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