Rapid and efficient chemoselective and multiple sulfations of phenols using sulfuryl imidazolium salts

Article abstract of DOI:10.1016/j.tetlet.2011.04.080

Phenolic sulfates protected with a trichloroethyl or trifluoroethyl group were rapidly and efficiently obtained by reacting phenols with sulfuryl imidazolium salts in the presence of DBU. Phenolic hydroxyl groups could be sulfated in good yield in the pre

Full text of DOI:10.1016/j.tetlet.2011.04.080

Tetrahedron Letters 52 (2011) 3353–3357
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid and efficient chemoselective and multiple sulfations of phenols using
sulfuryl imidazolium salts
⇑
Scott D. Taylor , Ahmed Desoky
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
a r t i c l e i n f o
a b s t r a c t
Article history:
Phenolic sulfates protected with a trichloroethyl or trifluoroethyl group were rapidly and efficiently
obtained by reacting phenols with sulfuryl imidazolium salts in the presence of DBU. Phenolic hydroxyl
groups could be sulfated in good yield in the presence of aliphatic hydroxyl groups and multiple sulf-
ations were also readily achieved.
Received 28 March 2011
Revised 18 April 2011
Accepted 19 April 2011
Available online 29 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sulfuryl imidazolium salts
Sulfation
Selectivity
Protecting group
1,8-Diazabicyclo[5.4.0]undec-7-ene
Sulfation is an important tactic by which nature mediates the
activity of biomolecules, such as carbohydrates and nucleosides
as well as phenolic derivatives, such as steroids, flavonoids, and
tyrosine residues within proteins.1–6 Sulfation is also a major
detoxication mechanism for endogenous compounds and xenobi-
otics containing phenolic and aliphatic hydroxyl groups.7 It has
recently been shown that highly sulfated polyphenols exhibit
interesting biological properties and are being examined as mimics
of glycosaminoglycans such as heparin.8 Sulfated phenols have tra-
ditionally been prepared by treating the substrate with a sulfating
agent, such as a sulfur trioxide–amine or amide complex, sulfuric
acid or sulfuric acid/DCC.9 Despite the success of this approach it
does have some limitations. Since the sulfated products are highly
polar and not highly soluble in most organic solvents, they are not
amenable to further transformations and so the sulfation step must
be carried out at or near the end of the synthesis. In the case of
multiple sulfations, as each sulfate group is introduced the nucle-
ophilicity of the remaining hydroxyl groups is reduced. Moreover,
charge repulsion between adjacent sulfate groups further affects
reactivity. Hence, a distribution of products is commonly observed
making the purification of the highly polar products very tedious
and time consuming.9 As a result of these issues more recent
efforts have focused on installing the sulfate group(s) as a pro-
tected sulfodiester(s).9 The advantage of this approach is that the
protected neutral sulfates can be purified by conventional meth-
ods, easily characterized and, if necessary, the product can be sub-
jected to further transformations and then deprotected under mild
conditions.
Several years ago we reported that the trichloroethyl (TCE)
group is an effective protecting group for aryl sulfates. It is intro-
duced using Cl3CCH2OSO2Cl (1) in the presence of Et3N and DMAP
in dry THF and removed using Pd/C or Zn in the presence of ammo-
nium formate.10 This methodology has now been widely used in
the preparation of aryl sulfates.11 Although reagent 1 gives the de-
sired protected arylsulfates in good yield, in some instances we
found that the results were less than optimal. For example, sulfa-
OH
OH
1.1 equiv 1
1,.1 equiv Et N
3
1.0 equiv DMAP
THF, 6h
HO
TCEOSO O
2
2
3 (63%)
Scheme 1. Sulfation of estradiol at O-3 using reagent 1.
CH3
X-
O
+
O
R
S
N
N
CH3
O
4, R = TCE, X = TfO-
5, R = TFE, X = TfO--
⇑
Corresponding author.
E-mail address: s5taylor@sciborg.uwaterloo.ca (S.D. Taylor).
