Microwave-accelerated solvent- and catalyst-free synthesis of 4-aminoaryl/alkyl-7-chloroquinolines and 2-aminoaryl/alkylbenzothiazoles

Article abstract of DOI:10.1071/CH06391

An efficient synthesis of 4-aminoaryl/alkyl-7-chloroquinolines and 2-aminoaryl/alkylbenzothiazoles has been developed by microwave-accelerated regioselective aromatic nucleophilic substitution of 4,7-dichloroquinoline and 2-chlorobenzothiazole with aromatic and aliphatic amines under solvent-free conditions in the absence of any added protic or Lewis acid catalyst. Chemoselective reaction with the amino group in preference to the phenolic hydroxy group was observed. Thus, the treatment of 4,7-dichloroquinoline (1 equiv.) with a mixture of aniline (2 equiv.) and phenol (2 equiv.) afforded exclusive formation of 4-aminophenyl-7-chloroquinoline. When 4,7-dichloroquinoline (1 equiv.) was separately treated with 2-aminophenol (2 equiv.) and 4-aminophenol (2 equiv.), 4-(2'-hydroxyphenyl)-7-chloroquinoline and 4-(4'-hydroxyphenyl)-7-chloroquinoline, respectively, were formed. CSIRO 2007.

Full text of DOI:10.1071/CH06391

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 369–374
Microwave-Accelerated Solvent- and Catalyst-Free
Synthesis of 4-Aminoaryl/alkyl-7-chloroquinolines
and 2-Aminoaryl/alkylbenzothiazoles
Hashim F. Motiwala,A Raj Kumar,A and Asit K. ChakrabortiA,B
ADepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India.
BCorresponding author. Email: akchakraborti@niper.ac.in
An efficient synthesis of 4-aminoaryl/alkyl-7-chloroquinolines and 2-aminoaryl/alkylbenzothiazoles has been devel-
oped by microwave-accelerated regioselective aromatic nucleophilic substitution of 4,7-dichloroquinoline and
2-chlorobenzothiazole with aromatic and aliphatic amines under solvent-free conditions in the absence of any added
protic or Lewis acid catalyst. Chemoselective reaction with the amino group in preference to the phenolic hydroxy group
was observed. Thus, the treatment of 4,7-dichloroquinoline (1 equiv.) with a mixture of aniline (2 equiv.) and phenol
(2 equiv.) afforded exclusive formation of 4-aminophenyl-7-chloroquinoline. When 4,7-dichloroquinoline (1 equiv.) was
separately treated with 2-aminophenol (2 equiv.) and 4-aminophenol (2 equiv.), 4-(2ꢀ-hydroxyphenyl)-7-chloroquinoline
and 4-(4ꢀ-hydroxyphenyl)-7-chloroquinoline, respectively, were formed.
Manuscript received: 23 October 2006.
Final version: 15 March 2007.
Ar(R)
Introduction
Cl
N
HN
N
The synthesis of heteroaryl/alkyl amines is of importance to
synthetic organic/medicinal chemists because of the poten-
tial therapeutic application of these compounds. For example,
the 4-aminoquinoline moiety has been recognized as a ver-
satile pharmacophore as compounds containing this structural
framework possess a broad spectrum of biological activities
such as antimalarial,[1] inhibitors of C5a receptor binding,[2]
anti-neoplastic,[3] and anti-inflammatory,[4] to name a few.
4-Aminoarylquinolines serve as starting material for the synthe-
sis of complex heterocycles such as 1H-indolo[3,2]quinolines
that possess cytotoxic activity against the growth of human
promyelocytic leukaemia cells (HL-60)[5] and γ-carbolines.[6]
The versatile biological activity of 4-aminoquinoline deriva-
tives, and our recent efforts[7] in the search of non-
sulfonyl heterocyclic compounds as a novel class of selective
COX-2 inhibitors, led us to synthesize 4-aminoaryl/alkyl-7-
chloroquinolines. The general approach for the synthesis of
4-aminoquinolines involves aromatic nucleophilic substitution
of 4-chloroquinolines with aryl/alkyl amines (Scheme 1).
However, the reported procedures required the use of high-
boiling solvents such as N-methylpyrrolidine[1a] that are difficult
to recover, additional reagents such as inorganic and organic
bases,[1a] corrosive acids,[3,5] long reaction times (4–48 h),[1,3,5]
and provide only moderate yields of products. This led us to
develop a better method as the growing concern of the develop-
ment of sustainable chemistry[8] necessitates discovering newer
synthetic methodologies to (i) avoid the use of auxiliary sub-
stances such as solvent, (ii) minimize generation of waste arising
due to use of acid or base, and (iii) cut down energy consump-
tion by acceleration of the reaction rate. Thus, recent efforts
Ar(R)
H2N
ϩ
R1
R1
Scheme 1. General synthetic strategy for 4-aminoaryl/alkylquinolines.
towards environmentally benign methodologies have focussed
on solventless organic reactions[9] and solvent-free accelerated
organic synthesis using microwave technology.[10] The fulfil-
ment of the triple bottom line philosophy[11] of green chemistry
demands procedures that do not involve the use of auxiliary sub-
stances such as solvents and catalysts and that can be performed
in short times. This led us to develop various solvent-free syn-
theticmethodologiesundermicrowaveirradiation.[12] Hence, we
plannedtodevelopamicrowave-acceleratedsolvent-freesynthe-
sis of 4-aryl/alkylquinolines. The limited reports of amination
of haloaromatics under microwave irradiation require: (i) the
presence of palladium catalyst and costly phosphine ligand, sto-
ichiometric amount of NaOBut and toluene or benzotrifluoride
as solvent;[13] (ii) the presence of strong electron-withdrawing
groups (e.g., NO2, COMe, CHO) and the use of difficult high
boiling solvents such as DMSO or DMF[14] that are washed out
during aqueous workup increasing the burden of environmental
pollution; and (iii) applicable to more nucelophilic secondary
aliphatic amines (e.g., piperidine and morpholine).[13,14] In
all of these reports the haloaromatics are benzenoid deriva-
tives, and the reaction of 3-chloropyridine with an aliphatic
amine (e.g., benzylamine) is the sole example involving a
haloheteroaromatic.[13]
© CSIRO 2007
10.1071/CH06391
0004-9425/07/050369

370
H. F. Motiwala, R. Kumar, and A. K. Chakraborti
Results and Discussion
In each occasion, a single product was obtained. The influ-
ence of microwave irradiation in accelerating the reaction
was proven by the observation that when the reaction of 4,7-
dichloroquinoline (1 mmol) with aniline (2 equiv.) was carried
out under classical heating at 100◦C (oil bath) for 1 h, a 40%
conversion into 4-aminophenyl-7-chloroquinoline took place
compared to 95% yield obtained under microwave irradiation
(entry 5, Table 1).
