An efficient and extremely mild method for protecting alcohols as 2-tetrahydrofuranyl ethers

Article abstract of DOI:10.1016/S0040-4039(00)01045-5

Reaction of primary or secondary alcohols with BrCCl₃ and tetrahydrofuran, usually in the presence of 2,4,6-collidine, leads to the formation of 2-tetrahydrofuranyl ethers in good to excellent yield (56-92%). The reaction mechanism is believed to involve a free-radical chain reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01045-5

Tetrahedron Letters 41 (2000) 6249±6252
An ecient and extremely mild method for protecting
alcohols as 2-tetrahydrofuranyl ethers
Jenny M. Barks,a Bruce C. Gilbert,b Andrew F. Parsonsb,* and Bala Upeandranb
aZeneca Agrochemicals, Process Technology Department, Leeds Road, Hudders®eld HD2 1FF, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 25 May 2000; accepted 20 June 2000
Abstract
Reaction of primary or secondary alcohols with BrCCl3 and tetrahydrofuran, usually in the presence of
2,4,6-collidine, leads to the formation of 2-tetrahydrofuranyl ethers in good to excellent yield (56±92%).
The reaction mechanism is believed to involve a free-radical chain reaction. # 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: acetals; protecting groups; radicals and radical reactions; oxygen heterocycles.
A very important method for protecting alcohol functional groups in synthesis involves their
conversion to acetals.1 Conversion to tetrahydropyranyl (THP) ethers is very common and these
are generally prepared from an acid-catalysed addition of the alcohol to dihydropyran (DHP).
The resultant THP ethers are stable to strongly alkaline conditions, Lewis acids or organometallic
reagents (although low temperatures are often required), and can be hydrolysed back to the
alcohol using mild acid. In comparison, the related tetrahydrofuranyl (THF) ethers o€er the same
stability to a variety of alkaline and organometallic conditions, but have the advantage that they
can be hydrolysed under even milder acidic conditions. Indeed, THF ethers can be selectively
cleaved in the presence of THP ethers. Although a number of methods have been reported for
the synthesis of THF ethers (using, for example, THF in combination with SO2Cl2,2 CAN,3
5
TsCl/NaH4 or CrCl2/CCl4 ) this paper reports a new approach to these derivatives using THF
and BrCCl3, usually in the presence of 2,4,6-collidine. This method allows the ecient protection
of a variety of primary and secondary alcohols under very mild reaction conditions. The reagents
are inexpensive and also less toxic than those previously employed to make THF ethers.
Our initial experiments involved the reaction of 2-phenylethanol 1 with BrCCl3 and THF under
a variety of conditions (Scheme 1). For example, when alcohol 1(10 mmol, 1 equiv.) was added to
BrCCl3 (3 equiv.) in (degassed) THF (15 cm3) and the solution stirred overnight at re¯ux (under
* Corresponding author. Tel: +44 1904 432608; fax: +44 1904 432516; e-mail: afp2@york.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01045-5

