Ullmann-type: N-arylation of anilines with alkyl(aryl)sulfonium salts

Article abstract of DOI:10.1039/c9cc06535k

A palladium/copper-cocatalyzed Ullmann-type N-arylation of anilines using alkyl(aryl)sulfonium triflates as arylation reagents has been accomplished. The reaction enabled C_aryl-S bond cleavage over C_alkyl-S bond breakage of alkyl(aryl)sulfoniums by Pd(P(tBu)₃)₂/CuI and gave the corresponding N-arylated products in good to high yields. It was also significant that the reactions of aniline with asymmetric butyl(mesityl)(aryl)sulfonium triflates showed excellent selectivity, in which the aryl groups other than the bulky and electron-rich mesityl moieties were transformed.

Full text of DOI:10.1039/c9cc06535k

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Tian and C.
Zhang, Chem. Commun., 2019, DOI: 10.1039/C9CC06535K.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC06535K
COMMUNICATION
Ullmann-type N-Arylation of Anilines with Alkyl(aryl)sulfonium
Salts
Received 00th January 20xx,
Accepted 00th January 20xx
Ze-Yu Tian,a,b Cheng-Pan Zhanga,b,
*
DOI: 10.1039/x0xx00000x
A
palladium/copper-cocatalyzed Ullmann-type N-arylation of the preparation of N-arylated amine derivatives.13 Since the
anilines using alkyl(aryl)sulfonium triflates as arylation reagents aromatic amines have found wide applications in
has been accomplished. The reaction enabled Caryl-S bond cleavage pharmaceuticals, natural products, organic materials and
over Calkyl-S bond breakage of alkyl(aryl)sulfoniums by catalysts, these strategies have been continually innovated by
Pd(P(tBu)3)2/CuI and gave the corresponding N-arylated products extensive investigations of the reaction mechanisms and
in good to high yields. It was also significant that the reactions of development of new ligands and precatalysts. The
aniline with asymmetric butyl(mesityl)(aryl)sulfonium triflates optimizations, combined with
a wide range of amine
showed excellent selectivity, in which the aryl groups other than nucleophiles and aryl halides or pseudohalides, have rendered
the bulky and electron-rich mesityl moieties were transformed.
the Cu- and Pd-catalyzed methods as appealing alternatives to
the traditional approaches for the synthesis of arylamines.
These include the improved Ullmann reaction,14 Buchwald-
Hartwig reaction,15 Chan-Evans-Lam reaction,16 C(sp2)-H
amination,17 and decarboxylative amination,18 which have
resulted in the discovery of N-arylation reactions of
considerable generality.
Alkyl(aryl)sulfonium salts are versatile chemical reagents that
have been widely applied in organic synthesis due to their easy
preparation, convenient to use, good thermal stability, high
reactivity, and broad structural diversity.1-3 They can be used
as ylide precursors to construct useful cyclic compounds in the
presence of appropriate bases.4 They are also powerful alkyla-
ion reagents, which is devoted to transition-metal-free
electrophilic alkylation5 and palladium-catalyzed direct ortho
C-H alkylation.6 Moreover, the transition-metal-catalyzed
transformation of alkyl(aryl)sulfonium salts as aryl
pseudohalides has proved that alkyl(aryl)sulfoniums are
excellent arylation cross-coupling partners in the Suzuki-
Miyaura reactions with arylboronic acids/esters or
tetraarylborates,7 the Mizoroki-Heck reactions with alkenes,8
the Sonogashira reactions with alkynes,9 the borylation with
bis(pinacolato)diboron,10 and the alkoxycarbonylation with CO
and alcohols or phenols.11 Recently, the transition-metal-free
N-arylation of amines by triarylsulfonium salts via an aryne
intermediate was implemented.12a However, N-arylation of
amines by alkyl(aryl)sulfonium salts was not realized as the
reactions of anilines with alkyl(aryl)sulfoniums under the basic
conditions gave only N-alkylated products.5a,12
sulfur ylides
DG
base
R2
R3
Ar
[Pd]
[M]
R1
Ar
R3 = aryl, alkenyl, alkynyl
boronates, etc.
