Tandem Oxidative Phenol Dearomatization/Formal [3+2] Annulation Protocol en Route to Highly Functionalized Benzothiophenes

Article abstract of DOI:10.1055/s-0036-1588415

A new strategy for the synthesis of benzothiophenes through formal [3+2] annulation of sulfanylacetaldehyde and cyclohexa-2,4-dien-1-one monoketals has been developed. This approach relies on the ease of aromatization of tetrahydrobenzothiophenone derivatives prepared by the aforementioned protocol. Given the ready accessibility of various substituted cyclohexa-2,4-dien-1-one monoketals, a range of benzothiophene derivatives became available.

Full text of DOI:10.1055/s-0036-1588415

SYNLETT
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4
3
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2
0
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©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
A
letter
Synlett
S. K. Chittimalla, C. Bandi
Letter
Tandem Oxidative Phenol Dearomatization/Formal [3+2] Annula-
tion Protocol En Route to Highly Functionalized Benzothiophenes
Santhosh Kumar Chittimalla*
Chennakesavulu Bandi
2 3
1. PhI(OAc) , CH OH, 0 °C to r.t., 15 min then
OH
OH
S
X
X
OH
3
H CO
H3CO
NaHCO3 (5.0 equiv),HO
X
(0.6 equiv), 4 h
S
Medicinal Chemistry Department, AMRI Singapore Research
Centre, 61 Science Park Road, #05-01, The Galen, Science Park
II, Singapore 117525, Singapore
R1
R1
S
2. HCl, 1,4-dioxane, 50 °C, 2 h to 16 h
R2
R2
X = H or CH3
santhosh.chittimalla@amriglobal.com
up to 84% over 3 steps
chemcsk@gmail.com
Tandem dearomatization−[3+2] annulation followed by
rearomatization leads to benzothiophenes
Received: 26.10.2016
O
Accepted after revision: 17.01.2017
Published online: 09.02.2017
DOI: 10.1055/s-0036-1588415; Art ID: st-2016-b0727-l
N
N
Benocyclidine
dopamine reuptake
inhibitor
S
O
Abstract A new strategy for the synthesis of benzothiophenes
through formal [3+2] annulation of sulfanylacetaldehyde and cyclo-
hexa-2,4-dien-1-one monoketals has been developed. This approach
relies on the ease of aromatization of tetrahydrobenzothiophenone de-
rivatives prepared by the aforementioned protocol. Given the ready ac-
cessibility of various substituted cyclohexa-2,4-dien-1-one monoketals,
a range of benzothiophene derivatives became available.
OH
CH3
HO
S
O
Raloxifene
S
N
estrogen receptor
modulator
OH
HO
HO
HO
Zileuton
5-lipoxygenase inhibitor
NH2
O
Cl
N
S
N
OH
O
O
OH
Cl
Key words cyclohexadienones, benzothiophenes, cycloaddition, tan-
dem reactions, dearomatization
HO
H
S
O
Sertaconazole
antifungal agent
Echinothiophene
Cl
O
In recent years, the sulfanylacetaldehyde dimer 1,4-
dithiane-2,5-diol (1) has proved to be an excellent precur-
sor for the synthesis of thiaheterocycles. Numerous hetero-
Figure 1 Structures of several pharmaceuticals and a natural product
containing a benzothiophene ring
1
2
3
cyclic systems, including thiophenes, thiazoles, thiazines,
thiazolidinethiones,4 oxathiazines, and benzothiophenes6
have been prepared by using 1,4-dithiane-2,5-diol (1) as a
reactant. For instance, unsaturated functionalities including
5
nylacetaldehyde (1′) to synthesize benzothiophene deriva-
tives. For such a study, an appropriate choice of a Michael
acceptor was crucial. Our recent work had shown that cy-
clohexa-2,4-dien-1-one monoketals 3, produced by dearo-
matization of the corresponding 2-methoxyphenols 2
(Scheme 1), are useful Michael acceptors.14 Additionally, for
the first time, these linear conjugate dienone system have
been shown to participate readily in the Baylis–Hillman re-
action,15 i.e., the Michael addition of a tertiary amine cata-
lyst (nucleophile) to a dienone 3, followed by an intermolec-
ular aldol reaction with an aryl aldehyde (electrophile), and
finally elimination of the tertiary amine catalyst. Conse-
quently, we surmised that the cyclohexa-2,4-dien-1-one
monoketal 3 might undergo a tandem thia-Michael addi-
tion/intramolecular aldol reaction (a formal [3+2] annula-
tion) with sulfanylacetaldehyde (1′), which contains both
nucleophilic and electrophilic reaction centers, to give the
corresponding tetrahydrobenzothiophenone derivative 4.
