Metal-Free Synthesis of 4-Aryl-2-quinolone Derivatives by Iodine-Mediated Intramolecular C?H Amidation

Article abstract of DOI:10.1002/adsc.201900530

A metal-free synthesis of a range of 4-aryl-2-quinolone derivatives has been developed which utilizes an iodine-mediated intramolecular C?H amidation of 3,3-diarylacryl amides as the key step. Electron-withdrawing or -donating substituents in either of th

Full text of DOI:10.1002/adsc.201900530

Title: Metal-Free Synthesis of 4-Aryl-2-quinolone Derivatives by Iodine-
Mediated Intramolecular C-H Amidation
Authors: subhankar ghosh and Shital Kumar Chattopadhyay
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Synthesis of 4-Aryl-2-quinolone Derivatives by Iodine-
Mediated Intramolecular C-H Amidation
a
a
Subhankar Ghosh and Shital K Chattopadhyay *
a
Department of Chemistry, University of Kalyani, Kalyani - 741235, WB, INDIA
Tel:+91-33-25828750; Fax: +91-33-25828282; e-mail:shitalchem19@klyuniv.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://
Abstract. A metal-free synthesis of a range of 4-aryl-2- Moreover, the methodology overcomes some of the
quinolone derivatives has been developed which utilizes an difficulties associated with metal-mediated approaches such
iodine-mediated intramolecular C-H amidation of 3,3- as regio-isomeric product formation, and E-Z isomerization.
diarylacryl amides as the key step. Electron-withdrawing or We propose a mechanism involving the in situ generation
-donating substituents in either of the aryl rings display of hypoiodous acid as source of positive iodine.
marginal influence on the course of the reaction. However, Keywords: C-H amidation; iodine; heterocycles; catalysis,
the presence of the diarylalkene moiety has been found to be synthetic methods
crucial for the success of the reaction. The reaction proceeds
in very good yield and is applicable to a range of substrates.
and other reasons, continuing efforts have been
expended to develop new methodology towards the
synthesis of this important heterocyclic motif.
Introduction
Although classical cyclization methods such as
4
-Aryl-2-quinolones are important as naturally
[3]
occurring compounds and pharmaceutically relevant Knöevenegal condensation / Knorr-type cyclization
[4]
[5]
structures since they exhibit a range of biological
activities. For example, they have been found to
inhibit the enzymes acyl coenzyme A and cholesterol
acyl transferase, act as K-channel openers, and
endothelin receptor antagonists. Moreover, some of
these derivatives (e.g. Tipifarnib, 2, Figure 1) also
exhibit useful level of anti-cancer activity. For this,
/ Friedländer-type cyclization / protic and Lewis
acid-mediated cyclization of N,3-
[6]
diarylpropiolamides are popular, several elegant
transition metal catalyzed procedures have been
developed in recent years. Among these, palladium-
[1]
[2]
[7]
[8]
[9]
,
copper- and gold-catalyzed hydroarylation;
[10]
transition metal-mediated /transition metal-free
carbonylation
ruthenium-catalyzed C-H activation,
catalyzed intramolecular amination
among others,
catalyzed intramolecular amidation of 3,3-diarylacryl
amides (6, Scheme 1), either pre-formed
Cl
[11]
[12]
of 2-alkenyl anilines; palladium-
/
[
13]
NMe
and Pd-
reactions,
N
O
[14]
NH2
OH
OMe
[15]
have emerged. Similarly, metal-
N
O
Cl
N
O
[16]
H
Me
or in situ
[
17]
generated from cinnamide 5 in a domino process
1
, Yaequinolone
2, Tipifarnib (zarnestra)
involving synergistic catalysis by Pd/Cu/Ag/Ir species
has given fascinating results. Nonetheless, these have
necessitated the use of sophisticated ligands, and
simultaneous use of two or more heavy metal
catalysts. Moreover, problems of electronic influence,
compromise in regioselectivity and/or E-Z
isomerization have occasionally been observed. In
recent years, iodine-mediated heterocyclization
N
F
Cl
N
O
N
O
H
H
[18]
3
, HBV inhibitor
4, Kinase inhibitor
reactions
variants
have gained importance as metal-free
for heterocyclic synthesis. Herein, we
[19]
Figure 1. Structures of some important 4-aryl-2-
describe a metal-free molecular iodine-mediated
quinolone derivatives
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
synthesis of the 4-aryl-2-quinolone ring system be sufficiently nucleophilic for intramolecular
substitution due to possible α-effect of the oxygen
atom. Thus, we looked into iodine-mediated C-H
amidation of the N-benzyloxy-3, 3-diphenylacryl
amide 6a in greater detail.
involving intramolecular C-H amidation of
diarylacrylamides as the key step.
(a) Earlier work
Pd/Cu [
16a,15g]
16b]
[
Pd/Cu/Ag
[
16c]
Pd-Ag
O
The required model substrate 6a was prepared by
EDCI-mediated amide bond formation of 3,3-
diphenylacrylic acid (8a) with O-benzylhydroxyl
amine in the conventional way (Scheme 3).
[
16d]
Cu
Ar B(OH)2[17a]
ArI/Pd[17b]
[
16e]
NHR
Ir
HN
R
O
N
R
7
O
6
( R= H, Bn, OBn, OMe)
5
(b) Present work:
Iodine–mediated intramolecular C-H amidation of 6a
was initially attempted with some of the reported
conditions. Compound 6a when treated with
equimolar mixture of molecular iodine and KI in
refluxing toluene, almost no conversion was detected.
I2/H2O2/NaOAc
HN
R
O
N
O
R
6
(R = OBn, OMe)
7 (R = OBn, OMe)
Adding an equivalent of NaHCO did induce the
3
desired conversion to the quinolone derivative 7a but
the yield was very poor even after prolonged reflux.
Changing the base to sodium acetate improved the
yield to a minor extent (27%) but the starting material
remained largely unreacted. Increasing the molar
equivalents of each of the ingredients of the
Scheme 1. Previous and present work
Results and Discussion
I /KI/NaOAC combination from 1 to 2.5 improved
2
the yield significantly. Further increase of the
equivalents of KI and NaOAc to 5 from 2.5 delivered
an acceptable yield of 66% in refluxing toluene (entry
Iodine-mediated intramolecular amination has been
carried out using hypervalent iodine compounds
[20]
under oxidative conditions. Iodine (III) reagents have
also been recently used to prepare 2-quinolone ring
4). Changing the solvent to DMF slightly lowered the
system. [ N-Iodosuccinimide has been extensively
21]
[22]
yield and also increasing the temperature had a further
deleterious effect.
used in heterofunctionalization reactions. In recent
[23]
years, molecular iodine is being increasingly used
Table1. Optimization of the conversion 6a → 7a
in heterocyclic synthesis because of its distinct
advantage as a cyclization agent. However, molecular
iodine-mediated synthesis of 2-quinolones is less well
documented. Our initial attempts at molecular iodine
mediated cyclization of diphenylacrylamide 6*
Entry Reagent (eqv)
Conditions
%
7
a
1
2
I
I
(
I
2
2
(1) /KI (1)
(1) /KI (1)/ NaHCO
1)
(1)/KI (1)/NaOAc (1) Toluene, reflux, 16
h
(2.5)/KI(5)/NaOAc
Toluene, reflux, 16h trace
3
Toluene, reflux, 16
h
14
27
66
43
9
(
Scheme 2) under a range of conditions proved to be
3
2
2
unsuccessful. It is anticipated that simple amides are
perhaps poor substrates for intramolecular amidation
due to the weak nucleophilicity of the amide nitrogen.
