Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation

Article abstract of DOI:10.1021/acscatal.8b00373

A ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes has been developed for the synthesis of indoles. Electric current is used to recycle the active ruthenium-based catalyst and promote H₂ evolution. The electrolysis reaction is operationally convenient as it employs a simple undivided cell, proceeds efficiently in an aqueous solution, and is insensitive to air.

Full text of DOI:10.1021/acscatal.8b00373

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Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation
Fan Xu, Yan-Jie Li, Chong Huang, and Hai-Chao Xu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00373 • Publication Date (Web): 09 Mar 2018
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ACS Catalysis
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Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne An-
nulation
Fan Xu,† YanꢀJie Li,† Chong Huang, and HaiꢀChao Xu*
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State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province,
Collaborative Innovation Center of Chemistry for Energy Materials, and College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005 (P. R. China)
ABSTRACT: A rutheniumꢀcatalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes has
been developed for the synthesis of indoles. Electric current is used to recycle the active rutheniumꢀbased catalyst and promote H₂
evolution. The electrolysis reaction is operationally convenient as it employs a simple undivided cell, proceeds efficiently in an
aqueous solution, and is insensitive to air. KEYWORDS: electrochemistry, C–H activation, ruthenium, annulation, indole
Introduction
important indole products through (3+2) annulation of aniline
derivatives with internal alkynes without the use of chemical
oxidants (Scheme 1c).
Transition metalꢀcatalyzed C–H activation reactions have sigꢀ
nificantly streamlined organic synthesis often by eliminating
the need of substrate preꢀfunctionalization. Particularly, dehyꢀ
drogenative alkyne annulation has emerged as an enabling tool
for the preparation of heterocycles.1 However, the method
generally requires a stoichiometric amount of organic or metꢀ
alꢀbased oxidant, which is a common characteristic of oxidaꢀ
tive C–H functionalization reactions. Like many other oxidaꢀ
tive C–H functionalization reactions, these reactions usually
employ stoichiometric amount of metal, such as CuII or AgI, or
organic oxidants. The potential safety and environmental imꢀ
pacts of these oxidative reagents, consequently, have substanꢀ
tially limited the application scope and industrial utility of the
C–H functionalization reactions.2
Previous work
a) Electrochemical C–H activation/functionalization
M
C
H
C
X
M = Pd, Co
b) CuII-mediated annulation by Ackermann (Ref. 34)
R2
R2
cat. RuII
R1
R3
R1
+
NH
N
Cu(OAc)2 (2 equiv)
R3
N
N
N
N
This work
c) Ru-catalyzed annulation via H2 evolution
Electrosynthesis, which achieves redox reactions with traceꢀ
less electric current, is an attractive synthetic tool3ꢀ9 and has
led to the development of various oxidantꢀfree dehydrogenaꢀ
tive coupling reactions.10ꢀ21 Particularly, few elegant studies
have achieved Pdꢀcatalyzed electrochemical C–H activation to
form C–C and C–heteroatom bonds (Scheme 1a).22ꢀ26 A comꢀ
mon theme in these methodologies involves the use of divided
cells to avoid the cathodic deactivation or decomposition of
the metal catalysts. Very recently, Ackermann and coworkers
reported Coꢀcatalyzed electrochemical C–H functionalization
reactions.27,28
R2
R2
R1
R3
R1
Ru
+ H2
+
NH
N
R3
N
N
N
N
Undivided cell
Annulation
Scheme 1. Transition Metal-Catalyzed Electrochemical C–
H Activation
We began our study by optimizing the reaction conditions
for the coupling of Nꢀ2ꢀpyrimidyl substituted aniline 1 and
diphenylacetylene 2 (Table 1). The 2ꢀpyrimidyl group had
been shown by Ackermann to be an effective and removable
directing group for ruthenium catalyzed C–H functionalization
reactions.34,37 The setup for the constant current electrolysis
consisted of an undivided cell (a threeꢀnecked roundꢀbottomed
flask) equipped with a reticulated vitreous carbon (RVC) anꢀ
ode and a Pt plate cathode. The reaction was conducted using
2 equiv of 2 under reflux in the presence of 20 mol % of
KPF638 and 20 mol % of NaOAc.33, 40ꢀ42 The salt additives also
served as supporting electrolytes. Under these conditions, the
annulation product 3 was formed in 37% yield after the conꢀ
Ruthenium is an attractive metal for C–H bond activation
due to its excellent catalytic reactivity and relatively low cost
when compared with Pd and Rh.29ꢀ32 Ruꢀcatalyzed annulation
reactions via C–H activation33,34 have been developed for the
synthesis of various heterocyclic compounds including indoles
(Scheme 1b).34 We have been interested in electrochemical
dehydrogenative annulation reactions35,36 and have previously
described the facile preparation of (aza)indoles via intramoꢀ
lecular C–H/N–H functionalization.35 Here we report a Ruꢀ
catalyzed electrochemical C–H activation reaction using a
simple undivided cell. Our method allows efficient access to
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sumption of 3.2 F mol−1 of electricity. A variety of organic coꢀ
Page 2 of 6
of the less reactive substrates. When the Nꢀ(2ꢀ
pyrimidyl)aniline was substituted at one of the meta positions,
the electrolytic annulation resulted in regioselective formation
of 6ꢀsubstituted indoles (7, 8). Sterically hindered substrates,
such as that derived from 3,5ꢀdimethylaniline, exhibited poor
reactivity and did not afford any target products (15). These
results suggested the importance of steric effects for regioseꢀ
lectivity and reactivity. On the other hand, diphenylacetylene 2
could be replaced with an internal alkyne functionalized with
an alkyl group on one terminus and an aryl on the other, which
led to the preferential formation of 2ꢀaryl indoles (16–23).
