McMurry couplings

Alkenes may be generated via the intra- or intermolecular reductive coupling of carbonyl compounds in a titanium-mediated process known as the McMurry coupling.  

The reaction is a versatile strategy for carbon-carbon bond construction as evidenced by the large number of natural and non-natural compounds that have been synthesized using the McMurry reaction as a key step. Furthermore, the reaction has stimulated a significant number of theoretical studies, including examinations of the unique and often highly-strained molecules that can be prepared using the McMurry reaction and of the mechanism of the reaction itself. 

If both carbonyl substrates have sufficiently different redox potentials, a reasonable yield of crossed product is obtained without resorting to using one substrate in excess. This result was unexpected given the relative ease that a bisaromatic ketone should undergo ketyl formation followed by self pinacol coupling and was one of the first results that indicated more than one mechanism may be operative in McMurry couplings. In this case, the diaryl ketone may be reduced selectively to a dianion, which then undergoes nucleophilic addition to the saturated ketone. 

In cases where the formation of alkene geometrical isomers was possible the more stable isomer usually predominated. Notably, it was demonstrated that the stereoselectivity was kinetically-controlled no alkene isomerization was observed when single geometrical isomers were resubmitted to the reaction conditions.  

The robust nature of the coupling reaction was repeatedly demonstrated through the synthesis of unusual ring structures as exemplified by the key bond-forming step of Hopfs synthesis of triply-bridged cyclophanes.  

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A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

Highly strained cyclic compounds are accessible by an intramolecular variant. An instructive example for the synthetic potential of the McMurry coupling reaction is the synthesis of 3,3-dimethyl-1,2-diphenylcyclopropene 8 ... 

Markovnikov addition 85 Matteson reaction 7181 Matteson s reagent 7241 McMurry coupling 17,658,6661, 671... 

R2 = Et) have been prepared15 by McMurry coupling of the corresponding tetrapyrroledicarb-aldehydes and subsequent oxidation of the dihydro intermediates which were, as in the por-phycene series, initially formed. 

A 2,3-dihydroporphycene can also be obtained25 from the initially formed intermediate of the McMurry coupling of bipyrroledicarbaldehydes (see Section 1.7.1., p 677, and vide infra) when oxidation is suppressed so that the intermediate can undergo a prototopic shift to the 2,3-dihydro derivative. 

As in the porphycene series one method to obtain an isocorroie is based on the McMurry coupling of a tetrapyrroledicarbaldehyde, e.g. 1.2 4 The reductive cyclization forms a C —C double bond bridge leading directly to the isocorroie, e.g. 2, which is at the correct oxidation level. 

This rational approach for the synthesis of isocorroles is complemented by observations discovered in investigations on porphycencs. Firstly as minor side products of the McMurry coupling of 2,2 -bipyrroles-5,5 -dicarbaldehydes, e.g. 3, isocorroles arc formed, e.g. 5.2... 

The formation of the isocorrolecarbaldehyde 5 may be best explained if one invokes 1,2-diol 4 as an intermediate of the McMurry coupling which would then react in a titanium(IV) chloride induced Wagner-Meerwein rearrangement to yield the isocorrole 5 as a minor product during... 

Oda et al. recently reported the synthesis of the highly strained trimeric meta-PAM 139 (Scheme 32) [82]. The required triene 140 was prepared from a,m-dial-dehyde 141 by an intramolecular McMurry coupling reaction. Bromination/dehy-drobromination of 140 furnished 139 as moderately stable, colorless crystals which decomposed above 180°C. The greater degree of strain in 139 compared to... 

Covalent attachment of adamantane molecules is a key strategy to string them together and construct molecular rods. The McMurry coupling reaction was employed to obtain polyadamantane molecular rods (see Fig. 35) [170]. As another example, synthesis of tetrameric 1,3-adamantane and its butyl derivative has been reported [171] (see Fig. 36). 

McMurry coupling reaction. The mechanism of the McMurry coupling reaction consists of two defined steps the reductive dimerization of the... 

Catalytic turn-over [59,60] in McMurry couplings [61], Nozaki-Hiyama reactions [62,63], and pinacol couplings [64,65] has been reported by Fiirst-ner and by Hirao by in situ silylation of titanium, chromium and vanadium oxo species with McaSiCl. In the epoxide-opening reactions, protonation can be employed for mediating catalytic turn-over instead of silylation because the intermediate radicals are stable toward protic conditions. The amount of Cp2TiCl needed for achieving isolated yields similar to the stoichiometric process can be reduced to 1-10 mol% by using 2,4,6-collidine hydrochloride or 2,6-lutidine hydrochloride as the acid and Zn or Mn dust as the reduc-tant (Scheme 9) [66,67]. 

A third method for the synthesis of cycl[3.2.2]azines, from iV-(aroylmethyl)pyridinium salts via indolizines, involves intramolecular (reductive) McMurry coupling of the latter. For example, 3,5-dibenzoylindolizines, obtained from 2-benzoyl-iV-phenacylpyridinium bromide as shown (Scheme 91), are cyclized using zinc and titanium(iv) chloride to give the 3,4-diphenylcyclazines 352 in high yield (>90%). The reaction cannot be applied, however, to... 

A McMurry coupling reaction involving 3-aza-1,5-dicarbonyl compounds gave 2,5-dihydro-3,4-diarylpyrroles <06SL490>. The latter were converted into the corresponding 3,4-diarylpyrroles by irradiation (Hg lamp, 500 W) in acetonitrile. 

Another well-known transformation of carbonyl derivatives is their conversion to pinacols (1,2-diols) via an initial one-electron reduction with highly active metals (such as sodium, magnesium, aluminum, samarium iodide, cerium(III)/ I2, yttrium, low-valent titanium reagents (McMurry coupling), etc.), amines, and electron-rich olefins and aromatics as one-electron donors (D).43 Ketyl formation is rapidly followed by dimerization44 (equation 22). 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

TABLE 21. Dienes and polyenes through McMurry coupling... 

Reductive Cyclizations of Dicarbonyl Compounds (Pinacol and McMurry Couplings) 529... 

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