Synthesis of substituted coumarins and 2-quinolinones by cycloisomerisation of (hydroxy/aminophenyl)propargyl alcohols

Article abstract of DOI:10.1002/ejoc.201200782

A new cycloisomerization strategy for the synthesis of coumarins and quinolinones is described. The addition of ethoxyacetylide to 2-hydroxyacetophenones directly resulted in 4-substituted coumarins by 6-endo-dig cycloisomerisation of the intermediate 3-ethoxy-1-(2-hydroxyphenyl)- 2-propyn-1-ols. Under similar conditions, 2-aminoacetophenone produced 2-ethoxyquinoline, a masked quinolinone, which was converted into the quinolinone by acid treatment. N-Protected intermediate 8 was isolated and converted into the quinolinone [with In(OTf)₃ or H₂SO ₄] or the 3-iodo-2-quinolinone (with I₂ and H ⁺).

Full text of DOI:10.1002/ejoc.201200782

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FULL PAPER
DOI: 10.1002/ejoc.201200782
Synthesis of Substituted Coumarins and 2-Quinolinones by Cycloisomerisation
of (Hydroxy/aminophenyl)propargyl Alcohols[‡]
Maddi Sridhar Reddy,*[a] Nuligonda Thirupathi,[a] and Madala Hari Babu[a]
Keywords: Cycloisomerization / Cyclization / Alkynes / Oxygen heterocycles / Nitrogen heterocycles
A new cycloisomerization strategy for the synthesis of cou- duced 2-ethoxyquinoline, a masked quinolinone, which was
marins and quinolinones is described. The addition of eth-
oxyacetylide to 2-hydroxyacetophenones directly resulted in
4-substituted coumarins by 6-endo-dig cycloisomerisation of
the intermediate 3-ethoxy-1-(2-hydroxyphenyl)-2-propyn-1-
ols. Under similar conditions, 2-aminoacetophenone pro-
converted into the quinolinone by acid treatment. N-Pro-
tected intermediate 8 was isolated and converted into the
quinolinone [with In(OTf)3 or H2SO4] or the 3-iodo-2-
quinolinone (with I2 and H+).
development of practical and efficient methods for syn-
thesising these moieties has been an area of intensive re-
search.[3]
Introduction
One of the emerging approaches to the synthesis of di-
verse heterocyclic compounds is the cycloisomerisation of
alkynes tethered to various nucleophilic functional
groups.[1,2] An alkyne activated by an alkynophilic catalyst
or reagent (Au-, Pd-, Hg-, Cu-, Ag-, Fe-, Bi-, Co-, or Ir-
based metal complexes, Brønsted acids, or electrophilic
halogen sources) is susceptible to reaction with various
combinations of nucleophiles and electrophiles, intra- or
intermolecularly. Coupled with this, metal-specific ring-size
selectivities (4-, 5-, 6-, 7-exo or -endo), tandem eliminations,
isomerisations, or multiple cyclisations, can lead to various
known or new heterocycles with a vast array of substitution
patterns. In this area, we have previously reported the syn-
thesis of butyrolactones, quinolines, spiroketals, and furans
by cycloisomerisation of alkynols and alkynamines.[2] In a
continuation of our interest in this field, in this paper, we
report the synthesis of substituted coumarins, 2-ethoxy-
quinolines, and 2-quinolinones from 2-hydroxyphenyl or 2-
aminophenyl carbonyl compounds by an exclusive 6-endo-
dig cycloisomerisation of the intermediate alkynols or
alkynamines, respectively, without using transition metal
catalysts.
Results and Discussion
Based on our previous observations, we developed a
new concept for the synthesis of coumarins and quinol-
inones, as shown in Scheme 1 [Equation (3), based on
Equations (1)[2c,4] and (2)[2a]].
Coumarin, quinoline and quinolinone scaffolds occur in
a range of biologically active compounds, including natural
products and designed medicinal agents. Consequently, the
[‡] CDRI Communication No. 8285
[a] Medicinal & Process Chemistry Division, CSIR – Central Drug
Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405, -2623938
E-mail: msreddy@cdri.res.in
sridharreddymaddi@yahoo.com
Homepage: http://www.cdriindia.org/MaddiReddy.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200782.
Scheme 1. Development of the concept for the synthesis of unsatu-
rated lactones and lactams.
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Accordingly, we planned the synthesis of A, which has 89%), as shown in Table 1. The electron-donating (in 1h–i)
the required leaving groups at C1 and C3, starting from 1a or -withdrawing (in 1d–g) nature of the substituents on the
(Table 1). However, treatment of 1a with ethoxyacetylide, phenyl ring did not have a great impact on the reactivity of
followed by quenching with aqueous ammonium chloride, the substrates, which results in a wide substrate scope.
