Efficient one-pot formation of 4-N-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones from primary amines using N′-(ethoxymethylene)hydrazinecarboxylic acid methyl ester

Article abstract of DOI:10.1016/j.tetlet.2006.07.089

(E)-N′-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yield. This reagent was successfully applied to the one-pot synthesis of 4-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones from readily available primary alkyl and aryl amines. This reaction process is relatively mild and easy to carry out. It is especially useful for the formation of sterically hindered triazolinones, which are otherwise difficult to obtain via existing literature procedures. A possible mechanistic pathway for the transformation is outlined.

Full text of DOI:10.1016/j.tetlet.2006.07.089

Tetrahedron Letters 47 (2006) 6743–6746
Efficient one-pot formation of 4-N-substituted
2,4-dihydro-3H-1,2,4-triazolin-3-ones from primary amines using
N0-(ethoxymethylene)hydrazinecarboxylic acid methyl ester
Ning Shao, Cheng Wang, Xianhai Huang,* Dong Xiao,* Anandan Palani,
Robert Aslanian and Neng-Yang Shih
Department of Medicinal Chemistry, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA
Received 5 July 2006; revised 14 July 2006; accepted 19 July 2006
Available online 8 August 2006
Abstract—(E)-N0-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester was synthesized in one step in good yield. This reagent
was successfully applied to the one-pot synthesis of 4-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones from readily available pri-
mary alkyl and aryl amines. This reaction process is relatively mild and easy to carry out. It is especially useful for the formation of
sterically hindered triazolinones, which are otherwise difficult to obtain via existing literature procedures. A possible mechanistic
pathway for the transformation is outlined.
Ó 2006 Elsevier Ltd. All rights reserved.
2,4-Dihydro-3H-1,2,4-triazolin-3-ones
(triazolinones)
A),8 and intramolecular condensation of an amidrazone
3 (aminoalkylidenehydrazine carboxylate) (pathway B)9
(Scheme 1). However, the application of these two
routes to the preparation of triazolinones 4 (R = H),
which is the interest of our research is very limited.
Herein, we report a general and efficient method to syn-
thesize 2,4-dihydro-3H-1,2,4-triazolin-3-ones 4 (R = H)
(Scheme 1) from primary amines. We have recently
are important pharmacophores in the drug discovery
process. Their biological activity and diverse medicinal
uses are exemplified by a range of therapeutic agents
such as antiviral and antitumor agents,1 antihistamines,2
antibacterial agents,3 cytidine aminohydrolase inhibi-
tors,4 antihypertensive agents,5 and central nervous sys-
tem drugs.6 Among the reported synthetic methods for
the construction of triazolinones, one of the most often
used is nucleophilic substitution of an alkyl halide5 or
Mitsunobu reaction7 of an alcohol with a triazolinone
synthon. However, these reactions do not work well
for sterically hindered substrates because of their SN2
reaction character. Thus, alternative methods to con-
struct hindered triazolinones are of increasing interest
because of the growing demand for these moieties in
the pharmaceutical industry. Two primary synthetic
routes have been reported to synthesize non sterically
O
HN
N
R
NH2
H
O
NH
R1
R3
R2
R1
R3
R2
1
2
pathway A
hindered
2-hydro-4-substituted-3H-1,2,4-triazolin-3-
ones 4 (R = aryl or alkyl): through intramolecular
condensation of a 1-acyl semicarbazide 2 (pathway
R
HN
R1
N
NHCO2Me
HN
R1
N
O
R
N
pathway B
R3
Keywords: (E)-N0-(Ethoxymethylene)hydrazinecarboxylic acid methyl
ester; One pot; Sterically hindered triazolinones.
R2
R3
R2
*
3
R = H, alkyl, or aryl
Corresponding authors. Tel.: +1 908 740 3487; fax: +1 908 740
7664; e-mail addresses: xianhai.huang@spcorp.com; dong.xiao@
spcorp.com
4
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.089

