Microwave-assisted solvent- and ligand-free copper-catalysed cross-coupling between halopyridines and nitrogen nucleophiles

Abstract

N-Heteroarylated products are obtained in good yields by microwave-assisted solvent- and ligand-free copper-catalysed amination of halopyridines with nitrogen nucleophiles.

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Substituted N-heterocycles are prevalent in biologically active compounds. Pyridine derivatives such as N-pyridinylpyrazoles, -imidazoles, -pyrroles, -indoles and -amides have attracted particular attention, and several of those compounds have found use in the biological, pharmaceutical and material sciences.¹ Furthermore, they proved promising as ligands in metal catalysis.² The required core structures can generally be assembled in a straightforward manner by copper-catalysed Ullmann-type reactions. However, the classical versions of this cross-coupling³ have several drawbacks, which greatly restrict their applications in industry. For example, they often require stoichiometric amounts of a copper reagent, a high reaction temperature and a polar solvent. Consequently, great efforts have been made to improve the efficiency of Ullmann-type reactions.⁴ Although many copper/ligand combinations are known to perform these transformations under comparatively mild conditions, there is still a need to find even simpler catalyst systems.^4a,5 Ideally, they should be ligand-free⁶ and proceed in “green” solvents or even be solvent-free.^7,8 Also microwave irradiation is of great importance in the context of green synthesis and sustainable chemistry,⁹ and it is also known to accelerate copper-mediated C–N coupling.^6i,7b–c,10 In 2004, Gawley and co-workers reported S_NAr reactions of halopyridines with pyrrolidine and piperidine derivatives under microwave irradiation, but a high temperature (130 °C) was required, and 3-halopyridines did not react at all.^7b More recently, Liu and co-workers described copper-promoted amination reactions using microwave techniques.⁶ⁱ This method, however, needs stoichiometric amounts of copper reagents. In a continuation of our search for simple and environmentally friendly catalyst systems for C–N couplings,^6b we herein disclose our findings on microwave-assisted solvent- and ligand-free copper-catalysed amination of halopyridines with various nitrogen nucleophiles leading to pyridinyl-substituted pyrazoles, imidazoles, pyrroles, indoles and amides.¹¹

To establish the most efficient solvent- and ligand-free catalyst system under microwave irradiation conditions, various bases and copper sources were screened using the coupling of 3-iodopyridine (1a) with pyrazole (2a) as a model reaction. The results are summarised in Table 1. With reference to our previous report on ligand-free copper-catalysed N-arylation,^6b all experiments were initially performed with 10 mol% of Cu₂O and 2.0 equiv. of base under microwave irradiation at 100 °C for 0.5 h (Table 1, entries 1–8).¹² Several bases proved applicable furnishing the coupling product, N-pyridinylpyrazole (3a), in yields ranging from 10–91%. Use of Cs₂CO₃ and K₃PO₄·H₂O gave the best results affording the coupling product in 83 and 91% yield, respectively (entries 1 and 7). Using an excess of 3-iodopyridine resulted in a decrease in yield (entry 8). Also other copper sources such as CuI and CuBr catalysed the coupling reaction, but the yields of 3a were slightly lower than with Cu₂O (entries 9 and 10). Control experiments confirmed that neither with the base alone (entry 11) nor in the absence of copper and base (entry 12) was the heteroarylated product formed. Thus, the cross-coupling did not proceed by a S_NAr mechanism.¹³

Table 1 Screening of bases and copper sources in the N-arylation of pyrazole^a

Entry	Cu source	Base	Yield of 3a (%)^b
a Reaction conditions: 3-iodopyridine (1a, 0.5 mmol), pyrazole (2a, 0.65 mmol), copper source (0.05 mmol), base (1.0 mmol), 100 °C, MW (50 W), 0.5 h. b Referring to the amount of product isolated by chromatography. c Use of 0.65 mmol of 1a and 0.5 mmol of 2a.
1	Cu2O	Cs2CO3	83
2	Cu2O	K2CO3	70
3	Cu2O	Na2CO3	10
4	Cu2O	t-BuOK	39
5	Cu2O	t-BuONa	69
6	Cu2O	K3PO4	76
7	Cu2O	K3PO4·H2O	91
8^c	Cu2O	K3PO4·H2O	61
9	CuI	K3PO4·H2O	66
10	CuBr	K3PO4·H2O	77
11	—	K3PO4·H2O	Traces
12	—	—	0