Similarly, the corresponding N-benzyl derivative 6**
proved to be resistant to cyclization. We wondered
whether the corresponding N-hydroxyamides would
4
I
(
I
Toluene, reflux, 24
h
5)
(2.5)/KI(5)/NaOAc
5
2
DMF, 140 ºC, 16 h
(5)
I
+
-
6
2
(2.5 )/nBu
4
N I
Toluene, reflux, 16
h
(5 )/NaOAc (5)
7
NIS(2.5 )/KI(5)/NaOAc Toluene, reflux, 16
33
21
(5 )
h
O
8
I
2
(0.45)/H
2
2
2
O
O
O
2
2
2
2
(8)
(8)
(8)
(8)
(8)
Toluene, 110 ºC, 24
h
I2/conditions
NHR
Table-1
9
I
2
(0.45)/H
Toluene, reflux, 48 h 15
Toluene, 110 ºC , 24 h 95
Toluene, 80 ºC, 48 h 70
Toluene, 110 ºC , 24 h 10
N
R
O
/
KI(5)
6
6
6
*, R = H
10
I (0.45)/H
2
7
a, R = OBn
**, R = Bn
a, R = OBn
/
NaOAc (5)
(0.45)/H
NaOAc (5)
KI (5.0)/ H
NaOAc (5)
1
1
1
2
I
/
2
2
O
Scheme2. Conversion of 3,3-diphenylacrylamides to
-phenyl-2-quinolones.
O
2
4
2
/
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
Similarly, use of tetra-n-butylammonium iodide in products could be differentiated by observing the
place of KI was also found to be ineffective. Modest nature of the high field
yield of the desired product 7a was noticed when N-
iodosuccinimide (entry 7) was used in place of Table 2. Products from symmetrical substrates
molecular iodine. In an attempt to achieve the desired
transformation using catalytic amount of iodine in
combination with an oxidant, we opted to try the
cheaper I
2
/H
2
O combination for in situ generation of
2
hypoiodous acid as possible source of electrophilic
iodine. [ After some experimentation, it was found
that the reaction could be induced in the presence of
24]
at least 0.45 equivalent amount of I but only when
2
excess of hydrogen peroxide at elevated temperature
was used (entry 8). Even an excess amount of KI had
little influence (entry 9) on the course of the reaction;
but, use of NaOAc (entry 10) significantly improved
the yield to near completion (95%). The reaction was
found to be slower at lower temperature, and longer
time was required to achieve acceptable yield.
Similarly, lesser equivalents of the base were of little
use. Replacing iodine by KI (entry 12) keeping the
other ingredients unchanged was also of no avail. We
thus, followed the optimized condition (entry 10) to
examine the substrate scope and generality of the
reaction. To this end, compounds 6b-p (Scheme 3)
were prepared from corresponding known carboxylic
acids 8b-p, prepared following literature.
Scheme 3. Preparation of N-benzyloxy- 3,3-
diarylacrylamides 6a-p
The symmetrical 4,4′-disubstituted diarylacrylamides
6b-f having either electron-donating or electron-
withdrawing substituents reacted with more or less
equal facility under the developed conditions
providing the respective products 7b-f (Table 2) in
very good yield.
The symmetrical 3,3′- disubstituted diarylacrylamides
6
g-j electronically behaved similarly (Table 3) with
aromatic carbon C-8 (~112-114 ppm) in DEPT
experiment wherein in compound 7g it appeared as a
C-H carbon as against a quaternary carbon that would
appear from the alternative structure 7g*. Even more
interesting was the behaviour of the singly substituted
diarylacryl amides 6k-p wherein only one of the two
rings contains a substituent. In each of these cases, a
the added advantage that only one regioisomer (7g-j)
was formed in each case. The isomeric products 7g*-
[17b]
7i* were not detected. It was earlier reported
that
in metal mediated C-H amidation reactions mixture of
regioisomers were formed. The isomeric pair of
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
single product (7k-p) was found to be formed in very The identity of the isomeric pairs 7k/7l and 7o/7p
good yield and with negligible electronic influence of could be ascertained following the splitting pattern of
the substituent.
the designated C8-H which appears as a doublet (δ
.68, J = ~2 Hz) with meta-coupling. For the pair
7m/7n, even more diagnostic is the appearance of the
C-8 at very high field at δ 95.7 ppm.
7
Table 3. Products from unsymmetrical substrates
The direction of the cyclization in each case is
dictated by preferred proximity of the amide group in
the Z-substrate. It may be noted that during metal-
promoted
cyclization
of
unsymmetrical
diarylacrylamides, an E/Z-isomerization leading to
[
15b, 16a,
formation of mixture of products was observed.
1
7a, 17b]
The present methodology thus appears to be of
somewhat broader scope.
On the other hand, its limitations also were significant
(
Figure 2). Thus, neither of the cis- or trans- N-
benzyloxycinnamides 9 and 10 underwent any
conversion. Similarly, the corresponding saturated
derivative 11 or its homologue 12 equally frustrated
our attempts. The diarylpropanamide 13
also
remained unchanged. The ß-methyl substituted
cinnamide 14 (~ 2:1 mixture of E/Z-isomers) also
proved to be unreactive. On the other hand, the N-
methoxyacrylamide
6q
smoothly
underwent
conversion to the desired 7q.
Figure 2. Limitations of the methodology
These studies led us to conclude that the presence of
the diarylethylene linkage and a N-alkoxy substituent
are crucial to the success of the reaction.
Based on the above experiments, a tentative
[25]
mechanism
/KI/NaOAc protocol, it may go through the
formation of the iodonium intermediate 15
mechanism A). Intramolecular nucleophilic capture
is proposed in Scheme 4. For the
I
2
(
by the proximal activated nitrogen and subsequent
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
base-mediated loss of HI leads to overall C(sp2)-H to the corresponding cation 21, resonance stabilised to
amidation. However, for the I
2
2
/H O
2
/NaOAc it is
22. Base-mediated loss of proton leads to overall
C(sp2)-H amidation. Oxidative regeneration of iodine
may continue the catalytic cycle. The proposed
mechanism may explain some of the observations e.g.
the negligible E/Z-isomerization (as the double bond
is not involved before cyclization), necessity of the
extra aryl ring at C
regio-selectivity in the meta-substituted case
predominant steric influence since there is little
4
(participation in resonance), and
(
electronic influence). However, our attempts to trap
the radical intermediate 19 using Tempo, and 2,6-di-
tert-butyl-4-methylphenol did not meet with success,
although somewhat lowering of yield (~20%) was
observed in each case. Thus other mechanistic
[26]
possibilities may exist.
Conclusion
In conclusion, we have developed a metal-free
procedure for the synthesis of the important 4-aryl-2-
quinolone ring system involving the less explored I
2
-
H
2
O
2
combination for an intramolecular C-H
amidation. The reaction proceeds in very good yield
and it also overcomes some of the difficulties
associated with some related metal-mediated
procedures. The developed methodology may thus
complement the existing procedures and hence may
find general application. It may also encourage the
exploration of the intramolecular amidation of other
substrates involving the in situ generation of
hypoiodous acid.
