An efficient and general urazole synthesis

Article abstract of DOI:10.1016/j.tetlet.2012.04.131

A general two-step scheme for the synthesis of N4 substituted urazoles (i.e., 1,2,4-triazolin-3,5-diones) is described. The first step involves the reaction of a primary amine with 2.5 equiv of phenyl chloroformate to produce diphenyl (N-substituted)imidodicarbonates. The second step involves the reaction of these compounds with hydrazine to produce N4 substituted urazoles. The mild reaction conditions permit synthesis of N4 oxygenated urazoles, not available via existing methodology. Bicyclic urazoles can be prepared through the subsequent reaction of these N4-protected urazoles with 2.5 equiv of NaH in DMF together with either 1,3-dibromopropane or 2-(tert-butyldimethylsilyloxy)-1,3- dibromopropane in the presence of NaI. The resultant bicyclic urazoles are observed to display varying degrees of pyrimidalization at N1 and N2, depending on substituents.

Full text of DOI:10.1016/j.tetlet.2012.04.131

Tetrahedron Letters 53 (2012) 3514–3517
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Tetrahedron Letters
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An efficient and general urazole synthesis
⇑
Weirui Chai, Yuan Chang, John D. Buynak
Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general two-step scheme for the synthesis of N4 substituted urazoles (i.e., 1,2,4-triazolin-3,5-diones) is
described. The first step involves the reaction of a primary amine with 2.5 equiv of phenyl chloroformate
to produce diphenyl (N-substituted)imidodicarbonates. The second step involves the reaction of these
compounds with hydrazine to produce N4 substituted urazoles. The mild reaction conditions permit
synthesis of N4 oxygenated urazoles, not available via existing methodology. Bicyclic urazoles can be
prepared through the subsequent reaction of these N4-protected urazoles with 2.5 equiv of NaH in
DMF together with either 1,3-dibromopropane or 2-(tert-butyldimethylsilyloxy)-1,3-dibromopropane
in the presence of NaI. The resultant bicyclic urazoles are observed to display varying degrees of
pyrimidalization at N1 and N2, depending on substituents.
Received 5 March 2012
Revised 24 April 2012
Accepted 29 April 2012
Available online 3 May 2012
Keywords:
Urazole
Imidodicarbonate
Synthesis
Alkoxyurazole
Ó 2012 Elsevier Ltd. All rights reserved.
Urazoles (1,2,4-triazolidine-3,5-diones, 1) represent poten-
tially important scaffolds for the design of pharmacologically ac-
tive materials,1 and polymers.2 The oxidized forms of these
heterocycles, 1,2,4-triazole-3,5-diones (in particular 4-phenyl-
1,2,4-triazole-3,5-dione, 2, R3 = Ph) have been used extensively
as reactive dienophiles as shown in Scheme 1.3 Despite this,
the number of synthetic routes leading to the urazole scaffold
is very limited. The classic synthetic route4 is illustrated in
Scheme 2, and involves the formation and base-promoted cycli-
zation of diacylhydrazide 4, which is usually performed at sub-
stantial dilution. Most commonly, an aryl substituent is
attached at N4, although N4 alkyl derivatives have also been pre-
pared by this route.
In our desire to generate the potentially hydrolytically labile N4
oxygenated urazoles (i.e., 1, R3 = OR), we sought to devise a general
route to the urazole scaffold that did not involve heating with alk-
oxide as the final step. To this end, we explored the preparation of
diphenyl N-substituted (imidodicarbonates) 6, and their reaction
with hydrazine as shown in Scheme 3.
imidocarbonates could be further purified by column
chromatography.
Table 2 illustrates the reaction of these imidodicarbonates with
hydrazine. These reactions proceeded in dichloromethane at room
temperature.6 The 1,2-unsubstituted urazole products were fre-
quently sparingly soluble (in dichloromethane) solids, that could
be isolated by simple filtration from the reaction mixture, or the
solvent could be replaced with ether-hexane mixtures to precipi-
tate the urazole and dissolve the product phenol. The products
could also be purified by column chromatography using metha-
nol/dichloromethane as eluent.
Since we desired to prepare bicyclic urazoles incorporating
more strain than the triazolopyridazines prepared by Diels–Alder
cycloaddition of the corresponding triazoles, representative
examples of these 1,2-unsubstituted urazoles were instead trea-
ted with 2.5 equiv of NaH, in DMF, followed by either 1,3-dibro-
mopropane or 2-tert-butyldimethylsilyloxy-1,3-dibromopropane
and NaI, to generate the bicyclic pyrazolotriazolidinediones
8a–8h7 as shown in Table 3. Crystals of 8c and 8g for X-ray were
grown from dichloromethane/hexane, with structures shown in
Figure 1.
Table
1 illustrates the synthesis of a series of N-substi-
tuted(imidodicarbonates) by reaction of 2.5 equiv of phenyl chlo-
roformate with an amine (or O-alkylhydroxylamine) in the
presence of 4 equiv of triethylamine and 1 equiv of DMAP. The
reactions proceed in refluxing dichloromethane.5 Upon workup,
these materials were clean enough (with phenol as the main
impurity) to be utilized in the following reaction, although the
Conclusions
In conclusion, we have described a mild method for the
preparation of the urazole scaffold that is amenable to the
preparation of N4-alkoxyurazoles. We have also explored the
reaction of these urazoles with 1,3-dibromopropane, and with
1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane to generate
dihydropyrazolotriazoldiones.
⇑
Corresponding author. Tel.: +1 214 768 2484; fax: +1 214 768 4089.
E-mail address: jbuynak@smu.edu (J.D. Buynak).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.131

