CuI assisted desulfurative Sonogashira reaction of mercapto N-heterocyclic derivatives with alkynes

Abstract

A palladium catalyzed Sonogashira reaction of mercapto N-heterocyclic derivatives with terminal alkynes by using CuI as the desulfurative reagent was described in this report. It provided an effective strategy for obtaining sp–sp² cross-coupling products in good yields. The reaction mechanism was also investigated by density functional theory (DFT) calculation.

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Transition metal catalyzed C–C bond forming reactions provide an exceptionally useful method for the synthesis of many important organic compounds.¹ The Sonogashira reaction provides a strategy for the coupling of terminal alkynes with aryl or vinyl halides to form Csp–Csp² bonds.² Organic sulfur compounds, such as aryl thioethers, cyclic thioamides and mercaptopyrimidine, are important intermediates, and have been used in C–C or C–hetero bond formation in recent years.³ The Liebeskind and Srogl⁴ research group performed a lot of work on desulfurative coupling reactions, which played an important role in the development of organic synthesis. Liebeskind–Srogl reaction and Sonogashira reaction provides us with an important idea to complete a type reaction of mercapto N-heterocyclic derivatives and terminal alkynes.

However, the dissociation energy of the C(sp²)–S bond is relatively high, and alternative catalysts for activating the C(sp²)–S bond are rare.⁵ Van der Eycken and co-workers reported⁶ a microwave-assisted desulfurative Sonogashira cross-coupling protocol for the alkynylation of the C-3 of phenylsulfanylated-2(1H)-pyrazinones under Liebeskind–Srogl reaction conditions. Tatibouet developed⁷ the desulfurative Sonogashira cross coupling of 1,3-oxazolidine-2-thiones (OZTs) and 1,3-oxazoline-2-thiones (OXTs) by a cooperative effect of Pd and CuTC, and this method leads to a new synthetic methodology in the synthesis of natural products. Suzenet reported⁸ a π-electron assisted desulfurative Sonogashira-type cross-coupling reaction of 3-cyanomercaptoquinolone derivatives with terminal alkynes, and CuTC and Pd as the catalyst and NEt₃ as the optimal base. These coupling reactions were all catalysed by Pd with CuTC as the desulfurative reagent. So, it is extremely important to develop a novel catalytic system for broadening the application of desulfurative Sonogashira coupling reaction. Herein, we disclosed a way for desulfurative Sonogashira reaction of mercapto N-heterocyclic derivatives with terminal alkynes (Scheme 1).

Scheme 1 Mercapto N-heterocyclic derivatives desulfurative Sonogashira type reactions.

Initially, the reaction of mercaptoaldehyde 1a with tert-butylacetylene 2a was selected for screening the reaction conditions. Upon treatment of 1a with 2a in the presence of NEt₃ in DMF at 110 °C under N₂ and using 2 mol% of Pd, 10% of PPh₃ as the ligand, 3.0 equiv. of CuI as the desulfurative reagent (Table 1, entry 1), the desired coupling product of 3a was isolated in 60% yield after 1 h. On the basis of this result, various copper(I) and copper(II) salts were investigated, and CuI was shown to be best for this reaction (Table 1, entries 2–6). Reduction in the amount of the CuI resulted in a significant decrease in yield, and there was no generation of product 3a when 1.0 equiv. CuI was employed (Table 1, entries 7 and 8). Furthermore, in the absence of Pd(OAc)₂, there was no generation of product 3a (Table 1, entry 9). Compared with NEt₃, i-Pr₂NEt, piperidine and CH₃COONa, Na₂CO₃ was the optimal base in promoting this reaction (up to 92% yield) (Table 1, entries 10–14). Other solvents, such as toluene (Tol), THF, CH₃CN and dioxane (Diox) were screened for the reaction, and DMF was found to be optimal for this reaction (Table 1, entries 15–18). When the reaction temperature was increased (130 °C) or decreased (80 °C), no improvement in the product yield was observed (Table 1, entries 19–22). However, only a low yield of the expected product was found when the reaction was performed in open air (Table 1, entry 23). Thus, the optimal reaction condition is as follows: 1a (1 equiv.), 2a (2 equiv.), Pd(OAc)₂ (2 mol%), PPh₃ (10%), CuI (3 equiv.), and Na₂CO₃ (5 equiv.) in DMF at 110 °C for 1 h.

