Reformatsky reaction preparation

A similar Reformatsky reaction, prepared from the cheaper precursor, ethyl chlorodifluoroacetate in dry DMF, has been reported by Lang and Schaub [259] (Scheme 85). Later, Lang demonstrated the preparation of 2,2-difluoro-4-pente-... 

CH2Br COOH. White crystalline solid, m.p. 50"C, b.p. 208 C. Soluble in water and alcohol. Prepared by the action of dry bromine on dry ethanoic acid in presence of small amounts of red phosphorus. Produces sores upon the skin used in chemical syntheses. See Reformatski reaction. 

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. 

Bromination of the methyl group of (249) with A -bromosuccinimide, followed by reaction with excess secondary amine gave (250) which shows combined analgesic and antitussive properties. The Reformatsky reaction has also been used for the preparation of 2-amino-ethyl 3,3-diaryl-3-hydroxypropanates (251) as well as their dehydration products. The propene amides (252) have also been prepared for pharmacological evaluation. In l-methyl-3-bis (2-thienyl)-... 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

Two further methods for the preparation of p-ketoesters consist of the Reformatsky reaction of pyrazolides[67] (a) and the magnesium bromide-induced Claisen condensation of pyrazolides[68] (b). 

Highly reactive zinc can be prepared by reduction of anhydrous ZnC with potassium/THF or sodium/DME(l 7,29). This zinc has been shown to undergo rapid oxidative additions with alkyl bromides to produce near quantitative yields of the corresponding dialkylzinc. It also underwent oxidative addition with phenyl iodide and bromide. Moreover, the zinc was found to be useful in the Reformatsky reaction. Reactions could be carried out in diethyl ether at room temperature to generate near quantitative yields of the 3-hydroxyester. 

The 3,4-dihydrodiol of BcP was synthesized from 4-oxo-l,2,3,4-tetrahydro-BcP (15) by Method I (66). The ketone L was itself prepared from 4-oxo-l,2,3,4-tetrahydrophenanthrene via a multistep sequence entailing Reformatsky reaction with methyl bromocrotonate, dehydration of the resulting alcohol, isomerization to the aryl-butyric acid, and cyclization of its acid chloride with SnCl - Full... 

Higher-molecular-weight normal 2-alkenoic acids have been prepared in poor yields by the Doebner condensation of aldehydes with malonic acid,5-7 and by the Reformatsky reaction of aldehydes with ethyl bromoacetate followed by dehydration.8 The a-iodo acid, prepared from the bromo acid, has been dehydrohalogenated with potassium hydroxide in ethanol,9 but large quantities of the a-hydroxy acid are formed as a by-product which is difficult to separate in some instances. The present procedure is an adaptation of a published method.6... 

This procedure is an adaptation of ones described by Dunna-vant and Hauser.2-4 Ethyl /3-hydroxy-/S,/3-diphenylpropionate has been prepared previously using the Reformatsky reaction by condensing ethyl a-bromoacetate with benzophenone by means of zinc metal.5... 

This procedure illustrates the use of lithio esters for the preparation of /3-hydroxy esters. Isopropyl and /-butyl /3-hydroxy-/8,/3-diphenylpropionate may be prepared in approximately 80% yields by using isopropyl or /-butyl acetates in place of ethyl acetate.2 This procedure is generally more convenient than the Reformatsky reaction for the preparation of such esters. Under similar conditions ethyl acetate may conveniently be condensed with various aldehydes or ketones to give the corresponding /8-hydroxy esters.4... 

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

Carbohydrate lactones have been used as the carbonyl reagent in the Reformatsky reaction. Thus, 2,3 5,6-di-O-cyclohexylidene-D-mannono-1,4-lactone [44, obtained by oxidation of the mannofuranose derivative (49)] reacted with ethyl bromoacetate and zinc to give the protected 2-deoxy-3-octulosonic acid ethyl ester (45a) in 69% yield (50). Ketonic hydrolysis with potassium hydroxide in aqueous methanol, followed by acidification and heating, afforded the 1-deoxyheptulose derivative 45b. Similarly, starting from compound 44, the 1-C-substituted allyl and propar-gyl lactols were prepared on reaction with allyl or propaigyl bromides in the presence of zinc (51). 

Improvement to the Reformatsky reactions was achieved (53) by the use of a highly activated zinc - silver couple dispersed on the surface of graphite. T reatment of protected aldono-1,4-lactones 10b or 25b and 1,5-lactones 51a or 51b with a Reformatsky reagent prepared from a-haloesters or alkyl 2-(bromomethyl)acrylates resulted in the formation of the corresponding 3-or 4-glyculofuranos (or pyranos)onates 49a,b-50a,b, or 52a,b, respectively, under mild conditions (— 40 ° to 00) and in very good yields. Ethyl 2-deoxy-2-fluoro (and 2-bromo)-a-D-wa o-3,6-furanos-3-octulosonate derivatives were also obtained. 

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. 

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

Esters of cyclohexylideneacetic acid have been prepared by the Reformatsky reaction followed by acylation and pyrolysis, a laborious procedure giving low yields. The phosphonate car-banion procedure would appear to be the method of choice for preparation of these esters. 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

An alternative strategy to improve the efficiency of Reformatsky reactions makes use of freshly prepared metal couples, particularly the Zn—Cu couple32 and the Zn—Ag couple33 in TFIF as solvent. 

Even more reactive was then found to be Zn/Ag-Gr, prepared by the reduction of a ZnCl2/AgOAc mixture (0.1 molar ratio) with CgK with this powder Reformatsky reactions could be run at —78°C12f 46. 

Electrochemistry offers alternative routes to the preparation of active zinc for the Reformatsky reactions, for instance exploiting the cathodic reduction (—0.8 V v.v SCE) of ZnBr2 in acetonitrile containing Bu4N+BF4 as supporting electrolyte53. 

Exotic metals of the sixth row have been also reported to promote Reformatsky reactions for example Rieke-barium74, which reacts efficiently with a-chloroketones, low-valent tantalum75 prepared from TaCL and Zn(0), and low-valent bismuth76 prepared from 3 and A1(0), which works in water as solvent. 

On the way to prepare metabolites of equine norethandrolone, a Reformatsky reaction has been applied to epiandrosterone acetate 44 in refluxing benzene the authors succeeded... 

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. 

A synthesis of the monomeric unit 128 of a peptide nucleic acid analog (PNA) offers an example of stereospecific cross-coupling of a Reformatsky reagent with (Z)-vinylic iodide 126. The coupling reaction of the preformed Reformatsky reagent prepared in dimethoxymethane (methylal) with 126 is carried out using 8% of Pd(PPh3)4 in DMPU as the solvent at 65 °C to afford 127 (equation 70)161. 

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