Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover

Article abstract of DOI:10.1021/jacs.8b05243

A benchtop stable, bifunctional reagent for the redox-neutral cyclopropanation of olefins has been developed. Triethylammonium bis(catecholato)iodomethylsilicate can be readily prepared on multigram scale. Using this reagent in combination with an organic photocatalyst and visible light, cyclopropanation of an array of olefins, including trifluoromethyl- and pinacolatoboryl-substituted alkenes, can be accomplished in a matter of hours. The reaction is highly tolerant of traditionally reactive functional groups (carboxylic acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds. Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3-exo-tet ring closure, a pathway consistent with experimental and computational data.

Full text of DOI:10.1021/jacs.8b05243

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar
Crossover
James P. Phelan,†,§ Simon B. Lang,†,§ Jordan S. Compton,† Christopher B. Kelly,† Ryan Dykstra,‡
Osvaldo Gutierrez,*,‡ and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: A benchtop stable, bifunctional reagent for the
redox-neutral cyclopropanation of olefins has been developed.
Triethylammonium bis(catecholato)iodomethylsilicate can be
readily prepared on multigram scale. Using this reagent in
combination with an organic photocatalyst and visible light,
cyclopropanation of an array of olefins, including trifluor-
omethyl- and pinacolatoboryl-substituted alkenes, can be
accomplished in a matter of hours. The reaction is highly
tolerant of traditionally reactive functional groups (carboxylic
acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds.
Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3-exo-tet ring closure, a pathway consistent
with experimental and computational data.
INTRODUCTION
■
The cyclopropyl group is a common motif found in many
pharmaceutical products1 and secondary metabolites.2 It is
employed to increase metabolic stability, enhance potency, and
decrease plasma clearance.1a Consequently, cyclopropane rings
appear in 10 of the top 200 highest grossing pharmaceutical
products from 20161b and in 124 approved or investigational
drugs (Figure 1).1c Furthermore, the substitution pattern of
these rings can impart bioisosteric properties. Trifluoromethyl-
substituted cyclopropanes (TFCps) are salient examples of the
unique bioisosterism possible with cyclopropanes; TFCps are
tert-butyl isosteres that improve in vitro and in vivo stability
while retaining biological activity.3−5 A TFCp was utilized in
the development of a selective, brain-penetrating T-type
calcium channel blocker (ACT-709478) with a safety profile
suitable for advancement into Phase I clinical trials (Figure
1).3d
Among the more popular strategies for cyclopropane
assembly are [2 + 1]-type reactions with olefins. Some
examples include the use of carbenoids generated from
diethylzinc and halomethanes (Simmons−Smith),6 or via
diazo compounds.7 In some cases, a two-step process
(Michael-type addition followed by intramolecular nucleo-
philic displacement) can be employed for the direct cyclo-
propanation of certain olefins (e.g., sulfur ylides with enones in
the Corey−Chaykovsky reaction).7b,8 Although these routes
are well-established in the literature, they are often lacking in
broad functional group tolerance or operational simplicity, and
rarely employ mild conditions. Specifically, state-of-the-art
methods for TFCp synthesis by cyclopropanation rely on
Figure 1. Cyclopropane-containing pharmacons and trifluoromethyl
cyclopropanes.
multistep sequences involving treatment of the corresponding
trifluoromethylalkene with diazomethane followed by a retro-
[3 + 2]-cycloaddition in refluxing xylenes (Figure 2A).3a,4
Alternate strategies that do not rely on cyclopropanation of
Received: May 18, 2018
© XXXX American Chemical Society
A
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Figure 3. Convergent strategies to TFCps from commercial materials.
Scheme 1. Synthesis and Optimization of the Bifunctional
Silicate Reagent
Figure 2. Synthesis of trifluoromethyl-substituted cyclopropanes.
CF3-substituted olefins do exist (e.g., cationic ring closure,5a,b
Minisci-type alkylation5c), but their scope is constrained by
inherent mechanistic limitations.
