Preparation of trifluoroethyl- and phenyl-protected sulfates using sulfuryl imidazolium salts

Article abstract of DOI:10.1016/j.tet.2010.11.085

Sulfuryl imidazolium salts (SIS's), a new class of sulfating agents, were prepared bearing the trifluoroethyl (TFE) and phenyl groups, two functionalities that have been used for the protection of sulfate monoesters, by subjecting the corresponding sulfonyl imidazoles with methyl triflate. In contrast, SIS's bearing the electron donating neopentyl and isobutyl groups, two moieties that have also been used for the protection of sulfates, were found to be unstable and could not be isolated though SIS's bearing electron donating aryl groups, such as a p-methoxyphenyl or p-thiomethylphenyl group were readily prepared and are stable compounds. In most instances, TFE-protected phenolic and carbohydrate sulfates were obtained in good yield by reaction of the corresponding SIS's with steroids and carbohydrates. Phenyl-protected carbohydrates were also readily prepared using the corresponding SIS's. Those SIS's having a methyl group at the 2-position of the imidazole ring were, in general, superior sulfating agents to those, which lacked a methyl group at this position. The use of SIS's to prepare TFE-protected sulfates represents a significant improvement of the previous reported procedure, which involved treating unprotected sulfates with trifluorodiazoethane. The TFE protecting group was removed from steroidal sulfates and secondary sulfates in carbohydrates in high yields using NaN₃ in warm DMF, conditions that are less vigorous than those previously reported for removing this group. Deprotection of TFE-protected 6-sulfated carbohydrates using NaN₃ in warm DMF proceeded in lower yields due to partial desulfation.

Full text of DOI:10.1016/j.tet.2010.11.085

Tetrahedron 67 (2011) 1281e1287
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of trifluoroethyl- and phenyl-protected sulfates using sulfuryl
imidazolium salts
*
Ahmed Y. Desoky, Jennifer Hendel, Laura Ingram, Scott Douglas Taylor
Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, ON, Canada N2L 3G1
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2010
Received in revised form 23 November 2010
Accepted 24 November 2010
Available online 1 December 2010
Sulfuryl imidazolium salts (SIS’s), a new class of sulfating agents, were prepared bearing the tri-
fluoroethyl (TFE) and phenyl groups, two functionalities that have been used for the protection of sulfate
monoesters, by subjecting the corresponding sulfonyl imidazoles with methyl triflate. In contrast, SIS’s
bearing the electron donating neopentyl and isobutyl groups, two moieties that have also been used for
the protection of sulfates, were found to be unstable and could not be isolated though SIS’s bearing
electron donating aryl groups, such as a p-methoxyphenyl or p-thiomethylphenyl group were readily
prepared and are stable compounds. In most instances, TFE-protected phenolic and carbohydrate sulfates
were obtained in good yield by reaction of the corresponding SIS’s with steroids and carbohydrates.
Phenyl-protected carbohydrates were also readily prepared using the corresponding SIS’s. Those SIS’s
having a methyl group at the 2-position of the imidazole ring were, in general, superior sulfating agents
to those, which lacked a methyl group at this position. The use of SIS’s to prepare TFE-protected sulfates
represents a significant improvement of the previous reported procedure, which involved treating un-
protected sulfates with trifluorodiazoethane. The TFE protecting group was removed from steroidal
sulfates and secondary sulfates in carbohydrates in high yields using NaN3 in warm DMF, conditions that
are less vigorous than those previously reported for removing this group. Deprotection of TFE-protected
6-sulfated carbohydrates using NaN3 in warm DMF proceeded in lower yields due to partial desulfation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Sulfation
Protecting groups
Carbohydrates
Steroids
1. Introduction
by Perlin and Penney who examined the phenyl group as a pro-
tecting group for sulfated carbohydrates.8 It was introduced by
Sulfated biomolecules constitute a wide range of compounds,
such as sulfated carbohydrates,1 nucleosides,2 steroids,3 phero-
mones,4 proteins,5 and peptides.6 Their synthesis has become the
focus of considerable interest due to the important roles that these
molecules play in a wide variety of crucial biological processes.
