Linear Synthesis of 10-Hydroxy-N,N-dimethyl-N-((3-(tosyloxy)pyridin-2-yl)methyl)decan-1-aminium Bromide

Abstract

In 2019, carbamates derived from 3-hydroxypyridine were classified as nerve agents and subsequently included in the Annex on Chemicals by the Conference of the States Parties. Herein, we describe the preparation of a structural simulant of this class of compounds, 10-hydroxy-N,N-dimethyl-N-((3-(tosyloxy)pyridin-2-yl)methyl)decan-1-aminium bromide. The compound was synthesized via tosylation of 2-((N,N-dimethylamino)methyl)pyridin-3-ol with tosyl chloride in the presence of sodium hydride, followed by alkylation of the resulting ((N,N-dimethylamino)methyl)pyridin-3-yl 4-methylbenzenesulfonate with 10-bromodecan-1-ol.

1. Introduction

Over the past few decades, organic synthesis has advanced rapidly in the preparation of a wide variety of structural motifs. Significant progress has been achieved, for example, in the stereoselective synthesis of trisubstituted [1,2,3,4] and tetrasubstituted alkenes [5,6,7], polycyclic aromatic hydrocarbons [8,9], and heterocyclic compounds [10,11]. The continuous exploration of synthetic methodologies is driven by the fact that numerous organic derivatives have found valuable applications in materials chemistry [12,13,14] and organic synthesis [15].

A typical example of an important structural motif is the carbamate group, well known for its role in cholinesterase inhibition [16]. The incorporation of the carbamate functionality into 3-hydroxypyridine derivatives has led to the development of a new class of cholinesterase inhibitors, which have been recognized by the Organisation for the Prohibition of Chemical Weapons (OPCW). These pyridine carbamate derivatives belong to the group of nerve agents and were added to the Annex on Chemicals by the Conference of the States Parties in 2019 [17].

Despite the fact that carbamates 1 and 2 are classified as chemical warfare agents—or perhaps precisely because of this—their synthesis remains insufficiently explored and rarely disclosed in the open literature (Figure 1). A comprehensive search in the SciFinderⁿ and Reaxys databases revealed only three patent records describing the synthesis of compound 1. The reported procedure for carbamate 1 involves the direct reaction of 2-(N,N-dimethylamino)ethanol with the corresponding carbamate under reflux in acetonitrile, yielding compound 1 in 71% isolated yield (Scheme 1a). The easy availability of compounds incorporating the structural motifs of 1 and 2 would greatly facilitate further studies of their physicochemical properties and potential applications, especially those of their less hazardous analogues (simulants). To this end, as part of our activities devoted to the development of nerve agent chemosensors [18], we have designed a concise and operationally simple route to model compounds exemplified by derivative 3, which is obtained via straightforward alkylation of a more nucleophilic nitrogen atom with 10-bromodecan-1-ol (Scheme 1b).

2. Results

Starting material 4 was prepared by reacting 3-hydroxypyridine (3) with an aqueous solution of N,N-dimethylamine and formaldehyde under reflux (Scheme 1b) [19]. The resulting compound was obtained in quantitative yield after extractive work-up and used without further purification. The ¹H and ¹³C NMR spectra of the crude product are provided in the Supporting Information. Since the synthesis of the tosylated derivative 5 has not been reported in the literature, we developed a straightforward tosylation of pyridine 4 with tosyl chloride in the presence of a base. Tosylation of 3-hydroxypyridine is a known transformation and is typically carried out by reacting 3-hydroxypyridine with tosyl chloride. Various bases have been employed for this transformation, including DABCO [20], pyridine [21], triethylamine [22], cesium carbonate [23], sodium hydroxide [24], and HOBt [25]. However, we avoided using nitrogenous bases for the tosylation of pyridine 4, as this reaction is accompanied by the formation of quaternary ammonium salts that must be separated from the desired product. Although sodium hydroxide initially appeared to be a suitable alternative, repeating the reported procedure for tosylation of 3-hydroxypyridine [24] afforded derivative 5 in only 63% isolated yield. In contrast, using a 60% suspension of sodium hydride in mineral oil afforded pyridine derivative 5 in 80% yield. The quaternary ammonium salt 6 was subsequently obtained by reacting compound 5 with 10-bromodecan-1-ol in acetonitrile at 80 °C. After 16 h, the desired product 6 was isolated in 78% yield, corresponding to an overall yield of 62% for the three-step sequence starting from 3-hydroxypyridine (3). Thus, the proposed route for the preparation of the simulant of compound 1 differs from the published procedure while maintaining comparably high efficiency.