Single-electron approaches for the cyclopropanations of
alkenes are much less well-developed. Leading methods rely on
the use of diazo compounds,9 prefunctionalized substrates,10 or
methods that require large excesses of reagents and multiple
additives.11 Thus, these methods are not easily employed in
late-stage functionalization of complex molecules. Photoredox
catalysis has enabled the operationally simple generation of
radicals while maintaining the broad functional group tolerance
and orthogonality to acidic or basic residues that is associated
with processes proceeding through open shell intermediates.12
However, no photooxidizable C1 reagent for radical cyclo-
propanation is described in the literature. We thus directed our
efforts toward designing such a species to fill this gap. We
envisioned that a reagent furnishing a halomethyl radical could
operate as a cyclopropanating reagent where, following radical
addition to an olefin, a 3-exo-tet cyclization would forge the
second C−C bond required for cyclopropanation (Figure 2B).
In addition to serving as an effective cyclopropanating reagent,
successful design of a reagent furnishing a halomethyl radical
would allow the properties of this reactive odd-electron
intermediate to be probed.13
a
Reaction conditions: halomethylsilicate (1.5 equiv, 0.15 mmol),
alkene (1.0 equiv, 0.1 mmol), 4CzIPN (5 mol %, 0.005 mmol),
DMSO (0.1 M), 3 h, irradiating with blue LEDs (30 W). See the
b
Supporting Information for details. Ratio determined via 19F NMR.
would not only leverage the wide functional group tolerance
that is characteristic of photoredox catalyzed radical reactions,
but would stand in contrast to the typical approaches to
cyclopropanation (harsh bases, poor safety profiles, and/or
toxic reagents). Although a variety of radical precursors were
explored (e.g., potassium organotrifluoroborates, 4-alkyldihy-
dropyridines, α-halocarboxylates, etc.), α-halomethyl bis-
(catecholato)silicates were ultimately identified as best ful-
filling these criteria (see the Supporting Information for details
on assessment of other halomethyl radical precursors).
Alkylbis(catecholato)silicates can be prepared from commod-
ity materials on multigram scale, have low, leveled oxidation
potentials, and are typically free-flowing, bench-stable powders
compatible with organic photocatalysts.14 We anticipated that
single electron oxidation by the excited state of the
photocatalyst would furnish the desired halomethyl radical
intermediate. Once formed, the radical would readily add to an
alkene 2, and an anionic (SN2) or radical (SH2) 3-exo-tet
DISCUSSION
■
Reagent Design and Development. In devising this
reagent, several parameters were considered: (i) an ability to
be bifunctional in nature (i.e., able to engage in two distinct
C−C bond forming events), (ii) bench stability, (iii) ease of
photooxidation, (iv) a practical, inexpensive, direct preparation
from commercial materials, and (v) potential to operate in a
redox-neutral and metal-free reaction manifold. Such a reagent
B
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a b
,
Table 1. Iodomethylsilicate Enables Facile Synthesis of TFCps
a
b
All values indicate the yield of the isolated product. pin = 2,3-dimethylbutane-2,3-diol. General reaction conditions: iodosilicate (1.5 equiv, 0.75
mmol), alkene (1.0 equiv, 0.50 mmol), 4CzIPN (5 mol %, 0.025 mmol), DMSO (0.1 M), 3 h, irradiating with blue LEDs (30 W). See the
c
d
e
Supporting Information for details. Isolated yield on 5 mmol scale. Conducted using 2.0 equiv of silicate. Conducted using 1.75 equiv of silicate.
f
g
h
Reaction run for 24 h. Isolated as a 95:5 mixture of product and 2-methylated product. 77:23 ratio of cyclopropane to fluoride elimination via
i
19F NMR of the crude reaction mixture; olefin removed via Ag-doped SiO2. 92:8 ratio of cyclopropane to fluoride elimination, via 19F NMR of the
crude reaction mixture; olefin removed via Ag-doped SiO2.
simple chemical steps. These reagents could, in all cases, be
prepared on multigram scale in good yield, without any
chromatography, and were isolated as free-flowing powders.
Trifluoromethyl-substituted alkenes 2 were initially selected
for exploring the proposed cyclopropanation given their known
compatibility with photoredox catalysis and proficiency as
radical acceptors.15,16 In addition, success here would allow the
mild, one-step preparation of valuable TFCps 3 from
trifluoromethyl-substituted alkenes. Given the ease with
which these olefins can now easily be accessed from
commercially available trifluoromethyl ketones,15b aryl hal-
ides,15c or organoboron reagents,15a success here would
provide a regiospecific means to install the TFCp motif on
virtually any scaffold (arene, hetereoarene, aliphatic, etc.,
Figure 3).
