A Class of Amide Ligands Enable Cu-Catalyzed Coupling of (Hetero)aryl Halides with Sulfinic Acid Salts under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.8b00888

The amide derived from 4-hydroxy-l-proline and 2,6-dimethylaniline is a powerful ligand for Cu-catalyzed coupling of (hetero)aryl halides with sulfinic acid salts, allowing the formation of a wide range of (hetero)aryl sulfones from the corresponding (hetero)aryl halides at considerably low catalytic loadings. The coupling of (hetero)aryl iodides and sodium methanesulfinate proceeds at room temperature with only 0.5 mol % CuI and ligand, representing the first example for Cu-catalyzed arylation at both low catalytic loading and room temperature.

Full text of DOI:10.1021/acs.joc.8b00888

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Article
A Class of Amide Ligands Enable Cu-Catalyzed Coupling of
(Hetero)aryl Halides with Sulfinic Acid Salts under Mild Conditions
Jinlong Zhao, Songtao Niu, Xi Jiang, Yongwen Jiang, Xiaojing Zhang, Tiemin Sun, and Dawei Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00888 • Publication Date (Web): 22 May 2018
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A Class of Amide Ligands Enable Cu-Catalyzed Coupling of
(Hetero)aryl Halides with Sulfinic Acid Salts under Mild
Conditions
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Jinlong Zhao,1 Songtao Niu,1 Xi Jiang,2 Yongwen Jiang,2 Xiaojing Zhang,1 Tiemin
Sun1* and Dawei Ma2*
1Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang
Pharmaceutical University, Ministry of Education, Shenyang 110016, China
2State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, China
suntiemin@126.com, madw@sioc.ac.cn
Abstract
The amide derived from 4ꢀhydroxyꢀLꢀproline and 2,6ꢀdimethylaniline is a
powerful ligand for Cuꢀcatalyzed coupling of (hetero)aryl halides with sulfinic acid
salts, allowing the formation of a wide range of (hetero)aryl sulfones from the
corresponding (hetero)aryl halides at considerably low catalytic loadings. The
coupling of (hetero)aryl iodides and sodium methanesulfinate proceeds at room
temperature with only 0.5 mol % CuI and ligand, representing the first example for
Cuꢀcatalyzed arylation at both low catalytic loading and room temperature.
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Introduction
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Aryl sulfone has been one of the top 5 most frequently used scaffolds in drug
structure on the basis of 6932 FDAꢀapproved drugs and experimental drugs.1 The
prominent drugs containing aryl sulfone unit include two recently approved
antiꢀtumor drugs Ceritinib2 (Figure 1) and Vismodegib;3 antipsychotic drug
Amisulpride,4 Intepirdine5 in phase III clinical trials for treatment Alzheimer's disease,
and Xiidra6 for the treatment of signs and symptoms of dry eye disease.
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Figure 1．Structures of some pharmaceutically important (hetero)aryl sulfones
The classical method for preparing aryl sulfones is direct sulfonylation of arenes.
This approach is not favorable for lateꢀstage manipulation in medicinal chemistry
because of its unsatisfactory regioselectivity and poor functional group tolerance.7
During the past decades, considerable efforts have been attempted to develop new
methods for preparing aryl sulfones.7ꢀ13 Among emerging methods, Cu or
Pdꢀcatalyzed arylation of sulfinic acid salts has received more and more attention and
has been applied in the assembly of designed aryl sulfones.6ꢀ12 Several aromatic
electrophiles have been demonstrated as suitable substrates in this transformation,
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which include (hetero)aryl halides,8,9 aryl boronic acids,10 arenediazonium salts11 and
nitroarenes.12 Although the progress in this area is significant, further improvements
are still needed. For example, aryl chlorides as the cheapest and most abundant
aromatic electrophiles are difficult substrates for either Cuꢀ or Pdꢀcatalyzed coupling
reaction,7ꢀ9 while higher catalytic loadings (>10 mol % for both copper salt and ligand)
are required for Cuꢀcatalyzed coupling with aryl iodides and bromides.8 Additionally,
limited reaction scope was seen in case of aryl bromides as the coupling partners.
Recently, we reported the first metalꢀcatalyzed coupling reaction of (hetero)aryl
chlorides with sodium methanesulfinate by combining CuI and a new class of amide
ligands with hybrid structures of 4ꢀhydroxyꢀLꢀproline and oxalic diamides (Figure
2).14 During our studies on copper salts/oxalic diamides catalyzed coupling
reactions,15 we found that when ligands that were suitable for Cuꢀcatalyzed coupling
reactions with (hetero)aryl chlorides, were applied for coupling reactions with more
reactive (hetero)aryl bromides and iodides, both catalytic loadings and reaction
temperatures could be greatly reduced. Accordingly, we explored the possibility if a
more practical method for preparing aryl sulfones could be discovered by using these
newlyꢀdeveloped amide ligands.
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Figure 2. CuI/pyrrolidineꢀ2ꢀcarboxamideꢀcatalyzed coupling reactions of (hetero)aryl
halides with sulfinic acid salts
Results and Discussions
Because CuI/Lꢀproline could not efficiently catalyze the coupling of (hetero)aryl
bromides and relatively bulky sodium benzenesulfinate,8c we chose the coupling of
4ꢀbromoanisole with sodium benzenesulfinate as a model reaction to screen suitable
ligands, and the results are summarized in Table 1. Initially, we examined
(2S,4R)ꢀ4ꢀhydroxyꢀNꢀ(2ꢀmethylnaphthalenꢀ1ꢀyl)pyrrolidineꢀ2ꢀcarboxamide
(L1,
HMNPC),14 the best ligand for Cu
-catalyzed coupling reaction of (hetero)aryl
chlorides and sodium methanesulfinate. It was found that under the action of 2 mol %
CuI and L1, the reaction completed after 24 h at 100 oC to afford
1ꢀmethoxyꢀ4ꢀ(phenylsulfonyl)benzene (2a) in 99% yield (entry 1). The hydroxyl
group in this ligand seemed to play an important role, as evident from that the yield
decreased dramatically in case of L2 as the ligand (entry 2). The similar trend was
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seen when aniline part was changed to naphthaleneꢀ1ꢀyl or 2,6ꢀdimethylphenyl
(entries 3ꢀ6). When benzylamineꢀderived ligand L7 was used, a poor yield was
observed (entry 7), indicating that the aromatic amides are better ligands than
aliphatic ones. Almost no conversion was observed in case of Lꢀproline, implying that
the amido moiety in the ligands is essential for this transformation. We also examined
two oxalic diamides that showed excellent activity in Cuꢀcatalyzed amination of aryl
chlorides,15a,15c and found that they are less powerful than prolineꢀderived
monoꢀamides (entries 9 and 10). Since L1 and L6 ((2S,4R)ꢀNꢀ(2,6ꢀdimethylphenyl)ꢀ
4ꢀhydroxypyrrolidineꢀ2ꢀcarboxamide, DMPHPC) gave the almost same results and
2,6ꢀdimethylaniline is much cheaper than (2ꢀmethylnaphthalenꢀ1ꢀyl)amine, we
decided to use L6 as the ligand for subsequent reaction scope study. The excellent
performance displayed by L1 and L6 might partially result from the better solubility
of the corresponding copper salts. Among the solvents examined, DMSO gave the
best result, tꢀBuOH or 2ꢀmethoxyethanol could serve as the alternative solvents
(entries 11 and 12), while DMF or dioxane gave no conversion (entries 13 and 14).
