Palladium meets copper: One-pot tandem synthesis of pyrido fused heterocycles: Via Sonogashira conjoined electrophilic cyclization

Article abstract of DOI:10.1039/c6ob01539e

An efficient step-economical tandem approach for the direct synthesis of pyrido fused indole, quinoline, benzofuran and benzothiophene derivatives using a bimetallic Pd/Cu catalytic system has been described. The three component reaction of o-halo aldehyd

Full text of DOI:10.1039/c6ob01539e

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Palladium Meets Copper: One-Pot Tandem Synthesis of Pyrido
Fused Heterocycle via Sonogashira Conjoined Electrophilic
Cyclization
Received 00th January 20xx,
Accepted 00th January 20xx
Sonu Kumar, Rakesh K. Saunthwal, Trapti Aggarwal, Siva K. Reddy Kotla and Akhilesh K. Verma*
DOI: 10.1039/x0xx00000x
An efficient step-economical tandem approach for the direct synthesis of pyrido fused indoles, quinolines, benzofurans
and bezothiophenes derivatives using bimetallic Pd/Cu catalytic system has been described. The three component reaction
of o-halo aldehydes, alkynes and tert-butylamine leads to synthesis of biologically active polyheterocycles. The present
strategy inolves the dual role of tert-butylamine and copper (I) in Sonogashira coupling followed by electrophilic cyclization
through imine formation. The chemistry has been validated by X-ray crystallographic studies.
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activities including anticancer, antiproliferative activity and
topoisomerase I inhibitor (Figure 1, i)4a, cytotoxic activity
Introduction
(Figure 1, ii),4b antibacterial activity,4c
HIV-1 integrase
Owing to the great diversity of heterocyclic core in many
natural product and biologically active compounds,1 numerous
efforts have been focused on the development of improved
methods for the synthesis of fused heterocycles. Previously,
reported protocols for the construction of heterocycles
required harsh conditions,2 however, now a day’s tandem
alkyne cyclization approach has proved to be an advantageous
alternatives. The transition-metal catalyzed annulation
reaction, has gained considerable attention as it provide a
valuable approach for the construction of a wide variety of
heterocycles.3
inhibitory activity,4d FGF receptor-1 tyrosine kinase,4e and
hCRTh2 antagonist (Figure 1, iii)4f. Similarly, O-heterocycles
show nonitercalative topoisomerase I and II dual catalytic
inhibitor (Figure 1, iv)5a while, S-heterocycles acts as binding
receptors and show affinity for the 5-HT1A receptor (Figure 1,
v).5b
Over the past few decades, one-pot transition-metal-catalyzed
reactions have emerged as a proficient tool for the synthesis of
polyheterocycles,6 because of their exclusive property to
activate alkynes, toward intermolecular and intramolecular
nucleophilic attack.7. A variety of metal catalysts were
exploited for electrophilic cyclization, however Pd/Cu-
catalyzed reaction of terminal alkynes with halides provides a
useful strategy for constructing conjugated alkyne substituted
compounds, which further cyclized to afford complex
molecules.8 The electrophilic cyclization utilizing copper is
extensively studied due to its low cost, easily availability and
high tolerance towards diverse functional groups. While, there
are relatively few synthetic studies on Cu-catalyzed three
component tandem reaction for the synthesis of
polyheterocycles.
Previously, Pictet and Ishikawa have developed the
renowned Pictet-Spengler9 and Bischler-Napieralski10 reaction
for the synthesis of tetrahydroisoquinolines and β-
tetrahydrocarbinols but the reaction conditions are tolerable
Figure 1. Important biologically active N-, O-, S-heterocycles.
Due to wide availability of polyheterocycles in biological and
pharmaceutical field it has been an active research area.
Significantly, N-heterocycles have shown distinctive biological
only
for
the
electron-deficient
system
like
tetrahydronaphthyridines.11 In 2002, Larock and Co-workers12
have reported the Pd-Cu catalyzed synthesis of γ-carbolines via
iminium intermediate (Scheme 1). Later, Chen13a and Boruah
a.Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
b.University of Delhi, Delhi – 110007, India
† E-mail: averma@acbr.du.ac.in.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
13b
mentioned the microwave-assisted synthesis of
thienopyridine derivatives using Pd(OAc)2 as
a catalyst.
Recently, our group accomplished the synthesis of
benzothieno- and benzofuropyridines from o-alkynyl aldehyde
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via silver catalyzed 6-endo-dig ring closure approach.14 In DMSO, 1,4-dioxane and DCE (entries 9-11). In case of Pd(dba)2
addition, application of tandem reactions in the synthesis of and Pd(CH3CN)2(BF4)2 the cyclic product was obtained in 10-
heterocycles and natural products like scaffolds using o-halo 15% yield. Other metal catalyst failed to provide the cyclised
aldehydes has been highlighted by Larock,15 Yamamoto,16 product 4a. Thus CuI was chosen as co-catalyst probably due
Wu,17 Verma18 and others.19 Although till now, there was no to the formation of copper acetylide which enhances the rate
report which shows dual behavior of Cu-catalyst as well as of Sonogashira coupling reaction. While trace amount of
tert-butylamine for synthesis of polyheterocycles. In product 4a was observed when n-butyl amine was used as a
continuation of our interest in the synthesis of heterocyclic solvent (entry 14).
scaffolds using o-halo aldehydes, herein we report our efforts Table 1. Optimization of Reaction Conditiona
to synthesize structurally diverse naphthyridine, isoquinolines
and pyrido fused indoles, benzothiophene, benzofuran in one-
pot using Pd/Cu-catalyzed Sonogashira coupling with
subsequent 6-endo dig cyclization.
Pervious work
t-BuNH2
entry
Catalyst
/mol %
temp
solvent
yieldb
i) Larock and co-workers (2002)
Ph
(equiv)
I
Ph
1. cat Pd
2. cat. Cu
1
2
3
4
5
Pd(OAc)2/5
Pd(OAc)2/5
Pd(OAc)2/5
Pd(OAc)2/5
Pd(OAc)2/5
PdCl2/5
PdCl2/5
PdCl2/8
PdCl2/5
PdCl2/5
1.5
1.5
1.5
3.0
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
70
90
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
DCE
5
20
30
50
65
75
15
73
50
30
30
10
15
trace
N
N
t-Bu
N
N
Me
100
100
100
100
100
100
100
100
70
Me
ii) Chen and co-workers (2012)
R2
Br
R2
6
R1
1. Pd(OAc)2/PPh3
2. NH4OAc/mw
R1
7c
8
N
O
X
H
X
X = S, O
9
iii) Verma and co-workers (2015)
R
10
11
12
PdCl2/5
Pd(dba)2/5
R
100
100
100
DMF
DMF
DMF
AgNO3
N
t-BuNH2
O
13 Pd(CH3CN)2(BF4)2/5 4.5
14d
PdCl2/5
X = S, O
X
-
X
aReactions were performed using 0.5 mmol of 1a with 2a (0.6
mmol), using Pd-catalyst, 15 mol % of PPh3 as a ligand and 5
mol % of CuI in 2.0 mL solvent for 8 h. bIsolated yield. cWithout
using CuI. d using 4.5 equiv of n-butylamine.
