Sage Journals: Discover world-class research

Abstract

A Selectfluor-initiated cyanation of disulfides to thiocyanates has been developed. In this process, Selectfluor was employed as the oxidant and trimethylsilyl cyanide was used as the cyanation reagent. It provides an eco-friendly and simple way to synthesize the thiocyanates.

Keywords

cyanation disulfide Selectfluor thiocyanates

A simple, efficient, and green procedure for the synthesis of thiocyanates prompted by Selectfluor was developed.

Introduction

Thiocyanates are very useful synthetic building blocks¹ since thiocyano groups widely exist in natural products and pharmaceutical ingredients.² Importantly, thiocyano groups can be converted to other useful sulfur-containing functional groups.^3–9 Thus, the introduction of thiocyano groups is of great importance. Much effort has been made toward the synthesis of thiocyanates so far. Generally, thiocyanates can be synthesized via the following two major routes (Scheme 1(a)): (1) thiocyanation of organic partners (arenes, organic halides, diazonium salts, and arylboronic acids) in the presence of inorganic thiocyanates^10–15 and (2) cyanation of organosulfur compounds including thiols, disulfides, and sulfinates with electrophilic and nucleophilic cyanation reagents.^16–20 Thiocyanates can also be prepared via CuCN-mediated direct aerobic oxidative cyanation of thiophenols and diaryl disulfides.²¹ While acknowledging the pioneering work in this field, the aforementioned methods still have some drawbacks. For example, the electrophilic thiocyanation process usually requires the use of (SCN)₂ or XSCN (X = halogen), which is highly unstable and toxic.²² Although the combination of N-chlorosuccinimide (NCS)/NH₄SCN was shown to be a good alternative thiocyanating reagent, the substrate scope was limited.¹² For the cyanation process, the thiol derivatives are usually odorous and some cyanating reagents such as hypervalent iodine-based reagents^20,23 are either toxic or expensive. In some cases, metal catalysts or bases were necessary.^19,20,23 Moreover, the selective cyanation of both aromatic and aliphatic thiol derivatives has been rarely reported. Thus, a user-friendly, operationally simple, and efficient procedure for the synthesis of thiocyanates is still highly desirable.

Scheme 1.

Synthetic methods for the synthesis of thiocyanates.

Herein, we wish to report a simple, efficient, and user-friendly protocol for the synthesis of thiocyanates (Scheme 1(b)). This reaction proceeded through cyanation of disulfides using Selectfluor as the oxidant and trimethylsilyl cyanide (TMSCN) as the less toxic cyanation reagent. Both aromatic and aliphatic disulfides survived the reaction conditions.

Results and discussion

Initially, we started to optimize the reaction conditions using diphenyldisulfide 1a as the model substrate and TMSCN as the cyanating reagent in acetonitrile at 80 °C (Table 1). The tentative reaction in the presence of TMSCN (1.0 equiv.) and Selectfluor (1.5 equiv.) gave the desired product 2a in 24% yield (entry 1). The amount of TMSCN and Selectfluor significantly affect the yield. Further study showed that a 93% yield was obtained while using 3.0 equiv. of TMSCN and 2.0 equiv. of Selectfluor (entry 5). Different oxidants were then evaluated (entries 6–11). The results showed that N-fluorobis(benzenesulfonyl)imide (NFSI) was as efficient as Selectfluor (entry 6, 86%). However, the use of other oxidants such as diethylaminosulfur trifluoride (DAST), oxone, K₂S₂O₈, NCS, and PhI(OAc)₂ failed to provide the desired product. The solvent also had a significant influence on the reaction (entries 12–15). The reaction in dimethylformamide (DMF) delivered 2a in 16% yield. However, only trace amount of the desired product was observed when reaction was carried out either in dimethylsulfoxide (DMSO), EtOAc, or 1,4-dioxane. Finally, the reaction temperature was checked. It was found that the reaction at lower temperature (60 °C) gave a lower yield (81%), while raising the temperature to 100 °C had little effect on the reaction.

