Halo carbonyl substrates

With alkyl halide substrates, the first step of the oxidation is the Sn2 displacement of the halide with tosylate anion. Next the alkyl tosylate undergoes a second Sn2 reaction with the nucleophilic oxygen atom of the DMSO to form the alkoxysulfonium salt that undergoes deprotonation to give the alkoxysulfonium ylide, which upon a [2,3]-sigmatropic shift affords the carbonyl compound. In the case of a-halo carbonyl substrates, the deprotonation takes place at the more acidic a-carbon instead of the methyl group attached to the sulfur atom of the alkoxysulfonium salt. 

Instead of a-halo esters, related reactants can be used e.g. the a-halo derivatives of ketones, nitriles, sulfones and A,A-disubstituted amides. The Darzens condensation is also of some importance as a synthetic method because a glycidic acid can be converted into the next higher homolog of the original aldehyde, or into a branched aldehyde (e.g. 5) if the original carbonyl substrate was a ketone ... 

The carbonyl substrate 3 to be reacted with the organozinc compound 2 can be an aldehyde or ketone that may contain additional functional groups. With a vinylogous halo ester—i.e. a y-halocrotyl ester—the corresponding y-crotylzinc derivative is formed. 

Mannich bases (see 16-15) and p-halo carbonyl compounds can also be used as substrates these are converted to the C=C—Z compounds in situ by the base (16-15, 17-12). Substrates of this kind are especially useful in cases where the C=C—Z compound is unstable. The reaction of C=C—Z compounds with enamines (12-18) can also be considered a Michael reaction. Michael reactions are reversible. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

A lot of methods are available for the synthesis of this heterocycle, and most of them rely on the formation of the five-membered ring. In this section, only the methodologies of reasonable scope will be reported. The most classical method involves the cyclocondensation of 2-aminopyridine with an a-halo carbonyl compound. Due to the broad availability of the required substrates and the efficiency of this cyclocondensation, it continues to be the method of choice to prepare this heterocycle. New examples highlighting the generality of this reaction are collected in Table 14. 

In order to improve this reaction, a proper understanding of all parameters affecting product yield is desired. Clearly, the high enzyme consumption is a major obstacle for an efficient and economically feasible process. A likely cause of the inefficient use of DERA in this conversion is enzyme deactivation resulting from a reaction of the substrates and (by-) products with the enzyme. In general, aldehydes and (z-halo carbonyls tend to denature enzymes because of irreversible reactions with amino acid residues, especially lysine residues. From the three-dimensional structure it is known that DERA contains several solvent-accessible lysine residues [25]. Moreover, the complicated reaction profile as shown in Scheme 6.5 indicates the potential pitfalls of this reaction. 

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). 

The Reformatsky reaction is most commonly conducted in a single step by addition of a mixture of a-halo ester and carbonyl substrate to a suspension of zinc in a suitable solvent. This one-stage procedure clearly minimizes any problems due to instability of the Reformatsky reagent. Since 1953, solutions of the reagent have occasionally been prepared, with varying degrees of success, by reaction of the a-halo ester with zinc in an initial separate step of a two-stage procedure. 

Single-stage procedures are most commonly used for the Reformatsky reaction with aldehydes and ketones. A mixture of a-halo ester and carbonyl substrate is added to a suspension of zinc at a rate sufficient to maintain the reaction. In the original procedure of Reformatsky, no solvent was used but modem practice is to use benzene or an ether solvent such as diethyl ether, THF, glyme or dimethoxymethane. The reaction is often conducted at reflux temperature, probably to avoid surges from the highly exothermic nature of the reaction. However, in a comparison with a number of aldehydes and ketones, much higher yields were obtained at room temperature than at reflux in benzene (equation 11). ... 

Halogen can be tolerated either in the carbonyl substrate or in the bromo ester component of the Reformatsky reaction. It is noteworthy that the intermediate zinc aldolate (11) does not internally substitute halogen until HMPA is added (Scheme 7). For reactions with a-halo ketone substrates in a A -buten-... 

The range of suitable participants in the Michaelis-Becker reaction is essentially the same as for the Michaelis-Arbuzov reaction. Halo-aldehyde and -ketone substrates suffer the competing reaction of direct attack at the carbonyl group leading to Perkow reaction products (with a-halocarbonyl compounds) or Pudovik reaction products, which often cyclize (cf. Sections 4 and 6). 

With a-halo- and a,P-unsaturated carbonyl compounds the issue of chemo-/regioselectivity arises, these substrates are discussed in Sections 4 and 8, respectively. 

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