Synthesis and cyclization of 8-formyl-2-(phenoxymethyl)quinoline-3- carboxylic acids

Article abstract of DOI:10.1002/cjoc.201100420

A facile synthesis of a series of new quinoline-8-carbaldehyde compounds, namely 8-formyl-2-(phenoxymethyl)quinoline-3-carboxylic acids (4a-4h) and 13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]quinoline-8-carbaldehyde (5a-5g) is described, involving the one-pot synthesis reaction of ethyl 2-(chloromethyl)-8-formylquinoline-3-carboxylate (3) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline-8-carbaldehydes 4a-4h and 5a-5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.

Full text of DOI:10.1002/cjoc.201100420

FULL PAPER
DOI: 10.1002/cjoc.201100420
Synthesis and Cyclization of 8-Formyl-2-(phenoxymethyl)-
quinoline-3-carboxylic Acids
Gao, Wentao*(高文涛)
Zhao, Zhigang(赵治刚)
Li, Yang(李阳)
Yan, Yan(闫岩)
Li, Feng(李凤)
Institute of Superfine Chemicals, Bohai University, Jinzhou, Liaoning 121000, China
A facile synthesis of a series of new quinoline-8-carbaldehyde compounds, namely 8-formyl-2-
(phenoxymethyl)quinoline-3-carboxylic acids (4a—4h) and 13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]quinoline-
8-carbaldehyde (5a—5g) is described, involving the one-pot synthesis reaction of ethyl 2-(chloromethyl)-8-
formylquinoline-3-carboxylate (3) with substituted phenols followed by the intramolecular cyclization reaction via
the treatment with polyphosphoric acid (PPA). Quinoline-8-carbaldehydes 4a—4h and 5a—5g are novel and their
structures were supported by IR, 1H NMR, 13C NMR, MS and elemental analysis.
Keywords benzoxepinoquinoline, quinoline-8-carbaldehyde, one-pot, polyphosphoric acid (PPA), cyclization re-
action
Introduction
erable attention from both medicinal and synthetic or-
ganic chemists in recent years.[18-21]
The quinoline ring system is one of the most ubiqui-
tous heterocycles in nature and an important structural
component in many pharmaceutical agents.[1-3] There-
fore synthesis and functionalization of quinolines has
been a major area of focus for synthetic organic chem-
ists.[4-6] Many functionalized quinolines scaffold in the
framework of various pharmacologically active com-
pounds have been recognized to show a spectrum of
biological activities.[7,8] Among them, quinoline alde-
hydes derivatives exhibit potent pharmacological activi-
ties such as antibacterial and antioxidant.[9] Moreover,
quinoline aldehydes are important synthetic intermedi-
ates in the synthesis of interesting quinoline heterocy-
cles bearing diverse bioactivities such as antimicrobial,
antituberculosis, antifungal activities.[10-12] For example,
2-chloro-3-formylquinolines have been extensively used
as reactive species for building chemical diversity and
for various functional group interconversions.[13-15]
On the other hand, a number of benzoxepine deriva-
tives containing a fused heterocyclic ring were known to
display an important structural unit present in many
biologically important molecules such as doxaminol
(vasodilator and b-sympathomimetic agent), isoxepac
(anti-inflammatory agent), oxepinac (antiinflammatory,
analgesic, antipyretic agent), and have been proven to
be lead compounds for psychoactive drugs for the
treatment of anxiety disorder, depression, and in par-
ticular schizophrenic Psychoses.[16,17] Therefore, such
benzoxepino-fused heterocycles have attracted consid-
In light of the above reports and in diversifying our
work on the synthesis of new quinoline compounds,[22-25]
we would like to report herein a facile and inexpensive
one-pot procedure for the preparation of 8-formyl-2-
(phenoxymethyl)quinoline-3-carboxylic acid derivatives
and subsequent intramolecular cyclization reaction to
construct benzoxepino[3,4-b]quinoline framework.
Experimental
Melting points were determined with a WRS-1B
1
melting point apparatus and are uncorrected. H NMR
and 13C NMR spectra were recorded on a Bruker
Avance NMR spectrometer using CDCl3 or DMSO-d6
as the solvent. The reported chemical shifts (δ values)
are given downfield from tetramethylsilane (TMS) as
the internal standard. The mass spectra were determined
using a MSD VL ESI1 spectrometer. Elemental analy-
ses were performed for C, H, and N using an Elementar
Vario EL-III element analyzer and were within ±0.4%
of the calculated values. The progress of reactions was
monitored by thin layer chromatography (TLC) on silica
gel GF254 using ethyl acetate as mobile phase.
