A general and efficient method for the palladium-catalyzed cross-coupling of thiols and secondary phosphines

Article abstract of DOI:10.1016/j.tet.2004.05.044

The general and efficient cross-coupling of thiols with aryl halides was developed utilizing Pd(OAc)₂/1,1′-bis(diisopropylphosphino) ferrocene as the catalyst. The substrate scope is broad and includes a variety of aryl bromides and chlorides,

Full text of DOI:10.1016/j.tet.2004.05.044

Tetrahedron 60 (2004) 7397–7403
A general and efficient method for the palladium-catalyzed
cross-coupling of thiols and secondary phosphines
*
Miki Murata and Stephen L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave. Bldg 18-305, Cambridge, MA 02139, USA
Received 30 March 2004; revised 17 May 2004; accepted 19 May 2004
Available online 7 June 2004
Dedicated to Professor Bob Grubbs in recognition of his continuing contributions to organic chemistry and for his mentoring over the years
0
Abstract—The general and efficient cross-coupling of thiols with aryl halides was developed utilizing Pd(OAc) /1,1 -bis(diisopropylphos-
2
phino)ferrocene as the catalyst. The substrate scope is broad and includes a variety of aryl bromides and chlorides, which can be coupled to
aliphatic and aromatic thiols. This catalyst system has the widest substrate scope of any reported to date. The present catalyst system also
enables the palladium-catalyzed coupling of secondary phosphines with aryl bromides and chlorides.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
Some success has been realized using bidentate phos-
3
6
–8
phines
protocols, however, lack generality: electron-rich or steri-
or dialkylphosphine oxides as ligands. These
During the past few years, significant progress in palladium-
catalyzed methods for the formation of carbon–nitrogen
and –oxygen bonds has been achieved. In particular, by the
use of bulky and electron-rich monophosphine ligands, not
only aryl bromides and iodides but also aryl chlorides can be
used as substrates for palladium-catalyzed cross-couplings.
In contrast, methods for the analogous formation of carbon–
sulfur and –phosphorus bonds have lagged behind. In fact,
examples of the coupling of aryl chlorides with sulfur- and
4
phosphorus-based nucleophiles are rare. This may be due
to the high coordinating abilities of both the substrates and
products. In this paper, we wish to report a general protocol
for palladium-catalyzed synthesis of aryl sulfides and
tertiary phosphines via cross-coupling protocols. Our
method overcomes a number of limitations of previous
systems and is the most general system that is available to
date.
9
cally-hindered substrates are often problematic. While the
1
10
11
nickel- and copper-catalyzed cross-coupling of thiols
has been reported, these methods are limited to aryl iodides.
Based on our success in related chemistry, we decided to
determine whether we could contribute to this area.
2
In our initial screening experiments, 4-bromoanisole and
benzenethiol were used as substrates for discovery of
suitable reaction conditions (Fig. 1, series 1). All reagents
except for the substrates were stirred together at room
temperature for 1 h before the thiol and the aryl bromide
were added. If all reaction components were simply mixed
together, low conversion to the desired product was
3
6
6
8
0
observed. As shown, use of DPPF, DPEphos and 1,1 -bis-
(diisopropylphosphino)ferrocene (DiPPF) as supporting
ligand gave the best results. The use of BINAP for this
coupling was unsuccessful. This is not unexpected as in
previous work on the reaction of aryl triflates with aliphatic
thiols using tol-BINAP, the reaction of aromatic thiols
2
. Results and discussion
7
were not suitable substrates. We found that inclusion of
2
1
1
0 mol% PhB(OH)2 in the reaction mixture with BINAP
2
.1. Palladium-catalyzed carbon–sulfur bond formation
as ligand allowed the reaction to proceed to full conversion.
Thus, it appears that reduction from Pd(II) to Pd(0) is slow
when BINAP is used with aromatic thiols. This is consistent
with the notion that BINAP is bulkier than DPPF and more
5
Despite the early work of Migita, the preparation of aryl
sulfides by C–S bond-forming reactions using palladium
catalysis has only recently received increased attention.
2
rigorously h than DPPF or DPEphos. Our bulky mono-
dentate phosphines were also ineffective under these
reaction conditions; inclusion of 10% PhB(OH)2 with
these ligands led to ca. 50% yield (GC analysis). Our
supposition is that a chelating ligand is necessary to prevent
Keywords: Palladium catalysis; Thiol cross-coupling; Phosphine cross-
coupling.
*
Corresponding author. Tel.: þ1-6172531852; fax: þ1-6172533297;
e-mail address: sbuchwal@mit.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.044

7398
M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
The reaction conditions described above were applied to the
coupling of a number aryl bromides and chlorides at 100 8C
(Table 1). As can be seen, the reactions of both of electron-
rich 4-haloanisoles
3
,6,7
8
and di-ortho-substituted halides,
which were problematic substrates in previous catalyst
systems, proceeded in high yield (entries 1, 3, 7 and 8). The
present technique tolerated a broad range (in terms of size)
of aliphatic thiols, including primary, secondary and tertiary
1
3
thiols. In addition, commercially available DiPPF
provides a general catalyst system for C–S bond formation
Table 1. Pd-catalyzed C–S bond formation
Entry
1
Product
X of Ar–X
Yield (%)
98
X¼Br
2
3
4
X¼Cl
95
X¼Cl
X¼Cl
X¼Cl
X¼Cl
99
95
77
85
a
5
b
6
Figure 1. Screen for ligand efficiency in Pd-catalyzed C–S bond-forming
reactions. Reaction conditions: ArBr (1.0 mmol), RSH (1.0 mmol),
7
8
X¼Br
X¼Br
93
95
Pd(OAc)
dioxane (2 mL) at 60 8C for 18 h.
