Solid-phase synthesis of 5-biphenyl-2-yl-1h-tetrazoles

Article abstract of DOI:10.1021/ol0498848

(Equation presented) The combinatorial synthesis of novel biphenyl tetrazoles is described. Key steps include the simultaneous biphenyl formation and phenol deallylation under Suzuki cross-coupling conditions as well as the tetrazole ring formation on solid support. A representative library of 20 biphenyl tetrazoles was synthesized.

Full text of DOI:10.1021/ol0498848

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1143-1146
Solid-Phase Synthesis of
5-Biphenyl-2-yl-1H-tetrazoles
,§
Olga Kivrakidou, Stefan Bra1se,† Frank Hu1lshorst,‡ and Nils Griebenow*
Bayer AG, Bayer Health Care, Pharma Research, Building 460,
D-42096 Wuppertal, Germany, Institut fu¨r Organische Chemie, UniVersita¨t Karlsruhe,
Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany, and Sugaris GmbH,
Nottulner Landweg 90, D-48161 Mu¨nster, Germany
nils.griebenow.ng@bayer-ag.de
Received January 19, 2004
ABSTRACT
The combinatorial synthesis of novel biphenyl tetrazoles is described. Key steps include the simultaneous biphenyl formation and phenol
deallylation under Suzuki cross-coupling conditions as well as the tetrazole ring formation on solid support. A representative library of 20
biphenyl tetrazoles was synthesized.
The combinatorial synthesis of low-molecular-weight com-
pounds along with high-throughput screening continues to
be a promising strategy for the discovery of new pharma-
ceutical lead structures.1 Within this context, the synthesis
of combinatorial libraries based on so-called “privileged
structures”2 is of considerable interest, because such struc-
tures combine druglike properties with the ability to address
various biological targets, depending on their substitution
pattern. Examples include the combinatorial synthesis of
benzodiazepines,3 benzopyrans,4 biphenyls,5 phenyl pipera-
zines,6 and spiro-piperidines.7
we were interested in the combinatorial diversification of
the biphenyl tetrazole scaffold, another example of a “priv-
ileged structure”.8 Biphenyl tetrazoles, when appropriately
substituted, exert potent and selective actions at diverse sets
of protein targets, including G protein-coupled receptors,
enzymes, and ion channels. Besides their well-known anti-
hypertensive activity found in therapeutics such as Losartan
(1),9 biphenyl tetrazoles have also demonstrated activities
(3) (a) Ramdas, L.; Bunnin, B. A.; Plunkett, M. J.; Sun, G.; Ellman, J.
A.; Gallick, G.; Budde, R. J. A. Arch. Biochem. Biophys. 1999, 368, 394.
(b) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555. (c) Herpin,
T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudinie`re, R. F. J.
Comb. Chem. 2000, 2, 513.
(4) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
(5) Neustadt, B. R.; Smith, E. M.; Lindo, N.; Nechuta, T.; Bronnenkant,
A.; Wu, A.; Armstrong, L.; Kumar, C. Bioorg. Med. Chem. Lett. 1998, 8,
2395.
(6) Nilsson, J. W.; Thorstensson, F.; Kvarnstro¨m, I.; Oprea, T.; Sam-
uelsson, B.; Nilsson, I. J. Comb. Chem. 2001, 3, 546.
(7) Rohrer, S. P.; Birzin, E. T.; Mosley, R. T.; Berk, S. C.; Hutchins, S.
M.; Shen, D.-M.; Xiong, Y.; Hayes, E. C.; Parmar, R. M.; Foor, F.; Mitra,
S. W.; Degrado, S. J.; Shu, M.; Klopp, J. M.; Cai, S.-J.; Blake, A.; Chan,
W. W. S.; Pasternak, A.; Yang, L.; Patchett, A. A.; Smith, R. G.; Chapman,
K. T.; Schaeffer, J. M. Science 1998, 282, 737.
In the course of our ongoing efforts directed toward the
solid-phase synthesis of general-purpose screening libraries,
* To whom correspondence should be addressed. Fax: +49-202-364624.
† Universita¨t Karlsruhe.
‡ Sugaris GmbH.
§ Bayer AG.
(1) For a recent review of combinatorial chemistry, see: Dolle, R. E. J.
Comb. Chem. 2003, 5, 693.
(2) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson,
P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
(b) Patchett, A. A.; Nargund, R. P. Annu. Rep. Med Chem. 2000, 35, 289.
(c) Ding, S.; Gray, N. S.; Wu. X,; Ding, Q.; Schultz, P. G. J. Am. Chem.
Soc. 2002, 124, 1594. (d) Breinbauer, R.; Vetter, I. R.; Waldmann, H.
Angew. Chem., Int. Ed. 2002, 41, 2878.
(8) (a) Mason, J. S.; Morize, I.; Menard, P. R.; Cheney, D. L.; Hulme,
C.; Labaudinie`re, R. F. J. Med. Chem. 1999, 42, 3251. (b) Bondensgaard,
K.; Ankersen, M.; Thøgersen, H.; Hansen, B. S.; Wulff, B. S.; Bywater, R.
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10.1021/ol0498848 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/02/2004

