Abstract
For over a century, the structures and reactivities of strained organic compounds have captivated the chemical community. Whereas triple-bond-containing strained intermediates have been well studied, cyclic allenes have received far less attention. Additionally, studies of cyclic allenes that bear heteroatoms in the ring are scarce. We report an experimental and computational study of azacyclic allenes, which features syntheses of stable allene precursors, the mild generation and Diels–Alder trapping of the desired cyclic allenes, and explanations of the observed regio- and diastereoselectivities. Furthermore, we show that stereochemical information can be transferred from an enantioenriched silyl triflate starting material to a Diels–Alder cycloadduct by way of a stereochemically defined azacyclic allene intermediate. These studies demonstrate that heteroatom-containing cyclic allenes, despite previously being overlooked as valuable synthetic intermediates, may be harnessed for the construction of complex molecular scaffolds bearing multiple stereogenic centres.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Heaney, H. The benzyne and related intermediates. Chem. Rev. 62, 81–97 (1962).
Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).
Dubrovskiy, A. V., Markina, N. A. & Larock, R. C. Use of benzynes for the synthesis of heterocycles. Org. Biomol. Chem. 11, 191–218 (2013).
Goetz, A. E., Shah, T. K. & Garg, N. K. Pyridynes and indolynes as building blocks for functionalized heterocycles and natural products. Chem. Commun. 51, 34–45 (2015).
Wittig, G. & Fritze, P. On the intermediate occurrence of 1,2-cyclohexadiene. Angew. Chem. Int Ed. 5, 846 (1966).
Angus, R. O., Schmidt, M. W. & Johnson, R. P. Small-ring cyclic cumulenes: theoretical studies of the structure and barrier to inversion in cyclic allenes. J. Am. Chem. Soc. 107, 532–537 (1985).
Engels, B., Schöneboom, J. C., Münster, A. F., Groetsch, S. & Christl, M. Computational assessment of electronic structures of cyclohexa-1,2,4-triene, 1-oxacyclohexa-2,3,5-triene (3δ2-pyran), their benzo derivatives, and cyclohexa-1,2-diene. An experimental approach to 3δ2-pyran. J. Am. Chem. Soc. 124, 287–297 (2002).
Hänninen, M. M., Peuronen, A. & Tuononen, H. M. Do extremely bent allenes exist? Chem. Eur. J. 15, 7287–7291 (2009).
Daoust, K. J. et al. Strain estimates for small-ring cyclic allenes and butatrienes. J. Org. Chem. 71, 5708–5714 (2009).
Johnson, R. P. Strained cyclic cumulenes. Chem. Rev. 89, 1111–1124 (1989).
Wentrup, C., Gross, G., Maquestiau, A. & Flammang, R. 1,2-Cyclohexadiene. Angew. Chem. Int. Ed. Engl. 22, 542–543 (1983).
Nendel, M., Tolbert, L. M., Herring, L. E., Islam, M. N. & Houk, K. N. Strained allenes as dienophiles in the Diels–Alder reaction: an experimental and computational study. J. Org. Chem. 64, 976–983 (1999).
Moore, W. R. & Moser, W. R. The reaction of 6,6-dibromobicyclo[3.1.0]hexane with methyllithium. Evidence for the generation of 1,2-cyclohexadiene and 2,2′-dicyclohexenylene. J. Am. Chem. Soc. 92, 5469–5474 (1970).
Quintana, I., Peña, D., Pérez, D. & Guitián, E. Generation and reactivity of 1,2-cyclohexadiene under mild reaction conditions. Eur. J. Org. Chem. 2009, 5519–5524 (2009).
Christl, M., Fischer, H., Arnone, M. & Engels, B. 1-Phenyl-1,2-cyclohexadiene: astoundingly high enantioselectivities on generation in a Doering–Moore–Skattebøl reaction and interception by activated olefins. Chem. Eur. J. 15, 11266–11272 (2009).
Bottini, A. T., Hilton, L. L. & Plott, J. Relative reactivities of 1,2-cyclohexadiene with conjugated dienes and styrene. Tetrahedron 31, 1997–2001 (1975).