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Table 1. CuI/LigandꢀCatalyzed Coupling of 4ꢀBromoanisole and Sodium
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Benzenesulfinatea
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Entry
Ligand
L1
Yield (%)b
Entry
8
Ligand
L8
Yield (%)b
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99
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94
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trace
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L2
L9
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L3
L10
L6
82c
74d
0e
L4
L5
L6
L6
L6
0f
L7
L6
aReaction conditions: 1a (5 mmol), PhSO2Na (6.5 mmol), CuI (0.1 mmol), ligand (0.1
o
b
1
mmol), K3PO4 (5 mmol), DMSO (2.5 mL), 100 C, 24 h. Determined by H NMR
c
d
analysis of the crude product using CH2Br2 as the internal standard. In tꢀBuOH. In
2ꢀmethoxyethanol. eIn DMF. fIn 1,4ꢀdioxane.
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By employing L6 as the ligands, we examined the coupling reaction with a series
of (hetero)aryl bromides and sulfinic acid salts. As illustrated in Table 2, under the
catalysis of 2 mol % CuI and L6, coupling reaction completed at 100 oC in most cases
to afford the corresponding diaryl sulfones 2aꢀ2l in 62ꢀ98% yields. The substrates
with coordination ability such as amino (2k) and amido (2e) moieties required higher
catalytic loadings (5 mol %) to ensure a complete conversion. Additionally, a variety
of heteroaryl bromides were applicable under these conditions to afford the
corresponding heteroaryl sulfones 2mꢀ2s. Using sodium isopropylsulfinate as a
coupling partner, 2ꢀ(isopropylsulfonyl)aniline 3a was obtained in 70% yield. In this
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case complete conversion was observed at 90 C. Similarly, a large number of
substituted aryl and heteroaryl bromides coupled smoothly with sodium
methanesulfinate at 90 oC, delivering (hetero)aryl methylsulfones 4aꢀ4o and 4qꢀ4z in
good to excellent yields. However, coupling reaction of 2ꢀmethylbromobenzene was
quite sluggish, and only 29% yield of 4p was obtained even using 5 mol % CuI and
L6. This result indicated that the present coupling was very sensitive to steric
hindrance.
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Table 2. CuI/L6 Catalyzed Coupling of (Hetero)aryl Bromides with Sulfinic Acid
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Saltsa
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aRaection condition: (hetero)aryl bromide (5 mmol), RSO2Na (6.5 mmol), K3PO4 (5
mmol), CuI (0.1 mmol), L6 (0.1 mmol), DMSO (3 mL), 100 oC (for producing 2), or
o
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c
90 C (for producing 3 and 4), 24 h. 5 mol % CuI and L6 were used. 10 mmol of
K3PO4 was used.
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Since earlier report on Cu/ligandꢀcatalyzed coupling reactions of aryl iodides and
sulfinic acid salts required more than 10 mol % copper salts and ligands with reaction
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temperature at 90ꢀ110 C,8 we next investigated whether the catalytic system of
CuI/L6 could lead to milder reaction conditions. To our delight, under the catalysis of
0.5 mol % CuI and L6, the coupling reaction of 4ꢀiodoanisole with sodium
methanesulfinate proceeded at room temperature to afford 4a in 98% yield (Table 3).
Further studies illustrated that a wide range of 4ꢀsubstituted aryl iodides are
compatible with these reaction conditions, providing the corresponding aryl
methylsulfones in good to excellent yields. Generally, electronꢀpoor aryl iodides are
less reactive than electronꢀrich ones, and therefore in some cases increased catalytic
loadings and reaction temperatures were required to get complete conversion (4ab,
o
4j-4l, 4ac). Some 3ꢀsubstituted aryl iodides also worked well at rtꢀ50 C to give the
related coupling products in good yields. The coupling of several heteroaryl iodides
could also run at room temperature, leading to the formation of 4ahꢀ4aj and 4x in
62ꢀ91% yields. The 2ꢀaminoꢀ5ꢀiodopyridine was less reactive than other heteroaryl
iodides, presumably because the aminopyridine moiety could coordinate with Cu and
therefore reduce the activity of the present catalytic system.
When more bulky sulfinic acid salts were used, the coupling reaction turned out
to be slow. But they gave satisfactory results when the coupling reaction was
conducted at rtꢀ50 oC with the employment of 1ꢀ5 mol % CuI and L6 as the catalysts.
Noteworthy is that sodium benzenesulfinate and sodium pyridineꢀ3ꢀsulfinate were
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workable under these conditions, providing a variety of diaryl (2a, 2f and 2g),
arylꢀheteroaryl (2n, 2t and 5a) and diheteroaryl sulfones (5b).
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Table 3. CuI/L6 Catalyzed Coupling of (Hetero)aryl Iodides with Sulfinic Acid Saltsa
aReaction condition: (hetero)aryl iodide (5 mmol), RSO2Na (6.5 mmol), K3PO4 (5
b
mmol), CuI (0.025 mmol), L6 (0.025 mmol), DMSO (4 mL), rt, 24 h. 1 mol % CuI
and L6 were used. c2 mol % CuI and L6 were used. d3 mol % CuI and L6 were used.
e5 mol % CuI and L6 were used. fAt 50 oC. g10 mmol of K3PO4 was used.
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It is notable that several coupling products in the present study are valuable
building blocks for assembling bioactive agents. For example, 4g16 and 4j17 have been
used for preparing COXꢀ2 inhibitors, respectively, while 3a is a key intermediate for
the synthesis of antitumor drug Ceritinib.2 To further demonstrate the usage of this
method, we attempted to prepare RIP2 kinase inhibitor GSK21418 and
antiꢀAlzheimer's disease drug Intepirdine.5 As shown in Scheme 1, nucleophilic
replacement of 6ꢀbromoꢀ4ꢀchloroquinoline 7 with 5ꢀfluoroꢀ1Hꢀindazolꢀ3ꢀamine 6 in
refluxed MeCN provided bromide 8, which was coupled with sodium
iꢀpropaneꢀ2ꢀsulfinate under the catalysis of 2 mol % CuI and L6 to deliver GSK 214
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in 92% yield. In
a
parallel procedure, CuI/L6ꢀcatalyzed coupling of
8ꢀfluoroꢀ3ꢀiodoquinoline 9 with sodium benzenesulfinate proceeded smoothly at 70
oC to afford sulfone 10 in 73% yield, which was subjected to a nucleophilic
replacement reaction with piperazine to furnish Intepirdine in 86% yield.
Scheme 1. Synthesis of GSKꢀ214 and Intepirdine
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A possible mechanism for our reaction is depicted in Scheme 2. After reaction with
K3PO4, ligand L6 could give a deprotonated salt, which would react with CuI to
deliver Cu(I) complex A. Oxidative addition of A to (hetero)aryl halides could
provide Cu(III) complex B, which would undergo ligand exchange to afford complex
C. Reductive elimination of C would produce (hetero)aryl sulfones and regenerate the
catalytic species A.
