Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides

Article abstract of DOI:10.1002/anie.201801982

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes.

Full text of DOI:10.1002/anie.201801982

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Synthesis of C2 Substituted Benzothiophenes via an Interrupted
Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of
Benzothiophene S-Oxides
Authors: Zhen He, Harry Shrives, José A Fernández-Salas, Alberto
Abengózar, Jessica Neufeld, Kevin Yang, Alex P Pulis, and
David John Procter
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801982
Angew. Chem. 10.1002/ange.201801982
Link to VoR: http://dx.doi.org/10.1002/anie.201801982
http://dx.doi.org/10.1002/ange.201801982

10.1002/anie.201801982
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of C2 Substituted Benzothiophenes via an Interrupted
Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of
Benzothiophene S-Oxides
Zhen He, Harry J. Shrives, José A. Fernández-Salas, Alberto Abengózar, Jessica Neufeld, Kevin Yang,
Alexander P. Pulis and David J. Procter*
Abstract: Functionalized benzothiophenes are important scaffolds
found in molecules with wide ranging biological activity and in
A: Importance of functionalized benzothiophenes
organic materials. We describe an efficient, metal-free synthesis of
OH
N
O
Br
O
HN
S
C2 arylated, allylated and propargylated benzothiophenes. The
reaction utilizes synthetically unexplored yet readily accessible
benzothiophene S-oxides and phenols, allyl- or propargyl silanes in
a unique cascade sequence. An interrupted Pummerer reaction
between benzothiophene S-oxides and the coupling partners yields
sulfonium salts that lack aromaticity and therefore allow facile [3,3]-
O
CO2Et
OH
S
NHBn
S
HO
Raloxifene - osteoporosis[2a]
Anti-fungal[2c]
Anti-inflammatory[2d]
N
O
NHAr
Cl
O
X
O
OMe
N
sigmatropic
rearrangement.
The
subsequently
generated
S
N
S
S
HO
Anti-bacterial[2h]
benzothiophenium salts undergo
a
previously unexplored 1,2-
BTBT - organic
semiconductor (X = S)
BTBF (X = O)
Arzoxifene - breast cancer
therapy[2e,f]
migration to access C2 functionalized benzothiophenes.
B: Metal-free synthesis of C2 functionalized benzothiophenes (CP = coupling partner)
R
R
R
CP
interrupted
Pummerer
[1,2]-
migration
R
Functionalized benzothiophenes are important heterocycles and
are commonly found in molecules with wide ranging biological
activity,[1,2] and are components in many organic functional
materials (Scheme 1A).[3]
[3,3]
CP
S
S
S
CP H/SiMe3
Previously
unexplored
S
O
CP
C2 arylation
C2 alkylation
I
II
benzothiophene
S-oxides
OH
• Readily
accessible
• Synthetically
unexplored
Substituted benzothiophenes can be constructed by
annulation of either ring or by functionalization of the
benzothiophene core.[4] An attractive strategy for the preparation
of C2 substituted benzothiophenes involves functionalization of
C-H bonds found in the parent heterocyclic motif.[5] Due to the
increased acidity of the C2 C-H bond, classical methods for
introducing carbon substituents at the expense of C-H bonds at
C2 of benzothiophenes require stoichiometric metallation and
such processes employ highly basic organometallic reagents.[6]
Alternatively, Friedel-Crafts alkylation processes can be used
but often give mixtures of C2 and C3 substituted products.[7] In
addition to these limitations, both strategies are restricted to the
use of electrophilic coupling partners.
Transition metals are able to mediate regioselective C-H
arylation at the C2 position of benzothiophenes.[8] However,
transition metal catalyzed C2 C-H alkylation of benzothiophenes
is considerably more challenging as it requires high
temperatures and is only reported in isolated cases.[9]
Furthermore, metal contamination remains an issue when
certain transition metals are used, especially when the products
are destined for human consumption[10] or when trace metal
contamination can affect product performance, such as in
organic electronics.[11] Thus, a method that selectively introduces
a carbon substituent at C2 in place of the C-H bonds of
benzothiophenes under transition metal-free conditions is an
attractive proposition.
CP
Scheme 1. Importance of functionalized benzothiophenes and our metal-free
strategy for their synthesis.