S
R2
arylation
alkylation
X
R1 = aryl, alkyl
R2 = alkyl
H
N
nucleophile
N-arylation
Ar
Ar
X = OTf, BF4, etc.
R2
alkylation
metal-free
this work
Nu
Scheme 1. The utility of alkyl(aryl)sulfonium salts in organic synthesis.
N-Arylation of anilines by aryl sulfides has also been
harnessed under Pd-catalyzed or transition-metal-free
conditions,19 but the reactions require use of strong bases
and/or electron-deficient aryl sulfides bearing a cyano group,
which limited the scope of substrates. Compared to aryl
sulfides, use of arylsulfonium salts as arylation reagents offers
advantages such as: 1) the much easier oxidative addition of
Caryl-S bonds of arylsulfonium cations to transition metals than
those of aryl sulfides; 2) the sulfide byproducts less poisonous
to catalysts than the anionic thiolate species derived from aryl
sulfides.3b Although the employment of alkyl(aryl)sulfonium
salts in place of aryl sulfides improved the arylation power, the
alkylation ability was also significantly enhanced, leading to
alkyl(aryl)sulfoniums being both powerful arylation and
alkylation reagents. We wondered whether the selective
cleavage of the Caryl-S bonds of alkyl(aryl)sulfoniums in
The metal-catalyzed Caryl-N bonds formation between amines
and aryl halides or pseudohalides has been a general tool for
a. School of Materials Science and Engineering, Wuhan University of Technology,
122 Luoshi Road, Wuhan, 430070, China.
b. School of Chemistry, Chemical Engineering and Life Science, Wuhan University of
Technology, 205 Luoshi Road, Wuhan, 430070, China.
*E-mail: cpzhang@whut.edu.cn, zhangchengpan1982@hotmail.com.
Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
presence of a suitable catalyst would enable mild and efficient was formed but 42% of 4b was observed (entry 8V,ieTwaAbrlteicleSO8n).linIef
N-arylation of anilines over N-alkylation.5a
2a was treated with 1b and K3PO4 (1.2 equiv) in the absence of
Pd[P(tBu)3]2 and CuBr, there was no 3a obtained either (entry
9, Table S8). These results indicated that the palladium catalyst
was very essential for the N-phenylation and that the copper
salt might benefit the transformation by both enhancing N-
phenylation and suppressing N-alkylation.
DOI: 10.1039/C9CC06535K
Scheme 2. Pd/Cu-Catalyzed N-phenylation of 2a by different
alkyl(phenyl)sulfonium triflates (1) under the same reaction conditions.a
2a
)
PhNH2
(
H
N
Pd[P(tBu)3]2 (7.5 mol%)
R2
S
CuBr (5 mol%)
OTf
R1
K3PO4 (1.2 equiv)
CH3CN, 60 oC, 16 h, N2
1
3a
(1.2 equiv)
Scheme 3. Pd/Cu-Catalyzed N-phenylation of arylamines by 1b.a
OTf
Pd[P(tBu)3]2 (7.5 mol%)
Et
S
H
nBu
Me
NH2
S
R
S
S
S
N
CuBr (5 mol%)
K3PO4 (1.2 equiv)
CH3CN, 60 oC, 16 h, N2
S
OTf
+
OTf
OTf
1h
, 83% (83%)
Ar
OTf
Et
nBu
Me
Ar
OTf
nBu
1b
(1.2 equiv)
1a
1b
1c
1d
, R = Et, 94%
, R = nBu, >99% (94%)
, R = nPr, 94%
1e
, 14%
1f
1g
, 77%
, 72%
2
3
, R = Me, 31%
3a
3b
3c
3d
3e
, R = H, 94%
, R = OMe, 84%
, R = Me, 94%
, R = NHBoc, 87%
, R = NHBz, 87%
, R = CO2Me, 96%
H
N
H
N
a
Reaction conditions: 2a (0.2 mmol), 1 (0.24 mmol), K3PO4 (0.24 mmol), Pd[P(tBu3)2]
R
(0.015 mol), CuBr (0.01 mmol), CH3CN (2 mL), 60 oC, N2, 16 h. The yields were
determined by HPLC using diphenylamine as an external standard (tR = 5.86 min, λ =
284 nm, water/methanol = 15/85 (v/v)). Isolated yield is depicted in the parenthesis.
