Palladium-catalyzed desulfitative C-C cross-coupling reaction of (hetero)aryl thioesters and thioethers with arylsiloxanes

Article abstract of DOI:10.1002/adsc.200800395

The first desulfitative Hiyama-type cross-coupling protocol is reported and exemplified by the synthesis of substituted 5-chloro-3-arylpyrazinones. The method has also been successfully applied for the arylation of other (hetero)aryl thioethers and thioes

Full text of DOI:10.1002/adsc.200800395

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DOI: 10.1002/adsc.200800395
À
Palladium-Catalyzed Desulfitative C C Cross-Coupling Reaction
of (Hetero)Aryl Thioesters and Thioethers with Arylsiloxanes
Vaibhav Pravinchandra Mehta,a Anuj Sharma,a and Erik Van der Eyckena,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium
Fax : (+32)-16-327-990; phone: (+32)-16-327-406; e-mail: erik.vandereycken@chem.kuleuven.be
Received: June 25, 2008; Revised: August 1, 2008; Published online: October 7, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800395.
À
Abstract: The first desulfitative Hiyama-type cross-
coupling protocol is reported and exemplified by
the synthesis of substituted 5-chloro-3-arylpyrazi-
nones. The method has also been successfully ap-
plied for the arylation of other (hetero)aryl thioeth-
ers and thioesters.
on the coupling of C X electrophiles, X being halide
or triflate. Until now, we are unaware of any example
À
of Hiyama coupling with activated Csp2 S electro-
philes. Pursuant to our long-standing interest in the
synthesis and decoration of the pyrazin-2(1H)-one
scaffold[9] and to our recently described protocol for
the transition metal-catalyzed orthogonal decoration
of the 2(1H)-pyrazinone scaffold using a sulfur
linker,[10] we were keen to investigate whether a de-
sulfitative Hiyama-type reaction at the C-3 position of
5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones would
be possible. Tests were performed with 5-chloro-1-(4-
methoxybenzyl)-3-(phenylsulfanyl)pyrazin-2(1H)-one
(1a) and trimethoxyphenylsilane as a model system.
Keywords: copper(I); cross-coupling; desulfitative
procedure; Hiyama reaction; homogeneous cataly-
sis; pyrazinones
À
À
Palladium-catalyzed C C and C heteroatom bond- Applying the standard conditions for the Hiyama pro-
forming cross-coupling reactions are among the most cess [5 mol% Pd(II), 10 mol% ligand, 2 equiv. TBAF,
powerful methods in organic synthesis.[1] Such proce- THF], 75% conversion of the starting material was
dures involve the coupling of an activated electrophil- observed (Table 1, entry 1). However, surprisingly, the
ic partner with a nucleophilic organometallic donor major product turned out to be the C-3 methoxylated
through a palladium-assisted cross-coupling cascade. pyrazinone and only 35% of the expected C-3 arylat-
For this purpose a number of organometallic donors ed compound was observed.[11] To our satisfaction we
have been explored, mainly organoborons,[2] organo- found that addition of CuI[12] effectively suppressed
stannanes,[3] and organozinc reagents.[4] Seminal work the formation of 4a, hence acting as a reaction switch
by Liebeskind and co-workers describes the coupling between methoxylated and arylated products. After
of aryl or heteroaryl thioethers with organoboron, or- extensive investigation of the reaction parameters, we
ganotin or organoindium compounds.[5] However in- found that 1.5 equiv. of phenyltrimethoxysilane 2a, 5
stability, difficulty in preparation and, most impor- mol% of PdACHTRE(UGN PPh3)4, 0.3 mmol of CuI (1.0 equiv.),
tantly, toxicity of most organometallic reagents keep 0.6 mmol of TBAF (1M soln. in THF, 2 equiv.) in
chemists searching for alternatives. Hiyama demon- THF at 608C for 3 h under conventional heating is
strated the potential of the use of organosilicon re- optimal for the formation of 3a in 79% yield beside
agents as nucleophilic coupling partners having the traces of 4a (Table 1, entry 5).
advantage of being environmentally safe and posing
Having optimized the conditions we reacted an
no toxicity hazards.[6] Since then, an increasing array of differently substituted 5-chloro-3-(phenylsul-
number of publications has appeared dealing with the fanyl)pyrazin-2(1H)-ones (1a–f) with trimethoxyaryl-
coupling of activated (hetero)aromatic systems with silanes (Table 2). The corresponding arylated products
organosilicon reagents, applying this Hiyama proto- were obtained in excellent yields. The method was
col.[7] Denmark et al. have successfully applied a vari- also evaluated for the application of alkylsiloxanes.
ety of silanols as active transmetallating species.[8] Surprisingly, reaction of 1a with methyl-or vinylsilox-
However, nearly all Hiyama protocols have focused ane using the optimized protocol, provided the me-
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Adv. Synth. Catal. 2008, 350, 2174 – 2178

