Aust. J. Chern.

, 1982, 35, 2025-34

Substituent Effects on the Isomer Ratios in the Rearrangement of Some 2- and 4-Nitraminopyridines

Leslie W. Deady, Olga L. Korytsky and JefSrey E. Rowe

Organic Chemistry Department, La Trobe University, Bundoora, Vic. 3083.

Abstract The preparation, and rearrangement in 92 % sulfuric acid, of 4-X-2-nitramino- (I), 2-X-4-nitramino(2), and 6-X-2-nitramino-pyridines (3) is reported (X = H, Me, MeO, Br, C1, C02H). The product isomer ratios can be explained by differential electronic stabilization of the appropriate a complexes for aromatic nitration and steric effects seem relatively unimportant. Deuteration [3-D in series (I), X = Me] had no effect on the product distribution.

Introduction

The pyridine nitramine rearrangement (Scheme 1) has been known for a long time' though, compared to the effort devoted to the analogous phenyl nitramine rearrangement,233relatively little work has been reported on the mechanism. The rearrangement occurs for both 2- and 4-nitraminopyridines and, while some substituted nitramines have been rearranged on a preparative scale, an extensive investigation of substituent effects on this reaction has not been reported.

N*2

Scheme 1

Our interest in this aspect arose from a previous publication4 in which we clarified some of the characteristics of the 2-nitraminopyridine rearrangement. However, of the limited range of compounds studied, 4-methyl-2-nitraminopyridine gave unexpected results. Thus, more than expected of the 3-nitro isomer (40%) was produced, when compared with that from the unsubstituted compound (10%). With other kinetic findings, this result was hard to reconcile with the operation of a standard S,Ar nitration reaction, though other results could be accommodated by proposing such a reaction between pyridinamine and nitronium ion fragments produced by prior dissociation of the protonated nitramine.
Schofield, K., 'Heteroaromatic Nitrogen Compounds' p. 172 (Butterworths: London 1967). White, W. N., in 'Mechanisms of Molecular Migrations' (Ed. B. S. Thyagarajan) Vol. 3, p. 109 (Wiley-Interscience: New York 1971). Williams, D. L. H., in 'Comprehensive Chemical Kinetics' (Eds C. H. Bamford and C. F. H. Tipper) Vol. 13, p. 433 (Elsevier: Amsterdam 1972). Deady, L. W., Grimmett, M. R., and Potts, C. H., Tetrahedron, 1979, 35, 2895.

L. W. Deady, 0. L. Korytsky and J. E. Rowe

Because of this mechanistic uncertainty, and because of the small number of compounds investigated, it seemed important to carry out a systematic study of substituent effects on this reaction. This paper is concerned with the preparation of a representative series of nitramines and determination of the isomer ratios of products from the rearrangement in concentrated sulfuric acid, while the following paper deals with some kinetic results and the question of mechanism. Three series of compounds are considered, (1)-(3).

A number of the nitramines in question had previously been prepared and rearranged in preparative experiments, and some products isolated, but no quantitative study of isomer ratios has been reported.

Results and Discussion Compounds A requirement for a complete substituent effect study on any reaction is a comprehensive range of substituents exhibiting all combinations of electronic effects. The range of substituted pyridinamines that were synthetically accessible and which were stable in concentrated sulfuric acid was less than ideal but the series X = H, Me, C1, Br, MeO, C0,H was sufficient to provide interesting results. As an example of a limitation, it was hoped to include the CN substituent as an electron-withdrawing group with a lesser steric effect than that of the carboxyl function. However, when the appropriate nitramine in (1) was added to sulfuric acid, it was found that conversion into the carboxamide occurred more rapidly than did ring nitration. The required pyridinamines were known compounds but we found it necessary to modify or use alternatives to some literature methods. A summary of successful literature routes, with additional detail where necessary, is given in the experimental section. In most examples, the halopyridinamines were prepared from the corresponding halopyridinecarboxylic acids by the Curtius rearrangement. The classical , , Curtius rearrangement (acid - ester -t hydrazide -t azide - amine) had been previously used to prepare 4-5 and 6-chloropyridin-2-amines6 and we initially used this method. However, the many steps are inconvenient and the rearrangement step is complicated by concomitant formation of symmetrical ureas. A more recent modification,' in which the acid is treated with diphenylphosphoryl azide in t-butyl alcohol to give the amine by way of a readily hydrolysed carbamate, was subsequently employed and gave general success (a side reaction does occur, more particularly with the 6-halo compounds, but this has not been investigated). This method was used even for preparation of 6-halopyridin-2-amines, since treatment of 2,6-dichloroor 2,6-dibromo-pyridines with ammonia persistently gave pyridine-2,6-diamine.
Graf, R., Ber. Dtsch. Chem. Ges., 1931, 64, 21. Cava, M. P., and Bhattacharyya, N. K., J. Org. Chem., 1958, 23, 1287. Ninomiya, K., Shioiri, T., and Yamada, S., Tetrahedron, 1974, 30, 2151.

