Stille cross-coupling reactions of aryl mesylates and tosylates using a biarylphosphine based catalyst system

Article abstract of DOI:10.3987/COM-09-S(S)105

A catalyst system for the Stille cross-coupling reactions of aryl mesylates and tosylates is reported. Using the combination of Pd(OAc)₂, XPhos, and CsF in t-BuOH an array of aryl and heteroaryl sulfonates were successfully employed in these reactions. Morever, heteroarylstannanes, such as furyl, thienyl, and N-methylpyrrolyl, which are often prone to decomposition, were efficiently coupled under these conditions. Ortho-substitution on the stannane coupling partner was well tolerated; however, the presence of ortho substituents on the aryl sulfonates greatly reduced the efficiency of these reactions.

Full text of DOI:10.3987/COM-09-S(S)105

HETEROCYCLES, Vol. 80, No. 2, 2010
1215
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1215 - 1226. © The Japan Institute of Heterocyclic Chemistry
Received, 4th August, 2009, Accepted, 25th August, 2009, Published online, 27th August, 2009
DOI: 10.3987/COM-09-S(S)105
STILLE CROSS-COUPLING REACTIONS OF ARYL MESYLATES AND
TOSYLATES USING A BIARYLPHOSPHINE BASED CATALYST
SYSTEM‡
John R. Naber, Brett P. Fors, Xiaoxing Wu, Jonathon T. Gunn, and Stephen
L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA. E-mail: sbuchwal@mit.edu
Abstract – A catalyst system for the Stille cross-coupling reactions of aryl
mesylates and tosylates is reported. Using the combination of Pd(OAc)2, XPhos,
and CsF in t-BuOH an array of aryl and heteroaryl sulfonates were successfully
employed in these reactions. Morever, heteroarylstannanes, such as furyl, thienyl,
and N-methylpyrrolyl, which are often prone to decomposition, were efficiently
coupled under these conditions. Ortho-substitution on the stannane coupling
partner was well tolerated; however, the presence of ortho substituents on the aryl
sulfonates greatly reduced the efficiency of these reactions.
INTRODUCTION
The Stille cross-coupling reaction is a versatile method for the formation of carbon–carbon bonds and the
construction of molecules containing sp2-sp2 bonds.1 Since its introduction by Migita2 and its subsequent
exploration by Stille,3 it has evolved into one of the most robust of the palladium-catalyzed
cross-coupling reactions and has found applications in drug discovery,4 natural products synthesis,5 and
materials chemistry.6 The toxicity of organostannanes,7 and the difficulty in the removal of the tin
byproducts have lead to an increase in the popularity of other C–C cross-coupling methods, specifically
the Suzuki-Miyaura reaction,8 but for difficult cases and late stage synthetic transformations the Stille
reaction is still widely employed due to its reliable nature.
A great deal of effort in the field of Pd-catalyzed cross-coupling has been devoted to the development of
catalysts that allow for less reactive and more stable aryl halides or pseudohalides to be employed in these
reactions. Early methods utilized activated electrophilic coupling partners, such as aryl iodides,
electron-deficient aryl bromides, and in the case of the Stille reaction, acid chlorides.3 The advent of more
‡ This paper is dedicated to Prof. Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
active catalysts, based on electron-rich phosphine ligands, has allowed for reactions of unactivated aryl
bromides, aryl chlorides, and aryl sulfonates to be carried out efficiently.9 Aryl triflates were initially the
most successfully employed aryl sulfonates for cross-coupling reactions.10 However, due to the fact that
aryl tosylates and mesylates are less expensive and more stable than the corresponding aryl triflates,
recent research has focused on utilizing these substrates in many cross-coupling reactions.11 Specifically,
aryl tosylates have been shown to be effective coupling partners in Suzuki-Miyaura, Kumada-Corriu, and
C-N cross-coupling reactions;12 aryl mesylates have been efficiently employed in Hiyama,
Suzuki-Miyaura, and C–N cross-coupling reactions, as well as Pd-catalyzed carbonylation reactions.13
Further, vinyl tosylates have also been utilized in Stille cross-coupling reactions;14 however, to date no
examples of the Stille cross-coupling reactions of aryl tosylates and mesylates have been reported.