À
Palladium-Catalyzed Desulfitative C C Cross-Coupling Reaction
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Table 1. Optimization of the desulfitative arylation of thioether 1a with silane 2a.[a]
Entry Pd catalyst [mol%]
Silane
[equiv.]
Cu
[equiv.]
Solvent Time
[h]
Conversion[b] Yield 3a
Yield 4a
[%][c]
[%][c]
1
2
3
4
5
6
7
8
PdCl2 (5)/PPh3 (10)
1.5
1.5
1.5
1.5
1.1
1.2
1.2
1.2
–
–
–
THF
THF
THF
6
6
6
4
3
2.5
6
6
75%
60%
80%
80%
100%
100%
75%
85%
35
35
50
55
79
80
64
69
40
25
29
20
traces
traces
traces
traces
Pd
Pd
Pd
C
CuI (0.1) THF
CuI (1.0) THF
CuI (2.0) THF
CuI (0.5) THF
CuBr
(1.0)
CuI (1.0) THF
CuI (1.0) THF
CuI (1.0) THF
Pd
A
Pd
Pd
Pd
U
THF
9
–
8
6
5
0%
0[d]
60
41
66
28
39
0[d]
-
-
34
70
39
10
Pd
A
1.2
1.1
1.2
1.5
1.5
70%
50%
100%
100%
80%
11[e] Pd
N
12
13
14
Pd
Pd
Pd
U
CuI (1.0) Toluene 4
CuI (1.0) MeCN
CuI (1.0) o-
xylene
4
4
15
16
17
18
19
20
21
Pd
Pd
Pd
Pd
Pd
Pd
C
1.5
1.5
1.2
1.2
1.2
1.5
1.5
CuI (1.0) PhCN
4
5
4
4
4
4
4
100%
50%
100%
100%
90%
56
0
44
40
51
58
54
40
35
CuI (1.0)
–
CuI (1.0) THF
CuI (1.0) THF
CuI (1.0) THF
CuI (1.0) THF
CuI (1.0) THF
49
42
36
60
65
CHTREUNG
100%
100%
Herrmannꢁs palladacycle
(5)
[a]
Reactions were run on a 0.3 mmol scale of 1a in dry THF (4 mL) with phenyltrimethoxysilane 2a (1.1–1.5 equiv.), Pd
source, Cu (0.1–2.0 equiv.) (entries 5–21), TBAF (1M solution in THF, 2 equiv.). The mixture was flushed 3 times with
argon. Then it was kept in a preheated oil bath at a temperature of 608C for the stipulated time.
Conversion based on GC-MS analysis.
Isolated yield, single runs.
Unreacted starting material recovered.
[b]
[c]
[d]
[e]
1.0 equiv of TBAF used.
thoxylated product in very high yield with no trace of corresponding arylated compounds in excellent yields
the alkylated product (Table 2, entries 9 and 10).
Having successfully established the methodology
for the pyrazine scaffold, we were keen to extend the been established allowing the desulfitative C C cross-
protocol to substituted arylthioesters. Gratifyingly, the coupling of thioethers and thioesters with various ar-
respective diaryl ketones were obtained in high yields ylsiloxanes. The judicious combination of a Cu(I) salt
(Table 3, entries 12–17).
In conclusion, for the first time conditions have
À
(Table 3, entries 1–11). Moreover, when 5a was react- with PdACHTRE(UNG PPh3)4 as catalytic system allows us to sup-
ed with Me(SiOMe)3, the methyl ester was obtained press efficiently the formation of the methoxylated
ACHTREUNG
in quantitative yield indicating the favoring of the me- compound in favor of the arylated one. High yields,
thoxy group compared to the methyl group (Table 3, tolerance towards a range of functional groups, ap-
entry 18). Finally, the method was also evaluated for plicability on a range of siloxanes and novelty are the
the heteroaromatic thioethers 6a–c: applying substi- merits of the protocol. The extension of the protocol
tuted arylsiloxanes resulted in the formation of the toward different systems will be investigated in due
course.
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Vaibhav Pravinchandra Mehta et al.
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Table 2. Scope and limitations of the desulfitative arylative protocol.
Entry
R1
R6
R3
Product
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
9
Bn
Me
H
H
Ph
Ph
Ph
Ph
3b
3c
3d
3e
3f
3g
3h
3i
2.5
1
1
1.5
1.5
1
88
89
90
90
95
98
89
A
CH2-cyclohexyl
PMB
PMB
PMB
PMB
PMB
PMB
PMB
4-MeO-C6H4
Bn
H
H
H
H
H
Ph
4-MeO-C6H4
4-Me-C6H4
4-Cl-C6H4
Me
2
1.5
1.5
1.5
92
4a
4a
90[b]
94[b]
10
vinyl
[a]
Isolated yields, single runs.
