- Email: [email protected]
Ligand-free copper nanoparticle promoted N-arylation of azoles with aryl and heteroaryl iodides
Tetrahedron Letters 55 (2014) 941–944
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Ligand-free copper nanoparticle promoted N-arylation of azoles with aryl and heteroaryl iodides Gita Pai, Asoke P. Chattopadhyay ⇑ Department of Chemistry, University of Kalyani, Kalyani 741235, India
a r t i c l e
i n f o
Article history: Received 8 July 2013 Revised 13 December 2013 Accepted 17 December 2013 Available online 25 December 2013
a b s t r a c t A relatively mild, efficient, and inexpensive method for the nucleophilic aromatic substitution of the N–H heterocycles with various aryl and heteroaryl iodides using copper nanoparticles (Cu-NP) is reported. The coupling reaction has been successfully achieved with moderate to good yields. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Copper nanoparticles N-Arylindoles N-Arylpyrroles Aryl iodides Ullmann–Goldberg coupling
N-Arylazoles (e.g. N-arylindoles, N-arylpyrroles and N-arylimidazoles, etc.) are important compounds widely employed in organic synthesis, pharmaceutical, and biological areas.1 N-Arylazoles are of interest as antiallergic,2 antipsychotic agents,3 angiotensin II antagonists,4 melatonin receptor MT1 agonists,5 COX-2 inhibitors,6 herbicides,7 and as selective ligands for the G2 binding sites.8 Apart from their biological activities they are used as key intermediates in the synthesis of some biologically active compounds.9 Many synthetic strategies have been developed for the N-arylation of indoles and other heterocycles. In the past few years, significant advances have occurred in the development of cross-coupling methodology. Traditionally, the copper-catalyzed Ullmann–Goldberg coupling is a well-known method for the introduction of amine functionality with the use of aromatic halides, though the scope of these reactions is limited because of high temperatures (150–200 °C), use of stoichiometric amounts of copper reagents, and low yield with longer reaction time.10 Therefore their applications would be restricted. In previous years, great efforts have been directed toward developing highly efficient methods for constructing N-arylazoles11 using some low-cost and efficient ligands such as diamines,12 diimines,13 amino acids,14 b-keto esters,15 diols,16 aminoarenethiolate,17 phosphine ligands,18 hydrazones,19 N-hydroxyimides,20 and hydroxyquinoline21 under mild conditions. Although Pd catalyzed C–N bond formation reactions
⇑ Corresponding author. Tel.: +91 33 2582 8750x305/307 (O), +91 33 2582 9699 (Res); fax: +91 33 2582 8282. E-mail addresses: [email protected], [email protected] (A.P. Chattopadhyay). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.12.065
are well known,22 the ligand-promoted Cu-catalyzed chemistry became general for the N-arylation of indoles, imidazoles, etc. We noticed a remarkable success in the recent Cu-catalyzed C– N coupling reaction in our laboratory. In connection with this, we wish to report herein a general and efficient arylation of N-heterocycles using Cu nanoparticles (Cu-NP), recently synthesized in our laboratory,23 K3PO4 as base in DMSO at 80 °C. The success of previously reported Cu-NP promoted C–C coupling reactions24 encouraged us to extend the application of Cu-NP to the synthesis of N-arylazoles. This is in agreement with a large number of observations worldwide, and is usually explained by the greater surface to volume ratio for metal nanoparticles, also exposing them to oxidation, thereby increasing their reactivity.25 A set of experiments was carried out to optimize the reaction conditions. The C–N coupling