Bottini, A. T., Corson, F. P., Fitzgerald, R. & Frost, K. A. II Reactions of 1-halocyclohexenes and methyl substituted 1-halocyclohexenes with potassium t-butoxide. Tetrahedron 28, 4883–4904 (1972).
Barber, J. S. et al. Nitrone cycloadditions of 1,2-cyclohexadiene. J. Am. Chem. Soc. 138, 2512–2515 (2016).
Lofstrand, V. A. & West, F. G. Efficient trapping of 1,2-cyclohexadienes with 1,3-dipoles. Chem. Eur. J. 22, 10763–10767 (2016).
Uyegaki, M., Ito, S., Sugihara, Y. & Murata, I. 1-Benzoxepin and its valence isomers, 4,5-benz-3-oxatricyclo[4.1.0.02,7]heptene and 3,4-benz-2-oxabicyclo[3.2.1]hepta-3,6-diene. Tetrahedron Lett. 49, 4473–4476 (1976).
Schreck, M. & Christl, M. Generation and interception of 1-oxo-3,4-cyclohexadiene. Angew. Chem. Int. Ed. 26, 690–692 (1987).
Christl, M. & Braun, M. Friesetzung und Abfangreaktionen von 1-oxa-2,3-cyclohexadien. Chem. Ber. 122, 1939–1946 (1989).
Ruzziconi, R., Naruse, Y. & Schlosser, M. 1-Oxa-2,3-cyclohexadiene (‘2H-isopyran’): a strained heterocyclic allene undergoing cycloaddition reactions with characteristic typo-, regio-, and stereoselectivities. Tetrahedron 47, 4603–4610 (1991).
Jamart-Grégoire, B., Mercier-Girardot, S., Ianelli, S., Nardelli, M. & Caubère, P. Aggregative activation and heterocyclic chemistry. II Nucleophilic condensation of ketone enolates on dehydrodihydropyran generated by complex bases. Tetrahedron 51, 1973–1984 (1995).
Christl, M., Braun, M., Wolz, E. & Wagner, W. 1-Phenyl-1-aza-3,4-cyclohexadien, das erste Isodihydropyridin: ertzeugung und abfangreaktionen. Chem. Ber. 127, 1137–1142 (1994).
Drinkuth, S., Groetsch, S., Peters, E., Peters, K. & Christl, M. 1-Methyl-1-azacyclohexa-2,3-diene(N–B)borane—generation and interception of an unsymmetrical isodihydropyridine. Eur. J. Org. Chem. 14, 2665–2670 (2001).
Elliott, R. L. et al. Cycloadditions of cephalosporins. A comprehensive study of the reaction of cephalosporin triflates with olefins, acetylenes, and dienes to form [2+2] and [4+2] adducts. J. Org. Chem. 62, 4998–5016 (1997).
Elliott, R. L., Takle, A. K., Tyler, J. W. & White, J. Cycloadditions of cephalosporins. A general synthesis of novel 2,3-fused cyclobutane and cyclobutene cephems. J. Org. Chem. 58, 6954–6955 (1993).
Elliott, R. L. et al. Cycloadditions of cephalosporins. The formation of [4+2] adduct with 5-membered heterocycles. J. Org. Chem. 59, 1606–1607 (1994).
Musch, P. W., Scheidel, D. & Engles, B. Comprehensive model for the electronic structures of 1,2,4-cyclohexatriene and related compounds. J. Phys. Chem. A 107, 11223–11230 (2003).
Emanuel, C. J. & Shelvin, P. B. Mechanism of the reaction of atomic carbon with pyrrole. Evidence for the intermediacy of a novel dehydropyridinium ylide. J. Am. Chem. Soc. 116, 5991–5992 (1994).
Pan, W. & Shelvin, P. B. The chemistry of the N-methyl-3-dehydropyridinium ylid. J. Am. Chem. Soc. 119, 5091–5094 (1997).
