A novel titanium-catalyzed cyclization of olefinic iodoethers to tetrahydrofurans

Article abstract of DOI:10.1021/jo026290e

A catalytic reductive cyclization of olefinic iodoethers was achieved by use of cat. Cp₂TiCl₂ in the presence of Mn and Me₃SiCl. This protocol provides a versatile method for the selective formation of multisubstituted tet

Full text of DOI:10.1021/jo026290e

TABLE 1. In tr a m olecu la r Cycliza tion of 1a w ith
Va r iou s Red u cta n tsa
A Novel Tita n iu m -Ca ta lyzed Cycliza tion of
Olefin ic Iod oeth er s to Tetr a h yd r ofu r a n s
yield (%)
Longhu Zhou1 and Toshikazu Hirao*
entry
catalyst
time (h)
2a
35
45
16
22
86
3a
1
2
Cp2TiCl2
Cp2VCl2
36
24
24
24
3
10
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Yamada-oka, Suita,
Osaka 565-0871, J apan
trace
trace
trace
trace
3b,c
4c
5
d
Cp2TiCl2
PbCl2
PbCl2
PbCl2
PbCl2
hirao@chem.eng.osaka-u.ac.jp
Received August 6, 2002
6b
7
4
96
24
24
8b,c,e
9c,e
trace
trace
36
15
a
Reaction conditions: 1a (0.25 mmol), catalyst (10 mol %), Mn
Abstr a ct: A catalytic reductive cyclization of olefinic iodo-
ethers was achieved by use of cat. Cp2TiCl2 in the presence
of Mn and Me3SiCl. This protocol provides a versatile
method for the selective formation of multisubstituted
tetrahydrofurans.
(2 mmol), Me3SiCl (0.5 mmol), THF (5 mL) unless otherwise stated,
and room temperature. Me3SiCl (5 µL) was used. c The reaction
b
was conducted at 65 °C. Cp2TiCl2 (0.25 mmol) was used. e THF
d
(4 mL) and DMF (2 mL) were used.
intramolecular radical cyclization reactions prior to anion
formation through further one-electron reduction have
been achieved by using a stoichiometric amount of
metallic reductant,8,9 only a few examples have been
found for the catalytic reaction.10 With this consideration
in mind, we here wish to report a novel intramolecular
cyclization of olefinic iodides induced by a titanium or
vanadium catalytic system.
The cyclization of the olefinic iodide 1a was examined
with the catalytic system (Table 1). When a catalytic
amount of Cp2TiCl2 or Cp2VCl2 was employed as a
catalyst in the presence of Mn and Me3SiCl (freshly
distilled over CaH2), a moderate yield of the cyclization
product 2a was obtained as shown in eq 1 (entries 1 and
The explosive growth in free radical chemistry in
recent years reflects its significance as a powerful tool
in modern synthetic chemistry.2 Although the stereo- and
chemoselectivity of the substrate-controlled reactions
have reached a high level,3 little attention has been paid
to the reagent-controlled catalytic transformation of
radicals not proceeding via chain reactions.4 Low-valent
titanium compounds have been used as a useful one-
electron reductant, but more than stoichiometric amounts
of the reductant are usually required to accomplish the
reduction reactions, which is clearly disadvantageous
from a synthetic viewpoint.5 Construction of a catalytic
system is of great importance. It has been recently
reported that the use of a chlorosilane in combination
with a catalytic amount of early transition metal com-
pound such as titanium or vanadium and a stoichiometric
co-reductant successfully effects the catalytic reagent-
controlled pinacol coupling and reductive epoxide opening
reactions. 4, 6
The 5-hexenyl radical cyclization has been extensively
investigated for the construction of carbocyclic as well
as oxacyclic skeletons, leading to cyclopentane and tetra-
hydrofuran derivatives, respectively.7 Although some
(1) Present address: Department of Chemistry, Xuzhou Normal
University, Xuzhou 221009, P. R. China.
(2) For a general review and book, see: (a) Giese, B. Radical in
Organic Synthesis: Formation of C-C Bonds; Pergmon Press: Oxford,
UK, 1986. (b) Curran, D. P. Synthesis 1988, 417 and 489. (c) Curran,
D. P. In Comprehensive Organic Synthesis; Trost, B. M., Flamin, I.,
Semmelhack, M. F., Eds.; Pergmon Press: Oxford, UK, 1991; Vol. 4,
pp 715 and 779. (d) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic Press: London, UK, 1992.
(e) Fossey, J .; Lefort, D.; Sorba, J . Free Radical in Organic Chemistry;
Wiley: New York, 1995.
(3) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, Germany, 1996.
(4) (a) Gansa¨uer, A. Synlett 1998, 801. (b) Hirao, T. Synlett 1999,
175.