reaction between aryl halide and N-heterocycles using Cu-NP was studied with indole (1a) and 1iodo-4-(trifluoromethyl) benzene (2a). The results of these experiments are summarized in Table 1. As expected, in the absence of Cu-NP, the desired product 3a was not obtained (Table 1, entry 1). From entries 2–4, it is observed that yield of the desired product is improved by adding Cu-NP 0.1– 1 equiv. Addition of 3 equiv of Cu-NP and carrying out the reaction at 80 °C for 8 h in DMSO afforded the desired product 3a in a 60% yield (Table 1, entry 2). However, when similar reaction was carried out with 1.6 equiv of Cu-NP, the desired N-arylindole was formed in a 68% yield (Table 1, entry 3). On the other hand, when the reaction time is decreased from 8 h to 5 h, compound 3a was obtained in 82% yield (entry 4). If temperature of the reaction is increased to 110 °C, then the yield of the desired product is
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G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
Table 1 Optimization of conditions for Cu-NP promoted N-arylation of indoles with 1-iodo-4(trifluoromethyl) benzenea
1a
N H
CF3
+ I
Cu-NP, K3PO4
CF3
N
o
DMSO, 80 C, 5h 3a
2a c
Entry
Solvent
Base
Cu-NP (equiv)
Time (h)/(°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF Toluene Dioxane CH3CN DMSO DMSO DMSO DMSO DMSO
K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 KOtBu NaOtBu Et3N Cs2CO3 K2CO3
00 0.1 0.5 1 3 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6
8/80 8/80 8/80 8/80 8/80 8/80 5/80 5/110 5/80 5/80 5/80 5/80 5/80 5/80 5/80 5/80 5/80
00 28 45 54 60 68 82 49 42 30 27 38 55 49 24 66 50
a Reaction conditions: all reactions were performed with 1 mmol of 1a, 1 mmol of 2a, 2 mmol of base, in 1 mL of solvent under an argon atmosphere. b Yield based on LCMS analysis 26. c The same reactions were carried out with Cu(I) and Cu(II) also. For details see Supporting information.
decreased to 49% (entry 5). From entries 6–9, it is apparent that the solvent has a significant role on the reaction; DMSO was found to be quite successful for the transformation. Compound 3a was obtained in 42% yield, when DMF was used instead of DMSO (Table 1, entry 6). When toluene, 1,4-dioxane, and acetonitrile were used as solvents, the desired product was obtained in only 30%, 27%, and 38% yields, respectively (Table 1, entries 7–9). Different bases were also tested in this reaction system (Table 1, entries 10–14) and K3PO4 found to be superior to KOtBu, NaOtBu, Et3N, Cs2CO3, and K2CO3. Thus the optimized reaction condition was found to be 1.6 equiv Cu-NP and 2 equiv K3PO4 in DMSO as solvent at 80 °C for 5 h under an argon atmosphere. After getting optimized reaction conditions, the scope of the N-arylation of pyrroles, indoles, and azaindoles with various substituted aryl and heteroaryl iodides has been examined and the results are summarized in Table 2.27 Aryl and heteroaryl iodides with electron-withdrawing groups in the ortho, meta, or para position afforded the coupling products in excellent yields (Table 2, entries 1, 3, 4, 8, 9, 11, 13, 14 and 16). The reaction of 4-iodopyridine 2f with 1a, 1b, 1c, 1d, and 1e afforded the coupling products in 92%, 94%, 89%, 90%, and 87% yields (Table 2, entries 6, 7, 10, 12 and 15). The electron-donating groups like methyl and methoxy groups in the para position of the aryl halide provided the coupling products in good yields (Table 2, entries 2, 5 and 17) but when the electron donating group is in ortho position, the yield became lower because of steric hindrance (Table 2, entry 18). In conclusion, we have established that Cu-NP is inexpensive and useful for the synthesis of N-arylindoles and N-arylpyrroles.
