Bromo esters

Ethyl 3-amlnopropsnoate (5). To a tu solution of 4 in THF (frem the bromo ester with NaN3 In OMSO) was added a molar equivalent of Ph3P, t 5 equiv of water and a boiling chip (N2 evolution) Alter 8 h at 20°C and evaporation, the residue was treated with El20-hexane and PhaPO was filtered This process was repeated and 5 was distilled at 40-45° and 10.5 torr (83%). 

This method with some slight modihcations is applied in the synthesis of to-bromo esters from Cs to Cn. Methyl 5-bromovalerate has been prepared by treating the silver salt of methyl hydrogen adipate with bromine. The ethyl ester has been prepared from the acid by esterification or through the acid chloride. ... 

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 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... 

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>... 

Double hydrophilic star-block (PEO-fo-PAA)3 copolymers were prepared by a combination of anionic and ATRP of EO and fBuA [150]. Three-arm PEO stars, with terminal - OH groups were prepared by anionic polymerization, using l,l,l-tris(hydroxymethyl)ethane, activated with DPMK as a trifunctional initiator. The hydroxyl functions were subsequently transformed to three bromo-ester groups, which were utilized to initiate the polymerization of f-butyl acrylate by ATRP in the presence of CuBr/PMDETA. Subsequent hydrolysis of the f-butyl groups yielded the desired products (Scheme 74). 

Bipyridine-centered triblock copolymers of the type BA-bpy-AB were prepared by a combination of ATRP and ROMP [159]. 4,4 -Bis(hydroxymelhyl)-2,2/-bipyridine was employed for the polymerization of lactic acid, LA or CL in the presence of Sn(Oct)2 in bulk at 130 and 110°C, respectively. The hydroxyl end groups were converted to tertiary or secondary bromo esters by reaction with 2-bromoisobutyryl bromide or 2-bromopropionyl bromide. The reaction yields were very high (> 80%) but not quantitative. These products were used as macroinitiators for the ATRP of MMA or tBuA in the presence of CuBr/HMTETA. 4,4/-bis(Chloromethyl)-2,2 -bipyridine was employed to promote the ATRP of MMA or styrene followed by the addition... 

We felt the Reformatsky reaction was a worthwhile target because it is the most generally applicable method for converting aldehydes and ketones to ff-hydroxyesters(25). The improvements in yield and reaction time exceeded our expectations. Essentially quantitative conversion to the 0-hydroxyester was effected in a matter of a few minutes(26). The absence of other products, such as a, 0-unsaturated esters, resulting from dehydration, and dimers of the bromo ester and the carbonyl are probably the result of running... 

The yield in this reaction is improved by an excess of zinc and bromoester relative to aldehyde. The present ratio of zinc bromo-ester aldehyde (3 3 1) gives 87% of intermediate /3-hydroxy ester when the ratio is reduced to 2 3 1, the yield is lowered to about 68%. 

Commercially available 2-ethylhexanal (Eastman practical grade) is purified by fractional distillation b.p. 163-163.2°/atm., no 1.4133. Other aldehydes are conveniently prepared by the Rosenmund reduction.2 If the aldehyde is relatively unstable toward autoxidation,3 a catalytic amount (0.5-1.0 g.) of hydroquinone is added with the aldehyde-bromo ester solution. 

Ethyl a-bromopropionate is available commercially (Sapon Laboratories, % 1.4452) and is employed without purification. Bromo esters are severe lachrymators, and operations that involve transferring these compounds from one vessel to another should be conducted in a well-ventilated hood. 

Alkylation of Z-aldoximes (144) and (145) with bromo esters (146) and (147) provides good yields of high purity DEEPN and EPPyON nitrones (Scheme 2.52) (306). 

