Multi-gram scale mercury-free synthesis of optically pure 3,4,5-trisubstituted 1,2,4-triazoles using silver benzoate

Article abstract of DOI:10.1016/j.tetlet.2010.03.037

We report a new method using silver benzoate instead of mercury salts as a key reagent for the synthesis of 3,4,5-trisubstituted 1,2,4-triazoles. This method allows the introduction of a large variety of substituents in the three positions. We demonstrate

Full text of DOI:10.1016/j.tetlet.2010.03.037

Tetrahedron Letters 51 (2010) 2660–2663
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Tetrahedron Letters
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Multi-gram scale mercury-free synthesis of optically pure
3,4,5-trisubstituted 1,2,4-triazoles using silver benzoate
1
*
Mathieu Bibian, Anne-Laure Blayo, Aline Moulin , Jean Martinez, Jean-Alain Fehrentz
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS—Université Montpellier 1—Université Montpellier 2, 15 avenue Charles Flahault,
BP14491 34093 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new method using silver benzoate instead of mercury salts as a key reagent for the synthesis
of 3,4,5-trisubstituted 1,2,4-triazoles. This method allows the introduction of a large variety of substitu-
ents in the three positions. We demonstrated that we could introduce one chiral center without any loss
of the optical purity. This method is compatible with at least multi-gram scale-up.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 9 February 2010
Revised 9 March 2010
Accepted 10 March 2010
Available online 15 March 2010
Keywords:
Heterocycles
Silver
1,2,4-Triazole
Scale-up
Enantiopure
Triazoles are an important class of heterocyclic compounds.
They are well-known for their antifungal,1,2 antimicrobial,3 antivi-
ral,4 anti-inflammatory,5 anti-asthmatic,6 antiproliferative,7,8 and
hypotonic activities.9 1,2,4-Triazoles were also used as amide bond
isosteres for the design of receptor ligands in order to enhance
their pharmacokinetic properties10,11 or to mimic the cis configura-
tion of the amide function observed in several peptides.12 More re-
cently, triazole-based agonists or antagonists targeting different
receptors were described,13,14 especially molecules based on the
3,4,5-trisubstituted 1,2,4-triazole scaffold.15–18
the synthesis of bioactive compounds, especially for batches dedi-
cated to preclinical or clinical trials, because of the well-known
toxicity of mercury derivatives. The replacement of mercury salts
by a safer alternative was thus explored. We focused our work
on the use of silver salts. A recent publication of Weibel et al.20
extensively reviewed the use of silver in coupling and heterocycli-
zation reactions. Silver salts are generally used for their halogeno-
Table 1
Coupling-cyclization step of thioamide 5a–h with hydrazides
R''
N
We previously reported the synthesis of 3,4,5-trisubstituted
1,2,4-triazoles using mercury II diacetate as a key reagent during
the ring formation.19 However, this method has to be avoided for
H
N
AgOBz (2 equiv.)
O
R'
R'
R'''
R''
H2NHN
R'''
AcOH (3 equiv.)
DCM, rt, 6 h
S
N
N
(1.2 equiv.)
5 (a-h)
6 (a-h)
7 (a-h)
R''
N
R''
N
H
N
AgOBz (2 equiv.)
7
R0
R00
R000
Yield
(%)
O
R'
R'
R'
R'''
R''
H2NHN
R'''
THF
S
Phenethyl
Indolethyl
2,4-Dimethoxy
benzyl
2,4-Dimethoxy
benzyl
Benzyl
Benzyl
Benzyla
Benzyla
49
47
N
N
O
O
a
(1.2 equiv.)
1
2
4
3
b
U.V. (214nm)
absorption percentage
c
d
e
Isopentyl
2-Pyridyl
3,4-Dichloro
phenyl
Benzyla
Benzyla
Benzyla
90
70
80
40%
60%
2,4-Dimethoxy
benzyl
Scheme 1. Synthesis of 1,2,4-triazole using silver benzoate and main side reaction.
f
3,4-Dichloro
phenyl
Phenethyl
Phenethyl
Benzyl
4-Methoxy
benzyla
66
Benzyla
43
76
* Corresponding author. Tel.: +33 467548651; fax: +33 467548654.
E-mail address: jean-alain.fehrentz@univ-montp1.fr (J.-A. Fehrentz).
g
h
4-Methylbenzyl
3,4-Dichloro benzyl
Benzyla
1
Present address: Flamel Technologies, 33 avenue du Dr. Georges Levy, 69693
a
Products obtained from commercial sources.
Venissieux Cedex, France.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.037