Table 2 Cu-NP promoted reaction of aryl and heteroaryl iodides with pyrrole, indole, and azaindolea
I Y R1
R
+ X 1a-e
N H
2a-h
2
1.6 equiv Cu-NP, 2 equiv K3 PO4, DMSO 80o C, 5h
Y
X R1
R1
R2
N
3a-r
X = N, = H, Y= CH X= CH, R 1 = H,Y = N X= CH, R 1 = OMe, Y= CH Entry
Indole/pyrrole
1
1a
ArI
CF3
I
2
3
N H
2a
2b
I
O
I
NO2
3a19
3b19
NO2 2d
5
2e
6
2f
I
I
3e19
N
CF3
N
O
79
75
N
84c
O2N 3d29
I
N
NO2 3c28
2c
4
Yieldb (%)
Product
3f30
N
86c
N 78
N
N 92
943
G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944 Table 2 (continued) Entry
Indole/pyrrole
ArI
7
1b
N
N
I N H
O
Yieldb (%)
Product
N
3gd
2f
94
O
NO2
8
N
I
2d
O2N
3hd
80c
O
Cl 9
N
1c
N H
2g
I
Cl N
3id
77
N N
I 10
2f
N
3jd
N 89
N
NO2 11
N
3kd
I
2d
O2N 80c
N N 12
N H
1d
N
I
90
N
NO2 13
N
N 3ld
2f
I
2d
O2N N
3md
79c
N
O2N
NO2 14
1e
N H
3n31
2d
I
15
2f
16
2g
17
2e
N
I
3od
83c
N N
N
Cl
Cl 3p32
I I
3q31
a b c d
2h
I
78
N N
O 18
87
86
O
3r33
75
N
All reactions were carried out using 1 mmol of azoles, 1 mmol of ArI, 2 mmol of K3PO4 in 1 mL DMSO at 80 °C for 5 h. Isolated yields. Reaction was carried out at 80 °C for 2 h. New compounds. Some information given in Supporting information (representative examples of each class above); for example, data for product 3a are given in Ref. 27.
Such ligand-free C–N bond formation reaction was achieved efficiently, under relatively mild conditions and with moderate to good yields. This advantage would prompt the synthetic applications of this Cu-NP mediated C–N bond formation reaction.
Help with laboratory facilities from Prof. T. Basu, Department of Biochemistry & Biophysics of the same university is acknowledged. Assistance from DST-PURSE Grant to the University of Kalyani is hereby acknowledged.
Acknowledgements
Supplementary data
The authors wish to record the help provided by the NMR facility installed in the Department of Chemistry, University of Kalyani, Kalyani, India under the DST-FIST scheme. Helpful discussion with Dr. K. Ghosh of the same department is gratefully acknowledged.
Supplementary data (analytical information and 1H NMR, C NMR and mass spectra of some product compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.065.
13
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G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
References and notes 1. For reviews, see: (a) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton, C. J., Ed.; ; Pergamon Press: New York, 1991; Vol. 8, (b) Negwer, M. In Organic Chemical Drugs and Their Synonyms: An International Survey; Akademic Verlag: Berlin, 1994. 7th ed.; (c) Buckingham, J. B. In Dictionary of Natural Products In ; Chapman and Hall: London, 1994; Vol. 1,. 2. Unangst, P. C.; Connor, D. T.; Stabler, S. S.; Weikert, R. J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.; Chestnut, J. C.; Adolphson, R. L.; Conroy, M. C. J. Med. Chem. 1989, 32, 1360. 3. (a) Perregaard, J.; Arnt, J.; Bogeso, K. P.; Hyttel, J.; Sanchez, C. J. Med. Chem. 1992, 35, 1092; (b) Anderson, K.; Liljefors, T.; Hyttel, J.; Perregaard, J. J. Med. Chem. 1996, 39, 3723. 4. Jahangir Stabler, S. R. Synth. Commun. 1994, 24, 123. 5. Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; DiGiacomo, B.; Tontini, A.; Tarzia, G.; Mor, M.; Plazzi, P. V.; Rivara, S.; Nonno, R.; Pannacci, M.; Lucini, V.; Fraschini, F.; Stankov, B. M. J. Med. Chem. 1998, 41, 3624. 6. Sano, H.; Noguchi, T.; Tanatani, A.; Hashimoto, Y.; Miyachi, H. Bioorg. Med. Chem. 2005, 13, 3079. 7. Pallos, F. M.; Matheus, C. J. U. S. Patent 5, 739, 353 (1996). 8. (a) Sanchez, C.; Arnt, J.; Costall, B.; Kelly, M. E.; Naylor, R. J.; Perregaard, J. J. Pharmacol. Exp. Ther. 1997, 283, 1323; (b) Perregaard, J.; Moltzen, E. K.; Meier, E.; Sanchez, C. J. Med. Chem. 1998, 1995, 38; (c) Sarges, R.; Howard, H. R.; Koe, H. B. K.; Weissman, A. J. Med. Chem. 1989, 32, 437; (d) Wust, F. R.; Kniess, T. J. Labelled Compd. Radiopharm. 2005, 48, 31. 9. (a) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761; (b) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431. 10. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382; (b) Lindley, J. Tetrahedron 1984, 40, 1433; (c) Schnürch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283. 11. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. 12. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. 13. Cristau, H. J.; Cellier, P.; Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004, 10, 5607. 14. Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 695. 15. Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863. 16. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. 17. Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. Org. Lett. 2005, 7, 5241. 18. (a) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005, 61, 6553; (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636; (c) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435. 19. Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614. 20. Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943. 21. Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem. 2005, 70, 10135.
22. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. 23. Chatterjee, A. K.; Sarkar, R. K.; Chattopadhyay, A. P.; Aich, P.; Chakraborty, R.; Basu, T. Nanotechnology 2012, 23, 85103. 24. Pai, G.; Chattopadhyay, A. P. Synthesis 2013, 45(11), 1475. 25. Nanoparticles and Catalysis; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2008. 26. Method of LCMS analysis: In an HPLC machine, the mobile phase was chosen as a mixture of buffer (10 mM ammonium acetate solution in water) and acetonitrile, with a flow rate of 1.2 ml/min. From an initial 90% buffer and 10% acetonitrile, the composition was changed to 70% buffer and 30% acetonitrile after 1.5 min from beginning. This was further changed to 10% buffer and 90% acetonitrile after 3 min from beginning. This was switched to the initial composition after 4 min, and kept thus for 1 min more for a total run time/sample of 5 min. Detection was at 220 and 260 nm, and a c-18, 5 micron column was used. 27. General procedure for Cu-NP catalyzed N-arylations of azoles with aryl halides (Table 2): An oven dried two-necked round bottom flask was charged with aryl halide (1 mmol) and K3PO4 (2 mmol), evacuated, and backfilled with argon. The azole compound (1 mmol) and 2 mL of DMSO were added under argon. After that Cu-NP (1.6 mmol) was added and the flask was again backfilled with argon. The flask was then immersed in a preheated oil bath at 80 °C until the conversion was completed (detected by TLC). The cooled mixture was partitioned between ethyl acetate (10 mL) and saturated NH4Cl (10 mL). The aqueous layer was extracted with ethyl acetate (2 10 mL), the organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate in hexane (1.5–10%) as eluent to afford the desired product. All the products have been characterized by 1H NMR, 13C NMR, and mass spectroscopy. For new products, FTIR data were also recorded. Analytical data of compound 3a: 1H NMR (CDCl3, 500 MHz): d 7.94 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.70–7.68 (m, 2H), 7.27– 7.24 (m, 1H), 7.20–7.17 (m, 1H), 6.79 (d, J = 3.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d 142.8, 135.5, 129.7, 128.3, 127.4, 126.9 (q, J = 59 Hz), 125.4 (q, J = 362 Hz), 123.9, 122.9, 121.4, 121.0, 110.3, 104.9; MS(EI) 262.4 (M+). Anal. Calcd for C15H10F3N: C, 68.96, H, 3.86, N, 5.36. Found: C, 68.89, H, 3.88, N, 5.33. 28. Rao, R. K.; Naidu, A. B.; Jaseer, E. A.; Sekar, G. Tetrahedron 2009, 65, 4619. 29. Xu, H.; Liu, W. Q.; Fan, L. L.; Chen, Y.; Yang, L. M.; Lv, L.; Zheng, Y. T. Chem. Pharm. Bull. 2008, 56, 720. 30. Aoki, H.; Harada, S.; Ishikawa, Y.; Tsujiyama, S.; Fujifilm Fine Chemicals Co., Ltd; Patent, EP1897875 A1, March 12, 2008. 31. Yang, K.; Qiu, Y.; Jiang, S.; Wang, Z.; Li, Z. J. Org. Chem. 2011, 76, 3151. 32. Wilson, M. A.; Filzen, G.; Welmaker, G. S. Tetrahedron Lett. 2009, 50, 4807. 33. Prakash Reddy, V.; Vijay Kumar, A.; Rama Rao, K. Tetrahedron Lett. 2011, 52, 777.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Ligand-free copper nanoparticle promoted N-arylation of azoles with aryl and heteroaryl iodides Gita Pai, Asoke P. Chattopadhyay ⇑ Department of Chemistry, University of Kalyani, Kalyani 741235, India
a r t i c l e
i n f o
Article history: Received 8 July 2013 Revised 13 December 2013 Accepted 17 December 2013 Available online 25 December 2013
