Cu(acac)2 catalyzed oxidative C–H bond amination of azoles with amines under base-free conditions

Tetrahedron Letters 53 (2012) 6500–6503

Contents lists available at SciVerse ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Cu(acac)2 catalyzed oxidative C–H bond amination of azoles with amines under base-free conditions Yogesh S. Wagh, Bhalchandra M. Bhanage ⇑ Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai 400019, India

a r t i c l e

i n f o

Article history: Received 7 August 2012 Revised 13 September 2012 Accepted 15 September 2012 Available online 2 October 2012 Keywords: Aminoheterocycles Oxidative amination C–H activation Homogeneous catalysis Azoles

a b s t r a c t This work reports a simple and efficient methodology for oxidative C–H bond amination of azoles with aromatic/aliphatic amines using copper-bis-acetylacetonate complex catalyst. The catalyst works very well in the absence of external acid or base and requires only molecular oxygen as an oxidant. The methodology is applicable for the oxidative C–H bond amination of various azoles with different types of aromatic/aliphatic amines for the synthesis of various aminoheterocycles with good to excellent yields. Ó 2012 Elsevier Ltd. All rights reserved.

Transition-metal-catalyzed C–N bond formation reactions of heteroarenes are very important transformations in organic synthesis. Aminoheterocycles are widely applicable in biological systems, pharmaceuticals, and material sciences.1 They can be synthesized via palladium-catalyzed Buchwald–Hartwig coupling2 and copper-catalyzed Ullmann and Goldberg coupling3 reactions. Although considerable progress has been made in this direction, still there are some disadvantages, such as requirement of high temperature, longer reaction time, requirement of ligands, and non-economic effects. Hence, to develop greener and more simplified methods, direct C–H bond amination of heteroarenes has been reported by several researchers.4,5 The transition-metal-catalyzed selective C–H bond functionalization reactions of arenes and heteroarenes have significant importance in organic synthesis because of its high atom efficiency compared to related cross-coupling reactions using organometallic compounds. In particular, the oxidative C–H bond amination reaction of heteroarenes for the synthesis of various aminoheterocycles is important because of its wide range of applications in the synthesis of biologically active compounds and organic intermediates.6,7 Selective oxidative functionalization of C–H bonds in heteroarenes with amines is one of the challenging transformations. In this direction various research groups have reported oxidative C–H bond amination reactions of azoles using various transition metal catalysts such as Cu(II), Ag(I), Co(II), Mn(II), and

Fe(III).8 The oxidative C–H bond amination of benzoxazoles has been explored satisfactorily and successfully at metal-free conditions.9 Although there are several reports on oxidative C–H bond amination of benzoxazoles, the reported protocols have some drawbacks such as the use of stoichiometric amount of carboxylic acid as a promoter and non-greener peroxide oxidants. Oxidative C–H bond amination of other azoles is comparatively more challenging and was not well studied. In this direction, Mori and coworkers for the first time developed a copper-catalyzed oxidative C–H bond amination of azoles in the presence of phosphine ligand and stoichiometric amount of base under oxygen atmosphere.10 However, the use of stoichiometric amount of base and phosphine ligand is not attractive as phosphines are highly susceptible for oxidation in the presence of molecular oxygen. In this context, herein we describe a simple, efficient, and well defined copper-bis-acetylacetonate [Cu(acac)2] catalyzed methodology for direct oxidative C–H bond amination of azoles under base-free and any additional ligand-free conditions (Scheme 1).11 High solubility of Cu(acac)2 complex in organic solvents, indefinite shelf life, stability toward air, and compatibility with various

R1

N H + HN

R2

X

⇑ Corresponding author. Tel.: +91 22 33612601; fax: +91 22 33611020. E-mail addresses: [email protected], [email protected] (B.M. Bhanage). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.09.064

1 X= S/O/NR

2

Cu(acac)2, O2 xylene, 140°C

R1

N N X 3

Scheme 1. Cu(acac)2 catalyzed oxidative amination of azoles.