Table 1 Optimization of conditions^a

Entry	Additive	Base	Solvent	Temp. [°C]	Yield of 3a^b [%]
a Reaction condition: 1a (1 eq.), 2a (2 eq.), Pd(OAc)2 (2%), PPh3 (10%) copper salt (3 eq.), base (5 eq.), solvent (2 ml), in N2 for 1 h.b GC yield is based on the 1a.c CuI (1.0 eq.) was used.d CuI (2.0 eq.) was used.e Without Pd(OAc)2(PPh3)2.f Under open air.
1	CuI	NEt3	DMF	110	60
2	CuBr	NEt3	DMF	110	25
3	Cu2O	NEt3	DMF	110	Trace
4	CuCl	NEt3	DMF	110	13
5	CuTC	NEt3	DMF	110	54
6	Cu(OAc)2·H2O	NEt3	DMF	110	Trace
7^c	CuI	NEt3	DMF	110	Trace
8^d	CuI	NEt3	DMF	110	20
9^e	CuI	NEt3	DMF	110	NR
10	CuI	—	DMF	110	NR
11	CuI	Na2CO3	DMF	110	92
12	CuI	CH3COONa	DMF	110	70
13	CuI	i-Pr2NEt	DMF	110	54
14	CuI	Piperidine	DMF	110	35
15	CuI	Na2CO3	Tol	110	12
16	CuI	Na2CO3	THF	110	37
17	CuI	Na2CO3	CH3CN	110	65
18	CuI	Na2CO3	Diox	110	74
19	CuI	Na2CO3	DMF	80	44
20	CuI	Na2CO3	DMF	100	76
21	CuI	Na2CO3	DMF	120	50
22	CuI	Na2CO3	DMF	130	41
23^f	CuI	Na2CO3	DMF	110	40

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Under the optimal reaction conditions, a variety of mercapto N-heterocyclic derivatives and terminal alkynes that undergo the C–S bond cleavage were studied. As shown in Table 2, when mercaptopyrimidine served as the substrates, electron-donating terminal alkynes, such as tert-butylacetylene 2a, octyne 2b and decyne 3c, showed slightly high reactivity, and corresponding coupled products were isolated in good yields (65–85%). Similarly, with the decline in the electron-withdrawing ability of the substituent on the benzene, the coupling product yield decreased to 50% (3d–3g). The trimethylsilylacetylene failed to produce the anticipative product 3h. Meanwhile, a low yield was noted for the mercaptopyrimidine with 1-ethynyl-1-cyclohexanol (2i) as a result of its high reactivity in this reaction condition. However, mercaptoaldehyde and 1,1-dimethylpropargylamine delivered the anticipative product 3j (complex mixture along with the starting material). This might be due to the unstable nature of the alkynyl, –SH group, –NH₂ group and –CHO group under this reaction condition.⁹ Similarly, ethyl propiolate (2k), when reacted with mercaptoaldehyde, yielded a negligible amount of anticipative product.

Table 2 Scope of substrates^a,b

a Reaction condition: 1 (1.0 mmol), 2 (2.0 mmol), Pd(OAc)₂ (2%), PPh₃ (10%), CuI (3.0 mmol), Na₂CO₃ (10 mmol), DMF (4 ml), in N₂ for 1 h.b Isolated yield.

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The substrate scope with respect to mercapto N-heterocyclic derivatives was also investigated. 2-Mercaptobenzothiazole, 2-mercapto-5-(1,3-dioxolan-2-yl)pyrinidine, 4,6-dimethyl-2-mercaptopyrimidine, 2-mercaptopyrimidine, 2-mercaptobenzoxazole also reacted with alkynes, forming desulfitative coupling product 3l–3r, 3u–3w in good yields. Furthermore, this desulfitative coupling condition could also be suitable with (2-mercaptopyrimidn-5-yl)methylenedicetate and ethyl-4-methyl-6-phenyl-2-mercapto-6H-1,3-thiazine-5-carboxylate substrate, and gave the products in a low yields (3s–3t).

