Efficient, protection-free Suzuki-Miyaura synthesis of ortho- biphenyltetrazoles

Article abstract of DOI:10.1016/j.tetlet.2005.07.082

We describe an efficient protocol for the Suzuki-Miyaura synthesis of ortho-biphenyltetrazoles from non-protected 2-bromophenyltetrazole and arylboronic acids. The optimised conditions were achieved using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst and Na₂CO₃ as base. A panel of structurally diverse arylboronic acids was used to demonstrate the scope of the coupling procedure.

Full text of DOI:10.1016/j.tetlet.2005.07.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6529–6532
Efficient, protection-free Suzuki–Miyaura synthesis of
ortho-biphenyltetrazoles
Nicolas Cousaert,a Patrick Toto,a Nicolas Willanda,* and Benoˆıt Depreza
aLaboratoire de Chimie Generale et de Chimie Organique, UMR 8525, Faculte des Sciences Pharmaceutiques et Biologiques,
3 rue du Professeur Laguesse, F 59006 Lille Cedex, France
Received 14 April 2005; revised 12 July 2005; accepted 19 July 2005
Abstract—We describe an efficient protocol for the Suzuki–Miyaura synthesis of ortho-biphenyltetrazoles from non-protected 2-
bromophenyltetrazole and arylboronic acids. The optimised conditions were achieved using [1,10-bis(diphenylphosphino)ferro-
cene]dichloropalladium(II) as catalyst and Na2CO3 as base. A panel of structurally diverse arylboronic acids was used to demon-
strate the scope of the coupling procedure.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The palladium-catalysed Suzuki–Miyaura cross-cou-
pling reaction of aryl halides with arylboronic acids
and esters has become a common and convenient syn-
thetic method for the production of biaryl compounds.1
This method has been introduced with success for the
preparation of ortho-biphenyltetrazoles2 and applied
for the industrial-scale synthesis of a non-peptide angio-
tensin II receptor antagonist.3
All reported syntheses to date make use of a two steps
protection–deprotection sequence. The classical protect-
ing group employed for tetrazole is the trityl group.8 In
this paper, we describe an optimised Suzuki–Miyaura
cross-coupling of non-protected and commercial
2-bromophenyltetrazole with arylboronic acids.
The first part of the study aims at the optimisation of
reaction conditions for the Suzuki–Miyaura microwave
synthesis using the coupling reaction of 2-bromophenyl-
tetrazole (1a) and 3-methoxyphenylboronic acid (2a) as
a model.
In addition to their pivotal pharmacophoric role in the
binding to the angiotensin II receptors, biphenyltetraz-
oles provide unique pharmacokinetics properties.4
Biphenyltetrazoles have thus been introduced in the
design of non-peptidic ligands for GHS receptor.5
Three parameters have been investigated: (1) nature of
the palladium catalyst, (2) palladium catalyst concentra-
tion and (3) nature of the base.
More recently, this privileged structure has been used
for the design of biphenyltetrazole derivatives showing
competitive inhibition potency for the Carbapenem-
and Cephamycin-resistant dinuclear zinc metallo-b-lac-
tamase from Bacteroides fragilis.6
Firstly, based on known conditions, we examined differ-
ent catalysts (Pd(PPh3)2Cl2,9a Pd(PPh3)4,9b Pd(OAc)2,9c
Pd/C,9d PdCl2(dppf)9e) using Na2CO3 as base and a
mixture of DME/H2O as solvent, at 115 ꢁC. Microwave
irradiation conditions were used to speed up the synthe-
sis. The results are presented in Table 1.
Xu et al. have also published potent 3-biphenyltetrazole
containing inhibitors of DPP-IV, a novel therapeutic
approach to the treatment of type 2 diabetes.7
The highest conversion to 3a (83%) was observed in the
presence of 10% PdCl2(dppf) as catalyst together with
the lowest occurrence of the debrominated side product
4a (16%) (entry 5).
Keywords: ortho-Biphenyltetrazole; Suzuki–Miyaura cross-coupling;
Microwave synthesis.