This work
PdCl2 (5 mol %)
PPh3 (15 mol%)
R
O
N
Het
Het
tert-BuNH2
X
CuI 5 mol %, DMF,
100 oC, 8-30 h
R
(4.5 equiv)
Scheme 2. Pd-Catalyzed Tandem Synthesis of Naphthyridine.a,b
X = Br, Cl
Scheme 1. Designed Tandem Approach for the Synthesis N-
heterocycles
Results and discussion
To identify the optimal reaction condition, we started our
study by synthesizing o-halo-aldehydes according to the
literature procedures.20 Initially, we carried out the reaction of
2-chloroquinoline-3-carbaldehyde 1a with 1.5 equiv of tert-
butylamine 3 using 5 mol % Pd(OAc)2, CuI (5 mol %) and 15 mol
% PPh3 in 2.0 ml of DMF at 70 °C for 3 h, trace amount of
product was obtained (entry 1). Increasing the reaction
o
temperature from 90 to 100 C afforded the desired product
3a in lower yield (entries 2 and 3). When the amount of tert-
butylamine was increased from 3.0 to 4.5 equiv, the desired
product was obtained in 50 and 65% yields, respectively
(entries 4 and 5). Reaction using PdCl2 (5 mol %) provided the
product 4a in 75% yield (entry 6). However, in the absence of
CuI the product 4a was obtained in 15% yield along with 85%
of uncyclized product (entry 7). On increasing the catalyst
a
b
loading, the yield of the product 4a slightly decreased (entry Using optimized conditions (entry 6, Table 1). Isolated yield.
CCDC number of 4b is 1486060.
8). Inferior results were obtained with other solvents such as
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With optimal reaction conditions in hand, we explored the
The optimized strategy was then utilized for reacting o-
scope of the reaction by allowing
chloroquinoline-3-carbaldehydes 1a–c with terminal alkyne
and tert-butylamine in presence of Pd/Cu catalytic system; poor alkynes (Scheme 4). The reaction proceeded well and
the results were concise in Scheme 2. Phenyl and electron- afforded the desired isoquinoline analogues 8a
donating groups bearing alkynes reacted well with 2- yield. Comparatively higher yield of products 8e
a
variety of 2- bromo benzaldehyde 7a and 1,3-dioxolane fused o-bromo
2
benzaldehyde 7b with a variety of electron-rich and electron
3
−
g
in 70
−
82%
was
−
g
chloroquinoline-3-carbaldehyde 1a and tert-butylamine
provided the desired products 4a–d in good yields. Substrates
1b–c having electron-donating group, afforded the
3
obtained with 1,3-dioxolane fused o-bromo benzaldehyde 7b.
Scheme 5. One-Pot Synthesis of Benzothienopyridines
corresponding product 4e–h in 77
2-chloronicotinaldehyde 1d
ethynylbenzene gave fruitful result.
–
78% yields. The reaction of
with 1-(tert-butyl)-4-
Scheme 3. Pd-Catalyzed one pot Synthesis of Pyridoindole.a,b
In recent years, benzothienopyridines derivatives have
−A dye
emerged as an important class that widely occur in D−π
-
sensitized solar cells and exhibit significant biological activity.
21 The scope of the present Pd-Cu catalytic system was further
evaluated for the synthesis of thiophene substituted
derivatives. The reaction successfully constructs the
benzothienopyridine derivative 10a−d in good yields (Scheme
5). Aromatic and heteroaromatic alkynes were reacted with 3-
bromobenzo[b]thiophene-2-carbaldehyde 9 to afford 3-
substituted benzo[4,5]thieno[2,3-c]pyridine 10a-d.
Scheme 6. Pd-Catalyzed Tandem Synthesis of Benzofuro Pyridines
aUsing optimized conditions (entry 6, Table 1). bIsolated yield.
The generality of the tandem approach was then extended
for synthesizing important analogues of pharmaceutically4f
Substrate scope of the developed methodology was further
extended for the synthesis of biologically active22 benzofuropyridine
analogues under the optimized reaction condition. The reaction of
2-chlorobenzofuran-3-carbaldehyde 11 with various electron-
neutral, releasing and withdrawing alkynes provided the
corresponding benzofuro[3,2-c]pyridines 12a−d in 72-76% yields
(Scheme 6).
active pyridoindoles 6a
bromo-1-methyl-1H-indole-3-carbaldehyde
well as aliphatic alkyne gave the corresponding products in
good yields. The alkynes having neutral and electron-rich
substitution afforded the desired products 6a in 76-80%
yield. The reaction of 3-ethynylthiophene with substrate
−i
(Scheme 3). The reactions of 2-
5
with aromatic as
2
−
d
5
gave 82% yield of product 6e. The electron-deficient alkyne
bearing −CF3 group at para position on phenyl ring to carbon-
carbon triple bond provided the corresponding product 6f in
68% yield. However, the reaction with aliphatic alkyne gave
Scheme 7. Mechanistic Experiment
the corresponding product 6g−i in 62−65% yield.
Scheme 4. One-pot Isoquinoline Synthesis.a,b
To support our proposed mechanistic pathway and role of copper in
the reaction, an array of preliminary experiments was performed
aUsing optimized conditions (entry 6, Table 1). bIsolated yield.
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(Scheme 7). Initially, we performed our reaction only in the
presence of Pd-catalyst at 70 °C for 2 h, and to our surprise reaction
stops at Songashira coupled product 13 (Scheme 7, i). When we
role of tert-butyl amine and CuI. The reported protocol is
general, operationally simple and expands the synthetic utility
of o-halo aldehydes and alkynes for the synthesis of
biologically importance fused heterocyclic scaffold.
increase
the
temperature
of
the
reaction,
phenylethynylquinolinylamine 14 was obtained in 70% yield along
with trace amount of product 4a (Scheme 7, ii). Further the
Acknowledgements
23
uncyclized imine product 14 was treated with Cu (I), leading to
The work was supported by SERB (DST) and University of Delhi.
S.K and R.K.S. are thankful to CSIR and UGC for fellowship.
the formation of cyclized product in 2 h (Scheme 7, iii). Next, we
carried out the reaction of 2-(phenylethynyl)quinoline-3-
carbaldehyde (13) with 5 mol % of CuI in DMF, the cyclized product
4 was obtained in 76% yield (Scheme 7, iv). Although it was well
documented in literature that Sonogashira coupling proceed
smoothly in presence of palladium without using copper in mild
base;23 however it requires longer reaction time. Thus, the results
of the control experiments revealed the dual role of Cu: i) enhance
the rate of Sonogashira coupling; ii) and to assist the electrophilic
cyclization.
EXPERIMENTAL SECTION
General Method. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded in CDCl3/DMSO-d6. Chemical shifts for
protons and carbons are reported in ppm from
tetramethylsilane and are referenced to the carbon resonance
of the solvent. Data are reported as follows: chemical shift,
multiplicity (s = singlet, br s = broad singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, dd = doublet of doublet),
coupling constants in Hertz and integration. High-resolution
mass spectra were recorded on electrospray mass
spectrometer. Crystal structure analysis was accomplished on
single needles X-ray diffractometer. TLC analysis was
performed on commercially prepared 60 F254 silica gel plates
and visualized by either UV irradiation or by staining with I2. All
purchased chemicals were used as received. All melting points
are uncorrected.