Based on the above results and the extant literature on the traditional Liebeskind–Srogl cross-coupling involving desulfurative Sonogashira reactions, the possible mechanism of this novel protocol was shown in Scheme 2, and the free energy profile for the Pd catalyzed C–S bond cleavage was evaluated by theoretical study. In the case of mercaptoaldehyde, 3.0 equiv. of CuI were needed as the desulfurative reagent in order to achieve high yields. Under the impacts of the Na₂CO₃, PPh₃, and CuI, the copper(I)thiolate (a) was formed, which made the Pd(0) oxidative addition of the C–S bond comparatively easily by the DFT study. Next, the Pd(0) complex formed a complex intermediate b¹⁰ with a. Once transition state b was formed, the reaction will undergo the traditional Pd/Cu catalytic recycle. Then, the Pd(0) insertion of b into the C–S bond with copper-alkynes leads to the formation of the key intermediate c.¹¹ Finally, reductive elimination of d receives the products 3a and the regenerated Pd(0) catalyst returned to the next catalytic cycle. Cu₂S in the reaction solid mixture has been detected by XRD analysis (see the ESI†).

Scheme 2 Proposed mechanism for the catalytic process.

The free energy profiles calculated¹² by DFT methods B3LYP for the proposed catalytic process was shown in Scheme 3. The Pd(0) complex (b) might undergo oxidative addition through TS1 to produce a Pd(II) complex c. The activation free energy of the oxidative addition was calculated to be 24.2 kcal mol⁻¹. The transmetalation step energy (7.0 kcal mol⁻¹) was lower than the oxidative addition step. Thus, the rate determining step to this reaction was the Pd(0) activated the C–S bond reaction.

Scheme 3 Energy profiles for the C–S bond cleavage. The values given in kcal mol⁻¹ are the B3LYP calculated relative free energies.

Conclusions

In summary, we have successfully developed a novel and efficient CuI assisted Pd catalyzed desulfurative Sonogashira cross-coupling reaction. To the best of our knowledge, this process for the reaction of using CuI as the desulfurative reagent based on Pd catalyzed C–S bond activation has not been previously explored. We believe that the discovery of the facile C–S bond activation should pave the way for establishing some new and efficient Pd catalyzed transformations. Further work on the applications and extension of the scope of the protocol, as well as the precise reaction mechanisms, are currently under investigation in our laboratory.

Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 21476068).

