Zinc bromide-promoted tosylation of alcohols allows efficient temperature-controlled primary hydroxy sulfonylation

Article abstract of DOI:10.1246/cl.2001.706

The combination of zinc bromide with tosyl chloride promoted sulfonylation, allowing temperature-controlled regioselective sulfonylation of carbohydrates which possess both primary and secondary hydroxy groups.

Full text of DOI:10.1246/cl.2001.706

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06
Chemistry Letters 2001
Zinc Bromide-Promoted Tosylation of Alcohols Allows Efficient Temperature-Controlled
Primary Hydroxy Sulfonylation
Hatsuo Yamamura,* Jyumpei Kawasaki, Hirokazu Saito, Shuki Araki, and Masao Kawai
Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555
(Received March 5, 2001; CL-010188)
The combination of zinc bromide with tosyl chloride pro-
moted sulfonylation, allowing temperature-controlled regiose-
lective sulfonylation of carbohydrates which possess both pri-
mary and secondary hydroxy groups.
A sulfonate ester is one of the most useful intermediates in
organic chemistry and sulfonylation of alcohols by use of tosyl
chloride is one of the most prevalent reactions. It is possible to
selectively tosylate primary over secondary alcohols in pyridine
at 0 °C.1 It is also possible to tosylate nonprotected hydroxy
functionalities regioselectively by use of organotin
compounds.2 However, application of these methods to rela-
tively large molecules possessing a number of primary and sec-
ondary hydroxy groups is not always straightforward, as dis-
crimination of the hydroxy groups is difficult. In the case of the
preparation of hepta-6-O-sulfonylated β-cyclodextrin 1 which
is considered a suitable intermediate for hepta-6-functionalized
derivatives, a significant amount of the 2-O-sulfonylated deriv-
3
ative 2 (1:2 = 5:3 molar ratio) was also produced. In the syn-
thetic study to improve the yield of 1, we found a unique role of
zinc bromide to promote sulfonylation and here we will
describe the results.
Steric crowding on the primary side of a cyclodextrin dur-
ing the later stages of sulfonylation to prepare the derivative 1
may enable the reaction of the less reactive secondary hydroxy
groups before the completion of 6-O-sulfonylation. The effect
of metal halides as additives was studied because either selec-
tive activation or protection of hydroxy groups by coordination
of metal ion was expected. The results are shown in Figure 1.
ZnCl and KBr in place of ZnBr did not give comparable
2
2
results on sulfonylation to those on addition of ZnBr , suggest-
2
ing that the greater effect of ZnBr may be due to conversion of
2
the sulfonyl chloride to more reactive sulfonyl bromide on the
coordination sphere of zinc atom at the first step of the reaction.
It is reasonable that zinc bromide might additionally coordi-
nates an oxygen atom of a hydroxy group of cyclodextrin to
bring the two reactants close (Figure 2). Dose effect is shown
2
+
2+
Metal ions such as Mg and Ca suppressed the sulfonylation
reaction. In contrast, zinc halides facilitated the reaction.
4
,5
Among them ZnBr showed the highest acceleration effect,
2
although the ratio of the tosylate 1 and the additionally 2-O-sul-
fonylated 2 was the same as that observed on a reaction without
in Figure 3. Addition of ZnBr at 10.5 times the concentration
2
the additive. The lack of selectivity suggests that ZnBr pro-
2
motes tosylation on both primary and secondary hydroxy
groups. A possible role of ZnBr is considered to be coordina-
2
tion to an oxygen atom of the sulfonyl moiety making the halo-
gen a better leaving group. Coordination of ZnBr to tosyl
2
chloride is suggested by the fact that the solubility of a mixture
of ZnBr and tosyl chloride, in a mole ratio of 1:1.5, in pyridine
2
is greater than the metal halide itself. Use of a mixture of
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
707
both ZnBr and tosyl chloride (two and three mole equivalents,
2
respectively) converted the glucoside in 20 min to the mono-
