Cross coupling of benzylammonium salts with boronic acids using a well-defined N-heterocyclic carbene-palladium(ii) precatalyst

Article abstract of DOI:10.1039/c8ra10439e

N-heterocyclic carbene-palladium(ii)-catalyzed cross-coupling of benzylammonium salts with arylboronic acids for the synthesis of diarylmethane derivatives via C-N bond activation has been developed. Notably, in the presence of the easily prepared and bench-stable Pd-PEPPSI precatalyst, the Csp³-N bond activation of the benzylammonium salt even proceeded smoothly in isopropanol at room temperature.

Full text of DOI:10.1039/c8ra10439e

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Cross coupling of benzylammonium salts with
boronic acids using a well-defined N-heterocyclic
carbene–palladium(II) precatalyst†
Cite this: RSC Adv., 2019, 9, 5738
ab
ab
ab
ab
ab
Tao Wang,
*
Jiarui Guo, Xiaojuan Wang, Han Guo, Dingli Jia,
ab
ab
Hengjin Wang and Lantao Liu
*
Received 20th December 2018
Accepted 11th February 2019
N-heterocyclic carbene–palladium(II)-catalyzed cross-coupling of benzylammonium salts with arylboronic
acids for the synthesis of diarylmethane derivatives via C–N bond activation has been developed. Notably, in
DOI: 10.1039/c8ra10439e
3
the presence of the easily prepared and bench-stable Pd-PEPPSI precatalyst, the Csp –N bond activation of
rsc.li/rsc-advances
the benzylammonium salt even proceeded smoothly in isopropanol at room temperature.
Studies on synthetic methods of diarylmethane derivatives have aqueous media or at room temperature, are still worthwhile
10
attracted considerable attention because the compounds are projects. In this present contribution, we have developed
1
1–13
important structural units in organic synthesis, materials efficient catalytic systems
for the Suzuki–Miyaura coupling
1
science and pharmaceutical development. Among the of benzyl chlorides with arylboronic acids, producing the cor-
synthetic approaches explored, transition metal catalyzed responding diarylmethane derivatives in high yields. In a recent
Suzuki coupling is one of the most important and frequently communication, the N-heterocyclic carbene–palladium(II)
used methods. Over the past decade, the most popular strate- complexes were also found to be active catalysts for the Suzuki–
2
gies for the cross coupling of benzyl halides and benzyl sulfo- Miyaura cross-coupling of N-acylsuccinimides with arylboronic
3
14
nates with aryl boric acid using Pd-catalysis have been acids via C–N bond activation. Considering our successful
reported. Disappointingly, some obvious drawbacks are experience with the applications of this complexes in the cross-
involved with the use of benzyl halides and benzyl sulfonates as coupling reaction, we then turned our recent interest to the
the electrophiles. These reagents are sometimes difficult in coupling reaction between benzylammonium salt and arylbor-
terms of substrate tolerance and storage. During recent years, onic acids for the formation of diarylmethane derivatives. In
the transition metal catalyzed Suzuki coupling reactions by the such context, we herein report the rst example of NHC–Pd-
4
C–N bonds cleavage have been developed. Among them, the PEPPSI catalyzed coupling reactions of benzylammonium
3
cross coupling of quaternary ammonium salts has been quite salts with arylboronic acids via Csp –N bond activation under
well explored because they are more easily available from amine mild conditions (Scheme 1).
precursors or benzyl halides and they are also stable to long-
It is initiated by investigating the crossing coupling of 4-
term storage. Since the pioneering work of MacMillan and co- methoxyphenyl boronic acid with benzyltrimethylammonium
5
workers in 2003, with aryltrimethylammonium salts as the bromide 1a, which is readily prepared quantitatively via the
electrophiles in various catalytic reactions such as cross- reaction of trimethylamine and benzyl bromide. The details
6
7
8
coupling, C–H arylation, borylation and reductive carboxyla- were shown in Table 1. The choice of base is crucial to the yield
9
15
tion reactions have been carried out. Although excellent results of the reaction (Table 1, entries 1–9). In the presence of the
have been obtained, the optimization and development of IPr–Pd-PEPPSI complex 4a as the catalyst, K PO $3H O as the
3
4
2
3
ꢀ
cross-coupling reactions involving Csp –N bond cleavage of base in isopropanol at 70 C, we were delighted to observe that
benzylammonium salts under mild conditions, such as in the reaction gave the corresponding diarylmethanes
a
Henan Engineering Laboratory of Green Synthesis for Pharmaceuticals, School of
Chemistry and Chemical Engineering, Shangqiu Normal University, Shangqiu,
Henan, 476000, People's Republic of China. E-mail: wt67751726@126.com;
liult05@iccas.ac.cn; Fax: +86-0370-2595126; Tel: +86-0370-2595126
b
Henan Key Laboratory of Biomolecular Recognition and Sensing, School of Chemistry
and Chemical Engineering, Shangqiu Normal University, Shangqiu, Henan, 476000,
People's Republic of China
†
Electronic supplementary information (ESI) available: Characterization data
Scheme 1 NHC–Pd(II) catalyzed coupling reactions of benzylammo-
nium salts with arylboronic acids via Csp –N bond activation.
