A-Haloesters

Since the exocyclic sulfur is more reactive in the ambident anion than in A-4-thiazoIine-2-thione. greater nucleophilic reactivity is to be expected. Thus a large variety of thioethers were prepared in good yields starting from alkylhalides (e.g.. Scheme 38 (54, 91, 111, 166-179). lactones (54, 160), aryl halides (54, 152. 180, 181), acyl chlorides (54. 149, 182-184). halothiazoles (54, 185-190), a-haloesters (149. 152. 177. 191-194), cyanuric chloride (151). fV.N-dimethylthiocarbamoyl chloride (151, 152. 195. 196), /3-chloroethyl ester of acrylic acid (197), (3-dimethylaminoethyl chloride (152). l,4-dichloro-2-butyne (152), 1,4-dichloro-2-butene (152), and 2-chloro-propionitrile (152). A general... 

Synthesis of glycidic esters (amides) from an aldehyde or ketone and an a-haloester (amide). 

FRANCHIMOND Cyano Succinic Acid Synthesis Condensation of a-haloesters to succinic acid derivalives in the presence of CN ... 

REFORMATSKY BLAISE Zincahyiallon Synthesis of -hydrexyesters from cartxinyl derivatives arxl a-haloesters via a zmc reagent (Reformatsky). Synthesis ol eloesleis from nitriles and a-haloesters via a zinc reagent (QIaise). 

A solution of the sulfoxide in THF is added to a slight molar excess of LDA in Till- while maintaining the temperature below —75 C. then the a-haloester is added dropwisc to the yellowish solution of the anion at the same temperature. The usual workup gives optically active product in high yield. 

PVC formed with diacyl peroxide or peroxydicarbonate initiators will contain a proportion of potentially labile a-haloester chain ends (6, Scheme 8.9). However, it is believed that most chain ends in PVC are formed by transfer to monomer as is discussed in Sections 4.3.1.2 and 6.2.6.3.47... 

There are related reactions in which the sulfur is at the sulfoxide or sulfilimine oxidation level. Another example of the addition-cyclization route involves a-haloesters, which react to form epoxides by displacement of the halide ion. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

An interesting intramolecular disnlacement occurs in the Darzens reaction, in which carbanions derived from a-haloesters react with carbonyl compounds to yield a-epoxyesters ... 

While a "Perkow-route"71 81 for product formation generally ensues when a-halocarbonyl substrates are challenged with Michaelis-Becker reagents,173-175 ethyl 4-bromoacetylaceto-nate provides a simple substitution product.176 Simple substitution occurs also with a-haloesters and a-halophospho-nates.177/178... 

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. 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

It was shown a few years ago that a-haloesters can react with an aryl-nickel compound generated electrochemically in a divided cell (Eq. 8) [57]. The main drawback for this two-step method is the use of a large excess of PPhs to prevent the homocoupling reaction ... 

Darzen s reaction org chem Condensation of aldehydes and ketones with a-haloesters to produce glycidic esters. dar-zonz re.ak-shon ... 

Nucleophilic addition of organozinc reagents generated from a-haloesters to carbonyls. 

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. Some typical examples of enamine alkylation reactions are shown in Scheme 1.10. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

Examples of radical-mediated C-alkylations are listed in Table 5.4. In these examples, radicals are formed by halogen abstraction with tin radicals (Entries 1 and 2), by photolysis of Barton esters (Entry 3), and by the reduction of organomercury compounds (Entry 4). Carbohydrate-derived, polystyrene-bound a-haloesters undergo radical allylation with allyltributyltin with high diastereoselectivity (97% de [41]). Cleavage from supports by homolytic bond fission with simultaneous formation of C-H or C-C bonds is considered in Section 3.16. 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Carbon-Nitrogen Bonds. Several groups have studied the synthesis of optically active a-amino acids from inexpensive and readily available a-haloesters by displacement with phthalimide in the presence of chiral cinchona catalysts [1 le,24h,24i,47e,60d,77]. Early studies, with chiral, non-racemic starting material, showed that this reaction occurs with partial... 

Glycidic esters are prepared by the reaction of an aldehyde or ketone with an a-haloester in the presence of base (sodium ethoxide, sodamide, finely divided sodium or potassium t-butoxide) (the Darzens glycidic ester condensation). 

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. 

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