A thioannulation approach to substituted thiophenes from morita-baylis-hillman acetates of acetylenic aldehydes

Article abstract of DOI:10.1021/jo400567h

A new protocol has been developed for the synthesis of substituted thiophenes under mild and metal-free reaction conditions via the base-promoted thioannulation of Morita-Baylis-Hillman acetates of acetylenic aldehydes with potassium thioacetate involving a tandem allylic substitution/deacetylative 5-exo-dig-thiocycloisomerization. The obtained products provide an entry to 4H-thieno[3,2-c]chromene and thieno[3,2-c]dihydroquinoline.

Full text of DOI:10.1021/jo400567h

Article
pubs.acs.org/joc
A Thioannulation Approach to Substituted Thiophenes from Morita−
Baylis−Hillman Acetates of Acetylenic Aldehydes
Chada Raji Reddy,* Reddi Rani Valleti, and Motatipally Damoder Reddy
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
S
* Supporting Information
ABSTRACT: A new protocol has been developed for the
synthesis of substituted thiophenes under mild and metal-free
reaction conditions via the base-promoted thioannulation of
Morita−Baylis−Hillman acetates of acetylenic aldehydes with
potassium thioacetate involving a tandem allylic substitution/
deacetylative 5-exo-dig-thiocycloisomerization. The obtained
products provide an entry to 4H-thieno[3,2-c]chromene and
thieno[3,2-c]dihydroquinoline.
Scheme 1. Access to Substituted Thiophenes from Alkynyl
Thiols
INTRODUCTION
■
Thiophenes are important motifs in several bioactive natural
products as well as pharmaceuticals.1 Moreover, thiophene
derivatives also serve in organic material science due to their
structural rigidity and distinct electronic properties.2 Although
over the years efforts have been made aimed at the synthesis of
substituted thiophenes, they are limited numbers when
compared to furans or pyrroles. The majority of the methods
involve the substitution of thiophene ring via metalation or
halogenations,3 while thiophene syntheses from the corre-
sponding acyclic precursors are limited.4−8 Among these,
Gewald reaction4 and Paal−Knorr thiophene synthesis5 are
traditional methods in which the sulfur atom is introduced
using elemental sulfur and H2S or Lawesson’s reagent,
respectively, besides others.6,7 Alternatively, thioannulation of
alkynyl thiol is an attractive method to access substituted
thiophenes, and very few such methods are available (Scheme
1).8 In 1993, Marshall and DuBay reported the cyclization of β-
and α-alkynyl thiols under strongly basic conditions using
8a
t
KOtBu in BuOH in the presence of 18-crown-6 (eq 1). In
2000, Gabriele and co-workers described the palladium-
catalyzed cycloisomerization of (Z)-2-en-4-yne-1-thiols (eq
2).8b Recently, they have also reported two more methods,
an iodocyclization8c and palladium-catalyzed heterocyclodehy-
dration of 1-mercapto-3-yn-2-ols (eq 3).8d Although these
methods are efficient, they necessitate preconstruction of the
desired alkynyl thiol. Further, the majority of these methods
require the use of either a metal catalyst or higher temperature
or strong base. In this Article, we report a novel thioannulation
approach for the synthesis of substituted thiophenes under mild
and metal-free conditions starting from easily accessible
Morita−Baylis−Hillman (MBH) acetate of acetylenic alde-
hydes. During our recent studies,9 we envisaged that an
intermolecular allylic substitution of MBH acetate of acetylenic
aldehyde with a suitable thio-reagent followed by deacetylative
intramolecular 5-exo-dig-thiocycloisomerization in one pot
(two C−S bond formations) would be a convenient process
for the synthesis of substituted thiophenes (Scheme 1).
RESULTS AND DISCUSSION
■
To find the suitable reaction conditions for the proposed
thioannulation, MBH acetate 1a, derived from the reaction of
3-phenylpropiolaldehyde with methyl acrylate, was employed as
a model substrate. Initially, compound 1a was treated with
Na2S·9H2O (1 equiv) in CH2Cl2 at room temperature, wherein
the formation of a (Z)-dialkyl thio-ether 3 was observed in 94%
yield (entry 1, Table 1).10,11 Next, few other thio-reagents were
examined, and it was found that the reaction of 1a with KSAc in
the presence of K2CO3 produced the thiophene 2a in 94% yield
(entry 6, Table 1). In the absence of K2CO3, the reaction of 1a
Received: March 18, 2013
© XXXX American Chemical Society
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Table 1. Optimization of Reaction Conditions
a
entry
thio-reagent
Na2S·9H2O
base
solvent
CH2Cl2
T (°C)
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
rt
rt
9
4
3
94
92
KSAc
CH3CN
4
Lawesson’s reagent
NaHS
CH2Cl2
24
20
20
18
20
20
complex mixture
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeOH
2a
2a
2a
2a
2a
49
35
94
41
KSAc
CH3CN/MeOH
MeOH
KSAc
KSAc
DMF/MeOH
THF
KSAc
a
Isolated yield.
a
with KSAc provided the (Z)-allylic thioacetate 4 (entry 2, Table
1).11 While Lawesson’s reagent did not promote the product
formation (entry 3, Table 1), sodium hydrosulfide provided the
thiophene 2a in only 49% yield (entry 4, Table 1). In the series
of examined solvents (CH3CN/MeOH, MeOH, DMF/MeOH,
THF), methanol proved to be the best solvent for this one-pot
reaction (entries 5−8, Table 1).
Table 2. Synthesis of 2,4-Disubstituted Thiophenes
Under the optimized conditions, the scope of this annulation
reaction using a variety of MBH acetates of acetylenic
aldehydes was evaluated (Table 2). The results revealed that
the approach serves as a general and efficient method for the
synthesis of diversely substituted thiophenes in good yields. In
addition, the substitution and their electronic properties on
alkyne were found to have a limited effect on this
thioannulation. MBH acetates 1b and 1c containing p-tolyl
and 1-naphthyl groups on alkyne provided the corresponding
thiophenes 2b and 2c, respectively, in excellent yields (entries
2,3, Table 2). For the substrates bearing aryl substitution with
either electron-donating or electron-withdrawing group on
alkyne functionality, 1d−1g, the reaction proceeded smoothly
to give the desired thiophenes 2d−2g in good yield (entries 4−
7, table 2). The presence of halo groups on phenyl ring
enhances the possibility of synthetic utility of the present
method by structural modification. Heteroaryl-substituted
MBH acetates, 1h (3-indolyl) and 1i (2-thiophenyl), were
also effectively employed in the described reaction (entries 8
and 9, Table 2). The present annulation reaction was equally
successful when applied to MBH acetates derived from
acetylenic aldehydes containing aliphatic substitution on alkyne
functionality, 1j−1l, to give the corresponding thiophenes 2j−
2l, respectively (entries 10−12, Table 2). Additionally, we
extended the scope of MBH acetates derived from different
activated alkenes such as tert-butyl acrylate or methyl vinyl
ketone. Gratifyingly, the annulation reaction of substrates 1m−
1o worked well to furnish thiophenes 2m−2o in good yield
(entries 13−15, Table 2). Treatment of substrate 1p, which
contains two MBH acetate groups tethered to phenyl ring, with
KSAc in the presence of K2CO3 in MeOH resulted in a smooth
reaction to deliver bis-thiophene 2p in 68% yield (Scheme 2).
