Clemmensen method

Aliphatic hydrocarbons can be prepared by the reduction of the readily accessible ketones with amalgamated zinc and concentrated hydrochloric acid (Clemmensen method of reduction). This procedure is particularly valuable for the prep>aration of hydrocarbons wdth an odd number of carbon atoms where the Wurtz reaction cannot be applied with the higher hydrocarbons some secondary alcohol is produced, which must be removed by repeated distillation from sodium. 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

It was also suggested that the relationship of the two forms (A) and (B) might be that of stereoisomerides of the cis-trans decalin type and a good deal of work was done to provide experimental evidence for this view or the alternative that they are structural isomerides. It was also found that of the methods used to synthesise the pyridocoline system all but one gave norlupinane (A) on reduetion, the exceptional formation of uorlupinane (B) being limited to reduction of the 1-keto compound by the Clemmensen method. 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

The intermediate formation of iminium salts is postulated in the reduction of (x-amino ketones by the Clemmensen method, occurring with concomitant ring enlargement or contraction (244-246). Reduction of l,2,2-trimethyl-3-piperidone (154) in this manner gave l-methyl-2-iso-propylpyrrolidine (155). 

Tin and HCl reduce out the ben/.ylic OH from (43) in high yield.The Mannich base (45) decomposes to (41) simply on heating. Cyanide addition gives (46) which can be hydrolysed to (40), but a short cut is to hydrolyse to amide (47) and reduce out the carbonyl group by the Clemmensen method (Table T 24.1). Under these conditions the amide is hydrolysed to the acid. Cyclisation to (38) occurs with strong acid, acid anhydrides, or by AlClg-catalysed reaction of the acid chloride. 

A simple application of the reaction may be mentioned. Refluxing of (I) with 48 per cent, hydrobromic acid and glacial acetic acid leads to hydrolysis and decarboxylation and the production of a mixture of the y-lactone yy-di-phenylbutyrolactone (II) and the isomeric unsaturated acid yy-dlphenyl-vinylacetic acid (III) reduction by the Clemmensen method or catalytically... 

The reduction of vanillin by the Clemmensen method using toluene as an auxiliary solvent has been reported.3 By following these directions, a yield of 49% of creosol was obtained with large amounts of tar. 

The non-catalytic reduction of kojic acid has not been reported, but some conclusions concerning the probable results may be drawn from the following observations. Woods reduced 6-benzoylkojic acid (LXXXIII), by the Clemmensen method, to 6-benzylkojic acid (LXXXIY),89 and, likewise,... 

Alkyl-substituted thienothiophenes can be prepared by reducing acetyl or formyl derivatives (see refs. 18,21,25,26,28,44,57,67,68). Wolff-Kishner reduction is preferred to the Clemmensen method, since the latter requires hot concentrated hydrochloric acid, which may cause resinification. ... 

Tetrafluoro-3-oxo-4-phenylbutanoic acid is reduced at both the activated a,a -positions and the carbonyl group to give 4-phenylbutanoic acid by the Clemmensen method in quantitative yield.125 In contrast, only the highly activated C3-F bonds are selectively reduced in ethyl 2,2,4,4,4-pentafluoro-3-oxobutanoate by treatment with sodium in diethyl ether (Table 3).126 A more efficient zinc reduction of ethyl 4.4,4-trifluoro-3-oxobutanoate in refluxing acetic acid results in complete hydrodefluorination of the trifluoromethyl group to give 21.104... 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

When the Clemmensen method fails, or when strongly acidic conditions are precluded owing to the presence of acid-sensitive functional groups, the Wolff-Kishner reduction or the Huang-Minlon modification of it may succeed. The latter method is also discussed in Section 6.1.1, p. 827, and illustrated in Expt 6.4, Method A. 

Reaction of succinic anhydride with benzene in the presence of anhydrous aluminium chloride (slightly over two equivalents see above) yields 3-benzoylpropanoic acid. This may be reduced by the Clemmensen method in the presence of a solvent (toluene) immiscible with the hydrochloric acid to 4-phenylbutanoic acid. Cyclisation to a-tetralone (Expt 6.123) is then effected smoothly by treatment with hot polyphosphoric acid. This reaction sequence represents the first stages in the Haworth procedure for the synthesis of polycyclic aromatic hydrocarbons (see Section 6.1.4, p. 839). 

Catalytic hydrogenation over palladium-on-charcoal with perchloric acid promoter is more satisfactory than the Clemmensen method for the reduction of a-phenyl-/3-benzoylpropionic acid to a,y-diphenylbutyric acid (83%). Several other keto acids have been successfully hydrogenated over this catalyst. ... 

Clemmensen reaction. The Clemmensen method of reduction (1913) consists in refluxing a ketone with amalgamated zinc and hydrochloric acid. Acetophenone, for example, is reduced to ethylbenzene. The method is applicable to the reduction of most aromatic-aliphatic ketones to at least some aliphatic and alicyclic ketones, to the y-keto acids obtainable by Friedel-Crafts condensations with succinic anhydride (succinolylation), and to the cyclic ketones formed by intramolecular condensation. 

Any of the methods (Tabie 24.1) for removing a carbonyl group might work as the molecule is tough enough to survive all three. The Clemmensen method has been used and must be carried out while the two carbonyl groups are still different, before the cyclisation. 

The following types of compound can be reduced by the Clemmensen method ... 

If a carbonyl compound cannot be reduced satisfactorily by the Clemmensen method, the Wolff-Kishner procedure usually gives better results (cf. page 74). 

Another alternative approach primarily intended for the synthesis of 3-alkylphenols consisted in the reaction of (i) alkylmagnesiumbromides with 3-methoxybenzamide to afford the corresponding 3-methoxyphenyl n-alkylketone which was reduced (ii) by the Clemmensen method to the n-alkyl-3-methoxybenzene, demethylation of which with aluminium chloride was considered to give the 3-n-alkylphenol (ref. 15). 

A further synthesis of quinuclidine was devised by Clemo and Metcalfe (197), who decarboxylated 2,4-lutidinic acid (CLVIII), obtuned by oxidation of 2,4-lutidine, and reduced the resulting pyridine-4-carT boxylic acid (CLIX) with sodium and alcohol. Esterification of the product afforded ethyl piperidine-4-carboxylate (CLX), which was condensed with ethyl chloroacetate to give ethyl piperidine-l-acetate-4-carboxylate (CLXII). Dieekmann cyclization followed by decarboxylation yielded 3-ketoquinuclidine, which on reduction by the Wolff-Kishner or Clemmensen methods gave quinuclidine. 

Notice the use of a cyclic anhydride in the first Friedel-Crafts acylation. It doesn t matter where the acylation occurs and the reaction stops there as the ring is deactivated by the ketone and the carboxylic acid released in the reaction is much less electrophilic than the anhydride. The ketone is then reduced to a CH2 group by the Clemmensen method (see Chapter 23) and polyphosphoric acid is used to carry out the intramolecular acylation step. 

Cannizzaro reaction, 60,66-67 Claisen condensation, 17, 21-22, 74-75 Claisen rearrangement, 33, 35 Clemmensen method, 5, 8-9 Curtius reaction, 132-133 Curtius rearrangement, 108 Cyanoethylation reaction, 172... 

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