Sequential hydration-condensation-double cyclization of pyridine-substituted 2-alkynylanilines: An efficient approach to quinoline-based heterocycles

Article abstract of DOI:10.1055/s-0030-1260001

An environmentally benign and atom-economical process to construct a unique quinoline-based tetracyclic scaffold, through sequential hydration- condensation-double cyclization reactions, has been described. The reaction starts with readily available pyrid

Full text of DOI:10.1055/s-0030-1260001

PAPER
1723
Sequential Hydration–Condensation–Double Cyclization of Pyridine-
Substituted 2-Alkynylanilines: An Efficient Approach to Quinoline-Based
Heterocycles
An
E
fficient Ap
i
proach
j
toQui
i
noline-
e
BasedHeterocyc
P
les eng, Honggen Wang, Changlan Peng, Ke Ding,* Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, P. R. of China
Fax +86(20)32015299; E-mail: ding_ke@gibh.ac.cn; E-mail: zhu_qiang@gibh.ac.cn
Received 1 March 2011; revised 26 March 2011
Equation 3).6 When R2 is a phenyl, the yield is relatively
low, which can be explained by the poor regioselectivity
during the hydration process. We conceived that higher
efficiency could be achieved by introduction of an elec-
Abstract: An environmentally benign and atom-economical pro-
cess to construct a unique quinoline-based tetracyclic scaffold,
through sequential hydration–condensation–double cyclization re-
actions, has been described. The reaction starts with readily avail-
able pyridine-substituted o-alkynylanilines and b-keto esters, tron-deficient pyridine at the other end of the triple bond.
promoted by p-toluenesulfonic acid in ethanol in one pot. In the ab-
sence of b-keto esters, multisubstituted quinolines are formed bimo-
lecularly in reasonable yields.
Furthermore, the pyridine motif could serve as a nucleo-
phile, cyclizing the pyridine nitrogen with the carboxylic
ester at C-3 (Scheme 1, equation 4). Thus, additional com-
plexity can be introduced to the quinoline scaffold. In ad-
Key words: alkynes, cyclization, heterocycles, quinoline, tandem
reaction
dition, the pyridine moiety is ubiquitously distributed in
natural products and synthetic compounds of pharmaceu-
tical interests.7 And the resulting multicyclic heterocycles
The addition of water to C≡C bonds catalyzed by mercu-
ry(II), known as hydration of alkynes for more than a cen-
tury ago, produces the corresponding carbonyl
compounds under mild conditions.1 Over the last 30 years,
much attention has been paid to the development of mer-
cury-free catalysts with improved efficiency and regiose-
lectivity and applying the process to tandem reactions
involving carbonyl compounds due to the environmental
concern and the convenient accessibility of alkynes.1 A
mixture of two ketones is usually obtained from asymmet-
ric internal alkynes when substitution patterns are similar
(Scheme 1, Equation 1). Regioselective hydration of aryl-
alkynes bearing alkyl groups at the other end of the triple
bond can be achieved via Brønsted acid catalyzed hydra-
tion, affording 2-substituted acetophenones (Scheme 1,
Equation 2).2 For asymmetric diarylalkynes, the selectiv-
ity is usually poor unless one of the aromatic ring is elec-
tron-rich and the other one is electron-poor or at least
electron-neutral. Therefore, the electron-rich o-alkynyla-
nilines are ideal precursors for 2-substituted 2¢-aminoace-
tophenones upon hydration in the presence of Brønsted
acids (Scheme 1, Equation 3).3 The resulting 2-substituted
2¢-aminoacetophenones can serve as versatile building
blocks in the synthesis of N-heterocycles.3,4
containing both pyridine and quinoline moieties are ex-
pected to be biologically active.8 In this proposed reac-
tion, three chemical bonds – C=N, C=C, C–N – will be
formed sequentially in one operation with high bond-
forming efficiency and atom-economy.
The pyridine-substituted o-alkynylanilines 3 with elec-
tron-donating and -withdrawing groups on both of the ar-
omatic rings were readily accessible from Sonogashira
coupling of o-ethynylanilines 15a,b and substituted 2-bro-
mopyridines 2 in good to excellent yields as outlined in
Scheme 2.
The proposed reaction was tested between o-[2-(pyridin-
2-yl)ethynyl]aniline (3a; R1, R2 = H) and ethyl acetoace-
tate (4a; R3 = Me) under the conditions reported previous-
ly by us.6 The desired cyclization did take place by
forming an amide bond between the pyridine nitrogen and
the carboxylic ester in high yield in the presence of p-tol-
uenesulfonic acid (5a, Table 1). The unique tetracyclic
heterocycle was constructed via sequential formations of
three chemical bonds with one molecule of ethanol and
water as the only waste products. Substrates with methyl
groups at three out of the four possible positions on the py-
ridine ring were successfully applied (5b–d, Table 1). 6-
Methyl-substituted pyridine failed to cyclize due to the
steric hindrance around nitrogen. Surprisingly, the quino-
line intermediate before cyclization was not isolated ei-
ther. Although the nucleophilicity of pyridine nitrogen
was reduced by electron-withdrawing groups, such as Cl
and CN, corresponding products were obtained in excel-
lent yields (5e–f, Table 1). And more importantly, these
functionalities provided handles for further modification
on the scaffold. The fluoro substitution at C-5 also deliv-
ered the corresponding product 5g in reasonable yield.