7
8
9
10
11
cyclic enone, alkyne, nitrile, carbonyl,
imine,
azomethine imine groups participate efficiently in formal
3+2]- or [3+3]-annulation reactions with sulfanylacetalde-
or
12
[
hyde (1′), generated in situ from its dimer 1, to give the re-
quired thiaheterocycles. Benzothiophene, an aromatic thia-
heterocycle, is generally recognized as a privileged struc-
ture in medicinal chemistry. A few illustrative examples of
pharmaceuticals and a natural product containing a ben-
zothiophene moiety are shown in Figure 1.
Although several procedures have been reported in the
13
literature, new synthetic methods for preparing ben-
zothiophene derivatives from readily accessible materials in
a simple and efficient manner are highly desirable. With
considerable literature on hand, we were interested in ex-
tending a formal [3+2]-annulation protocol involving sulfa-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Synlett
S. K. Chittimalla, C. Bandi
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Furthermore, we predicted that such a product would read-
ily undergo aromatization to generate the oxygenated ben-
zothiophene 5. Here, we report our initial results for this
approach and we show it to be a worthy addition to the list
of protocols available for the synthesis of benzothiophenes.
the two steps (Scheme 1). The stereochemistry of com-
pound 4a was assigned on the basis of the observed 2D
NOESY cross-peaks. In the case of phenol 2d, although the
[3+2]-annulated product 4d was not isolated, we were
pleased to obtain the dihydrobenzothiophene 6d in 89%
yield (Scheme 1), formed through the partial aromatization
of 4d during column chromatographic purification of the
product.
OH
O
OH
PhI(OAc)2, CH3OH, 0 °C, 15 min
then NaHCO3 followed by
H3CO
H CO
H
H3CO
R1
3
S
S
OH
R1
S
Next, to expand the generality of the reaction, we
turned our attention to the 4-substituted phenols 2g–i as
substrates. The in situ generated 4-tert-butyl-substituted
dienone 3g, upon [3+2] cycloaddition with sulfanylacetal-
dehyde (1′), gave an inseparable mixture of two diastereo-
mers 4g and 4g′ in a 1:1.5 ratio. Surprisingly, the reaction of
sulfanylacetaldehyde (1′) with 4-bromo- or 4-chloro-sub-
stituted cyclohexa-2,4-dien-1-ones 3h and 3i, respectively,
generated in situ, was complex. Evidently, the expected tet-
rahydrobenzothiophenones 4h(h′) and 4i(i′) were unstable
H
R2
a–i
1
r.t., 4 h
R2
2
HO
4a–h
a
4
a / 90%; 4b / 85%; 4c / 88%; 4d / --- ;
b
4
e / 85%; 4f / 90%; 4g/4g': 84% (dr, 1:1.5) ;
O
1
c,d
4h(h') or 4i(i') / --- (highly unstable)
H3CO 6
H3CO
2
H
OH
OH
5
HS
3
R1
O
H3CO
4
R2
3
1'
S
H3CO2C
3
and 1' are generated in situ
6
d / A: 89%
a): R1 = OCH3, R2 = H; (b): R1 = CH3, R2 = H; (c): R1 = ketal, R2 = H;
d): R1 = CO2CH3, R2 = H; (e): R1 = Br, R2 = H; (f): R1 = Cl, R2 = H;
g): R1 = H, R2 = t-Bu; (h): R1 = H, R2 = Br; (i): R1 = H, R2 = Cl
(
(
(
ketal:
O
19
and decomposed during the course of isolation. Moving
forward, we were pleased to find that the naphthoquinone
monoketals 3j and 3k participated in the formal [3+2]-an-
nulation reactions with in situ generated sulfanylacetalde-
hyde (1′) to give the diastereomeric tetrahydronaph-
O
O
O
O
OH
OH
H3CO
H3CO
H3CO
H3CO
H
H
H3CO
H3CO
H
H
1
20
S
+
S
thothiophenone derivatives 4j/4j′ and 4k/4k′, respectively.