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Scheme 2. Possible catalytic cycle
In conclusion, we have demonstrated a superior method for promoting the
coupling of (hetero)aryl halides and sulfinic acid salts by employing the combination
of CuI and DMPHPC as the catalytic system, which allows the coupling with
(hetero)aryl iodides and bromides to proceed at low catalytic loadings. Notably, the
coupling of (hetero)aryl iodides occurs at room temperature with a broad reaction
scope. This applicability for preparing various aryl or alkyl sulfones from aryl
bromides and iodides, together with that the extraordinary broad range of functional
group compatibility (such as alcohol, amine, aldehyde, ketone, ester, nitro, nitrile,
chloro and bromo) make the present method very attractive for a diverse set of
aryl/heteroaryl sulfones. Additionally, the excellent performance displayed by
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pyrrolidineꢀ2ꢀcarboxamide ligands will stimulate further ligand design for greater
applicability of Cuꢀcatalyzed coupling reactions.
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Experimental
General procedure for ligand preparation. To a solution of Nꢀ(tertꢀbutoxycarbonyl)ꢀ
Lꢀproline
(6.456
g,
30
mmol) or
(2S,4R)ꢀ1ꢀ(tertꢀbutoxycarbonyl)ꢀ4ꢀ
hydroxypyrrolidineꢀ2ꢀcarboxylic acid (6.933 g, 30 mmol) in CH2Cl2 (100 mL) were
sequentially added Et3N (3.939 g, 39 mmol, 1.3 equiv) and isoꢀbutyl chloroformate
o
(4.914 g, 36 mmol, 1.2 equiv) at 0 C. The resulting mixture was stirred at room
temperature for 1 h before aryl amine (36 mmol, 1.2 equiv) added. The solution was
stirred overnight at room temperature, and then trifluoroacetic acid (20 g) was added.
After the mixture was stirred at room temperature for another 5 h, it was concentrated
in vacuo. The residue was added into saturated sodium bicarbonate (30 mL) and the
mixture was stirred to give a precipitate, which was collected and purified by flash
chromatography (eluting with 25:1ꢀ20:1 dichloromethane/methanol) to afford the
ligand.
(2S,4R)-4-Hydroxy-N-(2-methylnaphthalen-1-yl)pyrrolidine-2-carboxamide
(L1).14
o
1
White solid (6.244 g, 77% yield); mp 163ꢀ165 C; H NMR (500 MHz, CD3OD) δ
7.84 (dd, J = 8.3, 2.7 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.1 Hz, 1H), 7.45
(t, J = 7.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 4.4 Hz, 1H), 4.27 (t, J = 8.4
Hz, 1H), 3.20 (dd, J = 12.0, 4.1 Hz, 1H), 3.03 (dt, J = 12.0, 1.6 Hz, 1H), 2.41ꢀ2.37 (m,
13
1H), 2.36 (s, 3H), 2.13ꢀ2.06 (m, 1H); C NMR (125 MHz, CD3OD) δ 176.1, 134.2,
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134.2, 131.9, 131.0, 129.7, 129.0, 128.5, 127.5, 126.3, 123.3, 73.5, 61.0, 56.2, 41.3,
18.6; ESIꢀMS m/z 271 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C16H19O2N2 [M + H]+
271.1441, found 271.1440.
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(S)-N-(2-Methylnaphthalen-1-yl)pyrrolidine-2-carboxamide (L2).14 White solid
(5.951 g, 78% yield); mp 94ꢀ95 oC; 1H NMR (500 MHz, CD3OD) δ 7.86 (s, 1H), 7.83
(d, J = 8.0 Hz, 1), 7.75 (d, J = 8.5 Hz, 1H), 7.53ꢀ7.47 (m, 1H), 7.44 (t, J = 7.1 Hz, 1H),
7.36 (d, J = 8.5 Hz, 1H), 4.68 (t, J = 7.8 Hz, 1H), 3.38ꢀ3.30 (m, 2H), 2.70ꢀ2.59 (m,
1H), 2.35 (s, 3H), 2.31ꢀ2.21 (m, 1H), 2.15ꢀ2.00 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 174.1, 132.8, 132.5, 130.4, 130.1, 128.9, 128.1, 127.0, 126.4, 125.2, 122.3, 61.0,
47.6, 31.2, 26.5, 18.8; ESIꢀMS m/z 255 [M + H]+; HRMS (ESIꢀTOF) Calcd. for
C16H19ON2 [M + H]+ 255.1492, found 255.1492.
(S)-N-(Naphthalen-1-yl)pyrrolidine-2-carboxamide (L3).14 White solid (5.983 g, 83%
yield); mp 117ꢀ119 oC; 1H NMR (500 MHz, DMSOꢀd6) δ 10.62 (s, 1H), 8.10ꢀ8.04 (m,
1H), 8.00ꢀ7.95 (m, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.62ꢀ7.50
(m, 3H), 4.63 (t, J = 7.8 Hz, 1H), 3.38 (s, 1H), 3.37ꢀ3.27 (m, 2H), 2.58ꢀ2.51 (m, 1H),
2.18ꢀ2.10 (m, 1H), 2.04ꢀ1.98 (m, 2H); 13C NMR (125 MHz, DMSOꢀd6) δ 168.3,
134.2, 132.8, 128.7, 128.2, 126.7, 126.6, 126.6, 126.0, 123.0, 122.6, 60.1, 46.2, 30.3,
24.1; ESIꢀMS m/z 241 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C15H17ON2 [M + H]+
241.1335, found 241.1335.
(2S,4R)-4-Hydroxy-N-(naphthalen-1-yl)pyrrolidine-2-carboxamide (L4).14 White
solid (5.459 g, 71% yield); mp 151ꢀ153 oC; 1H NMR (500 MHz, CD3OD) δ 7.93 (d, J
= 8.3 Hz, 1H), 7.91ꢀ7.85 (m, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.58ꢀ7.51 (m, 2H),
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7.51ꢀ7.45 (m, 1H), 4.45 (s, 1H), 4.22 (t, J = 8.4 Hz, 1H), 3.15ꢀ3.04 (m, 2H), 2.39ꢀ2.32
(m, 1H), 2.08ꢀ2.01 (m, 1H); 13C NMR (125 MHz, CD3OD) δ 176.0, 135.6, 133.5,
129.6, 128.8, 127.4, 127.1, 126.9, 126.6, 122.2, 121.5, 73.8, 61.5, 56.0, 40.8; ESIꢀMS
m/z 257 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C15H17O2N2 [M + H]+ 257.1285,
found 257.1282.
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(S)-N-(2,6-Dimethylphenyl)pyrrolidine-2-carboxamide (L5).14 White solid (5.370 g,
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82% yield); mp 126ꢀ127 C; H NMR (500 MHz, DMSOꢀd6) δ 9.39 (s, 1H), 7.05 (s,
3H), 3.73 (dd, J = 8.8 Hz, 5.4 Hz, 1H), 2.92 (t, J = 6.6 Hz, 2H), 2.12 (s, 6H),
2.09ꢀ2.01 (m, 1H), 1.87ꢀ1.78 (m, 1H), 1.74ꢀ1.65 (m, 2H); 13C NMR (125 MHz,
DMSOꢀd6) δ 172.9, 135.1, 134.9, 127.6, 126.1, 60.4, 46.8, 30.7, 25.8, 18.0; ESIꢀMS
m/z 219 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C13H19ON2 [M + H]+ 219.1492,
found 219.1491.
