Pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 73
2H, -OCH2CH3, J ) 7.2 Hz), 2.69 (s, 3H, CH3), 1.43-1.40
(t, 3H, -OCH2CH3, J ) 7.3 Hz). 13C NMR (125 MHz,
CDCl3): δ 161.0, 158.8, 144.5, 139.3, 136.7, 129.7, 129.2,
125.7, 108.5, 61.4, 14.5, 14.2. HRMS (ESI, C14H13N5O3+Na)
calcd: 322.0916, found: 322.0945.
129.0, 128.7, 128.2, 117.8, 50.0, 31.1, 28.8, 26.0, 22.3, 14.0,
13.8. HRMS (ESI, C17H21N5O+Na) calcd: 334.1644, found:
334.1649.
3,7,8-Triphenylpyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)-
one 1n. 1H NMR (500 MHz, CDCl3): δ 7.70-7.36 (m, 15H,
ArH). 13C NMR (125 MHz, CDCl3): δ 156.5, 142.7, 140.4,
137.2, 130.6, 130.0, 129.7, 129.4, 129.3, 129.1, 128.8, 128.7,
128.6, 126.0, 118.3. HRMS (ESI, C22H15N5O+Na) calcd:
388.1174, found: 388.1175.
Ethyl 3-(4-Chlorophenyl)-7-methyl-4-oxo-3,4-dihydro-
pyrazolo[5,1-d][1,2,3,5]tetrazine-8-carboxylate 1g. 1H NMR
(500 MHz, Acetone-d6): δ 7.80-7.67 (m, 4H, ArH), 4.44-
4.40 (q, 2H, -OCH2CH3, J ) 7.2 Hz), 2.62 (s, 3H, CH3),
1.42-1.39 (t, 3H, -OCH2CH3, J ) 6.9 Hz). 13C NMR (125
MHz, Acetone-d6): δ 162.5, 159.0, 146.7, 141.2, 138.0,
136.5, 130.8, 127.7, 109.2, 62.3, 15.3, 15.2. HRMS (ESI,
C14H12ClN5O3+Na) calcd: 356.0526, found: 356.0516.
3-Benzyl-7,8-diphenylpyrazolo[5,1-d][1,2,3,5]tetrazin-
1
4(3H)-one 1o. H NMR (300 MHz, CDCl3): δ 7.65-7.32
(m, 15H, ArH), 5.62 (s, 2H, ArCH2). 13C NMR (125 MHz,
CDCl3): δ 156.1, 143.3, 140.5, 134.7, 130.7, 129.9, 129.6, 129.1,
128.8, 128.7, 128.5 (×2), 128.2, 127.7, 117.6, 53.4. HRMS
(ESI, C23H17N5O+Na) calcd: 402.1331, found: 402.1340.
3,7-Diphenylpyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)-
one 1p.2a 1H NMR (500 MHz, CDCl3): δ 8.07-7.49 (m,
10H, ArH), 7.40 (s, 1H, CCH). 13C NMR (125 MHz, CDCl3):
δ 158.4, 146.3, 140.4, 137.1, 130.4 (×2), 129.6, 129.0, 127.0,
126.0, 102.0. HRMS (ESI, C16H11N5O+Na) calcd: 312.0861,
found: 312.0821.
Ethyl 3-Benzyl-7-methyl-4-oxo-3,4-dihydropyrazolo-
1
[5,1-d][1,2,3,5]tetrazine-8-carboxylate 1h. H NMR (500
MHz, CDCl3): δ 7.52-7.32 (m, 5H, ArH), 5.61 (s, 2H,
ArCH2), 4.47-4.43 (q, 2H, -OCH2CH3, J ) 7.2 Hz), 2.69
(s, 3H, CH3), 1.44-1.41 (t, 3H, -OCH2CH3, J ) 7.3 Hz).13C
NMR (125 MHz, CDCl3): δ 161.3, 158.7, 145.1, 139.6,
134.1, 129.1, 129.0 (×2), 108.2, 61.4, 54.0, 14.6, 14.3.
HRMS (ESI, C15H15N5O3+Na) calcd: 336.1073, found:
336.1072.
Acknowledgment. We thank the National University of
Singapore for financial support of this work.
Ethyl 4-Oxo-3-phenyl-3,4-dihydropyrazolo[5,1-d]-
[1,2,3,5]tetrazine-8-carboxylate 1i.2a 1H NMR (300 MHz,
CDCl3): δ 8.42-8.41 (d, 1H, NdCH, J ) 3.3 Hz),
7.56-7.42 (m, 5H, ArH), 4.41-4.34 (q, 2H, -OCH2CH3, J
) 7.1 Hz), 1.37-1.32 (t, 3H, -OCH2CH3, J ) 7.1 Hz). 13C
NMR (75 MHz, CDCl3): δ 160.1, 147.6, 143.6, 139.5, 136.7,
129.8, 129.3, 125.7, 110.9, 61.7, 14.2. HRMS (ESI,
C13H11N5O3+Na) calcd: 308.0760, found: 308.0743.
1
Supporting Information Available. H and 13C NMR
spectra of compounds 1a-1p, 4-6, IR spectra of resin 9-11,
HPLC,1H NMR, and MS data of unpurified compound 2,
crude yields of compounds 2a, 2d, 2e, 2f, 2i, 2j, 2n, and
2p, and the crystallographic file in CIF format of 1l. This
material is available free of charge via the Internet at http://
pubs.acs.org.