Scheme 2. Zero Precaution Reaction
cyclization would furnish the desired cyclopropane 3 (Figure
2C).
To assess the feasibility of the envisioned process, three
bifunctional silicates (α-chloro 1a, α-bromo 1b, and α-iodo
1c) were prepared from commercially available chloromethyl-
trimethoxysilane (∼$0.26 per mmol) in either one or two
In addition to their inherent synthetic value, the known
ability for trifluoromethylalkenes to undergo a competitive
anionic fluoride elimination would provide a handle through
C
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a
Table 2. Cyclopropanation of Non-α-Trifluoromethyl-
Substituted Olefins
Scheme 4. Insensitivity of Cyclopropanation to Electronics
a b
,
a
Reaction conditions: iodosilicate (1.5 equiv, 0.75 mmol), alkene (1.0
equiv, 0.50 mmol), 4CzIPN (5 mol %, 0.025 mmol), DMSO (0.1 M),
3 h, irradiating with blue LEDs (30 W). See the Supporting
Information for details.
Scheme 5. Influence of Halogen Substituent on the Barriers
a
for the SH2-Type 3-exo-tet Cyclization Pathway
a
Free energies [DLPNO−CCSD(T)/def2-TZVPP-THF(SMD)//
UM06-2X/DGDXVP-THF(SMD)] are in kcal mol−1, and selected
distances are in Ångstroms.
a
b
All values indicate the yield of the isolated product. General
reaction conditions: iodosilicate (1.5 equiv, 0.75 mmol), alkene (1.0
equiv, 0.50 mmol), 4CzIPN (5 mol %, 0.025 mmol), DMSO (0.1 M),
3 h, irradiating with blue LEDs (30 W). See the Supporting
1). Using 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile
(4CzIPN)18 as photocatalyst and dimethyl sulfoxide
(DMSO) as solvent, we not only observed the desired
reactivity, but found that the ratio of cyclopropane 3 to
undesired gem-difluoroalkene 4 was strongly dependent on the
halogen leaving group; a complete inversion in selectivity was
observed when moving from the chloro- to bromo- to
iodosilicate (Scheme 1).
c
Information for details. Conducted using 2.0 equiv of silicate.
d
e
Reaction run for 18 h. Conducted using 1.75 equiv of silicate.
f
Product isolated as a 94:6 mixture of product and starting material.
Scheme 3. Stereoconvergent Cyclopropanation
Given its innate selectivity for cyclopropanation and
inexpensive nature (∼$1.10 per mmol), further optimization
of this annulation process utilized iodomethyl-based silicate
reagent 1c, providing reaction conditions that do not require
the use of additives (see Supporting Information for details on
optimization). Use of 30 W blue LEDs lamps as the light
source allowed the shortest reaction times (0.5−24 h,
depending on scale and substrate). The reaction proceeded
equally well in the presence of other, more cost-effective, light
sources (e.g., 21 W CFLs) with only the reaction time being
impacted (see Supporting Information for detail on light
source studies). Control reactions confirmed this indeed was a
photocatalytic process; in the absence of light or photocatalyst,
no reaction occurred (see Supporting Information). An
additional control reaction where reaction progress was
evaluated over alternating periods of irradiation and darkness
(the so-called “light/dark” experiment) was performed. More
rigorous evaluation of the photochemical aspect of this process
(e.g., Stern−Volmer emission quenching, quantum yield
which insight could be gained as to whether ring closure would
occur via an anionic or radical pathway (Figure 2C, see
Mechanistic Studies for further details).16e,f,17
With these considerations in mind, we evaluated the
selectivity for cyclization versus fluoride elimination (Scheme
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a
Scheme 6. Energetics of Anionic 3-exo-tet Cyclization versus E1cb-Type Fluoride Elimination
a
Free energies [DLPNO−CCSD(T)/def2-TZVPP-THF(SMD)//UM06-2X/DGDXVP-THF(SMD)] are in kcal mol−1, and selected distances are
in Ångstroms.
a
Scheme 7. Energetics of Anionic versus Radical 3-exo-tet Cyclization in a Non-α-Trifluoromethyl System
a
Free energies [DLPNO−CCSD(T)/def2-TZVPP-THF(SMD)//UM06-2X/DGDXVP-THF(SMD)] are in kcal mol−1 and selected distances are
in Ångstroms.
determination) was performed as well (see Mechanistic
Studies for further details), ultimately ruling out an unassisted,
self-sustaining chain process.
alkyne (3e) functional group. Additionally, a wide range of
nitrogen-containing substrates, including aryl nitrile 3g, Boc-
protected and N-methyl-anilines 3h−3j, a Boc-protected
benzylic amine 3k, and a secondary amide 3l, all cyclo-
propanated successfully. The reaction even proceeds smoothly
in the presence of an acidic ammonium chloride salt (3m).