Experimental Section
Experimental Details
Infrared spectra were recorded with a Perkin–Elmer
1
13
Infrared Spectrometer model No L120–000A. H and
C
NMR spectra were recorded with a Bruker400 MHz
Ultrashield NMR spectrometer purchased through a DST-
FIST grant. Mass spectra were recorded with a Water Xevo
QTOF mass spectrometer purchased through DST-PURSE
grant. Elemental analysis was performed with a Perkin–
Scheme 4. Suggested mechanisms for the formation Elmer 2400 series II Instrument. All solvents obtained from
commercial sources were dried with appropriate drying
of 4 under two different conditions.
agents and were immediately distilled before use. Column
chromatography was performed with silica gel (230–400)
more likely that a radical species may be involved. purchased from Spectrochem India Pvt. Ltd. Thin-layer
chromatography was performed with pre-coated silica
Iodine reacts with H
2
O to form hypoiodous acid.
2
plates and was visualized under a UV lamp or with an
+
Being a source of I , this may lead to formation of the iodine spray. Melting points were determined in open
capillaries and are uncorrected.
N-iodo derivative 18. Homolytic cleavage of the later
may form the N-centered radical 19. Because of the
General procedure for the synthesis of N-(benzyloxy)-
proximity to the aryl ring, the radical 19 may undergo
addition to it preferably at the sterically more
accessible para-position due to the presence of the
bulky N-substituent. In the highly redox environment,
3
,3-diarylacrylamides 6a-p
EDC.HCl (0.48 g, 2.5 mmol) was added portion wise to a
stirred solution of 3,3-diphenylacrylic acid (0.33 g, 1.5
mmol) in dry DCM (10 mL) at 0 ºC during 15 minutes.
the newly formed radical 20 may undergo oxidation Then a solution of O-benzylhydroxylamine hydrochloride
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
(
0.25 g, 1.5 mmol) and N-methylmorpholine (0. 15 mL, 137.1, 135.8, 133.8, 132.7, 131.0, 129.4, 128.7, 128.6,
1
.5 mmol) in dry DCM (5 ml) was added dropwise over 10 128.3, 127.9, 119.7, 76.8. Elemental analyses: calcd for
NO ; C, 66.34; H, 4.30; N, 3.52; obsd. C, 66.22;
min to the solution of the acid at the same temperature. The
C
22
H
17Cl
2
2
reaction mixture was allowed to come to rt and stirred for H, 4.42; N, 3.69.
6 h. It was then diluted with DCM (20 ml) and the
combined organic solution was washed successively with
saturated aqueous solution of NaHCO (2 × 15 mL), HCl
2N, 2 × 10 ml), H O (1 × 20 mL), brine (1 × 20 mL), and
then dried (Na SO ).It was then concentrated under
1
N-(Benzyloxy)-3,3-bis(4-fluorophenyl)acrylamide (6f):
3
(
2
[
27c]
This was prepared from the acid 8f
and the product 6f
2
4
was obtained as a colourless viscous liquid ; yield 331 mg
reduced pressure and the residue was purified by column
chromatography on silica gel using a mixture of petroleum
ether: ethyl acetate (70:30) as eluent to provide the product
(
72%); IR (neat): 3738, 3419, 2923, 2346, 1639, 1602,
-
1 1
1
6
539 cm . H NMR (400 MHz, DMSO-d ) : δ 11.24 (1H,
s), 7.41-7.38 (5H, m), 7.33-7.21 (8H, m), 6.33 (1H, s), 4.76
6
a (300 mg, 76%) as colourless viscous liquid.
13
(
6
2H, s). C NMR (100 MHz, DMSO-d ): δ (ppm) 163.8 (d,
1
1
1
JC,F = 60 Hz), 163.2, 161.4 (d, 1JC,F = 58 Hz), 148.8, 137.8,
N-(Benzyloxy)-3,3-diphenylacrylamide (6a) :
36.4, 135.2, 131.9 (d, 3JC,F = 8 Hz), 130.3 (d, 3JC,F = 8 Hz),
29.2, 128.8, 128.7, 119.5, 116.0 (d, 2JC,F = 21 Hz), 115.4
-
1
1
IR (neat): 3418, 2919, 1646, 1455 cm . H NMR (400 (d, 2JC,F = 21 Hz), 77.2 . Elemental analyses: calcd for
MHz, CDCl
.23-7.19 (6H, m), 6.24 (1H, s), 4.71 (2H, s) . C NMR 4.57; N, 3.95.
100 MHz, CDCl ): δ (ppm) 164.9, 151.6, 140.5, 138.2,
35.3, 129.7, 129.3, 129.2, 129.0, 128.8, 128.5, 128.4,
28.1, 127.7, 118.9, 77.9. Elemental analyses: calcd for
; C, 80.22; H, 5.81; N, 4.25; obsd, C, 80.12; H,
.95; N, 4.32.
3
): δ (ppm): 8.05 (1H, brs), 7.34-7.26 (9H, m),
22 17 2 2
C H F NO ; C, 72.32; H, 4.69; N, 3.83; obsd, C, 72.43; H,
13
7
(
3
1
1
N-(Benzyloxy)-3,3-di-m-tolylacrylamide (6g):
C
22
H
19NO
2
[
27c]
This was prepared from the acid 8g
was obtained as a colourless viscous liquid. Yield 299 mg
and the product 6g
5
-
1
1
(
67%). IR (neat): 3419, 2925, 1603, 1570, 1429 cm . H
NMR (400 MHz,DMSO-d ): δ (ppm) 11.14 (1H, s), 7.36-
.33 (3H, m), 7.31-7.27 (2H, m),7.24 (2H, dd, J = 7.6, 2Hz),
N-(Benzyloxy)-3,3-di-p-tolylacrylamide (6b) :
6
7
This was prepared from the acid 8b[ and the product 6b 7.17-7.15 (2H, m) 7.05 (1H, brs), 6.97-6.94 (3H, m) , 6.29
13
27a]
as an yellowish viscous liquid; yield 317 mg (71%); IR (1H, s), 4.66 (2H, s), 2.28 (3H, s), 2.26 (3H, s). C NMR
-
1 1
(
neat): 3419, 2925, 1603, 1570, 1429 cm . H NMR (400 (100 MHz, DMSO-d
6
): δ (ppm) 163.6, 151.1, 141.5, 139.1,
MHz,CDCl
3
): δ (ppm) 8.23 (1H, brs), 7.18-7.13 (3H, m), 138.1, 137.4, 137.2, 136.3, 130.0, 129.9, 129.2, 129.0,
7
2
.10 (2H, brs), 7.00-6.95 (8H, m), 6.08 (1H, s), 4.61 (2H, s), 128.8, 128.7, 128.5, 128.2, 126.8, 125.5, 119.1, 77.2, 21.5,
13
.23 (3H, s), 2.21 (3H, s) . C NMR (100 MHz, CDCl
3
): δ 21.4. Elemental analyses: calcd for C24
H
23NO
2
; C, 80.64; H,
(
ppm) 165.3, 151.8, 139.3, 138.6, 138.0, 135.4, 129.3, 6.49; N, 3.92; obsd, C, 80.57; H, 6.62; N, 3.78.
1
2
8
29.1, 129.0, 128.8, 128.5, 128.4, 128.2, 125.8, 117.7, 77.9,
1.4, 21.3. Elemental analyses: calcd for C24 ; C,
0.64; H, 6.49; N, 3.92; obsd, C, 80.76; H, 6.37; N, 4.12.