Procedure for the preparation of ethyl 2-(chloro-
methyl)-8-formylquinoline-3-carboxylate (3)
A mixture of 2-aminobenzaldehyde (1 mmol, 0.121
g) and ethyl 4-chloroacetoacetate (1 mmol, 0.165 g) was
added into Vilsmeier reagent (11 mL). The reaction
*
E-mail: bhuzh@163.com; Tel.: 0086-0416-3400266; Fax: 0086-0416-3400266
Received September 28, 2011; accepted November 29, 2011; published online May 7, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc201100420 or from the author.
Chin. J. Chem. 2012, 30, 1127—1132
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Gao et al.
FULL PAPER
mixture was magnetically stirred at 90 ℃ for 1 h. After
completion of the reaction (TLC), the mixture was
cooled to room temperature, poured into ice-water and
filtered to give the crude product. The resulting crude
was recrystalized from 95% ethanol to afford ethyl
2-(chloromethyl)-8-formylquinoline-3-carboxylate (3)
128.95, 129.50, 129.83, 131.89, 139.52, 147.33, 155.39,
156.63, 167.52; IR (KBr) ν: 3435 (OH), 1706 (C＝O),
－
＋
1
1614 (C＝O) cm ; ESI-MS m/z: 321.1 (M ). Anal.
calcd for C19H15NO4: C 71.02, H 4.71, N 4.36; found C
70.92, H 4.80, N 4.32.
1
8-Formyl-2-[(3-methylphenoxy)methyl]quinoline-3-
carboxylic acid (4c)
as a brown solid in 58% yield. m.p. 113—115 ℃; H
NMR (DMSO-d6, 600 MHz) δ: 1.48 (t, J＝6.6 Hz, 3H,
CH3), 4.49 (q, J＝7.2 Hz, 2H, CH2), 5.28 (s, 2H,
Cl-CH2-Ar), 7.62 (t, J＝7.8 Hz, 1H, ArH), 7.83 (t, J＝
6.6 Hz, 1H, ArH), 7.91 (d, J＝8.4 Hz, 1H, ArH), 8.12 (d,
J＝8.4 Hz, 1H, ArH), 8.82 (s, 1H, CHO); 13C NMR
(DMSO-d6, 150 MHz) δ: 14.20, 46.58, 61.87, 123.18,
126.66, 127.87, 128.47, 129.31, 132.05, 140.89, 148.30,
155.67, 165.66; IR (KBr) ν: 3048, 2985, 1715 (C＝O),
1H NMR (DMSO-d6, 600 MHz) δ: 2.27 (s, 3H, CH3),
5.56 (s, 2H, OCH2-Ar), 6.76 (d, J＝7.8 Hz, 1H, ArH),
6.80 (dd, J＝8.4, 2.4 Hz, 1H, ArH), 6.84 (s, 1H, ArH),
7.16 (t, J＝7.8 Hz, 1H, ArH), 7.71 (t, J＝7.2 Hz, 1H,
ArH), 7.89—7.91 (m, 1H, ArH), 8.07 (d, J＝8.4 Hz, 1H,
ArH), 8.17 (d, J＝7.8 Hz, 1H, ArH), 8.90 (s, 1H, CHO),
13.42 (s, 1H, COOH); 13C NMR (DMSO-d6, 150 MHz)
δ: 21.18, 70.46, 111.67, 115.49, 121.61, 125.09, 126.45,
127.74, 128.65, 128.96, 129.24, 131.92, 138.97, 139.54,
147.32, 155.29, 158.73, 167.49; IR (KBr) ν: 3400 (OH),
－
＋
1
1617 (C＝O) cm ; EI-MS m/z (%): 277.1 (M ). Anal.
calcd for C14H12ClNO3: C 60.55, H 4.36, N 5.04; found
C 60.53, H 4.32, N 4.98.
－
1
1703 (C＝O), 1693 (C＝O) cm ; ESI-MS m/z: 321.1
(M＋). Anal. calcd for C19H15NO4: C 71.02, H 4.71, N
4.36; found C 71.19, H 4.56, N 4.40.