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Encouraged by the results of the reaction between 1a and 2a, the substrate scope of the microwave-assisted solvent- and ligand-free coupling was investigated. As shown in Table 2, the reactions between 3-iodopyridine (1a) and various heterocycles such as pyrazole, imidazole, pyrrole and indole proceeded well. In all cases the corresponding N-3-pyridinyl-substituted heterocycles were obtained, and the yields were moderate to excellent (up to 91%, Table 2, entries 1–4). Furthermore, 2-pyrrolidinone and acetamide coupled well with 1a affording the corresponding products in 90 and 74% yields, respectively (entries 5 and 6). The N-heteroarylation of phenylmethyl sulfoximine¹⁴ gave product 3g in 55% yield (entry 7).¹⁵Alkyl and aromatic amines did not react with 1a under these conditions (entries 8 and 9). However, when the temperature was raised to 130 °C and Cs₂CO₃ was used instead of K₃PO₄·H₂O the coupling between 3-iodopyridine (1a) and benzylamine led to 3h albeit only in 12% yield (entry 8).

Table 2 Coupling of 3-iodopyridine (1a) with various nitrogen nucleophiles under microwave-assisted solvent- and ligand-free conditions

Entry	RR′NH	Product		Yield (%)^a
a Referring to the amount of product isolated by chromatography. b Cs2CO3 was used instead of K3PO4·H2O. c In parentheses: reaction performed at 130 °C.
1			3a	91
2			3b	87
3^b			3c	50
4^b			3d	64
5^b			3e	90
6			3f	74
7^b			3g	55
8			3h	0 (12)^c
9			3i	0

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To compare relative reactivity, coupling between pyrazole (2a) and substituted pyridines having various leaving groups in 2,- 3- or 4-position was examined. The data are shown in Table 3. The best results were achieved in coupling of the iodo-substituted pyridines leading to the corresponding products in up to 91% (entries 1, 6, and 10). Also bromo derivatives coupled, but the yields are lower (up to 74%; entries 2, 7, and 11). 3-Chloro- and 3-fluoropyridine showed a very low reactivity, and the corresponding product was obtained in only 7 and 10% yield, respectively (entries 3 and 4). The coupling of pyrazole with 2-fluoropyridine and the hydrochlorides of 4-chloro- and 4-fluoropyridine afforded the products in moderate yields (entries 8, 9 and 13), and those reactions probably involved a S_NAr mechanisms. Low yields were observed in coupling of 2-chloropyridine (entry 12) and 3-substituted chloro- fluoro- and trifluoromethylsulfonyl pyridines (entries 3–5). Overall the following reactivity order could be inferred: I > Br ≫ Cl ≈ F ≫ OTf.¹³

Table 3 N-Heteroarylation of pyrazole with various halopyridines under microwave-assisted solvent- and ligand-free conditions

Entry	Halopyridine	Product		Yield (%)^a
a Referring to the amount of product isolated by chromatography. b Starting from hydrochloride of the halo pyridine and using 3.0 equiv. of K3PO4·H2O.
1			3a	91 (X = I)
2				60 (X = Br)
3				7 (X = Cl)
4				10 (X = F)
5				0 (X = OTf)
6			4	86 (X = I)
7^b				42 (X = Br)
8^b				58 (X = Cl)
9^b				47 (X = F)
10			5	80 (X = I)
11				74 (X = Br)
12				22 (X = Cl)
13				50 (X = F)

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In summary, copper-catalysed coupling reaction of halo pyridines with various nitrogen nucleophiles can be performed under microwave-assisted solvent- and ligand-free conditions providing the corresponding coupling products in moderate to high yields. Further studies to find alternative and “greener” catalyst systems and to expand the substrate scope are currently in progress in our laboratories.

Experimental section

Procedure for N-heteroarylations of nitrogen nucleophiles (example: synthesis of 3-(1H-pyrazol-1-yl)pyridine (3a)

After cooling of an oven-dried tube to room temperature under argon, it was charged with 3-iodopyridine (1a, 102.5 mg, 0.5 mmol), pyrazole (2a, 45 mg, 0.65 mmol), Cu₂O (7.2 mg, 0.05 mmol) and K₃PO₄·H₂O (231 mg, 1.0 mmol). The tube was sealed under argon and placed into a CEM Discover microwave apparatus. Initially, an irradiation power of 50 W was applied. When the temperature reached 100 °C, the instrument automatically adjusted the power to maintain a constant temperature. After a total heating time of 1 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL; use of less solvent can reduce the yield.) The resulting solution was filtered through a pad of silica gel and concentrated to give the crude product. Purification by silica gel chromatography (1 : 1 pentane/ethyl acetate) gave 3-(1H-pyrazol-1-yl)pyridine (3a, 66 mg, 91%) as a yellowish oil. The identity and purity of the product was confirmed by ¹H and ¹³C NMR spectroscopic analysis. See the ESI† for full details.

Acknowledgements

We are grateful to the Fonds der Chemischen Industrie for financial support. ZJL thanks Bayer CropScience for postdoctoral funding.

