Copper-catalyzed synthesis of quinoline derivatives via tandem Knoevenagel condensation, amination and cyclization

Article abstract of DOI:10.1039/c6ra03798d

A novel regioselective synthesis of 2-aminoquinolines and 2-arylquinoline-3-carbonitriles is described via copper-mediated tandem reaction. Formation of substituted quinolines involves Knoevenagel condensation of ortho-bromobenzaldehyde with active methylene nitriles followed by copper-catalyzed reductive amination and intramolecular cyclization.

Full text of DOI:10.1039/c6ra03798d

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Copper-Catalyzed Synthesis of Quinoline Derivatives via Tandem
Knoevenagel Condensation, Amination and Cyclization§
Received 00th January 20xx,
Accepted 00th January 20xx
Shiv Dhiman, Hitesh Kumar Saini, Nitesh Kumar Nandwana, Dalip Kumar and Anil Kumar*
A novel regioselective synthesis of 2-aminoquinolines and 2-arylquinoline-3-carbonitriles is described via copper-mediated
tandem reaction. Formation of substituted quinolines involves Knoevenagel condensation of ortho-bromobenzaldehyde
with active methylene nitriles followed by copper-catalyzed reductive amination and intramolecular cyclization.
DOI: 10.1039/x0xx00000x
www.rsc.org/
reactions.13 In past, these reactions have been successfully
employed for quinoline synthesis but they require stoichiometric
amounts of acidic reagents and are often performed under harsh
Introduction
Quinoline skeleton is one of the most prevalent motifs found in
many drugs, natural products and pharmacologically active
substances.1 Compounds with this motif have been found to
possess a broad range of biological activities such as anticancer,2
antifungal,3 antimalarial,4 antituberculosis,5 antiprotozoal,6
antiinflammatory,7 and antineoplastic,8 inhibition of epidermal
growth factor receptor (EGFR) and human epidermal growth factor
receptor-2 (HER-2) kinases.9 Functionalized quinolines are also used
as dyestuff,10 asymmetric catalysts,11 ligands for transition metal
complexes and for the preparation of nano- and mesostructures
with improved electronic and photonic properties.12 Some
promising compounds with quinoline motif are shown in Figure 1.
conditions. Moreover, use of harsh reaction conditions and highly
reactive acid catalysts restrict involvement of functionally
substituted substrates for synthesis of corresponding quinolines. In
recent years, several approaches based on tandem reactions,
transition metal catalysts and alternative starting materials have
been developed for mild and efficient syntheses of quinolines.14 For
example, Li et. al have developed a copper-catalyzed synthesis of
quinolines from ortho-acylanilines and alkenyl iodides.15 Yu and co-
workers developed synthesis of quinolines from 2-
aminobenzylamine and ketones via copper-catalyzed C–N bond
cleavage.16 Consisting CuI and a secondary amine, Patil group
developed a co-operative catalytic system for the synthesis of 2-
substituted quinolines by utilizing 2-aminobenzaldehydes and
terminal alkynes.17 In particular, 2-aminoquinolines are important
target molecules because of their sub-nanomolar potency for BACE
inhibition18 and selective neuronal nitric oxide synthase (nNOS)
inhibition activities.19 Only a handful reports are available for
synthesis of 2-aminoquinoline derivatives.20 Tomioka et. al have
reported one-pot synthesis of 2-aminoquinolines from 2-
nitrobenzaldehydes and acetonitrile via stereoselective olefination
followed by reductive cyclization.20a Jiang group have synthesized 2-
Cl
N
Me
Et
N
N
HO
NH
N
HN
N
Et
N
N
H
N
N
CN
MeO
O
EtO
Cl
N
NH2
N
EGFR & HER-2 inhibitor
Antimalarial agent
Anticancer agent
Antimalarial, Analgesic
O
Cl
O
O
O
N
O
N
OEt
Ir
N
N
O
N
NH
NHPh
H
2
N
NH2
O
aminoquinolines
by
Pd-catalyzed
reactions
of
gem-
NR
red-emitting Ir(III) complexes
dibromovinylanilines and tert-butyl isocyanide.20b, 20c Liu et. al have
utilized 4-halo-2-aminoquinolines in a Pd-catalyzed intermolecular
aerobic oxidative cyclization of 2-ethynylanilines with isocyanide to
prepare 2-aminoquinolines.20d Owing to potential applications in
various fields, quinolines continue to attract the attention of
scientists from different areas, and the development of new
synthetic methods for quinolines are still of great interest.
p38 MAPK inhibitor
BACE inhibitor
Figure 1: Some promising quinoline derivatives
Generally, quinoline and its derivatives are prepared by
conventional methods including Friedländer, Pfitzinger,
Doebner−von Miller, Skraup, Combes and Conrad−Limpach
Furthermore, the direct amination of aryl halides using NaN3 or
TMSN3 as the amino source in the presence of copper or copper
salt has been reported.21 Trapping of the intermediate azide or
amine of this copper catalyzed reductive amination have resulted in
the synthesis of bioactive heterocycles such as quinolones, 3-
aminoquinolines, 3-aminocoumarines, tetracyclic indoloindol-3-
ones, pseudo-indoxyl derivatives, indazole and 2-aroylindoles.22 As a
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part of our continuous efforts in the development of new synthetic stopped at the Knoevenagel adduct in the absence of catalyst
methods for heterocyclic compounds by employing C–C /C–N (Table 1, entry 26) and yield of desired product 4aa was diminished
coupling reactions,23 herein we report our results on one-pot in the absence of L-proline (Table 1, entry 27).
copper-catalyzed regioselective synthesis of 2-aminoquinolines and
2-arylquinoline-3-carbonitriles via tandem reactions involving 2-
bromobenzaldehydes, active methylene nitriles and sodium azide
(Scheme 1).
Table 1: Optimization of reaction conditions.a
Entry Catalyst
(mol %)
Ligand
Base
Solvent
Yield
(%)b
35
9
(mol %)
(2.5 equiv)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
tBuOK
CsCO3
Na2CO3
NaOMe
Et3N
1
CuI (10)
L-proline (20)
L-proline (20)
L-proline (20)
DMF
2
CuCl2 (10)
CuBr (10)
DMF
3
DMF
20
13
31
26
55
50
38
30
10
8
4
Cu(OAc)2 (10) L-proline (20)
DMF
Scheme 1: Synthesis of 2-aminoquinolines and 2-arylquinoline-3-carbonitriles
5
CuOTf (10)
CuSO4 (10)
CuI (20)
CuI (30)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
-
L-proline (20)
L-proline (20)
L-proline (40)
L-proline (60)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
L-proline (40)
Glycine (40)
DMEDA (40)
1,10-Phene (40)
8-HQf (40)
DMF
6
DMF
7
DMF
Results and discussion
8
DMF
Our initial study began with the reaction of 2-
bromobenzaldehyde (1a) with ethyl cyanoacetate (2a) and sodium
azide (3) in the presence of CuI (10 mol %), L-proline (20 mol %),
K2CO3 (2.5 equiv) in N,N'-dimethylformamide (DMF) at 150 °C under
air atmosphere for 3 h. Gratifyingly, ethyl 2-aminoquinoline-3-
carboxylate (4aa) was isolated in 35% yield (entry 1). The structure
of 4aa was characterized by various spectroscopic techniques such
as IR, NMR and mass spectrometry. In IR spectrum of 4aa, strong
peaks at 3410 and 1697 cm‒1 are indicative of -NH2 and -C=O
functionalities, respectively. In 1H NMR spectrum, characteristic
singlets at δ 8.77 and δ 7.26 (broad) for C4‒H and NH2 protons were
observed. The carbonyl carbon of CO2Et appeared at δ 166.5 along
with all other expected peaks in 13C NMR spectrum of 4aa. Further,
the structure was ascertained by HRMS analysis of 4aa which
9
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
DMF
DMF
DMF
DMF
11
c
-
DMF
DBU
DMF
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
NMP
62
28
37
10d
DMA
Dioxane
Toluene
PEG-400
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
-
+
showed a molecular ion C12H13N2O2 [M+H]+ peak at m/z 217.0976
in agreement with the calculated mass 217.0972.
