Transition-Metal-Free Synthesis of Fused Quinazolinones by Oxidative Cyclization of N-Pyridylindoles

Article abstract of DOI:10.1021/acs.joc.9b01170

An unprecedented synthesis of fused quinazolinones from N-pyridylindoles under oxidative conditions using a combination of (diacetoxyiodo)benzene and K₂S₂O₈ is reported. The reaction is metal-free, has a broad substrate scope, is operationally simple with short reaction time, and provides 11H-pyrido[2,1-b]quinazolin-11-one derivatives in moderate to high yields. It is believed to proceed via an in situ generated 2-hydroxy-1-(pyridin-2-yl)indolin-3-one as the key reaction intermediate, which undergoes a C-C bond cleavage to produce an electrophilic C-3 site in N-pyridyl indole. Subsequent nucleophilic attack by pyridyl nitrogen results in its cyclization.

Full text of DOI:10.1021/acs.joc.9b01170

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Article
Transition metal-free synthesis of fused quinazolinones
by oxidative cyclization of N-pyridylindoles
Alankrita Garia, and Nidhi Jain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01170 • Publication Date (Web): 03 Jul 2019
Downloaded from http://pubs.acs.org on July 3, 2019
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Page 1 of 10
The Journal of Organic Chemistry
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Transition metal-free synthesis of fused quinazolinones by oxidative
cyclization of N-pyridylindoles
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Alankrita Garia and Nidhi Jain*
Department of Chemistry, Indian Institute of Technology, New Delhi-110016
O
DIB, K2S2O8
X
Het/Ar
N
N
X
Het/Ar
25 examples Transition-Metal free!
Ligand-free!
MeCN, 80 oC, 2 h
N
N
Y
Base-free!
Short reaction time!
55- 85% yield
X,Y= CH3, OCH3, I, Br, Cl, F, NO2
Y
ABSTRACT: An unprecedented synthesis of fused quinazolinones from N-pyridylindoles under oxidative conditions using a
combination of DIB [(diacetoxy)iodo]benzene and K2S2O8 is reported. The reaction is metal-free, has a broad substrate scope, is
operationally simple with short reaction time, and provides 11H-pyrido[2,1-b]quinazolin-11-one derivatives in moderate to high
yields. It is believed to proceed via an in-situ generated 2-hydroxy-1-(pyridin-2-yl)indolin-3-one as the key reaction intermediate,
which undergoes a C-C bond cleavage to produce an electrophilic C-3 site in N-pyridyl indole. Subsequent nucleophilic attack by
pyridyl nitrogen results in its cyclization.
INTRODUCTION
linear and angular fused quinazolinones directly from 2-
aminopyridine and 2-bromoflourobenzene by palladium
catalyzed carbonylation/ nucleophilic aromatic substitution
sequence (Scheme 1A(ii)).12 Alternatively, copper mediated
strategies have also been reported (Scheme 1B). Yin and
Haung (Scheme 1B(iii)) demonstrated copper catalyzed
domino reaction between isatins and 2-bromopyridines for the
synthesis of 11H-pyrido[2,1-b]quinazolin-11-one.13 In another
report, the synthesis was achieved by copper-catalyzed tandem
benzylic oxidation, intramolecular cyclization, and
decarbonylation of N-pyridylarylacetamides (Scheme
1B(iv)).14 Recently, Liu and coworkers reported copper-
mediated tandem C(sp2)-H amination and annulation of arenes
with 2-aminopyridine using 8-aminoquinoline as a removable
bidentate directing group (Scheme 1B(v)).15 A metal-free
synthetic route was demonstrated by Pan and Su involving
carbodiimide mediated condensation between anthranilic acid
and pyridine16 (Scheme 1C). Till date, the known synthetic
procedures suffer from limitations of transition metal catalysts,
expensive ligands and long reaction times, thus restricting
their ease and generality.17
Aza-heterocycles are useful structural motifs found in many
naturally occurring alkaloids1 and bioactive molecules. Among
them, quinazolinones are privileged structural scaffolds which
show a broad spectrum of potent biological activity, and find
wide applications in medicinal chemistry as anti-
inflammatory,2 anti-allergic,3 anti-convulsant,4 anti-cancer,5
anti-hypertensive,6 anti-tumor,7 hypolipemic agents8 and HIV-
1 integrase inhibitor9 (Figure 1).
O
O
N
N
OMe
OMe
N
N
N
N
H
H
Euxylophoricine B
(alkaloid)
Rutaecarpine
O
N
O
COOH
N
R
N
N
Anti allergic
Anti tumor
IDO-1 inhibitor
Figure 1. Biologically active molecules with fused quinazolinone
core.
In the past few years, hypervalent iodine compounds have
found wide recognition in organic synthesis as selective
oxidants and environmentally benign reagents. They have
been employed in a variety of synthetic transformations such
as halogenations, oxidations, rearrangements, aminations,
C−C bond-formations, and transition metal-catalyzed
reactions.18 Compounds of iodine possess reactivity similar to
that of transition metals, and have high versatility and low
toxicity. Cognizant of these advantages, in this work, we
In view of the profound biological importance of pyrido-fused
quinazolinones, different approaches for their synthesis have
been developed. Previously, they were constructed via
reaction of 2-chlorobenzoic acid and 2-aminopyridine under
acidic and basic conditions.10 In recent years, new synthetic
strategies involving transition-metal catalysis have emerged.
As shown in Scheme 1A(i), the synthesis of
pyridoquinazolinones has been carried out by palladium
catalyzed carbonylation of N-aryl-2-aminopyridines using a
carbonyl source, ligand and oxidant.11 In 2014, Beller and Wu
demonstrated a base controlled selectivity for the synthesis of
report
a
simple transition metal-free strategy for
pyridoquinazolinone synthesis starting from N-pyridylindoles
as easily available substrates (Scheme 1).
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Scheme 1. Different methods for synthesis of completion (entries 8-11, Table 1). Use of (NH4)2S2O8 as
1
2
3
4
5
6
7
8
pyridoquinazolinones
oxidant gave similar yield as K2S2O8 (entry 12). Screening of
solvents like dichloroethane, dioxane, water, methanol and
DMSO (entries 13-17, Table 1) was done, and lower yields
were obtained in all cases. Acetonitrile was found to be the
best solvent. The optimum reaction time was found to be 2 h,
and lower yields were obtained at 1 h and 4 h of reaction time
(entry 18, Table 1).
O
(iii)
(iv)
Br
Previous work
+
O
N
(i)
H
O
N
N
H
(B)
(A)
N
Pd(OAc)2
N
H
N
N
Cu salt
H/Br
CO source
Oxidant, Base
Ligand
CO source
Oxidant, Base
Ligand
(ii)
O
N
Br
Br
F
+
(C) EDCI, O2
O
H
(v)
O
N
NH2
N
NH2
DCM
N
(vi)
Table 1. Reaction Optimizationa
N
+
OH
H
N
+
NH2
9
O
Our work
Iodine reagent
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O
N
N
N
X
DIB, K2S2O8
Het/Ar
Transition-metal free
Ligand-free
Short reaction time
oxidant, solvent
N
X
Het/Ar
25 examples
MeCN
80 oC, 2 h
80 o
C
N
N
N
N
Y
1a
55- 85%
2a
Y
X,Y= CH3, OCH3, I, Br, Cl, F, NO2
Entry Iodine reagent
(equiv)
Oxidant
(equiv)
Solvent
% Yield
2a
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
DIB (2)
DIB (3)
DIB (1)
DIB (3)
PhIO (2)
I2 (2)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (1)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
78
40
35
45
60
0
The original objective of our work was to carry out palladium
catalyzed hydroxylation of N-pyrimidyl indole (Ia) using
pyrimidine as directing group. After careful optimization of
reaction conditions, it was found that in the presence of DIB
[(diacetoxyiodo)benzene]
[PhI(OAc)2]and
K2S2O8,
hydroxylation took place even in the absence of palladium,
and 2-hydroxy-1-(pyrimidin-2-yl)indolin-3-one (IIa) was
obtained in 51% yield (Scheme 2). With 5-methoxy derivative
(Ib), 2-hydroxy-5-methoxy-1-(pyrimidin-2-yl)indolin-3-one
(IIb) formed in 55% yield. The surprise element came in when
the same reaction conditions were applied to N-pyridyl indole
(1a) as the substrate. A 100% conversion of 1a took place but
the desired product, 2-hydroxy-1-(pyridin-2-yl)indolin-3-one
was not isolated. A new product, characterized as 11H-
pyrido[2,1-b]quinazolin-11-one (2a) was formed instead.
