A novel one-pot oxidative deformylation of N-formyldihydroquinolines employing ferric chloride hexahydrate. Synthesis of 4-chloro-2-phenylquinolines and 4-chloro-2-(1,3-diphenyl-1H-pyrazol-4-yl)quinolines

Article abstract of DOI:10.1002/jhet.5570450248

(Chemical Equation Presented) A novel versatile one-pot oxidative deformylation approach has been developed to synthesize 4-chloro-2- phenylquinolines and 4-chloro-2-(1,3-diphenyl-1H-pyrazol-4-yl)quinolines from the corresponding N-formyldihydroquinolines

Full text of DOI:10.1002/jhet.5570450248

Mar-Apr 2008
597
A Novel One-Pot Oxidative Deformylation of N-
Formyldihydroquinolines Employing Ferric Chloride Hexahydrate.
Synthesis of 4-Chloro-2-phenylquinolines and 4-Chloro-2-(1,3-
diphenyl-1H-pyrazol-4-yl)quinolines.
Kalvi. Hemanth Kumar and Paramasivan. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adayar, Chennai-20, India
Received April 17, 2007
Cl
Cl
FeCl3.6H2O
Methanol, reflux
4-8 h
N
X
N
X
CHO
(78-89 %)
N
X =
or
R
N
R
A novel versatile one-pot oxidative deformylation approach has been developed to synthesize 4-chloro-
2-phenylquinolines and 4-chloro-2-(1,3-diphenyl-1H-pyrazol-4-yl)quinolines from the corresponding N-
formyldihydroquinolines.
J. Heterocyclic Chem., 45, 597 (2008).
INTRODUCTION
Scheme 1
4-Chloroquinolines are very useful intermediates in the
synthesis of the highly active 4-aminoquinoline groups of
potential antimalarial drugs and 4-quinolyl isothio-
cyanates [1-3]. However a few methods have been
developed in the literature towards construction of
quinoline molecules that have involved tedious
procedures [4]. Nevertheless, it is still of continued
interest and great significance to explore novel and
efficient synthetic approaches for this class of
compounds.
Cl
N
Cl
FeCl3.6H2O
N
Methanol
reflux 4-6 h
R
R
CHO
of 2'-aminochalcones with the Vilsmeier reagent [8]. In
the present work, the initial studies were performed on the
oxidative deformylation with different oxidizing agents.
Among the oxidizing agents screened only FeCl3.6H2O
led to the effective oxidative deformylation while the rest
failed. The results are summarized in Table 1.
RESULTS AND DISCUSSION
In recent years ferric chloride hexahydrate has been
increasingly utilized in a wide variety of organic reactions
such as the oxidation of benzoin, Michael reaction and in
deprotection chemistry [5]. Generally N-deformylation of
formamides was achieved by heating in strongly acidic or
basic solutions or by the other methods reported in
literature [6]. To the best of our knowledge FeCl3.6H2O
had never been studied for the oxidative deformylation of
N-formyldihydroquinolines. As a continuation of our
studies on the synthesis of heterocyclic compounds with
potential medicinal values from 2'-aminochalcones and 2'-
hydroxychalcones [7] in this letter we wish to report a
one-pot oxidative deformylation of N-formyldihydro-
quinolines by employing a mild and cheap reagent,
FeCl3.6H2O in methanol (Scheme 1).
Table 1
The oxidative deformylation of N-formyldihydroquinolines with
different oxidizing agents.
#
Oxidizing agent
Equi-
time
Yield
(%)
1
2
3
4
5
6
7
8
9
Mn(OAc)3
2.5
2.5
2:1
1:1
2.5
1.0
1.1
1:1
2.2
2.2
10 h
-
-
-
-
CAN
10 h
10 h
10 h
4 h
Mn(OAc)3-Cu(OAc)2
Cu(OAc)2-K2S2O8
FeCl3.6H2O
NBS
88
-
10 h
10 h
10 h
10 h
10 h
I2
-
Co(NO3)2-K2S2O8
PCC
-
The various substituted N-formyldihydroquinolines
required for this reaction were prepared by the cyclization
-
10
TBADC
-

598
K. H. Kumar and P. T. Perumal
Vol 45
Table 3
To extend the scope of this reaction, a wide range of
The oxidative deformylation of pyrazolylquinoline-1(2H)-carbaldehydes
by FeCl3.6H2O
substituted and structurally diverse N-formyldihydro-
quinolines were subjected to this reaction. The reaction
proceeded in a similar fashion. Substituted quinolines
were obtained in good yields. The results are summarized
in Table 2.
