Tandem Approach to Benzothieno- and Benzofuropyridines from o-Alkynyl Aldehydes via Silver-Catalyzed 6-endo-dig Ring Closure

Article abstract of DOI:10.1021/acs.joc.5b01647

An operationally simple silver-catalyzed tandem strategy for the synthesis of benzothienopyridines 7a-t and benzofuropyridines 8a-p by the reaction of o-alkynyl aldehyde 4a-t and 5a-p with tert-butylamine 6 under mild reaction conditions is described. The

Full text of DOI:10.1021/acs.joc.5b01647

Article
pubs.acs.org/joc
Tandem Approach to Benzothieno- and Benzofuropyridines from
o‑Alkynyl Aldehydes via Silver-Catalyzed 6-endo-dig Ring Closure
Sonu Kumar,† Carlos Cruz-Hernandez,‡ Shilpi Pal,† Rakesh K. Saunthwal,† Monika Patel,†
́
Rakesh K. Tiwari,∥ Eusebio Juaristi,‡ and Akhilesh K. Verma*,†,§
†Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007, India
‡Departamento de Química, Centro de Investigacion
́
y de Estudios Avanzados, Apdo. Postal 14-740, Mex
́
ico City 07000, Mexico
§School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India
∥Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California
92618, United States
S
* Supporting Information
ABSTRACT: An operationally simple silver-catalyzed tandem strategy for the synthesis of benzothienopyridines 7a−t and
benzofuropyridines 8a−p by the reaction of o-alkynyl aldehyde 4a−t and 5a−p with tert-butylamine 6 under mild reaction
conditions is described. The present methodology provides a facile conversion of easily accessible o-alkynyl aldehydes into
medicinally useful heterocycles in good to excellent yields under mild and environmentally friendly reaction conditions with
excellent regioselectivity. The developed chemistry has been successfully extended for the selective synthesis of C-4 deuterated
benzothienopyridines 7u−v and benzofuropyridines 8q−r. The role of the ethanolic proton in the reaction was validated by
deuterium-labeling experiments.
to the development of D−π−A dye-sensitized solar cells
(Figure 1, iii).4 As a privileged fragment, the benzofuropyridine
skeleton is another important heterocycle and displays wide
application in pharmaceutical research. Their derivatives have
shown topoisomerase inhibitor activity (Figure 1, iv),5
analgesics,6 antibacterial,7,8b anxiolytics (Figure 1, v),8 Eg5
kinesin inhibitors,9 and phosphodiesterase activity.10 Apart
from the significant biological activity, those compounds were
identified as host materials for green and blue phosphorescent
organic light emitting diodes (PHOLEDs).11
INTRODUCTION
■
Nitrogen- and sulfur-containing fused heterocycles are an
important class of compounds because of their presence in a
variety of pharmaceuticals, natural products, drug-like scaffolds,
as well as organic materials.1 Among them, the reduced and
oxidized forms of benzothienopyridines exhibit a wide range of
biological activities including as an appetite depressant (Figure
1, i)2 and anticonflict activity (Figure 1, ii).3 In recent years,
benzothienopyridines have received considerable attention due
Over the past few decades, transition-metal-catalyzed organic
transformations using alkyne substrates have emerged as one of
the most widely used protocols for the synthesis of a wide
variety of heterocyclic/carbocyclic compounds and natural-
product-like frameworks toward C−C and C−N bond
formations12 because of the exceptional ability of transition
metals to trigger the π systems at low catalyst loading as well as
tolerance toward various functional groups. Among them,
silver-catalyzed13 tandem cyclization14,15 has gained consid-
erable attention in the past decade because these reactions can
Figure 1. Significant examples of biologically active benzothienopyr-
idine and benzofuropyridine cores.
Received: July 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01647
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Scheme 1. Designed Tandem Approach for the Synthesis of Benzothienopyridines and Benzofuropyridines
Scheme 2. Synthesis of 3-Aryl/alkylethynyl-benzothiophene-2-carbaldehydes and 2-Aryl/alkylethynyl-benzofuran-3-
carbaldehydes
quickly synthesize the complex molecules from simple starting
materials.
reaction of (E)-4-(2-hydroxyphenyl)but-3-en-2-ones with α-
bromo ketones (Scheme 1, iii).
Previously, tetrahydrobenzothieno[2,3-c]pyridines and
dihydrobenzothieno[2,3-c]pyridines were synthesized using
Pictet−Spengler16 and Bischler−Napieralski reactions.17 In
2002 Larock and co-workers18 reported a well-designed
synthesis of β-carbolines starting from 3-iodo-1-methyl-1H-
indole-2-carbaldehyde via formation of imine intermediate
followed by reaction with alkynes under palladium catalysis
(Scheme 1, i). In 2012 Chen and co-workers19 reported the
palladium-catalyzed tandem synthesis of isoquinolines, thieno-
pyridines, and furopyridines by the reaction of o-haloaldehydes
with a variety of alkynes under microwave irradiation (Scheme
1, ii). Recently, Yin and co-workers20 reported a metal-free
approach for the synthesis of substituted benzofuropyridines by
Application of tandem/domino/cascade reactions in the
synthesis of heterocycles/carbocycles and natural-products-like
scaffolds using o-alkynyl aldehydes or o-haloaldehydes has been
highlighted recently. Larock,21 Yamamoto,22 Wu,23 and
others24 have made significant contributions in this direction
using alkyne substrate. In a continuation of our interest in the
synthesis of heterocyclic scaffolds25 using o-alkynylaldehydes,
herein we report the synthesis of benzothienopyridines26 and
benzofuropyridines from their corresponding o-alkynylaldehyde
in one-pot operation using environmentally friendly reaction
conditions.
B
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(entries 9 and 10). Use of other catalyst AuCl3, AuCl, Ag2O,
PdCl2, and Cu(OTf)2 was found to be inferior for the reaction
(entries 11−15). However, when the reaction was performed in
the absence of catalyst, we failed to obtain the desired product
7a (entry 16).
RESULTS AND DISCUSSION
■
Synthesis of 3-Aryl/alkylethynyl-benzothiophene-2-
carbaldehydes and 2-Aryl/alkylethynyl-benzofuran-3-
carbaldehydes. Starting substrates 3-aryl/alkylethynyl-benzo-
thiophene-2-carbaldehydes 4a−t and 2-aryl/alkylethynyl-ben-
zofuran-3-carbaldehydes 5a−p required for examining the
scope and generality of this designed chemistry were readily
prepared by the standard Sonogashira coupling of o-
haloaldehydes 1 and 2 with commercially available terminal
alkynes 3a−t (Scheme 2).27
To identify the optimal reaction conditions, a variety of
catalyst and solvents was examined in the reaction of 3-
(phenylethynyl) benzo[b]thiophene-2-carbaldehyde 4a with
tert-butylamine 6. Initially we carried out the reaction of 4a
(0.5 mmol) with 0.52 mmol of tert-butylamine 6 using 10 mol
% AgOTf in 2.0 mL of dichloroethane at 25 °C for 12 h; the
desired product 7a was obtained in 5% yield (Table 1, entry 1).
Synthesis of Substituted Benzo[4,5]thieno[2,3-c]-
pyridine. The scope and generality of the reaction was
examined by employing a variety of o-alkynylbenzo[b]-
thiophene-2-carbaldehydes 4a−t with tert-butylamine 6 for
the synthesis of a diverse library of 3-aryl/alkylbenzo[4,5]-
thieno[2,3-c]pyridine 7a−t (Table 2). The substrates 4b−g
bearing an electron-donating substituent such as Me, Et, n-Bu,
t-Bu, OMe, and NMe2 at para position to the triple bond of the
phenyl ring showed the capability to trigger the 6-endo-dig
cyclization29 and provided the respective desired products 7a−
g in good yields. However, substrates 4h and 4i bearing an
electron-releasing substituent on the ortho and meta position of
the phenyl ring afforded the desired product 7h and 7i
comparatively in similar yields. Substrate 4j bearing an electron-
rich heterocycle thiophene on reaction with amine 6 proved to
be favorable for the reaction and afforded the desired product
7j in 71% yield. Substrate 4k, bearing an OCF3 at the para
position of the phenyl ring, provided the product 7k in 69%
yield. Reaction of substrate 4l bearing two OMe groups at the 3
and 5 position of the phenyl ring provided the product 7l in
68% yield. Exploring the reaction with substrate 4m bearing an
electron-withdrawing −CF3 group at the para position of the
phenyl ring retarded the reaction, and product 7m was obtained
in 65% yield after running the reaction for 55 h.
a
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (mol %)
solvent
temp (°C) time (h) yield (%)
1
AgOTf/10
AgOTf/10
AgOTf/10
AgNO3/10
AgNO3/10
AgNO3/10
AgNO3/20
AgNO3/10
AgNO3/10
AgNO3/10
AuCl3/10
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
MeOH
EtOH
25
70
70
70
65
70
70
70
70
100
70
70
70
70
70
70
12
18
36
36
36
36
36
24
24
36
36
36
36
36
36
36
5
2
30
48
55
60
72
65
60
30
35
53
60
35
28
20
nr
Further exploring the reaction of 3-((4-nitrophenyl)ethynyl)-
benzo[b]thiophene-2-carbaldehyde (4n), bearing a strong
electron-withdrawing nitro group at the para position of the
phenyl ring attached to alkyne, fails to afford the desired
product 7n. o-Alkynylaldehydes 4o and 4p bearing −OMe-
substituted naphthyl and phenanthrene groups, respectively on
the alkyne fruitfully provided the desired products 7o and 7p in
75% and 74% yields, respectively. After obtaining successful
results with aromatic alkynes we further explored the developed
protocol with aliphatic alkynes 4q−s; the reaction proceeded
well and provided the desire products 7q−s in moderate to
good yields; however, an inseparable complex mixture was
obtained when TMS-substituted alkyne 4t was reacted with
tert-butylamine 6. All synthesized products were fully
3
4
5
6
7
EtOH
8
EtOH
9
H2O
10
11
12
13
14
15
16
DMSO
EtOH
AuCl/10
EtOH
Ag2O/10
EtOH
PdCl2/10
EtOH
Cu(OTf)2/10
EtOH
EtOH
1
characterized by H NMR, 13C NMR, HRMS, and finally X-
a
Reactions were performed using 0.5 mmol of 4a and tert-butylamine
6 (0.52 mmol) and catalyst in 2.0 mL of solvent. Isolated yield.
ray crystallographic studies of compound 7i.30
b
Synthesis of Substituted Benzofuro[3,2-c]pyridines.