2
(2.0 mol%), Ligand (Pd/P¼1.0/1.2), t-BuONa (1.2 mmol) in
binding of more than one substrate that could lead to
catalyst deactivation. It must, however, be of a suitable size
or flexibility to allow for reduction of Pd(II) to Pd(0) to
occur.
c,d
9
X¼Cl
X¼Cl
X¼Cl
89
82
91
We also examined the reaction of 4-chloroanisole with
2
1
1
0
1
-methyl-2-propanethiol (Fig. 1, series 2). DiPPF proved to
be the most effective ligand for the coupling of unactivated
aryl chlorides. In this case, DPPF and DPEphos were
inefficient, as expected. NaOt-Bu proved to be the most
generally useful base in these C–S coupling reactions.
Tertiary amines were also found to be effective as bases for
c,d,e
Reaction conditions: ArX (1.0 mmol), RSH (1.0 mmol), Pd(OAc)
2.0 mol%), DiPPF (2.4 mol%), t-BuONa (1.2 mmol) in dioxane (2 mL)
2
6
,7
the reactions of aryl bromides with aliphatic thiols. The
use of NaOt-Bu was essential, however, for the reactions of
(
at 100 8C for 18 h.
a
8
1.02 mmol of t-BuONa was used.
The reaction was carried out in toluene (2.0 mL).
aromatic thiols. The use of other bases such as Et N or
3
b
Cs CO gave no product. Dioxane proved to be the most
2
c
3
In Bu
3
N (2.0 mL).
.0 mol% of catalyst was used.
At 120 8C.
generally effective solvent, while the use of toluene resulted
in slower conversion to product.
d
e
3

M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
7399
1
4
6
). In contrast to the couplings of aliphatic thiols, the
reactions of aryl chlorides with aromatic thiols were initially
problematic. Under the standard reaction conditions, the
desired product was formed along with symmetrical
diarylsulfides. For example, the reaction of 4-n-butylchloro-
benzene and 4-methoxybenzenethiol in dioxane gave the
desired product along with 4-n-butylphenyl sulfide and
1
0
4
-methoxyphenyl sulfide (Scheme 1). Several attempts to
alleviate this problem including using lower reaction
temperatures, or lower quantities of catalyst, or through
the use of toluene as solvent resulted in low conversion to
product, although the selectivity of the process was
increased. We found, however, aryl–aryl scrambling
could be prevented by the use of Bu N as a solvent, and
3
the products were obtained in high yields (entries 9 and 10).
Scheme 1. Coupling of aromatic thiols with aryl chlorides.
2.2. Palladium-catalyzed carbon–phosphorus bond
formation
for aryl chlorides substrates, even electron-rich 4-chloro-
anisole can be processed in excellent yield (entry 3). Several
functional groups in the starting aryl halides were tolerated,
including a nitrile and a methyl ester (entries 5 and 10). In
the case of the methyl ester, it was necessary to use a
stoichiometric quantity of base; the use of excess amount of
base caused the formation of the t-butyl ester as a side
product. It was also found that triisopropylsilanethiol, an
The results presented above suggested to us that bidentate
ligands having di(sec-alkyl)phosphino groups could be
highly efficient as supporting ligands for the coupling of
aryl bromides and chlorides in situation in which the
nucleophile and/or the product could potentially slow the
desired catalytic process. In light of our results in C–S
coupling reactions, we proceeded to examine the same
catalyst system in carbon–phosphorus bond-forming
H S surrogate, coupled well under these conditions (entry
2
Table 2. Pd-catalyzed C–P bond formation
Entry
Product
X of Ar–X
Base
Solvent
Toluene
Temp. (8C)
Yield (%)
a
1
X¼Br
NaOt-Bu
80
87
2
3
X¼Br
X¼l
Cs
2
2
CO
3
3
Dioxane
Dioxane
80
80
82
85
Cs
CO
4
X¼Br
NaOt-Bu
Toluene
100
76
b
5
X¼Br
X¼Cl
Cs
2
CO
3
DMF
120
120
63
75
6
Cs
2
CO
3
Diglyme
Reaction condition: ArX (1.0 mmol), R
a
The reaction was carried out for 6 h.
2
PH (1.0 mmol), Pd(OAc)
2
(2.0 mol%), DiPPF (2.4 mol%), base (1.2 mmol) in solvent (1 mL) for 18 h.
b
2
0.5 mmol of ArBr was used.

7400
M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
reactions (Table 2). The palladium-catalyzed coupling
of various phosphorus-based nucleophiles, such as
4. Experimental
4.1. General considerations
1
5
16
17
phosphites, phosphine oxides, phosphines, and phos-
1
8
phine–borane complexes, has previously been reported.
This has been stimulated by a need to access tertiary
phosphines, which are widely used as ligands for transition
metal-catalyzed reactions. Secondary phosphines have
been employed as coupling partners with transition-
0
(DiPPF) were purchased from Strem Chemical Co. and
Pd(OAc)2 and 1,1 -bis(diisopropylphosphino)ferrocene
t
used without further purification. Anhydrous NaO Bu was
purchased from Aldrich and Cs CO was purchased from
2
3
1
9
metal catalysts based on palladium, nickel or copper
2
complexes. Common protocols, however, have been
Chemetall; the bulk of the material was stored under
nitrogen in a Vacuum Atmospheres glovebox. Small
portions (1–2 g) were removed from the glovebox in glass
vials, stored in the air, and weighed in the air. Anhydrous
dioxane, diglyme, and DMF were purchased from Aldrich
in Sure/Sealw bottles and used without further purification.
