A Copper-Catalyzed Synthesis of Symmetrical Diarylsulfanes

Abstract

A room-temperature, copper-catalyzed synthesis of symmetrical diarylsulfanes has been developed. The reaction proceeds from aryl iodides and elemental sulfur (S₈) by the action of copper(I) salts in the presence of N-ethyl-N-isopropylpropan-2-amine to afford the corresponding diarylsulfanes in good yields.

Cross-coupling reactions performed between aryl halides and various nucleophiles in the presence of copper catalysts are powerful methods for carbon–heteroatom bond formation.[1] [2] The importance of the aryl–sulfur bond stems from its presence in molecules of pharmaceutical and material interest. For example, diarylthioether moieties have been found in numerous drugs.[3] A common method for the synthesis of diarylsulfanes is the transition-metal-catalyzed cross-coupling reaction between aryl halides and thiophenoles. Different transition metals including palladium,[4,5] nickel,[6] [7] iron,[8] [9] and copper[10] [11] [12] [13] have been reported to catalyze the formation of diarylsulfanes. Less common strategies for the synthesis of thioether moieties involve the use of thioureas,[14] disulfides,[15] 2-(iodoaryl)thioureas,[16] thoicyanates,[17] and aryl halides in the presence of copper catalysts. Recently, we have developed an efficient copper-catalyzed C–N cross-coupling.[18] Herein, we report a route to C–S cross-coupling at room temperature. To the best of our knowledge, no synthetic routes by copper catalysis at ambient temperature aimed to the synthesis of symmetrical diarylsulfanes have been reported.

Initially, the reaction between iodobenzene (3 mmol) and elemental sulfur (1.1 mmol), in the presence of copper(I) iodide (10 mol%), acetylacetone (1.1 mmol), and N-ethyl-N-isopropylpropan-2-amine (EIPA, 2 mmol) in DMSO at 25 °C was selected as a model for the synthesis of symmetrical diarylsulfanes (Table [1]). Changing the solvent to DMSO led to good yields, but the use of other solvents resulted in significantly reduced yields. Bases other than EIPA afforded lower yields, and copper catalysts other than copper(I) iodide exhibited reduced activities. Among the ligands tested, acetylacetone showed a superior effect on the reaction yields (Table [1]).

Table 1 Synthesis of Diarylsulfanes 2 ^a

Catalyst	Ligand	Base	Solvent	Yield (%)
CuI	L1	EIPA	DMSO	87
CuI	L2	EIPA	DMSO	33
CuI	L3	EIPA	DMSO	49
CuI	L4	EIPA	DMSO	76
CuI	L5	EIPA	DMSO	62
CuI	L6	EIPA	DMSO	62
CuI	L1	EIPA	DMF	64
CuI	L1	EIPA	NMP	32
CuI	L1	EIPA	MeCN	9
CuI	L1	EIPA	toluene	–
CuCl	L1	EIPA	DMSO	54
CuBr	L1	EIPA	DMSO	47
Cu2O	L1	EIPA	DMSO	58
CuI	L1	Et3N	DMSO	71
CuI	L1	DABCO	DMSO	43
CuI	L1	DBU	DMSO	61
CuI	L1	Cs2CO3	DMSO	10

^a Reactions conditions: iodobenzene (2 mmol), S₈ (1.1 mmol), copper source (0.10 mmol), ligand (1.1 mmol), base (2.0 mmol), solvent (2 mL), 25 °C, 8 h, under argon.

After the optimized reaction conditions were established, a number of aryl iodides was examined to explore the scope of this reaction. As summarized in Table [2], various aryl iodides were converted into the corresponding diarylsulfanes in good yields.[19]

Table 2 Copper-Catalyzed C–S Coupling of Aryl Iodides with Elemental Sulfur

Entry	ArX	Product	Yield (%)
1	1a	2a	87
2	1b	2b	84
3	1c	2c	71
4	1d	2d	68
5	1e	2e	91
6	1f	2f	72
7	1g	2g	71
8	1h	2h	81
9	1i	2i	80

In conclusion, a novel copper-mediated procedure was developed for the preparation of symmetrical diarylsulfanes from aryl iodides at ambient temperature. This protocol, allowing the formation of two C–S bonds in a one-pot reaction, is distinguished by avoiding the use of foul smelling thiophenols and strong inorganic bases.