6250
Scheme 1.
an atmosphere of nitrogen), the desired THF ether 2 was formed in only 8% yield.6 TLC analysis
indicated the remaining starting material and the formation of bromoalcohol 3, but the major
by-product was bromoacetal 4, which proved dicult to separate from 2 on column chromatography.
The use of dry (degassed) THF, or the addition of AIBN, had little e€ect on the reaction and 2
was isolated in similar yield (9±16%). However, when THF was added slowly to alcohol 1 and
BrCCl3 (at 60ꢀC) over 6 h, in the presence of 2,4,6-collidine (1 equiv.), then the yield of 2
improved to an excellent 92% (after column chromatography).7
The protection of alternative alcohols, under similar reaction conditions, was then investigated
as shown in Table 1. Hence the reaction of 1-octanol gave the desired THF ether in 88% yield, in
the absence of 2,4,6-collidine (entry 1). Whereas 1-octanol was eciently protected in the absence
of base, for most alcohols, a good yield of the THF ether was only realised when 2,4,6-collidine
was added to the reaction mixture. The addition of 2,4,6-collidine also minimised the formation
of the by-product bromoalcohol 3, which simpli®ed product puri®cation and therefore
subsequent reactions (entries 2±8) were carried out in the presence of 2,4,6-collidine. The
protection of primary benzylic alcohols is also possible (entries 3±5) although for these reactions,
competitive (alcohol to aldehyde) oxidation was observed and benzaldehyde derivatives were
isolated in 3±21% yield. Secondary alcohols can be protected as shown by the reactions of
cyclohexanol, (1S,2R,5S)-menthol and 1-phenylethanol (entries 6±8). For these reactions, the
presence of 2,4,6-collidine proved crucial. For example, the reaction of cyclohexanol in the
presence of alternative nitrogen bases (e.g. DBU, Et3N or DMAP), or the reaction of (1S,2R,
5S)-menthol in the absence of 2,4,6-collidine, gave the corresponding THF ethers in 17±37%
yield.
Although both primary and secondary alcohols were eciently protected, reaction of tertiary
alcohols [such as PhC(OH)Me2] was more problematic. The reactions proved to be very slow and
yields of the THF ethers were, at best, modest. Low yields were also observed when using allylic
alcohols and reaction with cinnamyl alcohol, for example, gave the corresponding THF ether in
only 20% yield.
The proposed mechanism for the formation of the THF ethers is outlined in Scheme 2. It is
anticipated that autoxidation of THF generates a small quantity of hydroperoxide 5 which
produces oxygen-centred radicals (on homolysis of the weak oxygen oxygen bond) which react
with THF to generate radical 6. This radical could react with BrCCl3 to give bromide 8 in one of
two ways. Firstly, by abstraction of a bromine atom from BrCCl3 or, alternatively, radical 6
could be oxidised by BrCCl3 (in a single electron transfer process) to produce carbocation 7
which subsequently reacts with the bromide anion. The resulting bromide 8 can then react with
the alcohol, presumably via the intermediate carbocation 7, to generate the desired THF ether 9.
Alternatively, carbocation 7 could react with THF to give the byproduct bromoacetal 4. Slow
addition of THF (to the alcohol and BrCCl3) therefore increases the yield of 9 because a low

6251
Table 1
Protection of alcohols as tetrahydrofuranyl ethers. aCarried out in the absence of 2,4,6-collidine. bYield based on
recovered starting material. cBenzaldehyde was also isolated in 3% yield. d4-Methoxybenzaldehyde was also isolated in
21% yield. eMethyl 4-formylbenzoate was also isolated in 11% yield. fCarried out in the presence of DBU rather than
g
h
2,4,6-collidine. Isolated as a mixture of diastereomers. Acetophenone was also isolated in 11% yield.
Scheme 2.

6252
concentration of THF minimises the competing pathway (leading to 4). The formation of 9
results in the formation of HBr which can be quenched by reaction with 2,4,6-collidine, and this
reduces the (acidic) ring-opening of THF, leading to byproduct 3. It should also be noted that
the trichloromethyl radical is formed during the reaction and it is likely that this abstracts an
a-hydrogen atom from THF so as to regenerate radical 6.
The formation of THF ethers derived from both primary and secondary alcohols can therefore
be carried out eciently by reaction with BrCCl3 and THF, generally in the presence of 2,4,6-
collidine. For ecient conversions, the reaction is limited to primary and secondary alcohols.
Reactions of tertiary alcohols are much slower and lower yielding, presumably due to steric
e€ects, while competitive hydrogen-atom abstraction and/or radical addition (to the alkene
double bond) may explain the low yields observed when using allylic alcohols. This extremely
mild and simple method of alcohol protection has the advantage of using readily available and
economical reagents. The method works extremely well when using THF; attempts at forming
THP ethers, by reaction of alcohols with THP, were considerably lower yielding.8 This is
presumably due to the slower rate of autoxidation of THP compared to THF.9
Acknowledgements
We would like to thank the EPSRC and Zeneca Agrochemicals for a CASE award (to B.U.).
References
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3. Maione, A. M.; Romeo, A. Synthesis, 1987, 250±251.
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6. All new compounds exhibited satisfactory spectral and analytical (high resolution mass) data.
7. Typical procedure. To a stirred solution of the alcohol (5 mmol, 1 equiv.), 2,4,6-collidine (1 equiv.) and BrCCl3 (3±
3.75 equiv.) was added degassed THF (HPLC grade, 15±35 cm3) over 6 h while the mixture was heated at 60ꢀC
(under an atmosphere of nitrogen). After 8±15 h, sat. aq. ammonium chloride (20 cm3) was added and the mixture
extracted three times with diethyl ether (3Â20 cm3). The (combined) organic layer was washed with water,
followed by brine, dried (MgSO4) and evaporated under reduced pressure. Puri®cation by column
chromatography a€orded the THF ethers as oils (56±92%).
8. Reaction of 1-octanol with THP, under the same reaction conditions as for the THF reaction, gave the
corresponding THP ether in 6% yield.
9. Howard, J. A.; Ingold, K. U. Can. J. Chem. 1969, 47, 3809±3815.