The unprecedented pentacyclic heterocycle containing a
As part of our continuing interest in diversified quinoline
synthesis,5 we reported a Friedländer type reaction for the
synthesis of multisubstituted 4-alkylquinolines from o-
alkynylanilines and activated ketones in the presence of p-
toluenesulfonic acid in ethanol under reflux (Scheme 1,
SYNTHESIS 2011, No. 11, pp 1723–1732
x
x.
x
x
.
2
0
1
1
Advanced online publication: 15.04.2011
DOI: 10.1055/s-0030-1260001; Art ID: H23611SS
© Georg Thieme Verlag Stuttgart · New York

1724
L. Peng et al.
PAPER
mercury(II) or
mercury-free
O
R2
R1
R1
R2
R2
+
(1)
(2)
R1
hydration
O
internal alkyne
R2
O
R2
H+
2 = alkyl
R1
R1
R
R2
O
O
R2
H+
O
R3
OEt
R2
COOEt
R3
(3)
R1
R1
R1
H+
ref. 6
NH2
N
NH2
R
2 = substituted phenyl; 55–80%
R2
R2
R2
O
O
N
O
R1
R1
H+
R3
OEt
R1
N
(4)
N
O
H+
NH2
NH2
N
R3
higher regioselectivity
more complexity
this work
Scheme 1 Hydration of alkynes and its application
R2
N
R1
R1
PdCl2(PPh3)2, CuI
Et3N, DMF, 60 °C
R2
+
Br
N
NH2
77–95%
NH2
3a–n
2
1
R1 = H, Me, Cl
2 = H, 3-Me, 4-Me, 5-Me, 3-Cl, 4-CN, 5-F, 3,4-benzo
R
Scheme 2 Synthesis of pyridine substituted o-alkynylanilines
quinoline and an isoquinoline moiety was obtained in ex- was not incorporated. A reasonable explanation was that
cellent yield (5h, Table 1). Quinoline-substituted o-alky- the diethoxyketal of the highly electrophilic trifluoro-
nylaniline did not furnish a similar product as 5h probably methyl ketone was formed in ethanol catalyzed by PTSA
for steric reasons. Alteration of substituents on the aro- before it could condense with the amino group. The pres-
matic ring of aniline did not affect the efficiency of cy- ence of 4j had nothing to do with the formation of 6a. In-
clization, yielding 5i and 5j almost quantitatively. deed, the same product 6a was obtained in 70% yield
Reactions of 3a with ethyl 3-oxohexanoate (4b) and ethyl when 3a was the only substrate in the reaction mixture
3-oxo-5-phenylpentanoate (4c) provided the correspond- (Scheme 3). Obviously, 6a was formed bimolecularly
ing n-propyl- and phenethyl-substituted 5k and 5l in ex- through Friedländer reaction of the hydrated intermediate
cellent yields. The unexpected lower yield of 5m and 5n
was probably due to the steric hindrance of the benzyl
N
group as well as the activity of the methylene group under
the reaction conditions. Variation of R3 from alkyl groups
N
p-TsOH (2.0 equiv)
EtOH, reflux, 24 h
to aryl ones 5o,p were also successful, albeit longer reac-
N
tion times were required. As expected, 3-oxobutanamide
(4h) and 3-oxo-3-phenylpropanenitrile (4i) could be used
as surrogates of b-keto esters 4a and 4f, providing respec-
tive 5a and 5o in good yields.
70%
N
NH2
3a
6a
H2N
O
To our surprise, a new product was separated from the re-
action of 3a and ethyl 4,4,4-trifluoroacetoacetate (4j) un-
der the same reaction conditions as described above. The
structure was identified as multisubstituted quinoline 6a,
in which the other reactant, 4,4,4-trifluoroacetoacetate,
N
7a
NH2
Scheme 3 Formation of multisubstituted quinoline 6a
Synthesis 2011, No. 11, 1723–1732 © Thieme Stuttgart · New York

PAPER
An Efficient Approach to Quinoline-Based Heterocycles
1725
7a, which was detected during the reaction. The methyl- plex quinoline scaffold was constructed in an atom-eco-
ene group in 7a was double activated by the carbonyl nomic manner from two molecules of simple pyridine-
group and the pyridine ring, which facilitated the substituted o-alkynylanilines, without wasting any atoms
Friedländer reaction under the mild conditions.4 The com- in substrate 3a.
Table 1 Synthesis of Multicyclic Heterocycles Containing Pyridines and Quinolines in One Pota
R2
R2
N
N
R1
O
R1
PTSA (2.0 equiv)
EtOH, reflux, 15–60 h
O
R4
+
R3
NH2
N
R3
3
4 R4 = COOEt, CONH2, CN
5
Entry Substrate 3
Substrate 4
Product 5
Time (h) Yield (%)b
O
O
N
N
1
15
15
92
93
OEt
O
4a
4a
NH2
N
3a
5a
N
N
2
O
NH2
N
3b
5b
N
N
3
4a
15
92
O
NH2
N
3c
5c
N
N
4
4a
4a
15
15
85
90
O
NH2
N
3d
5d
Cl
Cl
N
N
5
O
NH2
N
3e
5e
CN
N
CN
N
6
4a
15
90
O
NH2
N
3f
5f
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L. Peng et al.
