Diversity-oriented synthesis of quinolines via Friedlaender annulation reaction under mild catalytic conditions

Article abstract of DOI:10.1021/cc900129t

An efficient and practical method has been manifested for the diversity-oriented synthesis of quinolines via Friedlaender annulation reaction for the generation of a wide range of structurally interesting and pharmacologically significant compounds by using eerie ammonium, nitrate as a catalyst (10 mol %) at ambient temperature in 45 min, A variety of functional groups are introduced at various positions of the quinoline moiety, and further the diversity of the core skeleton was expanded at R₁ and R ₂ positions by the synthesis of various hybrids. Initial screening of the compounds for cytotoxicity against a series of cancer cell lines showed promising results.

Full text of DOI:10.1021/cc900129t

100
J. Comb. Chem. 2010, 12, 100–110
Diversity-Oriented Synthesis of Quinolines via Friedla¨nder Annulation
Reaction under Mild Catalytic Conditions
D. Subhas Bose,*,† Mohd. Idrees,† N. M. Jakka,‡ and J. Venkateswara Rao‡
Organic Chemistry DiVision-III, Fine Chemicals Laboratory, and Biology DiVision, Indian Institute of
Chemical Technology, Tarnaka, Hyderabad 500 607, India
ReceiVed August 20, 2009
An efficient and practical method has been manifested for the diversity-oriented synthesis of quinolines via
Friedla¨nder annulation reaction for the generation of a wide range of structurally interesting and
pharmacologically significant compounds by using ceric ammonium nitrate as a catalyst (10 mol %) at
ambient temperature in 45 min. A variety of functional groups are introduced at various positions of the
quinoline moiety, and further the diversity of the core skeleton was expanded at R1 and R2 positions by the
synthesis of various hybrids. Initial screening of the compounds for cytotoxicity against a series of cancer
cell lines showed promising results.
Introduction
lines), natural topoisomerase I inhibitors lutonin A and
camptothecin and tyrosine kinase PDGF-RTK inhibitor9
(Figure 1), hence continues to spur synthetic efforts regarding
their acquisition.10 In addition to this, quinolines are valuable
synthons used for the preparation of nanostructures and
polymers that combine enhanced electronic, optoelectronic,
or non-linear optical properties with excellent mechanical
properties.11 In light of the broad array of biological activity,
In the postgenomic era, the rapid identification of small-
molecules having efficacy to perturb the macromolecular
receptors is a major challenge for understanding the complex
biological events of life and hence diseases.1 In this direction,
the recent trend showed a drastic shift of the focus from
natural products to the combinatorial chemistry and diversity-
oriented synthesis (DOS). This shift is evident by the recent
successes of DOS2 and further supported by a chemoinfor-
matics data mining study which revealed that, on average,
natural products have higher molecular weights, less nitrogen
atoms but more oxygen atoms, and are more complex with
large number of rings and chiral centers than the correspond-
ing members from combinatorial libraries.3 Unlike target-
oriented synthesis of natural products and their analogues,
the goal of DOS is the facile generation of small molecules
of structurally diverse nature from simple starting materials.
DOS involves deliberate, simultaneous, rapid, and efficient
synthesis of more than one target compound for lead
identification and optimization.4 As molecular structure is
the intrinsic requirement for a biological function, privileged
structures represent an ideal source of basic scaffolds for
lead generation and are defined as “a single molecular
framework able to provide ligands for diverse receptors”.5
Diversity-oriented syntheses around privileged structures has
been called as “rational DOS”.6
Figure 1. Some biologically active quinolines.
several methods for the construction of this heterocyclic nucleus
have been reported. Although methods such as the Skraup,
Doebner von Miller, and Combes procedures have been reported
in the literature,12,13 the Friedla¨nder annulation is a staple
reaction of organic synthesis to produce poly substituted
quinolines. The reaction involves an acid or base catalyzed
annulation reaction between 2-aminoaryl ketone and a carbonyl
compound possessing a reactive R-methylene group. Classically,
the Friedla¨nder reaction is carried out either by refluxing an
aqueous or alcoholic solution of reactants in the presence of
base or by heating at high temperature ranging from 150-220
°C in the absence of catalyst.14 Recently, improved protocols,
new catalysts, and ionic liquids have been reported for this
reaction that avoid the use of strongly basic conditions.15
Subsequent work showed that acid catalysts are more effective
than base catalysts for the Friedla¨nder annulation. Several acid
catalysts have been used in the Friedla¨nder reaction including
ZnCl2, phosphoric acid, sodium fluoride, silver phosphotung-
state, and AuCl3 · 3H2O among others.16 Unfortunately, many
of these approaches have significant drawbacks such as low
As a privileged fragment, quinoline is a common structural
motif found in many natural products with remarkable
pharmacological properties. Members of this family have
wide applications in medicinal chemistry, being used as
antimalarial (chloroquine and mefloquine), anti-inflammatory,
antiasthmatic, antibacterial, and antihypersensitive activities,7,8
cytotoxic agents (e.g., benzo[5,6]pyrrolizino[1,2-b]quino-
* To whom correspondence should be addressed. E-mail: dsb@
iict.res.in, bose_iict@yahoo.co.in. Fax: +91-40-27160387.
† Organic Chemistry Division-III, Fine Chemicals Laboratory.
‡ Biology Division.
10.1021/cc900129t CCC: $40.75  2010 American Chemical Society
Published on Web 12/11/2009

Synthesis of Quinolines via Friedla¨nder Annulation
Table 1. CAN Catalyzed Synthesis of Substituted Quinolinesa b c
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 101
,
,
a Reaction conditions: o-aminoarylketone (10 mmol), R-methyleneketone (10 mmol), CAN (10 mol %) MeOH (10 mL), RT; all products were
characterized by mp, IR, H NMR, 13C NMR and mass spectroscopy. b Yields refer to pure isolated products after chromatography. c Conc. H2SO4 used
1
instead of CAN.
yields of the products, prolonged reaction times, harsh condi-
tions, stoichiometric quantities of reagents, difficult to handle
especially on large scale, and often do not allow for adequate
diversity on the quinoline ring system. Moreover, the potential
application of this reaction in the DOS for the generation of
biologically active quinolines is yet to be explored. Herein, we
describe an efficient utilization of ceric ammonium nitrate
(CAN) catalyzed Friedlander annulation reaction for the DOS
of a wide range of structurally interesting and biologically active
quinolines.
deprotection sequences, oxidation, oxidative free-radical reac-
tions in green media such as water, and ionic liquids via single-
electron transfer mechanism or by Lewis acid catalysis. As a
part of one of the ongoing investigations in our laboratory
toward the development of new protocols for the expeditious
synthesis of biologically relevant heterocycles through transition
metal catalyzed tandem reactions,18 we observed the high
efficiency of CAN catalysis in sequential condensation/annu-
lation reactions of o-aminoaryl carbonyls 1 and ketones contain-
ing an active methylene group 2 for the synthesis of substituted
quinolines 3. It is remarkable to note that the reaction proceeds
efficiently in high yields at ambient conditions within a few
minutes with low catalyst concentration (5-10 mol %). To the
best of our knowledge there have been no reports on the
utilization of cerium(IV) complexes for DOS of quinolines via
Friedla¨nder annulation reaction.19
Results and Discussion
Among the various cerium(IV) complexes, cerium(IV) am-
monium nitrate (CAN) is one of the most important oxidants
in organic synthesis. It is non-toxic, sufficiently stable in
different solvents including water, and it is commercially
available.17 Owing to its unique catalytic properties, it has been
extensively used for a plethora of organic transformations such
as carbon-carbon bond formation, halogenation, protection/
In an attempt to find the optimum reaction conditions, a
systematic study was carried out on a representative case
by varying the concentration of the catalyst, solvent, and the

102 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Bose et al.
reaction temperature. In screening a set of solvents, we
observed a direct correlation between polarity and yield
(MeOH >EtOH > CH3CN > THF > CH2Cl2 > toluene). Thus,
the high yields were obtained in polar solvents particularly
MeOH, whereas cyclohexane proved to be the least effective
(for details see the Supporting Information).
