Bis-chlorodibutyltin oxide as a new reagent for a mild, versatile and regioselective ring-opening of epoxides

Article abstract of DOI:10.1055/s-2001-9727

A convenient and efficient procedure for the ring-opening of epoxides by means of alcohols and bis-chlorodibutyltin oxide is described. The cleavage of the oxiranes is found to proceed regioselectively under mild reaction conditions. Thus, several haloalkanols, useful intermediates toward biological active molecules, are easily obtained in very good yields.

Full text of DOI:10.1055/s-2001-9727

LETTER
65
Bis-Chlorodibutyltin Oxide as a New Reagent for a Mild, Versatile and
Regioselective Ring-Opening of Epoxides
Claudio J. Salomon
Departamento Farmacia, IQUIOS (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario,
Suipacha 531, 2000, Rosario, Argentina
E-mail: salomon@citynet.net.ar
Received 14 September 2000
acid on the epoxide-opening reactions with a variety of
O-nucleophiles. In the present communication we report
the results that successfully led to the development of a
novel, simple method for the cleavage of epoxides in pres-
Abstract: A convenient and efficient procedure for the ring-open-
ing of epoxides by means of alcohols and bis-chlorodibutyltin oxide
is described. The cleavage of the oxiranes is found to proceed regi-
oselectively under mild reaction conditions. Thus, several haloal-
kanols, useful intermediates toward biological active molecules, are ence of several alcohols.
easily obtained in very good yields.
We reported the cleavage of styrene oxide (1a) with
Key words: bis-chlorodibutyltin oxide, epoxides, regioselective,
haloalkanols, b-chlorohydrin
MeOH assisted by (ClBu2Sn)2O. Thus, 2-Methoxy-2-b-
Phenylethanol (2a) was isolated as single isomer in 88%
yield.11 When the reaction was carried out in presence of
i-PrOH, the corresponding 2-isopropoxy-2-phenylethanol
(2b) was isolated in 53% yield. Surprisingly, a minor
product was detected by TLC, isolated and characterized
as the b-chlorohydrin 2c (30%) (Scheme 1). In the pres-
ence of t-BuOH, 2c was isolated in 51% yield, after 72 h.
Epoxides are among the most useful synthetic intermedi-
ates towards the synthesis of many biologically active
compounds.1 Due to their particular polarity and strain of
their three member ring, they undergo facile, regio- and
stereoselective ring-opening reactions with a wide variety
of nucleophiles, providing a powerful strategy for organic
synthesis.2,3
Fluorine substituted organic compounds gain a growing
interest because of their unique properties due to the influ-
ence of the electronegative fluorine substituent on the
neighboring positions. However, the preparation of fluo-
rohydrins from epoxides has always been a difficult trans-
formation in fluorine chemistry,12 therefore we first
investigated the ring-opening of styrene oxide (1a) with
2-fluoroethanol in presence of bis-chlorodibutyltin oxide.
The fluorophenylethanol 2d was easily obtained as a sin-
gle regioisomer in 88% yield.
These transformations are generally promoted by differ-
ent types of Lewis acid, which induce the nucleophilic at-
tack over the position that can best accommodate the
positive charge.4 Many organotin reagents acting as Lewis
acids have been used for the regiospecific conversion of
epoxides into 1,2-amino4- 1,2-halo5-, 1,2-alkoxy6- and
1,2-azido7- alcohols. However, some of the drawbacks are
the long reaction times,8 low chemo-, regio- and stereose-
lectivity,9 and the strong reaction conditions that promote
extensive polymerization.7
Treatment of styrene oxide with 2-chloroethanol and
(ClBu2Sn)2O afforded the aromatic chloroalcohol 2e regi-
oselectively in 87% yield. The bromophenylethanol 2f
was obtained in 83% yield when 2-bromoethanol cleaved
regiospecifically styrene oxide in presence of the orga-
nostannane. (Table 1)
For the past ten years, we have been involved in the devel-
opment of efficient methods for esterification, transester-
ification and deesterification mediated by organotin
oxides.10 Recently, we have demonstrated that bis-tribu-
tyltin oxide and bis-chlorodibutyltin oxide, are effective
reagents for the regio- and stereoselective ring-opening of
R-(-)-styrene oxide.11
In order to study the reactivity of the aliphatic epoxides
and the regioselectivity of the ring opening with
(ClBu2Sn)2O, 1b was reacted with MeOH, and surprising-
ly, two compounds were formed. The corresponding
1-methoxy-arylalcohol 2g was obtained in very low yield
(15%), and the unexpected b-chlorohydrin 2h was isolat-
ed in high yield (84%). In the presence of i-PrOH, 2h was
In view of the great utility of epoxides as synthetic inter-
mediates in organic chemistry, it is worthwhile to explore
the versatility of the bis-chlorodibutyltin oxide as Lewis
Scheme 1
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66
C. J. Salomon
LETTER
Table 1 Ring-opening of Styrene Oxide (1a) with Alcohols in the Presence of (ClBu2Sn)2O, at 90 °C
a As nucleophile and solvent. b Identified by 1H, and 13C NMR, and M.S. c Isolated yields. d The b-chlorohydrin 2c
was isolated in 30%. e Styrene oxide (1a) was recovered in 10-15%.
Scheme 2
obtained in moderate yield as single isomer. Interestingly, Based on a similar mechanisms,18 we postulate that the
when the oxirane 1b reacted with 2-fluoroethanol, the unexpected formation of the b-chlorohydrins (entries 2, 8,
only compound isolated was the chlorohydrin 2h in 78% 13 and 15) might be due to the coordination of the alcohol
yield. The ring opening of 1b with (ClBu2Sn)2O using 2- toward the tin atom, followed by a coordination of the ox-
chloroethanol afforded the chlorohydrin 2h in excellent ygen atom of the epoxide at one of the tin atoms of the or-
yield (93%). (Scheme 2).
