5982
L. Troisi et al. / Tetrahedron Letters 51 (2010) 5980–5983
(a) Adding the 2,2,6,6-tetramethyl-1-oxy-piperidine (TEMPO,
yields (35%). We then decided to extend this protection methodol-
ogy to more complex alcohols, encouraged by these results. The
tyrosol and the p-hydroxybenzyl alcohol were transformed into
compounds 11 and 13 in 45% and 40% of isolated yields, respec-
tively (Chart 1), the tetrahydrofuranylation occurring at the alco-
holic function only. The methoxytyrosol was transformed into
product 12 in 61% of isolated yield. The hydroxytyrosol, a known
powerful antioxidant present in the olive tree leaves, underwent
a degradation: no tetrahydrofuranylation product was isolated.
Rather, protecting the two phenolic functions by methoxy groups,
the tetrahydrofuranylation of the free alcoholic group of the pro-
tected hydroxytyrosol afforded ether 14 in an isolated yield of
88% (Chart 1).
1.2 mmol) to a benzyl alcohol–THF and allyl chloride mix-
ture, ether 5a was not formed (entry 7, Table 2). This result
supports, once more, the radical mechanism of the reaction
as the TEMPO is responsible for neutralizing the formed rad-
ical, inhibiting the radical mechanism and then the tetrahy-
drofuranyl ether formation.
(b) A greater isolated yield was observed increasing the allyl
chloride amount (3.0 mmol), under same operating condi-
tions (entry 8, Table 2). This result supports the hypothesis
of the allyl radical as the propagator of the radical chain.
(c) A solution of the only allyl chloride in THF, at reflux temper-
ature for few hours, gave the 2-Cl-tetrahydrofuran. This
compound is the outcome of the radical mechanism
(Scheme 3), which undergoes, in a second instance, a nucle-
ophilic substitution by the alcohol.
The reaction easiness allowed us to functionalise also more
complex molecules such as the cholesterol and the 1,2,5,6-di-
O-isopropyliden-a-D-glucofuranose: ethers 15 and 16 were formed
in fairly good isolated yields of 55% and 60%, respectively. For in-
stance, compound 15 (as epimer at the THF ring), already isolated
in a diastereoisomeric mixture by Hon et al.,14 was formed with a
diastereomeric enrichment (de) >99% as the sole diastereomer
As the commercial THF (Aldrich) contains stabilizers, the differ-
ent results reported in the literature for similar reactions are prob-
ably due to the different kinds of THF used. For instance, the THF
used for each process reported in this manuscript was previously
distilled in order to free it of any radical stabilizers. The distilled
solvent was then ready to allow the tetrahydrofuranyl radical for-
mation by simple action of the atmospheric oxygen (Scheme 3).
Moreover, when the THF was used for alcohol tetrahydrofuranyla-
tion without distillation, the products were not observed or ob-
served only in traces. These considerations highlight that the use
of the stabilized THF should need, as reported in the literature,
the addition of an oxidant that firstly reacts with the stabilizer
and then can form the furanyl radical. In order to support this
hypothesis, the tetrahydrofuranylation reaction was performed
on benzyl alcohol and allyl chloride using the commercial stabi-
lized THF. After 15 h of refluxing, only few traces of the functional-
ised alcohol were observed. When the oxidant CrCl2 (1.0 mmol)11
was added to this reaction mixture, the expected ether was formed
very quickly, as reported in the literature.
ð½a 2D2
ꢁ
ꢀ 25:6Þ.15 The high stereoselectivity observed for this reac-
tion could be due to a better asymmetric induction which seems
to be favoured by our synthetic methodology (with no metal or
peroxide catalyst). Product 16 was obtained with a de = 20% and
was isolated as a diastereomeric mixture, according to what was
previously reported in the literature.12
Because of the easy 2-tetrahydrofuranyl radical formation, the
THF was also reported in the literature to be widely used in the
radical addition reactions to C@N and C@O bonds, but in the pres-
ence of Me2Zn and air. Under similar conditions, arylamines, alk-
oxyamines and dialkylhydrazines were reported to react with
THF to give amino alcohols, oximes and hydrazones, respectively.16
In order to show that the tetrahydrofuranyl radical generation if
performed in unstabilized THF did not need oxidant addition, ex-
cept for the atmospheric oxygen already present, the same kind
of reaction described above was carried out with some imines.
The obtained results are reported in Table 3.
The reactions were carried out in freshly distilled and unstabilized
THF, at reflux temperature for 15 h. The addition to the C@N
double bond occurred regioselectively: the THF radical carbon bore
the imine carbon while the THF hydrogen linked the imine
nitrogen, respectively. The supposed mechanism is still radical,
having oxygen as the initiator and the allyl system increasing the
THF radical formation. The resulting tetrahydrofuranyl amine
was the outcome of the THF radical addition to the C@N double
bond (Scheme 4).
At the end of this deep investigation, the best experimental con-
ditions for a good yield in ether 5a resulted those reported on Ta-
ble 2, entry 8. For instance,
a representative experimental
procedure for the tetrahydrofuranylation of alcohols is hereafter
reported. A solution of benzyl alcohol (1 mmol) and allyl chloride
(3 mmol) in unstabilized THF (20 mL) was refluxed for 15 h. The
solvent was removed under reduced pressure, and the crude prod-
uct was purified by silica gel chromatography (ethyl ether/petro-
leum ether = 2:8) to afford the pure ether 5a. The same synthetic
protocol was then applied for the tetrahydrofuranylation of simple
alcohols. The use of ethanol, 2-butanol and cyclohexanol gave
compounds 7–9, in 60%, 55% and 55% of isolated yields, respec-
tively (Chart 1).
An analogous reaction, probably following a similar mechanism,
was performed on the alkyne function. For instance, the THF
The phenolic function underwent the tetrahydrofuranylation
too, being transformed into ether 10 in slightly lower isolated
Table 3
Reaction of imines with allyl chloride in THF at refluxing temperatures for 15 h
affording the tetrahydrofuranyl amines 17–19
O
Ar
OR
H
Ar'
Cl
O
CH
O
Ar'
N
C
+
N
H
13: R = CH2
(40 %)
Ar
OH
7: R =
8: R =
CH2CH3 (60 %)
OCH3
CH3
CHCH2
CH3
(55%)
17-19
14: R = CH2CH2
OCH3 (88 %)
(55%)
Entry
Ar0
Ar
Product
Yielda,b (%)
9: R =
(55%)
(35%)
15: R =
1
2
3
Ph
Ph
17
18
19
35
69
87
BTzc
3-Py
3-Pyd
4-Cl–Ph
10: R =
O
11: R = CH2CH2
12: R = CH2CH2
OH (45 %)
OCH3 (61 %)
O
O
a
b
c
16: R =
(60%)
Transformation yield calculated by GC.
Diastereomeric mixture of products.
BTz = 2-benzothiazolyl.
O
O
d
3-Py = 3-pyridinyl.
Chart 1.