a b s t r a c t A relatively mild, efficient, and inexpensive method for the nucleophilic aromatic substitution of the N–H heterocycles with various aryl and heteroaryl iodides using copper nanoparticles (Cu-NP) is reported. The coupling reaction has been successfully achieved with moderate to good yields. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Copper nanoparticles N-Arylindoles N-Arylpyrroles Aryl iodides Ullmann–Goldberg coupling
N-Arylazoles (e.g. N-arylindoles, N-arylpyrroles and N-arylimidazoles, etc.) are important compounds widely employed in organic synthesis, pharmaceutical, and biological areas.1 N-Arylazoles are of interest as antiallergic,2 antipsychotic agents,3 angiotensin II antagonists,4 melatonin receptor MT1 agonists,5 COX-2 inhibitors,6 herbicides,7 and as selective ligands for the G2 binding sites.8 Apart from their biological activities they are used as key intermediates in the synthesis of some biologically active compounds.9 Many synthetic strategies have been developed for the N-arylation of indoles and other heterocycles. In the past few years, significant advances have occurred in the development of cross-coupling methodology. Traditionally, the copper-catalyzed Ullmann–Goldberg coupling is a well-known method for the introduction of amine functionality with the use of aromatic halides, though the scope of these reactions is limited because of high temperatures (150–200 °C), use of stoichiometric amounts of copper reagents, and low yield with longer reaction time.10 Therefore their applications would be restricted. In previous years, great efforts have been directed toward developing highly efficient methods for constructing N-arylazoles11 using some low-cost and efficient ligands such as diamines,12 diimines,13 amino acids,14 b-keto esters,15 diols,16 aminoarenethiolate,17 phosphine ligands,18 hydrazones,19 N-hydroxyimides,20 and hydroxyquinoline21 under mild conditions. Although Pd catalyzed C–N bond formation reactions
⇑ Corresponding author. Tel.: +91 33 2582 8750x305/307 (O), +91 33 2582 9699 (Res); fax: +91 33 2582 8282. E-mail addresses: [email protected], [email protected] (A.P. Chattopadhyay). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.12.065
are well known,22 the ligand-promoted Cu-catalyzed chemistry became general for the N-arylation of indoles, imidazoles, etc. We noticed a remarkable success in the recent Cu-catalyzed C– N coupling reaction in our laboratory. In connection with this, we wish to report herein a general and efficient arylation of N-heterocycles using Cu nanoparticles (Cu-NP), recently synthesized in our laboratory,23 K3PO4 as base in DMSO at 80 °C. The success of previously reported Cu-NP promoted C–C coupling reactions24 encouraged us to extend the application of Cu-NP to the synthesis of N-arylazoles. This is in agreement with a large number of observations worldwide, and is usually explained by the greater surface to volume ratio for metal nanoparticles, also exposing them to oxidation, thereby increasing their reactivity.25 A set of experiments was carried out to optimize the reaction conditions. The C–N coupling reaction between aryl halide and N-heterocycles using Cu-NP was studied with indole (1a) and 1iodo-4-(trifluoromethyl) benzene (2a). The results of these experiments are summarized in Table 1. As expected, in the absence of Cu-NP, the desired product 3a was not obtained (Table 1, entry 1). From entries 2–4, it is