*
Corresponding author. Tel.: +33 3209 64261; fax: +33 3209 64709;
e-mail: nwilland@pharma.univ-lille2.fr
Next, we examined the effect of base in the cross-cou-
URL: http://www.magicbullet.org.
pling of 2-bromophenyltetrazole (1a) and 3-meth-
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.082

6530
N. Cousaert et al. / Tetrahedron Letters 46 (2005) 6529–6532
Table 1. Effects of palladium catalyst nature on the Suzuki–Miyaura cross-coupling of 1a and 2aa
CH3
N
N
N
NH
N
N
N
NH
O
N
N
N
NH
B(OH)2
10% catalyst, µwave 115°C
Na2CO3, DME/ H2O
Br
H
+
+
O
CH3
1a
Catalyst
2a
3a
4a
Entry
3a formation (%)b
4a formation (%)b
Conversion (%)b
1
2
3
4
5
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd/C
53
53
17
31
83
40
25
39
31
16
93
78
56
62
99
PdCl2(dppf)
a All couplings were carried out with 0.3 mmol of 2-bromophenyltetrazole, 0.6 mmol of 3-methoxyphenylboronic acid, 0.45 mmol of Na2CO3 and
0.03 mmol of Pd catalyst in a mixture of 1.5 mL of DME and 0.6 mL of H2O under Argon at 115 ꢁC in microwave for 30 min.
b Formation is controlled with HPLC at 215 nm.
Table 2. Effect of base on the Suzuki–Miyaura cross-coupling of 1a and 2a with 10% PdCl2(dppf)a
CH3
N
N
N
NH
N
N
N
NH
O
N
N
N
NH
B(OH)2
10% PdCl2(dppf), µwave 115°C
base, DME/ H2O
Br
H
+
+
O
CH3
1a
2a
3a
4a
Entry
Base
3a formation (%)b
4a formation (%)b
Conversion (%)b
1
2
3
4
Na2CO3
CsF
NaOH
NaHCO3
83
4
8
16
48
45
34
99
52
53
72
38
a All couplings were carried out with 0.3 mmol of 2-bromophenyltetrazole, 0.6 mmol of 3-methoxyphenylboronic acid, 0.45 mmol of base and
0.03 mmol of PdCl2(dppf) in a mixture of 1.5 mL of DME and 0.6 mL of H2O under Argon at 115 ꢁC in microwave for 30 min.
b Formation is controlled with HPLC at 215 nm.
oxyphenylboronic acid (2a) in the presence of 10%
PdCl2(dppf). The results are shown in Table 2.
centration or reactivity of one of the two implied part-
ners: (a) Ar–Pd(II)L2–X and (b) Ar–BðOHÞꢀ. Without
3
transmetallation the Ar–Pd(II)L2–X complex evolves
The results show a dramatic effect of the nature of the
base by the conversion to the desired biphenyltetrazole
3a and on the formation of the undesired debrominated
phenyltetrazole 4a. The formation of this side product is
increased when using non-carbonate bases such as CsF
or NaOH. The best results were obtained using Na2CO3.
to give Ar–H (4a).
Moreover the reaction was carried out with a classic
heating mode (oil bath) as shown in Table 4. The forma-
tion of 3a in such conditions is much slower than with
the microwave one and the presence of by-product 4a
is also less significant.
Finally, we investigated the minimum quantity of cata-
lyst required to achieve a fast and complete conversion.
We compared four conditions with decreasing amount
of PdCl2(dppf) using Na2CO3 as base. The results are
shown in Table 3. The best results were obtained in
the presence of a 10% catalyst concentration.
To evaluate the scope and limitations of this procedure
we examined the reaction of a variety of arylboronic
acids using the following optimised conditions: 10%
PdCl2(dppf) catalyst, Na2CO3 as base in DME/H2O,
30 min at 115 ꢁC under microwaves. The results are pre-
sented in Table 5.
The formation of 4a could be explained by a failure in
the transmetallation step of the catalytic cycle. This
bimolecular step could be compromised by a low con-
4-Pyridineboronic acid did not react quantitatively. By
contrary, arylboronic acids with electron-withdrawing

N. Cousaert et al. / Tetrahedron Letters 46 (2005) 6529–6532
6531
Table 3. Effects of PdCl2(dppf) concentrations on the Suzuki–Miyaura cross-coupling of 1a and 2aa
CH3
N
N
N
NH
N
N
N
NH
O
N
N
N
NH
B(OH)2
PdCl2(dppf), µwave 115°C
Na2CO3, DME/ H2O
Br
H
+
+
O
CH3
1a
2a
3a
4a
Entry
PdCl2(dppf) (equiv)
3a formation (%)b
4a formation (%)b
Conversion (%)b
1
2
3
4
0.1
0.033
0.01
83
55
30
20
16
31
33
35
99
86
63
55
0.0025
a All couplings were carried out with 0.3 mmol of 2-bromophenyltetrazole, 0.6 mmol of 3-methoxyphenylboronic acid, 0.45 mmol of Na2CO3 and x
equiv of PdCl2(dppf) in a mixture of 1.5 mL of DME and 0.6 mL of H2O under Argon at 115 ꢁC in microwave for 30 min.
b Formation is controlled with HPLC at 215 nm.
