4- -2-chloropyridine

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). 

Nitrogen bears a portion of the negative charge in the anionic intermediate formed in the nucleophilic addition step in 4-chloropyridine, but not in 3-chloropyridine. 

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. ... 

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. ... 

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)]. 

By treating 3-bromo- (27, X = Br) or 3-chloropyridine (27, X = Cl) with lithium piperidide (2.2 equivalents) and piperidine (2.8 equivalents) in boiling ether, mixtures of 3- (29, Y = NC5H10) and 4-piper-idinopyridine (34, Y = NC5H10) were obtained in 85-90% total yield. In both reactions the ratio of the 3- to 4-piperidino compounds was 48 52. Support for the hetaryne mechanism as the sole pathway for these reactions comes from the fact that increasing the amounts of lithium piperidide and piperidine to 5 and 10 equivalents, respectively, scarcely changed the composition of the reaction products. If addition-elimination had occurred concomitantly with reaction via the hetaryne, more of the 3-piperidino compound would have been formed, since the reconversion of the hthium intermediate 30 into 27 by piperidine would be accelerated by the enhancement of the concentration of this substance. 

The effect of a carboxy group is illustrated by the reactivity of 2-bromopyridine-3- and 6-carboxylic acids (resonance and inductive activation, respectively) (cf. 166) to aqueous acid under conditions which do not give hydroxy-debromination of 2-bromopyridine and also by the hydroxy-dechlorination of 3-chloropyridine-4-car-boxylic acid. The intervention of intermolecular bifunctional autocatalysis by the carboxy group (cf. 237) is quite possible. In the amino-dechlorination (80°, 4 hr, petroleum ether) of 5-carbethoxy-4-chloropyrimidine there is opportunity for built-in solvation (167) in addition to electronic activation. This effect of the carboxylate ion, ester, and acid and its variation with charge on the nucleophile are discussed in Sections I,D,2,a, I,D,2,b, and II,B, 1. A 5-amidino group activates 2-methylsulfonylpyridine toward methanolic am-... 

Dassbjerg and Lund (1992) showed that treating arenediazonium or 3-pyridinedi-azonium fluoroborates with ferrous chloride in a 3 1 mixture of tetrachloromethane and acetonitrile (but not acetonitrile alone) yields the corresponding aryl chlorides or 3-chloropyridine respectively, in nearly quantitative yield. 

More challenging are the (hetero)aryl chlorides, since they are cheaper and more widely available than the corresponding bromides and iodides. Maes et al. published the first examples of microwave-assisted Buchwald-Hartwig aminations on (hetero)aryl chlorides in a commimication in 2003 [99]. The substrates 2- and 3-chloropyridine as well as 2-chloroquinoline were smoothly coupled with N-methylaniline and p-toluidine within only 10 min using a catalyst loading of only 1 mol% (Schemes 96 and 97). The diazine... 

The N-silylated enol acetate 1523 is cyclized by TMSOTf 20 in CHCI3, in 95% yield, giving the oxazole 1524 [57]. The dimeric derivative 1525 affords the 2,2 -bis-oxazole 1526 in 46% yield [57]. 2-Benzoylamino-3-chloropyridine 1527 is cyclized by polyphosphoric acid trimethylsilyl ester (PPSE) 195 on heating for 15 h in boiling 1,2-dichlorobenzene to give 40-60% 2-phenyloxazolo[5,4-f)]pyridine 1528 [58] (Scheme 9.34). 

General procedure for C-S bond formation. A 50 mL of reactor was charged with 232.5 mg (0.25 mm) of POPdl, 1.36 g (12.0 mmol) of 3-chloropyridine, 1.18 g (10.0 mmol) of 1-hexanethiol and 1.92 g (20.0 mmol) of NaO-tBu in 15.0 mL of toluene. The resulting mixture was refluxed for 16 h before the mixture was cooled to room temperature and quenched with 100 mL of H20. The mixture was transferred to a separatory funnel, and extracted with EtOAc (2 X 200 mL). The layers were separated, and organic layer was washed with H20 (100 mL), brine (150 mL), and dried over MgS04, filtered, and the solvents removed from the filtrate by rotary evaporation. The final product was chromatographed on silica gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation to yield 1.90 g (97% yield) of 3-hexylthiopyridine. 

The parent heterocycle of pyrido[2,3-e][l,2,4]triazine and its phenyl derivative 39 were prepared (89JHC475) by cyclization with polyphos-phoric acid of 3-acyIhydrazino-2-aminopyridines 36, obtained by reduction of the corresponding 3-acylhydrazino-2-nitropyridines 35. Compounds 35 were obtained from 3-fluoro-2-nitropyridine 34 either by reaction with benzoylhydrazine or by reaction with hydrazine and subsequent for-mylation of the initially formed 3-hydrazino-2-nitropyridine 38. Attempts to prepare 38 from 3-chloro-2-nitropyridine gave 2-hydrazino-3-chloropyridine 37. These results could be explained by semiempirical calculations (CNDO and MNDO calculations). 

The triselenadiborolanes 3,5-R2-l,2,4,3,5-Se3B2 R=Et (33), Pr readily formed coordination adducts with two equivalents of pyridine, 3,5-dime-thylpyridine, and 3-chloropyridine.168 With one equivalent of base, only one of the B atoms became coordinated, and surprisingly, the system was not fluxional at room temperature.168 The addition of two equivalents of pyrazole to 33 (Scheme 7) resulted in a brown suspension and a yellow solution. Crystals of a B2N4Se2-bicyclo[2.2.2]octane were formed upon cooling this solution to —80 °C. With bulkier pyrazole derivatives (phenyl-pyrazole), the B2N4Se-bicyclo[2.2.1] heptanes were formed.169... 

Several methods exist for the synthesis of intricate, commercially unavailable halopyridines. By taking advantage of the different kinetic acidity at each site [C(4) > C(3) > C(2)], Gribble and Saulnier deprotonated 3-halopyridine regioselectively at C(4) and quenched the resulting 4-lithio-3-halopyridine with iodine to give 4-iodo-3-chloropyridine [1],... 

Due to the abundance of halopyridines, Suzuki reactions in which they serve as electrophiles have been used to synthesize a plethora of arylpyridines and heteroarylpyridines [39, 40]. 6-Phenyl-2-nitro-3-methylpyridine (55) was obtained via the reaction of 6-bromo-2-nitro-3-methylpyridine (54) and phenylboronic acid [39]. Not surprisingly, 3-chloropyridine was virtually inert under such conditions in contrast to 2-chloro- and 4-chloropyridine. The Suzuki coupling of 2-hydroxy-6-bromopyridine failed as well, possibly because 2-hydoxypyridines exist almost entirely in the keto form. 

Carbonylation of chloropyridines is less straightforward than that of bromo- and iodopyridines. The a and y positions are sufficiently activated to undergo facile oxidative addition to Pd(0), whereas the reactivity is greatly diminished at (3 positions. Thus, 2,6-dichloropyridine was converted to the corresponding dimethyl ester in good yield under normal Pd-catalyzed carbonylation conditions [152], and 2-chloropyridine was readily carbonylated to furnish methyl 2-pyridinecarboxylate (191), but 3-chloropyridine gave no carbonylated products under the same conditions [153,154],... 

Ab initio and density functional calculations indicate that the first step of the abnormal Reimer-Tiemann reaction involves barrierless formation of an intermediate by nucleophilic attack on CCl2 of the /3-carbon of pyrrole anion. " This is followed by a single, concerted step to give the product, 3-chloropyridine. 

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

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