Rapid palladium-catalyzed cross-coupling in the synthesis of aryl thioethers under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2006.04.049

A Pd-catalyzed coupling of aromatic iodides or bromides and tin-thiolates under microwave conditions was developed to synthesize aromatic thioethers without concomitant formation of the reduced products. Ligand screening revealed DiPPF and BINAP-Tol as th

Full text of DOI:10.1016/j.tetlet.2006.04.049

Tetrahedron Letters 47 (2006) 4449–4452
Rapid palladium-catalyzed cross-coupling in the synthesis
of aryl thioethers under microwave conditions
Lisheng Cai,a,* Jessica Cuevas,a Yi-Yuan Pengb and Victor W. Pikea
aPET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health,
National Institutes of Health, Building 10, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
bKey Laboratory of Green Chemistry, Jiangxi Province and Department of Chemistry, Jiangxi Normal University,
Nanchang 330027, China
Received 3 February 2006; revised 6 April 2006; accepted 11 April 2006
Available online 15 May 2006
Abstract—A Pd-catalyzed coupling of aromatic iodides or bromides and tin-thiolates under microwave conditions was developed to
synthesize aromatic thioethers without concomitant formation of the reduced products. Ligand screening revealed DiPPF and
BINAP-Tol as the most generally useful ligands for this transformation. A variety of iodides or bromides were coupled to give
the thioethers rapidly (10 min) in 60–95% isolated yield.
Ó 2006 Elsevier Ltd. All rights reserved.
Aromatic thiothers often feature as important synthetic
intermediates and biologically interesting compounds,
including several therapeutic drugs.1,2 Homogeneous
catalysts based on either copper(I) or palladium have
been developed for their syntheses.2–4 Mechanistic stud-
ies of palladium-catalyzed aromatic substitution of halo
or triflate groups by thiolate show that both three and
four coordinate intermediates might be involved.5–7 In-
deed, both mono and bidentate phosphine ligands have
been developed for this type of reaction.8–13 Copper(I)-
based catalysts for similar syntheses are mechanistically
much less clear.14–18
tution in aryl halides by thiolates that would satisfy a
number of requirements. Some of these were not appar-
ent until this study, such as avoidance of competing
reductive removal of the halogen substituent. We set
our goals to achieve the following for aryl thioether syn-
theses: (a) one-step introduction of a thioether group into
a halogen position in an aryl ring; (b) selective introduc-
tion of a thioether group at an iodo position in the pres-
ence of other halogen substituents, such as bromo; (c)
tolerance of functional groups, especially amino groups;
and (d) fast microwave-assisted reaction conditions.
Herein, we present a general, efficient, and operationally
simple palladium-catalyzed aryl thioether synthesis.
In our program to develop new IMPY [6-iodo-2-(40-N,
N-dimethylamino)phenylimidazo[1,2-a]pyridine] deriva-
tives (1, Scheme 1) as radiotracers for imaging brain
b-amyloid19 with positron emission tomography (PET),
we desired to synthesize several aryl thioethers as novel
candidates. The most attractive approach is to introduce
the thioether group in the last step in order to avoid
manipulation and protection of this sensitive group in
the synthesis of the IMPY skeleton. The required aro-
matic halide substrates (e.g., 1) for potential substitution
by thiolates are generally accessible in multiple step syn-
theses.19 We needed a catalytic method of halogen substi-
4-(6-Iodoindolizin-2-yl)-N-methylbenzeneamine (2) plus
2-mercaptoacetamide or 2-mercaptoethanol were used
as the prototypical substrate combination for prelimin-
ary investigation of the reaction conditions for aryl thio-
ether synthesis (Schemes 1 and 2). Since copper(I)
compounds are inexpensive and easily available, we
initially selected CuI for investigation as a catalyst.
Two ligands, ethylene glycol and ethylene diamine, were
evaluated along with a variety of bases and solvents
(Table 1). Low conversion of the iodo compound was
observed with a catalytic amount of CuI. The reaction
went to completion only when a greater than stoichio-
metric amount of CuI was used. For 2-mercaptoaceta-
mide, the majority of the reaction product arose from
reductive removal of the iodo group. For 2-mercapto-
ethanol, substitution of the iodo group was nearly
*
Corresponding author. Tel.: +1 301 451 3905; fax: +1 301 480
5112; e-mail: cail@intra.nimh.nih.gov
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.049

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L. Cai et al. / Tetrahedron Letters 47 (2006) 4449–4452
CuI
L: ethylene glycol, or ethylene diamine
t
-BuOK, K2CO3, or Cs2CO3
R2SH
+
S: ethylene glycol, DMSO, NMP, dioxane, or Py
S
X
130oC, 10 min, 50 W, 300 p.s.i.