3
and NMR spectra of the catalysis products. See DOI: 10.1039/c8ra10439e
5738 | RSC Adv., 2019, 9, 5738–5741
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a
Table 1 Optimization of the cross-coupling reaction on substrate 1a
Table 2 Scope of the coupling reaction with respect to the arylboric
acid
ꢀ
c
Entry Cat. Base
Solvent
Temp ( C) Yield (%)
t
i
1
2
3
4
5
6
7
8
9
1
1
1
1
1
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
KO Bu
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
50
rt
89
Trace
91
Trace
70
>99
Trace
90
98
47
98
88
30
59
54
82
99
96
92
90
i
Na
CO
NaHCO
2
CO
3
i
K
2
3
i
3
i
K
K
3
PO
PO
NaOAc
NaOH
KOH
4
i
3
4
$3H
2
O
i
i
i
PrOH
0
1
2
3
4
5
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
$3H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
THF
1,4-Dioxane
EtOH
Toluene
CH
3
CN
1
H
2
O
b
i
a
1
6
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH : H
PrOH : H
PrOH : H
PrOH : H
PrOH : H
PrOH : H
PrOH : H
All reactions were carried out using 1a (0.20 mmol), 2 (0.40 mmol),
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
17
18
19
20
21
22
23
24
25
26
27
28
29
30
K PO $3H O (2.0 equiv.), cat. 4a (5.0 mol%) in PrOH (0.1 M) at room
temperature for 15 h. All reactions were carried out using 1a (0.20
3
4
2
b
rt
rt
rt
rt
mmol), 2 (0.40 mmol), K
mixture solvent ( PrOH : H O [v / v] ¼ 1 : 1, 0.1 M) at 50 C for 15 h.
3
PO
2
4
$3H
2
O (2.0 equiv), cat. 4a (5.0 mol%) in
i
ꢀ
22
42
16
75
97
91
90
86
of NHC–Pd(II) catalysts demonstrates that the coordination
environment of the NHC–Pd(II) complexes had an obvious effect
on the yield (Table 1, entries 18–23). When a solvent mixture of
isopropanol and water was tested, the yield of the product
rt
4a
4a
4b
4c
4d
4e
4f
2
2
2
2
2
2
2
O (1 : 1) rt
O (1 : 1) 50
O (1 : 1) 50
O (1 : 1) 50
O (1 : 1) 50
O (1 : 1) 50
O (1 : 1) 50
ꢀ
reduced to 76% (Table 1, entry 24). In this case, heating to 50 C
was found to be necessary (Table 1, entry 25). Then the perfor-
mance of the other ve NHC–Pd(II) complexes 4b–f in this
reaction condition was examined, and IPr–Pd-PEPPSI complex
6
Trace
a
All reactions were carried out using 1a (0.20 mmol), 2a (0.40 mmol),
4a was found to be optimal (Table 1, entry 25 vs. entries 26–30).
b
base (2.0 equiv.), cat. (5.0 mol%) in solvent (0.1 M) for 15 h. Cat.
c
Since the reaction was performed in isopropanol at room
(2.0 mol%). Isolated yields.
temperature as well as in a solvent mixture consisting of iso-
ꢀ
propanol (1.0 mL) and water (1.0 mL) at 50 C rather well, they
quantitatively. Several other solvents including THF, EtOH, 1,4-
dioxane, toluene, CH CN and H O were tested, and the yield
was not enhanced further (Table 1, entries 10–15). When
.0 mol% of complex 4a was tested, the yield of cross coupling
product was obtained in 82% yield (Table 1, entry 16). It is worth
mentioning that the IPr–Pd-PEPPSI complex 4a still gave good
yield at room temperature (Table 1, entry 18). Further screening
were both applied as the reaction conditions in the following
experiments to explore the scope of the cross coupling. As
shown in Table 2, a series of aromatic boronic acids with ben-
zyltrimethylammonium bromide were investigated in PrOH in
the presence of 5.0 mol% complex 4a and 2.0 equiv.
