Urazole synthesis. Part 2: Facilitating N4 substitution

Article abstract of DOI:10.1016/j.tetlet.2013.02.042

The di-tert-butyl-di-p-nitrophenyl ester of hydrazinetetracarboxylic acid was prepared and shown to be useful in the preparation of urazoles (i.e., 1,2,4-triazolidine-3,5-diones), by reaction with a primary amine using either n-BuLi or pyridine as base, d

Full text of DOI:10.1016/j.tetlet.2013.02.042

Tetrahedron Letters 54 (2013) 2308–2310
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Tetrahedron Letters
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Urazole synthesis. Part 2: facilitating N4 substitution
Weirui Chai a, Emily Nguyen b, Jennifer Doran a, Katie Han c, Alexander Weatherbie a, Daniel Fernandez a,
Sarah Karimi a, Ritwick Mynam d, Caroline Humphrey e, Sara Rana b, John D. Buynak a,f,
⇑
a Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA
b The Hockaday School, Dallas, TX 75229, USA
c Coppell High School, Coppell, TX 75019, USA
d Texas Academy of Mathematics and Science, Denton, TX 76203, USA
e Plano East Senior High, Plano, TX 75074, USA
f Center for Drug Discovery, Design, and Delivery, Dedman College, Southern Methodist Univeristy, Dallas, TX 75275, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The di-tert-butyl-di-p-nitrophenyl ester of hydrazinetetracarboxylic acid was prepared and shown to be
useful in the preparation of urazoles (i.e., 1,2,4-triazolidine-3,5-diones), by reaction with a primary amine
using either n-BuLi or pyridine as base, depending on the desired N4 substituent. With more electroneg-
ative N4 substituents, pyridine is the preferred base. This work complements our reported urazole syn-
thesis, which introduced the N4 substituent early in the sequence and thus did not facilitate variation
at N4 for library synthesis.
Received 18 December 2012
Revised 3 February 2013
Accepted 8 February 2013
Available online 4 March 2013
Keywords:
Urazole
Ó 2013 Elsevier Ltd. All rights reserved.
Imidodicarbonate
Synthesis
Alkoxyurazole
Since the synthesis of phenytoin (1, Fig. 1) in 1908,1 and the
subsequent recognition of its anticonvulsant properties in 1939,2
hydantoins have served as useful scaffolds for drug discovery.3,4
This heterocycle provides a rigid framework to which pharmaco-
phoric groups can be attached.5 By contrast, the five membered
heterocycle with one of the hydantoin carbons replaced by nitro-
gen (i.e., the urazole, or 1,2,4-triazolidine-3,5-dione (2)) has re-
mained under-utilized in medicinal chemistry.6 Synthetically,
urazoles (especially N4-phenylurazole) are best known for their
ability to be oxidized to the corresponding 1,2,4-triazoline-3,5-
diones, which serve as super-dienophiles as shown in Scheme 1.
Contributing to their underuse has been the scarcity of
methodology for the rapid preparation of diverse urazoles. The
most commonly employed synthetic route to such compounds is
shown in Scheme 2,7 and involves sequential introduction of the
nitrogen atoms, with relatively little capability to vary substituents
as required for the preparation of a urazole library. Also, the neces-
sity of employing strong base at the end of the sequence does not
H
N
O
O
HN
Ph
Ph
1
Figure 1. Phenytoin.
O
N
R3
N
R3
N
R3
PhI(OAc)2
O
O
N
O
O
R
N
N
N
(R1, R2 = H)
N
N
R
O
R1
R2
3
2
Scheme 1. Use of urazoles (2) in synthesis of 1,2,4-triazoline-3,5(4H)-diones (3) and reaction with dienes.
⇑
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 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.042

W. Chai et al. / Tetrahedron Letters 54 (2013) 2308–2310
2309
O
H
N
O
O
O
NaOEt
NR
EtO
NHNR
ArNCO
RNHNH2
ArN
EtO
NHNHR
EtO
Cl
EtOH, Δ
O
O
ArNH
4
5
6
Scheme 2. Classic synthetic route to urazoles.
R
O
O
2.5 eq PhOCOCl
1.1 eq H2NNH2
CH2Cl2, rt
N
RNH2
O
O
PhO
N
R
OPh
4 eq Et3N, 1 eq DMAP,
HN NH
CH2Cl2, rt to 40 o
C
8
7
Scheme 3. Recently reported urazole synthesis.
