Pd2(dba)3/Xantphos-catalyzed cross-coupling of thiols and aryl bromides/triflates

Article abstract of DOI:10.1016/j.tet.2005.03.078

The cross-coupling of aliphatic and aromatic thiols and aryl bromides/triflates mediated by a Pd₂(dba)₃/Xantphos catalytic system in refluxing xylene (140°C) affords the corresponding aryl thioethers in good to excellent yields.

Full text of DOI:10.1016/j.tet.2005.03.078

Tetrahedron 61 (2005) 5253–5259
Pd2(dba)3/Xantphos-catalyzed cross-coupling of thiols and aryl
bromides/triflates
a
Clotilde Mispelaere-Canivet, Jean-Francis Spindler, Stephane Perrio and Pierre Beslin
b
a,
a
*
´
a
´ ´
Laboratoire de Chimie Moleculaire et Thio-organique (UMR CNRS 6507), ENSICaen-Universite de Caen Basse-Normandie,
´
6 Boulevard du Marechal Juin, F-14050 Caen, France
b
`
RHODIA, Centre de Recherches de Lyon, POP/ISV, 85 Avenue des Freres Perret, BP 62, F-69192 Saint-Fons, France
Received 25 January 2005; revised 9 March 2005; accepted 22 March 2005
Available online 25 April 2005
Abstract—The cross-coupling of aliphatic and aromatic thiols and aryl bromides/triflates mediated by a Pd2(dba)3/Xantphos catalytic
system in refluxing xylene (140 8C) affords the corresponding aryl thioethers in good to excellent yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
triflates) or aryl bromides as starting materials. As part of
our program concerning the creation of a carbon–sulfur
bond on an aromatic ring, our motivation turned towards
this chemistry.13 Among the few examples already
described when we initiated the project, we paid particularly
attention to a work from Merck dedicated to the palladium
cross-coupling of thiols with aryl triflates.6 The protocol
involves an initial deprotonation of the mercaptan with
sodium t-butoxide followed by heating the resulting sodium
thiolate with the aromatic triflate in the presence of
Pd(OAc)2 and (R)-(C)-Tol-BINAP 1a (see Table 1 for
the ligand structure). However the methodology suffers
from a few limitations, such as the incompatibility with
aromatic thiols. As a consequence, the search of novel
conditions leading to various thioethers, especially both
alkyl aryl and diaryl compounds remained of interest.
Additional attractive features would be to proceed under
mild and friendly conditions (base, solvent) compatible with
industrial constraints and allow bromo arenes14 as sub-
strates. We wish to present herein the results from our
investigation that led to the development of a new catalytic
system.
Aryl sulfides are useful intermediates in organic synthesis.
In addition, this sulfur fragment is incorporated in a number
of natural products or compounds exhibiting important
biological activities.1 The more conventional route to these
compounds involves the displacement reaction of an
arenethiolate with the appropriate alkyl halide.2 Other
reported procedures are based on the creation of the aryl–
sulfur bond, thus including nucleophilic aromatic substi-
tution3 or treatment4 of aryllithium or Grignard reagents
with sulfurated electrophiles. In 1980, Migita introduced the
Pd-catalyzed cross-coupling reaction of aryl bromides with
thiols.5 Since then, various efficient catalytic systems using
bidentate phosphines or dialkylphosphine oxides 1 have
been described (Scheme 1).6–9 Furthermore, reactions
mediated with other transition metals (Ni, Cu) have been
investigated very recently.10–11
Scheme 1. Pd-catalyzed Ar–S bond formation.
2. Results and discussion
The Pd-catalyzed strategy previously mentioned is particu-
larly attractive for industry, as revealed by the recent
contributions in this area.12 One major reason of this interest
is the use of readily available phenol derivatives (i.e.,
In our initial screening experiments, n-butanethiol and
phenyltriflate were selected as substrates for discovery of
optimal conditions. Reaction times were arbitrary set at
24 h. Selected conditions we tested are listed in Table 1. We
began with the conditions developed by the Merck group
for, which n-butyl phenyl sulfide was isolated in 71.5%
yield (entry 1). Various bidentate phosphine ligands,
Keywords: Palladium catalysis; Thiol cross-coupling.
*
Corresponding author. Tel.: C33 231 452 884; fax: C33 231 452 877;
e-mail: stephane.perrio@ensicaen.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.078

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C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
Table 1. Evaluation of various catalytic systems for cross-coupling of n-BuSH and PhOTf to give sulfide 2a (RZn-Bu, ArZPh) according to Scheme 1a
Entry
Base
Pd source
Ligand
Solvent, T (8C)
Yield (%)
1
2
3
4
5
6
7
8
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
K2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1a
1b
1c
1d
1e
1a
1e
1e
1e
1e
1f
Toluene, 80
Toluene, 80
Toluene, 80
Toluene, 80
Toluene, 80
Toluene, 80
Toluene, 80
Toluene, 110
Xylene, 140
Xylene, 140
Xylene, 140
Toluene, 110
71.5
7.5
33
0
20
88
0
74
82
80
Traces
0
9
10
11
12
K2CO3
K2CO3
1f
a Reaction conditions: n-BuSH (1 mmol), base (0.5 mmol), PhOTf (0.8 mmol), Pd source (0.08 mmol), ligand 1 (0.09 mmol), solvent (12 mL) for 24 h.
including dppp 1b, meso-BIPNOR 1c, DPEphos 1d and
Xantphos 1e were tested but all afforded disappointing
results, with chemical yields below 33% (entries 2–5). Use
of Pd2(dba)3 as a direct palladium(0) source in the presence
of (R)-(C)-Tol-BINAP 1a led to an excellent 88% yield
(entry 6). In contrast, no cross-coupling was observed when
combined with Xantphos 1e (entry 7). However, an
elevation of the temperature to 110 8C (refluxing toluene)
and even to 140 8C (reflux of xylene) in the presence of this
ligand 1e led to a dramatic improvement. In the last case, the
product was obtained in 82% yield (entry 9). Using
potassium carbonate as base instead of sodium t-butoxide
gave an analogous excellent yield (entry 10). As the use of a
bulkier and more electron-rich ligand could in principle
allow a reduced reaction temperature, we designed the
unprecedented Xantphos analogue 1f with bis-(t-butyl-
phosphino) substituents (see Fig. 1 for the X-ray structure).
