Nickel Dual Photoredox Catalysis for the Synthesis of Aryl Amines

Article abstract of DOI:10.1021/acs.organomet.8b00121

In this work, a new dual photoredox nickel catalysis system has been utilized for the synthesize of aryl amines. Previously, our group has shown that a nickel catalyst in conjunction with a photosensitizer and a sacrificial electron donor can cross-couple C-C bonds via photoredox-assisted reductive coupling. Here we have built upon that system to develop a redox-neutral cross-coupling system for the formation of C-N bonds. The catalytic system is composed of just a nickel cross-coupling catalyst, a Ru photocatalyst, and base and is capable of coupling amines with aryl halides in good to excellent yields. Furthermore, it was found that these reactions are functional under ambient conditions with catalyst loadings of 1 mol %. Spectroscopic studies provide support that this amination mechanism proceeds via a nitrogen-based radical intermediate. This N-radical mechanism offers direct synthetic access to di- and triaryl amines from nickel photocatalysis.

Full text of DOI:10.1021/acs.organomet.8b00121

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Nickel Dual Photoredox Catalysis for the Synthesis of Aryl Amines
Ryan J. Key and Aaron K. Vannucci*
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States
S
* Supporting Information
ABSTRACT: In this work, a new dual photoredox nickel
catalysis system has been utilized for the synthesize of aryl
amines. Previously, our group has shown that a nickel catalyst
in conjunction with a photosensitizer and a sacrificial electron
donor can cross-couple C−C bonds via photoredox-assisted
reductive coupling. Here we have built upon that system to
develop a redox-neutral cross-coupling system for the
formation of C−N bonds. The catalytic system is composed
of just a nickel cross-coupling catalyst, a Ru photocatalyst, and
base and is capable of coupling amines with aryl halides in
good to excellent yields. Furthermore, it was found that these
reactions are functional under ambient conditions with catalyst
loadings of 1 mol %. Spectroscopic studies provide support that this amination mechanism proceeds via a nitrogen-based radical
intermediate. This N-radical mechanism offers direct synthetic access to di- and triaryl amines from nickel photocatalysis.
INTRODUCTION
■
Thermally controlled cross-coupling reactions rely on ligand
exchange mechanisms, such as transmetalation. This synthetic
approach has continued to advance, but some cross-coupling
reactions and products have been limited under thermal
control.1,2 The development of new cross-coupling method-
ologies, which may avoid ligand exchange mechanisms, have
been achieved recently. These catalytic methodologies, such as
reductive coupling3 and photoredox coupling,4−6 have shown
the ability to perform previously unachieved cross-coupling
reactivity. Of specific importance to this report, dual photo-
redox catalysis enables routes for previously unattainable small-
Figure 1. Comparison of the proposed reactions for the formation of a
NiIII oxidation state during dual photoredox catalysis.
molecule activations and bond-forming reactions. Dual photo-
redox catalysis utilizes these single-electron transfers to activate
a secondary transition-metal catalyst for small-molecule
activations and bond-forming reactions.6−19
ate,4,5,12,13,26 which was also observed in our laboratory (Figure
1c).27 This radical reactivity avoids ligand exchange mecha-
nisms and can lead to previously unexplored product formation
and reactivity.
Predominately, dual photoredox systems utilize nickel cross-
coupling catalysts. Proposed mechanisms involve nickel
catalysts in oxidation states that range from Ni0 to NiIII. At
room temperature, it has been shown that the NiIII oxidation
state is necessary to promote product formation through
reductive elimination.20,21 For dual photoredox cross-coupling
from nickel−polypyridyl catalysts, multiple routes to form the
important NiIII oxidation state have been proposed. One
proposed route is the oxidative addition of a carbon
electrophile to a NiI intermediate (Figure 1a).8,14,22−24 Another
route proposes that the NiIII intermediate is formed via
photocatalyst oxidation of a NiII intermediate (Figure 1b).10,25
The NiI oxidative addition and NiII oxidation routes both tend
to operate in mechanisms that rely on ligand exchange
reactions to ultimately form the desired cross-coupled product.
