Synthesis of Dinitrochloromethyl Pyridine Derivatives - Springer Link

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15, Cheboksary, 428015 Russia. *e-mail: [email protected] b Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia.
ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 7, pp. 1036–1039. © Pleiades Publishing, Ltd., 2017. Original Russian Text © O.V. Ershov, V.N. Maksimova, M.Yu. Ievlev, M.Yu. Belikov, V.A. Tafeenko, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 7, pp. 1025–1027.

Synthesis of Dinitrochloromethyl Pyridine Derivatives O. V. Ershova,* V. N. Maksimovaa, M. Yu. Ievleva, M. Yu. Belikova, and V. A. Tafeenkob a

b

I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia *e-mail: [email protected]

Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia Received April 21, 2017

Abstract—Reactions of 2-halo-6-methylpyridine-3,4-dicarbonitriles with nitric acid in the presence of hydrochloric acid led to the formation of 6-(chlorodinitromethyl)-2-halopyridine-3,4-dicarbonitriles.

DOI: 10.1134/S1070428017070120 Nitration reactions and synthesis of nitro compounds are very important for synthetic organic chemistry. Nitro compounds have found wide applications; in particular, they are used as starting compounds for the preparation of medicines, dyes, fertilizers, and energetic materials [1–8]. Therefore, nitration, specifically nitration of heterocyclic compounds, is a significant research line of modern organic chemistry. Among a variety of nitro compounds, gem-dinitroalkyl-substituted pyridines can be regarded as difficultly accessible pyridine derivatives. Only a few methods for their preparation have been reported [9–18], each method being represented by a single example and characterized by a low yield. The synthesis of geminal di- or trinitroalkyl derivatives via direct nitration of alkylpyridines was described in only five publications [9–13]. The reaction of 2,5-dimethylpyridine with nitric acid in trifluoroacetic anhydride gave 10% of 5-methyl-2-(trinitromethyl)pyridine [9]. Treatment of 2-ethylpyridine with nitrogen dioxide in the presence of ozone afforded 8% of 2-(1,1-dinitroethyl)pyridine [10]. 6-Methylpyrazino[2,3-c]isoquinoline reacted with potassium nitrate in sulfuric acid to produce a compound containing a trinitromethylpyridine fragment in 31% yield [11]. The nitration of pyridine3,4-dicarbonitriles fused to cycloalkanes with nitric acid led to the formation of a series of gem-dinitro derivatives in 55–86% yield [12, 13]. In this article we describe the nitration of 2-halo-6-methylpyridine-3,4dicarbonitriles 1a–1c [19–21] with 55–60% nitric acid in the presence of concentrated hydrochloric acid, which afforded 43–64% of 2-halo-6-(chlorodinitromethyl)pyridine-3,4-dicarbonitriles 2a–2c (Scheme 1).

The structure of 2a–2c was confirmed by IR, H NMR, and mass spectra, as well as by X-ray analysis of compounds 2a and 2c (see figure). The most interesting structural feature of chlorodinitromethylpyridines 2a and 2c is the arrangement of two geminal nitro groups. The molecular geometry suggests that mutual repulsion of the nitro groups (and hence the energy of this fragment) is partially reduced due to effective interaction between one oxygen atom (partial negative charge) of one nitro group and the nitrogen atom (partial positive charge) of the other nitro group. This follows from the interatomic distances between the oxygen and nitrogen atoms, which range from 2.50 to 2.53 Å; these distances are considerably shorter than the sum of the corresponding van der Waals radii (N · · · O interactions are shown with dashed lines in figure). The bonds angles N5C7N4 in 2a (102.56°) and N5C11N4 in 2c 103.32° are considerably smaller than the two other bond angles in the same fragments (109–111°), which is likely to result from the above interaction as well. 1

Presumably, the nitration of 1a–1c with nitric acid initially gives dinitromethyl derivative A (Scheme 2).

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Scheme 1. CN R

CN CN

R

HNO3, HCl

CN

O2N Me

N

N

X Cl

1a–1c

NO2 2a–2c

R = Me, X = Cl (a), Br (b); R = Et, X = Cl (c).

X

SYNTHESIS OF DINITROCHLOROMETHYL PYRIDINE DERIVATIVES

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O1

Analogous structures were obtained by us previously from cycloalka[b]pyridines possessing a methylene group on the α-carbon atom in the pyridine ring [12, 13]. Oxidation of hydrogen chloride with nitric acid generates molecular chlorine with replaces the proton in the CH fragment activated by two nitro groups (Scheme 2).

O3

O2

N4

N5 C7 Cl2

Scheme 2.

C6

N1

CN 1

R

HNO3

CN

O2N

N

C8

HNO3, HCl

4

C

C10 N3

O3 O4

O1 N5

1d

N4

CN

I

R

HNO3

CN

HO O

N H

N2 2a

Scheme 3. CN

N

C3

C9

No trinitro derivatives were isolated, regardless of whether hydrochloric acid was added or not. Presumably, introduction of the third nitro group is hindered due to competing oxidation and hydrolysis. This is confirmed by the reaction of 2-iodo-5,6-dimethyl-pyridine-3,4-dicarbonitrile (1d) with nitric acid, which led to the formation of 30% of 4,5-dicyano-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3) (Scheme 3).

