Angewandte
Chemie
DOI: 10.1002/anie.201404355
Synthetic Methods
Palladium-Catalyzed Amination of Aryl Sulfides with Anilines**
Tomohiro Sugahara, Kei Murakami,* Hideki Yorimitsu,* and Atsuhiro Osuka
Abstract: A combination of a palladium–NHC catalyst and
potassium hexamethyldisilazide enables the amination of aryl
sulfides with anilines to afford a wide variety of diarylamines.
The reaction conditions are versatile enough for the reaction of
even bulky ortho-substituted aryl sulfides. This amination can
be applied to the modular synthesis of N-aryl carbazoles from
the corresponding ortho-bromothioanisoles. As aryl sulfoxides
undergo extended Pummerer reactions to afford ortho-sub-
stituted aryl sulfides, the Pummerer products are thus useful
substrates for the amination to culminate in efficient syntheses
of a 2-anilinobenzothiophene and an indole as proof-of-
principle of the utility of the extended Pummerer reaction/
amination cascade.
reactions of aryl sulfides.[16] We envisioned that such elec-
tron-donating and bulky ligands would also aid the catalytic
amination of aryl sulfides. Herein, we report amination
reactions of aryl sulfides with aryl amines using a Pd–NHC
catalyst.
The reaction conditions were first optimized for the
amination reaction (Table 1; for details of the catalysts used,
see Figure S1 in the Supporting Information). Treatment of
Table 1: Optimization of the amination reaction conditions.
T
he transition-metal-catalyzed amination of aryl halides[1,2]
has attracted considerable attention from material and
medicinal chemists because a significant number of functional
molecules[3] and drugs[4] contain aryl amine structures.
Entry
Catalyst
Base
Yield [%][a]
1
2
3
4
5
6
7
8
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
None
K2CO3
KOH
KOtBu
0
0
7
À
Although aminations of inert C O bonds of phenol deriva-
KHMDS/Toluene
NaHMDS/THF
LiHMDS/THF
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
KHMDS/Toluene
76[b]
38
5
tives, such as mesylate,[5] tosylates,[6] carbamates,[7] sulfama-
tes,[7a,8] pivalate esters,[9] phosphate,[10] and methyl ethers,[11]
0
À
are established, it is still difficult to convert C S bonds of aryl
sulfides into C N bonds.
a difficult transmetalation step, which is caused by the strong
interaction between a cationic transition-metal center and an
[12,13]
SingaCycle-A1
SingaCycle-A3
84
88[b]
72
50
84
91[b,c]
0
5
25
0
À
The difficulty originates from
9
10
11
12
13
14
15
16
17
[IPrPdCl(p-allyl)]
[Pd2(dba)3]/IPr·HCl
[{(p-allyl)PdCl}2]/IPr·HCl
SingaCycle-A3
Pd-PEPPSI-IMes
Pd-PEPPSI-IPent
Pd-PEPPSI-SIPr
NiBr2·diglyme/IPr·HCl
À
anionic thiolate moiety. Although many conversions of C S
bonds into C C bonds are known,[14,15] no catalytic conversion
À
À
À
of C S into C N bonds has been reported.
Our recent studies showed that palladium and nickel
catalysts bearing an N-heterocyclic carbene (NHC) ligand are
À
sufficiently active for C C bond-forming cross-coupling
[a] Product yield calculated from 1H NMR experiments. Diphenylme-
thane was used as an internal standard. [b] Yield of isolated product.
[c] p-Toluidine (1.2 equiv), SingaCycle-A3 (2.5 mol%), KHMDS/toluene
(2.5 equiv), dioxane (0.5m). Highlighted line indicates optimum reaction
conditions.
[*] T. Sugahara, Prof. Dr. K. Murakami, Prof. Dr. H. Yorimitsu,
Prof. Dr. A. Osuka
Department of Chemistry
Graduate School of Science, Kyoto University
Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan)
E-mail: yori@kuchem.kyoto-u.ac.jp
thioanisole with p-toluidine (1.5 equiv) in the presence of the
catalyst Pd-PEPPSI-IPr[1c,d,h] (5 mol%; PEPPSI = pyridine-
enhanced pre-catalyst preparation, stabilization, and initia-
tion; IPr= 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
and K2CO3 (3 equiv) in dioxane at 1008C for 12 h gave none
of the expected diaryl amine 1a (entry 1). We speculated that
Prof. Dr. K. Murakami
The Hakubi Center for Advanced Research
Kyoto University (Japan)
E-mail: kmura@kuchem.kyoto-u.ac.jp
Prof. Dr. H. Yorimitsu
ACT-C, JST (Japan)
[**] This work was supported by Grants-in-Aid from MEXT (Nos.:
24106721 “Reaction Integration” and 25107002 “Science of Atomic
Layers”) and from JSPS (Nos.: 24685007 (Young Scientists (A)),
23655037, and 26620081 (Exploratory Research)). K.M. acknowl-
edges JSPS Postdoctoral Fellowship for Young Scientists. Mr.
Vincent Guꢀrin and Dr. Alexandre Baralle are acknowledged for
preparation of starting materials.
this disappointing result is caused by
a
sluggish
transmetalation step.[17] The same reaction was tested using
stronger bases to accelerate the transmetalation step
(entries 2–6). Although KOH and KOtBu were not effective,
employment of KHMDS (potassium hexamethyldisilazide)
provided 1a in 76% yield (entries 2–4). The choice of
countercation was important: analogues NaHMDS and
LiHMDS afforded 1a in only 38% and 5% yields, respec-
Supporting Information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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