6744
N. Shao et al. / Tetrahedron Letters 47 (2006) 6743–6746
reported the application of pathway A to the synthesis
of triazolinones 4 (R = H);10 in this letter, we examine
the feasibility of pathway B.
When a mixture of 5 (5 equiv) and 6 in ethanol was
heated at 50 °C for 72 h, intermediate 7 could be isolated
Many of the methods reported in the literature to pre-
pare amidrazone 3 involve the reaction of a hydrazino-
carboxylate with an iminoyl chloride, which often
needs to be synthesized from an appropriate amine.
Thus, this latter operation contributes an extra step to
the synthetic sequence. Secondly, another disadvantage
is potential sensitivity of other functional groups in the
molecule to the iminoyl chloride moiety. Most impor-
tantly, none of the existing methods to convert 3 to 4
worked well for sterically hindered triazolinones such
as those in which we were interested. Thus, new methods
to prepare 3 and new conditions to transform 3 to 4 are
of general interest. We surmised that 3 could be ob-
tained in one step if a reagent could be prepared that
would readily react with amines 1. Thus, we turned
our attention to the preparation of reagent N0-(eth-
oxymethylene)hydrazinecarboxylic acid methyl ester 5,
which should react with amines under very mild condi-
tions.11,12 Fortunately, when methyl hydrazinocarboxyl-
ate was heated in neat triethyl orthoformate at 88 °C
for 64 h, compound 5 was obtained in good yield as a
white solid (Scheme 2). This reagent is stable for months
under ambient conditions and its shelf life can be
extended by storage over an appropriate drying agent.
1H-NOESY NMR spectroscopic studies showed the
structure of 5 prepared under these reaction conditions
to be the E-isomer.
Table 1. Efficient one-pot formation of 4-N-substituted 2,4-dihydro-
3H-1,2,4-triazolin-3-ones from primary amines using N0-(ethoxymeth-
ylene)hydrazinecarboxylic acid methyl estera
Entry
Amine
Triazolinone (yield)b
O
N
NH2
NH
1
MeO
N
MeO
9
17 (74%)
HN
N
NH2
O
N
2
10
18 (94%)
HN
N
NH2
O
N
3
4
11
19 (76%)
N
N
O
N
NH2
NH
N
With compound 5 in hand, we proceeded to explore the
synthesis of intermediate 3 and its subsequent conver-
sion to triazolinone 4. Since we were interested particu-
larly in the formation of hindered triazolinones, we
chose tert-alkyl amine 6 as an initial starting material.
12
20 (65%)
HN
N
H2N
O
N
5
6
7
8
88 oC
13
NHCO2Me
H2NNHCO2Me
+
CH(OEt)3
EtO
N
21 (81%)
HN
65%
5
N
NH2.HCl
Scheme 2.
O
Ph
N
Ph
14
22 (55%)
H
N
N
CO2Me
NH2
EtOH, 50 oC
80%
N
NHCO2Me
NH
EtO
N
+
HN
H2N
N
O
6
5
7
conditions
low yield
15
23 (76%)
H
N
HN
O
N
N
NH
H2N
NH2
N
EtOH, 50 oC then
NaOMe/MeOH, 75 oC
N
O
O
N
N
16
70%
24 (34%)
one pot
8
a See Supplementary data for detailed procedure.
b Isolated yield of spectroscopically pure product.
Scheme 3.

