Efficient and rapid Friedlander synthesis of functionalized quinolines catalyzed by neodymium(III) nitrate hexahydrate

Article abstract of DOI:10.1055/s-2006-950296

Friedlander synthesis of quinolines catalyzed by neodymium nitrate [Nd(NO₃)₃·6H₂O, 5 mol%] in ethanol at room temperature was achieved in moderate to excellent yields (62-94%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950296

PAPER
3825
Efficient and Rapid Friedlander Synthesis of Functionalized Quinolines
Catalyzed by Neodymium(III) Nitrate Hexahydrate
S
ynthesis of Quin
a
olines Cata
v
lyzed by Ne
i
odymium(III)
V
Nitrate Hexahydr
a
ate rala, Ramu Enugala, Srinivas R. Adapa*
Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: rvarala_iict@yahoo.co.in
Received 26 June 2006; revised 13 July 2006
tween 2-aminophenyl methyl ketone (1 mmol) and ethyl
acetoacetate (EAA, 1.2 mmol) in ethanol at ambient tem-
perature for ten hours (Table 1). To our surprise,
Nd(NO3)3·6H2O gave the best yield of quinoline 1
(Table 1, entry 9). The optimum product yield was ob-
tained when a 2-aminophenyl methyl ketone/ethyl aceto-
acetate ratio of 1:1.2 was used. Ethanol was the best
among the solvents tested (MeCN, THF, CH2Cl2, EtOH,
dioxane, CHCl3). The reaction also proceeded under sol-
vent-free conditions, but the yields were poor compared to
those obtained with Nd(NO3)3·6H2O for the specified
time. In the absence of catalyst, the product could not be
Abstract: Friedlander synthesis of quinolines catalyzed by neody-
mium nitrate [Nd(NO3)3·6H2O, 5 mol%] in ethanol at room temper-
ature was achieved in moderate to excellent yields (62–94%).
Key words: 2-aminophenyl ketones, neodymium(III) nitrate, quin-
olines, annulations, domino reactions
Quinolines are important scaffolds with wide applications
in medicinal chemistry,1 as antimalarial, anti-inflammato-
ry, antiasthmatic, antibacterial, antihypertensive, and ty-
rosine kinase PDGF-RTK inhibiting agents.2 In addition,
quinolines are valuable synthons, used for assembling
nano- and mesostructures with enhanced electronic and
photonic properties.3 Although other methods such as
Skraup, Doebner von Miller, and Combes procedures
have been reported4 for the preparation of quinolines, the
Friedlander annulation is one of the most simple and
straightforward methods for the synthesis of substituted
quinolines.
Table 1 Effect of Different Lewis Acid Catalysts on the Reaction
between 2-Aminophenyl Methyl Ketone and Ethyl Acetoacetate
O
Me
O
O
CO2Et
Me
Me
Lewis acid
OEt
EtOH, r.t.
+
Me
NH2
N
1
The Friedlander synthesis is an acid- or base-catalyzed
condensation between a 2-aminoaryl ketone and a second
carbonyl compound containing a reactive a-methylene
group followed by a cyclodehydration. Generally, this re-
action is carried out by refluxing an aqueous or alcoholic
solution of reactants in the presence of base at high tem-
perature.5 Under thermal- or base-catalysis conditions, 2-
aminophenyl phenyl ketone fails to react with simple ke-
tones such as cyclohexanone and b-keto esters.6 Recently,
Lewis acids such as ZnCl2, NaF, FeCl3, Sc(OTf)3, silver
phosphotungstate, ionic liquids, NaAuCl4·2H2O, and mo-
lecular iodine have been shown to be effective for the syn-
thesis of quinolines.7 However, most of the methods have
significant drawbacks such as low yields of the products,
harsh reaction conditions, difficulties in workup, and use
of stoichiometric quantities of reagents. Since quinoline
derivatives are increasingly useful and important in drugs
and pharmaceuticals, the development of a simple, effi-
cient, and environmentally benign protocol is still desir-
able.
