Stereoselective Synthesis of N-Acylhydrazones
[5] H. J. C. Bezerra-Netto, D. I. Lacerda, A. L. P. Miranda, H. M.
Alves, E. J. Barreiro, C. A. M. Fraga, Bioorg. Med. Chem. 2006,
14, 7924–7935.
[6] R. C. Maia, L. L. Silva, E. F. Mazzeu, M. M. Fumian, C. M.
Rezende, A. C. Doriguetto, R. S. Correa, A. L. P. Miranda,
E. J. Barreiro, C. A. M. Fraga, Bioorg. Med. Chem. 2009, 17,
6517–6525.
[7] A. E. Kümmerle, M. Schmitt, S. V. Cardozo, C. Lugnier, P.
Villa, A. B. Lopes, N. C. Romeiro, H. Justiniano, M. A. Mar-
tins, C. A. Fraga, J. J. Bourguignon, E. J. Barreiro, J. Med.
Chem. 2012, 55, 7525–7555.
[8] R. Kulandasamy, A. V. Adhikari, J. P. Adhikari, Eur. J. Med.
Chem. 2009, 44, 3672–3679.
perature reported in Table 3. The progress of the reaction was mon-
itored by TLC. At appropriate time intervals, standardized samples
were removed from the reaction mixture with a capillary tube and
dissolved in THF (0.3 mL), and then the sample solution was ap-
plied to the TLC plate (suitable solvent system as eluent). Chroma-
tograms were visualized under UV light (254 nm) and iodine vapor,
and the consumption of the reactants was determined by the disap-
pearance of their spots on the TLC plate. The stirring was then
stopped, and the ethanol was removed under reduced pressure
without heat. The crude product was dried under vacuum and then
analyzed by 1H NMR spectroscopy. The completion of the reaction
was confirmed by the absence (except for compound 21) of signals
for the hydrazido protons (–CONHNH2), which were at δ = 9.30–
9.80 (–CONH–) and at 4.40–5.60 ppm (–NH2). The crude product
was recrystallized from a suitable solvent to give the pure product,
which was characterized by melting point and 1H NMR, 13C NMR
and IR spectroscopy. The proton and carbon signals were assigned
by comparison with reported NMR spectroscopic data.
[9] R. Kulandasamy, A. V. Adhikari, J. P. Stables, Eur. J. Med.
Chem. 2009, 44, 4376–4384.
[10] J. M. dos Santos Filho, A. C. L. Leite, B. G. de Oliveira,
D. R. M. Moreira, M. S. Lima, M. B. P. Soares, L. F. C. C.
Leite, Bioorg. Med. Chem. 2009, 17, 6682–6691.
[11] J. M. dos Santos Filho, D. R. M. Moreira, C. A. de Simone,
R. S. Ferreira, J. H. McKerrow, C. S. Meira, E. T. Guimarães,
M. B. P. Soares, Bioorg. Med. Chem. 2012, 20, 6423–6433.
[12] a) R. Narang, B. Narasimhan, S. Sharma, Curr. Med. Chem.
2012, 19, 569–612; b) S. Rollas, S¸. G. Küçükgüzel, Open Drug
Deliv. J. 2008, 2, 77–85; c) S. Rollas, S¸. G. Küçükgüzel, Mol-
ecules 2007, 12, 1910–1939.
[13] a) C. S. de Oliveira, B. F. Lira, V. S. Falcão-Silva, J. P. Siqueira-
Junior, J. M. Barbosa-Filho, P. F. de Athayde-Filho, Molecules
2012, 17, 5095–5107; b) D. Kumar, V. Judge, R. Narang, S.
Sangwan, E. De Clercq, J. Balzarini, B. Narasimhan, Eur. J.
Med. Chem. 2010, 45, 2806–2816; c) S. D. Toliwal, J. Kalpesh,
G. Akshay, B. Anjum, J. Appl. Chem. Res. 2009, 10, 64–72.
[14] a) W. Gu, R. Wu, S. Qi, C. Gu, F. Si, Z. Chen, Molecules 2012,
17, 4634–4650; b) G. K. Friestad, A. Ji, J. Baltrusaitis, C. S.
Korapala, J. Qin, J. Org. Chem. 2012, 77, 3159–3180; c) J. Qin,
G. K. Friestad, Tetrahedron 2003, 59, 6393–6402; d) J. M.
Figueiredo, C. A. Câmara, E. G. Amarante, A. L. P. Miranda,
F. M. Santos, C. R. Rodrigues, C. A. M. Fraga, E. J. Barreiro,
Bioorg. Med. Chem. 2000, 8, 2243–2248.
