Manipulation of N,O-nucleophilicity: Efficient formation of 4-N-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones

Article abstract of DOI:10.1021/ol0478638

(Chemical Equation Presented) A new efficient two-step synthesis of 2,4-dihydro-3H-1,2,4-triazolin-3-ones (triazolinones) from readily available amines is reported. Our novel conditions using hexamethyl disilazane, bromotrimethylsilane, and a catalytic amount of ammonium sulfate smoothly cyclize 1-formyl and 1-acetyl semicarbazides to the target triazolinones. This transformation features simultaneous manipulation of N- and O-nucleophilicity as well as differentiation of the nucleophilicity of a urea and an acyl carbonyl.

Full text of DOI:10.1021/ol0478638

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4795-4798
Manipulation of N,O-Nucleophilicity:
Efficient Formation of 4-N-Substituted
2,4-Dihydro-3H-1,2,4-Triazolin-3-ones
Xianhai Huang,* Anandan Palani, Dong Xiao, Robert Aslanian, and
Neng-Yang Shih
Department of Medicinal Chemistry, Schering-Plough Research Institute,
Kenilworth, New Jersey 07033
xianhai.huang@spcorp.com
Received October 15, 2004
ABSTRACT
A new efficient two-step synthesis of 2,4-dihydro-3H-1,2,4-triazolin-3-ones (triazolinones) from readily available amines is reported. Our novel
conditions using hexamethyl disilazane, bromotrimethylsilane, and a catalytic amount of ammonium sulfate smoothly cyclize 1-formyl and
1-acetyl semicarbazides to the target triazolinones. This transformation features simultaneous manipulation of N- and O-nucleophilicity as well
as differentiation of the nucleophilicity of a urea and an acyl carbonyl.
2,4-Dihydro-3H-1,2,4-triazolin-3-ones (triazolinones) have
been very 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 inhibitors,4 antihypertensive
agents,5 and central nervous system drugs.6 Recently, we
have become interested in 4-N-substituted triazolinones 3
as part of our own research program. Among the synthetic
methods for the construction of triazolinones, three are most
often used: the first is nucleophilic substitution of an alkyl
halide5 or Mitsunobu reaction7 of an alcohol with a tri-
azolinone synthon, the second is intramolecular condensation
of a 1-acyl semicarbazide,8
and the third is intramolecular
condensation of an amidrazone (aminoalkylidenehydrazine
carboxylate).9 In our synthetic efforts, however, we found
that all existing methods proved to be fruitless for formation
of the sterically hindered neopentyl triazolinones 3. Our
primary focus was on intramolecular condensation of formyl
semicarbazides 1 (Scheme 1) since this is one of the most
commonly used methods in the literature. However, with the
typical literature procedures, hydrolytic base-induced con-
densation conditions (aqueous KOH or NaOH with heat),4,10
our compounds simply decomposed. When we tried to
activate the 1-formyl group by formation of an imidoyl
(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.
(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.
(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.
(3) Malbec, F.; Milcent, R.; Vicart, P. J. Heterocycl. Chem. 1984, 21,
1769.
(4) Hrebabecky, H.; Beranek, J. Collect. Czech. Chem. Commun. 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, 3741, and references 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.
(8) Madding, G. D.; Smith, D. W.; Sheldon, R. I.; Lee, B. J. Heterocycl.
Chem. 1985, 22, 1121.
(9) (a) Uneyamma, K.; Yamashita, F.; Sugimoto, K.; Morimoto, 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. IL 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.
10.1021/ol0478638 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/10/2004

