A-Bromoacetamides

Bromine monofluoride [13863-59-7], BrF, can be prepared by the direct reaction of Br2 and F2, but because it readily disproportionates it has never been prepared in pure form (57). However, BrF can be prepared in situ by the reaction of Br2 with AgF in benzene (58) or by the reaction of A/-bromoacetamide and HF in ether (59). BrF adds to simple alkenes at room temperature to give products of trans-addition. Bromine trifluoride [7787-71-5], BrF, can be formed from gaseous fluorine and Hquid bromine (60). Bromine pentafluoride [7789-30-2], BrF, is formed from the reaction of BrF vapor with gaseous fluorine at 200°C (60). The tri- and pentafluorides are commercially available. As strong fluorinating agents they are useful in... 

A/-bromoacetamide [79-15-2] CH3CONHB1 102-105 hrominating agent, oxidizes 1° and 2° alcohols, irritant 117... 

A(-Bromoacetamide [79-15-2] M 138.0, m 102-105 , 107-109 , 108 (anhyd). Possible contaminant is CH3CONBr2. Recrystd from CHCl3/hexane (1 1, seed if necessary) or water and dried over CaCl2. [Oliveto and Gerold Org Synth Coll Vol IV 104 1963). 

Bromination is selective for the 3-ketone under these mild conditions. Other reagents will also do this e.g. A/-bromoacetamide, mono- and dibromo-... 

A iD-Corticoids have been important intermediates since it was shown ° that substitution at C-9 enhances anti-inflammatory activity. These olefins are usually obtained from 11a- or 11)5-alcohols, and consequently several refined methods have been devised for effecting this dehydration. It is desirable that such methods be compatible with the presence of A" -3-ketone and 17-hydroxy functions. The first direct procedure for which high yields were claimed was described in a patent issued to Upjohn. According to this method, the alcohol (11a or )5) is treated first with A-bromoacetamide in pyridine, then with sulfur dioxide. Recently it has been claimed " that the A-haloamide/sulfur dioxide method gives results superior to other methods, although the methanesulfonyl chloride/sulfur dioxide procedure (see below) apparently was not compared (see also ref. 94). 

Cathylates are stable to oxidation with potassium chromate in acetic acid and with A-bromoacetamide, acetylation and formylation with 85 % formic acid at room temperature. They are cleaved by bases to give the parent alcohol, carbon dioxide and ethanol. 

The method of Fried and Sabo for the in situ preparation of hypobromous acid from A-bromoacetamide (or A-bromosuccinimide) in aqueous dioxane or acetone containing perchloric acid is commonly used, e.g., (81) (82). 

The elements of bromine azide have been added to steroid olefins. The addition can be rationalized as proceeding through a positive bromonium ion under the ionic conditions of Hassner and Boerwinkle (bromine plus sodium azide and hydrochloric acid in nitromethane-dichloromethane) or Ponsold (A-bromosuccinimide or A-bromoacetamide in chloroform contain-... 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

Bromination of triazolium salts and triazolium oxides has been achieved using bromine and. A/ -bromoacetamide. The salt (18) itself acts as a brominating agent in basic solution, giving (Scheme 43) a mixture containing the dibromo derivative (19).216,225... 

Initial halogenation of the oxime can use chlorine, hypobromite, bromine, or A-bromoacetamide. " Oxidation of the a-halonitrosoalkane can be achieved with nitric acid, nitric acid-hydrogen peroxide, " atmospheric oxygen, ozone, or a peroxyacid. Reduction of thea-halonitroalkaneis achieved with sodium borohydride or by catalytic hydrogenation, although potassium hydroxide in ethanol has been used for the conversion. 

A-Bromoacetamide, 0784 1-Bromoaziridine, 0783 3 -Bromo-3 (4-nitrophenyl)-3// -diazirine, 2645 A-Bromo-3-nitrophthalimide, 2884 N -Bromosuccinimide, 1425 N -Bromotetramethylguanidine, 2002 A-Bromotrimethylammonimn bromide( ), 1300 Chloramine, 4000... 

Wohl in 1919 reported that A -bromoacetamide (CH CONHBr) induced allylic bromination. " Then iV-bromosuccinimide (30) was described in 1942 by Ziegler and co-workers to be useful in such free radical bromination reactions (equation 41), " and this widely utilized procedure is known as the Wohl-Ziegler reaction. In 1963 the mechanism of the reaction was proposed to involve halogen atoms in the hydrogen abstraction step " " " instead of succinimidyl radicals as had been commonly supposed. The halogen atom mechanism had previously been proposed by Gosselain et al. for reactions of yV-chlorosuccinimide. " ... 