Diversification at R1. Initially, a series of 1,3-dicarbonyl
compounds (6a-d) was synthesized by heating a mixture
of selected nucleophiles (e.g., morpholine, piperidine, R-
phenethylamine, and (-)-menthol) and tert-butylacetoacetate
(TBAA, 5) in dry xylene for 5 min in 95-98% yields
(Scheme 2).22 The 1H NMR of the intermediate 1,3-
dicarbonyl compounds (6a, 6b, and 6d) showed that keto
and enol forms are in the ratio of 3:1 in deuterated chloroform
(Table 2). Compound 6c did not show any significant enol
As depicted in Table 1, various 1,3-dicarbonyl compounds
including alkyl acetoacetates and acetyl acetone, cyclic ꢀ-dike-
tones and acyclic ketones reacted with 2-aminoaryl ketones to
give the corresponding substituted quinolines without any side
products. Interestingly, cyclic ketones such as 4-tert-butylcy-
clohexanone and dimedone reacted with 2-aminoaryl ketones
to afford the respective tricyclic quinolines in good yields. To
improve the yields, we performed the reactions using different
catalyst concentrations. The optimum results were obtained with
a 0.1:1:1 ratio of CAN, o- aminoaryl ketone, R-methylene
ketone or ꢀ-diketones in methanol solvent. However, condensa-
tion of 2-aminobenzophenone with benzoylacetonitrile requires
a higher molar ratio of catalyst, longer reaction time, and gives
relatively low yield (Table 1, entry 7). Furthermore, the
condensation of o-aminobenzophenone with ethyl acetoacetate
in the presence of conc. H2SO4 afforded the quinoline product
in only 65% yield (Table 1, entry 1). It is also interesting to
note here that when 1,1,1-trifluoroacetylacetone was used as
1,3-dicarbonyl compound, a regioselective condensation reaction
at the acetyl group led to ꢀ-enaminone 4 as the major reaction
product (70%) (Scheme 1). The sequential condensation/
annulation reaction to form 3k was accomplished by heating
the reaction mixture at 75 °C for 8 h. It may be presumed that
the strong electro-withdrawing trifluoroacetyl group affects the
annulation step (Scheme 1).
1
peaks in H NMR.
Scheme 2. Synthesis of Quinolines 7a-da b
,
a Reagents and conditions: (a) Nucb, xylene, ∆, 95-98%(b) 2-amino-
5-chlorobenzophenone, MeOH, cerric ammonium nitrate 10 mol %, RT,
45 min, 90-95%. b Nuc ) morpholine, piperidine, R-phenethylamine, and
(-)-menthol.
These 1,3-dicarbonyl compounds (6a-d) were then re-
acted with 2-amino-5-chlorobenzophenone and CAN 10 mol
% using MeOH at room temperature (RT) for a period of
45 min to obtain a series of novel quinoline amides and esters
in 90-95% yields (7a-d) mentioned in Table 2.
Table 2. Structures of Intermediates 6a-d and Quinolines
7a-da
Scheme 1
Having established the mild catalytic route for the expedi-
tious generation of quinoline scaffolds, we then proceeded
to further expand the scope of this reaction. A vast array of
quinolines with maximum structural diversity was synthe-
sized as an effort for the generation of drug-like compounds
with broad spectrum of biological activities particularly
anticancer ones. The diversity of this core skeleton (Figure
2) was expanded by following three major forward synthetic
strategies, (a) diversification at R1, (b) substitutions at R2
diversity point, and (c) generation of quinoline and pyrrol-
5-one fused heterocyclic systems involving both R1 and R2
diversity points.
a
1H-NMR (in CDCl3) of the compounds (6a-d) showed keto-enol
tautomeric forms in 3:1 ratio.
Second, making use of TBAA (5) and cyclization of
thioformanilides by Dess-Martin periodinane (DMP) to generate
benzothiazole ring system,23 we synthesized a novel quinoline-
benzothiazole hybrid molecule (Compound 9 in Scheme 3). This
scheme was started by heating a mixture of tert-butylacetoac-
etate and p-toluidine in dry xylene for a period of 5 min to
afford a 1,3-dicarbonyl compound (6e) in 95% yield. Interest-
ingly, this compound 6e did not show any tautomeric peaks in
1H NMR. Compound 6e upon treatment with 2-amino-5-
chlorobenzophenone and CAN 10 mol % using MeOH at RT
for 45 min gave the quinoline amide 7e in 90% yield. Quinoline
amide 7e was then treated with Lawesson’s reagent in dry
toluene for a period of 1-2 h to afford quinoline thioamide 8
in 80% yield. Compound 8 was finally cyclized by reacting it
Figure 2. Diversity points.

Synthesis of Quinolines via Friedla¨nder Annulation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 103
Scheme 3. Synthetic Route of Quinoline-Benzothiazole Hybrid Molecule 9a b
,
a Reagents and conditions: (a) p-toluidine, xylene, ∆, 5 min, 95% (b) 2-amino-5-chlorobenzophenone, MeOH, cerric ammonium nitrate 10 mol %, RT,
b
45 min, 90% (c) Lawesson’s reagent, dry toluene, reflux, 1-2 h, 80% (d) DMP, CH2Cl2, 15 min, RT, 85%. 1H-NMR (in CDCl3) of the compound 6e did
not showed keto-enol tautomerism significantly.
with DMP in CH2Cl2 solvent at RT for a period of 15 min to
give quinoline-benzothiazole hybrid molecule 9 in 85% yield
after column purification.
chloromethyl group at second position of the quinoline ring
system. Nucleophiles such as S-prolinol, N-boc-piperizine,
and morpholine were substituted on the methylene group
present at second position to afford compounds (11, 12, and
13). Similarly, to incorporate interesting thiourea pharma-
cophore (frequently found in anti-HIV, and antitumor drug
designing reports)25 in between two quinoline moieties, we
synthesized the C2 symmetric quinoline dimer molecule 14
in 75% yield by reacting 2.0 equiv of the compound 10 with
1.0 equiv of thiourea in dry acetonitrile using NaH at 80-82
°C for a period of 5-6 h (Scheme 5).
Substitutions at R2 Diversity Point. Substitution reactions
at R2 diversity point generated a diverse array of quinoline
scaffolds. In this direction initially we prepared ethyl
6-chloro-2-(chloromethyl)-4-phenylquinoline-3-carboxy-
late24 (10) by the treatment of 2-amino-5-chlorobenzophe-
none with 4-chloroethylacetoacetate in MeOH using CAN
10 mol % as catalyst at RT for a period of 45 min to afford
the compound 10 in 95% yield (Scheme 4).
Further, we substituted the active chloro functionality of
compound 10 with D-glucose diacetonide to obtain quinoline
1,2:5,6-diisopropylidene-D-glucose ester 15 (Scheme 6). This
was synthesized in 85% yield by treating a mixture of
D-glucose diacetonide and NaH in dry tetrahydrofuran (THF)
with compound 10 at 0 °C followed by stirring at RT for
5-6 h until the TLC showed completion of the reaction.
Compound 15 was then treated with 0.8% H2SO4 in MeOH
and stirred for 12 h to afford quinoline 1,2-isopropylidene-
Scheme 4. Formation of Quinoline 10
Compound 10 was highly reactive toward nucleophilic
substitution reactions because of the presence of active
Scheme 5. Diversification of Compound 10a
a Reagents and conditions: (a) S-prolinol, pyridine, CH3CN, cat. DMAP, RT, 5-6 h, 75% (b) N-Boc-piperizine, pyridine, CH3CN, cat. DMAP, RT, 5-6
h, 85% (c) morpholine, CH3CN, cat. DMAP, RT, 5-6 h, 85% (d) thiourea, NaH, CH3CN, reflux, 5-6 h, 75%.