O
O
Boc
Boc
H
N
Boc
N
CO2PNP
CO2PNP
Boc
Boc
NH
NH
N
N
a
b
c
N
R
N R
N
N
H
Boc
O
O
9
10
11
Scheme 4. Reagents and conditions: (a) 2.2 equiv p-NO2C6H4OCOCl, 3.0 equiv Et3N, CH2Cl2 reflux overnight, yield, 92%; (b) 1 equiv RNH2, 2.5 equiv n-BuLi, THF ꢀ78 °C, or
1 equiv RNH2, pyridine 70–90 °C; (c) excess TFA, anhyd CH2Cl2, rt.
Table 1
Synthesis of N1,N2-di-Boc protected Urazoles Using n-BuLi10
O
O
NR
Boc
Boc
1eq RNH2
2.5 eq n-BuLi
Boc
Boc
N
N
N
N
O-PNP
O-PNP
THF, -78 oC
O
O
9
10
Entry
Compound #
R
Yield (%)
1
2
3
4
5
6
7
10a
10b
10c
10d
10e
10f
PhCH2
PhCH2CH2
p-MeOC6H4CH2
Allyl
AllylOCO
t-Butyl
p-MeOC6H4
42
28
27
21
29
31
11
Figure 2. X-ray structure of 10a.
known compound is a crystalline solid and is readily purified by
precipitation from the product mixture using diethyl ether.9 Subse-
quent reaction of this intermediate with primary amines, either at
ꢀ78 °C, employing n-BuLi as base, or alternatively at 75 °C in pyr-
idine as solvent, produced N1,N2 protected urazoles (10) in accept-
able yields as shown in Table 1. An X-ray structure of one of these
N1,N2-diBoc protected urazoles (10a) is shown in Figure 2. The pyr-
idine procedure seemed superior for the preparation of urazoles
containing potentially anion-stabilizing substituents (e.g., aryl,
alkoxy, etc.) at N4. As shown in Table 2, the N1, N2 Boc groups
can be removed with excess TFA in dry CH2Cl2. In most cases, these
intermediate highly electron deficient N1,N2-di-Boc protected
urazoles were unstable toward column chromatography and/or
to washing with aqueous Na2CO3 (to remove p-nitrophenol) and
thus, as shown in Table 3, without purification, they could directly
be converted into the stable parent urazoles (11) by subsequent re-
moval of the Boc protecting groups in good overall yield. The N1,N2
unsubstituted urazoles (11) are usually insoluble in CH2Cl2, but can
be purified by column chromatography using CH2Cl2/MeOH mix-
tures or by direct precipitation from the reaction medium.
10g
permit the preparation of hydrolytically labile urazoles, including
N4-alkoxyurazoles and urazoles where one or more of the nitrogen
atoms are protected by a carbamate (e.g., Boc) group.
We recently reported the new synthetic methodology shown in
Scheme 3, which allows the preparation of some potentially hydro-
lytically labile urazoles, including the N4-alkoxyurazoles (R = OR0).8
Although this methodology avoids strong base, and permits the
synthesis of numerous substituted urazoles, it suffers from the
limitation that the N4 substituent is introduced early in the se-
quence, thereby again posing some constrains on the facile gener-
ation of urazole libraries. Thus we desired to devise methodology
which would enable expeditious modification at N4).
After exploring numerous strategies, we were able to success-
fully prepare the di-tert-butyl-di-p-nitrophenyl ester of hydrazine-
tetracarboxylic acid (9) from commercially available di-tert-butyl
hydrazodicarboxylate as shown in Scheme 4. This previously un-

2310
W. Chai et al. / Tetrahedron Letters 54 (2013) 2308–2310
Table 2
H.; Sun, J.; Umland, S.; Lundell, D. J.; Niu, X.; Kozlowski, J. A. Bioorg. Med. Chem.
Lett. 2010, 20, 5286; 1-adrenoreceptor antagonists: (b) Handzlik, J.;
Removal of Boc protecting groups11
a
Szyman´ ska, E.; Wójcik, R.; Dela, A.; Jastrze˛bska-Wie˛sek, M.; Karolak-
Wojciechowska, J.; Fruzin´ ski, A.; Siwek, A.; Filipek, B.; Kiec´-Kononowicz, K.
Bioorg. Med. Chem. Lett. 2012, 20, 4245; b2-adrenergic receptor agonists: (c)
Procopiou, P. A.; Barrett, V. J.; Bevan, N. J.; Butchers, P. R.; Conroy, R.; Emmons,
A.; Ford, A. J.; Jeulin, S.; Looker, B. E.; Lunniss, G. E.; Morrison, V. S.; Mutch, P. J.;
Perciaccante, R.; Ruston, M.; Smith, C. E.; Somers, G. Bioorg. Med. Chem. 2011,
19, 4192; selective inhibitors of the vesicular glutamate transporter (VGLUT):
(d) Ahmed, S. K.; Etoga, J. L. G.; Patel, S. A.; Bridges, R. J.; Thompson, C. M. Bioorg.