Conversely, the NiIII intermediate has been shown to form via a
reaction between a carbon radical and a NiII intermedi-
Traditional amination pathways use palladium phosphane
catalysts to form new C−N bonds and operate through Pd0/
PdII oxidation states.28 The phosphane ligands require precise
electron-donating/-withdrawing properties and steric encum-
brance to promote product formation via reductive elimination
from the PdII intermediate.28−30 Utilizing dual photoredox
nickel catalysis with simple ligand environments for the
construction of C−N bonds, therefore, is highly desirable. In
addition, the range of electrophiles amenable to nickel cross-
coupling reactions should allow for a wide diversity of aminated
products.31−33 Reactions that construct new C−N bonds are
Received: February 27, 2018
© XXXX American Chemical Society
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also of great importance to pharmaceutical synthesis,
constituting roughly 27% of pharmaceutical reactions.34
Recently dual photoredox nickel catalysis for the synthesis of
diaryl amines has been achieved.23,25 Both studies were able to
achieve diaryl amine products using ligandless nickel salts as the
cross-coupling catalysts, which illustrates the advantages of dual
photoredox cross-coupling in comparison to thermally
controlled reactions. Furthermore, the C−N photoredox
coupling for the synthesis of aryl amines has been achieved
using organic dyes.35 For one of the studies, generation of the
important NiIII intermediate was proposed to occur through
oxidation of a NiII intermediate, as illustrated in Figure 1b.25
Formation of amine radicals was not proposed for this
mechanism. For the second study, it was postulated that
formation of the NiIII intermediate occurred through oxidative
addition of aryl halides to a NiI intermediate, as shown in
Figure 1a.23 Computational insight into possible reaction
mechanisms for these systems was also recently reported.24,36
Comparison of these mechanisms to our work is discussed in
further detail later in this paper.
degassing, illustrating the ease of reaction setup for this
approach.
Variations of the optimized conditions are shown in Table 1.
Using Ir(ppy)2(dtbpy)+ as the photocatalyst resulted in
comparable yields in comparison to Ru(phen)32+, likely due
to the similar excited state oxidation potentials of the two
photocatalysts. Using the highly oxidizing Ir(dF-CF3-
ppy)2(dtbpy)+ photocatalyst led to drastically lower product
yields. Attempting to perform the experiment with NiCl2 and
2,2′:6′,2″-terpyridine ligand added instead of the preformed
catalyst did not produce product, as has been observed with this
nickel salt/ligand combination.27 Lack of C−N cross-coupling
from simple nickel salts is, however, a deviation from previously
reported nickel dual photoredox C−N coupling.23,25 Changing
the base from K3PO4 to triethanolamine or changing the
reaction solvent resulted in no product formation. Complete
removal of any of the catalytic componentsnickel catalyst,
photocatalyst, base, or lightalso led to the lack of product
formation. Finally, the addition of water to the reaction mixture
did not increase or negatively affect the product yield; hence,
the use of dried solvents is not necessary for this catalytic
system.
With the optimized reaction conditions in hand, we explored
the substrate scope for this catalytic system. First, p-
methoxyaniline was used as a general and efficient amine
coupling partner to examine the range of possible aryl coupling
partners. Aryl iodides resulted in greater product yields in
comparison to aryl bromides, which is consistent with
previously reported nickel dual photoredox aryl amine
syntheses.23 Figure 2 shows that cross-coupling yields up to
RESULTS AND DISCUSSION
■
To optimize our dual photoredox catalytic system for the
construction of C−N bonds and the synthesis of diaryl amines,
cross-coupling between 4-methoxyaniline and iodobenzene was
chosen as a test reaction. Blue light irradiation of the coupling
substrates in the presence of the [Ni(tpy)(py)](PF3)2 cross-
coupling catalyst (tpyNi),27 Ru(phen)3 photocatalyst, and a
2+
potassium phosphate base in acetonitrile resulted in 76% yield
of the desired cross-coupled diaryl amine product (Table 1, row
1). It was observed that a small excess of aryl halide led to
greater product yields. This result is consistent with previously
reported coupling between aryl halides and in situ generated
radicals.27 These reactions were set up on the benchtop without
a
Table 1. Optimization of Reaction Conditions
variation
yield (%)
none
76
0
no Ru(phen)3
Ir(ppy)2(dtbpy) instead of Ru(phen)3
Ir(dF-CF3-ppy)2(dtbpy) instead of Ru(phen)3
no tpyNi
74
9
Figure 2. Catalytic dual photoredox cross-coupling between p-
methoxyaniline and aryl halides. Conditions: 100 mM aniline, 200
mM aryl halide in 5 mL of acetonitrile. The mole percentages and
percent yields are based on limiting reagent.