Sulfated compounds are typically constructed using a sulfating
agent, such as a sulfur trioxide amine complex.7 The sulfation step
is usually carried out at or near the end of the synthesis due to the
highly polar nature of the sulfated products, which makes further
manipulations challenging. Moreover, the sulfate group is acid
sensitive, which further complicates additional manipulations. Fi-
nally, intensive protecting group manipulations are required at the
end of the syntheses when preparing sulfated compounds bearing
multiple reactive groups, such as sulfated carbohydrates. To over-
come these difficulties several groups including ourselves have
proposed introducing the sulfate group as a protected sulfodiester
at the beginning of the syntheses. This approach was first suggested
subjecting the carbohydrate to NaH and then PhOSO2Cl and is re-
moved by hydrogenation of the benzene ring using Pt2O/H2 fol-
lowed by treatment with base. Proud et al. and later Karst et al.,
examined the trifluoroethyl (TFE) moiety as a sulfate protecting
group in carbohydrates.9,10a,b However, Proud et al. reported that
they were unable to introduce this group using TFEOSO2Cl and had
to resort to first preparing unprotected sulfate monoesters using
pyr/SO3 followed by treatment with 2,2,2-trifluorodiazoethane,
a reagent that must be prepared fresh and is highly toxic and po-
tentially explosive. Moreover, the somewhat harsh conditions that
are most commonly employed for its removal, KOt-Bu in refluxing
HOt-Bu, can result in substrate decomposition and consequently
low or moderate sulfate deprotection yields.10b Both the neopentyl
(nPt) and isobutyl (i-Bu) groups have been examined as sulfate
protecting groups.11 They are introduced by reacting sodium alk-
oxides with ROSO2Cl (R¼i-Bu or nPt) at ꢀ78 ꢁC and removed using
nucleophiles such as NaN3 in warm DMF.11 Several years ago we
reported that the trichloroethyl (TCE) group can be used as a sulfate
protecting group.12 TCE-protected phenyl sulfates can be readily
prepared by reacting phenols with readily prepared and stable
TCEOSO2Cl (1) and the TCE group easily removed using Zn or Pd/C
* Corresponding author. Tel.: þ1 519 888 4567x3325; fax: þ1 519 746 0435;
e-mail address: s5taylor@sciborg.uwaterloo.ca (S.D. Taylor).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.085

1282
A.Y. Desoky et al. / Tetrahedron 67 (2011) 1281e1287
in the presence of ammonium formate.12 The TCE group is now the
most widely used protecting group for aryl sulfates.13 However, we
found that reagent 1 did not work well for introducing TCE-pro-
tected sulfate esters into non-phenolic substrates, such as carbo-
hydrates.14 This led us to develop reagents 2 and 3, the first
examples of sulfuryl imidazolium salts (SIS’s) (Fig. 1).14 These re-
agents are powerful sulfating agents capable of sulfating phenolic
and non-phenolic substrates including carbohydrates in good
yield.14e16 To date, the only SIS’s described to date are those bearing
the TCE group. In this report we describe the synthesis of SIS’s
bearing other groups such as the phenyl and TFE groups and de-
termine what groups are compatible with SIS formation. We also
show that both phenyl- and TFE-protected sulfates can be in-
troduced using SIS’s and also report alternative conditions for TFE
removal.
Fig. 2. Sulfuryl imidizolates 16 and 17.
methoxy group at the 4-position of the phenyl ring and is readily
prepared by reacting 4-methoxyphenol with sulfuryl diimidazole
in the presence of a base.18 We also found that the 4-methyl-
mercapto derivative 17 (Fig. 2) could prepared in a similar manner
and is a stable compound.19
Attempts to convert 10 and 11 into SIS’s by treating them, im-
mediately after purification by chromatography, with MeOTf in
Et2O resulted in the precipitation of a white powder, which rapidly
decomposed after filtration and drying under high vacuum. In
contrast, subjecting compounds 12e15 to methyl triflate in ether
resulted in the precipitation of SIS’s 20e23 as white powders in
high yield (Table 2) and can be stored for at least 2 years at ꢀ20 ꢁC
with showing any detectable decomposition. Although the
p-methoxyphenyl and p-thiomethylphenyl groups have not been
employed as sulfate protecting groups we subjected compounds 16
and 17 to MeOTf to determine if SIS’s bearing an electron donating
group on the phenyl ring could be prepared. As with SIS’s 20e23,
the resulting SIS’s 24 and 25 readily precipitated out of solution and
were found to be very stable and can be stored at ꢀ20 ꢁC for at least
a year without any detectable decomposition.
Fig. 1. Sulfuryl imidazolium salts 2 and 3.
