Photoredox/Nickel-Catalyzed Single-Electron Tsuji–Trost Reaction: Development and Mechanistic Insights

Article abstract of DOI:10.1002/anie.201809919

A regioselective, nickel-catalyzed photoredox allylation of secondary, benzyl, and α-alkoxy radical precursors is disclosed. Through this manifold, a variety of linear allylic alcohols and allylated monosaccharides are accessible in high yields under mild reaction conditions. Quantum mechanical calculations [DFT and DLPNO-CCSD(T)] support the mechanistic hypothesis of a Ni⁰ to Ni^II oxidative addition pathway followed by radical addition and inner-sphere allylation.

Full text of DOI:10.1002/anie.201809919

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Accepted Article
Title: Photoredox/Nickel-Catalyzed Single-Electron Tsuji-Trost
Reaction: Development and Mechanistic Insight
Authors: Gary Molander, Jennifer Matsui, Alvaro- Gutierrez-Bonet,
Madeline Rotella, Rauful Alam, and Osvaldo Gutierrez
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10.1002/anie.201809919
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Photoredox/Nickel-Catalyzed Single-Electron Tsuji-Trost
Reaction: Development and Mechanistic Insight
Jennifer K. Matsui,† Álvaro Gutiérrez-Bonet,† Madeline Rotella,‡ Rauful Alam,† Osvaldo Gutierrez‡* and
Gary A. Molander†*
palladium/photoredox
cross-coupling,
facilitating
the
Abstract:
A
regioselective, nickel-catalyzed photoredox
allylation of secondary, benzyl, and a-alkoxy radical precursors
is disclosed. Through this manifold, a variety of linear allylic
alcohols and allylated monosaccharides are accessible in high
yields under mild reaction conditions. Quantum mechanical
calculations [DFT and DLPNO-CCSD(T)] support the
mechanistic hypothesis of a Ni(0) to Ni(II) oxidative addition
pathway followed by radical addition and inner-sphere allylation.
decarboxylative allylation of a-amino carboxylic acids.
Unfortunately, when Tunge and coworkers shifted to
intermolecular allylation chemistry, only unsubstituted allyl
groups were successfully coupled with alkyl carboxylic acid
13
partners.
Given the excellent precedent for merging photoredox and nickel
catalysis in alkylation reactions established by our laboratory
14
and others, we sought to expand this paradigm to radical-based
Tsuji-Trost reactions (Scheme 1). In particular, numerous radical
Over the course of the past 30 years, the Tsuji-Trost allylation
has been a workhorse reaction within the field of synthetic
precursors
(e.g.,
alkyltrifluoroborates,
carboxylates,
alkylsilicates, and 1,4-dihydropyridines) derived from diverse
1
organic chemistry. A particularly striking advantage of the
15
commodity chemicals have been developed. Although such
Tsuji-Trost reaction is the ability to forge C(sp3)–C(sp3) bonds
under mild reaction conditions, typically using palladium as the
transition metal in conjunction with an appropriate phosphine
reagents have been extensively utilized in conjunction with
16
17
photoredox/Ni dual cross-coupling with aryl- and alkenyl
electrophiles, we have also begun to expand the scope of
electrophilic partners for such transformations (e.g., using
2
ligand. Although the breadth of electrophilic allyl partners has
been quite thoroughly explored, nucleophilic partners have
18
19
20
isocyanate, acyl chloride, carboxylic acid, and acyl imide
primarily been limited to two-electron carbon- or nitrogen-
21
electrophiles ). In a continuation of that effort, the cost-effective
3
centered moieties (Scheme 1). Specifically, for C–C bond
nature of Ni-based catalysts and the slow b-hydride elimination
of alkylnickel species relative to that of palladium was
considered to investigate how this approach could be applied to
formation, “soft” nucleophiles (e.g., malonates) are frequently
employed, wherein addition occurs by an outer-sphere
mechanism.1
22
the Tsuji-Trost reaction.
The choice of nucleophile in these transformations is primarily
limited by pKa constraints, because anions derived from
pronucleophiles with pKa >25 are not appropriately tuned to
4
react with the incipient π-allyl transition metal intermediate.
Recent reports by Walsh and coworkers have pointed to the
utility of diarylmethane nucleophiles (pKa up to 32) in Pd-
catalyzed allylic substitution reactions, broadening the
5
6
nucleophile window of Tsuji-Trost reactions. Alternatively, Zn,
7
8
9
10
11
Sn, B, Mg, Si, and Li-based enolates have been used
successfully
as
nucleophilic
partners
in
related
transformations.2b, However, a major limitation of enolate-
based methods is the prerequisite for highly basic conditions. To
overcome these limitations, pioneering work by Tunge shifted
efforts toward radical-based intramolecular allylations via a
12
Scheme 1. Exploring radical-based Tsuji-Trost reactivity under photoredox conditions.