Herein, we report a catalyst, based on 1 (XPhos), for the Pd-catalyzed Stille cross-coupling reactions of
aryl mesylates and tosylates.
RESULTS AND DISCUSSION
We began our studies by investigating the reaction of 3-methoxyphenyl methanesulfonate and
tri-n-butyl(phenyl)stannane. Attempts to use reaction conditions previously reported by our group for
the Stille reaction of aryl chlorides,15 employing Pd(OAc)2 and 1 in either 1,4-dioxane or DME as solvent
provided very low yields (Table 1, entries 1 and 2). An examination of the use of non-ethereal solvents
showed that a polar aprotic solvent, DMF, gave no desired product; while alcoholic solvents proved to be
the best, with t-BuOH giving the highest yield (Table 1, entries 3-5).
OMe
PCy2
MeO
PCy2
H2N
Cl
PCy2
PCy2
i-Pr
i-Pr
i-Pr
i-Pr
Pd
MeO
OMe i-PrO
Oi-Pr
XPhos
i-Pr
XPhos - 1
i-Pr
BrettPhos - 2
5
RuPhos - 4
SPhos - 3
Figure 1: Biaryl-monophosphine Ligands
We next explored other biarylphosphine ligands and Pd sources in this reaction. Catalysts based on 2
(BrettPhos), which has been shown to form an efficient catalyst for the C–N cross-coupling of aryl
mesylates, and 3 (SPhos) provided yields of 60% and 52% respectively (table 1, entries 6 and 7). Using
a catalyst comprised of Pd(OAc)2 and 4 (RuPhos) increased the yield of the reaction to 76% (Table 1,
entry 8); however, 1 formed the most efficient catalyst system and furnished the desired product in 93%
yield (Table 1, entry 3). While other Pd sources, such as allylpalladium chloride dimer and 5, a single
component precatalyst developed in our group,16 gave results similar to palladium acetate for this reaction,

HETEROCYCLES, Vol. 80, No. 2, 2010
1217
we chose to continue our studies with the latter because of its low cost and stability (Table 1, entries 8
and 9). Pd2dba3 was also examined, and its use only produced a 22% yield of the desired product (Table 1,
entry 10). Finally, we wanted to explore the effect of increasing the L:Pd ratio on the efficiency of the
reaction. Entries 12-14 show these results. While the yields of the three ratios of L:Pd examined were
similar, we found that a 2:1 ratio was optimal (Table 1, entries 11-13).
Table 1: Palladium-catalyzed Stille couplings of 3-methoxyphenyl methanesulfonate
Pd, Ligand
CsF
MeO
OMs
MeO
+
Solvent
110 °C, 14 h
Bu3Sn
Yieldb
Entry
Ligand
L:Pd
Solvent
Pd Source
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(AllylPdCl)2
Pd2dba3
5
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
4
1,4-dioxane
DME
1
1
1
1
1
2
3
4
1
1
1
1
1
1
0
3
93
48
0
t-BuOH
n-BuOH
DMF
4
5
6
60
52
76
88
22
86
83
96
95
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
7
8
9
10
11
12
13
14
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1.1:1
2:1
3:1
(a) Reaction Conditions: 0.5 mmol of Ar-OMs, 0.6 mmol of Ar-SnBu3, 1.1 mmol
of CsF, 1.0 mL of t-BuOH, 2.0 mol% of [Pd], DME = dimethoxyethane, DMF =
dimethylformamide.
(b) GC Yield.
