Ruthenium-catalyzed Suzuki coupling of anilines with alkenyl borates via selective aryl C–N bond cleavage

Article abstract of DOI:10.1016/j.catcom.2020.106009

Herein, we developed a new ruthenium(0)-catalyzed Suzuki-coupling of N,N-dimethyl-2-(pyridin-2-yl) anilines with alkenyl borates to synthesize 2-phenylolefins via the cleavage of neutral aryl C–N bond. In the absence of ligand and additives, by using pyridine as the directing group, the desired 2-phenylolefins were obtained in good to excellent yields with high stereoselectivity (E/Z > 20:1).

Full text of DOI:10.1016/j.catcom.2020.106009

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Ruthenium-catalyzed Suzuki coupling of anilines with alkenyl
borates via selective aryl C-N bond cleavage
Jian-Xing Xu, Fengqian Zhao, Robert Franke, Xiao-Feng Wu
PII:
S1566-7367(20)30085-6
DOI:
https://doi.org/10.1016/j.catcom.2020.106009
CATCOM 106009
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
16 March 2020
2 April 2020
2 April 2020
Please cite this article as: J.-X. Xu, F. Zhao, R. Franke, et al., Ruthenium-catalyzed Suzuki
coupling of anilines with alkenyl borates via selective aryl C-N bond cleavage, Catalysis
Communications (2019), https://doi.org/10.1016/j.catcom.2020.106009
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Ruthenium-Catalyzed Suzuki Coupling of Anilines with Alkenyl Borates via Selective
Aryl C-N Bond Cleavage
a
a
b
a
‡
Jian-Xing Xu, ‡ Fengqian Zhao, Robert Franke, and Xiao-Feng Wu*
a. Leibniz-Institutfür Katalysean der UniversitätRostock e. V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany, E-mail:
xiao-feng.wu@catalysis.de
b. Evonik Industries AG, Paul-Baumann-Str. 1, D-45772 Marl, Germany, and Lehrstuhl für Theoretische Chemie, Ruhr-
UniversitätBochum, Universitätsstraße150, D-44780 Bochum, Germany
‡ Jian-Xing Xu and Fengqian Zhao contributed equally
Keywords: Ruthenium Catalyst; Aniline; Alkenes; C-Coupling; Alkenyl Borates; C-N Bond Cleavage
Abstract: Herein, we developed a new ruthenium(0)-catalyzed Suzuki-coupling of N,N-dimethyl-2-(pyridin-2-yl) anilines with alkenyl
borates to synthesize 2-phenylolefins via the cleavage ofneutralaryl C-N bond. In the absence ofligand and additives, byusingpyridine as
the directing group, the desired 2-phenylolefins were obtained in good to excellent yields with high stereoselectivity ( E/Z > 20:1).
Transition-metal catalyzed functionalization of non-activated bonds, such as C-H, C-O, C-F, and C-N bonds has become one of the
most powerful protocols in modern organic synthesis.1 Among the substrates, anilines are versatile chemical building blocks for
many organic molecules in the manufacture of advanced materials, pharmaceuticals and agricultural chemicals.2 Due to the
accepted importance, numerous synthetic approaches have been developed for the aryl C-N bond formation during the past
decades, such as Buchwald-Hartwig amination,3 Ullmann cross-coupling reaction,4 C-H amination and etc.5 In contrast, the
functionalization of anilines via cleavage of the aryl C-N bond is much less reported. Given the abundance and wide availability of
anilines, it is important and attractive to develop new methods for their synthetic transformations. Many other useful
functionalized organic molecules can be obtained by cleavage of the aryl C-N bond. Such process can open possibilities on using
amino group as a site for the late-stage functionalization of molecules. However, the aryl C-N bond usually has high dissociation
energy, and chemically inert which lead the direct transformation challenge.6 Conventionally, activation of the aryl C-N bond is
conversing the aryl C-N bond into the corresponding diazonium salts,7 or ammonium salts,8 which contain much higher reactivity
(Figure 1, eq a). Remarkably, this challenge has been partly overcome by the research groups of Chatani, Shi, and Xia (Figure 1,
eq b).9 Suzuki-coupling, Kumada-coupling, borylation and reduction reactions of neutral anilines via the direct aryl C-N bond
cleavage have been successfully developed with nickel as the catalyst without directing group.
On the other hand, chelation-assisted inert bonds cleavage at 2-position of the directing groups has been identified as a
powerful strategy for regioselective C-X (X = H, O, F, N, etc.) bond functionalization.10 This strategy has also been successfully
explored in the functionalization of neutral aryl C-N bonds (Figure 1, eq c).11 To date, four examples have been successfully
developed on the chelation-assisted inert neutral aryl C-N bond cleavage. In 2007, Kakiuchi and co-workers reported
a
RuH2(CO)(PPh3)3-catalyzed Suzuki-coupling of o-NMe2 substituted pivalophenones.11a,11b By using ketone as the directing group
(DG), organic boronic acid 2,2-dimethyl-1,3-propanediol esters were coupled via aryl carbon−nitrogen bond cleavage in refluxing
toluene. Later on, the research groups of Snieckus and Szostak successfully used amides11c and imines11d as the DGs for this
Suzuki-type C(aryl)−N bond cleavage reaction. In 2017, Zeng and co-workers also reported a mild chromium-catalyzed Kumada-
coupling of neutral anilines using imine as the directing group.11e Herein, we developed a new ruthenium(0)-catalyzed Suzuki-
coupling of N,N-dimethyl-2-(pyridin-2-yl) anilines with alkenyl borates to synthesize 2-phenylolefins via the cleavage of neutral
aryl C-N bond by using pyridine as the directing group. The desired 2-phenylolefins can be obtained in good to excellent yields
with high stereoselectivity by using Ru3(CO)12 as the only catalyst.