Med. Chem. Lett. 2011, 21, 4358; inhibitors of insulin-like growth factor 1
receptor kinase (IGF-1R kinase): (e) Lesuisse, D. et al Bioorg. Med. Chem. Lett.
2011, 21, 2224; Androgen receptor (AR) modulators: (f) Nique, F. et al J. Med.
Chem. 2012, 55, 8225; (g) Yoshino, H. et al Bioorg. Med. Chem. 2010, 18, 8150;
type 5 phosphodiesterase (PDE5) inhibitors: (h) Daugan, A. et al J. Med. Chem.
2003, 46, 4525; inhibitors of fatty acid amide hydrolase (FAAH): (i) Muccioli, G.
G. et al J. Med. Chem. 2006, 49, 417.
O
O
Boc
N
excess TFA
HN
HN
NR
N
NR
anh CH2Cl2, rt
Boc
O
O
10
11
Entry
Compound #
R
Yield (%)
1
2
3
4
5
11a
11b
11c
11d
11g
PhCH2
PhCH2CH2
p-MeOC6H4CH2
Allyl
p-MeOC6H4
71
80
98
99
93
5. Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Bioorg. Med. Chem. Lett. 1998, 8,
2375.
6. For examples, see: (a) Boatman, P. D.; Urban, J.; Nguyen, M.; Qabar, M.; Kahn,
M. Bioorg. Med. Chem. Lett. 2003, 13, 1445; (b) Izydore, R. A.; Hall, I. H. US Patent
4,866,058, Chem. Abstr. 1990, 112, 151876X.
7. (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) Gilbertson, T. J.; Ryan, T.
Synthesis 1982, 159; (d) Park, K.-H.; Cox, L. J. Tetrahedron Lett. 2002, 43, 3899–
3901; (e) Malakpour, S.; Rafiee, Z. Synth. Commun. 1927, 2007, 37; (f)
Malakpour, S.; Rafiee, Z. Synlett 2007, 1255.
Table 3
Synthesis of urazoles in pyridine as solvent12
O
O
1) 1eq RNH2, pyr, 75 o
C
Boc
Boc
8. Chai, W.; Chang, Y.; Buynak, J. D. Tetrahedron Lett. 2012, 53, 3514.
9. Procedure for synthesis of the di-tert-butyl-di-p-nitrophenyl ester of
hydrazinetetracarboxylic acid (9): To a chilled (0 °C) solution of di-tert-butyl
hydrazodicarboxylate (2.0 g, 8.61 mmol) in dry dichloromethane (30 mL),
triethylamine (2.61 g, 3.6 mL, 25.8 mmol) and p-nitrophenyl chloroformate
(3.82 g, 18.9 mmol) were added. The reaction was stirred for 30 min at 0 °C and
then was heated to reflux overnight. The resultant reaction mixture was cooled
to room temperature and washed with water and then with brine. The organic
layer was dried over Na2SO4 and the solvent evaporated in vacuo. The resultant
solid was then slurried with excess diethyl ether (approx. 40 mL) and allowed
to stir for 30 min. Then the precipitated white solid was filtered, washed with
additional diethyl ether, and further dried under vacuum to produce 4.45 g
(92%) of 9. 1H NMR (400 MHz, CDCl3): d 8.32 (d, 4H, J = 9 Hz), 7.39 (d, 4H,
J = 9 Hz), 1.59 (s, 18H); 13C NMR (100 MHz, CDCl3): d 147.61, 141.79, 141.20,
138.84, 118.43, 115.10, 79.61, 20.81; IR (thin film, cmꢀ1): 1820, 1781, 1593,
1528, 1490, 1371, 1348, 1281, 1198, 1146, 1110 (mp = 165.5–166.3 °C).
10. General procedure for synthesis of Boc protected urazoles (1). To a cold (ꢀ78 °C)
solution of the di-tert-butyl-di-p-nitrophenyl ester of hydrazinetetracarboxylic
HN
HN
N
N
O-PNP
O-PNP
NR
2) excess TFA, anh CH2Cl2, rt
O
O
9
11
Entry
Compound #
11f
11g
11h
R
Yield (%)
1
2
3
t-Butyl
p-MeOC6H4
PhCH2O
21
71
50
Conclusions
acid (1.0 g, 1.78 mmol) in THF (15 mL), was added benzylamine (0.19 g, 195 lL,
1.78 mmol) and then n-BuLi (2.2 M solution in hexanes, 2.18 mL, 4.79 mmol).
