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

Abstract

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 Nbromosuccinimide (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,transdibromides. 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 transdibromides, 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 transdibromides 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.

Why trans- or cis-Dimethyl Fumarate Addition to 2,5-Dimethylpyrrole Gives Exclusively trans-7-Azanorbornane

“…This process is endergonic by 1.7 kcal/mol. From 2[W]-iso-a to TS3[W]-iso-a, the H−C 4 distance is stretched from 1.102 to 1.319 Å, the H−C 5 distance is reduced from 2.158 to 1.320 Å, and the NBO charges become less negative for C 4 atom (−0.538e to −0.352e) and less positive for C 5 atom (0.320e to 0.111e), showing that the hydrogen transfers from C 4 into C 5 atom with negative charge (a [1,5] hydride migration). This step is exergonic by 3.0 kcal/ mol with a free-energy barrier of 26.0 kcal/mol.…”

“…This step is also [1,5]-hydride migration and endergonic by 11.8 kcal/mol with a free-energy barrier of 41.4 kcal/mol.…”

“…8 Ag(I)F-catalyzed intramolecular [3 + 2] cycloaddition of N-alkyl α,α′-bis(trimethylsilyl)cyclic amines can give 7-azanorbornane derivatives with 60−70% yield. 9 Os-(NH 3 ) 5 (OTf)-catalyzed cycloaddition of pyrrole with alkene has been used to provide 7-azanorbornane derivatives 10 with 70−90% yield. However, the synthetic methods above usually are short of stereoselectivities and need harsh reaction conditions.…”

Synthesis of alpha‐methyl selenocysteine and its utilization as a glutathione peroxidase mimic

“…The transformation of 4 to a carbamate proved problematic because of the steric hindrance of the adjacent α‐carbon as well as the bulkiness of the alcohols used. Copper(I) chloride, titanium(IV) isopropoxide, and titanium(IV) tert ‐butoxide were tested as Lewis acids to assist in the conversion to the Fmoc‐protected amine; however, titanium(IV) tert ‐butoxide was found to give the best yield. From 5 , hydrolysis of the methyl ester yielded 6 , which was used in synthesis of the target peptides.…”

Direct Enzymatic Route for the Preparation of Novel Enantiomerically Enriched Hydroxylated β-Amino Ester Stereoisomers

“…A number of cyclic β -amino acids exhibit biological activity ( e.g. cispentacin [ 1 , 2 ] and Icofungipen [ 3 , 4 ]), and in addition they have also been used in peptide (modified activities and stabilities [ 5 ] and well-defined three-dimensional structures [ 6 , 7 , 8 , 9 ]), in heterocyclic [ 10 , 11 , 12 , 13 ] and combinatorial [ 14 , 15 , 16 ] chemistry, and in drug research [ 9 , 17 , 18 ]. Hydroxylated β -amino acids represent a valuable class of amino acids, due to their importance from both biological and chemical aspects.…”