1- Butanol 3-keto

The direct base-catalyzed alkylation of 3-keto steroids is generally not a very satisfactory method for the preparation of monoalkylated products. However, under optimum conditions (short reaction time with methyl iodide, a Modest excess of potassium t-butoxide in boiling t-butanol) modest yields of... 

The acid-catalyzed decarboxylation (e.g., hydrochloric acid in methanol or /-butanol) of A -3-keto-19-carboxylic acids affords a very efficient method... 

White-rot fungus has been used as a biocatalyst for reduction and alkylation. The reaction of aromatic -keto nitriles with the white-rot fungus Curvularia lunata CECT 2130 in the presence of alcohols afforded alkylation-reduction reaction [291]. Alcohols such as ethanol, propanol, butanol, and isobutanol could be used (Figure 8.39d). 

Benzene represents aromatics and olefins. Pentanone represents keto compounds and esters. Butanol represents alcohols and weak acids. Nitropropane represents nitro- and nitrile compounds. Pyridine represents N-heterocyles. 

Hydrolysis of 20 with the aid of butanol followed by syn-selective reduction of jS-keto ester 21 and protection as the isopropylidene acetal was accomplished in 87% yield. L1A1H4 reduction and TBS protection of the primary alcohol gave 22 in very good yields. In this strategy, the furan residue serves as an aldehyde synthon and ozonolysis followed by esterification gave the corresponding methyl ester. Reduction and consecutive oxidation established aldehyde 23 in 71% yield. 

Irradiation of y-ketoamide 41 affords stereoisomeric lactams 42a and b via hydride abstraction from e-position to the keto group (88H(27)133, 98T2529). The observed stereoselectivity in dichloromethane (88% 42a) is significantly higher than that obtained in ferf-butanol. An additional stereocenter in j5-position to the keto group of amide 41 inverts the dia-stereoselectivity (98MI1). 

Higher Alcohols. The most abundant, volatile minor products of alcoholic fermentation are the higher alcohols or fusel alcohols. The most important are isoamyl (3-methyl-l-butanol), d-active amyl (2-methyl-l-butanol), isobutyl (2-methy 1-1-propanol), and n-propyl (1-propanol) alcohols. It is now recognized (4, 5, 6, 7) that these higher alcohols are formed by decarboxylation of particular a-keto acids to yield the corresponding aldehydes, and these in turn are reduced to the alcohols in a manner analogous to the formation of ethyl alcohol from pyruvic acid. 

Separation of a number of keto acid hydrazones may be accomplished as their free hydrazones [37], as sodium salts [38] or as ammonium salts [39]. For TLC separation of the sodium salts a plate (20 X 20 cm) is coated with a 0.25-mm layer of a mixture of silica gel and 0.1 N sodium bicarbonate (1 2 w/v). The plate is activated by heating at 110 °C for 40 min and is then cooled and kept in a desiccator until required. The solvent systems are ethyl acetate (saturated with 0.1 N sodium bicarbonate)-methanol (5 1) and butanol-ethanol-0.1 N sodium bicarbonate (10 3 10) (upper layer). The plates are developed for 2.5 h at room temperature. For quantitation, the spots may be removed from the plate and dissolved in 2.07V sodium hydroxide for color development and determination in solution. Treatment of the plate directly with base (as a spray) should also be possible for quantitation in situ. The wavelengths of the absorption maxima of a number of DNPH-keto acids in aqueous base are listed in Table 4.6... 

The unsubstituted aglucon, 3-keto-l-butanol, was not affected by the same treatment. 

Aldonic and ketoaldonic acids may be difficult to separate. Norris and Campbell separated ketogluconic acid from gluconic acid by preparing the phenylhydrazone of the keto acid, which is then easily separable from gluconic acid. A methanol-ethanol-water solvent mixture was used.64 Another useful solvent developer is 1-butanol-formic acid-water.133 Macek and Tadra separated a series of ketoaldonic acids in a number of acidic solvent developers.134 Color reagents which may be used include ammoniacal silver nitrate,94 o-phenylenediamine dihydrochloride,84 and aniline acid oxalate.138 Lactones are detectable with hydroxylamine followed by ferric chloride.128... 

