One-pot synthesis of aryl sulfones from organometallic reagents and iodonium salts

Article

pubs.acs.org/joc

One-Pot Synthesis of Aryl Sulfones from Organometallic Reagents

and Iodonium Salts

Natalie Margraf and Georg Manolikakes*

Department of Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany

S

* Supporting Information

ABSTRACT: A transition-metal-free arylation of lithium,

magnesium, and zinc sulﬁnates with diaryliodonium salts is

described. The sulﬁnic acid salts were prepared from the reaction

of the corresponding organometallic reagents and sulfur dioxide.

Combination of the three single steps (preparation of the

organometallic compound, sulﬁnate formation, and arylation) leads to a one-pot sequence for the synthesis of aryl sulfones from

simple starting materials. The chemoselectivity of unsymmetrical diaryliodonium salts has been investigated. Potential and

limitations of this method will be discussed.

Scheme 1. Routes to Aryl Sulfones Based on Diaryliodonium

Salts

INTRODUCTION

■

The sulfonyl moiety is an important motif in organic

synthesis^1,2and especially in medicinal chemistry.³Aryl

sulfones are useful building blocks and found in many drugs,

such as the antibacterial Dapsone,⁴Laropiprant,⁵a prostaglan-

din D₂antagonist, or the COX-2 inhibitor Vioxx (Figure 1).⁶

Furthermore, diaryl sulfones have shown promising antitumor

and antifungal activities or inhibition of the HIV-1 reverse

transcriptase.⁷

(hetero)arenes into diaryl sulfones. Herein report the extension

of this method to the arylation of magnesium and zinc

sulﬁnates and the corresponding one-pot protocols as well as

the scope and limitations of these methods.

RESULTS AND DISCUSSION

■

Aryl Sulfones from Organolithium Reagents. In

preliminary studies, we investigated the reaction of diphenylio-

donium triﬂate 3a and benzenesulﬁnic acid lithium salt 2a,

prepared in quantitative yield from phenyllithium and sulfur

dioxide (Table 1).¹⁸The best results were achieved in aprotic

polar solvents such as DMF, DMSO, and NMP (entries 1−3).

Aprotic nonpolar solvents such as THF or dioxane gave lower

yields (entries 4 and 5). The arylation reaction is insensitive to

air and moisture and can be performed with commercial grade

solvents without an inert atmosphere in similar yields (entries 6

and 7). The nature of the diphenyliodonium counterion X⁻has

a marked eﬀect on the yield. While similar yields were obtained

Figure 1. Biologically active aryl sulfones.

Due to this importance, numerous strategies for synthesis

have been reported. The most common are the oxidation of

sulﬁdes^1,2and the sulfonylation of arenes in the presence of

strong acids.^1,2In recent years eﬃcient routes based on

transition-metal-catalyzed^8,9and transition-metal-free¹⁰cou-

pling reactions of sodium sulﬁnates have been introduced. In

the course of our investigations toward new methods for the

synthesis of sulfonyl-group-containing molecules, we were able

to develop a mild, transition-metal-free protocol based on the

reaction between arylsulﬁnic acid sodium salts and diary-

liodonium salts (Scheme 1).^11,12

with non-nucleophilic counterions (OTf⁻, PF₆, or BF₄)

(entries 7−9), a signiﬁcant decrease of the yield was observed

for more nucleophilic counterions, such as OTs⁻or Cl⁻

(entries 10 and 11).²⁰To our delight, it was possible to

merge the two single steps, generation of the lithium sulﬁnate

−

Although various diaryliodonium salts are commercially

available or can be prepared easily,^13,14the access to aryl

sulﬁnic acid sodium salts is rather limited.¹⁵⁻¹⁷Therefore, we

developed a method based on the in situ generation of

arylsulﬁnic acid lithium salts from the corresponding organo-

lithium reagents.^18,19This method allows the direct trans-

formation of readily availbale (hetero)aromatic halides and

Received: December 5, 2014

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the direct deprotonation/lithiation of acidic C−H groups.²²To

our delight, both procedures are compatible with our direct

arylation approach. The combination of a lithiation reaction

with our arylation protocol leads to a four-step, one-pot

reaction sequence for the synthesis of aryl sulfones. This

sequence consists of the following: (1) generation of the

organolithium reagent via exchange or deprotonation; (2)

reaction of the lithium reagent with liquid SO₂; (3) removal of

excess SO₂and solvent exchange; (4) treatment of the obtained

crude lithium sulﬁnate with diaryliodonium salts. Using this

protocol we were able to transform various (hetero)arenes 5

and (hetero)aromatic halides 6 directly into the corresponding

diaryl sulfones 4 (Table 3).²³Thus, benzene 5a can be

transformed directly into diaryl sulfone 4a in 52% yield (entry

1). Diaryl sulfone 4g could be obtained either via direct

deprotonation of dimethoxybenzene 5b or from the corre-

sponding iodoarene 6a in similar yields (entries 2 and 3).

Several anisole derivatives could be functionalized in a similar

manner (entries 4−8). Generation of the organolithium reagent

via deprotonation or lithium−halogen exchange can be used as

complementary methods. Depending on the eﬃciency of both

methods, either similar results are obtained (entries 2 and 3) or

one procedure leads to higher yields (entries 4 and 5). Similar

results were observed for the lithium-exchange protocol with

diﬀerent halogenated arenes. In the case of aryl sulfone 4e

better results were obtained with the corresponding aryl

bromide 6d (entires 7 and 8). For aryl sulfone 4k, the reaction

with the aryl iodide 6h furnished the product in higher yield

(entries 10 and 11). Arenes bearing “directed metalation

groups” (DMG),²⁴such as a carbamate 5d and amide 5e, could

be successfully transformed directly into the diaryl sulfones 4l

and 4m (entries 12 and 13). More importantly, diﬀerent

heteroarenes, such as thiophene (5f), N-methylpyrrole (5g),

pyridines 5h and 6i, or ferrocene (5i), could be functionalized

in a similar manner (entries 14−18).

Table 1. Survey of Solvents and Inﬂuence of the

Counterion

a

b

entry

solvent

DMF

salt

X⁻

yield (%)

1

2

3

4

5

3a

3b

3c

3d

3e

3a

OTf⁻

84

80

83

47

26

79

86

91

65

60

83

DMSO

NMP

1,4-dioxane

THF

c

6

c

DMSO

DMF

7

−

8

DMF

PF₆

−

9

DMF

BF₄

10

11

DMF

OTs⁻

Cl⁻

OTf⁻

DMF

d

12

DMF

a

Reaction conditions: 1.5 equiv of 2a and 1.0 equiv of 3 in 1.0 mL of

b

c

solvent at 90 °C for 24 h. Isolated yield. Reaction run without

exclusion of air or moisture. Performed as one-pot-reaction/without

d

isolating the sulﬁnic acid salt.

and arylation with an iodonium salt, into a one-pot sequence.

Thus, the reaction of PhLi with sulfur dioxide followed by

removal of solvents and excess SO₂and subsequent reaction of

the crude sulﬁnate with Ph₂IOTf furnished the desired sulfone

4a in comparable 83% yield (compare entries 1 and 12).²¹

With the optimized conditions in hand, we started to

investigate the scope of this reaction. First we performed the

reaction between benzenesulﬁnic lithium salt (2a) and various

symmetrical diaryliodonium salts 3 (Table 2). Good to

excellent yields were obtained in all cases (entries 1−6).

Two of the most common procedures for the preparation of

organolithium reagents are the lithium−halogen exchange and

a

Table 2. Arylation of Benzenesulﬁnic Acid Lithium Salt 2a

a

b

c

Reaction conditions: 1.5 equiv of 2a and 1.0 equiv of 3 in 1.0 mL of DMF for 24 h at 90 °C at a 0.5 mmol scale. Isolated yield. Tosylate as

counterion.

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a

Table 3. Direct Lithiation Approach to Diaryl Sulfones

a

Reaction conditions: sulﬁnate 2 (prepared from 1.5 equiv of 5 or 6) and 1.0 equiv of 3a in 1.0 mL of DMF for 24 h at 90 °C at a 0.5 mmol scale.

Isolated yield. Organolithium compound was prepared via deprotonation. Organolithium compound was prepared via halogen−metal exchange.

b

c

d

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To our delight, this method is not limited to (hetero)-

aryllithium reagents, as in the case of the corresponding sodium

sulﬁnates. By using primary, secondary, or tertiary alkyllithium

reagents 1b−e, the desired alkyl aryl sulfones 7a−d are

obtained in excellent yields (Scheme 2).

the reaction mixture via GC/MS shows the formation of

considerable amounts of halobenzenes 6. These side-products

can be formed in a competing arylation of the halide

counterions.²⁹Considering this side-reaction, a decreased

yield in the presence of more nucleophilic counterions or

excess lithium chloride should be expected. Unfortunately,

various additives or cosolvents could not suppress this side-

reaction and improve the overall yield. The only option to

enhance the yield of the desired sulfone, is the use of a 3-fold

excess of the iodonium reagent. By employing a great excess of

the iodonium salt, the yield can be increased considerably for all

types of Grignard reagent (entries 8−10).

Scheme 2. Synthesis of Alkyl Aryl Sulfones

With the insights gained from the optimization study, we

investigated the reaction of benzenesulﬁnic acid magnesium

chloride salt 2f with various symmetrical diaryliodonium salts 3

(Table 5). In some cases good yields were obtained using slight

excess of the magnesium sulﬁnate (entries 1−3). In other cases

the yield of the desired sulfone could be increased dramatically

by employing a 3-fold excess of the iodonium salt (entries 4−

6).

Aryl Sulfones from Organomagnesium Reagents. The

lithiation approach is inherently limited by the low functional

group tolerance of organolithium reagents. As shown in Table

3, the direct functionalization of sensitive heteroaromatics, such

as the pyridine derivatives 5h or 6i, leads to the desired

heteroaryl sulfones in low to moderate yields. Therefore, we

investigated similar reactions with organomagnesium reagents.

