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Article

A One-Pot Approach to Pyridyl Isothiocyanates from Amines

Department of Applied Chemistry, College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(9), 13631-13642; https://doi.org/10.3390/molecules190913631
Submission received: 9 August 2014 / Revised: 27 August 2014 / Accepted: 28 August 2014 / Published: 2 September 2014
(This article belongs to the Section Organic Chemistry)

Abstract

:
A one-pot preparation of pyridyl isothiocyanates (ITCs) from their corresponding amines has been developed. This method involves aqueous iron(III) chloride-mediated desulfurization of a dithiocarbamate salt that is generated in situ by treatment of an amine with carbon disulfide in the present of DABCO or sodium hydride. The choice of base is of decisive importance for the formation of the dithiocarbamate salts. This one-pot process works well for a wide range of pyridyl ITCs. Utilizing this protocol, some highly electron-deficient pyridyl and aryl ITCs are obtained in moderate to good yields.

Graphical Abstract

1. Introduction

Isothiocyanates (ITCs) constitute an important class of natural products that are abundant in many cruciferous vegetables [1]. ITCs have versatile biological activities, ranging from anticancer and chemoprotective properties [2,3,4] to agrochemical activities [5,6,7], and they are also useful intermediates for the synthesis of various sulfur- and nitrogen-containing organic compounds [8], especially for heterocycles [9,10,11,12].
Numerous methods for preparing ITCs have been developed using different starting materials such as amines [13,14,15,16,17,18,19], tertiary alcohols [20], halides [21,22], nitrile oxides [23], azides [5], isocyanides [24,25]. Among these starting materials, amines are usually employed because of their broad availability and versatility. Most reported methods are highly effective for the synthesis of alkyl and electron-rich aryl ITCs, but their applicability to pyridyl-substituted ITCs is limited due to the lower nucleophilicity of pyridyl amines. In fact, the synthesis of ITCs from pyridyl amines proved to be more difficult than that from aryl amines.
There are two main methods to convert substituted aminopyridines into the corresponding ITC analogue (Scheme 1). The most well-known method is based on thiophosgene [9], and later refinements of ‘thiocarbonyl transfer’ reagents such as thiocarbonyl-diimidazole [26] and dipyridyl-thionocarbonate [27]. The high toxicity and incompatability of thiophosgene with many functional groups limit its general use, furthermore, these ‘thiocarbonyl transfer’ reagents are not readily available and often do not work as desired due to the formation of thiourea byproducts. Another two-step approach, based on reagent-promoted decomposition of dithiocarbamate salts into ITCs, was first reported by Le Count [28] in 1977. The intermediate dithiocarbamate salts are generated by treatment of amines with carbon disulfide and Et3N. Although some desulfurylating reagents for this approach were developed [17,28], the first step, preparing the N-pyridyldithiocarbamate salts, was often neglected. Most of these methods are efficient only for electron-rich pyridyl ITCs, because electron-deficient aminopyridines lack enough reactivity to form dithiocarbamate salts, which results in low yield or excess (hundredfold) use of carbon disulfide. Thus, so far few efficient and general methods have been reported for the preparation of pyridyl ITCs, especially for those with highly electron-withdrawing groups. Therefore, research into an improved method for pyridyl ITCs, which can be used for a broad range of substituents, remains a topic of considerable interest.
Scheme 1. Methods for conversion of amines to pyridyl ITCs.
Scheme 1. Methods for conversion of amines to pyridyl ITCs.
Molecules 19 13631 g001