A possible reaction mechanism is shown in Scheme 3. In the
first step, MBH acetate 1a reacts with KSAc to provide allylic
thioacetate 4.12 Next, K2CO3-mediated deacetylation of 4
provides the thiol 4a,13 which further undergoes 5-exo-dig-
a
Reaction conditions: MBH acetate 1 (1 mmol), KSAc (1.1 mmol),
b
K2CO3 (2.2 mmol), MeOH (5 mL), rt. All of the products were
c
characterized by H, 13C NMR, IR, and MS spectra. Isolated yield.
1
cyclization to yield the intermediate 4b and subsequent
isomerization furnishes the thiophene 2a.8b,14 The intermediate
compounds 4 (entry 2, Table 1) and 4a (at lower temperature)
were isolated and fully characterized. Further, 4 and 4a were
also independently treated with K2CO3 in MeOH, and the
successful formation of 2a was observed in both cases.
B
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Scheme 2. Synthesis of Bis-thiophene 2p
Scheme 5. Synthesis of 4H-Thieno[3,2-c]chromene (12a)
and Thieno[3,2-c]dihydroquinoline (12b)
Scheme 3. Proposed Mechanism for the Thioannulation
Inspired by these results, we predicted that the present
reaction could find potential applications in organic synthesis
because the obtained thiophenes have two reactive sites: (i) C-
5 position and (ii) C-4 ester group, as a handle for additional
diversification. Indeed, this assumption was proved by further
investigation using 2a as a substrate. For example, a direct C5-
substitution was successfully accomplished via an acid-catalyzed
electrophilic substitution reaction of 2a with diphenylmethanol
in the presence of BF3·Et2O (5 mol %) to give 5 in 95% yield.
The treatment of 2a with 4-nitrobenzaldehyde in the presence
of BF3·Et2O (20 mol %) provided the triaryl methane 6 in 79%
yield. Palladium-catalyzed C−H activation of 2a with 4-iodo
toluene in the presence of Pd(OAc)2 gave 7 in 65% yield.
Alternatively, bromination of 2a with NBS in acetonitrile
provided the bromothiophene 6 in 81% yield, which can be
further diversified through Pd-catalyzed coupling reaction
(Scheme 4).
bromide 10. The bromide 10 was used in O-alkylation of 2-
bromophenol to get 11a, and subsequent cyclization through
an intramolecular Pd-catalyzed C−H activation offered the
desired 4H-thieno[3,2-c]chromene (12a) in 78% yield.15
Similarly, N-alkylation of 2-iodo N-tosylaniline with 10 to
11b followed by cyclization gave thieno[3,2-c]dihydroquinoline
(12b) in good yield (85%).
In conclusion, we have developed a new, versatile, and metal-
free method for the synthesis of substituted thiophenes from
MBH acetates of acetylenic aldehydes. A simple base (K2CO3)
promotes the [4 + 1]-thioannulation of KSAc with MBH
acetates through a tandem allylic substitution/deacetylative
thiocycloisomerization (two C−S bond formations). This
strategy complements previously described methods based on
metal-catalyzed cyclization of alkynyl thiols. The utility of the
obtained thiophenes as handy synthons in the construction of
other thiophene-based heterocycles was also demonstrated.
Further, the present method may find various applications
toward novel thiophene-based heterocycles.
In addition, thiophene 2a was conveniently utilized in the
synthesis of 4H-thieno[3,2-c]chromene (12a) and thieno[3,2-
c]dihydroquinoline (12b) as shown in Scheme 5. First, ester
group of 2a was reduced (DIBAL-H) to alcohol 9, which upon
treatment with PBr3 in CH2Cl2 provided the corresponding
a
Scheme 4. C5-Functionalization Reactions of 2a
EXPERIMENTAL SECTION
■
General. Reactions were monitored by thin-layer chromatography
carried out on silica plates using UV-light and anisaldehyde or
potassium permanganate or β-naphthol for visualization. Column
chromatography was performed on silica gel (60−120 mesh) using n-
hexane and ethyl acetate as eluent. Evaporation of solvents was
conducted under reduced pressure at temperatures less than 45 °C.
FTIR spectra were recorded on KBr thin film. 1H NMR and 13C NMR
spectra were recorded in CDCl3 solvent on a 300, 500, and 600 MHz
NMR spectrometer. Chemical shifts δ and coupling constants J are
given in ppm (parts per million) and Hz (hertz), respectively.
Chemical shifts are reported relative to residual solvent as an internal
standard for 1H and 13C (CDCl3: δ 7.26 ppm for 1H and 77.0 ppm for
13C). Mass spectra were obtained on VG 70-70H or LC/MSD trapSL
spectrometer operating at 70 eV using direct inlet system.
a
Reagents and conditions: (a) diphenyl methanol, BF3·Et2O (5 mol
Morita−Baylis−Hillman acetates 1a−1p have been prepared using
the literature procedure9,16 and known compound data as compared to
the reported data. Characterization data for new compounds (1b, c, f,
g, h, l, m, and 1p) are given below.
%), CH2Cl2, rt, 1 h, 95%; (b) 4-nitro benzaldehyde, BF3·Et2O (20 mol
%), CH2Cl2, reflux, 24 h, 79%; (c) 4-iodo toluene, Pd(OAc)2 (10 mol
%), DMA, 80 °C, 12 h, 65%; (d) NBS, CH3CN, 0 °C to rt, 24 h, 81%.
C
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Methyl 3-Acetoxy-2-methylene-5-(p-tolyl)pent-4-ynoate
Dimethyl 5,5′-(1,3-Phenylene)bis(3-acetoxy-2-methylene-
1
1
(1b). 1.02 g, 86%; pale yellow solid; mp 60−62 °C. H NMR (500
pent-4-ynoate) (1p). 0.93 g, 75%; pale yellow oil. H NMR (500
MHz, CDCl3): δ 7.35 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H),
6.52 (d, J = 5.9 Hz, 2H), 6.34 (s, 1H), 3.81 (s, 3H), 2.35 (s, 3H) 2.12
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.2, 164.8, 139.0, 136.6,
131.7, 129.0, 128.9, 118.7, 87.3, 83.0, 62.1, 52.1, 21.4, 20.7. IR (KBr):
νmax = 2950, 2924, 2853, 2230, 1742, 1725, 1510, 1438, 1365, 1252,
1219, 1145, 1026, 975, 921, 815, 528 cm−1. MS (ESI): m/z 295 (M +
Na)+. HRMS (ESI): m/z calcd for C16H16O4Na (M + Na)+, 295.0940;
found, 295.0940.
