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
. 2018 Dec 19;10(7):2212-2217.
doi: 10.1039/c8sc04277b. eCollection 2019 Feb 21.

Alder-ene reactions driven by high steric strain and bond angle distortion to form benzocyclobutenes

Saswata Gupta  1 , Yongjia Lin  2 , Yuanzhi Xia  2 , Donald J Wink  1 , Daesung Lee  1
Affiliations

Alder-ene reactions driven by high steric strain and bond angle distortion to form benzocyclobutenes

Saswata Gupta et al. Chem Sci. .

Abstract

A unique aryne-based Alder-ene reaction to form benzocyclobutene is described. In this process, the thermodynamic barrier to form a four-membered ring is compensated by the relief of the strain energy of an aryne intermediate. On the other hand, the driving force to overcome the high kinetic barrier is provided by the gearing effect of the bulky substituent at the ortho-position of the ene-donor alkene. To maximize the steric strain by the ortho-substituent, a structural element for internal hydrogen bonding is installed, which plays a crucial role for both the hexadehydro Diels-Alder and the Alder-ene reactions. DFT calculations show that the bulky hydrogen bonding element lowers the activation barrier for the Alder-ene reaction by destabilizing the intermediate, which is due to the severe bond angle distortion. The preferred formation of cis-isomers can also be explained by the extent of bond angle distortion.

PubMed Disclaimer

Figures

Scheme 1
Scheme 1. Aryne-mediated Alder-ene driven by hydrogen bonding and steric pressure.
Scheme 2
Scheme 2. Inter vs. intramolecular Alder-ene reaction.
Scheme 3
Scheme 3. DFT-based analysis of the energy profiles of Alder-ene reactions and the origin of cis-selectivity.
Scheme 4
Scheme 4. Reactions of benzocyclobutene derivatives. Conditions: (a) 10-camphorsulfonic acid, MeOH–CH2Cl2 (1 : 1), rt, 80%. (b) MnO2 (excess), CH2Cl2, rt, 72%. (c) Dess–Martin periodinane, CH2Cl2, rt, 82%. (d) TMSCHN2, BF3·Et2O, CH2Cl2, –20 °C, 55%. (e) TBAF, THF, rt, 86%. (f) NaH, THF, 50 °C, 81%.
See this image and copyright information in PMC

References

    1. General reviews on aryne chemistry:

    2. Tadross P. M., Stoltz B. M. Chem. Rev. 2012;112:3550–3577. - PubMed
    3. Gampe C. M., Carreira E. M. Angew. Chem., Int. Ed. 2012;51:3766–3778. - PubMed
    4. Bhojgude S. S., Bhunia A., Biju A. T. Acc. Chem. Res. 2016;49:1658–1670. - PubMed
    5. Roy T., Biju A. T. Chem. Commun. 2018;54:2580–2594. - PubMed
    1. Review: Karmakar R., Lee D., Chem. Soc. Rev., 2016, 45 , 4459 –4470 , , and references therein . - PubMed
    1. Jayanth T. T., Jeganmohan M., Cheng M.-J., Chu S.-Y., Cheng C.-H. J. Am. Chem. Soc. 2006;128:2232–2233. - PubMed
    2. Candito D. A., Panteleev J., Lautens M. J. Am. Chem. Soc. 2011;133:14200–14203. - PubMed
    3. Candito D. A., Dobrovolsky D., Lautens M. J. Am. Chem. Soc. 2012;134:15572–15580. - PubMed
    4. Chen Z., Liang J., Yin J., Yu G.-A., Liu S. H. Tetrahedron Lett. 2013;54:5785–5787.
    5. Niu D., Hoye T. R. Nat. Chem. 2014;6:34–40. - PMC - PubMed
    6. Pérez P., Domingo L. R. Eur. J. Org. Chem. 2015;2015:2826–2834.
    7. Zhang J., Niu D., Brinker V. A., Hoye T. R. Org. Lett. 2016;18:5596–5599. - PMC - PubMed
    8. Trinchera P., Sun W., Smith J. E., Palomas D., Crespo-Otero R., Jones C. R. Org. Lett. 2017;19:4644–4647. - PubMed
    1. Karmakar R., Mamidipalli P., Yun S. Y., Lee D. Org. Lett. 2013;15:1938–1941. - PubMed
    2. Gupta S., Xie P., Xia Y., Lee D. Org. Lett. 2017;19:5162–5165. - PubMed

    1. . For reviews:

    2. Bradley A. Z., Johnson R. P. J. Am. Chem. Soc. 1997;119:9917–9918.
    3. Miyawaki K., Suzuki R., Kawano T., Ueda I. Tetrahedron Lett. 1997;38:3943–3946.
    4. Hoye T. R., Baire B., Niu D., Willoughby P. H., Woods B. P. Nature. 2012;490:208–212. - PMC - PubMed
    5. Hu Y., Hu Y., Hu Q., Ma J., Lv S., Liu B., Wang S. Chem.–Eur. J. 2017;23:4065–4072. - PubMed
    6. Holden C., Greaney M. F. Angew. Chem., Int. Ed. 2014;53:5746–5749. - PMC - PubMed
    7. Diamond O. J., Marder T. B. Org. Chem. Front. 2017;4:891–910.