Various procedures for the synthesis of these Grignard reagents

exist. In addition, highly functionalized organomagnesium

reagents, bearing various sensitive groups, can be prepared

eﬃciently.^25,26We envisioned that the higher functional group

compatibility of Grignard reagents should lead to a broader

scope of our one-pot sequence.²⁷

In initial investigations with diﬀerent phenyl magnesium

sulﬁnates we observed a pronounced eﬀect of the Grignard

counterion. We started our experiments with a study of the

inﬂuence of diﬀerent solvents and counterions (Table 4). As

model system, we chose the reaction between benzenesulﬁnic

acid magnesium salts 2b−e, prepared from diﬀerent phenyl-

magnesium halides, and diphenyliodonium triﬂate (3a). For the

reaction with the benzenesulﬁnic acid magnesium salt 2b best

results were obtained with DMSO as solvent (entry 3). Other

polar aprotic solvents, such as NMP or DMF, lead to lower

yield (entries 1 and 2). Unfortunately, the yield decreases for

sulﬁnates prepared from other “Knochel”-type phenyl-

Grignards.²⁸The presence of additional LiCl in the reaction

mixture leads to a slightly lower yield (entry 4). Changing the

Grignard counterion from chloride to bromide or iodide, has a

marked eﬀect on the reaction yield. In the case of the sulﬁnate

prepared from PhMgI·LiCl the yield drops to 22%. Analysis of

As mentioned previously, Grignard reagents can be prepared

by various protocols (see above). To our delight, two of those

methods, the direct insertion of magnesium into organic halides

(in the presence or absence of lithium chloride)²⁸and the

magnesium−halogen exchange³⁰are compatible with our

arylation protocol. Therefore, we were able to develop a

similar one-pot, four-step synthesis of arylsufones via in situ-

generated organomagnesium reagents. Generation of the

organomagnesium species followed by the reaction of the

Grignard reagent with SO₂, removal of excess SO₂, solvent

exchange, and treatment of the obtained crude magnesium

sulﬁnate with a diaryliodonium salt leads to the desired aryl

sulfones (Table 6). Various aryl chlorides and bromides can be

transformed rapidly into the corresponding diaryl sulfones

(entries 1 and 2). Especially the halogen−magnesium exchange

with iPrMgCl·LiCl³⁰is well suited for a combination with our

arylation procedure. It enables the in situ preparation of the

(hetero)arylmagnesium chlorides even from the corresponding

bromo- or iodo(hetero)arenes, thus avoiding the formation of

more nucleophilic counterions.³¹Using the halogen−magne-

sium exchange reaction even aryl iodides bearing sensitive

functional groups, such as an ester or cyano group, can be

transformed directly into the desired aryl sulfones (entries 4

and 5). In general, higher yields were obtained with an excess of

a

Table 4. Survey of Solvents and Inﬂuence of the Grignard Counterion

b

entry

X

sulﬁnate

equiv of PhSO₂MgX

equiv of Ph₂IOTf

solvent

t (h)

yield (%)

1

2

3

4

5

6

7

8

9

10

Cl

2b

2c

2d

2e

2b

2c

2d

2e

1.3

1.0

3.0

DMF

24

31

22

NMP

c

DMSO

75 (57)

62

Cl·LiCl

Br·LiCl

I·LiCl

Cl

31

22

90

Cl·LiCl

Br·LiCl

I·LiCl

81

40

37

a

b

c

Reaction conditions: equiv of reagents as indicated in 1.0 mL of solvent for 24 h at 90 °C at a 0.5 mmol scale. Isolated yield. Reaction run without

exclusion air or moisture.

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a

Table 5. Arylation of Benezesulﬁnic Acid Magnesium Salt 2b

a

Reaction conditions: 1.5 equiv of benzenesulﬁnic acid salt 2b, 1.0 equiv of iodonium salt 3 in 1.0 mL of DMSO at 90 °C for 24 h at a 0.5 mmol

b

c

d

scale. Isolated yields. 1.0 equiv of salt 2b and 3.0 equiv of salt 3. Tosylate as counterion.

the iodonium salt (compare entries 3, 5−8). In some cases the

yield could be doubled by reversing the reaction stoichiometry

(entries 3, 5, 7, and 8). This method is not limited to aryl

Grignard reagents. The reaction of alkyl organomagnesium

reagents, prepared either in situ or obtained from commercial

sources, leads to the desired alkyl aryl sulfones in 17−72% yield

(entries 9−11).

The deprotonation of acidic C−H-bonds with suitable

magnesium amide bases is another very eﬃcient approach for

the synthesis of Grignard reagents.³²Unfortunately, this

procedure is not compatible with our arylation approach.

Although thiophene could be transformed into the desired

sulfone in 50% overall yield, the direct functionalization of

several other heterocycles, such as furan or several nitrogen

heterocycles, with tmpMgCl·LiCl was not successful (Scheme

3).

LiCl.³⁵Unfortunately, the above-mentioned reactions con-

ditions for benzenesulﬁnic acid zinc salt proved unsuitable for

various other aryl and alkyl zinc reagents. Therefore, we

decided to investigate the reaction of the zinc sulﬁnate 2g in

more detail. The ester-substituted zinc sulﬁnate 2g was

prepared from the corresponding aryl iodide via magnesium−

halogen exchange with iPrMgCl·LiCl, transmetalation with

ZnCl₂, and subsequent reaction with SO₂. With this speciﬁc

synthesis of the zinc sulﬁnate, we were able to examine worst

case reaction conditions in the presence of a great excess of

halide ions (Table 8). Indeed the reaction of 1.5 equiv of the

sulﬁnic acid zinc salt with 1.0 equiv of diphenyliodonium triﬂate

in diﬀerent polar aprotic solvents furnished the desired sulfone

in low yields (entries 1−3). Performing the reaction in DMSO

with 3.0 equiv of the iodonium salt did not aﬀect the yield

(entry 4). However, the yield could be improved dramatically

by performing the reaction in NMP or DMF and employing a

3-fold excess of the iodonium salt (entries 5 and 6).

With these optimized reaction conditions, various organozinc

reagents could be transformed into the corresponding aryl

sulfones (Table 9). Several highly functionalized aryl sulfones

or heteroaryl sulfones could be prepared in high yields (entries

2−6 and 8). The organozinc reagents were obtained via

transmetalation from the corresponding organomagensium

compounds (entries 1−8) or from direct zinc insertion in the

presence of LiCl (entries 9−11). The latter procedures allow

the direct synthesis of aryl alkyl sulfones from functionalized

alkyl iodides (entries 10 and 11).

Aryl Sulfones from Organozinc Compounds. Next we

turned our attention to reactions with organozinc compounds.

Organozinc reagents are known for their exceptional functional

group compatibility and can be prepared via various eﬃcient

procedures.^25,26,33,34Therefore, one could expect a broader

scope for our one-pot aryl sulfone synthesis. We started our

investigations with the reaction between benzenesulﬁnic acid

zinc salt and various diaryliodonium salts (Table 7). The zinc

sulﬁnate was prepared from phenylmagnesium chloride via

transmetalation with ZnCl₂and subsequent reaction with sulfur

dioxide. Although this procedure leads to the formation of

stoichiometric amounts of halide ions, our optimized

conditions from the corresponding transformation with

Grignard reagents (DMSO, 1.5 equiv of RSO₂Met, 1.0 equiv

of Ar₂IOTf) proved to be suitable for reactions with the

benzenesulﬁnic acid zinc salt. The desired diaryl sulfones were

obtained in very good yields (entries 1−3, 5, and 6).

SO₂Surrogates. SO₂is a toxic and corrosive gas, which

requires careful handling and the appropriate equipment and

safety procedures. Although the proper handling of sulfur

dioxide should cause no problems for a well-trained chemist,

the replacement of gaseous sulfur dioxide with solid SO₂

surrogates should lead to a simpler process. Therefore, we

performed our one-pot sequence with two common SO₂

surrogates, the DMAP·SO₂complex from Vogel³⁶and the

We next examined the scope of our one-pot aryl sulfone

synthesis with diﬀerent organozinc reagents obtained via

transmetalation or direct zinc insertion in the presence of

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a

Table 6. Direct Magnesiation Approach to Diaryl Sulfones

a

b

Reaction conditions: 1.5 equiv of aryl halide and 1.0 equiv of Ph₂IOTf in 1.0 mL of DMSO for 24 h at 90 °C at a 0.5 mmol scale. Isolated yield.

c

d

e

Grignard reagent was prepared by halogen−metal exchange with iPrMgCl·LiCl. Grignard reagent was prepared by insertion of magnesium. 1.0

equiv of aryl halide, 3.0 equiv of Ph₂IOTf in 1.0 mL of DMSO for 24 h at 90 °C at a 0.5 mmol scale.

alternative.^13,14Therefore, we investigated the chemoselectivity

Scheme 3. Direct Metalation Approach by Deprotonation

with tmpMgCl·LiCl

of several selected diaryliodonium salts in reactions with

diﬀerent benzenesulﬁnic acids salts (Table 10). In the case of

the iodonium salt 3m bearing an electron-rich 4-methox-

yphenyl and an electron-poor 3-triﬂuoromethylphenyl group, a

highly selective transfer of the electron-poor aryl moiety was

observed for reactions with the lithium and zinc sulﬁnate

(selectivity >12:1) (entries 3-1 and 3-3). Interestingly, reaction

of the benzenesulﬁnic acid magnesium salt delivered the

sulfone 4m with the highest degree of selectivity (entry 3-2).

Next, we performed reactions with unsymmetrical iodonium

salts 3k and 3l, containing one phenyl group and one aryl group

with substituents in the ortho positions. In all cases the bulky

ortho-substituted aryl moiety was transferred selectively

(entries 1 and 2).³⁸

The chemoselectivity of unsymmetrical diaryliodonium salts

with diﬀerent steric bulk in the ortho positions was further

investigated with the model substrate (2-methylphenyl)(2,4,6-

trimethylphenyl)iodonium triﬂate 3n (Scheme 5). In the

reaction of 3n with benezenesulﬁnic acid lithium salt (2a) a

mixture of the two diaryl sulfones 4c and 4v was obtained, with

the sterically more demanding mesityl group being transferred

DABSO reagent pioneered by Willis.¹⁷Unfortunately, the yield

decreased considerably to 54% with DABSO and 37% with

DMAP·SO₂(Scheme 4). We assume, that the nucleophilic

nitrogen bases DABCO and DMAP can undergo a competing

side-reaction with diaryliodonium salt.³⁷These results show

that gaseous sulfur dioxide is the optimal SO₂source for this

one-pot sequence.

Selectivity Studies. During our initial investigations with

sodium sulﬁnates, we observed a highly chemoselective transfer

of one aryl moiety from unsymmetrical diaryliodonium salts.¹¹

Since the preparation of symmetrical diaryliodonium salts can

be diﬃcult or expensive, unsymmetrical salts oﬀer an attractive

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a

Table 7. Arylation of Benzenesulﬁnic Acid Zinc Salt 2f

a

b

Reaction conditions: 1.5 equiv of benzenesulﬁnic acid salt 2f, 1.0 equiv of salt 3 in 1.0 mL of DMSO at 90 °C for 24 h at a 0.5 mmol scale. Isolated

c

yields. OTs as counterion.

a

sulfones can be prepared using this straightforward procedure.

Reactions with magnesium and zinc sulﬁntes are inherently

limited due to side-reactions of their halide counterions with

the iodonium salts. This limitation can be avoided by the

employment of an excess of the iodonium salt.