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Figure 1. The methods to active aryl C-N bonds. (a) Converse the aryl C-N bond into the corresponding highly reactive
ammonium salts or diazonium salts; (b) Nickel-catalyzed direct coupling of relatively reactive neutral amines; (c) DG assisted
cross-coupling reaction of neutral anilines.
To begin this study, we chose N,N-dimethyl-2-(pyridin-2-yl) aniline (1a) and (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-
dioxaborolaneas (2a) as the model substrate to establish the reaction conditions. After extensive experimentation, we found
that the (E)-2-(2-styrylphenyl) pyridine (3a) was obtained in 89% yield with Ru3(CO)12 (5 mol %) as the catalyst in o-Xylene under
Argon at 140 °C without any ligand or additives (Table 1, entry 1). Here, it is worthy to mention that almost quantitative yield of
the desired product could be obtained with 0.5 equivalent of the catalyst. Other ruthenium catalysts, such as [Ru(p-cymene)Cl]2,
Ru(PPh3)3Cl2, and RuH2(CO)(PPh3)3 were submitted to the transformation to replace Ru3(CO)12. However, only RuH2(CO)(PPh3)3
delivered 3a in moderate yield (Table 1, entries 2-4), which was an efficient catalyst in the other catalytic cleavage of aryl C-N
bond reactions.11a,b,c We also investigated other metal catalysts, including NiCl2(PCy3)2, Rh4(CO)12, Re2(CO)10, and Co2(CO)8 (Table
1, entries 5-8). Unfortunately, these catalysts are not able to break the aryl C-N bond and substrate stays non-converted. In
addition, other solvents such as toluene, anisole or chlorobenzene were less effective than o-xylene for this transformation
(Table 1, entry 9). Different styrylboron reagents were also examined, and organoboronic esters show good results than the
corresponding boronic acid which may be caused by the difference on the stability of the boron reagents (Table 1, entries 10-11).
Other additives such as CsF, KF, usually act as accelerators in Suzuki-coupling reactions, is disadvantageous for this
transformation (Table 1, entry 12). Furthermore, decreasing the catalyst loading led to reduced yield of 3a (Table 1, entry 13).
Table 1. Optimization of the Reaction Conditions .a
variation from the standard
conditions
yield
(%)b
entry
1
2
3
4
-
89
n.r.
n.r.
59
[Ru(p-cymene)Cl]2 instead of
Ru3(CO)12
Ru(PPh3)3Cl 2 instead of Ru3(CO)12
RuH2(CO)(PPh3)3 instead of
Ru3(CO)12
5
6
7
8
NiCl2(PCy3)2 instead of Ru3(CO)12
Rh4(CO)12 instead of Ru3(CO)12
Re2(CO)10 instead of Ru3(CO)12
Co2(CO)8 instead of Ru3(CO)12
n.r.
n.r.
n.r.
n.r.