PAPER
Table 1 Synthesis of Multicyclic Heterocycles Containing Pyridines and Quinolines in One Pota (continued)
R2
R2
N
N
R1
O
R1
PTSA (2.0 equiv)
EtOH, reflux, 15–60 h
O
R4
+
R3
NH2
N
R3
3
4 R4 = COOEt, CONH2, CN
5
Entry Substrate 3
Substrate 4
Product 5
Time (h) Yield (%)b
F
F
N
N
7
4a
15
70
O
NH2
N
3g
5g
8
4a
15
92
N
N
O
N
NH2
N
3h
5h
N
9
10
11
4a
4a
15
15
36
96
95
88
O
NH2
N
3i
5i
N
N
Cl
Cl
O
NH2
N
3j
5j
O
O
N
3a
OEt
O
4b
N
5k
O
O
N
OEt
12
3a
20
96
O
N
4c
5l
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An Efficient Approach to Quinoline-Based Heterocycles
1727
Table 1 Synthesis of Multicyclic Heterocycles Containing Pyridines and Quinolines in One Pota (continued)
R2
R2
N
N
R1
O
R1
PTSA (2.0 equiv)
EtOH, reflux, 15–60 h
O
R4
+
R3
NH2
N
R3
3
4 R4 = COOEt, CONH2, CN
5
Entry Substrate 3
Substrate 4
Product 5
Time (h) Yield (%)b
N
O
O
O
13
3a
60
35
OEt
N
4d
5m
N
O
F
O
O
14
3a
60
74
N
OEt
4e
F
5n
O
O
N
OEt
15
3a
60
70
O
N
4f
5o
O
O
N
OEt
16
3a
O
48
58
MeO
N
4g
OMe
5p
5a
O
O
17
18
3a
3a
15
42
68
75
NH2
CN
4h
O
5o
Ph
4i
a Reaction conditions: 3 (0.5 mmol), 4 (0.75 mmol), PTSA (1.0 mmol), EtOH (4.0 mL), reflux, 15–60 h.
b Yield of isolated 5.
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L. Peng et al.
PAPER
Table 2 Synthesis of Multisubstituted Quinoline 6a
A few of pyridine-substituted o-alkynylanilines 3 were se-
lected to examine the generality of the reaction and the re-
sults are listed in Table 2. The transformation was
applicable to substrates with various substitutions on the
pyridine ring to give 6b–d. Chloro substitution on the
aniline ring also provided 6e in moderate yield. o-[2-(Py-
ridin-3-yl)ethynyl]aniline (3k) and o-[2-(pyridin-4-
yl)ethynyl]aniline (3l), variants of 3a in terms of the nitro-
gen position in the pyridine substituent, delivered corre-
sponding products 6f and 6g in moderate yields.
Entry Substrate 3
Product 6
Yield
(%)b
N
N
1
3b
60
N
To simplify the diagram, 3a is used to elucidate the reac-
tion pathways to 5a and 6a in the presence and absence of
4a, respectively (Scheme 4). Regioselective hydration of
3a triggers the sequential reactions via the protonated in-
termediate A, which is stabilized by the aniline ring. Con-
densation of the resulting 7a with b-keto ester 4a forms
the imine intermediate C and its enamine tautomer D.
Subsequent cyclocondensation and dehydrative aromati-
zation delivers the quinoline intermediate E under the aid
of acid. A second cyclization takes place by nucleophilic
attack of the pyridine nitrogen at 3-carboxylic ester, form-
ing the final tetracyclic product 5a after deprotonation
from intermediate F. Four individual reactions take place
in order under the same conditions. When 4a is absent, the
amino group in 7a condenses with the ketone moiety of
another molecule of 7a, resulting in dimeric intermediate
G. Following a classical Friedländer quinoline synthesis,
multisubstituted quinoline 6a is formed.
H2N
6b
N
2
3d
N
64
N
H2N
6c
F
F
N
3
3g
60
N
N
H2N
6d
In summary, a unique quinoline-based tetracyclic scaffold
is constructed through sequential hydration–condensa-
tion–double cyclization reactions starting with readily
available pyridine-substituted o-alkynylanilines and b-
keto esters in one pot promoted by p-toluenesulfonic acid
in ethanol. It is an environmentally benign and atom-eco-
nomical process since no metal catalyst is involved and
the only wastes are alcohol and water. A C=N bond, a
C=C bond, and a C–N bond are formed sequentially in
one operation. In the absence of b-keto esters, the hydrat-
ed intermediates condense with themselves to produce
multisubstituted quinolines with no atom wasted. Biolog-
ical activity evaluation of these heterocycles containing
both the quinoline and pyridine motifs is underway in our
laboratories.
N
Cl
N
4
5
6
3j
42
Cl
N
H2N
6e
N
N
N
31
N
NH2
H2N
3k
All reagents were purchased and used without further purification
unless otherwise noted. DMF was distilled under reduced pressure
before use. Reactions were monitored using TLC on commercial
silica gel plates (GF254). Visualization of the developed plates was
performed under UV light (254 nm, 365 nm). Flash column chro-
matography was performed on silica gel (200–300 mesh). Melting
points were measured on a OptiMelt MPA 100 melting point appa-
ratus and are uncorrected. 1H and 13C NMR spectra were recorded
on a Bruker AV-400 or 500 MHz spectrometer. Chemical shifts (d)
were reported in ppm referenced to an internal TMS (CDCl3) or the
residual peak of solvents (DMSO-d6: d = 2.50; acetone-d6: d = 2.05;
acetic acid-d4: d = 2.04) for 1H NMR. Chemical shifts of 13C NMR
were reported relative to CDCl3 (d = 77.0), DMSO-d6 (d = 39.5) or
acetone-d6 (d = 29.8). For some cases, about 10–20% of MeOH or
AcOH was added to improve the solubility for 13C NMR. Coupling
6f
N
N
N
59
N
NH2
H2N
3l
6g
a Reaction conditions: 3 (0.5 mmol), PTSA (1.0 mmol), EtOH (4.0
mL), reflux, 24 h.
b Yield of isolated 6.