Notes and references

1. (a) T. T. Denton, X. Zhang and J. R. Cashman, J. Med. Chem., 2005, 48, 224; (b) H.-C. Zhang, C. K. Derian, D. F. McComsey, K. B. White, H. Ye, L. R. Hecker, J. Li, M. F. Addo, D. Croll, A. J. Eckardt, C. E. Smith, Q. Li, W.-M. Cheung, B. R. Conway, S. Emanuel, K. T. Demarest, P. Andrade-Gorden, B. P. Damiano and B. E. Maryanoff, J. Med. Chem., 2005, 48, 1725; (c) J. Roppe, N. D. Smith, D. Huang, L. Tehrani, B. Wang, J. Anderson, J. Brodkin, J. Chung, X. Jiang, C. King, B. Munoz, M. A. Varney, P. Prasit and N. D. P. Cosford, J. Med. Chem., 2004, 47, 4645; (d) Y. Wang, Y. Li and B. Wang, Int. J. Mol. Sci., 2007, 8, 166; (e) N. P. Buu-Hoi, R. Rips and R. Cavier, J. Med. Chem., 1960, 2, 335; (f) A. M. Crider, R. Lamey, H. G. Floss and J. M. Cassady, J. Med. Chem., 1980, 23, 848; (g) L. He, L. Duan, J. Qiao, R. Wang, P. Wei, L. Wang and Y. Qiu, Adv. Funct. Mater., 2008, 18, 2123.
2. (a) K. H. Sugiyarto and H. A. Goodwin, Aust. J. Chem., 1988, 41, 1645; (b) J. Elguero, A. Fruchier, A. de la Hoz, F. A. Jalón, B. R. Manzano, A. Otero and F. Gómez-de la Torre, Chem. Ber., 1996, 129, 589; (c) J. A. A. W. Elemans, E. J. A. Bijsterveld, A. E. Rowan and R. J. M. Nolte, Eur. J. Org. Chem., 2007, 751.
3. (a) F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 2382; (b) F. Ullmann, Ber. Dtsch. Chem. Ges., 1904, 37, 853.
4. For reviews, see: (a) F. Monnier and M. Taillefer, Angew. Chem. Int. Ed., 2009, 48, 6954; (b) D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 1450; (c) S. V. Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003, 42, 5400; (d) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428; (e) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337; (f) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651; (g) M. Carril, R. SanMartin and E. Domínguez, Chem. Soc. Rev., 2008, 37, 639.
5. F. Monnier and M. Taillefer, Angew. Chem. Int. Ed., 2008, 47, 3096.
6. For examples of ligand-free catalyst systems, see: (a) M. Taillefer, N. Xia and A. Oualli, Angew. Chem. Int. Ed., 2007, 46, 934; (b) A. Correa and C. Bolm, Adv. Synth. Catal., 2007, 349, 2673; (c) E. Sperotto, J. G. de Vries, G. P. M. van Klink and G. van Koten, Tetrahedron Lett., 2007, 48, 7366; (d) T. Kubo, C. Katoh, K. Yamada, K. Okano, H. Tokuyama and T. Fukuyama, Tetrahedron, 2008, 64, 11230; (e) J. L. Bolliger and C. M. Frech, Tetrahedron, 2009, 65, 1180; (f) X.-M. Wu and Y. Wang, J. Chem. Res., 2009, 555; (g) L. Zhu, P. Guo, G. Li, J. Lan, R. Xie and J. You, J. Org. Chem., 2007, 72, 8535; (h) J. W. W. Chang, X. Xu and P. W. H. Chan, Tetrahedron Lett., 2007, 48, 245; (i) H. Huang, X. Yan, W. Zhu, H. Liu, H. Jiang and K. Chen, J. Comb. Chem., 2008, 10, 617.
7. For examples of solvent-free catalyst systems, see: (a) F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 5, 793; (b) S. Narayan, T. Seelhammer and R. E. Gawley, Tetrahedron Lett., 2004, 45, 757; (c) W. S. Chow and T. H. Chan, Tetrahedron Lett., 2009, 50, 1286; (d) general review: P. J. Walsh, H. Li and C. Anaya de Parrodi, Chem. Rev., 2007, 107, 2503.
8. It should be, however, noted that solvent-free exothermic reactions can be problematic because a thermal buffer is missing. For a related study, see: L. Balland, N. Mouhab, J.-M. Cosmao and L. Estel, Chem. Eng. Proc., 2002, 41, 395.
9. (a) Microwave Methods in Organic Synthesis, ed. M. Larhed and K. Olofsson, Springer-Verlag, Berlin, 2006; (b) Microwaves in Organic Synthesis, 2nd edition, ed. A. Loupy, Wiley-VCH, Weinheim, 2006; (c) C. O. Kappe and A. Stadler, Microwaves in Organic and Medicinal Chemistry, Wiley-VCH, Weinheim, 2005.