Toluene was purchased from J. T. Baker in CYCLE-
TAINERw solvent delivery kegs, which were vigorously
purged with argon for 2 h, and further purified by passing
the solvent through two packed columns of neutral alumina
and copper(II) oxide under argon pressure. All other
reagents were purchased from Alfa Aesar or Aldrich or
Strem Chemcal Co., and used without further purification.
All reactions were carried out under an argon atmosphere in
oven-dried glassware. Melting points were obtained on a
Mel-Temp capillary melting point apparatus. IR spectra
were obtained by placing neat samples directly on the
DiComp probe of an ASI REACTIR in situ IR instrument.
0
2
1
inefficient for the coupling of aryl bromides, and there
has been no report of the coupling of aryl chlorides with
secondary phosphines. In addition, previous reports have
focused on the reaction of diarylphosphines; the literature
on the coupling reactions of dialkylphosphine with aryl
2
0a
halides is sparse.
The reaction conditions for the C–P coupling was
optimized using 5-bromo-m-xylene and dicyclohexylphos-
phine as substrates. Phosphination proceeded in high yield
at 80 8C using the Pd(OAc) /DiPPF catalyst system (Table
2
2, entry 1). In contrast, DPPF and DtBPF proved ineffective
as supporting ligands for this coupling process. NaOt-Bu/
toluene and Cs CO /dioxane were found to be effective
2
3
combinations of base and solvent for C–P coupling
reactions, whereas tertiary amines, which were used in the
previous studies, were ineffective. The coupling of ortho-
substituted aryl halides could also be accomplished,
although a small amount of reduction product was observed
in several reactions (entries 2–5). Chemoselective phos-
phination of 1,2-dihalobenzenes could be successfully
carried out to obtain (2-halophenyl)dialkylbenzenes using
Cs CO as base (entries 2 and 3). Interestingly, the present
1
13
31
H NMR, C NMR and P NMR spectra were recorded on
a Bruker 400 MHz with chemical shifts reported in ppm
relative to the residual deuterated solvent, the internal
standard tetramethylsilane, or external 85% H PO for
3
4
3
1
P. Elemental analyses were performed by Atlantic
Microlabs, Norcross, GA. Gas chromatography analyses
were performed on a Hewlett Packard 6890 instrument with
a FID detector and a Hewlett Packard 25 m£0.2 mm i.d.
HP-1 capillary column. Mass spectra (GC-MS) were
recorded on a Hewlett Packard model G1800B. Flash
chromatography was performed on E.M. Science Kieselgel
60 (230–400 mesh). Yields refer to isolated yields of com-
pounds greater than 95% purity as determined by capillary
2
3
reaction was selective for the diphosphination of
0 0
22
2
,2 -dibromo-1,1 -biphenyl (entry 5). Although the crude
product was contaminated with reduced (2-biphenyl)di-
cyclopentylphosphine (25% yield), no monophosphinated
0
0
2
-bromo-2 -dicyclopentylphosphino-1,1 -biphenyl was
observed. The coupling of dicyclohexylphosphine with
electron-deficient aryl chlorides could be carried out in
good yield, although a reaction temperature of 120 8C was
required (entry 6). Unfortunately, the reaction of electron-
neutral 4-chlorotoluene with dicyclohexylphosphine
resulted in only 36% conversion and GC yield of product
under these reaction conditions (120 8C). To the best of
our knowledge, this is the first example of a palladium-
catalyzed cross-coupling reaction of aryl chlorides with
secondary phosphines.
1
GC and H NMR analysis. Yields reported in Tables 1 and 2
are an average of two independent runs. The procedures
described in this section are representative; thus, the yields
may differ slightly from those given in Tables. All new com-
pounds were further characterized by elemental analysis.
4.2. General procedure for palladium-catalyzed
carbon–sulfur bond formation
t
Pd(OAc)2 (0.020 mmol), DiPPF (0.024 mmol), NaO Bu
(
1.2 mmol) and the aryl halide (1.0 mmol) (if a solid)
were added to an oven-dried re-sealable Schlenk tube (Table
). The tube was evacuated and backfilled with argon (3
3. Conclusion
1
We have developed a general method for the cross-coupling
0
cycles) and then charged with dioxane (2.0 mL). The
solution was stirred for 1 h at room temperature. Then aryl
halide (1.0 mmol) (if a liquid) and the thiol (1.0 mmol) were
added by syringe. The Schlenk tube was sealed with a
Teflon valve, heated to 100 8C and stirred for 18 h. The
reaction mixture was then allowed to reach room tempera-
ture. Ether (ca. 3 mL) was added and an aliquot was
removed and analyzed by GC. The reaction mixture
was then filtered and concentrated. The crude product was
purified by flash column chromatography on silica gel to
afford the desired thioether.
of thiols with aryl halides using Pd(OAc) /1,1 -bis(diiso-
2
propylphosphino)ferrocene (DiPPF) as the catalyst. The
substrate scope is significantly broader than previous
methods and includes electron-rich and sterically-hindered
aryl halides as well as primary, secondary and tertiary and
aromatic thiols. In addition, the present system is efficient
for the coupling of thiols with unactivated aryl chlorides.