Entry
1
Producta
Cl
Time (h)
6 h
Yield (%)b
Substrate
Cl
84
N
N
Ph
N
N
Ph
N
CHO
Table 2
N
The oxidative deformylation of N-formyldihydroquinolines by FeCl3.6H2O
Cl
N
Cl
Producta
Cl
Time (h)
Yield (%)b
Entry
Substrate
Cl
89
6 h
2
N
Ph
N
N
Ph
4
88
1
N
CHO
N
N
N
CHO
Cl
MeO
OMe
OMe
MeO
Cl
Cl
Cl
N
4
5
85
80
2
3
4
5
3
8 h
85
OMe
OMe
OMe
OMe
N
N
N
N
Ph
N
Ph
CHO
CHO
N
N
Cl
Cl
EtO
Cl
EtO
N
N
Cl
N
CHO
7 h
78
F
F
4
N
Cl
Cl
N
Ph
N Ph
CHO
N
N
6
82
N
N
CHO
aall products were characterized by 1H NMR and mass spectra and by
elemental analysis.bYield of isolated products.
Cl
Cl
4
84
N
N
We believe that this procedure will provide a better scope
and more practical alternative to the existing procedures for
the synthesis of 4-chloro-2-phenylquinolines and 4-chloro-
2-(1,3-diphenyl-1H-pyrazol-4-yl)quinolines from the
corresponding N-formyldihydroquinolines.
CHO
Cl
Cl
N
6
5
76
N
CHO
Cl
Cl
EXPERIMENTAL
aall products were characterized by 1H NMR and mass spectra and by
elemental analysis.b Yield of isolated products.
General procedure for the oxidative deformylation of N-
formyldihydroquinolines. N-Formyldihydroquinoline (1 mmol)
was taken in a 100 mL RB flask containing 15 mL methanol to
this FeCl3.6H2O (2.5 mmol) was added and the reaction mixture
was refluxed on an oil-bath for adequate time at 100°C until the
disappearance of the starting material in TLC. Then ice-cold
water was added to the reaction mixture and extracted with ethyl
acetate (4x20ml) and the extract was dried over anhydrous
sodium sulfate. Removal of the solvent under reduced pressure
gave the crude product, which was further purified by column
chromatography on silica gel ethyl acetate-hexane (1:9) as
eluent to afford pure product.
Pyarazole nucleosides have shown potent and selective
antiviral antitumor activity [9]. Thus to synthesize pyrazole
nucleoside having quinoline unit we have extended this
oxidative deformylation approach to synthesize 4-chloro-2-(1,3-
diphenyl-1H-pyrazol-4-yl)-quinolines under similar conditions
(Scheme 2) and the results are summarized in Table 3.
Scheme 2
Cl
N
Cl
Spectral data.
FeCl3.6H2O
4-Chloro-2-(4-methoxyphenyl)quinoline (Entry 1, Table 2).
White solid. Mp : 77-78˚C, FT-IR (KBr) νmax cm-1 : 1594, 1508,
1415, 1218. 1H NMR (500 MHz, CDCl3) δ : 3.86(s, 3 H, OCH3),
7.01(d, J = 8.55 Hz, 2 H), 7.54-7.57(m, 1 H), 7.71-7.74(m, 1 H),
N
N
Ph
N
Ph
CHO
N
N
Methanol
reflux 6-8 h
7.89(s, 1 H, H-3), 8.09(m, 3 H), 8.2(d, J = 7.45 Hz, 1 H, H-5). 13
C
R
R

Mar-Apr 2008
Deformylation of N-Formyldihydroquinolines
599
NMR (125 MHz, CDCl3) δ : 55.46, 114.37, 118.67, 124.00,
125.08, 126.89, 128.95, 129.91, 130.56, 131.17, 143.02, 149.16,
156.87, 161.24. MS m/z : 269 (M+). Anal. calcd for C16H12NOCl :
C, 71.25; H, 4.48; N, 5.19. Found : C, 71.08; H, 4.19; N, 5.06.
4-Chloro-2-(3,4-dimethoxyphenyl)quinoline (Entry 2,
Table 2). White solid. Mp : 116-117 ˚C. FT-IR (KBr) νmax cm-1 :
1593, 1515, 1400, 1216. 1H NMR (500 MHz, CDCl3) δ : 3.94(s,
3 H, OCH3), 4.03(s, 3 H, OCH3), 6.95(d, J = 8.4 Hz, 1 H), 7.55-
7.83(m, 4 H), 7.91(s, 1 H, H-3), 8.13(d, J = 8.45 Hz, 1 H, H-8),
8.17(d, J = 8.4 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3) δ :
56.09, 56.13, 110.30, 111.08, 118.73, 120.36, 124.01, 125.15,
126.98, 129.89, 130.59, 131.43, 143.02, 149.07, 149.51, 150.82,
156.80.MS m/z : 299 (M+). Anal. calcd for C17H14NO2 Cl : C,
68.12; H, 4.71; N, 4.67. Found C, 67.88; H, 4.69; N, 4.49.