0
NiCl2 and tpy in situ instead of tpyNi
no base
0
0
TEOA instead of K3PO4
no light
0
0
93% can be achieved by varying the aryl iodide. In every case,
further reactions of the diaryl amine products to form triaryl
amines were not observed and no homocoupled biaryl products
were observed. Leftover starting reactants, after the 24 h
reaction time, were observed with GC/MS analysis of the
reaction mixtures. Both electron-donating and -withdrawing
groups are tolerated. Good yields were obtained regardless of
functional group position, as seen with the para (2)- and meta-
positioned (3) iodoanisole substrates. Ortho-substituted aryl
iodides such as 2-iodotoluene (4), however, exhibited lower
yields than p-iodotoluene (5). It is suspected that these lower
addition of 200 μL H2O
1/1 amine/aryl halide
76
42
0
DCM instead of MeCN
toluene instead of MeCN
DMF instead of MeCN
0
0
a
The solvent was acetonitrile (MeCN) and base was K3PO4 unless
otherwise stated. Abbreviations: tpy, 2,2′:6′,2″-terpyridine; phen, 1,10-
phenanthroline; (dF-CF3-ppy), 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)phenylpyridine; dtbpy, 4,4′-ditert-butyl-2,2′-bipyri-
dine. Reactions were carried out for 24 h.
B
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yields can partially be attributed to steric effects; however, the
sterically hindered 1-iodonaphthalene did lead to good yields
(9). Therefore, the electron-donating/-accepting abilities of the
methyl group versus the increased aromaticity of the naphthyl
ring also has an effect on product yield. Coupling of heteroaryl
iodides with 4-methoxyaniline was also successful (7 and 8).
A variety of amine coupling partners were also well tolerated
by this catalytic system. Figure 3 shows that ortho, meta, and
access to a NiIII oxidation state is essential to forming cross-
coupled products during room-temperature dual photoredox
catalysis. Three mechanistic routes for the formation of a NiIII
oxidation state have been proposed (Figure 1). In our previous
work, we have observed that a carbon-based radical formed
during photoredox cross-coupling catalysis was essential for
mediating the oxidation state of the tpyNi catalyst.27 With this
radical-based mechanism in mind, we set to examine the
interaction between the amine substrates and the Ru
photoredox catalyst. Recently, during cyclization reactions,
the Knowles group has shown that nitrogen-based radicals can
be formed via photoredox oxidative proton-coupled electron
transfer (PCET).37 Thus, we aimed to explore the possibility
that forming amine radicals is a key step for our dual
photoredox catalytic system.
Various fluorescence quenching experiments involving
combinations of the Ru photocatalyst in the presence of p-
methoxyaniline, K3PO4 base, and the entire catalytic reaction
mixture were performed. A Stern−Volmer analysis showed that
the Ni(II) catalyst does not quench the photocatalyst (Figure
SI-2). Furthermore, the base alone does not quench the Ru
photocatalyst (Figure SI-3). The p-methoxyaniline substrate in
both the absence and presence of base, however, did quench
the photocatalyst (Figures SI-3 and SI-4). The Stern−Volmer
plots for amine quenching exhibited a linear fit, indicating the
quenching was first order with respect to the aniline substrate.
These data suggest that electron transfer occurs directly
between the aniline substrate and the photocatalyst and that
PCET does not appear to be the dominant pathway. Instead, it
is proposed that electron transfer between the aniline substrate
and the photocatalyst occurs first, followed by deprotonation of
the oxidized aniline by the added base. This electron transfer
followed by proton transfer mechanism for the formation of
nitrogen radicals has been previously reported.38,39
To test if quenching of the photocatalyst by the amine
substrate was catalytically feasible, quenching experiments were
performed using conditions identical with the optimized
reaction conditions. Fluorescence quenching was once again
observed under optimized reaction conditions (Figure SI-5).
The slope of the Stern−Volmer plot for the entire reaction
mixture was similar to the slope of the Stern−Volmer plot
obtained from the photocatalyst in the presence of the aniline
substrate plus base. The similarity in slopes indicates that
quenching of the photocatalyst by the aniline substrate is
catalytically feasible within the reaction mixture.
A likely mechanism for this catalytic system is shown in
Figure 4. The Ru photocatalyst absorbs a photon of light to
generate a long-lived excited state (RuII*). The blue light
source has a maximum intensity at 480 nm, which overlaps well
with the Ru photocatalyst absorbance spectrum. The Ni catalyst
does not absorb light in the visible region (Figure S1); thus, Ni
catalyst light absorbance is not expected to play a role in the
operative mechanism.