resulted, surprisingly and pleasingly, in the formation of fi-
Based on the above observation, we anticipated that a
nal target product 2a in 70% yield (Table 1). The slight similar reaction starting from 2-aminoacetophenones may
acidity of the ammonium chloride induced the cycloiso- produce quinolinones. Thus, 2-aminoacetophenone 3a was
merisation of intermediate A to produce coumarin 2a via treated with ethoxyacetylide, but this gave 2-ethoxyquin-
probable intermediates B and C. We then set out to investi- oline 4a rather than 2-quinolinone 5a. The reaction took
gate the generality of the method. Various 2-hydroxyaceto- place by dehydration, assisted by the presence of the second
phenones (i.e., 1a–i) were tested, and the corresponding proton on the amino group, rather than hydrolysis of inter-
coumarins (i.e., 2a–i) were formed in consistent yields (68– mediate E, as shown in Table 2. Thus, we identified a new
and direct access to 2-ethoxyquinolines from 2-aminoace-
tophenones. These 2-ethoxyquinolines can be considered to
Table 1. Synthesis of coumarins 2 by cycloisomerisation of A.
be masked 2-quinolinones. Thus, we could easily convert 4a
to 5a by treatment with KI in AcOH.[5] To evaluate the
practicality of this approach to synthesise 2-quinolinones,
we screened various 2-aminoacetophenones (i.e., 3a–h).
Substrates with varied electron densities and extended con-
jugations showed almost no difference in reactivity, and
gave the corresponding 2-ethoxyquinolines (i.e., 4a–h) and
2-quinolinones (i.e., 5a–h) in good to moderate yields (i.e.,
59–75% and 71–90%, respectively).
We then became curious to know the reactivity of N-
protected aminoacetophenones, as they may, in principle,
lead to quinolinones rather than quinolines, due to the ab-
sence of a second proton for dehydrative aromatisation as
in the case of E in Table 2. Accordingly, we treated (tosyl-
amino)acetophenone 6 and (acetylamino)acetophenone 7
with ethoxyacetylide (Scheme 2). This yielded intermediate
propargyl alcohols 8 and 9, which did not cyclise in situ,
probably due to the reduced nucleophilicity of the amino
group. Our initial attempts to cycloisomerise intermediate
[a] All reactions were conducted with 2 mmol of substrate, 5 mmol
of ethoxyacetylene and 5 mmol of nBuLi (0.25 m in THF). [b] Iso-
lated yields.
Scheme 2. Cycloisomerisation of 8 and 9 to quinolinone 5a.
2
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Synthesis of Substituted Coumarins and 2-Quinolinones
Table 2. Synthesis of 2-quinolinones 5 by cycloisomerisation of D.
[a] All reactions were conducted with 2 mmol of substrate, 6 mmol of ethoxyacetylene and 6 mmol of nBuLi (0.25 m in THF). [b] Isolated
yields.
8
with various catalysts, such as AuCl3, Hg(OTf)2, merisation of 9 to give product 5a in 60% yield. We thus
In(OTf)3, or TfOH, either resulted in no reaction or pro- showed that even protected aminoacetophenones can be
duced α,β-unsaturated ester 10 by a Meyer–Schuster re- converted into 2-quinolinones in two steps.
arrangement.[6] This transformation has been reported by
Finally, we envisaged that intermediate 8 could be used
Dudley et al. using AuCl3, but under those conditions, con- to synthesise 3-iodo-2-quinolinones by using I2 as the
jugated carbonyl groups failed to give the products as single cyclising agent. An iodo group can be used as a versatile
isomers. We found here that In(OTf)3 also promotes this handle for the introduction of a vast array of substituents
transformation, with a marked selectivity for the trans iso- by various coupling reactions (as shown in Scheme 3).[7]
mer. Finally, we observed that the treatment of 8 with aque- Thus, as shown in Scheme 3, exposure of 8 to I2 in
[2b]
ous H2SO4 resulted in the deprotection of the tosyl group CH2Cl2
produced 2-ethoxy-3-iodoquinoline 11, which
followed by cycloisomerisation, or vice versa, to give prod- on treatment with KI in AcOH, cleanly gave 3-iodo-2-quin-
uct 5a cleanly. Also, In(OTf)3 could catalyse the cycloiso- olinone 12 in 52% yield over two steps.
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M. Sridhar Reddy, N. Thirupathi, M. H. Babu
FULL PAPER
centrated under vacuum. The residue was purified by column
chromatography (neutral alumina; 2–4% MeOH/CH2Cl2) to give
5.
Synthesis of 5a from 8:[10] Tosylated derivative 8 (357 mg, 1 mmol)
and concd. sulfuric acid (5 mL) were heated at 100 °C for 4 h. The
solution was then added dropwise to ice/water, and any precipitate
formed was removed by filtration. The resulting solution was
treated with saturated aqueous Na2CO3, and extracted with ethyl
acetate (2ϫ 10 mL). The combined organic extracts were washed
with brine, dried with Na2SO4, and concentrated under vacuum.
The residue was purified by column chromatography (neutral alu-
mina; 2–4% MeOH/CH2Cl2) to give 5a (128 mg, 80%).
Synthesis of 5a from 9: In(OTf)3 (28 mg, 0.05 equiv.) and H2O
(90 mg, 5 mmol) were added to a solution of 8 (357 mg, 1 mmol)
in CH3CN (6 mL). The mixture was stirred at 80 °C for 16 h. After
TLC indicated completion of the reaction, the reaction mixture was
cooled to room temperature, quenched with NaHCO3, and ex-
tracted with EtOAc (2ϫ 10 mL). The combined organic extracts
were dried with Na2SO4, filtered, and concentrated under vacuum.