104 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Scheme 6. Synthesis of Quinoline-Glucose Hybrida
Bose et al.
a Reagents and conditions: (a) D-glucose diacetonide, NaH, dry THF, 0 °C-RT, 5-6 h, 85% yield (b) 0.8% H2SO4, MeOH, RT, 12 h, 65% yield.
Generation of Quinoline and Pyrrol-5-one Fused Het-
erocyclic Systems. Finally it is interesting to report here two
novel 2,3-dihydropyrrolo[3,4-b]quinolin-1-ones (17 and 18,
Figure 3) synthesized, structurally related to the DNA
Figure 3. Novel quinolin-pyrrolone fused compounds.
topoisomerase I inhibiting cytotoxic quinoline alkaloids such
as camptothecin,28 luotonin A, and isoluotonin A.29
D-glucose ester 16 in 65% yield. We rationalized the
synthesis of quinoline-D-glucose hybrid molecule 16 by
keeping in view that leaving the fifth and sixth positions free
in the hybrid molecule would lead to its entry in the
cytoplasm of the targeted cell by the natural enzymatic
process called phosphorylation at sixth position. After the
phosphorylation step it would get accumulated in the
cytoplasm without being metabolized further as positions
first, second, and third are blocked. Now the quinoline
fragment may act on the biological system within the cell to
give the required biological activity, and the accumulated
modified glucose fragment may in turn inhibit the phospho-
rylation step. This approach of utilizing carbohydrates
especially D-glucose in the design of antitumor compounds
is reported in the literature with successful results as tumor
cells rely more on glycolysis rather than oxidative phospho-
rylation (Warburg effect).26,27
Compound 17 was synthesized by treating compound 10
with S-phenylalaninol and pyridine in acetonitrile for 2-3
h at RT to give an intermediate ester 17a, which upon further
stirring for 12 h at 40-45 °C afforded compound 17 in 80%
yield (Scheme 7). Similarly, compound 10 was reacted with
R-phenethylamine and pyridine in acetonitrile for a period
of 2-3 h at RT to obtain an intermediate ester 18a, which
upon stirring at 40-45 °C gave compound 18 in 75% yield.
Conversion of 18a to the cyclized form 18 was nicely
1
detected by H NMR spectrum.
Cytotoxicity Evaluation
The cytotoxic activities of the compounds 7a-e, 8, 9, and
11-18 were evaluated in vitro against four tumor cell lines:
THP-1 (human acute monocytic leukemia), U-937 (human
histiocytic lymphoma), HL-60 (human promyelocytic leu-
kemia), and Jurkat (Human T-cell leukemia). In all the
Scheme 7
Table 3. In Vitro Cytotoxicity Data of Substituted Quinolines on THP-1,U-937, HL-60, and Jurkat Tumor Cell Lines
IC50 (µM) ( SE
compound
THP-1
U-937
HL-60
Jurkat
14
15
16
18
22.45 ( 3.97
6.02 ( 0.68
9.02 ( 0.77
3.51 ( 0.42
0.071 ( 0.0053
2.16 ( 0.15
45.51 ( 5.57
3.79 ( 0.41
5.89 ( 0.67
5.02 ( 0.56
1.980 ( 0.11
17.94 ( 1.19
20.20 ( 4.96
4.20 ( 0.55
5.65 ( 0.89
2.51 ( 0.40
0.600 ( 0.03
1.83 ( 0.20
18.74 ( 2.72
2.59 ( 0.40
3.45 ( 0.52
5.18 ( 0.28
0.026 ( 0.002
5.35 ( 0.63
camptothecin
etoposide

Synthesis of Quinolines via Friedla¨nder Annulation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 105
experiments, the cell lines were seeded at a final density of
2 × 104 cells per well in 96 well microtiter plates. All
leukemia cell lines (THP-1, U-937, HL-60, and Jurkat) were
cultured in RPMI-1640. The media were supplemented with
10% heat inactivated FCS, 1 mM NaHCO3, 2 mM L-
glutamine, and penicillin-streptomycin in a humidified
atmosphere of 95%, 5% CO2 at 37 °C. Cytotoxicity was
measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrasolium bromide) as described by Mosmann.30
The stock solutions of the testing compounds were prepared
by dissolving 8 mg of each compound in 1 mL of dimeth-
ylsulfoxide (DMSO) and further diluted to obtain required
experimental stock solutions from 0.5 to 50 ppm. The cells
were treated with different concentrations of the test com-
pounds, and their cytotoxicities were compared with the
activity of positive controls, camptothecin and etoposide, at
identical conditions with five replicates each. The tumor cells
(2 × 104) were seeded in each well containing 0.1 mL of
RPMI medium in 96 well plates. After 24 h different test
concentrations were added, and cell viability was assessed
after 48 h by adding 10 µL of MTT (5 mg/mL) per well.
The plates were incubated at 37 °C for additional 4 h. The
rate of color production was measured at 570 nm in a
spectrophotometer (Spectra Max Plux; supported by SOFT-
max PRO-3.0).
Among 15 compounds tested in this series, compounds
14, 15, 16, and 18 showed significant cytotoxic activities
(the remaining compounds showed IC50 values more than
100 ppm). On the basis of the regression equation, IC50
values (average concentration of the drug required to produce
50% cell growth inhibition) of the selected potent compounds
were calculated, and the results are presented in Table 3. As
evident from the table, all the compounds (except compound
14 which showed moderate activity) showed potent cyto-
toxicity against the four tumor cell lines. Compounds 15,
16, and 18 showed IC50 values in the range of 2.59 to 9.02
µM, which are comparable with camptothecin and in some
cases better than the marketed anticancer drug Etoposide.
10.0 mmol), and CAN (0.548 g, 1 mmol, 10 mol %) in
methanol (10 mL) was stirred at RT for 45 min. After
completion of the reaction (monitored by TLC), the reaction
mixture was diluted with EtOAc (30 mL), and washed with
water (15 mL), dried (Na2SO4), and concentrated in vacuo.
The resulting residue was purified by silica gel column
chromatography using EtOAc: petroleum ether (1:10) to
afford the pure product 3f (3.48 g, 94%). mp 110-120 °C.1H
NMR (300 MHz, CDCl3, TMS) δ 3.47 (s, 3H, CH3), 3.71
(s, 3H, CH3), 4.18 (s, 2H, ArCH2), 7.31-7.35 (m, 2H, ArH),
7.47-7.55 (m, 4H, ArH), 7.64-7.69 (dd, 1H, J1 ) 9.06, J2
)2.26 Hz, ArH), 8.02-8.06 (d, 1H, J ) 9.06 Hz, ArH). 13
C
NMR (75 MHz, CDCl3): δ 43.1, 52.2, 125.4, 126.5, 127.2,
128.4, 128.5, 128.8, 129.0, 129.1, 131.0, 131.5, 133.2, 135.3,
146.2, 147.1, 151.6, 168.2, 170.3. HRMS (ESI) calcd for
C20H16NO4Cl 370.0846 [M+H]+, found 370.0837. This
procedure was followed for the preparation of all the
substituted quinolines (3a-j) mentioned in Table 1.
Ethyl 2-Methyl-4-phenyl-3-quinolinecarboxylate (3a).
mp 99-102 °C (Lit. m.p.20 99-100 °C). H NMR (300
1
MHz, CDCl3, TMS) δ 0.89-0.96 (t, 3H, J ) 7.55 Hz, CH3),
2.76 (s, 3H, ArCH3), 3.98-4.06 (q, 2H, J ) 7.55 Hz, CH2),
7.32-7.56 (m, 7H, ArH), 7.65-7.71 (m, 1H, ArH), 8.02-8.06
(d, 1H, J ) 8.31 Hz, ArH). MS (EI): m/z (%) ) 291 (M+,
95), 246 (100), 218 (50), 176 (20), 85 (20), 71 (40), 57 (80),
43 (70).
