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Metal-Free Sulfoxide-Directed Cross-Coupling
A thesis submitted to The University of Manchester for the degree
of Master of Philosophy
in the Faculty of Science and Engineering
2018
Kevin Yang
School of Chemistry
2
Contents
List of Abbreviations 3 Abstract 5 Declaration 6 Copyright Statement 7 Acknowledgements 8 1 Introduction 9
1.1 Pummerer Reactions and Variations 10 1.1.1 Pummerer Fragmentation Reaction 10 1.1.2 Vinylogous Pummerer Reactions 12 1.1.3 Interrupted Pummerer Reactions 14 1.1.4 Additive Pummerer Reactions 19 1.1.5 Aromatic Pummerer Reactions 21
1.2 Metal-Free Cross-Coupling via an Interrupted Pummerer/Sigmatropic Rearrangement Sequence 24
1.2.1 Metal-Free C3 Arylation/Alkylation of Benzo[b]thiophenes 25 1.2.2 Metal-Free Functionalisation of Aromatics Directed by a Sulfoxide group 27 1.2.3 Sulfoxide-Meditated α-Arylation of Carbonyl Compounds and Amides 31 1.2.4 Allylic C-H Alkylation of Tri- and Disubstituted Olefins 34
1.3 Proposed Work 35 2 Results and Discussion 36
2.1 Transition Metal-Free Synthesis of C3 Arylated Benzofurans 36 2.1.1 Mechanistic Investigation 41 2.1.2 Scope 43 2.1.3 Palladium-Catalysed Desulfinylative Cross-Coupling 48 2.1.4 One-Pot Synthesis of Thioacetal S,S-Dioxides 51
2.2 Conclusion and Future Work 52 3 Experimental 55
3.1 General Experimental and General Procedures 55 3.2 Synthesis of Thioacetals 58 3.3 Synthesis of Thioacetal S,S-Dioxides 68 3.4 Synthesis of C3-Arylated Benzofurans 82 3.5 Desulfinylative Cross-Coupling Benzofuran Products 93 3.6 X-Ray Crystal Structures 97
4 References 98
3
List of Abbreviations Ac Acetyl
APCI Atmospheric Pressure Chemical Ionisation
Ar Aryl
CSA Camphorsulfonic Acid
Cy Cyclohexyl
d Doublet
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloromethane
DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone
δ Chemical Shift
DMF Dimethylformamide
E Electrophile
EDG Electron Donating Group
EI Electron Ionisation
equiv. Equivalent
EWG Electron Withdrawing Group
GCMS Gas Chromatography Mass Spectrometry
HRMS High Resolution Mass Spectrometry
IR Infrared
J Coupling Constant
KDM Ketene dithioacetal monoxides
mCPBA meta-Chloroperbenzoic Acid
Me Methyl
mp Melting Point
MS Mass Spectrum
NMR Nuclear Magnetic Resonance
Nu Nucleophile
Ph Phenyl
PMB para-Methoxybenzyl
q Quartet
quin Quintet
4
RT Room Temperature
t Triplet
TBAF Tetrabutylammonium Fluoride
TBDPSCl tert-Butyldiphenylsilyl Chloride
Tf Trifluoromethanesulfonyl
TFA Trifluoroacetic Acid
TFAA Trifluoroacetic Anhydride
THF Tetrahydrofuran
TMS Trimethylsilyl
Ts p-Toluenesulfonyl
s Singlet
5
Abstract
Metal-catalysed cross-coupling reactions enable the selective formation
of carbon-carbon bonds, which is crucial in the synthesis of
pharmaceuticals and materials. Most of these cross-coupling reactions
are catalysed by late transition metals, such as palladium, which are
expensive and/or toxic. The development of alternative cross-coupling
procedures that do not rely on the use of metals would therefore be
attractive.
In this work, the metal-free sulfoxide-directed cross-coupling method has
been further developed to provide a viable alternative to transition metal-
catalysed cross-coupling. The metal-free process has been applied to the
construction of C3-arylated benzo[b]furans.
6
Declaration
No portion of the work referred to in the dissertation has been submitted
in support of an application for another degree or qualification of this or
any other university or other institute of learning.
7
Copyright Statement
The author of this dissertation (including any appendices and/or
schedules to this dissertation) owns any copyright in it (the “Copyright”)
and s/he has given The University of Manchester the right to use such
Copyright for any administrative, promotional, educational and/or
teaching purposes.
Copies of this dissertation, either in full or in extracts, may be made only
in accordance with the regulations of the John Rylands University Library
of Manchester. Details of these regulations may be obtained from the
Librarian. This page must form part of any such copies made.
The ownership of any patents, designs, trade marks and any and all other
intellectual property rights except for the Copyright (the “Intellectual
Property Rights”) and any reproductions of copyright works, for example
graphs and tables (“Reproductions”), which may be described in this
dissertation, may not be owned by the author and may be owned by third
parties. Such Intellectual Property Rights and Reproductions cannot and
must not be made available for use without the prior written permission of
the owner(s) of the relevant Intellectual Property Rights and/or
Reproductions.
Further information on the conditions under which disclosure, publication
and exploitation of this dissertation, the Copyright and any Intellectual
Property Rights and/or Reproductions described in it may take place is
available from the Head of the School of Chemistry.
8
Acknowledgements
I would like to thank Professor David J. Procter for the opportunity to
carry out my MPhil project in his research group and for his excellent
supervision throughout my degree. I am grateful to have worked on such
an exciting project and research area.
I am thankful for all the training and support that I have received from the
rest of the group, which has developed my experimental and analytical
skills considerably. Lastly, I would like to thank the entire Procter group
again for being very welcoming, helpful and supportive.
9
1 Introduction
The selective formation of carbon-carbon bonds is one of the most
important aspects of synthetic chemistry. To achieve this, a wide range of
metal-catalysed cross-couplings have been developed and many have
found their way into industrial processes, particularly in the production of
pharmaceuticals. Unfortunately many of these cross-coupling reactions
are catalysed by late transition metals that are toxic and expensive. The
removal of metal catalysts from products in industrial processes can also
be very costly and problematic, especially for the synthesis of medicines
and organic materials, where traces of transition metals are not permitted.
This makes metal-free cross-coupling an attractive alternative to
transition metal catalysis.
Sulfoxides are classic directing groups for metal-catalysed C-H
activation and are also well known for undergoing the Pummerer
rearrangement.1 In recent times the unique reactivity of sulfoxides has
been exploited for direct C-H functionalization, due to its ability to react at
both the oxygen and sulfur atom. The oxygen atom of sulfoxides can
react with an activator to become a potential leaving group, which in turn
makes the sulfur atom electrophilic and susceptible to attack by a
nucleophile. By manipulating this mode of reactivity, sulfonium
intermediates can be generated and used in metal-free C-H
functionalisation through a sequence involving interrupted Pummerer
reaction and sigmatropic rearrangement.2 Metal-free cross-coupling
through sulfonium intermediates has shown to be a promising alternative
to late transition metal-catalysed cross-coupling. This section will provide
examples, applications and recent advancements in sulfoxide-directed
metal-free cross-coupling processes.
10
1.1 Pummerer Reactions and Variations
One of the well-known reactions in organosulfur chemistry, the
Pummerer rearrangement, is named after Rudolf Pummerer who first
observed the reaction in 1903.3 The reaction involves the activation of
alkyl sulfoxide groups through activators, such as acetic anhydride and
trifluoroacetic anhydride. Following activation of the sulfoxide, a simple
elimination occurs that results in the formation of a thionium ion 3. A
nucleophile that is unreactive towards the activator can then be
introduced to the system, leading to a nucleophilic attack at the α-position
of the thionium ion resulting in the product 4 (Scheme 1).
Scheme 1: Pummerer rearrangement
Ever since, many variations of the reaction have been reported
and the Pummerer rearrangement has become an important tool in
synthetic chemistry.4 Advances in the selection of activators have also
broadened the scope of compatible nucleophiles,5 which has made the
rearrangement a much more versatile method. These factors have
resulted in the Pummerer rearrangement being utilised in many areas
such as total synthesis (examples in 1.1.2). This section will include a
brief summary of the variations of the Pummerer rearrangement and its
applications.
1.1.1 Pummerer Fragmentation Reaction
A Pummerer fragmentation occurs when X, the α-substituent of the
activated alkyl sulfoxide, undergoes elimination instead of the α-proton
(Scheme 2).
R1SO
R2
H
ER1SOE
R2
HR1S R2 Nu
R1S R2
Nu1 2 3 4
11
Scheme 2: Pummerer fragmentation mechanism with TFAA activator.
Lacour and co-workers first reported this reaction in 2005 to
resolve chiral cationic dyes.6 The propensity of a Pummerer reaction to
proceed through the fragmentation pathway, in comparison to the
“classical” pathway was later investigated using sulfoxides with a variety
of stable carbenium ions as the α-substituent (pKR+ approximately
ranging from 9.4 to 23.7) (Scheme 3).7 The sulfoxides were subjected to
Pummerer reactions under typical conditions (TFAA as the activator in
dichloromethane solvent). Experimental data indicated that sulfoxides 9A (pKR+ ≈ 23.7) and 9B (pKR+ ≈ 19) were able to undergo fragmentation
exclusively. This was proven by isolating near quantitative yields of the
respective carbenium salts 12A and 12B. Sulfoxide 9C (pKR+ ≈ 14.5)
however, gave a mixture of products including the Pummerer
rearrangement product 11C and carbenium salt 12C. This indicates the
occurrence of both the rearrangement and fragmentation pathway. Lastly,
sulfoxide 9D (pKR+ ≈ 9.4) underwent the Pummerer rearrangement
exclusively with no sign of fragmentation.
ArSO
X
H
TFAAAr
SO
X
H
O
F3C
F3CCO2Ar
S H
XF3CCO2
F3CCO2
NuAr
S H
Nu5 6
7 8
12
Scheme 3: Mechanistic study of the Pummerer fragmentation
versus classical Pummerer reaction.
These mechanistic studies led to the conclusion that in order to
promote the fragmentation pathway, R must be able to form a stable
carbocation with pKR+ values above 14.5.
1.1.2 Vinylogous Pummerer Reactions
Vinylogous Pummerer reactions employ α,β-unsaturated
sulfoxides in comparison to the typical alkyl sulfoxides. Following
activation of the α,β-unsaturated sulfoxide 13, the acidity of the γ-proton
allows it to undergo elimination in the presence of a base (from the
activator) generating a conjugated thionium ion 15 with two electrophilic
sites. A nucleophilic addition at the α or the γ position of the thionium ion
N
N NnPr nPr
nPr
O
N OnPr
Me2N
NMe2
NMe2
N
O
NnPr
Me OMe
ApKR+ ≈ 23.7
BpKR+ ≈ 19
CpKR+ ≈ 14.5 D
pKR+ ≈ 9.4
TolSO
Xp
TFAA
CH2Cl2
TolS O CF3
O
p TolS O CF3
O
p
X
X CO2CF3
9 10 11
12
X =
13
can then occur giving either one of two products (16 or 17) or a mixture
(Scheme 4). Optimisation studies by Shibasaki and co-workers indicated
that the choice of base and solvent could influence the regioselectivity of
the reaction. They showed that during the total synthesis of ent-hyperforin
20, the combination of hindered bases with polar solvents could provide
good selectivity for the formation of the γ-isomer 19 (dr >33:1), despite
evident competition for the formation of the α-isomer (Scheme 5).8
Scheme 4: Vinylogous Pummerer reaction with TFAA activator.
Scheme 5: Vinylogous Pummerer reaction in the synthesis of ent-
hyperforin.
R1 SO
TFAA
F3CCO2
R2 R1 SO
R2F3C
O
HR1 S R2
NuNu
R1S R2
Nu
R1S R2
Nu
γ-isomer
α-isomer
13 14
15
16
17
O O
OMe
SO
18
TFAA2,6-di-tert-butylpyridine
CH2Cl2 -40 oC, H2O
O O
OMe
S
19
OH
O O
OMe
HO
20 ent-hyperforin
O
14
Vinylogous Pummerer reactions have been utilised in the
synthesis of a range of complex molecules such as spirocyclic oxindoles9
and natural products, such as ent-hyperforin as previous mentioned. In
2010, Fukuyama and co-workers reported the total synthesis of the
natural product lyconadin A 24, which includes a vinylogous Pummerer
reaction as one of the key steps (Scheme 6).10 Sulfoxide 21 underwent
vinylogous Pummerer reaction to give the γ-product 22 in high yield. Acid
hydrolysis of compound 22 then gave access to the exocyclic conjugated
enone 23, which was one of the key intermediates in the synthesis. The
regioselectivity for the γ-product 22 could be rationalised by the steric
environment of the molecule. The addition of the nucleophile would occur
at the least hindered electrophilic site; therefore the formation of the α-
isomer is disfavoured due to steric congestion.
Scheme 6: Vinylogous Pummerer rearrangement in the synthesis of
lyconadin A
1.1.3 Interrupted Pummerer Reactions
An interrupted Pummerer reaction occurs when the sulfur atom of
the sulfonium salt 26 is attacked by a nucleophile, leading to a
H
MeH
H
H
S PhO
N
Ac2O, CSAPhMe, reflux
H
MeH
H
H
SPh
NOAc
86%
H2SO4HgSO4
H2O, 70 oCH
MeH
H
H
O
N
H
MeH
H
H
N
63%
HNO
24 lyconadin A
21 22 23
15
nucleophilic substitution reaction and formation of a new sulfonium salt
27. It is then possible for the R2 group of 27 to undergo displacement to
generate sulfide 28 (Scheme 7). The direct nucleophilic attack at the
sulfur atom of 26 is usually as a result of the lack of acidic α-protons,
although we have found that even when acidic α-protons are present, the
interrupted Pummerer reaction can dominate.
Scheme 7: Interrupted Pummerer reaction
Kawasaki and co-workers have reported the allylic oxidation of a
protected indole derivative 29 through an interrupted Pummerer reaction,
deprotonation and subsequent nucleophilic attack by a sulfoxide.11 The
sulfur-containing moiety is also eliminated in the process of the reaction
(Scheme 8). It has been proposed that this reaction sequence involving
the interrupted Pummerer reaction could be extended to the synthesis of
bioactive tetrahydrocarbazoles.
Scheme 8: Allylic oxidation through an interrupted Pummerer reaction.
R1 SR2
OE
R1 SR2
OE
R1 SNu
NuR1 S
R2
Nu
25 26 27 28
- R2
NPMB
RSR
O CF3
O
NPMB
SRR
NPMB
SRR
RSR
NPMB
OS
HR
R
NPMB
O
29 31
33
30
32
34
H
O2CCF3
O2CCH3F3
O
16
Oshima and Yorimitsu have also used the interrupted Pummerer
reaction in the cyclisation of ketene dithioacetal monoxides (KDM) 35 for
and synthesis of substituted benzothiophenes.12 Activation of KDM 35 is
followed by the formation of cyclised intermediate 38 from the direct
attack of the aromatic ring onto sulfur. Rearomatisation occurs
subsequently to generate benzothiophenes. The reaction proceeded in
good yield regardless of the double bond geometry of the KDM that was
employed. This is explained by the formation of a dicationic intermediate
37, which enables C-C bond rotation; therefore allowing the molecule to
rotate into the correct orientation for cyclisation to occur (Scheme 9). The
reaction generally proceeded with good yields and good functional group
tolerance.
Scheme 9: Synthesis of benzothiophenes from KDMs.
This method was later extended by Osuka and Yorimitsu and
applied to synthesis of 2-(methylthio)benzo[b]furans 41 from KDMs and
phenol coupling-partners.13 The methylthio group of the benzo[b]furan
product could be reduced or used in nickel-catalysed cross-couplings.
R2S
SMeR1
O MeTf2O, K2CO3
R2S
SMeR1
TfO Me
SSMe
Me
R2
R1
R2S
SMeR1
Me
Hethanolamine
SSMe
R2
R1
35 36 37
38 39
39a: R1 = H R2 = Ph, 86%39b: R1 = H R2 = CF3, 90%39c: R1 = 4-OMe R2 = Ph, 66%39d: R1 = 5-OMe R2 = Ph, 87%39e: R1 = 6-OMe R2 = CF3, 87%
17
Scheme 10: Synthesis of 2-(methylthio)benzo[b]furans.
Procter and co-workers have reported the metal-free synthesis of
diaryl sulfides from aryl methyl sulfoxides (Scheme 11).14 The mechanism
of the process proceeds through an interrupted Pummerer reaction.
Firstly sulfoxide 42 is activated by Tf2O, which increases the
electrophilicity of the sulfur atom. An aryl nucleophile can now attack the
electrophilic sulfur atom to form intermediate 45. Lastly, a simple
demethylation using DBU generates the diarylsulfide product 46. The
reaction exhibits high functional group tolerance and is compatible with
aryl nucleophiles with complex structures, as shown in the examples
affording estrone methyl ester ether 46b and dextromethorphan 46c.
Most importantly it avoids the use of transition metals, which is the
common way of constructing diaryl sulfides,15,16 making it a more
sustainable method for synthesis.
OH
R R1 S
SMeMe
O
+TFAA
CH2Cl2, 25 ºC O
R1
SMeR
41a: R = 4-tBu R1 = Ph, 87%41b: R = 4-Bpin R1 = Ph, 76%41c: R = 4-tBu R1 = Me, 78%41d: R = 4-CF3 R1 = Ph, 60%41e: R = 3-OMe R1 = Ph, 63%
40 41
18
Scheme 11: Metal-free thioarylation of arenes.
Yorimitsu, Oshima and co-workers demonstrated the construction
of five-membered heteroarenes going involving both the additive and
interrupted Pummerer reactions of ketones.17 The research group
developed sulfoxide 47 as a trifluoromethyl-containing substrate for
Pummerer reactions and it was employed in this reaction sequence.
Sulfoxide 47 was first activated and then underwent nucleophilic attack at
the sulfur atom (interrupted Pummerer reaction) from the carbonyl group
of the ketone 48, giving the sulfonium salt 50. With the nucleophile now
tethered to the sulfur atom of the sulfonium species, [3,3]-sigmatropic
rearrangement, followed by rearomatisation gave the product 52
(Scheme 12). These products were then shown to be able to be
transformed into five-membered heteroarenes, such as furans and
thiophenes.
H+
SMe
O
Tf2O, CH2Cl2 SR1 R2
SMe
OTfS
R1 R2
Me
DBUR1
42 43
44 45
46
MeO
SH
H
H
O
46b: 84%
S
MeO
MeN
H
46c: 70%
S
I
46a: 91%
R2
R2
19
Scheme 12: Pummerer reaction with ketone nucleophile.
The trifluoromethyl group in 49 was found to play an important role
in inhibiting the formation of undesired dicationic intermediate 54; the
trifluoromethyl group is strongly electron withdrawing and therefore it
would be unfavourable to form the dicationic intermediate.(Scheme 13).
Scheme 13: inhibiting the formation of a dicationic intermediate.
In the past years this unique sequence of interrupted
Pummerer/sigmatropic rearrangement has been exploited for metal-free
cross-coupling reactions and in the synthesis of heteroaromatics, notably
by the groups of Procter, Maulide and Yorimitsu. This work will be
covered in more detail in section 1.2.
1.1.4 Additive Pummerer Reactions
The additive Pummerer reactiont involves nucleophilic addition to
an activated α,β-unsaturated sulfoxide 56, followed by a subsequent
nucleophilic attack on the newly formed thionium ion 57 to generate the
product 58 (Scheme 14). This reaction pathway is in direct competition
S
S
O
CF3
Tf2O
H HH
Ph OS
S
TfO
CF3
S
S
O
CF3
Ph
[3,3]S
SPh
O H CF3
S
SPh
O CF3
47 48 49 50
51 52
O EtPh
CF3
53
S
S
TfO
CF3
S
SCF3
49 54
20
with the vinylogous Pummerer reaction (section 1.1.2), as it is possible for
the sulfonium salt 56 to either undergo nucleophilic attack (additive
pathway) or have its γ-proton abstracted to form a conjugated thionium
ion (vinylogous pathway).
Scheme 14: Additive Pummerer reaction
Both the vinylogous and additive Pummerer reaction can lead to
the same product; therefore in some circumstances it can be difficult to
establish which pathway is in operation.
Haraguchi and co-workers have employed the additive Pummerer
reaction in the synthesis of thionucleosides (Scheme 15).18 A cyclic α,β-
unsaturated sulfoxide 59 was first activated by Ac2O and boron trifluoride
diethyletherate, leading to an additive Pummerer reaction affording
diacetate compound 62. Further manipulation of 62 was conducted to
afford the desired thionucleoside 63.
Scheme 15: Additive Pummerer reaction in the synthesis of
thionucleosides.
R2SR1
O Nu
ER2
SR1
OE
R2SR1
Nu
Nu
R2SR1
Nu
Nu
55 56 57 58
SO
O
O
SitBu
tBu
Ac2OBF3
.OEt2
TMSOAc
SOAc
O
O
SitBu
tBu OAc
S
O
O
SitBu
tBu OAc
OAc
S
O
O
SitBu
tBu OAc
OAc
62: 61%
TMSOTf, MeCNCH2Cl2bis(TMS)uracil
S
O
O
SitBu
tBu OAc
NNH
O
O
59 60 61
63
21
1.1.5 Aromatic Pummerer Reactions
Substituted aromatics are common systems in molecules with
many important applications. With the advances in Pummerer chemistry,
sulfur-mediated aromatic substitutions have been explored. Following
Procter and co-workers’ work on the metal-free synthesis of diaryl
sulfides,14 which proceeds through an interrupted Pummerer reaction
(see section 1.1.3), Yorimitsu and co-workers reported the synthesis of
diaryl sulfides, but through an aromatic Pummerer reaction (Scheme
16).19 Activated sulfoxide 69 is highly electron deficient; this allows a
nucleophilic aromatic substitution to occur at the para-position (to the
activated sulfoxide group). In this case an aryl sulfide 68 is employed as
the nucleophile and this leads to the regioselective sulfanylation of the
arene unit. A 1:2 mixture of activators, triflic anhydride to trifluoroacetic
anhydride, was found to be the most optimal condition. It was suggested
that the triflic acid generated after activation of the sulfoxide by triflic
anhydride could degrade either the substrates or products. The presence
of trifluoroacetic anhydride would be able to spontaneously consume the
triflic acid generated through the formation of TFA, which is less acidic.
The reaction in general proceeds in good yields, tolerating a variety of
functional groups, such as halides, carbonyls and heteroaromatics on the
sulfide coupling partner.
22
Scheme 16: C-H Sulfanylation of aryl sulfoxides (A2O = acid anhydride).