Rearrangement of Some Nitraminopyridines

2027

Methoxypyridinamines were made directly from the corresponding chloropyridinamines and carboxyl functions were obtained by standard permanganate oxidation of acetylaminomethylpyridines. Entry to the pyridin-4-amine series was by nitration of the appropriate 1-oxide. For the 2-halo substituents, reduction with ironlacetic acid gave the amine in one step. For the 2-methyl substituent, reduction was most successfully accomplished in a reproducible manner by, firstly, deoxygenating, followed by reaction with hydrazine hydrate and palladium/charcoal. In an attempt to see if ring deuteration affected the ratio of nitropyridinamine rearrangement isomers, mono-deuteration of 4-methylpyridin-2-amine was carried out. The 5-position was blocked with bromine and the 3-position was deuterated by heating in (D,)sulfuric acid. The bromo group was then removed by hydrogenation. The fact that heating was necessary to bring about hydrogen exchange meant that back exchange was not a problem in the standard rearrangement conditions. The nitramines were made by treatment with nitric/sulfuric acids and, with one exception, were isolated. For 6-methoxypyridin-2-amine, further reaction occurred under the standard nitramine preparation conditions and no nitramine could be isolated. In this case, the nitration reaction was carried out by adding potassium nitrate to a solution of the amine in sulfuric acid. It has been shown previously4 that this produces the same isomer ratio as does rearrangement of a nitramine. It was found, for some basic pyridin-Gamines, that the compound which separated when the nitramine preparation solution was added to ice was the nitrate salt of the nitramine (when treated under the rearrangement conditions, such compounds gave rise to dinitro products). Increasing the pH of the solution to 3 before filtration ensured that the compound isolated was the free nitramine, and this procedure was routinely adopted. Rearrangement The rearrangements of (1) and (3) were achieved by adding the nitramine to cold concentrated (92% by weight) sulfuric acid and then allowing the mixture to come to room temperature. Reactions were monitored by n.m.r. and gave a clean conversion into nitropyridinamines within a few minutes at these concentrations (c. 0.4 M). An exception was 2-nitraminopyridine-6-carboxylic acid where rearrangement was rather slower and was accompanied by formation of an equal amount of 6-0x0-1,6dihydropyridine-2-carboxylic acid. By contrast, rearrangements in series (2) were much slower and it was necessary to heat the solutions at 75" for, typically, 1-2 h to ensure complete reaction. In the few cases where rearrangement gave only one nitro product, this was isolated and characterized. The general proposition that the observed products were, in fact, the ring-nitrated products was considered proven from literature results and our previous report, and no attempt was made on these small-scale reactions to isolate products when isomer mixtures were formed. Identijication o Rearrangement Products f Since the rearrangement reactions were generally clean, it was possible to determine the product isomer ratios directly from an analysis of the ring proton signals of the

L. W. Deady, 0. L. Korytsky and J. E. Rowe

simple n.m.r. spectra of the reaction mixture in concentrated sulfuric acid. Chemical shift data, relative to added dioxan, are given in Table 1. Analysis was straightforward for (1) and (2) where the two products had different n.m.r. patterns, i.e., two singlets for 2,4,5-trisubstitution and two doublets for the 2,3,4-case. It was noted that, in many cases, the signal for H 6 had greater multiplicity than expected, probably due t o coupling with the protonated ring nitrogen.
Table 1. Chemical shifts (in 6 relative to dioman) of ring protons and of methyls in 92% sulfuric acid gave singlet signals except where noted Pyridine

JVi, 8-10 Hz; signals are doublets (6 of centre quoted) unless otherwise indicated. Isolated protons
H3
H4 H5
H6

Me

Ref. 4.

