A new method for the generation of azoalkenes from ketohydrazones and its application to the synthesis of tetrahydropyridazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.06.007

The reaction of ketohydrazones containing an α-methylene group with chloramine-T followed by treatment with triethylamine leads to the formation of azoalkenes via an α-chloroazo-compound, which can react intermolecularly and in situ with olefinic compounds to produce tetrahydropyridazine derivatives in good yield.

Full text of DOI:10.1016/j.tetlet.2005.06.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5969–5970
A new method for the generation of azoalkenes from
ketohydrazones and its application to the synthesis of
tetrahydropyridazine derivatives
S. L. Gaonkar and K. M. Lokanatha Rai*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
Received 4 December 2004; revised 26 May 2005; accepted 1 June 2005
Available online 18 July 2005
Abstract—The reaction of ketohydrazones containing an a-methylene groupwith chloramine-T followed by treatment with
triethylamine leads to the formation of azoalkenes via an a-chloroazo-compound, which can react intermolecularly and in situ
with olefinic compounds to produce tetrahydropyridazine derivatives in good yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Cycloaddition reactions in which an azo grouppartici-
pates as the 2p-electron component have been known
for several years.1 Azoalkenes can also act as the 4p-
electron component in [4+2]cycloaddition reactions.
[4+2]Cycloaddition reactions of azoalkenes with olefinic
compounds are of synthetic interest since tetrahydropyrid-
azine derivatives formed are important in the synthesis
of an antihypertensive agent,2 vasodilators,3 glyco-
sidase inhibitors,4 etc. The generation of azoalkenes
can be difficult. They are unstable and normally are only
observed in solution, their presence sometimes being
detectable by blue coloration.5 The usual method of gen-
erating azoalkenes is via elimination of a hydrogen
halide from the hydrazones of a-monohaloketones.6
However, azoalkenes are highly reactive and unstable,
hence they are usually only generated in situ. The yield
of the cycloaddition products is often low and side reac-
tions can predominate, hence an improved procedure
for the generation of azoalkenes is of interest.
chloramine-T. During the course of these studies, it
was observed that treatment of cyclohexanone oxime
with chloramine-T produced a blue colour suggestive
of the formation of 1-chloro-1-nitroso cyclohexane.7
This observation prompted us to treat the hydrazones
of several ketones bearing reactive methylene groups
with chloramine-T to generate the corresponding a-
chloroazo-compound. Interestingly, we were able to iso-
late the a-chloroazo-compounds. We now report the use
of chloramine-T as a new and efficient reagent for the
conversion of ketohydrazones bearing a reactive methyl-
ene groupinto a-chloroazo-compounds, which are suit-
able for the in situ generation of azoalkenes for
[4+2]cycloadditions to olefins. Typically, the cycloaddi-
tion is carried out by refluxing an equimolecular mixture
of the ketohydrazone and chloramine-T trihydrate in
ethanol followed by the addition of triethylamine and
the alkene in ethanol at rt. In general, tetrahydropyrid-
azine derivatives were obtained in good yields (Scheme
1).
We have used chloramine-T extensively for the prepara-
tion of biologically active heterocycles via [3+2]cyclo-
addition reactions of 1,3-dipolar species such as nitrile
oxides and nitrile imines with olefinic compounds. We
have successfully isolated the reactive intermediate
nitrile oxides during the oxidation of aldoximes with
The reaction with chloramine-T proceeds with aromatic
as well as aliphatic ketohydrazones bearing an a-hydro-
gen [e.g., 1a–e] followed by the cycloaddition with styr-
ene, acrylonitrile and 1-methyl styrene.
1H NMR, 13C NMR, MS studies and elemental analyses
confirmed the structures of the pyridazine derivatives.
As expected, the cycloadditions were regioselective. H
1
Keywords: Chloramine-T; Tetrahydropyridazine; Azoalkenes.
*
NMR indicated the presence of a single isomer in all
cases. All the H NMR spectra of the cycloadducts 5,
Corresponding author. Tel.: +91 821 2515110; fax: +91 821
2421263; e-mail: kmlrai@eth.net
1
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.007

