Switching on elusive organometallic mechanisms with photoredox catalysis

Article abstract of DOI:10.1038/nature14875

Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(iii) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(iii) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

Full text of DOI:10.1038/nature14875

LETTER
doi:10.1038/nature14875
Switching on elusive organometallic mechanisms
with photoredox catalysis
Jack A. Terrett1, James D. Cuthbertson1, Valerie W. Shurtleff1 & David W. C. MacMillan1
Transition-metal-catalysed cross-coupling reactions have become and aryl pseudohalides1,2. Hartwig and colleagues have reported a
one of the most used carbon–carbon and carbon–heteroatom
bond-forming reactions in chemical synthesis. Recently, nickel
catalysis has been shown to participate in a wide variety of C2C
bond-forming reactions, most notably Negishi, Suzuki–Miyaura,
Stille, Kumada and Hiyama couplings1,2. Despite the tremendous
advances in C2C fragment couplings, the ability to forge C2O
bonds in a general fashion via nickel catalysis has been largely
unsuccessful. The challenge for nickel-mediated alcohol couplings
has been the mechanistic requirement for the critical C–O bond-
forming step (formally known as the reductive elimination step) to
occur via a Ni(III) alkoxide intermediate. Here we demonstrate that
visible-light-excited photoredox catalysts can modulate the pre-
ferred oxidation states of nickel alkoxides in an operative catalytic
cycle, thereby providing transient access to Ni(III) species that
readily participate in reductive elimination. Using this synergistic
merger of photoredox and nickel catalysis, we have developed a
highly efficient and general carbon–oxygen coupling reaction
using abundant alcohols and aryl bromides. More notably, we have
developed a general strategy to ‘switch on’ important yet elusive
organometallic mechanisms via oxidation state modulations using
only weak light and single-electron-transfer catalysts.
Visible-light-mediated photoredox catalysis has gained momentum
over the past decade as a platform for the development of novel syn-
thetic transformations via the implementation of non-traditional
open-shell mechanisms. This catalysis field employs transition metal
polypyridyl complexes or organic dyes that, upon excitation by visible
light, readily engage in an array of single-electron transfer (SET) pro-
cesses3–5 that often include oxidation, reduction or redox pathways
that have previously been elusive6–9. Indeed, several research groups
have demonstrated that photoredox catalysis can be combined with
transition metal catalysis to achieve a series of unique bond-forming
reactionsthat take advantageof theknown reactivityof each individual
mode of catalysis10–16. We recently questioned whether the combina-
tion of photoredox catalysis and transition metal catalysis might be
capable of delivering fundamentally new organometallic reactivity by
providing access to currently unknown or inaccessible mechanistic
pathways.
Ni(COD)2-catalysed aryl etherification at elevated temperature using
three preformed oxides, namely sodium methoxide, ethoxide and
tert-butyldimethylsiloxide with electron-deficient aryl bromides26.
However, a general nickel-catalysed C–O coupling strategy under
mild conditions has thus far been elusive and no examples with alco-
hols have been documented. We recently questioned whether photo-
redox catalysis might be used to modulate the range of nickel alkoxide
oxidation states that can be accessed during a conventional catalytic
cycle. More specifically, we recognized that it should be possible to
utilize the photonic energy of weak visible light to expand thermo-
dynamically the number of nickel-catalyst oxidation states via two
discrete photocatalyst SET events: first, oxidation of Ni(II) to the
elusive Ni(III)–alkoxide complex (which we assumed would facilitate
the critical C–O bond-forming step); and second, reduction of Ni(I) to
Ni(0), to enable the subsequent aryl bromide oxidative addition steps.
If successful, we recognized that this new synergistic catalysis pathway
might provide (1) the first general example of a nickel-catalysed C2O
coupling reaction employing simple alcohols and aryl halides, and
OH
Br
O
Pd, Cu = common
Ni = elusive
Alcohols
Aryl halides
C–O coupling
Energetic profiles of reductive elimination reactions to form C–O bonds
E
C
O
C
O
C
O
L
L
L
L
L
L
PdII
NiII
NiIII
C–O
C–O
C–O
PdII: exothermic
NiII: endothermic
NiIII: exothermic
In a series of seminal studies, Hillhouse and colleagues demonstrated
that Ni(II) alkoxide complexes do not readily undergo reductive elim-
ination at ambient or elevated temperature and that stoichiometric
conversion to a less stable Ni(III) system is required for productive
C–O bond formation17–19. Similarly, C–heteroatom reductive elimina-
tion has been demonstrated when stoichiometrically accessing Ni(IV)
intermediates20,21. In fact, computational studies have revealed that
Ni(II) alkoxide reductive elimination is endothermic, in contrast to
Pd, Pt or alkyl Ni(II) variants, which are exothermic (Fig. 1)22.