Table 8. Survey of Solvents and Inﬂuence of Stoichiometry

b

c

entry equiv of Ar-SO₂-ZnX equiv of Ph₂I⁺OTf⁻solvent yield (%)

1

2

3

4

5

6

1.5

1.0

3.0

DMSO

NMP

DMF

37

8

EXPERIMENTAL SECTION

■

15

43

75

85

General Considerations. All anhydrous solvents were purchased

from commercial suppliers and stored over MS4A under an

atmosphere of argon. Solvents for column chromatography were

technical standard. All starting materials, which were purchased from

commercial sources, were used without further puriﬁcation. SO₂

(sulfur dioxide 3.8) was used directly without further puriﬁcation.

Commercially available diphenyliodonium salts were purchased.

Following diaryliodonium salts were synthesized according to

literature: Bis(4-methylphenyl)iodonium triﬂate (3f), bis(2,4,6-

trimethylphenyl)iodonium triﬂate (3g),^14dbis(2,4-dimethylphenyl)-

iodonium triﬂate (3h),^14dbis(4-methoxyphenyl)iodonium tosylate

(3i),^14bbis(4-chlorophenyl)iodonium triﬂate (3j),^14d(2,4,6-trimethyl-

phenyl)(phenyl)iodonium triﬂate (3k),^14d(2,4,6-triisopropylphenyl)-

(phenyl)iodonium triﬂate (3l),^20a(3-triﬂuoromethylphenyl)(4-meth-

oxyphenyl)iodonium tosylate (3m).¹⁴Chromatography column chro-

matography was performed with silica 0.04−0.063 mm/230−400

mesh. Thin layer chromatography was performed using aluminum

plates coated with SiO₂. The spots were visualized by ultraviolet light.

NMR spectroscopy ¹H and ¹³C NMR spectra were recorded at 400 or

500 MHz and 101 or 126 MHz, respectively. Chemical shifts are

reported as δ-values relative to the residual CDCl₃peak (δ = 7.26 ppm

for ¹H and δ = 77.16 ppm for ¹³C). Coupling constants (J) are given in

hertz and multiplicities of the signals are abbreviated as follows: s =

singlet; d = doublet; t = triplet; q = quartet; sp = septet; m = multiplet;

dd = doublet of doublets; dt = doublet of triplets. Mass spectrometry

spectra (MS) were measured using ESI (electrospray ionization)

techniques. High resolution mass spectra (MALDI-HRMS) were

measured using MALDI (matrix-assisted laser desorption/ionization)

techniques. Melting points are uncorrected.

DMSO

NMP

DMF

a

Reaction conditions: equiv of reagents as indicated in 1.0 mL of

solvent for 24 h at 90 °C at a 0.5 mmol scale. Preformed organozinc

reagent. Isolated yields.

b

c

preferentially (selectivity 3.3:1). Interestingly, the chemo-

selectivity can be reversed by the addition of a transition-

metal catalyst. Performing the reaction in the presence of

catalytic amounts of CuI leads to a preferential transfer of the

less bulky o-tolyl moiety (selectivity 2.6:1).³⁹

CONCLUSION

■

In summary, we have developed a synthesis of aryl sulfones

from sulﬁnic acid lithium, magnesium, and zinc salts. This

reaction has a very broad scope, and both aryl and alkyl

sulﬁnates can be arylated in an eﬃcient manner. Reactions with

unsymmetrical diaryliodonium salts show high chemoselectiv-

ity. On the basis of these reactions, we could develop a practical

one-pot-protocol for the direct transformation of (hetero)-

aromatic and aliphatic halides as well as (hetero)arenes into aryl

sulfones. This protocol consists of the following: (1) generation

of the organometallic reagent via metal−halogen exchange, and

direct metal insertion or deprotonation; (2) reaction of the

organometallic reagent with sulfur dioxide; (3) removal of

excess sulfur dioxide; (4) treatment of the formed crude

sulﬁnate with a diaryliodonium salt. Various aryl- and heteroaryl

Reactions All reactions were carried out under an inert atmosphere

in dried glassware unless otherwise noted. All yields refer to isolated

yields of compounds estimated to be >95% pure as determined by ¹H

NMR. Working with SO₂: SO₂is a toxic and corrosive gas! It

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a

Table 9. Zincation Approach to Diaryl Sulfones

a

b

c

Reaction conditions: 1.0 equiv of (hetero)aryl halide, 3.0 equiv of Ph₂IOTf in 1.0 mL of DMF for 24 h at 90 °C. Isolated yield. 1.5 equiv of

d

(hetero)aryl halide, 1.0 equiv of Ph₂IOTf. Reaction carried out in DMSO.

pressure. The residue was coevaporated with CH₂Cl₂(1.5 mL). This

procedure was used for all experiments.

Scheme 4. SO₂Surrogates

Procedure B. Excess SO₂was removed by passing Ar through the

solution for 30 min. Diaryliodonium salt 3 and solvent (1.0 mL) were

added directly to the remaining solution/suspension. The ﬂask was

charged with a small distillation head and heated to 90 °C. After the

lower boiling solvents (THF or Et₂O) were distilled oﬀ (typically

within 1 h), the ﬂask was capped with a rubber septum and heated for

the remaining time. (As an alternative, the ﬂask can be capped directly

with a rubber septum pierced with a 20G needle and heated to 90 °C

for 24 h. Low boiling solvents are evaporated directly into the

atmosphere! This should be performed only in a closed, well-

ventilated fume-hood!).

Preparation of Benzenesulﬁnic Lithium Salt 2a. A dry, Ar-ﬂushed

Schlenk-ﬂask equipped with a magnetic stirrer and a rubber septum

was charged with phenyllithium (1a) (32.2 mL, 50 mmol, 1.55 M

solution in Et₂O, 1.0 equiv) and cooled to −40 °C. At this

temperature, liquid SO₂(1.1 mL, 55 mmol, 1.1 equiv) was added

and the reaction mixture was allowed to warm to 25 °C within 90 min.

It was then concentrated under reduced pressure and coevaporated

two times with CH₂Cl₂(150 mL) to aﬀord the solid benzenesulﬁnic

lithium salt (2a) (11.32 g). Note: The theoretical amount of lithium

salt 2a (formula weight: 148.11 g/mol) from 32.3 mL of phenyllithium

(1a) is 7.41 g. The material obtained (11.32 g) should therefore

contain 65% of 2a (assuming 100% conversion). A purity of 65% of

this material was thus assumed in later calculations.

should be handled with care only in a well-ventilated fume-hood

with the necessary precaution! It is possible to obtain the crude

magnesium or zinc sulﬁnates by passing a stream of sulfur dioxide

through the solution of the organometallic reagent. However, with this

technique a great excess of SO₂is introduced into the reaction and has

to be removed afterward. In general, better and more reproducible

yields were obtained by using a deﬁned amount of liquid SO₂.

Therefore, SO₂was condensed into a dry and Ar-ﬁlled Schlenk-ﬂask,

cooled to −78 °C. Because of its high heat of evaporation, liquid and

cooled SO₂can be easily handled, measured, and transferred with

syringes. For small scale reactions, we recommend this procedure.

For the removal of excess SO₂, we employed the two following

procedures. (For the removal of excess SO₂(gaseous or liquid),

appropriate measures to trap and destroy SO₂should be taken, e.g.,

passing the SO₂stream through an aq NaOH solution.)

Procedure A. After warming the reaction mixture to 25 °C within

90 min, the solvents and excess SO₂were removed under reduced

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a

Table 10. Selectivity Studies with Sterically Diﬀerent Demanding Aryl Substituents

a

b

Reaction conditions: 1.5 equiv of 2 and 1.0 equiv of 3 in 1.0 mL of DMF for 24 h at 90 °C at a 0.5 mmol scale. Isolated yield.

to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was added and the

aqueous layer was extracted three times with CH₂Cl₂(15 mL). The

combined organic layers were washed with dist. H₂O (15 mL) and

dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (cyclohexane:E-

tOAc) aﬀorded the analytically pure product.

Scheme 5. Selectivity Studies

TP 3: Typical Procedure for the Preparation of Sulfones from

Benzenesulﬁnic Acid Magnesium Chloride Salt (2b) (Table 5). A dry,

Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer and a rubber

septum was charged with benzenesulﬁnic acid magnesium chloride salt

(2b) (1.5 equiv or 1.0 equiv), diaryliodonium salt 3 (1.0 equiv or 3.0

equiv, respectively) and DMSO (2.0 mL/mmol iodonium salt, 0.5 M).

The reaction mixture was heated to 90 °C and stirred at this

temperature for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl

solution (10 mL) was added and the aqueous layer was extracted three

times with CH₂Cl₂(10 mL). The combined organic layers were

washed with sat. aqueous NaCl solution (10 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (hexanes:EtOAc) aﬀorded the

analytically pure product.

TP 4: Typical Procedure for the Preparation of Sulfones from

Grignard Reagents (Table 6). A dry, Ar-ﬂushed Schlenk-ﬂask

equipped with a magnetic stirrer and a rubber septum was charged

with a corresponding Grignard reagent (1)²⁹(solution in THF) in

THF (total volume 1.5 mL) and cooled to −40 °C, liquid SO₂(0.1

mL, 5.0 mmol, 10.0 equiv) was added, and the mixture was allowed to

warm to 25 °C within 90 min. After removal of excess SO₂and

solvents, diphenyliodonium triﬂate (3a) and DMSO (2.0 mL/mmol

limiting factor, 0.5 M) were added and the reaction mixture was heated

to 90 °C and stirred at this temperature for 24 h. After cooling to 25

°C, sat. aqueous NH₄Cl solution (10 mL) was added and the aqueous

layer was extracted three times with CH₂Cl₂(10 mL). The combined

organic layers were washed with sat. aqueous NaCl solution (10 mL)

and dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (hexanes:EtOAc)

aﬀorded the analytically pure product.

TP 5: Typical Procedure for the Preparation of Sulfones from in

Situ-Generated Benzenesulﬁnic Acid Zinc Salt (2f) (Table 7). A dry,

Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer and a rubber

septum was charged with phenylmagnesium chloride (1f) (0.53 M in

THF, 1.4 mL, 0.75 mmol, 0.5 equiv), and zinc chloride (0.7 M in

THF, 1.1 mL, 0.8 mmol, 1.6 equiv) was added dropwise. After stirring

at 25 °C for 30 min, the mixture was cooled to −40 °C, liquid SO₂

(0.1 mL, 5.0 mmol, 10.0 equiv) was added, and the mixture was

allowed to warm to 25 °C within 90 min. After removal of excess SO₂

and solvents from the crude benzenesulﬁnic zinc salt (2k),

diaryliodonium salt 3 (1.0 equiv) and DMSO (2.0 mL/mmol

iodonium salt, 0.5 M) were added and the reaction mixture was

heated to 90 °C and stirred at this temperature for 24 h. After cooling

to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was added and the

Preparation of Benzenesulﬁnic Magnesium Chloride Salt 2b. A

dry, Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer and a

rubber septum was charged with phenylmagnesium chloride (1f) (70

mL, 74.2 mmol, 1.06 M solution in 1.0 equiv) and cooled to −40 °C.

