Synthesis of benzothiophene derivatives by Pd-catalyzed or radical-promoted heterocyclodehydration of 1-(2-Mercaptophenyl)-2-yn-1-ols

Article abstract of DOI:10.1021/jo201471k

Novel and convenient approaches to benzothiophene derivatives 3 and 5 have been developed, based on heterocyclization reactions of 1-(2-mercaptophenyl)-2- yn-1-ols 2 or 4, respectively, readily available from alkynylation of 2-mercaptobenzaldehydes or 1-(2-mercaptophenyl) ketones 1. In particular, 1-(2-mercaptophenyl)-2-yn-1-ols 2, bearing a CH₂R substituent on the triple bond (R = alkyl, aryl), were conveniently converted in fair to good yields (55-82%) into (E)-2-(1-alkenyl)benzothiophenes 3 when allowed to react in the presence of catalytic amounts (2 mol %) of PdI₂ in conjunction with KI (KI:PdI₂ molar ratio =10) at 80-100 °C in MeCN as the solvent, through a heterocyclodehydration process. On the other hand, 2-alkoxymethylbenzothiophenes 5 were selectively obtained in fair to excellent yields (49-98%) via a radical-promoted substitutive heterocyclodehydration process, by reacting 1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an alkyl or aryl substituent on the triple bond) in alcoholic media at 80-100 °C in the presence of a radical initiator, such as AIBN.

Full text of DOI:10.1021/jo201471k

ARTICLE
pubs.acs.org/joc
Synthesis of Benzothiophene Derivatives by Pd-Catalyzed
or Radical-Promoted Heterocyclodehydration
of 1-(2-Mercaptophenyl)-2-yn-1-ols
Bartolo Gabriele,*,† Raffaella Mancuso,‡ Elvira Lupinacci,‡ Lucia Veltri,‡ Giuseppe Salerno,‡ and
Carla Carfagna§
†Dipartimento di Scienze Farmaceutiche, Universitꢀa della Calabria, 87036 Arcavacata di Rende (CS), Italy
‡Dipartimento di Chimica, Universitꢀa della Calabria, 87036 Arcavacata di Rende (CS), Italy
§Dipartimento di Scienze Biomolecolari, Universitꢀa di Urbino, 61029, Urbino, Italy
S Supporting Information
b
ABSTRACT: Novel and convenient approaches to benzothio-
phene derivatives 3 and 5 have been developed, based on
heterocyclization reactions of 1-(2-mercaptophenyl)-2-yn-1-
ols 2 or 4, respectively, readily available from alkynylation of
2-mercaptobenzaldehydes or 1-(2-mercaptophenyl) ketones 1.
In particular, 1-(2-mercaptophenyl)-2-yn-1-ols 2, bearing a
CH2R substituent on the triple bond (R = alkyl, aryl), were
conveniently converted in fair to good yields (55ꢀ82%) into
(E)-2-(1-alkenyl)benzothiophenes 3 when allowed to react in
the presence of catalytic amounts (2 mol %) of PdI2 in
conjunction with KI (KI:PdI2 molar ratio =10) at 80ꢀ100 °C in MeCN as the solvent, through a heterocyclodehydration process.
On the other hand, 2-alkoxymethylbenzothiophenes 5 were selectively obtained in fair to excellent yields (49ꢀ98%) via a radical-
promoted substitutive heterocyclodehydration process, by reacting 1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an alkyl or aryl
substituent on the triple bond) in alcoholic media at 80ꢀ100 °C in the presence of a radical initiator, such as AIBN.
’ INTRODUCTION
1-(2-mercaptophenyl)-2-yn-1-ols 2 or 4, readily available from
alkynylation of 2-mercaptobenzaldehydes or 1-(2-mercaptophenyl)
ketones 1. We have found that, depending on the substrate
substitution pattern and reaction conditions, either Pd-catalyzed
heterocyclodehydration or radical-promoted substitutive hetero-
cyclodehydration may take place, with selective formation of (E)-
2-(1-alkenyl)benzothiophenes 3 or 2-alkoxymethylbenzothio-
phenes 5, respectively, in good to high yields (Scheme 1).
Benzothiophenes are a very important class of heterocyclic
compounds. The benzothiophene core is present in many natural
and pharmacologically active compounds.1 Moreover, benzothio-
phenes find extensive application in materials science.2
Several methods are known at present for the synthesis of the
benzothiophene ring system starting from acyclic precursors.3,4
Classical reactions include Bischler-type cyclizations of α-arylthio
ketones to give 3-substituted benzothiophenes,3a,b the two-step
formation of 2,3-disubstituted benzothiophenes, bearing an
acyl group at C-2, from 1-(2-mercaptophenyl) ketones through
S-alkylation followed by intramolecular condensation,3c and the
benzannulation of a thiophene moiety.3d More recently, 2-sub-
stituted benzothiophenes have been obtained by lithiation of
S-(2-methylphenyl) N,N,N0,N0-tetramethylphosphorodiamidothioate
followed by acylation and acidic treatment.3e Other recently
developed methods include metal-promoted annulation pro-
cesses, such as the Pd-catalyzed formation of benzothiophenes
from gem-dihalovinyl thiophenols,4f the acid-catalyzed hetero-
cyclization of 2-(1-alkynyl)methylthiobenzene under MW irra-
diation,4c and the iodocyclization of suitable substrates, such as
1-[2-(methylthio)phenyl]-2-yn-1-ols.4o
’ RESULTS AND DISCUSSION
Pd-Catalyzed Heterocyclodehydration of 1-(2-Mercapto-
phenyl)-2-yn-1-ols 2 for the Synthesis of (E)-2-(1-Alkenyl)-
benzothiophenes 3. Metal-catalyzed heterocyclodehydration
of suitably functionalized and readily available acyclic substrates
is an attractive and convenient method for the regioselective syn-
thesis of substituted heterocycles.5 In particular, we have recently
reported the formation of quinoline, furan, and pyrrole deriva-
tives by Pd- or Cu-catalyzed heterocyclodehydration of 1-(2-
aminoaryl)-2-yn-1-ols,5f,l 3-yne-1,2-diols,5a,c and N-protected
1-amino-3-yn-2-ols,5a respectively.
In this work, we report a novel approach to the direct syn-
thesis of benzothiophene derivatives by heterocyclization of
Received: July 15, 2011
Published: September 08, 2011
r
2011 American Chemical Society
8277
dx.doi.org/10.1021/jo201471k J. Org. Chem. 2011, 76, 8277–8286
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1
Scheme 2
Prompted by these results, we have investigated the possibility
to realize a direct synthesis of (E)-2-(1-alkenyl)benzothiophenes
3 by metal-catalyzed heterocyclodehydration of 1-(2-mercapto-
phenyl)-2-yn-1-ols 2, according to the mechanistic hypotheses
shown in Scheme 2.
as the solvent with a substrate concentration of 0.02 mmol/mL of
MeCN, at 80 °C for 5 h, in the presence of PdI2 in conjunction
with 10 equiv of KI.8 Under these conditions, benzothiophene 3a
was obtained in 70% isolated yield, based on starting 2-mercap-
tobenzaldehyde 1a (Table 2, entry 1).
In pathway a, triple bond coordination to the metal center
would activate the triple bond toward the 5-exo-dig nucleophilic
attack by the thiol group,6 with formation of a vinylmetal inter-
mediate, whose protonolysis and dehydration would lead to 3.
Alternatively, a metal sulfide species could be formed,7 followed
by triple bond insertion, protonolysis, and dehydration (pathway b).
The first substrate we tested was 1-(2-mercaptophenyl)hept-
2-yn-1-ol 2a (R2 = Pr), which was used as the crude product
deriving from the alkynylation reaction of 2-mercaptobenzalde-
hyde 1a with 1-hexylymagnesium bromide (see the Experimental
Section for details). This substrate was allowed to react in MeCN
at 100 °C in the presence of different metal species, based on Pd,
Zn, Cu, and Au; the results obtained are shown in Table 1. As can
be seen from Table 1, the desired product 3a was formed with
practically all the catalysts tested, thus confirming the validity of
our initial work hypothesis. However, the selectivity of the pro-
cess toward 3a greatly depended on the nature of the metal
complex used: in particular, the catalytic system PdI2/KI8
showed the highest activity (54% yield after 6 h, entry 2), while
ZnCl2 and CuI led to only traces amounts of 3a (entries 4 and 6,
respectively). We also run a blank experiment, in the absence
of metal species, which, as expected, led to no product formation
(entry 9). We accordingly carried out the next experiments,
aimed at optimizing the product yield, using PdI2/KI as the cata-
lytic system. The results obtained by varying the KI/PdI2 molar
ratio, substrate concentration, temperature, and solvent are shown
in Table 1, entries 10ꢀ22. The final optimized conditions, ensu-
ing from this reaction parameters screening, corresponded to MeCN
In order to assess the generality of the process, the reac-
tion was then extended to other differently substituted sub-
strates. While 1-(2-mercaptophenyl)-4-phenylbut-2-yn-1-ol 2b
and 1-(2-mercaptophenyl)-5-phenylpent-2-yn-1-ol 2d behaved
similarly to 2a (Table 2, entries 2 and 4, respectively), the other
substrates tested (2c, 2eꢀh) were less reactive, so the best results
in terms of product yield were achieved working at 80ꢀ100 °C
for 15 h (entries 3 and 5ꢀ8). In any case, the desired (E)-2-(1-
alkenyl)benzothiophenes 3bꢀh were selectively obtained in fair
to good yields, based on the starting 2-mercaptobenzaldehyde or
1-(2-mercaptophenyl) ketones 1aꢀc (55ꢀ82%). This synthetic
result is noteworthy, also considering the well-known thiophilicity
of Pd(II), which is often associated with the “poisoning effect” of
the sulfur atom on palladium catalysis involving thiophenes and
benzothiophenes.9
Radical-Promoted Substitutive Heterocyclodehydration
of 1-(2-Mercaptophenyl)-2-yn-1-ols 4 for the Selective Syn-
thesis of 2-Alkoxymethylbenzothiophenes 5. When 1-(2-
mercaptophenyl)hept-2-yn-1-ol 4a (R3 = Bu) was allowed to
react under conditions similar to those shown in entry 1 of Table 2,
but in a nucleophilic solvent such as MeOH for 15 h, the reaction
course changed completely, with formation of 2-(1-methoxy-
pentyl)benzothiophene 5a in 40% yield (Table 3, entry 1). The
selective formation of 5a, corresponding to a substitutive hetero-
cyclization, suggested that a different reaction mechanism could
take place in MeOH, possibly not involving metal catalysis. To
confirm this hypothesis, a reaction without metal catalysts was
carried out in MeOH as the solvent, which indeed led to the
8278
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
Table 1. Heterocyclodehydration Reactions of 1-(2-Mercaptophenyl)hept-2-yn-1-ol 2a Under Different Conditionsa
entry
metal catalyst
solvent
T (°C)
substrate concentrationb
conversion of 2ac (%)
yield of 3ad (%)
1
PdCl2 + 10KCl
PdI2 + 10KI
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DME
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.50
0.10
0.05
0.02
0.22
0.22
0.02
0.02
0.22
0.22
0.22
88
25
54
13e
3e
10e
tracese
11e
24
0
2
100
59
3
Pd(NO3)2 2H2O
3
4
ZnCl2
52
5
CuCl2
63
6
CuI
18
7
AuCl
64
8
AuCl3
86
9
none
7
10
11
12
13
14
15
16
17
18
19
20
21
22
PdI2 + 2KI
PdI2 + 20KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 2KI
PdI2 + 10KI
PdI2 + 10KI
PdI2 + 10KI
100
100
100
100
100
100
100
79
46
32
48
55
58
62
55
26
67
63
45
45
36
60
80
100
100
100
100
100
80
100
100
100
DMA
dioxane
a Crude 2a (obtained from the alkynylation reaction between 2-mercaptobenzaldehyde 1a with 1-hexynylmagnesium bromide) was directly used as
substrate without further purification (see the Experimental Section for details). Unless otherwise noted, all reactions were carried out for 6 h in the
presence of 2 mol % of catalyst. b Millimoles of starting 1a per milliliter of solvent. c Determined by GLC. d Isolated yield based on starting 1a. The
formation of unidentified heavy products (chromatographically immobile materials) accounted for the difference between the substrate conversion and
the product yield. e The reaction led to a complex mixture of products.
formation of 5a in 45% yield (Table 3, entry 2). Considering
the well-known tendency of thiols to produce thiyl radicals,10 we
then verified if a radical mechanism could be at work by con-
ducting an experiment in the presence of a radical inhibitor, such as
2,2,6,6-tetramethylpiperidinoxyl (TEMPO). No reaction occurred
in the presence of TEMPO (Table 3, entry 3), which clearly
indicated a free-radical mechanism for the conversion of 4a into 5a
in MeOH as the solvent. In order to further favor the radical process
leading to 5a, the next experiment was carried out in MeOH in the
presence of a classical radical initiator such as AIBN. As expected, 5a
was obtained in a higher yield with respect to the reaction carried
out in MeOH alone (70% after 8 h, Table 3, entry 4), thus further
confirming the involvement of a free-radical mechanism. The
reaction was quite slower and less selective at 60 °C, as shown in
entry 5 of Table 3, while a somewhat lower yield was obtained by
working under more concentrated conditions (Table 3, entry 6).