Table 4. Effects of the microwave on the kinetic of the Suzuki–Miyaura cross-coupling of 1a and 2aa
Heating mode
Reaction time
3a formation (%)b
4a formation (%)b
Conversion (%)b
Oil bathc
Microwaved
96 h
0.5 h
47
83
0.6
16
48
99
a All couplings were carried out with 0.3 mmol of 2-bromophenyltetrazole, 0.6 mmol of 3-methoxyphenylboronic acid, 0.45 mmol of Na2CO3 and
0.03 mmol of Pd catalyst in a mixture of 1.5 mL of DME and 0.6 mL of H2O under Argon.
b Formation is controlled with HPLC at 215 nm.
c Temperature: 90 ꢁC.
d Temperature 115 ꢁC, pressure between 8 and 12 bar.
Table 5. PdCl2(dppf) catalysed Suzuki–Miyaura cross-coupling of 2-bromophenyltetrazole 1a and arylboronic acidsa
N
N
N
NH
N
N
N
NH
N
N
N
NH
B(OH)2
10% PdCl2(dppf), µwave 115°C
Na2CO3, DME/ H2O
Br
H
+
+
R1
R1
2
1a
3
4a
Entry
Product
R1
3 formation (%)b
4a formation (%)b
Yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3-OCH3
4-CH2OH
4-CF3
4-C(CH3)3
4-CHO
3-F
83
82
73 (23c)
73
88
91
93
40
16
17
4
5
7
6
5
10
58
55
55
57
55
58
60
30
3g
3h
3-NH2
4-pyridine
a All couplings were carried out with 0.3 mmol of 2-bromophenyltetrazole, 0.6 mmol of 3-methoxyphenylboronic acid, 0.45 mmol of Na2CO3 and
0.03 mmol of PdCl2(dppf) in a mixture of 1.5 mL of DME and 0.6 mL of H2O under Argon at 115 ꢁC in microwave for 30 min.
b Formation is controlled with HPLC at 215 nm.
c Formation of hydrolysed by-product.
substituents such as CF3, CHO, F or electron-donating
substituents such as NH2, OCH3 coupled readily with
non-protected 2-bromophenyltetrazole with excellent
yields (73–93%). Compound 3b, with a free alcohol

6532
N. Cousaert et al. / Tetrahedron Letters 46 (2005) 6529–6532
3H, OCH3); 13C NMR (75 MHz, DMSO-d6): d = 132.1
(CHarom); 131.4 (1CHarom); 131.3 (1CHarom); 130.1
(1CHarom); 128.2 (1CHarom); 121.2 (1CHarom); 111.5
(1CHarom); 55.31 (O–CH3), LCMS (EI): m/z = 253 (base
peak).
group, was obtained with high yield, indicating that this
group does not require a specific protection under the
coupling conditions.10
In summary, this study shows that non-protected 2-
bromophenyltetrazole can be efficiently coupled with a
wide variety of arylboronic acids under PdCl2(dppf)
catalysed Suzuki–Miyaura cross-coupling procedure.
This procedure is efficient, rapid and the compounds
are recovered after a simple liquid/liquid extraction.
This methodology is an efficient tool for the introduc-
tion of the 5-biphenyl-2-yl-1H-tetrazole core and the
synthesis of biphenyltetrazoles, which are gaining
increasing interest in medicinal chemistry.
[20-(1H-Tetrazol-5-yl)-biphenyl-4-yl]-methanol
(3b):
1
Yield: 55%, colourless oil, H NMR (300 MHz, DMSO-
d6): d = 7.69 (m, 2H, Harom); 7.58 (m, 2H, Harom); 7.20
(t, 1H, JCH = 7.8 Hz, Harom); 6.87 (dd, 1H,
JCH = 8.1 Hz, JHH = 1.8 Hz, Harom); 6.63 (m, 2H,
Harom); 3.67 (s, 2H, CH2OH), 13C NMR (75 MHz,
DMSO-d6): d = 131.7 (1CHarom); 131.2 (1CHarom);
130.0 (1CHarom); 127.6 (1CHarom); 121.7 (1CHarom);
115.0 (1CHarom); 113.7 (1CHarom); 55.6 (1CH2OH),
LCMS (EI): m/z = 253 (base peak), 235.