Indeed, the use of palladium and copper catalysis to generate aryl ethers
from alcohols is well precedented and broadly employed23–25. The util-
ization of nickel catalysis in C–O bond construction would be an
important complementary method, considering the diversity of elec-
trophiles amenable to nickel cross-couplings, such as alkyl halides
Can dual catalysis unlock previously inaccessible mechanistic pathways?
e
L
L
L
L
OR
Ar
OR
Ar
NiII
NiIII
*IrIII
IrII
Inert to reductive
elimination
Facile reductive
elimination
Figure 1
|
Modulating oxidation states of nickel enables challenging
carbon–heteroatom coupling. Pd(II)-catalysed C–O reductive elimination is
an exothermic process and well precedented. Ni(II) C–O reductive elimination
is thermodynamically disfavoured—we postulated that accessing Ni(III) by
photoredox-mediated oxidation state manipulation could switch on C–O
coupling in a general fashion, circumventing this thermodynamic restriction.
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.
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RESEARCH LETTER
(2) a demonstration of a new strategy by which elusive organometallic Ni(II) complex 3 and the highly oxidizing photoexcited *Ir(III) 5 to
couplings can be ‘switched on’ via oxidation state modulation.
A detailed description of our proposed mechanistic cycle for the
photoredox/nickel-catalysed C2O coupling is outlined in Fig. 2a.
Oxidative addition of Ni(0) (species 1) into an aryl bromide would
deliver a Ni(II) aryl complex 2 (ref. 27). At this stage, ligand exchange
(displacement of the bromide ion with the substrate alcohol) would
produce the Ni(II) aryl alkoxide (3)—an organometallic species
that traditionally represents a catalytic ‘dead end’. At the same time,
visible light irradiation of heteroleptic iridium(III) photocatalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 [dF(CF3)ppy 5 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine, dtbbpy 5 4,49-di-tert-butyl-2,29-bipyridine]
(4) would produce the long-lived photoexcited *IrIII state 5 (excited-
state lifetime t 5 2.3 ms) (ref. 28). At this juncture, we hypothesized that
the nickel and photoredox cycles would merge via SET between the
generate the critical Ni(III) aryl alkoxide 6 and the reduced Ir(II)
photocatalyst 7. On the basis of the established redox potentials of
these catalytic intermediates, we envisioned this key electron transfer
step to be kinetically and thermodynamically favourable under stand-
red
ard reaction conditions (half-reaction reduction potential E1/2
[*IrIII/IrII] 5 11.21 V versus the saturated calomel electrode (SCE)
in CH3CN, E1/2red [NiIII/NiII] 5 10.71 V versus Ag/AgCl in CH2Cl2
for (bpy)NiII(Mes)OMe)28,29. Once formed, we assumed the transient
Ni(III) complex 6 would rapidly undergo reductive elimination to
forge the desired C2O bond, while delivering the aryl ether product
and Ni(I) complex 8. At this stage, we envisioned both catalytic cycles
merging for a second time, enabling the single-electron reduction
of Ni(I) to Ni(0) by Ir(II) species 7 (E1/2red [IrIII/IrII] 5 21.37 V versus
SCE in CH3CN), thereby completing the nickel and photoredox cata-
lytic cycles at the same moment28.
