Rapid ring-opening reactions of epoxides using microwave irradiation

Article abstract of DOI:10.1080/00397910701738982

Copper tetrafluoroborate catalyzes the ring-opening of epoxides with primary, secondary, and tertiary alcohols in short reaction times under microwave irradiation to give β-alkoxyalcohol products in excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701738982

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Rapid Ring‐Opening Reactions of Epoxides
using Microwave Irradiation
Christian Torborg a , David D. Hughes a , Richard Buckle b , Mathew W. C.
Robinson b , Mark C. Bagley a & Andrew E. Graham b
a School of Chemistry , Cardiff University , Cardiff, Wales, U.K.
b Department of Chemistry , University of Wales Swansea , Swansea, U.K.
Published online: 18 Jan 2008.
To cite this article: Christian Torborg , David D. Hughes , Richard Buckle , Mathew W. C. Robinson , Mark C.
Bagley & Andrew E. Graham (2008) Rapid Ring‐Opening Reactions of Epoxides using Microwave Irradiation,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:2, 205-211, DOI: 10.1080/00397910701738982
To link to this article: http://dx.doi.org/10.1080/00397910701738982
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Synthetic Communicationsw, 38: 205–211, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701738982
Rapid Ring-Opening Reactions of Epoxides
using Microwave Irradiation
Christian Torborg,1 David D. Hughes,1 Richard Buckle,2
Mathew W. C. Robinson,2 Mark C. Bagley,1 and Andrew E.
Graham2
1School of Chemistry, Cardiff University, Cardiff, Wales, U.K.
2Department of Chemistry, University of Wales Swansea, Swansea, U.K.
Abstract: Copper tetrafluoroborate catalyzes the ring-opening of epoxides with
primary, secondary, and tertiary alcohols in short reaction times under microwave
irradiation to give b-alkoxyalcohol products in excellent yields.
Keywords: b-alkoxyalcohols, copper tetrafluoroborate, microwave irradiation
Epoxides are highly versatile synthetic intermediates in organic synthesis and
undergo ring-opening reactions to give b-substituted alcohols with a variety of
nucleophilic species with high regio- and stereoselectivity.[1] These reactions
occur under a variety of conditions, although the most practical and widely
employed strategy for the synthesis of these 1,2-bifunctional compounds
utilizes Lewis acid promoters. However, the standard methods used are
often far from ideal and suffer from disadvantages such as the highly toxic
and corrosive nature of the promoter, high acidity, the requirement to use stoi-
chiometric quantities of the promoter, long reaction times, and inconvenient
handling procedures.[2] Therefore, the introduction of new methods for the
nucleophilic ring-opening of epoxides that work under mild conditions is an
area of ongoing interest.
Received in Poland May 3, 2007
Address correspondence to Andrew E. Graham, Department of Chemistry, Univer-
sity of Wales Swansea, Singleton Park, Swansea SA2 8PP, U.K. E-mail: a.e.graham@
swansea.ac.uk
205

206
C. Torborg et al.
The Lewis acid–catalyzed alcoholysis of epoxides to produce b-alkox-
yalcohols provides an ideal example of these limitations, and their synthesis
has attracted significant attention because of the synthetic utility of these
materials.[3] Although the use of alcohols in epoxide ring-opening reactions
is a well-established route to b-alkoxyalcohols, the poor nucleophilicity of
substrates other than primary alcohols means that these transformations
often require harsh reaction conditions and lack regioselectivity.[4] Significant
and important progress has been made in the development of efficient catalytic
methods that are successful under mild heterogeneous conditions;[5] however,
a number of these catalysts are not commercially available, are expensive, or
have environmental implications. Barluenga recently reported the use of com-
.
mercially available copper tetrafluoroborate (Cu(BF4)2 nH2O) to catalyze
epoxide ring-opening reactions under mild conditions.[6] The reactions
proceed at room temperature to give the b-alkoxyalcohol products in good
to excellent yields, although sterically demanding alcohols or alkyl
epoxides required extended reaction times (12–33 h).
Microwave dielectric heating has found increasing use in synthetic
chemistry in recent years.[7] Microwave-assisted procedures benefit from
increased energy efficiency, higher product yields, and faster reaction rates
and have been introduced for a wide range of synthetic transformations,
which, with the advent of specialized instruments that focus microwaves in
a monomodal cavity, are reliable, reproducible, and operationally facile.[8]
Microwave dielectric heating in pressurized systems can rapidly increase
temperatures far above the boiling point of the solvent and leads to efficient
energy transfer to the reactants. Indeed, the addition of 1-butanol to styrene
oxide using supported acid catalysts on carbon has been shown to accelerate
the addition reaction with varying degrees of success.[9] Herein, we report that
microwave irradiation dramatically accelerates the copper tetrafluoroborate–
catalyzed epoxide ring-opening reaction under very mild conditions (358C),
even with sterically hindered alcohols, to give b-alkoxyalcohols in high
yields (Scheme 1).
We initially investigated reaction conditions for the addition of methanol
to styrene oxide (1) to ascertain the potential for microwave acceleration of
this reaction (Scheme 1). Gratifyingly, good conversions to the b-alkoxyalco-
hol product (2a) were observed after irradiation at 358C for 5–10 min under
similar reaction conditions to those described by Barluenga (1 mol%
catalyst with four equivalents of methanol). Disappointingly, however,
attempts to further improve these yields by increasing the initial microwave
Scheme 1. Methanolysis of styrene oxide under microwave conditions.