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PAPER
An Efficient Approach to Quinoline-Based Heterocycles
1729
1. hydration
OH
H+
N
H2O, – H+
N
N
– H+
NH2
B
NH2
A
NH2 3a
N
2. condensation
O
N
O
4a, – H2O
N
N
O
H2O, – 4a
7a
O
NH2
NH OEt
C
D
OEt
O
– H2O
O
H2O
N
3. cyclocondensation
– H2O
H
N
N
– EtO–
O
N
COOEt
4. acyl substitution
N
N
N
F
G
NH2
– H+
E
– H2O
5a
6a
Scheme 4 Proposed reaction pathways to 5a and 6a
constants (J) are reported in hertz (Hz). High-resolution mass spec-
tra (HRMS) were obtained on a Q-STAR Elite ESI-LC-MS/MS
Spectrometer.
13C NMR (125 MHz, CDCl3 + MeOH): d = 161.8, 158.9, 145.5,
142.2, 140.2, 132.0, 131.2, 130.5, 128.4, 126.0, 125.9, 122.9, 121.5,
113.4, 109.0, 91.9, 28.0, 19.2.
HRMS: m/z [M + H]+ calcd for C18H15N2O: 275.1179; found:
275.1185.
Compounds 5a–n; General Procedure
To a solution of o-[2-(pyridin-2-yl)ethynyl]aniline 3 (0.5 mmol)
and 4 (0.75 mmol) in anhyd EtOH (4 mL), was added PTSA·H2O
(190 mg, 1.0 mmol), and the mixture was stirred at reflux under air.
When TLC (CH2Cl2–MeOH; 50:1) showed that almost all of the
raw material 3 was consumed, CH2Cl2 (60 mL) was added. The or-
ganic layer was washed with sat. aq NaHCO3 (3 × 20 mL) and brine
(20 mL), and dried (Na2SO4). The residue obtained by the removal
of the solvent by rotary evaporation was purified by column chro-
matography over silica gel using CH2Cl2–MeOH (100:1 to 50:1) as
eluent to provide the desired product (Table 1).
6,11-Dimethyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-
one (5c)
Yield: 126 mg (92%); yellow solid; mp 232–233 °C.
1H NMR (400 MHz, acetone-d6): d = 8.99 (d, J = 7.6 Hz, 1 H), 8.54
(d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.78 (t, J = 7.6 Hz, 1
H), 7.68 (s, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.55 (s, 1 H), 6.95 (dd,
J = 7.2, 1.8 Hz, 1 H), 3.14 (s, 3 H), 2.44 (s, 3 H).
13C NMR (125 MHz, CDCl3 + MeOH): d = 161.8, 158.4, 144.8,
142.8, 142.2, 140.9, 131.1, 127.5, 126.6, 126.0, 123.1, 123.0, 121.3,
117.1, 108.3, 94.2, 27.4, 20.9.
6-Methyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5a)
Yield: 120 mg (92%); yellow solid; mp 243–244 °C.
1H NMR (400 MHz, acetone-d6): d = 9.08 (d, J = 7.2 Hz, 1 H), 8.59
(d, J = 7.6 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.85 (s, 1 H), 7.83–
7.79 (m, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.56–7.52 (m, 1 H), 7.09 (t,
J = 7.2 Hz, 1 H), 3.16 (s, 3 H).
HRMS: m/z [M + H]+ calcd for C18H15N2O: 275.1179; found:
275.1180.
6,10-Dimethyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-
one (5d)
Yield: 116 mg (85%); yellow solid; mp 211–212 °C.
13C NMR (125 MHz, CDCl3): d = 161.7, 158.5, 146.0, 141.8, 140.8,
131.1, 130.4, 129.0, 127.4, 125.9, 125.5, 123.1, 121.3, 113.6, 109.5,
95.2, 28.6.
1H NMR (400 MHz, acetone-d6): d = 8.88 (s, 1 H), 8.56 (d, J = 8.0
Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.81–7.73 (m, 3 H), 7.60 (t,
J = 7.6 Hz, 1 H), 7.43 (dd, J = 9.2, 1.6 Hz, 1 H), 3.16 (s, 3 H), 2.41
(d, J = 0.8 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C17H13N2O: 261.1022; found:
13C NMR (125 MHz, CDCl3 + MeOH): d = 161.9, 158.2, 145.2,
140.8, 140.2, 134.1, 131.1, 128.2, 126.0, 125.0, 124.4, 124.1, 123.0,
121.4, 109.1, 95.1, 28.0, 18.5.
HRMS: m/z [M + H]+ calcd for C18H15N2O: 275.1179; found:
275.1182.
261.1026.
6,12-Dimethyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-
one (5b)
Yield: 127 mg (93%); yellow solid; mp 220–221 °C.
1H NMR (400 MHz, acetone-d6): d = 9.04 (d, J = 7.6 Hz, 1 H), 8.68
(d, J = 8.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1
H), 7.73 (s, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.44 (d, J = 7.2 Hz, 1 H),
7.02 (t, J = 7.2 Hz, 1 H), 3.16 (s, 3 H), 2.67 (s, 3 H).
12-Chloro-6-methyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyri-
din-7-one (5e)
Yield: 132 mg (90%); yellow solid; mp 330–332 °C.
