Regioselective Reaction of 5,6-Dialkyl-2-halopyridine - Springer Link

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ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 426–429. © Pleiades Publishing, Ltd., 2012. Original Russian Text © V.N. Maksimova, O.V. Ershov, K.V. Lipin, A.V. Eremkin, O.E. Nasakin, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 3, pp. 429–431.

Regioselective Reaction of 5,6-Dialkyl-2-halopyridine3,4-dicarbonitriles with Ammonia V. N. Maksimova, O. V. Ershov, K. V. Lipin, A. V. Eremkin, and O. E. Nasakin I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia e-mail: [email protected] Received July 4, 2011

Abstract—The reaction of 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles with alcoholic ammonia under elevated pressure gave 5,6-dialkyl-2-aminopyridine-3,4-dicarbonitriles as a result of nucleophilic replacement of the halogen atom by amino group. 6,7-Dialkyl-4-halo-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diimines were formed in analogous reaction at room temperature in the presence of potassium carbonate.

DOI: 10.1134/S1070428012030153 in obtaining 5,6-dialkyl-2-aminopyridine-3,4-dicarbonitriles IIa and IIb in 72–82% yield by carrying out the reaction under elevated pressure in ethanol saturated with ammonia (Scheme 1). Replacement of the chlorine atom in compounds Ia and Id by amino group required a shorter time than analogous reactions with bromo- and iodo-substituted derivatives Ib, Ic, and Ie. Presumably, the formation of the corresponding intermediate from chloropyridine derivatives is more favorable for steric reasons, as well as from the viewpoint of its better stabilization due to higher electronegativity of chlorine as compared to bromine and iodine. The observed pattern is consistent with the assumed addition–elimination mechanism of aromatic nucleophilic replacement (SNAr).

Molecules of 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles [1–4] possess several reaction centers, namely halogen atom, cyano groups, and alkyl groups. The halogen atom in 2-halopyridine-3-carbonitriles is activated by the neighboring cyano group, and it can be readily replaced under mild conditions, e.g., by nitrogen-containing nucleophiles [5–19]. Depending on the substrate and reagent nature, these transformations may be catalyzed by the reacting nucleophile [5, 6] or other base such as potassium [7, 8] or cesium carbonate [9, 10], sodium hydrogen carbonate [11, 12], triethylamine [13, 14], ethyl(diisopropyl)amine [15, 16], etc. Taking into account reduced nucleophilicity and high volatility of ammonia compared to primary and secondary amines, 2-aminopyridine-3-carbonitriles are synthesized under pressure [12, 17, 18] or microwave irradiation [19].

With a view to accelerate halogen replacement in 5,6-dialkyl-2-halopyridine-3,4-dicarbonitriles Ia–Ie in the reaction with ammonia, we added potassium carbonate to the reaction mixture. The use of K2CO3 as catalyst in nucleophilic substitution reactions of 2-halopyridine-3-carbonitriles with various amines was reported in [7, 8]. However, the reaction of compounds

The halogen atom in 5,6-dialkyl-2-halopyridine3,4-dicarbonitriles Ia–Ie was not replaced by amino group on prolonged heating in aqueous ammonia or in organic solvents saturated with ammonia (ethanol, propan-2-ol, 1,4-dioxane, acetonitrile). We succeeded

Scheme 1. HN CN R

2

R1

CN N

NH2

NH3, EtOH

R

2

1

2

CN

R1

IIa, IIb 1

NH

CN

N

R

NH3, EtOH, K2CO3

R1

Hlg

Ia–Ie 2

1

2

NH N

Hlg

IIIa–IIIe

2

1

2

II, R = R = Me (a), R R = (CH2)4 (b); I, III, R = R = Me, Hlg = Cl (a), Br (b), I (c); R R = (CH2)4, Hlg = Cl (d), Br (e).

