Reduction, Wolff-Kishner

Carbonyl reduction to methylene using basic hydrazine. 

Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487. (the Huang-Minlon modification). 

Example 1, Huang Minion modification, with loss of ethylene here  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 274, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 293, Springer International Publishing Switzerland 2014 

Mergott, D. J. Woodward c s-dihydroxylation. In Name Reactions for Functional Group Transformations, Li, J. J., Ed. Wiley Hoboken, NJ, 2007, pp 327-332. (Review). 

The mechanism of the reduction is believed to involve deprotonation of the hydrazone to give the anion 121 (7.109). This is followed by the rate-limiting protonation at the carbon atom and deprotonation of the terminal nitrogen atom to give 122. Loss of nitrogen and protonation of the carbanion gives the product. In line with this mechanism, the polar aprotic solvent DMSO increases the rate of the reaction, and with potassium tert-butoxide in DMSO reduction can even be carried out at room temperature. 

Reduction of conjugated unsaturated aldehydes or ketones is sometimes accompanied by a shift in the position of the double bond (7.110). In other cases pyrazoline derivatives may be formed these decompose yielding cyclopropanes isomeric with the expected alkene (7.111). 

With carbonyl compounds carrying a leaving group in the a-position elimination may accompany reduction. Useful in this regard is the reductive opening of a, -epoxyketones to provide allylic alcohol products. For example, treatment of the ketone 123 with hydrazine and triethylamine gave the allylic alcohol 124 (7.112).  

The Wolff-Kishner Reduction does nothing more than reduce a Ketone or aldehyde by removing the oxygen and replacing h with two hydrogens. You can do the same thing by adding hot acid to a ketone or aldehyde, but some ketones and aldehydes can t survive the hot acid. That s where the Wolff-Kishner Reduction comes in. 

Formation of the Hydrazone See Key Mechanism 18-5. Proton transfer from N to C  

Propose a mechanism for both parts of the Wolff-Kishner reduction of cyclohexanone the formation of the hydrazone, then the base-catalyzed reduction with evolution of nitrogen gas. 

Reactions of ketones and aldehydes at their a positions This large group of reactions is covered in Chapter 22. 

Clemmensen reduction The deoxygenation of a ketone or aldehyde by treatment with zinc amalgam and dilute HCl. (p. 854) 

McLafferty rearrangement In mass spectrometry, the loss of an alkene fragment by a cyclic rearrangement of a carbonyl compound having y hydrogens, (p. 814) nitrile A compound containing the cyano group, C = N. (p. 824) 

The rate-determining step is the proton capture at the carbon terminal. This process takes place in a concerted fashion with the solvent-induced proton abstraction at the nitrogen terminus to form a diimide that undergoes a loss of N2. 

The asymmetric syntheses of (-)-methyl kaur-16-en-19-oate and (-)-methyl trachyloban-19-oate was achieved by M. lhara and co-workers. One of the last transformations was the deoxygenation of the ketone carbonyl group of the tetracyclic intermediate, which was effected by the Wolff-Kishner reduction. Under the strongly basic conditions the ester functionality was hydrolyzed, so an esterification using diazomethane was necessary as the final step. The major deoxygenated product was (-)-methyl kaur-16-en-19-oate (59%). The minor product was identified as (-)-methyl trachyloban-19-oate (16%). 

Dysidiolide is the first compound found to be a natural inhibitor of protein phosphatase cdc25A that is essential for cell proliferation. Y. Yamada et al. develcyed a novel total synthesis of this natural product using an intramolecular Diels-Alder cycloaddition as the key step. Deoxygenation of the advanced bicyclic intermediate at the C24 position was achieved under Woiff-Kishner reduction conditions to afford the C24 methyl group. 

A novel two-step one-pot modified Woiff-Kishner reduction protocol was developed in the laboratory of A.G. Myers Myers modification). The carbonyl compound was first converted to the A/-TBS-hydrazone followed by the addition of KOf-Bu/f-BuOH in DMSO at or above room temperature. 

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Wolff - Kishner reduction of aldehydes and ketones. Upon heating the hydrazoiie or semicarbazone of an aldehyde or ketone with potassium hydroxide or with sodium ethoxide solution (sealed tube), the corresponding hydrocarbon is obtained ... 

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. 

Method B (Huang - Minion modification of Wolff - Kishner reduction)... 

Williamson synthesis Wohl-Ziegler reaction Wolff rearrangement Wolff Kishner reduction Wurtz reaction Wurtz-Fittig reaction... 

Both the Clemmensen and the Wolff-Kishner reductions are designed to carry out a specific functional group transformation the reduction of an aldehyde or ketone carbonyl to a methylene group Neither one will reduce the carbonyl group of a carboxylic acid nor... 

The key here is to recognize that an ethyl substituent can be introduced by Fnedel-Crafts acylation followed by a Clemmensen or Wolff-Kishner reduction step later in the syn thesis If the chlorine is introduced prior to reduction it will be directed meta to the acetyl group giving the correct substitution pattern... 