W. Chai et al. / Tetrahedron Letters 53 (2012) 3514–3517
3515
O
R3
N
R3
N
N
N
R3
PhI(OAc)2
O
O
N
O
O
R
N
N
(R1, R2 = H)
N
N
R
O
R1
R2
2
1
Scheme 1. Use of urazoles (1) in synthesis of 1,2,4-triazole-3,5(4H)-diones (2) and subsequent reaction with dienes.
O
H
N
O
O
O
NaOEt
NR
EtO
NHNR
ArNCO
RNHNH2
ArN
EtO
NHNHR
EtO
Cl
EtOH, Δ
O
O
ArNH
3
4
5
Scheme 2. Classic synthetic route to urazoles.
R3
N
O
O
2.5 eq PhOCOCl
1.1 eq H2NNH2
DCM, rt
R3NH2
O
O
PhO
N
R3
OPh
4 eq Et3N, 1 eq DMAP,
DCM, rt to 40 o
HN NH
C
6
7
Scheme 3. Synthetic route to urazoles via intermediate diphenyl imidodicarbonates.
Figure 1. X-ray structures of bicyclic urazoles.

3516
W. Chai et al. / Tetrahedron Letters 53 (2012) 3514–3517
Table 1
Table 2 (continued)
Synthesis of diphenyl imidodicarbonates by reaction of amines or O-alkylhydroxyl-
amines with phenyl chloroformate
Entry
3
R3
Imidodicarbonate
Yield %
20
mp (°C)
OCH2Ph
N
O
O
2.5 eq PhOCOCl
R3NH2
O
O
PhCH2O
128–130
7c
PhO
N
OPh
4 eq Et3N, 1 eq DMAP,
R3
NH
HN
DCM, rt to 40 o
C
6
OCH2-p-C6H4NO2
N
O
O
O
O
Entry R3
Imidodicarbonate
Yield % mp (°C)
4
5
6
p-NO2C6H4CH2O
p-MeOC6H4CH2
Allyl
28
55
57
152–154
189–191
150–152
7d
HN NH
O
O
O
1
PhCH2
82
62
⁄
CH2-p-C6H4OMe
6a
PhO
PhO
N
OPh
OPh
N
CH2Ph
O
7e
7f
HN NH
O
N
CH2CH=CH2
6b
6c
2
PhCH2CH2
52–54
N
O
Ph
HN NH
O
O
O
O
O
3
4
5
PhCH2O
89
40
90
69–72
PhO
PhO
PhO
PhO
N
OPh
Table 3
OCH2Ph
Synthesis of bicyclic urazoles using NaH and dibromopropanes
R3
N
O
R3
O
O
1) 2.5 eq NaH, 1 eq NaI, DMF
N
p-NO2C6H4CH2O
p-MeOC6H4CH2
127–129
84–85
N
OPh
6d
O
O
OCH2-p-C6H4NO2
N
N
2) 1.1 eq
HN NH
Br
Br
R4
O
R4 = H or OTBS
OTBS
mp (°C)
6e
N
OPh
Entry
1
R3
Bicyclic Urazole
Yield %
70
CH2-p-C6H4OMe
CH2Ph
N
O
O
O
O
O
O
8a
PhCH2
⁄
6f
N
OPh
6
Allyl
71
⁄
N
N
N
N
⁄: This product is viscous oil.
CH2CH2Ph
N
O
8b
8c
2
3
4
5
PhCH2CH2
95
60
71
84
⁄
N
Table 2
Formation of urazoles by reaction of diphenyl imidodicarbonates with hydrazine
OCH2Ph
R3
O
O
N
O
1.1 eq H2NNH2
DCM, rt
PhCH2O
84–86
141–143
⁄
N
O
O
PhO
N
R3
OPh
N
HN NH
7
6
OCH2-p-C6H4NO2
Entry
1
R3
Imidodicarbonate
Yield %
mp (°C)
N
O
p-NO2C6H4CH2O
8d
CH2Ph
N
N
N
N
7a
7b
O
O
O
PhCH2
64
161–163
NH
HN
CH2-p-C6H4OMe
N
O
CH2CH2Ph
O
p-MeOC6H4CH2
N
O
8e
2
PhCH2CH2
62
191–193
N
HN NH