Previous studies reported that when the reaction of N-
protected indoles was carried out using DIB in acetic acid, it
resulted either in C-2,3-diacetoxylation, C-3 acetoxylation or
C-2 acetoxylation and C-3 oxidation depending upon the
stoichiometry of DIB.19 However, report of a cyclization event
yielding pyridoquinazolinones did not exist.
C6H5I(OCOCF3)2
(2)
0
8
DIB (2)
DIB (2)
DIB (2)
DIB (2)
DIB (2)
KHSO5 (3)
TBHP (3)
O2 (3)
MeCN
MeCN
MeCN
MeCN
50
30
40
10
70
9
10
11
12
BQ (3)
(NH4)2S2O8 MeCN
(3)
13
14
15
16
17
18
DIB (2)
DIB (2)
DIB (2)
DIB (2)
DIB (2)
DIB (2)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
DCE
60
Dioxane 64
Water
45
MeOH
DMSO
MeCN
35
Scheme 2. Synthesis of 2-hydroxy-1-(pyrimidin-2-
yl)indolin-3-ones
5
55c, 62d
O
X
X
aReaction conditions: 1a (0.515 mmol), DIB [(diacetoxyiodo)benzene]
DIB (2 equiv)
OH
IIa
, X=H, 51%
IIb
, X=OCH3, 55%
K2S2O8 (3 equiv)
DCE, 80 oC, 2 h
[PhI(OAc)2], K2S2O8 in solvent (4 mL), 80 oC for 2h. bBased on GC
N
Ia
, X=H
Ib
N
, X=OCH3
c
N
N
analysis with MeCN as internal solvent. Reaction was carried out for 1h
N
I
N
II
and d4h.
Scheme 3. Control experiments for mechanistic
investigation
Intrigued by curiosity, we decided to examine the reaction in
detail. Optimizing the conditions with different
stoichiometries of DIB and K2S2O8 divulged that the highest
yield of 2a was obtained with 1a, DIB, and K2S2O8 in the ratio
1:2:3 (entries 1-4, Table 1). Replacing DIB with PhIO (2
equiv) decreased the yield to 60% (entry 5, Table 1) while
with
I2
and
(Bis(trifluoroacetoxy)iodo)benzene
[C6H5I(OCOCF3)2] as the iodine reagents, 2a did not form at all
(entries 6 and 7, Table 1). Other oxidants such as KHSO5,
TBHP (tert-butyl hydroperoxide), atmospheric oxygen and
BQ (1,4-benzoquinone) dropped the yield to 50%, 30%, 40%
and 10% respectively, and the reactions did not go to
2
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The Journal of Organic Chemistry
DIB (2 equiv)
2a
15%
PhIO (2 equiv)
K2S2O8
initiated by generation of an electrophilic adduct A which
(a)
1a
1a
2a
(e)
(f)
MeCN, 80 o
C
1a
(3 equiv)
MeCN, 80 oC, 2 h
60%
1
2
3
4
5
6
7
8
undergoes nucleophilic attack from 1a to generate
intermediate B. Intramolecular nucleophilic attack of iodine in
B generates an iodonium salt C.21 Attack of sulphate anion at
C-3 position of C affords D which undergoes elimination of
PhI and KHSO5 to yield E. This reacts with another molecule
of protonated PhIO to generate F, which undergoes reductive
elimination to yield cationic intermediate G; identified
through ESI-MS (see supporting information Figure S3). The
electrophilic C-2 position of G is attacked by hydroxide ions
resulting in formation of H, as evidenced by time dependent
NMR studies and HR-MS of the reaction mixture (Scheme
3g). Appearance of signals at around 5.39-5.51 (Ha), 4.94-5.23
2 h
K2S2O8 (3 equiv)
(b)
(c)
No reaction
MeCN, 80 o
2 h
C
DIB (2 equiv)
2a
N
py
MeCN, 80 o
C
K2S2O8(3 equiv)
MeCN, 80 oC, 2 h
I
70%
Ph
DIB + K2S2O8
O
1a'
py = pyridyl
O
C1
C
N
Ha
2 OHb
PhIO (2 equiv)
(d) 1a
2a
10%
(g)
MeCN, 80 o
C
[M+ Na]+ = 249.0634 Calculated
[M+ Na]+ = 249.0615 Found
2 h
N
H
Intermediate
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60
Next, some control experiments were carried out in order to
understand the mechanism of the reaction (Scheme 3). The
reaction of 1a with DIB alone did not go to completion and
gave only 15% yield of 2a. Similarly, with K2S2O8 alone, no
product formation was seen (Scheme 3a and 3b). Further, a
reaction between DIB (2 equiv) and K2S2O8 (3 equiv) resulted
in the formation of iodosyl benzene (PhIO) within few
minutes (Scheme 3c). To confirm if PhIO formed in situ was
the actual reactive species; a reaction of 1a was carried out
with PhIO (2 equiv). The product 2a, however, was obtained
in only 10% yield (Scheme 3d). Notably, when K2S2O8 (3
equiv) was added to it, the yield increased to 60% (Scheme
3e). This indicated that both DIB and K2S2O8 were necessary
for the reaction to proceed smoothly. It is perhaps the low
solubility of PhIO in non-protic media20 which gravely
minimizes its reactivity as the active species. Interestingly,
even 2-methyl substituted indole derivative (1a’) furnished 2a
in 70% yield on reaction with DIB and K2S2O8 suggesting an
oxidative removal of C-2 carbon (Scheme 3f).
1
(Hb) ppm in HNMR, and at 195.6 ppm (for carbonyl C1) and
82.0 ppm (C2) in 13CNMR indicated the formation of
intermediate H in the reaction mixture (see supporting
information Figure S1, S2, S4). This oxidative intermediate H
further reacts with PhIO to generate I, which after reductive
elimination undergoes cleavage of C-C bond to generate a
highly reactive acylium cation J. Nucleophilic attack by
pyridyl nitrogen at the cationic center produces K, which on
attack by hydroxide anion at amidic bond followed by
elimination of formic acid (see supporting information Figure
S5) affords 2a.
With the optimized reaction conditions in hand and some
mechanistic insights, the substrate scope was examined.
Different substituents were taken on indole, and a 100%
conversion of the starting material was seen in most cases
(Scheme 5). It was found that 5-substituted indoles bearing
electron-donating (-OCH3, -CH3) and mild electron-
withdrawing groups (-Cl, -Br, -I) delivered the corresponding
derivatives of 11H-pyrido[2,1-b]quinazolin-11-one (2b-2f) in
moderate to good yields. Strong electron withdrawing groups
like 5,6-difluoro, 5-nitro, and 4-cyano gave lower yields of the
corresponding derivatives (2g-2i). Position of methyl
substituent at (5 or 7) did not affect the product yield (2c,
82%; 2j, 80%). The results suggested a better resonance
stabilization of the intermediate with electron-donating groups
on indole ring. It is noteworthy to mention that the halo groups
remained intact after the reaction, available for further
functionalizations. This is in contrast to the previous transition
metal-catalyzed routes where the halo substituted substrates
suffered from the side cross-coupling reactions.12,14
Scheme 4. Plausible reaction mechanism
F
O
F
O
O
S
O
S
OAc
OAc
+
KO
S
O
O
I
S
OK
(1)
(2)
Ph
I
KO
O
O
OK
O
O
O
O
O
Ph
Ph
F
O
N
I
OSO3K
F
O
H
F
Ph
I
O
I
Ph
F
Ph
+
I
+
N
O
F
N
N
N
N
(A)
N
N
1a
(C)
(D)
(B)
- PhI
- KHSO5
O
O
OSO3K
O
N
OH
Ph
PhIO
H+
OH
I
Scheme 5. Scope with functionalized indoles 1a-j
OH
-PhI
N
N
N
N
N
N
N
O
(G)
(H)
DIB, K2S2O8
(F)
X
(E)
N
N
m/z = 209.0700
X
MeCN, 80 oC, 2-3.5 h
N
N
PhIO
1a-j
2a-j
O
O
O
N
O
N
N
F
O
O
Ph
O
X
O
N
X
N
N
N
I
OH
N
N
F
N
-PhI
N
N
N
2a
X= H ( ), 75%
X= OCH3
X= CH3
2d
X= Cl ( ), 70%
2g
, 60%
OH
H
N
-OH
2b
-O
(
), 82%
O
H
(J)
O
H
(K)
2e
X= Br ( ), 72%
(L)
(I)
2c
(
), 2 h, 82%
2f
X= I ( ), 72%
O
O
N
-HCOOH
CN
O
O2N
N
N
N
O
N
N
N
CH
2h
, 65%
3 2j
, 80%
2i,
70%
N
2a
aReaction conditions: 1a-j (0.515 mmol), DIB (2.0 equiv), K2S2O8 (3.0
Based on these observations, a plausible mechanism has been
proposed (Scheme 4). It is believed that the reaction is
equiv), MeCN, 80 oC, 2-3.5 h.
