Methyl bromoacetate, Reformatsky reaction

A successive refinement (MNDO-PM3) of the reaction of the Reformatsky derivative of methyl bromoacetate with both formaldehyde and methanimine was carried out including coordinated THF molecules. It identified a twist-boat transition structure as the most stable TS for the transformation of G into H7. 

To better compare modern protocols for the Reformatsky reactions, hereinafter discussed in this section, it is interesting to read, as an example, the experimental procedure reported by R. B. Woodward and coworkers in 1956 for the synthesis of the Lysergic acid precursor 3 (equation 2)14. The procedure adopted was a Barbier-like protocol, involving the addition of Zn and of methyl bromoacetate (la) in three portions to a solution of 2 in hot benzene. 

A synthesis of a higher sugar, 2-deoxy-4-octulose, has been carried out using, as the key step, the Reformatsky reaction of methyl bromoacetate (la) with the /i-D-arabino-hexos-2-ulopyranose derivative 36, which affords the manno-derivative 37 in good d.e. (equation 26)102. The same authors developed analogous diastereoselective syntheses of... 

A nickel-catalysed electro-Reformatsky reaction has been previously presented (Section . . , Figure 5)57. Based on a formally related catalytic cycle, a nickel-catalysed 3-component route to /J-arnino esters and amides has been proposed (equation 41). To a CH2CI2 solution of an aldehyde and an aromatic amine are successively added dimethylz-inc, methyl bromoacetate (la) and bistriphenylphosphine nickel dichloride. After 1-3 h at rt, products were isolated in very high yield, and this procedure was exploited for the preparation of a chemical library of 64 members, using 4 aldehydes, 4 cr-haloesters and 4 substituted anilines58. 

The Reformatsky reaction has been applied to the synthesis of fused pyranones and provides an example of selective isomer formation by careful choice of substrate. Hydroxy-methylenecyclohexanone (315) and methyl bromoacetate give 5,6,7,8-tetrahydro-l-benzopyran-2-one (316) through alkylation at the hydroxymethylene carbon atom (54JA6388). However, the benzoyl derivative (317) is unable to form an enolate salt and alkylation occurs at the carbonyl carbon atom, leading to 5,6,7,8-tetrahydro-2-benzopyran-3-one (318) (45HCA771). 

Methyl 4-bromobut-2-enoate (BrCH2-CH=CH,C02Me, a vinyl analogue of ethyl bromoacetate, Expt 5.69) can also be used in the Reformatsky reaction, and its use permits an analogous four-carbon atom chain extension process. 

The Reformatsky reaction of methyl bromoacetate with the 2-oxohexanoylcephalotaxine (26) in the presence of freshly prepared active zinc afforded a mixture of deoxyharringtonine (27) and its C-2 epimer, which were separated by fractional crystallization of their picrates.19 Partial syntheses of homoharringtonine from cephalotaxine have also been reported.20,21... 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

Interest has been expressed by the People s Republic of China in the preparation of cephalotaxine ester alkaloids and analogues, no doubt for the purpose of evaluation of antitumour activity. Thus a number of esters, e.g. (34), (R = Me2CHCH2CH2COCO or PhCOCO), were subjected to Reformatsky reaction with methyl bromoacetate to give, e.g., [34 R = Me2CHCH2CH2C(OH)-(CH2C02Me)C0] (deoxyharringtonine) and [34 R = PhC(0H)(CH2C02Me)C0]. 

Zhao and co-workers 48) reported the first synthesis of homoharringtonine (3) in 1980 (Scheme 20). Unsaturated keto acid 151, prepared either from 5,5-dimethyl-5-valeroIactone 150, or by chain extension from the commercially available bromide 149, was esterified with cephalotaxine to give the cephalotaxyl derivative 152, which reacted with methyl bromoacetate under Reformatsky conditions to yield a mixture of epimers of dehydro-homoharringtonine 153. This mixture was converted to homoharringtonine and its epimer by means of oxymercuration, as well as by acid catalysis. As in the aforementioned syntheses of harringtonine, the Reformatsky reaction proceeded with no stereoselectivity, and diastereomeric mixtures resulted from all of these approaches. 

Two new cephalotaxine esters having significant antileukemic activity, neoharringtonine (11) and anhydroharringtonine (12), were isolated in 1992 by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1) produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. 

The condensation reaction of an imine derived from an aldehyde with ethyl bromoacetate under Reformatsky53 conditions led to a mixture of amino-esters and P-lactams. When acetaldehyde was condensed with methylamine, Schiff base 4.116 was the product A Reformatsky reaction with ethyl bromoacetate gave a mixture of the P-lactam (4.117) and the amino-ester (4.118). Acid hydrolysis and hydrogenation led to the P-amino acid N-methyl-3-aminobutanoic acid (4.119). When benz-aldehyde was the aldehyde starting material, 3-(N-methylamino)-3-phenylpropanoic acid (4.120) was the final product. ... 

Protonation of (tropone)Fe(CO)3 in CF3CO2H occurs at C-2 from the exo-side, whereas protonation in sulphuric acid is non-stereoselective. Hydride transfer to the protonated species occurs from the exo-side and gives tricar-bonylcyclohepta-2,4-dienoneiron (348) protonation then occurs on oxygen. The complex (348) undergoes the Mannich reaction, and gives (349) in the Reformatsky reaction with methyl bromoacetate. Proton abstraction from (349) leads to (350). Compound (351 R, R = H or alkyl) may be converted into heptafulvene complexes. ... 

The reaction of ethyl a-bromoacetate with 17-keto steroids such as estrone methyl ether or dehydroepiandrosterone acetate " under standard Reformatsky conditions is stereospecific, producing the 17 -ol in up to 80% yields. Ethyl a-bromopropionate reacts similarly but the yields are somewhat lower. 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

Many of the procedures given above have been utilized for the preparation of mevalonolactone labeled with isotopes of carbon, hydrogen, and oxygen.7-9 Mevalonolactone-14C has been prepared with the label at all six positions l-,7 29 2-,7 143 24 3-,llb 3 -, 203,30 4-,7,183 and 5-14C.19 Preparations of singly and doubly labeled meva-lonolactone-13C have been reported recently 2-,26,31 3-,32 4-,33 3, 4-,7,183 3,4-,26,33b and 4,5-13C.34 The procedure described here26 for the preparation of mevalonolactone-2-13C is both convenient and economical compared to the usual Reformatsky methods since acetic acid-2-13C is utilized directly in the condensation reaction, rather than methyl or ethyl bromoacetate. The overall yield of mevalonolactone-2-13C is 46-52% based on acetic acid-2-13C. 

C-metalated species is normally referred to as the Reformatsky reagent. These two species may further aggregate to form dimer by elimination of alkoxyzinc bromide, though the C-metalated species is the active one in this reaction. This assertion is supported first by the partial recovery of ketone during the complete consumption of zinc when an equivalent zinc and ketone are used and second, by the titration experiment on ethyl a-bromoisobutyrate, in which 70% active reagent and 30% dimeric substance were identified. According to these experimental results, an illustrative mechanism is proposed here using acetone and methyl a-bromoacetate as an example. 

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