Application of a 2-aryl indenylphosphine ligand in the Buchwald-Hartwig cross-coupling reactions of aryl and heteroaryl chlorides under the solvent-free and aqueous conditions

Article abstract of DOI:10.1039/c7ob01199g

An efficient solvent-free protocol for the Buchwald-Hartwig cross-coupling reaction of aryl and heteroaryl chlorides with primary and secondary amines using the Pd(dba)₂/ligand 1 catalytic system has been developed. Notably, the catalytic system also efficiently catalyzed the reaction under aqueous conditions.

Full text of DOI:10.1039/c7ob01199g

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Application of 2-Aryl Indenylphosphine Ligand in the
Buchwald-Hartwig Cross-Coupling Reactions of Aryl and Hereoaryl
Chlorides under the Solvent-Free and Aqueous Conditions
Yan Liu,a,b,c Jia Yuan,a,b,c Zi-Fei Wang,a Si-Hao Zeng,a Meng-Yue Gao,a Mei-Lin
Ruan,a,b Jian Chena,b and Guang-Ao Yu*a,b
aKey Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, People’s Republic of
China.
bChemical Biology Center, College of Chemistry, Central China Normal University,
Wuhan 430079 (P. R. China)
cThese authors contributed equally to this work
* Corresponding authors: E-mail address, yuguang@mail.ccnu.edu.cn.
Abstract
An efficient solvent-free protocol for the Buchwald–Hartwig cross-coupling reaction
of aryl and heteroaryl chlorides with primary and secondary amines using the
Pd(dba)2/ligand 1 catalytic system has been developed. Notably, the catalytic system
also efficiently catalyzed the reaction under aqueous conditions.
Introduction
There has been a growing interest in developing cleaner and greener reactions for
chemical transformations. It is one of the central subjects to develop efficient,
environmental benefits and safe protocols for organic reactions, such as using water
as a solvent or performing reactions without solvent.1 The palladium-catalyzed
Buchwald–Hartwig cross-coupling reaction is undoubtedly one of the most versatile
tools for the formation of C–N bonds and has been widely applied in the
pharmaceutical and fine-chemical industries.2 Despite significant improvements in the
amination of aryl chlorides, a comparably large amount of the palladium catalyst (>1
mol%), sensitive phosphine ligands and harmful and uneasily recoverable organic
solvents, such as toluene and dioxane, still have to be used for the Buchwald–Hartwig
cross-coupling reaction. 3-6
The first example of a solvent-free Pd-catalyzed C–N cross-coupling reaction was
reported in 2003 by Beletskaya et al.7a Meanwhile, the use of water in Pd-catalyzed
C–N cross-coupling reactions was disclosed by Buchwald et al.8a Since then, several
strategies for C–N cross-coupling reactions under solvent-free and aqueous conditions
1

