Alkylation of α-Oxo-Compounds through C(sp3)-H Functionalization of 2-Methyl Quinolines Under Catalyst- and Solvent-Free Conditions

Article abstract of DOI:10.1002/ejoc.202000511

Highly facile approach of chemoselective alkylation of α-oxo compounds such as α-keto amides, α-keto esters, isatins, and cyclic-α-diketones is developed through C(sp³)-H functionalization of 2-methyl quinolines under solvent and catalyst-free

Full text of DOI:10.1002/ejoc.202000511

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Alkylation of a -Oxo-compounds through C(sp3)-H
Functionalization of 2-Methyl Quinolines Under Catalyst- and
Solvent-Free Conditions
Authors: Yadavalli Subbarao, Dandugula Snehalatha, Nagaraju
Devunuri, Abdulrahman Almansour, Natarajan Arumugam,
and Srinivasarao Yaragorla
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000511
Link to VoR: https://doi.org/10.1002/ejoc.202000511
01/2020

10.1002/ejoc.202000511
European Journal of Organic Chemistry
Alkylation of -Oxo-compounds through C(sp3)-H
Functionalization of 2-Methyl Quinolines Under Catalyst- and
Solvent-Free Conditions
Yadavalli Subba Rao,a,b Dandugula Sneha Latha,a Nagaraju Devunuri,b Abdulrahman I. Almansour,c
Natarajan Arumugam,c and Srinivasarao Yaragorla*a
the core structure of fluorenol(1st row) and 9,9-diaryl-9H-fluorenol (2nd row).
Abstract: Highly facile approach of chemoselective alkylation of
-oxo compounds such as α-keto amides, α-keto esters, isatins,
and cyclic--diketones is developed through C(sp3)-H
Therefore, integrating these two structural motifs becomes an
interesting topic to synthetic and medicinal chemists, anticipating
functionalization of 2-methyl quinolines under solvent and
the better activity.9-18 Several synthetic efforts have been
catalyst-free conditions. Further, we complemented the efficacy
accomplished for the nucleophilic addition of 2-methyl quinolines
of this green synthetic protocol by demonstrating the broad
to α-keto compounds as shown in Scheme 1. For example,
substrate diversity, gram-scale synthesis and new synthetic
hydroxylation of α-keto amides with 2-methyl quinolines is
transformations of the obtained products.
reported by heating the reaction mixture with zinc triflate as the
catalyst in tert-butanol at 70-100 oC for 14-72 h, the products are
isolated in the range of 25-95%.9 Later the same group
Introduction
developed binaphthyl supported Pd- nanoparticles (Pd-BNPs)
catalyzed nucleophilic addition of 2-methyl quinolines to α-keto
α-Keto compounds such as α-keto amides, α-keto esters and
esters and α-keto amides by heating the reaction mixture at 70
oC in PEG-200 for 24-48 h.10 Another report on Iron-catalyzed
their derivatives are essential building blocks of natural
products,1 biologically important molecules possessing antiviral,
addition of 2-methyl aza-arenes to α-ketoesters was reported by
anti-HIV, antitumor, anti-inflammatory, antibacterial activities2
o
refluxing in dioxane at 120-130 C for 24 h, and the yields are
and part of drugs and drug candidates.3 They are also excellent
inhibitors of hydrolytic enzymes such as serine and cysteine
proteases, by the formation of a stable tetrahedral adduct
between the α-keto groups and nucleophilic residues at the
enzyme active sites.4 The reduction or the alkylation of the α-
keto group to corresponding -hydroxy amides or esters is an
important strategy due to the biological and catalytic importance
of these compounds.5 On the other hand, catalytic C(sp3)-H
functionalization of 2-methyl quinolines has emerged as a
promising synthetic strategy for making quinoline based new
chemical entities due to the importance of quinoline structure in
natural products,6 and pharmaceuticals (Figure 1).7,8
ranging from 26- 90%.11 Interestingly, a good number of catalytic
methods are available for the alkylation of isatins, such as
refluxing with triflic acid in dioxane at 120 oC for 48 h (yields:31-
85%);12 heating with Yb(OTf)3 at 140 oC (yields:11-82%);13
refluxing with silica-supported dodeca-tungstophoric acid (DTP)
in DMF at 120 oC for 8 h (yields: 43-94%);14 refluxing with
Fe(OAc)2 in dioxane at 120 oC for 24 h (yields: 35-90%);11
microwave irradiation at 100 C with TBAF;15 heating at 120 C
in 1,4-dioxane with H3O40PW12.xH2O/Al2O as the catalyst for 24
h (Yields: 65-92%);16 and by refluxing with -cyclodextrin in
water at 80 oC.17 In continuation of these reports, the addition of
2-methyl azaarenes to aceanaphthylene-1,2-diones to get cyclic-
α-hydroxy ketone is achieved by refluxing with -cyclodextrin in
the water at 80 oC.17a At a glance, all these methods involve the
usage of catalysts, high boiling solvents, base, high
temperatures (up to 140 oC) and long reaction times for the
hydroxylation of α-oxo compounds with 2-methyl quinolines.
o
o
OMe
OMe
OMe
MeO
OH
N
O
O
N
O
OMe
N
N
Me
OMe
Skimmianine
N
Chimanine A
Quinine
Graveolinine
Me
COOH
Owing to our interest in the development of green synthetic
methods for C(sp3)-H functionalization of 2-methyl quinolines,18
we have developed solvent-free functionalization,18a using water
as the solvent18b and catalyst-free approaches.18c With this
MeO
CF3
N
Me
OH
S
H2N
Cl
N
N
OMe
H
expertise, we anticipated developing
a
green synthetic
Tafenoquine(antimalarial)
Montelukast(antiasthmatic)
procedure to functionalize a large variety of α-oxo-compounds
with 2-methyl quinolines in an aqueous medium with Ca(II) salts
as sustainable catalysts.19 Excitingly, these experiments lead us
to discover a solvent-and catalyst-free C(sp3)-H functionalization
of 2-methyl quinolines by the nucleophilic addition to a variety of
α-keto compounds (Scheme 1).
Figure 1. Representative examples of biologically active natural products with
[a] Mr.Y. Subbarao, Ms. D. Sneha Latha & Prof. Srinivasarao
Yaragorla (corresponding author), School of Chemistry, University
of
Hyderabad, 5000046, Telangana State, India.
E-mail: srinivas.yaragorla@uohyd.ac.in
Home page: http://chemistry.uohyd.ac.in/ysr.htm
[b] Mr. Y. Subbarao, Dr. D. Nagaraju, Division of Chemistry,
Vignan's Foundation for Science, Technology and Research
(VFSTR), Guntur - 522 213, India
[c] Dr. A.I.Almansour, Dr. N. Arumugam, Department of Chemistry,
College of Science, King Saud University, P.O. Box 2455, Riyadh
11451, Saudi Arabia
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
available literature, we realized that most of the C(sp3)-H
functionalization reactions utilized three equivalents of
quinaldine,9-17 therefore, we repeated the conditions of entry-2,
with three equivalents of 1a and one equivalent of 2a, as
anticipated the product yield increased to 71%. Though the
reaction showed an appreciable increase in the reaction yield by
using three equivalents of 1a, it is economically not viable. To
check the need for excess substrate, we performed the reaction
with two equivalents of 1a and found that the reaction gave a
similar yield (entry 3). So, we considered two equivalents of 1a
and one equivalent of 2a as the appropriate combination
because of the use of 1.5 equiv. of 1a gave poor yield (entry 4).
With this improvement of minimum usage of 1a, we planned to
check the feasibility of this reaction under neat conditions.
Accordingly, a mixture of 1a (0.88 mmol), 2a (0.44 mmol) and
Ca(OTf)2/nBu4NPF6 (10/10 mol%) was heated at 120 oC and
noticed that the reaction completed in 8 h to yield 70% of 3a
(entry 5). Encouraged by the progress of the reaction under
solvent-free condition, we then planned to check the role of
additive and catalyst by performing the reaction in the absence
of additive (entry 6) and the absence of a catalyst (entry 7);
these results indicate that the reaction yield is unchanged in
their absence. This observation prompted us to examine the
reaction in the absence of any catalyst. To our excitement, the
reaction still gave the product 3a with the same yield when we
heated the mixture of 1a and 2a directly at 120 oC (entry 8).
O
H
HO Ar
O
H
R
+
N
R
N
Ar
Ar1
N
Ar1
N
CH3
O
method-2.ref-9
method-1.ref-10
Zn(OTf)2 (15-20 mol%)
tBuOH, 70-100 oC, 14-72 h
Pd-BNP (2 mol%)
PEG 200, 70 oC, 24-48 h
O
O
R2
HO
N
R
R
R1
O
+
N
N
CH3
N
R2
method-4.ref-10
method-5.ref-12
method-3.ref-15
R1
TfOH (10 mol%)
dioxane, 120 oC, 48 h
Pd-BNP (2 mol%)
PEG 200, 70 oC, 15-48 h
TBAF.3 H2O (10 mol%)
MW, H2O 100 oC, 5 min
method-8.ref-11
method-7.ref-13
method-6.ref-14
Fe(OAc)2 (10 mol%)
Yb(OTf)3 (0.02 mmol)
THF, 140 oC, 48 h
DTP/SiO2 (20 mol%)
DMF, 120 oC, 8 h
1,4-dioxane, 120 o
N2, 24-48 h
C
method-9.ref-16
H3O40PW12xH2O/Al2O3(0.03 equiv)
dioxane, 120 oC, 24 h
O
O
OH
O
-cyclodextrin
N
water, 80 oC17
R
R
+
N
N
CH3
R
Fe(OAc)2 (5 mol%)11
HO CF3
O
O
R
OEt
OEt
+
F3C
N
1,4-dioxane,
CH3
120-130 oC, 24 h
O
only 2 examples
Encouraged
by
this
catalyst-free
and
solvent-free
O
HO
R
no-report
functionalization reaction, we aimed to check the temperature
R
OR1
OR1
R
R
+
o
R
N
effect and hence performed the reaction at 140 C (entry 9) and
N
N
CH3
O
O
160 oC (entry 10).