6 4.90 (H2).

Assignment not certain.

For (3), however, both products, (4) and (5), give the same pattern. Furthermore, since protons ortho and para to the amino group are affected about equally, the two upfield doublets could not be used for assignment. It transpired that the signal for H 4 was more informative in that this occurred at lower field by 0.4-0-9 ppm when the nitro group was next to the amino group.

Rearrangement of Some Nitraminopyridines

2029

This was noted first for X = H [4.97 (4);" 4.43 (91 and X = Me [4.77 (4); 4.42 (91 where authentic compounds were available. It also applies to 5-methyl-3nitropyridin-2-amine4 (4.78") and 3-methyl-5-nitropyridin-2-amine4 (4.23). Thus, for X = Br, C1, and CO,H, the low field doublet was assigned to H 4 of (4). For X = MeO, only one product was formed and this was assigned as (4) from the value of 4.74 for the shift of the H 4 signal. This assignment was proved by the synthesis of the same compound by a different route (Scheme 2). Nitration of (7) had been reported8 to lead to 2-bromo-6-methoxy-5-nitropyridine and subsequent amination t o (5) [with m.p. close to that of our assigned (4)] though no supporting evidence for the orientation of the groups was presented. The correct orientation was proved by reduction to (9), with its characteristic n.m.r. spectrum.

Table 2. Isomer ratios (as % 5-nitro compound) for rearrangement of nitraminopyridines in 92 % sulfuric acid Values in parentheses are literature values for isolated yields of 5- and 3-nitro products, respectively, from preparative experiments

H Me Me0 C02H Br C1 Me (3-D)

A

90A(63 ; 20') 60A(47 ; 22*) <4 >95 40 40 (17; 53F) 60

50 20(-; 80') <4 > 95 20 (- ; 63") 30 (- ; 27G)

90 74" (46; 24') <4 75D 75 78

Pino, L. N., and Zehrung, W. S., J. Am. Chem. Soc., 1955, 77, 3154. Ref. 4. Brekiesz-Lewandowska, B., and Talik, Z., Rocz. Chem., 1970, 44, 69 (Chem. Abstr., 1970,74,45415n). Nitro products represented 50% of the total, the rest being 6-0x01,6-dihydropyridine-2-carboxylic acid. ETalik, T., and Talik, Z., Rocz. Chem., 1963,37, 75 (Chem. Abstr., 1963, 59, 8698b). De Roos, K. B., and Salemink, C. A., Jain, P. C., Chatterjee, S. K., and Recl Trav. Chim. Pays-Bas, 1969, 88, 1263. Anand, N., Indian J. Chem., 1966, 4, 403.

Isomer Ratio in Rearrangemerzt A summary of the results reported in the literature from previous preparative experiments is also included in Table 2. The range of substituted compounds eventually synthesized in this present work was sufficient to reveal some interesting trends in the results. Consider (2), where both reaction sites, positions 3 and 5, are equivalent with respect to the nitramino (or amino) group, and where the problem then reduces

* Our reported4 assignment is wrong.

The deshielding effect of an ortho nitro group exceeds that of an u-protonated aza function and the reported shifts for H 4 and H 6 should be reversed.

* Martani, A., Fravolini, A., Schiaffella, F., Orzalesi, G., Selleri, R., and Volpato, I., Boll. Chim. Farm., 1975, 114, 590.