3
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O
N
The electronic effect exercised by substituents on pyridine
DIB, K2S2O8
MeCN, 80 oC, 2- 3 h
1
2
3
4
5
6
7
8
N
ring was examined next, and was found to be quite significant
(Scheme 6). With 4-bromopyridine substituted indole, the
corresponding products 4a and 4b were obtained in 62% and
68% yields respectively along with formation of some
unidentified side products. On changing to 5-bromo
substitution; the yield of the corresponding quinazolinones 4c-
4f increased slightly. This could be attributed to the reduced
nucleophilicity of the pyridyl nitrogen due to 4-bromo
substitution, as well as the instability of the resonant stabilized
intermediate (R2) where a partial positive charge resides on
carbon bearing 4-bromo group (Figure 2). Both 4- and 5-
methylpyridine substituted indoles gave high yield of the
corresponding quinazolinone derivatives 4g-4j consistent with
the electron donating ability of the methyl group. With 5-CF3
substitution in pyridine, the yield of 4k dropped to 50%,
owing to its electron withdrawing effect. Further, with 5-
fluoro pyridyl derivative, the desired quinazolinone formed
only in trace amount as evidenced by HRMS of the reaction
mixture (see supporting information Figure S6), but could not
be isolated.
Y
N
N
N
N
5a-d
6a-d
Y
O
O
N
Y
N
N
N
N
N
b
6a
Y= H ( ), 85%, 76%
Cl
6d
, 72%
6b
( ), 78%
Y= Br ( ), 75%
Y= CH3
6c
9
aReaction conditions: 5a-d (0.515 mmol), DIB (2.0 equiv), K2S2O8 (3.0
equiv), MeCN, 80 oC, 2-3 h. bReaction carried out with 1 g of 5a.
10
11
12
13
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15
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48
49
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57
58
59
60
CONCLUSIONS
In conclusion, we have developed an unprecedented transition
metal-free and ligand-free synthesis of 11H-pyrido[2,1-
b]quinazolin-11-one derivatives using DIB and K2S2O8. A vast
array of pyridoquinazolinones has been generated in moderate
to good yields within a short reaction time. 2-hydroxy-1-
(pyridin-2-yl)indolin-3-one has been identified as the key
reaction intermediate. The strategy provides a useful synthetic
route to access biologically interesting class of compounds
from easy available starting materials and easy to handle
oxidants.
Scheme 6. Scope with functionalized pyridines 3a-ka
O
DIB, K2S2O8
MeCN, 80 oC, 2-3.5 h
X
N
N
X
N
N
Y
3a-k
4a-k
Y
O
N
O
O
N
O
O
X
Br
Experimental section
General Information:
Br
Br
F
F
N
N
N
N
N
N
Br
N
, 62%
Br
N
4c
( ), 70%
X= H
4b
, 68%
4g
, 75%
4a
4f,
66%
4d
X= Cl ( ), 61%
4e
X= I
(
), 65%
O
N
O
N
O
N
O
N
All reagents and solvents were of pure analytical grade. Thin
layer chromatography (TLC) was performed on 60 F254 silica
gel, pre-coated on aluminum plates and revealed with either a
UV lamp (λmax= 254 nm). The products were purified by
H3CO
O2N
CF3
N
N
N
N
4h
, 72%
4j
, 70%
4i
, 75%
4k,
50%
aReaction conditions: 3a-k (0.515 mmol), DIB (2.0 equiv), K2S2O8 (3.0
equiv), MeCN, 80 oC, 2- 3.5 h.
1
column chromatography on silica gel 230−400 mesh. H and
13C NMR spectra were recorded on a 300 MHz (1H 300MHz,
13C 75 MHz), 400 MHz spectrometer (1H 400 MHz, 13C 100
MHz) and 500 MHz spectrometer (1H 500 MHz) using CDCl3
and MeOD as the solvent with tetramethylsilane (TMS) as the
internal standard at room temperature. Chemical shifts are in δ
(ppm) relative to TMS. The coupling constants (J) are in Hz.
High resolution mass spectra (HRMS) were recorded on a
mass spectrometer using electrospray ionization-time-of-flight
(ESI-TOF) reflectron experiments.
O
O
N
O
O
O
O
+
+
N
N
H
N
N
H
N
H
N
H
N
+
N
Y
N
N
Y
Y
N
Y
Y
Y
O
H
O
O
H
O
O
O
R2
R1
R3
R4
Figure 2. Resonating structures of the plausible intermediate J.
The scope was further extended to N-pyridyl azaindoles, and it
furnished 5H-dipyrido[1,2-a:2’,3’d]pyrimidin-5-one
derivatives (Scheme 7). These compounds are medicinally
potent and show high fungicidal activity against Fusarium.22
The reaction worked well both with unsubstituted pyridine as
well as with 5-methyl and 5-bromo substituted pyridyl
derivatives, and gave the desired products (6a-6c) in 75-85%
yields. With 3-Cl substituted pyridine, 6d was obtained in
72% yield. The reaction was carried out on gram-scale under
the optimized conditions using 1g of 5a, and the desired
quinazolinone derivative 6a was obtained in 76% yield (767.8
mg).
General procedure A for synthesis of compounds (1/3/5):
NaH (60% dispersion in mineral oil, 512 mg, 21.36 mmol)
was added at 0 °C, to a stirring solution of indole (1 g, 8.54
mmol) in DMF (15 mL). After stirring for 30 min at 0 °C, 2-
bromopyridine derivative (1.37 g, 10.24 mmol) was added and
the mixture was stirred at 130 °C in oil bath for 24 h.23 The
reaction mixture was then cooled to RT, poured onto ice and
extracted with ethyl acetate and the organic extract was
washed successively with brine. The combined organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The product was purified by column chromatography
on silica gel using ethyl acetate- hexane. Synthesized
compounds were confirmed by 1H NMR, 13C NMR.
Scheme 7. Scope with N-pyridyl azaindoles 5a-da
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1
General procedure for synthesis of fused quinazolinones
(2/4/6):
White solid, Hexane/EtOAc = 96/4, yield 70% (0.92 g); H
NMR (500 MHz, CDCl3): δ 8.58 (d, J = 4.5 Hz, 1H), 8.06 (d, J
= 9 Hz, 1H), 8.01 (s, 1H), 7.83 (t, 1H), 7.67 (d, J = 3.5 Hz,
1H) 7.56 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.21-
7.19 (m, 1H), 6.65 (d, J = 3.5 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 152.1, 149.0, 138.4, 134.3, 132.8, 131.4,
129.8, 126.5, 120.4, 115.2, 114.4, 104.6, 84.9; MS (ESI) m/z
1
2
3
4
5
6
7
8
To a 25 mL round-bottom flask was added 1a (100 mg, 0.515
mmol),
K2S2O8
(417
mg,
1.5
mmol),
DIB
(diacetoxyiodo)benzene [PhI(OAc)2] (342 mg, 1.03 mmol)
and solvent MeCN (4 mL). The reaction mixture was stirred
320 [M+H]+; HRMS Calculated for C13H10IN2 320.9883;
+
o
for 2-3.5 h at 80 C in oil bath, and reaction was monitored
Found: 320.9870 [M+H]+.
through TLC. After completion of reaction, it was diluted with
water, extracted with ethyl acetate and concentrated at reduced
pressure. The product was purified by column chromatography
on silica gel using ethyl acetate-hexane. Synthesized
9
5,6-Difluoro-1-(pyridin-2-yl)-1H-indole (1g):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
compounds were characterized by H NMR, 13C NMR and
1
Yellow solid, Hexane/EtOAc = 96/4, yield 67% (1.0 g); H
HRMS studies.