as stimulators of growth hormone release (2),10 metallo-
protease inhibitors (3, 4),11,12 and chloride channel blockers
(5)13 (Figure 1).
Further diversification of the scaffold could be accomplished
by the elaboration of the deprotected phenolic group via the
Mitsunobu reaction with alcohols. It was envisaged further
that the Suzuki cross-coupling reaction and the allyl depro-
tection could be accomplished under the same conditions
simultaneously. Finally, the nitrile group of scaffold 11 was
expected to be a suitable precursor for tetrazole formation.
The scaffold 11 was synthesized in five linear steps and 15%
overall yield from ethyl acetylacetate (6) as outlined in
Scheme 1.
Scheme 1. Scaffold Synthesis
Figure 1. Examples of pharmaceutically relevant biphenyl tetra-
zoles.
A literature survey revealed two reports describing the
solid-phase synthesis of biphenyl tetrazoles.14 In both
methods, a preformed phenyl tetrazole derivative was at-
tached to the resin and elaborated further via Suzuki cross-
coupling to the biphenyl core. Thus, diversity is limited to
one of the phenyl rings. With the aim of synthesizing bi-
phenyl tetrazoles with points of diversity at both phenyl rings,
we considered the synthesis of the 2-allyloxy-5-cyano-4-iodo-
benzoic acid 11 as a key intermediate for the solid-phase
synthesis. The scaffold offers three sites of diversification:
the carboxylic acid, the iodo substituent, and the allyl-
protected phenol. The carboxylic acid should serve as a solid-
phase attachment point via an amide linkage while the
aromatic iodine functionality allows the construction of the
biphenyl core by Suzuki cross-coupling with boronic acids.
The amino salicylate 8 was prepared according to the
published method.15 Thus, the ethyl acetylacetate (6) was
treated with triethyl orthoformiate to give the acrylic acid
ester 7 as an E/Z mixture,16 which was subsequently sub-
jected to a sodium ethanolate mediated addition of malono-
nitrile. An acidic workup gave the amino salicylate 8. Con-
version of the amino functionality of 8 via anhydrous di-
azotation17 followed by treatment with NaI in acetone18
afforded the iodo salicylate 9. Typical aqueous Sandmeyer
conditions gave a significantly lower yield (48%). Treatment
of 9 with allyl bromide in the presence of Cs2CO3 gave the
allyl-protected ester 10, which was subsequently saponified
providing scaffold 11.
(9) (a) Smith, R. D.; Sweet, C. S.; Goldberg, A. Timmermans, P. B. M.
W. M. Drugs Today 1996, 32, 1. (b) Dickstein, K.; Timmermans, P. B. M.
W. M.; Segal, R. Exp. Opin. InVest. Drugs 1998, 7, 1897.
(10) Smith, R. G.; Cheng, K.; Schoen, W. R.; Pong, S.-S.; Hickey, G.;
Jacks, T.; Butler, B.; Chan, W. W.-S.; Chaung, L.-Y. P.; Judith, F.; Taylor,
J.; Wyvratt, M. J.; Fisher, M. H. Science 1993, 260, 1640.
(11) Green, B. G.; Toney, J. H.; Kozarich, J. W.; Grant, S. K. Arch.
Biochem. Biophys. 2000, 375, 355.
(12) (a) Toney, J. H.; Fitzgerald, P. M. D.; Grover-Sharma, N.; Olson,
S. H.; May, W. J.; Sundelof, J. G.; Vanderwall, D. E.; Cleary, K. A.; Grant,
S. K.; Wu, J. K.; Kozarich, J. W.; Pompliano, D. L.; Hammond, G. G.
Chem. Biol. 1998, 5, 185. (b) Toney, J. H.; Cleary, K. A.; Hammond, G.
G.; Yuan, X.; May, W. J.; Hutchins, S. M.; Ashton, W. T.; Vanderwall, D.
E. Bioorg. Med. Chem. Lett. 1999, 9, 2741.
(13) Christophersen, P.; Dahl, B. H. WO Patent 0024707, 2000.
(14) (a) Yoo, S.-E.; Seo, J.-S.; Yi, K.-Y.; Gong, Y.-D. Tetrahedron Lett.
1997, 38, 1203-1206. (b) Severinsen, R.; Lau, J.; Begtrup, M.; Ankersen,
M. Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA,
March 23-27, 2003; American Chemical Society: Washington, DC, 2003;
ORGN 105.
The solid-phase synthesis of biphenyl tetrazoles using 11
is outlined in Scheme 2. Initially, Rink amide polystyrene
resin19 was Fmoc-deprotected with 25% piperidine in DMF
to give the free amine resin, which was loaded with the
(15) Schmidt, H.-W.; Junek, H. Liebigs Ann. Chem. 1979, 2005.
(16) Crombie, L.; Games, D. E.; James, A. W. G. J. Chem. Soc., Perkin
Trans. 1 1979, 464.
(17) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572.
(18) Venuti, M. C.; Jones, G. H.; Alvarez, R.; Bruno, J. J. J. Med. Chem.
1987, 30, 303.
(19) Obtained from Rapp Polymere GmbH, Germany (polystyrene AM
RAM, 1% divinylbenzene, 100-200 mesh, 0.773 mmol/g).
1144
Org. Lett., Vol. 6, No. 7, 2004

