CN and CS bond forming cross coupling in water with amphiphilic resin-supported palladium complexes

Article abstract of DOI:10.1246/cl.2011.934

Catalytic CN and CS bond forming reactions of haloarenes with secondary amines and benzenethiols were achieved in water under heterogeneous conditions by the use of immobilized palladium complexes coordinated with the amphiphilic polystyrenepoly( ethylene glycol) resin-supported di(tert-butyl)phosphane ligand to afford aryl(dialkyl)amines and diaryl sulfides in high yield.

Full text of DOI:10.1246/cl.2011.934

doi:10.1246/cl.2011.934
934
Published on the web September 5, 2011
C-N and C-S Bond Forming Cross Coupling in Water
with Amphiphilic Resin-supported Palladium Complexes
Yoshinori Hirai1,2 and Yasuhiro Uozumi*1
1Institute for Molecular Science (IMS), 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787
2Frontier Biochemical and Medical Research Laboratories, KANEKA Corporation, Takasago, Hyogo 676-8688
(Received April 18, 2011; CL-110324; E-mail: uo@ims.ac.jp)
Table 1. Amination of halobenzene in watera
Catalytic C-N and C-S bond forming reactions of
[L/Pd] (cat)
haloarenes with secondary amines and benzenethiols were
achieved in water under heterogeneous conditions by the use
of immobilized palladium complexes coordinated with the
amphiphilic polystyrene-poly(ethylene glycol) resin-supported
di(tert-butyl)phosphane ligand to afford aryl(dialkyl)amines and
diaryl sulfides in high yield.
aq. KOH
+
X
HN
O
N
O
1a (X = Br)
1a′ (X = Cl)
2
4
5
+
1a
HNPh2
NPh2
3
Entry
L
P/Pd
Product
Yield/%b
1
2
3
4c
5
L1
L2
L3
L3
L3
1/1
1/1
1/1
1/1
2/1
4
4
4
4
4
10
22
74
64
86
Organic reactions in water have recently received much
attention because water is a readily available, safe, and environ-
mentally benign solvent.1-3 On the other hand, clean organic
synthesis by use of solid-supported reagents has been recognized
as an effective methodology to prevent contamination of the
reagent residue in the products by simple manipulations.2,3
We have developed amphiphilic polystyrene-poly(ethylene
glycol) (PS-PEG) resin-supported palladium-phosphane com-
plexes, which catalyze various palladium-mediated reactions,
including cross-coupling reactions, smoothly in water under
heterogeneous conditions to meet the requirements of green,
safe, and clean organic synthesis.4 Thus, for example, various
C-C bond forming cross-couplings, e.g., the Suzuki-Miyaura
cross-coupling,4a,4b,4e,4f the Mizoroki-Heck reaction,4c and the
Sonogashira4d,4g reaction, have been achieved in water using
palladium complexes immobilized by coordination with a
phosphane ligand anchored on an amphiphilic PS-PEG resin.
As part of our effort to demonstrate the wide utility of this
catalyst system, we decided to examine the Buchwald-Hartwig
type C-N and C-S bond forming reactions.5 While, we have
previously reported the Buchwald-Hartwig amination of aryl
halides with diarylamines in water to form triarylamines,6 the
aqueous-switching of C-N coupling with alkylamines and C-S
coupling reactions still remains a major challenge. We report
herein our results demonstrating that coupling reactions of
various aryl halides with amines and thiols proceed in water
in the presence of a palladium complex of a PS-PEG resin-
supported tert-butylphosphane ligand.
6
7
8
9c
10
11d
12
L1
L2
L3
L3
L3
L3
L4
1/1
1/1
1/1
1/1
2/1
2/1
1/1
5
5
5
5
5
5
5
<1
<1
82
81
92
95
41
aAll reactions were carried out with PhBr (1a) in 20 M aqueous KOH
solution under reflux in the presence of 5 mol % 1/2[PdCl(©3-C3H5)]2
and a polymeric ligand (L) for 17-24 h, unless otherwise noted. The
ratio of 1 (mol)/2 or 3 (mol)/H2O (L) = 1.0/1.5/2.0. Isolated yields.
cPhCl (1a¤) was used. dRecycled polymeric palladium complex (L3/
b
Pd; 5th reuse) was used.
O
C
O
C
H
H
N
PS-
PS-
PEG
N
CH2CH2
P
P
PEG
L1
L3
L2
P
PS-
PEG
P
O
Fe
H
PS-
PEG
N
C
L4
We have examined several amphiphilic PS-PEG resin-
supported phosphane ligands for the amination reaction of
bromobenzene (1a) (Table 1). Thus, the C-N bond forming
coupling reaction of 1a with morpholine (2) was carried out in
refluxing aqueous KOH solution in the presence of a PS-PEG
resin-supported palladium catalyst for 24 h. After being cooled
the reaction mixture was filtered, and the catalyst beads were
rinsed with EtOAc to extract the organic compounds. The
combined extract was concentrated and the resulting residue was
chromatographed on silica gel to give the N-phenylmorpholine
(4) (Entries 1-5). The results reveal that the palladium-complex
bound to the PS-PEG-di(tert-butyl)phosphane resin L3 is the
best catalyst for the amination reaction of 1a and 2 in water.
Thus, the palladium complex immobilized by coordination with
an alkyl[di(tert-butyl)]phosphane group which was anchored on
an amphiphilic PS-PEG resin catalyzed the reaction of 1a and 2
in an aqueous KOH solution to give 74% isolated yield of
N-phenylmorpholine (4) (Entry 3). Lower catalytic activity was
observed in water with the PS-PEG resin-supported triarylphos-
phane L1 and aryl[di(tert-butyl)]phosphane ligand L2 (Entries 1
and 2). It is noteworthy that the polymeric palladium complex of
L3 also promoted the C-N coupling of chlorobenzene (1a¤)
under similar conditions to give 64% yield of 4 (Entry 4). The
best result was obtained with a palladium complex prepared by
mixing L3 and [PdCl(©3-C3H5)]2 in a ratio of P/Pd = 2/1 where
the target compound 4 was obtained in 86% yield (Entry 5). A
Chem. Lett. 2011, 40, 934-935
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