R2

6501

Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503 Table 1 Oxidative C–H bond amination reaction of benzothiazole (1) with N-methylaniline (2a)a

N S

Ph

1 Entry 1 2 3 4 5 6 7 8 a

Entry

N

Cu catalyst

H + HN

Table 2 Optimization of oxidative C–H bond amination reactiona

N

xylene, 140°C

S

2a

Ph

3

Copper catalyst (10 mol %)

Oxidant

Cu(OAc)2 Cu(OTf)2 Cu(acac)2 Cu(TMHD)2 CuBr2 Cu(acac)2 Cu(acac)2 Cu(acac)2

O2 O2 O2 O2 O2 O2 Air —

Base (2 mmol)

GC yield (%)

NaOAc NaOAc NaOAc NaOAc NaOAc — — —

54 34 72 55 22 70 40 tr

Reaction condition: 1 (1 mmol), 2a (2 mmol), xylene (5 mL) at 140 °C, 24 h.

hindered and functionalized amines make it an ideal catalyst for such type of reactions. Molecular oxygen is successfully utilized as a green oxidant. It is an ideal oxidant because of its easy availability, low cost, and absence of toxic side-products in the reaction mixture. Benzothiazole (1) and N-methylaniline (2a) were chosen as model substrates for the purpose of optimization of reaction conditions for oxidative C–H bond amination reaction. Initially, various copper catalysts such as Cu(OAc)2, Cu(OTf)2, Cu(acac)2, Cu(TMHD)2 [Copper-bis(2,2,6,6-tetramethyl-3,5-heptanedionate)], and CuBr2 were screened for the C–H bond amination reaction of 1 (1 mmol) and 2a (2 mmol) using sodium acetate (2 mmol) as a base in xylene solvent at 140 °C with continuous bubbling of oxygen into the reaction mixture (Table 1, entries 1–5). The reaction in the presence of Cu(OAc)2 afforded 54% yield of the amination product 3 (Table 1, entry 1). Further, Cu(OTf)2, Cu(acac)2, Cu(TMHD)2, and CuBr2 were screened under the same reaction conditions (Table 1, entries 2–5). It has been observed that, Cu(acac)2 has shown a good catalytic activity among all the above catalysts screened and furnished 72% yield of 3 (Table 1, entry 3). To check the role of base for oxidative C–H bond amination reaction, the reaction of 1 with 2a was performed in the absence of sodium acetate (Table 1, entry 6). To our surprise, we observed 70% yield of 3 in the absence of base. Further, the reaction was performed under air bubbling into the reaction mixture, however, reaction proceeds sluggishly with decrease in yield up to 40% of product 3 (Table 1, entry 7). Only a trace amount of product 3 was observed when the reaction was performed without any oxidant (Table 1, entry 8). Furthermore, we have examined the influence of various reaction parameters like solvent, temperature, time, and catalyst loading (Table 2). Initially, the influence of various organic solvents with a different polarity was studied for oxidative C–H bond amination reaction (Table 2, entries 1–5). Xylene was found to be the best solvent among all the solvents screened and provided 70% yield of the desired product 3 (Table 2, entry 1). Only 30% yield of product 3 was observed when toluene was used as a solvent (Table 2, entry 2). However, other low boiling solvents were not effective and gave only traces of desired product 3 (Table 2, entries 3–5). The reaction requires optimized reaction temperature of 140 °C and many of these solvents were not able to reach that under reflux conditions. It can be concluded that aromatic solvents are necessary for this reaction as other types of solvents were not able to get the products even in a trace amount even at 80 °C. The reactions were performed at various reaction tempera-

a

Solvent

Cu(acac)2 (mol %)

Temperature (°C)

Time (h)

GC yield

Influence 1 2 3 4 5

of solvent Xylene Toluene Cyclohexane Dioxane Acetonitrile

10 10 10 10 10

140 110 80 100 80

24 24 24 24 24

70 30 02 tr tr

Influence 6 7 8

of temperature Xylene Xylene Xylene

10 10 10

110 120 140

24 24 24

28 46 70

Influence 9 10 11 12

of time Xylene Xylene Xylene Xylene

10 10 10 10

140 140 140 140

12 16 20 30

40 62 70 71

Influence 13 14 15 16

of catalyst loading Xylene 5 Xylene 10 Xylene 15 Xylene 20

140 140 140 140

20 20 20 20

45 70 79 85

Reaction condition: 1 (1 mmol), 2a (2 mmol), O2 gas (bubbling), solvent (5 mL).