It was found that the use of a para-substituted aryl sulfoxide 72
could generate the ortho-substituted product 74, but in poor yield as a
complex mixture was generated (Scheme 17).
Scheme 17: Reaction of a para-substituted aryl sulfoxide.
Kita and co-workers demonstrated the synthesis of para-quinones
from para-sulfinylphenols.20 Sulfoxide 75 was first activated by TFAA
giving intermediate 76. An elimination reaction initiated from the hydroxy
group of 76 expels the trifluoroacetate to give thionium intermediate 77. A
subsequent attack on thionium 76 from the expelled trifluoroacetate group
generates 78, which undergoes hydrolysis to give the desired quinone
product 79 (Scheme 18).
S R1
O
A2O
S R1
OA
SR2 R3
S
S R1R3
R2H
SR1
R2S-R3
S R1
O
Tf2O(CF3CO)2O
CH2Cl2, rt, 0.5 hthen ethanolamine
SR1
MeS+ Ar-SMe
64 65 66
67 68 69 70 71
SS O
MeSMeS
MeS
S
Me
Me
Me71a: 96% 71b: 85% 71c: 56%
S R1
O
Me Tf2O(CF3CO)2O
CH2Cl2, rt, 0.5 hthen ethanolamine
SAr
MeS
+Me
MeS
ArS
73: 0% 74: 12%
+ Ar-SMe
72 65
23
Scheme 18: Synthesis of para-quinones from para-sulfinylphenols.
Kita and co-workers have also reported the construction of highly
substituted indoles through aromatic Pummerer rearrangement (Scheme
19).21 Sulfinyl aniline 80 was first activated by TFAA, followed by
deprotonation of the amine unit. This leads to the elimination of the
trifluoroacetate group and delivers 82. 82 then undergoes vinylogous
Pummerer reaction with alkene 83 to generate intermediate 84.
Subsequent cyclisation and oxidation provided highly substituted indoles
86 as the products. The regioselectivity observed in the electrophilic
addition of alkene 83 can be explained by the reaction proceeding via the
most stable carbocation.
OH
SPh O
TFAA
OH
SPh O
F3C O
O
SPh
O CF3
O
O
F3C(O)CO SPh
NaHCO3MeOH
O
O
75 76 77 78
79: 84 %
24
Scheme 19: Synthesis of highly substituted indoles from sulfinyl aniline.
1.2 Metal-Free Cross-Coupling via an Interrupted Pummerer/Sigmatropic Rearrangement Sequence
Reaction cascades involving of interrupted Pummerer/charge
accelerated [3,3]-sigmatropic rearrangements have emerged as a facile
way to access complex aromatics and heteroaromatics without the aid of
transition metals. This involves the formation of either sulfonium or
sulfoxonium salts resulting from interrupted Pummerer reactions and
these intermediates have shown the ability to take part in charge
accelerated [3,3]-sigmatropic rearrangement providing metal-free cross-
coupling products.
This section will cover the recent advances made in metal-free
cross coupling, using an interrupted Pummerer/sigmatropic
rearrangement sequence.
S
NHR1
Ph
O
TFAAMeCN S
NR1
Ph
OC(O)CF3
H
O CF3
O
N
S
R1
Ph
R2R3
N
R3R2
H
R1
PhS
NR1
R3
R2 DDQ
benzene, reflux PhS
NTs
Me
C6H3(OMe)2
80 81
82
84 85 86, 75 %
83
25
1.2.1 Metal-Free C3 Arylation/Alkylation of Benzo[b]thiophenes
Arylation of benzothiophene in either the C2 or C3 position often
requires transition metals22 and/or harsh conditions. Moreover, alkylation
of benzo[b]thiophene is more difficult with only very few reports and the
requirement for directing groups.23,24 Selectivity for the C2/C3 position is
also a common problem faced by many of the methods reported.
Recently, Procter and co-workers described a regioselective metal-free
C3 arylation/alkylation process for the functionalization of
benzo[b]thiophene.25 This method utilises an interrupted Pummerer/[3,3]-
sigmatropic rearrangement cascade. Firstly benzo[b]thiophene is oxidised
to benzo[b]thiophene S-oxide 87 using mCPBA with boron trifluoride
diethyletherate. Benzothiophene S-oxide 87 can then be activated with
TFAA and then the phenol coupling partner can attack sulfonium salt 89 giving intermediate 90. Intermediate 90 then undergoes a facile charge
accelerated [3,3]-sigmatropic rearrangement forming thioacetal
intermediate 92. Treatment of 92 with p-TsOH opens the 5-membered
ring and after subsequent rearomatisation delivers the C3 arylated
benzo[b]thiophene product 88 (Scheme 20). Substitution on all positions
on the benzo[b]thiophene S-oxide coupling partner is possible, including
the C2 position, without affecting the [3,3]-sigmatropic rearrangement
process.
26
Scheme 20: Metal-free C3 arylation of benzothiophene.
C3 alkylation of benzo[b]thiophenes was also reported. Allyl or
propargyl silane (Scheme 21) coupling partners were employed and the
coupling proceeded via a similar mechanism involving interrupted
Pummerer/[3,3]-sigmatropic rearrangement cascade sequence.
SO
TFAA, DCM
S
OH
SO
TFAA
SOC(O)CF3
SO
[3,3]
S
HO
O
H
S O S
OHTsOH
Phenol
-40 oC to RTpTsOH, 45 oC
87 88
89 90
91 92
S
OH
S
OH
F3C
S
OH
PhS
OH
88a: 79% 88b: 80% 88c: 40% 88d: 72%
Br
R R
R
R
R
R
R
R
87
88
27
Scheme 21: Metal-free C3 alkylation of benzothiophene.
This metal-free method is completely regioselective and has high
functional group tolerance.
1.2.2 Metal-Free Functionalisation of Aromatics Directed by a Sulfoxide group
Procter and co-workers have also reported a metal-free CH-CH
type cross-coupling of arenes with alkynes, which employs sulfoxides as
directing groups.26 The reaction operates under mild conditions in
contrast to the harsh conditions previously reported for CH-CH type
cross-couplings.27 It is proposed that the reaction first proceeds by the
activation of the aryl sulfoxide with triflic anhydride. Intermediate 99 undergoes an interrupted Pummerer reaction with an alkyne coupling
SO
TFAASiMe3
S
SO
TFAA
SOC(O)CF3
S
[3,3]
SiMe3
S
H
S
MeCN, 0 oC to RTR1
R1
R1 R1
R1R1
+
87 93 94
R1
89 95
96
S
Br
Me
S
Br
C(O)Me
S
nBu
94a: 88% 94b: 58% 94c: 60%
87
94
28
partner 99 to form sulfonium salt 101. Intermediate 101 can then be
deprotonated giving 102, which leads to a [3,3]-sigmatropic
rearrangement followed by a base-assisted rearomatisation to provide
ortho-propargylated product 104 (Scheme 22). The reaction proceeds in
moderate to good yields. Electron donating groups on the arene coupling
partner resulted in lower reactivity, whereas electron-withdrawing groups
were better tolerated.
Scheme 22: Metal-free cross-coupling of aryl sulfoxides and alkynes.
Undesired side reactions were observed. It was suspected that the
formation of ylide 102, from 101, is in competition with several undesired
reactions including the hydrolysis of the triflate, demethylation of sulfur,
and also deprotonation of SMe. This makes the selection of the alkyne
coupling partner crucial for the success of the reaction. Alkynes bearing
H
SO
R1 Tf2O SR1
OTfOTf
Me
Me
SR1
H
MeOTf
OTf
SR1
H
Me
OTf
BaseSR1
Me
OTf
[3,3]SR1
Me
OTf
OTf
OTf
OTf
HbaseH
baseH
-TfOH-Base•HOTf
MeSR1
H
S(O)R1
+
R2
HR3 Tf2O
2,6-LutidineCH2Cl2
-78 oC to 0 oC to 65 oC16 h
R2
SR1R3
95 96 97
95 98
99100
101102103
104
SPhtBu
SMeTIPS
97a: 64% 97b: R = pOMe, 43%97c: R = pCF3, 92%97d: R = oBr, 95%
R
29
large substituents gave rise to 101 with a large R2 group. Bulky R2 groups
can block undesired deprotonation, demethylation and hydrolysis of the
triflate due to the steric protection it affords the SMe and triflate group.
Figure 1: Steric protection preventing undesired reactions.
Yorimitsu and co-workers developed a metal-free synthesis of
biaryls from aryl sulfoxides and phenols, with broad substrate scope and
good yields.28 A variety of aryl sulfoxides, including sulfoxide substituted
benzofurans, benzothiophenes, and indoles were shown to be viable
coupling partners. The reaction proceeds with complete regioselectivity.
Aryl sulfoxide 105 is first activated and undergoes an interrupted
Pummerer reaction forming a tethered sulfonium intermediate 109.
Subsequent [3,3]-sigmatropic rearrangement of 109 and rearomatisation
delivered biaryl 107 with synthetically useful hydroxy and sulfanyl
moieties, thus providing opportunities for further functionalisation
(Scheme 23).
Electron donating groups at the 3- and 5- position of the aryl ring of
the aryl sulfoxide coupling partner stabilises the cationic intermediate
110, which facilitates the preceding [3,3]-sigmatropic rearrangement step.
The use of 4-methoxyphenyl methyl sulfoxide as the aryl sulfoxide
coupling partner led to a trace amount of the desired product 107d. This
is due to the methoxy substituent at the 4-position stabilising 109, which
raised the activation energy barrier for the subsequent [3,3]-sigmatropic
rearrangement.
S
H
R2
OTf
OTfUndesired
- Deprotonation of SMe- Demethylation of sulfur- Hydrolysis of triflate
Desired
- Deprotonation of γ-proton- Ylide formation
H
101
30
Scheme 23: Metal-free synthesis of biaryls.
Mechanistic investigations were conducted, which supported the
proposed mechanism (Scheme 24). A benzothiophene sulfoxide 105a
was coupled with 2,6-dimethyl phenol 106a. If a Friedel-Crafts pathway
was in operation then one would expect to obtain 111 as the major
product; however it was obtained as a minor isomer with the major
product being 107e. The meta-selective coupling arises due to both ortho
positions of the phenol coupling partner being blocked. It is proposed that
after [3,3]-sigmatropic rearrangement, intermediate 112 undergoes a
protonation-induced 1,2-shift, which is responsible for the meta-
selectivity. The formation of intermediate 112 was proved by quenching
the coupling reaction after five seconds and 112 was isolated in 58%
yield.
SR
O
R1 + R2
OH
TFAA
CH2Cl2, RT
SROH
R1
R2
TFAA
SR
R1
OC(O)CF3SR
R1 O
R2
SR
R1 O
R2HH
SMeOH
NTs
SMe
OH
OSMe
OH
MeO
SMeOH
107d: trace
105 106 107
108 109 110
107a: 84% 107b: 89% 107c: 90%
31
Scheme 24: Mechanistic probe for the synthesis of biaryls.
1.2.3 Sulfoxide-Meditated α-Arylation of Carbonyl Compounds and Amides
Maulide and co-workers have reported the α-arylation of cyclic ß-
ketoesters.29 In the proposed mechanism, aryl sulfoxide 114 was first
activated by TFAA and a subsequent interrupted Pummerer reaction with
the enol tautomer of cyclic ß-ketoester 113 leads to sulfoxonium
intermediate 117. A spontaneous charge accelerated [3,3]-sigmatropic
rearrangement occurs, followed by rearomatisation generating the
product 115 in generally good yields (>10 examples, 40-91%) (Scheme
25).
OH
TFAA
CH2Cl2, RT
SS(O)Me +
Me Me
SSMe
Me
OH
Me
+
SSMe
Me
OHMe
80%107e/111 = 8/1
SSMe
OMe
Me
Can be isolated
105a 106a 107e 111
112
32
Scheme 25: α-Arylation of carbonyl compounds.
Five and six-membered cyclic ß-ketoesters bearing different ester
groups were well tolerated. Interestingly, the presence of electron
withdrawing groups on the aromatic ring of aryl sulfoxides gave higher
yields. The generation of product 115c, which is formed from an acyclic
ß-ketoester, was found to be much slower; however stirring at room
temperature for two days afforded the product in acceptable yield (46%). Maulide and co-workers later described the direct α-arylation of
unactivated amides (Scheme 26).30 Amide 119 was first activated by triflic
anhydride to form 120 and in the presence to 2-iodopyridine, 120 formed
either 121 or 122. Both 121 and 122 are high energy intermediates, which
then gives give 123. 2-Iodopyridine is subsequently displaced from 123
by diphenyl sulfoxide to form enamine 124. [3,3]-Sigmatropic
rearrangement followed by rearomatisation delivers arylated amide
product 126.
R1
O
R2
+Ph
SPh
OTFAA
MeCN, 25 ºC
TFAA
SPh
OC(O)CF3
R1
R2
O
O2CCF3 SPh
O
R1
R2
HS
R2O
R1
Ph
R2O
R1
SPh
113 114 115
116
113117 118
OCO2Et
PhS
MeO
CO2Et
PhS
MeMeOC
CO2Et
PhS
115a: 80% 115b: 73% 115c: 41%
H
33
The base used plays a crucial role in the reaction. It must be
nucleophilic enough to convert 120 to 121 and also have a good leaving
group ability, so it can be displaced by diphenyl sulfoxide to form enamine
124. Only tertiary amides were present on the scope.
Scheme 26: α-Arylation of amides.
Although this reaction does not include the interrupted Pummerer
reaction, the reaction follows a similar rearrangement to those reported in
this section. In all cases the reactivity of aryl sulfoxides is exploited to set
up a charge accelerated [3,3]-sigmatropic rearrangement that delivers the
desired product.
R1N
OR1
N
OTfOTf
NI
-HOTf
N I
NR1
2 OTf
119 120 121
Tf2O
or
OTf• NR1
122
NIN I
NR1
OTfSO
PhPh
- 2-iodopyridine
R1N
OSPh
R1
O
NH
SPh
OTf OTf
123
124 125
R1N
OSPh
- HOTf
126
N
O
PhS
126a: 90%
N
O
PhS
126b: 83%
N
O
PhS
MeO
O
126c: 78%
34
1.2.4 Allylic C-H Alkylation of Tri- and Disubstituted Olefins
Li and co-workers reported a metal-free allylic C-H alkylation of tri-
and disubstituted olefins (Scheme 27).31 The reaction employs an
activated sulfoxide, which reacts with a substituted olefin via an
interrupted Pummerer mechanism. Subsequent loss of the terminal
proton by a triflate anion generates an allylic sulfonium intermediate 132.
The addition of a base provides sulfur ylide 133, which allows a [2,3]-
sigmatropic rearrangement to occur to give the product 129.
Scheme 27: Allylic C-H alkylation of tri- and disubstituted olefins
It was shown that this allylic C-H alkylation protocol could be
extended to intramolecular reactions to yield cyclised products (Scheme
28).
H +R
SMe
O Tf2O, CH2Cl2
then tBuOKSR
Tf2O
RS
Me
OTf OTf
HR
SMe
HOTf
RSMe
RSCH2tBuOK
127 128 129
130131 132 133
SPh
R
SPh
SMe129a: R = H, 60%129b: R = OMe, 48%129c: R = Br, 57%
129d: 61% 129e: 58%
R1
R1R1 R1
R1
R1
35
Scheme 28: Intramolecular allylic C-H alkylation
1.3 Proposed Work
Benzo[b]furan and its derivatives are a class of heterocyclic
compound that exists widely in natural products. In recent years the
benzo[b]furan motif has emerged as a promising scaffold for drug
discovery,32 due to its presence in a wide range of biologically active
molecules with properties such as anti-inflammatory,33 antitumor,34 and
antifungal.35 As benzo[b]furans are of great medicinal and pharmaceutical
interest; therefore it is important to develop new and efficient synthetic
routes to them. Currently many synthetic routes to access benzofurans
require transition metals or heavily pre-functionalised substrates. The
synthesis of C3 arylated benzofurans has also proved to be challenging
due to regioselectivity issues arising from direct arylation.36
Procter and co-workers have reported the metal-free C3 arylation
of benzo[b]thiophene25 through the coupling of benzo[b]thiophene S-
oxide with phenol. Interestingly, the reaction proceeds through a
potentially versatile thioacetal intermediate 92, which can be isolated
(Scheme 29). The treatment of the intermediate with p-TsOH leads to the
ring opening of the substrate to form C3 arylated benzo[b]thiophenes,
through the breakage of the C-O bond. My project will aim to exploit such
intermediates for the transition metal-free synthesis of C3 arylated
benzo[b]furans. This will be achieved by the development of a
regioselective ring opening reaction that targets specifically the C-S bond
H
SPh
O
SPh
SPh
OTf
Tf2O, CH2Cl2
then tBuOK
134 135
136
Tf2O tBuOK
36
of the thioacetal in comparison to the C-O bond that leads to the
formation of benzo[b]thiophenes.
Scheme 29: Potential access to substituted benzo[b]furans.
Yorimitsu, Osuka and co-workers have previously reported the
metal-free construction of 2-(methylthio)benzo[b]furans13 (see section
1.1.3) through an interrupted Pummerer/[3,3]-sigmatropic rearrangement
sequence. Our method in comparison will employ readily and
commercially available benzo[b]thiophenes and phenols as starting
materials. There will be the opportunity to functionalise the aryl ring on
the C3 position of the benzo[b]furan. The C2 position can also potentially
be substituted with a variety of substituents and functional groups.
2 Results and Discussion
2.1 Transition Metal-Free Synthesis of C3 Arylated Benzofurans from Benzothiophenes
To begin the investigation, benzo[b]thiophene 137a was oxidised
to sulfoxide 138a by mCPBA in the presence of BF3•OEt2 according to
the literature.37 In situ activation of 138a with TFAA, followed by the
addition of phenol, leads to an interrupted Pummerer/charge accelerated
[3,3]-sigmatropic rearrangement to generate the thioacetal 139a on gram
scale (Scheme 30).
S OS
OH
O
SH
C3-ArylatedBenzothiophene
C3-Arylated Benzofuran
p-TsOHR
R
92
H
H
37
Benzo[b]thiophene S-oxide 138a is unstable at high temperature
and cannot be isolated;38 however it can be used after oxidation as a
dilute solution. Filtration of the reaction mixture through a plug of MgSO4
and K2CO3 afforded a solution of 138a in CH2Cl2, which was used
immediately. Over oxidation of 137a to the corresponding sulfone was not
observed, as once the S-oxide is formed it is prevented from further
oxidation by coordination to BF3•OEt2.37
Scheme 30: Synthesis of thioacetal.
The reaction mechanism for the synthesis of thioacetal 139a is depicted
in Scheme 31. Firstly, benzo[b]thiophene S-oxide 138a is activated by
TFAA to generate sulfoxonium salt 140. An interrupted Pummerer
reaction then leads to the formation of aryloxy sulfonium salt 141,
allowing a facile charge accelerated [3,3]-sigmatropic rearrangement to
deliver the phenol coupling partner to the C3 position. Subsequent
rearomatisation of the phenyl ring of 142 delivers thioacetal intermediate
139a.
Scheme 31: Mechanism for the synthesis of 139a.
Thioacetal containing thioglycosides can be activated using NIS to
generate a reactive boat-shaped oxocarbenium ion intermediate (Scheme
S
mCPBA (1.2 eq)BF3.OEt2 (8 eq)
CH2Cl2, -20 oC SO
CH2Cl2, -40 oC to RTS O
139a: 60%
Phenol (1.5 eq)TFAA (1.5 eq)
138a137a
H
H
SOC(O)CF3OH
Interrupted Pummerer
SO
S
OH
S O
[3,3]
140 141 142 139a
H
H
38
32).39 It was hoped that similar reactivity would occur if these reaction
conditions were applied to the thioacetal compound 139a; however
benzo[b]furan product was not observed and iodination of the starting
material was observed.
Scheme 32: Proposed reactivity of thioacetal 139a with NIS based on
thioglycoside activation.
An alternative approach to overcome the problem of selective C-S
bond cleavage was to further functionalise the thioacetal compound 139a;
therefore driving the selectivity for the breakage of the C-S bond to form
benzo[b]furan product. Oxidation to sulfone 143a, which is a good leaving
group, was seen as an attractive approach and the sulfone was obtained
by reacting 139a with excess mCPBA (Scheme 33).
Scheme 33: Thioacetal oxidation to the corresponding sulfone.
A variety of bases were then tested with the sulfone at room
temperature, in an attempt to initiate the ring opening reaction to generate
OAcOAcO OAc
SR
OAcNIS/TfOH
OAcOAcO OAc
SR
OAc
I O
OAc
AcOAcO
OAc
Proposed reactivity for thioacetal:
Thioglycoside activation:
S O
NIS/TfOH
S OI
O
SH
139a
H
H
H
H
S O
mCPBA (2.4 eq)
CH2Cl2, -20 oCS O
O O
143a: 68%139a
H
H
H
H
39
the benzo[b]furan (Table 1). Unfortunately none of the bases (Table 1,
entries 1-3) tested were capable of initiating an elimination reaction to
break the C-S bond and no reaction was observed. The reaction was
later attempted with sodium methoxide at an elevated temperature of 50
°C in methanol/dichloromethane solvent (Table 1, entry 4,). The reaction
was left stirring for 5 hours and full conversion of starting material to
benzo[b]furan benzene sulfinate 144 was observed (Scheme 34).
Entry Base Solvent Time
(h)
Temp
(°C)
Conversion
of SM (%)
1 NaOH CH2Cl2/MeOH 5 25 0
2 t-BuOK CH2Cl2/MeOH 5 25 0
3 Et3N CH2Cl2/MeOH 5 25 0
4 NaOMe CH2Cl2/MeOH 5 50 100
Table 1: Optimisation of the elimination of sulfone 143a
Scheme 34: Benzo[b]furan benzene sulfinate synthesis.
Despite the efficient conversion, the purification of sulfinate 144 was problematic. Sulfinate 144 was not particularly stable and due to its
very high polarity, purification using flash chromatography was difficult.
