Dual Cobalt and Photoredox Catalysis Enabled Intermolecular Oxidative Hydrofunctionalization

Article abstract of DOI:10.1021/acscatal.0c01209

A general protocol has been developed for the Markovnikov-selective intermolecular hydrofunctionalization based on visible-light-mediated Co/Ru dual catalysis. The key feature involves the photochemical oxidation of an organocobalt(III) intermediate deriv

Full text of DOI:10.1021/acscatal.0c01209

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Letter
Dual Cobalt and Photoredox Catalysis Enabled
Intermolecular Oxidative Hydrofunctionalization
Han-Li Sun, Fan Yang, Wei-Ting Ye, Jun-Jie Wang, and Rong Zhu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01209 • Publication Date (Web): 09 Apr 2020
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ACS Catalysis
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Dual Cobalt and Photoredox Catalysis Enabled Intermolecular
Oxidative Hydrofunctionalization
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Han-Li Sun, Fan Yang, Wei-Ting Ye, Jun-Jie Wang and Rong Zhu*
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Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871,
China
Supporting Information Placeholder
eventually lead to traditional radical-based reactions via Co−C
bond homolysis. For instance, the resulting radical D once escaped
from a solvent cage could dimerize, abstract a halogen atom, or
react with trace dioxygen. It is thus predicted that the reaction
efficiency would be largely limited by the electronic property of
the alkyl group in A and the nucleophilicity of the reaction
partner.10 In other words, the outcome would be highly
substrate-dependent. Indeed, we observed contrasting behaviors
of p-methoxystyrene (2a) and p-chlorostyrene (2b) under the
standard reaction conditions (Scheme 1c). The former produced
Markovnikov adduct in quantitative yield, while the latter virtually
only underwent reductive dimerization.
ABSTRACT: A general protocol has been developed for the
Markovnikov-selective intermolecular hydrofunctionalization
based on visible-light-mediated Co/Ru dual catalysis. The key
feature involves the photochemical oxidation of an
organocobalt(III) intermediate derived from hydrogen atom
transfer, which is supported by electrochemical analysis, quenching
studies and stoichiometric experiments. This redox process
enables
the
efficient
branch-selective
alkylation
of
pharmaceutically important nucleophiles (phenols, sulfonamides
and various N-heterocycles) using a wide range of alkenes
including moderately electron-deficient ones. Moreover,
light-gated polar functionalization via organocobalt species was
demonstrated.
In order to overcome this limitation by
a
general
catalyst-controlled solution, a natural thought would be to modify
the structure of the cobalt salen complex. However, such
approach would likely lead to marginal effect because both A and
C are subjected to change in a rather similar way. Therefore, we
sought an alternative mechanism involving a stronger catalytic
oxidizing species that is compatible with the HAT conditions. In
this work, we report the realization of this approach via a merger
of a photoredox cycle with HAT catalysis. The dual catalysis
significantly expands the viable redox window, and thus leads to
an efficient and general single-step entry into a range of
pharmaceutically relevant structures. The regioselectivity and
scope of this protocol complement established methodologies, for
KEYWORDS: Hydrogen Atom Transfer, Radicals, Cobalt, Photoredox
Catalysis, Hydrofunctionalization
The Brønsted acid-mediated intermolecular Markovnikov addition
has been known for more than a hundred years.1 On paper, it
offers
pharmaceutically
a
straightforward and modular approach to many
relevant structures such as
branched-alkyl-substituted phenols and N-heterocycles, without
resorting to pre-activated coupling partners or subsequent
multi-step conversions (Scheme 1a).2 Not surprisingly, such
transformations in practice are often complicated by the
thermodynamically disfavored protonation process and
high-energy carbocations involved.3 To this, chemists have been
searching for catalytic alternatives mimicking this process in a
more controlled fashion.4 Guided by the rich literatures on the
first-row transition metal,5 in particular the cobalt-catalyzed
hydroelementations via hydrogen atom transfer (HAT),6 we
recently introduced an I(III)-promoted intermolecular oxidative
example
the
anti-Markovnikov
dehydrogenative
hydrofunctionalizations via cobaloxime catalysis.11 In addition, we
provide a rare example where the polar reactivity of an
organocobalt intermediate was gated by external physical stimuli.
