Reformatsky reactions electrophiles

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

The Reformatsky reactions are run following two basic procedures (i) a two-step Grignard-type protocol which first involves the formation of an organometallic zinc eno-late derivative followed by addition of the electrophile, and (ii) a Barbier-type protocol where the bromoester and the electrophile are simultaneously exposed to the action of zinc metal. 

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. 

There are many odier named reactions that follow die same general features but differ as to die type of enolate or the carbon electrophile. These include the Reformatski reaction, the Darzens reaction, and the Dieckmann ring closure. They were in widespread use for many years and were named as a convenient way to characterize the reactants employed and type of product which results. The reason that diere are so many variations on the same theme is that control of the reaction products depends on die ability to generate a particular enolate nucleophile and... 

In a general sense, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt into a carbon-halogen bond activated by a vicinal carbonyl group, followed by reaction of the enolates thus formed with an appropriate electrophile (Scheme 14.1).1-3 The insertion of metallic zinc into a-haloesters is the historically first and still most widely used form of this process,4 to which this chapter is confined. It is the mode of enolate formation that distinguishes the Reformatsky reaction from other fields of metal enolate chemistry. 

Scheme 14.1 The Reformatsky reaction X = halogen, E =+ electrophile, M = Zn (this chapter) or another metal or low-valent metal salt.

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... 

Table 14.2 Reformatsky reactions with less conventional electrophiles selected examples...

See the following for leading references on Reformatsky reactions with unconventional electrophiles which are not yet covered by the reviews1-3 (a) Michael, J. P. ... 

A Sml2-mediated Reformatsky reaction involving formaldehyde as the electrophile has been exploited by Otaka in a synthesis of a dipeptide isostere treatment of y,y-difluoro-ot,p-enoate 130 with Sml2 in the presence of in situ-generated formaldehyde gave adduct 131 in good yield (Scheme 5.92).145... 

Sml2 Reformatsky methodology is now sufficiently robust that Linhardt employed Reformatsky-type addition to carbon electrophiles in a solid-phase synthesis of C-sialosides (see Chapter 7, Section 7.3).146 The use of a-halo ketones in intermolecular Reformatsky reactions is less common and is typically restricted to simple coupling partners. For example, Ohta showed that... 

An aldol reaction using the enolate of acetaldehyde and requiring it to react with a ketone is doomed to failure acetaldehyde itself is far too good an electrophile. In the forward synthesis, therefore, this first step was carried out at the ester oxidation level (using a Reformatsky reaction), and the ester was subsequently converted to the aldehyde by a reduction of the kind discussed in Chapter 24. 

Leaving groups on the a-carbon of carbonyl compounds (e.g., Br and OR) are reduced away by one-electron reducing agents. a-Bromocarbonyl compounds are reduced to the corresponding enolates by Zn in the Reformatsky reaction (Chapter 2). After the initial electron transfer, several pathways are possible, but all lead to the enolate. The enolate is usually allowed to react immediately with an electrophile such as another carbonyl compound. Before the advent of strong, non-nucleophilic bases, the Reformatsky reaction was the only way to prepare enolates of simple carbonyl compounds quantitatively. 

Palladium catalysis promotes the Reformatsky reaction. Heteroaryl iodides are better substrates than bromides and chlorides. Iodine in electrophilic positions in the substrate, but not in the benzenoid position, were active in the Reformatsky reaction (277,278) (Scheme 63). Homo-coupling is the major pathway for iodo derivatives in the benzenoid position, with formation of 3,3 -biquinoline (279) (85CPB4309). 

The mechanisms of the usual organic reactions are now clearly established, and the reactions are classified as ionic, radical, and molecular. More detailed classifications have also been made. The mechanisms of many reactions involving non-transition metal compounds are clear enough for example, in the Grig-nard or Reformatsky reaction, the first step is the irreversible oxidative addition of alkyl halides to form Mg-carbon or Zn-carbon bonds, in which the carbon is considered to be a nucleophilic center or carbanion which reacts with various electrophiles. 

This reaction is basically an electrophilic substitution, followed by hydrolysis. The Reformatsky reaction, which follows, is an organometallic reaction which yields a B-hydroxy ester or acid. Upon heating, we get the corresponding a,B-unsaturated product ... 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

The formation of an organometallic reagent in the presence of an electrophilic partner is a synthetic process of historical value, illustrated by the Barbier and Reformatsky reactions. In their first versions, these processes consisted of additions to carbonyl compounds. They have now been extended to a wide variety of substrates and were reviewed in a recent book.250... 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

Another useful application of these Reformatsky reagents is their conversion to difluaraketene silyl acetals and subsequent reaction of these ketene silyl acetals with electrophiles [86, 89, 90] (equation 59)... 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

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