To avoid these problems, sulfinate 144 was functionalised by reacting
with an electrophile. Iodomethane was selected as the electrophile for its
simplicity and three different reaction procedures were investigated to find
the optimal route to the sulfone 145a (Scheme 41). The first route
(Scheme 35.1) gave the desired product 145a; however the reaction of
the sulfinate group with iodomethane was extremely slow, even under
reflux conditions. The second approach (Scheme 35.2) involved a change
of solvent to DMF after the formation of the sulfinate 144. The reaction
S OO
O
NaOMe (1.5 eq)
MeOH/CH2Cl2, 50 oC
O
SONa
O
143a 144
H
H
40
temperature could then be raised, which accelerated the rate of reaction
with iodomethane. Lastly DMF (with minimal amounts of MeOH to
dissolve the base) was used throughout the whole reaction sequence
(Scheme 35.3). Pleasingly, the formation of the benzo[b]furan benzene
sulfinate 144 was not negatively affected in DMF and this was determined
to be the most optimal route. Overall, a one-pot synthesis of C3 arylated
benzofuran had been realised from a unique thioacetal dioxide, which in
turn arose from a benzo[b]thiophene.
Scheme 35: Optimisation of the reaction route to sulfone 145a.
The reaction conditions were then optimised. Using the model
reaction, the effect of reaction temperature, time and ratio of reagents
used was investigated (Table 2). Increasing the temperature led to more
effective formation of 145a and gave the best results, similar to other
S OO O
NaOMe
MeOH/CH2Cl2, 50 oCO
S OO Me
O
SONa
O MeI
S OO O
NaOMe
MeOH/CH2Cl2 50 oC, 4h
O
SONa
O MeI
DMF, 80 oC
O
S OO Me
S OO O
NaOMe
DMF/MeOH, 80 oC
O
S OO Me
O
SONa
O MeI
1.
2.
3.
143a 144 145a
143a 144 145a
143a 144 145a
H
H
H
H
H
H
41
conditions reported in the literature for the functionalisation of sulfinate
salts.40 Entries 1-4 generated an unidentified side product, which was not
observed when using the condition described in entry 5. Interestingly, an
increased amount of sodium methoxide (Table 2, entry 4) was able to
inhibit the reaction, which may be caused by interactions of the base with
iodomethane, as sodium methoxide is also capable of acting as a
nucleophile.
Entry Temp (°C) Time (h) NaOMe
eq.
MeI eq. Yield
1 70 1 1.5 1.5 55%
2 80 4 1.5 1.5 68%
3 100 4 1.5 3 60%
4 100 4 3 1.5 Trace
5 120 18 1.5 1.5 81%
Table 2: Optimisation of reaction conditions.
2.1.1 Mechanistic Investigation
The proposed reaction mechanism for the ring opening
reaction of sulfone 143 is shown in Scheme 36. It was speculated
that the reaction proceeds through an E2 elimination mechanism
and mechanistic studies were conducted. Firstly, sulfone 143a was
heated overnight and no reaction was observed with only starting
material detected. This result ruled out an alternative reaction
mechanism proceeding through thermally initiated cleavage of the
C-S bond (Scheme 37.2). Sulfone 146 was then synthesised and
O
SO
OMe
S OO O
NaOMeDMF/MeOH80 oC, 2h
143a 145a
then, MeI, T
H
H
42
was subjected to standard reaction conditions. With the absence of
the benzylic Ha no reaction occurred. This result suggested the
presence of Ha is crucial for the reaction. Both results supported the
proposed E2 elimination mechanism (Scheme 36). There is
precedent for the elimination of aryl sulfones, initiated by a base, to
form aryl sulfinate salts.41
Scheme 36: Proposed mechanism for sulfinate salt formation.
Scheme 37: Mechanistic Investigation.
S OO O
Ha
OMe
O
SO
O
Na
Na
R X
O
SRO
OR-X
143
RR R
145
H
S OO O
NaOMe
MeOH / CH2Cl2, 50 oC
Me
146
S OO O
MeOH / CH2Cl2, 50 oC
O
SO
O
143a
S OO O O
S OO
O
S OO50 oC
143a
1.
2.
H
H
H
H
H
43
2.1.2 Scope
Having identified optimal conditions, the scope of the reaction was
explored. Firstly, a range of thioacetals were synthesised by reacting
benzo[b]thiophene S-oxide with various substituted phenol coupling
partners (Scheme 38). Electron withdrawing groups such as CF3 and NO2
were well tolerated and afforded 139b and 139d respectively in good
yields. Electron donating methyl groups on the phenol coupling partner
could also be tolerated. Substitution on any position of the phenol
coupling partner was allowed and the majority of reactions gave
moderate to good yields. Substitution on the 3 position of phenol
however, leads to a mixture of regioisomers (139h/139h’). Substituted benzo[b]thiophene S-oxide coupling partners were
also explored. Substitution at the C2 position of the benzo[b]thiophene S-
oxide did not affect the [3,3]-sigmatropic rearrangement process to form
the thioacetal (139o-q); however the inclusion of cyano and ketone
functional groups did not yield any product. Previous work in the group on
the C3 alkylation of benzothiphenes25 showed that the [3,3]-sigmatropic
rearrangement process was not effected when a cyano group was
present at the C2 position of the benzothiophene S-oxide; therefore it is
highly possible that the cyano-thioacetal formed is unstable. A similar
argument may apply when a ketone functional group is present on the C2
position of the benzo[b]thiophene S-oxide coupling partner. Substitutions
on all other positions were allowed; however it is known that from the
proposed mechanism for the formation of benzo[b]furan (Scheme 38) that
it is necessary to keep the C3 position of the benzo[b]thiophene coupling
partner unsubstituted, so that the E2 elimination of sulfone can be
exploited.
Overall this reaction proceeds with high functional group tolerance
leading to thioacetals containing amide (139g), halides (139m), ester
(139q) and pharmaceutically relevant CF3 groups (139b).
44
Scheme 38: Scope of thioacetals formed by interrupted Pummerer/[3,3]-
sigmatropic rearrangement.
The thioacetals 139a-q synthesised were then oxidised to the
corresponding sulfones in generally good yields with high functional
group tolerance. Sulfones bearing nitro groups 143d and 143f had
solubility issues due to their very high polarity, which might have
contributed to lower yields. Thioacetals bearing amide (143g), halide
(143j) or ester groups (143q) underwent smooth oxidation with no
chemoselectivity issues. This functional group tolerance opens up
S O
R1 139a, R1 = H, 60% (gram scale)139b, R1 = CF3, 68%139c, R1 = C(O)Ph, 68%139d, R1 = NO2, 70%
S O R1
139e, R1= Br, 22%139f, R1 = NO2, 61%139g, R1 = C(O)NEt2, 39%
S O
MeMe
139i, 54%
138a-q 139a-q
S O
R
S OR2
S O
Br
S OBr
S O
Br
139l, 55%
139n, 51%
139m, 66%
139j, R = Cl, 68%139k, R = Me, 48%
139o, R2 = Me, 63%139p, R2 = Ph, 78%139q, R2 = CO2Me, 60%
S O
Br
73%* (73/26) as regioisomeric mixture
S O
Br
139h 139h’
+
*Total yield of mixture
OH
R1+ TFAASO
R
S O
R1R2
R2
R2
CH2Cl2-40 oC to RT, 16h
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
45
opportunities for the further functionalisation of these sulfones before
employing them in the ring opening reaction to access highly substituted
benzo[b]furans. The structure of sulfone 143b was confirmed by X-ray
crystallography (Scheme 39).
Scheme 39: Scope of sulfones formed by oxidation of thioacetals.
Lastly, the sulfones 143a-q produced were subjected to the
optimised reaction conditions for the ring opening reaction, leading to a
variety of benzo[b]furans. Again, the reaction proceeds with high
CH2Cl2, -20 oC
S O
R1143a, R1 = H, 68%143b, R1 = CF3, 89%143c, R1 = C(O)Ph, 82%143d, R1 = NO2, 57% S O R1
143e, R1 = Br, 69%143f, R1 = NO2, 52%143g, R1 = C(O)NEt2, 61%
S O
Br
S O
MeMe
O OO O
O O O O143, 70%
S O
R
S OR2
S O
Br
S OBr
S O
Br
143l, 80%
143n, 75%
143m, 43%
143j, R3 = Cl, 64%143k, R3 = Me, 50%
OO
OO
O O
OO
OO
143i, 78%
139a-q 143a-q
143o, R2 = Me, 75%143p, R2 = Ph, 69%143q, R2 = CO2Me, 63%
X-ray structure 143b
mCPBA
S O
R1
R
S O
R1
OO
R
R2 R2
H
H H
HH
H
H
H
H
H
H
H
H
H
H
H
H
HH
46
functional group tolerance and generally gives moderate to good yields.
The scope includes substrates bearing esters (145q) and halide groups
(145e, 145h, 145j and 145l-n), in a variety of positions. These groups are
usually not tolerated by metal-mediated processes, which are the main
methods for the synthesis of benzo[b]furans. These functional handles
will allow facile further functionalisation of the products at almost any
position of the molecule. The structure of benzofuran 145b was confirmed
by X-ray crystallography (Scheme 40). It is worth noting that the C2
substituent of the benzo[b]thiophene starting material eventually becomes
the C2 substituent of the final benzo[b]furan. In conclusion, the reaction
sequence developed can provide access to C3 arylated and C2
substituted benzofurans by the re-purposing of benzo[b]thiophenes.
47
Scheme 40: Scope of benzo[b]furan formation by elimination of sulfones.
Functionalisation of sulfinate salts with electrophiles other than MeI
was explored next. Electrophiles bearing various functional groups were
chosen and all gave the desired products (Table 3). Surprisingly, benzyl
bromide in conjunction with NaOMe gave poor yields; however a switch
of base to t-BuOK gave a better yield. This may be due to the non-
nucleophilic nature of t-BuOK in comparison to NaOMe, which may have
reacted with benzyl bromide in an unwanted side reaction. The use of a
Michael acceptor instead of a regular alkyl halide electrophile was also
O
SO
OMeR1
145a, R1 = H, 81%145b, R1 = CF3, 62%145c, R1 = C(O)Ph, 87%145d, R1 = NO2, 80%
O
SO
OMe
Br O
SO
OMe
Me
Me
O
SO
OMe
R1
145e, R1 = Br, 68%145f, R1 = NO2, 70%145g, R1 = C(O)NEt2, 65%
145h, 75%
143a-q
145i, 72%
O
SO
OMe
R
O
SO
OMe
Br
O
SO
OMe
Br
O
SO
OMe
Br
O
SO
OMe
R2
145j, R = Cl, 80% 145k, R = Me, 52%
145l, 72% 145m, 52%
145n, 54%
145o R2 = Me, 63% 145p, R2 = Ph, 67%145q, R2 = CO2Me, 62%
X-ray structure 145b
NaOMe
DMF/MeOH80 oC, 2h
145a-q
S O
R1
OO
R
R2
H
O
SOONa 120 oC, 18h
R1
R
O
SO
OMe
R1
R
R2 R2
MeI
48
attempted. When a simple Michael acceptor, cyclohex-2-en-1-one, was
employed there was no reaction even at an elevated temperature of 150
ºC.
Table 3: Scope of sulfone formation by sulfinate salt alkylation.
2.1.3 Palladium-Catalysed Desulfinylative Cross-Coupling
Sulfinate salts are a versatile class of compounds and in recent
years they have emerged as an alternative to boronic acids as coupling
O
SO
ORS O
O O
Me I
Br
I
OEt
O
Yield equiv.
81% 1.5
3
3
3I
78%
Product
145a
147
148
149
Electrophile
O
SO
OMe
O
SO O
O
SO O
O
SO O
143a
Product
56%*
82%
*tBuOK used instead of NaOMe
Electrophile
O
SO
ONa 120 oC, 18hNaOMe
DMF/MeOH80 oC, 2h
145a, 147-149
H
H
Ph
OEt
O
49
partners for palladium catalysed cross-coupling reactions.42 It was
therefore envisioned that benzo[b]furan benzene sulfinate salts e.g. 144 could be utilised in palladium catalysed desulfinylative cross-coupling
(Scheme 41). This method would allow further functionalization of the C3
aryl ring of 144, moreover, sulfur would be lost from the molecule and
thus no trace of the benzo[b]thiophene starting material would remain.
To realise this reaction sequence in an efficient one-pot synthesis,
DMF had to be replaced by MeOH/CH2Cl2; solvents that are easier to
remove prior to the second step of the reaction. This requires a longer
reaction time to generate sulfinate intermediate 144. Intermediate 144 was then used directly, without purification, for the palladium catalysed
desulfinylative cross-coupling with bromobenzene using a modified
literature procedure.43 The one-pot synthesis was successful and
afforded 150 in high yield. The scope was explored with other aryl
bromide coupling partners, which includes heterocycles (Scheme 42). 5-
and 6-Membered heterocycles, thiophene 154 and pyridine 152,
respectively, were tolerated. Reactions involving substrates bearing
electron deficient or electron donating donating groups, such as CF3 155
and OMe 153, proceeded with high yields and substitution at any position
of the aryl bromide cross-coupling partner was possible (151, 153 and
155).
Scheme 41: Generation of benzofuran sulfinate intermediate and
subsequent desulfinylative cross-coupling in a one-pot procedure.
S OO O O
SO
ONa
O
Pd(OAc)2, PCy3K2CO3
dioxane, 150 oC
NaOMe
MeOH / CH2Cl2 50 oC, 5h
PhBr
143a 150144
H
H
50
Scheme 42: Scope of the one-pot desulfinylative cross-coupling.
A catalytic cycle for the desulfinylative cross-coupling is shown in
Scheme 43. Firstly oxidative addition occurs with the aryl bromide
coupling partner giving Pd(II) complex 156, followed by ligand exchange
with the sulfinate salt. SO2 extrusion then leads to 159, where reductive
elimination gives the product and regenerates the Pd(0) catalyst.
S OO
O O
SO
ONa
O
Pd(OAc)2, PCy3K2CO3
Dioxane, 150 oC NaOMe
MeOH / CH2Cl2 50 oC, 5h
ArBr
143a
Ar
O
N
O
150, 74% 151, 85% 152, 65%
O CO2Me
O
153, 82%
O
154, 75%
O
155, 84%
OMeS
CF3
144 150-155
H
H
51
Scheme 43: Proposed catalytic cycle for desulfinylative cross-coupling of
benzo[b]furan benzene sulfinate 144.
2.1.4 One-Pot Synthesis of Thioacetal S,S-Dioxides
Despite efficient formation of a variety of C3-arylated
benzo[b]furans from thioacetal S,S-dioxides 143a-q, we wanted to
streamline the process. To allow facile access to these compounds, a
one-pot synthesis from benzothio[b]phene S-oxides and phenols directly
to thioacetal S,S-dioxides was envisioned. Benzothio[b]phene S-oxides
were activated by TFAA and reacted with phenol coupling partners
through interrupted Pummerer/[3,3]-sigmatropic rearrangement. At this
stage mCPBA could be added to the pot in order oxidise thioacetal 139 to
the desired product thioacetal S,S-dioxide 143. The one-pot synthesis
was successful and also proceeded in high yield. This one-pot procedure
was then used to synthesise thioacetal S,S-dioxides 143a-q that were
previously synthesised in 2 separate steps (Scheme 44). All previously
Pd0L2PhBr
PdIIL2Br
Ph
O
SO
ONa
NaBr
O
SO
OPdIIL2
PhO
SOO
PdIIL2Ph
SO2
O
PdIIL2Ph
O
Ph
156
144
157158
159
150
PCy3
PdII
52
attempted substrates were amenable to the process and the yields for the
one pot procedure were generally greater than the overall yield when
done in two separate steps.
Scheme 44: One-pot synthesis of thioacetal S,S-dioxides
2.2 Conclusion and Future Works
In conclusion unusual thioacetal compounds discovered in the C3
arylation of benzo[b]thiophenes were exploited for the transition metal
143a-q138a-q
TFAA, CH2Cl2
then mCPBA-20 ºC to RT
S O
R1 143a, R1 = H, 86% 143b, R1 = CF3, 58% 143c, R1 = C(O)Ph, 65% 143d, R1 = NO2, 63%
S O R1
143e, R1 = Br, 44% 143f, R1 = NO2, 49% 143g, R1 = C(O)NEt2, 43%
S O
Br
S O
MeMe
OO
OO
OO
OO
143h, 41%
S O
R
S OR2
S O
Br
S OBr
S O
Br
143l, 62%
143n, 45%
143m, 79%
143j, R3 = Cl, 47% 143k, R3 = Me, 53%
OO
O OO O
O O OO
143i, 52%
143o, R2 = Me, 62% 143p, R2 = Ph, 66%143q, R2 = CO2Me, 39%
-40 oC to RT, 16hOH
R1+SO
R
S O
R1
OO
R
R2
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HH
H
53
free synthesis of C3 arylated benzofurans. Thioacetal S,S-dioxides were
synthesised in a one-pot (2 step) procedure using readily available
benzo[b]thiophene S-oxide and phenol starting materials. Treatment of
the thioacetal S,S-dioxides with sodium methoxide leads to benzo[b]furan
benzene sulfinate salts, which could be subsequently functionalised with
a variety of electrophiles or participate in palladium-catalysed
desulfinylative cross-coupling to give C3-arylated benzofurans.
The sulfinate salts have been shown to be able to participate in
palladium-catalysed desulfinylative cross-couplings. A simple reductive
desulfinylation would provide additional flexibility to the synthesis.
Attempts have been made to reduce the sulfinate group. TFA was
reported to be able to reduce alkyl sulfinates44 and this method was
attempted on our aryl sulfinates. Following the literature conditions, a new
product was obtained; however the product was identified to be a
sulfinate ester 160 and not the desired product. It is speculated that TFA
mediated a reaction between the sulfinate group and the excess sodium
methoxide that was used to generate the benzo[b]furan sulfinate salt in
the first place. The identity of the product was confirmed by X-ray
crystallography (Scheme 45).
54
Scheme 45: Attempted reduction of sulfinate salt with TFA
Reduction of the sulfinate group with palladium and formic acid
was also attempted (Scheme 46). Unfortunately the desired product was
not observed. However, many alternative conditions can still be
attempted, such as different palladium catalysts, proton sources and
bases. Further investigation would be beneficial.
Scheme 46: Attempted Pd-catalysed reduction of an aryl sulfinate
S OO
O O
SO
ONa
O
TFA, 50 oC
NaOMe
MeOH / CH2Cl2 50 oC, 5h
CF3
F3C
F3C
O
F3C SO
OMe160 X-ray structure
143b
160
H
H
S OO O O
SO
ONaO
Pd(OAc)2
K2CO3
dioxane, 150 oC
NaOMe MeOH / CH2Cl2
50 oC, 5h
Formic acid
Benzoquinone
CF3
F3CF3C
143b
H
H
55
3 Experimental
3.1 General Experimental and General Procedures All experiments were performed under a nitrogen atmosphere and
anhydrous solvents were used, unless stated otherwise. THF was
distilled from sodium/benzophenone. All other commercial solvents and
reagents were used without additional purification. 1H NMR spectra were
recorded on NMR spectrometers at 400 MHz and 500 MHz and 13C NMR
at 101 MHz and 126 MHz. 1H NMR chemical shifts (δH) and 13C NMR
chemical shifts (δC) were measured in parts per million (ppm) referenced
to 0 ppm for trimethylsilane (TMS). Coupling constants (J) are quoted in
Hertz (Hz). Abbreviations for NMR data are s (singlet), d (doublet), t
(triplet), q (quartet), quin (quintet), sxt (sextet), and m (multiplet). Infrared
(IR) spectra were recorded over the range of 400-4000 cm-1 on a FTIR
spectrometer and only intense peaks were reported. Mass spectra were
obtained using positive or negative electrospray ionisation (ESI),
atmospheric pressure chemical ionization (APCI), gas chromatography–
mass spectrometry (GC-MS), electron impact ionisation (EI) or chemical
ionisation (CI) techniques. Flash column chromatography was carried out
using silica gel 60 Angstrom (Ǻ), 240-400 mesh. Thin layer
chromatography (TLC) was performed on aluminium sheets pre-coated
with silica gel, 0.20 mm (Macherey-Nagel, Polygram® Sil G/UV254). TLC
plates were visualised by UV absorption, phosphomolybdic acid, vanillin
or potassium permanganate solution and heating. Melting points were
measured using a Stuart Scientific SMP10.
56
General Procedure A: Preparation of thioacetals through oxidation and subsequent coupling of benzo[b]thiophenes with phenols.
The benzo[b]thiophene (0.5 mmol) was dissolved in CH2Cl2 (2 mL, 0.25
M) in an oven dried tube flushed with N2 at −20 ºC and BF3•OEt2 (8
equiv.) was added. The reaction was left stirring and mCPBA (1.2 equiv.)
was then added in 3 portions over 1.5 h at the same temperature. The
reaction was monitored by TLC, and after the disappearance of the
starting material, saturated Na2CO3 (0.2 mL) was added to the mixture,
followed by K2CO3 (100 mg) at −20 ºC. The mixture was then filtered
through a plug loaded with MgSO4 and K2CO3, washing with CH2Cl2. The
resulting solution was cooled to −40 ºC and TFAA (0.75 mmol, 1.5 equiv.)
was added. After 5 min, the corresponding phenol (1.5 equiv.) was added
at the same temperature. The mixture was stirred for 15 min at −40 ºC
before warming to room temperature and stirring overnight (16 h). The
solution was quenched with saturated NaHCO3 and the aqueous layer
was extracted with CH2Cl2 (3 × 10 mL) and washed with water. The
combined organic layers were dried (MgSO4) and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel
eluting with the indicated solvent.
General Procedure B: Oxidation of isolated thioacetals to thioacetal S,S-dioxides
The S,O-acetal (0.5 mmol) was dissolved in CH2Cl2 (3 mL, 0.25 M) in an
oven dried tube flushed with N2 at −20 ºC. mCPBA (2.4 equiv.) was then
added in 3 portions over 1.5 h at the same temperature. The reaction was
monitored by TLC, and after the disappearance of the starting material
the reaction was stopped. The mixture was then filtered through a plug
loaded with MgSO4 and K2CO3, washing with CH2Cl2. Next; the filtrate
was concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with the indicated solvent.
57
General Procedure C: One-Pot Synthesis of thioacetal S,S-dioxides
The benzo[b]thiophene (0.5 mmol) was dissolved in CH2Cl2 (2 mL, 0.25
M) in an oven dried tube flushed with N2 at −20 ºC and BF3・OEt2 (8
equiv.) was added. The reaction was left stirring and mCPBA (1.2 equiv.)
was then added in 3 portions over 1.5 h at the same temperature. The
reaction was monitored by TLC, and after the disappearance of the
starting material, saturated Na2CO3 (0.2 mL) was added to the mixture,
followed by K2CO3 (100 mg) at −20 ºC. The mixture was then filtered
through a plug loaded with MgSO4 and K2CO3, washing with CH2Cl2. The
resulting solution was cooled to −40 ºC and TFAA (0.75 mmol, 1.5 equiv.)
was added. After 5 min, the corresponding phenol (1.5 equiv.) was added
at the same temperature. The mixture was stirred for 15 min at −40 ºC
before warming to room temperature and left stirring overnight (16 h).