Methyl 3-Acetoxy-2-methylene-5-(naphthalen-1-yl)pent-4-
ynoate (1c). 1.04 g, 90%; pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ 8.27 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.70 (d, J
= 7.1 Hz, 1H), 7.62−7.49 (m, 2H), 7.45−7.38 (m, 1H), 6.68 (s, 1H),
6.58 (s, 1H), 6.43 (s, 1H), 3.85 (s, 3H), 2.17 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 169.2, 164.8, 136.5, 133.2, 132.9, 130.9, 129.3, 129.1,
128.1, 126.9, 125.7, 124.9, 119.3, 126.3, 88.4, 85.2, 62.2, 52.1, 20.8. IR
(KBr): νmax = 2951, 2229, 1726, 1639, 1437, 1368, 1262, 1222, 1147,
1018, 991, 801, 773 cm−1. MS (ESI): m/z 331 (M + Na)+. HRMS
(ESI): m/z calcd for C19H16O4Na (M + Na)+, 331.0940; found,
331.0940.
Methyl 3-Acetoxy-5-(2-iodophenyl)-2-methylenepent-4-
ynoate (1f). 0.90 g, 80%; white solid; mp 40−41 °C. 1H NMR
(300 MHz, CDCl3): δ 7.83 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 7.7, 1.7
Hz, 1H), 7.31 (dd, J = 7.5, 1.1 Hz, 1H), 7.03 (dd, J = 7.5, 1.7 Hz, 1H),
6.59−6.56 (m, 2H), 6.51 (s, 1H), 3.82 (s, 3H), 2.14 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 169.1, 164.7, 138.6, 136.0, 133.0, 129.9, 129.7,
128.3, 127.6, 100.5, 88.7, 87.3, 61.9, 52.1, 20.7. IR (KBr): νmax = 2950,
1725, 1634, 1434, 1365, 1258, 1219, 1147, 763 cm−1. MS (ESI): m/z
385 (M + H)+. HRMS (ESI): m/z calcd for C15H14O4I (M + H)+,
384.9931; found, 384.9924.
Methyl 3-Acetoxy-2-methylene-5-(3-(trifluoromethyl)
phenyl)pent-4-ynoate (1g). 0.94 g, 82%; pale yellow oil. 1H
NMR (300 MHz, CDCl3): δ 7.72 (s, 1H), 7.67−7.56 (m, 2H), 7.49−
7.41 (m, 1H), 6.54 (d, J = 4.7 Hz, 2H), 6.32 (s, 1H), 3.83 (s, 3H), 2.14
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.2, 164.7, 136.2, 134.9,
129.1, 128.8, 128.7, 128.6, 125.4, 125.5, 122.7, 85.4 (2), 61.8, 52.2,
20.7. IR (KBr): νmax = 2956, 2851, 1749, 1730, 1437, 1369, 1334,
1271, 1224, 1168, 1130, 1034, 805, 696, 605 cm−1. MS (ESI): m/z 349
(M + Na)+. HRMS (ESI): m/z calcd for C16H13F3O4Na (M + Na)+,
349.0658; found, 349.0663.
MHz, CDCl3): δ 7.56 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.8
Hz, 1H), 6.51 (d, J = 5.8 Hz, 4H), 6.30 (s, 2H), 3.82 (s, 6H), 2.13 (s,
6H). 13C NMR (75 MHz, CDCl3): δ 169.2, 164.8, 136.4, 135.3, 132.2,
129.2, 128.4, 122.2, 85.9, 84.6, 61.9, 52.2, 20.8. IR (KBr): νmax = 2924,
2853, 1746, 1727, 1440, 1366, 1261, 1223, 1147, 1019, 974, 809, 686
cm−1. MS (ESI): m/z 461 (M + Na)+. HRMS (ESI): m/z calcd for
C24H22O8Na (M + Na)+, 461.1206; found, 461.1196.
General Procedure for the Preparation of Substituted
Thiophenes (2a−2p). To a solution of MBH acetate (1.0 mmol)
and potassium thioacetate (1.1 mmol) in 5 mL of MeOH was added
potassium carbonate (2.2 mmol) at room temperature. The reaction
mixture was stirred at the same temperature for 4−30 h (Table 2).
After the completion of the reaction (monitered by TLC), the mixture
was evaporated in vacuo. Residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford the
corresponding substituted thiophene.
Methyl 5-Benzylthiophene-3-carboxylate (2a). 218 mg, 94%;
1
pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.32−
7.27 (m, 2H), 7.25−7.18 (m, 4H), 4.10 (s, 2H), 3.81 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 163.1, 144.9, 139.4, 132.9, 131.5, 128.5,
128.4, 126.6, 125.4, 51.9, 35.9. IR (KBr): νmax = 3109, 3025, 2946,
1716, 1458, 1393, 1244, 1084, 740 cm−1. MS (ESI): m/z 233 (M +
H)+. HRMS (ESI): m/z calcd for C13H13O2S (M + H)+, 233.0631;
found, 233.0613.
Methyl 5-(4-Methylbenzyl)thiophene-3-carboxylate (2b).
234 mg, 95%; pale yellow solid, mp 52−54 °C. 1H NMR (300
MHz, CDCl3): δ 7.91 (d, J = 1.5 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H),
7.13 (s, 4H), 4.08 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 163.2, 145.4, 136.4, 136.2, 132.9, 131.4, 129.3, 128.4,
125.2, 51.6, 35.6, 20.9. IR (KBr): νmax = 2950, 2920, 1717, 1460, 1242,
1220, 1082, 989, 772 cm−1. MS (ESI): m/z 247 (M + H)+. HRMS
(ESI): m/z calcd for C14H15O2S (M + H)+, 247.0787; found,
247.0775.
Methyl 5-(Naphthalen-1-ylmethyl)thiophene-3-carboxylate
1
(2c). 237 mg, 84%; pale yellow solid, mp 60−62 °C. H NMR (300
MHz, CDCl3): δ 8.02−7.96 (m, 1H), 7.90−7.85 (m, 2H), 7.79 (d, J =
7.9 Hz, 1H), 7.52−7.36 (m, 4H), 7.20 (d, J = 2.2 Hz, 1H), 4.57 (s,
2H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 163.2, 144.9, 135.2,
133.9, 133.0, 131.5, 131.3, 128.7, 127.8, 126.9, 126.2, 125.7, 125.5,
123.7, 125.4, 51.6, 33.5. IR (KBr): νmax = 2924, 1720, 1539, 1463,
1389, 1241, 1082, 982, 849, 773 cm−1. MS (ESI): m/z 283 (M + H)+.
