Ni-Catalyzed Electrochemical Decarboxylative C-C Couplings in Batch and Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.8b00070

An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp³)-C(sp²) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.

Full text of DOI:10.1021/acs.orglett.8b00070

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni-Catalyzed Electrochemical Decarboxylative C−C Couplings in
Batch and Continuous Flow
Hui Li,† Christopher P. Breen,†,‡ Hyowon Seo,‡ Timothy F. Jamison,*,‡ Yuan-Qing Fang,*,†
and Matthew M. Bio*,†
†Snapdragon Chemistry Inc., Cambridge, Massachusetts 02140, United States
‡Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: An electrochemically driven, nickel-catalyzed
reductive coupling of N-hydroxyphthalimide esters with aryl
halides is reported. The reaction proceeds under mild
conditions in a divided electrochemical cell and employs a
tertiary amine as the reductant. This decarboxylative C(sp3)−
C(sp2) bond-forming transformation exhibits excellent sub-
strate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using
a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.
he formation of Csp3−Csp2 bonds is a powerful means of
1
Tsynthesizing high-value chemicals. Nickel catalysis has
offered numerous avenues to Csp3−Csp2 bond assembly via cross
coupling of Csp3 electrophiles. Most methods make use of
organometallic compounds as transmetalating agents, which are
reminiscent of classic Kumada, Negishi, and Suzuki couplings.2
The needs of using these highly sensitive, less functional group
compatible organometallic reagents necessitated the develop-
Figure 1. Nickel-catalyzed sp3−sp2 cross-couplings using carboxylic
ment of additional modes of nickel-catalyzed Csp3−Csp2 bond
acids/derivatives and aryl halides as coupling partners.
formation using native functional groups as latent nucleophiles.
These include cross-coupling methods that combine single-
electron-transfer catalytic cycles of nickel with iridium photo-
redox cocatalysts3 and cross-electrophile reductive couplings
relying on an exogenous, stoichiometric metallic powder
reductant (e.g., Zn, Mn) to transfer electrons to nickel catalysts.4
Herein, we report a novel and powerful approach for
electrochemical generation of highly reactive radicals and their
incorporation into a Ni-catalyzed Csp3−Csp2 coupling manifold
to construct structurally diverse molecules in both batch and
continuous flow.
One seminal example in this field reported by MacMillan and
Doyle elegantly utilized an Ir-photoredox/Ni dual catalyst
system to achieve decarboxylative Csp3−Csp2 coupling (Figure
1). The requirement of an α-heteroatom in the starting material
carboxylic acid limits its broad use of inexpensive and readily
available aliphatic carboxylic acids. To utilize more general
carboxylic acids, Weix group demonstrated a complementary
approach of Ni-catalyzed cross coupling of N-hydroxyphthali-
mide (NHP) esters in the presence of zinc powder as a reducing
agent.5 Nonetheless, reactive metal powders are generally
challenging to work with, in particular on large scales due to
purity, surface oxidation, and safety issues. Mechanistically, many
electron-transfer steps in photoredox-catalytic cycle or chemical
reduction parallels electrochemical processes. Instead of intrinsi-
cally less efficient electron-photon-electron conversion (e.g.,
LED light) or stoichiometric amounts of metal reductants, we
thought direct reduction of NHP esters using electric current
would be a much more energy efficient and safer method to
introduce reactive radical species into a catalytic cycle.6
Interest in electrochemical methods has recently been revived
as an attractive solution to lingering problems in organic
synthesis.7 By tuning the applied potential and current,
electrochemistry offers precise, selective formation and regulated
generation of reactive species, enabling predictable and control-
lable chemoselectivity.8 Such advantages render electrochemistry
a sustainable, economically practical, and environmentally
benign technique for chemical synthesis.
We reasoned that cathodic reduction of the redox active NHP
ester 19,10 would result in a decarboxylative fragmentation
resulting in generation of the Csp3 radical 2 (Figure 2).
