Silver(I) oxide mediated highly selective monotosylation of symmetrical diols. Application to the synthesis of polysubstituted cyclic ethers

Article abstract of DOI:10.1021/ol020071y

(Matrix Presented) The reaction of symmetrical diols and oligo(ethylene glycol)s with a stoichiometric amount of p-toluenesulfonyl chloride in the presence of silver(I) oxide and a catalytic amount of potassium iodide led selectively to the monotosylate derivatives in high yields. Polysubstituted cyclic ethers were obtained readily upon treatment of the corresponding diols with an excess of silver oxide. The high selectivity was explained on the basis of the difference in acidity between the two hydroxy groups, which undergo an intramolecular hydrogen bonding.

Full text of DOI:10.1021/ol020071y

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2329-2332
Silver(I) Oxide Mediated Highly Selective
Monotosylation of Symmetrical Diols.
Application to the Synthesis of
Polysubstituted Cyclic Ethers
,†
Abderrahim Bouzide* and Gilles Sauve´
Pharmacor Inc., 535 BouleVard Cartier Ouest, LaVal, QC, Canada H7V 3S8, and
INRS_Institut Armand Frappier, 531 BouleVard des prairies, LaVal, QC,
Canada H7V 1B7
abouzide@inVenux.com
Received April 8, 2002
ABSTRACT
The reaction of symmetrical diols and oligo(ethylene glycol)s with a stoichiometric amount of p-toluenesulfonyl chloride in the presence of
silver(I) oxide and a catalytic amount of potassium iodide led selectively to the monotosylate derivatives in high yields. Polysubstituted cyclic
ethers were obtained readily upon treatment of the corresponding diols with an excess of silver oxide. The high selectivity was explained on
the basis of the difference in acidity between the two hydroxy groups, which undergo an intramolecular hydrogen bonding.
Monofunctionalization of symmetrical diols has been of
considerable interest in organic synthesis. While selective
monosulfonylation of a primary alcohol in the presence of a
secondary or tertiary alcohol is well established,1 the
monosulfonylation of symmetrical diols can still present a
synthetic problem. To monotosylate 1,4-butanediol, Ahlberg
and Wu have added an excess of diol in the presence of
triethylamine without solvent.2 Those authors found that the
utilization of solvent favors the formation of the ditosylate,
due the high solubility of the monotosylate compared to the
diol. Choudary et al. have recently reported a monotosylation
of diol mediated by metal-exchanged montmorillonite clay
catalyst, employing p-toluenesulfonic acid as tosylation
agent.3 A strong base such as BuLi was also used to achieve
the monotosylation of diols.4 All these methods suffer from
the use of an excess of diol, which is difficult to remove
from the reaction mixture, or from harsh conditions, not often
compatible with acid- or base-sensitive functional groups.
Recently, we reported a new practical sulfonylation of
alcohols in the presence of silver oxide (Ag2O) and a catalytic
amount of potassium iodide (KI).5 This method has proven
to be an excellent protocol to mediate monotosylation of
symmetrical diols and oligo(ethylene glycol)s (OEGs) under
neutral conditions using a stoichiometric amount of tosylating
agent (Scheme 1).
For example, a solution of 1,4-butanediol in dichloro-
methane treated with Ag2O (1.5 equiv) and TsCl (1.1 equiv)
in the presence of KI (0.2 equiv) at room temperature yielded
† Present address: Invenux, Inc., 6840 N. Broadway, Suite F, Denver,
CO 80221.
(1) (a) O’Donnell, C. J.; Burke, S. D. J. Org. Chem. 1998, 63, 8614-
8616. (b) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450. (c) Bucher,
B.; Curran, D. P. Tetrahedron Lett. 2000, 41, 9617-9621. (d) Martinelli,
M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V. Kosmrlj, B.
J. Am. Chem. Soc. 2002, 124, 3578-3585.
(3) Choudhary, B. M.; Chowdary, N. S.; Kantam, M. Tetrahedron 2000,
56, 7291-7298.
(4) (a) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1989, 30,
3999-4000. (b) Marshall, J. A.; Hinkle, K. J. Org. Chem. 1997, 62, 5989-
5995.
(5) Bouzide, A.; LeBerre, N.; Sauve´, G. Tetrahedron Lett. 2001, 42,
8781-8783.
(2) Ahlberg, P.; Wu, Y. J. Org. Chem. 1994, 59, 5076-5077.
10.1021/ol020071y CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/11/2002

