Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles

Article abstract of DOI:10.1021/ol048863a

(Equation Presented) An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles has been developed, utilizing a wide range of substituted primary amines and acyl hydrazides.

Full text of DOI:10.1021/ol048863a

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2969-2971
Efficient and Regiospecific One-Pot
Synthesis of Substituted 1,2,4-Triazoles
Michael J. Stocks,* David R. Cheshire, and Rachel Reynolds
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough, Leics LE11 5RH, United Kingdom
mike.stocks@astrazeneca.com
Received June 16, 2004
ABSTRACT
An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles has been developed, utilizing a wide range of substituted primary
amines and acyl hydrazides.
Many 1,2,4-triazoles are of biological interest,1 and as a
consequence, a number of synthetic methods have been
developed to construct this ring system.2 To date, there have
been no viable one-pot convergent syntheses reported. We
wish to communicate our initial work for an efficient one-
pot synthesis of substituted 1,2,4-triazoles 1, employing
readily available starting materials.
zonoformamide (3, R2 ) H, R3 ) Me) with a primary amine
followed by acid-catalyzed ring closure.3 The starting N′-
acetyl-N,N-dimethylhydrazonoformamide could be generated
in situ from the reaction of acetic hydrazide with dimeth-
ylformamide dimethyl acetal DMFDMA (Scheme 1).
We envisaged that substituted 1,2,4-triazoles 1 could be
obtained from the reaction of N′-acetyl-N,N-dimethylhydra-
Scheme 1. Proposed Retrosynthetic Pathway
(1) For selected recent examples, see: (a) Armour, D. R.; Baxter, A.
D.; Bryans, J. S.; Dack, K. N.; Johnson, P. S.; Lewthwaite, R. A.; Newman,
J.; Rawson, D. J.; Ryckmans, T. WO2004037809, 2004; Chem. Abstr. 2004,
140, 370921. (b) Cho, I.; Park, H.-J.; Noh, J.; Ryu, H.; Park, S.; Jung, S.;
Lee, S.; Kim, J.; Lim, J.; Lyu, C.; Kim, D.; Kim, Y.; Yeon, K.; Chae, M.;
Min, I.; Jin, H.; Kang, K. WO2004014878, 2004; Chem. Abstr. 2004, 140,
181455. (c) Krueger, M.; Petrov, O.; Thierauch, K.-H.; Siemeister, G.
WO2002094814, 2002; Chem. Abstr. 2002, 138, 4620. (d) Geslin, M.; Gully,
D.; Maffrand, J.-P.; Roger, P. WO2001044207, 2001; Chem. Abstr. 2001,
135, 46184. (e) Pascal, J.-C.; Carniato, D. EP1099695, 2001; Chem. Abstr.
2001, 134, 353312. (h) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.;
Csoregh, I.; Hessellink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112. (f)
Armour, D. R.; Price, David A.; Stammen, B. L. C.; Wood, A.; Perros, M.;
Edwards, M. P. WO2000039125, 2000; Chem. Abstr. 2000, 133, 74024.
(2) For selected methods of synthesis, see: (a) Garratt, P. J. In
ComprehensiVe Heterocyclic Chemistry II; Storr, R. C., Ed.; Elsevier:
Oxford, 1996; Vol. 4, pp 127-163, 905-1006. (b) Turnbull, K. In Progress
in Heterocyclic Chemistry; Elsevier: Oxford, 1998; Vol. 10, p 153. (c)
Balasubramanian, M.; Keay, J. G.; Scriven, E. F. V.; Shobana, N.
Heterocycles 1994, 37 (3), 1951. (d) Vanek, T. Velkova, V.; Gut, T. Collect.
Czech. Chem. Commun. 1984, 249, 2492. (e) Dunstan, A. R.; Weber, H.-
P.; Rihs, G.; Widner, H.; Dziadulewicz, E. K. Tetrahedron Lett. 1998, 39,
7983. (f) Vanden Eynde, J. J.; Estievenart, L.; Haverbeke, Y. V. Heterocycl.
Commun. 2000, 6, 412. (g) Lee, C. H.; Lee, K.-J. J. Heterocycl. Chem.
2002, 39, 845.
In our initial studies, N′-acetyl-N,N-dimethylhydrazono-
formamide4 4 was generated by combining acetic hydrazide
with DMFDMA in acetonitrile at 50 °C (see Scheme 2);
however, upon addition of a primary amine no further
reaction occurred, even at elevated temperatures. This is in
(3) Bartsch, H.; Erker, T. J. Heterocycl. Chem. 1990, 27, 991.
(4) Isolated as a crystalline solid; see the Supporting Information.
10.1021/ol048863a CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/22/2004