The residue was purified by column chromatography (silica gel, 2–
4% MeOH in CH2Cl2) to give 5a (95.4 mg, 60%).
Scheme 3. Synthesis of 3-iodo-2-quinolinone 12.
Conclusions
We have demonstrated a concise and straightforward
route for the synthesis of coumarins, 2-ethoxyquinolines,
and 2-quinolinones starting from commercially available
simple 2-hydroxyacetophenones and 2-aminoacetophen-
ones by a 6-endo selective cycloisomerisation of intermedi-
ate propargyl alcohols. Unlike typical cycloisomerisation re-
actions of alkynols and alkynamines, no transition metal
catalysts were required, making this an environmentally
highly benign and mild method.
2H-Chromen-2-one (2a):[11] 203 mg, 70% yield. Pale brown solid.
M.p. 81–83 °C. Rf
=
0.4 (EtOAc/hexanes, 4:6). 1H NMR
(300 MHz, CDCl3): δ = 7.7 (d, J = 9.4 Hz, 1 H), 7.56 (d, J =
2.9 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.3 (d, J = 2.9 Hz, 1 H),
7.27 (t, J = 2.9 Hz, 1 H), 6.43 (d, J = 9.6 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 160.7, 154.0, 143.5, 131.8, 127.9, 124.4,
118.8, 116.8, 116.6 ppm. IR (KBr): ν = 2924, 1709, 1449, 1105,
˜
759 cm–1. ESI-MS: m/z = 147.2 [M + H]+. HRMS (ESI): calcd. for
C9H6O2 [M + H]+ 147.0446; found 147.0456.
Experimental Section
4-Methyl-2H-Chromen-2-one (2b):[12] 236 mg, 74% yield. Pale
brown solid. M.p. 73–75 °C. Rf = 0.5 (EtOAc/hexanes, 3:7). 1H
NMR (300 MHz, CDCl3): δ = 7.6 (d, J = 7.6 Hz, 1 H), 7.35 (t, J
= 7.6 Hz, 1 H), 7.3 (t, J = 7.6 Hz, 1 H), 7.2 (d, J = 7.6 Hz, 1 H),
6.3 (s, 1 H), 2.4 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 160.1, 153.6, 153.4, 132.4, 125.8, 124.8, 120.0, 116.9, 114.8,
General Methods: Melting points were determined in capillary
tubes with a Precision melting point apparatus containing silicon
oil. IR spectra were recorded with a Perkin–Elmer RX I FTIR
spectrophotometer. 1H and 13C NMR spectra were recorded either
with a Bruker DPX-200 or a Bruker Avance DRX-300 FT spec-
trometer with TMS as an internal standard. ESI-MS data were
recorded with a MICROMASS Quadro-II LCMS system. HRMS
data were recorded in the ESI mode with an Agilent 6520 Q-TOF,
LC-MS/MS mass spectrometer.
18.4 ppm. IR (KBr): ν = 2933, 1721, 1608, 1256, 764 cm–1. ESI-
˜
MS: m/z = 161.1 [M + H]+.
8-tert-Butyl-2H-chromen-2-one (2c):[13] 334 mg, 83% yield. Brown
1
oil. Rf = 0.3 (EtOAc/hexanes, 2:8). H NMR (300 MHz, CDCl3):
General Procedure A, for the Synthesis of 2a–i from 1a–i, and 4a–h
from 3a–h:[8] nBuLi (3.12 mL, 5 mmol, 1.6 m in hexanes) was added
dropwise to a THF solution (3 mL) of ethyl ethynyl ether (0.35 g,
ca. 5 mmol, ca. 40% by weight in hexanes) at –78 °C under an inert
gas over 20 min. The solution was kept at –78 °C for 2 h, and then
at 0 °C for a further 2 h. The solution was then recooled to –78 °C,
and carbonyl compound 1 or 4 (2 mmol) in THF (3 mL) was added
dropwise. The solution was kept at –78 °C for 1 h, then allowed to
warm to room temperature. After stirring at room temperature for
1 h, saturated aqueous NH4Cl was added to quench the reaction,
and the mixture was extracted with ethyl acetate. The organic ex-
tract was washed with water and brine, dried with Na2SO4, filtered,
and concentrated under vacuum. The residue was purified by col-
umn chromatography (EtOAc in hexanes) to give the product in
pure form.
General Procedure B, for the Synthesis of 5a–h from 4a–h:[9] KI
(1.66 g, 10 mmol) was added to a solution of 4 (0.374 g, 2 mmol)
in AcOH (6 mL). The mixture was heated at 110 °C for 4 h, then
it was cooled to room temperature, basified with saturated aqueous
NaHCO3, and extracted with ethyl acetate (2ϫ 25 mL). The com-
bined organic extracts were dried with Na2SO4, filtered, and con-
δ = 7.6 (d, J = 9.7 Hz, 1 H), 7.5 (d, J = 7.6 Hz, 1 H), 7.3 (d, J =
7.6 Hz, 1 H), 7.2 (t, J = 7.5 Hz, 1 H), 6.4 (d, J = 9.7 Hz, 1 H), 1.5
(s, 9 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.4, 152.1,
145.1, 136.6, 129.1, 126.9, 124.0, 119.1, 115.2, 34.4, 29.4 ppm. IR
(KBr): ν = 2926, 1640, 1219, 770, 671 cm–1. ESI-MS: m/z = 203.2
˜
[M + H]+. HRMS (ESI): calcd. for C13H14O2 [M + H]+ 203.1027;
found 203.1036.