W. Chai et al. / Tetrahedron Letters 53 (2012) 3514–3517
3517
4. (a) Acree, S. F. Am. Chem. J. 1908, 38, 1–91; (b) Zinner, G.; Deucker, W. Arch.
Pharm. Ber. Dtsch. Pharm. Ges. 1961, 294, 370–372; (c) Park, K.-H.; Cox, L. J.
Tetrahedron Lett. 2002, 43, 3899–3901.
Table 3 (continued)
Entry
R3
Bicyclic Urazole
CH2CH=CH2
Yield %
30
mp (°C)
5. General procedure for synthesis of diphenyl imidodicarbonates: Diphenyl (4-
methoxybenzyl)imidodicarbonate (6e): To a solution of 4-methoxybenzylamine
(0.80 g, 0.76 mL, 5.8 mmol) in dichloromethane (100 mL), triethylamine (2.36 g,
3.25 mL, 23.3 mmol) was added. The solution was cooled to 0 °C, and phenyl
chloroformate (2.27 g, 1.82 mL, 14.5 mmol) and DMAP (0.708 g, 5.8 mmol) were
added. The mixture was heated to 40 °C overnight. The resultant reaction
mixture was washed with water and two times with dilute aq HCl. The organic
layer was dried over Na2SO4 and evaporated in vacuo. This material could be
utilized in the subsequent urazole synthesis as such, or purified by flash
chromatography (silica gel, CH2Cl2). Yield (2.0 g, 90%, mp = 84–85 °C). 1H NMR
(400 MHz, CDCl3): d 7.44 (d, 2H, J = 8 Hz), 7.39 (t, 4H, J = 5 Hz), 7.28 (q, 2H,
N
O
O
6
Allyl
⁄
8f
N
N
Ph
N
O
O
J = 8 Hz), 7.16 (d, 4 H, J = 8 Hz), 6.92 (d, 2H, J = 8 Hz), 5.08 (s, 2H), 3.83 (s, 3H); 13
C
NMR (100 MHz, CDCl3):
d 152.16, 145.08, 143.41, 122.67, 122.37, 122.31,
N
N
7
Ph
36
200–202
8g
121.77, 119.03, 114.18, 133.69, 106.76, 48.00, 42.82; IR (thin film, cmꢀ1): 1745,
1705, 1512, 1487,1435, 1374, 1353, 1320, 1200, 1172, 1157.
6. General procedure for synthesis of urazoles: 4-(40-methoxybenzyl)-1,2,4-
OTBS
triazolidine-3,5-dione
methoxybenzyl)imidodicarbonate (0.502 g, 1.33 mmol) in dichloromethane
(50 mL) at room temperature, anhydrous hydrazine (51 mg, 50 L, 1.58 mmol)
(7e):
To
a
solution
of
diphenyl
(4-
l
CH2CH=CH2
was added over 2 min. The reaction was stirred overnight. The solvent was
removed in vacuo and the residue was stirred with an ether–hexane mixture for
