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Cite this: DOI: 10.1039/c5cc00360a Received 14th January 2015, Accepted 8th March 2015
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Copper-catalyzed aerobic oxidative cleavage of C–C bonds in epoxides leading to aryl nitriles and aryl aldehydes† Lijun Gu*a and Cheng Jinb
DOI: 10.1039/c5cc00360a www.rsc.org/chemcomm
Novel copper-catalyzed aerobic synthesis of aryl nitriles and aldehydes from epoxides via C–C single bond cleavage has been discovered. This reaction provides a practical method toward the synthesis of aryl nitriles and aldehydes, which are versatile intermediates and building blocks in organic synthesis.
The carbon–carbon bond is the most widespread and fundamental bond in organic compounds. Since the 19th century, the efforts of organic chemists have mostly been directed towards building carbon–carbon bonds in a predictable and efficient manner, while controlling all required stereogenic centers.1 Despite this intense activity, there are still many molecular frameworks that are extremely challenging to synthesize and, new and efficient approaches are constantly needed. Although the approach of creating new bonds has clearly dominated the field of organic chemistry, carbon–carbon bond cleavage is now seen as an alternative method for the construction of interesting molecular skeletons.2 The selective oxidative cleavage of C–C single bonds remains one of the biggest challenges in both chemistry and biology. Chemists have long sought new methods to overcome these challenges. Despite numerous reports describing carbon– carbon single-,3 double-,4 and triple-bond cleavage,5 the development of a C–C bond disconnection approach to construct a new C–X (X = C, N, O, etc.) bond still remains a formidable task. Epoxides are one of the most important and fundamental organic functional groups. Transformation and modification of epoxides are common strategies in organic synthesis to prepare complex and value-added molecules.6 As reactive functional groups, epoxides have been mainly used in transformations involving ring opening with nucleophilic reagents (Scheme 1a).6 Feng and coworkers have described an elegant transformation of 2,2,3-trisubstituted epoxides into optically active 1,3-dioxolanes
a
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, Yunnan, 650500, China. E-mail: [email protected] b New United Group Company Limited, Changzhou, Jiangsu, 213166, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc00360a
This journal is © The Royal Society of Chemistry 2015
Scheme 1
Direct transformations of epoxides.
or 2,5-dihydrofurans via chiral Lewis acid-mediated C–C bond cleavage (Scheme 1b).7 In 2013, the group of Beller made the remarkable observation that anilines react with 2,3-disubstituted epoxides in the presence of Ru3(CO)12 as a catalyst to form indosle (Scheme 1c).8 Recently, we reported the copper-catalyzed aerobic synthesis of ketones from 2,3-disubstituted epoxides via C–C single bond cleavage (Scheme 1d).9 There are, however, few examples of such successful transformations and, new methods for cleavage of the C–C single bonds of 2,3-disubstituted epoxides using inexpensive copper catalysts were reported. Aryl nitriles and aryl aldehydes are common structural motifs in natural products and are versatile building blocks
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in the synthesis of more complex natural products, pharmaceuticals, agricultural chemicals, dyes, and other commercially important materials.5e,10 We reasoned that sodium azide could be used as an additional reagent to initiate copper-catalyzed cleavage of C–C single bonds in 2,3-disubstituted epoxides. Herein, we report an unprecedented copper-catalyzed aerobic synthesis of aryl nitriles and aryl aldehydes from 2,3-disubstituted epoxides via cleavage of C–C single bonds (Scheme 1e). Our initial investigations began with reaction of the model substrate, 2,3-diphenyloxirane 1a with sodium azide in the presence of different catalysts under an O2 atmosphere. Gratifyingly, benzaldehyde 2a and benzonitrile 3a were obtained when the reaction was carried out in the presence of CuCl2 (10 mol%) at 100 1C in dimethylsufoxide (DMSO) for 10 h (Table 1, entry 1). Of the solvents tested, DMF proved particularly suitable (Table 1, entries 1–5). Hydrated CuCl2 was superior to other copper salts as the catalyst (Table 1, entries 6–11). We were surprised to find that azidotrimethylsilane did not afford the desired product (Table 1, entry 12). Notably, the absence of sodium azide in the reaction mixture resulted in no detectable amounts of benzonitrile 2a and benzaldehyde 3a (Table 1, entry 13). Both hydrated CuCl2 and O2 are essential for reaction to take place (Table 1, entries 14 and 15). After determining