Synthesis of 1,5-disubstituted tetrazoles via Suzuki-Miyaura cross-coupling of 5-chloro-1-phenyltetrazole

Article abstract of DOI:10.1016/j.tetlet.2010.04.091

Suzuki-Miyaura coupling reactions of 5-chloro-1-phenyl-tetrazole with various functionalized arylboronic acids were investigated. In the presence of catalytic amounts of SPhos/Pd(OAc)₂ or RuPhos/Pd(OAc)₂, the reaction proceeded smoot

Full text of DOI:10.1016/j.tetlet.2010.04.091

Tetrahedron Letters 51 (2010) 3473–3476
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Tetrahedron Letters
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Synthesis of 1,5-disubstituted tetrazoles via Suzuki–Miyaura cross-coupling
of 5-chloro-1-phenyltetrazole
b
Qing Tang a, , Ryan Gianatassio
*
a Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA
b University of Massachusetts at Boston, 100 Morrissey Blvd., Boston, MA 02135, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Suzuki–Miyaura coupling reactions of 5-chloro-1-phenyl-tetrazole with various functionalized aryl-
boronic acids were investigated. In the presence of catalytic amounts of SPhos/Pd(OAc)2 or RuPhos/
Pd(OAc)2, the reaction proceeded smoothly to afford 1,5-diaryltetrazoles in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 April 2010
Revised 21 April 2010
Accepted 21 April 2010
Available online 28 April 2010
Keywords:
Suzuki–Miyaura reaction
5-Chloro-1-phenyl-chlorotetrazole
Arylboronic acids
The Suzuki–Miyaura cross-coupling reaction is a powerful
method for carbon–carbon bond formation in organic synthesis1
and has been widely used to synthesize biologically active mole-
cules because of the commercial availability, functional group
compatibility, and low toxicity of boronic acids, as well as the facile
removal of the side products.
Reaction conditions were screened using common Pd catalysts
(5 mol %), with or without a variety of ligands (10 mol %, Fig. 1).
Results are summarized in Table 1. The commonly used catalysts
Pd(PPh3)4 and PdCl2(dppf) proved ineffective in the coupling of
our unactivated chlorotetrazole. The catalyst Pd[P(tBu)3]2, which
had been successfully used for the room temperature cross-cou-
pling reaction of aryl chlorides,6 was effective in catalyzing the
cross-coupling of 5-chloro-1-phenyl-tetrazole, which proceeded
at room temperature to afford the desired product in 40% yield
(Table 1, entry 3). Increasing the reaction temperature did not
While tremendous progress has been made in the development
of catalytic systems for coupling aryl chlorides and hindered aryl-
boronic acids,2 the cross-coupling reaction of heteroaryl halides,
particularly five- or six-membered heteroaryl chlorides, remains
problematic.3 The Suzuki–Miyaura cross-coupling of chlorotetraz-
oles is particularly difficult; despite the utility of 1,5-disubstituted
tetrazoles as anti-inflammatory and anti-hypertensive agents,4
their synthesis via the Suzuki–Miyaura cross-coupling of 5-chloro-
tetrazole is exceedingly rare.5 Furthermore, 1-aryl-5-chlorotetraz-
oles are poorer coupling partners, because of their electron-rich
nature as well as their potential to bind Pd catalysts. Therefore,
our goal was to identify robust Suzuki–Miyaura reaction conditions
to couple 5-chloro-1-phenyl-tetrazoles with a variety of boronic
acids and esters. These reaction conditions may then have the
potential to be expanded to Suzuki–Miyaura cross-coupling of other
heteroaryl chlorides.
7
improve the reaction yield. The catalysts PdCl2[PtBu2(PhNMe2)]2
and
Pd(OAc)2/BuPAd2
(di-(1-adamantyl)-n-butylphosphine)8
afforded poor yields of desired product. We also examined the
N-heterocyclic carbene, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene (IMes), as ligand9 in combination with Pd2dba3, but this
proved to be an ineffective catalytic system for our substrate (Table
1, entry 6). Pentaphenylferrocenyl di-t-butylphosphine (QPhos)10
was similarly disappointing, yielding only complex reaction mix-
tures under similar conditions. However, the use of Pd(OAc)2 with
2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl (XPhos) or
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl (SPhos)11 was
promising (Table 1, entries 9 and 10), affording 47 and 55%, respec-
tively, the desired product. The encouraging results obtained with
SPhos and XPhos were partially attributed to these ligands’ in-
creased steric bulk and, in the case of SPhos, the presence of two
methoxy groups with potential to interact with palladium.5a In-
deed, Martin and Buchwald reported that the use of electron-rich
and bulky phosphine ligands enhanced the rate of the oxidative
addition and reductive elimination processes in Suzuki catalytic
Our study began with the optimization of reaction conditions
for the cross-coupling of 5-chloro-1-phenyl-tetrazole with 2-meth-
oxyphenylboronic acid (Scheme 1).
* Corresponding author. Tel.: +1 617 444 6738; fax: +1 617 444 7823.
E-mail address: qing_tang@vrtx.com (Q. Tang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.091