-
To further improve the yield of tandem product 4aa, various
experimental conditions were screened by varying copper catalysts,
ligands, bases and solvents (Table 1). Firstly, screening of various
copper salts such as CuI, CuCl2.H2O, CuBr, Cu(OAc)2.H2O, CuOTf and
CuSO4 revealed that CuI was the best catalyst for this
transformation giving highest yield of 4aa (Table 1, entries 1‒6).
Further investigations on the effect of catalyst loading suggested
that 20 mol % CuI afforded 4aa in highest yield (55%) (Table 1,
entries 1, 7- 8). Among various bases (K2CO3, K3PO4, tBuOK, Cs2CO3,
Na2CO3, NaOMe, Et3N and DBU) examined (Table 1, entries 7, 9‒
16), K2CO3 was found to be the most suitable base. In case of
triethylamine, the reaction exclusively led to Knoevenagel adduct
(Table 1, entry 14). Reactions in different solvents namely DMSO,
N,N-dimethylacetamide (DMA), toluene, N-methyl-2-pyrrolidone
(NMP), 1,4‒dioxane and PEG-400 (Table 1, entries 16‒21) revealed
DMSO as a the solvent of choice for this reaction. When the
reaction was performed in toluene at 120 °C only Knoevenagel
adduct was obtained in 45% yield (Table 1, entry 20). Finally, by
screening of different ligands (Table 1, entries 16, 21‒25), L-proline
was found to be the most effective ligand. The reaction was
38
42
12
9
L-proline (40)
-
-
CuI (20)
20
aReaction conditions: 1a (0.54 mmol), 2a (0.65 mmol) NaN3 (3) (0.81 mmol),
catalyst, ligand, base (2.5 equiv.), 150 °C, air atmosphere, 3 h. bIsolated yields.
cReaction time 12h, only Knoevenagel adduct 6. dKnoevenagel adduct 6 (120 °C,
45%). e1,10-Phen = 1,10-Phenanthroline. f8-HQ = 8-Hydroxyquinoline.
With the optimized reaction condition in hand (Table 1, entry 16),
we explored the substrate generality for this tandem reaction by
employing the substituted 2-bromobenzaldehydes and active
methylene nitriles (Table 2). Reactions of substituted 2-
bromobenzaldehydes 1a-c with different active methylene nitriles
2a-e gave corresponding 2-aminoquinolines in moderate to good
yields (4aa‒ae). The method tolerated different functional groups
such as cyano, methoxy, ester, and amide. Structures of all the
2 | J. Name., 2012, 00, 1-3
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compounds were confirmed by IR, NMR (1H & 13C) and HRMS data benzoyl-3-(2-bromophenyl)acrylonitrile (10) which on reaction with
(Supporting Information). NaN3, CuI, L-proline and K2CO3 at 150 C after 2 h resulted in
°
Notably, when benzoylacetonitrile (X = ArCO, 2) was used as an exclusive formation of 5aa (Scheme 2G and 2H). This may be
active methylene nitrile, instead of expected 2-aminoquinoline, 2- attributed to the relative electrophilicity of carbonyl group over
phenylquinoline-3-carbonitrile (5aa) was obtained in 62% yield. nitrile group. Structure of 10 was confirmed NMR, mass and single
Formation of 5aa prompted us to evaluate the regioselectivity of X-ray analysis (CCDC 1433055, Figure 2).
this reaction for benzoylacetonitriles. As can be seen from Table 2,
O
CHO
benzoylacetonitriles containing methyl, methoxy, dioxole and
chloro substituent reacted efficiently with 2-bromobenzaldehydes
O
OEt
K2CO3, DMSO
rt, 30 min
(A)
CN
CN
EtO
OEt
Br
6, 78%
Br
2a
1a
6
O
O
to give corresponding quinoline-3-carbonitriles
(
5aa-ah
)
in
CN
O
NaN3, CuI, L-Proline
OEt
moderate to good yields. Similarly, 2-bromobenzaldehydes bearing
methoxy and chloro groups were treated with different substituted
benzoylacetonitriles to give corresponding 2-arylquinoline-3-
carbonitriles in moderate to good yields (5ca‒cd).
or
(B)
(C)
CN
K2CO3, DMSO
150°C, 2 h
N
NH2
N
Br
H
4aa, 70%
7, not observed
CHO
CHO
Br
NaN3, CuI, L-Proline
O
DMSO
O
NH2
OEt
OEt
8, 64%
1a
Table 2 Synthesis of 2-aminoquinolines.a,b
CN
NH2
O
CN
EtO
CHO
Br
9, 50%
100 °C
2 h
OEt
(D)
O
CuI (20 mol %)
CHO
CN
Ar
NaN3, CuI, L-Proline
X
L-Proline (40 mol %)
CN
R'
Br
NaN3
R'
or
XCH2CN
R'
K2CO3, DMSO, rt, 30 min.
Br
K2CO3 (2.5 eq), DMSO
150 °C, 3 h
NH2
N
N
1a
6
O
O
1
2
3
4
5
N
NH2
4aa, 8%
OEt
OEt
NH2
CuI, K2CO3, DMSO
O
CN
CN
CN
O
(E)
(F)
CN
OEt
NH2
NH2
N
4aa, 67%
OEt
NH2
150 °C, 2 h
N
Ph
N
N
N
9
MeO
OEt
N
Me
OMe
CN
Ph
5ac, 45%
CN
4aa, 62%
4ba, 66%
5aa, 59%
5ab, 41%
CHO
Br
K2CO3, DMSO
rt, 30 min
O
CN
CN
O
O
CN
MeO
MeO
O
Ph
Ph
NH2
NH2
Br
N
N
N
10, 70 %
N
NH2
N
1a
Me
OMe
MeO
5af, 45%
O
CN
4ca, 53%
4ab, 52%
5ad, 50%
5ae, 32%
OMe
CN
NaN3, CuI, L-Proline
O
O
Ph
NH2
CN
CN
CN
MeO
MeO
(G)
(H)
NH2
NH2
NH2
NH2
O
K2CO3, DMSO
150°C, 2 h
N
Ph
N
O
O
Br
N
N
MeO
N
Ph
N
MeO
N
5aa, 73%
Not formed
10
Cl
4bb, 55%
5ag, 42%
4cb, 55%
5ah, 65%
5ba, 62%
O
O
O
O
O
O
NaN3, CuI,
L-Proline
Cl
CN
Ph
MeO
CN
Ph
MeO
MeO
CN
Ph
OEt
OEt
CN
N
N
OEt
OEt
NH2
O
N
N
CN
CN
N
NH2
N
N
NH2
80 oC, DMSO
N3
Br
NH2
N
5ea, 25%
5ca, 41%
5da, 60%
4ac, 40%
4ad, 35%
9, 15%
4aa, 7%
6
11, 9%
MeO
MeO
OMe
CN
MeO
CHNH
CN
MeO
MeO
CN
NH2
N
MeO
Me
N
N
Scheme 2: Control experiments.
