π-deficient 2-(arylsulfonyl)ethyl esters as protecting groups for carboxylic acids

Article abstract of DOI:10.1055/s-2003-36844

Several π-deficient 2-(arylsulfonyl)ethyl groups have been studied as carboxylic acid protecting groups. The 2-[3,5-bis(trifluoromethyl)phenylsulfonyl]ethyl group is the most easily removed protecting group for acids under mild basic conditions using aqueous NaHCO₃.

Full text of DOI:10.1055/s-2003-36844

PAPER
277
π-Deficient 2-(Arylsulfonyl)ethyl Esters as Protecting Groups for Carboxylic
Acids
π
-Deficient 2-(Ary
i
lsulfon
e
yl)ethyl
E
s
g
ter
s
asProte
o
c
tingGroups for Ca
A
r
boxylic
A
cids . Alonso, Carmen Nájera,* Montserrat Varea
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: cnajera@ua.es
Received 5 November 2002
aqueous dioxane at room temperature2a or tetrabutyl-
Abstract: Several π-deficient 2-(arylsulfonyl)ethyl groups have
been studied as carboxylic acid protecting groups. The 2-[3,5-
bis(trifluoromethyl)phenylsulfonyl]ethyl group is the most easily
removed protecting group for acids under mild basic conditions us-
ing aqueous NaHCO3.
ammonium fluoride in THF at 0 °C,2f can be used for the
β-elimination process. In order to favour the cleavage of
the protecting group, the simplest strategy is to improve
the lability of the arylsulfonyl group by means of electron-
withdrawing substituents. This strategy has been studied
with (arylsulfonyl)ethoxycarbonyl groups such as the p-
nitro-, p-bromo- and p-methylsulfonyl-derivatives (Nsc,
Bsc and Mpc), for the carbamate protection of amino
groups1f,k (Figure 1). We have recently shown that π-defi-
cient α-(arylsulfonyl)acetates such as the 3,5-bis(tri-
fluoromethyl)phenylsulfonyl derivatives (Figure 1), are
very soft nucleophiles and efficient precursors for the one-
pot synthesis of (E)-aconitates.5 In this communication we
have studied diverse π-deficient 2-(arylsulfonyl)ethanols
as protecting groups for carboxylic acids in order to find
the mildest reaction conditions for the deprotection of the
carboxy function.
Key words: alcohols, carboxylic acids, eliminations, protecting
groups, sulfones
There is a permanent need for the protection of functional
groups under mild and specific reaction conditions in the
synthesis of complex molecules. In the case of carboxylic
acids, mainly esters are used as blocking functions.1 The
base-labile protecting groups 2-(p-toluenesulfonyl)ethyl
(TSE),2 2-(phenylsulfonyl)ethyl (PSE)3 and 2-(methane-
sulfonyl)ethyl4 esters (Figure 1) have been widely used
and can be cleaved by a base-induced β-elimination
mechanism. These protecting groups have been employed
in several total syntheses of different natural macrolides
such as (±)-pyrenophorin,2a,b colletodiol,2d–f (–)-coll-
etallol3a and pyrenophorol.3b They have been used as well
in the synthesis of bacterial cell wall precursor UDP-N-
acetylmuramylpentapeptide and in the synthesis of
carbohydrates3f employed in the discovery of new antibi-
otics, the natural products (±)-surugatoxin4 and the pep-
tide calcitonin.3h These β-hydroxyalkyl sulfone-derived
esters can be prepared by carbodiimide-mediated esterifi-
cation and cleaved using organic bases such as DBU. Al-
ternatively, NaOH or Na2CO3 (but not NaHCO3) in
The π-deficient 2-(arylsulfonyl)ethanols 3 were prepared
in very good yields by reaction of thiophenols 1 with 2-
bromoethanol using Et3N as base in acetonitrile at room
temperature to afford the corresponding sulfides 2, which
were purified and further oxidized with H2O2 (30%) in the
presence of a buffer solution of NaHCO3 and catalytic
amounts of MnSO4 H2O (1 mol%) in acetonitrile at room
temperature6 (Scheme 1, Table 1). Sulfones 3 were ob-
tained pure and did not need any further purification. The
oxidation step could be carried out with Oxone®, but the
yields were generally lower and purification by flash
F3C
O2
S
O
EWG
S
O2
R
S
O2
CO2R
O
F3C
R = Me (TSE), H (PSE), MeSO2
EWG = NO2 (Nsc), Br (Bsc), MeSO2 (Mpc)
Figure 1
Scheme 1
Synthesis 2003, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2003,0,02,0277,0287,ftx,en;P06002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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D. A. Alonso et al.
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Table 1 Synthesis of π-Deficient 2-(Arylsulfonyl)ethanols 3
Entry
Ar
2
3
No.
Yield (%)a
Rfb
No.
Yield (%)c
Mp (°C)d or Rfe
1
2
3
4
5
3,5-(CF3)2C6H3
3-CF3C6H4
4-NO2C6H4
3,4-Cl2C6H3
Ph
2a
2b
2c
2d
2e
97
80
86
82
0.49
0.40
0.22
0.46
0.37
3a
3b
3c
3d
3e
93 (79)
80 (70)
81 (81)
72 (68)
68 (62)
116–117
0.66
118–119f
81–82
0.59g
g
–
a Isolated yield after flash chromatography.
b Hexane–EtOAc, 2:1.
c Isolated crude yield. All crude alcohols 3 gave satisfactory spectroscopic data (1H and 13C NMR, IR and MS). In brackets, isolated yield of
sulfones 3, employing Oxone® as oxidant.
d Hexane–CH2Cl2.
e EtOAc.
f Lit.7 126–127 °C (CHCl3).
g Commercially available.
Table 2 Protection of Cinnamic and Hydrocinnamic Acids with 2-
(Arylsulfonyl)ethanols 3
chromatography was required to obtain sulfones 3 pure
(Table 1).
En-
try
Ar
R
Product
No.
To optimize the conditions for the protection reaction and
find the most efficient protecting group, hydrocinnamic
and trans-cinnamic acids were chosen as the model sub-
strates. The coupling reactions were performed in the
presence of EDC [1-(3-dimethylaminopropyl)-3-ethylcar-
bodiimide hydrochloride], and DMAP in ethanol-free
CH2Cl2 [Scheme 2, R = PhCH2CH2, trans-PhCH=CH].
When DCC was used as coupling agent, the resulting es-
ters 4 had to be purified by flash chromatography, purifi-
cation that was avoided with the water soluble reagent
EDC. Furthermore, when the solvent contained EtOH, we
could observe the formation of ethyl esters as secondary
products in the protection reaction, which decreased to
some extent the yield of the reaction. The best results in
the protection step, were obtained with 2-[3,5-bis(tri-
fluoromethyl)phenylsulphonyl]ethanol (3a), 2-(4-nitro-
phenylsulphonyl)ethanol (3c) and 2-(3,4-dichloro-
phenylsulphonyl)ethanol (3d) (Table 2, Entries 1, 2 and
5–8), where the corresponding crude esters were obtained
pure, as determined by 1H NMR, and in high yields. The
low yield observed with the 3-(trifluoromethyl)phenylsul-
phonyl derivative, was due to partial decomposition of the
alcohol under the reaction conditions (Table 2, Entries 3
and 4). Under the above mentioned reaction conditions, 2-
(phenylsulphonyl)ethanol (3e), a frequently used carbox-
ylic acid protecting group, afforded the corresponding es-
ters 4ea and 4eb in a low yield (Table 2, Entries 9 and 10).
Yield Mp (ºC)b
(%)a or Rfc
CF3
1
PhCH2CH2
4aa
80
0.63
F3C
2
3
PhCH=CH
PhCH2CH2
4ab
4ba
92
41
0.51
0.37
CF3
4
5
PhCH=CH
PhCH2CH2
4bb
4ca
35
84
0.41
115–116
O2N
6
7
PhCH=CH
PhCH2CH2
4cb
4da
88
80
161–162
80–81
Cl
Cl
8
9
PhCH=CH
PhCH2CH2
4db
4ea
79
50
0.42
0.41
O
R
EDC, DMAP
CH2Cl2, r.t.
OH
ArO2S
RCO2H
+
ArO2S
O
10
PhCH=CH
4eb
56
0.44
3
4
a Isolated crude yield. All crude compounds gave satisfactory spectro-
scopic data (1H and 13C NMR, IR and MS).
b Hexane–CH2Cl2.
Scheme 2
c Hexane–EtOAc, 2:1.
