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Electrophilic Bromination of N ‐Acylated Cyclohex‐3‐en‐1‐amines: Synthesis of 7‐Azanorbornanes
Author(s) -
Kapferer Peter,
Vasella Andrea
Publication year - 2004
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200490249
Subject(s) - chemistry , halogenation , bicyclic molecule , intramolecular force , reagent , medicinal chemistry , electrophile , stereoselectivity , oxazines , ether , stereochemistry , organic chemistry , catalysis
The 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. Br 2 in CH 2 Cl 2 transformed the alkenes 8 and 9 predominantly into diaxial trans , trans ‐dibromides. Bromination of 9 with PhMe 3 NBr 3 or with Br 2 in the presence of Et 4 NBr 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 PhMe 3 NBr 3 was accompanied by intramolecular side reactions that were suppressed by the addition of excess Et 4 NBr. Under these conditions, 11 gave diastereoselectively trans ‐dibromides, while its reaction with Br 2 gave trans ‐dibromides along with the dihydrooxazinone 31 . Also the carbamate 13 reacted with PhMe 3 NBr 3 /Et 4 NBr selectively to the trans ‐dibromide 32 and with Br 2 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 Br 2 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 PhMe 3 NBr 3 /Et 4 NBr to the dihydrooxazinone 38 , and with Br 2 to the oxazinone 38 and the bicyclic ether 39 . The high stereoselectivity of the bromination with PhMe 3 NBr 3 /Et 4 NBr 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.