Patrick Robichaux Tang Group University of Wisconsin-Madison Department of Chemistry Literature Seminar 04/28/2011 1

History Overview Preparation Regioselectivity Application 2

History Overview Preparation Regioselectivity Application 3

Evidence for Benzyne Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75 , 3290.

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Neutral Benzyne Intermediate?

Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75 , 3290.

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Singlet or Triplet?

• hν = diradical?

• Benzyne actually • singlet singlet-triplet splitting of 37.5 kcal/mol • lifetime at least 20 ms Wittig, G.; Ebel, H. F. Angew. Chem. 1960, 72 , 564.

Wentrup, C. Aust. J. Chem. 2010, 63 , 979.

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History Overview Preparation Regioselectivity Application 7

Traditional Formation of Benzyne Kitamura, T. Aust. J. Chem. 2010, 63 , 987.

Wentrup, C. Aust. J. Chem. 2010, 63 , 979.

Pellissier, H.; Santelli, M. Tetrahedron 2003, 59 , 701.

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Synthesis of Silyltriflate Bronner, S. M.; Garg, N. K. J. Org. Chem. 2009 ,

74

, 8842-8843.

Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224-1227.

Wu, Q.-c.; Li, B.-s.; Shi, C.-q.; Chen, Y.-x. Hecheng Huaxue 2007 , 111.

Himeshima, Y.; Sonada, T.; Kobayashi, H. Chem. Lett. 1983 , 1211.

Peña, D.; Cobas, A.; Pérez, D.; Guitián, E. Synthesis 2002. 1454.

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Activation Domino Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S. Org. Lett. 2011 ,

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, 1730.

• Silyl protecting group tolerant 10

New Method: C-H activation CHEAP!

• highly solvent and concentration dependent • Optimized conditions: Pd(OAc) 2 Cu(OAc) 2 (10 mol %) (0.75 equiv.) 1,10-phenanthroline (10 mol %) K 2 HPO 4 (2 equiv.) , TBAB (1 equiv.) sulfonane, 4 Å MS <47% yield + side products 11 Cant, A. A.; Roberts, L.; Greaney, M. F. Chemical Communications 2010 ,

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, 8671-8673.

History Overview Preparation Regioselectivity Application 12

Regioselectivity: Sterics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.

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Regioselectivity: Sterics vs. Electronics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341.

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Regioselectivity: Electronics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011 , 341.

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Distortion/Interaction Model Cheong, P. H. Y.; Paton, R. S.; Bronner, S. M.; Im, G. Y. J.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132 , 1267.

Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010 ,

132

, 17933.

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Reactivity of Indolyne Systems Im, G. Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H. Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010 ,

132

, 17933.

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History Overview Preparation Regioselectivity Application 18

Nucleophilic Additions 19

Acyl-Alkylation of Arynes Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127 , 5340.

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Acyl-Alkylation of Arynes Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128 , 11752.

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Indolines and Isoquinolines Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130 , 1558.

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Indolyne: Regioselectivity Reversal Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133 , 3832.

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Indole Synthesis

E +

H 2 O Bu 3 SnCl PhCHO Me 2 CO ClCO 2 Et PhCH-NPh BrCH 2 CH 2 Br

E

H SnBu 3 PhC(H)OH Me2COH CO 2 Et PhCHNHPh Br

Yield (%)

75 67 69 73 73 59 61 Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chemistry-a European Journal 2002, 8 , 2034.

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Biaryl Synthesis Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126 , 13028.

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Cycloadditions 26

Enamide Cascade Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11 , 3666.

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[4+2] Cycloaddition on Arene System Nishimura, T.; Nagaosa, M.; Hayashi, T. Chem.Lett.2008, 37 , 860.

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Metal Free Click Chemistry Lin, Y.; Chen, Y.; Ma, X.; Xu, D.; Cao, W.; Chen, J. Tetrahedron 2011, 67 , 856.

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Indole Synthesis Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40 , 3784.

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Transition Metal Reactions 31

3-Component Benzyne Coupling Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128 , 14042.

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3-Component Benzyne Coupling Larrosa, I.; Da Silva, M. I.; Gómez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128 , 14042.

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Catalytic Carbonylation Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2001, 123 , 12686.

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Pd-catalyzed Heck: Suzuki: Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2005, 7 , 2921.

Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9 , 5589.

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Image from google images Conclusions

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Acknowledgments • • • • Professor Weiping Tang Tang and Hsung group Kat Myhre Practice Talk Attendees: – Jenny B. Werness – Dongxu Shu – – Wei Zhang Renhe Liu – – – Xiaoxun Li Dr. Xingzhong Shu Suyu Huang – – Andrew G. Lohse Kyle Dekorver 37