2030

L. W. Deady, 0. Korytsky and J. E. Rowe L.

to a choice of reaction ortho or para to substituent X . In spite of greater steric hindrance to reaction at position 3, only for the carboxyl-substituted compound is the major reaction at position 5. It is our contention that steric effects in fact have a minor influence and the major substituent-directing effect is an electronic one. Thus, the chloro and bromo groups have much the same effect and the methoxy group directs virtually completely to the 3-position." The results for the halo substituents seem to be very significant. While these are, overall, electron-withdrawing substituents, they direct nitration to the 3-position as well as does the methyl group. The distinguishing feature of the carboxyl substituent is that it alone is a resonance-withdrawing group. It seems, therefore, that 3-substitution is powerfully aided by resonance donation and it is possible to explain such an effect reasonably. If the nitration occurs on the monoprotonated amine and if the immediate precursors of the ring-nitrated products can be represented as o complexes (both reasonable hypotheses), then this complex will carry a double positive charge and delocalization of this charge will have a powerful stabilizing effect. Only for substitution in the 3-position can the resonance effect of the amino group and donating substituent occur together [(lo) and (1 I)].

The situation is essentially the same in (I). Again, only the resonance-withdrawing carboxyl group gives predominant (in fact, entire) 5-substitution. The doubly charged complex that is formed for 3-substitution can be stabilized by contributions from both amine and Csubstituent groups. Quite different results are obtained for (3). Now, the methoxy is the exceptional substituent, the others all directing the major nitration to the 5-position, irrespective of electronic effect, to much the same extent. It seems that, here, the amino group exerts the major directing effect to the position para to it (see the result for X = H) except when opposed by the methoxy group. The lack of a directing resonance effect from the other substituent is explicable because, here, both complexes can be equally stabilized by dual donation from substituent and amino groups [(12) and (13)l. It was found that deuteration of 4-methylpyridin-2-amine in the 3-position had no effect on the product isomer ratio from rearrangement. Such a result is taken to be evidence against a mechanism involving initial attack at the 3-position followed by a competition between proton loss to give the 3-nitro product and rearrangement to a 5-substituted intermediate. The aim of the quantitative study of substituent effects on rearrangement product isomer ratios reported here was to allow the conclusions which could be drawn from

* For (2; X = MeO) and (3; X = MeO), no signals which could be assigned to a minor isomer were seen, while for (I), a small peak adjacent to the main Me0 signal could have arisen from the minor isomer.

Rearrangement of Some Nitraminopyridines

203 1

previous limited preparative work to be clarified. This has been achieved and further discussion on the rearrangement mechanism is reserved for the following paper.

Experimental
2-Methylpyridine 1-oxideg was nitrated1 and deoxygenated to 2-methyl-4-nitropyridine with phosphorus trichloride in benzene1' (initially at a temperature less than 10" and then at room temperature overnight). Reduction with hydrazine hydrate in the presence of 5 % Pd/charcoal12 gave 2methylpyridin-4-amine, m.p. 91-92" (from light petroleum/benzene) (lit.13 95-96').
2-Chloro- and 2-Bromo-pyridin-4-amines Nitration of 2-chloropyridine 1-oxide,14 followed by reduction with iron/acetic acidi4 gave 2-chloropyridin-4-amine, m.p. 90-91' (from hexanelbenzene) (lit.14 88-90"). 2-Bromopyridin-4amine, m.p. 95-96' (from light petroleum/benzene) (lit.13 97-98.5"), was prepared by the same sequence.