The groups of Yorimitsu,[12] Maulide,[13] Procter[14] and
others[15] have contributed to a growing body of work describing
the use of sulfonium intermediates[16-18] in the ortho C-H
alkylation and arylation of aromatic sulfoxides. We have recently
reported the use of benzothiophene S-oxides in the synthesis of
C3-arylated and –alkylated benzothiophenes via an interrupted
Pummerer[19]/[3,3]-sigmatropic rearrangement[16,20] cascade.[21]
Herein we report a metal-free synthesis of C2 functionalized
benzothiophenes (Scheme 1B). Using readily available, yet
synthetically underutilized benzothiophene S-oxides as novel
starting materials, we engage phenol, and allyl and propargyl
strategy that delivers C2 substituted
regioselective manner under mild
conditions. The C2 C-H alkylation and arylation processes
operate via an interrupted Pummerer/[3,3]-sigmatropic
rearrangement sequence to generate 3,3-disubstituted
silanes in
benzothiophenes in
a
a
benzothiophenium salts II, that subsequently undergo
previously unexplored 1,2-migration.
a
In
comparison
to
regular
aromatic
sulfoxides,
benzothiophene S-oxides (1) have received little attention as
synthetic intermediates. Until recently, their use in Pummerer-
type processes had not been described[21, 22] and reports of their
reactivity was limited to cycloaddition and SNAr type
processes,[23] even though benzothiophene S-oxides are readily
prepared from the parent benzothiophene by oxidation with H2O2
and TFA,[24] or with mCPBA and BF3•OEt2,[25] without over
oxidation.
[*]
Dr. Z. He, H. J. Shrives, Dr. J. A. Fernández-Salas, A. Abengózar, J.
Neufeld, Kevin Yang, Dr. A. P. Pulis and Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Rd, Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201801982
Angewandte Chemie International Edition
COMMUNICATION
We have shown that benzothiophene S-oxides 1 serve as
precursors to benzothiophenium salts (cf. I) via an interrupted
Pummerer reaction with suitable nucleophilic coupling
partners.[21] We proposed that salts I would be predisposed to
facile [3,3]-sigmatropic rearrangement, and that the 3,3-
disubstituted benzothiophenium intermediates (cf. II) would then
be able to undergo 1,2-migration and thus deliver C2
functionalized products. However, questions remained as to
whether an existing substituent at C3 would affect the [3,3]-
sigmatropic rearrangement, the key process that delivers the
coupling partner to the benzothiophene scaffold, and whether
selective migration of the coupling partner could be achieved.
Notably, while 1,2-migrations of the related 3,3-disubstituted
indolenines are well established,[26] the analogous reaction of
3,3-disubstituted benzothiopheniums (cf. II) has not been
previously explored.[27]
We began by investigating the coupling between C3 methyl
benzothiophene S-oxide 1a and p-cresol (2a) (Scheme 2A).
Upon treating 1a and 2a with TFAA in CH2Cl2, isolable thioacetal
3a was formed in 75% yield, indicating that the [3,3]-sigmatropic
rearrangement occurs efficiently despite the presence of a C3
substituent. Pleasingly, reaction of 3,3-disubstituted thioacetal
3a with catalytic BF3•OEt2 induced opening of the thioacetal and
selective 1,2-migration of the aryl group to form the C2
functionalized benzothiophene 4a.[28]
The coupling of 1a and p-cresol (2a) could be carried out in
a one-pot procedure, leading to 4a in 80% isolated yield
(Scheme 2B). The scope of the C2 C-H arylation was surveyed
by varying the phenol and benzothiophene S-oxide coupling
partners in the one-pot process. Functional groups, including
bromo (4b,f,i), trifluoromethyl (4c), keto (4d), nitro (4e, 4g), and
amido (4h) were well tolerated in the phenol coupling partner. In
the coupling of 3-bromophenol (formation of 4i), complete
selectivity for the least hindered ortho position was observed.