M. Bibian et al. / Tetrahedron Letters 51 (2010) 2660–2663
2661
H
N
H
N
H
N
c
c
a
H
N
N
OH
OH
BocHN
BocHN
BocHN
N
N
10
O
O
X
8 X=O
b
9 X=S
H
N
H
N
H
N
a
H
N
N
BocHN
BocHN
BocHN
N
N
13
X
11
X=O
b
12
X=S
Scheme 2. Synthesis of triazoles 10 and 13. Reagents and conditions: (a) DIEA, BOP (1 equiv), benzylamine (1.1 equiv), DCM, 30 min, rt; (b) Lawesson reagent (0.55 equiv),
DME, 2 h, 80 °C; (c) phenylacetic hydrazide (1.2 equiv), AgOBz (2 equiv), AcOH (3 equiv), DCM, 6 h, rt. Chiral analysis parameters: column Chiracel OD, eluent system 70/30
hexane/isopropanol (v/v) 1‰ Et2NH, monitoring at 280 nm.

2662
M. Bibian et al. / Tetrahedron Letters 51 (2010) 2660–2663
Table 2
After intensive optimization we found that running reaction in
Coupling-cyclization step of 16a–d
dichloromethane in mild acidic media (here 3 equiv of acetic acid)
allowed us to obtain only triazole 3.23 An interesting fact is that the
reaction time was reduced from three days to six hours just by
changing thiophilic salt and reaction conditions, compared with
the previous methodology using mercury II diacetate.
Exploration of the scope of the reaction led us to synthesize a
small library of compounds with different substituents. Yields of
the coupling–cyclization step are reported in Table 1.
R
H
N
Pathway 1
AgOBz (2 equiv.),
AcOH (3 equiv.),
DCM
R'
BocHN
S
R
R'
N
14 (a-d)
R''
O
BocHN
Pathway 2
Hg(OAc)2 (2 equiv.)
THF
N
N
H2N
N
H
R''
16 (a-d)
(1.2 equiv.)
Yields reported in Table 1 are from moderate to good and are irre-
spectiveofboththeelectron-withdrawingandelectron-donatingef-
fects and to the nature of side chains (aromatic or alkyl groups).
We recently reported a new series of GHS-R1a ligands based on
the triazole scaffold24 and so obtained potent agonists and antago-
nists compounds. These antagonists are of great interest for the
development of anti-obesity drugs. Our team is currently working
on preclinical tests with some of these molecules. So we were
interested in synthesizing such compounds using this new meth-
odology. However, as the target compounds included a chiral car-
bon atom on the R0 position in their structure, we had to check that
the whole process kept the molecule stereochemistry unchanged.
For this purpose, amides 8 and 11 were synthesized, starting
15 (a-d)
16
R
R0
R00
Yield
(pathway 1)
(%)
Yield
(pathway 2)
(%)
a
b
Indol 4-Phenylbenzyl
Indol 4-Methoxy
benzyl
Indol 2,4-Dimethoxy
benzyl
Phenethyl 74
Phenethyl 73
67
65
c
Phenethyl 65
Phenethyl 87
65
64
d
Indol 1-Naphthyl
methyl
All products were characterized by 1H and 13C NMR spectroscopy and LC/MS. No
differences could be detected for the same compounds synthesized by both
pathways.
from commercially available N-protected
L and D tryptophan,
respectively. After thionation reaction with the Lawesson reagent
and purification, we obtained thioamides 9 and 12. The cou-
pling–cyclization reaction was carried out in the presence of silver
benzoate to afford, respectively, triazoles 10 and 13. Purification
was performed on preparative reverse-phase HPLC. It was assumed
that in this non-chiral purification environment enantiomers can-
not be separated (Scheme 2).
After analysis by chiral HPLC we could conclude that our reac-
