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Synlett 2016; 27(11): 1743-1747
DOI: 10.1055/s-0035-1561946
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© Georg Thieme Verlag Stuttgart · New York

Copper(I)-Promoted C–N Cross-Coupling of N-Heterocyclic Compounds with 1,2-Di(pyrimidin-2-yl) Disulfides

Kai-Jie Wei
a   Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b   Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Gansu 730070, P. R. of China, Email: quanzhengjun@hotmail.com   Email: wangxicun@nwnu.edu.cn
,
Zheng-Jun Quan*
a   Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b   Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Gansu 730070, P. R. of China, Email: quanzhengjun@hotmail.com   Email: wangxicun@nwnu.edu.cn
,
Zhang Zhang
a   Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b   Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Gansu 730070, P. R. of China, Email: quanzhengjun@hotmail.com   Email: wangxicun@nwnu.edu.cn
,
Yu-Xia Da
a   Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b   Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Gansu 730070, P. R. of China, Email: quanzhengjun@hotmail.com   Email: wangxicun@nwnu.edu.cn
,
Xi-Cun Wang*
a   Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
b   Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Gansu 730070, P. R. of China, Email: quanzhengjun@hotmail.com   Email: wangxicun@nwnu.edu.cn
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Further Information

Publication History

Received: 25 January 2016

Accepted after revision: 06 March 2016

Publication Date:
01 April 2016 (online)

 
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Abstract

A CuTC-promoted C–N cross-coupling of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocyclic compounds including indoles, triazole benzotriazole, and benzoimidazole by C–S cleavage of the disulfides is reported.


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Key words

N-heterocycles - indoles - disulfides - CuTC - C–N cross-coupling

Transition-metal-catalyzed C–N cross-coupling reactions are considered one of the most powerful methods for the construction of nitrogen-containing skeletons.[1] Especially, the N-aryl nitrogen heterocycle motif is present in a multitude of bioactive natural products[2] and pharmaceutically interesting compounds.[3] Ullmann coupling and Buchwald–Hartwig reactions are typical efficient methods for us to construct the C–N bond. Generally, such procedures involve the coupling of an activated electrophilic substrate[4] with a nucleophile through a transition-metal-mediated cross-coupling reaction. However, most of the reactions require stringent conditions, such as the use of noble or transition metals as catalyst (palladium[5] and nickel[6]), and aryl halides[7] or aryl sulfonates[8] [6b] as electrophiles. Generally, the synthesis of aryl halides often involves tedious steps, harsh reaction conditions, and waste production.[9] Therefore the focus of attention has been the search for inexpensive catalysts and alternative electrophiles as substrates instead of organic halides for cross-coupling reactions.[10]

Organic disulfides are structurally symmetrical. Particularly, diaryl disulfides are air stable and easy to handle. They are common intermediates for organic transformations and are widely used as sulfenyl and sulfinyl reagents through S–S cleavage with various reagents.[11] More recently, some groups independently developed the C–H thiolation of heterocycles including indole and imidazoheterocycles with disulfides achieving C–S coupling in the presence of oxidants such as I2/(NH)2S2O8,[12a] I2/FeF3,[12b] and AgNO3 [12c] (Scheme [1, a]).[12]

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Scheme 1 Cross-coupling of disulfide with N-heterocycles

To our surprise, before 2014, there has been a notable absence of examples of C–C couplings between a disulfide and an arylboronic acid or an alkyne. In 2014, we reported the first metal-catalyzed and copper(I) carboxylate-mediated C–C cross-coupling reaction of disulfides through C–S bond cleavage of di(hetero)aryl disulfides with arylboronic acids or alkynes, which employed a nitrogen-containing diheteroaryl disulfide.[13a] In 2015, our group developed a simple and efficient method for the cross-coupling of di(hetero)aryl disulfides with Grignard reagents, providing C–S and C–C products with excellent chemoselectivity.[13b] However, to the best of our knowledge, there is no report on the C–N cross-coupling reaction of disulfides with N-heterocycles. Based on these examples, we believed that it is possible to achieve the copper-promoted C–N coupling reaction of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocycles (Scheme [1, b]). Herein, we demonstrate that simple and readily available 1,2-di(pyrimidin-2-yl) disulfides[13] are excellent substrates for the copper(I)-catalyzed C–N cross-coupling reaction with a series of N-heterocycles, and in doing so add to the motifs (pyrimidine, indole, triazole, benzotriazole, and benzoimidazole) available for use in these valuable C–N coupling processes.