Entry
1
Lewis acid
Pd(acac)2
Yielda,b (%)
n.r.
28
55
n.r.
58
61
n.r.
62
78
18
35
65
n.r.
10
60
2
Co(acac)3
3
VO(acac)3
Ru(acac)3
4
5
PrCl3·6H2O
SmCl3·6H2O
YbCl3·6H2O
TbCl3·6H2O
6
7
8
9
Nd(NO3)3·6H2O
LiBr
10
11
12
13
14
15
FeCl3
La(NO3)3·6H2O
TBAB/H2O
RhCl3
In continuation of our efforts to explore novel synthetic
routes to form carbon–carbon and carbon–heteroatom
bonds and heterocycles,8 we studied the efficacy of vari-
ous reagents (5 mol% as standard) in a model reaction be-
Sm(NO3)3·6H2O
a Yield determined by GC.
b n.r. = no reaction.
SYNTHESIS 2006, No. 22, pp 3825–3830
Advanced online publication: 09.10.2006
x
x
.x
x
.
2
0
0
6
DOI: 10.1055/s-2006-950296; Art ID: P07706SS
© Georg Thieme Verlag Stuttgart · New York

3826
R. Varala et al.
PAPER
Table 2 Neodymium(III) Nitrate Hexahydrate Catalyzed Condensation of Various 1,3-Diketones with 2-Aminoacetophenone
Entry
1
1,3-Diketone
Product
No
Yielda (%)
78
1
H3C
OC2H5
Me
O
O
O
O
O
OEt
Me
OEt
O
N
Me
O
2
3
4
5
2
3
4
5
82
70
75
62
CH3
H3C
Ph
Me
N
Me
O
OC2H5
Me
O
O
N
Ph
O
Me
H3C
F3C
O
O
O
O
O
N
Me
O
OC2H5
Me
OEt
N
CF3
a Yield of pure, isolated product.
isolated, even after two days. Further, 5 mol% catalyst the optimized reaction parameters (Table 2). Among the
was sufficient, and the reaction was sluggish when higher various 1,3-diketones tested, the order of reactivity to-
or lower catalyst loadings were used. To the best of our wards 2-aminophenyl methyl ketone is as follows: pen-
knowledge, there are no earlier reports on the use of tane-2,4-dione (Table 2, entry 2) > ethyl acetoacetate
Nd(NO3)3·6H2O as a Lewis acid catalyst in the prepara- (entry 1) > allyl acetoacetate (entry 4) > ethyl benzoylac-
tion of quinolines.
etate (entry 3) > ethyl 4,4,4-trifluoro-3-oxobutanoate (en-
try 5).
Intrigued by the results obtained, we studied the scope of
the reaction by investigating the condensation of various
1,3-diketones with 2-aminophenyl methyl ketone under
Table 3 Neodymium(III) Nitrate Hexahydrate Catalyzed Synthesis of Quinolines by Condensation of Various a-Methylene Ketones with
Various 2-Aminophenyl Ketones
Entry
1
Ketone
Aminea
A
Product
No
Yield (%)b
77
6
O
N
N
2
3
A
A
7
8
80
85
O
O
O
N
O
4
B
9
90
Ph
O
O
O
N
Synthesis 2006, No. 22, 3825–3830 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinolines Catalyzed by Neodymium(III) Nitrate Hexahydrate
3827
Table 3 Neodymium(III) Nitrate Hexahydrate Catalyzed Synthesis of Quinolines by Condensation of Various a-Methylene Ketones with
Various 2-Aminophenyl Ketones (continued)
5
6
7
O
O
B
B
B
10
11
12
92
88
84
Ph
O
OEt
OEt
N
O
Ph
N
O
Ph
O
O
N
8
9
C
C
13
14
85
90
Ph
O
O
O
O
O
O
Cl
OEt
OEt
N
Ph
Cl
Cl
N
10
11
C
D
15
16
78
82
Ph
n = 0
n = 1
O
n
N
N
n
12
87
O
O
O
OEt
Cl
Cl
Cl
OEt
13
D
17
94
O
O
O
Cl
N
a Amines:
CH3
Ph
Ph
Cl
Cl
O
O
Cl
O
O
NH2
NH2
NH2
NH2
A
C
B
D
b Yield of isolated, pure product after column chromatography.