tures ranging from 110–140 °C (Table 2, entries 6–8), in which 140 °C reflects to be the optimum reaction temperature (Table 2, entry 8). The time of the reaction was also optimized (Table 2, entries 9–12) and a maximum yield of product 3 was obtained within 20 h (Table 2, entry 11). The effect of catalyst loadings ranging from 5–20 mol % was studied and it can be seen that an increase in catalyst loading up to 20 mol % led to a remarkable increase in the yield of the desired product 3 that is up to 85% (Table 2, entry 16). Thus, the optimized reaction conditions are 1 (1 mmol), 2a (2 mmol), Cu(acac)2 (20 mol %) in xylene (5 mL) under continuous bubbling of O2 into the reaction mixture at 140 °C for 20 h. To study the scope and generality of the present protocol, various azoles such as benzothiazole, benzoxazole, 4,5-dimethylthiazole, and N-methylbenzimidazole were studied for the oxidative C–H bond amination reaction with aromatic amine, that is N-methylaniline under the above optimized reaction conditions (Table 3, entries 1–4). The reactions were monitored on GC and the respective aminoheterocycles were isolated with good to excellent yield (82–85%) after complete consumption of starting azoles. The reactions of benzoxazoles (4a) with various aliphatic cyclic and acyclic amines were performed under the optimized reaction conditions (Table 3, entries 4–12). Cyclic aliphatic amines such as morpholine, piperidine, pyrrolidine, N-methylpiperazine, N-acetylpiperazine, and 1,2,3,4-tetrahydroisoquinoline were treated with 4a. All these cyclic aliphatic amines reacted smoothly with 4a and gave good to excellent yields of corresponding aminobenzoxazoles (Table 3, entries 5–10). Further, 4a was reacted with aliphatic acyclic secondary amines such as dibutylamine and N-methylbenzylamine (Table 3, entries 11–12). It was observed that, both the aliphatic acyclic secondary amines tolerated very well under the present optimized reaction conditions, yielded 78% and 81% respective aminobenzoxazoles. Later, 5-methylbenzoxazole (4b) was reacted with morpholine and piperidine, it showed that, respective aminobenzoxazoles 5j and 5k were obtained in moderate to good yields (Table 3, entries 13–14). In conclusion, we have developed Cu(acac)2 catalyzed base-free protocol for the oxidative C–H bond amination of azoles using molecular oxygen as an oxidant. Present protocol is simple, effi-

6502

Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503

Table 3 Oxidative C–H bond amination of azoles with aminesa Entry

Azole

Amine (2)

N 1

N

HN Ph

S

N 2a

O

85

Ph

18

88

20

84

20

82

12

90

14

88

12

88

12

85

14

82

15

84

15

78

16

81

14

86

14

81

5a

N

N N

3

N Ph

N

2a 7

6

N

N 2a

S

N Ph

S

8

9

HN 5

20

N

O

4a

4

Ph

3

N 2

Yieldb (%)

N

S

2a

1

Time (h)

Product (3)

4a

N

O

N

O

2b

O

5b

N

HN 6

4a

N

O

2c 5c

O

HN 7

4a

N

N

2d 5d

HN 8

4a

N

N

O

2e

N

N

N

N

5e

9

HN

4a

N

O

N O

2f

5f

O 10

NH

4a

O

N

N

2g 5g

nBu 11

HN

4a

HN 12

4a

O

Ph

N

N

O 2b

4b

N

4b

N

O

5j

O 14

Ph

5i

O N

nBu

5h

2i

13

N

N

nBu

2h

nBu

O

2c

N

N

5k a b

Reaction condition: azole (1 mmol), amine (2 mmol), Cu(acac)2 (20 mol %), O2 gas (bubbling), xylene (5 mL) at 140 °C. Isolated yield.

cient, and applicable for C–H bond amination of various azoles with different aromatic as well as aliphatic amines. Varieties of aminoheterocycles have been successfully synthesized with good to excellent yield under the present reaction condition.