6-Chloro-2H-chromen-2-one (2d):[14] 244 mg, 68% yield. Yellow so-
lid. M.p. 148–150 °C. Rf = 0.2 (EtOAc/hexanes, 2:8). 1H NMR
(300 MHz, CDCl3): δ = 7.6 (d, J = 9.7 Hz, 1 H), 7.5 (d, J = 2.6 Hz,
1 H), 7.4 (d, J = 9.7 Hz, 1 H), 7.29 (d, J = 9.59 Hz, 1 H), 6.47 (d,
J = 9.59 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
159.4, 152.1, 142.9, 131.4, 128.2, 127.4, 120.6, 118.2, 117.3 ppm.
IR (KBr): ν = 2899, 1726, 1216, 768 cm–1. ESI-MS: m/z = 181.0
˜
[M + H]+. HRMS (ESI): calcd. for C9H5ClO2 [M + H]+ 181.0056;
found 181.0055.
6-Bromo-2H-chromen-2-one (2e):[15] 397 mg, 89% yield. White so-
lid. M.p. 168–170 °C. Rf = 0.5 (EtOAc/hexanes, 2:8). 1H NMR
(300 MHz, CDCl3): δ = 7.65–7.60 (m, 3 H), 7.2 (d, J = 9.4 Hz, 1
H), 6.8 (d, J = 9.4 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ
4
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Synthesis of Substituted Coumarins and 2-Quinolinones
= 159.9, 152.9, 142.1, 134.6, 130.2, 120.3, 118.6, 117.8, 117.0 ppm.
6-Chloro-2-ethoxy-4-phenylquinoline (4d):[21] 424 mg, 75% yield.
Yellow solid. M.p. 120–122 °C. Rf = 0.7 (EtOAc/hexanes, 0.5:9.5).
1H NMR (300 MHz, CDCl3): δ = 7.8 (dd, J = 9.0, 2.9 Hz, 1 H),
7.7 (s, 1 H), 7.56–7.45 (m, 5 H), 7.25 (d, J = 2.9 Hz, 1 H), 6.8 (s,
1 H), 4.5 (q, J = 3.05 Hz, 2 H), 1.5 (t, J = 3.5 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 162.0, 150.3, 145.8, 137.4, 130.0,
129.5, 129.3, 129.2, 128.8, 128.7, 124.87, 124.81, 114.0, 61.9,
ESI-MS: m/z = 225.1 [M + H]+.
6,8-Dichloro-2H-chromen-2-one (2f):[16] 297 mg, 70% yield. Pale
1
brown solid. M.p. 148–150 °C. Rf = 0.4 (EtOAc/hexanes, 2:8). H
NMR (300 MHz, [D6]DMSO): δ = 8.0 (d, J = 9.6 Hz, 1 H), 7.9 (d,
J = 2.3 Hz, 1 H), 7.8 (d, J = 2.3 Hz, 1 H), 6.6 (d, J = 9.6 Hz, 1 H)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 158.3, 147.8, 142.7,
14.7 ppm. IR (KBr): ν = 1601, 1206, 1042, 769 cm–1. ESI-MS: m/z
˜
130.9, 128.1, 126.66, 121.0, 120.8, 118.0 ppm. IR (KBr): ν = 2260,
˜
=
284.2 [M
+
H]+. HRMS (ESI): calcd. for C17H14ClNO
1738, 1646, 1216, 1027, 997, 761 cm–1. ESI-MS: m/z = 214.1 [M +
[M + H]+ 284.0842; found 284.0836.
H]+.
2-Ethoxy-6-nitro-4-phenylquinoline (4e): 358 mg, 61% yield. Yellow
oil. Rf = 0.5 (EtOAc/hexanes, 1:9). H NMR (300 MHz, CDCl3):
δ = 8.7 (d, J = 2.3 Hz, 1 H), 8.4 (dd, J = 7.6, 2.3 Hz, 1 H), 7.9 (d,
J = 7.6 Hz, 1 H), 7.58–7.48 (m, 5 H), 6.9 (s, 1 H), 4.5 (q, J =
7.3 Hz, 2 H), 1.5 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.1, 152.5, 150.8, 143.8, 136.5 129.3, 129.1, 128.9,
6,8-Dibromo-2H-chromen-2-one (2g):[17] 534 mg, 89% yield. Pale
yellow solid. M.p. 164–165 °C. Rf = 0.3 (EtOAc/hexanes, 2:8). H
NMR (300 MHz, [D6]DMSO): δ = 8.3 (d, J = 2.06 Hz, 1 H), 8.03
(d, J = 9.6 Hz, 1 H), 8.01 (d, J = 2.06 Hz, 1 H), 6.6 (d, J = 9.6 Hz,
1 H) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 158.6, 149.4,
1
1
142.8, 136.3, 130.2, 121.5, 117.9, 116.1, 110.3 ppm. IR (KBr): ν =
˜
123.3, 123.1, 122.9, 115.0, 62.6, 29.8 ppm. IR (KBr): ν = 3022,
˜
3019, 1742, 1639, 1361, 1217, 764 cm–1. ESI-MS: m/z = 302.1 [M
2930, 1639, 1215, 765 cm–1. ESI-MS: m/z = 295.1 [M + H]+.
