A mixture of finely ground 5-chloro-N-methylisatoic anhydride (5.19 g), 2.25g of glycine, 4.15 ml of triethylamine. and 30 ml of water was stirred at room temp for 5 hours. All solid material had disappeared after 3.5-4 h. Voilatile material was removed as completely as possible on a rotavap and the residue treated with 60 ml glacial acetic acid and heated to reflux for 4.5 hours. After the mixture cooled, as much acetic acid as possible was removed on the rotary evaporator, and the tan oily residue was treated with 30 ml of ether. On brief swirling of the mixture, crystallization set in, and the colorless crystalline materiual was collecting after standing overnight and was washed with ether (4.60g, mp 176.5-178°C). The etheral filtrate (two phases) was diluted with enough ethyl acetate to render it homogenous, washed twice with dilute sodium carbonate, then with water, filtered through anhydrous sodium sulfate, and concentrated. Recrystallization of the crystalline residue (0.53g) gave 0.43 g of product, mp 177-179°C. Total yield 5.03g (91.8%).
This implies that we have an initial basic aqueous environment, and we have an acidic aqueous environment afterwards.
The glyine is deprotonated by the triethylamine to form $(1)$.
The nitrogen in the primary amine carboxylate attacks the carbon of one of the carboxylates in the 5-chloro-N-methylisatoic anhydride to form the complex $(2)$.
Some rearrangements of the electrons give $(3)$.
Decarboxylation gives $(4)$.
Then, our environment becomes acidic. All the carboxylate anions are protonated to become carboxylic acids. The ketone is not protonated. We have a neutral complex $(5)$.
It proceeds through addition/elimination to give us our desired product.
- In $(4)$, we have a negative charge on the nitrogen, in a basic environment, which shouldn't be favoured.
- The nitrogen in $(5)$ isn't exactly nucleophilic enough.