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π-Deficient 2-(Arylsulfonyl)ethyl Esters as Protecting Groups for Carboxylic Acids
279
The optimization of the reaction conditions for the depro- which has been previously reported for efficient deprotec-
tection of carboxylic esters 4 was carried out with com- tion of TSE-protected carboxylic acids,2f gave very poor
pound 4ab as a model substrate. Ester 4ab, derived from results in the deprotection reaction at 0 °C of the 3,5-
2-[3,5-bis(trifluoromethyl)phenylsulfonyl]ethanol
and bis(trifluoromethyl)phenylsulfonyl derivative 4ab (30
trans-cinnamic acid, was subjected to deprotection under and 21% of recovered sulfone and carboxylic acid, re-
different basic conditions (Scheme 3, Table 3). When us- spectively) (Table 3, Entry 8). When TBAOH was used as
ing NaOAc as base, very low conversions for the depro- base, a 64% yield of dimeric sulfone 7 was obtained in-
tection reaction were observed both in aqueous methanol stead of the vinylic sulfone (Scheme 4, Table 3, Entry 9).
and aqueous acetone (Table 3, Entries 1–4). When the re- Finally, we found that the best conditions for the deprotec-
action was carried out in MeOH–H2O (1:1) at 65 °C, an tion of ester 4ab employed 1.5 equivalents of NaHCO3 in
80% yield of methyl ether 6 was obtained as a conse- acetone–H2O (1:1), yielding the vinylic sulfone and the
quence of a Michael addition of the solvent over the pre- recovered trans-cinnamic acid with very high yields after
viously formed vinylic sulfone 5a (Scheme 4). With the acid–base extractive work-up (Table 3, Entries 10 and
stronger bases such as KOH, only decomposition products 11).
were observed when the reaction was carried out in ace-
tone–H2O (1:1) (Table 3, Entry 5). Changing the solvent
to MeOH or t-BuOH, led to high conversions of ether 6
and dimeric sulfone 7, respectively. Sulfone 7 was gener-
ated as a result of a Michael addition of alcohol 3a (prob-
ably generated by hydrolysis of ester 4ab) to the
previously formed vinylic sulfone 5a (Scheme 4). TBAF,
Once we optimized the conditions for the deprotection
step, and in order to find out the π-deficient derivative
with the best ability as leaving group, we carried out the
deprotection of the diverse π-deficient esters 4 previously
prepared under the above-mentioned conditions
(Scheme 5, Table 4).
CF3
CF3
O
Base
+
O
Ph
Solvent, T
Ph
OH
F3C
S
O2
F3C
S
O2
O
5a
4ab
Scheme 3
Table 3 Deprotection of Ester 4ab; Reaction Conditions Optimization
Entry
Base (equiv)
NaOAc (2.2)
NaOAc (2.2)
NaOAc (2.2)
NaOAc (2.2)
KOH (1.5)
Solvent
Temp (°C)
t (h)
48
24
48
24
12
12
12
5
Yield (%)a
38 (30)
(40)b
1
2
MeOH–H2O (1:1)
MeOH–H2O (1:1)
acetone–H2O (1:1)
acetone–H2O (1:1)
acetone–H2O (1:1)
MeOH–H2O (1:1)
t-BuOH–H2O (1:1)
THF
25
65
25
60
25
25
25
0
–
3
25 (20)
28 (25)
4
c
5
–
6
KOH (1.5)
–
–
(37)b
(51)d
7
KOH (1.5)
8
TBAF (3)
30 (21)e
(41)f
9
TBAOH (3)
NaHCO3 (1.5)
NaHCO3 (1.5)
THF
0
1
–
10
11
MeOH–H2O (1:1)
acetone–H2O (1:1)
25
25
12
12
80 (91)
87 (96)
a Isolated crude yield of vinyl sulfone 5a. In brackets, isolated crude yield of trans-cinnamic acid. All crude compounds gave satisfactory spec-
troscopic data (1H and 13C NMR, IR and MS).
b Compound 6 (see Scheme 4) was also obtained in a 80% yield.
c Only decomposition of starting material was observed (1H NMR).
d Compound 7 (see Scheme 4) was also obtained in a 88% yield.
e Compound 7 (see Scheme 4) was also obtained in a 22% yield.
f Compound 7 (see Scheme 4) was also obtained in a 64% yield.
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D. A. Alonso et al.
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CF3
MeOH, base
OMe
F3C
S
O2
CF3
6
F3C
S
O2
CF3
CF3
5a
t-BuOH, base
CF3
O
F3C
S
O2
S
O2
CF3
OH
F3C
S
O2
7
3a
Scheme 4
Table 4 Deprotection of Cinnamic and Hydrocinnamic Esters
Entry
Ar
R
No.
5
Mp (°C)b or Rfc
112–114
Recovered Acid
Yield (%)a
Yield (%)a
1
PhCH2CH2
4aa
84
93
CF3
F3C
2
3
PhCH=CH
PhCH2CH2
4ab
4ba
87
60
96
42
0.62
CF3
d
d
4
5
PhCH=CH
PhCH2CH2
4bb
4ca
-
-
74
115–117
59–60
74
O2N
6
7
PhCH=CH
PhCH2CH2
4cb
4da
69
82
57
68
Cl
Cl
8
9
PhCH=CH
PhCH2CH2
4db
4ea
77
60
61
62
69–70e
10
PhCH=CH
4eb
58
60
a Isolated crude yield. All crude compounds gave satisfactory spectroscopic data (1H and 13C NMR, IR and MS).
b Hexane–CH2Cl2.
c Hexane–EtOAc, 2:1.
d Only decomposition products were observed in the crude reaction mixture (1H NMR).
e Commercially available.
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π-Deficient 2-(Arylsulfonyl)ethyl Esters as Protecting Groups for Carboxylic Acids
281
with sat. aq NH4Cl (10 mL) and extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried (Na2SO4), the solvents
were removed and, after flash chromatography of the residue (silica
gel; hexane–EtOAc), pure sulfides 2 were obtained. Yields and
physical data are included in Table 1. Spectral and analytical data
follow.
O
R
NaHCO3 (1.5 equiv)
Acetone/H2O, r.t.
ArSO2
RCO2H
+
ArSO2
O
4
5
Scheme 5
2-[3,5-Di(trifluoromethyl)phenylsulfanyl]-1-ethanol (2a)
IR (film): 3394, 1355, 1281, 1180, 1137 cm–1.
In all the cases, the deprotection process took place easily
and under very mild conditions, except for the 3-trifluoro-
methyl derivative 4bb, which totally decomposed during
the deprotection reaction (Table 4, Entry 4). The 2-[3,5-
bis(trifluoromethyl)phenylsulfonyl]ethyl esters (Table 4,
Entries 1 and 2), gave the highest yield of recovered cin-
namic and hydrocinnamic acids. It is important to com-
pare these results with those obtained when 2-
(phenylsulfonyl)ethanol (3e) was used as the protecting
group, which afforded a modest yield in the deprotection
reaction under the described conditions (Table 4, Entries
9 and 10).
1H NMR (300 MHz, CDCl3–TMS): δ = 7.76 (s, 2 H, ArH), 7.66 (s,
1 H, ArH), 3.86 (t, J = 6.1, 2 H, CH2O), 3.23 (t, 2 H, J = 6.1, CH2S),
2.97 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3–TMS): δ = 139.81 (ArC), 132.04 (q,
JCF = 33.0, 2 × CF3), 127.97, 127.92, 119.43 (ArCH), 122.91 (q,
JCF = 271.9, 2 × CCF3), 60.31 (CH2O), 35.82 (CH2S).
MS: m/z = 291 [(M + 1)+, 20], 290 (M+, 66), 271 (13), 261 (17), 260
(63), 259 (64), 246 (100), 245 (34), 244 (18), 240 (24), 239 (65),
227 (64), 226 (22), 225 (28), 195 (66), 190 (12), 189 (11), 182 (17),
176 (14), 163 (19), 157 (12), 144 (14), 132 (15).
HRMS: m/z calcd for C10H8SOF6: 290.0200 (M+); found: 290.0195.
2-[3-(Trifluoromethyl)phenylsulfanyl]-1-ethanol (2b)
Finally, reaction of different carboxylic acids with alcohol
3a under the above mentioned conditions, afforded pure
esters after extractive work-up [Scheme 2, Ar = 3,5-
bis(trifluoromethyl)phenyl, Table 5]. Yields were gener-
ally high for the protection and deprotection procesess and
the reactions took place easily with aliphatic and aromatic
carboxylic acids, even in the case of hindered substrates
(Table 5, Entries 6 and 7). Enantiomerically pure carbox-
ylic acids were protected and deprotected with no loss in
the optical yield (Table 5, Entries 8, 10, 11 and 12). Base-
sensitive N-protecting groups such as Fmoc remained in-
tact as in the case of the reaction of Fmoc-protected phe-
nylalanine (Table 5, Entry 10).
