Dichlorocarbene reaction with pyrroles

The 3- and 5-methyl groups of 4//-pyrazoles are sufficiently acidic to exchange with D20 in base10,11 rearrangement of 20 to 119 (Scheme 30) also involves base attack at this position, the reaction being analogous to that for dichlorocarbene adducts of pyrroles.82... 

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. 

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

The reaction of pyrrole with dichlorocarbene proceeds in part via a dichlorocyclopropane intermediate, ring expansion of which leads to S-chloropyridine." " V-Methylpyrrole with ethoxycarbonylcarbene gives only snbstitntion products." ... 

The reaction of pyrrole with dichlorocarbene has been known for a long time and was at one time a main route to 2-formylpyrrole. The reaction is of mechanistic interest in that it proceeds in part via a dichlorocyclopropane intermediate, ring expansion of which leads to 3>chloropyridine. Formation of the ring-expanded products can be encouraged by the generation of dichlorocarbene in neutral aprotic solution. ... 

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. 

Pyrroles may be ring-expanded to pyridines in reactions having a greater academic than practical interest. Treatment of pyrrole with chloroform and sodium ethoxide (in effect, with dichlorocarbene, CCl2) gives a low yield of 3-chloropyridine [626-60-8]. A much better yield (33%) is obtained if chloroform and pyrrole are heated together in the vapor phase at 550°C some 2-chloropyridine (17) is also formed (71). 

The Ciamician-Dennstedt reaction can be thought of as the complement to the Reimer-Tiemann reaction (Scheme 8.3.2). The first step of both reactions is cyclopropanation of one of the carbon-carbon double bonds of a pyrrole with a dichlorocarbene, resulting in intermediate 3. The Ciamician-Dennstedt reaction results from cleavage of the internal C-C bond and elimination of chloride (path a), while the Reimer-Tiemann reaction results from cleavage of the exocyclic bond, and subsequent hydrolysis of the dichloromethyl moiety to furnish aldehyde 5 (path b). 

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. 

Carbon tetrachloride was also found to react with pyrryl potassium to give 3-chloropyridine, however the mechanism is obscure and would justify further investigation. In a preparatively useful reaction, pyrrole and chloroform in the vapor phase at 500-550° gave 3-chloro-pyridine (33%) and a little 2-chloropyridine (2-5%). No interconversion of the isomers occurred under these conditions, though pyrolytic rearrangement of N-alkylpyrrole to 3-substituted pyridines is considered to involve 2-alkylpyrroles as intermediates. There is some independent evidence that dichlorocarbene is formed in the vapor phase decomposition of chloroform. ... 

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). 

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]. 

Aminomethylfurans are converted into 3-hydroxypyridines by acid and an oxidizing agent, e.g. (219) —+ (220). 2-Hydroxymethylfurans with chlorine in aqueous methanol give 3-hydroxy-4-pyrones. 3-Hydroxypyridines can conveniently be prepared by reaction of 2-acylfurans with ammonia (Scheme 75). Pyrrole and dichlorocarbene give some 3-chloropyridine (Section 3.3.1.7.1). 

A very versatile and easy entry into the chemistry of calixpyridines, recently reported, is predicated on the use of calixpyrroles as starting materials. This route, illustrated in Scheme 2, involves reaction of a calix[4]pyrrole with dichlorocarbene and provides a ready access into the previously unknown calix[3)pyridino[l]pyrrole and calix-[4]pyridine families. It also allows for the facile synthesis of calix[ I ]pyridino[3)pyrroles and calix(2Jpyridino[2Jpyr-roles, species that Floriani and coworkers have also produced from calix(4]pyrroles using alternative organo-metallic-based procedures. ... 

It was found that when we.w-octamethylcalix[4]pyrrole (1) was reacted with 15 molar equivalents of s ium trichloroacetate (the dichlorocarbene source), a 2.4 1 mixture of the mono- and dipyridine macrocycles (21 and 22) was produced.When the same reaction conditirms were employed using 1,2-dimethoxyethane as the. solvent, a mixture of di- (22a or 22b), tri- (23) and tetrapyridine (20) species was obtained in a 1 I I ratio. Improved yields of... 

Methylpyrroles have been converted into pyridines by hydrochloric acid under severe conditions, and also by pyrolysis (p. 109). The formation of a 3-chloropyridine derivative from a pyrrole under Reimer-Tiemann conditions has been mentioned (p. 63). This type of reaction was discovered by Ciamician and Dennstedt treated pyrrole with chloroform in ether and isolated a small yield of 3-chloropyridine. Subsequently, similar reactions were realized with bromoform, carbon tetrachloride, methylene iodide and benzal chloride. Those of several of these reagents with lithium pyrrole in ether and sodium pyrrole under various conditions have been compared. The yields of pyridine derivatives were always low. In submitting 2,5-dimethylpyrrole to the Reimer-Tiemann reaction, Plancher and Ponti23 isolated a pyrrolenine (7). This and its analogues are not intermediates in the conversion of pyrroles into 3-chloropyridines. The idea that dichlorocarbene is the active reagent in reactions using chloroform is supported by recent work 22 ... 

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