2. Results and discussion
We initially examined the preparation of SIS’s bearing moieties
that have been studied as sulfate protecting groups such as the TFE,
phenyl, isobutyl, and neopentyl groups (Table 1). Thus, sulfuryl
chlorides 4e78a,11,12,17 were reacted with imidazole or 2-methyl-
imidazole to give compounds 8e15. Compounds 8 and 9 formed by
the reaction of imidazole with neopentyl and isobutylsulfuryl
chloride were found to be very unstable and decomposed shortly
after chromatographic purification. The 2-methylimidazole de-
rivatives of 8 and 9, compounds 10 and 11, were slightly more stable
yet still decomposed within 6e12 h after chromatography. In con-
trast those bearing the trifluoroethyl or phenyl groups were readily
obtained suggesting that electron withdrawing groups on the ester
portion are important for stability and electron donating alkyl
groups decrease stability. However, sulfuryl imidazolides bearing
electron donating aryl groups can be prepared as exemplified by
the known compound 16 (Fig. 2), which has an electron donating
Table 2
Yields of SIS’s 20e25
R2
N+ CH3
R2
1 equiv
MeOTf
ether
O
S
O
O
S
O
R1O
N
R1O
N
N
TfO-
12-17
18-25
Product
R1
R2
Yield (%)
18
19
20
21
22
23
24
25
nPt
i-Bu
TFE
TFE
Ph
Ph
4-MeOPh
4-MeSPh
CH3
CH3
H
CH3
H
0
0
92
91
92
93
90
86
CH3
H
H
Table 1
Yields of compounds 8e15
R2
R2
O
S
O
THF, 0 oC, 1h
NH
then 1h rt
Introduction of TFE-protected sulfates into carbohydrates was
examined using SIS’s 20 and 21. Subjecting carbohydrate 26 to
2 equiv 20 in the presence of 2.5 equiv N-methyl imidazole (NMI) in
THF gave sulfated carbohydrate 36 in a 45% yield. However,
switching to 2,6-lutidine as base and performing the reaction in
CH2Cl2 gave 36 in an 88% yield (entry 1). Using 2 equiv of SIS 21 in
the presence of 2.5 equiv 1,2-dimethylimidazole (DMI) in CH2Cl2
gave 36 in an 86% yield (entry 2). Carbohydrate 37 was obtained in
an 80% yield using SIS 21 and DMI (entry 3). In contrast, carbohy-
drates 36 and 37 were prepared by Proud et al. in 60% and 51%
yields, respectively, using the pyr/SO3/2,2,2-trifluorodiazoethane
methodology.9 In general, sulfations using SIS 21 and DMI gave
higher yields than those using SIS 20 and 2,6-lutidine (entries 3e8).
Further studies with SIS 21 using DMI as base revealed that most of
the sulfated carbohydrates could be obtained in good yield though
in some instances yields were modest even when a considerable
excess of SIS and base were used with prolonged reaction times
(entries 8 and 10). The TFE-protected sulfate group could be in-
troduced selectively into 2,3-diols of benzylidene acetals in good
O
S
O
R1O
Cl
+
R1O
N
N
N
R2 = H or Me
4, R1 = nPt
8-15
5, R1 = i-Bu
6, R1 = TFE
7, R1 = Ph
Product
R1
R2
Yield (%)
8
9
nPt
i-Bu
nPt
i-Bu
TFE
TFE
Ph
H
H
0a
0a
10
11
12
13
14
15
CH3
CH3
H
CH3
H
0b
35b,c
84
87
75
85
Ph
CH3
a
Decomposed within 1 h of chromatography.
Decomposed within 6e12 h of chromatography.
Contained 13% DMI as impurity.
b
c

A.Y. Desoky et al. / Tetrahedron 67 (2011) 1281e1287
1283
yield by the slow addition of a solution of DMI to a solution of the
carbohydrate and SIS 21 (entries 10e13). The selectivities are
consistent with the intrinsic reactivities of the hydroxyl groups of
the respective carbohydrates.16 Using estrone (46) and estradiol
(47) as model aryl substrates it was found that the TFE-protected
sulfate group can also be introduced into aryl substrates using SIS
21 in good to excellent yields and relatively good selectivity could
be achieved for the phenolic OH in estradiol (Scheme 1).
SIS’s bearing an electron-donating p-methoxyphenyl or p-thio-
methylphenyl group were readily prepared and are stable com-
pounds. In most instances, both TFE- and phenyl-protected sulfates
were easily prepared using reagents 20e23 though reagents 21 and
23havinga methyl group atthe 2-positionof the imidazole ringwere,
in general, superior sulfating agents in comparison to reagents 20 and
22, which lacked a methyl group at this position. In general, the use
SIS’s 20e23 to prepare TFE- or phenyl-protected sulfates represent
a significant improvement over the previous approaches to these
compounds. Deprotection of carbohydrate substrates bearing a pri-
mary sulfate group using NaN3 in warm DMF proceeded in lower
yields due to competing attack of the azide ion at C-6. However the
TFE group can be removed from secondary sulfates in carbohydrates
andarylsulfatesinexcellentyieldsusingNaN3 inDMF, conditionsthat
we believe are superior to the previous conditions using refluxing
KOt-Bu in t-BuOH. Overall, these results make the TFE group a more
viable alternative for sulfate protection.
