Wolff-Kishner modified reduction

The disadvantages associated with the Clemmensen reduction of carbonyl compounds (see 3 above), viz., (a) the production of small amounts of carbinols and unsaturated compounds as by-products, (h) the poor results obtained with many compounds of high molecular weight, (c) the non-appUcability to furan and pyrrole compounds (owing to their sensitivity to acids), and (d) the sensitivity to steric hindrance, are absent in the modified Wolff-Kishner reduction. 

Common catalyst compositions contain oxides or ionic forms of platinum, nickel, copper, cobalt, or palladium which are often present as mixtures of more than one metal. Metal hydrides, such as lithium aluminum hydride [16853-85-3] or sodium borohydride [16940-66-2] can also be used to reduce aldehydes. Depending on additional functionahties that may be present in the aldehyde molecule, specialized reducing reagents such as trimethoxyalurninum hydride or alkylboranes (less reactive and more selective) may be used. Other less industrially significant reduction procedures such as the Clemmensen reduction or the modified Wolff-Kishner reduction exist as well. 

The classical procedure for the Wolff-Kishner reduction—i.e. the decomposition of the hydrazone in an autoclave at 200 °C—has been replaced almost completely by the modified procedure after Huang-Minlon The isolation of the intermediate is not necessary with this variant instead the aldehyde or ketone is heated with excess hydrazine hydrate in diethyleneglycol as solvent and in the presence of alkali hydroxide for several hours under reflux. A further improvement of the reaction conditions is the use of potassium tcrt-butoxide as base and dimethyl sulfoxide (DMSO) as solvent the reaction can then proceed already at room temperature. ... 

Modified Wolff-Kishner methods work well on ordinary cyclobutanones. Generally, the hydrazones are made at fairly mild reaction temperatures, base is added and the cyclobutane is distilled directly from the hot reaction mixture.237,272 279-284 The hydrazone can also be isolated prior to the reduction.285 The relatively facile reduction of cyclobutanones which occurs before that of larger ring ketones can be utilized in the selective reduction of cyclobutanones in the presence of, for example, a cyclohexanone, i.e. pentaspiro[3.1.3.3.3.3]heneicosane-5,11,19-trione was reduced in a stepwise manner to pentaspiro[3.1.3.3.3.3]heneicosane-5-one.237... 

Further examples of the modified Wolff-Kishner reduction of cyclobutanones to cyclobutanes are given in Table 13. 

Acylation. One of the most useful and important methods for preparations of alkylthiophenes is acylation. This is the reaction of carboxylic acids and carboxylic acid chlorides with thiophenes in the presence of a suitable catalyst and leads to 2-acylthiophenes in good yields (typically ca. 60-80% e.g. 23). Reduction of the ketone functionality by either a modified Wolff-Kishner procedure (8, 24) or with a mixed hydride, formed from aluminium trichloride and lithium aluminium hydride (25), yields the alkylthiophene (Figure 6). Alternatively, the ketone group can be alkylated, thereby giving access to 2-(r-alkyl)alkylthiophenes. 

A modified Houben-Hoesch reaction of the nitrile 84 gave 31% of the azaazulenone 85, which was transformed to 63 by Wolff-Kishner reduction (62JOC1652). Similarly, 86 has been converted into 87 (78CB2407). Acid 88 gave ketone 89 with polyphosphoric acid (69JCS(C)1028) as was 91 formed from 90 (79JHC1443). 

A modified Wolff-Kishner reduction employing hydrazine in glycol has been used to prepare 10-phenyldecanoic acid from the 10-keto acid (70%) and palmitic acid labeled with C14 at carbon atom 6 from the corresponding 5-keto acid. As in the Clemmensen reduction, the thiophene nucleus is unaffected. ... 

Ethylthiophene may be obtained in 91% yield by a modified Wolff-Kishner reduction of 2-acetylthiophene. Other thiophene ketones, also aldehydes, have been converted in the same way in 70% to 90% yields. Reduction by the Clemmensen procedure gives 38% to 55% yields. °°... 

The main use of hydrazine in steroid chemistry has been in the reduction of keto-groups to give unsubstituted methylene groups by the Wolff-Kishner process, particularly as modified by Huang-Minion fij. Hydrazones of simple ketones react rapidly at 200° in hydroxylic solvents such as "diethylene glycol containing strong alkali. 