The reaction was kept at ꢀ78 °C for one hour, then quenched with acetic acid
(approx. 1 mL, 16.6 mmol). The resultant reaction mixture was evaporated in
vacuo and purified by flash chromatography (silica gel, CH2Cl2). 10c: 1H NMR
(400 MHz, CDCl3): d 8.13 (d, 2H, J = 8 Hz), 7.04 (d, 2H, J = 8 Hz), 4.81 (s, 2H),
4.02 (s, 4H), 1.72 (s, 18H); 13C NMR (100 MHz, CDCl3): d 152.63, 140.46, 139.17,
123.64, 119.32, 107.01, 79.49, 48.15, 36.22, 20.66; IR (thin film, cmꢀ1): 1762,
1513, 1253, 1149. (mp = 120.8–121.1 °C).
We have devised a second new route to the urazole scaffold.
This methodology complements our earlier reported urazole syn-
thesis in that it introduces the N4 substituent late in the sequence
and thus facilitates variation at this position. The readily available
crystalline intermediate 9 is useful in urazole preparation, and may
be of value in the preparation of other heterocycles. Two variations
of this procedure employ either n-BuLi or pyridine as base, with
pyridine being preferred for more electronegative N4 substituents.
11. General procedure for removing the Boc protecting groups: To a solution of 4-
methoxybenzyl-1,2-di-Boc protected urazole (0.5 g, 1.19 mmol) in anhyd
CH2Cl2 (15 mL), TFA (1 mL, 13.1 mmol) was added. The reaction mixture was
stirred for three hours at room temperature. The solvents were removed in
vacuo and the residue was stirred with an ether/hexane (1:1, 5 mL) mixture for
20 min. The precipitated urazole was isolated by filtration. Alternatively, the
concentrated crude reaction mixture could be purified by flash
chromatography (silica gel, CH2Cl2/methanol). 11c: 1H NMR (400 MHz, 2%
CD3OD in CDCl3): d 7.35 (d, 2H, J = 8); 6,79 (d, 2H, J = 8); 4.59 (s, 2H); 3.71 (s,
3H); 13C NMR (100 MHz, 2% CD3OD in CDCl3): d 159.15, 155.26, 129.76, 127.82,
113.83, 55.08, 41.80; IR (thin film, cmꢀ1): 1683, 1467, 1251, 1176, 1130, 1033.
12. General procedure for direct synthesis of N1,N2 unsubstituted urazoles using
pyridine as solvent: To a solution of di-tert-butyl-di-p-nitrophenyl ester of
hydrazinetetracarboxylic acid (9) (1.0 g, 1.78 mmol) in dry pyridine (15 mL), p-
anisidine (0.219 g, 1.78 mmol) was added. The reaction was heated at 75 °C for
one hour. The resultant reaction mixture was evaporated in vacuo to remove
pyridine. The resultant product was dissolved in anh CH2Cl2 (15 mL) and
treated with TFA (1 mL, 13.1 mmol) and stirred for 3 h at room temp and the
product isolated as above. 11g: 1H NMR (400 MHz, CDCl3): d 7.42 (m, 2H), 7.04
(m, 2H), 3.87 (t, 3H, J = 2); 13C NMR (100 MHz, CDCl3): d 162.96, 158.04, 131.01,
127.23, 118.02, 59.01; IR (thin film, cmꢀ1): 1683, 1515, 1455, 1302, 1251, 1201,
1137, 1037.
Acknowledgment
Support for E. N. and S. R. was provided by The Hockaday
School, Dallas, TX.
References and notes
1. Biltz, H. Chem. Ber. 1908, 41, 1379.
2. Merritt, H. H.; Putnam, T. J. T. Am. Neurol. Assoc. 1939, 158.
3. For reviews, see: (a) Meusel, M.; Guetschow, M. Org. Prep. Proced. Int. 2004, 36,
391; (b) Ware, E. Chem. Rev. 1950, 46, 403; (c) Lopez, C. A.; Trigo, G. G. Adv.
Heterocycl. Chem. 1985, 38, 177; (d) Volonterio, A.; Zanda, M. Tetrahedron Lett.
2003, 44, 8549.
4. For recent examples of drug candidates derived from hydantoin scaffolds. TACE
inhibitors: (a) Yu, W.; Tong, T.; Kim, S. H.; Wong, M. K. C.; Chen, L.; Yang, D.-Y.;
Shankar, B. B.; Lavey, B. J.; Zhou, G.; Kosinski, A.; Rizvi, R.; Li, D.; Feltz, R. J.;
Piwinski, J. J.; Rosner, K. E.; Shih, N. Y.; Siddiqui, M. A.; Guo, Z.; Orth, P.; Shah,