N
4ae, 31%
Cl
5cd, 43%
5cb, 30%
5cc, 35%
Control experiments were performed to evaluate the possible
reaction pathway for the tandem sequences to produce 4aa and
5aa (Scheme 2). Initially, 2-bromobenzaldehyde (1a) was reacted
with ethyl cyanoacetate using K2CO3 in DMSO at room temperature
for 30 min, only Knoevenagel adduct
(Scheme 2A). When adduct , NaN3, CuI, L-proline and K2CO3were
heated at 150 C for 2 h, only the desired product 4aa was isolated
in 70% yield (Scheme 2B). Exclusive formation of 4aa can be due to
the relative reactivity of cyano group over ester in . Reaction of 1a
with NaN3, CuI, L-proline and K2CO3 at 120 °C gave 2-
aminobenzaldehyde in 64% yield (Scheme 2C). However,
6 was obtained in 78% yield
6
°
Figure 2: ORTEP diagram (with 35% ellipsoid probability) for 10 (CCDC 1433055).
6
On the basis of control experiments and literature reports,22a, 24
possible mechanism for the copper-catalyzed tandem reaction has
been described (Scheme 3). Initially, the reaction of 2-
brombenzaldehye and ethyl cyanoacetate generated Knoevenagel
a
(8)
treatment of 1a with ethyl cyanoacetate in the presence of NaN3,
CuI, L-proline and K2CO3 at room temperature exclusively resulted
in adduct 6. When the same reaction mixture was heated at 100 °C,
ethyl 3-(2-aminophenyl)-2-cyanoacrylate (9) was obtained in 50%
adduct
presence
aminobenzylidene)malononitrile (
6
. Reductive amination of
of copper catalyst
). This is in accordance with
6
using sodium azide in the
produced 2-(2-
yield along with the desired product 4aa in 8% yield (Scheme 2D).
9
Further, when
DMSO, 4aa was obtained in 33% yield after 5 h, and
recovered in 46% yield (Scheme 2E) From these control
experiments, we concluded that ethyl 3-(2-bromophenyl)-2-
cyanoacrylate (6) and ethyl 3-(2-aminophenyl)-2-cyanoacrylate (
are key intermediates for the formation of 2-aminoquinoline.
Similarly, reaction of 1a with in absence of copper catalyst gave 2-
9
was heated at 150
°
C in the presence of K2CO3 in
earlier reports wherein sodium azide has been used as ammonia
surrogate to prepare primary amines and nitrogen containing
heterocycles in a copper catalyzed reductive amination of aryl
9
was
.
halides.14f, 22c, 22d Subsequently, intramolecular cyclization of
9
led to
9)
the formation of ethyl 2-aminoquinoline-3-carboxylate
(4) via
nucleophilic attack of amine onto nitrile followed by
4
tautomerization. In case of benzoylacetonitrile, intermediate 10
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formed after Knoevenagel condensation underwent reductive published procedure.25 All other chemicals were obtained from the
amination followed by intramolecular condensation to afford 2- commercial suppliers and used without further purification.
arylquinoline-3-carbonitrile (5).
Representative procedure for synthesis of 2–aminoquinolines
(4): A mixture of 2-bromobenzaldehyde (100 mg, 0.54 mmol), ethyl
cyanoacetate (73 mg. 0.65 mmol), sodium azide (52 mg, 0.81
mmol), CuI (20 mol %), L-proline (40 mol %) and K2CO3 (186 mg, 2.5
equiv.) in DMSO (2 mL) was mixed under air atmosphere at room
temperature and then heated to 150 °C for 3 h. After cooling to
ambient temperature, the reaction mass was quenched with ice-
cold aqueous solution of NH4Cl (30 mL), filtered through a bed of
celite and the plug washed with ethyl acetate (20 mL). The resulting
filtrate was extracted with ethyl acetate (2 × 20 mL) and the
combined organic layers dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Desired product 4aa (72 mg,
62%) was isolated by column chromatography on silica gel (100-200
mesh) using ethyl acetate/ hexane (30%, v/v) as eluant.
Scheme 3: A plausible mechanism for the synthesis of
4 and 5.
Next, the synthetic worth of the developed methodology was
demonstrated by one-pot synthesis of pyrimido[4,5-b]quinolin-
4(3H)-one derivatives (12a-c). In all the cases, reactions underwent
smooth conversion to afford the corresponding pyrimido[4,5-
b]quinolin-4(3H)-ones 12a-c in moderate to good (52-43%) yields
(Scheme 4).
Ethyl 2-aminoquinoline-3-carboxylate (4aa): Yellow solid; 72 mg
(62%); mp 134 – 136 °C; 1H NMR (400 MHz, DMSO–d6) δ 8.77 (s,
1H), 7.86 (dd, J = 8.1, 1.3 Hz, 1H), 7.63 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H),
7.49 (d, J = 8.2 Hz, 1H), 7.26 (bs, 2H), 7.25 – 7.21 (m, 1H), 4.36 (q, J =
7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO–d6) δ
166.5, 156.7, 150.0, 142.8, 133.0, 129.9, 125.1, 122.7, 122.0, 110.5,
61.6, 14.6; IR (KBr): 3418, 1697, 1628, 1288, 1080 cm-1; HRMS for
C12H13N2O2 [M+H+] calcd 217.0972, found 217.0976.
Ethyl 2-amino-7-methoxyquinoline-3-carboxylate (4ba): Yellow
1
solid; 87 mg (66%); mp 138 – 140 °C; H NMR (400 MHz, DMSO–d6)
δ 8.65 (s, 1H), 7.74 (d, J = 9.5 Hz, 1H), 7.23 (bs, 2H), 6.86 (d, J = 6.2
Hz, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H);
13C NMR (100 MHz, DMSO–d6) δ 166.8, 163.5, 157.4, 152.5, 142.1,
131.2, 117.1, 115.1, 107.1, 104.5, 61.3, 55.8, 14.6; IR (KBr): 3433,
1697, 1620, 1257, 1080 cm-1; HRMS for C13H15N2O3 [M+H+] calcd
247.1077, found 247.1087.
Scheme 4: Synthesis of pyrimido[4,5-b]quinolin-4(3H)-one.
Conclusions
Ethyl 2-amino-6,7-dimethoxyquinoline-3-carboxylate (4ca)
:
In conclusion, we have successfully developed an efficient and
straightforward copper-catalyzed regioselective synthesis of 2-
aminoquinolines and 2-arylquinoline-3-carbonitriles from
readily available 2-bromobenzaldehydes, active methylene
nitriles and sodium azide. The developed three-component,
one-pot tandem protocol displays broad substrate scope, good
functional group tolerance and gives quinolines in moderate to
good yields. The developed methodology can further be
utilized for one-pot synthesis of pyrimido[4,5-b]quinolin-4(3H)-
ones.
