Journal of the American Chemical Society
Article
and trifluoromethyl (17q) substituted quinolines. Never-
theless, several functional groups did react under these
conditions, during the basic KOH-hydrolysis/cycloreversion
step, providing new functionalities. For example, the nitrile
15p hydrolyzed to yield amide 17p and 4-chloro-2-
(trifluoromethyl)quinoline (15q) was sufficiently electron-
deficient to undergo SNAr with the solvent and base (EtOH/
KOH) to yield compound 17q. Also, the pivalate group in
substrate 15r underwent hydrolysis during the cycloreversion
step, delivering 4-pyridone-fused oxepine 17r. Moreover, with
use of isoquinolines as substrates, this method enabled access
to the complementary oxepino[4,5-c]pyridines 17s−17u.
Finally, benzo-fused heterocycles containing more than one
nitrogen can be used, as exemplified with preparation of
oxepino[4,5-d]pyrimidine (17v) from quinazoline. We were
pleased to note that both epoxidation and cycloreversion could
be performed on a gram scale, as demonstrated with
Derivatization of Products. The chemistry described
herein can be extended greatly through the functionalization of
the obtained reactive intermediatesarene oxides and
oxepinesultimately giving access to diverse and structurally
elaborated small molecules (Figure 3). For example, benzene-
derived bicyclic epoxide 8a underwent two complementary
acid-mediated hydrolyses to provide aminocyclitol 18 or its
dichloro derivative 19. Moreover, arene oxide 13b derived
from tert-butylbenzene (9b, see Table 3) was directly
converted to γ-hydroxyenone 20 or syn-1,4-diol 21 through
the intermediacy of an endoperoxide.23
These examples demonstrate that the arenophile-based
preparation of arene oxides can be applied for downstream
chemistry, bypassing the highly unstable nature of these
compounds. In addition, benzoxepines could serve as
intermediates for further derivatization, as confirmed with
substrates 17a and 17o. Thus, partial or full hydrogenation of
benzoxepine 17a provided 22 and 24. The dihydrobenzox-
epine 22 was further elaborated via bromohydrin chemistry to
the functionalized ether 23. Also, benzoxepine 17a could serve
as a viable cycloaddition partner, undergoing nitrile oxide
mediated [3 + 2] dipolar cycloaddition24 to give product 25
(7:1 ratio of constitutional isomers). Finally, further derivatiza-
tion was also possible by conducting a Suzuki reaction on the
brominated oxepinopyridine (17o → 26), highlighting the
ability to utilize these unexplored heterocycles as practical
building blocks for medicinal chemistry.
application of this dearomative strategy in the preparation of
high-value intermediates.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
sı
Full experimental procedures and characterization data
1
for all new compounds; H and 13C NMR spectra and
crystallographic information for 8a, 16f, 16q, and 17a
(Crystallographic data for 8a CIF)
(Crystallographic data for 16f CIF)
(Crystallographic data 16q CIF)
(Crystallographic data 17a CIF)
AUTHOR INFORMATION
Corresponding Author
■
David Sarlah − Roger Adams Laboratory, Department of
Chemistry, University of Illinois, Urbana, Illinois 61801, United
Authors
Zohaib Siddiqi − Roger Adams Laboratory, Department of
Chemistry, University of Illinois, Urbana, Illinois 61801, United
States
William C. Wertjes − Roger Adams Laboratory, Department of
Chemistry, University of Illinois, Urbana, Illinois 61801, United
States
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the University
of Illinois, the National Science Foundation (CAREER Award
No. CHE-1654110), and the NIH/National Institute of
General Medical Sciences (R01 GM122891). Amgen, Eli
Lilly, and Bristol-Myers Squibb are also acknowledged for
unrestricted research support. W.C.W. acknowledges support
from Springborn Fund and NSF (GRFP). We also thank Dr.
D. Olson and Dr. L. Zhu for NMR spectroscopic assistance,
Dr. D. L. Gray, Dr. T. Woods, and Mr. A. Shved for X-ray
crystallographic analysis assistance, and F. Sun for mass
spectrometric assistance.
CONCLUSION
■
We have developed a dearomative strategy for epoxidation of
simple arenes. Our approach features an arenophile-based
cycloaddition and epoxidation, followed by cycloreversion to
reveal arene oxides and 3-benzoxepines. Several benzene
derivatives were converted to the corresponding arene oxides
with complementary chemoselectively to known methods and
without any noticeable decomposition to phenols. Moreover,
this protocol converted polycyclic arenes and heteroarenes into
the corresponding oxepines with a broad functional group
tolerability. Importantly, the described chemistry enables
formal epoxidation of naphthalenes at positions 2 and 3, a
biomimetic epoxidation for which no chemical equivalent
exists. Given the lack of chemical methods for molecular
editing of this type, as well as practical gram-scale feasibility
and further options for elaboration, we anticipate the
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