Methyl 2-Ethyl-4-phenyl-3-quinolinecarboxylate (3b).
1
mp 105-106 °C. H NMR (300 MHz, CDCl3, TMS) δ
1.38-1.47 (t, 3H, J ) 7.43 Hz, CH3), 2.95-3.08 (q, 2H, J
) 7.43 Hz, ArCH2), 3.53 (s, 3H, CO2CH3), 7.31-7.58 (m,
7H, ArH), 7.64-7.73 (m, 1H, ArH), 8.05-8.11 (d, 1H, J )
8.18 Hz, ArH). MS (EI): m/z (%) ) 291 (M+, 100), 276
(95), 260 (10), 232 (40), 204 (45), 177 (10), 71 (10), 57
(30), 43 (25).
1-(2-Methyl-4-phenyl-3-quinolyl)ethanone (3c). mp
111-112 °C (Lit. m.p.21 113-114 °C). 1H NMR (300 MHz,
CDCl3, TMS) δ 1.96 (s, 3H, COCH3), 2.67 (s, 3H, ArCH3),
7.32-7.73 (m, 8H, ArH), 8.01-8.07 (d, 1H, J ) 8.17 Hz,
ArH). 13C NMR (75 MHz, CDCl3): δ 23.7, 31.7, 124.9,
126.0, 126.3, 128.5, 128.7, 129.9, 134.7, 135.1, 143.7, 147.4,
153.3, 205.4. MS (EI): m/z (%) ) 261 (M+, 50), 246 (100),
218 (55), 176 (25), 57 (10), 43 (25).
Conclusion
In summary, an efficient DOS of privileged quinoline
scaffolds has been described by using Friedlander annulation
reaction using CAN catalysis at ambient temperature in a
short period of time. This approach has led to the generation
of a diverse array of functionalized quinoline scaffolds of
considerable relevance for chemistry-driven drug discovery.
Moreover, in the preliminary studies, compounds 14, 16, 17,
and 18 have shown promising activities against a series of
cancer cell lines. We anticipate that the protocol of quinoline
synthesis and the DOS strategies described in the manuscript
could be explored further to have interesting implications in
the fields of combinatorial chemistry and chemistry-driven
drug discovery.
2-(tert-Butyl)-7-chloro-9-phenyl-1,2,3,4-tetrahydroacri-
1
dine (3d). mp 148-150 °C. H NMR (300 MHz, CDCl3,
TMS) δ 0.87 (s, 9H, 3 × CH3), 1.41-1.62 (m, 2H, CH2),
2.10-2.18 (m, 1H, CH), 2.22-2.34 (m, 1H, ArCH),
2.59-2.68 (m, 1H, ArCH), 3.00-3.15 (m, 1H, ArCH),
3.22-3.33 (m, 1H, ArCH), 7.18-7.23 (m, 3H, ArH),
7.46-7.58 (m, 4H, ArH), 7.89-7.92 (d, 1H, J ) 8.87 Hz,
ArH). 13C NMR (75 MHz, CDCl3): δ 24.1, 27.1, 29.4, 32.5,
34.8, 44.6, 124.5, 127.4, 128.1, 128.7, 128.8, 128.9, 129.2,
129.8, 130.0, 131.1, 136.3, 144.6, 145.9, 159.7. HRMS (ESI)
calcd for C23H24NCl 350.1675 [M + H]+, found 350.1680.
7-Chloro-3,3-dimethyl-9-phenyl-1,2,3,4-tetrahydro-1-
acridinone (3e). mp 219-220 °C.1H NMR (300 MHz,
CDCl3, TMS) δ 1.17 (s, 6H, 2 × CH3), 2.52 (s, 2H, COCH2),
3.23 (s, 2H, ArCH2), 7.11-7.15 (m, 2H, ArH), 7.36-7.37
(m, 1H, ArH), 7.48-7.53 (m, 3H, ArH), 7.64-7.69 (dd, 1H,
J1 ) 9.06, J2 )2.26 Hz, ArH), 7.95-7.99 (d, 1H, J ) 9.06
Experimental Section
Typical Procedure for the Synthesis of Methyl 6-Chloro-
2-(2-methoxy-2-oxoethyl)-4-phenyl-3-quinolinecarboxy-
late (3f). A mixture of 2-amino-5-chlorobenzophenone (2.31
g, 10.0 mmol), dimethyl 1,3-acetonedicarboxylate (1.74 g,

106 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Bose et al.
Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 28.3, 32.2, 48.2,
54.1, 123.2, 126.7,127.8, 127.9, 128.0, 128.1, 128.2, 128.3,
130.1, 132.4, 136.7, 147.3, 150.0, 161.4, 197.6. MS (ESI)
m/z 336 ([M + H]+, 100). HRMS (ESI) calcd for
C21H18NOCl 336.1155 [M + H]+, found 336.1146.
6-Chloro-3-cyano-2,4-diphenylquinoline(3g).mp192-194
°C.1H NMR (300 MHz, CDCl3, TMS) δ 7.46-7.72 (m, 9H,
ArH), 7.75-7.81 (dd, 1H, J1 ) 9.63, J2 )3.02 Hz, ArH),
7.96-8.02 (m, 2H, ArH), 8.15 (d, 1H, J ) 8.87 Hz, ArH).13C
NMR (75 MHz, CDCl3): δ 116.8, 128.6, 129.0, 129.1, 129.2,
129.3, 129.6, 130.0, 130.1, 130.8, 131.7, 133.4, 133.9, 133.8,
137.7, 147.0, 155.5, 158.7. EIMS: m/z (%) 343 (M+2, 25),
341 (72), 157 (12), 117 (15), 101 (45), 79 (100). Anal. Calcd
for C22H13N2Cl: C, 77.53, H, 3.84, N, 8.22. Found: C, 77.38,
H, 3.76, N, 8.17. IR (KBr): 2219 cm-1.
Ethyl 6-Chloro-2-(2-phthalimidoethoxy)methyl-4-phe-
nylquinoline-3-carboxylate (3h). mp 165-166 °C.1H NMR
(300 MHz, CDCl3, TMS) δ 0.92 (t, 3H, J ) 7.55 Hz, CH3),
3.68-3.74 (t, 2H, J ) 6.04 Hz, OCH2), 3.81-3.87 (t, 2H, J
) 6.04 Hz, NCH2), 4.00-4.08 (q, 2H, J ) 7.55 Hz,
CO2CH2), 4.91 (s, 2H, ArCH2), 7.29-7.34 (m, 2H, ArH),
7.45-7.51 (m, 4H, ArH), 7.61-7.73 (m, 3H, ArH), 7.77-7.83
(m, 2H, ArH), 7.80-8.02 (d, 1H, J ) 9.06 Hz, ArH). 13C
NMR (75 MHz, CDCl3): δ 13.5, 37.4, 61.4, 67.6, 73.5, 123.2,
123.3, 125.3, 127.0, 127.1, 128.3, 128.5, 128.7, 129.3, 131.0,
131.2, 132.1, 133.2, 133.8, 134.9, 145.5, 146.4, 155.0, 167.5,
168.1. HRMS (ESI) calcd for C29H23N2O5Cl 515.1373 [M
+ H]+, found 515.1359.
tert-Butyl 6-chloro-2-methyl-4-phenyl-3-quinolinecar-
boxylate (3i). mp 141-143 °C.1H NMR (300 MHz, CDCl3,
TMS) δ 1.21 (s, 9H, 3 × CH3), 2.73 (s, 3H, ArCH3), 7.22
(tt, 2H, J ) 8.6, 2.1 Hz, ArH), 7.32-7.37 (m, 2H, ArH),
7.42-7.44 (d, 1H, J ) 2.26 Hz, ArH), 7.47-7.54 (m, 3H,
ArH), 7.58-7.63 (dd, 1H, J1 ) 9.06, J2 )2.26 Hz, ArH),
7.96-8.00 (d, 1H, J ) 9.06 Hz, ArH).13C NMR (75 MHz,
CDCl3): δ 23.5, 27.5, 82.6, 125.1, 126.1, 128.3, 128.6, 129.5,
130.4, 130.8, 132.1, 135.0, 144.5, 145.8, 154.8, 167.0. MS
(ESI) m/z (%) 354 (M + H, 100). HRMS (ESI) calcd for
C21H21NO2Cl 354.1260 [M + H]+, found 354.1246.
