1.4- Diketones Clemmensen reduction

The Clemmensen reduction of j8-diketones (1,3-diketones) is rather complicated. The first step in the reaction of 2,4-pentanedione with zinc amalgam is an intramolecular pinacol reduction leading to a cyclopropanediol. Next the cyclopropane ring is opened in the acidic medium, and a rearrangement followed by a reduction gives the final product, a ketone, with a changed carbon skeleton [924, 925]. The ketone is usually accompanied by small amounts of the corresponding hydrocarbon [924] or an a-hydroxy ketone [925]. 

In the Clemmensen reduction of 1,4-cyclohexanedione, all the products isolated from the reduction of 2,5-hexanedione were found in addition to 2,5-hexanedione (20%) and 2-methylcyclopentanone (6%). The presence of the two latter compounds reveals the mechanism of the reduction. In the first stage the carbon-carbon bond between carbons 2 and 3 ruptured, and the product of the cleavage, 2,5-hexanedione, partly underwent aldol condensation, partly its own further reduction [927], The cleavage of the carbon-carbon bond in 1,4-diketones was noticed during the treatment of 1,2-diben-zoylcyclobutane which afforded, on short refluxing with zinc dust and zinc chloride in ethanol, an 80% yield of 1,6-diphenyl-1,6-hexanedione [75<5]. 

The Tafel rearrangement only occurs in acid medium. Simultaneous reduction of both carbonyl groups leads to interaction and formation of a cyclopropane. Acid catalysed cyclopropane ring opening follows to yield an a-diketone 28 which undergoes the electrochemical Clemmensen reduction step to the hydrocarbon. Side products include the two monoketones derived by partial deoxygenation of the a-diketone and the secondary alcohols from reduction of these raonoketones. Separate experiments show that the a-diketone 28 can be reduced to the hydrocarbon. 

For a review of Clemmensen reduction of diketones and unsaturated ketones, see Buchanan Woodgate Q. Rev. Chem. Soc. 1969, 23, 522-536. 

Intramolecular cyclisation of a 4-arylbutanoic acid system is also an important step in a convenient synthesis of the polycyclic system, chrysene, which is formulated and described in Expt 6.12. Here, methyl cinnamate is first subjected to reductive dimerisation to give methyl meso-ft,y-diphenyladipate, which is accompanied by some of the ( + )-form. The meso isomer (16) is the most easily isolable and cyclisation occurs smoothly in sulphuric acid to yield the diketone 2,1 l-dioxo-l,2,9,10,ll,18-hexahydrochrysene, which is obtained as the trans form (17) as shown in the following formulation. Clemmensen reduction of this ketone followed by dehydrogenation (in this case using selenium) completes the synthesis of chrysene. 

Similar rearranged products can be seen in the Clemmensen reduction of many cyclic and acyclic compounds carrying the 1,3-diketone system. The intermediacy of a cyclopropanediol derivative was established by Curphey et al., who showed that the cyclopropane diacetate (19) can be obtained in high yield by reaction of (18) with zinc dust in acetic anhydride and hydrogen chloride, as well as by electrolysis. The diketone (18) gives a mixture of rearranged products (20 and 21) under normal Clemmensen... 

As mentioned in Section 1.13.2.2 (Clemmensen reduction), 1,3-diketone derivatives give rise to ring contraction products via cyclopropanediols, which can be trapped as acetates. On electrolysis using a Hg cathode in the presence of acetic anhydride, the 1,3-diketone (18) afforded a mixture of stereoisomers (19) in 33% yield, and a similar electrolysis of (56) gave (57) in 71% yield (equation 29). ... 

A sterically shielded cyclopropanediol has been isolated from a Clemmensen reduction. Other reducing conditions such as sodium dispersion in diethyl ether, lithium in tetrahydrofuran/ ammonia, or eleetrochemical reduction can be applied to 1,3-diketones, and the resulting cyclopropanediols can be trapped with acetic anhydride or chlorotrimethylsilane. (see Houben-Weyl, Vol. 4/lc, p734 Vol. 6/ld, pp 656-657 Vol.6/la, part 2, p812 Vol. 6/lb, p477-478). 

The Clemmensen reduction of 6-oxocamphor (225), in addition to providing information about the mechanism of the Clemmensen reduction of 1,3-diketones, leads to an interesting bridgehead-hydroxylated isocamphanone (226) probably having an exo-methyl group, via the route shown. 