Vinyl epoxides have been employed previously in palladium-
23
catalyzed allylations, but to the best of our knowledge, reports
using a nickel-based catalyst — a non-precious, inexpensive
24
catalyst — are scarce, with only a few examples being reported
[a]
[b]
Dr. J. K. Matsui, Dr. A. Gutiérrez-Bonet, Dr. R. Alam, Prof. G. A.
Molander
Department of Chemistry
involving cycloaddition reactions. At the outset of substrate
exploration, a variety of benzyltrifluoroborates were selected;
early results demonstrated a diversity of electron-withdrawing
and electron–donating groups were accommodated (Table 1).
Additionally, modestly sterically hindered substrates could also
be used. For example, ortho-substitution afforded 62% of desired
product 1f. As the radical precursor search was expanded, a-
alkoxytrifluoroborates were next targeted. Generally, E/Z
selectivity was high, although the ratio was severely diminished
to 53:47 when tert-butyl ether moieties were explored (1j).
University of Pennsylvania
Roy and Diana Vagelos Laboratories, Philadelphia, Pennsylvania
19104-6323. United States of America
E-mail: gmolandr@sas.upenn.edu
M. Rotella, Prof. O. Gutierrez
Department of Chemistry and Biochemistry
University of Maryland
College Park, Maryland
20742, United States of America
Email: ogs@umd.edu
Moving forward, the breadth of carbon-centered radicals was
expanded by targeting unstabilized secondary alkyl radical
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809919
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precursors. Under the standard and modified reaction conditions,
secondary alkyltrifluoroborates formed complex mixtures (e.g.,
25
homocoupling, aldehydic side products). Therefore, DHPs (1,4-
dihydropyridines) were investigated as alternative radical
–
26
27
precursors
with 4CzIPN [2,4,5,6-tetra(9H-carbazol-9-
yl)isophthalonitrile] organophotocatalyst.
Table 1. Reactions were conducted on 0.50 mmol scale. Standard reaction
conditions employed butadiene monoxide (1.0 equiv), alkyltrifluoroborate (1.5
equiv), Ir[dFCF3ppy]2(bpy)PF6 (2 mol %), [Ni(dtbbpy)(H2O)4]Cl2 (3 mol %), and
2,6-lutidine
(3.5
equiv)
in
acetone/MeOH
(9:1).
aFor
a-
alkoxyalkyltrifluoroborates, a solvent mixture of acetonitrile/tert-butanol (10:1)
Table 2. Reactions were conducted on 0.50 mmol scale. Standard reaction
conditions employed butadiene monoxide (1.0 equiv), 1,4-dihydropyridine (1.5
equiv), 4CzIPN (2 mol %), and [Ni(dtbbpy)(H2O)4]Cl2 (3 mol %) in acetone. For
trifluoroborates, standard reaction conditions employed butadiene monoxide
(1.0 equiv), alkyltrifluoroborate (1.5 equiv), Ir[dFCF3ppy]2(bpy)PF6 (2 mol %),
[Ni(dtbbpy)(H2O)4]Cl2 (3 mol %), and 2,6-lutidine (3.5 equiv) in acetone/MeOH
(9:1). For a-alkoxyalkyltrifluoroborates, a solvent mixture of acetonitrile/tert-
butanol (10:1) was used.
was used.
During the exploration of various DHPs, heterocyclic (2a and
2e) and alkenyl moieties (2c) were successfully incorporated
within the coupling partners under the optimized reaction
conditions. A desire to integrate greater functional density within
the radical precursor led to the exploration of monosaccharide
moieties that were recently highlighted in publications from our
28
Finally, although the allylic alcohol products themselves are
versatile moieties, we aimed to make the protocol more general
group.
Pleasingly, pyranose DHP afforded the allylated
29
products 2i-j in high E/Z ratios and diastereoselectivity.
by exploring electrophiles as π-allylnickel precursors. First,
various leaving groups were surveyed (i.e., bromide, chloride,
Subsequently, substitution on the vinyl epoxide moiety was
probed, starting with methyl substitution on the requisite epoxide
(2f–2h). Notably, the stereochemical outcome of the
photoredox/Ni dual catalyzed alkylation is complementary to
that of the Pd-catalyzed transformations. The latter provide net
retention via double inversion,26 whereas in the present case 1,2-
epoxy-3,4-cyclohexene afforded primarily the trans isomer
(2m), suggesting the nickel coordinates the alkene and adds to
the opposite face of the epoxide, but then the resulting nickel
complex engages the radical and undergoes reductive
elimination by a stereoretentive, inner-sphere mechanism. This
hypothesis was further supported by both DFT and DLPNO-
CCSD(T) quantum mechanical calculations (vide infra).