HO
R
HO
R
This Work
R
H
N
OR1
R1
No Catalyst
No Solvent
140 oC, short time
N
Table 1. Optimization of the reaction conditions for the
functionalization of 1a, 2a.[a]
O
O
O
O
H
OR1
N
R
R
R1
O
O
R
O
O
N
CH3
O
R1
O
O
OH
O
N
R2
R2
N
Entry
1d
Catalyst (mol%)
Solvent
H2O
H2O
H2O
H2O
-
Temperatu
reb
Time
(h)
24
Yield
(%)c
32
HO
N
R
N
100 oC
R
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2 (10)
Bu4NPF6 (10)
-
R1
2d
120 oC
120 oC
120 oC
120 oC
24
24
24
8
46
71
54
70
Scheme 1. Synthetic strategies from in situ generated homo-
allenylketone(previous and current)
3e
4f
Results and Discussion
5e
We have selected 7-chloro-2-methyl quinoline (1a) and 2-oxo-
N,2-diphenylacetamide (2a) as the reactants to search for the
optimum green reaction conditions to obtain 3-(7-chloroquinolin-
2-yl)-2-hydroxy-N,2-diphenylpropanamide (3a). Owing to the
large abundance, less toxic nature, moisture tolerance, less
expensive and biodegradable nature of calcium, calcium-based
catalysts such as Ca(OTf)2 and Ca(NTf)2 become an alternative
and sustainable catalysts for various synthetic transformations.19
Therefore, we commenced by refluxing a mixture of 1a (0.44
mmol), 2a (0.44 mmol) and Ca(OTf)2/nBu4NPF6 (10/10 mol%) in
water for 24 h, delightfully the desired product 3a was obtained,
but in poor yield (entry1, Table 1). To increase the reaction yield,
we performed the reaction at 120 oC and noticed a slight
increase in the yield from 32 to 46% (entry 2). According to the
6e
-
-
-
-
-
120 oC
120 oC
120 oC
140 oC
160 oC
10
10
12
7
71
70
7e
8e
74
9e
-
-
g79
h72
10e
7
aReaction conditions; bOil bath temperature; cIoslated yields; d1a(1 equiv), 2a(1 equiv);
e1a(2 equiv), 2a(1 equiv); f1a(1.5 equiv), 2a(1 equiv); gOptimum condition;
hdecomposed after 7 h
o
The reaction yielded the best at 140 C in 7 h (79% of 3a), and
at 160 oC it started decomposing (though we could able to
isolate 72%). The usage of the elevated reaction temperature is
not a drawback in this reaction because, even in the previous
reports the reactions were refluxed at high temperatures along
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10.1002/ejoc.202000511
European Journal of Organic Chemistry
with a catalyst (and additives), solvents and of course with
excess quinaldine. Therefore, the best condition for the
synthesis of 3a (79%, 7 h) is to heat 1a (0.88 mmol) and 2a
(0.44 mmol) at 140 oC without any solvent and the catalyst (entry
9, Table 1).
Once the optimum reaction conditions for the functionalization of
7-chloroquinaldine (1a) with 2-oxo-N,2-diphenylacetamide (2a)
are developed, then we sought to check the generality of this
protocol. Accordingly we have treated a variety of 2-methyl
azaarenes such as 2-methylquinoline (1b), 2-methylquinoxaline
(1c), (2-methyl-4-phenylquinolin-3-yl)(phenyl)methanone (1d), 1-
(2-methyl-4-phenylquinolin-3-yl)ethan-1-one (1e), 1-(6-chloro-2-
methyl-4-phenylquinolin-3-yl)ethan-1-one (1f), and 1-(6-chloro-4-
(2-fluorophenyl)-2-methylquinolin-3-yl)ethan-1-one (1g) with 2a
and obtained corresponding 2-hydroxy amides 3b-3g in good
yields, however functionalization of 2-methylpyridine (1h) with
2a yielded 3h in poor yield (Scheme 2). Next, we found that the
substitutions on α-keto amides were tolerated by this reaction
conditions in producing the corresponding products 3i-3o in
good yields (Scheme 2).
O
R1
R1
H
Ph
O
HO
H
N
140 oC, 7 h
N
X
X
+
Ph
N
N
CH3
O
R2
R2
3
2
1
N
N
HO Ph
O
HO Ph
O
H
H
N
N
X
N
3c (65%)
X=Cl; 3a (79%)
X=H; 3b (78%)
Ph
N
e
M
Ph
O
O
10 mol%
C
h
P
140 oC, 7 h
Ca(OTf)2
O
O
Ph
C
H
H
Ph
N
H
H
H
H
D
D
N
N
N
O
D2O, 100 oC, 24 h
N
H
N
O
H
D
O
1b
3e (70%)
1i (91%)
Ph
3d (63%)
O
2a
10 mol% Ca(OTf)2
D2O, 100 oC, 12 h
F
e
e
M
O
O
M
Cl
O
C
C
Cl
Ph OH
Ph
Ph
O
H
N
H
H
H
N
H
N
N
N
N
D
N
O
D
D
O
H
O
H
1j (89%)
3f (72%)
3g (45%)
3p (45%)
O
H
N
Ph OH
H
HO Ph
O
Ph
H
N
N
HO Ph
H
N
N
O
N
2a
N
D H
O
140 oC, 7 h
O
3q (51%)
3h (36 %)
3o (52%)
Scheme 3. C(sp3)-D/H functionalization
HO Ph
HO Ph
O
H
H
N
N
The exclusive formation of compounds 3d-3g indicates the
chemoselectivity of the protocol (functionalization of methyl
ketone versus 2-methyl quinoline). The structural conformation
of the compound 3d was supplemented with the single crystal x-
ray without any ambiguity (Figure 2).20 Later, 2-methyl quinoline
(1b) was deuterated by refluxing in D2O with Ca(OTf)2 to get fully
deuterated compound 1i in 91% yield, and the deuterated 2-
methyl quinoline (1i) was subjected to C(sp3)-D functionalization
with -keto amide 2a at 140 oC under solvent & catalyst-free
conditions (Scheme 3). As expected, the reaction yielded the
product 3p in 45% yield after 7 h (the change in the yield can be
understood based on the strength of C-D bond versus C-H
bond). We were also able to isolate the mono-deuterated
quinaldine (1j) by stopping calcium-catalyzed deuteration
reaction after 12 h, and then subjected to functionalization by
heating with 2a at 140 oC to obtain 3q in 51% yield. Interestingly
this also become the first calcium-catalyzed deuteration of 2-
methyl quinoline.21
N
N
O
Me
Me
Br
3i (75%)
3l (80%)
HO Ph
O
HO Ph
O
H
N
H
N
Cl
N
Cl
N
Br
3m (70%)
3j (69%)
Ph
N
Ph
e
e
M
O
O
M
O
O
C
C
Ph
Ph
H
H
H
H
N
N
N
O
O
Br
Me
3n (68%)
3k (72%)
Scheme 2. Substrate scope of
functionalization
-keto amides
.
Figure 2. Single crystal X-ray structure of compound 3d
(CCDC: 1985211)
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10.1002/ejoc.202000511
European Journal of Organic Chemistry
R
R
R
N
R1
R1
R
N
R1
HO
O
140 oC, 7 h
O
O
R1
OR3
Ph
O
140 oC,1-2 h
+
OR3
Ph
O
H
N
X
N
CH3
N
+
O
X
R4
O
CH3
R5
4
1
5
N
R4
1
6
7
R5
HO Ph
O
HO Ph
O
O
Me
O
Me
N
Cl
N
O
O
N H
O
H
N
H
N
5b (79%)
5a (75 %)
O
O
O
NH
N
N
Me
Ph
HO Ph
e
M
O
O
O
Me
C
H
Cl
N
Ph
7a (92%)
7b (73%)
O
Me
O
Me
7c (92%)
N
5d (72%)
O
5c (67 %)
N
O
H
O
H
N
N
O
H
N
O
HO Ph
O
O
O
HO Ph
O
Ph
O
Me
Me
N
NH
N
NH
NH
Me
O
O
5f (64%)
Cl
5e (75%)
7d (65%)
7f (91%)
7g (87%)
Ph
N
e
M
O
Ph
C
Me
Ph OH
O
H
Me
O
O
O
X
N
COMe
COMe
Me
O
Me
X=Cl; 5g (64%)
X=H; 5h (59%)
5i (60%)
O
H
O
H
N
N
O
O
NH
N
Scheme 4. Functionalization of 2-methyl quinolines with -keto
esters
7h (74%)
7e (92%)
Encouraged by this success, we are keen to extend this strategy
to the analogous compounds, α-keto esters. To the best of our
knowledge, there is a single report available for the addition of 2-
methyl quinoline to trifluoromethyl keto-esters by refluxing with
Scheme 5. Substrate scope of cyclic -keto amides (isatins)
functionalization.
o
iron acetate in dioxane at 120-130 C for 24 h, however, only
two examples were made in this report.11 So, we felt that it
would be useful to develop a new method for this less studied
transformation. At the same time, we were also very curious to
see, whether the catalyst and solvent-free approach will work on
these systems. Hence quinaldine (1a) was heated with ethyl 2-
oxo-2-phenylacetate (4a) at 140 oC; gratifyingly the reaction
yielded the desired product 5a in 75% yield in short reaction time
(Scheme 4). Further, we extended this reaction to different -
keto esters and 2-methyl quinolines to check the feasibility as on
other -keto esters. Using this method, we made a total of nine
compounds 5a-5i in good yields under the solvent-and catalyst-
free functionalization conditions. The exclusive chemoselectivity
was observed while synthesizing 5i. Interestingly, the
compounds 5g, 5h and 5i were isolated as an inseparable
mixture of 1:1 diastereomers, which was confirmed by the 1H
NMR spectra.
Figure 3. Single crystal X-ray structure of compound 7c
(CCDC:1982003)
Owing to the biological importance of oxindole derived
compounds,22 more than a half a dozen of catalytic methods
were developed for the alkylation of isatins with 2-methyl
quinolines through benzylic C-H functionalization,11-17 and all of
them were carried out at high temperatures using a catalyst and
solvents. Therefore, we were keen to extend our methodology to
these, as desired we heated quinaldine 1b with isatin 6a at 140
oC in neat condition. Delightfully this reaction gave a nearly
quantitative yield of 7a within an hour (Scheme 5). With this
excitement, we screened the reactivity of various quinolines with
isatins and concluded all of them exhibited excellent reactivity
with this green approach to produce 7a-7h in high yields within
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10.1002/ejoc.202000511
European Journal of Organic Chemistry
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
Preparation of deuterated quinaldine (1i & 1j): A mixture of 2-methyl
quinoline 1b (0.44 mmol), calcium triflate (10 mol %) and D2O (1 mL)
were taken in a round bottom flask and stirred at 100 C for 12 to 24 h.
After completion of the reaction (monitored by TLC), the obtained crude
product was purified by silica gel column chromatography (2-5 % EtOAc
in petroleum ether) and isolated the desired products 1i & 1j in 91% and
89% yields.
At a high temperature, two moles of quinolines will interact with
each other, in which the nitrogen atom behaves as a Bronsted
base and accepts the methyl protons to give the corresponding
enamine intermediate. If this step proceeds through eight-
membered transition state as depicted, then the two moles of
quinolines will produce two moles of reactive enamines.
However, this may not be exactly the case, but definitely one of
the quinolines acts as a base, and thus the required enamine
formation takes place. In the next step, the activated carbonyl
compound interacts with the enamine intermediate through a
six-membered transition state to furnish the desired compound.
o
General experimental procedure for the addition of 2-methyl
quinoline to α-keto esters: A mixture of 2-methyl azaarens 1 (1.12
mmol) and α-keto ester 4 (0.56 mmol) was heated directly at 140oC for 7
hours. After completion of the reaction (monitored by TLC), the obtained
crude product was purified by silica gel column chromatography (15-
20 % EtOAc in petroleum ether) and isolated the desired products 5a-5i.
General experimental procedure for the addition of 2-methyl
quinolines to isatins: A mixture of 2-methyl azaarens 1 (1.36 mmol)
and isatin 6 (0.68 mmol) was heated directly at 140 oC for 1-2 hours.