(2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide (L6). White
solid (6.255 g, 89% yield); mp 164ꢀ166 oC; 1H NMR (500 MHz, DMSOꢀd6) δ 9.92 (s,
1H), 9.01 (s, 1H), 7.14ꢀ7.07 (m, 3H), 5.55 (s, 1H), 4.55ꢀ4.46 (m, 2H), 3.36 (dd, J =
12.1, 3.9, 1H), 3.11 (d, J = 12.1, 1H), 2.43 (dd, J = 13.0, 7.1, 1H), 2.14 (s, 6H),
2.07ꢀ2.00 (m, 1H); 13C NMR (125 MHz, DMSOꢀd6) δ 166.5, 135.0, 133.8, 127.8,
126.9, 69.1, 58.1, 53.2, 39.0, 18.0; ESIꢀMS m/z 235 [M + H]+ HRMS (ESIꢀTOF)
Calcd. for C13H19O2N2 [M + H]+ 235.1441, found 235.1445.
(2S,4R)-N-Benzyl-4-hydroxypyrrolidine-2-carboxamide (L7). Yellow solid (5.155 g,
78% yield); mp 105ꢀ107 oC; 1H NMR (500 MHz, CD3OD) δ 7.37ꢀ7.24 (m, 5H), 4.41
(s, 2H), 4.39ꢀ4.36 (m, 1H), 3.95 (t, J = 8.3, 1H), 3.02 (dd, J = 12.0, 4.1, 1H), 2.91 (dt,
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J = 12.0, 1.8, 1H), 2.22ꢀ2.16 (m, 1H), 1.91ꢀ1.84 (m, 1H); C NMR (125 MHz,
CD3OD) δ 176.9, 139.9, 129.5, 128.4, 128.2, 73.5, 60.7, 56.0, 43.7, 41.0; ESIꢀMS m/z
221 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C12H17O2N2 [M + H]+ 221.1285, found
221.1285.
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General procedure for the CuI-catalyzed coupling of (hetero)aryl bromides with
sulfinic acid salts. A 25 mL resealable screwꢀcap test tube equipped with a
Teflonꢀcoated magnetic stir bar was charged with CuI (0.1ꢀ0.25 mmol), L6 (0.1ꢀ0.25
mmol), (hetero)aryl bromide (if solid) (5.0 mmol), RSO2Na (6.5 mmol) and K3PO4 (5
mmol). The tube was then evacuated and backfilled with argon, and (hetero)aryl
bromide (if liquid) (5.0 mmol) and solvent (3 mL, DMSO) were then added into the
tube via syringe. The reaction mixture was stirred at 90ꢀ100°C in an oil bath for 24 h.
After cooling to room temperature, the crude product was diluted with ethyl acetate,
and filtrated through silica gel and kieselguhr. Then the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography (eluting with ethyl
acetate/hexanes or dichloromethane/methanol) to afford the corresponding aryl
sulfone.
General procedure for the CuI-catalyzed coupling of (hetero)aryl iodides with
sulfinic acid salts. A 25 mL resealable screwꢀcap test tube equipped with a
Teflonꢀcoated magnetic stir bar was charged with CuI (0.025ꢀ0.25 mmol), L6
(0.025ꢀ0.25 mmol), (hetero)aryl iodide (if solid) (5.0 mmol), RSO2Na (6.5 mmol) and
K3PO4 (5 mmol). The tube was then evacuated and backfilled with argon, and
(hetero)aryl iodide (if liquid) (5.0 mmol) and solvent (4 mL, DMSO) were then added
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into the tube via syringe. The reaction mixture was stirred at rtꢀ50 °C in an oil bath for
24 h. After cooling to room temperature, the crude product was diluted with ethyl
acetate, and filtrated through silica gel and kieselguhr. Then the filtrate was
concentrated in vacuo. The residue was purified by flash chromatography (eluting with
1:10ꢀ1:3 ethyl acetate/hexanes) to afford the corresponding aryl sulfone.
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1-Methoxy-4-(phenylsulfonyl)benzene (2a).8c Yield (1.214 g, 98% for aryl bromide;
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1.140 g, 92% for aryl iodide); Physical appearance: White solid; mp 90ꢀ91 C; H
NMR (500 MHz, CDCl3) δ 7.93ꢀ7.90 (m, 2H), 7.88 (d, J = 9.0 Hz, 2H), 7.56ꢀ7.51 (m,
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1H), 7.51ꢀ7.46 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H); C NMR (125 MHz,
CDCl3) δ 163.5, 142.5, 133.3, 133.0, 130.0, 129.3, 127.4, 114.6, 55.8; EIꢀMS m/z 248
(M+).
Methyl(4-(phenylsulfonyl)phenyl)sulfane (2b).19a Yield (1.250 g, 95% for aryl
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bromide); Physical appearance: White solid; mp 106ꢀ108 C; H NMR (500 MHz,
DMSOꢀd6) δ 7.93 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.3 Hz,
13
1H), 7.59 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 2.49 (s, 3H); C NMR (125
MHz, DMSOꢀd6) δ 146.6, 141.4, 136.5, 133.5, 129.7, 127.7, 127.1, 125.6, 13.8;
ESIꢀMS m/z 265 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C13H12NaO2S2[M + H]+
287.0171, found 287.0179.
1-(tert-Butyl)-4-(phenylsulfonyl)benzene (2c).19b Yield (1.301 g, 95% for aryl
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bromide); Physical appearance: White solid; mp 129ꢀ131 C; H NMR (500 MHz,
CDCl3) δ 7.95 (d, J = 7.2, 2H), 7.86 (d, J = 8.4, 2H), 7.56ꢀ7.52 (m, 1H), 7.52ꢀ7.47 (m,
13
4H), 1.30 (s, 9H); C NMR (125 MHz, CDCl3) δ 157.2, 142.1, 138.7, 133.1, 129.3,
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127.7, 127.6, 126.4, 35.3, 31.6, 31.1; ESIꢀMS m/z 275 [M + H]+; HRMS (ESIꢀTOF)
Calcd. for C16H19O2S [M + H]+ 275.1100, found 275.1103.
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1-(tert-Butoxy)-4-(phenylsulfonyl)benzene (2d). Yield (1.276 g, 88% for aryl bromide);
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Physical appearance: White solid; mp 78ꢀ79 C; H NMR (500 MHz, DMSOꢀd6) δ
7.95ꢀ7.92 (m, 2H), 7.87ꢀ7.83 (m, 2H), 7.69ꢀ7.64 (m, 1H), 7.63ꢀ7.58 (m, 2H),
7.18ꢀ7.14 (m, 2H), 1.36 (s, 9H); 13C NMR (125 MHz, DMSOꢀd6) δ 160.0, 141.7,
133.8, 133.4, 129.7, 129.1, 127.1, 122.0, 79.8, 28.3; ESIꢀMS m/z 291 [M + H]+;
HRMS (ESIꢀTOF) Calcd. for C16H19O3S [M + H]+ 291.1049, found 291.1048.