The successful synthesis of 2-(1-methoxypentyl)benzothio-
phene 5a by a simple procedure based on substitutive hetero-
cyclodehydration of 1-(2-mercaptophenyl)hept-2-yn-1-ol 4a
opened the way to the development of a general, novel, and
convenient approach to functionalized benzothiophenes, such as
2-alkoxymethylbenzothiophenes 5, starting from readily available
acyclic substrates. We accordingly tested the reactivity of other
differently substituted 1-(2-mercaptophenyl)-2-yn-1-ols 4 in MeOH
under radical-promoted conditions, and the results obtained are
shown in Table 4, entries 1ꢀ14. As can be seen from Table 4, fair to
excellent yields were obtained starting from a variety of substrates,
including those bearing a highly bulky substituent on the triple bond,
such as tert-butyl, working at 80ꢀ100 °C for 8ꢀ15 h. The reaction
also worked nicely using EtOH or i-PrOH rather than MeOH as the
reactant and solvent, as shown by entries 15ꢀ21 of Table 4.
A plausible mechanism for the formation of benzothio-
phenes 5 from 4 under radical conditions is shown in Scheme 3.
Formation of the thiyl radical I followed by its intramolecular
addition to the triple bond may occur, followed by ionic frag-
mentation of the ensuing radical species II to give a radical cation
species III with elimination of HOꢀ.11 Reaction of III with ROH
and HOꢀ would lead to the benzylic-type radical IV with eli-
mination of water. The radical chain then propagates through the
reaction between IV and the substrate, with formation of product
5 and regeneration of the thiyl radical I.
’ CONCLUSIONS
In conclusion, we have shown that readily available 1-(2-
mercaptophenyl)-2-yn-1-ols 2 and 4, easily obtained as crude
8279
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
products from alkynylation of 2-mercaptobenzaldehydes or 1-(2-
mercaptophenyl) ketones 1, are excellent and versatile substrates
for the direct synthesis of benzothiophene derivatives 3 and 5,
respectively, through novel and efficient heterocyclization pro-
cesses. In particular, (E)-2-(1-alkenyl)benzothiophenes 3 are
selectively produced in fair to good yields (55ꢀ82%) via PdI2/
KI-catalyzed heterocyclodehydration of 2 (bearing a CH2R2
substituent on the triple bond, R2 = alkyl, aryl) carried out
at 80ꢀ100 °C in MeCN as the solvent. On the other hand,
Table 2. Synthesis of (E)-2-(1-Alkenyl)benzothiophenes 3 by
Pd-Catalyzed Heterocyclodehydration of 1-(2-Mercaptophenyl)-
2-yn-1-ols 2, Obtained by Alkynylation of 2-Mercaptobenzalde-
hyde or 1-(2-Mercaptophenyl) Ketones 1a
1-(2-mercaptophenyl)-2-yn-1-ols 4 (bearing an R3 substituent
on the triple bond, R3 = alkyl, aryl) can also be selectively
converted into 2-alkoxymethylbenzothiophenes 5 in fair to
excellent yields (49ꢀ98%) when allowed to react with an alcohol
(also used as the reaction medium) in the presence of AIBN,
through a substitutive heterocyclodehydration process taking
place under radical conditions. These novel approaches to the
synthesis of benzothiophenes 3 and 5 represent convenient
alternative methods with respect to the procedures reported so
far for their production.12,13
’ EXPERIMENTAL SECTION
General Experimental Methods. Melting points are uncor-
1
rected. H NMR and 13C NMR spectra were recorded at 25 °C in
CDCl3 solutions at 300 and 75 MHz, respectively, with Me4Si as
internal standard. Chemical shifts (δ) and coupling constants (J) are
given in ppm and in hertz, respectively. IR spectra were taken with an
FT-IR spectrometer. Mass spectra were obtained using a GC-MS
apparatus at 70 eV ionization voltage. Microanalyses were carried out
at our analytical laboratory. All reactions were analyzed by TLC on
silica gel 60 F254 and by GLC using a gas chromatograph and capillary
columns with polymethylsilicone + 5% phenylsilicone as the station-
ary phase. Column chromatography was performed on silica gel 60
(70ꢀ230 mesh). Evaporation refers to the removal of solvent under
reduced pressure.
entry
1
R1
R2
Pr
2
T (°C) t (h)
3
yield of 3b (%)
1
2
3
4
5
6
7
8
1a
1a
1a
H
H
H
2a
80
80
80
80
80
80
80
100
5
3a
3b
3c
3d
3e
3f
70
75
55
76
70
56
73
82
Ph 2b
Bn 2c
5
15
5
1b Me Pr
2d
1b Me Bn 2e
15
15
15
15
Starting 2-mercaptobenzaldehyde (1a),14 2-mercaptoacetophenone
(1b)15 and 2-mercaptobenzophenone (1c)16 were prepared according
to literature procedures.
1c Ph
1c Ph
1c Ph
Bn 2f
Ph 2g
3g
3h
General Procedure for the Preparation of Crude 1-(2-
Mercaptophenyl)-2-yn-1-ols 2 and 4. To a suspension of Mg
turnings (410 mg, 16.9 mmol) in anhydrous THF (2.0 mL), maintained
under nitrogen and under reflux was added pure EtBr (0.4 mL) to start
the formation of the Grignard reagent. The remaining bromide was added
dropwise (ca. 20 min) in THF solution (0.9 mL of EtBr in 15.0 mL of
THF; total amount of EtBr added: 1.78 g, 16.3 mmol). The mixture was
then allowed to reflux for additional 20 min. After cooling, the solution
of EtMgBr thus obtained was transferred under nitrogen to a dropping
funnel and was added dropwise to a solution of the 1-alkyne (16.3 mmol)
in anhydrous THF (7.0 mL) at 0 °C with stirring. After additional
stirring at 0 °C for 15 min, the mixture was allowed to warm to room
Pr
2h
a Crude 2 [obtained from the alkynylation reaction between 2-mercap-
tobenzaldehyde 1a or 1-(2-mercaptophenyl) ketones 1b,c with 1-alky-
nylmagnesium bromide] was directly used as substrate without further
purification (see the Experimental Section for details). All reactions were
carried out in MeCN (0.02 mmol of starting 1 per mL of solvent; 0.5
mmol scale based on 1) in the presence of 2 mol % of PdI2 in
conjunction with KI (KI:PdI2 molar ratio = 10). Substrate conversion
was quantitative in all cases. b Isolated yield based on starting 1. The
formation of unidentified heavy products (chromatographically immo-
bile materials) accounted for the difference between the substrate
conversion and the product yield.
Table 3. Substitutive Heterocyclodehydration Reactions of 1-(2-Mercaptophenyl)hept-2-yn-1-ol 4a Under Different Conditionsa
entry
radical initiator
T (°C)
t (h)
substrate concentrationb
conversion of 4ac (%)
yield of 5ad (%)
1e
2
3f
none
80
80
80
80
60
80
15
15
15
8
0.02
0.02
0.02
0.02
0.02
0.22
100
100
23
40
45
0g
none
none
4
AIBNh
AIBNh
AIBNh
100
41
70
20
62
5
15
6
15
100
a Crude 4a (obtained from the alkynylation reaction between 2-mercaptobenzaldehyde 1a with 1-hexynylmagnesium bromide) was directly used as
substrate without further purification (see the Experimental Section for details). All reactions were carried out in MeOH. b Millimoles of starting 1a per
milliliter of solvent. c Determined by GLC. d Isolated yield based on starting 1a. The formation of unidentified heavy products (chromatographically
immobile materials) accounted for the difference between the substrate conversion and the product yield. e The reaction was carried out in the presence
of 2 mol % of PdI2 in conjunction with KI (KI:PdI2 molar ratio = 10). f The reaction was carried out in the presence of TEMPO (50% with respect to 4a,
w/w). g The reaction led to a complex mixture of products. h 20% with respect to 4a (w/w).
8280
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
Table 4. Synthesis of 2-Alkoxymethylbenzothiophenes 5 by
Substitutive Heterocyclodehydration of 1-(2-
Scheme 3
Mercaptophenyl)-2-yn-1-ols 4, Obtained by Alkynylation of
2-Mercaptobenzaldehyde or 1-(2-Mercaptophenyl) Ketones
1, under Radical Conditionsa
entry
1
R1
R3
4
R
T (°C) t (h)
5
yield of 5b (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
H
H
H
Bu
Bn
Bn
4a Me 80
4b Me 80
4b Me 100
4c Me 100
8
5a
70
52
52
98
71
73
68
49
60
53
60
55
80
61
63
95
55
54
51
58
60
15 5b
5b
8
1b Me Bu
15 5c
15 5d
15 5e
15 5f
from 0.50 mmol of 1) was diluted with MeCN (25 mL). To the result-
ing mixture were added PdI2 (3.6 mg, 0.01 mmol) and KI (16.7 mg,
0.1 mmol), and the mixture was heated at the temperature and for the
time required (see Table 2). The solvent was evaporated, and the crude
products 3 were purified by column chromatography on silica gel using
95:5 hexaneꢀEt2O as eluent.
1b Me (CH2)2Ph 4d Me 100
1c Ph (CH2)2Ph 4e Me 100
1c Ph Bn
1c Ph Bu
4f Me 100
4g Me 100
4h Me 80
4i Me 100
4j Me 80
4k Me 80
4l Me 100
4m Me 100
8
5g
1a
H
H
Ph
15 5h
15 5i
2-Pent-1-enylbenzo[b]thiophene (3a). Yield: 71 mg (70%, based on
starting 1a, Table 2, entry 1). Yellow solid, mp 57ꢀ59 °C. IR (KBr): ν =
3057 (w), 2960 (s), 2929 (m), 2870 (m), 1677 (w), 1457 (s), 1436 (s),
1378 (w), 1156 (w), 953 (s), 839 (m), 744 (s), 725 (s) cmꢀ1; 1H NMR
(300 MHz, CDCl3): δ = 7.74ꢀ7.69 (m, 1 H), 7.65ꢀ7.60 (m, 1 H),
7.31ꢀ7.20 (m, 2 H), 7.02 (s, 1 H), 6.63ꢀ6.54 (m, 1 H), 6.15 (dt, J =
15.3, 7.2, 1 H), 2.24ꢀ2.13 (m, 2 H), 1.59ꢀ1.42 (m, 2 H), 0.96 (t, J = 7.3,
3 H); 13C NMR (75 MHz, CDCl3): δ = 141.4, 137.8, 136.9, 133.4,
127.6, 124.5, 124.0, 122.2, 122.1, 121.5, 35.5, 22.6, 13.9, ; GC-MS: m/z =
204 (3) [(M + 2)+], 203 (10), 202 (62) [M+], 184 (4), 174 (14), 173
(100), 172 (13), 171 (19), 160 (22), 147 (9), 134 (15), 129 (32), 128
(14), 115 (14). Anal. Calcd for C13H14S (202.32): C, 77.18; H, 6.97; S,
15.85; found C, 77.31; H, 6.95; S, 15.74.
