Palladium-catalyzed monoarylation of aryl amine with aryl tosylates

Article abstract of DOI:10.1055/s-0030-1259728

The bulky and electron-rich MOP-type ligand was efficient for the Pd-catalyzed amination of aryl tosylates. The in situ generated Pd(0) was a more efficient catalyst precursor than Pd(dba)₂. In the presence of Pd(OAc)₂, PhB(OH)₂, and a hindered and electron-rich MOP-type ligand, a variety of primary aryl amines reacted with various aryl tosylates to form the corresponding secondary aryl amines in high yields with high selectivity. Furthermore, the catalyst system was also efficient for the arylation of indoles and hydrazones with aryl tosylates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259728

LETTER
955
Palladium-Catalyzed Monoarylation of Aryl Amine with Aryl Tosylates
P
alladium-Catalyz
i
e
d
Mon
a
oarylation
o
of
A
ryl
A
mi
m
ne in Xie,*a Gang Ni,b Fangfang Ma,a Lina Ding,c Sheng Xu,*b Zhaoguo Zhanga
a
b
c
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
P. R. of China
Fax +86(21)54748925; E-mail: xiaominxie@sjtu.edu.cn
School of Chemistry and Molecular Engineering, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, P. R. of China
Fax +86(21)64251851; E-mail: xusheng@ecust.edu.cn
School of Chemistry Chemical Engineering & Materials, Heilongjiang University, 74 Xuefu Road, Harbin 150000, P. R. of China
Received 29 December 2010
This paper is dedicated to Professors Xiyan Lu and Lixin Dai for their life-long contributions to the development of organic chemistry
prepared from inexpensive, commercially available mate-
Abstract: The bulky and electron-rich MOP-type ligand was effi-
rials, and turned out to be an excellent catalyst for palladi-
cient for the Pd-catalyzed amination of aryl tosylates. The in situ
um-catalyzed amination of aryl chlorides.8 As part of our
continuing work, we explored the possibility for the ami-
generated Pd(0) was a more efficient catalyst precursor than
Pd(dba)2. In the presence of Pd(OAc)2, PhB(OH)2, and a hindered
and electron-rich MOP-type ligand, a variety of primary aryl nation of aryl tosylates by utilizing such ligand. Herein,
amines reacted with various aryl tosylates to form the correspond-
we report our findings in this study.
ing secondary aryl amines in high yields with high selectivity. Fur-
thermore, the catalyst system was also efficient for the arylation of
indoles and hydrazones with aryl tosylates.
Key words: palladium, ligand, monoarylation, aryl tosylate, aryl
amine
Pt-Bu2
Oi-Pr
Palladium-catalyzed sp2 C–N bond-forming reactions
have evolved into a highly versatile and synthetically
attractive transformation in targeting pharmaceutically
useful intermediates and material science.1 In these trans-
formations, electrophilic substrates have been largely lim-
ited to aryl halides.2 As synthetic equivalents of aryl
halides, aryl tosylates are easily prepared from cheap and
readily available starting materials, convenient to handle,
as well as stable, crystalline solids. Furthermore, use of
these compounds has advantages over the corresponding
aryl halides because the phenol is a useful directing group
for the introduction of other functional groups on the aro-
matic ring, and this fact can allow access to a wider sub-
strate scope.3 Therefore, aryl sulfonates are very attractive
as coupling partners for the transition-metal-catalyzed
processes. They are also a challenging class of coupling
substrates because of their very low activity toward oxida-
tive addition, which is a critical initial step in the metal-
catalyzed coupling reaction.4 Since Hartwig realized the
amination of inactive aryl tosylates by the application of
hindered, chelating alkyl phosphine ligands and hindered
bases,5 some ligands have been investigated to tackle the
difficult palladium-catalyzed couplings of aryl tosylate.6
Nevertheless, the couplings of primary amines with aryl
tosylates are rare.7
L1
Figure 1 The structure of the bulky and electron-rich MOP-type
ligand
Diarylamines are important synthetic intermediates of
dyestuffs, pesticides, and pharmaceuticals,9 and are used
as antioxidants for rubbers and elastomers,10 or as the im-
portant intermediate of organic electroluminescent and
photoconductors materials.11 The research of the efficient
synthesis of diarylamines appears attractive. Therefore,
