Dichlorocarbene reaction with heterocycles

In this review an attempt is made to discuss all the important interactions of highly reactive divalent carbon derivatives (carbenes, methylenes) and heterocyclic compounds and the accompanying molecular rearrangements. The most widely studied reactions have been those of dihalocarbenes, particularly dichlorocarbene, and the a-ketocarbenes obtained by photolytic or copper-catalyzed decomposition of diazo compounds such as diazoacetic ester or diazoacetone. The reactions of diazomethane with heterocyclic compounds have already been reviewed in this series. ... 

An efficient two-step procedure for the introduction of an acetic acid substituent into the 4-posltion of 2-methyl-l(2H)-isoquinollnone Involves reaction with ethyl diazoacetate in the presence of a copper catalyst to give a mixture of exo and endo adducts, which are then isomerlzed t g4-carboethoxymethyl-N-methyl-2(lH)-isoqulnollnog0 with ethanolic HCl. Uracil 5-acetlc acids could be prepared analogously. The cyclopropane adduct from 2-methyl-l(2H)-lsoquinolinone and dichlorocarbene can be ring-contracted to an isolndole, or ring-expanded to a benzazeplnone P The reaction of carbenes with other heterocyclic enamides has been reviewed. 

There are a few scattered references to the reaction of nonphenohc six-membered heterocyclics with dichlorocarbene under Reimer-Tiemann conditions. Thus a mixture of 2-methylpyridine, chloroform, and sodium hydroxide is reported to contain sorbic acid and cyanide ions after standing for several months. Another similar reaction of... 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

Similarly, the (phosphino)(silyl)carbene 2a reacts at -30°C with a slight excess of the tert-butylphosphaalkyne cleanly affording the 2-phosphino-2//-phosphirene 34.53 The reaction leading to 34 is strictly analogous to that observed on reacting the transient dichlorocarbene with the tert-butyl-phosphaalkyne, in which the 2//-phosphirene 36 was obtained.54 The three-membered heterocycle 34 appeared to be rather unstable and rearranged, quantitatively, to afford the lA5,2A3-diphosphete 35 after 3 h at room temperature.55 Once again, these results as a whole indicate that a concerted [1 + 2]-cycloaddition process is involved in the formation of the 2//-phosph-irene 34. 

Some of the ring expansion reactions discussed in Section 2.03.3.3.1 can be extended to five-membered heterocycles containing two or more heteroatoms. Reaction of imidazoles and pyrazoles with dichlorocarbene, for example, gives chloropyrimidines together with small amounts of chloro-pyrazines or -pyridazines, and oxidative ring expansion of 1-aminopyrazole with nickel peroxide gives 1,2,3-triazine (this, in fact, constitutes the only known synthesis of the unsubstituted triazine). There are, however, a number of interesting and useful transformations which are unique to five-membered polyheteroatom systems. 

When pyrroles, triazoles and other nitrogen containing heterocyclic compounds react with dichlorocarbene, no addition to their carbon-carbon double bonds has been observed. In some cases the formation of cyclopropane adducts has been suspected however, alternate ways to explain the reaction products cannot be excluded [228]. 

Jones, R. L., Rees, C. W. Mechanism of heterocyclic ring expansions. III. Reaction of pyrroles with dichlorocarbene. J. Chem. Soc. C1969, 2249-2251. 

As a rule, the reaction of aromatic nitrogen heterocycles with dichlorocarbene does not give cyclopropane derivatives. The adducts (if they are formed at all), react further to give the final products in variable yields. These reactions are discussed in Houben-Weyl, Vol. El9b, ppl557 and 1559-1562. 

No isolable cyclopropane-containing products have been obtained by the reaction of indoles with carbenes (cf. section 13.10) but a dichlorocyclopropane is believed to be an intermediate in the pathway which leads from 2,3-dimethylin-dole to 3-chloro-2,4-dimethylquinoline the second product arises via nucleophilic attack by the indolyl anion on the electrophilic dichlorocarbene. In the comparable reaction of indole itself, only the second pathway operates and 3-formylindole, the hydrolysis product of the 3-dichloromethyl-substituted heterocycle, is isolated. 

Reactions of carbenes other than cyclopropanation can also be performed, and recent examples include the ring expansion of five-ring heterocycles, such as the indoles (18), to their six-membered counterparts (19), and the production of formamides from secondary amines (Scheme 7), both with dichlorocarbene. The latter method is of interest because of its relation to the catalysis of dichlorocarbene generation by tertiary amines in two-phase systems. Recent work indicates that such catalysis is possible because the carbene, after generation at the phase boundary, is transferred into the organic phase (to undergo reaction) in the form of the N-ylid adduct (20). 

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