Unfortunately, all attempts with this ligand failed and a total
inhibition of the coupling was observed (entries 11 and 12).
manuscript, a Japanese group reported the same catalytic
system for this reaction.16 The difference consists in the
use of i-Pr2NEt or Cs2CO3 (2 equiv) and 1,4-dioxane,
respectively, as base and solvent.
To investigate the scope of the reaction, a broad range of
aliphatic thiols including primary, secondary and tertiary
structures were then used. The thiolate was generated by
deprotonation of the thiol at 0 8C and was then added to a
mixture of all other reagents. When all reaction components
were simply mixed together, lower conversions to the
desired product were observed. For example, sulfide 2a was
In summary, these preliminary studies revealed that the best
reaction conditions involve potassium thiolates obtained by
mixing the thiol precursor with a stoichiometric amount of
potassium carbonate and a Xantphos 1e/Pd2(dba)3 as the
catalytic system in refluxing xylene (entry 10).15 The main
features of these cross-coupling conditions are the com-
bined use of a cheap, stable, mild and easy handling mineral
base and the readily available ligand 1e. Even if the boiling
point of xylene is relatively high (140 8C), this is not a
crucial drawback for further industrial applications, the
products being in general non-volatile solids. The catalyst
loading was deliberately not optimized at our laboratory
scale (1 mmol) and more significant results involving until
500 ppm of Pd can in principle be obtained during a scale-
up investigation on a specific substrate. In addition the effect
of the Pd/ligand ratio was not examined at this point.
Important to note is that during the preparation of this
Figure 1. ORTEP diagram of ligand 1f.

C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
5255
Table 2. Coupling of aliphatic thiols with Pd2(dba)3/Xantphos 1e according
to Scheme 1a
obtained only in 43% yield (compare with the 80% yield
obtained above).
Entry
1
X of ArX
OTf
Sulfide
Yield (%)b
80
All alkyl aryl sulfides were produced in good to excellent
yields as outlined in Table 2, except for the trityl derivative
(entry 17). Bromobenzene was shown to be an efficient
electrophile (entry 2) and the use of the chloride analogue
led to a lower 19% yield (entry 3). However, chlorinated
arenes can be suitable substrates when activated with an
electron withdrawing group. For example, the cross-
coupling of compound possessing a trifluoromethyl sub-
stituent gave rise to a 75% yield (entry 7). Total
chemoselectivities were observed with substrates posses-
sing two potential leaving groups. Substitution took place
only at the more reactive C–Br or C–OTf bonds and the
mesyl, tosyl and fluoro groups remained unchanged (entries
4–6). Interestingly, sterically hindered thiols were also
suitable substrates, thioethers derived from bornane-2-thiol
and t-butanethiol being isolated in 59 and quantitative
yields, respectively. With ethanethiol, a disappointing 35%
yield was obtained and this was interpreted by the volatility
of the precursor (entry 9). A significant improvement
leading to a 94% yield was observed employing an isolated
and accurately weighted thiolate (deprotonation with NaOH
followed by concentration and drying under vacuum until
constant weight). As a consequence, we were also able to
couple efficiently commercially available sodium methane-
thiolate (entry 10). A base sensitive functional groups,
namely a methyl ester, in the starting thiol was also tolerated
(entry 12). Interestingly, b-sulfanylesters that can thus be
produced have very recently been identified as convenient
and efficient thiol surrogates.17
2
3
Br
Cl
80
2a
19c
4
5
6
7
8
9
Br
Br
Br
Cl
Br
Br
80
2b
2c
2d
2e
2f
87
93c
75d
75
35 (94)
2g
10
11
12
13
Br
Br
Br
Br
K(86)
97
2h
2i
Arenethiols were also found to be effective nucleophiles
under the reactions conditions as can be seen from Table 3.
Important to remember is that such substrates were
problematic with the Merck procedure. Reaction of simple
thiophenol with bromobenzene and phenyltriflate afforded
diphenyl sulfide 2p in quantitative yields (entries 1 and 2).
Extension to the access of a naphthyl derivative was also
achieved in an excellent 93% yield (entry 3). Introduction of
an ortho-methoxy group on the aromatic thiol led to the
sulfide product in a moderate 41% yield. As can be seen
from the results in entries 4 and 6, the protocol can be even
applied to electron-deficient thiols. A lower conversion was
however observed with the thiol possessing an N,N-
dimethylaminoethyl group (entry 7), probably due to a
competing complexation of the nitrogen atom on palladium.
Furthermore, pyridine-2-thiol did not react under these
reaction conditions (entry 8).
