Acetic bromo-, esters

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>... 

To a solution of MgBr2Et20 in dichloromethane was added a-bromo ester (0.1 M) of dichloromethane. The mixture was stirred for 5 min at 25 °C, and then cooled at 0 °C. After addition of Bu3SnH (2 eq.), Et3B (1 M, hexane solution), divided to 3 parts (0.2 eq. X 3 = 0.6 eq.), was added to the mixture within 15 min. After 2 h at 0 °C, m-dinitrobenzene (0.5 eq.) was added to the reaction mixture, which was further washed with aq. NaHC03 solution, extracted with dichloromethane, and dried over MgS04. After filtration and removal of the solvent, the residue was poured into hexane and Bu4N+F (2.5 eq.) was added to the hexane solution and stirred for 5 min at 25 °C. After column chromatography (eluent ethyl acetate/hexane = 15/85), a reduction product was obtained in 91% yield with symanti = 33 1 [1]. 

In a parallel study, it was found that chelating chiral diamines 208 or 209 are well suited as ligands to promote Kumada-type couplings of primary and secondary alkyl halides 202 with aryl Grignard reagents 203 (entry 4) [281]. This reaction was applicable to alkyl bromides and alkyl iodides, while alkyl chlorides gave only low yields. Acetal and ester functions are tolerated. A notable feature is the stereoretentive arylation of fra s-a-bromo acetals with excellent diastereo-selectivity. The involvement of radicals is supported by the stereoconvergent formation of cxo-phenvI norbornane from both endo- or exo-bromonorbomane (cf. Part 1, Fig. 9) and radical 5-exo cyclizations (see below). 

Reaction of halides with silver nitrate to give nitrate esters has been known for years, but its synthetic application is more recent. Komblum showed that the nitrate esters derived from a-bromo ketones and esters decompose smoothly with catalytic sodium acetate in DMSO to give the a-dicarbonyl compounds in high yield. It was found unnecessary to isolate the nitrate ester after reaction of the halide with silver nitrate the solution was filtered to remove AgBr, concentrated, and added to DMSO containing catalytic sodium acetate. The method complements the others for the synthesis of a-dicarbonyl compounds since it employs nonacidic, nonbasic conditions. Unfortunately, the method gave variable results with benzyl halides. The application of the method to bromo esters other than bromoacetates was not reported. Some related oxidations are shown in equations (41) and (42), and Schemes 9 and 10. The oxidation of an iminium salt is notable. 

Malonic acid, ethyl malonate, and their monoalkyl derivatives can be readily halogenated in ether solution subsequent decarboxylation leads to the corresponding a-halogenated acetic acid in 55-80% yield. The reaction of the potassium salts of monoethyl alkylmalonates with bromine provides the a-bromo esters directly, although the yields ate relatively low. ... 

The procedure has been extended to the formation of difunctional compounds like 3-methyl-3-butenal diethyl acetal (24%), 1,1-diethoxy-2-butyne (80%), and /3-ethoxyethyl methyl ketone diethyl ketal (92%). A somewhat related reaction is the formation of diethyl acetals of a-formyl esters by treatment of a-bromo esters with zinc and ethyl ortho formate (45 60%). ... 

Reaction of 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-dienecarhoxylic esters 1229 with 2-amino- or 2-aminomethyl-anilines 1230 produces r-5-(benzimidazol-2-yl)pyrroline-2-acetic acid esters 1231 from a double Michael addition process. Substituents on the nitrogen atoms or in the aromatic ring are tolerated as long as they do not strongly reduce the nucleophilicity of the nitrogen atoms (Scheme 307) <2005S2357>. 

The Michaelis-Becker reaction has been investigated with a-chloro-, a-bromo-, and a-iodoac-etates. In contrast to a-chloroacetates, on treatment with sodium diethyl phosphite, a-bromo- and a-iodoacetates undergo reduction to the corresponding acetates. Low yields (18-30%) of unsubstituted and a-alkyl substituted / w(2,2,2-trilluorocthyl) l-(ethoxycarbonyl)methylphosphonates, prepared from sodium bE(2,2,2-trifluoroethyl) phosphite and the corresponding a-bromo esters, have recently been reported. ... 