4- and 6-Bromo- and -Chloro-pyridin-2-amines 2-Methyl-4-nitropyridine (above) was converted into 4-bromo-2-methylpyridine by reaction with acetyl bromide1 (in toluene rather than in benzene) which was oxidized with aqueous potassium permanganate to 4-bromopyridine-2-carboxylic acid.I5 Anhydrous diphenylphosphoryi azide (1.9 g) was added, with stirring, to a mixture of 4-bromopyridine-2-carboxylic acid (1.4 g), triethylamine (0.7 g) and t-butyl alcohol (40 ml). The mixture was refluxed for 26 h and the t-butyl alcohol was distilled off. The residue was dissolved in benzene (200 ml) washed with 5 % citric acid solution (2 x 30 ml), water (2 x 30 nd), saturated sodium bicarbonate solution (2 x 30 ml), saturated sodium chloride solution (70 ml), dried (Na2S04),and concentrated to give a yellow semi-solid. Repeated crystallization from hexane gave the carbamate (1.4 g, 74%), m.p. 139-140' (Found: C, 44.0; H, 4.7; N, 10.1. C10H13BrN202 requires C, 44.0; H, 4.8 ; N, 10.3 %). Also prepared by this general method were : t-butyl N-(4-chloro-2-pyridiny1)carbamate, m.p. 110-112' (from ethanollwater) (from 4-chloropyridine-2-carboxylic acid16), t-butyl N-(6-chloro-2-pyridinyl)carbamate, m.p. 83-84" (from hexane) (Found: C, 52.4; H, 5.5; N, 12.5. CloHlJClN202requires C, 52.5 ; H,5.7; N, 12.3 %) (6-methylpyridin-2-amine was converted into through 6-methyl-2-~hloropyridine'~ 6-chloropyridine-2-carboxylic acid6), t-butyl N-(6-bromo2-pyridiny1)carbamate (used for further reaction in an unpurified state). 'H n.m.r. 6 (CDCI,) 1.62, s, But; 7.17, d, J 10 Hz, H 3 ; 7.53, t, J 10 Hz, H 4; 7.94, d, H 5 (6-methylpyridin-2-amine was converted through 6-methyl-2-bromopyridine18 into 6-bromopyridine-2-carboxylic acidLg).
Boekelheide, V., and Linn, W. J., J. Am. Chem. Soc., 1954, 76, 1286. Katritzky, A. R., Randall, E. W., and Sutton, L. E., J. Chem. Soc., 1957, 1769. '' Ochiai, E., and Suzuki, I., Pharm. Bull., 1954, 2, 147 (Chem. Abstr., 1956, 50, 1015b). l 2 Clark, G. J., and Deady, L. W., Aust. J . Chem., 1981, 34, 927. l 3 Hertog, H. J. den, Kolder, C. R., and Combe, W. P., Recl Trac. Chim. Pays-Bas, 1951, 70, 591. l 4 Jain, P. C., Chatterjee, S. K., and Anand, N., Indian J. Chem., 1966, 4, 403. l 5 Deady, L. W., Shanks, R. A., Campbell, A. D., and Chooi, S. Y., Aust. J. Chem., 1971,24, 385. l6 Meyer, H., and Graf, R., Ber. Dtsch. Chem. Ges., 1928, 61, 2202. l 7 Bell, C. L., Egan, R. S., and Bauer, L., J. Heferocycl. Chem., 1965, 2, 420. Adams, R., and Miyano, S., J. Am. Chem. Soc., 1954,76, 3168. Buchmann, G., Rehor, H., and Wegwart, H., Phnrmazie, 1968, 23, 557 (Chem. Abstr., 1969, 70, 47236s).
'O

L. W. Deady, 0. L. Korytsky and J. E. Rowe

Treatment of the appropriate carbamate with 25 % hydrobromic acid at room temperature for 2 h, with subsequent basification and extraction gave the pyridinamines, 4-chloropyridin-2-amine, m.p. 128-129" (from light petroleum, b.p. 60-90") (Ik5 130-13l0), 6-chloropyridin-2-amine, m.p. 68-70" (from light petroleum, b.p. 40-70") (lite6 65-67"), 6-bromopyridin-2-amine, m.p. 86-87" (from light petroleum, b.p. 60-90") (lit.20 90), 4-bromopyridin-2-amine, m.p. 140-142" (from water) (lit.21 143-144.5'). It was also possible to by-pass isolation of the amine by decomposing the carbamate in concentrated sulfuric acid and forming the nitramine directly on the resulting solution. Methoxypyridinamines A solution of sodium (2.8 g) in methanol (25 ml) was added to 4-chloropyridin-2-amine (2 g) and the whole was heated in a sealed tube at 140' for 7 h. The tube was rinsed with methanol and concentrated hydrochloric acid was added, to pH 8. The solution was then evaporated to dryness in vacuum and the residue was extracted with hot ether (3 x 50ml). The combined extracts were dried and evaporated and the residue was recrystallized from 1 : 1 benzenellight petroleum (b.p. 60-90") to give the amine (0.85 g, 44%), m.p. 114-115" (lit.22 115-1 16'). In the same manner were prepared 6-methoxypyridin-2-amine (liquid, used without further purification) and 2-methoxypyridin-4-amine, m.p. 85-86' (1 : 1 bemenellight petroleum) (lit." 88-89"). AminopyridinecarboxylicAcids