3n
3o
3p
, R = 3-Me, 87%
, R = 2-Me, 83%
, 63%
NH
H
N
3f
3g, R = COMe, 98%
3h
3i
3j
, R = NO2, 92%
, R = CN, 98%
, R = F, 97%
R
H
N
Initially, reaction of aniline (2a) with ethyl(diphenyl)sulfonium
triflate (1a, 1.5 equiv) in DMF in the presence of Pd[P(tBu)3]2
(10 mol%) and K3PO4 (1 equiv) at 60 oC for 12 h gave N-
ethylaniline (4a) in 41% yield and diphenylamine (3a) in a trace
amount (entry 1, Table S1). When 10 mol% CuI was used as a
cocatalyst in the same reaction, 3a was formed in 7% yield
together with 16% of 4a (entry 2, Table S1). Taking Pd(PPh3)4,
Pd(PCy3)2, Pd2(dba)3, Pd(OAc)2, and Pd(PPh3)2Cl2 instead of
Pd[P(tBu)3]2 led to almost no production of 3a (Table S1). The
choice of solvents had an influence on the reaction. The
investigation showed that CH3CN was a better solvent than
DMF, NMP, toluene, 1,4-dioxane, THF, DCE, DMSO, PhCN and
MeNO2, which afforded 3a in 52% yield (Table S2). The copper
reagents also affected the N-phenylation (Table S3). CuOAc,
3k
, R = Cl, 84%
N
H
b
3l
, R = Br, messy
CO2Me
3m
, R = I, messy
3q
, 67%, 45%
S
c
3r
, 91%, 96%
H
N
O
N
S
Me
N
N
O
N
H
3s
, 61%
3u
, 55%
O
d,e
3w
, 76%
H
N
Ph
N
N
Cl
N
H
N
MeO
3v
N
H
d
3t
, 25%, 53%
d,e
, 42%
3x
, 5% HPLC yield
a
Reaction conditions: 2 (0.2 mmol), 1b (0.24 mmol), K3PO4 (0.24 mmol),
Pd[P(tBu)3]2 (7.5 mol%), CuBr (5 mol%), CH3CN (2 mL), 60 oC, N2, 16 h. Isolated
yield. b K3PO4 (0.48 mmol). c On a 5.0 mmol scale. d 80 oC. e 24 h.
Scheme 4. Symmetric and asymmetric butyl(diaryl)sulfonium triflates as
CuOTf, CuCN, CuTc, Cu(CH3CN)4PF6, Cu2O, CuCl2, Cu(OAc)2, and arylation reagents for aniline.a
Cu could slightly improve the yield of 3a (56-68%). If CuBr (10
Pd[P(tBu)3]2 (7.5 mol%)
Ar
H
N
Ar
NH2
mol%) was employed in the reaction of 2a, 1a (1.5 equiv),
K3PO4 (1.0 equiv), and Pd[P(tBu)3]2 (10 mol%) in CH3CN at 60 oC
for 12 h, 3a was obtained in 76% yield and 4a in 18% yield
(entry 1, Table S4). Decreasing the catalyst loadings of
Pd[P(tBu)3]2 and CuBr from 10 mol% to 7.5 mol% and 5 mol%,
respectively, could further inhibit the formation of 4a,
affording 3a in 77% yield (entry 6, Table S4). Among bases such
as K2HPO4, K2CO3, Cs2CO3, Na2CO3, NaHCO3, KOH, NaOAc, KF
and DBU (Table S5), K3PO4 appeared to be the best for the
reaction, in which a higher yield of 3a and a lower yield of 4a
were achieved. Encouragingly, reaction of 2a with 1a (1.2
equiv) and K3PO4 (1.2 equiv) in the presence of Pd[P(tBu)3]2
CuBr (5 mol%)
S
OTf
+
Ar
nBu
1
K3PO4 (1.2 equiv)
CH3CN, 60 oC, 16 h, N2
2a
3
(1.2 equiv)
MeO
Cl
MeO
Ar
Ar
Mes
Mes
S
S
S
S
OTf
OTf
OTf
OTf
nBu
nBu
nBu
1l
nBu
1i
, Ar = 4-MeOC6H4
1j
1m
, Ar = 4-ClC6H4
3b
, 88%
3k
3b, 76%
, 70%
3a
, 86%
Me
Me
Me
Mes
F
Mes
Mes
S
nBu
S
S
Mes
OTf
OTf
OTf
S
nBu
1p
nBu
1q
OTf
nBu
1n
1o
3c
, 76%
3j
, 50%
3o
, 84%
3n
, 76%
Cl
NC
O2N
Ph
o
(7.5 mol%) and CuBr (5.0 mol%) at 60 C for 16 h provided 3a
Mes
Mes
Mes