we chose the coupling reaction of phenyl tosylate and
aniline as the model reaction to test the limit on activity
and selectivity of our ligand. The results are summarized
in Table 1. The coupling reaction of aniline with phenyl
tosylate occurred in low yield under the identical condi-
tions as for the amination of aryl chloride (Table 1, entry
1).8 On the basis of the report that the oxidative additions
of aryl tosylates were faster in more polar solvents,12 the
solvent was replaced by t-BuOH, however, still no cou-
pled product was obtained. As Pd(dba)2 was used as a
Pd(0) source, the backbond existed between Pd(0) and the
electron-poor dba ligand. Using the strongly electron-
donating phosphine as ligand increased the backbonding,
therefore, it inhibited the dissociation of dba to form the
active species Pd(0)-L1,7 and consequently, the concen-
We recently reported the synthesis of the bulky and elec- tration of the active species and the rate of the oxidative
tron-rich MOP-type ligand (Figure 1), which was readily addition decreased.13 Thus, an alternative precatalyst
Pd(0) was needed. Pd(OAc)2 in combination with
PhB(OH)2 is an efficient method to generate Pd(0) by
double transmetalation and reductive elimination. Grati-
fyingly, the monoaryl product of aniline was obtained in
SYNLETT 2011, No. 7, pp 0955–0958
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259728; Art ID: W34910ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

956
X. Xie et al.
LETTER
38% yield (Table 1, entry 3) and no diaryl product was diarylamine (Table 2, entries 1–3). Even inactive elec-
formed when 2 mol% of Pd(OAc)2, 5 mol% of PhB(OH)2, tron-rich aryl tosylates were coupled in excellent yields
and 3 mol% of L1 were used. In the absence of PhB(OH)2, and selectivities (Table 2, entries 4 and 5). Generally, the
no reaction occurred (Table 1, entry 4). Decreasing the strongly electron-withdrawing groups could promote both
basicity of bases favored controlling the O–S cleavage of the C–O cleavage (the desired reaction) and the O–S
the tosylates. When the weaker bases, K3PO4 and Cs2CO3, cleavage (side reaction).15 When p-benzoyl-substituted
were used, the monoaryl yield was increased to 85% and phenyl tosylate was used as substrate, an excellent yield of
99%, respectively (Table 1, entries 5 and 6). However, the desired product was obtained (Table 2, entry 6). Due
when the reaction was run in the presence of K2CO3, only to the steric hindrance of the ligand, the reaction was
19% yield was obtained (Table 1, entry 7). With respect to slightly sensitive to the steric effects of the substrates. The
the applicability and availability, K3PO4 was employed as reaction of aryl tosylates with only one substituent (ortho)
the base in further studies. By replacing solvent t-BuOH occurred in good yield (Table 2, entry 2); when 2,6-dime-
with n-BuOH, elevating reaction temperature to 110 °C thylphenyl tosylate was employed as substrate, the cou-
led to a higher yield of 99% (Table 1, entry 9). In addition, pling yield decreased to 74% (Table 2, entry 7). The steric
the coupling reaction could be finished in short time, the effects of the aryl amine were similar. For example, when
yield of coupling product reached 99% after two hours 2,6-dimethylaniline was used, a decreased yield was af-
(Table 1, entry 10). Thus, under the optimized reaction forded (Table 2, entry 10). Furthermore, the reaction was
conditions illustrated in entry 9 (Table 1), the catalytic also slightly influenced by the electronic properties of aryl
system was efficient for the coupling reaction of inactivat- amines. The electron-rich aryl amines were coupled in
ed aryl tosylates with aniline and showed high selectivity good yields (Table 2, entries 8 and 12); for the electron-
for monoarylation vs. diarylation.
deficient aryl amines, the decreased nucleophilicity led to
decreased coupling yields. For instance, p-methylaniline
was monoarylated in 91% yield (Table 2, entry 8), while
p-trifluoromethylaniline was monoarylated in 59% yield
(Table 2, entry 11). Consistent with the high selectivity
for reactions of primary arylamines, the reactions of sec-
ondary amines were much slower. The reactions of aryl
tosylates with diphenylamine gave no coupled products
(Table 2, entry 13).