Brown solid; 79 mg (53%); mp 190 – 193 °C; 1H NMR (400 MHz,
DMSO–d6) δ 8.60 (s, 1H), 7.28 (s, 1H), 6.99 (bs, 2H), 6.89 (s, 1H),
4.33 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 1.35 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, DMSO–d6) δ 166.9, 156.3, 155.3, 148.0,
146.9, 140.4, 116.7, 107.8, 106.8, 105.0, 61.2, 56.1, 56.0, 14.6; IR
(KBr): 3410, 1697, 1628, 1227, 1080 cm-1; HRMS for C14H17N2O4
[M+H+] calcd 277.1183, found 277.1189.
2-Aminoquinoline-3-carboxamide (4ab): Light orange solid; 53
mg (52%); mp 195 – 196 °C; 1H NMR (400 MHz, DMSO–d6) δ 8.48 (s,
1H), 8.24 (bs, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.61 (bs, 1H), 7.57 (ddd, J
= 8.4, 6.9, 1.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.29 – 7.17 (m, 3H);
13C NMR (100 MHz, DMSO–d6) δ 170.4, 157.1, 149.2, 138.6, 131.6,
129.1, 125.3, 122.3, 122.2, 114.6; IR (KBr): 3410, 3194, 1636, 1389,
1227 cm-1; HRMS for C10H10N3O [M+H+] calcd 188.0818, found
188.0824.
Experimental Section
Melting points were determined in open capillary tubes on an
automated melting point apparatus and are uncorrected. Reactions
were monitored by using thin layer chromatography (TLC) on 0.2
mm silica gel F254 plates. The chemical structures of final products
were determined by their NMR spectra (1H and 13C NMR). Chemical
shifts are reported in parts per million (ppm) using deuterated
solvent peak or tetramethylsilane as an internal standard. The
2-Amino-7-methoxyquinoline-3-carboxamide (4bb)
:
Orange
1
solid; 64 mg (55%); mp 221 – 224 °C; H NMR (400 MHz, DMSO–d6)
δ 8.42 (s, 1H), 8.14 (bs, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.50 (bs, 1H),
7.27 (bs, 2H), 6.91 – 6.81 (m, 2H), 3.85 (s, 3H); 13C NMR (100 MHz,
DMSO–d6) δ 170.2, 162.4, 157.6, 151.3, 138.3, 130.3, 117.0, 114.4,
111.6, 104.7, 55.7; IR (KBr): 3378, 3209, 1620, 1381, 1227 cm-1;
HRMS for C11H12N3O2 [M+H+] calcd 218.0924, found 218.0930.
HRMS data were recorded on
a mass spectrometer with
electrospray ionization and TOF mass analyzer. Some of benzoyl
acetonitriles and 2-cyano acetamides were synthesized according to
4 | J. Name., 2012, 00, 1-3
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2-Amino-6,7-dimethoxyquinoline-3-carboxamide (4cb):
Yellow 1H), 7.40 (d, J = 7.9 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
solid; 73 mg (55%); mp 232 – 234 °C; 1H NMR (400 MHz, DMSO–d6) δ 158.0, 148.7, 144.2, 140.6, 134.9, 132.9, 129.9, 129.5, 129.1,
δ 8.33 (s, 1H), 8.07 (bs, 1H), 7.43 (bs, 1H), 7.02 (s, 1H), 6.98 (bs, 2H), 127.9, 127.7, 124.9, 118.1, 105.5, 21.4; IR (KBr): 2916, 2222, 1612,
6.89 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO–d6) 1481, 1188 cm-1; HRMS for C17H13N2 [M+H+] calcd 245.1073, found
δ 170.4, 156.3, 154.1, 146.6, 146.3, 137.0, 116.4, 111.5, 107.2, 245.1070.
105.3, 56.0; IR (KBr): 3380, 3210, 1623, 1381, 1225 cm-1; HRMS for
C12H14N3O3 [M+H+] calcd 248.1030, found 248.1037.
2-(4-Methoxyphenyl)quinoline-3-carbonitrile (5ac)
: Off white
solid; 63 mg (45%); mp 174 – 177 °C; 1H NMR (400 MHz, CDCl3) δ
(2-Aminoquinolin-3-yl)(pyrrolidin-1-yl)methanone (4ac): Brown 8.65 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.07 – 7.99 (m, 2H), 7.95 – 7.87
1
oil; 52 mg (40%); H NMR (400 MHz, DMSO–d6) δ 8.07 (s, 1H), 7.71 (m, 2H), 7.69 – 7.61 (m, 1H), 7.14 – 7.06 (m, 2H), 3.92 (s, 3H); 13C
(d, J = 7.7 Hz, 1H), 7.57 – 7.46 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 6.49 NMR (100 MHz, CDCl3) δ 161.5, 157.5, 148.7, 144.3, 132.9, 130.7,
(s, 2H), 3.52 (t, J = 6.7 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 1.92 – 1.80 (m, 130.2, 129.8, 127.8, 127.7, 124.8, 118.3, 114.2, 105.3, 55.5; IR (KBr):
4H); 13C NMR (100 MHz, DMSO–d6) δ 166.6, 155.1, 148.1, 136.2, 2914, 2221, 1612, 1481, 1173 cm-1; HRMS for C17H13N2O [M+H+]
130.7, 128.6, 125.4, 122.3, 120.1, 48.7, 46.2, 26.2, 24.4; IR (KBr): calcd 261.1022, found 261.1028.
3410, 1651, 1457, 1380 cm-1; HRMS for C14H16N3O [M+H+] calcd
2-(3,4-Dimethoxyphenyl)quinoline-3-carbonitrile (5ad)
:
Off
white solid; 78 mg (50%); mp 174 – 177 °C; 1H NMR (400 MHz,
242.1288, found 242.1292.
(2-Aminoquinolin-3-yl)(morpholino)methanone (4ad): Yellow CDCl3) δ 8.67 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.89 (dd, J
semisolid; 49 mg (35%); 1H NMR (400 MHz, DMSO– d6) δ 7.94 (s, = 7.5, 1.2 Hz, 1H), 7.67 (ddd, J = 9.2, 8.2, 1.6 Hz, 2H), 7.62 (d, J = 2.1
1H), 7.72 (d, J = 7.4 Hz, 1H), 7.57 – 7.49 (m, 2H), 7.22 (t, J = 7.9 Hz, Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 4.00 (s, 3H); 13C NMR
1H), 6.38 (bs, 2H), 3.62 (bs, 2H), 3.26 (bs, 2H), 1.60 (bs, 4H); 13C (100 MHz, CDCl3) δ 157.4, 150.8, 149.1, 148.7, 144.4, 133.0, 130.2,
NMR (100 MHz, CDCl3) δ 167.8, 155.0, 147.6, 136.0, 130.9, 127.9, 129.8, 127.8, 127.7, 124.8, 122.4, 118.3, 112.1, 111.0, 105.3, 56.1,
125.8, 123.2, 122.6, 118.0, 65.9, 24.5; IR (KBr): 3410, 1653, 1458, 56.0; IR (KBr): 2916, 2222, 1615, 1483, 1180 cm-1; HRMS for
1381 cm-1; HRMS for C10H8N3 [M+H+] calcd 258.1237, found C18H15N2O2 [M+H+] calcd 291.1128, found 291.1124.
258.1243.