After completion of the reaction (monitored by TLC), the obtained crude
product was purified by silica gel column chromatography (40-50 %
EtOAc in petroleum ether) and isolated the desired products 7a-7h.
General experimental procedure for the addition of 2-methyl
quinolines to acenaphthaquinone: A mixture of 2-methyl quinolines 1
(1.09 mmol) and acenaphthoquinone 8 (0.55 mmol) was taken in a round
bottom flask and stirred at 140 oC under solvent-free conditions for 1 h.
After completion of the reaction (monitored by TLC), the obtained crude
product was purified by silica gel column chromatography (30-40 %
EtOAc in petroleum ether) and isolated the desired products 9a-9d.
Experimental procedure for the addition of 2-methyl quinoline to
phenylglyoxal: A mixture of phenylglyoxal monohydrate 10 (0.74 mmol)
O
H
R
H
H
N
N
-keto compound
N
H
H
enamine
H
H
O
HO R
o
and 2-methyl quinoline 1b (0.89 mmol) was heated at 140 C under the
N
R
N
solvent-free condition for 1.5 hours. After completion of the reaction
(monitored by TLC), the obtained crude product was purified by silica gel
column chromatography (15-20% EtOAc in petroleum ether) and isolated
the desired product 11 in 73% yield.
++
H
final product
Scheme 11. General reaction mechanism
Experimental procedure for the synthesis of 3-(7-chloroquinolin-2-
yl)-N,2-diphenylacrylamide (14): A mixture of 3a (0.24 mmol), calcium
triflate (0.02 mmol), Bu4NPF6 (0.02 mmol) and acetonitrile (2 mL), was
heated at 120 oC for 12 h. After completion of the reaction (monitored by
TLC), the obtained crude product was purified by silica gel column
chromatography (40% EtOAc in petroleum ether) and isolated the
desired product 14 in 82% yield.
Conclusion
In conclusion, we have developed a diversity-oriented, green
synthetic methodology for the functionalization of 2-methyl
quinolines with -oxo compounds under solvent and catalyst-
free conditions. We have demonstrated the generality of this
protocol by the functionalization of -keto amides, -keto esters,
isatins, and acenaphthoquinones with 2-methyl quinoline
Experimental procedure for the synthesis of 3-(quinolin-2-
ylmethylene)indolin-2-one (15): Methanesulfonic acid (20 mol%) was
added dropwise to the solution of 7a (0.52 mmol) in acetonitrile (1.5 mL)
under nitrogen atmosphere at 0 oC and the reaction mixture was slowly
allowed to attain room temperature. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with ice-cold
water and neutralized with NaHCO3 solution until effervescence
disappeared. The aqueous layer was extracted with CH2Cl2; the
combined organic layer was separated, dried over Na2SO4, evaporated
under reduced pressure and purified by column chromatography (40%
EtOAc in petroleum ether) to isolate the desired product 15 in 89% yield.
Experimental procedure for the synthesis of N-(2-oxo-3-(quinolin-2-
ylmethyl)indolin-3-yl)acetamide (16): To a mixture of tert-alcohol 7a in
acetonitrile (2 mL), triflic acid (2 mL) was added dropwise under nitrogen
atmosphere at 0 oC, after the addition, the reaction mixture was slowly
allowed to attain room temperature. After completion of the reaction
(monitored by TLC), the reaction mixture was quenched with ice-cold
water and neutralized with aqueous NaHCO3 solution. The aqueous layer
was extracted with CH2Cl2, and the combined organic layer was
separated, dried over Na2SO4 and evaporated under reduced pressure.
The crude product was purified by column chromatography (80% EtOAc
in petroleum ether) to isolate the desired amide 16 in 51% yield.
Experimental procedure for the synthesis of 17 and 18: To a solution
of alcohol 9a in acetonitrile (2 mL), triflic acid ( 2 mL) was added
dropwise under nitrogen atmosphere at 0 oC, and after the addition of the
triflic acid, the reaction mixture was allowed to attain room temperature.
After completion of the reaction (monitored by TLC), the reaction mixture
was quenched with ice-cold water and neutralized with aqueous NaHCO3
solution. The aqueous layer was extracted with CH2Cl2, and the
combined organic layer was separated, dried over Na2SO4 and
evaporated under reduced pressure. The crude product was purified by
column chromatography (30-40% EtOAc in petroleum ether) and isolated
the desired products 17 & 18 in 34% and 38% yields.
derivatives.
Synthetic
transformations,
gram
scale
demonstration (5.36 g), shorter reaction times indicate the scope
and sustainable nature of this reaction. Despite the development
of a novel strategy, the products formed belongs to the
privileged class of molecules hence may exhibit important
biological properties.
Experimental Section
General information: Unless otherwise noted, all reagents were used as
received from commercial suppliers. Ca(OTf)2 and Bu4NPF6 were
obtained from Sigma-Aldrich and used without further purification.
Reactions were performed in flame-dried or oven-dried glassware with
magnetic stirring. Reactions were monitored using thin-layer
chromatography (TLC) with aluminium sheets silica gel 60 F254 from
Merck. TLC plates were visualized with UV light (254 nm), iodine
treatment. Column chromatography was carried out using silica gel 60-
120 mesh as the stationary phase. NMR spectra were recorded at 500
MHz and 400 MHz (H) and 125 MHz and 100 MHz (C), respectively on
Avance Bruker spectrometer. Chemical shifts (δ) are reported in ppm,
using the residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 77.0
ppm) as an internal standard, and coupling constants (J) are given in Hz.
Melting points were measured with LABINDIA mepa melting apparatus.
General experimental procedure for the functionalization of 2-
methyl quinolines with α-keto amides: A mixture of 2-methyl quinoline
1 (0.88 mmol) and α-keto amide 2 (0.44 mmol) was taken in a round
3-(7-chloroquinoline-2-yl)-2-hydroxy-N,2-diphenylpropanamide (3a).
the product was purified by column chromatography (60-120 silica
mesh,in 15% EtOAc/petroleum ether) and obtained as colorless solid
(Yield-79%); MP:141-143oC;1H NMR (400 MHz, CDCl3): δ= 8.90 (s,1H),
8.45(bs, 1H), 8.07 (d, J=8.4Hz,1H), 7.98 (d ,J = 2Hz, 1H),7.83-7.81(m,
2H),7.71(d, J=8.8 Hz, 1H),7.47-7.44 (m, 3H),7.38-7.34 (m, 3H), 7.29-
7.20(m, 3H), 7.03-6.99(m, 1H), 4.02(d, J = 15.2 Hz, 1H), 3.52(d, J= 15.2
o
bottom flask and heated at 140 C under solvent-free conditions for 7 h.
After completion of the reaction (monitored by TLC), the obtained crude
product was purified by silica gel column chromatography (60-120 mesh)
using 10-15 % EtOAc in petroleum ether as eluents to isolate the desired
products 3a-3q.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
Hz, 1H); 13CNMR(125 MHz, CDCl3): δ 172.2, 161.1, 146.7, 142.2, 137.7,
137.4, 136.1, 129.1, 130, 128.5, 127.8, 127.7, 127.4, 125.5, 125.2, 124.2,
123.2, 119.6, 80.1, 45.1 ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated
for C24H19ClN2O2H: 403.1213; found:403.1216; IR(film): νmax 3374, 3054,
1735, 1667, 1612, 1594, 1438, 1195, 1066 cm-1.
(d, J = 2.0 Hz, 1H), 6.78-6.72 (m, 3H), 5.34-5.31 (m, 1H), 5.29 (s, 1H),
4.01 (d, J = 18 Hz, 1H), 3.79 (d, J = 18 Hz, 1H), 1.52 (s, 3H); 13C
NMR(125 MHz, CDCl3): δ 172.9, 155.2, 145.3, 137.5, 137.1, 134.5,
133.1, 131.1, 131.0, 130.2, 129.9, 129.7, 129.0, 128.7, 128.6,127.4,
125.4, 125.1, 124.3, 124.2, 123.8, 123.6, 115.7, 115.6, 94.1, 81.2, 41.7,
23.6 ppm; LCMS 8040-ESI-001.lcd m/z [M+H]+ calculated for
C32H24ClFN2O3H: 539.1538; found: 539.400; HRMS(ESI-TOF): m/z
[M+H]+ calculated for C32H24ClFN2O3H: 539.1538; found: 539.1539 ; IR
(film): νmax 2920, 2851, 2160, 2022, 1693, 1613, 1477, 1201, 1079, 961
cm-1.
2-Hydroxy-N,2-diphenyl-3-(quinoline-2-yl)propanamide
(3b).
the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
1
78%); MP:154-156oC; H NMR (400 MHz, CDCl3): δ= 8.95 (s, 1H), 8.83
(s. 1H). 8.10 (d, J= 8.4 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.84 (d, J= 7.6
Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.71-7.67(m, 1H), 7.51(t, J = 7.2 Hz,
1H), 7.45(d, J= 8 Hz, 2H), 7.36(t, J = 8.4 Hz, 3H),7.28-7.26 (m, 1H),7.21(t,
J = 7.6 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 4.04 (d, J = 15.2 Hz, 1H), 3.52 (d,
J = 15.2 Hz, 1H); 13C NMR(100 MHz, CDCl3): δ 172.4. 159.9, 146.4,
142.3, 137.8, 137.6, 130.1, 128.9, 128.4, 128.3, 127.9, 127.7, 127.1,
126.6, 125.3, 124.2, 123.0, 119.6, 80.1, 44.9 ppm; HRMS(ESI-TOF): m/z
[M+H]+ calculated for C24H20N2O2H: 369.1603;found:369.1605; IR(film):
νmax3350, 2920, 2359, 1672, 1593, 1511, 1493, 1382, 1339, 1190, 1057,
477 cm-1.
2-Hydroxy-N,2-diphenyl-3-(pyridine-2-yl)propanamide
(3h).
the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as white solid (Yield-36%);
o
1
MP: 130-132 C; H NMR (400 MHz, CDCl3): δ = 8.94 (s, 1H), 8.50 (bs,
1H), 8.41 (d, J = 4 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 6.4 Hz,
1H), 7.47 (d, J = 8 Hz, 2H),7.34 (t,J = 7.2 Hz, 2H), 7.26-7.22 (m, 4H),
7.15 (t, J = 5.2 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 3.82 (d, J = 14.8 Hz, 1H),
3.37 (d, J = 15.2 Hz, 1H); 13C NMR(125 MHz, CDCl3): δ 172.3, 158.8,
147.8, 142.3, 137.8, 137.7, 129.0, 128.4, 127.7, 125.3, 125.0, 124.1,
122.2, 119.5, 79.9, 44.4 ppm;LCMS 8040-ESI-001.lcd m/z [M+H]+
calculated for C20H18N2O2H: 319.1447; found: 319.300;HRMS(ESI-TOF):
m/z [M+H]+ calculated for C20H18N2O2H: 319.1447; found: 319.1448; IR
(film): νmax3351, 2918, 1659, 1595, 1439, 1258, 1178 cm-1.