Observation of an irreversible reduction using cyclovoltametry
of model substrate 4 at −1.2 V (vs Ag/AgCl) supported this
initial hypothesis. Alkyl radical 2 is then intercepted by a
homogeneous nickel catalyst, which could be either Ni(0) or
Ni(II) generated from oxidative addition of aryl halides. The
challenge in this case is whether or not a highly reactive radical
Received: January 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
experiments (Table 1) indicate that the reaction proceeds with
superior chemoselectivity for the desired coupling pathway
versus Kolbe-type coupling in a divided H-cell over an undivided
cell. The superior performance in a divided cell is likely due to
competitive anodic oxidation of low-valent nickel species in an
undivided cell (entries 1 and 2). Diminished yield and
chemoselectivity (entry 3) occurred when nickel foam was
used as the cathode material compared to using RVC. A cursory
solvent and ligand screening did not afford improved reaction
outcome (entries 4−7) from the original condition. Increasing
the catalyst loading of NiII/dtbbpy combination to 30 mol %
promoted the yield of 5 (entry 8). Further optimization of the
electrolyte counteranion identified PF6− as providing an optimal
yield of 5 and high chemoselectivity (74%, > 10:1, entry 10).12 As
expected, a control experiment performed in the absence of
electron current resulted in no product formation. Performing
the reaction without a nickel catalyst present resulted in
formation of Kolbe coupling dimer 6 along with a significant
amount of hydrocinnamic acid 7 (entries 11 and 12). It is worth
noting that formation of 7 was observed under all productive
conditions (entries 1−10, 12). Water content of the reaction
mixture (∼100 ppm) only accounted for ∼6 mol % of 7. The
results suggest a competitive electrochemically mediated path-
way is presumably responsible for the formation of 7.
Figure 2. Proposed electrochemical-driven nickel-catalyzed decarbox-
ylative arylation unit steps.
species generated on a solid-state electrode surface would have
sufficient lifetime to interact with nickel catalyst before Kolbe
dimerization or sequential over reduction into carbanion. Upon
generation of Ni(III) species 3, the alkyl and aryl groups are
expected to undergo reductive elimination to form the Csp3−Csp2
coupling product. The resulting Ni(I) would be reduced at the
cathode to Ni(0), thus closing the catalytic cycle. Notably, we
propose to use electron-rich tertiary amines as sacrificial
reductants, which would easily undergo anodic oxidation and
donate electrons to the electrochemical system.11
With this mechanistic hypothesis in mind, we set out to
explore the feasibility of our proposed decarboxylative arylation
reaction (Table 1). Our investigations began with the coupling
between NHP ester 4 and iodobenzene using triethylamine as
the sacrificial reductant, reticulated vitreous carbon (RVC) as
cathode and anode material, and with maximum potential (V)
and current (A) output set at 10 V and 20 mA, respectively. Initial
With optimized conditions identified, we then explored the
reaction scope (Scheme 1). The reaction tolerated a range of
primary and secondary NHP esters, including esters derived
from natural products (e.g., 10q, 10r). NHP esters with
constrained α-carboxyl quaternary sp3 centers can be incorpo-
rated with good efficiency (10f), but nonconstrained quaternary
centers are beyond the range of the present system (10g).
Scheme 1. Reaction Scope of Nickel-Catalyzed
Electrochemical Decarboxylative Arylations
Table 1. Initial Studies toward Nickel-Catalyzed
Electrochemical Decarboxylative Arylation Reactions
b
yield (%)
a
entry
deviation from above
5
6
7
1
none
54
6
11
39
23
20
26
23
14
9
22
18
21
21
19
24
25
18
15
14
0
2
undivided cell
3
nickel foam cathode
41
49
48
47
49
67
65
74
0
4
DMF instead of DMA
CH3CN instead of DMA
bpy instead of dtbbpy
dmebpy instead of dtbbpy
30 mol % NiII/dtbbpy
30 mol % NiII/dtbbpy, Bu4NClO4
30 mol % NiII/dtbbpy, Bu4NPF6
no electricity
5
6
7
8
9
10
6
10
11
12
0
no NiBr2·glyme
0
44
38
a
b
2 mmol scale. Yield determined by calibrated HPLC assay.
c
Maximum potential and current output set at 10 V and 20 mA.