Naphthalen-1-ol and naphthalen-2-ol coupling partners were
also amenable to the process (4k,l), and the hindered biaryls 4j
and 4k were formed in good yields. The regioselectivity of the
metal-free C2-arylation was confirmed by NMR studies and by
X-ray crystallographic analysis of 4d and 4q’.[29]
A variety of benzothiophene S-oxides 1 was also evaluated
in the C2 arylation and we found that the reaction embraces
many substitution patterns and functional groups (4m-ac). Alkyl
(4m,r,s), bromo (4n), propargyl (4o), allyl (4p,q), and aryl (4v-z)
proved to be compatible C3 substituents. The coupling of C3
allyl benzothiophene S-oxide with phenol, gave 4q selectively
substituent had a comparable migratory aptitude: For example,
in 4x where C3 bears a para-methoxyphenyl group (vide infra).
Me
OH
TFAA
Me
Me
Me
A:
BF3•OEt2
(20 mol%)
Me
H
CH2Cl2
H
S
O
S
−40 oC to rt
rt
S
O
HO
Me
1a
2a
3a, 75%
[X-ray]
4a, 99%
R1
B:
R1
H
TFAA, CH2Cl2
HO
+
Ar
H
Ar
Ar
–40 °C to rt
BF3•OEt2
(20 mol%), rt
Ar
S
S
O
HO
1
2
4
4a, R2 = Me, 80%
4b, R2 = Br, 75%
4c, R2 = CF3, 65%
4d, R2 = C(O)Ph, 99%
[X-ray]
R2
Me
4f, R3 = Br, 75%
4g, R3 = NO2, 63%
4h, R3 = C(O)NEt2, 63%
R3
S
HO
HO
4e, R2 = NO2, 88%
Me
HO
Br
Me
HO
HO
4k, 76%[a,b]
HO
4l, 48%[a]
4i, 95%
4j, 56%
Me
R4
4r, R4 = Me, 60%
4s, R4 = Cl, 99%
4m, R1 = Me, 83%
4n, R1 = Br, 50%
HO
S
4o, R1
=
, 81%
nBu
X
R1
Me
Cl
4p, R1
=
, 83%
N
O
S
4q, R1
=
, 90%
S
S
4t, X = NMe, 19%
4u, X = O, 16%
4q', 70%[c] [X-ray]
4
R6
4v, R6 = H, 83%
3
4w, R6 = 4-CF3, 65%
4x, R6 = 4-OMe, 61%
4y, R6 = 2-OH, 38%
OR5
2
4aa, R5 = C6H5, 57%
4ab, R5 = 4-BrC6H4, 75%
4ac, R5 = 4-OMeC6H4, 71%
4z, R6 = 2-OH-3-NO2, 39%
S
S
Scheme 2. Development of the metal-free C2 arylation of benzothiophene S-
oxide (A) and scope (B). Conditions: 1 (0.1 mmol), CH2Cl2 (1.0 ml), –40 °C;
TFAA (0.15 mmol); 2 (0.15 mmol), 15 min; rt, overnight; BF3•OEt2 (0.02 mmol),
rt, 1 h. Isolated yields. [a] THF used instead of CH2Cl2. [b] Heated at 45 °C
after BF3•OEt2 added. [c] Heated at 60 °C after BF3•OEt2 added.
R5
R2
R1
R3
R1
R1
TFAA, MeCN
H
0 oC to 80 o
C
R4
O
S
O
S
S
coupling partner
1
7
8
SiMe3
Me
Br
Cl
OMe
R3
under
the
standard
conditions,
whereas
employing
R2
5
7a
7b
7c
7d
7e
stoichiometric BF3•OEt2 and heating allowed for in situ
cyclization of the phenolic oxygen onto the alkene to form the
benzoxepine 4q’.
Noteworthy is the efficient synthesis of the C3 bromo- (4n),
and C3 oxygenated- C2 arylated products (4aa-ac) that bear the
key structural features of some biologically active
benzothiophenes (see Scheme 1). The analogous C3 nitrogen
substituted benzothiophene S-oxides were also successfully
arylated, albeit in lower isolated yields (4t,u).