2-Hydroxy-N-,2-diphenyl-3-(quinoxalin-2-yl)propanamide(3c).
the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as pink solid (Yield-65%);
MP:278-280oC; 1H NMR (500 MHz, CDCl3): δ=8.81 (s, 2H), 8.08-8.06
(m,1H), 7.98-7.97 (m,1H), 7.82-7.80 (m,2H), 7.75-7.72(m,2H), 7.53 (s,
1H),7.45-7.43(m, 2H),7.38-7.35(m, 2H), 7.30-7.20(m, 3H), 7.03-
7.00(m,1H), 4.10(d, J = 15.5 Hz, 1H), 3.58(d, J = 16 Hz, 1H); 13CNMR
(125 MHz, CDCl3): δ171.7, 154.4. 146.7, 141.8, 141.6, 140.3,
2-hydroxy-2-phenyl-3-(quinolin-2-yl)-N-(p-tolyl)propanamide (3i). the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as pale pink solid (Yield-
75%); MP: 151-153 oC;1H NMR (500 MHz, CDCl3): δ = 8.89 (s, 1H), 8.76
(s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz 1H), 7.83 (d, J = 8 Hz,
2H), 7.76 (d, J = 8 Hz, 1H), 7.70-7.66 (m, 1H), 7.49 (t, J = 7 Hz, 1H),
7.36-7.24 (m, 6H), 7.0 (d, J = 8.5 Hz, 2H), 4.03 (d, J = 15 Hz, 1H), 3.52
(d, J = 15.5 Hz, 1H), 2.22 (s, 3H); 13CNMR(100 MHz, CDCl3): δ 172.2,
159.9, 146.3, 142.4, 137.6, 135.2, 133.7, 130.1, 129.4, 128.4, 128.3,
127.9, 127.7, 127.1, 126.5, 125.3, 123.0, 119.6, 80.1, 45.0, 20.9 ppm;
HRMS(ESI-TOF): m/z [M+Na]+ calculated for C25H22N2O2Na: 405.1579;
found: 405.1579 ; IR (film): νmax3351, 3025, 2159, 1976, 1670, 1515,
1448 cm-1.
137.5,130.7,
125.1,124.4,119.6,80.2,42.7
129.9,129.6,129.0,
ppm;
128.6,
HRMS(ESI-TOF):
128.3,
128.1,
m/z[M+H]+
calculated for C23H19N3O2H: 370.1556; found:370.1558; IR(film):
νmax3363, 2922, 2359, 1671, 1519, 1437, 1316, 1107, 947 cm-1.
3-(3-benzoyl-4-phenylquinolin-2-yl)-2-hydroxy-N,2-
diphenylpropanamide(3d). the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as colorless solid (Yield-63%); MP:194-196oC;1H NMR (400
MHz, CDCl3): δ=8.99(s, 1H), 8.85(s,1H), 8.03(d, J = 8.4Hz, 1H), 7.75-
7.71(m, 1H),7.67(d,J = 7.2 Hz, 2H),7.59-7.51 (m,5H),7.75-7.42(m,2H),
7.27-7.15 (m, 12H), 7.03 (t, J = 7.6 Hz, 1H), 3.87 (d, J = 17.2 Hz, 1H),
3.56 (d, J = 16.8 Hz 1H); 13C NMR(125 MHz, CDCl3): δ197.2, 172.4,
156.5, 146.9, 146.1, 142.0, 138.0, 137.3, 134.5, 133.7, 133.1, 130.8,
130.1, 129.7, 130.0, 128.6, 128.4(2), 128.3, 128.1, 127.7, 127.3, 126.6,
125.6, 125.3, 124.1, 119.6, 80.0, 42.8ppm;HRMS(ESI-TOF): m/z[M+Na]+
calculated for C37H28N2O3Na:571.1998;found: 571.1997; IR(film):
νmax3056, 2359, 2160, 1971, 1737, 1671, 1593, 1478, 1228 cm-1.
3-(3-acetyl-4-phenylquinolin-2-yl)-2-hydroxy-N,2-
diphenylpropanamide (3e). the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as colorless solid (Yield-70%); MP: 165-167oC;1H NMR
(400 MHz, CDCl3): δ= 8.96(s, 1H), 8.94(s. 1H). 8.01(d, J = 8.4 Hz, 1H),
7.80(d, J = 7.6 Hz, 2H), 7.72(t, J = 6.8 Hz, 1H), 7.64(d, J =8.4 Hz,1H),
7.55-7.43(m, 8H), 7.38(t, J = 7.2 Hz, 2H), 7.32-7.21(m, 3H), 7.02(t, J =
7.2 Hz, 1H), 3.92(d, J = 16.4 Hz, 1H), 3.37(d, J = 16.4 Hz, 1H), 2.11(s,
3H);13C NMR(125 MHz, CDCl3): δ205.6,172.7, 155.4, 145.8, 145.3,
142.2, 137.9, 135.4, 134.9, 130.8, 130.4, 129.9, 129.3, 129.2, 129.0,
128.6, 128.5, 128.4, 127.9, 127.3, 126.5, 125.5, 125.1, 124.2, 119.6,
80.5, 42.7, 32.4 ppm;DEPT-135 (100 MHz, CDCl3): δ 130.6, 130.3, 129.8,
129.2, 129.1, 128.9, 128.5, 128.4, 128.3, 127.8, 127.2, 126.4, 125.0,
124.1, 119.5, 42.6, 32.3 ppm. HRMS(ESI-TOF): m/z [M+H]+ calculated
for C32H26N2O3H: 487.2022; found: 487.2027; IR(film): νmax 3348, 3058,
2920, 1970, 1690, 1560, 1438, 1268 cm-1.
3-(3-acetyl-6-chloro-4-phenylquinolin-2-yl)-2-hydroxy-N,2-diphenyl
propanamide (3f): the product was purified by column chromatography
(60-120 silica mesh, in 15% EtOAc /petroleum ether) and obtained as
yellow solid (Yield-72%); MP:230-232oC;1H NMR (400 MHz, CDCl3): δ=
7.97(d, J = 8.8 Hz, 1H), 7.81-7.79(m, 2H), 7.60 (dd,J1=2.4 Hz, J2=9.2 Hz,
1H), 7.49-7.32(m,9H), 7.24(s, 1H), 7.10(d, J = 7.2 Hz, 1H), 6.94-6.91(m,
2H), 6.77(d, J = 8 Hz, 2H), 5.33(d, J = 7.6 Hz, 1H), 4.03(d, J = 18 Hz, 1H),
3.77(d, J = 18 Hz, 1H), 1.40(s, 3H);13C NMR(125 MHz, CDCl3): δ 172.8,
155.1, 145.2, 143.4, 137.5, 135.7, 134.5, 132.6, 130.9, 130.1, 130.0,
129.8, 129.6, 129.1, 128.9, 128.6, 128.5, 128.4, 128.3(2), 128.0, 127.8,
126.0, 125.4, 94.3, 81.2, 41.6, 25.6 ppm; HRMS(ESI-TOF): m/z
[M+NH3]+ calculated for C32H25ClN2O3NH3:537.1819; found: 537.1029;
IR(film): νmax 3053, 2922, 2852, 2359, 1716, 1596, 1570, 1493, 1366,
1190, 1076, 947 cm-1.
3-(7-chloroquinolin-2-yl)-2-hydroxy-2-phenyl-N-(p-tolyl)propanamide
(3j). the product was purified by column chromatography (60-120 silica
mesh, in 10% EtOAc /petroleum ether) and obtained as pale pink solid
(Yield-69%); MP: 120-122oC;1H NMR (400 MHz, CDCl3): δ= 8.84(s,
1H),8.38(s,1H),8.05(d, J = 8.4 Hz, 1H), 7.97(d, J = 2 Hz, 1H), 7.82(d, J =
7.6 Hz, 2H),7.69 (d,
J = 8.4 Hz,1H),7.45(dd, J1= 1.6Hz, J2 =
8.4Hz,1H),7.37-7.25(m,6H),7.01(d, J = 8.4 Hz, 2H),4.01(d, J = 15.6 Hz,
1H), 3.51(d, J = 15.6 Hz, 1H),2.23(s,3H); 13C NMR(125 MHz, CDCl3): δ
172.0, 161.2, 146.7, 142.3, 137.3, 136.1, 135.2, 133.8, 129.4, 129.1,
128.4, 127.8, 127.6, 127.3, 125.4, 125.2, 123.2, 119.6, 80.0, 45.2, 20.9
ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated for C25H21ClN2O2H:
417.1370; found: 417.1377; IR(film): νmax3357, 3202, 1666, 1613, 1401
cm-1.
3-(3-acetyl-4-phenylquinolin-2-yl)-2-hydroxy-2-phenyl-N-(p-
tolyl)propanamide (3k): the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as colorless solid (Yield-72%); MP:169-171oC;1H NMR (400
MHz, CDCl3): δ = 8.90-8.89 (d, J = 3.6 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H),
7.81 -7.79 (m, 2H), 7.73 -7.69 (m, 1H),7.64 -7.62 (m, 1H), 7.52 -7.25 (m,
11H),7.02 (m, J = 8.4 Hz, 2H), 3.91 (d, J = 16.4 Hz, 1H), 3.36 (d, J = 16.4
Hz, 1H), 2.23 (s, 3H), 2.11 (s, 3H);13C NMR(100 MHz, CDCl3): δ 205.5,
172.5, 155.5, 145.9, 145.3, 142.3, 135.4, 135.3, 134.9, 133.8, 130.7,
130.4, 129.9, 129.4, 129.2, 129.3, 128.6, 128.5, 128.4, 127.9, 127.3,
126.5 125.5, 125.2, 119.7, 80.5, 42.8, 32.4, 20.9 ppm; HRMS(ESI-TOF):
m/z [M+H]+ calculated for C33H28N2O3H: 501.2178; found: 501.2177;
IR(film): νmax 3345, 2921, 2851, 2160, 1685, 1520, 1404, 1315 cm-1.
N-(4-bromophenyl)-2-hydroxy-2-phenyl-3-(quinolin-2-
yl)propanamide (3l). the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as white solid (Yield-80%); MP:144-146oC; 1H NMR (400
MHz, CDCl3): δ= 8.95(s, 1H), 8.83(s, 1H), 8.09(d, J = 8.4 Hz, 1H), 7.96(d,
J = 8.4 Hz, 1H), 7.83-7.80(m, 2H), 7.77(d, J = 8.4 Hz, 1H),7.71-7.67(m,
1H), 7.52-7.48(m, 1H),7.37-7.26(m, 8H), 4.01(d, J = 15.6 Hz, 1H), 3.52(d,
J = 15.2 Hz, 1H);13C NMR(100 MHz, CDCl3): δ172.5, 159.7, 146.3, 142.1,
137.7, 136.9, 131.9, 130.2, 128.5, 128.2, 127.9, 127.8, 127.1, 126.6,
125.2, 122.9, 121.1, 116.7, 80.1, 44.9 ppm; HRMS(ESI-TOF): m/z
[M+H]+ calculated for C24H19BrN2O2H: 447.0708; found: 447.0709;
IR(film): νmax 3359, 2159, 2029, 1671, 1506, 1408, 1306 cm-1.