8-Methyl-3,7-diphenylpyrazolo[5,1-d][1,2,3,5]tetrazin-
4(3H)-one 1j.2a 1H NMR (500 MHz, CDCl3): δ 7.73-7.43
(m, 10H, ArH), 2.66 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3): δ 155.2, 141.7, 140.2, 137.1, 129.3, 129.2 (×2),
128.8 (×2), 128.5, 118.8, 115.0, 14.1. HRMS (ESI,
C17H13N5O+Na) calcd: 326.1018, found: 326.1003.
References and Notes
(1) (a) Hickman, J. A.; Stevens, M. F. G.; Gibson, N. W.;
Langdon, S. P.; Fizames, C.; Lavelle, F.; Atassi., G.; Lunt,
E.; Tilson, R. M. Cancer Res. 1985, 45, 3008–3013. (b)
Harding, M. J.; Northcott, D.; Smyth, J.; Stuart, N. S.; Green,
J. A.; Newlands, E. Br. J. Cancer 1988, 57, 113–114. (c)
Newlands, E. S.; Stevens, M. F. G.; Wedge, S. R.; Wheel-
house, R. T.; Brock, C. Cancer Treat. ReV. 1997, 23, 35–61.
(d) Cheng, C. C.; Elslager, E. F.; Werbel, L. M.; Leopold,
W. R., III. J. Med. Chem. 1986, 29, 1544–1547. (e) Zhu, Y.-
Q.; Wu, C.; Li, H.-B.; Zou, X.-M.; Si, X.-K.; Hu, F.-Z.; Yang,
H.-Z. J. Agric. Food Chem. 2007, 55, 1364–1369. (f) Paull,
K. D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scudiero,
D. A.; Rubinstein, L.; Plowman, J.; Boyd, M. R. J. Natl.
Cancer Inst. 1989, 81, 1088–1092. (g) Lunt, E.; Newton,
C. G.; Smith, C.; Stevens, G. P.; Stevens, M. F. G.; Straw,
C. G.; Walsh, R. J. A.; Warren, P. J.; Fizames, C.; Lavelle,
F.; Langdon, S. P.; Vickers, L. M. J. Med. Chem. 1987, 30,
357–366. (h) Stevens, M. F. G.; Hickman, J. A.; Stone, R.;
Gibson, N. W.; Baig, G. U.; Lunt, E.; Newton, C. G. J. Med.
Chem. 1984, 27, 196–201.
3-Benzyl-8-methyl-7-phenylpyrazolo[5,1-d][1,2,3,5]tet-
1
razin-4(3H)-one 1k. H NMR (500 MHz, CDCl3): δ 7.67
-7.31 (m, 10H, ArH), 5.56 (s, 2H, ArCH2), 2.61 (s, 3H,
CH3). 13C NMR (125 MHz, CDCl3): δ 154.7, 142.2, 140.4,
134.7, 129.1, 129.0, 128.9, 128.7, 128.5, 128.3, 118.1, 53.2,
14.0. HRMS (ESI, C18H15N5O+Na) calcd: 340.1174, found:
340.1177.
8-Methyl-3-phenethyl-7-phenylpyrazolo[5,1-d][1,2,3,5]-
tetrazin-4(3H)-one 1l. 1H NMR (500 MHz, CDCl3): δ 7.58-
7.13 (m, 10H, ArH), 4.59-4.56 (t, 2H, ArCH2CH2, J ) 7.6
Hz), 3.16-3.13 (t, 2H, ArCH2CH2, J ) 7.9 Hz), 2.53 (s,
3H, CH3). 13C NMR (125 MHz, CDCl3): δ 154.8, 142.2,
140.4, 136.8, 129.1, 129.0, 128.8 (×2), 128.3, 126.9, 118.0,
50.9, 35.0, 14.1. HRMS (ESI, C19H17N5O+Na) calcd:
354.1331, found: 354.1311.
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1375–1395. (b) Ege, G.; Gilbert, K. Tetrahedron Lett. 1979,
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2827–2830. (c) Blass, B. E.; Srivastava, A.; Coburn, K. R.;
Faulkner, A. L.; Janusz, J. J.; Ridgeway, J. M.; Seibel, W. L.
Tetrahedron Lett. 2004, 45, 1275–1277. (d) Dodd, D. S.;
Martinez, R. L.; Kamau, M.; Ruan, Z.; Kirk, K. V.; Cooper,
C. B.; Hermsmeier, M. A.; Traeger, S. C.; Poss, M. A.
3-Hexyl-8-methyl-7-phenylpyrazolo[5,1-d][1,2,3,5]tetrazin-
1
4(3H)-one 1m. H NMR (500 MHz, CDCl3): δ 7.67-7.37
(m, 5H, ArH), 4.43-4.40 (t, 3H, NCH2, J ) 7.3 Hz), 2.61
(s, 3H, CH3), 1.94-1.88 (m, 2H, NCH2CH2), 1.41-1.28 (m,
6H, CH3(CH2)3), 0.88-0.85 (t, 3H, CH3(CH2)3, J ) 7.3 Hz).
13C NMR (125 MHz, CDCl3): δ 154.6, 142.3, 140.4, 129.1,