To assist the design, we began by evaluating the electrochemical
properties of cobalt salen complexes 1a and 1b, as well as an
alkylcobalt(III) complex 6 bearing an isopropyl group as a model
for A (Scheme 1c).12 The E1/2 for the 1a+/1a redox couple locates
at −0.02 V vs Fc+/Fc in dichloromethane, and is slightly lower
than that of the 1b+/1b couple (0.11 V).13 Complex 6 displayed an
irreversible oxidation wave at Ep/2 = −0.01 V vs Fc+/Fc, likely
corresponding to the R−Co(III)/R−Co(IV) oxidation based on
hydrofunctionalization reaction catalyzed by
a cobalt salen
complex.7 Highly chemo- and regio-selective additions to
unactivated terminal olefins and electron-rich styrenes have been
realized with a number of heteroatom-based nucleophiles, which
includes carboxylic acids, phenols, and sulfonamides. More
recently, benzotriazoles have also been added as viable reaction
partners by Yahata and Akai.8 A key mechanistic hypothesis of this
transformation involves the oxidation of an organocobalt(III)
intermediate A into a Co(IV) species B, an organometallic radical
cation that displays polar reactivity (Scheme 1b).9 Our studies
suggested that a Co(III)−X complex (X = counterion/anionic
ligand) C likely functions as the oxidant for this process, whose
reduction potential lies close to the oxidation potential of A.
14
literature reports.9a, The measured potentials corroborates the
previous mechanistic hypothesis regarding the SET between Co
complexes, which was further supported by
a titration
experiment.15 It is noted that the Co complexes undergo additional
redox events at both more positive and negative parts of the
spectrum. Ideally, a photoredox catalyst should not trigger such
undesired processes.
Guided by the electrochemical data, we envisioned that the excited
state of Ru(bpy)32+ (bpy = 2,2’-bipyridyl, E1/2[*RuII/RuI] = 0.77 V
vs SCE in acetonitrile) might allow for the efficient oxidation of
organocobalt(III) complex A.16 A proposed catalytic cycle is
depicted in Scheme 1e. It commences with the formation of A via
HAT between a Co−H species and an alkene 2 followed by cage
collapse. The key step might involve the facile reductive quenching
of visible light-generated *Ru(II) by A, which would efficiently
produce the electrophilic Co(IV) complex B with minimal reverse
As part of the continuing effort exploring the oxidative
functionalization of organocobalt complexes in catalysis by a
mechanistic-driven approach, it came to our attention that such
reversible electron transfer between cobalt species could be a
major limiting factor. When either the oxidation of A or the
following nucleophilic trapping of B is sluggish, significant
increase in the concentration of A is anticipated, which would
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Scheme 1. Mechanistically-Guided Design of a Dual-Catalysis Approach to Broad-Spectrum Oxidative Hydrofunctioalization.