Scheme 8. Plausible Mechanism
General Procedure for the Synthesis of Functionalized
Heterocycles.
In an oven-dried round bottom flask, a solution of ortho helo
aldehyde (0.5 mmol), alkyne
2 (0.6 mmol), t-butyl amine 3
(4.5 equiv) using PdCl2-catalyst (5 mol%), 15 mol% of PPh3 as a
ligand and 5 mol % of CuI in 2.0 mL DMF The resulting reaction
mixture was heated at 100 °C for 8−14 h. Progression of the
reaction was monitored by TLC analysis; after complete
consumption of starting material, the reaction was cooled to
room temperature. The reaction mixture was diluted with
ethyl acetate (10 mL) and water (15 mL). The layers were
On the basis of preliminary results, a plausible catalytic cycle for
above three-component tandem reaction is discussed in Scheme 8.
It involves the formation of C−C and C−N bond via Sonogashira separated, and the organic layer was washed with aqueous
coupling and electrophilic cyclization, respectively. The reaction of
o-halo aldehydes with terminal alkynes would generates the o-
alkynyl aldehydes intermediate 13, which on reaction with tert-
butyl amine led to the formation of imine P. π-Complexation
between the alkyne of intermediate 13 and the copper (I) renders
saturated brine solution and dried over Na2SO4. Organic layer
was concentrated under reduced pressure. The crude material
so obtained was purified by column chromatography on silica
gel (100−200) (hexane:ethyl acetate; 95/05). The structure and
purity of known starting materials and product 13 and 14 were
confirmed by comparison of their physical and spectral data
(1H NMR, 13C NMR, and HRMS) with those reported in the
literature.25
species
P which is highly susceptible towards the attack of
nucleophile. Thus copper intermediate Q was formed by the
intramolecular attack of the imine nitrogen on the copper
coordinated alkyne. The presence of tert-butyl group enhances the
formation of intermediate S by the elimination of isobutylene24
fragment, which on protodemetalation forms the desired cyclized
product 4, 6, 8, 10 and 12.
3-Phenylbenzo[b][1,6]naphthyridine (4a). The product was
obtained as yellow needles (96.1 mg, 75 %): mp 190–192 °C;
1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.85 (s, 1H), 8.35 (s,
1H), 8.17–8.15 (m, 3H), 7.97 (d, J = 8.2 Hz, 1H), 7.82–7.78 (m,
1H), 7.52–7.45 (m, 3H), 7.40–7.36 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 154.7, 153.8, 152.0, 150.3, 138.8, 137.2, 132.6, 129.4,
129.2, 129.0, 128.9, 127.2, 126.3, 121.1, 116.5; HRMS (EI-TOF)
Calcd for [C18H12N2] requires [M]+ 256.1000, found [M]+
256.0999.
Conclusions
In summary, we have designed a one-pot three-component
tandem apporach for the synthesis of naphthyridine,
isoquinoline, pyrido indole, benzothienopyridines and
benzofuropyridines derivatives from corresponding o-
haloaldehyde, alkyne and tert-butyl amine via electrophilic
cyclization. This developed tandem approach employed dual
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3-(p-Tolyl)benzo[b][1,6]naphthyridine
(
4b). The product was 3-(4-(tert-Butyl)phenyl)-8-methoxybenzo[b][1,6]
4h). The product was obtained as pale yellow
obtained as a dark yellow dark yellow needles (104.0 mg, 82 naphthyridine
(
%): mp 195–197 °C; 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), crystals (133.5 mg, 78%): mp 220–222 °C; 1H NMR (400 MHz,
8.84 (s, 1H), 8.34 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.2 CDCl3): δ 9.41 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 8.13–8.04 (m,
Hz, 2H), 7.97 (d, J = 8.7 Hz, 1H), 7.84–7.81 (m, 1H), 7.52 (t, J = 3H), 7.54–7.48 (m, 3H), 7.07 (s, 1H), 3.89 (s, 3H), 1.37 (s, 9H);
7.1 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 2.4 (s, 3H); 13C NMR (100 13C NMR (100 MHz, CDCl3): δ 157.2, 153.8, 152.8, 152.2, 149.0,
MHz, CDCl3): δ 154.5, 153.8, 151.9, 150.3, 139.2, 137.2, 135.9, 148.7, 136.0, 134.3, 130.6, 127.8, 126.7, 125.8, 121.1, 115.9,
132.5, 129.6, 129.2, 128.9, 127.1, 126.8, 126.2, 120.9, 115.8, 114.0, 103.6, 55.5, 34.6, 31.2; HRMS (EI-TOF) Calcd for
21.3; HRMS (EI-TOF) Calcd for [C19H14N2] requires [M]+ [C23H22N2O] requires [M]+ 342.1732, found [M]+ 342.1732.
270.1157, found [M]+ 270.1156.
7-(4-(tert-Butyl)phenyl)-1,6-naphthyridine
(4i). The product
3-(4-Butylphenyl)benzo[b][1,6]naphthyridine
(4c).
The was obtained as yellow crystals (85.2 mg, 65%): mp 165–170
1
product was obtained as yellow needles (118.7 mg, 76 %): mp °C; H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 9.05–9.04 (m, 1H),
142–145 °C; 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.8 (s, 8.31 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H),
1H), 8.3 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.45–7.42 (m, 1H), 1.36 (m, 9H). 13C
7.99 (d, J = 8.2 Hz, 1H), 7.83–7.79 (m, 1H), 7.53–7.49 (m, 1H), NMR (100 MHz, CDCl3) δ 155.0, 154.8, 152.5, 152.3, 151.2,
7.28 (d, J = 8.2 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.63–1.58 (m, 135.8, 135.4, 126.8, 125.8, 122.4, 121.8, 117.1, 34.6, 31.2;
2H), 1.36–1.28 (m, 2H), 0.92–0.86 (m, 3H); 13C NMR (100 MHz, HRMS (EI-TOF) calcd for [C18H18N2] requires [M]+ 262.1470,
CDCl3): δ 154.6, 154.0, 152.1, 150.5, 144.4, 137.3, 136.2, 132.6, found [M]+ 262.1470.
129.3, 129.1, 127.1, 127.0, 126.3, 121.1, 115.9, 35.5, 33.5, 5-Methyl-3-phenyl-5H-pyrido[4,3-b]indole
(
6a).
This
22.4, 14.0; HRMS (EI-TOF) Calcd for [C22H20N2] requires [M]+ compound was obtained as a yellow crystals (98.1 mg, 76%),
312.1626, found [M]+ 312.1625.
mp 95–99 °C; 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.06 (d,
3-(Thiophen-3-yl)benzo[b][1,6]naphthyridine
(4d).