a
Modulating nickel oxidation states with photoredox catalysis
On the basis of this synergistic catalysis design plan, we began our
investigations into the proposed nickel-catalysed aryl–alcohol ether-
ification using 1-hexanol and 4-bromoacetophenone. As expected, the
use of traditional nickel cross-coupling conditions (that is, without
photoredox), led to no observable product despite the implementation
of a range of Ni(II) and Ni(0) complexes (Fig. 2b, equation (1)). By
contrast, we found that the desired C2O bond could be forged in
excellent yield (86%) at room temperature via the introduction of
the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 in the presence of
Ni(COD)2, dtbbpy, quinuclidine, K2CO3 and blue light-emitting
diodes (LEDs) as the visible light source. Given the inherent advan-
tages of employing a bench-stable Ni(II) catalyst in lieu of Ni(COD)2,
we hypothesized that a catalytically active Ni(0) species 1 might be
accessible in situ via two SET reductions of (dtbbpy)Ni(II)Cl2 using the
Br
Alcohol
Aryl bromide
R
OH
X
Br
LnNiII Ar
2
RO NiIILn
Ar
3
LnNi0
Ni(II)
Ni(0)
1
*IrIII (5)
IrIII (4)
Oxidant
SET
SET
Catalytic
cycle
Photoredox
iridium photocatalyst (E1/2 [IrIII/IrII] 5 21.37 V versus SCE in
red
CH3CN, E1/2red [NiII/Ni0] 5 21.2 V versus SCE in N,N-dimethylfor-
mamide (DMF))28,30. In this vein, we hypothesized that quinuclidine
may also serve as a sacrificial reductant and were pleased to observe
that with NiCl2(dtbbpy) the desired fragment etherification was
accomplished in 91% yield (Fig. 2b, equation (2)).
IrII (7)
reductant
Br
RO NiIIILn
Ar
6
LnNiIBr
Ni(III)
Ni(I)
Nickel
catalytic cycle
8
With the optimal conditions in hand, we next sought to explore the
scope of the aryl bromide component in this new nickel-catalysed
C2O coupling reaction. As shown in Fig. 3, a diverse array of
electron-deficient bromoarenes with a variety of functional groups
(ketones, trifluoromethyls, nitriles, sulfones, esters) perform well using
this synergistic protocol (compounds 9–14, 88–96% yield). Moreover,
3-bromoanisole was found to be a competent substrate in this trans-
formation, demonstrating the diversity of substituents that can be
tolerated (26, 80% yield). Notably, bicyclic aromatics such as phthali-
mides and phthalides couple with high levels of efficiency (15 and 16,
92% and 80% yield, respectively). With respect to heteroaromatic
coupling partners, we have found that a range of pyridines with sub-
stitution at the 2 and 3 positions (nitrile, trifluoromethyl, methyl) are
effective electrophiles in this protocol (17–20, 67–91% yield).
Furthermore, quinolines, azaindoles and pyrimidines can be employed
without loss in efficiency (21–23, 60–88% yield). Perhaps most impor-
tantly, this transformation is not limited to electron-deficient aryl
bromides. For example, phenyl and tert-butylphenyl can be readily
incorporated in this nickel etherification (24 and 25, 68% and 77%
yield, respectively). It should be noted that comparable yields of aryl
ether product 13 were achieved when either coupling partner was
employed in excess (1.5 equiv.) (see Supplementary Information).
We next turned our attention to the alcohol reaction component. As
shown in Fig. 3, we discovered that a host of primary alcohols were
effective coupling partners, including substrates that incorporate
benzyl, tert-butyl, cyclopropyl and alkene functionalities (27230,
77289% yield). Moreover, carbamates and ester groups are tolerated,
as exemplified by the etherification of a serine derivative in 78%
yield (31). Interestingly, trifluoroethanol couples proficiently in this
reaction despite its diminished nucleophilicity (32, 77% yield). Both
R
O
X
Aryl ether
b
Ni catalysis alone; equation (1)
n-pent
O
n-pent
Br
OH
Nickel catalyst
Quinuclidine, K2CO3, MeCN
Ac
0% yield
Ac
Photoredox with Ni; equation (2)
Ir photocatalyst 4
n-pent
O
n-pent
Br
OH
Nickel catalyst
Ac
Quinuclidine, K2CO3, MeCN
91% yield
Ac
Figure 2
|
Proposed mechanism by which photoredox catalysis switches on
challenging nickel-catalysed C–O coupling. a, The catalytic cycle begins
with oxidative addition of Ni(0) (species 1) into an aryl bromide to give Ni(II)
aryl 2. Ligand exchange with an alcohol under basic conditions produces Ni(II)
aryl alkoxide 3. Excitation of photocatalyst 4 gives the excited state 5,
which can then oxidize 3 to the key Ni(III) intermediate 6 and generate
Ir(II) 7. Ni(III) 6 readily reductively eliminates to form the aryl ether product
and Ni(I) 8. A second SET event closes the two catalytic cycles, regenerating
Ni(0) 1 and Ir(III) 4. b, Nickel-catalysed C–O reductive elimination can be
turned on by addition of a photoredox catalyst and visible light.