The benzofuropyridine nucleus represents an important class of
heterocyclic compounds which shows a wide range of
significant biological and pharmaceutical properties.31 After
successful synthesis of a variety of medicinally useful
benzothienopyridines and to gain further insight into the
reaction, we continued our study by examining various oxygen-
containing substrates 5a−p with tert-butylamine 6, which
furnished differently substituted benzofuro[3,2-c]pyridines 8a−
p (Table 3). We observed that reaction of alkynes 5a−p with
tert-butylamine 6 provided the desired products 8a−p in good
yield and less reaction time (36 vs 24 h) in comparison to
benzothienopyridines 7a−t (compare Table 2 vs Table 3).
Reaction of o-alkynylaldehydes 5a with tert-butylamine 6
using optimized reaction conditions provided the desired
product 8a in 74% yield in 24 h (Table 3). o-Alkynylaldehydes
5b−g bearing an electron-releasing substituent on the phenyl
ring attached to the alkyne provided the respective desired
When increasing the reaction time from 12 to 18 h and the
temperature from 25 to 70 °C, the desired product 7a was
obtained in higher yield (Table 1, entries 2 and 3). When
AgNO3 was used as catalyst, a significant improvement in the
yield of the product 7a was observed because silver has superior
alkynophilicity due to π coordination with the carbon−carbon
triple bond (entry 4).28 Interesting use of MeOH as solvent
provided the product 7a selectively in 60% yield (entry 5).
However, when reaction was performed using ecofriendly
solvent EtOH at 70 °C for 36 h, the desired product 7a was
obtained in 72% yield (entry 6). No significant effect on the
yield of product 7a was observed by increasing the catalyst
loading (entry 7). A decrease in the reaction time from 36 to 24
h gave the product 7a in lower yield (entry 8). When the
reactions were carried out in water and DMSO, the desired
product 7a was obtained in 30% and 35% yields, respectively
C
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a
Table 2. Silver-Catalyzed Tandem Synthesis of Benzothienopyridines
a
Reactions were performed using 0.5 mmol of o-alkynylaldehydes 4a−t, tert-butylamine 6 (0.52 mmol), and AgNO3 (10 mol %) in 2.0 mL of EtOH
b
c
d
e
at 70 °C for 36 h. Isolated yield. Time = 55 h. Inseparable complex mixtures. Time = 65 h.
products 8b−g in good to excellent yields. For substrate 5h
bearing a strong electron-donating group such as the thienyl
group as R, the reaction proceeded well and afforded the
product 8h in 81% yield; however, reaction of 5i with an OCF3
group at the para position of the phenyl ring provided the
product 8i in 74% yield. Reaction of o-alkynylaldehyde 5j−k
with an electron-withdrawing group (m-OMe and 3,5 di-OMe)
on the phenyl ring afforded the desired products 8j−k in 72%
and 70% yields, respectively. Substrate 5l with a phenoxymethyl
group successfully provided the desired product 8l in 64%
yield; however, alkyl-substituted o-alkynylaldehydes 5m and 5n
gave the desired products 8m and 8n in 62% and 66% yields,
respectively, after running the reaction for 45 h. TMS-
substituted alkyne 5o failed to provide the desired product
8o. When we carried out the reaction of 2-(6-hydroxyhex-1-yn-
1-yl)benzofuran-3-carbaldehyde 5p with tert-butylamine 6 the
desired product 8p was obtained in 55% yield (Table 3).
Encouraged by the above results, we explored the reaction
with the regioisomer of o-alkynylaldehydes; the tandem
cyclization of 3-ethynylbenzofuran-2-carbaldehyde 5q and 5r
with tert-butylamine 6 provided the fused products 3-
arylbenzofuro [2,3-c]pyridine 9a and 9b in 75% and 80%
yields, respectively (Scheme 3).
performed a comparison of the reactivity between two
nucleophiles (amine vs alcohol). We carried out the reaction
of substrate 5a with tert-butylamine (6) and tert-butanol (10) in
DCE at 70 °C for 24 h; product 8a was obtained in 70% yield;
however, 1-(tert-butoxy)-3-phenyl-1H-pyrano[4,3-b]-
benzofuran (11) was not obtained. The possible reason for
the formation of product 8a over product 11 could be due to
preferential formation of imine intermediate Y over hemiacetal
intermediate Z (Scheme 4, i).32
It is apparent that products 7a−t synthesized from substrate
4a−t required a longer reaction time in comparison to products
8a−p/9a−b synthesized from substrate 5a−r. To validate the
reactivity behavior of the substrates, we performed a control
experiment. We carried out reaction between substrates 4a (1.0
equiv) and 5q (1.0 equiv) with tert-butylamine (1.2 equiv)
using optimized reaction conditions for 36 h (Scheme 4, ii).
These results show that the benzofuropyridine 9a was obtained
in 70% yield; however, product 7a was observed in a trace
amount. This result indicates that substrate benzofuran-2-
carbaldehyde (5q) is more reactive in comparison to substrate
benzothiophene-2-carbaldehyde (4a). The above observation
could be explained on the basis of the reactivity behavior of o-
alkynylaldehydes. In the case of 3-(arylethynyl)benzo[b]-
thiophene-2-carbaldehydes (4), the presence of an electron-
rich thiophene ring system (+R effect)25c decreases the
reactivity of the aldehydic group as well as intramolecular
Competitive Study. In order to understand the regio- and
chemoselectivity of the reaction, we designed two sets of
experiments (Scheme 4). In the first set of experiments we
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a
Table 3. Silver-Catalyzed Tandem Synthesis of Benzofuropyridines
a
Reactions were performed using 0.5 mmol of o-alkynylaldehydes 5a−p, amine 6 (0.52 mmol), and AgNO3 (10 mol %) in 2.0 mL of EtOH at 70 °C
b
c
d
for 24 h. Isolated yield. Time = 45 h. Inseparable complex mixtures.
5). This study also supports our proposed mechanism and role
of ethanol as a solvent in the reaction.
Scheme 3. Silver-Catalyzed Tandem Synthesis of
Benzofuropyridinesa
On the basis of the above control experiments, a plausible
mechanism for the formation of products 7a−v and 8a−r is
described in Scheme 6. The reaction of o-alkynyl aldehyde 4
and 5 with tert-butylamine 6 will form imine intermediates P
and P′. Under silver catalysis intramolecular attack of imine
nitrogen on alkyne will generate quinolinium intermediate Q
and Q′. Subsequently, deuteration/protonation (from MeOD
or ethanol) followed by elimination of isobutylene34 with the
help of methoxide ion will result in the formation of products 7
and 8 via formation of intermediate R, R′ and S, S′.
attack of imine on alkyne, whereas in case of 3-(arylethynyl)-
benzofuran-2-carbaldehydes (5) the presence of a compara-
tively less electron-rich furan ring system (due to the −I effect)
increases the relative reactivity of the aldehydic group of 5,
which facilitates formation of the key intermediate imine
(Scheme 4, ii). The reaction of 2-(phenylethynyl)benzofuran-3-
carbaldehyde (5a, 1.0 equiv) and 3- phenylethynyl)benzofuran-
2-carbaldehyde (5q, 1.0 equiv) with tert-butylamine (1.2 equiv)
using optimized reaction conditions for 24 h provided the fused
product 9a in 65% yield; however, the product 8a was obtained
in only 10% yield. The higher reactivity of substrate 5q over 5a
is due to the −I effect of the oxygen (Scheme 4, iii).
Synthesis of Deuterated Compounds. In recent years
synthesis of deuterated compounds and deuterated drugs has
gained significant attention in the pharmaceutical industry
because of the medicinal value and their application in the
study of metabolism of drugs and toxic substances in the
animals.33 To further extend the scope of the developed
chemistry, we synthesized deuterated benzothienopyridine 7u
and 7v and benzofuropyridine 8q−r from respective starting
substrates in moderate to good yields using MeOD as solvent
as well as a source of deuterium under silver catalysis (Scheme
CONCLUSION
■
In conclusion, we developed a versatile and environmentally
benign tandem protocol which provided a broad range of
functionalized benzothienopyridines and benzofuropyridines in
good to excellent yield from easily accessible starting substrates
with excellent regioselectivity. This developed chemistry has
been successfully extended for the selective synthesis of C-4
deuterated benzothienopyridines and benzofuropyridines.
