metal-free sulfoxide-directed cross-coupling

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


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


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


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


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


(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



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



bromophenol (397 mg, 2.25 mmol), BF3⋅OEt2 (1.5


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,


nitrophenol (320 mg, 2.25 mmol), BF3⋅OEt2 (1.5


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


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



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), 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


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


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


(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


bromobenzo[b]thiophene (200 mg, 0.93 mmol),

phenol (130 mg, 1.40 mmol), BF3⋅OEt2 (0.92


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


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


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),


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-



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



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),


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), 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’




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).


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).


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).



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


(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


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).


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


CH2Cl2 (8 mL) gave 143d as a white solid (129

mg, 0.43 mmol, 57%). Eluted with n-hexane/



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),


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


CH2Cl2 (2 mL) gave 143e as a white solid (76

mg, 0.23 mmol, 69%). Eluted with n-hexane/



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


acetate (8:2).



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), 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).


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


CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143f as a


acetate (4:6).


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).


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


(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).


0.75 mmol), 3-bromophenol (197 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL,


CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143h as a


acetate (1:1).



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



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




0.75 mmol), 3,5-dimethylphenol (137 mg, 1.13 mmol), BF3⋅OEt2 (0.74 mL,


CH2Cl2 (3 mL) and then mCPBA (400 mg, 1.79 mmol) gave 143i as a


acetate (1:1).


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


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).


1H, ArCH), 7.65 (d, J = 2.0 Hz, 1H, ArCH), 7.50 (dd, J = 8.3, 1.7 Hz, 1H,


7.07 – 7.00 (m, 2H, ArCH), 5.90 (d, J = 8.2 Hz, 1H, CH), 5.32 (d, J = 8.2





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


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


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



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


(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,


CH2Cl2 (2 mL) gave 143l as a white solid (81 mg,


acetate (7:3).

Or as described in general procedure C, 4-bromobenzo[b]thiophene (100


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



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


(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



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).


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


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,


acetate (7:3).

Or as described in general procedure C, 7-bromobenzo[b]thiophene (100


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



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


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


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


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).


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



(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,


acetate (6:4)

S O

H

MeOO

S O

H

PhOO

81

Or as described in general procedure C, 2-phenylbenzo[b]thiophene (40


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




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



(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,


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/


S O

H

CO2MeOO

82


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),



(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,


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),


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


(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


7.9 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), 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


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),


dimethylformamide (1 mL) gave 145e as an oil (18


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), 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,



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


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,



dimethylformamide (1 mL) gave 145g as an oil (17



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), 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


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)


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,



dimethylformamide (1 mL) gave 145j gave as an

oil (21 mg, 0.07 mmol, 80%). Eluted with n-


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


(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



dimethylformamide (1 mL) gave 145k as an oil (11


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),


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)


3-(2-Bromo-6-(methylsulfonyl)phenyl)benzofuran 145l As described in general procedure D, 143l (20 mg,



dimethylformamide (1 mL) gave 145l as an oil (15



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


(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



dimethylformamide (1 mL) gave 145m as an oil (7



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),


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)


3-(3-Bromo-2-(methylsulfonyl)phenyl)benzofuran 145n As described in general procedure D, 143n (15



dimethylformamide (1 mL) gave 145m as an oil (8



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), 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,



dimethylformamide (1 mL) gave 145o as an oil (10


acetate (7:3); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.80 – 7.72 (m, 1H,


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), 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



dimethylformamide (1 mL) gave 145p as a white



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),



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



dimethylformamide (1 mL) gave 145q as a white


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), 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,


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




(CH2); IR νmax (neat)/cm-1 696, 1153, 1313, 1452; HRMS (GCMS)


3-(2-(Allylsulfonyl)phenyl)benzofuran 148 As described in general procedure D, 143a (20


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


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


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)


3.5 Desulfinylative Cross-Coupling of Benzofuran Products 3-([1,1'-Biphenyl]-2-yl)benzofuran 150

As described in general procedure E, 143a (80


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


O

O

SO O

OEt

O

94


(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,


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), 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


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


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),




(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),


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


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,


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



(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


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),


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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metal-free sulfoxide-directed cross-coupling

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