In a model study, 4,7-dichloroquinoline was treated with aniline,
4-methylaniline, and 4-acetylaniline, three compounds repre-
senting an aromatic amine, an electron-rich aromatic amine, and
an electron-deficient aromatic amine, respectively (Scheme 2).
The reactions were carried out using various amounts of
the amine under different conditions such as changing the
microwave output power and reaction time to determine the
optimum reaction conditions (Table 1). The best results were
obtained by treatment of 4,7-dichloroquinoline with 2 equiv. of
the amine using 600W microwave output power. The reaction
time varied with the substituent of the amine.
As the presence of two halogen atoms raised the question of
regioselectivity, the C8 aromatic proton of 4,7-dichloroquinoline
that appeared as a singlet at δ 8.0 was used as the probe atom
to determine the regioselectivity. We thought that the product
formed by nucleophilic substitution of the C7 chlorine atom of
4,7-dichloroquinoline by the amine should have the C8 proton
singlet resonating at a δ value significantly lower than 8.0 ppm,
as the C7 nitrogen lone pair would induce a shielding effect at the
C8 proton because of resonance.The presence of one proton sig-
nal at δ 7.96, 7.89, and 8.0 in the 1H NMR spectra of the product
obtained from the reaction of 4,7-dichloroquinoline with aniline,
4-methylaniline, and 4-acetylaniline, respectively, confirmed the
formation of the corresponding 4-aminoaryl-7-chloroquinoline
derivative. The regioselective nucleophilic displacement of the
C4Clatomwasinconformitywiththeliteratureobservationdur-
ing the reaction of 4,7-dichloroquinoline with aliphatic amines
under classical heating.[1,15] We reasoned that the nitrogen atom
of the heteroaromatic ring of 4,7-dichloroquinoline makes the
C4 chlorine atom more susceptible to nucleophilic displacement
compared to the C7 chlorine atom.
R
NH2
Cl
N
HN
N
Microwave
ϩ
Cl
Cl
R
Scheme 2. Reaction of 4,7-dichloroquinoline with aromatic amines under
microwave irradiation.
Table 1. Reaction of 4,7-dichloroquinoline with a few representative
aromatic amines under micro mode irradiation
A mixture of 4,7-dichloroquinoline (1 mmol) and the amine in a beaker
(10 mL) was heated in a domestic microwave oven under catalyst- and
solvent-free conditions using the micro mode of operation
To further prove the aspect of regioselectivity, 7-chloro-
4-hydroxyquinoline was treated with aniline (2 equiv.) under
microwave irradiation for 10 min using 600W microwave
output power (Scheme 3). The MALDI mass spectrum of
the crude reaction mixture revealed the presence of an
ion peak at m/z 255.5 corresponding to the MH+ ion of
4-aminophenyl-7-chloroquinoline (formed due to the nucle-
ophilic displacement of the 4-OH group)[2] along with a peak
at m/z 180.3 corresponding to the MH+ ion of unreacted
7-chloro-4-hydroxyquinoline. No ion peaks at m/z 236.5 and
311.3 corresponding to 7-aminophenyl-4-hydroxyquinoline and
4,7-bisaminophenylquinoline, respectively, were observed.
We next treated 4,7-dichloroquinoline with various sub-
stituted amines under microwave irradiation using 600W
power (Table 2). Excellent yields were obtained affording
4-aminoaryl/alkyl-7-chloroquinoline as the only regioisomer.
The reactions with aminophenols (entries 13 and 14) exhibited
excellent chemoselectivity, with no product arising out of the
substitution by the hydroxyl group. Similarly the reaction with
4-acetylaniline (entry 15) occurred chemoselectively with the
amine group, and no product (O/C-substituted) due to compet-
itive nucleophilic substitution involving the enol of the ketone
moiety was formed asevidenced by the IR, NMR, and mass spec-
tra of the product.To establish the efficiency of this methodology
Entry
Amine
p-NH2C6H4R
Equiv.A
PowerB [W]
Time
[min]
YieldC,D
[%]
1
2
3
4
5
6
7
8
R = H
2
2
1
1.5
2
2
1
1.5
2
2
300
450
600
600
600
450
600
600
600
600
300
450
600
600
10
10
10
10
10
10
15
10
10
15
5
50
95
70
85
95E
75
75
80
85
98
50
65
70
80
R = H
R = H
R = H
R = H
R = Me
R = Me
R = Me
R = Me
R = Me
R = COMe
R = COMe
R = COMe
R = COMe
9
10
11
12
13
14
2
2
2
2
10
10
20
AMolar equivalents of the amine used with respect to 4,7-dichloroquinoline.
BMicrowave output.
CIsolated yield of the corresponding 4-aminoaryl-7-chloroquinoline.
DThe products were characterized by IR, NMR, and mass spectroscopy.
E4-Aminophenyl-7-chloroquinoline was formed in 40% yield when the
mixture was heated at 100◦C (oil bath) for 1 h.