the optimal reaction conditions, the scope of usable substrates 1 was investigated. As summarized in Table 2, the standard reaction conditions were found to be compatible with a wide range of symmetrical 2,3-diaryloxiranes 1. Different symmetrical para-substituted 2,3-diaryloxiranes could be converted into the corresponding aryl nitriles and aryl aldehydes in moderate to good yields, and both electron-donating and electron-withdrawing groups tolerated the reaction (Table 2, entries 1–6). When using ortho-substituted 2,3-diaryloxirane as the substrate, the corresponding aryl nitrile 2h and aryl aldehyde 3h were formed in 60% and 52% yield, respectively (Table 2, entry 7). When the meta position was substituted with a chlorine atom, products 2i and 3i Table 1
Table 2
Scope of 2,3-diaryloxiranes 1a
Yieldb (2) (%)
Yieldb (3) (%)
1
2b (73)
3b (65)
2
2c (64)
3c (60)
3
2d (58)
3d (54)
4
2e (70)
3e (67)
5
2f (59)
3f (55)
6
2g (63)
3g (58)
7
2h (60)
3h (52)
8
2i (54)
3i (50)
9
2j (69)
3j (65)
10
2k (72)
3k (67)
11
2l (53)
3l (47)
Entry
Ar
Optimization of the reaction conditionsa
a
Entry
Catalyst
Solvent
Yieldb (2a) (%)
Yieldb (3a) (%)
1 2 3 4 5 6 7 8 9 10 11 12c 13d 14 15e
CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl Cu(OTf)2 CuBr2 Cu(OAc)2 CuO CuCl22H2O CuCl22H2O CuCl22H2O None CuCl22H2O
DMSO CH2Cl2 EtOAc THF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF
53 Trace 41 Trace 68 27 Trace Trace 39 58 77 0 0 Trace 0
47 Trace 34 Trace 64 20 Trace Trace 33 52 71 0 0 Trace 0
a
Reaction conditions: 1a (0.3 mmol), catalyst (15 mol%), NaN3 (0.40 mmol), solvent (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b Isolated yield. c Azidotrimethylsilane was used instead of NaN3. d Without NaN3. e Under an Ar atmosphere.
Chem. Commun.
Reaction conditions: 1 (0.3 mmol), CuCl22H2O (10 mol%), NaN3 (0.40 mmol), DMF (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b Isolated yield.
were obtained in 54% and 50% yield, respectively (Table 2, entry 8). It is noteworthy that the symmetrical 2,3-diaryloxirane gave desired products 2j and 3j with a good yield (Table 2, entry 9). Reaction of substrate 1k with a naphthyl group delivered the desired products 2k and 3k in 72% and 67% yield, respectively (Table 2, entry 10). Interestingly, the introduction of heterocycles into the system made this methodology more useful for the preparation of pharmaceuticals and other commercially useful compounds (Table 2, entry 11). To highlight the utility of the transformation, a series of asymmetrical 2,3-disubstituted epoxides 1 were subjected to the standard reaction conditions. It was found that reaction of asymmetrical 2,3-diaryloxiranes with sodium azide afforded a
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mixture of aryl nitriles and aryl aldehydes in low yield. Several substituents, including Me, F and Cl, were well tolerated on the aryl ring of epoxides (Table 3, entries 1–3). Importantly, the halogens F and Cl were tolerated under the reaction conditions, thereby facilitating additional modifications at the halogenated positions. Unfortunately, epoxides bearing one or two aliphatic groups did not deliver the corresponding nitriles and aldehydes under the same reaction conditions (Table 3, entries 4 and 5). Some control experiments were carried out in order to probe the mechanism of this transformation. When the reaction was carried out under an 18O2 atmosphere, no 18O-labeled product 3a was detected. It has been reported that epoxides can be transformed into aldehydes.9 To rule out this possibility, we checked for the formation of aldehydes in the reaction of 2,3-diphenyloxirane 1a (0.3 mmol), in the presence of CuCl22H2O (10 mol%), at 100 1C in DMF under an O2 atmosphere. Aldehyde 3 was not detected. When 1.0 equivalent of TEMPO, a radical-trapping reagent, was added to the reaction under standard conditions, the same yields of 2a and 3a were obtained, suggesting that free radical intermediates were not involved in the reaction. On the basis of these preliminary results and those of previous studies,11 a plausible mechanism for the copper-catalyzed C–C bond cleavage of 2,3-diaryloxiranes leading to aryl nitriles and aryl aldehydes was proposed. Ring opening of 2,3-diphenyloxirane 1a with sodium azide and Cu(II) gives intermediate A. With the aid of H2O, intermediate A generates 2-azido-1,2-diphenylethanol B. Subsequent rearrangement of intermediate B via its resonance Table 3
Scope of 2,3-disubstituted epoxides 1a
Yieldb (2) (%)
Yieldb (3) (%)
2a: (25) 2b: (31)
3a: (22) 3b: (21)
2a: (29) 2d: (26)
3a: (28) 3d: (24)
2a: (31) 2e: (34)
3a: (27) 3e: (29)
4
0
0
5
0
0
Entry
Epoxides 1
1
2
3
a
Reaction conditions: 1 (0.3 mmol), CuCl22H2O (10 mol%), NaN3 (0.40 mmol), DMF (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b GC yield.