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and carbonate), with allyl bromide affording the highest yield of
product under the initial reaction conditions.
Table 3. Expanding the allylic handle.
Table 4. All reactions were performed using 0.75 mmol of allyl bromide, 0.25
mmol of 1,4-dihydropyridine, 4CzIPN (2 mol %), [Ni(dtbbpy)(H2O)4]Cl2 (3 mol
%) in acetone with blue LED irradiation for 24 h.
Motivated by the advantageous biological properties demon-
strated by molecules containing alkyl-substituted carbohydrate
31
the underlying mechanism of this transformation. As shown in
30
substructures,
DHP monosaccharides were successfully
Figure 1 (squares), complexation of Ni(0) to vinyl epoxide (A’’)
is energetically favored over that of complexation to benzyl
radical (A’; presumably formed from the photocatalytic cycle,
see Supporting Information for energetics) by 8.9 kcal/mol.
Subsequently, this vinyl epoxide-Ni(0) (A’’) complex can
quickly undergo an SN2-like ring-opening (via A’’-TS; barrier is
only 3.1 kcal/mol from A’’) to form π-allylnickel(II)
intermediate B’’. As anticipated by previous calculations,32 the
nickel(II) intermediate B” can quickly engage the benzyl radical,
generated by SET oxidation of BnBF3K by the photocatalyst (see
Supporting Information for energetics), to form Ni(III)
intermediate C (via B’’-C-TS). Overall, radical addition is facile
(the barrier is ca. 1-3 kcal/mol, dependent on the method).
Finally, inner-sphere C(sp2)-C(sp3) bond formation via C-TSL
(the barrier is 8.9 kcal/mol from C) leads to formation of the
linear product (PL), 50.3 kcal/mol downhill in energy.
allylated under the dual catalytic conditions with modest to high
diastereoselectivities (Table 4). Pyranose and furanose
backbones with benzyl-, methoxy-, and dioxolane protecting
groups were conserved. Further studies on substituent effects
were conducted using difluoroallyl bromide. Under the
established reaction conditions, 4c was isolated as a single
regioisomer. Presumably, oxidative addition to allyl bromide
followed by bromide expulsion generates the key π-allylnickel
complex which, via an inner-sphere mechanism (vide infra),
intercepts the a-alkoxy radical to undergo diastereoselective
reductive elimination, forming the allylated products.
Intrigued by the stereoselectivity of these processes and
questions regarding the order of reaction events, quantum
mechanical calculations were undertaken to gain insight into
Figure 1. Competing Ni(0)/Ni(I)/Ni(III) (circles), Ni(0)/Ni(II)/Ni(III) (squares), Ni(0)/Ni(II) (squares-triangles), pathways leading to C(sp3)-C(sp3) bond formation
.
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systems, as opposed to the net retention via double inversion
observed in the traditional Pd-catalyzed processes.
A series of reductive elimination transition states leading to for-
mation of branched product (e.g., C-TSB) were also located, but
these were much higher in energy (>5 kcal/mol) than C-TSL,
presumably because of unfavorable electronic repulsion and
steric interactions between the charged oxygen and the benzyl
group. Moreover, C(sp2)-C(sp3) bond formation via an outer
sphere pathway (squares-triangles) was also found higher in
energy. Formation of Ni(III) complex C from a Ni(0)-Ni(I)-
Ni(III) pathway (Figure 1, circle) is also overall higher in energy
than the Ni(0)-Ni(II)-Ni(III) pathway (squares). Albeit low, the
barrier for radical addition (A-TS) from Ni(0) is still 7.3
kcal/mol higher in energy than oxidative addition to vinyl
epoxide (via A’’-TS). However, it is likely that formation of C
is highly dependent on the local concentration of benzyl radical
and vinyl epoxide. Overall, DFT and DLPNO-CCSD(T)
calculations support a Ni(0)-Ni(II)-Ni(III) reaction pathway and
an inner sphere reductive elimination as the product-determining
step, leading to formation of the linear product as the major
To gain insight into the mechanistic pathway, studies
incorporating quantum mechanical calculations [using
dispersion corrected (U)DFT and DLPNO-CCSD(T) methods]
were conducted to determine the energetic favorability of the
oxidative addition step. Here, a Ni(0) to Ni(II) oxidative addition
step was calculated to occur before radical addition to the nickel
center; this is a deviation from previous mechanistic studies of
photoredox/Ni dual cross-coupling pathways where Ni(0) to
Ni(I) has been involved in the putative pathway.32 Given the mild
reaction conditions and availability of numerous radical
precursors, the disclosed method provides a useful complement
to the traditional, palladium-catalyzed Tsuji-Trost reaction.
