Journal of the American Chemical Society
Communication
hydrogen bonding effects. This substrate was effectively
predicted by the steric model, consistent with the hydrogen-
bonding hypothesis.
compensates for the lack of C−C (σ) → C−Cl (σ*)
interaction in the transition state.88,89
In conclusion, we have demonstrated that chlorodiazirine
reagents enable a versatile new ring expansion reaction of
pyrrole and indole substrates through the generation of aryl
carbynyl cation equivalents. Mechanistic experiments and
computations indicate that the regioselectivity is controlled
by steric effects in a selectivity-determining cyclopropanation
step, with diminished torquoselectivity effects in the
subsequent ring opening due to homopyrrole character in
the product-forming transition state. Ring expansion of fused
indoles allows access to otherwise challenging quinolino-
phanes, and the method is applicable to the skeletal editing of
medicinally relevant compounds. This method, coupled with
the predictive model for its deployment, promises to enable
direct interrogation of aromatic heterocycle skeletal editing as
an innovative approach to synthetic and structural optimiza-
tion campaigns.
Armed with this insight into selectivity, we examined the
late-stage skeletal editing of 4r (N-des-alkyl Lipitor) and 4s
(Molindone). Both compounds afforded one major isomer
5r showing hydrogen-bond-donor-controlled selectivity and 5s
with a regioselectivity that was accurately predicted by our
quantitative model. We note despite our moderate yields that
the classical Ciamician−Dennstedt induces decomposition of
molindone with no detectable pyridine formation. These
examples showcase the potential for skeletal editing approaches
to offer access to new chemical space in a medicinal chemistry
campaign.
For some substrates, unusual ortho and para insertion
products were observed (5t, 5v, 5w). These cannot be
accounted for by a 2,3-cyclopropanation mechanism alone,
forcing us to reexamine the potential reaction pathways
(Figure 4).77,78 We considered the possibility that cyclo-
propanation is followed by cyclization to afford an
azabenzvalene intermediate.79−82 However, DFT computa-
tions suggest that such a mechanism is implausible. The
transition state for azabenzvalene formation from the exo-
chlorocyclopropane 6 is predicted to be ∼16 kcal/mol higher
in energy than the corresponding electrocyclic ring opening to
afford 5t. Instead, we suggest that cyclopropanation (or
aziridination) of the 3,4 (or 1,2) linkage (respectively) is
operative in the generation of the unusual regioisomeric
products 5t′, 5v′, and 5w. A plausible pathway was located
computationally in which metastable zwitterionic 3,4-cyclo-
propane 7 forms through stepwise attack and ring closure (see
likely stabilized by its phenyl substituent, as evidenced by the
exclusive formation of the typical meta isomer from di-tert-
butylpyrrole 4u.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures and characterization data
Computational procedures and data (PDF)
Accession Codes
CCDC 2090443 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Finally, because our reagent generates a monochlorocarbene,
cyclopropanation can in principle afford diastereomeric
cyclopropanes, unlike the classical use of dichlorocarbene.
Based on precedent in cyclopropyltosylate solvolyses, these
diastereomers were expected to exhibit dramatically different
rates of ring opening.83−85 Our computational investigations
suggest that the intrinsic diastereoselectivity of the initial
cyclopropanation is quite low, such that both diastereomers are
likely formed under the reaction conditions. Despite these
considerations, no cyclopropane byproducts have been
detected, and experimental yields range as high as 90%.
Moreover, the computationally predicted barrier for ring
opening by the putatively forbidden pathway is surprisingly
low.
In order to better understand this unexpected phenomenon,
we analyzed the bond lengths and Nucleus Independent
Chemical Shift (NICS) of each transition state.86,87 As
expected, the disallowed transition state (TS2-exo, red)
shows a lesser degree of C−Cl bond breaking than the
allowed transition state (TS2-endo, blue), 1.85 Å vs 1.95 Å.
However, this is accompanied by a greater degree of
cyclopropane C−C bond-breaking (2.00 Å vs 1.86 Å), and a
far more negative NICS0 value (−14.9 vs −11.4, compared to
−11.5 for the parent pyrrole) indicating a greater degree of
aromaticity in the disallowed transition state. Taken together,
these results indicate that a substantial degree of homoar-
omaticity in the pyrrolic ring of the disallowed transition state
AUTHOR INFORMATION
■
Corresponding Author
Mark D. Levin − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
Authors
Balu D. Dherange − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
Patrick Q. Kelly − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States
Jordan P. Liles − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
Matthew S. Sigman − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States;
Complete contact information is available at:
Funding
M.D.L. thanks the ACS PRF (61497-DNI1). M.S.S. would like
to thank the NIH (R35 GM136271).
Notes
The authors declare no competing financial interest.
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J. Am. Chem. Soc. 2021, 143, 11337−11344