2. Results and Discussion

In Le Count’s work, iron(III) chloride has been proved to be effective for the decomposition of dithiocarbamate salts, but the preparation of N-pyridyldithiocarbamate salts was seldom investigated, so it became crucial for us to improve their preparation, because once the dithicarbamates were obtained, the desulfurylation step proceeded smoothly [13,16]. In the initial study, 3-amino-6-chloropyridine (1g) was chosen as a model substrate to prepare ITCs in a one-pot process (Table 1). At first, the effect of various bases was evaluated by performing the model reaction in tetrahydrofuran (entries 1–9). When inorganic bases (K2CO3, KOH) and organic bases like 1,8-bis(dimethylamino)naphthalene (Proton Sponge™) or pyridine were employed, the conversion of 1g was rather low, even after 12 h, giving less than 30% of 4g (entries 1–4). When triethylamine and potassium tert-butoxide was used, the conversion was significantly improved after 12 h (entries 5–6), however, a large amount of thiourea was formed in the case of t-BuOK. To our delight, when 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP) or 1,4-diazabicyclo[2.2.2]octane (DABCO) were used as base, the conversion was complete within 4 h and 4g was obtained in excellent yield (entries 7–9). The results was summarized in Table 1 and could not be explained by the strength of the base (pKa), for example, the substrate 1g reacted with CS2 in the presence of DABCO (pKa 8.7) and Et3N (pKa 10.7), but it did not in the presence of pyridine (pKa 5.4) and Proton Sponge™ (pKa 12.1). The pKa values for protonated base are determined in polar solvents (water, MeCN, DMSO), in which they are dissociated as free ions [29]. However, THF is a nonpolar solvent and has a low dielectric constant, thus, the corresponding ammonium salts in nonpolar solvents are present entirely as ion pairs rather than free ions. To measure ion pairs basicity of some amines in THF, Streitwieser introduced the concept of pKip [30], which refers to the equilibrium between the base and the acid with the H-bonded ion pair, and found that the pKip values are inconsistent with their corresponding pKa values [31].
Table 1. Optimization of reaction conditions for the synthesis of 2-chloro-5-isothiocyanatopyridine a.
Molecules 19 13631 i001
Table 1. Optimization of reaction conditions for the synthesis of 2-chloro-5-isothiocyanatopyridine a.
Molecules 19 13631 i001
EntrySolventBasePKa bPKip cConversion of 1g (%)Overall Yield (%)
1THFK2CO310.3 3111
2THFKOH15.7 4625
3THFpyridine5.42.20trace
4THFProton sponge12.1 0trace
5THFEt3N10.72.18577
6THFt-BuOK29.0 78trace
7THFDABCO8.70.810096
8THFDBU11.6−3.810090
9THFDMAP9.90.6110090
10DMFDABCO 9587
11acetoneDABCO 8670
12MeCNDABCO 8470
13EtOHDABCO 0trace
14CH2Cl2DABCO 6048
Notes: a Reaction conditions: 1g (1 equiv), CS2 (3 equiv), base (2 equiv), solvent, r.t.; FeCl3·6H2O (2 equiv), r.t., 1 h; b The dissociation constant of the protonated base in water. Values were collected from refs [32,33]; c The equilibrium between the base and acidic indicator hydrocarbons InH with the H-bonded ion pairs. pKip = −logKip [30].
A possible mechanism for the formation of pyridyl dithiocarbamate salts is proposed in Scheme 1. The first step, the attack of amine on carbon disulfide to form dithiocarbamic acid, is likely reversible. The driving force of the reaction is most likely the reaction of the dithiocarbamic acid with base to generate the stable dithiocarbamate salts. A greater ion pair basicity corresponds to a tighter ion pair, which facilitates the generation of dithiocarbamates, the ion pair basicities of Et3N (pKip 2.1) and DABCO (pKip 0.8) agree with their observed different reactivity. When we used DABCO as the base, an examination of different solvents showed that THF was the best solvent compared with DMF, acetone, MeCN, EtOH, CH2Cl2 (entries 10–14). Finally, with the optimized conditions for the formation of 2g, we then found that upon addition of aqueous FeCl3 to unpurified 2g in one-pot, complete conversion to 4g was observed in about 1 h at room temperature.
Under the reaction conditions outlined above (Table 1, entry 7), the substrate scope of various aminopyridines was examined next (Table 2). The electronic effect of the substituents has a significant influence on the reaction outcome.
Table 2. Preparation of aromatic ITCs a.