R2 = CH2CONH2 or CH2CH2OH
R
N
R
N
R2
N
N
N
N
1, R = Me
2, R = H
Scheme 1. Copper-mediated syntheses of aryl thioethers.
10% Pd2dba3
20% DiPPF
S
R1
R2
Toluene
150oC, 10 min, 300 W, 300 p.s.i.
R3
R4
R5
+
R3
R6
R7
S
R4
R5
R2
N
N
R6
R7
X
N
X = I, Br
N
N
R1 = H, or SnMe3
N
R2 = CH2CH2OH, CH2CONH2, CH2C6H4OCH3
R3 = R4 = H or R3R4 = CH2CH2
R5 = H, Me, Br
R6 = H, or Me
R7 = H, Me, Ac
Scheme 2. Palladium-catalyzed syntheses of aryl thioethers.
Table 1. The copper(I)-mediated coupling of aryl iodides (1 or 2) with thiols (Scheme 1)
Entry
R
Method
Conversion (%)
Ratio of substitution:reduction
1
2
3
4
5
6
7
R2 = –CH2CONH2, R = Me
R2 = –CH2CONH2, R = Me
R2 = –CH2CONH2, R = H
R2 = –CH2CONH2, R = H
R2 = –CH2CONH2, R = H
R2 = –CH2CH2OH, R = Me
R2 = –CH2CH2OH, R = H
A1
A2
A1
A2
A3
A1
A1
100
81
81
100
100
60
1.0:4.0
0:1
1:8.3
1:4.1a,b
0:1
Messy
1:0.038
96
Note: R, substituents shown in Scheme 1; general conditions: 130 °C, 10 min, 50 W, 300 psi, substrate:thiol = 1:1.2–5; A1, 1–5 equiv CuI, 2 equiv
ethylene diamine, 2 equiv t-BuOK or K2CO3 in DMSO, N-methylpyrrolidin-2-one (NMP) or dioxane; A2, 1–5 equiv CuI, 2 equiv ethylene glycol,
2 equiv t-BuOK in Py; A3, 0.05 equiv CuI, 2 equiv Cs2CO3 in NMP.
a Without thiol, the reaction generated reduced and HOCH2CH2O-substituted products.
b No reaction was observed when 1,2-dimethoxyethane was used instead of ethylene glycol.
quantitative for one substrate when 5 equiv of CuI was
used. However, no catalytic or general reaction was
observed and so no further effort was expended on this
NMe2
PCy2
P-tBu2
P-tBu2
PCy2
approach for other substrates.
The palladium-catalyzed coupling of aryl iodides with
thiols (Scheme 2) was evaluated using the protocol origi-
nally established by Buchwald et al.,8 who used aryl
bromides as substrates. Variations here included the
use of (i) catalysts, such as (DPPF)PdCl2; (ii) catalyst
precursors, such as Pd2dba3 and Pd(OAc)2; (iii) ligands
(L) as shown in Figure 2; (iv) bases, such as NEt3,
t-BuOK; and (v) solvents, such as NMP, dioxane, or
toluene. Multiple products in similar amounts were
generated, including the desired substitution products.
Given the success of a number of bulky monophosphines
in the catalysis of aryl C–N and C–O formation,7,20 we
evaluated a number of bulky monophosphines (Fig. 1).
In our general conditions (150 °C, 10 min, 300 W,
L3
L1
L2
L4
Figure 1. Mono-phosphine ligands.
300 psi with 0.05 equiv Pd2dba3, 0.1 equiv L, 2–4 equiv
of NEt3 or t-BuOK, and ethanol or toluene as solvent),
the new ligands behave similarly like PPh3, giving less
than 10% total conversion of aryl iodide and ratios of
substitution and reduction ranging from 0.4 to 15. No
further reaction progress was observed on extended
reaction time.
A number of thiolates instead of free thiols have been
used for the aromatic substitution reaction.1,21 When

L. Cai et al. / Tetrahedron Letters 47 (2006) 4449–4452
4451
PPh2
P(i-Pr)2
P(i-Pr)2
PTol2
PTol2
PPh2
PPh2
Fe
Fe
PPh2
DPPF
DiPPF
BINAP-Tol
BINAP
Figure 2. Bis-phosphine ligands.
