Alcohols reductive elimination

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

A large variety of methods is applicable to the formation of isolated double bonds. This permits selection of reagents compatible with other functionality present. Alcohol dehydration, ester elimination and other nonreductive p eliminations are the most common methods. Reductive elimination of halo-hydrins, vic-dihalides, etc., and of a variety of ketone derivatives has also been used. 

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

This procedure illustrates a general method for the stereoselective synthesis of ( P)-disubstitnted alkenyl alcohols. The reductive elimination of cyclic /3-halo-ethers with metals was first introduced by Paul3 and one example, the conversion of tetrahydrofurfuryl chloride [2-(chloromethyl)tetrahydrofuran] to 4-penten-l-ol, is described in an earlier volume of this series.4 In 1947 Paul and Riobe5 prepared 4-nonen-l-ol by this method, and the general method has subsequently been applied to obtain alkenyl alcohols with other substitution patterns.2,6-8 (I )-4-Hexen-l-ol has been prepared by this method9 and in lower yield by an analogous reaction with 3-bromo-2-methyltetra-hydropyran.10... 

This species adds a ketone yielding the alkoxide complex (84) which, after reductive elimination of the corresponding alcohol, generates the 16-electron species (85). This intermediate undergoes oxidative addition of 2-propanol (species (86)) and subsequent reductive elimination of acetone, regenerating the hydride complex (83). 

In order to establish the correct absolute stereochemistry in cyclopentanoid 123 (Scheme 10.11), a chirality transfer strategy was employed with aldehyde 117, obtained from (S)-(-)-limonene (Scheme 10.11). A modified procedure for the conversion of (S)-(-)-limonene to cyclopentene 117 (58 % from limonene) was used [58], and aldehyde 117 was reduced with diisobutylaluminium hydride (DIBAL) (quant.) and alkylated to provide tributylstannane ether 118. This compound underwent a Still-Wittig rearrangement upon treatment with n-butyl lithium (n-BuLi) to yield 119 (75 %, two steps) [59]. The extent to which the chirality transfer was successful was deemed quantitative on the basis of conversion of alcohol 119 to its (+)-(9-methyI mande I ic acid ester and subsequent analysis of optical purity. The ozonolysis (70 %) of 119, protection of the free alcohol as the silyl ether (85 %), and reduction of the ketone with DIBAL (quant.) gave alcohol 120. Elimination of the alcohol in 120 with phosphorus oxychloride-pyridine... 

In addition to /3-H elimination, olefin insertion, and protonolysis, the cr-metal intermediate has also proved to be capable of undergoing a reductive elimination to bring about an alkylative alkoxylation. Under Pd catalysis, the reaction of 4-alkenols with aryl halides affords aryl-substituted THF rings instead of the aryl ethers that would be produced by a simple cross-coupling mechanism (Equation (126)).452 It has been suggested that G-O bond formation occurs in this case by yy/z-insertion of a coordinated alcohol rather than anti-attack onto a 7r-alkene complex.453... 

In comparison to the N- and S-counterparts, alkoxides possess lower nucleophilicity. Therefore, the reductive elimination process to form the C—O bond is much slower than those to form C— N and C—S bonds [103]. Palucki, Wolfe and Buchwald developed the first intramolecular Pd-catalyzed synthesis of cyclic aryl ethers from o-haloaryl-substituted alcohols [104]. For example, 3-(2-bromophenyl)-2-methyl-2-butanol (91) was converted to 2,2-dimethylchroman (92) under the agency of catalytic Pd(OAc)2 in the presence (S)-(-)-2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl (Tol-BINAP) as the ligand and K2CO3 as the base. The method worked well for the tertiary alcohols, moderately weE for cychc secondary alcohols, but not for acyclic secondary alcohols. 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

The last possibility for ester formation (20, Figure 12.15) comprises the reductive elimination of esters from acyl-alkoxy-palladium complexes 17, formed by deprotonation of the alcohol adducts 16. Clearly, it requires cis coordination of the alkoxide and acyl fragment. Since monodentates have a preference for ester formation, it was thought that this mechanism was very unlikely. 

Pseudo-first-order rate constants for carbonylation of [MeIr(CO)2l3]" were obtained from the exponential decay of its high frequency y(CO) band. In PhCl, the reaction rate was found to be independent of CO pressure above a threshold of ca. 3.5 bar. Variable temperature kinetic data (80-122 °C) gave activation parameters AH 152 (+6) kj mol and AS 82 (+17) J mol K The acceleration on addition of methanol is dramatic (e. g. by an estimated factor of 10 at 33 °C for 1% MeOH) and the activation parameters (AH 33 ( 2) kJ mol" and AS -197 (+8) J mol" K at 25% MeOH) are very different. Added iodide salts cause substantial inhibition and the results are interpreted in terms of the mechanism shown in Scheme 3.6 where the alcohol aids dissociation of iodide from [MeIr(CO)2l3] . This enables coordination of CO to give the tricarbonyl, [MeIr(CO)3l2] which undergoes more facile methyl migration (see below). The behavior of the model reaction closely resembles the kinetics of the catalytic carbonylation system. Similar promotion by methanol has also been observed by HP IR for carbonylation of [MeIr(CO)2Cl3] [99]. In the same study it was reported that [MeIr(CO)2Cl3]" reductively eliminates MeCl ca. 30 times slower than elimination of Mel from [MeIr(CO)2l3] (at 93-132 °C in PhCl). 

Hydride reduction of esters to alcohols involves elimination steps, in addition to hydride transfer. 

In this cyclodecarbonylation reaction, a ketene species is unlikely to be the reaction intermediate as added alcohols produce no esters. As shown in Scheme 6.26, the ruthenium acyl species 72 is likely to be the intermediate [25], which is prone to decarbonylationto give ruthena-cyclohexadiene 73 this species undergoes subsequent reductive elimination to form 2H-indene. Addition of proton or Ru to species 74 generated the benzylic cation 75, which after a 1,2-aryl shift gave the observed products. 

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