B
DOI: 10.1021/acs.orglett.8b00070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Various electron-neutral and electron-deficient (hetero)aryl
halides are suitable partners and coupled efficiently (e.g., 10h−
l). Electron-rich 4-iodoanisole was also amenable to the current
electrochemical condition (10m), albeit in modest yield. The
mild nature of the current protocol facilitates broad functional
group compatibility, tolerating ketone (10p), esters (10o),
alkene (10q), protected nitrogen (10b, 10c, 10r), and boronic
ester (10r) moieties. Benzylic alcohol (10n) and terminal alkyne
(10s) containing substrates, however, are not compatible with
the current reaction conditions.
Organic electro-synthesis carried out in laboratory batch cells
(e.g., H-cells) represents a useful approach for small scale (<5
mmol) electrochemical reactions but presents limitations for
larger scale production. One potential approach to address
practically and economically the scalability issue is operation
under continuous flow conditions.13 Owing to the decreased
interelectrode distance and increased interfacial ratio of electrode
versus reaction stream within an electrochemical flow cell, the
efficiency of mass, energy, and electron transfer may be enhanced
significantly.
The intermediacy of radical species 2 was supported by a
radical-clock experiment (eq 1). Coupling of NHP ester 11 with
To examine these potential advantages, the electrochemical
nickel-catalyzed decarboxylative reactions were evaluated under
flow conditions (Table 2). RVC foam pieces were attached to the
Table 2. Continuous-Flow Ni-Catalyzed Electrochemical
Decarboxylative Arylations
iodobenzene provided 12 exclusively in 46% yield, which is
consistent with rapid ring opening of the intermediate
cyclopropylmethyl radical resulting from decarboxylative
fragmentation of the carboxyl radical.
The kinetic profile of the reaction of 4 with iodobenzene was
examined to gain insight into the decarboxylative coupling
reaction (entry 1, Table 1). As shown in Figure 3, very little
d
yield (%)
a
b
c
entry
reactor
j (mA/cm3)
tR (min)
5
6
7
1
2
3
4
flow cell
flow cell
flow cell
38
29
3.8
4.2
54
62
81
74
33
17
6
8
10
8
14
8.3
d
H-cell
3−4.5
410
6
14
a
Cathode stream: 4 (0.1 M), PhI (2 equiv) NiBr2 dme/dtbbpy (30
mol %), Bu4NPF6 (0.2 M); anode stream: NEt3 (6 equiv), Bu4NPF6
b
(0.2 M). j = current density, mA per cubic centimeter of RVC carbon
c
foam (100 ppi). Internal wet volume of anode or cathode flow cell is
d
0.5 mL. Yield determined by calibrated HPLC assay.
anode and cathode graphite plates of a C-flow electrochemical
flow cell, to provide increased surface area of both electrodes (see
SI). A cathodic stream (containing NHP ester 4, iodobenzene,
NiII/dtbbpy, and Bu4NPF6) and an anodic stream (containing
triethylamine and Bu4NPF6) were flowed into the electro-
chemical cell. A Nafion membrane was utilized to separate the
two streams, allowing cross-membrane flow of ions but not
neutral molecules.14 Adjustment of flow rates at a given current
density allowed full conversion of NHP ester 4 after a single pass
through the cell. Increased flow rates showed a positive effect on
the chemoselectivity to favor decarboxylative arylation over
Kolbe-type dimerization. This is likely a result of improved
mixing at increased flow rates (see the SI). With a current density
of 38 mA per cubic centimeter of RVC carbon foam (100 ppi),
55% of decarboxylative arylation product 5 was produced along
with significant amount of dimer 6 (33%, entry 1). This indicates
that the rate of homobenzyl radical generation is faster than the
nickel-based catalytic cycle turnover frequency. We then fine-
tuned the current density to match more closely the kinetics of
these two chemical events. Indeed, improved chemoselectivity
occurred at lower current density (entries 2 and 3). Under the
optimized condition, 81% of 5 was furnished at a current density
Figure 3. Kinetic profile of decarboxylative coupling between NHP ester
and iodobenzene (“e” denotes electron).
coupling product 5 was observed during the initial hour of
electrolysis. The major cathodic event is likely the reduction of
NiII to NiI/Ni0 species. This is supported by the observation of a
reduction event at −0.8 V in a cyclic voltammetry experiment (vs
Ag/AgCl). Such a voltage is below the reductive potential of both
NHP ester 4 at −1.2 V and iodobenzene at −2.3 V (see the
Supporting Information). The onset of product 5 formation
appears around 70 min, at which time 0.79 mmol of electrons
have been passed through the system. This value is very close to
the theoretical amount of electrons (i.e., 0.8 mmol) required to
completely reduce NiII to Ni0. Interestingly, neither the dimer 6
nor hydrocinnamic acid 7 is observed until about 3 h of
electrolysis. This observation suggests that deactivation of the
nickel catalyst occurs after ∼3 h of electrolysis. As indicated in
Figure 3, the production rate of 6 and 7 increases while the rate of
the desired pathway decreases. This regime is reminiscent of the
reaction pathway devoid of nickel (entry 12, Table 1).
