurred, the proposed mechanism suggests that the hydroxide-promoted C-3 deacetylation occurs first followed by saponification.
The chemoselective cleavage of a C-C bond in the absence of catalytic acid or a transition- metal catalyst is a desirable achievement.226 The β-diketones have been widely used as substrates for C-C cleavage for the construction α-functionalised ketones. In this regard, Lei et al.227 pioneered the Cu-catalysed deacetylation of β-diketones and arylation for the synthesis of α-aryl ketones. Other C-C bond cleavage transformations include Pd-catalysed deacetylative allylation for the preparation of α-allyl ketones,228 the Cu-catalysed synthesis of α-thioaryl ketones229 and, the deacetylation catalysed by triflic acid (CF3SO3H) in the synthesis of 3- acylindoles.230
It has been reported elsewhere226 that when heating a reaction mixture of α-acetylacetophenone 143 and sodium benzenesulphinate 144 in the presence of a catalytic amount of sodium sulphite (Na2SO3) and iodine (I2) at 60 °C, the acetyl group was replaced by a benzenesulfonyl group to yield compound 145 (Scheme 32). A mechanism which is similar to our proposed mechanism in Scheme 30 but using a sulfite mediated process rather than one mediated by NaOH was reported (Scheme 34).
85 Scheme 33. One pot synthesis of β-keto sulphone.
Scheme 34. Proposed mechanism for the synthesis of compound 145. 226
Among the pool of available saponification reagents,231 trimethyltin hydroxide (Me3SnOH) has been reported to be a high yielding, mild and selective agent for the hydrolysis of esters under extremely mild conditions in a few hours.222, 232
2.2.4. Exploratory studies of the synthesis of indolizine-2-carboxamides
Despite the medicinal significance of amides and their ubiquity in drugs, the development of an effective and comprehensive amide synthetic method remains a challenge. Most of the established methods are relatively inefficient, with adverse environmental impacts and difficulties in purification of the product.233 Amides can be prepared via a wide range of different reaction pathways using a variety of appropriate precursors. A direct and simple method of preparing amides involves the condensation of a carboxylic acid and an amine.
However, this method usually requires high temperature reaction conditions in order to achieve conversion of the initially formed ammonium carboxylate salts to the desired amide; such conditions are not compatible with the use of sensitive reagents.234 Consequently, amides are generally formed through activation of the acid by a stoichiometric coupling reagent. The ongoing search for effective catalysts for direct amidation has led to an arsenal of coupling agents with some offering considerably increased efficiency, albeit with limited substrate scope.233 Moreover, due to complications regarding toxicity of some coupling agents, purification and, in some cases, sensitivity and tedious work-up, the pharmaceutical
86 significance of the amide bond inspired the chemists to invest in developing benign and inexpensive amide formation reactions.235, 236 Herein, we report the attempted atom- economical, boron-catalysed synthesis of the indolizine-2-carboxamides from indolizine-2- carboxylic acid and the non-catalyzed amide formation using the acid 132 and amine or an amine surrogate such as isocyanate.
2.2.4.1. Boron-catalysed amide bond formation
The stoichiometric application of organoboron derivatives as effective Lewis acid catalysts in the formation of amides has been known since 1965.237 In their review, de Figuiredo et al.234 listed twenty-three organoboron-derived catalysts that are frequently employed in amide synthesis. The inexpensive, commercially available and environmentally friendly boric acid, B(OH)3, has been extensively employed as an effective catalyst for direct amidation.238 Consequently, our expectation was that refluxing the carboxylic acid and the amine in a high- boiling solvent with concomitant water removal, would afford the desired amides. Using a Dean-Stark apparatus, mixtures of indolizine-2-carboxylic acid 138 (1 eq.) and each of the amines, 2,4-imidazolidinedione 147, 1-methylimidazolidine-2,4-dione 148 and picolylamine 151 (1.2 eq.) and 20 mol% B(OH)3 were subjected to 6 hours of vigorous reflux in toluene.
However, TLC analysis revealed that none of the expected products were formed. The catalyst was gradually increased to one equivalent but even after refluxing for 12 hours TLC analysis revealed the absence of any product. The catalyst was changed to trimethyl borate and to phenyl boronic acid but, following the same procedure, the reactions still failed to afford any product.
Changing the solvent to acetonitrile and, thereafter, to methanol also proved unsuccessful.
The expensive borate ester, tris(2,2,2-trifluoroethyl)borate, which is known to exhibit good functional group tolerance and is insensitive to moisture was found to facilitate direct amidation of the indolizine-2-carboxylic acid 138. Thus, a mixture of the borate ester (2 eq.), indolizine- 2-carboxylic acid 138 and 2-aminothiazole 153 in acetonitrile was refluxed for 24 hours, after which TLC analysis showed the formation of a product. The solvent was removed in vacuo and the crude product purified by column chromatography [elution with hexane:EtOAc (1:5)]
to afford, as yellow crystals, the N-(2-thiazolyl)indolizine-2-carboxamide 154 in an extremely low yield of 2%. While the tris(2,2,2-trifluoroethyl)borate-catalysed reaction presented some amidation potential, its efficacy under varying conditions was not explored. Furthermore, it was expected that amidation involving secondary or sterically hindered amines was unlikely to succeed. Considerable efforts were made to develop an effective, boron-catalysed coupling
87 methodology as shown in Scheme 35 which summarises attempted amidation reactions with the boron catalysts such as, boric acid, borate esters and, tris(2,2,2-trifluoroethyl)borate.