The J = 7.3 Hz, 1H), 8.02–8.00 (m, 2H), 7.57 (s, 1H), 7.46–7.39 (m,
product was obtained as brown needles (104.9 mg, 80 %): mp 3H), 7.34–7.31 (m, 2H), 7.26–7.22 (m, 1H), 3.76 (s, 3H); 13C
208–210 °C; 1H NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 8.91 (s, NMR (100 MHz, CDCl3): δ 153.5, 146.0, 142.2, 141.4, 140.5,
1H), 8.26 (s, 1H), 8.21–8.17 (m, 2H), 8.04 (d, J = 8.2 Hz, 1H), 128.7, 128.4, 127.2, 126.6, 121.3, 120.6, 120.5, 118.6, 108.8,
7.89–7.85 (m, 1H), 7.79–7.78 (m, 1H), 7.57 (t, J = 8.2 Hz, 1H), 100.5, 29.0; HRMS (EI-TOF): [M]+ Calcd for [C18H14N2] :
7.46–7.44 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 154.9, 152.0, 258.1157, found : 258.1156.
150.4, 150.0, 141.7, 137.4, 132.7, 129.3, 129.1, 126.9, 126.8, 5-Methyl-3-(p-tolyl)-5H-pyrido[4,3-b]indole
126.3, 126.0, 124.8, 121.2, 115.7; HRMS (EI-TOF) Calcd for compound was obtained as a pale brown crystals (106.2 mg,
[C16H10N2S] requires [M]+ 262.0565, found [M]+ 262.0565. 78%), mp 104–107 °C; 1H NMR (400 MHz, CDCl3): δ 9.29 (s,
8-Methyl-3-(p-tolyl)benzo[b][1,6]naphthyridine 4e). The 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.58 (s,
(
6b).
This
(
product was obtained as yellow crystals (110.8 mg, 78%): mp 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.31–7.27
220–222 °C; 1H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H), 8.66 (s, (m, 3H), 3.79 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
1H), 8.26 (s, 1H), 8.03 (d, J = 8.2 Hz, 3H), 7.65–7.59 (m, 2H), 153.5, 146.1, 142.1, 141.4, 138.2, 137.7, 129.4, 127.0, 126.5,
7.25 (d, J = 8.2 Hz, 2H), 2.47 (s, 3H), 2.35 (s, 3H); 13C NMR (100 121.3, 120.5, 120.4, 118.4, 108.8, 100.1, 29.0, 21.2; HRMS (EI-
MHz, CDCl3): δ 154.4, 153.4, 150.9, 149.8, 139.1, 136.2, 136.1, TOF) :[M]+ Calcd for [C19H16N2] : 272.1313, found : 272.1313.
136.0, 135.5, 129.6, 128.9, 127.0, 126.9, 121.1, 115.9, 21.7, 3-(4-Butylphenyl)-5-methyl-5H-pyrido[4,3-b]indole (6c). This
21.3; HRMS (EI-TOF) Calcd for [C20H16N2] requires [M]+ compound was obtained as a brown crystals (121.0 mg, 77%),
1
284.1313, found [M]+ 284.1313.
mp 74–78 °C; H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.02–
4f). 7.97 (m, 1H), 7.93–7.86 (m, 2H), 7.50 (s, 1H), 7.43–7.36 (m,
3-(4-Ethylphenyl)-8-methylbenzo[b][1,6]naphthyridine
(
The product was obtained as brown crystals (114.8 mg, 77%): 1H), 7.29–7.25 (m, 1H), 7.23–7.14 (m, 3H), 3.71 (s, 3H), 2.60–
mp 190–192 °C; 1H NMR (400 MHz, CDCl3): δ 9.36 (s, 1H), 8.58 2.53 (m, 2H), 1.60–1.52 (m, 2H), 1.35–1.25 (m, 2H), 0.86 (t, J =
(s, 1H), 8.23 (s, 1H), 8.05–7.97 (m, 3H), 7.57–7.55 (m, 2H), 7.26 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.4, 146.1, 143.4,
(d, J = 9.6 Hz, 2H), 2.64 (q, J = 7.8 Hz, 2H), 2.42 (s, 3H), 1.21 (t, J 141.9, 141.4, 137.6, 128.8, 127.0, 126.6, 121.2, 120.5, 118.4,
= 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 154.3, 153.4, 150.8, 108.8, 100.2, 35.3, 33.5, 29.0, 22.3, 13.9; HRMS (EI-TOF) :[M]+
149.7, 145.4, 136.2, 136.1, 135.8, 135.4, 128.8, 128.4, 127.1, Calcd for [C22H22N2] : 314.1783, found : 314.1783.
126.9, 121.0, 115.8, 28.7, 21.8, 15.4. HRMS (EI-TOF) Calcd for 3-(4-Methoxyphenyl)-5-methyl-5H-pyrido[4,3-b]indole
[C21H18N2] requires [M]+ 298.1470, found [M]+ 298.1471.
This compound was obtained as a brown crystals (115.3 mg,
8-Methoxy-3-phenylbenzo[b][1,6]naphthyridine
4g). The 80%), mp 173–175 °C; 1H NMR (400 MHz, CDCl3): δ 9.27 (s,
(6d).
(
product was obtained as pale yellow crystals (110.2 mg, 77%): 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.54 (s,
mp 98–100 °C; 1H NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 8.56 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.29 (t, J =
(s, 1H), 8.26 (s, 1H), 8.12–8.10 (m, 2H), 8.00 (d, J = 9.1 Hz, 1H), 7.9 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H);
7.46–7.42 (m, 3H), 7.37–7.35 (m, 1H), 7.02 (d, J = 2.7 Hz, 1H), 13C NMR (100 MHz, CDCl3): δ 160.0, 153.1, 146.1, 142.0, 141.4,
3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.6, 154.1, 153.0, 133.0, 128.3, 126.5, 121.3, 120.5, 120.4, 118.1, 114.0, 108.8,
149.3, 148.8, 139.1, 134.5, 130.9, 129.1, 129.0, 128.1, 128.0, 99.6, 55.3, 28.9; HRMS (ESI) :[M+H]+ Calcd for [C19H16N2O] :
127.2, 116.7, 103.8, 55.7; HRMS (EI-TOF) Calcd for [C19H14N2O] 289.1341, found : 289.1342.
requires [M]+ 286.1106, found [M]+ 286.1105.
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DOI: 10.1039/C6OB01539E
ARTICLE
Journal Name
5-Methyl-3-(thiophen-3-yl)-5H-pyrido[4,3-b]indole
(6e). This 3.6 Hz, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H),
compound was obtained as a brown crystals (108.3 mg, 82%), 7.68–7.64 (m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.8 Hz,
1
mp 108–110 °C; H NMR (400 MHz, CDCl3): δ 9.24 (s, 1H), 8.11 2H), 2.71 (q, J = 7.3 Hz, 2H), 1.28 (t, J = 8.0 Hz, 3H); 13C NMR
(d, J = 7.9 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.74–7.72 (m, 1H), (100 MHz, CDCl3): δ 152.3, 151.3, 144.7, 137.0, 136.6, 130.4,
7.53–7.48 (m, 2H), 7.41–7.38 (m, 2H), 7.30 (t, J = 7.3 Hz, 1H), 128.3, 127.5, 126.9, 126.8, 116.0, 28.6, 15.5; HRMS (EI-TOF):
3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 149.3, 142.0, 141.9, [M]+ Calcd for [C17H15N] : 233.1204, found : 233.1205.