• References and Notes

• 1 Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
  CrossrefPubMedSearch in Google Scholar
• 2 Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 2
  CrossrefSearch in Google Scholar
• 3 Liu G, Huth JR, Olejniczak ET, Mendoza F, DeVries P, Leitza S, Reilly EB, Okasinski GF, Fesik SW, Von Geldern TW. J. Med. Chem. 2001; 44: 1202
  CrossrefPubMedSearch in Google Scholar
• 4 Nielsen SF, Nielsen EØ, Olsen GM, Liljefors T, Peters D. J. Med. Chem. 2000; 43: 2217
  CrossrefSearch in Google Scholar
• 5 Murata M, Buchwald SL. Tetrahedron 2004; 60: 7397
  CrossrefSearch in Google Scholar
• 6 Fernandez MA, Shen Q, Hartwig JF. J. Am. Chem. Soc. 2006; 128: 2180
  CrossrefSearch in Google Scholar
• 7 Zhang Y, Ngeow KN, Ying JY. Org. Lett. 2007; 9: 3495
  Search in Google Scholar
• 8 Correa A, Carril M, Bolm C. Angew. Chem. Int. Ed. 2008; 47: 2880
  CrossrefPubMedSearch in Google Scholar
• 9 Buchwald SL, Bolm C. Angew. Chem. Int. Ed. 2009; 48: 5586
  CrossrefSearch in Google Scholar
• 10 Sperotto E, van Klink GP. M, de Vries JG, van Koten G. J. Org. Chem. 2008; 73: 5625
  CrossrefSearch in Google Scholar
• 11 Xu H, Zhao X, Fu Y, Feng Y. Synlett 2008; 3063
  Thieme Connect
• 12 Xu R, Wan J, Mao H, Pan Y. J. Am. Chem. Soc. 2010; 132: 15531
  CrossrefSearch in Google Scholar
• 13 Prasad D, Sekar G. Synlett 2010; 79
• 14 Firouzabadi H, Iranpoor N, Gholinejad M. Adv. Synth. Catal. 2010; 352: 119
  CrossrefSearch in Google Scholar
• 15 Wang H, Jiang L, Chen T, Li Y. Eur. J. Org. Chem. 2010; 2324
• 16 Ramana T, Saha P, Das M, Punniyamurthy T. Org. Lett. 2010; 12: 84
  CrossrefSearch in Google Scholar
• 17 Ke F, Qu Y, Jiang Z, Li Z, Wu D, Zhou X. Org. Lett. 2011; 13: 454
  CrossrefSearch in Google Scholar
• 18 Yavari I, Ghazanfarpour-Darjani M, Ahmadian S, Solgi Y. Synlett 2011; 1745
  Thieme Connect
• 19 General Procedure for the Synthesis of Products 2 A mixture of aryl iodide (2 mmol), CuI (0.10 mmol), ligand (1.1 mmol), and S₈ (1.1 mmol) were added to an oven-dried reaction tube equipped with a septum. The reaction tube was evacuated and back-filled with argon. Under a counterflow of argon, EIPA (0.258 g, 2 mmol) and DMSO (2 mL) were added, and the mixture stirred at r.t. for 8 h. After complete disappearance of aryl iodide (monitored by TLC), H₂O (5 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic phases were dried (on MgSO₄) and filtered before evaporation of the solvent. The residue was purified on silica gel, eluting with PE–EtOAc (20:1), to give product 2. Analytical and spectroscopic data for all derivatives, except 2g–i have been reported previously.¹⁹ Bis(2-trifluoromethylphenyl)sulfane (2g) Colorless oil; yield: 0.23 g (71%). IR (KBr): ν_max = 2915, 1591, 1443, 1313, 1264, 1170, 1128, 1034, 756 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (2 H, d, ³ J = 8.0 Hz, 2 CH), 7.36–7.44 (4 H, m, 4 CH), 7.74 (2 H, d, ³ J = 7.5 Hz, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 123.6 (2 CF₃, q, ¹ J _CF = 272.0 Hz), 126.9 (2 CH, q, ³ J _CF = 5.5 Hz), 127.5 (2 CH), 131.0 (2 C, q, ² J _CF = 30.2 Hz), 132.4 (2 CH), 134.7 (2 CH), 134.8 (2 C, q, ³ J _CF = 5.0 Hz). MS (EI, 70 eV): m/z (%) = 322 [M + 1], 301 (55), 252 (33), 233 (99), 184 (59), 157 (50), 133 (17), 108 (36). Bis(3-trifluoromethylphenyl)sulfane (2h) Colorless oil; yield: 0.26 g (81%). IR (KBr): ν_max = 2928, 1589, 1422, 1316, 1145, 755 cm^–1. ¹H NMR (500 MHz, CDCl₃) δ = 7.46 (2 H, d, ³ J = 7.2 Hz, 2 CH), 7.49–7.55 (4 H, m, 4 CH), 7.62 (2 H, s, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 123.6 (2 CF₃, q, ¹ J _CF = 271 Hz), 124.4 (2 CH, q, ³ J _CF = 3.5 Hz), 127.7 (2 CH, q, ³ J _CF = 3.7 Hz), 129.9 (2 CH), 131.9 (2 C, q, ² J _CF = 32.4 Hz), 134.2 (2 CH), 136.2 (2 C). MS (EI, 70 eV): m/z (%) = 322 [M + 1], 301 (26), 233 (69), 184 (35), 157 (40), 133 (11), 108 (25). Bis(4-cyanophenyl)sulfane (2i) Colorless solid; mp 174–176 °C; yield: 0.19 g (80%). IR (KBr): ν_max = 3424, 2370, 2218, 1582, 1482, 818 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.55 (4 H, d, ³ J = 8.4 Hz, 4 CH), 7.61 (4 H, d, ³ J = 8.4 Hz, 4 CH).¹³C NMR (125.7 MHz, CDCl₃): δ = 110.9 (2 C), 118.1 (2 CN), 126.5 (4 CH), 132.8 (4 CH), 142.1 (2 C). MS (EI, 70 eV): m/z (%) = 236 [M + 1], 204 (14), 166 (11), 134 (100), 107 (30), 90 (51), 82 (15), 75 (24), 69 (45), 63 (46), 57 (16), 51 (16).