Only formation of methoxylated products is observed. PMB=p-methoxybenzyl.
[b]
Experimental Section
analysis. Once the product was identified after complete
conversion, the general work-up procedure for compound
isolation was followed. The reaction mixture was cooled to
room temperature, poured into water and extracted with di-
chloromethane (2”50 mL). The combined organic layers
were washed with water and dried over MgSO4. The solvent
was removed under reduced pressure and the residue was
subjected to silica gel column chromatography from (5% to
20% EtOAc in heptane) to afford 5-chloro-3-phenyl-1-(4-
General Methods
1H NMR spectra were recorded on
a Bruker Avance
300 MHz instrument using CDCl3 and DMSO-d6 as solvent
unless otherwise stated. The 1H and 13C NMR chemical
shifts are reported in parts per million relative to tetrame-
thylsilane as an internal standard. Mass spectra were record-
ed by using a Kratos MS50TC and a Kratos Mach III
system. The ion source temperature was 150–2508C, as re-
quired. High-resolution EI-mass spectra were performed
with a resolution of 10,000. The low-resolution spectra were
obtained with an HP5989A MS instrument. For thin-layer
chromatography, analytical TLC plates [Alugram SIL G/
UV254 and 70–230 mesh silica gel (E. Merck)] were used. All
the solvents were distilled prior to use. All chemicals were
purchased and used as available.
methoxybenzyl)-2(1H)-pyrazinone (3a) as
a yellow oil;
1
yield: 79%. H NMR (300 MHz, CDCl3): d=8.36–8.33 (m,
2H), 7.44–7.42 (m, 3H), 7.31–7.28 (d, 2H, J=8.2 Hz), 7.16
(s, 1H), 6.91–6.88 (d, 2H, J=9.12 Hz), 5.04 (s, 2H), 3.79 (s,
3H); 13C NMR (75 MHz, CDCl3): d=160.10, 154.50, 152.24,
134.94, 130.74, 130.46, 129.37, 128.21, 126.56, 126.35, 125.22,
114.68, 55.41, 52.48; HR-MS (EI): m/z=326.0817, calcd. for
C18H15O2N2Cl: 326.0822.
Supporting Information
Typical Procedure for the Synthesis of Representative
Compound 3a
Additional experimental procedure and spectra data for
new compounds are available as Supporting Information.
Under air, a vial equipped with a stir-bar was charged with
thioether 1a, (0.3 mmol, 1 equiv.), Pd source (5 mol%), CuI
(0.3 mmol, 1.0 equiv.), sealed with septum and purged with
argon. Distilled THF was added by syringe and the mixture
stirred for 1–2 min, after which the siloxane reagent
(0.33 mmol, 1.1 equiv.) was added in one shot by syringe and
then tetrabutylammonium fluoride (TBAF) (0.6 mmol,
2 equiv) was added in one shot via syringe. The septum was
replaced with a Teflon-lined screw cap under an argon at-
mosphere and the reaction mixture was allowed to stir for
approximately 3 h at 658C prior to GC/MS and/or TLC
Acknowledgements
Support was provided by the research fund of the University
of Leuven and the FWO [Fund for Scientific Research –
Flanders (Belgium)]. A.S. is thankful to the Katholieke Uni-
versitiet Leuven for provision of a postdoctoral fellowship.
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Palladium-Catalyzed Desulfitative C C Cross-Coupling Reaction
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Table 3. Palladium-catalyzed desulfitative C-C cross coupling of thioethers and thioesters using silanes.
Entry Substrate Product
Time Yield[a] Entry Substrate Product
Time Yield[a]
[h]
[%]
[h]
[%]
1
2
3
5a
5a
5a
7a
7b
7c
0.5
88
10
11
12
5d
5e
6a
7j
7k
7l
1.5
88
1
1
93
96
1.5
2
92
91
4
5
6
5a
5a
5a
7d
7e
7f
1.5
1
90
88
92
13
14
15
6a
6a
6a
7m
7n
7o
1.5
1.5
2.5
94
98
90
0.5
7
8
5a
5b
5c
7g
7h
7i
2
84
96
86
16
17
18
6b
6c
5a
7p
7q
7r
82
6
3.5
0.5
79
9
1.5
Quant
[a]
Isolated yield are the average of two runs.
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