Ph
Ph
OH
N
OH
N
HN
N
HN
N
PhNH2
(2 equiv.)
ϩ
ϩ
HN
Ph
Microwave,
600 W,
10 min
HN
Ph
Cl
Cl
MW 254.5
Only product
formed
MW 236.3
Not formed
MW 311.3
Not formed
Scheme 3. Reaction of 7-chloro-4-hydroxyquinoline with aniline under microwave irradiation.

Synthesis of 4-Aminoquinolines and 2-Aminobenzothiazoles
371
for reaction with aliphatic amines, morpholine (entry 24) and
benzylamine (entry 25) were taken as representative examples
of secondary and primary aliphatic amines, respectively.
The chemoselective reaction with the amino group in case
of aminophenols (entries 13 and 14; Table 2) encouraged us to
study the chemoselectivity during intermolecular competition
studies. Thus, a mixture of 4,7-dichloroquinoline (1 mmol), ani-
line (2 mmol), and phenol (2 mmol) was heated under microwave
irradiation for 15 min using 600W output power (Scheme 4).
4-Aminophenyl-7-chloroquinoline was obtained in 90% yield.
The excellent results obtained with the reaction of 4,7-
dichloroquinoline encouraged us to extend this methodology for
other chloroheteroaromatics to claim the generality for the syn-
thesis of heteroaryl/alkyl amines. Thus, 2-chlorobenzothiazole
was treated with various aryl, aryl alkyl, and alkyl amines under
microwave dielectric heating in a domestic microwave oven in
the absence of any catalyst and solvent (Scheme 5).
The desired 2-aminoaryl/alkylbenzothiazoles were obtained
in 70–80% yields (Table 3). The reactions took place rapidly and
werecompleteafter15 s–15 min.Theinfluenceofthemicrowave
heating in accelerating the reaction was established by the obser-
vation that 2-aminophenylbenzothiazole was formed in 20%
yield when the mixture of 2-chlorobenzothiazole (1 mmol) and
aniline (2 mmol) was heated on an oil bath at 100◦C for 1 h.
Table 2. Reaction of 4,7-dichloroquinoline with various aromatic and
aliphatic amines under microwave dielectric heating
A mixture of 4,7-dichloroquinoline (1 mmol) and the amine (2 equiv.)
was heated in a domestic microwave oven under catalyst- and solvent-free
conditions using 600W power and micro mode of operation
NH2
R5
R4
R1
R2
Conclusions
R3
In conclusion, a high yielding synthesis of 4-aminoaryl/alkyl-
7-chloroquinolines and 2-aminoaryl/alkylbenzothiazoles has
Entry Amine
Time [min] YieldA,B [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
R1 = R2 = R3 = R4 = R5 = H
7
15
10
10
20
15
5
5
5
8
10
10
10
15
20
15
15
15
15
95
98
92
93
80
75
96
93
90
93
90
95
91
75
80
82
78
92
85
90
96
S
N
S
N
Microwave
600 W
R1 = R2 = R4 = R5 = H, R3 = Me
R1 = R3 = R4 = R5 = H, R2 = Me
R1 = Me, R2 = R3 = R4 = R5 = H
R1 = R3 = R5 = Me, R2 = R4 = H
R1 = R5 = Me, R2 = R3 = R4 = H
R1 = R2 = R4 = R5 = H, R3 = Cl
R1 = R3 = R4 = R5 = H, R2 = Cl
R1 = Cl, R2 = R3 = R4 = R5 = H
R1 = R2 = R4 = R5 = H, R3 = F
R1 = F, R2 = R3 = R4 = R5 = H
R1 = R2 = R4 = R5 = H, R3 = Br
R1 = R2 = R4 = R5 = H, R3 = OH
R1 = R3 = R4 = R5 = H, R2 = OH
ϩ
H2NAr(R)
Cl
NHAr(R)
Scheme 5. Reaction of 2-chlorobenzothiazole with various amines under
microwave heating.
Table 3. Reaction of 2-chlorobenzothiazole with various aromatic and
aliphatic amines under microwave dielectric heating
A mixture of 2-chlorobenzothiazole (1 mmol) and the amine (2 equiv.)
was heated in a domestic microwave oven under catalyst- and solvent-free
conditions using 600W power and micro mode of operation
NH2
R1
R1 = R2 = R4 = R5 = H, R3 = COMe
R1 = R2 = R4 = R5 = H, R3 = CO2Me
R1 = R2 = R4 = R5 = H, R3 = OMe
R1 = R2 = R4 = R5 = H, R3 = NO2
R1 = R3 = R4 = R5 = H, R2 = NO2
R1 = F, R2 = R3 = R5 = H, R4 = Cl
R1 = R4 = R5 = H, R2 = Cl
R2
Entry
Amine
Time [min]
YieldA,B [%]
3.5
1
1
2
3
4
5
6
R1 = R2 = H
15
4
75C
80
70
70
75
72
H
N
R1 = H, R2 = Me
R1 = H, R2 = Cl
R1 = H, R2 = F
R1 = F, R2 = H
PhCH2NH2
22
2
85
0.33
4
2
N
NH2
23
8
60
5
N
7
0.25
80
O
NH
24
25
2.5
90
70
O
NH
AIsolated yield of the corresponding 2-aminoaryl/alkylbenzothiazole.
BThe products were characterized by IR, NMR, and mass spectroscopy.
CA 20% yield of the product was formed after 1 h when the reaction was
carried out under classical heating at 100◦C (oil bath).
PhCH2NH2
7
AIsolated yield of the corresponding 4-substituted product.
BThe products were characterized by IR, NMR, and mass spectroscopy.
HN
Cl
O
NH2
OH
Microwave
ϩ
ϩ
ϩ
600 W,
15 min
Cl
N
90%
Cl
N
Cl
N
Trace
1 mmol
2 mmol
2 mmol
Scheme 4. Reaction of 4,7-dichloroquinoline with aniline and phenol during intermolecular competition study.