10 1a
t-Bu
11 1b Me Ph
12 1b Me t-Bu
13 1c Ph Ph
14 1c Ph t-Bu
8
8
5j
5k
15 5l
8
5m
15 1a
H
Bu
4a Et
4c Et
4g Et
4h Et
4j Et
4k Et
80
80
100
80
80
80
15 5a0
15 5c0
16 1b Me Bu
17 1c Ph Bu
8
5 g0
18 1a
H
Ph
15 5 h0
15 5j0
19 1b Me Ph
20 1b Me t-Bu
8
5k0
5i00
2-Styrylbenzo[b]thiophene (3b).4c,f Yield: 89 mg (75% based on
starting 1a, Table 2, entry 2). Yellow solid, mp 123ꢀ125 °C. IR (KBr):
ν = 2921 (m), 1447 (w), 1225 (w), 1074 (m), 948 (s), 818 (m), 740 (s),
691 (s) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.81ꢀ7.76 (m, 1 H),
7.71ꢀ7.67 (m, 1 H), 7.55ꢀ7.48 (m, 2 H), 7.42ꢀ7.24 (m, 7 H), 6.99
(distorted d, J = 16.2, 1 H); 13C NMR (75 MHz, CDCl3): δ = 142.9,
140.2, 138.9, 136.7, 130.9, 128.8, 128.0, 126.6, 124.8, 124.5, 123.4, 123.3,
122.3, 122.2; m/z = 238 (5) [(M + 2)+], 237 (20), 236 (100) [M+], 235
(87), 234 (55), 221 (18), 203 (8), 202 (21), 189 (6), 165 (3), 134 (5),
117 (14), 104 (8), 101 (7), 89 (5), 77 (7). Anal. Calcd for C16H12S
(236.33): C, 81.31; H, 5.12; S, 13.57; found C, 81.27; H, 5.14; S, 13.59.
2-(3-Phenylpropenyl)benzo[b]thiophene (3c). Yield: 69 mg (55%
based on starting 1a, Table 2, entry 3). Yellow solid, mp 59ꢀ60 °C. IR
(KBr): ν = 2947 (m), 2877 (m), 1631 (m), 1450 (m), 1385 (m), 1080
(w), 1026 (m), 949 (m), 833 (m), 749 (s), 698 (m) cmꢀ1; 1H NMR
(300 MHz, CDCl3): δ = 7.77ꢀ7.62 (m, 2 H), 7.37ꢀ7.16 (m, 7 H), 7.07
(s, 1 H), 6.64 (distorted d, br, J = 15.7, 1 H), 6.30 (dt, J = 15.3, 6.9, 1 H),
3.57 (d, J = 6.9, 2 H); 13C NMR (75 MHz, CDCl3): δ = 142.7, 140.2,
139.5, 138.7, 132.0, 128.8, 128.6, 126.4, 125.0, 124.4, 124.3, 123.2, 122.1,
121.8, 39.2 ; GC-MS: m/z = 252 (10) [(M + 2)+], 251 (24), 250 (100)
[M+], 249 (41), 235 (32), 215 (18), 202 (12), 173 (21), 171 (15), 147
(22), 128 (19), 115 (34), 91 (10), 89 (11), 77 (12). Anal. Calcd for
C17H14S (250.36): C, 81.56; H, 5.64; S, 12.81; found C, 81.51; H, 5.63;
S, 12.86.
21 1a
H
t-Bu
4i i-Pr 80
8
a Crude 4 [obtained from the alkynylation reaction between 2-mercap-
tobenzaldehyde 1a or 1-(2-mercaptophenyl) ketones 1b,c with 1-alky-
nylmagnesium bromide] was directly used as substrate without further
purification (see the Experimental Section for details). All reactions were
carried out in ROH (0.02 mmol of starting 1 per mL of solvent, 0.5 mmol
scale based on1) inthe presence of20% ofAIBN (w/w with respect to 4).
Substrate conversion was quantitative in all cases. b Isolated yield based on
starting 1. The formation of unidentified heavy products (chromato-
graphically immobile materials) accounted for the difference between the
substrate conversion and the product yield.
temperature, and then it was maintained at 50 °C for 2 h and used as such
at the same temperature for the next step. The 2-mercaptophenyl
carbonyl compound 1 (6.52 mmol) was dissolved under nitrogen in
anhydrous THF (15.0 mL) and then added dropwise to the solution of
the alkynylmagnesium bromide in THF (prepared as described above)
under nitrogen. After stirring at 50 °C for 2 h, the mixture was cooled to
room temperature. Saturated NH4Cl was added with stirring to achieve
weakly acidic pH. After additionalstirring at room temperature for 15 min,
Et2O (ca. 20 mL) was added and phases were separated. The aqueous
phase was extracted with Et2O (3 ꢁ 50 mL), and the collected organic
layers were washed with brine to ca. neutral pH and eventually dried over
Na2SO4. After filtration, the solvent was evaporated and crude products 2or
4 were diluted with Et2O and transferred into a volumetric flask (50 mL).
General Procedure for the Synthesis of (E)-2-(1-Alkenyl)-
benzothiophenes 3. A 3.8 mL of the ethereal solution of 2 (obtained
as described above) were evaporated, and the residue (formally deriving
3-Methyl-2-pent-1-enylbenzo[b]thiophene (3d). Yield: 82 mg (76%
based on starting 1b, Table 2, entry 4). Yellow solid, mp 63ꢀ65 °C. IR
(KBr): ν = 2957 (m), 2927 (m), 2870 (m), 1460 (m), 1435 (m), 1379
1
(w), 1198 (w), 1017 (w), 950 (s), 752 (s), 727 (m) cmꢀ1; H NMR
8281
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
(300 MHz, CDCl3): δ = 7.69 (dd, J = 6.9, 1.6, 1 H), 7.56 (dd, J = 6.9, 1.6,
1 H), 7.36ꢀ7.17 (m, 2 H), 6.69 (dt, J = 15.3, 1.2, 1 H), 6.12 (dt, J = 15.3,
7.3, 1 H), 2.39 (s, 3 H), 2.21 (qd, J = 7.3, 1.2, 2 H), 1.57ꢀ1.43 (m, 2 H),
0.95 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3): δ = 141.3, 137.7,
136.8, 133.3, 127.5, 124.4, 123.9, 122.1, 122.0, 121.4, 35.4, 22.5, 13.7,
11.6; GC-MS: m/z = 218 (5) [(M + 2)+], 217 (12), 216 (82) [M+], 187
(100), 174 (19), 173 (18), 172 (48), 171 (37), 154 (11), 147 (24), 128
(16), 115 (19), 77 (9). Anal. Calcd for C14H16S (216.34): C, 77.72; H,
7.45; S, 14.82; found C, 77.85; H, 7.43; S, 14.72.
(obtained as described above) was evaporated, and the residue (formally
deriving from 0.50 mmol of 1) was diluted with ROH (R = Me, Et, i-Pr)
(25 mL). To the resulting mixture was added AIBN (20% w/w with
respect to 4), and the mixture was heated at the temperature and for the
time required (see Table 4). The solvent was evaporated, and the crude
products 5 were purified by column chromatography on silica gel using
as eluent: 95:5 hexaneꢀAcOEt (5a, 5a0, 5b, 5e, 5f, 5g, 5 h0, 5k0, 5i00, 5j0,
5l, 5m); 99:1 hexaneꢀAcOEt (5d, 5i, 5 g0); 9:1 hexaneꢀAcOEt (5c, 5c0,
5h, 5j, 5k).
3-Methyl-2-(3-phenylpropenyl)benzo[b]thiophene (3e). Yield: 93
mg (70% based on starting 1b, Table 2, entry 5). White solid, mp
62ꢀ63 °C. IR (KBr): ν = 2918 (m), 2855 (w), 1601 (w), 1495 (m),
1464 (m), 1437 (m), 1418 (w), 957 (m), 933 (w), 752 (m), 741 (s), 727
(m), 700 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.72ꢀ7.67 (m,
1 H), 7.61ꢀ7.56 (m, 1 H), 7.35ꢀ7.17 (m, 7 H), 6.76 (dt, J = 15.3, 1.2,
1 H), 6.25 (dt, J = 15.3, 6.9, 1 H), 3.58 (d, br, J = 6.9, 2 H), 2.35 (s, 3 H);
13C NMR (75 MHz, CDCl3): δ = 141.1, 139.7, 137.8, 136.2, 131.3,
128.7, 128.5, 128.3, 126.3, 124.6, 124.0, 123.2, 122.1, 121.6, 39.5, 11.7;
GC-MS: m/z = 266 (6) [(M + 2)+], 265 (20), 264 (100) [M+], 250
(13), 249 (64), 234 (11), 216 (15), 215 (10), 187 (6), 185 (5), 173 (23),
171 (22), 161 (16), 160 (12), 147 (15), 128 (16), 116 (19), 115 (95), 91
(29), 77 (13). Anal. Calcd for C18H16S (264.38): C, 81.77; H, 6.10; S,
12.13; found C, 81.86; H, 6.08; S, 12.06.
3-Phenyl-2-(3-phenylpropenyl)benzo[b]thiophene (3f). Yield:
92 mg (56% based on starting 1c, Table 2, entry 6). Yellow solid, mp
59ꢀ62 °C. IR (KBr): ν =1597 (w), 1489 (m), 1435 (m), 1385 (w), 1207
(m), 1153 (w), 1068 (m), 1022 (w), 949 (s), 748 (s), 694 (s) cmꢀ1; 1H
NMR (300 MHz, CDCl3): δ = 7.74 (dd, J = 6.9, 1.6, 1 H), 7.54ꢀ7.36
(m, 6 H), 7.33ꢀ7.14 (m, 7 H), 6.54 (distorted d, br, J = 15.3, 1 H), 6.32
(dt, J = 15.3, 7.3, 1 H), 3.48 (d, J = 7.3, 2 H); 13C NMR (75 MHz,
CDCl3): δ = 140.4, 139.7, 138.2, 137.8, 134.9, 134.4, 132.2, 130.4, 128.5,
127.6, 126.3, 124.8, 124.3, 124.1, 122.9, 122.1, 39.4; GC-MS: m/z = 328
(2) [(M + 2)+], 327 (14), 326 (37) [M+], 236 (23), 235 (100), 234 (89),
221 (28), 115 (19), 91 (21). Anal. Calcd for C23H18S (326.45): C, 84.62;
H, 5.56; S, 9.82; found C, 84.71; H, 5.53; S, 9.76.