Molecules 19 13631 i002
Table 2. Preparation of aromatic ITCs a.
Molecules 19 13631 i002
EntryAminesProductCS2 (equiv)Time (h) bOverall Yield (%)
Molecules 19 13631 i003 Molecules 19 13631 i004
1R = H4a3487
2R = Me4b3488
Molecules 19 13631 i005 Molecules 19 13631 i006
3R = F4c31276
4R = Cl4d101281
5R = Br4e101283
6R = CF34f202442
7 Molecules 19 13631 i0074g3496
8 Molecules 19 13631 i0084h3291
9 Molecules 19 13631 i0094i101273
Molecules 19 13631 i010 Molecules 19 13631 i011
10R = CN4j41287
11R = NO24k52477
12R = CF34l41285
13 Molecules 19 13631 i0124m41266
Notes: a Reaction conditions: 1 (8.0 mmol), CS2 (excess), DABCO (16.0 mmol), THF (10 mL), r.t.; FeCl3·6H2O (16.0 mmol), r.t., 1 h; b The reaction time for the first step.
For example, aminopyridines containing electron donating groups (Me, OMe) afforded good yields of 87%–91% in a relatively short reaction time (entries 2 and 8). Incidently, the corresponding ITCs from 2-aminopyridine and 2-amino-5-methylpyridine have been obtained as dimers, and such dimers slowly dissociate to monomers in hot organic solvent [34,35]. When the 2- or 4-aminopyridines contained halides (entries 3–5, 9), longer reaction times and more equivalents of CS2 were required to access 2, but the corresponding ITCs were still obtained in moderate to good yields, ranging from 73% to 83%. Meanwhile, the position of the amino group on the pyridine also exerted an influence on the reaction outcome; for example, the overall yield of C6H3ClN2S varies for 2-(3-or 4-)aminopyridines (entries 4, 7, 9), and a greater yield was obtained when the amino group is at the meta position with respect to the nitrogen atom in the pyridine (96%, entry 7). To our delight, several anilines with strong electron-withdrawing groups, such as NO2, CN, and CF3 (entries 10–12), were also smoothly converted into the desired ITCs in 77%–87% yields. The approach also worked well for the five-membered heterocyclic substrate (entry 13). However, the desired ITCs could not be detected when highly electron-deficient aminopyridines (such as those with NO2, CN, CO2Me substituents) were used. Only 5-trifluoromethylpyridyl-2-amine afforded the corresponding ITC in a low yield (42%, entry 6), even after prolonged reaction time and with excess CS2. For halide substituents in the ortho position of the amino group, no corresponding ITCs were observed. Thus, additional investigations are necessary to develop methods for the preparation of some highly electron-deficient pyridyl ITCs.
Table 3. Preparation of highly electron-deficient pyridyl ITCs a.
Molecules 19 13631 i013
Table 3. Preparation of highly electron-deficient pyridyl ITCs a.
Molecules 19 13631 i013
EntryAmineProductOverall Yield (%)
Molecules 19 13631 i014 Molecules 19 13631 i015
1R1 = H, R2 = CN4n51
2R1 = H, R2 = NO24o31
3R1 = H, R2 = CO2Me4p63
4R1 = Cl, R2 = Cl4q77
5R1 = Cl, R2 = H4r84
6R1 = F, R2 = H4s72
7 Molecules 19 13631 i0164t49
Notes: a Reaction conditions: 1 (8.0 mmol), CS2 (32.0 mmol), NaH (9.6 mmol), DMF (8 mL), r.t., 6 h; Et3N (8.0 mmol), FeCl3·6H2O (16.0 mmol), r.t., 1 h.
The observed deficiencies in the synthesis of highly electron-deficient pyridyl ITCs inspired us to further optimize the process. The difficulty in the generation of dithiocarbamates is likely due to the weaker nucleophilicity of these amine substrates. In an effort to improve the reactivity, higher reaction temperatures in a variety of solvents were tested. Using methyl 6-aminonicotinate as a test substrate, we found that after 20 h of reflux in THF or DMF, only trace amounts of the corresponding ITCs were observed. We therefore investigated next the use of the strong base NaH to generate the more nucleophilic amide anions prior to CS2 addition. After testing various solvents, the use of NaH in DMF was found to be the best choice. The amines was treated with NaH in DMF at 0 °C, then CS2 was added, and after 6 h at room temperature, when the amines were fully consumed as monitored by TLC, the reaction mixtures were slowly treated with aqueous FeCl3. Using this process, we were able to obtain reasonable yields of several pyridyl ITCs with strong electron-withdrawing groups, such as NO2, CN, CO2Me, and 3,5-Cl2 (Table 3, entries 1–4, 31%–77% yield). This method was also effective for substrates bearing halide substituents in the ortho position of the amino moiety (entries 5–7, 49%–84% yield).