A further method to induce chirality in the pyridoxamine-mediated transamination reactions was developed by Kuzuhara et al. [13]. They synthesized optically resolved pyridinophanes (21, 22) having a nonbranched ansa chain" between the 2 - and 5 -positions of pyridoxamine. With the five-carbon chain in 21 and 22, the two isomers do not interconvert readily. In the presence of zinc(n) in organic solvents such as methanol, tert-butanol, acetonitrile, and nitromethane, they observed stereoselective transamination between pyridinophanes and keto acids. The highest ee%s are 95 % for d-and L-leucine by reaction of the corresponding a-keto acid with (S)- and (R)- 22, respectively. On the basis of kinetic analysis of the transamination reactions, Kuzuhara et al. originally proposed a mechanism for the asymmetric induction through kinetically controlled stereoselective protonation to the carboanion attached to an octahedral Zn(n) chelate intermediate. However, they subsequently raised some questions about this proposal [14]. 

Reduction of pyridazin-4-ones seems not to have been reported, f. Derivatives of Cinnoline. 3-Hydroxycinnoline (222)44 is reduced in a two-electron wave from pH 0 to 11. In strongly acid solution the main product is 1-aminooxindole (223), which is also obtained on reduction with zinc and sulfuric acid.232 Reduction in an emulsion of an aqueous phosphate buffer (pH 6.5) and n-butanol produced a nearly quantitative yield of 3-keto-l,2,3,4-tetrahydrocinnoline (224) this compound was easily reoxidized to 3-hydroxycinnoline. 

Stereoselective Alkylation. Chiral tricyclic lactams can be prepared from (l/ ,2/ ,35,5/ )-ATBH and y-keto acids by heating in toluene with a catalytic amount of p-toluenesulfonic acid (eq 7). Enolization of the resulting lactams with sec-butyllithium, followed by trapping with methyl iodide, furnishes the methylated products in high diastereoselectivity. Subsequent enolization and alkylation with benzyl bromide affords a single diastereomer in 82% yield. Further acidic hydrolysis in butanol provides the desired ester with a quaternary asymmetric center (eq 7). ... 

The method was used successfully for conversion of (7) to the aldehyde (9). The precursor (8) is obtained by Michael addition to the steroidal 3-keto-1,4,6-triene of nitromethane in /-butanol in the presence of potassium f-butoxide. 

The photolysis of the 6-oxo-3a,5a-cyclo-19-oic acid (520) gives initially the 4-en-6-one (521), but in t-butanol a rapid photo-addition then affords the 4a-t-butoxy-6-hydroxy-lactone (522). Similar reactions transformed the methyl ester (523) into the ketonic derivative (525). Photolysis of the saturated keto-acid (526), in an alcohol as solvent, gave first the corresponding 6-monoester (527) of the 5,6-seco-6,19-dioic acid, and finally the 6,19-anhydride (528). Formation of the 6-ester (527) probably involves addition of the solvent alcohol to a keten intermediate. ... 

Table lists the results of the additions of both chiral and achiral alkoxytrialkylaluminates (20) to chiral a-keto esters (21). Some trends arc readily tqiparent (i) sodium is a superior cation as compared to lithium and potassium (entries 11-14) (ii) the configuration of the chiral moiety of the ester substrate dictates the facial preference (entries 1-7) and the preference follows the dictates of Prelog s rule (iii) there is an observable solvent effect with a preference for hexane/ether mixtures (iv) either (+)- or ( )-(2S,3/ )-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol (Darvon alcohol or (Zhirald) is the best of the... 

For the perfluorooctyl substituent, the reaction yields 60% of the acid (tcrt-butanol, H20, Ca(OH)2, 120°C, 50-bar CO, 24 hr, CT 75) (319a). Alkyl halides react with carbon monoxide and aqueous lithium hydroxide to give carboxylic acids and a-keto carboxylic acids according to... 

The studies of Ban and Wakamatsu culminated in the preparation of three natural compounds from a single synthetic route (Scheme 1.15). The enediol bis silyl ether 63 was converted to the dianion and immediately alkylated with l-iodo-3-butanol to give glycol 64 as a mixture of diastereomers in 87% yield. Diol fragmentation with lead tetraacetate afforded keto lactone 65 in quantitative yield. Formation of the dithioketal and subsequent Raney nickel desulfurization then gave 66 (81%). Macrocyclic lactone 66 is the simple natural product... 

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