Benzynes Dorothy Ackerman Townsend Group Meeting December 2, 2014
Jan 15, 2016
Benzynes
Dorothy AckermanTownsend Group Meeting
December 2, 2014
History and Structure1942: Wittig – dehyrobenzol intermediate
1945: Gilman – rearrangement
1946: Bergstrom – action of bases on tolyl halides
1953: Roberts – 14C 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.
Wittig’s Initial Explanation: Zwitterion Intermediate
G. Wittig, Naturwissenschafter 1942, 30, 696.
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:
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 regiochemistry2. No isomerization of reactants or products under
reactions coniditions:
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 regiochemistry2. No isomerization of reactants or products under
reactions coniditions3. No reaction occurs in the benzene series where a
hydrogren is not attached to the position adjacent to the leaving group
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
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
Crystal Structure of Metal-Bound Benzyne
Shrock, 1979 Evans and Smart, 1980 Buchwald, 1986
McLain, S. J.; Shrock, R. R.; Sharp, P. R.; Churchill, M. P.; Youngs, W. J. J. Am. Chem. Soc. 1979, 101 , 263Buchwald, 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
Generation of Benzyne Intermediates
Tadross, P. M.; Stoltz, B. M.; Chem. Rev. 2012, 112, 3550
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, 5th Ed., 2007
Reactions of Arynes
Tadross, P. M.; Stoltz, B. M.; Chem. Rev. 2012, 112, 3550
[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
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, 5th Ed., 2007
[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.
[2+2] Cycloadditions
76% (single regioisomer)
δ-
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
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
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
Electrophillic Nature of Benzyne
• Deviation from preferred bond angle (180o) 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, 3766Carey, F. A.; Sundberg, R. J., Advanced Organic Chemistry Part B: Reactions and Synthesis, 5th Ed., 2007
Nucleophilic Additions
• Variety of Nucleophiles
• And Arynes
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.
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.
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
Metal Catalyzed Reactions
Pd-catalyzed [2+2+2] Cycloaddition
Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004, 43, 2436.
Heteroarynes
Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34
benzofuanyne 2,3-indolyne pyrrolyne thiophyne benzothiophyne
4,5-indolyne quinolyne pyrimidyne pyridyne
Pyridyne Generation
Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34
Indolyne Generation
Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34
Natural Products from Heterocyclic Arynes
Goetz, A.; Shah, T.; Garg, N. Chem. Commun., 2015, 51, 34