NMR (500 MHz, CDCl3): δ 8.55 (d, J = 5.0 Hz, 1H), 8.29-
8.25 (m, 1H), 7.83- 7.80 (m, 1H), 7.65 (d, J = 3.5 Hz, 1H),
7.40−7.34 (m, 2H), 7.19-7.17 (m, 1H), 6.65 (d, J = 3.5 Hz,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 152.3, 149.2 (dd,
Physical Properties and Characterization Data of the
Synthesized Compounds:
1JC-F = 149.2 Hz, JC-F = 14.9 Hz), 148.8, 147.3 (dd, JC-F
=
2
1
2
3
1-(Pyridin-2-yl)-1H-indole (1a):23, 24
145.1 Hz, JC-F = 14.8 Hz), 138.6, 130.3 ( JC-F = 10.8 Hz),
126.6 (4JC-F = 4.0 Hz), 125.5 (3JC-F = 8.2 Hz), 120.2, 113.6,
107.2 (2JC-F = 18.9 Hz), 105.4 (4JC-F = 3.0 Hz), 102.6 (2JC-F
=
1
White solid, Hexane/EtOAc = 96/4, yield 89% (1.47 g); H
23.6 Hz); MS (ESI) m/z 230 [M+H]; HRMS Calculated for
NMR (300 MHz, CDCl3): δ 8.49 (d, J = 4.8 Hz, 1H), 8.26 (d, J
= 8.4 Hz, 1H), 7.69-7.66 (m, 2H), 7.63-7.58 (m, 1H), 7.34-
7.30 (m, 2H), 7.26-7.21 (m, 1H), 7.06-6.98 (m, 1H), 6.70 (d, J
= 3.3 Hz, 1H).
+
C13H9F2N2 231.0728; Found: 231.0710 [M+H]+.
5-Nitro-1-(pyridin-2-yl)-1H-indole (1h):23, 25
1
5-Methoxy-1-(pyridin-2-yl)-1H-indole (1b):23, 24
Yellow solid, Hexane/EtOAc = 95/5 yield 55% (0.81 g); H
NMR (500 MHz, CDCl3): δ 8.62-8.61 (m, 1H), 8.59 (d, J =
2.1, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.19 (dd, J1 = 9.2 Hz, J2 =
2.2 Hz, 1H), 7.92-7.88 (m, 1H), 7.81 d, J = 3.5 Hz, 1H), 7.49
(d, J = 8.4 Hz, 1H), 7.30-7.27 (d, J = 8.0 Hz, 1H), 6.87 (d, J =
3.4 Hz, 1H).
1
Orange solid, Hexane/EtOAc = 95/5, yield 60% (0.91 g); H
NMR (500 MHz, CDCl3): δ: δ 8.73 (s, 1H), 8.69 (d, J = 4.7
Hz, 2H), 8.26 (d, J = 3.5 Hz, 1H), 7.28 (s, 1H), 7.11 (d, J = 2.1
Hz, 1H), 7.04 (t, 1H), 7.00-6.91 (m, 1H), 6.65 (d, J = 3.4 Hz,
1H), 3.90 (s, 3H).
1-(Pyridin-2-yl)-1H-indole-4-carbonitrile (1i):
5-Methyl-1-(pyridin-2-yl)-1H-indole (1c):25
1
White solid, Hexane/EtOAc = 96/4 yield 80% (1.2 g); H
1
NMR (500 MHz, CDCl3): δ 8.63 (d, J = 4.5 Hz, 1H), 8.55 (d, J
= 8.5 Hz, 1H), 7.92− 7.89 (m, 1H), 7.86 (d, J = 3.5 Hz, 1H),
7.58 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.36 (t, 1H),
7.28 (t, 1H), 6.96 (d, J = 3.5 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 151.9, 149.1,138.8, 134.96, 131.7, 128.3,
126.3, 122.8, 121.0,118.3, 118.2, 114.7, 104.1, 103.5; MS
White solid, Hexane/EtOAc = 96/4, yield 62% (0.98 g); H
NMR (500 MHz, CDCl3): δ 8.58 (d, J = 6.7 Hz, 1H), 8.11 (d, J
= 8.5 Hz, 1H), 7.85−7.81 (m, 1H), 7.72 (d, J = 3.4 Hz, 1H)
7.51 (d, J = 8.2 Hz, 1H), 7.46 (s, 1H) 7.18- 7.13 (m, 2H), 6.65
(d, J = 3.4 Hz, 1H), 2.49 (s, 3H).
(ESI) m/z 220 [M+H]+; HRMS Calculated for C14H10N3
+
5-Chloro-1-(pyridin-2-yl)-1H-indole (1d):24, 25
220.0869; Found: 220.0852 [M+H]+.
1
White solid, Hexane/EtOAc = 96/4, yield 61% (0.92 g); H
7-Methyl-1-(pyridin-2-yl)-1H-indole (1j): 25
NMR (500 MHz, CDCl3): δ 8.56 (d, J = 6.0 Hz, 1H), 8.24 (d, J
= 8.9 Hz, 1H), 7.80-7.77 (m, 1H), 7.70 (m, J = 3.5 Hz, 1H),
7.64 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 3.5 Hz, 1H), 7.28-7.26
(m, 1H), 7.18-7.16 (m, 1H), 6.65 (d, J = 3.4 Hz, 1H).
White solid, yield 72% (1.14 g); 1H NMR (500 MHz, CDCl3 δ
8.69 (d, J = 6.1 Hz, 1H), 7.92- 7.88 (m, 1H), 7.45 (d, J = 8.0
Hz, 1H), 7.43-7.41 (m, 1H), 7.35-7.32 (s, 1H), 7.18-7.16 (m,
2H), 6.47 (s, 1H), 2.5(s, 1H).
5-Bromo-1-(pyridin-2-yl)-1H-indole (1e): 23, 25
1-(4-Bromopyridin-2-yl)-1H-indole (3a):
Colourless liquid, Hexane/EtOAc = 96/4, yield 65% (0.90 g);
1H NMR (500 MHz, CDCl3): δ 8.48-8.47 (m, 1H), 8.06 (d, J =
8.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.69(d, J = 1.9 Hz, 1H), 7.59
(d, J = 3.4 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.29-7.27 (m,
1H), 7.11-7.08 (m, 1H), 6.55 (d, J = 3.3 Hz, 1H).
Colourless liquid, Hexane/EtOAc = 96/4, yield 47% (1.08 g);
1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 5.3 Hz, 1H), 8.23
(d, J = 8.3 Hz, 1H), 7.67-7.64 (m, 3H), 7.33-7.29 (m, 2H),
7.25-7.22 (m, 1H), 6.72 (d, J = 3.5 Hz, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ153.2, 149.7, 135.0, 134.2, 130.5, 128.1,
125.6, 123.5, 121.6, 121.2, 117.3, 113.2, 106.4; MS (ESI) m/z
5-Iodo-1-(pyridin-2-yl)-1H-indole (1f):
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+
273 [M+H]+; HRMS Calculated for C13H10BrN2 273.0022;
5-Bromo-1-(4-methylpyridin-2-yl)-1H-indole (3g):19
Found: 273.0003 [M+ H]+.
1
2
3
4
5
6
7
8
White solid, Hexane/EtOAc = 96/4, yield 65% (0.95 g);1H
NMR (500 MHz, CDCl3): δ 8.28 (d, J = 5.1 Hz, 1H), 8.01 (d, J
= 8.7 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 3.3 Hz,
1H), 7.25 (dd, J1 = 8.8 Hz, J2 = 2.1 Hz, 1H), 7.09 (s, 1H), 6.87
(d, J = 5.1 Hz, 1H), 6.49 (d, J = 3.3 Hz, 1H), 2.30 (s, 3H).
