Titanium(III)-induced intramolecular radical cyclization of epoxyallene ethers: an efficient method for synthesis of multifunctional tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2007.11.097

Ti(III)-mediated intramolecular free radical cyclization of epoxyallene ethers in an exo-mode was studied. The reaction afforded an efficient and highly regioselective method of synthetically important 3-vinyl-4-hydroxymethyl tetrahydrofurans.

Full text of DOI:10.1016/j.tetlet.2007.11.097

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Tetrahedron Letters 49 (2008) 500–503
Titanium(III)-induced intramolecular radical cyclization
of epoxyallene ethers: an efficient method for synthesis
of multifunctional tetrahydrofurans
a
a,b,
*
Lubin Xu , Xian Huang
a
Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, PR China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
b
Received 24 July 2007; revised 13 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
Ti(III)-mediated intramolecular free radical cyclization of epoxyallene ethers in an exo-mode was studied. The reaction afforded an
efficient and highly regioselective method of synthetically important 3-vinyl-4-hydroxymethyl tetrahydrofurans.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Titanocene monochloride; Radical cyclization; Allene; Multifunctional tetrahydrofurans
Intramolecular radical cyclization has created a new era
in recent years for carbon–carbon bond formation, and it
reflects its significance as a powerful tool in modern syn-
thetic chemistry.1 In addition to the reactive nature of car-
bon radicals, high regioselectivity is frequently achieved in
intramolecular reactions. The mildness and regio- and
stereoselectivities of 5-hexenyl radical cyclization have
extensively been used2 for the construction of five-mem-
bered rings.
Tetrahydrofuran derivatives, especially containing vinyl
and hydroxymethyl groups, are versatile precursors for the
synthesis of naturally occurring cytotoxic3or antiplatelet-
aggregation, vascular relaxing and antimutagenic activi-
ties4 and also for the construction of a variety of furfuran
lignans5 and other natural products.6 However, the
synthetic methods for this kind of compounds need either
complicated substrates5b,c,6 or multiple reaction
steps,3,4,5a,b,d,7 so developing a short and efficient method
to synthesize this kind of compounds is of interest and
value.
The reductive opening of an epoxide via single-electron
transfer (SET) to a radical intermediate promoted by
titanocene monochloride (Cp2TiCl) and the subsequent
5-exo radical trapping reaction represents a valuable
synthetic tool that has been used in intramolecular car-
bon–carbon bond forming reactions.8 Thus, epoxides can
provide an excellent source of functionalized radicals.9
The high regioselectivity of the epoxide cleavage via C–O
homolysis is guided by the relative stabilities of the interme-
diate radicals. The trapping groups are usually unsaturated
system such as alkenes, alkynes8e,10 and nitriles.8g However,
to the best of our knowledge, very little is known concerning
the Ti(III)-mediated intramolecular free radical addition to
the allenes. Radical reactions of allenes have been paid
much attention because of the unique bonding character,11
and are of current interest.12 To expand upon the aforemen-
tioned chemistry, intramolecular cyclizations of epoxy-
allene ethers were investigated. In addition to achieving a
new approach for constructing functional oxygen hetero-
cycles, this investigation also presents an opportunity to
address the regioselectivity issue in radical processes involv-
ing allenes, which is not a well-resolved problem.13
*
The exo-cyclization (path a) of radical intermediate 2
would lead to a vinyl radical 3, and central-cyclization
Corresponding author. Tel./fax: +86 571 88807077.
E-mail address: huangx@mail.hz.zj.cn (X. Huang).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.097