N-(4-(Phenylsulfonyl)phenyl)acetamide (2e).8c Yield (0.935 g, 68% for aryl bromide);
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Physical appearance: Yellow solid; mp 191ꢀ193 C; H NMR (500 MHz, CDCl3) δ
8.00 (s, 1H), 7.89 (d, J = 7.2, 2H), 7.83 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 7.55 (t,
J = 7.4, 1H), 7.48 (t, J = 7.5, 2H), 2.16 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 169.0,
142.7, 141.7, 135.8, 133.2, 129.3, 128.9, 127.4, 119.6, 24.6; ESIꢀMS m/z 274 [M –
H]+; HRMS (ESIꢀTOF) Calcd. for C14H14O3NS [M + H]+ 276.0689, found 276.0691.
4-(Phenylsulfonyl)-1,1'-biphenyl (2f).8f Yield (1.398 g, 95% for aryl bromide; 1.230 g,
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84% for aryl iodide); Physical appearance: White solid; mp 150ꢀ151 C; H NMR
(500 MHz, CDCl3) δ 8.03ꢀ7.97 (m, 4H), 7.70 (d, J = 8.5 Hz, 2H), 7.60ꢀ7.55 (m, 3H),
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7.52 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.43ꢀ7.38 (m, 1H); C NMR (125
MHz, CDCl3) δ 146.3, 141.9, 140.2, 139.3, 133.3, 129.4, 129.2, 128.7, 128.3, 128.1,
127.8, 127.5; EIꢀMS m/z 294 (M+); HRMS (EIꢀTOF) Calcd. for C18H14O2S (M+)
294.0715, found 294.0718.
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0.997 g, 77% for aryl iodide); Physical appearance: White solid; mp 132ꢀ134 C; H
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1H), 7.54ꢀ7.50 (m, 2H), 2.61 (s, 3H); C NMR (125 MHz, CDCl3) δ 196.8, 145.5,
140.9, 140.4, 133.8, 129.6, 129.2, 128.1, 128.0, 27.0; EIꢀMS m/z 260 (M+); HRMS
(EIꢀTOF) Calcd. for C14H12O3S (M+) 260.0507, found 260.0513.
1-(Phenylsulfonyl)-4-(trifluoromethyl)benzene (2h).19a Yield (1.139, 74% for aryl
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bromide); Physical appearance: White solid; mp 90ꢀ92 C; H NMR (500 MHz,
CDCl3) δ 8.07 (d, J = 8.2, 2H), 7.96 (d, J = 7.5, 2H), 7.76 (d, J = 8.4, 2H), 7.60 (t, J =
13
7.4, 1H), 7.53 (t, J = 7.6, 2H); C NMR (125 MHz, CDCl3) δ 145.33 (s), 140.7 (s),
134.9 (q, J = 33.1), 133.9 (s), 129.6 (s), 128.3 (s), 128.0 (s), 126.6 (q, J = 3.7), 123.2
(q, J = 273.1); ESIꢀMS m/z 309 [M + Na]+; HRMS (ESIꢀTOF) Calcd. for
C13H9O2F3SNa [M + Na]+ 309.0168, found 309.0169.
4-(Phenylsulfonyl)benzonitrile (2i).8d Yield (0.821 g, 62% for aryl bromide); Physical
appearance: Yellow solid; mp 125ꢀ127 oC; 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J =
8.6, 2H), 7.94 (d, J = 7.3, 2H), 7.79 (d, J = 8.7, 2H), 7.64ꢀ7.59 (m, 1H), 7.53 (t, J =
7.7, 2H); 13C NMR (125 MHz, CDCl3) δ 145.9, 140.2, 134.1, 133.2, 129.7, 128.3,
128.0, 117.2, 117.0; ESIꢀMS m/z 266 [M + Na]+; HRMS (ESIꢀTOF) Calcd. for
C13H9O2NSNa [M + H]+ 266.0246, found 266.0252.
1-Methoxy-3-(phenylsulfonyl)benzene (2j).19a Yield (1.190 g, 96% for aryl bromide);
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Physical appearance: White solid; mp 89ꢀ91 C; H NMR (500 MHz, DMSOꢀd6) δ
8.02ꢀ7.96 (m, 2H), 7.71ꢀ7.65 (m, 1H), 7.64ꢀ7.59 (m, 2H), 7.56ꢀ7.48 (m, 2H),
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7.45ꢀ7.43 (m, 1H), 7.27ꢀ7.21 (m, 1H), 3.82 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6)
δ 159.7, 142.3, 141.0, 133.7, 131.0, 129.7, 127.4, 119.5, 119.4, 112.1, 55.7; EIꢀMS
m/z 248 (M+).
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2-(Phenylsulfonyl)aniline (2k).19c Yield (0.839 g, 72% for aryl bromide); Physical
appearance: Yellow solid; mp 117ꢀ118 oC; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J =
7.7, 2H), 7.84 (dd, J = 8.0, 1.0, 1H), 7.56 (t, J = 7.4, 1H), 7.48 (t, J = 7.7, 2H),
7.31ꢀ7.27 (m, 1H), 6.79 (t, J = 7.6, 1H), 6.65 (d, J = 8.2, 1H), 5.13 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 146.4, 142.0, 135.1, 133.2, 130.1, 129.1, 127.0, 122.0, 118.0,
117.8; ESIꢀMS m/z 234 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C12H12O2NS [M +
H]+ 234.0583, found 234.0584.
2-(Phenylsulfonyl)naphthalene (2l).19a Yield (1.261 g, 94% for aryl bromide);
Physical appearance: White solid; mp 119ꢀ121 oC; 1H NMR (500 MHz, CDCl3) δ 8.58
(s, 1H), 8.03ꢀ7.99 (m, 2H), 7.97 (d, J = 7.9, 1H), 7.92 (d, J = 8.7, 1H), 7.88ꢀ7.83 (m,
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2H), 7.64ꢀ7.57 (m, 2H), 7.54 (t, J = 7.3, 1H), 7.49 (t, J = 7.4, 2H); C NMR (125
MHz, CDCl3) δ 141.7, 138.5, 135.1, 133.3, 132.3, 129.8, 129.5, 129.4, 129.2, 129.2,
128.0, 127.8, 127.7, 122.8; ESIꢀMS m/z 269 [M + H]+; HRMS (ESIꢀTOF) Calcd. for
C16H13O2S [M + H]+ 269.0631, found 269.0636.
2-Methoxy-6-(phenylsulfonyl)pyridine (2m).19d Yield (1.011 g, 82% for aryl bromide);
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Physical appearance: Yellow solid; mp 74ꢀ76 C; H NMR (500 MHz, DMSOꢀd6) δ
8.03ꢀ7.95 (m, 3H), 7.77 (d, J = 7.3 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.8
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Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H); C NMR (125 MHz, DMSOꢀd6) δ
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[M + H]+.