H
23NO
2
N-(Benzyloxy)-3,3-bis(3-chlorophenyl)acrylamide (6h):
[
27c]
This was prepared from the acid 8h
and the product 6h
N-(Benzyloxy)-3,3-bis(4-methoxyphenyl)acrylamide
6c):
was obtained as a colourless viscous liquid ; yield 258 mg
(
-1
(
60%) ; IR (neat): 3728, 3149, 2925, 1657, 1603, 1547 cm .
1
H NMR (400 MHz,CDCl
3
): δ (ppm) 7.87 (1H, s), 7.40-
[
27a]
This was prepared from the acid 8c
and the product 6c 7.33 (7H, m), 7.27-7.16 (3H, m), 7.11-7.08 (2H, m), 6.99
13
was obtained as a yellowish viscous liquid ; yield 350 mg (1H, d, J = 7.2Hz), 6.14 (1H, s) , 4.71 (2H, s) . C NMR
-
1
1
(
(
75%); IR (neat) 3217, 2947, 1657, 1624 cm . H NMR (100 MHz, CDCl
3
): δ (ppm) 164.1, 149.3, 139.3, 135.1,
400 MHz, CDCl ): δ (ppm) 7.78 (1H, s), 7.33-7.31 (3H, 134.6, 129.9, 129.8, 129.5, 129.1, 128.9, 128.8, 128.0,
3
m), 7.26-7.25 (2H, m), 7,17-7.11 (4H, m), 6.87-6.80 (4H, 127.5, 127.0, 126.3, 120.1, 78.1. Elemental analyses: calcd
m), 6.14 (1H, brs), 4.78 (2H, s), 3.82 (3H, s), 3.80 (3H, s). for C22
H
17Cl
2
NO
2
; C, 66.34; H, 4.30; N, 3.52; obsd, C,
1
1
1
3
3C NMR (100 MHz, CDCl ): δ (ppm) 165.7, 160.5, 160.0, 66.45; H, 4.17; N, 3.61.
51.1, 135.4, 133.3, 130.8, 130.4, 129.7, 129.0, 128.5,
16.7, 114.0, 113.7, 77.9, 55.3, 55.2. Elemental analyses:
N-(Benzyloxy)-3,3-bis(3-fluorophenyl)acrylamide (6i):
calcd for C24
H
23NO
4
; C, 74.02; H, 5.95; N, 3.60; obsd. C,
7
4.14 ; H, 5.79; N, 3.72.
[
27c]
This was prepared from the acid 8i
and the product 6i
was obtained as a colourless viscous liquid ; yield 56%. IR
N-(Benzyloxy)-3,3-bis(4-tert-butylphenyl)acrylamide
-1
(
neat): 3449, 2928, 1619, 1610, 1523 cm . 1H NMR (400
MHz, CDCl ): δ (ppm) 8.07 (1H, brs), 7.32-7.16 (10H, m),
.98-6.90 (4H, m), 6.81 (2H, dd, J = 1.6, 6.4Hz), 6.16 (1H,
(
6d):
3
6
This was prepared from the acid 8d [27b] and the product 6d brs), 4.69 (2H, s). C NMR (100 MHz,CDCl
13
3
): δ (ppm)
obtained as a colourless viscous liquid ; yield 360 mg 164.2, 163.9, 161.7, 161.5, 161.4, 149.4, 142.2, 135.1,
-
1
1
(
68%); IR (neat): 3409, 2918, 2120, 1640, 1431 cm . H 130.4, 130.3, 130.1, 130.0, 129.3, 128.9, 128.7, 128.6,
NMR (400 MHz,CDCl ): δ (ppm) 7.54 (1H, brs), 7.31- 125.0, 125.0, 124.2,123.7, 119.8, 116.4, 116.3, 116.2,
.24 (8H, m), 7.12-7.07 (5H, m), 6.21 (1H, s), 4.64 (2H, s), 116.1, 115.8, 115.1, 114.9, 78.08; Elemental analyses:
3
7
1
d
1
3
7
1
3
.27 (9H, s), 1.23 (9H, s) . C NMR (100 MHz, DMSO- calcd for C22
): δ (ppm) 163.7, 151.9, 150.7, 138.9, 136.4, 136.2, 129.6, 72.43 ; H, 4.57; N, 3.95.
29.2, 128.8, 128.0, 125.7, 125.0, 118.4, 77.2, 34.8, 31.6,
1.5. Elemental analyses: calcd for C30 ; C, 81.59; H,
.99; N, 3.17; obsd, C, 81.67; H, 7.86; N, 3.28.
17 2 2
H F NO ; C, 72.32 ; H, 4.69; N, 3.83; obsd, C,
6
H
35NO
2
N-(Benzyloxy)-3,3-bis(3-methoxyphenyl)acrylamide
6j):
(
N-(Benzyloxy)-3,3-bis(4-chlorophenyl)acrylamide (6e):
[27c]
This was prepared from the acid 8j
and the product 6j
was obtained as a colourless viscous liquid ; yield 285 mg
This was prepared from the acid 8e [27c] and the product 6e (61%) ; IR (neat): 3118, 2928, 1649, 1614 cm . H NMR
-1
1
was obtained as a yellowish viscous liquid ; yield 284 mg (400 MHz,CDCl ) δ (ppm): 7.77 (1H, brs), 7.24-7.23 (3H,
66%); IR (neat): 3738, 3184, 1648, 1611, 1590 cm . H m), 7.19-7.12 (4H, m), 6.80 (2H, dt, J = 8.0, 2.0 Hz), 6.75-
): δ (ppm) 11.26 (1H, s), 7.47- 6.69 (3H, m), 6.65 (1H, brs ), 6.21 (1H, s), 4.65 (2H, s),
3
-
1
1
(
NMR (400 MHz, DMSO-d
6
13
7
7
3
.41 (4H, m), 7.39-7.35 (5H, m), 7.25 (2H, d, J = 8.4Hz), 3.67 (6H, s). C NMR (100 MHz, CDCl ): δ (ppm) 164.9,
.18 (2H, d, J = 8.4Hz), 6.73 (1H, s), 4.74 (2H, m). 13C 159.7, 159.5, 150.7, 141.5, 139.3, 135.2, 129.9, 129.4,
NMR (100 MHz, DMSO-d
6
): δ (ppm) 162.5, 148.1, 139.3, 128.9, 128.5, 121.4, 120.6, 119.4, 114.7, 114.6, 114.3,
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
1
13.7, 77.9, 55.3, 55.2 . Elemental analyses: calcd for (Z)-N-(Benzyloxy)-3-(4-chlorophenyl)-3-
; C, 74.02; H, 5.95; N, 3.60; obsd, C, 74.14; H, phenylacrylamide (6p):
.86; N, 3.69.
