Photochemical C-H Activation Enables Nickel-Catalyzed Olefin Dicarbofunctionalization

Article abstract of DOI:10.1021/jacs.0c13077

Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.

Full text of DOI:10.1021/jacs.0c13077

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Photochemical C−H Activation Enables Nickel-Catalyzed Olefin
Dicarbofunctionalization
Mark W. Campbell, Mingbin Yuan,¶ Viktor C. Polites,¶ Osvaldo Gutierrez,* and Gary A. Molander*
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ABSTRACT: Alkenes, ethers, and alcohols account for a
significant percentage of bulk reagents available to the chemistry
community. The petrochemical, pharmaceutical, and agrochemical
industries each consume gigagrams of these materials as fuels and
solvents each year. However, the utilization of such materials as
building blocks for the construction of complex small molecules is
limited by the necessity of prefunctionalization to achieve
chemoselective reactivity. Herein, we report the implementation
of efficient, sustainable, diaryl ketone hydrogen-atom transfer
(HAT) catalysis to activate native C−H bonds for multicomponent
dicarbofunctionalization of alkenes. The ability to forge new
carbon−carbon bonds between reagents typically viewed as
commodity solvents provides a new, more atom-economic outlook
for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the
reactivity of this transformation was uncovered.
Dicarbofunctionalization of styrenes has also been achieved via
radical-polar crossover mechanisms.19,20
INTRODUCTION
■
Among the most prevalent materials available to the chemistry
community are hydrocarbons (alkanes and alkenes) and their
oxygenated derivatives (alcohols and ethers). Despite their
ubiquity in nature and chemical industries, the preparation of
complex small molecules from these commodity materials
remains a pertinent synthetic challenge. Prefunctionalization,
typically requiring multistep sequences, is often necessary for
promoting selective reactivity of simple building blocks. In an
effort to overcome the inefficiency of non-native functional
group installation, several research programs have been
initiated that focus on the selective functionalization of C−H
bonds.1
Despite significant advancements in this arena, multi-
component C−H functionalizations are still exceedingly
rare.2 This stands in stark contrast to the advancements in
the field of multicomponent, transition metal-mediated cross-
couplings that utilize prefunctionalized substrates.3,4 Dicarbo-
functionalizations (DCF) are a subset of multicomponent
reactions that employ an alkene or alkyne as a “linchpin”,
facilitating the regioselective construction of two C−C bonds.
Early work in nickel-catalyzed DCF employed aryl- and
alkylmetallic coupling partners (e.g., organozinc and organo-
boron reagents).5−9 Significant advancement in functional
group compatibility has been achieved in nickel-catalyzed DCF
reactions by leveraging radical-based mechanisms.10 More
recently, photoredox/Ni dual catalysis has dramatically
expanded the suite of installable fragments by exploiting a
well-developed library of divergent radical precursors.11−18
Although synthetically enabling, even the most modern DCF
reactions do not address the longstanding challenge of utilizing
commodity reagents in multicomponent reactions, instead
relying on prefunctionalized radical precursors that typically
exhibit poor atom economy. To address these limitations, we
sought to develop a radical-based DCF strategy enabled by the
selective homolysis of C−H bonds. At the outset, various
intermolecular hydrogen-atom transfer (HAT) catalysts (e.g.,
tertiary amines or tungsten-based salts) were considered to
achieve the desired transformation, but these either require
activation via organometallic photocatalysts or lack sufficient
chemoselectivity.21−26 Notably, diaryl ketones have been
identified as effective HAT catalysts that are photoactive,
sustainable, and chemoselective, thus overcoming the inherent
challenges of the aforementioned HAT agents. In this vein,
diaryl ketone HAT catalysis has been used in the hydro-
alkylation of activated alkenes as well as the arylation of C−H
bonds via Ni-catalyzed cross-coupling.27−31 We envisioned
that the merger of these two fundamental transformations,
Received: December 17, 2020
Published: March 4, 2021
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achieved by synergistic diaryl ketone/Ni dual catalysis, could
overcome the inherent limitations of prefunctionalized radical
precursors in multicomponent cross-coupling reactions. In
addition to developing this transformation, we performed
quantum mechanical calculations to provide insight into the
mechanism and the origin of selectivity of this protocol.