With these conditions in hand, we wanted to explore the scope of the Stille cross-coupling reaction of aryl
sulfonates using Pd(OAc)2 and XPhos. The results are summarized in Table 2. We found that a variety of
aryl and heteroaryl mesylates and tosylates could be coupled in moderate to good yields with aryl
stannanes. These results represent the first reported Stille couplings of these sulfonates. Unactivated aryl
mesylates and tosylates were coupled in good yields (Table 2, entries 1-4). Slightly activated aryl
mesylates, such as 3-methoxyphenyl mesylate and 4-fluorophenyl mesylate were also suitable coupling
partners (Table 2, entries 5-6). Heteroaryl containing mesylates (Table 2, entries 7-8), which have been
difficult substrates in other cross-coupling reactions, and a heteroaryl tosylate (Table 2, entry 9) were
successfully combined with arylstannanes in good to moderate yields.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Table 2: Stille couplings of aryl sulfonates with XPhos
Pd(OAc)2
OSO2R'
R''
XPhos
R''
+
R
R
Bu3Sn
CsF, t-BuOH
110 °C, 14 h
Yieldb
Entry
Product
Sulfonate
Stannane
MeO
MeO
OMs
1
78
Bu3Sn
t-Bu
OMe
N
t-Bu
OMe
Me
OMs
Me
N
63d
2
3
Bu3Sn
F3C
OMs
OTs
64
Bu3Sn
CF3
CF3
F3C
4
58c
t-Bu
Bu3Sn
t-Bu
MeO
OMs
MeO
78
51
78
5
6
7
Bu3Sn
Me
Me
Me
Me
OMs
Bu3Sn
F
Me
Me
F
OMs
O
O
Bu3Sn
Bu3Sn
Me
N
Me
N
O
OMs
O
58
N
N
8
9
OTs
60c
64
N
Bu3Sn
Bu3Sn
N
S
OMs
OTs
10
11
S
N
NC
F3C
F3C
84
Bu3Sn
Bu3Sn
H
N
H
N
Me
OMs
61c
Me
12
O
O
(a) Reaction Conditions: 1.0 mmol of Ar-OMs, 1.2 mmol of Ar-SnBu3, 2.2 mmol of CsF, 2.0 mol% of
Pd(OAc)2, 4.0 mol% of XPhos, 2.0 mL of t-BuOH.
(b) Isolated yields (average of two runs).
(c) 2.0 mol% of pre-milled Pd(OAc)2:XPhos (1:2)
(d) 4.0 mol% of Pd(OAc)2, 8.0 mol% of XPhos
For example, the reaction of 2-methylquinolin-6-yl methanesulfonate and tri-n-butyl(furan-2-yl)stannane
provided the desired product in 78% yield. Finally, reactions were carried out with aryl sulfonates
containing functional groups. Electron-withdrawing groups such as nitriles and trifluoromethyl groups
were tolerated in this reaction (Table 2, entries 10-11), as well as an acetamide that contained a free
N-H(Table 2, entry 12).

HETEROCYCLES, Vol. 80, No. 2, 2010
1219
A range of tri-n-butylarylstannanes were also explored and found to work well in these coupling reactions.
The simplest arylstannane, tri-n-butyl(phenyl)stannane, was combined with weakly activated mesylates
(Table 2, entry 5), functional group containing mesylates (Table 2, entries 11-12) and heteroaryl tosylates
(Table 2, entry 9) with high efficiency. Arylstannanes containing ortho substitution, such as
tri-n-butyl(2,6-dimethoxyphenyl)stannane (Table 2, entry 1), tri-n-butyl(2-(trifluoromethyl)-
phenyl)stannane (Table 2, entries 3-4), and tri-n-butyl(mesityl)-stannane (Table 2, entry 6) were
effectively reacted with unactivated mesylates and tosylates. Additionally, heteroarylstannanes such as
2-furyl-, 2-thienyl-, and 2-(N-methylpyrrolyl)tri-n-butylstannane were shown to be proficient substrates in
these reactions. (Table 2, entries 2, 7, 8 and 10).
