1. Benzynes Dorothy Ackerman Townsend Group Meeting December 2, 2014

2. History and Structure 1942: Wittig – dehyrobenzol intermediate 1945: Gilman – rearrangement 1946: Bergstrom – action of bases on tolyl halides 1953: Roberts – 14 C labeled G. Wittig, Naturwissenschafter 1942, 30, 696. H. Gilman, S. Avakian, J. Am. Chem. Soc. 1945, 67, 349. F. W. Bergstrom, C. H. Horning, J. Org. Chem. 1946, 11, 334. J. D. Roberts, H. E. Simmons Jr., L. A. Carlsmith, C. W. Vaughan, J. Am. Chem. Soc. 1953, 75, 3290.

3. Wittig’s Initial Explanation: Zwitterion Intermediate G. Wittig, Naturwissenschafter 1942, 30, 696.

4. Wittig’s Initial Explanation: Zwitterion Intermediate G. Wittig, Naturwissenschafter 1942, 30, 696. Roberts, J. D.; Simmons Jr., H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290 1. Fails to explain observed regiochemistry:

5. Wittig’s Initial Explanation: Zwitterion Intermediate G. Wittig, Naturwissenschafter 1942, 30, 696. Roberts, J. D.; Simmons Jr., H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290 1.Fails to explain observed regiochemistry 2.No isomerization of reactants or products under reactions coniditions:

6. Wittig’s Initial Explanation: Zwitterion Intermediate G. Wittig, Naturwissenschafter 1942, 30, 696. Roberts, J. D.; Simmons Jr., H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290 1.Fails to explain observed regiochemistry 2.No isomerization of reactants or products under reactions coniditions 3.No reaction occurs in the benzene series where a hydrogren is not attached to the position adjacent to the leaving group

7. Roberts Introduces Benzyne Concept “Elimiation-addition mechanism involving…an electrically neutral ‘benzyne’ intermediate” The proposed symmetrical intermediate supposes an equal amount of the products, which corresponds to experimental results Roberts, J. D.; Simmons Jr., H. E.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290

8. Further Evidence for Support of Benzyne Intermediate 1955: Wittig and Pohmer – Benzyne Diels-Alder 1963: Huisgen and Knorr – reactivity of benzyne from different precursors G. Wittig, L. Pohmer, Angew. Chem. 1955, 67(13), 348. R. Huisgen, R. Knorr, Tetrahedron Lett. 1963, 1017

9. Crystal Structure of Metal-Bound Benzyne Shrock, 1979Evans and Smart, 1980Buchwald, 1986 McLain, S. J.; Shrock, R. R.; Sharp, P. R.; Churchill, M. P.; Youngs, W. J. J. Am. Chem. Soc. 1979, 101, 263 Buchwald, S. L.; Watson, B. T. J. Am. Chem. Soc. 1986, 108, 7411 Brown, S. C.; Evans, J.; Smart, L. E. J. Am. Chem. Soc. Chem Comm. 1980, 21, 1021

10. Generation of Benzyne Intermediates Tadross, P. M.; Stoltz, B. M.; Chem. Rev. 2012, 112, 3550

11. Generation of Benzyne Intermediates Y = EDG, product A is favored Y= EWG, product B is favored Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry Part B: Reactions and Synthesis, 5 th Ed., 2007

12. Reactions of Arynes Tadross, P. M.; Stoltz, B. M.; Chem. Rev. 2012, 112, 3550

13. [4+2] Cycloadditions 1955: Wittig and Pohmer 1992: Davies et al. 1965: Kornfeld et al. G. Wittig, L. Pohmer, Angew. Chem. 1955, 67, 348. Davies, J. W.; Durrant, M. L.; Walker, M. P.; Belkacemi, D.; Malpass, J. R. Tetrahedron 1992, 48, 861 – 884. E. C. Kornfeld, P. Barney, J. Blankley, W. Faul, J. Med. Chem. 1965, 8, 342

14. Regiochemistry of [4+2] Cycloadditions δ- δ+ Polar groups at the 3 position influence selectivity Partial positive charge at the meta position to the EWG helps stabilize the developing negative charge Friedal Craft chemistry: methoxy is donating and ortho/para directing Benzyne chemistry: methoxy is “withdrawing” and meta directing Biehl, E. R.; Nieh, E; Hsu, K. C., J. Org. Chem., 34, 3595 (1969) Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry Part B: Reactions and Synthesis, 5 th Ed., 2007

15. [4+2] Cycloadditions Total synthesis of the Gilvocarcins Kitamura, T.; Fukatsu, N.; Fujiwara, Y. J. Org. Chem. 1998, 63, 8579 – 8581. Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568 – 3570 Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004 – 1015.

16. [2+2] Cycloadditions 76% (single regioisomer) δ- δ+ δ- [2+2] is not thermally allowed, so a stepwise mechanism is proposed R. V. Stevens, G. S. Bisacchi, J. Org. Chem. 1982, 47, 2396

17. Tandem [2+2]-[4+2] Feltenberger, J. B., Hayaski, R., Tang, Y., Babiash, E. S. C., and Hsung, R. P., Org. Lett. 2009, 11, 3666

18. 1,3-Dipolar Cylcoadditions Matsumoto, T.; Sohma, T.; Hatazaki, S.; Suzuki, K. Synlett, 1993, 843 Kitamura, T.; Fukatsu, N.; Fujiwara, Y. J. Org. Chem. 1998, 63, 8579

19. Electrophillic Nature of Benzyne Deviation from preferred bond angle (180 o ) lowers LUMO A lower LUMO correlates to increased reactivity towards nucleophiles δ- δ+ Polar groups at the 3 position influence selectivity Partial positive charge at the meta position to the EWG helps stabilize the developing negative charge Gampe, C. M.; Carreira, E. M., ACIE, 2012, 51, 3766 Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry Part B: Reactions and Synthesis, 5 th Ed., 2007

20. Nucleophilic Additions Variety of Nucleophiles And Arynes

21. Nucleophilic Additions Carbon Nucleophiles Nitrogen Nucleophiles Kakusawa, N.; Sakamoto, K.; Kurita, J.; Tsuchiya, T. Heterocycles 1996, 43, 2091 – 2094. Self, J. L.; Khanapure, S. P.; Biehl, E. R. Heterocycles 1991, 32, 311–318.

22. Multicomponent Reactions Dehydroaltenuene B Yoshida, H.; Fukushimda, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron 2007, 63, 4793–4805 Soorukram, D.; Qu, T.; Barrett, A. G. M. Org. Lett. 2008, 10, 3833.

23. Carbon-Carbon σ-bond Insertions Initial Report: 1973, Guvat et al. Guyot, M.; Molho, D. Tetrahedron Lett. 1973, 14, 3433 Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Comm, 2005, 3292

24. Metal Catalyzed Reactions Pd-catalyzed [2+2+2] Cycloaddition Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004, 43, 2436.

25. Heteroarynes Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34 benzofuanyne2,3-indolyne pyrrolyne thiophynebenzothiophyne 4,5-indolynequinolynepyrimidynepyridyne

26. Pyridyne Generation Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34

27. Indolyne Generation Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34

28. Natural Products from Heterocyclic Arynes Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34