Et3N
With tetrahydrobenzothiophenones 4 in hand, our next
objective was to convert these products into the corre-
sponding benzothiophenes. Initially we treated a solution
of compound 4a in 1,4-dioxane with 4 N HCl and heated the
mixture to 50 °C. After one hour of reaction time, the ex-
pected benzothiophene 5a was produced in 82% yield. From
this result, it became clear that both the tandem phenol ox-
idation/formal [3+2] annulation and aromatization reac-
tions were clean and high-yielding. Consequently, in the re-
action sequence to prepare the benzothiophene derivatives
CH2Cl2
r.t., 8 h
X
X
X
X = H: 4j+4j' (47%, 0.6:1.0)b
X = Br: 4k / 45%
3
j: X = H; 3k: X = Br
4j' / 38%
4k' / 37%
O
Hd
H3CO
Hc
Hb
OH
He
Hf
OH
H3CO
H3CO
H3CO
4
N HCl
S
H3CO
1,4-dioxane
50 °C, 1 h
S
Ha
4a
5a / 82%
Scheme 1 Synthesis of tetrahydrobenzothiophenones 4 through a for-
mal [3+2] annulation of a cyclohexa-2,4-dien-1-one 3 with sulfanylacet-
aldehyde (1′), both formed in situ. The H NMR of the crude reaction
mixture indicated that compound 4d exists as a single isomer. Ratio
obtained by H NMR integration of diagnostic peaks. The formation of
5
from phenols 2, we decided to skip the purification after
a
1
the [3+2] annulation stage, thereby simplifying the synthet-
ic protocol. At the outset, with phenols 2a, 2b, 2d, and 2l,
after the tandem dearomatization/formal [3+2]-annulation
process, the crude reaction mixture was treated with 4 N
b
1
c
1
compound 4i(i′) was confirmed by acquiring the H NMR spectra of col-
umn fractions (which eventually became complex), whereas 4h(h′) be-
17
came complex during purification. d See ref. 18.
HCl in 1,4-dioxane and heated to 50 °C for two hours. To
our gratification, the corresponding benzothiophene deriv-
atives 5a (84%), 5b (72%), 5d (70%), and 5l (79%) were ob-
tained in good yields over the three synthetic steps (Table 1,
entries 1, 2, 4, and 7). We realized that minimal workup af-
ter the [3+2] annulation was required for the aromatization
step to proceed efficiently. Due to the acidic reaction condi-
tions, deprotection of the ketal functional group (Table 1,
entry 3) was expected; however, the formation of product
8c was not. Under these conditions, we believe that the in-
termediate [3+2]-annulation product 4c is prone to dime-
thoxyacetal deprotection before aromatization, thereby de-
livering product 8c (Scheme 2). A similar result was ob-
tained in the case of 4-chloro-2-methoxyphenol (2i) (entry
8) and the naphthoquinone monoketal 2j (entry 10); how-
ever the extent of dimethoxyacetal deprotection was de-
First, it was essential to study the [3+2]-cycloaddition
reaction of dienones 3 and sulfanylacetaldehyde (1′) to give
the corresponding tetrahydrobenzothiophenones 4. Conse-
quently, PhI(OAc) was added to methanolic solutions of
2
2
-methoxyphenols 2 at 0 °C, and the mixture was stirred
for 15 minutes. Once TLC indicated the disappearance of
the starting phenol 2, 5.0 equivalents of NaHCO and 0.6
3
equivalents of 2,5-dihydroxy-1,4-dithiane (1) were added
16–18
to the mixture.