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Scheme 2
Plausible mechanism.
structure C produces phenylmethanimine D and benzaldehyde 3a through C–C bond cleavage with release of molecular nitrogen. In the presence of Cu and O2, phenylmethanimine D is readily transformed into benzonitrile 2a.12 In summary, we have developed a novel approach for the synthesis of aryl nitriles and aryl aldehydes via aerobic oxidative C(sp3)–C(sp3) cleavage of 2,3-diaryloxiranes. The method advantageously enriches and complements the existing toolbox used by synthetic chemists, and allows straightforward access to a wide range of functionalized products. In addition, the catalytic reaction with O2 as the terminal oxidant generates water and nitrogen as by-products and provides a new approach to synthesize aryl nitriles and aryl aldehydes. Considering the wide utility of nitriles and aldehydes, these results will certainly pave the way for important applications and developments in both the academic and industrial fields through the shortening and simplification of synthetic sequences (Scheme 2). We are grateful for the financial support from Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (IRTSTYN 2014-11) and the State Ethnic Affairs Commission (12YNZ05).
Notes and references 1 (a) P. A. Wender and B. L. Miller, Nature, 2009, 460, 197; (b) P. S. Baran, T. J. Maimone and J. M. Richter, Nature, 2007, 446, 404. 2 For reviews on the cleavage of C–C bonds, see: (a) A. Masarwa and I. Marek, Chem. – Eur. J., 2010, 16, 9712; (b) M. Murakami and T. Matsuda, Chem. Commun., 2011, 47, 1100; (c) T. Seiser, T. Sage, D. N. Tran and N. Cramer, Angew. Chem., Int. Ed., 2011, 50, 7740; (d) M. Tobisu and N. Chatani, Chem. Soc. Rev., 2008, 37, 300; (e) F. Chen, T. Wang and N. Jiao, Chem. Rev., 2014, 114, 8613; ( f ) T. Wang and N. Jiao, Acc. Chem. Res., 2014, 47, 1137. 3 For selected examples of cleavage of C–C single bonds, see: (a) C. Zhang, P. Feng and N. Jiao, J. Am. Chem. Soc., 2013, 135, 15257; (b) X. Huang, X. Li, M. Zou, S. Song, C. Tang, Y. Yuan and N. Jiao, J. Am. Chem. Soc., 2014, 136, 14858; (c) A. Maji, S. Rana, Akanksha and D. Maiti, Angew. Chem., Int. Ed., 2014, 53, 2428; (d) Q. Xing, P. Li, H. Lv, R. Lang, C. Xia and F. Li, Chem. Commun., 2014, 50, 12181; (e) K. Ruhland, Eur. J. Org. Chem., 2012, 2683; ( f ) T. Nagata, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2014, 79, 8960; ( g) C. Qin, T. Shen, C. Tang and N. Jiao, Angew. Chem., Int. Ed., 2012, 51, 6971; (h) C. He, S. Guo, L. Huang and A. Lei, J. Am. Chem. Soc., 2010, 132, 8273; (i) H. Li, Y. Li, X. S. Zhang, K. Chen, X. Wang and Z. J. Shi, J. Am. Chem. Soc., 2011, 133, 15244; ( j) L. Zhang, X. Bi, X. Guan, X. Li, Q. Liu, B. Barry and P. Liao, Angew. Chem., Int. Ed., 2013, 52, 11303; (k) K. Chen, H. Li, Y. Li, X. Zhang, Z. Li and Z. Shi, Chem. Sci., 2012, 3, 1645; (l ) M. Tobisu, H. Kinuta, Y. Kit, E. Remond and N. Chatani, J. Am. Chem. Soc., 2012, 134, 115; (m) Y. Kuninobu, H. Matsuzaki, M. Nishi and K. Takai, Org. Lett., 2011, 13, 2959.