3
2
2
i
K
3
PO
4
$3H
2
O at room temperature for 15 h. Gratifyingly, most of
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the coupling reaction proceeded rapidly and efficiently to provide
the corresponding diarylmethane derivatives in excellent yields. It
seems that the electronic effect and the steric effect of the
substituents on the aromatic boronic acids have little effect on the
reaction efficiency. No matter electron-donating (3aa–3ah) or
-withdrawing (3ai–3aj) groups on the phenyl ring of boronic acids,
good to excellent yields were obtained. The reaction was quite
feasible with benzyltrimethylammonium bromide when the ortho-
substituted aryl boronic acid was used (3ac and 3ag). In addition,
in the case of 1-naphthylboronic acid or 2-naphthylboronic acid
afforded in high reaction efficiency under the present reaction
conditions (3ak–3al). Particularly, when heteroaromatic boronic
acid, such as thienyl, was used as the substrate, high yield of the
corresponding product was always observed (3am). Subsequently,
a
series of aromatic boronic acids with benzyl-
i
trimethylammonium bromide were investigated in PrOH–H
2
O in
the presence of 5.0 mol% complex 4a and 2.0 equiv. K
3
PO
4
$3H
2
O
ꢀ
at 50 C for 15 h. All of the above substrates still worked well to
afford the desired products in good to almost quantitative yields.
Inspired by these results and our attention was next turned to
the cross coupling reaction of benzylammonium salts with 4-
methoxyphenyl boronic acid. As shown in Table 3, the reactions
proceed smoothly to afford diarylmethanes in excellent yields.
Roughly, the electron-donating group in the phenyl ring of ben-
zylammonium salts showed some benecial effect on the yields of
Scheme 2 Proposed reaction mechanism.
the catalysis products. Benzylammonium salts bearing uorine substituent showed good reactivity in this transformation (3be).
Substrate 1 having naphthalene ring substituent was also suitable
for such transformation to afford products 3bg and 3bh in good
Table 3 Scope of the coupling reaction with respect to the benzy- yields under appropriate conditions. In addition, when benzyl-
lammonium salts
trimethylammonium triate was used as the substrate, high yield
of the corresponding product was always observed (3bi).
10b
On the basis of the mechanism of previous reports and our
results, a putative reaction mechanism was then proposed in
Scheme 2. First, oxidative addition of Pd(0) I produced in situ,
with benzyltrimethylammonium salt 1 formed intermediate II
with the release of trimethylamine. Then a transmetalation
reaction of the intermediate II with aryl boronic acid converted to
intermediate IV, which followed by reductive elimination to the
product 3 with simultaneous regeneration of the Pd(0) catalyst.
Conclusions
In summary, we have developed the rst example of NHC–Pd(II)
catalyzed cross-coupling of benzylammonium salts with aryl-
boronic acids to form diarylmethane derivatives, a very important
skeleton in synthetic chemistry. The current process tolerates
broad scope with respect to both the boronic acid and benzy-
lammonium salts under mild conditions. Further exploration of
these N-heterocyclic carbene–palladium(II) complexes and their
catalytic applications in other reactions is in progress.
Experimental
General remarks
a
All reactions were carried out using 1 (0.20 mmol), 2a (0.40 mmol),
i
K
3
PO
4
$3H
2
O (2.0 equiv.), cat. 4a (5.0 mol%) in PrOH (0.1 M) at room
b
temperature for 15 h. All reactions were carried out using 1 (0.20
mmol), 2a (0.40 mmol), K
in mixture solvent ( PrOH : H
The catalytic reactions were carried out under a nitrogen
atmosphere. Benzylammonium salts were prepared according
to the literature method.