2-o-Tolylquinoline-3-carbonitrile (5ae): Yellow solid; 42 mg
2-Aminoquinoline-3-carbonitrile (4ae): Yellow semisolid; 28 mg (32%); mp 163 – 164 °C; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H),
(31%); 1H NMR (400 MHz, DMSO–d6) δ 8.69 (s, 1H), 7.75 (dd, J = 8.1, 8.11 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.82 – 7.78 (m, 1H),
1.2 Hz, 1H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.51 (d, J = 8.6 Hz, 7.60 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.33 (ddd, J = 9.6, 6.4, 2.7 Hz,
1H), 7.28 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.98 (bs, 2H); 13C NMR (100 2H), 7.27 (d, J = 7.0 Hz, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
MHz, DMSO–d6) δ 156.2, 149.6, 145.8, 133.3, 129.0, 125.9, 123.2, δ 159.9, 148.3, 142.5, 137.6, 136.1, 132.9, 130.8, 129.8, 129.6,
121.4, 117.0, 95.0; IR (KBr): 3444, 2253, 1659, 1480, 1373 cm-1; 129.2, 128.2, 127.9, 126.0, 125.1, 117.1, 107.5, 19.7; IR (KBr): 3015,
HRMS for C10H8N3 [M+H+] calcd 170.0713, found 170.0719.
2222, 1616, 1473, 1170 cm-1; HRMS for C17H13N2 [M+H+] calcd
245.1073, found 245.1076.
Representative procedure for synthesis of 2-arylquinoline-3-
carbonitriles (5): A mixture of 2-bromobenzaldehyde (100 mg, 0.54
2-(2-Methoxyphenyl)quinoline-3-carbonitrile (5af): Pale yellow
mmol), benzoylacetonitriles (94 mg, 0.65 mmol), sodium azide (52 solid; 63 mg (45%); mp 150 – 153 °C; 1H NMR (400 MHz, CDCl3) δ
mg, 0.81 mmol), CuI (20 mol %), L-proline (40 mol %) and K2CO3 8.61 (s, 1H), 8.23 (d, J = 9.3 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.89
(186 mg, 2.5 equiv.) in DMSO (2 mL) was mixed under air (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.69 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H),
atmosphere at room temperature and then heated to 150 °C for 3 7.59 – 7.49 (m, 2H), 7.17 (td, J = 7.5, 0.9 Hz, 1H), 7.09 (d, J = 8.3 Hz,
h. After cooling to ambient temperature, the reaction mass was 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 157.0, 148.7,
quenched with ice-cold aqueous solution of NH4Cl (30 mL), filtered 142.3, 132.5, 131.5, 131.0, 130.0, 128.0, 127.3, 125.1, 121.2, 117.7,
through a bed of celite and the plug washed with ethyl acetate (20 111.3, 108.8, 55.4; IR (KBr): 3015, 2222, 1616, 1473, 1170 cm-1;
mL). The resulting filtrate was extracted with ethyl acetate (2 × 20 HRMS for C17H13N2O [M+H+] calcd 261.1022, found 261.1032.
mL) and the combined organic layers dried over anhydrous Na2SO4
2-(Benzo[d][1,3]dioxol-5-yl)quinoline-3-carbonitrile (5ag): Light
brown solid; 62 mg (42%); mp 187 – 189°C; 1H NMR (400 MHz,
CDCl3) δ 8.64 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.88 (t, J = 7.4 Hz, 2H),
7.64 (t, J = 7.2 Hz, 1H), 7.55 (dd, J = 8.1, 1.7 Hz, 1H), 7.50 (d, J = 1.6
and concentrated under reduced pressure. Desired product 5aa (73
mg, 59%) was isolated by column chromatography on silica gel
(100-200 mesh) using ethyl acetate/ hexane (10%, v/v) as eluant.
2-Phenylquinoline-3-carbonitrile (5aa): Off white solid; 73 mg Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H); 13C NMR (100 MHz,
1
(59%); m.p 193 – 195 °C; H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), CDCl3) δ 157.3, 149.4, 148.6, 148.2, 144.4, 133.0, 131.7, 129.8,
8.23 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 7.8, 1.7 Hz, 2H), 7.97 – 7.89 (m, 127.9, 127.7, 124.9, 123.9, 118.1, 109.5, 108.5, 105.3, 101.6; IR
2H), 7.75 – 7.66 (m, 1H), 7.64 – 7.52 (m, 3H); 13C NMR (100 MHz, (KBr): 3015, 2222, 1616, 1473, 1170 cm-1; HRMS for C17H11N2O2
CDCl3) δ 158.1, 148.7, 144.3, 137.7, 133.1, 130.1, 129.9, 129.2, [M+H+] calcd 275.0815, found 275.0820.
128.8, 128.1, 127.8, 125.0, 117.9, 105.5; IR (KBr): 3055, 2222, 1620,
2-(4-Chlorophenyl)quinoline-3-carbonitrile (5ah): White solid; 93
1450, 1373 cm-1; HRMS for C16H11N2 [M+H+] calcd 231.0917, found
mg (65%); mp 188 – 190 °C; 1H NMR (400 MHz, CDCl3) δ 8.69 (s,
231.0920.
1H), 8.21 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.93 (t, J = 7.1
2-p-Tolylquinoline-3-carbonitrile (5ab): Pale yellow solid; 54 mg Hz, 2H), 7.70 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H); 13C NMR (100
(41%); mp 174 – 177 °C; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), MHz, CDCl3) δ 156.7, 148.6, 144.3, 136.5, 136.1, 133.2, 130.5, 129.9,
8.21 (d, J = 9.1 Hz, 1H), 8.01 – 7.84 (m, 4H), 7.67 (td, J = 7.4, 1.0 Hz, 129.0, 128.3, 127.8, 125.1, 117.8, 105.3; IR (KBr): 2914, 2221, 1612,
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1481, 1173 cm-1; HRMS for C16H10ClN2 [M+H+] calcd 265.0527, CDCl3) δ 155.5, 155.2, 151.2, 146.5, 141.3, 136.4, 136.1, 130.3,
found 265.0524.
128.9, 121.2, 118.4, 108.2, 104.5, 102.9, 56.54, 56.3; IR (KBr): 2947,
2222, 1697, 1504, 1165 cm-1; HRMS for C18H14ClN2O2 [M+H+] calcd
325.0738, found 325.0734.
7-Methoxy-2-phenylquinoline-3-carbonitrile (5ba)
solid; 87 mg (62%); mp 164 – 166 °C; 1H NMR (400 MHz, CDCl3) δ
: Off white
8.56 (s, 1H), 7.99 (d, J = 6.2 Hz, 2H), 7.80 (d, J = 9.0 Hz, 1H), 7.60 –
Ethyl 3-(2-bromophenyl)-2-cyanoacrylate (6): Colorless oil, 78%;
7.51 (m, J = 5.8 Hz, 3H), 7.52 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 9.0, 2.3 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.17 (dd, J = 7.8, 1.6 Hz,
Hz, 1H), 4.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.6, 158.8, 1H), 7.71 (dd, J = 8.0, 1.2 Hz, 1H), 7.46 (td, J = 7.4, 0.8 Hz, 1H), 7.38
150.9, 143.3, 137.9, 130.0, 129.1, 128.9, 128.7, 121.7, 120.4, 118.4, (td, J = 7.7, 1.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 1H), 1.41 (t, J = 7.1 Hz,
107.7, 102.9, 55.9; IR (KBr): 3015, 2214, 1620, 1443, 1142 cm-1; 2H); 13C NMR (100 MHz, CDCl3) δ 161.8, 153.9, 133.7, 133.6, 131.7,
HRMS for C17H13N2O [M+H+] calcd 261.1022, found 261.1028.