While we have revealed that this method tolerates a range of substrates, we also discovered some
limitations in its scope. As described above, steric hindrance was well tolerated on the arylstannane, as
shown by the reactions of tin reagents containing an o-CF3 group, two o-OMe groups, and even two o-Me
groups. However, attempts to utilize ortho-substituted aryl sulfonate resulted in greatly reduced reaction
rates.17 In addition, there were certain classes of heterocycles that were not tolerated under these reaction
conditions. While 3-pyridyltosylate was successfully coupled, the analogous mesylate, along with
2-pyridylmesylate provided no product; in both cases only the products of hydrolysis (3-hydroxypyridine
and 2-pyridone, respectively) were observed. Similarly, use of several heteroarylstannanes provided no
coupling product and only decomposition of the mesylate coupling partners to their parent phenols were
observed. These stannanes included the 2-thiazole, 2-oxazole, 2-pyrazinyl and 2-pyridyl derivatives.
In conclusion, a catalyst system comprised of XPhos and Pd(OAc)2 used with CsF in t-BuOH was
developed for the Stille cross-coupling of aryl mesylates and aryl tosylates with aryl- and heteroaryl-
stannanes. A total of 11 examples were reported including unactivated aryl mesylates and aryl tosylates,
functional group containing aryl mesylates and both heteroaryl mesylates and heteroaryl tosylates. The
biaryl products were obtained in yields that ranged from 51-84%, and represent the first biaryl
compounds made by Stille cross-coupling of aryl mesylates and tosylates.
EXPERIMENTAL
General Reagent Information
All reactions were carried out under an argon atmosphere. The tert-butanol, 1,4-dioxane, DME, and DMF
were purchased from Aldrich Chemical Company in Sure-Seal bottles and were used as received. Toluene
was purchased from J.T. Baker in CYCLE-TAINER® solvent-delivery kegs and vigorously purged with
argon for 2 h. The solvent was further purified by passing it under argon pressure through two packed
columns of neutral alumina and copper (II) oxide. Aryl mesylates, tosylates, and benzenesulfonates were
synthesized using literature procedures. Aryl tin reagents were purchased from Aldrich Chemical

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HETEROCYCLES, Vol. 80, No. 2, 2010
Company, Alfa Aesar, and Gelest and were used as received. 2,14 4,18 and 517 were synthesized using
literature procedures. Ligands 119 and 320 were purchased from Strem Chemicals and the CsF, Pd2(dba)3,
PdCl2(CH3CN)2, and [(allyl)PdCl]2 were purchased from Aldrich Chemical Company. Pd(OAc)2 was
received as a gift from BASF. Flash chromatography was performed using a Biotage SP4 instrument with
prepacked silica cartridges.
General Analytical Information
All compounds were characterized by 1H NMR, 13C NMR, and IR spectroscopy. Copies of the 1H and 13C
spectra can be found in the Supporting Information. Nuclear Magnetic Resonance spectra were recorded
on a Varian 300 MHz instrument or a Bruker 400 MHz instrument. All 1H NMR experiments are reported
in ꢀ units, parts per million (ppm), and were measured relative to the signals for residual chloroform
13
(7.26 ppm) in the deuterated solvent, unless otherwise stated. All C NMR spectra are reported in ppm
1
relative to deuterochloroform (77.23 ppm), unless otherwise stated, and all were obtained with H
decoupling. All IR spectra were taken on a Perkin – Elmer 2000 FTIR. All GC analyses were performed
on a Agilent 6890 gas chromatograph with an FID detector using a J & W DB-1 column (10 m, 0.1 mm
I.D.).
General Procedure for Table 1
An oven-dried test tube, which was equipped with a magnetic stir bar and fitted with a Teflon screw-cap
septum, was charged with the Pd source (2 mol% Pd), ligand (4 mol%), and CsF(1.1 mmol). The vessel
was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then the
3-methoxyphenyl methanesulfonate (101 mg, 0.5 mmol), tri-n-butyl(phenyl)stannane (221 mg, 0.6 mmol),
and t-BuOH (1 mL) were added via syringe. The solution was heated to 110 °C for 14 h and then the
reaction mixture was cooled to room temperature and filtered through a plug of silica (eluting with
EtOAc). Biphenyl was then added as an internal standard and the reaction was analyzed by GC.