Furthermore, aldehyde 3n, phenol 3o, benzyl alcohol 3p,
benzoic acid 3q, and methyl ester 3r were all compatible,
illustrating both the broad functional group tolerance and the
compatibility of protic groups. Other valuable synthetic
lynchpins such as an aryl Bpin (3s), primary alkyl iodide
(3t), and a secondary alkyl chloride (3u) were also tolerated.
The chemoselectivity of the transformation was evaluated
using the geraniol analog 3v, where cyclopropanation was
With these conditions in hand, the scope of the trans-
formation was explored. A variety of structurally diverse α-
trifluoromethyl alkenes were amenable to cyclopropanation,
generally providing products in good yield and with excellent
functional group compatibility (Table 1). Bromo-substituted
arenes (3a−3d) reacted efficiently to provide the desired
products. Steric effects did have some influence on the
reaction. ortho-Substitution itself was not deleterious, but
larger substituents did seem to have a more pronounced effect
(e.g., 3c required longer reaction times and a slightly higher
loading of 1c). The reaction tolerated a potentially reactive
E
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a b
,
conducted on a 5 mmol scale with virtually no effect on the
yield (3a). It should also be noted that these sorts of CF3-
substituted olefins fail to react under previously reported
radical cyclopropanation methods (see Supporting Information
for comparison studies).
Table 3. Cyclopropanation Using Chloromethylsilicate
Alteration of the perfluoroalkyl chain was also explored.
Both pentafluoroethyl and 1,1-difluoroethyl-substituted al-
kenes reacted to give the corresponding substituted cyclo-
propanes (3ae and 3af, respectively). Interestingly, the more
electron-deficient and sterically encumbered pentafluoroethyl
2ae gave a 77:23 mixture of cyclopropane 3ae and fluoride
elimination product, as determined by 19F NMR of the crude
reaction mixture, suggesting that the side chain can perturb the
relative rates of cyclization versus elimination.
Lastly, to demonstrate the user-friendly nature of this
reaction, the cyclopropanation of trifluoromethyl alkene 2d
was conducted in the presence of an air atmosphere and using
wet, nondegassed DMSO (Scheme 2). Although the reaction
did proceed to full conversion, the product was isolated in a
slightly lower yield. However, the result is still a testament to
the robustness of the transformation.
We next explored the generality of this reagent for
cyclopropanation, and thus other olefins were examined.
Overall, various electronically distinct olefins were amenable
to cyclopropanation, and the functional group tolerance
matched that observed with trifluoromethyl-substituted
alkenes. α,β-Unsaturated esters, amides, and ketones (6a−
6e) readily underwent the cyclopropanation to give the
corresponding trans products (Table 2). A key intermediate
(6c) used in the synthesis of platelet aggregation inhibitor
Ticagrelor (AstraZeneca, Figure 1)20 was prepared using this
reagent and isolated as an approximately 1:1 mixture of trans-
cyclopropane diastereomers. Several alkenes bearing 1,1-
disubstitution were readily cyclopropanated (6f−6k). The
reaction was further extended to 1,1-diarylethylenes to furnish
1,1-diaryl cyclopropanes (6i, 6j). Even a trisubstituted alkene
was converted to its corresponding cyclopropane without issue
(6k). Additionally, trans-anethole reacted to give only the
corresponding trans-cyclopropane 6l, and terminally unsub-
stituted styrenes (which are typically incompatible with radical
cyclopropanation)11a gave the corresponding monosubstituted
cyclopropanes (6m and 6n). Furthermore, many examples
(e.g., 6a, 6d, 6e, 6i, 6l, and 6m) displayed more successful
reactivity when using 1c as compared to previously reported
radical cyclopropanation methods.11
a
b
All values indicate the yield of the isolated product. General
reaction conditions: iodosilicate (1.5 equiv, 0.75 mmol), alkene (1.0
equiv, 0.50 mmol), 4CzIPN (5 mol %, 0.025 mmol), DMSO (0.1 M),
3 h, irradiating with blue LEDs (30 W). See the Supporting
c
Information for details. Conducted using 2.0 equiv of silicate.