3,3-Dimethyl-9-methyl-1,2,3,4-tetrahydro-1-acridino-
ne (3j). mp 104-106 °C.1H NMR (300 MHz, CDCl3, TMS)
δ 1.12 (s, 6H, 2 × CH3), 2.66 (s, 2H, ArCH3), 3.06 (s, 2H,
COCH2), 3.18 (s, 2H, ArCH2), 7.55 (ddd, 1H, J ) 8.2, 6.8,
1.2 Hz, ArH), 7.75 (ddd, 1H, J ) 8.2, 6.8, 1.2 Hz, ArH),
8.02 (d, 1H, J ) 8.2 Hz, ArH), 8.21 (d, 1H, J ) 8.2 Hz,
ArH).13C NMR (75 MHz, CDCl3): δ 15.6, 28.2, 31.2, 47.9,
54.7, 124.1, 125.5, 126.3, 127.5, 129.1, 130.7, 148.1, 150.0,
160.6, 200.2. HRMS (ESI) calcd for C16H17NO 239.1310
[M + H]+, found 239.1304.
(m, 2H, ArH), 7.57-7.68 (m, 5H, ArH), 7.92 (m, 1H, ArH),
8.12 (d, J ) 8.4 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3):
δ 23.8, 115.6 (q, J ) 308 Hz), 126.1, 127.1, 127.6, 128.5,
129.1, 129.4, 130.3, 131.3, 131.6, 147.5, 148.3, 153.3, 189.2
(q, J ) 38 Hz). MS (ESI) m/z (%) 316 (M + H, 100).
Typical Procedure for the Preparation of (6-Chloro-
2-methyl-4-phenyl-3-quinolyl)(morpholino)methanone (7a).
A mixture of 2-amino-5-chlorobenzophenone (1.155 g, 5.0
mmol), 1-morpholino-1,3-butanedione, 6a (0.855 g, 5.0
mmol), and CAN (0.274 g, 0.5 mmol, 10 mol %) in methanol
(5 mL) was stirred at RT for 60 min. After completion of
the reaction (monitored by TLC), the mixture was diluted
with ethyl acetate (30 mL), and washed with water (15 mL),
dried (Na2SO4), and concentrated under reduced pressure.
The resulting residue was purified by silica gel column
chromatography using EtOAc: petroleum ether (1:10) to
afford the pure product 7a (1.65 g, 90%). mp 187-189 °C;
1H NMR (200 MHz, CDCl3, TMS) δ 2.68 (s, 3H, ArCH3),
2.75-2.91 (m, 2H, CH2), 2.97-3.22 (m, 2H, CH2), 3.27-3.40
(m, 2H, CH2), 3.45-3.63 (m, 2H, CH2), 7.23-7.33 (m, 1H,
ArH), 7.46-7.68 (m, 6H, ArH), 7.95-8.03 (d, 1H, J ) 9.14
Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 23.4, 41.36, 46.4,
66.3, 124.9, 125.7, 128.1, 129.0, 129.1, 129.3, 130.1, 130.5,
130.9, 132.4, 134.2, 143.2, 146.1, 155.1, 167.0. MS (ESI):
m/z (%) ) 367 (M+H, 100). This procedure was followed
for the preparation of the compounds 7b-d.
(6-Chloro-2-methyl-4-phenyl-3-quinolyl)(piperidi-
no)methanone (7b). m.p.170-171 °C; 1H NMR (300 MHz,
CDCl3, TMS) δ 1.15-1.58 (m, 6H, 3 × CH2), 2.71 (s, 3H,
ArCH3), 2.76-2.86 (m, 1H, CH), 3.00-3.09 (m, 1H, CH),
3.33-3.42 (m, 1H, CH), 3.48-3.59 (m, 1H, CH), 7.29-7.35
(m, 1H, ArH), 7.46-7.67 (m, 6H, ArH), 7.98-8.03 (d, 1H,
J ) 8.30 Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 23.4,
24.0, 25.1, 25.9, 124.9, 125.9, 127.7, 128.8, 129.0, 129.4,
130.0, 130.4, 130.5, 132.2, 134.3, 142.9, 145.9, 155.3, 166.6.
MS (ESI): m/z (%) ) 365 (M + H, 100).
N3-[(1R)-1-Phenylethyl]-6-chloro-2-methyl-4-phenyl-3-
quinolinecarboxamide (7c). mp 225-227 °C; 1H NMR (300
MHz, CDCl3, TMS) δ 1.13-1.91 (d, 3H, J ) 6.80 Hz, CH3),
2.77 (s, 3H, ArCH3), 4.99-5.10 (q, 1H, J1 ) 6.80 Hz, J2 )
7.55 Hz, CH), 5,48-5.58 (broad doublet, 1H, J ) 7.55 Hz,
CONH), 6.91-7.00 (m, 2H, ArH), 7.19-7.29 (m, 4H, ArH),
7.34-7.43 (m, 2H, ArH), 7.47-7.56 (m, 3H, ArH), 7.61-7.66
(dd, 1H, J1 ) 9.06 Hz, J2 ) 2.26 Hz, ArH), 7.97-8.02 (d,
1H, J ) 9.06 Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 20.4,
23.5, 48.6, 125.1, 126.0, 127.3, 128.7, 128.8, 129.3, 129.4,
130.5, 130.7, 130.8, 132.2, 134.7, 141.8, 144.0, 145.9, 155.8,
166.7. MS (ESI): m/z (%) ) 401 (M + H, 100).
(1R,2R,5R)-2-Isopropyl-5-methylcyclohexyl-6-chloro-2-
methyl-4-phenyl-3-quinolinecarboxylate (7d). [R]D -68.93°
(Z)-4-(2-Benzoylphenylamino)-1,1,1-trifluoropent-3-en-
2-one (4). 1H NMR (300 MHz, CDCl3, TMS) δ 2.05 (s, 3H,
CH3), 5.42 (s, 1H, )CH), 7.26-7.69 (m. 9H, ArH). 13C
NMR (75 MHz, CDCl3): δ 20.3, 91.5, 114.5 (q, J ) 218
Hz), 127.1, 127.3, 128.5, 129.4, 130.3, 130.7, 131.7, 133.5,
134. 4, 137.6, 176.6 (q, J ) 34 Hz), 195.3. MS (ESI) m/z
(%) 334 (M + H, 100).