The solution was quenched with a minimal amount of saturated NaHCO3
at −20 ºC. The mixture was stirred and mCPBA (2.4 equiv.) was then
added at the same temperature. After stirring overnight (18 h), the
solution was quenched with saturated Na2S2O3 and the organic layer was
collected and washed with water and saturated NaHCO3. The organic
layer was then dried (MgSO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel eluting with
the indicated solvent.
General Procedure D: Synthesis of benzofurans from thioacetal S,S-dioxides
The sulfone (0.01 mmol) and NaOMe (1.5 equiv.) were added to an oven
dried vial flushed with N2. The sulfone was dissolved upon addition of
DMF (1 mL) to the vial and the remaining NaOMe was dissolved using a
minimal amount of MeOH. The mixture was then stirred at 80 ºC for 1.5 h
before the addition of the electrophile (1.5 equiv.) (indicated if different
equivalents used). After, the reaction was heated to 120 ºC and left
58
stirring overnight (16 h). The reaction was stopped and the mixture was
diluted by Et2O and water. The organic layer was collected and washed
with water (5 x 10 mL), dried (MgSO4), and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel
eluting with the indicated solvent.
General Procedure E: Desulfinylative cross-coupling of benzofuran benzene sulfinates with aryl bromides
The sulfone (0.01 mmol, 2 equiv.) and NaOMe (3 equiv.) were added to
an oven dried vial flushed with N2. The reagents were then dissolved in
methanol (1 mL) and with a minimum amount of CH2Cl2. The reaction
was heated to 50 ºC and was left stirring for 5 h. The reaction was then
stopped and the solvent was evaporated. Next, the vial was flushed with
N2. To the vial Pd(OAc)2 (10 mol %), PCy3 (20 mol %), K2CO3 (1.5
equiv.), 1,4-dioxane (2 mL) and aryl bromide (1 equiv.) were added. The
reaction was then stirred at 150 ºC overnight (18 h). The reaction was
allowed to cool down to room temperature and the mixture was filtered
through Celite, washing with water and ethyl acetate. The aqueous layer
was extracted with ethyl acetate and the combined organic layers were
collected and washed with brine, dried (MgSO4), and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel eluting with the indicated solvent.
3.2 Synthesis of Thioacetals
5a,10b-Dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139a
As described in general procedure A,
benzo[b]thiophene (1.63 g, 11.9 mmol), phenol
(1.68 g, 17.9 mmol), BF3⋅OEt2 (11.8 mL, 95.2
mmol), mCPBA (3.2 g, 14.3 mmol), TFAA (2.5 mL,
17.9 mmol) and CH2Cl2 (48 mL) gave 139a as a white solid (1.61 g, 7.14
mmol, 60%), Eluted with n-hexane/ ethyl acetate (9:1); m.p: 124-125 ºC;
S O
H
H
59
1H NMR (500 MHz, CDCl3) δ (ppm) 7.41 (t, J = 7.1 Hz, 2H, ArCH), 7.20-
7.14 (m, 3H, ArCH), 7.10 (ddd, J = 8.0, 5.7, 2.8 Hz, 1H, ArCH), 6.94 (t, J
= 7.5 Hz, 1H, ArCH), 6.88 (m, 2H, CH, ArCH), 5.26 (d, J = 8.0 Hz, 1H,
CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.3 (ArC), 139.4 (ArC), 138.9
(ArC), 129.1 (ArCH), 128.6 (ArCH), 127.7 (ArC), 125.1 (ArCH), 124.5
(ArCH), 124.1 (ArCH), 122.1 (ArCH), 121.7 (ArCH), 110.4 (ArCH), 94.8
(CH), 56.5 (CH); IR νmax (neat)/cm-1 742, 750, 923, 1476; HRMS (ESI)
calculated for C14H11OS [M+H]+: 227.0525. Found [M+H]+: 227.0512.
2-(Trifluoromethyl)-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139b
As described in general procedure A,
benzo[b]thiophene (368 mg, 2.60 mmol), 4-
(trifluoromethyl)phenol (640 mg, 4.4 mmol),
BF3⋅OEt2 (2.6 mL, 20.8 mmol), mCPBA (0.70 g,
3.12 mmol), TFAA (0.55 mL, 4.4 mmol) and
CH2Cl2 (11 mL) gave 139b as a crystalline solid (518 mg, 1.77 mmol,
68%), Eluted with n-hexane/ ethyl acetate (7:3); m.p: 154-155 ºC; 1H
NMR (500 MHz, CDCl3) δ (ppm) δ 7.71 (s, 1H, ArCH), 7.51 (d, J = 8.5 Hz,
1H, ArCH), 7.46 (d, J = 7.6 Hz, 1H, ArCH), 7.31 (d, J = 1.3 Hz, 1H,
ArCH), 7.23 (d, J = 7.8 Hz, 1H, ArCH), 7.23-7.16 (m, 1H, ArCH), 7.02 –
6.95 (m, 2H, ArCH, CH), 5.34 (d, J = 8.1 Hz, 1H, CH); 13C NMR (126
MHz, CDCl3) δ (ppm) 161.0 (ArC), 138.7 (ArC), 138.4 (ArC), 129.0
(ArCH), 128.8 (ArC), 127.0 (q, J = 3.6 Hz, ArCCF3), 125.6 (ArCH), 124.5
(ArCH), 124.4 (ArCH), 124.1 (ArCH), 122.2 (ArCH), 121.5 (q, J = 4.1 Hz,
CF3), 110.5 (ArCH), 95.6 (CH), 56.1 (CH); IR νmax (neat)/cm-1 746, 1100,
1148, 1324; HRMS (APCI) calculated for C15H10NO3S [M+H]+: 295.0399.
Found [M+H]+: 295.0391.
(5a,10b-Dihydrobenzo[4,5]thieno[2,3-b]benzofuran-2-yl)(phenyl)methanone 139c
As described in general procedure A,
benzo[b]thiophene (368 mg, 2.60 mmol), (4-
S O
H
H
C(O)Ph
S O
CF3
H
H
60
hydroxyphenyl)(phenyl)methanone (770 mg, 4.4 mmol), BF3⋅OEt2 (2.6
mL, 20.8 mmol), mCPBA (0.70 g, 3.12 mmol), TFAA (0.55 mL, 4.4 mmol)
and CH2Cl2 (11 mL) gave 139c as a pink solid (565 mg, 1.77 mmol,
68%), Eluted with n-hexane/ ethyl acetate (9:1); m.p: 128-130 ºC; 1H
NMR (500 MHz, CDCl3) δ (ppm) 8.03 (s, J = 1.9 Hz, 1H, ArCH), 7.76 –
7.71 (m, 2H, ArCH), 7.66 (dd, J = 8.3, 1.9 Hz, 1H, ArCH), 7.61 – 7.54 (m,
1H, ArCH), 7.48 (t, J = 7.6 Hz, 2H, ArCH), 7.43 (d, J = 7.6 Hz, 1H, ArCH),
7.21 (d, J = 4.2 Hz, 2H, ArCH), 7.13 (dt, J = 8.2, 4.2 Hz, 1H, ArCH), 6.95
(d, J = 8.1 Hz, 1H, CH), 6.89 (d, J = 8.4 Hz, 1H, ArCH), 5.32 (d, J = 8.0
Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ 195.5 (CO), 162.3 (ArC),
138.7 (ArC), 138.6 (ArC), 138.3 (ArC), 133.3 (ArC), 132.2 (ArCH), 131.7
(ArCH), 129.9 (ArCH), 128.9 (ArCH), 128.9 (ArCH), 128.4 (ArCH), 126.5
(ArC), 125.6 (ArCH), 124.6 (ArCH), 122.2 (ArCH), 109.7 (ArCH), 95.8
(CH), 56.0 (CH); IR νmax (neat)/cm-1 693, 746, 918, 1256, 1649; HRMS
(APCI) calculated for C21H13O2S [M-H]-: 329.0642. Found [M-H]-:
329.0651.
2-Nitro-5a,10b-Dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139d
As described in general procedure A,
benzo[b]thiophene (368 mg, 2.60 mmol), 4-
nitrophenol (550 mg, 4.4 mmol), BF3⋅OEt2 (2.6
mL, 20.8 mmol), mCPBA (0.70 g, 3.12 mmol),
TFAA (0.55 mL, 4.4 mmol) and CH2Cl2 (11 mL)
gave 139d as a yellow solid (490 mg, 1.82 mmol, 70%). Eluted with n-
hexane/ethyl acetate (1:1); m.p: 193-195 ºC; 1H NMR (500 MHz, CDCl3)
δ (ppm) 8.33 (d, J = 2.4 Hz, 1H, ArCH), 8.15 (dd, J = 8.8, 2.4 Hz, 1H,
ArCH), 7.44 (d, J = 7.6 Hz, 1H, ArCH), 7.26 – 7.20 (m, 2H, ArCH), 7.17
(td, J = 7.3, 6.5, 1.8 Hz, 1H, ArCH), 6.99 (d, J = 8.1 Hz, 1H, CH), 6.91 (d,
J = 8.8 Hz, 1H, ArCH), 5.33 (d, J = 8.0 Hz, 1H, CH); 13C NMR (126 MHz,
CDCl3) δ (ppm) 164.0 (ArC), 143.1 (ArC), 138.8 (ArC), 138.1 (ArC), 129.9
(ArCH), 129.5 (ArCH), 126.7 (ArC), 126.1 (ArCH), 124.8 (ArCH), 122.6
(ArCH), 120.8 (ArCH), 110.6 (ArCH), 96.9 (CH), 56.0 (CH); IR νmax
S O
H
H
NO2
61
(neat)/cm-1 732, 748, 1332, 1512; HRMS (APCI) calculated for
C14H10NO3S [M+H]+: 272.0331. Found [M+H]+: 272.0365.
4-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139e
As described in general procedure A,
benzo[b]thiophene (212 mg, 1.50 mmol), 2-
bromophenol (397 mg, 2.25 mmol), BF3⋅OEt2 (1.5
mL, 12.0 mmol), mCPBA (0.40 g, 1.8 mmol),
TFAA (0.32 mL, 2.25 mmol) and CH2Cl2 (6 mL) gave 139e as a white
solid (112 mg, 0.33 mmol, 22%). Eluted with n-hexane/CH2Cl2 (7:3); m.p:
155-158 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) δ 7.39 – 7.29 (m, 3H,
ArCH), 7.20 (m, 2H, ArCH), 7.11 (m, 1H, ArCH), 6.94 (d, J = 8.0 Hz, 1H,
CH), 6.82 (t, J = 7.7 Hz, 1H, ArCH), 5.34 (d, J = 8.0 Hz, 1H, CH); 13C
NMR (126 MHz, CDCl3) δ (ppm) 155.9 (ArC), 138.9 (ArC), 138.7 (ArC),
132.3 (ArC), 129.2 (ArCH), 128.9 (ArCH), 125.4 (ArC), 124.4 (ArCH),
123.1 (ArCH), 123.0 (ArCH), 122.2 (ArCH), 103.3 (ArCH), 95.1 (CH), 57.4
(CH); IR νmax (neat)/cm-1 625, 766, 830, 940, 1076, 1233, 1612; HRMS
(GCMS) calculated for C14H8BrOS [M-H]-: 302.9474. Found [M-H]-:
302.9480.
4-Nitro-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139f As described in general procedure A,
benzo[b]thiophene (212 mg, 1.50 mmol), 2-
nitrophenol (320 mg, 2.25 mmol), BF3⋅OEt2 (1.5
mL, 12.0 mmol), mCPBA (0.40 g, 1.8 mmol),
TFAA (0.32 mL, 2.25 mmol) and CH2Cl2 (6 mL) gave 139f as a red solid
(250 mg, 0.92 mmol, 61%), Eluted with n-hexane/ ethyl acetate (8:2);
m.p: 167-171 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) δ 7.98 (d, J = 8.4
Hz, 1H, ArCH), 7.71 (d, J = 7.3 Hz, 1H, ArCH), 7.38 (d, J = 7.6 Hz, 1H,
ArCH), 7.23 (m, 2H, ArCH), 7.14 (m, 1H, ArCH), 7.10 – 7.01 (m, 2H,
ArCH, CH), 5.33 (d, J = 8.0 Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ
(ppm) 153.7 (ArC), 139.1 (ArC), 138.2 (ArC), 133.7 (ArC), 133.4 (ArCH),
130.2 (ArCH), 129.5 (ArC), 125.9 (ArCH), 125.2 (ArCH), 124.6 (ArCH),
S O
H
HBr
S O NO2
H
H
62
122.7 (ArCH), 122.0 (ArCH), 97.6 (CH), 55.8 (CH); IR νmax (neat)/cm-1
740, 1206, 1309, 1339, 1511; HRMS (APCI) calculated for C14H10NO3S
[M+H]+: 272.0376. Found [M+H]+: 272.0369.
N,N-Diethyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran-4-carboxamide 139g
As described in general procedure A,
benzo[b]thiophene (212 mg, 1.50 mmol),
N,N-diethylsalicylamide (450 mg, 2.25
mmol), BF3⋅OEt2 (1.5 mL, 12.0 mmol),
mCPBA (0.40 g, 1.8 mmol), TFAA (0.32 mL, 2.25 mmol) and CH2Cl2 (6
mL) gave 139g as a brown solid (188 mg, 0.59 mmol, 39%). Eluted with
n-hexane/ ethyl acetate (7:3); m.p: 110-113 ºC; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.40 (m, 2H, ArCH), 7.22 – 7.07 (m, 4H, ArCH), 6.99 –
6.94 (m, 2H, ArCH, CH), 5.26 (d, J = 8.2 Hz, 1H, CH), 3.56 (q, J = 7.1 Hz,
2H, CH2), 3.22 (q, J = 7.3 Hz, 2H, CH2), 1.24 (t, J = 7.1 Hz, 3H, CH3),
1.06 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 167.1
(CO), 153.6 (ArC), 138.8 (ArC), 138.7 (ArC), 128.4 (ArCH), 128.1 (ArCH),
127.5 (ArC), 124.9 (ArCH), 124.5 (ArC), 124.2 (ArCH), 121.8 (ArCH),
121.7, (ArCH) 120.4 (ArCH), 95.2 (CH), 56.0 (CH), 42.9 (CH2), 39.0
(CH2), 14.1 (CH3), 12.8 (CH3); IR νmax (neat)/cm-1 743, 749, 979, 1289,
1614, 1625; HRMS (APCI) calculated for C19H20NO2S [M+H]+: 326.1209.
Found [M+H]+: 326.1197.
3-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139h
As described in general procedure A,
benzo[b]thiophene (368 mg, 2.60 mmol), 3-
bromophenol (690 mg, 4.4 mmol), BF3⋅OEt2
(2.6 mL, 20.8 mmol), mCPBA (0.70 g, 3.12
mmol), TFAA (0.55 mL, 4.4 mmol) and CH2Cl2 (11 mL) gave 139h as a
regioisomeric mixture with 139h’. Total yield of regioisomeric mixture
139h/139h’ (74/26) (579 mg, 1.90 mmol, 73%). Yield of individual
isomers 139h (54%) and 139h’ (19%) by NMR analysis. Eluted with n-
S O
H
HC(O)NEt2
S O
H
H
Br
63
hexane/ ethyl acetate (50:1); For a mixture of 139h and 139h’, 1H NMR
(400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.7 Hz, 1H, ArCH), 7.33 (d, J = 7.5
Hz, 1H, ArCH), 7.27 – 7.19 (m, 4H, ArCH), 7.17 (d, J = 4.0 Hz, 2H,
ArCH), 7.12 – 7.02 (m, 3H, ArCH), 7.02 - 6.96 (d, J = 1.6 Hz, 2H, ArCH),
6.86 (d, J = 8.0 Hz, 1H, ArCH), 6.71 (d, J = 7.9 Hz, 1H, CH ), 6.55 (d, J =
6.8 Hz, 1H, CH), 5.23 (d, J = 6.8 Hz, 1H, CH), 5.17 (d, J = 8.0 Hz, 1H,
CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 160.2 (ArC), 159.3 (ArC), 138.7
(ArC), 138.7 (ArC), 138.7 (ArC), 138.5 (ArC), 130.3 (ArCH), 129.4
(ArCH), 129.0 (ArC), 128.8 (ArC), 127.1 (ArCH), 126.1 (ArCH), 125.6
(ArCH), 125.3 (ArCH), 125.2 (ArCH), 125.0 (ArCH), 124.7 (ArCH), 124.4
(ArCH), 122.6 (ArCH), 122.2 (ArC), 122.2 (ArC), 118.3 (ArCH), 114.0
(ArCH), 109.0 (ArCH), 95.6 (CH), 94.7 (CH), 57.5 (CH), 56.1 (CH); HRMS
(APCI) calculated for C14H9BrOS [M+H]+: 304.9630. Found [M+H]+:
304.9621.
1,3-Dimethyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139i As described in general procedure A,
benzo[b]thiophene (212 mg, 1.50 mmol), 3,5-
dimethylphenol (278 mg, 2.25 mmol),
BF3⋅OEt2 (1.5 mL, 12.0 mmol), mCPBA (0.40
g, 1.8 mmol), TFAA (0.32 mL, 2.25 mmol) and
CH2Cl2 (6 mL) gave 139i as a white solid (219 mg, 0.81 mmol, 54%).
Eluted with n-hexane/CH2Cl2 (7:3); m.p: 160-163 ºC; 1H NMR (500 MHz,
CDCl3) δ (ppm) δ 7.36 (d, J = 7.7 Hz, 1H, ArCH), 7.24 (d, J = 7.9 Hz, 1H,
ArCH), 7.18 (t, J = 7.6 Hz, 1H, ArCH), 7.06 (t, J = 7.5 Hz, 1H, ArCH), 6.62
– 6.56 (m, 2H, ArCH, CH), 6.48 (s, 1H, ArCH), 5.14 (d, J = 6.9 Hz, 1H,
CH), 2.57 (s, 3H, CH3), 2.25 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ
(ppm) 159.2 (ArC), 139.4 (ArC), 138.8 (ArC), 138.7 (ArC), 133.6 (ArC),
128.3 (ArC), 125.3 (ArCH), 125.0 (ArCH), 123.8 (ArCH), 123.7 (ArCH),
122.4 (ArCH), 108.0 (ArCH), 94.7 (CH), 55.7 (CH), 21.3 (CH3), 20.1
(CH3); IR νmax (neat)/cm-1 738, 908, 1044, 1267, 1440, 1462; HRMS
(APCI) calculated for C16H15OS [M+H]+: 255.0838. Found [M+H]+:
255.0835.
S O
H
H
MeMe
64
9-Chloro-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139j As described in general procedure A, 5-
chlorobenzo[b]thiophene (200 mg, 1.19 mmol),
phenol (167 mg, 1.78 mmol), BF3⋅OEt2 (1.17 mL,
9.49 mmol), mCPBA (0.32 g, 1.42 mmol), TFAA
(0.25 mL, 1.78 mmol) and CH2Cl2 (5 mL) gave 139j as a white solid (210
mg, 0.81 mmol, 68%). Eluted with n-hexane/ethyl acetate (9:1); m.p: 172-
174 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.41 (d, J = 7.4 Hz, 1H,
ArCH), 7.35 (s, 1H, ArCH), 7.19 (t, J = 7.7 Hz, 1H, ArCH), 7.14 (d, J = 8.4
Hz, 1H, ArCH), 7.09 (d, J = 8.2 Hz, 1H, ArCH), 6.97 (t, J = 7.5 Hz, 1H,
ArCH), 6.91 – 6.85 (m, 2H, ArCH, CH), 5.22 (d, J = 8.0 Hz, 1H, CH); 13C
NMR (126 MHz, CDCl3) δ (ppm) 158.0 (ArC), 141.0 (ArC), 137.3 (ArC),
130.7 (ArC), 129.2 (ArCH), 128.4 (ArCH), 126.7 (ArC), 124.5 (ArCH),
123.8 (ArCH), 122.7 (ArCH), 121.7 (ArCH), 110.3 (ArCH), 94.9 (CH), 56.2
(CH); IR νmax (neat)/cm-1 747, 813, 916, 1083, 1205, 1459; HRMS
(GCMS) calculated for C14H10ClOS [M+H]+: 261.0135. Found [M+H]+:
261.0134.
9-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139k
As described in general procedure A, 5-
methylbenzo[b]thiophene (150 mg, 1.00 mmol),
phenol (143 mg, 1.50 mmol), BF3⋅OEt2 (1 mL, 8
mmol), mCPBA (0.27 g, 1.2 mmol) TFAA (0.21
mL, 1.5 mmol) and CH2Cl2 (4 mL) gave 139k as a
white solid (115 mg, 0.48 mmol, 48%). Eluted with n-hexane/ethyl acetate
(10:1); m.p: 157-159 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.43 (d, J =
7.4 Hz, 1H, ArCH), 7.20 (s, 1H, ArCH), 7.16 (t, J = 7.8 Hz, 1H, ArCH),
7.06 (d, J = 7.9 Hz, 1H, ArCH), 6.99 (d, J = 8.0 Hz, 1H, CH), 6.94 (t, J =
7.5 Hz, 1H, ArCH), 6.86 (m, 2H, ArCH), 5.19 (d, J = 7.9 Hz, 1H, CH), 2.31
(s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.6 (ArC), 139.7
(ArC), 135.6 (ArC), 135.3 (ArC), 129.7 (ArCH), 129.3 (ArCH), 128.1
(ArCH), 125.5 (ArC), 124.3 (ArCH), 122.1 (ArCH), 121.9 (ArCH), 110.6
S O
H
H
Cl
S O
H
H
Me
65
(ArCH), 95.3 (CH), 56.8 (CH), 21.4 (CH3); IR νmax (neat)/cm-1 748, 803,
920, 1167, 1205, 1221, 1458; HRMS (GCMS) calculated for C15H13OS
[M+H]+: 241.0682. Found [M+H]+: 241.0678.