yielded 79% of the monotosylate along with 15% of the
ditosylate. The reaction was slightly exothermic and complete
within 5 min. When the reaction was achieved at 0 °C, the
monotosylate was obtained in 92% accompanied with only
5% of the ditosylate15 (Table 2). Note that in both 3 and 13
the hydoxy groups are separated by five atom units; however,
better selectivity was achieved in the case of 13 (vide infra).
Other commercially available OEGs (12, 14-17) were
subjected to the described conditions and gave good to
excellent yields of the monotosylate ester except for 12,
which afforded moderate selectivity. Remarkably, treatment
of the synthetic glycol derivatives 18, where the two hydroxy
groups are separated by 20 atom units, gave a good yield of
the corresponding monotosylate (Table 2). Moderate selec-
tivity, however, was obtained in the case of 19 and 20.
Scheme 1
within 40 min the monosulfonate ester in 91% yield, while
the ditosylate byproduct was isolated in only 6% yield (Table
1, entry 2).
Table 1. Monotosylation of Symmetrical Diols
We next took advantage of this reaction to prepare in one
step polysubstituted cyclic ethers from the corresponding
diols. For example, when diol 67 was treated with TsCl (1.2
equiv) and an excess of Ag2O (3 equiv) for 15 h (Table 3,
conditions A), disubstituted tetrahydrofuran 23 was obtained
in 75% yield. Treatment of diol 2116 under similar conditions
(6) (a) General Procedure for the Monotosylation of Symmetrical
Diols. To a stirred solution of diol (1 mmol) in CH2Cl2 or toluene (10 mL)
were added fresh Ag2O (350 mg, 1.5 mmol), TsCl (210 mg, 1.1 mmol),
and KI (33 mg, 0.2 mmol). The reaction mixture was stirred at room
temperature for alkanediols and at 0 °C for OEGs for 5 min to 8 h and then
filtered through a small pad of silica gel and washed with EtOAc.
Evaporation of the solvent, followed by column chromatography, gave the
desired monotosylate product. (b) The use of fresh Ag2O is recommended
because on standing for a few months on bench, Ag2O became less active
due to its oxidation to AgO and its decomposition to metallic silver: L’vov,
B. V. Thermochim. Acta 1999, 333, 13-19. (c) Ag2O can be easily prepared
by reacting AgNO3 with NaOH, Tanabe, M.; Peters, R. H. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, pp 386-392.
(7) (a) Nemto, H.; Takamatsu, S.; Yamamoto, Y. J. Org. Chem. 1991,
56, 1321-1322. (b) Kalinovski, H. O.; Crass, G.; Seebach, D. Chem. Ber.
1981, 114, 477. We found that diol 6 can be prepared readily in good yield
from dimethyl L-tartrate without isolating the intermediate. Reaction of
dimethyl L-tartrate with Ag2O in the presence of BnBr at reflux of CH2Cl2;
after filtration and evaporation of the solvent, the crude was treated with
LiAlH4 in THF to afford 6 in 88% overall yield after purification.
(8) (a) Burgess, K.; Henderson, I. Tetrahedron Lett. 1991, 32, 5701-
5704. (b) Burgess, K.; Chaplin, D. A.; Henderson, I. J. Org. Chem. 1992,
57, 1103-1109.
(9) 8 was prepared in three steps from commercially available 3,4-O-
isopropylidene-D-mannitol: (i) Bu2SnO, CsF, p-methoxybenzyl chloride
(PMBCl), (ii) BnBr, NaH, DMF, (iii) SnCl2, EtSH, CH2Cl2.
(10) Zuccarello, G.; Bouzide, A.; Kvarnstro¨m, I.; Niklasson, G.; Svens-
son, S. C. T.; Brisander, M.; Danielsson, H.; Nillroth, U.; Karle´n, A.;
Hallberg, A.; Classon, B.; Samuelsson, B. J. Org. Chem. 1998, 63, 4898-
4906.
(11) 11 was prepared readily from commercially available 3,4-O-
isopropylidene-D-mannitol: (i) Bu2SnO, Toluene, (ii) 4F-BnBr, CsF, DMF.
(12) (a) Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry;
VCH: Weinheim, 1993. (b) Pederson, C. J. J. Am. Chem. Soc. 1967, 89,
7017-7036. (c) Izzat, R. M.; Pawlak, K.; Bradshaw, J. S. Chem. ReV. 1995,
95, 2529-2586 and references therein.
(13) (a) Roberts, C.; Chen, C. S.; Mrksich, M.; Martinochonok, V.;
Ingeber, D. E.; Whitesides, G. M. J. Am. Chem. Soc. 1998, 120, 6548-
6555. (b) Wittman, V.; Takayama, S.; Gong, K. W.; Weitz-Schmidt, G.;
Wong, C.-H. J. Org. Chem. 1998, 63, 5137-5143. (c) Valiokas, R.;
Svedhem, S.; Svensson, S. C. T.; Lieberg, B. Langmuir 1999, 15, 3390-
3394.
(14) (a) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489-509. (b)
Houseman, B.; Mrksich, M. J. Org. Chem. 1998, 63, 7552-7555. (c)
Bettinger, T.; Remy, J.-S.; Erbacher, P.; Behr, J.-P. Bioconjugate Chem.
1998, 9, 842-846.
(15) Only 54% of the monotosylate was obtained when stoichiometric
amount of TsCl and pyridine were employed; see: MacMahon, S.; Fong,
R., II; Baran, P. S.; Safonov, I.; Wilson, S. R.; Schuster, D. I. J. Org. Chem.
2001, 66, 5449-5455. Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem.
1991, 56, 4326-4329.
a Isolated yield.
As illustrated in Table 1, other primary as well as
secondary symmetrical diols underwent selective monoto-
sylation in high yields.6
Monosulfonation of OEGs, which is often the first step in
the preparation of crown ether type derivatives,12 hydrophilic
tethers for linkage of bio-molecules,13 and spacers in solid-
phase synthesis,14 was undertaken. Thus, treatment of di-
(ethylene glycol) 13 under the conditions described above
2330
Org. Lett., Vol. 4, No. 14, 2002

