THE SYNTHESIS OF SOME SUBSTITUTED METHYL PYRIDINECARBOXYLATES

II.* !METHYL 4-SUBSTITUTED PICOLINATES, METHYL 5-SUBSTITUTED

PICOLINATES, AND METHYL 5-SUBSTITUTED NICOTIWATES

By L. W. DEADY,? R. A. SHANKS,? A. D. CAMPBELL,$ and S. Y. CHOOI$

[Manuscript received August 5, 19701

Abstract

General methods are described for the synthesis of three series of substituted methyl pyridinecarboxylates from readily available starting materials. Methyl 4-X-picolinates and methyl 5-X-picolinates (X = XOz, Br, MeO, NezN) are pre- pared from 2-picoline via 4-nitro-2-picoline N-oxide and 2-amino-5-nitropyridine respectively. Methyl 5-X-nicotinates (X = Br, MeO, MezN) are prepared from 5-bromonicotinic acid. Preparations of methyl 4-methylpicolinat'e and methyl 5-methylnicotinate from the corresponding lutidines and methyl 5-methylpicolinate from 2-amino-5-methylpyridine are described.

I n the previous paper1 methods for the synthesis of methyl 6-X-picolinates, methyl 6-X-nicotinates, and methyl 2-X-isonicotinates (X = NOz, Br, Me, MeO, Me&) were described. We now wish to present synthetic routes to three further series of substituted methyl pyridine carboxylic esters which were prepared for a kinetic study of substituent effects in the pyridine ring, namely the methyl 4-X- picolinates, methyl 5-X-picolinates, and methyl 5-X-nicotinates (X = NOz, Br, Me, MeO, MezN) .

Experimental details are given for the preparation of new compounds or for the synthesis of known cornpounds2-14 by new or improved methods. A complete

* P a r t I, Aust. J . Chem., 1971, 24, 377. -f Organic Chemistry Division, La Trobe University, Bundoora, Vic. 3083. $ Department of Chemistry, University of Otago, Dunedin, New Zealand.

1 Campbell, A. D., Chan, E., Chooi, S. Y., Deady, L. W., and Shanks, R. A., Aust. J . Chem., 1971, 24, 377.

2 Ochiai, E., J . org. Chem., 1958, 18, 535. 3 Ochiai, E., and Suzuki, I., Pham. Bull. Japan, 1954, 2, 147 (Chem. Abstr., 1956, 50,

1015). 4 Brown, E. V., J. Am. chem. Soc., 1954, 76, 3167. 5 Clemo, G. R., and Gourley, W. M., J. chem. Soc., 1938, 478. 6 q-2- UiLuu, M., a d ??akashi~a, T., Chem. P-betr., 1460, 54, 2470.5. . 7 Klingsberg, E., (Ed.) "The Chemistry of Heterocyclic Compounds." Pyridine and its

Derivatives, Part 3, p. 283. (Interscience: New York 1962.) 8 Schmidt-Thome, J., and Goebel, H., Chem. Abstr., 1955, 49, 3188. 9 Graf, R., J . prakt. Chem., 1932, 133, 19.

references 10-14 ow page 386

Aust. J . Chem., 1971,24, 385-92

386 L. W. DEADY ET AL.

summary of the various transformations which have been tested and found to afford the required products in reasonable overall yield is presented in tabulated form (see Tables 1-3).

I n the present three series the starting materials are quite unrelated. Therefore for convenience in discussion the reactions have been grouped according to the position of the substituent.

D ~ s o u s s ~ o ~

Methyl 4-X-Picolinates

4-Nitro-2-picoline N-oxide obtained by the facile nitration2 of 2-picoline N - oxide15 proved to be a versatile intermediate for the synthesis of methyl 4-X-pico- linates (X = NOz, Br, NeO, Me2S).

Reduction of the pyridine N-oxides to the corresponding bases mas accom- plished with phosphorus trichloride but although 4-methoxy-2-picoline N-oxide and 4-bromo-2-picoline N-oxide were reduced in good yield in refluxing chloroform or benzene3 these reaction conditions proved unsatisfactory for 4-nitro-2-picoline N-oxide which required prolonged reduction a t temperatures below 10".

