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

2. Overview HistoryPreparation RegioselectivityApplication 2

3. Overview HistoryPreparation RegioselectivityApplication 3

4. Evidence for Benzyne Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290. 4

5. Neutral Benzyne Intermediate? Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290. 5

6. 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. 6

7. Overview HistoryPreparation RegioselectivityApplication 7

8. 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. 8

9. 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. 9

10. Activation Domino Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S. Org. Lett. 2011, 13, 1730. Silyl protecting group tolerant 10

11. New Method: C-H activation highly solvent and concentration dependent Optimized conditions: Pd(OAc) 2 (10 mol %) Cu(OAc) 2 (0.75 equiv.) 1,10-phenanthroline (10 mol %) K 2 HPO 4 (2 equiv.), TBAB (1 equiv.) sulfonane, 4 Å MS Cant, A. A.; Roberts, L.; Greaney, M. F. Chemical Communications 2010, 46, 8671-8673. 11 CHEAP! <47% yield + side products

12. Overview HistoryPreparation RegioselectivityApplication 12

13. Regioselectivity: Sterics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341. 13

14. Regioselectivity: Sterics vs. Electronics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341. 14

15. Regioselectivity: Electronics Diemer, V.; Begaud, M.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011, 341. 15

16. 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. 16

17. Reactivity of Indolyne Systems 17 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.

18. Overview HistoryPreparation RegioselectivityApplication 18

19. Nucleophilic Additions 19

20. Acyl-Alkylation of Arynes Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340. 20

21. Acyl-Alkylation of Arynes Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752. 21

22. Indolines and Isoquinolines Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558. 22

23. Indolyne: Regioselectivity Reversal Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832. 23

24. Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chemistry-a European Journal 2002, 8, 2034. E+E+ EYield (%) H2OH2OH75 Bu 3 SnClSnBu 3 67 PhCHOPhC(H)OH69 Me 2 COMe2COH73 ClCO 2 EtCO 2 Et73 PhCH-NPhPhCHNHPh59 BrCH 2 CH 2 BrBr61 Indole Synthesis 24

25. Biaryl Synthesis Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028. 25

26. Cycloadditions 26

27. Enamide Cascade Feltenberger, J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666. 27

28. [4+2] Cycloaddition on Arene System Nishimura, T.; Nagaosa, M.; Hayashi, T. Chem.Lett.2008, 37, 860. 28

29. Metal Free Click Chemistry Lin, Y.; Chen, Y.; Ma, X.; Xu, D.; Cao, W.; Chen, J. Tetrahedron 2011, 67, 856. 29

30. Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784. Indole Synthesis 30

31. Transition Metal Reactions 31

32. 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. 32

33. 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. 33

34. Catalytic Carbonylation Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2001, 123, 12686. 34

35. 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. 35

36. Conclusions 36 = Image from google images

37. 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