Full details of an interesting total synthesis of steviol have appeared. The key stage involved the Clemmensen reduction of the diketone (132) to form the... 

The Clemmensen reduction of aldehydes and ketones to methyl or methylene groups takes place by heating with zinc and hydrochloric acid. A non-miscible solvent can be used and serves to keep the concentration in the aqueous phase low, and thus prevent bimolecular condensations at the metal surface. The choice of acid is confined to the hydrogen halides, which appear to be the only strong acids whose anions are not reduced with zinc amalgam. The Clemmensen reduction employs rather vigorous conditions and is not suitable for the reduction of polyfunctional molecules, such as 1,3- or 1,4-diketones, or of sensitive compounds. However, it is effective for simple compounds that are stable to acid (7.38). A modification under milder conditions uses zinc dust and HCl dissolved in diethyl ether (ethereal HCl). Other methods for converting C=0 to CH2 are described in Schemes 7.87 and 7.105. 

Carbonyl groups as in quinones or a-diketones can be reduced on sonication with zinc in presence of trimethylchlorosilane. The Clemmensen reduction can also be carried out by sonication in better yields. ... 

The second group of workers (16) obtained 1,2,8,10-tetramethyl-phenanthrene (IX) from the diketone VI-B by the reaction with methyl-lithium followed by a dehydrogenation with selenium. Compound VI-B was prepared from C-3 desoxycassenic acid obtained from a Clemmensen reduction of diketocassenic acid. Further, the acetoxy diketone VI-A was converted to 1,2,8-trimethylphenanthrene by a Wolff-Kishner reduction and mild chromic acid oxidation followed by the Grignard and dehydrogenation sequence. 

Chapman et al. (32) also studied the isomerization of the methyl group in the diketones analogous to XXI and XXII. These authors concluded in variance with the work of Turner that the methyl at C-14 is /3 in cassamic acid and consequently in cassaic acid. This assignment was ultimately based on the isolation of XLI from the ozonolysis of 7-desoxo-cassamic acid obtained from cassamic acid by a Clemmensen reduction. The configuration of rings B and C in XLI was shown by ORD-data. 

The Clemmensen reduction of 1,4-diketones has been investigated by two groups. Alcohols with unchanged carbon skeletons are obtained when conformational mobility allows the two carbonyl groups to approach each other for example, hexane-2,5-dione gives a mixture of hexan-2-ol and cis- and /ra/z5-hex-4-en-2-ol the participation of the carbonyl oxygen in the solvolysis of intermediates such as (165) is proposed (Scheme 92). Pinacol-type prod-... 

Generally, zinc reductions of /3-diketones under Clemmensen conditions have been known to afford a complex mixture. However, when treated with Zn—AcaO—HC1 gas (0°, 2 hr), 1-acetyl-1-methylcyclo-hexanone (69) was readily converted into the diacetoxycyclopropane 70 in more than 80% yields, as shown below (32). 

With 1,4-diketones the distribution of the reduction products is dependent on the stereochemical situation of the two carbonyl functions. In acyclic derivatives, with no stereochemical interaction between the two carbonyl functions, the ketone groups are independently reduced to give methylene products in the usual manner. On the other hand, cyclic 1,4-diketones react differently. For example, cyclohexane-1,4-dione (22) suffers ring opening to give hexane-2,5-dione and hex-5-en-2-one derivatives, and products of further reduction are also detectable (equation 11). A 1,4-diketone (23) in which the two carbonyls are stereochemically close, gave the diketone (24) under relatively mild conditions (Zn/AcOH, 25 C), formed by the same C—C bond cleavage as seen in cyclohexane-1,4-dione. Under Clemmensen conditions this derivative was then converted to cyclobutane-1,4-diol (25 equation 12) in 98% yield, which is closely related to the aforementioned cyclopropanediol intermediate. ... 

Cyclopropanol Derivatives by Clemmensen and Related Reductions of a,/ -Unsaturated Ketones, a,/ -Unsaturated Aldehydes or 1,3-Diketones... 

Finally, when the acetoxy diketone (XC) is catalytically reduced, the reduction product saponified, and the last substance reduced by Clemmensen s method, there is obtained a saturated tetracyclic hydrocarbon, Ci9H,2 (XCV) (20). 

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