l-Proline-catalyzed intramolecular cyclization of 5-hydroxypentene to β-halogenated tetrahydrofuran

Article abstract of DOI:10.1016/j.tetlet.2007.07.069

A series of β-bromo- and β-iodotetrahydrofurans was synthesized from the reaction mixture of 5-hydroxypentene, l-proline, NBS (or I₂) in THF at 0 °C for 10 min. This l-proline-catalyzed intramolecular cyclization provides a simple and efficient

Full text of DOI:10.1016/j.tetlet.2007.07.069

Tetrahedron Letters 48 (2007) 6790–6793
L-Proline-catalyzed intramolecular cyclization of
5-hydroxypentene to b-halogenated tetrahydrofuran
a
a
a
Adam Shih-Yuan Lee,a,b, Kuo-Wei Tsao, Yu-Ting Chang and Shu-Fang Chu
*
aDepartment of Chemistry, Tamkang University, Tamsui, Taipei 251, Taiwan
bGraduate Institute of Life Sciences, Tamkang University, Tamsui, Taipei 251, Taiwan
Received 29 May 2007; revised 11 July 2007; accepted 12 July 2007
Available online 17 July 2007
Abstract—A series of b-bromo- and b-iodotetrahydrofurans was synthesized from the reaction mixture of 5-hydroxypentene, L-pro-
line, NBS (or I2) in THF at 0 ꢀC for 10 min. This L-proline-catalyzed intramolecular cyclization provides a simple and efficient
method for the preparation of b-halogenated tetrahydrofuran.
ꢁ 2007 Elsevier Ltd. All rights reserved.
The tetrahydrofuran ring is a very important structural
moiety, which is present in a large variety of natural
products such as polyether antibiotics.1–4 The intramo-
lecular alkoxylation reaction, the addition of alcohol
onto carbo-carbon multiple bonds, provides an efficient
and direct access to tetrahydrofuran functionality.5 5-
Hydroxypentenes have received much more attention
as synthetic intermediates for synthesis of this class of
heterocycles.6–16 The intramolecular cyclization (5-exo-
trig) of 5-hydroxypentene to tetrahydrofuran ring has
been reported and achieved by activation of alkene from
halogen17–20 or Lewis acid,21,22 epoxidation of alkene
followed by intramolecular C–O bond formation,23–26
and palladium-catalyzed cyclization.27–29 Halogenated
tetrahydrofurans, especially derivatives with an exocy-
clic bromo- or iodo- functionality located in the b-posi-
tion to the ring oxygen atom, have become attractive
synthesis targets because of the discovery of b-bromi-
nated tetrahydrofurans, which were occurred widely as
secondary metabolites in the marine environment.30
The most simple and direct procedure for the synthesis
of b-halogenated tetrahydrofurans is the reaction of 5-
hydroxypentene with molecular halogen (Br2, I2) or hal-
ogenating reagent (NBS, IBr, ICl) via intramolecular
cyclization (5-exo-trig). Herewith, we wish to report a
simple and highly efficient method for synthesis of b-
bromo and b-iodotetrahydrofuranyl compounds from
5-hydroxypentenes (Scheme 1).
OH
20% Proline, 1.1 NBS (or 3.0 I2),
THF, 0 oC, 10min
Br(I)
R
R
O
Scheme 1.
5-Hydroxypentenes were prepared by the reaction of 4-
bromobutene with aldehydes under a sonochemical Bar-
bier reaction condition.31 Thus, we firstly investigated
the bromocyclization of 1-phenylpentenol with NBS
(N-bromosuccinimide)20 at room temperature and b-
bromo-phenyltetrahydrofuran was produced in 60%
yield after 3 days. The small amount of HBr added to
NBS liberates more Br2 molecule32 and this reaction
condition was investigated for bromocyclization of 1-
phenylpentenol. The trace amount of concd HBr
(20 lL/equiv) was added to a reaction mixture of 1-phen-
ylpentenol and NBS in CH2Cl2 at 0 ꢀC and 96% yield
of b-bromo-phenyltetrahydrofuran was obtained after
30 min (Scheme 2). The catalytic amount of HBr pro-
moted the formation yield of b-bromotetrahydrofuran
and the reaction time decreased dramatically.
A series of 5-hydroxypentenes was investigated under
this HBr-catalyzed bromocyclization reaction condition
OH
O
Ph
Br
Ph
1.5 NBS, 2 mL CH2Cl2, 0oC- 25oC, 72 h
1.1 NBS, 4 mL CH2Cl2, 20μL HBr(aq), 0o C, 0.5 h
60%
96%
*
*
*
Corresponding author. Tel.: +886 2 2621 5656x2543; fax: +886 2
26222 3830; e-mail: adamlee@mail.tku.edu.tw
Scheme 2.
0040-4039/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.069