The structures of the synthesized compounds were unambiguously confirmed by 1D and 2D NMR spectroscopy (¹H, ¹³C{¹H}, ¹H–¹H COSY, ¹H–¹³C HMQC, ¹H–¹³C HMBC). In the ¹H NMR spectrum of compound 5, characteristic resonances of the tosyl group were observed—two doublets at 7.74 and 7.34 ppm attributable to aromatic ortho protons, and a singlet at 2.45 ppm corresponding to the methyl substituent (Figure S3). Three additional pyridine signals appeared at 8.51, 7.48, and 7.18 ppm. Notably, the spectrum also displays resonances of the methylene group (H–7) and the N,N-dimethylamino group (H–8) at 3.34 and 2.17 ppm, respectively (Figure 2). Upon quaternization of compound 5, the proton signals H–7 and H–8 shifted markedly downfield to 4.60 and 3.42 ppm (Figure S8). Furthermore, the ¹H NMR spectrum exhibits resonances of the methylene protons H–14 and H–23, aliphatic CH₂ groups, and a single signal at 2.03 ppm attributable to the hydroxyl proton.

3. Materials and Methods

Materials and Methods

All reactions were carried out in a dry argon atmosphere. The progress of the reactions was monitored by thin-layer chromatography and ¹H NMR spectroscopy. NMR spectra were measured using and JEOL JNM-ECZL400G (¹H, 400.13 MHz; ¹³C, 100.61 MHz) spectrometer at 298 K. The multiplicities are reported as follows: (s) singlet, (br s) broad singlet, (d) dublet, (dd) dublet of dublets, and (m) multiplet. Mass spectra were measured using a Thermo Scientific (Waltham, MA, USA) LTQ Orbitrap Velos (Orbitrap mass analyzer). Dry and degassed THF was prepared using PureSolv MD7. Silica gel (Merck, (Darmstadt, Germany) silica gel 60, 40–63 μm or Merck, silica gel 60, 63–200 μm) was used for column chromatography. 3-Hydroxypyridine, 10-bromodecan-1-ol and other compounds were purchased from Sigma-Aldrich (St. Louis, MO, USA).

2-((N,N-Dimethylamino)methyl)pyridin-3-yl 4-methylbenzenesulfonate (5)

Sodium hydride (1.577 g, 39.4 mmol, 60% suspension in mineral oil) was added in one portion to a solution of 2-((N,N-dimethylamino)methyl)pyridin-3-ol (6.0 g, 39.4 mmol) in dry THF (100 mL), cooled to 0 °C. Then the resultant mixture was stirred for 1 h at 23 °C. The resultant mixture was again cooled to 0 °C followed by addition of tosyl chloride (7.512 g, 39.4 mmol) in one portion. The mixture was stirred for 16 h at 23 °C. Then the mixture filtrate through cellite pad and the solvents were evaporated under reduced pressure and the title compound was isolated by column chromatography (silica gel, ethyl acetate/methanol 9:1, R_f ≈ 0.2) 9.620 g (80%) as a white solid, m.p. = 53.0–54.8 °C; ¹H NMR (400 MHz, CDCl₃): 8.51 (dd, J = 4.7, 1.5 Hz, 1H, H–6), 7.74 (d, J = 8.4 Hz, 2H, H–10), 7.48 (dd, J = 8.3, 1.5 Hz, 1H, H–4), 7.34 (d, J = 8.1 Hz, 2H, H–11), 7.18 (dd, J = 8.3, 4.7 Hz, 1H, H–5), 3.34 (s, 2H, H–7), 2.45 (s, 3H, H–13), 2.17 (s, 6H, H–8); ¹³C NMR (101 MHz, CDCl₃): δ 152.39 (C–2), 147.87 (C–6), 146.09 (C–12), 145.32 (C–3), 132.53 (C–9), 130.18 (C–11), 130.13 (C–4), 128.56 (C–10), 123.03 (C–5), 59.25 (C–7), 45.68 (C–8), 21.87 (C–13); HR MS (APCI) m/z: [M+H]⁺ Calcd. for C₁₅H₁₈N₂O₃S 307.1111; Found 307.1112.