4-Chloro-2-(4-fluorophenyl)quinoline (Entry 3, Table 2).
White solid. Mp : 87-89 ˚C. FT-IR (KBr) νmax cm-1 : 1592, 1522,
1420, 1229. 1H NMR (500 MHz, CDCl3) δ : 7.18-7.21(m, 2 H),
7.59-7.78(m, 2 H), 7.90(s, 1 H, H-3), 8.11-8.15(m, 3 H), 8.19(d,
J = 8.0 Hz, 1 H, H-5) 13C NMR (125 MHz, CDCl3) δ : 115.90,
116.07, 118.80, 124.05, 125.28, 127.38, 129.45, 129.52, 130.04,
134.80, 143.37, 149.07, 156.18. MS m/z : 257 (M+). Anal. calcd
for C15H9NClF : C, 69.91; H, 3.52; N, 5.44. Found : C, 69.67;
H, 3.69; N, 5.38.
4-Chloro-2-(4-methylphenyl)quinoline (Entry 4, Table 2).
White solid. Mp : 94-95 ˚C. FT-IR (KBr) νmax cm-1 : 1589, 1519,
1430, 1209. 1H NMR (500 MHz, CDCl3) δ : 2.43(s, 3 H, CH3),
7.32(d, J = 8.0 Hz, 2 H), 7.74-7.77(m, 2 H), 7.94(s, 1 H, H-3),
8.03(d, J = 8.6 Hz, 2 H), 8.15(d, J = 8.6 Hz, 1 H, H-8), 8.19(d, J
= 7.45 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3) δ : 21.51,
119.02, 119.08, 123.84, 125.30, 127.42, 127.51, 129.61, 129.84,
130.57, 135.86, 140.08, 143.10, 157.33. MS m/z : 253 (M+).
Anal. calcd for C16H12NCl : C, 75.74; H, 4.77; N, 5.44. Found :
C, 75.64; H, 4.56; N, 5.40.
4-Chloro-2-phenylquinoline (Entry 5, Table 2). White
solid. Mp : 82-83 ˚C. FT-IR (KBr) νmax cm-1 : 1582, 1521, 1428,
1200. 1H NMR (500 MHz, CDCl3) δ : 7.30-7.78(m, 5 H), 7.93(s,
1 H, H-3), 8.03(d, J = 8.6 Hz, 2 H), 8.16(d, J = 8.6 Hz, 1 H, H-
8), 8.20(d, J = 7.45 Hz, 1 H, H-5). 13C NMR (125 MHz, CDCl3)
δ : 119.02, 119.08, 123.84, 125.30, 127.42, 127.51, 129.61,
129.84, 130.57, 135.86, 140.08, 143.10, 157.33. MS m/z : 239
(M+). Anal. calcd for C15H10NCl : C, 75.31; H, 4.18; N, 5.85.
Found: C, 75.34; H, 4.26; N, 5.50.
4-Chloro-2-(4-chlorophenyl)quinoline (Entry 6, Table 2).
White solid. Mp : 102-104˚C. FT-IR (KBr) νmax cm-1 : 1590,
1525, 1421, 1219. 1H NMR (500 MHz, CDCl3) δ : 7.20-7.23(m,
2 H), 7.60-7.80(m, 2 H), 7.93(s, 1 H, H-3), 8.14-8.17(m, 3 H),
8.20(d, J = 8.0 Hz, 1 H, H-5) 13C NMR (125 MHz, CDCl3) δ :
115.93, 116.17, 117.90, 123.55, 125.48, 127.39, 129.45, 129.60,
130.14, 134.85, 143.42, 149.17, 156.18. MS m/z : 273 (M+).
Anal. calcd for C15H9NCl2 : C, 65.93; H, 3.29; N, 5.12. Found :
C, 65.67; H, 3.19; N, 5.38.
4-Chloro-2-[3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-
yl]quinoline (Entry 2, Table 3). White solid. Mp: 136-137 ˚C.
