Vanadium(III) chloride (VCl3): Efficient reagent for the introduction of tetrahydrofuran-based acetal protecting groups for alcohols

Article abstract of DOI:10.1002/hlca.200790223

Treatment of different types of alcohols with tetrahydrofuran (THF) in the presence of VCl₃ and CCl₄ smoothly afforded the corresponding THF-based acetals in excellent yields. The reaction is fast at room temperature, and several functional groups are tolerated, with no racemization being observed. A radical mechanism, based on Cl₃C ^? as the active species, is proposed for this novel kind of transformation, which complements the classical tetrahydro-2H-pyran-2-yl (THP) protocol.

Full text of DOI:10.1002/hlca.200790223

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Vanadium(III) Chloride (VCl3): Efficient Reagent for the Introduction
of Tetrahydrofuran-Based Acetal Protecting Groups for Alcohols1)
by Biswanath Das*, Maddeboina Krishnaiah, Vtukuri Saidi Reddy, and Keetha Laxminarayana
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
Treatment of different types of alcohols with tetrahydrofuran (THF) in the presence of VCl3 and
CCl4 smoothly afforded the corresponding THF-based acetals in excellent yields. The reaction is fast at
room temperature, and several functional groups are tolerated, with no racemization being observed. A
.
radical mechanism, based on Cl3C as the active species, is proposed for this novel kind of transformation,
which complements the classical tetrahydro-2H-pyran-2-yl (THP) protocol.
Introduction. – The protection of hydroxy (OH) functions as tetrahydrofuran-2-yl
(THF) ethers is an important strategy in organic synthesis [1]. THF Ethers are acid
labile and are preferred sometimes in the synthetic sequence over the more commonly
used tetrahydro-2H-pyran-2-yl (THP) ethers [1]. Different methods are available for
the introduction of the THF moiety [2]. However, the reagents used in many of these
methods are often commercially not available, expensive, and toxic, or their
introduction may effect other functionalities.
In continuation of our work on the development of useful synthetic methodologies
[3], we herein report a novel method for the introduction of the THF (protective)
group by CÀO bond-formation with a broad variety of alcohols in the presence of
VCl3.
Results and Discussion. – We observed that alcohols can efficiently be protected
with the tetrahydrofuranyl group by employing a mixture of VCl3 and CCl4 in THF
proper. As can be seen from the results presented in the Table, primary, secondary,
tertiary, allylic, and benzylic alcohols were smoothly converted into the corresponding
tetrahydrofuran-2-yl ethers at room temperature. The conversion was complete within
2 to 4 h in all cases, and good-to-excellent yields (75 – 90%) of the acetals were
obtained. Our results demonstrate that even acid-sensitive and oxidation-labile OH
groups can conveniently be tetrahydrofuranylated.
A further advantage is the observation that C¼C and CꢀC bonds (Table, Entries 8
and 9, resp.) are unaffected, and that ether linkages (Entry 6) also remain intact.
Further, there was no racemization of a chiral secondary alcohol, i.e., menthol
(Entry 12). However, we found that acetals do not tolerate the reaction conditions. An
1
)
Part 134 in the series ꢁStudies on Novel Synthetic Methodologiesꢂ.
ꢀ 2007Verlag Helvetica Chimica Acta AG, Zürich

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Table. Tetrahydrofuranylation of Alcohols. For details, see Exper. Part.
Entry Product
Yield [%]a) Entry Product
Yield [%]a)
82
1
84
8
2
78
9
70
3
4
82
80
10
11
72
78
5
85
12
13
90b)
6
7
86
75
78
a) After chromatographic purification. b) 1 : 1 Diastereoisomer mixture.
alcohol containing an acetal, when subjected to the above procedure, gave rise to a
mixture of products due to deprotection and re-protection in situ.
VCl3 as a reagent in organic synthesis [4] is relatively unexplored, although it is
commercially available and not too expensive. The mechanism of the above conversion
possibly involves single electron transfer [2h] from VCl3 to CCl4 to form a
.
trichloromethyl radical (Cl3C ; Scheme). The latter then abstracts a H-atom from the
a-CH2 group of THF to form CHCl3 and a heteroatom-stabilized radical, which, in turn,
may react with another molecule of CCl4 to form 2-chlorotetrahydrofuran and a new
.
Cl3C species. Finally, 2-chlorotetrahydrofuran, on reaction with an alcohol, produces
.
the desired THF ethers. The newly formed Cl3C may again propagate the reaction, or it