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Communication 4 For selected examples of cleavage of C–C double bonds, see: (a) T. Wang and N. Jiao, J. Am. Chem. Soc., 2013, 135, 11692; (b) G. Wang, X. Li, J. Dai and H. Xu, J. Org. Chem., 2014, 79, 7220; (c) R. Lin, F. Chen and N. Jiao, Org. Lett., 2012, 14, 4158; (d) A. Sattler and G. Parkin, Nature, 2010, 463, 523; (e) V. Kogan, M. M. Quintal and R. Neumann, Org. Lett., 2005, 7, 5039; ( f ) T. Takemori, A. Inagaki and H. Suzuki, J. Am. Chem. Soc., 2001, 123, 1762; ( g) L. Gu, J. Liu and H. Zhang, Chin. J. Chem., 2014, 32, 1267. 5 For selected examples of cleavage of C–C triple bonds, see: (a) L. J. Wang, H. T. Zhu, L. Lu, F. Yang, X. Y. Liu and Y. M. Liang, Org. Lett., 2012, 14, 1990; (b) T. Shimada and Y. Yamamoto, J. Am. Chem. Soc., 2003, 125, 664; (c) Y. Liu, F. Song and S. Guo, J. Am. Chem. Soc., 2006, 128, 11332; (d) C. H. Jun, H. Lee, C. W. Moon and H. S. Hong, J. Am. Chem. Soc., 2001, 123, 860; (e) T. Shen, T. Wang, C. Qin and N. Jiao, Angew. Chem., Int. Ed., 2013, 52, 6677; ( f ) Q. Jiang, A. Zhao, B. Xu, J. Jia, X. Liu and C. Guo, J. Org. Chem., 2014, 79, 2709; ( g) D. V. Patil, H. Park, J. Koo, J. Han and S. Shin, Chem. Commun., 2014, 50, 12722; (h) J. Sun, F. Wang, H. Hu, X. Wang, H. Wu and Y. Liu, J. Org. Chem., 2014, 79, 3992; (i) L. Gu and H. Zhang, RSC Adv., 2015, 5, 690. 6 (a) G. L. Borosky and K. K. Laali, Org. Biomol. Chem., 2009, 5, 2234; (b) S. Regati, Y. He, M. Thimmaiah, P. Li, S. Xiang, B. Chen and J. C. Zhao, Chem. Commun., 2013, 49, 9836; (c) K. Seth, S. R. Roy, B. V. Pipaliya and A. K. Chakraborti, Chem. Commun., 2013, 49, 5886; (d) Y. Morimoto, E. Takeuchi, H. Kambara, T. Kodama, Y. Tachi and K. Nishikawa, Org. Lett., 2013, 15, 2966; (e) X. Wang, H. Guo, M. Liu, X. Wang and D. Deng, Chin. Chem. Lett., 2014, 25, 243; ( f ) Y. Nie and Q. D. You, Chin. Chem. Lett., 2013, 24, 183; ( g) C. Beattie and
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M. North, ChemCatChem, 2014, 6, 1252; (h) S. Huang, Z. Xiao, F. Wang, L. Gan, X. Zhang, X. Hu, S. Zhang, M. Lu, Q. Pan and L. Xu, J. Org. Chem., 2004, 69, 2442; (i) X. Yang, S. Huang, Z. Jia, Z. Xiao, Z. Jiang, Q. Zhang, L. Gan, B. Zheng, G. Yuan and S. Zhang, J. Org. Chem., 2008, 73, 2518; ( j) Y. Tajima, K. Takeshi, Y. Shigemitsu and Y. Numata, Molecules, 2012, 17, 6395; (k) Z. Chen, L. Wei and J. Zhang, Org. Lett., 2011, 13, 1170; (l) T. Wang, C. Wang and J. Zhang, Chem. Commun., 2011, 47, 5578; (m) Z. Chen, Z. Tian, J. Zhang, J. Ma and J. Zhang, Chem. – Eur. J., 2012, 18, 8591. (a) W. Chen, L. Lin, Y. Cai, Y. Xia, W. Cao, X. Liu and X. Feng, Chem. Commun., 2014, 50, 2161; (b) W. Chen, X. Fu, L. Lin, X. Yuan, W. Luo, J. Feng, X. Liu and X. Feng, Chem. Commun., 2014, 50, 11480. ´pez, H. Neumann and M. Beller, Chem. – Eur. J., 2014, M. P. Lo 20, 1818. L. Gu, C. Jin, H. Zhang and L. Zhang, J. Org. Chem., 2014, 79, 8453. (a) B. Yu, Y. Zhao, H. Zhang, J. Xu, L. Hao, X. Gao and Z. Liu, Chem. Commun., 2014, 50, 2330; (b) X. Jiang, J. Wang, Y. Zhang, Z. Chen, Y. Zhu and S. Ji, Org. Lett., 2014, 16, 3492; (c) K. Natte, A. Dumrath, H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2014, 