The synthesis of α -benzotriazolyl ketones from acid halides

Reactions of benzotriazolylacetic acid 7 dianion with electrophiles gave 2-benzotriazolylcarboxylic acids 9a–c . Dianions of 9a–c were transformed with acid halides to α - benzotriazolylketones 12a–i .


Scheme 2
We have now established the capability of the benzotriazolyl group in 2-benzotriazolylacetic acid 7 to stabilize the dianions in successive subsequent reactions with alkyl halides 8a-c and acid halides 10a-d and then to induce decarboxylation to give α-benzotriazolyl ketones 12a-i (Scheme 3).The new transformations now reported of acid halides with dianions of 2benzotriazolylcarboxylic acids 9a-c, derived from 2-benzotriazolylacetic acid 7, provide a facile route to diverse α-benzotriazolyl ketones 12a-i in good overall yields.
The compounds 9a-c were dilithiated with n-butyllithium (2.2 eq.) at -78 °C for 2 h (deep red color of reaction mixture) followed by addition of corresponding acid chlorides 10a-d (1.0-1.1 eq.) at the same temperature to give intermediate lithium salts 11.The decarboxylation of 11 upon acidification of the reaction mixture with mineral acid (hydrochloric or sulfuric) to pH=4-5 gave α-benzotriazolyl ketones 12a-i in 60-84% overall yields.The attempted preparation of ketone 12a using methyl 4-methylbenzoate, as an electrophile instead of 4-methylbenzoyl chloride 10b, gave ketone 12a in only 30% yield.The structures of ketones 12a-i were supported by their 1 H NMR and 13 C NMR spectra.The 13 C NMR spectra of 12a-i no longer show carbon signals in the 169.9-170.9ppm range, which corresponds to the carboxyl group in 9a-c.For 12a-i, new signals in 189.9-202.9ppm range were assigned to the carbonyl group of α-benzotriazolyl ketones 12a-i.Scheme 3.For designation of R and R 1 in 9a-c, 11, and 12a-i see Table 1.

General procedure for the preparation of α-benzotriazolylalkylcarboxylic acids 9a-c
A solution of n-butyllithium (6.9 mL, 11.0 mmol, 1.6 M in hexane) was added dropwise to a stirred solution of benzotriazolylacetic acid 7 (0.89 g, 5 mmol) in THF (30 mL) at -78 °C.The reaction mixture was stirred at this temperature for 2 h and corresponding 8a-c (7.5 mmol) in THF (10 mL) was added dropwise to the reaction mixture.The reaction mixture was stirred at -78 °C for 2 h and then for an additional 2 h at 20-25 °C.An aqueous sodium hydroxide solution (3%, 30 mL) was added to the reaction mixture and the mixture was washed with diethyl ether (3x30 mL).Diethyl ether remaining in the aqueous layer was removed in vacuum and the aqueous layer was acidified with concentrated hydrochloric acid to pH = 3-4.The precipitate was filtered off, washed with cold water (20-30 mL) and dried in vacuum to give pure 9a-c.

General procedure for the preparation of α-benzotriazolyl ketones 12a-i
A solution of n-butyllithium (2.45 mL, 3.9 mmol, 1.6 M in hexane,) was added dropwise to a stirred solution of 7 or 9a-c (1.8 mmol) in THF (30 mL) at -78 °C.The reaction mixture was stirred at this temperature for 2 h and corresponding acid chloride 10a-d (1.9 mmol) was added dropwise.The reaction mixture was stirred at -78 °C for 15-30 min and then for an additional 15 min at 20-25 °C.A diluted hydrochloric acid was added to the reaction mixture to adjust pH=5 and product was extracted with diethyl ether (2x50 mL).The extract was concentrated in vacuum and the product 12a-i was purified by column chromatography or recrystallized.

Table 1 .
Synthesis of α-benzotriazolylcarboxylic acids 9a-c and α-benzotriazolyl ketones 12a-i All melting points were determined on a Mel-Temp II melting point apparatus and are uncorrected.NMR spectra were recorded on a Varian Gemini 300 spectrometer in chloroform-d and DMSO-d 6 with TMS as internal reference for 1 H (300 MHz) or a solvent as the internal reference for 13 C (75 MHz).The elemental analyses were performed on a Carlo Erba EA-1108 instrument.THF was dried over sodium / benzophenone and used freshly distilled.Column chromatography was conducted on silica gel 200−425 meshes.All of the chemicals were employed as supplied.
a Methyl 4-methylbenzoate was used instead of 4-methylbenzoyl chloride.In summary, a novel and efficient procedure was developed for the preparation of αbenzotriazolyl ketones.ISSN 1424-6376Page 25 © ARKAT USA, Inc Experimental Section General Procedures.