3-(3-acetyl-6-chloro-4-(2-fluorophenyl)quinolin-2-yl)-2-hydroxy-
N,2diphenyl propanamide (3g): the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as yellow semi-solid (Yield-45%); 1H NMR (500 MHz,
CDCl3): δ = 8.0 (d, J = 9 Hz, 1H), 7.80 (d, J = 7.5 Hz, 2H),7.63 (dd, , J1 =
2 Hz, J2 = 8.5 Hz, 1H), 7.49- 7.32 (m, 8H), 7.13 (t, J = 9.0 Hz, 1H), 6.91
N-(4-bromophenyl)-3-(7-chloroquinolin-2-yl)-2-hydroxy-2-phenyl
propanamide (3m): the product was purified by column chromatography
(60-120 silica mesh, in 15% EtOAc /petroleum ether) and obtained as
pale pink solid (Yield-70%); MP:162-164oC; 1H NMR (400 MHz, CDCl3):
δ= 8.90(s, 1H), 8.46(s, 1H), 8.07(d, J = 8.4 Hz, 1H), 7.97(d, J = 2 Hz, 1H),
7.81-7.79(m, 2H),7.71(d, J = 8.8 Hz, 1H),7.46(dd,J1=2 Hz, J2= 8.4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
Hz,1H ), 7.47-7.27(m, 8H), 3.99(d, J = 15.6 Hz, 1H), 3.52(d, J = 15.6 Hz,
1H); 13C NMR(100 MHz, CDCl3): δ 172.4, 161.0, 146.7, 141.9, 137.5,
136.8, 136.2, 131.9, 129.1, 128.5, 127.9, 127.7, 127.3, 125.5, 125.2,
123.2, 121.2, 116.8, 80.1, 45.0 ppm; HRMS(ESI-TOF): m/z [M+H]+
calculated for C24H18BrClN2O2H: 481.0318; found: 481.0318; IR(film):νmax
3394, 2359, 1685, 1590, 1511, 1410, 1303 cm-1.
3-(3-acetyl-4-phenylquinolin-2-yl)-N-(4-bromophenyl)-2-hydroxy-2-
phenyl propanamide (3n): the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as colorless solid (Yield-68%); MP: 118-120oC; 1H NMR
(400 MHz, CDCl3): δ= 8.96 (s, 1H), 8.92 (bs,1H), 7.78(d, J = 7.2 Hz, 1H),
7.74-7.65 (m, 3H), 7.63-7.54 (m,1H), 7.53-7.27(m,13H),3.9(d, J = 16.4
Hz,1H), 3.38(d, J = 16.8 Hz,1H),2.09(s,3H); 13C NMR(100 MHz, CDCl3):
δ172.8, 155.3, 145.8, 145.4, 141.9, 136.9, 135.3, 134.8, 131.9, 130.8,
130.4, 129.9, 129.3, 129.2,128.6, 128.3, 128.0, 127.4, 126.6, 125.5,
125.1,121.2, 116.7, 80.5, 42.7, 32.4 ppm; HRMS(ESI-TOF): m/z [M+H]+
calculated for C32H25BrN2O3H: 565.1127; found:565.1128; IR(film):
νmax3376, 3301, 3060, 2919, 2850, 2359, 2160, 1976, 1695, 1671, 1515
cm-1.
322.1443; found:322.1447; IR(film): νmax3181, 2983, 2360, 2339, 2159,
2027, 1974, 1728, 1596, 1428, 1178 cm-1.
Ethyl
3-(3-acetyl-4-phenylquinolin-2-yl)-2-hydroxy-2-
phenylpropanoate (5c). the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as white solid (Yield-67%); MP: 152-154oC; 1H NMR (400
MHz, CDCl3): δ= 8.04(d, J = 8 Hz, 1H), 7.77-7.71(m,3H) , 7.66(dd, J1 =
0.8Hz, J2=8.4 Hz, 1H), 7.54-7.30(m, 9H),7.12 (s,1H),4.20-4.10 (m,2H),
3.92(d, J =16.8 Hz, 1H), 3.38(d, J = 16.8Hz, 1H), 2.0 (s, 3H), 1.15 (t, J =
6.8 Hz, 3H);13C NMR(125 MHz, CDCl3): δ 205.1, 174.6, 154.8, 146.3,
145.0, 141.5, 135.1, 135.0,130.6, 130.2, 130.1, 129.3, 129.0, 128.8,
128.7, 128.5, 127.9, 127.3, 126.4, 125.3(2), 78.9, 61.6, 45.0, 32.2, 14.2
ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated for C28H25NO4H:440.1862;
found: 440.1862; IR(film): νmax3410, 2978, 2160, 1975, 1720, 1683, 1441,
1244 cm-1.
Isopropyl
3-(7-chloroquinolin-2-yl)-2-hydroxy-2-phenylpropanoate
(5d). the product was purified by column chromatography (60-120 silica
mesh, in 15% EtOAc /petroleum ether) and obtained as pale yellow solid
1
(Yield-72%); MP:103-105oC; H NMR (500 MHz, CDCl3): δ= 8.06 (d, J =
3-(7-chloroquinolin-2-yl)-2-hydroxy-N-(napthalen-1-yl)-2-
8.5 Hz, 1H), 7.99 (d, J = 2 Hz, 1H), 7.75-7.71(m, 3H), 7.47(dd, J1= 2 Hz,
J2= 9 Hz, 1H), 7.39(t, J = 7 Hz, 2H), 7.32-7.28(m, 2H), 6.70(s, 1H), 4.96-
4.91(m, 1H), 3.99(d, J = 15.5 Hz, 1H), 3.48(d, J = 15.5 Hz, 1H), 1.12(d, J
= 6.5 Hz, 3H), 1.03(d, J = 6.5 Hz, 3H); 13C NMR(125 MHz, CDCl3): δ
173.7, 160.7, 147.1, 141.5, 136.7, 135.8, 128.9, 128.4, 127.9, 127.6,
127.5 (2), 125.3, 122.8, 78.7, 69.3, 47.1, 21.7, 21.5 ppm; HRMS(ESI-
TOF): m/z [M+H]+ calculated for C21H20ClNO3H:370.1210; found:
370.1034; IR(film): νmax 3212, 2983, 1730, 1613, 1453 cm-1.
phenylpropanamide (3o): the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as dark brown solid (Yield-52%); MP: 141-143oC; H NMR
1
(400 MHz, CDCl3): δ= 9.45 (s, 1H), 8.66 (bs,1H), 8.07-8.04 (m,
2H),7.92(d, J = 7.6 Hz, 2H), 7.73(t, J = 6.8 Hz, 2H), 7.70 (d, J = 8.8 Hz,
1H),7.59(t, J = 9.2 Hz, 2H),7.46(dd, J1 = 2 Hz, J2 = 8.8 Hz, 1H),7.43-
7.30(m, 7H),4.11 (d, J = 15.2 Hz, 1H), 3.57 (d, J = 15.6 Hz, 1H); 13C
NMR(125 MHz, CDCl3): δ 172.8, 161.3, 146.7, 142.2,137.4, 136.2, 134.1,
132.1, 130.2, 129.2, 128.7, 128.5,127.9, 127.7, 127.3, 127.1, 126.2,
126.0, 125.7, 125.5, 125.3, 123.3, 120.6, 120.1, 80.6, 45.3 ppm;
HRMS(ESI-TOF): m/z [M+H]+ calculated for C28H21ClN2O2H: 453.1370;
found: 453.1377; IR(film): νmax 3395, 3053, 2359, 2340, 1682, 1495,
1343 cm-1.
3p: the product was purified by column chromatography (60-120 silica
mesh, in 10% EtOAc /petroleum ether) and obtained as white solid
(Yield-45%); MP: 220-222 oC; 1H NMR (500 MHz, CDCl3): δ = 8.95(s,
1H), 8.81 (s, 1H), 8.08 (d, J = 8 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.85 (d,
J = 7 Hz, 2H), 7.76 (d, J = 8 Hz, 1H), 7.70-7.67 (m, 1H), 7.51-7.44 (m,
3H), 7.37-7.34 (m, 3H), 7.28-7.19 (m, 3H), 7.00-6.98 (m, 1H); 13C
NMR(125 MHz, CDCl3): δ 172.4, 159.8, 146.3, 142.3, 137.7, 137.6,
130.1, 128.9, 128.4, 128.2, 127.9, 127.7, 127.1, 126.5, 125.2, 124.1,
122.9, 119.5, 80.0, 44.5ppm;HRMS(ESI-TOF): m/z [M+H]+ calculated for
C24H18D2N2O2H: 371.1730; found: 371.1712; IR (film): νmax 3351, 3145,
1671, 1515, 1313, 1179, 1072 cm-1.
Isopropyl 2-hydroxy-2-phenyl-3-(quinolin-2-yl)propanoate (5e). the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as white solid (Yield-75%);
MP:93-95oC; 1H NMR (400 MHz, CDCl3): δ= 8.10(d, J = 8.4 Hz, 1H ),
8.0(d, J = 8.4 Hz, 1H), 7.79-7.68(m, 4H), 7.54-7.28(m, 5H), 7.23 (s, 1H),
4.94-4.88(m, 1H), 4.0(d,J = 15.6 Hz, 1H), 3.48(d,J = 15.6 Hz, 1H), 1.10(d,
J = 6 Hz, 3H), 1.01(d, J = 6.4 Hz, 3H);13C NMR(125 MHz, CDCl3): δ
173.8, 159.6, 146.7, 141.8, 137.0, 130.0, 128.6, 128.4, 127.8, 127.7,
127.0, 126.4, 125.3, 122.5, 78.9, 69.1, 47.0, 21.7, 21.5 ppm; HRMS(ESI-
TOF): m/z [M+H]+ calculated for C21H21NO3H: 336.1600; found:
336.1603; IR(film): νmax 3206, 2981, 1723, 1596, 1428, 1199, 1060 cm-1.
Benzyl 2-hydroxy-2-phenyl-3-(quinolin-2-yl)propanoate (5f). the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
64%); MP:105-107oC; 1H NMR (400 MHz, CDCl3): δ= 8.04(d, J = 8.4 Hz,
1H), 7.92(d, J = 8.4 Hz, 1H), 7.78-7.51(m, 6H), 7.40-7.23(m, 4H), 7.15-
7.0(m, 5H),5.05(q, J = 12.4 Hz, 2H),4.02(d, J = 16 Hz, 1H), 3.48(d, J =
15.6Hz, 1H); 13C NMR(125 MHz, CDCl3): δ 174.2, 159.4, 146.7, 141.5,
137.1, 135.8, 130.0, 128.7, 128.5, 128.3, 128.0(2), 127.9, 127.7, 127.0,
126.5, 125.4, 122.4, 79.1, 67.1, 46.7 ppm; HRMS(ESI-TOF): m/z [M+H]+
calculated for C25H21NO3H: 384.1600; found: 384.1563; IR(film):
νmax3384, 3056, 1727, 1599, 1195, 1097 cm-1.