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is reduced to CHCl3 by VCl3 in the presence of HCl generated during etherification.
Notably, when the THF protection of menthol (Table, Entry 12) was carried out as
above, but in the presence of styrene, a mixture of the expected THF adduct and (3,3,3-
.
trichloropropyl)benzene was found, indicating the formation of Cl3C during the
reaction.
Scheme. Proposed Mechanism for the Formation of THF-Based Acetals from Alcohols in the Presence of
VCl3 and CCl4
In conclusion, we have developed a simple, mild, and efficient protocol for the
tetrahydrofuranylation of alcohols using the poorly explored reagent VCl3.
We wish to thank CSIR and UGC (New Delhi, India) for financial assistance.
Experimental Part
General. 1H-NMR Chemical shifts d (at 200 MHz in CDCl3) and coupling constants J are provided
in ppm (rel. to Me4Si) and in Hz, resp. Mass-spectrometric (MS) data are reported in m/z.
General Procedure. To a mixture of an alcohol (1 mmol) and CCl4 (1.5 mmol) in anh. THF (5 ml) was
added VCl3 (1.5 mmol), and the mixture was stirred at r.t. After completion of the reaction (TLC
control), H2O (10 ml) was added, and the mixture was extracted with AcOEt (3 ꢁ 10 ml). The combined
org. extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column
1
chromatography (SiO2; hexane/AcOEt) to afford the pure THF ether. The H-NMR and MS data of
some representatives are given below (see Table entries).
2-[2-(Thiophen-3-yl)ethoxy]tetrahydrofuran (see Entry 2). 1H-NMR: 7.08 (d, J ¼ 4.5, 1 H); 6.89 (dd,
J ¼ 4.5, 2.0, 1 H); 6.80 (d, J ¼ 2.0, 1 H); 5.10 (m, 1 H); 3.92 – 3.80 (m, 3 H); 3.60 – 3.52 (m, 1 H); 3.30 (t,
J ¼ 7.0, 2 H); 2.06 – 1.75 (m, 4 H). FAB-MS: 199 ([M þ 1]þ).
2-(Cyclopentylmethoxy)tetrahydrofuran (see Entry 4). 1H-NMR: 5.04 (m, 1 H); 3.91 – 3.76 (m, 2 H);
3.48 (m, 1 H); 3.19 (m, 1 H); 2.18 – 1.43 (m, 11 H); 1.31 – 1.09 (m, 2 H). FAB-MS: 171 ([M þ 1]þ).
2-[(4-Methoxybenzyl)oxy]tetrahydrofuran (see Entry 6). 1H-NMR: 7.21 (d, J ¼ 8.0, 2 H); 6.90 (d,
J ¼ 8.0, 2 H); 5.11 (m, 1 H); 4.59 (d, J ¼ 12.0, 1 H); 4.36 (d, J ¼ 12.0, 1 H); 3.95 – 3.81 (m, 2 H); 3.77 (s,
3 H); 2.05 – 1.76 (m, 4 H). FAB-MS: 209 ([M þ 1]þ).
2-(2,3-Dihydro-1H-inden-2-yloxy)tetrahydrofuran (see Entry 11). 1H-NMR: 7.19 – 7.04 (m, 4 H);
5.25 (m, 1 H); 4.55 (m, 1 H); 3.92 – 3.81 (m, 2 H); 3.24 – 3.10 (m, 2 H); 2.99 – 2.87( m, 2 H); 2.06 – 1.74 (m,
4 H). FAB-MS: 205 ([M þ 1]þ).

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Received June 29, 2007