Chromatography-Free and Eco-Friendly Synthesis of Aryl Tosylates and Mesylates

Article abstract of DOI:10.1055/s-0034-1378867

Two chromatography-free and eco-friendly protocols have been developed to synthesize aryl tosylates and mesylates by the tosylation and mesylation of the corresponding hydroxyarenes, respectively. These protocols are superior to other known ones regarding

Full text of DOI:10.1055/s-0034-1378867

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2578–2585
psp
2578
X. Lei et al.
PSP
Synthesis
Chromatography-Free and Eco-Friendly Synthesis of Aryl
Tosylates and Mesylates
Xiangyang Lei*
TsCl, 15% NaOH or 10% K2CO3
THF–H2O, 0 °C to r.t., 2 h
· chromatography-free
· non-halogenated solvents
· open to air
· short reaction time
· broad range of substrates
· good to excellent yields
· 43 examples
Anusha Jalla
Ar OTs
Mhd A. Abou Shama
Jamie M. Stafford
Billy Cao
Ar OH
MsCl, Et3N
Ar OMs
EtOAc, 0 °C to r.t., 10 min
Department of Chemistry and Biochemistry, Lamar University,
Beaumont, TX 77710, USA
xlei@lamar.ed
Received: 10.05.2015
Accepted after revision: 10.06.2015
Published online: 23.07.2015
special equipment or reagent. Currently, the sulfonation of
hydroxyarenes with tosyl chloride (TsCl) or mesyl chloride
(MsCl) in the presence of an amine base such as pyridine
and triethylamine in an anhydrous organic solvent such as
dichloromethane is the prevailing method to prepare aryl
tosylates1b,2d,11 and mesylates,1a,c,d,2c,12 respectively. Al-
though this conventional method is mostly simple and effi-
cient, it involves halogenated solvent, anhydrous condi-
tions, and inert atmosphere, and the products need to be
purified by recrystallization or column chromatography in
most cases. Herein, we report the chromatography-free, en-
vironmentally friendly, and economically viable methods
for the synthesis of aryl tosylates and mesylates.
DOI: 10.1055/s-0034-1378867; Art ID: ss-2015-m0308-psp
Abstract Two chromatography-free and eco-friendly protocols have
been developed to synthesize aryl tosylates and mesylates by the to-
sylation and mesylation of the corresponding hydroxyarenes, respec-
tively. These protocols are superior to other known ones regarding the
simplicity, reaction time and conditions, the range of substrates, yields,
and environmental friendliness.
Key words aryl tosylates, aryl mesylates, tosylation, mesylation,
green chemistry
Introduction
Scope and Limitations
Aryl tosylates and mesylates are important intermedi-
ates in organic synthesis.1 Recently, they have attracted
considerable attention as the alternative electrophiles to
aryl halides in the transition-metal-catalyzed cross-cou-
pling reactions.2 Substitution of aryl halides with aryl to-
sylates and mesylates can make chemical processes more
environmentally friendly by reducing the production of ha-
lide waste.
Various methods have been reported to prepare aryl to-
sylates and mesylates. The methods for the synthesis of aryl
tosylates include transition-metal-catalyzed sulfonylation,3
solvent-free synthesis with4 or without5 microwave activa-
tion, heteropolyacid-catalyzed tosylation,6 reaction of phe-
nols with thiols using H2O2/POCl3 system,7 and tosyloxyl-
ation of anilides.8 Aryl mesylates have been synthesized via
one-pot demethylation–mesylation of aryl methyl ethers9
and thermal decomposition of dry arenediazonium o-ben-
zenedisulfonimides in methanesulfonic acid.10 However,
these methods have one or more drawbacks, such as long
reaction time, high temperature, low reactivity for phenols
bearing electron-withdrawing groups, and requirement for
In order to optimize the tosylation conditions, ethyl 4-
hydroxybenzoate (A), whose ester group is subject to hy-
drolysis under basic conditions, and 4-methoxyphenol (B),
whose methoxy group is inert under basic conditions, were
chosen as model substrates (Table 1). During this study the
reactions were monitored by thin-layer chromatography.
Generally, both substrates A and B were completely con-
sumed within two hours, so the reaction time was set as
two hours for all reactions. In order to reduce organic
waste, only readily available and inexpensive inorganic bas-
es, including NaOH, KOH, Na2CO3, and K2CO3, were exam-
ined. It has been reported that water is an efficient solvent
for the tosylation of alkanols.13 However, using water as the
sole solvent, the reactions of phenols A and B with TsCl, re-
spectively, in the presence of 5% NaOH were sluggish be-
cause of their poor solubility in water. According to the sol-
vent selection guide,14 THF is an usable solvent while ethyl
acetate is a preferred solvent for organic reactions and
workup. Therefore, THF was chosen, in which most hy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2578–2585

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PSP
Synthesis
droxyarenes are soluble, as solvent for the tosylation reac-
tions and ethyl acetate for the subsequent workup. TsCl is
subject to hydrolysis under basic conditions at ambient
temperature, so it is critical to control the reaction tem-
perature at 0 °C during its addition. After the bases, solvent,
and reaction temperature were selected, the use of TsCl and
bases was optimized and tested at different concentrations
of strong bases to obtain pure aryl tosylates in high yields.