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have been developed.7–10 However, a number of challenges remain unresolved. For
example, the coupling of the readily available and low-cost aryl and heteroaryl
chlorides continues to pose difficulties with additives required to be added in some
cases. We have recently developed a series of aryl-substituted indenyl phosphine
ligands, which display excellent activity in Pd-catalyzed cross-coupling reactions.11
Herein, we report the Pd(dba)2/ligand 1 catalytic system, which exhibits high activity
in the Buchwald–Hartwig cross-coupling reaction of aryl and heteroaryl chlorides
with primary and secondary amines under solvent-free and aqueous conditions.
Results and discussion
Initially, the reaction of chlorobenzene with aniline was investigated as a model
reaction under solvent-free conditions for screening and optimization of the reaction
conditions (Table 1). For example, 1.0 mol% of Pd(dba)2, 2.0 mol% of ligand 1 and
t
1.4 equivalents of BuONa were used to obtained the coupling product in 71% yield
(Table 1, entry 1), whereas low conversions were observed in the reaction with
indenyl phosphine ligands 2 and 3 (Table 1, entries 2, 3). The temperature and
reaction time was found to be crucial for a high yield in the reaction, the reaction
conducted with 1.0 mol% of Pd(dba)2 and 2.0 mol% ligand 1 gave 87% conversion at
110ºC after 24 h (Table 1, entry 5). For comparison, several commercially available
Pd sources, such as Pd(OAc)2, Pd(acac)2, PdCl2(MeCN)2 and PdCl2 all provided
disappointing results (Table 1, entries 6-9). Besides ligands 1―3, various structurally
diverse phosphine ligands were also examined for comparison. The reactions were
carried out at 110ºC for 24 h with Pd(dba)2 as the catalyst precursor. Moderate
conversions were generally observed in the cross-coupling reactions with ligands such
t
as DiPPF, DPPF, DavePhos, CyJohnPhos, BuXPhos and SPhos (Table 1, entries
10-15), whereas the corresponding product was obtained in high yields with ligands
t
RuPhos, BuDavePhos and XPhos (Table 1, entries 16-18).To further expand the
application of this catalytic system, the optimized reaction conditions were
t
established using Pd(dba)2 (1.0 mol%)/1 (2.0 mol%) as the catalyst, BuONa as the
base at 110ºC for 24 h.
With the optimized reaction conditions in hand, we then investigated the substrate
scope of the Pd(dba)2/ligand 1 catalytic system in the C–N cross-coupling reaction of
aryl chlorides with amines. As shown in Table 2, chlorobenzene and aryl chlorides
bearing an electron-donating group on the aromatic ring were proven to be suitable in
the C–N cross-coupling reaction with various primary aryl amines and gave the
desired products in moderate to good yield (52%–75%) (Table 2, entries 1–13). The
reactions using 1-(4-chlorophenyl)ethan-1-one were also effective, albeit in giving the
desired products in low to moderate yield (28%–59%) (Table 2, entries 14–17). It was
observed that the reactions with aryl chlorides bearing an electron-donating group on
the aromatic ring were more active. For example, m-toluidine reacted with
1-chloro-2-methylbenzene and 1-chloro-3-methylbenzene to give the corresponding
products in 73% and 63% yield, respectively (Table 2, entries 5 and 10). However,
m-toluidine reacted with 1-(4-chlorophenyl)ethan-1-one to give the desired product in
only 28% yield (Table 2, entry 15). Additionally, the reactions of the secondary amine
2

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N-methylaniline
with
chlorobenzene,
1-chloro-2-methylbenzene,
1-chloro-3-methylbenzene and 1-(4-chlorophenyl)ethan-1-one gave the desired
product in 75%, 73%, 64% and 28% yield, respectively (Table 2, entries 3, 7, 12 and
17). Morpholine also reacted smoothly to yield the corresponding C–N cross-coupling
products in 29%–62% yield (Table 2, entries 4, 8 and 13).
To further extend the scope of our catalytic system, we carried out the reaction with
various heteroaryl chlorides. As shown in Table 3, 2-chloropyridine, 3-chloropyridine,
8-chloroquinoline and 2-chloropyrazine successfully underwent the desired C–N
cross-coupling reaction with anline, m-toluidine and 2-methoxyaniline to afford the
corresponding products in moderate to good yields (44%–82%). Most of the reactions
using the secondary amines N-methylaniline and morpholine also occurred smoothly
to give the corresponding C–N cross-coupling products in moderate yield. However,
the reactions of morpholine with 3-chloropyridine and 8-chloroquinoline only gave
the desired product in 30% and 26% yield, respectively (Table 3, entries 10 and 19).
Notably, the reaction of morpholine with 2-chloropyrazine gave the desired product in
75% yield (Table 3, entry 15).
Recently, performing organic transformations in or with water has gained
increasing attention due to water being a cheap, green and safe solvent.12, 13 However,
little attention has been given to investigating the Buchwald–Hartwig cross-coupling
reaction conducted under strictly aqueous conditions.8–10 In general, additives
including co-solvents and surfactants are required in the reaction.9 The substrate scope
is often limited in terms of the diversity of the amine substrates employed, and
examples involving heteroaryl chlorides are scarce. Despite the Pd(dba)2/ligand 1
catalytic system efficiently catalyzing the C–N cross-coupling reaction of various aryl
and heteroaryl chlorides under solvent-free conditions, low yields were obtained in
some cases. At the same time, we found the C–N cross-coupling reaction of
chlorobenzene with aniline gave the corresponding product in 79% yield using the
Pd(dba)2/ligand 1/tBuONa catalytic system under aqueous conditions. Therefore, we
then investigated the reaction of various aryl and heteroaryl chlorides with amines
using the Pd(dba)2/ligand 1/tBuONa catalytic system under aqueous conditions, the
results are summarized in Table 4. All substrate pairings were successful in the C–N
cross-coupling reaction and gave the desired products in moderate to good yield
(50%–88%). Heteroaryl chlorides proved to suitable cross-coupling substrates as well
as aryl chlorides (Table 4, entries 11-23). In addition, the secondary amines
N-methylaniline and morpholine also reacted smoothly to give the corresponding C–N
cross-coupling products in moderate yield (51%–79%). Interestingly, some reactions
gave comparable yields to those observed in our investigations using solvent-free
conditions, such as the reaction of 1-chloro-2-methylbenzene with m-toluidine (Table
2, entry 5 and Table 4, entry 4). Some reactions afforded higher yields under aqueous
conditions, especially the reactions using 1-(4-chlorophenyl)ethan-1-one (Table 4,
entries 9, 10). For example, a 28% yield was obtained in the reaction of
1-(4-chlorophenyl)ethan-1-one with N-methylaniline under solvent-free conditions,
but it was dramatically increased to 60% yield under aqueous conditions (Table 2,
entry 17 and Table 4, entry 10).
3

