Electrochemically Enabled Chan-Lam Couplings of Aryl Boronic Acids and Anilines

Article abstract of DOI:10.1021/acs.orglett.9b01434

The Chan-Lam reaction remains a highly utilized transformation for C-N bond formation. However, anilines remain problematic substrates due to their lower nucleophilicity. To address this problem, we developed an electrochemically mediated Chan-Lam coupling of aryl boronic acids and amines utilizing a dual copper anode/cathode system. The mild conditions identified have enabled the preparation of a wide range of functionalized biarylanilines in good yields and chemoselectivities.

Full text of DOI:10.1021/acs.orglett.9b01434

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Electrochemically Enabled Chan−Lam Couplings of Aryl Boronic
Acids and Anilines
Ryan P. Wexler, Philippe Nuhant, Timothy J. Senter, and Zachary J. Gale-Day*
Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States
*
S Supporting Information
ABSTRACT: The Chan−Lam reaction remains a highly utilized
transformation for C−N bond formation. However, anilines remain
problematic substrates due to their lower nucleophilicity. To address
this problem, we developed an electrochemically mediated Chan−
Lam coupling of aryl boronic acids and amines utilizing a dual copper
anode/cathode system. The mild conditions identified have enabled
the preparation of a wide range of functionalized biarylanilines in good yields and chemoselectivities.
he formation of carbon−nitrogen bonds via metal-
Scheme 1. Chan−Lam Coupling through Electron-Poor
II
T
catalyzed cross-coupling reactions has been one of the
Cu
most impactful classes of reactions in recent decades due to
their ability to provide robust access to a wide-range of
medicinally relevant molecules. As a result, these reactions are
1
−5
commonly utilized in industry.
A method for N,O-arylation
6
7
8
was developed by Chan , Lam (N-arylation) and Evans (O-
arylation) that allowed for the formation of carbon−
heteroatom bonds using boronic acid coupling partners,
which are widely available due to the popularity of Suzuki
9
coupling. Despite the wide availability of the reaction
components and the ability to access medicinally relevant
compounds, the Chan−Lam coupling remains relatively
11,13,15−17
underutilized in the synthetic community
due to
slow rates, stoichiometric copper, water sensitivity, side-
product formation, incompatibility with boronic ester coupling
10
partners and consumption of the boronic acid partner.
In particular, anilines are problematic substrates when used
in the Chan−Lam coupling due to their low nucleophilicity
resulting in the slow formation of the catalytically active copper
1
0,11
complexes.
In addition, there are several substrates in the
12,13
to substrates such as aryl iodides, which are reduced by the
literature that have been identified to be challenging.
For
11
photoexited Ir(ppy) (Scheme 1b, vide infra). Finally, we
instance, the coupling of anilines with electron-deficient
3
aimed to elucidate the mechanism by which our conditions
may enable the reaction to proceed.
boronic acids are generally characterized by yields consistent
12
with little to no catalytic turnover (Scheme 1a). Despite
10,14
Herein, we report an electrochemically enabled protocol that
achieves improved yields for these historically difficult
products. To ensure the practicality of this method, we
constrained our optimization to a reaction time of less than 1
day at room temperature with a catalytic amount of copper and
readily available starting materials.
recent advances in the mechanistic understanding
and
general synthetic methodology to achieve these transforma-
tions, electron-deficient boronic acids remain challenging
1
1,13,15−17
substrates for traditional Chan−Lam methodologies.
Inspired by a report on the electrochemical conversion of
aryl boronic acids to either primary anilines or phenols
Scheme 1c) using ammonia or water, respectively, we
18
A summary of the most relevant preliminary results is
depicted in Table 1 using aniline 1a and boronic acid 2a and
(
envisioned that the drawbacks of the Chan−Lam reaction
described previously could be solved by developing an
electrochemical version of the reaction and testing it for
traditionally difficult substrates (e.g., electron-deficient boronic
acids and anilines). In addition, the application of a well-tuned
and mild electrochemical current would allow us to broaden
the substrate scope as compared to the photochemical method
inexpensive and widely available Cu(OAc) . Inspired by the
2
reaction conditions for the electrochemical conversion of aryl
18
boronic acids to either primary anilines or phenols, a dual
Received: April 24, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01434
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Electrochemical Chan−Lam
Scheme 2. Aniline Substrate Scope with Boronic Acid 2a
,
a b
Coupling of 1a and 2a.