L. Xu, X. Huang / Tetrahedron Letters 49 (2008) 500–503
501
HO
HO
(IV)TiO
R1
R2
R1
R2
b
O
O
o
O
x
e
a
Cp2TiCl
THF
4
3
(IV)TiO
R1
R2
R1
R2
O
O
2
(IV)TiO
c
e
n
R1
R2
t
l
R1
R2
r
a
1
O
O
5
6
Scheme 1. Probable reaction pathways.
(path b) would give the energetically more favoured allyl
radical 5 (Scheme 1). Since this is an intramolecular
radical process, endo-cyclization might be prohibited due
to geometric constrains. With these issues in mind, we
report here a highly regioselective radical cyclization of
epoxyallene ethers for the synthesis of multifunctional
tetrahydrofurans.
The first substrate we examined for this reaction was
cyclopentyl epoxyallene ether14 (1a). The radical cycli-
zation of 1a using Cp2TiCl in THF15 under nitrogen for
1 h afforded the cyclization product 4a containing a vinyl
group at C-3 and hydroxymethyl group at C-4 position
in 84% yield, along with 6% of deoxygenation product15
7a indicating that the radical cyclization was conducted
with high regioselectivity in an exo-mode (Scheme 2). The
central-cyclized product 6a was not found.
Compared with the literature,10b,c our results indicated that
the major isomer of products was the one with the vinyl
and hydroxymethene groups at cis-position.17Attempts to
separate products 4j,k by HPLC to provide the ratios of
stereoisomers did not yield good separation results.18
Besides the ethereal substrates, this radical cyclization
can also be extended to synthesize multifunctional
pyrrolidines. As shown in Scheme 3, when the N-tosyl
containing epoxide 8 was subjected to the reaction condi-
tions, the corresponding N-tosyl pyrrolidine 9 was isolated
in 80% yield, the ratio of two inseparable diastereoisomers
as 55:45.19 It is important to note that substituted pyrrol-
idines are important structural features in many natural
products.
In conclusion, we have developed the radical cyclization
of epoxyallene ethers induced by titanocene monochloride
(Cp2TiCl) with high regioselectivity in an exo-mode. This
reaction also provided a useful way for the synthesis of
3-vinyl-4-hydroxymethyl tetrahydrofuran derivatives.
Further studies of titanocene monochloride mediated
radical cyclization of epoxyallenes are ongoing in our
laboratory.
On the basis of this promising result, the Ti(III)-medi-
ated cyclization of a variety of epoxyallene ethers was
tested.16 The results are summarized in Table 1. From
Table 1, similar results were obtained for both monosubsti-
tuted and disubstituted epoxyallene ethers. For the ring
substituted substrates 1a–e, the multifunctional oxaspiro-
compounds 4a–e were isolated in good yields (entries
1–5). And for the two same alkyl substituted substrates
1f,g, 4f,g were obtained in similarly good yields (entries 6
and 7). Compared with the two same substituted sub-
strates, the different substituted and racemic substrates
1j,k also afforded the corresponding cyclized products in
good yields (entries 10 and 11). However, to our surprise,
when both the substituted groups were hydrogen and phen-
yl, an unidentified mixture was obtained (entries 8 and 9).
As indicated in Table 1, products 4a–g were obtained in
an inseparable mixture of diastereoisomers with the ratio
range as 56:44 to 70:30. The ratio of diastereoisomers of
Table 1
Ti(III)-mediated radical cyclization of epoxyallene ethers
O
HO
H3O+
Cp2TiCl
THF
4
3
R1
R2
R1
R2
R1
R2
2
O
O
O
4
7
1
Entry
R1
R2
Yieldsa of
4/7 (%)
Ratio of
diastereoisomerb
1 (1a)
2 (1b)
3 (1c)
4 (1d)
–(CH2)4–
–(CH2)5–
–(CH2)6–
–(CH2)7–
84(4a)/6
72(4b)/8
76(4c)/8
71(4d)/7
64:36
64:36
63:37
62:48
1
each compounds 4a–g was determined by H NMR based
(CH2)2CH(CH2)2
CH3
on the splitting pattern for hydrogen atom at C-3 position.
5 (1e)
72(4e)/8
60:40
6 (1f)
7 (1g)
8 (1h)
9 (1i)
10 (1j)
11 (1k)
a
C2H5
n-C3H7
H
C6H5
H
CH3
C2H5
n-C3H7
H
C6H5
C6H5
CH3OC6H4CH2
75(4f)/8
77(4g)/7
—(4h)c
—(4i)c
80(4j)/7
74(4k)/8
70:30
70:30
—
—
—
HO
H3O+
O
Cp2TiCl
THF
4
3
2
O
6%
7a
O
84%
4a
O
—
Isolated yield.
1a
The ratio was determined by 1H NMR of the isolated product.
Unidentified mixture was obtained.
b
c
Scheme 2. The formation of multifunctional tetrahydrofuran 4a.