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Conclusions
In summary, we have developed an efficient method to carry out the Buchwald–
Hartwig cross-coupling reaction of aryl and heteroaryl chlorides with primary or
secondary amines using the Pd(dba)2/ligand 1 catalytic system under solvent-free
conditions. Meanwhile, the reactions can also proceed smoothly using the same
catalytic system under aqueous conditions with some reactions obtained in higher
yields when compared with the solvent-free conditions. Further applications of this
and related ligands in the development of more green metal-catalyzed transformations
are currently in progress.
Acknowledgements
The authors would like to thank the National Natural Science Foundation of China
(Nos. 21472060 and 21072071), the 111 project B17019, self-determined research
funds of CCNU from the colleges’ basic research and operation of MOE (Nos.
CCNU17QN0021, CCNU17CG0011 and CCNU17KYZHSY07).
Notes and references
1 (a) M.-O. Simon and C.-J. Li, Chem. Soc. Rev., 2012, 41, 1415; (b) M. Lamblin, L.
Nassar-Hardy, J. C. Hierso, E. Fouquet and F.-X. Felpin, Adv. Synth. Catal., 2010, 352, 33; (c)
R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302; (d) K. H. Shaughnessy, Chem. Rev.,
2009, 109, 643; (e) U. M. Lindström, Chem. Rev., 2002, 102, 2751; (f) P. B. Dzhevakov, M. A.
Topchiy, D. A. Zharkova, O. S. Morozov, A. F. Asachenko and M. S. Nechaev, Adv. Synth.
Catal., 2016, 358, 977.
2 (a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org. Biomol. Chem., 2006, 4, 2337;
(b) D. S. Surry and S. L. Buchwald, Angew. Chem. Int. Ed., 2008, 47, 6338; (c) C. Torborg and
M. Beller, Adv. Synth. Catal., 2009, 351, 3027; (d) C. Fischer and B. Koenig, Beilstein J. Org.
Chem., 2011, 7, 59; (e) C. Valente, S. Calimsiz, K. H. Hoi, D. Mallik, M. Sayah and M. G.
Organ, Angew. Chem. Int. Ed., 2012, 51, 3314; (f) J. Bariwal and E. Van der Eycken, Chem. Soc.
Rev., 2013, 42, 9283.
3 (a) D. S. Surry and S. L. Buchwald, Chem. Sci., 2011, 2, 27; (b) D. Maiti, B. P. Fors, J. L.
Henderson, Y. Nakamura and S. L. Buchwald, Chem. Sci., 2011, 2, 57; (c) N. C. Bruno, M. T.
Tudge and S. L. Buchwald, Chem. Sci., 2013, 4, 916; (d) T. Noël, J. R. Naber, R. L. Hartman, J.
P. McMullen, K. F. Jensen and S. L. Buchwald, Chem. Sci., 2011, 2, 287.
4 (a) N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig, J. Org. Chem., 2002, 67, 5553; (b) Q.
Shen, T. Ogata and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 6586.
5 F. Rataboul, A. Zapf, R. Jackstell, S. Harkal, T. Riermeier, A. Monsees, U. Dingerdissen and M.
Beller, Chem. Eur. J., 2004, 10, 2983.
6 Y. Zhang, V. César, G. Storch, N. Lugan and G. Lavigne, Angew. Chem. Int. Ed., 2014, 53, 6482.
7 (a) G. A. Artamkina, M. V. Ermolina and I. P. Beletskaya, Mendeleev Commun., 2003, 158; (b)
L. Basolo, A. Bernasconi, E. Borsini, G. Broggini and E. M. Beccalli, ChemSusChem, 2011, 4,
1637; (c) L. Basolo, A. Bernasconi, G. Broggini, S. Gazzola and E. M. Beccalli, Synthesis, 2013,
45, 3151; (d) B. J. Tardiff and M. Stradiotto, Eur. J. Org. Chem., 2012, 3972; (e) A. Chartoire, A.
4