The Pd(OAc) /DiPPF catalyst system is also effective for
2
the palladium-catalyzed coupling of secondary phosphines
with aryl bromides and chlorides.

M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
7401
4
.2.1. 2,6-Dimethylphenyl 2-methyl-2-propyl sulfide
Following the general procedure, slightly modified so
that the reaction was carried out in toluene (2 mL), the
coupling of 4-butylchlorobenzene and triisopropylsilane-
2
3
(
entry 1). Following the general procedure, the coupling
of 2-bromo-m-xylene and 2-methyl-2-propanethiol afforded
91 mg (99% yield) of the title compound as a colorless oil.
1
thiol afforded 263 mg (82% yield) of the title compound as a
1
1
H NMR (CDCl ) d 1.29 (s, 9H), 2.58 (s, 6H), 7.12 (s, 3H).
3
colorless oil. H NMR (CDCl ) d 0.91 (t, J¼7.3 Hz, 3H),
3
1
3
C NMR (CDCl ) d 23.3, 31.8, 49.4, 128.1, 128.5, 132.4,
3
1.07 (d, J¼7.2 Hz, 18H), 1.1–1.6 (m, 7H), 2.55 (t, J¼
13
45.4. IR (neat, cm2 ) 2962, 1578, 1457, 1362, 1165, 1055.
1
7.6 Hz, 2H), 7.01 (d, J¼8.1 Hz, 2H), 7.39 (d, J¼8.1 Hz,
1
MS (EI) m/z (relative intensity) 194 (M , 6), 138 (100).
þ
Anal. Calcd for C H S, C: 74.16, H: 9.34. Found C: 74.20,
H: 9.41.
2H). C NMR (CDCl ) d 13.1, 13.9, 18.4, 22.2, 33.5, 35.1,
127.7, 128.7, 135.3, 141.6. IR (neat, cm ) 2944, 2865,
3
2
1
1
2 18
þ
7), 279 (100). Anal. Calcd for C H SSi, C: 70.73, H:
1492, 1461, 1383. MS (EI) m/z (relative intensity) 322 (M ,
1
10.62. Found C: 70.51, H: 10.45.
19 34
4.2.2. 4-Butylphenyl hexyl sulfide (entry 2). Following the
general procedure, the coupling of 4-butylchlorobenzene
and hexanethiol afforded 236 mg (95% yield) of the title
1
4.2.7. 4-Methoxyphenyl phenyl sulfide (entry 7).25
Following the general procedure, the coupling of 4-bromo-
compound as a yellow oil. H NMR (CDCl ) d 0.88 (t, J¼
3
7
.0 Hz, 3H), 0.92 (t, J¼7.3 Hz, 3H), 1.2–1.7 (m, 12H), 2.57
anisole and thiophenol afforded 206 mg (95% yield) of the
1
(
8
t, J¼7.6 Hz, 2H), 2.88 (t, J¼7.5 Hz, 2H), 7.09 (d, J¼
title compound as a colorless oil. H NMR (CDCl ) d 3.82
3
1
3
.1 Hz, 2H), 7.25 (d, J¼8.1 Hz, 2H). C NMR (CDCl ) d
(s, 3H), 6.90 (d, J¼8.8 Hz, 2H), 7.1–7.3 (m, 5H), 7.42 (d,
21
3
1
3
1
1
1
3.9, 13.9, 22.3, 22.5, 28.5, 29.2, 31.4, 33.5, 34.3, 35.1,
28.9, 129.6, 133.5, 140.8. IR (neat, cm ) 2927, 2858,
J¼8.8 Hz, 2H). C NMR (CDCl ) d 55.7, 115.4, 124.8,
3
2
1
126.2, 128.7, 129.3, 135.7, 139.0, 160.3. IR (neat, cm
3058, 3004, 2941, 2834, 1592, 1492, 1287, 1243, 1171. MS
)
þ
3), 207 (54), 166 (27), 123 (100). Anal. Calcd for C H S,
493, 1466, 1092. MS (EI) m/z (relative intensity) 250 (M ,
þ
Calcd for C H OS, C: 72.19, H: 5.59. Found C: 72.31, H:
5
C: 76.73, H: 10.46. Found C: 76.73, H: 10.51.
(EI) m/z (relative intensity) 216 (M , 100), 201 (53). Anal.
1
6 26
1
3 12
5.50.
4
3
4
1
.2.3. 4-Methoxyphenyl 2-methyl-2-propyl sulfide (entry
). Following the general procedure, the coupling of
2
5
4.2.8. 2,6-Dimethylphenyl phenyl sulfide (entry 8).
Following the general procedure, the coupling of
-chloroanisole and 2-methyl-2-propanethiol afforded
94 mg (99% yield) of the title compound as a colorless
2-bromo-m-xylene and thiophenol afforded 202 mg (94%
1
1
oil. H NMR (CDCl ) d 1.26 (s, 9H), 3.81 (s, 3H), 6.86 (d,
3
yield) of the title compound as a colorless oil. H NMR
13
1
3
J¼8.7 Hz, 2H), 7.44 (d, J¼8.7 Hz, 2H). C NMR (CDCl3)
(CDCl ) d 2.42 (s, 6H), 6.9–7.2 (m, 8H). C NMR (CDCl3)
3
d 31.0, 45.7, 55.5, 114.2, 123.9, 139.1, 160.5. IR (neat,
cm ) 2960, 1590, 1492, 1362, 1285, 1245, 1169, 1102,
d 22.3, 125.1, 126.1, 128.9, 129.3, 129.7, 131.0, 138.5,
21
2
1
144.3. IR (neat, cm ) 3058, 2975, 1582, 1476, 1461, 1439,
1376. MS (EI) m/z (relative intensity) 214 (M , 100), 136
þ
100). Anal. Calcd for C H OS, C: 67.30, H: 8.22. Found
þ
(48). Anal. Calcd for C H S, C: 78.46, H: 6.58. Found C:
78.34, H: 6.53.