At this temperature, liquid SO₂(2.0 mL, 90 mmol, 1.2 equiv) was

added, and the reaction mixture was allowed to warm to 25 °C within

90 min. It was then concentrated under reduced pressure and

coevaporated two times with 150 mL of CH₂Cl₂to aﬀord the solid

benzenesulﬁnic magnesium chloride salt (2b) (21.18 g). Note: The

theoretical amount of magnesium chloride salt 2b (formula weight:

200.93 g/mol) from 74.2 mL of phenylmagnesium chloride (1f) is

14.9 g. The material obtained (21.18 g) should therefore contain 70%

of 2b (assuming 100% conversion). A purity of 70% of this material

was thus assumed in later calculations.

TP 1: Typical Procedure for the Preparation of Sulfones from

Benzenesulﬁnic Lithium Salt (Table 2). A dry, Ar-ﬂushed Schlenk-

ﬂask equipped with a magnetic stirrer and a rubber septum was

charged with benzenesulﬁnic acid lithium salt 2a (1.5 equiv),

aryliodonium salt 3 (1.0 equiv), and DMF (2.0 mL/mmol iodonium

salt, 0.5 M). The reaction mixture was heated to 90 °C and stirred at

this temperature for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl

solution (10 mL) was added and the aqueous layer was extracted three

times with CH₂Cl₂(15 mL). The combined organic layers were

washed with dist. H₂O (15 mL) and dried over Na₂SO₄, and the

solvents were removed under reduced pressure. Puriﬁcation by column

chromatography (cyclohexane:EtOAc) aﬀorded the analytically pure

product.

TP 2: Typical Procedure for the Preparation of Sulfones from

Alkyllithium Reagents (Scheme 2). A dry, Ar-ﬂushed Schlenk-ﬂask

equipped with a magnetic stirrer and a rubber septum was charged

with alkyllithium 1 (1.5 equiv) cooled to −78 °C, liquid SO₂(10

equiv) was added, and the mixture was warmed to 25 °C within 90

min. After removal of SO₂and solvents according to procedure A,

diphenyliodonium triﬂate (3a) and 1.0 equiv and DMF (2.0 mL/

mmol iodonium salt, 0.5 M) were added. The reaction mixture was

heated to 90 °C and stirred at this temperature for 24 h. After cooling

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aqueous layer was extracted three times with CH₂Cl₂(10 mL). The

combined organic layers were washed with sat. aqueous NaCl solution

(10 mL) and dried over Na₂SO₄, and the solvents were removed under

reduced pressure. Puriﬁcation by column chromatography (hexane-

s:EtOAc) aﬀorded the analytically pure product.

as a colorless solid (72.2 mg, 62%). Table 8, entry 2: 4b was also

synthesized according to TP 4 from in situ-generated benzenesulﬁnic

acid zinc salt (2f) (assume 0.75 mmol) and bis(2,4-dimethylphenyl)-

iodonium triﬂate (3f) (229.1 mg, 0.5 mmol) in DMSO (1.0 mL).

Puriﬁcation by column chromatography (hexanes:EtOAc 9:1 → 4:1)

yielded the product as a colorless solid (86.6 mg, 75%). Table 9, entry

3: To a dry, Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer

and a rubber septum charged with tolylmagnesium bromide·LiCl (1j)

(0.9 M in THF, 0.85 mL; 0.75 mmol, 1.5 equiv) was added ZnCl₂(0.7

M in THF, 1.1 mL, 0.83 mmol, 1.65 equiv) and stirred at 25 °C for 30

min. After cooling to −40 °C, liquid SO₂(0.1 mL, 5.0 mmol, 10.0

equiv) was added and the mixture was allowed to warm to 25 °C

within 90 min. After removal of excess SO₂and solvents,

diphenyliodonium triﬂate (3a) (215.1 mg, 0.5 mmol, 1.0 equiv) and

DMSO (1.0 mL) were added and the reaction mixture was heated to

90 °C and stirred at this temperature for 24 h. After cooling to 25 °C,

sat. aqueous NH₄Cl solution (10 mL) was added and the aqueous

layer was extracted three times with CH₂Cl₂(10 mL). The combined

organic layers were washed with sat. aqueous NaCl solution (10 mL)

and dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (hexanes:EtOAc

20:1 → 4:1) aﬀorded the analytically pure product as a colorless solid

TP 6: Typical Procedure for the Preparation of Sulfones from

Organozinc Reagents (Table 9). A dry, Ar-ﬂushed Schlenk-ﬂask

equipped with a magnetic stirrer and a rubber septum was charged

with a corresponding organozinc reagent (1)³⁵(solution in THF, 0.5

mmol, 1.0 equiv) in THF (total volume 1.5 mL) and cooled to −40

°C, liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added, and the

mixture was allowed to warm to 25 °C within 90 min. After removal of

excess SO₂and solvents, diphenyliodonium triﬂate (3a) (645.3 mg, 1.5

mmol, 3.0 equiv) and DMF (2.0 mL/mmol organozinc reagent, 0.5

M) were added and the reaction mixture was heated to 90 °C and

stirred at this temperature for 24 h. After cooling to 25 °C, sat.

aqueous NH₄Cl solution (10 mL) was added and the aqueous layer

was extracted three times with CH₂Cl₂(10 mL). The combined

organic layers were washed with sat. aqueous NaCl solution (10 mL)

and dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (hexanes:EtOAc)

aﬀorded the analytically pure product.

4a:¹⁸Table 2, entry 1. 4a was prepared from benzenesulﬁnic acid

lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol) and

diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol) in DMF (1.0

mL). Puriﬁcation by chromatography (cyclohexane:EtOAc 9:1 → 4:1)

yielded the product as a colorless solid (91.3 mg, 84%). Table 3, entry

1: To a solution of nBuLi (0.34 mL, 2.45 M in hexanes, 0.80 mmol, 1.6

equiv) and TMEDA (0.11 mL, 0.75 mmol, 1.5 equiv) in a dry, Ar-

ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer and a rubber

septum was added benzene (5a) (67 μL, 0.75 mmol, 1.5 equiv)

(lithiation according to ref 22b). The mixture was stirred at 25 °C for

90 min. After removal of excess SO₂and solvents by procedure A,

diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and

DMF (1.0 mL) were added and the mixture was stirred at 90 °C for 24

h. After cooling to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was

added and the aqueous layer was extracted three times with CH₂Cl₂

(15 mL). The combined organic layers were washed with dist. H₂O

(15 mL) and dried over Na₂SO₄, and the solvents were removed under

reduced pressure. Puriﬁcation by column chromatography (cyclo-

hexane:EtOAc 9:1 → 4:1) aﬀorded the analytically pure product as a

colorless solid (56.6 mg, 52%). Tables 5 and 6, entry 1: According to

TP 3 4a was synthesized from benzenesulﬁnic acid magnesium

chloride salt (2b) (70 wt %, 215.3 mg, 0.75 mmol) and

diphenyliodonium triﬂate (3a) (215.1 mg, 0.5 mmol) in DMSO

(1.0 mL). Puriﬁcation by column chromatography (hexanes:EtOAc

20:1 → 4:1) yielded the product as a colorless solid (82.0 mg, 75%).

Table 7, entry 1: According to TP 4, 4a was prepared from crude

benzenesulﬁnic acid zinc salt (2f) (assume 0.75 mmol) and

diphenyliodonium triﬂate (3a) (215.1 mg, 0.5 mmol) in DMSO

(1.0 mL). Puriﬁcation by column chromatography (hexanes:EtOAc

9:1 → 4:1) yielded the product as a colorless solid (72.8 mg, 67%).

mp: 123−125 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.00−7.90 (m, 4H),

7.60−7.53 (m, 2H), 7.53−7.46 (m, 4H). ¹³C NMR (101 MHz,

CDCl₃) δ 141.7, 133.3, 129.4, 127.8. MS: m/z: calcd for C₁₂H₁₀O₂S

+Na⁺241.03, found 241.08. IR (cm⁻¹): 3070 (w), 2923 (w), 1581

(w), 1477 (w), 1447 (m), 1308 (s, -SO₂-), 1294 (s). 1181 (m), 1151

(s, -SO₂-), 1103 (s), 1068 (m), 1023 (m), 997 (m), 935 (w), 759 (s),

726 (s), 682 (s), 582 (s), 557 (s), 427 (w). R_f(hexanes:EtOAc 9:1):

0.19.

1

(76.0 mg, 65%). mp: 126−128 °C. H NMR (500 MHz, CDCl₃) δ

7.95−7.91 (m, 2H), 7.84−7.81 (m, 2H), 7.56−7.52 (m, 1H), 7.51−

7.47 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H). ¹³C NMR (126

MHz, CDCl₃) δ 144.3, 142.1, 138.8, 133.1, 130.0, 129.4, 127.9, 127.6,

21.7. MS: m/z: calcd for C₁₃H₁₂O₂S+Na⁺255.05, found 255.10. IR

(cm⁻¹): 1592 (w), 1447 (m), 1305 (m, -SO₂-), 1293 (m), 1152 (s,

-SO₂-), 1105 (s), 1070 (m), 1043 (w), 1018 (w), 997 (w), 815 (m),

757 (w), 724 (s), 703 (m), 686 (s), 650 (s), 573 (s), 545 (s), 487 (m),

445 (w). R_f(hexanes:EtOAc 9:1):0.19.

4c:¹⁸Table 2, entry 3. 4c was prepared according to TP 1 from

benzenesulﬁnic acid lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol)

and bis(2,4,6-trimethylphenyl)iodonium triﬂate (3g) (257.2 mg, 0.50

mmol) in DMF (1.0 mL). Puriﬁcation by chromatography (cyclo-

hexane:EtOAc 20:1 → 9:1) yielded the product as a colorless solid

(87.3 mg, 67%). Table 5, entry 4: 4c was prepared according to TP 3

from benzenesulﬁnic acid magnesium chloride salt (2b) (55 wt %,

182.7 mg, 0.5 mmol) and bis(2,4,6-trimethylphenyl)iodonium triﬂate

(3g) (771.5 mg, 1.5 mmol) in DMSO (1.0 mL). Puriﬁcation by

column chromatography (hexanes:EtOAc 20:1 → 4:1) yielded the

product as a colorless solid (104.0 mg, 80%). Table 7, entry 3: 4c was

also prepared according to TP 4 from in situ-generated benzenesulﬁnic

acid zinc salt (2f) (assume 0.75 mmol) and bis(2,4,6-trimethylphenyl)-

iodonium triﬂate (3g) (257.2 mg, 0.5 mmol) in DMSO (1.0 mL).