5-(40-Trifluoromethyl-biphenyl-2-yl)-1H-tetrazole
(3c):
Yield: 55%, pale yellow oil, 1H NMR (300 MHz,
DMSO-d6): d = 7.67 (m, 6H, Harom); 7.33 (d, 2H,
JCH = 7.8 Hz, Harom); 13C NMR (75 MHz, DMSO-d6):
d = 131.7 (1CHarom); 131.4 (1CHarom); 130.4
(2CHarom); 129.2 (1CHarom); 125.6 (2CHarom); 113.5
(1CHarom); LCMS (EI): m/z = 291 (base peak).
Acknowledgements
The authors would like to thank Professors Jean-Claude
`
´
Gesquiere and Andre Tartar for helpful discussions,
Gerard Montagne and Nathalie Azaroual from Lille 2
Biophysics laboratories for NMR experiments.
5-(40-tert-Butyl-biphenyl-2-yl)-1H-tetrazole (3d): Yield:
57%, yellow oil, 1H NMR (300 MHz, DMSO-d6):
d = 7.62 (m, 4H, Harom); 7.33 (d 2H, JHH = 8.4 Hz,
Harom); 7.02 (d, 2H, JHH = 8.4 Hz, Harom); 1.26 (s, 9H,
C(CH3)3), 13C NMR (75 MHz, DMSO-d6): d = 131.7
(1CHarom); 131.3 (2CHarom); 129.1 (2CHarom); 128.1
(1CHarom); 125.7 (2CHarom); 31.6 (C(CH3)3), LCMS
(EI): m/z = 279 (base peak).
References and notes
1. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
2. (a) Kerdesky, F. A. J. et al. Synth. Commun. 1996, 26,
1007–1014; (b) Yoo, S. et al. Tetrahedron Lett. 1997, 38,
1203–1206.
3. Larsen, R. D. et al. J. Org. Chem. 1994, 59, 6391.
4. Johnston, Colin I. The Lancet 1995, 346, 1403–1407.
5. Lin, Petre et al. Bioorg. Med. Chem. Lett. 1999, 9, 3237–
3242.
20-(1H-Tetrazol-5-yl)-biphenyl-4-carbaldehyde (3e): Yield:
55%, pale yellow solid mp: 162–164 ꢁC, 1H NMR
(300 MHz, DMSO-d6): d = 10.05 (s, 1H, CHO); 7.85 (d,
2H, JCH = 7.5 Hz, Harom); 7.62 (m, 4H, Harom); 7.33 (m,
2H, JCH = 7.5 Hz, Harom), 13C NMR (75 MHz, DMSO-
d6): d = 193.4 (1CHO); 135.4 (1CHarom); 131.8
(1CHarom); 131.3 (1CHarom); 130.3 (1CHarom); 130.0
(1CHarom); 129.25 (1CHarom); 128.9 (1CHarom); 127.6
(1CHarom), LCMS (EI): m/z = 251 (base peak).
6. Toney, J. H. et al. Chem. Biol. 1998, 185.
7. Xu, J. et al. Bioorg. Med. Chem. Lett. 2005, 15, 2533–
2536.
8. (a) Kerdesky, F. A. J.; Sowin, T. J. Synth. Commun. 1996,
26, 1007–1013; (b) Smith, G. B. et al. J. Org. Chem. 1994,
59, 8151–8156.
9. (a) Kra¨mer, C. S. et al. Tetrahedron Lett. 2001, 42, 8619–
8624; (b) Alo, B. I. et al. J. Org. Chem. 2001, 56, 3763–
3768; (c) Wallow, T. I. et al. J. Org. Chem. 1994, 59,
5034–5037; (d) Marck, G. et al. Tetrahedron Lett. 1994,
35, 3277–3280; (e) Morris, Gregory A.; Nguyen, SonBinh
T. Tetrahedron Lett. 2001, 42, 2093–2096.
10. Suzuki–Miyaura cross-coupling reaction: General proce-
dure A glass tube was loaded with 2-bromophenyltetrazole
(68 mg, 0.3 mmol), the appropriate arylboronic acid
(0.6 mmol), Na2CO3 (48 mg, 0.45 mmol), PdCl2(dppf)
(24.5 mg, 0.03 mmol), DME (1.5 mL) and H2O (0.6 mL).