Scheme 1. Synthesis of TFE-protected estrone and estradiol-3-sulfates.
4. Experimental
The synthesis of phenyl-protected sulfated carbohydrates was ex-
amined using reagents 22 and 23 and carbohydrates 28e31 (Table 4).
Using reagent 22/NMI or 23/DMI carbohydrates 50 and 51 were
obtained in 90e95% yields. In contrast, carbohydrate 51 was prepared
in a 75% yield by Penney and Perlin using NaH/PhOSO2Cl.8a Carbohy-
drates 52 and 53, which were obtained in a modest yield using reagent
22 were obtained in good yield using reagent 23.
4.1. General remarks
All reactions were carried out under argon with freshly distilled
solvents unless otherwise noted. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium metal in the presence of
benzophenone under argon. CH2Cl2 was distilled from calcium
hydride under nitrogen. Flash chromatography was performed
The conditions that are most commonly employed for depro-
tecting TFE-protected sulfates are refluxing KOt-Bu in
t-BuOH.9,10b,20 These harsh conditions have severely limited the use
of the TFE moiety as a suflate protecting group as the deprotection
yields are often low.10b As part of our efforts to find more suitable
conditions for removing this group we evaluated NaN3 in warm
DMF since these conditions have been used for removing neopentyl
groups from sulfates sometimes in very highyield.11 Subjecting fully
protected carbohydrates bearing secondary suflate groups, 37, 40,
42, and 44 to 1.4 equiv of NaN3 in warm DMF (65e70 ꢁC) for 10e16 h
resulted in removal of the TFE group in high yields (Table 5). The
crude products were passed through a small silica column using
CH2Cl2/MeOH or CH2Cl2/MeOH/NH4OH as eluent, which effectively
removed any contaminating NaN3 and gave the desired deprotected
sulfates as their sodium or ammonium salts depending on the sol-
vent system used for chromatographic purification. However,
deprotections of substrates bearing a primary sulfate group, 36 and
38, proceeded in lower yields due to competing attack of the azide
ion at C-6 followed by partial desulfation. This side reaction was also
noted by Karst et al. during the attempted removal of a TFE group
from the 6-position of a fully protected disaccharide substrate using
KOt-Bu in refluxing HOt-Bu though it appears that this problem can
be reduced or eliminated when free OH groups are present in the
substrate.9,10b This side reaction was also found to occur during
removal of the neopentyl group from neopentyl-protected glucose-
3-sulfate though in this case complete loss of the sulfate group
occurred.11 The phenolic sulfates 48 and 49 were deprotected in
almost quantitative yield within 1e3 h using 1.4 equiv NaN3 in DMF
at 65e70 ꢁC.
using silica gel 60 A (234e400 mesh). Chemical shifts (
d
) for 1H
ꢀ
NMR spectra are reported in parts per million (ppm) relative to
residual solvent peaks (CDCl3, 7.24; DMSO-d6, 2.49; CD3OD
3.31) and are reported as follows: chemical shift (ppm), multi-
d
d
d
plicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broadened), integration, coupling constant in hertz, and assign-
ment. Chemical shifts (
per million relative to the residual solvent peaks (CDCl3,
central peak; DMSO-d6, 39.4, central peak; CD3OD central peak,
49.0). Chemical shifts (
) for 19F spectra are reported in ppm
d
) for 13C NMR spectra are reported in parts
d
77.0,
d
d
d
relative to an external fluoroform standard (d 0.0, CFCl3). All melt-
ing points are uncorrected.
4.2. Syntheses
4.2.1. Representative procedure for the preparation of compounds
11e15 (Table 1, compound 13). To a solution of 2-methylimidazole
(13.6 g, 0.165 mol, 3.0 equiv) in dry THF (60 mL) at 0 ꢁC was added
dropwise a solution of reagent 617 (11.0 g, 0.055 mol,1.0 equiv) in THF
(40 mL). The reaction was stirred at 0 ꢁC for 1 h, warmed to room
temperature, and stirred for an additional 1 h. The reaction mixture
was filtered, the residue was washed with THF, and the filtrate was
concentrated under vacuum. The crude residue was purified by flash
chromatography (1:2 EtOAc/hexanes) to give 13 as a colorless oil
(11.8 g, 87%): 1H NMR (300 MHz, CDCl3)
d 2.57 (s, 3H, CH3), 4.44 (q, 2H,
J¼7.55 Hz, CH2), 6.90 (s, 1H),7.24 (s, 1H); 13C NMR (75 MHz, CDCl3)
d
14.5, 67.2 (q, 1C, JCF¼150 Hz, CH2CF3),120.0,121.0(q,1C,JCF¼316.5 Hz,
CF3),128.3,146.4; 19F NMR (282 MHz, CDCl3)
d
ꢀ73.5; HRMS (EIþ) m/z
calcd for [C6H7F3N2O3S]þ: 244.0129 [M]þ; found: 244.0131.