3
PO
4
$3H
2
O (2.0 equiv.), cat. 4a (5.0 mol%)
i
ꢀ
2
O [v / v] ¼ 1 : 1, (0.1 M)) at 50 C for 15 h.
16
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palladium(II) complexes were synthesized according to our
C. S. Cazin, J. Organometallics, 2010, 29, 1443; (i) R. Singh,
M. S. Viciu, N. Kramareva, O. Navarro and S. P. Nolan, Org.
Lett., 2005, 7, 1829; (j) S. M. Nobre and A. L. Monteiro,
Tetrahedron Lett., 2004, 45, 8225.
3 X.-X. Wang, B.-B. Xu, W.-T. Song, K.-X. Sun and J.-M. Lu, Org.
Biomol. Chem., 2015, 13, 4925.
11b
previous report. Solvents were dried by standard methods
and freshly distilled prior to use. All other chemicals were used
1
13
as purchased. H and C NMR spectra were recorded on
a Bruker DPX 400 instrument using TMS as an internal
standard.
4
(a) C. Liu, G. Li, S. Shi, G. Meng, R. Lalancette, R. Szostak and
M. Szostak, ACS Catal., 2018, 8, 9131; (b) C. Wang, L. Huang,
F. Wang and G. Zou, Tetrahedron Lett., 2018, 59, 2299; (c)
P. Lei, G. Meng and M. Szostak, ACS Catal., 2017, 7, 1960;
General procedure for the cross-coupling of benzylammonium
salts with arylboronic acids
A Schlenk ask was charged with the required benzylammo-
nium salts 1a (0.20 mmol, 46.0 mg), (4-methoxyphenyl)boronic
acid (0.40 mmol, 60.8 mg), N-heterocyclic carbene–palladium(II)
complex 4a (5 mol%, 6.8 mg), K PO $3H O (2.0 equiv., 106.5
(
d) P. Lei, G. Meng, Y. Ling, J. An, S. P. Nolan and
M. Szostak, Org. Lett., 2017, 19, 6510; (e) G. Meng,
R. Szostak and M. Szostak, Org. Lett., 2017, 19, 3596; (f)
P. Lei, G. Meng, Y. Ling, J. An and M. Szostak, J. Org.
Chem., 2017, 82, 6638; (g) P. Lei, G. Meng, S. Shi, Y. Ling,
J. An, R. Szostak and M. Szostak, Chem. Sci., 2017, 8, 6525;
3
4
2
i
i
mg), and PrOH (0.1 M) [or PrOH : H O [v / v] ¼ 1 : 1, 0.1 M].
2
ꢀ
The mixture was stirred at room temperature [or 50 C] for 15 h
under N
product was isolated by by preparative TLC on silica gel plates
eluting with CH Cl /petroleum ether to afford the diaryl-
2
. Aer cooling, the mixture was evaporated and the
(
h) G. Meng, R. Lalancette, R. Szostak and M. Szostak, Org.
Lett., 2017, 19, 4656; (i) G. Meng and M. Szostak, Org. Lett.,
015, 17, 4364.
S. B. Blakey and D. W. C. MacMillan, J. Am. Chem. Soc., 2003,
25, 6046.
(a) G. Li, Y. Chen and J. Xia, Chin. J. Org. Chem., 2018, 38,
949; (b) X.-Y. Liu, H.-B. Zhu, Y.-J. Shen, J. Jiang and T. Tu,
2
2
2
methane. The puried products were identied by NMR spectra
and their analytical data are given in the ESI.†
5
6
1
Conflicts of interest
1
Chin. J. Chem., 2017, 28, 350; (c) D. M. Shacklady-McAtee,
K. M. Roberts, C. H. Basch, Y.-G. Song and M. P. Watson,
Tetrahedron, 2014, 70, 4257; (d) J. T. Reeves, D. R. Fandrick,
Z. Tan, J. J. Song, H. Lee, N. K. Yee and C. H. Senanayake,
Org. Lett., 2010, 12, 4388; (e) P. Maity, D. M. Shacklady-
McAtee, G. P. A. Yap, E. R. Sirianni and M. P. Watson, J.
Am. Chem. Soc., 2013, 135, 280.
There are no conicts to declare.
Acknowledgements
We gratefully acknowledge nancial support from the National
Natural Science Foundation of China (No. U1504207, 21572126),
the Key Science Research of Education Committee in Henan
Province (19A150035) and the Program of Science and Tech-
nology Innovation Talents of Henan Province (2018JQ0011).