Table 1 Optimization of Reaction Conditions for Coupling of Ben-
zyl Tosylate 1a with Aniline 2aa
H
N
OTs
NH2
Pd, ligand
+
base, solvent
1a
2a
3aa
Entry Pd
Base
Solvent
Additive
Yield
(%)b
Table 2 Palladium-Catalyzed Amination of Aryl Tosylatesa
1
2
Pd(dba)2
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
K3PO4
toluene
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
dioxane
n-BuOH
n-BuOH
–
17
0
Entry Aryl tosylate
Amine
Yield (%)
3ba 94
3ca 93
3da 96
3ea 96
3fa 81
3ha 95
3ia 74
Pd(dba)2
–
1
2
1b 4-MeC6H4OTs
2a PhNH2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PhB(OH)2
–
38
0
1c 2-MeC6H4OTs
1d C10H7-2-OTs
1e 4-MeOC6H4OTs
1f 4-NHBocC6H4OTs
1h 4-C(O)PhC6H4OTs
1i 2,6-Me2C6H3OTs
1a PhOTs
2a PhNH2
4c
5
3
2a PhNH2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
85
99
19
4
4
2a PhNH2
6
Cs2CO3
K2CO3
5
2a PhNH2
7
6
2a PhNH2
8
K3PO4
7
2a PhNH2
9
K3PO4
99
99
8
2b 4-MeC6H4NH2
2c 2-MeC6H4NH2
3ba 91
3ca 88
10d
K3PO4
9
1a PhOTs
a Reaction condition: PhOTs (1mmol), PhNH2 (1.2 mmol), Pd (2
mol%), L1 (3 mol%), PhB(OH)2 (5 mol%), base (1.5 mmol), solvent
10
11
12
13
14
15
1a PhOTs
2d 2,6-Me2C6H3NH2 3ia 54
(2 mL), 15 h.
1a PhOTs
2e 4-F3CC6H4NH2
2f 4-MeOC6H4NH2
2h Ph2NH
3ae 59
3ea 95
0
b GC yield.
c L1 (5 mol%).
d Reaction time: 2 h.
1a PhOTs
1a PhOTs
1a PhOTs
2i indole
3ai 67
3ak 62
The scope of the catalytic system Pd(OAc)2–PhB(OH)2–
L1 was examined by reacting various aryl tosylates and
amines under the optimized reaction conditions
(Table 2).14 Alkyl-substituted aryl tosylates reacted in ex-
cellent yields with aniline without formation of any
1a PhOTs
2k Ph2C=NNH2
a Reaction conditions: ArOTs (1 mmol), amine (1.2 mmol), Pd(OAc)2
(2 mol%), L1 (3 mol%), PhB(OH)2 (5 mol%), K3PO4 (2.0 mmol),
n-BuOH (2 mL), 110 °C, 15 h.
Synlett 2011, No. 7, 955–958 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Monoarylation of Aryl Amine
957
(2) (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
Nitrogen-containing heterocycles are interesting sub-
strates for the N-arylation since many pharmaceuticals
possess such functionality.16 The catalyst system was ef-
ficient for the coupling reaction of indole and aryl tosy-
lates. N-Benzylindole (3ai) was obtained in 67% (Table 2,
entry 14), and no C-arylation product was isolated. The
weaker nucleophilicity and more steric hindrance of in-
dole relative to primary amine led to the decrease of the
coupling yield.
(b) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 13001. (c) Littke, A. F.; Fu,
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(4) (a) Jutand, A.; Hii, K. K. M.; Thornton-Pett, M.; Brown,
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L. M.; Hartwig, J. F.; Liable-Sands, L. M.; Guzei, I. A.
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M.; Hartwig, J. F. Organometallics 2002, 21, 491. (d) Roy,
A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704.
(5) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369.
Moreover, the catalytic system was efficient for the cou-
pling reaction of aryl tosylate and (diphenylmethy-
lene)hydrazine, the desired product N-aryl hydrazone, an
important intermediate for the synthesis of indoles,17 was
obtained in 62% yield (Table 2, entry 15).