10-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139l
As described in general procedure A, 4-
bromobenzo[b]thiophene (200 mg, 0.93 mmol),
phenol (130 mg, 1.40 mmol), BF3⋅OEt2 (0.92 mL, 7.5
mmol), mCPBA (0.25 g, 1.1 mmol), TFAA (0.20 mL,
1.40 mmol) and CH2Cl2 (4 mL) gave 139l as a white solid (157 mg, 0.52
mmol, 55%). Eluted with n-hexane/ethyl acetate (50:1); m.p: 134-136 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.74 (d, J = 7.7 Hz, 1H, ArCH), 7.24
(m, 2H, ArCH), 7.13 (d, J = 8.0 Hz, 1H, CH), 7.03 – 6.88 (m, 4H, ArCH),
5.49 (d, J = 8.0 Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 157.8
(ArC), 141.9 (ArC), 139.3 (ArC), 130.2 (ArCH), 129.9, (ArCH) 128.8
(ArCH), 126.7 (ArC), 125.9 (ArCH), 122.6 (ArCH), 120.9 (ArCH), 119.9
(ArC), 111.5 (ArCH), 95.3 (CH), 57.8 (CH); IR νmax (neat)/cm-1 743, 755,
766, 1001, 1208, 1456, 1473; HRMS (GCMS) calculated for C14H10BrOS
[M+H]+: 304.9630. Found [M+H]+: 304.9629.
8-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139m
As described in general procedure A, 6-
bromobenzo[b]thiophene (200 mg, 0.93 mmol),
phenol (130 mg, 1.40 mmol), BF3⋅OEt2 (0.92
mL, 7.5 mmol), mCPBA (0.25 g, 1.1 mmol),
TFAA (0.20 mL, 1.40 mmol) and CH2Cl2 (4 mL) gave 139m as a white
solid (187 mg, 0.62 mmol, 66 %). Eluted with n-hexane/ethyl acetate
(8:2); m.p: 142-145 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.36 (d, J =
7.4 Hz, 1H, ArCH), 7.31 (d, J = 1.7 Hz, 1H, ArCH), 7.26 – 7.15 (m, 3H,
ArCH), 6.95 (t, J = 7.5 Hz, 1H, ArCH), 6.89 (d, J = 8.0 Hz, 1H, ArCH),
6.87 (d, J = 8.0 Hz, 1H, CH), 5.19 (d, J = 8.0 Hz, 1H, CH); 13C NMR (126
MHz, CDCl3) δ 157.9 (ArC), 141.2 (ArC), 138.3 (ArC), 129.1 (ArCH),
S O
H
H
Br
S O
H
H
Br
66
128.0 (ArCH), 126.8 (ArC), 125.3 (ArCH), 124.5 (ArCH), 123.7 (ArCH),
122.0, (ArCH) 121.7 (ArC), 110.4 (ArCH), 94.8 (CH), 55.8 (CH); IR νmax
(neat)/cm-1 770, 803, 910, 1220, 1456, 1473; HRMS (GCMS) calculated
for C14H10BrOS [M+H]+: 304.9630. Found [M+H]+: 304.9623.
7-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139n As described in general procedure A, 7-
bromobenzo[b]thiophene (47 µL, 0.35 mmol),
phenol (50 mg, 0.53 mmol), BF3⋅OEt2 (0.40 mL,
2.8 mmol), mCPBA (95 mg, 0.42 mmol), TFAA (73
µL, 0.53 mmol) and CH2Cl2 (1.5 mL) gave 139n as a white solid (54 mg,
0.18 mmol, 51%). Eluted with n-hexane/ethyl acetate (10:1); m.p: 155-
158; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.39 – 7.30 (m, 3H, ArCH), 7.19
(td, J = 7.8, 1.3 Hz, 1H, ArCH), 6.99 – 6.93 (m, 2H, ArCH, CH), 6.88 (m, J
= 9.5, 8.0 Hz, 2H, ArCH), 5.39 (d, J = 8.1 Hz, 1H, CH); 13C NMR (126
MHz, CDCl3) δ 158.0 (ArC), 141.4 (ArC), 140.4 (ArC), 131.3 (ArCH),
129.1 (ArCH), 126.9 (ArC), 126.4 (ArCH), 123.7 (ArCH), 122.8 (ArCH),
121.7 (ArCH), 115.5 (ArC), 110.4 (ArCH), 93.0 (CH), 57.7 (CH); IR νmax
(neat)/cm-1 743, 1222, 1414, 1476; HRMS (GCMS) calculated for
C14H10BrOS [M+H]+: 304.9630. Found [M+H]+: 304.9628.
5a-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139o As described in general procedure A, 2-
methylbenzo[b]thiophene (164 mg, 1.10 mmol),
phenol (156 mg, 1.65 mmol), BF3⋅OEt2 (1.1 mL, 8.8
mmol), mCPBA (0.30 g, 1.32 mmol), TFAA (0.23
mL, 1.65 mmol) and CH2Cl2 (4 mL) gave 139o as an oil (166 mg, 0.69
mmol, 63%). Eluted with n-hexane/ethyl acetate (9:1); 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.85 – 7.80 (m, 1H, ArCH), 7.40 – 7.28 (m, 4H, ArCH),
7.22 (dd, J = 7.6, 1.7 Hz, 1H, ArCH), 7.11 – 7.02 (m, 2H, ArCH), 4.91 –
4.89 (m, 1H, CH), 2.46 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ 154.1
(ArC), 140.1 (ArC), 139.7 (ArC), 139.1 (ArCH), 131.6 (ArCH), 130.2
(ArCH), 128.2 (ArCH), 125.0 (ArC), 124.7 (ArCH), 122.8 (ArCH), 122.5
S O
H
HBr
S O
H
Me
67
(ArCH), 121.2 (ArCH), 121.1 (CCH3), 116.1 (CH), 14.9 (CH3); IR νmax
(neat)/cm-1 760, 1176, 1204, 1433, 1484; HRMS (GCMS) calculated for
C15H13OS [M+H]+: 241.0682. Found [M+H]+: 241.0677.
5a-Phenyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 139p As described in general procedure A, 2-
phenylbenzo[b]thiophene (119 mg, 0.57 mmol),
phenol (80 mg, 0.86 mmol), BF3⋅OEt2 (0.56 mL, 4.6
mmol), mCPBA (0.15 g, 0.68 mmol), TFAA (0.12
mL, 0.86 mmol) and CH2Cl2 (2 mL) gave 139p as an oil (134 mg, 0.44
mmol, 78%). Eluted with n-hexane/ethyl acetate (7:3); 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.90 – 7.84 (m, 1H, ArCH), 7.42 (dd, J = 8.3, 1.3 Hz, 1H,
ArCH), 7.40 – 7.21 (m, 8H, ArCH), 7.18 (dd, J = 8.0, 1.7 Hz, 1H, ArCH),
6.97 (t, J = 7.2 Hz, 2H, ArCH), 4.88 (s, 1H, CH); 13C NMR (126 MHz,
CDCl3) δ 153.9 (ArC), 142.4 (ArC), 141.0 (ArC), 139.5 (ArC), 133.9
(ArCH), 131.9 (ArCH), 130.3 (ArCH), 129.1 (ArCH), 129.1 (ArCH), 128.8
(ArCH), 127.4 (ArC), 125.5 (ArCH), 125.3 (ArCH), 123.8 (ArCH), 122.6
(ArCH), 121.7 (ArCH), 121.3 (CPh), 116.4 (CH); IR νmax (neat)/cm-1 713,
1147, 1197, 1431, 1480; HRMS (GCMS) calculated for C20H15OS [M+H]+:
303.0838. Found [M+H]+: 303.0826.
Methyl benzo[4,5]thieno[2,3-b]benzofuran-5a(10bH)-carboxylate 139q
As described in general procedure A, methyl
benzo[b]thiophene-2-carboxylate (200 mg, 1.04
mmol), phenol (147 mg, 1.56 mmol), BF3⋅OEt2 (1.0
mL, 8.32 mmol), mCPBA (280 mg, 1.25 mmol),
TFAA (0.22 mL, 1.56 mmol) and CH2Cl2 (4 mL) gave 139q as a white
solid (171 mg, 0.60 mmol, 59%). Eluted with n-hexane/ethyl acetate (6:4);
m.p: 72-75 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.46 (d, J = 7.4 Hz,
1H, ArCH), 7.37 (d, J = 7.5 Hz, 1H, ArCH), 7.24 – 7.10 (m, 4H, ArCH),
7.02 – 6.93 (m, 2H, ArCH), 5.66 (s, 1H, CH), 3.91 (s, 3H, CH3); 13C NMR
(126 MHz, CDCl3) δ 168.8 (CO), 157.0 (ArC), 138.9 (ArC), 137.9 (ArC),
S O
H
Ph
S O
H
CO2Me
68
129.6 (ArCH), 129.0 (ArCH), 127.2 (ArC), 126.0 (ArCH), 124.8 (ArCH),
124.2 (ArCH), 122.9 (ArCH), 121.9 (ArCH), 111.3 (ArCH), 105.3
(CCO2Me), 59.6 (CH), 54.1 (CH3); IR νmax (neat)/cm-1 744, 1048, 1239,
1270, 1461, 1746; HRMS (GCMS) calculated for C16H13O3S [M+H]+:
285.0580. Found [M+H]+: 285.0573.
10b-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 146’
As described in general procedure A, 3-
methylbenzo[b]thiophene (100 mg, 0.67 mmol),
phenol (95 mg, 1.0 mmol), BF3⋅OEt2 (0.67 mL, 5.4
mmol), mCPBA (181 mg, 0.80 mmol), TFAA (0.12
mL, 1.0 mmol) and CH2Cl2 (3 mL) gave 146 as an oil (84 mg, 0.35 mmol,
52%). Eluted with n-hexane/ethyl acetate (7:3); 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.39 (d, J = 7.4 Hz, 1H, ArCH), 7.30 (d, J = 7.6 Hz, 1H,
ArCH), 7.21 – 7.08 (m, 4H, ArCH), 6.96 (t, J = 7.5 Hz, 1H, ArCH), 6.84 (d,
J = 8.0 Hz, 1H, ArCH), 6.34 (s, 1H, CH), 1.74 (s, 3H, CH3); 13C NMR (126
MHz, CDCl3) δ (ppm) 158.1 (ArC), 143.6 (ArC), 137.7 (ArC), 132.1 (ArC),
128.5 (ArCH), 128.1 (ArCH), 125.2 (ArCH), 123.5 (ArCH), 122.5 (ArCH),
122.0 (ArCH), 121.5 (ArCH), 110.0 (ArCH), 101.2 (CH), 62.2 (CCH3),
24.9 (CH3); IR νmax (neat)/cm-1 739, 914, 1204, 1459, 1473. HRMS
(GCMS) calculated for C15H13OS [M+H]+: 241.0682. Found [M+H]+:
241.0677.
3.3 Synthesis of Thioacetal S,S-Dioxides 5a,10b-Dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143a
As described in general procedure B, 139a (1.12 g,
4.96 mmol), mCPBA (2.44 g, 10.9 mmol) and
CH2Cl2 (30 mL) gave 143a as a white solid (871 mg,
3.37 mmol, 68%). Eluted with n-hexane/ ethyl
acetate (1:1).
S O
Me
H
S O
H
HOO
69
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), phenol (103 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL, 5.96 mmol),
mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol), CH2Cl2 (3
mL) and then mCPBA (400 mg, 1.79 mmol) gave 143a as a white solid
(166 mg, 0.65 mmol, 86%), Eluted with n-hexane/ ethyl acetate (1:1).
m.p: 163-164 ºC; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.79 (d, J = 7.8 Hz,
1H, ArCH), 7.73-7.66 (m, 2H, ArCH), 7.53 (ddd, J = 8.1, 5.6, 2.7 Hz, 1H,
ArCH), 7.36 (d, J = 7.6 Hz, 1H, ArCH), 7.25 (t, J = 7.9 Hz, 1H, ArCH),
7.06-6.97 (m, 2H, ArCH), 5.90 (d, J = 8.2 Hz, 1H, CH), 5.26 (d, J = 8.2
Hz, 1H, CH); 13C NMR (101 MHz, CDCl3) δ (ppm) 158.1 (ArC), 137.0
(ArC), 136.5 (ArC), 134.8 (ArCH), 130.2, (ArCH), 130.0, (ArCH), 126.8
(ArC), 125.4 (ArCH), 124.1 (ArCH), 123.0, (ArCH), 122.6 (ArCH), 111.3
(ArCH), 94.3 (CH), 47.5 (CH); IR νmax (neat)/cm-1 722, 829, 1035, 1123,
1151, 1176, 1302, 1316, 1461, 1477; HRMS (ESI) calculated for
C15H13O3S [M+H]+: 259.0415. Found [M+H]+: 259.0423.
2-(Trifluoromethyl)-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143b
As described in general procedure B, 139b (200
mg, 0.68 mmol), mCPBA (0.37 g, 1.63 mmol) and
CH2Cl2 (4 mL) gave 143b as a white solid (197
mg, 1.45 mmol, 89%). Eluted with n-hexane/ ethyl
acetate (6:4).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), 4-(trifluoromethyl)phenol (181 mg, 1.13 mmol), BF3⋅OEt2
(0.74 mL, 5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL,
1.13 mmol), CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave
143b as a white solid (141 mg, 0.44 mmol, 58%), Eluted with n-hexane/
ethyl acetate (6:4).
m.p: 155-157 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.82 (d, J = 7.8 Hz,
1H, ArCH), 7.76 (t, J = 7.6 Hz, 1H, ArCH), 7.71 (d, J = 7.7 Hz, 1H, ArCH),
S O
H
HOO
CF3
70
7.59 (d, J = 7.3 Hz, 2H, ArCH), 7.54 (d, J = 8.7 Hz, 1H, ArCH), 7.13 (d, J
= 8.5 Hz, 1H, ArCH), 5.97 (d, J = 8.3, 1.5 Hz, 1H, CH), 5.40 (d, J = 8.3
Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 160.6 (ArC), 136.9
(ArC), 135.3 (ArC), 135.2 (ArCH), 130.4 (ArCH), 128.1 (q, J = 3.9 Hz,
ArCH), 126.8 (ArC), 126.4 (ArCH), 125.6 (q, J = 32.9 Hz, ArCCF3), 124.0
(q, J = 271.8 Hz, CF3), 122.8 (ArCH), 121.7 (q, J = 3.9 Hz, ArCH), 111.6
(ArCH), 94.7 (CH), 47.0 (CH); IR νmax (neat)/cm-1 661, 739, 756, 834,
1037, 1114, 1149, 1169, 1315, 1331; HRMS (ESI) calculated for
C15H10F3O3S [M-H]-: 325.0152. Found [M-H]-: 325.0147.
(6,6-Dioxido-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran-2-yl)(phenyl)methanone 143c
As described in general procedure B, 139c
(200 mg, 0.61 mmol), mCPBA (0.33 g, 1.46
mmol) and CH2Cl2 (4 mL) gave 143c as a
white solid (180 mg, 0.5 mmol, 82%). Eluted
with n-hexane/ ethyl acetate (6:4).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), (4-hydroxyphenyl)(phenyl)methanone (226 mg, 1.13 mmol),
BF3⋅OEt2 (0.74 mL, 5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA
(0.16 mL, 1.13 mmol), CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79
mmol) gave 143c as a white solid (175 mg, 0.49 mmol, 65%), Eluted with
n-hexane/ ethyl acetate (7:3).
m.p: 218-219 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.97 (s, 1H, ArCH),
7.82 (d, J = 7.9 Hz, 1H, ArCH), 7.76-7.65 (m, 4H, ArCH), 7.62 – 7.54 (m,
3H, ArCH), 7.47 (t, J = 7.7 Hz, 2H, ArCH), 7.11 – 7.06 (m, 1H, ArCH),
6.00 (d, J = 8.3, 1H, CH), 5.42 (d, J = 8.3 Hz, 1H, CH); 13C NMR (126
MHz, CDCl3) δ (ppm) 195.4 (CO), 161.8 (ArC), 138.1 (ArC), 137.2 (ArC),
135.9 (ArC), 135.4 (ArCH), 134.3 (ArCH), 133.3 (ArCH), 132.8 (ArC),
130.6 (ArCH), 130.2 (ArCH), 128.8 (ArCH), 127.2 (ArC), 126.9 (ArCH),
126.7 (ArCH), 123.0 (ArCH), 110.9 (ArCH), 95.1 (CH), 47.2 (CH); IR νmax
S O
H
HOO
C(O)Ph
71
(neat)/cm-1 646, 694, 732, 752, 760, 797, 956, 1091, 1178, 1262, 1294,
1320, 1448, 1592, 1654; HRMS (ESI) calculated for C21H15O4S [M+H]+:
363.0686. Found [M+H]+: 363.0683.
2-Nitro-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143d
As described in general procedure B, 139d (200
mg, 0.75 mmol), mCPBA (0.40 g, 1.80 mmol) and
CH2Cl2 (8 mL) gave 143d as a white solid (129
mg, 0.43 mmol, 57%). Eluted with n-hexane/
ethyl acetate (6:4).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), 4-nitrophenol (155 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL, 5.96
mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol),
CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143d as a
white solid (143 mg, 0.47 mmol, 63%), Eluted with n-hexane/ ethyl
acetate (7:3).
m.p: 236-238 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.27 – 8.20 (m, 2H,
ArCH), 7.83 (d, J = 7.8 Hz, 1H, ArCH), 7.81 – 7.73 (m, 2H, ArCH), 7.61 (t,
J = 7.5 Hz, 1H, ArCH), 7.15 (d, J = 8.9 Hz, 1H, ArCH), 6.04 (d, J = 8.3
Hz, 1H, CH), 5.43 (d, J = 8.3 Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ
(ppm) 163.2 (ArC), 142.4 (ArC), 137.3 (ArC), 135.7 (ArC), 134.8 (ArCH),
131.0 (ArCH), 127.6 (ArCH), 127.5 (ArC), 127.1 (ArCH), 123.2 (ArCH),
121.0 (ArCH), 111.9 (ArCH), 95.5 (CH), 46.9 (CH); IR νmax (neat)/cm-1
664, 730, 744, 750, 761, 1030, 1109, 1120, 1145, 1177, 1158, 1213,
1236, 1324, 1344, 1463, 1517; HRMS (ESI) calculated for C14H10NO5S
[M+H]+: 304.0274. Found [M+H]+: 304.0265.
4-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 4e
S O
H
HOO
NO2
72
As described in general procedure B, 139e (100
mg, 0.33 mmol), mCPBA (0.18 g, 0.79 mmol) and
CH2Cl2 (2 mL) gave 143e as a white solid (76
mg, 0.23 mmol, 69%). Eluted with n-hexane/
ethyl acetate (6:4).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), 2-bromophenol (0.13 mL, 1.13 mmol), BF3⋅OEt2 (0.74 mL,
5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol),
CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143e as a
white solid (112 mg, 0.34 mmol, 45%), Eluted with n-hexane/ ethyl
acetate (8:2).
m.p: 214-216 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.81 (d, J = 7.7 Hz,
1H, ArCH), 7.70 (t, J = 7.5 Hz, 1H, ArCH), 7.65 (d, J = 7.8 Hz, 1H, ArCH),
7.56 (t, J = 7.5 Hz, 1H, ArCH), 7.40 (d, J = 7.9 Hz, 1H, ArCH), 7.29 - 7.26
(m, 1H, ArCH), 6.88 (t, J = 7.8 Hz, 1H, ArCH), 5.95 (d, J = 8.2 Hz, 1H,
CH), 5.43 (d, J = 8.3 Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm)
155.9 (ArC), 137.4 (ArC), 136.0 (ArC), 135.1 (ArCH), 133.6 (ArCH), 130.5
(ArCH), 127.0 (ArC), 126.9 (ArCH), 124.5 (ArCH), 123.3 (ArCH), 123.1
(ArCH), 104.4 (ArC), 94.3 (CH), 48.5 (CH); IR νmax (neat)/cm-1 749, 766,
778, 783, 903, 1053, 1117, 1129, 1171, 1316, 1325, 1440, 1446; HRMS
(GCMS) calculated for C14H8BrO3S [M-H]-: 334.9383. Found [M-H]-:
334.9389.
4-nitro-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143f
As described in general procedure B, 139f (145 mg, 0.53 mmol), mCPBA (0.29 g, 1.27
mmol) and CH2Cl2 (9 mL) 143f as a white solid
(84 mg, 0.28 mmol, 52%). Eluted with n-
hexane/ ethyl acetate (4:6).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
S O
H
HOO
Br
S O
H
HOO
NO2
73
0.75 mmol), 2-nitrophenol (155 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL, 5.96
mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol),
CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143f as a
white solid (110 mg, 0.37 mmol, 49%), Eluted with n-hexane/ ethyl
acetate (4:6).
m.p: 245-246 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.06 (d, J = 8.4 Hz,
1H, ArCH), 7.84 (d, J = 7.9 Hz, 1H, ArCH), 7.77 - 7.66 (m, 2H, ArCH),
7.65 - 7.55 (m, 2H, ArCH), 7.14 (t, J = 8.0 Hz, 1H, ArCH), 6.13 (d, J = 8.4
Hz, 1H, CH), 5.43 (d, J = 8.4 Hz, 1H, CH); 13C NMR (126 MHz, DMSO-
d6) δ (ppm) 151.9 (ArC), 136.3 (ArC), 135.7 (ArC), 135.5 (ArC), 132.9
(ArCH), 131.8 (ArCH), 131.3 (ArCH), 130.5 (ArCH), 128.0 (ArC), 125.2
(ArCH), 123.6 (ArCH), 122.2 (ArCH), 95.5 (CH), 46.0 (CH); IR νmax
(neat)/cm-1 629, 713, 732, 847, 1036, 1125, 1152, 1308, 1318, 1457,
1525; HRMS (GCMS) calculated for C14H8NO5S [M-H]-: 302.0129. Found
[M-H]-: 302.0128.
N,N-Diethyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran-4-carboxamide 6,6-dioxide 143g
As described in general procedure B,
139g (130 mg, 0.40 mmol), mCPBA (0.22
g, 0.96 mmol) and CH2Cl2 (3 mL) gave
143g as a white solid (87 mg, 0.24 mmol,
61%). Eluted with n-hexane/ ethyl acetate (3:7).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), N,N-diethylsalicylamide (220 mg, 1.13 mmol), BF3⋅OEt2 (0.74
mL, 5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13
mmol), CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143g as a white solid (115 mg, 0.32 mmol, 43%), Eluted with n-hexane/ ethyl
acetate (4:6).