Acknowledgment The author (Y.S.W.) is greatly thankful to the Council of Scientific and Industrial Research (CSIR), India for providing fellowship.

References and notes 1. (a) Amino Group Chemistry from Synthesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008; (b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284–287; (c) Seregin, I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36, 1173–1193. and references therein. 2. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209; (b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361; (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544. 3. (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079; (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–796; (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (d) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003,

Y. S. Wagh, B. M. Bhanage / Tetrahedron Letters 53 (2012) 6500–6503

4.

5.

6.

7. 8.

9.

10. 11.

5, 2453–2455; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054–3131; (f) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 1114–1116. (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013–3039; (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698–1712; (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238. (a) Mori, A.; Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548–561; (b) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991–9016; (c) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205; (d) Seregin, I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36, 1173–1193. (a) Yasuo, S.; Megumi, Y.; Satoshi, Y.; Tomoko, S.; Midori, I.; Tetsutaro, N.; Kokichi, S.; Fukio, K. J. Med. Chem. 1998, 41, 3015–3021; (b) Yoshida, S.; Shiokawa, S.; Kawano, K.-I.; Ito, T.; Murakami, H.; Suzuki, H.; Yasuo, S. J. Med. Chem. 2005, 48, 7075–7079; (c) Gao, M.; Wang, M.; Hutchins, G. D.; Zheng, Q.H. Eur. J. Med. Chem. 2008, 43, 1570–1574; (d) Sato, Y.; Imai, M.; Amano, K.; Iwamatsu, K.; Konno, F.; Kurata, Y.; Sakakibara, S.; Hachisu, M.; Izumi, M.; Matsuki, N.; Saito, H. Biol. Pharm. Bull. 1997, 20, 752–755; (e) Verderame, M. J. Med. Chem. 1972, 15, 693–694; (f) Liu, K. G.; Lo, J. R.; Comery, T. A.; Zhang, G. M.; Zhang, J. Y.; Kowal, D. M.; Smith, D. L.; Di, L.; Kerns, E. H.; Schechter, L. E.; Robichaud, A. J. Bioorg. Med. Chem. Lett. 2009, 19, 1115–1117. Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282–2285. and references therein. (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900–6901; (b) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127–9130; (c) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899–9903; (d) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2011, 47, 3652–3654; (e) Li, Y.; Xie, Y.; Zhang, R.; Jin, K.; Wang, X. Duan., C J. Org. Chem. 2011, 76, 5444–5449. (a) Joseph, J.; Kim, Y. J.; Chang, S. Chem. Eur. J. 2011, 17, 8294–8298; (b) Froehr, T.; Sindlinger, C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. J. Org. Lett. 2011, 13, 3754–3757; (c) Lamani, M.; Prabhu, K. R. J. Org. Chem. 2011, 76, 7938– 7944; (d) Wagh, Y. S.; Sawant, D. N.; Bhanage, B. M. Tetrahedron Lett. 2012, 53, 3482–3485. Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607– 1610. General experimental procedure: In a 25 mL two necked round bottom flask, azole (1 mmol), amine (2.0 mmol), Cu(acac)2 (52.6 mg, 20 mol %), and 5 mL xylene were added. The above mixture was kept under reflux condition and then molecular oxygen was bubbled into the reaction mixture till the completion of reaction. The progress of reaction was monitored using gas chromatography. After completion of the reaction, the reaction mixture was filtered through celite bed. The organic solvent was

