Microwave-assisted cyclocondensation of hydrazine derivatives with alkyl dihalides or ditosylates in aqueous media: Syntheses of pyrazole, pyrazolidine and phthalazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.07.018

Direct syntheses of 4,5-dihydro-pyrazole, pyrazolidine, and 1,2-dihydro-phthalazine derivatives via double-alkylation of hydrazines by alkyl dihalides or ditosylates were accomplished in aqueous media under microwave irradiation conditions; the environmen

Full text of DOI:10.1016/j.tetlet.2005.07.018

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6011–6014
Microwave-assisted cyclocondensation of hydrazine derivatives
with alkyl dihalides or ditosylates in aqueous media: syntheses
of pyrazole, pyrazolidine and phthalazine derivatives
Yuhong Ju and Rajender S. Varma*
Clean Processes Branch, Sustainable Technology Division, National Risk Management Research Laboratory,
US Environmental Protection Agency, MS 443, 26 W. Martin Luther King Drive, Cincinnati, OH 45268, USA
Received 17 May 2005; revised 5 July 2005; accepted 6 July 2005
Available online 25 July 2005
Abstract—Direct syntheses of 4,5-dihydro-pyrazole, pyrazolidine, and 1,2-dihydro-phthalazine derivatives via double-alkylation of
hydrazines by alkyl dihalides or ditosylates were accomplished in aqueous media under microwave irradiation conditions; the envi-
ronmentally friendlier chemical transformation occurred in a single step and eliminated the use of expensive metal catalysts in build-
ing two C–N bonds.
Ó 2005 Elsevier Ltd. All rights reserved.
Heterocyclic compounds occur very widely in nature and
are essential to life. Nitrogen-containing heterocyclic
molecules constitute the largest portion of chemical enti-
ties, which are part of many natural products, fine chemi-
cals, and biologically active pharmaceuticals vital for
enhancing the quality of life.1 4,5-Dihydro-pyrazoles,2
pyrazolidines,3 and 1,2-dihydro-phthalazines4 are
important classes of heterocycles useful as pesticides,
anticonvulsants, and potent vasorelaxing agents. The
standard preparation of 4,5-dihydro-pyrazoles involves
the cyclocondensation of hydrazine derivatives with
a,b-unsaturated carbonyl compounds,5 or the reaction
of hydrazine with substituted cyclopropanes6 often
requiring the use of a crown ether as a phase transfer cat-
alyst.7 Pyrazolidines are usually prepared by the conden-
sation reaction of hydrazines with b-diketones or b-keto
esters or alternatively by reacting a protected hydrazine,
di-tert-butyldihydrazodiformate, with 1,3-dibromopro-
pane in the presence of a phase transfer catalyst ulti-
mately requiring a sequential deprotection of Boc
group in 4 M HCl.8 Syntheses of 4,5-dihydro-pyrazole,
pyrazolidine, and 1,2-dihydro-phthalazine via direct
heterocyclization of hydrazine derivatives and alkyldi-
halides or ditosylates have never been fully explored.
Microwave (MW) irradiation has gained popularity in
the past decade as a powerful tool for rapid and efficient
synthesis of a variety of organic compounds because of
the selective absorption of microwave energy by polar
molecules.9 The application of MW irradiation to pro-
vide enhanced reaction rate and improved product yield
in chemical synthesis has been extended to modern drug
discovery10 in complex multi-step synthesis,11 and it is
proving quite successful in the formation of a variety
of carbon–heteroatom and carbon–carbon bonds.12
During our ongoing efforts to explore organic syntheses
in aqueous reaction media using MW irradiation,13 we
discovered that the cyclocondensation of phenyl hydra-
zines with 1,3-dihalopropanes or 1,3-glycol disulfonate
in aqueous alkaline medium surprisingly afforded
4,5-dihydro-pyrazole as major product instead of the
anticipated pyrazolidine (Scheme 1). We wish to report
herein a ÔcleanerÕ synthesis of nitrogen-containing
heterocycles in mildly alkaline water under microwave
irradiation conditions.
The microwave-assisted reaction was also examined
under solventless conditions and using various reaction
media such as water, polyethylene glycol (PEG 300),
toluene, and N,N-dimethylformamide. Reactions under
solventless condition afforded very low yield (less than
20%) because the reactants were immiscible with
the base, potassium carbonate. PEG 300 is a promis-
ing medium to replace volatile organic solvents for
Keywords: Cyclocondensation; Microwave irradiation; Heterocycles;
4,5-Dihydro-pyrazole; 1,2-Dihydro-phthalazine.
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569
7677; e-mail: Varma.Rajender@epa.gov
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.018

