1,3-Dipolar cycloaddition of nitrous oxide with highly strained cycloalkynes Oliver Plefka and Klaus Banert Chemnitz University of Technology, Institute of Chemistry, Organic Chemistry Straße der Nationen 62, D-09111 Chemnitz, Germany Introduction N2O as 1,3-dipolar reagent For many decades 1,3-dipolar cycloaddition reactions are well known in Another, but very unreactive, 1,3-dipolar reagent is nitrous oxide (N 2O). There organic chemistry to synthesize highly functionalized 5-membered heterocyclic are just a few articles from 1951 and some other since 2002 where N2O was rings. used in reactions with olefins under (sometimes) very extensive and A A A A dangerous conditions (up to 500 atm and 400°C) to get nitrogen-free products, E E E B B + B B which could be explained via an initial 1,3-dipolar cycloaddition of N 2O to the D D D [2] C C C C double bond. N The most common 1,3-dipolar reagents are, for example, ozone, azides or N2O (500 atm) N –N diazo compounds. [1] 300°C 2 O O Atom economical 1,3-dipolar cycloaddition of N 2O Recently, we developed a method to perform 1,3-dipolar cycloadditions of the low- Cyclooctyne (3) is the smallest unsubstituted cycloalkyne which is isolable at room cost reagent N2O under very mild conditions (–25°C and ~15 bar) using highly temperature. We were able to perform 1,3-dipolar cycloaddition reactions between [3] strained cycloalkynes like the literature-known thiacycloheptyne 1. Under these cyclooctyne (3) and N 2O at room temperature in polar protic solvents to get the conditions, it is even possible to maintain all three atoms of the N2O molecule in the complex products 4. Again, all three atoms of the added N2O molecule are part of the desired, literature-known [4] but short-lived α-diazoketone 2. We were also able to products 4. The mechanism for the formation of 4 from 3 is described below. analyze the α-diazoketone 2 – which is unstable at room temperature – by NMR spectroscopy at –25°C. 4a (XH = MeOH): 48% 4b (XH = EtOH): 32% N N2 N2O (~50 bar) N2O (~15 bar) O 4c (XH = PhOH): 37% S S N S RT CDCl 80% 4d (XH = PhNH2): 60% 3 O X-H N (NMR) O 4e (XH = PhNHMe): 48% –25°C, 72 h 3 X 6 N H 1 2 X O The higher strained and reactive cycloocten-5-yne ( 5) (compared to 6a (XH = MeOH): 69% cyclooctyne (3)) reacts in the same way with nitrous oxide like N2O (~50 bar) 6b (XH = EtOH): 45% cyclooctyne (3) in polar protic solvents to get the desired analogous RT 6d (XH = PhNH2): 50% X-H products 6. N 6e (XH = PhNHMe): 66% 5 N H Mechanism for the reaction of cyclooctyne (3) and cyclocten-5-yne ( 5) with N 2O to 4 and 6: N N2 N2O N 4 / 6 1,3-dipolar 1,3-dipolar 1,3-dipolar 1,2-acyl X-H O cycloaddition cycloreversion O cycloaddition N migration N 3 / 5 N N O O Acknowledgement and literature The authors thank the "Studentenwerk Chemnitz-Zwickau" for financial support of this work via two "Sächsische Landesstipendien" from July to December 2007 and from July to December 2008. The authors also thank Dr. M. Hagedorn for some initial experiments concerning this work. [1] a) R. Huisgen, Angew. Chem. 1963 , 75 , 604–637; Angew. Chem. Int. Ed. Engl. 1963 , 2, 565–598. b) A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 , Wiley, New York, 1984 . [2] a) F. S. Bridson-Jones, G. D. Buckley, L. H. Cross, A. P. Driver, J. Chem. Soc. (London) 1951 , 2999–3008. b) F. S. Bridson-Jones, G. D. Buckley, J. Chem. Soc. (London) 1951 , 3009–3016. c) G. D. Buckley, W. J. Levy, J. Chem. Soc. (London) 1951 , 3016–3018. d) G. I. Panov, K. A. Dubkov, E. V. Starokon, V. N. Parmon, React. Kinet. Catal. Lett. 2002 , 76 , 401–406. e) G. I. Panov, K. A. Dubkov, E. V. Starokon, V. N. Parmon, React. Kinet. Catal. Lett. 2002 , 77 , 197–205. f) E. V. Starokon, K. A. Dubkov, D. E. Babushkin, V. N. Parmon, G. I. Panov, Adv. Synth. Catal. 2004 , 346 , 268–274. g) S. V. Semikolenov, K. A. Dubkov, E. V. Starokon, D. E. Babushkin, G. I. Panov, Russ. Chem. Bull. Int. Ed. 2005 , 54 , 948–956. h) E. V. Starokon, K. A. Dubkov, V. N. Parmon, G. I. Panov, React. Kinet. Catal. Lett. 2005 , 84 , 383–388. [3] A. Krebs, H. Kimling, Liebigs Ann. Chem. 1974 , 2074–2084. [4] Ä. de Groot, J. A. Boerma, J. de Valk, H. Wynberg, J. Org. Chem. 1968 , 33 , 4025–4029..