3- Chloropyridine, from pyrrole

Under conditions more similar to those of the Reimer-Tiemann reaction 3-bromopyridine was obtained from pyrrole and bromo-form. Treatment of pyrrole with chloroform and aqueous alkali gave pyrrole-2-aldehyde curiously, the formation of 3-chloropyridine under these conditions does not appear to have been reported, in spite of being frequently quoted. However, indole gave both indole-3-aldehyde and 3-chloroquinoline under these conditions [Eq. (10)]. 

The reaction of pyrrole with dichlorocarbene proceeds in part via a dichlorocyclo-propane intermediate, ring expansion of which leads to 3-chloropyridine." There are relatively few (section 14.1.2) reported isolable cyclopropane-containing adducts from pyrroles - l-methoxycarbonylpyrrole ° or N -acylpyrroles. 1-Methylpyrrole with ethoxycarbonylcarbene gives only substitution products. " ... 

The Ciamician-Dennstedt reaction involves the reaction of a pyrrole (1) with the carbene generated from chloroform and a base to provide a 3-chloropyridine (2, Scheme 8.3.1). 

Ciamician and Dennstedt reacted the potassium salt of pyrrole with chloroform in ether and isolated, after much purification, 3-chloropyridine, which was confirmed by crystallization with platinum. While the pyrrole salt can be used as the base, the chloroform carbene is typically formed with an alkali alcohol. Forty years later, Robinson and co-workers made 3-chloroquinolines from indoles using the Ciamician-Dennstedt reaction. ... 

Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCI3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine. 

Singlet dichlorocarbene (generated from chloroform by the action of a strong base, such as potassium r r/-butoxide, KOCMe3), reacts with the anion of pyrrole to give an adduct, which then ring expands to give 3-chloropyridine (Scheme 6.11). 

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. 

As shown in Figure 7.11, the accepted reaction mechanism of the formation of 3-chloropyridine system 17 from a pyrrole ring 12 and dichlorocarbene (ref. 6) is also generated from the educts and products by RAIN under suitable chosen conditions. 

The abnormal Reimer-Tiemann reaction involves a ring expansion, in the classical case from a pyrrole to a 3-chloropyridine, resulting from an attack of dichlorocarbene on a double bond. An electrochemical equivalent can be made by electrolysis in a chloroform solution, where the electrogenerated base produces dichlorocarbene. By using this method, 2,3-dimethylindole could be transformed to 3-chloro-2,4-dimethylquinoline in fair yield some of the normal Reimer-Tiemann product, 3-dichloromethyl-2,3-dimethyl-3//-indole, was also formed [164]. 

A claim has been made in patents issued to Auzies (374) that nicotine can be prepared on an industrial scale from ammonia and butadiene. This process is reported to involve the production of pyrrole by the catalytic interaction of ammonia and butadiene, the methylation and hydrogenation of pyrrole, the conversion of ZV-methylpyrrolidine to 8-chloropyridine by heating over a thorium catalyst with chloroform, and the interaction of /8-chloropyridine with A-methylpyrrolidine over the same catalyst. The process, however, does not seem to have been put into practice and the reactions described have never been confirmed by a precise chemical investigation. 

Under strongly basic conditions (generation of dichlorocarbene from chloroform and potassium hydroxide), electrophilic substitution of pyrrole by dichlorocarbene dominates, leading eventually to pyr-role-2-carbaldehyde. In a weakly basic medium (generation of dichlorocarbene by heating sodium tri-chloroacetate), the [2+1] cycloaddition prevails. The primary product eliminates hydrogen chloride to give 3-chloropyridine. 

Later suggestions concerning pyridine followed closely the pattern of the history of benzene structures. Consideration of the conversion of pyrrole to 3-chloropyridine (see p. 88) led Ciamician and Dennstedt " to propose a prism formula. Riedel , from the degradation of acridine to quinoline, and thence to pyridine derivatives, supposed the diagonal structure which he had proposed for acridine (9) to persist in pyridine (10), while Bamberger (see below) suggested a centric structure (11), and a Thiele formula was also considered. 

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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