84
2j
94
2k
2l
14
15
Br
Br
89
59
2m
2n
2o
16
17
Br
Br
100
0
While the precise mechanistic details of the C–S coupling
reaction remain to be established, it is assumed that the
overall catalytic cycle of the synthesis is similar to that
postulated for palladium catalyzed aminations and ethera-
tions.18 The reasons for the beneficial influence of the
Xantphos 1e ligand are not straightforward to elucidate. It is
likely that the close proximity of the oxygen atom to the
palladium center (with the possibility of assisting the
displacement of the leaving group from palladium)19 and
the known ability of chelating diphosphines with large bite
angles20 to accelerate reductive elimination rates21 play a
crucial role.
a Reaction conditions: RSH (1 mmol), K2CO3 (0.5 mmol), ArX (0.
8 mmol), Pd2(dba)3 (0.08 mmol), Xantphos 1e (0.09 mmol) in xylene
(12 mL) at 140 8C for 24 h.
b The yields obtained using isolated sodium thiolates are shown in
parentheses.
c Deprotonation with t-BuONa.
d Yield of the corresponding sulfone 3 obtained after oxidation of sulfide 2e
with m-CPBA.

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C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
Table 3. Coupling of aromatic thiols with Pd2(dba)3/Xantphos 1e according
to Scheme 1a
multiplicity of the signals: sZsinglet; dZdoublet; tZ
triplet; qZquartet; mZmultiplet, and combinations thereof.
The chemical shifts are calibrated to TMS (d H 0.00) or
residual proton and carbon resonance of the solvent CDCl3
(d H 7.26 and d C 77.16). 31P and 19F chemical shifts are
referred to external 85% phosphoric acid and CFCl3,
respectively. IR spectra were recorded on a Perkin–Elmer
16 PC FT-IR instrument. Mass spectra were recorded on a
Varian GC/MS/MS instrument. Only peaks of an intensity
O10% (except decisive ones) are listed. Elemental analyses
were performed with a C, H, N, S, O Thermoquest
apparatus.
Entry
X of ArX
Sulfide
Yield (%)
1
2
Br
100
100
2p
OTf
3
Br
93
2q
2r
4
Br
83
3.2. Ligand 1f
3.2.1. Synthesis of 1f. n-BuLi (1.7 mL of a 1.6 M solution in
hexanes, 2.9 mmol) was added dropwise at room tempera-
ture to a stirred solution of 9,9-dimethylxantene (200 mg,
0.9 mmol) and TMEDA (360 mL, 2.3 mmol) in heptane
(6 mL). After stirring for 15 h, neat chlorodi-t-butyl-
phosphine (3 mmol) was added dropwise and the reaction
mixture was stirred at 60 8C for 24 h. The solvent was
removed in vacuo and the resulting beige residue
was dissolved in CH2Cl2 (10 mL). The resulting solution
was washed with water, dried over MgSO4 and concentrated
to dryness. The resulting oil was then washed with
petroleum ether and crystallized from n-propyl alcohol to
afford the desired diphosphine 1f as air-stable crystals
(170 mg, 0.34 mmol, 38%). White crystals, mp 155–156 8C
5
6
Br
Br
41
57
2s
2t
7
8
Br
Br
2519
2u
2v
0
1
(n-propyl alcohol). H NMR (250 MHz): d 1.21–1.26 (m,
36H), 1.57 (s, 6H), 7.02 (t, JZ7.6 Hz, 2H), 7.38 (dd, JZ7.6,
1.5 Hz, 2H), 7.60 (d, JZ7.6 Hz, 2H). 13C NMR
(100.63 MHz): d 30.8 (m), 31.1, 32.7 (m), 35.0, 121.5,
125.5 (m), 126.6 (m), 130.7 (m), 133.7, 155.8 (m). 31P NMR
(101.3 MHz): d 12.4. Anal Calcd for C31H48OP2, C: 74.65,
H: 9.71. Found: C: 74.71, H: 9.63.
a Reaction conditions: RSH (1 mmol), K2CO3 (0.5 mmol), ArX (0.
8 mmol), Pd2(dba)3 (0.08 mmol), Xantphos 1e (0.09 mmol) in xylene
(12 mL) at 140 8C for 24 h.
In conclusion, we have developed an efficient and fairly
general Pd(0)-catalyzed aryl–sulfur bond formation from
aromatic and aliphatic thiols. The successful reaction
partners are aryl bromides, triflates and even activated
chlorobenzenes. An important value of the protocol we
described lies in the use of a classical mild mineral base
(K2CO3) and a readily available and cheap catalytic system
based on Pd2(dba)3 and Xantphos.