7
8
(a) H. J. Davis, M. T. Mihai and R. J. Phipps, J. Am. Chem. Soc.,
2016, 138, 12759; (b) F. Zhu, J.-L. Tao and Z.-X. Wang, Org.
Lett., 2015, 17, 4926.
(a) J. Hu, H. Sun, W. Cai, X. Pu, Y. Zhang and Z. Shi, J. Org.
Chem., 2016, 81, 14; (b) C. H. Basch, K. M. Cobb and
M. P. Watson, Org. Lett., 2016, 18, 136; (c) H. Zhang,
S. Hagihara and K. Itami, Chem. Eur. J., 2015, 21, 16796.
9 T. Moragas, M. Gaydou and R. Martin, Angew. Chem., Int. Ed.,
2016, 55, 5053.
Notes and references
1
(a) J. D. Houwer and B. U. W. Maes, Synthesis, 2014, 2533; (b)
S. Messaoudi, A. Hamze, O. Provot, B. Tr ´e guier, J. Rodrigo De
Losada, J. Bignon, J.-M. Liu, J. Wdzieczak Bakala, S. Thoret,
J. Dubois, J.-D. Brion and M. Alami, ChemMedChem, 2011,
6
,
488; (c) A. V. Cheltsov, M. Aoyagi, A. Aleshin, 10 (a) P. L. T u¨ rtscher, H. J. Davis and R. J. Phipps, Synthesis,
E. C.-W. Yu, T. Gilliland, D. Zhai, A. A. Bobkov, J. C. Reed,
2018, 50, 793; (b) T. Wang, S. Yang, S. Xu, C. Han, G. Guo
R. C. Liddington and R. Abagyan, J. Med. Chem., 2010, 53,
and J. Zhao, RSC Adv., 2017, 7, 15805.
3
899; (d) B. Liegault, J.-L. Renaud and C. Bruneau, Chem. 11 (a) T. Wang, K. Xu, A. Zhang, W. Wang and L. Liu, Chin. J.
Soc. Rev., 2008, 37, 290.
Org. Chem., 2018, 38, 259; (b) T. Wang, H. Xie, L. Liu and
2
(a) V. Ramakrishna, M. J. Rani and N. D. Reddy, Eur. J. Org.
W.-X. Zhao, J. Organomet. Chem., 2016, 804, 73.
Chem., 2017, 48, 7238; (b) G. Zhao, K. Zhang, L. Wang, 12 T. Wang, K. Xu, W. Wang, A. Zhang and L. Liu, Transition
J. Li, D. Zou, Y. Wu and Y. Wu, Tetrahedron Lett., 2015, 56,
Met. Chem., 2018, 43, 347.
700; (c) Z. Guan, B. Li, G. Hai, X. Yang, T. Li and B. Tan, 13 T. Wang, L. Liu, K. Xu, H. Xie, H. Shen and W.-X. Zhao, RSC
6
RSC Adv., 2014, 4, 36437; (d) M. Micksch, M. Tenne and
Adv., 2016, 6, 100690.
T. Strassner, Organometallics, 2014, 33, 3966; (e) 14 T. Wang, J. Guo, H. Wang, H. Guo, D. Jia, W. Zhang and
F. Chahdoura, C. Pradel and M. Gomez, Adv. Synth. Catal.,
L. Liu, J. Organomet. Chem., 2018, 877, 80.
013, 355, 3648; (f) K. Karami, C. Rizzoli and M. M. Salah, 15 K. Ouyang and Z. Xi, Acta Chim. Sinica., 2013, 71, 13.
J. Organomet. Chem., 2011, 696, 940; (g) A. John, 16 (a) S. Yu, S. Liu, Y. Lan, B. Wan and X. Li, J. Am. Chem. Soc.,
2
M. M. Shaikh, R. J. Butcher and P. Ghosh, Dalton Trans.,
010, 39, 7353; (h) O. Diebolt, V. Jurcik, R. Correada Costa,
P. Braunstein, L. Cavallo, S. P. Nolan, A. M. Z. Slawin and
2015, 137, 1623; (b) K. H. Jensen and J. E. Hanson, Chem.
Mater., 2002, 14, 918.
2
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