To our satisfaction, the dienone 3 and
sulfanylacetaldehyde (1′), both generated in situ, under-
went a formal [3+2] cycloaddition to give the corresponding
tetrahydrobenzothiophenone derivatives 4a–c, 4e, and 4f
after a four hour reaction time in 85–90% isolated yield over
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Synlett
S. K. Chittimalla, C. Bandi
Letter
pendent on the substrate (8i: 16%, along with 5i: 60%, and
j: 74%). When the aromatization step was conducted at
Table 1 (continued)
Entry Reactant
8
b
Product(s) (yield [%])
21
room temperature, product 9 (62%) was isolated along
with the desired benzothiophene 5e (20%) (entry 5 and
Scheme 2). To our delight, upon heating the reaction mix-
ture and prolonging the reaction time, benzothiophene 5e
was produced exclusively in 78% yield. However, with the
chlorophenol 2f, this was not the case (entry 6); even after
conducting the reaction with prolonged heating, the by-
product 10 was isolated in 14% yield, although major reac-
tion product, the benzothiophene derivative 5f, was formed
O
OH
S
OH
OH
H
H
H3CO
H3CO
Cl
H3CO
Cl
6d
Cl
S
Cl
2
f
e
5
f (58);
10 (14)
OH
OH
H3CO
H3CO
14d,22
7
3
H C
3
H C
in 58% yield. Next, the dienone 4m,
prepared in situ
S
H3C
H3C
from phenol 2m, was treated with sulfanylacetaldehyde (1′)
for four hours. The crude reaction mixture from this step,
on treatment with 4 N HCl at 50 °C, gave benzothiophene
CH3
CH3
2l
5l (79)
OH
OH
OH
5m in 73% yield over the three steps (entry 9).
H3CO
H3CO
HO
8
Table 1 A Three-Step Phenol Dearomatization/Formal [3+2] Annula-
S
S
tion/Aromatization Protocol for the Synthesis of Highly Oxygenated
Benzothiophene Derivatives
Cl
Cl
Cl
a
2i
5i (60);
8i (16)
OH
OH
1. PhI(OAc)2, CH3OH
0
°C to r.t., 15 min then NaHCO3 (5.0 equiv)
H3CO
H3CO
OH
S
OH
R2
HO
OH
9
H3CO
H3CO
S
S
1
(0.6 equiv), 4 h
CH3
O
CH3
R1
R1
S
2. HCl, 1,4-dioxane, 50 °C, 2 h to 16 h
2
m
5m (73)
R2
2
5
OH
H3CO
H3CO
b
HO
Entry Reactant
Product(s) (yield [%])
1
0
S
OH
OH
OH
OH
OH
H3CO
H3CO
1
2
j
8j (74)
S
S
H3CO
H3CO
a
b
c
See ref. 17.
From observed 2D NOESY cross-peaks.
The reaction was conducted at r.t. for 1.5 h.
2
a
5a (84)
d
e
After HCl addition, the mixture was heated at 50 °C for 8 h.
See Scheme 2. The stereochemistry is tentatively assigned.