IR (film): 3368, 1323, 1274, 1169, 1128 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 7.59 (s, 1 H, ArH), 7.51 (d,
1 H, J = 7.3, ArH), 7.44–7.33 (m, 2 H, ArH), 3.78 (t, 2 H, J = 6.2,
CH2O), 3.37 (br s, 1 H, OH), 3.14 (t, 2 H, J = 6.2, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 137.08 (ArC), 131.15 (q,
JCF = 31.8, CF3), 132.06, 129.19, 125.45, 125.41, 122.78, 122.73,
122.67 (ArCH), 122.26 (q, JCF = 272.2, CCF3), 60.24 (CH2O),
36.08 (CH2S).
MS: m/z (%) = 223 [(M + 1)+, 31], 222 (M+, 32), 203 (15), 193 (24),
192 (34), 192 (36), 191 (30), 179 (13), 178 (100), 177 (31), 172
(14), 171 (23), 170 (36), 159 (70), 158 (31), 157 (34), 145 (34), 133
(12), 127 (34), 125 (13), 122 (10), 114 (22), 109 (10), 108 (25), 95
(16), 75 (12), 69 (12), 63 (10).
HRMS: m/z calcd for C9H9SOF3: 222.0326 (M+); found:
222.01328.
In conclusion, we have introduced the 2-[3,5-bis(tri-
fluoromethyl)phenylsulfonyl]-1-ethanol (3a) as a new
stable and crystalline reagent, which can be used as an ef-
ficient protecting group for carboxylic acids. The high
yields, simplicity and very mild conditions required for
the protection–deprotection sequence favour this new re-
agent as a good alternative to established carboxylic acid
base-labile protecting agents.
2-(3,4-Dichlorophenylsulfanyl)-1-ethanol (2d)
IR (film): 3338, 1336, 1280, 1176, 1128, 846, 716 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 7.42 (d, 1 H, J = 2.1, ArH),
7.32 (d, 1 H, J = 8.4, ArH), 7.16 (dd, 1 H, J = 8.4, 2.1, ArH), 3.76
(t, 2 H, J = 6.3, CH2O), 3.44 (br s, 1 H, OH), 3.09 (t, 2 H, J = 6.3,
CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 135.84, 135.78, 132.59
(ArC), 130.34, 130.25, 128.23 (ArCH), 60.16 (CH2O), 37.27
(CH2S).
MS: m/z (%) = 224 [(M + 2)+, 48], 222 (M+, 70), 195 (13), 193 (68),
192 (13), 191 (100), 180 (40), 179 (11), 178 (59), 156 (17), 155
(13), 145 (13), 144 (14), 143 (23), 142 (34), 121 (13), 111 (12), 109
(20), 108 (12), 107 (13), 75 (15), 74 (14), 63 (12).
Commercial chemicals and solvents were used without further pu-
rification unless otherwise stated. Flash chromatography (FC): sili-
ca gel 60 (0.040–0.063 mm; Merck). TLC: Polygram® SIL G/
UV254 plates; detection with hexane–EtOAc (2:1). Mp (hexane–
CH2Cl2): Reichert Thermovar. IR Spectra: Nicolet Impact 400D-FT
spectrophotometer; in cm–1. NMR Spectra: Bruker AC-300 spec-
trometer; CDCl3, δ in ppm rel. to SiMe4 ( = 0 ppm), J in Hz. EI-MS:
Mass Selective Detector G2579A from Agilent Tecchologies
5973N; in m/z (rel. intensity in% of base peak). HRMS: Finningan
MAT95S apparatus. Elemental analysis: Carlo Erba EA 1108
(CHNS-O); by the corresponding services at the University of Ali-
cante. EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride.
HRMS: m/z calcd for C8H8SOCl2: 221.9673 (M+); found: 221.9699.
Oxidation of Thioethers 2 with H2O2–MnSO4–NaHCO3; Gener-
al Procedure6
To a stirred solution of the corresponding thioether 2 (1 mmol) and
MnSO4 H2O (2 mg, 1 mol%) in MeCN (23 mL) was added at r.t. a
mixture, previously prepared at 0 °C, of H2O2 (30%; 515 µL, 5
mmol) and a buffer solution of NaHCO3 (0.2 M; 17 mL). The reac-
tion mixture was vigorously stirred for 15–30 min at r.t., treated
with sat. aq NaCl (30 mL) and extracted with EtOAc (2 × 20 mL).
The combined organic layers were dried (Na2SO4), and evaporation
2-(Arylsulfanyl)ethanols 2; General Procedure
To a stirred solution of the corresponding thiol 1 (5 mmol) and Et3N
(1.4 mL, 10 mmol) in MeCN (15 mL), was added 2-bromoethanol
(908 µL, 5.5 mmol). The reaction was stirred for 1 d at r.t., treated
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D. A. Alonso et al.
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Table 5 Protection–Deprotection of Carboxylic Acids with 2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethanol (3a)
4
5
Entry
1
RCO2H
No.
Yield (%)a
80
Mp (°C)b or Rfc
0.63
Yield (%)d
4aa
84 (93)
CO2H
CO2H
Ph
Ph
2
3
4
4ab
4ac
4ad
92
86
98
98–99
0.64
84 (91)
91 (95)
81 (94)
CO2H
CO2H
0.52
Br
5
6
4ae
4af
79
40
160–161
0.38
79 (91)
91 (98)
NC
CO2H
OMe
CO2H
MeO
7
4ag
65
167–168
84 (83)
CO2H
NH2
N
8
9
4ah
4ai
90e
96
0.61
0.52
80 (73)f
98 (99)g
Me
NHBoc
HO2C
10
11
4aj
87e
168–169
0.67
83 (85)h
94 (97)i,j
Ph
NHFmoc
HO2C
4ak
>99
12
4al
98
0.60
92 (87)k
Me
O
Cl
CO2H
a Isolated crude yield. All crude compounds gave satisfactory spectroscopic data (1H and 13C NMR, IR and MS).
b Hexane–CH2Cl2.
c Hexane–EtOAc, 2:1.
d Isolated crude yield of vinyl sulfone 5. In brackets, isolated yield of recovered carboxylic acid. Both products gave satisfactory spectroscopic
data (1H and 13C NMR, IR and MS).
e Isolated yield after flash chromatography.
f [α]D25 –25 (c 2.26, HOAc) {lit.8 [α]D25 –27 (c 2.26, HOAc)}.
g 6 Equiv of NaHCO3 were used.
h [α]D37 –31 (c 1, DMF) {lit.8 [α]D25 –37.6 (c 1, DMF)}.
i 3 Equiv of NaHCO3 were used.
j [α]D26 +64 (c 1, CHCl3) {lit.8 [α]D25 +66 (c 1, CHCl3)}.
k [α]D29+18 (c 1, CH2Cl2) {lit.9 α]D29 +18.1 (c 1, CH2Cl2)}.
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283
under reduced pressure of the organic solvents, afforded the corre-
2-(3,4-Dichlorophenylsulfonyl)-1-ethanol (3d)
sponding pure sulfones 3 (>95% by 1H NMR).
IR (KBr): 3409, 1310, 1231, 1147, 1088, 821, 722 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.03 (s, 1 H, ArH), 7.79–
7.75 (m, 1 H, ArH), 7.69–7.65 (m, 1 H, ArH), 4.04 (t, 2 H, J = 5.6,
CH2O), 3.39 (t, 2 H, J = 5.6, CH2S), 2.51 (s exch., 1 H, OH).
13C NMR (75 MHz, CDCl3–TMS): δ = 139.14, 138.94, 134.11
(ArC), 131.46, 129.98, 127.05 (ArCH), 58.39 (CH2O), 56.10
(CH2S).
MS: m/z (%) = 256 [(M + 2)+, 22], 254 (M+, 33), 227 (26), 226 (42),
213 (55), 212 (13), 211 (78), 210 (12), 209 (28), 195 (27), 193 (48),
164 (37), 163 (14), 162 (62), 161 (27), 159 (18), 150 (21), 149 (26),
148 (82), 147 (81), 146 (76), 145 (100), 133 (12), 112 (10), 111
(48), 110 (29), 109 (75), 84 (10), 83 (12), 75 (49), 74 (41).