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6-(Phenylsulfonyl)quinolone (2n). Yield (1.124 g, 84% for aryl bromide; 1.141 g, 85%
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for aryl iodide); Physical appearance: Yellow solid; mp 125ꢀ127 C; H NMR (500
MHz, CDCl3) δ 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.30 (d, J =
8.4 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.09 (dd, J = 8.9, 2.1 Hz, 1H), 8.03ꢀ8.00 (m,
2H), 7.59ꢀ7.56 (m, 1H), 7.54ꢀ7.50 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 153.5,
149.6, 141.2, 139.4, 137.5, 133.6, 131.5, 129.6, 129.2, 128.0, 127.5, 126.6, 122.8;
EIꢀMS m/z 269 (M+); HRMS (EIꢀTOF) Calcd. for C15H11NO2S (M+) 269.0511, found
269.0521.
6-(Phenylsulfonyl)isoquinoline (2o). Yield (1.070 g, 80% for aryl bromide); Physical
appearance: Yellow solid; mp 184ꢀ186 oC; 1H NMR (500 MHz, DMSOꢀd6) δ 9.42 (s,
1H), 8.77 (s, 1H), 8.64 (d, J = 5.7 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.12ꢀ8.01 (m,
4H), 7.68 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.5 Hz, 2H); 13C NMR (125 MHz,
DMSOꢀd6) δ 152.6, 144.5, 142.2, 140.3, 134.3, 134.0, 130.0, 129.8, 128.9, 127.6,
127.3, 123.9, 121.3; ESIꢀMS m/z 270 [M + H]+; HRMS (ESIꢀTOF) Calcd. for
C15H12O2SN [M + H]+ 270.0583, found 270.0581.
2-Methyl-6-(phenylsulfonyl)quinoline (2p). Yield (1.3 g, 92% for aryl bromide);
Physical appearance: Yellow solid; mp 157ꢀ158 oC; 1H NMR (500 MHz, DMSOꢀd6) δ
8.73 (d, J = 1.7 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.11ꢀ8.05 (m, 2H), 8.03 (d, J = 7.3
Hz, 2H), 7.69 (t, J = 6.8 Hz, 1H), 7.63 (t, J = 7.7 Hz, 2H), 7.57 (d, J = 8.5 Hz, 1H);
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2.68 (s, 3H); C NMR (125 MHz, DMSOꢀd6) δ 162.7, 148.6, 140.9, 137.6, 137.5,
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133.8, 130.2, 129.8, 129.1, 127.4, 126.1, 125.4, 123.8, 25.1; ESIꢀMS m/z 284 [M +
H]+; HRMS (ESIꢀTOF) Calcd. for C16H14O2SN [M + H]+ 284.0740, found 284.0738.
1-Benzyl-5-(phenylsulfonyl)-1H-indole (2q). Yield (1.507 g, 87% for aryl bromide);
Physical appearance: Yellow solid; mp 105ꢀ106 oC; 1H NMR (500 MHz, DMSOꢀd6) δ
8.29 (d, J = 1.2 Hz, 1H), 7.96ꢀ7.91 (m, 2H), 7.72 (d, J = 3.2 Hz, 1H), 7.70ꢀ7.63 (m,
2H), 7.61ꢀ7.50 (m, 3H), 7.29ꢀ7.25 (m, 2H), 7.24ꢀ7.16 (m, 3H), 6.74 (d, J = 3.7 Hz,
1H), 5.47 (s, 2H); 13C NMR (125 MHz, DMSOꢀd6) δ 142.6, 137.6, 137.5, 132.9,
132.1, 131.6, 129.5, 128.6, 127.8, 127.5, 127.0, 126.9, 121.4, 119.8, 111.2, 103.0,
49.3; ESIꢀMS m/z 348 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C21H18O2SN [M + H]+
348.1053, found 348.1052.
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Ethyl 1-benzyl-5-(phenylsulfonyl)-1H-indole-2-carboxylate (2r). Yield (1.782 g, 85%
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for aryl bromide); Physical appearance: Yellow solid; mp 123ꢀ125 C; H NMR (500
MHz, CDCl3) δ 8.43 (d, J = 1.5, 1H), 7.97 (d, J = 7.1, 2H), 7.78 (dd, J = 8.9, 1.7, 1H),
7.53ꢀ7.44 (m, 4H), 7.42 (d, J = 8.9, 1H), 7.26ꢀ7.18 (m, 3H), 7.02 (d, J = 7.1, 2H), 5.84
(s, 2H), 4.35 (q, J = 7.1, 2H), 1.36 (t, J = 7.1, 3H); 13C NMR (125 MHz, CDCl3) δ
161.3, 142.5, 141.0, 137.3, 133.9, 132.9, 130.4, 129.2, 128.8, 127.6, 127.5, 126.3,
125.6, 124.1, 123.6, 112.1, 111.9, 61.2, 48.3, 14.3; ESIꢀMS m/z 420 [M + H]+; HRMS
(ESIꢀTOF) Calcd. for C24H22O4NS [M + H]+ 420.1264, found 420.1267.
5-(Phenylsulfonyl)benzo[b]thiophene (2s). Yield (1.284 g, 94% for aryl bromide);
Physical appearance: White solid; mp 126ꢀ128 oC; 1H NMR (500 MHz, DMSOꢀd6) δ
8.60 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 7.9 Hz, 2H), 7.96 (d, J = 5.5 Hz,
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1H), 7.86 (d, J = 8.6 Hz, 1H), 7.68ꢀ7.61 (m, 2H), 7.59 (t, J = 7.6 Hz, 2H); C NMR
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(125 MHz, DMSOꢀd6) δ 143.9, 141.5, 139.4, 137.3, 133.5, 130.7, 129.6, 127.2, 124.5,
124.1, 123.3, 121.8; ESIꢀMS m/z 275 [M + H]+; HRMS (ESIꢀTOF) Calcd. for
C14H11O2S2 [M + H]+ 275.0195, found 275.0193.
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2-(Phenylsulfonyl)thiophene (2t).8c Yield (0.705 g, 67% for aryl iodide); Physical
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appearance: White solid; mp 119ꢀ121 C; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J =
7.6 Hz, 2H), 7.69 (d, J = 3.7 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H), 7.57 (t, J = 7.3 Hz,
1H), 7.51 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
143.1, 142.2, 134.0, 133.5, 133.4, 129.4, 128.0, 127.4; EIꢀMS m/z 224 (M+); HRMS
(EIꢀTOF) Calcd. for C10H8O2S2 (M+) 223.9966, found 223.9967.
2-(iso-Propylsulfonyl)aniline (3a).19e Yield (0.701 g, 70% for aryl bromide); Physical
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appearance: Yellow solid; mp 83ꢀ84 C; H NMR (500 MHz, CDCl3) δ 7.61 (dd, J =
8.0 Hz, 1.5 Hz, 1H), 7.34ꢀ7.30 (m, 1H), 6.78ꢀ6.74 (m, 1H), 6.71 (dd, J = 8.3 Hz, 0.8,
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1H), 5.09 (br s, 2H), 3.31 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); C NMR
(125 MHz, CDCl3) δ 147.3, 135.1, 131.3, 118.1, 117.6, 117.5, 54.2, 15.3; ESIꢀMS m/z
200 [M + H]+.
