Microwave enhanced greener synthesis of indazoles via nitrenes

Article abstract of DOI:10.1016/j.tetlet.2006.07.062

Non-traditional methods (grinding, water-based biphasic reactions, microwave chemistry) were used for the preparation of Schiff bases from several amines and 2-nitrobenzaldehydes. These nitro compounds were allowed to react with triethyl phosphite under m

Full text of DOI:10.1016/j.tetlet.2006.07.062

Tetrahedron Letters 47 (2006) 6795–6797
Microwave enhanced greener synthesis of indazoles via nitrenes
Deepu John Varughese, Maghar S. Manhas and Ajay K. Bose*
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Received 15 June 2006; revised 13 July 2006; accepted 14 July 2006
Available online 4 August 2006
Dedicated to Richard Glazer
Abstract—Non-traditional methods (grinding, water-based biphasic reactions, microwave chemistry) were used for the preparation
of Schiff bases from several amines and 2-nitrobenzaldehydes. These nitro compounds were allowed to react with triethyl phosphite
under microwave irradiation for the generation of nitrenes that underwent insertion reactions to form indazoles. This procedure
constitutes an energy-efficient, greener chemistry version of the Cadogan reaction for nitrene-based formation of nitrogen
heterocycles.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
R'
R'
CHO
NO2
MW
H2N
N
R
+
Cadogan and co-workers published a series of papers
starting in 1962 that described the synthesis of a variety
of nitrogen containing heterocycles by the deoxygen-
ation of aromatic nitro compounds; an excess of triethyl
phosphite served as the reducing agent at high tempera-
ture under nitrogen; several hours of reaction time were
required.1 The reaction mechanism involves the forma-
tion of a nitrene that undergoes an insertion reaction
to form another nitrogen containing ring. In the course
of our studies on redesigning classical reactions by using
Microwave-induced Organic Reaction Enhancement
(‘MORE’) chemistry techniques,2–4 the Cadogan reac-
tion was re-investigated.5
R
NO2
1
2
3
P(OEt)3
MW
R
R'
a)
b) OMe
c)
d) OEt
e) Me
H
H
H
R'
H
OMe
H
H
N
R
N
4
Scheme 1.
A detailed description of the synthesis of 2-phenylind-
azole (Scheme 1, 4:R=R0=H) is given in Organic Synthe-
ses as described by Cadogan and Mackie and checked
by Dauben et al.6 The first step was the preparation of
a Schiff base from o-nitrobenzaldehyde and p-anisidine
by heating under reflux for a period of 2 h; ethyl alcohol
was used as the solvent. The second step was the reac-
tion of the Schiff base with excess triethyl phosphite by
refluxing for 8 h under an inert atmosphere followed
by a long work-up procedure ending with recrystalliza-
tion of the crude product from alcohol. These steps have
been greatly shortened and improved in our laboratory
by using microwave chemistry. Described below are
energy-efficient greener chemistry approaches that were
developed for this purpose.
2. Preparation of Schiff bases
Three green chemistry methods were studied for prepar-
ing Schiff bases:
Keywords: Microwaves; Nitrenes; Nitro group reduction; Indazoles;
Cadogan reaction; Nitrogen heterocycles; Energy efficiency.
(a) Microwave assisted synthesis. Easily available
isopropyl alcohol (sold in drug stores as rubbing
alcohol) is a convenient and inexpensive reaction
*
Corresponding author. Tel.: +1 610 258 8624; fax: +1 610 438
8232; e-mail: abose@stevens.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.062