In order to compensate for its loss due to hydrolysis, extra
TsCl was needed, but too much TsCl might result in impure
product with TsCl as impurity. As shown in Table 1, an
amount of 1.20 equivalents of TsCl was needed when NaOH
or KOH was used as base (entries 1–3 and 6–8). Due to its
slower hydrolysis in weaker bases such as 10% Na2CO3 and
10% K2CO3, an amount of 1.01 equivalents of TsCl were
enough (entries 4, 5, 9, and 10). For the tosylation of sub-
strate A, when 5% NaOH was used as the base, an amount of
3.30 equivalents of base gave a higher yield (entries 1 and
2). The increase of the concentration of NaOH solution re-
sulted in lower yields (entries 2 and 3), which is probably
due to the faster hydrolysis of the ethyl ester group in the
more concentrated NaOH solution. Pleasingly, substitution
of strong bases with relatively weaker base 10% Na2CO3 or
10% K2CO3 gave almost quantitative yields (entries 4 and 5).
For substrate B, which is a weaker acid than substrate A,
among all bases examined, 15% NaOH gave the best yield
(entries 6–10). Therefore, for phenols with functional
groups that are reactive under basic conditions, the optimal
tosylation conditions were set as entry 5 in Table 1, while
for phenols with functional groups that are inert under ba-
sic conditions, the optimal tosylation conditions were set as
entry 7 in Table 1.
With the optimized reaction conditions in hand, the
scope of these new tosylation protocol was explored. A
wide range of commercially available or readily prepared
hydroxyarenes with various steric and electronic properties
were examined, and the results are summarized in Table 2.
With 15% NaOH as base, the tosylation of monohydric phe-
nols bearing electron-donating groups, which are stable
under basic conditions, and unsubstituted phenols and
naphthalenols gave the corresponding aryl tosylates in ex-
cellent yields (entries 1–14). For the same substrates, sub-
stitution of 15% NaOH with 10% K2CO3 as base generally re-
sulted in lower yields of aryl tosylates (entries 5–7 and 9–
11). The yield difference is particularly notable for sub-
strates bearing a bulky allyl (entry 5) or tert-butyl group
(entries 6 and 7) and for the one with methoxy groups on
both ortho-positions (entry 11). These results confirm that
15% NaOH is a better choice as base for substrates that are
relatively weaker acids. Monohydric phenols bearing elec-
tron-withdrawing groups are stronger acids than those un-
substituted and those with electron-donating groups. With
10% K2CO3 as base, their tosylation yielded the correspond-
ing tosylates in excellent yields (entries 15–31), which
Table 1 Optimization of Tosylation Conditionsa
TsCl, base, THF–H2O
R
OH
R
OTs
0 °C to r.t., 2 h
A: R = CO2Et
B: R = OMe
Entry
Substrate Base
Molar ratio
(phenol/TsCl/base)
Yield
(%)b
1
2
A
A
A
A
A
B
B
B
B
B
5% NaOH
5% NaOH
1.00:1.20:2.40
1.00:1.20:3.30
1.00:1.20:3.30
1.00:1.01:1.88
1.00:1.01:1.88
1.00:1.20:3.30
1.00:1.20:3.30
1.00:1.20:3.30
1.00:1.01:1.88
1.00:1.01:1.88
85
91
83
98
99
89
96
87
93
94
3
10% NaOH
10% Na2CO3
10% K2CO3
10% NaOH
15% NaOH
10% KOH
4
5
6
7
8
9
10% Na2CO3
10% K2CO3
10
a Reaction conditions: phenol (25.0 mmol), base (aq solution in wt%), and
THF (15 mL to dissolve phenol and 35 mL to dissolve TsCl).
b Isolated yields.
demonstrates that our tosylation method is superior to oth-
ers that gave somewhat lower yields of tosylates for phe-
nols bearing electron-withdrawing groups.3,5 The tosylation
protocol with 15% NaOH as base worked efficiently for the
synthesis of heteroaryl tosylates (entries 32–36) that have
potential applications in the synthesis of biologically active
molecules. With 15% NaOH as base, the tosylation of dihy-
dric phenols and naphthalenols and bisphenols also gave
good to excellent yields (entries 37–43). Slight steric effects
were observed as the substrates with substituents at the or-
tho-position(s) generally have lower yields than their iso-
mers with substituents on the para- or meta-position(s)
under the same reaction conditions (entries 8, 11, 16, 21,
28, and 30). Notably, for all these tosylation reactions, the
workup procedure was very simple and straight-forward.