372
H. F. Motiwala, R. Kumar, and A. K. Chakraborti
been achieved by aromatic nucleophilic substitution of 4,7-
dichloroquinoline and 2-chlorobenzothiazole with amines,
accelerated by microwave irradiation under solvent-free condi-
tions in the absence of any added protic/Lewis acid catalyst. The
reactions with 4,7-dichloroquinoline exhibited excellent regios-
electivity and the products from substitution of the C4 chlorine
atom were obtained exclusively. The presence of the chlorine
atom at C7 in the products provide a handle for further syn-
thetic manipulation so as to introduce various substitution at
C7 and generate libraries of compounds for lead generation
and optimization. Approximately 90% of drug candidates are
N-containing,[16] and as arylation at nitrogen is the major reac-
tion in the construction of such molecules,[17] the convenient
N-arylation procedure developed in the present study should
provide a major breakthrough for high-throughput synthesis of
potential drug candidates.
The remaining reactions were carried out following this
general procedure. The products were purified either by recrys-
tallization (MeOH) or by passing through a column of silica
gel and eluting with 5–10% MeOH in CHCl3. The spectro-
1
scopic data (IR, H/13C NMR and mass spectra) of all known
compounds were in full agreement with those of authentic
compounds. The following compounds were unknown.
4-(4ꢀ-Methylphenyl)amino-7-chloroquinoline
(Entry 2, Table 2)
Mp 208–209◦C. Found: C 71.5, H 4.9, N 10.4. Calc. for
C16H13ClN2: C 71.5, H 4.9, N 10.4%. νmax(KBr)/cm−1 3151,
3047, 2925, 1574, 1512, 1426, 1374, 1325, 1251, 1163, 1079,
815. δH (300 MHz, CDCl3 + CD3OD) 8.34 (d, J 5.4, 1H), 8.12
(d, J 8.8, 1H), 7.89 (s, 1H), 7.43 (d, J 8.8, 1H), 7.23 (br s, 4H),
6.82 (d, J 5.4, 1H), 2.38 (s, 3H). δC (75 MHz, CDCl3 + CD3OD)
153.99, 153.33, 151.88, 140.01, 138.63, 138.06, 133.12, 129.82,
128.60, 126.98, 126.20, 121.19, 104.24, 23.53. m/z (APCI) 269
(MH), 271 (MH + 2).
Experimental
General
4-(3ꢀ-Methylphenyl)amino-7-chloroquinoline
(Entry 3, Table 2)
1H and 13C NMR spectra were recorded on BrukerAvance DPX
300 (300 MHz) spectrometer in CDCl3 using TMS as internal
standard. IR spectra were recorded on a Nicolet Impact 400 spec-
trometer as KBr pellets for solids and neat for liquid samples.
The reactions were monitored by TLC (silica gel-G) and Shi-
madzu QP 5000 GCMS. Evaporation of solvents was performed
at reduced pressure, using a Büchi rotary evaporator.
Mp 232–233◦C. Found: C 71.5, H 4.9, N 10.4. Calc. for
C16H13ClN2: C 71.5, H 4.9, N 10.4%. νmax(KBr)/cm−1 3166,
3047, 2924, 1595, 1566, 1538, 1485, 1372, 1324, 1266, 1161,
1082, 820. δH (300 MHz, CDCl3 + CD3OD) 8.35 (d, J 3.7, 1H),
8.19 (d, J 8.6, 1H), 7.53 (s, 1H), 7.87 (s, 1H), 7.44 (d, J 8.6, 1H),
7.30 (m, 1H), 7.16 (s, 1H), 7.04 (s, 1H), 6.91 (d, J 3.7, 1H), 2.38
(s, 3H). δC (75 MHz, CDCl3 + CD3OD) 151.73, 150.58, 149.63,
140.37, 140.19, 136.27, 129.99, 127.55, 126.45, 126.31, 124.75,
123.87, 121.19, 119.03, 102.31, 21.65. m/z (APCI) 269 (MH),
271 (MH + 2).
Typical Experimental Procedure
Reaction with 4,7-Dichloroquinoline:
4-Aminophenyl-7-chloroquinoline (Entry 1, Table 2)
A mixture of 4,7-dichloroquinoline (0.198 g, 1 mmol) and
aniline (0.186 g, 2 mmol) in a beaker (10 mL) was irradiated
at 600W for 10 min in a domestic microwave oven (SAM-
SUNG, M197DN: maximum output power 1000W, operating
frequency 2450 MHz) using the micro mode of operation. The
reaction mixture was cooled to room temperature and recrystal-
lized from methanol to afford 4-aminophenyl-7-chloroquinoline
as green crystals (0.242 g, 95%). mp 288–292◦C. νmax/cm−1
3416, 2922, 2644, 1611, 1540, 1454, 1365, 1212, 1093, 898,
743. δH (300 MHz, CD3OD) 8.60 (d, J 9.3, 1H), 8.35 (d, J 7.2,
1H), 7.96 (s, 1H), 7.74–7.78 (dd, J1,2 1.5, J1,3 9.3, 1H), 7.55–
7.60 (m, 2H), 7.43–7.48 (m, 3H), 6.87 (d, J 7.2, 1H). m/z (APCI)
255 (MH), 257 (MH + 2). The spectra were identical with those
of an authentic compound.[18]
4-(2ꢀ-Methylphenyl)amino-7-chloroquinoline
(Entry 4, Table 2)
Mp 167–168◦C. Found: C 71.5, H 4.9, N 10.4. Calc. for
C16H13ClN2: C 71.5, H 4.9, N 10.4%. νmax(KBr)/cm−1 3431,
3143, 3062, 2923, 1567, 1489, 1373, 1322, 1248, 1161, 1119,
815. δH (300 MHz, CDCl3 + CD3OD) 8.32 (d, J 4.8, 1H), 8.06
(d, J 8.8, 1H), 7.93 (s, 1H), 7.43 (d, J 8.8, 1H), 7.27–7.33 (m, 4H),
6.28 (d, J 4.8, 1H), 2.24 (s, 3H). δC (75 MHz, CDCl3 + CD3OD)
151.67, 149.42, 138.31, 136.17, 131.92, 128.11, 127.83, 127.78,
127.36, 126.07, 123.97, 118.31, 101.56, 17.72. m/z (APCI) 269
(MH), 271 (MH + 2), 4.6.