Table 1.

Optimization of reaction conditions.^a

Entry	TMSCN (equiv.)	Oxidant (equiv.)	Solvent	Temperature (°C)	Yield (%)^b
1	1.0	Selectfluor (1.5)	MeCN	80	24
2	2.0	Selectfluor (1.5)	MeCN	80	67
3	3.0	Selectfluor (1.5)	MeCN	80	85
4	3.0	Selectfluor (1.0)	MeCN	80	74
5	3.0	Selectfluor (2.0)	MeCN	80	93
6	3.0	NFSI (2.0)	MeCN	80	86
7	3.0	DAST (2.0)	MeCN	80	0
8	3.0	Oxone (2.0)	MeCN	80	0
9	3.0	K₂S₂O₈ (2.0)	MeCN	80	0
10	3.0	NCS (2.0)	MeCN	80	0
11	3.0	PhI(OAc)₂ (2.0)	MeCN	80	0
12	3.0	Selectfluor (2.0)	DMF	80	16
13	3.0	Selectfluor (2.0)	DMSO	80	Trace
14	3.0	Selectfluor (2.0)	EtOAc	80	Trace
15	3.0	Selectfluor (2.0)	1,4-dioxane	80	Trace
16	3.0	Selectfluor (2.0)	MeCN	60	81
17	3.0	Selectfluor (2.0)	MeCN	100	94

TMSCN: trimethylsilyl cyanide; NFSI: N-fluorobis(benzenesulfonyl)imide; DAST: diethylaminosulfur trifluoride; NCS: N-chlorosuccinimide.

Reaction conditions: 1a (0.2 mmol), TMSCN, oxidant, solvent (2 mL), 4 h.

Isolated yield.

To evaluate the scope and limitations of this protocol, a series of disulfides were tested under the optimized reaction conditions. The results are summarized in Table 2. In general, all the reactions proceeded smoothly to give the corresponding products in good yields (65%–93%). Aromatic disulfides bearing both electron-withdrawing and electron-donating groups showed good activities. Steric hindrance was also examined and ortho-substituted disulfides gave slightly lower yields. Notably, 4,4′-disulfanediyldiphenol (1d) survived the reaction conditions to give the desired product 2d in moderate yield (entry 4). Nitro-substituted disulfides 1h and 1l also reacted with TMSCN smoothly, affording the corresponding products in good yields. 2,2′-Dipyridyl disulfide (1n) worked well under the standard conditions to provide 2n in 71% yield. Particularly, alkyl disulfides also reacted well, and good yields were obtained (entries 15 and 16).

Table 2.

Reaction scope.^a

Entry	R	Product	Yield (%)^b
1	C₆H₅	2a	93
2	4-CH₃C₆H₄	2b	86
3	4-CH₃OC₆H₄	2c	84
4	4-OHC₆H₄	2d	65
5	4-ClC₆H₄	2e	88
6	4-BrC₆H₄	2f	85
7	4-MeO₂CC₆H₄	2g	86
8	4-NO₂C₆H₄	2h	84
9	2-CH₃C₆H₄	2i	81
10	2-ClC₆H₄	2j	78
11	3-ClC₆H₄	2k	83
12	3-NO₂C₆H₄	2l	82
13	2-Naphthyl	2m	89
14	2-Pyridinyl	2n	71
15	Benzyl	2o	79
16	Cyclohexyl	2p	72

Reaction conditions: 1 (0.2 mmol), TMSCN (3.0 equiv.), Selectfluor (2.0 equiv.), MeCN (2 mL), 80 °C, 4 h.

Isolated yield.

Some control experiments were then conducted to gain some insight into the reaction (Scheme 2). No product 2a was observed when the reaction was carried out in the absence of Selectfluor (Scheme 2, equation (1)). When 3 equiv. of the radical scavenger 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) was added to the reaction, no desired product was detected. Instead, 1-cyanato-2,2,6,6-tetramethylpiperidine (3) was observed by gas chromatography–mass spectrometry (GC-MS), indicating a radical pathway might be involved (Scheme 2, equation (2)). Considering that disulfide might be attacked by CN anion, 1 equiv. of KF was used alone, however, only trace amount of the desired product was observed (Scheme 2, equation (3)).