2
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LETTER RESEARCH
F3
C
Catalyst combination
F
F
1 mol% Ir photocatalyst 4
t-Bu
t-Bu
N
t-Bu
F
F
Br
O
5 mol% NiCl2•glyme, 5 mol% dtbbpy
N
Cl
Cl
N
N
Ir
R
R
Ni
N
OH
Alcohol
N
10 mol% quinuclidine
K2CO3, MeCN, room temperature, 24 h
blue LEDs
t-Bu
Aryl bromide
Aryl ether
F3
C
4
Aryl bromides
O
O
O
O
O
F
O
CF3
n-hex
n-hex
n-hex
n-hex
n-hex
n-hex
CF3
SO2Me
CO2Me
Ac
CN
F
9
91% yield
10 90% yield
11 91% yield
12 93% yield
13 88% yield
14 96% yield
O
O
O
O
n-hex
O
CF3
O
Me
O
CF3
n-hex
n-hex
NMe
n-hex
n-hex
n-hex
O
O
N
N
N
CN
N
O
15 92% yield
16 80% yield
17 88% yield
18 67% yield
19 91% yield
20 82% yield
O
O
O
O
O
OMe
NTs
n-hex
O
n-hex
N
n-hex
n-hex
n-hex
n-hex
N
N
N
t-Bu
21 60% yield
22 88% yield
23 75% yield
24 68% yield
25 77% yield
26 80% yield
Secondary alcohols
Primary alcohols
R
O
27
30
28
31
29
37
Me
Me
O
O
Me
O
O
Ac
Me
Ac
38 R = Me
39 R = Ph
40 R = CH2OCH3 83% yield
82% yield
79% yield
Ac
Ac
Ac
86% yield
82% yield
89% yield
82% yield
O
Me
Me
Me
41
42 N-Boc fluoxetine
32
NHBoc
O
CF3
F3
C
O
4
MeO
82% yield
O
O
O
O
Ac
Ac
Ac
Me
N
74% yield
77% yield
78% yield
O
77% yield
O
Ac
Boc
Ac
36
RO
O
O
Water
HO
Me
Me
43
44
HO
HO
Ac
35
Ac
O
O
33 R = CH3 87% yield
34 R = CD3 81% yield
Me
Ac
CN
Me
Me
82% yield
71% yield, 6:1 rr
65% yield
62% yield
Figure 3
|
Alcohol and aryl halide scope in the photoredox-nickel-catalysed functionalities. Both primary and secondary alcohols are proficient coupling
C–O coupling reaction. A broad range of aryl bromides and alcohols are
efficiently coupled to produce aryl ethers under the standard reaction
conditions (top, generalized reaction). The aryl bromide scope includes
electron-deficient and electron-neutral arenes and heteroarenes with diverse
partners under the standard conditions. Water can be employed as the
nucleophile to generate phenol derivatives in a single step. Isolated yields
are indicated below each entry. See Supplementary Information for
experimental details.
methanol and d4-methanol are effective substrates, providing a valu- was indeed operative in this new photoredox protocol. As shown in
able strategy for installing H3CO– and D3CO– groups on arenes (33 Fig. 4a, we preformed the stable Ni(II)(aryl)(alkoxide) complex 45 to
and 34, 87% and 81% yield, respectively).
examine whether C2O reductive elimination might be achieved under
various photoredox or non-photoredox conditions. Importantly, in
the absence of either light or photocatalyst, none of the desired aryl
ether product 46 was observed. However, when complex 45 was
Relatively complex substrates are also tolerated in this transforma-
tion, as demonstrated by the etherification of a protected pyranose
in excellent yield (35, 82% yield). Notably, secondary alcohols are
equally effective in this etherification protocol—alkyl, benzyl and pro- exposed to Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4) and a visible light source,
tected ether functionalities all being amenable to this technology thedesired ether product 46 was formed in 59% yield. We attribute this
(37240, 79286% yield). Moreover, secondary alcohols possessing result to the formation of a transient Ni(III) complex 47 via the single-
b-quaternary carbons could be employed with good levels of efficiency electron reduction of *IrIII, thereby enabling the favourable Ni(III)
(41, 74% yield). In the case of a substrate possessing both a primary C2O reductive elimination, a result that is consistent with the
and secondary alcohol, the less hindered site is arylated predomi- seminal studiesof Hillhouse. Furthermore, cyclic voltammetryof com-
nantly, as demonstrated by product 36 (71% yield, 6:1 regiomeric ratio plex 45 showed an irreversible oxidation at 10.83 V versus SCE in
(rr)). This nickel-catalysed process can be applied to the expedient CH3CN (Fig. 4b), which we attribute to the oxidation of Ni(II) to Ni(III)
synthesis of medicinally relevant molecules, such as the antidepressant
(45 to 47). As such, we expect the oxidation of Ni(II) aryl alkoxides
red
fluoxetine (Prozac), in three chemical steps (42, 82% yield for coupling such as 3 to be readily accomplished by *IrIII photocatalyst 5 (E1/2
[*IrIII/IrII] 5 11.21 V versus SCE)28. Finally, Stern–Volmer fluor-
step). It is important to note that using H2O as the nucleophile delivers
the corresponding phenol product in a single step from commercially
available materials (43 and 44, 65% and 62% yield, respectively).
