4244
T.-H. Tsang, D. A. Gubler / Tetrahedron Letters 53 (2012) 4243–4244
conditions used in the synthesis of 2, provided 1 in high yield
(70%, six total steps, 11% overall yield). Characterization data (1H
NMR, 13C NMR, HRMS, IR and MP) obtained for 1 matched with
the data reported for the natural material.8
In conclusion, farylhydrazones A (1) and B (2), the first natural
products found to contain the phenylhydrazone moiety, were syn-
thesized in six and five steps respectively starting from o-nitroben-
zoic acid in good overall yield (11% for 1 and 30% for 2). Each step
in the synthesis is amendable for the preparation of large amounts
of 1 and 2. Additionally, analogues of 1 and 2 can be easily envi-
sioned due to the highly convergent nature of the synthesis. Stud-
ies on the biological activity of 1 and 2 and derivative synthesis are
currently in progress in our laboratory.
Scheme 1. Reagents and conditions: (a) H2SO4, MeOH, 65 °C, 5 d, 90%; (b) Zn dust
(5.0 equiv), NH4Cl (10.0 equiv), acetone/water (4:1), 40 °C, 12 h, 74%; (c) NaNO2
(0.90 equiv), SnCl2Á2H2O (1.8 equiv), HCl, H2O, 0 °C, 1 h; (d) Pyruvic acid (1.7 equiv),
HCl, H2O, rt, 45 min, 46% (two steps); (e) NaOH (0.5 N), H2O/MeOH (1:1), reflux, 1 h,
99%; (f) Gly-OMeÁHCl (1.0 equiv), DMAP (2.0 equiv), EDCÁHCl (1.0 equiv), CH2Cl2,
0 °C to rt, 16 h, 52%; (g) NaOH (0.5 N), H2O/MeOH (1:1), reflux, 1 h, 70%.
Acknowledgments
We would like to thank the Brigham Young University-Hawaii
mentored research program for funding, Mr. Wesley Yoshida at
the University of Hawaii at Manoa for obtaining the NMR spectra,
and Dr. Bruce Jackson at Brigham Young University for Hi-Res MS
analysis.
excellent yield (90%). Esterification was followed by reduction of
the nitro arene using zinc dust and ammonium chloride to give
the corresponding aniline in good yield. Hydrazine formation using
sodium nitrite and tin(II) chloride under acidic conditions fur-
nished hydrazine 6.6 Coupling of 6 with pyruvic acid 3 under
previously reported conditions used for hydrazine7 provided
farylhydrazone B methyl ester 7 in 46% yield (two steps). Saponifi-
cation of 7 proceeded quantitatively and furnished farylhydrazone
B (2) in five total steps from o-nitrobenzoic acid in 30% overall
yield. Characterization data (1H NMR, 13C NMR, HRMS, IR and
MP) of 2 were in excellent agreement with the same characteriza-
tion data for the authentic sample.8 Additionally, each step in the
synthesis is scalable, thus allowing for the preparation of multi-
gram quantities of 2.
With large quantities of farylhydrazone B (2) in hand, we then
turned our attention to the synthesis of farylhydrazone A (1) start-
ing from farylhydrazone B methyl ester (7) (Scheme 1). Peptide
coupling of 7 with glycine methyl ester hydrochloride salt using
DMAP and EDCÁHCl provided the coupled product which, upon
saponification of the bis-methyl ester compound under identical
Supplementary data
Supplementary data (complete experimental details and spec-
troscopic data for all new compounds) associated with this article
References and notes
1. Ma, C.; Li, Y.; Niu, S.; Zhang, H.; Liu, X.; Che, Y. J. Nat. Prod. 2011, 74, 32–37.
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3. Winkler, D. Econ. Bot. 2008, 62, 291–305.
4. For
a review on the biological activity of hydrazones see: (a) Narang, R.;
Narasimhan, B.; Sharma, S. Curr. Med. Chem. 2012, 19, 569–612; (b) Rollas, S.;
Güniz Küçükgüzel, S. Molecules 2007, 12, 1910–1939.
5. 100 g of 2-nitrobenzoic acid from Sigma–Aldrich (Aldrich product number:
127698) = $28.00.
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8. See the Supplementary data section for a more detailed comparison of the
spectral data for synthetic 1 and 2 compared with the natural samples.