Intermediates, reactive methylene

Since the isolation of reaction intermediate (32 equation 30) by Hurd and Mori there has been no further work to illustrate the mechanism for its formation, nor has there been any further work to unravel the mechanism for its conversion to product under the reaction conditions. Only recently for hydrazone precursor (33), where R = Me and R1 = alkyl or aryl groups, it has been reported that cyclization predominates at the more reactive methylene site rather than the methyl site (81CB2938). Other workers have shown that when sulfur dichloride (SC12) is substituted for thionyl chloride, 1,2,3-thiadiazoles are still formed from a-methylene hydrazones. In several instances sulfur dichloride afforded products in higher yield than did thionyl chloride (81G289). 

It would be expected that the highly reactive methylene-radical intermediate would react quickly with any available styrene. 

Initially, a Knoevenagel condensation between the carbonyl compound and the reactive methylene group takes place. The a,y -unsaturated nitriles 19 that are formed are cyclized by the sulfur, probably via sulfanyl derivatives of 19 as intermediates. 

Azo coupling reactions are frequently observed in diazo transfer processes in which 4-toluenesulfonyl and other azides react with highly reactive methylene compounds, e. g., with dicarbonyl compounds (see Sect. 2.6, Schemes 2-56, 2-59, and 2-63). Such reactions were not, however, investigated mechanistically. Thus, although it is likely that alkanediazonium ions are intermediates, there is no direct evidence for their intermediacy. 

Carbenes ( CR2) are the most reactive organic intermediates. The Simmons-Smith reaction (see chapter 6) tamed the extraordinarily reactive methylene ( CH2) in the form of a metal-carbenoid ( ICH2ZnI ). In 1964, Ernest Otto Fischer made the first metallocarbenes [e.g., (C0)5W=CCH3(0CH3)] and they were stable enough for X-ray diffraction studies on crystalline samples. Although unsuspected at the time, metallo-carhenes would hold the secret to the magic of olefin metathesis. 

A proposed mechanism for the condensation of formamidine sulfinic acid with the dicarbonyl equivalent involves attack of the amidine nitrogen atoms on both of the electrophilic centers with loss of water. The imidazole phosphonium salt does not react directly with sodium methoxide but instead generates the reactive methylene imidazole intermediate, which is trapped by MeOH. Reactivation can be promoted in protic solvents to elongate the chain to provide cimetidine. 

Use of ethyl 3-keto-quinuclidine-2-carboxylate, an intermediate product in the synthesis of quinuclidon-3, having an advantageously highly reactive methylene in the a-position with respect to the carbonyl of quinuclidon-3, lead to preparation of various 2,3- and 2-substituted quinuclidines. 

Aniiinovinyl derivatives condense with methyl or methylene reactive groups of heterocycloammonium or ketomethylene. and are useful intermediates in the syntheses of thiazolotnmethine cyanines and thiazolodimethine neulrocyanine. They are prepared according to the following methods ... 

The reason for this relative lack of reactivity of 2-methylthiazoIium is probably due to the too-weak nucleophilic character of its carbon-2. For example, any /S-alkoxyalcene (29) derivatives resulting from the condensation of o-ester could never have been isolated, whereas they constitute the essential intermediate step in trimethine syntheses for rings of acidic character (64). However, even if a negative 5-substituent such as ethoxy-carbonyl increases the yield (61) by promoting independently the possible formation of the methylene base, it may be stressed that the presence of this base is not the essential condition of the reaction, since the isolated anhydrobase itself is not reactive toward the o-ester (Scheme 41). 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

CHt, CPhi (methylenes) Reactive intermediates with 2 unpaired electrons... 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

Ethyl (Z)-2-bromomethyl-2-heptenoate and aldehydes condense on reaction with chromium(II) chloride to furnish cw-3,4-disubstituted dihydro-3-methylene-2(3 //)-( uranones exclusively16, indicating that a (Z)-allylchromium complex might serve as reactive intermediate in the. mv-selec-tive addition step due to the bulky 2-substitucnt. Alternatively, an acyclic transition state for the reaction of the ( )-diastereomer, mediated by the Lewis acid dichloroaluminum hydride, has been discussed16. 

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

Although this mechanism could explain the inertness of di-t-butyl sulphide towards oxidation due to the absence of a-hydrogen atoms, it was later ruled out by Tezuka and coworkers They found that diphenyl sulphoxide was also formed when diphenyl sulphide was photolyzed in the presence of oxygen in methylene chloride or in benzene as a solvent. This implies that a-hydrogen is not necessary for the formation of the sulphoxide. It was proposed that a possible reactive intermediate arising from the excited complex 64 would be either a singlet oxygen, a pair of superoxide anion radical and the cation radical of sulphide 68 or zwitterionic and/or biradical species such as 69 or 70 (equation 35). 

---