HRMS (ESI): calcd. for C17H14N2O3 [M + H]+ 295.1083; found
295.1086.
+ H]+.
6-Methoxy-2H-chromen-2-one (2h):[18] 249 mg, 71% yield. Brown
1
oil. Rf = 0.3 (EtOAc/hexanes, 4:6). H NMR (300 MHz CDCl3): δ
2-Ethoxy-4-phenylquinoline (4f):[22] 349 mg, 70% yield. Yellow so-
lid. M.p. 144–146 °C. Rf = 0.7(EtOAc/hexanes, 1:9). 1H NMR
(300 MHz, CDCl3): δ = 7.8 (d, J = 8.1 Hz, 1 H), 7.7 (d, J = 7.4 Hz,
1 H), 7.6 (t, J = 7.4 Hz, 1 H), 7.4 (s, 5 H), 7.2 (t, J = 7.4 Hz, 1 H),
6.8 (s, 1 H), 4.5 (q, J = 7.1 Hz, 2 H), 1.4 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 161.8, 151.4, 147.4, 138.1, 129.4,
128.5, 128.4, 127.7, 125.8, 124.0, 123.9, 113.1, 61.7, 14.7 ppm. IR
= 7.6 (d, J = 9.5 Hz, 1 H), 7.2 (d, J = 2.7 Hz, 1 H), 7.1 (dd, J =
9.04, 2.7 Hz, 1 H), 6.9 (d, J = 2.7 Hz, 1 H), 6.4 (d, J = 9.5 Hz, 1
H), 3.8 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.0,
155.5, 147.8, 143.9, 119.3, 119.1, 117.2, 116.5, 110.6, 55.6 ppm.
ESI-MS: m/z = 177.1 [M + H]+. HRMS (ESI): calcd. for C10H8O3
[M + H]+ 177.0552; found 177.0536.
(KBr): ν = 3150, 1608, 1214, 767 cm–1. ESI-MS: m/z = 250.1 [M +
7-Methoxy-4-phenyl-2H-chromen-2-one (2i):[19] 372 mg, 74% yield.
Pale yellow solid. M.p. 122–124 °C. Rf = 0.4 (EtOAc/hexanes, 2:8).
1H NMR (300 MHz, [D6]DMSO): δ = 7.57–7.52 (m, 5 H), 7.32 (d,
J = 8.8 Hz, 1 H), 7.0 (d, J = 2.0 Hz, 1 H), 6.9 (dd, J = 8.8, 2.0 Hz,
1 H), 6.23 (s, 1 H), 3.8 (s, 3 H) ppm. 13C NMR (50 MHz, [D6]-
DMSO): δ = 162.5, 159.9, 155.5, 155.1, 135.0, 129.6, 128.8, 128.4,
˜
H]+.
6-Chloro-4-(2-chlorophenyl)-2-ethoxyquinoline (4g): 455 mg, 72%
1
yield. Colourless oil. Rf = 0.6 (EtOAc/hexanes, 0.5:9.5). H NMR
(300 MHz, CDCl3): δ = 7.8 (d, J = 8.8 Hz, 1 H), 7.5 (t, J = 3.18 Hz,
1 H), 7.52 (t, J = 2.86 Hz, 1 H), 7.4 (d, J = 3.1 Hz, 1 H), 7.3 (t, J
= 2.75 Hz, 1 H), 7.29 (t, J = 2.5 Hz, 1 H), 7.2 (t, J = 2.5 Hz, 1 H),
6.8 (s, 1 H), 4.5 (q, J = 7.09 Hz, 2 H), 1.4 (t, J = 7.09 Hz, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 161.9, 147.7, 145.5, 136.1,
133.2, 131.2, 130.2, 130.1, 130.0, 129.6, 129.2, 127.0, 124.8, 124.6,
127.7, 112.3, 111.7, 111.2, 101.1, 55.9 ppm. IR (KBr): ν = 2368,
˜
1713, 1613, 1371, 1216, 765 cm–1. ESI-MS: m/z = 253.3 [M + H]+.
2-Ethoxy-4-methylquinoline (4a): 223 mg, 60% yield. Yellow oil. Rf
1
= 0.6 (EtOAc/hexanes, 1:9). H NMR (300 MHz, CDCl3): δ = 7.8
114.8, 62.1, 14.7 ppm. IR (KBr): ν = 2933, 1218, 770 cm–1. ESI-
(t, J = 9 Hz, 2 H), 7.5 (t, J = 7.6 Hz, 1 H), 7.4 (t, J = 7.6 Hz, 1
H), 6.75 (s, 1 H), 4.5 (q, J = 7.11 Hz, 2 H), 2.6 (s, 3 H), 1.4 (t, J =
7.11 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 162.0 146.6,
146.5, 129.1, 127.7, 125.3, 123.6, 113.2, 61.4, 18.5, 14.6 ppm. IR
˜
MS: m/z = 318.1 [M + H]+. HRMS (ESI): calcd. for C17H13Cl2NO
[M + H]+ 318.0452; found 318.0457.
