Dichlorocarbene reaction with indoles

The reaction of pyrrole with dichlorocarbene, generated from chloroform and strong base, gives a bicyclic intermediate which can be transformed to either 3-chloropyridine (155) or pyrrole-2-carbaldehyde (156). Indole gives a mixture of 3-chloroquinoline (157) and indole-3-carbaldehyde (158). The optimum conditions involve phase transfer (76S249, 76S798). Benzofuran reacts with dichlorocarbene in hexane solution to give the benzopyran (159), whereas benzothiophene fails to react. 

The addition of dichlorocarbene to the C2-C3 double bonds of 2-methylfuran, 2-methyl thiophene, and 2-methylbenzofuran is similar to reaction of dichlorocarbene with indole [42]. Simple mono-adducts of dichlorocarbene are not isolated but rather products arising from these initial adducts by the following reaction sequence [43]. Ionization of this initial adduct followed by ring opening yields a pentadienylic car-bonium ion/chloride ion pair. Loss of a proton from the methyl group yields a ring expanded triene with an exocyclic double bond. A similar process has been observed in the addition of dichlorocarbene to 2-methylnorbornene. Finally, addition of a second equivalent of dichlorocarbene to the exocyclic double bond yields product (Eq. 2.26). 

Dichlorocarbene generated under phase transfer catalytic conditions adds to a variety of substituted indoles to give an adduct (see Sect. 2.7 and Eq. 2.25) which undergoes ring expansion resulting in the production of substituted chloroquinolines. Similar reactions with substituted pyrroles yield substituted chloropyridines. 

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). 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

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. 

NaOH deprotonates CHCI3, and will give dichlorocarbene by an a-elimination reaction. This Intermediate Is very electrophilic, and will rapidly react with suitable nucleophiles. Under these conditions, the Indole Is very susceptible to electrophilic aromatic substitution. 

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