After the reaction was complete, a two-phase mixture was
obtained with the organic layer on the top and the aqueous
layer at the bottom. Since an excess of base was used in the
procedure, any unreacted hydroxyarene would stay in the
aqueous phase as its sodium or potassium salt during ex-
traction with ethyl acetate. Pure tosylates were obtained
without further purification, and many of these aryl to-
sylates in Table 2 have been successfully used in the nickel-
catalyzed cross-coupling reactions in our laboratory.2a
However, this tosylation method did not work efficiently on
several substrates (not shown in Table 2). Thus, the tosyla-
tion of 1,5-dihydroxynaphthalene did not yield the pure di-
tosylate due to its poor solubility under the optimal reac-
tion conditions. With 2-hydroxypyridine as substrate, the
product is a mixture resulting from O-tosylation and N-to-
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PSP
Synthesis
Table 2 (continued)
sylation due to the presence of two tautomers and there-
fore two reactive sites.15 For the extremely bulky substrate
such as 2,6-di-tert-butyl-4-methylphenol, a mixture of the
starting phenol and the desired tosylate was obtained
when 15% NaOH was used as base under the optimal reac-
tion conditions. For these substrates, no further study was
carried out to optimize their tosylation conditions.
Entry
ArOTs
Yield (%)b
35
36
37
38
39
40
41
2,4-Me2-3-TsO-thiophene (T35)
4-TsO-coumarin (T36)
93c
77c
84e
82e
75e
96e
72e
1,2-(TsO)2-benzene (T37)
1,3-(TsO)2-benzene (T38)
1,4-(TsO)2-benzene (T39)
2,3-(TsO)2-naphthalene (T40)
2,7-(TsO)2-naphthalene (T41)
Table 2 Scope of the Tosylation Protocola
TsCl, base, THF–H2O
Ar OH
Ar OTs
0 °C to r.t., 2 h
OTs
OTs
Entry
ArOTs
Yield (%)b
42
94e
1
2
4-MeC6H4OTs (T1)
99c
99c
3-MeC6H4OTs (T2)
(T42)
3
2-MeC6H4OTs (T3)
99c
OTs
OTs
4
2,5-Me2C6H3OTs (T4)
2-AllylC6H4OTs (T5)
98c
100c, 76d
99c, 71d
99c, 83d
97c
43
94e
5
6
4-t-BuC6H4OTs (T6)
(T43)
7
3-t-BuC6H4OTs (T7)
a Reaction conditions: ArOH (25.0 mmol), TsCl (5.72 g, 30.0 mmol when
15% NaOH was used as base or 4.81 g, 25.2 mmol when 10% K2CO3 was
used as base), and THF (15 mL to dissolve ArOH and 35 mL to dissolve
TsCl).
8
2,4-(t-Bu)2C6H3OTs (T8)
4-MeOC6H4OTs (T9)
2-MeOC6H4OTs (T10)
2,6-(MeO)2C6H3OTs (T11)
PhOTs (T12)
9
96c, 94d
99c, 98d
90c, 62d
100c
96c
b Isolated yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
c Base: 15% NaOH (22.00 g, 82.5 mmol).
d Base: 10% K2CO3 (65.00 g, 47.0 mmol).
e TsCl (11.44 g, 60.0 mmol), 15% NaOH (44.00 g, 165.0 mmol), and THF
(15 mL to dissolve ArOH and 70 mL to dissolve TsCl).
1-TsO-naphthalene (T13)
2-TsO-naphthalene (T14)
4-ClC6H4OTs (T15)
100c
94d
For the mesylation of hydroxyarenes, the mesylation of
4-methoxyphenol with MsCl was chosen as a model reac-
tion to optimize the reaction conditions. As shown in Table
3, initially the above tosylation methods that use THF as
solvent and inorganic 5% NaOH or 10% K2CO3 as base were
attempted. Unfortunately, a mixture of the starting phenol
and its mesylate was obtained in each case (entries 1, 2).
Since MsCl is more reactive to water than TsCl, solid K2CO3
powder was used as base to reduce the hydrolysis of MsCl.