3. Conclusions
4.2.2. Representative procedure for the preparation of sulfuryl imi-
dazolium salts (Table 2 compound 21). To a solution of compound 13
(9.8 g, 0.04 mol, 1.0 equiv) in dry Et2O (70 mL) at 0 ꢁC was added
methyl triflate (4.6 mL, 0.04 mol,1.0 equiv)dropwise for 30 min. The
reaction was stirred for 3 h at 0 ꢁC during which time a white pre-
cipitate formed. The mixturewas filtered. The filtercake was washed
with cold ether, which afforded compound 21 as a white solid
In summary, we have shown that SIS’s bearing the TFE (com-
pounds 20 and 21) and phenyl (22 and 23) groups, two functionalities
thathave been usedfor the protectionofsuflate groups, canbereadily
prepared. SIS’s bearing the electron donating neopentyl and isobutyl
groups, two moieties that have also been used for the protection of
sulfates, were found to be unstable and could not be isolated though
(14.8 g, 91%): 1H NMR (300 MHz, CD3OD)
d 2.87 (s, 3H, CH3-imi), 3.90

1284
A.Y. Desoky et al. / Tetrahedron 67 (2011) 1281e1287
Table 3
Synthesis of TFE-protected sulfocarbohydrates with sulfuryl imidazolium salts 20 and 21
Entry
Substrate
Sulfating agent
Product
OSO3TFE
Yield (%)
45,a 88b
86c
OH
O
O
O
O
O
O
O
O
1
2
3
4
5
6
7
8
20
21
20
21
20
21
20
21
O
O
26
36
26
36
O
O
O
OH
O
OSO TFE
3
O
O
70b
O
O
O
O
27
37
27
37
80c
OSO TFE
3
OH
O
O
BnO
BnO
BnO
BnO
77b
OBn
OBn
BnO
BnO
38
28
28
38
79c
OBn
OBn
BnO
HO
BnO
O
O
26b
TFEO SO
3
OBn
OBn
OBn
OBn
39
29
29
39
58c
Ph
Ph
O
O
O
O
O
O
9
21
80d
OMP
OMP
HO
TFEO SO
3
BzO
BzO
30
40
O
O
Ph
Ph
O
O
O
O
TFEO3SO
HO
10
11
21
21
52e
CbzO
CbzO
OMe
OMe
41
31
Ph
Ph
O
O
O
O
O
O
75,f 89g
OMP
OMP
HO
TFEO3SO
HO
HO
32
42
O
O
O
Ph
Ph
O
O
O
89g
85g
OMP
OMP
HO
TFEO3SO
12
13
21
21
HO
HO
33
43
O
O
Ph
Ph
O
O
O
O
HO
HO
HO
TFEO3SO
OMe
OMe
34
44
Ph
Ph
O
O
O
O
78,f 91g
O
O
14
21
SPh
SPh
HO
TFEO3SO
HO
HO
35
45
a
2.5 equiv 20, 2 equiv NMI, THF, 24 h.
b
c
d
e
f
2.0 equiv 20, 1.1 equiv 2,6-lutidine CH2Cl2, 24 h.
2 equiv 21, 2.5 equiv DMI, CH2Cl2, 24e30 h.
3 equiv 21, 4 equiv DMI, CH2Cl2, 30 h.
5 equiv 21, 6 equiv DMI, CH2Cl2, 72 h.
1.2 equiv 21, 2 equiv DMI, CH2Cl2, 30 h.
4 equiv 21, 5 equiv DMI, CH2Cl2, 30 h.
g

A.Y. Desoky et al. / Tetrahedron 67 (2011) 1281e1287
1285
Table 4
Synthesis of phenyl-protected sulfocarbohydrates with sulfuryl imidazolium salts 22 and 23
Entry
Substrate
Sulfating agent
Product
Yield (%)
OSO Ph
3
OH
O
O
O
O
O
O
O
1
2
3
4
5
6
7
22
23
22
23
22
23
90a
95b
92a
93b
60a
80b
O
O
O
26
50
26
50
O
O
O
O
OH
OSO Ph
3
O
O
O
O
O
O
27
51
51
27
OH
OSO3Ph
O
O
BnO
BnO
BnO
BnO
OBn
OBn
BnO
BnO
28
28
52
52
OBn
OBn
BnO
BnO
O
O
22
23
51a
75b
PhO3SO
HO
OBn
OBn
OBn
OBn
53
29
29
8
53
a
2e2.5 equiv 22, 2 equiv NMI, THF, 24 h.