6-Chloro-2-ethoxy-4-(2-fluorophenyl)quinoline (4h): 360 mg, 60%
(KBr): ν = 2924, 1640, 1217, 768 cm–1. ESI-MS: m/z = 188.1 [M +
˜
1
yield. Colourless oil. Rf = 0.5 (EtOAc/hexanes, 0.5:9.5). H NMR
H]+. HRMS (ESI): calcd. for C12H13NO [M + H]+ 188.1075; found
188.1085.
(300 MHz, CDCl3): δ = 7.8 (d, J = 8.7 Hz, 1 H), 7.5 (d, J = 1.0 Hz,
1 H), 7.5 (d, J = 2.2 Hz, 1 H), 7.4 (d, J = 1.7 Hz, 1 H), 7.35 (t, J
= 6.4 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.2 (t, J = 1.2 Hz, 1 H),
6.8 (s, 1 H), 4.5 (q, J = 7.01 Hz, 2 H), 1.4 (t, J = 7.01 Hz, 3 H)
2-Ethoxyquinoline (4b):[20] 210 mg, 61% yield. Yellow solid. M.p.
92–94 °C. Rf = 0.5 (EtOAc/hexanes, 1:9). 1H NMR (300 MHz,
CDCl3): δ = 7.9 (d, J = 8.8 Hz, 1 H), 7.8 (d, J = 8.1 Hz, 1 H), 7.69 ppm. 13C NMR (75 MHz, CDCl3): δ = 161.9, 145.6, 144.5, 131.5
(d, J = 7.6 Hz, 1 H), 7.6 (t, J = 7.7 Hz, 1 H), 7.3 (t, J = 7.4 Hz, 1
H), 6.8 (d, J = 8.8 Hz, 1 H), 4.5 (q, J = 7.06 Hz, 2 H), 1.4 (t, J =
7.06 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 162.2, 146.8,
138.6, 129.5, 127.5, 127.3, 125.1, 123.9, 113.4, 61.7, 29.8 ppm. ESI-
MS: m/z = 174.0 [M + H]+.
(d, J = 3 Hz), 130.86 (d, J = 7.9 Hz), 130.2, 129.7, 129.3, 124.9,
124.6, 124.6, 124.5, 116.4, 116.1, 115.2, 62.0, 29.8 ppm. IR (KBr):
ν˜ = 1631, 1217, 770 cm–1. ESI-MS: m/z = 302.1 [M + H]+. HRMS
(ESI): calcd. for C17H13ClFNO [M + H]+ 302.0748; found
302.0752.
2-Ethoxy-6,7-dimethoxyquinoline (4c): 274 mg, 59% yield. Pale yel-
low oil. Rf = 0.5 (EtOAc/hexanes, 2:8). 1H NMR (300 MHz,
CDCl3): δ = 7.8 (d, J = 8.8 Hz, 1 H), 7.2 (s, 1 H), 6.9 (s, 1 H), 6.75
(d, J = 8.8 Hz, 1 H), 4.4 (q, J = 7.05 Hz, 2 H), 4.0 (s, 3 H), 3.9 (s,
3 H), 1.4 (t, J = 7.05 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 161.5, 152.2, 147.5, 143.1, 137.2, 119.5, 110.6, 107.1, 106.0,
4-Methylquinolin-2(1H)-one (5a):[23] 253 mg, 80% yield. White so-
lid. M.p. 220–222 °C. Rf = 0.4 (MeOH/CH2Cl2, 1:9). 1H NMR
(300 MHz, CDCl3): δ = 12.5 (s, 1 H), 7.6 (d, J = 7.6 Hz, 1 H), 7.5
(t, J = 7.7 Hz, 1 H), 7.5 (d, J = 7.7 Hz, 1 H), 7.2 (t, J = 7.6 Hz, 1
H), 6.5 (s, 1 H), 2.5 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 162.1, 148.3, 139.1, 130.7, 125.1, 122.1, 121.3, 120.0, 115.8,
61.5, 56.1, 56.0, 29.7 ppm. IR (KBr): ν = 2920, 1610, 1220,
18.9 ppm. IR (KBr): ν = 3017, 1654, 1216, 764 cm–1. ESI-MS: m/z
˜
˜
768 cm–1. ESI-MS: m/z = 234.1 [M + H]+. HRMS (ESI): calcd. for
= 160.2 [M + H]+. HRMS (ESI): calcd. for C10H9NO [M + H]+
160.0762; found 160.0771.
C13H15NO3 [M + H]+ 234.1130; found 234.1128.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20782
/KAP1
Date: 29-08-12 15:12:02
Pages: 8
M. Sridhar Reddy, N. Thirupathi, M. H. Babu
FULL PAPER
Quinolin-2(1H)-one (5b):[24] 219 mg, 76% yield. Pale brown solid.