d
e
Conducted using 1.75 equiv of silicate. Isolated 66% yield of
f
noncyclized Giese-type addition product. Reaction run for 18 h.
g
Isolated product contained 2% yield of noncyclized Giese-type
h
addition product. Isolated 60% yield of noncyclized Giese-type
addition product. See Supporting Information for details.
Scheme 8. Bracketing Experiment
The stereochemical outcome when using trans-anethole
prompted us to interrogate whether stereoconvergence
occurred using the method outlined here. Cyclopropanation
of an E/Z mixture of 5l as well as a trisubstituted alkene 5o
(e.g., Scheme 3) provided trans-cyclopropane as the exclusive
stereoisomer. In addition, use of pure cis- or pure trans β-
methylstyrene resulted in the same stereochemical result.
Exclusive formation of the trans-cyclopropane was observed,
although these isomeric olefins appear to react at different
rates. Stereoconvergence here is likely achieved via diaster-
eoselective ring closure following radical addition to either
isomer (made possible by the rapid interconversion of a radical
intermediate). However, given that photochemical isomer-
ization is a background reaction for some olefins, stereo-
convergence via preferential reaction with one alkene isomer
cannot be conclusively ruled out for some systems (see
Supporting Information for further details).
observed exclusively at the electron-deficient trifluoromethyl-
substituted olefin. The reaction was not limited to α-styryl
trifluoromethyl-substituted alkenes. A representative trifluor-
omethyl-substituted aliphatic alkene (3w) also efficiently
underwent cyclopropanation, albeit at an extended reaction
time and with higher silicate loading. In addition, a variety of
heteroaryl trifluoromethyl alkenes including indole 3x, indazole
3y, pyrido[2,3-b]pyrazine 3z, imidazole-pyrimidine 3aa,
pyridine 3ab,19 a caffeine derivative 3ac, and thiophene 3ad
were readily cyclopropanated. Finally, the reaction could be
F
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a
Scheme 9. Energetics of Ring Opening versus Anionic Cyclization
a
Free energies [DLPNO−CCSD(T)/def2-TZVPP-THF(SMD)//UM06-2X/DGDXVP-THF(SMD)] are in kcal mol−1, and selected distances are
in Ångstroms.
implicit solvent.21 Further, to assess the influence of dynamic
correlation, open-shell, domain-based local pair, and natural
orbital Coupled-Cluster calculations using single and double
excitations with perturbative triple excitations (DLPNO−
CCSD(T)) using def2-TZVPP basis using ORCA were also
performed.22 This latter method provides accurate energies
(within 3 kJ mol−1) with the computational cost comparable to
DFT calculations.23 Single point energy calculations in implicit
solvent using (D3(BJ)-B3LYP)/def2-TZVPP and UM06-2X/
def2-TZVPP were performed in parallel for comparison, which
revealed identical trends and very similar energetic profiles as
the DLPNO−CCSD(T) method (see Supporting Informa-
tion).24 For simplicity, only DLPNO−CCSD(T) free energies
are presented and discussed explicitly in the text. All 3D
structures were generated using CYLview.25
We initially sought the energetics of the radical 3-exo-tet
cyclization. In this pathway (Figure 2C), radical intermediate
2′ presumably arises from Giese-type addition26 of the
halomethyl radical 1′ to the alkene 2, which can undergo
ring-closure via SH2-type mechanism to deliver the desired
TFCp 3. Thus, we populated the potential energy surface of
this pathway (Scheme 5). Note that energetics of the initial
radical addition to the alkene show regioselective formation of
α-radical INT-I, implying that α-radical formation is both
kinetically and thermodynamically favored over β-radical
formation (see the Supporting Information for additional
details). With the exception of the iodo system (22.0 kcal
mol−1 barrier of cyclization from INT-I), the barriers for the
radical cyclization (SH2-type pathway, TS-II and TS-III,
respectively) are not feasible under experimental conditions
(barriers are 27.6 kcal mol−1 and 34.5 kcal mol−1). All other
methods predicted similar barriers (see Supporting Informa-
tion). This is surprising given that formation of cyclopropane
was observed with all halomethyl silicates. Even more
surprising was the fact that, in all cases, the reactions are net
endergonic. Notably, the barriers and (endergonic) reaction
energies are consistent with the strength of the C−X bond
(C−X bond dissociation energies for C−I, C−Br, and C−Cl
are ∼57, ∼71, and ∼85 kcal mol−1, respectively).27 The
computed barriers for a possible radical-mediated fluoride
elimination to give the gem-difluoroalkene (not shown) were
too high to be feasible and were universally highly endergonic
(∼63 kcal mol−1 between all adducts of halomethyl addition).