Mes
S
S
S
S
nBu
OTf
OTf
OTf
OTf
in 94% yield (entry 6, Table S6). If ethyl(diphenyl)sulfonium (1a)
was replaced by butyl(diphenyl)sulfonium (1b) under the same
conditions, 3a was obtained in >99% yield (94% isolated yield)
and the formation of N-alkylated product (4b) was completely
prohibited (entry 3, Table S8). Moreover, reaction of 2a, 1b,
K3PO4 (1.2 equiv), and Pd[P(tBu)3]2 in the absence of CuBr
afforded 3a in 84% yield and 4b in 15% yield (entry 7, Table S8),
which proved again the importance of CuBr in N-phenylation.
When 2a reacted similarly with 1b, K3PO4 (1.2 equiv) and CuBr
in the absence of Pd[P(tBu)3]2, no N-phenylated product (3a)
nBu
nBu
nBu
1u
1r
, 34%, 69%
1s
1t
b
b
b
b
c
3h
, 78%
3k
3y
, 52%, 62%
3i
, 53%, 72% , 63%
a
Reaction conditions: 2a (0.2 mmol), 1 (0.24 mmol), K3PO4 (0.24 mmol),
Pd[P(tBu)3]2 (7.5 mol%), CuBr (5 mol%), CH3CN (2 mL), 60 oC, N2, 16 h, isolated
yield. b 40 oC. c r.t.
To understand the effects of alkyl groups of al-
kyl(aryl)sulfonium salts on the Pd/Cu-catalyzed N-phenylation,
several alkyl(diphenyl)- or dialkyl(phenyl)sulfonium triflates
were compared under the same reaction conditions (Scheme
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
ChemComm
Journal Name
COMMUNICATION
2). It was found that propyl(diphenyl)sulfonium triflate (1c, 1.2 of small amounts of the starting anilineVsi.ew AErtlieclveaOtnilninge
o
o
DOI: 10.1039/C9CC06535K
equiv) reacted with 2a and K3PO4 (1.2 equiv) in the presence of temperature from 60 C to 80 C in the reaction of 2t could
Pd[P(tBu)3]2 (7.5 mol%) and CuBr (5 mol%) at 60 oC for 16 h to promote the production of 3t (53%). Furthermore, the
give 3a in 94% yield, which was identical to that obtained from secondary aniline derivatives like N-methylaniline (2w) and
the reaction of 1a. However, if 2a was mixed with diphenylamine (3a) reacted with 1b, K3PO4, and
o
methyl(diphenyl)sulfonium triflate (1d) in a similar manner, Pd[P(tBu)3]2/CuBr at 80 C for 24 h to construct N-methyl-N-
only 31% of 3a was furnished. The lower yield of 3a from 1d phenylaniline (3w) and triphenylamine (3x) in 76% and 5%
might be attributed to the stronger alkylation ability of 1d than yields, indicating the compatibility of this method.
1a-c, which have longer alkyl groups. In addition, treatment of
Scheme 5. Reaction of butyl(phenyl)(p-tolyl)sulfonium triflate (1k) with 2a under the
standard conditions.
dimethyl(phenyl)sulfonium (1e), diethyl(phenyl)sulfonium (1f),
1-phenyltetrahydro-1H-thiophen-1-ium
(1g),
and
2a
)
PhNH2
(
H
N
dibutyl(phenyl)sulfonium (1h) triflates with 2a under the same
conditions afforded 3a in 14%, 72%, 77%, and 83% yields,
respectively. The results once again demonstrated that
alkyl(phenyl)sulfoniums bearing long-chain alkyl groups were
more efficient phenyl transfer reagents for aniline than those
with short alkyl chains.