It is reported16 that reaction of 5-ethyl-4-nitro-2-picoline AT-oxide with phos- phorus tribroniide simultaneously acconlplishes the reduction of the AT-oxide and replacement of the nitro group but this method proved unreliable when applied to the synthesis of 4-bromo-2-picoline. Ochiai and Suzuki3 prepared 4-bromo-2-picoline by treating the corresponding nitro compound with acetyl bromide. We find that this method gives satisfactory yields and also that the overall yield is similar whether the N-oxide is reduced before or after replacement of the nitro group.

Although 6-bromo-2-picoline and 6-bromopicolinic acid are readily converted17 into the 6-dimethylamino derivatives on heating with dimethylamine, 4-bromo- picolinic acid did not give the expected product. The white water-soluble product contained ionic bromide and gave an analysis corresponding to a double molecule. However, when this crystalline material was treated with methanol containing sulphuric acid a good yield of methyl 4-dimethylaminopicolinate was obtained. The nature of the intermediate mas not elucidated.

Oxidation with neutral aqueous permanganate is a general method for the oxidation of a methyl substituent. 4-Bromopicolinic acid was obtained in good yield from 4-bromo-2-picoline but oxidation of 4-nitro-2-picoline proved difficult although Brown4 reports reasonable yields in this reaction. 4-?llethylpicolinic acid was obtained from 2,4-lutidine by oxidation of the intermediate 2-styryl derivative5 with permanganate. The use of 50% aqueous acetone a t 0' instead of acetone in- creased the solubility of the reagent and facilitated the reaction although some 2,4-

10 Heyns, K., and Vogelsang, G., Chem. Ber., 1954, 87, 13. 11 Cantwell, N. H., and Brown, E. V., J. Am. chem. Soc., 1952, 74, 5967 '2 GmF, E., et ai., Z. prakt. Chem., 1933, 138, 244. 1 3 McElvain, S. N., and Goese, M. A., J. Am. chem. Snc., 1943, 65, 2233. 14Urban, R., and Schnider, O., Helw. chim. Acta, 1964, 47, 363. 1 5 Boekelheide, V., and Linn, W. J., J. Am. chem. Soc., 1954, 76, 1286. 16 Lee, T. B., and Sivan, G. A., J. chem. SOC., 1956, 771. 17 Gilman, H., and Spatz, 8. M., J. org. Chem., 1951, 16, 1485.

SUBSTITUTED METHYL PYRIDINECARBOXYLATES. I1 387

dicarboxylic acid was obtained. A useful alternative route to 4-methylpicolinic acid involves the reaction of 2-bromo-4-methylpyridine with cuprous cyanide followed by hydrolysis of the resulting product, a mixture of nitrile and carboxamide, with acid.

TABLE 1

SYNTHESIS O F 2,4-DISUBSTITUTED PYRIDIXE DERIVATIVES

Reactant Product X Y N N

Methyl 5-X-Picolinates Starting material for the methyl 5-X-picolinates (X = NOz, Br, 31\10, MezN)

mas 2-amino-5-nitropyridine. The bromo derivative obtained by a Sandmeyer reaction mas treated with cuprous cyanide in nitrobenzene as solvent to give a mixture of the nitrile and carboxamide which was hydrolysed to 5-nitropicolinic acid. Nitrobenzene proved to be a much superior solvent to diphenyla for the reaction with cuprous cyanide while dimethylformamide gave 2-dimethylamino-5-nitro- pyridine rather than the expected nitrile. Further investigation of this latter reaction revealed that although 2,4-dinitrobromobenzene gave largely 2,4-dinitrodimethyl- aniline when refluxed in dimethylformamide, 4-bromopicoline did not react. 2-Bromo- 5-methyipyridine reacteci as expected wit11 cuprona cj-anide in climcthy!f~rmadde and the resulting product was hydrolysed to 5-methylpicolinic acid.

5-Aminopicolinic acid, obtained by reduction of the 5-nitro derivative with hydrogen sulphide in ammonia,a was readily converted into the previously unreported 5-dimethylaminopicolinic acid by reductive alkylation.