General procedure for the preparation of 8-formyl-
2-(phenoxymethyl)quinoline-3-carboxylic acid de-
rivatives (4a—4h)
A mixture of ethyl 2-(chloromethyl)-8-formylquino-
line-3-carboxylate (3) (1 mmol, 0.278 g), each phenol (1
mmol) and K2CO3 (2.5 mmol, 0.346 g) was stirred in
refluxing CH3CN (15 mL). The conversion was moni-
tored by TLC. After the reaction was complete, CH3CN
was evaporated to dryness. 60% Ethanolic potassium
hydroxide solution (15 mL) was added to the reaction
mixture and continued to reflux for 1 h, cooled, and
acidified with 1 mol/L HCl solution. The resulting crude
product was recrystallized from ethanol to afford the
corresponding products 4. Yields and melting points are
indicated in Table 1.
8-Formyl-2-[(2-methylphenoxy)methyl]quinoline-3-
carboxylic acid (4d)
1H NMR (DMSO-d6, 600 MHz) δ: 2.13 (s, 3H, CH3),
5.58 (s, 2H, OCH2-Ar), 6.84 (t, J＝7.2 Hz, 1H, ArH),
7.05 (d, J＝8.4 Hz, 1H, ArH), 7.13 (t, J＝6.6 Hz, 2H,
ArH ), 7.72 (t, J＝7.8 Hz, 1H, ArH), 7.89—7.92 (m, 1H,
ArH), 8.07 (d, J＝8.4 Hz, 1H, ArH), 8.17 (d, J＝8.4 Hz,
1H, ArH), 8.88 (s, 1H, CHO), 13.41 (s, 1H, COOH);
13C NMR (DMSO-d6, 150 MHz) δ: 15.99, 70.75, 111.56,
120.46, 125.40, 126.02, 126.50, 126.95, 127.76, 128.67,
128.93, 130.44, 131.87, 139.35, 147.21, 155.39, 156.72,
167.72; IR (KBr) ν: 3425 (OH), 1714 (C＝O), 1628 (C
－
＋
1
＝O) cm ; ESI-MS m/z: 321.1 (M ). Anal. calcd for
C19H15NO4: C 71.02, H 4.71, N 4.36; found C 71.21, H
4.62, N 4.34.
8-Formyl-2-(phenoxymethyl)quinoline-3-carboxylic
acid (4a)
1H NMR (DMSO-d6, 600 MHz) δ: 5.60 (s, 2H,
OCH2), 6.95 (t, J＝7.2 Hz, 1H, ArH), 7.02 (d, J＝8.4
Hz, 2H, ArH), 7.29 (t, J＝7.2 Hz, 2H, ArH), 7.71 (t, J＝
7.8 Hz, 1H, ArH), 7.89—7.91 (m, 1H, ArH), 8.06 (d,
J＝8.4 Hz, 1H, ArH), 8.17 (d, J＝7.8 Hz, 1H, ArH),
8.91 (s, 1H, CHO), 13.45 (s, 1H, COOH); 13C NMR
(DMSO-d6, 150 MHz) δ: 70.52, 114.79, 120.85, 125.03,
126.46, 127.75, 128.66, 128.98, 129.52, 131.94, 139.61,
147.35, 155.27, 158.73, 167.50; IR (KBr) ν: 3450 (OH),
8-Formyl-2-((3-methoxyphenoxy)methyl)quinoline-
3-carboxylic acid (4e)
1H NMR (DMSO-d6, 600 MHz) δ: 3.72 (s, 3H,
OCH3), 5.58 (s, 2H, OCH2-Ar), 6.52 (dd, J＝7.8, 1.8 Hz,
1H, ArH), 6.58—6.60 (m, 2H, ArH), 7.18 (t, J＝8.4 Hz,
1H, ArH), 7.71 (t, J＝7.2 Hz, 1H, ArH), 7.90 (t,
J＝7.2 Hz, 1H, ArH), 8.07 (d, J＝8.4 Hz, 1H, ArH),
8.17 (d, J＝8.4 Hz, 1H, ArH), 8.91 (s, 1H, CHO), 13.45
(s, 1H, COOH); 13C NMR (DMSO-d6, 150 MHz) δ:
70.52, 116.63, 124.16, 24.42, 126.65, 127.43, 128.55
129.04, 129.45, 132.21, 132.36, 139.67, 147.00, 154.40,
158.62, 167.74; IR (KBr) ν: 3429 (OH), 1773 (C＝O),
－
1
1703 (C＝O), 1658 (C＝O) cm ; ESI-MS m/z: 307.1
(M＋). Anal. calcd for C18H13NO4: C 70.35, H 4.26, N
4.56; found C 70.42, H 4.18, N 4.52.