Figure 4. Plausible mechanism for cyclopropanation.
Mechanistic Studies. Having explored the synthetic scope
and utility of this reagent, we next turned our attention to the
reaction mechanism, specifically whether the proposed 3-exo-
tet cyclization proceeded via an anionic (SN2) or radical (SH2)
pathway. Although the identity of the halogen of the
halomethyl radical does dramatically impact the reaction
pathway, that alone cannot distinguish between anionic or
radical ring closure (i.e., iodide is both more prone to
nucleophilic displacement and is more homolytically labile
than bromine or chlorine). Experiments to explore the
influence of electronics on product distributions were initially
conducted. However, no strong electronic correlation between
the ratio of cyclopropane to gem-difluoroalkene was observed
(Scheme 4).
Of note, the reaction could also be conducted in the
presence of 3 equiv of trifluoroacetic acid (TFA) without any
change in ratio or reaction conversion. Although intriguing,
these results were not sufficient to preclude one of the two
cyclization pathways. We next turned to quantum mechanical
calculations to evaluate these mechanistic postulates more
conclusively. Specifically, we sought to determine which of the
two mechanisms more accurately described the observed
results (i.e., the effect on product selectivity by the structure of
α-halomethyl radical, etc.). Calculations were initially
performed at the UM06-2X/DGDXVP level of theory in
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(ΔΔG‡ is 1.1 kcal mol−1 for TS-V versus TS-VIII) in favor of
gem-difluoroalkene formation. Finally, in the chloro-system, the
elimination transition state (TS-IX) is favored by 2 kcal mol−1
over the substitution pathway (via TS-VI), thus further
favoring the formation of the alkene.
Table 4. Comparison of Radical Cyclopropanation
Methods
a b
,
Not only do the barriers for cyclization explain the observed
selectivity (and, because of their less energy-demanding nature,
rule out the SH2-type pathway), but they agree with our
experimentally observed results. Both pathways rule against
intermolecular (bimolecular) protonation as a viable reaction
outcome because the reaction is likely proceeding at catalytic
concentrations of anionic and radical intermediates, and the
barriers for intramolecular cyclization and elimination are low
(<9 kcal mol−1). This rationalizes not only how the reaction
proceeds in the presence of an ammonium ion but also how it
can operate even when a highly acidic species such as TFA is
added. This same insensitivity toward acid likely rules out the
formation of an iodomethyl anion (and thus the formation of
carbene). Moreover, it explains how gem-difluoroalkene
formation is the predominant pathway when using nonbifunc-
tional radicals, rather than traditional Giese-type hydro-
alkylation.16d,f Finally, the very low barrier for cyclization
from the iodomethyl-derived anion (Scheme 5, TS-IV)
explains the relative insensitivity to varying electronics of the
arene.
Next, we wondered whether the mechanistic findings would
translate to the nontrifluoromethylated systems successfully
cyclopropanated using 1c. More specifically, the possibility of a
mechanistic spectrum where the electronics of an α-substituent
would control whether the cyclization proceeds through a
radical or anionic pathway. Whereas photoredox Giese-type
processes are established for α-carbonyl28 and α-boryl29
olefins, similar reactivity in more electron-rich olefins is not
established. Thus, we evaluated the energetics of anionic and
radical ring closure for a representative system, 1,1-diphenyl-
ethylene (Scheme 7). The result of this set of calculations rules
out a mechanistic spectrum; the energetic trends are similar to
the α-trifluoromethyl systems. That is, the barrier for radical
cyclization is ∼20 kcal mol−1 (via TS-XIII) from the
corresponding 1,1-diphenyl-3-iodopropyl radical, while the
barrier for the cyclization from the corresponding 1,1-
diphenyl-3-iodopropyl anion is virtually barrierless (∼3 kcal
mol−1; via TS-X). Importantly, the anionic mechanism is
contingent on a rather fast (and favorable) SET reduction of
the intermediate radical. Other halomethyl radical additions
show similar trends.
