A-Bromo esters

This is a general method for preparing a-bromo acids. By using exactly analogous directions -bromo- -caproic acid may be obtained in 65-70 per cent yields from w-butylmalonic ester a-bromo-isocaproic acid in 65-70 per cent yields from isobutylmalonic ester and a-bromo-/3-methyl valeric acid in 75-80 per cent yields from sec.-butylmalonic ester. 

A variety of bases have been used to effect dehydrohalogenation of halo acids and halo esters. a-Bromo esters or a-bromo acyl halides give a,/3 lefinic acids with alcoholic potassium hydroxide. Yields are poor with the higher-molecular-weigbt a-bromo acids other products are those formed by substitution of the halogen atom by the basic anions. 

Reformatski reaction Aldehydes and ketones react with a-bromo- fatty acid esters in the presence of zinc powder to give -hydroxy-esters which may be dehydrated to give a-, 0-unsaturated esters. a-Chloroesters will react if copper powder is used in conjunction with the zinc. 

The 7 a-bromo steroid (9) can also be treated with sodium phenyl selenolate (41). The resultant 7 P-phenyl selenide (13) can be oxidized and the corresponding phenyl selenoxide elirninated to form the 7-dehydtocholesteryl ester (11). 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Kitazume and Kasai [55] have investigated the Reformatsky reaction in three ionic liquids. This reaction involves treatment of an a-bromo ester with zinc to give an a-zinc bromide ester, which in turn reacts with an aldehyde to give an addition product. An example is given in Scheme 5.1-26. Moderate to good yields (45-95 %) were obtained in ionic liquids such as [EDBU][OTf] for the reactions between ethyl bro-moacetate or ethyl bromodifluoroacetate and benzaldehyde [55]. 

The intermediate o-bromo acid bromide undergoes a nucleophilic acyl substitution reaction with methanol to give an a-bromo ester. 

Corey s auxiliary reagent 10 is also applied in order to obtain a f/-2-bromo-3-hydroxy-carboxylic esters in enantiomeric purities of 91-98%. The a-bromo esters thus obtained are useful intermediates for the preparation of a-unsubstituted /Miydroxy esters as well as for 2-amino-3-hydroxy- and 3-amino-2-hydroxycarboxylates64a b. 

The chemistry of indium metal is the subject of current investigation, especially since the reactions induced by it can be performed in aqueous solution.15 The selective reductions of ethyl 4-nitrobenzoate (entry 1), 2-nitrobenzyl alcohol (entry 2), l-bromo-4-nitrobenzene (entry 3), 4-nitrocinnamyl alcohol (entry 4), 4-nitrobenzonitrile (entry 5), 4-nitrobenzamide (entry 6), 4-nitroanisole (entry 7), and 2-nitrofluorenone (entry 8) with indium metal in the presence of ammonium chloride using aqueous ethanol were performed and the corresponding amines were produced in good yield. These results indicate a useful selectivity in the reduction procedure. For example, ester, nitrile, bromo, amide, benzylic ketone, benzylic alcohol, aromatic ether, and unsaturated bonds remained unaffected during this transformation. Many of the previous methods produce a mixture of compounds. Other metals like zinc, tin, and iron usually require acid-catalysts for the activation process, with resultant problems of waste disposal. 

Pyridone IV was converted to its sodium salt by treatment with an equimolar amount of sodium methoxide in methanol (see procedure below under formation of the 3-phenyl-2(lH)pyridone sulfonates). The sodium salt was next treated with the methyl ester of a-bromo-p-toluic acid, obtained by treatment of the acid with BF3 etherate. 

B. Reactions.—(/) Halides. Whereas ylides are alkylated in the normal way on treatment with a-bromo- or a-iodo-esters, quite different reactions occur with a-fluoro- and a-chloro-acetates. When salt-free ylides were refluxed in benzene with ethyl fluoroacetate or trifluoroacetate normal Wittig olefin synthesis took place with the carbonyls of the ester groups to give vinyl ethers, e.g. (14). On the other hand, methyl chloroacetate with... 

The mechanism of these alkylations involves a tetracoordinate boron intermediate formed by addition of the enolate of the a-bromo ester to the organoborane. The migration then occurs with displacement of bromide ion. In agreement with this mechanism, retention of configuration of the migrating group is observed.23... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Another Lewis acid-catalyzed atom-transfer domino radical cyclization, to produce various bicyclic and tricyclic ring skeletons, has been developed by Yang and coworkers [54]. Reactions of the a-bromo-(3-keto ester 3-125 with Yb(OTf)3 and Et3B/02 led to the bicycle 3-126 in 85 % yield (Scheme 3.33). The reaction proceeds via a (>-endo-Irig and 5-exo-trig cyclization after initial abstraction of the bromine... 

The reaction of potassium 3-amino-4-oxo-3,4-dihydroquinazoline-2-thiolate 62 with a-bromophenylacetic acid 63 resulted in the formation of (3-amino-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-phenyl-acetic acid methyl ester 64 which on alkali treatment and subsequent acidification resulted in the synthesis of 2-phenyl- 1-thia-4,4a,9-triaza-anthracene-3,10-dione 65 <1999JCR(S)86>. Similarly, the reaction of potassium 3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- pyrimidine-2-thiolate 66 with a-bromo-ester 67 resulted in the formation of 2-(3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- / pyrimidin-2-ylsulfanyl)-propionic acid ethyl ester 68. Subsequent treatment with alkali followed by acidification resulted in the formation of 2,3,7-trimethyl-3a,9a-dihydro-l,8-dithia-4a,5,9-triazacyclopenta[ ]naphthalene-4,6-dione 69 <2000JHC1161>... 

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