A One-Pot Approach to Pyridyl Isothiocyanates from Amines

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.

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.

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 (pK_a), for example, the substrate 1g reacted with CS₂ in the presence of DABCO (pK_a 8.7) and Et₃N (pK_a 10.7), but it did not in the presence of pyridine (pK_a 5.4) and Proton Sponge™ (pK_a 12.1). The pK_a 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 pK_ip [30], which refers to the equilibrium between the base and the acid with the H-bonded ion pair, and found that the pK_ip values are inconsistent with their corresponding pK_a values [31].

Table 1. Optimization of reaction conditions for the synthesis of 2-chloro-5-isothiocyanatopyridine ^a.

Entry	Solvent	Base	PKa b	PKip c	Conversion of 1g (%)	Overall Yield (%)
1	THF	K2CO3	10.3		31	11
2	THF	KOH	15.7		46	25
3	THF	pyridine	5.4	2.2	0	trace
4	THF	Proton sponge	12.1		0	trace
5	THF	Et3N	10.7	2.1	85	77
6	THF	t-BuOK	29.0		78	trace
7	THF	DABCO	8.7	0.8	100	96
8	THF	DBU	11.6	−3.8	100	90
9	THF	DMAP	9.9	0.61	100	90
10	DMF	DABCO			95	87
11	acetone	DABCO			86	70
12	MeCN	DABCO			84	70
13	EtOH	DABCO			0	trace
14	CH2Cl2	DABCO			60	48

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. pK_ip = −logK_ip [30].

Table 1. Optimization of reaction conditions for the synthesis of 2-chloro-5-isothiocyanatopyridine ^a.

Entry	Solvent	Base	PKa b	PKip c	Conversion of 1g (%)	Overall Yield (%)
1	THF	K2CO3	10.3		31	11
2	THF	KOH	15.7		46	25
3	THF	pyridine	5.4	2.2	0	trace
4	THF	Proton sponge	12.1		0	trace
5	THF	Et3N	10.7	2.1	85	77
6	THF	t-BuOK	29.0		78	trace
7	THF	DABCO	8.7	0.8	100	96
8	THF	DBU	11.6	−3.8	100	90
9	THF	DMAP	9.9	0.61	100	90
10	DMF	DABCO			95	87
11	acetone	DABCO			86	70
12	MeCN	DABCO			84	70
13	EtOH	DABCO			0	trace
14	CH2Cl2	DABCO			60	48

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. pK_ip = −logK_ip [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 (pK_ip 2.1) and DABCO (pK_ip 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.

Entry	Amines	Product	CS2 (equiv)	Time (h) b	Overall Yield (%)
1	R = H	4a	3	4	87
2	R = Me	4b	3	4	88
3	R = F	4c	3	12	76
4	R = Cl	4d	10	12	81
5	R = Br	4e	10	12	83
6	R = CF3	4f	20	24	42
7		4g	3	4	96
8		4h	3	2	91
9		4i	10	12	73
10	R = CN	4j	4	12	87
11	R = NO2	4k	5	24	77
12	R = CF3	4l	4	12	85
13		4m	4	12	66

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.

Table 2. Preparation of aromatic ITCs ^a.

Entry	Amines	Product	CS2 (equiv)	Time (h) b	Overall Yield (%)
1	R = H	4a	3	4	87
2	R = Me	4b	3	4	88
3	R = F	4c	3	12	76
4	R = Cl	4d	10	12	81
5	R = Br	4e	10	12	83
6	R = CF3	4f	20	24	42
7		4g	3	4	96
8		4h	3	2	91
9		4i	10	12	73
10	R = CN	4j	4	12	87
11	R = NO2	4k	5	24	77
12	R = CF3	4l	4	12	85
13		4m	4	12	66

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.

Entry	Amine	Product	Overall Yield (%)
1	R1 = H, R2 = CN	4n	51
2	R1 = H, R2 = NO2	4o	31
3	R1 = H, R2 = CO2Me	4p	63
4	R1 = Cl, R2 = Cl	4q	77
5	R1 = Cl, R2 = H	4r	84
6	R1 = F, R2 = H	4s	72
7		4t	49

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.

Table 3. Preparation of highly electron-deficient pyridyl ITCs ^a.

Entry	Amine	Product	Overall Yield (%)
1	R1 = H, R2 = CN	4n	51
2	R1 = H, R2 = NO2	4o	31
3	R1 = H, R2 = CO2Me	4p	63
4	R1 = Cl, R2 = Cl	4q	77
5	R1 = Cl, R2 = H	4r	84
6	R1 = F, R2 = H	4s	72
7		4t	49

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 4a–m

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 4n–t

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, ¹J_C-F = 253.3Hz), 141.14 (d, ⁴J_C-F = 2.7Hz), 139.59 (NCS), 137.98 (d, ²J_C-F = 26.3 Hz), 126.71 (d, ²J_C-F = 20.6 Hz), 121.57 (d, ³J_C-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, ³J_C-F = 4.1 Hz), 144.58 (NCS), 135.95 (q, ³J_C-F = 3.4 Hz), 124.89 (q, ²J_C-F = 33.7 Hz), 122.98 (q, ¹J_C-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, ²J_C-F = 32.9 Hz), 126.76 (q, ³J_C-F = 3.7 Hz), 125.92, 123.55 (q, ¹J_C-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, ¹J_C-F = 262.7 Hz), 144.90 (NCS), 144.40 (d, ³J_C-F = 5.8 Hz), 134.95 (d, ²J_C-F = 13.3 Hz), 124.13 (d, ²J_C-F = 16.8 Hz), 123.19 (d, ⁴J_C-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.