Oxidation of Thioethers 2 with Oxone®; General Procedure
To a stirred solution of the corresponding thioether 2 (1 mmol) in
MeOH–H2O (1:1; 20 mL) was added portionwise at 0 °C Oxone®
(15.37 g, 10 mmol). The reaction mixture was vigorously stirred for
1 d at r.t. After evaporation of the MeOH, CH2Cl2 (20 mL) was add-
ed, and the mixture was washed with a sat. aq NaCl (3 × 20 mL).
The organic layer was dried (Na2SO4) and solvent removal and flash
chromatography of the residue (silica gel; hexane–EtOAc) afforded
pure sulfones 3. Yields and physical data are included in Table 1.
Spectral and analytical data follow.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]-1-ethanol (3a)
HRMS: m/z calcd for C8H8SO3Cl2: 253.9571 (M+); found:
253.9583.
IR (KBr): 3496, 1367, 1282, 1186, 1141 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (s, 2 H, ArH), 8.18 (s,
1 H, ArH), 4.13 (t, 2 H, J = 4.9, CH2O), 3.47 (t, 2 H, J = 4.9, CH2S),
2.47 (br s, 1 H, OH).
Anal. Calcd for C8H8SO3Cl2 H2O: C, 35.30; H, 3.71; S, 11.76.
Found: C, 35.34; H, 2.97; S, 11.98.
13C NMR (75 MHz, CDCl3–TMS): δ = 142.46 (ArC), 133.19 (q,
JCF = 34.2, 2 × CF3), 128.65, 128.59, 127.56 (ArCH), 122.29 (q,
Protection of Carboxylic Acids; General Procedure
A solution of the corresponding alcohol 3 (1 mmol), EDC (1.2
mmol, 235 mg), DMAP (0.1 mmol, 17 mg) and the carboxylic acid
(1 mmol) in distilled CH2Cl2 (15 mL), was stirred under at r.t. for 12
h. After hydrolysis with aq HOAc (5%; 20 mL) and extraction with
CH2Cl2 (2 × 15 mL), the organic phases were dried (Na2SO4) and
evaporated to afford pure esters 4 (>95% by 1H NMR). Yields and
physical data are included in Tables 2 and 5. Spectral and analytical
data follow.
JCF = 273.4, 2 × CCF3), 58.45 (CH2O), 56.23 (CH2S).
MS: m/z (%) = 322 (M+, 3), 321 [(M – 1)+, 2], 303 (23), 292 (22),
279 (100), 277 (29), 261 (39), 259 (21), 230 (18), 227 (40), 214
(28), 213 (93), 195 (40), 194 (37), 163 (34), 145 (47), 144 (29), 143
(15).
HRMS: m/z calcd for C10H8SO3F6: 322.0098 (M+); found:
322.0097.
Anal. Calcd for C10H8SO3F6: C, 37.27; H, 2.50; S, 9.93. Found: C,
36.78; H, 2.50; S, 9.82.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 3-Phenylpro-
panoate (4aa)
IR (film): 1744, 1358, 1336, 1281, 1182, 1146, 1111 cm–1.
2-[3-(Trifluoromethyl)phenylsulfonyl]-1-ethanol (3b)
1H NMR (300 MHz, CDCl3–TMS): δ = 8.39 (s, 2 H, ArH), 8.17 (s,
1 H, ArH), 7.30–7.14 (m, 3 H, ArH), 7.09 (d, 2 H, J = 6.9, ArH),
4.47 (t, 2 H, J = 5.9, CH2O), 3.47 (t, 2 H, J = 5.9, CH2S), 2.81 (t, 2
H, J = 7.6, CH2CO), 2.39 (t, 2 H, J = 7.6, PhCH2).
13C NMR (75 MHz, CDCl3–TMS): δ = 171.85 (C=O), 142.50,
139.72 (ArC), 133.26 (q, JCF = 34.0, 2 × CF3), 128.65, 128.47,
128.10, 127.54, 126.40 (ArCH), 122.25 (q, JCF = 274.4, 2 × CCF3),
57.13 (CH2O), 55.22 (CH2S), 35.05 (CH2CO), 30.44 (CH2Ph).
MS: m/z (%) = 454 (M+, 1), 453 [(M – 1)+, 5], 277 (11), 213 (97),
133 (12), 131 (10), 107 (19), 105 (100), 104 (12), 103 (26), 91 (45),
79 (19), 78 (12), 77 (28).
HRMS: m/z calcd for C19H16SO4F6: 454.0674 (M+); found:
454.0653.
IR (film): 3350, 1327, 1237, 1143, 1073 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.22 (s, 1 H, ArH), 8.16 (d,
1 H, J = 7.9, ArH), 7.96 (d, 1 H, J = 7.9, ArH), 7.78 (t, 1 H, J = 7.9,
ArH), 4.46 (t, 2 H, J = 5.8, CH2O), 3.55 (t, 2 H, J = 5.8, CH2S),
3.50 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3–TMS): δ = 140.44 (ArC), 131.80 (q,
JCF = 32.5, CF3), 130.67, 130.25, 125.12, 125.07 (ArCH), 122.96
(q, JCF = 272.2, CCF3), 58.24 (CH2O), 56.08 (CH2S).
MS: m/z (%) = 254 (M+, 8), 225 (58), 226 (32), 224 (46), 213 (11),
212 (18), 211 (45), 210 (21), 209 (29), 194 (17), 193 (77), 191 (18),
172 (70), 165 (15), 163 (10), 162 (57), 160 (10), 159 (100), 147
(26), 146 (45), 145 (22), 143 (12), 133 (11), 127 (90), 126 (80), 125
(99), 119 (18), 114 (12), 96 (31), 95 (89), 76 (20), 75 (76), 69 (10),
65 (11), 63 (12), 51 (11).
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl (E)-3-Phenyl-
2-propenoate (4ab)
HRMS: m/z calcd for C9H9SO3F3: 254.0224 (M+); found: 254.0221.
IR (film): 1696, 1382, 1281, 1192, 1138 cm–1.
2-(4-Nitrophenylsulfonyl)-1-ethanol (3c)7
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (s, 2 H, ArH), 8.05 (s,
1 H, ArH), 7.51–7.35 (m, 6 H, ArH and CH=), 6.01 (d, 1 H,
J = 16.1, CH=), 4.60 (t, 2 H, J = 5.6, CH2O), 3.70 (t, 2 H, J = 5.6,
CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 165.75 (C=O), 142.70,
139.72 (ArC), 146.53, 115.58 (CH=CH), 133.29 (q, JCF = 34.0,
2 × CF3), 130.89, 128.96, 128.93, 128.65, 128.14 (ArCH), 122.25
(q, JCF = 273.3, 2 × CCF3), 57.59 (CH2O), 55.38 (CH2S).
MS: m/z (%) = 452 (M+, 5), 213 (95), 175 (10), 148 (11), 147 (12),
103 (45), 102 (100), 77 (97).
HRMS: m/z calcd for C19H14SO4F6: 452.0517 (M+); found:
452.0529.
IR (KBr): 3531, 1534, 1348, 1289, 1137, 1080, 1026 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.44 (d, 2 H, J = 8.9, ArH),
8.16 (d, 2 H, J = 8.9, ArH), 4.08 (t, 2 H, J = 5.4, CH2O), 3.44 (t, 2
H, J = 5.4, CH2S), 1.58 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3–TMS): δ = 142.71, 126.35 (ArC),
129.60, 124.55 (ArCH), 58.38 (CH2O), 56.23 (CH2S).
MS: m/z (%) = 223 [(M + 1)+, 31], 231 (M+, 10), 203 (18), 201 (78),
190 (17), 189 (29), 188 (59), 187 (12), 186 (34), 171 (17), 170 (73),
166 (17), 157 (16), 149 (38), 141 (27), 140 (11), 139 (25), 136 (11),
124 (95), 123 (100), 122 (98), 109 (31), 106 (21), 95 (11), 93 (19),
92 (57), 90 (10), 78 (28), 77 (91), 76 (86), 75 (99), 74 (41), 65 (63),
64 (31), 63 (51), 51 (44).
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D. A. Alonso et al.
PAPER
2-[3-(Trifluoromethyl)phenylsulfonyl]ethyl 3-Phenylpropan-
oate (4ba)
13C NMR (75 MHz, CDCl3–TMS): δ = 165.70 (C=O), 150.82,
145.24, 133.51 (ArC), 146.18, 115.93 (CH=CH), 130.94, 129.73,
129.03, 127.99, 124.43 (ArCH), 57.51 (CH2O), 55.20 (CH2S).
