Stereochemistry and reactivity of the HPA-imine Mannich intermediate

Abstract

Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal [4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical outcome of this reaction is consistent with an open transition state comprising an iminium species and enolized HPA, leading to a short-lived amino-anhydride intermediate. In the case of N-tert-butylbenzalimine, this Mannich-type intermediate, which would normally cyclize at low temperature to a single isomer of the delta-lactam, is intercepted by base treatment to afford beta-lactam products. A pathway featuring ketene formation followed by ring closure is implicated.

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron‐Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes

“…It is reasonable to expect that oximes 11 (similarly to imines 8 ) react with HPA through the initial Mannich‐type addition of the HPA enolate followed by intramolecular aminolysis of the HPA moiety in intermediate 14 (sterically hindered N‐alkyl analogues of which have been recently isolated or trapped; see Scheme ). The observed behavior of oximes 11 in the presence of HPA (see above) suggests that the formation of Mannich adduct 14 is likely a slow process and the formation of 13 via kinetically favored O‐acylation dominates.…”

Stereoelectronic Features of a Complex Ketene Dimerization Reaction

“…We recently participated in the development of SJ733 ( Figure 1 ), an ATP4 inhibitor now in phase 2 clinical trials [ 4 , 5 , 6 ], and also explored improvements in its synthesis [ 7 , 8 , 9 , 10 ]. The tetrahydroisoquinolin-1-one (THIQ) 4-carboxanilide core requires an amidation reaction as a key step.…”

Unusually Reactive Cyclic Anhydride Expands the Scope of the Castagnoli–Cushman Reaction

“…The latter is perfectly set to undergo the intramolecular N -acylation (or aminolysis of the cyclic anhydride) to give lactam 2 . The greater plausibility of mechanism B is supported by the comprehensive computational analysis of both reaction mechanisms (in favor of the latter) by Shaw and the recent isolation as well as trapping of intermediate 5 . The existence, in principle, of the acylation-Mannich pathway A is supported by the frequently observed formation of byproduct monoamide 6 which is likely formed via hydrolysis of intermediate 3 .…”

“…The spectra of the cis-diastereomer (cis-8a) contain signals of the trans-counterpart (trans/cis ∼ 1:3). 1 H NMR (400 MHz, acetone-d 6 ) δ (signals cis-diastereomer) 7.22−7.21 (m, 1H, 6-H), 7.05 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H),6.85 (dd, J = 3.7, 1.5 Hz, 1H, 7-H), 6.22 (m, 1H, 8-H), 5.48 (d, J = 4.9 Hz, 1H, 4-H), 5.16 (d, J = 4.9 Hz, 1H, 3-H), 3.87 (dq, J = 14.2, 7.1 Hz, 1H, CHCH 3 ), 3.02 (dt, J = 14.2, 7.1 Hz, 1H, CHCH 3 ), 2.25 (s, 3H, CH 3 ), 1.10 (t, J = 7.1 Hz, 3H, CH 2 CH 3 ) 13. C NMR (100 MHz, acetone-d 6 ) δ (signals cisdiastereomer) 168.0 (CO 2 H), 158.6 (1-C), 139.3, 134.7, 130.1, 129.1, 126.6 (8a-C), 125.4 (6-C), 113.8 (7-C), 110.5 (8-C), 62.7 (3-C), 60.9 (4-C), 40.6 (CH 2 CH 3 ), 21.2 (CH 3 ), 13.9 (CH 2 CH 3 ).…”