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L. Peng et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 9.06 (d, J = 7.6 Hz, 1 H), 8.74
(s, 1 H), 8.08 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.86–7.83 (m, 2 H),
7.68–7.64 (m, 1 H), 7.20 (t, J = 6.8 Hz, 1 H), 3.12 (s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.7, 157.2, 145.7,
139.6, 136.6, 134.2, 134.0, 133.1, 128.5, 126.2, 123.3, 122.9, 122.7,
117.3, 105.8, 96.3, 23.0.
1H NMR (400 MHz, DMSO-d6): d = 9.01 (d, J = 8.0 Hz, 1 H), 8.67
(d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.94 (s, 1 H), 7.90–
7.86 (m, 2 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.10 (t, J = 7.2 Hz, 1 H),
3.12 (s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.2, 157.8, 141.3,
141.2, 140.8, 132.6, 132.2, 129.3, 127.5, 127.0, 125.3, 123.4, 121.4,
113.3, 108.3, 92.9, 25.2.
HRMS: m/z [M + H]+ calcd for C17H12ClN2O: 295.0633; found:
295.0628.
HRMS: m/z [M + H]+ calcd for C17H12ClN2O: 295.0633; found:
295.0631.
6-Methyl-7-oxo-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridine-
11-carbonitrile (5f)
Yield: 128 mg (90%); orange solid; mp 309–310 °C.
6-Propyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5k)
Yield: 127 mg (88%); yellow solid; mp 162–164 °C.
1H NMR (400 MHz, acetic acid-d4): d = 9.18 (d, J = 7.2 Hz, 1 H),
8.63 (d, J = 8.4 Hz, 1 H), 8.36 (s, 1 H), 8.19 (d, J = 8.4 Hz, 1 H),
8.00 (t, J = 7.6 Hz, 1 H), 7.94 (s, 1 H), 7.85 (t, J = 7.6 Hz, 1 H), 7.32
(d, J = 7.6 Hz, 1 H), 3.33 (s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.4, 157.0, 142.7,
142.3, 137.4, 133.5, 132.8, 129.0, 128.4, 123.8, 122.4, 121.4, 117.1,
115.2, 113.7, 109.2, 98.4, 23.5.
1H NMR (400 MHz, DMSO-d6): d = 9.02 (d, J = 7.2 Hz, 1 H), 8.60
(d, J = 8.0 Hz, 1 H), 7.95–7.92 (m, 2 H), 7.83–7.79 (m, 2 H), 7.64
(t, J = 7.6 Hz, 1 H), 7.59–7.55 (m, 1 H), 7.12 (t, J = 6.8 Hz, 1 H),
3.53–3.49 (m, 2 H), 1.83–1.74 (m, 2 H), 1.04 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 165.1, 157.9, 141.7, 141.1, 131.0,
130.4, 129.1, 127.5, 125.9, 125.4, 123.0, 121.3, 113.6, 108.9, 95.3,
42.1, 23.0, 14.6.
HRMS: m/z [M + H]+ calcd for C18H12N3O: 286.0975; found:
286.0976.
HRMS: m/z [M + H]+ calcd for C19H17N2O: 289.1335; found:
289.1337.
10-Fluoro-6-methyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyri-
din-7-one (5g)
Yield: 77 mg (70%); yellow solid; mp 228–229 °C.
6-Phenethyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5l)
Yield: 168 mg (96%); orange solid; mp 183–184 °C.
1H NMR (400 MHz, acetone-d6): d = 8.96 (dd, J = 6.0, 2.4 Hz, 1 H),
8.59 (d, J = 8.0 Hz, 1 H), 7.99–7.90 (m, 3 H), 7.82 (t, J = 7.6 Hz, 1
H), 7.64 (t, J = 7.6 Hz, 1 H), 7.60–7.56 (m, 1 H), 3.17 (s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.8, 156.9, 156.1,
154.1, 143.6, 140.7, 135.1, 133.2, 128.6, 128.5, 128.4, 123.9, 121.5,
120.9, 114.7, 114.4, 105.8, 96.9, 30.2.
1H NMR (400 MHz, DMSO-d6): d = 9.06 (d, J = 7.6 Hz, 1 H), 8.61
(d, J = 8.4 Hz, 1 H), 7.97–7.95 (m, 2 H), 7.85–7.81 (m, 2 H), 7.66
(t, J = 7.6 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 2
H), 7.32 (t, J = 7.6 Hz, 2 H), 7.20 (t, J = 7.2 Hz, 1 H), 7.13 (t, J = 7.2
Hz, 1 H), 3.84–3.79 (m, 2 H), 3.09–3.05 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 163.9, 157.9, 146.0, 142.8, 141.7,
141.0, 131.0, 130.4, 129.2, 128.9, 128.2, 127.5, 126.0, 125.6, 125.4,
123.1, 121.3, 113.5, 108.9, 95.2, 42.1, 35.4.
HRMS: m/z [M + H]+ calcd for C17H12FN2O: 279.0928; found:
279.0926.
6-Methyl-7H-benzo[f]isoquinolino[2,1-b][2,7]naphthyridin-7-
one (5h)
HRMS: m/z [M + H]+ calcd for C24H19N2O: 351.1492; found:
351.1490.
Yield: 143 mg (92%); yellow solid; mp 259–260 °C.
6-Benzyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5m)
Yield: 59 mg (35%); pale yellow solid; mp 254–255 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.09–9.03 (m, 2 H), 8.76 (d,
J = 8.0 Hz, 1 H), 8.60 (s, 1 H), 7.59 (d, J = 7.6 Hz, 1 H), 7.87–7.69
(m, 5 H), 7.28 (d, J = 8.0 Hz, 1 H), 3.11 (s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 161.6, 158.0, 142.8,
141.5, 139.4, 132.7, 132.6, 131.5, 129.2, 127.7, 127.3, 125.1, 125.0,
123.8, 123.5, 122.2, 121.4, 115.2, 109.1, 92.2, 24.2.