H3CO
H3C
H3CO
H3C
2
O
H
OH
OH
OH
2
b
bb (72)
H3CO
R
5
H CO
HO
3
OH
S
S
S
R
R
H3CO
Ketal
HO
Cl
9, 10
5
8
3
4
Cl–
S
OHC
2
c
8c (65)
O
O
OH
OH
OH
OH
H3CO
O
H+
4
H3CO
H3CO
S
S
R
R
I
II
S
H3CO2C
H3CO2C
2
d
5d (70)
Scheme 2 Possible pathway for the formation of products 5, 8, 9, and
1
0
O
OH
OH
OH
H
H
H3CO
Br
H3CO
Br
H3CO
Next, we examined the possibility of a base-catalyzed
5
aromatization process.23 However, when compound 4a was
treated with t-BuOK, the unexpected product 11 was ob-
S
S
Br
Cl
2
e
c
d
9e (62)c
5
e (20) , (78) ;
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
Synlett
S. K. Chittimalla, C. Bandi
Letter
tained in a high yield probably through aerial oxidation of
the tetrahydrobenzothiophenone 4a under the basic condi-
tions (Scheme 3). However, when tetrahydrobenzothiophe-
none 4b was subjected to the same reaction conditions, al-
though the aromatized product 5b was obtained, the major
byproduct was dienone 2b (formed by the retro-aldol/ret-
ro-Michael process). It therefore appeared that basic reac-
tion conditions are inappropriate to effect the desired con-
version. The functional groups present in compounds 5
suggest that further derivatization might be feasible. For ex-
ample, a methanolic solution of benzothiophene 5a on oxi-
S
OH
13
O
O
H3C
H3CO
H3CO
S
Et N
H3CO
H3CO
OH
HO
3
CH2Cl2
r.t., 30 min
S
R
R
4
N HCl
1,4-dioxane
R = OCH3 (3a); CH3 (3b); t-Bu (3l)
50 °C, 16 h
OH
CH3
OH
OH
CH3
CH3
H3CO
H3C
H3CO
H3CO
H3CO
H3C
S
S
S
dation with PhI(OAc) gave product 11 in quantitative yield
H3C
CH3
2
(Scheme 3). Furthermore, the free hydroxy group in ben-
14a 55%
14b 30%
14l 31%
zothiophene 5a could be methylated under general alkyla-
tion conditions to give the trimethoxybenzothiophene 12
OH
H3CO
H3CO
O
S
CH3
(Scheme 3).
1
5 19%
O
H3CO
H3CO
Scheme 4 A two-step formal [3+2]-annulation/aromatization protocol
for the synthesis of benzothiophene derivatives using 1-sulfanylpropan-
2-one as a three-atom source
KOt-Bu (2.0 equiv)
PhI(OAc)2
4a
5a
S
THF
0 °C, 1 h
H3CO
CH3OH
r.t., 30 min
5
11
CH3I
62%
95%
(
2.0 equiv) CH CN
3
K2CO3 50 °C, 3 h
2.5 equiv)
(
KOt-Bu (2.0 equiv)
4b
5b + 2b
1:3)
derivatives. Efforts to improve the yields of the 3-methyl-
benzothiophene derivatives 14 are being pursued. At the
same time, studies on applications of these findings are un-
derway.
THF
0 °C, 1 h
OCH3
(
5
1
H NMR
H3CO
H3CO
integration of
crude reaction
mixture
S
1
2 / 95%
Scheme 3 Attempted base-catalyzed aromatization of the [3+2]-annu-
lation products 4a and 4b, and further reactions of benzothiophene 5a
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588415.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
Next, we explored the use of 1-sulfanylpropan-2-one
commercially available as its dimer) as a potential three-
(
References and Notes
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three-step tandem phenol dearomatization/[3+2] annula-
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be unsuitable, providing a complex mixture of products.
Consequently, we treated 1-sulfanylpropan-2-one, generat-
ed in situ, with a column-purified cyclohexa-2,4-dien-1-
one 3a, 3b, or 3l for 30 minutes until TLC indicated con-
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(
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(
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
Synlett
S. K. Chittimalla, C. Bandi
Letter
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(
10) (a) Goodyear, M. D.; Hill, M. L.; West, J. P.; Whitehead, A. J. Tetra-
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96 mg, 0.63 mmol, 1.0 equiv). After 2 h reaction time, 4 N HCl in
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994.
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(
(
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Ed. 2016, 55, 6506.