S O
H
HOO
C(O)NEt2
74
m.p: 221-222 ºC;1H NMR (400 MHz, CDCl3) δ (ppm) 7.80 (d, J = 7.8 Hz,
1H, ArCH), 7.73 (m, J = 5.5 Hz, 2H, ArCH), 7.57 (t, J = 7.0 Hz, 1H,
ArCH), 7.37 – 7.29 (m, 1H, ArCH), 7.24 (s, 1H, ArCH), 7.03 (t, J = 7.6 Hz,
1H, ArCH), 5.96 (d, J = 8.5 Hz, 1H, CH), 5.35 (d, J = 8.5 Hz, 1H, CH),
3.70 (dq, J = 14.2, 7.3 Hz, 1H, CH2), 3.48 (dq, J = 15.0, 8.1 Hz, 1H, CH2),
3.40 – 3.24 (m, 2H, CH2), 1.28 (t, J = 7.2 Hz, 3H, CH3), 1.06 (t, J = 7.2
Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 166.7 (CO), 154.0
(ArC), 137.5 (ArC), 135.9 (ArC), 135.1 (ArCH), 130.4 (ArCH), 128.9
(ArCH), 127.2 (ArCH), 126.0 (ArC), 124.9 (ArCH), 123.6 (ArC), 122.9
(ArCH), 122.1 (ArCH), 95.0 (CH), 47.6 (CH), 43.5 (CH2), 39.7 (CH2), 14.6
(CH3), 13.4 (CH3); IR νmax (neat)/cm-1 739, 1042, 1149, 1289,1302, 1435,
1618; HRMS (GCMS) calculated for C19H20NO4S [M+H]+: 358.1108.
Found [M+H]+: 358.1102.
3-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143h
As described in general procedure B, a
regioisomeric mixture of 139h/139h’ (74/26)
(200 mg, 0.66 mmol), mCPBA (0.35 g, 1.58
mmol) and CH2Cl2 (4 mL) gave 143h as a
white solid (156 mg, 0.46 mmol, 70%). Eluted with n-hexane/ ethyl
acetate (1:1).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), 3-bromophenol (197 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL,
5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol),
CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143h as a
white solid (104 mg, 0.31 mmol, 41%), Eluted with n-hexane/ ethyl
acetate (1:1).
m.p: 222-224 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.80 (d, J = 7.8 Hz,
1H, ArCH), 7.70 (t, J = 7.6 Hz, 1H, ArCH), 7.64 (d, J = 7.7 Hz, 1H, ArCH),
7.55 (t, J = 7.5 Hz, 1H, ArCH), 7.23 – 7.17 (m, 2H, ArCH), 7.14 - 7.10 (m,
1H, ArCH), 5.90 (d, J = 8.2, 1H, CH), 5.30 (d, J = 8.1 Hz, 1H, CH); 13C
S O
H
HOO
Br
75
NMR (126 MHz, CDCl3) δ (ppm) 159.2 (ArC), 137.3 (ArC), 136.0 (ArC),
135.2 (ArCH), 130.5 (ArCH), 126.9 (ArC), 126.5 (ArCH), 125.3 (ArCH),
125.0 (ArCH), 123.7 (ArCH), 123.0 (ArC), 115.3 (ArCH), 95.0 (CH), 47.3
(CH); IR νmax (neat)/cm-1 744, 766, 802, 852, 887, 1036, 1126, 1153,
1310, 1471; HRMS (APCI) calculated for C14H10BrO3S [M+H]+: 336.9529.
Found [M+H]+: 336.9522.
1,3-Dimethyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143i
As described in general procedure B, 139i (180 mg, 0.47 mmol), mCPBA (0.26 g, 1.13
mmol) and CH2Cl2 (3 mL) gave 143i as a
white solid (105 mg, 0.37 mmol, 78%). Eluted
with n-hexane/ ethyl acetate (1:1).
Or as described in general procedure C, benzo[b]thiophene (105 mg,
0.75 mmol), 3,5-dimethylphenol (137 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL,
5.96 mmol), mCPBA (200 mg, 0.89 mmol), TFAA (0.16 mL, 1.13 mmol),
CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143i as a
white solid (121 mg, 0.39 mmol, 52%), Eluted with n-hexane/ ethyl
acetate (1:1).
m.p: 180-181 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.81 (d, J = 7.7 Hz,
1H, ArCH), 7.68 - 7.63 (m, 2H, ArCH), 7.52 (t, J = 7.5 Hz, 1H, ArCH),
6.67 (s, 1H, ArCH), 6.63 (s, 1H, ArCH), 5.80 (d, J = 7.5, 1H, CH), 5.30 (d,
J = 7.6 Hz, 1H, CH), 2.49 (s, 3H, CH3), 2.26 (s, 3H, CH3); 13C NMR (126
MHz, CDCl3) δ (ppm) 159.1 (ArC), 141.0 (ArC), 137.3 (ArC), 136.6 (ArC),
134.6 (ArC), 134.5 (ArCH), 130.1 (ArCH), 128.6 (ArCH), 125.8 (ArC),
123.1 (ArCH), 121.7 (ArCH), 109.6 (ArCH), 95.3 (CH), 47.6 (CH), 21.8
(CH3), 20.7 (CH3); IR νmax (neat)/cm-1 754, 1034, 1122, 1148, 1311;
HRMS (GCMS) calculated for C16H13O3S [M-H]-: 285.0580. Found [M-H]-:
285.0591.
S O
H
HOO
MeMe
76
9-Chloro-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143j
General Procedure B or C. As described in
general procedure B, 139j (120 mg, 0.46 mmol),
mCPBA (0.25 g, 1.10 mmol) and CH2Cl2 (3 mL)
gave 143j as a white solid (86 mg, 0.29 mmol,
64%). Eluted with n-hexane/ ethyl acetate (7:3).
Or as described in general procedure C, 5-chlorobenzo[b]thiophene (100
mg, 0.59 mmol), phenol (84 mg, 0.89 mmol), BF3⋅OEt2 (0.59 mL, 4.72
mmol), mCPBA (159 mg, 0.71 mmol), TFAA (0.13 mL, 0.89 mmol),
CH2Cl2 (3 mL) and then mCPBA (318 mg, 1.42 mmol) gave 143j as a
white solid (81 mg, 0.28 mmol, 47 %), Eluted with n-hexane/ ethyl acetate
(7:3).
m.p: 207-209 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (d, J = 8.3 Hz,
1H, ArCH), 7.65 (d, J = 2.0 Hz, 1H, ArCH), 7.50 (dd, J = 8.3, 1.7 Hz, 1H,
ArCH), 7.37 (d, J = 7.5 Hz, 1H, ArCH), 7.27 (t, J = 8.1 Hz, 1H, ArCH),
7.07 – 7.00 (m, 2H, ArCH), 5.90 (d, J = 8.2 Hz, 1H, CH), 5.32 (d, J = 8.2
Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.3 (ArC), 141.3
(ArC), 138.7 (ArC), 135.8 (ArC), 130.7 (ArCH), 130.7 (ArCH), 127.1
(ArC), 124.9 (ArCH), 124.3 (ArCH), 124.1 (ArCH), 123.4 (ArCH), 111.7
(ArCH), 94.8 (CH), 47.5 (CH); IR νmax (neat)/cm-1 605, 762, 780, 836,
904, 1042, 1085, 1151, 1180, 1193, 1214,1291, 1302, 1312, 1464, 1479,
1589; HRMS (GCMS) calculated for C14H10ClO3S [M+H]+: 293.0034.
Found [M+H]+: 293.0029.
9-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143k
As described in general procedure B, 139k (80
mg, 0.33 mmol), mCPBA (0.18 g, 0.79 mmol) and
CH2Cl2 (2 mL) gave 143k as a white solid (45 mg,
S O
H
HOO
Cl
S O
H
HOO
Me
77
0.40 mmol, 50%). Eluted with n-hexane/ ethyl acetate (7:3).
Or as described in general procedure C, 5-methylbenzo[b]thiophene (100
mg, 0.67 mmol), phenol (95 mg, 1.0 mmol), BF3⋅OEt2 (0.67 mL, 5.36
mmol), mCPBA (181 mg, 0.80 mmol), TFAA (0.14 mL, 1.0 mmol), CH2Cl2
(3 mL) and then mCPBA (362 mg, 1.60 mmol) gave 139k as a white solid
(97 mg, 0.36 mmol, 53%), Eluted with n-hexane/ ethyl acetate (7:3).
m.p: 176-178 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.66 (d, J = 8.0 Hz,
1H, ArCH), 7.45 (s, 1H, ArCH), 7.37 (d, J = 7.5 Hz, 1H, ArCH), 7.32 (d, J
= 8.0 Hz, 1H, ArCH), 7.24 (t, J = 7.6 Hz, 1H, ArCH), 7.05 – 6.96 (m, 2H,
ArCH), 5.87 (d, J = 8.2 Hz, 1H, CH), 5.29 (d, J = 8.2 Hz, 1H, CH), 2.49 (s,
3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.4 (ArC), 146.2 (ArC),
137.1 (ArC), 134.5 (ArC), 131.2 (ArCH), 130.4 (ArCH), 127.2 (ArC), 125.7
(ArCH), 124.4 (ArCH), 123.1 (ArCH), 122.6 (ArCH), 111.6 (ArCH), 94.9
(CH), 47.6 (CH), 22.3 (CH3); IR νmax (neat)/cm-1 658, 728, 744, 802, 822,
1047, 1126, 1152, 1177, 1313, 1323, 1462; HRMS (GCMS) calculated for
C15H13O3S [M+H]+: 273.0580. Found [M+H]+: 273.0574. 10-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143l
As described in general procedure B, 139k (92 mg,
0.30 mmol), mCPBA (0.16 g, 0.72 mmol) and
CH2Cl2 (2 mL) gave 143l as a white solid (81 mg,
0.24 mmol, 80%). Eluted with n-hexane/ ethyl
acetate (7:3).
Or as described in general procedure C, 4-bromobenzo[b]thiophene (100
mg, 0.47 mmol), phenol (66 mg, 0.71 mmol), BF3⋅OEt2 (0.46 mL, 3.76
mmol), mCPBA (126 mg, 0.56 mmol), TFAA (99 µL, 0.71 mmol), CH2Cl2
(2 mL) and then mCPBA (252 g, 1.13 mmol) gave 143l as a white solid
S O
H
HOO
Br
78
(98 mg, 0.29 mmol, 62%), Eluted with n-hexane/ ethyl acetate (7:3).
m.p: 215-217 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.94 – 7.88 (m, 1H,
ArCH), 7.77 – 7.67 (m, 2H, ArCH), 7.46 – 7.40 (m, 1H, ArCH), 7.31 –
7.23 (m, 1H, ArCH), 7.12 – 7.05 (m, 1H, ArCH), 6.97 (td, J = 7.6, 1.0 Hz,
1H, ArCH), 5.92 (dd, J = 8.2, 2.1 Hz, 1H, CH), 5.60 (d, J = 8.1 Hz, 1H,
CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.9 (ArC), 140.0, (ArC) 138.3
(ArC), 136.3 (ArCH), 131.8 (ArCH), 130.7 (ArCH), 125.7 (ArC), 124.7
(ArCH), 123.4 (ArCH), 122.9 (ArC), 122.1 (ArCH), 111.6 (ArCH), 95.5
(CH), 48.4 (CH); IR νmax (neat)/cm-1 727, 757, 767, 1044, 1127, 1173,
1227, 1304, 1314, 1322, 1461, 1476; HRMS (GCMS) calculated for
C14H10BrO3S [M+H]+: 336.9529. Found [M+H]+: 336.9526.
8-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143m
As described in general procedure B, 139m
(100 mg, 0.33 mmol), mCPBA (0.18 g, 0.79
mmol) and CH2Cl2 (2 mL) gave 143m as a
white solid (47 mg, 0.14 mmol, 43%). Eluted
with n-hexane/ ethyl acetate (7:3).
Or as described in general procedure C, 6-bromobenzo[b]thiophene
thiophene (100 mg, 0.47 mmol), phenol (66 mg, 0.71 mmol), BF3⋅OEt2
(0.46 mL, 3.76 mmol), mCPBA (126 mg, 0.56 mmol), TFAA (99 µL, 0.71
mmol), CH2Cl2 (2 mL) and then mCPBA (252 g, 1.13 mmol) gave 143m as a white solid (125 mg, 0.37 mmol, 79%), Eluted with n-hexane/ ethyl
acetate (7:3).
m.p: 178-180 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.89 – 7.87 (m, 1H,
ArCH), 7.80 – 7.76 (m, J = 8.3, 1.5 Hz, 1H, ArCH), 7.55 (d, J = 8.2 Hz,
1H, ArCH), 7.32 (dd, J = 7.5, 1.3 Hz, 1H, ArCH), 7.28 – 7.23 (m, 1H,
ArCH), 7.05 – 6.97 (m, 2H, ArCH), 5.90 (d, J = 8.1, 1H, CH), 5.30 (d, J =
S O
H
HOO
Br
79
8.1 Hz, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm) 158.3 (ArC), 139.0
(ArC), 138.2 (ArC), 135.5 (ArCH), 130.7 (ArCH), 128.5 (ArCH), 125.8
(ArCH), 125.0 (ArC), 124.2 (ArCH), 123.9 (ArC), 123.4 (ArCH), 111.7
(ArCH), 94.9 (CH), 47.5 (CH); IR νmax (neat)/cm-1 738, 1043, 1148, 1181,
1301, 1434, 1617; HRMS (GCMS) calculated for C14H11BrO3S [M+H]+:
336.9529. Found [M+H]+: 336.9521.
7-Bromo-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143n
As described in general procedure B, 139n (36
mg, 0.12 mmol), mCPBA (63 mg, 0.29 mmol) and
CH2Cl2 (1 mL) gave 143n as a white solid (30 mg,
0.09 mmol, 75%). Eluted with n-hexane/ ethyl
acetate (7:3).
Or as described in general procedure C, 7-bromobenzo[b]thiophene (100
mg, 0.47 mmol), phenol (66 mg, 0.71 mmol), BF3⋅OEt2 (0.46 mL, 3.76
mmol), mCPBA (126 mg, 0.56 mmol), TFAA (99 µL, 0.71 mmol), CH2Cl2
(2 mL) and then mCPBA (252 g, 1.13 mmol) gave 143n as a white solid
(70 mg, 0.21 mmol, 45%), Eluted with n-hexane/ ethyl acetate (7:3).
m.p: 192-196 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.61 – 7.57 (m, 2H,
ArCH), 7.48 (t, J = 7.8 Hz, 1H, ArCH), 7.30 – 7.24 (m, 1H, ArCH), 7.25 –
7.18 (m, 1H, ArCH), 7.03 – 6.97 (m, 1H, ArCH), 6.95 (td, J = 7.5, 1.0 Hz,
1H, ArCH), 5.87 (d, J = 8.4 Hz, 1H, CH), 5.27 (d, J = 8.5 Hz 1H, CH); 13C
NMR (126 MHz, CDCl3) δ (ppm) 158.3 (ArC), 139.8 (ArC), 136.9 (ArC),
135.7 (ArCH), 134.4 (ArCH), 130.6 (ArCH), 125.9 (ArCH), 125.1 (ArC),
124.4 (ArCH), 123.3 (ArCH), 117.8 (ArC), 111.7 (ArCH), 95.2 (CH), 46.7
(CH); IR νmax (neat)/cm-1 752, 764, 1135, 1257, 1275; HRMS (GCMS)
calculated for C14H10BrO3S [M+H]+: 336.9529. Found [M+H]+: 336.9522.
5a-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143o
S O
H
HOOBr
80
As described in general procedure B, 139o (151
mg, 0.63 mmol), mCPBA (0.134 g, 1.51 mmol) and
CH2Cl2 (4 mL) gave 143o as an oil (128 mg, 0.47
mmol, 75%). Eluted with n-hexane/ ethyl acetate
(7:3).
Or as described in general procedure C, 2-methylbenzo[b]thiophene (100
mg, 0.67 mmol), phenol (95 mg, 1.0 mmol), BF3⋅OEt2 (0.67 mL, 5.36
mmol), mCPBA (181 mg, 0.80 mmol), TFAA (0.14 mL, 1.0 mmol), CH2Cl2
(3 mL) and then mCPBA (362 mg, 1.60 mmol) gave 143o as a white
solid (114 mg, 0.42 mmol, 62%), Eluted with n-hexane/ ethyl acetate
(7:3).
m.p: 129-131 ºC; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.78 – 7.71 (m, 1H,
ArCH), 7.51 – 7.39 (m, 2H, ArCH), 7.35 (td, J = 7.6, 1.7 Hz, 1H, ArCH),
7.15 (dt, J = 7.7, 1.7 Hz, 1H, ArCH), 7.12 – 7.08 (m, 1H, ArCH), 7.03 (dt,
J = 12.5, 5.2 Hz, 2H, ArCH), 6.01 – 5.76 (m, 1H, CH), 2.04 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ (ppm) 153.4 (ArC), 136.6 (ArC), 135.6
(ArC), 134.9 (ArCH), 133.4 (ArCH), 133.1 (ArCH), 131.0 (ArCH), 129.7
(ArCH), 129.1 (ArC), 123.6 (ArCH), 121.1 (ArCH), 120.6 (ArCH), 116.6
(CCH3), 116.5 (CH), 7.6 (CH3); IR νmax (neat)/cm-1 752, 771, 1158, 1140,
1271, 1451; HRMS (GCMS) calculated for C15H13O3S [M+H]+: 273.0580.
Found [M+H]+: 273.0574.
5a-Phenyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143p
As described in general procedure B, 139p (86 mg,
0.28 mmol), mCPBA (153 mg, 0.67 mmol) and
CH2Cl2 (2 mL) gave 143p as a white solid (65 mg,
0.19 mmol, 69%). Eluted with n-hexane/ ethyl
acetate (6:4)
S O
H
MeOO
S O
H
PhOO
81
Or as described in general procedure C, 2-phenylbenzo[b]thiophene (40
mg, 0.19 mmol), phenol (27 mg, 0.29 mmol), BF3⋅OEt2 (0.19 mL, 1.52
mmol), mCPBA (51 mg, 0.23 mmol), TFAA (41 µL, 0.29 mmol), CH2Cl2 (2
mL) and then mCPBA (102 mg, 0.58 mmol) gave 143p as a white solid
(38 mg, 0.13 mmol, 66%), Eluted with n-hexane/ ethyl acetate (7:3).
m.p: 227-228 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.85 – 7.81 (m, 1H,
ArCH), 7.58 – 7.50 (m, 4H, ArCH), 7.39 – 7.27 (m, 4H, ArCH), 7.22 –
7.16 (m, 2H, ArCH), 7.02 (tq, J = 7.5, 1.1 Hz, 1H, ArCH), 6.94 (dt, J = 7.9,
1.3 Hz, 1H, ArCH), 5.08 (s, 1H, CH); 13C NMR (126 MHz, CDCl3) δ (ppm)
153.5 (ArC), 139.1 (ArC), 136.4 (ArC), 134.7 (ArC), 134.0 (ArCH), 133.2
(ArCH), 131.7 (ArCH), 130.6 (ArCH), 130.6 (ArCH), 130.5 (ArCH), 129.3
(ArCH), 128.9 (ArCH), 127.3 (ArC), 124.8 (ArCH), 121.9 (ArCH), 121.8
(CPh), 117.9 (ArCH), 117.3 (CH); IR νmax (neat)/cm-1 755. 1119, 1146,
1280, 1451; HRMS (GCMS) calculated for C20H15O3S [M+H]+: 335.0736.
Found [M+H]+: 335.0723.
Methyl benzo[4,5]thieno[2,3-b]benzofuran-5a(10bH)-carboxylate 6,6-dioxide 143q
As described in general procedure B, 139q (117
mg, 0.41 mmol), mCPBA (222 mg, 0.99 mmol) and
CH2Cl2 (3 mL) gave 143q as a white solid (82 mg,
0.26 mmol, 63%). Eluted with n-hexane/ ethyl
acetate (6:4)
Or as described in general procedure C, methyl benzo[b]thiophene-2-
carboxylate (100 mg, 0.52 mmol), phenol (73 mg, 0.78 mmol), BF3⋅OEt2
(0.51 mL, 4.16 mmol), mCPBA (140 mg, 0.62 mmol), TFAA (0.11 mL,
0.78 mmol), CH2Cl2 (2 mL) and then mCPBA (280 g, 1.24 mmol) gave
143q as a white solid (64 mg, 0.20 mmol, 39%), Eluted with n-hexane/
ethyl acetate (6:4).
S O
H
CO2MeOO
82
m.p: 226-228 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.78 (d, J = 7.8 Hz,
1H, ArCH), 7.76 – 7.69 (m, 2H ArCH), 7.55 (ddd, J = 8.2, 5.5, 3.0 Hz, 1H,
ArCH), 7.35 – 7.30 (m, 1H, ArCH), 7.30 – 7.23 (m, 1H, ArCH), 7.10 (d, J
= 8.1 Hz, 1H, ArCH), 7.02 (td, J = 7.6, 0.9 Hz, 1H, ArCH), 5.63 (s, 1H,
CH), 3.96 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 165.0 (CO),
157.7 (ArC), 136.5 (ArC), 136.1 (ArC), 135.3 (ArCH), 130.6 (ArCH), 130.3
(ArCH), 127.1 (ArC), 125.1 (ArCH), 124.2 (ArCH), 123.7 (ArCH), 123.1
(CCO2Me), 111.8 (ArCH), 102.0 (ArCH), 54.6 (CH3), 51.8 (CH); IR νmax
(neat)/cm-1 749, 1084, 1151, 1312, 1461, 1756; HRMS (GCMS)
calculated for C16H13O5S [M+H]+: 317.0478. Found [M+H]+: 317.0469.