5970
S. L. Gaonkar, K. M. L. Rai / Tetrahedron Letters 46 (2005) 5969–5970
Z
Ph
N
Ph
N
Ph
N
Ph
Z
X
NH
N
chloramine-T
ethanol
TEA
X
N
N
N
4
R'
R'
R'
Cl
R'
1
2
3
5
R'
Ph
p-ClC6H4-
X
Z
1
a
4
Ph
CN
Ph
a
b
c
H
H
b
p-NO2C6H4-
c
Me
Ethyl
Furyl
d
e
Scheme 1.
Table 1.
when X = H, showed signals due to H-6 as a doublet of
doublets in the region d 3.5–4.5 while in cycloadduct 5c
(X = CH3) there was no signal in this region and the H-4
protons appeared as a triplet in the region d 1.2–1.7. The
H-5 protons appeared as multiplets in the region d 1.7–
2.3.
Entry Keto-hydrazone Product Mp/bp (ꢁC) Yield (%)
+ alkene
1
1a+4a
1a+4b
1a+4c
1b+4a
1b+4b
1b+4c
1c+4a
1c+4b
1c+4c
1d+4a
1d+4b
1d+4c
1e+4a
1e+4b
1e+4c
5a
5b
5c
5d
5e
5f
116–118
96–98
74
78
65
70
80
62
72
75
68
69
76
65
70
74
65
2
3
109–111
Thick oil
Thick oil
Thick oil
142–143
Thick oil
134–136
Thick oil
Thick oil
Thick oil
122–124
Thick oil
105–106
4
In the 13C NMR spectra, all the pyridazines gave consis-
tent signals for the newly formed ring carbons. For
example, the signals due to C-6 appeared in cycloadduct
5 (when X = H) as a doublet in the region d 65–75
while in cycloadduct 5c (X = CH3), C-6 appeared as a
singlet in the region d 65–75; C-5 and C-4 appeared as
triplets in the region d 25–35 and d 20–30, respectively.
The formation of the product was further supported
by mass spectra and correct elemental analyses.
5
6
7
5g
5h
5i
8
9
10
11
12
13
14
15
5j
5k
5l
5m
5n
5o
Typical procedure: 1,3,6-Triphenyl-1,4,5,6-tetrahydropyrid-
azine (5a): A mixture of acetophenone phenylhydra-
zone (1a, 0.50 g, 2.38 mmol) and chloramine-T trihydrate
(0.68 g, 2.41 mmol) in ethanol (20 mL) was refluxed for
2 h. The mixture was cooled to rt, triethylamine (1 mL)
was added and the mixture was stirred for 15 min. A
solution of styrene (4a, 0.25 g, 2.40 mmol) in ethanol
(5 mL) was then added and the mixture was stirred at
rt for 2 h. It was then concentrated under reduced pres-
sure and the residue was extracted with diethyl ether
(25 mL). The extract was washed with water (15 mL)
and 1 N aq NaOH (2 · 5 mL), then dried (Na2SO4).
The solvent was evaporated and the remaining yellow
oil was stirred in n-hexane. The resulting solid was fil-
tered and recrystallized from ethanol:n-hexane (1:1) to
gave 5a as a pale yellow crystalline solid (0.55 g, 74%),
H, 6.44, N, 8.94. The same procedure was used in all
cases (Table 1).
In summary, we have demonstrated that tetrahydropyrid-
azines can be synthesized by the reaction of ketohydra-
zones bearing an a-methylene groupwith alkenes in the
presence of chloramine-T and triethylamine in typically
62–80% yields.
References and notes
1. Brandman, H. A.; Conley, R. T. J. Org. Chem. 1973, 38,
2236–2239.
2. Lednicer, D.; Ronaix, A. In OrganicChemistry of Drug
Synthesis; Wiley-Interscience Publication, 1998; Vol. 2, pp
304–305.
3. Lednicer, D. Strategies for OrganicDrug Synthesis and
Design; Wiley-Interscience Publication, 1998, pp 257–260.
4. Osborn, H. M. I.; Coisson, D. Mini-Rev. Org. Chem. 2004,
1, 41–45.
5. Deady, L. W. Tetrahedron 1967, 23, 3505–3508.
6. Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Perkin. Trans.
1 1979, 249–257, and references cited therein.
7. Hassner, A.; Rai, K. M. L. Synthesis 1989, 57–59.
1
mp116–118 ꢁC. H NMR (300 MHz, CDCl3) d 1.26–
1.29 (t, 2H, J = 6.9 Hz, CH2), 1.74–1.77 (m, 2H, CH2),
3.81–3.87 (dd, 1H, J = 9.2, 2.1 Hz, CH), 6.60–6.68 (m,
3H, ArH), 7.10–7.19 (m, 7H, ArH), 7.35–7.45 (m, 5H,
ArH). 13C NMR (75 MHz, CDCl3) d 25.1 (t), 29.4 (t),
71.10 (d), 110.6 (d), 118.9 (d), 124.2 (d), 128.1 (d),
128.8 (d), 129.2 (d), 129.5 (d), 131.1 (d), 132.3 (s), 138.0
(s), 143.5 (s) 156.1 (s). MS m/z: 313 (MH+), 312 (M+),
208, 181, 104, 103, 102, 77 (100%). Anal. Calcd for
C22H20N2: C, 84.58, H, 6.45, N, 8.97. Found: C, 84.62,