3-Phenyl-2-styrylbenzo[b]thiophene (3g). Yield: 114 mg (73% based
on starting 1c, Table 2, entry 7). Yellow solid, mp 57ꢀ59 °C. IR (KBr):
ν = 2923 (m), 2850 (w), 1599 (w), 1494 (m), 1432 (m), 1318 (w), 1221
(w), 1072 (w), 951 (m), 769 (s), 692 (s), cmꢀ1; 1H NMR (300 MHz,
CDCl3): δ = 7.78 (dd, J = 6.9, 1.6, 1 H), 7.59ꢀ7.16 (m, 14 H), 7.04
(distorted d, J = 16.2, 1 H); 13C NMR (75 MHz, CDCl3): δ = 140.5,
138.5, 138.1, 136.9, 136.0, 134.8, 131.2, 130.5, 128.6, 127.9, 127.7, 126.6,
125.1, 124.5, 123.0, 122.1, 121.4; GC-MS: m/z = 314 (7) [(M + 2)+],
313 (24), 312 (100) [M+], 311 (40), 297 (17), 279 (5), 235 (37), 234
(46), 221 (10), 202 (11), 189 (8), 178 (4), 163 (5), 147 (3), 139 (3),
102 (3), 89 (3), 78 (28), 77 (18). Anal. Calcd for C22H16S (312.43): C,
84.57; H, 5.16; S, 10.26; found C, 84.49; H, 5.18; S, 10.33.
2-(1-Methoxypentyl)benzo[b]thiophene (5a). Yield: 82 mg (70%
based on starting 1a, Table 4, entry 1). Yellow oil. IR (film): ν = 2956
(s), 2931 (s), 2859 (m), 2821 (m), 1458 (s), 1436 (w), 1126 (m), 1091
(s), 829 (w), 746 (m), 727 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ =
7.86ꢀ7.78 (m, 1 H), 7.75 ꢀ7.68 (m, 1 H), 7.37ꢀ7.25 (m, 2 H), 7.18 (s,
1 H), 4.41 (t, J = 6.7, 1 H), 3.30 (s, 3 H), 2.03ꢀ1.88 (m, 1 H), 1.86ꢀ1.71
(m, 1 H), 1.48ꢀ1.21 (m, 4 H), 0.88 (t, J = 6.9, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 147.5, 139.7, 139.4, 124.1, 123.3, 122.6, 121.8, 80.2, 56.7,
37.7, 27.9, 22.5, 14.0; GC-MS: m/z = 236 (1) [(M + 2)+], 235 (2), 234
(14) [M+], 178 (13), 177 (100), 162 (12), 161 (16), 147 (12), 134 (11),
115 (7), 89 (8). Anal. Calcd for C14H18OS (234.36): C, 71.75; H, 7.74;
S, 13.68; found C, 71.77; H, 7.72; S, 13.73.
2-(1-Methoxy-2-phenylethyl)benzo[b]thiophene (5b). Yield: 70 mg
(52% based on starting 1a, Table 4, entry 2). Yellow solid, mp
63ꢀ64 °C. IR (KBr): ν = 2927 (m), 2852 (w), 1495 (w), 1456 (m),
1434 (w), 1384 (s), 1102 (s), 1079 (w), 871 (w), 842 (w), 756 (s), 727
(m), 705 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.87ꢀ7.78 (m, 1
H), 7.71ꢀ7.63 (m, 1 H), 7.38ꢀ7.13 (m, 7 H), 7.04 (s, 1 H), 4.65 (t, J =
7.0, 1 H), 3.30 (s, 3 H), 3.28 (distorted dd, J = 13.9, 7.0, 1 H), 3.07
(distorted dd, J = 13.9, 7.0, 1 H); 13C NMR (75 MHz, CDCl3): δ =
146.4, 139.7, 139.3, 137.8, 129.4, 128.2, 126.4, 124.2, 123.4, 122.6, 122.2,
81.3, 56.9, 44.6; GC-MS: m/z = 270 (0.2) [(M + 2)+], 269 (0.8), 268 (4)
[M+], 178 (12), 177 (100), 162 (12), 161 (14), 134 (9). Anal. Calcd for
C17H16OS (268.37): C, 76.08; H, 6.01; S, 11.95; found C, 76.13; H,
5.99; S, 11.93.
2-(1-Methoxypentyl)-3-methylbenzo[b]thiophene (5c). Yield: 122
mg (98% based on starting 1b, Table 4, entry 4). Yellow oil. IR (film):
ν = 2955 (s), 2931 (s), 2859 (m), 1460 (m), 1437 (m), 1177 (w), 1094
(s), 754 (s), 729 (m) cmꢀ1 1H NMR (300 MHz, CDCl3): δ =
;
7.84ꢀ7.78 (m, 1 H), 7.69ꢀ7.63 (m, 1 H), 7.41ꢀ7.27 (m, 2 H), 4.61
(t, J = 7.0, 1 H), 3.28 (s, 3 H), 2.38 (s, 3 H), 2.04ꢀ1.90 (m, 1 H),
1.83ꢀ1.69 (m, 1 H), 1.47ꢀ1.21 (m, 4 H), 0.88 (t, J = 6.9, 3 H); 13C
NMR (75 MHz, CDCl3): δ = 141.3, 140.6, 138.9, 128.7, 124.2, 123.8,
122.6, 121.5, 76.6, 56.6, 37.7, 27.9, 22.6, 14.0, 11.9; GC-MS: m/z = 250
(1) [(M + 2)+], 249 (2), 248 (12) [M+], 192 (14), 191 (100), 176 (14),
175 (13), 161 (9), 148 (9), 147 (16), 128 (5), 115 (5). Anal. Calcd for
C15H20OS (248.38): C, 72.53; H, 8.12; S, 12.91; found C, 72.57; H,
8.10; S, 12.89.
2-Pent-1-enyl-3-phenylbenzo[b]thiophene (3h). Yield: 114 mg
(82% based on starting 1c, Table 2, entry 8). Pale yellow solid, mp
61ꢀ63 °C. IR (KBr): ν = 2958 (s), 2928 (s), 2870 (m), 1487 (w), 1457
(m), 1434 (s), 1206 (m), 1157 (w), 1071 (w), 1020 (w), 956 (s), 767
2-(1-Methoxy-3-phenylpropyl)-3-methylbenzo[b]thiophene (5d).
Yield: 105 mg (71% based on starting 1b, Table 4, entry 5). Yellow
oil. IR (film): ν = 2924 (m), 2859 (w), 2818 (w), 1496 (w), 1455 (m),
1437 (m), 1340 (w), 1178 (w), 1102 (s), 942 (w), 754 (s), 729 (m), 700
1
(s), 753 (m), 732 (s), 717 (m), 701 (s) cmꢀ1; H NMR (300 MHz,
1
(m) cmꢀ1; H NMR (300 MHz, CDCl3): δ = 7.84ꢀ7.79 (m, 1 H),
CDCl3): δ = 7.78ꢀ7.72 (m, 1 H), 7.53ꢀ7.44 (m, 3 H), 7.44ꢀ7.37 (m,
3 H), 7.30ꢀ7.21 (m, 2 H), 6.53 (distorted dt, J = 15.3, 1.2, 1 H), 6.20
(distorted dt, J = 15.3, 7.3, 1 H), 2.13 (qd, J = 7.3, 1.2, 2 H), 1.44
(hexuplet, J = 7.3, 2 H), 0.91 (t, J = 7.3, 3 H);13C NMR (75 MHz,
CDCl3): δ = 140.6, 138.8, 137.7, 135.0, 134.3, 130.4, 128.5, 127.5, 124.6,
124.3, 122.9, 122.8, 122.0, 35.2, 22.4, 13.7; GC-MS: m/z = 280 (5)
[(M + 2)+], 279 (17), 278 (75) [M+], 263 (1), 250 (12), 249 (60), 247
(18),236(26),235(100),234(86),221(33),216(16),215(20),202(12),
189 (9), 171 (10), 165 (5), 115 (10). Anal. Calcd for C19H18S (278.41):
C, 81.97; H, 6.52; S, 11.52; found C, 82.01; H, 6.51; S, 11.48.
7.68ꢀ7.63 (m, 1 H), 7.40ꢀ7.24 (m, 4 H), 7.22ꢀ7.14 (m, 3 H), 4.58
(distorted dd, J = 7.7, 6.1, 1 H), 3.28 (s, 3 H), 2.82ꢀ2.63 (m, 2 H),
2.38ꢀ2.26 (m, 1 H), 2.29 (s, 3 H), 2.13ꢀ2.01 (m, 1 H); 13C NMR (75
MHz, CDCl3): δ = 141.5, 140.7, 140.6, 138.9, 128.9, 128.5, 128.4, 125.9,
124.3, 123.8, 122.6, 121.5, 77.4, 56.6, 39.2, 31.9, 11.8; GC-MS: m/z =
298 (1) [(M + 2)+], 296 (14) [M+], 264 (1), 192 (14), 191 (100), 176
(12), 175 (11), 161 (3), 147 (14), 91 (28). Anal. Calcd for C19H20OS
(296.43): C, 76.98; H, 6.80; S, 10.82; found C, 77.01; H, 6.81; S, 10.79.
2-(1-Methoxy-3-phenylpropyl)-3-phenylbenzo[b]thiophene (5e).
Yield: 131 mg (73% based on starting 1c, Table 4, entry 6). Yellow
solid, mp 62ꢀ63 °C. IR (KBr): ν = 2931 (m), 2858 (w), 1493 (w),
1442 (m), 1385 (w), 1261 (w), 1074 (s), 1026 (w), 941 (w), 748 (s),
General Procedure for the Synthesis of 2-Alkoxymethyl-
benzothiophenes 5. A 3.8 mL amount of the ethereal solution of 4
8282
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
690 (s) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.92ꢀ7.84 (m, 1 H),
7.53ꢀ7.04 (m, 13 H), 4.55ꢀ4.44 (m, 1 H), 3.21 (s, 3 H), 2.83ꢀ2.56 (m,
2 H), 2.38ꢀ2.19 (m, 1 H), 2.16ꢀ1.98 (m, 1 H); 13C NMR (75 MHz,
CDCl3): δ = 143.3, 141.4, 140.1, 138.9, 136.0, 134.8, 129.9, 128.6, 128.4,
128.3, 127.6, 125.8, 124.6, 124.1, 123.0, 122.5, 76.6, 56.6, 39.8, 31.9; GC-
MS: m/z = 360 (1) [(M + 2)+], 359 (5), 358 (17) [M+], 254 (21), 253
(100), 237 (17), 234 (10), 221 (37), 165 (12), 91 (23). Anal. Calcd for
C24H22OS (358.50): C, 80.41; H, 6.19; S, 8.94; found C, 80.45; H, 6.17;
S, 8.96.
1312 (m), 1187 (m), 1171 (m), 1094 (s), 1070 (s), 1029 (w), 960 (m),
1
732 (s), 730 (s), 700 (s) cmꢀ1; H NMR (300 MHz, CDCl3): δ =
7.79ꢀ7.74 (m, 1 H), 7.68ꢀ7.62 (m, 1 H), 7.47ꢀ7.40 (m, 2 H),
7.38ꢀ7.23 (m, 5 H), 5.70 (s, 1 H), 3.45 (s, 3 H), 2.41 (s, 3 H); 13C
NMR (75 MHz, CDCl3): δ = 140.9, 140.5, 140.3, 139.1, 128.5, 127.8,
126.7, 124.2, 123.8, 122.5, 121.6, 79.7, 57.1, 12.0; GC-MS: m/z = 270
(3) [(M + 2)+], 269 (10), 268 (52) [M+], 253 (16), 238 (18), 237 (100),
236 (12), 222 (12), 221 (18), 203 (9), 191 (21), 175 (11), 147 (15),
134 (6), 121 (8), 105 (16), 91 (10), 77 (38). Anal. Calcd for C17H16OS
(268.37): C, 76.08; H, 6.01; S, 11.95; found C, 76.12; H, 5.99; S, 11.94.