Yield

i %)

H CH3 NOz CH3 0 SO2 CH3 SO2 CH3 Br CH3 CH3 CH3 CH3 Br NO2 CH3 0 OMe CH3 XOz COzH Br COzH OMe COzH CH3 COzH Br COzH

Lltsrature values in parentheses. b B.p. 68-70'154 mm (1it.3 47-M0/5 mm). C B.p. 88-89'118 mnl (lit.6 60°/5 mm). d B.p. 135-138117 mm (lit.? 129-134117 mm).

NO2 CH3 0 NO2 CH3 X0z COzH Br CH3 Br C02H CH3 CO2H CH3 COzH OlIe CH3 OMe C02H NOz C02Me Br C02Me OMe CO&e CH3 C021VIe ;'\'Me2 CO&e

7 9 183.5-1.55.5" (156-156.5O)z 93 43-44 (42-45)' 14 150-151 (152)4 65 b

46 176-178 136-137 (136-137)s

25 136 60 c

44 196-197 (19O)a 95 88-89 7 7 53-55 55 49-50 (49-50)6 97 d

42 108-109

388 L. W. DEADY ET AL.

Factors influencing the methylation of phenols with diazomethane are discussed by Gompper.18 Although Marion and Cockburn19 obtained the methyl ether when 5-hydroxy-2-methylpyridine was treated with diazomethane in methanol we find that under similar reaction conditions 5-hydroxypicolinic acid gave the N-methyl derivative. The required methyl 5-methoxypicolinate was obtained using diazo- methane with t-butan0114 as the solvent. Sodium methoxide did not react with 5-bromopicolinic acid as expected. Even under drastic conditions (140' for 4 days) only partial hydrolysis to 6-hydroxypicolinio acid occurred.

Reactant X Y

KO2 NHz NO2 COzH NHz COzH NHz COzH OH COzH O H COzMe NH2 COzH NHz COzH CH3 Br14 NO% COzH Br COzH NMez COzH CH3 COzH

Product X Y

NO2 COzH NHz COzH Br COzH O H COzH O H COzMe OMe COzMe OMe COzMe NMez COzH CH3 COzH NO2 COzMe Br COzMe NMez COzMe CH3 COzMe

Yield

(%)

a Literature values in parentheses.

Methyl 5-X-Nicotinates

Methyl 5-X-nicotinates (X = Br, MeO, Me2N) were prepared starting from nicotinic acid. Nicotinoyl chloride hydrochloride is readily brominatedzo to give the 5-bromo derivative which may be converted into 5-aminonicotinic acid by the copper-catalysed reaction21 with ammonia in a sealed tube. 5-Dimethylamino- nicotinic acid was obtained from this 5-amino derivative by reductive alkylation with formaldehyde and formic acid but it could not be prepared directly by treating 5-bromonicotinic acid with dimethylamine.

5-Hydroxyniootinic acid was obtained from the 5-amino derivative by way of the intermediate diazonium salt.12 The large quantity of sodium sulphate, which

la Gompper, R., Chem. Ber., 1960, 93, 187, 198. 19 Marion, L., and Cockburn, W. F., J. Am. chem. Soc., 1949, 71, 3402. 20Bachmann, G. B., and Micucci, D. D., J. Am. chern. Soc., 1948, 70, 2381. 21 Hawkins, G. F., and Roe, A., J. ovg. Chem., 1949, 14, 328.

SUBSTITUTED METHYL PYRIDINECARBOXYLATES. I1 389

separated along with the product from this reaction on adjusting to pH 3 with sodium hydroxide, was eliminated by careful washing with cold water. Methyl 5-methoxynicotinate was obtained from this hydroxy acid by esterification followed by reaction with diazomethane in t-butanol.14

Direct oxidation of 3,5-lutidine is reported22 to give the dibasic acid but we find that careful control of reaction conditions and separation at the ester stage gives the required methyl 5-methylnicotinate by a much less tedious route than those previously used.13~23

TABLE 3

SYNTHESIS OF 2,3,5-TRISUBSTITUTED PYRIDINE DERIVATIVES

-

Reactant Product X Y z z

The synthesis of 5-nitronicotinic acid proved to be difficult. Brow114 obtained 5-nitronicotinic acid in a low yield oxidation of 3-methyl-5-nitropyridine prepared by a long sequence from 2-amino-5-methylpyridine but although we obtained a small quantity of the required nitro compound, oxidation gave insufficient nitro acid. A recent shorter route2%nvolving direct introduction of a nitro group into the 5- position of ethyl nicotinate-N-oxide also proved unsatisfactory in our hands. The synthesis was satisfactorily accomplished from 6-hydroxynicotinic acid, which was readily converted into methyl 5-nitro-6-chloronicotinate.25 Dechlorination was achieved by treatment of the intermediate hydrazino derivative with aqueous silver acetate. More silver acetate was used, with a better yield, than previously reported24 for this type of reactioii.