6,7-Dimethoxy-2-phenylquinoline-3-carbonitrile (5ca)
yellow solid; 64 mg (41%); mp 196 – 199 °C; 1H NMR (400 MHz,
130.1, 128.1, 126.6, 114.7, 106.4, 63.0, 14.2; HRMS for C12H11BrNO2
[M+H+] calcd 279.9968, found 279.9973 and 281.9954 [M+2+H+].
:
Pale
2-Aminobenzaldehyde (8): Pale yellow liquid; 42 mg (64%); 1H
CDCl3) δ 8.45 (s, 1H), 7.97 (dd, J = 8.0, 1.4 Hz, 2H), 7.59 – 7.52 (m, NMR (400 MHz, DMSO–d6) δ 9.81 (d, J = 0.4 Hz, 1H), 7.53 (dd, J =
3H), 7.51 (s, 1H), 7.10 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H); 13C NMR 7.8, 1.6 Hz, 1H), 7.30 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 7.12 (bs, 2H),
(100 MHz, CDCl3) δ 156.6, 155.3, 151.0, 146.5, 141.2, 138.0, 129.7, 6.76 (d, J = 8.4 Hz, 1H), 6.64 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H).; 13C NMR
129.0, 128.7, 121.0, 118.6, 108.3, 104.6, 103.2, 56.5, 56.3; IR (KBr): (100 MHz, DMSO–d6) δ 194.5, 151.2, 136.0, 135.5, 118.2, 116.3,
2924, 2222, 1620, 1504, 1185 cm-1; HRMS for C18H15N2O2 [M+H+] 115.4; HRMS for C7H8NO [M+H+] calcd 122.0600, found 121.0581.
calcd 291.1128, found 291.1125.
Ethyl 3-(2-aminophenyl)-2-cyanoacrylate (9): Brown solid; 58 mg
6-Methoxy-2-phenylquinoline-3-carbonitrile (5da): Yellow solid; (50%); mp 123-125 °C; 1H NMR (400 MHz, DMSO–d6) δ 8.55 (s, 1H),
1
84 mg (60%); mp 167 – 168 °C; H NMR (400 MHz, CDCl3) δ 8.54 (s, 8.32 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.2 Hz,
1H), 8.11 (d, J = 9.2 Hz, 1H), 8.00 (dd, J = 8.0, 1.5 Hz, 2H), 7.63 – 7.50 3H), 7.47 (t, J = 7.4 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1
(m, 4H), 7.13 (d, J = 2.7 Hz, 1H), 3.99 (s, 3H); 13C NMR (101 MHz, Hz, 3H); 13C NMR (100 MHz, DMSO–d6) δ 165.50, 147.65, 141.08,
CDCl3) δ 158.9, 155.7, 145.0, 142.5, 137.8, 131.3, 129.8, 129.0, 133.74, 130.93, 130.68, 125.00, 120.86, 117.26, 110.72, 62.23,
1
128.7, 126.2, 126.1, 118.2, 105.7, 104.6, 55.8; IR (KBr): 2945, 2222, 14.54; H NMR (400 MHz, DMSO–d6, D2O exchange) δ 8.58 (s, 1H),
1620, 1489, 1034 cm-1; HRMS for C17H13N2O [M+H+] calcd 261.1022, 8.26 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.85 (t, J = 7.6 Hz,
found 261.1025.
1H), 7.47 (t, J = 7.3 Hz, 1H), 4.39 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0
Hz, 3H); HRMS for C12H13N2O2 [M+H+] calcd 217.0972, found
217.0975.
6-Chloro-2-phenylquinoline-3-carbonitrile (5ea)
: Pale yellow
1
solid; 36 mg (25%); mp 190 – 193 °C; H NMR (400 MHz, CDCl3) δ
8.61 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.04 – 8.00 (m, 2H), 7.92 (d, J =
2-Benzoyl-3-(2-bromophenyl)acrylonitrile (10): Crystalline off
2.3 Hz, 1H), 7.85 (dd, J = 9.0, 2.3 Hz, 1H), 7.62 – 7.57 (m, 3H); 13C white solid; 234 mg (70%); mp 126 ― 128 °C; 1H NMR (400 MHz,
NMR (101 MHz, CDCl3) δ 158.2, 147.1, 143.2, 137.3, 134.1, 133.9, CDCl3) δ 8.37 (s, 1H), 8.25 (d, J = 7.1 Hz, 1H), 7.94 (d, J = 7.3 Hz, 2H),
131.5, 130.4, 129.1, 128.8, 126.3, 125.6, 117.6, 106.6; IR (KBr): 7.73 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz,
3053, 2222, 1597, 1489, 1026, 764 cm-1; HRMS for C16H10ClN2 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H); 13C NMR (100
[M+H+] calcd 265.0527, found 265.0524.
MHz, CDCl3) δ 188.8, 154.1, 135.3, 133.8, 133.7, 133.6, 132.1,
130.10, 129.6, 128.8, 128.2, 126.5, 115.7, 113.6; HRMS for
C16H11BrNO [M+H+] calcd 312.0019, found 312.0015.
6,7-Dimethoxy-2-
p
-tolylquinoline-3-carbonitrile (5cb)
:
Pale
yellow solid; 49 mg (30%); mp 198 – 200 °C; 1H NMR (400 MHz,
1
CDCl3) δ 8.44 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.51 (s, 1H), 7.37 (d, J =
Ethyl 3-(2-azidophenyl)-2-cyanoacrylate (11): H NMR (400 MHz,
7.9 Hz, 2H), 7.09 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 2.46 (s, 4H); 13C CDCl3) δ 8.79 (s, 1H), 8.78 (d, J = 9.0 Hz, 1H), 8.14 (dd, J = 8.1, 1.1 Hz,
NMR (101 MHz, CDCl3) δ 156.6, 155.3, 150.9, 146.5, 141.3, 139.9, 1H), 8.04 (td, J = 8.4, 7.9, 1.3 Hz, 1H), 7.85 – 7.80 (m, 1H), 4.64 (q, J
135.1, 129.4, 128.9, 120.9, 118.7, 108.27, 104.6, 103.1, 56.5, 56.3, = 7.1 Hz, 2H), 1.55 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
21.4; IR (KBr): 2924, 2214, 1690, 1504, 1211 cm-1; HRMS for 162.6, 145.7, 138.1, 133.6, 132.0, 130.5, 128.6, 122.7, 117.2, 117.1,
C19H17N2O2 [M+H+] calcd 305.1285, found 305.1291.
62.7, 14.4. MS (ESI) m/z cacld for C12H11N4O2 [M+H+] 243.09, found
243.15.
6,7-Dimethoxy-2-(4-methoxyphenyl)quinoline-3-carbonitrile
(5cc): Pale yellow solid; 60 mg (35%); mp 178 – 180 °C; 1H NMR (400
MHz, CDCl3) δ 8.41 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 7.08
Representative procedure for synthesis of pyrimido[4,5-
b]quinolin-4(3H)-ones (12): A mixture of 2-bromobenzaldehyde
(d, J = 5.0 Hz, 2H), 7.06 (s, 1H), 4.07 (s, 3H), 4.05 (s, 3H), 3.90 (s, 3H); (100 mg, 0.54 mmol), 2-cyanoacetamide (54 mg, 0.65 mmol),
13C NMR (100 MHz, CDCl3) δ 160.9, 156.1, 155.2, 150.8, 146.5, sodium azide (52 mg, 0.81 mmol), CuI (20 mol %), L-proline (40 mol
141.3, 130.5, 130.4, 120.7, 118.83, 114.1, 108.2, 104.5, 102.9, 56.5, %) and K2CO3 (186 mg, 2.5 equiv.) in DMSO (2 mL) was mixed under
56.3, 55.4; IR (KBr): 2925, 2213, 1612, 1494, 1173 cm-1; HRMS for air atmosphere at room temperature and then heated to 150 °C for
C19H17N2O3 [M+H+] calcd 321.1234, found 321.1238.