3474
Q. Tang, R. Gianatassio / Tetrahedron Letters 51 (2010) 3473–3476
OMe
N N
N N
HO
OH
Pd(OAc)2, L, base
N
B
N
Cl
N
N
+
OMe
solvent
MW, 30 min, 150oC
Scheme 1.
PCy2
P(tBu)2
Ph
Fe
PCy2
OMe
PCy2
Ph
Ph
iPr
iPr
MeO
O
O
Ph
Ph
iPr
XPhos
Q-Phos
SPhos
RuPhos
Cl
tBu
tBu
P
Me2N
P Pd P
NMe2
N
N
tBu
tBu
Cl
Cl
PdCl2[PtBu2(Ph-NMe2)]2
IMes
BuPAd2
Figure 1. Ligands or Pd catalyst used in the Suzuki reaction.
Table 1
superior ligand for our substrate. This hypothesis proved to be cor-
rect, and the use of RuPhos yielded increased isolated yields of de-
sired product, as shown in Table 1 (entries 11–13). We ultimately
settled on Pd(OAc)2 with RuPhos with either K3PO4 or CsCO3 in 3:1
n-butanol/water under microwave conditions as our preferred
method.12
Screening conditions for the coupling of 2-methoxyphenyl boronic acid with 1-
phenyl-5-chlorotetrazolea
OMe
N N
N N
HO
OH
N
B
Catalyst, ligand,
Base, solvent
N
Cl
N
N
OMe
Having established practical and good-yielding reaction condi-
tions, we investigated next the substrate scope of this method.
Table 2 shows the reaction of 5-chloro-1-phenyl-tetrazole with
various aryl- and heteroaryl-boronic acids and pinacol esters.
5-chloro-1-phenyl-tetrazole coupled to phenylboronic acids in
excellent yields under our optimized conditions (Table 2, entries
1–5). Slightly lower yields were achieved with electron-deficient
phenylboronic acids (entries 3–5). We also found that Pd(OAc)2
in combination with RuPhos, SPhos, or XPhos were all effective
catalyst systems for the coupling of heteroaryl-boronic acids with
5-chloro-1-phenyl-tetrazole. Thiopheneboronic acids were cou-
pled in excellent yields using Pd(OAc)2 with SPhos and RuPhos
(entries 6 and 7). Furan-2-boronic acid (entry 8) was coupled to
5-chloro-1-phenyl-tetrazole in moderate yield using SPhos. This
lower yield is presumably due to the slow oxidative addition of
the aryl chloride, as well as the instability of furan boronic acids.
Reaction of 1-methylpyrazole-4-boronic acid using XPhos also
afforded the desired biaryl compounds in moderate yield. Finally,
coupling of an alkenyl boronate also proceeded in respectable yield
(entry 10) using XPhos.
+
Entry
Catalyst/ligand
Base
Solvent
Yieldb (%)
1
Pd(PPh3)4
PdCl2(dppf)
Pd[P(tBu)3]2
PdCl2[PtBu2(Ph-NMe2)]2
Pd(OAc)2/BuPAd2
Pd2(dba)3/IMes
Pd(OAc)2/QPhos
Pd2(dba)3/PCy3
Pd(OAc)2/XPhos
Pd(OAc)2/SPhos
Pd(OAc)2/RuPhos
Pd(OAc)2/RuPhos
Pd(OAc)2/RuPhos
K3PO4
K3PO4
K3PO4
K3CO3
K3PO4
CsCO3
K2CO3
K3PO4
K3PO4
K3PO4
CsCO3
CsCO3
K3PO4
n-BuOH
n-BuOH
Trace
Trace
40
Trace
20
Trace
Trace
10
47
55
51
63
2
3c
4
Dioxane
Toluene/H2Od
n-BuOH
5
6
7
8
Dioxane
Dioxane
Dioxane/H2Od
n-BuOH/H2Od
n-BuOH/H2Od
Toluene/H2Od
n-BuOH/H2Od
n-BuOH/H2Od
9
10
11
12
13
71
a
Reaction conditions: ArCl (1 equiv), 2-methoxyphenylboronic acid (1.1 equiv),
Pd catalyst (5%), ligand (10%), solvents (2 mL), base (3 equiv), MW 30 min at 150 °C.
b
Isolated yield after silica gel chromatography.
Room temperature, 24 h.
3:1 ratio.
c
d
In summary, we have identified highly active catalytic systems
comprising Pd(OAc)2 and the dialkylbiphenylphosphino ligands
SPhos, XPhos, or RuPhos for the Suzuki–Miyaura cross-coupling
of 5-chloro-1-phenyl-tetrazoles with a variety of aryl- and hetero-
aryl-boronic acids.
cycle.2b Therefore, it seemed possible that the RuPhos ligand, with
its increased steric bulk and electron-rich character, would be a