HRMS (ESI): m/z calcd for C17H15O2S (M + H)+, 283.0787; found,
283.0755.
tert-Butyl 3-(3-Acetoxy-4-(methoxycarbonyl)pent-4-en-1-
yn-1-yl)-1H-indole-1-carboxylate (1h). 0.89 g, 80%; yellow solid;
1
mp 92−93 °C. H NMR (300 MHz, CDCl3): δ 8.14 (d, J = 8.3 Hz,
1H), 7.80 (s, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.40−7.29 (m, 2H), 6.59
(s, 1H), 6.56 (s, 1H), 6.40 (s, 1H), 3.83 (s, 3H), 2.15 (s, 3H), 1.67 (s,
9H). 13C NMR (75 MHz, CDCl3): δ 169.3, 164.9, 148.8, 136.6, 134.5,
130.2, 129.7, 129.1, 125.2, 123.2, 119.9, 115.2, 101.9, 87.2, 84.4, 79.4,
62.3, 52.2, 28.0, 20.8. IR (KBr): νmax = 2978, 2230, 1738, 1633, 1451,
1369, 1262, 1227, 1156, 1098, 1045, 1023, 915, 748, 609 cm−1. MS
(ESI): m/z 420 (M + Na)+. HRMS (ESI): m/z calcd for
C22H23NO6Na (M + Na)+, 420.1418; found, 420.1420.
Methyl 5-(4-Methoxybenzyl)thiophene-3-carboxylate (2d).
215 mg, 82%; pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.91 (s,
1H), 7.19 (s, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H),
4.06 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 163.1, 158.3, 145.7, 132.9, 131.5, 131.3, 129.5, 125.1, 113.9, 55.1,
51.5, 35.1. IR (KBr): νmax = 2951, 2921, 1717, 1611, 1512, 1462, 1248,
1034, 740 cm−1. MS (ESI): m/z 263 (M + H)+. HRMS (ESI): m/z
calcd for C14H15O3S (M + H)+, 263.0736; found, 263.0710.
Methyl 5-(4-Chlorobenzyl)thiophene-3-carboxylate (2e). 195
Methyl 3-Acetoxy-2-methylenetridec-4-ynoate (1l). 0.99 g,
85%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.45 (s, 1H), 6.29 (s,
1H), 6.24 (s, 1H), 3.79 (s, 3H), 2.23 (dt, J = 6.7, 1.5 Hz, 2H), 2.09 (s,
3H), 1.54−1.48 (m, 2H), 1.40−1.33 (m, 2H), 1.32−1.21 (m, 8H),
0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.2, 165.0,
137.0, 128.7, 88.6, 74.8, 62.0, 52.0, 31.7, 29.1, 28.9, 28.7, 28.2, 22.5,
20.8, 18.6, 14.0. IR (KBr): νmax = 2928, 2856, 2236, 1748, 1731, 1269,
1225, 989 cm−1. MS (ESI): m/z 317 (M + Na)+. HRMS (ESI): m/z
calcd for C17H26O4Na (M+Na)+, 317.1723; found, 317.1731.
1
mg, 73%; pale yellow solid; mp 52−53 °C. H NMR (500 MHz,
CDCl3): δ 7.92 (d, J = 1.4 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.20 (s,
1H), 7.16 (d, J = 7.9 Hz, 2H), 4.09 (s, 2H), 3.84 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 163.0, 144.3, 137.9, 133.1, 132.5, 131.6, 129.9,
128.7, 125.6, 51.7, 35.3. IR (KBr): νmax = 3109, 2950, 2917, 1716,
1546, 1462, 1246, 1087, 741 cm−1. MS (ESI): m/z 267 (M + H)+.
HRMS (ESI): m/z calcd for C13H12O2ClS (M + H)+, 267.0241; found,
267.0246.
tert-Butyl 3-Acetoxy-2-methylene-5-phenylpent-4-ynoate
1
(1m). 1.09 g, 94%; pale yellow oil. H NMR (300 MHz, CDCl3): δ
Methyl 5-(2-Iodobenzyl)thiophene-3-carboxylate (2f). 293
mg, 82%; pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J =
1.3 Hz, 1H), 7.85 (dd, J = 7.9, 1.5 Hz, 1H), 7.34−7.28 (m, 1H), 7.27−
7.20 (m, 2H), 6.95 (td, J = 7.7, 1.7 Hz, 1H), 4.24 (s, 2H), 3.83 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 163.1, 143.2, 142.1, 139.6, 132.9,
7.49−7.43 (m, 2H), 7.37−7.29 (m, 3H), 6.51 (s, 1H), 6.43 (s, 1H),
6.23 (s, 1H), 2.13 (s, 3H), 1.51 (s, 9H). 13C NMR (75 MHz, CDCl3):
δ 169.3, 163.6, 138.1, 131.9, 128.8, 128.3, 128.0, 121.9, 87.0, 83.9, 81.7,
62.2, 28.0, 20.9. IR (KBr): νmax = 2972, 2923, 2853, 2230, 1747, 1718,
1367, 1253, 1220, 1145, 1016, 983, 919, 846, 770, 757, 690 cm−1. MS
(ESI): m/z 323 (M + Na)+. HRMS (ESI): m/z calcd for C18H20O4Na
(M + Na)+, 323.1253; found, 323 0.1253.
131.6, 129.8, 128.5, 128.5, 125.9, 100.3, 51.6, 41.0. IR (KBr): νmax
=
2947, 1714, 1634, 1460, 1241, 1082, 1011, 770, 741 cm−1. MS (ESI):
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m/z 359 (M + H)+. HRMS (ESI): m/z calcd for C13H12O2IS (M +
H)+, 358.9597; found, 358.9608.
1453, 1396, 1242, 757, 700 cm−1. MS (ESI): m/z 217 (M + H)+.
HRMS (ESI): m/z calcd for C13H13OS (M + H)+, 217.0682; found,
217.0672.
((Methoxybenzyl)thiophen-3-yl)ethanone (2o). 209 mg, 85%;
yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.83 (s, 1H), 7.21 (s, 1H),
7.15 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.06 (s, 2H), 3.79
(s, 3H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 192.3, 158.3,
146.2, 142.3, 131.5, 131.3, 129.5, 124.2, 114.0, 55.2, 35.2, 29.6. IR
(KBr): νmax = 2925, 2851, 1672, 1610, 1510, 1454, 1246, 1177, 1032,
761 cm−1. MS (ESI): m/z 247 (M + H)+. HRMS (ESI): m/z calcd for
C14H15O2S (M + H)+, 247.0787; found, 247.0804.