10-Hydroxy-N,N-dimethyl-N-((3-(tosyloxy)pyridin-2-yl)methyl)decan-1-aminium Bromide (6)

10-Bromodecan-1-ol (1.186 g, 5.0 mmol) was added to a solution of 2-((N,N-dimethylamino)methyl)pyridin-3-yl 4-methylbenzenesulfonate (1.532 g, 5.0 mmol) in dry acetonitrile (40 mL). The resultant mixture was stirred for 16 h at 80 °C. Then the solvent was removed under reduced pressure and column chromatography gave 2.109 g (78%) of the title compound as a light brown oil, which crystallized within 14 days, m.p. = 81.2–83.6. ¹H NMR (400 MHz, CDCl₃): 8.58 (dd, J = 3.9, 2.2 Hz, 1H, H–6), 7.80 (d, J = 8.4 Hz, 2H, C-10), 7.45–7.42 (m, 4H, H–11 and H–5 and H–4), 4.60 (s, 2H), 3.75–3.67 (m, 2H, H–14), 3.60–3.56 (m, 2H, H–23), 3.42 (s, 6H, H–8), 2.48 (s, 3H, H–13), 2.03 (br s, 1H, OH), 1.80–1.75 (m, 2H), 1.57–1.46 (m, 2H), 1.39–1.13 (m, 15H). ¹³C NMR (101 MHz, CDCl₃); 148.37 (C–6), 147.46 (C–12), 146.40 (C–3), 142.89 (C–2), 131.32 (C–4), 131.17 (C–9), 130.81 (C–11), 128.54 (C–10), 126.47 (C–5), 65.49 (C–14), 62.75 (C–23), 60.76 (C–7), 52.18 (C–8), 32.74 (^aliphCH₂), 29.28 (^aliphCH₂), 29.24 (^aliphCH₂), 29.14 (^aliphCH₂), 29.03 (^aliphCH₂), 26.07 (^aliphCH₂), 25.71 (^aliphCH₂), 22.99 (^aliphCH₂), 22.05 (C–13). HR MS (APCI) m/z: [M+H]⁺ Calcd. for C₂₅H₃₈N₂O₄S 463.2625; Found 463.2623.

4. Conclusions

A new and efficient procedure for the preparation of 10-hydroxy-N,N-dimethyl-N-((3-(tosyloxy)pyridin-2-yl)methyl)decan-1-aminium bromide (6) has been developed. The synthetic route involves tosylation of 2-((N,N-dimethylamino)methyl)pyridin-3-ol (5) with tosyl chloride in the presence of sodium hydride as a base, followed by alkylation of the resulting ((N,N-dimethylamino)methyl)pyridin-3-yl 4-methylbenzenesulfonate (5) with 10-bromodecan-1-ol in acetonitrile at 80 °C. The structures of intermediates and final products 5 and 6 were unambiguously confirmed by ¹H and ¹³C NMR spectroscopy, including 2D experiments (¹H–¹H COSY, ¹H–¹³C HMBC, ¹H–¹³C HMQC).