1
032. MS (EI) m/z (relative intensity) 196 (M , 11), 140
(
C: 66.51, H: 8.27.
1
1
16
14 14
4
.2.4. 2,5-Dimethylphenyl 2-methyl-2-propyl sulfide
4.2.9. 4-Butylphenyl 4-methoxyphenyl sulfide (entry 9).
The coupling reaction of 4-butylchlorobenzene and 4-meth-
oxybenzenethiol was carried out in Bu N (2 mL) using
3
2
4
(
entry 4). Following the general procedure, the coupling
of 2-chloro-p-xylene and 2-methyl-2-propanethiol afforded
77 mg (91% yield) of the title compound as a colorless oil.
1
Pd(OAc)2 (6.8 mg, 0.030 mmol) and DiPPF (15.0 mg,
0.036 mmol). The reaction mixture was heated to 100 8C,
stirred for 18 h, then allowed to reach room temperature.
After ether (ca. 6 mL) was added, the resulting mixture was
washed with 1 M HCl aq. (3£5 mL), dried over Na SO ,
1
H NMR (CDCl ) d 1.29 (s, 9H), 2.31 (s, 3H), 2.47 (s, 3H),
3
7
.07 (d, J¼7.7 Hz, 1H), 7.16 (d, J¼7.7 Hz, 1H), 7.35 (s,
H). C NMR (CDCl ) d 20.9, 21.5, 31.3, 47.3, 129.9,
3
1
3
1
1
1
2
1
30.4, 132.0, 135.4, 139.7, 140.8. IR (neat, cm ) 2962,
488, 1455, 1362, 1158. MS (EI) m/z (relative intensity) 194
2
4
and concentrated. The crude product was purified by
þ
.34. Found C: 74.01, H: 9.24.
(
M , 11), 138 (100). Anal. Calcd for C H S, C: 74.16, H:
1
column chromatography to afforded 231 mg (85% yield)
1
2 18
9
of the title compound as a colorless oil. H NMR (CDCl ) d
3
0
.93 (t, J¼7.3 Hz, 3H), 1.3–1.6 (m, 4H), 2.55 (t, J¼7.8 Hz,
4.2.5. Methyl 3-(cyclohexylsulfanyl)benzoate (entry 5).
Following the general procedure, slightly modified so that a
2H), 3.80 (s, 3H), 6.87 (d, J¼8.9 Hz, 2H), 7.06 (d, J¼
13
8.3 Hz, 2H), 7.13 (d, J¼8.3 Hz, 2H), 7.37 (d, J¼8.9 Hz,
t
stoichiometric quantity of NaO Bu (98 mg, 1.02 mmol) was
used, the coupling of methyl 3-chlorobenzoate and cyclo-
2H). C NMR (CDCl ) d 13.9, 22.3, 33.5, 35.1, 55.3, 114.9,
125.5, 129.1, 129.2, 134.4, 134.6, 141.1, 159.5. IR (neat,
3
2
1
hexanethiol afforded 263 mg (82% yield) of the title
1
cm ) 2929, 2858, 1592, 1492, 1287, 1245, 1171. MS (EI)
m/z (relative intensity) 272 (M , 62), 229 (100). Anal. Calcd
þ
for C H OS, C: 74.96, H: 7.40. Found C: 74.67, H: 7.31.
compound as a yellow oil. H NMR (CDCl ) d 1.2–2.0
3
(
1
(
1
m, 10H), 3.14 (br s, 1H), 3.92 (s, 3H), 7.57 (d, J¼7.8 Hz,
1
7 20
1
3
H), 7.88 (d, J¼7.8 Hz, 1H), 8.06 (s, 1H). C NMR
CDCl ) d 25.9, 26.2, 33.4, 46.7, 52.5, 127.9, 128.9, 130.9,
3
4.2.10. 3-Cyanophenyl phenyl sulfide (entry 10).26
Following the above procedure, slightly modified so that
the reaction was carried out at 100 8C using Pd(OAc)2
(0.020 mmol) and DiPPF (0.024 mmol), the coupling of
3-chlorobenzonitrile and thiophenol afforded 162 mg (77%
2
1
32.6, 136.2, 136.3, 166.9. IR (neat, cm ) 2931, 2854,
719, 1573, 1436, 1258. MS (EI) m/z (relative intensity) 250
1
(
þ
H: 7.25. Found C: 67.41, H: 7.31.
M , 22), 168 (100). Anal. Calcd for C H O S, C: 67.16,
14 18 2
1
yield) of the title compound as a colorless oil. H NMR
1
3
4
.2.6. 4-Butylphenyl triisopropylsilyl sulfide (entry 6).
(CDCl ) d 7.3–7.5 (m). C NMR (CDCl ) d 113.3, 118.2,
3 3

7402
M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
1
1
28.8, 129.5, 129.5, 129.8, 131.6, 132.2, 132.8, 133.3,
2
J¼16 Hz), 126.2, 130.0, 130.4, 134.9, 135.7 (d, J¼25 Hz),
6 6
21
1
31
40.0. IR (neat, cm ) 3060, 2231, 1567, 1474, 1439, 1405.
þ
142.8 (d, J¼26 Hz). P NMR (C D ) d 24.75. IR (neat,
MS (EI) m/z (relative intensity) 211 (M , 100), 184 (16).