2-(1-Methoxy-2,2-dimethylpropyl)-3-methylbenzo[b]thiophene
(5k). Yield: 68 mg (55% based on starting 1b, Table 4, entry 12). White
solid, mp 56ꢀ58 °C. IR (KBr): ν = 2965 (m), 2929 (m), 2818 (m), 1480
(w), 1460 (s), 1436 (m), 1385 (m), 1362 (s), 1264 (w), 1169 (s), 1156
2-(1-Methoxy-2-phenylethyl)-3-phenylbenzo[b]thiophene (5f).
Yield: 117 mg (68% based on starting 1c, Table 4, entry 7). Yellow
solid, mp 70ꢀ71 °C. IR (KBr): ν = 2921 (w), 1489 (w), 1440 (m), 1304
(s), 1333 (w), 1195 (w), 1092 (m), 974 (m), 770 (m), 757 (m), 698
1
(s) cmꢀ1; H NMR (300 MHz, CDCl3): δ = 7.93ꢀ7.87 (m, 1 H),
1
7.40ꢀ7.24 (m, 7 H), 7.22ꢀ7.15 (m, 3 H), 7.08ꢀ7.01 (m, 3 H), 4.61
(distorted dd, J = 7.5, 6.5, 1 H), 3.26 (distorted dd, J = 13.3, 6.5, 1 H),
3.18 (s, 3 H), 3.09 (distorted dd, J = 13.3, 7.5, 1 H); 13C NMR (75 MHz,
CDCl3): δ = 142.2, 140.1, 138.9, 137.5, 136.8, 134.6, 129.8, 129.5, 128.4,
128.2, 127.5, 126.4, 124.6, 124.1, 123.1, 122.6, 79.0, 56.5, 44.7; GC-MS:
m/z = 346 (0.1) [(M + 2)+], 345 (0.5), 344 (2) [M+], 254 (18), 253
(100), 237 (21), 221 (37), 208 (6), 165 (14), 91 (30). Anal. Calcd for
C23H20OS (344.47): C, 80.19; H, 5.85; S, 9.31; found C, 80.22; H, 5.84;
S, 9.29.
(w), 1092 (s), 960 (m), 912 (w), 755 (s), 739 (s) cmꢀ1; H NMR
(300 MHz, CDCl3): δ = 7.83ꢀ7.77 (m, 1 H), 7.69ꢀ7.63 (m, 1 H),
7.40ꢀ7.27 (m, 2 H), 4.28 (s, 1 H), 3.24 (s, 3 H), 2.37 (s, 3 H), 1.03 (s,
9 H); 13C NMR (75 MHz, CDCl3): δ = 140.3, 139.1, 139.0, 130.0, 124.1,
123.5, 122.2, 121.3, 86.1, 57.6, 36.9, 26.5, 12.8; GC-MS: m/z = 250 (1)
[(M + 2)+], 249 (2), 248 (9) [M+], 217 (1), 192 (17), 191 (100), 176
(19), 175 (17), 147 (17), 115 (4), 77 (2). Anal. Calcd for C15H20OS
(248.38): C, 72.53; H, 8.12; S, 12.91; found C, 72.55; H, 8.11; S, 12.94.
2-(Methoxyphenylmethyl)-3-phenylbenzo[b]thiophene (5l). Yield:
132 mg (80% based on starting 1c, Table 4, entry 13). Yellow solid, mp
106ꢀ107 °C. IR (KBr): ν = 2994 (m), 2925 (m), 2815 (m), 1494 (m),
1440 (s), 1384 (m), 1317 (m), 1185 (m), 1133 (m), 1077 (s), 1028 (m),
970 (m), 857 (w), 771 (s), 751 (s), 700 (s), 667 (m) cmꢀ1; 1H NMR
(300 MHz, CDCl3): δ = 7.82ꢀ7.75 (m, 1 H), 7.54ꢀ7.15 (m, 13 H),
5.54 (s, 1 H), 3.35 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 142.5,
141.2, 139.9, 139.3, 135.8, 134.9, 130.1, 128.7, 128.4, 127.8, 127.7, 126.6,
124.6, 124.1, 123.1, 122.4, 79.4, 56.8; GC-MS: m/z = 332 (4) [(M +
2)+], 331 (16), 330 (61) [M+], 315 (3), 300 (18), 299 (70), 298 (27),
297 (13), 253 (15), 237 (11), 222 (17), 221 (100), 208 (9), 165 (15),
149 (6), 105 (16), 77 (32). Anal. Calcd for C22H18OS (330.44): C,
79.96; H, 5.49; S, 9.70; found C, 80.01; H, 5.47; S, 9.69.
2-(1-Methoxypentyl)-3-phenylbenzo[b]thiophene (5g). Yield:
76 mg (49% based on starting 1c, Table 4, entry 8). Yellow oil. IR
(film): ν = 2984 (m), 2858 (s), 2818 (m), 1603 (w), 1489 (m), 1456 (s),
1435 (s), 1350 (w), 1335 (m), 1251 (w), 1194 (m), 1124 (w), 1089 (m),
1030 (w), 949 (w), 768 (s), 733 (s), 701 (s), 649 (w), 603 (m) cmꢀ1; 1H
NMR (300 MHz, CDCl3): δ = 7.88ꢀ7.82 (m, 1 H), 7.54ꢀ7.24 (m, 8
H), 4.45 (t, J = 6.8, 1 H), 3.21 (s, 3 H), 2.01ꢀ1.86 (m, 1 H), 1.85ꢀ1.70
(m, 1 H), 1.41ꢀ1.15 (m, 4 H), 0.82 (t, J = 7.0, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 143.7, 140.1, 138.8, 136.0, 135.1, 130.0, 128.6, 127.7, 124.5,
124.1, 123.0, 122.5, 77.5, 56.5, 38.1, 27.9, 22.5, 13.9; GC-MS: m/z = 312
(1) [(M + 2)+], 311 (3), 310 (14) [M+], 254 (18), 253 (100), 237 (16),
221 (33), 178 (3), 165 (11). Anal. Calcd for C20H22OS (310.45): C,
77.38; H, 7.14; S, 10.33; found C, 77.35; H, 7.14; S, 10.35.
2-(1-Methoxy-2,2-dimethylpropyl)-3-phenylbenzo[b]thiophene
(5m). Yield: 95 mg (61% based on starting 1c, Table 4, entry 14). White
solid, mp 99ꢀ100 °C. IR (KBr): ν = 2983 (s), 2919 (m), 2868 (m),
2817 (m), 1600 (w), 1477 (m), 1459 (s), 1389 (m), 1364 (m), 1193
(w), 1179 (w), 1133 (m), 1068 (s), 963 (m), 755 (s), 735 (s), 700 (s),
654 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.3, 1 H),
7.53ꢀ7.23 (m, 8 H), 4.22 (s, 1 H), 3.30 (s, 3 H), 0.90 (s, 9 H); 13C NMR
(75 MHz, CDCl3): δ = 140.8, 140.1, 139.1, 137.6, 135.7, 128.6, 127.5,
124.4, 123.9, 122.9, 122.1, 85.6, 57.3, 36.4, 26.6; GC-MS: m/z = 312
(0.3) [(M + 2)+], 311 (0.9), 310 (4) [M+], 254 (18), 253 (100), 237
(15), 221 (30), 208 (4), 165 (9). Anal. Calcd for C20H22OS (310.45): C,
77.38; H, 7.14; S, 10.33; found C, 77.34; H, 7.14; S, 10.36.
2-(Methoxyphenylmethyl)benzo[b]thiophene (5h). Yield: 76 mg
(60% based on starting 1a, Table 4, entry 9). Yellow solid, mp 60ꢀ61 °C.
IR (KBr): ν = 2930 (m), 2830 (m), 1493 (m), 1451 (m), 1384 (w), 1338
(w), 1307 (w), 1195 (m), 1090 (s), 1026 (w), 964 (w), 833 (m), 782 (s),
1
715 (s), 660 (m), 641 (m) cmꢀ1; H NMR (300 MHz, CDCl3): δ =
7.80ꢀ7.72 (m, 1 H), 7.69ꢀ7.63 (m, 1 H), 7.50ꢀ7.20 (m, 7 H), 7.07 (s,
1 H), 5.52 (s, 1 H), 3.43 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ =
147.1, 140.8, 140.1, 139.4, 128.5, 128.1, 126.9, 124.1, 123.5, 122.4, 121.8,
81.9, 57.1; GC-MS: m/z = 256 (4) [(M + 2)+], 255 (9), 254 (53) [M+],
224 (20), 223 (100), 222 (21), 221 (32), 208 (9), 178 (17), 177 (19),
161 (17), 134 (9), 133 (8), 111 (15), 105 (43), 89 (21), 77 (31). Anal.
Calcd for C16H14OS (254.35): C, 75.55; H, 5.55; S, 12.61; found C,
75.56; H, 5.54; S, 12.63.
2-(1-Methoxy-2,2-dimethylpropyl)benzo[b]thiophene (5i). Yield:
62 mg (53% based on starting 1a, Table 4, entry 10). Yellow solid,
mp 96ꢀ97 °C. IR (KBr): ν = 2960 (m), 2925 (m), 2867 (w), 1460 (m),
1384 (s), 1187 (w), 1127 (m), 1087 (s), 966 (w), 836 (s), 759 (s), 728
(m), 676 (w) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.85ꢀ7.78 (m, 1
H), 7.76ꢀ7.69 (m, 1 H), 7.38ꢀ7.23 (m, 2 H), 7.14 (s, 1 H), 4.07 (s, 1
H), 3.30 (s, 3 H), 1.01 (s, 9 H); 13C NMR (75 MHz, CDCl3): δ = 144.9,
139.8, 139.3, 124.0, 123.8, 123.2, 123.1, 122.2, 88.9, 57.9, 35.7, 26.3; GC-
MS: m/z = 236 (0.4) [(M + 2)+], 235 (1), 234 (9) [M+], 178 (12), 177
(100), 162 (12), 161 (17), 147 (4), 134 (10), 115 (2), 89 (5). Anal.
Calcd for C14H18OS (234.36): C, 71.75; H, 7.74; S, 13.68; found C,
71.71; H, 7.76; S, 13.70.
2-(1-Ethoxypentyl)benzo[b]thiophene (5a0). Yield: 78 mg (63%
based on starting 1a, Table 4, entry 15). Yellow oil. IR (film): ν =
2955 (m), 2936 (m), 2859 (m), 1457 (m), 1438 (w), 1398 (w), 1318
(m), 1105 (m), 1087 (m), 938 (w), 872 (w), 836 (s), 750 (s), 727
1
(s) cmꢀ1; H NMR (300 MHz, CDCl3): δ = 7.85ꢀ7.77 (m, 1 H),
7.75ꢀ7.67 (m, 1 H), 7.37ꢀ7.25 (m, 2 H), 7.16 (s, 1 H), 4.52 (t, J = 6.9,
1 H), 3.59ꢀ3.35 (m, 2 H), 2.02ꢀ1.88 (m, 1 H), 1.87ꢀ1.71 (m, 1 H),
1.47ꢀ1.15 (m, 4 H), 1.20 (t, J = 7.1, 3 H), 0.88 (t, J = 7.1, 3 H); 13C
NMR (75 MHz, CDCl3): δ = 148.5, 139.6, 139.4, 124.1, 124.0, 123.2,
122.6, 121.3, 78.3, 64.3, 37.9, 27.9, 22.5, 15.3, 14.0; GC-MS: m/z = 250
(1) [(M + 2)+], 249 (3), 248 (20) [M+], 192 (15), 191 (100), 163 (75),
161 (15), 147 (23), 135 (42), 134 (13), 115 (10), 91 (23), 89 (9). Anal.
Calcd for C15H20OS (248.38): C, 72.53; H, 8.12; S, 12.91; found C,
72.56; H, 8.11; S, 12.87.