Methyl 5-(3-(Trifluoromethyl)benzyl)thiophene-3-carboxy-
late (2g). 228 mg, 76%; pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ 7.95 (d, J = 1.4 Hz, 1H), 7.54−7.41 (m, 4H), 7.23 (d, J =
1.4 Hz, 1H), 4.18 (s, 2H), 3.84 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 163.0, 143.5, 140.3, 133.2,131.9, 131.8, 129.1, 125.9, 125.2, 125.2,
123.7, 123.6, 51.7, 35.7. IR (KBr): νmax = 2953, 1718, 1463, 1332,
1251, 1164, 1124, 1074, 989, 854, 769, 742, 703 cm−1. MS (ESI): m/z
301 (M + H)+. HRMS (ESI): m/z calcd for C14H12F3O2S (M + H)+,
301.0505; found, 301.0511.
tert-Butyl 3-((4-(Methoxycarbonyl)thiophen-2-yl)methyl)-
Dimethyl 5,5′-(1,3-Phenylenebis(methylene))bis(thiophene-
1
1
1H-indole-1-carboxylate (2h). 256 mg, 69%; pale yellow oil. H
3-carboxylate) (2p). 263 mg, 68%; pale yellow oil. H NMR (300
NMR (300 MHz, CDCl3): δ 8.12 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H),
7.56−7.41 (m, 2H), 7.39−7.27 (m, 2H), 7.29−7.04 (m, 1H), 4.21 (s,
2H), 3.83 (s, 3H) 1.67 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 163.2,
143.8, 132.9, 131.4, 129.7, 125.4, 124.5, 124.4, 123.9, 123.6, 122.5,
119.0, 118.6, 115.3, 83.7, 51.7, 29.6, 28.1. IR (KBr): νmax = 2924, 2852,
1724, 1455, 1369, 1303, 1251, 1157, 1079, 1015, 856, 743 cm−1. MS
(ESI): m/z 394 (M + Na)+. HRMS (ESI): m/z calcd for C20H25N2O4S
(M + NH4)+, 389.1535; found, 389.1562.
MHz, CDCl3): δ 7.92 (d, J = 1.3 Hz, 2H), 7.29−7.10 (m, 6H), 4.10 (s,
4H), 3.84 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 163.2, 144.8, 139.9,
133.0, 131.5, 129.0, 128.8, 127.0, 125.5, 51.6, 35.9. IR (KBr): νmax
=
3418, 3108, 2949, 1715, 1460, 1247, 1084, 989, 855, 742 cm−1. MS
(ESI): m/z 387 (M + H)+. HRMS (ESI): m/z calcd for C20H19O4S2
(M + H)+, 387.0719; found, 387.0734.
(2Z,2′Z)-Dimethyl 2,2′-(Thiobis(methylene))bis(5-phenyl-
pent-2-en-4-ynoate) (3). To a solution of MBH acetate (1.0
mmol) in 5 mL of dichloromethane was added Na2S·.9H2O (1.1
mmol) at room temperature. The reaction mixture was stirred at the
same temperature for 9 h. After the completion of the reaction
(monitered by TLC), the mixture was diluted with water (10 mL) and
extracted with dichloromethane (2 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford compound
3 as a pale yellow oil (404 mg, 94%). 1H NMR (300 MHz, CDCl3): δ
7.53−7.44 (m, 4H), 7.40−7.28 (m, 6H), 6.90 (s, 2H), 3.87 (s, 4H),
3.78 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 166.3, 160.4, 137.7,
Methyl 5-(Thiophen-2-ylmethyl)thiophene-3-carboxylate
1
(2i). 215 mg, 90%; pale yellow oil. H NMR (300 MHz, CDCl3): δ
7.94 (s, 1H), 7.29 (dd, J = 2.7, 1.5 Hz, 1H), 7.20−7.17 (m, 1H), 6.94
(dd, J = 5,3, 2.7 Hz, 1H), 6.90−6.87 (m, 1H), 4.32 (s, 2H), 3.84 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 162.9, 144.0, 141.8, 132.9,
131.5, 126.7, 125.5, 125.4, 124.3, 51.5, 30.0. IR (KBr): νmax = 3108,
2950, 2846, 1715, 1544, 1462, 1260, 1234, 770 cm−1. MS (ESI): m/z
239 (M + H)+. HRMS (ESI): m/z calcd for C11H11O2S2 (M + H)+,
239.0195; found, 239.0194.
Methyl 5-Butylthiophene-3-carboxylate (2j). 135 mg, 68%;
pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 1H), 5.78 (t, J
= 7.5 Hz, 1H), 4.13−4.10 (m, 2H), 3.78 (s, 3H), 2.06 (q, J = 7.3 Hz,
2H), 1.55−1.42 (m, 2H), 0.94 (t, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 163.3, 146.5, 130.4, 123.7, 124.3, 51.6, 33.4, 29.5,
22.0, 13.7. IR (KBr): νmax = 3447, 2962, 1719, 1632, 1461, 1240, 749
cm−1. MS (ESI): m/z 237 (M + K)+. HRMS (ESI): m/z calcd for
C10H13O2S (M − H)+, 197.0630; found, 197.0638.
Methyl 5-Heptylthiophene-3-carboxylate (2k). 168 mg, 70%;
pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.10 (s, 1H), 5.77 (t, J
= 7.5 Hz, 1H), 4.11 (s, 2H), 3.77 (s, 3H), 2.07 (q, J = 8.4 Hz, 2H),
1.48−1.41 (m, 2H), 1.36−1.24 (m, 6H), 0.88 (t, J = 6.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 163.4, 146.6, 130.5, 124.4, 123.7, 51.6,
31.7, 31.4, 29.8, 29.0, 28.9, 22.6, 14.0. IR (KBr): νmax = 2926, 2856,
1718, 1460, 1386, 1235, 1086, 767 cm−1. MS (ESI): m/z 241 (M +
H)+. Anal. Calcd for C13H20O2S: C, 64.96; H, 8.39; S, 13.34. Found:
C, 64.88; H, 8.52; S, 13.19.
Methyl 5-Nonylthiophene-3-carboxylate (2l). 166 mg, 62%;
pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.18 (s,
1H), 3.84 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 1.70−1.63 (m, 2H), 1.39−
1.22 (m, 12H), 0.90−0.86 (m, 3H). 13C NMR (75 MHz, CDCl3): δ
163.3, 146.5, 132.8, 130.4, 124.3, 51.6, 39.1, 31.8, 31.3, 29.8, 29.4, 29.2,
28.9, 22.6, 14.0. IR (KBr): νmax = 2926, 2854, 1720, 1543, 1461, 1380,
1240, 1087, 990, 859, 744 cm−1. MS (ESI): m/z 307 (M + K)+. HRMS
(ESI): m/z calcd for C15H23O2S (M − H)+, 267.1413; found,
267.1419.