3.2.2. Crystal structure determination of 1f. Single
crystals of ligand 1f suitable for X-ray crystallographic
analysis were obtained by slow evaporation of n-propyl
alcohol solution. X-ray diffraction experiments for mono-
crystal of 1f were performed at 293.2 K with graphite-
monochromatized Mo Ka radiation on an Enraf-Nonius
CAD-4 diffractometer. Formula C31H48OP2, formula
weight 498, crystal system triclinic, space group PK1 (no
3. Experimental
3.1. General
˚
˚
˚
2), aZ12.477(4) A, bZ12.550(4) A, cZ12.934(3) A, aZ
3
˚
117.00(2)8, bZ92.82(4)8, gZ116.98(3)8, VZ1523.(1) A ,
ZZ2, rcalcdZ1.087 g/cm3, mZ1.430 mmK1, RZ0.046,
˚
All reactions were performed in oven-dried Schlenk tubes,
under an atmosphere of dry nitrogen. Due to the stench of
thiols, all glassware and syringes were washed with bleach
after use. Reactions were purified by chromatography
column with Merck silica gel Geduran Si 60 (0.040–
0.063 nm). Thin layer chromatography was carried out on
silica gel 60 F254 (1.1 mm, Merck) with spot detection under
UV light or through I2 or KMnO4 oxidation. Melting points
were obtained on a Reichert 7905 hot-stage microscope or
an Electrothermal IA9000 capillary apparatus and are
uncorrected. NMR spectra were recorded at room tempera-
ture on Bruker DPX 250 or DRX 400 spectrometers. All
chemical shifts (d) and coupling constants are quoted in
parts per million (ppm) and Hertz (Hz), respectively. The
following abbreviations are used to designate the
wRZ0.056. Selected bond lengths (A) and angles (deg):
P1–C4 1.847(2), P1–C13 1.882(3), P1–C17 1.901(2), P2–
C5 1.850(2), P2–C21 1.892(2), P2–C25 1.881(2), O1–C4a
1.378(2), O1–C10a 1.378(2), C4–P1–C13 100.6(1), C4–P1–
C17 105.7(1), C13–P1–C17 111.4(1), C5–P2–C21 105.3(1),
C5–P2–C25 100.2(1), C21–P2–C25 111.1(1), C4a–O1–
C10a 120.6(2). Data reduction: TEXSAN (Molecular
Structure Corporation). Program(s) used to solve structure:
SIR92. Program(s) used to refine structure: TEXSAN.
Software used to prepare material for publication:
TEXSAN. Crystallographic data for compound 1f have
been deposited at the Cambridge Crystallographic Data
Centre, CCDC No 255820. Copies of this information may
be obtained free of charge from The Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (C44 1223

C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
5257
336408; e-mail: deposit@ccdc.cam.ac.uk or http://www.
ccdc.cam.ac.uk).
116.6. MS (EI) m/z (relative intensity) 184 (MC, 41), 128
(100), 83 (29), 45 (44).
3.4.5. 1-(Butylsulfanyl)-4-trifluoromethylbenzene 2e
(entry 7, Table 1).22b Due to contamination with di-n-
butyl disulfide and difficult separation of both products, the
mixture was subjected to oxidation with m-CPBA. Spectral
data of the sulfone 3 derived from sulfide 2e thus obtained.
3.3. Typical experimental procedure for cross-coupling
In a Schlenk tube were charged successively K2CO3 (74 mg,
0.5 mmol) and degassed xylene (2 mL). After purging with
N2 using 3 evacuate-fill cycles, the slurry was cooled to 0 8C
and the thiol (1 mmol) was added dropwise. The resulting
mixture was then allowed to warm to room temperature and
stirred for 1 h. To a Schlenk tube were placed successively
the aryl substrate (0.8 mmol), Pd2(dba)3 (0.08 mmol),
Xantphos 1e (0.09 mmol) and degassed xylene (10 mL).
After purging with N2 using 3 evacuate-fill cycles, the
mixture was stirred at room temperature for 20 min and
transferred via a cannula to the previously formed potassium
thiolate. The dark solution was then purged with N2 and
heated to reflux for 24 h. After cooling to room temperature,
the mixture was diluted with EtOAc (20 mL), washed with
water (3!20 mL), dried over MgSO4 and concentrated
under reduced pressure. The crude product was then purified
by silica gel chromatography to afford the anticipated
thioether 2.
1-(Butylsulfonyl)-4-trifluoromethylbenzene 3. White solid,
1
mp 40 8C. H NMR (250 MHz): d0.91 (t, JZ7.3 Hz, 3H),
1.42 (sextet, JZ7.3 Hz, 2H), 1.64–1.77 (m, 2H), 3.09–3.16
(m, 2H), 7.75–7.79 (m, 2H), 7.97–8.00 (m, 2H). 13C NMR
(62.9 MHz): d13.5, 21.6, 24.6, 56.1, 123.2 (q, JCF
270.4 Hz), 126.5 (q, JCFZ3.8 Hz), 128.9, 135.4 (q, JCF
Z
Z
33.3 Hz), 142.9. 19F NMR (235.3 MHz): dK63.6. MS (EI)
m/z (relative intensity) 267 (MHC, 1), 145 (26), 57 (100),
56 (37). HRMS (EI) m/z 266.0629 (Calcd for C11H13F3O2S
266.0588).
3.4.6. 1-(1,1-Dimethylethyl)-4-propylsulfanylbenzene 2f
1
(entry 8, Table 1).22c Yellowish oil. H NMR (250 MHz):
d1.01 (t, JZ7.3 Hz, 3H), 1.29 (s, 9H), 1.65 (sextet, JZ
7.3 Hz, 2H), 2.86 (t, JZ7.3 Hz, 2H), 7.25–7.31 (m, 4H). 13C
NMR (62.9 MHz): d 13.5, 22.8, 31.4, 34.5, 36.2, 126.0,
129.4, 133.4, 149.0. MS (EI) m/z (relative intensity) 209
(MHC, 49), 208 (89), 195 (40), 194 (80), 193 (100), 149
(34), 45 (54), 43 (95).
3.4. Spectral data of sulfides 2
3.4.1. Butylsulfanylbenzene 2a (entries 1–3, Table 1).11e
1
Colorless oil. H NMR (250 MHz): d0.90 (t, JZ7.4 Hz,
3H), 1.43 (sextet, JZ7.4 Hz, 2H), 1.62 (quint, JZ7.4 Hz,
2H), 2.90 (t, JZ7.4, 2H), 7.12–7.33 (m, 5H, m). 13C NMR
(62.9 MHz): d 13.7, 22.0, 31.3, 33.3, 125.6, 128.7, 128.8,
137.1. MS (EI) m/z (relative intensity) 166 (MC, 46), 123
(28), 110 (100), 45 (38), 41 (53), 39 (478).