2 equiv 21, 2.5 equiv DMI, CH2Cl2, 24e30 h.
b
(s, 3H, CH3), 5.16 (q, 2H, J¼7.6 Hz, CH2), 7.71 (d, 1H, J¼2.3 Hz, Himi),
30 h. The reaction was diluted with CH2Cl2, washed with brine,
dried (MgSO4) and concentrated to crude brown oil. Flash chro-
matography (1:4, EtOAc/hexanes) gave compound 40 as a white
8.01 (d, 1H, J¼2.3 Hz, Himi); 13C NMR (75 MHz, CD3OD)
d 10.4, 35.3,
69.3 (q, 1C, JCF¼150 Hz, CH2CF3), 120.7, 121.0 (2q, 2C, 2CF3, JCF¼303,
316.5 Hz, CF3), 123.6, 148.8; 19F NMR (300 MHz, CD3OD)
solid (0.32 g, 80%): mp 128e130 ꢁC; 1H NMR (300 MHz, CDCl3)
d 3.6
d
ꢀ75.1,ꢀ79.7; HRMS (ESI) m/z calcd for [C7H10F3N2O3S]þ: 259.0364
(br s, 1H, H5), 3.71 (s, 3H, OCH3), 4.13, 4.41 (AB system, 2H,
J¼12.5 Hz, H6, H60), 4.23e4.34 (m, 2H, CH2CF3), 4.64 (d, 1H,
J¼3.3 Hz, H4), 4.99 (dd,1H, J¼10.2, 3.2 Hz, H3), 5.04 (d,1H, J¼7.9 Hz,
H1), 5.56 (s, 1H, CHPh), 5.88 (t, 1H, J¼9.6 Hz, H2), 6.73, 6.92 (AA0BB0
system, 4H, J¼8.7, 8.6 Hz, ArH), 7.47 (m, 8H, ArH), 8.04 (d, 2H,
[MꢀOTf]þ; found: 259.0363.
4.2.3. Representative procedure for the synthesis of TFE-protected
sulfocarbohydrates using reagent 20 and 2,6-lutidine (Table 3, com-
pound 36). To a solution of carbohydrate 26 (0.25 g, 0.95 mmol) in
CH2Cl2 (4.2 mL) at 0 ꢁC (ice bath) was added 2,6-lutidine (0.123 mL,
1.05 mmol, 1.1 equiv) followed by reagent 20 (0.19 g, 0.48 mmol,
0.5 equiv). The reaction was stirred for 1 h at 0 ꢁC and gradually
allowed to warm to room temperature. After every 2 h another
0.19 g of reagent 20 was added until the total was equal to 2 equiv
and the reaction was stirred overnight for a total of 24 h. The re-
action was quenched with water, extracted with EtOAc, washed
with brine, dried (MgSO4), and concentrated to a crude brown oil.
Flash chromatography (1:4, EtOAc/hexanes) gave compound 36 as
a white solid (0.28 g, 88%): mp 34e35 ꢁC; 1H NMR (300 MHz,
J¼7.8 Hz ArH); 13C NMR (75 MHz, CDCl3)
d 55.5, 65.9, 67.2 (q, 1C,
JCF¼150 Hz, CH2CF3), 68.3, 68.7, 73.0, 82.1, 101.2, 101.5, 114.4, 119.4,
134.0 (q, 1C, JCF¼304.5 Hz, CF3)126.4, 128.4, 128.6, 129.6, 129.8,
133.6, 136.7, 150.9, 155.9, 164.9; 19F NMR (282 MHz, CDCl3)
d
ꢀ73.5;
HRMS (ESI) m/z calcd for [C29H27F3O11SNa]þ: 663.1124 [MþNa]þ;
found: 663.1111.
4.2.5. Representative procedure for the selective sulfation of com-
pounds 42, 43, 44, and 45 (Table 3, compound 45). To carbohydrate
3522 (0.2 g, 0.55 mmol) in dry CH2Cl2 (4 mL) at 0 ꢁC (ice bath) was
added reagent 21 (0.45 g, 1.1 mmol), followed by the addition of
a solution of DMI (0.26 g, 2.77 mmol) in CH2Cl2 (2 mL) for 8 h
using a syringe pump. During the addition of the DMI another
portion of reagent 21 (0.45 g, 1.1 mmol) was added after 6 h and
the ice bath was removed after the initial 1 h. The reaction was left
stirring until the reaction was complete by TLC (approx. 30 h). The
reaction was diluted with CH2Cl2, washed with brine, dried
(MgSO4), and concentrated to brown crude oil. Flash chromatog-
raphy (1:4, EtOAc/hexanes) gave compound 45 as a colorless syrup
CDCl3)
d 1.30 (s, 6H, 2CH3), 1.41 (s, 3H, CH3), 1.49 (s, 3H, CH3), 4.09
(br d, 1H, J¼5.6 Hz, H5), 4.15 (dd, 1H, J¼7.7, 1.8 Hz, H4), 4.32 (t, 1H,
J¼4.8 Hz, H2), 4.41 (dd, 2H, J¼5.8, 2.5 Hz, H6, H60), 4.52e4.63 (m,
3H, CH2CF3, H3), 5.49 (d, 1H, J¼4.6 Hz, H1); 13C NMR (75 MHz,
CDCl3)
d
24.3, 24.7, 25.8, 25.5, 65.6, 66.6 (q, 1C, JCF¼150 Hz, CH2CF3),
70.1, 70.4, 70.6, 72.5, 96.1, 109.1, 110.1, 121.6 (q, 1C, JCF¼303 Hz, CF3);
19F NMR (282 MHz, CDCl3)
d
ꢀ73.8; HRMS (ESI) m/z calcd for
[C14H22F3O9S]þ: 423.0937 [MþH]þ; found: 423.0952.
