Facile, diversity-orientated one-pot synthesis of ethyl 1,5-disubstituted-1H-1,2,4-triazole-3-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2012.08.130

Access to the 1,5-disubstituted-1H-1,2,4-triazole-3-carboxamide motif is quite laborious and requires forcing conditions to effect the cyclocondensation step. Herein, we report an efficient and mild one-pot protocol to access this substructure in good che

Full text of DOI:10.1016/j.tetlet.2012.08.130

Tetrahedron Letters 53 (2012) 6078–6082
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile, diversity-orientated one-pot synthesis of ethyl
1,5-disubstituted-1H-1,2,4-triazole-3-carboxylates
Sébastien Degorce a,b, Bénédicte Delouvrié a, Paul R. J. Davey b, Myriam Didelot a, Hervé Germain a,
Craig S. Harris a, , Christine Lambert-van der Brempt a,b, Honorine Lebraud a, Gilles Ouvry a
⇑
a AstraZeneca Oncology iMed, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
b AstraZeneca Oncology iMed, Alderley Park, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Access to the 1,5-disubstituted-1H-1,2,4-triazole-3-carboxamide motif is quite laborious and requires
forcing conditions to effect the cyclocondensation step. Herein, we report an efficient and mild one-
pot protocol to access this substructure in good chemical yields with high regiocontrol.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 July 2012
Revised 2 August 2012
Accepted 29 August 2012
Available online 4 September 2012
Keywords:
Ethyl 1,5-disubstituted-1H-1,2,4-triazole
carboxylates
Regioselective acylation of N-substituted
hydrazines
Cyclodehydration
During a recent programme, the 1-alkylated-5-aryl-1H-1,2,4-
triazole-3-carboxamide ‘‘Motif 1’’ and the 1-arylated-5-alkylated-
1H-1,2,4-triazole-3-carboxamide ‘‘Motif 2’’ presented themselves
as interesting focal points for our research (Fig. 1). We were partic-
ularly interested in developing flexible methodology that would al-
low us to vary the two key diversity points at N-1 and C-5 and
studied multiple routes to the logical building ester blocks 1 and
2 (Schemes 1 and 2).
From our retrosynthetic analysis we generated 3 logical routes
(A, B and C) to the key building block 1. We quickly excluded Route
A as we found that access to 3 was going to be quite problematic
due to poor selectivity at the alkylation step of 4.1 Route B and Route
C are similar disconnections with a change in the order of the re-
agents. Route B allowed us to vary the substitution at N-1 easily
and with high selectivity as acylation of N-substituted hydrazines
(9) is well documented at the most substituted nitrogen within rea-
son (i.e., i-Pr but not t-Bu or Ar) affording 7.2 However, cyclisation of
7 with commercially-available ethyl 2-amino-2-thioxoacetate (5)
has only ever been reported in a two-step manner with unsubsti-
tuted primary acyl hydrazides3 and the final intramolecular cyclisa-
tion step involves very harsh conditions (n-BuOH,4 solvent-
free,3,5,8b DMF/KOH,6 pyridine and7 inert high boiling solvents such
as m-xylene8 usually at >150 °C) with variable yields. Route C
involved pre-synthesising the cyclisation precursor (10)6 and
carrying out a cyclodehydration reaction with the chosen carbox-
ylic acid (8).
Therefore, we decided to focus our efforts on Routes B and C in
order to achieve our goal. For Route B, regioselective acylation of
methylhydrazine was best achieved using EDCI/ Pfp-OH (pentaflu-
orophenol) with a model substrate, piperonylic acid (12), affording
a 8/2 mixture of regioisomers that were easily separated by stan-
dard chromatographic techniques. As we eluded to earlier in the
Letter, application of the cyclisation protocol to substituted acyl
hydrazides (i.e., 13) was very sketchy.9 After several trials in pyri-
dine, xylene, DMF at 90–160 °C, we found the combination of tol-
uene–AcOH (10:1) at 90–100 °C gave 14 in satisfactory yield. In
parallel, we investigated Route C. Condensation of 6 with meth-
ylhydrazine afforded a 1:1 mixture of 11 and the more lipophilic
regioisomer that was easily removed by chromatography. After
considerable process development, the amide coupling step with
11 proceeded in good yield using T3P as the coupling agent to af-
ford an unstable intermediate that was immediately cyclised
in situ using our mild protocol after concentration of the amide
coupling mixture. Unfortunately, although carboxylic acids are
readily commercially-available, we were forced to exclude this
route as 11 was not found to be sufficiently thermally-stable by
DSC testing (Scheme 2).10
We tested the scope of Route B by preparing a small library of 1,5-
disubstituted triazole products (Table 1). Use of the EDCI/Pfp-OH
coupling protocol proved advantageous in terms of favouring N-1
acylation (entries 1–5, 8–12) compared to previous carbodiimide
⇑
Corresponding author. Tel.: +33 3 26 61 5912; fax: +33 3 26 61 6842.
E-mail address: craig.harris2@astrazeneca.com (C.S. Harris).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.130

