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Metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides
Tetrahedron Letters 52 (2011) 1430–1431
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides Lili Ou a, Jiaan Shao a, Guolin Zhang a,⇑, Yongping Yu a,b,⇑ a b
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e
i n f o
Article history: Received 15 September 2010 Revised 10 November 2010 Accepted 19 November 2010 Available online 24 November 2010
a b s t r a c t A novel and efficient metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides is reported. The reaction is fairly general for the preparation of secondary aromatic amines. Furthermore, the reaction is very functional-group tolerant. A possible mechanism is also proposed. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: C–N formation Arylboronic acids Organic azides Metal-free
The selective formation of carbon–nitrogen bonds is a fundamental transformation in organic synthesis. Although enormous approaches are available, the development of methods which are advantageous in the aspects of simplicity, selectivity, functionalgroup tolerance, and availability of starting materials would be valued in organic synthesis. Over the past decades, transition-metal-catalyzed aromatic C–N bond-forming reactions have been intensively studied due to the importance of aromatic amines in chemistry related fields.1 The most well-known method is palladium-, nickel-, or copper-catalyzed coupling reactions between aryl halides and amines,2 arylboronic acids and amines.3 The arylboronic acids are popular owing to their advantages in terms of stability, low toxicity, and commercial availability. To the best of our knowledge, all the arylboronic acid mediated C–N bondforming coupling reactions need metal catalysts. It will be beneficial if metal-free C–N bond formation coupling reactions can be developed because it will eliminate the necessity for disposing the catalysts from the reaction residues and separating the traceless metal from the products. Organic azides are versatile synthetic intermediates that participate in various important organic reactions, such as Huisgen reaction, Staudinger reaction, Schmidt rearrangement, and aza-Wittig reaction.4 Recently, it was reported that diazo compounds could be coupled with arylboronic acids to form C–C bonds without the use of metal catalysts.5 Thus, we herein wish to report a novel ⇑ Corresponding authors. Tel.: +86 571 88208450 (G.Z.), +86 571 88208452 (Y.Y.). E-mail addresses: [email protected] (G. Zhang), [email protected] (Y. Yu). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.11.103
methodology for a metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides. Initially, the reaction conditions were optimized using phenylboronic acid (1a) and benzyl azides (2a) as starting substrates (Table 1). When the reaction was carried out in ethanol, THF, 1,4-dioxane, xylene, DMF at 80 °C for 24 h, no reaction occurred (entries 1–5). When the temperature was increased to 100 °C, there was still no reaction in DMF (entry 6), but it gave relatively
Table 1 Optimization of reaction conditionsa
a b
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12
Ethanol THF 1,4-Dioxane Xylene DMF DMF 1,4-Dioxane Xylene Xylene Xylene Xylene Xylene
80 80 80 80 80 100 100 100 120 140 Reflux 140
24 24 24 24 24 24 24 24 24 24 24 48
0 0 0 0 0 0 15 20 32 55 53 82
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), xylene (5 ml), N2. The yield of the isolated product.
L. Ou et al. / Tetrahedron Letters 52 (2011) 1430–1431
1431
Table 2 Coupling reaction between arylboronic acids and organic azidesa
Entry
Ar
R
Product
Yieldb (%)
1 2 3 4 5 6c 7 8 9 10 11 12 13 14 15 16 17 18 19
Ph Ph Ph Ph Ph 3-CHOC6H4 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3-F-C6H4 3-F-C6H4 3-F-C6H4 4-MeOC6H4 4-MeOC6H4 4-MeC6H4 4-Pyridyl 2-Thienyl
Benzyl CH3(CH2)6CH2 Ph 4-MeOC6H4 4-MeC6H4 4-MeOC6H4 CH3(CH2)6CH2 4-MeOC6H4 4-MeC6H4 2-BrC6H4 4-NO2C6H4 Benzyl 4-MeOC6H4 4-ClC6H4 Benzyl 4-MeC6H4 Benzyl 4-MeOC6H4 4-MeOC6H4
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s
82 35 36 67 48 60 60 85 75 58 44 85 75 46 58 40 74 0 0
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), xylene (5 ml), N2, 140 °C, 24– 48 h. b The yield of the isolated product. c Reaction temperature is 120 °C.