tion pathway did not induce any epimerization on the carbon atom
on R0 (in the limit of detection of the analytical method used).
To compare the synthesis using mercury II diacetate with the
one using silver benzoate we synthesized a library of compounds
by these two methodologies (Table 2).
Table 3
Multi-gram synthesis of triazole 16b
NH
OMe
H
N
H
N
H2N
BocHN
O
S
(1.2 equiv.)
14b
15b
AcOH (3 equiv.)
DCM, rt, 6h
AgOBz (2 equiv.)
Yields were clearly improved when using silver benzoate com-
pared to mercury II diacetate.
As we are involved in the development of GHS-R1a ligands,
large quantities of advanced intermediates bearing a chiral cen-
ter-like triazoles 16 were necessary for intensive structure–activity
relationship studies. Moreover, some compounds with interesting
pharmacodynamic properties had to be resynthesized for further
pre-clinical evaluations. With this new methodology in our hands,
we were interested in performing the synthesis of several triazole
derivatives in a multi-gram scale. Triazole 16b was thus synthe-
sized at different scales.25 Yields are reported in Table 3.
Quantities could be increased up to 18 mmol of thioamide 14b
with no significant problem. This methodology using silver benzoate
to achieve the coupling–cyclization step is robust enough to allow
the synthesis of several grams of 3,4,5-trisubstituted 1,2,4-triazoles.
In conclusion, we report here a new method using silver benzo-
ate as a key reagent for the synthesis of 3,4,5-trisubstituted 1,2,4-
triazoles. This method allows the introduction of a large variety of
substituents in the 3,4,5-positions, including chiral moieties in po-
sition 3, keeping the optical purity of the chiral center unchanged.
This method is compatible with the synthesis of multi-gram
batches of biological interesting compounds, due to the low toxic-
ity of silver derivatives and the robustness of the reaction.
NH
OMe
N
BocHN
N
N
16b
Scale (mmol/g of thioamide 14b)
Triazole 16b (mmol/g)
Yield (%)
2.3 mmol/1.0 g
7.0 mmol/3.1 g
15.6 mmol/6.9 g
18.2 mmol/ 8.0 g
1.8 mmol/1.0 g
5.1 mmol/2.8 g
12.3 mmol/6.8 g
13.5 mmol/7.4 g
79
73
79
74
philicity and alkynophilicity whereas thiophilicity does not seem
to be a much exploited property. Mercury salts are used for their
thiophilicity properties more often than silver salts because of bet-
ter specificity. We will demonstrate in this Letter that silver salts
can be a very interesting alternative to mercury salts for the syn-
thesis of 3,4,5-trisubstituted 1,2,4-triazoles.
Starting from thioamide and hydrazide19,21 obtained using previ-
ously described synthetic methods, we ran a model reaction using
various silver salts. Silver trifluoromethane sulfonate, silver(I) oxide,
silveracetate, andsilverbenzoateweretested. Exceptfortrifluorom-
ethane sulfonate, all the salts led to the desired product in different
levels of purity. The best results were obtained using silver benzoate.
We decided to optimize the reaction conditions with this salt. The
main problem we encountered was the formation of benzoylated
amide 4 (Scheme 1), previously described by Avalos et al.22
Supplementary data
Supplementary data (spectra, procedures and characterization
data for products) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.037.