24 4
C H23NO
5
[
27c]
This was prepared from the acid 8p
and the product 6p
(
E)-N-(Benzyloxy)-3-phenyl-3-p-tolylacrylamide (6k):
was obtained as a colourless viscous liquid ; yield 296 mg
-
1 1
(
68%); IR (neat): 3447, 2851, 1666, 1604 cm . H NMR
(400 MHz, CDCl ) : δ 7.70 (1H, s), 7.34-7.22 (10H, m),
.13-7.07 (4H, m), 6.15 (1H, s), 4.74 (2H, s). C NMR
): δ (ppm) 163.3, 150.1, 140.9, 137.9,
36.2, 133.0, 131.5, 129.6, 129.3, 129.2, 129.1, 128.8,
28.4, 128.1, 119.4, 77.3. Elemental analyses: calcd for
; C, 72.62; H, 4.99; N, 3.85; obsd, C, 72.74; H,
[
27d]
3
This was prepared from the acid 8k
was obtained as a colourless viscous liquid ; yield 259 mg
and the product 6k
13
7
-
1
1
(100 MHz, DMSO-d
6
(
63%); IR (neat): 3427, 2915, 1637, 1603, 1429 cm . H
): δ 11.12 (1H, s), 7.37-7.31
8H, m), 7.18-7.09 (6H, m), 6.26 (1H, s), 4.67 (2H, s), 2.30
1
1
NMR (400 MHz, DMSO-d
6
(
(
13
C
22
H
18ClNO
2
3H, s). C NMR (100 MHz, DMSO-d
6
): δ (ppm) 163.0,
50.4, 138.8, 138.4, 138.1, 135.9, 129.2, 129.0, 128.9,
28.7, 128.3, 128.2, 127,7, 127.6, 117.9, 76.7, 20.7.
; C, 80.44; H, N-Methoxy-3,3-diphenylacrylamide (6q):
.16; N, 4.08; obsd, C, 80.53; H, 6.27; N, 3.98.
4
.84; N, 3.92
1
1
Elemental analyses: calcd for C23
H
21NO
2
6
This was prepared from the acid 8a following the general
procedure but using O-methylhydroxylamine hydrochloride
as the coupling partner. The product was purified using a
mixture of hexane: ethyl acetate (60:40) as eluent to give
(
Z)-N-(Benzyloxy)-3-phenyl-3-p-tolylacrylamide (6l):
[
27d]
This was prepared from the acid 8l
and the product 6l
6
q as a colourless viscous liquid; yield: 230 mg (76%). IR
was obtained as a yellowish viscous liquid. Yield 263 mg
-1
-
1
1
(neat): 3231, 2924, 1655, 1603, 1578 cm . NMR (400
MHz, CDCl ): δ (ppm) 7.93 (1H, s), 7.33-7.31 (3H, m),
.29-7.22 (3H, m), 7.22-7.17 (4H, m), 6.21 (1H, s), 3.45
(
(
64%). IR (neat): 3438, 2818, 1647, 1613 cm . H NMR
400 MHz, DMSO-d ): δ 11.18 (1H, s), 7.41-7.36 (8H, m),
.26-7.21 (4H, m), 7.09 (2H, d, J = 8Hz), 6.28 (1H, s), 4.75
3
6
7
7
13
1
3
(3H, s). C NMR (100 MHz, CDCl
3
): δ (ppm) 165.1, 151.4,
40.3, 138.2, 129.3, 129.2, 128.9, 128.7, 128.4, 128.1,
19.0, 64.0. Elemental analyses: calcd for C16 ; C,
5.87; H, 5.97; N, 5.53; obsd, C, 75.98; H, 5.79; N, 5.65.
(
(
2H, s), 2.39 (3H, s). C NMR (100 MHz, DMSO-d
ppm) 163.6, 150.9, 141.7, 137.6, 136.4, 136.2, 129.7,
6
): δ
1
1
7
H
15NO
2
1
2
6
29.5, 129.2, 128.9, 128.7, 128.6, 128.2, 128.1, 119.1, 77.2,
1.3. Elemental analyses: calcd for C23
H
21NO
2
; C, 80.44; H,
.16; N, 4.08; obsd, C, 80.33; H, 6.31; N, 4.01.
General procedure for the synthesis of 4-aryl-2-
quinolones 7a-p:
(
E)-N-(Benzyloxy)-3-(4-methoxyphenyl)-3-
phenylacrylamide (6m):
To a round bottom flask (25 mL) fitted with a condenser
containing a solution of compound 6a (100 mg, 0.30
mmol) in toluene (3.0 mL) was added sequentially
molecular iodine (34 mg, 0.13 mmol), NaOAc (124 mg,
[
27d]
This was prepared from the acid 8m
and the product
6
m was obtained as a colourless viscous liquid ; yield 341
-1
mg (79%); IR (neat): 3488, 3136, 1667, 1610, 1517 cm .
1
2 2
1.51 mmol) and H O (0.8 mL, 30%, 4 equiv) at room
3
H NMR (400 MHz,CDCl ): δ (ppm) 7.73 (1H, s), 7.27-
temperature. Then, the round bottom flask was placed in a
7
6
.23 (6H, m), 7.20-7.08 (4H, m), 7.08-7.04 (2H, m), 6.78-
.72 (2H, m), 6.14 (1H, brs), 4.64 (2H, s), 3.71 (3H, s) .
ο
pre-heated oil bath at 110 C under gentle relux for 16 h.
13
The flask was lifted from the bath, cooled to rt, and then
3
C NMR (100 MHz, CDCl ): δ (ppm) 165.2, 160.0, 151.1,
2 2
another lot of H O (0.4 mL, 30%, 2 equiv) was added.
1
1
38.4, 135.3, 132.7, 130.8, 130.2, 129.5, 129.2, 129.0,
28.5, 128.4, 127.0, 117.1, 113.8, 78.0, 55.3. Elemental
Heating was continued for an additional 8 h. The reaction
mixture was allowed to cool to room temperature, diluted
with water (10 mL) and then extracted with EtOAc (2× 25
ml). The combined organic extract was washed with
analyses: calcd for C23
H
21NO
3
; C, 76.86; H, 5.89; N, 3.90;
obsd, C, 76.94; H, 5.78; N, 3.97.
saturated aqueous solution of Na
2
S
2
O
3
(2 × 10 mL), water
(
Z)-N-(Benzyloxy)-3-(4-methoxyphenyl)-3-
(
20 mL), brine (20 mL), and then dried (MgSO ). It was
4
phenylacrylamide (6n):
filtered and the filtrate was concentrated under reduced
pressure to leave a residue which was passed through a
This was prepared from the acid 8n[ and the product 6n short pad of silica using a mixture of hexane-ethyl acetate
27e]
was obtained as an yellowish viscous liquid ; yield 288 mg (4:1) as eluent to afford 7a (94 mg, 0.28 mmol, 95%) as a
-
1
1
(
67%). IR (neat): 3188, 2932, 1647, 1604, 1510 cm . H colourless solid. Compounds 7b-q were prepared
NMR (400 MHz, CDCl
3
): δ (ppm) 7.74(1H, brs), 7.28-7.22 analogously.
6H, m), 7.21-7.13 (4H, m), 7.07 (2H, d, J = 8.4Hz), 6.78
2H, d, J = 8.8 Hz), 6.12 (1H, brs) , 4.71 (2H, s), 3.75 (3H,
(
(
1
-(Benzyloxy)-4-phenylquinolin-2(1H)-one (7a):
1
3
s). C NMR (100 MHz, DMSO-d
6
): δ (ppm) 163.8, 159.5,
50.7, 142.0, 136.4, 131.2, 129.2, 128.9, 128.7, 128.3,
18.7, 113.7, 77.2, 55.5. Elemental analyses: calcd for
21NO23; C, 76.86; H, 5.89; N, 3.90; obsd, C, 76.73; H,
.92; N, 3.74.
