Electrophilic Bromination of N‐Acylated Cyclohex‐3‐en‐1‐amines: Synthesis of 7‐Azanorbornanes

Abstract

AbstractThe intramolecular bromo‐amidation and the dibromination‐cyclisation of the N‐acylcyclohex‐3‐en‐1‐amines 4, 8, 9, 11, 13, 14, and 16 was studied in view of the synthesis of bicyclic amines that are of interest as building blocks and potential glycosidase inhibitors. The trifluoroacetamides 4, 9, and 14 reacted with N‐bromosuccinimide (NBS) in AcOH to give dihydro‐1,3‐oxazines in good yields. The stereoselectivity of the dibromination of the alkenes 8 and 9 depends on the nature of the protecting group, the reagent, and the reaction conditions. Br2 in CH2Cl2 transformed the alkenes 8 and 9 predominantly into diaxial trans,trans‐dibromides. Bromination of 9 with PhMe3NBr3 or with Br2 in the presence of Et4NBr gave predominantly the diequatorial trans,cis‐27 besides some trans,trans‐28. A similar bromination of the C(5)‐substituted N‐acyl‐4‐aminocyclohexenes 11, 13, 14, and 16 with PhMe3NBr3 was accompanied by intramolecular side reactions that were suppressed by the addition of excess Et4NBr. Under these conditions, 11 gave diastereoselectively trans‐dibromides, while its reaction with Br2 gave trans‐dibromides along with the dihydrooxazinone 31. Also the carbamate 13 reacted with PhMe3NBr3/Et4NBr selectively to the trans‐dibromide 32 and with Br2 to the trans‐dibromides 32 and 33, the dihydrooxazinone 34, and the bicyclic ether 35. Similarly, the trifluoroacetamide 14 provided the dibromide 36 (89%), while its reaction with Br2 led to the dihydrooxazine 22, and the dibromides 36 and 37. The N‐benzyl‐N‐Boc derivative 16 did not yield any dibromide; it reacted with PhMe3NBr3/Et4NBr to the dihydrooxazinone 38, and with Br2 to the oxazinone 38 and the bicyclic ether 39. The high stereoselectivity of the bromination with PhMe3NBr3/Et4NBr suggests an anchimeric assistance of the NHR substituent. Deprotection, cyclisation, and carbamoylation transformed the dibromides 27, 29, and 32 into the 7‐azanorbornanes 42, 49, and 53. The diols 45 and 57 were obtained from 42 and 53 via HBr elimination and stereoselective dihydroxylation; they proved weak inhibitors of several glycosidases. In no case could the formation of a bicyclic azetidine (6‐azabicyclo[3.1.1]heptane) from the dibromides 26 and 30 be observed.