Figure 1. Structures of sulfuryl imidazolium salts 4 and 5.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.080

3354
S. D. Taylor, A. Desoky / Tetrahedron Letters 52 (2011) 3353–3357
Table 1
Monosulfation of phenols using reagents 4 and 5 and DBUa
1.1 equiv 4 or 5
1 equiv DBU
solvent, rt, 3-10 min
substrate
product
Entry
Substrate
Sulfating agent
Product
% Yield
O
O
1
2
4
5
96 (8)
98 (9)
RO SO
HO
3
6
8, R = TCE
9, R = TFE
O
O
O
O
N3
N3
TFEO3SO
3
5
89
HO
10
11
4
5
86
HO
N
TFEO SO
3
N
3
3
12
13
OH
OH
NH
OH
OH
NH
5
6
7
4
4
4
90
HO
HO
TCEO SO
3
2
3
OH
OH
88b
TCEO SO
3
14
15
2
2
80
HO
HO
TCEO SO
3
16
CH OH
17
CH OH
2
2
8
4
4
4
84
84
0
TCEO SO
3
18
19
CH2OH
CH OH
2
9
OH
OSO TCE
3
20
21
CH2OH
CH OH
2
10
OH
OSO3TCE
22
23

S. D. Taylor, A. Desoky / Tetrahedron Letters 52 (2011) 3353–3357
3355
Table 1 (continued)
Entry
Substrate
Sulfating agent
Product
% Yield
CH2CH2OH
CH2CH2OH
11
4
83
HO
TCEO3SO
24
25
a
All reactions were conducted in CH2Cl2 unless stated otherwise.
Conducted in DMF–CH2Cl2.
b
tion of the phenolic OH of estradiol (2, Scheme 1) using reagent 1
for 24 h gave a mixture of mono- and disulfated products and, after
a tedious purification the desired compound 3 was isolated in only
modest yield. Therefore, we began to look for alternative ap-
proaches or reagents for performing this transformation.
We recently developed sulfuryl imidazolium salts, such as com-
pounds 4 and 5, for introducing TCE and trifluoroethyl (TFE) -pro-
tected sulfates into compounds having aliphatic hydroxyls such as
carbohydrates (Fig. 1).12–14 The TFE group is removed using t-BuOK
in refluxing t-BuOH15,16 or with NaN3 in warm DMF.14 Our success
with using these reagents for sulfating alkyl hydroxyls prompted
us to examine these reagents for preparing aryl sulfates. Here we
report that protected aryl sulfates can be prepared in excellent
yields using sulfuryl imidazolium salts 4 and 5 and DBU. Sulfations,
including multiple sulfations of polyphenols, that previously took
hours using reagents such as 1 can now be accomplished in high
yield within minutes and sulfation of phenolic hydroxyls in the
presence of other nucleophilic residues can be now be achieved
rapidly and with good chemoselectivity.
We reasoned that the sulfations could be achieved more rapidly
and perhaps more chemoselectively by using a base that was
stronger than Et3N and so generate a higher concentration of the
phenoxide anion. We wished to avoid the use of very strong bases,
such as t-BuOK, NaH, NaHMDS, etc., and so focused on DBU. Using
estrone (6, Table 1) as a model substrate we initially attempted the
sulfation by adding 1 equiv of DBU to a solution of estrone in dry
CH2Cl2 followed by the addition of 1.1 equiv 1 or TFEOSO2Cl (7).
However, after several hours the reaction had not gone to comple-
tion. In contrast, when the reaction was performed using 1.1 equiv
of imidazolium salts 4 and 5 compounds 810 and 914 were obtained
in almost quantitative yields in just 5 min (Table 1, entries 1 and
2). Similar results were found with estrone derivatives 10 and 12
Table 2
Polysulfation of phenols using reagents 4 and 5 and DBU
Entry
Substrate
Conditions
Product
% Yield
CH3
O
CH3
O
RO3SO
RO3SO
HO
HO
2.2 equiv 4 or 5
2.0 equiv DBU
CH2Cl2, 13 min
1
2
93 (27)
91 (28)
O
O
26
27, R = TCE
28, R = TFE
OH
OSO TCE
3
HO
TCEO SO
3
OH
OSO TCE
3
3.3 equiv 4
3
4
3.0 equiv DBU
CH2Cl2, 16 min
90
96
29
OH
30
OSO3TCE
HO
HO
TCEO3SO
TCEO3SO
3.3 equiv 4
3.0 equiv DBU
CH2Cl2, 16 min
COOnPr
COOnPr
OSO3TCE
31
32
OH
OH
OH
4.4 equiv 4
4.0 equiv DBU
CH2Cl2–DMF
19 min
OH
OH
OSO3TCE
OSO3TCE
5
86
HO
HO
O
TCEO3SO
O
33
34
OH
OSO R
3
OH
OSO R
3
O
RO SO
O
O
3
5.5 equiv 4 or 5
5.0 equiv DBU
DMF
6
7
90 (36)
92 (37)
OH
OSO R
3
22 min
OH
O
RO SO
3
35
36, R = TCE
37, R = TFE

3356
S. D. Taylor, A. Desoky / Tetrahedron Letters 52 (2011) 3353–3357