M.p. 198–200 °C. Rf = 0.5 (EtOAc/hexanes, 5:5). 1H NMR 10 mL). The combined organic extracts were dried with Na2SO4,
(300 MHz, [D6]DMSO): δ = 11.7 (s, 1 H), 7.9 (d, J = 9 Hz, 1 H), filtered, and concentrated under vacuum. The residue was purified
with NaHCO3, the reaction mixture was extracted with EtOAc (2ϫ
7.6 (d, J = 9 Hz, 1 H), 7.5 (t, J = 9 Hz, 1 H), 7.3 (d, J = 9 Hz, 1 by column chromatography (silica gel; 10% EtOAc in hexanes) to
H), 7.1 (t, J = 9 Hz, 1 H), 6.5 (d, J = 9 Hz, 1 H) ppm. 13C NMR give 10 (287 mg, 80%) as a colourless oil. Rf = 0.4 (EtOAc/hexanes,
1
(75 MHz, [D6]DMSO): δ = 161.9, 140.2, 138.8, 130.3, 127.8, 121.9,
3:7). H NMR (300 MHz, CDCl3): δ = 7.65 (d, J = 8.1 Hz, 1 H),
7.61 (d, J = 7.9 Hz, 2 H), 7.3 (t, J = 7.6 Hz, 1 H), 7.2 (d, J =
7.9 Hz, 2 H), 7.1 (t, J = 7.6 Hz, 1 H), 7.0 (d, J = 7.6 Hz, 1 H), 6.6
(s, 1 H), 5.4 (s, 1 H), 4.2 (q, J = 7.3 Hz, 2 H), 2.3 (s, 3 H), 2.1 (s,
3 H), 1.3 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 165.6, 153.3, 144.2, 136.1, 132.3, 129.8, 129.0, 127.9, 127.3,
125.2, 122.3, 121.4, 60.3, 29.81, 21.6, 20.6, 14.3 ppm. HRMS (ESI):
calcd. for C19H22NO4S [M + H]+ 360.1270; found 360.1269.
121.7, 119.1, 115.1 ppm. ESI-MS: m/z = 146.1 [M + H]+.
6,7-Dimethoxyquinolin-2(1H)-one (5c):[25] 298 mg, 73% yield. White
solid. M.p. 228–230 °C. Rf = 0.3 (EtOAc/hexanes, 7:3). H NMR
(300 MHz, [D6]DMSO): δ = 11.5 (s, 1 H), 7.7 (d, J = 9.4 Hz, 1 H),
7.1 (s, 1 H), 6.89 (s, 1 H), 6.3 (d, J = 9.4 Hz, 1 H), 3.7 (s, 3 H), 3.7
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 161.8, 151.8,
144.7, 139.7, 134.5, 118.7, 112.3, 108.8, 97.6, 55.7, 55.5 ppm. ESI-
MS: m/z = 206.1 [M + H]+.
1
2-Ethoxy-3-iodo-4-methylquinoline (11): I2 (253 mg, 1 equiv.) was
added to a solution of 8 (357 mg, 1 mmol) in CH2Cl2 (6 mL), and
the mixture was stirred at room temperature for 20 min. Saturated
sodium thiosulfate solution was added to quench the reaction, and
the mixture was extracted with CH2Cl2 (2ϫ 10 mL). The combined
organic extracts were dried with Na2SO4, filtered, and concentrated
under vacuum. The crude product was purified by by column
chromatography (silica gel, 5–7% EtOAc in hexanes) to give 11
6-Chloro-4-phenylquinolin-2(1H)-one (5d):[26] 458 mg, 90% yield.
1
White solid. M.p. 256–258 °C. Rf = 0.5 (MeOH/CH2Cl2, 1:9). H
NMR (300 MHz, [D6]DMSO): δ = 12.0 (s, 1 H), 7.6 (d, J = 2.8 Hz,
1 H), 7.58–7.51 (m, 5 H), 7.48 (dd, J = 7.8, 2.8 Hz, 1 H), 7.2 (d, J
= 7.8 Hz, 1 H), 6.4 (s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 161.0, 150.4, 138.0, 136.0, 130.4, 129.0, 128.8, 128.5, 125.7,
124.9, 122.3, 119.6, 117.7 ppm. IR (KBr): ν = 3306, 3019, 1660,
˜
1
1216, 767, 670 cm–1. ESI-MS: m/z = 256.0 [M + H]+. HRMS (ESI):
(203 mg, 65%) as a yellow oil. Rf = 0.3 (EtOAc/hexanes, 1:9). H
calcd. for C15H10ClNO [M + H]+ 256.0529; found 256.0517.
NMR (300 MHz, CDCl3): δ = 7.9 (d, J = 8.1 Hz, 1 H), 7.8 (d, J =
8.4 Hz, 1 H), 7.6 (t, J = 7.1 Hz, 1 H), 7.3 (t, J = 7.16 Hz, 1 H), 4.5
(q, J = 7.04 Hz, 2 H), 2.8 (s, 3 H), 1.5 (t, J = 7.03 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 158.5, 150.4, 145.7, 129.6, 127.6,
125.4, 124.3, 124.2, 90.0, 63.3, 29.8, 24.7 ppm.
6-Nitro-4-phenylquinoline-2(1H)-one (5e): 398 mg, 75% yield.