935
Table 2. C-S Coupling of bromoarenes in watera
[L3/Pd] (cat)
[L3/Pd] (cat)
aq. KOH
Br
HS
S
aq. KOH
+
+
Br
Br
N
HN
HN
+
Y
Y
Z
Z
86%
8
6
7
9
1a-j
11A-F
12aA-jF
Entry
1
11
Y
Z
Product Yield/%b
NPh
N
NPh
75%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a 11A
1a 11B
1a 11C
1a 11D
1a 11E
1a 11F
H
H
H
H
H
H
2-CH3
3-CH3
2-CH3O
3-CH3O
4-CH3O
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
4-t-Bu
12aA
12aB
12aC
12aD
12aE
12aF
12bF
12cF
12dF
12eF
12fF
12gF
12hF
12iF
74
71
71
68
93
91
84
75
78
96
82
86
57
72
61
10
1a
Scheme 1. C-N coupling with nitrogen heterocycles.
similar trend was also observed in the reaction of 1a with
diphenylamine (3) (Entries 6-12).6 The amination with di-
phenylamine hardly proceeded with a palladium complex of
polymeric arylphosphanes (Entries 6 and 7). Ferrocenyl[di(tert-
butyl)]phosphane L4 gave a moderate yield of triphenylamine
(5) under similar conditions (Entry 12). A palladium complex of
sterically demanding alkylphosphane L3 promoted the amina-
tion of bromobenzene (1a) as well as chlorobenzene (1a¤) in
refluxing aqueous KOH solution to give triphenylamine (5) in
82 and 81% yield, respectively (Entries 8 and 9). A polymeric
palladium complex prepared from L3 (P/Pd = 2/1) provided
5 in 92-95% yield through 5 reuses of the catalyst beads
(Entries 10 and 11). Amination reactions with indoline (7) and
N-phenylpiperazine (9) were also examined successfully with
L3 under otherwise the same conditions to afford N-biphenyl-4-
ylindoline (8) and N,N¤-diphenylpiperazine (10) in 86 and 75%
yield, respectively (Scheme 1).
With the efficient aqueous heterogeneous catalytic system
for the C-N bond forming coupling in hand, we next examined
the C-S bond forming catalysis with the catalytic system
(Table 2). Thus, bromobenzene (1a) reacted with 2-methyl-
benzenethiol (11A) in refluxing aqueous KOH solution in the
presence of 5 mol % Pd of the polymeric palladium complex
L3/Pd for 24 h to give 74% isolated yield of 2-methylphenyl
phenyl sulfide (12aA) (Entry 1).7 Benzenethiol bearing 3-methyl
(11B), 2-methoxy (11C), 3-methoxy (11D), 4-methoxy (11E),
and 4-tert-butyl (11F) reacted with 1a under similar conditions
to afford the corresponding substituted diphenyl sulfide in 68-
93% yield (Entries 2-6). Bromoarenes bearing electron-with-
drawing and -donating substituents at the ortho-, meta-, and
para-positions are also tolerated as coupling partners. Thus, 2-,
3-, and 4-(trifluoromethyl)bromobenzenes 1b-1d reacted with
4-(tert-butyl)benzenethiol (11F) under similar conditions to give
4-(tert-butyl)phenyl n-trifluoromethylphenyl sulfides (n = 2
(12bF), 3 (12cF), and 4 (12dF)), respectively (Entries 7-9).
Bromotoluenes 1e-1g and bromoanisoles 1h-1j also underwent
the C-S coupling under the same catalytic conditions to afford
the corresponding diaryl sulfides 12eF-12jF in 57-96% yield
(Entries 10-15).
1b 11F 2-CF3
1c 11F 3-CF3
1d 11F 4-CF3
1e 11F 2-CH3
1f 11F 3-CH3
1g 11F 4-CH3
1h 11F 2-CH3O 4-t-Bu
1i 11F 3-CH3O 4-t-Bu
1j 11F 4-CH3O 4-t-Bu
12jF
aAll reactions were carried out with PhBr in 20 M aqueous KOH
solution under reflux in the presence of 5 mol % 1/2[PdCl(©3-C3H5)]2