2,2,2-Trifluoro-1-(2-methyl-4-phenylquinolin-3-yl)etha-
none (3k). mp 82-84 °C (Lit.16c mp 80-81 °C). 1H NMR
(300 MHz, CDCl3, TMS) δ 2.61 (s, 3H, ArCH3), 7.36-7.41
1
(c 1.03, CHCl3, 20 °C). m.p.146-147 °C; H NMR (200
MHz, CDCl3, TMS) δ 0.55-0.63 (d, 1H, J ) 7.03 Hz, CH),
0.69-0.89 (dd, 6H, J1 ) 15.62 Hz, J2 ) 7.03 Hz, 2 × CH3),
0.90-1.28 (m, 3H, CH3), 1.29-1.69 (m, 7H, 3 × CH2 +
CH), 2.73 (s, 3H, ArCH3), 4.57-4.72 (dt, 1H, J1 ) 10.94
Hz, J2 ) 4.68 Hz, OCH), 7.27-7.67 (m, 7H, ArH),
7.94-8.03 (d, 1H, J ) 8.59 Hz, ArH). 13C NMR (75 MHz,
CDCl3): δ 15.8, 20.9, 22.0, 22.9, 23.8, 25.6, 31.4, 39.9, 46.7,
75.9, 125.2, 126.2, 128.6, 128.9, 129.6, 129.9, 130.0, 132.4,

Synthesis of Quinolines via Friedla¨nder Annulation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 107
ether (1:3) as eluent to give compound 9 as a light yellow
solid (0.341 g) in 85% yield. m.p.185-187 °C; H NMR
134.8, 144.7, 146.1, 154.8, 167.9. MS (ESI): m/z (%) ) 436
(M + H, 100).
1
(300 MHz, CDCl3, TMS) δ 2.47 (s, 3H, ArCH3), 2.65 (s,
3H, ArCH3), 7.23-7.33 (m, 6H, ArH), 7.50-7.52 (m, 2H,
ArH), 7.64-7.69 (m, 1H, ArH), 7.88-7.92 (d, 1H, J ) 8.50
Hz, ArH), 8.03-8.07 (d, 1H, J ) 9.06 Hz, ArH). 13C NMR
(75 MHz, CDCl3): δ 21.5, 24.7, 121.1, 122.9, 126.4, 127.5,
127.7, 128.2, 128.4, 130.0, 130.6, 131.2, 132.2, 134.8, 135.5,
136.6, 146.3, 147.8, 151.0, 157.7, 163.6. MS (ESI): m/z (%)
) 401 (M + H, 100).
N1-(4-Methylphenyl)-3-oxobutanamide (6e). A mixture
of tert-butyl acetoacetate (1.58 g, 10.0 mmol), and p-toluidine
(1,07 g, 10.0 mmol), in 10 mL of dry xylene was heated in
a 50 mL beaker for a period of 5 min until colorless vapors
of tert-butanol came out. TLC (EtOAc: petroleum ether, 1:2),
showed the completion of the reaction. The reaction mixture
was cooled and washed with hexane. Upon flash chroma-
tography of this crude solid resulted in a pure cream colored
1
solid 6e (1.81 g, 95% yield). mp 92-93 °C; H NMR (300
Ethyl 6-Chloro-2-(chloromethyl)-4-phenyl-3-quinolin-
ecarboxylate (10). A mixture of 2-amino-5-chlorobenzophe-
none (2.31 g, 10.0 mmol), ethyl 4-chloroacetoacetate (2.07
g, 10 mmol), and CAN (0.548 g, 1 mmol, 10 mol %) in
methanol (15 mL) was stirred at RT for 60 min. After
completion of the reaction (monitored by TLC), the mixture
was diluted with ethyl acetate (40 mL), and washed with
water (25 mL), dried (Na2SO4), and concentrated under
reduced pressure. The resulting residue was purified by silica
gel column chromatography using petroleum ether to afford
the pure product 10 (3.41 g, 95%). mp 105-106 °C; Lit.
106-108 °C.24 1H NMR (300 MHz, CDCl3, TMS) δ
0.87-0.93 (t, 3H, J ) 7.55 Hz, CH3), 3.97-4.05 (q, 2H, J
) 7.55 Hz, CO2CH2), 4.97 (s, 2H, ArCH2), 7.32-7.36 (m,
2H, ArH), 7.48-7.55 (m, 4H, ArH), 7.66-7.70 (dd, 1H, J1
) 9.06 Hz, J2 ) 2.66 Hz, ArH), 8.04-8.08 (d, 1H, J )
9.06 Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 13.1, 45.5,
61.4, 124.7, 126.3, 126.6, 128.5, 128.9, 129.0, 131.4, 131.8,
132.9, 134.1, 145.1, 146.9, 153.0, 166.2. MS (FAB): m/z
(%) ) 360 (M+, 45), 362 (M+2, 28), 363 (M+3, 4), 364
(M+4, 4).
MHz, CDCl3, TMS) δ 2.30 (s, 3H, COCH3), 2.31 (s, 3H,
ArCH3), 3.51 (s, 2H, COCH2CO), 7.04-7.10 (d, 1H, J )
8.31 Hz, ArH), 7.36-7.41 (d, 1H, J ) 8.31 Hz, ArH), 9.09
(broad singlet, 1H, CONH). MS (ESI): m/z (%) ) 192 (M
+ H, 100), 214 (M + Na+, 20).
N3-(4-Methylphenyl)-6-chloro-2-methyl-4-phenyl-3-quin-
olinecarboxamide (7e). A mixture of 2-amino-5-chloroben-
zophenone (1.155 g, 5.0 mmol), N1-(4-methylphenyl)-3-
oxobutanamide, 6e (0.955 g, 5.0 mmol), and CAN (0.274 g,
0.5 mmol, 10 mol %) in methanol (5 mL) was stirred at RT
for 60 min. After completion of the reaction (monitored by
TLC), the reaction mixture was diluted with ethyl acetate
(30 mL), and washed with water (15 mL), dried (Na2SO4),
and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography
using EtOAc: petroleum ether (1:1) to afford the pure product
1
7e (1.74 g, 90%). mp 227-229 °C; H NMR (300 MHz,
CDCl3, TMS) δ 2.29 (s, 3H, ArCH3), 2.83 (s, 3H, ArCH3),
6.80 (s, 1H, CONH), 6.93-7.01 (m, 4H, ArH), 7.40-7.55
(m, 6H, ArH), 7.62-7.67 (dd, 1H, J1 ) 9.06 Hz, J2 ) 2.66
Hz, ArH), 7.97-8.01 (d, 1H, J ) 9.06 Hz, ArH). MS (ESI):
m/z (%) ) 387.20 (M + H, 100).
Ethyl 6-Chloro-2-[(2S)-2-(hydroxymethyl)tetrahydro-
1H-1-pyrrolyl]methyl-4-phenyl-3-quinolinecarboxylate (11).
A (0.718 g, 2) mmol portion of compound 10 was dissolved
in CH3CN followed by the addition of Et3N (1 mL) and
catalytic DMAP. Stirring was continued for a period of 30
min at RT followed by the addition of S-prolinol (0.202 g,
2 mmol). Reaction was continued until complete disappear-
ance of the starting material was observed with TLC. CH3CN
was removed in vacuo, quenched with cold water, and
extracted with ethyl acetate (2 × 5 mL). The combined
organic layers were washed with brine, dried over anhydrous
sodium sulfate, and concentrated in vacuo to afford the crude
product. Column chromatography of the crude product gave
a dark red color solid compound 11 (0.637 g, 75% yield).
N3-(4-Methylphenyl)-6-chloro-2-methyl-4-phenyl-3-quin-
olinecarbothioamide (8). Lawesson’s reagent (0.404 g, 1.0
mmol) was added to the stirred solution of quinoline amide
7f (0.774 g, 2.0 mmol) in dry toluene 5 mL at 60 °C. The
reaction mixture was refluxed for 1-2 h, and after the
completion of the reaction (monitored by TLC) toluene was
removed by vacuo distillation. Sodium hypochlorite was
added to the residue to quench the reaction. Ice-cubes were
added to get a dark yellow crude solid which was filtered
through a Buchner funnel. Recrystallization using acetone:
water afforded pure pale yellow prisms of compound 8 (0.645
1
g) in 80% yield. mp 179-180 °C; H NMR (200 MHz,
1
CDCl3, TMS) δ 2.35 (s, 3H, ArCH3), 2.75 (s, 3H, ArCH3),
6.34 (s, 1H, CSNH), 7.05-7.17 (d, 1H, J ) 8.53 Hz, ArH),
7.29-7.63 (m, 9H, ArH), 7.98-8.05 (d, 1H, J ) 9.30 Hz,
ArH). MS (ESI): m/z (%) ) 403 (M + H, 100).