1H NMR (400 MHz, DMSO-d6): d = 8.99 (d, J = 7.2 Hz, 1 H), 8.65
(d, J = 7.6 Hz, 1 H), 8.01–7.98 (m, 2 H), 7.88–7.82 (m, 2 H), 7.69
(t, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.29 (m, 2 H), 7.20 (t,
J = 7.6 Hz, 2 H), 7.14–7.09 (m, 2 H), 4.99 (s, 2 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.9, 156.9, 144.0,
141.4, 137.1, 134.2, 132.3, 129.3, 128.3, 128.0, 127.6, 126.6, 125.8,
124.1, 123.3, 121.4, 115.6, 106.6, 95.5, 40.8.
HRMS: m/z [M + H]+ calcd for C21H15N2O: 311.1179; found:
311.1179.
2,6-Dimethyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5i)
HRMS: m/z [M + H]+ calcd for C23H17N2O: 337.1335; found:
Yield: 132 mg (96%); yellow solid; mp 243–244 °C.
337.1338.
1H NMR (400 MHz, DMSO-d6): d = 8.97 (d, J = 7.2 Hz, 1 H), 8.37
(s, 1 H), 7.88 (s, 1 H), 7.81–7.77 (m, 2 H), 7.63 (d, J = 8.0 Hz, 1 H),
7.56 (t, J = 7.6 Hz, 1 H), 7.10 (t, J = 6.8 Hz, 1 H), 3.07 (s, 3 H), 2.56
(s, 3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 161.1, 157.4, 144.4,
140.5, 138.3, 135.9, 134.4, 134.0, 127.6, 126.2, 123.1, 122.4, 121.1,
116.0, 106.6, 95.9, 23.9, 21.6.
6-(4-Fluorobenzyl)-7H-benzo[f]pyrido[1,2-b][2,7]naphthyri-
din-7-one (5n)
Yield: 131 mg (74%); pale yellow solid; mp 277–278 °C.
1H NMR (400 MHz, CDCl3 + acetic acid-d4): d = 9.00 (d, J = 6.4
Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H), 7.70
(t, J = 6.8 Hz, 1 H), 7.65–7.58 (m, 2 H), 7.54 (t, J = 7.2 Hz, 1 H),
7.38–7.35 (m, 3 H), 7.07 (t, J = 4.8 Hz, 1 H), 6.85 (t, J = 7.6 Hz, 2
H), 5.01 (s, 2 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.7, 162.6, 160.8,
156.8, 145.3, 141.6, 136.5, 135.9, 133.0, 131.5, 130.8, 130.7, 128.4,
128.3, 126.0, 123.6, 122.2, 121.7, 116.6, 115.1, 114.9, 105.6, 96.2,
38.9.
HRMS: m/z [M + H]+ calcd for C18H15N2O: 275.1179; found:
275.1177.
2-Chloro-6-methyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyri-
din-7-one (5j)
Yield: 140 mg (95%); yellow solid; mp 239–240 °C.
Synthesis 2011, No. 11, 1723–1732 © Thieme Stuttgart · New York

PAPER
An Efficient Approach to Quinoline-Based Heterocycles
1731
HRMS: m/z [M + H]+ calcd for C23H16FN2O: 355.1241; found:
355.1245.
H), 7.57 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 7.2 Hz, 1 H), 7.23 (d,
J = 7.2 Hz, 1 H), 7.12 (dd, J = 7.6, 4.8 Hz, 1 H), 6.96 (dd, J = 7.2,
4.8 Hz, 1 H), 6.87 (td, J = 7.2, 1.2 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 1
H), 6.17 (t, J = 7.2 Hz, 1 H), 5.50 (br, 2 H), 4.55 (d, J = 16.4 Hz, 1
H), 4.38 (d, J = 16.4 Hz, 1 H), 2.00 (s, 3 H), 1.49 (s, 3 H).
6-Phenyl-7H-benzo[f]pyrido[1,2-b][2,7]naphthyridin-7-one
(5o)
Yield: 113 mg (70%); pale yellow solid; mp 265–266 °C.
13C NMR (125 MHz, DMSO-d6): d = 157.2, 157.1, 156.8, 146.7,
146.3, 146.1, 145.9, 145.9, 137.4, 136.9, 133.6, 133.2, 130.8, 130.6,
129.3, 129.0, 128.6, 127.2, 126.4, 125.6, 123.6, 122.4, 121.1, 115.8,
115.0, 33.0, 18.1, 17.5.
HRMS: m/z [M + H]+ calcd for C28H25N4: 417.2074; found:
417.2076.
1H NMR (400 MHz, DMSO-d6): d = 8.85 (d, J = 7.2 Hz, 1 H), 8.73
(d, J = 7.6 Hz, 1 H), 8.07 (s, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.91–
7.86 (m, 2 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H),
7.52–7.49 (m, 2 H), 7.43–7.40 (m, 3 H), 7.10 (t, J = 6.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3 + AcOH): d = 162.0, 157.6, 143.4,
143.2, 141.4, 140.6, 132.1, 131.9, 128.4, 127.9, 127.7, 127.3, 125.6,
123.3, 121.7, 114.4, 107.5, 95.5.
2-{3-(5-Methylpyridin-2-yl)-4-[(5-methylpyridin-2-yl)meth-
yl]quinolin-2-yl}aniline (6c)
Yield: 67 mg (64%); pale yellow solid; mp 87–88 °C.