133.5, 121.3, 114.4, 114.1, 103.4, 84.7, 55.2, 31.1. IR (KBr): νmax
=
2947, 2443, 1935, 1732, 1593, 1517, 1343, 1037, 851 cm−1. MS (ESI):
m/z 431 (M + H)+. HRMS (ESI): m/z calcd for C26H23O4S (M +
H)+, 431.1312; found, 431.1318.
(Z)-Methyl 2-((Acetylthio)methyl)-5-phenylpent-2-en-4-
ynoate (4). To a solution of MBH acetate (1.0 mmol) in 5 mL of
acetonitrile was added potassium thioacetate (1.1 mmol) at room
temperature. The reaction mixture was stirred at the same temperature
for 4 h. After the completion of the reaction, the mixture was
evaporated in vacuo. Residue was purified by column chromatography
on silica gel (EtOAc:hexanes) to afford the compound 4 as a pale
yellow oil (252 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.59−7.54
(m, 2H), 7.40−7.34 (m, 3H), 6.94 (s, 1H), 4.18 (s, 2H), 3.81 (s, 3H),
2.34 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 194.2, 165.9, 137.3,
132.0, 129.4, 128.4, 122.4, 122.1, 104.5, 85.1, 52.2, 30.1, 27.2. IR
(KBr): νmax = 2951, 2195, 1714, 1609, 1437, 1356, 1255, 1095, 758
cm−1. MS (ESI): m/z 297 (M + Na)+. HRMS (ESI): m/z calcd for
C15H14O3NaS (M + Na)+, 297.0556; found, 295.0559.
(Z)-Methyl 2-(Mercaptomethyl)-5-phenylpent-2-en-4-
ynoate (4a). To a solution of MBH acetate (1.0 mmol) and
potassium thioacetate (1.1 mmol) in 5 mL of MeOH was added
potassium carbonate (2.2 mmol) at −5 °C. The reaction mixture was
stirred at −5 to 0 °C for 30 min. After the completion of the reaction
(monitered by TLC), the reaction mixture was diluted with water (15
mL) and extracted with dichloromethane (4 × 10 mL). The combined
organic extracts were washed with brine (10 mL), dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford compound 4a
as a pale yellow solid (150 mg, 65%); mp 122−124 °C. 1H NMR (300
MHz, CDCl3): δ 7.53−7.46 (m, 2H), 7.43−7.31 (m, 3H), 6.76 (s,
1H), 4.30 (s, 2H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 164.4,
144.8, 134.5, 128.5, 128.2, 127.1, 123.4, 97.2. 84.1, 52.0, 40.1. IR
(KBr): νmax = 2924, 2854, 1695, 1597, 1440, 1343, 1232, 1079, 915,
744, 687 cm−1. MS (ESI): m/z 231 (M − H)+. Anal. Calcd for
C13H12O2S: C, 67.21; H, 5.21; S, 13.80. Found: C, 67.28; H, 5.25; S,
13.75.
tert-Butyl 5-Benzylthiophene-3-carboxylate (2m). 141 mg,
88%; pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 2.0
Hz, 1H), 7.33−7.29 (m, 2H), 7.25−7.22 (m, 3H), 7.17 (s, 1H), 4.11
(s, 2H), 1.55 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 162.1, 144.5,
139.6, 135.1, 130.8, 128.6, 128.5, 126.6, 125.6, 80.7, 36.1, 28.1. IR
(KBr): νmax = 3028, 2975, 2927, 1709, 1544, 1456, 1367, 1251, 1163,
1081, 851, 739, 699 cm−1. MS (ESI): m/z 297 (M + Na)+. HRMS
(ESI): m/z calcd for C16H18O2NaS (M + Na)+, 297.0919; found,
297.0920.
1-(5-Benzylthiophen-3-yl)ethanone (2n). 186 mg, 86%; pale
1
yellow oil. H NMR (300 MHz, CDCl3): δ 7.85 (d, J = 1.3 Hz, 1H),
7.36−7.29 (m, 2H), 7.28−7.21 (m, 4H), 4.12 (s, 2H), 2.47 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 192.2, 145.4, 142.3, 139.3, 131.3,
128.6, 128.5, 126.7, 124.4, 36.0, 27.0. IR (KBr): νmax = 2916, 1672,
Methyl 2-Benzhydryl-5-benzylthiophene-3-carboxylate (5).
To a solution of substituted thiophene 2a (1.0 mmol) and
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diphenylmethanol (1.2 mmol) in dichloromethane (5 mL) was added
BF3·Et2O (5 mol %) at 0 °C, and the mixture was stirred at room
temperature for 1 h. After completion of the reaction (monitored by
TLC), the reaction mixture was diluted with water (10 mL) and
extracted with dichloromethane (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc:hexanes) to afford compound
Anal. Calcd for C13H11BrO2S: C, 50.17; H, 3.56; S, 10.30. Found: C,
50.23; H, 3.8; S, 10.42.
(5-Benzylthiophen-3-yl)methanol (9). To a stirred solution of
thiophene 2a (1 g, 4.31 mmol) in CH2Cl2 (50 mL) was added DIBAL-
H (25% w/v in toluene, 9.2 mL, 12.93 mmol) at −78 °C, and the
mixture was stirred at the same temperature for 1 h. The mixture was
warmed to 0 °C, quenched with aqueous saturated sodium potassium
tartarate (20 mL), and the mixture was stirred for 3 h. The aqueous
phase was extracted with ethyl acetate (2 × 10 mL). The combined
organic layer was washed with brine (25 mL), dried over Na2SO4, and
evaporated the organic solvent under reduced pressure. The crude
residue was purified by flash column chromatography (silica gel,
hexanes:EtOAc = 90:10) to give 9 (817 mg, 93%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ 7.36−7.28 (m, 2H), 7.27−7.20 (m,
3H), 7.01 (d, J = 1.5 Hz, 1H), 6.77 (s, 1H), 4.58 (s, 2H), 4.11 (s, 2H).