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3
(
(
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H), 3.29 (s, 3 H), 2.89 (dd, J = 11.6, 2.8 Hz, 1 H), 2.50 (d, J = 5.2 Hz,
13
1 H). C NMR (100 MHz, CDCl ): δ = 200.4 (C), 152.1 (C), 101.9
3
3876. (b) Yu, H.; Zhang, M.; Li, Y. J. Org. Chem. 2013, 78, 8898.
(CH), 96.8 (C), 74.6 (CH), 58.5 (CH), 55.4 (CH ), 52.2 (CH ),
3
3
(
(
2
c) Wu, B.; Yoshikai, N. Angew. Chem. Int. Ed. 2013, 52, 10496.
d) Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem.
011, 76, 7546. (e) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew.
51.5 (CH ), 42.6 (CH), 39.9 (CH ). ESI-MS: m/z = 229 [C11H16O5S
3
2
+
– CH OH + H] .
3
1
5a: H NMR (400 MHz, CDCl ): δ = 7.39 (dd, J = 5.6, 0.8 Hz, 1 H),
3
Chem. Int. Ed. 2006, 45, 4473. (f) Yue, D.; Larock, R. C. J. Org.
Chem. 2002, 67, 1905. For non-metal-mediated processes, see:
7.19 (d, J = 5.6 Hz, 1 H), 6.94 (app s, 1 H), 6.21 (br s, 1 H), 3.925
13
(s, 3 H), 3.921 (s, 3 H). C NMR (100 MHz, CDCl ): δ = 151.4 (C),
3
(g) Kong, Y.; Yu, L.; Fu, L.; Cao, J.; Lai, G.; Cui, Y.; Hu, Z.; Wang, G.
143.7 (C), 136.4 (C), 132.7 (C), 123.3 (C), 122.9 (CH), 120.1 (CH),
Synthesis 2013, 45, 1975. (h) Zhang, X.; Zeng, W.; Yang, Y.;
Huang, H.; Liang, Y. Synlett 2013, 24, 1687. (i) Hessian, K. O.;
Flynn, B. L. Org. Lett. 2003, 5, 4377.
96.4 (CH), 61.3 (CH ), 56.0 (CH ). ESI-MS: m/z = 211 [C10H10O S +
H] .
3
3
3
+
6-Chloro-5-methoxy-1-benzothiophene-4-ol (5f)
1
(
14) (a) Chittimalla, S. K.; Bandi, C. Tetrahedron Lett. 2016, 57, 15.
brown solid: yield: 78 mg (58%). H NMR (400 MHz, CDCl ): δ =
3
(
2
b) Chittimalla, S. K.; Kuppusamy, R.; Akavaram, N. Synlett 2015,
6, 613. (c) Chittimalla, S. K.; Kuppusamy, R.; Bandi, C. Synlett
7.43 (td, J = 5.6, 0.8 Hz, 2 H), 7.35 (d, J = 5.6 Hz, 1 H), 6.13 (s, 1 H),
13
3.95 (s, 3 H). C NMR (100 MHz, CDCl ): δ = 144.3 (C), 138.7 (C),
3
2
014, 25, 1991. (d) Chittimalla, S. K.; Bandi, C.; Putturu, S.;
136.9 (C), 128.4 (C), 126.1 (CH), 124.6 (C), 120.2 (CH), 114.5
+
Kuppusamy, R.; Boellaard, K. C.; Tan, D. C. T.; Lum, D. M. J. Eur. J.
Org. Chem. 2014, 2565. (e) Vitaku, E.; Njardarson, J. T. Eur. J. Org.
Chem. 2016, 3679.
(CH), 61.5 (CH ); ESI-MS: m/z = 215 [C H ClO S + H] .
3
9
7
2
5-Methoxy-7-methyl-1-benzothiophene-4-ol (5m)
1
brown solid: yield: 103 mg (73%). H NMR (400 MHz, CDCl ): δ =
3
(15) Chittimalla, S. K.; Koodalingam, M.; Bandi, C.; Putturu, S.;
Kuppusamy, R. RSC Adv. 2016, 6, 1460.