8-Formyl-2-[(4-methylphenoxy)methyl]quinoline-3-
carboxylic acid (4b)
－
＋
1
1705 (C＝O) cm ; ESI-MS m/z: 337.1 (M ). Anal.
calcd for C19H15NO5: C 67.65, H 4.48, N 4.15; found C
67.72, H 4.39, N 4.21.
1H NMR (DMSO-d6, 600 MHz) δ: 2.22 (s, 3H, CH3),
5.56 (s, 2H, OCH2-Ar), 6.90 (d, J＝8.4 Hz, 2H, ArH),
7.08 (d, J＝8.4 Hz, 2H, ArH), 7.71 (t, J＝7.8 Hz, 1H,
ArH), 7.88—7.91 (m, 1H, ArH), 8.06 (d, J＝8.4 Hz, 1H,
ArH), 8.16 (d, J＝7.8 Hz, 1H, ArH), 8.90 (s, 1H, CHO),
13.44 (s, 1H, COOH); 13C NMR (DMSO-d6, 150 MHz)
δ: 20.15, 70.63, 114.67, 125.06, 126.43, 127.71, 128.66,
2-((4-Chlorophenoxy)methyl)-8-formylquinoline-3-
carboxylic acid (4f)
1H NMR (DMSO-d6, 600 MHz) δ: 5.61 (s, 2H,
OCH2-Ar), 7.04 (d, J＝8.4 Hz, 2H, ArH), 7.32 (d, J＝
9.0 Hz, 2H, ArH), 7.71 (t, J＝7.8 Hz, 1H, ArH),
1128
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Chin. J. Chem. 2012, 30, 1127—1132

Synthesis and Cyclization of 8-Formyl-2-(phenoxymethyl)quinoline-3-carboxylic Acids
7.88—7.91 (m, 1H, ArH), 8.04 (d, J＝8.4 Hz, 1H, ArH),
8.17 (d, J＝8.4 Hz, 1H, ArH), 8.93 (s, 1H, CHO), 13.47
(s, 1H, COOH); 13C NMR (DMSO-d6, 150 MHz) δ:
70.82, 116.59, 124.50, 124.74, 126.44, 127.78, 128.65,
129.00, 129.25, 132.01, 139.79, 147.35, 154.94, 157.61,
167.36; IR (KBr) ν: 3446 (OH), 1761 (C＝O), 1697
(C＝O) cm ; ESI-MS m/z: 341.1 (M ). Anal. calcd for
C18H12ClNO4: C 63.26, H 3.54, N 4.10; found C 63.37,
H 3.41, N 4.06.
13C NMR (DMSO-d6, 150 MHz) δ: 76.25, 120.94,
122.93, 125.34, 127.13, 127.88, 128.66, 129.69, 131.59,
132.29, 132.53, 136.12, 139.65, 148.35, 154.59, 160.96,
－
1
187.73; IR (KBr) ν: 1701 (C＝O), 1641 (C＝O) cm ;
ESI-MS m/z: 289.3 (M＋). Anal. calcd for C18H11NO3: C
74.73, H 3.83, N 4.84; found C 74.84, H 3.71, N 4.80.
－
＋
1
2-Methyl-13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde (5b)
1H NMR (DMSO-d6, 600 MHz) δ: 2.36 (s, 3H, CH3),
5.51 (s, 2H, OCH2-Ar), 7.11 (d, J＝8.4 Hz, 1H, ArH),
7.47 (dd, J＝8.4, 1.8 Hz, 1H, ArH), 7.74 (t, J＝7.2 Hz,
1H, ArH), 7.93—7.96 (m, 1H, ArH), 7.99 (d, J＝1.2 Hz,
1H, ArH), 8.13 (d, J＝8.4 Hz, 1H, ArH), 8.24 (d, J＝7.8,
1H, ArH), 8.94 (s, 1H, CHO); 13C NMR (DMSO-d6,
150 MHz) δ: 20.1, 76.33, 120.87, 125.03, 127.15,
127.87, 128.65, 129.68, 131.10, 131.99, 132.26, 137.00,
139.70, 148.33, 154.80, 159.11, 187.69; IR (KBr) ν:
2-((4-Bromophenoxy)methyl)-8-formylquinoline-3-
carboxylic acid (4g)
1H NMR (DMSO-d6, 600 MHz) δ: 5.60 (s, 2H,
OCH2-Ar), 6.97—6.99 (m, 2H, ArH), 7.43—7.46 (m,
2H, ArH), 7.69—7.73 (m, 1H, ArH), 7.88—7.91 (m, 1H,
ArH), 8.04 (d, J＝8.4 Hz, 1H, ArH), 8.17 (d, J＝7.8 Hz,
1H, ArH), 8.93 (s, 1H, CHO), 13.46 (s, 1H, COOH);
13C NMR (DMSO-d6, 150 MHz) δ: 70.74, 112.21,
117.13, 124.74, 126.44, 127.79, 128.65, 129.01, 132.02,
132.14, 139.79, 147.34, 154.92, 158.06, 167.35; IR
－
1
1689 (C＝O), 1629 (C＝O) cm ; ESI-MS m/z: 303.3
(M＋). Anal. calcd for C19H13NO3: C 75.24, H 4.32, N
4.62; found C 75.36, H 4.29, N 4.58.