General Procedure for Table 2
An oven-dried test tube, which was equipped with a magnetic stir bar and fitted with a Teflon screw-cap
septum, was charged with the Pd(OAc)2 (2 mol%), 1 (4 mol%), and CsF (2.2 mmol). The vessel was
evacuated and backfilled with argon (this process was repeated a total of 3 times) and then the aryl
sulfonate (1.0 mmol), stannane (1.2 mmol), and t-BuOH (2 mL) were added via syringe (aryl mesylates,
tosylates, or benzenesulfonates that were solids at room temperature were added with the catalyst and
base). The solution was heated to 110 °C for 44 h and then the reaction mixture was cooled to room
temperature, filtered through a plug of silica (eluting with EtOAc), concentrated in vacuo, and purified

HETEROCYCLES, Vol. 80, No. 2, 2010
1221
via the Biotage SP4 (silica-packed 50 or 100 g snap cartridge).
4'-tert-Butyl-2,6-dimethoxybiphenyl21 (Table 2, entry 1) Following the general procedure, a mixture of
4-tert-butylphenyl methanesulfonate (228 mg, 1.0 mmol), tri-n-butyl(2,6-dimethoxyphenyl)stannane (514
mg, 1.2 mmol), Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH
(2 mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed
50 g snap column; 0-5% EtOAc/hexanes) to provide the title compound as a white solid (211 mg, 87%),
mp = 129 – 130 °C. 1H NMR (300 MHz, CDCl3) ꢀ: 7.43 (d, J = 8.7 Hz, 2H), 7.32 – 7.22 (m, 3H), 6.46
13
(d, J = 8.4 Hz, 2H), 3.75 (s, 6H), 1.37 (s, 9H) ppm. C NMR (75 MHz, CDCl3) ꢀ: 157.9, 149.3, 131.0,
130.6, 128.6, 124.8, 119.5 ppm. IR (neat, cm-1): 2961, 1587, 1471, 1430, 1384, 1245, 1109, 825, 723,
563.
2-(Biphenyl-4-yl)-1-methyl-1H-pyrrole (Table 2, entry 2) Following the general procedure, a mixture of
biphenyl-4-yl methanesulfonate (248 mg, 1.0 mmol), 1-methyl-2-(tri-n-butylstannyl)-1H-pyrrole (445 mg,
1.2 mmol), Pd(OAc)2 (8.8 mg, 4.0 mol%), 1 (38 mg, 8 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2
mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50
g snap column; 0-40% EtOAc/hexanes) to provide the title compound as a white solid (151 mg, 65%), mp
1
= 125 – 127 °C. H NMR (300 MHz, CDCl3) ꢀ: 7.64 (m, 4H), 7.49 (m, 4H), 7.39 (m, 1H), 6.76 (t, J
13
=2.4 Hz, 1H), 6.30 (m, 1H), 6.25 (t, J = 2.4 Hz, 1H), 3.73 (s, 3H) ppm. C NMR (75 MHz, CDCl3) ꢀ:
140.9, 139.6, 134.4, 132.5, 129.1, 129.0, 127.5, 127.3, 127.2, 124.1, 109.0, 108.1, 35.4 ppm. IR (neat,
cm-1): 2953, 1478, 1446, 1408, 1309, 1061, 846, 765, 713, 695.