4-(2ꢀ,4ꢀ,6ꢀ-Trimethylphenyl)amino-7-chloroquinoline
(Entry 5, Table 2)
Mp 277–279◦C. Found: C 72.8, H 5.8, N 9.4. Calc. for
C18H17ClN2: C 72.8, H 5.8, N 9.4%. νmax(KBr)/cm−1 3430,
3011, 2762, 2271, 1614, 1544, 1516, 1484, 1374, 1204, 1165,
1081, 891, 816. δH (300 MHz, CDCl3 + CD3OD) 8.63 (d, J 8.8,
1H), 8.32 (d, J 6.7, 1H), 7.99 (s, 1H), 7.79–7.83 (dd, J1,2 1.7,
J1,3 8.8, 1H), 7.11 (s, 2H), 6.19 (d, J 6.7, 1H), 2.35 (s, 3H), 2.17
(s, 6H). δC (75 MHz, CDCl3 + CD3OD) 157.34, 143.72, 140.85,
139.96, 139.81, 136.26, 131.73, 130.32, 128.60, 125.56, 120.05,
116.09, 100.13, 20.53, 17.18. MS (APCI): m/z 297 (MH), 299
(MH + 2).
Reaction with 2-Chlorobenzothiazole:
2-Morpholin-4-ylbenzothiazole (Entry 7, Table 3)
A mixture of 2-chlorobenzothiazole (0.259 mL, 2 mmol) and
morpholine (0.35 mL, 4 mmol, 2 equiv.) was irradiated at 600W
for 15 s in a domestic microwave oven using the micro mode
of operation. The reaction mixture was cooled to room temper-
ature and purified by column chromatography using gradient
elution with 3–5% EtOAc in hexane to afford 2-morpholin-4-
ylbenzothiazole as a white solid (0.350 g, 80%). mp 112–113◦C.
νmax(KBr)/cm−1 2919, 2854, 1594, 1563, 1542, 1441, 1378,
1341, 1290, 1270, 1229, 1113, 1068, 1032, 1017, 945, 864, 757,
727, 657. δH (300 MHz, CDCl3) 7.61 (d, J 8.1, 1H), 7.57 (d, J 8.1,
1H), 7.28–7.33 (t, J 7.4, 1H), 7.07–7.12 (t, J 7.4, 1H), 3.82–3.85
(m, 4H), 3.61–3.64 (m, 4H). MS (APCI): m/z 221 (M + 1). The
spectra were identical with those of an authentic compound.[19]
4-(2ꢀ,6ꢀ-Dimethylphenyl)amino-7-chloroquinoline
(Entry 6, Table 2)
Mp 166–168◦C. Found: C 72.2, H 5.3, N 9.9. Calc. for
C17H15ClN2: C 72.2, H 5.4, N 9.9%. νmax(KBr)/cm−1 3158,

Synthesis of 4-Aminoquinolines and 2-Aminobenzothiazoles
373
3033, 2924, 2856, 1574, 1498, 1369, 1321, 857, 815. δH
(300 MHz, CDCl3 + CD3OD) 8.45 (d, J 5.2, 1H), 8.01 (s, 1H),
7.88 (d, J 8.9, 1H), 7.44 (d, J 8.9, 1H), 7.07–7.25 (m, 3H), 6.48
(s, 1H, NH), 6.33 (d, 1H, J 5.2), 2.37 (s, 3H), 2.20 (s, 3H). δC
(75 MHz, CDCl3 + CD3OD) 148.81, 146.34, 145.79, 133.53,
131.99, 131.39, 131.08, 129.00, 125.77, 124.81, 123.20, 122.65,
118.06, 114.30, 98.55, 17.87, 14.56. m/z (APCI) 283 (MH), 285
(MH + 2).
δC (75 MHz, CDCl3 + CD3OD) 153.69, 148.63, 144.08, 140.28,
138.96, 138.27, 130.25, 129.79, 127.11, 123.84, 120.75, 119.79,
118.68, 116.00, 100.18. m/z (APCI) 300 (M + 1).
4-(5ꢀ-Chloro-2ꢀ-fluorophenyl)amino-7-chloroquinoline
(Entry 20, Table 2)
Mp 325–327◦C. Found: C 58.7, H 3.0, N 9.1. Calc. for
C15H9Cl2FN2: C 58.7, H 3.0, N 9.1%. νmax(KBr)/cm−1 3402,
3003, 2885, 2593, 1616, 1588, 1541, 1495, 1447, 1366, 1209,
1168, 1096, 818, 789. δH (300 MHz, CDCl3 + CD3OD) 8.57 (d,
J 8.1, 1H), 8.46 (d, J 5.6, 1H), 8.0 (s, 1H), 7.80 (d, J 8.1, 1H),
7.38–7.54 (m, 3H), 6.70 (s, 1H). m/z (APCI) 307 (MH), 309
(MH + 2), 311 (MH + 4).
4-(4ꢀ-Fluorophenyl)amino-7-chloroquinoline
(Entry 10, Table 2)
Mp 212–213◦C. Found: C 66.0, H 3.7, N 10.3. Calc. for
C15H10ClFN2: C 66.1, H 3.7, N 10.3%. νmax(KBr)/cm−1 3254,
3055, 2926, 1614, 1575, 1511, 1431, 1373, 1217, 1096, 819, 781.
