Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

Abstract

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.

Optimized binding of substituted quinoline ALLINIs within the HIV-1 integrase oligomer

“…The NGJ9002 compound was synthesized as described previously ( 19 , 38 ). The synthesis of the multisubstituted quinolines series is detailed in the Supporting information .…”

2-Azidobenzaldehyde-Based [4+2] Annulation for the Synthesis of Quinoline Derivatives

“…Other than aniline-based [3+3] annulation [ 137 ] and [4+2] annulation [ 138 ] reactions for making 4-hydroxyquinolines, 2-azidobenzaldehydes have also been employed for the [4+2] annulation-based synthesis of 4-alkoxy quinolines. Gharpure and coworkers reported the reactions of 1 with hydroxyalkynes for the synthesis of different kinds of 4-alkoxy quinolines, 107 , 108 , and 109 ( Scheme 22 ) [ 139 , 140 , 141 ].…”

“…The reaction of 1 and α -fluoro- β -ketoesters 121 or 123 via sequential aldol, aza-Wittig, and dehydrofluorinative aromatization reactions gives quinolin-4-ols 122 or 124 ( Scheme 24 ) [ 83 ]. Green chemistry metrics analysis for this one-pot synthesis and two reported multi-step syntheses [ 138 ] of HAT inhibitor 144a was conducted [ 79 , 82 , 147 ] to validate synthetic efficiency and low waste generation ( Scheme 25 ).…”

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC

“…The p K a of the methine hydrogen has not been reported but is likely lower than 10 as it can be deprotonated with a tertiary amine or bicarbonate base. Therefore, MAC reagents can be exploited in a variety of bond transformations, including alkylations [ 1 , 6 , 7 ], addition to imines [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and aldehydes [ 15 , 16 , 17 , 18 , 19 , 20 ], as well as conjugate addition to enones [ 21 , 22 ] and quinone methides [ 23 ]. It has also been used as a linchpin or as a one-carbon homolog in the total synthesis of complex natural products [ 24 , 25 , 26 , 27 ].…”

“…These factors contributed to inconsistent yields and reproducibility in our hands. Our group's interest in TBS-MAC (1) is from our research in the development of new organocatalyzed reactions and the synthesis of small molecule inhibitors of the HIV integrase enzyme [20,31,32]. Due to our need for TBS-MAC on several projects, a reliable and scalable synthesis of both acetylmalononitrile (7) and TBS-MAC (1) was required to access these valuable synthons.…”