13C NMR (75 MHz, CDCl3): δ 145.5, 142.3, 140.4, 129.0, 128.9,
1
5 as a white solid (378 mg, 95%); mp 122−123 °C. H NMR (600
MHz, CDCl3): δ 7.31−7.24 (m, 7H), 7.23−7.18 (m, 5H), 7.17−7.14
(m, 3H), 7.11 (s, 1H), 6.57 (s, 1H), 4.00 (s, 2H), 3.68 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 163.3, 156.2, 143.4, 141.5, 139.3, 128.8,
128.5 (2), 128.2, 127.7, 126.9, 126.6 (2), 51.3, 50.4, 35.9. IR (KBr):
νmax = 2950, 2920, 1952, 1717, 1546, 1479, 1292, 1225, 1190, 1147,
1005, 777, 696 cm−1. MS (ESI): m/z 399 (M + H)+. HRMS (ESI): m/
z calcd for C26H23O2S (M + H)+, 399.1413; found, 399.1417.
Dimethyl 2,2′-((4-Nitrophenyl)methylene)bis(5-benzylthio-
phene-3-carboxylate) (6). To a solution of substituted thiophene
2a (1.0 mmol) and 4-nitrobenzaldehyde (1.2 mmol) in dichloro-
methane (5 mL) was added BF3·Et2O (20 mol %) at room
temperature, and the mixture was stirred at reflux for 24 h. After
completion of the reaction (monitored by TLC), the reaction mixture
was diluted with water (10 mL) and extracted with dichloromethane
(3 × 10 mL). The combined organic extracts were washed with brine
(10 mL), dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc:hexanes)
to afford compound 6 as a brown solid (472 mg, 79%); mp 112−114
°C. 1H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz, 2H), 7.58 (s,
1H), 7.38 (d, J = 8.5 Hz, 2H), 7.33−7.28 (m, 5H), 7.20−7.17 (m,
5H), 7.13 (s, 2H), 4.02 (s, 4H), 3.71 (s, 6H). 13C NMR (75 MHz,
CDCl3): δ 162.9, 152.8, 150.2, 146.8, 142.1, 139.0, 129.3, 128.7, 128.6,
128.5, 127.1, 126.7, 123.6, 51.5, 44.8, 35.9. IR (KBr): νmax = 2924,
2851, 1711, 1520, 1484, 1346, 1250, 1201, 1015, 758, 700 cm−1. MS
(ESI): m/z 598 (M + H)+. HRMS (ESI): m/z calcd for C33H28NO6S2
(M + H)+, 598.1352; found, 598.1354.
126.8, 125.2, 120.8, 61.0, 36.5. IR (KBr): νmax = 3028, 2900, 2873,
1602, 1493, 1453, 1019, 770, 698 cm−1. MS (ESI): m/z 205 (M + H)+.
Anal. Calcd for C12H12OS: C, 70.55; H, 5.92; S, 15.70. Found: C,
70.23; H, 5.99; S, 15.64.
2-Benzyl-4-((2-bromophenoxy)methyl)thiophene (11a). To a
stirred solution of alcohol 9 (400 mg, 1.96 mmol) in CH2Cl2 (15 mL)
was added PBr3 (0.40 mL, 1.96 mmol) at 0 °C, and the mixture was
stirred at the same temperature for 30 min. The reaction mixture was
then quenched by the dropwise addition of saturated NaHCO3 (20
mL), and the aqueous phase was extracted with dichloromethane (2 ×
15 mL). The combined organic layer was washed with aqueous
saturated NaHCO3 (2 × 25 mL) and brine (25 mL) and dried over
Na2SO4, and the volatiles were evaporated under reduced pressure to
get the bromide 10.
To a stirred solution of bromide 10 (160 mg, 0.60 mmol) in dry
DMF (3 mL) were added 2-bromophenol (102 mg, 0.60 mmol) and
K2CO3 (166 mg, 1.20 mmol) at room temperature, and the mixture
was stirred at 70 °C for 15 h. The reaction mixture was then diluted by
the addition of ice cold water (15 mL), and the aqueous phase was
extracted with ethyl acetate (2 × 10 mL). The combined organic layer
was washed with brine (25 mL), dried over Na2SO4, and evaporated
under reduced pressure. The crude residue was purified by flash
column chromatography (silica gel, hexanes:EtOAc = 97:3) to give
11a as a pale yellow oil (112 mg, 52%). 1H NMR (300 MHz, CDCl3):
δ 7.54 (d, J = 7.9 Hz, 1H), 7.35−7.18 (m, 6H), 7.16 (s, 1H), 6.92 (d, J
= 8.3 Hz, 1H), 6.88−6.80 (m, 2H), 5.05 (s, 2H), 4.13 (s, 2H). 13C
NMR (75 MHz, CDCl3): δ 154.9, 145.1, 140.0, 137.1, 133.3, 128.6,
128.5, 128.3, 126.5, 124.7, 122.1, 121.3, 113.9, 112.5, 67.1, 36.2. IR
(KBr): νmax = 2921, 1636, 1476, 1277, 1221, 1027, 754, 699 cm−1. MS
(ESI): m/z 383 (M + Na)+. Anal. Calcd for C18H15BrOS: C, 60.17; H,
4.21; S, 8.92. Found: C, 60.33; H, 4.12; S, 9.02.
Methyl 5-Benzyl-2-(p-tolyl)thiophene-3-carboxylate (7). To a
stirred solution of thiophene 2a (100 mg, 0.43 mmol) in
dimethylacetamide (4 mL) waere added 4-iodotoluene (92 mg, 0.43
mmol), KOAc (84 mg, 0.86 mmol) ,and Pd(OAc)2 (9.6 mg, 0.043
mmol) at room temperature. The reaction mixture was stirred at 80 °C
for 12 h. The mixture was then diluted by the addition of ice cold
water (15 mL), and the aqueous phase was extracted with ethylacetate
(2 × 10 mL). The combined organic layer was washed with brine (25
mL), dried over Na2SO4, and the organic solvent was evaporated
under reduced pressure. The crude residue was purified by flash
column chromatography (silica gel, hexanes:EtOAc = 95:05) to give 7
1
as a pale yellow oil (90 mg, 65%). H NMR (300 MHz, CDCl3): δ
N-((5-Benzylthiophen-3-yl)methyl)-N-(2-iodophenyl)-4-
methylbenzenesulfonamide (11b). To a stirred solution of
bromide 10 (200 mg, 0.75 mmol) in dry DMF (4 mL) were added
2-iodo (NTs) aniline (276 mg, 0.75 mmol) and K2CO3 (260 mg, 1.87
mmol) at room temperature, and the mixture was stirred at the same
temperature for 3 h. Next, the mixture was diluted by the addition of
ice cold water (15 mL), and the aqueous phase was extracted with
ethyl acetate (2 × 10 mL). The combined organic layer was washed
with brine (25 mL), dried over Na2SO4, and evaporated under reduced
pressure. The crude residue was purified by flash column
chromatography (silica gel, hexanes:EtOAc = 93:07) to give 11b as
a pale yellow oil (289 mg, 69%). 1H NMR (300 MHz, CDCl3): δ 7.81
(dd, J = 1.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.35−7.10 (m, 8H),
6.95 (dt, J = 7.7, 1.5 Hz, 1H), 6.79 (dd, J = 1.5 Hz, 1H), 6.72 (s, 1H),
6.62 (s, 1H), 4.63 (s, 2H), 4.01 (s, 2H), 2.44 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 143.5, 144.2, 140.9, 140.2, 140.1, 136.6, 135.5, 131.3,
129.7, 129.4, 128.4, 128.1, 126.9, 126.4, 123.6, 124.4, 119.0, 102.5,
50.0, 36.0, 21.5. IR (KBr): νmax = 2921, 2851, 1464, 1348, 1219, 1160,
1089, 809, 772, 713, 568 cm−1. MS (ESI): m/z 582 (M + Na)+. HRMS
(ESI): m/z calcd for C25H23INO2S2 (M + H)+, 560.0209; found,
560.0229.