1-(4-Bromopyridin-2-yl)-5-methyl-1H-indole (3b):
White solid, Hexane/EtOAc = 96/4, yield 52% (1.13 g);1H
NMR (400 MHz, CDCl3): δ 8.18 (d, J = 5.2 Hz, 1H), 8.0 (d, J
= 8.5 Hz, 1H), 7.48-7.46 (m, 2H), 7.29 (s, 1H), 7.09 (dd, J1 =
5.3 Hz, J2 = 1.5 Hz, 1H), 7.01-6.98 (m, 1H), 6.49 (d, J = 3.4
Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
153.3, 149.4, 134.1, 133.3, 131.1, 130.9, 125.5, 125.0, 122.7,
121.0, 116.8, 113.1, 106.2, 21.4; MS (ESI) 287 [M+H]+;
1-(5-Methylpyridin-2-yl)-1H-indole (3h):
9
1
White solid, Hexane/EtOAc = 96/4, yield 73% (1.29 g); H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.14 (d, J = 8.5 Hz,
1H), 7.72−7.68 (m, 1H), 7.67- 7.65 (m, 1H), 7.43 (d, J = 8.5
Hz, 2H), 7.32- 7.28 (m, 1H), 7.23-7.20 (m, 1H), 6.72 (d, J = 3
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 150.4, 149.0,
138.9, 135.0, 130.2, 129.6, 126.1, 122.9, 121.0 (2C), 114.4,
112.6, 104.9, 17.8; MS (ESI) 208 [M+H]+; HRMS Calculated
for C14H13N2+ 209.1073; Found: 209.1058 [M+H]+.
+
HRMS Calculated for C14H12BrN2 287.0178; Found:
287.0155 [M+H]+.
1-(5-Bromopyridin-2-yl)-1H-indole (3c):26a
Colourless liquid, Hexane/EtOAc = 96/4, yield 75% (1.73
g);1H NMR (500 MHz, CDCl3): δ 8.62 (d, J = 2.5 Hz, 1H),
8.22 (d, J = 8.0 Hz, 1H), 7.90- 7.88 (m, 1H), 7.70-7.76 (m,
2H), 7.38-7.33 (m, 2H), 7.28-7.25 (m, 1H), 6.75 (d, J = 3.5
Hz, 1H).
5-Methoxy-1-(5-methylpyridin-2-yl)-1H-indole (3i):24, 25
1
White solid, Hexane/EtOAc = 96/4, yield 76% (1.23 g); H
NMR (500 MHz, CDCl3 δ 8.39 (s, 1H), 8.10 (d, J = 9 Hz, 1H),
7.68 (d, J = 3.5 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.39 (d, J =
7.5 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 6.95 ( dd, J1 = 8.7 Hz, J2
= 2.5 Hz, 1H), 6.64 (d, J = 4 Hz, 1H).
1-(5-Bromopyridin-2-yl)-5-chloro-1H-indole (3d):
1
White solid, Hexane/EtOAc = 96/4, yield 72% (1.44 g); H
NMR (500 MHz, CDCl3): δ 8.61 (d, J = 2.0 Hz, 1H), 8.21 (d, J
= 8.5 Hz, 1H), 7.92 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 7.66-
7.63 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 7.28- 7.26 (m, 1H),
6.68 (d, J = 3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
150.8, 149.8, 141.0, 133.4, 131.5, 127.1, 126.7, 123.6, 120.5,
115.8, 115.1, 114.5, 105.7; MS (ESI) m/z 306 [M+H]+; HRMS
1-(5-Methylpyridin-2-yl)-5-nitro-1H-indole (3j):
1
Yellow solid, Hexane/EtOAc = 96/4, yield 72% (1.12 g) H
NMR (500 MHz, CDCl3): δ 8.58 (s, 1H), 8.42 (s, 1H), 8.23-
8.21 (m, 1H), 8.16- 8.14 (m, 1H), 7.76 (d, J = 3.8 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.84 (d, J =
3.0 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 149.5, 149.2,
142.5, 139.4, 137.9, 131.2, 129.5, 129.1, 118.3, 117.8, 114.7,
113.0, 106.6, 17.9; MS (ESI) 254 [M+H]+; HRMS Calculated
for C14H12N3O2+ 254.0924; Found: 254.0900 [M+H]+.
+
Calculated for C13H9BrClN2 306.9632; Found: 306.9611
[M+H]+.
1-(5-Bromopyridin-2-yl)-5-iodo-1H-indole (3e):
1
White solid, Hexane/EtOAc = 96/4, yield 72% (1.8 g); H
NMR (400 MHz, CDCl3): δ 8.42 (d, J = 2.16 Hz, 1H), 7.85-
7.81 (m, 2H), 7.74 (dd, J1 = 6.6 Hz, J2 = 2.4 Hz, 1H), 7.42-
7.37 (m, 2H), 7.17-7.14 (d, J = 9.6 Hz, 1H), 6.47 (d, J = 3.32
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 150.8, 149.8,
141.0, 134.2, 132.8, 131.7, 129.9, 126.2, 115.9, 115.3, 115.2,
105.3, 85.3; MS (ESI) 397 [M+H]+; HRMS Calculated for
1-(5-(Trifluoromethyl)pyridin-2-yl)-1H-indole (3k):26b
1
Orange solid, Hexane/EtOAc = 96/4 yield 75% (1.67 g); H
NMR (500 MHz, CDCl3): δ 8.79 (s, 1H), 8.33 (d, J = 8.5 Hz,
1H), 7.97 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.64
(d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.32 (t, 1H),
7.25- 7.22 (m, 1H), 6.73 (d, J = 3.5 Hz, 1H).
+
C13H9BrIN2 398.8988; Found: 398.895 [M+H]+.
1-(Pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (5a):27
1-(5-Bromopyridin-2-yl)-5,6-difluoro-1H-indole (3f):
1
Light brown solid, Hexane/EtOAc = 96/4 ,yield 75% (1.50 g);
1H NMR (500 MHz, CDCl3): δ 8.58 (d, J = 2.5 Hz, 1H), 8.25-
8.21 (m, 1H), 7.89 (dd, J1 = 7.5 Hz, J2 = 2 Hz, 1H), 7.58 (d, J
= 3.5 Hz, 1H), 7.36-7.33 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H),
6.64 (d, J = 3.5 Hz, 1H) ; 13C{1H} NMR (125 MHz, CDCl3):
White solid, Hexane/EtOAc = 95/5, yield 82% (1.35 mg); H
NMR (500 MHz, CDCl3): δ 8.94 (d, J = 8.5 Hz, 1H), 8.51 (d,
J= 4.5 Hz, 1H), 8.43- 8.42 (m, 1H), 8.39 (d, J = 4.0 Hz, 1H)
7.98 (d, J = 5.4 Hz, 1H), 7.91- 7.87 (m, 1H), 7.20- 7.17 (m,
2H), 6.66 (d, J = 4.0 Hz, 1H).
1
2
δ 150.8, 149.5, 147.4 (dd, JC-F = 147.4 Hz, JC-F = 15.1 Hz),
146.8 (dd, 1JC-F = 146.8 Hz, 2JC-F = 15.1 Hz), 141.0, 130.2 (3JC-
1-(5-Methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (5b):
= 10.6 Hz) , 126.2 (4JC-F = 4.2 Hz) , 125.6 (3JC-F = 8.1 Hz) ,
F
115.7, 114.5, 107.4 (2JC-F = 19.0 Hz), 106.1 (4JC-F = 2.8 Hz),
1
Yellow solid, Hexane/EtOAc = 95/5, yield 70% (1.23 g); H
102.9 (4JC-F = 23.0 Hz);MS (ESI) 308 [M+H]+; HRMS
NMR (500 MHz, CDCl3): δ 8.74 (d, J = 8.5 Hz, 1H), 8.40 (d, J
= 4.5 Hz, 1H), 8.32 (d, J =3.5 Hz, 2H), 7.97 (d, J = 7.5 Hz,
1H), 7.69 (d, J = 8.5 Hz, 1H), 7.17- 7.15 (m, 1H), 6.64 (d, J =
+
Calculated for C13H8BrF2N2 308.9833; Found: 308.9803
[M+H]+.
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3.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 150.4, Yellow solid, Hexane/EtOAc = 93/7, yield 82% (82.9 mg); 1H
1
2
3
4
5
6
149.0, 138.9, 135.0, 130.2, 129.6, 126.1, 122.9, 121.0, 114.4,
NMR (300 MHz, CDCl3): δ 8.88 (d, J = 8.3 Hz, 1H), 7.77-
7.73 (m, 2H), 7.51−7.46 (m, 3H), 6.89−6.84 (m, 1H), 3.97 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3): δ 157.7, 156.3, 145.0,
142.7, 131.8, 127.6, 125.8, 125.3 (2C), 115.8, 111.5, 104.1,
54.8; MS (ESI) m/z 227 [M+H]+; HRMS Calculated for
112.6, 104.9, 17.8; MS (ESI) m/z 210 [M+H]+; HRMS
+
Calculated for C13H12N3 210.1026; Found: 210.1017 [M +
H]+.