Page 5 of 12
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01199G
5
Boreux, A. R. Martin and S. P. Nolan, RSC Adv., 2013, 3, 3840; (f) M. A. Topchiy, P. B.
Dzhevakov, M. S. Rubina, O. S. Morozov, A. F. Asachenko and Mikhail S. Nechaev, Eur. J. Org.
Chem. 2016, 1908.
8 (a) X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars and S. L. Buchwald, J. Am. Chem.
Soc., 2003, 125, 6653; (b) Y. Hirai and Y. Uozumi, Chem. Commun., 2010, 46, 1103; (c) Y.
Hirai and Y. Uozumi, Chem. Lett., 2011, 40, 934; (d) V. Kogan, Z. Aizenshtat, R. Popovitz-Biro
and R. Neumann, Org. Lett., 2002, 4, 3529.
9 (a) R. Kuwano, M. Utsunomiya and J. F. Hartwig, J. Org. Chem., 2002, 67, 6479; (b) C. Xu, J.-F.
Gong and Y. J. Wu, Tetrahedron Lett., 2007, 48, 1619; (c) B. H. Lipshutz, D. W. Chung and B.
Rich, Adv. Synth. Catal., 2009, 351, 1717; (d) B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser,
T. Nishikata, C. Duplais, A. Krasovskiy, R. D. Gaston and R. C. Gadwood, J. Org. Chem., 2011,
76, 4379.
10 B. J. Tardiff and M. Stradiotto, Eur. J. Org. Chem., 2012, 3972.
11 (a) L. Chen, F. Li, X. Zhu, B. Zhang, R. Guo, X. Li, Q. Yang, S. Jin, C. Liu, G.-A. Yu and S.-H.
Liu, J. Organomet. Chem., 2010, 695, 1768; (b) M.-Q. Yan, J. Yuan, Y.-X. Pi, J.-H. Liang, Y.
Liu, Q.-G. Wu, X. Luo, S.-H. Liu, J. Chen, X.-L. Zhu and G.-A. Yu, Org. Biomol. Chem., 2016,
14, 451; (c) Y. Chen, H. Peng, Y.-X. Pi, T. Meng, Z.-Y. Lian, M.-Q. Yan, Y. Liu, S.-H. Liu and
G.-A. Yu, Org. Biomol. Chem., 2015, 13, 3236; (d) X. Hao, J. Yuan, G.-A. Yu, M.-Q. Qiu, N.-F.
She, Y. Sun, C. Zhao, S.-L. Mao, J. Yin and S.-H. Liu, J. Organomet. Chem., 2012, 706-707, 99;
(e) S.-L. Mao, Y. Sun, G.-A. Yu, C. Zhao, Z.-J. Han, J. Yuan, X. Zhu, Q. Yang and S.-H. Liu,
Org. Biomol. Chem., 2012, 10, 9410; (f) Y. Liu, H. Peng, J. Yuan, M.-Q. Yan, X. Luo, Q.-G. Wu,
S.-H. Liu, J. Chen and G.-A. Yu, Org. Biomol. Chem., 2016, 14, 4664.
12 (a) K. H. Shaughnessy and R. B. DeVasher, Curr. Org. Chem., 2005, 9, 585; (b) C. J. Li and L.
Chen, Chem. Soc. Rev., 2006, 35, 68; (c) K. H. Shaughnessy, Chem. Rev., 2009, 109, 643; (d) M.
Carril, R. SanMartin and E. Domínguez, Chem. Soc. Rev., 2008, 37, 639.
13 (a) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and P. T. Anastas, Science, 2002, 297, 807; (b)
C.-J. Li, Chem. Rev., 2005, 105, 3095.
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Figure Legends
Table 1. Optimization conditions for the Buchwald-Hartwig cross-coupling reactions of
chlorobenzene with aniline a
Entry
[Pd] (mol%)
Ligand (mol%)
Time (h) Yieldb (%)
T (℃)
1
2
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (0.1)
Pd(dba)2 (1.0)
Pd(OAc)2 (1.0)
Pd(acac)2 (1.0)
PdCl2(MeCN)2 (1.0)
PdCl2 (1.0)
1 (2.0)
2 (2.0)
100
100
100
100
110
110
110
110
110
110
110
110
110
110
110
110
110
110
20
20
20
20
24
24
24
24
24
24
24
24
24
24
24
24
24
24
71
64
61
35
87
33
19
24
22
61
68
68
70
68
57
85
84
83
3
3 (2.0)
4
1 (0.2)
5
1 (2.0)
6
1 (2.0)
7
1 (2.0)
8
1 (2.0)
9
1 (2.0)
10
11
12
13
14
15
16
17
18
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
Pd(dba)2 (1.0)
DiPPF (2.0)
DPPF (2.0)
DavePhos (2.0)
CyJohnPhos (2.0)
tBuXPhos (2.0)
SPhos (2.0)
RuPhos (2.0)
tBuDavePhos(2.0)
XPhos (2.0)
a Reaction conditions: chlorobenzene (2.5 mmol), aniline (3.0 mmol), [Pd] (1 mol% or 0.1
t
mol%), Ligand (2 mol% or 0.2 mol%) and BuONa (1.4 equiv, 3.5 mmol) at the required
temperature for 20-24 h. b Isolated yield.
O
PCy2
O
PCy2
PCy2
2
1
3
6