3.4.7. 1-Ethylsulfanyl-4-(1,1-dimethylethyl)benzene 2g
1
(entry 9, Table 1).22d Colorless oil. H NMR (250 MHz):
d1.30 two signals overlapping (t, JZ7.3 Hz, 3H) and (s,
9H), 2.92 (q, JZ7.3 Hz, 2H), 7.25–7.35 (m, 4H). 13C NMR
(62.9 MHz): d14.7, 28.2, 31.4, 34.6, 126.0, 129.5, 133.1,
149.3. MS (EI) m/z (relative intensity) 194 (MC, 27), 179
(100), 151 (38), 116 (31), 77 (35).
3.4.2. 4-Butylsulfanylphenyl methanesulfonate 2b (entry
4, Table 1). White solid, mp 54 8C. 1H NMR (250 MHz): d
0.93 (t, JZ7.2 Hz, 3H), 1.44 (sextet, JZ7.2 Hz, 2H), 1.61
(quint, JZ7.2 Hz, 2H), 2.92 (t, JZ7.2 Hz, 2H), 3.13 (s, 3H),
7.17–7.35 (m, 4H). 13C NMR (62.9 MHz): d 13.7, 22.1,
31.2, 33.6, 37.5, 122.6, 130.1, 137.0, 147.2. MS (EI) m/z
(relative intensity) 260 (MC, 44), 181 (100), 125 (97), 57
(72). HRMS (EI) m/z 260.0499 (Calcd for C11H16O3S2
260.0541).
3.4.8. 1-(1,1-Dimethylethyl)-4-methylsulfanylbenzene 2h
(entry 10, Table 1).22e White solid, mp 30–31 8C. 1H NMR
(250 MHz): d1.29 (s, 9H), 2.45 (s, 3H), 7.18–7.33 (m, 4H).
13C NMR (62.9 MHz): d16.2, 31.2, 34.3, 125.8, 126.8,
134.8, 148.3. MS (EI) m/z (relative intensity) 180 (MC,
.99), 165 (100), 150 (22), 137 (46), 117 (24), 45 (22).
3.4.9. (Phenylmethylsulfanyl)benzene 2i (entry 11,
Table 1).16 White solid, mp 41–41.5 8C. 1H NMR
(250 MHz): d3.98 (s, 2H), 7.00–7.22 (m, 10H). 13C NMR
(100 MHz): d39.48, 126.76, 127.59, 128.90, 129.25, 130.26,
136.80, 137.89. MS (EI) m/z (relative intensity) 200 (MC,
100), 51 (50).
3.4.3. 4-Butylsulfanylphenyl 4-methylbenzenesulfonate
2c (entry 5, Table 1). Yellowish oil. 1H NMR (250 MHz): d
0.90 (t, JZ7.2 Hz, 3H), 1.49 (sextet, JZ7.2 Hz, 2H), 1.59
(quint, JZ7.2 Hz, 2H), 2.42 (s, 3H), 2.87 (t, JZ7.2 Hz, 2H),
6.84–6.91 (m, 2H), 7.15–7.20 (m, 2H), 7.27–7.31 (m, 2H),
7.66–7.70 (m, 2H). 13C NMR (62.9 MHz): d 13.6, 21.7,
21.9, 31.0, 33.3, 122.8, 128.5, 129.4, 129.5, 132.3, 136.4,
145.5, 147.5. MS (EI) m/z (relative intensity) 336 (MC, 55),
181 (100), 125 (33), 91 (15). HRMS (EI) m/z 336.0820
(Calcd for C17H20O3S2 336.0854).
3.4.10. 3-Phenylsulfanylpropanoic acid ethyl ester 2j
(entry 12, Table 2).22f Colorless oil. 1H NMR (250 MHz):
d1.24 (t, JZ7.1 Hz, 3H), 2.61 (t, JZ7.4 Hz, 2H), 3.16 (t,
JZ7.4 Hz, 2H), 4.13 (q, JZ7.1 Hz, 2H), 7.16–7.38 (m, 5H).
13C NMR (62.9 MHz): d14.2, 29.1, 34.5, 60.7, 126.5, 129.0,
130.1, 135.4, 171.7. IR (NaCl, cmK1) 1732 (C]O). MS
(EI) m/z (relative intensity) 210 (MC, 77), 196 (35), 137
(100), 135 (30), 123 (32), 109 (25).
3.4.4. 1-(Butylsulfanyl)-4-fluorobenzene 2d (entry 6,
1
Table 1).22a Colorless oil. H NMR (250 MHz): d0.90 (t,
JZ7.2 Hz, 3H), 1.37–1.62 (m, 4H), 2.85 (t, JZ7.2 Hz, 2H),
6.93–7.00 (m, 2H), 7.24–7.35 (m, 2H). 13C NMR
(62.9 MHz): d13.5, 21.7, 31.2, 34.6, 115.8 (d, JCF
Z
3.4.11. 1-Cyclohexylsulfanyl-4-(1,1-dimethylethyl)-
benzene 2k (entry 13, Table 1).11b Colorless oil. 1H
NMR (250 MHz): d1.22–1.34 (m, 5H), 1.29 signal
21.4 Hz), 131.9 (d, JCFZ3.1 Hz), 132.0 (d, JCFZ7.5 Hz),
161.6 (d, JCFZ245.3 Hz). 19F NMR (235.3 MHz): dK

5258
C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
overlapping with the previous multiplet (s, 9H), 1.54–1.62
(m, 1H), 1.74–1.78 (m, 2H), 1.90–1.99 (m, 2H), 2.99–3.09
(m, 1H), 7.26–7.35 (m, 4H). 13C NMR (62.9 MHz): d25.9,
26.1, 31.4, 33.5, 34.5, 46.9, 125.8, 131.9, 132.2, 149.9. MS
(EI) m/z (relative intensity) 248 (MC, 25), 166 (42), 151
(100), 122 (40), 90 (33), 55 (96).
