4- Chloro pyridine

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 aza-effects at all positions are available only for 2-chloro-pyridine, and these show the reactivity sequence p > o m. 

A similar kinetic effect was reported for the reaction of 4-chloro-pyridine 1-oxide with methoxide ion at 50°, and still larger effects were obtained with the 2- and 3-isomers at the same temperature. ... 

Relative reactivity wiU vary with the temperature chosen for comparison unless the temperature coefficients are identical. For example, the rate ratio of ethoxy-dechlorination of 4-chloro- vs. 2-chloro-pyridine is 2.9 at the experimental temperature (120°) but is 40 at the reference temperature (20°) used for comparing the calculated values. The ratio of the rate of reaction of 2-chloro-pyridine with ethoxide ion to that of its reaction with 2-chloronitro-benzene is 35 at 90° and 90 at 20°. The activation energy determines the temperature coefficient which is the slope of the line relating the reaction rate and teniperature. Comparisons of reactivity will of course vary with temperature if the activation energies are different and the lines are not parallel. The increase in the reaction rate with temperature will be greater the higher the activation energy. 

The inferior activation in the 3- or 6eto-position is illustrated by the very large difference in reactivity in the following aminations and alkoxylations. In the reaction of 2-chloro-5-iodopyridine or 2,3-dibromopyridine (cf. 295) with boiling methanolic methoxide, only the 2-halogen is displaced as is also the case in the amination of 2-chloro-3,5-diiodopyridine and of 2,3,6-tribromopyridine. 4-Amination of 3,4-dibromo-, 2,3,4,5-tetrabromo-, and 3-bromo-4-chloro-pyridine occurred. Only 2-amination (aqueous NH3, 190°, 36 hr) occurred with 2,3-dichloropyridine (295) and only 4-ethoxyla-tion (alcoholic ethoxide, 160°, 4 hr) with 3,4-dichloropyridine. ... 

The monoazanaphthalenes provide a good illustration of the effect of henzo-fusion onto an azine and of the variation of the effect with the position of fusion. A benzo ring can be fused onto 2-chloro-pyridine at the 3,4- [leading to 1-chloroisoquinoline (393)], at the 4,6- [forming 3-chloroisoquinoline (394)], or at the 5,6-position [yielding 2-chloroquinoline (395)]. The first and the last fusions... 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Besides addition reactions, azides or hydrazoic acid can also yield tetrazoles through displacement reactions. Thus, halide displacement in imide chloride (78) yields 1,5-disubstituted tetrazoles (79), and in 2-chloro-pyridine (80), yields tetrazolopyridine (81) (Eq. 16a,b).141 143 Vinylogous... 

Cobaloxime(I), electrochemically regenerated from chloro(pyridine)-cobaloxime (III) (232), has been employed as a mediator in the reductive cleavage of the C—Br bond of 2-bromoalkyl 2-alkynyl ethers (253), giving (254) through radical trapping ofthe internal olefin (Scheme 95) [390]. An interesting feature of the radical cyclization (253) (254) is the reaction in methanol, unlike the trialkyltin hydride-promoted radical reactions that need an aprotic nonpolar solvent. An improved procedure for the electroreductive radical cyclization of (253) has been attained by the combined use of cobaloxime(III) (232) and a zinc plate as a sacrificial anode in an undivided cell [391]. The procedure is advantageous in terms of the turnover of the catalyst and the convenience of the operation. 

The one-pot synthesis of 4-azaindole is also initiated by photoirradiation 3-amino-2-chloro-pyridine and acetaldehyde are the starting materials (Fontan et al. 1981 Scheme 7.37). 

Reductive cyclization onto an unactivated alkene or alkyne is also catalysed by chloro(pyridine)cobaloxine(ni). These reactions have been carried out in a divided... 

The reaction of the three chloro pyridines 244 with lithium in the presence of a catalytic amount of naphthalene (4%) and different electrophiles in THF at —78°C gave, after hydrolysis, the expected functionalized pyridines 245 (Scheme 82) . 

Bond S-Chloro pyridin-2-oneb Pyridin-2-onea,c Pyridin-2-onei 6-Chloro- 2-hydroxy- pyrtdine° (30) (31) Pyridin-2-one (calc.) ... 