1-(iso-Propylsulfonyl)-4-methoxybenzene (3b).19f Yield (0.926 g, 87% for aryl iodide);
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Physical appearance: White solid; mp 125ꢀ126 C; H NMR (500 MHz, CDCl3) δ
7.79 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.19ꢀ3.11 (m, 1H),
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1.27 (d, J = 6.9 Hz, 6H); C NMR (125 MHz, CDCl3) δ 163.8, 131.3, 128.5, 114.4,
55.9, 55.8. 16.0; EIꢀMS m/z 214 (M+); HRMS (EIꢀTOF) Calcd. for C10H14O3S (M+)
214.0664, found 214.0657.
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6-(iso-Propylsulfonyl)quinolone (3c). Yield (0.986 g, 84% for aryl iodide); Physical
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appearance: Yellow solid; mp 115ꢀ117 C; H NMR (500 MHz, CDCl3) δ 9.06ꢀ9.01
(m, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H),
8.05 (dd, J = 8.8, 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 3.33ꢀ3.21 (m, 1H), 1.29
(d, J = 6.9 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 153.5, 149.7, 137.0, 134.8, 131.0,
131.0, 127.4, 127.2, 122.7, 55.7, 15.7; EIꢀMS m/z 235 (M+); HRMS (EIꢀTOF) Calcd.
for C12H13NO2S(M+) 235.0667, found 235.0663.
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1-Methoxy-4-(methylsulfonyl)benzene (4a).8c Yield (0.911 g, 98% for aryl bromide;
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0.914 g, 98% for aryl iodide); Physical appearance: White solid; mp 118ꢀ120 C; H
NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s,
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3H), 3.03 (s, 3H); C NMR (125 MHz, CDCl3) δ 163.7, 132.3, 129.5, 114.5, 55.7,
44.8; EIꢀMS m/z 186 (M+).
1-(tert-Butoxy)-4-(methylsulfonyl)benzene (4b). Yield (1.073 g, 94% for aryl bromide);
Physical appearance: White solid; mp 93ꢀ95 oC; 1H NMR (500 MHz, CDCl3) δ = 7.81
(d, J = 8.8, 2H), 7.09 (d, J = 8.8, 2H), 3.03 (s, 3H), 1.41 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 160.8, 133.9, 128.9, 122.8, 80.3, 77.4, 77.2, 76.9, 44.8, 28.9; ESIꢀMS m/z
251 [M + Na]+; HRMS (ESIꢀTOF) Calcd. for C11H17O3S [M + H]+ 229.0893, found
229.0899.
N-(4-(Methylsulfonyl)phenyl)acetamide (4c).8c Yield (0.801 g, 75% for aryl bromide);
Physical appearance: White solid; mp 185ꢀ187 oC; 1H NMR (500 MHz, DMSOꢀd6) δ
10.37 (s, 1H), 7.86ꢀ7.79 (m, 4H), 3.15 (s, 3H), 2.10 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 169.1, 143.8, 134.4, 128.2, 118.6, 43.8, 24.2; EIꢀMS m/z 213 [M + H]+.
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4-(Methylsulfonyl)phenol (4d).8c Yield (0.783 g, 91% for aryl bromide); Physical
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1H), 7.73 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.10 (s, 3H); C NMR (125
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MHz, DMSOꢀd6) δ 161.9, 130.9, 129.4, 115.7, 44.1; EIꢀMS m/z 172 [M + H]+.
Methyl (4-(methylsulfonyl)phenyl)sulfane (4e).8b Yield (0.950 g, 94% for aryl bromide;
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0.946 g, 90% for aryl iodide); Physical appearance: White solid; mp 97ꢀ99 C; H
NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 3.03 (s,
13
3H), 2.53 (s, 3H); C NMR (125 MHz, CDCl3) δ 147.3, 136.4, 127.8, 125.6, 44.8,
14.9; EIꢀMS m/z 202 (M+).
(4-(Methylsulfonyl)phenyl)methanol (4f).14 Yield (0.761 g, 82% for aryl bromide;
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0.801 g, 86% for aryl iodide); Physical appearance: White solid; mp 82ꢀ84 C; H
NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.77 (s,
2H), 3.01 (s, 3H), 2.64 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 147.4, 139.4, 127.7,
127.3, 64.2, 44.7; EIꢀMS m/z 186 (M+); HRMS (EIꢀTOF) Calcd. for C8H10O3S (M+)
186.0351, found 186.0347.
Methyl 2-(4-(methylsulfonyl)phenyl)acetate (4g).19g Yield (0.992 g, 87% for aryl
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bromide); Physical appearance: White solid; 84ꢀ85 C; H NMR (500 MHz,
DMSOꢀd6) δ 7.89 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 3.85 (s, 2H), 3.63 (s,
3H), 3.21 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ 171.4, 140.8, 139.9, 130.9,
127.4, 52.4, 44.0, 40.2; ESIꢀMS m/z 228 [M + H]+.
4-(Methylsulfonyl)-1,1'-biphenyl (4h).8c Yield (1.105 g, 95% for aryl bromide; 1.116 g,
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96% for aryl iodide); Physical appearance: White solid; mp 139ꢀ141 C; H NMR
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(500 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.61 (d, J =
7.2 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 3.10 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 146.9, 139.3, 139.2, 129.2, 128.8, 128.1, 128.0, 127.5, 44.8;
EIꢀMS m/z 232 (M+).
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1-(Methylsulfonyl)-4-(trifluoromethyl)benzene (4i).8b Yield (0.873 g, 78% for aryl
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bromide); Physical appearance: Yellow solid; mp 109ꢀ110 C; H NMR (500 MHz,
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DMSOꢀd6) δ 8.17 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 3.32 (s, 3H); C
NMR (125 MHz, DMSOꢀd6) δ 144.6, 133.2 (q, J = 32.3 Hz), 128.1, 126.6 (q, J = 3.8
Hz), 123.4 (q, J = 273.0 Hz), 43.1; EIꢀMS m/z 224 (M+).
1-(4-(Methylsulfonyl)phenyl)ethan-1-one (4j).8c Yield (0.793 g, 80% for aryl bromide;
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0.823 g, 83% for aryl iodide); Physical appearance: White solid; mp 125ꢀ127 C; H
NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 3.08 (s,
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3H), 2.67 (s, 3H); C NMR (125 MHz, CDCl3) δ 196.8, 144.3, 141.0, 129.3, 128.0,
44.5, 27.1; EIꢀMS m/z 198 (M+).
1-(Methylsulfonyl)-4-nitrobenzene (4k).8b Yield (0.624 g, 62% for aryl bromide; 0.792
o
g, 79% for aryl iodide); Physical appearance: Yellow solid; mp 125ꢀ126 C; 1H NMR
(500 MHz, CDCl3) δ 8.41 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 3.12 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 151.0, 146.1, 129.1, 124.8, 44.4; EIꢀMS m/z 201 (M+).
Methyl 4-(methylsulfonyl)benzoate (4l).8c Yield (0.900 g, 84% for aryl bromide; 0.877
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g, 82% for aryl iodide); Physical appearance: White solid; mp 120ꢀ121 C; H NMR
(500 MHz, CDCl3) δ 8.23 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 3.98 (s, 3H),
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3.08 (s, 3H); C NMR (125 MHz, CDCl3) δ 165.5, 144.4, 135.0, 130.7, 127.6, 52.9,
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44.4; EIꢀMS m/z 214 (M+).