Table S6). Nonpolar, aprotic solvents, such as benzene and
α,α,α-trifluorotoluene (TFT), were critical for the successful
formation of the desired product; in all other cases, high ratios
of alkene hydroalkylation were observed.
With a suitable set of conditions established (see SI for full
optimization details), the scope of each reaction component
was evaluated (Table 1). Use of cyclopentyl methyl ether
(CPME) as the C−H precursor provided good yields across a
range of aryl halides; however, i-PrOH was found to be
superior in several instances. Arene substructures that
contained other activated C−H bonds were accommodated
under the standard conditions, but fared better when the
loading of the C−H precursor was increased to that of a
cosolvent with TFT (1:1 v/v). In general, aryl bromides
bearing electron withdrawing groups resulted in the best yields
of DCF products, while electron-neutral and electron-donating
arenes returned some starting material and protodebromina-
tion byproducts. However, incorporation of electron-neutral
and electron-donating aryl iodides at extended reaction times
provided significantly improved yields (SI Table S5). A range
of bifunctional arenes were evaluated with excellent chemo-
selectivity, generating products that could serve as linchpins for
subsequent diversification of the arene region (17−19). An
arene derived from the GABA-receptor antagonist, Flumazenil,
was incorporated into the DCF reaction with moderate yield
(24). In addition to the diverse array of aryl halides, selected
heteroaryl halides were competent in the DCF reaction (25−
31).
RESULTS AND DISCUSSION
■
We envisioned that the desired hydrogen atom transfer-
mediated DCF would operate via the mechanism outlined in
Figure 1. Photoexcitation of a diaryl ketone (I) would access
We then turned our attention to the scope of C−H
precursors. Several ether and thioether structures were utilized
with good success (32−39). In the case of C−H precursors
that generated secondary radicals, some of the aryl bromide
was consumed via two-component cross-coupling with the C−
H precursor, consistent with previous studies using alkyl
radicals generated from organotrifluoroborates.13 However,
increased loading of the alkene provided synthetically useful
yields of the DCF product. Free alcohols performed
extraordinarily well in the targeted reaction (40−44). These
DCF products bear both a nucleophilic hydroxyl, as well as an
electrophilic ester, offering several complementary avenues for
downstream functionalization. To that end, lactonization of
selected DCF products was accomplished with excellent yields
(S5−S7). Several α-amido radicals were also quite effective in
this protocol (45−47). Gratifyingly, utilization of 2-oxazolidi-
none as a C−H precursor generated only an α-amido
substituted product (47), demonstrating the inherent
selectivity of the benzophenone catalyst. Attempts to use
alkyl amines as C−H precursors furnished the DCF product in
only low yields, likely because of undesired interactions
between the excess amine and the Ni catalyst. Finally,
substrate 48 was generated from C−H abstraction alpha to a
pinacol boronate, which, to our knowledge, is the first example
of a photochemically mediated HAT of an α-boronate C−H
bond. This example is particularly useful as a synthetic building
block given the well-established array of transformations of
alkyl boronates.35
Figure 1. Proposed mechanism for three-component HAT-mediated
photoredox/nickel dual-catalyzed DCF of alkenes. BDE were
calculated at the (U)B3LYP-D3/def2-TZVPP//(U)B3LYP-D3/
def2-SVP level of theory.
the triplet-state diradical II. This persistent radical would
perform selective homolysis of an activated C−H bond (BDE
= 90.4 kcal/mol; see SI Figure S6 for full details), generating
the desired carbon-centered radical (IV) with concomitant
formation of ketyl radical III. In turn, this alkyl radical would
undergo regioselective Giese addition to an activated alkene V,
leading to the corresponding radical adduct VI. The newly
formed radical adduct (VI) could be captured by a Ni0 species
(VII), and the resulting NiI complex would undergo
subsequent oxidative addition with an aryl halide, affording
IX (blue pathway). Alternatively, the aryl halide could first
undergo oxidative addition with the Ni0 species prior to radical
capture (VII to X; green pathway). After reversible square
planar-tetrahedral isomerism, VI could then add to the
productive tetrahedral NiII intermediate X,32 forming complex
IX. Reductive elimination from IX would produce the desired
DCF product XII and NiI complex XI.33 Finally, single-
electron transfer (SET) from ketyl radical III to XI would
regenerate I and VII, respectively, completing both catalytic
cycles.
