Efficient Synthesis of 4-Amino-2,6- Dichloropyridine and Its Derivatives

Heterocycl. Commun. 2016; 22(5): 251–254

Preliminary Communication

Congming Ma, Zuliang Liu* and Qizheng Yao* Efficient synthesis of 4-amino-2,6- dichloropyridine and its derivatives

DOI 10.1515/hc-2016-0132 consuming the oxygen provided by the nitro groups. The Received August 12, 2016; accepted August 22, 2016; previously presence of nitro groups tends to decrease the heat of for- published online September 24, 2016 mation but contributes markedly to the overall energetic performance. Also, the nitro groups enhance the oxygen Abstract: A facile synthetic route to an important inter- balance and density, which improves the detonation mediate 4-amino-2,6-dichloropyridine was developed. performances (pressure and velocity) [7, 8]. On the other Oxidation of 2,6-dichloropyridine as a starting material hand, one of the effective approaches used to synthesize gave pyridine N-oxide derivative which was subjected to insensitive high explosives (IHE) is to basically incorpo- nitration followed by reduction. Subsequent nitration of rate a maximum possible percentage of nitrogen into ener- the product and nucleophilic displacement reaction were getic materials. The insensitivity is achieved basically by carried out to afford fully substituted energetic pyridine (i) use of nitrogen-rich heterocycle or its N-oxide as key derivatives. Most of the synthetic reactions proceeded synthons for the synthesis of IHE and (ii) introduction of under mild conditions. nitro and amino groups in the ring ortho to each other. The Keywords: 4-amino-2,6-dichloropyridine; energetic mate- formation of a hydrogen bond between these two groups rials; organic synthesis. increases stability of the molecule [9, 10]. Pyridine compounds have attracted renewed atten- tion, and the potential use of nitro derivatives of pyri- Introduction dines and their bicyclic analogs has been reported for the synthesis of novel insensitive explosives [11–13]. In a The synthesis and development of new energetic materi- continuing effort to seek more powerful, and less sensitive als continues to focus on new heterocyclic compounds energetic materials, we are interested in amino-nitropyri- with high densities, high heats of formation and good det- dines, and fused heterocyclic compounds that contain a onation properties but high performance and low sensitiv- high percentage of both nitrogen and oxygen. However, ity continue to be of keen concerns [1–3]. The requirements the difficulty of synthesizing some nitroheteroaromatic of insensitivity and high energy with concomitant positive systems may be attributed to their electron deficiency, oxygen balance are often contradictory to each other, making electrophilic aromatic substitution problematic. making the development of new high energy density By the addition of electron donating substituents, such as materials an interesting and challenging problem [4, 5]. the amino group to the heteroaromatic ring, nitration may Highly energetic compounds substituted with nitro proceed more readily. Based on our successful synthesis of groups are an important class of useful energetic materials some new 4-amino-3,5-dinitropyridine derivatives under [6]. Traditional polynitro compounds produce energy pri- mild conditions using 4-amino-2-chloropyrine as the marily from combustion of the carbon backbone while starting material [14], we herein would like to report the synthesis of 4-amino-2,6-dichloro-3,5-dinitropyridine (7) from readily available 2,6-dichloropyridine (1), followed *Corresponding authors: Zuliang Liu, School of Chemical Engineering, Nanjing University of Science and Technology, by nucleophilic displacement reactions to form fully sub- Nanjing 210094, China, e-mail: [email protected]; and stituted energetic pyridine derivatives (Scheme 1). Qizheng Yao, School of Chemical Engineering, Nanjing University Polyamino- and polynitro-substituted pyridine- of Science and Technology, Nanjing 210094, China; and School of 1-oxide with alternating amino and nitro groups are Pharmacy, China Pharmaceutical University, Nanjing 210009, China, high performance explosives that are inherently stable e-mail: [email protected] Congming Ma: School of Environment and Biological Engineering, and insensitive, with an additional energy contribu- Nanjing University of Science and Technology, Nanjing 210094, tion from the N-oxide functionality [15]. On the basis China of the synthesis of 4-amino-2-chloro-3,5-dinitropyridine 252 C. Ma et al.: Efficient synthesis of 4-amino-2,6-dichloropyridine

NO2 NO2 NH2

urea H2SO4 CH3COOH H2SO4 + H O KNO Fe KNO Cl N Cl 2 2 Cl N Cl 3 3 Cl N Cl Cl N Cl Cl N Cl O O 1 2 3 4 5

