Chemoselective reducing agents ketones

Reductions using Boron Compounds.—The advantages of lithium triethylboro-hydride as a very powerful reducing agent, and of amine—boranes derived from primary and secondary amines as mild, chemoselective reducing agents for aldehydes and ketones, have been extolled. Several reagents are recom-... 

Reduction.—/8-(3 -Methyl-2 -butyl)-9-borabicyclo[3,3,l]nonane and the 9-borabicyclo[3,3,l]nonane-pyridine complex are mild chemoselective reducing agents for aldehydes. Tri-n-butyltin hydride on dried silica gel reduces aldehydes rapidly and unhindered ketones relatively slowly yielding the corresponding alcohols in high yields. Sodium borohydride adsorbed on to alumina and the zirconium borohydride (9) reduce aldehydes and ketones to alcohols in aprotic... 

The use of B-alkyl-9-BBN compounds, especially (15), as mild and very chemoselective reducing agents for aldehydes (Scheme 8), even in the presence of ketones, has been explored and the variation in reducing ability with different S-alkyl groups examined. The cyclic transition state (16) is consistent with an increase in rate both with increase in substitution /3- to boron and when the B—C C—H unit can adopt a planar arrangement. This system has also been... 

Chemoselectivity between aldehydes and ketones is demonstrated by this method in the competitive reduction of a mixture of pentanal and cyclohexanone. The ratios of primary and secondary alcohols are 75 25 when catechol is used at 0° and 79 21 when 2,2/-dihydroxybiphenyl is used at room temperature. These regents are not as chemoselective as other reducing agents such as LiAlH(OBu-i)3 (87 13) and LiAlH(OCEt3)3 (94 6) at 0°.93... 

The relatively inexpensive and safe sodium borohydride (NaBH4) has been extensively used as a reducing agent because of its compatibility with protic solvents. Varma and coworkers reported a method for the expeditious reduction of aldehydes and ketones that used alumina-supported NaBH4 and proceeded in the solid state accelerated by microwave irradiation (Scheme 7) [50]. The chemoselectivity was apparent from the reduction of frarcs-cinnamaldehyde to afford cinnamyl alcohol. 

We shall use this synthesis as a basis for discussion on chemoselectivity in reductions. In the first step, sodium borohydride leaves the black carbonyl group of the ester untouched while it reduces the ketone (in yellow) in the last step, lithium aluminium hydride reduces the ester (in black). These chemoselectivities are typical of these two most commonly used reducing agents borohydride can usually be relied upon to reduce an aldehyde or a ketone in the presence of an ester, while lithium aluminium hydride will reduce almost any carbonyl group. 

A comparison of four tri-f-alkoxyaluminum hydrides revealed that lithium tris[(3-ethyl-3-pen-tyl)oxy]aluminum hydride, prepared from LAH and 3-ethyl-3-pentanol, was the most selective for reduction of aldehydes over ketones of all types. Even the less reactive benzaldehyde was reduced in THE at -78 C faster than cyclohexanone (97.7 2.3). A good correlation between the steric demands of the reducing agent and the observed chemoselectivity was observed. 

The requirement for a powerful nucleophilic hydride reagent able to reduce even very hindered ketones rapidly and quantitatively has been satisfied by lithium triethylborohydride which was screened against selected representative functional groups. The quest for increased chemoselectivity in total synthesis has led to the development of reducing agents that will discriminate between various classes of ketone or between ketones and other carbonyl groups. 

Potassium triisopropoxyborohydride, a mild selective reducing agent, rapidly converted ketones and aldehydes to the corresponding alcohols, while many common functional groups were inert.The reaction of potassium hydride with triphenylborane produced the triphenylborohydride, which is highly hindered and which exhibited excellent chemoselectivity between ketones. Cyclohexanone was reduced in preference to cyclopentanone (97 3) and 4-heptanone (99.4 0.6), while methyl ketones were more reactive than 4-heptanone (2-heptanone, 94 6 acetophenone, 97.8 2.2). 

Zinc-modified cyanoborohydride, prepared from anhydrous zinc chloride and sodium cyanoborohy-dride in the ratio 1 2 in ether, selectively reduced aldehydes and ketones but not acids, anhydrides, esters and tertiary amides. In methanol the reactivity paralleled the unmodified reagent. Zinc and cadmium borohydrides form solid complexes with DMF, which may prove to be convenient sources of the reducing agents.Aromatic and a,p-unsaturated ketones were reduced much more slowly than saturated ketones, so chemoselective reduction should be possible. 

The concept of in situ protection of the less hindered or more Lewis basic of two ketones to enable selective reduction of the usually less reactive groups has been successfully developed. The sterically hindered Lewis acid MAD (78) derived from BHT and trimethyl aluminum was used to coordinate preferentially to the less hindered ketone and DIBAL-H reduced the more hindered ketone that remained un-complexed. An approximate order of comparative reactivity for various classes of ketones has been established. The selectivity was improved by using the more hindered Lewis acid MAB (79) and/or di-bromoalane as the reducing agent. The discrimination between aromatic ketones is good but less successful between two dialkyl ketones. The chemoselectivity was demonstrated in the reduction of diketone (80) to keto alcohol (81) in 87% yield and excellent selectivity (equation 20). 

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