3. Experimental Section

3.1. General Information

Tetrahydrofuran was redistilled in the presence of sodium/benzophenone. Unless otherwise stated, all reagents were commercially available and were used without purification. TLC was performed on pre-coated silica gel glass plates. Flash column chromatography was performed using flash silica gel (200–300 mesh) (Qingdao Haiyang, Qingdao, China). HPLC analyses were performed on an Agilent 1200 Series instrument (Santa Clara, CA, USA, column: Agilent Eclipse XDB-C18, 5 μm, 4.6 × 150 mm). Melting points were determined using a Stuart melting point apparatus and were uncorrected. 1H- and 13C-NMR spectra were recorded with a 300 MHz spectrometer (Bruker, Fallanden, Switzerland). HRMS and GC-MS were recorded on an Agilent mass spectrometer by the ESI and EI techniques, respectively. All yields given refer to isolated yields.

3.2. General Procedure for the Preparation of Isothiocyanates 4am

To a solution of amine 1 (8.0 mmol) and DABCO (16 mmol) in anhydrous THF (10 mL) was added dropwise a certain amount of CS2. The resulting mixture was stirred at r.t. for several hours until completion by TLC analysis. Then a solution of FeCl3·6H2O (16 mmol) in water (15 mL) was added rapidly to the well suspended dithiocarbamate 2, and stirring was continued for 1 h. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic phase was washed with water (2 × 10 mL), and dried over MgSO4. After removal of the solvent, the product was purified by flash column chromatography (petroleum ether–EtOAc) to give the corresponding ITCs 4.

3.3. General Procedure for the Preparation of Isothiocyanates 4nt

To an ice-cold stirred solution of amine 1 (8.0 mmol) in DMF (8 mL) was added NaH (60% in mineral oil; 9.6 mmol) in two portions. After the evolution of gas from the reaction mixture ceased, CS2 (32 mmol) was added via syringe pump over about 30 min. The resulting mixture was brought up to r.t. and kept for 6 h, then the mixture was cooled on an ice bath. Et3N (8.0 mmol) and a solution of FeCl3·6H2O (16 mmol) in water (15 mL) were successively added to the dithiocarbamate 3. After the additions, the mixture was stirred at r.t. for 1 h. The subsequent operations were the same as the workup in the experimental procedure described above.