1
1
C
[
16b]
M.p 140-141 ºC (Lit.
viscous oil). IR (neat): 3424, 2923,
-1 1
2
3
847, 1669, 1608, 1512 cm ; H NMR (400 MHz,CDCl ):
23
H
δ (ppm) 7.72 (1H, d, J = 8.4Hz), 7.66-7.42 (2H, m), 7.60-
5
7
.54 (3H, m), 7.51-7.49 (3H, m), 7.45-7.35 (5H, m), 7.18
13
(
(
1
1
1H, t, J = 7.2 Hz), 6.74 (1H, s), 5.32 (2H, s); C NMR
100 MHz, CDCl ): δ (ppm) 157.6, 150.8, 138.7, 136.7,
33.9, 131.0, 129.9, 129.3, 128.9, 128.7, 128.6, 127.5,
22.6, 122.0, 119.6, 112.5, 77.3(overlapped); HRMS (TOF
328.1338;
(
E)-N-(Benzyloxy)-3-(4-chlorophenyl)-3-
3
phenylacrylamide (6o):
This was prepared from the acid 8o[
27d]
and the product 6o MS ES+): m/z [M + H]+ calcd. for C22
H
18NO
2
was obtained as a colourless viscous liquid ; yield 283 mg found 328.1396.
-
1 1
(
(
65%); IR (neat): 3422, 2919, 1663, 1589 cm . H NMR
400 MHz,CDCl ): δ (ppm) 7.41 (1H, brs), 7.36-7.28 (4H,
3
1
-(Benzyloxy)-7-methyl-4-p-tolylquinolin-2(1H)-one
m), 7.25 (3H, brs), 7.21-7.16 (2H, m), 7.12-7.11 (3H, m),
(
7b):
13
7
.08-7.06 (2H, m), 6.17 (1H,s), 4.66 (2H, s) . C NMR
(
3
100 MHz, CDCl ) : δ (ppm) 164.7, 150.2, 138.9, 137.7,
This was prepared from the amide 6b and the product 7b
was obtained as a pale yellow solid; yield 91 mg (92%);
m.p 150-152 ºC; IR (neat): 3423, 2917, 2855, 1662, 1614,
1
1
35.3, 134.6, 130.7, 130.1, 129.4, 129.2, 128.9, 128.7,
28.6, 128.0, 119.3, 78.0 ; Elemental analyses: calcd for
C
22
H
18ClNO
2
; C, 72.62 ; H, 4.99; N, 3.85; obsd, C, 72.54;
-
1 1
3
cm ; H NMR (400 MHz,CDCl ):δ (ppm) 7.66-7.64 (2H,
H, 5.09; N, 3.76.
m), 7.48 (2H, d, J = 8Hz), 7.45-7.41 (3H, m), 7.34-7.32
(
2
4H, m), 6.99 (1H, d, J = 8Hz), 6.66 (1H, s), 5.30 (2H, s),
13
.47 (3H, s), 2.45 (3H, s) ; C NMR (100 MHz, CDCl
3
): δ
7
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
(
ppm) 157.9, 150.7, 141.8, 138.8, 138.7, 134.1, 134.0, (400 MHz,CDCl
3
): δ (ppm) 7.58-7.52 (3H, m), 7.38-7.31
1
1
29.9, 129.3, 129.2, 128.8, 128.7, 127.4, 124.0, 120.6, (5H, m), 7.23 (2H, d, J = 8Hz), 7.15 (2H, d, J = 8.8Hz),
13
17.5, 112.5, 76.8, 22.0, 21.3; HRMS (TOF MS ES+): m/z 6.62 (1H, s), 5.23 (2H, s), 2.37 (3H, s), 2.27 (3H, s);
C
[
M+H]+ calcd. for C24
H
22NO
2
356.1651; found 356.1641.
NMR (100 MHz, CDCl
3
) δ (ppm) 157.5 (C), 150.7 (C),
1
1
1
1
38.4(C), 136.8(C), 136.7(C), 134.0 (C),, 132.3(CH),
32.2(C), 129.9(CH), 129.5(CH), 129.2(CH), 128.7(CH),
28.4(CH), 127.2(CH), 126.0(CH), 121.9(CH), 119.7 (C),
12.4 (CH), 77.3 (CH2), 21.5 (CH3), 20.9 (CH3) ;
1
2
-(Benzyloxy)-7-methoxy-4-(4-methoxyphenyl)quinolin-
(1H)-one (7c):
Elemental analyses: calcd for C24
H
21NO
2
; C, 81.10; H,
This was prepared from the amide 6c and the product 7c
was obtained as a colourless solid; yield 90 mg (91%);
m.p 159-160 ºC; IR (neat): 3421, 2922, 2840, 1747, 1657,
5
.96; N, 3.94; obsd, C, 81.27 ; H, 6.12; N, 3.85.
-
1
1
1-(Benzyloxy)-7-chloro-4-(3-chlorophenyl)quinolin-
(1H)-one (7h):
1
3
606 cm ; H NMR (400 MHz,CDCl ) δ (ppm) 7.55-7.52
2
(
2H, m), 7.40 (1H, d, J = 8.8Hz), 7.35-7.33 (3H, m), 7.28
(
2H, d, J = 8.8Hz), 7.01 (1H, d, J = 2Hz), 6.94 (2H, d, J =
8
.8Hz), 6.66 (1H, dd, J = 8.8,2.4Hz), 6.48 (1H, s), 5.24 (2H, This was prepared from the amide 6h and the product 7h
13
s), 3.80 (3H, s), 3.75 (3H, s); C NMR (100 MHz, CDCl
3
): was obtained as a colourless solid; yield 86 mg (87%); m.p
-
1
δ (ppm) 162.1, 160.1, 158.3, 150.4, 140.5, 134.2, 130.2, 126-127 ºC; IR (neat): 3423, 2917, 2855, 1662, 1614 cm ;
1
7
29.9, 129.3, 129.0, 128.8, 118.5, 114.0, 113.6, 111.4, 95.6, 1H NMR (400 MHz,CDCl
3
) δ (ppm) 7.63-7.58 (3H, m),
7.5, 55.6, 55.4 ; Elemental analyses: calcd for C24 7.52 (1H, d, J = 2Hz), 7.50-7.47 (2H, m), 7.45-7.41 (4H,
H
4
21NO ;
C, 74.40; H, 5.46; N, 3.62; obsd, C, 74.29 ; H, 5.64; N, m), 7.29 (1H, td, J = 1.6, 6.8 Hz), 6.75 (1H, s), 5.31 (2H,
1
3
3
.53.
s) ; C NMR (100 MHz, CDCl
3
): δ (ppm) 157.0 (C),
1
1
1
1
48.3(C),137.7(C),137.3(C),134.9(C),133.5(C), 131.4(CH),
30.2(CH),130.0(CH),
129.5(CH),
129.4(CH),
1
-(Benzyloxy)-7-tert-butyl-4-(4-tert-
28.8(CH),128.5 (C) 126.9(CH), 126.3(CH), 123.5(CH),
20.2(C), 114.3(CH), 77.6 (CH2). Elemental analyses:
butylphenyl)quinolin-2(1H)-one (7d):
calcd for C22
C, 66.97; H, 3.93; N, 3.66.
