Efficient synthesis of 4-amino-2,6-dichloropyridine and its derivatives

Introduction

The synthesis and development of new energetic materials continues to focus on new heterocyclic compounds with high densities, high heats of formation and good detonation properties but high performance and low sensitivity continue to be of keen concerns [1], [2], [3]. The requirements of insensitivity and high energy with concomitant positive oxygen balance are often contradictory to each other, making the development of new high energy density materials an interesting and challenging problem [4], [5].

Highly energetic compounds substituted with nitro groups are an important class of useful energetic materials [6]. Traditional polynitro compounds produce energy primarily from combustion of the carbon backbone while consuming the oxygen provided by the nitro groups. The presence of nitro groups tends to decrease the heat of formation but contributes markedly to the overall energetic performance. Also, the nitro groups enhance the oxygen balance and density, which improves the detonation performances (pressure and velocity) [7], [8]. On the other hand, one of the effective approaches used to synthesize insensitive high explosives (IHE) is to basically incorporate a maximum possible percentage of nitrogen into energetic materials. The insensitivity is achieved basically by (i) use of nitrogen-rich heterocycle or its N-oxide as key synthons for the synthesis of IHE and (ii) introduction of nitro and amino groups in the ring ortho to each other. The formation of a hydrogen bond between these two groups increases stability of the molecule [9], [10].

Pyridine compounds have attracted renewed attention, and the potential use of nitro derivatives of pyridines and their bicyclic analogs has been reported for the synthesis of novel insensitive explosives [11], [12], [13]. In a continuing effort to seek more powerful, and less sensitive energetic materials, we are interested in amino-nitropyridines, and fused heterocyclic compounds that contain a high percentage of both nitrogen and oxygen. However, the difficulty of synthesizing some nitroheteroaromatic systems may be attributed to their electron deficiency, making electrophilic aromatic substitution problematic. By the addition of electron donating substituents, such as the amino group to the heteroaromatic ring, nitration may proceed more readily. Based on our successful synthesis of some new 4-amino-3,5-dinitropyridine derivatives under mild conditions using 4-amino-2-chloropyrine as the 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 by nucleophilic displacement reactions to form fully substituted energetic pyridine derivatives (Scheme 1).

Scheme 1

Polyamino- and polynitro-substituted pyridine-1-oxide with alternating amino and nitro groups are high performance explosives that are inherently stable and insensitive, with an additional energy contribution from the N-oxide functionality [15]. On the basis of the synthesis of 4-amino-2-chloro-3,5-dinitropyridine derivatives [14] and a rather lengthy and tedious synthesis of 4-amino-2,6-dichloropyridine-1-oxide [16], in the present work, 2,6-dichloropyridine (1) was used as the starting material for the synthesis of several pyridine derivatives (Scheme 1). Compound 1 was oxidized to the oxide 2 with hydrogen peroxide. Then, nitration of 2,6-dichloropyridine-1-oxide (2) gave a mixture of 2,6-dichloro-4-nitropyridine-1-oxide (3) and 2,6-dichloro-4-nitropyridine (4) that was difficult to separate even using chromatography [17]. This crude mixture was 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 the N-oxide functionality was lost, compound 5 can also serve as an important intermediate in the synthesis of fully substituted energetic pyridine materials.

Thus, nitration of aminopyridine 5 with a mixture of concentrated sulfuric acid and potassium nitrate at 25°C furnished a mixture of 4-amino-2,6-dichloro-3-nitropyridine (6) and 4-amino-2,6-dichloro-3,5-dinitropyridine (7) which was separated into individual components. Compound 6 is an important medicinal intermediate, which has been synthesized previously in seven cumbersome steps starting with citrazinic acid [18]. It is important to note that the present synthetic route to 6 has the advantage of a readily available starting material, few operation steps and simplicity of workup. Nitration of either 5 or 6 at 50°C (not shown) furnished the dinitropyridine 7 in high yield. Treatment of 7 with sodium methoxide followed by ammonolysis of the resultant dimethoxy intermediate product 8 gave 2,4,6-triamino-3,5-dinitropyridine (9). Oxidation of 9 with hydrogen peroxide in glacial acetic acid afforded the desired 2,4,6-triamino-3,5-dinitropyridine-1-oxide (10) albeit in low yield.

In summary, in this report we described a novel and practical protocol for synthesis of 4-amino-2,6-dichloropyridine with 2,6-dichloropyridine as the starting material. Synthesis of fully substituted energetic pyridine derivatives was also discussed.

Experimental

Caution: Some compounds are energetic materials that tend to explode under certain conditions. Proper protective measures (work with small quantities, safety glasses, face shields) should be observed.

General: Melting points were measured on an X-4 melting point apparatus and are uncorrected. ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) spectra were recorded on a Bruker Avance Spectrometer. High-resolution mass spectra were recorded on a Finnigan TSQ Quantum ultra AM mass spectrometer. Elemental analysis was carried out on a Perkin-Elmer instrument.