ACS Catalysis
Letter
effect of elevated temperature on the proportion of rearranged
product, this finding led us to propose a mechanism in which
the addition of the initially formed primary radical to the
acceptor is in direct competition with the 1,2-migration to
form the more stable tertiary radical. While the 1,2-migration is
in principle reversible, two factors indicate that the reverse
reaction is likely to be heavily outcompeted by trapping of the
tertiary radical by the electron-deficient olefin. Tertiary radicals
exhibit greater nucleophilicity compared to primary radicals,64
so trapping of the rearranged radical is likely to be significantly
more rapid. Moreover, the initial formation of the cyclo-
propyloxy radical is significantly accelerated by a Thorpe−
Ingold effect that is absent in the reverse reactionthe
cyclization of 3-butenyl radical to cyclopropylcarbinyl radical is
3 orders of magnitude slower than the analogous reaction with
the 2,2-dimethyl-3-butenyl radical.65 Under this regime, the
rate constant for the 1,2-migration can serve as a convenient
radical clock to determine the rate constants for the addition of
the pinacolone primary radical to various acceptors.
Working from the known rate constant for 1,2-migration for
di-tert-butyl ketone,25 we determined the corresponding rate
constant for pinacolone to be 2.9 × 104 s−1 (see Supporting
Information). Initial rate experiments were then conducted
using the 1,2-migration as a radical clock. The calculated rate
constants for the addition of the pinacolone primary radical to
the acceptors tested span slightly more than an order of
magnitude (Scheme 5A). The values are also generally
consistent with the ir values observed in our reactions, with
the least reactive acceptors giving the greatest proportions of
rearrangement product. Comparison of our rate constants to
the known rate constants for methyl and tert-butyl radical
addition to similar acceptors64,66−69 (see SI for a detailed
table) shows that the pinacolone radical generally adds more
slowly than both, reflecting its high steric hindrance and low
nucleophilicity (as a primary radical). The fairly low spread of
the rate constants is also consistent with literature data sets.
Giese-type additions are known to be highly exothermic and
therefore have early transition states that are less sensitive to
the structure of the electrophilic alkene relative to analogous
ionic additions.66 Rate constants for alkyl radical addition to
15, 18, 19, and 24 were not previously known.
With substrates that only give moderate isomeric ratios, the
selectivity can be tuned in either direction with further
modifications to the reaction conditions (Scheme 5B). Under
Conditions A, diisopropyl ketone 25 gives a moderate ir of
2.3:1. Performing the reaction at a higher concentration
increases the ir to almost 4:1 (entry 3). Similarly, the ir of 1:3.2
under conditions B can be increased to 1:5.9 by the addition of
benzyl acrylate in five equal portions over 60 h (entry 4). In
line with our proposed mechanism, increasing or decreasing
the effective concentration of the acceptor in the reaction
mixture yields a correspondingly smaller or greater proportion
of rearrangement product.
In conclusion, we report an iron-catalyzed, photocatalytic
method for the divergent alkylation of C(sp3)−H bonds
mediated by a 1,2-skeletal rearrangement. Unlike typical
radical-mediated skeletal rearrangements, no prefunctionaliza-
tion is required, and control over the ratio of unrearranged to
rearranged product can be achieved by simple modifications to
the reaction conditions or the choice of acceptor. The 1,2-
rearrangement was also utilized as a radical clock to determine
the rate constants for the addition of nucleophilic radicals to
various electron-deficient olefins.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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sı
Experimental details and compound characterization
AUTHOR INFORMATION
Corresponding Author
■
Tomislav Rovis − Department of Chemistry, Columbia
University, New York 10027, United States; orcid.org/
Authors
Yi Cheng Kang − Department of Chemistry, Columbia
University, New York 10027, United States
Sean M. Treacy − Department of Chemistry, Columbia
University, New York 10027, United States
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank NIGMS (GM125206) for support. We thank Dr.
Brandon Fowler for HRMS analysis and Dr. Manju Rajeswaran
for X-ray crystallography. We are also grateful to Prof. Jack
Norton (Columbia University) for valuable discussions about
the kinetics experiments.
REFERENCES
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