(0.26 g, 91%): 1H NMR (300 MHz, CDCl3)
d 2.57 (br, 1H, OH), 3.57
4.2.4. Representative procedure for the synthesis of TFE-protected
sulfocarbohydrates using reagent 21 and DMI (Table 3, compound
40). To a solution of carbohydrate 3021 (0.3 g, 0.62 mmol) in CH2Cl2
(5 mL) at 0 ꢁC (ice bath) were added DMI (0.15 g, 1.56 mmol) and
reagent 21 (0.51 g, 1.25 mmol). The ice bath was removed and the
reaction allowed to warm to room temperature and then stirred for
(br s, 1H, H5), 3.93 (t, 1H, J¼9.5 Hz, H2), 4.03, 4.39 (AB system, 2H,
J¼12.4 Hz, H6, H60), 4.41e4.68 (m, 5H, H4, H1, CH2CF3, H3), 5.50 (s,
1H, CHPh), 7.29 (m, 8H, ArH), 7.65 (d, 2H, J¼7.3 Hz, ArH); 13C NMR
(75 MHz, CDCl3)
d
65.2, 67 (q, 1C, JCF¼150 Hz, CH2CF3), 68.9, 69.6,
73.4, 84.8, 87.0, 101.1, 123.0 (q, 1C, JCF¼305.5 Hz, CF3),126.3, 128.2,
128.8, 129.1, 129.2, 129.4, 134.0, 137.0; 19F NMR (282 MHz, CDCl3)

1286
A.Y. Desoky et al. / Tetrahedron 67 (2011) 1281e1287
Table 5
NMR (125 MHz, CDCl3)
d 11.0, 23.1, 26.1, 26.8, 29.5, 30.5, 36.6, 38.1,
Deprotection of TFE-protected sulfates with NaN3
38.2, 43.1, 44.1, 50.0, 67.5 (q, 1C, JCF¼150 Hz, CH2CF3), 81.7, 117.7,
120.8, 121.2 (q, 1C, JCF¼308 Hz, CF3), 127.1, 139.4, 140.4, 147.8; 19F
Substrate
Product
Yield (%)
65
NMR (282 MHz, CDCl3)
d
ꢀ73.3; HRMS (EIþ) m/z calcd for
-
OSO3 NH4
+
OSO TFE
3
O
O
[C20H25F3O5S]þ: 434.1375 [M]þ; found: 434.1364.
O
O
O
O
O
O
O
O
4.2.7. Representative procedure for synthesis of phenyl-protected
sulfocarbohydrates using sulfuryl imidazolium salt 23 (Table 4,
compound 50). To a solution of carbohydrate 26 (0.25 g, 0.96 mmol)
in CH2Cl2 (4.2 mL) at 0 ꢁC (ice bath) was added 2-methylimidazole
(0.23 mL, 2.4 mmol) followed by reagent 23 (0.77 g,1.92 mmol). The
reaction was stirred for 1 h at 0 ꢁC and gradually allowed to warm to
room temperature. The reaction was stirred overnight (24 h), then
diluted with CH2Cl2, washed with brine, dried (MgSO4) and con-
centrated to a crude brown oil. Flash chromatography (1:4, EtOA-
c:hexanes) gave compound 50 as a white solid (0.38 g, 95%): mp
36
54
O
O
O
O
OSO TFE
3
OSO Na
3
O
O
90
55
95
88
95
O
O
O
O
37
55
-
OSO NH
+
OSO TFE
3
3
4
O
O
BnO
BnO
BnO
BnO
OBn
OBn
77e79 ꢁC; 1H NMR (300 MHz, CDCl3)
d 1.30 (2s, 6H, 2CH3), 1.42 (s,
BnO
BnO
38
56
3H, CH3), 1.51 (s, 3H, CH3), 4.15 (t, 1H, J¼6.6 Hz, H5), 4.21 (dd, 1H,
J¼7.8,1.8 Hz, H4), 4.32 (dd,1H, J¼4.8, 2.4 Hz, H2), 4.47e4.56 (dd, 2H,
J¼5.8, 2.5 Hz, H6, H60), 4.62 (dd, 1H, J¼7.7, 2.2 Hz, H3), 5.51 (d, 1H,
Ph
Ph
O
O
O
O
J¼4.9 Hz, H1), 7.32 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3)
d 24.3,
O
O
OMP
OMP
TFEO3SO
H4NO3SO
BzO
BzO
24.8, 25.9, 25.9, 65.7, 70.2, 70.5, 70.6, 72.3, 96.1, 109.0, 109.8, 121.4,
127.4, 129.8, 150.3; HRMS (EI) m/z calcd for [C17H21O9S]þ: 401.0906
[MꢀCH3]þ; found: 401.0905.