Again, however, a mixture was obtained (entry 3), which
was probably due to the poor solubility of K2CO3 in THF. In
order to facilitate the mesylation reaction, the organic base,
triethylamine, was chosen because it is readily available
and superior to pyridine in the sulfonylation reactions.16
With triethylamine as the base and THF as the solvent, the
mesylation reaction was complete within 10 minutes after
MsCl was added in one portion into the reaction mixture at
0 °C (entry 4). The same reaction in ethyl acetate also gave
an excellent yield in 10 minutes (entry 5). For both reac-
tions, good stirring was needed because thick slurry was
formed right after the addition of MsCl. Since the solvents
THF and ethyl acetate were used as received and may con-
tain a trace amount of water, an excess amount of MsCl was
used to compensate for its hydrolysis by residual water in
2,4-Cl2C6H3OTs (T16)
4-CHOC6H4OTs (T17)
1-CHO-2-TsO-naphthalene (T18)
4-AcC6H4OTs (T19)
98d
96d
94d
100d
99d
3-AcC6H4OTs (T20)
2-AcC6H4OTs (T21)
95d
4-AcNHC6H4OTs (T22)
4-CO2EtC6H4OTs (T23)
3,5-(CO2Me)2C6H3OTs (T24)
4-CNC6H4OTs (T25)
3,5-F2C6H3OTs (T26)
3-F3CC6H4OTs (T27)
2-F3CC6H4OTs (T28)
4-O2NC6H4OTs (T29)
2-O2NC6H4OTs (T30)
4-F3COC6H4OTs (T31)
3-TsO-pyridine (T32)
8-TsO-quinoline (T33)
1-Me-5-TsO-pyrazole (T34)
99d
99d
95d
99d
96d
100d
97d
96d
96d
99d
93c
98c
88c
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PSP
Synthesis
the solvent. Between THF and ethyl acetate, ethyl acetate is
preferred because it is more eco-friendly than THF.14 In ad-
dition, with ethyl acetate as solvent, it is not necessary to
use additional solvent in the workup step, and the separa-
tion is generally easier and faster. Therefore, the optimal re-
action conditions for mesylation were set as entry 5 in Ta-
ble 3.
tion of hydroxyarenes provides a useful catalogue to the
synthetic chemistry community as both aryl tosylates and
mesylates are important substrates in a variety of organic
reactions.
Table 4 Scope of the Mesylation Protocola
MsCl, Et3N, EtOAc
Ar OH
Ar OMs
Table 3 Optimization of Mesylation Conditionsa
0 °C to r.t., 10 min
Entry
ArOMs
Yield (%)b
MsCl, base, solvent
MeO
OH
MeO
OMs
0 °C to r.t.
1
2
4-MeC6H4OMs (M1)
100
100
100
98
98
100
98
94
99
97
90
97
99
94
97
97
96
96
99
98
97
88
99
97
98
99
97
96
97
94
98
71
85
74
99
92
98c
3-MeC6H4OMs (M2)
Entry
Solvent
Base
Molar ratio
(phenol/MsCl/base)
Time
Yield
(%)[b]
3
2-MeC6H4OMs (M3)
c
4
2,5-Me2C6H3OMs (M4)
2-AllylC6H4OMs (M5)
1
2
3
4
5
THF
5% NaOH
1.00:1.25:2.00
1.00:1.45:2.40
1.00:1.25:2.00
1.00:1.25:2.00
1.00:1.25:2.00
2 h
–
c
5
THF
10% K2CO3
K2CO3
Et3N
2 h
–
c
6
4-t-BuC6H4OMs (M6)
THF
24 h
–
7
3-t-BuC6H4OMs (M7)
THF
10 min
10 min
99
99
8
2,4-t-Bu2C6H3OMs (M8)
4-MeOC6H4OMs (M9)
2-MeOC6H4OMs (M10)
2,6-(MeO)2C6H3OMs (M11)
PhOMs (M12)
EtOAc
Et3N
a Reaction conditions: 4-methoxyphenol (25.0 mmol) and solvent (75 mL).
9
b Isolated yields.
c Not isolated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
In order to define the scope of the mesylation protocol,
a wide range of commercially available or readily prepared
hydroxyarenes with various steric and electronic properties
were examined, and the results are summarized in Table 4.
No obvious electronic effects were observed as all substrates
bearing electron-donating (entries 1–11) or electron-with-
drawing (entries 15–31) groups and unsubstituted sub-
strates (entries 12–14) gave excellent yields. This method is
also applicable to the synthesis of heteroaryl mesylates (en-
tries 32–36) and dimesylates (entries 37–43), giving good
to excellent yields. Only slight steric effects were observed
in several cases (entries 8 and 11). In all cases aryl
mesylates were obtained in high purity without further pu-
rification, as side product triethylamine hydrochloride salt
and any remaining MsCl and triethylamine were removed
by washing with water in the workup step. Again, many of
these aryl mesylates have been successfully used in the Ni-
catalyzed cross-coupling reactions in our laboratory, and
the manuscript is in preparation for publication. Similar to
the tosylation protocol, however, the mesylation of 1,5-di-
hydroxynaphthalene, 2-hydroxypyridine, and 2,6-di-tert-
butyl-4-methylphenol did not yield pure mesylate under
the optimal reaction conditions.