Selective formation of C-4 deuterated products further supports
the proposed mechanism as well as the role of alcohol (solvent)
in the reaction. Alkynes bearing electron-releasing, electron-
withdrawing, alkyl, acyl, and thienyl groups successfully
provided the desired products in good yields. Substrates 2-
(phenylethynyl)benzofuran-3-carbaldehydes 5a−p were found
to be more reactive in comparison to 3-(phenylethynyl)benzo-
[b]thiophene-2-carbaldehydes 4a−t, as validated by the control
experiments. Developed tandem approach is general and
operationally simple and expands the synthetic utility of o-
alkynyl aldehydes for the synthesis of a variety of
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Scheme 4. Competitive Study
deuterated solvent. Chemical shifts were reported as parts per million
(δ in ppm) using tetramethylsilane (TMS) as internal standard or by
reference to proton resonances resulting from incomplete deuteration
of the NMR solvent. The following abbreviations were used to
describe the multiplicities: when appropriate s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, dd = doublet of doublet.
Reactions were monitored using thin-layer chromatography on
commercially prepared silica gel plates and visualized by either UV
irradiation or by staining with I2. Chemical yields are referred to the
pure isolated substances. Chromatographic purification of the label
compounds was accomplished by column chromatography using 100−
200 mesh size silica gels.
Scheme 5. Synthesis of C-4 Deuterated Benzothieno- and
Benzofuropyridines
General Procedure for the Synthesis of Starting Materials 4
and 5. The starting materials 4 and 5 were prepared by the
Sonogashira coupling reaction27 of corresponding 2-bromobenzofur-
ancarbaldehyde and bromobenzothiophenecarbaldehyde with terminal
alkynes using the reported procedure and confirmed by comparison of
its physical and spectral data (1H NMR, 13C NMR, and HRMS), and
infrared spectra were recorded on a FTIR spectrophotometer. The
structure and purity of known starting materials 4a, 4b, 4e, 4f, 4j, 4m,
4s, 4t, and 5a were confirmed by comparison of their physical and
spectral data (1H NMR and 13C NMR) with those reported in the
literature.35
benzothienopyridines and benzofuropyridines which are of
great importance in medicinal chemistry.
3-((4-Ethylphenyl)ethynyl)benzo[b]thiophene-2-carbaldehyde
(4c). The product was obtained as yellow needles (223.5 mg, 77%):
mp 116−118 °C; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.07
(d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.50−7.42 (m, 4H), 7.18
(d, J = 7.6 Hz, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.99 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 184.6, 146.2, 143.1, 141.0, 139.4,
EXPERIMENTAL SECTION
■
General Information and Method. Nuclear magnetic resonance
spectra were recorded in CDCl3, 1H NMR (400 MHz) and 13C NMR
(100 MHz), at ambient temperature. Chemical shifts (δ) for all
protons are reported in parts per million (ppm) and were measured
relative to the residual CHCl3 resonance as an internal reference in the
132.0, 128.8, 128.2, 125.5, 125.1, 123.3, 119.0, 99.4, 80.0, 28.9, 15.3;
F
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Scheme 6. Plausible Mechanism
FTIR (Zn−Se ATR, cm−1) 2961, 2919, 2193, 1663, 833; HRMS (ESI)
calcd for [C19H14OS] requires [M + H]+ 291.0844, found 291.0861.
3-((4-Butylphenyl)ethynyl)benzo[b]thiophene-2-carbaldehyde
128.9, 127.1, 125.7, 124.9, 123.4, 121.1, 120.6, 119.0, 97.3, 81.3; FTIR
(Zn−Se ATR, cm−1) 2923, 2202, 1663, 1200, 854; HRMS (ESI) calcd
for [C18H9F3O2S] requires [M + Na]+ 369.0173, found 369.0166.
3-((3,5-Dimethoxyphenyl)ethynyl)benzo[b]thiophene-2-carbal-
dehyde (4l). The product was obtained as yellow needles (238.5 mg,
74%): mp 140−144 °C; 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H),
8.08−8.06 (m, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.50−7.42 (m, 2H), 6.70
(d, J = 2.4 Hz, 2H), 6.4 (t, J = 2.4 Hz, 1H), 3.76 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 184.5, 160.7, 143.5, 141.0, 139.3, 128.8, 127.6,
125.6, 125.0, 123.3, 123.0, 109.6, 102.8, 99.0, 80.0, 55.5; FTIR (Zn−Se
ATR, cm−1) 2961, 2919, 2210, 1663, 1259, 796, 758; HRMS (ESI)
calcd for [C19H14O3S] requires [M]+ 322.0664, found 322.0664.
3-((4-Nitrophenyl)ethynyl)benzo[b]thiophene-2-carbaldehyde
(4n). The product was obtained as brown needles (208.9 mg, 68%):
mp 116−118 °C; 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.25−
8.22 (m, 2H), 8.07 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.74−
7.71 (m, 2H), 7.54−7.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
183.9, 147.7, 144.7, 141.0, 139.1, 133.4, 132.7, 129.1, 128.6, 125.9,
124.8, 123.9, 123.7, 123.4, 96.3, 85.1; FTIR (Zn−Se ATR, cm−1) 2933,
2333, 1694, 1510, 1310; HRMS (ESI) calcd for [C17H9NO3S] requires
[M]+ 307.0303, found 307.0301.
1
(4d). The product was obtained as a brown oil (238.8 mg, 75%); H
NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.08−8.06 (m, 1H), 7.81−
7.78 (m, 1H), 7.49−7.41 (m, 4H), 7.17−7.15 (m, 2H), 2.58 (t, J = 7.7
Hz, 2H), 1.58−1.51 (m, 2H), 1.34−1.25 (m, 2H), 0.86 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 184.6, 145.0, 143.0, 141.0,
139.4, 131.90, 131.87, 128.79, 128.76, 128.1, 125.5, 125.1, 123.3,
118.9, 99.5, 80.0, 35.7, 33.3, 22.3, 13.9; FTIR (Zn−Se ATR, cm−1)
2955, 2861, 2202, 1668, 838; HRMS (ESI) calcd for [C21H18OS]
requires [M]+ 318.1078, found [M]+ 318.1078.
3-((4-(Dimethylamino)phenyl)ethynyl)benzo[b]thiophene-2-car-
baldehyde (4g). The product was obtained as a pale yellow needles
1
(250.1 mg, 82%): mp 126−130 °C; H NMR (400 MHz, CDCl3) δ
10.36 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.46−
7.37 (m, 4H), 6.60 (d, J = 8.40 Hz, 2H), 2.94 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 184.7, 150.8, 141.6, 141.1, 139.4, 133.3, 129.2, 128.7,
125.3, 125.1, 123.2, 111.7, 108.0, 101.4, 79.4, 40.1; FTIR (Zn−Se
ATR, cm−1) 2923, 2852, 2193, 1655, 1267, 816; HRMS (ESI) calcd
for [C19H15NOS] requires [M]+ 305.0874, found 305.0875.
3-(o-Tolylethynyl)benzo[b]thiophene-2-carbaldehyde (4h). The
product was obtained as yellow needles (210.0 mg, 76%): mp 128−
134 °C; 1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 8.05 (d, J = 7.6
Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48−7.41
(m, 2H), 7.26−7.20 (m, 2H), 7.17−7.13 (m, 1H), 2.51 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 184.4, 143.1, 141.0, 140.5, 139.3, 132.4,
129.8, 129.6, 128.8, 128.0, 125.9, 125.6, 124.9, 123.3, 121.7, 98.0, 84.3,
21.0; FTIR (Zn−Se ATR, cm−1) 2923, 2844, 2189, 1655; HRMS
(ESI) calcd for [C18H12OS] requires [M]+ 276.0609, found 276.0609.
3-(m-Tolylethynyl)benzo[b]thiophene-2-carbaldehyde (4i). The
product was obtained as yellow needles (201.7 mg, 73%): mp 121−
128 °C; 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.05−8.03 (m,
1H), 7.77−7.75 (m, 1H), 7.46−7.40 (m, 2H), 7.38−7.34 (m, 2H),
7.21 (t, J = 7.3 Hz, 1H), 7.15−7.13 (m, 1H), 2.30 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 184.4, 143.1, 140.9, 139.3, 138.3, 132.4, 130.4,
129.0, 128.8, 128.4, 127.8, 125.5, 124.9, 123.2, 121.6, 99.3, 80.1, 21.2;
FTIR (Zn−Se ATR, cm−1) 2921, 2854, 2199, 1666, 688, 801; HRMS
(ESI) calcd for [C18H12OS] requires [M]+ 276.0609, found [M]+
276.0608.
3-((6-Methoxynaphthalen-2-yl)ethynyl)benzo[b]thiophene-2-
carbaldehyde (4o). The product was obtained as yellow needles
1
(273.6 mg, 80%): mp 150−154 °C; H NMR (400 MHz, CDCl3) δ
10.44 (s, 1H), 8.15−8.12 (m, 1H), 8.03 (s, 1H), 7.83−7.81 (m, 1H),
7.69 (d, J = 8.7 Hz, 2H), 7.56−7.54 (m, 1H), 7.50−7.46 (m, 2H),
7.14−7.12 (m, 1H), 7.08−7.07 (m, 1H), 3.87 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 184.6, 158.9, 143.1, 141.1, 139.4, 134.8, 132.2, 129.5,
128.8, 128.7, 128.4, 128.1, 127.2, 125.6, 125.1, 123.3, 119.8, 116.6,
105.9, 99.9, 80.3, 55.4; FTIR (Zn−Se ATR, cm−1) 2961, 2923,
2193,1655, 1263; HRMS (ESI) calcd for [C22H14O2S] requires [M]+
342.0715, found 342.0715.