Procedure for Synthesis of Standard Compound 1 (Multigram
Scale): A mixture of benzohydrazide (5.0 g, 36.7 mmol), benzalde-
hyde (3.90 g, 36.7 mmol), and cerium(III) chloride heptahydrate
(0.1368 g, 3.67 mmol, 1 mol-%) in ethanol (10 mL) was stirred at
20 °C. After 6.5 min, TLC indicated that the reaction had reached
completion. The mixture was cooled and filtered. The crystals were
washed with water (10 mL), dried under vacuum, and then charac-
terized. The filtrate was concentrated to dryness under reduced
pressure. The resulting solid residue was suspended in dichloro-
methane, and the suspension was filtered. The resulting solid was
reused for additional synthetic cycles, and the amounts of the reac-
tants were adjusted each time to the recovered amount of CeCl3.
The successive yields of (E)-NЈ-benzylidenebenzohydrazide (1) for
1
each cycle were 94, 92, 93, and 91%. The H NMR spectroscopic
data were the same for each sample.
[15] J. M. dos Santos-Filho, J. G. de Lima, L. F. C. C. Leite, E. A.
Ximenes, J. B. P. da Silva, P. C. Lima, I. R. Pitta, Heterocycl.
Chem. 2005, 11, 29–36.
[16] a) R. Properzi, E. Marcantoni, Chem. Soc. Rev. 2014, 43, 779–
791; b) G. Bartoli, E. Marcantoni, M. Marcolini, L. Sambri,
Chem. Rev. 2010, 110, 6104–6143.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR, 13C NMR, and IR spectra of all compounds.
[17] a) C. Feng, Y. Yan, Z. Zhang, K. Xu, Z. Wang, Org. Biomol.
Chem. 2014, 12, 4837–4840; b) C. C. Silveira, S. R. Mendes,
G. M. Martins, S. C. Schlösser, T. S. Kaufman, Tetrahedron
2013, 69, 9076–9085; c) D. S. Bose, L. Fatima, H. B. Mereyala,
J. Org. Chem. 2003, 68, 587–590; d) Z. Xiao, J. W. Timberlake,
Tetrahedron 1998, 54, 4211–4222.
Acknowledgments
The author is grateful to Ms Eliete de Fátima V. B. N. da Silva, Ms
Abene Silva Ribeiro, and the Analytical Centre of Fundamental
Chemistry Department, Universidade Federal de Pernambuco, for
the NMR experiments. Additional acknowledgments are given to
Prof. Savio Moita Pinheiro (UFPB-Brazil) for the helpful dis-
cussions and to Dr. Kyan James Allahdadi (Hospital São Rafael-
Brazil) for proofreading the manuscript.
[18] a) P. Barbazán, R. Carballo, U. Abram, G. Pereiras-Gabián,
E. M. Vázquez-López, Polyhedron 2006, 25, 3343–3348; b) Z.-
L. Lu, W. Xiao, B.-S. Kang, C.-Y. Su, J. Liu, J. Mol. Struct.
2000, 523, 133–141.
[19] A. V. Gudmundsdottir, M. Nitz, Carbohydr. Res. 2007, 342,
749–752.
[20] M. O. Forster, J. R. Trotter, J. Weintraube, J. Chem. Soc. Trans.
1911, 99, 1982–1992.
[21] M. M. Andrade, M. T. Barros, J. Comb. Chem. 2010, 12, 245–
247.
[1] F. R. Pavan, P. I. S. Maia, S. R. A. Leite, V. M. Deflon, A. A.
Batista, D. N. Sato, S. G. Franzblau, C. Q. F. Leite, Eur. J.
Med. Chem. 2010, 45, 1898–1905.
[2] D. Sriram, P. Yogeeswari, K. Madhu, Bioorg. Med. Chem. Lett.
2005, 15, 4502–4505.
[3] K. M. Dawood, H. Abdel-Gawad, H. A. Mohamed, F. A. Bad-
ria, Med. Chem. Res. 2011, 20, 912–919.
[4] O. I. El-Sabbagh, H. M. Rady, Eur. J. Med. Chem. 2009, 44,
3680–3686.
[22] J. M. de los Santos, Y. López, D. Aparicio, F. Palacios, J. Org.
Chem. 2008, 73, 550–557.
[23] G. Bartoli, M. Bosco, M. C. Berlucci, E. Marcantoni, L. Sam-
bri, E. Torregiani, Eur. J. Org. Chem. 1999, 3, 617–620.
Received: May 20, 2014
Published Online: August 29, 2014
Eur. J. Org. Chem. 2014, 6411–6417
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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