Puriﬁcation by column chromatography (hexanes:EtOAc 20:1 → 9:1)

yielded the product as a colorless solid (44.6 mg, 34%). Table 10,

entry 1: Li: 4c was synthesized according to TP 1 from benzenesulﬁnic

acid lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol) and (2,4,6-

trimethylphenyl)(phenyl)iodonium triﬂate (3k) (236.1 mg, 0.50

mmol) in DMF (1.0 mL). Puriﬁcation by chromatography (cyclo-

hexane:EtOAc 20:1 →9:1) yielded the product as a colorless solid

(94.5 mg, 73%). Mg: 4c was prepared according to TP 3 from

benzenesulﬁnic acid magnesium chloride salt (2b) (55 wt %, 182.7 mg,

0.5 mmol) and bis(2,4,6-trimethylphenyl)iodonium triﬂate (3k)

(771.5 mg, 1.5 mmol) in DMSO (1.0 mL). Puriﬁcation by column

chromatography (hexanes:EtOAc 20:1 → 4:1) yielded the product as a

colorless solid (104.0 mg, 80%). Zn: 4c was prepared according to TP

4 from in situ-generated benzenesulﬁnic acid zinc salt (2f) (assume

0.75 mmol) and bis(2,4,6-trimethylphenyl)iodonium triﬂate (3k)

(257.2 mg, 0.5 mmol) in DMSO (1.0 mL). Puriﬁcation by column

chromatography (hexanes:EtOAc 20:1 → 9:1) yielded the product as a

4b:¹⁸Table 2, entry 2. 4b was prepared according to TP 1 from

benzenesulﬁnic acid lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol)

and bis(4-methylphenyl)iodonium triﬂate (3f) (229.1 mg, 0.50 mmol)

in DMF (1.0 mL). Puriﬁcation by chromatography (cyclohexane:E-

tOAc 20:1 → 9:1) yielded the product as a colorless solid (93.3 mg,

80%). Table 5, entry 2: According to TP 3, 4b was synthesized from

benzenesulﬁnic acid magnesium chloride salt (2b) (70 wt %, 215.3 mg,

0.75 mmol) and bis(2,4-dimethylphenyl)iodonium triﬂate (3f) (229.1

mg, 0.5 mmol) in DMSO (1.0 mL). Puriﬁcation by column

chromatography (hexanes:EtOAc 20:1 → 4:1) yielded the product

1

colorless solid (76.7 mg, 59%). mp: 82−84 °C. H NMR (500 MHz,

CDCl₃) δ 7.82−7.75 (m, 2H), 7.57−7.51 (m, 1H), 7.50−7.44 (m,

2H), 6.94 (s, 2H), 2.59 (s, 6H), 2.30 (s, 3H). ¹³C NMR (101 MHz,

CDCl₃) δ 143.6, 143.5, 140.2, 133.9, 132.7, 132.3, 129.0, 126.4,

23.0.95, 21.2. MS: m/z: calcd for C₁₅H₁₆O₂S+Na⁺283.08, found

283.13. IR (cm⁻¹): 1600 (m), 1447 (s), 1348 (m), 1290 (s), 1145 (s),

1093 (s), 1072 (m), 1050 (m), 1030 (s), 999 (m), 855 (s), 761 (s),

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645 (s), 585 (s), 572 (s), 530 (s) 495 (m). R_f(hexanes:EtOAc 9:1):

0.30.

chloride salt (2b) (55 wt %, 91.3 mg, 0.25 mmol) and bis(4-

methoxyphenyl)iodonium tosylate (3i) (380.1 mg, 0.75 mmol) in

DMSO (0.5 mL). Puriﬁcation by column chromatography (hexane-

s:EtOAc 9:1 → 4:1) yielded the product as a colorless solid (38.4 mg,

62%). Table 7, entry 5: 4e was prepared according to TP 4 from in

situ-generated benzenesulﬁnic acid zinc salt (2f) (assume 0.75 mmol)

and bis(4-methoxyphenyl)iodonium tosylate (3i) (256.2 mg, 0.5

mmol) in DMSO (0.5 mL). Puriﬁcation by column chromatography

(hexanes:EtOAc 9:1 → 4:1) yielded the product as a colorless solid

(86.0 mg, 70%). Table 9, entry 1: To a dry, Ar-ﬂushed Schlenk-ﬂask

equipped with a magnetic stirrer and a rubber septum charged with

bromo(4-methoxyphenyl)magnesium·LiCl⁶(1h) (0.9 M in THF, 0.85

mL; 0.75 mmol, 1.5 equiv) was added ZnCl₂(0.7 M in THF, 1.1 mL,

0.80 mmol, 1.6 equiv) and stirred at 25 °C for 30 min. After cooling to

−40 °C, liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added and the

mixture was allowed to warm to 25 °C within 90 min. After removal of

excess SO₂and solvents, diphenyliodonium triﬂate (3a) (215.1 mg, 0.5

mmol, 1.0 equiv) and DMSO (1.0 mL) were added and the reaction

mixture was heated to 90 °C and stirred at this temperature for 24 h.

After cooling to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was

added and the aqueous layer was extracted three times with CH₂Cl₂

(10 mL). The combined organic layers were washed with sat. aqueous

NaCl solution (10 mL) and dried over Na₂SO₄, and the solvents were

removed under reduced pressure. Puriﬁcation by column chromatog-

raphy (hexanes:EtOAc 9:1 → 4:1) aﬀorded the analytically pure

product as a colorless solid (55.1 mg, 44%). mp: 90−92 °C. ¹H NMR

(500 MHz, CDCl₃) δ 7.93−7.90 (m, 2H), 7.90−7.86 (m, 2H), 7.57−

7.51 (m, 1H), 7.51−7.45 (m, 2H), 6.99−6.93 (m, 2H), 3.84 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 163.5, 142.5, 133.2, 133.0, 130.0,

129.3, 127.4, 114.6, 55.8. MS: m/z: calcd for C₁₃H₁₂O₃S+Na⁺271.04,

found 271.09. IR (cm⁻¹): 1590 (s), 1576 (s), 1496 (s), 1464 (m),

1445 (s), 1315 (s, -SO₂-), 1297 (s), 1260 (s), 1185 (m), 1147 (s,

-SO₂-), 1104 (s), 1071 (s), 1019 (s), 998 (s), 832 (s), 802 (s), 755

(m), 728 (s), 709 (s), 686 (s), 628 (m), 576 (s), 552 (s), 453 (m). R_f

(hexanes:EtOAc 9:1): 0.22.

4d:¹⁸Table 2, entry 4. 4d was prepared according to TP 1 from

benzenesulﬁnic acid lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol)

and bis(2,4-dimethylphenyl)iodonium triﬂate (3h) (243.1 mg, 0.50

mmol) in DMF (1.0 mL). Puriﬁcation by chromatography (cyclo-

hexane:EtOAc 20:1 → 9:1) yielded the product as a colorless solid

(94.2 mg, 76%). Table 5, entry 3: According to TP 3, 4d was

synthesized from benzenesulﬁnic acid magnesium chloride salt (2b)

(70 wt %, 215.3 mg, 0.75 mmol) and bis(2,4-dimethylphenyl)-

iodonium triﬂate (3h) (243.2 mg, 0.5 mmol) in DMSO (1.0 mL).

Puriﬁcation by column chromatography (hexanes:EtOAc 9:1 → 4:1)

yielded the product as a colorless solid (68.5 mg, 56%). Table 7, entry

4: According to TP 2, 4d was prepared from in situ-generated

benzenesulﬁnic acid zinc salt (2f) (assume 0.75 mmol) and bis(2,4-

dimethylphenyl)iodonium triﬂate (3h) (243.2 mg, 0.5 mmol) in

DMSO (1.0 mL). Puriﬁcation by column chromatography (hexane-

s:EtOAc 9:1 → 4:1) yielded the product as a colorless solid (90.6 mg,

74%). mp: 110−111 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.04 (s, 1H),

7.88−7.82 (m, 2H), 7.60−7.54 (m, 1H), 7.53−7.46 (m, 2H), 7.28 (dd,

J = 7.7, 1.3 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 2.41 (s, 3H), 2.37 (s,

3H). ¹³C NMR (126 MHz, CDCl₃) δ 141.6, 138.5, 136.6, 134.9, 134.5,

133.1, 132.7, 129.9, 129.1, 127.7, 21.0, 19.8. MS: m/z: calcd for

C₁₄H₁₄O₂S+Na⁺269.06, found 269.11. IR (cm⁻¹): 3096 (w), 2923

(w), 1490 (w), 1450 (m), 1292 (s, -SO₂-), 1201 (w), 1154 (s, -SO₂-),

1143 (s, -SO₂-), 1092 (m), 1055 (m), 999 (w), 900 (w), 884 (w), 821

(m), 764 (m), 723 (s), 693 (m), 595 (s), 579 (s), 523 (s), 494 (m),

472 (w), 457 (m), 435 (w). R_f(hexanes:EtOAc 9:1): 0.27.

4e:¹⁸Table 2, entry 5. 4e was synthesized from benzenesulﬁnic acid

lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol) and bis(4-

methoxyphenyl)iodonium tosylate (3i) (256.2 mg, 0.50 mmol) in

DMF (1.0 mL). Puriﬁcation by chromatography (cyclohexane:EtOAc

9:1 → 1:1) yielded the product as a colorless solid (91.5 mg, 74%).

