Palladium-catalyzed amination of aryl mesylates

Article abstract of DOI:10.1002/anie.200802157

(Chemical Equation Presented) Aminated adventures: The new phosphine ligand L in combination with a Pd(OAc)₂ precursor provides the first palladium-catalyzed amination of unactivated aryl mesylates. This catalyst system can be applied in an aqueous reaction medium without detrimental effect.

Full text of DOI:10.1002/anie.200802157

Communications
DOI: 10.1002/anie.200802157
Homogeneous Catalysis
Palladium-Catalyzed Amination of Aryl Mesylates**
Chau Ming So, Zhongyuan Zhou, Chak Po Lau, and Fuk Yee Kwong*
À
Palladium-catalyzed C(sp ) N bond-forming reactions have
coupling reactions utilizing these reagents have the advantage
of higher atom economy than those employing the corre-
sponding aryl tosylates.[14] However, their relatively inert
leaving-group activity, with respect to tosylates, has limited
their application in coupling reactions (Figure 2).[15]
2
evolved into a highly versatile and synthetically attractive
transformation in targeting pharmaceutically useful inter-
mediates.[1] Since the discovery of the first catalytic amination
method,[2] efforts have been made toward increasing the
reaction efficacy.[3] Notable ligands, such as tBu3P, [4] Beller
and co-workersꢀ PAP,[5] Buchwald and co-workersꢀ biaryl
phosphines,[6] Hartwig and co-workersꢀ Q-Phos,[7] and Ver-
kade and co-workersꢀ amino phosphine[8] (Figure 1) provide
excellent catalytic activity in the cross-coupling of aryl halides
(especially aryl chlorides).[9,10] X-Phos, in particular, is
effective in the handling of aryl tosylate/benzenesulfonate
substrates in coupling reactions.[11]
Figure 2. A comparison on the leaving-group activity of commonly
used sulfonate groups, based on the pKa value of their conjugate acids
(given below names).
We recently reported the synthesis and application of an
amino phosphine ligand L1 (with phosphorus bound at N;
Figure 1), which showed excellent catalytic activity as a ligand
[16]
À
for palladium-catalyzed C C bond-forming reactions. The
versatile 2-arylindole scaffold can be simply synthesized and
diversified by Fischer indolization of acetophenones and
arylhydrazines. However, ligand L1 may undergo hydrolysis
under harsh reaction conditions. We therefore proceeded to
convert the amino phosphine ligand L1 into a class of
phosphine derivatives L2–L3 (in which phosphorus is bound
at C), without significant change to the ligand skeleton
(Figure 1).
Figure 1. Recent developments on effective phosphine ligands. Present
Precedent for palladium-catalyzed cross-coupling of aryl
mesylates is limited, with only one publication to date.[17] This
area remains highly challenging as mesylates are regarded as
the least active sulfonate leaving group. Therefore, there is
still a need to develop a general palladium catalyst for
coupling unactivated aryl mesylate substrates. We disclose
herein a highly active palladium indolyl phosphine catalyst
system, which allows the successful amination of aryl
mesylates for the first time. Notably, this reaction can be
performed in aqueous medium without diminishing the
product yields.
study depicted on the right.
Aside from the use of aryl tosylates (ArOTs) and
benzenesulfonates as electrophiles in palladium-catalyzed
[12]
À
À
C C and C X bond-forming reactions,
aryl mesylates
(ArOMs) have also seen some use in cross-coupling process-
es.[13] To our knowledge, they have never been applied to
amination reactions. Aryl mesylates can be easily accessed
from phenols and, owing to their lower molecular mass, cross-
We initially examined the feasibility of the amination of
[*] C. M. So, Prof. Dr. Z. Zhou, Prof. Dr. C. P. Lau, Prof. Dr. F. Y. Kwong
Open Laboratory of Chirotechnology of the
Institute of Molecular Technology for Drug Discovery and Synthesis
and
unactivated aryl mesylate compounds [Eq. (1)].[18] The ami-
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Hung Hom, Kowloon, Hong Kong (Hong Kong)
Fax: (+852)2364-9932
E-mail: bcfyk@inet.polyu.edu.hk
[**] We thank the Research Grants Council of Hong Kong (Project No.