After one vacuum/Argon cycle to remove oxygen, the
reaction tube was sealed; the mixture was stirred and
heated at 115 ꢁC in microwave oven for 30 min. The
mixture was diluted with NaHCO3 (5%) and ethyl acetate
(10 ml). The organic layer was extracted with NaHCO3
(5%) (4 · 20 mL) and aqueous layers were combined,
washed with ethyl acetate (5 mL), acidified (pH = 1) and
extracted with ethyl acetate (5 · 30 mL). The combined
organic layers were dried (MgSO4). The solvent was
removed in vacuo.
5-(30-Fluoro-biphenyl-2-yl)-1H-tetrazole (3f): Yield: 58%,
pale yellow solid; mp 128–129 ꢁC, 1H NMR (300 MHz,
DMSO-d6): d = 7.7 (m, 2H, Harom); 7.58 (m, 2H,
Harom); 7.34 (q, 1H, JCH = 6.3 Hz, Harom); 7.15 (td,
1H, JCH = 8.7 Hz, JHH = 2.4 Hz, Harom); 6.99 (dt, 1H,
JCH = 10.2 Hz, JHH = 2.4 Hz, Harom); 6.86 (d, 1H,
JCH = 7.5 Hz, Harom), 13C NMR (75 MHz, DMSO-d6):
d = 131.8 (1CHarom); 131.3 (1CHarom); 131.2
(1CHarom); 130.8 (d, 1Charom-F); 128.9 (1CHarom);
125.6 (1Charom-F); 116.3 (d, 1Charom-F); 115.0 (d,
1Charom-F), LCMS (EI): m/z = 241 (base peak).
20-(1H-Tetrazol-5-yl)-biphenyl-3-ylamine (3g): Yield: 60%,
white solid recovered as hydrochloride salt; mp P300 ꢁC;
1H NMR (300 MHz, DMSO-d6): d = 8.22 (sb, 2H, NH2);
7.80 (t, 1H, JHH = 4.2 Hz, Harom); 7.70 (m, 2H, Harom);
7.60 (t, 1H, JHH = 6.3 Hz, Harom); 7.50 (d, 1H, JHH
=
7.5 Hz, Harom); 7.43 (d, 2H, JHH = 4.8 Hz, Harom); 7.30
(t, 1H, JHH = 7.8 Hz, Harom); 13C NMR (75 MHz,
DMSO-d6): d = 131.9 (1CHarom); 131.7 (1Cq); 131.3
(1CHarom); 131.2 (1CHarom); 129.3 (1CHarom); 129.0
(1CHarom); 128.8 (1CHarom); 125.3 (1CHarom); LCMS
(EI): m/z = 238 (base peak).
4-[2-1H-Tetrazol-5-yl)-phenyl]-pyridine (3h): Yield: 30%,
white solid recovered as hydrochloride salt; mp P300 ꢁC,
1H NMR (300 MHz, DMSO-d6): d = 8.84 (m, 2H,
Harom); 8.32 (m, 2H, Harom), 7.84 (m, 4H, Harom); 13C
NMR (75 MHz, DMSO-d6): d = 142.3 (1CHarom); 140.6
(1CHarom); 132.1 (1CHarom); 131.6 (1CHarom); 131.3
(1CHarom); 131.2 (1CHarom); 127.9 (1CHarom); 125.3
(1CHarom); LCMS (EI): m/z = 224 (base peak).
5-(30-Methoxy-biphenyl-2-yl)-1H-tetrazole (3a): Yield:
58%, pale yellow oil, 1H NMR (300 MHz, DMSO-d6):
d = 7.60 (m, 3H, Harom); 7.43 (d, 1H, JHH = 7.5 Hz,
Harom); 7.30 (t, 1H, JHH = 7.5 Hz, Harom); 7.18 (d, 1H,
JHH = 6.3 Hz, Harom); 6.99 (t, 1H, JHH = 7.2 Hz,
Harom); 6.86 (d, 1H, JHH = 8.4 Hz, Harom); 3.30 (s,