A solution of 2-methylpyridin-4-amine (5 g), acetic anhydride (12 g) and triethylamine (20 g) in acetone (100 ml) was heated under reflux for 48 h. The solvents were evaporated, the oily residue was dissolved in water (20 ml) and the pH taken to 8-9 with 10% sodium hydroxide solution. A solid separated on cooling in ice. This was filtered off and recrystallized from water to give 4-acetylamino-2-methylpyridine (5.7 g, 83 %), m.p. 107-109". The amide was oxidized with aqueous potassium permanganate (10h at 75") to give 4-acetylaminopyridine-2-carboxylic acid hydrate, m.p. 253-255' (dec.) (from water) (Found: C, 48.4; H, 4.3; N, 13.9. CsHloN2O4requires C, 48.5; H, 5.1 ; N, 14.1 %), which was hydrolysed with hot 10% sodium hydroxide to 4-aminopyridine-2-carboxylic acid, m.p. 263-265' (dec.) (from water) (lit.I6 260'). 2-Acetylamino-4-methylpyridine and 2-acetylamino-6-methylpyridine were treated likewise to give, respectively, 2-aminopyridine-4-carboxylic acid, m.p. z 300' (dec.) (from water) (lit.23 300') and 6-aminopyridine-2-carboxylic acid, m.p. 314-316" (dec.) (from water) ( W 4 317-319').

5-Brom0-4-methylpyridin-2-amine~~ heated with (D2)sulfuric acid, at 100" for 3 days. was Basification and extraction with ether gave the 3-D compound (85 % by n.m.r. analysis, the deuterium level of our (D,)sulfuric acid). Treatment with hydrazine hydrate and Pd/charcoal12 gave 4-methyl(3-D)pyridin-2-amine, m.p. 95-96" (from ligroin), undepressed by admixture with the protio compound.

2-Aminopyridine-4-carboxylic acid (above) (2 g) in dry methanol (25 ml), at - 5-0, was saturated with hydrogen chloride. The solution was then heated under reflux for 3 h and concentrated. Water (15 ml) was added to the residue; the solution was cooled and taken to pH 8 with concentrated ammonium hydroxide. The product was filtered and recrystallized from water to give methyl 2-aminopyridine-4-carboxylate (1.3 g, 60%), m.p. 146-147" (MZ3148").
Z0

22 23 24

25

Hertog, H. J. den, and Wibaut, J. P., Recl Trav. Chim. Pays-Bas, 1936, 55, 122. Hertog, H. J. den, Recl Trav. Chim. Pays-Bas, 1945, 64, 85. Urban, R.,,and Schnider, O., Helv. Chim. Acta, 1964, 47, 363. Ferrari, G., and Marcon, E., Farmo (Pavia), 1958, 13, 485 (Chem. Abstr., 1959, 53, 7162b). Ferrari, G . , and Marcon, E., Farmo (Pavin), 1959, 14, 594 (Chem. Abstr., 1960, 54, 6709a). Graboyes, H., and Day, A. R., J. Am. Chem. Soc., 1957,79,6421.

Rearrangement of Some Nitraminopyridines

2033

This ester was stirred with concentrated ammonium hydroxide at room temperature for 3 days and the product was filtered, washed with methanol, and recrystallized from water to give 2-aminopyridine-4-carboxamide, m.p. 256-258" (lkz3258"), in 89 % yield. Dehydration was accomplished by a method reported for an isomeric speciesz6to give the nitrile, n1.p. 148-149" (lit.27 146-148').