C
DOI: 10.1021/acs.orglett.8b00070
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of 14 mA/cm3 and 8.3 min residence time, as compared to 74%
yield obtained in batch (H-cells) with 3−4.5 mA/cm3 current
density and 410 min residence time (entry 3 vs 4). Interestingly,
in continuous flow, the formation of byproduct 7 was suppressed
(entries 1−3 vs 4).
2014, 345, 437. For representative examples of using organoborons as
nucleophiles, see: (c) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science
2014, 345, 433.
(4) For representative reviews, see: (a) Weix, D. J. Acc. Chem. Res.
2015, 48, 1767. For selected examples, see: (b) Everson, D. A.;
Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920. (c) Wang, X.;
Wang, S.; Xue, W.; Gong, H. J. Am. Chem. Soc. 2015, 137, 11562. For
representative example of nonmetallic reductant, see: (d) Suzuki, N.;
Hofstra, J. L.; Poremba, K. E.; Reisman, S. Org. Lett. 2017, 19, 2150.
(e) Anka-Lufford, L. L.; Huihui, K. M. M.; Gower, N. J.; Ackerman, L. K.
G.; Weix, D. J. Chem. - Eur. J. 2016, 22, 11564. (f) Kuroboshi, M.; Waki,
Y.; Tanaka, H. Synlett 2002, 2002, 637.
(5) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.;
Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman,
L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016.
(6) Sambiagio, C.; Sterckx, H.; Maes, B. U. W. ACS Cent. Sci. 2017, 3,
686.
(7) For pioneering studies, see: (a) Durandetti, M.; Nedelec, J.;
Perichon, J. J. Org. Chem. 1996, 61, 1748. For representative reviews,
see: (b) Chaussard, J.; Folest, J.; Nedelec, J.; Perichon, J.; Sibille, S.;
Troupel, M. Synthesis 1990, 1990, 369. (c) Horn, E. J.; Rosen, B. R.;
Baran, P. S. ACS Cent. Sci. 2016, 2, 302. For representative examples,
see: (d) Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Org. Lett. 2017, 19,
3755. (e) Frankowski, K. J.; Liu, R.; Milligan, G. L.; Moeller, K. D.; Aube,
J. Angew. Chem., Int. Ed. 2015, 54, 10555. (f) Horn, E. J.; Rosen, B. R.;
Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016,
533, 77. (g) Kawamata, Y.; Yan, M.; Liu, Z.; Bao, D. − H.; Chen, J.; Starr,
J.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 7448. (h) Fu, N.; Sauer, G. S.;
Saha, A.; Loo, A.; Lin, S. Science 2017, 357, 575. (i) Fu, N.; Sauer, G. S.;
Lin, S. J. Am. Chem. Soc. 2017, 139, 15548. (j) Yang, Q.; Li, Y.; Ma, C.;
Fang, P.; Zhang, X.; Mei, T. J. Am. Chem. Soc. 2017, 139, 3293.
(k) Xiong, P.; Xu, H.; Xu, H. J. Am. Chem. Soc. 2017, 139, 2956. (l) Li, C.;
Kawamata, Y.; Nakamura, H.; Vantourout, J. C.; Liu, Z.; Hou, Q.; Bao,
D.; Starr, J. T.; Chen, J.; Yan, M.; Baran, P. S. Angew. Chem., Int. Ed. 2017,
56, 13088. (m) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017,
117, 13230.