141.5, 126.7, 126.3, 126.2, 123.0, 121.3, 120.7, 120.6, 118.4, 3-(3-Methoxyphenyl)isoquinoline
108.9, 100.2, 29.1; HRMS (EI-TOF): [M]+ Calcd for [C16H12N2S] : obtained as a yellow crystals (91.7 mg, 78%), mp 80–82 °C; H
(8c). This compound was
1
264.0721, found : 264.0721.
NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 8.04 (s, 1H), 7.97 (d, J =
8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.71–7.66 (m, 3H), 7.56 (t, J
5-Methyl-3-(4-(trifluoromethyl)phenyl)-5H-pyrido[4,3-
b]indole (6f). This compound was obtained as a pale yellow = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.97–6.94 (m, 1H), 3.90 (s,
1
crystals (110.9 mg, 68%), mp 166–168 °C; H NMR (400 MHz, 3H); 13C NMR (100 MHz, CDCl3): δ 160.1, 152.3, 151.0, 141.1,
CDCl3): δ 9.33 (s, 1H), 8.20–8.14 (m, 3H), 7.72 (d, J = 7.9 Hz, 136.6, 130.5, 129.7, 127.8, 127.5, 127.1, 126.9, 119.4, 116.7,
2H), 7.67 (s, 1H), 7.56–7.52 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 114.6, 112.1, 55.4; HRMS (EI-TOF): [M]+ Calcd for [C16H13NO] :
7.33 (t, J = 6.7 Hz, 1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3): 235.0997, found : 235.0998.
δ 151.8, 145.9, 143.8, 142.4, 141.6, 127.4, 127.0, 125.6 (q, J 3-(4-(Trifluoromethyl)phenyl)isoquinoline
(8d
)
.
This
=15.2 Hz, 1C), 121.1, 120.8, 119.2, 109.0, 101.1, 29.1; HRMS compound was obtained as a brown crystals (95.6 mg, 70%),
(EI-TOF): [M]+ Calcd for [C19H13F3N2] : 326.1031, found : mp 96–98 °C; 1H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 8.15 (d,
326.1030.
J = 8.2 Hz, 2H), 8.02 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.81 (d, J =
This 8.4 Hz, 1H), 7.68–7.62 (m, 3H), 7.56–7.52 (m, 1H); 13C NMR
5-Methyl-3-phenethyl-5H-pyrido[4,3-b]indole
(
6g).
compound was obtained as a semi-solid (93.0 mg, 65%); 1H (100 MHz, CDCl3): δ 152.6, 149.6, 142.9, 136.4, 130.8, 128.1,
NMR (400 MHz, CDCl3): δ 9.15 (s, 1H), 8.03 (d, J = 7.3 Hz, 1H), 127.7, 127.6, 127.2, 127.0, 125.7 (q, J = 8.44 Hz, 1C), 117.3;
7.45–7.41 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25–7.19 (m, 2H), HRMS (EI-TOF): [M]+ Calcd for [C16H10F3N] : 273.0765, found :
7.18–7.08 (m, 4H), 6.95 (s, 1H), 3.68 (s, 3H), 3.21–3.17 (m, 2H), 273.0765.
3.10–3.06 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 156.5, 146.0, 7-(4-Butylphenyl)-[1,3]dioxolo[4,5-g]isoquinoline
(8e). This
141.7, 141.5, 141.2, 128.5, 128.3, 126.5, 125.9, 121.3, 120.54, compound was obtained as a yellow crystals (126.7 mg, 83%),
120.49, 117.9, 108.9, 102.6, 40.6, 36.6, 29.0; HRMS (ESI) mp 120–123 °C; 1H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 7.95
:[M+H]+ Calcd for [C20H18N2] : 287.1548, found : 287.1524.
(d, J = 7.6 Hz, 2H), 7.83 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.16 (s,
(6h). This 1H), 7.06 (s, 1H), 6.05 (s, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.66–1.58
3-Cyclopropyl-5-methyl-5H-pyrido[4,3-b]indole
compound was obtained as a brown crystals (74.4 mg, 67%), (m, 2H), 1.41–1.32 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR
mp 74–76 °C; 1H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 7.97 (d, (100 MHz, CDCl3): δ 151.0, 150.6, 150.0, 148.1, 143.2, 137.0,
J = 7.9 Hz, 1H), 7.40–7.36 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.20– 135.0, 128.8, 126.6, 124.8, 115.9, 103.0, 102.7, 101.5, 35.3,
7.17 (m, 1H), 6.98 (s, 1H), 3.67 (s, 3H), 2.14–2.07 (m, 1H), 33.5, 22.3, 13.9; HRMS (EI-TOF): [M]+ Calcd for [C20H19NO2] :
1.05–1.01 (m, 2H), 0.97–0.92 (m, 2H); 13C NMR (100 MHz, 305.1416, found : 305.1423.
CDCl3): δ 158.4, 146.0, 141.6, 141.1, 126.2, 121.5, 120.3, 120.2, 4-([1,3]Dioxolo[4,5-g]isoquinolin-7-yl)-N,N-dimethylaniline
117.7, 108.7, 100.4, 28.9, 17.8, 9.7; HRMS (ESI) :[M+H]+ Calcd
for [C15H14N2] : 223.1235, found : 223.1239.
(
8f). This compound was obtained as a yellow crystals (114.0
mg, 78%), mp 184–186 °C; 1H NMR (400 MHz, CDCl3): δ 9.08 (s,
3-Butyl-5-methyl-5H-pyrido[4,3-b]indole (6i). This compound 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.86 (s, 1H), 7.24 (s, 1H), 7.13 (s,
was obtained as a semi-solid (73.8 mg, 62%); 1H NMR (400 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.14 (s, 2H), 3.10 (s, 6H); 13C NMR
MHz, CDCl3): δ 9.11 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.41 (t, J = (100 MHz, CDCl3): δ 150.9, 150.8, 150.6, 149.8, 147.7, 135.3,
7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.23–7.18 (m, 1H), 7.04 (s, 127.5, 124.2, 114.4, 112.4, 103.0, 102.5, 101.4, 40.4; HRMS
1H), 3.72 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 1.75–1.68 (m, 2H), (ESI) :[M+Na]+ Calcd for [C18H16N2O2] : 315.1109, found :
1.38–1.33 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, 315.1097.
CDCl3): δ 158.1, 146.0, 141.7, 141.1, 126.2, 121.4, 120.4, 120.3, 7-(4-(Trifluoromethyl)phenyl)-[1,3]dioxolo[4,5-g]isoquinoline
117.7, 108.7, 102.1, 38.7, 32.6, 28.9, 22.6, 14.0; HRMS (EI-
TOF): [M]+ Calcd for [C16H18N2] : 238.1470, found : 238.1470.