escence quenching experiments have demonstrated that the emission
intensity of *IrIII 5 is diminished in the presence of Ni(II) complex 45,
On the basis of our proposed design plan (Fig. 2a), we initiated presumably signifying an oxidation event to form Ni(III) 47 (see
mechanistic studies to determine if the critical Ni(III) oxidation state Supplementary Fig. 7).
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RESEARCH LETTER
a
b
–2.0
–1.6
–1.2
–0.8
–0.4
0
Room temperature, 24 h
No photocatalyst
CF3
t-Bu
t-Bu
O
N
N
NiII
CF3
F3C
CF3
t-Bu
t-Bu
O
N
N
Ir photocatalyst 4
NiII
Complex 45 recovered
No light, room temperature, 24 h
0.4
F3C
CF3
0
0.5
1.0
1.5
2.0
Potential (V)
Ni(II)dtbbpy aryl
47
CF3
F3C
O
alkoxide 45
Ir photocatalyst 4
t-Bu
t-Bu
O
N
Transient Ni(III) complex required
for C–O reductive elimination
NiIII
F3C
CF3
Room temperature, 24 h
N
F3
C
CF3
Aryl ether 46 59% yield
Figure 4
|
Mechanistic studies support the intermediacy of transient Ni(III) LEDs. See Supplementary Information for experimental details. b, Cyclic
complex to enable C–O reductive elimination. a, Reductive elimination
voltammogram of 45 shows NiIII/NiII couple at 10.83V versus SCE in CH3CN
to form C–O bond only occurs in the presence of photocatalyst and light.
with 0.1M tetrabutylammonium hexafluorophosphate as the supporting
Reactions performed on 5.55 mmol scale with 41 mol% photocatalyst 1 and blue electrolyte at 100mV s21
.
A further series of experiments were performed using Ni(COD)2 as
the nickel catalyst in lieu of NiCl2 (see Supplementary Fig. 1). In the
presence of this Ni(0) catalyst, the reaction proceeds with yields that
are comparable to the Ni(II) precatalyst; however, when the iridium
photocatalyst is omitted, the desired C2O coupling is not observed.
This result suggests again that reductive elimination does not occur
fromthe Ni(II) oxidation stateas a single-electronoxidation to Ni(III) is
required to enable product formation. Interestingly, when quinucli-
dine is omitted, the reaction efficiency is greatly diminished (8% yield
over 24 h). This effect can possibly be attributed to the amine function-
ing as an electron shuttle, facilitating reduction of Ni(I) and oxidation
of Ni(II); however, mechanistic studies are currently ongoing to elu-
cidate the role of quinuclidine in more detail.
We have developed a catalytic strategy for accessing transient
Ni(III) complexes through the use of visible-light-mediated photore-
dox catalysis for application in various challenging C2O cross-
couplings. This method of modulating transition metal oxidation
states has enabled a previously elusive transformation within the realm
of nickel catalysis. We anticipate that this new mechanistic paradigm
will find application in using nickel and other transition metals in a
series of challenging bond constructions.
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Author Contributions J.A.T., J.D.C. and V.W.S. performed and analysed experiments.
J.A.T., J.D.C., V.W.S. and D.W.C.M. designed experiments to develop this reaction
and probe its utility, and also prepared this manuscript.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper.
Correspondence and requests for materials should be addressed to D.W.C.M.
(dmacmill@princeton.edu).
Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support was provided by the National Institute of
General Medical Sciences (R01 GM093213-01) and gifts from Merck, AbbVie and
Bristol-Myers Squibb. J.A.T. thanks Bristol-Myers Squibb for a Graduate Fellowship.
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