We began optimization of the described DCF reaction with
a survey of several different HAT catalysts, which revealed that
diaryl ketones bearing one electron-rich and one electron-poor
arene were the most effective.27 We presume that such
catalysts have a longer-lived triplet state because of captodative
radical stabilization.34 Notably, quantum mechanical calcu-
lations revealed a general trend between the DCF product
In addition to the model acrylate, a range of sterically and
electronically dissimilar vinyl functional groups were incorpo-
rated into the DCF protocol (49−52). Furthermore, a variety
of internal alkenes were also competent, providing the DCF
products with superb diastereoselectivity (53−56). Utilizing
dimethyl fumarate as a radical acceptor produced two
stereoisomers; the syn diastereomer was obtained as the
1
yield (determined by crude H NMR) and the calculated
triplet state energy of a range of benzophenone derivatives (SI
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f
Table 1. Scope of Three-Component HAT/DCF
f
Values indicate yield of the isolated product. pin = pinacolato. Unless otherwise noted: aryl halide (1 equiv, 0.5 mmol), alkene (2 equiv, 1.0
mmol), C−H precursor (15 equiv, 7.5 mmol), Ni 2 (10 mol %, 0.05 mmol), benzophenone 1 (20 mol %, 0.10 mmol), K2HPO4 (2 equiv, 1.0
a
b
mmol), TFT (0.1 M), 24 h, irradiating with 390 nm Kessil lamp. Using the corresponding aryl iodide. Using a 1:1 v/v ratio of C−H precursor/
c
d
e
TFT. Reaction time extended to 48 h. Using 4 equiv of alkene. Isolated as the corresponding carboxylic acid after treatment with HCl in 1,4-
dioxane.
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Figure 2. Computational analysis of the divergent reactivity of alkyl radical in the isopropyl alcohol system. Electronic (in parentheses), enthalpy
(in bracket), and free energies (kcal/mol; 298 K) given were calculated at the (U)B3LYP-D3/def2-TZVPP-CPCM(benzene)//(U)B3LYP-D3/
def2-SVP-CPCM(benzene) (black) and DLPNO−CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) (blue) levels of method.
anticipated hydroxy succinate 61, while the anti diastereomer
underwent spontaneous lactonization to provide 62, as
previously observed with 29. Finally, we prepared a collection
of more complex substrates (57−59) based on natural product
scaffolds. The rapid assembly of substrates containing such
highly functionalized motifs validates the application of this
DCF strategy in the synthesis of complex molecular
architectures.
In an effort to lend further support for the mechanism
outlined in Figure 1, a series of control reactions were
conducted. In particular, we focused on understanding the role
of the excited-state benzophenone in the C−H abstraction
step. We considered alternative mechanistic scenarios such as
the liberation of bromide radical from 2 via direct photo-
chemical excitation or triplet-state energy transfer from 1.
However, in the absence of 1, the desired DCF product was
not observed when irradiating with either 390 or 300 nm light
sources (SI Figure S2). To rule out the action of bromide
radicals in the formation of the DCF product, we utilized
Ni(dtbbpy)(NO3)2 in conjunction with 4-iodobenzonitrile,
which, as anticipated, resulted in a good yield of the desired
product (SI Figure S3). Because hydrogen atom abstraction via
iodide radical is considerably endothermic (SI Figure S3), we
conclude that the mechanism of DCF product formation does
not depend on the participation of halide radicals. An
intermolecular competition reaction using i-PrOH and i-
PrOH-d7 resulted in a 3.6:1 ratio of 40 to 40-d6, indicative of
an exothermic radical C−H abstraction (SI Figure S4).36 As an
unsymmetrical ether, CPME allowed us to study the innate
HAT selectivity in the DCF protocol. In addition to the
desired DCF product, we also observed a cross-coupling
product derived from the generation of a primary α-alkoxy
radical as a minor byproduct. SI Figure S7 outlines a detailed
computational investigation of the HAT selectivity of 1 and
subsequent mechanistic pathways.