10. (a) L. Shi, M. Wang, C.-A. Fan, F.-M. Zhang and Y.-Q. Tu, Org. Lett., 2003, 5, 3515; (b) M. Meciarová, J. Podlesná and S. Toma, Monatsh. Chem., 2004, 135, 419; (c) S.-Y. Chen, H. Huang, X.-J. Liu, J.-K. Shen, H.-L. Jiang and H. Liu, J. Comb. Chem., 2008, 10, 358; (d) M. Poirier, S. Goudreau, J. Poulin, J. Savoie and P. L. Beauliu, Org. Lett., 2010, 12, 2334.
11. For other copper-catalysed N-heteroarylations of nitrogen nucleophiles with heteroaryl halides, see: (a) D. Cheng, F. Gan, W. Qian and W. Bao, Green Chem., 2008, 10, 171; (b) F. Li and T. S. A. Hor, Chem. Eur. J., 2009, 15, 10585; (c) Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chen and B. Wan, Tetrahedron, 2006, 62, 4435; (d) D. Zhu, R. Wang, J. Mao, L. Xu, F. Wu and B. Wan, J. Mol. Catal. A: Chem., 2006, 256, 256; (e) Z. Xi, F. Liu, Y. Zhou and W. Chen, Tetrahedron, 2008, 64, 4254; (f) P. Vera-Luque, R. Alajarín, J. Alvarez-Builla and J. J. Vaquero, Org. Lett., 2006, 8, 415; (g) M. A. Khan and J. B. Polya, J. Chem. Soc. (C), 1970, 85; (h) J. Baffoe, M. Y. Hoe and B. B. Touré, Org. Lett., 2010, 12, 1532; (i) F. Lang, D. Zewge, I. N. Houpis and R. P. Volante, Tetrahedron Lett., 2001, 42, 3251; (j) X. Han, Tetrahedron Lett., 2010, 51, 360; (k) V. S. C. Yeh and P. E. Wiedeman, Tetrahedron Lett., 2006, 47, 6011; (l) H. Zhang, Q. Cai and D. Ma, J. Org. Chem., 2005, 70, 5164; (m) J. B. Arterburn, M. Pannala and A. M. Gonzalez, Tetrahedron Lett., 2001, 42, 1475; (n) J. C. Antilla, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 11684; (o) H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer, Eur. J. Org. Chem., 2004, 695; (p) A. Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 8742; (q) X. Han, Tetrahedron Lett., 2010, 51, 360.
12. In the MW experiments, the temperature was measured by an internal thermocouple. The setting power of the MW instrument was 50 W during the entire reaction time. When the temperature reached 100 °C, the instrument automatically adjusted the power to maintain this temperature.
13. For recent mechanistic studies on copper-catalysed cross-couplings, see: (a) E. R. Strieter, B. Bhayana and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 78; (b) G. O. Jones, P. Liu, K. N. Houk and S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 6205; (c) P.-F. Larsson, C. Bolm and P.-O. Norrby, Chem. Eur. J. accepted for publication.
14. Sulfoximines have been found to be effective chiral ligands in several catalytic asymmetric reactions by our group. For recent examples, see: (a) M. Frings, I. Atodiresei, J. Runsink, G. Raabe and C. Bolm, Chem. Eur. J., 2009, 15, 1566; (b) M. Frings and C. Bolm, Eur. J. Org. Chem., 2009, 4085; (c) S.-M. Lu and C. Bolm, Chem. Eur. J., 2008, 14, 7513; (d) S.-M. Lu and C. Bolm, Adv. Synth. Catal., 2008, 350, 1101; (e) M. Langner and C. Bolm, Angew. Chem., Int. Ed., 2004, 43, 5984; (f) M. Langner, P. Rémy and C. Bolm, Chem. Eur. J., 2005, 11, 6254; (g) P. Rémy, M. Langner and C. Bolm, Org. Lett., 2006, 6, 1209; (h) C. Moessner and C. Bolm, Angew. Chem. Int. Ed., 2005, 44, 7564.
15. The optimised solvent- and ligand-free conditions [10 mol% of Cu₂O, 2.0 equiv. of Cs₂CO₃, 100 °C, MW (50 W), 1 h] can also be applied in the coupling between phenyl iodide and S-methyl-S-phenylsulfoximine to give the corresponding N-arylated product in 72% yield.

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Footnote

† Electronic supplementary information (ESI) available: Further experimental details. See DOI: 10.1039/c0gc00296h

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