3q: the product was purified by column chromatography (60-120 silica
mesh, in 10% EtOAc /petroleum ether) and obtained as white solid
(Yield-51%); MP: 156-158 oC; 1H NMR (400 MHz, CDCl3): δ = 8.95(s,
1H), 8.81(s, 1H), 8.09(d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.84(d,
J = 7.2 Hz, 2H), 7.77(d, J = 8 Hz, 1H), 7.71-7.67(m, 1H), 7.52-7.44(m,
3H), 7.35 (dd, J1 = 7.2 Hz, J2 = 8.4 Hz, 3H ), 7.29-7.19(m, 3H), 7.0(t, J =
7.2 Hz, 1H), 4.06-3.50(dd,J1 = 15.6 Hz, J2 = 15.6 Hz, 1H);13C NMR(100
MHz, CDCl3): δ 172.4, 159.9, 146.4, 142.4, 137.8, 137.6, 130.1, 128.5,
128.4, 128.3, 127.9, 127.8, 127.1, 126.6, 125.3, 124.2, 123.0, 119.6,
sec-Butyl
3-(7-chloroquinolin-2-yl)-2-hydroxy-2-phenylpropanoate
(5g). the product was purified by column chromatography (60-120 silica
mesh, in 15% EtOAc /petroleum ether) and obtained as colorless solid
(Yield-64%); MP:81-83oC; (Obtained as inseparable mixture of 1:1
diastereomers) 1H NMR (500 MHz, CDCl3): δ = 8.07 (d, J = 3 Hz, 1H),
8.06 (d, J = 2.5 Hz, 1H), 8.0-7.99 (m, 2H), 7.75-7.71 (m, 6H), 7.48 (d, J =
2.5 Hz, 1H), 7.46 (d, J = 2 Hz, 1H), 7.40-7.36 (m, 4H), 7.33-7.29 (m, 4H),
6.76 (s, 1H), 6.68 (s, 1H), 4.81-4.72 (m, 2H), 4.03 (d, J = 3.5 Hz, 1H), 4.0
(d, J = 3 Hz, 1H), 3.52 (d, J = 3 Hz, 1H), 3.49 (d, J = 3 Hz, 1H), 1.55-1.36
(m, 4H), 1.08 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6 Hz, 3H), 0.71 (t, J = 7.5
Hz, 3H), 0.58 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 173.9,
160.8, 160.7, 147.2, 147.1, 141.7(2), 136.7(2), 135.8, 128.9, 128.4(2),
127.9, 127.9, 127.7(2), 127.5, 125.4, 125.3, 122.9, 122.8, 78.8, 78.7,
74.0, 73.9, 47.0, 46.9, 28.8, 28.7, 19.3, 19.2, 9.6, 9.5ppm; HRMS (ESI-
TOF): m/z[M-H]+ calculated for C22H21ClNO3:382.1210; found: 382.1194;
HRMS (ESI-TOF): m/z [M+H]+ calculated for C22H22ClNO3H :384.1366;
found: 384.1158; IR(film): νmax 3258, 2972, 2929, 2359, 1716, 1495,
1262, 1055 cm-1.
sec-Butyl 2-hydroxy-2-phenyl-3-(quinolin-2-yl)propanoate (5h). the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
59%); MP: 83-85oC; (Obtained as inseparable mixture of 1:1
diastereomers) 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 2 Hz, 1H),
8.09 (d, J = 2 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.98 (d, J = 0.8 Hz, 1H),
7.79 (m, 6H), 7.72-7.68 (m, 2H), 7.54-7.50 (m, 2H), 7.41-7.36 (m, 4H),
7.33-7.27 (m, 6H), 4.78-4.71 (m, 2H), 4.04 (d, J = 4.4 Hz, 1H), 4.00 (d, J
= 4.4 Hz, 1H), 3.52 (d, J = 2.8 Hz, 1H), 3.48 (d, J = 2.8 Hz, 1H), 1.54-
1.33 (m, 4H), 1.06 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.68 (t, J
= 7.6 Hz, 3H), 0.55 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
173.9, 159.6, 159.5, 146.7(2), 141.8,136.9, 129.9, 128.6, 128.6, 128.4,
127.8, 127.8, 127.7, 126.9, 126.4, 125.3, 125.3, 122.5, 122.4, 79.0, 78.9,
80.1,
45.0
ppm;
HRMS(ESI-TOF): m/z [M+H]+
calculated
forC24H19DN2O2H:370.1668;found: 370.1668; IR (film): νmax3352, 3145,
2359, 1671, 1598, 1515, 1394, 1313 cm-1.
Ethyl 3-(7-chloroquinolin-2-yl)-2-hydroxy-2-phenylpropanoate (5a).
the product was purified by column chromatography (60-120 silica mesh,
in 15% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
75%); MP: 118-120oC; 1H NMR (500 MHz, CDCl3): δ= 8.08 (d, J = 8 Hz,
1H), 7.99 (d, J = 2 Hz, 1H), 7.75-7.72 (m, 3H), 7.48(dd, J1 = 2 Hz, J2=8.5
Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H),7.32-7.29(m, 2H), 6.84(s, 1H), 4.15-
4.09(m, 2H), 4.0(d, J = 16.0 Hz, 1H), 3.49(d, J = 15.5 Hz, 1H), 1.11 (s,
3H); 13C NMR(125 MHz, CDCl3): δ 174.2, 160.6, 147.1, 141.5, 136.8,
135.9, 129.0, 128.5, 127.9, 127.7, 127.6, 125.3(2), 122.8, 78.8, 61.8,
47.0, 14.17 ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated for
C20H18ClNO3H: 356.1053; found: 356.1058; IR(film): νmax3246, 2974,
2906, 1732, 1611, 1596, 1496 cm-1.
Ethyl 2-hydroxy-2-phenyl-3-(quinolin-2-yl)propanoate (5b). the
product was purified by column chromatography (60-120 silica mesh, in
15% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
79%); MP: 194-196oC; 1H NMR (400 MHz, CDCl3): δ= 8.10 (d, J = 8.4
Hz, 1H), 8.0 (d, J = 8.8 Hz, 1H), 7.79-7.68 (m, 4H), 7.54-7.26 (m, 6H),
4.13-4.05 (m, 2H), 4.01 (d, J = 15.6 Hz, 1H), 3.49 (d, J = 15.6Hz, 1H),
1.09 (t, J = 7.2 Hz,3H);13C NMR(125 MHz, CDCl3): δ 174.3, 159.5, 146.8,
141.7, 137.0, 130.0, 128.7, 128.5, 127.9, 127.7, 127.0, 126.5, 125.3,
122.5, 79.0, 61.6, 46.9, 14.1 ppm;DEPT-135 (100 MHz, CDCl3): δ 136.9,
129.9, 128.5, 128.3, 127.7, 127.6, 126.3, 125.1, 122.4, 61.5, 46.7, 14.0
ppm. HRMS(ESI-TOF): m/z [M+H]+ calculated for C20H19NO3H:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
73.7, 73.6, 46.7(2), 28.7, 28.6, 19.3, 19.1, 9.7, 9.4 ppm; HRMS (ESI-
TOF): m/z [M+H]+ calculated for (C22H23NO3)2H:350.1756; found:
350.1750; IR(film): νmax3343, 2971, 2873, 1706, 1598, 1447, 1266 cm-1.
409.1552; found: 409.1505; IR(film): νmax 3332, 3152, 2359, 1729, 1691,
1618, 1472, 1325, 1222, 1102 cm-1.
3-Hydroxy-5-methoxy-3-(quinoline-2-ylmethyl)indolin-2-one (7f). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as pale orange solid (Yield-
91%); MP: 165-167oC; 1H NMR (500 MHz, CDCl3): δ=8.14(d, J = 8.5 Hz,
1H), 8.11(d, J = 8.5 Hz, 1H), 7.84(d, J = 8 Hz, 1H),7.79 (s, 1H), 7.78-
7.74(m, 1H), 7.59-7.56(m, 1H), 7.26 (s, 1H), 7.21(d, J = 8 Hz, 1H), 6.76-
6.71(m, 2H), 6.46(d, J = 2.5 Hz, 1H), 3.57(s, 3H), 3.55(d, J = 15 Hz, 1H),
3.27(d, J = 15 Hz, 1H); 13C NMR(100 MHz, CDCl3): δ 178.9, 158.5, 156.0,
146.8, 137.3, 133.4, 132.9, 130.3, 128.8, 127.8, 127.2, 126.8, 122.9,
114.3, 111.5, 110.8, 77.4, 55.7, 43.4 ppm; HRMS(ESI-TOF): m/z
[M+Na]+ calculated for C19H16N2O3Na: 343.1059; found: 343.1057;
IR(film): νmax3314, 2359, 2341, 1704, 1599, 1485, 1266, 1155, 1029 cm-1.
5-chloro-3-hydroxy-3-(quinolin-2-ylmethyl)indolin-2-one (7g). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as pale orange solid (Yield-
87%); MP: 285-287oC; 1H NMR (500 MHz, CDCl3): δ= 8.17(d, J = 8.5 Hz,
1H), 8.10(d, J = 8.5 Hz, 1H), 7.97(s, 1H), 7.86(d, J = 8 Hz, 1H), 7.78(dd,
J1 = 7 Hz, J2 = 8.5 Hz, 1H), 7.60(t, J = 7.5 Hz, 1H), 7.26(d, J = 1 Hz, 1H),
7.21-7.16(m, 2H), 6.87(s, 1H), 6.77(d, J = 8.5 Hz, 1H), 3.52(d, J = 15.5
Hz, 1H), 3.27(d, J = 15 Hz, 1H);13C NMR(125 MHz, CDCl3): δ 177.6,
156.1, 145.9, 139.5, 134.9, 132.1, 128.3, 127.6, 127.5, 126.5, 125.6,
125.2, 125.1, 123.7, 121.7, 109.9, 75.1, 43.9 ppm; HRMS(ESI-TOF): m/z
[M+H]+ calculated for C18H13ClN2O2H: 325.0744; found: 325.0742;
IR(film): νmax 3088, 1712, 1615, 1424, 1319, 1143 cm-1.
sec-Butyl
3-(3-acetyl-4-phenylquinolin-2-yl)-2-hydroxy-2-
phenylpropanoate (5i) the product was purified by column
chromatography (60-120 silica mesh, in 15% EtOAc /petroleum ether)
and obtained as colorless solid (Yield-60%); MP:145-147oC; (Obtained
as inseparable mixture of 1:1 diastereomers) 1H NMR (400 MHz, CDCl3):
δ 8.05 (s, 1H), 8.03 (s, 1H), 7.76-7.71 (m, 6H), 7.66 (s, 1H), 7.64 (s, 1H),
7.55-7.47 (m, 8H), 7.41-7.37 (m, 6H), 7.33-7.31 (m, 4H), 7.09 (d, J = 2
Hz, 2H ), 4.84-4.76 (m, 2H), 3.94 (d, J = 6 Hz, 1H), 3.90 (d, J = 5.6 Hz,
1H), 3.41 (s, 1H), 3.36 (s, 1H), 2.01 (s, 3H), 2.00 (s, 3H) , 1.15-1.39 (m,
4H), 1.13 (d, J = 6 Hz, 3H), 0.97 (d, J = 6 Hz, 3H), 0.76 (t, J = 7.6 Hz, 3H),
0.54 (t, J = 7.6 Hz, 3H); 13C NMR(125 MHz, CDCl3): δ 205.2, 205.1,
174.3, 154.9 (2), 146.3, 145.0 (2), 141.6, 135.2, 135.1, 130.6(2), 130.3,
130.1, 129.3, 129.0, 128.8, 128.7(2), 128.5, 128.4, 127.9(2), 127.2, 126.4,
125.3(2), 79.0, 78.8, 73.8, 73.7, 45.0, 44.6, 32.3, 32.2, 28.9, 28.7, 19.5,
19.2, 9.8, 9.4 ppm; HRMS(ESI-TOF): m/z calculated for (C30H29NO4)2:
467.2097; found: 467.2017; IR(film): νmax 3272, 2971, 1712, 1697, 1558,
1265, 1078 cm-1.
