Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 17.
doi: 10.1039/d5sc04998a. Online ahead of print.

Two-carbon ring expansion of bicyclic aziridines to oxazocines via aryne insertion into a σ C-N bond

Daniel S Rampon  1 , Tuan Anh Trinh  1 , Yekun Pan  1 , Sierra Thein  1 , Jacob W Kailing  1 , Ilia A Guzei  1 , Israel Fernández  2 , Jennifer M Schomaker  1
Affiliations

Two-carbon ring expansion of bicyclic aziridines to oxazocines via aryne insertion into a σ C-N bond

Daniel S Rampon et al. Chem Sci. .

Abstract

Oxazocines are medium-sized N,O-heterocycles that are motifs in reported bioactive compounds; thus, methods for their rapid preparation and functionalization are of significant interest, particularly to increase their representation in current drug libraries. In this work, a mild method to access oxazocines through aryne insertion into the σ C-N bond of carbamate-tethered bicyclic aziridines is described. This work unlocks a complementary reactivity mode for bicyclic aziridines via a two-carbon ring expansion, which preserves both the strained ring and its stereochemical information for further modifications. Mechanistic studies of the reaction pathway using Density Functional Theory computations indicate that oxazocine formation via nucleophilic acyl substitution of the carbonyl group of the carbamate is kinetically preferred over alternative products arising from aziridine ring-opening pathways.

PubMed Disclaimer

Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. (A) Selected oxazocines in natural products and drugs. (B) General strategies to access oxazocines. (C) ‘Anomalous’ aziridine building blocks. (D) Reactions of aziridines and arynes.
Scheme 2
Scheme 2. Two-carbon ring expansion of 1a with benzyne to furnish 3a (Path A) and an alternative pathway to 4a (Path B), 5a (Path C) and 6a (Path D).
Scheme 3
Scheme 3. (A) Computed reaction profile for the reaction between benzyne and aziridine 1a. Relative enthalpies (ΔH) and free energies (ΔG) (within parentheses, at 298 K) are given in kcal mol−1. (inset): Computed condensed Fukui functions (f+) in INT1. (B) Intrinsic reaction coordinate computed for the transformation of INT1 into 3a. All data have been computed at the SMD(THF)-B3LYP-D3/def2-TZVPP//SMD(THF)-B3LYP-D3/def2-SVP level.
Scheme 4
Scheme 4. (A) Optimization studies. (B) Reaction of cis-1avs. trans-1b.
Scheme 5
Scheme 5. Proposed mechanism for N-allyl acridone (7) formation from 3y and 2a.
Scheme 6
Scheme 6. Synthetic utility of two-carbon ring expansion to oxazocines. (A) Gram-scale reaction. (B) Telescoped intramolecular aziridination/two-carbon ring expansion. (C) Stereochemical retention experiment. (D) Synthetic applications of oxazocines.
See this image and copyright information in PMC

References

    1. Marshall C. M. Federice J. G. Bell C. N. Cox P. B. Njardarson J. T. J. Med. Chem. 2024;67:11622–11655. - PubMed
    1. Vitaku E. Smith D. T. Njardarson J. T. J. Med. Chem. 2014;57:10257–10274. - PubMed
    2. Heravi M. M. Zadsirjan V. RSC Adv. 2020;10:44247–44311. - PMC - PubMed
    3. Bhutani P. Joshi G. Raja N. Bachhav N. Rajanna P. K. Bhutani H. Paul A. T. Kumar R. J. Med. Chem. 2021;64:2339–2381. - PubMed
    4. Jimenez D. G. Poongavanam V. Kihlberg J. J. Med. Chem. 2023;66:5377–5396. - PMC - PubMed
    1. Romines K. R. Watenpaugh K. D. Tomich P. K. Howe W. J. Morris J. K. Lovasz K. D. Mulichak A. M. Finzel B. C. Lynn J. C. Horng M.-M. Schwende F. J. Ruwart M. J. Zipp G. L. Chong K.-T. Dolak L. A. Toth L. N. Howard G. M. Rush B. D. Wilkinson K. F. Possert P. L. Dalga R. J. Hinshaw R. R. J. Med. Chem. 1995;38:1884–1891. - PubMed
    2. Bauer R. Wenderski T. Tan D. Nat. Chem. Biol. 2013;9:21–29. - PMC - PubMed
    3. Lee H. Kim J. Koh M. Molecules. 2024;29:1562. - PMC - PubMed
    4. Du Y. Semghouli A. Wang Q. Mei H. Kiss L. Baecker D. Soloshonok V. A. Han J. Arch. Pharm. 2025;358:e2400890. - PMC - PubMed
    1. Alfonsi P. Adam F. Passard A. Guignard B. Sessler D. Chauvin M. Anesthesiology. 2004;100:37–43. - PMC - PubMed
    2. Martin G. D. A. Tan L. T. Jensen P. R. Dimayuga R. E. Fairchild C. R. Raventos-Suarez C. Fenical W. J. Nat. Prod. 2007;70:1406–1409. - PubMed
    3. Scott J. P. Alam M. Bremeyer N. Goodyear A. Lam T. Wilson R. D. Zhou G. Org. Process Res. Dev. 2011;15:1116–1123.
    4. Dandapani S. Germain A. R. Jewett I. le Quement S. Marie J.-C. Muncipinto G. Duvall J. R. Carmody L. C. Perez J. R. Engel J. C. Gut J. Kellar D. Siqueira-Neto J. L. McKerrow J. H. Kaiser M. Rodriguez A. Palmer M. A. Foley M. Schreiber S. L. Munoz B. ACS Med. Chem. Lett. 2014;5:149–153. - PMC - PubMed
    5. Cañeque T. Gomes F. Mai T. T. Maestri G. Malacria M. Rodriguez R. Nat. Chem. 2015;7:744–751. - PMC - PubMed
    6. Parrino B. Cascioferro S. Carbone D. Cirrincione G. Diana P. Adv. Heterocycl. Chem. 2020;132:135–239.
    1. Pflantz R. Sluiter J. Krička M. Saak W. Hoenke C. Christoffers J. Eur. J. Org Chem. 2009;2009:5431–5436.
    2. Liu G. Huang W. Wang J. Liu X. Yang J. Zhang Y. Geng Y. Tan W. Zhang A. J. Med. Chem. 2017;60:8218–8245. - PubMed
    3. Barve I. J. Thikekar T. U. Sun C.-M. Org. Lett. 2017;19:2370–2373. - PubMed
    4. Lam H. Qureshi Z. Wegmann M. Lautens M. Angew. Chem., Int. Ed. 2018;57:16185–16189. - PubMed
    5. Choury M. Lopes A. B. Blond G. Gulea M. Molecules. 2020;25:3147. - PMC - PubMed
    6. Li Q. Pan R. Wang M. Yao H. Lin A. Org. Lett. 2021;23:2292–2297. - PubMed
    7. Kaur N., 8-Membered Heterocycle Synthesis, Elsevier, Amsterdam, 1st edn, 2023
    8. Yin L. Zhang Z. Huang S. Wang Z. Huang C. J. Org. Chem. 2024;89:13629–13640. - PubMed
    9. Li J. Dong Z. Zhao C. New J. Chem. 2024;48:4645–4669.
    10. Meng Q. Meng Y. Liu Q. Yu B. Li Z.-J. Li E.-Q. Zhang J. Adv. Sci. 2024;11:2402170. - PMC - PubMed

LinkOut - more resources