Yield

(%)

NHz COzH Hb XHz COzH H CH3 CH3 H Br COzH H OH COzH H OH COzMe H CH3 COzH H NMez CO2H H NO2 COzMe CIC NO2 COzMe NHNHz NO2 COzMe H

22 Durkopf, E., and Gottsch, H., Bey. dt. chem. Qes., 1890, 23, 1113. 2 3 Durkopf, E., and Gottsoh, H., Bey. dt. chem. Oes., 1890, 23, 1110. 24 Nakadate, M., et al., Chem. pharm. Bull., Tokyo, 1965, 13, 113. 25 Berrie, A. H., Newbold, G. T., and Spring, F. S., J. chem. Soc., 1951, 2690.

a Literature values in parentheses. b Bachmann, G. B., and Micucci, D. D., J. Am. chem. Soc., 1948,70, 2381.

Case, F. H., J. Am. chem. Soc., 1946, 68, 2574.

OH COzH H NMez COzH H CH3 COzH H Br COzMe H OH CO2Me H OMe COzMe H CH3 COziMe H NMez C02Me H NOz COzMe NHNHz NO2 COzMe H XOz COZH H

22 296' (299O)lz 62 262-264 (dec.) 10 208-212 (215-216)" 69 96-97 (98-99)'' 46 191-193 (192-193)" 8 1 59-60 (61-62)" 50 45-46 57 43-44

100 159-162 45 89-90 60 168-169 (170-171)4

390 L. W. DEADY ET AL.

Methyl 4-Nitropicolimte

Reaction of 4-nitropicolinic acid4 in methanol with ethereal diazomethane gave the methyl ester as yellow needles, m.p. 88-89", from light petroleum (Found: C, 46.5; H, 3.4. C7H6N204 requires C, 46.2; H, 3.3%).

4-Bromopicolinic Acid

Potassium permanganate (44 g) was added during 2 hr to a stirred mixture of 4-bromo- 2-picoline (19 g) in water (600 ml) a t 90". Precipitated manganese dioxide was filtered and washed with hot water. The combined filtrates were concentrated to 100 ml and acidified to pH 3-4 with conc. hydrochloric acid. The precipitated product was recrystallized from water to give the acid as fine needles, m.p. 177-178" (dec.) (Found: C, 35.9; H, 2.0; N, 6.9. CeH4BrN02 requires C, 35.6; H, 2.0; N, 6 - 9%). Unchanged bromopicoline (7 g) was recovered.

The acid was treated with diazomethane in ether to give the methyl ester as yellow needles, map. 63-55' (light petroleum) (Bound: C, 39.1 ; H, 3.0; N, 6.4. C7HbBrS02 requires C, 38.9; H, 2.8; N, 6.5%).

4-Methylpicolinic Acid

2-Bromo-4-methylpyridine (5 g) was refiuxed with dry cuprous cyanide (3.5 g) in dimethyl- formamide (10 ml) during 3 hr. The product was poured into a mixture of water (60 ml) and ethylenediamine (30 ml) and the resulting blue solution was extracted with chloroform (2 x 60 ml). The extract was washed with 10% sodium cyanide, dried, and the mixture of nitrile and carboxa- mide, obtained on evaporation of the solvent, was hydrolysed by refiuxing for 6 hr with a mixture of water (50 ml) and concentrated hydrochloric acid (15 ml). Following clarification with charcoal the copper complex of the picolinic acid was precipitated by the addition of copper carbonate and filtered off. The free acid was liberated by passing hydrogen sulphide gas into a suspension of the copper complex in water (250 ml). Precipitated copper sulphide was filtered off, the filtrate was concentrated to 20 ml, and remaining water was removed by azeotropic distillation with benzene. 4-Methylpicolinic acid (1.0 g) was obtained as a white powder, m.p. 136', on concentration of the benzene solution (lit.5 136-137").