3-(Phenanthren-9-ylethynyl)benzo[b]thiophene-2-carbaldehyde
(4p). The product was obtained as yellow needles (311.7 mg, 86%):
mp 170−174 °C; 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.65−
8.62 (m, 1H), 8.61−8.58 (m, 1H), 8.43−8.41 (m, 1H), 8.21−8.19 (m,
1H), 8.11 (s, 1H), 7.84−7.81 (m, 2H), 7.69−7.65 (m, 2H), 7.63−7.61
(m, 1H), 7.57−7.53 (m, 1H), 7.51−7.47 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 184.4, 143.5, 141.1, 139.4, 133.4, 130.9, 130.7, 130.6,
130.1, 128.9, 128.8, 128.2, 127.7, 127.43, 127.41, 127.2, 126.5, 125.8,
125.1, 123.4, 123.0, 122.7, 118.3, 97.5, 84.8; FTIR (Zn−Se ATR,
cm−1) 2923, 2197, 1668; HRMS (ESI) calcd for [C25H14OS] requires
[M]+ 362.0765, found 362.0765.
3-((4-(Trifluoromethoxy)phenyl)ethynyl)benzo[b]thiophene-2-
carbaldehyde (4k). The product was obtained as yellow needles
1
(245.8 mg, 71%): mp 90−94 °C; H NMR (400 MHz, CDCl3) δ
10.37 (s, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.60
(d, J = 8.8 Hz, 2H), 7.52−7.44 (m, 2H), 7.21−7.18 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 184.2, 149.8, 143.8, 141.0, 139.3, 133.5,
3-(4-Phenylbut-1-yn-1-yl)benzo[b]thiophene-2-carbaldehyde
(4q). The product was obtained as a pale yellow oil (216.3 mg, 74%);
1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.78−7.72 (m, 2H),
G
DOI: 10.1021/acs.joc.5b01647
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.41 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 6.6 Hz, 1H), 7.29−7.18 (m, 5H),
2.94 (t, J = 8.08 Hz, 2H), 2.83 (t, J = 7.3 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 184.8, 143.3, 141.0, 139.9, 139.7, 128.6, 128.5, 126.6,
125.3, 125.1, 123.1, 99.9, 73.1, 34.6, 21.9; FTIR (Zn−Se ATR, cm−1)
2923, 2852, 2222, 1655; HRMS (ESI) calcd for [C19H14OS] requires
[M]+ 290.0765, found 290.0765.
3-(Cyclopropylethynyl)benzo[b]thiophene-2-carbaldehyde (4r).
The product was obtained as yellow needles (162.9 mg, 72%): mp
117−121 °C; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.93 (d, J
= 7.3 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.45−7.36 (m, 2H), 1.57−
1.51 (m, 1H), 0.98−0.92 (m, 2H), 0.90−0.85 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 184.7, 143.1, 141.0, 139.7, 128.9, 128.6, 125.3,
125.0, 123.1, 104.5, 67.3, 9.4, 0.6; FTIR (Zn−Se ATR, cm−1) 2923,
2852, 2218, 1655; HRMS (ESI) calcd for [C14H10OS] requires [M +
H]+ 227.0531, found 227.0550.
2-(p-Tolylethynyl)benzofuran-3-carbaldehyde (5b). The product
was obtained as light brown needles (226.4 mg, 87%): mp 84−88 °C;
1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.18 (d, J = 6.8 Hz,
1H), 7.54−7.49 (m, 3H), 7.44−7.36 (m, 2H), 7.23 (d, J = 7.6 Hz,
2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.6, 154.6,
148.3, 141.0, 132.0, 129.5, 127.0, 125.1, 123.5, 123.4, 122.4, 117.3,
111.2, 101.4, 21.7; FTIR (Zn−Se ATR, cm−1) 2919, 2827, 2202, 1672,
808; HRMS (ESI) calcd for [C18H12O2] requires [M + H]+ 261.0916,
found 261.0932.
2-((4-Ethylphenyl)ethynyl)benzofuran-3-carbaldehyde (5c). The
product was obtained as yellow needles (235.9 mg, 86%): mp 74−78
°C; 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.08 (d, J = 6.8 Hz,
1H), 7.46 (d, J = 7.6 Hz, 2H), 7.41−7.39 (m, 1H), 7.35−7.27 (m,
2H), 7.16 (d, J = 7.6 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.16 (t, J =
7.64 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 185.5, 154.5, 148.3,
147.2, 132.1, 128.3, 127.0, 125.1, 123.5, 123.4, 122.4, 117.5, 111.2,
101.4, 28.9, 15.2; FTIR (Zn−Se ATR, cm−1) 2961, 2916, 2197, 1676,
837; HRMS (ESI) calcd for [C19H14O2] requires [M + H]+ 275.1072,
found 275.1098.
ATR, cm−1) 2957, 2836, 2197, 1663, 829; HRMS (ESI) calcd for
[C18H12O3] requires [M + H]+ 277.0865, found 277.0881.
2-(Thiophen-3-ylethynyl)benzofuran-3-carbaldehyde (5h). The
product was obtained as brown needles (206.8 mg, 82%): mp 113−
117 °C; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.10 (d, J = 7.6
Hz, 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.43−7.41 (m, 1H), 7.37−7.35 (m,
1H), 7.33−7.29 (m, 2H), 7.21 (d, J = 4.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 185.5, 154.6, 148.0, 132.1, 129.6, 127.1, 126.3, 125.2,
123.7, 123.4, 122.4, 119.6, 111.2, 96.2; FTIR (Zn−Se ATR, cm−1)
2961, 2206, 1668; HRMS (ESI) calcd for [C15H8O2S] requires [M +
H]+ 253.0323, found 253.0352.
2-((4-(Trifluoromethoxy)phenyl)ethynyl)benzofuran-3-carbalde-
hyde (5i). The product was obtained as yellow needles (250.9 mg,
1
76%): mp 92−94 °C; H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H),
8.06 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 9.1 Hz, 2H), 7.39−7.35 (m, 1H),
7.34−7.24 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 185.2, 154.7, 150.3, 147.3, 133.7, 127.2, 125.3, 125.2, 124.1,
123.2, 122.4, 121.0, 119.0, 111.2, 99.1, 77.8; FTIR (Zn−Se ATR,
cm−1) 2965, 2210, 1672, 1154; HRMS (ESI) calcd for [C18H9F3O3]
requires [M + H]+ 331.0582, found 331.0598.
2-((3-Methoxyphenyl)ethynyl)benzofuran-3-carbaldehyde (5j).
The product was obtained as brown needles (223.7 mg, 81%): mp
98−102 °C; 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.17 (d, J =
7.6 Hz, 1H), 7.51−7.49 (m, 1H), 7.44−7.38 (m, 2H), 7.36−7.30 (m,
1H), 7.25−7.22 (m, 1H), 7.13 (s, 1H), 7.02−7.00 (m, 1H), 3.83 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 185.4, 159.4, 154.6, 147.8,
129.8, 127.1, 125.1, 124.6, 123.8, 123.3, 122.4, 121.2, 117.0, 116.5,
111.2, 100.8, 77.3, 55.3; FTIR (Zn−Se ATR, cm−1) 2923, 2852, 2206,
1672, 1284, 683, 875; HRMS (ESI) calcd for [C18H12O3] requires [M
+ H]+ 277.0865, found 277.0885.
2-((3,5-Dimethoxyphenyl)ethynyl)benzofuran-3-carbaldehyde
(5k). The product was obtained as yellow needles (244.8 mg, 80%):
mp 100−104 °C; 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.16
(d, J = 7.6 Hz, 1H), 7.50−7.48 (m, 1H), 7.44−7.35 (m, 2H), 6.75 (s,
2H),6.55−6.54 (m, 1H), 3.81 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 185.4, 160.6, 154.6, 147.8, 127.1, 125.2, 123.9, 123.3, 122.4, 121.5,
111.2, 109.7, 103.7, 101.0, 76.5, 55.5; FTIR (Zn−Se ATR, cm−1) 2921,
2854, 2203, 1683; HRMS (ESI) calcd for [C19H14O4] requires [M +
H]+ 307.0970, found 307.0989.
2-((4-Butylphenyl)ethynyl)benzofuran-3-carbaldehyde (5d). The
product was obtained as a yellow oil (266.0 mg, 88%); 1H NMR (400
MHz, CDCl3) δ 10.27 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.47 (d, J =
7.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.39−7.29 (m, 2H), 7.16 (d, J =
7.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.58−1.50 (m, 2H), 1.33−1.24
(m, 2H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
185.6, 154.6, 148.3, 146.0, 132.1, 128.8, 127.0, 125.1, 123.5, 123.4,
122.4, 117.5, 111.2, 101.5, 35.7, 33.2, 22.3, 13.9; FTIR (Zn−Se ATR,
cm−1) 2961, 2932, 2206, 1672, 846; HRMS (ESI) calcd for
[C21H18O2] requires [M + H]+ 303.1385, found 303.1405.
2-(3-phenoxyprop-1-yn-1-yl)benzofuran-3-carbaldehyde (5l).
The product was obtained as a yellow oil (212.5 mg, 77%);1H
NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.13 (d, J = 7.64 Hz, 1H),
7.46−7.39 (m, 2H), 7.38−7.32 (m, 3H), 7.05−7.01 (m, 3H), 5.03 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 185.3, 157.2, 154.6, 146.5,
129.6, 127.4, 125.3, 124.8, 123.0, 122.5, 122.1, 114.9, 111.3, 96.0, 74.9,
56.1; FTIR (Zn−Se ATR, cm−1) 3062, 2854, 2356, 1672; HRMS
(ESI) calcd for [C18H12O3] requires [M]+ 277.0865, found 277.0881.
2-(Hex-1-yn-1-yl)benzofuran-3-carbaldehyde (5m). The product
2-((4-(tert-Butyl)phenyl)ethynyl)benzofuran-3-carbaldehyde (5e).
