S. Ozcan et al. / Tetrahedron Letters 52 (2011) 1495–1497
14. Xie, F.; Cheng, G.; Hu, Y. J. Comb. Chem. 2006, 8, 286.
1497
It is proposed that the first step is formation of hydrazide 9
(Scheme 5). Compound 9 may undergo a formylation reaction by
abstraction of one of the methylene protons by hydrazine followed
by reaction with dimethylformamide to give the ketoaldehyde 11.
Reaction of hydrazine with 11 then gives the hydrazone 12, which
can undergo a ring-opening reaction by attack of the amine group
on the carbonyl to produce 14 via intermediate 13. Further cycliza-
tion with the carbonyl oxygen atom of the formed pyrazolone
derivative 14 followed by displacement of the hydrazine moiety
and a subsequent H-shift in 16 results in formation of the target
compound 5a.
In summary, the present investigation resulted in the prepara-
tion of the 3,4-disubstituted pyrazoles, isochromeno[3,4-c]pyra-
zol-5(2H)-ones 5a–c, using a one-pot, three-component reaction.
This method should be suitable for the synthesis of synthetically
demanding pyrazoles containing fused rings. Further study of this
methodology is currently in progress.
15. (a) Deliömeroglu, M. K.; Özcan, S.; Balci, M. ARKIVOC 2010, ii, 148; (b) Ozcan, S.;
Balci, M. Tetrahedron 2008, 64, 5531; (c) Ozcan, S.; Sßahin, E.; Balci, M.
Tetrahedron Lett. 2007, 48, 2151; (d) Dengiz, C.; Özcan, S.; Sahin, E.; Balci, M.
Synthesis 2010, 1365.
16. (a) Nash, I. A.; Page, K. M.; Bethel, P. A. PCT Int. Appl. 2006, WO 2006067444;
Chem. Abstr. 2006, 145, 103576; (b) Lyssikatos, J. P.; Yang, B. V. U.S. 2003, US
6586447; Chem. Abstr. 2003, 139, 69147; (c) Martin, B.; Willis, P. PCT Int. Appl.,
2007, 2007149031; Chem. Abstr. 2007, 148, 100511.
17. (a) Billamboz, M.; Fabrice, B.; Barreca, M. L.; De Luca, L.; Mouscadet, J.-F.;
Calmels, C.; Andreola, M.-L.; Witvrouw, M.; Christ, F.; Debyser, Z.; Cotelle, P. J.
Med. Chem. 2008, 51, 7717; For bromination of deactivated aromatics using
potassium bromate, see: (b) Harrison, J. J.; Pellegrini, J. P.; Selwitz, C. M. J. Org.
Chem. 1981, 46, 2169.
18. (a) Hill, R. A.; Rudra, S.; Peng, B.; Roane, D. S.; Bounds, J. K.; Zhang, Y.; Adloo, A.;
Lu, T. Bioorg. Med. Chem. 2003, 11, 2099; (b) Belgaonkar, V. H.; Usgaonkar, R. N.
Tetrahedron Lett. 1975, 16, 3849; (c) Desai, H. K.; Usgaonkar, R. N. J. Indian
Chem. Soc. 1963, 40, 239; (d) Ungnade, H. E.; Nightingale, D. V.; French, H. E. J.
Org. Chem. 1945, 10, 533.
19. Isochromeno[3,4-c]pyrazole-5(2H)-one (5a): To
a solution of homophthalic
anhydride (3a) (0.6 g, 3.7 mmol) in DMF (5 mL), an excess amount of
hydrazine monohydrate (1.0 mL, 14.2 mmol) was added at room temperature
and the resulting mixture was refluxed overnight. After cooling to room
temperature, the residue was triturated with H2O (50 mL), filtered and dried to
give an analytically pure sample of 5a.
Acknowledgements
Isochromeno[3,4-c]pyrazole-5(2H)-one (5a): (isolated yield: 0.56 g, 81%); mp
263–264 °C. IR (KBr, cmÀ1): 3218, 2958, 1733, 1705, 1685, 1625, 1590, 1496,
1434, 1318, 1242, 1187, 1076, 1053, 942, 871, 757. 1H NMR: (400 MHz, DMSO-
d6) d 13.14 (br s, 1H, –NH), 8.46 (br s, 1H, H-1), 8.17 (br d, J6,7 = 7.9 Hz, 1H, H-6),
7.92 (br d, J9,8 = 7.7 Hz, 1H, H-9), 7.92 (br dd, J8,9 = 7.7 Hz, J8,7 = 7.5 Hz, 1H, H-8),
7.49 (br dd, J7,8 = 7.5 Hz, J7,6 = 7.9 Hz, 1H, H-7). 13C NMR: (100 MHz, DMSO-d6) d
161.8 (s, C-5), 157.3 (s, C-3a), 135.9 (d, C-8), 133.3 (s, C-9a), 131.2 (d, C-6),
127.2 (d, C-7), 125.6 (d, C-1), 123.7 (s, C-8a), 118.7 (s, C-5a), 100.0 (s, C-9b).