Scheme 2. Initial Results Employing 4-Fluorobenzylamine
Table 1. Results of Substituted 1,2,4-Triazole Synthesis
entry
R1-NH2
R2
R3
yielda (%)
1
2
3
4
5
6
7
8
9
4-fluorobenzylamine
4-fluorobenzylamine
benzylamine
4-methoxybenzylamine
4-nitrobenzylamine
aniline
aniline
4-methoxyaniline
4-methoxyaniline
Me Me
69
68
39
22
48
64
55
87
60
43
65
33
51
42
56
13
9
H
H
H
H
H
Me
Me
Me
Me
Me
agreement with Maquestiau,5 who suggested that the pro-
posed aminolysis would be disfavored by the presence of a
strong electron-donating group (NMe2) on the imino bond.
We decided to investigate this reaction further and
subjected the reaction to acidic catalysis as we envisaged
that protonation of the N′-acetyl-N,N-dimethylhydrazono-
formamide 3 would enhance the subsequent transamination
process. Interestingly, no reaction was observed with either
4 molar equiv of anhydrous hydrogen chloride or trifluoro-
acetic acid. However, gratifying evidence by LCMS of
conversion to N′-acetyl-N-(4-fluorobenzyl)hydrazonoforma-
mide (2, R1 ) 4-fluorobenzyl, R2 ) H, R3 ) Me) was
observed by the addition of either 4 molar equiv of acetic
or formic acid.
Me Me
Me
Me Me
H
10 ethyl 4-aminobenzoate
11 4-fluorobenzylamine
12 4-fluorobenzylamine
13 4-fluorobenzylamine
14 4-pyridylmethylamine
15 allylamine
16 propargylamine
17 cyclohexylamine
18 cyclohexylamine
H
H
H
H
H
H
H
H
H
Me
4-methylphenyl
4-methoxyphenyl
4-nitrophenyl
Me
Me
Me
Me
4-methylphenyl
13
a Yields refer to fully characterized and purified products.
the oxadiazole under the reaction conditions gave only a trace
amount of the desired compound 7; and the proposed
intermediary N′-acetyl-N,N-dimethylhydrazonoformamide 2
could be observed in the reaction mixture by LCMS, and
although isolation was difficult, a sample was obtained to
confirm the structure (2, R1 ) 4-fluorobenzyl, R2 ) H).
It has previously been reported that 1,2,4-triazoles can be
synthesized by cyclizing substituted (ethylamino)methylene-
hydrazides 2 in acetic acid at elevated temperatures.3 With
this knowledge, addition of acetic acid to the reaction mixture
containing the primary amine and 3, followed by increasing
the reaction temperature to 120 °C, afforded the desired 1,2,4-
triazoles6 (Scheme 2).
Further examination of the scope of the reaction revealed
that substituted anilines, benzylamines, and alkylamines can
also participate in the reaction. The role of the acyl group in
the hydrazide was also examined. The results are summarized
in Table 1.
Scheme 3. Alternative Reaction Pathway
Mechanistically, a second possible reaction pathway could
be envisaged (Scheme 3). In this process, 5 (R2 ) Me) could
cyclize under acidic conditions to generate 2,5-dimethyl-
1,3,4-oxadiazole7 6, which could then further react with a
primary amine to generate the substituted 1,2,4-triazole8 7.
We discount this alternative reaction pathway for the
following reasons: (1) the oxadiazole 6 was not detected in
the reaction mixture; (2) reaction of an authentic sample of
As can be seen from Table 1, the reaction is applicable to
a wide range of substituted primary amines, benzylamines,
and anilines; however, reaction with simple alkylamines
affords a low yield of product, and indeed in the case of
cyclohexylamine (entry 17), the major products detected were
the amidines 8 and 9 when DMFDMA was used (Scheme
4).
To investigate this reaction further, a series of dialkylfor-
mamide dimethyl acetals were prepared,9 and these were
subjected to the standard reactions conditions (see Table 2).
(5) Maquestiau, A.; Vanden Eynde, J.-J. Tetrahedron 1987, 43, 4195.
(6) General Procedure. In an open vessel, acetic hydrazide (407 mg,
5.5 mmol) was dissolved in acetonitrile (2 mL) and dimethylacetamide
dimethyl acetal (732 mg, 5.5 mmol) was added. The reaction mixture was
warmed to 50 °C for 30 min, and then 4-fluorobenzylamine (625 mg, 5
mmol) in acetonitrile (1 mL) was added followed by acetic acid (3 mL).
The reaction temperature was raised to 120 °C for 3 h, and then the mixture
was cooled and concentrated and the residue purified by chromatography
on silica gel eluting initially with ethyl acetate followed by 5% 0.7 N
ammonia in methanol in ethyl acetate to afford 4-(4-fluorobenzyl)-3,5-
dimethyl-4H-1,2,4-triazole (702 mg, 69%) as a white solid after trituration
with diethyl ether.
(8) (a) Reitz, D. B.; Finkes, M. J. J. Heterocycl. Chem. 1989, 26, 225.
(b) Carlsen, P. H. J.; Jorgensen, K. B. J. Heterocyl. Chem. 1994, 31, 805.
(c) Behringer, H.; Ramert, R. Justus Liebigs Ann. Chem. 1975, 7-8, 1264.
(d) Whittaker, M.; Davidson, A. H.; Spavold, Z. M.; Bowles, S. A.
WO9117157, 1991; Chem. Abstr. 1991, 117, 26321.
(7) (a) Tandon, V. K, and Chhor, R. B. Synth. Commun. 2001, 31, 1727.
(b) Ainsworth, C.; Hackler, R. E. J. Org. Chem. 1966, 31, 3442. (c) Boyd,
G. V.; Dando, S. R. J. Chem. Soc. C 1970, 1397.
2970
Org. Lett., Vol. 6, No. 17, 2004