40
57
Ph
Ph
O
O
O
O
O
O
4.2.8. Representative procedure for the deprotection of TFE-protected
sulfates with sodium azide (Table 5, compound 57). To a solution of
carbohydrate 40 (0.1 g, 0.156 mmol) in DMF (1 mL) was added so-
dium azide (0.014 g, 0.21 mmol) and the reaction was heated at
70 ꢁC (oil bath) for 10 h after which no starting material was
detected by TLC. The solvent was removed by rotary evaporation.
Flash chromatography of the residue (20:4:1 CH2Cl2/MeOH/
NH4OH) afforded 57 as a white solid (0.085 g, 95%): 1H NMR
OMP
OMP
TFEO3SO
H4NO3SO
HO
HO
42
58
O
O
Ph
Ph
O
O
O
O
HO
HO
TFEO3SO
NaO3SO
OMe
OMe
44
59
O
O
(300 MHz, DMSO-d6)
d 3.60 (s, 3H, OCH3), 3.91 (br s, 1H, H5), 4.08
(AB system, 2H, J¼12.4 Hz, H6, H60), 4.62 (m, 2H, H4, H3), 5.35 (m,
2H, H1, H2), 5.60 (s, 1H, CHPh), 6.76, 6.86 (AA0BB0 system, 4H, J¼8.7,
8.6 Hz, ArH), 7.04 (br, 4H, NH4), 7.47 (m, 6H, ArH), 7.59 (t, 1H,
J¼7 Hz, ArH), 7.95 (d, 2H, J¼7.8 Hz ArH); 13C NMR (75 MHz, CDCl3)
96
94
TFEO3SO
H4NO3SO
48
60
OH
OH
d
55.8, 66.5, 68.6, 70.0, 73.8, 74.6, 99.6, 100.3, 115.0, 118.1, 126.7,
128.4, 128.9, 129.2, 129.9, 130.5, 133.5, 138.8, 151.2, 155.1, 165.5;
HRMS (ESIꢀ) m/z calcd for [C27H25O11S]þ: 557.1118 [MꢀH]ꢀ; found:
557.1126.
TFEO3SO
NaO3SO
49
61
Acknowledgements
d
ꢀ73.8; HRMS (ESI) m/z calcd for [C21H22F3O8S2]þ: 523.0708
This research was supported by a Discovery Grant from the
Natural Sciences and Engineering Research Council (NSERC) of
Canada to S.D.T. We thank the Egyptian Ministry of Higher Educa-
tion for a scholarship to A.D. and Suez Canal University.
[MþH]þ; found: 523.0720.
4.2.6. Representative procedure for the synthesis of TFE-protected
estrone and estradiol-3-sulfates (Scheme 1, compound 49). To a so-
lution of estradiol (47, 0.3 g, 1.1 mmol) in dry CH2Cl2 (4 mL) at 0 ꢁC
(ice bath) was added reagent 21 (0.43 g, 1.1 mmol) followed by the
addition of a solution of DMI (0.26 g, 2.75 mmol) in CH2Cl2 (2 mL)
for 6 h using a syringe pump. During the addition of the DMI an-
other portions of reagent 21 (0.43 g, 1.1 mmol) was added after 4 h
and the ice bath was removed after the initial 1 h. The reaction was
left stirring until the reaction was complete by TLC (approx. 24 h).
The reaction was diluted with CH2Cl2, washed with brine, dried
(MgSO4), and concentrated to brown crude oil. Flash chromatog-
raphy (1:4, EtOAc/hexanes) gave compound 49 as a colorless syrup
(0.373 g, 78% of the monosulfated estradiolþ0.065 g, 10% of the
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.11.085. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
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