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toluene, anisole, or PhCl instead of
73, 69,
86
9
o-xylene
10
11
(E)-styrylboronic acid instead of 2a
51
(E)-5,5-dimethyl-2-styryl-1,3,2-
dioxaborinane instead of 2a
88
12
13
CsF, or KF(1.5 equiv.) as additive
2.5 mol% Ru3(CO)12
43,47
71
aReaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Ru3(CO)12 (5 mol %), N2, o-Xylene (2 mL), 140 °C, 20 h. bDetermined by GC
using hexadecane as the internal standard. n.r. is no reaction.
Scheme 1. The scope of various alkenyl borates in ruthenium-catalyzed coupling cleavage of aryl C-N bond. Reaction conditions:
1a (0.2 mmol), 2 (0.24 mmol), Ru3(CO)12 (5 mol %), N2, o-Xylene (2 mL), 140 °C, 20 h, isolated yields.
With the optimized reaction condition in hand, we next investigated the scope of substrates for this catalytic system. Firstly,
a range of alkenyl borates were tested in this cross-coupling reaction. As shown in Scheme 1, the styrylboronic acid pinacol
esters with electron-neutral groups gave the desired styrylbenzene in excellent yields (3b, 3c, and 3h), except 3d was achieved in
66% yield. Other synthetically valuable functionalized groups, such as fluoro-(3i), chloro-(3e), trifluoromethyl-(3f), methoxy-(3g),
were also well tolerated in this catalytic system. Furthermore, heterocyclic alkenyl borates, 2-(thiophen-3-yl) vinyl boronic acid
pinacol ester can also gave the desired product in high yield (3j). Besides, 2-(triethylsilyl) vinyl boronic acid pinacol ester able to
give the corresponding 3k in good yield as well, and 3k is a very useful synthetic intermediate for late-stage functionalization of
alkylsilyl.12 Interestingly, when we used allyl boronic acid pinacol ester as the reagent, the corresponding 2-(2-(prop-1-en-1-yl)
phenyl) pyridine(3l) as the single product was isolated in 65% yield (E/Z = 10:1), no product with terminal alkene was detected.
Moreover, phenylboronic acid ester was tested under the optimized conditions as well, only a trace amount of the target
biphenyl product was observed.
We then examined various N,N-dimethylanilines under our standard conditions (Scheme 2). Both alkyl- and halogen-
substituted substrates can be applied in this catalytic system and gave the corresponding diaryl alkenes products in good to
excellent yields (3m-3q). Naphthalene-2-amine is a highly reactive starting material, and the desired product was obtained in
excellent yield under the standard conditions (3r). Pyrimidine, considered as an analogue group of pyridine, can be applied as
directing group here as well and gave the corresponding product with moderate yield (3s). However, other directing groups, such
as pyrazole (3t) and 2-hydroxypyridine (3u), can’t promote the cleavage of aryl neutral C-N bond under our conditions.

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Scheme 2. The scope of various N,N-dimethylanilines in ruthenium-catalyzed coupling cleavage of aryl C-N bond. Reaction
conditions: 1a (0.2 mmol), 2 (0.24 mmol), Ru3(CO)12 (5 mol %), N2, o-Xylene (2 mL), 140 °C, 20 h, isolated yields.
Based on the above results and previous studies,9b,11,13 a plausible reaction pathway is proposed (Scheme 3). Firstly, substrate
1a coordinate with carbonyl ruthenium to give intermediate complex A. Then, intermediate B was generated through the
activation of C-N bond. After transmetlation, the intermediate C was achieved. Finally, the desired product 3a can be eliminated
through reductive elimination and the catalytic active ruthenium can be regenerated for the next catalytic cycle.
Scheme 3. Proposed Mechanism.
In summary, we have developed
a ruthenium(0)-catalyzed Suzuki-coupling of N,N-dimethyl-2-(pyridin-2-yl) anilines with
alkenyl borates to synthesize 2-phenylolefins via the cleavage of neutral aryl C-N bond using pyridine as directing group. In the
absence of ligand and additives, various 2-phenylolefins were obtained in good to excellent yields with high stereoselectivity (E/Z
> 20:1).
Conflicts of interest

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There are no conflicts to declare.
Acknowledgment
The authors thank the Chinese Scholarship Council for financial support. We thank the analytical department of Leibniz-Institute for
Catalysis at the University of Rostock for their excellent analytical service here.
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Graphic abstract:

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CreditAuthorStatement
X.W. directed the project. J.X. and F. Z. performed all the experiments. R. F. joined in the discussion. J. X., F. Z. and
X. W. prepared and revised the manuscript.

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We have no conflictof interest to declaration!

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1. A new ruthenium-catalyzed Suzuki-coupling of N,N-dimethyl-2-(pyridin-2-yl) anilines with alkenyl borates has
been developed.
2. The reaction proceeds via the cleavage of neutral aryl C-N bond.
3. Various desired alkenes were obtained in good to excellent yields with high stereoselectivity.