H
N
Pd[P(tBu)3]2 (7.5 mol%)
CuBr (5 mol%)
S
+
K3PO4 (1.2 equiv)
CH3CN, 60 oC, 16 h, N2
OTf
nBu
1k
(1.2 equiv)
3c
3a
3a 3c
= 1.3 : 1)
97% (
:
Scheme 6. One-pot N-arylation of 2a.
2a
, 0.2 mmol)
Pd[P(tBu)3]2 (7.5 mol%)
CuBr (5 mol%)
PhNH2
(
With the optimized conditions (entry 3, Table S8) in hand, the
substrate scope of the reaction was explored by using
butyl(diphenyl)sulfonium (1b) as a phenylation reagent. To our
delight, various arylamines bearing either electron-donating
groups (e.g., OMe (2b), Me (2c), NHBoc (2d), NHBz (2e)) or
electron-withdrawing groups (e.g., ester (2f), keto (2g), nitro
(2h), cyano (2i), fluoro (2j), chloro (2k) groups) on the aryl rings
were smoothly converted to form the corresponding N-
phenylated products (3b-k) in good to almost quantitative
yields. The sensitive Boc- and Bz-protected amino groups (2d-
e), nitro (2h), cyano (2i), and chloro (2k) groups were well
tolerated in the reactions. Nonetheless, 4-bromoaniline (2l)
and 4-iodoaniline (2m) reacted with 1b under the standard
conditions to provide complicated mixtures, in which no
desired products (3l and 3m) were isolated. The unavailability
of 2l and 2m in the reactions might be accounted for by the
competitive cleavage of the C-Br and C-I bonds. In addition,
reactions of m-toluidine (2n) and o-toluidine (2o) with 1b and
nBuOTf
H
N
S
(0.3 mmol)
K3PO4 (0.24 mmol)
DCE (2 mL)
60 oC, 17 h
CH3CN (2 mL), 60 oC, 16 h, N2
3a
(0.3 mmol)
92% HPLC yield
2a
, 0.2 mmol)
Pd[P(tBu)3]2 (7.5 mol%)
CuBr (5 mol%)
PhNH2
(
O
H
N
mesitylene (0.9 mmol)
Tf2O (0.36 mmol)
S
nBu
DCM (2 mL)
-78 oC to rt, 5 h
K3PO4 (0.6 mmol)
CH3CN (3 mL), 40 oC, 16 h, N2
NO2
O2N
3h
(0.3 mmol)
67% isolated yield
Next, other alkyl(diaryl)sulfonium salts were tested to further
illustrate the practicability of this reaction (Scheme 4).
Symmetric butylbis(4-methoxyphenyl)sulfonium triflate (1i)
and butylbis(4-chlorophenyl)sulfonium triflate (1j) reacted
with 2a under the standard conditions to afford 3b in 88%
yield and 3k in 70% yield, respectively. Asymmetric butyl-
(phenyl)(p-tolyl)sulfonium triflate (1k) reacted with 2a under
the same conditions to provide a mixture of 3a and 3c in 97%
yield (3a:3c = 1.3:1), the molar ratio of which was determined
1
o
by H NMR spectroscopy (Scheme 5 and SI). Since N-arylation
K3PO4 in the presence of Pd[P(tBu)3]2 and CuBr at 60 C for 16
of 2a by 1k showed poor selectivity, this sulfonium salt might
be less synthetically useful. We envisioned that incorporating
sterically hindered, electron-donating substituents into one of
the aryl rings (Ar) of asymmetric alkyl(diaryl)sulfonium would
significantly slow down the oxidative addition of CAr-S bond of
this Ar moiety by Pd[P(tBu)3]2 and lead to high selectivity of
arylation. Indeed, use of mesityl group as one of the aryl
sources in the structure of asymmetric alkyl(diaryl)sulfoniums,
butyl(mesityl)(aryl)sulfonium triflates (1l-u) were derived and
found to be excellent cross-coupling participants in the
selective N-arylation of aniline under Pd/Cu-catalysis. These