Scheme 2.

Control experiments.

Based on the above results, a mechanism is tentatively proposed (Scheme 3). Initially, Selectfluor obtains an electron from the disulfide to release the sulfur radical 4, nitrogen radical cation 5, and the fluoride anion.^24,25 The resulting fluoride anion can promote the generation of the CN⁻ nucleophile from TMSCN.²¹ Next, the CN anion can be oxidized by the nitrogen radical cation 5 to deliver a CN radical and 6. The CN radical then attacks the sulfur radical 4 to give the cyano sulfoniums 7, which reacts with 6 to provide the final product 3 and compound 8.

Scheme 3.

Proposed mechanism.

Conclusion

In summary, we have developed a simple and efficient procedure for cyanation of disulfides to thiocyanates. In this process, Selectfluor was employed as the oxidant and trimethylsilyl cyanide was used as the green cyanation reagent. A series of aromatic disulfides survived the reaction conditions to give the corresponding products in good yields. Notably, alkyl disulfides are tolerated well. The control experiments also showed that a radical pathway might be involved in this reaction.

Experiment

General

All of the reagents and solvents are commercially available and were used without further purification. Disulfides 1f, 1j, and 1k were purchased from Hubei Jusheng Technology Co., Ltd. Disulfides 1g and 1i were supplied by Jiangsu Aikon Biopharmaceutical R&D Co., Ltd. Other disulfides were purchased from Sigma Aldrich Corporation (Shanghai, China). Melting points were determined with a WRS-1B apparatus and were uncorrected. ¹H NMR spectra were recorded in CDCl₃ using a Bruker Avance III 400-MHz spectrometer. The GC-MS analyses were performed on a Thermo Scientific equipment. All the products are known compounds and their spectroscopic data are in accordance with those previously presented.

Typical procedure for the synthesis of 2a

A mixture of disulfide 1a (44 mg, 0.2 mmol), TMSCN (74 μL, 0.6 mmol), Selectfluor (142 mg, 0.4 mmol) was added to acetonitrile (2 mL). The mixture was stirred at 80 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with EtOAc (3 × 5 mL). The organic layer was concentrated and the resulting crude product was further purified by silica gel column chromatography to provide 2a in 93% (25 mg) yield.

Characterization data

Thiocyanatobenzene (2a)

Yield: 25 mg (93%); yellowish liquid.^20
¹H NMR (400 Hz, CDCl₃): δ 7.41–7.46 (m, 3H), 7.52–7.55 (m, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 110.5, 124.3, 129.5, 130.0, 130.2. MS (EI) m/z: 135 [M⁺].

1-Methyl-4-thiocyanatobenzene (2b)

Yield: 26 mg (86%); yellowish liquid.^20
¹H NMR (400 Hz, CDCl₃): δ 7.41–7.43 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 2.38 (s, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 21.1, 111.0, 120.5, 130.7, 130.9, 140.2. MS (EI) m/z: 149 [M⁺].

1-Methoxy-4-thiocyanatobenzene (2c)

Yield: 28 mg (84%); yellowish liquid.^20
¹H NMR (400 Hz, CDCl₃): δ 7.47–7.51 (m, 2H), 6.92–6.97 (m, 2H), 3.82 (s, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 55.5, 111.6, 113.7, 115.8, 133.8, 161.2. MS (EI) m/z: 165 [M⁺].

4-Thiocyanatophenol (2d)

Yield: 20 mg (65%); red liquid.^21
¹H NMR (400 Hz, CDCl₃): δ 7.42–7.47 (m, 2H), 6.86–6.91 (m, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 112.1, 113.4, 117.4, 134.2, 158.0. MS (EI) m/z: 151 [M⁺].