6796
D. J. Varughese et al. / Tetrahedron Letters 47 (2006) 6795–6797
medium for the preparation of Schiff bases. A solu-
the pure form. This procedure is rapid and simple
and the apparatus required is a container of an
appropriate size and an electric stirrer. The method
is suitable for small scale as well as multi-molar
scale reactions.
tion of an aldehyde (1) and an amine (2) was
exposed to microwave irradiation for 1 or 2 min;
the Schiff base (3) that was formed in high yield
crystallized out on cooling the reaction mixture. If
either the aldehyde or the amine is a liquid, it
may not be necessary to use a solvent.
For conducting a reaction by this method, a large
amount of water (e.g., 1 L) is placed in the container
and stirred. The reactants (e.g., several grams) are then
added slowly to the water. In a few minutes, an exother-
mic reaction starts and the temperature of the mixture
rises by 10–15 °C; cold water can be added to control
this temperature rise. After a few more minutes, the
solid product (Schiff base) begins to crystallize out in a
nearly pure form—suitable as an intermediate for reac-
tions without further purification. This method was
found to be rapid, clean, and eco-friendly; the product
was obtained in about 90% yield. Schiff bases in molar
quantity were prepared by this convenient method (see
Table 1).
(b) Grindstone chemistry: a friction activated synthesis.7
Exothermic reactions can be conducted by grinding
the reactants together for a few minutes without
using any organic solvent; this method does not
seem to be effective for endothermic reactions.
Since Schiff base formation is an exothermic reac-
tion, this approach was used for the preparation
of several Schiff bases. This procedure is a slight
modification of a method described by Toda et al.8
In a typical experiment, a mixture of equivalent
amounts of an amine and an aldehyde (a total of
2–10 g) was placed in a mortar and ground with a
pestle made of porcelain. The reaction mixture
thickened in 2–5 min and the temperature went up
by 5–10 °C.
3. Cadogan reaction: reduction with triethyl phosphite
A pilot experiment was performed with the Schiff base
derived from o-nitrobenzaldehyde 1 and p-anisidine 2b.
When this Schiff base 3b was suspended in an excess
of triethyl phosphite in a conical flask open to the atmo-
sphere and irradiated for about 4 min at 1000 W in an
unmodified domestic microwave oven, a yellow crystal-
line compound was obtained upon isolation and purifi-
cation. From the melting point and spectral
characteristics, this compound was identified as the tar-
get indazole 4b; the yield was about 82%. It should be
noted that an inert atmosphere recommended by Cado-
gan et al. was not employed (Scheme 1).
After storage at room temperature for 10–20 min,
the solid product was purified by crystallization
from isopropyl alcohol to give the pure Schiff base.9
(c) Water-based biphasic reactions. Recently a water-
based method was developed in our laboratory
for conducting exothermic reactions when the reac-
tants are organic liquids.10 It is a convenient and
effective green chemistry method—especially if the
product is a solid that crystallizes out—usually in
Table 1. Preparation of indazoles
H2N
R
R
N
Ar
N
Entry
N
NO2
R'
R'
Amine 2
Schiff basea
mp (°C)
3
Indazoleb
Ar
4
R
H
R0
H
a
64–65
84–85
b
OMe
H
OMe
c
H
OMe
H
68–70
86–87
MeO
d
OEt
OEt
Me
e
Me
H
129–130
a Yields for all Schiff base examples are about 90%.
b Yields for indazoles ranged from 60% to 65%.