2-(Methoxyphenylmethyl)-3-methylbenzo[b]thiophene (5j). Yield:
81 mg (60% based on starting 1b, Table 4, entry 11). Yellow oil. IR
(film): ν = 2985 (w), 2929 (m), 2820 (m), 1493 (m), 1460 (s), 1436 (s),
2-(1-Ethoxypentyl)-3-methylbenzo[b]thiophene (5c0). Yield: 125
mg (95% based on starting 1b, Table 4, entry 16). Colorless oil. IR
(film): ν = 2957 (m), 2931 (s), 2861 (s), 1460 (m), 1438 (m), 1380 (w),
8283
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
1331 (w), 1180 (w), 1089 (m), 756 (s), 729 (s) cmꢀ1; 1H NMR (300
MHz, CDCl3): δ = 7.79 (d, J = 8.1, 1 H), 7.64 (d, J = 8.1, 1 H),
7.40ꢀ7.24 (m, 2 H), 4.70 (t, J = 6.6, 1 H), 3.57ꢀ3.31 (m, 2 H), 2.36 (s,
3 H), 2.07ꢀ1.89 (m, 1 H), 1.85ꢀ1.68 (m, 1 H), 1.49ꢀ1.18 (m, 4 H),
1.19 (t, J = 6.6, 3 H), 0.88 (t, J = 7.3, 3 H); 13C NMR (75 MHz, CDCl3):
δ = 142.3, 140.7, 138.8, 128.1, 124.1, 123.7, 122.5, 121.4, 76.0, 64.2, 37.9,
27.9, 22.6, 15.3, 14.0, 11.9; GC-MS: m/z = 264 (2) [(M + 2)+], 263 (8),
262 (39) [M+], 206 (26), 205 (100), 177 (85), 161 (20), 149 (42), 147
(17), 134 (20), 115 (8). Anal. Calcd for C16H22OS (262.41): C, 73.23;
H, 8.45; S, 12.22; found C, 73.27; H, 8.47; S, 12.20.
2-(1-Isopropoxy-2,2-dimethylpropyl)benzo[b]thiophene (5i00). Yield:
79 mg (60% based on starting 1a, Table 4, entry 21). Yellow solid, mp.
83ꢀ84 °C. IR (KBr): ν = 2970 (s), 2929 (m), 2866 (m), 1462 (m), 1304
(s), 1315 (w), 1185 (w), 1125 (m), 1060 (s), 1031 (w), 937 (w), 868 (w),
834 (m), 751 (s), 728 (m), 719 (w), 684 (w) cmꢀ1; 1H NMR (300 MHz,
CDCl3): δ = 7.83ꢀ7.77 (m, 1 H), 7.73ꢀ7.67 (m, 1 H), 7.36ꢀ7.23 (m,
2 H), 7.11 (s, 1 H), 4.28 (s, 1 H), 3.54 (heptuplet, J = 6.6, 1 H), 1.12 (d, J =
6.6, 3 H), 1.11 (d, J = 6.6, 3 H), 0.99 (s, 9 H); 13C NMR (75 MHz,
CDCl3): δ = 146.9, 139.7, 139.4, 123.9, 123.6, 123.0, 122.4, 122.1, 83.5,
69.6, 35.5, 26.4, 23.3, 20.8; GC-MS: m/z = 264 (1) [(M + 2)+], 263 (1),
262 (5) [M+], 205 (26), 164 (12), 163 (100), 147 (5), 135 (22), 115 (2),
91 (11). Anal. Calcd for C16H22OS (262.41): C, 73.23; H, 8.45; S, 12.22;
found C, 73.27; H, 8.44; S, 12.19.
2-(1-Ethoxypentyl)-3-phenylbenzo[b]thiophene (5g0). Yield: 90 mg
(55% based on starting 1c, Table 4, entry 17). Colorless oil. IR (film):
ν = 2935 (m), 2856 (s), 1457 (m), 1377 (w), 1086 (m), 768 (m), 734
(m), 701 (m) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.88ꢀ7.80 (m,
1 H), 7.56ꢀ7.22 (m, 8 H), 4.56 (t, J = 6.7, 1 H), 3.58ꢀ3.42 (m, 1 H),
3.33ꢀ3.18 (m, 1 H), 2.03ꢀ1.87 (m, 1 H), 1.86ꢀ1.70 (m, 1 H),
1.42ꢀ1.09 (m, 4 H), 1.12 (t, J = 7.3, 3 H), 0.82 (t, J = 7.3, 3 H); 13C
NMR (75 MHz, CDCl3): δ = 144.8, 140.2, 138.8, 135.4, 135.2, 130.0,
128.6, 127.6, 124.4, 124.0, 122.9, 122.5, 75.6, 64.0, 38.3, 27.9, 22.4, 15.2,
13.9; GC-MS: m/z = 326 (1) [(M + 2)+], 325 (3), 324 (14) [M+], 268
(20), 267 (100), 239 (40), 221 (16), 211 (16), 178 (14), 165 (11). Anal.
Calcd for C21H24OS (324.48): C, 77.73; H, 7.46; S, 9.88; found C,
77.68; H, 7.49; S, 9.85.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: b.gabriele@unical.it.
2-(Ethoxyphenylmethyl)benzo[b]thiophene (5h0). Yield: 73 mg
(54% based on starting 1a, Table 4, entry 18). Yellow solid, mp.
34ꢀ35 °C. IR (KBr): ν = 2971 (m), 2890 (m), 2866 (m), 1492 (w),
1458 (s), 1433 (s), 1436 (m), 1384 (w), 1312 (w), 1216 (w), 1139 (m),
1083 (s), 1072 (s), 1009 (m), 818 (m), 756 (s), 728 (m), 701 (s), 640
’ ACKNOWLEDGMENT
Financial support from the Ministero dell’Istruzione,
dell’Universitꢀa e della Ricerca (MIUR, Rome, Italy), and from
the University of Calabria (Rende, Italy) is gratefully acknowledged
(Progetto di Ricerca d’Interesse Nazionale PRIN 2008A7P7YJ).
1
(m) cmꢀ1; H NMR (300 MHz, CDCl3): δ = 7.79ꢀ7.73 (m, 1 H),
7.69ꢀ7.63 (m, 1 H), 7.49ꢀ7.43 (m, 2 H), 7.40ꢀ7.22 (m, 5 H), 7.08 (s,
1 H), 5.64 (s, 1 H), 3.68ꢀ3.54 (m, 2 H), 1.29 (t, J = 7.0, 3 H); 13C NMR
(75 MHz, CDCl3): δ = 147.7, 141.3, 140.0, 139.4, 128.5, 128.0, 126.9,
124.09, 124.06, 123.5, 122.4, 121.6, 80.0, 64.9, 15.3; GC-MS: m/z = 270
(3) [(M + 2)+], 269 (11), 268 (56) [M+], 224 (32), 223 (100), 222 (20),
221 (30), 189 (8), 178 (21), 163 (11), 161 (12), 147 (6), 135 (10), 111
(12), 105 (53), 105 (53), 91 (10), 89 (21), 77 (26). Anal. Calcd for
C17H16OS (268.37): C, 76.08; H, 6.01; S, 11.95; found C, 76.11; H,
5.99; S, 11.97.
’ REFERENCES
(1) For recent representative examples, see: (a) Li, L.; Mathieu,
M.-C.; Denis, D.; Therien, A. G.; Wang, Z. Bioorg. Med. Chem. Lett. 2011,
21, 734–737. (b) Li, L.; Berthelette, C.; Chateauneuf, A.; Ouellet, M.;
Sturino, C. F.; Wang, Z. Bioorg. Med. Chem. Lett. 2010, 20, 7440–7443.
(c) Santillan, A.; McClure, K. J.; Allison, B. D.; Lord, B.; Boggs, J. D.;
Morton, K. L.; Everson, A. M.; Nepomuceno, D.; Letavic, M. A.; Lee-Dutra,
A.; Lovenberg, T. W.; Carruthers, N. I.; Grice, C. A. Bioorg. Med. Chem.
Lett. 2010, 20, 6226–6230. (d) Vangveravong, S.; Taylor, M.; Xu, J.; Cui,
J.; Calvin, W.; Babic, S.; Luedtke, R. R.; Mach, R. H. Bioorg. Med. Chem.
2010, 18, 5291–5300. (e) Mourey, R. J.; Burnette, B. L.; Brustkern, S. J.;
Daniels, J. S.; Hirsch, J. L.; Hood, W. F.; Meyers, M. J.; Mnich, S. J.;
Pierce, B. S.; Saabye, M. J.; Schindler, J. F.; South, S. A.; Webb, E. G.;
Zhang, J.; Anderson, D. R. J. Pharmacol. Exp. Ther. 2010, 333, 797–807.
(f) Davis, R. L.; Kahraman, M.; Prins, T. J.; Beaver, Y.; Cook, T. G.;
Cramp, J.; Cayanan, C. S.; Gardiner, E. M. M.; McLaughlin, M. A.; Clark,
A. F.; Hellberg, M. R.; Shiau, A. K.; Noble, S. A.; Borchardt, A. J. Bioorg.
Med. Chem. Lett. 2010, 20, 3361–3366. (g) Moree, W. J.; Jovic, F.; Coon,
T.; Yu, J.; Li, B.-F.; Tucci, F. C.; Marinkovic, D.; Gross, R. S.; Malany, S.;
Bradbury, M. J.; Hernandez, L. M.; O’Brien, Z.; Wen, J.; Wang, H.;
Hoare, S. R. J.; Petroski, R. E.; Sacaan, A.; Madan, A.; Crowe, P. D.;
Beaton, G. Bioorg. Med. Chem. Lett. 2010, 20, 2316–2320. (h) Shao, H.;
Li, D.; Yang, Y.; Guo, H.-F.; Liu, Z.-Y.; Si, S.-Y.; Yang, Z.; Li, Z.-R.
J. Enzyme Inhib. Med. Chem. 2010, 25, 282–289. (i) Wang, S.; Beck, R.;
Blench, T.; Burd, A.; Buxton, S.; Malic, M.; Ayele, T.; Shaikh, S.; Chahwala,
S.; Chander, C.; Holland, R.; Merette, S.; Zhao, L.; Blackney, M.; Watts, A.
J. Med. Chem. 2010, 53, 1465–1472.
2-(Ethoxyphenylmethyl)-3-methylbenzo[b]thiophene (5j0). Yield:
72 mg (51% based on starting 1b, Table 4, entry 19). Colorless oil. IR
(KBr): ν = 2974 (m), 2917 (s), 2849 (m), 1493 (w), 1453 (m), 1436
(m), 1381 (w), 1170 (m), 1155 (m), 1087 (s), 1070 (s), 733 (s), 729 (s),
700 (s) cmꢀ1; 1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 7.3, 1 H),
7.63 (d, J = 7.3, 1 H), 7.48ꢀ7.41 (m, 2 H), 7.37ꢀ7.20 (m, 5 H), 5.80 (s,
1 H), 3.71ꢀ3.51 (m, 2 H), 2.39 (s, 3 H), 1.28 (t, J = 7.3, 3 H); 13C NMR
(75 MHz, CDCl3): δ = 141.3, 141.1, 140.6, 139.1, 128.4, 128.2, 127.7,
126.7, 124.1, 123.8, 122.4, 121.5, 77.8, 64.8, 15.2, 12.0; GC-MS: m/z =
284 (4) [(M + 2)+], 283 (13), 282 (57) [M+], 267 (11), 238 (24), 237
(100), 236 (17), 221 (18), 205 (11), 177 (10), 149 (6), 134 (6), 115 (6),
105 (24), 77 (14). Anal. Calcd for C18H18OS (282.40): C, 76.56; H,
6.42; S, 11.35; found C, 76.59; H, 6.41; S, 11.38.
