An economic and practical synthesis of the 2-tetrahydrofuranyl ether protective group

Article abstract of DOI:10.1016/j.tetlet.2006.05.081

Primary, secondary, and tertiary alcohols as well as phenols and carbohydrates are efficiently transformed into the corresponding 2-tetrahydrofuranyl ethers by a combination of Mn(0) powder and CCl₄ in tetrahydrofuran.

Full text of DOI:10.1016/j.tetlet.2006.05.081

Tetrahedron Letters 47 (2006) 5111–5113
An economic and practical synthesis of the
2-tetrahydrofuranyl ether protective group
J. R. Falck,a,* De Run Li,a Romain Bejotb and Charles Mioskowskib,*
aDepartments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
b
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Laboratoire de Synthese Bio-Organique, UMR 7175 – LC1, Faculte de Pharmacie, Universite Louis Pasteur,
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74 Route du Rhin, BP 24, 67 401 Illkirch, France
Received 26 April 2006; revised 11 May 2006; accepted 12 May 2006
Available online 6 June 2006
Abstract—Primary, secondary, and tertiary alcohols as well as phenols and carbohydrates are efficiently transformed into the
corresponding 2-tetrahydrofuranyl ethers by a combination of Mn(0) powder and CCl4 in tetrahydrofuran.
Ó 2006 Elsevier Ltd. All rights reserved.
Despite its well-established reputation1 as a versatile,
orthogonal2 protecting group, the 2-tetrahydrofuranyl
(THF) ether is often disregarded in favor of its homolo-
gous relative, the tetrahydropyranyl (THP) ether. This is
due, in large measure, to limitations in the extant proce-
dures for its introduction, that is, the required reagents
not commercially available, corrosive, incompatible
with sensitive functionality, and/or unstable.2–11 To ad-
dress these issues, we introduced a convenient protocol
utilizing CrCl2 and CCl4 in tetrahydrofuran.12 However,
the high costs of CrCl2, the need for a large excess of
reagent, and chromium’s toxicity spurred us to seek a
more economic and environmentally benign alternative.
Likewise, secondary12 (entry 2), allylic15 (entry 3), and
benzylic12 (entry 4) THF ethers were easily obtained
from alcohols 3, 5, and 7, respectively. Less reactive
hydroxyls such as phenol (9) and the highly hindered
dimethylphenylcarbinol 11 were transformed without
complication into their THF derivatives 1012 (entry 5)
and 1212 (entry 6), respectively. Importantly, a variety
of common functionality proved compatible with the
standard reaction conditions. For instance, methylene-
dioxy (entry 7), acetonide (entry 8), and silyl (entry 9)
groups were all well tolerated and accordingly led to
THF ethers 14,12 16,15 and 18.15 The successful protec-
tion of labile 1,1,1-trichloride 19,12 acid sensitive epox-
ide 21, and a,b-unsaturated steroidal ketone 23, all in
excellent yields, are especially notable.15
Initially, a panel of readily available, eco-friendly metals
was evaluated for their ability to promote the 2-tetra-
hydrofuranylation of n-octanol (1) under a standard set
of reaction conditions (0.4 M in THF, 65 °C, 15 h,
1.5 equiv of CCl4). Fe(0) and Zn(0) furnished only mod-
est yields of 213 (73% and 63%, respectively). Mg(0),
with the largest reduction potential of all the metals
tested, gave rise to a disappointing 5% of the desired
THF ether. The most consistent results were obtained
with Mn(0) powder.14 Just 1.5 equiv of Mn(0) provided
an excellent yield of 2 (Table 1, entry 1); fewer equiva-
lents of Mn(0) led to proportionately lower yields of 2.
The mechanism of the tetrahydrofuranylation like most
parallels as that of the CrCl2-mediated reaction,12 that
is, single electron transfer from Mn(0)16 to CCl4 during
the initiation phase generates the well-known trichlo-
romethyl radical (Scheme 1). This radical subsequently
abstracts a hydrogen atom from the tetrahydrofuran
methylene adjacent to oxygen in the first step of the
propagation phase forming chloroform and a hetero-
atom stabilized radical that is chlorinated by a second
molecule of CCl4. The newly evolved trichloromethyl
radical can either propagate the reaction via hydrogen
atom abstraction from another equivalent of tetra-
hydrofuran or is further reduced and in the process
consumes the HCl produced during the etherification
step.
Keywords: Protecting group; Manganese; Radical reaction;
Tetrahydrofuran.
*
Corresponding authors. Tel.: +214 648 2406; fax: +214 648 6455
(J.R.F.); e-mail: j.falck@UTSouthwestern.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.081

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J. R. Falck et al. / Tetrahedron Letters 47 (2006) 5111–5113
Table 1. Preparation of THF ethers
Entry
1
Alcohol
THF ether
Time (h)
15
Yield (%)
96
2
15
99a
3
4
7
4
85a
93
5
6
6
6
91
88a
7
8
14
90
6
99a,b
9
3
4
96
10
11
88a
13
85a
12
8
91a,b
a
ꢀ1:1 Diastereomeric mixture by NMR analysis.
b 2 equiv each of Mn(0) and CCl4 were used.

