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(6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.3, 155.7, 155.0,
133.0, 120.8, 114.3, 97.0, 77.2, 55.6; m/z 487.0 (40, MH – ), 337.8
(100%); HRMS: MH – , found 487.1588. C 21 H 24 N 6 O 8 requires
487.1583.
4.2. 2,2'-[(4R,5R)- 1,4-dioxaspiro-[4.5]-decane-2,3-dicarbonyl)-
bis-(N-(4-methoxyphenyl) hydrazinecarboxamide] 8
Prepared from (2R,3R)-1,4-dioxaspiro-[4.5]-decane-2,3-di-carbohydrazide
2 and 4-methoxyphenyl isocyanate 4 (800.0 mg, 74%).
After 24 h or stirring at room temperature, water was added and
the solid was filtered off as a white solid precipitate (m.p. > 140
ºC); n max (solid) 3294, 1681 cm −1 ; d H (400 MHz DMSO-d 6 ) 9.99
(2H, brs, NHCO), 8.51 (2H,brs, NHCO), 8.09 (2H,brs, NHCO),
7.32 (4H, d, J 9.1 Hz, ArH), 6.76 (4H, d, J 8.7 Hz, ArH), 4.63
(2H, brs, CHCO), 3.64 (6H, brs, OMe), 1.73-1.55 (6H, m, CH 2 ),
1.53-1.49 (2H, m, CH 2 ), 1.33 (2H, m, CH 2 ); d C (100 MHz,
DMSO-d 6 ) 169.6, 156.1, 155.1, 132.8, 121.0, 114.4, 113.4, 76.8,
55.5, 36.0, 25.5, 25.2, 24.1; m/z 555.0 (52, MH – ), 405.9 (100%);
HRMS: MH – , found 555.2224. C 26 H 32 N 6 O 8 requires 555.2209.
4.3. 2,2'-[(4R,5R)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(2,4-dimethoxyphenyl)
hydrazinecarboxamide] 9
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide 1 and
2,4-dimethoxyphenyl isocyanate 5 (711.0 mg, 93%) as a white
solid precipitate (m.p. > 190 ºC); n max (solid) 3299, 1685 cm −1 ;
d H (400 MHz DMSO-d 6 ) 10.11 (2H, brs, NHCO), 8.48 (2H,brs,
NHCO), 7.88 (2H,brs, NHCO), 7.79 (2H, d, J 8.7 Hz, ArH), 6.56
(2H, s, ArH), 6.42 (2H, dd, J 6.4 Hz, ArH), 5.16 (2H, brs,
OCH 2 ), 4.63 (2H, brs, CHCO), 3.79 (6H, brs, OMe), 3.68 (6H,
brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.1, 155.6, 155.4, 149.7,
122.0, 120.1, 104.6, 99.2, 97.0, 77.1, 56.3, 55.7; m/z 547.0
(66, MH – ), 367.9 (100%); HRMS: MH – , found 547.1782.
C 23 H 28 N 6 O 10 requires 547.1794.
4.4. 2,2'-[(4R,5R)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-dimethylamino)
hydrazinecarboxamide] 10
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide 1 and
4-dimethylaminophenyl isocyanate 6 (705.0 mg, 89%) as a violet
solid precipitate (m.p. > 200 ºC); n max (solid) 3263, 1688 cm −1 ; d H
(400 MHz DMSO-d 6 ) 10.04 (2H, brs, NHCO), 8.37 (2H, brs,
NHCO), 7.95 (2H, brs, NHCO), 7.21 (4H, d, J 9.1 Hz, ArH),
6.62 (4H, d, J 9.1 Hz, ArH), 5.14 (2H, brs, OCH 2 ), 4.65 (2H, brs,
CHCO), 2.77 (12H, brs, NMe); d C (100 MHz, DMSO-d 6 ) 169.2,
155.8, 147.0, 129.7, 121.0, 113.5, 97.0, 77.2, 41.2; m/z 513.0 (70,
MH – ), 350.9 (100%); HRMS: MH – , found 513.2240. C 23 H 30 N 8 O 6
requires 513.2216.
4.5. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-methoxyphenyl)
hydrazinecarboxamide]11
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and
4-methoxyphenyl isocyanate 4 (910.0 mg, 96%) as a pale yellow
solid precipitate (m.p. 224-225 ºC); n max (solid) 3260, 1681 cm −1 ;
d H (400 MHz DMSO-d 6 ) 10.05 (2H, brs, NHCO), 8.54 (2H,brs,
NHCO), 8.04 (2H,brs, NHCO), 7.31 (4H, d, J 9.1 Hz, ArH), 6.79
(4H, d, J 9.1 Hz, ArH), 5.15 (2H, brs, OCH 2 ), 4.66 (2H, brs,
CHCO), 3.65 (6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.3,
155.7, 155.0, 133.0, 120.9, 114.3, 97.0, 77.2, 55.6; m/z 486.9
(100, MH – ), 337.9 (19%); HRMS: MH – , found 487.1570.
C 21 H 24 N 6 O 8 requires 487.1583.
