Iron-Catalyzed Photoinduced LMCT: A 1° C-H Abstraction Enables Skeletal Rearrangements and C(sp3)-H Alkylation

Article abstract of DOI:10.1021/acscatal.1c02285

Herein we disclose an iron-catalyzed method to access skeletal rearrangement reactions akin to the Dowd-Beckwith ring expansion from unactivated C(sp3)-H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates a chlorine radical, which abstracts electron-rich C(sp3)-H bonds. The resulting unstable alkyl radicals can undergo rearrangement in the presence of suitable functionality. Addition to an electron deficient olefin, recombination with a photoreduced iron complex, and subsequent protodemetalation allow for redox-neutral alkylation of the resulting radical. Simple adjustments to the reaction conditions enable the selective synthesis of the directly alkylated or the rearranged-alkylated products. As a radical clock, these rearrangements also enable the measurement of rate constants of addition into various electron deficient olefins in the Giese reaction.

Full text of DOI:10.1021/acscatal.1c02285

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Letter
Iron-Catalyzed Photoinduced LMCT: A 1° C−H Abstraction Enables
Skeletal Rearrangements and C(sp3)−H Alkylation
Yi Cheng Kang, Sean M. Treacy, and Tomislav Rovis*
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ABSTRACT: Herein we disclose an iron-catalyzed method to
access skeletal rearrangement reactions akin to the Dowd−
Beckwith ring expansion from unactivated C(sp3)−H bonds.
Photoinduced ligand-to-metal charge transfer at the iron center
generates a chlorine radical, which abstracts electron-rich C(sp3)−
H bonds. The resulting unstable alkyl radicals can undergo
rearrangement in the presence of suitable functionality. Addition to
an electron deficient olefin, recombination with a photoreduced
iron complex, and subsequent protodemetalation allow for redox-neutral alkylation of the resulting radical. Simple adjustments to the
reaction conditions enable the selective synthesis of the directly alkylated or the rearranged-alkylated products. As a radical clock,
these rearrangements also enable the measurement of rate constants of addition into various electron deficient olefins in the Giese
reaction.
KEYWORDS: LMCT, primary C(sp3)−H alkylation, iron catalysis, skeletal rearrangement, Dowd−Beckwith, photocatalysis
arbon skeleton rearrangements in which C−C sigma
bonds.26−30 Various reagents and catalysts have been
developed to exhibit excellent HAT regioselectivity despite
the high energy intermediates required to abstract strong
unpolarized C(sp3)−H bonds.31−34 Although much attention
has been paid toward the functionalization of C(sp3)−H bonds
adjacent to heteroatoms or other radical stabilizing functional
groups, less work has focused on the functionalization of
compounds bearing electron withdrawing moieties.35 Previous
investigations have shown that hydrogen atoms adjacent to
electron withdrawing groups are recalcitrant to HAT due to a
polarity mismatch,36−41 despite their lower bond dissociation
energies compared to unactivated C(sp3)−H bonds.42 We
postulated that the directing effect of carbonyls or other
electron-withdrawing groups could enable HAT selectively at
the beta-position to enable a skeletal rearrangement analogous
to the Dowd−Beckwith ring expansion directly from C(sp3)−
H bonds (Scheme 1B).
C
bonds are broken provide powerful bond disconnections
in organic synthesis.1,2 Owing to the largely inert nature of C−
C sigma bonds, formation of high energy intermediates such as
carbocations or radicals is usually necessary to generate a
sufficient thermodynamic driving force for their scission. While
carbocation-mediated transformations such as the Wagner-
Meerwein and pinacol rearrangements have been widely
studied and utilized in organic synthesis,3−5 there has been
less focus on their radical-mediated counterparts.6−8
The Dowd−Beckwith rearrangement is a radical-mediated
skeletal rearrangement that has found synthetic applications in
ketone ring expansions.9−17 Typically, a primary alkyl radical is
generated by halogen abstraction with a stannyl radical. This
then adds to a carbonyl, forming a cyclopropyloxy radical
which subsequently undergoes β-scission to give a more stable
radical that is then quenched with tributyltin hydride (Scheme
1A). Current limitations of the rearrangement include the
necessity for preinstallation of a functional handle and the use
of stoichiometric tin reagents.