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Table 2. Buchwald-Hartwig cross-coupling reactions of aryl chlorides with amines under
solvent-free conditionsa
Entry
1
ArCl
Amine
Product
Yield (%)b
62
2
3
52
75
29
73
64
58
62
57
63
62
4
5
6
7
8
9
10
11
7

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12
13
14
64
39
59
15
16
17
28
40
28
aReaction conditions: ArCl (1.25 mmol), Amines (1.5 mmol), Pd(dba)2 (1 mol%, 0.0125
mmol), ligand 1 (2 mol%, 0.025 mmol) and tBuONa (1.4 equiv, 1.75 mmol) at 110 ºC for 24
h. bIsolated yield.
8

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Table 3. Buchwald-Hartwig cross-coupling reactions of heteroaryl chlorides with amines
under solvent-free conditionsa
Entry
1
ArCl
Amine
Product
Yield (%)b
64
2
3
59
70
46
58
51
55
49
52
30
4
5
6
7
8
9
10
9

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10
11
12
13
14
15
78
82
64
48
75
16
17
18
19
44
67
65
26
aReaction conditions: heteroaryl chlorides (1.25 mmol), Amines (1.5 mmol), Pd(dba)2 (1
mol%, 0.0125 mmol), ligand 1 (2 mol%, 0.025 mmol) and tBuONa (1.4 equiv, 1.75 mmol)
at 110 ºC for 24 h. bIsolated yield.
10

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Table 4. Buchwald-Hartwig cross-coupling reactions of amines with aryl and heteroaryl
chlorides under aqueous conditionsa
Entry
1
ArCl
Amine
Product
Yield (%)c
50
2
3
4
5
79
51
71
61
6
7
8
9
53
73
73
74
10
60
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11
12
13
14
15
16
17
18
19
20
65
66
70
77
71
88
87
80
69
73
21
22
23
55
55
58
aReaction conditions: H2O (0.05 mL), ArCl (1.25 mmol), Amines (1.5 mmol), Pd(dba)2 (1
mol%, 0.0125 mmol), ligand 1 (2 mol%, 0.025 mmol) and tBuONa (1.4 equiv, 1.75 mmol)
at 110 ºC for 24 h. bIsolated yield.
12