127.1, 128.4, 129.2, 131.5, 131.7, 134.6, 157.4. MS (EI) m/z
(relative intensity) 216 (MC, 100), 201 (11).
3.4.19. 2-Phenylsulfanylbenzonitrile 2t (entry 6,
Table 2).11c White solid, mp 39–40 8C. 1H NMR
(250 MHz): d7.14–7.21 (m, 2H), 7.33–7.52 (m, 7H). 13C
NMR (62.9 MHz): d108.8, 118.8, 127.4, 129.8, 130.0,
130.9, 132.4, 134.6, 145.8. IR (KBr, cm–1) 2224 (CbN). MS
(EI) m/z (relative intensity) 211 (MC, 100), 210 (70), 51
(25).
3.4.12.
1-(1,1-Dimethylethyl)-4-(1-methylpropyl-
1
sulfanyl)benzene 2l (entry 14, Table 1). Colorless oil. H
NMR (250 MHz): d 1.01 (t, JZ7.4 Hz, 3H), 1.25 (d, JZ
6.7 Hz, 3H), 1.31 (s, 9H), 1.42–1.72 (m, 2H), 3.10 (sextet,
JZ6.7 Hz, 1H), 7.27–7.32 (m, 4H). 13C NMR (62.9 MHz):
d 11.6, 20.7, 29.6, 31.4, 34.6, 45.2, 125.8, 131.9, 132.2,
150.0. MS (EI) m/z (relative intensity) 222 (MC, 100), 207
(49), 166 (70), 151 (28). HRMS (EI) m/z 222.1368 (Calcd
for C14H22S 222.1442). Anal Calcd for C14H22S, C: 75.61,
H: 9.97, S: 14.42. Found: C: 75.57, H: 9.86, S: 14.77.
3.4.20.
1-[1-(N,N-Dimethylaminoethyl)]-2-phenyl-
sulfanylbenzene 2u (entry 7, Table 2). Brown oil. 1H
NMR (250 MHz): d 1.28 (d, JZ6.6 Hz, 3H), 2.20 (s, 6H),
3.93 (q, JZ6.6 Hz, 1H), 7.14–7.29 (m, 9H), 7.54–7.58 (m,
1H). 13C NMR (62.9 MHz): d 19.7, 43.4, 62.0, 126.6, 127.4,
127.6, 128.1, 129.2, 130.4, 133.4, 134.0, 137.4, 146.9. MS
(EI) m/z (relative intensity) 257 (MC, 28), 242 (100), 72
(68). HRMS (EI) m/z 257.1288 (Calcd for C16H19NS
257.1238).
3.4.13. (exo)-2-Phenylsulfanylbornane 2m (entry 15,
Table 1). Orange oil. H NMR (250 MHz): d 0.77 (s, 3H),
1
0.94 and 0.95 (2 s, 3H each), 1.12–1.16 (m, 2H), 1.30 (s,
9H), 1.60–1.80 (m, 3H), 1.95–2.05 (m, 2H), 3.15–3.30 (m,
1H), 7.26–7.30 (m, 4H). 13C NMR (62.9 MHz): d 14.0, 20.2,
20.5, 27.8, 31.4, 34.4, 38.5, 41.2, 45.9, 47.5, 49.8, 56.7,
125.8, 129.4, 135.8, 148.8. MS (EI) m/z (relative intensity)
302 (MC, 14), 137 (66), 95 (26), 81 (100). HRMS (EI) m/z
302.2082 (Calcd for C20H30S 302.2068).
Acknowledgements
We gratefully acknowledge financial support from the
`
‘Ministere de la Recherche et des Nouvelles Technologies’,
CNRS (Centre National de la Recherche Scientifique), the
´
‘Region Basse-Normandie’ and the European Union
(FEDER funding). We also thank Rhodia and the CNRS
´
for a doctoral fellowship (C.M.-C.) and Andre Durif
(LEDSS, Grenoble) for the X-ray structure of ligand 1f.
3.4.14. 1,1-Dimethylethylsulfanylbenzene 2n (entry 16,
1
Table 1).6a Colorless oil. H NMR (250 MHz): d1.29 (s,
9H), 7.31–7.55 (m, 5H). 13C NMR (62.9 MHz): d31.1, 45.9,
128.6, 128.8, 132.9, 137.6. MS (EI) m/z (relative intensity)
166 (MC, 34), 110 (100), 109 (36), 65 (28), 57 (75).
3.4.15. Phenylsulfanylbenzene 2p (entries 1 and 2,
References and notes
1
Table 2).11e Colorless oil. H NMR (250 MHz): d7.31–
7.48 (m, 10H). 13C NMR (62.9 MHz): d126.9, 129.1, 130.9,
135.7. MS (EI) m/z (relative intensity) 186 (MC, 100), 77
(24), 65 (25), 51 (57).
1. See for example: (a) Inoue, H.; Konda, M.; Hashiyama, T.;
Otsuka, H.; Takahashi, K.; Gaino, M.; Date, T.; Aoe, K.;
Takeda, M.; Murata, S.; Narita, H.; Nagao, T. J. Med. Chem.