and a polymeric ligand (L) for 24 h, unless otherwise noted. The ratio
b
of 1 (mol)/11 (mol)/H2O (L) = 1.5/1.0/2.0. Isolated yields.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
References and Notes
1
For recent reviews on organic reactions in water, see: a) U. M.
Lindström, Chem. Rev. 2002, 102, 2751. b) C.-J. Li, T.-H. Chan,
Comprehensive Organic Reactions in Aqueous Media, Wiley-Inter-
science, New Jersey, 2007.
For recent reviews on organic reactions in water, see: a) Y. Uozumi,
Immobilized Catalysts Solid Phases, Immobilization and Applications
in Topics in Current Chemistry, ed. by A. Kirschning, Springer, Berlin,
2004, Vol. 242, p. 77. doi:10.1007/b96874. b) M. Guinó, K. K. M. Hii,
Chem. Soc. Rev. 2007, 36, 608. c) Z. Wang, G. Chen, K. Ding, Chem.
Rev. 2009, 109, 322. d) J. Lu, P. H. Toy, Chem. Rev. 2009, 109, 815.
A review on heterogeneous palladium catalysis in water, see: M.
Lamblin, L. Nassar-Hardy, J.-C. Hierso, E. Fouquet, F.-X. Felpin, Adv.
Synth. Catal. 2010, 352, 33.
For studies on cross-coupling in water with polymeric palladium
complexes from the author’s group, see: a) Y. Uozumi, H. Danjo, T.
Hayashi, J. Org. Chem. 1999, 64, 3384. b) Y. Uozumi, Y. Nakai, Org.
Lett. 2002, 4, 2997. c) Y. Uozumi, T. Kimura, Synlett 2002, 2045. d) Y.
Uozumi, Y. Kobayashi, Heterocycles 2003, 59, 71. e) Y. Uozumi, M.
Kikuchi, Synlett 2005, 1775. f) Y. Uozumi, Y. Matsuura, T. Arakawa,
Y. M. A. Yamada, Angew. Chem., Int. Ed. 2009, 48, 2708. g) T. Suzuka,
Y. Okada, K. Ooshiro, Y. Uozumi, Tetrahedron 2010, 66, 1064.
For recent reviews, see: a) J. E. R. Sadig, M. C. Willis, Synthesis 2011,
1. b) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534. c) D. S. Surry,
S. L. Buchwald, Angew. Chem., Int. Ed. 2008, 47, 6338. d) R. Martin,
S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461. e) J.-P. Corbet, G.
Mignani, Chem. Rev. 2006, 106, 2651.
2
3
4
5
In conclusion, we have developed a novel C-N and C-S
bond forming catalytic protocol with an amphiphilic polymeric
palladium complex of sterically demanding alkylphosphane
ligand L3, which was carried out in water under heterogeneous
conditions to realize a high level of chemical greenness.
Synthetic application of this protocol is currently under inves-
tigation in our laboratory and will be reported in due course.
6
7
Y. Hirai, Y. Uozumi, Chem. Commun. 2010, 46, 1103; Y. Hirai, Y.
Uozumi, Chem.®Asian J. 2010, 5, 1788.
General procedure: A mixture of catalyst (L3-Pd complex (P/Pd =
2/1), 0.015 mmol of Pd), aryl halides (0.45mmol) and arylthiols
(0.30 mmol) in 20M KOH aqueous solution (0.6 mL) under a nitrogen
atmosphere was shaken for 24h under reflux conditions. After being
cooled, the mixture was filtered, the recovered resin beads were extracted
with EtOAc (2 mL © 4 times). The combined extracts were dried over
anhydrous Na2SO4, concentrated in vacuo, and the resulting residue was
chromatographed on silica gel to give the corresponding diaryl sulfides.
We acknowledge the JSPS (Grant-in-Aid for Scientific
Research on Innovative Area No. 2105) and the NEDO GSC
project for partial financial support of this work.
Chem. Lett. 2011, 40, 934-935
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/