6012
Y. Ju, R. S. Varma / Tetrahedron Letters 46 (2005) 6011–6014
H
N
NH2
NH
N
K2CO3,H2O
MW
+
N
N
+
X
X
R
R
R
major
minor
R = H, Me, Cl; X = Cl, Br, I, OTs
Scheme 1. MW-assisted synthesis of 4,5-dihydro-pyrazole.
green chemical synthesis under microwave irradiation14
but relatively more expensive than water, and it broke
down to ethylene glycol upon exposure to microwaves
under basic condition. The reaction in toluene was a
failure as the yield was less than 25%. N,N-Dimethyl-
formamide as a reaction medium gave rise to side reac-
tions and therefore low products yields (ꢀ40%). Water
is a good absorber for microwave energy15 and has
been successfully employed as solvent for various
organic syntheses.16 Utilization of water as a safer
reaction medium in conjunction with the use of micro-
wave irradiation as the heating source is gaining
widespread acceptance17 even though water is not an
ideal solvent for most organic compounds according
to the traditional belief Ôlike dissolves likeÕ. We find that
water is one of the best choices in view of its relatively
environmental-friendly nature and abundance. Further,
superheating of water above its boiling point by
microwave irradiation in an heterogeneous system
could substitute as a phase transfer catalyst without
using any phase transfer reagent, thus providing the
In conclusion, direct syntheses of 4,5-dihydro-pyrazole,
pyrazolidine, and 1,2-dihydro-phthalazine derivatives
via double-alkylation of hydrazine derivatives by alkyl
dihalides or ditosylates in aqueous media under micro-
wave irradiation were demonstrated. The general micro-
wave protocol enabled the synthesis of a wide variety of
useful precursors for pharmacologically active hetero-
cycles using water as reaction medium in the absence
of a phase transfer agent. This advantageous method-
ology shortened the reaction time significantly and
utilized unprotected hydrazine derivatives and alkyl
dihalides or ditosylates to construct heterocycles in a
single step, which has never been fully realized under
conventional heating conditions. Further, it eliminated
the need for a phase transfer catalyst and provided
water as an ideal substitute for hazardous organic
solvents. Efforts to define the reaction mechanism, the
scope of the reaction, and the application of this
method to synthesize complex heterocycles are currently
underway.
observed
acceleration
similar
to
ultrasound
All the starting hydrazines and hydrazine hydrochlo-
rides and alkyl dihalides were obtained from Aldrich
Chemical Co. and were used as such; 1,3-propane-diol-
ditosylates were prepared from 1,3-propanediol accord-
ing to literature.19 1,3-Dichloro-1,3-diphenylpropane
was synthesized by the reaction of benzaldehyde and
styrene using boron trichloride.20 The synthesized prod-
ucts were identified by GC/MS qualitative analysis
based on Wiley library database using an HP 6890 GC
system with an HP 5872 mass selective detector. The
irradiation.18
This general reaction is applicable to a variety of hydra-
zine derivatives such as substituted phenyl hydrazines,
1,2-dialkylhydrazines, hydrazine hydrochlorides, and
sulfates and for aliphatic dihalides and ditosylates
(Table 1).
As can be seen from Table 1, a variety of heterocycles
were synthesized by the cyclocondensation of hydrazine
derivatives with alkyl dihalides and ditosylates. Hydra-
zine and mono-substituted hydrazines afforded 4,5-
dihydro-pyrazole instead of pyrazolidine (entries 1–9, 11,
and 14) or 1,2-dihydro-phthalazine (entries 10 and 13);
disubstituted hydrazines furnished the expected pyraz-
olidine (entry 15) and 1,2,3,4-tetrahydro-phthalazine
(entry 16). Interestingly, the reaction of phenylhydrazine
with 1,3-dibromo-2-propanol gave rise to 1-phenyl-
1H-pyrazole (entry 12), which was the result of further
elimination of 1 equiv water from 1-phenyl-4,5-dihydro-
1H-pyrazol-4-ol in an alkaline medium. The anticipated
formation of two pairs of structural isomers occurred
1
identities were further confirmed by H and 13C NMR
spectra that were recorded for the pure products in
chloroform-d (CDCl3) with TMS as internal reference
using a Bruker Biospin 300 MHz NMR spectrometer.
The representative experimental procedure is as follows:
1,2-diethylhydrazine dihydrochloride (1 mmol, 0.161 g),
1,2-bis-chloromethyl-benzene (1 mmol, 0.175 g), 2 M
sodium hydroxide (1 mL), and potassium carbonate
(1 mmol, 0.138 g) in water (1 mL) were placed in a
10 mL crimp-sealed thick-walled glass tube equipped
with a pressure sensor and a magnetic stirrer. The reac-
tion tube was placed inside the cavity of a CEM Dis-
cover Focused Microwave Synthesis System, operated
at 120 5 °C (temperature monitored by a built-in infra-
red sensor), power 70–100 Watt and pressure 40–80 psi
for 20 min. After completion of the reaction, the bipha-
sic system was allowed to stir in the air for 6 h, and the
product was extracted into ethyl acetate. The removal of
the solvent under reduced pressure (rotary evaporator)
and flash column chromatography using hexane/ethyl
acetate (9/1) as eluent afforded the product, 2,3-
diethyl-1,2,3,4-tetrahydro-phthalazine 0.114 g (60% yield).
1
(entries 4 and 7) as ascertained by H NMR. The ease
of generation of carbon–nitrogen double bond in these
reactions (Table 1) was explored in two control experi-
ments by introducing oxygen into the system or alterna-
tively, using activated palladium on carbon as a
dehydrogenation catalyst. We found that oxygen in
the air played a critical role in promoting the formation
of C–N double bond via dehydrogenation mechanism as
was the case observed for palladium-catalyzed dehydro-
genation process.