Me

Cl1 C2

X

A

CN

C5

3

NO2

R

O4

C11

O2

C8

C6

Cl2

5

C

N1

O

C10 C8

3

Thus, we have developed a synthetic approach to 2-halo-6-(chlorodinitromethyl)pyridine-3,4-dicarbonitriles containing a rare chlorodinitromethyl substituent on the basis of a combination of nitration and chlorination processes by treatment of 2-halo-6methylpyridine-3,4-dicarbonitriles with nitric acid in the presence of hydrochloric acid. EXPERIMENTAL The IR spectra were recorded on an FSM-1202 spectrometer with Fourier transform from samples dispersed in mineral oil. The 1H NMR spectra were measured on a Bruker DRX-500 spectrometer at 500.13 MHz using DMSO-d6 as solvent and tetramethylsilane as internal standard. The mass spectra (electron impact, 70 eV) were obtained on a Shimadzu

Cl

1

2

C

N3

4

C3

C

C7 N2 2c Structures of the molecules of 2-chloro-6-(chlorodinitromethyl)-5-methylpyridine-3,4-dicarbonitrile (2a) and 2-chloro-6-(chlorodinitromethyl)-5-ethylpyridine-3,4-dicarbonitrile (2c) according to the X-ray diffraction data.

GCMS-QP 2010 SE instrument. The elemental compositions were determined on a Vario Micro Cube CHN analyzer. The purity of the isolated compounds was checked by TLC on Sorbfil PTSKh-AF-A-UF plates; spots were visualized under UV light, by treatment with iodine vapor, or by thermal decomposition.

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ERSHOV et al.

X-Ray analysis of compounds 2a and 2c. Crystals suitable for X-ray analysis were obtained by slow evaporation of a solution of 2a or 2c in acetonitrile at room temperature. The X-ray diffraction data were acquired with a CAD-4 diffractometer (Ag Kα radiation for 2c or Cu Kα radiation for 2a; graphite monochromator, ω-scanning). The structures were solved by the direct method and were refined in full-matrix anisotropic approximation for non-hydrogen atoms using SHELX [22]. Hydrogen atoms were localized by the Fourier difference syntheses or placed in calculated positions which were refined independently according to the riding model. Final divergence factors R = 0.027 [for reflections with F2 > 2σ(F2)] (2a), 0.051 (2c). The principal crystallographic and geometric parameters of compounds 2a and 2c were deposited to the Cambridge Crystallographic Data Center (CCDC entry nos. 1 541 949 and 1 541 948, respectively). The X-ray diffraction study was performed at the Moscow State University using the equipment provided by the Program for the development of Moscow University. Compounds 2a–2c (general procedure). Concentrated aqueous HCl, 2–3 drops, was added to 3 mL of 55–60% nitric acid, 0.005 mol of halopyridine 1a–1c was added, and the mixture was refluxed for 2–3 min until brown gas no longer evolved. The mixture was cooled, and the precipitate was filtered off and washed with water. An additional amount of compound 2a–2c can be isolated by evaporation of the filtrate. 2-Chloro-6-(chlorodinitromethyl)-5-methylpyridine-3,4-dicarbonitrile (2a). Yield 43%, mp 165– 166°C. IR spectrum, ν, cm–1: 2237 (C≡N), 1607, 1549, 1460. 1H NMR spectrum: δ 2.56 ppm, s (3H, CH3). Mass spectrum, m/z 315 (Irel 2%) [M]+. Found, %: C 34.15; H 0.96; N 22.18. C9H3Cl2N5O4. Calculated, %: C 34.20; H 0.96; N 22.16. M 316.05. 2-Bromo-6-(chlorodinitromethyl)-5-methylpyridine-3,4-dicarbonitrile (2b). Yield 64%, mp 188– 189°C. IR spectrum, ν, cm–1: 2234 (C≡N), 1602, 1547, 1487. 1H NMR spectrum: δ 2.29 ppm, s (3H, CH3). Mass spectrum, m/z (Irel, %): 359 (20), 361 (9) [M]+. Found, %: 30.03; H 0.84; N 19.47. C9H3BrClN5O4. Calculated, %: C 29.99; H 0.84; N 19.43. M 360.51. 2-Chloro-6-(chlorodinitromethyl)-5-ethylpyridine-3,4-dicarbonitrile (2c). Yield 55%, mp 121– 122°C. IR spectrum, ν, cm–1: 2243 (C≡N), 1613, 1549, 1464. 1H NMR spectrum, δ, ppm: 1.31 t (3H, CH3, J = 7.4 Hz), 2.82 q (2H, CH2, J = 7.4 Hz). Mass spectrum: m/z 329 (Irel 1%) [M]+. Found, %: C 36.34; H 1.52; N 21.25. C 10 H 5 Cl 2 N 5 O 4 . Calculated, %: C 36.39; H 1.53; N 21.22. M 330.08.