[R]D -21.20° (c 1.02, CHCl3, 20 °C). mp 172-174 °C; H
NMR (200 MHz, CDCl3, TMS) δ 0.76-0.86 (t, 3H, J )
7.35 Hz, CH3), 1.49-1.90 (m, 4H, 2 × CH2), 2.33 (m, 1H,
CH), 2.62-2.74 (m, 1H, CH), 2.85-2.97 (m, 1H, asym-
metric CH), 3.24-3.36 (m, 1H, OCH), 3.48-3.58 (m, 1H,
OCH), 3.80-4.03 (m, 3H, CO2CH2 + ArCH), 4.35-4.45
(m, 1H, ArCH), 7.26-7.41 (m, 2H, ArH), 7.45-7.57 (m,
4H, ArH), 7.61-7.69 (dd, 1H, J1 ) 8.81 Hz, J2 ) 2.20 Hz,
ArH), 7.99-8.05 (d, 1H, J ) 8.81 Hz, ArH). 13C NMR (75
MHz, CDCl3): δ 13.3, 23.8, 26.7, 55.1, 57.8, 62.0, 61.5, 68.3,
125.4, 126.8, 129.0, 129.0, 129.2, 131.0, 131.9, 133.8, 134.7,
145.4, 147.4, 167.7. MS (ESI): m/z (%) ) 425 (M + H,
100). This procedure was followed for the synthesis of the
compounds 12 and 13.
2-(6-Chloro-2-methyl-4-phenyl-3-quinolyl)-6-methyl-
1,3-benzothiazole (9). DMP (0.424 g, 1.1 mmol) was added
to a stirred solution of quinoline thioformanilide, 8 (0.403
g, 1.0 mmol) in CH2Cl2 (5 mL) at RT. The progress of the
reaction was monitored with TLC. After completion, it was
quenched with H2O (2 × 5 mL) and extracted with CH2Cl2
(2 × 5 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, and concentrated
in vacuo to afford the crude product which was purified by
column chromatography on silica gel using EtOAc:petroleum

108 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Bose et al.
Ethyl 2-[4-(tert-Butoxycarbonyl)piperazino]methyl-6-
chloro-4-phenyl-3-quinolinecarboxylate (12). mp 169-171
°C; 1H NMR (300 MHz, CDCl3, TMS) δ 0.79-0.84 (t, 3H,
J ) 7.55 Hz, CH3), 1.43 (s, 9H, 3 × CH3), 2.40-2.48 (m,
4H, 2 × CH2), 3.26-3.33 (m, 4H, 2 × CH2), 3.88-3.96
(m, 4H, CO2CH2 + ArCH2), 7.31-7.36 (m, 2H, ArH),
7.47-7.54 (m, 4H, ArH), 7.62-7.67 (dd, 1H, J1 ) 9.06 Hz,
J2 ) 2.26 Hz, ArH), 7.99-8.03 (d, 1H, J ) 9.06 Hz, ArH).
13C NMR (75 MHz, CDCl3): δ 13.4, 28.3, 43.7, 52.4, 60.8,
63.6, 79.6, 125.2, 127.0, 127.5, 128.3, 128.6, 129.2, 130.8,
131.0, 132.8, 135.0, 145.4, 146.2, 154.6, 156.5, 167.8. MS
(ESI): m/z (%) ) 510 (M + H, 100).
(Na2SO4) and concentrated under reduced pressure to afford
a solid residue, which was purified by silica gel column
chromatography (EtOAc: petroleum ether 2:5) gave a gummy
compound 15 (2.482 g, 85% yield). [R]D -28.481° (c 1.58,
CHCl3, 20 °C). 1H NMR (200 MHz, CDCl3, TMS) δ
0.77-0.86 (t, 3H, J ) 7.41 Hz, CH3), 1.24-1.49 (m, 12H,
4 × CH3), 3.86-4.08 (m, 6H, CO2CH2 + OCH2 + 2 × CH),
4.18-4.30 (m, 1H, CH), 4.59-4.63 (d, 1H, J ) 3.70 Hz,
CH), 4.98-5.05 (d, 2H, J ) 5.92 Hz, ArCH2), 5.76-5.81
(d, 1H, J ) 3.70 Hz, CH), 7.25-7.39 (m, 2H, ArH),
7.45-7.55 (m, 4H, ArH), 7.63-7.71 (dd, 1H, J1 ) 8.89 Hz,
J2 ) 2.22 Hz, ArH), 8.02-8.09 (d, 1H, J ) 8.89 Hz, ArH).
13C NMR (75 MHz, CDCl3): δ 13.3, 25.4, 26.2, 26.8, 61.3,
67.0, 72.4, 73.2, 81.0, 82.0, 83.0, 105.2, 108.9, 111.7, 125.3,
126.9, 127.0, 128.3, 128.8, 129.0, 129.3, 131.1, 131.4, 133.4,
135.0, 145.6, 146.6, 154.3, 167.6. MS (ESI): m/z (%) ) 584
(M + H, 100).
Ethyl 6-Chloro-2-(morpholinomethyl)-4-phenyl-3-quin-
1
olinecarboxylate (13). mp 162-164 °C; H NMR (300
MHz, CDCl3, TMS) δ 0.82-0.91 (t, 3H, J ) 7.34 Hz, CH3),
2.45-2.53 (t, 4H, J ) 5.14 Hz, 2 × CH2), 3.56-3.64 (t,
4H, J ) 5.14 Hz, 2 × CH2), 3.92-4.05 (m, 4H, CO2CH2 +
ArCH2), 7.31-7.39 (m, 2H, ArH), 7.46-7.58 (m, 4H, ArH),
7.63-7.70 (dd, 1H, J1 ) 8.81 Hz, J2 ) 2.20 Hz, ArH),
8.01-8.08 (d, 1H, J ) 9.55 Hz, ArH). 13C NMR (75 MHz,
CDCl3): δ 13.5, 53.1, 60.9, 64.0, 66.9, 125.3, 127.0, 127.6,
128.3, 128.6, 129.3, 130.8, 131.0, 132.8, 135.1, 145.4, 146.1,
156.5, 167.8. MS (ESI): m/z (%) ) 411 (M + H, 100).
Ethyl 2-[((3aS,5R,6S,6aS)-5-[(1S)-1,2-dihydroxyethyl]-
2,2-dimethylperhydrofuro[2,3-d][1,3]dioxol-6-yloxy)methyl]-
6-chloro-4-phenyl-3-quinolinecarboxylate (16). To a stirred
solution of compound 15 (1.168 g, 2 mmol) in MeOH (15
mL), was added aqueous 0.8% H2SO4 solution and stirred
for overnight. TLC (ethyl acetate: hexane, 1:1) showed the
completion of the reaction. Methanol was removed in vacuo,
and the residue was treated with saturated solution of
NaHCO3 and extracted with ethyl acetate (2 × 5 mL). The
combined organic extracts were washed with brine, dried
(Na2SO4), filtered, and the solvent was removed in vacuo.
Purification by column chromatography using EtOAc:petro-
leum ether (1:2) afforded a colorless solid compound 16
(0.707 g, 65% yield). [R]D -40.19° (c 1.02, CHCl3, 20 °C).