1-MsO-naphthalene (M13)
2-MsO-naphthalene (M14)
4-ClC6H4OMs (M15)
2,4-Cl2C6H3OMs (M16)
4-CHOC6H4OMs (M17)
1-CHO-2-MsO-naphthalene (M18)
4-AcC6H4OMs (M19)
3-AcC6H4OMs (M20)
2-AcC6H4OMs (M21)
4-AcNHC6H4OMs (M22)
4-CO2EtC6H4OMs (M23)
3,5-(CO2Me)2C6H3OMs (M24)
4-CNC6H4OMs (M25)
3,5-F2C6H3OMs (M26)
3-CF3C6H4OMs (M27)
2-CF3C6H4OMs (M28)
4-NO2C6H4OMs (M29)
2-NO2C6H4OMs (M30)
4-CF3OC6H4OMs (M31)
3-MsO-pyridine (M32)
8-MsO-quinoline (M33)
1-Me-5-MsO-pyrazole (M34)
2,4-Me2-3-MsO-thiophene (M35)
4-MsO-coumarin (M36)
1,2-(MsO)2-benzene (M37)
In conclusion, we have developed two efficient and
practical protocols to synthesize aryl tosylates and
mesylates, respectively, in good to excellent yields. All reac-
tions were carried out in nonhalogenated solvents in open
air with short reaction times. These protocols are simple,
chromatography-free, environmentally friendly, economi-
cally viable, and applicable to a wide range of substrates.
This first systematic investigation of tosylation and mesyla-
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2582
X. Lei et al.
PSP
Synthesis
Table 4 (continued)
slurry was then added H2O (50 mL). The two-phase mixture was sep-
arated. The organic layer was washed with H2O (25 mL) and dried
(MgSO4). Removal of solvent under reduced pressure gave the corre-
sponding pure aryl mesylate (Table 4).
Entry
ArOMs
Yield (%)b
38
39
40
41
1,3-(MsO)2-benzene (M38)
1,4-(MsO)2-benzene (M39)
2,3-(MsO)2-naphthalene (M40)
2,7-(MsO)2-naphthalene (M41)
99c
70c
88c
91c
3-tert-Butylphenyl Tosylate (T7)
Yield: 7.56 g (99%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 7.6 Hz, 2 H), 7.32 (d, J = 7.5
Hz, 2 H), 7.30–7.20 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.83 (s, 1 H), 2.46
(s, 3 H), 1.20 (s, 9 H).
OMs
OMs
13C NMR (100 MHz, CDCl3): δ = 153.2, 149.6, 145.3, 132.5, 129.6,
129.1, 128.7, 123.9, 119.6, 119.5, 34.7, 31.0, 21.8.
HRMS (EI): m/z (M+) calcd for C17H20O3S: 304.1133; found: 304.1135.
42
43
96c
(M42)
OMs
OMs
2,4-Di-tert-butylphenyl Tosylate (T8)
Yield: 8.78 g (97%); white solid; mp 56–58 °C.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.3 Hz, 2 H), 7.39–7.35 (m, 3
92c
H), 7.16–7.11 (m, 2 H), 2.46 (s, 3 H), 1.35 (s, 9 H), 1.28 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 148.5, 147.3, 145.1, 140.2, 134.9,
129.9, 128.0, 124.9, 123.9, 119.8, 34.9, 34.6, 31.4, 30.5, 21.7.
HRMS (ESI): m/z (M + Na)+ calcd for C21H28O3SNa: 383.1657; found:
(M43)
a Reaction conditions: ArOH (25.0 mmol), MsCl (3.72 g, 32.5 mmol), Et3N
(5.06 g, 50.0 mmol), and EtOAc (75 mL).
b Isolated yields.
c MsCl (7.44 g, 65.0 mmol), Et3N (10.12 g, 100.0 mmol), and EtOAc (150
mL).
383.1654.
2,6-Dimethoxyphenyl Tosylate (T11)
Yield: 6.92 g (90%); white solid; mp 95–97 °C.
All reactions were carried out in open air. Except for two phenols (en-
tries 42 and 43 in Tables 2 and 4) that were synthesized by literature
procedures,17 reagents and solvents were purchased from commercial
suppliers and used as received. NMR spectra were recorded on a
Bruker Avance 400 MHz spectrometer, and chemical shifts were re-
ported in ppm relative to TMS at δ = 0.00 as an internal reference.