J. R. Falck et al. / Tetrahedron Letters 47 (2006) 5111–5113
5113
8. THF/tetrabutylammonium peroxydisulfate: Jung, J. C.;
Choi, H. C.; Kim, Y. H. Tetrahedron Lett. 1993, 34, 3581–
3584.
9. p-TsCl/NaH/THF: Yu, B.; Hui, Y. Synth. Commun. 1995,
25, 2037–2042.
10. BrCCl3/2,4,6-collidine: Barks, J. M.; Gilbert, B. C.;
Parsons, A. F.; Upeandran, B. Tetrahedron Lett. 2000,
41, 6249.
11. tert-Butylperoxy-k3-iodane/CCl4: Ochiai, M.; Sueda, T.
Tetrahedron Lett. 2004, 45, 3557.
12. Baati, R.; Valleix, A.; Mioskowski, C.; Barma, D. K.;
Falck, J. R. Org. Lett. 2000, 2, 485–487.
13. Seiders, J. R., II; Wang, L.; Floreancig, P. E. J. Am. Chem.
Soc. 2003, 125, 2406.
14. Mn(0) powder was purchased from Aldrich Chem. (99%,
À325 mesh). While it could be weighed and handled
without special precautions, it was stored under an inert
atmosphere to help retain its full reactivity.
Scheme 1.
General Procedure: CCl4 (0.145 mL, 1.5 mmol,
1.5 equiv) was added via syringe to a stirring suspension
of alcohol (1 mmol, 1.0 equiv) and Mn(0) powder14 (83
mg, 1.5 mmol, 1.5 equiv) in anhydrous THF (3 mL) un-
der an argon atmosphere and then warmed to 65 °C. A
white precipitate of MnCl2 accumulated during the
course of the reaction. After the time periods indicated
in Table 1, the reaction mixture was cooled to room
temperature, diluted with ether (20 mL), filtered through
a pad of silica gel, and the filter cake was washed with
ether. In most cases, the residue after concentration in
vacuo required no further purification, but if necessary,
was passed over a SiO2 column to give the correspond-
ing THF ether in indicated yields (Table 1).
15. Spectral data for 6 (ꢀ1:1 diastereomeric mixture): 1H
NMR (300 MHz, CDCl3) d 5.86–5.68 (m, 4H), 5.32 (dd,
J = 4.2, 2.1 Hz, 1H), 5.29 (dd, J = 4.2, 1.8 Hz, 1H), 4.18–
4.11 (m, 2H), 3.94–3.82 (m, 4H), 2.02–1.84 (m, 20H); 13C
NMR (75 MHz, CDCl3) d 131.0, 130.6, 129.2, 127.9,
103.3, 102.0, 70.9, 69.7, 66.8 (2C), 32.9, 32.7, 30.5, 28.4,
25.3, 25.2, 23.7 (2C), 19.6, 19.4; HRMS (CI, CH4) calcd
for C10H17O2 (M+1) m/e 169.1228, found 169.1230.
Compound 16 (ꢀ1:1 diastereomeric mixture): 1H NMR
(400 MHz, CDCl3) d 5.87 (d, J = 4.0 Hz, 1H), 5.84 (d,
J = 3.2 Hz, 1H), 5.31 (t, J = 2.8 Hz, 1H), 5.24 (br s, 1H),
4.60 (d, J = 3.2 Hz, 1H), 4.51 (d, J = 3.6 Hz, 1H), 4.31 (d,
J = 3.6 Hz, 1H), 4.26–4.16 (m, 4H), 4.11–3.99 (m, 2H),
3.98–3.86 (m, 6H), 1.99–1.83 (m, 8H), 1.49 (s, 6H), 1.42 (s,
6H), 1.34 (s, 6H), 1.31 (s, 6H); 13C NMR (50 MHz,
CDCl3) d 111.8, 109.0, 108.8, 105.3, 101.2, 84.2, 82.4, 81.1,
80.2, 76.4, 72.8, 72.7, 67.4, 67.20, 67.16, 67.1, 32.4, 27.0,
26.9, 26.7, 26.3, 25.5, 23.4, 23.0. Compound 18 (ꢀ1:1
diastereomeric mixture): 1H NMR (400 MHz, CDCl3) d
5.09 (d, J = 3.2 Hz, 1H), 3.88–3.81 (m, 2H), 3.68–3.60 (m,