Methyl 4-Dimethylaminopicoli.nate

A mixture of 4-bromopicolinic acid (4.5 g) and dimethylamine (33 ml, 30% v/v) was heated in a sealed tube a t 160' for 19 hr. The reaction mixture was acidified with glacial acetic acid and concentrated under reduced pressure. Residual water was removed by azeotropic distillation with benzene. A sample of the residue gave brownish crystals, m.p. 260-262 (dec.) from methanol (Found: C, 46.6; H, 5.5; Br, 19.3; N, 13.3; 0 , 15.3. C16HZ5BrN4O4 requires C, 46.3; H, 5.5; Br, 19.3; N, 13.6; 0,15.4%).

The brown residue was refiuxed with absolute methanol (50 ml) and conc. sulphuric acid (3 ml) for 3 hr. The resulting solution was concentrated, poured onto ice, and made alkaline by the addition of solid sodium carbonate. The ester which was extracted in ether was obtained as colourless crystals, m.p. 108-109" (chloroform-light petroleum) (Found : C, 69.8; H. 6.8; m/e 180.0897. CgHlzNzOz requires C, 60.0; H, 6.7%; m/e 180.0899).

Methyl 5-Nitropicolinate

5-Nitropicolinic acids was treated with excess ethereal diazomethane to give the ester as fiat yellow needles, m.p. 154' (chloroform-hexane) (Found: C, 46.2 ; H, 3.6. C7H6N204 requires fi -3 46.2; H, 3.3%).

Methyl 5-Bromopicolinate

5-Bromopicolinic acid9 similarly esterified with diazomethane gave the ester as pale yellow plates, m.p. 100-101' (light petroleum) (Found: C, 39.2; H, 2.9. C7HeBrS02 requires C, 38.9; H, 2.8%).

SUBSTITUTED METHYL PYRIDINECARBOXYLATES. I1

Methyl 5-Methoxypicolinate

(i) Methyl 5-hydroxypicolinatelO (2.7 g) in t-butanol (75 ml) and dry ether (30 ml) was added, over a period of 1 hr with stirring and cooling below 0°, to ethereal diazomethane prepared from nitrosomethylurea (6 g). Further ethereal diazomethane (from 5 g nitrosomethylurea) was added after 1 .5 hr and the mixture was maintained a t 0' for 24 hr. Excess reagent was evaporated and the methoxy ester in ether was purified by passage through a column of alumina. Recrystallization from light petroleum gave pale yellow plates, 0.76 g, m.p. 73" (Found: C, 57.7; H, 5.4. CgHgPu'Os requires C, 5i .5; H, 5.4%).

(ii) 5-Aminopicolinic acid ( 3 g) in dry methanol (15 ml) containing conc. sulphuric acid (2 ml) was cooled to 5' and diazotized by the addition of sodium nitrite (1 g). After 15 hr a t 0' and 24 hr at room temperature the resulting mixture was refluxed for 4 hr. The solution was concentrated, poured onto ice, neutralized with solid sodium carbonate, and extracted with chloroform. Repeated crystallization of the residue obtained from the chloroform extract gave the ester as white plates (0.2 g), m.p. 69-72".

The acid obtained by hydrolysis of the ester with aqueous sodium hydroxide was purified through its copper salt and by sublimation yielding crystals, m.p. 167-167.5 (Found: C, 54.8; H,4 .7 ; N,9.4. C ~ H ~ N O Z require3 C,54.9; H , 4 . 6 ; N,9.2%).

5-Dimethylaminopicolinic Acid

A mixture of 5-aminopicolinic acids (6 g), formaldehyde (24 ml, 40% solution), and formic acid (34 ml) was refluxed for 24 hr. Water (250 ml) was added and the solution was concentrated, residual water being removed by azeotropic distillation with benzene. The residual oil was taken up in a large volume of benzene and concentrated to give the dimethylamino acid (3.2 g). A sublimed sample gave m.p. 166-168' (Pound: C, 57.8; H, 6.1; N, 16.7. CeHloNzOz requires C, 57.8; H, 6.0; N, 16.8%).

