Phthalimidoacetyl chloride

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

Amino-5-chlorobenzophenone Cyclopropane carboxylic acid chloride Phthalimidoacetyl chloride... 

Preparation of2-(N-Phthalimidoacetyl-N-Cyclopropylmethyl)-Amino-5-Chlorobemophenone To a solution of 36.0 g (0.126 mol) of 2-cyclopropylmethylamino-5-chlorobenzophenone in 500 ml of tetrahydrofuran is added 50.7 g (0.252 mol) of phthalimidoacetyl chloride. 

The presence of an excess of 3,4-dimethoxybenzylamine in the solution leads to the formation of an insoluble by-product resulting from the reaction of 3,4-dimethoxybenzylamine with phthalimidoacetyl chloride. It renders the final purification more ledious. 

The Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base with phthalimidoacetyl chloride has yielded the sugar-based monocyclic (3-lactam as a single isomer [88]. This latter could be transformed in several (3-lactams variously functionalized through ozonolysis, reduction, hydrolysis, and acetylation reactions, (Scheme 26). 

Reaction of D-phenylalanine ethyl ester with cinnamaldehyde has been reported to give a chiral Schiff base, that underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic... 

Benzodiazepines [95, 96] and triethylamine in CH2CI2 treated with acetoxyace-tyl chloride or phthalimidoacetyl chloride at 0°C afforded exclusively the p-lactam-fused 1,4-benzodiazepines [97]. In all the cases studied, the reaction provided the final tricyclic systems in very good yields. A high level of diastereoselectivity was achieved and the final products were isolated as single diastereomers, with a cis relationship between the aryl group from the benzodiazepine and the substituent of the ketene. 

A benzothiazepine-fused (3-lactam library has been reported to be obtained [106] via Staudinger cycloaddition of 2,3- dihydro-1,5-benzothiazepines and various acyl chlorides such as phthalimidoacetyl chloride (path a, Scheme 35), chloroacetyl chloride (path b, Scheme 35), dichloroacetyl chloride (path c, Scheme 35), and phenoxyacetyl chloride (path d, Scheme 35). 

Phthalimidoacetyl chloride Manganese dioxide Hydrazine hydrate... 

Preparation of 2-(N-Phthalimidoacetyl-N-Cyclopropylmethyl) -Amino-5-Chlorobenzophenone To a solution of 36.0 g (0.126 mol) of 2-cyclopropylmethylamino-5-chlorobenzophenone in 500 ml of tetrahydrofuran is added 50.7 g (0.252 mol) of phthalimidoacetyl chloride. The resulting solution is refluxed for 16 to 24 hours, the solvent removed under vacuum, the residual oil crystallized from 200 ml of ethanol and recrystallized from 500 ml of 80% ethanol-20% tetrahydrofuran giving 44.7 g of 2-(N-phthalimidoacetyl-N-cyclopropylmethyl)-amino-5-chlorobenzophenone, MP 163° to 164°C (75% yield). 

Oxaoctam derivatives are oxygen analogues of cephalosporins. Sheehan and Dadic employed phthalimidoacetyl chloride for the preparation of 1-oxaoctam (47a) [30J. Hydrazinolysis gave 2,4,4-trimethyl-6-phenyl-7-amino-l-oxaoctam (47b), an analogue of 7-aminocephalosporanic acid. Cycloaddition of dichloro or... 

A soln. of phthalimidoacetyl chloride in methylene chloride added dropwise by syringe during ca. 3 min. to a soln. of 4,4-dimethyl-J -oxazoline in the same solvent, then a mixture of triethylamine, methanol, and methylene chloride added also dropwise by syringe during ca. 15 min., and stirring continued 10 min. at room temp. 2-methoxy-4,4-dimethyl-3-phthalimidoacetyloxazolidine. Y 71%. F. e. s. B. T. Golding and D. R. Hall, Soc. Perkin I 1975, 1302 cf. Synth. Meth. 31, 473. 

---