Table 2. The palladium-catalyzed coupling of aryl iodides (1 or 2) with tin-thiolates (Scheme 2 with R1 = SnMe3, R3 = R4 = R5 = R6 = H, R7 = Me,
X = I)
Entry
R
Method
Ligand
Conversion (%)
Ratio of substitution:reduction
1
2
3
4
5
6
7
R2 = CH2CH2OH, R6 = Me
R2 = CH2CH2OH, R6 = Me
R2 = CH2CH2OH, R6 = H
R2 = CH2CH2OH, R6 = Me
R2 = CH2CONH2, R6 = H
R2 = CH2CONH2, R6 = Me
R2 = CH2CH2OH, R6 = H
a
b
c
d
e
f
BINAP
BINAP-Tol
DPPF
17
81
100
56
51
76
6
1:0.13
1:0.12
1:0
1:0.15
1:0.19
1:0.14
1:0.083
DPPF
DiPPF
DiPPF
DiPPF
g
Note: the ligand structures are shown in Figure 2; R, substituents as shown in Scheme 2; general conditions: 150 °C, 10 min, 300 W; 300 psi,
substrate:thiolate = 1:1 in toluene; a, 0.1 equiv Pd2(dba)3, 0.1 equiv L; b, 0.2 equiv Pd2(dba)3, 0.4 equiv L; c, 0.11 equiv Pd2(dba)3, 0.14 equiv L; d,
0.1 equiv Pd2(dba)3, 0.1 equiv L; e, 0.1 equiv Pd2(dba)3, 0.2 equiv L; f, 0.2 equiv Pd2(dba)3, 0.4 equiv L; g, 0.2 equiv Pd2(dba)3, 0.4 equiv L.
the tin-thiolates were used in Scheme 2, mainly substitu-
tion products accompanied by minor reduction products
were observed. Different kinds of bis-phosphine ligands
were evaluated (Fig. 2, Table 2). BINAP-Tol, DPPF,
and DiPPF are efficient ligands for the reaction. Since
a number of chelating phosphines have been used in
enantioselective hydrogenation,22 they provide further
excellent candidates for evaluation in this reaction
(Table 3). Once again, ferrocene-based bis-phosphine,
f-binaphane, provided the best combination of reactivity
and selectivity.
The combination of Pd2dba3 as catalyst, DiPPF as
ligand and tin-thiolate as reagent was used to synthesize
several aryl thiolates in moderate to high yield (Table 6).
When bromo and iodo groups were both present in the
same compound, selective substitution of the iodo group
was realized using the same reaction conditions devel-
oped above, using stoichiometric quantities of tin-thiol-
ates (Table 7).
Table 4. The palladium-catalyzed coupling of aryl iodide (2) with
tin-thiolates (Scheme
2
with R1 = SnMe3, R2 = CH2CONH2,
R3 = R4 = R5 = R6 = H, R7 = Me, X = I)
Palladium catalysts based on phosphine oxide ligands
are a new type of efficient, versatile, air-stable and pre-
formed homogeneous catalysts for the C–S bond forma-
tion.9–11 Ten of the most common catalysts were
evaluated. Generally, low reactivities and selectivities
were observed (Table 4).
Entry
Catalyst
Method
Conversion
(%)
Ratio of
substitution:
reduction
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
POPd
POPd
PXPd
B1
B3
B1
B1
B2
B3
B1
B2
B3
B1
B1
B1
B1
B2
B3
B1
B2
B1
0
0
2
7
2
3
0a,b
0
1
2
0
2
0
0
0
0
1:0.63
1:0.77
1:0.83
1:0.50
When aryl bromides were used to compare the reactivity
of thiols versus tin-thiolates, the thiols showed better
reactivity but less selectivity (Table 5 and Scheme 2),
as in reactions with the iodides.
PXPd7
PXPd7
PXPd7
POPd2
POPd2
POPd2
PXPd2
POPd6
PXPd6
POPd1
POPd1
POPd1
POPd7
POPd7
Ph1-Phoxide
1:0
1:1.7
Table 3. The palladium-catalyzed coupling of aryl iodide (2) with
thiolates (Scheme 2 with R1 = SnMe3, R2 = CH2CONH2, R3 = R4 =
R5 = R6 = H, R7 = Me, X = I)
1:2.5
Entry Ligand
Conversion (%) Ratio of
substitution:reduction
1
2
3
4
5
6
7
T-Phos
TangPhos
Binapine
f-Binaphane
C4TunePhos
DuanPhos
Binaphane
22
7
1
11
8
0
1:0.91
1:0.71
1:0.63
1:0.077
1:0.77
0
0
3
1:0.59
Note: the catalyst structures are shown in Refs. 8–10; general condi-
tions: 150 °C, 10 min, 300 W, 300 psi, substrate:thiolate = 1:1.5 in
toluene; B1, 2.5 equiv K2CO3; B2, 2.5 equiv K2CO3 and 2.5 equiv
TEA; B3, 2 equiv t-BuOK.
a When thiol was used, no reaction was observed.
b Other thiols, such as HSCH2CH2OH, also did not react.