δH (300 MHz, CDCl3 + CD3OD) 8.32 (d, J 5.7, 1H), 8.22 (d, J
8.9, 1H), 7.91 (s, 1H), 7.47 (d, J 8.9, 1H), 7.31–7.35 (m, 2H), 7.15
(t, J 8.4, 2H), 6.74 (d, J 5.7, 1H). δC (75 MHz, CDCl3 + CD3OD)
162.00, 159.62, 151.87, 150.09, 147.70, 137.32, 135.77, 127.02,
126.98, 118.32, 117.20, 101.69. m/z (APCI) 273 (M + 1).
4-(3ꢀ-Chloro-4ꢀ-fluorophenyl)amino-7-chloroquinoline
(Entry 21, Table 2)
Mp 298–300◦C. Found: C 58.7, H 3.0, N 9.1. Calc. for
C15H9Cl2FN2: C 58.7, H 3.0, N 9.1%. νmax(KBr)/cm−1 3003,
2888, 1634, 1611, 1587, 1538, 1496, 1449, 1328, 1256, 1164,
1094, 1061, 897, 807, 762. δH (300 MHz, CDCl3 + CD3OD)
8.49 (d, J 8.7, 1H), 8.36 (d, J 6.7, 1H), 7.92 (s, 1H), 7.74 (d, J
8.7, 1H), 7.61 (d, J 6.3, 1H), 7.41 (d, J 6.3, 2H), 6.80 (d, J 6.7,
1H). m/z (APCI) 307 (MH), 309 (MH + 2), 311 (MH + 4).
4-(2ꢀ-Fluorophenyl)amino-7-chloroquinoline
(Entry 11, Table 2)
Mp 179–180◦C. Found: C 66.1, H 3.7, N 10.3. Calc. for
C15H10ClFN2: C 66.1, H 3.7, N 10.3%. νmax(KBr)/cm−1 3439,
2929, 1577, 1535, 1503, 1444, 1372, 1257, 1207, 1082, 914, 877,
818, 752. δH (300 MHz, CDCl3 + CD3OD) 8.35–8.38 (m, 1H),
8.27–8.31 (dd, J1,2 2.8, J1,3 8.8, 1H), 7.88 (s, 1H), 7.47–7.51 (dd,
J1,2 2.0, J1,3 8.8, 1H), 7.42 (m, 1H), 7.23–7.28 (m, 3H), 6.51 (m,
1H). δC (75 MHz, CDCl3 + CD3OD) 157.34, 154.05, 149.41,
148.41, 147.10, 133.93, 125.74, 125.05, 124.06, 123.30, 121.82,
116.46, 115.03, 114.90, 100.17. m/z (APCI) 273 (M + 1).
4-(1ꢀ-Imidazolyl)-7-chloroquinoline (Entry 22, Table 2)
Mp 168–169◦C. Found: C 62.8, H 3.5, N 18.3. Calc. for
C13H13ClN2O: C 62.8, H 3.5, N 18.3%. νmax(KBr)/cm−1
3112, 2922, 2856, 1718, 1608, 1587, 1562, 1484, 1429,
1321, 1253, 1150, 1112, 1021, 869, 826, 747. δH (300 MHz,
CDCl3 + CD3OD) 7.32 (s, 1H), 7.56–7.59 (m, 2H), 7.65–7.68
(dd, J1,2 2.6, J1,3 8.9, 1H), 7.85 (d, J 9.7, 1H), 8.08 (s, 1H), 8.1
(s, 1H), 9.0 (m, 1H). δC (75 MHz) (CDCl3 + CD3OD) 90.87,
93.73, 94.26, 95.87, 98.74, 99.70, 99.90, 105.50, 106.23, 109.52,
114.99, 116.73. m/z (APCI) 230 (MH), 232 (MH + 2).
4-(4ꢀ-Hydroxyphenyl)amino-7-chloroquinoline
(Entry 13, Table 2)
Mp 253–255◦C. Found: C 66.5, H 4.1, N 10.4. Calc. for
C15H11ClN2O: C 66.6, H 4.1, N 10.4%. νmax(KBr)/cm−1 3461,
3332, 2926, 1582, 1511, 1371, 1243, 1119, 920. δH (300 MHz,
CDCl3 + CD3OD) 8.32 (d, J 5.3, 1H), 8.03 (d, J 8.9, 1H), 7.90
(s, 1H), 7.42 (d, J 8.9, 1H), 7.15 (d, J 8.0, 2H), 6.90 (d, J 8.0,
2H), 6.62 (d, J 5.3, 1H). δC (75 MHz, CDCl3 + CD3OD) 154.61,
150.42,150.06, 147.84, 134.46, 130.08, 125.67, 125.50, 124.24,
112.35, 116.85, 115.10, 99.54. m/z (APCI) 271 (M + 1).
4-(3ꢀ-Aminoquinolinyl)-7-chloroquinoline
(Entry 23, Table 2)
Mp 222–224◦C. Found: C 70.7, H 4.0, N 13.7. Calc. for
C18H12ClN3: C 70.7, H 4.0, N 13.7%. νmax(KBr)/cm−1 3222,
2929, 1609, 1573, 1499, 1438, 1380, 1314, 1275, 1074, 867,
750. δH (300 MHz, CDCl3 + CD3OD) 8.91 (s, 1H), 8.47 (d,
J 5.2, 1H), 8.31 (m, 1H), 8.22 (s, 1H), 8.04 (d, J 8.6, 1H),
7.92 (s, 1H), 7.87 (d, J 8.0, 1H), 7.68–7.73 (t, J 7.6, 1H), 7.58–
7.63 (t, J 7.6, 1H), 7.53 (d, J 8.6, 1H), 7.07 (d, J 5.2, 1H). δC
(75 MHz, CDCl3 + CD3OD) 151.94, 149.71, 149.65, 147.71,
145.28, 136.59, 134.98, 129.47, 129.37, 128.62, 128.27, 128.02,
127.65, 127.46, 126.81, 124.01, 119.39, 102.80. m/z (APCI) 306
(MH+), 308 (MH+ + 2).