Acknowledgements
33
product. This model is in accord with the stereochemical results
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.K.M. is supported by the Bristol-Myers
Squibb Graduate Fellowship for Synthetic Organic Chemistry.
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. Charles W. Ross,
III (University of Pennsylvania) for assistance in obtaining
HRMS data. Additionally, Dr. Jun Gu (University of
Pennsylvania) and Matt Bunner (University of Pennsylvania)
assisted in the acquisition and analysis of NMR data. The
alkyltrifluoroborates and the iridium (for photocatalyst
synthesis) were generously donated by Frontier and Johnson-
Matthey, respectively.
observed with cyclohexadiene monoxide (Table 2, 2m). Further,
although computational studies favored the linear product, the
branched pathway is only 5 kcal/mol higher in energy,
suggesting branched products may be observed in some cases
(likely dependent on the nature of the substrate, ligand, etc.). To
test this hypothesis, we subjected sterically hindered aryl-
substituted vinyl epoxides to the standard reaction conditions
and indeed found a mixture of linear and branched products,
albeit in low yields (Scheme 2).
Abbreviations
DHP, 1,4-dihydropyridine; SET, Single Electron Transfer;
4CzIPN, 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile.
Scheme 2. Observation of linear and branched mixtures.
Conflict of interest
In summary, a dual catalytic allylation reaction is reported that
demonstrates complementarity to traditional Tsuji-Trost reac-
tions. In juxtaposition with classical reactivity in the Pd-
catalyzed transformations (stabilized anionic carbon
nucleophiles), carbon-centered radicals were employed,
enabling the allylation of secondary, benzyl, and a-alkoxy
radical precursors. Additionally, net inversion of
stereochemistry is observed in the photoredox/Ni dual catalyzed
The author declare no conflict of interest.
Keywords: Photoredox, Nickel Catalysis, 1,4-Dihydropyridines,
Allylation, Tsuji-Trost
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31 For all of the calculations, dispersion-corrected, broken-spin (U)DFT functionals (UM06/6-311+G(d,p)-SMD(water)//UB3LYP/6-31G(d) and
UB3LYP-D3/6-311+G(d,p)-SMD(water)//UB3LYP/6-31G(d)) were used. Further, the energy profile using dynamic correlation, open-shell
domain-based local pair natural orbital coupled-cluster calculations (DLPNO-CCSD(T)/def2-TZVPP-SMD(water)//UB3LYP/6-31G(d)) were
compared, which are known to provide accurate energies (within 3 kJ mol-1) with the computational cost comparable to DFT calculations.
Overall, all methods provided similar conclusions (See Supporting Information for further details). For simplicity, only UM06/6-311+G(d,p)-
SMD(water)//UB3LYP/6-31G(d) energies will be discussed in the manuscript.
32 O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander, M. C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 4
896-4899
33 We also considered the protonation of B’’ followed by: (i) outer-sphere C(sp2)–C(sp3) bond formation and (ii) radical addition, with subsequent
inner sphere C(sp2)–C(sp3) bond formation. However, the barriers for both protonated inner sphere and outer sphere pathways were higher in
energy than the anionic pathway (see Supporting Information).
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inner-sphere
mechanism
O
O
OH
N
R
Ni
+
PC
Ni
N
R
RP
R = benzyl, secondary alkyl,
α-alkoxy
R
Dr. Jennifer K. Matsui, Dr. Álvaro Gutiérrez-Bonet, Madeline Rotella, Dr. Rauful Alam, Professor Osvaldo Gutierrez and
Professor Gary A. Molander
Shining New Light. Herein, we report a highly regioselective, intermolecular, nickel-catalyzed photoredox allylic substitution that
expands both the radical and electrophile scope of dual photoredox/Ni-catalyzed reactions. Quantum mechanical calculations shed
light on the disclosed mechanistic pathway, supporting a Ni(0) to Ni(II) oxidative addition followed by an inner-sphere radical
addition.
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