6503

removed under reduced pressure. The reaction mixture was analyzed using gas chromatography (Perkin Elmer, Clarus 400) equipped with a flame ionization detector (FID) and capillary column. The crude product was purified by column chromatography (silica gel, 100–200 mesh; petroleum ether/ethyl acetate, 90:10) to afford pure products. All the prepared compounds were confirmed by comparing with their authentic samples and were characterized by GC–MS (Shimadzu QP 2010), 1H NMR (Varian 500 MHz). N-Methyl-N-phenylbenzothiazol-2-amine (3, Table 3, entry 1): GC–MS (EI, 70 eV): m/z (%) = 240 (100), 239 (89), 106 (40), 77 (23). N-Methyl-N-phenylbenzoxazol-2-amine (5a, Table 3, entry 2): GC–MS (EI, 70 eV): m/z (%) = 224 (100), 223 (39), 106 (41), 77 (30). N,1-Dimethyl-N-phenyl-1H-benzoimidazol-2-amine (7, Table 3, entry 3): GC–MS (EI, 70 eV): m/z (%) = 237 (100), 236 (70), 91 (15), 77 (22). N,4,5-Trimethyl-N-phenylthiazol-2-amine (9, Table 3, entry 4): GC–MS (EI, 70 eV): m/z (%) = 218 (100), 217 (47), 77 (24), 51 (12). 2-Morpholinobenzoxazole (5b, Table 3, entry 5): GC–MS (EI, 70 eV): m/z (%) = 204 (79), 147 (100), 119 (29). 1H NMR (500 MHz, CDCl3, 25 °C): d = 7.37 (d, J = 7.0 Hz, 1 H), 7.26 (d, 1 H, J = 6.5 Hz), 7.18 (m, 1 H), 7.04 (m, 1 H), 3.82 (m, 4 H), 3.7 (m, 4 H) ppm. 2-(Piperidin-1-yl)benzoxazole (5c, Table 3, entry 6): GC–MS (EI, 70 eV): m/z (%) = 216 (100), 187 (23), 161 (29), 148 (50). 2-(Pyrrolidin-1-yl)benzoxazole (5d, Table 3, entry 7): GC–MS (EI, 70 eV): m/z (%) = 188 (100), 160 (58), 146 (15), 133 (92). 1H NMR (500 MHz, CDCl3, 25 °C): d = 7.36 (d, J = 7.5 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.00 (t, J = 8 Hz, 1 H), 3.65 (t, J = 6 Hz, 4 H), 2.05 (t, J = 6 Hz, 4 H) ppm. 2-(4-Methylpiperazin-1-yl)benzoxazole (5e, Table 3, entry 8): GC–MS (EI, 70 eV): m/z (%) = 217 (38), 160 (25), 147 (95), 70 (100). 1-(4-(Benzoxazol-2-yl)piperazin-1-yl)ethanone (5f, Table 3, entry 9): GC–MS (EI, 70 eV): m/z (%) = 245 (52), 160 (58), 147 (100), 43 (40). 1H NMR (500 MHz, CDCl3, 25 °C): d = 7.37 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.2 (t, J = 7.0 Hz, 1 H), 7.1 (t, J = 7.0 Hz, 1 H), 3.8–3.6 (m, 8 H), 2.16 (s, 3 H) ppm. 2-(3,4-Dihydroisoquinolin-2(1H)-yl)benzoxazole (5g, Table 3, entry 10): GC–MS (EI, 70 eV): m/z (%) = 250 (51), 134 (10), 117 (100), 104 (30). N,N-Dibutylbenzoxazol-2-amine (5h, Table 3, entry 11): GC–MS (EI, 70 eV): m/z (%) = 246 (30), 173 (21), 161 (46), 147 (100). N-Benzyl-N-methylbenzoxazol-2-amine (5i, Table 3, entry 12): GC–MS (EI, 70 eV): m/z (%) = 238 (66), 222 (41), 147 (46), 91 (100). 6-Methyl-2-morpholinobenzoxazole (5j, Table 3, entry 13): GC–MS (EI, 70 eV): m/z (%) = 218 (97), 161 (100), 94 (12), 77 (13). 6-Methyl-2-(piperidin-1-yl)benzoxazole (5k, Table 3, entry 14): GC–MS (EI, 70 eV): m/z (%) = 216 (100), 187 (23), 161 (29), 147 (31).