2). It should be noted that the reaction in the absence of
Cp2TiCl2 led to a much lower yield of 2a (entries 3 and
4). Furthermore, use of a stoichiometric amount of
Cp2TiCl2 resulted in a higher yield (entry 5). Although
the PbCl2/Mn/Me3SiCl reduction system has been re-
ported to be effective in radical carbon-carbon bond-
forming reactions,11 the cyclization reaction of 1a did not
proceed with this system in the presence of a catalytic
or even excess amount of Me3SiCl (entries 6-9). These
(5) Halterman, R. L. Chem. Rev. 1992, 92, 965.
(6) (a) Hirao, T.; Hasegawa, T.; Muguruma, Y.; Ikeda, I. Abstracts
for 6th International Conference on New Aspects of Organic Chemistry,
1994; p 175. (b) Hirao, T.; Hasegawa, T.; Muguruma, Y.; Ikeda, I. J .
Org. Chem. 1996, 61, 366. (c) Hirao, T.; Asahara, M.; Muguruma, Y.;
Ogawa, A. J . Org. Chem. 1998, 63, 2812. (d) Hatano, B.; Ogawa, A.;
Hirao, T. J . Org. Chem. 1998, 63, 9421. (e) Gansa¨uer, A.; Pierobon,
M.; Bluhm, H. Angew. Chem., Int. Ed. 1998, 37, 101. (f) Hirao, T.;
Hatano, B.; Imamoto, Y.; Ogawa, A. J . Org. Chem. 1999, 64, 7665.
(7) (a) Ladlow, M.; Pattenden, G. Tetrahedron Lett. 1984, 25, 4317.
(b) Stork, G.; Kahn, M. J . Am. Chem. Soc. 1985, 107, 500. (c) Stork,
G.; Sher, P. M. J . Am. Chem. Soc. 1986, 108, 303. (d) Stork, G.; Sher,
P. M.; Chen, H.-L. J . Am. Chem. Soc. 1986, 108, 6384. (e) Mandal, P.
K.; Maiti, G.; Roy, S. C. J . Org. Chem. 1998, 63, 2829.
10.1021/jo026290e CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/25/2003
J . Org. Chem. 2003, 68, 1633-1635
1633

TABLE 2. Effect of Solven t, Rea ction Tem p er a tu r e,
However, use of collidinium chloride, which is an effective
additive in the reagent-controlled catalytic pinacol cou-
pling reaction,4a resulted in the lower yield (entry 13).
These results indicate that the chlorosilane serves an
important role in the cyclization reaction.
Ad d itive, a n d Co-r ed u cta n t Meta l on th e Cycliza tion of
1a a
yield (%)
entry
additive
solvent
DME
DMF
THF
DMF
THF-DMFc
THF
THF
THF
THF
THF
metal time (h)
2a
3a
78
The optimized reaction conditions were employed for
the intramolecular cyclization of various olefinic iodides
1. The reaction of 1 induced by the cat. Cp2TiCl2/Me3SiCl/
Mn system in THF afforded the desired multisubstituted
tetrahydrofuran 2 stereoselectively as shown in Table 3.
The corresponding olefinic chloro analogue of 1a did not
undergo the reaction. An interesting feature is that the
stereoselectivity of 2 was enhanced in comparison to the
reported one with a stoichiometric amount of initiator.9f
This observation is suggestive of a similar transition state
in the cyclization step as described in the free radical
reaction. â-Alkoxy elimination products were nearly
undetectable in the reaction mixture. Thus, the halogen-
metal exchange might not take place in the cat. Cp2TiCl2/
Me3SiCl/Mn induced reactions.13 Generally, radical re-
actions offer suitable methods for generating quaternary
carbon atoms, and this is indeed the case as observed in
entries 6 and 9. Bicyclic product 2g was also formed
successfully.
A plausible reaction path is as follows. Reduction of
Cp2TiCl2 with manganese powder affords a low-valent
titanium species, which is able to reduce 1. The thus-
generated 3-oxa-5-hexenyl radical intermediate 4 under-
goes the carbon-carbon bond-forming cyclization to 5,
which is finally converted to 2. Chlorosilanes appear to
contribute to the catalytic reaction in various ways, which
involve the liberation of the TiIV species from the cycliza-
tion product as one of the possibilities.4 When the radical
4 is further reduced to the anionic species 6, â-elimination
leads to the olefinic compound 3. This process was mostly
observed when active zinc powder was used as a co-
reductant.14
1b
2b
3b
4
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Zn
1
48
36
24
24
24
23
Mn
Mn
Mn
Mn
Mn
Mn
Zn
33
35
58
46
87
62
trace
12
trace
5
6
7d
8
1.5
81
9
Al
48
24
24
24
24
10
11
12
13
Mg
Mn
Mn
Mn
15
trace
67
THF
Me2PhSiCl THF
collidinium THF
chloride
6
6
42
a
Reaction conditions: 1a (0.25 mmol), Cp2TiCl2 (10 mol %), Mn
(2 mmol), Me3SiCl (0.5 mmol), solvent (5 mL), 65 °C unless
otherwise stated. b Room temperature was employed. c THF (4 mL)
d
and DMF (2 mL) were used. Cp2VCl2 (10 mol %) was employed
as a catalyst.
findings suggest the involvement of the titanium catalyst
in the cyclization reaction.