1
FT-IR (KBr) νmax cm-1: 1599, 1532, 1426, 1219. H NMR (500
MHz, CDCl3) δ : 3.85(s, 3 H, OCH3), 6.94(d, J = 8.4 Hz, 2 H),
7.30(t, J = 7.40 Hz, 1 H, H-7), 7.43(s, 1 H, H-3), 7.46-7.76(m, 6
H), 7.83(d, J = 8.05 Hz, 2 H), 8.08(d, J = 8.4 Hz, 1 H, H-8),
8.16(d, J = 8.05 Hz, 1 H, H-5). 8.55(s, 1 H, pyrazole-CH). 13C
NMR (125 MHz, CDCl3) δ : 55.40, 114.08, 119.28, 121.20,
121.24, 121.97, 124.12, 125.14, 125.25, 126.92, 127.08, 128.87,
129.52, 129.57, 130.32, 130.64, 139.79, 142.39, 149.16, 151.34,
152.67. MS m/z : 411 (M+). Anal. calcd for C25H18N3OCl : C,
72.90; H, 4.40; N, 10.20 Found: C, 72.63; H, 4.28; N, 10.15.
4-Chloro-2-[3-(4-ethoxyphenyl)-1-phenyl-1H-pyrazol-4-yl]-
quinoline (Entry 3, Table 3). White solid. Mp: 140-142 ˚C. FT-
1
IR (KBr) νmax cm-1: 1588, 1539, 1428, 1210. H NMR (500
MHz, CDCl3) δ : 1.42(t, J = 6.85 Hz, 3 H), 4.06(q, J = 6.85,
13.75 Hz, 2 H), 6.93(d, J = 8.5 Hz, 2 H), 7.30(t, J = 7.45 Hz, 1
H, H-7), 7.43(s, 1 H, H-3), 7.46-7.76(m, 6 H), 7.83(d, J = 8.0
Hz, 2 H), 8.08(d, J = 8.0 Hz, 1 H, H-8), 8.16(d, J = 8.05 Hz, 1
H, H-5). 8.55(s, 1 H, pyrazole-CH). 13C NMR (125 MHz,
CDCl3) δ : 14.92, 63.60, 114.65, 119.28, 121.21, 121.25, 121.96,
124.11, 125.07, 125.14, 126.91, 127.06, 128.86, 129.52, 129.56,
130.28, 130.63, 139.79, 142.37, 149.16, 151.40, 152.89. MS m/z
: 425 (M+). Anal. calcd for C26H20N3OCl : C, 73.32; H, 4.73; N,
9.87. Found : C, 73.20; H, 4.35; N, 9.64.
4-Chloro-2-[3-(4-methylphenyl)-1-phenyl-1H-pyrazol-4-yl]-
quinoline (Entry 4, Table 3). White solid. Mp: 112-113 ˚C. FT-
IR (KBr) νmax cm-1: 1581, 1404, 1187, 1050. 1H NMR (500 MHz,
CDCl3) δ : 2.44(s, 3 H, CH3), 7.22-7.33(m, 3 H), 7.39(s, 1 H, H-
3), 7.43-7.77(m, 6 H), 7.84(d, J = 7.45 Hz, 2 H), 8.0(d, J = 8.0 Hz,
1 H, H-8), 8.16(d, J = 8.05 Hz, 1 H, H-5), 8.56(s, 1 H, pyrazole
CH). 13C NMR (125 MHz, CDCl3) δ : 21.51, 119.32, 121.24,
121.29, 122.14, 124.11, 125.15, 126.36, 127.06, 128.87, 129.33,
129.54, 129.81, 130.61, 138.57, 139.81, 142.34, 148.56, 149.17,
151.57, 152.68. MS m/z : 395.8 (M+). Anal. calcd for C25H18N3Cl :
C, 75.85; H, 4.58; N, 10.61. Found: C, 75.58; H, 4.29; N, 10.58.
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4-Chloro-2-(1,3-diphenyl-1H-pyrazol-4-yl)quinoline
(Entry 1, Table 3). White solid. Mp : 122-123 ˚C. FT-IR (KBr)
νmax cm-1 : 1596, 1545, 1419, 1223.1H NMR (500 MHz, CDCl3)
δ : 7.31(t, J = 7.45 Hz, 1 H, H-7), 7.40(s, 1 H, H-3), 7.42-
7.86(m, 11 H), 8.08(d, J = 8.0 Hz, 1 H, H-8), 8.16(d, J = 8.0 Hz,
1 H, H-5). 8.54(s, 1 H, pyrazole-CH). 13C NMR (125 MHz,
CDCl3) δ : 118.35, 118.99, 119.35, 120.65, 122.26, 123.82,
124.13, 127.13, 128.66, 128.74, 129.07, 129.60, 130.67, 132.83,
139.76, 142.40, 143.05, 149.64, 150.34, 156.16. MS m/z : 381
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(M+). Anal. calcd for C24H16N3Cl :
11.00. Found : C, 75.19; H, 4.39; N, 10.85.
C, 75.49; H, 4.22; N,
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