IR (film): 1740, 1327, 1235, 1142, 1104, 1074 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.20 (s, 1 H, ArH), 8.09 (d,
1 H, J = 7.9, ArH), 7.91 (d, 1 H, J = 7.9, ArH), 7.70 (t, 1 H, J = 7.9,
ArH), 7.32–7.07 (m, 5 H, ArH), 4.43 (t, 2 H, J = 5.9, CH2O), 3.44
(t, 2 H, J = 5.9, CH2S), 2.80 (t, 2 H, J = 7.6, CH2CO), 2.37 (t, 2 H,
J = 7.6, PhCH2).
MS: m/z (%) = 361 (M+, 99), 170 (15), 147 (98), 102 (100), 77 (27),
76 (14), 75 (11), 56 (41).
HRMS: m/z calcd for C17H15SO6N: 361.0620 (M+); found:
361.0637.
13C NMR (75 MHz, CDCl3–TMS): δ = 172.01 (C=O), 140.76,
140.19 (ArC), 132.09 (q, JCF = 34.2, 2 × CF3), 128.49, 128.22,
128.14, 126.37, 126.31, 126.18, 125.33 (ArCH), 122.99 (q,
2-(3,4-Dichlorophenylsulfonyl)ethyl 3-Phenylpropanoate (4da)
IR (KBr): 1743, 1302, 1287, 1141, 1098, 833, 698 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.00 (s, 1 H, ArH), 7.70 (d,
1 H, J = 8.4, ArH), 7.62 (d, 1 H, J = 8.4, ArH), 7.31–7.12 (m, 5 H,
ArH), 4.42 (t, 2 H, J = 6.0, CH2O), 3.42 (t, 2 H, J = 6.0, CH2S),
2.83 (t, 2 H, J = 7.5, CH2CO), 2.43 (t, 2 H, J = 7.5, PhCH2).
JCF = 273.3, 2 × CCF3), 57.36 (CH2O), 55.08 (CH2S), 35.12
(CH2CO), 30.57 (PhCH2).
MS: m/z (%) = 386 (M+, 0.44), 145 (36), 104 (34), 91 (13), 58 (100).
HRMS: m/z calcd for C18H17SO4F3: 386.0800 (M+); found:
386.0813.
13C NMR (75 MHz, CDCl3–TMS): δ = 171.94 (C=O), 139.88,
139.14, 139.08, 134.02 (ArC), 131.34, 130.17, 128.49, 128.14,
127.17, 126.35 (ArCH), 57.32 (CH2O), 55.11 (CH2S), 35.24
(CH2CO), 30.48 (PhCH2).
MS: m/z (%) = 388 [(M + 2)+, 2], 386 (M+, 4), 195 (19), 145 (99),
109 (11), 105 (100), 103 (20), 91 (39), 79 (14).
2-[3-(Trifluoromethyl)phenylsulfonyl]ethyl (E)-3-Phenyl-2-
propenoate (4bb)
IR (film): 1716, 1637, 1327, 1277, 1142, 1073 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.23 (s, 2 H, ArH), 8.15 (d,
1 H, J = 7.9, ArH), 7.86 (d, 1 H, J = 7.9, ArH), 7.71 (t, 1 H, J = 7.9,
ArH), 7.49–7.39 (m, 5 H, ArH and CH=), 6.06 (d, 1 H, J = 16.1,
CH=), 4.59 (t, 2 H, J = 5.8, CH2O), 3.60 (t, 2 H, J = 5.8, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 165.90 (C=O), 140.99,
133.81 (ArC), 146.10, 116.15 (CH=CH), 132.29 (q, JCF = 34.0,
2 × CF3), 131.53, 130.75, 130.53, 130.17, 128.95, 128.14, 125.39
(ArCH), 122.15 (q, JCF = 273.2, 2 × CCF3), 57.68 (CH2O), 55.31
(CH2S).
MS: m/z = 386 [(M + 2)+, 18], 385 [(M + 1)+, 56], 384 (M+, 90), 237
(13), 209 (21), 193 (19), 176 (12), 175 (100), 148 (61), 147 (81),
146 (20), 145 (95), 132 (92), 131 (32), 130 (38), 105 (13), 104 (88),
103 (66), 102 (58), 95 (12), 78 (11), 77 (93), 76 (25), 74 (14), 50
(31).
HRMS: m/z calcd for C17H16SO4Cl2: 386.0146 (M+); found:
386.0146.
2-(3,4-Dichlorophenylsulfonyl)ethyl (E)-3-Phenyl-2-propen-
oate (4db)
IR (film): 1705, 1638, 1323, 1298, 1181, 1144, 827, 721 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.04 (d, 1 H, J = 2.1, ArH),
7.76 (dd, 1 H, J = 8.5, 2.1, ArH), 7.61 (dd, 1 H, J = 8.5, 2.1, ArH),
7.49–7.37 (m, 6 H, ArH, CH=), 6.10 (d, 1 H, J = 16.1, CH=), 4.58
(t, 2 H, J = 5.6, CH2O), 3.57 (t, 2 H, J = 5.6, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 165.82 (C=O), 139.45,
139.08, 134.11, 133.76 (ArC), 146.20, 116.11 (CH=CH), 131.37,
130.78, 130.30, 128.94, 128.21, 127.23 (ArCH), 57.68 (CH2O),
55.34 (CH2S).
MS: m/z (%) = 386 [(M + 2)+, 2], 385 [(M + 1) +, 1], 384 (M+, 28),
209 (11), 195 (12), 175 (67), 147 (99), 145 (99), 104 (34), 103
(100).
HRMS: m/z calcd for C17H14SO4Cl: 349.0301 (M+); found:
349.0351.
HRMS: m/z calcd for C18H15SO4F3: 384.0643 (M+); found:
384.0639.
2-(4-Nitrophenylsulfonyl)ethyl 3-Phenylpropanoate (4ca)
IR (KBr): 1733, 1532, 1349, 1291, 1229, 1145, 1081 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.37 (d, 2 H, J = 8.7, ArH),
8.07 (d, 2 H, J = 8.7, ArH), 7.33–7.06 (m, 5 H, ArH), 4.43 (t, 2 H,
J = 5.9, CH2O), 3.47 (t, 2 H, J = 5.9, CH2S), 2.82 (t, 2 H, J = 7.7,
CH2CO), 2.38 (t, 2 H, J = 7.7, PhCH2).
13C NMR (75 MHz, CDCl3–TMS): δ = 171.93 (C=O), 150.88,
144.92, 139.85 (ArC), 129.64, 128.55, 128.11, 126.44, 124.41
(ArCH), 57.18 (CH2O), 55.00 (CH2S), 35.27 (CH2CO), 30.44
(PhCH2).
MS: m/z (%) = 363 (M+, 3), 308 (68), 186 (27), 140 (75), 122 (100),
107 (19), 106 (19), 105 (70), 104 (15), 103 (10), 92 (30), 91 (38), 84
(17), 81 (11), 79 (62), 78 (11), 77 (37), 76 (65), 65 (16).
HRMS: m/z calcd for C17H17SO6N: 363.0776 (M+); found:
363.0768.
2-(Phenylsulfonyl)ethyl 3-Phenylpropanoate (4ea)
IR (film): 1740, 1300, 1283, 1140, 1090 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 7.98–7.82 (m, 2 H, ArH),
7.75–7.47 (m, 4 H, ArH), 7.28–7.06 (m, 4 H, ArH), 4.38 (t, 2 H,
J = 6.0, CH2O), 3.43 (t, 2 H, J = 6.0, CH2S), 2.77 (t, 2 H, J = 7.7,
CH2CO), 2.36 (t, 2 H, J = 7.7, PhCH2).
13C NMR (75 MHz, CDCl3–TMS): δ = 171.91 (C=O), 139.84,
139.09 (ArC), 133.74, 129.10, 128.25, 127.94, 127.66, 126.09
(ArCH), 57.38 (CH2O), 55.89 (CH2S), 34.93 (CH2CO), 30.21
(PhCH2).
MS: m/z (%) = 318 (M+, 4), 241 (22), 213 (44), 195 (10), 185 (99),
169 (100), 149 (31), 133 (65), 105 (20), 91 (39), 77 (14).
HRMS: m/z calcd for C17H18SO4; 318.0926 (M+); found: 318.0956.
2-(4-Nitrophenylsulfonyl)ethyl (E)-3-Phenyl-2-propenoate
(4cb)
IR (KBr): 1712, 1628, 1529, 1328, 1300, 1262, 1141, 1079 cm–1.
2-(Phenylsulfonyl)ethyl (E)-3-Phenyl-2-propenoate (4eb)
IR (film): 1725, 1630, 1310, 1288, 1171, 1140 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.39 (d, 2 H, J = 8.5, ArH),
8.16 (d, 2 H, J = 8.5, ArH), 7.48–7.35 (m, 6 H, ArH, CH=), 6.03 (d,
1 H, J = 15.9, CH=), 4.59 (t, 2 H, J = 5.5, CH2O), 3.63 (t, 2 H,
J = 5.5, CH2S).
