N-Methylimidazole Promotes the Reaction of Homophthalic Anhydride with Imines

Abstract

The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described.

Dimerization and comments on the reactivity of homophthalic anhydride

“…4 One explanation for the role of NMI is that it intercepts an intermediate Mannich-type amino-anhydride 4 , and thereby promotes the N -cyclization process leading to lactam (here, 3 ) at the expense of a yield-reducing Knoevenagel-type elimination from 4 . However, for optimization of the imine reaction it was important to establish that parallel reaction of 1 with NMI doesn’t lead to side products that remove 1 from the desired pathway.…”

“…The reaction of HPA ( 1 , 1 equiv) with NMI (2 equiv) in dichloromethane-d 2 solution, equivalent to conditions under which 1 reacts rapidly with 2 , 4 was monitored by 1 H NMR spectroscopy (Scheme 4). After 2 min, small amounts of 7 and 8 were apparent, as evidence by their respective diagnostic signals at 4.31 (s) and 4.22 (s) ppm.…”

“…The 8:7 ratio and combined molar conversion is similar to that seen by 1 H NMR monitoring, suggesting that these products might form, at least in part, by double cyclization of 10 or 11 prior to the quench. One path to the diacid 5 before quench would be NMI mediated cyclization of E -11 (NMI is an acyl transfer promoter 4 ).…”

“…For the reaction of HPA and 2 at 23 °C, the ratio of cis - 3 to trans - 3 is 1.2:1. 4 If proposed transition states 14 and 15 control the stereochemistry of the products, then their energies are comparable. The intermediacy of the Mannich adducts 16 and 18 is also implicated by the earlier demonstration of the effect of NMI in promoting cyclization rather than elimination, both of which can occur from the Mannich intermediate 4 .…”

“…3 This reaction is facilitated by N -methylimidazole (NMI), and evidence has been presented that the role of NMI is to intercept the putative Mannich intermediate and promote ring closure, while suppressing Knoevenagel-type elimination. 4 Because HPA is known to dimerize under the influence of base, 5,6 and because this latter process would detract from the efficiency of the desired conversion, it was prudent to examine the control reaction in which the imine is not present. We report the results of that experiment, as well as a re-assignment of the stereochemistry of two of the reported HPA dimeric products.…”