Bromoesters

Great caro must be exercised in handling ethyl bromoacetate. Keep a 10 per cent, aqueous ammonia solution available to react with any bromoester which may be spilled. 

Simply mixing MeNHi and the y-bromoester A will give the heterocycle in one step. How might you make TM 248 ... 

By analogy with the Reformatsky reaction, the zinc derivative of a p-bromoester would do ... 

Synthesis The CO2H group spells trouble. We would certainly have to use an ester, but the a-bromoester is too reactive to use with an acetylene. Also there is a danger that the double bond in A will move into conjugation. We can get round all these problems with an epoxide and then oxidise at the end ... 

The conversion of chiral boronic esters iato optically pure B-aIkyl-9-BBN derivatives followed by reaction with a-bromoketones, a-bromoesters, or a-bromonitriles leads to the homologated P-chiral ketones, esters, and nitriles, respectively (526). 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

The reaction of bromine with (pyrazol-4-yl)acrylic acid and its esters and the subsequent dehydrobromination of the products have been investigated by Finar and Okoh [73JCS(P1)2008]. Attempts to dehydrobrominate bromoacrylic acids (20) to 3-( 1 -phenylpyrazol-4-yl)propiolic acids 22 failed, but were successful when bromoesters 21 were used (Scheme 32). 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

The mesogenic units with methylenic spacers were prepared by reacting the sodium salt of either 4-methoxy-4 -hydroxybiphenyl or 4-phenylphenol with a bromoester in DMF at 82° C for at least 4 hours in the presence of tetrabutylammonium hydrogen sulfate (TBAH) as phase transfer catalyst. In this way, ethyl 4-(4-oxybi-phenyl)butyrate, ethyl 4-(4-methoxy-4 -oxybiphenyl)butyrate, ethyl 4-(4-oxybiphenyl)valerate, ethyl 4-(4-methoxy-4 -oxybiphenyl)-valerate, n-propyl 4-(4-oxybiphenyl)undecanoate and n-propyl 4-(4-methoxy-4 -oxybiphenyl)undecanoate were obtained. These esters were hydrolyzed with base and acidified to obtain the carboxylic acids. The corresponding potassium carboxylates were obtained by reaction with approximately stoichiometric amounts of potassium hydroxide. Experimental details of these syntheses were described elsewhere (27). 

A drum containing distillation wastes of ethyl carbonate, ethyl bromoacetate and another bromoester (not intelligibly named) burst spontaneously, releasing a cloud which caused considerable lachrymation and respiratory irritation in nearby housing. Carbon dioxide was doubtless generated, but whether by water contamination or a previously unknown catalytic reaction of the known contents is unclear to the editor. 

Alternatively, reaction of A-(acylmethylene)naphthyridin-2-ones with ammonium acetate and acetic acid under microwave irradiation gives the imidazonaphthyridines 234 <2004JCM832>, and reaction of 2-amino[l,8]naphthyr-idines with a-bromoketones or a-bromoesters gives the same ring system (Scheme 56) <1996H(43)1229, 1997JHC765>. 

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%. 

This procedure has been applied successfully to the synthesis of other a-nitroesters from a-bromoesters,3 as listed below ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate. 

The reaction mixture becomes homogeneous and turns deep red-brown shortly after the addition of the a-bromoester. The deep color is, presumably, due to nitrosated phloroglucinol however, this in no way interferes with subsequent isolation of product. 

R1 to R3 with yields ranging from 20% to 90%. For the reaction of acetophenone, allyl bromide can be replaced with propargyl bromide, benzyl bromide, or an a-bromoester, affording the corresponding tertiary alcohols in 86%, 86%, and 66% yields, respectively. 

Around the same time, Metzger and co-workers synthesized f-butyl substituted binaphthyl tin hydride 59 independently using an alternate procedure and employed them in the reduction of bromoester 58 (Scheme 16) [49]. The reaction was highly efficient providing up to 52% enantioselectivity (entry 1). A full account of this work has been recently published [50]. 

Scheme 16 summarizes the results obtained by enantioselective radical reduction of a-bromoester by chiral binaphthyl-derived tin hydride. The reactions were generally performed at - 78 °C. An increase in the temperature resulted in the lowering of the selectivity. All reactions mediated by (S)-configured chiral tin hydride showed an (R)-selective preference in the product. The use of the opposite enantiomer of the chiral stannane resulted in a quantitative reversal of the selectivity (not shown). The selectivity remained modest on addition of magnesium Lewis acids. These reductions were also feasible when a catalytic amount of chiral tin hydride (1 mol %) was employed in combination with an excess of achiral hydride NaCNBH3, providing similar results. 

Metzger and co-workers have also described a reduction of a-bromoesters by chiral tin hydrides containing a diastereomeric mixture of 2-[(l-dimethyl-aminoalkyl)phenyl] (DAAP) ligands [51]. The observed enantioselectivities were dependent on the tin hydride used and on the substituents attached to the radical center. 

Recently, Kang and Kim developed new chiral ferrocenyl tin hydride derivatives 72 and 73 (Scheme 19) [60]. The authors screened the new chiral reagent in the reduction of a-bromoesters. Using one equivalent of 73 good ee s were obtained for ester 71. One drawback for this reagent, however, is the lengthy synthetic route for its preparation. 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

Catalytic one-pot procedure. Since in the described teUuronium ylide olefmation tellurox-ide is formed as a by-product, and the telluroxide is susceptible to reduction by triphenyl phosphite, a catalytic procedure can be employed, providing a practical one-pot synthesis of a, -unsaturated esters and ketones (method E). By this procedure, a catalytic amount of n-dibutyl telluride reacts with the a-bromoester or a-bromoketone, and the formed tel-luronium salt is converted in situ under phase transfer conditions (solid KjCOj/trace HjO) into the ylide, which reacts in turn with the aldehyde, giving the olefin. Since the reaction is performed in the presence of triphenyl phosphite, the formed dibutyl telluroxide is reduced back to the dibutyl telluride, which is then recycled. 

The mechanism of these alkylations involves a tetracoordmate boron intermediate formed by addition of the enolate of the a-bromoester 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.21... 

The first approach investigated was the L-leucine approach (Hoekstra et al., 1997), as shown in Scheme 16.14, in which L-leucine was converted to the bromoester 49. The bromide was displaced with excess diethyl sodiomalonate to give triester 50 in good yield. The t-butyl ester was deprotected by formic acid treatment and the resulting acid... 

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