Anal. Calcd for C H NS, C: 73.90, H: 4.29. Found C:
cm ) 2921, 2848, 1418, 1034. MS (EI) m/z (relative
þ
C H ClP, C: 70.00, H: 8.49. Found C: 69.85, H: 8.62.
intensity) 308 (M , 10), 273 (100). Anal. Calcd for
1
3 9
7
3.77, H: 4.26.
1
8 26
4
(
.2.11. 2,5-Dimethylphenyl 4-methoxyphenyl sulfide
entry 11). Following the above procedure, slightly
4.3.3. (2-Bromophenyl)dicyclohexylphosphine (entry 3).
Following the general procedure, the coupling of 2-bromo-
iodobenzene and dicyclohexylphosphine was carried out in
dioxane (1 mL) at 80 8C for 18 h using Cs CO (391 mg,
modified so that the reaction was carried out at 120 8C,
the coupling of 2-chloro-p-xylene and 4-methoxyben-
zenethiol afforded 225 mg (92% yield) of the title
2
3
1.2 mmol) as a base to afford 300 mg (85% yield) of the title
1
1
compound as a colorless oil. H NMR (CDCl ) d 2.20 (s,
3
compound as a white solid, mp 76–77 8C. H NMR (C D )
6 6
3
H), 2.32 (s, 3H), 3.79 (s, 3H), 6.8–6.9 (m, 4H), 7.06 (d,
1
d 1.0–2.0 (m, 22H), 6.73 (t, J¼7.7 Hz, 1H), 6.95 (t, J¼
3
J¼7.6 Hz, 1H), 7.29 (d, J¼8.7 Hz, 2H). C NMR (CDCl3)
7.4 Hz, 1H), 7.24 (d, J¼7.6 Hz, 1H), 7.49 (dd, J¼8.0,
1
3
d 19.8, 20.9, 55.3, 114.9, 125.1, 127.3, 130.1, 130.4, 133.9,
3.1 Hz, 1H). C NMR (C D ) d 27.0, 27.7 (d, J¼8 Hz),
6
6
34.5, 136.1, 136.1, 159.3. IR (neat, cm2 ) 2964, 2834,
1
27.8 (d, J¼12 Hz), 29.9 (d, J¼10 Hz), 31.0 (d, J¼17 Hz),
35.0 (d, J¼17 Hz), 127.0, 130.5, 134.1 (d, J¼3 Hz), 134.5
1
1
592, 1492, 1287, 1243, 1173. MS (EI) m/z (relative
3
1
intensity) 244 (Mþ, 100), 229 (17), 136 (49). Anal. Calcd
(d, J¼30 Hz), 134.9, 138.1 (d, J¼23 Hz). P NMR (C D )
6
6
d 2.26. IR (neat, cm2 ) 2919, 2848, 1019. MS (EI) m/z
1
for C H OS, C: 73.73, H: 6.60. Found C: 73.78, H: 6.61.
15 16
þ
Anal. Calcd for C H BrP, C: 61.20, H: 7.42. Found C:
þ
(
relative intensity) 354 (M , 6), 352 (M , 6), 273 (100).
4.3. General procedure for palladium-catalyzed
carbon–phosphorus bond formation
1
8 26
60.97, H: 7.40.
Pd(OAc)2 (4.5 mg, 0.020 mmol), DiPPF (10.0 mg,
0
(
resealable Schlenk tube (Table 2). The Schlenk tube was
evacuated and backfilled with argon (3 cycles) and then
charged with solvent (1.0 mL). The solution was stirred for
4.3.4. 2-(Dicyclopentylphosphino)biphenyl (entry 4).
Following the general procedure, the coupling of 2-bromo-
biphenyl and dicyclopentylphosphine was carried out in
toluene at 100 8C using NaO Bu as a base to afford 265 mg
(83% yield) of the title compound as a white solid, mp 88–
.024 mmol), base (1.2 mmol) and the aryl halide
1.0 mmol) (if a solid) were added to an oven-dried
t
1
89 8C. H NMR (C D ) d 1.3–2.2 (m, 18H), 7.2–7.4 (m,
6
6
1
3
1
h at room temperature. Then aryl halide (1.0 mmol) (if
6H), 7.48 (d, J¼8.1 Hz, 2H), 7.55 (d, J¼8.1 Hz, 1H).
C
liquid) and the secondary phosphine (1.0 mmol) were added
by syringe. The Schlenk tube was sealed with a Teflon
valve, heated and stirred for 18 h. The reaction mixture was
then allowed to reach room temperature. Ether (ca. 3 mL)
was added and the aliquot was analyzed by GC. The
reaction mixture was then filtered and concentrated. The
crude product was purified by flash column chromatography
on silica gel to afford the desired tertiary phosphine.
NMR (C D ) d 26.3 (d, J¼7 Hz), 27.3 (d, J¼8 Hz), 32.0 (d,
6
6
J¼24 Hz), 32.2 (d, J¼15 Hz), 40.0 (d, J¼14 Hz), 127.2,
127.7, 128.8, 130.7 (d, J¼5 Hz), 131.7 (d, J¼4 Hz), 132.9
(d, J¼3 Hz), 139.1 (d, J¼20 Hz), 143.7 (d, J¼6 Hz), 150.4
3
1
21
(d, J¼28 Hz). P NMR (C D ) d 212.42. IR (neat, cm
)
6
6
þ
97), 253 (20), 183 (100). Anal. Calcd for C H P, C: 81.95,
H: 8.44. Found C: 81.90, H: 8.49.