6-(2-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydronaphthalene (Table 2, entry 3) Following the general
procedure, a mixture of 5,6,7,8-tetrahydronaphthalen-2-yl methanesulfonate (237 mg, 1.0 mmol),
tri-n-butyl(2-(trifluoromethyl)phenyl)stannane (522 mg, 1.2 mmol), Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19
mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL) was heated to 110 °C for 14 h. The crude
product was purified via the Biotage SP4 (silica-packed 50 g snap column; 0-10% EtOAc/hexanes) to
provide the title compound as a yellow oil (152 mg, 55%). 1H NMR (300 MHz, CDCl3) ꢀ: 7.78 (d, J =
7.8 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 6.9 Hz, 1H), 7.14 (m, 2H), 7.09
(s, 1H), 2.86 (m, 4H), 1.89 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) ꢀ: 141.9, 141.8, 137.2, 136.7, 136.7,
132.4, 131.4, 131.4, 129.8, 129.8, 129.8, 129.8, 129.3, 128,8, 128.6, 128.4, 127.2, 126.3, 126.2, 126.1,
126.1, 125.6, 122.6, 29.6, 29.4, 23.6, 23.4 ppm. IR (neat, cm-1): 2931, 1604, 1486, 1449, 1315, 1168,
1127, 1036, 768, 650.

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HETEROCYCLES, Vol. 80, No. 2, 2010
4’-tert-Butyl-2-(trifluoromethyl)biphenyl22 (Table 2, entry 4) Following the general procedure, a
mixture of 4-tert-butylphenyl 4-tolylsulfonate (304 mg, 1.0 mmol), tri-n-butyl(2-(trifluoromethyl)-
phenyl)stannane (522 mg, 1.2 mmol), Pd(OAc)2 (2.0 mol%) and 1 (4 mol%) as a pre-milled mixture (23.6
mg), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL) was heated to 110 °C for 14 h. The crude product was
purified via the Biotage SP4 (silica-packed 50 g snap column; hexanes) to provide the title compound as a
colorless oil (170 mg, 61%). 1H NMR (400 MHz, CDCl3) ꢀ: 7.75 (d, J =7.5 Hz, 1H), 7.54 (t, J =7.5 Hz,
13
1H), 7.44 (m, 3H), 7.34 (d, J =7.5 Hz, 1H), 7.28 (d, J =7.5 Hz, 2H), 1.38 (s, 9H) ppm. C NMR (100
MHz, CDCl3) ꢀ: 150.7, 141.7, 141.7, 137.1, 132.4, 131.5, 129.1, 128.8, 128.8, 128.5, 128.2, 127.3, 126.3,
126.3, 126.2, 126.2, 125.8, 124.9, 123.1, 34.8, 31.6 ppm. IR (neat, cm-1): 2965, 2869, 1606, 1488, 1315,
1171, 1131, 1069, 1036, 768.
3-Methoxybiphenyl23 (Table 2, entry 5) Following the general procedure, a mixture of 3-methoxyphenyl
methanesulfonate (202 mg, 1.0 mmol), tri-n-butyl(phenyl)stannane (440 mg, 1.2 mmol), Pd(OAc)2 (4.4
mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL) was heated to 110 °C
for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap column; 0-10%
1
EtOAc/hexanes) to provide the title compound as a yellow oil (145 mg, 79%). H NMR (300 MHz,
CDCl3) ꢀ: 7.60 (d, J = 6.9 Hz, 2H), 7.45 (t, J = 7.2 Hz, 2H), 7.37 (m, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.14
(m, 1H), 6.91 (m, 1H), 3.89 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) ꢀ: 160.1, 143.0, 141.3, 130.0, 128.9,
127.6, 127.4, 119.9, 113.1, 112.8, 55.5 ppm. IR (neat, cm-1): 2937, 1599, 1573, 1479, 1421, 1296, 1213,
1020, 757, 697.
4'-Fluoro-2,4,6-trimethylbiphenyl24 (Table 2, entry 6) Following the general procedure, a mixture of
4-fluorophenyl methanesulfonate (190 mg, 1.0 mmol), tri-n-butyl(mesityl)-stannane (491 mg, 1.2 mmol),
Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL) was
heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap
column; 0-5% EtOAc/hexanes) to provide the title compound as a white solid (116 mg, 54%), mp = 65 –
67 °C (literature 64 – 65 °C). 1H NMR (300 MHz, CDCl3) ꢀ: 7.14 (s, 2H), 7.11 (s, 2H), 6.97 (s, 2H) ppm.