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REGIOSELECTIVE REACTION OF 5,6-DIALKYL-2-HALOPYRIDINE-3,4-DICARBONITRILES

Ia–Ie with ammonia in ethanol at room temperature in the presence of K2CO3 led to selective formation of pyrrolopyridines IIIa–IIIe (Scheme 1), whereas the halogen atom remained intact regardless of its nature. We believe that in this case initial nucleophilic attack by ammonia is directed at one cyano group, and the subsequent intramolecular heterocyclization with participation of the other cyano group gives pyrrole ring. Compounds IIIa–IIIe were formed in 64–84% yield. The structure of compounds II and III was confirmed by their IR, 1H NMR, and mass spectra. The IR spectra of II contained absorption bands in the regions 3388–3387 and 3339–3324 cm–1 due to antisymmetric and symmetric stretching vibrations of the amino group. Absorption bands belonging to vibrations of associated amino group were observed at 3175– 3147 cm–1. Compounds III displayed in the IR spectra absorption bands at 3440–3124 (N−H) and 1676– 1621 cm–1 (C=N). Unlike pyrrolopyridines III, absorption bands corresponding to stretching vibrations of conjugated cyano groups were present in the IR spectra of II at 2224–2221 cm–1. Protons in the methyl and methylene groups attached to the pyridine ring resonated in the 1H NMR spectra at δ 2.27–3.18 ppm. Signal from the amino group appeared as a singlet at δ 7.19– 7.21 ppm. The NH protons in 1H-pyrrolopyridinediimines III gave rise to three singlets in the region δ 7.31–9.38 ppm. The mass spectra of compounds II and III contained the molecular ion peaks, and the molecular ion peaks of halogen-containing compounds III were characterized by isotope ratios typical of chlorine (1 : 3) and bromine (1 : 1). EXPERIMENTAL

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propan-2-ol saturated with dry ammonia, and the mixture was heated in a sealed ampule for 7 h on a boiling water bath. The mixture was then evaporated, and the precipitate was filtered off and washed with water. Yield 0.134 g (78%), mp 230–232°C (decomp.) [20]. IR spectrum, ν, cm–1: 3388, 3339, 3175 (NH2); 2224 (C≡N). 1H NMR spectrum, δ, ppm: 2.27 s (3H, CH3), 2.38 s (3H, CH3), 7.21 s (2H, NH2). Mass spectrum: m/z 172 (Irel 100%) [M]+. Found, %: C 62.85; H 4.74; N 32.49. C 9 H 8 N 4 . Calculated, %: C 62.78; H 4.68; N 32.54. M 172. b. The reaction with 0.236 g (1 mmol) of 2-bromo5,6-dimethylpyridine-3,4-dicarbonitrile (Ib) was carried out in a similar way (reaction time 10 h). Yield 0.127 g (74%), mp 230–232°C (decomp.). c. The reaction with 0.286 g (1 mmol) of 2-iodo5,6-dimethylpyridine-3,4-dicarbonitrile (Ic) was carried out in a similar way (reaction time 12 h). Yield 0.124 g (72%), mp 230–232°C (decomp.). 2-Amino-5,6,7,8-tetrahydroquinoline-3,4-dicarbonitrile (IIb) was synthesized in a similar way from 0.217 g (1 mmol) of 2-chloro-5,6,7,8-tetrahydroquinoline-3,4-dicarbonitrile (Id). Yield 0.148 g (75%), mp 220–222°C (decomp.). IR spectrum, ν, cm–1: 3387, 3324, 3147 (NH2); 2221 (C≡N). 1H NMR spectrum, δ, ppm: 1.76 m (4H, CH2), 2.70 t (4H, CH2, 3J = 6 Hz), 7.19 s (2H, NH2). Mass spectrum: m/z 198 (Irel 100%) [M]+. Found, %: C 66.70; H 5.15; N 28.20. C11H10N4. Calculated, %: C 66.65; H 5.08; N 28.26. M 198. 4-Chloro-6,7-dimethyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diimine (IIIa). Potassium carbonate, 0.139 g (1 mmol), and compound Ia, 0.191 g (1 mmol), were added to 5 ml of ethanol saturated with dry ammonia. The mixture was stirred for 72 h at room temperature, and the precipitate was filtered off and washed with water. Yield 0.167 g (80%), mp 223– 225°C (decomp.). IR spectrum, ν, cm–1: 3440, 3344, 3220 (NH); 1671, 1626 (C=N). 1H NMR spectrum, δ, ppm: 2.54 s (3H, CH3), 2.66 s (3H, CH3), 7.38 s (1H, NH), 8.75 s (1H, NH), 9.38 s (1H, NH). Mass spectrum: m/z 210/208 (I rel 27/100%) [M] + . Found, %: C 51.89; H 4.41; N 26.80. C9H9ClN4. Calculated, %: C 51.81; H 4.35; N 26.85. M 209.45.