M. Bibian et al. / Tetrahedron Letters 51 (2010) 2660–2663
2663
16. Moulin, A.; Demange, L.; Berge, G.; Gagne, D.; Ryan, J.; Mousseaux, D.; Heitz, A.;
Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J. C.; Fehrentz, J. A.;
Martinez, J. J. Med. Chem. 2007, 50, 5790–5806.
17. Moulin, A.; Demange, L.; Ryan, J.; Mousseaux, D.; Sanchez, P.; Berge, G.; Gagne,
D.; Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J. C.; Fehrentz, J. A.;
Martinez, J. J. Med. Chem. 2008, 51, 689–693.
18. Zhang, Q.; Keenan, S. M.; Peng, Y.; Nair, A. C.; Yu, S. J.; Howells, R. D.; Welsh, W.
J. J. Med. Chem. 2006, 49, 4044–4047.
19. Boeglin, D.; Cantel, S.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Org. Lett. 2003, 5,
4465–4468.
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23. General procedurefor 1,2,4-triazole preparation: Thioamide(1 equiv)andhydrazide
(1.2 equiv) were diluted in the minimum of dichloromethane. Silver benzoate
(2 equiv) was then added immediately followed by acetic acid (3 equiv). The
mixture was stirred overnight at room temperature. Distillation of the solvent
under reduced pressure gave a black oil, which was diluted in a solution of
dichloromethane. A flash chromatography on silica gel, eluted with AcOEt/hexane
5/5 to MeOH 5% in AcOEt, afforded the pure triazole in 40–90% yield.
24. Fehrentz, J. A.; Bibian, M.; Moulin, A.; Martinez, J. WO2009/115503.
25. NMR and mass characterization of compound 16b 1H NMR (DMSO-d6,
300 MHz, 28 °C) d (ppm) 1.25 (s, 9H, CH3 Boc), 2.77–2.97 (m, 4H, CH2–CH2–
phenyl), 3.27–3.44 (m, 2H, CH2 b tryptophan), 3.70 (s, 3H, OCH3), 5.05 (q, 1H,
8 Hz, CH
a tryptophan), 5.18 (s, 2H, CH2 p-methoxybenzyl), 6.76 (d, 2H, 9 Hz,
H3 and H5 p-methoxybenzyl), 6.84 (d, 2H, 9 Hz, H2 and H6 p-methoxybenzyl),
6.92 (t, 1H, 8 Hz, H5 tryptophan), 7.03–7.28 (m, 7H, H2 and H6 tryptophan, H2
and H3 H4 H5 and H6 phenethyl), 7.34 (d, 2H, 8 Hz, H4 and H7 tryptophan), 7.73
(d, 1H, 8 Hz, NH Boc), 10.85 (s, 1H, NH tryptophan). 13C{1H} NMR (DMSO-d6,
28 °C):
tryptophan), 31.7 (CH2–CH2–phenyl), 45.8 (CH2–p-methoxyphenyl), 46.4 (CH
tryptophan), 55.1 (OCH3), 78.6 (C quat Boc), 109.3 (C3 tryptophan), 111.3 (C7
d (ppm) 25.9 (CH2–CH2–phenyl), 28.0 (CH3 Boc), 28.3 (CH2 b
a
tryptophan), 114.1 (C3 and C5 p-methoxybenzyl), 118.0 (C4 tryptophan), 118.4
(C5 tryptophan), 120.9 (C6 tryptophan), 124.0 (C2 tryptophan), 126.3 (C4
phenethyl), 126.4 (C1 p-methoxybenzyl), 127.0 (C9 tryptophan), 127.7 (C2 and
C6 p-methoxybenzyl), 128.2 (C2 C3 C5 and C6 phenethyl), 136.0 (C8 tryptophan),
15. Demange, L.; Boeglin, D.; Moulin, A.; Mousseaux, D.; Ryan, J.; Berge, G.; Gagne,
D.; Heitz, A.; Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J. C.; Fehrentz,
J. A.; Martinez, J. J. Med. Chem. 2007, 50, 1939–1957.
139.8 (C1 phenethyl), 154.4 (CO Boc), 155.1 and 155.5 (C quat triazole), 158.8
(C4 p-methoxybenzyl). MS (ES), m/z: 552.2 [M+H].