R1 = Me, 80% R1 = Me, 57% R1 = Me, 85% R1 = Me, 79% R1 = Me, 23%
nBu
Cy
TMS
TMS
SiMe3
R4
R5
6
nPr
8f, R1 = Br, 65%
8a, R1 = Br, 94%
8b, R1 = Me, 87%
8c,
8d, R1 = Br, 83% 8e, R1 = Br, 83%
R1
=
nBu
, 81%
Crucially, in all cases the phenol coupling partner exclusively
migrated from C3 to C2 in the 3,3-disubstituted
benzothiophenium intermediate (cf. II) formed after [3,3]-
sigmatropic rearrangement, even when the existing C3
Scheme 3. Scope of the metal-free C2 alkylation of benzothiophene S-oxides
1. Conditions: 1 (0.2 mmol), MeCN (2.0 ml), 0 °C; TFAA (0.4 mmol); 5 or 6
(0.3 mmol), 15 min; 80 °C, 3 h for allylation and 1 h for propargylation; Isolated
yields.
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10.1002/anie.201801982
Angewandte Chemie International Edition
COMMUNICATION
We next investigated the coupling of allyl (5) and propargyl
silanes (6) with benzothiophene S-oxides 1 in the interrupted
were reacted, phenyl (12c) and allyl (11c) migration occurred at
similar rates. These results are inline with the hypothesis that
3,3-disubstituted benzothiophenium intermediates II are formed
in the coupling process and that this is followed by 1,2-migration
to effect C2 functionalization. Based on these observations and
the results from Scheme 2, we are able to propose an order for
migratory aptitudes in the metal-free C2 functionalization
process to be: o-phenol>aryl~allyl >propargyl>alkyl.
Pummerer/[3,3]-sigmatropic
rearrangement/1,2-migration
cascade for the synthesis of C2 alkylated benzothiophenes
(Scheme 3). The allylation proceeded smoothly, even when the
allyl silane bore reactive functional groups such as β-bromo (7c),
β-chloromethyl (7d), and γ-ester (7e) substituents. Similarly,
propargyl silanes 6 containing alkyl (8a,b,c,d) and silyl (8e,f)
substituents at the terminal position underwent efficient metal-
free cross coupling. In addition, a more challenging, hindered
secondary propargyl silane delivered branched product 8f in
65% yield.
A: Proposed mechanism for the C2 alkylation and arylation of benzothiophene S-oxides
R
HO
OH
SiMe3
SiMe3
R1
R1
Ar
S
4
We propose that the metal-free C2 alkylation and arylation
reactions follow common mechanistic steps (Scheme 5A).
Electrophilic activation of the benzothiophene S-oxides 1 with
TFAA forms sulfoxonium salts III. The coupling partner then
engages III in an interrupted Pummerer reaction, were phenols
(2) react through oxygen,[12,17] and allyl (5)[14a,b, 18b] and propargyl
(6) silanes[14c-e] react though the γ-carbon in a SE’ fashion, to
deliver sulfonium salts I. Sulfonium salts, analogous to I, have
been formed and observed by NMR in the reaction of activated
aryl sulfoxides with allyl and propargyl silanes.[14b,c] However,
benzothiophenium salts I formed in the present study lack
aromaticity[30] and undergo facile charge accelerated [3,3]-
sigmatropic rearrangement[16,20] (at or below ambient
temperature) and therefore were not observed. The [3,3]-
sigmatropic rearrangement delivery mechanism ensures that C-
C bond formation occurs in a completely site selective manner in
terms of both the benzothiophene core and the coupling partner.
Support for the interrupted Pummerer/[3,3]-sigmatropic
rearrangement sequence is found in the regiospecificity of the
reaction: only ortho substituted phenols are formed in the
arylation, and allylated and propargylated products result from
double SE’-type substitution. Indeed, regioisomeric para
substituted phenols (9), and allylated and allenylated products
(10) were not observed.