3.4. Characterization Data

3-(Pyridin-2-yl)-2H-pyrido[1,2-a][1,3,5]triazine-2,4(3H)-dithione (4a) [34]. The crude product purified by column chromatography (petroleum ether/CHCl3 = 5:1~1:1, v/v), affording the dimer of 2-pyridyl isothiocyanate as a brick-red solid; yield: 0.95 g (3.48 mmol, 87%); m.p. 110.2–111.1 °C (lit. [28] 112 °C); 1H-NMR (CDCl3) δ 9.28–9.25 (m, 1H), 8.68–8.66 (m, 1H), 7.95–7.77 (m, 2H), 7.44–7.30 (m, 3H), 7.01–6.96 (m, 1H); 13C-NMR (CDCl3) δ 179.17 (C=S), 172.26 (C=S), 155.36, 150.34, 146.68, 142.16, 139.03, 132.75, 125.03, 124.14, 123.48, 115.62; HRMS (ESI): m/z [M+H]+ calcd for C12H9N4S2: 273.0269; found: 273.0272.
7-Methyl-3-(5-methylpyridin-2-yl)-2H-pyrido[1,2-a][1,3,5]triazine-2,4(3H)-dithione (4b) [28]. Brick-red solid, purified by column chromatography (petroleum ether/CHCl3 = 5:1~1:1, v/v); yield: 1.06 g (3.52 mmol, 88%); m.p. 137.0–137.4 °C; 1H-NMR (CDCl3) δ 9.10–9.09 (m, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.78–7.61 (m, 2H), 7.29–7.22 (m, 2H), 2.44 (s, 3H), 2.35 (s, 3H); 13C-NMR (CDCl3) δ 179.23 (C=S), 172.37 (C=S), 153.31, 150.60, 145.80, 145.07, 139.66, 134.18, 129.95, 126.01, 124.64, 122.71, 18.29, 18.17; HRMS (ESI): m/z [M+H]+ calcd for C14H13N4S2: 301.0582; found: 301.0585.
5-Fluoro-2-isothiocyanatopyridine (4c). Red solid purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v); yield: 0.94 g (6.08 mmol, 76%); m.p. 21.2–22.4 °C; 1H-NMR (CDCl3) δ 8.28 (d, J = 3.0 Hz, 1H), 7.46 (ddd, J = 8.7, 7.3, 3.0 Hz, 1H), 7.12 (dd, J = 8.7, 3.9 Hz, 1H); 13C-NMR (DMSO-d6) δ 158.03 (d, 1JC-F = 253.3Hz), 141.14 (d, 4JC-F = 2.7Hz), 139.59 (NCS), 137.98 (d, 2JC-F = 26.3 Hz), 126.71 (d, 2JC-F = 20.6 Hz), 121.57 (d, 3JC-F = 5.8 Hz); GC-MS (EI): m/z = 154 [M+].
5-Chloro-2-isothiocyanatopyridine (4d). White solid purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v); yield: 1.10 g (6.48 mmol, 81%); m.p. 43.5–44.5 °C (lit. [28] 41–43 °C); 1H-NMR (CDCl3) δ 8.38 (dd, J = 2.6, 0.5 Hz, 1H), 7.68 (dd, J = 8.5, 2.6 Hz, 1H), 7.05 (dd, J = 8.5, 0.5 Hz, 1H); 13C-NMR (CDCl3) δ 148.77, 144.61, 142.93 (NCS), 138.32, 130.22, 120.21; HRMS (ESI): m/z [M+H]+ calcd for C6H4ClN2S: 170.9784; found: 170.9766.
5-Bromo-2-isothiocyanatopyridine (4e). White solid purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v); yield: 1.42 g (6.64 mmol, 83%); m.p. 73.3–74.2 °C (lit. [28] 74–76 °C); 1H-NMR (CDCl3) δ 8.48 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.4, 2.5 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H); 13C-NMR (CDCl3) δ 151.02, 145.09, 143.00 (NCS), 141.15, 120.69, 118.46; HRMS (ESI): m/z [M + H]+ calcd for C6H4BrN2S: 214.9279; found: 214.9268.
2-Isothiocyanato-5-(trifluoromethyl)pyridine (4f) [36]. Red oil purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v) ; yield: 0.69 g (3.36 mmol, 42%); 1H-NMR (CDCl3) δ 8.73–8.66 (m, 1H), 8.02–7.92 (m, 1H), 7.23–7.20 (m, 1H); 13C-NMR (CDCl3) δ 149.69, 147.19 (q, 3JC-F = 4.1 Hz), 144.58 (NCS), 135.95 (q, 3JC-F = 3.4 Hz), 124.89 (q, 2JC-F = 33.7 Hz), 122.98 (q, 1JC-F = 270.7 Hz), 119.07; HRMS (ESI): m/z [M+H]+ calcd for C7H4F3N2S: 205.0047; found: 205.0047.