(entries 3 and 4). We also found that no drying of the CH2Cl2 was
necessary in order to obtain equivalent yields in the same reaction
times. Applying this methodology to estradiol resulted in almost
exclusive sulfation of the phenolic OH in excellent yield (entry
5). Estriol (14) and the b-17-amino steroid 16 were also sulfated
at the phenolic OH in excellent yields (entries 6 and 7). Due to
the poor solubility of the DBU salt of estriol in CH2Cl2 this reaction
had to be carried out in a DMF–CH2Cl2 mixture. Phenolic com-
pounds 18 and 20 having a hydroxymethyl group at the meta
and para positions were also sulfated chemoselectively at the phe-
nolic OH in good yield (entries 8 and 9) as was hydroxyethyl deriv-
ative 24 (entry 11). However, when the phenolic hydroxyl and
hydroxymethyl groups were ortho to one another a complex mix-
ture was obtained (compound 22, entry 10). All of the reactions in
Table 1 were complete within 3–10 min. We found that there was
no need for an aqueous workup for reactions carried out in CH2Cl2
as the products could be purified by applying the reaction mixture
directly to a silica gel column and eluting with EtOAc–hexane mix-
tures. Reactions carried out in DMF–CH2Cl2 were subjected to an aq
workup to remove the DMF before chromatography.17
We next applied our methodology to the synthesis of multisulf-
ated phenols and polyphenols. Several new approaches to such
compounds have recently been reported. A high temperature
(100 °C) microwave approach using SO3–pyridine or amine com-
plexes (NR3 where R = Me or Et) has been developed.18 This ap-
proach has been shown to work well in most cases though it
requires 6–9 molar equiv of sulfating agent per phenolic group
and is not amenable to scale-up. A low temperature (À20 to
20 °C), triflic acid-catalyzed (1.6–3.0 equiv/OH group) approach
has been reported using SO3–NEt3 complex (5 molar equiv per
OH group).19 Desai and coworkers reported using reagent 1 for pre-
paring multisulfated phenols and polyphenols.11k The reactions
were conducted in anhydrous THF in the presence of Et3N and
DMAP for 16 h. In most cases, the desired compounds were ob-
tained in excellent yield including a compound containing a
crowded 1,2,3-trisulfated structure, which is almost impossible
to isolate using traditional sulfation protocols and obtained in
modest yield using the microwave approach.18 Two- to four-fold
molar excess of reagent 1 per OH group was required to fully sul-
fate pentahydroxy flavones possibly due to the presence of mois-
ture tightly bound to the flavonoids substrates causing hydrolysis
of 1.
OSO3TCE
10 wt % of 10% Pd/C
24 eq. ammonium formate
MeOH-THF, 15 h
OH
OSO3TCE
OSO3TCE
TCEO3SO
O
purification by HPLC using
Et3NH+-OAc-CH3CN as eluent
34
OSO3-Et3NH+
OH
OSO3-Et3NH+
OSO3-Et3NH+
Et3NH+-O3SO
O
38 (88%)
Scheme 2. Deprotection of 35.
O
O
N
N
3
3
+-
NH O SO
4
3
TFEO SO
3
NaN , DMF
3
39 (95%)
11
O
O
o
70 C, 1.5 h
+-
NH O SO
TFEO SO
3
4
3
40 (82%)
13
N
N
3
3
Scheme 3. Deprotection of 11 and 13.
pounds decomposed upon heating. Compounds containing a single
TFE-protected sulfate, such as compounds 11 and 13, were depro-
tected in good yield using NaN3 in warm DMF (Scheme 3).
In summary, we have shown that protected aryl sulfates can be
prepared rapidly and in excellent yields using sulfuryl imidazolium
salts 4 and 5 and DBU. The sulfate groups could be introduced into
phenolic hydroxyl groups in the presence of aliphatic hydroxyls
with high chemoselectivity. Multiple sulfations were also readily
achieved using just a slight excess of sulfating agent per hydroxyl
group.
Acknowledgment
We acknowledge the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) for financial support of this work
through a Discovery Grant to S.D.T.
We have found that reagents 4 and 5 are very effective for the
synthesis of multisulfated phenols and polyphenols (Table 2).