• References and Notes

• 1 Evano G, Blanchard N, Toumi M. Chem. Rev. 2008; 108: 3054
  CrossrefPubMedSearch in Google Scholar
• 2 Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 2
  CrossrefSearch in Google Scholar
• 3 Liu G, Huth JR, Olejniczak ET, Mendoza F, DeVries P, Leitza S, Reilly EB, Okasinski GF, Fesik SW, Von Geldern TW. J. Med. Chem. 2001; 44: 1202
  CrossrefPubMedSearch in Google Scholar
• 4 Nielsen SF, Nielsen EØ, Olsen GM, Liljefors T, Peters D. J. Med. Chem. 2000; 43: 2217
  CrossrefSearch in Google Scholar
• 5 Murata M, Buchwald SL. Tetrahedron 2004; 60: 7397
  CrossrefSearch in Google Scholar
• 6 Fernandez MA, Shen Q, Hartwig JF. J. Am. Chem. Soc. 2006; 128: 2180
  CrossrefSearch in Google Scholar
• 7 Zhang Y, Ngeow KN, Ying JY. Org. Lett. 2007; 9: 3495
  Search in Google Scholar
• 8 Correa A, Carril M, Bolm C. Angew. Chem. Int. Ed. 2008; 47: 2880
  CrossrefPubMedSearch in Google Scholar
• 9 Buchwald SL, Bolm C. Angew. Chem. Int. Ed. 2009; 48: 5586
  CrossrefSearch in Google Scholar
• 10 Sperotto E, van Klink GP. M, de Vries JG, van Koten G. J. Org. Chem. 2008; 73: 5625
  CrossrefSearch in Google Scholar
• 11 Xu H, Zhao X, Fu Y, Feng Y. Synlett 2008; 3063
  Thieme Connect
• 12 Xu R, Wan J, Mao H, Pan Y. J. Am. Chem. Soc. 2010; 132: 15531
  CrossrefSearch in Google Scholar
• 13 Prasad D, Sekar G. Synlett 2010; 79
• 14 Firouzabadi H, Iranpoor N, Gholinejad M. Adv. Synth. Catal. 2010; 352: 119
  CrossrefSearch in Google Scholar
• 15 Wang H, Jiang L, Chen T, Li Y. Eur. J. Org. Chem. 2010; 2324
• 16 Ramana T, Saha P, Das M, Punniyamurthy T. Org. Lett. 2010; 12: 84
  CrossrefSearch in Google Scholar
• 17 Ke F, Qu Y, Jiang Z, Li Z, Wu D, Zhou X. Org. Lett. 2011; 13: 454
  CrossrefSearch in Google Scholar
• 18 Yavari I, Ghazanfarpour-Darjani M, Ahmadian S, Solgi Y. Synlett 2011; 1745
  Thieme Connect
• 19 General Procedure for the Synthesis of Products 2 A mixture of aryl iodide (2 mmol), CuI (0.10 mmol), ligand (1.1 mmol), and S₈ (1.1 mmol) were added to an oven-dried reaction tube equipped with a septum. The reaction tube was evacuated and back-filled with argon. Under a counterflow of argon, EIPA (0.258 g, 2 mmol) and DMSO (2 mL) were added, and the mixture stirred at r.t. for 8 h. After complete disappearance of aryl iodide (monitored by TLC), H₂O (5 mL) was added, and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic phases were dried (on MgSO₄) and filtered before evaporation of the solvent. The residue was purified on silica gel, eluting with PE–EtOAc (20:1), to give product 2. Analytical and spectroscopic data for all derivatives, except 2g–i have been reported previously.¹⁹ Bis(2-trifluoromethylphenyl)sulfane (2g) Colorless oil; yield: 0.23 g (71%). IR (KBr): ν_max = 2915, 1591, 1443, 1313, 1264, 1170, 1128, 1034, 756 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (2 H, d, ³ J = 8.0 Hz, 2 CH), 7.36–7.44 (4 H, m, 4 CH), 7.74 (2 H, d, ³ J = 7.5 Hz, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 123.6 (2 CF₃, q, ¹ J _CF = 272.0 Hz), 126.9 (2 CH, q, ³ J _CF = 5.5 Hz), 127.5 (2 CH), 131.0 (2 C, q, ² J _CF = 30.2 Hz), 132.4 (2 CH), 134.7 (2 CH), 134.8 (2 C, q, ³ J _CF = 5.0 Hz). MS (EI, 70 eV): m/z (%) = 322 [M + 1], 301 (55), 252 (33), 233 (99), 184 (59), 157 (50), 133 (17), 108 (36). Bis(3-trifluoromethylphenyl)sulfane (2h) Colorless oil; yield: 0.26 g (81%). IR (KBr): ν_max = 2928, 1589, 1422, 1316, 1145, 755 cm^–1. ¹H NMR (500 MHz, CDCl₃) δ = 7.46 (2 H, d, ³ J = 7.2 Hz, 2 CH), 7.49–7.55 (4 H, m, 4 CH), 7.62 (2 H, s, 2 CH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 123.6 (2 CF₃, q, ¹ J _CF = 271 Hz), 124.4 (2 CH, q, ³ J _CF = 3.5 Hz), 127.7 (2 CH, q, ³ J _CF = 3.7 Hz), 129.9 (2 CH), 131.9 (2 C, q, ² J _CF = 32.4 Hz), 134.2 (2 CH), 136.2 (2 C). MS (EI, 70 eV): m/z (%) = 322 [M + 1], 301 (26), 233 (69), 184 (35), 157 (40), 133 (11), 108 (25). Bis(4-cyanophenyl)sulfane (2i) Colorless solid; mp 174–176 °C; yield: 0.19 g (80%). IR (KBr): ν_max = 3424, 2370, 2218, 1582, 1482, 818 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.55 (4 H, d, ³ J = 8.4 Hz, 4 CH), 7.61 (4 H, d, ³ J = 8.4 Hz, 4 CH).¹³C NMR (125.7 MHz, CDCl₃): δ = 110.9 (2 C), 118.1 (2 CN), 126.5 (4 CH), 132.8 (4 CH), 142.1 (2 C). MS (EI, 70 eV): m/z (%) = 236 [M + 1], 204 (14), 166 (11), 134 (100), 107 (30), 90 (51), 82 (15), 75 (24), 69 (45), 63 (46), 57 (16), 51 (16).