entry
V
base (1.2 equiv)
additive (0.2 equiv)
yield (%)
c
1
2
3
4
5
6
7
8
9
0.40
0.40
0.40
0.30
0.35
0.45
0.50
0.40
0.40
0.40
0.40
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
21
45
d
60
e
nd
nd
e
39
42
65
98
45
80
54
2,6-lutidine
2,6-lutidine
2,6-lutidine
TEA
2,6-lutidine
2,6-lutidine
2,6-lutidine
TEA
DIPEA
−
TEA
TEA
TEA
10
11
12
13
14
−
−
0.40
f
47
g
<5
a
Reaction conditions: aniline 1a (0.55 mmol), 2a (0.71 mmol), 0.1 M
NBu ClO /ACN (4 mL), additive (0.11 mmol, 0.2 equiv), base (0.66
4
4
mmol, 1.2 equiv), Cu(OAc) (0.11 mmol, 20 mol %), rt, undivided
2
a
b
Reaction conditions: aniline 1a (0.55 mmol), 2a (0.71 mmol), 0.1 M
cell, air, 20 h. Yields determined by NMR integration using 1,4-
c
NBu ClO /ACN (4 mL), Et N (0.11 mmol, 0.2 equiv), 2,6-lutidine
dinitrobenzene as an internal standard. Reaction run under nitrogen
4
4
3
d
e
(
0.66 mmol, 1.2 equiv), Cu(OAc) (0.11 mmol, 20 mol %), rt,
2
b
in degassed ACN. Reaction run under O balloon. Current unable
2
f
g
undivided cell, air, 20 h. See the SI for procedure.
to flow. Heated to 35 °C. Cu(OAc) omitted.
2
1
9
copper anode/cathode system was utilized. The current was
cycled every 10 min in order to avoid electrode spoiling, and a
constant voltage of 0.4 V was applied over 24 h resulting a 21%
yield (entry 1). Subsequently, initial results indicated that
running the reaction under oxygen or air atmosphere was
crucial for the efficiency of our electrochemical coupling
resulting in 45% and 60% yields, respectively (entries 2 and 3).
Increasing the voltage to 0.5 V resulted in a messier reaction
profile (entry 7) with no improvement in yield (42%), whereas
voltage lower than 0.4 V resulted in a loss of current soon after
electrolysis was initiated (entries 4 and 5). We found that the
use of 2,6-lutidine significantly increased our yields to 65%
scope with respect to anilines coupling with boronic acid 2a.
As expected, electron-rich anilines 3a−e performed quite well.
Additionally, anilines bearing a para-halogen performed well
under the reaction conditions (3f, 3g, and 3m). Under
11
photoredox conditions, aryl iodides are partially reduced,
resulting in reduced yields (24%) when compared to this mild
electrochemical procedure (79%) which showed no dehaloge-
nation (3m). Electron-deficient anilines 3h−k,n and amino-
pyridine 3p were coupled in moderate yields, likely due to the
poor nucleophilicity of the aniline starting materials slowing of
II
10
the generation of the active Cu complex. Finally, N-
methylaniline-derived 3o also proceeded in modest yield, likely
due to increased steric hindrance.
(
entry 8). A further increase in yield was observed with the
addition of triethylamine (98%, entry 9). This could be
explained by helping with acceleration of the rate of the
Chan−Lam reaction through the generation of an improved
We next endeavored to understand our substrate scope with
respect to boronic acid coupling with aniline 1a (Scheme 3).
All substrates, including electron-poor boronic acids, yielded
product in good to excellent yields. This supports the role of
I
II
active catalyst complex and a greater rate of Cu /Cu
1
0
II
10
oxidation. Furthermore, the more nucleophilic Et N (TEA)
aniline in generating the active Cu complex. Once again,
Chan−Lam amination was selectively achieved for aryl iodide
4j. In addition, the conversion of electron-poor 4f was
achieved in good yield due to the mild potential employed,
which is well below the predicted redox potential of the nitro
3
was preferred versus DIPEA (entry 10), suggesting the
beneficial role of TEA to break up the copper paddlewheel
complex. Interestingly, 2,6-lutidine and TEA both appear to be
necessary for efficient reactivity, and using Et N alone resulted
3
red
20
in decreased yield (80%, entry 12). Finally, control experi-
ments were performed. When no current was applied at room
temperature or at 35 °C, lower yields were obtained
showcasing the benefits of using electrochemical versus classic
Chan−Lam conditions (entries 12 and 13). The omission of
the copper acetate ablated catalytic activity (<5%, entry 14),
showing the reaction is not mediated by the electrodes directly.