Table 3. Nitraminopyridines
Substituent Nitramine position 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 4 4 M.p. (OC) 180-181 185-186 203-204 202-203 217-218 192-193 182-183 163-165 98-100 110-1 12 225-226 228 201-202 151-152 181 152-153 212-214 Recryst. solvent Lit m.p. Found (%) C H N Required (%) C H N

H 4-Me 4-C1 4-Br 4-Me0 4-C02H 4-CN 6-Me 6-C1 6-Br 6-C02NH4F H 2-Me 2421 2-Br 2-Me0 2-C02NH,

EtOH/H20 1 EtOH/H20 182B EtOH/H20 204' 34.8 2.4 24.3 34.6 2.3 27.6 1.9 19.4 27.6 1.9 MezSO/H20 42.8 4.6 24.7 42.6 4.2 EtOH/H20 39.6 3.1 22.7 39.4 2.8 EtOH 43.5 2.5 33.8 43.9 2.5 EtOH EtOH/H20 165-166D ligroin/PhMeE 34.2 2 . 3 24.5 34.6 2.3 ligroin/PhMeE 27.7 2.0 19.6 27.6 1.9 EtOH/H20 33.3 4.1 25.3 33.0 4.6 MezSO/HzO 243-244G H20 197" EtOH/HzO 155' Hz0 181J 42.8 4.4 24.7 42.6 4.2 ligroin not acceptable EtOH/H20

24.2 19.3 24.8 23.0 34.1 24.2 19.3 25.7

24.8

A Razorenov, B. A., and Tschitschibabin, A. E., J. Russ. Phys. Chem. Soc., 1914, 46, 1236 (J. Chem. Soc. Abstr.(i) 1915, 992). Seide, O., Ber. Dtsch. Chem. Ges., 1924, 57, 791. De Roos, K. B., and Salemink, C. A., Recl Trao. Chim. Pays-Bas, 1969, 88, 1263. No analysis given. Ref. 4. 10: 1. Monohydrate. Koenigs, E., Kinne, G., and Weiss, W., Ber. Dtsch. Chem. Ges., 1924, 57, 1172. " Brekiesz-Lewandowska, B., and Talik, Z., Rocz. Chem., 1970, 44, 69 (Chem. Abstr., 1970, 73, 4541511). ' Ref. 14. Talik, T., and Talik, Z., Rocz. Chem., 1963, 37, 75 (Chem. Abstr., 1963, 59, 8698b).

Potassium nitrate (0.65 g) was added, with stirring, to a solution of 6-methoxypyridin-2-amine (0.3 g) in concentrated sulfuric acid, at 30'. The mixture was heated at 75' for 2 h, cooled, poured onto ice, neutralized with 10% sodium hydroxide solution, and extracted with chloroform. Evaporation of the solvent gave the nitropyridinamine (0.4 g; 92%), m.p. 165-167' (from ligroin) [M8 (for supposed 5-nitro isomer) 173"] (Found: C, 4 2 3 ; H, 4.3; N, 24.5. C6H,N303 requires C, 42.6; H, 4.2; N, 24.8%). 'H n m r . 6 (CDC13) 3.97, s, OMe; 6.14, d, J 1 0 Hz, H5; 8.26, d, H4.

The reaction of 2-bromo-6-methoxypyridinez8 (0.5 g) with potassium nitrate (0.7 g) in concentrated sulfuric acid was carried out as above. The crude product separated when the mixture was added to ice and recrystallization from light petroleum (b.p. 60-90") gave the product (0.55 g, 89 %), m.p. 84-85' [M8 (for supposed 5-nitro isomer) 92'1. Talik, T., and Plazek, E., Rocz. Chem., 1961, 35, 463 (Chem. Abstr., 1961, 55, 25943i). RUSSO, Boll. Chim. Farm., 1961, 100, 252 (Chem. Abstr., 1962, 56, 2418a). F., '* Plas, H. C. van der, Hijwegen, T., and Hertog, H. J. den, Recl Truv. Chim. Pays-Bas, 1965, 84, 53, with methanol substituted for ethanol.
26 27

L. W. Deady, 0. L. Korytsky and J. E. Rowe

The reaction of this compound with ammonia in ethanol (as for the ethoxy analoguez9) gave the same product as obtained above from nitration of 6-rnethoxypyridin-2-arnine. A sample of 2-bromo-6-methoxy-3-nitropyridine in ethanol was hydrogenated over 5 % Pd/calcium carbonate. After removal of the catalyst, the filtrate was evaporated, the residue was treated with 10% sodium hydroxide solution and extracted with chloroform to give a sample of 6-methoxypyridin-3-amine. 'H n.m.r. 6 (CDCI,) 3.63, bs, NH,; 3.84, s, OMe; 6.52, d, J 10 Hz, H5; 6.98, dd, H 4 ; 7.60, d, J 2 H z , H2.
Preparation of Nitramines