(
8g). This compound was obtained as a brown crystals (120.5
mg, 76%), mp 185–188 °C; 1H NMR (400 MHz, CDCl3): δ 9.05 (s,
3-Phenylisoquinoline (8a). This compound was obtained as a 1H), 8.16 (d, J = 7.9 Hz, 2H), 7.92 (s, 1H), 7.71 (d, J = 7.9 Hz,
1
yellow crystals (82.1 mg, 80%), mp 101–103 °C; H NMR (400 2H), 7.21 (s, 1H), 7.12 (s, 1H), 6.10 (s, 2H). 13C NMR (100 MHz,
MHz, CDCl3): δ 9.32 (s, 1H), 8.12–8.10 (m, 2H), 8.05 (s, 1H), CDCl3): δ 151.4, 150.3, 148.8, 142.9, 139.3, 135.0, 129.9, 127.0,
7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.69–7.65 (m, 125.6 (q, J = 15.2 Hz, 1C), 117.1, 114.0, 103.2, 102.9, 101.8;
1H), 7.58–7.54 (m, 1H), 7.51–7.47 (m, 2H), 7.42–7.40 (m, 1H); HRMS (EI-TOF): [M]+ Calcd for [C17H10F3NO2]: 317.0664, found :
13C NMR (100 MHz, CDCl3): δ 152.4, 151.3, 151.2, 139.6, 136.6, 317.0665.
130.5, 128.8, 128.5, 127.7, 127.6, 127.04, 126.98, 116.5; HRMS 3-Phenylbenzo[4,5]thieno[2,3-c]pyridine
(ESI) :[M+H]+ Calcd for [C15H11N] : 206.0970, found : 206.0970.
was obtained as brown oil (91.4 mg, 70%); H NMR (400 MHz,
3-(4-Ethylphenyl)isoquinoline 8b). This compound was CDCl3) 9.19 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.10
obtained as a yellow crystals (95.6 mg, 82%), mp 85–87 °C; H (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.65–7.50 (m, 4H),
NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 7.43 (t, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
152.7,
(10a). The product
1
(
δ
1
δ
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB01539E
Journal Name
ARTICLE
144.3, 142.8, 139.5, 134.6, 131.9, 129.1, 128.8, 128.6, 127.0, 3-(4-(Trifluoromethoxy)phenyl)benzofuro[3,2-c]pyridine
124.9, 123.4, 122.8, 114.0, 112.4; HRMS (EI-TOF) calcd for
[C17H11NS] requires [M]+ 261.0612, found 261.0612.
(
12d
)
.
The product was obtained as a yellow crystals (120.1
9.18 (s,
mg, 73%): mp 150–154 °C; 1H NMR (400 MHz, CDCl3)
δ
3-(p-Tolyl)benzo[4,5]thieno[2,3-c]pyridine
was obtained as dark yellow crystals (99.1 m g, 72%): mp 118– 7.54–7.52 (m, 1H), 7.47–7.43 (m, 1H), 7.36–7.32 (m, 1H), 7.27–
122 °C; 1H NMR (400 MHz, CDCl3) 9.11 (s, 1H), 8.31 (s, 1H), 7.25 (m, 2H); 13C NMR (100 MHz, CDCl3)
162.1, 156.4, 154.5,
(10b). The product 1H), 8.03–8.00 (m, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H),
δ
δ
8.23 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 7.8 149.8, 143.0, 138.0, 128.6, 128.3, 124.0, 121.4, 121.14, 121.11,
Hz, 1H), 7.54–7.50 (m, 1H), 7.48–7.44 (m, 1H), 7.26 (d, J = 7.8 120.6, 119.2, 112.0, 103.9; HRMS (ESI) calcd for [C18H10F3NO2]
Hz, 2H), 2.36 (s, 3H) ; 13C NMR (100 MHz, CDCl3) 152.6, 144.2, requires [M+H]+ 330.0742, found 330.0756.
δ
142.7, 141.4, 138.6, 136.7, 134.2, 133.9, 129.5, 129.0, 126.8,
124.8, 123.3, 122.8, 112.1, 21.2 ; HRMS (EI-TOF) calcd for
[C18H13NS] requires [M]+ 275.0769, found 275.0769.
Notes and references
3-(Thiophen-3-yl)benzo[4,5]thieno[2,3-c]pyridine
(10c). The
(1) (a) H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem.
Rev., 2008, 108, 264; (b) C. Bailly, Curr. Med. Chem.
Anticancer Agents., 2004, 4, 363; (c) B. Yao, M. R.
Prinsep, B. K. Nicholson and D. P. Gordon, J. Nat. Prod.,
2003, 66, 1074.
(2) (a) W. M. Whaley and T. R. Govindachari, Org. React.,
product was obtained as a pale yellow crystals (100.2 mg,
1
75%): mp 95–99 °C; H NMR (400 MHz, CDCl3)
δ 9.05 (s, 1H),
8.22–8.20 (m, 2H), 7.93–7.91 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H),
7.70–7.69 (m, 1H), 7.55–7.51 (m, 1H), 7.46 (t, J = 7.3 Hz, 1H),
7.39–7.37 (m, 1H) ; 13C NMR (100 MHz, CDCl3)
δ 145.0, 144.3,
1951, 6, 74; (b) Gensler, W. J. Org. React. 1951, 6, 191.
(3) (a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M.
Lemaire, Chem. Rev., 2002, 102, 1359; (b) I. Nakamura
and Y. Yamamoto, Chem. Rev., 2004, 104, 2127; (c) A.
Roglans, A. Pla-Quintana, Moreno-Manas, M. Chem.
Rev., 2006, 106, 4622; (d) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (e)
X. Chen, K. M. Engle, D. Wang and J. Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094; (f) B. A. Arndtsen,
Chem. Eur. J., 2009, 15, 302; (g) L. A. Wessjohann, D. G.
Rivera and O. E. Vercillo, Chem. Rev., 2009, 109, 796;
141.5, 134.0, 129.1, 128.6, 128.4, 127.9, 127.4, 127.0, 124.9,
123.4, 123.1, 122.9, 112.3; HRMS (EI-TOF) calcd for [C15H9NS2]
requires [M]+ 267.0176, found 267.0176.
3-(4-(Trifluoromethyl)phenyl)benzo[4,5]thieno[2,3-c]pyridine
(
10d). The product was obtained as a brown crystals (107.0
mg, 65%): mp 134–126 °C; 1H NMR (400 MHz, CDCl3)
δ 9.11 (s,
1H), 8.31 (s, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 8.2 Hz,
2H), 7.84 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.55–7.51
(m, 1H), 7.48–7.44 (m, 1H) ; 13C NMR (100 MHz, CDCl3)
δ 150.9,
(h) G. Cahiez and A. Moyeux, Chem. Rev., 2010, 110
,
144.6, 142.8, 141.4, 135.4, 133.7, 129.3, 127.2, 125.7 (q, J = 3.8
Hz, 1C), 125.0, 123.4, 122.9, 112.7; HRMS (EI-TOF) calcd for
[C18H10F3NS] requires [M]+ 329.0486, found 329.0487.
1435; (i) J. Magano and J. R. Dunetz, Chem. Rev., 2011,
111, 2177; (j) J. A. Gladysz, Chem. Rev. 2011, 111, 1167;
(k) C. C. C. Johansson Seechurn, M. O. Kitching, T. J.;
Colacot, Snieckus, V. Angew. Chem., Int. Ed., 2012, 51,
5062.
3-Phenylbenzofuro[3,2-c]pyridine
obtained as a yellow crystals (91.9 mg, 74%): mp 150–155 °C;
1H NMR (400 MHz, CDCl3)
9.23 (s, 1H), 8.02–7.97 (m, 3H),
7.85 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.48–7.43 (m, 3H), 7.39–
7.34 (m, 2H); 13C NMR (100 MHz, CDCl3)
162.2, 156.3, 156.1,
(12a). The product was
(4) (a) E. Kiselev, T. S. Dexheimer, Y. Pommier and M.