Ring-Opening Reactions of Epoxides
207
power led to the production of substantial quantities of phenylacetaldehyde,
generated in a competing rearrangement Meinwald reaction.[10] This undesir-
able side reaction could be suppressed by simply increasing the number of
equivalents of methanol. Therefore, under optimized conditions (358C,
100 W initial power, 15 min), essentially quantitative conversions for the
addition of methanol to styrene oxide were achieved using 8 equivalents of
the alcohol (Table 1). Under similar conditions, the more synthetically chal-
lenging addition of sterically hindered alcohols such as iso-propanol and
tert-butanol were successfully realized with excellent regioselectivity and in
excellent overall yields. These yields were obtained in significantly shorter
reaction times than those originally reported by Barluenga. The observed
increase in the rate of reaction cannot be attributed to the elevated quantities
of alcohol present nor the increase in bulk temperature, as control reactions
proceeded in similar reaction times and produced yields comparable to
those previously reported. Reaction of styrene oxide with 8 equivalents of
tert-butanol at room temperature gave 78% conversion to compound 2c
after 12 h compared with 87% with 4 equivalents (see Ref: [6]). Reaction of
styrene oxide with 4 equivalents of methanol at 358C gave a 3:1 mixture of
2a and starting material after 15 min.
The generality of this methodology is illustrated by the successful
addition of a range of alcohols to cyclohexene oxide to give b-alkoxyalcohol
products (3a–d). In this case, no competing rearrangement reaction was
observed, and the number of equivalents of the alcohol could be reduced
without a noticeable reduction in yield or consequent increase in reaction
times (entries 6 and 7). In keeping with previous literature observations,[11]
no regioselectivity was observed in the addition of alcohols to linear
epoxides. Thus, approximately equal amounts of a mixture of regioisomers
(5a and 5b) were produced by the addition of iso-propanol to 1,2-epoxyhex-
5-ene (4). However, under microwave-assisted conditions, this reaction
proceeded rapidly to produce the corresponding addition products in excellent
yield and in significantly shorter reaction times than those previously reported.[6]
In conclusion, the copper tetrafluoroborate–catalyzed addition of alcohols
to epoxides under microwave irradiation proceeds under mild reaction con-
ditions, in excellent yields, and in significantly reduced reaction times. Further-
more, the high product purities obtained without chromatographic separation
makes this a highly attractive alternative for the synthesis of b-alkoxyalcohols.
TYPICAL PROCEDURE
Copper tetrafluoroborate (1 mol%, 4 mg, 0.016 mmol) was added to a dichlor-
omethane solution (5 ml) of styrene oxide (0.20 g, 1.66 mmol) and methanol
(0.42 g, 13.28 mmol) in a Pyrexw tube. The vessel was sealed and irradiated
inside a self-tunable microwave synthesizer (CEM Discover) under the
stated reaction conditions. The reaction mixture was then diluted with water

.
Table 1. Cu(BF4)2 nH2O mediated additions to epoxides
Conditionsc
Yield
(%)
Entry
1
Epoxide
Alcohol
CH3OHa
(8C/Watts/min)
Productd,e
35/100/15
35/100/15
100
2
3
(CH3)2CHOHa
(CH3)3COHa
78
35/100/15
78
4
5
CH3OHb
35/100/15
35/100/15
98
95
(CH3)2CHOHb
6
(CH3)3COHa
35/100/15
86

7
(CH3)3COHb
35/100/15
85
8
9
35/100/15
35/100/15
84
(CH3)2CHOHa
90f
a8 Equivalents of alcohol.
b4 Equivalents of alcohol.
cPower indicates initial microwave power, which is modulated to maintain reaction temperature.
dAll products gave satisfactory spectroscopic data.
1
eRegioselectivity was determined from crude H NMR spectra.
1
fIsolated as a 1.1:1 mixture of 5b: 5a as determined by H NMR spectra of the crude reaction mixture.

210
C. Torborg et al.
(20 ml) and extracted with dichloromethane (3 ꢀ 20 ml). The combined
extracts were dried over MgSO4 and filtered, and the solvent was removed
under reduced pressure to give 2-methoxy-2-phenylethanol (2a) as a
colorless oil (250 mg, 100%), which was determined to be .98% pure by
1
1H NMR spectroscopy. H NMR (400 MHz; CDCl3) d ¼ 7.44–7.29 (5H,
m), 4.34 (1H, dd, J ¼ 4 and 9 Hz), 3.74–3.59 (2H, m), 3.34 (3H, s), 2.45
(1H, dd, J ¼ 4 and 9 Hz); 13C NMR (100 MHz; CDCl3) d ¼ 138.7, 129.4,
129.3, 128.9, 127.5, 127.4, 85.1, 67.8, 57.3; ymax (film)/cm21 3421, 2932,
2872, 1493, 1454, 1109, 1062, 1025, 865, 757, 699, 544; MS (EI) m/z 152
(M)þ; HRMS (CI, NH3) calculated for C9H16NO2 (M þ NH4)þ, 170.1176,
found (M þ NH4)þ 170.1176.
ACKNOWLEDGMENTS
The authors thank the Biotechnology and Biological Sciences Research
Council (BBSRC) (D. D. H.) and the European Union (EU) for funding
under the Erasmus program (C. T.), the Engineering and Physical Sciences
Research Council (EPSRC) National Mass Spectrometry Service, University
of Wales Swansea, U.K., and Nick Morgan for his thoughtful and helpful
insights.
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