2-(1-Ethoxy-2,2-dimethylpropyl)-3-methylbenzo[b]thiophene
(5k0). Yield: 76 mg (58% based on starting 1b, Table 4, entry 20). Yellow
solid, mp 49ꢀ51 °C. IR (KBr): ν = 2964 (m), 2931 (m), 2863 (m), 2837
(m), 1479 (w), 1461 (m), 1438 (m), 1384 (m), 1316 (m), 1263 (w),
1160 (m), 1072 (s), 996 (m), 916 (w), 763 (s), 736 (m), 715 (m) cmꢀ1
;
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 7.3, 1 H), 7.64 (d, J = 7.3,
1 H), 7.39ꢀ7.25 (m, 2 H), 4.37 (s, 1 H), 3.52ꢀ3.38 (m, 1 H), 3.34ꢀ3.21
(m, 1 H), 2.36 (s, 3 H), 1.15 (t, J = 7.0, 3 H), 1.02 (s, 9 H); 13C NMR (75
MHz, CDCl3): δ = 140.4, 140.2, 139.1, 129.4, 123.9, 123.5, 122.1, 121.3,
83.7, 64.9, 36.9, 26.5, 15.1, 12.8; GC-MS: m/z = 264 (0.5) [(M + 2)+],
263 (2), 262 (8) [M+], 206 (14), 205 (100), 177 (61), 149 (31), 147
(12), 134 (16), 115 (6). Anal. Calcd for C16H22OS (262.41): C, 73.23;
H, 8.45; S, 12.22; found C, 73.26; H, 8.44; S, 12.19.
(2) For recent representative examples, see: (a) Kovarova, A.;
Svoboda, J.; Novotna, V.; Glogavora, M.; Salamonczyk, M.; Pociecha,
D.; Gorecka, E. Liq. Cryst. 2010, 37, 1501–1513. (b) Luyksaar, S. I.;
Migulin, V. A.; Nabatov, B. V.; Krayushkin, M. M. Russ. Chem. Bull. 2010,
59, 446–451. (c) Jung, K. H.; Kim, K. H.; Lee, D. H.; Jung, D. S.; Park,
C. E.; Choi, D. H. Org. Electron. 2010, 11, 1584–1593. (d) Uemura, T.;
8284
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
Hirose, Y.; Uno, M.; Takimiya, K.; Takeya J. Appl. Phys. Expr. 2009,
2, article number 111501. (e) Pu, S.; Li, M.; Liu, G.; Le, Z. Aust. J. Chem.
2009, 62, 464–474. (f) Pu, S.; Li, M.; Fan, C.; Liu, G.; Shen, L. J. Mol.
Struct. 2009, 919, 100–111. (g) Um, M.-C.; Kwak, J.; Hong, J.-P.; Kang,
J.; Yoon, D. Y.; Lee, S. H.; Lee, C.; Hong, J.-I. J. Mater. Chem. 2008,
18, 4698–4703. (h) Yamaguchi, T.; Uchida, K.; Irie, M. Bull. Chem. Soc.
Jpn. 2008, 81, 644–652. (i) Lo, C.; Adenier, A.; Maurel, F.; Aaron, J. J.;
Kozmik, V.; Svoboda, J. Synth. Met. 2008, 158, 6–24. (j) Gao, P.;
Beckmann, D.; Tsao, H. N.; Feng, X.; Enkelmann, V.; Pisula, W.; Muellen,
K. Chem. Commun. 2008, 1548–1550. (k) Keshtov, M. L.; Mal’tsev, E. I.;
Lypenko, D. A.; Brusentseva, M. A.; Sosnovyi, M. A.; Il’ina, M. N.; Vasnev,
V. A.; Peregudov, A. S.; Petrovskii, P. V.; Vannikov, A. V.; Khokhlov, A. R.
Polym. Sci. Ser. A 2008, 50, 18–24. (l) Kurfurst, M.; Kozmik, V.; Svoboda,
J.; Novotna, V.; Glogarova, M. Liq. Cryst. 2008, 35, 21–31.
(3) (a) Werner, E. G. G. Rec. Trav. Chim. Pays-Bas 1949, 68,
509–519. (b) Capozzi, G.; Melloni, G.; Modena, G. J. Chem. Soc. C
1970, 2621–2625. (c) Mayer, F.; Mombour, A.; Lassmann, W.; Werner,
W.; Landmann, P.; Schneider, E. Liebigs Ann. Chem. 1931, 488, 259–296.
(d) Terpstra, J. W.; Van Lausen, A. M. J. Org. Chem. 1986, 51, 230–238.
(e) Watanabe, M.; Date, M.; Kawanishi, K.; Akiyoshi, R.; Furukawa, S.
J. Heterocycl. Chem. 1991, 28, 173–176.
(4) (a) Gonzalez, J. P.; Edgar, M.; Elsegood, M. R. J. Org. Biomol.
Chem. 2011, 9, 2294–2305. (b) Li, C.-L.; Zhang, X.-G.; Fang, R.-Y.;
Zhong, P.; Li, J.-H. J. Org. Chem. 2010, 75, 7037–7040. (c) Jacubert, M.;
Provot, O.; Peyrat, J.-F.; Hamze, A.; Brion, J.-D.; Alami, M. Tetrahedron
2010, 66, 3775–3787. (d) Hussain, M.; Malik, I.; Villinger, A.; Langer, P.
Synlett 2009, 2691–2695. (e) Gopinath, P.; Nilaya, S.; Debi, T. R.;
Ramkumar, V.; Muraleedharan, K. M. Chem. Commun. 2009, 7131–7133.
(f) Bryan, C. S.; Braunger, J. A.; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 7064–7068. (g) Capperucci, A.; Degl’Innocenti, A.; Nocentini, T.;
Pollicino, S. J. Sulfur Chem. 2009, 30, 319–326. (h) Toguem, S.-M. T.;
Hussain, M.; Malik, I.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009,
50, 4962–4964. (i) Jacubert, M.; Hamze, A.; Provot, O.; Peyrat, J.-F.;
Brion, J.-D.; Alami, M. Tetrahedron Lett. 2009, 50, 3588–3592. (j) Jeong,
H. J.; Yoon, U. Y.; Jang, S. H.; Yoo, U.-A.; Kim, S. N.; Truong, B. T.; Shin,
S. C.; Yoon, Y.-J.; Singh, O. M.; Lee, S.-G. Synlett 2007, 1407–1410. (k)
Kobayashi, K.; Fujita, S.; Hase, M.; Morikawa, O.; Konishi, H. Bull.
Chem. Soc. Jpn. 2007, 80, 763–767. (l) Barluenga, J.; Vazquez-Villa, H.;
Merino, I.; Ballesteros, A.; Gonzalez, J. M. Chem.—Eur. J. 2006, 12,
5790–5805. (m) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2006, 45, 4473–4475. (n) Barluenga, J.; Vazquez-Villa., H.;
Ballesteros, A.; Gonzalez, J. M. Adv. Synth. Catal. 2005, 347, 526–530.
(o) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377–4380. (p) Yang,
S. M.; Shie, J. J.; Fang, J. M.; Nandy, S. K.; Chang, H. Y.; Lu, S. H.; Wang,
G. J. Org. Chem. 2002, 67, 5208–5215. (q) Cabiddu, M. G.; Cabiddu, S.;
Cadoni, E.; Demontis, S.; Fattuoni, C.; Melis, S. Tetrahedron 2002, 58,
4529–4533. (r) Kim, S. K.; Yang, J.; DiNinno, F. Tetrahedron Lett. 1999,
40, 2909–2912. (s) Afxantidis, J.; Bouchry, N.; Aune, J. P. J. Mol. Catal.
A: Chem. 1995, 102, 49–58. (t) Liebeskind, L. S.; Wang, J. Y. J. Org.
Chem. 1993, 58, 3350–3356. (u) Buchwald, S. L.; Qun, F. J. Org. Chem.
1989, 54, 2793–2797.
(5) For representative examples, see: (a) Gabriele, B.; Plastina, P.;
Vetere, M. V.; Veltri, L.; Mancuso, R.; Salerno, G. Tetrahedron Lett.
2010, 51, 3565–3567. (b) Gabriele, B.; Mancuso, R.; Lupinacci, E.;
Salerno, G.; Veltri, L. Tetrahedron 2010, 66, 6156–6161. (c) Gabriele, B.;
Veltri, L.; Mancuso, R.; Plastina, P.; Salerno, G.; Costa, M. Tetrahedron
Lett. 2010, 51, 1663–1665. (d) Egi, M.; Azechi, K.; Akai, S. Org. Lett.
2009, 11, 5002–5005. (e) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques,
E. F. Org. Lett. 2009, 11, 4624–4627. (f) Gabriele, B.; Mancuso, R.;
Lupinacci, E.; Spina, R.; Salerno, G.; Veltri, L.; Dibenedetto, A. Tetra-
hedron 2009, 65, 8507–8512. (g) Yada, Y.; Miyake, Y.; Nishibayashi, Y.
Organometallics 2008, 27, 3614–3617. (h) Gabriele, B.; Mancuso, R.;
Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org. Chem. 2008, 73,
4971–4977. (i) Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina, P. J. Org.
Chem. 2008, 73, 756–759. (j) Hayes, S. J.; Knight, D. W.; Menzies,
M. D.; O’Halloran, M.; Tan, W.-F. TetrahedronLett. 2007, 48, 7709–7712.
(k) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J. Org. Chem. 2007,
72, 9278–9282. (l) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.;
Plastina, P. J. Org. Chem. 2007, 72, 6873–6877. (m)Gabriele, B.; Mancuso,
R.; Salerno, G.; Costa, M. Adv. Synth. Catal. 2006, 348, 1101–1109. (n)
Gabriele, B.; Mancuso, R.; Salerno, G.; Veltri, L. Chem. Commun.
2005, 271–273. (o) Knight, D. W.; Sharland, C. M. Synlett 2004,
119–121. (p) Sakai, M.; Sasaki, M.; Tanino, K.; Miyashita, M. Tetrahedron
Lett. 2002, 43, 1705–1708. (q) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron
1997, 53, 11061–11068. (r) McDonald, F. E.; Gleason, M. M. J. Am. Chem.
Soc. 1996, 118, 6648–6659. (s) McDonald, F. E.; Connolly, C. B.; Gleason,
M. M.; Towne, T. B.; Treiber, K. D. J. Org. Chem. 1993, 58, 6952–6953. (t)
Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H.
Tetrahedron 1985, 41, 3655–3661. (u) Utimoto, K.; Miwa, H.; Nozaki, H.
Tetrahedron Lett. 1981, 22, 4277–4278.
(6) For recent representative reviews on heterocyclization reactions
induced by triple bond activation by a metal center, see: (a) Yamamoto,
T.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075–5087.
(b) Luo, P.; Tang, R.; Zhong, P.; Li, J. Chin. J. Org. Chem. 2009, 29,
1924–1937. (c) Kirsch, S. F. Synthesis 2008, 3183–3204. (d) Shen, H. C.
Tetrahedron 2008, 64, 7847–7870. (e) Weibel, J.-M.; Blanc, A.; Pale, P.
ꢁ
Chem. Rev. 2008, 108, 3149–3173. (f) Alvarez-Corral, M.; Mu~noz-
Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174–3198.