N. Shao et al. / Tetrahedron Letters 47 (2006) 6743–6746
6745
in good yield. We then attempted to convert 7 to 8.
However, to our disappointment, when 7 was subjected
to literature methods for converting amidrazones to
triazolinones, such as heating to high temperature9a,b
or reacting under acidic conditions,9c,d 7 was reluctant
to cyclize or gave only a low yield of 8. We initially
thought the failure might be due to the steric hindrance
of the tert-alkyl group. After several failed attempts, we
surprisingly discovered that compound 8 could be iso-
lated in good yield when the reaction was carried out
in a one-pot fashion by addition of NaOMe/methanol
solution to the reaction mixture after the first step was
complete (Scheme 3).
obtained under the current conditions are slightly lower
than those obtained using pathway A; however, the
yield of the cyclization step is comparable despite that
the new conditions represent a two-step process per-
formed in a one-pot fashion. Although it appears that
this new method is only applicable to sterically hindered
triazolones of generic structure 4 (Scheme 1, R = H), as
reaction of an amine with a disubstituted hydrazone
could be slow, further investigation is in progress for
the efficient formation of 5-substituted triazolinones (4,
R = alkyl).
As shown above, the one-pot reaction proceeds well to
give the desired product. However, as described earlier,
the intermediate tert-alkyl amidrazone 7 does not cyclize
or gives only a low yield of 8 under a variety of condi-
tions when 7 is isolated in pure form. This apparently
contradictory result prompted us to formulate a possible
mechanistic pathway by which this reaction could take
place. Although it has been reported in the literature9
that 7 is a precursor for the formation of less sterically
hindered triazolinones, we propose that 25 could be an
alternative reaction intermediate in the formation of
more sterically hindered triazolinones. As outlined in
Scheme 4, in the one-pot reaction, we believe that com-
pound 6 first reacts with reagent 5 to give intermediate
25. Upon treatment with NaOMe, deprotonation of
the nitrogen proton alpha to the carboxylate in 25 gives
anion 26, which collapses to isocyanate 260. This reac-
tive isocyanate undergoes ring closure to give 27, which
then loses a molecule of EtOH to give the desired
product.
With the reaction conditions well established, the scope
of this synthetic method was investigated. A variety of
primary and aromatic amines react well to give the
desired product in good to excellent yield, as shown in
Table 1. n-Alkyl amines and aniline give excellent yields
of the products (entries 1 and 2). sec-Alkyl amines work
well as well (entries 3 and 4). More importantly, steri-
cally hindered tert-alkyl amines cyclize smoothly to give
desired triazolinones 21, 22, and 23 in moderate to good
yield (entries 5, 6, and 7). Furthermore, when two hin-
dered triazolinone units are present in the same sub-
strate (entry 8), a 34% yield of product 24 could be
obtained. The synthesis of such tert-alkyl triazolinones
under literature reported standard conditions9 is very
difficult. It is noteworthy that when the starting material
is an amine HCl salt, the reaction also proceeds
smoothly to give the desired product, albeit in slightly
lowered yield (entry 6). Since the reaction is carried
out under mild basic conditions (NaOMe/MeOH), func-
tional groups such as the phenolic methyl ether (entry
1), tertiary amine (entry 4), and alkyne (entry 7) are
all stable under the reaction conditions. Compared to
our previously reported route10 (Pathway A, Scheme
1), the current method utilizes a novel and readily syn-
thesized reagent 5 to form amidrazones, which are
otherwise difficult to synthesize from primary amines,
and which are subsequently converted to triazolinones
under relatively mild basic conditions. The yields
In the case of the stepwise process in which 7 is isolated
and then resubjected to cyclization conditions, extensive
NMR spectroscopic studies have shown that the config-
uration of the C@N bond of 7 is predominantly cis,
which should enable the closure of the ring. However,
steric hindrance and the ring strain caused by the double
bond may increase the difficulty to form the desired
product under traditional heating or acidic conditions.
Under the currently investigated basic conditions, two
OEt
NH2
NHCO2Me
HN
N
NHCO2Me
one pot
+
EtO
N
H
6
5
25
NaOMe/MeOH, 75 oC
O
HN NH
O
N
N
NH
HN
N
HN
N
- EtOH
good yield
EtO
O
OMe
EtO
N
NH
- MeO-
EtO
O
NH
27
8
26'
26
Scheme 4.

