N-Bromo amides

Other reagents have been used, among them HOCl, HOBr, and N-chloro and N-bromo amides (especially NBS and tetraalkylammonium polyha-... 

The function of the NBS is therefore to provide a source of Brj in a low, steady-state concentration and to use up the HBr liberated in step 1. " The main evidence for this mechanism is that NBS and Br2 show similar selectivity " and that the various N-bromo amides also show similar selectivity, " which is consistent with the hypothesis that the same species is abstracting in each case. " ... 

HI, or Cdl2 iodofluorination with mixtures of AgF and U and mixtures of N-bromo amides in anhydrous HF give bromofluorination. Bromo-, iodo-, and chlorofluorination have also been achieved by treatment of the substrate with a solution of Br2,12, or an N-halo amide in polyhydrogen fluoride-pyridine while... 

N-Bromo amides and imides. The very valuable brominating and oxidizing agents can be regenerated from the spent amides and imides by (V-bromination. Using NaBrOi and HBr (or NaBr) in the presence of sulfuric acid is an economical and convenient method. 

Conversion of acid derivatives into amines with the loss of the carbonyl group can be done in various ways. In chapter 36 we recommended the Curtius and the Hofmann. The Hofmann degradation is the easier if we start with an ester, converting into the amide with ammonia and then treating with bromine in basic solution. The N-bromo amide undergoes a-elimination to a nitrene that rearranges to an isocyanate. 

N-Chloro- and N-bromo-amides or imides are extremely active halogen... 

The cycloaddition of Weinreb amide functionalized nitrile oxide with a range of dipolarophiles has been studied. N-Methoxy-N-methylcarbonocyanidic amide, nitrile oxide 207 (i.e., a nitrile oxide of Weinreb amide type derivative) was generated from 2-chloro-2-(hydroxyimino)-N-methoxy-N-methylacetamide as intermediate and used in situ. Thus, addition of 3-bromo-l-propyne as dipolarophile to this precursor of 207, followed by quenching with triethylamine, gave 5-(bromo-methyl)-N-(methoxy)-N-methyl-3-isoxazolecarboxamide 208 in 55% to 60% yield (367). 

The use of N-glycosyl amides as glycosyl donors was reported by Pleuss and Kunz [240]. These amides were activated by Ph3P and CBr4 to produce bromo-N-imidates, which were spontaneously converted into the corresponding bromide concomitant with releasing nitrile, and then coupled with alcohols by activation with AgOTf (Scheme 5.86). 

Catalytic hydrogenation of (23-12) over palladium on charcoal results in the scission of the weak N—O bond and the formation of amino alcohol (24-1). This is converted to a pyrrolidine by an internal alkylation reaction. Thus, reaction of the intermediate with carbon tetrabromide and triphenyl phosphine presumably converts the alcohol to a bromide internal displacement by the primary amine forms the five-membered ring (24-2). Alkylation of that amine with the complex bromo amide (24-3) then affords the endothehn antagonist atrasentan (24-4) [25]. 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives.134 The acids or their chlorides or anhydrides can be a chlorinated by treatment with CuCl in polar inert solvents (e.g., sulfolane).135 Acyl halides can be a brominated or chlorinated by use of N-bromo- or N-chlorosuccinimide and HBr or HC1.136 The latter is an ionic, not a free-radical halogenation (see 4-2). Direct iodination of carboxylic acids has been achieved with L-Cu(II) acetate in HO Ac.137 Acyl chlorides can be a iodinated with L and a trace of HI.138 Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium N-isopropylcyclohexylamide in THF and treatment of this solution at - 78° with I2138 or with a carbon tetrahalide.139 Carboxylic acids, esters, and amides have been a fluorinated at -78°C with F2 diluted in Ni.,4°... 

BrF 98.92 20/ -33 + bromofluorinations, frequently in situ preparation of the agent from N-bromo-substituted amides and HF, HF-containing systems or AgF 4,7... 

Propanoate Ethyl 2-Bromo-3-fluoro-3-phenyl- ElOa. 123 (En + HF/ NBS) ElOb,. 339(En + HF N-Br—amide)... 

In 1882 Hofmann discovered that when amides are treated with bromine in basic solution, they are converted to amines with one carbon less than the starting amide.180 He also isolated the N-bromo amine (114) and the isocyanate (115) as intermediates on the reaction path. The mechanism in Equation 6.56 accounts for the products and the intermediates. This reaction (or the analogous rearrangement of the N-chloro amine) is now known as the Hofmann rearrangement or, because of its synthetic usefulness in eliminating a carbon atom, the Hofmann degradation. 