and disulfonates in the yield of 64 and 36 %, respectively. The
latter reaction needed less tosyl chloride to consume the gluco-
side. Taking into account differences between the two condi-
tions above in reaction temperature, amount of sulfonyl chlo-
ride, and reaction time, addition of ZnBr increased the efficien-
2
cy of conversion of the glucoside to sulfonates by a factor of
eighty. Lowering the reaction temperature from r.t. to –20 °C
resulted in preferential sulfonylation on primary hydroxy group,
as observed in the case of cyclodextrin, although the effect of
temperature was smaller than that of cyclodextrin. It is proba-
ble that macrocyclic structure of the cyclodextrin makes its sec-
ondary hydroxy groups more crowded than that of the gluco-
side, leading to a greater difference in reactivity between the
primary and secondary hydroxy groups.
In conclusion, zinc bromide promoted tosylation such that
less sulfonyl chloride was required. Further, the additive
enabled low temperature reactions, which gave selective reac-
tion on primary hydroxy groups, to be carried out efficiently.
Although the use of zinc halides as Lewis acids is known, this
is the first example of the influence of zinc bromide on the
reactivity of sulfonyl chloride with hydroxy groups, to the best
of our knowledge, in the literature. The results suggest the pos-
sibility of very rapid (“instant”) sulfonylation and the use of
much lower temperatures for sulfonylation in an effort to
increase specificity. Further studies including the application of
this process to other alcohols including carbohydrates and
cyclitols such as mannitol, are underway in our laboratory.
of cyclodextrin (1.5 times the concentration of the glucose
residues) reduced the reaction time by a factor of twelve.
While ZnBr promoted the sulfonylation at both primary
We thank Japan Maize Products Co. Ltd. for a generous
gift of β-cyclodextrin. We also thank Professor J´ozef
Drabowicz of Polish Academy of Science, Poland for discus-
sion on the sulfonylation shown here and Dr. Jason B. Harper
of University Chemical Laboratory, Cambridge, UK for helpful
comments on this paper.
2
and secondary hydroxy groups, it was found that low reaction
temperature effectively suppressed the undesirable 2-O-sul-
fonylation. On lowering the reaction temperature to below –20
°
7
C the yield of the desired product 1 increased to more than
0% in the absence of ZnBr . The HPLC chromatogram was
2
much simpler with fewer peaks. However, the reaction
required 25 mole equivalents of tosyl chloride and took more
than 30 h to obtain the maximal yield of 1. Use of ZnBr2
enabled reaction to be carried out at lower reaction temperature,
References and Notes
1
W. S. Johnson, J. C. Collins, Jr., R. Pappo, M. B. Rubin, P.
J. Kropp, W. F. Johns, J. E. Pike, and W. Bartmann, J. Am.
Chem. Soc., 85, 1409 (1963).
in a shorter time, and with less sulfonyl chloride, namely at –40
6
°
C, for 4 h, and in the presence of ZnBr and tosyl chloride,
2
3
4
Y. Tsuda, M. Nishimura, T. Kobayashi, Y. Sato, and K.
Kanemitsu, Chem. Pharm. Bull., 39, 2883 (1991).
H. Yamamura and K. Fujita, Chem. Pharm. Bull., 39, 2505
(1991).
2
ten and fifteen mole equivalents, respectively, to give the
desired product 1 in 84% yield. Through the use of twenty
mole equivalents of tosyl chloride at –40 °C the tosylate 1
(83%) was obtained within 1 h.
The reaction using ZnI gave a mixture of tosylates and
2
On tosylation of methyl α-D-glucoside in pyridine, similar
products with lower UV absorbance whose sulfonyl
groups were presumably replaced by iodides.
5
effects of ZnBr were demonstrated. The sulfonylation at r.t. in
2
the absence of ZnBr using ten mole equivalents of tosyl chlo-
ride took 30 min to consume the glucoside affording mono- and
ditosylate (57 and 43%, respectively). Reaction at –20 °C using
5
6
B. L. May, S. D. Kean, C. J. Easton and S. F. Lincoln, J.
Chem. Soc., Perkin Trans 1, 1997, 3157.
Reaction mixture in pyridine froze at –50 °C.
2