By means of nickel-catalyzed couplings of vinyl zirconocenes, Schwaebe et al. succeeded in obtaining fluorinated materials using a-bromo esters as electrophiles (Scheme 4.62) [113]. The yields achieved, albeit modest (24—65%), were far better using Ni(0) than those obtained in experiments based on several palladium(O) sources (no product observed). Isopropyl esters appear to be crucial, as competing 1,2-addition occurs with both ethyl and n-butyl analogues. Curiously, t-butyl esters were found to completely inhibit both modes of reaction of the zirconocene. 

The combination of Sml2 and HMPT effects a Barbier-type reaction of w-bromo esters with carbonyl compounds to provide y- and 8-lactones (equation I).14... 

In order to prove that fluorine was responsible for the lethal action in (I) and (II), the intermediate bromo esters were examined physiologically. Ethyl 5-bromopentanecarboxylate was found to be entirely without toxic action, and the toxicity of its 2-fluoroethyl ester was also of a low order, the l.d. 50 being about 75 mg./kg. 

Ethyl 10-fluorodecanecarboxylate was readily prepared by the fluorination of the corresponding bromo ester prepared by esterifying the acid with ethyl alcohol and sulphuric acid. 

B) a-Bromo-fi-methoxypropionic Acid.—Eight hundred grams of the bromo ester and 11. of 0.5 N sodium hydroxide are placed in a 5-I. three-necked flask equipped with an efficient stirrer and a separatory funnel, and cooled with running tap water. The stirrer is started, and 800 cc. of 5 N sodium hydroxide is added during the course of two hours. After the addition is complete, the solution is stirred for one hour and then neutralized with an equivalent quantity of sulfuric acid (Note n). The neutralized solution is extracted once with a i-l. portion, and three times with 500-cc. portions, of ether. The ether extracts are combined, washed once with a cold saturated solution of sodium sulfate, and dried over anhydrous sodium sulfate the ether is removed by distillation (Note 12). There remains 700-750 g. of crude bromo acid which is used without purification in the preparation of serine (Note 13). 

If the methyl acrylate solution has stood for some time, it is advisable to use a x0 per cent excess, since the solution slowly deteriorates. A low yield of bromo ester is usually caused by insufficient methyl acrylate. 

Direct conversion of a-bromo esters into amino esters by hydride reduction of the azido ester (without isolation) produces yields in excess of 80% [7]. However, bromomalonates fail to form the azido ester under similar conditions. Instead, oxidative dimerization occurs to yield the ethene-l,l,2,2-tetracarboxylate (see Section 6.1) [10]. 

The stereochemical control of the Gabriel reaction by chiral catalysts can be further enhanced in the synthesis of optically active a-amino acids when optically pure (-)-bornyl a-bromo esters are used (Table 12.8) [4]. 

Sharpless and his group have also studied a series of selective transformations of r/jreo-2,3-dihydroxy esters (6) -prepared by catalytic ADH of a,P-unsaturated esters 5- which lead to very useful and highly elaborated synthetic intermediates [36], such as a-(sulfonyloxy)-P-hydroxyesters (2), P-acetoxy-a-bromo esters or a-acetoxy-p-bromo esters (8 and 9), threo- and erythro-glycidxc. esters QO and U.) and P-hydroxy esters (12). The substituent at the p-position plays an important role in determining the regiochemistry of the bromination of the 2,3-dihydroxy esters whereas a P-alkyl substituent leads to p-acetoxy-a-bromo esters, a phenyl group directs formation of the a-acetoxy-P-bromo esters (Scheme 10.5). 

Methyl 2-bromo-2-cyclopropylideneacetate (11a) has never been tested in these reactions, but has been used as a starting material for the stepwise construction of 1,6-heptadienes with methylenecyclopropane units for intramolecular Heck reactions. Thus, bromo ester 11a, after reduction, subsequent conversion of the resulting alcohol to the bromide and coupling with enolates of substituted malonates, was transformed into dienes of the type 254 (Scheme 73) - versatile synthetic blocks for the preparation of functionally substituted spirocyclopropanated bicyclo[4.3.0]nonenes 255a-d by a domino Heck-Diels-Alder reaction [122a]. 

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