Because of the potential for alkyl radicals to undergo either
direct two-component cross-coupling (CC) or three-compo-
nent DCF, DLPNO−CCSD(T) and dispersion-corrected DFT
calculations were used to provide further insight into the
mechanism and selectivity (Figure 2; see Supporting
Information for full computational details). Such calculations
have recently been used by our group to study the mechanism
of a nickel-catalyzed photoredox single-electron Tsuji-Trost
reaction37 and provide accuracy at the level of coupled cluster
theory at the cost of DFT calculations.38 Consistent with
previous results,32 calculations showed that both the Ni0/NiII/
NiIII and Ni0/NiI/NiIII mechanisms are energetically feasible
for two- and three-component pathways, (SI Figure S8 and
S9), as observed in related systems,32 and converge on the
singlet, square planar complex 1C (Figure 2, inset). Two
plausible mechanisms for two-component cross-coupling (CC)
of radical fragment A are outlined in Figure 2 (left; blue/green
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Figure 3. Selectivities of various secondary radicals for competing DCF and CC pathways. (A) Values indicate ratio of DCF to CC product
1
determined by crude H NMR. Reaction conditions: 4-bromobenzonitrile (1 equiv, 0.1 mmol), tert-butyl acrylate or acrylonitrile (2 equiv or 4
equiv, 0.2 or 0.4 mmol), C−H precursor (15 equiv, 1.5 mmol), Ni 2 (10 mol %, 0.01 mmol), benzophenone 1 (20 mol %, 0.02 mmol), K2HPO4 (2
equiv, 0.2 mmol), TFT (0.1 M), 24 h, irradiating with 390 nm Kessil lamp. (B) NCI plots and the computed energetics (free energy, kcal/mol) of
the Giese addition transition states of various alkyl radicals to acrylate. (C) Proposed hydrogen bonding increases the rate of Giese-type addition vs
direct metalation in the reaction of secondary ethoxy radical. Free energies (kcal/mol; 298 K) given were calculated at the DLPNO−CCSD(T)/
def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) level of method.
pathways). After formation of the singlet, square planar
complex C, this species is expected to equilibrate rapidly
concentration of alkene, alkyl radical A is expected to produce
the direct (two component) cross-coupling product (Pcc) via
the green pathway. However, at high concentration of alkene,
alkyl radical A is expected to undergo irreversible Giese
addition to methyl acrylate via A-TS-D, which is isoenergetic
to the barrier for metalation of A (A-TS-B′). We also
considered radical addition of A to Ni0-bound alkene but
found this pathway less likely because of the inherent higher
concentration of alkene in the system with respect to nickel, as
1
under photocatalytic conditions to the triplet, tetrahedral
complex 3C.32,39,40 On the basis of prior work,34 alkyl radical A
1
is expected to add to either the “axial” position of C (blue
pathway, via A-TS-B, barrier of 12.8 kcal/mol) or the
“equatorial” position of 3C (green pathway, via A-TS-B′,
barrier of 11.5 kcal/mol), the latter being more energetically
favorable. On the basis of these calculations, at low
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Figure 4. Competition reactions and related computational details. (A) Hydroalkylation competition reactions, alkenes (1 equiv each, 0.1 mmol),
C−H precursor (15 equiv, 1.5 mmol), Ni 2 (10 mol %, 0.01 mmol), benzophenone 1 (20 mol %, 0.02 mmol), TFT (0.1 M), irradiating with 390
nm Kessil lamp for 30−90 min, reactions carried out to ∼25% conversion. (B) DCF competition reactions, standard reaction conditions as in Table
1. (C) Computed energetics for the Giese addition processes. Free energies (kcal/mol; 298 K) given were calculated at the DLPNO−CCSD(T)/
def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM (benzene) level of method. (D) Result of reaction of i-PrOH/acrylonitrile/p-BrC6H4CN under
standard reaction conditions.