The progress of reactions and the purity of products were monitored by thin-layer chromatography on Silufol UV-254 plates; spots were visualized under UV irradiation, by treatment with iodine vapor, or by thermal decomposition. The IR spectra were recorded from samples dispersed in mineral oil on an FSM-1202 spectrometer with Fourier transform. The 1H NMR spectra were measured on a Bruker DRX 500 instrument at 500.13 MHz using DMSO-d6 as solvent and tetramethylsilane as internal reference. The mass spectra (electron impact, 70 eV) were obtained on a Finnigan MAT INCOS 50 mass spectrometer.

Compounds IIIb–IIIe were synthesized in a similar way.

2-Amino-5,6-dimethylpyridine-3,4-dicarbonitrile (IIa). a. 2-Chloro-5,6-dimethylpyridine-3,4-dicarbonitrile (Ia), 0.191 g (1 mmol), was added to 5 ml of

4-Bromo-6,7-dimethyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diimine (IIIb). Yield 0.210 g (83%), mp 221–223°C (decomp.). IR spectrum, ν, cm–1: 3402,

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MAKSIMOVA et al.

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3235, 3213 (NH); 1673, 1626 (C=N). 1H NMR spectrum, δ, ppm: 2.55 s (3H, CH 3 ), 2.65 s (3H, CH 3 ), 7.31 s (1H, NH), 8.85 s (1H, NH), 9.35 s (1H, NH). Mass spectrum: m/z 254/252 (I rel 98/100%) [M]+. Found, %: C 42.78; H 3.64; N 22.08. C9H9BrN4. Calculated, %: C 42.71; H 3.58; N 22.14. M 253.9. 4-Iodo-6,7-dimethyl-1H-pyrrolo[3,4-c]pyridine1,3(2H)-diimine (IIIc). Yield 0.252 g (84%), mp 198– 200°C (decomp.). IR spectrum, ν, cm–1: 3406, 3303, 3240 (NH); 1674, 1623 (C=N). 1H NMR spectrum, δ, ppm: 2.53 s (3H, CH3), 2.64 s (3H, CH3), 7.33 s (1H, NH), 8.96 s (1H, NH), 9.20 s (1H, NH). Mass spectrum: m/z 300 (Irel 100%) [M]+. Found, %: C 36.08; H 3.06; N 18.62. C9H9IN4. Calculated, %: C 36.02; H 3.02; N 18.67. M 300.9. 4-Chloro-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diimine (IIId). Yield 0.150 g (64%), mp 173–175°C (decomp.). IR spectrum, ν, cm –1 : 3395, 3215, 3124 (NH); 1675, 1621 (C=N). 1 H NMR spectrum, δ, ppm: 1.78 m (2H, CH2), 1.85 m (2H, CH2), 2.91 t (2H, CH2, 3J = 6 Hz), 3.17 m (2H, CH2), 7.38 s (1H, NH), 8.80 s (1H, NH), 9.35 s (1H, NH). Mass spectrum: m/z 236/234 (Irel 32/100%) [M]+. Found, %: C 56.38; H 4.76; N 23.81. C11H11ClN4. Calculated, %: C 56.30; H 4.72; N 23.87. M 234.45. 4-Bromo-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-diimine (IIIe). Yield 0.204 g (73%), mp 140–142°C (decomp.). IR spectrum, ν, cm–1 : 3419, 3236, 3215 (NH); 1676, 1627 (C=N). 1 H NMR spectrum, δ, ppm: 1.75–1.80 m (2H, CH2), 1.82–1.87 m (2H, CH2), 2.93 t (2H, CH2, 3J = 6 Hz), 3.13–3.18 m (2H, CH2), 7.35 s (1H, NH), 9.08 s (1H, NH), 9.33 s (1H, NH). Mass spectrum, m/z 280/278 (I rel 90/94%) [M] + . Found, %: C 47.41; H 4.03; N 20.00. C11H11BrN4. Calculated, %: C 47.33; H 3.97; N 20.07. M 278.9. This study was performed in the framework of the Federal Special-Purpose Program “Scientific and Scientific–Pedagogical Staff of Innovation Russia” (state contract no. 16.740.11.0160). REFERENCES 1. Nasakin, O.E., Nikolaev, E.G., Terent’ev, P.B., Bulai, A.Kh., Khaskin, B.A., and Mikhailov, V.K., Khim. Geterotsikl. Soedin., 1984, p. 1574. 2. Nasakin, O.E., Nikolaev, E.G., Terent’ev, P.B., Bulai, A.Kh., and Lavrent’eva, I.V., Khim. Geterotsikl. Soedin., 1987, p. 653.

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