2-Chloro-5-isothiocyanatopyridine (4g) [37]. White solid purified by column chromatography (petroleum ether/EtOAc = 20:1, v/v); yield: 1.31 g (7.68 mmol, 96%); m.p. 56.0–57.9 °C; 1H-NMR (CDCl3) δ 8.31 (dd, J = 2.7, 0.7 Hz, 1H), 7.51 (dd, J = 8.5, 2.7 Hz, 1H), 7.35 (dd, J = 8.5, 0.7 Hz, 1H); 13C-NMR (CDCl3) δ 148.53, 146.29, 140.14 (NCS), 134.76, 128.41, 124.66; HRMS (ESI): m/z [M+H]+ calcd for C6H4ClN2S: 170.9784; found: 170.9784.
4-Isothiocyanato-2-methoxypyridine (4h). White solid purified by column chromatography (petroleum ether/EtOAc = 20:1, v/v); yield: 1.21 g (7.28 mmol, 91%); m.p. 32.4–33.5 °C; 1H-NMR (CDCl3) δ 8.12 (d, J = 5.5 Hz, 1H), 6.71 (dd, J = 5.5, 1.8 Hz, 1H), 6.52 (d, J = 1.8 Hz, 1H), 3.93 (s, 3H); 13C-NMR (CDCl3) δ 165.28, 148.18, 141.40, 139.83 (NCS), 113.79, 106.78, 53.75; HRMS (ESI): m/z [M+H]+ calcd for C7H7N2OS: 167.0279; found: 167.0273.
2-Chloro-4-isothiocyanatopyridine (4i) [17]. White solid purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v); yield: 0.99 g (5.84 mmol, 73%); m.p. 44.0–44.9 °C, 1H-NMR (CDCl3) δ 8.37 (dd, J = 5.4, 0.6 Hz, 1H), 7.16 (dd, J = 1.8, 0.6 Hz, 1H), 7.04 (dd, J = 5.4, 1.8 Hz, 1H); 13C-NMR (DMSO-d6) δ 151.47, 151.27, 141.03, 139.32 (NCS), 120.80, 120.11; HRMS (ESI): m/z [M+H]+ calcd for C6H4ClN2S: 170.9784; found: 170.9806.
4-Isothiocyanatobenzonitrile (4j). White solid purified by column chromatography (petroleum ether/EtOAc = 20:1, v/v); yield: 1.11 g (6.96 mmol, 87%); m.p. 121.4–122.5 °C (lit. [16] 121–122 °C); 1H-NMR (CDCl3) δ7.67 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H); 13C-NMR (CDCl3) δ 139.73 (NCS), 136.05, 133.55, 126.39, 117.79, 110.62; HRMS (ESI): m/z [M+H]+ calcd for C8H5N2S: 161.0173; found: 161.0158.
1-Isothiocyanato-4-nitrobenzene (4k). White solid purified by column chromatography (petroleum ether/EtOAc = 20:1, v/v); yield: 1.11 g (6.16 mmol, 77%); m.p. 109.4–110.2 °C (lit. [18] 108–109 °C); 1H-NMR (CDCl3) δ 8.25 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H); 13C-NMR (CDCl3) δ 145.80, 140.31 (NCS), 137.90, 126.32, 125.23; HRMS (ESI): m/z [M+H]+ calcd for C7H5N2O2S: 181.0072; found: 181.0054.
1-Isothiocyanato-4-(trifluoromethyl)benzene (4l). White solid purified by column chromatography (petroleum ether/EtOAc = 20:1, v/v); yield: 1.38 g (6.80 mmol, 85%); m.p. 40.1–41.2 °C (lit. [16] 40–41 °C); 1H-NMR (CDCl3) δ 7.61 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H); 13C-NMR (CDCl3) δ 138.47 (NCS), 135.00, 129.05 (q, 2JC-F = 32.9 Hz), 126.76 (q, 3JC-F = 3.7 Hz), 125.92, 123.55 (q, 1JC-F = 270.7 Hz); GC-MS (EI): m/z = 203 [M+].
Ethyl 2-isothiocyanato-4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carboxylate (4m). Yellow solid purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 1.41 g (5.28 mmol, 66%); m.p. 45.3–45.7 °C (lit. [17] 45–46 °C); 1H-NMR (CDCl3) δ 4.34 (q, J = 7.1 Hz, 2H), 2.77 (t, J = 5.7 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 1.83–1.76 (m, 4H), 1.40 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3) δ 161.89, 137.33 (NCS), 134.72, 132.55, 131.96, 126.49, 60.66, 26.07, 24.88, 22.62, 22.21, 14.35; GC-MS (EI): m/z = 267 [M+].