a
b
All values indicate the yield of the isolated product. Reactions using
c
condition B were performed exactly as described in ref 11a. Yield
reported in ref 11b. Yield reported in ref 11a.
d
The transition states for the reaction of olefin 5i with various
halomethyl radicals are suggestive that, if an anionic pathway is
indeed operative, cyclization should be feasible under
experimental conditions with even the less reactive chlor-
omethyl radical. In the absence of a fluoride elimination, only
intermolecular side reactions are possible in systems such as 5i.
To probe this prediction, the cyclopropanation of 5i using
chloromethylsilicate 1a was attempted under the conditions
optimized for 1c (Table 3). Indeed, cyclopropanation of 5i
gave a comparable yield when using chloromethylsilicate 1a in
place of iodomethylsilicate 1c. Further, examination of the
cyclopropanation of other non-CF3-bearing alkenes using 1a
resulted in varying levels of success. Overall, the isolated yields
were lower when using 1a, reflective of the higher barrier to
cyclization onto an alkyl chloride versus alkyl iodide.
Seemingly less-stabilized anions were more likely to engage
in appreciable cyclization. Substrates that proceed through
The energetic inconsistency of the radical cyclization
pathway with our experimental observations led us next to
investigate whether anionic pathways might be operative for
both cyclization and gem-difluoroalkene formation (Scheme 6).
In excellent agreement with experiment, the computed barriers
for the anionic pathway: (1) are feasible under experimental
conditions (∼4−9 kcal mol−1) and exergonic (∼ −4 to −43
kcal mol−1), and (2) qualitatively and quantitatively replicate
the experimental trends (Scheme 1C). Further, although the
barriers for the SN2-type cyclization increase with the leaving
group ability (I > Br > Cl), the barriers for the elimination
(E1cB pathway) remained relatively unchanged for all halo
systems (∼7 kcal mol−1). Therefore, for the iodo system,
cyclopropane formation P−IV (via SN2-type transition state) is
kinetically favored by 3.8 kcal mol−1 over the alkene product
(P−VII). However, for the bromo system, the energy
difference between these two competing pathways decreases
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Article
stabilized enolate anions (5a′, 5d, 5f) provide no cyclized
product. Additionally, some substrates preferentially under-
went protonation to give the uncyclized, alkyl chloride Giese-
type addition product (5g, 5n). On the whole, the observations
here are consistent with the proposed anionic cyclization
pathway.
To bracket the rate of radical reduction experimentally, 5p
was prepared and subjected to cyclopropanation. Surprisingly,
the major product was bis-cyclopropane 6p, albeit in low
isolated yield. Giese-type adduct 7 was not observed (Scheme
8). This implies that SET reduction exceeds the known rate
constant of ring opening for the related α-cyclopropyl benzyl
radical of 6.1 × 104 s−1, which corresponds to a barrier of
∼11.1 kcal mol−1 at 298 K.30 The experimental results are
again borne out in the computational model (Scheme 9). The
calculated thermodynamics of the ring opening process for this
system shows that the barrier for SET reduction must be lower
than the calculated barrier for ring-opening (13.3 kcal mol−1).
This is in agreement with the rate data. In addition, the low
barrier for cyclization from INT-VI (2.7 kcal mol−1) explains
the facile formation of bis-cyclopropane 6p.
same alkenes reacted to give solely cyclopropanated product.31
Given that the putative active species is the same in both cases,
the disparity in reactivity ultimately suggests that the redox
environment in which the radical is generated (i.e., the order of
SET events, presence of additives, etc.) dramatically influences
the reaction outcome. More broadly, this implies the redox
environment can open up, or close off, alternative mechanistic
pathways. This latter conclusion may be useful for methods
design in other reaction manifolds beyond cyclopropanation.