Ethyl 6-Chloro-2-([([6-chloro-3-(ethoxycarbonyl)-4-
phenyl-2-quinolyl]methylamino) carbothioyl]aminomethyl)-
4-phenyl-3-quinolinecarboxylate (14). To a solution of
thiourea (0.152 g, 2 mmol), in dry CH3CN was added NaH,
60% w/w (0.177 g, 4.4 mmol), in portions at 0 °C. After
stirring for 30 min compound 10 (1.436 g, 4.0 mmol) was
added, and the reaction mixture was refluxed for 5-6 h until
TLC showed complete disappearance of the starting materi-
als. CH3CN was removed in vacuo, and the reaction was
quenched with cold water (5 mL). Ethyl acetate (2 × 5 mL)
was used for extraction, which was washed simultaneously
with brine and dried (Na2SO4) and concentrated under
reduced pressure. Column chromatography on silica gel
(EtOAc: petroleum ether 1:3) gave a pale yellow solid
1
[R]D -40.19° (c 1.02, CHCl3, 20 °C). mp 104-106 °C; H
NMR (300 MHz, CDCl3, TMS) δ 0.80-0.90 (t, 3H, J )
7.55 Hz, CH3), 1.22-1.33 (m, 6H, 2 × CH3), 2.03 (s, 1H,
OH), 2.07 (s, 1H, OH), 3.70-3.77 (m, 1H, CH), 3.89-4.15
(m, 5H, CO2CH2, + OCH2 + CH), 4.22-4.30 (m, 1H, CH),
4.62-4.66 (d, 1H, J ) 3.77 Hz, CH), 4.86-4.94 (d, 1H, J
) 16.61 Hz, ArCH), 5.12-5.20 (d, 1H, J ) 16.61 Hz,
ArCH), 5.93-5.97 (d, 1H, J ) 3.77 Hz, CH), 7.27-7.34
(m, 2H, ArH), 7.49-7.56 (m, 4H, ArH), 7.69-7.74 (dd, 1H,
J1 ) 9.06 Hz, J2 ) 2.26 Hz, ArH), 8.18-8.23 (d, 1H, J )
9.06 Hz, ArH). 13C NMR (75 MHz, CDCl3): δ 13.4, 26.3,
26.8, 61.9, 64.7, 68.12, 69.1, 80.4, 81.9, 82.9, 105.8, 111.8,
125.4, 126.8, 128.5, 129.0, 130.0, 133.6, 132.1, 134.6, 145.2,
147.6, 153.9, 166.8. MS (ESI): m/z (%) ) 545 (M + H,
100).
1
compound 14 (1.084 g, 75% yield). H NMR (300 MHz,
CDCl3, TMS) δ 0.79-0.86 (t, 6H, J ) 6.80 Hz, 2 × CH3),
1.85 (s, 2 × NH), 3.90-3.98 (q, 4H, J ) 7.55 Hz, 2 × CH2),
4.28 (s, 4H, 2 × ArCH2), 7.12-7.19 (m, 2H, ArH),
7.42-7.51 (m, 4H, ArH), 7.60-7.66 (dd, 1H, J1 ) 9.06 Hz,
J2 ) 2.26 Hz, ArH), 7.81-7.86 (d, 1H, J ) 9.06 Hz, ArH).
13C NMR (75 MHz, CDCl3): δ 13.4, 37.6, 61.3, 125.2, 126.4,
126.9, 128.3, 128.6, 129.1, 131.0, 131.1, 132.8, 135.3, 145.5,
146.6, 155.7, 167.5. MS (ESI): m/z (%) ) 724 (M + H,
100).
2-[(1S)-1-Benzyl-2-hydroxyethyl]-7-chloro-9-phenyl-
2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (17). To a
mixture of compound 10 (0.718 g, 2 mmol), and Et3N (1
mL) in CH3CN (5 mL) was added S-phenylalaninol (0.302
g, 2 mmol). The stirring was continued for a period of 2-3
h at RT. TLC showed the appearance of a new spot
corresponding to the intermediate ester 17a. The reaction
mixture was further stirred at 40-45 °C for a period of 12 h,
until the TLC showed the complete disappearance of the
intermediate 17a. CH3CN was removed in vacuo, quenched
with cold water (5 mL), and extracted with ethyl acetate (2
× 5 mL). The combined organic extracts were washed with
brine, dried (Na2SO4), filtered, and the solvent was removed
Ethyl 2-[((3aS,5S,6S,6aS)-5-[(4S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-2,2-dimethylperhydrofuro[2,3-d][1,3]dioxol-
6-yloxy)methyl]-6-chloro-4-phenyl-3-quinolinecarboxy-
late (15). To a solution of D-glucose diacetonide (1.30 g, 5
mmol), in dry THF was added NaH, 60% w/w (0.200 g, 5.5
mmol), in portions at 0 °C. After stirring for 30 min
compound 10 (1.795 g, 5 mmol) was added and stirring was
continued for further 2-4 h at RT until TLC showed
complete disappearance of the starting materials. CH3CN was
removed in vacuo, and the reaction was quenched with cold
water (5 mL) and extracted with ethyl acetate (2 × 5 mL).
The combined extracts were washed with brine and dried

Synthesis of Quinolines via Friedla¨nder Annulation
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 109
(6) Reayi, A.; Arya, P. Curr. Opin. Chem. Biol. 2005, 9, 240–
in vacuo. Column chromatography of the crude product gave
a light red color compound 17 (0.686 g, 80 [R]D -91.000°
(c 1.00, CHCl3, 20 °C). mp 80-82 °C; 1H NMR (300 MHz,
CDCl3, TMS) δ 2.71 (broad singlet, 1H, OH), 3.00-3.07
(d, 2H, J ) 7.55 Hz, ArCH2), 3.72-3.85 (m, 2H, CH2),
4.42-4.53 (m, 3H, CH2-pyrrolone + asymmetric CH),
7.08-7.39 (m, 7H, ArH), 7.50-7.56 (m, 3H, ArH), 7.65-7.72
(m, 2H, ArH), 7.98-8.04 (d, 1H, J ) 9.06 Hz, ArH). 13C
NMR (75 MHz, CDCl3): 35.1, 49.3, 56.0, 62.7, 120.7, 126.0,
126.5, 127.8, 128.0, 128.5, 128.7, 129.0, 129.7, 130.4, 131.8,
132.7, 137.4, 146.7, 147.7, 160.9, 166.3. MS (ESI): m/z (%)
) 430 (M + H, 30), 380 (35), 366 (100). This procedure
was followed for the preparation of the compound 18.
7-Chloro-9-phenyl-2-[(1R)-1-phenylethyl]-2,3-dihydro-
1H-pyrrolo[3,4-b]quinolin-1-one (18). [R]D 266.05° (c 1.09,
247.
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1
CHCl3, 20 °C). mp 125-127 °C; H NMR (300 MHz,
CDCl3, TMS) δ 1.68-1.73 (d, 3H, J ) 7.55 Hz, CH3),
4.10-4.17 (d, 1H, J ) 16.61 Hz, CH-pyrrolone), 4.43-4.50
(d, 1H, J ) 16.61 Hz, CH-pyrrolone), 5.75-5.83 (q, 1H, J
) 7.55 Hz, asymmetric CH), 7.21-7.39 (m, 5H, ArH),
7.41-7.47 (m, 2H, ArH), 7.54-7.62 (m, 3H, ArH), 7.66-7.70
(dd, 1H, J1 ) 9.06 Hz, J2 ) 2.26 Hz, ArH), 7.74-7.76 (d,
1H, J ) 2.26 Hz, ArH), 8.00-8.04 (d, 1H, J ) 9.06 Hz,
ArH). 13C NMR (75 MHz, CDCl3): δ 17.0, 46.4, 49.1, 120.9,
126.1, 127.2, 127.8, 128.1, 128.7, 129.0, 129.8, 129.9, 130.6,
131.8, 132.0, 132.7, 139.9, 146.9, 148.0, 160.9, 165.0. MS
(ESI): m/z (%) ) 399 (M + H, 15).
Acknowledgment. Two of the authors (M.I. and N.M.J.)
thanks CSIR, New Delhi, for financial support.
Supporting Information Available. General experimental
information, experimental procedures, characterization data
and copies of 1H, 13C NMR and mass spectra of the
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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CC900129T