NH2 NH2 NH2 NH2 NH2 NO2 O2N NO2 CH ONaO2N NO2 NH3 O2N NO2 O O2N NO2 + 3

Cl N Cl Cl N Cl H3CO N OCH3 H2N N NH2 H2N N NH2 O 6 7 8 9 10

Scheme 1 derivatives [14] and a rather lengthy and tedious syn- Experimental thesis of 4-amino-2,6-dichloropyridine-1-oxide [16], in the present work, 2,6-dichloropyridine ( ) was used as 1 Caution: Some compounds are energetic materials that tend to the starting material for the synthesis of several pyri- explode under certain conditions. Proper protective measures (work dine derivatives (Scheme 1). Compound 1 was oxidized with small quantities, safety glasses, face shields) should be observed. to the oxide with hydrogen peroxide. Then, nitration 2 General: Melting points were measured on an X-4 melting point of 2,6-dichloropyridine-1-oxide (2) gave a mixture of apparatus and are uncorrected. 1H NMR (500 MHz) and 13C NMR (125 2,6-dichloro-4-nitropyridine-1-oxide (3) and 2,6-dichloro- MHz) spectra were recorded on a Bruker Avance Spectrometer. High- 4-nitropyridine (4) that was difficult to separate even resolution mass spectra were recorded on a Finnigan TSQ Quantum using chromatography [17]. This crude mixture was ultra AM mass spectrometer. Elemental analysis was carried out on a Perkin-Elmer instrument. treated with iron powder in acetic acid which resulted in reduction of both the N-oxide function and the nitro group to give 4-amino-2,6-dichloropyridine (5). Although Hydrogen peroxide urea the N-oxide functionality was lost, compound 5 can also serve as an important intermediate in the synthesis of Aqueous hydrogen peroxide (30%, 37.5 mL) in a 250-mL flask was fully substituted energetic pyridine materials. stirred vigorously and treated portion-wise with salicylic acid (0.4 g) Thus, nitration of aminopyridine 5 with a mixture of and urea (20.0 g, 333 mmol) at 15°C [17]. The mixture was stirred at this temperature for 1 h and at 5°C for another 24 h. The solid prod- concentrated sulfuric acid and potassium nitrate at 25°C uct was filtered and dried to give hydrogen peroxide urea as a white furnished a mixture of 4-amino-2,6-dichloro-3-nitropyri- solid; yield 30.0 g (96%). dine (6) and 4-amino-2,6-dichloro-3,5-dinitropyridine (7) which was separated into individual components. Com- 2,6-Dichloropyridine-1-oxide (2) pound 6 is an important medicinal intermediate, which has been synthesized previously in seven cumbersome This compound was obtained by two methods reported previously steps starting with citrazinic acid [18]. It is important to [19, 20]. Method 1: 2,6-Dichloropyridine (1, 12.0 g, 81.6 mmol), hydro- note that the present synthetic route to 6 has the advan- gen peroxide urea (28.2 g, 300 mmol) and trifluoroacetic anhydride tage of a readily available starting material, few operation (23 mL) were stirred in dichloromethane (150 mL) at 0°C for 30 min steps and simplicity of workup. Nitration of either 5 or 6 at and then at room temperature for another 6 h. Silica gel chromatog- 50°C (not shown) furnished the dinitropyridine 7 in high raphy gave product 2 as a colorless solid; yield 11.28 g (85%); mp 136–138°C [19, 20]. Method 2: A solution of 1 (12.0 g, 81.63 mmol) in yield. Treatment of with sodium methoxide followed 7 trifluoacetic acid (70 mL) was slowly treated at room temperature with by ammonolysis of the resultant dimethoxy intermediate 30% hydrogen peroxide (18 mL). After stirring for 20 min, the mixture product 8 gave 2,4,6-triamino-3,5-dinitropyridine (9). Oxi- was heated to 100°C, stirred at this temperature for 3 h, treated with dation of 9 with hydrogen peroxide in glacial acetic acid an additional amount of hydrogen peroxide (30%, 9 mL), and kept at afforded the desired 2,4,6-triamino-3,5-dinitropyridine- 100°C for an additional 5 h; yield 6.32 g (48%). 1-oxide (10) albeit in low yield. In summary, in this report we described a novel and 2,6-Dichloro-4-nitropyridine-1-oxide (3) and practical protocol for synthesis of 4-amino-2,6-dichloro- 2,6-dichloro-4-nitropyridine (4) pyridine with 2,6-dichloropyridine as the starting material. Synthesis of fully substituted energetic pyridine A solution of 2,6-dichloropyridine-1-oxide (2, 5.5 g, 33.7 mmol) in con- derivatives was also discussed. centrated sulfuric acid (60 mL) at room temperature was treated with C. Ma et al.: Efficient synthesis of 4-amino-2,6-dichloropyridine 253 potassium nitrate (5.1 g, 50.6 mmol) portionwise with vigorous stir- (0.06 g, 1.11 mmol). After stirring for 2 h, the pale yellow precipitate ring [21, 22]. Then the mixture was heated to 100°C for 7 h, cooled and was filtered, washed with cold methanol and dried to give 4-amino- poured over ice. The resultant solid was filtered, washed with water and 2,6-dimethoxy-3,5-dinitropyridine (8, 0.82 g, 85%); mp 192–193°C; 1H 13 dried to give a mixture (3.53 g) of 3 (major product) and 4 (minor prod- NMR (DMSO-d6): δ 7.97 (s, 2H), 4.01(s, 6H); C NMR (DMSO-d6): δ 156.9, 1 1 + uct); H NMR for 3 (CDCl3): δ 8.33(s); H NMR for 4 (CDCl3): δ 8.02 (s, 1H). 146.0, 115.3; ESI-MS: m/z 242.97 (M-H) . Anal. Calcd for C7H8N4O6: C, 34.43; H, 3.30; N, 22.95. Found: C, 34.48; H, 3.25; N, 23.05.