1-Chloro-4-thiocyanatobenzene (2e)

Yield: 30 mg (88%); yellowish liquid.^21
¹H NMR (400 Hz, CDCl₃): δ 7.46–7.48 (m, 2H), 7.40–7.43 (m, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 110.0, 122.7, 130.4, 131.4, 136.2. MS (EI) m/z: 169 [M⁺].

1-Bromo-4-thiocyanatobenzene (2f)

Yield: 36 mg (85%); yellowish liquid.^23
¹H NMR (400 Hz, CDCl₃): δ 7.48–7.52 (m, 2H), 7.31–7.35 (m, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 109.8, 123.4, 124.1, 131.4, 133.4. MS (EI) m/z: 213 [M⁺].

Methyl 4-thiocyanatobenzoate (2g)

Yield: 33 mg (86%); white solid; m.p.: 65–66 °C.^24
¹H NMR (400 Hz, CDCl₃): δ 8.07−8.12 (m, 2H), 7.55–7.58 (m, 2H), 3.93 (s, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 52.6, 109.1, 128.4, 130.4, 131.0, 131.2, 165.7. MS (EI) m/z: 193 [M⁺].

1-Nitro-4-thiocyanatobenzene (2h)

Yield: 30 mg (84%); white solid; m.p.: 127–129 °C.^21
¹H NMR (400 Hz, CDCl₃): δ 8.30 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 108.0, 125.0, 128.7, 133.3, 147.9. MS (EI) m/z: 180 [M⁺].

1-Methyl-2-thiocyanatobenzene (2i)

Yield: 24 mg (81%); yellowish liquid.^23
¹H NMR (400 Hz, CDCl₃): δ 7.54–7.56 (m, 1H), 7.18–7.29 (m, 3H), 2.41 (s, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 20.4, 110.4, 123.6, 127.8, 130.2, 131.5, 132.0, 139.3. MS (EI) m/z: 149 [M⁺].

1-Chloro-2-thiocyanatobenzene (2j)

Yield: 26 mg (78%); colorless liquid.^26
¹H NMR (400 Hz, CDCl₃): δ 7.67–7.69 (m, 1H), 7.32–7.44 (m, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 108.1, 123.8, 127.4, 128.8, 129.2, 129.3, 131.7. MS (EI) m/z: 169 [M⁺].

1-Chloro-3-thiocyanatobenzene (2k)

Yield: 28 mg (83%); colorless liquid.^26
¹H NMR (400 Hz, CDCl₃): δ 7.51 (d, J = 1.2 Hz, 1H), 7.35–7.41 (m, 3H).¹³C NMR (CDCl₃, 100 MHz) δ 109.5, 126.2, 127.7, 129.4, 129.8, 131.2, 136.0. MS (EI) m/z: 169 [M⁺].

1-Nitro-3-thiocyanatobenzene (2l)

Yield: 30 mg (82%); white solid; m.p.: 52–55 °C.^26
¹H NMR (400 Hz, CDCl₃): δ 8.36 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H).¹³C NMR (CDCl₃, 100 MHz) δ 108.6, 124.2 (2C), 127.2, 131.2, 134.9, 148.8. MS (EI) m/z: 180 [M⁺].

2-Thiocyanatonaphthalene (2m)

Yield: 33 mg (89%); white solid; m.p.: 33–35 °C.^20
¹H NMR (400 Hz, CDCl₃): δ 7.90−7.91 (m, 1H), 7.72−7.80 (m, 3H), 7.42−7.48 (m, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 109.6, 120.2, 125.2, 126.5, 126.6 (2C), 126.9, 128.8, 129.2, 132.0, 132.6. MS (EI) m/z: 185 [M⁺].

2-Thiocyanatopyridine (2n)

Yield: 19 mg (71%); colorless liquid.^23
¹H NMR (400 Hz, CDCl₃): δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 7.79 (td, J = 7.9, 1.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.30 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz) δ 108.9, 122.0, 122.7, 138.4, 149.9, 150.5. MS (EI) m/z: 136 [M⁺].