We then examined various structurally divergent 2-ami- (Table 3). The protocol presented here is equally effective
noaryl ketones, e.g. 2-aminophenyl phenyl ketone (B), 2- for both cyclic and acyclic ketones. In all cases, reactions
aminophenyl methyl ketone (A), 2-amino-5-chlorophenyl were clean, and selfcondensation products, normally ob-
phenyl ketone (C), and 2-amino-5-chlorophenyl 2-chlo- served under basic conditions, were absent. Furthermore,
rophenyl ketone (D) (Table 3) in the condensation with drastic conditions such as high temperatures are not re-
various a-methylene ketones, e.g. cyclopentanone, cyclo- quired.
hexanone,
and
5,5-dimethylcyclohexane-1,3-dione
Synthesis 2006, No. 22, 3825–3830 © Thieme Stuttgart · New York

3828
R. Varala et al.
PAPER
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.21; H, 5.92; N, 4.76.
In conclusion, we have demonstrated a mild and efficient
synthesis of quinolines, for which Nd(NO3)3·6H2O was
used as a novel Lewis acid catalyst. Notable advantages of
our protocol includes (a) operational simplicity, (b) good
substrate scope, (c) the relatively nontoxic reagents and
solvents, and (d) high yields of products.
Allyl 2,4-Dimethylquinoline-3-carboxylate (4)
Viscous oil.
IR (KBr): 3032, 2988, 2961, 1624, 1577, 1498, 1267, 1221, 759
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.57 (s, 3 H), 2.63 (s, 3 H), 4.81
(q, J = 7.03 Hz, 2 H), 5.41 (d, J = 1.56 Hz, 2 H), 6.49 (m, 1 H),
7.56–7.95 (m, 4 H).
Melting points were measured on a Buchi R-535 apparatus. IR spec-
tra were determined on a Bruker Vector-22 spectrometer of samples
prepared as KBr pellets. 1H NMR spectra (300 MHz) were recorded
on a Bruker Avance-300 spectrometer of samples in CDCl3, with
chemical shifts (d) given in ppm relative to TMS as an internal stan-
dard. 13C NMR spectra (75.5 MHz) were recorded on a Bruker
Avance-300 spectrometer with complete proton decoupling; chem-
ical shifts are reported in ppm relative to the solvent resonance as
the internal standard (CDCl3, d = 77.16). Mass spectra were record-
ed on a VG 7070H Micromass spectrometer. CHN analyses were
recorded on a Vario EL analyzer.
MS (EI, 70 eV): m/z = 241 [M+].
Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C,
74.66; H, 6.38; N, 5.82.
Ethyl 4-Methyl-2-(trifluoromethyl)quinoline-3-carboxylate (5)
Viscous oil.
IR (KBr): 2990, 2977, 1688, 1555, 1494, 1454, 1371, 1292, 1221,
754 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.32 (t, J = 7.03 Hz, 3 H), 2.55 (s,
3 H), 4.28 (q, J = 7.03 Hz, 2 H), 7.21–8.31 (m, 4 H).
MS (EI, 70 eV): m/z = 283 [M+].
Quinolines 1–17; General Procedure
A mixture of the appropriate 2-aminophenyl ketone (1 mmol), a-
methylene ketone (1.2 mmol), and Nd(NO3)3·6H2O (5 mol%) in
EtOH (3 mL) was stirred at r.t. After completion of the reaction as
indicated by TLC, the reaction mixture was quenched with H2O and
extracted with EtOAc (2 × 10 mL). Evaporation of the solvent fol-
lowed by purification by column chromatography (silica gel,
EtOAc–hexane, 1:9) afforded the corresponding pure quinoline de-
rivative.