The system A -bromoacetamide-hydrogen fluoride adds bromine monofluoride to acetylene derivatives.32 Hex-1-yne. hex-3-yne, 1.4-dichlorobut-2-yne, and phenylacetylene give the corresponding bromofiuoroalkenes, in no case is the addition of a second molecule of bromine monofluoride observed. Hex-1 -yne (3) produces 95% of the (E)- and 5% of the (Z)-isomcr 4. 

The oxidizing properties of positive halogen precursors have been reviewed by Filler.80 Compounds which have been used in steroid hydroxyl oxidations are A-bromosuccinimide (NBS),78,172 A-bromoacetamide (NBA),172 A-bro-mophthalimide,78 isocyanuric bromide (ICB),161 isocyanuric chloride (ICC)163 and A-chlorosuccinimide (NCS).91... 

A suspension of 17a,21-dihydroxypregna-4,9(ll)-diene-3,20-dione 21-acetate (0.77 g) and A-bromoacetamide (0.3 g) in anhydrous methylene dichloride (40 ml) is added over 2-3 min with stirring to a mixture of anhydrous hydrogen fluoride (10.19 g), and anhydrous tetrahydrofuran (18 g) in a polyethylene bottle at —80° (acetone-dry ice). After 1 hr at —80° the reaction mixture is kept for a further 1 hr at 0° and then added cautiously to an excess of an ice-cold solution of sodium carbonate. Extraction with methylene dichloride and crystallization from acetone-hexane furnish 9a-bromo-ll/ -fluoro-17a,21-dihydroxypregn-4-ene-3,20-dione 21-acetate (0.69 g), mp 205-208°, raised by several crystallizations from acetone-hexane to 215-217° [a]D 142° (CHC13) 2max 240-242 mju (e 15,500). 

Acetoxy-20-keto-17a-pregnanes via Acetylenic Carbinols.165 A mixture of 1.9 g of 17a-ethynylestradiol diacetate, 2.1 g of A-bromoacetamide, 2 g of anhydrous sodium acetate, 10 ml of water and 100 ml of acetic acid is left at... 

Over a decade ago, work on the enzyme aldolase reductase elegantly demonstrated this point. The noncovalent inhibitor alrestatin was modified to contain various electrophiles a-chloroacetamide, a-bromoacetamide or a-iodoacetamide. Noncovalent interactions between inhibitors and protein would not have changed, but molecules behaved differently based on the electrophile the weakest showed reversible inhibition, whereas the iodoacetamide displayed almost complete irreversible inhibition.1401 These results are an important warning if a reaction is too facile, irreversible reactions can obscure true binding affinities. 

The diazepinol (40) is readily obtained from ketone (10) with sodium borohydride and is converted back into 10 with A -bromoacetamide or by Oppenauer oxidation.32 In a similar manner 32 and the AT-acetyl derivative of 10 can be reduced to carbinols. Acylation of 40 or treatment of the reduction product of 32 with acetic acid gave the trans-annular oxide (41). The carbinol (40), the acetyl carbinol from 10, the oxide (41), and the diacetyl analog of 41 all undergo rearrangement with mineral acid to give the four furfurylhydrazines (42).32... 

Miscellaneous equations are contained in Table Id. Equation 76 is interesting in that steric, electronic, and lipophilic factors are all involved in the a-bromoacetamides. The positive dependence on both o- and E8 indicates that small electron-withdrawing groups enhance activity. The requirement of a large E8 value (or small size) for high activity in both Equations 76 and 77 reflects the fact that nucleophilic replacement of the a-bromo atom may be a critical step in the toxiphoric action. Electron-... 

The trans addition of BrF by A -bromoacetamide and hydrogen fluoride to dimethyl maleate and fumarate leads to dimethyl (2X, 3S )-2-bromo-3-fluorosuccinate [(25, 36 )-ll] and (25. 3/ )-2-bromo-3-fluorosuccinale, [(2S. 3/f )-ll], respectively. 

The reaction with A -bromosuccinimide or Af-bromoacetamide with or without added acid, on the other hand, leads predominantly to the same epoxide trans-6 as formed in the reaction with peracids. It is proposed that in the formation of cis-6 with acetyl hypobromite, hypobromous acid or A -chlorosuccinimide, nucleophilic attack of the halonium ion is fast. The epoxide ratio therefore is governed by the kinetically favored tran.v-halohydrin. However, in the reaction with A -bromosuccinimide or A -bromoacetamide the nucleophilic attack on the bromonium ion species becomes rate determining, attack of the nucleophile therefore follows the path of lowest activation energy. This is the attack on the c/.v-bromonium ion distant to the bulky tert-butyl group leading to the trans-diaxial bromohydrin, according to the Fiirst-Plattner rule, hence giving trans-6. 

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