1
Brown solid. M.p. 276–278 °C. Rf = 0.5 (MeOH/CH2Cl2, 1:9). H
NMR (300 MHz, [D6]DMSO): δ = 12.4 (s, 1 H), 8.3 (dd, J = 9,
2.4 Hz, 1 H), 8.2 (d, J = 2.4 Hz, 1 H), 7.6 (m, 5 H), 7.5 (d, J =
9 Hz, 1 H), 6.5 (s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 161.3, 151.1, 143.7, 141.5, 135.5, 129.3, 128.7, 128.5, 125.3, 122.9,
3-Iodo-4-methylquinolin-2(1H)-one (12): 456 mg, 80% yield. yellow
oil. Rf = 0.3 (EtOAc/hexanes, 7:3). 1H NMR (300 MHz, [D6]-
DMSO): δ = 12.0 (s, 1 H), 7.8 (d, J = 8.2 Hz, 1 H), 7.5 (t, J =
6.9 Hz, 1 H), 7.3 (d, J = 8.2 Hz, 1 H), 7.2 (t, J = 6.9 Hz, 1 H), 2.7
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 158.5, 151.9,
137.7, 130.7, 125.5, 122.2, 118.7, 115.4, 103.1, 25.5 ppm. ESI-MS:
m/z = 286.2 [M + H]+. HRMS (ESI): calcd. for C10H9INO [M +
H]+ 285.9729; found 285.9750.
122.3, 117.9, 116.8 ppm. IR (KBr): ν = 1664, 1344, 1216, 765 cm–1.
˜
ESI-MS: m/z = 267.2 [M + H]+. HRMS (ESI): calcd. for
C15H10N2O3 [M + H]+ 267.0770; found 267.0750.
4-Phenylquinolin-2(1H)-one (5f):[27] 313 mg, 71 yield. White solid.
M.p. 248–250 °C. Rf = 0.4 (MeOH/CH2Cl2, 1:9). 1H NMR
(300 MHz, [D6]DMSO): δ = 7.54 (d, J = 7.7 Hz, 1 H), 7.51–7.49
(m, 5 H), 7.4 (dd, J = 7.7, 2.6 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H),
7.14 (t, J = 7.03 Hz, 1 H), 6.3 (s, 1 H) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 161.3, 151.5, 139.3, 136.7, 130.5, 128.7, 128.7,
126.1, 121.8, 121.2, 118.3, 115.8 ppm. ESI-MS: m/z = 222.2 [M +
H]+.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of 2a–i, 4a–h and 10–12.
Acknowledgments
6-Chloro-4-(2-chlorophenyl)quinolin-2(1H)-one (5g):[28] 519 mg,
90% yield. Colourless oil. Rf = 0.3(EtOAc/hexanes, 6:4). 1H NMR
(300 MHz, [D6]DMSO): δ = 12.1 (s, 1 H), 7.5 (m, 6 H), 6.8 (d, J
= 2.9 Hz, 1 H), 6.4 (s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 161.1, 148.1, 137.7, 134.6, 131.6, 130.9, 130.7, 129.8, 127.8,
126.0, 124.6, 123.4, 119.5, 117.8 ppm. ESI-MS: m/z = 290.2 [M +
H]+. HRMS (ESI): calcd. for C15H9Cl2NO [M + H]+ 290.0139;
found 290.0130.
6-Chloro-4(2-fluorophenyl)quinolin-2(1H)-one (5h):[28] 463 mg, 85%
yield. Yellow oil. Rf = 0.3 (EtOAc/hexanes, 7:3). 1H NMR
(300 MHz, [D6]DMSO): δ = 12.1 (s, 1 H), 7.6 (dd, J = 8.5, 2.9 Hz,
2 H), 7.5 (t, J = 6.9 Hz, 1 H), 7.4 (d, J = 2.7 Hz, 1 H), 7.4 (d, J =
6.7 Hz, 1 H), 7.3 (d, J = 6.9 Hz, 1 H), 7.0 (t, J = 6.9 Hz, 1 H), 6.5
(s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.9, 144.9,
137.7, 131.7, 131.6 (d, J = 8.25 Hz), 131.1, 130.7, 126.0, 125.2,
124.6, 124.0, 119.4, 117.8, 116.1, 115.9 ppm. ESI-MS: m/z = 274.2
[M + H]+.
We thank the Council of Scientific and Industrial Research (CSIR)
for financial aid. We thank Prof. Pierre Deslongchamps, emeritus
professor at the University of Laval, Canada, and Dr. T. K. Chak-
raborty, Director CSIR-CDRI, for their constant encouragement.
We thank SAIF division CDRI for the analytical data support.
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6
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/KAP1
Date: 29-08-12 15:12:02
Pages: 8
Synthesis of Substituted Coumarins and 2-Quinolinones
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O20782
/KAP1
Date: 29-08-12 15:12:02
Pages: 8
M. Sridhar Reddy, N. Thirupathi, M. H. Babu
FULL PAPER
Cycloisomerisation
M. Sridhar Reddy,* N. Thirupathi,
M. H. Babu ....................................... 1–8
Synthesis of Substituted Coumarins and 2-
Quinolinones by Cycloisomerisation of
(Hydroxy/aminophenyl)propargyl Alcohols
Keywords: Cycloisomerization / Cycliza-
tion / Alkynes / Oxygen heterocycles / Ni-
trogen heterocycles
2-Hydroxyacetophenones and 2-amino-
acetophenones were converted into cou-
marins and quinolinones, respectively, by
metal-free cycloisomerisation of intermedi-
ate 3-ethoxy-1-(2-hydroxy/aminophenyl)-2-
propyn-1-ols.
8
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