7.39−7.24 (m, 7H), 7.19 (d, J = 3.0 Hz, 2H), 7.15 (s, 1H), 4.10 (s,
2H), 3.70 (s, 3H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 163.7,
150.1, 142.4, 139.5, 138.3, 130.4, 129.4, 128.7, 128.6, 128.6, 127.4,
126.8, 126.7, 51.4, 36.0, 21.2. IR (KBr): νmax = 2921, 2853, 1717, 1633,
1461, 1375, 1257, 1188, 1081, 1014, 811, 763, 703 cm−1. MS (ESI):
m/z 345 (M + Na)+. HRMS (ESI): m/z calcd for C20H18O2NaS (M +
H)+, 345.0919; found, 345.0918.
Methyl 5-Benzyl-2-bromothiophene-3-carboxylate (8). To a
stirred solution of thiophene 2a (100 mg, 0.43 mmol) in CH3CN (8
mL) was added NBS (90 mg, 0.51 mmol) at 0 °C, and the mixture was
stirred at room temperature for 24 h. The reaction mixture was then
diluted by the addition of ice cold water (15 mL), and the aqueous
phase was extracted with ethyl acetate (2 × 10 mL). The combined
organic layer was washed with brine (25 mL), dried over Na2SO4, and
evaporated the organic solvent under reduced pressure. The crude
residue was purified by flash column chromatography (silica gel,
hexanes:EtOAc = 95:05) to give 8 as a pale yellow oil (109 mg, 81%).
1H NMR (300 MHz, CDCl3): δ 7.36−7.27 (m, 3H), 7.25−7.19 (m,
2H), 7.07 (d, J = 1.5 Hz, 1H), 4.04 (s, 2H), 3.84 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 162.3, 144.6, 138.6, 130.4, 128.7, 128.5, 126.9,
126.5, 117.9, 51.7, 36.1. IR (KBr): νmax = 3450, 3026, 2948, 1716,
1458, 1242, 1022, 988, 769, 698 cm−1. MS (ESI): m/z 313 (M + H)+.
General Procedure for the Preparation of Compounds 12a
and 12b. To a stirred solution of compound 11a or 11b (0.17 mmol)
F
dx.doi.org/10.1021/jo400567h | J. Org. Chem. XXXX, XXX, XXX−XXX

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in dimethyleacetamide (4 mL) were added KOAc (0.34 mmol) and
Pd(OAc)2 (0.017 mmol) at room temperature, and the mixture was
stirred at 80 °C for 3 h. The mixture then was cooled to room
temperature, diluted by the addition of ice cold water (15 mL), and
the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The
combined organic layer was washed with brine (25 mL), dried over
Na2SO4, and evaporated under reduced pressure. Residue was purified
by column chromatography on silica gel (EtOAc:hexanes) to afford
the corresponding product 12a or 12b.
2-Benzyl-4H-thieno[3,2-c]chromene (12a). 37 mg, 78%; pale
yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.40−7.22 (m, 5H), 7.20−
7.14 (m, 1H), 7.13−7.03 (m, 1H), 6.94−6.83 (m, 2H), 6.51 (s, 1H),
5.19 (s, 2H), 4.13 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 151.7,
143.9, 139.8, 131.2, 128.7, 128.6, 128.5, 128.2, 126.6, 125.2, 122.5,
122.4, 121.7, 116.3, 66.3, 36.3. IR (KBr): νmax = 2922, 2851, 1633,
1475, 1217, 1031, 756, 697 cm−1. MS (ESI): m/z 277 (M − H)+.
HRMS (ESI): m/z calcd for C18H13OS (M − H)+, 277.0681; found,
277.0689.
2-Benzyl-5-tosyl-4,5-dihydrothieno[3,2-c]quinoline (12b). 62
mg, 85%; white solid; mp 131−132 °C. 1H NMR (300 MHz, CDCl3):
δ 7.77−7.73 (m, 1H), 7.41−7.27 (m, 4H), 7.25−7.16 (m, 3H), 7.09−
7.03 (m, 1H), 6.97−6.93 (m, 2H), 6.71−6.64 (m, 2H), 6.52 (s, 1H),
4.81 (s, 2H), 4.01 (s, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3):
δ 144.6, 142.8, 139.9, 134.4, 133.1, 132.6, 131.7, 128.6, 128.4, 128.3,
128.2, 128.0, 127.5, 126.9, 126.8, 126.7, 123.3, 122.8, 46.4, 36.4, 21.3.
IR (KBr): νmax = 2924, 2854, 1685, 1637, 1599, 1488, 1450, 1342,
1161, 1090, 1057, 854, 764, 743, 699, 665, 565 cm−1. MS (ESI): m/z
454 (M + Na)+. HRMS (ESI): m/z calcd for C25H22NO2S2 (M + H)+,
432.1086; found, 432.1093.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rajireddy@iict.res.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.R.V. and M.D.R. thank the Council of Scientific and
Industrial Research-New Delhi for the award of fellowships.
C.R.R. is thankful to the Department of Science and
Technology, New Delhi, for funding this project (SR/S1/
OC-66/2011).
(9) (a) Reddy, C. R.; Reddy, M. D.; Srikanth, B. Org. Biomol. Chem.
2012, 10, 4280. (b) Reddy, C. R.; Kumaraswamy, P.; Reddy, M. D.
Org. Biomol. Chem. 2012, 10, 9052. (c) Reddy, C. R.; Reddy, M. D.;
Srikanth, B.; Prasad, K. R. Org. Biomol. Chem. 2011, 9, 6027.
(10) Liu, Y.; Xu, D.; Xu, Z.; Zhang, Y. Heteroat. Chem. 2008, 19, 188.
(11) The Z-stereochemistry of 3 and 4 was determined using NOE
experiment, and no NOE cross peaks were observed between Ha and
Hb protons in both cases.
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