An efficient conversion of carboxylic acids into Weinreb amides

Efficient conversions of carboxylic acids into Weinreb amides were achieved by treatment of N - acylbenzotriazoles 2a–i with N , O -dimethylhydroxylamine hydrochloride under mild conditions. No racemization was found when optically active acids were employed.


Introduction
Recently, increasing attention has been paid to N-methoxy-N-methylamides (Weinreb amides) owing to their versatile reactivity with nucleophiles and selective reduction to aldehydes. 1 Weinreb amides derived from amino acids have found extensive use in the preparation of αamino aldehydes 2 and α-amino ketones. 3st direct conversions of carboxylic acids into the corresponding Weinreb amides have utilized peptide-coupling reagents such as benzotriazol-1-yl-N-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP) 4 N,N'-dicyclohexylcarbodiimide (DCC) 5 or propylphosphonic anhydride/N-ethylmorpholine. 6Other reagents such as carbon tetrabromide/triphenylphosphine, 7 2-chloro-1-methylpyridinium iodide (CMPI) and/or 2bromide-1-methylpyridinium iodide (BMPI), 8 and [bis-(2-methoxyethyl)-aminosulfur trifluoride (deoxo-fluor reagent) 9 have also been used as coupling reagents in the preparation of Nmethoxy-N-methylamides and involve in situ formation of the acyl halide.More recently, 2mercaptopyridone-1-oxide-based thiouronium salts have been reported as effective coupling reagents for the synthesis of Weinreb amides from carboxylic acids. 10cylbenzotriazoles are neutral acylating reagents. 11Recently, our group has demonstrated advantageous methods for the preparation of acylbenzotriazoles from carboxylate anions and used the acylbenzotriazoles for the preparation of primary, secondary and tertiary amides, 12 and

Results and Discussion
The acylbenzotriazoles 2a-i were readily prepared in 65-91% yields from the carboxylic acids 1a-i by reaction with BtMs by a previously reported procedure 14 .Reactions of the Nacylbenzotriazoles 2a-i with N,O-dimethylhydroxylamine hydrochloride in THF in the presence of a base at reflux afforded the corresponding Weinreb amides 3a-i in 73-97% yields (Scheme 1, Table 1).The benzotriazole by-product formed in the reaction can easily be removed and recovered by washing with saturated Na 2 CO 3 .The product isolation can be carried out by column chromatography or recrystallization.
This methodology is applicable to a variety of carboxylic acids with sensitive functional groups.For example, N-protected amino acid amides can be prepared readily from the corresponding amino acids (entries h-j).These reactions proceed without detectable racemization of the chiral center, as evidenced by comparison with literature optical rotation values. 9n conclusion, we have developed a practical and convenient method for the synthesis of various Weinreb amides from the corresponding carboxylic acids without detectable racemization when chiral substrates are employed using benzotriazole methodology.The simplicity, easy operation, mild reaction conditions, and low cost are advantageous.The use of the previously mentioned peptide coupling reagents also gives high yields with retention of chirality in optically active substrates; however, difficult-to-remove by-products, toxic coproducts (e.g., hexamethylphosphoramide for the BOP reagent), or the high cost of scale-up, can be disadvantageous.Experimental Section General Procedures.Melting points were determined on a MEL-TEMP capillary melting point apparatus equipped with a Fluke 51 digital thermometer.NMR spectra were recorded in CDCl 3 with tetramethylsilane as the internal standard for 1 H (300 MHz) and the solvent for 13 C (75 MHz) NMR.THF was distilled from sodium/benzophenone under nitrogen immediately prior to use.All reactions with air-sensitive compounds were carried out under argon atmosphere.
Column chromatography was conducted on silica gel (230-400 mesh).For the preparation and characterization of N-acylbenzotriazoles 2a-g see the literature. 12,13,15pical procedure for the preparation of N-acylbenzotriazoles 2a-i To a solution of the acid 1 (10mmol) in THF (10 mL), BtMs (11 mmol) and Et 3 N (11mmol) were added at room temperature.The reaction mixture was refluxed 6-12 h.The solvent was removed in vacuo to dryness.The residue was dissolved in ethyl acetate and washed sequentially with satd.citric acid, satd.Na 2 CO 3 and H 2 O, and dried over MgSO 4 .Concentration under reduced pressure gave the desired product, which was recrystallized from hexane-ethyl acetate.

Typical procedure for the preparation of Weinreb amides 3a-i
To a solution of N-acylbenzotriazole 2 (2 mmol) in dry THF (10 mL), a solution of N,Odimethylhydroxylamine in THF (prepared from 2.2 mmol of N,O-dimethylhydroxylamine hydrochloride, and 2.2 mmol of triethylamine in 5 mL of dry THF was added at 20 o C over 5 min.The reaction mixture was stirred at r.t. for 24 h.The solvent was removed in vacuo and the residue was dissolved in EtOAc.The organic layer was washed sequentially with saturated citric acid, satd.Na 2 CO 3 , H 2 O, and dried over MgSO 4 .Evaporation in vacuo to dryness gave the desired products, which were recrystallized from the appropriate solvent.N-Methoxy-N-methylbenzamide (3a).Colorless oil 8 (78%); 1H NMR δ 7.67 (d, J = 6.6 Hz, 2H), 7.41 (m, 3H), 3.56 (s, 1H), 3.37 (s, 1H); 13