S. Degorce et al. / Tetrahedron Letters 53 (2012) 6078–6082
6079
O
R'
O
O
O
R'
N
N
O
O
N
H
N
N
N
N
N
H
N
N
N
Ar
N
Ar
N
R
Ar
Ar
N
R
1
R
R
2
"Motif 1" with 3
"Motif 2" with 3
diversity points
diversity points
Figure 1. Key target motifs for our research.
O
O
O
O
O
O
R-X
Route A
N
N
N
N
N
N
N
R
Br
N
H2N
N
Br
H
H
O
O
3
S
4
5
O
Route B
Route C
O
N
N
NH2
O
NH2
Ar
N
H2N
HN
Ar
OH
N
R
Ar
R
O
R
9
6
7
8
R
1
HN
S
N
O
NH2
O
O
HN
R
H2N
H2N
Ar
OH
O
O
8
10
9
6
Scheme 1. Retrosynthetic analysis of first target synthon 1.
O
O
HN
O
S
N
N
N
N
O
a
O
O
O
O
b
O
OH
H2N
H2N
O
O
6
14
11
12
c
d
O
NH2
O
O
N
13
Scheme 2. Preparation of ethyl 3-(benzo[d][1,3]dioxol-5-yl)-1-methyl-1H-1,2,4-triazole-5-carboxylate (14). Reagents and conditions: (a) methylhydrazine sulfate, K2CO3,
EtOH, 0 °C to r.t., 20 h, 37%; (b) T3P (50% w/w in EtOAc), 3 equiv DIPEA, 1,4-dioxane, r.t. 1 h then concentrate and dissolve in AcOH/1,4-dioxane (1:1), 100 °C, 1 h, 64%; (c) EDCI,
Pfp-OH, DCM, r.t., 2 h then add methylhydrazine, 74%; (d) ethyl 2-amino-2-thioxoacetate (6), toluene/AcOH (10:1), 100 °C, 16 h, 64%.
reported methodology.2b As expected, acylation was entirely regio-
selective at N-2 in the case of t-butylhydrazine and p-methoxyphen-
ylhydrazine driven by the steric and electronic factors, respectively.
Application of our mild cyclisation protocol proceeded with good
overall isolated yields when cyclising the N-1 substituted acyl
hydrazides (entries 1–5, 8–12) perhaps with a notable exception
of entry 5 where there was some evidence of degradation during
cyclisation. However, cyclisation of N-2 alkylated acyl hydrazides
afforded very poor isolated yields of cyclised product that can be
attributed to steric hindrance (entry 6) and the poor nucleophilicity
of the terminal substituted nitrogen atom (entry 7).
as it relied on attaining good chemical and regiochemical yields (N-
1 v N-2) at the arylation step on 37. The synthesis of 37 could be
envisaged from substituted carboximidohydrazides (38) readily at-
tained from nucleophilic addition of hydrazine directly on the cy-
ano precursors (39)13 or passing via an intermediate imidate.14
Route E (like Route C in Scheme 1) had several advantages as the
regiochemistry is fixed at the first step and there is high conver-
gence with Routes B and C, all using commercially-available 6
(Scheme 3).
Consequently, we employed Route E (Scheme 3) and were de-
lighted to observe that the entire process from the aryl hydrazine15
reactant could be carried out in a one-pot manner. Firstly, conden-
sation of the aryl hydrazine (9) with 6 proceeded efficiently at
room temperature in toluene-AcOH (10:1) to afford the intermedi-
ate 41 that was simply treated with a threefold excess of the final
After having accessed ‘‘Motif 1’’, we turned our attention to ‘‘Mo-
tif 2’’ that required us to vary the aryl group at N-1, therefore, tar-
geting building block 2. Based on the few existing references in the
literature11,12 Route D (like Route A) was viewed as very ambitious