+
C13H11N2O2 227.0815; Found: 227.0812 [M + H]+.
1-(5-Bromopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (5c):28
7
8
9
2-Methyl-11H-pyrido[2,1-b]quinazolin-11-one (2c):11d
1
White solid, Hexane/EtOAc = 95/5, yield 73% (1.68 g); H
NMR (500 MHz, CDCl3): δ 8.96 (d, J = 8.5 Hz, 1H), 8.51 (d, J
= 2.3 Hz, 1H), 8.39 (dd, J = 4.7 Hz, J = 1.6 Hz, 1H), 8.32 (d, J
= 3.9 Hz, 1H) 7.96-7.94 (m, 2H), 7.18- 7.16 (m, 1H), 6.64 (d,
J = 3.9 Hz, 1H). HRMS Calculated for C12H9BrN3+ 273.9974;
Found: 273.9975 [M +H]+.
Yellow solid, Hexane/EtOAc = 93/7, yield 82% (82.7 mg); 1H
NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.76 (d, J = 6.1 Hz,
1H), 8.68 (s, 1H), 7.65-7.62 (m, 1H), 7.53-7.49 (m, 1H), 7.41-
7.38 (m, 1H), 7.26 (s, 1H), 2.40 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 158.9, 147.1, 146.6, 136.9, 135.4, 133.5,
126.7, 126.6, 126.3, 126.2, 116.0, 112.3, 21.3; MS (ESI) m/z
211 [M+H]+; HRMS Calculated for C13H11N2O+ 211.0866;
Found: 211.0870 [M+H]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(3-Chloropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (5d):
1
White solid, Hexane/EtOAc = 95/5 yield 58% (1.12g); H
NMR (400 MHz, CDCl3): δ 8.55 (dd, J1 = 4.68 Hz, J2 = 1.64
Hz, 1H) 8.34 (dd, J1 = 4.72 Hz, J2 = 1.52 Hz, 1H), 7.98- 7.93
(m, 2H), 7.48 (d, J = 3.6 Hz, 1H), 7.37- 7.33 (m, 1H) 7.15-
7.12 (m, 1H), 6.66 (d, J = 3.7 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 148.2, 147.9, 147.4, 143.8, 139.6, 129.2,
128.6, 128.0, 124.1, 121.1, 117.0, 102.4; MS (ESI) m/z 230
[M+H]+; HRMS Calculated for C12H9ClN3+ 230.0480; Found:
230.046 [M +H]+.
2-Chloro-11H-pyrido[2,1-b]quinazolin-11-one (2d):14
Yellow solid, Hexane/EtOAc = 94/6, yield 70% (70.6 mg); 1H
NMR (400 MHz, CDCl3): δ 8.87 (d, J = 6.84 Hz, 1H), 8.41 (s,
1H), 7.75 (d, J = 3.92 Hz, 2H), 7.55-7.50 (m, 2H), 6.93−6.89
(m, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.0, 147.7,
147.1, 135.6, 134.4, 130.7, 128.7, 126.7, 126.4, 126.2, 117.0,
112.9; MS (ESI) m/z 231 [M+H]+; HRMS Calculated for
C12H8ClN2O+ 231.0320; Found: 231.0332 [M + H]+.
2-Hydroxy-1-(pyrimidin-2-yl)indolin-3-one (IIa):
2-Bromo-11H-pyrido[2,1-b]quinazolin-11-one (2e):11d
Yellow solid, Hexane/EtOAc = 90/10, yield 51% (59.3 mg);
1H NMR (300 MHz, CDCl3): δ 8.66 (d, J = 8.4 Hz, 1H), 8.59
(d, J = 4.8 Hz, 2H), 7.78 (J = 6.9 Hz, 1H), 7.71−7.65 (m, 1H),
7.13 (t, 1H), 6.93 (t, 1H), 5.72 (s, 1H), 5.26 (s, 1H); 13C{1H}
NMR (75 MHz, CDCl3) δ 194.7, 158.2, 157.9 (2C) , 152.6,
137.8, 124.6, 122.7, 122.2, 116.9, 113.9, 82.1; MS (ESI): m/z
250 [M+Na]+; HRMS Calculated for C12H9N3NaO2+ 250.0587;
Found: 250.0582 [M + Na]+.
Yellow solid, Hexane/EtOAc = 94/6, yield 72% (72.5 mg); 1H
NMR (300 MHz, CDCl3): ) δ 8.87 (d, J = 7.41 Hz, 1H), 8.58
(d, J = 2.16 Hz, 1H), 7.88 (dd, J1 = 8.8 Hz, J2 = 2.3 Hz, 1H),
7.68 (d, J = 8.85 Hz, 1H), 7.59−7.52 (m, 2H), 6.93−6.88 (m,
1H); 13C{1H} NMR (75 MHz, CDCl3): δ 157.9, 147.9, 147.3,
138.3, 134.5, 129.5, 128.8, 126.8, 126.4, 118.3, 117.4, 113.0;
MS (ESI) m/z 274 [M+H]+; HRMS Calculated for
C12H8BrN2O+ 274.9815; Found: 274.9818 [M + H]+.
2-Hydroxy-5-methoxy-1-(pyrimidin-2-yl)indolin-3-one (IIb):
2-Iodo-11H-pyrido[2,1-b]quinazolin-11-one (2f):
Yellow solid, Hexane/EtOAc = 90/10, yield 55% (62.8 mg);
1H NMR (300 MHz, CDCl3): δ 8.60 (d, J = 9.3 Hz, 1H), 8.55
(d, J = 4.8 Hz, 2H), 7.32−7.28 (m, 1H), 7.23 (d, J = 2.7 Hz,
1H), 6.89(t, 1H), 5.71 (s, 1H), 5.28 (s, 1H), 3.84 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 194.7, 157.98 (2C),
157.90, 155.5, 147.6, 126.8, 122.7, 118.2, 113.5, 105.5, 82.6,
55.8; MS (ESI): m/z 280 [M+Na]+; HRMS Calculated for
Yellow solid, Hexane/EtOAc = 94/6, yield 72% (72.45mg); 1H
NMR (300 MHz, CDCl3): δ 8.88 (d, J = 7.4 Hz, 1H), 8.79 (s,
1H), 8.06 (dd, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H), 7.59-7.49 (m,
3H), 6.93- 6.88 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ
157.6, 148.0, 147.7, 143.6, 136.0, 134.6, 128.8, 126.8, 126.4,
117.9, 113.0, 88.8; MS (ESI) m/z 322 [M+H]+; HRMS
Calculated for C12H8IN2O+ 322.9676; Found: 322.9684
[M+H]+.
+
C13H11N3NaO3 280.0693; Found: 280.0697 [M + Na]+.
11H-Pyrido[2,1-b]quinazolin-11-one (2a):14
2,3-Difluoro-11H-pyrido[2,1-b]quinazolin-11-one (2g):
Yellow solid, Hexane/EtOAc = 93/7, yield 75% (75.77 mg);
1H NMR (300 MHz, CDCl3): δ 8.89 (d, J = 7.35 Hz, 1H), 8.46
(d, J = 8.10 Hz, 1H), 7.88−7.78 (m, 2H), 7.53−7.46 (m, 3H),
6.90−6.85 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.0,
148.6, 147.7, 135.0, 134.0, 127.3, 126.9, 126.7, 126.3, 125.2,
116.3, 112.4; MS (ESI): m/z 197 [M+H]+; HRMS Calculated
for C12H9N2O+ 197.0709; Found: 197.0704 [M + H]+.
1
Yellow solid, Hexane/EtOAc = 93/7 yield 60% (60.5 mg); H
NMR (300 MHz, CDCl3): δ 8.87 (d, J = 7.29 Hz, 1H), 8.22-
8.15 (m, 1H), 7.60−7.49 (m, 3H), 6.96−6.91 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 157.7 (4JC-F = 3.6 Hz), 155.9 (dd,
2
1
1JC-F = 257.5 Hz, JC-F = 15.35 Hz), 148.9 (dd, JC-F = 251.3
Hz, JC-F = 14.6 Hz), 148.0, 146.7 (3JC-F = 10.3 Hz), 134.6,
2
126.5, 126.1, 114.0 (d, 2JC-F = 17.4 Hz), 113.9 (dd, 2JC-F = 18.9
2-Methoxy-11H-pyrido[2,1-b]quinazolin-11-one (2b):14
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4
Hz, JC-F = 2.7 Hz), 113.1, 112.8 (4JC-F = 5.5 Hz); MS (ESI)
m/z 233 [M+H]+; HRMS Calculated for C12H7F2N2O+
233.0521; Found: 233.0531 [M+H]+.
