Brominated compounds amides

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

Moreover, the cyclization of the azetidinonc 11a, performed with AT-bromosuccinimide in acetonitrile, afforded the bicyclic product 13a only in quantitative yield, which is an intermediate in the synthesis of carbapenems. Under the same reaction conditions, lib afforded 13b in quantitative yield. The stereochemistry of both 13a and 13b was assigned either by NOE experiments or X-ray crystallographic analysis. The reaction proceeds via the intermediate /V-brominated compound 12. Bromine then migrates to the double bond and the amidic nitrogen attacks the formed halonium ion to give 13237. 

The Amathla genus has a wide geographical distribution and its members from different oceans have given a relatively large number of alkaloids which contain the p-phenylethylamine structural unit. The compounds are all bromine-containing amides. 

The rx bromination of carbonyl compounds by Br2 in acetic acid is limited tc aldehydes and ketones because acids, esters, and amides don t enolize to a suffi cient extent. Carboxylic acids, however, can be a brominaled by a mixture of Br and PBr3 in the HeJI-Volhard-Zelinskii (HVZ) reaction. 

The bromodihydrodibenz[/>,/]az.epine-5-carbonyl chloride 41, prepared by radical bromination of the 10,11-dihydro compound, on heating under pressure with ammonia undergoes dehydrobromination and amidation to yield Carbamazepine (42).122... 

Acetyl-lO,11-dibromo-5//-dibenz[7>,/]azepine (49), formed by addition of bromine to 5-acetyl-5/7-dibenz[7>,/]azepine, undergoes dehydrobromination to the 5-acetyldibenz[7>,/]-azepinc 50a on treatment with ethanolic potassium hydroxide.121-132 In contrast, on heating the dibromo compound under reflux with sodium methoxide in methanol, amide hydrolysis and methoxy denomination occur to give the 10-methoxy derivative 50b.132,1 33 Dehydrobromination of the dibromo compound 49, without hydrolysis or replacement of bromine, can be accomplished in hot dibutylamine.118... 

In the first step bromocriptine 2 is isomerized to 2a, followed by an attack on proline ring in aminocyclol moiety of the molecule (formation of a new double bound on lO -ll, and bromination). This dibromo-compound 5 is brominated additionally on C-2 -propyl group. Tribromo-compound fi is very lipophilic and practically devoid of pharmacological activity. Hydroxy group and amide groups remain intact after all these reactions. 

The compounds 12,14 and 15 can be prepared from parent lysergic acid amides by bromination with NBS or PHT, but not the compounds of the type 12. The latter structure is very sensitive and under these circumstances only degradation products were obtained. Besides it was necessary to use much milder reagent, e.g. bromine bonded onto polymeric matrix with polyvinylpyrrolidone or polyvinylpyridine structure (29) ... 

Dehydrogenation of hydrazo compounds with bromine, 32, 16 Dehydrohalogenation by sodium amide, 30, 72... 

Several min after addition of ethanol to a mixture of the amide chloride ( fusible white precipitate ) and iodine, an explosion occurs. Addition of the compound to chlorine gas or bromine vapour leads to a delayed violent or explosive reaction. Amminemetal salts behave similarly, and formation of A-halogen compounds is involved in all cases. 

Introduction of chlorine or bromine into the 3- and/or 4- positions of the side chain yields more potent compounds in terms of hypotension in rats and dopamine p- hydroxylase inhibition (31. 32). The analog YP-279 (XXXV) is also hypotensive in rats but is said not to affect brain norepinephrine biosynthesis unlike fusaric acid or dibromofusaric acid (33-35). Fusaric acid amide (bupicomide, Sch 10595, XXXVI) is clinically effective at 300 to 1800 mg per day and is said to have hemodynamic effects similar to hydralazine (36. 37). The amide is... 

The pyrimidone ring system is not fully aromatic, since such compounds exist as amides, rather than hydroxypyrimidines, and the rr-system does not extend fully around the ring. In the case of the uracils, the 5,6-double bond possesses allylic character, and various relatively stable adducts can be obtained, for example, with bromine or chlorine water [210, 486—488]. Catalytic reduction across the 5,6-double bond is also readily accomplished [441, 489—491]. 

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