Figure 3. Catalytic dual photoredox cross-coupling between aryl
iodide and various aniline substrates. Conditions: 100 mM anilines,
200 mM aryl iodide in 5 mL of acetonitrile. The mole percentages and
percent yields are based on limiting reagent.
para substitutions on aniline substrates all result in good yields
(1, 10, and 11). Highly substituted aniline substrates were also
successful (12). These reactions were also capable of coupling
complex heterocycles, such as 3,4-methylenedioxyaniline, as
amine coupling partners (15). Coupling of 4-chloroaniline,
which contains a synthetically useful chloro functional group,
was moderately tolerated (16). The possible C−C cross-
coupled side product for that reaction was not observed. Cross-
coupling involving sulfonamides was also successful (17).
Furthermore, starting with secondary amines as coupling
partners led to the formation of tertiary amine products, as
shown with products 18−21. Products 18 and 19 show that
amines containing both aryl groups and aliphatic groups are
capable of being utilized in C−N coupling reactions. A triaryl
amine, product 20, can be formed with 71% yield on starting
with the diaryl amine. Finally, dibenzyl amine was also a
suitable cross-coupling partner, forming the trisubstituted
amine 21 in good yield. Thus, this is the first dual photoredox
nickel catalysis system capable of the synthesis of both bi- and
triaryl amine products.
The excited state RuII* is then reductively quenched by the
aniline substrate to concurrently generate a reduced photo-
catalyst (RuI) and an oxidized amine. Formation of amine
radicals is supported by the fluorescence quenching studies and
was further supported by the fact that electron-rich aniline
substrates are more efficient coupling partners in comparison to
electron-deficient anilines. After oxidation of the aniline
substrate, the acidity of the amine group increases, leading to
subsequent deprotonation by the added base. The reduced
photocatalyst, RuI, then reduces the nickel catalyst for both the
To gain insight into how our catalytic system successfully
performs C−N cross-coupling reactions, we examined the
interaction between the amine substrates and the Ru
photoredox catalyst. As discussed in the Introduction, gaining
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which is commonly seen with this amine base.27 While our
proposed mechanism and their proposed mechanism differ just
slightly, the mechanistic differences once again lead to a
difference in accessible products. Both studies were able to
synthesize a variety of diaryl amines including sulfonamides;
however, the previous study reports an inability to synthesize
triphenyl amine and only a 9% yield for the formation of N-
methyl-N-phenylaniline, whereas the catalytic system reported
in this paper was able to synthesize those products with 71%
and 83% yields, respectively.
In conclusion, the differing aspects of the three reports on
nickel dual photoredox catalysis for the formation of aryl
amines show both the versatility and range of chemistries that
can be achieved using this approach. The catalytic system in
this report utilizes a Ru photocatalyst to generate amine radicals
for cross-coupling reactions with aryl iodide substrates. This
approach is amenable to a variety of both aryl iodide and amine
coupling partners and can be set up and performed under
ambient conditions. Both biaryl and tertiary amine products can
be accessed using this approach, which operates with only
added base and 1 mol % catalyst loadings.
Figure 4. Proposed mechanism for dual photoredox C−N cross-
coupling catalysis via an amine radical.
Ni(II/I) and Ni(I/0) couples. The reductive driving force of
the Ru(II/I) couple is −1.36 V vs the saturated calomel
electrode, while the Ni(I/0) couple requires −1.3 V.27
Oxidative addition of an aryl iodide to Ni0 in step 3 generates
a NiII−Ph intermediate. Steps 2 and 3 are consistent with
previously reported reactivity between tpyNi and aryl halides.27
In addition, the halide lost from the aryl group is likely picked
up by potassium from the added base to generate a potassium
iodide salt, as has been observed.27 The NiII−Ph intermediate
then reacts with the aniline radical to generate the important
NiIII intermediate in step 4, followed by reductive elimination in
step 5 to form the desired C−N cross-coupled product. Step 4
in the proposed cycle is analogous to the reports summarized in
Figure 1c.