CERG: PolyU5008/06P) and University Grants Committee Areas of
Excellence Scheme (Project No. AoE/P-10/01) for financial support.
nation reaction incorporating indolyl ligand L3 provided
excellent conversion while L2 was apparently ineffective.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802157.
6402
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These results indicated the great diversity of potential
reactions to which this ligand scaffold could be applied. We
next investigated the other reaction parameters, such as base
and solvent effects.[19] K2CO3, K3PO4, and CsF gave good
yields of the desired product whereas Cs2CO3 and Na2CO3
afforded the product in low yields. When NaOtBu was
employed as a base in the amination reaction, a significant
amount of phenolic side product was detected (as indicated by
GC-MS analysis). As a solvent, tBuOH was found to give the
best results. DMF and toluene afforded the product only in
moderate yield.
The scope of the amination reaction with regard to aryl
mesylates and amines was next investigated (Table 1). The
coupling of an unactivated aryl mesylate with N-methylani-
line was performed in good yield with 0.5 mol% of Pd
(Table 1; entry 2). Sterically hindered aniline and diphenyl-
amine were transformed to their corresponding product, also
in good yields (Table 1; entries 3,4). Secondary cyclic and
acyclic amines were effective coupling partners (Table 1;
entries 5–7). p-Cyanophenyl mesylate was found to be a
feasible substrate (Table 1; entry 10), as was the deactivated
p-anisyl mesylate (Table 1; entry 11). Conversely, on applica-
tion of the p-chlorophenyl mesylate substrate a highly
selective aryl chloride coupling took place (Table 1; entry 12).
To further explore the wide-ranging effectiveness of the
{Pd/L3} catalytic system, the cross-coupling of aryl mesylates
with a range of nitrogen heterocycles was investigated
(Table 2). Indole and substituted indoles were N-arylated
smoothly in good yields (Table 2; entries 1–4). Pyrrole and
carbazole were also effective substrates (Table 2; entries 5,6).
Furthermore, keto and methyl ester groups were shown to be
stable under these reaction conditions (Table 2; entries 7,8).
The amination of aryl mesylates has been shown to
proceed under solvent-free reaction conditions with no
detrimental effects (Table 3). More-
over, kinetic studies showed that
the rate of reaction is slightly higher
Table 1: Palladium-catalyzed amination of aryl mesylates.[a]
than when performed in organic
solvents, presumably owing to the
higher concentration of reactants.
Anilines, indole, and pyrrole were
all successfully coupled with aryl
Entry
ArOMs
Amine
Product
Pd [mol%]
Time [h]
Yield [%][b]
mesylates to generate the corre-
sponding products in good to excel-
lent yields (Table 3).
1
2
2
0.5
4
24
93
96
Recently, much attention has
been given to aqueous transition-
metal-catalyzed reactions.[20] Aryl
halides are reported to be applica-
ble substrates for cross-coupling in
aqueous media. However, sulfonate
couplings under aqueous conditions
are more challenging, as they are
known to be easily decomposed
through alkaline hydrolysis, to
form the phenolic side products.
Pleasingly, the {Pd/L3} catalyst
system can effect the amination of
aryl mesylate even in water
(Table 4). Under unoptimized reac-
tion conditions for this aqueous
catalysis, various anilines and
indole were successfully coupled
with aryl mesylates to afford the
corresponding products in good
yields.