Overall, C−N coupling was accomplished in a simple
undivided cell setup at room temperature overnight.
group (E1/2 = −1.19 V vs SCE). We have shown that with
our mild electrochemical method a wider range of substrates
can be achieved with yields comparable to those of the
previous state of the art.
Finally, we were interested in evaluating the mechanism by
which our applied voltage was mediating the Chan−Lam
coupling. In our CV studies, no oxidative peak was observed
within the relevant range, suggesting that it is unlikely that
II
III
direct oxidation of the Cu to the Cu intermediate, required
for reductive elimination, occurred (SI Figure 1). A hint of the
mechanism could be found by analyzing the structures and
abundance of the byproducts (SI Figure 5); the electro-
With our optimal conditions identified, we sought to
demonstrate the scope of this method on a variety of anilines
and boronic acids (Scheme 2). First, we explored the substrate
B
DOI: 10.1021/acs.orglett.9b01434
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
II
Scheme 3. Boronic Acid Substrate Scope with Aniline 1a
can then either be oxidized back to Cu by oxygen or plated to
2
2−24
the new cathode.
Beyond this step, the catalytic cycle is
10
II
identical to that previously reported. The initial Cu complex
I is broken up by the aniline to form II before transmetalation
of with the boronic acid coupling partner to form intermediate
II
III
III. This Cu complex is then oxidized to Cu via
disproportionation to form IV. Finally, reductive elimination
step yields the desired product and a Cu species V that is
I
either oxidized by oxygen or plated to the cathode as discussed
previously.
In summary, a new methodology has been developed to
allow access to traditionally challenging Chan−Lam substrates
under mild conditions. In comparison to previous methods,
this protocol has shown a broadened scope. Additionally, we
have made steps to elucidate the mechanism, identifying a
possible electrochemical refining process that limits side-
product formation and slows unproductive starting material
consumption. Further investigations into the scope and
applications of this process are currently underway in our
laboratories.
ASSOCIATED CONTENT
Supporting Information
■
a
*
S
Reaction conditions: aniline (0.55 mmol), 2a (0.71 mmol), 0.1 M
NBu ClO /ACN (4 mL), Et N (0.11 mmol, 0.2 equiv), 2,6-lutidine
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01434.
4
4
3
(
0.66 mmol, 1.2 equiv), Cu(OAc)2 (0.11 mmol, 20 mol %), rt,
undivided cell, 20 h.
Additional experiments (controls and reaction optimi-
1
13
chemical process showed decreased formation of the phenol,
known to arise from a Cu -mediated process.
zation); H and C spectra (PDF)
I
10
In order to probe the redox behavior of the reaction mixture
AUTHOR INFORMATION
■
CV was performed (see the SI for full discussion and spectra).
Corresponding Author
*E-mail: zachary_gale-day@vrtx.com.
ORCID
red
We observed a quasi-reversible deposition (E
= −0.35 V
1/2
0
vs Ag/AgCl) of an impure Cu /perchlorate film on the
electrode surface but no direct oxidation of the soluble Cu .
2
1
I
Using this finding, we propose the electrochemical refining
mechanism shown in Figure 1, where the less stable Cu
Philippe Nuhant: 0000-0001-7816-7474
Zachary J. Gale-Day: 0000-0002-8598-7048
Notes
I
generated during the reaction is plated to the cathode,
diminishing side product formation. When the current is
reversed after 10 min, the copper previously deposited as an
The authors declare no competing financial interest.
I
I
impure film is oxidized back to Cu at the new anode. The Cu
ACKNOWLEDGMENTS
■
We would like to thank Vertex Pharmaceuticals Inc. for
funding R.P.W.’s internship and Barry Davis (Vertex
Pharmaceuticals, Inc.) for HRMS data generation.
REFERENCES
■
(
1) Bariwal, J.; Van Der Eycken, E. C-N. Bond Forming Cross-
Coupling Reactions: An Overview. Chem. Soc. Rev. 2013, 42, 9283.
(2) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.
Copper Catalysed Ullmann Type Chemistry: From Mechanistic
Aspects to Modern Development. Chem. Soc. Rev. 2014, 43, 3525−
3
550.
(
3) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-
Catalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116,
2564−12649.
4) Brown, D. G.; Bostrom, J. Analysis of Past and Present Synthetic
̈
1
(
Methodologies on Medicinal Chemistry: Where Have All the New
Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458.
(5) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s
Toolbox: An Analysis of Reactions Used in the Pursuit of Drug
Candidates. J. Med. Chem. 2011, 54, 3451−3479.