philicity of the urea nitrogen by formation of an O-silylurea
5.
Scheme 1
chloride using PCl511 or POCl3,12 we did obtain some desired
product 3, but only in about 10% yield. The major product
isolated under these conditions was 1,3,4-oxadiazole 2. Two
possible pathways could lead to formation of 2. The first
pathway (route a, Scheme 2) is activation of the formyl group
However, no desired product 3 was obtained when 1 was
treated with 1 equiv of N,O-bis(trimethylsilyl)-acetamide
(BSA)13 or chlorotrimethylsilane (TMSCl) followed by 1
equiv of PCl5 to activate the formyl group. These failures
prompted us to wonder whether we could achieve activation
of both the proximal urea nitrogen and the formyl group
with silylation and thus realize the desired ring closure in
one pot. This in fact turned out to be the case, and we
eventually developed a new method to form hindered
triazolinones as reported herein.
Scheme 2
To test the idea of double activation, 1-formyl semicar-
bazide 8 was synthesized and subsequent cyclization condi-
tions were investigated (Table 1). We chose the hindered
Table 1. Optimization of Reaction Conditions for the
Synthesis of Triazolinone 9 from 1-Formyl Semicarbazide 8
entry
conditions
yield
1
2
3
4
5
6
7
HMDS/TMSCl/pya
<5c
15d
45d
<5c
<5c
<5e
65d
of 1 to form a terminal imidoyl chloride 4, followed by attack
of the urea carbonyl oxygen (e.g., 4a). Note that the imidoyl
chloride 4 may also cyclize via attack of the urea nitrogen
(e.g., 4b) to give 3. The second pathway to 2 (route b,
Scheme 2) is activation of the urea moiety to form amino
imidoyl chloride 6, which is attacked by the formyl oxygen.
Although we could not rule out either route to 2, to form
the desired triazolinone 3 we had to either improve the
nucleophilicity of the proximal urea nitrogen (4b, route a)
or block reaction of the urea carbonyl (route b and 4a, route
a). To stop formation of 6, we first tried to temporarily mask
the urea carbonyl and simultaneously improve the nucleo-
HMDS/(NH4)2SO4 (catalyst)b
HMDS/TMSCl/(NH4)2SO4 (catalyst)b
HMDS/TMSCl/(NH4)2SO4 (catalyst) in DMFa
b
HMDS/TMSCl/Sc(OTf)3
HMDS/TMSClb
HMDS/TMSBr/(NH4)2SO4 (catalyst)b
a Reaction was carried out at 100 °C. b Reaction was carried out at 140
°C with HMDS as a solvent. c Decomposition was observed. d Isolated yield.
e No reaction.
neopentylamine 7 in this model so that the conditions would
apply directly to our ongoing research program. Compound
8 was conveniently synthesized from amine 7 by treatment
with phosgene to form an intermediate isocyanate followed
by reaction with formyl hydrazide. With 8 in hand, we first
tried the cyclization under basic conditions with hexameth-
yldisilazane (HMDS) and TMSCl in pyridine1b at 100 °C
(entry 1); these conditions only resulted in the decomposition
(10) (a) Xu, Y.; Mayhugh, D.; Saeed, A.; Wang, X.; Thompson, R. C.;
Dominianni, S. J.; Kauffman, R. F.; Singh, J.; Bean, J. S.; Bensch, W. R.;
Barr, R. J.; Osborne, J.; Montrose-Rafizadeh, C.; Zink, R. W.; Yumibe, N.
P.; Huang, N.; Luffer-Atlas, D.; Rungta, D.; Maise, D. E.; Mantlo, N. B. J.
Med. Chem. 2003, 46, 5121. (b) Tanoury, G. J.; Senanayake, C. H.; Hett,
R.; Kuhn, A. M.; Kessler D. W.; Wald, S. A. Tetrahedron Lett. 1998, 39,
6845. (c) Pachuta-Stec, A.; Dobosz, M. Acta Pol. Pharm. 2001, 58, 307.
(11) (a) Langer, P.; Helmholz, F.; Schroeder, R. Synlett 2003, 2389. (b)
Vales, M.; Lokshin, V.; Pepe, G.; Guglielmetti, R.; Samat, A. Tetrahedron
2002, 58, 8543.
(13) (a) Xiang, G.; McLaughlin, L. W. Tetrahedron 1998, 54, 375. (b)
Meng, G.; Chen, F.-E.; Clercq, E. D.; Balzarini, J.; Pannecouque, C. Chem.
Pharm. Bull. 2003, 51, 779.
(12) Herbert, J. M.; Woodgate, P. D.; Denny, W. A. J. Med. Chem. 1987,
30, 2081.
4796
Org. Lett., Vol. 6, No. 25, 2004