H
15Cl
2
NO
2
; C, 66.68; H, 3.82; N, 3.53; obsd,
This was prepared from the amide 6d and the product was
7
d was obtained as a colourless solid; yield 92 mg (93%);
m.p 110-111 ºC; IR (neat): 3439, 2925, 2309 2, 1645, 1528,
-
1
1
1-(Benzyloxy)-7-fluoro-4-(3-fluorophenyl)quinolin-
cm ; H NMR (400 MHz,CDCl
1
(
3
): δ (ppm) 7.67 (1H, d, J =
.6Hz), 7.63-7.61 (2H, m), 7.55-7.50 (3H, m), 7.44-7.41
2
(1H)-one (7i):
3H, m), 7.40-7.36 (2H, m), 7.22 (1H, dd, J = 8.8,2Hz),
13
6
.70 (1H, s), 5.33 (2H, s), 1.39 (9H, s), 1.34 (9H, s);
): δ (ppm) 158.1, 154.8, 152.0, 7i was obtained as a colourless solid; yield 86 mg (87%);
50.6, 138.6, 134.1, 133.9, 130.1, 129.3, 128.8, 128.6, m.p 166-167 ºC; IR (neat): 3447, 2958, 2857, 1659, 1601
C
This was prepared from the amide 6i and the product was
NMR (100 MHz, CDCl
3
1
1
3
-
1 1
27.3, 125.5, 120.8, 120.5, 117.4, 109.1, 77.5, 35.3, 34.8, cm ; H NMR (400 MHz,CDCl
1.3, 31.2; HRMS (TOF MS ES+): m/z [M + H]+ calcd. = 9.2, 4.8 Hz), 7.62-7.59 (2H, m), 7.50 (1H, dt, J = 6, 8 Hz),
440.2590; found 440.2592. 7.45-7.42 (3H, m), 7.30 (1H, dq, J = 2.4, 8 Hz), 7.24-7.19
2H, m), 7.16 (1H, d, J = 2.4 Hz), 7.14 (1H, dd, J = 9.2, 2.0
3
): δ (ppm) 7.65 (1H, dd, J
for C30
H
34NO
2
(
1
3
Hz), 6.78 (1H, s), 5.32 (2H, s); C NMR (100 MHz,
1
2
-(Benzyloxy)-7-chloro-4-(4-chlorophenyl)quinolin-
(1H)-one (7e):
CDCl
3
): δ (ppm) 164.0 (d, JC,F = 250 Hz), 159.5 (d, JC,F
44 Hz), 157.0, 148.5, 138.2, 135.4, 133.6, 130.7 (d, J C,F
=
=
2
7
Hz), 129.9, 129.4, 128.8, 125.5, 123.6, 120.2 (d, J C,F = 9
This was prepared from the amide 6e and the product 7e
Hz), 119.3 (d, JC,F = 20 Hz), 116.2 (d, JC,F = 20 Hz), 115.9
was obtained as a colourless solid; yield 93 mg (94%); m.p
(
d, JC,F = 23 Hz), 114.5, 112.6 (d, JC,F = 24 Hz), 77.6 ;
Elemental analyses: calcd for C22 NO ; C, 72.72; H,
.16; N, 3.85; obsd, C, 72.93 ; H, 4.24; N, 3.69.
-
1
1
99-200 ºC; IR (neat): 3418, 2921, 2852, 1663, 1587 cm ;
H
15
F
2
2
1
H NMR (400 MHz,CDCl
3
): δ (ppm) 7.59 (1H, d, J =
.6Hz), 7.56-7.54 (2H, m), 7.42 (2H, d, J = 8.4Hz), 7.39-
.26 (6H, m), 7.06 (1H, dd, J = 8.4,1.6Hz), 6.62 (1H, s),
4
1
7
5
1
1
7
6
13
1-(Benzyloxy)-8-methoxy-4-(3-methoxyphenyl)quinolin-
(1H)-one (7j):
3
.23 (2H, s) ; C NMR (100 MHz, CDCl ) : δ (ppm) 157.4,
2
49.1, 139.5, 137.7, 135.4, 134.6, 133.5, 130.1, 130.0,
29.5, 129.1, 128.8, 128.4, 123.2, 122.1, 117.7, 112.7,
7.6 . Elemental analyses: calcd for C22
H
2
15Cl NO
2
; C, This was prepared from the amide 6j and the product 7j
6.68; H, 3.82; N, 3.53; obsd. C, 66.87; H, 4.04; N, 3.72.
was obtained as a pale yellow solid; yield 87 mg (88%);
-
1
m.p 152-153 ºC; IR (neat): 3402, 2923, 1657, 1593, cm ;
1
H NMR (400 MHz,CDCl
3
): δ (ppm) 7.64-7.62 (3H, m),
1
2
-(Benzyloxy)-7-fluoro-4-(4-fluorophenyl)quinolin-
(1H)-one (7f):
7
.44-7.04 (4H, m), 7.19 (1H, dd, J = 9.2, 2.8Hz), 7.03-7.01
(
3H, m), 6.97 (1H, t, J = 1.6 Hz), 6.75 (1H, s), 5.31 (2H, s),
13
3
3
.86 (3H, s), 3.73 (3H, s); C NMR (100 MHz, CDCl ): δ
This was prepared from the amide 6f and the product 7f
was obtained as a colourless solid; yield 94 mg (95%);
m.p 168-169 ºC; IR (neat): 3424, 2921, 1679, 1664, 1621
(
ppm) 159.7 (C), 157.2(C), 155.1(C), 149.9(C), 138.1(C),
1
1
1
5
33.9(C), 133.3(C), 129.9(CH), 129.8(CH), 129.3(CH),
28.7(CH), 122.6(CH), 121.1(CH), 120.4(C), 119.5(CH),
14.5(CH), 114.3(CH), 113.9(CH), 109.7(CH), 77.3(CH2),
5.7(CH3), 55.4(CH3); Elemental analyses: calcd for
-
1
1
3
cm ; H NMR (400 MHz,CDCl ): δ (ppm) 7.64-7.61 (2H,
m), 7.49-7.35 (7H, m), 7.24-7.19 (2H, m), 6.91 (1H, dt, J =
1
3
2
.4, 8Hz), 6.66 (1H, s), 5.31 (2H, s) ; C NMR (100 MHz,
CDCl ): δ (ppm) 165.1 (d, J C,F = 36 Hz), 162.6 (d, JC,F =
3 Hz), 157.7, 149.4, 140.4, 140.3, 133.5, 132.5, 130.7 (d,
C
24
H
21NO
4
; C, 74.40; H, 5.46; N, 3.62; obsd, C, 74.61 ; H,
3
5
.37; N, 3.78.