7.50 (d, J = 5.6 Hz, 1 H), 7.36 (d, J = 5.6 Hz, 1 H), 6.86 (s, 1 H), 5.87
13
(s, 1 H), 3.93 (s, 3 H), 2.50 (s, 3 H). C NMR (100 MHz, CDCl ): δ
3
(
16) (a) See the Supporting Information for the synthetic proce-
dures. (b) The relative stereochemistry of all the products was
tentatively assigned on the basis of the 2D NOESY spectra of 4a
= 142.4 (C), 138.5 (C), 134.0 (C), 128.4 (C), 125.6 (CH), 122.7 (C),
120.6 (CH), 111.1 (CH), 57.3 (CH ), 19.9 (CH ). ESI-MS: m/z = 195
3
3
+
[C10H10O S + H] .
2
7
and 4f. Literature precedents also indicate a similar stereo-
4,5-Dihydroxy-1-benzothiophene-6-carbaldehyde (8c)
1
chemical preference for the [3+2]-annulation product.
17) 3-Hydroxy-5,5,6-trimethoxy-3,3a,5,7a-tetrahydro-1-ben-
zothiophen-4(2H)-one (4a) and 5,6-dimethoxy-1-benzothio-
phene-4-ol (5a); Typical Procedure
dark orange solid: yield: 53 mg (65%). H NMR (400 MHz,
(
CDCl ): δ = 10.7 (s, 1 H), 9.95 (s, 1 H), 7.66 (d, J = 0.8 Hz, 1 H),
3
7.64 (d, J = 5.6 Hz, 1 H), 7.50 (dd, J = 5.6, 0.8 Hz, 1 H), 6.01 (br s, 1
13
H). C NMR (100 MHz, CDCl ): δ = 196.2 (C), 142.1 (C), 138.9
3
PhI(OAc) (251 mg, 0.78 mmol, 1.2 equiv) was added to a solu-
tion of 2,3-dimethoxyphenol (2a; 100 mg, 0.65 mmol, 1.0
(C), 134.3 (C), 132.2 (CH + C), 120.4 (CH), 119.7 (CH), 119.5 (C).
2
–
ESI-MS: m/z = 193 [C H O S – H] .
9
6
3
equiv) in MeOH (2 mL) at 0 °C, and the mixture was stirred for
6,7-Dichloro-3-hydroxy-5-methoxy-3,3a,7,7a-tetrahydro-1-
1
5 min, after which NaHCO (273 mg, 3.25 mmol, 5.0 equiv) and
benzothiophen-4(2H)-one (10)
orange gum: yield: 23 mg (14%). H NMR (400 MHz, CDCl ): δ =
3
1
2,5-dihydroxy-1,4-dithiane (1; 59 mg, 0.39 mmol, 0.6 equiv)
3
were added sequentially and the mixture was stirred at r.t. for 4
h. The solvent was then evaporated and residue was diluted
5.10 (t, J = 2.8 Hz, 1 H), 4.27–4.25 (m, 1 H), 3.85 (s, 3 H), 3.84–
3.83 (m, 1 H), 3.13–3.09 (m, 1 H), 2.92 (br s, 1 H), 2.86 (dd, J =
15.2, 1.6 Hz, 1 H), 2.59 (dd, J = 15.2, 3.2 Hz, 1 H). C NMR (100
13
with H O, and the mixture was extracted with EtOAc. The com-
2
bined organic extracts were dried (Na SO ), filtered, and con-
MHz, CDCl ): δ = 188.8 (C), 149.8 (C), 133.5 (C), 68.2 (CH), 60.8
2
4
3
centrated, and the crude residue was purified by column chro-
matography (silica gel, EtOAc–hexanes)/hexanes to give 4a as a
yellow-to-orange gum; yield: 151 mg (90%).
(CH ), 57.7 (CH), 56.5 (CH), 48.7 (CH), 28.6 (CH ). ESI-MS: m/z =
3
2
+
269 [C H Cl O S + H] .