HRMS: m/z [M + H]+ calcd for C22H15N2O: 323.1179; found:
323.1176.
1H NMR (400 MHz, DMSO-d6): d = 8.40 (s, 1 H), 8.23 (s, 1 H), 8.08
(d, J = 8.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1
H), 7.55 (t, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.01 (d,
J = 8.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H),
6.67 (t, J = 8.4 Hz, 2 H), 6.30 (t, J = 7.6 Hz, 1 H), 5.14 (br, 2 H),
4.41 (s, 2 H), 2.23 (s, 3 H), 2.18 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 158.0, 156.3, 154.5, 149.0,
148.9, 146.7, 146.2, 144.2, 137.0, 136.2, 134.4, 131.2, 130.6, 130.3,
129.4, 129.3, 128.4, 126.7, 126.0, 125.3, 125.1, 124.8, 122.2, 115.5,
115.4, 36.9, 17.6, 17.4.
6-(4-Methoxyphenyl)-7H-benzo[f]pyrido[1,2-b][2,7]naphthyri-
din-7-one (5p)
Yield: 102 mg (58%); yellow solid; mp 274–276 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.86 (d, J = 7.6 Hz, 1 H), 8.71
(d, J = 8.0 Hz, 1 H), 8.04 (s, 1 H), 8.00 (d, J = 7.2 Hz, 1 H), 7.89–
7.84 (m, 2 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.63–7.59 (m, 1 H), 7.50–
7.48 (m, 2 H), 7.10 (t, J = 6.8 Hz, 1 H), 6.98–6.96 (m, 2 H), 3.84 (s,
3 H).
13C NMR (125 MHz, CDCl3 + AcOH): d =161.2, 160.8, 157.4,
144.5, 141.7, 139.8, 134.1, 132.6, 130.1, 129.2, 128.2, 127.9, 125.8,
124.9, 123.5, 121.7, 115.5, 113.3, 106.2, 95.9, 55.1.
HRMS: m/z [M + H]+ calcd for C28H25N4: 417.2074; found:
417.2080.
HRMS: m/z [M + H]+ calcd for C23H17N2O2: 353.1285; found:
353.1288.
2-{3-(5-Fluoropyridin-2-yl)-4-[(5-fluoropyridin-2-yl)meth-
yl]quinolin-2-yl}aniline (6d)
Yield: 64 mg (60%); pale yellow solid; mp 79–80 °C.
Compounds 6a–f; General Procedure
To a solution of o-[2-(pyridin-2-yl)ethynyl]aniline 3 (0.5 mmol) in
anhyd EtOH (4 mL), was added PTSA·H2O (190 mg, 1.0 mmol),
and the mixture was stirred at reflux under air. When TLC (CH2Cl2–
MeOH; 50:1) showed that almost all of the raw material was con-
sumed, CH2Cl2 (60 mL) added. The organic layer was washed with
sat. aq NaHCO3 (3 × 20 mL) and brine (20 mL), and dried (Na2SO4).
The solvent was evaporated by rotary evaporation to give a residue,
which was purified by column chromatography over silica gel using
CH2Cl2–MeOH (100:1) as eluent to provide the desired product
(Table 2).
1H NMR (400 MHz, DMSO-d6): d = 8.54 (d, J = 2.8 Hz, 1 H), 8.36
(d, J = 2.8 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1
H), 7.79 (t, J = 7.2 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.55–7.49 (m,
2 H), 7.14–7.11 (m, 2 H), 6.91 (td, J = 7.6, 1.2 Hz, 1 H), 6.67–6.61
(m, 2 H), 6.31 (t, J = 7.2 Hz, 1 H), 5.16 (br, 2 H), 4.50 (s, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 158.9, 158.7, 157.9, 156.9,
156.7, 155.4, 155.4, 153.7, 153.7, 146.9, 146.2, 144.2, 136.7, 36.7,
136.6, 136.5, 133.6, 130.5, 129.7, 129.4, 128.5, 127.0, 127.0, 127.0,
126.0, 125.2, 124.3, 124.1, 124.1, 123.6, 123.5, 123.0, 122.9, 115.4,
115.3, 36.2.
HRMS: m/z [M + H]+ calcd for C26H19F2N4: 425.1572; found:
425.1575.
2-[3-(Pyridin-2-yl)-4-(pyridin-2-ylmethyl)quinolin-2-yl]aniline
(6a)
Yield: 68 mg (70%); pale yellow solid; mp 80–81 °C.
4-Chloro-2-[6-chloro-3-(pyridin-2-yl)-4-(pyridin-2-ylmeth-
yl)quinolin-2-yl]aniline (6e)
Yield: 48 mg (42%); pale yellow solid; mp 83–85 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.56 (d, J = 4.4 Hz, 1 H), 8.38
(d, J = 4.4 Hz, 1 H), 8.13 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1
H), 7.77 (t, J = 7.6 Hz, 1 H), 7.59–7.54 (m, 3 H), 7.23–7.20 (m, 1
H), 7.14–7.11 (m, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.0
Hz, 1 H), 6.88 (dd, J = 8.4, 1.6 Hz, 1 H), 6.66–6.63 (m, 2 H), 6.27
(t, J = 7.2 Hz, 1 H), 5.18 (br, 2 H), 4.50 (s, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 159.2, 157.9, 157.3, 148.8,
148.7, 146.7, 146.3, 144.0, 136.5, 135.8, 134.5, 130.6, 129.5, 129.3,
128.4, 126.8, 126.0, 125.6, 125.3, 124.5, 122.8, 122.2, 121.4, 115.4,
115.3, 37.2.