Anal. Calcd for C14H12F3NO2: C, 59.37; H, 4.27; N, 4.95. Found: C,
59.18; H, 4.44; N, 5.01.
9-Methyl-2,3-dihydro-1H-cyclopenta[b]quinoline (6)
Solid; mp 58–60 °C.
IR (KBr): 3065, 2957, 1613, 908, 751 cm–1.
Ethyl 2,4-Dimethylquinoline-3-carboxylate (1)
Oil.
1H NMR (300 MHz, CDCl3): d = 2.2 (m, 2 H), 2.49 (s, 3 H), 2.99 (t,
J = 7.5 Hz, 2 H), 3.3 (t, J = 6.9 Hz, 2 H), 7.46–8.01 (m, 4 H).
IR (KBr): 3070, 2930, 2873, 1725, 1614, 1589, 1214, 1082, 578
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (t, J = 7.17 Hz, 3 H), 2.63 (s,
3 H), 2.68 (s, 3 H), 4.45 (q, J = 7.17 Hz, 2 H), 7.46 (t, J = 7.6 Hz, 1
H), 7.66 (t, J = 7.6 Hz, 1 H), 7.91 (t, J = 8.3 Hz, 1 H), 7.99 (d,
J = 8.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 168.9, 154.2, 147.2, 141.1, 129.7
(2 C), 127.8, 126.1, 125.7, 123.6, 61.2, 23.6, 15.5, 14.1.
MS (EI, 70 eV): m/z = 229 [M+], 186, 158, 125, 77.
13C NMR (75 MHz, CDCl3): d = 166.7, 147.2, 137.8, 133.7, 128.9,
127.8, 126.9, 125.0, 123.1, 34.8, 29.4, 22.7, 14.6.
MS (EI, 70 eV): m/z = 183 [M+], 168, 154, 140, 127, 115, 102, 90,
77, 63, 57.
Anal. Calcd for C13H13N: C, 85.21; H, 7.15; N, 7.64. Found: C,
85.17; H, 7.07; N, 7.72.
9-Methyl-1,2,3,4-tetrahydroacridine (7)
Solid; mp 75–77 °C.
IR (KBr): 3068, 2935, 1614, 1581, 1350, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.73 (m, 4 H), 2.25 (s, 3 H), 2.61
(t, J = 7.6 Hz, 2 H), 2.94 (t, J = 7.6 Hz, 2 H), 7.24–7.83 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 157.9, 145.4, 140.7, 128.4, 127.6,
126.4 (2 C), 124.7, 122.8, 33.9, 26.5, 22.7, 22.3, 12.9.
Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C,
73.12; H, 6.67; N, 6.05.
1-(2,4-Dimethylquinolin-3-yl)ethanone (2)
Oil.
IR (KBr): 3068, 2959, 1703, 1614, 1585, 1208, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.57 (s, 3 H), 2.58 (s, 3 H), 2.62
(s, 3 H), 7.53–8.02 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 206.3, 152.4, 146.7, 138.4, 135.6
(2 C), 129.6, 129.0, 126.2, 123.5, 32.4, 23.3, 15.0.
MS (EI, 70 eV): m/z = 198 [M+], 125.
Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C,
85.19; H, 7.71; N, 7.02.
3,3,9-Trimethyl-3,4-dihydroacridin-1(2H)-one (8)
Solid; mp 105–107 °C.
MS (EI, 70 eV): m/z = 199 [M+], 158, 125.
IR (KBr): 2955, 2968, 1682, 1560,1494, 1373, 1280, 1215, 762
cm–1.
Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C,
78.32; H, 6.51; N, 7.07.
