1.3- Dicarbonyl compounds, reductive cyclization

Exploration of the reduction of dicarbonyl compounds has centered on attempts to achieve intramolecular coupling of radical intermediates to give a cyclic 1,2-diol. A mechanistic study of the production of cyclopropanediols, during the reduction of 1,3-dibenzoylpropane in acetonitrile, has been made [110]. It is suggested that the ratedetermining cyclization step is the addition of the radical anion from one ketone function onto the second carbonyl group in the same molecule. 

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

Given the large number of tandem cyclization processes that have been explored [63], it is disappointing to note that so few have been promoted electrochemi-cally. There appears to be a significant opportunity for additional exploration. Two tyiws of tandem cathodic cyclizations are discussed below. The first involves generation of a ketyl, and its subsequent cyclization onto a pendant alkene to afford a new radical that closes onto a second alkene [64,65]. The second focuses on chemistry not yet discussed involving the reductive cyclization of enol phosphates of 1,3-dicarbonyl compounds [66]. 

The reductive cyclization of readily available enol phosphates of 1,3-dicarbonyl compounds bearing pendant olefinic units has been explored [66,67]. The chemistry is exceptionally interesting, and provides a unique route to structures possessing a cyclopropyl unit which is suitable for structural elaboration. The reaction occurs in a manner wherein the phosphate-bearing carbon behaves like a carbene that adds to the pendant alkene to form a cyclopropane. While this provides a useful way of viewing the transformation, mechanistic studies indicate that a carbene is not an actual intermediate. Examples are portrayed in Table 11. 

Table 5 Reductive Cyclization of Oximino Malonates and Related Compounds with /3-Dicarbonyl Compounds...

Analogous reductive cyclization is also established via O-stannyl ketyls by using a dicarbonyl compound (Equation (9)). 

Cyclization with acid now causes a lot to happen. The 1,4-dicarbonyl compound cyclizes to a lactone, not to a furan, and the redundant ester group is lost by hydrolysis and decarboxylation. Notice that the double bond moves into conjugation with the lactone carbonyl group. Finally, the reduction gives the furan. No special precautions are necessary—as soon as the ester is partly reduced, it loses water to give the furan whose aromaticity prevents further reduction even with UA1H4. H... 

Titanium-based reductive cyclizations of dicarbonyl compounds provide a good method for preparing heteroar-enes. Treatment of selenoester 128 with titanium tetrachloride in the presence of zinc produced the dihydroseleno-phene 129 (Equation 23) <1998CL645>. The addition of zinc proved to be crucial for this transformation. 

The diaminobenzenes (phenylenediamines) are prepared by reduction of 1,3-dinitrobenzene and 2- and 4-nitroanilines. o-Phenylenediamine is of value in the synthesis of a range of nitrogen heterocycles. Thus reaction with organic acids produces benzimidazoles (8). With 1,2-dicarbonyl compounds, quinoxalines (9) are produced. Treatment with nitrous acid results in diazotization of one amino group followed by immediate cyclization to give benzotriazole (10). 

Such hydroxyimidazoles or oxides are capable of complete reduction to the unoxygenated imidazoles, while the 1-hydroxyimidazole 3-oxides can also be partically reduced with, for example, NaBUi [53], or completely deoxygenated with Raney nickel [52, 54], Although most cyclizations of a-ketooximes lead to A -oxygenated imidazoles, there are exceptions. When an o(-oximino-)6-dicarbonyl compound is refluxed with benzylamine in a suitable solvent (c.g. DMSO, acetonitrile, toluene), 4-acylimidazoles (11) are formed in moderate to good yields. The reaction is readily adapted to the synthesis of imidazole-4-carboxylates and -amides (Scheme 4.1.7)... 

Acylainino-4-acylimidazoles have been made from 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl reagents (see Section 2.2.1 and Scheme 2.2.5). 4(5)-Acylimidazoles can be derived from 4-acylaininoisoxazoles (see Section 6.1.2 and Scheme 6.1.3). (See also the discussion in Section 2.2.1 on 4-acylimidazole synthesis.) 5-Acyl-l-arylimidazoles can be made from or-oxoketene-SJV-acetals and nitrosoaromatics (see Section 3.2 and Scheme 3.2.5), and 4-acyl-imidazoles by nitration of 1,3-dicarbonyl compounds in their enolic forms, reduction to iV-alkenylformamides and subsequent cyclization (see Section 3.2 and Scheme 3.2.4). Examples have also been isolated from reactions of 2-oximino-l,2,3-tricarbonyls and amines (see Section 4.1 and Scheme 4.1.7), from compounds such as 3-chloro-4,4-dimethoxy-2-butanone and 3,4-disubstituted 3-buten-2-ones (see Section 4.3 and Scheme 4.3.5), and by ultraviolet irradiation of 1-alkenyltetrazoles which bear an acyl group conjugated with the exocyclic double bond (see Section 6.1.2.3). 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

Section II,B Nitration of symmetrical 1,3-dicarbonyl compounds using N2O4, followed by catalytic reduction of the product in acetic formic anhydride gives compounds of type MeCOC(NHCHO)=C(OH)Me which cyclize in formamide or formic acid to give 4-acetyl-5-methylimidazole. ... 

Intramolecular free radical cyclization of dicarboxylic esters leads to a-hydroxy ketones (acyloins). Reductive coupling of dicarbonyl compounds provides 1,2-diols ipinacols) and further reaction of these yields cycloalkenes (McMurry reaction). These cyclization reactions are especially valuable for the preparation of medium and large rings that are not readily accessible by other methods. 

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