1H NMR (300 MHz, CDCl3–TMS): δ = 7.88–7.74 (m, 2 H, ArH),
7.71–7.40 (m, 4 H, ArH), 7.28–6.98 (m, 5 H, ArH, CH=), 6.12 (d, 1
H, J = 16.1, CH=), 4.48 (t, 2 H, J = 5.8, CH2O), 3.53 (t, 2 H,
J = 5.8, CH2S).
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PAPER
π-Deficient 2-(Arylsulfonyl)ethyl Esters as Protecting Groups for Carboxylic Acids
285
13C NMR (75 MHz, CDCl3–TMS): δ = 165.72 (C=O), 139.45,
139.08 (ArC), 145.20, 117.11 (CH=CH), 130.97, 130.78, 129.30,
128.90, 127.91, 127.23 (ArCH), 57.12 (CH2O), 55.24 (CH2S).
MS: m/z (%) = 316 (M+, 18), 239 (17), 211 (34), 191 (16), 183 (67),
166 (100), 145 (29), 135 (22), 104 (10), 91 (66), 77 (44).
ArCH), 6.33 (dd, 1 H, J = 8.7, 2.2, ArCH), 4.66 (t, 2 H, J = 5.5,
CH2O), 3.84, 3.80 (2 s, 6 H, 2 × CH3O), 3.71 (t, 2 H, J = 5.5, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 164.95 (C=O), 163.90,
161.73, 142.72, 109.98 (ArC), 133.04 (q, JCF = 34.0, 2 × CF3),
133.47, 128.47, 128.43, 104.48, 98.74 (ArCH), 123.76 (q,
JCF = 273.3, 2 × CCF3), 57.40 (CH2O), 55.74, 55.49 (2 × CH3O),
55.46 (CH2S).
HRMS: m/z calcd for C17H16SO4: 316.0769 (M+); found: 316.0770.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl Butyrate (4ac)
MS: m/z (%) = 486 (M+, 3), 213 (17), 165 (42), 164 (50), 135 (100).
HRMS: m/z calcd for C19H16SO6F6: 486.0572 (M+); found:
IR (film): 1744, 1359, 1337, 1281, 1181, 1146, 1107 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (s, 2 H, ArH), 8.19 (s,
1 H, ArH), 4.50 (t, 2 H, J = 5.7, CH2O), 3.57 (t, 2 H, J = 5.7, CH2S),
1.99 (t, 2 H, J = 7.4, CH2CO), 1.46 (m, 2 H, J = 7.4, CH3CH2), 0.84
(t, 3 H, J = 7.4, CH3).
486.0547.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 2-Aminonicoti-
nate (4ag)
IR (KBr): 3474, 3365, 1710, 1621, 1366, 1295, 1249, 1180, 1141,
13C NMR (75 MHz, CDCl3–TMS): δ = 172.51 (C=O), 142.69
(ArC), 133.29 (q, JCF = 35.1, 2 × CF3), 128.74, 128.69 (ArCH),
122.28 (q, JCF = 274.4, 2 × CCF3), 57.13 (CH2O), 55.47 (CH2S),
35.35 (CH2CO), 17.94 (CH2), 13.35 (CH3).
MS: m/z (%) = 323 [(M – CF3)+, 19], 305 (35), 277 (79), 273 (23),
261 (35), 214 (27), 213 (67), 194 (19), 163 (17), 144 (13), 115
(100), 91 (12), 75 (12), 72 (16), 71 (87), 70 (98), 69 (14).
909, 735 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.37 (s, 2 H, ArH), 8.19 (dd,
1 H, J = 4.7, 1.7, ArH), 8.05 (s, 1 H, ArH), 7.49 (dd, 1 H, J = 7.8,
1.7, ArH), 6.48 (dd, 1 H, J = 7.8, 4.7, ArH), 6.20 (s exch., 2 H,
NH2), 4.71 (t, 2 H, J = 5.6, CH2O), 3.71 (t, 2 H, J = 5.6, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 165.77 (C=O), 159.26,
142.47, 127.46 (ArC), 154.30, 139.59, 128.41, 128.36, 127.50,
112.48 (ArCH), 133.28 (q, JCF = 35.1, 2 × CF3), 122.14 (q,
HRMS: m/z calcd for C13H14SO4F3: 323.0564 [M – CF3]+; found:
323.0555.
JCF = 273.1, 2 × CCF3), 57.68 (CH2O), 55.27 (CH2S).
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 2-Bromopro-
panoate (4ad)
MS: m/z (%) = 443 [(M + 1)+, 15], 442 (M+, 56), 279 (10), 277 (18),
213 (99), 194 (12), 165 (100), 163 (10), 122 (12), 120 (77), 92 (16).
HRMS: m/z calcd for C16H12SO4F6N2: 442.0424 (M+); found:
442.0430.
IR (film): 1749, 1340, 1280, 1183, 1146, 1108 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (s, 2 H, ArH), 8.20 (s,
1 H, ArH), 4.70–4.55 (m, 2 H, CH2O), 4.20–4.00 (m, 1 H, CHBr),
3.65–3.55 (m, 2 H, CH2S), 1.70 (d, 3 H, J = 6.9, CH3).
13C NMR (75 MHz, CDCl3–TMS): δ = 169.34 (C=O), 142.25
(ArC), 133.41 (q, JCF = 35.1, 2 × CF3), 128.71, 128.67, 127.85
(ArCH), 122.26 (q, JCF = 273.3, 2 × CCF3), 58.42 (CH2O), 55.09
(CH2S), 38.55 (CHBr), 21.08 (CH3).
MS: m/z (%) = 457 [(M + 2) +, 7], 455 (M+, 7), 305 (33), 279 (14),
278 (36), 277 (96), 261 (44), 261 (51), 214 (43), 213 (83), 194 (39),
181 (97), 179 (100), 163 (30), 144 (23), 143 (10), 137 (48), 136
(47), 136 (49), 135 (50), 134 (48), 134 (49), 109 (97), 107 (94), 100
(23), 63 (11), 56 (25), 55 (46).
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl (L)-N-(tert-
Butyloxycarbonyl)alaninate (4ah)
IR (film): 3373, 1752, 1707, 1514, 1363, 1280, 1170, 1146, 1109
cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (s, 2 H, ArH), 8.19 (s,
1 H, ArH), 4.84 (br s, 1 H, NH), 4.63–4.50 (m, 2 H, CH2O), 4.01–
3.91 (m, 1 H, CHN), 3.65–3.45 (m, 2 H, CH2S), 1.42 [s, 9 H,
(CH3)3C], 1.24 (d, 3 H, J = 7.1, CH3CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 172.73, 154.97 (C=O),
142.21 (ArC), 133.39 (q, JCF = 34.0, 2 × CF3), 128.63, 127.77
(ArCH), 122.26 (q, JCF = 273.3, 2 × CCF3), 80.13 [(CH3)3C], 57.62
(CH2O), 55.20 (CH2S), 28.18 [(CH3)3C], 14.15 (CH3CH).
HRMS: m/z calcd for C13H11SO4F6Br: 455.9466 (M+); found:
455.9486.
MS: m/z (%) = 323 [(M – C8H14O3N)+, 2], 213 (100), 88 (31).
1-[2-(4-Cyanophenylcarbonyloxy)ethylsulfonyl]-3,5-di(tri-
fluoromethyl)benzene (4ae)
HRMS: m/z calcd for C10H7SO3F6: 321.0020 (M+); found:
321.0098.
IR (KBr): 2229, 1734, 1333, 1279, 1141, 1113 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.39 (s, 2 H, ArH), 8.05 (s,
1 H, ArH), 4.80 (t, 2 H, J = 5.6, CH2O), 3.73 (t, 2 H, J = 5.6, CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 164.00 (C=O), 142.43,
132.30, 117.57 (ArC), 133.4 (q, JCF = 35.1, 2 × CF3), 132.22,
129.93, 128.44, 128.41, 127.54, 127.50 (ArCH), 117.57 (CN),
122.10 (q, JCF = 273.3, 2 × CCF3), 58.39 (CH2O), 55.04 (CH2S).
MS: m/z (%) = 451 (M+, 1), 261 (95), 214 (12), 213 (98), 194 (18),
175 (35), 174 (11), 163 (25), 147 (55), 144 (16), 131 (51), 103 (18),
102 (100), 76 (14), 75 (21), 51 (16).
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 4-(1,5-Dihy-
dro-6-pyrenyl)butanoate (4ai)
IR (film): 1742, 1338, 1279, 1185, 1147, 1106 cm–1.
