Production of Carbene

According to the catalyst type, several mechanisms have been invoked to account for the synthesis of the initial carbene. Two different types of catalysts can be envisaged those which require activation with an organo-metallic cocatalyst, and those which are active without cocatalysts. 

ALKYLIDENE GENERATION VIA REACTION WITH A METAL ALKYL COCATALYST 

The formation of the initial alkylidene sometimes occurs via an equilibrium of the type  

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The interaction between catalyst and diazo compound may be initialized by electrophilic attack of the catalyst metal at the diazo carbon, with simultaneous or subsequent loss of N2, whereupon a metal-carbene complex (415) or the product of carbene insertion into a metal/ligand bond (416) or its ionic equivalent (417) are formed. This is outlined in a simplified manner in Scheme 43, which does not speculate on the kinetics of such a sequence, nor on the possible interconversion of 415 and 416/417 or the primarily formed Lewis acid — Lewis base adducts. 

Under the same conditions a low yield of dithioacetal was isolated for R1 = t-Bu (23% with R3 = Et). Only dimerization products of carbene intermediates were obtained for R1 = phenyl however, the corresponding unstable magnesiodithioacetal could be trapped by addition of a good alkylating species before that of the Grignard reagent. An 80% yield of dithioacetal (R1 = Ph, R3 = Et or i-Pr, E = Me) was thus isolated. 

Three principal carbene-based approaches to the construction of heterocycles can be recognized. These include (1) the carbene cyclization reaction, (2) ring contraction or expansion with carbene intermediacy, and (3) cyclization or cycloaddition of unstable primary products of carbene reactions. 

Generation of carbenes. n-Butyllithium and methyllithium are both used for production of carbenes. For example, treatment of bromotrichloromethane with n-butyllithium in ether at —50° in the presence of cyclohexene gives 7,7-dichloronor-... 

Thermal decomposition of 2-diazohexafluoropropane, or 2-diazo-3,3,3-trifluoro-propanenitrile in excess benzene (150-200 "C, autoclave) resulted in efficient cyclopropanation of an aromatic C-C double bond. In solution, the 7-trifluoromethylnorcaradiene 9 (-bicyclo[4.1.0]hepta-2,4-diene) so formed is in rapid valence equilibrium with the corresponding cycloheptatriene 10 however, this equilibrium is shifted predominantly or completely to the cycloheptatriene side. As a byproduct in the synthesis, the product of carbene insertion into an aromatic C-H bond is obtained. An experimental procedure for the synthesis of 10b can be found in Houben-Weyl, Vol. 19 b, p 1031. 

Carbenoid addition of diazocarbonyl compounds to pyrrole, A -alkylpyrroles, indole, N-alkylindoles, imidazole, and benzimidazole does not result in cyclopropanation, but leads to the formal products of carbene insertion into a heterocyclic C-H bond (see Houben-Weyl, Vol.E19b, ppll58 and 1334). However, Af-acylpyrroles, and Af-acylindoles - " have successfully been converted into 2-azabicyclo[3.1.0]hex-3-ene-exo-6-carboxylates and alkyl-1,la,2,6b-tetrahydrocyclopropa[ ]indole-exo-l-carboxylate, respectively (for an experimental procedure, see Houben-Weyl, Vol.E19b, pll60). 

Alkenes with a fairly unreactive double bond additionally form the products of carbene insertion into the C-H bond (see Houben-Weyl, Vol. E19b, pp 1494 and 1495), e.g. formation... 

Extensive investigations by Liu confirmed a first-order reaction of thermal decomposition of chlorodiazirines as well as formation of typical stabilization products of carbenes. Thus tetrachloroethylene was formed from trichloromethylchlorodiazirine 178 norcaranes were obtained on decomposition of arylchlorodiazirines in cyclohexene from cyclooctylchloro-... 

Even thiophene itself will react with carbenes, at sulfur, to produce isolable thiophenium ylides, and in these, the sulfur is definitely tetrahedral. The rearrangement of thiophenium bis(ethoxycarbonyl) methylide to the 2-substituted thiophene provides a rationalisation for the reaction of thiophene with ethyl diazoacetate, which produces what appears to be the product of carbene addition to the 2,3-double bond perhaps this proceeds via initial attack at sulfur followed by S C-2 rearrangement, then collapse to the cyclopropane. Acid catalyses conversion of the cyclopropanated compound into a thiophene-3-acetic ester. ° 2,5-Dichlorothiophenium bis(methoxycarbonyl)methylide has been used as an efficient source of the carbene simply heating it in an alkene results in the transfer of (Me02C)2C to the alkene. ... 

Reaction products of carbene cation radicals formed from diazodiphenylmethane were investigated by Pragst and Jugelt (1970). Later, Parker and Bethell (1987) studied the products of diazodiphenylmethane and the two related compounds 9.58 and 9.59, which we discussed above in the context of kinetics. The major products are given in Table 9-1. 

However, a study of phenyl carbene generated directly and generated by a carbene-to-carbene rearrangement shows significant differences in product composition, so it is likely that at least some of the products reported as products of carbene reactions are formed directly from the carbene precursor, in a reaction which does not involve a carbene. 

In the 1950s and 1960s chemists learned how to generate carbenes from haloform, diazirine and diazo compound precursors as transient intermediates in solution. [1,5,6] The chemists of this era identified the products of carbene reactions and learned how to make these reactions synthetically useful. They postulated a framework for carbenes (Scheme 1) with ground or low lying triplet states which is still the starting point in all mechanistic discussions. 

As expected the yield of adduct 25 increases with increasing [TME], however, the yield of cyclobutene 24 is unchanged. [35] Thus, the simple mechanism of Scheme 4 cannot be correct. The apparent product of carbene rearrangement is not formed from the trappable carbene. Scheme 5 provides a better interpretation of the data. Once again a diazirinyl biradical (27) is postulated which can either form carbene 26 or form cyclobutene 24. 

In the presence of trap it forms adduct and a-chlorostyrenes, the apparent product of carbene rearrangement (Scheme 6). They discovered, however, that plots of the ratio of yields of 31/30 were clearly not linear and they realized that Scheme 6 was incorrect. 

The production of carbenes from haloforms (Eq. 10.54) is an interesting reaction. The reaction sequence displays second-order kinetics, first order in both base and haloform. This supports a mechanism involving an equilibrium deprotonation prior to rate-determining a-halogen departure. The loss of an equivalent of HCl from HCCI3 constitutes an elimination reaction, and is specifically called a 1,1-elimination or an a-elimination. 

The analogous methoxy carbene complexes could not be isolated by following this carbene transfer route, and instead products of carbene insertion into the palladium-aryl bond 54 are observed, for example. Equation (20). These reactions are directly analogous with those observed for alkyl- and arylpalladium heterocyclic carbene complexes, in which both reductive elimination and carbene insertion reactions have been observed (Section 8.04.2.3.4). 

The Puddephatt-Tipper team " have shown that reductive elimination involving the formation of cyclopropanes from platinacyclopropanes appears to involve a concerted process rather than the production of carbene-alkene intermediates (as does also the oxidative addition involving the reverse reaction, and the skeletal isomerization of platinacyclopropanes). They " have also proposed a similar concerted behavior for a reaction which could be looked upon either as a reductive elimination or a substitution, namely, the overall process in equation (46). 

However, the selectivity of these processes is difficult to mediate, as may be expected from the high reactivity of carbenes in addition to the above reaction, they also lead to insertion reactions into OH, NH and even aliphatic CH bonds. Moreover, the formation of the formal dimerization and polymerization products of carbenes very often contributes to a decrease in the yield of the desired reaction products. 

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