10b-Methyl-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 146
As described in general procedure B, 146’ (60 mg,
0.25 mmol), mCPBA (0.12 g, 0.60 mmol) and
CH2Cl2 (1.5 mL) gave 146 as a white solid (46 mg,
0.17 mmol, 68 %). Eluted with n-hexane/ ethyl
acetate (1:1); m.p: 182-183 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.76
(d, J = 7.8 Hz, 1H, ArCH), 7.72–7.65 (m, 2H, ArCH), 7.53–7.46 (m, 1H,
ArCH), 7.33 (dd, J = 7.7, 1.3 Hz, 1H, ArCH), 7.23 (td, J = 7.8, 1.4 Hz, 1H,
ArCH), 7.04–6.97 (m, 2H, ArCH), 5.45 (s, 1H, CH), 1.95 (s, 3H, CH3); 13C
NMR (126 MHz, CDCl3) δ (ppm) 157.4 (ArC), 141.3 (ArC), 136.7, (ArC),
135.0 (ArCH), 130.7 (ArC), 130.1 (ArCH), 129.6 (ArCH), 125.0 (ArCH),
123.1 (ArCH), 122.8 (ArCH), 122.4 (ArCH), 110.1 (ArCH), 100.1 (CH),
53.9 (CCH3), 26.2 (CH3); IR νmax (neat)/cm-1 723, 775, 827, 1039, 1126,
1154, 1194, 1478; HRMS (APCI) calculated for C15H13O3S [M+H]+:
273.0535. Found [M+H]+: 273.0560.
3.4 Synthesis of C3-Arylated Benzofurans
3-(2-(Methylsulfonyl)phenyl)benzofuran 145a
S O
Me
HOO
83
As described in general procedure D, 143a (20 mg,
0.08 mmol), sodium methoxide (6.3 mg, 0.12
mmol), iodomethane (7.4 µL, 0.12 mmol) and
dimethylformamide (1 mL) gave 145a as a white
solid (17 mg, 0.06 mmol, 81%). Eluted with n-
hexane/ ethyl acetate (8:2); m.p: 142-143 ºC; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.35 (dd, J = 8.1, 1.5 Hz, 1H, ArCH), 8.11 (s, 1H, ArCH), 7.76 (td,
J = 7.4, 1.4 Hz, 1H, ArCH), 7.64 (m, 3H, ArCH), 7.47 (d, J = 7.8 Hz, 1H,
ArCH), 7.44 - 7.39 (m, 1H, ArCH), 7.34 - 7.29 (td, J = 7.4, 1.0 Hz, 1H,
ArCH), 2.74 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ (ppm) 154.9
(ArC), 146.1 (ArCH), 139.8 (ArC), 133.5 (ArC), 133.1 (ArC), 130.7
(ArCH), 129.3 (ArCH), 128.4 (ArCH), 127.7 (ArCH), 125.2 (ArCH), 123.6
(ArC), 119.7 (ArCH), 116.7 (ArCH), 112.1 (ArCH), 42.4 (CH3); IR νmax
(neat)/cm-1 731, 1153, 1264; HRMS (ESI) calculated for C15H13O3S
[M+H]+: 273.0580. Found [M+H]+: 273.0573.
3-(2-(Methylsulfonyl)phenyl)-5-(trifluoromethyl)benzofuran 145b As described in general procedure D, 143b
(30 mg, 0.09 mmol), sodium methoxide (8 mg,
0.14 mmol), iodomethane (8.6 µL, 0.14 mmol)
and dimethylformamide (1 mL) gave 145b as
a white solid (19 mg, 0.06 mmol, 62 %).
Eluted with n-hexane/ ethyl acetate (8:2); m.p: 168-170 ºC; 1H NMR (500
MHz, CDCl3) δ (ppm) 8.34 (dd, J = 8.0, 1.8 Hz, 1H, ArCH), 8.18 (s, 1H,
ArCH), 7.78 (t, J = 7.6 Hz, 1H, ArCH), 7.74 – 7.63 (m, 4H, ArCH), 7.60 (d,
J = 7.6 Hz, 1H, ArCH), 2.72 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ
(ppm) 156.5 (ArC), 147.9 (ArC), 140.3 (ArC), 134.1 (ArCH), 133.3
(ArCH), 129.9 (ArCH), 129.9 (ArCH), 129.2 (ArC), 128.2 (ArC), 126.6 (q,
J = 32.4 Hz, ArCCF3), 124.5 (q, J = 272.1 Hz CF3), 122.7 (q, J = 3.4 Hz,
ArCH), 117.8 (q, J = 4.1 Hz, ArCCF3), 117.5 (ArCH), 112.9 (ArCH), 43.0
(CH3); IR νmax (neat)/cm-1 769, 1108, 1149, 1290, 1305, 1366; HRMS
(ESI) calculated for C16H12F3O3S [M+H]+: 341.0454. Found [M+H]+:
341.0440.
O
SO
OMe
O
SO
OMe
F3C
84
(3-(2-(Methylsulfonyl)phenyl)benzofuran-5-yl)(phenyl)methanone 145c
As described in general procedure D,
143c (30 mg, 0.08 mmol), sodium
methoxide (7 mg, 0.12 mmol),
iodomethane (8.0 µL, 0.12 mmol) and
dimethylformamide (1 mL) gave 145c as a
white solid (27 mg, 0.07 mmol, 87 %). Eluted with n-hexane/ ethyl acetate
(7:3); m.p: 128-131 ºC; 1H NMR (500 MHz, CDCl3) δ (ppm) 8.32 (d, J =
7.9 Hz, 1H, ArCH), 8.16 (s, 1H, ArCH), 7.99 (s, 1H, ArCH), 7.84 (dd, J =
8.6, 1.8 Hz, 1H, ArCH), 7.80 (d, J = 7.7 Hz, 2H, ArCH), 7.73 (t, J = 7.6
Hz, 1H, ArCH), 7.68 – 7.56 (m, 4H, ArCH), 7.49 (t, J = 7.6 Hz, 2H, ArCH),
2.75 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 196.7 (CO), 157.4
(ArC), 147.6 (ArC), 140.2 (ArC), 138.2 (ArC), 134.0 (ArCH), 133.9
(ArCH), 133.5 (ArCH), 132.8 (ArC), 130.4 (ArC), 130.1 (ArCH), 129.8
(ArCH), 129.1 (ArCH), 128.7 (ArCH), 128.4 (ArCH), 128.2 (ArCH), 123.0
(ArCH), 117.9 (ArC), 112.0 (ArCH), 43.0 (CH3); IR νmax (neat)/cm-1 726,
948, 1103, 1152, 1309, 1653; HRMS (GCMS) calculated for C23H16O4S
[M+H]+: 377.0842. Found [M+H]+: 377.0830.
3-(2-(Methylsulfonyl)phenyl)-5-nitrobenzofuran 145d
As described in general procedure D, 143d
(30 mg, 0.10 mmol), sodium methoxide (8
mg, 0.15 mmol), iodomethane (9.0 µL, 0.15
mmol) and dimethylformamide (1 mL) gave
145d as a white solid (25 mg, 0.08 mmol, 80
%). Eluted with n-hexane/ ethyl acetate (6:4); m.p: 192-193 ºC; 1H NMR
(400 MHz, CDCl3) δ (ppm) 8.40 – 8.29 (m, 3H, ArCH), 8.22 (s, 1H, ArCH),
7.80 (t, J = 7.7 Hz, 1H, ArCH), 7.75 – 7.65 (m, 2H, ArCH), 7.59 (d, J = 7.6
Hz, 1H, ArCH), 2.75 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm)
157.8 (ArC), 148.9 (ArC), 145.2 (ArCH), 140.3 (ArC), 134.3 (ArC), 133.4
(ArCH), 130.1 (ArCH), 129.6 (ArCH), 129.2 (ArC), 128.8 (ArCH), 121.4
(ArC), 118.4 (ArCH), 117.0 (ArCH), 112.9 (ArCH), 43.2 (CH3); IR νmax
O
SO
OMe
Ph(O)C
O
SO
OMe
O2N
85
(neat)/cm-1 735, 765, 1154, 1341, 1513; HRMS (GCMS) calculated for
C15H10NO5S [M-H]-: 316.0285. Found [M-H]-: 326.0288.
7-Bromo-3-(2-(methylsulfonyl)phenyl)benzofuran 145e
As described in general procedure D, 143e (25 mg,
0.08 mmol), sodium methoxide (6 mg, 0.11 mmol),
iodomethane (7.0 µL, 0.11 mmol) and
dimethylformamide (1 mL) gave 145e as an oil (18
mg, 0.05 mmol, 68%). Eluted with n-hexane/ ethyl
acetate (7:3); 1H NMR (500 MHz, CDCl3) δ (ppm)
8.32 (d, J = 7.9 Hz, 1H, ArCH), 8.12 (s, 1H, ArCH), 7.74 (t, J = 7.5 Hz,
1H, ArCH), 7.63 (t, J = 7.7 Hz, 1H, ArCH), 7.58 – 7.52 (m, 2H, ArCH),
7.37 (d, J = 7.7 Hz, 1H, ArCH), 7.18 (t, J = 7.4, 1.4 Hz, 1H, ArCH), 2.74
(s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 151.9 (ArC), 146.2
(ArCH), 139.8 (ArC), 133.4 (ArC), 132.9 (ArCH), 129.9 (ArCH), 129.2
(ArCH), 128.9 (ArCH), 128.6 (ArCH), 128.1 (ArC), 124.7 (ArC), 118.9
(ArCH), 117.6 (ArCH), 104.7 (ArC), 42.5 (CH3); IR νmax (neat)/cm-1 869,
1100, 1152, 1309, 1142; HRMS (GCMS) calculated for C15H12BrO3S
[M+H]+: 350.9685. Found [M+H]+: 350.9684.
3-(2-(Methylsulfonyl)phenyl)-7-nitrobenzofuran 145f As described in general procedure D, 143f (30 mg,
0.10 mmol), sodium methoxide (8 mg, 0.15 mmol),
iodomethane (9.0 µL, 0.15 mmol) and
dimethylformamide (1 mL) gave 145f as a yellow
solid (22 mg, 0.07 mmol, 70 %). Eluted with n-
hexane/ ethyl acetate (8:2); m.p: 184-186 ºC; 1H
NMR (500 MHz, CDCl3) δ (ppm) 8.36 – 8.31 (m, 1H, ArCH), 8.25 (d, J =
8.0 Hz, 1H, ArCH), 8.19 (s, 1H, ArCH), 7.80 – 7.73 (m, 2H, ArCH), 7.69
(t, J = 7.8 Hz, 1H, ArCH), 7.54 (d, J = 7.6 Hz, 1H, ArCH), 7.43 (t, J = 8.0,
1H, ArCH), 2.78 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 147.4
(ArC), 147.2 (ArC), 140.7 (ArCH), 134.7 (ArC), 134.1 (ArC), 133.6
(ArCH), 132.4 (ArCH), 130.1 (ArCH), 129.7 (ArCH), 129.3 (ArCH), 127.7
O
SO
OMe
Br
O
SO
OMe
NO2
86
(ArC), 123.9 (ArCH), 122.1 (ArC), 118.4 (ArCH), 43.5 (CH3); IR νmax
(neat)/cm-1 739, 1102, 1149, 1302, 1336, 1527; HRMS (GCMS)
calculated for C15H11NO5SK [M+K]+: 355.9990. Found [M+K]+: 355.9984.
N,N-Diethyl-3-(2-(methylsulfonyl)phenyl)benzofuran-7-carboxamide 145g
As described in general procedure D, 143g (25 mg,
0.07 mmol), sodium methoxide (6 mg, 0.11 mmol),
iodomethane (7.0 µL, 0.11 mmol) and
dimethylformamide (1 mL) gave 145g as an oil (17
mg, 0.05 mmol, 65%). Eluted with n-hexane/ ethyl
acetate (6:4); 1H NMR (400 MHz, CDCl3) δ (ppm)
8.35 – 8.30 (m, 1H, ArCH), 8.11 (s, 1H, ArCH), 7.74 (td, J = 7.5, 1.4 Hz,
1H, ArCH), 7.66 – 7.58 (m, 2H, ArCH), 7.46 (dd, J = 7.8, 1.3 Hz, 1H,
ArCH), 7.39 (dd, J = 7.4, 1.4 Hz, 1H, ArCH), 7.32 (t, J = 7.5 Hz, 1H,
ArCH), 3.68 (q, J = 7.1 Hz, 2H, CH2), 3.30 (q, J = 7.1 Hz, 2H, CH2), 2.72
(s, 3H, CH3), 1.35 (t, J = 7.1 Hz, 3H, CH3), 1.12 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ (ppm) 167.2 (CO), 150.8 (ArC), 146.8
(ArCH), 145.4 (ArC), 140.3 (ArC), 133.9 (ArCH), 133.4 (ArCH), 130.6
(ArCH), 129.8 (ArCH), 128.9 (ArCH), 128.6 (ArC), 124.2 (ArCH), 124.0
(ArCH), 121.1 (ArC), 117.4 (ArC), 43.8 (CH3), 42.9 (CH2), 39.9 (CH2),
14.7 (CH3), 13.5 (CH3); IR νmax (neat)/cm-1 713, 1102, 1630; HRMS
(GCMS) calculated for C20H22O4NS [M+H]+: 372.1251. Found [M+H]+:
372.1260. 6-Bromo-3-(2-(methylsulfonyl)phenyl)benzofuran 145h
As described in general procedure D, 143h (25
mg, 0.08 mmol), sodium methoxide (6 mg, 0.11
mmol), iodomethane (7.0 µL, 0.11 mmol) and
dimethylformamide (1 mL) gave 145h as an oil
(20 mg, 0.05 mmol, 75 %). Eluted with n-
hexane/ ethyl acetate (8:2); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31 (d, J
= 8.0, 1H, ArCH), 8.03 (s, 1H, ArCH), 7.78 (d, J = 1.6 Hz, 1H, ArCH), 7.73
O
SO
OMe
Br
O
S
CONEt2
OOMe
87
(td, J = 7.6, 1.4 Hz, 1H, ArCH), 7.62 (td, J = 7.7, 1.4 Hz, 1H, ArCH), 7.57
(dd, J = 7.6, 1.4 Hz, 1H, ArCH), 7.41 (dd, J = 8.3, 1.6 Hz, 1H, ArCH), 7.30
(d, J = 8.3 Hz, 1H, ArCH), 2.72 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3)
δ (ppm) 155.5 (ArC), 146.7 (ArCH), 140.4 (ArC), 133.9 (ArC), 133.4
(ArCH), 130.4 (ArCH), 129.8, (ArCH), 129.1 (ArCH), 127.4 (ArC), 127.3
(ArCH), 121.2 (ArC), 119.0 (ArCH), 117.3 (ArC), 115.9 (ArCH), 43.0
(CH3); IR νmax (neat)/cm-1 817, 951, 1182, 1160, 1379; HRMS (ESI)
calculated for C15H12BrO3S [M+H]+: 350.9685. Found [M+H]+: 350.9677.
4,6-Dimethyl-3-(2-(methylsulfonyl)phenyl)benzofuran 145i
As described in general procedure D, 143i (25
mg, 0.09 mmol), sodium methoxide (7 mg,
0.13 mmol), iodomethane (8.2 µL, 0.13 mmol)
and dimethylformamide (1 mL) gave 145i as a
white solid (19 mg, 0.07 mmol, 72 %). Eluted
with n-hexane/ ethyl acetate (8:2); m.p: 157-158 ºC; 1H NMR (500 MHz,
CDCl3) δ (ppm) 8.26 (d, J = 7.9 Hz, 1H, ArCH), 7.69 – 7.64 (m, 2H,
ArCH), 7.61 (t, J = 7.6, 1H, ArCH), 7.50 (d, J = 7.4 Hz, 1H, ArCH), 7.22
(s, 1H, ArCH), 6.83 (s, 1H, ArCH), 2.78 (s, 3H, CH3), 2.44 (s, 3H, CH3),
1.98 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 155.6, (ArC),
144.1 (ArCH), 141.0 (ArC), 135.7 (ArC), 134.6 (ArCH), 133.2 (ArC), 132.8
(ArC), 131.2 (ArCH), 129.0 (ArCH), 129.0 (ArC), 126.7 (ArCH), 124.3
(ArCH), 117.7 (ArC), 110.2 (ArCH), 43.7 (CH3), 21.9 (CH3), 19.4 (CH3); IR νmax (neat)/cm-1 767, 1096, 1150, 1304; HRMS (GCMS) calculated for
C17H17O3S [M+H]+: 301.0893. Found [M+H]+: 301.0889.
3-(5-Chloro-2-(methylsulfonyl)phenyl)benzofuran 145j As described in general procedure D, 143j (25 mg,
0.09 mmol), sodium methoxide (7 mg, 0.14 mmol),
iodomethane (8.0 µL, 0.14 mmol) and
dimethylformamide (1 mL) gave 145j gave as an
oil (21 mg, 0.07 mmol, 80%). Eluted with n-
hexane/ ethyl acetate (8:2); m.p: 104-106 ºC; 1H NMR (400 MHz, CDCl3)
O
SO
OMe
Me
Me
O
SO
OMe
Cl
88
δ (ppm) 8.26 (d, J = 8.6 Hz, 1H, ArCH), 8.10 (s, 1H, ArCH), 7.65 – 7.54
(m, 3H, ArCH), 7.47 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H, ArCH), 7.41 (ddd, J =
8.4, 7.2, 1.4 Hz, 1H, ArCH), 7.35 – 7.30 (m, 1H, ArCH), 2.71 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ (ppm) 154.9 (ArC), 146.4 (ArCH), 140.1
(ArC), 138.9 (ArC), 132.9 (ArC), 132.6 (ArCH), 130.9 (ArCH), 128.5
(ArCH), 127.2 (ArC), 125.5 (ArCH), 123.9 (ArCH), 119.5 (ArC), 115.8
(ArCH), 112.2 (ArCH), 42.5 (CH3); IR νmax (neat)/cm-1 1450, 1304, 1151,
1129, 750; HRMS (GCMS) calculated for C15H12ClO3S [M+H]+: 307.0190.
Found [M+H]+: 307.0187.
3-(5-Methyl-2-(methylsulfonyl)phenyl)benzofuran 145k As described in general procedure D, 143k (20
mg, 0.07 mmol), sodium methoxide (6 mg, 0.11
mmol), iodomethane (7.0 µL, 0.11 mmol) and
dimethylformamide (1 mL) gave 145k as an oil (11
mg, 0.04 mmol, 52%). Eluted with n-hexane/ ethyl
acetate (8:2); 1H NMR (500 MHz, CDCl3) δ (ppm) 8.19 (dd, J = 8.1, 1.5
Hz, 1H, ArCH), 8.05 (d, J = 1.6 Hz, 1H, ArCH), 7.60 (dd, J = 8.3, 1.5 Hz,
1H, ArCH), 7.48 – 7.36 (m, 4H, ArCH), 7.32 – 7.26 (m, 1H, ArCH), 2.69
(d, J = 1.6 Hz, 3H, CH3), 2.49 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ
(ppm) 154.6 (ArC), 145.7 (ArC), 144.2 (ArCH), 136.9 (ArC), 133.4 (ArC),
130.3 (ArCH), 129.2 (ArCH), 128.8 (ArCH), 127.6 (ArC), 124.9 (ArCH),
123.3 (ArCH), 119.6 (ArC), 116.6 (ArCH), 111.8 (ArCH), 42.4 (CH3), 21.3
(CH3); IR νmax (neat)/cm-1 1134, 1148, 1307, 1451; HRMS (GCMS)
calculated for C16H15O3S [M+H]+: 287.0736. Found [M+H]+: 287.0730.
3-(2-Bromo-6-(methylsulfonyl)phenyl)benzofuran 145l As described in general procedure D, 143l (20 mg,
0.06 mmol), sodium methoxide (5 mg, 0.09 mmol),
iodomethane (6.0 µL, 0.09 mmol) and
dimethylformamide (1 mL) gave 145l as an oil (15
mg, 0.04 mmol, 72%). Eluted with n-hexane/ ethyl
acetate (7:3); 1H NMR (500 MHz, CDCl3) δ (ppm) 8.29 (dd, J = 8.0, 1.3
O
SO
OMe
Me
O
SO
OMe
Br
89
Hz, 1H, ArCH), 8.01 (dd, J = 8.1, 1.2 Hz, 1H, ArCH), 7.83 (s, 1H, ArCH),
7.61 (d, J = 8.3, 1H, ArCH), 7.51 (d, J = 8.0 Hz, 1H, ArCH), 7.38 (ddd, J =
8.4, 6.8, 1.7 Hz, 1H, ArCH), 7.30 – 7.27 (m, 1H, ArCH), 7.26 – 7.23 (m,
1H, ArCH), 2.61 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 154.4
(ArC), 145.8 (ArCH), 143.0 (ArC), 137.9 (ArC), 131.4 (ArCH), 129.8
(ArCH), 128.4 (ArCH), 127.8 (ArC), 126.8 (ArCH), 124.9 (ArC), 123.3
(ArC), 120.0 (ArCH), 115.9 (ArCH), 112.1 (ArCH), 42.8 (CH3); IR νmax
(neat)/cm-1 775, 1140, 1312, 1452; HRMS (GCMS) calculated for
C15H12BrO3S [M+H]+: 350.9685. Found [M+H]+: 350.9679.
3-(4-Bromo-2-(methylsulfonyl)phenyl)benzofuran 145m As described in general procedure D, 143m (13
mg, 0.04 mmol), sodium methoxide (3 mg, 0.06
mmol), iodomethane (4.0 µL, 0.06 mmol) and
dimethylformamide (1 mL) gave 145m as an oil (7
mg, 0.02 mmol, 52%). Eluted with n-hexane/ ethyl
acetate (7:3); 1H NMR (500 MHz, CDCl3) δ (ppm)
7.90 (dd, J = 6.9, 2.4 Hz, 1H, ArCH), 7.65 (s, 1H, ArCH), 7.55 (dd, J =
8.2, 1.0 Hz, 1H, ArCH), 7.48 – 7.42 (m, 2H, ArCH), 7.37 – 7.30 (m, 2H,
ArCH), 7.25 – 7.23 (m, 1H, ArCH), 3.20 (s, 3H, CH3); 13C NMR (126 MHz,
CDCl3) δ (ppm) 154.3 (ArC), 142.1 (ArCH), 139.2 (ArC), 136.4 (ArC),
134.9 (ArCH), 133.5 (ArCH), 133.0 (ArCH), 128.7 (ArC), 124.6 (ArCH),
123.0 (ArC), 122.8 (ArC), 120.2 (ArCH), 119.5 (ArCH), 111.7 (ArCH),
43.8 (CH3); IR νmax (neat)/cm-1 1104, 1159, 1326, 1453; HRMS (GCMS)
calculated for C15H12BrO3S [M+H]+: 350.9685. Found [M+H]+: 350.9680.
3-(3-Bromo-2-(methylsulfonyl)phenyl)benzofuran 145n As described in general procedure D, 143n (15
mg, 0.04 mmol), sodium methoxide (4 mg, 0.06
mmol), iodomethane (4.0 µL, 0.06 mmol) and
dimethylformamide (1 mL) gave 145m as an oil (8
mg, 0.02 mmol, 54%). Eluted with n-hexane/ ethyl
acetate (6:4); 1H NMR (500 MHz, CDCl3) δ (ppm) 7.90 (dd, J = 7.0, 2.4
O
SO
OMe
Br
O
SO
OMe
Br
90
Hz, 1H, ArCH), 7.65 (s, 1H, ArCH), 7.55 (d, J = 8.2 Hz, 1H, ArCH), 7.48 –
7.42 (m, 2H, ArCH), 7.36 – 7.31 (m, 2H, ArCH), 7.27-7.24 (m, 1H, ArCH),
3.20 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 154.8 (ArC), 142.6
(ArCH), 139.7 (ArC), 136.9 (ArC), 135.4 (ArCH), 134.0 (ArCH), 133.6
(ArCH), 129.2 (ArC), 125.1 (ArCH), 123.6 (ArC), 123.3 (ArC), 120.7
(ArCH), 120.0 (ArCH), 112.2 (ArCH), 44.3 (CH3); IR νmax (neat)/cm-1
1105, 1160, 1327, 1454; HRMS (GCMS) calculated for C15H12BrO3S
[M+H]+: 350.9685. Found [M+H]+: 350.9681.