20 min. The precipitated urazole was isolated by filtration. Yield (0.16 g, 55%),
(mp = 189–191 °C). 1H NMR (400 MHz, CDCl3–CD3OD): d 7.34 (d, 2H, J = 8 Hz),
6.83 (d, 2H, J = 8 Hz), 4.59 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
157.28, 153.94, 128.63, 127.79, 112.54, 53.87, 39.55; IR (thin film, cmꢀ1): 1682,
1612, 1514, 1468, 1248.
N
O
O
8h
N
N
8
Allyl
22
⁄
OTBS
7. General procedure for synthesis of dihydropyrazolotriazolediones: Dihydropyrazolo-
4-(40-methoxybenzyl)-1,2,4-triazol-3,5-dione (8e): To
a
solution of 4-
⁄: This product is viscous oil.
methoxybenzyl urazole 7e (0.35 g, 1.58 mmol) in DMF (6 mL), NaH (91 mg,
3.8 mmol) was added. The reaction mixture was stirred for 30 min at room
temperature. Then 1,3-dibromopropane (0.351 g, 177 lL, 1.74 mmol) and NaI
(0.237 g, 1.58 mmol) were added. The reaction mixture was heated to 50 °C for
2 h. The reaction was quenched by water and extracted with ethyl acetate
(50 mL). Then the organic layer was washed with water three times. The organic
layers were dried over Na2SO4 and the solvent was evaporated in vacuo. The
product was further purified by flash chromatography (SiO2, 20% EtOAc/CH2Cl2).
Yield (0.35 g, 84%). 1H NMR (400 MHz, CDCl3): d 7.34 (d, 2H, J = 8 Hz), 6.83 (d,
2H, J = 8 Hz), 4.55 (s, 2H), 3.76 (s, 3H), 3.69 (t, 4H, J = 7.9 Hz), 2.27 (q, 2H,
J = 6.8 Hz); 13C NMR (100 MHz, CDCl3): 159.03, 155.44, 129.70, 127.73, 113.69,
54.96, 44.63, 42.36, 27.77; IR (thin film, cmꢀ1): 1768, 1701, 1612,1513, 1442,
1247.
References and notes
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Dhar, T. G. M. PCT Int. Appl. WO 2002094186 A2 20021128, 2002, p 44.; (b)
Boatman, P. D.; Urban, J.; Nguyen, M.; Qabar, M.; Kahn, M. Bioorg. Med. Chem.
Lett. 2003, 13, 1445–1449.
2. Mallakpour, S.; Dinari, M. High Perform. Polym. 2010, 22, 314–327.
3. (a) Radl, S. Adv. Heterocycl. Chem. 1996, 67, 119–205; (b) Alberti, M. N.;
Orfanopoulos, M. Org. Lett. 2009, 11, 1659–1662; (c) Alajarin, M.; Bonillo, B.;
Marin-Luna, M.; Sanchez-Andrada, P.; Vidal, A. Eur. J. Org. Chem. 2010, 694–704.