Ceric ammonium nitrate: An efficient catalyst for one-pot synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines

Article abstract of DOI:10.2174/157017810791130586

Ceric ammonium nitrate (CAN) catalyzed the one-pot synthesis of 2,2,4-trirnethyl-1,2-dihydroquinoline derivatives from substituted anilines and acetone via a modified Skraup reaction. The methodology was used to synthesize a novel dihydroquinoline-based compound derived from an anti-inflammatory agent nimesulide.

Full text of DOI:10.2174/157017810791130586

306
Letters in Organic Chemistry, 2010, 7, 306-310
Ceric Ammonium Nitrate: An Efficient Catalyst for One-Pot Synthesis of
2,2,4-Trimethyl-1,2-dihydroquinolines
Shylaprasad Durgadasa,b, Vijay K. Chatarec, Khagga Mukkantia and Sarbani Pal*,c
aJNT University, Kukatpally, Hyderabad-500085, India; bMSN Pharmachem Pvt. Ltd., Plot No 212/A,B,C,D, APIICL,
Phase-II, Pashamylaram, Patancheru (M), Medak District 502 307, Andhra Pradesh, India; cDepartment of Chemistry,
MNR Degree and PG College, Kukatpally, Hyderabad-500072, India
Received February 06, 2010: Revised March 16, 2010: Accepted March 19, 2010
Abstract: Ceric ammonium nitrate (CAN) catalyzed the one-pot synthesis of 2,2,4-trimethyl-1,2-dihydroquinoline
derivatives from substituted anilines and acetone via a modified Skraup reaction. The methodology was used to synthesize
a novel dihydroquinoline-based compound derived from an anti-inflammatory agent nimesulide.
Keywords: CAN, catalysis, aniline, dihydroquinoline.
2,2,4 Substituted 1,2-dihydroquinolines A (Fig. 1) have
been found to be integral part of many bioactive molecules
[1, 2]. They are also key synthetic precursors for a number of
pharmacologically important compounds possessing
antibacterial [3], antidiabetic [4] and anti-inflammatory [5]
activities. Nimesulide (B, Fig. 1) on the other hand is a well
known anti-inflammatory drug available for patient’s use to
treat pain [6]. We hypothesized that combination of
structural features of both A and B in a single molecule
would provide a novel dihydroquinoline C (Fig. 1) of
potential pharmacological interest and therefore we planned
to synthesize compound C.
chloride [22] and aluminum trichloride [23] were
occasionally used in an autoclave. The use of nonvolatile
homogeneous acids, such as p-aminobenzenesulfonic acid
[17], benzenesulfonic acid [19], and p-toluenesulfonic acid
[18-20] has also been reported. Recently, the use of
lanthanide catalysts and microwave technology has been
reported [24]. The methodology however, involved the use
of expensive catalysts such as Sc(OTf)3. Moreover, the use
of microwave is challenging in large scale synthesis. More
recently, synthesis via Bi(OTf)3 catalyzed condensation of
2,2-dimethoxypropane with aromatic amines has been
reported [25]. In our endeavor to develop a mild,
MeO2SHN
MeO2SHN
R3
Me
O
O
R2
HN
NO2
Me
N
H
R1
Me
A
C
B; nimesulide
Fig. (1). 2,2,4 Substituted 1,2-dihydroquinoline.
While a variety of methods [7-14] has been reported for
the synthesis of compound A the most commonly used
inexpensive and microwave free scalable method to prepare
compound C we now report ceric ammonium nitrate (CAN)
catalyzed one-pot synthesis of 2,2,4-trimethyl-1,2-
dihydroquinolines (2) from substituted anilines (1) and
acetone via the modified Skraup reaction (Scheme 1).
method however has been
a modified Skraup [15]
cyclization [16] due to its simplicity and easy availability of
starting materials. This method involves the reaction of an
aniline with acetone (or the desired ketone), in the presence
of a volatile catalyst e.g. iodine at 170-175 °C (or 145 °C
under pressure for 2–3 days). Other volatile catalysts, such
as hydrogen chloride [17-20] and bromine [17] have also
been used near the boiling point of aniline (184 °C) or lower
temperatures at around 100 °C. Boron trifluoride has been
used as a salt of aniline [21] or ether adduct [12]. Hydrogen
Our interest in the use of CAN stems from the fact that it
catalyzed the reaction of anilines with vinyl ethers to afford
4-alkoxy-2-methyl-1,2,3,4-tetrahydroquinolines [26]. In the
beginning of our study we carried out the reaction of aniline
(1a) with acetone in the presence or absence of CAN. The
results of this study are summarized in Table 1. Initially, the
reaction was carried out using 0.50 equiv of CAN when the
product 2a was isolated in 77% yield (entry 1, Table 1).
Encouraged by this observation we then planned to optimize