3 h. After cooling to ambient temperature, benzaldehyde (69 mg,
0.65 mmol) was added and reaction mixture was then again heated
to 150 °C for 2 h. After cooling to ambient temperature, the
reaction mass was quenched with ice-cold aqueous solution of
NH4Cl (30 mL), filtered through a bed of celite and the plug washed
with ethyl acetate (20 mL). The resulting filtrate was extracted with
2-(4-Chlorophenyl)-6,7-dimethoxyquinoline-3-carbonitrile (5cd)
:
White solid; 75 mg (43%); mp 234 – 235 °C; 1H NMR (400 MHz,
CDCl3) δ 8.45 (s, 1H), 7.98 – 7.90 (m, 2H), 7.57 – 7.51 (m, 2H), 7.49
(s, 1H), 7.11 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H); 13C NMR (100 MHz,
6 | J. Name., 2012, 00, 1-3
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ARTICLE
B. Pérez, A. Gomes, J. R. B. Gomes and P. Gomes, Chem.
Rev., 2014, 114, 11164-11220.
ethyl acetate (2 × 20 mL) and the combined organic layers dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
Desired product 12a (77 mg, 52%) was isolated by column
chromatography on silica gel (100-200 mesh) using ethyl acetate/
hexane (30%, v/v) as eluent.
5.
(a) S. Eswaran, A. V. Adhikari, I. H. Chowdhury, N. K. Pal
and K. D. Thomas, Eur. J. Med. Chem., 2010, 45, 3374-
3383; (b) K. D. Thomas, A. V. Adhikari, S. Telkar, I. H.
Chowdhury, R. Mahmood, N. K. Pal, G. Row and E.
Sumesh, Eur. J. Med. Chem., 2011, 46, 5283-5292; (c) A.
Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau and
A. P. Kozikowski, J. Med. Chem., 2009, 52, 2109-2118.
(a) F. Hayat, E. Moseley, A. Salahuddin, R. L. Van Zyl and A.
Azam, Eur. J. Med. Chem., 2011, 46, 1897-1905; (b) A.
Salahuddin, A. Inam, R. L. van Zyl, D. C. Heslop, C.-T. Chen,
F. Avecilla, S. M. Agarwal and A. Azam, Biorg. Med. Chem.,
2013, 21, 3080-3089.
R. de Oliveira Lopes, N. C. Romeiro, C. K. F. de Lima, L.
Louback da Silva, A. L. Palhares de Miranda, P. G. B. D.
Nascimento, F. Q. Cunha, E. J. Barreiro and L. M. Lima,
Eur. J. Med. Chem., 2012, 54, 264-271.
D. K. Heidary, B. S. Howerton and E. C. Glazer, J. Med.
Chem., 2014, 57, 8936-8946.
H.-R. Tsou, E. G. Overbeek-Klumpers, W. A. Hallett, M. F.
Reich, M. B. Floyd, B. D. Johnson, R. S. Michalak, R.
Nilakantan, C. Discafani, J. Golas, S. K. Rabindran, R. Shen,
X. Shi, Y.-F. Wang, J. Upeslacis and A. Wissner, J. Med.
Chem., 2005, 48, 1107-1131.
Z. Sadeghi and J. Safari, Dyes and Pigments, 2006, 70, 164-
170.
M. M. Biddle, M. Lin and K. A. Scheidt, J. Am. Chem. Soc.,
2007, 129, 3830-3831.
2-Phenylpyrimido[4,5-b]quinolin-4(3H)-one (12a): Yellow solid;
77 mg (52%); mp 356-357 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.71
(s, 1H), 9.32 (s, 1H), 8.30 – 8.27 (m, 3H), 8.10 (d, J = 8.6 Hz, 1H), 7.96
(t, J = 7.6 Hz, 1H), 7.72 – 7.57 (m, 4H); 13C NMR (100 MHz, DMSO-d6)
δ 163.7, 156.8, 156.3, 151.6, 138.6, 133.3, 133.1, 132.6, 130.0,
129.2, 128.9, 128.6, 126.9, 126.7, 116.1; HRMS for C17H12N3O [M +
H]+ calcd 274.0975, found 274.0978.
6.
7.
2-(p-Tolyl)pyrimido[4,5-
b
]quinolin-4(3H)-one (12b)
:
Orange
1
solid; 84 mg (54%); mp 304-306 ºC; H NMR (400 MHz, DMSO-d6) δ
12.62 (s, 1H), 9.29 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.0 Hz,
2H), 8.08 (d, J = 8.6 Hz, 1H), 7.94 (t, J = 8.5 Hz, 1H), 7.66 (t, J = 7.3
Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 163.7, 156.9, 156.1, 151.6, 142.8, 138.6, 133.3, 130.2,
130.0, 129.8, 128.9, 128.6, 126.8, 126.6, 116.0, 21.5; HRMS for
C18H14N3O [M + H]+ calcd 288.1131, found 288.1127.
8.
9.
2-(4-Chlorophenyl)pyrimido[4,5-
b]quinolin-4(3H)-one
(12c):
Yellow solid; 72 mg (43%); mp 376-378 ºC; 1H NMR (400 MHz,
DMSO-d6) δ 12.80 (s, 1H), 9.32 (s, 1H), 8.32 – 8.28 (m, 3H), 8.10 (d, J
= 8.6 Hz, 1H), 7.96 (t, J = 7.4 Hz, 1H), 7.70 – 7.67 (m, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 156.6, 151.5, 138.7, 137.5, 133.4, 132.0,
130.5, 130.1, 130.0, 129.3, 129.0, 128.9, 127.0, 126.7, 116.1; HRMS
for C17H11ClN3O [M + H]+ calcd 308.0585, found 308.0582.
10.
11.
12.
(a) H. Xu, R. Chen, Q. Sun, W. Lai, Q. Su, W. Huang and X.
Liu, Chem. Soc. Rev., 2014, 43, 3259-3302; (b) S. Tao, L. Li,
J. Yu, Y. Jiang, Y. Zhou, C.-S. Lee, S.-T. Lee, X. Zhang and O.
Kwon, Chem. Mater., 2009, 21, 1284-1287; (c) S.-J. Lee, J.-
S. Park, M. Song, I. A. Shin, Y.-I. Kim, J. W. Lee, J.-W. Kang,
Y.-S. Gal, S. Kang, J. Y. Lee, S.-H. Jung, H.-S. Kim, M.-Y.
Chae and S.-H. Jin, Adv. Funct. Mater., 2009, 19, 2205-
2212.
Acknowledgements
We sincerely acknowledge financial support from Ranbaxy
Laboratories Pvt. Ltd. (India) to carry out this work. HKS is
grateful to CSIR, New Delhi, India for senior research
fellowship. Authors thank Prof. Alaknanda Hajra for his help in
recording and analyzing single-crystal X-ray diffraction data for
intermediate 10 and Miss. Pinku Kaswan for her kind
suggestions and discussion.