Solvent or reaction temperature effect was next studied
as shown in Table 2. With DME as a solvent, the desired
product 2a was not detected with formation of only the
â-elimination product 3a (entry 1). The formation of 2a
was observed with DMF or THF as a solvent at room
temperature (entries 2 and 3). When the reaction was
conducted at 65 °C in DMF or THF-DMF, the yield was
improved (entries 4 and 5). Furthermore, a better result
was obtained in THF at this reaction temperature (entry
6). Cp2TiCl2 was found to be superior to Cp2VCl2 as a
catalyst under these reaction conditions (entry 7). The
effect of additive and co-reductant metal was also studied
as shown in Table 2. Although the cat. Cp2TiCl2/Me3SiCl/
Zn system works well for the diastereoselective cycliza-
tion of ketonitriles,12 no desired cyclization product of 1a
was detected with Zn, only giving the â-elimination
product 3a (entry 8). The reaction with Al or Mg as a
co-reductant was sluggish with a very poor result,
although the elimination product was not detected (en-
tries 9 and 10). Noteworthy is that only a trace amount
of 2a was formed in the absence of Me3SiCl as an additive
(entry 11). Me2PhSiCl was inferior to Me3SiCl (entry 12).
In conclusion, the cyclization of olefinic iodoethers was
promoted by using cat. Cp2TiCl2 in the presence of Mn
and Me3SiCl in THF at 65 °C. This synthetic method has
the potential to construct multisubstituted tetrahydro-
furans selectively.
(8) (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223. (b)
Malacria, M. Chem. Rev. 1996, 96, 289. (c) Snider, B. B. Chem. Rev.
1996, 96, 339.
(9) For the intramolecular radical carbon-carbon formation induced
by a stoichiometric amount of reducing reagent, see: (a) Nugent, W.
A.; RajanBabu, T. V. J . Am. Chem. Soc. 1988, 110, 8561. (b) Curran,
D. P.; Totleben, M. J . J . Am. Chem. Soc. 1992, 114, 6050. (c)
Hackmann, C.; Scha¨fer, H. J . Tetrahedron, 1993, 49, 4559. (d) Nakao,
J .; Inoue, R.; Shinokubo, H.; Oshima, K. J . Org. Chem. 1997, 62, 1910.
(e) Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J . Am. Chem.
Soc. 2001, 123, 3137. (f) Kita, Y.; Nambu, H.; Ramesh, N. G.;
Anilkumar, G.; Matsugi, M. Org. Lett. 2001, 3, 1157. (g) Friestad, G.
K. Tetrahedron 2001, 57, 5461.
(10) For the intramolecular radical carbon-carbon formation in-
duced by a catalytic amount of reducing reagent, see: (a) Hayashi, Y.;
Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 63. (b) Waka-
bayashi, K.; Yorimitsu, H.; Oshima, K. J . Am. Chem. Soc. 2001, 123,
5374.
Exp er im en ta l Section
1H NMR or 13C NMR spectra were recorded in chloroform-d
with tetramethylsilane or residual chloroform as an internal
standard. Mass spectra were recorded with LRMS and HRMS.
TLC was carried out on aluminum sheets precoated with silica
gel 60 F254 (E. Merck). Column chromatography was performed
on silica gel 60 (E. Merck). Me3SiCl and Me2PhSiCl were freshly
distilled under argon over calcium hydride before use. All
reagents were of commercial quality and were used without
(13) (a) Grubb, L. M.; Branchaud, B. P. J . Org. Chem. 1997, 62, 242.
(b) Kettschau, G.; Pattenden, G. Tetrahedron Lett. 1998, 39, 2027.
(14) Spencer, R. P.; Cavallaro, C. L.; Schwartz, J . J . Org. Chem.
1999, 64, 3987.
(11) Takai, K.; Ueda, T.; Ikeda, N.; Moriwake, T. J . Org. Chem. 1996,
61, 7990.
(12) Zhou, L.; Hirao, T. Tetrahedron Lett. 2000, 57, 6927.
