LETTER
1467
An Effective Nitrilimine Cycloaddition for the Synthesis of 1,3,5-Trisubsti-
tuted 1,2,4-Triazoles from Oximes with Hydrazonoyl Hydrochlorides
E
ffective Nitrili
i
mine
C
-
ycloadd
Y
ition for Synthesis
aof 1,3,5-Trisubst
W
a
The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, No. Hsueh 91, Shih Rd., Taichung, Taiwan
40402, R. O. C.
b
Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. Hsueh 91, Shih Rd., Taichung, Taiwan 40402,
R. O. C.
Fax +886(4)22078083; E-mail: ffwong@mail.cmu.edu.tw; E-mail: wongfungfuh@yahoo.com.tw
c
School of Pharmacy, China Medical University, No. Hsueh 91, Shih Rd., Taichung, Taiwan 40402, R. O. C.
Received 21 February 2011
I wish to acknowledge that our Synlett publication was composed of experimental data that are a duplication of those
tivated nitrile such as an imidate (Pinner reaction) or a
Abstract: An effective 1,3-dipolar cycloaddition for the synthesis
of 1,3,5-trisubstituted 1,2,4-triazole derivatives was developed by
thioamide (Pellizzari reaction) to form an acylamidrazone
contained in a paper by the same authors in Tetrahedron 2011, 67, 5339. In addition, I note the unfortunate omission of
intermediate.25 The subsequent cyclization of the acyl-
rreesapcteincgtivoexicmreossswriethfehryednrcaezosntooytlhhiysdpruocbhlliocraidtieosnu.sAinsgatrrieetshuyllt-, I retract this Synlett paper. I apologize for these serious
amidrazone intermediate was carried out at a high temper-
amine as a base. The desired 1,3,5-trisubstituted 1,2,4-triazoles
errors in judgment.
were obtained in good yields and the reaction was applicable to al- ature.25 The typical procedure often involves high reaction
iphatic, cyclic aliphatic, aromatic and heterocyclic oxime sub-
Sstirnacteesr.ely,
temperature and long reaction time but gives the product
in low yield.26
Key words: 1,2,4-triazoles, hydrazonoyl hydrochloride, nitrilimi-
Different approaches have been reported by using ami-
dines to replace the nitriles. However, only acetamidine
ne, 1,3-dipolar cycloaddition, oximes
Fung Fuh Wong (Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. Hsueh 91, Shih Rd.,
Taichung, Taiwan 40402, R. O. C.)
and benzamidine substrates were able to achieve good
yields.27 In this paper, we made use of the nitrilimine
1,2,4-Triazole is an important class of heterocyclic com-
cycloaddition28 for the synthesis of 1,3,5-trisubstituted
pounds responsible for the biological activity of many
1,2,4-triazole derivatives by reacting oximes with hydra-
pharmaceutically active compounds that show significant
zonoyl hydrochlorides in the presence of triethylamine as
antifungal,1–3 antiviral,4 anti-inflammatory,5 antiasthmat-
a base. The newly developed method is applicable to ali-
ic,6 antiproliferative,7,8 hypotonic activities,9 antibacterial,
phatic, cyclic aliphatic, aromatic and heterocyclic oximes
and antihelmintic activities.10 Some molecules based on
to provide target compounds in good yields.
triazole moiety also act as potent agonist or antagonist re-
Most of the oxime hydrochlorides 1–10 were prepared29
by reacting the corresponding aldehydes with hydroxyl-
amine hydrochloride, expect for the commercially avail-
able acetaloxime 1 and benzaloxime 7. It was well
established that in situ generation of nitrilimines from hy-
drazonoyl chlorides occurred under homogeneous condi-
tions upon base treatment, as hydrazonoyl chlorides were
often used as precursors for nitrilimines in 1,3-dipolar cy-
cloaddition.28,30 Compounds 11–18 were synthesized by
the treatment of various anilines with NaNO2–HCl,31 and
the resulting diazonium salts were reacted with methyl 2-
chloroacetoacetate to give the hydrazonoyl chlorides 11–
18.30
ceptor ligands,11,1,2 and the more selective alkylating
agents for the anticancer drugs.13 Recently, they were de-
veloped as mimics14,15 or isosteres16 of the amide bond in
attempts to increase bioavailability of the parent bioactive
molecules.17 Furthermore, triazole-based agonists or an-
tagonists targeting different receptors were described,18,19
especially construction molecules based on the 1,3,5-tri-
substituted 1,2,4-triazole scaffold.20–24
The conventional method for the preparation of triazole
rings contains a dehydrative condensation followed by the
cyclization of an acylamidrazone intermediate in two
steps.22 In the dehydrative condensation, a thermal fusion
was performed between a hydrazide and a nitrile, or an ac-
X
X
Cl⋅HCl
OH⋅HCl
Et3N
N
N
N
toluene, reflux, 3 h
+
R
NH
CO2Me
N
R
H
N
1–10
11–18
CO2Me
19–35
Scheme 1
SYNLETT 2011, No. 10, pp 1467–1471
x
x.
x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260759; Art ID: W05411ST
© Georg Thieme Verlag Stuttgart · New York
Wang, Li-Ya