asymmetric sulfonium salts were readily synthesized from
butyl(aryl)sulfoxides and mesitylene via a SEAr process in the
presence of Tf2O (see SI). Delightfully, reaction of
butyl(mesityl)(phenyl)sulfonium triflate (1l) with aniline (2a)
under the standard conditions gave N-phenylated products (3a)
in 86% yield. Other asymmetric butyl(mesityl)(aryl)sulfonium
triflates (1m-u) possessing either electron-rich or -poor aryl
groups were also applicable reagents in the reactions, which
worked with 2a under the same conditions to supply 3b, 3c, 3n,
3o, 3j, 3k, 3y, 3i, and 3h in 34-84% yields (Scheme 4). It
h afforded 3n in 87% yield and 3o in 83% yield, which were
comparable to that of 3c from 2c under the same conditions. If
the more sterically hindered 2,6-dimethylaniline (2p) was
treated with 1b, 63% of 2,6-dimethyl-N-phenylaniline (3p) was
obtained. The results suggested that the steric hindrance of
the substituents on the aryl rings of arylamines might have an
effect on the N-phenylation. Pleasingly, heteroarylamines
were also suitable substrates in the reaction. 1H-indol-5-amine
(2q) reacted with 1b, K3PO4, Pd[P(tBu)3]2 and CuBr under the
standard conditions to form N-phenyl-1H-indol-5-amine (3q) in
67% yield. There was no 1-phenylated product observed even
in the presence of a large excess of K3PO4 (2.4 equiv).
Analogously, reaction of methyl 3-aminothiophene-2-
carboxylate (2r) with 1b and K3PO4 furnished methyl 3-
(phenylamino)thiophene-2-carboxylate (3r) in 91% yield. A
scale-up synthesis of 3r from 2r and 1b at a 5 mmol scale could
give 3r in 96% yield. Treatment of benzo[d]thiazol-5-amine (2s),
pyridin-3-amine (2t), and drug molecules such as Procaine (2u)
and Metoclopramide (2v) with 1b, K3PO4, Pd[P(tBu)3]2 and
CuBr under the standard conditions supplied the respective N-
phenylated products (3s-v) in up to 61% yields, with recovery
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
Fajardo, M. R. Martin, W. Midura and M.VieMwiAkroticlalejOcznylinke,
Tetrahedron: Asymmetry, 2004, 15, 24D7O5.I: 10.1039/C9CC06535K
For selected examples see: (a) B. Badet, M. Julia and M.
Ramirez-Munoz, Synthesis, 1980, 11, 926; (b) S. J. Moons, R.
A. Mensink, J. P. J. Bruekers, M. L. A. Vercammen, L. M.
Jansen and T. J. Boltje, J. Org. Chem., 2019, 84, 4486.
C. D. Simkó, P. Elekes, V. Pázmándi and Z. Novák, Org. Lett.,
2018, 20, 676.
(a) J. Srogl, G. D. Allred and L. S. Liebeskind, J. Am. Chem. Soc.,
1997, 119, 12376; (b) D. Vasu, H. Yorimitsu and A. Osuka,
Angew. Chem. Int. Ed., 2015, 54, 7162; (c) D. Vasu, H.
Yorimitsu and A. Osuka, Synthesis, 2015, 47, 3286. (d) S.-M.
Wang, X.-Y. Wang, H.-L. Qin and C.-P. Zhang, Chem. Eur. J.,
2016, 22, 6542; (e) X.-Y. Wang, H.-X. Song, S.-M. Wang, J.
Yang, H.-L. Qin, X. Jiang and Zhang, C.-P., Tetrahedron, 2016,
72, 7606; (f) P. Cowper, Y. Jin, M. D. Turton, G.Kociok-Köhn
and S. E. Lewis, Angew. Chem. Int. Ed. 2016, 55, 2564.
S.-M. Wang, H.-X. Song, X.-Y. Wang, N. Liu, H.-L. Qin and
Zhang, C.-P. Chem. Commun., 2016, 52, 11893; (b) D. Uno, H.
