A convenient microwave-assisted arylstannane generation-Stille coupling protocol

Article abstract of DOI:10.1016/j.tetlet.2006.10.015

An efficient methodology for the synthesis of complex pyridin-3-yl-phenyl biaryl systems is described; microwave irradiation greatly enhances the rate of the two Pd-catalyzed key steps: formation of the stannane partner and its subsequent Stille coupling with a range of highly functionalized pyridines. Besides being fast and high yielding, this process also allows diversification of the pyridine at a late stage.

Full text of DOI:10.1016/j.tetlet.2006.10.015

Tetrahedron Letters 47 (2006) 8973–8976
A convenient microwave-assisted arylstannane
generation-Stille coupling protocol
*
´
´ ´
Veronique Dehlinger, Frederic Cordier, Colin P. Dell, Nicolas Dreyfus, Nikki Jenkins,
Adam J. Sanderson and Colin W. Smith
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Received 7 July 2006; revised 25 September 2006; accepted 4 October 2006
Available online 30 October 2006
Abstract—An efficient methodology for the synthesis of complex pyridin-3-yl-phenyl biaryl systems is described; microwave irradi-
ation greatly enhances the rate of the two Pd-catalyzed key steps: formation of the stannane partner and its subsequent Stille cou-
pling with a range of highly functionalized pyridines. Besides being fast and high yielding, this process also allows diversification of
the pyridine at a late stage.
Ó 2006 Elsevier Ltd. All rights reserved.
The biaryl motif is an important sub-unit found in many
areas of medicinal chemistry. Biologically relevant enti-
ties containing a pyridine-phenyl biaryl motif include
the 5HT-1A agonist Sarizotan and the HIV-1 protease
inhibitor Atazanavir (Fig. 1).1,2 Biaryls are also present
in a range of natural products, agrochemicals and
advanced materials.3
tions, including the Stille reaction in which organostann-
anes are used as reaction partners,5 can be significantly
accelerated by microwave irradiation.6
In the course of our studies on the design and synthesis
of novel ligands for b4 nicotinic acetylcholine receptors,
we became interested in pyridine-phenyl biaryls of type 3
(Scheme 1).7 In addition to a highly functionalized hete-
robiaryl system, 3 also contains a potentially labile thio-
ether moiety of defined stereochemistry. Therefore, we
required a robust but mild synthesis to accommodate
these sensitive functionalities. Additionally, we wanted
to be able to introduce R and R0 late in the synthesis
to allow convenient SAR exploration of this key region.
The transition-metal-catalyzed cross-coupling of orga-
nometallic reagents with halides or triflates represents
a powerful method for the synthesis of this privileged
scaffold.4 Moreover, a recent evidence suggests that
many of these transition-metal-catalyzed transforma-
N
Pd-catalyzed cross-couplings were appealing to us since
such reactions are known to tolerate sensitive function-
alities in one or both coupling partners.8 Although sev-
eral reports of Pd-catalyzed biaryl formation describe
microwave-assisted processes, these examples are most
frequently related to biphenyl systems and rarely for
heterobiaryls, being limited to simple unfunctionalized
systems.9 The same applies to the synthesis of hetero-
biaryls by Stille cross-coupling reaction with only the cou-
pling of unsubstituted pyridine or thiophene substrates
reported.10 Herein we report the microwave-assisted
synthesis of substituted pyridin-3-yl-phenyl biaryl
systems 3.
H
N
O
N
Sarizotan
F
O
OH
O
H
H
N
N
N
O
O
N
N
H
H
Atazanavir
O
O
Figure 1. Biologically active compounds containing a phenyl-pyridine
biaryl motif.
*
We initially envisaged forming the biaryl bond by classi-
cal Suzuki or Stille cross-coupling using conventional
Corresponding author. Tel.: +44 1276 483703; fax: +44 1276
483525; e-mail: dehlinger_veronique@lilly.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.015