－
1
(KBr) ν: 3428 (OH), 1780 (C＝O), 1695 (C＝O) cm ;
ESI-MS m/z: 384.9 (M＋). Anal. calcd for C18H12BrNO4:
C 55.98, H 3.13, N 3.63; found C 55.86, H 3.26, N 3.59.
3-Methyl-13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde (5c)
1H NMR (CDCl3, 600 MHz) δ: 2.39 (s, 3H, CH3),
5.48 (s, 2H, OCH2-Ar), 6.96 (s, 1H, ArH), 7.01 (d, J＝
8.4 Hz, 1H, ArH), 7.63 (t, J＝7.2 Hz ,1H, ArH ), 7.84 (t,
J＝7.8 Hz, 1H, ArH ), 7.98 (d, J＝7.8 Hz, 1H, ArH),
8.14 (d, J＝8.4 Hz, 1H, ArH), 8.22 (d, J＝8.4 Hz, 1H,
ArH), 8.83 (s, 1H, CHO); 13C NMR (CDCl3, 150 MHz)
δ: 21.51, 120.98, 123.36, 124.17, 127.59, 129.15,
129.19, 132.01, 132.07, 132.69, 139.85, 147.37, 148.96,
154.59, 161.53, 187.98; IR (KBr) ν: 1709 (C＝O), 1629
8-Formyl-2-((2-nitrophenoxy)methyl)quinoline-3-
carboxylic acid (4h)
1H NMR (DMSO-d6, 600 MHz) δ: 5.83 (s, 2H,
OCH2-Ar), 7.10—7.13 (m, 1H, ArH), 7.48 (d, J＝8.4
Hz, 1H, ArH), 7.60—7.63 (m, 1H, ArH), 7.70—7.73 (m,
1H, ArH), 7.87—7.91 (m, 2H, ArH), 7.99 (d, J＝8.4 Hz,
1H, ArH), 8.18 (d, J＝7.8 Hz, 1H, ArH), 8.98 (s, 1H,
CHO), 13.45 (s, 1H, COOH); 13C NMR (DMSO-d6, 150
MHz) δ: 71.74, 115.81, 120.78, 124.13, 124.94, 126.47,
127.86, 128.61, 129.10, 132.16, 134.34, 139.85, 140.34,
147.34, 151.71, 154.43, 166.90; IR (KBr) ν: 3438 (OH),
－
＋
1
(C＝O) cm ; ESI-MS m/z: 303.3 (M ). Anal. calcd for
C19H13NO3: C 75.24, H 4.32, N 4.62; found C 75.18, H
4.40, N 4.57.
－
1
1711 (C＝O), 1630 (C＝O) cm ; ESI-MS m/z: 351.9
(M＋). Anal. calcd for C18H12N2O6: C 61.37, H 3.43, N
7.95; found C 61.15, H 3.53, N 7.82.