The key skeletal rearrangement step in the Dowd-Beckwith
ring expansion is related to a family of radical 1,2-rearrange-
ments wherein a primary radical β to a π-system adds to it,
forming a transient cyclopropyl intermediate that then
undergoes β-scission to form a more stable tertiary
radical.18−20 The rate constants of these rearrangements have
been measured with various π-systems such as alkenes, alkynes,
arenes, carbonyls, and nitriles, and several have been used as
radical clocks.21−25
We recently reported the photocatalytic C(sp3)−H
alkylation of alkanes using copper(II) chloride. This system
mediates intermolecular HAT via the formation of a chlorine
radical which is readily generated by a photoinduced ligand-to-
metal charge transfer (Scheme 1C).43 Herein, we report a
redox-neutral, photocatalytic alkylation of unactivated C(sp3)−
Received: May 20, 2021
Revised: June 3, 2021
Published: June 8, 2021
Hydrogen atom transfer (HAT) has emerged as a powerful
mechanism for direct functionalization of C(sp3)−H
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Scheme 1. Radical Rearrangement via FeCl3 Ligand-to-Metal Charge-Transfer (LMCT) Provides Access to Divergent C(sp3)−
H Alkylation Products
Scheme 2. Mechanism of the 1,2-Rearrangement
a
H bonds distal from electron-withdrawing moieties using an
iron(III) chloride catalyst44−49 to enable access to divergent
products (Scheme 1D) via a skeletal rearrangement (Scheme
2). Of practical interest is that iron is the most abundant
transition metal in the Earth’s crust,50 making it inexpensive
and well-suited for use in large-scale syntheses.51 Simple
changes to the temperature and concentration of the reaction,
as well as the choice of the electron-deficient olefin partner,
allow for control of the ratio of unrearranged and rearranged
products.
Table 1. Optimization and Control Studies
entry
deviation from standard conditions
yield (%)
ir(3a:3b)
1
2
3
4
5
6
7
8
9
none
60 °C
64
65
67
52
0
0
2
3
47
1:1.4
1:4
1:10
1:1
Initial optimization of the reaction was conducted using
pinacolone and benzyl acrylate (Table 1). Early investigations
found a catalyst loading of 25 mol % FeCl3 and the use of
benzyl acrylate in limiting quantities to be effective. At room
temperature and a concentration of 0.3 M, we obtain an
isomeric ratio (ir) of unrearranged to rearranged product
(3a:3b) of 1:1.4. Hypothesizing that an increase in temper-
ature would reduce the rate of intermolecular radical trapping
relative to the intramolecular skeletal rearrangement, we
performed the reaction at 60 °C, and found that the ir indeed
increases to 1:4 in favor of the rearranged product. Decreasing
the reaction concentration to 0.1 M also promotes the 1,2-
migration, increasing the ir to 1:10. Given that reaction yields
remain comparable under these conditions, we selected these
conditions as optimal for promoting either the unrearranged
product (entry 1, Conditions A) or the rearranged product
(entry 3, Conditions B). UV−vis studies of FeCl3 in
acetonitrile reveal a peak with λmax = 361 nm, with a tail
into the visible region, along with two other maxima in the
ultraviolet region (see SI). These peaks closely match the
60 °C, 0.1 M
added LiCl (62.5 mol %)
0% FeCl3
in the dark
irradiate at 390 nm 1 h, then dark
427 nm LED
under air
n.d.
n.d.
1:1
a
Reactions were performed on a 0.3 mmol scale. Yields were
determined by 1H NMR using 1,3,5-trimethoxybenzene as the
internal standard. n.d.: not determined.
indicating that this is likely to be the photoactive species in
our system.52 The addition of lithium chloride to the solution
does not change any of the observed λmax values, further
supporting this possibility. However, unlike with CuCl2,43 we
found that exogenous chloride proved slightly detrimental to
the efficiency of the reaction (entry 4). Control reactions
reveal the necessity for light and FeCl3 in order to furnish the
desired product. Moreover, irradiating the reaction for 1 h and
−
reported absorption spectrum of FeCl4 in acetonitrile,
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Scheme 3. Scope of C−H Pronucleophiles for the 1,2-Migration
#
*With 50 mol % FeCl3 and 5 equiv. CF3COOH as an additive. With 5 equiv. CF3COOH as an additive. N.D.: not detected.
continuing the reaction in the dark leads to dramatically
reduced yields, disfavoring a radical chain mechanism where
FeCl3 acts as an initiator, although we cannot completely rule
out short chain processes; 427 nm irradiation is inefficient at
promoting the reaction. Finally, we found that the reaction
may be performed under air without significant loss in
efficiency.
The scope of substrates which undergo this 1,2-migration is
summarized in Scheme 3 (see Supporting Information for
additional substrates). Ketones other than pinacolone were
also found to be amenable to the transformation. Ketone 4
demonstrates a reduced propensity to undergo the 1,2-
migration (12:1 ir), which we propose is due to a smaller
Thorpe−Ingold effect compared to pinacolone.19,53−57 As
expected, the ir is shifted toward the rearranged product
(1.6:1) by performing the reaction under conditions B.
Pivaloyl chloride was also observed to undergo 1,2-migration
to a small extent, with an ir of 4:1 (5). The product was
isolated as the ethyl ester after workup in alkaline ethanol.