Anal. Calcd for C10H6N2O2: C, 64.52; H, 3.25; N, 15.05. Found: C, 64.25; H, 3.45;
N, 16.03. HRMS: m/z (M+H)+ Calcd for C10H7N2O2: 187.0508; found: 187.0506.
7-Bromoisochromeno[3,4-c]pyrazol-5(2H)-one (5b): white solid (1.164 g, 73%),
mp 322–324 °C. IR: (ATR, cmÀ1): 3216, 1735, 1622, 1586, 1485, 1231, 1177,
1072, 822. 1H NMR (400 MHz, DMSO-d6) d 13.27 (br s, 1H, NH), 8.57 (br s, 1H,
H-1), 8.28 (d, J6,8 = 2.1 Hz, 1H, H-6), 8.09 (dd, J8,9 = 8.4, J8,6 = 2.1 Hz, 1H, H-8),
7.95 (d, J9,8 = 8.4 Hz, 1H, H-9).13C NMR (100 MHz, DMSO-d6) d 160.2, 156.7,
138.0, 132.6, 132.0, 125.5, 125.1, 120.21, 118.7, 99.0. HRMS: m/z (M+H)+ Calcd
for C10H5N2O2Br: 264.9613; found: 264.9611.
The authors are indebted to TUBITAK (Scientific and Technolog-
ical Research Council of Turkey), (Grant 108-M168), the Depart-
ment of Chemistry at Middle East Technical University and TUBA
(Turkish Academy of Sciences) for financial support of this work.
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data, proton, and carbon spectra of all new compounds and
X-ray crystallographic data for 7) associated with this article can
7-Methoxyisochromeno[3,4-c]pyrazol-5(2H)-one (5c): pale yellow solid (235 mg,
63%), white solid, mp 275–276 °C. IR (ATR, cmÀ1) 3649, 3446, 1734, 1653, 998.
1H NMR (400 MHz, DMSO-d6) d 13.04 (br s, 1H, NH), 8.39 (d, J1,2 = 1.8 Hz, 1H,
H-1), 7.87 (d, J8,9 = 8.6 Hz, 1H, H-9), 7.60 (d, J6,8 = 2.7 Hz, 1H, H-6), 7.47 (dd,
J8,9 = 8.6 Hz, J6,8 = 2.8 Hz, 1H, H-8), 3.86 (s, 3H, H-1, –OCH3). 13C NMR (100 MHz,
DMSO-d6) d 161.2, 157.8, 156.3, 126.2, 124.5, 124.1, 123.9, 119.3, 112.5, 99.4,
55.5. HRMS: m/z (M+H)+ Calcd for C11H9N2O3: 217.0613; found: 217.0612.
tert-Butyl 5-oxoisochromeno[3,4-c]pyrazole-2(5H)-carboxylate (7): (0.532 g,
91%), mp 270.0–271.5 °C. IR (ATR, cmÀ1) 3649, 3446, 1734, 1653, 998. 1H NMR
(400 MHz, CDCl3) d 8.47 (s, 1H, H-1), 8.36 (br d, J6,7 = 7.9, 1H, H-6), 7.85–7.70
(m, 2H), 7.53 (dt, J = 7.51, J = 1.6 Hz, 1H, H-8), 1.69 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 160.4, 159.0, 147.4, 135.3, 131.9, 130.6, 128.5, 125.0, 123.1, 120.2,
105.2, 86.7, 27.9. HRMS: m/z (M+Na)+ Calcd for C15H14N2O4Na: 309.0850;
found: 309.0851.
References and notes
1. Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5,.
2. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
3. Haque, T. S.; Tadesse, S.; Marcinkevicience, J.; Rogers, M. J.; Sizemore, C.;
Kopcho, L. M.; Amsler, K.; Ecret, L. D.; Zhang, D. L.; Hobbs, F.; Slee, A.; Trainor, G.
L.; Stern, A. M.; Copeland, R. A.; Combs, A. P. J. Med. Chem. 2002, 45, 4669.
4. Wang, D. J.; Fan, L.; Zheng, C. Y.; Fang, Z. D. J. Fluorine Chem. 2010, 131, 584.
5. Terret, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6, 1819.
6. Gosselin, F.; O’Shea, P. D.; Webster, R. A.; Reamer, R. A.; Tillyer, R. D.;
Grabowski, E. J. J. Synlett 2006, 3267.
7. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 1015.
8. Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
9. Rosa, F. A.; Machado, P.; Vargas, P. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M.
A. P. Synlett 2008, 1673.
10. Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412.
11. Hari, Y.; Tsuchida, S.; Sone, R.; Aoyama, T. Synthesis 2007, 3371.
12. Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675.
20. Crystallographic data (excluding structure factors) for structure 7 have been
deposited (CCDC 800464) with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: (+44) 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk).
21. (a) Rosen, G.; Popp, F. D. J. Heterocycl. Chem. 1969, 6, 9; (b) Bihel, J.-J. F.; Hellal,
M.; Bourguignon, J.-J. Synthesis 2007, 3791.
22. Crockett, G. C.; Swanson, B. J.; Anderson, D. R.; Koch, T. H. Synth. Commun. 1981,
11, 447.
13. Gerstenberger, B. S.; Rauckhorst, M. R.; Starr, J. T. Org. Lett. 2009, 11, 2097.