6080
S. Degorce et al. / Tetrahedron Letters 53 (2012) 6078–6082
O
O
S
NH
N
HN
N
O
Route D
Ar-X
NH2
N
H2N
R
N
H
R
O
O
R
37
38
6
O
39
N
N
N
Ar
R
2
Route E
Ar
HN
S
O
N
H
N
O
O
H2N
Ar
NH2
R
LG
H2N
O
O
41
40
6
9
Scheme 3. Retrosynthetic analysis of second target synthon 2.
Ar
O
HN
N
O
H
N
N
N
a
b
O
Ar
NH2
N
H2N
Ar
6
O
O
9
R
2
R
LG
41
not isolated
40
Scheme 4. Preparation of ethyl 1-arylated-5-substituted-1H-1,2,4-triazole-3-carboxamides. Reagents and conditions: (a) ethyl 2-amino-2-thioxoacetate (6), toluene-AcOH
(10:1), r.t., 1 h, assumed quant.; (b) acylating reagent (3 equiv), 100 °C, 1 h, 27–71%.
Table 1
Selected results obtained after acylation of N-alkylhydrazines followed by cyclisation to the 1,2,4-triazole-3-carboxylic acid ethyl esters
O
O
EDCI, Pfp-OH,
DCM, r.t.
Toluene-AcOH
O
8
O
(10:1), 90 °C, 10 h
N
NH2
b
R
N
R
Ar
OH
Ar
N
a
b
NH2
HN
N
a
Ar
R
Entry
1
Compound
Ar
R
Acylation % yielda N1/N2
70/18
Compound
Cyclisation % yielda N1/N2
64/12
O
*
*
*
*
*
*
*
13a/b
CH3
Et
14a/b
O
O
2
3
4
5
6
7
15a
16a
17a
18a
19b
20b
70/traces
58/traces
65/traces
49/16
26a
27a
28a
29a
30b
31b
70/NA
60/NA
57/0
O
O
i-Pr
O
O
Ph
*
O
O
*
HO
35/NA
NA/traces
NA/14
O
O
t-Bu
traces/57a
traces/49a
O
O
*
O
O

S. Degorce et al. / Tetrahedron Letters 53 (2012) 6078–6082
6081
Table 1 (continued)
Entry
Compound
Ar
R
Acylation % yielda N1/N2
71/traces
Compound
Cyclisation % yielda N1/N2
Ph
O
8
21a
22a
CH3
32a
68/NA
53/NA
*
*
9
CH3
62/traces
33a
N
*
10
11
23a
24a
CH3
CH3
69/traces
48/traces
34a
35a
55/NA
64/NA
N
*
NC
*
12
25a
CH3
59/traces
36a
70/NA
N
H
NA = not applicable as the reaction was not carried out as only traces of the N-2 or N-1 isomer were isolated after the first step.
a
Isolated yields.
In conclusion and to the best of our knowledge, we have devel-
oped an efficient, rapid and diversity-orientated one-pot synthesis
to access the 1-5-disubstituted-1H-1,2,4-triazole-3-carboxylic acid
ethyl ester motif under mild conditions.
Table 2
Selected results obtained for the one-pot synthesis of 1-aryl-5-substituted-1H-1,2,4-
triazole-3-carboxylic acid ethyl esters (2)
Entry
Compound
Ar
R
% Yield
*
*
1
42
CH3
61
Acknowledgements
The authors would like to acknowledge Mr. Patrice Koza and
Mr. Christian Delvare for their analytical support, Dr. Stuart Wells
for the process safety evaluation and Dr. Gordon Currie, Dr. Arshed
Mahmood, Mr. Fabrice Renaud and Mr. Jonathan Lecoq for their
large-scale support.
2
3
42
43
CH3
CH3
41a
71
*
O
*
4
5
44
45
CH3
62
53
Supplementary data
Br
F
F
Supplementary data (Full experimental procedures and sup-
porting LCMS and 1H, 13C NMR and HRMS characterisation data
are available at noextra charge via the on-line version.) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.08.130.
*
CH3
CH3
N
*
*
6
7
46
47
44
35
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*
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O
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*
*
*
8
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48
49
27a
t-Bu
Traces
a
The corresponding acid chloride was used in the last step.
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