Melting points were determined using a Mel-Temp melting point ap-
paratus and are uncorrected. TLC was carried out on precoated silica
gel plates with PF254 indicator. High-resolution mass spectra (HRMS)
were obtained using a quadrupole instrument using either electron
ionization (EI) or electrospray ionization (ESI) as the ionization meth-
od. Characterization data of new aryl tosylates and mesylates and
those known, but not fully characterized are shown below.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 8.5
Hz, 2 H), 7.12 (t, J = 8.4 Hz, 1 H), 6.54 (d, J = 8.5 Hz, 2 H), 3.66 (s, 6 H),
2.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 144.4, 135.0, 129.1, 128.4,
128.3, 127.4, 105.0, 55.9, 21.6.
HRMS (ESI): m/z (M + H)+ calcd for C15H17O5S: 309.0797; found:
309.0794.
1-Formylnaphthalen-2-yl Tosylate (T18)
Yield: 7.70 g (94%); white solid; mp 130–132 °C.
1H NMR (400 MHz, CDCl3): δ = 10.39 (s, 1 H), 9.15 (d, J = 8.5 Hz, 1 H),
8.05 (d, J = 8.8 Hz, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.73 (d, J = 8.6 Hz, 2
H), 7.68–7.64 (m, 1 H), 7.58–7.55 (m, 1 H), 7.36 (d, J = 8.7 Hz, 2 H),
7.33 (d, J = 8.0 Hz, 1 H), 2.46 (s, 3 H).
Aryl Tosylates T1–T43; General Procedure
To a solution of hydroxyarene (25.0 mmol) in THF (15 mL) was added
10% K2CO3 (65.00 g, 47.1 mmol) or 15% NaOH (22.00 g, 82.5 mmol) as
an aq solution (wt%). After the resulting solution was cooled to 0 °C
with an ice-water bath, a solution of TsCl (4.82 g, 25.3 mmol for 10%
K2CO3 or 5.72 g, 30.0 mmol for 15% NaOH) in THF (35 mL) was slowly
added over 15 min at 0 °C. After the addition of TsCl, the ice-water
bath was removed and the reaction mixture was stirred for 2 h. To the
mixture was then added EtOAc (100 mL; more was needed when aryl
tosylate had poor solubility in EtOAc). The two-phase mixture was
separated. The organic layer was washed with H2O (50 mL) and dried
(MgSO4). Removal of solvent under reduced pressure gave the corre-
sponding pure aryl tosylate. Any trace amount of TsCl, if present, can
be removed by simply washing the product with hexanes (Table 2).
13C NMR (100 MHz, CDCl3): δ = 189.9, 153.2, 146.5, 136.5, 132.1,
131.3, 130.7, 130.3, 129.9, 128.6, 128.4, 127.2, 125.8, 123.0, 121.4,
21.8.
HRMS (ESI): m/z (M + H)+ calcd for C18H15O4S: 327.0691; found:
327.0692.
3,5-Difluorophenyl Tosylate (T26)
Yield: 6.84 g (96%); white solid; mp 60–62 °C.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2 H), 7.35 (d, J = 8.3
Hz, 2 H), 6.73 (tt, J = 6.5, 2.3 Hz, 1 H), 6.60 (dd, J = 7.1, 2.0 Hz, 2 H),
2.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.8 (dd, J = 250.6, 14.4 Hz), 150.6 (t,
J = 13.9 Hz), 146.1, 131.8, 130.1, 128.5, 106.7 (m), 103.0 (t, J = 25.7Hz),
21.8.
Aryl Mesylates M1–M43; General Procedure
To a solution of hydroxyarene (25.0 mmol) in EtOAc (75 mL) at 0 °C
was added Et3N (5.06 g, 50.0 mmol) followed by MsCl (3.72 g, 32.5
mmol). After the addition of MsCl, the ice-water bath was removed
and the resulting thick slurry was vigorously stirred for 10 min. To the
HRMS (EI): m/z (M+) calcd for C13H10F2O3S: 284.0319; found:
284.0323.
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1-Methyl-1H-pyrazol-5-yl Tosylate (T34)
13C NMR (100 MHz, CDCl3): δ = 147.4, 135.6, 133.0, 131.1, 127.8,
127.3, 122.0, 116.8, 38.2, 34.2.
Yield: 5.55 g (88%); white solid; mp 69–71 °C.
HRMS (EI): m/z (M+) calcd for C10H12O3S: 212.0507; found: 212.0506.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2 H), 7.37 (d, J = 8.1
Hz, 2 H), 7.31 (d, J = 2.2 Hz, 1 H), 5.69 (d, J = 2.3 Hz, 1 H), 3.56 (s, 3 H),
2.48 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.6, 143.1, 138.1, 131.2, 130.1,
128.8, 95.2, 34.8, 21.8.
3-tert-Butylphenyl Mesylate (M7)
Yield: 5.59 g (98%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.27 (m, 3 H), 7.10 (dd, J = 6.8, 2.2
Hz, 1 H), 3.12 (s, 3 H), 1.32 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 153.9, 149.3, 129.5, 124.4, 119.2,
HRMS (ESI): m/z (M + H)+ calcd for C11H13N2O3S: 253.0647; found:
253.0647.