Q. Tang, R. Gianatassio / Tetrahedron Letters 51 (2010) 3473–3476
3475
Table 2
Coupling of 1-phenyl-5-chlorotetrazole with various boronic acids and estersa
N
N
N
N
Pd(OAc)2, L, K3PO4
n-butanol/H2O (3:1)
N
Cl
N
Ar
N
N
+ ArB(OH)2
Entry
1
Ar-B(OH)2
Ligand
Products
Yield
B(OH)2
N
N
N
N
RuPhos
82c
N
N
B(OH)2
N
N
2
SPhos
93b
N
N
O
B
N
N
F
3
4
5
6
7
8
9
RuPhos
RuPhos
SPhos
63c
45b
68b
75b
71c
38b
O
F
N
N
O
B
N
N
NC
O
NC
O
B(OH)2
N
N
N
N
O
N
N
O
B
N
N
S
SPhos
O
S
B(OH)2
N
N
N
N
S
RuPhos
SPhos
S
N
N
O
N
N
B
O
O
O
N
N
O
N
N
N
N
B
XPhos
44b
O
N
N
(continued on next page)

3476
Q. Tang, R. Gianatassio / Tetrahedron Letters 51 (2010) 3473–3476
Table 2 (continued)
Entry
Ar-B(OH)2
Ligand
XPhos
Products
Yield
56
N
N
O
O
BocN
B
N
N
BocN
10
a
Reaction conditions: 1-phenyl-5-chlorotetrazole (1.0 equiv), boronic acid/ester (1.1 equiv), base (3 equiv), n-butanol/H2O (3:1) (2 mL/mmol of halide), 5% (Pd(OAc)2, 10%
ligand, 150 °C, 30 min. microwave.
b
K3PO4 was used.
Cs2CO3 was used.
c
7. (a) Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M.
Acknowledgments
J. J. Org. Chem. 2007, 72, 5104–5112; (b) Guram, A. S.; King, A. O.; Allen, J. G. Org.
Lett 2006, 8, 1787–1789.
The authors thank Jeremy Green and Anne-Laure Grillot for
valuable advice on preparation of this manuscript and Nigel Ewing
for help in generating HRMS data.
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References and notes
12. Experimental procedure:
A mixture of 1-phenyl-5-chlorotetrazole (180 mg,
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1 mmol), boronic acid (168 mg, 1.1 mmol), Pd(OAc)2 (11 mg, 0.05 mmol),
SPhos (41 mg, 0.1 mmol), and K3PO4 (636 mg, 3 mmol) in n-butanol (1.5 mL)
and water (0.5 mL) was purged with N2 for 10 min and was heated to 150 °C by
microwave for 10–30 minutes. The reaction mixture was diluted in EtOAc,
washed with H2O and brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The crude mixture was purified by flash
chromatography to afford the desired product. 1H NMR (500 MHz, CDCl3) 7.7
(dd, 1H), 7.55 (t, 1H), 7.49–7.50 (m, 3H), 7.32–7.43 (m, 2H), 7.15 (t, 1H), 6.88 (d,
1H). 13C NMR (500 MHz, CDCl3) 156.61, 152.11, 135.51, 133.14, 131.42, 129.91,
123.43, 123.11, 122.71, 121.13, 115.44, 113.32, 111.52, 54.84. FIA MS: m/z =
253.11 as [M+1] peak.
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