A-Halo aldehydes, preparation

Alkyl halides Aryl halides a-Halo aldehydes, preparation of, 703 a-Halo carboxylic acids... 

Exercise 17-11 The direct halogenation of aldehydes under either acidic or basic conditions is complicated by side reactions involving either oxidation of the aldehyde —CHO group or additions to the—CH—0 double bond. Therefore the synthesis of a-halo aldehydes by the procedure described for ketones is not of much practical value. a-Haio aldehydes can be prepared indirectly from the enol ethanoate of the aldehyde. The enol ethanoate is made by treating the aldehyde with ethanoic anhydride and potassium ethanoate. The overall sequence follows ... 

Preparation. The general preparation of y acids is by the hydrolysis of an a-halo acid or by the acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 

In a related process, a-halo ethers can be prepared by treatment of aldehydes and ketones with an alcohol and HX. The reaction is applicable to aliphatic aldehydes and ketones and to primary and secondary alcohols. The addition of HX to an aldehyde or ketone gives tx-halo alcohols, which are usually unstable, though exceptions are known, especially with perfluoro and perchloro species. °... 

Dithiobiurets react with a-halo ketones79-82 or aldehydes (generated in situ)63 to yield 2-thiureidothiazoles (40), which can be converted in two steps to 2-guanidinothiazoles.81 However, Beyer and Hantschel81 found that 2-guanidinothiazoles could be more conveniently prepared via the reaction of 1-amidino-2-thiourea with a-halo ketones or aldehydes. 

Preparation. The general preparation of u-hydroxy acids is by the hydrolysis of an a-halo acid or by Ihe acid hydrolysis of the cyanohydrins of an aldehyde or a ketone. 0-Hydroxy acids may be made by catalytic reduction of 0-keut esters followed by hydrolysis. 0-Hydroxy acids can also he prepared by ihe ReformaCsky reaction y-Hydroxy acids are seldom obtained in the free slate because of ihe case wilh which they form... 

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... 

Indium-mediated Barbier-type coupling between carbonyl compounds and allyl halides has been revealed to proceed effectively in diverse reaction media. Even under solvent-free conditions, allylation works well, although no reaction is observed with benzyl bromide and a-halo carbonyl compounds.59 Various aldehydes react with allyl bromide mediated by indium in liquid carbon dioxide to give homoallylic alcohols (Scheme 1). In contrast to the corresponding neat allylation, the liquid C02-mediated reaction can allylate solid aldehydes successfully.60 Indium-mediated allylations of carbonyl compounds with allyl bromide proceed in room temperature ionic liquids. In [bmim][BF4] and [bmim][PF6] (bmin l-butyl-3-methylimidazolium), the desired homoallylic alcohols are formed with good levels of conversion.61 Homoallyllic alcohols are also prepared by the reaction of resin-bound aldehydes (Equation (l)).62... 

Dihalides and 1,5-ditosylates have been used for the preparation of fully-saturated monocyclic 1,2-diazepines 165 (Scheme 83). 5-Halo-aldehydes and 5-halo-ketones react with a wide range of substituted hydrazines to give 4,5,6,7-tetrahydro-l,2-diazepines 166 <1976H(4)1509>. The reaction of 1,5-diketones with hydrazine has been much used as a source of 5,6-dihydro-4/7- 1,2-diazepines 167 . 

Benzofurans and benzothiophenes are sometimes obtained by condensation of active methylene and aldehyde groups in ortho substituents on the benzene ring. " The starting materials in the furan series are conveniently prepared in situ torn phenolic aldehydes and a-halo ketones or CL-halo esters. 

Nitrosobenzene, CjHsNO, which is obtained by the oxidation of phenylhydroxylamine, and p>nitrosodimethylaniline, p-(CH3)2NCjH4NO, which is easily prepared by the nitrosation of dimethylaniline, are fairly specific oxidizing agents for the preparation of aromatic aldehydes from benzyl halides or tosylates and of a-dicarbonyl compounds from from a-halo ketones [984, 985]. Also, a methylene group flanked by two carbonyls can be oxidized to a carbonyl group by nitrosodimethylaniline [986]. Pyridine is frequently used to form quaternary pyridinium salts from reactive halides prior to their oxidation to aromatic aldehydes, a-ketoaldehydes, or a-diketones [984] (equations 22 and 23). 

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