4-Methyl-13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde (5d)
1H NMR (CDCl3, 600 MHz) δ: 2.33 (s, 3H, CH3),
5.52 (s, 2H, OCH2-Ar), 7.08 (t, J＝7.8 Hz, 1H, ArH),
7.42 (d, J＝7.2 Hz, 1H, ArH), 7.62 (t, J＝7.8 Hz, 1H,
ArH), 7.84 (t, J＝7.8 Hz, 1H, ArH), 7.97 (d, J＝7.8 Hz,
1H, ArH), 8.14 (dd, J＝8.4, 4.2 Hz, 2H, ArH), 8.81 (s,
1H, CHO); 13C NMR (CDCl3, 150 MHz) δ: 16.54,
122.25, 125.79, 127.58, 129.14, 129.19, 129.78, 129.93,
132.01, 132.69, 136.72, 139.69, 148.99, 154.73, 159.79,
General procedure for the preparation of 13-oxo-
6,13–dihydro[1]benzoxepino[3,4-b]quinoline-8-carb-
aldehyde derivatives (5a—5g)
Quinolinic acids 4a—4g (1 mmol) and 12 g PPA
were added to 25 mL round flask and stirred at 125 ℃
for 3 h. Then the reaction mixture was poured slowly
with stirring into an icy saturated sodium carbonate so-
lution. The crude product was obtained after filtration
and washed with water. The pure products 5a—5g were
obtained by recrystalization from 95% ethanol. Yields
and melting points are indicated in Table 2.
－
1
188.98; IR (KBr) ν: 1716 (C＝O), 1643(C＝O) cm ;
ESI-MS m/z: 303.3 (M＋). Anal. calcd for C19H13NO3: C
75.24, H 4.32, N 4.62; found C 75.28, H 4.27, N 4.55.
13-Oxo-6,13–dihydro[1]benzoxepino[3,4-b]quinoline-
8-carbaldehyde (5a)
3-Methoxy-13-oxo-6,13-dihydro[1]benzoxepino[3,4-
b]quinoline-8-carbaldehyde (5e)
1H NMR (DMSO-d6, 600 MHz) δ: 5.56 (s, 2H,
OCH2-Ar), 7.22 (d, J＝8.4 Hz, 1H, ArH), 7.28 (t, J＝
7.8 Hz, 1H, ArH), 7.65—7.68 (m, 1H, ArH ), 7.74 (t,
J＝7.2, 1H, ArH), 7.94—7.96 (m, 1H, ArH), 8.14 (d,
J＝8.4 Hz, 1H, ArH), 8.21 (dd, J＝8.4, 1.8 Hz, 1H,
ArH), 8.24 (d, J＝7.8 Hz, 1H, ArH), 8.95 (s, 1H, CHO);
1H NMR (DMSO-d6, 600 MHz) δ: 3.84 (s, 3H,
OCH3); 5.51 (s, 2H, OCH2-Ar), 6.70 (d, J＝9.0 Hz, 1H,
ArH), 6.85 (dd, J＝9.0, 2.4 Hz, 1H, ArH), 7.70—7.73
(m, 1H, ArH), 7.91—7.94 (m, 1H, ArH), 8.11 (d, J＝8.4
Hz, 1H, ArH), 8.16 (d, J＝9.0 Hz, 1H, ArH), 8.22 (d,
J＝7.8 Hz, 1H, ArH), 8.92 (s, 1H, CHO); 13C NMR
Chin. J. Chem. 2012, 30, 1127—1132
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1129

Gao et al.
FULL PAPER
(DMSO-d6, 150 MHz) δ: 56.02, 76.39, 103.80, 111.23,
118.86, 127.22, 127.83, 128.64, 129.62, 132.40, 133.49,
139.58, 148.24, 154.49, 163.06, 165.48, 185.94; IR
(KBr) ν: 1695 (C＝O), 1598 (C＝O) cm ; ESI-MS m/z:
319.3 (M＋). Anal. calcd for C19H13NO4: C 71.47, H
4.10, N 4.39; found C 71.36, H 4.23, N 4.42.
Scheme 1 Synthesis of the title compounds 4 and 5
O
－
CHO
1
DMF/POCl3
O
O
O
N
CH2Cl
NH2
Cl
O
1
CHO
2
3
2-Chloro-13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde (5f)
R
OH
COOH
1H NMR (CDCl3, 600 MHz) δ: 5.49 (s, 2H,
OCH2-Ar), 7.12 (d, J＝9.0 Hz, 1H, ArH), 7.48 (dd,
J＝8.4, 1.8 Hz, 1H, ArH), 7.65 (t, J＝7.8 Hz, 1H, ArH),
7.86 (t, J＝7.2 Hz, 1H, ArH), 7.99 (d, J＝7.8 Hz, 1H,
ArH), 8.15 (d, J＝8.4 Hz, 1H, ArH), 8.28 (d, J＝2.4 Hz,
1H, ArH), 8.83 (s, 1H, CHO); 13C NMR (CDCl3, 150
MHz) δ: 122.82, 126.59, 127.52, 127.84, 128.38, 129.23,
129.27, 131.24, 132.01, 132.37, 135.49, 140.19, 149.14,
154.07, 160.05, 187.18; IR (KBr) ν: 1675 (C＝O), 1645
PPA
135 oC
O
(1) CH3CN/K2CO3
N
(2) 60 %KOH/EtOH
(3) 1 mol/L HCl
CHO
R
R
4
O
O
N
CHO
5
－
＋
1
(C＝O) cm ; ESI-MS m/z: 323.7 (M ). Anal. calcd for
C18H10ClNO3: C 66.78, H 3.11, N 4.33; found C 66.70,
H 3.20, N 4.30.
