Metal-Free Intramolecular Aminocyanation of

Alkenes via N–CN Bond Cleavage

Zhongda Pan

Advisor: Christopher J. Douglas

Department of Chemistry,

University of Minnesota, Minneapolis

ACS Division of Organic Chemistry

2014 Graduate Research Symposium

University of California, Irvine

July 26, 2014

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Introduction Metal-catalyzed bond activation — a “cut-and-sew” strategy

The concept of ‘cut-and-sew’: Xu, T., Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567. Hoang, G. T. Development of New Reaction Methodologies via Transition Metal Catalyzed

Bond Activation Processes. Ph.D. Thesis, University of Minnesota, 2012. 2

Introduction Challenges and strategies of C–C bond activation

Selected reviews on C–C bond activations: (a) Jun, C. H. Chem. Soc. Rev. 2004, 33, 610. (b) Murakami, M.; Makino, M.; Ashida, S.; Matsuda, T. Bull. Chem. Soc. Jpn. 2006, 79, 1315. (c) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41,

222. (d) Murakami, M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (e) Ruhland, K. Eur. J. Org. Chem. 2012, 14, 2683. (f) Etienne, M.; Weller, A. S. Chem. Soc. Rev. 2014, 43, 242. (g) Dermenci, A.; Coe, J. W.; Dong, G. Org. Chem. Front. 2014, 1,

567. 3

Introduction C–C bond activation and alkene functionalizations

Dreis, A. M.; Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412. For related mechanistic studies, see: (a) Rathbun, C. M.; Johnson, J. B. J. Am. Chem. Soc. 2011, 133, 2031. (b) Lutz, J. P.; Rathbun, C. M.; Stevenson, S. M.;

Powell, B. M.; Boman, T. S.; Baxter, C. E. Zona, J. M.; Johnson, J. B. J. Am. Chem. Soc. 2012, 134, 715. Xu, T., Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567. 4

Introduction C–CN activation and alkene cyano-functionalizations

Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. Rondla, N. R.; Ogilvie, J. M.; Pan, Z.; Douglas, C. J. Chem. Commun. 2014, 50, 8974.

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Introduction Oxycyanation: from C–CN to O–CN activation

Koester, D. C.; Kobayashi, M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134, 6544. 6

Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem. Soc. Perkin. Trans. 2, 1997, S1-S19. Cunningham, I. D.; Light, M. E.; Hursthouse, M. B. Acat Crystallogr., Sect. C: Cryst. Struct. Commun. 1999, 55, 1833.

Vliet, E. B. Org. Synth. 1941, 1, 20.

Introduction Inspirations

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Introduction Aminocyanation — what’s new?

Leading reviews on alkene difunctionalizations: (a) Minatti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142.

(b) Jensne, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083. (c) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. 8

Results and Discussion Substrate synthesis

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Results and Discussion Optimization

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Results and Discussion Optimization

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Results and Discussion Substrate scope and limitations

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Results and Discussion Substrate scope and limitations

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Results and Discussion Alternative mechanistic consideration

Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 5608. Anbarasan, P.; Neumann, H.; Beller, M. Chem. Eur. J. 2011, 17, 4217.

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Results and Discussion Alternative mechanistic consideration

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Results and Discussion Double cross-over experiments

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Results and Discussion Alternative mechanistic consideration

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More aminocyanations Nakao group’s aminocyanation

Pan, Z.; Pound, S. M. Rondla, N. R.; Douglas, C. J. Angew. Chem., Int. Ed. 2014, 53, 5170. Miyazaki,Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732.

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Evidence for N–CN oxidative addition

More aminocyanations

Miyazaki,Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732. 19

Evidence for N–CN oxidative addition

More aminocyanations

Miyazaki,Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732. 20

Summary and future work All roads lead to Rome

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Summary and future work

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Acknowledgement

Christopher Douglas Sarah Pound

Naveen Rondla Douglas group members

DOC 2014 Graduate Research Symposium

National Institutes of Health(R01 GM095559)

Douglas group @ Minneapolis

Sculpture Garden, 2013