In summary, we have demonstrated that electrochemically
generated, highly reactive, and short-lived radical species on a
solid-state electrode surface can be selectively incorporated into a
transition-metal catalysis manifold to form high-complexity
molecules productively. These electrochemically driven, Ni-
catalyzed decarboxylative Csp3−Csp2 cross-reductive couplings of
NHP ester with aryl halides exhibit broad substrate compatibility,
tolerance of a range of sterically and electronically diverse
coupling partners. Preliminary studies demonstrated improved
reaction performance and efficiency when carried out under
continuous flow conditions and delivered a method that is
amenable to rapid scale-up. The results reported herein provide a
new and practical method for the use of carboxylic acids as
precursors to C−C bond-forming reactions and allude to a broad
range of potential similar reaction manifolds that are currently
being pursued in our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00070.
Experimental procedure and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tfj@mit.edu.
*E-mail: eric.fang@snapdragonchemistry.com.
*E-mail: matt.bio@snapdragonchemistry.com.
(8) Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev. 2008,
108, 2265.
ORCID
(9) For pioneering studies, see: (a) Okada, K.; Okamoto, K.; Oda, M. J.
Am. Chem. Soc. 1988, 110, 8736. (b) Okada, K.; Okamoto, K.; Morita,
N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401.
(10) For selected recent examples, see: (a) Schnermann, M. J.;
Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576. (b) Cornella, J.;
Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio,
R.; Schmidt, M. A.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2016,
138, 2174. (c) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016,
352, 801. (d) Wang, J.; Qin, T.; Chen, T.-E.; Wimmer, L.; Edwards, J. T.;
Cornella, J.; Vokits, B.; Shaw, S. A.; Baran, P. S. Angew. Chem., Int. Ed.
2016, 55, 9676. (e) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.;
Dixon, D. D.; Creech, G.; Baran, P. S. J. Am. Chem. Soc. 2016, 138,
11132. (f) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse,
K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-
L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213.
(g) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017,
139, 12153. (h) Candish, L.; Teders, M.; Glorius, F. G. C. J. Am. Chem.
Soc. 2017, 139, 7440.
Timothy F. Jamison: 0000-0002-8601-7799
Yuan-Qing Fang: 0000-0002-8952-1018
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this work was partially provided by an SBIR
grant from NSF (164576). C.P.B, H.S., and T.F.J. also thank the
Bill and Melinda Gates Foundation (“Medicine for All”
Initiative) for financial support. H.S. thanks Amgen Graduate
Fellowship in Synthetic Chemistry.
REFERENCES
■
(1) (a) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Jana, R.; Pathak, T. P.;
Sigman, M. S. Chem. Rev. 2011, 111, 1417. (c) Manolikakes, G. 3.08
Coupling Reactions Between sp3 and sp2 Carbon Centers A2. In
Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P., Molander, G.
A., Eds.; Elsevier: Amsterdam, 2014; pp 392−464.
(11) For representative examples of photoredox/nickel catalysis with
nonmetallic terminal reductants, see: (a) Duan, Z.; Li, W.; Lei, A. Org.
Lett. 2016, 18, 4012. (b) Paul, A.; Smith, M. D.; Vannucci, A. K. J. Org.
Chem. 2017, 82, 1996. (c) Zhang, P.; Le, C.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2016, 138, 8084.
(2) For representative reviews, see: (a) Tasker, S. Z.; Standley, E. A.;
Jamison, T. F. Nature 2014, 509, 299. (b) Tellis, J. C.; Kelly, C. B.;
Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res.
2016, 49, 1429. (c) Fu, G. C. ACS Cent. Sci. 2017, 3, 692. (d) Lucas, E.
L.; Jarvo, E. R. Nature Rev. Chem. 2017, 1, 0065.
(3) For representative reviews, see: (a) Twilton, J.; Le, C. C.; Zhang, P.;
Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. Nature Rev. Chem.
2017, 1, 0052. For representative examples, see: (b) Zuo, Z.; Ahneman,
T.; Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Science
(12) Using DIPEA as an anodic sacrificial reductant furnished
comparable results.
(13) (a) Pletcher, D.; Green, R. A.; Brown, R. C. D. Chem. Rev. 2017,
DOI: 10.1021/acs.chemrev.7b00360. (b) Plutschack, M. B.; Pieber, B.;
Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796.
(14) HPLC analysis has shown that <1% substrate/product is present
in the outflow anodic stream.
D
DOI: 10.1021/acs.orglett.8b00070
Org. Lett. XXXX, XXX, XXX−XXX