The aminopyridine was dissolved in concentrated sulfuric acid (10 ml/g) and the solution cooled below 0". Fuming nitric acid (5 ml/g) was slowly added, with stirring. The mixture was stirred for a further 20 min and then poured onto ice. Ammonium hydroxide was added, to pH 3, and the nitramine was filtered, washed with water, and recrystallized. Product data are given in Table 3. With one exception, new compounds gave satisfactory microanalytical data. Ammonium 4-nitraminopyridine-2-carboxylatewas obtained as a hydrated species but was not analytically pure.
Rearrangement

The nitramine was added, in small portions, with stirring, to ice-cold concentrated sulfuric acid (20 ml/g). The solution was allowed to warm to room temperature (or heated at 75" for 4-nitramines) and the reaction was monitored by n.m.r. Where only one nitro isomer was formed the solution was poured onto ice. Basification with concentrated ammonia and extraction with chloroform gave: 4-methoxy-3nitropyridin-2-amine (93 %), m.p. 177-178" (from 50% ethanol) (Found: C, 42.3; H, 4.3; N, 24.5. C6H7N3O3requires C, 42.6; H, 4.2; N, 24.8%). 'H n.m.r. (CDCI,) 6 3.76, s, OMe; 6.15, d, J 10 Hz, H5; 7.89, d, H6. 2-Methoxy-3-nitropyridin-4-arnine (90 %), m.p. 156-158" (from ligroin) (lit.30 160'). 3-Nitropyridin-4-amine (65 %), m.p. 198-200' (lit., 200"). For 2-nitraminopyridine-4-carboxylic acid, solid sodium hydrogen carbonate was used to take the reaction mixture to pH 2.5-3, and the mixture was evaporated to dryness, in a vacuum. The residue was extracted (Soxhlet) with ethanol which, on evaporation, gave 95 % of 2-amino-5-nitropyridine-4-carboxylic acid, m.p. 243-244" (dec.) (from ethanol) (Found: C , 39.4; H, 2.8; N, 22.9. C&N304 requires C, 39.4; H, 2.8; N, 23.0%). 'H n.m.r. 6 (Me,SO) 6.63; s, H 3 ; 8.82, s, H6. For ammonium 4-nitraminopyridine-2-carboxylate, the reaction was adjusted to pH 3 by addition of concentrated ammonia and the product was filtered off and recrystallized from aqueous ethanol to give 4-amino-5-nitropyridine-2-carboxylic acid as the monohydrate, m.p. 226-227" (dec.) (Found: requires C, 35.8; H, 3.5; N, 20.9 %). Rearrangement C, 35.3; H, 3.5; N, 20.5. C6H7N305 of ammonium 2-nitraminopyridine-6-carboxylate (0.6 g) (solution heated at 75"/2 h) was accompanied by gas evolution. The cooled solution was poured onto ice and the pH was taken to 3-4 with concentrated ammonia. A yellow precipitate which formed (0.3 g) was filtered and recrystallized acid as an off-white powder, from ethanol/water to give 6-oxo-l,6-dihydropyridine-2-carboxylic m.p. 260-262" (dec.) (lit.,, 261-263').

Acknowledgment We thank Mr M. Stanborough for the preparation and hydrolysis of t-butyl N-(4-chloropyridin-2-y1)carbamate.

Manuscript received 12 May 1982

Hertog, H. J. den, and Jouwersma, C., Recl Trav. Chim. Pays-Bas, 1953, 72, 125. Barlin, G. B., and Pfleiderer, W., J. Chem. Soc. B, 1971, 1425. 3 1 Koenigs, E., Mields, M., and Gurlt, H., Ber. Drsch. Chem. Ges., 1924, 57, 1179. 32 Boyer, J. H., and Morgan, L. R., J. Am. Chem. Soc., 1960, 82, 4748.
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