Notes and references

1. (a) A. de Meijere and F. Diederich, Metal-Catalysed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 2004; (b) M. Beller and A. Zapf, Organo Palladium Chemistry for Organic Synthesis, Wiley, New York, 2002; (c) D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36, 234; (d) M. E. Harvey, D. G. Musaev and J. D. Bois, J. Am. Chem. Soc., 2011, 133, 17207; (e) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417; (f) F. Han, Chem. Soc. Rev., 2013, 42, 5270; (g) C. Sun and Z. Shi, Chem. Rev., 2014, 114, 9219; (h) L. Huang, M. Arndt, K. Goossen, H. Heydt and L. J. Goossen, Chem. Rev., 2015, 115, 2596.
2. (a) M. Carril, A. Correa and C. Bolm, Angew. Chem., Int. Ed., 2008, 47, 4862; (b) A. D. Finke, E. C. Elleby, M. J. Boyd, H. Weissman and J. S. Moore, J. Org. Chem., 2009, 74, 8897; (c) M. Eckhardt and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 13642; (d) D. Gelman and S. L. Buchwald, Angew. Chem., Int. Ed., 2003, 42, 5993; (e) J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung and S. Lee, Org. Lett., 2008, 10, 945; (f) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874; (g) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 16, 4467.
3. (a) K. Gao, H. Yorimitsu and A. Osuka, Angew. Chem., Int. Ed., 2016, 55, 4573; (b) S. Otsuka, H. Yorimitsu and A. Osuka, Chem.–Eur. J., 2015, 21, 14703; (c) Y. Dong, B. Liu, P. Chen, Q. Liu and M. Wang, Angew. Chem., Int. Ed., 2014, 53, 3442; (d) S. Kramer and T. Skrydstrup, Angew. Chem., Int. Ed., 2012, 51, 4681; (e) K. Gao, H. Yorimitsu and A. Osuka, Eur. J. Org. Chem., 2015, 2678; (f) M. Arisawa, F. Toriyama and M. Yamaguchi, Tetrahedron Lett., 2011, 52, 2344; (g) A. K. Yadav, H. Ila and H. Junjappa, Eur. J. Org. Chem., 2010, 338; (h) F. Pana and Z. Shiab, ACS Catal., 2014, 4, 280; (i) T. Sugahara, K. Murakami, H. Yorimitsu and A. Osuka, Angew. Chem., Int. Ed., 2014, 53, 9329; (j) K. Islam, R. S. Basha, A. A. Dar, D. K. Das and A. T. Khan, RSC Adv., 2015, 5, 79759; (k) B. C. Shook, D. Chakravarty and P. F. Jackson, Tetrahedron Lett., 2009, 50, 1013; (l) Z. Quan, W. Hu, X. Jia, Z. Zhang, Y. Da and X. Wang, Adv. Synth. Catal., 2012, 354, 2939.
4. (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260; (b) L. S. Liebeskind and J. Srogl, Org. Lett., 2002, 4, 979; (c) C. L. Kusturin, L. S. Liebeskind and W. L. Neumann, Org. Lett., 2002, 4, 983; (d) H. Yang, H. Li, R. Wittenberg, M. Egi, W. Huang and L. S. Liebeskind, J. Am. Chem. Soc., 2007, 129, 1132; (e) H. Prokopcova and C. O. Kappe, Angew. Chem., Int. Ed., 2009, 48, 2276.
5. Y.-R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, FL, 2007.
6. V. P. Mehta, A. Sharma and E. V. Eycken, Org. Lett., 2008, 10, 1147.
7. (a) S. Silva, B. Sylla, F. Suzenet, A. Tatibouet, A. P. Rauter and P. Rollin, Org. Lett., 2008, 10, 853; (b) X. Guinchard and E. Roulland, Org. Lett., 2009, 11, 4700.
8. Y. Wu, Y. Xing, J. Wang, Q. Sun, W. Konga and F. Suzenet, RSC Adv., 2015, 5, 48558.
9. (a) S. Yang, H. Yan, X. Ren, X. Shi, J. Li, Y. Wang and G. Huang, Tetrahedron, 2013, 69, 6431; (b) Z. Chen, H. Zeng, H. Gong, H. Wang and C. Li, Chem. Sci., 2015, 6, 4174; (c) Y. Nishibayashi, I. Wakiji and M. Hidai, J. Am. Chem. Soc., 2000, 122, 11019; (d) J. Li, H. Jiang and M. Chen, J. Org. Chem., 2001, 66, 3627; (e) C. Liu, S. Tang, L. Zheng, D. Liu, H. Zhang and A. Lei, Angew. Chem., Int. Ed., 2012, 51, 5662.
10. (a) I. Gosh and P. A. Jacobi, J. Org. Chem., 2002, 67, 9304; (b) W. P. Roberts, I. Ghosh and P. A. Jacobi, Can. J. Chem., 2004, 82, 279; (c) J. Srogl, G. D. Allred and L. S. Liebeskind, J. Am. Chem. Soc., 1997, 119, 12376.
11. Y. Yu and L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554.
12. Computational method: all the DFT calculations were carried out with the Gaussian 09 series of programs. Geometry optimizations and frequency calculations were performed with the B3LYP method with BSI. All the TS stationary points were correctly connected to the corresponding species. Vibrational frequency calculations also provide thermal corrections for enthalpies and Gibbs free energies (at 298.15 K and 1 atm).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra05104a

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