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2
3
4
5
6
7
a) Representative Disconnections Call for Chemoselective Intermolecular Hydrofunctionalization
d) Cyclic Voltammetry Curves of Co Complexes
Scan rate = 0.1 V/s
0.1 M NBu4ClO4 in CH2Cl2
Ar
Ar
CF3
N
O
tBu
N
O
tBu
H
Co
1a
N
tBu
tBu
tBu
tBu
CF3
N
N
N
HO
H
O
Me Me
O
20 A
Ar = 4-tBuC6H4
HO2C
Ph
NHMe
O
NH
NH
N
O
tBu
N
O
tBu
H
Ph
NHMe
Co
N
CO2H
6
Glucagon Receptor Antagonist
Fluoxetine
Me
Me
Me
8
9
5 A
Me
b) Challenge in Oxidative Hydrofunctionalization via HAT: Competing Pathways
N
N
Co
tBu
O
tBu
O
tBu
1b
LnCoII
tBu
LnCoIII
X
10
11
12
13
14
15
16
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C
Potential (V) vs. Fc+/Fc
R1
R2
Reacts via
Polar Pathways
e) Design of a General Solution via Visible Light-Mediated Co/Ru Dual-Catalysis
X
L
nCoIV
H
R1
R1
R2
B
R2
L
nCoII
H
2
L
nCoIII
Radical
Pathways
LnCoIII
R3Si OH(F)
H
R1
A
LnCoII
R2
Ln = Salen
HAT
Reacts via
Radical Pathways
D
R1
HAT Intermediate
R2
D
Ru(II)
Ru(II)
R3Si
H
+0.77 V
vs SCE
c) Example: Major Limitations Posed by Mismatched Redox Properties
R1
L
R2
LnCoIII OH(F)
nCoIII
Redox Matching
R
I
Me
O
SET
O


Low Co Loading
Broad Scope
e-Deficient Alkenes
Various Heterocycles
Photocontrolled Reactivity
A
-1.33 V
vs SCE
Ru(I)
Me
R
O
OTf
Me
or
1a
3 mol%
O
O
+
+
I
O
Me
N
F
I
Me
(Me2HSi)2O,
CH2Cl2, r.t.
OH
R
3
7

OH
Me
R
R1
Ln
2 e Oxidant
LnCoII
2
3
4
5
R2
CoIV
Hydrofunctionalization Reductive Dimerization
R
B
R1
R2
2a
2b
> 97%
Successful
Failed
OMe
Cl
n.d.
Nu
H
H
9%
81%
Nu
reaction. B is subsequently trapped by a nucleophile to give the
Markovnikov adduct. The resulting Ru(I) and Co(II) complexes
then react with a stoichiometric two-electron oxidant, either the
hypervalent iodine reagent 3 or an N-fluoropyridinium salt 7, to
regenerate Ru(II) and Co(III) species, respectively. The latter
finally reacts with a silane and return to the inital Co−H complex.
It is noted that an alternative mechanism involving the oxidative
quenching of *RuII cannot be excluded.
Table 1. Evaluation of the effect of photoredox catalysts.a
Cl
I
[Co]
PC
, Light
3 mol%
, 1 mol%
3
2.0 equiv.
2.0 equiv. (Me2HSi)2O
Me
Cl
O
+
O
Me
Cl
CH2Cl2, r.t.
Me
4b
Cl
2b
5b
Entry [Co]
PC
Light
-
4b (%) 5b (%)
1
2
1a
1a
1b
1b
-
-
Ru(bpy)3
-
9
81
9
2+
To test this hypothesis, we first evaluated the oxidative HAT
hydrofunctionalization reaction of 2b with 3 and a silane at room
temperature (Table 1). Compared to the original reaction catalyzed
solely by 3 mol% Co complex 1a (entry 1), the addition of 1 mol%
Ru(bpy)3Cl2•6H2O accompanied by blue LED irradiation
effectively suppressed the reductive dimerization and inverted the
selectivity completely, affording 4b in over 80% yield (entry 2).
The dark reaction using 1b gaves 30% yield of 4b, presumably due
to the slightly higher E1/2 of 1b+/1b (entry 3). The combination of
1b and the photoredox conditions further pushed the reaction to
quantitative conversion without observing any dimer formation
(entry 4). Control experiments under light irradiation leaving out
the Co or Ru catalyst confirmed the essential roles of both (entries
5-7). We next examined a few alternative metal-based photoredox
catalysts. For example, fac-Ir(ppy)3 (ppy = 2-phenylpyridine) did
not promote the desired transformation (entry 8). This could be
attributable to either the strongly reducing nature (E1/2[IrIV/*IrIII]
= −1.73 V vs SCE) or the high triplet state energy (57.8 kcal/mol)
that interferes with the HAT cycle, which also indicates that
energy transfer catalysis is unlikely involved in the productive
mechanism.17 Therefore, Ru(bpy)32+ seems to hit a sweet spot with
regard to redox matching, which is consistent with the observation
made with a different Ru catalyst of similar redox properties (entry
9). Finally, the loading of 1b in the dual catalyst system could be
reduced to 1 mol% without compromising the yield (entry 10).