6-Isothiocyanatonicotinonitrile (4n). Yellow solid purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 0.66 g (4.08 mmol, 51%); m.p. 68.3–69.5 °C; 1H-NMR (CDCl3) δ 8.72 (dd, J = 2.3, 0.8 Hz, 1H), 7.99 (dd, J = 8.3, 2.3 Hz, 1H), 7.18 (dd, J = 8.3, 0.8 Hz, 1H); 13C-NMR (CDCl3) δ 153.14, 149.86, 145.93 (NCS), 141.78, 119.30, 115.85, 107.82; HRMS (ESI): m/z [M+H]+ calcd for C7H4N3S: 162.0126; found: 162.0109.
2-Isothiocyanato-5-nitropyridine (4o). Yellow solid purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 0.45 g (2.48 mmol, 31%); m.p. 50.3–51.0 °C; 1H-NMR (CDCl3) δ 9.27 (d, J = 2.8 Hz, 1H), 8.51 (dd, J = 8.7, 2.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H); 13C-NMR (CDCl3) δ 151.57, 146.46, 146.06, 142.11 (NCS), 134.07, 119.08; HRMS (ESI): m/z [M+H]+ calcd for C6H4N3O2S: 182.0024; found: 182.0019.
Methyl 6-isothiocyanatonicotinate (4p). White solid purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 0.98 g (5.04 mmol, 63%); m.p. 87.2–88.2 °C; 1H-NMR (CDCl3) δ 9.03 (dd, J = 2.3, 0.8 Hz, 1H), 8.31 (dd, J = 8.3, 2.3 Hz, 1H), 7.15 (dd, J = 8.3, 0.8 Hz, 1H), 3.96 (s, 3H); 13C-NMR (CDCl3) δ 164.62, 151.51, 149.80, 143.86 (NCS), 139.76, 124.34, 118.96, 52.46; HRMS (ESI): m/z [M+H]+ calcd for C8H7N2O2S: 195.0228; found: 195.0263.
3,5-Dichloro-2-isothiocyanatopyridine (4q). White solid purified by column chromatography (petroleum ether/EtOAc = 15:1, v/v); yield: 1.26 g (6.16 mmol, 77%); m.p. 51.5–52.6 °C; 1H-NMR (CDCl3) δ 8.27 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H); 13C-NMR (CDCl3) δ 146.37, 144.32 (NCS), 142.07, 137.92, 129.92, 127.89; HRMS (ESI): m/z [M+H]+ calcd for C6H3Cl2N2S: 204.9394; found: 204.9374.
3-Chloro-2-isothiocyanatopyridine (4r). White oil purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 1.14 g (6.72 mmol, 84%); 1H-NMR (CDCl3) δ 8.32 (dd, J = 4.7, 1.6 Hz, 1H), 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.21 (dd, J = 8.0, 4.7 Hz, 1H); 13C-NMR (CDCl3) δ 147.36, 143.36, 142.91 (NCS), 138.37, 127.65, 122.82; HRMS (ESI): m/z [M+H]+ calcd for C6H4ClN2S: 170.9784; found: 170.9775.
3-Fluoro-2-isothiocyanatopyridine (4s). Red oil purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 0.89 g (5.76 mmol, 72%); 1H-NMR (CDCl3) δ 8.11–8.09 (m, 1H), 7.46–7.40 (m, 1H), 7.20–7.15 (m, 1H); 13C-NMR (CDCl3) δ 153.85 (d, 1JC-F = 262.7 Hz), 144.90 (NCS), 144.40 (d, 3JC-F = 5.8 Hz), 134.95 (d, 2JC-F = 13.3 Hz), 124.13 (d, 2JC-F = 16.8 Hz), 123.19 (d, 4JC-F = 3.0 Hz); HRMS (ESI): m/z [M+H]+ calcd for C6H4FN2S: 155.0079; found: 155.0051.
3-Chloro-4-isothiocyanatopyridine (4t). White solid purified by column chromatography (petroleum ether/EtOAc = 10:1, v/v); yield: 0.67 g (3.92 mmol, 49%); m.p. 30.4–31.5 °C; 1H-NMR (CDCl3) δ 8.62 (d, J = 0.5 Hz, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.11 (dd, J = 5.2, 0.5 Hz, 1H); 13C-NMR (CDCl3) δ 150.36, 148.81, 143.11 (NCS), 137.78, 128.99, 120.14; HRMS (ESI): m/z [M+H]+ calcd for C6H4ClN2S: 170.9784; found: 170.9771.