low yields in 1,4-dioxane compared to that in xylene (entries 7 and 8, respectively). With the temperature increasing, the yield of the reaction was improved (entries 8–10), but at reflux the yield was not further improved (entry 11). It was also found that the yield was increased when prolonging the reaction time (entry 12 compared to 10). Thus, the optimized condition for this reaction was achieved in xylene at 140 °C for 48 h. With the optimized reaction conditions in hand, the generality of this reaction was studied using a set of arylboronic acids 1 and organic azides 2 (Table 2). The alkyl azides were readily prepared from alkyl bromides by the nucleophilic substitution of bromide with sodium azide,6 while aromatic azides are commonly prepared from the corresponding aromatic amines via their diazonium salts.7 The coupling reaction was conducted over a broad range of reagents. Both alkyl azides and aromatic azides were coupled with various arylboronic acids in moderate to good isolated yields. When compared to octyl azide, benzyl azide showed better reaction activity (entries 1 and 2). In addition, when arylboronic acids were coupled with benzyl azides, electron-withdrawing substitution gave satisfactory coupling (entry 12), but the yields dropped off with electron-donating substitution (entries 15 and 17). Furthermore, the coupling of arylboronic acids with a series of aryl azides was investigated. Arylboronic acids containing electron-withdrawing groups provided higher yields than those with electron-donating groups (entries 5, 9, and 16). While the results with the aryl azides were the opposite (entries 3–5). Especially the aryl azides with strong electron-withdrawing groups such as –NO2, these hardly reacted with phenylboronic acid, but did reacted with 3,4,5-trifluorophenylboronic acid in moderate yield (entry 11). To our delight, the functional-group tolerance of the reaction was evident. The reaction was performed successfully in the presence of unprotected aldehydes (entry 6). The coupling was also conducted successfully with halogen substituted aromatic rings (entries 5, 7–14). However, with regard to heterocyclic boronic acids such as pyridine-4-boronic acid and thiophene-2-boronic acid reacting with 4-methoxylphenyl azide, no desired secondary
Scheme 1. Possible mechanism for coupling reactions between arylboronic acids and organic azides.
amines were found (entries 18 and 19). Instead, the self-coupled product, 1,2-bis (4-methoxyphenyl) diazene was obtained. The mechanism of this coupling reaction between arylboronic acids and organic azides was considered to be similar to the reaction between arylboronic acids with diazo compounds (Scheme 1).5 The reaction is proposed to be initiated by the nucleophilic attack of azide nitrogen to arylboronic acid to form the reversible intermediate A, followed by 1,2-migration of aromatic rings with the loss of nitrogen. Finally, the generated intermediate B is converted to product 3 upon protodeboronation. In conclusion, we have developed a novel, efficient, and metalfree reaction for carbon–nitrogen bond formation via arylboronic acids and organic azides. This reaction is fairly general and functional-group tolerant. Thus, we believe it will be widely applied in organic synthesis. Acknowledgments We thank the National Natural Science Foundation of China (Nos. 30772652 and 90813026) and National key Tech project for Major Creation of New Drugs (No. 2009ZX09501-010) for financial support. Supplementary data Supplementary data (experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for all products) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2010.11.103. References and notes 1. (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem. 2005, 48, 1729; (b) D’Aprano, G.; Leclerc, M.; Zotti, G.; Schiavon, G. Chem. Mater. 1995, 7, 33; (c) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159. 2. (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; (b) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423; (c) Chen, C.; Yang, L.-M. J. Org. Chem. 2007, 72, 6324; (d) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. 3. (a) Leyand, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (b) Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079; (c) Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.; Balasubrahmanyam, V. Synthesis 2008, 795; (d) Singh, B. K.; Stevens, C. V.; Acke, D. R. J.; Parmar, V. S.; Van der Eycken, E. V. Tetrahedron Lett. 2009, 50, 15. 4. (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188; (b) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018; (c) Nisic, F.; Andreini, M.; Bernardi, A. Eur. J. Org. Chem. 2009, 33, 5744; (d) Zhao, Y.-M.; Gu, P.; Tu, Y. Q.; Fan, C.-A.; Zhang, Q. Org. Lett. 2008, 10, 1763; (e) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org. Lett. 2008, 10, 2589. 5. (a) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11, 1667; (b) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Nat. Chem. 2009, 1, 494. 6. Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413. 7. Kamalraj, V. R.; Senthil, S.; Kannan, P. J. Mol. Struct. 2008, 892, 210.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides Lili Ou a, Jiaan Shao a, Guolin Zhang a,⇑, Yongping Yu a,b,⇑ a b