Table 3, entry 7: A dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was charged with 4-

bromoanisole (6d) (0.1 mL, 1.5 equiv, 0.75 mmol) in dry THF (1.0

mL) and cooled to −78 °C, and then nBuLi (0.38 mL, 2.13 M in

hexanes, 0.80 mmol, 1.6 equiv) was added dropwise (lithiation

according to ref 40). The mixture was stirred at this temperature for 2

h before liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added. After

warming to 25 °C within 90 min, excess SO₂and solvents were

removed according to procedure A. To the crude sulﬁnic acid lithium

salt were added diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol,

1.0 equiv) and DMF (1.0 mL). The reaction mixture was heated to 90

°C and stirred at this temperature for 24 h. After cooling to 25 °C, sat.

aqueous NH₄Cl solution (10 mL) was added and the aqueous layer

was extracted three times with CH₂Cl₂(15 mL). The combined

organic layers were washed with dist. H₂O (15 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (cyclohexane:EtOAc 9:1 →

4:1) yielded the product as a colorless solid (96.9 mg, 78%). Table 3,

entry 8: A dry, Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic

stirrer and a rubber septum was charged with 4-iodoanisole (6e)

(175.5 mg, 1.5 equiv, 0.75 mmol) in dry THF (1.0 mL) and cooled to

−78 °C, and then tBuLi (0.48 mL, 1.64 M in pentane, 0.8 mmol, 1.6

equiv) was added dropwise (lithiation according to ref 41). The

mixture was allowed to warm to −50 °C within 2 h before liquid SO₂

(0.1 mL, 5.0 mmol, 10.0 equiv) was added. After warming to 25 °C

within 90 min, excess SO₂and solvents were removed according to

procedure A. To the crude sulﬁnic acid lithium salt were added

diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and

DMF (1.0 mL). The reaction mixture was heated to 90 °C and stirred

at this temperature for 24 h. After cooling to 25 °C, sat. aqueous

NH₄Cl solution (10 mL) was added and the aqueous layer was

extracted three times with CH₂Cl₂(15 mL). The combined organic

layers were washed with dist. H₂O (15 mL) and dried over Na₂SO₄,

and the solvents were removed under reduced pressure. Puriﬁcation by

column chromatography (cyclohexane:EtOAc 9:1 → 4:1) yielded the

product as a colorless solid (65.2 mg, 53%). Table 5, entry 5: 4e was

prepared according to TP 3 from benzenesulﬁnic acid magnesium

4f:¹⁸Table 2, entry 6. 4f was prepared according to TP 1 from

benzenesulﬁnic acid lithium salt (2a) (65 wt %, 170.9 mg, 0.75 mmol)

and bis(4-chlorophenyl)iodonium triﬂate (3j) (249.5 mg, 0.50 mmol)

in DMF (1.0 mL). Puriﬁcation by chromatography (cyclohexane:E-

tOAc 20:1 → 9:1) yielded the product as a colorless solid (98.2 mg,

78%). Table 5, entry 6: 4f was prepared according to TP 3 from

benzenesulﬁnic acid magnesium chloride salt (2b) (55 wt %, 182.7 mg,

0.5 mmol) and bis(4-chlorophenyl)iodonium triﬂate (3j) (748.6 mg,

1.5 mmol) in DMSO (1.0 mL). Puriﬁcation by column chromatog-

raphy (hexanes:EtOAc 20:1 → 9:1) yielded the product as a colorless

solid (110.3 mg, 74%). Table 7, entry 6: 4f was prepared according to

TP 4 from in situ-generated benzenesulﬁnic acid zinc salt (2f) (assume

0.75 mmol) and bis(4-chlorophenyl)iodonium triﬂate (3j) (249.5 mg,

0.5 mmol) in DMSO (1.0 mL). Puriﬁcation by column chromatog-

raphy (hexanes:EtOAc 20:1 → 9:1) yielded the product as a colorless

solid (80.5 mg, 64%). mp: 94−96 °C. ¹H NMR (500 MHz, CDCl₃) δ

7.96−7.91 (m, 2H), 7.91−7.86 (m, 2H), 7.61−7.56 (m, 1H), 7.54−

7.49 (m, 2H), 7.49−7.45 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ

141.3, 140.3, 140.0, 133.6, 129.8, 129.6, 129.3, 127.8. MS: m/z: calcd

for C₁₂H₉ClO₂S+Na⁺274.99, found 275.04. IR (cm⁻¹): 1575 (m);

1474 (m), 1447 (m), 1391 (m), 1311 (s, -SO₂-), 1280 (m), 1177 (w),

1152 (s, -SO₂-), 1107 (s), 1085 (s), 1070 (s), 1028 (w), 10017 (m),

998 (m), 827 (m), 764 (s), 748 (s), 718 (s), 700 (m), 685 (s), 608 (s),

531 (s), 493 (s), 468 (m), 436 (m). R_f(hexanes:EtOAc 9:1): 0.22.

4g¹⁸(Table 3, entry 2): A dry, Ar-ﬂushed Schlenk-ﬂask equipped

with a magnetic stirrer and a rubber septum was charged with 1,3-

dimethoxybenzene (5b) (0.1 mL, 0.75 mmol, 1.5 equiv) in dry THF

(1.0 mL) and cooled to 0 °C with an ice-bath. At this temperature,

nBuLi (0.34 mL, 2.45 M solution in hexane, 0.83 mmol, 1.65 eqiuv)

was added dropwise and the mixture was stirred at 25 °C for 3.5 h

(lithiation according to ref 42). Then it was recooled to −30 °C, and

liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added at once. The

mixture was allowed to warm to 25 °C within 60 min, and then excess

SO₂was removed according to procedure A. To the crude sulﬁnic acid

lithium salt were added diphenyliodonium triﬂate (3a) (215.1 mg, 0.5

K

DOI: 10.1021/jo5027518

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

mmol, 1.0 equiv) and DMF (1.0 mL). The reaction mixture was

heated to 90 °C and stirred at this temperature for 24 h. After cooling

to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was added and the

aqueous layer was extracted three times with CH₂Cl₂(15 mL). The

combined organic layers were washed with dist. H₂O (15 mL) and

dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (cyclohexane:EtOAc

1:1) yielded the product as a colorless solid (110.3 mg, 79%). Table 3,

entry 3: To a solution of 2-iodo-1,3-dimethoxybenzene (6h) (198.1

mg, 0.75 mmol, 1.5 equiv) in dry hexanes (3.5 mL) in a dry, Ar-ﬂushed

Schlenk-ﬂask equipped with a magnetic stirrer and a rubber septum

was added nBuLi (0.40 mL, 2.13 M in hexane, 0.85 mmol, 1.65 equiv)

and the mixture stirred at 25 °C for 16 h (lithiation according to ref

43). After cooling to −78 °C, liquid SO₂(0.1 mL, 5.0 mmol, 10.0

equiv) was added and the mixture was allowed to warm to 25 °C

within 90 min. After removal of excess SO₂and solvents according to

procedure A, to the crude sulﬁnic acid lithium salt were added

diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and

DMF (1.0 mL). The reaction mixture was heated to 90 °C and stirred

at this temperature for 24 h. After cooling to 25 °C, sat. aqueous

NH₄Cl solution (10 mL) was added and the aqueous layer was

extracted three times with CH₂Cl₂(15 mL). The combined organic

layers were washed with dist. H₂O (15 mL) and dried over Na₂SO₄,

and the solvents were removed under reduced pressure. Puriﬁcation by

column chromatography (cyclohexane:EtOAc 4:1 → 1:1) yielded the

4:1) yielded the product as a colorless solid (120.2 mg, 97%). mp:

142−145 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.16 (dd, J = 7.9, 1.7

Hz, 1H), 8.00−7.94 (m, 2H), 7.58−7.52 (m, 2H), 7.51−7.45 (m, 2H),

7.13−7.08 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.75 (s, 3H). ¹³C NMR

(101 MHz, CDCl₃): δ = 157.2, 141.7, 135.6, 133.0, 130.0, 129.2,

128.6, 125.4, 120.7, 112.6, 56.00. MS: m/z: calcd for C₁₃H₁₂O₃S+Na⁺

271.04, found 271.40. IR (cm⁻¹): 1584 (m), 1479 (m), 1466 (m),

1452 (m), 1434 (m), 1304 (s, -SO₂-), 1280 (s), 1243 (m), 1180 (w),

1147 (s, -SO₂-), 1091 (s), 1059 (m), 1034 (m), 1014 (m), 799 (m),

164 (s), 733 (s), 717 (s), 692 (s), 584 (s), 559 (s), 537 (s), 509 (s),

469 (w), 448 (w). R_f(cyclohexane:EtOAc 9:1): 0.09.

4i¹⁸(Table 3, entry 6): A dry, Ar-ﬂushed Schlenk-ﬂask equipped

with a magnetic stirrer and a rubber septum was charged with nBuLi

(0.33 mL, 2.45 M in hexanes, 0.8 mmol, 1.6 equiv) and cooled to −70

°C. Then 3-bromoanisole (6c) (0.1 mL, 0.75 mmol, 1.5 equiv) was

added dropwise, and the reaction mixture stirred at this temperature

for 1 h (lithiation according to ref 40) before liquid SO₂(0.1 mL, 5.0

mmol, 10.0 equiv) was added. The mixture was allowed to warm to 25

°C within 90 min, and then excess SO₂and solvents were removed

according to procedure A. To the crude sulﬁnic acid lithium salt were

added diphenyliodonium triﬂate (3a) (215.1 mg, 0.5 mmol, 1.0 equiv)

and DMF (1.0 mL). The reaction mixture was heated to 90 °C and

stirred at this temperature for 24 h. After cooling to 25 °C, sat.

aqueous NH₄Cl solution (10 mL) was added and the aqueous layer

was extracted three times with CH₂Cl₂(15 mL). The combined

organic layers were washed with dist. H₂O (15 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (cyclohexane:EtOAc 9:1 →

4:1) yielded the product as a colorless solid (114.7 mg, 92%). mp: 89−

1

product as a colorless solid (103.0 mg, 74%). mp: 110−112 °C. H

NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 7.5 Hz, 2H), 7.55−7.42

(m, 3H), 7.39 (t, J = 8.4 Hz, 1H), 6.55 (d, J = 8.5 Hz, 2H), 3.75 (s,

6H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.6, 144.6, 135.1, 132.4,

128.3, 127.4, 118.1, 105.4, 56.6. MS: m/z: calcd for C₁₄H₁₄O₄S+Na⁺

301.05, found 301.30. IR (cm⁻¹): 2977 (w), 2945 (w), 1577 (s),1476

(s), 1427 (s), 1318 (m, -SO₂-), 1305 (s, -SO₂-), 1290 (m), 1254 (s),

1188 (w), 1150 (s, -SO₂-), 1107 (s), 1088 (s), 1043 (m), 1023 (m),

780 (s), 754 (s), 713 (m), 695 (s), 649 (m), 612 (m), 572 (s), 560 (s),

496 (m), 472 (m). R_f(cyclohexane:EtOAc 9:1): 0.05.

1

91 °C. H NMR (500 MHz, CDCl₃): δ = 7.98−7.91 (m, 2H), 7.59−

7.54 (m, 1H), 7.53−7.48 (m, 3H), 7.46−7.43 (m, 1H), 7.40 (t, J = 8.0

Hz, 1H), 7.07 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 3.84 (s, 3H). ¹³C NMR

(126 MHz, CDCl₃): δ = 160.2, 142.8, 141.7, 133.3, 130.5, 129.4,

127.8, 120.1, 119.7, 112.4, 55.8. MS: m/z: calcd for C₁₃H₁₂O₃S+Na⁺

271.04, found 271.13. IR (cm⁻¹): 1592 (m), 1474 (m), 1447 (s), 1421

(m), 1298 (s, -SO₂-), 1245 (s), 1181 (m), 1148 (s, -SO₂-), 1099 (s),

1069 (m), 1026 (s), 992 (m), 925 (w), 865 (m), 842 (w), 790 (s), 755

(w), 723 (s), 678 (s), 609 (s), 571 (s), 526 (s), 471 (m); 458 (m), 421

(w). R_f(cyclohexane:EtOAc 9:1): 0.15.