To optimize the reaction conditions, the C–N coupling of 1,2-di(pyrimidin-2-yl) disulfide 1a and indole (2a) in the presence of Cs2CO3 was used as a model reaction, and the results are summarized in Table [1]. No desired product was detected in the absence of catalyst, but the starting material 1a was recovered (Table [1], entry 1). Ni(PPh3)Cl2 and Ni(dppp)Cl2, used in the reaction, facilitated the formation of product 3a albeit with low yield of 45% and 53%, respectively (Table [1], entries 2 and 3). Subsequent evaluation of various copper sources was carried out. Among the used copper sources, CuCl or CuTC rather than CuI, Cu2O, or CuBr could remarkably increase the yield of 3a, and CuTC provided the best result (Table [1], entries 4–8). Next, the effects of bases in this reaction were investigated. Replacement of Cs2CO3 with either K3PO4, K2CO3, or t-BuONa led to inferior results (Table [1], entries 9–11). One more time, we experimented with CuTC and Ni(dppp)Cl2 as bimetallic catalyst, no significant effect on the yield was observed (Table [1], entry 12 vs. entry 8). Finally, the reaction gave trace amounts of 3a under an air atmosphere (Table [1], entry 12). Based on the above research, the reaction was best conducted with CuTC as the catalyst, Cs2CO3 as the base, and dioxane as the solvent at 120 °C for 12 hours. The product 3a was fully characterized by 1H NMR and 13C NMR, HRMS, and X-ray crystallographic studies (Figure1).[14]

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Figure 1 X-ray crystal structure of 3a

Table 1 Optimization of the Cross-Coupling Reaction of Disulfides 1a and Indole 2a a

Entry

Catalyst (equiv)

Base (3 equiv)

Yield (%)b

 1

–

Cs2CO3

N.R.

 2

Ni(PPh3)Cl2 (0.1)

Cs2CO3

45

 3

Ni(dppp)Cl2 (0.1)

Cs2CO3

53

 4

CuI (1.0)

Cs2CO3

43

 5

Cu2O (1. 0)

Cs2CO3

31

 6

CuBr (1. 0)

Cs2CO3

49

 7

CuCl (1. 0)

Cs2CO3

75

 8

CuTC (1. 0)

Cs2CO3

80

 9

CuTC (1. 0)

K3PO4

61

10

CuTC (1. 0)

K2CO3

37

11

CuTC (1. 0)

t-BuONa

72

12

Ni(dppp)Cl2 (0.1)
CuTC (1. 0)

Cs2CO3

82

13c

CuCl (1. 0)

Cs2CO3

<5

a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), dioxane (3 mL).

b Isolated yield after column chromatography (based on both pyrimidine groups from one molecule).

c The reaction was carried out at air atmosphere; Ph3P = triphenylphosphine hydrobromide; dppp = 1,3-bis(diphenylphosphino)propane; CuTC = copper(I) thiophene-2-carboxylate.

The above optimized conditions (Table [1], entry 8) were then applied to the C–N cross-coupling reactions of various 1,2-di(pyrimidin-2-yl) disulfides 1 and a diverse set of N-heterocyclic compounds 2 (Scheme [2]).[15] As show in Scheme [2], the process proved to be relatively broad in scope, tolerating a variety of steric and electronic changes to both reaction partners to give the products 3a–r with good yields. The reaction conditions were suitable for a variety of disulfides and indole to give products (3a–i). Similarly, diverse disulfides and benzoimidazole delivered the corresponding products in fairly good yields (3j–n). We could extend the scope of nitrogenous heterocyclic compounds to 1,2,4-1H-triazole and benzotriazole which are also competent reaction partners to give corresponding products in good yields (3o–r). We tried to extend the scope of disulfides to 2,2′-dithiodipyridine and diphenyl disulfide under optimized conditions (Table [1], entry 8) or bimetallic catalysts (Table [1], entry 12). Unfortunately, products 3s and 3t could not obtained. Compared with the tested 1,2-di(pyrimidin-2-yl) disulfides, both nitrogen-containing diheteroaryl disulfides and aryl disulfides showed much lower reactivity.