low yield to a slow rate of silylation under the reaction
conditions. To overcome this, TMSCl was used as an additive
and HMDS was used as a solvent (entry 3, Table 1). To our
delight, 9 was obtained in 45% yield under these conditions.
To further improve the reaction, DMF was employed as a
solvent, but this only resulted in decomposition of the starting
material (entry 4, Table 1). Since the protic salt ammonium
sulfate was a beneficial catalyst in this reaction, we inves-
tigated Lewis acid Sc(OTf)3 as an alternative. To our
disappointment, however, this Lewis acid only gave us a trace
amount of 9 (entry 5, Table 1). When the reaction was carried
out without any acid (entry 6, Table 1), the reaction did not
proceed, and only the starting material was recovered. This
suggested that the combination of HMDS, TMSCl, and a
catalytic amount of ammonium sulfate is essential for the
success of the one-pot silylation and triazolinone formation.
Finally, the optimized conditions (entry 7, Table 1) were
found by employing the more powerful co-silylating agent
TMSBr, and 9 was obtained in 65% yield.
Table 2. Efficient Ring Closure of 1-Formyl Semicarbazides to
Form Triazolinones Using HMDS/TMSBr/(NH4)2SO4
a
Encouraged by this result, the scope of this new synthetic
method for the efficient construction of 4-substituted tri-
azolinones was investigated. The 1-formyl semicarbazide
precursors were again synthesized from the corresponding
primary amines through isocynate formation followed by
reaction with formyl hydrazides, in good to excellent yields
(Table 2).
The ring closure reaction was carried out on semicarba-
zides 17-23 using the optimized combination of HMDS/
TMSBr/(NH4)2SO4 (catalyst) (Table 2). As shown in Table
2, starting from monoalkylamines (entry 1, Table 2) and
disubstituted alkylamines (entries 2-5, Table 2), the corre-
sponding triazolinones 24-28 were obtained in good to
excellent yields. More importantly, sterically hindered neo-
pentyl semicarbazides 22 and 23 cyclized smoothly to give
desired triazolinones 29 and 30 in excellent yields (entries
6 and 7, Table 2). The phenolic methyl ether (entry 1, Table
2), benzyl ether (entry 3, Table 2), and alkyne group (entry
7, Table 2) are all stable under the reaction conditions. One
interesting reaction worth mentioning is that of cyanoalkyl
semicarbazide 21 (entry 5, Table 2). Under the same reaction
conditions, a cyano group, which will not survive hydrolytic
conditions such as aqueous NaOH or KOH in ethanol, is
Scheme 3
a See Supporting Information for a detailed procedure. b Isolated yield
of spectroscopically pure product.
of the starting material. Since silylation with HMDS is most
commonly carried out with acid catalysis,14 we then tried
the reaction with a catalytic amount of the weak acid
ammonium sulfate (NH4)2SO4 (entry 2, Table 1) in the
presence of HMDS. These conditions did indeed provide
compound 9, although in only 15% isolated yield with most
of the starting material being recovered. We attributed the
(14) Langer, S. H.; Connell, S.; Wender, I. J. Org. Chem. 1958, 23, 50.
Org. Lett., Vol. 6, No. 25, 2004
4797

stable and 21 smoothly cyclized to give 28 in good yield.
This proves the mildness and usefulness of this reaction. To
this end, all reaction results suggest that activation of both
carbonyl groups in 1-formyl semicarbazides with silylation
is in fact possible and supports our proposed mechanism for
the formation of triazolinones (Scheme 3). Initial treatment
of 1 with HMDS/TMSBr/(NH4)2SO4 (catalyst) results in
double silylation to give 31. At this point, not only is the
nucleophlicity of the proximal urea nitrogen improved but,
in addition, only this nitrogen is available to attack the
terminal silyloxy imine to give 32. This ring-closed product
then loses a molecule of TMSOTMS to give triazolinone 3.
paves the way for synthesis of other structurally diverse
triazolinones.
In conclusion, we have developed new conditions using
HMDS, TMSBr, and catalytic (NH4)2SO4 to efficiently
convert 1-formyl semicarbazides into 4-substituted 2,4-
dihydro-3H-1,2,4-triazolin-3-ones (triazolinones). A possible
mechanism for this transformation is outlined that features
manipulation of N- and O-nucleophilicity as well as dif-
ferentiation of the nucleophilicity of a urea and an acyl
carbonyl. Formation of 4,5-disubstituted triazolinones can
also be realized under the same reaction conditions, providing
a new route to structurally diversified triazolinones. Given
the high efficiency and ease with both semicarbazide
formation and ring closure starting from very readily
available primary amines, this new method will be very
useful in targeted SAR development and possibly parallel
synthesis as well.
To further demonstrate the utility of this new reaction,
1-acetyl semicarbazide 33 was synthesized from amine 12
(Scheme 4). Compound 33 smoothly cyclized under the same
Scheme 4
Acknowledgment. We thank Dr. Ross Yang for mass
spectrometry assistance, Dr. Jared Cumming and Dr. Hong-
mei Li for helpful discussions and proofreading of the
manuscript, Dr. John Piwinski for strong support of the
program, and Sapna Shah, Ashwin Rao, and Xiao Chen for
general help.
Supporting Information Available: Experimental details
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
reaction conditions to give 4,5-disubtituted triazolinone 34
in 40% yield. This provides a route to incorporate other
functionality at the 5-position of the triazolinones and thus
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Org. Lett., Vol. 6, No. 25, 2004