3
JC,F = 8 Hz), 130.0, 129.7 (d, J C,F = 10 Hz), 129.5, 128.8,
1
-(Benzyloxy)-4-p-tolylquinolin-2(1H)-one (7k):
1
9
C
21.0, 116.0 (d, JC,F = 21 Hz) , 111.1 (d, J C,F = 24 Hz),
9.7 ( d, J C,F = 28 Hz), 77.5 ; Elemental analyses: calcd for
22
H
15
F
2
NO
2
; C, 72.72; H, 4.16; N, 3.85; obsd, C, 72.88 ; This was prepared from the amide 6k and the product 7k
H, 4.07; N, 3.92.
was obtained as a colourless solid; yield 88 mg (89%); m.p
68-170 ºC; IR (neat): 3425, 2920, 2852, 1660, 1593, 1510
1
-
1 1
cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 7.64 (1H, d, J =
.4Hz), 7.59-7.57 (2H, m), 7.52-7.48 (2H, m), 7.39-7.34
1
(
-(Benzyloxy)-8-methyl-4-m-tolylquinolin-2(1H)-one
7g):
8
(
3H, m), 7.28-7.23 (4H, m), 7.11 (1H, dt, J = 0.8, 7.6 Hz),
13
6
.66 (1H, s), 5.24 (2H, s), 2.38 (3H, s); C NMR (100
): δ (ppm) 157.7, 150.8, 138.9, 138.7, 133.9,
This was prepared from the amide 6g and the product 7g
MHz, CDCl
3
was obtained as a colourless viscous liquid; yield 90 mg
1
1
33.8, 130.9, 129.9, 129.3, 129.2, 128.8, 128.7, 127.6,
-
1
1
(
91%); IR (neat): 3428, 2881, 1645, 1589 cm ; H NMR
22.5, 121.9, 119.7, 112.5, 21.3; HRMS (TOF MS ES+):
8
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
m/z [M+H]+ calcd. for C23
H
20NO
2
342.1494; found
C
22
H
16ClNO
2
; C, 73.03; H, 4.46; N, 3.87; obsd, C, 72.94; H,
3
42.1491.
4.57; N, 3.76.
1
-(Benzyloxy)-7-methyl-4-phenylquinolin-2(1H)-one
1-Methoxy-4-phenylquinolin-2(1H)-one (7q):
(
7l):
This was prepared from the acid 6q and the product 7q
This was prepared from the amide 6l and the product 7l was obtained as a colourless solid; yield 92 mg (93%).
[
17a]
was obtained as a colourless solid; yield 92 mg (93%); m.p M.p. 96-97 ºC (Lit.
97-98 ºC). IR (neat): 3383, 2931,
66-167 ºC; IR (neat): 3426, 2919, 2851, 1655, 1613 cm ; 1661, 1589 cm . NMR (400 MHz,CDCl ): δ (ppm) 7.62
): δ (ppm) 7.69-7.67 (2H, m), (1H, d, J = 8.4Hz), 7.54 (1H, t, J = 8Hz), 7.47 (1H, d, J =
.54-7.50 (4H, m), 7.49-7.44 (6H, m), 7.01(1H, d, J = 8Hz), 7.42-7.40 (3H, m), 7.33-7.32 (2H, m), 7.12 (1H, t, J
-
1
-1
1
3
1
H NMR (400 MHz,CDCl
3
7
8
1
3
13
.4Hz), 6.70 (1H, s), 5.33 (2H, s), 2.50 (3H, s) ; C NMR = 7.6Hz), 6.62 (1H, s), 4.07 (3H, s); C NMR (100 MHz,
(
3 3
100 MHz, CDCl ): δ (ppm) 157.9, 150.7, 141.9, 138.7, CDCl ): δ (ppm) 157.3, 150.7, 138.1, 136.6, 131.2, 128.9,
1
1
36.9, 134.0, 129.9, 129.2, 128.9, 128.8, 128.7, 128.6, 128.8, 128.7, 127,7, 122.7, 121.9, 119.7, 112.1, 62.9.
27.3, 124.0, 120.8, 117.4, 112.5, 77.4, 22.0 ; Elemental
analyses: calcd for C23
H
19NO
2
; C, 80.92; H, 5.61; N, 4.10;
obsd, C, 80.79 ; H, 5.74; N, 4.03.
Acknowledgements
1
-(Benzyloxy)-4-(4-methoxyphenyl)quinolin-2(1H)-one
(
7m):
We are thankful to DST, New Delhi, for funds
EMR/2017/001336), and CSIR (New Delhi) for fellowship to one
(
of us (SG).
This was prepared from the amide 6m and the product 7m
was obtained as a colourless solid; yield 89 mg (90%); m.p
-
1 1
1
50-151 ºC; IR (neat): 3415, 2921, 1621, 1338, cm ; H
NMR (400 MHz, CDCl
3
): δ (ppm) 7.63 (1H, d, J = 8.4Hz),
.58-7.48 (4H, m), 7.39-7.38 (3H, m),7.33-7.30 (2H, m),
.12 (1H, t, J = 7.2Hz), 6.96 (2H, d, J = 8.4Hz), 6.65 (1H,
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7
1
3
s), 5.24 (2H, s), 3.82 (3H, s); C NMR (100 MHz, [1] a) K. M. Boy, J. M. Guernon, S. -Y. Sit, K. Xie, P.
CDCl
3
) :δ (ppm) 160.2, 157.7, 150.5, 138.7, 133.9, 130.9,
30.2, 129.9, 129.2, 129.0, 128.7, 127.5, 122.5, 121.8,
19.8, 114.1(two signals overlapped), 112.5, 55.4; HRMS
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1
(
TOF MS ES+): m/z [M + H]+ calcd. for C23
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H
20NO
3
3
1
-(Benzyloxy)-7-methoxy-4-phenylquinolin-2(1H)-one
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2, 1779-1783; c) W. W. K. R. Medereski M. Osswald,
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-
1
m.p 147-148 ºC; IR (neat): 3439, 2953, 1645, 1510, cm .
1
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H NMR (400 MHz,CDCl ): δ (ppm) 7.55-7.54 (2H, m),
7
6
.44-7.41 (3H, m), 7.38-7.32 (6H, m), 7.03 (1H, d, J = 2.4),
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095–1102.
13
(
3
3H, s) ; C NMR (100 MHz, CDCl ): δ (ppm) 162.1,
1
1
5
5
58.2, 150.7, 140.5, 137.0, 134.1, 130.2, 129.9, 129.3,
29.0, 128.8, 128.7, 128.6, 118.8, 113.5, 111.5, 95.6, 77.5,
5.6. Elemental analyses: calcd for C23 ; C, 77.29; H,
.36; N, 3.92; obsd, C, 77.47; H, 5.45; N, 4.03.
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-(Benzyloxy)-4-(4-chlorophenyl)quinolin-2(1H)-one
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1
1
1
89-190 ºC; IR (neat): 3418, 2857, 1648, 1589 cm ; H
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.57-7.49 (3H, m), 7.43-7.41 (3H, m), 7.37-7.35 (3H, m),
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7
1
3
s), 5.23 (2H, s). C NMR (100 MHz, CDCl
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1
1
57.4, 149.5, 138.7, 135.1, 135.0, 133.8, 131.3, 130.2,
29.9, 129.3, 129.0, 128.7, 127.2, 122.8, 122.2, 119.3,
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17ClNO
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84-186 ºC; IR (neat): 3447, 2957, 1654, 1545 cm ; H
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(
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1
1
30.0, 129.9, 129.5, 129.1, 129.0, 128.8, 127.2, 123.1,
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Advanced Synthesis & Catalysis
10.1002/adsc.201900530
FULL PAPER
Metal-Free Synthesis of 4-Aryl-2-quinolone
Derivatives by Iodine-Mediated Intramolecular C-
H Amidation
R2
O
R2
O
I / H O /NaOAC,
2
2
2
Toluene,110 0C, 24 h,
R1
R1
HN
N
Adv. Synth. Catal. Year, Volume, Page – Page
OBn
OBn
1
2
R ,R = methyl, t-butyl,
OMe, Cl, F,
1
7 examples
86-95%
Subhankar Ghosh and Shital K Chattopadhyay*
1
2
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