ganometallic reagent. Then, a nucleophilic attack by the
halide ion formed in situ, at one of the carbon atom of the
epoxide, affords the b-chlorohydrin.
The ring-opening of 1c with MeOH and (ClBu2Sn)2O af-
forded the b-chlorohydrin 2i in 87% yield isolated yield
with no formation of the other regioisomer. In presence of The regiochemical mode of the epoxide cleavage by the
iPrOH the same chlorohydrin was obtained in 70% yield. alcohols in the presence of (ClBu2Sn)2O can be viewed as
occurring via nucleophilic attack by the chloride or bro-
Furans have been proven to be useful precursor to cyclic
mide ion on the less sterically hindered epoxide carbon.
or acyclic functionalized compounds having a framework
As expected, in the case of styrene oxide (1a), the nucleo-
of four carbon atoms.14 The mildness of bis-chlorodibutyl-
tin oxide allowed the chemo- and regioselective opening
of the 2-substituted epoxyfuran 1d with MeOH, providing
1-Chloro-3-furfuryloxy-propan-2-ol (2j), in 62% yield,
phile regiospecifically attacked the more substituted car-
bon of the oxirane. These results clearly suggested that a
preferential cleavage of the benzylic C-O bond provided
stabilized benzylic cation species during the reaction.
and the b-methoxy alcohol 2k, in 27% yield. The reaction
of 1d with iPrOH afforded exclusively the polioxygenated In conclusion, (ClBu2Sn)2O can be regarded as a useful
b-chlorohydrin 2j in 64% yield. The preparation of 2j un- reagent for the oxirane ring-opening by means of different
der mild non-hydrolytic conditions is a valuable alterna- alcohols. The fluoro-, chloro- and bromoalcohol deriva-
tive to those methods using NaOH or H2SO4.15 (Table 2). tives (2d, 2e, and 2f) easily obtained by this procedure
provide a series of interesting intermediates of practical
The highly regioselective ring-opening of epoxides with
importance. The synthetic utility of the unexpected forma-
(ClBu2Sn)2O, by means of halogenated primary alcohols
tion of b-chlorohydrins is shown by the easy preparation
(entries 4-6, 9 and 10), as well as the moderate yields ob-
served when iso-propanol is the nucleophile (entries 2, 8,
13, and 15), could be a consequence of the particular ar-
rangement of tin and chloro atoms disclosed by Otera et
of the chloroalkanols 2h, useful precursor of compounds
with antiinflammatory activity,19 and 2i, key intermediate
toward the synthesis of atenolol and other related drugs
for the treatment of hypertension and angina.20
al. They described that 1,3-disubstituted tetraalkyldistan-
noxanes have a dimeric structure, therefore, it might be Due to the ease in handling and inertness towards several
possible that a chemical reaction carried out by one tin at- other functional groups (ClBu2Sn)2O is recommended
om, can be influenced by the other tin atom.17
when chemoselectivity is crucial.17 It is particularly note-
worthy that we have recently developed an easy protocol
Synlett 2001, No. 1, 65–68 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Bis-Chlorodibutyltin Oxide as a New Reagent
67
Table 2 Ring-opening of Aliphatic Epoxides with Alcohols in the Presence of (ClBu2Sn)2O, at 90 °C
a As nucleophile and solvent. b Identified by 1H, and 13C NMR, and M.S. c.Isolated yields. d 1-Methoxy-3-phenyl-2-propanol (2g)
was isolated in 10%. e Epoxide 1b was recovered in 15%.
for the disposal of organotin residues.21 Thus the use of
References and Notes
(ClBu2Sn)2O could be valuable given the increasing de-
(1) (a) Erden, I. In Comprehensive Heterocyclic Chemistry, 2nd
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and Biology 1998, 4, R73. (c) Corey, E. J.; Shibata, S.; Bakshi,
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mand for environmentally benign technology.22 Finally,
the present method offers considerable advantages in
terms of simplicity, high efficiency and very mild condi-
tions. Further studies toward a general application of this
novel method are in progress in our laboratory.
(2) a) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768.
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General procedure: To a solution of the epoxide (1 mmol) in alco-
hol (2 mL) was added (ClBu2Sn)2O (1 mmol).23 The reaction mix-
ture was magnetically stirred at 90 °C under N2 atmosphere,
monitoring the consumption of starting material by TLC (hex-
ane:ethyl acetate, 4:1). The solvent was removed under vacuum and
the residue was chromatographed on a silica-gel column eluted with
hexane (50 mL), and hexane-ethyl acetate (3 ¥ 40 mL:10 mL) to
provide pure compounds (see Tables 1 and 2).
For a recent reviews see: a) Hodgson, D. M.; Gibbs, A. R.;
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Experimental Section
(5) Einhorn, C.; Luche, J.-L. J. Chem. Soc. Chem. Commun.
1986, 1368
Alcohols were purified by distillation and stored under molecular
sieves. Epoxides and (ClBu2Sn)2O are commercially available from
Aldrich Chemical Comp, Inc. Flash column chromatography was
carried out according to the standard literature method using silica
gel 60 Merck (230-400 mesh). NMR spectra were measured in
CDCl3 and C6D6 at 200 MHz for 1H and 20.15 MHz for 13C, and re-
corded on a Bruker AC-200 spectrometer with TMS as internal
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ter.
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Acknowledgement
(10) (a) Salomon, C. J.; Mata, E. G. and Mascaretti, O. A.
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The author is very grateful to Consejo Nacional de Investigaciones
Técnicas y Científicas (CONICET), Agencia para la Promoción
Científica y Tecnológica, Fundación Antorchas, and the National
University of Rosario for the financial support.
Synlett 2001, No. 1, 65–68 ISSN 0936-5214 © Thieme Stuttgart · New York