Minami, S. Otsuka, K. Nogi and H. Yorimitsu, Chem. Asian. J.,
2018, 13, 2397.
seemed that the position of methyl groups on the aryl rings of
1n-p had little influence on the arylation (3c (76%) vs 3n (76%)
vs 3o (84%)). The reactions of (mesityl)(aryl)sulfonium triflates
containing electron-deficient aryl groups could be performed
5
o
at lower temperatures (40 C or r.t.), which gave higher yields
o
6
7
of products than those at 60 C (1r-u), indicating the relatively
high reactivities of these sulfonium salts. In all above cases,
there were no N-mesitylated products isolated under the
reaction conditions, suggesting good selectivity of these
arylations using (mesityl)(aryl)sulfonium triflates.
In conclusion, we have developed a Pd/Cu-catalyzed N-
arylation of anilines with alkyl(diaryl)sulfonium triflates,
wherein the N-alkylation process was inhibited. The reaction
o
proceeded at room temperature to 60 C and realized smooth
conversion of a wide ranges of substrates including complex
anilines and asymmetric alkyl(diaryl)sulfonium salts to form
the corresponding N-arylated products in good to high yields.
A combination of Pd[P(tBu)3]2 and CuBr was very essential for
the arylation as the absence of either led to significantly or
completely N-alkylated products. By installing the sterically
hindered and electron-rich mesityl group to sulfonium cations,
a series of new asymmetric butyl(aryl)sulfonium triflates were
synthesized. More importantly, these arylsulfoniums proved to
be reliable arylation reagents and undergo selective CAr-S bond
cleavage at the less steric aryl moieties, resulting in specific N-
arylation of aniline. Additionally, the successful production of
3a and 3h from diphenyl sulfide and 1-(butylsulfinyl)-4-
nitrobenzene (as examples) validated the one-pot N-arylation
of aniline from the very starting materials (Scheme 6 and SI).
Application of these advantageous alkyl(aryl)sulfonium salts in
other arylations is currently underway in our laboratory.
8
9
Z.-Y. Tian, S.-M. Wang, S.-J. Jia, H.-X. Song and C.-P. Zhang,
Org. Lett., 2017, 19, 5454.
10 (a) H. Minami, S. Otsuka, K. Nogi and H. Yorimitsu, ACS Catal.,
2018, 8, 579; (b) H. Minami, K. Nogi and H. Yorimitsu,
Heterocycles, 2018, 97, 998.
11 H. Minami, K. Nogi and H. Yorimitsu, Org. Lett., 2019, 21,
2518.
12 (a) Z.-Y. Tian, X.-X. Ming, H.-B. Teng, Y.-T. Hu and C.-P. Zhang,
Chem. Eur. J., 2018, 24, 13744. (b) During submission of our
manuscript, Ritter and coworkers reported a metal-catalyzed
C-N bond formation reaction with aryl thianthrenium salts (J.
Am. Chem. Soc. 2019, doi:10.1021/jacs.9b07323).
13 (a) P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116,
12564; (b) J. Jiao, K. Murakami and K. Itami ACS Catal., 2016,
6, 610.
14 (a) F. Y. Kwong, A. Klapars and S. L. Buchwald, Org. Lett.,
2002, 4, 581; (b) F. Y. Kwong and S. L. Buchwald, Org. Lett.,
2003, 5, 793; (c) A. Shafir and S. L. Buchwald, J. Am. Chem.
Soc., 2006, 128, 8742; (d) H. Xu and C. Wolf, Chem. Commun.,
2009, 1715; (e) C.-T. Yang, Y. Fu, Y.-B. Huang, J. Yi, Q.-X. Guo,
L. Liu, Angew. Chem. Int. Ed., 2009, 48, 7398.
We thank the National Natural Science Foundation of China
(21602165), the “Hundred Talent” Program of Hubei Province,
and the Fundamental Research Funds for the Central
Universities (2019-YB-002) for financial support.
15 (a) J. M. Dennis, N. A. White, R. Y. Liu and S. L. Buchwald, ACS
Catal., 2019, 95, 3822; (b) J. M. Dennis, N. A. White, R. Y. Liu
and S. L. Buchwald, J. Am. Chem. Soc., 2018, 140, 4721; (c) J.
P. Stambuli, R. Kuwano and J. F. Hartwig, Angew. Chem. Int.
Ed., 2002, 41, 4746; (d) D. S. Surry and S. L. Buchwald, Chem.