College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e
i n f o
Article history: Received 15 September 2010 Revised 10 November 2010 Accepted 19 November 2010 Available online 24 November 2010
a b s t r a c t A novel and efficient metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides is reported. The reaction is fairly general for the preparation of secondary aromatic amines. Furthermore, the reaction is very functional-group tolerant. A possible mechanism is also proposed. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: C–N formation Arylboronic acids Organic azides Metal-free
The selective formation of carbon–nitrogen bonds is a fundamental transformation in organic synthesis. Although enormous approaches are available, the development of methods which are advantageous in the aspects of simplicity, selectivity, functionalgroup tolerance, and availability of starting materials would be valued in organic synthesis. Over the past decades, transition-metal-catalyzed aromatic C–N bond-forming reactions have been intensively studied due to the importance of aromatic amines in chemistry related fields.1 The most well-known method is palladium-, nickel-, or copper-catalyzed coupling reactions between aryl halides and amines,2 arylboronic acids and amines.3 The arylboronic acids are popular owing to their advantages in terms of stability, low toxicity, and commercial availability. To the best of our knowledge, all the arylboronic acid mediated C–N bondforming coupling reactions need metal catalysts. It will be beneficial if metal-free C–N bond formation coupling reactions can be developed because it will eliminate the necessity for disposing the catalysts from the reaction residues and separating the traceless metal from the products. Organic azides are versatile synthetic intermediates that participate in various important organic reactions, such as Huisgen reaction, Staudinger reaction, Schmidt rearrangement, and aza-Wittig reaction.4 Recently, it was reported that diazo compounds could be coupled with arylboronic acids to form C–C bonds without the use of metal catalysts.5 Thus, we herein wish to report a novel ⇑ Corresponding authors. Tel.: +86 571 88208450 (G.Z.), +86 571 88208452 (Y.Y.). E-mail addresses: [email protected] (G. Zhang), [email protected] (Y. Yu). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.11.103
methodology for a metal-free carbon–nitrogen bond-forming coupling reaction between arylboronic acids and organic azides. Initially, the reaction conditions were optimized using phenylboronic acid (1a) and benzyl azides (2a) as starting substrates (Table 1). When the reaction was carried out in ethanol, THF, 1,4-dioxane, xylene, DMF at 80 °C for 24 h, no reaction occurred (entries 1–5). When the temperature was increased to 100 °C, there was still no reaction in DMF (entry 6), but it gave relatively
Table 1 Optimization of reaction conditionsa
a b
Entry
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12
Ethanol THF 1,4-Dioxane Xylene DMF DMF 1,4-Dioxane Xylene Xylene Xylene Xylene Xylene
80 80 80 80 80 100 100 100 120 140 Reflux 140
24 24 24 24 24 24 24 24 24 24 24 48
0 0 0 0 0 0 15 20 32 55 53 82
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), xylene (5 ml), N2. The yield of the isolated product.
L. Ou et al. / Tetrahedron Letters 52 (2011) 1430–1431
1431
Table 2 Coupling reaction between arylboronic acids and organic azidesa
Entry
Ar
R
Product
Yieldb (%)
1 2 3 4 5 6c 7 8 9 10 11 12 13 14 15 16 17 18 19
Ph Ph Ph Ph Ph 3-CHOC6H4 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3,4,5-tri-F-C6H2 3-F-C6H4 3-F-C6H4 3-F-C6H4 4-MeOC6H4 4-MeOC6H4 4-MeC6H4 4-Pyridyl 2-Thienyl
Benzyl CH3(CH2)6CH2 Ph 4-MeOC6H4 4-MeC6H4 4-MeOC6H4 CH3(CH2)6CH2 4-MeOC6H4 4-MeC6H4 2-BrC6H4 4-NO2C6H4 Benzyl 4-MeOC6H4 4-ClC6H4 Benzyl 4-MeC6H4 Benzyl 4-MeOC6H4 4-MeOC6H4
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s
82 35 36 67 48 60 60 85 75 58 44 85 75 46 58 40 74 0 0
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), xylene (5 ml), N2, 140 °C, 24– 48 h. b The yield of the isolated product. c Reaction temperature is 120 °C.