0
0
Note: the ligand structures are shown in Ref. 21; method, 150 °C,
10 min, 300 W, 300 psi, substrate:thiolate = 1:1, 0.1 equiv Pd2(dba)3
and 0.1 equiv L in toluene.

4452
L. Cai et al. / Tetrahedron Letters 47 (2006) 4449–4452
Table 5. The palladium-catalyzed coupling of aryl bromides with thiols or tin-thiolates (Scheme 2 with R3 = R4 = H, R5 = Me, R6 = H, R7 = Me,
X = Br)
Entry
R
Ligand
Method
Conversion (%)
Ratio of substitution:reduction
1
2
3
4
5
6
7
R1 = SnMe3, R2 = CH2CH2OH
R1 = SnMe3, R2 = CH2CH2OH
R1 = SnMe3, R2 = CH2CH2OH
R1 = SnMe3, R2 = CH2CH2OH
R1 = SnMe3, R2 = CH2CONH2
R1 = H, R2 = CH2CH2OH
BINAP
BINAP-Tol
DPPF
DiPPF
DiPPF
a
b
c
d
e
f, g
h
6
16
0.4
14
26
100
26
1:0
1:0
1:0
1:0
1:0
1:0.06
1:0.67
DiPPF
DiPPF
R1 = H, R2 = CH2CONH2
Note: the ligand structures are as shown in Figure 2; R, substituents shown in Scheme 2. General conditions for tin-thiolate reaction: 150 °C, 10 min,
300 W, 300 psi, substrate:thiolate = 1:1 in toluene; a, 0.1 equiv Pd2(dba)3 and 0.1 equiv L; b, 0.2 equiv Pd2(dba)3 and 0.2 equiv L; c, 0.1 equiv
Pd2(dba)3 and 0.1 equiv L; d, 0.2 equiv Pd2(dba)3 and 0.4 equiv L; e, 0.2 equiv Pd2(dba)3 and 0.4 equiv L. General conditions for thiol reaction:
150 °C, 10 min, 300 W, 300 psi, 11.2 equiv t-BuOK; f, 0.2 equiv Pd(OAc)2 and 0.23 equiv L in dioxane; g, 0.2 equiv Pd2(dba)3 and 0.23 equiv L in
toluene; h, 0.2 equiv Pd2(dba)3 and 0.23 equiv L in dioxane.
Table 6. Thioethers synthesized by palladium-based catalysis (Scheme
NIH, NIMH. Y.-Y.P. is grateful to the support of the
National Science Foundation of China (NSFC Nos.
20342007 and 20462003).
2 with R1 = SnMe3, R3 = R4 = H, R7 = Me)
X
R5
R6
R2
M
Yield (%)a
I
I
I
I
I
Br
Br
H
H
H
H
H
Me
Me
H
Me
H
Me
Me
H
CH2CONH2
CH2CONH2
CH2CH2OH
CH2CH2OH
CH2C6H4OCH3
CH2CONH2
CH2CH2OH
C1
C2
C1
C2
C3
C4
C4
78
85
91
89
85b
69
69
References and notes
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Pd2(dba)3 and 0.1 equiv L; method C2, 0.2 equiv Pd2(dba)3 and
0.4 equiv L; method C3, 0.2 equiv Pd2(dba)3 and 0.2 equiv L; method
C4, 0.2 equiv Pd2(dba)3 and 0.8 equiv L.
a Isolated yield of the substitution product from reverse phase HPLC.
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Table 7. Thioethers synthesized by palladium-based catalysis (Scheme
2 with R1 = SnMe3, R3R4 = CH2CH2, R5 = Br, R6 = Me, R7 = Ac)
X
R2
Yield (%)a
I
I
CH2CONH2
CH2CH2OH
60
94
Note: general conditions: 150 °C, 10 min, 300 W, 300 psi, sub-
strate:thiolate = 1:1, 0.1 equiv Pd2(dba)3, 0.1 equiv DiPPF in toluene.
a Isolated yield of the substitution product from reverse phase HPLC.
In summary, we have developed a method with micro-
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thiolates. This procedure is applicable to substrates with
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absence of a bromo group. Lower reactivity and higher
selectivity were observed as compared with those using
thiols as reagents. The corresponding reactions under
conventional heating did not generate any appreciable
amount of products except for those without any hetero-
atoms in the substrates (no data shown).
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We thank Drs. Shuiyu Lu and Umesha Shetty for
experimental assistance. This research was supported
in part by the Intramural Research Program of the