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Scheme 2The coupling reactions of disulfides with N-heterocyclic compounds

Next, we further explored the C–N coupling reaction of 2-methylindole with disulfides under the optimized conditions, but we did not detect the corresponding products, but achieved an unexpected C–S coupling product.[16] Thankfully, when we executed the reaction under bimetallic catalyst conditions (Table [1], entry 12), the C–N coupled products were obtained. The reaction conditions were suitable for a variety of disulfides and 2-methylindole to give the corresponding products (4a–e) in good yields (Scheme [3]).[17]

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Scheme 3 The coupling reactions of disulfides with 2-methylindole

After the tests towards symmetrical diheteroaryl disulfides, unsymmetrical disulfides 5a and 5b were examined in the C–N coupling reaction. Interestingly, the reaction of disulfide 5a with indole gave the C–N coupling product 3a in a high yield of 73% with the formation of diaryl disulfide 7 (37%), but compound 6 was not detected. Similarly, using disulfide 5b as substrate gave the corresponding 3c (78%) and 7 (46%, Scheme [4]).[16]

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Scheme 5
Zoom Image
Scheme 4 Cross-coupling of unsymmetrical disulfides

In conclusion, we have developed an efficient method for C–N cross-coupling reaction of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocycles via CuTC-promoted C–S bond cleavage of disulfides. The use of a copper salt such as CuTC or CuCl was necessary for an efficient formation of the C–N bond in this reaction. The reaction tolerated a wide substrate scope and achieved good to excellent yields.


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Acknowledgment

We are thankful for financial support from the National Natural Science Foundation of China (No. 21362032, 21362031 and 21562036), Gansu Provincial Department of Finance, and Natural Science Foundation of Gansu Province (No. 1308RJZA299).

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561946.
  • Supporting Information

  • References and Notes

  • 10 Fu G, Netherton M. Angew. Chem. Int. Ed. 2002; 41: 3910
    CrossrefSearch in Google Scholar
  • 14 The structure of 3a was determined by X-ray crystallographie. CCDC 1435800 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 15 General Procedure for the Synthesis of 3a Under an atmosphere of nitrogen, disulfide1 1a (1 mmol, 0.546 g), indole 2a (3 mmol, 0.351 g), CuTC (1.0 mmol, 0.191 g), and Cs2CO3 (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO3 and brine, dried over MgSO4, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 2-(1H-Indol-1-yl)-4-methyl-6-phenylpyrimidine-5-carboxylate (3a) Yield 80%, colorless crystals, mp 135–137 °C. 1H NMR (600 MHz, CDCl3): δ = 8.88 (d, J = 8.4 Hz, 1 H, ArH), 8.37 (d, J = 3.6 Hz, 1 H, ArH), 7.77–7.75 (m, 2 H, ArH), 7.62 (d, J = 7.8 Hz, 1 H, CH), 7.53–7.50 (m, 3 H, ArH), 7.34 (t, J = 7.8 Hz, 1 H, ArH), 7.25 (t, J = 7.2 Hz, 1 H, ArH), 6.71 (d, J = 3.6 Hz, 1 H, CH), 4.20 (q, J = 7.2 Hz, 2 H, OCH2), 2.70 (s, 3 H, CH3), 1.07 (t, J = 7.2 Hz, 3 H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.81, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64. HRMS (ESI+): m/z calcd for C22H20N3O2: 358.1550 [M + H]+; found: 358.1553.
  • 16 For the reaction of 1,2-di(pyrimidin-2-yl) disulfides with indole achieved the C–S coupling product, see Scheme 5.
  • 17 General Procedure for the Synthesis of 4a Under an atmosphere of nitrogen, disulfide13a (1 mmol, 0.546 g), 2-methylindole (2b, 3 mmol, 0.393 g), CuTC (1.0 mmol, 0.191 g), Ni(dppp)Cl2 (0.1 mol, 0.054 g), and Cs2CO3 (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO3 and brine, dried over MgSO4, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 4-Methyl-2-(2-methyl-1H-indol-1-yl)-6-phenylpyrimidine-5-carboxylate (4a) Yield 79%, yellow oil. 1H NMR (600 MHz, CDCl3): δ = 8.30 (d, J = 8.4 Hz, 1 H, ArH), 7.68–7.66 (m, 2 H, ArH), 7.55–7.54 (m, 3 H, ArH), 7.48 (d, J = 7.8 Hz, 1 H, ArH), 7.16–7.13 (m, 2 H, ArH), 6.51 (s, 1 H, CH), 4.19 (q, J = 7.2 Hz, 2 H, OCH2), 2.70 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 1.03 (t, J = 7.2 Hz, 3 H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.82, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64, 13.63. HRMS (ESI+): m/z calcd for C23H22N3O2: 372.1707 [M + H]+; found: 372.1710.