observed that yield of the desired product is improved by adding Cu-NP 0.1– 1 equiv. Addition of 3 equiv of Cu-NP and carrying out the reaction at 80 °C for 8 h in DMSO afforded the desired product 3a in a 60% yield (Table 1, entry 2). However, when similar reaction was carried out with 1.6 equiv of Cu-NP, the desired N-arylindole was formed in a 68% yield (Table 1, entry 3). On the other hand, when the reaction time is decreased from 8 h to 5 h, compound 3a was obtained in 82% yield (entry 4). If temperature of the reaction is increased to 110 °C, then the yield of the desired product is
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G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
Table 1 Optimization of conditions for Cu-NP promoted N-arylation of indoles with 1-iodo-4(trifluoromethyl) benzenea
1a
N H
CF3
+ I
Cu-NP, K3PO4
CF3
N
o
DMSO, 80 C, 5h 3a
2a c
Entry
Solvent
Base
Cu-NP (equiv)
Time (h)/(°C)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF Toluene Dioxane CH3CN DMSO DMSO DMSO DMSO DMSO
K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 KOtBu NaOtBu Et3N Cs2CO3 K2CO3
00 0.1 0.5 1 3 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6 1.6
8/80 8/80 8/80 8/80 8/80 8/80 5/80 5/110 5/80 5/80 5/80 5/80 5/80 5/80 5/80 5/80 5/80
00 28 45 54 60 68 82 49 42 30 27 38 55 49 24 66 50
a Reaction conditions: all reactions were performed with 1 mmol of 1a, 1 mmol of 2a, 2 mmol of base, in 1 mL of solvent under an argon atmosphere. b Yield based on LCMS analysis 26. c The same reactions were carried out with Cu(I) and Cu(II) also. For details see Supporting information.
decreased to 49% (entry 5). From entries 6–9, it is apparent that the solvent has a significant role on the reaction; DMSO was found to be quite successful for the transformation. Compound 3a was obtained in 42% yield, when DMF was used instead of DMSO (Table 1, entry 6). When toluene, 1,4-dioxane, and acetonitrile were used as solvents, the desired product was obtained in only 30%, 27%, and 38% yields, respectively (Table 1, entries 7–9). Different bases were also tested in this reaction system (Table 1, entries 10–14) and K3PO4 found to be superior to KOtBu, NaOtBu, Et3N, Cs2CO3, and K2CO3. Thus the optimized reaction condition was found to be 1.6 equiv Cu-NP and 2 equiv K3PO4 in DMSO as solvent at 80 °C for 5 h under an argon atmosphere. After getting optimized reaction conditions, the scope of the N-arylation of pyrroles, indoles, and azaindoles with various substituted aryl and heteroaryl iodides has been examined and the results are summarized in Table 2.27 Aryl and heteroaryl iodides with electron-withdrawing groups in the ortho, meta, or para position afforded the coupling products in excellent yields (Table 2, entries 1, 3, 4, 8, 9, 11, 13, 14 and 16). The reaction of 4-iodopyridine 2f with 1a, 1b, 1c, 1d, and 1e afforded the coupling products in 92%, 94%, 89%, 90%, and 87% yields (Table 2, entries 6, 7, 10, 12 and 15). The electron-donating groups like methyl and methoxy groups in the para position of the aryl halide provided the coupling products in good yields (Table 2, entries 2, 5 and 17) but when the electron donating group is in ortho position, the yield became lower because of steric hindrance (Table 2, entry 18). In conclusion, we have established that Cu-NP is inexpensive and useful for the synthesis of N-arylindoles and N-arylpyrroles.