Pan, W., Balci, M. & Shelvin, P. B. Thiacyclohexatriene–thiopheneylcarbene rearrangement. A sufur analog of the cycloheptatetraene–phenylcarbene rearrangement. J. Am. Chem. Soc. 119, 5035–5036 (1997).
Wang, J. & Sheridan, R. S. A singlet aryl-CF3 carbene: 2-benzothienyl(trifluoromethyl)carbene and interconversion with a strained cyclic allene. Org. Lett. 9, 3177–3180 (2007).
Schöneboom, J. C., Groetsch, S., Christl, M. & Engles, B. Computational assessment of the electronic structure of 1-azacyclohexa-2,3,5-triene(3δ2-1H-pyridine) and its benzo derivative (3δ2-1H-quinoline) as well as generation and interception of 1-methyl-3δ2-1H-quinoline. Chem. Eur. J. 9, 4641–4649 (2003).
Christl, M. & Drinkuth, S. 3δ2-Chromene (2,3-didehydro-2H-1-benzopyran): generation and interception. Eur. J. Org. Chem. 2, 237–241 (1998).
Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of structural diversity, substitution pattern, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
McMahon, T. C. et al. Generation and regioselective trapping of a 3,4-piperidyne for the synthesis of functionalized heterocycles. J. Am. Chem. Soc. 137, 4082–4085 (2015).
Brinck, T. & Linder, M. On the method-dependence of transition state asynchronicity in Diels–Alder reactions. Phys. Chem. Chem. Phys. 15, 5108–5114 (2013).
Houk, K. N. & Bickelhaupt, F. M. Analyzing reaction rates with the distortion/interaction-activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).
Christl, M. et al. The stereochemical course of the generation and interception of a six-membered cyclic allene: 3δ2-1H-napthalene (2,3-didehydro-1,2-dihydronaphthalene). Eur. J. Org. Chem. 2006, 5045–5058 (2006).
Carry, J.-C., Brohan, E., Perron, S. & Bardouillet, P.-E. Chiral supercritical fluid chromatography in the preparation of enantiomerically pure (S)-(+)-tert-butyl-3-hydroxyazepane-1-carboxylate. Org. Process Res. Dev. 17, 1568–1571 (2013).
Acknowledgements
The authors acknowledge the NIH-NIGMS (R01 GM090007 to N.K.G., R01 GM109078 to K.N.H. and F32 GM122245 to E.R.D.), the National Science Foundation (NSF; CHE-1361104 to K.N.H. and DGE-1144087 to M.M.Y.), the University of California, Los Angeles, the UCLA Cota Robles Fellowship Program (M.R.) and the Chemistry–Biology Interface training program (J.S.B., USPHS National Research Service Award 5T32GM008496-20) for financial support. Pier Champagne is acknowledged for computational assistance. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). Computations were performed with resources made available from the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575), as well as the UCLA Institute of Digital Research and Education (IDRE).
Author information
Authors and Affiliations
Contributions
J.S.B., M.M.Y., E.R.D. and R.R.K. designed and performed experiments and analysed experimental data. M.R. and F.L. designed, performed and analysed computational data. K.N.H. and N.K.G. directed the investigations and prepared the manuscript with contributions from all authors. All authors contributed to discussions.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Supplementary information
Supplementary information
Experimental procedures, compound characterization data, and data from computational analyses
Rights and permissions
About this article
Cite this article
Barber, J.S., Yamano, M.M., Ramirez, M. et al. Diels–Alder cycloadditions of strained azacyclic allenes. Nature Chem 10, 953–960 (2018). https://doi.org/10.1038/s41557-018-0080-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41557-018-0080-1
This article is cited by
-
Generation and reactivity of unsymmetrical strained heterocyclic allenes
Nature Synthesis (2023)
-
Intercepting fleeting cyclic allenes with asymmetric nickel catalysis
Nature (2020)
-
Bonding and Diels–Alder reactions of substituted 2-borabicyclo(1.1.0)but-1(3)-enes: a theoretical study
Theoretical Chemistry Accounts (2019)