8974
V. Dehlinger et al. / Tetrahedron Letters 47 (2006) 8973–8976
R
R
R'
N
Br
Br
Me3Sn
R'
N
N
N
Pd
Pd
N
μw
S
μw
S
S
Cl
Cl
1
2
3
Cl
Scheme 1.
ArB(OH)2
or
NEt3, MsCl
DCM, 0 oC to rt
TfO
Ar
N
N
N
N
ArSnR3
85%
MsO
S
HO
6
7
S
4 X=H
5 X=Cl
X
KSAc
X
THF, 80 o
C
52%
Scheme 2. Biaryl synthesis by classical Suzuki or Stille cross-coupling.
N
AcS
8
heating (Scheme 2). Attempts to couple triflate 4 to a
variety of substituted aryl and heteroaryl boronic acids,
including pyridines, under classical Suzuki conditions11
(NEt3, PdCl2(PPh3)2, DMF, 90 °C, 4 h) gave unsatisfac-
tory yields (0–15%). Slightly more promising results
were obtained for the coupling of 3-chloro-triflate 5
using the Stille conditions developed by Farina.12 The
coupling of 5 with 3-tributylstannylpyridine in the pres-
ence of Pd2(dba)3, Ph3As and LiCl in NMP at 100 °C for
2 h gave the desired biaryl in a 30% yield.
Br
NaOMe
9
DMF, 70 o
C
53%
F
Cl
Br
N
S
1
Cl
Scheme 3. Synthesis of bromo intermediate 1.
Although the Stille cross-coupling seemed a better
approach towards our biaryl targets, this synthetic route
implied that a diversification of the pyridine substituents
would require a synthesis of suitably substituted pyridyl
stannanes since only a limited number of them were
commercially available. We therefore envisaged synthe-
sizing the tropane-thioaryl stannane intermediate 2
(Scheme 1), which could then be coupled to a broad
range of commercially available bromopyridines. Bro-
mide 1 was synthetically more accessible than its triflate
analogue 5 and was therefore chosen as the stannane
precursor. Mesylate 7 could be prepared on a multigram
scale by standard manipulation of the commercially
available tropine 6 followed by displacement with potas-
sium thioacetate to give 8. Upon treatment with sodium
methoxide the thiolate was liberated and reacted in situ
with commercially available fluorobenzene 9 to produce
1 in an overall 23% yield (Scheme 3).
tion time from 20 h under conventional reflux to
3 min.15 Stannane 2 could be kept for days in the fridge
without any obvious degradation. To the best of our
knowledge, this is the first report on the microwave-
assisted synthesis of a trimethylstannane intermediate
from the corresponding bromide.
Intermediate 2 was then used in Stille cross-coupling
reactions with a variety of substituted 3-bromopyridines
using Pd(PPh3)4 and LiCl in a pressurized vessel under
microwave irradiation (Table 1).16
Table 1 demonstrates that these reaction conditions
provided satisfactory yields of biaryls and are tolerant
of a range of functionalities. In most cases, microwave
heating at 105 °C for 15 min was sufficient to achieve
complete consumption of starting stannane 2 although
the sterically hindered systems (Table 1, entries h and
i) required extended reaction times. Reaction progress
was monitored by LCMS and the reaction stopped when
complete consumption of 2 was achieved. Although
LCMS analysis indicated predominant formation of
biaryl product, several chromatographic methods were
necessary to obtain the purity required for biological
testing, thus leading to only moderate yields of isolated
products. As observed for the stannylation step, micro-
After heating bromide 1 in dry toluene in the presence of
hexamethylditin and Pd(PPh3)4 in a pressurized micro-
wave vessel for 3 min at 110 °C/200 W,13 stannane 2
was produced in a 79% yield after column chromatogra-
phy on silica (Scheme 4).14 These reaction conditions
had first been optimized on a model reaction, for which
microwave irradiation had led to a reduction of the reac-
Me3SnSnMe3 1 eq,
Br
Me3Sn
,
Pd(PPh3)4 5 mol%
Toluene
N
N
μw 110 oC / 200 W, 3 min
S
S
79%
1
2
Cl
Cl
Scheme 4. Microwave-assisted synthesis of stannane 2.

V. Dehlinger et al. / Tetrahedron Letters 47 (2006) 8973–8976
Table 1. Microwave-assisted Stille cross-coupling
8975
R
R
N
R' 1 eq
Br
Me3Sn
R'
N
LiCl 3 eq
Pd(PPh3)4 5 mol%
N
,
N
1,4-dioxane
S
μw, 105 oC / 200 W
S
3
2
Cl
Cl
Entry
R
R0
Product
Temperature (°C)
Time (min)
Yielda (%)
a
b
c
d
e
f
g
h
i
6-NO2
6-F
H
H
H
H
3a
3b
3c
3d
3e
3f
105
105
105
105
105
110
105
110
110
15
15
15
15
15
15
20
90
45
42
61
61
46
0
40
40
33
34
5-CO2Et
5-CONH2
6-NH2
6-NHAc
2-NHAc
6-NHAc
4-nBu
H
5-Me
5-Me
2-Me
H
3g
3h
3i
a Isolated yield after mass and/or UV guided preparative chromatography.
wave irradiation proved to greatly enhance the rate of
the Stille coupling. For the preparation of nitro com-
pound 3a we observed that 6 h were required to achieve
a complete consumption of stannane under thermal
conditions compared to only 15 min in the microwave
apparatus.
A similar microwave-assisted one-pot protocol was
recently reported for the Stille cross-coupling of benzylic
halides with chloro-pyrazones.20
In conclusion, we have developed a convenient two-step
protocol for the synthesis of a highly functionalized
pyridin-3-yl-phenyl system with microwave enhance-
ment of both the stannane generation step and the
subsequent Stille coupling step.
We found that it was essential to carry out the reactions
in a sealed vessel.17 When the synthesis of 3g was
attempted in an open vessel, no reaction was observed
after 20 min of microwave irradiation. A possible reason
for this is that in a pressurized vessel, under microwave
irradiation the reaction mixture is able to reach temper-
atures much above its conventional reflux temperature.6
The only functional group that was found to fail in the
coupling study was the amino group (Table 1, entry e),
which we attribute to poisoning of the catalyst. When
protected as the acetamide (Table 1, entries f–h), the
coupling was successful.
Acknowledgements
We thank Dr. Magnus Walter for helpful discussion and
encouragement during the preparation of this
manuscript.
References and notes
We are currently investigating the generation of the
stannane in situ followed by Stille coupling as a one-
pot process (Scheme 5). This was inspired by the meth-
odology developed by Hitchcock et al. consisting of a
tandem Pd-catalyzed cross-coupling reaction between
an aryl triflate and various aryl bromides.18 Initial stud-
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coupled under thermal conditions, in moderate yield,
thus proving the general feasibility of this approach.
We further observed a rate acceleration of this reaction
under microwave irradiation.19 Work is ongoing to
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V. Dehlinger et al. / Tetrahedron Letters 47 (2006) 8973–8976
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