Similarly, 4-lithiated 3-bromo and 3-chloro pyridines generated from substrates 40, are stable between -60 and -40°C, and lithium halide elimination to 2-fluoro-3,4-pyridyne occurs only upon warming to room temperature, as evidenced by the formation of adduct 41 (Scheme 13) [72CR(C)(275)1439, 72CR(C)(275)1535]. 

Thus, 2- and 4-DMG substituted pyridines may lead to 3-, 6- and 2-, 3-metalation results, respectively, while 3-DMG pyridines may provide 2-, 4-, and 6- metalation products. In general, the ring nitrogen always exhibits a weak DMG in 2- and 4-DMG pyridines, the major regioselectivity effect being manifested in 3-DMG pyridines of which the 3-fluoro and 3-chloro pyridines have been mostly investigated. 

JCS(P1)2409]. Thus, LDA metalation of 2-fluoro or 2-chloro-pyridine 8 followed by condensation with 2-nitrobenzaldehyde leads to 159 which, upon oxidation, provides the ketone 160. Catalytic reduction results in spontaneous cycUzation to afford aza-acridone 161 in quantitative yield. 

Since bromo(pyridine)cobaloxime(III) was not commerically available and its synthesis was not convenient36, we utilized chloro(pyridine)bis(dimethylglyoximato)-cobalt(III) (Equation 3) (also known as chloro(pyridine)cobaloxime (III)) instead. It has four cathodic waves in polarography when observed in acetonitrile. Its half wave potentials are located at -0.65, -1.45, -2.42, and -2.92 volts vs the Ag/AgNC>3 electrode, corresponding to the reduction of the cobalt from +3 to +2, +1, and 0, and the reduction of the ligand, respectively. 

The extent of the above so-called side reaction was determined by considering the decrease in the absorbance of the chloride band. We found that with the stoichiometric amount of chloro-(pyridine)cobaloxime(III), the side reaction was much more prominent than with the catalytic amount. Nevertheless, no appreciable unsaturation (the absence of CF=CF2 around 1790 cm1)39 was indicated in the IR spectra in both cases, implying that the undesired two-electron transfer process was not involved. 

Our first choice of alkene was allyltributyltin which had been previously studied by our group (see above). By employing the chloro(pyridine)cobaloxime(III)/magnesium redox couple in which chloro(pyridine)cobaloxime(III) was used in the catalytic amount, we were now able to synthesize the same allylated PCTFE (Eq. 4) with a higher degree of functionalization of approximately 50%. 

It should be noted that the similar addition did not succeed when a stoichiometric amount of chloro(pyridine)cobaloxime(III) was utilized. We found that the reaction of PCTFE did occur, but with a significant level of the side reaction (broad bands in 3100 -3700 and 1500 - 1800 cm-i regions in the IR spectrum. The rationale of the result was that a large number of PCTFE radicals were rapidly produced at one time. Some of these radicals were, therefore, available to react with THF concurrently with the desired addition to allyltributyltin. 

After the successful addition of PCTFE to allyltributyltin, the next alkene we examined was styrene. By treating PCTFE with styrene in the presence of magnesium and a catalytic amount of chloro(pyridine)cobaloxime(III), phenethylated PCTFE was obtained as depicted in Equation 5. 

Once again, it should be noted that the reductive condition in which the stoichiometric amount of chloro(pyridine)cobaloxime(III) was used, not only aided the addition of PCTFE to styrene, but also promoted the side reaction. In the IR spectrum of the resulting polymer, the reduction in the absorbance of the chloride band at 972 cm-i seemed to be too large, and the incorporation of oxygen in 3300 - 3600 cm-i region was also evident. The situation similar to the case of allyltributyltin might be applied in that THF possibly also took part in the reaction. 

Since the stoichiometric condition did provide the addition of PCTFE to ethyl acrylate but along with the side reaction, we expected that the chemospecificity of the addition might be improved by changing the condition to the catalytic one. This assumption was based on the result observed in the blanks — the less the amount of chloro(pyridine)cobaloxime(III) used, the lower the degree of the side reaction. 

It was shown that by employing the catalytic quantity of chloro(pyridine)cobaloxime(III) (Equation 6), the chemo-specificity of the addition was enhanced. In accordance with the IR spectrum of the functionalized PCTFE (Figure 6), the carbonyl band at 1736 cm- was much larger while the reduction in the absorbance of the chloride band at 972 cm- was much smaller, compared with those observed in the stoichiometric condition. However, the side reaction was not completely suppressed as the bands due to the side reaction were still present. 

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