Regioselective reactions of 3,4-pyridynes enabled

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Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model February 5th 2014 Patrick Cyr http://www.chem.ucla.edu/dept/Faculty/garg/Garg_Group/Hetarynes.html / predictive tools in aryne chemistry Adam E. Goetz and Neil K. Garg. Nat. Chem. 2013, 5, 54

Neil Garg 2000 - B. S. Chem. at New York University 2000-2005 - Ph.D. at Caltech (Pr. Brian Stoltz) 2005-2007 - N.I.H. postdoctoral fellow at University of California (Ir. - Pr. Larry Overman) 2007 - Assistant Professor at U.C.L.A . 2012 - Associate Professor at U.C.L.A. 2013 - Professor at U.C.L.A. Awards : UCLA Faculty Career Development Award / UCLA Faculty Research Grant NSF CAREER Award / Thieme Chemistry Journal Award / Dupont Young Professor Award Boehringer Ingelheim New Investigator Award . 41 publications in 7 years

Garg’s research interest

Aryne chemistry Stoermer & Kahlert 1902 First (possible) suggestion of Aryne

Aryne chemistry Wittig 1942 First suggestion of Benzyne Switterionic intermediate

Aryne chemistry Gilman 1945 First strong indication for a Benzyne intermediate

Aryne chemistry Roberts 1953 14C labeling experiment : proof of a symmetrical intermediate

Aryne chemistry Wittig and Levine 1955 First trapping of the benzyne intermediate First postulation of Pyridyne

Aryne chemistry Kauffmann 1962 First trapping of the pyridyne intermediate

Characteristic feature of Arynes Electrophilic specie Biradical character Gampe, C. M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3766. Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem. Int. Ed. 2003, 42, 502.

Benzyne preparation Kobayashi, Chem. Lett.1983, 1211. Kobayashi Tadross, P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550.

Aryne distortion model P character Less elctronegative = more stabilize hybridisation : More p character = LUMO lower Guitiàn. Synlett 1998, 157. Angew. Chem. Int. Ed. 2010, 49, 9132-9135. J. Am. Chem. Soc. 2010, 132, 1267-1269.

Aryne distortion model Prediction trick Addition places negative charge close to electron withdrawing group We have an urly T.S. so this tric is not the reality (would work for a late T.S.) Guitiàn. Synlett 1998, 157. Angew. Chem. Int. Ed. 2010, 49, 9132-9135. J. Am. Chem. Soc. 2010, 132, 1267-1269.

Hetarynes regioselectivity prediction Goetz, A. E.; Bronner, S. M.; Cisneros, J. D.; Melamed, J. M.; Paton*, R. S.; Houk*, K. N.; Garg*, N. K. Angew. Chem. Int. Ed. 2012, 51, 2758 –2762

Previous regioselective inductions 3,4 –pyridyne from 3-halo Mal, D.; Senapati, B. K.; Pahari, P. Synlett 2005, No. 6, 994. Vinter-Pasquier, K.; Jamart-Grégoire, B.; Caubère, P. Heterocycles 1997, 45, 2113.

Previous regioselective inductions 3,4 –pyridyne from Kobayashi’s precursor Tsukazaki, M.; Snieckus, V. Heterocycles 1992, 33, 533. Diaz,M. T.; Cobas, A.; Guitian, E.; Castedo, L. Synlett 1998, 157.

Garg’s predicted Effect of substituents DFT calculations

Regioselectivity studies

Regioselectivity studies Distortion model vs steric hindrance

Regioselectivity studies

Regioselectivity studies Yoshihiro Sato

Derivatizations of pyridyne adducts Reductive cleavage SIPr-HCl : 1,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride / TMDSO : Tetramethyldisiloxane First example of a reductive sulfamate cleavage

Derivatizations of pyridyne adducts Using synthetic handles Suzuki–Miyaura coupling / Buchwald–Hartwig amination / Ni Kumada–Corriu coupling / Ni Sulfamate amination

Conclusion First general method to control the 3,4-pyridyne regioselectivity Versatile synthetic handles were used as directing groups Improvement of the post-transformation of the sulfamate moiety needed Further validation of the aryne distortion model as a predictive tools for the regioselectivity on hetaryne This work should promote the use of pyridyne in total synthesis and in pharmaceutical industries

Back-up Benzyne * Tokiwa, H.; Akai, s. et al. J. Org. Chem. 2013, 78, 2965.

Back-up precursor synthesis Grignard: halogen exchange ? -> was done in a separate vial

Back-up Comparison between a C5 Bromide and Chloride

Back-up predicted Effect of substituents

Back-up 3,4 -pyridyne * Tsukazaki, M.; Snieckus, V. Heterocycles 1992, 33, 533. * Vinter-Pasquier, K.; Jamart-Grégoire, B.; Caubère, P. Heterocycles 1997, 45, 2113. * Diaz,M. T.; Cobas, A.; Guitian, E.; Castedo, L. Synlett 1998, 157.