The product was obtained as light yellow needles (263.0 mg, 87%):
1
mp 121−125 °C; H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.09
1
(d, J = 6.8 Hz, 1H), 7.50−7.48 (m, 2H), 7.43−7.41 (m, 1H), 7.37−
7.34 (m, 3H), 7.33−7.28 (m, 1H), 1.26 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 185.6, 154.6, 154.0, 148.3, 131.9, 127.0, 125.8, 125.1, 123.5,
123.4, 122.4, 117.3, 111.2, 101.4, 35.0, 31.0; FTIR (Zn−Se ATR,
cm−1) 2963, 2207, 1678, 835; HRMS (ESI) calcd for [C21H18O2]
requires [M + H]+ 303.1385, found 303.1405.
was obtained as a brown oil (162.7 mg, 72%); H NMR (400 MHz,
CDCl3) δ 10.14 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H),7.39−7.37 (m, 1H),
7.33−7.25 (m, 2H), 2.51(t, J = 6.8 Hz, 2H), 1.64−1.57 (m, 2H),
1.49−1.40 (m, 2H), 0.90 (t, J = 6.8 Hz, 3H) 13C NMR (100 MHz,
CDCl3) δ 185.8, 154.2, 148.8, 126.7, 125.0, 123.3, 123.2, 122.2, 111.1,
103.9, 69.1, 29.9, 22.0, 19.5, 13.5; FTIR (Zn−Se ATR, cm−1) 2956,
2868, 2229, 1676; HRMS (ESI) calcd for [C15H14O2] requires [M +
H]+ 227.1072, found 227.1092.
2-(Cyclohexylethynyl)benzofuran-3-carbaldehyde (5n). The
product was obtained as a brown oil (176.6 mg, 70%); 1H NMR
(400 MHz, CDCl3) δ 10.13 (s, 1H), 8.06−8.04 (m, 1H), 7.40−7.36
(m, 1H), 7.33−7.31 (m, 1H), 7.30−7.25 (m, 1H), 2.72−2.67 (m, 1H),
1.86−1.84 (m, 2H), 1.71−1.69 (m, 2H), 1.57−1.46 (m, 2H), 1.37−
1.30 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 185.9, 154.1, 149.0,
126.7, 125.0, 123.1, 122.2, 111.1, 107.6, 93.2, 69.1, 31.7, 29.8, 25.6,
24.6; FTIR (Zn−Se ATR, cm−1) 2930, 2856, 2196, 1707; HRMS
(ESI) calcd for [C17H16O2] requires [M + H]+ 253.1229, found
253.1242.
2-(o-Tolylethynyl)benzofuran-3-carbaldehyde (5f). The product
was obtained as brown needles (218.6 mg, 84%): mp 118−122 °C; 1H
NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H),
7.60−7.58 (m, 1H), 7.51−7.49 (m, 1H), 7.44−7.33 (m, 3H), 7.29−
7.22 (m, 2H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.3,
154.6, 148.1, 141.1, 132.4, 130.3, 129.8, 127.0, 125.9, 125.1, 123.6,
123.3, 122.3, 120.2, 111.2, 100.1, 80.8, 20.7; FTIR (Zn−Se ATR,
cm−1) 2957, 2819, 2197, 1680, 737; HRMS (ESI) calcd for
[C18H12O2] requires [M + H]+ 261.0916, found 261.0931.
2-((4-Methoxyphenyl)ethynyl)benzofuran-3-carbaldehyde (5g).
The product was obtained as yellow needles (248.6 mg, 90%): mp
122−126 °C; 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.08 (d, J
= 7.64 Hz, 1H), 7.50−7.47 (m, 2H), 7.41−7.39 (m, 1H), 7.34−7.27
(m, 2H), 6.84 (d, J = 6.84 Hz, 2H), 3.76 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 185.5, 161.2, 154.4, 148.5, 133.8, 126.8, 125.0, 123.4,
123.2, 122.3, 114.3, 112.2, 111.1, 101.5, 76.3, 55.4; FTIR (Zn−Se
2-((Trimethylsilyl)ethynyl)benzofuran-3-carbaldehyde (5o). The
product was obtained as a brown oil (174.4 mg, 72%); 1H NMR (400
MHz, CDCl3) δ 10.22 (s, 1H), 8.15−8.08 (m, 1H), 7.48−7.40 (m,
2H), 7.38−7.33 (m, 2H), 0.33 (s, 9H); 13C NMR (100 MHz, CDCl3)
H
DOI: 10.1021/acs.joc.5b01647
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The Journal of Organic Chemistry
Article
δ 185.5, 154.3, 147.3, 127.2, 126.0, 125.1, 124.3, 122.4, 121.6, 109.2,
91.2, -0.59; FTIR (Zn−Se ATR, cm−1) 2962, 2830, 2158, 1681;
HRMS (ESI) calcd for [C14H14O2Si] requires [M + H]+ 243.0841,
found 243.0861.
ATR, cm−1) 2969, 2932, 1601, 846; HRMS (ESI) calcd for
[C19H15NS] requires [M + H]+ 290.1003, found 290.1023.
3-(4-Butylphenyl)benzo[4,5]thieno[2,3-c]pyridine (7d). The prod-
uct was obtained as yellow needles (115.7 mg, 73%): mp 117−121 °C;
1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.27 (s, 1H), 8.18 (d, J =
7.3 Hz 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.51−
7.46 (m, 1H), 7.44−7.40 (m, 1H), 7.24 (d, J = 8.2 Hz, 2H), 2.60 (t, J =
7.3 Hz, 2H), 1.61−1.53 (m, 2H), 1.35−1.26 (m, 2H), 0.86 (t, J = 7.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.7, 144.2, 143.6, 142.7,
141.4, 136.9, 133.9, 129.0, 128.9, 126.8, 124.8, 123.3, 122.8, 112.1,
35.4, 33.6, 22.3, 14.0; FTIR (Zn−Se ATR, cm−1) 2923, 2857, 1601,
833; HRMS (ESI) calcd for [C21H19NS] requires [M]+ 317.1238,
found 317.1238
2-(6-Hydroxyhex-1-yn-1-yl)benzofuran-3-carbaldehyde (5p). The
1
product was obtained as light yellow oil (150.0 mg, 62%); H NMR
(400 MHz, CDCl3) δ 10.12 (s, 1H), 8.04 (d, J = 8.40 Hz, 1H), 7.36
(d, J = 7.6 Hz, 1H), 7.32−7.22 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 2.55
(t, J = 6.8 Hz, 2H), 1.93 (br s, 1H), 1.73−1.67 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 186.6, 164.5, 154.0, 125.3, 124.5, 121.5, 119.7,
111.1, 97.9, 69.4, 61.7, 34.0, 24.8, 18.6; FTIR (Zn−Se ATR, cm−1)
3441, 2943, 2873, 2207, 1664 1262; HRMS (ESI) calcd for
[C15H14O3] requires [M + H]+ 243.1021, found 243.1041.
3-(4-(tert-Butyl)phenyl)benzo[4,5]thieno[2,3-c]pyridine (7e). The
3-(Phenylethynyl)benzofuran-2-carbaldehyde (5q). The product
1
1
product was obtained as yellow oil (112.5 mg, 71%); H NMR (400
was obtained as yellow needles (221 mg, 90%): mp 94−98 °C; H
MHz, CDCl3) δ 9.08 (s, 1H), 8.26 (s, 1H), 8.17 (d, J = 7.3 Hz, 1H),
7.94 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.49−7.39 (m, 4H),
1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.6, 151.8, 144.2,
142.7, 141.4, 136.7, 134.2, 133.9, 129.0, 126.6, 125.8, 124.8, 123.3,
122.8, 112.2, 34.6, 31.3; FTIR (Zn−Se ATR, cm−1) 2961, 2927, 1597,
837; HRMS (ESI) calcd for [C21H19NS] requires [M]+ 317.1238,
found 317.1239.
NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H),
7.55−7.51 (m, 2H), 7.49−7.44 (m, 2H), 7.33−7.29 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 177.9, 155.3, 152.4, 131.9, 130.0, 129.5,
128.6, 127.4, 124.5, 122.5, 121.7, 115.8, 112.8, 100.0, 76.7; FTIR (Zn−
Se ATR, cm−1) 2920, 2824, 2207, 1675; HRMS (ESI) calcd for
[C17H10O2] requires [M + H]+ 247.0759 found 247.0781.
3-((4-Methoxyphenyl)ethynyl)benzofuran-2-carbaldehyde (5r).
The product was obtained as yellow needles (253 mg, 92%): mp
88−92 °C; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.88 (d, J =
7.6 Hz, 1H), 7.59−7.56 (m, 4H), 7.42−7.38 (m, 1H), 6.94 (d, J = 8.4
Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.0, 160.6,
155.4, 152.2, 133.6, 130.0, 127.5, 124.4, 123.0, 122.6, 114.3, 112.8,
111.5, 100 5, 76.1, 55.4; FTIR (Zn−Se ATR, cm−1) 2958, 2836, 2197,
1665, 830; HRMS (ESI) calcd for [C17H17NS] requires [M + H]+
277.0865 found 277.0884.