Y. Ju, R. S. Varma / Tetrahedron Letters 46 (2005) 6011–6014
6013
Table 1. Aqueous cyclocondensation of hydrazines with dihalides using MW irradiationa
Entry
1
Hydrazine derivatives
Dihalides or ditosylates
Main products
Yields (%)
H
68b
N
Cl
Br
Cl
Br
N
N
NH2
H
N
2
3
4
65b
N
N
NH2
H
N
70b
N
N
TsO
Br
OTs
NH2
1/1
H
N
65b,c
NH2
N
N
N
Br
N
Cl
H
Cl
Cl
N
5
64b
Br
Br
NH2 HCl
NH2 HCl
N
N
Cl
H
N
6
7
8
66b
TsO
Cl
OTs
N
N
H
N
1/1.2
63b,c
NH2 HCl
N
N
N
Cl
N
H
N
70b
N
N
Cl
Cl
Cl
Cl
NH2 HCl
NH2 2HCl
N
N
9
60b
89d
NH
H
N
Cl
Cl
10
NH2
N
N
Cl Cl
H
N
60b
N
N
11
NH2
NH2
H
N
Br
Br
N
12
13
81b
85d
OH
N
Br
Br
N
N
H
N
NH2
N
Cl Cl
HN
14
H2N–NH2 H2SO4
74b
Et
NH
N
N
80d
60b
2HCl
N
H
15
16
Br
Br
Et
Et
NH
Cl
Cl
N
N
2HCl
N
H
Et
a Reaction of 1 mmol scale, MW power 80–100 Watt, 120 °C, pressure 40–80 psi for 20 min.
b Isolated yields based on starting hydrazines.
c Structure isomer ratio determined by NMR.
d Yields based on quantitative GC–MS analysis of starting dihalides.

6014
Y. Ju, R. S. Varma / Tetrahedron Letters 46 (2005) 6011–6014
1H NMR (300 MHz, CDCl3/TMS) d ppm 7.16 (dd,
2H, J = 3.3, 5.7 Hz), 7.05 (t, 2H, J = 3.3 Hz), 3.88 (s,
4H), 2.63 (q, 4H, J = 7.2 Hz), 1.13 (t, 4H, J =
7.2 Hz); 13C NMR (75.5 MHz, CDCl3/TMS) d ppm
133.0, 117.9, 126.7, 126.1, 49.2, 43.0, 13.1; MS (EI)
m/z (relative intensity, %) 190 (M, 41), 161 (100), 105
(33), 104 (29), 91 (14).
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M. H. J. Heterocycl. Chem. 2001, 38, 613–616; (b) Ahn, J.
H.; Kim, J. A.; Kim, K.-M.; Kwon, H.-M.; Huh, S.-H.;
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oxygen or using palladium on carbon as dehydrogenat-
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extraction immediately after the completion of the
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Acknowledgements
This research was supported, in part, by Postgraduate
Research Program at the National Risk Management
Research Laboratory administered by the Oak Ridge
Institute for Science and Education through an inter-
agency agreement between the US Department of
Energy and the US Environmental Protection Agency.
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