Scheme 2. Solid-Phase Synthesis of Biphenyl Tetrazoles
Figure 2. Phenylboronic acids 13a-f used in the Suzuki cross-
coupling reaction. Purities (in %) correspond to the deallylated
biphenyls 14 cleaved from the resin and were based on the peak
area of HPLC traces at 214 nm.
using the standard Mitsunobu reaction protocol with 5 equiv
of the alcohols 15a-e as well as 5 equiv of DIAD and PPh3
in DMF as solvent.23 Using these reaction conditions, primary
and secondary alcohols afforded the ethers 16 in good purity,
as indicated by HPLC analysis of the detached products
(Figure 3).
scaffold 11 using the DIC/HOBt/DMF procedure. The
completion of loading was verified by the ninhydrin test.20
With the scaffold 11 successfully loaded onto the resin, our
efforts focused on the elaboration of the aromatic iodine
functionality to the biphenyl core via the Suzuki cross-
coupling reaction.
Thus, cross-coupling of the resin-bound scaffold 12 was
investigated using either the standard aqueous21 or anhy-
drous22 reaction conditions. Initially 2.5 equiv of boronic acid
13a, 5 mol % of Pd(PPh3)4, and 2.5 equiv of aqueous
Na2CO3 or excess of neat DIEA as base at 100 °C in DMF
were used. The resin was then subjected to the TFA/CH2Cl2
cleavage procedure to determine the extent of the coupling
reaction via HPLC analysis of the crude product. Both
protocols led predominately to deallylation at the phenol,
whereas only little biphenyl formation was observed. There-
fore, higher equivalents of reagents were used to drive the
reaction to completion. Best results were obtained when 20
mol % of catalyst and 10 equiv of phenyl boronic acid as
well as 10 equiv of aqueous Na2CO3 or excess of DIEA as
base were used. Consequently, the resin-bound biphenyl 14
(R1 ) Ph) was obtained in high purity in both cases. Using
the anhydrous reaction conditions, further boronic acids
13b-f were investigated in the Suzuki cross-coupling
reaction. The crude products cleaved from the resin showed
good to excellent purities as outlined in Figure 2.
Figure 3. Alcohols 15a-e used in the Mitsunobu reaction. Purities
(in %) correspond to the detached ethers 16 and were calculated
from the peak areas recorded by HPLC analysis at 214 nm of the
crude products.
Tetrazole ring formation from the resin-bound nitrile 16
(R1 ) Ph, R2 ) i-Bu) was accomplished with Me3SiN3 and
catalytic n-Bu2SnO for 50 h at 90 °C in o-xylene.24 Compared
with previously reported solid-phase protocols using azido-
trimethyltin4 or sodium azide,25 the method described herein
allows for the use of less toxic and hazardous reagents.24
Finally, cleavage from the resin with the TFA/CH2Cl2
procedure provided the fully functionalized tetrazole 18a in
74% purity.
To illustrate the versatility of this chemistry, a library of
20 compounds 18a-t was prepared, using a representative
set of five boronic acids 13a-e and four alcohols 15a-d.
All products were obtained in good to high purities as well
as moderate yields after HPLC purification,26 as shown in
Table 1.
Diversification of the deprotected phenolic group was
investigated with the resin-bound biphenyl 14 (R1 ) Ph)
(20) Kaiser, E. T.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 595.
(21) (a) Frenette, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177
and references therein. (b) Han, Y.; Walker, S. D.; Young, R. N. Tetrahedron
Lett. 1996, 37, 2703. (c) Bra¨se, S.; Ko¨bberling, J.; Griebenow, N. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.; Wiley: New York, 2002; Volume 2, Chapter X.
(23) (a) Krchna´k, V.; Flegelova´, Z.; Weichsel, A. S.; Lebl, M. Tetra-
hedron Lett. 1995, 36, 6193. (b) Rano, T. A.; Chapman, K. T. Tetrahedron
Lett. 1995, 36, 3789.
(22) (a) Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237.
(b) Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.; Schreiber S.
L. J. Am. Chem. Soc. 1999, 121, 9073.
(24) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139.
(25) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
(26) Bauser, M. J. Chromatogr. Sci. 2002, 40, 292.
Org. Lett., Vol. 6, No. 7, 2004
1145