53, 38; (d) Z. Shu, W. Ji, X. Wang, Y. Zhou, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2014, 53, 2186; (e) L. Gu, C. Jin, R. Wang and H. Ding, ChemCatChem, 2014, 6, 1225; ( f ) Z. Shu, Y. Ye, Y. Deng, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2013, 52, 10573. C. Tang and N. Jiao, Angew. Chem., Int. Ed., 2014, 53, 6528. (a) A. K. Yadav, V. P. Srivastava and L. D. S. Yadav, Synth. Commun., 2014, 44, 408; (b) M. B. Erman, J. W. Snow and M. J. Williams, Tetrahedron Lett., 2000, 41, 6749.
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Cite this: DOI: 10.1039/c5cc00360a Received 14th January 2015, Accepted 8th March 2015
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Copper-catalyzed aerobic oxidative cleavage of C–C bonds in epoxides leading to aryl nitriles and aryl aldehydes† Lijun Gu*a and Cheng Jinb
DOI: 10.1039/c5cc00360a www.rsc.org/chemcomm
Novel copper-catalyzed aerobic synthesis of aryl nitriles and aldehydes from epoxides via C–C single bond cleavage has been discovered. This reaction provides a practical method toward the synthesis of aryl nitriles and aldehydes, which are versatile intermediates and building blocks in organic synthesis.
The carbon–carbon bond is the most widespread and fundamental bond in organic compounds. Since the 19th century, the efforts of organic chemists have mostly been directed towards building carbon–carbon bonds in a predictable and efficient manner, while controlling all required stereogenic centers.1 Despite this intense activity, there are still many molecular frameworks that are extremely challenging to synthesize and, new and efficient approaches are constantly needed. Although the approach of creating new bonds has clearly dominated the field of organic chemistry, carbon–carbon bond cleavage is now seen as an alternative method for the construction of interesting molecular skeletons.2 The selective oxidative cleavage of C–C single bonds remains one of the biggest challenges in both chemistry and biology. Chemists have long sought new methods to overcome these challenges. Despite numerous reports describing carbon– carbon single-,3 double-,4 and triple-bond cleavage,5 the development of a C–C bond disconnection approach to construct a new C–X (X = C, N, O, etc.) bond still remains a formidable task. Epoxides are one of the most important and fundamental organic functional groups. Transformation and modification of epoxides are common strategies in organic synthesis to prepare complex and value-added molecules.6 As reactive functional groups, epoxides have been mainly used in transformations involving ring opening with nucleophilic reagents (Scheme 1a).6 Feng and coworkers have described an elegant transformation of 2,2,3-trisubstituted epoxides into optically active 1,3-dioxolanes
a
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, Yunnan, 650500, China. E-mail: [email protected] b New United Group Company Limited, Changzhou, Jiangsu, 213166, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc00360a
This journal is © The Royal Society of Chemistry 2015
Scheme 1
Direct transformations of epoxides.