118.8, 37.2, 34.9, 31.2.
HRMS (EI): m/z (M+) calcd for C11H16O3S: 228.0820; found: 228.0822.
2,4-Dimethylthiophen-3-yl Tosylate (T35)
Yield: 6.57 g (93%); off-white solid; mp 60–62 °C.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.8
Hz, 2 H), 6.62 (s, 1 H), 2.46 (s, 3 H), 2.04 (s, 3 H), 1.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.5, 141.0, 133.2, 131.7, 129.9,
128.6, 128.5, 116.5, 21.7, 13.3, 12.0.
HRMS (ESI): m/z (M + H)+ calcd for C13H15O3S2: 283.0463; found:
283.0461.
2,4-Di-tert-butylphenyl Mesylate (M8)
Yield: 6.67 g (94%); white solid; mp 58–60 °C.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.41 (m, 2 H), 7.22 (dd, J = 8.4, 2.5
Hz, 1 H), 3.23 (s, 3 H), 1.42 (s, 9 H), 1.31 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 148.9, 146.6, 139.8, 125.1, 124.3,
119.9, 39.1, 34.9, 34.7, 31.4, 30.5.
HRMS (EI): m/z (M+) calcd for C15H24O3S: 284.1446; found: 284.1447.
2,3-Ditosyloxynaphthalene (T40)
2,4-Dichlorophenyl Mesylate (M16)
Yield: 11.20 g (96%); white solid; mp 182–184 °C.
Yield: 5.85 g (97%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 2.5 Hz, 1 H), 7.40–7.37 (d,
J = 8.8 Hz, 1 H), 7.31–7.28 (dd, J = 8.8, 2.5 Hz, 1 H), 3.25 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 143.9, 133.4, 130.6, 128.4, 127.8,
125.4, 38.8.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.76 (dd, J = 6.3, 3.3 Hz, 2 H), 7.72
(s, 2 H), 7.66 (d, J = 8.5 Hz, 4 H), 7.53–7.51 (dd, J = 6.3, 3.3 Hz, 2 H),
7.26 (d, J = 8.6 Hz, 4 H), 2.44 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 139.4, 132.2, 131.6, 129.7,
128.6, 127.8, 127.3, 122.4, 21.8.
HRMS (EI): m/z (M+) calcd for C7H6Cl2O3S: 239.9415; found: 239.9417.
HRMS (ESI): m/z (M + H)+ calcd for C24H21O6S2: 469.0780; found:
469.0780.
4-Ethoxycarbonylphenyl Mesylate (M23)18
Yield: 6.06 g (99%); white solid; mp 40–42 °C.
2,2′-Methylenebis(4-methylphenyl) Ditosylate (T42)
Yield: 12.60 g (94%); white solid; mp 115–117 °C.
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 6.8 Hz, 2 H), 7.36 (d, J = 6.8
Hz, 2 H), 4.36 (q, J = 7.3 Hz, 2 H), 3.19 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.4, 152.4, 131.6, 129.6, 121.9, 61.4,
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.3 Hz, 4 H), 7.31 (d, J = 8.0
Hz, 4 H), 6.95–6.91 (m, 4 H), 6.65 (s, 2 H), 3.52 (s, 2 H), 2.45 (s, 6 H),
2.20 (s, 6 H).
37.8, 14.3.
13C NMR (100 MHz, CDCl3): δ = 145.9, 145.4, 136.8, 133.0, 132.5,
HRMS (ESI): m/z (M + H)+ calcd for C10H13O5S: 245.0484; found:
131.8, 129.9, 128.4, 128.1, 121.9, 29.3, 21.7, 20.9.
245.0481.
HRMS (ESI): m/z (M + H)+ calcd for C29H29O6S2: 537.1406; found:
537.1404.
Dimethyl 5-Mesyloxyisophthalate (M24)
Yield: 7.01 g (97%); white solid; mp 143–145 °C.
1H NMR (400 MHz, CDCl3): δ = 8.65 (t, J = 1.5 Hz, 1 H), 8.12 (d, J = 1.5
2,2′-Methylenebis[6-(1-methylethyl)phenyl] Ditosylate (T43)
Yield: 13.91 g (94%); white solid; mp 158–160 °C.
Hz, 2 H), 3.97 (s, 6 H), 3.24 (s, 3H).
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.2 Hz, 4 H), 7.32 (d, J = 8.0
Hz, 4 H), 7.17 (dd, J = 7.8, 1.7 Hz, 2 H), 7.09 (dd, J = 7.8, 7.8 Hz, 2 H),
6.72 (dd, J = 7.6, 1.6 Hz, 2 H), 3.84 (s, 2 H), 3.30 (sept, J = 6.8 Hz, 2 H),
1.15 (d, J = 6.8 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 149.0, 132.7, 129.4, 127.4, 52.8,
38.0.