Cushman, J. Med. Chem., 2010, 53, 8716; (b) L. W.
Deady, T. Rodemann, L. Zhuang, B. C. Baguley and W.
A. Denny, J. Med. Chem., 2003, 46, 1049; (c) H. Kondo,
M. Taguchi, Y. Inoue, F. Sakamoto and G. Tsukamoto, J.
Med. Chem., 1990, 33, 2012; (d) L.-F. Zeng, Y. Wang, R.
Kazemi, S. Xu, Z.-L. Xu, T. W. Sanchez, L.-M. Yang, B.
Debnath, S. Odde, H. Xie, Y.-T. Zheng, J. Ding, N.
Neamati and Y.-Q. Long, J. Med. Chem. 2012, 55, 9492;
(e) A. M. Thompson, C. J. C. Connolly, J. M. Hamby, S.
Boushelle, B. G. Hartl, A. M. Amar, A. J. Kraker, D. L.
Driscoll, R. W. Steinkampf, S. J. Patmore, P. W. Vincent,
B. J. Roberts, W. L. Elliott, W. Klohs, W. R. Leopold, H.
D. H. Showalter and W. A. Denny, J. Med. Chem., 2000,
43, 4200; (f) H. Fretz, A. Valdenaire, J. Pothier, K.
Hilpert, C. Gnerre, O. Peter, X. Leroy and M. A.
Riederer, J. Med. Chem., 2013, 56, 4899.
(5) (a) H.-B. Kwon, C. Park, K.-H. Jeon, E. Lee, S.-E. Park, K.-
Y. Jun, T.M. Kadayat, P. Thapa, R. Karki, Y. Na, M. S.
Park, S. B. Rho, E.-S. Lee and Y. Kwon, J. Med. Chem.,
2015, 58, 1100; (b) H. Kawakubo, S. Takagi, Y. Yamaura,
S. Katoh, Y. Ishimoto, T. Nagatani, D. Mochizuki, T.
Kamata and Y. Sasakis, J. Med. Chem., 1993, 36, 3526.
(6) (a) G. Wu, W. Yin, H. C. Shen and Y. Huang, Green
Chem., 2012, 41, 580; (b) M. Yamaguchi, T. Akiyama, H.
Sasou, H. Katsumata and K. Manabe, J. Org. Chem.,
2016, 81, 5450 and references cited therein.
δ
δ
142.9, 139.4, 129.0, 128.8, 128.1, 127.1, 123.8, 121.6, 121.1,
120.3, 111.9, 103.9; HRMS (ESI) calcd for [C17H11NO] requires
[M+H]+ 246.0919, found 246.0931.
3-(4-(tert-Butyl)phenyl)benzofuro[3,2-c]pyridine
product was obtained as a yellow crystals (114.5 mg, 76%): mp
146–150 °C; 1H NMR (400 MHz, CDCl3)
9.28 (s, 1H), 8.04–
(12b). The
δ
8.00 (m, 3H), 7.89 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.54–7.49 (m,
3H), 7.43–7.39 (m, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ
162.3 156.3, 156.1, 152.3, 142.9, 136.6, 128.0, 126.9, 125.8,
123.8, 121.7, 121.1, 120.1, 111.9, 103.6, 35.2, 31.3; HRMS (ESI)
calcd for [C21H19NO] requires [M+H]+ 302.1545, found
302.1568.
3-(3-Methoxyphenyl)benzofuro[3,2-c]pyridine
product was obtained as a yellow crystals (99.1 mg, 72%): mp
147–151 °C; 1H NMR (400 MHz, CDCl3)
9.27 (s, 1H), 8.03 (d, J
(12c). The
δ
= 8.4 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.63–7.60 (m, 2H), 7.52
(t, J = 7.9 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 6.99 (dd, J = 8.4 and
6.1 Hz, 1H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 162.2,
160.1, 156.3, 155.8, 142.9, 140.9, 129.8, 128.1, 123.8, 121.6,
121.1, 120.4, 119.5, 115.1, 112.3, 111.9, 104.1, 55.4; HRMS
(ESI) calcd for [C18H13NO2] requires [M+H]+ 276.1025, found
276.1042.
(7) (a) J. Shen, X. Wang, X. Lin, Z. Yang, G. Cheng and X.
Cui, Org. Lett., 2016, 18, 1378; (b) M. Bakthadoss and
R. Selvakumar, J. Org. Chem., 2016, 81, 3391; (c) X.
Huang, M. Liu, K. Pham, X. Zhang, W.-B. Yi, J. P. Jasinski
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and W. Zhang, J. Org. Chem., 2016, 81, 5362 and
references cited therein.
Verma, Org. Lett., 2012, 14, 5184; (e) A. K. Verma, V.
Rustagi, T. Aggarwal and A. P. Singh, J. Org. Chem.,
2010, 75, 7691; (f) T. Aggarwal, S. Kumar, D. K. Dhaked,
R. K. Tiwari, P. V. Bharatam and A. K. Verma, J. Org.
Chem., 2012, 77, 8562.
(8) (a) Q. Huang, J. A. Hunter and R. C. Larock, J. Org.
Chem., 2002, 67, 3437; (b) K. C. Nicolaou, P. G. Bulger
and D. Sarlah, Angew. Chem. Int. Ed., 2005, 44, 4442;
(c) B. S. Pilgrim, A. E. Gatland, C. H. A. Esteves, C. T.
McTernan, G. R. Jones, M. R. Tatton, P. A. Procopiou
and T. J. Donohoe, Org. Biomol. Chem., 2016, 14, 1065.
(9) (a) A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges.,
(19) (a) J. Barluenga, H. Vazquez-Vill, A. Ballesteros and J.
M. Gonzalez, J. Am. Chem. Soc., 2003, 125, 9028; (b) A.
B. Beeler, S. Su, C. A. Singleton and J. A. Jr. Porco, J.
Am. Chem. Soc., 2007, 129, 1413; (c) R. Yanada, K.
Hashimoto, R. Tokizane, Y. Miwa, H. Minami, K.
Yanada, M. Ishikura and Y. Takemoto, J. Org. Chem.,
1911, 44, 2030; (b) S. W. Youn, J. Org. Chem., 2006, 71
2521; (c) M. Lorenz, M. L. Van Linn and J. M. Cook,
Curr. Org. Synth., 2010, , 189; (d) E. D. Cox and J. M.
,
7
2008, 73, 5135; (d) X. Yao, C.-J. Li, Org. Lett., 2005, 7
4395; (e) D. Hojo and K. Tanaka, Org. Lett., 2012, 14
,
,
Cook, Chem. Rev., 1995, 95, 1797; (e) S. W. Youn, Org.
Prep. Proced. Int., 2006, 38, 505.
(10) (a) T. Ishikawa, K. Shimooka, T. Narioka, S. Noguchi, T.
Saito, A. Ishikawa, E. Yamazaki, T. Harayama, H. Seki
and K. Yamaguchi, J. Org. Chem., 2000, 65, 9143; (b) X.