However, a higher catalyst loading was found necessary when
1
2
3
4
5
6
7
8
solvents were tested (entries 2–6). Gratifyingly, the yield of 3
was boosted to 71% by using H2O/EtOH (1:1) as the solvent
(entry 2). Other alcohols such as iPrOH (entry 3), tBuOH (enꢀ
try 4), or tAmOH (entry 5) were more effective than EtOH
leading to the formation of 3 in around 90% yield. The use of
MeCN afforded only trace amount of 3 (entry 6). iPrOH was
selected as the coꢀsolvent for further optimization due to its
low cost. The yield was reduced to 70% when the amount of
the alkyne was reduced to 1.2 equiv (entry 7). While NaOAc
(entry 8) and KPF6 (entry 9) were important for optimal reacꢀ
tion efficiency, the Ruꢀcatalyst was indispensable for product
formation (entry 10). Screening of electrode materials revealed
that replacing the RVC anode with glassy carbon plate (entry
11) or graphite plate (entry 12) resulted in a sharp drop in
yield. On the other hand, nickel plate could effectively substiꢀ
tute for Pt as the cathode (entry 13), but not RVC (entry 14).
The method showed no apparent sensitivity to oxygen and
therefore could be performed under atmospheric conditions
(entry 15).
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R2
R2
RVC
Pt
R1
[RuCl2(p-cymene)]2 (5 mol %)
R3
NH
DG
R1
+
N
KPF6 (20 mol %), NaOAc (20 mol %)
H2O/iPrOH (1:1), reflux, 1.8–3.9 h
R3
DG
DG = 2-pyrimidyl
(2 equiv)
product, yielda
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
Me
F
Table 1. Optimization of Reaction Conditionsa
DG
DG
DG
OMe
F
DG
4
5
6
7
, 99%
, 95%
Ph
, 91%
, 94%
Ph
Ph
N
DG
Ph
Ph
MeO
Ph
Ph
Ph
N
N
DG
N
DG
MeO2C
DG
b
b
10, 70%
8
, 87%
9
11
, 86%
, 84%
Ph
Me
Ph
Ph
Ph
Br
F3C
Cl
Ph
Ph
Ph
Ph
Me
N
DG
N
N
DG
N
DG
MeO
DG
13, 78%b
12
14, 77%b
nBu
15
, 0%
, 69%
Et
nBu
nBu
S
Ph
R
OH
N
N
DG
N
DG
N
DG
DG
Me
Me
Me
, 63%b (6.9:1)
20
19, 69% (4.5:1)
16
17
18
, 89% (11:1)
, R = F, 73% (7:1)
, R = OMe, 83% (6:1)
Me
Me
OH
nBu
OH
Ph
nBu
Ph
N
DG
N
DG
N
DG
N
F
DG
, 98%b (14:1)
b
24, 75%b
21, 72%b (10:1)
22
23
, 39%
Scheme 2. Substrate Scope. Reaction conditions: Aniline deꢀ
rivative (0.3 mmol), 10 mA (janode ≅ 0.13 mA cm−2), 2.3–4.9 F
mol−1. aIsolated yield. Regioisomeric ratio in parenthesis was
determined by 1H NMR analysis of crude reaction mixture. bReacꢀ
tion with 10 mol % [RuCl2(pꢀcymene)]2 in H2O/tAmOH (1:1).
aReaction conditions: RVC anode (100 PPI), Pt plate cathode, 1
b
(0.3 mmol), solvent (6 mL), argon, 10 mA, 3.2 F mol−1. Yield
1
determined by H NMR analysis using 1,3,5ꢀtrimethoxybenzene
as the internal standard, unreacted 1 in parenthesis. cIsolated yield.
d1 cm x 1 cm.