13.
14.
G. Jones, in Chem. Heterocycl. Comp., John Wiley & Sons,
Inc., 2008, pp. 93-318.
(a) S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal
and H. D. Patel, RSC Adv., 2014, 4, 24463-24476; (b) H.
Batchu, S. Bhattacharyya and S. Batra, Org. Lett., 2012,
14, 6330-6333; (c) K. Wu, Z. Huang, C. Liu, H. Zhang and A.
Lei, Chem. Commun., 2015, 51, 2286-2289; (d) M. Rehan,
G. Hazra and P. Ghorai, Org. Lett., 2015, 17, 1668-1671;
(e) J. B. Bharate, R. A. Vishwakarma and S. B. Bharate, RSC
Notes and references
1.
(a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166-187; (b) J.
P. Michael, Nat. Prod. Rep., 2007, 24, 223-246.
Adv., 2015, 5, 42020-42053; (f) B. Li, C. Guo, X. Fan, J.
Zhang and X. Zhang, Tetrahedron Lett., 2014, 55, 5944-
5948.
2.
(a) S. H. Chan, C. H. Chui, S. W. Chan, S. H. L. Kok, D. Chan,
M. Y. T. Tsoi, P. H. M. Leung, A. K. Y. Lam, A. S. C. Chan, K.
15.
16.
17.
18.
L. Kong, Y. Zhou, H. Huang, Y. Yang, Y. Liu and Y. Li, J. Org.
Chem., 2015, 80, 1275-1278.
L.-Y. Xi, R.-Y. Zhang, L. Zhang, S.-Y. Chen and X.-Q. Yu, Org.
Biomol. Chem., 2015, 13, 3924-3930.
N. T. Patil and V. S. Raut, J. Org. Chem., 2010, 75, 6961-
6964.
Y. Cheng, T. C. Judd, M. D. Bartberger, J. Brown, K. Chen,
R. T. Fremeau, D. Hickman, S. A. Hitchcock, B. Jordan, V.
Li, P. Lopez, S. W. Louie, Y. Luo, K. Michelsen, T. Nixey, T.
S. Powers, C. Rattan, E. A. Sickmier, D. J. St. Jean, R. C.
H. Lam and J. C. O. Tang, ACS Med. Chem. Lett., 2013, 4,
170-174; (b) O. Afzal, S. Kumar, M. R. Haider, M. R. Ali, R.
Kumar, M. Jaggi and S. Bawa, Eur. J. Med. Chem., 2015,
97, 871-910.
(a) R. Musiol, J. Jampilek, V. Buchta, L. Silva, H. Niedbala,
B. Podeszwa, A. Palka, K. Majerz-Maniecka, B. Oleksyn
and J. Polanski, Biorg. Med. Chem., 2006, 14, 3592-3598;
(b) A. Oliva, K. M. Meepagala, D. E. Wedge, D. Harries, A.
L. Hale, G. Aliotta and S. O. Duke, J. Agric. Food. Chem.,
2003, 51, 890-896.
3.
4.
Wahl, P. H. Wen and S. Wood, J. Med. Chem., 2011, 54
,
(a) V. Korotchenko, R. Sathunuru, L. Gerena, D. Caridha,
Q. Li, M. Kreishman-Deitrick, P. L. Smith and A. J. Lin, J.
Med. Chem., 2015, 58, 3411-3431; (b) C. Teixeira, N. Vale,
5836-5857.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Please do not adjust margins
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Page 8 of 9
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DOI: 10.1039/C6RA03798D
ARTICLE
Journal Name
19.
M. A. Cinelli, H. Li, G. Chreifi, P. Martásek, L. J. Roman, T.
43-46; (f) J. Peng, Z. Xie, M. Chen, J. Wang and Q. Zhu,
Org. Lett., 2014, 16, 4702-4705.
L. Poulos and R. B. Silverman, J. Med. Chem., 2014, 57
,
1513-1530.
23.
24.
(a) N. K. Nandwana, K. Pericherla, P. Kaswan and A.
Kumar, Org. Biomol. Chem., 2015, 13, 2947-2950; (b) S.
Dhiman, K. Pericherla, N. K. Nandwana, D. Kumar and A.
Kumar, J. Org. Chem., 2014, 79, 7399-7404; (c) K.
Pericherla, P. Khedar, B. Khungar and A. Kumar, Chem.
Commun., 2013, 49, 2924-2926; (d) K. Pericherla, A. Jha,
B. Khungar and A. Kumar, Org. Lett., 2013, 15, 4304-4307.
(a) Y. Kim, M. R. Kumar, N. Park, Y. Heo and S. Lee, J. Org.
Chem., 2011, 76, 9577-9583; (b) D. Dhar and W. B.
Tolman, J. Am. Chem. Soc., 2015, 137, 1322-1329; (c) S.
Cenini, E. Gallo, A. Penoni, F. Ragaini and S. Tollari, Chem.
Commun., 2000, 2265-2266; (d) Q. Nguyen, T. Nguyen and
T. G. Driver, J. Am. Chem. Soc., 2013, 135, 620-623; (e) F.-
C. Jia, C. Xu, Z.-W. Zhou, Q. Cai, D.-K. Li and A.-X. Wu, Org.
Lett., 2015, 17, 2820-2823.
20.
(a) T. Tomioka, Y. Takahashi and T. Maejima, Org. Biomol.
Chem., 2012, 10, 5113-5118; (b) L. Hu, W. Gui, Z. Liu and
B. Jiang, RSC Adv., 2014,
and W. Gui, RSC Adv., 2014,
Gao, Y. Yu, W. Wu and H. Jiang, J. Org. Chem., 2013, 78
10319-10328; (e) L. Zhang, L. Zheng, B. Guo and R. Hua, J.
Org. Chem., 2014, 79, 11541-11548.
(a) J. T. Markiewicz, O. Wiest and P. Helquist, J. Org.
Chem., 2010, 75, 4887-4890; (b) S. Messaoudi, J. D. Brion
4
, 38258-38262; (c) B. Jiang, L. Hu
4
, 13850-13853; (d) B. Liu, H.
,
21.
22.
and M. Alami, Mini-Rev. Med. Chem., 2011, 8, 448-454.
(a) T. Maejima, Y. Shimoda, K. Nozaki, S. Mori, Y. Sawama,
Y. Monguchi and H. Sajiki, Tetrahedron, 2012, 68, 1712-
1722; (b) S. Messaoudi, J.-D. Brion and M. Alami, Adv.
Synth. Catal., 2010, 352, 1677-1687; (c) Y. Goriya and C. V.
Ramana, Chem. Commun., 2013, 49, 6376-6378; (d) Y.
Goriya and C. V. Ramana, Chem. Commun., 2014, 50
7790-7792; (e) A. M. Kulkarni, K. Srinivas, M. V.
Deshpande and C. V. Ramana, Org. Chem. Front., 2016, 3,
25.
(a) J. Shen, D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C.
Liu, X. Zhao, C. Chu and R. Liu, Org. Lett., 2014, 16, 350-
353; (b) K. Wang, K. Nguyen, Y. Huang and A. Dömling, J.
Comb. Chem., 2009, 11, 920-927.
,
8 | J. Name., 2012, 00, 1-3
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