(g) Shen, H. C. Tetrahedron 2008, 64, 3885–3903. (h) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442. (i) Gabriele, B.; Salerno,
G.; Costa, M. Top. Organomet. Chem. 2006, 18, 239–272. (j) Wolfe, J. P.;
Thomas, J. S. Curr. Org. Chem. 2005, 9, 625–655. (k) Nakamura, I.;
Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198. (l) Zeni, G.; Larock,
R. C. Chem. Rev. 2004, 104, 2285–2309. (m) Alonso, F.; Beletskaya, I. P.;
Yus, M. Chem. Rev. 2004, 104, 3079–3160. (n) Gabriele, B.; Salerno, G.;
Costa, M. Synlett 2004, 2468–2483. (o) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 4101–4111. (p) Gabriele, B.;
Salerno, G. PdI2. In e-EROS (Electronic Encyclopedia of Reagents for
Organic Synthesis); Crich, D., Ed.; John Wiley & Sons: Chichester, 2006.
(q) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet.
Chem. 2003, 687, 219–228.
(7) For recent leading examples of reactions involving metal sulfide
intermediates, see:(a) Ananikov, V. P.; Zalesskiy, S. S.; Kachala, V. V.;
Beletskaya, I. P. J. Organomet. Chem. 2011, 696, 400–405. (b) Ananikov,
V. P.; Gayduk, K. A.; Orlov, N. V.; Beletskaya, I. P.; Khrustalev, V. N.;
Antipin, M. Y. Chem.—Eur. J. 2010, 16, 2063–2071. (c) Ananikov, V. P.;
Gayduk, K. A.; Beletskaya, I. P.; Khrustalev, V. N.; Antipin, M. Y. Eur. J.
Org. Chem. 2009, 1149–1161. (d) Ananikov, V. P.; Gayduk, K. A.;
Beletskaya, I. P.; Khrustalev, V. N. Chem.—Eur. J. 2008, 14, 2420–2434.
(e) Beletskaya, I. P.; Ananikov, V. P. Eur. J. Org. Chem. 2007, 3431–3444.
(f) Ananikov, V. P.; Orlov, N. V.; Beletskaya, I. P.; Khrustalev, V. N.;
Antipin, M. Y.; Timofeeva, T. V. J. Am. Chem. Soc. 2007, 129, 7252–7253.
(8) The use of KI was needed in order to solubilize PdI2 by forming
the PdI42- anion. As we already observed in other cases, the excess of KI
tended to stabilize the anionic complex. For recent examples on the use
of the PdI2/KI system in heterocycles synthesis, see refs 5aꢀ5c, 5f, 5h,5i,
5kꢀ5n, 6i, 6n, 6p, 6q and (a) Gabriele, B.; Veltri, L.; Salerno, G.;
Mancuso, R.; Costa, M. Adv. Synth. Catal. 2010, 352, 3355–3363. (b)
Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Costa, M.; Dibene-
detto, A. Tetrahedron Lett. 2009, 50, 7330–7332. (c) Della Cꢀa, N.;
Campanini, F.; Gabriele, B.; Salerno, G.; Massera, C.; Costa, M. Adv.
Synth. Catal. 2009, 351, 2423–2432. (d) Gabriele, B.; Mancuso, R.;
Salerno, G. J. Org. Chem. 2008, 73, 7336–7341. (e) Gabriele, B.; Plastina,
P.; Salerno, G.; Mancuso, R.; Costa, M. Org. Lett. 2007, 9, 3319–3322.
(f) Gabriele, B.; Plastina, P.; Salerno, G.; Mancuso, R. Synthesis 2006,
4247–4251. (g) Gabriele, B.; Salerno, G.; Fazio, A.; Veltri, L. Adv. Synth.
Catal. 2006, 348, 2212–2222. (h) Gabriele, B.; Salerno, G.; Veltri, L.;
Mancuso, R.; Li, Z.; Crispini, A.; Bellusci, A. J. Org. Chem. 2006, 71,
7895–7898. (i) Bacchi, A.; Costa, M.; Della Cꢀa, N.; Gabriele, B.; Salerno,
G.; Cassoni, S. J. Org. Chem. 2005, 70, 4971–4979. (j) Gabriele, B.;
Plastina, P.; Salerno, G.; Costa, M. Synlett 2005, 935–938. (k) Gabriele,
B.; Salerno, G.; Plastina, P. Lett. Org. Chem. 2004, 1, 134–136. (l) Costa,
M.; Della Cꢀa, N.; Gabriele, B.; Massera, C.; Salerno, G.; Soliani, M. J. Org.
Chem. 2004, 69, 2469–2477. (m) Gabriele, B.; Salerno, G.; Plastina, P.;
Costa, M.; Crispini, A. Adv. Synth. Catal. 2004, 346, 351–358. (n) Bacchi, A.;
Costa, M.; Della Cꢀa, N.; Fabbricatore, M.; Fazio, A.; Gabriele, B.; Nasi, C.;
8285
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286

The Journal of Organic Chemistry
ARTICLE
Salerno, G. Eur. J. Org. Chem. 2004, 574–585. (o) Gabriele, B.; Salerno, G.;
Fazio, A. J. Org. Chem. 2003, 68, 7853–7861. (p) Gabriele, B.; Salerno, G.;
Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251–6259. (q) Gabriele, B.;
Veltri, L.; Salerno, G.; Costa, M.; Chiusoli, G. P. Eur. J. Org. Chem. 2003,
1722–1728. (r) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J. Org.
Chem. 2003, 68, 601–604. (s) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.;
Salerno, G. J. Org. Chem. 2002, 67, 4450–4457. (t) Gabriele, B.; Salerno, G.;
Veltri, L.; Costa, M.; Massera, C. Eur. J. Org. Chem. 2001, 4607–4613. (u)
Gabriele, B.; Salerno, G.; Fazio, A. Org. Lett. 2000, 2, 351–352. (v) Gabriele,
B.; Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli, G. P. J. Org. Chem. 1999,
64, 7693–7699. (w) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999,
64, 7687–7692. (x) Chiusoli, G. P.; Costa, M.; Gabriele, B.; Salerno, G.
J. Mol. Catal. 1999, 143, 297–310. (y) Fazio, A.; Gabriele, B.; Salerno, G.
Tetrahedron 1999, 55, 485–502. (z) Gabriele, B.; Salerno, G.; Costa, M.;
Chiusoli, G. P. Tetrahedron Lett. 1999, 40, 989–990.
Valova, T. M.; Golotyuk, Z. O.; Barachevsky, V. A. Russ. Chem. Bull. 2005,
54, 2697–2700. To the best of our knowledge, no methods are known so
far for the synthesis of 5 by heterocyclization of acyclic precursors.
(14) Toste, F. D.; Lough, A. J.; Still, I. W. J. Tetrahedron Lett. 1995,
36, 6619–6622.
(15) Topolski, M. J. Org. Chem. 1995, 60, 5588–5594.
(16) Schellenberg, K. A.; Westheimer, F. H. J. Org. Chem. 1965, 30,
1859–1862.
(9) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000; pp 233, 260.
(10) For recent reviews on reactivity of thiols, see: (a) Koval’, I. V.
Russ. J. Org. Chem. 2007, 43, 319–346. (b) Koval’, I. V. Russ. J. Org. Chem.
2005, 41, 631–648. For a recent review on thiol-mediated radical
cyclization, see:(c) Majumdar, K. C.; Debnath, P. Tetrahedron 2008,
64, 9799–9820.
(11) For some other examples of radical cation formation induced by
an initial thiyl radical addition, see: (a) Crich, D.; Mo, X.-S. J. Am. Chem.
Soc. 1997, 119, 249–250. (b) Gabriele, B.; Mancuso, R.; Salerno, G. Eur.
J. Org. Chem. 2010, 3459–3464. (c) For a literature overview on ionic
fragmentation of radical intermediates to give radical cations, see: Crich,
D.; Shirai, M.; Brebion, F.; Rumthao, S. Tetrahedron 2006, 62, 6501–6518.
(12) (E)-2-(1-Alkenyl)benzothiophenes 3 have been mainly pre-
pared by coupling, condensation, or olefination reactions starting from
the corresponding functionalized benzothiophene precursors; for recent
examples, see: (a) Aloui, F.; Moussa, S.; Hassine, B. B. Tetrahedron Lett.
2011, 52, 572–575. (b) Zhing, M.; Zhou, J.; Kan, J.; Wang, M.; Su, W.;
Hong, M. Chem. Commun. 2010, 46, 5455–5457. (c) Fu, Z.; Huang, S.;
Su, W.; Hong, M. Org. Lett. 2010, 12, 4992–4995. (d) Tseng, N.-W.;
Lautens, M. J. Org. Chem. 2009, 74, 1809–1811. (e) Zhao, J.; Huang,
L.; Cheng, K.; Zhang, Y Tetrahedron Lett. 2009, 50, 2758–2761. (f)
Hussein, M.; Malik, I.; Villinger, A.; Langer, P. Synlett 2009, 2691–2695.
(g) Chintareddy, V. R.; Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009,
74, 8118–8132. (h) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org.
Lett. 2008, 10, 1159–1162. (i) Um, M.-C.; Hong, J.-P.; Kang, J.; Yoon,
D. Y.; Lee, S. H.; Hong, J.-I.; Jang, J.; Kim, J.-J. New J. Chem. 2008, 32,
2006–2010. (j) Choi, H.; Lee, J. K.; Song, K.; Kang, S. O.; Ko, J.
Tetrahedron 2007, 63, 3115–3121. (k) Buszek, K. R.; Brown, N. Org.
Lett. 2007, 9, 707–710. (l) Chu, L.-T.; Yu, P.-C.; Wu, B.-J.; Liao, Y.-C.;
Chou, C.-H. Heterocycles 2007, 71, 165–173. (m) Hopf, H.; Hucker, J.;
Ernst, L. Eur. J. Org. Chem. 2007, 1891–1904. (n) Choi, H.; Lee, J. K.;
Song, K.; Kang, S. O.; Ko, J. Tetrahedron 2007, 63, 3115–3121. (o)
Yamano, Y.; Fujita, Y.; Mizuguchi, Y.; Nakagawa, K.; Okano, T.; Ito, M.;
Wada, A. Chem. Pharm. Bull. 2007, 55, 1365–1370. (p) Sato, K.; Katayama,
Y.; Yamagishi, T.; Arai, S. J. Heterocycl. Chem. 2006, 43, 177–181.
(q) Modzelewska, A.; Pettit, C.; Achanta, G.; Davidson, N. E.; Huang,
P.; Khan, S. R. Bioorg. Med. Chem. 2006, 14, 3491–3495. (r) Palmer,
B. D.; Thompson, A. M.; Booth, R. J.; Dobrusin, E. M.; Kraker, A. J.; Lee,
H. H.; Lunney, E. A.; Mitchell, L. H.; Ortwine, D. F.; Smaill, J. B.; Swan,
L. M.; Denny, W. A. J. Med. Chem. 2006, 49, 4896–4911. (s) Paizs, C.;
Katona, A.; Retey, J. Chem.—Eur. J. 2006, 12, 2739–2744. A few
methods based on heterocyclization reactions have also been developed:
see, for example, refs 4c and 4f.
(13) Only a few examples are reported in the literature on the
synthesis of 2-alkoxymethylbenzothiophenes 5, mainly based on alkyla-
tion of the corresponding alcoholic derivatives: (a) Voskressensky, L. G.;
Kovaleva, S. A.; Borisova, T. N.; Listratova, A. V.; Varlamov, A. V.; Eresko,
A. B.; Tolkunov, V. S.; Tolkunov, S. V. Tetrahedron 2010, 66, 9421–9430.
(b) Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.; Sorokina,
E. A.; Tolkunov, S. V.; Varlamov, A. V. Russ. Chem. Bull. 2007, 56,
1041–1048. (c) Yarovenko, V. N.; Es’kov, A. A.; Semenov, S. L.; Zavarzin,
I. V.; Kadentsev, V. I.; Kalik, M. A.; Krayushkin, M. M.; Strokach, Y. P.;
8286
dx.doi.org/10.1021/jo201471k |J. Org. Chem. 2011, 76, 8277–8286