(6) For C–N bond formation, see: (a) Klapars, A.; Campos,
K. R.; Chen, C.; Volante, R. P. Org. Lett. 2005, 7, 1185.
(b) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(c) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131,
11049. For C–C bond formation: (d) Ackermann, L.;
Althammer, A.; Fenner, S. Angew. Chem. Int. Ed. 2009, 48,
201. (e) Gooßen, L. J.; Rodríguea, N.; Lange, P. P.; Linder,
C. Angew. Chem. Int. Ed. 2010, 49, 111. (f) Choy, P. Y.;
Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem.
Eur. J. 2010, 16, 9982. (g) Pschierer, J.; Plenio, H. Eur. J.
Org. Chem. 2010, 2934. (h) Munday, R. H.; Martnelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754.
(i) Zhang, L.; Wu, J. J. Am. Chem. Soc. 2008, 130, 12250.
(j) Bhayana, B.; Fors, B.; Buchwald, S. L. Org. Lett. 2009,
11, 3954.
In addition, the activity of tosylates relative to chlorides
was also investigated. In our catalytic system, aryl chlo-
rides reacted faster than aryl tosylates. The reaction of 4-
chlorophenyl tosylate led to a coupling product at the C–
Cl bond (Scheme 1). These results were in parallel to
those catalyzed by Pd-Buchwald ligand,18 but different
from those catalyzed by Pd-Josiphos.7
Cl
NHPh
Pd(OAc)2, L1
+
PhNH2
PhB(OH)2, K3PO4, BuOH
2a
OTs
OTs
(7) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
13848.
(8) Xie, X.; Zhang, T. Y.; Zhang, Z. J. Org. Chem. 2006, 71,
6522.
1l
3la 88%
Scheme 1 The coupling reaction of 4-chlorophenyl tosylate with
aniline
(9) Belfield, A. J.; Brown, G. R.; Foubister, A. J. Tetrahedron
1999, 55, 11399.
(10) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.
Synth. Catal. 2006, 348, 23.
In summary, the bulky and electron-rich MOP-type ligand
was efficient for the Pd-catalyzed amination of aryl tosy-
lates. The active catalyst was formed in situ from
Pd(OAc)2, PhB(OH)2, and air- and moisture-stable phos-
phines. The optimized system showed high catalytic ac-
tivity for monoarylation of aryl amines, indoles, and
hydrazones. In the competitive reaction, the reaction rates
of aryl chlorides are faster than those of aryl tosylates.
(11) (a) Law, K. Y. Chem. Rev. 1993, 93, 449. (b) Ferreira, I. C.
F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59,
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Koie, Y. Tetrahedron Lett. 2000, 41, 481.
(12) Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 194.
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Organometallics 2006, 25, 1795. (b) Fairlamb, I. J. S.;
Kapdi, A. R.; Lee, A. F.; McGlackem, G. P.; Weissburger,
F.; de Vries, A. H. M.; Van de Vondervoort, L. S. Chem.
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Buchwald, S. L. Org. Lett. 2010, 12, 2350.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(14) Typical Procedure
A flame-dried Schlenk tube was charged with Pd(OAc)2 (4.5
mg, 0.02 mmol), L1 (13.7 mg, 0.03 mmol), PhB(OH)2 (6.1
mg, 0.05 mmol), and n-BuOH (2 mL) under an atmosphere
of nitrogen. The solution was stirred at r.t. for 15 min then
K3PO4 (424.5 mg, 2.0 mmol) and ArOTs 1 (1mmol) were
added, followed by aryl amine 3 (1.2 mmol). The reaction
was heated to 110 °C and stirred for 15 h. The reaction
mixture was cooled to r.t. and diluted with Et2O (5 mL) and
H2O (3 mL). After separation of the layers, the aqueous
phase was extracted with Et2O (3 × 5 mL), and the combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. Purification of the crude product by flash column
chromatography (silica gel; PE–Et3N, 99:1) yielded
compound 3.
Acknowledgment
We thank the National Natural Science Foundation of China for fi-
nancial support.
References and Notes
(1) (a) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599. (b) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organopalladium Chemistry of Organic
Synthesis, Vol. 1; Wiley-Interscience: New York, 2002,
1051. (c) Muci, A.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131.
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958
X. Xie et al.
LETTER
(15) Gao, C.; Yang, L. J. Org. Chem. 2008, 73, 1624.
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M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
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(18) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem.
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Synlett 2011, No. 7, 955–958 © Thieme Stuttgart · New York

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