CONCLUSIONS
■
Herein, the successful development of a new reagent for the
redox-neutral cyclopropanation of olefins under mild, photo-
catalytic conditions is disclosed. This reagent has not only
resulted in the generation of a suite of TFCps, but also enabled
radical/polar crossover cyclopropanation of a diverse range of
olefins to be accomplished with ease and excellent functional
group compatibility. Combined theoretical and experimental
mechanistic studies revealed that the reaction likely proceeds
via a photooxidatively generated iodomethyl radical addition to
an olefin followed by radical SET reduction, culminating in an
anionic 3-exo-tet ring closure. Further applications for this
reagent are under development and will be reported in due
course. More generally, the findings disclosed here not only
enable facile access to halomethyl radicals, but also begin to
shed light on the unique capabilities of these C1 synthons.
With all these data in hand, we suggest the following order
of events as the operative mechanism (Figure 4) under the
developed reaction conditions: (1) Visible light-mediated
photoexcitation of 4CzIPN to its excited state. (2) Reductive
quenching of 4CzIPN* by halomethyl silicate 1. This mode of
quenching is supported by Stern−Volmer emission quenching
experiments (see Supporting Information) and also by the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05243.
■
generally low, favorable oxidation potentials of silicates (E1/2
=
S
+0.4−0.7 vs SCE) and the high, unfavorable reduction
potentials of primary iodides (e.g., E1/2 = −1.44 V vs SCE
for CH2I2).11a Subsequent fragmentation of oxidized 1
furnishes halomethyl radical 1′. (3) After radical generation,
Giese-type addition by the halomethyl radical generates
adducts 2′ or 5′. (4) SET reduction of these adducts by the
reduced state of 4CzIPN gives anions 2″ or 5″ and returns
4CzIPN to its original ground state. (5) Anionic cyclization of
2″ or 5″ furnishes cyclopropanes 3 or 6. Ultimately, this
process is a closed cycle and does not appear to operate by a
chain mechanism. The quantum yield of this process was
determined to be 0.066, implying that an assisted chain process
is not operative.
In cases where the olefin is 1,2-disubstituted or trisub-
stituted, stereoconvergence is observed. Stereoconvergence
likely arises from rapid equilibration of Giese-adduct 2/5 to
the most stable conformation followed by stereoretentive
reduction and rapid ring closure (see Supporting Information
for calculations supporting this hypothesis). Alternatively,
because photochemical isomerization of the starting olefin is
possible, a dynamic kinetic resolution-type scenario may arise.
The results obtained and subsequent mechanistic postulate
stands in stark contrast to literature reports employing the
iodomethyl radical, which propose ring closure through an
SH2-type 3-exo-tet cyclization.11 At the request of a reviewer, a
direct comparison using a representative set of substrates was
made between the method reported here and the method
previously reported by Suero and co-workers (Table 4). For
some substrates, the reactions gave comparable yields (6d, 6e,
and 6l), while for others distinctly different reactivities were
observed. Specifically, alkenes 5i and 5l gave exclusive
noncyclized iodoalkylation products under the conditions
previously reported by Suero et al., whereas under the redox-
neutral, radical/polar crossover conditions reported here, the
Experimental details and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: gmolandr@sas.upenn.edu.
*E-mail: ogs@umd.edu.
■
ORCID
Simon B. Lang: 0000-0001-5380-2996
Jordan S. Compton: 0000-0001-7099-3456
Christopher B. Kelly: 0000-0002-5530-8606
Osvaldo Gutierrez: 0000-0001-8151-7519
Gary A. Molander: 0000-0002-9114-5584
Author Contributions
§J.P.P. and S.B.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
NIGMS (R01 GM 113878 to G.M.) and NSF (CAREER,
1751568 to O.G.). J.P.P. is grateful for an NIH NRSA
postdoctoral fellowship (F32 GM125241). C.B.K. is grateful
for an NIH NRSA postdoctoral fellowship (F32 GM117634).
O.G. is grateful to the University of Maryland College Park for
start-up funds and computational resources from UMD
Deepthought2 and MARCC/BlueCrab HPC clusters and
XSEDE (CHE160082 and CHE160053). We thank Dr.
David Primer (Celgene) and Rebecca Wiles (UPenn) for
stimulating discussions. We thank Dr. Charles W. Ross, III
(UPenn) for his assistance in obtaining HRMS data. We
I
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Article
̌
̌
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with quantum yield determination. We thank Kessil Lighting
for the generous donation of a prototype PR160 Rig.
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