Other halides may be used in place of the bromo ester. Reaction of a pro-pargyl halide, for example, with various carbonyl compound gives y,d-acetylenic alcohols of type (6) in good yield.223 Also the carbonyl component may be replaced by an orthoformic ester, which leads to a malonic monoester monoaldehyde acetal of type (7) in 44-58% yield.224... 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

Polyenes. Ethanolic Na-ethoxide added dropwise to a cold soln. of all-trans-3,1-dimethyl -1 - (p-phenoxyphenylsulf onyl) -9- (2,6,6- trimethy Icyclohexen -1 -yl) -2,4,6,8-nonatetraene and the startg. bromo ester in dimethylformamide, stirring continued 5 hrs. at 0° under Ng, then poured into aq. acetic acid ethyl all-trans-2,6,11,15-... 

Dilithium tetrachlorocuprate is recommended as an additive for cross coupling of Grignard compounds with tosylates even allylic and benzylic acetates give good yields . a-Methylene-ketones, -carboxylic acids and -lactones have been prepared via sulfides and sulfoxides. A convenient and general synthesis of acetylene derivatives from boranes via the reaction of iodine with lithium 1-alkynyltriorganoborates has been published ar-Nitrostyrenes can be easily obtained by a Wittig synthesis with formaldehyde in an aqueous medium . A new synthesis of unsym. ketones by reaction of dialkyldiloroboranes with lithium aldimines has recently been published . Metallo aldimines have also served for the synthesis of a variety of other compound classes such as a-hydroxyketones, a-keto acids, nitriles, and for the asym. synthesis of a-amino acids . Polycondensations of malononitriles with benzylic chlorides have been carried out quantitatively under mild conditions in dimethyl sulfoxide with triethylamine as acid acceptor . Carbonyl compounds can react with dibromoacetonitrile to yield a-bromo esters with additional carbon atom . ... 

Keto-esters.—Further examples of alkylations of the acyl anion equivalent (105) have been reported (c/. 2, 226 3, 16). Only in some cases can good yields of a-keto-ester dimethyl acetals be realized. In an extension of earlier work, N-aryl-triflamides have been found to be useful reagents for the overall oxidation of a-bromo-esters to a-keto-esters. Benzoylformates are accessible by carboxylation of anions derived from 2-aryl-l,3-dithians this approach seems to be an improvement on existing methods. 

Scheme 8 Synthesis of iaryl acetic acid ester 32 from p-bromo aniline...

This preparation illustrates the Reformatsky reaction, which consists in the interaction of a carbonyl compound, an a-halogen ester (e.g., ethyl bromo-acetate) and zinc In the presence of ether or benzene, followed by hydrolysis. 

This synthesis came shortly after one by Prelog, Kohlberg, Cerkovnikov, Rezek and Piantanida (1937) based on a series of reactions which, with modifications and extensions. Prelog and his colleagues have applied to the syntheses of bridged heterocyclic nuclei, of which this is an example. 4-Hydroxymethyltetrahydropyran (VI R =. OH) is converted via the bromo-compound (VI R = Br) and the nitrile (VI R = CN) into tetrahydropyran-4-acetic acid of which the ethyl ester (VII) is reduced to 4-()3-hydroxyethyl)-tetrahydropyTan (VIII). This is converted by fuming hydrobromic acid into 3-(2-bromoethyl)-l 5-dibromopentane (IX) which with ammonia in methyl alcohol yields quinuclidine (V). 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Phenyl-ethyl alcohol can be prepared by numerous methods, several of which are the subject-matter of patents. It may be prepared, for example, by the conversion of phenyl-bromo-lactic acid into phenyl-acetaldehyde, and then reducing this body with sodium. Or it may be prepared by reducing phenyl-acetic esters with sodium and absolute alcohol in the folio-wing manner —... 

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