HRMS (ESI): m/z (M + H)+ calcd for C11H13O7S: 289.0382; found:
289.0378.
13C NMR (100 MHz, CDCl3): δ = 145.5, 145.2, 142.9, 134.3, 134.0,
129.9, 128.8, 128.0, 127.2, 125.3, 31.5, 27.5, 23.6, 21.7.
HRMS (ESI): m/z (M + H)+ calcd for C33H37O6S2: 593.2032; found:
2-(Trifluoromethyl)phenyl Mesylate (M28)
Yield: 5.80 g (96%); colorless oil.
593.2030.
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 7.8 Hz, 1 H), 7.62–7.57 (m, 2
H), 7.38 (dd, J = 7.2, 7.2 Hz, 1 H), 3.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.6 (q, J = 2.2 Hz), 133.8, 127.7 (q,
J = 5.2 Hz), 127.0, 123.1, 122.8 (q, J = 272.0 Hz), 122.6 (q, J = 32.0 Hz),
33.9.
2-Allylphenyl Mesylate (M5)
Yield: 5.19 g (98%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.22 (m, 4 H), 5.99–5.89 (m, 1 H),
5.13–5.08 (m, 2 H), 3.49 (d, J = 6.6 Hz, 2 H), 3.17 (s, 3 H).
HRMS (EI): m/z (M+) calcd for C8H7F3O3S: 240.0068; found: 240.0063.
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4-Trifluoromethoxyphenyl Mesylate (M31)
Acknowledgment
Yield: 6.29 g (98%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 9.0 Hz, 2 H), 7.27 (d, J = 9.1
Hz, 2 H), 3.17 (s, 3 H).
We thank the Robert A. Welch Foundation (Grant No. V-1815) for fi-
nancial support of this research.
13C NMR (100 MHz, CDCl3): δ = 147.8, 147.2, 123.7, 122.7, 120.5 (q,
J = 258.2 Hz), 37.6.
HRMS (EI): m/z (M+) calcd for C8H7F3O4S: 256.0017; found: 256.0016.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378867.
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p
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1-Methyl-1H-pyrazol-5-yl Mesylate (M34)
Yield: 3.25 g (74%); pale yellow oil.
References
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 2.1 Hz, 1 H), 6.08 (d, J = 2.2
Hz, 1 H), 3.79 (s, 3 H), 3.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 142.6, 138.4, 94.7, 37.5, 35.1.
HRMS (ESI): m/z (M + H)+ calcd for C5H9N2O3S: 177.0334; found:
177.0336.
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Yield: 5.12 g (99%); off-white solid; mp 54–56 °C.
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2.17 (s, 3 H).
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HRMS (ESI): m/z (M + H)+ calcd for C7H11O3S2: 207.0150; found:
207.0146.
1,3-Dimesyloxybenzene (M38)
Yield: 6.60 g (99%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.48 (t, J = 8.3 Hz, 1 H), 7.31–7.26 (m, 3
H), 3.24 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 149.5, 131.0, 121.2, 116.7, 37.6.
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266.9996.
2,2′-Methylenebis(4-methylphenyl) Dimesylate (M42)
Yield: 9.23 g (96%); white solid; mp 112–114 °C.
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1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 8.5 Hz, 2 H), 7.07 (d, J = 8.3
Hz, 2 H), 6.94 (s, 2 H), 4.09 (s, 2 H), 3.11 (s, 6 H), 2.29 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.2, 137.3, 132.1, 132.0, 128.7,
121.9, 38.1, 30.6, 21.0.
HRMS (ESI): m/z (M + H)+ calcd for C17H21O6S2: 385.0780; found:
385.0773.
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2,2′-Methylenebis[6-(1-methylethyl)phenyl] Dimesylate (M43)
Yield: 10.13 g (92%); white solid; mp 136–138 °C.
1H NMR (400 MHz, CDCl3): δ = 7.27 (dd, J = 7.8, 1.5 Hz, 2 H), 7.18 (dd,
J = 7.5, 7.5 Hz, 2 H), 6.83 (dd, J = 7.5, 1.5 Hz, 2 H), 4.29 (s, 2 H), 3.49
(sept, J = 6.8 Hz, 2 H), 3.25 (s, 6 H), 1.26 (d, J = 7.0 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 143.0, 133.3, 128.6, 127.6,
125.8, 39.0, 32.0, 27.5, 23.7.
HRMS (ESI): m/z (M + H)+ calcd for C21H29O6S2: 441.1406; found:
441.1406.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2578–2585

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2578–2585