Scheme 4. Reaction of Cyclohexylamine with Acetic
Table 2. Variation in Dialkylformamide Dimethyl Acetals:
Reaction with Cyclohexylamine
Hydrazide and DMFDMA
R1
R2
R3
yielda (%)
-(CH2)4-
-(CH2)5-
Me
Me
Me
Me
Me
8
11
9
Me
Me
-(CH2)2NMe2
52
a Yields refer to fully characterized and purified products.
An efficient one-pot, three-component synthesis of sub-
stituted 1,2,4-triazoles is reported. The reaction has scope
for parallel synthesis employing commercial or readily
available compounds. So far, the reaction is applicable to a
wide range of substituted primary amines, benzylamines, and
anilines; however, reaction with simple alkylamines, such
as cyclohexylamine, initially resulted in poor yields. This
has been overcome by using N-(dimethoxymethyl)-N,N′,N′-
trimethylethane-1,2-diamine instead of DMFDMA. We have
concentrated on the use of DMFDMA in the reaction
sequence due to its commercial availability. However, the
use of N-(dimethoxymethyl)-N,N′,N′-trimethylethane-1,2-
diamine appears to have a wider potential, and work is
underway in our laboratory to further explore the scope of
this reaction.
There was no increase in yield observed when either
1-(dimethoxymethyl)pyrrolidine or 1-(dimethoxymethyl)-
piperidine was employed; however, a dramatic increase in
yield was observed when N-(dimethoxymethyl)-N,N′,N′-
trimethylethane-1,2-diamine was used and probably results
from facile intramolecular protonation of the N,N,N′-tri-
methylethane-1,2-diamine in the transamination process.10
Improvements in the yield of two of the low-yielding
compounds noted in Table 1 were gained by using N-
(dimethoxymethyl)-N,N′,N′-trimethylethane-1,2-diamine. The
4- to 5-fold increase in yield (entry 16 increased from 13 to
55% and entry 18 from 13 to 41%) enforces the successful
replacement using N-(dimethoxymethyl)-N,N′,N′-trimethyl-
ethane-1,2-diamine instead of DMFDMA in these low-
yielding cases.11
Acknowledgment. We are grateful to Dr. Tony Ingall
for helpful discussions.
(9) (a) Kump, W.; Traxler, P.; Scartazzini, R. EP49683, 1982; Chem.
Abstr. 1982, 97, 72194. (b) Ott, P.; Hansen, H.-J. HelV. Chim. Acta 2001,
84, 2670.
(10) A similar example of this effect observed employing N-(dimethoxy-
methyl)-N,N′,N′-trimethylethane-1,2-diamine as a leaving group under acidic
catalysis was observed in the comparison of the acidic hydrolysis of
substituted benzamides; see: Comins, D. L.; Brown, J. D. Tetrahedron Lett.
1983, 24, 5465.
(11) In the case of entry 2, a comparable yield of product was obtained
when either DMFDMA or N-(dimethoxymethyl)-N,N′,N′-trimethylethane-
1,2-diamine was used.
Supporting Information Available: 1H and 13C NMR,
microanalysis, and MS data for the products illustrated in
Table 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048863A
Org. Lett., Vol. 6, No. 17, 2004
2971