3
1
24
90
4
4
1
2
4
24
18
24
24
80
90
93
81
5
6[c]
7[c]
8
1
24
87
9
2
1
24
24
85
82
10
To afford a better structural
insight into the new palladium cat-
alyst system, we attempted to pre-
pare the complex from the indolyl
phosphine ligand L3. Palladium
complex 4 was synthesized from
Pd(OAc)2 with L3 under basic con-
ditions at room temperature
[Eq. (2)]. Single crystals of 4 were
grown from a CH2Cl2 solution lay-
11
2
1
24
24
78
89
12[d]
[a] Reaction conditions: ArOMs (1.0 mmol), amine (1.5 mmol), K2CO3 (2.5 mmol), Pd(OAc)2/L3 (mol%
as indicated), PhB(OH)2 (0.04 mmol) tBuOH (4.0 mL), at 1108C under N2 for the indicated time (see
Supporting Information for experimental details). [b] Yield of isolated product. [c] K3PO4 was used in
place of K2CO3. [d] ArOMs (1.5 mmol), amine (1.0 mmol).
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Table 2: Palladium-catalyzed N-arylation of nitrogen heterocycles.[a]
ered with hexane at room tem-
perature. The X-ray crystallo-
graphic data revealed that 4 is a
dimeric complex with two ace-
tate bridging groups (Figure 3).
The six-membered cyclometal-
lated ring is puckered and the
bite angle of C10-Pd1-P1 is
82.01(10)8. The bond length on
the palladacyclic Pd–Cs bond
Entry ArOMs
1
N-heterocycle Product
Pd [mol%] Time [h] Yield [%][b]]
1
1
24
20
93
89
2
3
Pd1-C10
is
1.986(3) Š,
(Figure 3) similar to other palla-
[21]
1
24
96
dacycles
but is significantly
shorter than Pd–Cipso coordina-
tion (c.f. 2.191(3) Š).[22]
In summary, we have suc-
ceeded in showing the first ami-
nation of aryl mesylates. The new
ligand L3 in combination with
the precatalyst Pd(OAc)2 can is
applicable to a range of aryl
mesylate substrates as well as
amine nucleophiles including
4
5
2
1
24
24
84
80
6[c]
2
24
98
anilines,
aliphatic
amines,
indole, pyrrole, and carbazole.
Notably, we also showed the
first examples of aryl mesylate
coupling that can be performed
under aqueous basic medium
with no detrimental effects. Fur-
ther expanding the scope and
detail of the reaction, kinetic
7
8
1
1
24
24
88
79
[a] Reaction conditions: ArOMs (1.0 mmol), N-heterocycle (1.5 mmol), K2CO3 (2.5 mmol), Pd(OAc)2/L3
(mol% as indicated), PhB(OH)2 (0.04 mmol) tBuOH (4.0 mL), at 1108C
Table 4: Pd-catalyzed amination of aryl mesylates in aqueous medium.[a]
under N2 for indicated period of time. [b] Yield of isolated product.
[c] ArOMs (1.5 mmol), carbazole (1.0 mmol) were used.
Table 3: Palladium-catalyzed solventless amination of aryl mesylates.[a]
Entry ArOMs
1
Amine
Product
Yield [%][b]
90
Entry ArOMs
1
Amine
Product
Yield [%][b]
93
2
3
4
5
77
89
86
75
2
3
4
97
91
83
[a] Reaction conditions: ArOMs (1.0 mmol), amine (5.0 mmol), K2CO3
(2.5 mmol), Pd(OAc)2/L3 (1 mol%), PhB(OH)2 (0.04 mmol) in solvent-
free conditions at 1108C under N2 (reaction times are unoptimized).
[b] Yield of isolated product.
[a] Reaction conditions: ArOMs (1.0 mmol), amine (2.0 mmol), K2CO3
(2.5 mmol), Pd(OAc)2/L3 (2 mol%, unoptimized), PhB(OH)2
(0.04 mmol), water (3.0 mL) at 1108C under N2 (Note: reaction
parameters are unoptimized). [b] Yield of isolated product.
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2.117(2), Pd2–O2 2.124(2), Pd2–P2 2.2036(7), C10–Pd1–O3
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À
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activity) are underway.
Received: May 8, 2008
Published online: July 11, 2008
[13]Aryl mesylate couplings have rarely been studied, only nickel-
À
catalyzed C C bond couplings have been reported, see: a) V.
Keywords: amination · cross-coupling · mesylates · palladium ·
phosphanes
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Communications
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