1H NMR (400 MHz, DMSO-d6): d = 8.49 (dd, J = 4.4, 1.2 Hz, 1 H),
8.21 (d, J = 8.4 Hz, 1 H), 8.16 (dd, J = 4.4, 1.2 Hz, 1 H), 8.09 (d,
J = 7.6 Hz, 1 H), 7.83 (td, J = 8.0, 0.8 Hz, 1 H), 7.73 (dd,
J = 8.0, 1.2 Hz, 1 H), 7.65–7.61 (m, 2 H), 7.28 (dd, J = 8.4, 4.8 Hz,
1 H), 7.15 (dd, J = 8.0, 4.4 Hz, 1 H), 6.88 (td, J = 8.0, 1.2 Hz, 1 H),
6.67 (d, J = 7.6 Hz, 1 H), 6.57 (dd, J = 7.6, 1.2 Hz, 1 H), 6.18 (td,
J = 7.6, 0.8 Hz, 1 H), 5.43 (br, 2 H), 4.75 (d, J = 16.8 Hz, 1 H), 4.54
(d, J = 16.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 157.2, 155.2, 154.9, 147.4,
147.2, 146.9, 146.5, 145.1, 137.0, 136.5, 131.8, 131.7, 130.2, 129.8,
129.7, 129.0, 128.7, 126.9, 126.7, 125.7, 124.0, 123.0, 122.8, 115.8,
114.8, 33.0.
HRMS: m/z [M + H]+ calcd for C26H21N4: 389.1761; found:
389.1759.
2-{3-(3-Methylpyridin-2-yl)-4-[(3-methylpyridin-2-yl)meth-
yl]quinolin-2-yl}aniline (6b)
Yield: 62 mg (60%); pale yellow solid; mp 197–198 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.47 (d, J = 3.6 Hz, 1 H), 8.05
(t, J = 8.0 Hz, 1 H), 7.97 (d, J = 3.6 Hz, 1 H), 7.78 (t, J = 7.6 Hz, 1
HRMS: m/z [M + H]+ calcd for C26H19Cl2N4: 457.0981; found:
457.0978.
Synthesis 2011, No. 11, 1723–1732 © Thieme Stuttgart · New York

1732
L. Peng et al.
PAPER
2-[3-(Pyridin-3-yl)-4-(pyridin-3-ylmethyl)quinolin-2-yl]aniline
(6f)
References
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Yield: 30 mg (31%); pale yellow solid; mp 92–93 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.35–8.32 (m, 3 H), 8.27 (s, 1
H), 8.09 (d, J = 6.8 Hz, 1 H), 8.03 (d, J = 6.8 Hz, 1 H), 7.79 (t,
J = 6.0 Hz, 1 H), 7.61–7.58 (m, 2 H), 7.37 (t, J = 6.4 Hz, 1 H), 7.22–
7.20 (m, 2 H), 6.88 (t, J = 6.0 Hz, 1 H), 6.82 (d, J = 6.0 Hz, 1 H),
6.53 (d, J = 6.4 Hz, 1 H), 6.35 (t, J = 6.0 Hz, 1 H), 4.93 (s, 2 H), 4.35
(s, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 158.5, 149.8, 149.1, 148.1,
147.3, 147.2, 145.6, 143.3, 137.0, 135.4, 135.1, 133.7, 132.6, 130.2,
129.7, 129.5, 128.3, 127.0, 125.7, 125.0, 124.9, 123.5, 122.5, 115.1,
114.8, 31.9.
HRMS: m/z [M + H]+ calcd for C26H21N4: 389.1761; found:
389.1763.
2-[3-(Pyridin-4-yl)-4-(pyridin-4-ylmethyl)quinolin-2-yl]aniline
(6g)
Yield: 57 mg (59%); pale yellow solid; mp 202–203 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.39–8.37 (m, 4 H), 8.09 (d,
J = 8.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1 H),
7.59 (t, J = 7.2 Hz, 1 H), 7.21 (d, J = 3.6 Hz, 2 H), 7.06 (d, J = 3.6
Hz, 2 H), 6.89 (t, J = 6.8 Hz, 1 H), 6.80 (d, J = 7.2 Hz, 1 H), 6.57 (d,
J = 8.0 Hz, 1 H), 6.34 (t, J = 7.2 Hz, 1 H), 4.98 (br, 2 H), 4.32 (s, 2
H).
(6) Peng, C.; Wang, Y.; Liu, L.; Wang, H.; Zhao, J.; Zhu, Q.
13C NMR (125 MHz, DMSO-d6): d = 157.5, 149.4, 148.7, 148.2,
147.0, 145.9, 145.6, 141.7, 133.5, 130.0, 129.5, 128.3 127.0, 125.5,
124.8, 124.6, 124.5, 123.3, 114.9, 115.7, 33.8.
Eur. J. Org. Chem. 2010, 818.
(7) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2010,
12, 2978; and references cited therein.
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R.; Prakash, O. Eur. J. Med. Chem. 2003, 38, 533. (c)Kym,
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HRMS: m/z [M + H]+ calcd for C26H21N4: 389.1761; found:
389.1759.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful for the support of this work by a Start-up Grant from
Guangzhou Institutes of Biomedicine and Health (GIBH), and
Guangzhou Municipal Foundation for Science and Technology
(2010Y1-C241).
Synthesis 2011, No. 11, 1723–1732 © Thieme Stuttgart · New York