1H NMR (300 MHz, CDCl3/TMS): δ = 8.37 (s, 2 H, ArH), 8.24–
8.06 (m, 6 H, ArH), 8.02 (s, 1 H, ArH), 7.98 (d, 2 H, J = 7.8, ArH),
7.78 (d, 1 H, J = 7.8, ArH), 4.40 (t, 2 H, J = 5.6, CH2O), 3.41 (t, 2
H, J = 5.6, CH2S), 3.31 (t, 2 H, J = 7.4, CH2CO), 2.22–2.14 (m, 2
H, ArCH2CH2), 2.12–1.80 (m, 2 H, ArCH2CH2).
13C NMR (75 MHz, CDCl3–TMS): δ = 172.32, 142.53, 135.04,
131.32, 130.76, 129.99 (ArC), 133.20 (q, JCF = 35.1, 2 × CF3),
128.67, 128.62, 127.39, 127.23, 126.76, 125.86, 125.00, 124.97,
124.87, 124.76, 124.72, 123.02 (ArCH), 122.24 (q, JCF = 274.4,
2 × CCF3), 57.10 (CH2O), 55.13 (CH2S), 33.01, 32.45, 26.13
[(CH2)3CO].
Anal. Calcd for C18H11SO4F6N: C, 47.89; H, 2.46; S, 7.09; N, 3.10.
Found: C, 47.69; H, 2.41; S, 7.13; N, 2.90.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 2,4-Dimeth-
oxybenzoate (4af)
IR (film): 1724, 1609, 1334, 1280, 1178, 1145, 1090 cm–1.
MS: m/z (%) = 592 (M+, 1), 589 (27), 588 (100), 588 (51), 587 (52),
288 (39), 271 (22), 261 (41), 242 (18), 241 (21), 239 (20), 229 (20),
228 (44), 227 (27), 226 (20), 217 (10), 216 (93), 215 (11), 214 (17),
213 (94), 202 (18), 189 (21), 107 (48).
1H NMR (300 MHz, CDCl3–TMS): δ = 8.34 (s, 2 H, ArH), 7.93 (s,
1 H, ArH), 7.31 (d, 1 H, J = 8.7, ArCH), 6.39 (d, 1 H, J = 2.2,
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D. A. Alonso et al.
PAPER
HRMS: m/z calcd for C30H22SO4F6: 592.1143 (M+); found:
592.1130.
(19), 144 (10), 143 (52), 127 (21), 125 (64), 107 (23), 100 (26), 99
(16), 89 (23), 55 (47).
HRMS: m/z calcd for C10H7SO2F6: 305.0054 (M+); found:
305.0060.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl N-(9-Fluor-
enylmethyloxycarbonyl)phenylalaninate (4aj)
IR (KBr): 3338, 1744, 1679, 1535, 1365, 1286, 1186, 1138 cm–1.
Deprotection of Esters 4; General Procedure
1H NMR (300 MHz, CDCl3–TMS): δ = 8.37 (s, 2 H, ArH), 8.18 (s,
1 H, ArH), 7.76 (d, 2 H, J = 7.4, ArH), 7.56–7.50 (m, 2 H, ArH),
7.43–7.19 (m, 8 H, ArH), 7.06 (d, 1 H, J = 5.8, ArH), 5.15 (d, 1 H,
J = 7.7, NH), 4.58–4.27 (m, 5 H, CH2CH2O, CHC, CHCH2O), 4.18
(t, 1 H, J = 6.7, CHN), 3.50–3.30 (m, 2 H, CH2S), 3.01–2.95 (m, 2
H, PhCH2).
13C NMR (75 MHz, CDCl3–TMS): δ = 171.01, 154.43 (C=O),
143.71, 143.64, 142.05, 141.29, 135.29, 127.88 (ArC), 133.43 (q,
JCF = 35.1, 2 × CF3), 129.10, 128.70, 128.62, 127.93, 127.72,
127.33, 127.04, 125.03, 124.97, 119.98 (ArCH), 122.26 (q,
JCF = 273.3, 2 × CCF3), 67.00 (CHCH2O), 57.57 (CH2CH2O),
54.90 (CH2S), 54.75 (CHN), 47.06 (CHC), 37.91 (PhCH2).
A solution of the corresponding ester 4 (0.2 mmol) and NaHCO3
(0.3 mmol, 26 mg) in acetone–H2O (1:1; 2 mL) was stirred at r.t. for
12 h. The reaction mixture was basified (pH 10) with sat. aq
NaHCO3, and extracted with EtOAc (2 × 10 mL). The organic
phase was dried (Na2SO4) and evaporation of the solvent afforded
the corresponding pure vinyl sulfone 5. The basic aq phase, was
acidified with aq HCl (2 M) (pH 2) and extracted with EtOAc
(2 × 10 mL). The organic phase was dried (Na2SO4) and evapora-
tion of the solvent afforded the corresponding pure carboxylic ac-
ids. Yields are included in Tables 4 and 5. Physical data for
compounds 5 are included in Table 4. Spectral and analytical data
follow.
MS: m/z (%) = 691 (M+, 0.02), 453 [(M – NHFmoc)+, 2], 452 (8),
261 (46), 213 (20), 179 (55), 178 (43), 166 (33), 165 (53), 104 (25),
91 (65), 57 (100), 55 (37).
HRMS: m/z calcd for C34H27SO6F6N: 691.1463 (M+); found:
691.1431.
3,5-Bis(trifluoromethyl)phenyl Vinyl Sulfone (5a)
IR (KBr): 1627, 1365, 1287, 1178, 1142 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.35 (s, 2 H, ArH), 8.14 (s,
1 H, ArH), 6.80–6.38 (m, 2 H, 1 × CH2=CH, CH2=CH), 6.25 (d, 1
H, J = 8.2, 1 × CH2=CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 142.69 (ArC), 137.03
(CH2=CH), 133.33 (q, JCF = 34.0, 2 × CF3), 130.92 (CH2=CH),
128.30, 128.26 (ArCH), 122.30 (q, JCF = 273.3, 2 × CCF3).
MS: m/z (%) = 304 (M+, 1), 263 (16), 261 (76), 213 (17), 189 (12),
122 (24), 121 (31), 91 (13), 79 (16), 72 (11), 71 (100), 56 (16).
HRMS: m/z calcd for C10H6SO2F6: 303.9992 (M+); found:
303.9995.
Anal. Calcd for C34H27SO6F6N: C, 59.03; H, 3.94; S, 4.63; N, 2.03.
Found: C, 58.97; H, 3.90; S, 4.49; N, 2.06.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 2-(6-Methoxy-
2-naphthyl)propanoate (4ak)
IR (film): 1736, 1627, 1335, 1278, 1142, 1100, 1026 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.37 (s, 2 H, ArH), 8.14 (s,
1 H, ArH), 7.66 (d, 2 H, J = 2.7, ArH), 7.63 (s, 1 H, ArH), 7.25–7.05
(m, 3 H, ArH), 4.58–4.33 (m, 2 H, CH2O), 3.89 (s, 3 H, CH3O),
3.57–3.36 (m, 3 H, CH2S, CH3CH), 1.44 (d, 3 H, J = 7.1, CH3CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 173.82 (C=O), 157.82,
142.43, 134.49, 133.77, 128.80 (ArC), 133.31 (q, JCF = 34.1,
2 × CF3), 129.18, 128.68, 128.62, 127.30, 125.85, 125.67, 119.21,
105.58 (ArCH), 122.26 (q, JCF = 273.3, 2 × CCF3), 57.44 (CH2O),
55.29 (CH3O), 55.24 (CH2S), 45.00 (CH3CH), 18.32 (CH3CH).
MS: m/z (%) = 536 [(M + 2)+, 28], 535 [(M + 1)+, 76], 534 (M+,
100), 487 (23), 261 (15), 213 (46), 212 (22), 186 (76), 185 (75), 184
(34), 171 (11), 170 (46), 169 (12), 155 (12), 154 (22), 153 (25), 142
(26), 141 (45), 115 (16), 92 (12).
3-(Trifluoromethyl)phenyl Vinyl Sulfone (5b)
IR (film): 1610, 1326, 1146 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.17 (s, 1 H, ArH), 8.11 (d,
1 H, J = 7.9, ArH), 7.91 (d, 1 H, J = 7.9, ArH), 7.74 (t, 1 H, J = 7.9,
ArH), 7.23 (dd, 1 H, J = 16.5, 9.5, CH2=CH), 6.55 (d, 1 H, J = 16.5,
1 × CH2=CH), 6.16 (d, 1 H, J = 9.5, 1 × CH2=CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 140.89 (ArC), 137.66
(CH2=CH), 131.98 (q, JCF = 34.0, 2 × CF3), 131.14, 130.25,
130.19, 124.91 (ArCH), 129.29 (CH2=CH), 123.00 (q, JCF = 273.3,
2 × CCF3).