1634 J . Org. Chem., Vol. 68, No. 4, 2003

TABLE 3. In tr a m olecu la r Cycliza tion of 1 w ith ca t. Cp 2TiCl2/Me3SiCl/Mn System a
entry
1
R1
R2
R3
R4
R5
R6
time (h)
2
yield (%) (trans:cis)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
BuO
H
Me
H
H
Me
H
H
Me
H
H
Me
H
H
H
H
H
H
Pr
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
Me
H
24
24
24
24
28
48
36
30
36
30
2a
2b
2c
2c
2e
2f
2g
2h
2i
83 (80:20)
64 (85:15)
63 (80:20)
61 (71:39)
59c
H
H
Pr
H
H
H
56
-(CH2)3-
59d
Me
H
H
H
H
H
73 (69:31)
45
70 (60:40)
BuO
BuO
10
1j
H
2j
a
Reaction conditions: 1 (0.5 mmol), Cp2TiCl2 (10 mol %), Mn (4 mmol), Me3SiCl (1 mmol), THF (8 mL), 65 °C. b The ratio was determined
by 1H NMR. c Obtained as a mixture. Obtained as a mixture of exo and endo isomers (60:40).
d
purification. All dry solvents were freshly distilled under argon
over an appropriate drying agent. The reactions were carried
out under argon, using the syringe and Schlenk-type technique.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1a -j. The
olefinic iodide 1 was prepared according to the literature
procedure.15 Under argon, an allyl alcohol (7.52 mmol) was added
to a solution of an olefin (3.76 mmol) in dry CH2Cl2 (25 mL) at
room temperature. After being stirred for 5 min, the reaction
mixture was cooled to -78 °C. N-Iodosuccinimide (1.27 g, 5.64
mmol) was then added to the mixture, which was allowed to
reach 0 °C within 6 h. A saturated aqueous solution of Na2S2O3
was added to the reaction mixture, which was stirred vigorously
for 5 min. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2. The combined organic layer was
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel eluting with
hexane/Et2O (20:1-1:1) to give the iodide 1.
water (10 mL), and brine (10 mL), dried over MgSO4, and
concentrated. The residue was purified by flash column chro-
matography on silica gel (20 g; eluent, hexane/ethyl acetate )
50:0, 48:2, 46:4, 44:6, 42:8, 40:10, 38:12, 35:15, 32:18, 28:22, 25:
25, 50 mL × each), giving 2a :15 colorless oil. Trans: 1H NMR
(CDCl3) δ 1.09 (d, 3H, J ) 6.9 Hz), 1.85-2.04 (m, 2H), 2.36-
2.50 (m, 1H), 3.45 (dd, 1H, J ) 8.1, 6.9 Hz), 3.80 (s, 3H), 4.20
(dd, 1H, J ) 8.4, 6.9 Hz), 4.97 (t, 1H, J ) 6.9 Hz), 6.85-6.89 (m,
2H), 7.23-7.29 (m, 2H); 13C NMR (CDCl3) 17.9, 33.3, 42.6, 55.2,
75.5, 79.7, 113.5, 126.7, 135.6, 158.5 ppm. Cis: 1H NMR (CDCl3)
δ 1.10 (d, 3H, J ) 6.9 Hz), 1.88-2.04 (m, 1H), 2.39-2.50 (m,
2H), 3.57 (t, 1H, J ) 8.1 Hz), 3.80 (s, 3H), 4.07 (t, 1H, J ) 8.1
Hz), 4.86 (dd, 1H, J ) 10.0, 5.7 Hz), 6.85-6.89 (m, 2H), 7.23-
7.29 (m, 2H); 13C NMR (CDCl3) 17.6, 34.9, 43.8, 55.2, 75.2, 81.3,
113.6, 126.8, 135.1, 158.6 ppm. MS (EI): 192 (M+, 64), 191 (73),
161 (35), 135 (100). HRMS (EI) Calcd for C12H16O2 (M+):
192.1150. Found: 192.1144.
Rep r esen ta tive P r oced u r e for th e In tr a m olecu la r Cy-
cliza tion of 1a . To a mixture of Cp2TiCl2 (12.5 mg, 0.050 mmol)
and manganese powder (220 mg, 4.0 mmol) in THF (6 mL) was
added Me3SiCl (0.13 mL, 1.0 mmol) at room temperature under
argon. After the mixture was stirred for 30 min, a solution of
1a (0.5 mmol) in THF (3 mL) was added. The mixture was kept
at the indicated temperature with magnetic stirring for the time
indicated in the table. Then, the reaction mixture was subjected
to workup with 1 M HCl (3 mL) and ether (50 mL). The organic
layer was washed with saturated aqueous Na2S2O3 (10 mL),
Ack n ow led gm en t. Thanks are due to the Analyti-
cal Center, Faculty of Engineering, Osaka University
for assistance in obtaining mass spectra. L.Z. acknowl-
edges the J apan Society for the Promotion of Science
(J SPS) for a postdoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedure as well as H NMR, 13C NMR, MS, and HRMS data for
the products 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi,
M. Org. Lett. 2001, 3, 1157.
J O026290E
J . Org. Chem, Vol. 68, No. 4, 2003 1635