4h¹⁸(Table 3, entry 4): To a solution of anisole (5c) (0.82 mL,

0.75 mmol, 1.5 equiv) and TMEDA (0.22 mL, 1.5 mmol, 3.0 equiv) in

dry Et₂O (1.0 mL) in a dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was added nBuLi (0.61 mL, 2.45

M in hexanes, 1.5 mmol, 3.0 equiv) dropwise (lithiation according to

ref 44). The mixture was stirred at 25 °C for 30 min and then cooled

to −78 °C, and liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added.

After warming to 25 °C within 90 min, excess SO₂and solvents were

removed by procedure A. To the crude sulﬁnic acid lithium salt were

added diphenyliodonium triﬂate (3a) (215.1 mg, 0.5 mmol, 1.0 equiv)

and DMF (1.0 mL). The reaction mixture was heated to 90 °C and

stirred at this temperature for 24 h. After cooling to 25 °C, sat.

aqueous NH₄Cl solution (10 mL) was added and the aqueous layer

was extracted three times with CH₂Cl₂(15 mL). The combined

organic layers were washed with dist. H₂O (15 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (cyclohexane:EtOAc 20:1 →

4:1) yielded the product as a colorless solid (75.7 mg, 61%). Table 3,

entry 5: A dry, Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic

stirrer and a rubber septum was charged with nBuLi (0.33 mL, 2.45 M

in hexanes, 0.80 mmol, 1.6 equiv) and cooled to −78 °C. Then 2-

bromoanisole (6b) (0.1 mL, 0.75 mmol, 1.5 equiv) was added

dropwise, and the reaction mixture stirred at this temperature for 1 h

(lithiation according to ref 40) before liquid SO₂(0.1 mL, 5.0 mmol,

10.0 equiv) was added. The mixture was allowed to warm to 25 °C

within 90 min, and then excess SO₂and solvents were removed

according to procedure A. To the crude sulﬁnic acid lithium salt were

added diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0

equiv) and DMF (1.0 mL). The reaction mixture was heated to 90 °C

and stirred at this temperature for 24 h. After cooling to 25 °C, sat.

aqueous NH₄Cl solution (10 mL) was added and the aqueous layer

was extracted three times with CH₂Cl₂(15 mL). The combined

organic layers were washed with dist. H₂O (15 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (cyclohexane:EtOAc 9:1 →

4j¹⁸(Table 3, entry 9): To a solution of 1-bromo-2,4-

dimethoxybenzene (6f) (0.11 mL, 0.75 mmol, 1.5 equiv) in dry

THF (1.0 mL) in a dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was added nBuLi (0.56 mL, 1.2

mmol, 2.4 equiv) dropwise at 25 °C and then stirred for 2 h (lithiation

according to ref 45). After cooling to −78 °C, liquid SO₂(0.1 mL, 5.0

mmol, 10.0 equiv) was added. After warming to 25 °C within 90 min,

excess SO₂and solvents were removed according to procedure A. To

the crude sulﬁnic acid lithium salt were added diphenyliodonium

triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and DMF (1.0 mL).

The reaction mixture was heated to 90 °C and stirred at this

temperature for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl

solution (10 mL) was added and the aqueous layer was extracted three

times with CH₂Cl₂(15 mL). The combined organic layers were

washed with dist. H₂O (15 mL) and dried over Na₂SO₄, and the

solvents were removed under reduced pressure. Puriﬁcation by column

chromatography (cyclohexane:EtOAc 9:1 → 1:1) yielded the product

as a colorless solid (58.4 mg, 42%). mp: 107−109 °C. ¹H NMR: (500

MHz, CDCl₃): δ = 8.08 (d, J = 8.8 Hz, 1H), 7.96−7.92 (m, 2H),

7.56−7.51 (m, 1H), 7.49−7.44 (m, 2H), 6.58 (dd, J = 8.8, 2.3 Hz,

1H), 6.38 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H). ¹³C NMR:

(101 MHz, CDCl₃): δ = 165.8, 158.8, 142.3, 132.7, 131.9, 128.6,

128.2, 121.5, 104.8, 99.6, 556.00, 55.9. MS: m/z: calcd for C₁₄H₁₄O₄S

+Na⁺301.05, found 302.30. HRMS: m/z: calcd for C₁₄H₁₄O₄S+H⁺

279.06856, found 279.06858. IR (cm⁻¹): 1578 (m), 1489 (w), 1458

(m), 1432 (w), 1408 (w), 1321 (m, -SO₂-), 1299 (S, -SO₂-), 1251

(m), 1210 (s), 1144 (s), 1145 (s, -SO₂-), 1091 (s), 1064 (s), 1020 (s),

938 (w), 920 (m), 840 (w), 829 (m), 813 (w), 792 (w), 765 (m), 733

(s), 708 (m), 691 (s), 658 (m), 641 (m), 592 (s), 555 (s), 528 (s), 470

(w), 454 (m). R_f(cyclohexane:EtOAc 9:1): 0.08.

L

DOI: 10.1021/jo5027518

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The Journal of Organic Chemistry

Article

4k¹⁸(Table 3, entry 10): A dry, Ar-ﬂushed Schlenk-ﬂask equipped

with a magnetic stirrer and a rubber septum was charged with nBuLi

(0.38 mL, 2.13 M in hexanes, 0.8 mmol, 1.6 equiv) in dry Et₂O (1.0

mL) and cooled to 0 °C. At this temperature, 3-bromobenzotriﬂuoride

(6g) (0.1 mL, 0.75 mmol, 1.5 equiv) was added dropwise and the

mixture stirred for 1 h at 0 °C (lithiation according to ref 46). Then it

was cooled to −78 °C, and liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv)

was added. After warming to 25 °C within 90 min, excess SO₂and

solvents were removed according to procedure A. To the crude sulﬁnic

acid lithium salt were added diphenyliodonium triﬂate (3a) (215.1 mg,

0.50 mmol, 1.0 equiv) and DMF (1.0 mL). The reaction mixture was

heated to 90 °C and stirred at this temperature for 24 h. After cooling

to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was added and the

aqueous layer was extracted three times with CH₂Cl₂(15 mL). The

combined organic layers were washed with dist. H₂O (15 mL) and

dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (cyclohexane:EtOAc

20:1 → 9:1) yielded the product as a colorless solid (106.3 mg, 74%).

Table 3, entry 11: A dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was charged with nBuLi (0.38

mL, 2.13 M in hexanes, 0.8 mmol, 1.6 equiv) in dry Et₂O (1.0 mL)

and cooled to −78 °C. At this temperature, 3-iodobenzotriﬂuoride

(6h) (0.1 mL, 0.75 mmol, 1.5 equiv) was added dropwise and the

mixture stirred for 1 h at −78 °C (lithiation according to ref 47). Then

liquid SO₂(0.1 mL, 5.0 mmol, 10 equiv) was added. After warming to

25 °C within 90 min, excess SO₂and solvents were removed according

to procedure A. To the crude sulﬁnic acid lithium salt were added

diphenyliodonium triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and

DMF (1.0 mL). The reaction mixture was heated to 90 °C and stirred

at this temperature for 24 h. After cooling to 25 °C, sat. aqueous

NH₄Cl solution (10 mL) was added and the aqueous layer was

extracted three times with CH₂Cl₂(15 mL). The combined organic

layers were washed with dist. H₂O (15 mL) and dried over Na₂SO₄,

and the solvents were removed under reduced pressure. Puriﬁcation by

column chromatography (cyclohexane:EtOAc 20:1 → 9:1) yielded the

product as a colorless solid (118.9 mg, 83%). Table 6, entry 6: A dry,

Ar-ﬂushed Schlenk-ﬂask equipped with a magnetic stirrer and a rubber

septum was charged with iPrMgCl·LiCl in THF (in total 1.5 mL

solvent) (1.04 M in THF, 0.53 mL, 0.55 mmol, 1.1 equiv) and cooled

to −20 °C. Then 3-bromobenzotriﬂuoride (6g) (72 μL, 0.50 mmol,

1.0 equiv) was added dropwise. After complete addition, the mixture

was stirred at this temperature for 30 min. Then it was cooled to −40

°C, liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added, and the

mixture was allowed to warm to 25 °C within 90 min. After removal of

excess SO₂and solvents, diphenyliodonium triﬂate (3a) (643.3 mg, 1.5

mmol, 3.0 equiv) and DMSO (1.0 mL) were added and the reaction

mixture was heated to 90 °C and stirred at this temperature for 24 h.

After cooling to 25 °C, sat. aqueous NH₄Cl solution (10 mL) was

added and the aqueous layer was extracted three times with CH₂Cl₂

(10 mL). The combined organic layers were washed with sat. aqueous

NaCl solution (10 mL) and dried over Na₂SO₄, and the solvents were

removed under reduced pressure. Puriﬁcation by column chromatog-

raphy (hexanes:EtOAc 9:1) aﬀorded the analytically pure product as a

colorless solid (53.3 mg, 38%). Table 9, entry 4: To a solution of

iPrMgCl·LiCl in THF (1.04 M in THF, 0.53 mL, 0.55 mmol, 1.1

equiv) cooled to −20 °C was added 3-iodobenzotriﬂuoride (6h) (72

μL, 0.5 mmol, 1.0 equiv). After stirring 30 min at this temperature,

ZnCl₂(0.7 M in THF, 0.79 mL, 0.55 mmol, 1.1 equiv) was added and

the mixture was allowed to warm to 25 °C. After cooling to −40 °C,

liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was added and the mixture

was allowed to warm to 25 °C within 90 min. After removal of excess

SO₂and solvents, diphenyliodonium triﬂate (3a) (645.3 mg, 1.5

mmol, 3.0 equiv) and DMF (1.0 mL) were added and the mixture was

stirred at 90 °C for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl

solution (10 mL) was added and the aqueous layer was extracted three

times with CH₂Cl₂(10 mL). The combined organic layers were

washed with sat. aqueous NaCl solution (10 mL) and dried over

Na₂SO₄, and the solvents were removed under reduced pressure.