well as the low barrier for the oxidative addition of aryl
bromide to the Ni0 center (see SI Figure S10 for more detailed
discussion). Finally, subsequent metalation of D to C affords
presence of an α-oxygen increases the nucleophilic character of
the radical, accelerating the Giese addition. Notably, the
secondary radical generated from EtOH gave a significantly
higher DCF:CC ratio than cyclic α-alkoxy radicals. The DCF
selectivity was also severely eroded in the case of the α-thio-
substituted radical derived from tetrahydrothiophene (entry
10). Satisfyingly, α-amido radicals exhibited the highest
DCF:CC selectivity of all the examined secondary radicals
(entry 11). Further, we found that the trends of experimentally
observed DCF:CC selectivities is also consistent with the
computed barriers (SI Table S7). That is, in general, the
DCF:CC selectivity arises from competitive alkyl radical Giese
addition versus metalation to the tetrahedral NiII species,
which could be operative in related transformations involving
secondary α-heterosubstituted alkyl radicals.
Given the unique reactivity exhibited by secondary α-
hydroxy radicals (e.g., derived from EtOH), we speculated that
hydrogen bonding could influence the selectivity for the two
competing pathways. Prior studies revealed that the presence
of hydrogen bonding significantly accelerates radical addition
of alcohols into alkenes,22,42,43 presumably by weakening the
α-hydroxy C−H bond in the presence of exogenous hydrogen
bond acceptors. However, there are very few computational
studies that examine the role of hydrogen bonding between the
radical component and Giese acceptor.44 We hypothesized that
this type of hydrogen bonding interaction could play a
paramount role in controlling selectivity for this DCF protocol.
On the basis of our calculations, we attribute the increased
DCF selectivity in entry 2 compared with entries 5−9 to an
accelerated Giese addition via hydrogen bonding as demon-
3
the key NiIII intermediate E, which will quickly undergo
reductive elimination (via E-TS-F) to form the desired, three-
component product (PDCF) and bromo-NiI species F. Notably,
both metalation (via A-TS-B′) and Giese addition (via A-TS-
D) of radical A were found to be irreversible, and their
transition states higher in energy than the subsequent reductive
eliminations (B′-TS-F and E-TS-F, respectively). Thus, these
calculations demonstrate that the kinetic product selectivity for the
competing pathways (DCF vs CC) is determined by the relative
energy difference between the metalation (A-TS-B′) versus Giese
addition (A-TS-D) transition states and, given the small energetic
difference between these, is highly dependent on the relative
concentration of nickel to alkene. Analysis of a secondary α-ether
system (THF, SI Figure S11) is also in agreement with these
findings.
We then examined the DCF:CC selectivity for a range of
sterically and electronically unique alkyl radicals. As was
established previously by our group and others, tertiary radicals
are reluctant to undergo direct metalation by nickel32,41 and in
the presence of an activated alkene, undergo exclusive Giese
addition (Figure 2, red pathway). Under similar conditions in
our previous report,13 we observed that direct two-component
CC was favored over three-component DCF (∼3:1 NMR
ratio) for unstabilized, secondary alkyl radicals generated from
organotrifluoroborates. In contrast, secondary α-alkoxy radicals
gave approximately equimolar ratios of DCF to CC products
(Figure 3A, entries 4−9). These results suggest that the
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Figure 5. Experiments with 1-cyclopropylethanol as C−H precursor. (A) DCF reactions with 1-cyclopropylethanol; standard reaction conditions as
in Table 1. (B) Proposed pathway of the formation of cyclopentane-containing DCF product. (C) Computational analysis of the competing ring-
opening and Giese addition of tertiary radical in acrylate and acrylonitrile systems. Electronic (in parentheses), enthalpy (in bracket), and free
energies (kcal/mol; 298 K) given were calculated at the (U)B3LYP-D3/def2-TZVPP-CPCM(benzene)//(U)B3LYP-D3/def2-SVP-CPCM-
(benzene) (black) and DLPNO−CCSD(T)/def2-TZVPP//(U)B3LYP-D3/def2-SVP-CPCM(benzene) (blue) levels of method.