4.6. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl) -bis-(N-(2,4-dimethoxyphenyl)
hydrazinecarboxamide] 12
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and
2,4-dimethoxyphenyl isocyanate 5 (735.0 mg, 99%) as a pale
yellow solid precipitate (m.p. > 190 ºC); n max (solid) 3297, 1696
cm −1 ; d H (400 MHz DMSO-d 6 ) 10.13 (2H, brs, NHCO), 8.50
(2H,brs, NHCO), 7.90 (2H,brs, NHCO), 7.90 (2H, d, J 8.7 Hz,
ArH), 6.57 (2H, s, ArH), 6.42 (2H, dd, J 6.4 Hz, ArH), 5.18 (2H,
brs, OCH 2 ), 4.66 (2H, brs, CHCO), 3.79 (6H, brs, OMe), 3.68
(6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.2, 155.6, 155.4,
149.7, 121.9, 120.2, 104.6, 99.2, 97.1, 77.2, 56.2, 55.7; m/z 547.0
(39, MH – ), 367.9 (100%); HRMS: MH – , found 547.1799.
C 23 H 28 N 6 O 10 requires 547.1794.
4.7. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-dimethylamino)
hydrazinecarboxamide] 13
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and
4-dimethylaminophenyl isocyanate 6 (740.0 mg, 93%) as a violet
solid precipitate (m.p. > 210 ºC); n max (solid) 3256, 1688 cm −1 ; d H
(400 MHz DMSO-d 6 ) 10.04 (2H, brs, NHCO), 8.37 (2H,brs,
NHCO), 7.95 (2H,brs, NHCO), 7.21 (4H, d, J 9.1 Hz, ArH), 6.61
(4H, d, J 9.1 Hz, ArH), 5.14 (2H, brs, OCH 2 ), 4.64 (2H, brs,
CHCO), 2.76 (12H, brs, NMe); d C (100 MHz, DMSO-d 6 ) 169.3,
155.8, 147.0, 129.7, 121.0, 113.5, 97.0, 77.2, 41.2; m/z 513.1 (31,
MH – ), 350.9 (100%); HRMS: MH – , found 513.2233. C 23 H 30 N 8 O 6
requires 513.2216.
Acknowledgments
H. Nour deeply thanks Deutscher Akademischer Austausch
Dienst (DAAD) for financial support and Jacobs University for
excellent facilities.
References and notes
1. Bogaschenko, T. Y.; Lyapunov, A. Y.; Kikot’, L. S.; Mazepa, A.
V.; Botoshansky, M. M.; Fonari, M. S.; Kirichenko, T. I.
Tetrahedron 2012, 68, 4757.
2. Xie, T.-Z.; Guo, C.; Yu, S.-Y.; Pan, Y.-J. Angew. Chem. Int. Ed.
2012, 51, 1177.
3. Kuchelmeister, H. Y.; Schmuck, C. Chem. Eur. J. 2011, 17, 5311.
4. Zhu, Z.; Cardin, C. J.; Gan, Y.; Colquhoun, H. M. Nat. Chem.
2010, 2, 653.
5. Nishiuchi, T.; Kuwatani, Y.; Nishinaga, T.; Iyoda, M. Chem. Eur.
J. 2009, 15, 6838.
6. Hayashi, N.; Ujihara, T. Tetrahedron 2009, 65, 8209.
7. Wennemers, H.; Nold, M. C.; Conza, M. M.; Kulicke, K. J.;
Neuburger, M. Chem. Eur. J. 2003, 9, 442.
8. Chen, C.-W.; Whitlock, H.W. J. Am. Chem. Soc. 1978, 100, 4921.
9. Vicente, A. I.; Caio, J. M.; Sardinha J.; Moiteiro, C.; Delgado, R.;
Félix, V. Tetrahedron 2012, 68, 670.
10. Barnhill, D. K.; Sargent, A. L.; Allen, W. E. Tetrahedron 2005, 61
8366.
11. Ishi-i, T.; Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.;
Shinkai, S. Angew. Chem. Int. Ed. 2002, 41, 1924.
12. Kuchelmeister, H. Y.; Schmuck, C. Eur. J. Org. Chem. 2009,
4480.
13. Liu, S.-Y.; He, Y.-B.; Wu, J.-L.; Wei, L.-H.; Qin, H.-J.; Meng, L.-
Z.; Hu, L. Org. Biomol. Chem. 2004, 2, 1582.
14. Zimmerman, S. C.; VanZyl, C. M. J. Am. Chem. Soc. 1987, 109,
7894.
15. Zimmerman, S. C.; Wu, W. J. Am. Chem. Soc. 1989, 111, 8054.
16. Zimmerman, S. C. In Topics in Current Chemistry; SpringerLink:
1993, Vol. 165/1993, 71-102, DOI: 10.1007/BFb0111281.
17. Iorio, E. J.; Still W. C. Bioorg. Med. Chem. Lett. 1996, 6, 2673.
18. Iorio, E. J.; Still W. C. Bioorg. Med. Chem. Lett. 1999, 9, 2145.
19. Chen, X.; Du, D.-M.; Hua, W.-T. Tetrahedron: Asymm. 2003, 14
999.
20. Shepherd, J.; Gale, T.; Jensen, K. B.; Kilburn, J. D. Chem. Eur. J.
2006, 12, 713.
21. Braxmeier, T.; Demarcus, M.; Fessmann, T.; McAteer, S.;
Kilburn, J. D. Chem. Eur. J. 2001, 7, 1889.
22. Nestler, H. P. Mol. Divers. 1996, 2, 35.
23. Conza, M.; Wennemers, H. J. Org. Chem. 2002, 67, 2696.
24. Wennemers, H.; Bernard, J. Org. Lett. 2007, 9, 4284.
25. Wennemers, H.; Krattiger, P. Synlett 2005, 4, 706.
26. Bernard, J.; Wennemers, H. Org. Lett. 2007, 9, 4283.
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