the reaction conditions. Accordingly, a series of reactions
were carried out changing the equiv of CAN used, reaction
*Address correspondence to this author at the Department of Chemistry,
MNR Degree and PG College, Kukatpally, Hyderabad 500 072, India;
Tel: 90-40-23041488; E-mail: sarbani277@yahoo.com
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Ceric Ammonium Nitrate
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
307
NH2
H
N
CAN
CH3COCH3
+
50-55 oC,
20-24h
R
R
2
1
Scheme 1. CAN-mediated synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines.
Table 1. The Effect of Reaction Conditions on the Reaction of Aniline and Acetonea
NH2
H
N
CAN
CH3COCH3
+
2a
1a
Entry
equiv of CAN used
Temp (°C)
Time (h)
% yieldb of 2a
1
2
3
4
5
6
0.50
0.25
0.10
0.0
50-55
50-55
24
24
24
24
12
24
77
80
62
Nil
59
10
50-55
50-55
0.25
50-55
0.25
Room temp
aAll the reactions were carried out using aniline 1a (1.0 mmol) and acetone (10 mL per 1.0 g of compound 1a).
bIsolated yield.
temp and time. We observed that 0.25 equiv was the
minimum amount of CAN necessary to achieve the
maximum yield of product 2a (Entry 1 vs 2 vs 3, Table 1).
The reaction was entirely suppressed in the absence of CAN
(entry 4, Table 1) indicating the key role of this catalyst. All
these reactions were carried out at 50-55 °C for 24h.
Decrease in reaction time (entry 5, Table 1) or lowering of
reaction temperature (entry 6, Table 1) either decreased the
product yield or suppressed the product formation
significantly. It is worthy to mention that this reaction does
not need the use of inert or anhydrous atmosphere and can be
carried out in an open reaction vessel. In other words this
reaction was not sensitive towards the atmospheric oxygen
which is beneficial for a large scale synthesis.
spectra of 2a-h indicated the presence of a vinylic proton, a
vinylic methyl and two other methyl groups.
Due to our continued interest in the synthesis of
nimesulide derivatives of potential pharmacological interest
we applied our present methodology for the preparation of
compound C. Thus reduction of nimesulide B was carried
out according to a known procedure [30] to afford the
required aniline derivative 3 (Scheme 2). The compound 3
was then treated with acetone in the presence of CAN to give
the desired dihydroquinoline derivative C in 80% yield [31].
Notably, preparation of compound C was also attempted by
using the conventional iodine-mediated method [16] in our
laboratory but the reaction yielded an inseparable mixture of
unidentified compounds instead of desired product C. The
1H and 13C NMR spectra of compound C is shown in Fig.
(2).
Having established the optimum reaction condition we
then decided to examine the generality and scope of this
CAN-catalyzed synthesis of dihydroquinoline. Thus a
number of substituted anilines (1) were employed under the
condition of entry 2 of Table 1 [27]. The reaction proceeded
well in all these cases providing 2,2,4-trimethyl-1,2-
dihydroquinolines (2) in good yield (entries 1-8, Table 2).
The aniline may contain an electron withdrawing groups
such as NO2 or CF3 (entry 2 and 8, Table 2) or electron
donating substituents such as Me, OMe (entry 3 and 4, Table
2) or halogens e.g. F, Cl or Br (entry 5, 6 and 7, Table 2).
The use of other ketone e.g. 2-butanone was also examined
under the reaction condition employed and the
corresponding dihydroquinoline 2i was isolated in 70% yield
(entry 9, Table 2). Structures of all the compounds
synthesized were confirmed by spectral (NMR, IR & MS)
and analytical data. Appearance of a peak in the region 5.3-
Mechanistically, this reaction seems to proceed via an
imine intermediate E1 generated in situ followed by an
electrophilic attack at the ortho position by another ketone
molecule in the presence of CAN (Scheme 3). Presumably,
the simultaneous interaction of CAN with imine nitrogen of
E1 and the carbonyl oxygen of the reacting ketone favored
the ortho attack to give E2. An intramolecular cyclization of
E2 involving the imine and ene moiety promoted by CAN
provided E3 which on subsequent isomerization yielded the
product 2. A similar type of intramolecular cyclization of
imine under photo irradiation has been reported earlier [32].
In conclusion, we have developed a new and practical
method for the synthesis of 2,2,4-trimethyl-1,2-
dihydroquinolines via a CAN mediated modified Skraup
1
5.6 (1H), 1.9-2.0 (3H) and 1.2-1.3 ꢀ (6H) in the H NMR