(6) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P. New
N- and O-Arylations with Phenylboronic Acids and Cupric Acetate.
Tetrahedron Lett. 1998, 39, 2933−2936.
Figure 1. Proposed mechanism.
C
DOI: 10.1021/acs.orglett.9b01434
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
7) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. New Aryl/Heteroaryl C-N Bond
Cross-Coupling Reactions via Arylboronic Acid/Cupric Acetate
Arylation. Tetrahedron Lett. 1998, 39, 2941−2944.
(
8) Evans, D. A.; Katz, J. L.; West, T. R. Synthesis of Diaryl Ethers
through the Copper-Promoted Arylation of Phenols with Arylboronic
Acids. An Expedient Synthesis of Thyroxine. Tetrahedron Lett. 1998,
3
(
9, 2937−2940.
9) Hall, D. G. Structure, Properties, and Preparation of Boronic
Acid Derivatives. Overview of Their Reactions and Applications. In
Boronic Acids; Wiley-VCH: Weinheim, 2006; pp 1−99.
(
10) Vantourout, J. C.; Miras, H. N.; Isidro-Llobet, A.; Sproules, S.;
Watson, A. J. B. Spectroscopic Studies of the Chan-Lam Amination: A
Mechanism-Inspired Solution to Boronic Ester Reactivity. J. Am.
Chem. Soc. 2017, 139, 4769−4779.
(
11) Yoo, W. J.; Tsukamoto, T.; Kobayashi, S. Visible-Light-
Mediated Chan-Lam Coupling Reactions of Aryl Boronic Acids and
Aniline Derivatives. Angew. Chem., Int. Ed. 2015, 54, 6587−6590.
(
12) Antilla, J. C.; Buchwald, S. L. Copper-Catalyzed Coupling of
Arylboronic Acids and Amines. Org. Lett. 2001, 3, 2077−2079.
(
13) Munir, I.; Zahoor, A. F.; Rasool, N.; Naqvi, S. A. R.; Zia, K. M.;
Ahmad, R. Synthetic Applications and Methodology Development of
Chan−Lam Coupling: A Review. Mol. Diversity 2019, 23, 215.
(
14) King, A. E.; Ryland, B. L.; Brunold, T. C.; Stahl, S. S. Kinetic
and Spectroscopic Studies of Aerobic Copper(II)-Catalyzed Methox-
ylation of Arylboronic Esters and Insights into Aryl Transmetalation
to Copper(II). Organometallics 2012, 31, 7948−7957.
(
15) Lam, P. Y. S. Chan−Lam Coupling Reaction: Copper-
Promoted C−Element Bond Oxidative Coupling Reaction with
Boronic Acids. Synthetic Methods in Drug Discovery; Royal Society of
Chemistry, 2016; Chapter 7.
(
16) Qiao, J. X.; Lam, P. Y. S. Copper-Promoted Carbon-
Heteroatom Bond Cross-Coupling with Boronic Acids and Deriva-
tives. Synthesis 2011, 2011, 829−856.
(
17) Hardouin Duparc, V.; Bano, G. L.; Schaper, F. Chan−Evans−
Lam Couplings with Copper Iminoarylsulfonate Complexes: Scope
and Mechanism. ACS Catal. 2018, 8, 7308−7325.
(
18) Qi, H.-L.; Chen, D.-S.; Ye, J.-S.; Huang, J.-M. Electrochemical
Technique and Copper-Promoted Transformations: Selective Hy-
droxylation and Amination of Arylboronic Acids. J. Org. Chem. 2013,
7
(
8, 7482−7487.
19) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(
20) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and
Calculated Electrochemical Potentials of Common Organic Molecules
for Applications to Single-Electron Redox Chemistry. Synlett 2016,
2
(
7, 714.
21) Pekmez, K.; Avci, E.; Baumgartel, H. G.; Donner, C. The
̈
Under Potential Deposition of Cu on Au (111) in Nonaqueous
Acetonitrile. Z. Phys. Chem. 2012, 226, 953−963.
(
22) Izutsu, K. Use of Non-Aqueous Solutions in Modern
Electrochemical Technologies. Electrochem. Nonaqueous Solut. 2002,
(Iv), 313−330.
23) Macleod, I. D.; Parker, A. J.; Singh, P. Electrochemistry of
Copper in Aqueous Acetonitrile. J. Solution Chem. 1981, 10, 757−774.
24) See the SI for a detailed mechanistic discussion and
investigation.
5
(
(
D
DOI: 10.1021/acs.orglett.9b01434
Org. Lett. XXXX, XXX, XXX−XXX