[1,2]-migration
2
5
6
R
R
[3,3]
2
OBF3
S
R
then BF3•OEt2
(via 3)
S
I-A
I-B
O
II-A
II-B
TFAA
1
R
S
5
or 6
R
[3,3]
III
OC(O)CF3
R1
S
S
R
products of direct addition not
[1,2]-migration
observed:
R
R
R1
R
OH
S
S
10
R1
9
S
7 or 8
B: Mechanistic probe for the C2 alkylation and arylation
R
R
Me3Si
TFAA, MeCN
5a
II-B
R
+
0 to 80 o
C
or
S
S
S
O
11
12
Me3Si
1b, R = CH2CHCH2
1c, R = Ph
nBu
6a
nBu
nBu
nBu
nBu
Ph
+
+
Ph
S
90%
S
S
67%
S
11a
23:77
12a
20:80
11b
12b
Ph
+
In the case of C2 arylation, C-C bond formation also occurs
initially at C3, as shown by X-ray crystallographic analysis of
thioacetal 3a (see Scheme 2A). Upon treating thioacetals 3 with
BF3•OEt2, we propose that the formed 3,3-disubstituted
benzothiophenium II-A undergoes 1,2-migration of the coupling
partner to C2. Similarly, with allyl and propargyl silanes,
intermediate II-B undergoes 1,2-migration. As previously
reported, when R = H in II, rearomatisation occurs and C3
substituted benzothiophenes are formed.[21, 31]
Ph
S
96%
56:44
S
11c
12c
Scheme 5. Mechanistic hypothesis for the metal-free functionalization of
benzothiophene S-oxides (A) and mechanistic probes (B).
We have begun to examine the synthetic utility of the products of
metal-free C2 arylation (Scheme 6). In the field of organic
electronics, benzothiophene ladder-type p-conjugated molecules
such as benzothieno[3,2-b]benzothiophene (BTBT, see Scheme
1, X = S) and derivatives are key components in organic light-
emitting diodes (OLEDs), organic field effect transistors (OFETs),
and photovoltaic cells.[3a] Replacing one sulfur atom in BTBT
leads to benzothieno[3,2-b]benzofuran (BTBF) type materials
that have interesting yet underexplored physical and chemical
properties, such as luminescence and liquid crystallinity.[32]
Current synthetic strategies towards BTBF materials have high
step counts or rely on transition metals.[33] Given that metal
contamination can adversely affect the performance of organic
materials,[11] a short, modular, transition metal-free route to
BTBF materials is highly desirable. We therefore utilized a
The 1,2-migration, that transfers the coupling partner from
C3 to C2, is a unique facet of the cascade. Literature precedent
for this mechanistic pathway is scarce,[27] which is likely due to
the
challenge
of
synthesizing
3,3-disubstituted
benzothiopheniums and their precursors. We therefore sought
experimental evidence to shed light on this key process by
coupling C3-allyl (1b), and C3-Ph (1c) benzothiophene S-oxides
with propargyl (6a) and allyl (5a) silanes (Scheme 5B). In the
case of C3-allyl benzothiophene S-oxide 1b and propargyl silane
(6a), the major product 12a is formed as a result of allyl
migration along with minor product 11a arising from propargyl
migration. Similarly, major product 12b was formed as a result of
phenyl migration when C3-Ph benzothiophene S-oxide 1c was
reacted with propargyl silane 6a. When 1c and allyl silane 5a
This article is protected by copyright. All rights reserved.

10.1002/anie.201801982
Angewandte Chemie International Edition
COMMUNICATION
benzothiophene S-oxide bearing a C3 OMe substituent and
phenol in the coupling to generate benzothiophene 4ad
(Scheme 6A). Upon heating 4ad under acidic conditions, the
phenolic oxygen displaced the C3 OMe group to generate BTBF
in high yield. Unsymmetrical BTBT materials display more
uniform crystallinity in thin films which results in enhanced
mobility and increased thermal durability.[34] The versatility of our
metal free strategy was demonstrated in the modular synthesis
of two novel BTBF analogues, Ph-BTBF-10 and 10-BTBF-Ph,
whose structures are analogous to one of the best performing
unsymmetrical BTBT materials.[34]
metal-free alkylation and arylation processes will be of broad
utility.
Acknowledgements
We thank EPSRC (Postdoctoral Fellowships to Z.H. and J.A.F.-
S.; Established Career Fellowship to D.J.P.), The University of
Manchester (Lectureship to A.P.P.; Studentship to H.J.S.),
Novartis (Studentship to H.J.S.) Ministerio de Educación,
Cultura y Deporte, Spain (Predoctoral FPU Fellowship to A.A.),
and Erasmus+ (placement for J.N.) for their generous support.
Finally, BTBF was readily oxidized to the corresponding S-
oxide 13. Subsequent metal-free coupling with phenols gave
unusual and novel heteropropellane type thioacetal structures,
14a-h (Scheme 6B).