MS: m/z (%) = 209 [(M – CH2=CH)+, 13], 193 (11), 145 (100), 111
(17).
HRMS: m/z calcd for C9H7SO2F3: 236.0119 (M+); found:
HRMS: m/z calcd for C34H27SO6F6N: 691.1463 (M+); found:
691.1431.
2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethyl 2-(4-Chloro-2-
methylphenoxy)propanoate (4al)
C9H7SO2F3; 236.0119.
IR (film): 1758, 1489, 1357, 1280, 1185, 1146, 1107, 734 cm–1.
4-Nitrophenyl Vinyl Sulfone (5c)7
IR (KBr): 1607, 1531, 1305, 1151 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.39 (s, 2 H, ArH), 8.18 (s,
1 H, ArH), 7.12 (d, 1 H, J = 2.5, ArH), 7.03 (dd, 1 H, J = 8.6, 2.5,
ArH), 6.54 (d, 1 H, J = 8.6, ArH), 4.79–4.48 (m, 3 H, CH2O,
CH3CH), 3.54–3.48 (m, 2 H, CH2S), 2.21 (m, 3 H, CH3Ar), 1.52 (d,
3 H, J = 6.7, CH3CH).
1H NMR (300 MHz, CDCl3–TMS): δ = 8.41 (d, 2 H, J = 8.6, ArH),
8.11 (d, 2 H, J = 9.2, ArH), 6.71 (dd, 1 H, J = 16.5, 9.2, CH2=CH),
6.60 (d, 1 H, J = 16.5, 1 × CH2=CH), 6.22 (d, 1 H, J = 9.2,
1 × CH2=CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 171.23 (C=O), 154.11,
142.12, 129.55, 126.35 (ArC), 133.49 (q, JCF = 34.0, 2 × CF3),
130.88, 128.59, 128.55, 127.74, 126.25, 113.03 (ArCH), 122.20 (q,
JCF = 273.3, 2 × CCF3), 72.67 (CH3CH), 57.45 (CH2O), 54.99
(CH2S), 18.18 (CH3Ar), 16.04 (CH3CH).
MS: m/z (%) = 520 [(M + 2)+, 32], 518 (M+, 100), 517 (76), 516
(44), 277 (73), 214 (15), 213 (66), 171 (17), 170 (31), 169 (14), 168
13C NMR (75 MHz, CDCl3–TMS): δ = 150.66, 145.27 (ArC),
137.20 (CH2=CH), 130.33 (CH2=CH), 129.26, 124.49 (ArCH).
MS: m/z (%) = 214 [(M + 1)+, 7], 213 (M+, 71), 186 (13), 172 (60),
171 (90), 170 (15), 168 (22), 167 (12), 155 (19), 140 (57), 124 (18),
123 (18), 122 (88), 118 (14), 112 (26), 96 (10), 92 (43), 91 (25), 84
(34), 77 (75), 76 (74), 75 (100), 74 (44), 65 (25), 64 (23), 63 (24),
59 (11), 51 (25).
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π-Deficient 2-(Arylsulfonyl)ethyl Esters as Protecting Groups for Carboxylic Acids
287
3,4-Dichlorophenyl Vinyl Sulfone (5d)10
References
IR (KBr): 1613, 1320, 1149, 820, 698 cm–1.
(1) (a) Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd. ed.; Wiley: New York, 1999.
1H NMR (300 MHz, CDCl3–TMS): δ = 7.89 (s, 1 H, ArH), 7.68–
7.53 (m, 2 H, ArH), 6.60 (dd, 1 H, J = 16.5, 9.8, CH2=CH), 6.43 (d,
1 H, J = 16.5, 1 × CH2=CH), 6.07 (d, 1 H, J = 9.8, 1 × CH2=CH).
13C NMR (75 MHz, CDCl3–TMS): δ = 139.27, 138.53, 133.81
(ArC); 137.51 (CH2=CH), 131.34 (CH2=CH), 129.65, 129.20,
126.84 (ArCH).
MS: m/z (%) = 239 [(M + 3)+, 4], 238 [(M + 2)+, 4], 237 [(M + 1)+,
3], 236 (M+, 6), 211 (32), 209 (60), 208 (31), 207 (60), 206 (91), 205
(93), 204 (76), 195 (28), 193 (45), 181 (17), 180 (10), 179 (95), 178
(15), 177 (100), 172 (12), 171 (24), 170 (32), 169 (66), 161 (13),
159 (12), 149 (12), 148 (12), 147 (69), 146 (22), 145 (84), 144 (34),
143 (14), 142 (94), 135 (15), 134 (29), 133 (20), 111 (25), 110 (16),
109 (55), 107 (14), 97 (12), 75 (28), 74 (21), 69 (15), 63 (11), 59
(13), 57 (18).
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1-(2-Methoxyethylsulfonyl)-3,5-bis(trifluoromethyl)benzene
(6)
(2) (a) Miller, A. W.; Stirling, C. J. M. J. Chem. Soc. C 1968,
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(6) This is a mild oxidation process for the general preparation
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Mp 66–67 °C.
IR (film): 1365, 1285, 1170, 1139 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.39 (s, 2 H, ArH), 8.13 (s,
1 H, ArH), 3.81 (t, 2 H, J = 5.2, CH2O), 3.46 (t, 2 H, J = 5.2, CH2S),
3.18 (s, 3 H, CH3O).
13C NMR (75 MHz, CDCl3–TMS): δ = 143.32 (ArC), 132.67 (q,
J
J
CF = 35.1, 2 × CF3), 129.02, 128.97, 127.09 (ArCH), 122.43 (q,
CF = 273.3, 2 × CCF3), 65.89 (CH2O), 58.53 (CH3O), 56.84
(CH2S).
MS: m/z (%) = 336 (M+, 4), 335 [(M – 1)+, 10], 281 (21), 255 (12),
243 (13), 228 (23), 189 (13), 156 (10), 111 (13), 104 (12), 98 (12),
97 (25), 82 (13), 78 (12), 57 (100).
HRMS: m/z calcd for C11H10SO3F6: 336.0255 (M+); found: 336.02.
1-(2-{2-[3,5-Bis(trifluoromethyl)phenylsulfonyl]ethoxy}ethyl-
sulfonyl)-3,5-di(trifluoromethyl)benzene (7)
Mp 170–171 ºC.
IR (KBr): 1329, 1284, 1144 cm–1.
1H NMR (300 MHz, CDCl3–TMS): δ = 8.30 (s, 4 H, ArH), 8.13 (s,
4 H, ArH), 3.89 (t, 4 H, J = 5.6, 2 × CH2O), 3.30 (t, 4 H, J = 5.6,
2 × CH2S).
13C NMR (75 MHz, CDCl3–TMS): δ = 142.86 (2 × ArC), 133.07 (q,
JCF = 35.1, 4 × CF3), 128.59, 127.43 (2 × ArCH), 122.29 (q,
JCF = 273.3, 4 × CCF3), 64.41 (2 × CH2O), 56.02 (2 × CH2S).
MS: m/z (%) = 626 (M+, 0.13), 607 (12), 606 (57), 350 (13), 349
(86), 348 (66), 330 (15), 307 (11), 306 (24), 305 (79), 279 (23), 278
(39), 277 (65), 261 (46), 228 (12), 214 (57), 213 (52), 195 (22), 194
(38), 163 (26), 144 (20), 70 (100).
Anal. Calcd for C20H14SO5F12: C, 38.34; H, 2.25; S, 10.21. Found:
C, 38.28; H, 2.47; S, 9.86.
(8) Commercially available compounds.
(9) Tottie, L.; Baeckström, P.; Moberg, C.; Tegenfeldt, J.;
Heumann, A. J. Org. Chem. 1992, 57, 6579.
(10) Reddy, D. B.; Reddy, P. S.; Reddy, B. V.; Reddy, P. A.
Synthesis 1987, 74.
Acknowledgement
This work has been supported by the Dirección General de Investig-
ación of the Ministerio de Ciencia y Tecnología (MCyT), project:
(BQU2001-0724-CO2-01). D. A. A thanks the Spanish Ministerio
de Ciencia y Tecnología (MCyT) for a contract under the program
Ramón y Cajal.
Synthesis 2003, No. 2, 277–287 ISSN 0039-7881 © Thieme Stuttgart · New York