Friedel-Crafts acylation followed by Clemmensen or Wolff-Kishner reduction is a standard sequence used to introduce a primary alkyl group onto an aromatic ring... 

Table 17 2 summarizes the reactions of aldehydes and ketones that you ve seen m ear her chapters All are valuable tools to the synthetic chemist Carbonyl groups provide access to hydrocarbons by Clemmensen or Wolff-Kishner reduction (Section 12 8) to alcohols by reduction (Section 15 2) or by reaction with Grignard or organolithmm reagents (Sections 14 6 and 14 7)... 

Two methods for converting carbonyl groups to methylene units are the Clem mensen reduction (zinc amalgam and con centrated hydrochloric acid) and the Wolff-Kishner reduction (heat with hydra zine and potassium hydroxide in a high boiling alcohol)... 

Wolff-Kishner reduction (Section 12 8) Method for reducing the carbonyl group of aldehydes and ketones to a methylene... 

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. 

Carbonyl deductions. The classical Wolff-Kishner reduction of ketones (qv) and aldehydes (qv) involves the intermediate formation of a hydrazone, which is then decomposed at high temperatures under basic conditions to give the methylene group, although sometimes alcohols may form (40). 

Several methods are available to supplement the phenol alkylations described above. Primary alkylphenols can be produced using the more traditional Friedel-Crafts reaction. Thus an -butylphenol can be synthesized direcdy from a butyl haUde, phenol, and mild Lewis acid catalyst. Alternatively, butyryl chloride can be used to acylate phenol producing a butyrophenone. Reduction with hydrazine (a Wolff-Kishner reduction) generates butylphenol. 

Aryl-4,5-dihydropyridazine-3(2//)-one undergoes ring opening when submitted to Wolff-Kishner reduction, while with lithium aluminum hydride the corresponding 2,3,4,5-tetrahydro product is obtained. 

H-l-Benzazepin-4-one, 2,3,4,5-tetrahydro-2-phenyl-Wolff-Kishner reduction, 7, 525... 

Beckmann rearrangement, 4, 292 pyrolysis, 4, 202 synthesis, 4, 223 Wittig reaction, 4, 294 Wolff-Kishner reduction, 4, 291 Indole, 1-acyl-2,3-disubstituted photoisomerization, 4, 204 photo-Fries rearrangement, 4, 204 photoisomerization, 4, 42 synthesis, 4, 82 Indole, 2-acyl acidity, 4, 297 synthesis, 4, 337, 360 Indole, 3-acyl-acidity, 4, 297 cleavage, 4, 289 reduction, 4, 289 synthesis, 4, 360 Indole, 7-acyl-synthesis, 4, 246... 

Deuterium labeling of C-18 has also been accomplished by an alternate procedure adapted from the Nagata steroid synthesis. During the course of the total synthesis of pregnanolone, thevC-18 function is introduced in the form of a nitrile group. Reduction of this function in intermediate (247) with lithium aluminum deuteride leads to a deuterated imine (248), which upon Wolff-Kishner reduction and acid-catalyzed hydrolysis... 

Both the Wolff-Kishner and Clemmensen reductions of a, -unsaturated ketones give olefins. There has been considerable confusion concerning the exact product composition in the case of A -3-ketones. Wolff-Kishner reduction gives A" -, 5a-A - and 5 -A -olefins, and, depending on the substrate reaction conditions and work-up, any one or more of these may be isolated. (See ref. 287 for a recent review of the Wolff-Kishner reduction.)... 

A third type of reduction of a-substituted ketones is typified by the expulsion of the substituent and the reduction of the keto function to form an olefin. Wolff-Kishner reductions of a-hydroxy, a-acetoxy, " a-halo, °° and a-epoxy (see below) ketones are the most frequently encountered steroid examples of this general class. ... 

The nitrate group is stable to the dilute alkaline conditions required for saponification of secondary acetates although it is cleaved during Wolff-Kishner reduction.Nitrates are stable to chromic acid oxidation in acetic acid, to organic peracids, and to lead tetraacetate.This group is readily split by reduction with zinc in acetic acid. 

The stereochemistry of the product resulting from the reaction of a 17-keto steroid with ethylidenetriphenylphosphorane is different from that of the 17-ethylidene steroids obtained by dehydration of 17a-ethyl-17/ -hydroxy compounds, Wolff-Kishner reduction of A -20-keto steroids or by sodium-alcohol or sodium-ammonia " reductions of 17-ethynyl carbinols. These latter products have generally been assumed to possess the trans configuration (C-21 methyl away from the bulk of the ring system) because of anticipated greater stability. The cis configuration for... 

The latter compound can be isolated from the reaction mixture by chromatography on acid-washed alumina. Similar treatment of the trans-ketone (117a) followed by isolation and chromatography on alumina gives the same equilibrium mixture. The structure of the thermodynamically more stable ketone (116a) was proved by its conversion by Wolff-Kishner reduction to the hydrocarbon (118) independently synthesized from the known... 

B-norketone (119) by enlarging ring A with diazomethane to give A-homo-B-norketone (120). Wolff-Kishner reduction of (120) gave hydrocarbon (118) identical to the product from ketone (116a). 

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