460 nm
-
83
3
30
59
2+
2+
2+
4
Ru(bpy)3
Ru(bpy)3
Ru(bpy)3
-
460 nm
460 nm
-
97
n.d.
n.d.
59
5
n.d.
15
6
1b
1b
1b
1b
1b
7
460 nm
380 nm
410 nm
460 nm
31
57
8
fac-Ir(ppy)3
< 5
n.d.
n.d.
n.d.
2+
9
10b
Ru(phen)3
89
2+
Ru(bpy)3
98 c
aStandard conditions: 2b (0.10 mmol), 1b (3 mol%), photocatalyst (1 mol%),
(Me2SiH)2O (0.20 mmol), 3 (0.20 mmol) in 1.0 mL CH2Cl2 at r.t. for 18 h. The
yields were determined by 1H NMR analysis of the crude reaction mixture. The
yields of 5b refer to the corresponding 2b converted. See Table S2 for details. b
2a (0.30 mmol), 1b (1 mol%), photocatalyst (1 mol%), (Me2SiH)2O (0.60 mmol),
3 (0.60 mmol) in 1.0 mL CH2Cl2 at 25 ˚C for 36 h. cIsolated yield.
The divergent reactivities observed in the presence/absence of
light prompted us to compare their kinetic profiles (Figure 1a).
The light-mediated reaction displayed substantially greater rate
throughout the course of the reaction (plot 1). In contrast,
induction periods of different lengths were observed for both the
formation of 4b (plot 3) and 5b (plot 4) in the absence of light.
Interestingly, the reductive dimerization started to take off at t = 4
h, then rapidly overwhelmed the desired transformation, which
seems to reflect a dynamic equilibrium involving cobalt species.
The light-controlled switch was clearly illustrated by a reaction
carried out with intermitent irradiation (plot 2, light exposure
between t = 4-6, 7.5-9 h). It is well-known that the homolysis of
an organocobalt(III) can be photochemically controlled, a feature
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ACS Catalysis
that is particularly useful for radical polymerizations.18 However,
light-regulation of polar reactivity has been essentially
unexplored.19 To this, our dual catalyst system seems to provide an
interesting demonstration.
1
2
3
To further probe whether such dramatic improvement stems from
the photochemical oxidation of the organocobalt(III) intermediate
A as proposed, Stern-Volmer quenching studies were carried out
(Figure 1b). The excited state *Ru(II) was found to be readily
quenched by the model compound 6, which is consistent with the
hypothesized reductive quenching process. Meanwhile, the
stoichiometric oxidant 3 did not quench *Ru(II) efficiently, which
is in line with the reduction potential in literature (< −0.8 V vs.
SCE).20 In addition, mixing 6 and 3 either in the presence or
absence of the Ru catalyst in dark resulted in no oxidative
4
5
6
7
8
9
O
O
10
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Me
Me
I
OH
3
O
I
Me
Me
Conditions
Yield(%)
10 equiv.
N
O
N
O
Co
N
O
In dark
n.d.
tBu
tBu
THF, r.t.,15 min
functionalization product
8
as expected from measured
10% Ru(bpy)3Cl2•6H2O, In dark n.d.
10% Ru(bpy)3Cl2•6H2O, 460 nm 15
tBu
tBu
Conditions
8
electrochemical data (Figure 1c). However, when the
photocatalyst-containing mixture was exposed to blue light, 8 was
formed in 15% yield. Collectively, these results strongly support
that an analogous photochemical oxidation of A by Ru species
might take place in the catalytic reaction.