1991, 34, 675. (b) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.;
Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; von
Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med.
Chem. 2000, 43, 4025.
3.4.16. 2-Phenylsulfanylnaphthalene 2q (entry 3,
1
Table 2).22g White solid, mp 50 8C. H NMR (250 MHz):
d7.22–7.46 (m, 8H), 7.71–7.82 (m, 4H). 13C NMR
(62.9 MHz): d 126.7, 127.0, 127.5, 127.9, 128.2, 129.2,
129.3, 129.7, 130.4, 131.4, 132.8, 133.5, 134.3, 136.3. MS
(EI) m/z (relative intensity) 236 (MC, 100), 235 (67), 234
(48), 118 (27).
2. Wardell, J. L. In Patai, S., Ed.; The Chemistry of the Thiol
Group; Wiley: Chichester, 1974.
3. (a) Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.;
Montanucci, M. Synthesis 1983, 751. (b) Dickens, M. J.;
Gilday, J. P.; Mowlem, T. J.; Widdowson, D. A. Tetrahedron
1991, 47, 8621. (c) Oae, S.; Kiritani, R. Bull. Chem. Soc. Jpn.
1965, 38, 1381. (d) Phadnis, S. P. Indian J. Chem. 1972, 10,
699. Reaction with photochemical irradiation: (e)
Beugelmans, R.; Bois-Choussy, M.; Boudet, B. Tetrahedron
1983, 39, 4153.
3.4.17. 2-Phenylsulfanylbenzoic acid methyl ester 2r
(entry 4, Table 2).11e White solid, mp 46–47.5 8C. 1H NMR
(250 MHz): d3.93 (s, 3H), 6.81 (d, JZ8.0 Hz, 1H), 7.13 (t,
JZ7.2 Hz, 1H), 7.21 (dt, JZ8.0, 1.6 Hz, 1H), 7.39–7.42 (m,
3H), 7.53–7.57 (m, 2H), 7.97 (dd, JZ8.0, 1.6 Hz, 1H). 13C
NMR (62.9 MHz): d52.1, 124.3, 126.8, 127.4, 129.0, 129.7,
4. (a) Ham, J.; Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236.
(b) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org.
Lett. 2002, 4, 3619.
131.0, 132.3, 132.6, 135.5, 143.1, 166.8. IR (KBr, cmK1
)
1716 (C]O). MS (EI) m/z (relative intensity) 244 (MC,
73), 200 (100), 50 (93).
5. Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-i.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385.
6. (a) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong,
J. D.; Volante, R. P. J. Org. Chem. 1998, 63, 9606. (b)
McWilliams, J. C.; Fleitz, F. J.; Zheng, N.; Armstrong, J. D.
Org. Synth. 2003, 79, 43.
3.4.18. 1-Methoxy-2-phenylsulfanylbenzene 2s (entry 5,
1
Table 2).11e Colorless oil. H NMR (250 MHz): d3.85 (s,
3H), 6.82–6.90 (m, 2H), 7.06–7.10 (m, 1H), 7.19–7.37 (m,
6H, m). 13C NMR (62.9 MHz): d56.0, 111.0, 121.3, 124.2,

C. Mispelaere-Canivet et al. / Tetrahedron 61 (2005) 5253–5259
5259
7. (a) Rane, A. M.; Miranda, E. I.; Soderquist, J. A. Tetrahedron
Lett. 1994, 35, 3225. (b) Arnould, J. C.; Didelot, M.; Cadilhac,
C.; Pasquet, M. J. Tetrahedron Lett. 1996, 37, 4523. (c)
Moreau, X.; Campagne, J.-M. J. Organomet. Chem. 2003, 687,
322. (d) Rajagopalan, S.; Radke, G.; Evans, M.; Tomich, J. M.
Synth. Commun. 1996, 26, 1431. (e) Wendeborn, S.; De
Mesmaeker, A.; Brill, W. K.-D.; Berteina, S. Acc. Chem. Res
2000, 33, 215. (f) Schopfer, U.; Schlapbach, A. Tetrahedron
2001, 57, 3069. (g) Hartwig, J. F. Acc. Chem. Res 1998, 31,
852. (h) Li, G. Y. Angew. Chem. Int. Ed. 2001, 40, 1513. (i) Li,
G. Y. J. Org. Chem. 2002, 67, 3643. (j) Li, G. Y.; Zheng, G.;
Noonan, A. F. J. Org. Chem. 2001, 66, 8677. (k) Harr, M. S.;
substrates with various nucleophiles: (a) Prim, D.; Campagne,
J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(b) Zapf, A. Angew. Chem. Int. Ed. 2003, 42, 5394. (c)
Baran˜ano, D.; Mann, G.; Hartwig, J. F. Curr. Org. Chem.
1997, 1, 287. (d) Kondo, T.; Mitsudo, T.-a. Chem. Rev. 2000,
100, 3205.
13. Our previous work focused on the Newman–Kwart rearrange-
ment: Beslin, P.; Desmurs, J. -R.; Mispelaere, C.; Quesnel, Y.;
ˆ
Spindler, J. -F. Rhone Poulenc Chimie. France Patent WO
9,932,440, 1999.
14. These substrates were not examined by the Merck group.
15. Xantphos can be purchased from Strem Chemical Co. This
ligand was first developed by van Leeuwen and co-workers:
(a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081. For excellent reviews on
Xantphos ligands in transition-metal complexes and catalysis:
(b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H.