strated by the NCI plots (Figure 3B).45 In the case of the α-
alkoxy systems, the higher barrier for Giese addition (owing to
the lack of hydrogen bonding) and the lower barrier for direct
radical addition to the Ni center results in increased formation
of the CC product (see SI Table S7 for the computed barriers
of each system). Further support for the influence of hydrogen
bonding was found when replacing tert-butyl acrylate with
acrylonitrile as the Giese acceptor (entry 2 vs 3). The dramatic
erosion of DCF to CC selectivity could be attributed to the
inability of acrylonitrile to engage in hydrogen bonding with
the hydroxyl group. However, considering the similar barrier of
Giese addition for acrylonitrile and an acrylate (Figure 3C, TS-
66 vs TS-68), we propose that the carbonyl of the acrylate
“locks” the hydroxyl via an intramolecular hydrogen bond,
facilitating efficient arylation of α-carboxy radical int-66. Upon
closer inspection of the NiIII intermediates that result from
metalation of radical adducts int-66 and int-68, we found that
the hydroxyl group remains oriented toward the carbonyl in
66, while pointing to Br atom in 68. We presume that the
alternate orientation of the hydroxyl in complex 68 negatively
impacts the arylation step, leading to hydroalkylation of
acrylonitrile. The exact mechanistic details concerning the
formation of this hydroalkylation product have not yet been
fully elucidated. Interestingly, the α-thio-substituted radical
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(Figure 3A, entry 10) shows a low barrier for metalation, but a
much higher barrier for Giese addition, which makes the
generation of cross-coupling product more favorable (SI Table
S7). Overall, these results convincingly demonstrate an
unappreciated yet critical effect of hydrogen bonding in
controlling product formation in metallaphotoredox cross-
couplings.
tert-butyl acrylate under standard conditions was the three-
component cyclopropane-containing adduct 75. An additional
product, a [3 + 2] cycloaddition adduct (76), was isolated as
well. This product was presumably generated from cyclo-
propane ring opening followed by Giese addition and cis-
selective 5-exo-trig cyclization to achieve a cyclopentane-
containing α-hydroxy radical (vide infra), which could undergo
subsequent DCF reactivity (Figure 5B).46 Similar reactivity
was observed in our previous DCF report when employing an
organotrifluoroborate derived from (S)-verbenone, which
produced a [4 + 2] cycloaddition adduct.13 Under identical
conditions, reaction with acrylonitrile produced some cyclo-
propane-containing DCF product (78). However, the major
product obtained in this system was a two-component cross-
coupled product (77), which stemmed from α-cyclopropyl
radical ring opening. Computed energetics for these systems
(Figure 5C) show that ring opening of the α-cyclopropyl
radical (TS-81) is competitive with Giese addition to either
acrylate or acrylonitrile and thus account for the mixture of
both cyclopropyl DCF products (75 and 78) and various ring
opened products (76 and 77). We propose that 76 and 77
stem from primary radical 81 (generated from reversible
cyclopropane ring opening), which could undergo either Giese
addition to the corresponding alkene or metalation to the Ni
center (not calculated). The formation of 77 as the major
product in the reaction with acrylonitrile suggests that TS-82 is
higher than the barrier for metalation of 81. Conversely, the
absence of 77 and the formation of 76 in the reaction with tert-
butyl acrylate is rationalized by the significantly lower barrier of
Giese addition of 81 to the acrylate. As demonstrated by the
transition state structure (TS-84), hydrogen bonding between
81 and acrylate is responsible for the accelerated Giese
addition leading to 84. We therefore conclude that hydrogen
bonding is again a prevailing factor in determining product
selectivity in this DCF protocol.