3-Hydroxy-3-(quinolin-2-ylmethyl)indolin-2-one (7a). the product was
purified by column chromatography (60-120 silica mesh, in 30% EtOAc
/petroleum ether) and obtained as pale yellow solid (Yield-92%); MP:
177-179 oC; 1H NMR (500 MHz, CDCl3): δ = 9.89 (s, 1H), 8.11 (d, J = 8.5
Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.73-7.69 (m,
1H), 7.58-7.53(m, 1H), 7.30(d, J = 8.5 Hz, 1H), 7.22 (s, 1H), 7.13-7.09(m,
1H), 6.81-6.78(m, 3H), 3.55(d, J = 14.5 Hz, 1H), 3.31(d, J = 14.5 Hz, 1H);
13C NMR(100 MHz, CDCl3): δ 178.2, 157.2, 146.1, 140.7, 135.6, 130.6,
128.9, 128.3, 127.9, 126.9, 126.1, 125.5, 123.6, 122.2, 121.0, 109.3,
75.6, 43.8 ppm; HRMS(ESI-TOF): m/z [M+Na]+ calculated for
C18H14N2O2Na: 313.0953; found: 313.0927; IR(film): νmax 3319, 3058,
2808, 1706, 1620, 1471, 1286, 1175, 1112 cm-1.
3-((3-acetyl-4-phenylquinolin-2-yl)methyl)-1-benzyl-3-
hydroxyindoline-2-one (7h): the product was purified by column
chromatography (60-120 silica mesh, in 30% EtOAc /petroleum ether)
and obtained as pale yellow solid (Yield-74%); MP:164-166oC; 1H NMR
(500 MHz, CDCl3): δ= 8.14(d, J = 8.5 Hz, 1H), 7.99(s, 1H), 7.80-7.76(m,
1H), 7.69(d, J = 8.5 Hz, 1H), 7.53-7.49(m, 5H),7.31-7.15(m, 8H), 6.97(t, J
= 15 Hz, 1H), 6.71(d, J = 8 Hz, 1H), 4.90(d, J = 15.5 Hz, 1H), 4.82(d, J =
16 Hz, 1H),3.39(s, 2H), 1.68(s, 3H); 13C NMR(125 MHz, CDCl3): δ 205.6,
177.2, 153.7, 146.3, 145.4, 142.3, 135.7, 135.4, 135.0, 131.1, 130.9,
130.3, 130.2, 129.6, 129.3, 129.0(2), 128.9,128.8, 127.7, 127.5, 127.3,
126.4, 125.3, 124.2, 123.0, 109.5, 76.3, 43.7, 40.4, 32.2ppm;HRMS(ESI-
TOF): m/z [M+H]+ calculated for C33H26N2O3H: 499.2022; found:
499.2023; IR(film): νmax3272, 3063, 2359, 1715, 1682, 1612, 1466, 1356,
1176, 1046 cm-1.
2-hydroxy-2-(quinolin-2-ylmethyl)acenaphthylen-1(2H)-one (9a). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as pale yellow solid (Yield-
80%); MP: 134-136oC; 1H NMR (500 MHz, CDCl3): δ= 8.11 (t,J = 8.5 Hz,
3H), 7.99 (d, J = 7 Hz, 2H), 7.84 (d, J = 8 Hz, 1H), 7.81 (d, J = 8.5 Hz,
1H),7.77-7.72 (m, 2H), 7.59-7.55 (m, 1H), 7.44 (J1 = 7 Hz, J2 = 8.5 Hz,
1H), 7.12(d, J = 8.5 Hz, 1H), 7.04(d, J = 7 Hz, 1H), 3.65(d, J = 15 Hz, 1H),
3.28(d, J = 15 Hz, 1H); 13C NMR(100 MHz, CDCl3): δ 203.4, 159.2, 146.7,
141.0, 140.9, 137.2, 131.9, 130.8, 130.7, 130.2, 128.8, 128.7, 128.3,
3-Hydroxy-1-methyl-3-(quinolin-2-ylmethyl)indolin-2-one (7b). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
73%); MP: 152-154oC; 1H NMR (500 MHz, CDCl3): δ= 8.13(d, J = 8.5 Hz,
1H), 8.09(d, J = 8.5 Hz, 1H), 7.87-7.83(m, 2H), 7.75(dd, J1 = 7 Hz, J2= 8
Hz, 1H), 7.57(t, J = 8 Hz, 1H), 7.27-7.24(m, 1H), 7.17(d, J = 8.5 Hz, 1H),
6.88(t, J = 7.5 Hz, 1H), 6.82(d, J = 8 Hz, 2H), 3.56(d, J = 15 Hz, 1H),
3.23(d, J = 15 Hz, 1H), 3.20(s, 3H); 13C NMR(100 MHz, CDCl3): δ 176.7,
158.7, 146.7, 143.1, 137.2, 131.3, 130.2, 129.4, 128.8, 127.8, 127.1,
126.6, 124.1, 122.8, 122.8, 108.4, 76.4, 43.2, 26.3 ppm; HRMS(ESI-
TOF): m/z [M+Na]+ calculated for C19H16N2O2Na:327.1109; found:
327.1109; IR(film): νmax3275, 3049, 1689, 1612, 1469, 1245, 1065 cm-1.
1-Benzyl-3-hydroxy-3-(quinolin-2-ylmethyl)indolin-2-one (7c). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as colorless solid (Yield-
1
92%); MP: 150-153oC; H NMR (400 MHz, CDCl3): δ= 8.12(dd, J1 = 8.4
Hz, J2 = 13.6 Hz, 2H), 7.92(bs, 1H), 7.84(d, J = 7.6 Hz, 1H),7.78-7.73(m,
1H), 7.59-7.55(m, 1H), 7.29-7.23(m, 5H), 7.19(d, J = 8.4 Hz, 1H), 7.15-
7.11(m, 1H), 6.89-6.83(m, 2H), 6.69(d, J = 8 Hz, 1H), 4.96(d, J = 15.6 Hz,
1H), 4.81(d, J = 15.6 Hz, 1H), 3.61(d, J = 14.8 Hz, 1H), 3.30(d, J = 15.2
Hz, 1H);13C NMR(100 MHz, CDCl3): δ 176.9, 158.5, 146.7, 142.1, 137.2,
135.7, 131.2, 130.2, 129.4, 128.8 (2), 127.8, 127.6, 127.3, 127.1, 126.7,
124.2, 122.9, 122.8, 109.4, 76.5, 43.8, 43.5 ppm; HRMS(ESI-TOF): m/z
calculated for C25H20N2O2: 380.1525; found: 380.1477; IR(film): νmax3142,
2359, 1712, 1613, 1598, 1351, 1076 cm-1.
3-Hydroxy-3-(quinoxalin-2-ylmethyl)indolin-2-one (7d). the product
was purified by column chromatography (60-120 silica mesh, in 30%
EtOAc /petroleum ether) and obtained as pink solid (Yield-65%); MP:
159-161oC; 1H NMR (500 MHz, CDCl3): δ= 8.66(s, 1H), 8.49(s, 1H), 8.08-
8.03(m, 2H), 7.78-7.72(m, 2H), 7.17-7.14(m, 1H), 6.98(d, J = 7.5 Hz, 1H),
6.93(t, J = 7.5 Hz, 1H), 6.77(d, J = 7.5 Hz, 1H), 6.08(s, 1H), 3.56(d, J =
14.5 Hz, 1H), 3.46(d, J = 14.5 Hz, 1H); 13C NMR(125 MHz, CDCl3): δ
178.3, 152.2, 146.8, 141.4, 141.1, 140.5, 130.7, 129.5, 129.0, 128.9,
128.6, 128.5, 124.4, 121.1, 109.4, 75.4, 43.6 ppm; HRMS(ESI-TOF): m/z
[M+Na]+ calculated for C17H13N3O2Na: 314.0905; found: 314.0906;
IR(film): νmax 3286, 1697, 1618. 1469, 1184, 979 cm-1.
127.8,
127.1,
126.6,
125.1,
122.7,
122.3,
120.6,
80.1,
43.0ppm;HRMS(ESI-TOF): m/z [M+H]+ calculated forC22H15NO2H:
326.1181; found: 326.1183; IR(film): νmax3208, 1713, 1619, 1419, 1344,
1141, 1036 cm-1.
2-hydroxy-2-(quinolin-2-ylmethyl)acenaphthylen-1(2H)-one (9b). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as pink solid (Yield-65%);
MP: 183-185oC; 1H NMR (500 MHz, CDCl3): δ= 8.63(s, 1H), 8.13-7.99(m,
4H), 7.86(d, J = 8.5 Hz, 1H), 7.80-7.74(m, 3H), 7.53(dd, J1 = 7 Hz, J2=
8.5 Hz, 1H), 7.18(d, J = 6.5 Hz, 1H), 6.02(s, 1H), 3.68(d, J = 15 Hz, 1H),
3.51(d, J = 15 Hz, 1H);13C NMR(100 MHz, CDCl3): δ 203.3, 153.1, 146.3,
141.7, 141.1, 141.0, 139.6, 132.1, 130.8, 130.6, 130.5, 129.9, 129.4,
128.9, 128.7, 128.5, 125.6, 122.5, 120.7, 79.8, 41.6 ppm; LCMS8040-
ESI-001.lcd m/z [M+H]+ calculated for C21H14N2O2H:327.1134; found:
327.300;HRMS(ESI-TOF):
m/z
[M+H]+
calculated
for
C21H14N2O2H:327.1134; found: 327.1135;IR(film): νmax3200, 1713, 1604,
1492, 1363, 1176, 1083 cm-1.
2-((3-acetyl-4-phenylquinolin-2-yl)methyl)-2-hydroxyacenaphthylen-
1(2H)-one (9c): the product was purified by column chromatography
(60-120 silica mesh, in 30% EtOAc /petroleum ether) and obtained as
pale yellow solid (Yield-64%); MP: 190-192oC; 1H NMR (500 MHz,
CDCl3): δ= 8.14-8.10(m, 2H), 7.98(d, J = 7 Hz, 1H), 7.86(d, J = 8.5 Hz,
1H), 7.82-7.40(m, 3H), 7.71(d, J = 8.5 Hz, 1H),7.58-7.50(m, 5H), 7.41-
7.33(m, 3H), 3.52(d, J = 16 Hz, 1H), 3.40(d, J = 16 Hz, 1H), 1.67(s, 3H);
13C NMR(125 MHz, CDCl3): δ 205.3, 203.6, 154.1, 146.4, 145.4, 141.1,
140.9, 135.3,135.1, 132.0, 130.9(2), 130.3, 130.2, 129.3, 129.0, 128.9(2),
128.8, 128.5, 127.5, 126.5, 125.4, 122.3, 120.7, 80.1, 40.5, 32.2 ppm;
HRMS(ESI-TOF): m/z [M+H]+ calculated for C30H21NO3H:444.1600;
found: 444.1600; IR(film): νmax3182, 3059, 1712, 1689, 1556, 1437, 1214,
1058 cm-1.