  • References and Notes

  • 10 Fu G, Netherton M. Angew. Chem. Int. Ed. 2002; 41: 3910
    CrossrefSearch in Google Scholar
  • 14 The structure of 3a was determined by X-ray crystallographie. CCDC 1435800 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 15 General Procedure for the Synthesis of 3a Under an atmosphere of nitrogen, disulfide1 1a (1 mmol, 0.546 g), indole 2a (3 mmol, 0.351 g), CuTC (1.0 mmol, 0.191 g), and Cs2CO3 (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO3 and brine, dried over MgSO4, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 2-(1H-Indol-1-yl)-4-methyl-6-phenylpyrimidine-5-carboxylate (3a) Yield 80%, colorless crystals, mp 135–137 °C. 1H NMR (600 MHz, CDCl3): δ = 8.88 (d, J = 8.4 Hz, 1 H, ArH), 8.37 (d, J = 3.6 Hz, 1 H, ArH), 7.77–7.75 (m, 2 H, ArH), 7.62 (d, J = 7.8 Hz, 1 H, CH), 7.53–7.50 (m, 3 H, ArH), 7.34 (t, J = 7.8 Hz, 1 H, ArH), 7.25 (t, J = 7.2 Hz, 1 H, ArH), 6.71 (d, J = 3.6 Hz, 1 H, CH), 4.20 (q, J = 7.2 Hz, 2 H, OCH2), 2.70 (s, 3 H, CH3), 1.07 (t, J = 7.2 Hz, 3 H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.81, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64. HRMS (ESI+): m/z calcd for C22H20N3O2: 358.1550 [M + H]+; found: 358.1553.
  • 16 For the reaction of 1,2-di(pyrimidin-2-yl) disulfides with indole achieved the C–S coupling product, see Scheme 5.
  • 17 General Procedure for the Synthesis of 4a Under an atmosphere of nitrogen, disulfide13a (1 mmol, 0.546 g), 2-methylindole (2b, 3 mmol, 0.393 g), CuTC (1.0 mmol, 0.191 g), Ni(dppp)Cl2 (0.1 mol, 0.054 g), and Cs2CO3 (3.0 mmol, 0.978 g) were added to an oven-dried Schlenk tube. The tube was stoppered and degassed with nitrogen three times. Water-free dioxane (3 mL) was added by syringe, the mixture was stirred for 12 h at 120 °C, and the reaction was monitored by TLC analysis. Then, diluted HCl (2 mL) was added to the mixture to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with aq NaHCO3 and brine, dried over MgSO4, filtered, and the volatiles were removed in vacuo. The residue was purified by column chromatography on silica gel (EtOAc–PE = 1:30) to give the corresponding products. Ethyl 4-Methyl-2-(2-methyl-1H-indol-1-yl)-6-phenylpyrimidine-5-carboxylate (4a) Yield 79%, yellow oil. 1H NMR (600 MHz, CDCl3): δ = 8.30 (d, J = 8.4 Hz, 1 H, ArH), 7.68–7.66 (m, 2 H, ArH), 7.55–7.54 (m, 3 H, ArH), 7.48 (d, J = 7.8 Hz, 1 H, ArH), 7.16–7.13 (m, 2 H, ArH), 6.51 (s, 1 H, CH), 4.19 (q, J = 7.2 Hz, 2 H, OCH2), 2.70 (s, 3 H, CH3), 2.62 (s, 3 H, CH3), 1.03 (t, J = 7.2 Hz, 3 H, CH2CH3). 13C NMR (150 MHz, CDCl3): δ = 168.12, 167.31, 165.39, 156.44, 138.06, 135.48, 131.49, 130.13, 128.52 (2 C), 128.36 (2 C), 126.04, 123.74, 122.31, 120.82, 120.57, 116.62, 107.24, 61.69, 22.97, 13.64, 13.63. HRMS (ESI+): m/z calcd for C23H22N3O2: 372.1707 [M + H]+; found: 372.1710.

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Zoom Image
Scheme 1 Cross-coupling of disulfide with N-heterocycles
Zoom Image
Figure 1 X-ray crystal structure of 3a
Zoom Image
Scheme 2The coupling reactions of disulfides with N-heterocyclic compounds
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Scheme 3 The coupling reactions of disulfides with 2-methylindole
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Scheme 5
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Scheme 4 Cross-coupling of unsymmetrical disulfides