13C NMR (75 MHz, CDCl3) ꢀ: 163.5, 160.3, 138.2, 137.0, 137.0, 136.4, 131.1, 130.9, 128.3, 115.7, 115.4,
109.9, 21.2, 21.0 ppm. IR (neat, cm-1): 2921, 1601, 1511, 1478, 1217, 1151, 1087, 1008, 854, 815.
6-(Furan-2-yl)-2-methylquinoline (Table 2, entry 7) Following the general procedure, a mixture of
2-methylquinolin-6-yl methanesulfonate (237 mg, 1.0 mmol), tri-n-butyl(furan-2-yl)stannane (430 mg,
1.2 mmol), Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2
mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50

HETEROCYCLES, Vol. 80, No. 2, 2010
1223
g snap column; 0-40% EtOAc/hexanes) to provide the title compound as a white solid (175 mg, 84%), mp
= 57 – 59 °C. 1H NMR (300 MHz, CDCl3) ꢀ: 7.97 (m, 4H), 7.48 (s, 1H), 7.19 (d, J =8.4 Hz, 1H), 6.71
(d, J = 3.3 Hz, 1H), 6.47 (m, 1H), 2.69 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) ꢀ: 158.9, 153.5, 147.3,
142.6, 136.3, 129.1, 128.1, 126.7, 125.9, 122.6, 121.5, 112.0, 106.1 ppm. IR (neat, cm-1): 1640, 1385,
1125, 1385, 1125, 885, 816, 744, 596, 456.
1-(4-(Furan-2-yl)phenyl)-1H-pyrrole (Table 2, entry 8) Following the general procedure, a mixture of
4-(1H-pyrrol-1-yl)phenyl methanesulfonate (237 mg, 1.0 mmol), tri-n-butyl(furan-2-yl)stannane (430 mg,
1.2 mmol), Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2
mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50
g snap column; 0-40% EtOAc/hexanes) to provide the title compound as a white solid (123 mg, 59%), mp
= 189 – 191 °C. 1H NMR (300 MHz, CDCl3) ꢀ: 7.72 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.41
(d, J = 9.0 Hz, 2H), 7.12 (t, J = 2.4 Hz, 2H), 6.65 (d, J = 3.3 Hz, 1H), 6.49 (m, 1H), 6.37 (t, J = 2.4 Hz,
13
2H) ppm. C NMR (75 MHz, CDCl3) ꢀ: 153.4, 142.3, 139.8, 128.5, 125.1, 120.7, 119.3, 112.0, 110.8,
105.1 ppm. IR (neat, cm-1): 2360, 1523, 1329, 1250, 1007, 831, 718, 594.
3-Phenylpyridine25 (Table 2, entry 9) Following the general procedure, a mixture of pyridin-3-yl
4-methylbenzenesulfonate (249 mg, 1.0 mmol), tri-n-butyl(phenyl)stannane (440 mg, 1.2 mmol),
Pd(OAc)2 (2.0 mol%) and 1 (4 mol%) as a pre-milled mixture (23.6 mg), CsF (334 mg, 2.2 mmol), and
t-BuOH (2 mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4
(silica-packed 25 g snap column; 20% EtOAc/hexanes) to provide the title compound as a pale yellow oil
(85 mg, 55%). 1H NMR (400 MHz, CDCl3) ꢀ: 8.82 (s, 1H), 8.55 (d, J =5.0 Hz, 1H), 7.82 (d, J =7.5 Hz,
1H), 7.54 (d, J =7.5 Hz, 2H), 7.44 (t, J =7.5 Hz, 2H), 7.37 (m, 1H), 7.31 (dd, J = 7.5, 5.0 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3) ꢀ: 148.7, 148.5, 138.0, 136.8, 134.6, 129.3, 128.3, 127.3, 123.8 ppm. IR
(neat, cm-1): 3400, 3031, 1581, 1473, 1450, 1407, 1006, 754, 711, 698.