68
C. J. Salomon
LETTER
Trans. 1 1998, 355. (f) Mascaretti, O. A.; Furlán, R. L.;
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(16) (a) 1-Methoxy-3-furfuryloxy-propan-2-ol (2h): 1H NMR d
2.64 (1H, m); 3.36-3.51 (7H, m); 3.96 (1H, m); 4.49 (2H, s);
6.33-638 (2H, m); 7.40-7.42 (1H, m); 13C NMR d 59.04;
65.05; 69.21; 70.99; 73.57; 109.36; 110.14; 142,74; 151,31.
MS (70eV) m/z 186 (M, 48%), 145 (5%), 97 (76%), 81
(100%).
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(b) 1-Chloro-3-furfuryloxy-propan-2-ol (2i): 1H NMR d
2.56 (1H, dd, J = 8.5 and 4.4 Hz); 3.56-3.62 (4H, m); 3.95-
3.98 (1H, m); 4.51 (2H, s); 6.34-635 (2H, m); 7.40-7.42 (1H,
m); 13C NMR d 69.21; 70.65; 71.99, 74.34; 109.36; 110.14;
142,74; 151,31. MS (70eV) m/z 190 (M, 26%), 137 (5%), 97
(43%), 81 (100%), 53 (34%).
(13) (a) 2-Phenyl-2-(2-fluoroethoxy)-ethanol (2c): 1H NMR d
2.42 (1H, s); 3.67-3.75 (4H, m); 4.41-4.46 (2H, m); 4.68 (1H,
m); 7.30-7.35 (5H, m); 13C NMR d 67.90; 69.56; 81.45;
125.90; 128.01; 128,90; 136,77; MS (70eV) m/z 184 (M, 2%),
153 (100%), 121 (6%), 107 (50%), 79 (40%).
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(23) When the reaction was carried out using 0.1 equiv of
(ClBu2Sn)2O, the product was isolated in very low yield,
recovering the starting epoxide in 30-50%.
(b) 2-Phenyl-2-(2-chloroethoxy)-ethanol (2d): 1H NMR d
2.42 (1H, s); 3.63-3.67 (6H, m); 4.48 (1H, dd, J = 6.0 and 4.4
Hz); 7.31-7.35 (5H, m); 13C NMR d 67.23; 68.95; 83.45;
126.66; 128.22; 128,51; 137,87. MS (70eV) m/z 200 (M, 4%),
169 (100%), 121 (16%), 107 (62%), 79 (71%).
(c) 2-Phenyl-2-(2bromoethoxy)-ethanol (2e): 1H NMR d
2.44 (1H, dd, J = 8.5 and 4.4 Hz); 3.46-349 (2H, m); 3.52-3.83
(4H, m); 4.47 (1H, dd, J = 5.8 and 4.2 Hz); 7.30-7.37 (5H, m);
13C NMR d 67.23; 68.73; 83.39; 126.63; 128.20; 128,47;
137,85. MS (70eV) m/z 244 (M, 2 Br isotopes, 2%), 213
(72%), 133 (18%), 121 (17%), 105 (100%), 77 (72%).
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Article Identifier:
1437-2096,E;2001,0,01,0065,0068,ftx,en;S06100ST.pdf
Synlett 2001, No. 1, 65–68 ISSN 0936-5214 © Thieme Stuttgart · New York