We next explored the reaction scope by varying both couꢀ
pling substrates (Scheme 2). As shown, the aniline could be
unsubstituted (4) or carry functional groups of different elecꢀ
tronic properties at various positions (5–14), although substitꢀ
uents such as CO2Me (8) and CF3 (13) showed a detrimental
effect on reactivity and thus required a higher catalyst loading
to ensure complete substrate conversion. Note that for less
efficient substrates, tAmOH was used as the coꢀsolvent instead
of iPrOH to provide a higher reaction temperature. Attempts to
increase the conversion by passing more charge was unsucꢀ
cessful suggesting catalyst deactivation during the electrolysis
Scheme 3. Synthetic Application
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Mechanistic investigation of the Ruꢀcatalyzed electrochemꢀ
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2
3
4
5
6
7
8
the internal alkyne carried a thiophene (20), a secondary (22)
or hydroxylꢀsubstituted (21, 23) alkyl group.43 5ꢀDecyne was
also compatible with our electrolytic annulation reaction (24).
ical reaction indicated that the activation of the aryl C–H bond
in the aniline derivative was reversible and did not involve the
alkyne substrate, as evidenced by the finding that the H/D
exchange at the ortho position of 1 in deuterated solvent was
independent of 2 (Scheme 4a). The H/D exchange also ocꢀ
curred at rt albeit at a slower rate than reflux. Competition
experiments using anilines or alkynes with different electronic
properties revealed that the annulation could be facilitated by
increased electron density in the coupling partners (Scheme
4b, c), in consistence with what Ackermann et al. observed in
the CuIIꢀmediated oxidative C–H activation reactions.34 The
reduced yield of compounds 17 and 18 in the competition exꢀ
periment was due to decreased conversion, which suggested
an inhibitory effect of the alkyne coupling partner.43 Indeed,
the conversion of 1 was reduced when the alkyne 37 was inꢀ
creased from 2 equiv to 6 equiv (Scheme 4d). Performing the
reaction of 1 and 2 in the presence of 1 equiv of RuII but withꢀ
out electricity afforded the product 3 in 71% yield (Scheme
4e). These results suggested that the electric current served to
regenerate the active ruthenium catalyst and did not affect
other steps of the catalytic cycle.
The synthetic utility of our method was further demonstratꢀ
ed by the electrochemical annulation of 25 and 26 (Scheme 3),
which was performed on a gram scale and furnished the exꢀ
pected indole derivative 27 in 88% yield (10.6 g). The 2ꢀ
pyrimidyl group could then be removed by following a reportꢀ
ed procedure34 to generate the free indole 28, a critical synthetꢀ
ic precursor to the antiꢀosteoporotic drug bazedoxifene.44
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Besides indole synthesis, preliminary results showed that
the Ruꢀcatalyzed electrochemical C–H activation method
could also be employed to accomplish (4+2) annulation of
benzylamine with alkynes for the preparation of isoquinolines
as demonstrated by the synthesis of compounds 31 and 33 [Eq.
(1)].45
Scheme 5. Proposed Mechanism
A plausible mechanism for the RuIIꢀcatalyzed electrolytic
annulation reaction was proposed based on the findings in this
and previous studies,33,34 though further investigation would be
needed to elucidate its details (Scheme 5). In the presence of
the NaOAc, the dimeric preꢀcatalyst [RuCl2(pꢀcymene)]2 is
converted to the ruthenium diacetate complex A. Reaction of
A with the alkyne may lead to unproductive complexes and
result in the observed inhibitory effect at high concentration of
the alkyne.43 Complexation of A with 1, followed by reversiꢀ
ble C–H activation, forms the sixꢀmembered ruthenacycle C,
whose acetate ligand is subsequently displaced by the alkyne
substrate 2 as a result of πꢀcoordination to give D. The coordiꢀ
nation of 2 prompted its migratory insertion into the Ru–C
bond, triggering the metal center to dissociate from the pyrimꢀ
idyl nitrogen and instead complex with the amino group of the
aniline moiety to obtain the sixꢀmembered ruthenacycle in the
resultant intermediate E. The sensitivity of the annulation reꢀ
action to the electronic and steric properties of the aniline ring
and the alkyne substituents suggests that the insertion step
might be rateꢀlimiting. Eventually, reductive elimination of E
Scheme 4. Mechanistic Studies
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furnishes the indole product 3 and a Ru0 species (F), the latter
of which is oxidized on the anode to regenerate the catalyticalꢀ
ly active RuII complex. Correspondingly, protons are reduced
on the cathode to generate H2, which obviates the need for
external oxidants or Hꢀacceptors. In the preparative scale elecꢀ
trolysis, the catalyst resting state was most likely more reꢀ
sistant to cathodic reduction than the protons, allowing the use
of an undivided cell.
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In summary, we have demonstrated that electric current can
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of indole derivatives from easily accessible alkynes and aniꢀ
line derivatives, and is fully compatible with a simple undividꢀ
ed cell.
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AUTHOR INFORMATION
Corresponding Author
*haichao.xu@xmu.edu.cn
Author Contributions
†F.X. and Y.ꢀJ.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information. The experimental procedure, characterꢀ
ization data, and copies of 1H and 13C NMR spectra. The Supportꢀ
ing Information is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful for financial support of this research from MOST
(2016YFA0204100), NSFC (21672178), the “Thousand Youth
Talents Plan”, and Fundamental Research Funds for the Central
Universities.
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lyzed C–H functionalization with Electrochemical Oxidation. Tetra-
hedron Lett. 2017, 58, 797–802.
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