Reaction with diazomethane followed by repeated recrystallization from light petroleum gave the methyl ester as yellow plates, m.p. 91-102' (Found: C, 60.0; H, 6.6; m / e 180.0902. CgH12N202 requires C, 60.0; H, 6.7%; m / e 180.0899).

5-1Methylpicolinic Acid

2-Bromo-5-picoline26 (5 g) was treated with dry cuprous cyanide in dimethylformamide as described above for 4-methylpicolinic acid. The resulting mixture of nitrile and carboxamide was hydrolysed by aqueous sodium hydroxide and the acid (1.5 g) was isolated as before, m.p. 160-164" (lit.11 163-164").

Esterification with diazomethane afforded the methyl ester as white crystals, m.p. 54-55', from light petroleum (Found: C, 63.7; H, 6.1 ; T;, 9.5. CsHgSOz requires C, 63.6; H, 6.0; N, 9.3%).

5-Dimethylaminonicotinic Acid

5-Aminonicotinic acid21 (2.4 g) was refluxed for 2.5 hr with a mixture of formaldehyde (10 ml; 40% solution) and formic acid (14 ml). The product which separated on concentration was recrystallized from ethanol to give the dimethylamino acid (1.8 g; 62%), m.p. 262-264' (dec.) (Found: C, 57.4; H, 5.9; N, 16.8. CsHloKzOz requires C, 57.8; H, 6.0; N, 16.9%).

Refluxing with methanol containing conc. sulphuric acid gave the methyl ester, m.p. 43-44' (pentane) (Found: C, 59.9; H, 6.7; N, 15.7. C9H12N202requiresC, 60.0; H, 6.7; X, 15.6%).

5-Methylnicotinic Acid

Potassium permanganate (SO gj was added to a stirred mixture of 3,5-iu~idine (22 g) in water (100 ml). After 24 hr a t room temperature manganese dioxide was filtered off and the filtrate was concentrated and acidified with conc. hydrochloric acid. The acid (2.5 g), m.p. 208-212' (lit.13 215-216"), which separated was esterified by refluxing with methanol containing

2 6 Case, F. H., J. A m . chem. Soc., 1946, 68, 2574.

392 L. W. DEADY ET AL.

cone. sulphuric acid for 4 hr. The mono ester isolated in the usual way had m.p. 45-46' (pentane) (Found: C, 63.2; H, 6.0; N, 9.5. CsHgNOz requires C, 63.5; H, 6.0; N, 9.3%).

Methyl 6-Hydrazino-5-nitro-nkotinate

Hydrazine hydrate (5 g) was added dropwise, with stirring, to a solution of methyl 5-nitro- 6-chloronicotinate25 (5 g) in methanol (100 ml). A copious orange precipitate rapidly formed. This was filtered and washed with methanol to give the product (4.9 g), m.p. 160-162'.

Methyl 5-hTitronicotinate

The hydrazino compound (4.9 g) was added, with stirring, to a solution of silver acetate (11 g) in water (50 ml), a t 70-76'. After heating for a further 0 - 5 hr, the mixture was cooled and filtered. The precipitate was washed thoroughly with ether and the filtrate was extracted with three portions of ether. The combined, dried (MgS04), ether extracts were evaporated to dryness under vacuum. Recrystallization of the residue from light petroleum gave the ester (1.9 g), m.p. 89-90" (Found: C, 46.25; H, 3.2; N, 15.1. C7H6N204 requires C, 46.2; H, 3.3; N, 15.4%).

The ester was warmed (50-60') for 0 .5 hr with 75% methanol-water containing a slight excess of sodium hydroxide. After neutralizing with conc, hydrochloric acid the solution was concentrated under vacuum and the residue was extracted with ether. Removal of the ether gave 5-nitronicotinic acid, m.p. 168-169" (lit.4 170-171').

ACKNOWLEDGMENTS

The authors are indebted to the Research Committee of the New Zealand Grants Committee for grants for the purchase of apparatus. We are grateful for financial assistance from the Mellor Fund of the University of Otago (S.Y.C.) and from La Trobe University (R.A.S.). We thank Mr P. M. Harrison for carrying out the synthesis of methyl 5-nitronicotinate and for checking some of the other reactions.