Yellow solid, Hexane/EtOAc = 94/6, yield 70% (70.4 mg);1H
1
2
3
4
5
6
7
8
NMR (300 MHz, CDCl3): δ 9.01 (s, 1H), 8.47 (d, J = 8.0 Hz,
1H), 7.90- 7.85 (m, 1H), 7.80-7.78 (m, 1H), 7.55-7.50 (m,
2H), 7.42-7.38 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ
158.0, 148.1, 145.9, 137.5, 135.3, 127.47, 127.46, 127.1,
126.5, 125.9, 116.2, 107.6; MS (ESI) 274 [M+H]+; HRMS
Calculated for C12H8N2BrO+ 274.9815; Found: 274.9814 [M +
H]+.
2-Nitro-11H-pyrido[2,1-b]quinazolin-11-one (2h):13
1
Yellow solid, Hexane/EtOAc = 93/7 yield 65% (65.5 mg); H
NMR (400 MHz, CDCl3 δ 9.35 (s, 1H), 8.95 (d, J = 6.6 Hz,
1H), 8.59 (d, J = 8.04 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.72
(s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H); 13C{1H} NMR
(75 MHz, CDCl3 δ 158.3, 152.2, 149.8, 143.9, 136.7, 128.7,
128.4, 127.1, 126.6, 124.8, 115.3, 114.1; MS (ESI) m/z 242
[M+H]+; HRMS Calculated for C12H8N3O3+ 242.0560; Found:
242.0557 [M+H]+.
8-Bromo-2-chloro-11H-pyrido[2,1-b]quinazolin-11-one (4d):
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yellow solid, Hexane/EtOAc = 94/6, yield 61% (61.4 mg); 1H
NMR (400 MHz, CDCl3): δ 8.99 (s, 1H),8.40 (s, 1H), 7.79-
7.72 (m, 2H), 7.56- 7.53 (m, 1H), 7.41- 7.38 (m, 1H); 13C{1H}
NMR (75 MHz, CDCl3): δ 157.0, 146.6, 145.9, 137.8, 135.9,
131.5, 128.9, 127.5, 126.5, 126.4, 117.0, 108.2; MS (ESI) m/z
308 [M+H]+; HRMS Calculated for C12H7BrClN2O+ 308.9425;
Found: 308.9408 [M + H]+.
1-Cyano-11H-pyrido[2,1-b]quinazolin-11-one (2i):
Yellow solid, Hexane/EtOAc = 94/6, yield 70% (70.3 mg); 1H
NMR (300 MHz, CDCl3): δ 8.96 (d, J = 7.3 Hz, 1H), 8.02-
7.97 (m, 1H), 7.87 (d, J = 4.68 Hz, 2H), 7.69-7.64 (m,
1H),7.58- 7.54 (m, 1H), 7.04- 6.99 (m, 1H); 13C{1H} NMR
(75 MHz, CDCl3): δ 156.8, 149.3, 148.6, 135.7, 133.9, 133.0,
132.1, 126.8, 126.2, 117.8, 115.3, 113.8, 111.3; MS (ESI) m/z
260 [M+K]+; HRMS Calculated for C13H7KN3O+ 260.0221;
Found: 260.0228 [M + K]+.
8-Bromo-2-iodo-11H-pyrido[2,1-b]quinazolin-11-one (4e):
Yellow solid, Hexane/EtOAc = 94/6, yield 65% (65.3 mg); 1H
NMR (300 MHz, CDCl3): δ 8.9 (s, 1H), 8.7 (s, 1H), 8.08 (d, J
= 8.7 Hz, 1H), 7.57- 7.49 (m, 2H), 7.39 (d, J = 9.6 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 156.6, 147.3, 146.2,
143.8, 138.0, 136.1, 129.0, 127.5, 126.7, 117.8, 108.5, 89.7;
MS (ESI) 400 [M+H]+; HRMS Calculated for C12H7BrIN2O+
400.8781; Found: 400.8771 [M + H]+.
4-Methyl-11H-pyrido[2,1-b]quinazolin-11-one (2j):11d
Yellow solid, Hexane/EtOAc = 94/6, yield 80% (80.7 mg); 1H
NMR (400 MHz, CDCl3): δ 8.77 (d, J = 7.32 Hz, 1H), 8.22 (d,
J = 8.08 Hz, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 9.0 Hz,
1H), 7.41-7.37 (m, 1H) 7.28 (d, J = 7.6 Hz, 1H), 6.76 (t, J =
6.4 Hz, 1H), 2.61 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3):
δ158.3, 146.4, 145.6, 134.3, 134.0, 132.3, 125.8, 125.5, 123.9,
123.7, 115.1, 111.3, 16.6; MS (ESI) m/z 211 [M+H]+; HRMS
Calculated for C13H11N2O+ 211.0866; Found: 211.0863 [M +
H]+.
8-Bromo-2,3-difluoro-11H-pyrido[2,1-b]quinazolin-11-one
(4f):
Yellow solid, Hexane/EtOAc = 93/7, yield 66% (65.7 mg); 1H
NMR (400 MHz, CDCl3): δ 8.9 (s, 1H), 8.20-8.15 (m, 1H),
7.58- 7.52 (m, 2H), 7.40- 7.37 (m, 1H) ; 13C{1H} NMR (100
1
2
MHz, CDCl3): δ 157.7, 155.7 (dd, JC-F = 202.7 Hz, JC-F
=
1
2
14.8 Hz), 149.2 (dd, JC-F = 251.3 Hz, JC-F = 15.6 Hz),
3
146.3(d, JC-F =11.7 Hz), 138.0, 127.2, 126.4, 114.5, 114.3,
114.1 (2JC-F = 19.1 Hz, JC-F = 2.7 Hz) ,112.9 (4JC-F = 5.5 Hz),
4
7-Bromo-11H-pyrido[2,1-b]quinazolin-11-one (4a):14
108.3; MS (ESI) 310 [M+H]+; HRMS Calculated for
C12H6BrF2N2O+ 310.9626; Found: 310.9617 [M + H]+.
Yellow solid, Hexane/EtOAc = 94/6, yield 62% (62.4 mg); 1H
NMR (300 MHz, CDCl3): δ 8.72 (dd, J1 = 7.8 Hz, J2 = 2.6 Hz,
1H), 8.43 (d, J = 8.16 Hz, 1H), 7.88-7.82 (m, 1H), 7.77-7.74
(m, 1H), 7.71-7.70 (m,1H) 7.53-7.47 (m, 1H), 6.94-6.89 (m,
1H); 13C{1H} NMR (75 MHz, CDCl3): δ158.6, 148.5, 147.0,
135.4, 129.7, 127.8, 127.4, 127.2, 127.1, 125.6, 116.6, 116.3;
MS (ESI) m/z 274 [M+H]+; HRMS Calculated for
C12H8BrN2O+ 274.9815; Found: 274.9814 [M + H]+.
7-Bromo-2-methyl-11H-pyrido[2,1-b]quinazolin-11-one (4g):
Yellow solid, Hexane/EtOAc = 94/6, yield 68% (68.4 mg);1H
NMR (300 MHz, CDCl3): δ 8.77 (d, J = 7.4 Hz, 1H), 8.52 (s,
1H), 7.86 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.26 (s,
1H), 6.75 (d, J = 7.5 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 157.9, 148.0, 147.7, 146.3, 138.1, 129.5,
128.6, 126.0 123.8, 117.6, 117.1, 116.0, 21.5; MS (ESI) 288
[M+H]+; HRMS Calculated for C13H10BrN2O+ 288.9971;
Found: 288.9960 [M + H]+.