In an effort to understand the hydrogen bonding
interactions between various radical and alkene components
in the Giese addition step more fully, we performed
hydroalkylation competition reactions (Figure 4). Isopropanol
preferentially engaged acrylates and acrylonitrile in hydro-
alkylation in comparison to the less electrophilic acrylamide
(Figure 4A; entries 1 and 2). However, i-PrOH underwent
hydroalkylation with only a slight preference for acrylonitrile
over adamantyl acrylate. Complete selectivity for addition to
acrylonitrile over adamantyl acrylate was observed using
diisopropyl ether as a C−H precursor (Figure 4A, entry 4).
The calculations in Figure 4C rationalize the dissimilar
selectivities of alcohols and ethers observed in the hydro-
alkylation competition reactions. In particular, we attribute the
significant decrease in ΔΔG‡
for i-PrOH compared to
CN/CO2R
diisopropyl ether to the presence of hydrogen bonding
between the hydroxyl and the acrylate. Addition of a
chaotropic reagent (MgCl2) in entry 5 resulted in high
selectivity for hydroalkylation of acrylonitrile with i-PrOH. We
attribute the dissimilar selectivities in entries 3 and 5 to the
disruption of hydrogen bonding between i-PrOH and
adamantyl acrylate when MgCl2 is present. A control reaction
demonstrated that hydroalkylation of adamantyl acrylate with
i-PrOH is not inhibited by the presence of excess MgCl2.
Furthermore, a similar trend in chemoselectivity for i-PrOH
and diisopropyl ether was observed in competition reactions
between acrylonitrile and phenyl vinyl sulfone, which is again
attributed to the presence/absence of hydrogen bonding in the
Giese addition transition states (entries 6 and 7).
As evident in entry 8, the presence of β-substitution on the
alkene significantly retards the rate of Giese addition. Next,
equimolar ratios of acrylonitrile and tert-butyl acrylate were
subjected to the standard DCF conditions using either i-PrOH
or CPME as the C−H precursor (Figure 4B). When i-PrOH
was used as the C−H precursor, the ratio of DCF products
greatly favored the acrylate. However, CPME exhibited an
equivalent ratio of DCF products. Because of these unexpected
results, we conducted a DCF reaction of i-PrOH with
acrylonitrile under standard conditions, which produced an
atypically high ratio of hydroalkylation/DCF products (Figure
4D). On the basis of these experiments and calculated
transition state energies in Figure 4C, it is apparent that the
ratio of DCF products in these complex reaction systems is not
solely governed by the rates of each Giese addition. As such,
we conclude that the arylation step is significantly impacted by
the steric and electronic nature of Giese adducts (69−72) as
well as the presence or absence of hydrogen bonding in NiIII
complexes (66668, 74). We are currently pursuing further
detailed calculations (including quasi-classical molecular
dynamic simulations) to probe this hypothesis and these
results will be reported in due course.
CONCLUSIONS
■
A novel multicomponent DCF strategy has been developed
that relies on a sustainable and chemoselective mode of HAT
catalysis. New insights into the nature and effect of hydrogen
bonding in radical/alkene reactivity as well as metallaphotor-
edox cross-coupling have been discovered. We anticipate that
not only will these findings provide a new and efficient strategy
for small molecule synthesis but also that the mechanistic
insights will prompt further discovery in the area of radical
reactivity mediated by hydrogen bonding.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13077.
Experimental details and spectral data (PDF)
Accession Codes
CCDC 2046230 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Finally, we employed 1-cyclopropyl ethanol as a C−H
precursor, anticipating that the resultant alkyl radical could
trigger ring-opening of the α-cyclopropane ring prior to
undergoing Giese addition and/or metalation (Figure 5A). To
our astonishment, the major product from the reaction with
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Article
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AUTHOR INFORMATION
Corresponding Authors
■
Gary A. Molander − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States;
orcid.org/0000-0002-9114-5584; Email: g molandr@
sas.upenn.edu
Osvaldo Gutierrez − Department of Chemistry and
Biochemistry, University of Maryland, College Park,
Maryland 20742, United States; orcid.org/0000-0001-
8151-7519; Email: ogs@umd.edu
Authors
Mark W. Campbell − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States
Mingbin Yuan − Department of Chemistry and Biochemistry,
University of Maryland, College Park, Maryland 20742,
United States
Viktor C. Polites − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States
(11) Zhu, C.; Yue, H. F.; Chu, L. L.; Rueping, M. Recent advances in
photoredox and nickel dual-catalyzed cascade reactions: pushing the
boundaries of complexity. Chemical Science 2020, 11 (16), 4051−
4064.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13077
(12) Garcia-Dominguez, A.; Mondal, R.; Nevado, C. Dual
Photoredox/Nickel-Catalyzed Three-Component Carbofunctionaliza-
tion of Alkenes. Angew. Chem., Int. Ed. 2019, 58 (35), 12286−12290.