4-(4ꢀ-Nitrophenyl)amino-7-chloroquinoline
(Entry 18, Table 2)
Mp 265–267◦C. Found: C 60.1, H 3.4, N 14.0. Calc. for
C15H10ClN3O2: C 60.1, H 3.4, N 14.0%. νmax(KBr)/cm−1 3082,
1608, 1571, 1503, 1432, 1317, 1260, 1114, 1077, 867, 746. δH
(300 MHz, CDCl3 + CD3OD) 8.61 (d, J 5.3, 1H), 8.25–8.30 (m,
3H), 7.96 (s, 1H), 7.48–7.61 (m, 3H), 7.40 (d, J 5.3, 1H). δC
(75 MHz, CDCl3 + CD3OD) 151.71, 149.80, 148.40, 147.48,
142.64, 136.76, 127.82, 127.29, 126.15, 124.10, 120.48, 119.28,
106.76. m/z (APCI) 300 (M + 1).
4-Morpholinyl-7-chloroquinoline (Entry 24, Table 2)
Mp 224–226◦C. Found: C 62.8, H 5.3, N 11.3%. Calc. for
C13H13ClN2O: C 62.8, H 5.3, N 11.3%. νmax(KBr)/cm−1 3351,
3099, 2855, 2654, 1627, 1602, 1543, 1514, 1456, 1364, 1244,
1107, 1024, 874, 796. δH (300 MHz, CDCl3 + CD3OD) 8.54 (d,
J 6.9, 1H), 8.22 (d, J 9.3, 1H), 7.99 (s, 1H), 7.68 (d, J 9.3, 1H),
7.24 (d, J 6.9, 1H), 3.93 (s, 8H). δC (75 MHz, CD3OD) 161.05,
141.61, 139.95, 139.27, 127.98, 126.61, 118.82, 117.47, 105.45,
65.73, 52.05. m/z (APCI) 249 (MH), 251 (MH + 2).
4-(3ꢀ-Nitrophenyl)amino-7-chloroquinoline
(Entry 19, Table 2)
Mp 234–237◦C. Found: C 60.1, H 3.4, N 14.0. Calc. for
C15H10ClN3O2: C 60.1, H 3.4, N 14.0%. νmax(KBr)/cm−1 3070,
2928, 2702, 1586, 1541, 1520, 1448, 1360, 1333, 1210, 1096,
815, 734. δH (300 MHz, CDCl3 + CD3OD) 8.54 (d, J 9.4, 1H),
8.48 (d, J 7.0, 1H), 8.36–8.37 (m, 1H), 8.27 (d, J 8.5, 1H), 7.99 (s,
1H), 7.90 (d, J 8.5, 1H), 7.78–7.84 (m, 2H), 7.06 (d, J 7.0, 1H).
4-Aminomethylphenyl-7-chloroquinoline
(Entry 25, Table 2)
Mp 128–130◦C. Found: C 71.5, H 4.9, N 10.4. Calc. for
C16H13ClN2: C 71.5, H 4.9, N 10.4%. νmax(KBr)/cm−1 3344,

374
H. F. Motiwala, R. Kumar, and A. K. Chakraborti
3026, 2925, 2748, 1609, 1589, 1563, 1448, 1355, 1214, 1161,
1086, 889, 808, 749. δH (300 MHz, CDCl3 + CD3OD) 8.50
(d, J 9.0, 1H), 8.33 (d, J 6.3, 1H), 7.89 (s, 1H), 7.69 (d, J
9.0, 1H), 7.28–7.43 (m, 5H), 6.79 (d, J 6.3, 1H), 4.83 (s, 2H).
δC (75 MHz, CD3OD) 155.56, 141.61, 138.82, 137.79, 135.07,
127.85, 126.80, 126.66, 126.17, 123.93, 118.18, 114.83, 98.25,
45.78. m/z (APCI) 269 (MH), 271 (MH + 2).
CDCl3 + CD3OD) 7.51 (d, J 7.6, 1H), 7.18–7.41 (m, 7H), 6.98–
7.03 (t, J 7.4, 1H), 4.58 (s, 2H). δC (75 MHz, CDCl3 + CD3OD)
172.45, 156.20, 142.50, 134.36, 132.77, 131.73, 131.62, 130.05,
125.86, 124.95, 122.23. m/z (APCI) 241 (M + 1).
References
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2-Aminophenylbenzothiazole (Entry 1, Table 3)
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1999, 45, 269.
Mp 194–195◦C. Found: C 69.0, H 4.5, N 12.4. Calc. for
C13H10N2S: C 69.0, H 4.5, N 12.4%. νmax(KBr)/cm−1 3235,
3188, 3054, 2936, 1626, 1571, 1498, 1466, 1446, 1324, 1273,
1249, 1225, 1173, 1129, 1020, 921, 744, 720. δH (300 MHz,
CDCl3 + CD3OD) 7.55–7.63 (m, 4H), 7.30–7.40 (m, 3H), 7.08–
7.17 (m, 2H). δC (75 MHz, CDCl3 + CD3OD) 168.08, 155.18,
143.88, 133.56, 133.02, 129.77, 127.35, 126.13, 124.43, 123.20,
122.81. m/z (APCI) 227 (M + 1).
2-(4ꢀ-Methylphenyl)aminobenzothiazole (Entry 2, Table 3)
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2003, 38, 101. doi:10.1016/S0223-5234(02)01420-4
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hedron Lett. 1993, 34, 2673. doi:10.1016/S0040-4039(00)77653-2
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4, 603.