1H NMR (300 MHz, CDCl3): d = 1.14 (s, 6 H), 2.67 (s, 2 H), 3.08
(s, 3 H), 3.19 (s, 2 H), 7.57 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.77
(ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 8.22 (d,
J = 8.4 Hz, 1 H).
Ethyl 4-Methyl-2-phenylquinoline-3-carboxylate (3)
Viscous oil.
IR (KBr): 3046, 2971, 1704, 1612, 1588, 1479, 902 cm–1.
13C NMR (75 MHz, CDCl3): d = 200.32, 160.94, 149.56, 148.12,
131.33, 129.09, 127.55, 126.28, 125.41, 124.05, 54.74, 48.43,
31.97, 28.20 (2 C), 15.81.
1H NMR (300 MHz, CDCl3): d = 1.26 (q, J = 7.03 Hz, 3 H), 2.76 (s,
3 H), 4.15 (q, J = 7.03 Hz, 2 H), 7.41–8.16 (m, 9 H).
MS (EI, 70 eV): m/z = 291 [M+].
MS (EI, 70 eV): m/z = 239 [M+].
Synthesis 2006, No. 22, 3825–3830 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinolines Catalyzed by Neodymium(III) Nitrate Hexahydrate
3829
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C,
80.21; H, 7.21; N, 5.78.
13C NMR (75 MHz, CDCl3): d = 168.0, 154.0, 146.1, 145.3, 135.0,
132.3, 131.0, 130.5, 129.2, 128.7, 128.4, 127.6, 125.9, 125.1, 61.4,
23.6, 13.5.
1-(2-Methyl-4-phenylquinolin-3-yl)ethanone (9)
Solid; mp 114–116 °C.
IR (KBr): 3027, 2960, 1705, 1610, 1569, 1485, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.95 (s, 3 H), 2.60 (s, 3 H), 7.25–
7.31 (m, 2 H), 7.35 (t, J = 8.01 Hz, 1 H), 7.40–7.51 (m, 3 H), 7.55
(d, J = 8.1 Hz, 1 H), 7.65 (t, J = 8.1 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1
H).
MS (EI, 70 eV): m/z = 325 [M+], 296, 280, 252, 217, 189, 176, 149,
123, 109, 88, 71, 57.
Anal. Calcd for C19H16ClNO2: C, 70.05; H, 4.95; N, 4.29. Found: C,
70.09; H, 4.90; N, 4.36.
1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone (14)
Solid; mp 149–150 °C.
13C NMR (75 MHz, CDCl3): d = 205.6, 153.0 (2 C), 147.0, 144.3,
134.7 (2 C), 129.5 (2 C), 128.4, 128.1, 126.0, 125.6, 124.5, 31.4,
23.3.
IR (KBr): 3029, 2960, 1701, 1606, 1567, 1481, 909, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.66 (s, 3 H), 7.32–
7.98 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 204.9, 153.8 (2 C), 145.8, 142.9,
135.4, 134.5, 132.3, 130.8, 129.8, 129.1, 128.8, 125.8, 124.7, 31.6,
23.6.
MS (EI, 70 eV): m/z = 261 [M+], 246, 218, 176, 150, 43.
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C,
82.64; H, 5.84; N, 5.32.
MS (EI, 70 eV): m/z = 295 [M+], 280, 252, 217, 189, 176, 149, 109,
94, 75.
Ethyl 2-Methyl-4-phenylquinoline-3-carboxylate (10)
Solid; mp 98–99 °C.
IR (KBr): 3030, 2960, 1700, 1605, 1568, 1482, 905 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.03 Hz, 3 H), 2.80 (s,
3 H), 4.05 (q, J = 7.03 Hz, 2 H), 7.35–7.51 (m, 6 H), 7.55 (d, J = 8.1
Hz, 1 H), 7.70 (t, J = 7.9 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H).
Anal. Calcd for C18H14ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C,
73.01; H, 4.82; N, 4.66.
7-Chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline (15,
n = 1)
Solid; mp 104–106 °C.