Xu, S. Guo, Q. Dang, J. Chen and X. Bai, J. Comb. Chem.,
1492; (f) G. Mariaule, G. Newsome, P. Y. Toullec, P.
Belmont and V. Michelet, Org. Lett., 2014, 16, 4570; (g)
S. Dhara, R. Singha, Y. Nuree, J. K. Ray Tetrahedron
Letters 2014, 55, 795.
(20) (a) M. Tiano and P. Belmont, J. Org. Chem., 2008, 73
,
2007,
9
, 773.
4101; (b) H. D. H. Showalter, A D. Sercel, B. M. Leja, C.
D. Wolfangel, L. A. Ambroso, W. L. Elliott, D. W. Fry, A.
J. Kraker, C. T. Howard, G. H. Lu, C. W. Moore, J. M.
Nelson, B. J. Roberts, P. W. Vincent, W. A. Denny and A.
M. Thompson, J. Med. Chem., 1997, 40, 413; (c) P. K.
Kalita, B. Baruah and P. J. Bhuyan, Tetrahedron Lett.,
2006, 47, 7779.
(11) F. A. Davis, J. Y. Melamed and S. S. Sharik, J. Org.
Chem., 2006, 71, 8761.
(12) H. Zhang and R. C. Larock, J. Org. Chem., 2002, 67
7048.
(13) (a) D. Yang, S. Burugupalli, D. Daniel and Y. Chen, J.
Org. Chem., 2012, 77, 4466; (b) K. Shekarrao, P. P.
,
Kaishap, S. Gogoi, R. C. Boruah, RSC Adv. 2014,
14013; (c)
4,
(21) (a) Y. Ooyama, T. Sat, Y. Harima and J. Ohshita, J.
Mater. Chem. A, 2014, 2, 3293; (b) I. A. Khan, M. V.
(14) S. Kumar, C. Cruz-Hernandez, S. Pal, R. K. Saunthwal,
M. Patel, R. K. Tiwari, E. Juaristi and A. K. Verma, J. Org.
Chem., 2015, 80, 10548.
Kulkarni, M. Gopal, M. S. Shahabuddin and C.-M. Sun,
Bioorg. Med. Chem. Lett., 2005, 15, 3584; (c) B. Fevrier,
G. Dupas, J. Bourguignon and G. Queguiner J.
Heterocycl. Chem., 1993, 30, 1085; (d) B. Xia, W. Ma, B.
Zheng, X. Zhang and B. Fan, Eur. J. Med. Chem., 2008,
43, 1489; (e) M. Vennemann, T. Baer and G. Groeger,
Benzothienopyridines for use as Inhibitors of EG5
Kinesin. U.S. Patent 8,044065 B2, Oct 25, 2011.
(15) (a) S. Roy, S. Roy, B. Neuenswander, D. Hill and Larock,
R. C. J. Comb. Chem. 2009, 11, 1061. (b) N. A. Markina,
R. Mancuso, B. Neuenswander, G. H. Lushington and R.
C. Larock, ACS Comb. Sci., 2011, 13, 265; (c) K. R.
Roesch and R. C. Larock, J. Org. Chem., 2002, 67, 86; (d)
Q. Huang, J. A. Hunter and R. C.; Larock, J. Org. Chem.,
2002, 67, 3437; (e) G. Dai and R. C. Larock, J. Org.
Chem., 2002, 67, 7042; (f) G. Dai and R. C. Larock, J.
Org. Chem., 2003, 68, 920; (g) T. Yao and R. C. Larock, J.
Org. Chem., 2003, 68, 5936; (h) Q. Huang and R. C.
Larock, J. Org. Chem., 2003, 68, 980; (i) Zhang, H.;
Larock, R. C. J. Org. Chem. 2003, 68, 5132; (j) Dai, G.;
(22) (a) B. Voigt, L. Meijer, O. Lozach, C. Schachtele, F.
Totzke and A. Hilgeroth, Bioorg. Med. Chem. Lett.,
2005, 15, 823; (b) R. Menegatti, G. M. S. Silva, G.
Zapata-Sudo, J. M. Raimundo, R. T. Sudo, E. J. Barreiro,
and C. A. M. Fraga, Bioorg. Med. Chem., 2006, 14, 632;
(c) M. Anzini, A. Cappelli, S. Vomero, G. Giorgi, T.
Langer, M. Hamon, N. Merahi, B. M. Emerit, A.
Cagnotto, M. Skorupska, T. Mennini, and J. C. Pinto, J.
Med. Chem., 1995, 38, 2692.
Larock, R. C. Org. Lett., 2002,
(16) (a) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108
4, 193.
,
3395; (b) N. Asao, S. S. Yudha, T. Nogami, Y. Yamamoto,
Angew. Chem., Int. Ed., 2005, 44, 5526; (c) K. Sato, N.
Asao and Y. Yamamoto, J. Org. Chem., 2005, 70, 8977;
(d) N. Asao, K. Sato, Menggenbateer and Y. Yamamoto,
J. Org. Chem. 2005, 70, 3682; (e) Asao, N.; Aikawa, H.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458; (f) N.
Asao, C. S. Chan, K. Takahashi and Y. Yamamoto,
(23) (a) Y. Liang, Y.-X. Xie, J.-H. Li, J. Org. Chem. 2006, 71,
379; (b) B. Liang, M. Dai, J. Chen, Z. Yang, J. Org.
Chem., 2005, 70, 391.
(24) G. Wu, A. L. Rheingold, S. J. Geib, R. F. Heck
Organometallics 1987, 6, 1941.
(25) (a) S. Rudys and I. Cikotiene, Chem. Heterocycl. Comp.,
2007, 44, 1416; (b) T. Xu, G. Liu, Org. Lett., 2012, 14
5416.
,
Tetrahedron, 2005, 61
,
11322; (g) M. Ohtaka, H.
Nakamura and Y. Yamamoto, Tetrahedron Lett., 2004,
45, 7339.
(17) (a) Q. Ding and J. Wu, Org. Lett., 2007, 9, 4959; (b) K.
Gao and J. Wu, J. Org. Chem., 2007, 72, 8611; (c) W.
Sun, Q. Ding, X. Sun, R. Fan and J. Wu, J. Comb. Chem.,
2007, 9, 690; (d) Z. Chen, X. Yang and J. Wu, Chem.
Commun., 2009, 3469; (e) X. Yu and J. Wu, J. Comb.
Chem., 2010, 12, 238; (f) Q. Ding, B. Wang, J. Wu,
Tetrahedron, 2007, 63, 12166.
(18) (a) R. R. Jha, R. K. Saunthwal and A. K. Verma, Org.
Biomol. Chem., 2014, 12, 552; (b) A. K. Verma, D.
Choudhary, R. K. Saunthwal, V. Rustagi, M. Patel and R.
K. Tiwari, J. Org. Chem., 2013, 78, 6657; (c) A. K. Verma,
S. K. R. Kotla, D. Choudhary, M. Patel, and R. K. Tiwari,
J. Org. Chem., 2013, 78, 4386; (d) T. Aggarwal, R. R. Jha,
R. K. Tiwari, S. Kumar, S. K. R. Kotla, S. Kumar, A. K.
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