Mp 177–178◦C. Found: C 69.9, H 5.1, N 11.7, S 13.4. Calc. for
C14H12N2S: C 70.0, H 5.0, N 11.7, S 13.3%. νmax(KBr)/cm−1
3183, 2980, 2925, 1623, 1609, 1571, 1514, 1486, 1455, 1395,
1370, 1275, 1205, 1164, 1138, 1018, 889, 814, 745, 724.
δH (300 MHz, CDCl3 + CD3OD) 7.63 (d, J 7.5, 1H), 7.50–
7.55 (m, 3H), 7.26–7.31 (t, J 7.7, 1H), 7.09–7.17 (m, 3H).
δC (75 MHz, CD3OD) 165.36, 153.46, 139.43, 134.03, 131.43,
130.64, 126.99, 123.42, 121.76, 120.58, 120.11, 20.92. m/z
(APCI) 241 (M + 1).
(b) C. Selvam, S. M. Jachak, R. Thilagavathi, A. K. Chakraborti,
Bioorg. Med. Chem. Lett. 2005, 15, 1793. doi:10.1016/J.BMCL.2005.
02.039
(c) A. K. Chakraborti, R. Thilagavathi, Int. Elec. J. Mol. Design 2004,
3, 704.
(d) C. Selvam, S. M. Jachak, R. G. Oli, R. Thilagavathi,
A. K. Chakraborti, K. K. Bhutani, Tetrahedron Lett. 2004, 45, 4311.
doi:10.1016/J.TETLET.2004.04.010
(e) A. K. Chakraborti, R. Thilagavathi, Bioorg. Med. Chem. 2003, 11,
3989. doi:10.1016/S0968-0896(03)00404-8
2-(4ꢀ-Chlorophenyl)aminobenzothiazole (Entry 3, Table 3)
Mp 206–207◦C. Found: C 59.9, H 3.5, N 10.7, S 12.3. Calc. for
C13H9ClN2S: C 59.9, H 3.5, N 10.7, S 12.3%. νmax(KBr)/cm−1
3229, 3178, 2900, 1619, 1566, 1445, 1311, 1247, 1225, 1092,
1014, 814, 747, 722. δH (300 MHz, CDCl3 + CD3OD) 7.58–
7.81 (m, 4H), 7.30–7.33 (m, 3H), 7.13–7.18 (t, J 7.5, 1H). m/z
(APCI) 261 (M + 1).
[8] J. H. Clark, Green Chem. 1999, 1, 1. doi:10.1039/A807961G
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(b) P. Lidström, J. Tierney, B. Wathey, J. Westman, Tetrahedron 2001,
57, 9225. doi:10.1016/S0040-4020(01)00906-1
2-(4ꢀ-Fluorophenyl)aminobenzothiazole (Entry 4, Table 3)
Mp 195–196◦C. Found: C 63.9, H 3.7, N 11.5, S 13.1. Calc. for
C13H9FN2S: C 63.9, H 3.7, N 11.5, S 13.1%. νmax(KBr)/cm−1
3196, 3139, 1626, 1574, 1511, 1455, 1445, 1328, 1273,
1215, 1129, 1094, 1013, 922, 834, 745, 722. δH (300 MHz,
CDCl3 + CD3OD) 7.49–7.55 (m, 3H), 7.40 (d, J 7.8, 1H),
7.13–7.18 (t, J 7.7, 1H), 6.89–7.01 (m, 3H). m/z (APCI) 245
(M + 1).
(c) K. Bougrin, A. Loupy, M. Soufiaoui, J. Photochem. Photobiol.
C: Photochem. Rev. 2005, 6, 139. doi:10.1016/J.JPHOTOCHEMREV.
2005.07.001
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doi:10.1021/AR040278M
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J. Miyamoto, M. Polyakoff, W. Tumas, Pure Appl. Chem. 2000,
72, 1207.
(b) J. Elkington, http://www.sustainability.co.uk/sustainability.htm
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2005, 1401.
(b) A. K. Chakraborti, C. Selvam, G. Kaur, S. Bhagat, Synlett 2004,
851. doi:10.1055/S-2004-820012
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Tetrahedron 2005, 61, 10338. doi:10.1016/J.TET.2005.07.105
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2471. doi:10.1016/S0040-4039(98)00308-6
2-(2ꢀ-Fluorophenyl)aminobenzothiazole (Entry 5, Table 3)
Mp 217–219◦C. Found: C 63.9, H 3.7, N 11.5, S 13.1. Calc. for
C13H9FN2S: C 63.9, H 3.7, N 11.5, S 13.1%. νmax(KBr)/cm−1
3058, 2809, 2107, 2036, 1586, 1498, 1466, 1386, 1262, 1188,
1105, 1018, 950, 747. δH (300 MHz, CDCl3 + CD3OD) 7.90
(d, J 8.0, 1H), 7.51–7.72 (m, 4H), 7.39–7.46 (m, 3H), 5.07 (br
s, 1H). δC (75 MHz, CD3OD) 113.64, 115.98, 116.23, 121.87,
122.72, 124.53, 126.06, 127.23, 130.01, 137.33, 154.03, 157.34,
168.12. m/z (APCI) 245 (M + 1).
[15] D. De, L. D. Byers, D. J. Krogstad, J. Heterocycl. Chem. 1997, 34, 315.
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p. 60 (Engel Publishing Partners: Newtown, PA).
2-Methylphenylaminobenzothiazole (Entry 6, Table 3)
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Chem. 2006, 4, 2337. doi:10.1039/B602413K
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2000, 56, 8567. doi:10.1016/S0040-4020(00)00802-4
Mp 155–157◦C. Found: C 69.9, H 5.1, N 11.7, S 13.4.
Calc. for C14H12N2S: C 70.0, H 5.0, N 11.7, S 13.3%.
νmax(KBr)/cm−1 3179, 2898, 2853, 1615, 1572, 1454, 1371,
1355, 1270, 1260, 1124, 1030, 972, 883, 743, 697. δH (300 MHz,