IR (KBr): 3060, 2958, 1606, 1487, 828, 715 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.12 (m, 2 H), 2.87 (t, J = 7.2 Hz,
2 H), 3.19 (t, J = 7.01 Hz, 2 H), 7.32–7.98 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 153.6, 147.8, 145.7, 135.7
(2 C), 129.5, 129.1, 128.2, 127.8, 126.4, 126.1, 125.1, 96.1, 68.8,
23.3, 13.6.
MS (EI, 70 eV): m/z = 291 [M+], 263, 246, 218, 176, 150.
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.42; H, 5.91; N, 4.88.
13C NMR (75 MHz, CDCl3): d = 167.7, 146.3, 141.8, 135.9, 134.3,
131.2, 130.3, 129.0, 128.6, 128.2, 126.9, 124.4, 35.0, 30.2, 23.3.
MS (EI, 70 eV): m/z = 279 [M+], 244, 202, 167, 121, 114, 94, 87,
75, 63.
9-Phenyl-1,2,3,4-tetrahydroacridine (11)
Solid; mp 140–142 °C.
IR (KBr): 3057, 2945, 1609, 1575, 1480, 1210, 708 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.75–1.85 (m, 2 H), 1.95–2.05 (m,
2 H), 2.60 (t, J = 6.71 Hz, 2 H), 3.21 (t, J = 6.9 Hz, 2 H), 7.19–7.32
(m, 3 H), 7.41–7.62 (m, 5 H), 8.01 (d, J = 8.2 Hz, 1 H).
Anal. Calcd for C18H14ClN: C, 77.28; H, 5.04; N, 5.01. Found: C,
77.19; H, 4.94; N, 4.86.
7-Chloro-9-phenyl-1,2,3,4-tetrahydroacridine (15, n = 2)
Solid; mp 163 °C.
13C NMR (75 MHz, CDCl3): d = 158.4, 146.5, 146.1, 137.3, 129.2,
128.7, 128.5, 128.2, 127.9, 127.5, 126.6, 125.6, 125.2, 34.1, 27.8,
23.1, 22.7.
IR (KBr): 3060, 2944, 1604, 1572, 1481, 1215, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 (m, 2 H), 1.59 (m, 2 H), 2.56
(t, J = 6.5 Hz, 2 H), 3.30 (t, J = 7.01 Hz, 2 H), 7.22–8.02 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 145.8, 144.8, 136.5, 131.3,
130.2, 129.5, 129.3, 129.1, 128.9, 128.2, 127.5, 124.6, 34.3, 28.2,
23.1.
MS (EI, 70 eV): m/z = 259 [M+], 230, 182, 176, 57.
Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C,
88.02; H, 6.59; N, 5.56.
MS (EI, 70 eV): m/z = 293 [M+], 278, 258, 242, 230, 201, 189, 176,
150, 89, 77.
3,3-Dimethyl-9-phenyl-3,4-dihydroacridin-1(2H)-one (12)
Solid; mp 65–66 °C.
IR (KBr): 3060, 2958, 1710, 1601, 1575, 1208, 735 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (s, 6 H), 2.55 (s, 2 H), 3.30
(s, 2 H), 7.11–7.20 (m, 2 H), 7.35–7.49 (m, 5 H), 7.75 (t, J = 7.9 Hz,
1 H), 8.05 (d, J = 8.1 Hz, 1 H).
Anal. Calcd for C19H16ClN: C, 77.68; H, 5.49; N, 4.77. Found: C,
77.59; H, 5.34; N, 4.68.
Ethyl 6-Chloro-4-(2-chlorophenyl)-2-methylquinoline-3-car-
boxylate (16)
Solid; mp 115–117 °C.
IR (KBr): 3061, 2979, 1725, 1602, 905, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95–0.98 (m, 3 H), 2.81 (s, 3 H),
4.06–4.08 (m, 2 H), 7.27–7.55 (m, 6 H), 8.02 (d, J = 9.3 Hz, 1 H).