These sulfations were achieved by adding 1.0 equiv of DBU to a
solution of the substrate in CH2Cl2, DMF or CH2Cl2–DMF mixtures
followed by the addition of 1.1 equiv 4 or 5 and stirred for about
3 min and then this process was repeated for each OH group. After
the final addition the mixture was stirred for an additional 10 min.
In most cases, the use of dry solvents was unnecessary and no
aqueous workup was required for reactions carried out in the ab-
sence of DMF cosolvent. Compounds containing the three adjacent
hydroxy groups were sulfated in excellent yield (entries 3 and 4).
Compound 33 was chemoselectively sulfated at all four phenolic
OH’s leaving the secondary aliphatic OH untouched (entry 5). Sul-
fation of pentahydroxy flavone 35 was previously accomplished in
82% yield in 16 h using 4 equiv reagent 1 per OH group.11k We
accomplished its synthesis in 90% yield in just 22 min using
1.1 equiv reagent 4 per OH group.20
It has been shown that trichloroethyl-protected multisulfated
phenols such as 36 can be readily deprotected using Pd/C and ex-
cess ammonium formate.11k We also found this to be the case as
demonstrated by the deprotection of 34 in excellent yield (Scheme
2). However, attempts to deprotect compounds containing multi-
ple TFE-protected sulfates 28 and 37 using t-BuOK in refluxing t-
BuOH or with NaN3 in warm DMF was unsuccessful as these com-
Supplementary data
Additional experimental details and characterization data and
1H and 13C NMR spectra for all novel compounds. Experimental de-
tails for the synthesis of 38–40. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.04.080.
References and notes
1. Kovensky, J. Curr. Med. Chem. 2009, 16, 2338.
2. (a) Schroeder, F. C.; Taggi, A. E.; Gronquist, M.; Malik, R. U.; Grant, J. B.; Eisner,
T.; Meinwald, J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 14283; (b) Kaysser, L.;
Eitel, K.; Tanino, T.; Siebenberg, S.; Matsuda, A.; Ichikawa, S.; Gust, B. J. Biol.
Chem. 2010, 285, 12684.
3. D’Auria, M. V.; Minale, L.; Raffaele Riccio, R. Chem. Rev. 1993, 93, 1839.
4. Hoye, T. R.; Dvornikovs, V.; Fine, J. M.; Anderson, K. R.; Jeffrey, C. S.; Muddiman,
D. C.; Shao, F.; Sorensen, P. W.; Wang, J. J. Org. Chem. 2007, 72, 7544.
5. Seibert, C.; Sakmar, T. P. Pept. Sci. 2008, 90, 459.
6. Tomishima, M.; Ohki, H.; Yamada, A.; Makib, K.; Ikeda, F. Bioorg. Med. Chem.
Lett. 2008, 18, 2886.
7. Zamek-Gliszczynski, M. J.; Hoffmaster, K. A.; Nezasa, K.; Tallman, M. N.;
Brouwer, K. L. Eur. J. Pharm. Sci. 2006, 27, 447–486.

S. D. Taylor, A. Desoky / Tetrahedron Letters 52 (2011) 3353–3357
3357
8. Desai, U. R. Med. Res. Rev. 2004, 24, 151.
9. Al Horani, R. A.; Desai, U. R. Tetrahedron 2010, 66, 2907.
hexane. Elution with the same solvent system (Rf = 0.3) gave pure 3 as a white
solid (0.211 g, 90% yield). Mp = 81–82 °C; 1H NMR (300 MHz, CDCl3) d 0.75 (s,
3H), 1.10–1.60 (m, 7H), 1.11–1.58 (m, 7H), 1.68 (dd, J = 8.8, 13.1 Hz, 1H), 1.77–
2.35 (m, 6H), 2.84 (br s, 2H), 3.70 (t, J = 7.8 Hz, 1H), 4.80 (s, 2H), 7.02 (s, 1H),
7.07 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 11.1,
23.1, 26.1, 26.8, 29.5, 30.5, 36.6, 38.3, 43.2, 44.1, 50.0, 80.3, 817, 92.5, 117.9,
121.0, 127.0, 139.3, 140.3, 147.9; HRMS (EI+): calcd for C20H25Cl3O5S (M+):
482.0488, found 482.0491.