3-((3-acetyl-4-phenylquinolin-2-yl)methyl)-3-hydroxyindolin-2-one
(7e). the product was purified by column chromatography (60-120 silica
mesh, in 30% EtOAc /petroleum ether) and obtained as pale yellow solid
1
(Yield-92%); MP: 174-176oC; H NMR (400 MHz, CDCl3): δ= 8.16(d, J =
8 Hz, 1H), 7.90 (bs, 1H), 7.82-7.78(m, 2H), 7.70(d, J = 8 Hz, 1H), 7.56-
7.50(m, 4H), 7.40-7.18(m, 3H), 7.06(d, J = 7.2 Hz, 1H), 6.95(t, J = 0.4 Hz,
1H), 6.83(d, J = 8 Hz, 1H), 3.40(d, J = 15.6 Hz, 1H), 3.30(d, J = 15.6 Hz,
1H),1.74(s, 3H);13C NMR(100 MHz, CDCl3): δ 205.4, 179.1, 153.7, 146.4,
145.5, 140.2, 135.5, 135.0, 131.7, 131.0, 130.3, 130.1, 129.6 (2), 129.4,
129.1, 129.0, 127.6, 126.5, 125.4, 124.5 122.9, 110.4, 76.7, 40.5, 32.3
ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated for C26H20N2O3H:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
2-(7-chloroquinolin-2-yl)methyl)-2-hydroxyacenaphthylen-1(2H)-one
(9d). the product was purified by column chromatography (60-120 silica
mesh, in 30% EtOAc /petroleum ether) and obtained as colorless solid
(Yield-75%); MP 151-153oC; 1H NMR (500 MHz, CDCl3): δ= 8.09-8.06(m,
3H), 7.97(d, J = 5 Hz, 1H), 7.81(d, J = 7.5 Hz, 1H), 7.75(t, J = 8.5 Hz,2H),
7.51-7.46(m, 3H), 7.13-7.10(m, 2H), 3.61(d, J = 15 Hz, 1H), 3.34(d, J =
14.5 Hz, 1H); 13C NMR(100 MHz, CDCl3): δ 203.4, 160.2, 147.0, 141.0,
140.6, 137.0, 136.0, 132.0, 130.7, 130.6, 129.0, 128.7, 128.3, 127.7,
127.6, 125.4, 125.2, 122.9, 122.3, 120.6, 80.0, 43.3ppm; LCMS8040-
ESI-001.lcd m/z [M+H]+ calculated for C22H14ClNO2H: 360.0791; found:
360.0792;HRMS(ESI-TOF): m/z [M+H]+ calculated forC22H14ClNO2H:
360.0791; found: 360.0792; IR(film): νmax3310, 3050, 1721, 1597, 1494,
1323, 1194 cm-1.
2-hydroxy-1-phenyl-3-(quinolin-2-yl)propan-1-one (11). the product
was purified by column chromatography (60-120 silica mesh, in 20%
EtOAc /petroleum ether) and obtained as deep brown semi-solid (Yield-
73%); 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 3H), 8.0 (d, J =
8.4 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.71-7.67 (m, 1H), 7.60 (t, J = 7.2 Hz,
1H), 7.52-7.48 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H), 5.65 (dd, J1 = 3.6 Hz,
J2= 8 Hz, 1H), 3.54 (dd, J1 = 3.2 Hz, J2= 14.8 Hz, 1H), 3.29 (dd, J1 = 8 Hz,
J2= 15.2 Hz, 1H); 13C NMR(100 MHz, CDCl3): δ 200.8, 158.8, 147.6,
136.6, 134.5, 133.7, 129.7, 129.1, 128.8(2), 127.6, 127.0, 126.2, 122.4,
73.4, 42.7 ppm; HRMS(ESI-TOF): m/z [M+Na]+ calculated for
C18H15NO2Na: 300.1000; found: 300.0991; IR (film): νmax3428, 3058,
1670, 1596, 1504, 1268, 1120 cm-1.
(E)-3-(7-chloroquinolin-2-yl)-N,2-diphenylacrylamide (14). the product
was purified by column chromatography (60-120 silica mesh, in 40%
EtOAc /petroleum ether) and obtained as pale pink solid (Yield-82%);
MP: 220-222 oC; 1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 8.4 Hz, 1H),
7.87 (s, 1H), 7.74-7.71 (m, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (dd, J1 =
7.6 Hz, J2 = 13.6 Hz, 3H), 7.43-7.36 (m, 6H), 7.21 (s, 1H), 7.18 (t, J = 7.2
Hz, 1H); 13C NMR(125 MHz, CDCl3): δ 167.6, 155.0, 148.3, 143.2, 138.1,
136.5 (2), 135.9, 129.4, 129.2, 129.1, 128.7, 128.6, 127.9, 127.6, 126.9,
125.6, 124.8, 122.1, 120.2 ppm; HRMS(ESI-TOF): m/z [M+H]+ calculated
for C24H17ClN2OH: 385.1108; found: 385.1106; IR(film): νmax 3248, 3057,
2160, 1656, 1438, 1064 cm-1.
135.6, 134.9, 133.7, 131.4, 130.7, 129.8, 129.6, 128.7, 128.3, 127.9,
127.7, 127.4, 125.9, 123.9, 121.6, 117.2 ppm; LCMS8040-ESI m/z
[M+H]+ calculated for C22H13NOH: 308.1075; found: 308.300;IR
(film):νmax 3046, 1705, 1630, 1427, 1207, 1022 cm-1
Acknowledgements
SY thankful to UGC-NRC, School of Chemistry, University of Hyderabad
for the facilities. SLD thankful to School of Chemistry, University of
Hyderabad for the facilities and the fellowship. The authors (AA&NA)
acknowledge the Deanship of scientific research at King Saud University
for funding this work through the research grant RG-1440-071.
Keywords: C(sp3)-H functionalization, 2-methyl quinolines,
catalyst-free, solvent-free, -keto esters, -keto amides
References
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= 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 7.85 (d,J = 8 Hz, 1H),
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(t, J = 7.0 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H); 13
C
NMR(125 MHz, CDCl3): δ 167.5, 153.7, 148.3, 140.3, 137.2, 136.0,
130.2, 129.9, 129.8, 129.7, 128.0, 127.7, 127.6, 125.0, 124.0, 122.5,
120.7, 109.8 ppm; LCMS8040-ESI (m/z) [M+H]+ calculated for
C18H12N2OH: 273.1028; found: 273.250; IR(film): νmax3167, 1681, 1469,
1336, 1205 cm-1.
6.
N-(2-oxo-3-(quinolin-2-ylmethyl)indolin-3-yl)acetamide
(16).
the
product was purified by column chromatography (60-120 silica mesh, in
40% EtOAc /petroleum ether) and obtained as yellow solid (Yield-51%);
MP: 278-280oC; 1H NMR (500 MHz, CDCl3): δ = 9.24 (s, 1H), 8.19 (s,
1H), 8.12 (dd, J1 = 3 Hz, J2 = 8.5 Hz, 2H), 7.87 (d, J = 8 Hz, 1H), 7.82-
7.59 (m, 2H), 7.16-7.12 (m, 1H), 7.06 (d, J = 8 Hz, 1H), 6.86 (d, J = 7.5
Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 7.5 Hz, 1H), 3.54 (d, J = 14
Hz, 1H), 3.02 (d, J = 14 Hz, 1H), 2.02 (s, 3H);13C NMR(125 MHz,
CDCl3): δ 177.6, 169.0, 157.2, 147.5, 140.8, 136.9, 130.2, 130.1, 129.0,
128.9, 128.0, 127.3, 126.9, 123.8, 123.1, 122.1, 110.4, 61.6, 43.4,
22.9ppm; LCMS8040-ESI m/z [M+H]+ calculated for C20H17N3O2H:
332.1399; found:332.300;IR(film): νmax 3250, 2923, 1714, 1617, 1470,
1211 cm-1.
N-(2-oxo-1-(quinolin-2-ylmethyl)-1,2-dihydroacenaphthylen-1-
yl)acetamide (17). the product was purified by column chromatography
(60-120 silica mesh, in 40% EtOAc /petroleum ether) and obtained as
yellow solid(Yield-67%); MP:163-165oC;1H NMR (500 MHz, CDCl3): δ =
7.99 (t, J = 8 Hz, 3H), 7.76 (d, J = 8.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.58-
7.55 (m, 1H), 7.45-7.40 (m, 3H), 7.25 (s, 1H), 7.04 (d, J = 7 Hz, 1H), 3.89
(d, J = 14 Hz, 1H), 3.58 (d, J = 14 Hz, 1H), 2.08 (s, 3H);13C NMR(125
MHz, CDCl3): δ199.9, 169.1, 155.6, 147.4,140.7, 136.5, 135.8, 131.7,
131.5, 130.5, 129.4, 129.0, 128.2, 127.9, 127.4, 126.9, 126.3, 125.9,
122.9, 121.9, 120.8, 84.0, 45.2, 20.73 ppm; LCMS8040-ESI m/z [M+Na]+
7.
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calculated
for
C24H18N2O2Na:
389.1266;
found:
389.300;IR
(film):νmax3043, 1724, 1503, 1365, 1242, 1039 cm-1.
(E)-2-(quinolin-2-ylmethylene)acenaphthylen-1(2H)-one (18). the
product was purified by column chromatography (60-120 silica mesh, in
30% EtOAc /petroleum ether) and obtained as yellow solid (Yield-
87%);MP: 186-188oC;1H NMR (500 MHz, CDCl3): δ = 8.88 (d, J = 8.5 Hz,
1H ), 8.25 (d, J = 8.5 Hz, 1H), 8.11 (t, J = 8.5 Hz, 2H), 8.01 (d, J = 6.5 Hz,
1H), 7.91-7.85 (m, 4H), 7.75-7.68 (m, 3H), 7.57 (t, J = 7.5 Hz, 1H);13
C
NMR(125 MHz, CDCl3): δ 191.7, 154.1, 148.3, 139.2, 136.5, 135.8,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000511
European Journal of Organic Chemistry
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10.1002/ejoc.202000511
European Journal of Organic Chemistry
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C(sp3)-H Functionalization of 2-Methyl
Quinolines*
Yadavalli Subba Rao,a,b Dandugula Sneha
Latha,a Nagaraju Devunuri,b
AbdulrahmanI. Almansour,c Natarajan
Arumugam,c and Srinivasarao Yaragorla*
Highly
Facile approach of chemoselective alkylation of -oxo compounds such as α-keto amides,
α-keto esters, isatins, and cyclic--diketones is developed through C(sp3)-H functionalization
of 2-methyl quinolines under solvent and catalyst-free conditions
Page No. – Page No.
Alkylation of -Oxo-compounds
through C(sp3)-H Functionalization of
2-Methyl Quinolines Under Catalyst-
and Solvent-Free Conditions
This article is protected by copyright. All rights reserved.