Table 2 Cu-NP promoted reaction of aryl and heteroaryl iodides with pyrrole, indole, and azaindolea
I Y R1
R
+ X 1a-e
N H
2a-h
2
1.6 equiv Cu-NP, 2 equiv K3 PO4, DMSO 80o C, 5h
Y
X R1
R1
R2
N
3a-r
X = N, = H, Y= CH X= CH, R 1 = H,Y = N X= CH, R 1 = OMe, Y= CH Entry
Indole/pyrrole
1
1a
ArI
CF3
I
2
3
N H
2a
2b
I
O
I
NO2
3a19
3b19
NO2 2d
5
2e
6
2f
I
I
3e19
N
CF3
N
O
79
75
N
84c
O2N 3d29
I
N
NO2 3c28
2c
4
Yieldb (%)
Product
3f30
N
86c
N 78
N
N 92
943
G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944 Table 2 (continued) Entry
Indole/pyrrole
ArI
7
1b
N
N
I N H
O
Yieldb (%)
Product
N
3gd
2f
94
O
NO2
8
N
I
2d
O2N
3hd
80c
O
Cl 9
N
1c
N H
2g
I
Cl N
3id
77
N N
I 10
2f
N
3jd
N 89
N
NO2 11
N
3kd
I
2d
O2N 80c
N N 12
N H
1d
N
I
90
N
NO2 13
N
N 3ld
2f
I
2d
O2N N
3md
79c
N
O2N
NO2 14
1e
N H
3n31
2d
I
15
2f
16
2g
17
2e
N
I
3od
83c
N N
N
Cl
Cl 3p32
I I
3q31
a b c d
2h
I
78
N N
O 18
87
86
O
3r33
75
N
All reactions were carried out using 1 mmol of azoles, 1 mmol of ArI, 2 mmol of K3PO4 in 1 mL DMSO at 80 °C for 5 h. Isolated yields. Reaction was carried out at 80 °C for 2 h. New compounds. Some information given in Supporting information (representative examples of each class above); for example, data for product 3a are given in Ref. 27.
Such ligand-free C–N bond formation reaction was achieved efficiently, under relatively mild conditions and with moderate to good yields. This advantage would prompt the synthetic applications of this Cu-NP mediated C–N bond formation reaction.
Help with laboratory facilities from Prof. T. Basu, Department of Biochemistry & Biophysics of the same university is acknowledged. Assistance from DST-PURSE Grant to the University of Kalyani is hereby acknowledged.
Acknowledgements
Supplementary data
The authors wish to record the help provided by the NMR facility installed in the Department of Chemistry, University of Kalyani, Kalyani, India under the DST-FIST scheme. Helpful discussion with Dr. K. Ghosh of the same department is gratefully acknowledged.
Supplementary data (analytical information and 1H NMR, C NMR and mass spectra of some product compounds) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.065.
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References and notes 1. For reviews, see: (a) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton, C. J., Ed.; ; Pergamon Press: New York, 1991; Vol. 8, (b) Negwer, M. In Organic Chemical Drugs and Their Synonyms: An International Survey; Akademic Verlag: Berlin, 1994. 7th ed.; (c) Buckingham, J. B. In Dictionary of Natural Products In ; Chapman and Hall: London, 1994; Vol. 1,. 2. Unangst, P. C.; Connor, D. T.; Stabler, S. S.; Weikert, R. J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.; Chestnut, J. C.; Adolphson, R. L.; Conroy, M. C. J. Med. Chem. 1989, 32, 1360. 3. (a) Perregaard, J.; Arnt, J.; Bogeso, K. P.; Hyttel, J.; Sanchez, C. J. Med. Chem. 1992, 35, 1092; (b) Anderson, K.; Liljefors, T.; Hyttel, J.; Perregaard, J. J. Med. Chem. 1996, 39, 3723. 4. Jahangir Stabler, S. R. Synth. Commun. 1994, 24, 123. 5. Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; DiGiacomo, B.; Tontini, A.; Tarzia, G.; Mor, M.; Plazzi, P. V.; Rivara, S.; Nonno, R.; Pannacci, M.; Lucini, V.; Fraschini, F.; Stankov, B. M. J. Med. Chem. 1998, 41, 3624. 6. Sano, H.; Noguchi, T.; Tanatani, A.; Hashimoto, Y.; Miyachi, H. Bioorg. Med. Chem. 2005, 13, 3079. 7. Pallos, F. M.; Matheus, C. J. U. S. Patent 5, 739, 353 (1996). 8. (a) Sanchez, C.; Arnt, J.; Costall, B.; Kelly, M. E.; Naylor, R. J.; Perregaard, J. J. Pharmacol. Exp. Ther. 1997, 283, 1323; (b) Perregaard, J.; Moltzen, E. K.; Meier, E.; Sanchez, C. J. Med. Chem. 1998, 1995, 38; (c) Sarges, R.; Howard, H. R.; Koe, H. B. K.; Weissman, A. J. Med. Chem. 1989, 32, 437; (d) Wust, F. R.; Kniess, T. J. Labelled Compd. Radiopharm. 2005, 48, 31. 9. (a) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761; (b) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431. 10. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382; (b) Lindley, J. Tetrahedron 1984, 40, 1433; (c) Schnürch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283. 11. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. 12. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. 13. Cristau, H. J.; Cellier, P.; Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004, 10, 5607. 14. Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 695. 15. Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863. 16. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. 17. Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. Org. Lett. 2005, 7, 5241. 18. (a) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005, 61, 6553; (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636; (c) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435. 19. Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614. 20. Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943. 21. Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem. 2005, 70, 10135.
22. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. 23. Chatterjee, A. K.; Sarkar, R. K.; Chattopadhyay, A. P.; Aich, P.; Chakraborty, R.; Basu, T. Nanotechnology 2012, 23, 85103. 24. Pai, G.; Chattopadhyay, A. P. Synthesis 2013, 45(11), 1475. 25. Nanoparticles and Catalysis; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2008. 26. Method of LCMS analysis: In an HPLC machine, the mobile phase was chosen as a mixture of buffer (10 mM ammonium acetate solution in water) and acetonitrile, with a flow rate of 1.2 ml/min. From an initial 90% buffer and 10% acetonitrile, the composition was changed to 70% buffer and 30% acetonitrile after 1.5 min from beginning. This was further changed to 10% buffer and 90% acetonitrile after 3 min from beginning. This was switched to the initial composition after 4 min, and kept thus for 1 min more for a total run time/sample of 5 min. Detection was at 220 and 260 nm, and a c-18, 5 micron column was used. 27. General procedure for Cu-NP catalyzed N-arylations of azoles with aryl halides (Table 2): An oven dried two-necked round bottom flask was charged with aryl halide (1 mmol) and K3PO4 (2 mmol), evacuated, and backfilled with argon. The azole compound (1 mmol) and 2 mL of DMSO were added under argon. After that Cu-NP (1.6 mmol) was added and the flask was again backfilled with argon. The flask was then immersed in a preheated oil bath at 80 °C until the conversion was completed (detected by TLC). The cooled mixture was partitioned between ethyl acetate (10 mL) and saturated NH4Cl (10 mL). The aqueous layer was extracted with ethyl acetate (2 10 mL), the organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate in hexane (1.5–10%) as eluent to afford the desired product. All the products have been characterized by 1H NMR, 13C NMR, and mass spectroscopy. For new products, FTIR data were also recorded. Analytical data of compound 3a: 1H NMR (CDCl3, 500 MHz): d 7.94 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.70–7.68 (m, 2H), 7.27– 7.24 (m, 1H), 7.20–7.17 (m, 1H), 6.79 (d, J = 3.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): d 142.8, 135.5, 129.7, 128.3, 127.4, 126.9 (q, J = 59 Hz), 125.4 (q, J = 362 Hz), 123.9, 122.9, 121.4, 121.0, 110.3, 104.9; MS(EI) 262.4 (M+). Anal. Calcd for C15H10F3N: C, 68.96, H, 3.86, N, 5.36. Found: C, 68.89, H, 3.88, N, 5.33. 28. Rao, R. K.; Naidu, A. B.; Jaseer, E. A.; Sekar, G. Tetrahedron 2009, 65, 4619. 29. Xu, H.; Liu, W. Q.; Fan, L. L.; Chen, Y.; Yang, L. M.; Lv, L.; Zheng, Y. T. Chem. Pharm. Bull. 2008, 56, 720. 30. Aoki, H.; Harada, S.; Ishikawa, Y.; Tsujiyama, S.; Fujifilm Fine Chemicals Co., Ltd; Patent, EP1897875 A1, March 12, 2008. 31. Yang, K.; Qiu, Y.; Jiang, S.; Wang, Z.; Li, Z. J. Org. Chem. 2011, 76, 3151. 32. Wilson, M. A.; Filzen, G.; Welmaker, G. S. Tetrahedron Lett. 2009, 50, 4807. 33. Prakash Reddy, V.; Vijay Kumar, A.; Rama Rao, K. Tetrahedron Lett. 2011, 52, 777.