2-Methyl-3-(2-(methylsulfonyl)phenyl)benzofuran 145o As described in general procedure D, 143o (15 mg,
0.06 mmol), sodium methoxide (5 mg, 0.8 mmol),
iodomethane (5.0 µL, 0.08 mmol) and
dimethylformamide (1 mL) gave 145o as an oil (10
mg, 0.03 mmol, 63%). Eluted with n-hexane/ ethyl
acetate (7:3); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.80 – 7.72 (m, 1H,
ArCH), 7.51 – 7.39 (m, 3H, ArCH), 7.21 (dd, J = 7.5, 1.8 Hz, 1H, ArCH),
7.13 – 6.97 (m, 3H, ArCH), 3.77 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C NMR
(126 MHz, CDCl3) δ (ppm) 157.1 (ArC), 136.3 (ArC), 135.9 (ArC), 135.4
(ArC), 133.7 (ArCH), 133.1 (ArCH), 130.9 (ArCH), 130.2 (ArCH), 128.8
(ArC), 123.5 (ArCH), 121.0 (ArCH), 120.7 (ArCH), 119.0 (ArCH), 111.3
(ArC), 55.3 (CH3), 7.7 (CH3); IR νmax (neat)/cm-1 1167, 1247, 1296, 1492; HRMS (GCMS) calculated for C16H15O3S [M+H]+: 287.0736. Found
[M+H]+: 287.0732.
3-(2-(Methylsulfonyl)phenyl)-2-phenylbenzofuran 145p
As described in general procedure D, 143p (20
mg, 0.06 mmol), sodium methoxide (5 mg, 0.09
mmol), iodomethane (6.0 µL, 0.09 mmol) and
dimethylformamide (1 mL) gave 145p as a white
solid (14 mg, 0.04 mmol, 67%). Eluted with n-
hexane/ ethyl acetate (7:3); m.p: 183-185 ºC; 1H NMR (500 MHz, CDCl3)
δ (ppm) 7.86 – 7.79 (m, 1H, ArCH), 7.54 – 7.46 (m, 4H, ArCH), 7.43 (ddd,
O
SOOMe
Me
O
SOOMe
Ph
91
J = 9.0, 7.4, 1.7 Hz, 1H, ArCH), 7.35 – 7.27 (m, 3H, ArCH), 7.15 (dd, J =
7.4, 1.7 Hz, 1H, ArCH), 7.11 – 7.04 (m, 1H, ArCH), 7.02 – 6.95 (m, 2H,
ArCH), 3.66 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 157.2
(ArC), 138.0 (ArC), 135.9 (ArC), 135.9 (ArC), 133.3 (ArCH), 133.2 (ArC),
130.9 (ArCH), 130.3 (ArCH), 129.5 (ArCH), 129.4 (ArCH), 128.6 (ArCH),
128.5 (ArCH), 127.6 (ArCH), 124.1 (ArCH), 121.0 (ArC), 121.0 (ArCH),
119.8 (ArC), 111.3 (ArCH), 55.2 (CH3); IR νmax (neat)/cm-1 755, 760,
1015. 1150, 1245, 1275, 1289, 1460; HRMS (GCMS) calculated for
C21H17O3S [M+H]+: 349.0893. Found [M+H]+: 349.0887.
Methyl 3-(2-(methylsulfonyl)phenyl)benzofuran-2-carboxylate 145qAs described in general procedure D, 143q (20
mg, 0.06 mmol), sodium methoxide (5 mg, 0.09
mmol), iodomethane (6.0 µL, 0.09 mmol) and
dimethylformamide (1 mL) gave 145q as a white
solid (13 mg, 0.04 mmol, 62%). Eluted with n-
hexane/ ethyl acetate (7:3);m.p: 187-191 ºC; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.31 – 8.24 (m, 1H, ArCH), 7.78 – 7.61 (m, 3H, ArCH), 7.51 (ddd,
J = 8.5, 5.8, 2.7 Hz, 1H, ArCH), 7.42 – 7.37 (m, 1H, ArCH), 7.34 – 7.27
(m, 2H, ArCH), 3.82 (s, 3H, CH3), 2.82 (s, 3H, CH3); 13C NMR (101 MHz,
CDCl3) δ (ppm) 160.4 (CO), 154.6 (ArC), 142.0 (ArC), 140.1 (ArC), 133.9
(ArC), 132.6 (ArC), 131.5 (ArCH), 130.1 (ArCH), 129.8 (ArCH), 129.7
(ArCH), 128.8 (ArCH), 126.7 (ArC), 124.7 (ArCH), 122.5 (ArCH), 112.8
(ArCH), 52.83 (OCH3), 44.4 (CH3); IR νmax (neat)/cm-1 754, 957, 1149,
1156, 1300, 1713; HRMS (GCMS) calculated for C17H15O5S [M+H]+:
331.0635. Found [M+H]+: 331.0627.
3-(2-(Benzylsulfonyl)phenyl)benzofuran 147 As described in general procedure D, but
with potassium tert-butoxide instead of
sodium methoxide, 143a (20 mg, 0.08
mmol), potassium tert-butoxide (13 mg, 0.12
mmol), benzyl bromide (28 µL, 0.11 mmol, 3
O
SOOMe
CO2Me
O
SO O
92
equiv.) and dimethylformamide (5 mL) gave 147 as a yellow oil (15 mg,
0.04 mmol, 56%). Eluted with n-hexane/ ethyl acetate (9:1); 1H NMR (400
MHz, CDCl3) δ (ppm) 8.17 (s, 1H, ArCH), 8.04 (dd, J = 8.1, 1.3 Hz, 1H,
ArCH), 7.73 – 7.57 (m, 3H, ArCH), 7.56 – 7.51 (m, 1H, ArCH), 7.51 –
7.37 (m, 2H, ArCH), 7.34 (td, J = 7.5, 1.1 Hz, 1H, ArCH), 7.23 – 7.14 (m,
3H, ArCH), 6.97 – 6.89 (m, ArCH, 2H), 4.01 (s, 2H, CH2); 13C NMR (126
MHz, CDCl3) δ (ppm) 155.4 (ArC), 146.7 (ArCH), 137.8 (ArC), 133.9
(ArC), 133.3 (ArCH), 131.6 (ArCH), 131.4 (ArCH), 131.2 (ArC), 129.1
(ArCH), 128.9 (ArC), 128.4 (ArCH), 128.1 (ArCH), 127.9 (ArCH), 125.6
(ArCH), 124.0 (ArCH), 120.0 (ArC), 117.1 (ArCH), 112.5 (ArCH), 60.4
(CH2); IR νmax (neat)/cm-1 696, 1153, 1313, 1452; HRMS (GCMS)
calculated for C21H17O3S [M+H]+: 349.0893. Found [M+H]+: 349.0887.
3-(2-(Allylsulfonyl)phenyl)benzofuran 148 As described in general procedure D, 143a (20
mg, 0.08 mmol), sodium methoxide (6 mg, 0.11
mmol), allyl iodide (22 µL, 0.11 mmol, 3 equiv.)
and dimethylformamide (1 mL) gave 148 as an
oil (18 mg, 0.06 mmol, 78%). Eluted with n-
hexane/ ethyl acetate (8:2); 1H NMR (500 MHz, CDCl3) δ (ppm) 8.24 (d, J
= 8.0 Hz, 1H, ArCH), 8.11 (s, 1H, ArCH), 7.72 (t, J = 7.6 Hz, 1H, ArCH),
7.64 – 7.55 (m, 3H, ArCH), 7.46 – 7.37 (m, 2H, ArCH), 7.30 (t, J = 7.5 Hz,
1H, ArCH), 5.61 – 5.48 (m, 1H, CH), 5.10 (d, J = 10.1 Hz, 1H, CH2), 4.81
(d, J = 17.0 Hz, 1H, CH2), 3.48 (d, J = 7.3 Hz, 2H, CH2); 13C NMR (126
MHz, CDCl3) δ (ppm) 155.2 (ArC), 146.5 (ArCH), 137.7 (ArC), 133.8
(ArC), 133.2 (ArC), 131.3 (ArCH), 131.1 (ArCH), 128.4 (ArC), 128.0
(ArCH), 125.5 (CH=CH2), 124.8 (CH=CH2), 124.8 (ArCH), 123.9 (ArCH),
119.9 (ArCH), 116.9 (ArCH), 112.4 (ArCH), 58.6 (CH2); IR νmax (neat)/cm-
1 773, 1090, 1124, 1144, 1452; HRMS (GCMS) calculated for C17H15O3S
[M+H]+: 299.0736. Found [M+H]+: 299.0733.
Ethyl 2-((2-(benzofuran-3-yl)phenyl)sulfonyl)acetateone 149
O
SO O
93
As described in general procedure D, 143a
(20 mg, 0.08 mmol), sodium methoxide (5
mg, 0.12 mmol), ethyl iodoacetate (28 µL,
0.12 mmol, 3 equiv.) and
dimethylformamide (1 mL) gave ethyl 149
as a yellow oil (22 mg, 0.07 mmol, 82%). Eluted with n-hexane/ ethyl
acetate (7:3); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (dd, J = 8.3, 1.4
Hz, 1H, ArCH), 8.04 (s, 1H, ArCH), 7.75 (td, J = 7.5, 1.5 Hz, 1H, ArCH),
7.61 (tt, J = 8.2, 1.1 Hz, 3H, ArCH), 7.47 – 7.35 (m, 2H, ArCH), 7.32 –
7.27 (m, 1H, ArCH), 3.98 (q, J = 7.1 Hz, 2H, CH2), 3.74 (s, 2H, CH2), 1.05
(t, J = 7.1 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ (ppm) 162.5 (CO),
155.3 (ArC), 146.3 (ArCH), 138.5 (ArC), 134.2 (ArC), 133.5 (ArCH), 131.6
(ArCH), 130.7 (ArCH), 128.6 (ArCH), 128.1 (ArCH), 125.6 (ArC), 124.0
(ArCH), 120.3 (ArC), 116.9 (ArCH), 112.4 (ArCH), 62.6 (CH2), 58.9 (CH2),
14.2 (CH3); IR νmax (neat)/cm-1 1108, 1151, 1323, 1741; HRMS (GCMS)
calculated for C18H17O5S [M+H]+: 345.0791. Found [M+H]+: 345.0786.
3.5 Desulfinylative Cross-Coupling of Benzofuran Products 3-([1,1'-Biphenyl]-2-yl)benzofuran 150
As described in general procedure E, 143a (80
mg, 0.31 mmol), sodium methoxide (25 mg, 0.47
mmol), methanol (3 mL) and then Pd(OAc)2 (4 mg,
10 mol %), PCy3 (9 mg, 20 mol %), K2CO3 (30 mg,
0.23 mmol), 1,4-dioxane (4 mL) and
bromobenzene (16 µL, 0.16 mmol) gave 150 as an oil (31 mg, 0.11
mmol, 68%). Eluted with n-hexane/ CH2Cl2 (10:1); 1H NMR (500 MHz,
CDCl3) δ (ppm) 7.60 – 7.56 (m, 1H, ArCH), 7.51 – 7.40 (m, 4H, ArCH),
7.34 (d, J = 7.9 Hz, 1H, ArCH), 7.27 – 7.16 (m, 7H, ArCH), 7.14 – 7.08
(m, 1H, ArCH); 13C NMR (126 MHz, CDCl3) δ (ppm) 154.9 (ArC), 142.8
(ArCH), 141.4 (ArC), 141.3 (ArC), 130.6 (ArC), 130.5 (ArCH), 129.8
(ArCH), 129.2 (ArCH), 127.9 (ArCH), 127.8 (ArCH), 127.34 (ArCH), 127.2
O
O
SO O
OEt
O
94
(ArCH), 126.8 (ArC), 124.0 (ArCH), 122.5 (ArCH), 121.0 (ArC), 120.4
(ArCH), 111.2 (ArCH); IR νmax (neat)/cm-1 645, 908, 1453; HRMS
(GCMS) calculated for C20H15O [M+H]+: 271.1117. Found [M+H]+:
271.1116.
Methyl 2'-(benzofuran-3-yl)-[1,1'-biphenyl]-4-carboxylate 151As described in general procedure E, 143a
(60 mg, 0.23 mmol), sodium methoxide
(18 mg, 0.35 mmol), methanol (2 mL) and
then Pd(OAc)2 (3 mg, 10 mol %), PCy3 (7
mg, 20 mol %), K2CO3 (23 mg, 0.17), 1,4-
dioxane (2 mL) and methyl 4-bromobenzoate (25 mg, 0.12 mmol) gave
151 as an oil (32 mg, 0.10 mmol, 84 %). Eluted with n-hexane/ ethyl
acetate (9:1); 1H NMR (500 MHz, CDCl3) δ (ppm) 7.93 – 7.86 (m, 2H,
ArCH), 7.60 (dt, J = 6.5, 2.8 Hz, 1H, ArCH), 7.49 (t, J = 2.9 Hz, 3H,
ArCH), 7.45 (d, J = 8.2 Hz, 1H, ArCH), 7.33 (t, J = 7.8 Hz, 3H, ArCH),
7.28 – 7.20 (m, 2H, ArCH), 7.12 (t, J = 7.5 Hz, 1H, ArCH), 3.88 (s, 3H,
CH3); 13C NMR (126 MHz, CDCl3) δ (ppm) 167.3 (CO), 155.4 (ArC),
146.6 (ArC), 143.3 (ArCH), 140.9 (ArC), 131.2 (ArC), 130.9 (ArCH), 130.3
(ArCH), 129.8 (ArCH), 129.7 (ArC), 128.9 (ArCH), 128.6 (ArCH), 128.5
(ArCH), 127.6 (ArC), 124.7 (ArCH), 123.1 (ArCH), 121.3 (ArC), 120.7
(ArCH), 111.9 (ArCH), 52.5 (CH3); IR νmax (neat)/cm-1 1103, 1452, 1278,
1720; HRMS (GCMS) calculated for C22H17O3 [M+H]+: 329.1172. Found
[M+H]+: 329.1166.
3-(2-(Benzofuran-3-yl)phenyl)pyridine 152 As described in general procedure E, 143a (60
mg, 0.23 mmol), sodium methoxide (18 mg, 0.35
mmol), methanol (2 mL) and then Pd(OAc)2 (3
mg, 10 mol %), PCy3 (7 mg, 20 mol %), K2CO3
(23 mg, 0.17), 1,4-dioxane (2 mL) 3-
bromopyridine (11 µL, 0.12 mmol ) gave 152 as an oil (21 mg, 0.08
mmol, 65%). Eluted with n-hexane/ ethyl acetate (6:4); 1H NMR (500
MHz, CDCl3) δ (ppm) 8.55 (s, 1H, ArCH), 8.41 (dd, J = 4.9, 1.7 Hz, 1H,
O
N
O CO2Me
95
ArCH), 7.60 – 7.56 (m, 1H, ArCH), 7.52 – 7.46 (m, 4H, ArCH), 7.45 –
7.39 (m, 1H, ArCH), 7.26 – 7.19 (m, 3H, ArCH), 7.12 – 7.04 (m, 2H,
ArCH); 13C NMR (126 MHz, CDCl3) δ (ppm) 155.0 (ArC), 149.7 (ArCH),
148.0 (ArC), 142.8 (ArC), 137.7 (ArC), 136.9 (ArCH), 136.3 (ArCH), 130.9
(ArCH), 130.5 (ArCH), 130.2 (ArCH), 128.3 (ArCH), 128.2 (ArCH), 126.9
(ArC), 124.3 (ArCH), 122.7 (ArCH), 122.7 (ArCH), 120.7 (ArC), 120.2
(ArCH), 111.4 (ArCH); IR νmax (neat)/cm-1 733, 1265, 1452; HRMS
(GCMS) calculated for C19H14NO [M+H]+: 272.1070. Found [M+H]+:
272.1068
3-(2'-Methoxy-[1,1'-biphenyl]-2-yl)benzofuran 153As described in general procedure E, 143a (40
mg, 0.15 mmol), sodium methoxide (13 mg,
0.23 mmol), methanol (2 mL) and then
Pd(OAc)2 (2 mg, 10 mol %), PCy3 (4 mg, 20
mol %), K2CO3 (12 mg, 0.12 mmol), 1,4-
dioxane (2 mL) and 2-bromoanisole (20 µL, 0.08 mmol) gave 153 as an
oil (19 mg, 0.06 mmol, 82%). Eluted with n-hexane/ CH2Cl2 (8:2); 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.65 – 7.58 (m, 1H, ArCH), 7.5 – 7.53
(m, 1H, ArCH), 7.50 – 7.38 (m, 4H, ArCH), 7.29 – 7.14 (m, 4H, ArCH),
7.05 – 7.02 (m, 1H, ArCH), 6.90 (m, 1H, ArCH), 6.72 (dt, J = 8.1, 1.5 Hz,
1H, ArCH), 3.27 (d, J = 2.2 Hz, 3H, OCH3); 13C NMR (126 MHz, CDCl3) δ
(ppm) 156.7 (ArC), 155.3 (ArC), 142.6 (ArCH), 138.7 (ArC), 131.7 (ArC),
131.7 (ArC), 131.5 (ArCH), 130.9 (ArCH), 130.0 (ArCH), 129.2 (ArCH),
128.1 (ArCH), 128.0 (ArCH), 128.0 (ArC), 124.4 (ArC), 123.0 (ArCH),
121.6 (ArCH), 121.0 (ArCH), 120.8 (ArCH), 111.7 (ArCH), 111.1 (ArCH),
55.4 (OCH3); IR νmax (neat)/cm-1 703, 732, 1264, 1453; HRMS (GCMS)
calculated for C21H17O2 [M+H]+: 301.1224. Found [M+H]+: 301.1219.
3-(2-(Thiophen-2-yl)phenyl)benzofuran 154 As described in general procedure E, 143a (40
mg, 0.15 mmol), sodium methoxide (13 mg, 0.23
mmol), methanol (2 mL) and then Pd(OAc)2 (2 mg,
O
S
O
OMe
96
10 mol %), PCy3 (4 mg, 20 mol %), K2CO3 (12 mg, 0.12 mmol), 1,4-
dioxane (2 mL) and 2-bromothiophene (8 µL, 0.08 mmol) gave 154as an
oil (16 mg, 0.06 mmol, 65%). Eluted with n-hexane/ ethyl acetate (8:2);1H NMR (400 MHz, CDCl3) δ (ppm) 7.65 – 7.61 (m, 1H, ArCH), 7.53 –
7.45 (m, 3H, ArCH), 7.45 – 7.38 (m, 2H, ArCH), 7.27 (dd, J = 4.9, 1.5 Hz,
1H, ArCH), 7.25 – 7.23 (m, 1H, ArCH), 7.16 (dd, J = 5.0, 1.2 Hz, 1H,
ArCH), 7.13 – 7.09 (m, 1H, ArCH), 6.87 (dd, J = 3.6, 1.2 Hz, 1H, ArCH),
6.83 (dd, J = 5.1, 3.5 Hz, 1H, ArCH); 13C NMR (126 MHz, CDCl3) δ (ppm)
154.9 (ArC), 142.5 (ArCH), 142.5 (ArC), 134.2 (ArC), 131.2 (ArC), 130.7
(ArCH), 130.1 (ArCH), 128.0 (ArCH), 127.7 (ArCH), 127.4 (ArCH), 126.9
(ArCH), 126.6 (ArC), 125.5 (ArCH), 124.1 (ArCH), 122.6 (ArCH), 121.4
(ArC), 120.3 (ArCH), 111.3 (ArCH); IR νmax (neat)/cm-1 698, 1106, 1214,
1453; HRMS (GCMS) calculated for C18H14OS [M+H]+: 277.0682. Found
[M+H]+: 277.0680.
3-(3'-(Trifluoromethyl)-[1,1'-biphenyl]-2-yl)benzofuran 155 As described in general procedure E, 143a
(40 mg, 0.15 mmol), sodium methoxide (13
mg, 0.23 mmol), methanol (2 mL) and then
Pd(OAc)2 (2 mg, 10 mol %), PCy3 (4 mg, 20
mol %), K2CO3 (12 mg, 0.12 mmol), 1,4-
dioxane (2 mL) and 1-bromo-3-
(trifluoromethyl)benzene (11 µL, 0.08 mmol) gave 155 as an oil (22 mg,
0.07 mmol, 84%). Eluted with n-hexane/ ethyl acetate (10:1); 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.64 – 7.56 (m, 2H, ArCH), 7.52 – 7.47 (m,
3H, ArCH), 7.44 (dd, J = 8.5, 3.7 Hz, 2H, ArCH), 7.39 (d, J = 7.9 Hz, 1H,
ArCH), 7.31 – 7.21 (m, 4H, ArCH), 7.10 (t, J = 7.5 Hz, 1H, ArCH); 13C
NMR (126 MHz, CDCl3) δ (ppm) 155.2 (ArC), 143.0 (ArCH), 142.2 (ArC),
140.1 (ArC), 132.8 (ArC), 131.1 (ArCH), 130.7 (q, J = 32.5 Hz, ArCCF3),
130.5 (ArCH), 130.2 (ArCH), 128.5 (ArCH), 128.4 (ArCH), 128.4 (ArCH),
127.2 (ArC), 126.2 (q, J = 3.8 Hz, ArCH), 124.5 (ArCH), 124.1 (q, J =
272.4 Hz, CF3) 123.8 (q, J = 3.8 Hz, ArCH), 122.8 (ArCH), 121.1 (ArC),
120.4 (ArCH), 111.6 (ArCH); IR νmax (neat)/cm-1 1125, 1166, 1333; HRMS
O
CF3
97
(GCMS) calculated for C21H13F3O [M+H]+: 339.0991. Found [M+H]+:
339.0980.
3.6 X-Ray Crystal Structures
2-(Trifluoromethyl)-5a,10b-dihydrobenzo[4,5]thieno[2,3-b]benzofuran 6,6-dioxide 143b
3-(2-(Methylsulfonyl)phenyl)-5-(trifluoromethyl)benzofuran 145b
Methyl 2-(5-(trifluoromethyl)benzofuran-3-yl)benzenesulfinate 160
S O
CF3
OO
H
H
O
SO
OMeF3C
O
F3C SO
OMe
98
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