6
Figure 1. Mechanistic Studies. a) Reaction profiles. Conditions: 2b (1.0 equiv.),
3 (2.0 equiv.), (Me2SiH)2O (2.0 equiv.) at r.t. in CH2Cl2. ●/○: 3% 1b, 1% [Ru];
■/▲: 3% 1b only. Solid lines: exposed to 460 nm light; dash lines: in the
2+
absence of light. b) Stern-Volmer quenching studies of Ru(bpy)3 in the
prescence of 3 or 6. c) Stoichiometric experiments showing that photochemical
oxidation of 6 led to oxidative functionalization product. The yields were
determined by 1H NMR analysis of the crude reaction mixtures.
Scheme 2. Scope of the Dual-Catalyzed Oxidative Hydrofunctionalization via HAT.a
a) Evaluation of the Scope of Styrene Derivativesb
b) Addition of Phenolsc
F3C
1b
3 mol%
1% Ru(bpy)3Cl2•6H2O
3
, (Me2SiH)2O
1b
1 or 3 mol%
O
1% Ru(bpy)3Cl2•6H2O
2.0 equiv. (Me2SiH)2O
O
I
CF3
Z
O
O
R
+
+
O
Z =
R
Ar
Ar
CH2Cl2, r.t.
Me
CH2Cl2, r.t.
I
HO
Br
OH
460 nm
460 nm
2.0 equiv.
Br
2
3
4
2.0 equiv.
9a
38% (1%)
CF3
1% [Co]
3% [Co]
-Substituted Styrenes
Electron-Deficient
Styrene
Z
CF3
Z
Z
Me
O
Me
H
O
ref. 2a
Same Above
tBuO
N
Ph
Cl
75% (3%)
Ph
Cl
Ph
Cl
R
Ph
N
38%
N
O
O
Single-Step
4f
4h
86% (3%)
Yield
R
9b
Antifungal
Vinyl
Heteroarene
Z
4b
4c
4d
4e
Cl
H
F
98% (8%)
99% (6%)
99% (5%)
95% (4%)
Z
Me
Previous Routes
2-3 Steps
O
Ph
OAc
Br
MeO
N
Ph
Cl
4g
4i
66%
58%
c) N-Alkylation of Heterocycles and Sulfonamidesd
1b
3 mol%
Pyrazoles
Ph
1% Ru(bpy)3Cl2•6H2O
2.0 equiv. (Me2SiH)2O
Ph
Ph
Nu
N
N
7
1.2 equiv.
DCE, r.t.
460 nm
R
N
N
N
N
+
NuH
R
Ar
Ar
Ph
10a
10b
49%e
F
2
2.0 equiv.
Boc
Me
82% (47%)
Me
10
Indazolesf
Cl
tBuO
O
X-ray
Cl
I
Cl
N
Cl
CO2Me
N
N
Ph
N
N
N
N
NH
O
N
Cl
Me
N
N
Me
Me
I
Me
10c
10d
10e
10f
10gg
N2:N1= 5.0 : 1
N2:N1= 4.0 : 1
N2: 67% (32%)
N2:N1= 4.1 : 1
N2: 70%
N2:N1= 3.9 : 1
N2: 69%
N2:N1= 6.7 : 1
N2: 49%
N2 + N1: 69% (13%)
Imidazoles
Carbazoles
Sulfonamides
Me
O
O
S
Br
Br
NHTs
Me
N
N
N
N
N
N
H
N
N
N
Cl
F3C
CF3
Me
CF3
Me
Cl
Cl
Me
10h
Me
Derivatization of Celecoxib
Cl
Br
MeO2C
10m
10k
62%
10l
54% (35%)
10i
10j
50% (29%)
54%
41% (26%)
54%
Me
a Unless otherwise noted, yields correspond to isolated, analytically pure materials. Yields of control reactions performed in the absence of light and photocatalyst (shown in
parentheses) were estimated by 1H NMR analysis of crude reaction mixtures. b Conditions: 2 (0.30 mmol), 1b (1 or 3 mol%), photocatalyst (1 mol%), (Me2SiH)2O (0.60
mmol), 3 (0.60 mmol) in 1.0 or 3.0 mL CH2Cl2 with blue LED irradiation at r.t. c Conditions: 2 (0.30 mmol), 1b (3 mol%), photocatalyst (1 mol%), (Me2SiH)2O (0.60 mmol),
d
3 (0.60 mmol), 4-trifluoromethylphenol (0.60 mmol) in 3.0 mL CH2Cl2 with blue LED irradiation at r.t. Conditions: 2 (0.30 mmol), 1b (3 mol%), photocatalyst (1 mol%),
e
1
(Me2SiH)2O (0.60 mmol), 7 (0.36 mmol), NuH (0.60 mmol) in 3.0 mL 1,2-dichloroethane with blue LED irradiation at r.t. Determined by H NMR analysis of the crude
1
reaction mixture. f The regiomeric ratios were determined by H NMR analysis of the crude mixtures. The major isomers were shown. The yields correspond to isolated
N2-adduct except 10g. g10 mol% 1b was used.