(13) Campbell, M. W.; Compton, J. S.; Kelly, C. B.; Molander, G. A.
Three-Component Olefin Dicarbofunctionalization Enabled by
Nickel/Photoredox Dual Catalysis. J. Am. Chem. Soc. 2019, 141
(51), 20069−20078.
Author Contributions
¶These authors contributed equally.
Funding
The authors are grateful for the financial support provided by
NIGMS (R35 GM 131680 to G.A.M.). O.G. acknowledges the
NIGMS NIH (R35GM137797) for funding and UMD
Deepthought2, MARCC/BlueCrab HPC clusters, and
XSEDE (CHE160082 and CHE160053) for computational
resources. M.W.C. is grateful for the financial support provided
by NSF Graduate Research Fellowships. The NIH supple-
ments awards 3R01GM118510−03S1 and 3R01GM087605−
06S1, and Vagelos Institute for Energy Science and
Technology supported the purchase of NMR spectrometers
used in this study
(14) Guo, L.; Tu, H. Y.; Zhu, S. Q.; Chu, L. L. Selective,
Intermolecular Alkylarylation of Alkenes via Photoredox/Nickel Dual
Catalysis. Org. Lett. 2019, 21 (12), 4771−4776.
(15) Guo, L.; Song, F.; Zhu, S. Q.; Li, H.; Chu, L. L. syn-Selective
alkylarylation of terminal alkynes via the combination of photoredox
and nickel catalysis. Nat. Commun. 2018, 9, 69049 DOI: 10.1038/
s41467-018-06904-9.
(16) Sun, S. Z.; Duan, Y. Y.; Mega, R. S.; Somerville, R. J.; Martin, R.
Site-Selective 1,2-Dicarbofunctionalization of Vinyl Boronates
through Dual Catalysis. Angew. Chem., Int. Ed. 2020, 59 (11),
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Notes
The authors declare no competing financial interest.
(17) Mega, R. S.; Duong, V. K.; Noble, A.; Aggarwal, V. K.
Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters
using Metallaphotoredox Catalysis. Angew. Chem., Int. Ed. 2020, 59
(11), 4375−4379.
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W. R.; Yuan, W. M. Selective 1,2-Aryl-Aminoalkylation of Alkenes
Enabled by Metallaphotoredox Catalysis. Angew. Chem., Int. Ed. 2020,
59, 17910−17916.
(19) Wang, X.; Han, Y. F.; Ouyang, X. H.; Song, R. J.; Li, J. H. The
photoredox alkylarylation of styrenes with alkyl N-hydroxyphthali-
mide esters and arenes involving C-H functionalization. Chem.
Commun. 2019, 55 (97), 14637−14640.
(20) Ouyang, X. H.; Li, Y.; Song, R. J.; Hu, M.; Luo, S. L.; Li, J. H.
Intermolecular dialkylation of alkenes with two distinct C(sp(3))-H
bonds enabled by synergistic photoredox catalysis and iron catalysis.
Science Advances 2019, 5 (3), eaav9839.
(21) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.;
MacMillan, D. W. C. Native functionality in triple catalytic cross-
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ACKNOWLEDGMENTS
■
The authors thank Dr. Charles W. Ross, III (University of
Pennsylvania) for obtaining HRMS data. We gratefully
acknowledge Dr. Mike Gao and Dr. Pat Carroll (University
of Pennsylvania) for acquiring X-ray crystal structures. We
acknowledge Frontier Scientific and Johnson-Matthey for fine
chemicals donations and Kessil Lighting for lights used in this
study.
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