or 2,5-dihydrofurans via chiral Lewis acid-mediated C–C bond cleavage (Scheme 1b).7 In 2013, the group of Beller made the remarkable observation that anilines react with 2,3-disubstituted epoxides in the presence of Ru3(CO)12 as a catalyst to form indosle (Scheme 1c).8 Recently, we reported the copper-catalyzed aerobic synthesis of ketones from 2,3-disubstituted epoxides via C–C single bond cleavage (Scheme 1d).9 There are, however, few examples of such successful transformations and, new methods for cleavage of the C–C single bonds of 2,3-disubstituted epoxides using inexpensive copper catalysts were reported. Aryl nitriles and aryl aldehydes are common structural motifs in natural products and are versatile building blocks
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in the synthesis of more complex natural products, pharmaceuticals, agricultural chemicals, dyes, and other commercially important materials.5e,10 We reasoned that sodium azide could be used as an additional reagent to initiate copper-catalyzed cleavage of C–C single bonds in 2,3-disubstituted epoxides. Herein, we report an unprecedented copper-catalyzed aerobic synthesis of aryl nitriles and aryl aldehydes from 2,3-disubstituted epoxides via cleavage of C–C single bonds (Scheme 1e). Our initial investigations began with reaction of the model substrate, 2,3-diphenyloxirane 1a with sodium azide in the presence of different catalysts under an O2 atmosphere. Gratifyingly, benzaldehyde 2a and benzonitrile 3a were obtained when the reaction was carried out in the presence of CuCl2 (10 mol%) at 100 1C in dimethylsufoxide (DMSO) for 10 h (Table 1, entry 1). Of the solvents tested, DMF proved particularly suitable (Table 1, entries 1–5). Hydrated CuCl2 was superior to other copper salts as the catalyst (Table 1, entries 6–11). We were surprised to find that azidotrimethylsilane did not afford the desired product (Table 1, entry 12). Notably, the absence of sodium azide in the reaction mixture resulted in no detectable amounts of benzonitrile 2a and benzaldehyde 3a (Table 1, entry 13). Both hydrated CuCl2 and O2 are essential for reaction to take place (Table 1, entries 14 and 15). After determining the optimal reaction conditions, the scope of usable substrates 1 was investigated. As summarized in Table 2, the standard reaction conditions were found to be compatible with a wide range of symmetrical 2,3-diaryloxiranes 1. Different symmetrical para-substituted 2,3-diaryloxiranes could be converted into the corresponding aryl nitriles and aryl aldehydes in moderate to good yields, and both electron-donating and electron-withdrawing groups tolerated the reaction (Table 2, entries 1–6). When using ortho-substituted 2,3-diaryloxirane as the substrate, the corresponding aryl nitrile 2h and aryl aldehyde 3h were formed in 60% and 52% yield, respectively (Table 2, entry 7). When the meta position was substituted with a chlorine atom, products 2i and 3i Table 1
Table 2
Scope of 2,3-diaryloxiranes 1a
Yieldb (2) (%)
Yieldb (3) (%)
1
2b (73)
3b (65)
2
2c (64)
3c (60)
3
2d (58)
3d (54)
4
2e (70)
3e (67)
5
2f (59)
3f (55)
6
2g (63)
3g (58)
7
2h (60)
3h (52)
8
2i (54)
3i (50)
9
2j (69)
3j (65)
10
2k (72)
3k (67)
11
2l (53)
3l (47)
Entry
Ar
Optimization of the reaction conditionsa
a
Entry
Catalyst
Solvent
Yieldb (2a) (%)
Yieldb (3a) (%)
1 2 3 4 5 6 7 8 9 10 11 12c 13d 14 15e
CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl Cu(OTf)2 CuBr2 Cu(OAc)2 CuO CuCl22H2O CuCl22H2O CuCl22H2O None CuCl22H2O
DMSO CH2Cl2 EtOAc THF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF
53 Trace 41 Trace 68 27 Trace Trace 39 58 77 0 0 Trace 0
47 Trace 34 Trace 64 20 Trace Trace 33 52 71 0 0 Trace 0
a
Reaction conditions: 1a (0.3 mmol), catalyst (15 mol%), NaN3 (0.40 mmol), solvent (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b Isolated yield. c Azidotrimethylsilane was used instead of NaN3. d Without NaN3. e Under an Ar atmosphere.
Chem. Commun.