Chloromethylquinoline 3 was first subjected to the Wil-
liamson reaction with substituted phenols. Because the
reaction product does not interfere with further hydroly-
sis reaction, purification at this stage is unnecessary.
Thus, we simply added 60% aqueous ethanolic potas-
sium hydroxide solution 15 mL to this reaction mixture
under reflux. After the reaction was complete and acidi-
fied with 1 mol/L HCl, the major product was identified
as 8-formyl-2-(phenoxymethyl) quinoline-3-carb-
oxylic acid derivatives (4a—4h) as expected. For ex-
2-Bromo-13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde (5g)
1H NMR (CDCl3, 600 MHz) δ: 5.49 (s, 2H,
OCH2-Ar), 7.06 (d, J＝8.4 Hz, 2H, ArH ), 7.61 (d, J＝
8.4 Hz, 1H, ArH), 7.65 (t, J＝7.2 Hz, 1H, ArH), 7.87 (t,
J＝7.2 Hz, 1H, ArH), 7.99 (d, J＝8.4 Hz, 1H, ArH),
8.15 (d, J＝8.4 Hz, 1H, ArH), 8.43 (s, 1H, ArH), 8.83 (s,
1H, CHO); 13C NMR (CDCl3, 150 MHz) δ: 115.59,
123.13 126.99, 127.53, 127.85, 129.24, 129.27, 132.05,
132.38, 134.32, 138.33, 140.14, 149.15, 153.99, 160.54,
1
ample, their H NMR spectra showed the presence of a
carboxylic OH signal at δ 13.41—13.47, which disap-
peared with the addition of D2O. The singlet resonance
at δ 8.88—8.93 was assigned to aldehyde proton (it did
not disappear with the addition of D2O). Moreover, the
proposed structures of 4a—4h were also confirmed by
their 13C NMR spectra, which revealed the presence of
carboxyl carbon, formyl carbon, and methylene carbon
besides the signals due to quinoline and benzene ring
carbons. Further, the structures assigned for this reac-
tion products were fully supported by their mass spectra,
which showed the molecular ion (M＋) peak matching
the expected molecular weight. Moreover, the obtained
elemental analysis values were also in agreement with
theoretical data. This novel one-pot procedure provides
quick and easy access to the incorporation of quinoline
acid with good yields and simple workup.
－
1
187.14; IR (KBr) ν: 1679 (C＝O), 1643 (C＝O) cm ;
ESI-MS m/z: 366.9 (M＋). Anal. calcd for C18H10BrNO3:
C 58.72, H 2.74, N 3.80; found C 58.86, H 2.68, N 3.76
Results and Discussion
The synthetic route developed in our laboratory for
the preparation of 8-formyl-2-(phenoxymethyl) quino-
line-3-carboxylic acid derivatives 4a—4h and subse-
quent intramolecular Friedel-Crafts cyclization reaction
to synthesize quinoline-fused 13-oxo-6,13-dihydro[1]-
benzoxepino[3,4-b]quinoline-8-carbaldehyde
tives 5a—5h is summarized in Scheme 1.
deriva-
Recently, our laboratory has reported a one-pot
two-step reaction of bromomethyl- or chloromethyl-
quinolines with substituted salicylaldehydes to give the
corresponding quinoline carboxylic acid ethers as key
precursors for heterocycle-fused quinoline compounds.
The next step involves the construction of the ben-
zoxepinoquinolines from quinoline-3-carboxylic acids
4a—4h as outlined in Scheme 1. The synthetic se-
quence employed in our laboratories for the preparation
of the 13-oxo-6,13-dihydro[1]benzoxepino[3,4-b]-
quinoline-8-carbaldehyde derivatives 5a—5h mainly
relied on the intramolecular Friedel-Crafts acylation
reaction of 4. Of the commonly available cyclization
agents screened for the intramolecular cyclization (e.g.