Since its introduction early in this century, the deoxygenation of aldehydes and ketones to methyl or methylene derivatives, respectively, via base treatment of hydrazone intermediates (equation 1) has proven to be one of the most convenient and synthetically useful processes available for this important type of transformation. The reaction is termed the Wolff-Kishner reduction in recognition of the two original independent discoverers.However, the initial recipes introduced proved tedious and unreliable with many structural, especially hindered, examples. This led to substantial efforts devoted over the years to developing more convenient and successful experimental procedures, resulting in a number of improved and more reliable modifications which are most often utilized at present. More recently, modified procedures have been provided which utilize hydride reductions of p-toluenesulfonylhydrazone (to-sylhydrazone) derivatives and subsequent decomposition to release the hydrocarbon products under much milder and less basic conditions than those normally required for Wolff-Kishner reductions (equation 2). 

The shortest synthesis of papaverine was achieved in the laboratory of R. Hirsenkom starting from racemic stilbene oxide and using a modified Pomeranz-Fritsch reaction The aminolysis of the stilbene oxide led to the formation of the cyclization precursor, which upon treatment with excess benzoyl chloride, underwent cyclization to give the N-benzoyl 1,2-dihydroisoquinoline derivative. Reduction under Wolff-Kishner conditions afforded papaverine. 

Huang, M., Chung, T. S. Conversion of 16a,17a-epoxypregnenolone into 3p,16a-dihydroxy-5,17(20)-pregnadiene by the modified Wolff-Kishner reduction. Tetrahedron Lett. 1961, 666-668. 

Huang, M. Reduction of steroid ketones and other carbonyl compounds by modified Wolff-Kishner method. J. Am. Chem. Soc. 1949, 71, 3301-3303. 

Furrow, M. E., Myers, A. G. Practical Procedures for the Preparation of N-tert-ButyIdimethylsilylhydrazones and Their Use in Modified Wolff-Kishner Reductions and in the Synthesis of Vinyl Halides and gem-Dihalides. J. Am. Chem. Soc. 2004,126, 5436-5445. 

Barton, D.H.R., Bashiardes, G. and Fourrey, J.-L. (1983) An improved preparation of vinyl iodides. Tetra/iedronLeffew, 24, 1605-1608 Barton, D.H.R., Chen, M., Jaszberenyi, J.C. and Taylor, D.K. (1997) Preparation and reaction of 2-tert-butyl-l,L3,3-tetramethylguanidine 2,2,6-trimethylcyclohexen-l-yl iodide. Organic Syntheses, 74, 101-105 Furrow, M.E. and Myers, A.G. (2004) Practical procedures for the preparation of A-tert-butyldimethylsilylhy-drazones and their use in modified Wolff-Kishner reductions and in the synthesis of vinyl halides and gem-dihalides. Journal of the American Chemical Society, 126, 5436-5445. 

With the above methodology in hand, a similar strategy was attenq)ted for the synthesis of the aryl acetic acid 7 (Scheme 7). The aniline 5 was treated with 2,5-dimethoxytetrahy ofuran in toluene and acetic acid to get the W-aryl pyrrole 28. The Vilsmeier/Triedel-Crafts acylation of 28 followed by decarbonylation afforded the keto ester 30. However, the reduction of the keto ester proved to be difficult. Most of the general methods employed for the reduction of ketones gave a mixture of products. However, a two step process involving the formation of the thioketal 31 followed by desulfurization with Ni proved to be successful. Although, the standard Wolff-Kishner conditions could not be employed in the system due to the susceptibility of the nitrile to hydrolysis, a modified Wolff-Kishner reduction (8) proved to be fruitful. 

The preparation of butyric-4-C acid (50% yield) involves a two-step synthesis starting viuth glutamic-l,2-C acid (Mosbach et at., 195i). The procedure requires a deamination to succinaldehydic acid which is followed by a modified Wolff-Kishner reduction. In the first step the doubly labeled glutamic acid loses one labeled C moiety to become a singly labeled aldehyde. The unstable intermediary succinaldehydic acid is prepared as needed. Coon and Abrahamsen (1952) and Zabin and Bloch (1951) prepared butyric-3-C add from ethyl-l-G iodide in yields of 41 and 51%, respectively. 

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