Reaction conditions: 1 (0.3 mmol), CuCl22H2O (10 mol%), NaN3 (0.40 mmol), DMF (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b Isolated yield.
were obtained in 54% and 50% yield, respectively (Table 2, entry 8). It is noteworthy that the symmetrical 2,3-diaryloxirane gave desired products 2j and 3j with a good yield (Table 2, entry 9). Reaction of substrate 1k with a naphthyl group delivered the desired products 2k and 3k in 72% and 67% yield, respectively (Table 2, entry 10). Interestingly, the introduction of heterocycles into the system made this methodology more useful for the preparation of pharmaceuticals and other commercially useful compounds (Table 2, entry 11). To highlight the utility of the transformation, a series of asymmetrical 2,3-disubstituted epoxides 1 were subjected to the standard reaction conditions. It was found that reaction of asymmetrical 2,3-diaryloxiranes with sodium azide afforded a
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mixture of aryl nitriles and aryl aldehydes in low yield. Several substituents, including Me, F and Cl, were well tolerated on the aryl ring of epoxides (Table 3, entries 1–3). Importantly, the halogens F and Cl were tolerated under the reaction conditions, thereby facilitating additional modifications at the halogenated positions. Unfortunately, epoxides bearing one or two aliphatic groups did not deliver the corresponding nitriles and aldehydes under the same reaction conditions (Table 3, entries 4 and 5). Some control experiments were carried out in order to probe the mechanism of this transformation. When the reaction was carried out under an 18O2 atmosphere, no 18O-labeled product 3a was detected. It has been reported that epoxides can be transformed into aldehydes.9 To rule out this possibility, we checked for the formation of aldehydes in the reaction of 2,3-diphenyloxirane 1a (0.3 mmol), in the presence of CuCl22H2O (10 mol%), at 100 1C in DMF under an O2 atmosphere. Aldehyde 3 was not detected. When 1.0 equivalent of TEMPO, a radical-trapping reagent, was added to the reaction under standard conditions, the same yields of 2a and 3a were obtained, suggesting that free radical intermediates were not involved in the reaction. On the basis of these preliminary results and those of previous studies,11 a plausible mechanism for the copper-catalyzed C–C bond cleavage of 2,3-diaryloxiranes leading to aryl nitriles and aryl aldehydes was proposed. Ring opening of 2,3-diphenyloxirane 1a with sodium azide and Cu(II) gives intermediate A. With the aid of H2O, intermediate A generates 2-azido-1,2-diphenylethanol B. Subsequent rearrangement of intermediate B via its resonance Table 3
Scope of 2,3-disubstituted epoxides 1a
Yieldb (2) (%)
Yieldb (3) (%)
2a: (25) 2b: (31)
3a: (22) 3b: (21)
2a: (29) 2d: (26)
3a: (28) 3d: (24)
2a: (31) 2e: (34)
3a: (27) 3e: (29)
4
0
0
5
0
0
Entry
Epoxides 1
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Reaction conditions: 1 (0.3 mmol), CuCl22H2O (10 mol%), NaN3 (0.40 mmol), DMF (2.0 mL), 100 1C under an O2 atmosphere for 10 h. b GC yield.
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Scheme 2
Plausible mechanism.
structure C produces phenylmethanimine D and benzaldehyde 3a through C–C bond cleavage with release of molecular nitrogen. In the presence of Cu and O2, phenylmethanimine D is readily transformed into benzonitrile 2a.12 In summary, we have developed a novel approach for the synthesis of aryl nitriles and aryl aldehydes via aerobic oxidative C(sp3)–C(sp3) cleavage of 2,3-diaryloxiranes. The method advantageously enriches and complements the existing toolbox used by synthetic chemists, and allows straightforward access to a wide range of functionalized products. In addition, the catalytic reaction with O2 as the terminal oxidant generates water and nitrogen as by-products and provides a new approach to synthesize aryl nitriles and aryl aldehydes. Considering the wide utility of nitriles and aldehydes, these results will certainly pave the way for important applications and developments in both the academic and industrial fields through the shortening and simplification of synthetic sequences (Scheme 2). We are grateful for the financial support from Program for Innovative Research Team (in Science and Technology) in University of Yunnan Province (IRTSTYN 2014-11) and the State Ethnic Affairs Commission (12YNZ05).
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