H2SO4, p-TsOH, TiCl4, and P2O5), the use of polyphos-
phoric acid (PPA) was found to be the most suitable for
this reaction as shown in Table 1.
[23,24]
In order to continue our interest in the develop-
ment of bioactive quinoline alkaloids, the objective of
the present work is to extend the reaction of ethyl
2-(chloromethyl)-8-formylquinoline-3-carboxylates (3)
with some substituted phenols, in which the presence of
alhedhyde functional group may provide opportunity for
further manipulation. The starting material 3 was pre-
pared according to the method of literature.[26,27]
In the reaction with concentrated H2SO4 (Entry 1),
1130
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1127—1132

Synthesis and Cyclization of 8-Formyl-2-(phenoxymethyl)quinoline-3-carboxylic Acids
Table 1 Synthesis of 5a using various cyclization agents
good yield, short reaction time, and high purity as well.
In addition, there was no further improvement in the
yield upon increasing the reaction time. As far as the
amount of PPA is concerned, the use of 12 g PPA to 1
mmol of 4a was found most suitable to provide maxi-
mum yield and there was no further improvement in the
yield with increasing the amount of PPA. Some repre-
sentative results are summarized in Table 2. The result-
ing 13-oxo-6,13-dihydro[1]benzo-xepino-[3,4-b]quino-
line-8-carbaldehyde deriveatives 5a—5g are novel and
their structures were established based on spectral data
and elemental analyses. All data were fully consistent
with the assigned molecular structure (see Experimental
Section).
As seen in Table 2, the electronic nature of the sub-
stituents on phenols has no significant effect on the one-
pot synthesis of 8-formyl-2-(phenoxymethyl) quinoline-
3-carboxylic acids (4a—4h); all the 8-formyl-quinoline-
3-carboxylic acid derivatives with electron-donating
(Entries 2—5) or electron-withdrawing groups (Entries
6—8) were obtained in good yields, showing little dis-
tinction. On the other hand, as regards the cyclized qui-
noline-fused products 13-oxo-6,13-dihydro[1]benzo-
Entry
Agent
H2SO4
p-TsOH
TiCl4
P2O5
Time/h
10
Yielda,b/%
1
2
3
4
5
26
10
17
10
Trace
20
10
PPA
3
67
a Isolated yields. b Reaction temperature at 125 ℃.
the cyclized product 5a was obtained in a rather low
yield (26%) after 10 h. Unfortunately, the yield could
not be further improved when using either p-TsOH (En-
try 2) or P2O5 (Entry 4), for which the desired product
was isolated in lower yields of 17% and 20%, respec-
tively. The reaction with TiCl4 (Entry 3) was also found
to be ineffective and only trace amounts of the product
was observed. Moreover, in the cases of Entries 1—4,
we could not further improve the yield by increasing the
amount of the cyclization agent, reaction temperature or
reaction time. Comparatively, upon using PPA as the
cyclization reagent (Entry 5), the reaction was complete
within 3 h as observed on TLC with the advantages of
Table 2 Yields and physical properties of the compounds 4a—4h and 5a—5h
Yielda/% m.p./℃
Compound 5
Entry Compound 4
Yielda/%
67
m.p./℃
O
COOH
O
1
2
3
4
5
6
71
77
80
69
74
86
166—167
165—166
164—165
173—174
182—184
232—233
188—189
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
N
N
O
N
CHO
CHO
CHO
Me
O
O
COOH
O
73
78
72
76
72
189—190
210—211
169—170
199—200
192—194
O
O
N
N
Me
CHO
CHO
COOH
O
Me
N
CHO
Me
O
O
COOH
O
N
O
O
Me
N
N
CHO
Me
CHO
CHO
COOH
O
OMe
N
CHO
OMe
Cl
O
COOH
O
N
O
CHO
N
Cl
CHO
Chin. J. Chem. 2012, 30, 1127—1132
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1131

Gao et al.
FULL PAPER
Continued
Entry Compound 4
Yielda/%
66
m.p./℃
Compound 5
Yielda/%
77
m.p./℃
Br
O
COOH
O
7
8
264—265
196—198
4g
4h
5g
5h
N
N
O
O
N
N
CHO
Br
CHO
CHO
O
COOH
O
71
174—175
0
―
NO2
CHO
O2N
a Isolated yield.
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In conclusion, the present method offered a facile
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1132
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1127—1132