This proposed mechanism differs from each of the previously
proposed nickel dual photoredox mechanisms for the formation
of biaryl amines. The MacMillan group reported that the
formation of the important NiIII intermediate occurred via
oxidation of a NiII-amido complex by an iridium photocatalyst,
as shown in Figure 1b.25 That mechanism relied on ligand
exchange between the amine substrates and halide groups of
the nickel center and did not propose the formation of an
amine radical. In addition, the formation of aryl amines was
only observed when amines containing α-hydrogens were
present. Recent computational work gave insight into the
requirement for α-hydrogen-containing heterocycles.36 In that
paper, the authors propose that the hydrogen atom transfer
reagent DABCO generates a pyrrolidine radical that helps
generate a Ni0 intermediate capable of activating aryl halides.36
The catalytic system reported in this paper does not require
substrates containing α-hydrogens or the addition of hydrogen
atom transfer reagents. Instead, this catalytic system was able to
directly synthesize bi- and triaryl amines with only the addition
of a common base to the dual photoredox catalysts.
EXPERIMENTAL SECTION
■
Instrumentation. All separations were conducted on a Reveleris
X2 flash chromatography system using a 40 μM silica column or via
preparative-scale TLC. Solvents used for purification were ethyl
acetate and hexane of ACS grade or better (≥99%) and were used
without further purification.
1H NMR spectroscopy was performed using a 300 MHz instrument
using deuterated chloroform as the solvent with a calibrated peak at
7.26 ppm. 13C NMR was conducted on a 300 MHz instrument set to a
frequency of 75 MHz using chloroform as the solvent and a calibrated
solvent peak at 77.33 ppm. The light source used for all experiments
was a 34 W Kessil H150W-BLUE light exciting at 400−500 nm with a
maximum intensity at 480 nm. The light source was placed 6 in. from
the reaction vials with aluminum foil located 2 in. behind the vials to
redirect incident light. The temperature was monitored during the
reactions, and no increase above room temperature was observed.
Emission spectra were acquired on an Edinburgh FS5 fluorescence
spectrometer equipped with a 150 W continuous wave xenon lamp
source for excitation. Emission measurements on degassed solution
samples were collected on solutions of appropriate materials inside a
1.0 cm quartz cuvette using the SC-05 standard cuvette module.
General Procedure for Photoredox-Assisted Amination
Reactions. In a 12 mL glass vial with a TFE/SIL O/T cap were
placed [Ni(tpy)(py)(MeCN)2]PF6 (0.005 mmol, 1% loading),
2+
Ru(phen)3 (0.005 mmol, 1% loading), amine (0.5 mmol), aryl
iodide (1.0 mmol), and base (0.5 mmol) and dissolved in 5 mL of
acetonitrile. The vial was then placed in front of the blue LED light
source on a stir plate and was irradiated for 24 h with stirring. After 24
h, the solution was then separated via flash chromatography using
ethyl acetate and hexanes. The isolated products were then analyzed
In another study by researchers at AstraZeneca,23 fluo-
rescence quenching studies provided evidence for the formation
of amine radicals during dual photoredox biaryl synthesis, as
was observed in this study. The authors, however, proposed
that the amine radical reacted directly with the Ni0 intermediate
to generate a NiI-amine intermediate. It was then proposed that
the NiI intermediate was capable of activating aryl halides in a
reaction such as that shown in Figure 1a. Radical reactivity with
Ni0 complexes and aryl halide activation by NiI intermediates
has been supported by computational work.24 In addition,
fluorescence quenching of their photocatalyst also occurred in
the presence of the triethyl amine base used in their study,
1
via H NMR and 13C NMR to confirm purity. Standard chemical
safety procedures should be used with all chemicals, but it is worth
noting that inhalation of p-methoxyaniline can be fatal; thus, a mask is
required while handling that solid substrate.
Stern−Volmer Experiments. Fluorescence quenching experi-
ments were performed with N2-purged solutions of 5 × 10−6
M
2+
Ru(phen)3 in acetonitrile at room temperature. The solutions were
irradiated at 480 nm, and fluorescence was measured at 598 nm. Each
peak intensity is the average of three experimental spectra. Data can be
found in the Supporting Information.
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Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137, 4896−4899.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00121.
■
S
(26) Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192−
16197.
Fluorescence quenching data, H and 13C NMR data,
and references to previously reported products (PDF)
1
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AUTHOR INFORMATION
Corresponding Author
*E-mail for A.K.V.: vannucci@mailbox.sc.edu.
ORCID
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Aaron K. Vannucci: 0000-0003-0401-7208
Notes
The authors declare no competing financial interest.
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