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NMR (500 MHz, CDCl3) δ 7.53ꢀ7.50 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.44ꢀ7.43 (m,
1H), 7.18ꢀ7.15 (m, 1H), 3.87 (s, 3H), 3.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
160.2, 141.9, 130.6, 120.3, 119.6, 112.0, 55.9, 44.6; EIꢀMS m/z 186 (M+); HRMS
(EIꢀTOF) Calcd. for C8H10O3S (M)+ 186.0351, found 186.0347.
3-(Methylsulfonyl)aniline (4n).19h Yield (0.770 g, 90% for aryl bromide); Physical
appearance: Yellow solid; mp 165ꢀ167 C; 1H NMR (500 MHz, DMSOꢀd6) δ 7.25 (t,
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J = 7.9 Hz, 1H), 7.08 (t, J = 2.0 Hz, 1H), 7.02ꢀ6.96 (m, 1H), 6.87ꢀ6.81 (m, 1H), 5.65
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(s, 2H), 3.10 (s, 3H); C NMR (125 MHz, DMSOꢀd6) δ 150.0, 141.8, 130.3, 118.6,
113.8, 111.4, 44.1; ESIꢀMS m/z 171 [M + H]+.
1-Methyl-3-(methylsulfonyl)benzene (4o).19i Yield (0.798 g, 94% for aryl bromide);
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7.41ꢀ7.39 (m, 2H), 2.99 (s, 3H), 2.39 (s, 3H); C NMR (125 MHz, CDCl3) δ 140.4,
139.6, 134.4, 129.2, 127.6, 124.4, 44.4, 21.3; ESIꢀMS m/z 171 [M + H]+; HRMS
(ESIꢀTOF) Calcd. for C8H10O2SNa [M + Na]+ 193.0294, found 193.0293.
1-Methyl-2-(methylsulfonyl)benzene (4p).8c Yield (0.246 g, 29% for aryl bromide);
Physical appearance: Yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 7.9, 1.4
Hz, 1H), 7.51 (td, J = 7.5, 1.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz,
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1H), 3.06 (s, 3H), 2.70 (s, 3H); C NMR (125 MHz, CDCl3) δ 138.8, 137.6, 133.8,
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132.8, 129.3, 126.8, 43.8, 20.4; EIꢀMS m/z 170 (M+).
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2-(Methylsulfonyl)aniline (4q).19j Yield (0.608 g, 71% for aryl bromide); Physical
appearance: Yellow solid; mp 84ꢀ85 oC; 1H NMR (500 MHz, DMSOꢀd6) δ 7.53 (dd, J
= 8.0 Hz, 1.5 Hz, 1H), 7.37ꢀ7.32 (m, 1H), 6.89 (dd, J = 8.3 Hz, 0.9 Hz, 1H),
6.72ꢀ6.67 (m, 1H), 6.03 (s, 2H), 3.09 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ
147.2, 134.7, 128.6, 120.4, 117.2, 115.8, 41.9; ESIꢀMS m/z 172 [M + H]+.
N-(2-(Methylsulfonyl)phenyl)acetamide (4r).19j Yield (0.770 g, 72% for aryl bromide);
Physical appearance: Yellow solid; mp 145ꢀ147 oC; 1H NMR (500 MHz, DMSOꢀd6) δ
9.57 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 7.9 Hz, 1.4 Hz, 1H), 7.74ꢀ7.68 (m,
1H), 7.44ꢀ7.38 (m, 1H), 3.26 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, DMSOꢀd6) δ
168.9, 136.5, 134.7, 130.9, 129.2, 125.6, 125.2, 43.4, 24.1; ESIꢀMS m/z 214 [M +
H]+.
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3-(Methylsulfonyl)pyridine (4s).8c Yield (0.487 g, 62% for aryl bromide); Physical
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appearance: Yellow solid; mp 52ꢀ54 C; 1H NMR (500 MHz, CDCl3) δ = 9.12 (d, J =
1.2, 1H), 8.85 (d, J = 4.1, 1H), 8.21 (td, J = 8.0, 1.8, 1H), 7.51 (dd, J = 8.0, 4.9, 1H),
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3.09 (s, 3H). C NMR (125 MHz, CDCl3) δ 154.4, 148.6, 137.0, 135.3, 124.0, 44.9;
ESIꢀMS m/z 158 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C6H8O2NS [M + H]+
158.0270, found 158.0274.
2-(Methylsulfonyl)pyridine (4t).19h Yield (0.667 g, 85% for aryl bromide); Physical
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8.80ꢀ8.77 (m, 1H), 8.16 (td, J = 7.7 Hz, 1.7 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H),
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139.1, 127.9, 120.7, 39.8; ESIꢀMS m/z 157 [M + H]+.
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Physical appearance: Yellow solid; mp 238ꢀ240 C; H NMR (500 MHz, CD3OD) δ
8.83 (d, J = 2.0, 1H), 8.38 (d, J = 5.7, 1H), 8.10 (dd, J = 8.9, 2.0, 1H), 7.95 (d, J = 8.9,
1H), 6.74 (d, J = 5.7, 1H), 3.21 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 156.3, 152.4,
150.4, 137.4, 129.4, 128.0, 125.2, 118.7, 104.8, 44.5; ESIꢀMS m/z 223 [M + H]+;
HRMS (ESIꢀTOF) Calcd. for C10H11O2N2S [M + H]+ 223.0536, found 223.0537.
3-(Methylsulfonyl)quinoline (4v).19l Yield (0.838 g, 81% for aryl bromide); Physical
appearance: Yellow solid; mp 139ꢀ140 oC; 1H NMR (500 MHz, CDCl3) δ 9.28 (d, J =
2.2, 1H), 8.76 (d, J = 1.9, 1H), 8.17 (d, J = 8.5, 1H), 7.95 (d, J = 8.1, 1H), 7.90ꢀ7.85
(m, 1H), 7.70ꢀ7.64 (m, 1H), 3.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 149.8, 146.6,
137.3, 133.5, 133.0, 129.7, 129.3, 128.6, 126.2, 77.4, 45.1; ESIꢀMS m/z 208 [M + H]+;
HRMS (ESIꢀTOF) Calcd. for C10H10O2NS [M + H]+ 208.0427, found 208.0426.
6-(Methylsulfonyl)isoquinoline (4w). Yield (0.880 g, 85% for aryl bromide); Physical
o
1
appearance: White solid; mp 134ꢀ136 C; H NMR (500 MHz, DMSOꢀd6) δ 9.47 (s,
1H), 8.67 (d, J = 5.7 Hz, 1H), 8.65 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.13 (dd, J = 8.6
Hz, 1.6 Hz, 1H), 8.07 (d, J = 5.7 Hz, 1H), 3.37 (s, 3H); 13C NMR (125 MHz,
DMSOꢀd6) δ 152.6, 144.4, 142.0, 134.2, 129.6, 129.1, 126.8, 123.8, 121.4, 43.2;
ESIꢀMS m/z 208 [M + H]+; HRMS (ESIꢀTOF) Calcd. for C10H10NO2S[M + H]+
208.0427, found 208.0425.
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