Acc. Chem. Res 2001, 34, 895. Recently, Pd2(dba)3–Xantphos
combination was efficiently used for the synthesis of sulfones
through the cross-coupling of sulfinate salts and aryl/vinyl
halides/triflates: (c) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Parisi, L. M.; Bernini, R. J. Org. Chem. 2004, 69, 5608.
16. Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
`
Presley, A. L.; Thorarensen, A. Synlett 1999, 1579. (l) Foa, M.;
Santi, R.; Garavaglia, F. J. Organomet. Chem. 1981, 206, C29.
(m) Kato, K.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38,
1805. (n) Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron
Lett. 1998, 39, 543. (o) Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1995, 36, 4133. (p) Wang, L.; Chen, Z. C.
Synth. Commun. 2001, 31, 1227. (q) Gao, G.-Y.; Colvin, A. J.;
Chen, Y.; Zhang, X. P. J. Org. Chem. 2004, 69, 8886. (r) Wolf,
C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077. (s) Gareau, Y.;
´
Pellicelli, J.; Laliberte, S.; Gauvreau, D. Tetrahedron Lett.
¨
2003, 44, 7821. (t) Kreis, M.; Brase, S. Adv. Synth. Catal.
2004, 347, 313.
8. The catalytic system decribed very recently by Buchwald
[Pd(OAc)2/1,10-bis(diisopropylphosphino)ferrocene] has the
widest substrate scope to date, enabling the coupling of aryl
chlorides: Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60,
7397.
17. (a) Becht, J.-M.; Wagner, A.; Mioskowski, C. J. Org. Chem.
2003, 68, 5758. (b) Becht, J.-M.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 2004, 45, 7031.
18. (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 125. (c) Hartwig, J. F. In Astruc, D., Ed.; Modern
Arene Chemistry; Wiley-VCH: Weinheim, 2002; p 107.
19. (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Zuideveld, M. A.; Swennenhuis, B. H. G.; Boele, M. D. K.;
Guari, Y.; van Strijdonck, G. P. F.; Reek, J. N. H.; Kamer,
P. C. J.; Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L.; van
Leeuwen, P. W. N. M. J. Chem. Soc., Dalton Trans. 2002,
2308.
9. For examples with a protected form of thiols: (a) Ishiyama, T.;
Mori, M.; Suzuki, A.; Miyaura, N. J. Organomet. Chem. 1996,
525, 225. (b) Still, I. W. J.; Toste, F. D. J. Org. Chem. 1996,
61, 7677. (c) Harayama, H.; Nagahama, T.; Kozera, T.;
Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. Bull. Chem.
Soc. Jpn. 1997, 70, 445. (d) Kundu, N. G.; Nandi, B.
Tetrahedron 2001, 57, 5885. (e) Kosugi, M.; Ogata, T.;
Terada, M.; Sano, H.; Migita, T. Bull. Chem. Soc. Jpn. 1985,
58, 3657. (f) Jixiang, X.; Crisp, G. T. Synth. Commun. 1992,
22, 683.
20. For a recent review on wide bide angle diphosphines in
transition metal catalysis, see: van Leeuwen, P.W.N. M.;
Kamer, P.C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev. 2000,
100, 2741.
10. Nickel(0)-catalyzed reaction: (a) Cristau, H. J.; Chabaud, B.;
ˆ
Chene, A.; Christol, H. Synthesis 1981, 892. (b) Millois, C.;
Diaz, P. Org. Lett. 2000, 2, 1705. (c) Percec, V.; Bae, J. Y.;
Hill, D. H. J. Org. Chem. 1995, 60, 6895.
11. Copper(I) catalyzed reactions: (a) Palomo, C.; Oiarbide, M.;
21. (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
3694. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1998, 120, 7369. (c) Mann, G.; Baranano, D.; Hartwig, J. F.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120,
9205. See also ref. 7g.
´
´
Lopez, R.; Gomez-Bengoa, E. Tetrahedron Lett. 2000, 41,
1283. (b) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org.
Lett. 2000, 2, 2019. (c) Wu, Y.-J.; He, H. Synlett 2003, 1789.
(d) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (e)
Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803. (f) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org.
Lett. 2002, 4, 4309. (g) Taniguchi, N.; Onami, T. J. Org.
Chem. 2004, 69, 915. (h) Bates, C. G.; Saejueng, P.; Doherty,
M. Q.; Venkataraman, D. Org. Lett. 2004, 26, 5005. For a
recent review: (i) Ley, S. V.; Thomas, A. W. Angew. Chem.
Int. Ed. 2003, 42, 5400.
22. (a) Clennan, E. L.; Yang, K. J. Org. Chem. 1992, 57, 4477. (b)
Taniguchi, N. J. Org. Chem. 2004, 69, 6904. (c) Kuliev, A. M.;
Gasanov, F. I. Prisadki Smaz Maslam 1967, 48. (d) Czarnik,
A. W. J. Org. Chem. 1984, 49, 924. (e) Pryor, W. A.;
Hendrickson, W. H., Jr. J. Am. Chem. Soc. 1983, 105, 7114. (f)
Waugh, K. M.; Berlin, K. D.; Ford, W. T.; Holt, E. M.; Carrol,
J. P.; Schomber, P. R.; Thompson, M. D.; Schiff, L. J. J. Med.
Chem. 1985, 28, 116. (g) Furman, F. M.; Thelin, J. H.; Hein,
D. W.; Hardy, W. B. J. Am. Chem. Soc. 1960, 82, 1450.
12. For reviews concerning Pd-catalyzed reactions of aryl