Keywords: Sulfoxides
•
Pummerer reactions
•
Sulfur
heterocycles • Sigmatropic rearrangement • Cascade reactions
A:
OMe
p-TsOH
toluene/
H2O
[1]
[2]
For a review of benzothiophenes found in biologically active molecules,
see: R. S. Keri, K. Chand, S. Budagumpi, S. B. Somappa, S. A. Patil, B.
M. Nagaraja, Eur. J. Med. Chem. 2017, 138, 1002.
TFAA
−40 °C to rt
OMe
O
R1
S
O
R1
R
R
BF3•OEt2
30 min
S
1
2
140 °C
30 min
R
S
HO
a) D. B. Muchmore, Oncologist 2000, 5, 388; b) S. A. Scott, C. T.
Spencer, M. C. O’Reilly, K. A. Brown, R. L. Lavieri, C. H. Cho, D. I.
Jung, R. C. Larock, H. A. Brown, C. W. Lindsley, ACS Chem. Biol. 2015,
10, 421; c) E. Pinto, M. R. P. Queiroz, L. A. Vale-Silva, J. F. Oliveira, A.
Begouin, J.-M. Begouin, G. Kirsch, Bioorg. Med. Chem. 2008, 15, 2172;
d) T. Banerjee, S.K. Sharma, N. Kapoor, V. Dwivedi, N. Surolia, A.
Surolia, IUBMB Life 2011, 63, 1101; e) M. Sato, C. H. Turner, T. Wang,
M. D. Adrian, E. Rowley, H. U. Bryant, J. Pharmacol. Exp. 1998, 287, 1;
f) P. N. Munster, A. Buzdar, K. Dhingra, N. Enas, L. Ni, M. Major, A.
Melemed, A. Seidman, D. Booser, R. Theriault, L. Norton, C. Hudis, J.
Clin. Oncol. 2001, 19, 2002; g) E. von Angerer, S. Erber, J. Steroid
Biochem. Mol. Biol. 1992, 41, 557; h) G. Naganagowda, P.
Thamyongkit, R. Klai-U-dom, W. Ariyakriangkrai, A. Luechai, A. Petsom,
J. Sulf. Chem. 2011, 32, 235.
4ad, R = H, R1 = H, 95%
4ae, R = Ph, R1 = nC10H21, 85%
4af, R = nC10H21, R1 = Ph, 90%
BTBF, R = H, R1 = H, 98% [X-ray]
Ph-BTBF-10, R = Ph, R1 = nC10H21, 93%
10-BTBF-Ph, R = nC10H21, R1 = Ph, 90%
HO
R1
3
14a, R2 = H, 99%
4
R2
2
B:
TFAA
CH2Cl2
14b, R2 = 4-NO2, 61% [X-ray]
14c, R2 = 4-Me, 48%
14d, R2 = 4-Br, 58%
O
mCPBA
O
BTBF
O
−40 °C
to rt
BF3•OEt2
CH2Cl2
−20 °C
S
S
14e, R2 = 4-CF3, 89%
14f, R2 = 4-C(O)Ph, 71%
14g, R2 = 2-Br, 48%
O
OH
13, 80%
2
14h, R2 = 3,5-(Me)2, 92%
R2
3
4
Scheme 6. Transition metal-free synthesis of BTBF type materials (A) and
heteropropellanes 14 (B).
[3]
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formed
after
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COMMUNICATION
Benzothiophene S-oxides are
Zhen He, Harry J. Shrives, José A.
transformed into C2 functionalized
benzothiophenes in a cascade
sequence involving an interrupted
Pummerer, [3,3]-sigmatropic
Fernández-Salas, Alberto Abengózar,
Jessica Neufeld, Kevin Yang, Alexander
P. Pulis and David J. Procter*
Page No. – Page No.
rearrangement, and an unexplored
1,2-migration. The reaction operates
under metal-free conditions and
delivers C2-arylated, -allylated and -
propargylated benzothiophenes.
Synthesis of C2 Substituted
Benzothiophenes via an Interrupted
Pummerer/[3,3]-Sigmatropic/1,2-
Migration Cascade of
Benzothiophene S-Oxides
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