moderate yields when tribenzyl L-arabitol 78 and dibenzyl
L-threitol 23, respectively, were treated under the same
conditions. On the other hand, the yields of cyclic ethers
were significantly increased when the reaction were per-
formed under the previously described conditions, followed
by treatment of the crude product with potassium carbonate
in methanol (Table 3, conditions B).
Table 2. Monotosylation of OEGs
The silver oxide mediated monosulfonylation of diols has
proven to be an excellent method for the straightforward
synthesis of crown ether type derivatives as exemplified in
the synthesis of 5-O-crown ether 3118 (Scheme 2). Reaction
Scheme 2. Synthesis of 5-O-Crown Ether 31
a Isolated yield. b 1:1 regiosiomers were obtained (1H, 13C NMR).
yielded the C-glycosyl 24 in 70% yield. The trisubstituted
tetrahydropyran 25 and the oxirane 2617 were obtained in
of the monotosylate 27, which was obtained in excellent yield
from 13 (Table 2), with 2,2′-biphenol 28 yielded diol 29 in
76% yield. Submission of 29 to the above monotosylation
conditions afforded the monosulfonic ester 30 with excellent
selectivity even though the two OH groups are separated by
16 atom units.19 Treatment of 30 in the presence of base
under dilute conditions afforded 31 in good yield.
Table 3. Synthesis of Cyclic Ethers from Symmetrical Diols
Although we do not have any material evidence, one can
attribute this highly selective monotosylation of symmetrical
diols to an internal hydrogen bonding (IHB) (Scheme 3, I).
Scheme 3
The hydrogen atom Ha involved in the IHB becomes less
acidic than Hb, which is in contrast more activated by this
(16) Compound 21 was prepared in three steps starting from com-
mercially available 1,2,5,6-di-O-isopropylidene-D-mannitol: (i) PMBCl,
NaH, DMF, (ii) aqueous AcOH (70%), 40 °C, (iii) Bu2SnO, CsF, BnBr.
(17) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Magolda, R.
L.; Dolle, R. E. J. Org. Chem. 1985, 50, 1440-1456.
a Conditions A: Ag2O (3 equiv), KI (0.2 equiv), TsCl (1.2 equiv),
CH2Cl2, 15 h. Conditions B: (i) Ag2O (1.5 equiv), KI (0.2 equiv), TsCl
(1.2 equiv), CH2Cl2, 2-4 h, (ii) K2CO3 (2 equiv), MeOH.
Org. Lett., Vol. 4, No. 14, 2002
2331