4-Amino-2,6-dichloropyridine (5) 2,4,6-Triamino-3,5-dinitropyridine (9) A solution of the mixture of 3 and 4 obtained as described above (1.96 g) in acetic acid (40 mL) was treated with iron powder (1.96 g, 35 mmol), Method 1: Dry ammonia was bubbled through a stirred solution of and the reaction mixture was heated to 45°C for 3 h, after which time 4-amino-2,6-dichloro-3,5-dinitropyridine (7, 1.0 g, 4.0 mmol) in etha- complete consumption of the starting material was observed by TLC nol (8 mL) for 30 min at 0°C and for another 6 h at room temperature. [23]. Quenching with water was followed by extraction with ethyl ace- The resultant precipitate was filtered, washed with water and dried tate (2 × 50 mL). Concentration of the extract afforded compound5 as a to give compound 9 as a yellow solid; yield 0.80 g (95%); mp 352– 1 1 white solid; yield 1.30 g; mp 175–177°C [23]; H NMR (DMSO-d6): δ 6.80 354°C (dec.) [24]; H NMR (DMSO-d6): δ 10.26 (s, 2H), 8.75 (s, 2H), 8.23 13 13 (s, 2H), 6.60 (s, 2H); C NMR (DMSO-d6): δ 158.1, 148.7, 106.0. (s, 2H); C NMR (DMSO-d6): δ 155.5, 150.9, 109.6; ESI-MS: m/z 212.95 + (M-H) . Anal. Calcd for C5H6N6O4: C, 28.04; H, 2.82; N, 39.25. Found: C, 28.10; H, 2.89; N, 39.29.

4-Amino-2,6-dichloro-3-nitropyridine (6) and Method 2: Dry ammonia was bubbled through a stirred solution of 4-amino-2,6-dichloro-3,5-dinitropyridine (7) 4-amino-2,6-dimethoxy-3,5-dinitropyridine (8, 0.5 g, 2.1 mmol) in ethanol (8 mL) for 12 h at 40°C. The resultant precipitate was filtered, washed with water and dried to give compound as a yellow solid; 4-Amino-2,6-dichloropyridine (5, 1.30 g, 8.0 mmol) was dissolved in 9 concentrated sulfuric acid (60 mL) at room temperature, and potas- yield 0.38 g (87%). sium nitrate (1.54 g, 15.25 mmol) was added in portions with vigorous stirring. The reaction mixture was held at room temperature fot 6 h, after wich time complete consumption of substrate 5 was observed 2,4,6-Triamino-3,5-dinitropyridine-1-oxide (10) by TLC. After pouring over ice the resultant precipitate was filtered, washed with water and dried. Purification by silica gel chromatogra- A solution of 2,4,6-triamino-3,5-dinitropyridine (9, 0.21 g, 1 mmol) in phy eluting with ethyl acetate/petroleum ether (1:8) afforded6 which glacial acetic acid (10 mL) was treated dropwise at room tempera- was eluted first and then7 . ture with 30% hydrogen peroxide (1 mL) and the mixture was heated under reflux for 5 h, then cooled, diluted with water (50 mL) and 4-Amino-2,6-dichloro-3-nitropyridine (6) White solid; yield allowed to stand for 12 h. The resultant yellow precipitate of com- 0.71 g (43%); mp 142–144°C; 1H NMR (DMSO-d ): δ 7.65 (s, 2H), 6.86 6 pound 10 was filtered and washed successfully with water and etha- 13 (s, 1H); C NMR (DMSO-d6): δ 142.7, 124.1, 123.7 [23]. 1 nol; yield 0.02 g (9%); mp 350–352°C (dec.) [24]; H NMR (DMSO-d6): δ 10.17 (s, 2H), 9.58 (s, 2H), 8.83 (s, 2H); ESI-MS: m/z 229.97 (M-H)+. 4-Amino-2,6-dichloro-3,5-dinitropyridine (7) Yellow solid; yield Anal. Calcd for C H N O : C, 26.09; H, 2.63; N, 36.52. Found: C, 26.19; 0.35 g (17%); mp 159–161°C; 1H NMR (DMSO-d ): δ 8.25 (s); 13C NMR 5 6 6 5 6 H, 2.80; N, 36.59. (DMSO-d6): δ 142,4, 141.0, 132.0. Anal. Calcd for C5H2Cl2N4O4: C, 23.74; H, 0.80; N, 22.14. Found: C, 23.65; H, 1.02; N, 22.19. Funding: National Natural Science Foundation of China, (Grant/Award Number: ‘21102125’).

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