4,5-Dicyano-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3). Iodopyridine 1d, 0.005 mol, was added to 3 mL of 55–60% nitric acid, and the mixture was refluxed for 5 min until brown gas no longer evolved. The mixture was cooled, and the precipitate was filtered off and washed with cold water. An additional amount of acid 3 was isolated by evaporation of the filtrate. Yield 30%, mp 181–182°C (decomp.). IR spectrum, ν, cm–1: 3413 (OH), 3311 (NH), 2233 (C≡N), 1666–1592, 1528, 1461. 1H NMR spectrum, δ, ppm: 2.39 s (3H, CH3), 13.50 br.s (1H, NH). Mass spectrum: m/z 203 (Irel 32%) [M]+. Found, %: C 53.18; H 2.50; N 20.69. C9H5N3O3. Calculated, %: C 53.21; H 2.48; N 20.68. M 203.03. This study was performed in the framework of the base part of state assignment of the Ministry of Education and Science of the Russian Federation (project no. 4.6283.2017/8.9). REFERENCES 1. Badgujar, D.M., Talawar, M.B., Asthana, S.N., and Mahulikar, P.P., J. Hazard. Mater., 2008, vol. 151, p. 289. 2. Pagoria, P.F., Lee, G.S., Mitchell, A.R., and Schmidt, R.D., Thermochim. Acta, 2002, vol. 384, p. 187. 3. Shvekhgeimer, G.A., Zvolinskii, V.I., and Kobrakov, K.I., Chem. Heterocycl. Compd., 1986, vol. 22, p. 353. 4. Winkler, R. and Hertweck, R.C., ChemBioChem, 2007, vol. 8, p. 973. 5. Patterson, S. and Wyllie, S., Trends Parasitol., 2014, vol. 30, p. 289. 6. Raether, W. and Hänel, H., Parasitol. Res., 2003, vol. 90, p. S19. 7. Wilkinson, S.R., Curr. Top. Med. Chem., 2011, vol. 11, p. 2072. 8. Kaap, S., Quentin, I., Tamiru, D., Shaheen, M., Eger, K., and Steinfelder, H.J., Biochem. Pharmacol., 2003, vol. 65, p. 603. 9. Katritzky, A.R., Scriven, E.F., Majumder, S., Akhmedova, R.G., Vakulenko, A.V., Akhmedov, N.G., Murugan, R., and Abboud, K.A., Org. Biomol. Chem., 2005, vol. 3, p. 538. 10. Suzuki, H., Kozai, I., and Murashima, T., J. Chem. Res., Synop., 1993, p. 156. 11. Deady, L.W. and Quazi, N.H., Aust. J. Chem., 1992, vol. 45, p. 2083. 12. Ershov, O.V., Maksimova, V.N., Lipin, K.V., Belikov, M.Yu., Ievlev, M.Yu., Tafeenko, V.A., and Nasakin, O.E., Tetrahedron, 2015, vol. 71, p. 7445.

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SYNTHESIS OF DINITROCHLOROMETHYL PYRIDINE DERIVATIVES 13. Ershov, O.V., Tafeenko, V.A., Fedoseev, S.V., Eremkin, A.V., and Nasakin, O.E., Russ. J. Org. Chem., 2016, vol. 52, p. 827. 14. Gakh, A.A., Kiselyov, A.S., and Semenov, V.V., Tetrahedron Lett., 1990, vol. 31, p. 7379. 15. Gakh, A.A. and Khutoretskii, V.M., Bull. Acad. Sci. USSR, Div. Chem. Sci., 1983, vol. 32, p. 2386. 16. Novikov, S.S., Khmel’nitskii, L.I., Novikova, T.S., and Lebedev, O.V., Chem. Heterocycl. Compd., 1970, vol. 6, p. 543. 17. Bark, T., Stoeckli-Evans, H. and Von Zelewsky, A., J. Chem. Soc., Perkin Trans. 1, 2002, p. 1881.

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18. Luk’yanov, O.A. and Zhiguleva, T.I., Bull. Acad. Sci. USSR, Div. Chem. Sci., 1982, vol. 31, p. 1270. 19. Lipin, K.V., Maksimova, V.N., Ershov, O.V., Eremkin, A.V., Kayukov, Ya.S., and Nasakin, O.E., Russ. J. Org. Chem., 2010, vol. 46, p. 617. 20. Ershov, O.V., Ievlev, M.Yu., Belikov, M.Yu., Lipin, K.V., Naydenova, A.I., and Tafeenko, V.A., RSC Adv., 2016, vol. 6, p. 82 227. 21. Belikov, M.Yu., Ievlev, M.Yu., Ershov, O.V., Lipin, K.V., Legotin, S.A., and Nasakin, O.E., Russ. J. Org. Chem., 2014, vol. 50, p. 1372. 22. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008, p. 112.

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