Halolactamization.3 Unsaturated amides generally form lactones when cyclized by Br2 or I2. However the unsaturated N-tosyl amide I, when treated with Br2 in the presence of N a HC03, forms the bromo N-tosyl /J-lactam 2 (67%yield). Dehalogenation of 2 is best effected with Bu3SnH. 

Fig. 28 Nickel-catalyzed cyclization of N-allyl a-bromo amides...

Nucleophilic Reactions. Useful nucleophilic substitutions of halothiophenes are readily achieved in copper-mediated reactions. Of particular note is the ready conversion of 3-bromoderivatives to the corresponding 3-chloroderivatives with copper(I)chloride in hot N,N-dimethylform amide (26). High yields of alkoxythiophenes are obtained from bromo- and iodothiophenes on reaction with sodium alkoxide in the appropriate alcohol, and catalyzed by copper(II) oxide, a trace of potassium iodide, and in more recent years a phase-transfer catalyst (27). 

Lactams (7, 335). Cyclization of /3-halopropionamides to N-alkyl unsubstituted -lactams is usually not an attractive method because of competing /3-elimination. However, dilution favors the desired intramolecular displacements. Under favorable conditions this route can be useful. /3-Bromo amides are cyclized in higher yields than /3- chloro amides. The structure of the R group on nitrogen also can influence the course of the reaction. ... 

PMR spectra cannot indicate the presence of amide hydrogen because of rapid exchange of the proton with deuterium oxide solvent. We have found that nitrogen-cobalt bonded complexes with infrared absorptions at 1575 cm. may be formed when N-bromo primary amides react with pentacyanocobaltate(II). Comparison with the spectrum of a complex formed from an N-bromo secondary amide, in which no acidic hydrogen would be present, should help resolve this problem. 

Alkoxy bromides are obtained by treating a compound containing aC=C bond with A-bromoacetamide297 or another bromo amides (e.g., N,N-di-bromobenzenesulfonamide302,303), not in an aqueous medium but in anhydrous methanol or ethanol at 0-20° acyloxy bromides are obtained in glacial acetic acid.297,304... 

The incorporation of unnatural amino acids into peptides to enhance their metabolic stability and activity is an area of major interest in peptidomimetic chemistry. In order to accomplish this goal. Park and colleagues have developed nucleophilic substitutions of a-bromo amides derived from L-amino acids in the presence of amine nucleophiles on the basis of DKR processes. Whereas moderate stereoselectivities were obtained when using benzylamine as the nucleophile, the nucleophilic substitution reactions of various a-bromo amides with the more sterically demanding secondary amine nucleophile, dibenzylamine, allowed the stereoselectivity of the reactions to be increased remarkably. This methodology provided, in the presence of tetra-n-butyl-ammonium iodide (TBAI) and TEA, the corresponding dipeptide analogues in up to 98% yield and 98% de (Scheme 1.15). 

HOBr and HOCl are equal in microbicidal activity. However, since HOBr dissociates at a higher pH range than HOCl, HOBr is often used in place of HOCl in water systems operated at pH values >7, e.g. pH 8.5. Another benefit of the application of HOBr instead of HOCl are reduced corrosion rates. In the presence of amino groups containing substances HOBr forms (as does HOCl) N-bromo-amines or amides which are more effective than corresponding chlorine releasing chloramines. A disadvantage of HOBr is that it is very susceptible to oxidant demand. 

General Procedure for the Preparation of Compound 123 [48] A solution of allylic chloride 121 (0.50 mmol) in THF (2.0 mL) was added to a mixture of K2CO3 (0.60 mmol), (S)-124 (5 mmol, 1 mol%), bromo amide 122 (0.60 mmol), and 3 A molecular sieve (MS), and then stirred for 15h at 30 C. After dilution with diethyl ether, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using a solvent gradient from toluene up to 7 3 Hex/EtOAc), followed by recrystallization from n-hexane to give pure 123 as a colorless crystal. 

Figure 6.34 Use of bromo[ C]acetyl bromide in N-acylation of amides, imides and sulfonamides preparation of (2S-N-bromo[ " C]acetyl)bornane-10,2-sultam...

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