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electrochemical analysis. It enables the previously difficult addition
of important nucleophiles, such as phenols and various
N-hetereocycles. Assisted by the photoredox cycle, 1 or 3 mol%
Co catalyst was sufficient to attain a good yield in most cases.
Mechanistically, quenching studies and stoichiometric reactions
provided evidence for the involvement of photochemical
oxidation of organocobalt(III) species. Based on these results
along with the observed light-gated conversion, we anticipate
possible spatial-temporal control on this bifurcated radical/polar
reactivity, which may find applications in a broader context.
1
2
3
4
5
6
7
8
With these results in hand, we set out to apply the new dual
catalysis protocol to a series of vinylarene substrates (Scheme 2a).
They typically failed or led to very low turnover number under
previous oxidative hydrofunctionalization conditions as indicated
by the results of control experiments shown in parentheses.
Quantitative to good yields were obtained for styrenes,
-substituted styrenes and a vinylpyridine derivative (4b-i). In all
cases, no reductive dimerization was detected. It is worth noting
that a moderately electron-withdrawing amide group at the
para-position is well tolerated, showcasing the significantly
expanded redox window brought by the photoredox cycle (4f).21
The fact that such alkenes can be functionalized directly represents
an additional notable advantage over traditional acid-mediated
processes besides chemoselectivity.
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Corresponding Author
* rongzhu@pku.edu.cn
Notes
The authors declare no competing financial interest.
This protocol proved readily amenable for phenol addition
(Scheme 2b). The yields were moderate because of the competing
addition of 2-iodobenzoic acid. Nonetheless, it allows for
single-step modular assembly of useful structures that would
otherwise require multi-step synthesis. For instance, starting from
simple cinnamyl chloride, one could rapidly access 9b, which is a
common intermediate en route to a series of biologically active
ASSOCIATED CONTENT
Supporting
Information.
Experimental
procedures,
characterization, crystal structure and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
b
molecules.2a, While the highly reactive allylic C−Cl bond in
ACKNOWLEDGMENT
cinnamyl chloride is typically susceptible to nucleophiles including
low-valent transition metal complexes, it did not interfere with the
nucleophile addition under the oxidative hydrofunctionalization
conditions.
Financial support was provided by the Natural Science Foundation
of China (21901011), the “Thousand Talent Plan” Youth Program,
and startup fund from College of Chemistry and Molecular
Engineering, Peking University and BNLMS. The authors would
like to thank Dr. Qing Zhang (PKU) for kind assistance, and Dr.
Jie Su (PKU) for X-ray crystallography.
To further demonstrate the synthetic utility and generality of this
method, we next show that a reasonably broad scope of
nitrogen-based heterocycles can be efficiently alkylated using 3
mol% catalyst 1b (Scheme 2b). This includes pyrazoles (10a-b),
indazoles (10c-g), imidazoles (10h-i) and carbazoles (10j-k). To
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a
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3
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ee).
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Cl
H
LnCoII
R1
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Ru
R1
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CO2Me
N
nCoIV
N
nCoIII
L
R2
Radical Pathways
460 nm
H
I
Polar Pathways
CoH
3% [Co], 1% [Ru], 69% Yield
Broad Scope
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Hydrofunctionalization
Light-Gated Reactivity
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