D. J. Varughese et al. / Tetrahedron Letters 47 (2006) 6795–6797
6797
H2N
CHO
N
(EtO)3P
N
MW
MW
NO2
N
NO2
1st stage (2 min)
2nd stage (Temp. max. 150oC)
Scheme 2.
Excess triethyl phosphite was removed in early experi-
ments by reaction with aqueous formaldehyde solution
instead of distillation under reduced pressure as
described by previous authors. A greener chemistry
procedure was then sought that avoided reaction with
formaldehyde.
homogeneity of the field. Synthetic experiments con-
ducted by us on a multiple gram scale (5–50 g) using this
device gave essentially the same yields in repeated runs.
Acknowledgments
Advantage was taken of the fact that triethyl phosphate
is soluble in water. Conversion of triethyl phosphite to
the corresponding phosphate was easily achieved in a
few minutes by room temperature oxidation with 3%
hydrogen peroxide. Washing with water removed the
phosphates from the organic reaction mixture. The
organic products were purified by crystallization from
suitable solvents. Several indazoles were prepared on
0.5 g–2 g scale (Table 1) by this procedure in 60–70%
yield based on the starting aldehyde.
We are grateful to the Union Mutual Foundation, New
York Cardiac Center and Stevens Institute of Technol-
ogy for financial support. We thank Dr. F. T. Jones
for useful discussions.
References and notes
1. Cadogan, J. I. G. Quart. Rev. 1962, 6, 208.
2. For a recent review on ‘MORE’ Chemistry see: Bose, A.
K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.; Banik,
B. K. Synthesis 2002, 1578.
3. Bose, A. K.; Manhas, M. S.; Banik, B. K.; Robb, E. W.
Res. Chem. Intermed. 1994, 20, 1.
3.1. One pot synthesis of indazoles
As an additional modification, we examined the possi-
bility of forming the Schiff base in situ as an intermedi-
ate for the corresponding indazole. The two step
Cadogan reaction for the synthesis of indazoles was sub-
sequently modified and simplified to a one pot reaction
under microwave irradiation (Scheme 2).
4. Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman,
M.; Manhas, M. S. CHEMTECH 1997, 27, 18.
5. Varughese, Deepu J. MS Thesis, Stevens Institute of
Technology, 2005.
6. Cadogan, J. I.; Mackie, G. Org. Syn. Coll. Vol. 5, 1973,
941.
7. Bose, A. K.; Pednekar, S.; Ganguly, S. N.; Chakraborty,
G.; Manhas, M. S. Tetrahedron Lett. 2004, 45, 8351.
8. Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
9. For larger scale preparations, a glass or porcelain bowl of
appropriate size and a hand-held electric (food) mixer with
stainless steel rotors were used. It should be noted that the
chemical reaction is exothermic; the temperature rise
depends on the quantity of the material used and the
exothermal nature of the reaction. The mixer was started
at the lowest speed and then the speed was gradually
increased to produce gentle but thorough mixing; the
temperature rise was not allowed to exceed 20 °C above
the room temperature. This method was found suitable
even if one or both components were liquids but the Schiff
base was a solid.
For example, a mixture of equivalent amounts of
2-nitrobenzaldehyde and aniline 2a (Table 1) and an
excess of triethyl phosphite was irradiated with micro-
waves for 10 min. For the first 2 min the power level
was kept low (about 200 W), so that the temperature
of the mixture was kept below 70 °C; then the tempera-
ture was allowed to rise to 150 °C by increasing the
power to about 400 W (it should be noted that these
parameters will depend on the particular microwave
oven in use). The reaction was monitored by GC–MS.
It was found that the reaction proceeds in two stages:
the initial 2 min are the first stage that involves the for-
mation of the Schiff base 3a (Table 1), in the second
stage cyclization to indazole 4a (Table 1) occurs as the
temperature is raised to about 150 °C.
If both components were liquid, coarsely crystalline
Epsom salt (MgSO4Æ7H2O) or sand was added for
increasing friction. If Epsom salt had been added, it was
removed by adding water in which the salt is easily
soluble. When sand was added instead of the Epsom salt,
the organic product was extracted with an organic solvent,
such as isopropyl alcohol or dichloromethane. The Schiff
base was purified by crystallization from isopropyl alcohol
or methanol.
3.2. Microwave equipment used
The experimental results reported in this letter were
obtained a few years ago in the course of a carefully
conducted Master’s Thesis by Deepu J. Varughese
entitled ‘Microwave Assisted Nitrene Chemistry.’
10. (a) Bose, A. K.; Manhas, M. S.; Pednekar, S.; Ganguly, S.
N.; Dang, H.; He, W.; Mandadi, A. Tetrahedron Lett.
2005, 46, 1901; (b) Bose, A. K.; Manhas, M. S.; Ganguly,
S. N.; Pednekar, S.; Mandadi, A. Tetrahedron Lett. 2005,
46, 3011.
The microwave equipment available at that time for
synthetic work was the Milestone Microwave Labsta-
tion. A turntable was used for providing a reasonable