General Procedure for the Synthesis of Substituted
Benzothienopyridine 7a−t and 8a−p. In a oven-dried round-
bottom flask, a solution of 3-(arylethynyl)benzo[b]thiophene-2-
carbaldehyde 4a−t and 5a−p (0.5 mmol), 2.0 mL of EtOH, AgNO3
(10 mol %), and tert-butylamine 6 (0.52 mmol) were added under
inert atmosphere. The resulting reaction mixture was heated at 70 °C
for 24−65 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) and then filtered
through a plug of Celite. The layers were separated, and the organic
layer was washed with aqueous 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; 98/02). The structure and
purity of known starting materials were confirmed by comparison of
their physical and spectral data (1H NMR, 13C NMR, and HRMS),
and infrared spectra were recorded on a FTIR spectrophotometer. The
structure and purity of known final product 7a were confirmed by
comparison of their physical and spectral data (1 H NMR and 13C
NMR) with those reported in the literature.36
3-(p-Tolyl)benzo[4,5]thieno[2,3-c]pyridine (7b). The product was
obtained as dark yellow needles (103.26 m g, 75%): mp 118−122 °C;
1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.31 (s, 1H), 8.23 (d, J =
7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.54−
7.50 (m, 1H), 7.48−7.44 (m, 1H), 7.26 (d, J = 7.8 Hz, 2H), 2.36 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 152.6, 144.2, 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 ; FTIR (Zn−Se ATR, cm−1) 2923, 2857, 1597, 816;
HRMS (ESI) calcd for [C18H13NS] requires [M]+ 275.0769, found
275.0769.
3-(4-Ethylphenyl)benzo[4,5]thieno[2,3-c]pyridine (7c). The prod-
uct was obtained as yellow needles (107.0 mg, 74%): mp 119−124 °C;
1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.24−8.22 (m, 1H),
8.15−8.14 (m, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.78−7.75 (m, 1H),
7.47−7.44 (m, 1H), 7.41−7.37 (m, 1H), 7.24 (d, J = 7.6 Hz, 2H), 2.62
(q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.7, 144.9, 144.2, 142.7, 141.4, 137.0, 134.2, 133.9, 129.0,
128.3, 126.9, 124.8, 123.3, 122.8, 112.0, 28.6, 15.5; FTIR (Zn−Se
3-(4-Methoxyphenyl)benzo[4,5]thieno[2,3-c]pyridine (7f). The
product was obtained as yellow needles (113.6 g, 78%): mp 116−
1
120 °C; H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.26 (s, 1H),
8.22 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 7.6 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 9.1
Hz, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 152.4,
144.2, 142.8, 141.4, 133.9, 133.8, 132.2, 129.0, 128.2, 124.8, 123.4,
122.8, 114.2, 111.7, 55.4; FTIR (Zn−Se ATR, cm−1) 2923, 2840,
1601, 1242, 833; HRMS (ESI) calcd for [C18H13NOS] requires [M +
H]+ 292.0796, found 292.0810.
4-(Benzofuro[3,2-c]pyridin-3-yl)-N,N-dimethylaniline (7g). The
product was obtained as yellow needles (109.4 mg, 72%): mp 131−
1
135 °C; H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.26−8.21 (m,
2H), 8.01 (d, J = 9.1 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.54−7.51 (m,
1H), 7.48−7.44 (m, 1H), 6.82 (d, J = 9.1 Hz, 2H), 3.00 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 152.9, 150.8, 143.9, 142.7, 141.3, 134.0,
132.9, 128.8, 127.7, 127.4, 124.6, 123.2, 122.7, 112.3, 110.8, 40.3;
FTIR (Zn−Se ATR, cm−1) 2923, 2848, 1597, 1259, 804; HRMS (ESI)
calcd for [C19H16N2S] requires [M]+ 304.1034, found 304.1035.
3-(o-Tolyl)benzo[4,5]thieno[2,3-c]pyridine (7h). The product was
1
obtained as yellow needles (96.2 mg, 70%): mp 115−119 °C; H
NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.22−7.92 (m, 3H), 7.59−
7.48 (m, 3H), 7.32−7.24 (m, 3H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 154.8, 143.9, 142.3, 141.3, 140.4, 136.0, 134.1, 133.8, 130.7,
129.8, 129.1, 128.2, 125.9, 124.9, 123.3, 122.9, 116.0, 20.4; FTIR (Zn−
Se ATR, cm−1) 2923, 2857, 1597, 741; HRMS (ESI) calcd for
[C18H13NS] requires [M]+ 275.0769, found 275.0769.
3-(m-Tolyl)benzo[4,5]thieno[2,3-c]pyridine (7i). The product was
1
obtained as yellow needles (99.0 mg, 72%): mp 118−122 °C; H
NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.30 (s, 1H), 8.21 (d, J = 7.8
Hz, 1H), 7.86−7.78 (m, 3H), 7.53−7.49 (m, 1H), 7.46−7.42 (m, 1H),
7.35−7.31 (m, 1H), 7.18−7.16 (m, 1H), 2.40 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 152.8, 144.3, 142.8, 141.4, 139.5, 138.5, 134.4, 133.9,
129.4, 129.0, 128.7, 127.7, 124.8, 124.0, 123.3, 122.9, 112.5, 21.6;
FTIR (Zn−Se ATR, cm−1) 2933, 2867, 1601, 770; HRMS (ESI) calcd
for [C18H13NS] requires [M]+ 275.0769, found 275.0770.
3-(Thiophen-3-yl)benzo[4,5]thieno[2,3-c]pyridine (7j). The prod-
uct was obtained as light yellow needles (94.9 mg, 71%): mp 95−99
°C; 1H 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, 144.2, 141.5, 134.0, 129.1, 128.6,
128.4, 127.9, 127.4, 127.0, 124.9, 123.4, 123.1, 122.9, 112.2; FTIR
(Zn−Se ATR, cm−1) 2919, 1597, HRMS (ESI) calcd for [C15H9NS2]
requires [M]+ 267.0176, found 267.0176.
3-(4-(Trifluoromethoxy)phenyl)benzo[4,5]thieno[2,3-c]pyridine
(7k). The product was obtained as brown needles (119.1 mg, 69%):
mp 117−119 °C; 1H NMR (400 MHz, CDCl3) δ 9.1 (s, 1H), 8.29 (s,
I
DOI: 10.1021/acs.joc.5b01647
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 8.22 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 8.2
Hz, 1H), 7.56−7.51 (m, 1H), 7.49−7.45 (m, 1H), 7.30−7.27 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 151.3, 149.7, 144.6, 142.9, 141.6,
138.3, 135.0, 133.9, 129.4, 128.5, 125.1, 123.6, 123.0, 121.3, 119.3,
112.5; FTIR (Zn−Se ATR, cm−1) 2919, 1601, 1263, 850; HRMS
(ESI) calcd for [C18H10F3NOS] requires [M]+ 345.0435, found
345.0434.
2.0−1.97 (m, 2H), 1.85−1.82 (m, 2H), 1.73−1.70 (m, 1H), 1.61−1.50
(m, 2H), 1.48−1.35 (m, 2H), 1.31−1.17 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 161.3, 143.8, 142.5, 141.3, 133.9, 133.2, 128.8, 124.6,
123.2, 122.7, 112.6, 46.3, 33.4, 26.6, 26.1; FTIR (Zn−Se ATR, cm−1)
2926, 2853, 1599; HRMS (ESI) calcd for [C17H17NS] requires [M +
H]+ 268.1160 found 268.1172.
3-Phenylbenzofuro[3,2-c]pyridine (8a). The product was obtained
1
as yellow needles (90.7 mg, 74%): mp 150−155 °C; H NMR (400
3-(3,5-Dimethoxyphenyl)benzo[4,5]thieno[2,3-c]pyridine (7l).
MHz, CDCl3) δ 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) δ 162.2, 156.3, 156.1, 142.9, 139.4, 129.0,
128.8, 128.1, 127.1, 123.8, 121.6, 121.1, 120.3, 111.9, 103.9; FTIR
(Zn−Se ATR, cm−1) 2924, 2857, 1597; HRMS (ESI) calcd for
[C17H11NO] requires [M + H]+ 246.0919, found 246.0931.
The product was obtained as brown needles (109.2 mg, 68%): mp
1
159−163 °C; H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.30 (s,
1H), 8.22 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.6
Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.24−7.22 (m, 2H), 6.52−6.51 (m,
1H), 3.87 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.2, 152.3,
144.1, 142.7, 141.7, 141.3, 134.8, 133.8, 129.1, 124.9, 123.3, 122.8,
112.6, 105.0, 100.9, 55.5; FTIR (Zn−Se ATR, cm−1) 2959, 2925,
1590, 1259; HRMS (ESI) calcd for [C19H15NO2S] requires [M + Na]+
344.0721, found 344.0717.
3-(p-Tolyl)benzofuro[3,2-c]pyridine (8b). The product was ob-
tained as yellow needles (101.1 mg, 78%): mp 144−148 °C; 1H NMR
(400 MHz, CDCl3) δ 9.28 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.97−
7.95 (m, 2H), 7.87 (s, 1H), 7.61−7.59 (m, 1H), 7.55−7.49 (m, 1H),
7.43−7.39 (m, 1H), 7.31 (d, J = 7.6 Hz, 2H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 162.3, 156.3, 156.1, 142.8, 139.1, 136.6, 129.6,
128.0, 127.0, 123.8, 121.7, 121.1, 120.1, 111.9, 103.6, 21.3; FTIR (Zn−
Se ATR, cm−1) 2921, 2854, 1594, 814; HRMS (ESI) calcd for
[C18H13NO] requires [M + H]+ 260.1075, found 260.1092.
3-(4-(Trifluoromethyl)phenyl)benzo[4,5]thieno[2,3-c]pyridine
(7m). The product was obtained as brown needles (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, 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; FTIR (Zn−Se ATR, cm−1) 2923, 1613, 1325, 1092;
HRMS (ESI) calcd for [C18H10F3NS] requires [M]+ 329.0486, found
329.0487.