9
10
2
3
5,6-dimethoxy-3-methyl-1-benzothiophene-4-ol
Typical Procedure
(14a);
Alternatively, the crude product was diluted with 1,4-dioxane
(
6
0.5 mL), followed by addition of 4 N HCl in 1,4-dioxane (1 mL,
.15 mmol, ~9.5 equiv). The resulting mixture was then heated
at 50 °C for 2 h to give the benzothiophene derivative 5a; yield:
15 mg (84%). All the benzothiophene derivatives were
2,5-Dimethyl-2,5-dihydroxy-1,4-dithiane (13; 97 mg, 0.54
mmol, 1.0 equiv) and Et N (0.075 mL, 0.54 mmol, 1.0 equiv)
3
were added sequentially to a solution of the cyclohexa-2,4-
1
dien-1-one 3a (100 mg, 0.54 mmol, 1.0 equiv) in CH Cl (2 mL)
2
2
obtained as dark-orange to brown solids.
at r.t. After 30 min, the mixture was diluted with H O, and
2
Note 1: In the case of quinone monoketals 3j (100 mg, 0.49
mmol, 1.0 equiv) and 3k (100 mg, 0.35 mmol, 1.0 equiv), 1.0
equivalent each of 2,5-dihydroxy-1,4-dithiane and triethyl-
amine were used.
extracted with EtOAc. The organic extracts were then dried
(Na SO ), filtered, and concentrated. The crude product was
treated with 4 N aq HCl (1 mL, 7.4 mmol, ~14 equiv) and the
mixture was stirred at r.t. for 10 min, then heated to 50 °C for
16 h. The solvents were evaporated and the residue was diluted
2
4
Note 2: In the case of 4-chloro-2-methoxyphenol (2i; 100 mg,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
Synlett
S. K. Chittimalla, C. Bandi
Letter
with H O then extracted with EtOAc. The organic extracts were
(20) (a) Although products 4k and 4k′ were eventually separated, to
our disappointment, only 4j′ could be cleanly separated from
4j/4j′. (b) The diastereoisomers were tentatively assigned on the
2
dried (Na SO ), filtered, and concentrated, and the residue was
2
4
purified by column chromatography (silica gel, EtOAc–hexanes)
to give a brown solid: yield: 80 mg (55%). All benzothiophene
derivatives 14 were obtained as brown solids.
1
13
basis of H and C NMR δ values. See the Supporting Informa-
tion.
(
18) When in situ-generated cyclohexa-2,4-dien-1-ones were used
(21) Compound 9, on heating to 50 °C for 3 h in the presence of 4 N
HCl in 1,4-dioxane, gave a 4:1 ratio of 5e and 9, as indicated by
in the subsequent reactions, NaHCO was added to the mixture
3
1
to neutralize AcOH released from PhI(OAc) ; see: (a) Liu, W.-C.;
diagnostic peak integration of the H NMR spectra of the crude
2
Liao, C.-C. Chem. Commun. 1999, 117. (b) Liao, C.-C.; Chu, C.-S.;
Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-D.; Shiao, H.-C. J. Org. Chem.
reaction mixture.
(22) (a) Chittimalla, S. K.; Bandi, C. RSC Adv. 2013, 3, 13663. (b) Liao,
C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
1999, 64, 4102. (c) Chu, C.-S.; Lee, T.-H.; Liao, C.-C. Synlett 1994,
6
35.
(23) Chittimalla, S. K.; Kuppusamy, R.; Thiayagarajan, K.; Bandi, C.
Eur. J. Org. Chem. 2013, 2715.
(24) To our surprise, upon column chromatography of one of the
reactions at the [3+2]-annulation stage, dienone 3a was recov-
ered in 50% yield. This result indicated that either the Michael
adduct or the Michael–aldol product is unstable to isolation.
(
19) Nevertheless, small amounts of unexpected products were iso-
lated from these reactions. See the Supporting Information.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F