502
L. Xu, X. Huang / Tetrahedron Letters 49 (2008) 500–503
MCPBA
TsCl
Br
TsN
TsN
O
NH2
O
H
H
K2CO3
pyridine
O
C
HO
H3O
80%
Cp2TiCl
THF
CuBr, HCHO
i-Pr2NH
TsN
N
Ts
N
Ts
9 (55:45)
8
Scheme 3.
1993, 1032–1033; (d) Satoshi, Y.; Tomoko, I.; Takuya, K.; Toshiya,
M. Biosci., Biotechnol., Biochem. 2004, 183–192.
Acknowledgement
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We are grateful to the National Natural Science Foun-
dation of China (Project No. 20332060, 20472072) for its
financial support.
´
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Int. Ed. 1998, 37, 101–103; (c) Fernandez-Mateos, A.; Martın de la
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14. The epoxyallene ethers were prepared from the corresponding allenyl
alcohols treated with NaH, then added epichlorohydrin and refluxed.
15. The radical initiator Cp2TiCl was generated in situ from commercially
available titanocene dichloride (Cp2TiCl2) and Zn dust in tetra-
hydrofuran under nitrogen. See Ref. 8a and references cited therein.
16. Typical procedure for radical cyclization reaction. Preparation of 4a: A
solution of titanocene dichloride (0.5 g, 2 mmol) in dry tetrahydrofu-
ran (15 mL) was stirred with activated zinc dust (0.39 g, 6 mmol) for
1 h under nitrogen (activated zinc dust was prepared by washing 20 g
of commercially available zinc dust with 60 mL of 4 N HCl and
thoroughly washing with water and finally with dry acetone and then
drying in vacuo). The resulting green solution was then added
dropwise to a stirred solution of epoxide 1a (0.18 g, 1 mmol) in dry
tetrahydrofuran (10 mL) at room temperature under nitrogen during
15 min. The reaction mixture was stirred for an additional 1 h and
quenched with 10% H2SO4 (15 mL). Most of the solvent was removed
under reduced pressure, and the residue was extracted with diethyl
ether (4 · 15 mL). The ether layer was washed with saturated NaHCO3
(2 · 10 mL) and dried (Na2SO4). After removal of solvent, the crude
residue was purified by column chromatography over silica gel (25%
ethyl acetate/light petroleum) to afford alcohol 4a (0.15 g, 84%) as a
viscous liquid. Compound 4a: 1H NMR (400 MHz, CDCl3) d 5.76–
5.62 (m, 1H), 5.08–5.04 (m, 2H), 3.95–3.89 (m, 1H), 3.68–3.63 (m, 1H),
3.61–3.57 (m, 1H), 3.52–3.47 (m, 1H), 2.71–2.66 (m, 0.36 H), 2.59–2.54
3. Akindele, T.; Marsden, S. P.; Cumming, J. G. Tetrahedron Lett. 2005,
7235–7238.
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L. Xu, X. Huang / Tetrahedron Letters 49 (2008) 500–503
18. HPLC conditions: CH3CN/H2O = 1:1, ODS column.
503
(m, 0.36H), 2.35–2.30 (m, 0.64H), 2.29–2.24 (m, 0.64H), 2.15 (s, 1H,
OH), 1.75–1.41 (m, 8H). 13C NMR (100 MHz, CDCl3) d 136.99,
135.50, 117.49, 117.17, 94.17, 93.98, 68.24, 67.81, 64.12, 62.34, 53.60,
53.51, 47.15, 45.45, 37.92, 36.48, 33.97, 32.06, 24.12, 23.93, 23.56,
23.23. IR(neat): 3418, 2956, 1639, 1428, 1018, 916 cmÀ1; MS (EI): m/z
(%) = 80 (100), 151 (43), 165 (26), 182 (M+, 9), 183 (M++1, 51). Anal.
Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.45; H, 10.01.
17. The observed cis-isomer as the major isomer was in accordance with
the Beckwith-Houk rules, see: (a) Curran, D. P.; Porter, N. A.; Giese,
B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996; (b)
Backwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925; (c)
Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
19. The spectra data of compound 9: 1H NMR (400 MHz, CDCl3) d 7.73–
7.69 (m, 2H), 7.35–7.32 (m, 2H), 5.68–5.49 (m, 1H), 5.06–5.02 (m,
2H), 3.62–3.35 (m, 4H), 3.25–3.12 (m, 2H), 3.02–2.92 (m, 0.45H),
2.87–2.75 (m, 0.55H), 2.52–2.40 (m, 0.45H), 2.44 (s, 3H), 2.37–2.26
(m, 0.55H), 2.16 (s, 1H, OH). 13C NMR (100 MHz, CDCl3) d 143.52,
143.50, 136.76, 134.09, 133.41, 133.18, 129.62, 127.44, 127.35, 117.27,
117.12, 62.25, 61.06, 52.56, 51.96, 50.46, 49.61, 46.11, 44.65, 44.19,
44.00, 21.42. IR(neat): 3523, 3078, 2929, 1597, 1400, 1340, 1161,
924 cmÀ1; MS (EI): m/z (%) = 42 (100), 91 (56), 126 (55), 155 (18), 184
(14), 251 (21), 282 (M++1, 2). Anal. Calcd for C14H19NO3S: C, 59.76;
H, 6.81. Found: C, 59.53; H, 6.93.