chelation, and therefore, Hb will be first deprotonated by
Ag2O. Our results are consistent with earlier work that has
shown that IHB exists in 1,n-alkanediols (n ) 2-6)20 and
that 1,4-butanediol has the strongest IHB despite its seven-
membered ring chelate.21 The high selectivity obtained in
the sulfonylation of OEGs compared to that obtained in
alkanediols may be explained by the coordination of Ag+
(or K+) with ether oxygen atoms in the OEGs.22 This chelate
makes the two OH groups closer to favor an IHB (Scheme
3, II). On the other hand, the moderate selectivity obtained
in the case of 19 and 20 can be attributed to the remoteness
of the two OH groups. In the case of ethylene glycol 12, its
low selectivity is probably due to the chelation of Ag+ (or
K+) with the oxygen electron pairs, which can prevent any
IHB (Scheme 3, III).
In summary, we report an easy method to monotosylate
symmetrical diols under neutral conditions using a stoichio-
metric amount of tosyl chloride in the presence of Ag2O and
a catalytic amount of KI. The reaction does not require any
workup, and the monotosylate esters are often isolated after
filtration of insoluble material followed, if necessary, by a
simple purification by column chromatography. Another key
merit of the present reaction is the ease by which substituted
cyclic ethers can be obtained from the corresponding diols.
Acknowledgment. We thank Dr. Gervais Berube´ (Uni-
versity of Trois-Rivie`res) and Ms. Ming Chou (Invenux, Inc.)
for their comments on the manuscript.
Supporting Information Available: Experimental pro-
cedures for the monotosylation of diols and for the synthesis
of cyclic ether 23-26 and 31. Characterization data for the
monotosylation products of diols 6, 7, 13, 14, 19, and 20,
for cyclic ethers 23-26, and for compounds 29-31. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Kohama, H.; Yoshinaga, M.; Ishizu, K. Bull. Chem. Soc. Jpn. 1980,
53, 3707-3708.
(19) The ditosylate byproduct was isolated in only 5% yield.
(20) Busfield, W. K.; Ennis, M. P.; McEwen, I. J. Spectrochim. Acta
1973, 29A, 1259-1264.
(21) (a) Fishman, E.; Chen, T. L. Spectrochim. Acta 1969, 25A, 1231-
1242. (b) Morantz, D. J.; Waite, M. S. Spectrochim. Acta 1971, 27A, 1133-
1137.
(22) Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1997, 38, 5945-5948.
OL020071Y
2332
Org. Lett., Vol. 4, No. 14, 2002