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,