10. Liu, Y.; Lien, I. F. F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D. Org. Lett. 2004, 6, 209.
11. (a) Fukuda, T.; Ohta, T.; Saeki, S.; Iwao, M. Heterocycles 2010, 80, 841; (b)
Bunschoten, A.; Kruijtzer, J. A. W.; Ippel, J. H.; de Haas, C. J. C.; van Strijp, J. A. G.;
Kemmink, J.; Liskamp, R. M. J. Chem. Commun. 2009, 2999; (c) Li, X. S.;
Robertson, L. W.; Wehmler, H. J. Chem. Cent. J. 2009, 3. doi:10.1186/1752-153X-
3-5.; (d) Ali, A. M.; Hill, B.; Taylor, S. D. J. Org. Chem. 2009, 74, 3583; (e) Chen, J.;
Yu, B. Tetrahedron Lett. 2008, 49, 1682; (f) Lu, C. P.; Ren, C. T.; Wu, S. H.; Chu, C.
Y.; Lo, L. C. ChemBioChem 2007, 8, 2187; (g) Furstner, A.; Domostoj, M. M.;
Scheiper, B. J. Am. Chem. Soc. 2006, 128, 8087; (h) Yamaguichi, T.; Fukada, T.;
Ishibashi, F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755; (i) Furstner, A.;
Domostoj, M. M.; Scheiper, B. J. Am. Chem. Soc. 2005, 127, 11620; (j) Ahmed, V.;
Ispahany, M.; Ruttgaizer, S.; Guillemette, G.; Taylor, S. D. Anal. Biochem. 2005,
340, 80; (k) Gunnarsson, G. T.; Riaz, M.; Adams, J.; Desai, U. R. Bioorg. Med.
Chem. 2005, 13, 1783.
18. Raghuraman, A.; Riaz, M.; Hindle, M.; Desai, U. R. Tetrahedron Lett. 2007, 48,
6754.
19. Krylov, V. B.; Ustyuzhanina, N. E.; Grachev, A. A.; Nifantiev, N. E. Tetrahedron
Lett. 2008, 49, 5877.
20. Representative procedure for multisulfations: Synthesis of compound 36. To a
solution 35 (0.05 g, 0.17 mmol) in dry DMF (3 mL) was added 1 equiv DBU.
Reagent 4 (0.076 g, 0.182 mmol) was added and the mixture was stirred for
approximately 3 min. This process was repeated four more times. After the
final addition the mixture was stirred for 10 min then diluted with Et2O
(30 mL) and washed with 0.1 N HCl, water and satd brine. The organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue was purified by
flash chromatography (30% EtOAc:70% hexane, Rf = 0.5) to give pure 36 as a
white foam (0.203 g, 90% yield). 1H NMR (300 MHz, CDCl3) d 4.92 (s, 2H), 4.96
(s, 2H), 4.97 (2, 2H), 5.14 (s, 2H), 5.17 (s, 2H), 7.58 (d, J = 2.2 Hz, 1H), 7.70 (d,
J = 2.0 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.7, 8.8 Hz, 1H), 8.17 (d,
J = 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 81.1, 81.2, 81.4, 91.7, 92.0, 92.2,
110.7, 114.0, 116.4, 123.7, 123.9, 128.5, 129.6, 134.2, 141., 143.8, 148.4, 153.0,
156.1, 156.5, 168.7; HRMS (ESI+): calcd for C25H16Cl15O22S5 (M+H): 1352.406,
found 1352.387.
12. Ingram, L. J.; Taylor, S. D. Angew. Chem., Int. Ed. 2006, 3503.
13. Ingram, L. J.; Desoky, A.; Ali, A. M.; Taylor, S. D. J. Org. Chem. 2009, 74, 6479.
14. Desoky, A.; Taylor, S. D. Tetrahedron 2011, 67, 1281.
15. Proud, A. D.; Prodger, J. C.; Flitsch, S. L. Tetrahedron Lett. 1997, 41, 7243.
16. Karst, N. A.; Islam, T. F.; Avci, F. Y.; Lindhardt, R. J. Tetrahedron Lett. 2004, 45,
6433.
17. Representative procedure for monosulfations: Synthesis of compound 3. To a
suspension of estradiol (2) (0.136 g, 0.5 mmol) in CH2Cl2 (3 mL) was added
1 equiv DBU. The mixture was stirred until it became homogeneous
(approximately 10 min). Reagent 4 (0.254 g, 0.55 mmol) was added in three
portions over 1 min and the mixture stirred for an additional 4 min. The
mixture was applied directly to a silica column prepared using 30% EtOAc:70%