2944, 2863, 1463. MS (EI) m/z (relative intensity) 321 (M ,
2
2 27
0
0
(entry 5). Following the general procedure, the coupling
4
.3.1. Dicyclohexyl(3,5-dimethylphenyl)phosphine
entry 1). Following the general procedure, the coupling
4.3.5. 2,2 -Bis(dicyclopentylphosphino)-1,1 -biphenyl
(
of 5-bromo-m-xylene and dicyclohexylphosphine was
0
0
of 2,2 -dibromo-1,1 -biphenyl (0.5 mmol) and dicyclo-
pentylphosphine (1.0 mmol) was carried out in DMF
(1 mL) at 120 8C using Cs CO (1.2 mmol) as a base.
Additional recrystallization from methanol/CH Cl was
2 2
required to provide the analytically pure product, afforded
159 mg (65% yield) of the title compound as a white solid,
t
carried out in toluene (1 mL) at 80 8C for 6 h using NaO Bu
115 mg, 1.2 mmol) as a base to afford 255 mg (84% yield)
(
2
3
1
of the title compound as a white solid, mp 77–78 8C. H
NMR (C D ) d 1.0–2.0 (m, 22H), 2.16 (s, 1H), 6.82 (s, 1H),
7
6
6
1
3
.34 (d, J¼7.1 Hz, 2H). C NMR (C D ) d 21.7, 27.2, 27.8
6
6
1
(
d, J¼7 Hz), 27.9 (d, J¼12 Hz), 29.8 (d, J¼8 Hz), 31.1 (d,
mp 158–159 8C. H NMR (C D ) d 1.3–2.2 (m, 36H), 7.3–
6
6
1
3
J¼17 Hz), 33.7 (d, J¼14 Hz), 131.3, 133.4 (d, J¼20 Hz),
7.4 (m, 6H), 7.61 (d, J¼6.7 Hz, 2H). C NMR (C D ) d
6
6
3
1
1
3
35.9 (d, J¼19 Hz), 137.7 (d, J¼7 Hz). P NMR (C D ) d
26.1 (t, J¼4 Hz), 26.7 (t, J¼4 Hz), 26.9 (t, J¼3 Hz), 28.1 (t,
J¼4 Hz), 31.7 (t, J¼9 Hz), 32.0 (t, J¼7 Hz), 32.4 (t, J¼
11 Hz), 32.8 (t, J¼14 Hz), 37.5 (dd, J¼8, 5 Hz), 43.0 (dd,
J¼8, 5 Hz), 127.4, 127.8, 132.3 (t, J¼4 Hz), 132.6, 139.3
6
6
2
1
.62. IR (neat, cm ) 2921, 2848. MS (EI) m/z (relative
þ
intensity) 302 (M , 26), 247 (23), 220 (95). Anal. Calcd for
C H P, C: 79.43, H: 10.33. Found C: 79.29, H: 10.43.
2
0 31
3
1
(
dd, J¼10, 6 Hz), 150.1 (t, J¼18 Hz). P NMR (C D ) d
6
6
2
1
4
.3.2. (2-Chlorophenyl)dicyclohexylphosphine (entry 2).
213.01. IR (neat, cm ) 2948, 2863, 1426. Anal. Calcd for
C H P, C: 78.34, H: 9.04. Found C: 78.51, H: 8.99.
Following the general procedure, the coupling of 2-chloro-
bromobenzene and dicyclohexylphosphine was carried out
in dioxane at 80 8C using Cs CO as a base to afford 259 mg
3
2 44
4.3.6. 3-(Dicyclohexylphosphino)benzonitrile (entry 6).
Following the general procedure, the coupling of 3-chloro-
benzonitrile and dicyclohexylphosphine was carried out in
diglyme (1 mL) at 120 8C for 18 h using Cs CO as a base to
2
3
(
8
84% yield) of the title compound as a white solid, mp
1
2–83 8C. H NMR (C D ) d 1.0–2.0 (m, 22H), 6.82 (t,
6 6
J¼7.6 Hz, 1H), 6.91 (t, J¼7.4 Hz, 1H), 7.2–7.4 (m, 2H).
2
3
1
3
C NMR (C D ) d 26.8, 27.5 (d, J¼8 Hz), 27.6 (d, J¼
afford 210 mg (70% yield) of the title compound as a white
1
6
6
1
2 Hz), 29.7 (d, J¼7 Hz), 30.9 (d, J¼18 Hz), 34.2 (d,
solid, mp 77–78 8C. H NMR (C D ) d 0.9–1.8 (m, 22H),
6
6

M. Murata, S. L. Buchwald / Tetrahedron 60 (2004) 7397–7403
7403
6
.72 (t, J¼7.7 Hz, 1H), 7.00 (d, J¼7.7 Hz, 1H), 7.36 (t,
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120,
9205.
10. Takagi, K. Chem. Lett. 1987, 2221.
1
3
J¼6.5 Hz, 1H), 7.68 (t, J¼5.2 Hz, 1H). C NMR (C D ) d
6
6
2
8
7
1
4
6.9, 27.4 (d, J¼7 Hz), 27.6 (d, J¼12 Hz), 29.5 (d, J¼
Hz), 30.6 (d, J¼17 Hz), 33.1 (d, J¼14 Hz), 113.4 (d, J¼
Hz), 119.2, 128.8 (d, J¼7 Hz), 132.5, 138.1 (d, J¼19 Hz),
11. (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(b) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803.