6746
N. Shao et al. / Tetrahedron Letters 47 (2006) 6743–6746
H
N
Acknowledgements
N
CO2Me
NH2
EtOH, 50 oC
isolation
NHCO2Me
NH
We thank Drs. T.-M. Chan and Ross Yang for NMR
spectrometry and mass spectrometry assistance, respec-
tively; Dr. Michael Wong for helpful discussions and
proof-reading of the manuscript; and Drs. Catherine
Strader, John Piwinski, and Satwant Narula for their
strong support of the postdoctoral program.
+
EtO
N
6
5
7
NaOMe/MeOH, 75 oC
OMe
N
NH
Supplementary data
N
N CO2Me
NCO2Me
HN
N
O
N
NH
H
low yield
Experimental details and spectral data for all new com-
pounds. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.07.089.
25'
8
28
References and notes
NH2
NHCO2Me
1. (a) Michael, J.; Larson, S. B.; Vaghefi, M. M.; Robins, R.
K. J. Heterocycl. Chem. 1990, 27, 1063; (b) Haines, D. R.;
Leonard, N. J.; Wiemer, D. F. J. Org. Chem. 1982, 47,
474.
+
MeO
N
6
5'
2. Loev, B.; Musser, J. H.; Brown, R. E.; Jones, H.; Kahen,
R.; Huang, F.-C.; Khandwala, A.; Sonnino-Goldman, P.;
Leibowitz, M. J. Med. Chem. 1985, 28, 363.
3. Malbec, F.; Milcent, R.; Vicart, P. J. Heterocycl. Chem.
1984, 21, 1769.
Scheme 5.
possible intermediates, 250 and 28, can be formed
(Scheme 5) when 7 is treated with NaOMe/MeOH.
Intermediate 250 can either undergo the same process
as intermediate 25 (Scheme 4) to give the desired prod-
uct, or alternatively dissociate to starting material 6
and compound 50, which is unlikely to revert to 250 un-
der the reaction conditions because the formation of 250
requires an excess of reagent 50 (5 equiv) as well as pro-
longed reaction time. For intermediate 28, the anion
formed is a more stabilized one than that in 26 and it
may not follow the same reaction pathway as intermedi-
ate 26. So either way (through intermediate 250 or 28)
will give low yield of compound 8 for sterically hindered
cases. However, we are not ruling out 7 as the interme-
diate for less sterically hindered substrates because 7 is
the observed intermediate by both mass spectroscopy
and after isolation in all cases. Further investigation into
the reaction pathway is underway, and will be reported
in due course.
4. Hrebabecky, H.; Beranek, J. Collect. Czech. Chem. Com-
mun. 1985, 50, 779.
5. Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Chen,
T.-B.; O’Malley, S. S.; Zingaro, G. J.; Kivlighn, S. D.;
Siegl, P. K. S.; Lotti, V. J.; Chang, R. S. L.; Greenlee, W.
J. Med. Chem. 1995, 38, 3758, and references cited therein.
6. Cowden, C. J.; Wilson, R. D.; Bishop, B. C.; Cottrel, I. F.;
Davies, A. J.; Dolling, U.-H. Tetrahedron Lett. 2000, 41,
8661.
7. Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Rivero, R.
A.; Chen, T.-B.; O’Malley, S. S.; Zingaro, G. J.; Kivlighn,
S. D.; Siegl, P. K. S.; Lotti, V. J.; Chang, R. S. L.;
Greenlee, W. J. Bioorg. Med. Chem. Lett. 1994, 4, 2787.
8. Madding, G. D.; Smith, D. W.; Sheldon, R. I.; Lee, B. J.
Heterocycl. Chem. 1985, 22, 1121.
9. (a) Uneyama, K.; Yamashita, F.; Sugimoto, K.; Mori-
moto, O. Tetrahedron Lett. 1990, 31, 2717; (b) Moffett, R.
B.; Kamdar, B. V. J. Heterocycl. Chem. 1979, 16, 793; (c)
Bartsch, H.; Erker, T. J. Heterocycl. Chem. 1988, 25, 1151;
(d) Bartsch, H.; Erker, T. J. Heterocycl. Chem. 1990, 27,
991; (e) Grandolini, G.; Ambrogi, V.; Perioli, L. Farmaco
1996, 51, 203; (f) Shapiro, R.; DiCosimo, R.; Hennessey,
S. M.; Stieglitz, B.; Campopiano, O.; Chiang, G. C. Org.
Proc. Res. Dev. 2001, 5, 593.
In conclusion, we have synthesized (E)-N0-(ethoxymeth-
ylene)hydrazinecarboxylic acid methyl ester in good
yield. This reagent was successfully applied to the one-
pot synthesis of 4-substituted 2,4-dihydro-3H-1,2,4-
triazolin-3-ones from readily available aromatic and
primary amines. This reaction process is relatively mild
and easy to carry out. It is especially useful for the
formation of sterically hindered triazolinones, which
are otherwise difficult to synthesize using existing litera-
ture procedures. A possible mechanistic pathway for the
transformation was outlined and further studies of the
reaction pathway are ongoing.
10. Huang, X.; Palani, A.; Xiao, D.; Aslanian, R.; Shih, N.-Y.
Org. Lett. 2004, 6, 4795.
11. Pathak, U. S.; Rathod, I. S.; Patel, M. B.; Shirsath, V. S.;
Jain, K. S. Indian J. Chem., Sect. B 1995, 34, 617.
12. (Z)-N0-(Ethoxymethylene)hydrazinecarboxylic acid ethyl
ester was prepared over two decades ago, but few synthetic
applications of this reagent have been reported. See:
Milcent, R.; Vicart, P.; Bure, A.-M. Eur. J. Med. Chem.
Chim. Ther. 1983, 18, 215.