4-(Thien-2-yl)benzonitrile26 (Table 2, entry 10) Following the general procedure, a mixture of
4-cyanophenyl methanesulfonate (197 mg, 1.0 mmol), tri-n-butyl(thiophen-2-yl)stannane (448 mg, 1.2
mmol), Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL)
was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g
snap column; 0-40% EtOAc/hexanes) to provide the title compound as a white solid (120 mg, 65%), mp
1
= 90 – 92 °C (literature 91 – 92 °C). H NMR (300 MHz, CDCl3) ꢀ: 7.68 (m, 4H), 7.41 (m, 2H), 7.13
13
(m, 1H) ppm. C NMR (75 MHz, CDCl3) ꢀ: 142.1, 138.7, 132.8, 128.7, 119.0, 110.6 ppm. IR (neat,
cm-1): 2218, 1600, 1424, 852, 821, 718, 551.

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HETEROCYCLES, Vol. 80, No. 2, 2010
3-(Trifluoromethyl)biphenyl24 (Table 2, entry 11) Following the general procedure, a mixture of
3-trifluoromethylphenyl tosylate (300 mg, 1.0 mmol), tri-n-butyl(phenyl)stannane (442 mg, 1.2 mmol),
Pd(OAc)2 (4.4 mg, 2.0 mol%), 1 (19 mg, 4 mol%), CsF (334 mg, 2.2 mmol), and t-BuOH (2 mL) was
heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4 (silica-packed 50 g snap
column; 0-3% EtOAc/hexanes) to provide the title compound as a clear oil (194 mg, 86%). 1H NMR (300
13
MHz, CDCl3) ꢀ: 7.93 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.70 – 7.47 (m, 7H) ppm. C NMR (75 MHz,
CDCl3) ꢀ: 142.3, 140.0, 131.6, 131.2, 130.7, 130.7, 129.5, 129.3, 128.3, 127.5, 126.3, 124.3, 124.2, 124.2,
124.1, 124.1, 122.7 ppm. IR (neat, cm-1): 3037, 1425, 1335, 1262, 1167, 1097, 1047, 899, 759, 702.
N-(Biphenyl-3-yl)acetamide27 (Table 2, entry 12) Following the general procedure, a mixture of
3-acetamidophenyl methanesulfonate (229 mg, 1.0 mmol), tri-n-butyl(phenyl)stannane (440 mg, 1.2
mmol), Pd(OAc)2 (2.0 mol%) and 1 (4 mol%) as a pre-milled mixture (23.6 mg), CsF (334 mg, 2.2 mmol),
and t-BuOH (2 mL) was heated to 110 °C for 14 h. The crude product was purified via the Biotage SP4
(silica-packed 50 g snap column; 20-60% EtOAc/hexanes) to provide the title compound as a white solid
1
(120 mg, 57%), mp = 143 - 145 °C (literature 146 °C). H NMR (400 MHz, CDCl3) ꢀ: 7.98 (s, 1H),
7.73 (s, 1H), 7.50 (m, 3H), 7.37 (t, J =7.2 Hz, 2H), 7.30 (m, 3H), 2.14 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) ꢀ: 169.1, 142.2, 140.9, 138.6, 129.5, 129.0, 127.7, 127.3, 123.3, 119.1, 119.0, 24.7 ppm. IR (neat,
cm-1): 3294, 1665, 1555, 1480, 1402, 1317, 1013, 891, 759, 700.
ACKNOWLEDGEMENTS
We thank the National Institutes of Health (GM-46059) for financial support of this project. We thank
Merck, Boehringer Ingelheim, BASF (Pd(OAc)2), and Nippon Chemical for additional support. BPF
thanks Merck for a fellowship.
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