(Thiocyanatomethyl)benzene (2o)

Yield: 24 mg (79%); white solid; m.p.: 39–40 °C.^26
¹H NMR (400 Hz, CDCl₃): δ 7.25−7.43 (m, 5H), 4.16 (s, 2H).¹³C NMR (CDCl₃, 100 MHz) δ 38.3, 111.9, 128.9 (2C), 129.1 134.3. MS (EI) m/z: 149 [M⁺].

Thiocyanatocyclohexane (2p)

Yield: 20 mg (72%); yellowish liquid.^26
¹H NMR (400 Hz, CDCl₃): δ 3.20–3.26 (m, 1H), 2.10–2.13 (m, 2H), 1.82–1.84 (m, 2H), 1.55–1.66 (m, 3H), 1.25–1.41 (m, 3H). ¹³C NMR (CDCl₃, 100 MHz) δ 24.9, 25.9, 33.6, 47.9, 111.6. MS (EI) m/z: 141 [M⁺].

Supplemental Material

Support_Information – Supplemental material for Selectfluor-initiated cyanation of disulfides to thiocyanates

Supplemental material, Support_Information for Selectfluor-initiated cyanation of disulfides to thiocyanates by Pengpeng Zhou, Chuan Chen and Shubai Li in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was financially supported by the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B178).

ORCID iD

Shubai Li

Supplemental material

The 1H NMR and 13C NMR spectra of the compounds are given in the Support Information.

References

Castanheiro

Suffert

Donnard

, et al. Chem Soc Rev 2016; 45: 494.

Guy

. The chemistry of functional groups: syntheses and preparative applications of thiocyanates. New York: John Wiley, 1977, p. 833.

Huang

Wang

, et al. Chem Sci 2017; 8: 7047.

Pawliczek

Garve

LKB

Werz

. Org Lett 2015; 17: 1716.

Exner

Bayarmagnai

Jia

, et al. Chem Eur J 2015; 21: 17220.

Bayarmagnai

Matheis

Jouvin

, et al. Angew Chem Int Ed 2015; 54: 5753.

Brown

Smith

III . J Am Chem Soc 2015; 137: 4034.

Wang

Chen

Deng

, et al. J Org Chem 2012; 77: 4148.

Melzig

Rauhut

Naredi-Rainer

. Chem Eur J 2011; 17: 5362.

10.

Venkanna

Rajanna

Kumar

, et al. Synlett 2016; 27: 237.

11.

Wang

, et al. Chin J Chem 2016; 34: 1081.

12.

Wang

Liu

, et al. Tetrahedron Lett 2016; 57: 1771.

13.

Sun

Zhang

, et al. Synlett 2013; 24: 1443.

14.

Akhlaghinia

Pourali

Rahmani

. Synth Commun 2012; 42: 1184.

15.

Vaddula

Varma

Leazer

. Eur J Org Chem 2012: 6852.

16.

Guo

Tan

Zhao

, et al. J Org Chem 2018; 83: 6580.

17.

Zhou

Sun

, et al. ACS Sustainable Chem Eng 2018; 7: 1574.

18.

Zhou

, et al. Org Biomol Chem 2018; 16: 9064.

19.

Frei

Courant

Wodrich

. Chem Eur J 2015; 21: 2662.

20.

Yamaguchi

Sakagami

Miyamoto

, et al. Org Biomol Chem 2014; 12: 9200.

21.

Castanheiro

Gulea

Donnard

, et al. Eur J Org Chem 2014: 7814.

22.

Toste

De Stefano

Still

IWJ

. Synth Commun 1995; 25: 1277.

23.

Teng

Yang

, et al. Chem Commun 2014; 50: 12139.

24.

Chen

, et al. J Org Chem 2019; 84: 9044.

25.

Wang

, et al. Tetrahedron Lett 2015; 56: 5067.

26.

Lin

Shen

, et al. Org Lett 2016; 18: 592.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.93 MB