7-Bromo-2-methyl-11H-pyrido[2,1-b]quinazolin-11-one (4b):
Yellow solid, Hexane/EtOAc = 94/6, yield 68% (68.4 mg);1H
NMR (300 MHz, CDCl3): δ 8.76 (d, J = 7.4 Hz, 1H), 8.52 (s,
1H), 7.84 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.26 (s,
1H), 6.74 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ 158.5, 146.6, 146.4, 137.2, 135.9, 129.1,
127.8, 127.2, 126.9, 126.3, 116.4, 116.1, 21.4; MS (ESI) 288
[M+H]+; HRMS Calculated for C13H10 BrN2O+ 288.9971;
Found: 288.9963 [M + H]+.
8-Methyl-11H-pyrido[2,1-b]quinazolin-11-one (4h):11d
Yellow solid, Hexane/EtOAc = 94/6 yield 72% (72.35 mg); 1H
NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.47 (d, J = 7.8Hz,
1H), 7.84−7.81 (m, 1H), 7.78- 7.76 (m, 1H), 7.46 (d, J = 5.0
Hz, 2H), 7.40- 7.37 (m, 1H), 2.36 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 158.8, 148.5, 146.9, 137.5, 134.8, 127.3,
8-Bromo-2-iodo-11H-pyrido[2,1-b]quinazolin-11-one (4c):26
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The Journal of Organic Chemistry
126.8, 125.8, 125.0, 123.5, 122.4, 116.2, 18.3; MS (ESI) 211
8-Bromo-5H-dipyrido[1,2-a:2',3'-d]pyrimidin-5-one (6c):
[M+H]+; HRMS Calculated for C13H11N2O+ 211.0866; Found:
1
2
3
4
5
6
7
8
211.0867 [M + H]+.
Yellow solid, Hexane/EtOAc = 70/30, yield 75% (75.9 mg);
1H NMR (400 MHz, CDCl3): δ 9.11 (d, J = 2.4 MHz, 1H),
8.75-8.70 (m, 2H), 7.86 (d, J = 1.6 Hz, 1H), 7.46-7.42 (m,
1H), 7.06 (dd, J1 = 5.0 Hz, J2 =0.5 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 159.3, 158.0, 157.4, 149.1, 137.1, 131.7,
128.3, 127.1, 121.0, 117.7, 111.4; MS (ESI) m/z 275 [M+H]+;
HRMS Calculated for C11H7BrN3O+ 275.9767; Found:
275.9754 [M +H]+.
2-Methoxy-8-methyl-11H-pyrido[2,1-b]quinazolin-11-one
(4i):11d
Yellow solid, Hexane/EtOAc = 94/6, yield 75% (75.5 mg); 1H
NMR (300 MHz, CDCl3 δ 8.68 (s, 1H), 7.76-7.71 (m, 2H),
7.49 – 7.43 (m, 2H), 7.33 (dd, J1 = 9.3 Hz, J2 = 1.8 Hz, 1H),
3.96 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
158.5, 157.2, 145.3, 143.7, 136.2, 128.6, 126.7, 125.8, 123.2,
122.4, 116.8, 105.0, 55.8, 18.3; MS (ESI) 241 [M+H]+; HRMS
Calculated for C14H13N2O2+ 241.0972; Found: 241.0964 [M +
H]+.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8-Chloro-5H-dipyrido[1,2-a:2',3'-d]pyrimidin-5-one (6d):
Yellow solid, Hexane/EtOAc = 70/30 yield 72% (72.6 mg); 1H
NMR (300 MHz, CDCl3): δ 9.01 (s, 1H) 8.44 (d, J = 8.18 Hz,
1H), 7.87 (t, J = 7.08 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.55-
7.50 (m, 1H) 7.41 (d, J = 9.6 Hz, 1H); 13C{1H} NMR (75
MHz, CDCl3): δ 157.9, 148.1, 145.9, 137.5, 135.3, 127.4,
127.1, 126.5, 125.9, 116.2, 107.6; MS (ESI) m/z 232 [M+H]+;
HRMS Calculated for C11H7ClN3O+ 232.0272; Found:
232.0270 [M +H]+.
8-Methyl-2-nitro-11H-pyrido[2,1-b]quinazolin-11-one (4j):
1
Yellow solid, Hexane/EtOAc = 94/6, 70% (70.56 mg) H
NMR (400 MHz, CDCl3): δ 9.3 (s, 1H), 8.75 (s, 1H), 8.54 (d, J
= 1.72 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.60-7.54 (m, 2H),
2.43 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 158.1,
152.1, 148.9, 143.8, 140.0, 128.4, 128.3, 126.0, 124.8, 124.3,
124.1, 115.1, 18.3; MS (ESI) 256 [M+H]+; HRMS Calculated
Iodosyl benzene:30
+
for C13H10N3O3 256.0717; Found: 256.0709 [M + H]+.
1
Yellow solid, H NMR (300 MHz, MeOD): δ 8.11 (d, J = 7.8
Hz, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H);
13C{1H} NMR (75 MHz, CD3OD): δ 135.7, 133.8, 132.4,
123.1; MS (ESI) m/z 220 [M+H]+; HRMS Calculated for
C6H6IO+ 220.9458; Found: 220.9458 [M +H].
8-(Trifluoromethyl)-11H-pyrido[2,1-b]quinazolin-11-one
(4k):13
Yellow solid, Hexane/EtOAc = 93/7, yield 50% (50.5 mg); 1H
NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.47 (d, J = 8.0 Hz,
1H), 7.89 (d, J = 6.7 Hz, 1H), 7.83 (d, J = 8.1Hz, 1H), 7.58-
7.52 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.6,
148.2, 146.7, 135.8, 128.9 (4JC-F = 2.6 Hz), 127.8, 127.6,
127.4, 126.6 (3JC-F = 5.6 Hz), 126.3, 122.9 (1JC-F = 269.7 Hz),
116.3 (2JC-F = 29.8 Hz); MS (ESI) m/z 265 [M+H]+; HRMS
Calculated for C13H8F3N2O+ 265.0583; Found: 265.0590 [M +
H]+.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H NMR, 13C NMR and HR-MS for all the
synthesized compounds, and data for mechanistic studies has
been included. This material is available free of charge on the
ACS Publications website.
Corresponding Author
*E-mail: njain@chemistry.iitd.ac.in
5H-dipyrido[1,2-a:2',3'-d]pyrimidin-5-one (6a):11c
ACKNOWLEDGMENT
A.G. thanks UGC for her graduate fellowship. The authors thank
DST-FIST for funding the ESI-HRMS facility at IIT Delhi.
Yellow solid, Hexane/EtOAc = 70/30, yield 85% (85.8 mg);1H
NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.89 (d, J= 6.76 Hz,
1H), 8.77 (d, J = 7.8 Hz, 1H), 7.70-7.64 (m, 2H), 7.44- 7.40
(m, 1H), 7.00- 6.96 (m, 1H); 13C{1H} NMR (75 MHz,
CDCl3): δ 159.76, 157.8, 157.4, 149.8, 137.0, 135.7, 127.0,
126.7, 120.6, 113.4, 111.3; MS (ESI) m/z 198 [M+H]; HRMS
Calculated for C11H8N3O+ 198.0666; Found: 198.0662 [M +
H]+.
REFERENCES
(1) (a) Hamid, A.; Elomri, A.; Daïch, A. Expedious And Practical
Synthesis of the Bioactive Alkaloids Rutaecarpine, Euxylophoricine
A, Deoxyvasicinone and their Heterocyclic Homologues. Tetrahedron
Lett. 2006, 47, 1777. (b) Lee, S. H.; Son, J. K.; Jeong, B. S.; Jeong, T.
C.; Chang, H. W.; Lee, E. S.; Jahng, Y. Progress in the Studies on
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8-Methyl-5H-dipyrido[1,2-a:2',3'-d]pyrimidin-5-one (6b): 29
Yellow solid, Hexane/EtOAc = 70/30, yield 78% (78.7 mg);
1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.76 (d, J = 6.16
Hz, 1H), 8.68(s, 1H), 7.64 (d, J = 9.12 Hz, 1H), 7.51 (d, J =
7.6 Hz, 1H), 7.41-7.38 (m, 1H), 2.04 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ 159.6, 157.6, 157.3, 149.0, 139.0, 137.0,
126.4, 123.7, 123.5, 120.4, 111.1, 18.3; MS (ESI) m/z 212
[M+H]+; HRMS Calculated for C12H10N3O+ 212.0818; Found:
212.0812 [M + H]+.
T.
A
New
Indolopyridoquinazoline-Type
Alkaloid
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The Journal of Organic Chemistry
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