LETTER
▌637
Letter
Expedient Microwave-Assisted Synthesis of Novel 6-Substituted
5-Alkoxy(benzyloxy)-3,6-dihydro-2H-1,3,4-oxadiazin-2-ones
Synthesis of Novel 6-Substituted 5-Alkoxy(benzyloxy)-3,6-dihydro-2H-1,3,4-oxadiazin-2-ones
Detlef Geffken,* Finn K. Hansen, Mehdi Khankischpur, Tobias Mauz, Ronald Meurer
Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
Fax +49(40)428386573; E-Mail: geffken@chemie.uni-hamburg.de
Received: 14.10.2011; Accepted after revision: 04.01.2012
ed synthesis of compounds 5a–j by intramolecular cycli-
zation of α-hydroxyhydrazonates 4.
Abstract: Novel 6-substituted 5-alkoxy(benzyloxy)-3,6-dihydro-
2H-1,3,4-oxadiazin-2-ones have been prepared in good yields and
very short reaction times by intramolecular cyclization of α-hy-
droxyhydrazonates in the presence of sodium ethoxide under micro-
wave irradiation.
R4
O
O
O
O
Key words: hydrazonates, nitrogen heterocycles, cyclization, mi-
crowave-assisted synthesis, ring closure
HN
NH
N
HO
R1
N
O
R1
R3
R3
R2
R2
O
Due to the development of highly productive screening
systems for drug targets the time-efficient construction
and modification of biologically active heterocyclic com-
pounds is becoming very important in drug discovery. Mi-
crowave irradiation has been applied to a large number of
chemical modifications in recent years, and there are now
very few areas of synthetic organic chemistry that have
not been shown to be enhanced using microwave-assisted
synthesis.1–4 In particular, this method of energy transfer
to a reaction mixture can grant access to synthetic trans-
formations, which may be prohibitively long or low yield-
ing using conventional reaction conditions.1–4
4
5
Figure 1 Antiplasmodial active α-hydroxyhydrazonates 4 and tar-
geted heterocyclic analogues 5
The α-hydroxyhydrazonates 4 have been prepared accord-
ing to our recently disclosed three-step protocol starting
from literature-known cyanohydrins 1,11 which upon a
Pinner reaction12 delivered α-hydroxyimidatehydrochlo-
rides 2. Unfortunately, the reaction of 2 with carbazates
provided amidrazones 6 as byproducts (see Supporting In-
formation) and the desired α-hydroxyhydrazonates 4a–d
were obtained in only moderate yields of 36–41%. Con-
sequently, we developed a more efficient synthesis for the
key intermediates 4. Treatment of 2 with a saturated solu-
tion of hydrogen sulfide in dry dichloromethane–
pyridine13 afforded the α-hydroxythiocarboxylic-O-esters
3 in 82–88% yield, which upon reaction with carbazates
furnished smoothly the desired α-hydroxyhydrazonates
4e–j in 73–81% yield as mixtures of E- and Z-isomers
(Scheme 1, Table 1).
The esters of hydrazonoic acids, namely hydrazonates, are
important building blocks in heterocyclic chemistry and
have been utilized for the synthesis of numerous five-, six-
and seven-membered heterocycles as well as fused deriv-
atives thereof.5–8 Moreover, hydrazonates have continued
to attract great attention of the scientific community, par-
ticularly because of their presence in various biologically
active compounds. Hydrazonates offer a wide range of in-
teresting biological activities including anthelmintic, anti-
fungal, and anti-inflammatory properties.9 In addition, the
hydrazonate moiety has been identified as pharmacophore
in bactericides and herbicides.10 Very recently, we found
that α-hydroxyhydrazonates of type 4 display excellent
antiplasmodial activity.11
Next, we investigated the ring-closing reaction of the α-
hydroxyhydrazonates by refluxing a solution of 4a–c in
ethanol in the presence of one equivalent of sodium eth-
oxide. Followed by a simple workup procedure the de-
sired heterocycles 5a–c were obtained in 74–80% yield.
However, relatively long reaction times were required (2–
8ꢀh). Therefore, we repeated the synthesis of 5 by means
of microwave irradiation. The reaction conditions were
optimized regarding to temperature and power to increase
the yields and shorten the reaction times. In all cases com-
pletion of the reaction was monitored by IR spectroscopy
as well as TLC. Best results were achieved using
Tmax = 100ꢀ°C and Pmax = 200ꢀW. Under these conditions
the targeted 6-substituted 5-alkoxy(benzyloxy)-3,6-di-
hydro-2H-1,3,4-oxadiazin-2-ones 5a–j were isolated in
78–87ꢁ% yield within only 5–10 minutes (Scheme 2,
Table 2, see Supporting Information). Heterocycles 5 dis-
As part of our ongoing research directed to biological ac-
tive heterocyclic compounds we became interested in the
synthesis of 6-substituted 5-alkoxy(benzyloxy)-3,6-di-
hydro-2H-1,3,4-oxadiazin-2-ones 5, which can be consid-
ered as semicyclic hydrazonate derivatives and rigid
analogues of the α-hydroxyhydrazonates 4 (Figure 1). We
here describe a simple and convenient microwave-assist-
SYNLETT 2012, 23, 637–639
Advanced online publication: 03.02.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290160; Art ID: ST-2011-D0557-L
© Georg Thieme Verlag Stuttgart · New York
Geffken, Detlef