low yields in 1,4-dioxane compared to that in xylene (entries 7 and 8, respectively). With the temperature increasing, the yield of the reaction was improved (entries 8–10), but at reflux the yield was not further improved (entry 11). It was also found that the yield was increased when prolonging the reaction time (entry 12 compared to 10). Thus, the optimized condition for this reaction was achieved in xylene at 140 °C for 48 h. With the optimized reaction conditions in hand, the generality of this reaction was studied using a set of arylboronic acids 1 and organic azides 2 (Table 2). The alkyl azides were readily prepared from alkyl bromides by the nucleophilic substitution of bromide with sodium azide,6 while aromatic azides are commonly prepared from the corresponding aromatic amines via their diazonium salts.7 The coupling reaction was conducted over a broad range of reagents. Both alkyl azides and aromatic azides were coupled with various arylboronic acids in moderate to good isolated yields. When compared to octyl azide, benzyl azide showed better reaction activity (entries 1 and 2). In addition, when arylboronic acids were coupled with benzyl azides, electron-withdrawing substitution gave satisfactory coupling (entry 12), but the yields dropped off with electron-donating substitution (entries 15 and 17). Furthermore, the coupling of arylboronic acids with a series of aryl azides was investigated. Arylboronic acids containing electron-withdrawing groups provided higher yields than those with electron-donating groups (entries 5, 9, and 16). While the results with the aryl azides were the opposite (entries 3–5). Especially the aryl azides with strong electron-withdrawing groups such as –NO2, these hardly reacted with phenylboronic acid, but did reacted with 3,4,5-trifluorophenylboronic acid in moderate yield (entry 11). To our delight, the functional-group tolerance of the reaction was evident. The reaction was performed successfully in the presence of unprotected aldehydes (entry 6). The coupling was also conducted successfully with halogen substituted aromatic rings (entries 5, 7–14). However, with regard to heterocyclic boronic acids such as pyridine-4-boronic acid and thiophene-2-boronic acid reacting with 4-methoxylphenyl azide, no desired secondary
Scheme 1. Possible mechanism for coupling reactions between arylboronic acids and organic azides.
amines were found (entries 18 and 19). Instead, the self-coupled product, 1,2-bis (4-methoxyphenyl) diazene was obtained. The mechanism of this coupling reaction between arylboronic acids and organic azides was considered to be similar to the reaction between arylboronic acids with diazo compounds (Scheme 1).5 The reaction is proposed to be initiated by the nucleophilic attack of azide nitrogen to arylboronic acid to form the reversible intermediate A, followed by 1,2-migration of aromatic rings with the loss of nitrogen. Finally, the generated intermediate B is converted to product 3 upon protodeboronation. In conclusion, we have developed a novel, efficient, and metalfree reaction for carbon–nitrogen bond formation via arylboronic acids and organic azides. This reaction is fairly general and functional-group tolerant. Thus, we believe it will be widely applied in organic synthesis. Acknowledgments We thank the National Natural Science Foundation of China (Nos. 30772652 and 90813026) and National key Tech project for Major Creation of New Drugs (No. 2009ZX09501-010) for financial support. Supplementary data Supplementary data (experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for all products) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2010.11.103. References and notes 1. (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem. 2005, 48, 1729; (b) D’Aprano, G.; Leclerc, M.; Zotti, G.; Schiavon, G. Chem. Mater. 1995, 7, 33; (c) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159. 2. (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; (b) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423; (c) Chen, C.; Yang, L.-M. J. Org. Chem. 2007, 72, 6324; (d) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397; (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. 3. (a) Leyand, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (b) Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079; (c) Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.; Balasubrahmanyam, V. Synthesis 2008, 795; (d) Singh, B. K.; Stevens, C. V.; Acke, D. R. J.; Parmar, V. S.; Van der Eycken, E. V. Tetrahedron Lett. 2009, 50, 15. 4. (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188; (b) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018; (c) Nisic, F.; Andreini, M.; Bernardi, A. Eur. J. Org. Chem. 2009, 33, 5744; (d) Zhao, Y.-M.; Gu, P.; Tu, Y. Q.; Fan, C.-A.; Zhang, Q. Org. Lett. 2008, 10, 1763; (e) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org. Lett. 2008, 10, 2589. 5. (a) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11, 1667; (b) Barluenga, J.; Tomás-Gamasa, M.; Aznar, F.; Valdés, C. Nat. Chem. 2009, 1, 494. 6. Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413. 7. Kamalraj, V. R.; Senthil, S.; Kannan, P. J. Mol. Struct. 2008, 892, 210.