Crossed-Cannizzaro reduction

During the large-scale, high-yield, one-pot synthesis of 4-chloro-3-(hydroxymethyl)pyridine, a starting material for the preparation of several polyfunctionalized molecules that can be linked to cephalosporines, M. Penso and co-workers utilized the combination of direct regioseiective iithiation/formyiation and crossed-Cannizzaro reduction of 4-chloropyridine. ... 

A crossed Cannizzaro reduction alone is involved in reaction of p-tolualdehyde (3 moles) with formalin (3.9 moles of CH2O) and aqueous potassium hydroxide (7.6 moles) to formp-tolylcarbinol. ... 

Reduction. The familiar preparation of pentaerythritol from acetaldehyde and formaldehyde involves aldolization and crossed Cannizzaro reduction. In the same way, cyclohexanone reacts with 5 moles of formaldehyde to give the pentaol (3). The reaction is conducted by adding calcium oxide (1,25 moles) to a stirred mixture O OH... 

Chemical reduction of aromatic aldehydes to alcohols was accomplished with lithium aluminum hydride [5i], alane [770], lithium borohydride [750], sodium borohydride [757], sodium trimethoxyborohydride [99], tetrabutylam-monium borohydride [777], tetrabutylammonium cyanoborohydride [757], B-3-pinanyl-9-borabicyclo[3.3.1]nonane [709], tributylstannane [756], diphenylstan-nane [114], sodium dithionite [262], isopropyl alcohol [755], formaldehyde (crossed Cannizzaro reaction) [i7i] and others. 

The first reaction provides a route for the reduction of alkyl halides since the carbo-cation (isopropyl, in Rl) may be prepared from action of AICI3 on the corresponding alkyl halide. Reactions of the type Rl are also important in the process, catalytic cracking, in the manufacture of gasoline. They have also been studied in mass spectro-metric experiments [235]. Reaction R2 is one route to the preparation of carbocations under stable ion conditions. Reaction R3 is employed in the laboratory synthesis of the tropylium cation. Reaction R4, the (crossed) Cannizzaro reaction, is unusual in that it takes place under strongly basic conditions. The oxy dianion is an intermediate in the reaction of concentrated hydroxide with the aldehyde, R HO. None of R1, R2, or R3 may have hydrogen atoms a to the carbonyl groups. Formaldehyde (R1 = H) is readily... 

Hydroxjrmethylbenzof Jthiophenes are most conveniently prepared by reduction with lithium aluminum hydride of the corresponding carboxylic acid78,100 S37 485,486,521,528,540 or ester.77,87,336,337, 52i, 526 Lesg frequently, they are prepared by reduction of the corresponding aldehyde 100,487 or acid chloride,618 with sodium boro-hydride, or, in the case of 2-hydroxymethylbenzo[6]thiophenes, by reaction of the 2-lithium derivative with formaldehyde.90,628 3-Hydroxymethylbenzo[6]thiophene has been prepared from the corresponding aldehyde by means of a crossed Cannizzaro reaction... 

The so-called crossed Cannizzaro reaction is synthetically more useful than the Cannizzaro reaction itself, as it can be applied for the preparation of alcohols in high yields, without loss of 50% of the product in the formation of the corresponding carboxylic acid. Typically, paraformaldehyde is used as a sacrificial reducing agent, together with the carbonyl compound which is to be transformed into the alcohol. The reaction thus serves as an alternative method to the use of complex hydrides for the reduction of aromatic aldehydes. 

Dismutations of the same type, but involving two unlike aldehyde molecules, will be classed as crossed Cannizzaro reactions. The reduction of benzaldehyde to benzyl alcohol by means of formaldehyde and alkali is an example. 

Aldehydes with One a-Hydrogen Atom. Aldehydes of the type RR CHCHO under suitable conditions39 (Table I) can be made to condense smoothly to the aldols. Under other conditions the aldol condensation may be the first step, followed by a crossed Cannizzaro reaction between the aldol and the original aldehyde. The products of this reaction are the glycol formed by reduction of the aldol and the acid formed by oxidation of the original aldehyde.29 39 40 41 v i... 

The Cannizzaro and crossed Cannizzaro reactions can be carried out with a minimum expenditure of time and do not require elaborate equipment or special reagents. For the convenient reduction of an aldehyde which is inexpensive and readily obtainable, these procedures, especially the latter, are particularly mitable. Indeed, the reservation regarding cost and availability scarcely applies to the crossed reaction since it is convenient and affords excellent yields. 

The aldolization mentioned was subsequently used461 for an interesting synthesis of branched-chain sugars. Thus, on reaction with formaldehyde, 78 gives, stereospecifically, 1,6-anhydro-3-C-(hydro xy-methyl)-2,3-0-isopropylidene-/3-D-(yxo-hexopyranos-4-ulose, which subsequently undergoes reduction at C-4 by a crossed Cannizzaro reaction leading to l,6-anhydro-3-C-(hydroxymethyl)-2,3-0-isopropyl-idene-/3-D-talopyranose. On the other hand, an attempt to condense 78 with ethyl formate did not result in the expected 3-C-formyl derivative only the dimer 88 was obtained.461... 

Since few aldehydes lack a-hydrogen atoms, the Cannizzaro reaction is of limited use in modern synthetic sequences, although a variation called the crossed Cannizzaro is occasionally used for the reduction of aromatic aldehydes. In this reaction excess formaldehyde is mixed with the aromatic aldehyde and becomes preferentially activated by base since it is present in excess. Thus, the aldehyde present to the lesser extent is reduced to the primary alcohol in high yield. For example. 

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