3-(6-Methoxynaphthalen-2-yl)benzo[4,5]thieno[2,3-c]pyridine
(7o). The product was obtained as yellow needles (128.0 mg, 75%):
mp 134−138 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.43−
8.39 (m, 2H), 8.23 (d, J = 7.9 Hz, 1H), 8.13−8.11 (m, 1H), 7.83 (d, J
= 7.9 Hz, 1H), 7.79−7.76 (m, 2H), 7.52−7.48 (m, 1H), 7.46−7.42 (m,
1H), 7.11−7.09 (m, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.1, 152.3, 144.1, 142.7, 141.7, 141.4, 134.8, 133.8, 129.1, 124.9,
123.3, 122.9, 112.6, 105.0, 100.9, 55.5; FTIR (Zn−Se ATR, cm−1)
2925, 2858, 1603, 1095; HRMS (ESI) calcd for [C22H15NOS] requires
[M]+ 341.0874, found 341.0874.
3-(Phenanthren-9-yl)benzo[4,5]thieno[2,3-c]pyridine (7p). The
product was obtained as brown needles (133.5 mg, 74%): mp 161−
165 °C; 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.78 (d, J = 8.2
Hz, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J = 7.3 Hz,
1H), 8.13 (d, J = 8.2 Hz, 1H), 7.95−7.93 (m, 3H), 7.70−7.66 (m,
2H), 7.63−7.54 (m, 3H), 7.50−7.46 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 154.0, 144.2, 142.5, 141.4, 137.2, 134.6, 133.8, 131.4, 130.8,
130.6, 130.4, 129.2, 128.9, 128.6, 127.0, 126.8, 126.7, 126.6, 126.57,
124.9, 123.3, 123.0, 122.9, 122.5, 117.0; FTIR (Zn−Se ATR, cm−1)
2921, 1590; HRMS (ESI) calcd for [C25H15NS] requires [M]+
361.0925, found 361.0924.
3-(4-Ethylphenyl)benzofuro[3,2-c]pyridine (8c). The product was
1
obtained as yellow needles (103.8 mg, 76%): mp 136−140 °C; H
NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.95−7.91 (m, 3H), 7.79 (s,
1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45−7.40 (m, 1H), 7.33 (d, J = 7.6 Hz,
1H), 7.26 (d, J = 7.6 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2 156.3, 156.2, 145.4,
142.9, 136.9, 128.4, 128.0, 127.1, 123.8, 121.7, 121.0, 120.0, 111.9,
103.5, 28.6, 15.5; FTIR (Zn−Se ATR, cm−1) 2965, 2927, 1601, 833;
HRMS (ESI) calcd for [C19H15NO] requires [M + H]+ 274.1232,
found 274.1256.
3-(4-Butylphenyl)benzofuro[3,2-c]pyridine (8d). The product was
1
obtained as yellow needles (113.0 mg, 75%): mp 111−114 °C; H
NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.94−7.90 (m, 3H), 7.79 (s,
1H), 7.52 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.32 (t, J = 6.8
Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.60−1.52
(m, 2H), 1.35−1.27 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 162.2, 156.2, 156.2, 144.0, 142.8, 136.8, 128.9, 128.0,
127.0, 123.8, 121.9, 121.0, 120.0, 111.8, 103.5, 35.4, 33.5, 22.3, 13.9;
FTIR (Zn−Se ATR, cm−1) 2952, 2932, 1597, 816; HRMS (ESI) calcd
for [C21H19NO] requires [M + H]+ 302.1545, found 302.1562.
3-(4-(tert-Butyl)phenyl)benzofuro[3,2-c]pyridine (8e). The prod-
uct was obtained as yellow needles (108.4 mg, 72%): mp 146−150 °C;
1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.04−8.00 (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, 126.8, 125.8, 123.8, 121.7, 121.1, 120.1,
111.9, 103.6, 35.2, 31.3; FTIR (Zn−Se ATR, cm−1) 2957, 2935, 1592,
829; HRMS (ESI) calcd for [C21H19NO] requires [M + H]+ 302.1545,
found 302.1568.
3-Phenethylbenzo[4,5]thieno[2,3-c]pyridine (7q). The product
1
was obtained as brown needles (89.7 mg, 62%): mp 88−92 °C; H
NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H),
7.80 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.50−7.46 (m, 1H), 7.42−7.38
(m, 1H), 7.25−7.16 (m, 4H), 7.13−7.11 (m, 1H), 3.21−3.17 (m, 2H),
3.09−3.05 (m, 2H) ; 13C NMR (100 MHz, CDCl3) δ 155.8, 144.0,
142.4, 141.6, 141.3, 133.7, 133.4, 128.9, 128.5, 128.4, 126.0, 124.7,
123.3, 122.8, 114.7, 40.1, 36.5; FTIR (Zn−Se ATR, cm−1) 2923, 2852,
1601; HRMS (ESI) calcd for [C19H15NS] requires [M]+ 289.0925,
found 289.0924.
3-(o-Tolyl)benzofuro[3,2-c]pyridine (8f). The product was ob-
1
tained as yellow needles (94.6 mg, 73%): mp 131−135 °C; H NMR
(400 MHz, CDCl3) δ 9.23 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.56−
7.53 (m, 2H), 7.47−7.41 (m, 2H), 7.35 (t, J = 6.8 Hz,1H), 7.27−7.24
(m, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 158.2,
156.1, 142.5, 140.4, 135.8, 130.8, 129.8, 128.3, 128.1, 125.9, 123.8,
121.5, 121.0, 119.8, 111.8, 107.5, 20.4; FTIR (Zn−Se ATR, cm−1)
2952, 2927, 1605, 746; HRMS (ESI) calcd for [C18H13NO] requires
[M + H]+ 260.1075, found 260.1098.
3-Cyclopropylbenzo[4,5]thieno[2,3-c]pyridine (7r). The product
was obtained as brown needles (76.6 mg, 68%): mp 134−136 °C; 1H
NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H),
7.79−7.74 (m, 2H), 7.49−7.37 (m, 2H), 2.15−2.09 (m, 1H), 1.04−
0.94 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 157.5, 143.9, 142.2,
141.4, 133.6, 132.6, 128.8, 124.6, 123.2, 122.7, 113.0, 17.2, 9.8; FTIR
(Zn−Se ATR, cm−1) 2919, 2857, 1592; HRMS (ESI) calcd for
[C14H11NS] requires [M]+ 225.0612, found 225.0612.
3-(4-Methoxyphenyl)benzofuro[3,2-c]pyridine (8g). The product
was obtained as yellow needles (115.6 mg, 84%): mp 151−155 °C; 1H
NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.03−7.97 (m, 3H), 7.79 (s,
1H), 7.58−7.56 (m, 1H), 7.50−7.46 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H),
7.01 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.2, 160.4, 156.2, 155.7, 142.7, 132.0, 128.3, 127.8, 123.7, 121.7,
120.9, 119.7, 114.1, 111.8, 102.9, 55.3; FTIR (Zn−Se ATR, cm−1)
2998, 2836, 1592, 1255, 837; HRMS (ESI) calcd for [C18H13NO2]
requires [M + H]+ 276.1025, found 276.1051.
3-Cyclohexylbenzo[4,5]thieno[2,3-c]pyridine (7s). The product
1
was obtained as a brown oil (82.8 mg, 62%); H NMR (400 MHz,
CDCl3) δ 8.98 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.82−7.78 (m, 2H),
7.49 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 2.84−2.78 (m, 1H),
J
DOI: 10.1021/acs.joc.5b01647
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-(Thiophen-3-yl)benzofuro[3,2-c]pyridine (8h). The product was
obtained as yellow needles (101.7 mg, 81%): mp 133−137 °C; H
(t, J = 6.1 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.24 (br s, 1H), 1.87−1.80
(m, 2H), 1.64−1.58 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.0,
160.5, 156.0, 142.4, 127.9, 123.7, 121.7, 120.9, 119.5, 111.8, 106.1,
62.3, 37.9, 32.0, 26.2; FTIR (Zn−Se ATR, cm−1) 3245, 2965, 2923,
1592; HRMS (ESI) calcd for [C15H15NO2] requires [M + H]+
242.1181, found 242.1184.
1
NMR (400 MHz, CDCl3) δ 9.1 (s, 1H), 7.95−7.92 (m, 2H), 7.72 (s,
1H), 7.65 (d, J = 5.3 Hz 1H), 7.54−7.53 (m, 1H), 7.44 (t, J = 7.6 Hz,
1H), 7.37−7.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.1,
156.3, 151.9, 142.9, 142.0, 128.1, 126.5, 126.3, 123.9, 123.8, 121.7,
121.0, 120.1, 111.9, 103.6; FTIR (Zn−Se ATR, cm−1) 2980, 1597;
HRMS (ESI) calcd for [C15H9NOS] requires [M + H]+ 252.0483,
found 252.0510.
4D-3-Phenylbenzo[4,5]thieno[2,3-c]pyridine (7u). The product
was obtained as yellow needles (78.7 mg, 60%): mp 114−118 °C;
1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.24 (s, 0.1H), 8.34 (d, J
= 7.6 Hz, 1H), 8.04 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H),
7.55−7.44 (m, 4H), 7.38−7.35 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 152.7, 144.4, 142.7, 141.4, 139.5, 134.6, 133.9, 129.1, 128.8,
128.6, 127.0, 124.9, 123.4, 122.9, 112.5, 112.2 (t, J = 118.2 Hz, 1C);
FTIR (Zn−Se ATR, cm−1) 3057, 2923, 1592; HRMS (ESI) calcd for
[C17H10DNS] requires [M + H]+ 263.0753, found 263.0747.
4D-3-(4-Methoxyphenyl)benzo[4,5]thieno[2,3-c]pyridine (7v).