MS (EI, 70 eV): m/z = 301 [M+], 272, 246, 218, 190.
Anal. Calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C,
83.72; H, 6.29; N, 4.71.
Ethyl 6-Chloro-2-methyl-4-phenylquinoline-3-carboxylate (13)
Solid; mp 108 °C.
MS (EI, 70 eV): m/z = 360.
Anal. Calcd for C19H15Cl2NO2: C, 70.05; H, 4.95; N, 4.29. Found:
C, 70.09; H, 4.90; N, 4.36.
IR (KBr): 3064, 2983, 1725, 1605, 1224, 907, 732 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.01 Hz, 3 H), 2.73 (s,
3 H), 4.05 (q, J = 7.01 Hz, 2 H), 7.32–8.01 (m, 8 H).
Synthesis 2006, No. 22, 3825–3830 © Thieme Stuttgart · New York

3830
R. Varala et al.
PAPER
(4) (a) Jones, G. In Comprehensive Heterocyclic Chemistry,
1-[6-Chloro-4-(2-chlorophenyl)-2-methylquinolin-3-yl]ethan-
one (17)
Solid; mp 138–140 °C.
IR (KBr): 3025, 2978, 1701, 1604, 1570, 1484, 911, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 3 H), 2.71 (s, 3 H), 7.23–
7.28 (m, 2 H), 7.40–7.67 (m, 4 H), 8.01 (d, J = 9.2 Hz, 1 H).
Vol. 5; Katritzky, A. R.; Ress, C. W., Eds.; Pergamon: New
York, 1996, 167. (b) Cho, C. S.; Oh, B. H.; Kim, T. J.; Shim,
S. C. Chem. Commun. 2000, 1885. (c) Jiang, B.; Si, Y. C. J.
Org. Chem. 2002, 67, 9449. (d) Skraup, H. Ber. Dtsch.
Chem. Ges. 1880, 13, 2086. (e) Friedlander, P. Ber. Dtsch.
Chem. Ges. 1882, 15, 2572. (f) Mansake, R. H.; Kulka, M.
Org. React. 1953, 7, 59. (g) Linderman, R. J.; Kirollos, S. K.
Tetrahedron Lett. 1990, 31, 2689. (h) Theclitou, M. E.;
Robinson, L. A. Tetrahedron Lett. 2002, 43, 3907.
(5) (a) Cheng, C. C.; Yan, S. J. Org. React. 1982, 28, 37.
(b) Thummel, R. P. Synlett 1992, 1. (c) Eckert, H. Angew.
Chem., Int. Ed. Engl. 1981, 20, 208. (d) Gladiali, S.;
Chelucci, G.; Mudadu, M. S.; Gastaut, M. A.; Thummel, R.
P. J. Org. Chem. 2001, 66, 400.
(6) Fehnel, E. A. J. Heterocycl. Chem. 1966, 31, 2899.
(7) (a) Strekowski, L.; Czamy, A. J. Fluorine Chem. 2000, 104,
281. (b) Hu, Y.; Zang, Z. G.; Thummel, R. P. Org. Lett.
2003, 5, 2251. (c) Arcadi, A.; Chiarini, M.; Di Giuseppe, S.;
Marinelli, F. Synlett 2003, 203. (d) McNaughton, B. R.;
Miller, B. L. Org. Lett. 2003, 5, 4257. (e) Yadav, J. S.;
Reddy, B. V. S.; Premlatha, K. Synlett 2004, 963.
MS (EI, 70 eV): m/z = 212.
Anal. Calcd for C18H13Cl2NO: C, 65.47; H, 3.97; N, 4.24. Found: C,
65.36; H, 4.04; N, 4.31.
Acknowledgment
R.V. thanks DIICT, Dr. J. S. Yadav, and the Council of Scientific
Industrial Research (CSIR, India) for financial support.
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