Reformatsky reaction condition

Example 59 Caruthers and his associates have synthesized esterified acetic acids phosphonodiamidites under Reformatsky reaction conditions [96]. 

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. 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

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... 

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. 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

The next task was to form the C2-C3 aldol bond stereoselectively. However, asymmetric coupling of acetate derivatives to aldehydes is often accompanied by poor / -induction [89]. Moreover, the C3-C4 bond is particularly sensitive to retro-aldol reaction, especially under basic conditions. In the natural products, this was observed to be the main decomposition reaction. The first total syntheses of epothilones circumvented this problem by constructing this part of the molecule in an indirect manner, e.g., by using reduced forms at Cl or C5. We decided to employ our chromium-Reformatsky methodology, which avoids these problems and allows the direct use of reagents in the correct oxidation state. The non-basic reaction conditions, the intermediacy of a chromium(III) aldolate that is resistant to retro-aldol reaction, and the potential of a direct asymmetric carboxymethyl ( acetate ) transfer favor the use of this method [90]. 

On the way to fluorinated target molecules, a CF2 group may be also incorporated in the ketone framework in this case drastic conditions are required to promote the Reformatsky reaction with ethyl bromoacetate (lb). The example reported in equation 19 was carried out on 100 g scale and was directed to the synthesis of a fluoro analogue 23 of the anticancer drug chlorambucil94. 

Esters are rarely used as electrophiles in Reformatsky reactions. An example was reported by Atkins and coworkers the quinohne ester 89 failed to react with butanoic acid esters in classical Claisen condensation conditions, but was found to smoothly react with f-butyl ester 90 in the presence of zinc in good yield (equation 54)138. 

Ethyl bromodifluoroacetate is one of the fluorinated building blocks used most widely. There are scores of examples of the important Reformatsky reaction with aldehydes which occurs in THF/ether solvent mixtures, sometimes under sonication conditions (Eq. 62). 

Generally carried out under basic conditions, often starting from the organozinc or organomagnesium derivative of an a-bromoester, the Reformatsky reaction. Equilibrium is shifted toward product by formation of a chelate structure with the metal ion. 

The 1,4-conjugate addition of ester enolates to a, 3-enones was first reported by Kohler in 1910,138a c as an anomalous Reformatsky reaction, but chemoselectivity was dependent on the structure of the a,(3-enone and restricted to bromozinc enolates obtained from either a-bromoisobutyrate or bromomalonate esters (Scheme 66).138d,e Further evaluation, with lithio ester enolates and lithio amide enolate additions, has resulted in identification of four factors that affect the chemoselectivity and diastereoselectivity of additions to a, 3-enones.139 These factors are (a) enolate geometry, (b) acceptor geometry, (c) steric bulk of the -substituent on the acceptor enone and (d) reaction conditions. In general, under kinetic reaction conditions (-78 °C), ( )-ester enolates afford preferential 1,2-addition products while (Z)-ester enolates afford substantial amounts of 1,4-addition products however, 1,2 to 1,4 equilibration occurs at 25 C in the presence of HMPA. The stereostructure of the 1,4-adducts is dependent on the initial enolate structure for example, with ( )-enones, (Z)-ester enolates afford anti adducts, while (E)-ester enolates afford syn adducts (Scheme 54). In contrast, amide enolates show a modest preference for anti diastereomer formation. 

The 3-hydroxytetradecanoic acid required in the next step was obtained as the racemic mixture from n-dodecan-al and ethyl bromoacetate in a Reformatsky condensation (12), and saponification of the ester formed with potassium hydroxide. The enantiomers were then separated as their dehydroabietylamine salts according to Demary et al. (12). All reactions described below were carried out using first the racemic mixture of the acid,and, when reaction conditions were established, with pure (3R)-3-hydroxytetradecanoic acid. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

Reformatsky reactions have a bad reputation as being difficult to entrain. To the authors experience, however, the reactive donors such as alkyl bromo-acetates do not pose particular problems even under rather conventional conditions. Commercial zinc dust activated by pre-treatment with either iodine of preferentially with cuprous chloride (i.e. Zn(Cu)) readily inserts into these halocarbonyl compound with formation of the corresponding zinc enolates. Protocols 1 and 2 describe prototype examples for Reformatsky reaction in the conventional two-step or Barbier-type set-up, respectively. 

The electrosynthesis of /Miydroxy esters (220), 2,3-epoxy esters (221) and /Miydroxy nitriles (222) was achieved under nickel-catalyzed conditions, obviating Reformatsky reaction 70(equation 112-114). The reaction proceeds in excellent yield when a sacrificial zinc rod is used as the anode. A mechanism has been proposed which involves reduction of a Ni(II) complex to a Ni(0) complex, oxidative addition of the a-chloroester to the Ni(0) complex, and a zinc (II)/Ni(II) exchange, leading to an organozinc reagent, in analogy to the Reformatsky reactions. 

Indium mediates the Reformatsky reaction of y>-quinones to give good yields of />-quinols under mild conditions. Naturally occurring quinol esters such as jacaranone are conveniently prepared in a one-pot synthesis (Scheme 90).326... 

The Sml2-mediated Reformatsky reaction provides a useful alternative to traditional versions of the reaction as it proceeds under mild, homogeneous conditions, with high chemo- and diastereoselectivity. Although a-halo esters are the most common substrates for the reaction, in principle any a-halo carbonyl compound can be employed in the reaction. The reactions are most often carried out by the addition of Sml2 to a 1 1 mixture of the a-halocarbonyl compound and the coupling partner. These are often referred to as Barbier conditions (see Section 5.4). 

Reformatsky-type reactions and reductions. Enolates generated from a-bromoketones by reaction with BiClj-Al in an aqueous medium condense with various aldehydes to give J-hydroxy ketones." A modification of reaction conditions (BiClj-NaBH ) and in the absence of aldehydes leads to hydrodehalogenation of the haloketones. ... 

To avoid side products derived from further addition of the Reformatsky reagent to the newly formed resin-bound ester, careful optimization of the reaction conditions was undertaken. The best yields, without detectable amounts of side products, were obtained by using 10 equiv. of the Reformatsky reagent. For each supported amino acid (except, of course, for glycine), a pair of diastereoisomers was formed, the ratio of which was found to be strongly dependent on the nature of the aldehyde employed. 

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. 

Fe2(CO)g and CeClj—SnClj the latter present some advantages like lower toxicity, lower temperature and homogeneous reaction conditions. The first step in the reaction ofa,a -dibromoketone 56 with CeClj—SnClj (equation 10) involves a single debromina-tion in analogy with a Reformatsky reaction to afford a cerium a-bromo enolate 57, This intermediate suffers from further elimination of bromide via ionization to oxyallyl cation 58 which undergoes the [3 + 2] cycloaddition to the enamine. The aminocyclo-pentanonc 59 obtained was easily deaminated to cyclopentenone 60. 

Reformatsky reaction. The Reformatsky reaction is normally conducted at reflux temperatures in benzene or benzene-ether as solvent. Rathke and Lindert2 studied the Reformatsky reaction of acetaldehyde and ethyl bromoacetate under various conditions the yield of ethyl 3-hydroxybutanoate obtained in benzene at... 

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