3
1
38.4 (d, J¼26 Hz), 139.3 (d, J¼21 Hz). P NMR (C D ) d
6
6
2
1
.28. IR (neat, cm ) 2923, 2850. MS (EI) m/z (relative
12. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
13. $144 for 2 g from Strem Chemical Co.
þ
intensity) 299 (M , 19), 244 (17), 217 (79). Anal. Calcd for
C H NP, C: 76.22, H: 8.75. Found C: 75.98, H: 8.70.
1
9 26
1
4. Sodium silathiolates have been used as nucleophiles Arnould,
J.-C.; Didelot, M.; Pasquet, M.-J.; Cadilhac, C. Tetrahedron
Lett. 1996, 37, 4523.
Acknowledgements
1
5. Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.
Bull. Chem. Soc. Jpn 1982, 55, 909.
We thank the National Institutes of Health (GM 58160) for
supporting this work. We are grateful to Pfizer, Merck,
Novartis and Rhodia for additional unrestricted support. We
also thank Mr. Eric R. Strieter for help in preparing this
manuscript. M.M. was supported by the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
16. Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1984, 781.
17. (a) Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52, 748.
(b) Herd, O.; Hessler, A.; Hingst, M.; Tepper, M.; Stelzer, O.
J. Organomet. Chem. 1996, 522, 69. (c) Ager, D. J.; East,
M. B.; Eisenstadt, A.; Laneman, S. A. Chem. Commun. 1997,
2
359. (d) Martorell, G.; Garc ´ı as, X.; Janura, M.; Sa a´ , J. M.
J. Org. Chem. 1998, 63, 3463. (e) Kwong, F. Y.; Chan, K. S.
Chem. Commun. 2000, 1069. (f) Stadler, A.; Kappe, C. O. Org.
Lett. 2002, 4, 3541. (g) Brauer, D. J.; Hingst, M.; Kottsieper,
K. W.; Liek, C.; Nickel, T.; Tepper, M.; Stelzer, O.; Sheldrick,
W. S. J. Organomet. Chem. 2002, 645, 14.
References and notes
1
. For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131. (b) Hartwig, J. F. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley: New York, 2002; p 1051. (c) Prim, D.;
Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
18. (a) Imamoto, T. Pure Appl. Chem. 1993, 65, 655. (b) Lipshutz,
B. H.; Buzard, D. J.; Yun, C. S. Tetrahedron Lett. 1999, 40,
201. (c) Al-Masum, M.; Livinghouse, T. Tetrahedron Lett.
1999, 40, 7731. (d) Gaumont, A.-C.; Hursthouse, M. B.; Coles,
S. J.; Brown, J. M. Chem. Commun. 1999, 63.
2
002, 58, 2014.
2
3
. For a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176.
19. Synthesis of BINAP has been reported. Cai, D.; Payack, J. F.;
Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J.
J. Org. Chem. 1994, 59, 7180.
. (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (b) Li,
G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677.
(
c) Li, G. Y. J. Org. Chem. 2002, 67, 3643.
. Montchamp, J.-L.; Dumond, Y. R. J. Am. Chem. Soc. 2001,
23, 510.
20. (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5,
2315. (b) Allen, D. V.; Venkataraman, D. J. Org. Chem. 2003,
68, 4590.
4
5
1
. (a) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-I.; Kato,
Y.; Kosugi, M. Bull. Chem. Soc. Jpn 1980, 53, 1385.
21. The asymmetric coupling using Pd(Me-Duphos)(Ph)(I) at
50 8C was reported. Only one example of aryl bromide,
however, was provided. Moncarz, J. R.; Laritcheva, N. F.;
Glueck, D. S. J. Am. Chem. Soc. 2002, 124, 13356.
(b) Kosugi, M.; Ogata, T.; Terada, M.; Sano, H.; Migita, T.
Bull. Chem. Soc. Jpn 1985, 58, 3657.
. (a) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
0
6
7
22. The selective monophosphinylation of 1,1 -binaphthyl 2,
0
1
W. K.-D.; DeMesmaeker, A. Synlett 1998, 671.
995, 36, 4133. (b) Wendeborn, S.; Berteina, S.; Brill,
2 -ditriflate have been reported. (a) Kurz, L.; Lee, G.;
Morgans, D., Jr.; Waldyke, M. J.; Ward, T. Tetrahedron
Lett. 1990, 31, 6321. (b) Uozumi, Y.; Tanahashi, A.; Lee,
S.-Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945.
23. Davis, F. A.; Jenkins, R. H.; Rizvi, S. Q. A.; Yocklovich, S. G.
J. Org. Chem. 1981, 46, 3467.
. (a) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong,
J. D., III.; Volante, R. P. J. Org. Chem. 1998, 63, 9606.
(b) McWilliams, J. C.; Fleitz, F. J.; Zheng, N.; Armstrong,
J. D., III. Org. Synth. 2002, 79, 43.
8
. Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069.
. The effect of 4-methoxy and 2,6-dimethyl substrates on the
rate of C–S bond-forming processes has been reported.
24. Nakazumi, H.; Kitaguchi, T.; Ueyama, T.; Kitao, T. Synthesis
1984, 518.
9
25. Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803.
26. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(
a) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
17, 2937. (b) Mann, G.; Baranano, D.; Hartwig, J. F.;
1