Sci., 2011, 2, 27.
Conflicts of interest
There are no conflicts to declare.
16 (a) D. M. Chan, K. L. Monaco, R.-P. Wang and M. P. Winters,
Tetrahedron Lett., 1998, 39, 2933; (b) P. Y. Lam, C. G. Clark, S.
Saubern, J. Adams, M. P. Winters, D. M. Chan and A. Combs,
Tetrahedron Lett., 1998, 39, 2941; (c) J. C. Antilla and S. L.
Buchwald, Org. Lett., 2001, 3, 2077; (d) C. C. Tzschucke, J. M.
Murphy and J. F. Hartwig, Org. Lett., 2007, 9, 761; (e) R. P.
Rucker, A. M. Whittaker, H. Dang and G. Lalic, Angew. Chem.
Int. Ed. 2012, 51, 3953.
17 (a) Y. N. Timsina, B. F. Gupton and K. C. Ellis, ACS Catal. 2018,
8, 5732; (b) Y. Park, Y. Kim and S. Chang, Chem. Rev. 2017,
117, 9247; (c) J. Roane, O. A. Daugulis, J. Am. Chem. Soc.,
2016, 138, 4601; (d) H.-W. Wang, Y. Lu, B. Zhang, J. He, H.-J.
Xu, Y.-S. Kang, W.-Y. Sun and J.-Q. Yu, Angew. Chem. Int. Ed.,
2017, 56, 7449.
18 M. P. Drapeau, J. Bahri, D. Lichte and L. J. Goossen, Angew.
Chem. Int. Ed., 2019, 58, 892.
19 (a) T. Sugahara, K. Murakami, H. Yorimitsu and A. Osuka,
Angew. Chem. Int. Ed., 2014, 53, 9329; (b) X. Wang, X. Tang,
C.-Y. Long, W.-K. Dong, C. Li, X. Xu, W. Zhao and X.-Q. Wang,
Org. Lett., 2018, 20, 4749.
Notes and references
1
(a) C. J. M. Stirling and S. Patai, The chemistry of the
sulfonium group, Part 1 and Part 2; John Wiley and Sons:
New York, 1981; (b) D. Kaiser, I. Klose, R. Oost, J. Neuhaus
and N. Maulide, Chem. Rev., 2019, 119, 8701.
Selected examples: (a) K. Miyatake, K. Yamamoto, K. Endo
and E. Tsuchida, J. Org. Chem., 1998, 63, 7522; (b) H.-X. Song,
S.-M. Wang, X.-Y. Wang, J.-B. Han, Y. Gao, S.-J. Jia and C.-P.
Zhang, J. Fluorine Chem., 2016, 192, 131; (c) X. Li, Y. Sun, X.
Huang, L. Zhang, L. Kong and B. Peng, Org. Lett., 2017, 19,
838.
2
3
4
Selected reviews: (a) Z.-Y. Tian, Y.-T. Hu, H.-B. Teng and C.-P.
Zhang, Tetrahedron Lett., 2018, 59, 299; (b) S. Otsuka, K.
Nogi and H. Yorimitsu, Top. Curr. Chem., 2018, 376, 13.
(a) P. Cyr, J. Flynn-Robitaille, P. Boissarie and A. Marinier, Org.
Lett., 2019, 21, 2265; (b) K. J. Hock, R. Hommelsheim, L.
Mertens, J. Ho, T. V. Nguyen and R. M. Koenigs, J. Org. Chem.,
2017, 82, 8220; (c) Y. Duan, B. Zhou, J.-H. Lin and J.-C. Xiao,
Chem. Commun., 2015, 51, 13127; (d) J. L. García Ruano, C.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC06535K
Graphic Abstract
ArNHR
Pd[P(tBu)3]2 (7.5 mol%)
R
N
Ar
R2
CuBr (5 mol%)
Ar
Ar
S
R1
K3PO4 (1.2 equiv)
CH3CN, 40-80 oC, 16 h
OTf
up to 98% yield
Caryl-S bond vs Calkyl-S bond cleavage
The first Ullmann-type N-arylation over traditional N-alkylation of anilines by
using alkyl(aryl)sulfonium triflates is developed.