Table 1. Examples of Biphenyl Tetrazoles Synthesized on Solid Support
puritya yieldb
puritya yieldb
compound
R1
R2
(%)
(%)
compound
R1
R2
(%)
(%)
18a
18b
18c
18d
18e
18f
18g
18h
18i
phenyl
isobutyl
isobutyl
isobutyl
isobutyl
74
77
70
93
76
68
66
65
81
81
44
25
14
36
24
29
21
23
27
30
18k
18l
phenyl
2-phenylethyl
2-phenylethyl
2-phenylethyl
2-phenylethyl
73
81
73
84
88
75
75
59
91
74
36
42
41
25
27
39
44
24
32
18
4-methylphenyl
4-chlorophenyl
2-chlorophenyl
3-methoxyphenyl isobutyl
phenyl
4-methylphenyl
4-chlorophenyl
2-chlorophenyl
4-methylphenyl
4-chlorophenyl
2-chlorophenyl
3-methoxyphenyl 2-phenylethyl
phenyl
4-methylphenyl
4-chlorophenyl
2-chlorophenyl
18m
18n
18o
18p
18q
18r
18s
18t
2-isopropoxy-ethyl
2-isopropoxy-ethyl
2-isopropoxy-ethyl
2-isopropoxy-ethyl
isopropyl
isopropyl
isopropyl
isopropyl
18j
3-methoxyphenyl 2-isopropoxy-ethyl
3-methoxyphenyl isopropyl
a Calculated from integrated peak areas recorded by HPLC analysis (214 nm) of the crude products. b Yields of the purified material were calculated on
the basis of the initial loading of the resin.
In conclusion, we have developed a straightforward pro-
cedure for the synthesis of structurally diverse biphenyl
tetrazoles. The synthesis includes a novel one-step procedure
for biphenyl formation and phenol deprotection under Suzuki
cross-coupling reaction conditions, as well as a convenient
synthesis protocol for tetrazole formation on solid support.
The further elaboration of the scaffold 11 at the carboxylic
acid using amine-loaded resins as an additional point of
diversity is ongoing. In addition, the preparation and biologi-
cal screening of a larger library is in progress.
Acknowledgment. The authors thank Dr. Franz v. Nuss-
baum and Dr. Leila Telan (Bayer AG) for helpful discussion
and critical reading of the manuscript.
Supporting Information Available: Detailed experi-
mental procedure and analytical data for compounds 7-11
and 18a-t. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0498848
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Org. Lett., Vol. 6, No. 7, 2004