3H), 3.40–3.34 (m, 1H), 2.01–1.79 (m, 4H), 1.61–1.54 (m,
4H), 0.91 (s, 9H), 0.03 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 103.9, 67.1, 66.8, 63.1, 32.4, 29.7, 26.3, 26.1 (3C),
23.6, 18.5, À5.1 (2C); HRMS (CI, CH4) calcd for
C15H33O3Si (M+1) m/e 289.2199, found 289.2198. Com-
pound 22: 1:1 diastereo mixture; 1H NMR (300 MHz,
CDCl3): d = 5.38 (dd, J = 4.2, 1.8 Hz, 1H), 5.13 (dd,
J = 4.2, 1.8 Hz, 1H), 3.89–3.59 (m, 10H), 3.50–3.41 (m,
2H), 1.84–1.71 (m, 16H), 1.58–1.20 (m, 18H), 0.81–0.77
(m, 6H); 13C NMR (75 MHz, CDCl3): d = 104.0, 103.0,
82.6, 80.0, 78.1, 77.8, 77.7, 68.5, 68.0, 67.0, 66.8, 32.6, 32.5,
32.2, 32.1, 32.0, 30.8, 28.5, 27.3, 26.2, 26.0, 25.6, 25.2, 23.7,
22.8, 22.7, 14.1 (2C); HRMS (CI, CH4) calcd for
C14H27O3 (M+1) m/e 243.1960, found 243.1960. Com-
pound 24 (ꢀ1:1 diastereomeric mixture): 1H NMR
(300 MHz, CDCl3) d 5.72 (s, 2H), 5.39–5.37 (m, 1H),
5.34–5.32 (m, 1H), 3.94–3.88 (m, 2H), 3.79–3.74 (m, 2H),
2.50–2.22 (m, 8H), 2.19–1.24 (m, 26H), 1.24 (s, 3H), 1.22
(s, 3H), 1.21 (s, 3H), 1.19 (s, 3H), 1.02–0.86 (m, 4H), 0.85
(s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d 199.8
(2C), 171.1, 171.6, 124.0 (2C), 100.0, 99.6, 86.2, 85.8, 66.9,
66.7, 54.0 (2C), 49.9, 49.8 (2C), 46.6, 46.1, 38.8, 36.6, 36.5,
36.4, 36.1, 35.9 (2C), 34.1 (2C), 33.6, 33.5, 33.0 (2C), 32.6,
32.0 (2C), 31.7, 24.1 (2C), 23.7, 23.3, 23.2, 22.5, 20.9, 20.8,
17.6 (2C), 14.4, 14.2; HRMS (CI, CH4) calcd for
C24H37O3 (M+1) m/e 373.2743, found 373.2740.
In summary, an operationally simple, inexpensive, and
efficient method to make THF ethers has been devel-
oped. Its mild reaction conditions and general tolerance
of most functional groups make it widely applicable in
the synthesis of complex molecules.
Acknowledgments
Financial support was provided by the Robert A. Welch
Foundation, NIH (GM31278, DK38226), and Ministere
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delegue a l’Enseignement superieur et a la Recherche.
References and notes
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Organic Chemistry; Wiley: New York, 1999; Chapter 2, pp
57–58.
2. THF ethers can be selectively cleaved in the presence of
THP ethers, for example, see Refs. 1,3.
3. 2-Chlorotetrahydrofuran: Kruse, C. G.; Broekhof, N. L.
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1728.
4. Dihydrofuran: Sosnovsky, G. J. Org. Chem. 1965, 33, 2441.
5. Hon, Y. S.; Lee, C. F. Tetrahedron Lett. 1999, 40, 2389–
2392.
6. Acetal exchange: Kruse, C. G.; Poels, E. K.; Jonkers, F.
L.; van der Gen, A. J. Org. Chem. 1978, 43, 3548.
7. THF/ceric ammonium nitrate: Maione, A. M.; Romeo, A.
Synthesis 1987, 250.
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H. Bull. Chem. Soc. Jpn. 2003, 76, 347–353.