4. Conclusions

In summary, we have developed a facile and environmentally friendly method for the preparation of various pyridyl ITCs from amines via a one-pot process. In comparison to existing methods, our procedure for the synthesis of highly electron-deficient pyridyl ITCs without using dangerous thiophosgene is simple yet efficient. The employed reagents are inexpensive and of low toxicity and the procedure is operationally simple, affording a wide range of pyridyl ITCs in moderate to excellent yields. Based on these characteristics, we envision that this method will be useful to the synthetic community.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/19/9/13631/s1.

Supplementary Files

Supplementary File 1

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 21172256), the National Basic Research Program of China (No. 2010CB126104), the National S&T Pillar Program of China (No. 2012BAK25B03) and China Agriculture University Scientific Fund (No. 2013YJ010).

Author Contributions

Hao Zhang and Shang-Zhong Liu conceived of this study and carried out most of compounds synthesis as well as manuscript preparation. Rui-Quan Liu, Ke-Chang Liu participated in compounds synthesis. Qi-Bo Li and Qing-Yang Li assisted in characterization experiments. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 4at are available from the authors.

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MDPI and ACS Style

Zhang, H.; Liu, R.-Q.; Liu, K.-C.; Li, Q.-B.; Li, Q.-Y.; Liu, S.-Z. A One-Pot Approach to Pyridyl Isothiocyanates from Amines. Molecules 2014, 19, 13631-13642. https://doi.org/10.3390/molecules190913631

AMA Style

Zhang H, Liu R-Q, Liu K-C, Li Q-B, Li Q-Y, Liu S-Z. A One-Pot Approach to Pyridyl Isothiocyanates from Amines. Molecules. 2014; 19(9):13631-13642. https://doi.org/10.3390/molecules190913631

Chicago/Turabian Style

Zhang, Hao, Rui-Quan Liu, Ke-Chang Liu, Qi-Bo Li, Qing-Yang Li, and Shang-Zhong Liu. 2014. "A One-Pot Approach to Pyridyl Isothiocyanates from Amines" Molecules 19, no. 9: 13631-13642. https://doi.org/10.3390/molecules190913631

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