Puriﬁcation by column chromatography (hexanes:EtOAc 9:1 → 4:1)

aﬀorded the product as a colorless solid (105.8 mg, 74%). mp: 82−84

°C. ¹H NMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 8.13 (d, J = 7.9 Hz,

1H), 8.00−7.95 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.9 Hz,

1H), 7.64−7.60 (m, 1H), 7.57−7.53 (m, 2H). ¹³C NMR (126 MHz,

CDCl₃) δ 143.1, 140.8, 133.9, 132.2 (q, J = 33.6 Hz), 130.3, 130.0 (q, J

= 3.5 Hz), 129.7, 128.0, 124.8 (q, J = 3.9 Hz), 123.2 (q, J = 273.0 Hz).

MS: m/z: calcd for C₁₃H₉F₃O₂S+Na⁺309.02, found 309.07. IR

(cm⁻¹): 3064 (w), 1737 (w), 1609 (w), 1586 (w), 1480 (w), 1449

(w), 1432 (w), 1323 (s, -SO₂-), 1306 (s, -SO₂-), 1180 (m), 1155 (s,

-SO₂-), 1124 (s, -SO₂-), 1109 (s), 1067 (s), 998 (w), 930 (m), 842

(w), 821 (w), 803 (m), 757 (m), 731 (s), 686 (s), 649 (m), 634 (m),

584 (s), 553 (s), 500 (m), 459 (w), 424 (w), 407 (w). R_f

(hexanes:EtOAc 9:1): 0.16.

4l¹⁸(Table 3, entry 12): To a solution of sBuLi (0.70 mL, 1.2 M in

cyclohexane, 0.83 mmol, 1.65 equiv) and TMEDA (0.12 mL, 0.83

mmol, 1.65 equiv) in a dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was added N,N-diisopropylben-

zamide (5d) (154.0 mg, 0.75 mmol, 1.5 equiv) in dry THF (1.0 mL)

at −78 °C (lithiation according to ref 48). The mixture was stirred for

1 h at this temperature, and then liquid SO₂(0.1 mL, 5.0 mmol, 10.0

equiv) was added. The reaction was allowed to warm to 25 °C within

90 min. After removing excess SO₂by procedure B, diphenyliodonium

triﬂate (3a) (215.1 mg, 0.5 mmol, 1.0 equiv) and DMF (1.0 mL) were

added and the reaction was stirred at 90 °C for 24 h. After cooling to

25 °C, sat. aqueous NH₄Cl solution (10 mL) was added and the

aqueous layer was extracted three times with CH₂Cl₂(15 mL). The

combined organic layers were washed with dist. H₂O (15 mL) and

dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (cyclohexane:EtOAc

4:1) yielded the product as a colorless solid (117.5 mg, 68%). mp:

198−200 °C. ¹H NMR (400 MHz, CDCl3): δ = 8.11−8.07 (m, 2H),

8.05 (d, J = 7.4 Hz, 1H), 7.58−7.44 (m, 5H), 7.22 (d, J = 6.8 Hz, 1H),

3.68−3.50 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H), 1.55 (d, J = 6.8 Hz, 3H),

1.30 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H). ¹³C NMR (101

MHz, CDCl₃): δ = 167.9, 141.7, 138.5, 137.7, 133.6, 133.3, 130.4,

129.1, 129.0, 128.5, 127.0, 51.5, 46.0, 20.6, 20.5, 19.9, 19.6. MS: m/z:

calcd for C₁₉H₂₃NO₃S+Na⁺368.13, found 368.30. HRMS: m/z: calcd

for C₁₉H₂₃NO₃S+H⁺346.14714, found 346.14703. IR (cm⁻¹): 1628

(s), 1476 (w), 1442 (m), 1371 (m), 1340 (m, -SO₂-), 1317 (s, -SO₂-),

1297 (w), 1212 (w), 1186 (w), 1153 (s, -SO₂-), 1130 (m, -SO₂-), 1105

(m), 1090 (w), 1058 (w), 1035 (w), 782 (m), 759 (m), 730 (m), 710

(m), 688 (m), 656 (w), 590 (s), 568 (s), 533 (w), 502 (w).R_f

(cyclohexane:EtOAc 9:1): 0.07

4m¹⁸(Table 3, entry 13): To a solution of sBuLi (0.70 mL, 1.2 M in

cyclohexane, 0.83 mmol, 1.65 equiv) and TMEDA (0.12 mL, 0.83

mmol, 1.65 equiv) in a dry, Ar-ﬂushed Schlenk-ﬂask equipped with a

magnetic stirrer and a rubber septum was added phenyl

diethylcarbamate (5e) (154.0 mg, 0.75 mmol, 1.5 equiv) at −78 °C

(lithiation according to ref 49). The mixture was stirred for 1 h at this

temperature, and then liquid SO₂(0.1 mL, 5.0 mmol, 10.0 equiv) was

added. The reaction was allowed to warm to 25 °C within 90 min.

After removing excess SO₂by procedure A, to the crude sulﬁnic acid

lithium salt were added diphenyliodonium triﬂate (3a) (215.1 mg, 0.5

mmol, 1.0 equiv) and DMF (1.0 mL) and the reaction was stirred at

90 °C for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl solution

(10 mL) was added and the aqueous layer was extracted three times

with CH₂Cl₂(15 mL). The combined organic layers were washed with

dist. H₂O (15 mL) and dried over Na₂SO₄, and the solvents were

removed under reduced pressure. Puriﬁcation by column chromatog-

raphy (cyclohexane:EtOAc 50:1 → 9:1) yielded the product as a

1

colorless solid (77.8 mg, 47%). mp: 92−93 °C. H NMR (500 MHz,

CDCl₃): δ = 8.15 (dd, J = 7.9, 1.6 Hz, 1H), 7.88−7.80 (m, 2H), 7.65−

7.52 (m, 2H), 7.52−7.42 (m, 2H), 7.37 (td, J = 7.8, 1.1 Hz, 1H), 7.21

(dd, J = 8.2, 0.9 Hz, 1H), 3.43 (q, J = 7.1 Hz, 2H), 3.23 (q, J = 7.1 Hz,

2H), 1.21 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H). ¹³C NMR (126

MHz, CDCl₃): δ = 152.4, 149.4, 141.5, 134.9, 133.3, 132.7, 130.1,

129.0, 127.4, 125.5, 125.1, 42.2, 41.9, 14.3, 13.3. MS: m/z: calcd for

C₁₇H₁₉NO₄S+H⁺334.10, found 334.45. HRMS: m/z: calcd for

C₁₇H₁₉NO₄S+K⁺372.06664, found 372.06664. IR (cm⁻¹): 2983

(w), 1723 (s), 1468 (w), 1448 (w), 1410 (m), 1382 (w), 1321 (s,

-SO₂-), 1257 (s), 1201 (s), 1141 (s, -SO₂-), 1093 (s), 1060 (m), 1040

M

DOI: 10.1021/jo5027518

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(w), 999 (w), 950 (m), 838 (w), 824 (w), 788 (w), 771 (m), 750 (w),

731 (s), 718 (m), 691 (s), 586 (s), 567 (s), 507 (m). R_f

(cyclohexane:EtOAc 4:1): 0.17.

layer was extracted three times with CH₂Cl₂(10 mL). The combined

organic layers were washed with sat. aqueous NaCl solution (10 mL)

and dried over Na₂SO₄, and the solvents were removed under reduced

pressure. Puriﬁcation by column chromatography (hexanes:EtOAc

9:1) aﬀorded the analytically pure product as a colorless solid (66.4

mg, 59%). mp: 122−123 °C. ¹H NMR 500 MHz, CDCl₃) δ 8.02−7.96

(m, 2H), 7.70 (dd, J = 3.8, 1.3 Hz, 1H), 7.64 (dd, J = 5.0, 1.3 Hz, 1H),

7.60−7.56 (m, 1H), 7.54−7.50 (m, J = 10.4, 4.7 Hz, 2H), 7.08 (dd, J =

4.9, 3.8 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 143.2, 142.2, 134.0,

133.5, 133.4, 129.5, 128.07.99, 127.5. MS: m/z: calcd for

C₁₀H₁₈O₂S₂+Na⁺246.99, found 247.03. IR (cm⁻¹): 3093 (w), 1503

(w), 1445 (m), 1398 (m), 1343 (w, -SO₂-), 1314 (s, -SO₂-), 1302 (s),

1228 (m), 1147 (s, -SO₂-), 1002 (m), 1081 (m), 11067 (m), 1014 (s),

998 (m), 923 (w), 855 (m), 753 (m), 722 (s), 682 (s), 660 (s), 590

(s), 567 (s), 451 (w), 437 (m). R_f(hexanes:EtOAc 9:1): 0.17.

4o¹⁸(Table 3, entry 15): A dry, Ar-ﬂushed Schlenk-ﬂask equipped

with a magnetic stirrer and a rubber septum was charged with N-

methylpyrrole (5g) (66 μL, 0.75 mmol, 1.5 equiv) and TMEDA (0.12

mL, 0.83 mmol, 1.65 equiv), and then nBuLi (0.34 mL, 2.45 M in

hexanes, 0.83 mmol, 1.65 equiv) was added dropwise and the mixture

was heated to 55 °C for 15 min (lithiation according to ref 50). The

mixture was then cooled to −78 °C, and liquid SO₂(0.1 mL, 5.0

mmol, 10.0 equiv) was added. After warming to 25 °C within 90 min,

excess SO₂and solvents were removed according to procedure A. To

the crude sulﬁnic acid lithium salt were added diphenyliodonium

triﬂate (3a) (215.1 mg, 0.50 mmol, 1.0 equiv) and DMF (1.0 mL).

The reaction mixture was heated to 90 °C and stirred at this

temperature for 24 h. After cooling to 25 °C, sat. aqueous NH₄Cl

solution (10 mL) was added and the aqueous layer was extracted three

times with CH₂Cl₂(15 mL). The combined organic layers were

washed with dist. H₂O (15 mL) and dried over Na₂SO₄, and the

solvents were removed under reduced pressure. Puriﬁcation by column

chromatography (cyclohexane:EtOAc 9:1 → 4:1) yielded the product

4n¹⁸(Table 3, entry 14): A dry, Ar-ﬂushed Schlenk-ﬂask equipped

with a magnetic stirrer and a rubber septum was charged with nBuLi

(0.34 mL, 2.45 M in hexanes, 0.83 mmol, 1.5 equiv) and cooled to

−78 °C. Then thiophene (5f) (0.06 mL, 0.75 mmol, 1.5 equiv) was

added dropwise, and the mixture was allowed to warm to 0 °C and

stirred at this temperature for 2 h (lithiation according to ref 22b).

Then it was recooled to −78 °C, and liquid SO₂(0.1 mL, 5.0 mmol,

10.0 equiv) was added. After warming to 25 °C within 90 min, excess

SO₂and solvents were removed by procedure A. To the crude sulﬁnic