The product was obtained as yellow needles (93.5 mg, 64%): mp
118−122 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.25 (d, J =
7.63 Hz, 1H), 8.04 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 8.3 Hz, 1H), 7.58−
7.54 (m, 1H), 7.51−7.48 (m, 1H), 7.02 (d, J = 9.1 Hz, 2H), 3.86 (s,
3H) ; 13C NMR (100 MHz, CDCl3) δ 160.2, 152.3, 144.2, 142.7,
141.4, 133.9, 133.8, 132.1, 129.0, 128.2, 124.8, 123.3, 122.8, 114.1,
111.3 (t, J = 110.6 Hz, 1C), 55.3; FTIR (Zn−Se ATR, cm−1) 3056,
2931, 2839, 1602, 1248, HRMS (ESI) calcd for [C18H12DNOS]
requires [M + H]+ 293.0859, found 293.0860.
4D-3-Phenylbenzofuro[3,2-c]pyridine (8q). The product was
obtained as yellow needles (80 mg, 65%): mp 156−160 °C; 1H
NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.98−7.96(m, 2H), 7.89 (d,
J = 7.6 Hz, 1H), 7.49−7.47 (m, 1H), 7.42−7.37 (m, 3H), 7.35−7.27
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.1, 156.2, 155.9, 142.9,
139.3, 128.9, 128.8, 128.0, 127.1, 123.8, 121.5, 121.0, 120.2, 111.8,
103.6 (t, J = 99.2 Hz, 1C); FTIR (Zn−Se ATR, cm−1) 3061, 2923,
1592; HRMS (ESI) calcd for [C17H10DNO] requires [M + H]+
247.0982, found 247.0998.
3-(4-(Trifluoromethoxy)phenyl)benzofuro[3,2-c]pyridine (8i). The
product was obtained as yellow needles (121.8 mg, 74%): mp 150−
1
154 °C; H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.03−8.00 (m,
2H), 7.95 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.54−7.52 (m, 1H), 7.47−
7.43 (m, 1H), 7.36−7.32 (m, 1H), 7.27−7.25 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 162.1, 156.4, 154.5, 149.8, 143.0, 138.0, 128.6,
128.3, 124.0, 121.4, 121.14, 121.11, 120.6, 119.2, 112.0, 103.9; FTIR
(Zn−Se ATR, cm−1) 2927, 1597, 1259, 1150, 846; HRMS (ESI) calcd
for [C18H10F3NO2] requires [M + H]+ 330.0742, found 330.0756.
3-(3-Methoxyphenyl)benzofuro[3,2-c]pyridine (8j). The product
was obtained as yellow needles (99.1 mg, 72%): mp 147−151 °C; 1H
NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.03 (d, J = 8.40 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, 160.0, 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, 104.0, 55.4; FTIR (Zn−Se ATR, cm−1) 2936, 2836,
1605, 1054, 750, 691; HRMS (ESI) calcd for [C18H13NO2] requires
[M + H]+ 276.1025, found 276.1042.
3-(3,5-Dimethoxyphenyl)benzofuro[3,2-c]pyridine (8k). The
product was obtained as yellow needles (109.9 mg, 72%): mp 156−
160 °C; 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.95 (d, J = 7.6
Hz, 1H), 7.79 (s, 1H), 7.54−7.52 (m, 1H), 7.46−7.42 (m, 1H), 7.34
(t, J = 7.6 Hz, 1H), 7.17−7.16 (m, 2H), 3.81 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 162.2, 161.1, 156.4, 155.8, 142.7, 141.6, 128.2, 123.9,
121.6, 121.1, 120.6, 111.9, 105.2, 104.1, 101.4, 55.5; FTIR (Zn−Se
ATR, cm−1) 2950, 2890, 1650, 1110, 1050; HRMS (ESI) calcd for
[C19H15NO3] requires [M + H]+ 306.1130, found 306.1152.
4D-3-(4-Ethylphenyl)benzofuro[3,2-c]pyridine (8r). The product
was obtained as light yellow needles (93.2 mg, 68%): mp 137−141 °C;
1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 9.91 (d, J = 8.4 Hz, 3H),
7.51−7.49 (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6, Hz, 1H),
7.25 (d, J = 8.4 Hz, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.1 156.2, 156.1, 145.3, 142.8,
136.8, 128.3, 127.9, 127.0, 123.7, 121.7, 121.0, 120.0, 111.8, 103.2 (t, J
= 99.2 Hz, 1C), 28.6, 15.5; FTIR (Zn−Se ATR, cm−1) 3032, 2957,
2927, 1592, 829; HRMS (ESI) calcd for [C19H14DNO] requires [M +
H]+ 275.1295, found 275.1296.
3-(Phenoxymethyl)benzofuro[3,2-c]pyridine (8l). The product was
1
obtained as yellow needles (88.0 mg, 64%): mp 134−138 °C; H
NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H),
7.67 (s, 1H), 7.54−7.51 (m, 1H), 7.44 (t, J = 6.8 Hz, 1H), 7.34 (t, J =
7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 6.97−6.95 (m, 2H), 6.91 (t, J =
6.0 Hz, 1H), 5.29 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.0,
158.2, 156.2, 155.9, 142.6, 129.6, 128.2, 123.8, 121.5, 121.2, 121.0,
120.7, 114.8, 112.0, 105.0, 70.4; FTIR (Zn−Se ATR, cm−1) 2923,
2857, 1605, 1054; HRMS (ESI) calcd for [C18H13NO2] requires [M +
H]+ 276.1025, found 276.1051.
3-Phenylbenzofuro[2,3-c]pyridine (9a). The product was obtained
1
as yellow needles (91 mg, 75%); mp 128−132 °C; H NMR (400
MHz, CDCl3) δ 8.98 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 7.6
Hz, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.60−7.54 (m, 2H), 7.51−7.47 (m,
2H), 7.42−7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.1,
152.0, 151.5, 139.6, 133.5, 131.9, 129.8, 128.7, 128.3, 126.9, 123.3,
122.3, 121.9, 112.4, 111.8; FTIR (Zn−Se ATR, cm−1) 2923, 1569,
1449, 1189; HRMS (ESI) calcd for [C17H11NO] requires [M + H]+
246.0919 found 246.0931.
3-Butylbenzofuro[3,2-c]pyridine (8m). The product was obtained
as a yellow oil (100.5 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 9.07
(s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.51−7.49 (m, 1H), 7.43−7.39 (m,
1H), 7.33−7.29 (m, 1H), 7.27 (s, 1H), 2.88 (t, J = 8.0 Hz, 2H), 1.74−
1.67 (m, 2H), 1.39−1.30 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 162.0, 161.0, 155.9, 142.3, 127.8, 123.7, 121.7,
120.9, 119.4, 111.8, 105.9, 38.3, 32.3, 22.4, 13.9; FTIR (Zn−Se ATR,
cm−1) 2925, 2858, 1599; HRMS (ESI) calcd for [C15H15NO] requires
[M + H]+ 226.1232, found 226.1251.
3-Cyclohexylbenzofuro[3,2-c]pyridine (8n). The product was
obtained as a yellow oil (82.9 mg, 66%); 1H NMR (400 MHz,
CDCl3) δ 9.07 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.52−7.50 (m, 1H),
7.45−7.39 (m, 1H), 7.33−7.29 (m, 2H), 2.84−2.78 (m, 1H), 1.99−
1.95 (m, 2H), 1.84−1.80 (m, 2H), 1.72−1.69 (m, 1H), 1.56−1.43 (m,
2H), 1.41−1.34 (m, 2H), 1.29−1.17 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 165.4, 162.1, 156.0, 142.3, 127.7, 124.3, 123.6, 121.8, 121.5,
120.8, 119.4, 111.8, 104.1, 46.8, 33.2, 26.6, 26.0; FTIR (Zn−Se ATR,
cm−1) 2926, 2854, 1599; HRMS (ESI) calcd for [C17H17NO] requires
[M + H]+ 252.1388, found 252.1408.
3-(4-Methoxyphenyl)benzofuro[2,3-c]pyridine (9b). The product
1
was obtained as yellow needles (110 mg, 80%): mp 122−126 °C; H
NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.15 (s, 1H), 8.02−7.98 (m,
3H), 7.62−7.58 (m, 2H), 7.41−7.37 (m, 1H), 7.03−7.01 (m, 2H),
3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 157.2, 151.7,
151.3, 133.4, 132.3, 132.0, 129.8, 128.2, 123.3, 122.4, 122.0, 114.1,
112.4, 111.0, 55.3; FTIR (Zn−Se ATR, cm−1) 2926, 2839, 1607, 1244,
1108; HRMS (ESI) calcd for [C18H14NO2] requires [M + H]+
276.1025 found 276.1041.
ASSOCIATED CONTENT
■
S
* Supporting Information
4-(Benzofuro[3,2-c]pyridin-3-yl)butan-1-ol (8p). The product was
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01647.
1
obtained as brown needles (82.2 mg, 55%): mp 104−108 °C; H
NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H),
7.52−7.50 (m, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.34−7.29 (m, 2H), 3.64
CIF for compounds 7i (CIF)
K
DOI: 10.1021/acs.joc.5b01647
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H and 13C NMR and HRMS spectral data for all new
compounds (PDF)
(d) Ooyama, Y.; Nagano, T.; Inoue, S.; Imae, I.; Komaguchi, K.;
Ohshita, J.; Harima, Y. Chem. - Eur. J. 2011, 17, 14837.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: averma@acbr.du.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Department of Science and
Technology (INT/MEXICO/P-8/2012), UPE-II, Jawaharlal
Nehru University, and University of Delhi. S.K., S.P., R.K.S.,
and M.P. are thankful to the Council of Scientific and Industrial
Research, University Grants Commission, for fellowships. We
gratefully acknowledge USIC-University of Delhi and AIRF-
JNU for providing the instrumentation facilities.
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