308 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Durgadas et al.
Table 2. CAN Catalyzed One-Pot Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolinesa
% Yieldb
Ref.
Arylamine (1)
Product (2)
Entry
Time
H
N
NH2
1
24
80
[28]
[25]
[28]
--
1a
2a
H
N
O2N
Me
MeO
F
NH2
2
3
4
5
6
7
8
24
20
20
24
24
24
24
65
70
75
72
70
75
68
O2N
Me
MeO
F
1b
1c
1d
1e
1f
2b
H
N
NH2
NH2
NH2
NH2
NH2
NH2
2c
H
N
2d
H
N
--
2e
H
N
Cl
[28]
[28]
--
Cl
2f
H
N
Br
Br
1g
2g
H
N
F3C
F3C
1h
2h

Ceric Ammonium Nitrate
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
309
(Table 2). Contd…..
Entry
% Yieldb
Ref.
Arylamine (1)
Product (2)
Time
H
N
NH2
9
20
70
[29]
1a
2ic
aAll the reactions were carried out using aniline 1 (1.0 mmol), acetone (10 mL per 1.0 g of compound 1) and CAN (0.25 mmol) at 50-55 °C.
bIsolated yield.
c2-butanone was used in place of acetone.
NHSO2Me
O
CH3COCH3
NHSO2Me
NHSO2Me
O
CAN
O
Ref [30]
55 oC, 24h
Yield 80%
NH
NH2
NO2
B
C
3
Scheme 2. Synthesis of novel dihydroquinoline-based compound derived from nimesulide.
Fig. (2). 1H and 13C NMR of compound C in DMSO-d6.
CeIV
N
N
O
O
NH2
N
2
R
R
R
R
1
E1
E2
E3
Scheme 3. Proposed mechanism for CAN-mediated synthesis of 2,2,4-trimethyl-1,2-dihydroquinolines.

310 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Durgadas et al.
[1,5] dipolar
via
6ꢁ-electrocyclic
rearrangements
or
reaction. The reaction does not require the use of expensive
catalyst or reagent and can be carried out in an open vessel.
The methodology was used to synthesize
dihydroquinoline-based compound derived from anti-
inflammatory agent nimesulide. Due to its operational
simplicity and easy availability of required raw materials we
expect that the present methodology would find wide usage
in the preparation of dihydroquinoline-based library of small
molecules.
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ACKNOWLEDGEMENT
The author (S.D.) thanks management of MSN Pharma-
chem for constant encouragement.
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