Aromatic substituents also participate in this 1,2-migration,
albeit less efficiently than carbonyl substituents. Tert-
butylbenzene gives an ir of 16:1 under conditions A (6),
likely because the formation of the cyclopropyl intermediate
disrupts aromaticity. The rate constant of this rearrangement is
known to be 4 × 102 s−1 (298 K),58 which provides a lower
limit for the rate of radical addition to ethyl acrylate under our
reaction conditions. We found that substituent effects can exert
a strong influence on the propensity of the substrate to
undergo migration. Electron-withdrawing substituents (−Ac,
−CN) in the para-position lead to a complete inversion in ir.
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Scheme 4. Scope of Acceptors for the 1,2-Migration
*1 equiv. trifluoroacetic acid used as an additive.
Under conditions A, the rearranged products predominate, and
under conditions B they are formed exclusively (7−8). As
expected, weakly electron-donating substituents such as
acetoxy (9) exert only a minor effect on the rate of the 1,2-
migration, yielding comparable ir values to the unsubstituted
substrate 6. Ketone 10, containing both a phenyl and an acyl
substituent adjacent to the site of initial radical formation, acts
as a competition experiment between cyclization onto the
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Scheme 5. (A) Rate Constants of Addition to Various Alkenes. (B) Modifications to the Reaction Conditions Allow for Further
Control of the Isomeric Ratio (ir)
1
*Yields were determined by H NMR using 1,3,5-trimethoxybenzene as the internal standard.
arene and the carbonyl moieties. We exclusively obtained the
rearrangement product resulting from a 1,2-acyl shift (10b).
This complete selectivity occurs because the rate of the 1,2-
acyl shift is more than 2 orders of magnitude greater than that
of the 1,2-phenyl shift.25 Ring-expansion products similar to
the Dowd−Beckwith reaction can be obtained starting with
completely unfunctionalized cyclic ketones (11). Exclusive
selectivity for the ring-expanded rearrangement product 11b is
observed regardless of the conditions used. Given that
electron-deficient arenes (7−8) strongly promote the rear-
rangement, we wondered whether protonated heteroarenes
could function similarly. Indeed, di-tert-butylpyridine 12 reacts
in moderate yields, favoring the rearranged product relative to
tert-butylbenzene. With benzothiazole 13, the rearranged
product is formed exclusively under Conditions B.
We next examined how the choice of electron-withdrawing
olefin would affect the amount of 1,2-migration observed
(Scheme 4). Maleic anhydride and N-methylmaleimide react
in moderate to good yields. We isolated roughly equimolar
mixtures of unrearranged and rearranged product (14−15)
under conditions A, but mostly rearranged product (1:8)
under conditions B. To our surprise, despite being significantly
weaker electrophiles than maleic anhydride and N-methyl-
maleimide in previous studies with closed-shell nucleo-
philes,59,60 benzyl acrylate, acrylonitrile, and ethyl methacrylate
react with comparable ir values under the two conditions (3,
16−17). Other electron-withdrawing groups on the olefin are
also tolerated, including sulfones, amides and free acids (18−
20). These acceptors generally give comparable to slightly
higher ratios of rearranged product compared to benzyl
acrylate. Reaction with fumaronitrile proceeds in good yields
under both reaction conditions (21), with a similarly greater
proportion of rearrangement product. Again, this was contrary
to our expectations, since fumaronitrile is known to be a
stronger electrophile than the acrylates based on previous
studies of polar reactions.60 Dimethyl fumarate (22) gives a
slightly higher ir in favor of the rearrangement compared to
fumaronitrile, while the cis isomer dimethyl maleate (23)
heavily favors the rearrangement under both conditions. Small
proportions of cyclized rearranged product 22c are observed
under conditions B but not under conditions A, suggesting a
possible thermally driven aldol-type reaction. Finally, benzyli-
denemalononitrile, which displays similar electrophilicity to
maleic anhydride in polar reactions,61 also unexpectedly yields
high proportions of rearrangement product (24). The alkylated
product is isolated exclusively as a cyclized adduct, presumably
formed from attack of the bis(cyano)-stabilized anion onto the
ketone. The diastereoselectivity of the cyclization was
unambiguously confirmed by X-ray crystallography.
To better understand these unexpected observations, we
sought to benchmark the rate constants for the addition of
radical nucleophiles to these acceptors. Initial experiments
demonstrated a linear dependence of the ratio of unrearranged
to rearranged product on the concentration of acceptor used
(see SI). This linear dependence argues against a Curtin−
Hammett scenario62,63 wherein the primary and tertiary
radicals are rapidly equilibrating and the product ratio is
determined by the energy barriers for the trapping of the two
radicals, since the ratio of products would be largely insensitive
to acceptor concentration under that regime. Along with the
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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 reactionthe
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
https://pubs.acs.org/doi/10.1021/acscatal.1c02285.
■
sı
Experimental details and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tomislav Rovis − Department of Chemistry, Columbia
University, New York 10027, United States; orcid.org/
0000-0001-6287-8669; Email: tr2504@columbia.edu
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:
https://pubs.acs.org/10.1021/acscatal.1c02285
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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.
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