A. S.-Y. Lee et al. / Tetrahedron Letters 48 (2007) 6790–6793
Table 1. HBr-catalyzed bromocyclization of 5-hydroxypentene
6791
OH
O
Ph
Yielda (cis/trans)b
Br
Entry
1
R
Product
Ph
1.1 NBS, 20μL HBr, 4 mL CH2Cl2, 0oC, 30min
72% (26:74)
96%
Br
Br
*
*
*
O
O
1.1 NBS, 1.1 NaHCO3, 4 mL CH2Cl2, 0oC, 30 min
99%
99%
2
3
4
5
6
7
88% (44:56)
92% (26:74)
96% (30:70)
95% (32:68)
99% (35:65)
98% (39:61)
1.1 NBS , 20 mol% L
-Proline, 5 mL THF,0oC, 10 min
Br
Br
Scheme 3.
O
O
vated carbon–carbon double bond. The stoichiometric
amount of a base such as NaHCO3 was added to a mix-
ture of 5-hydroxypentene and NBS and it was stirred at
0 ꢀC for 30 min (Scheme 3). The introduction of a base
improves the reaction rate and yield which presents the
same effect as the addition of HBr. Thus, we think the
introduction of an amino acid such as proline33–36 may
exhibit the similar improvement for this intramolecular
cyclization. To a reaction mixture of 1-phenylpentenol
and NBS in THF at 0 ꢀC was added natural proline.
The reaction mixture was stirred at 0 ꢀC for 10 min
and 99% yield of b-bromo-phenyltetrahydrofuran was
obtained. A catalytic amount of L-proline accelerated
this bromocyclization of 5-hydroxypentene compound
and a high formation yield was also achieved.
Br
O
F
F
Br
O
Br
Br
Br
O
H3CO
S
H3CO
S
Br
Br
8
9
75% (40:60)
64% (30:70)
93% (37:63)
O
O
N
O
N
O
Br
10
O
O
O
A series of 5-hydroxypentenes was investigated under
this proline-catalyzed bromocyclization and the results
are shown in Table 2. The typical procedure for synthe-
sis of a b-bromotetrahydrofuran in the presence of pro-
line as catalyst is as follows: To a reaction mixture of 5-
hydroxypentene (1.0 mmol) and NBS (1.1 mmol) in
THF at 0 ꢀC was added L-proline (100 lL, 2 M aqueous
solution). After the reaction mixture was stirred at 0 ꢀC
for 10 min, water (10 mL) was added, and extracted with
ether (3 · 20 mL). The combined organic layer was
washed with Brine (30 mL), dried with MgSO4, filtered,
and then the organic solvent was removed under
reduced pressure. Further purification was achieved on a
flash chromatograph with silica gel and ethyl acetate/
hexanes.
11
12
99% (37:63)
80% (42:58)
Br
O
Br
O
N
N
Ts
Ts
a The yields were determined after chromatographic purifications.
b The cis/trans ratio is determined by 1H NMR spectral analysis.
and the results are shown in Table 1. The typical proce-
dure for synthesis of a b-bromotetrahydrofuran is as fol-
lows: To a reaction mixture of 5-hydroxypentene
(1.0 mmol) and NBS (1.1 mmol) in CH2Cl2 at 0 ꢀC
was added concentrated HBr (20 lL). After the reaction
mixture was stirred at 0 ꢀC for 30 min, water (10 mL)
was added and extracted with ether (3 · 20 mL). The
combined organic layer was washed with Brine
(30 mL), dried with MgSO4, filtered, and then the organ-
ic solvent was removed under reduced pressure. Further
purification was achieved on a flash chromatograph
with silica gel and ethyl acetate/hexanes.
The yields and stereoselectivities (cis/trans) of b-bromo-
tetrahydrofuranyl compounds, which were obtained
from the L-proline-catalyzed reaction conditions, usu-
ally are better than the product obtained by HBr-cata-
lyzed cyclization reaction condition. Alkyl-substituted
5-hydroxypentenes afford much higher yields of tetra-
hydrofuranyl compounds under proline-catalyzed cycliza-
tion reaction condition. Heterocyclic tetrahydrofuranyl
compounds were easily synthesized under the reaction
conditions.
Good to excellent yields of the investigated compounds
in Table 1 were afforded under this HBr-catalyzed reac-
tion condition. The diastereoselectivity (cis/trans) ratios
were also determined by 1H NMR spectral analysis. The
coupling constant values of 2- and 5-position protons
were measured and as reference for the determination
of cis/trans ratio.
b-Iodotetrahydrofuranyl compounds were typically pre-
pared from the intramolecular cyclization of 5-hydroxy-
pentenes by using I2 as iodinating reagent. Thus, we
investigated the intramolecular cyclization of 1-phenyl-
pentenol with iodine and the expected product was not
produced after 24 h (Scheme 4). Another iodinating re-
agent IBr was also investigated and generated 68% yield
of b-iodotetrahydrofuran after 2 h stirring at 0 ꢀC. The
b-iodophenyltetrahydrofuran was obtained with a 54%
The addition of HBr catalyzed the bromocyclization of
5-hydroxypentene. Thus, we think the addition of a base
may accelerate the cyclization step by deprotonation of
alcohol which becomes a better nucleophile to the acti-

6792
A. S.-Y. Lee et al. / Tetrahedron Letters 48 (2007) 6790–6793
Table 3. Proline-catalyzed iodocyclization of 5-hydroxypentene
Table 2. Proline-catalyzed bromocyclization of 5-hydroxypentene
Entry
1
R
Product
Yielda (cis/trans)b
Entry
1
R
Product
Yielda (cis/trans)b
98% (24:76)
97% (30:70)
Br
Br
I
I
O
O
O
O
2
3
94% (30:70)
94% (6:94)
2
3
4
88% (34:66)
96% (25:75)
99% (30:70)
Br
Br
I
O
O
I
4
5
99% (35:65)
99% (28:72)
O
O
Br
I
O
5
6
7
93% (23:77)
99% (24:76)
92% (51:49)
O
F
F
F
F
Br
6
7
95% (27:73)
98% (24:76)
O
I
O
Br
Br
Br
Br
Br
O
I
H3CO
S
O
I
H3CO
S
H3CO
S
H3CO
S
Br
Br
8
9
94% (30:70)
57% (28:72)
86% (26:74)
O
O
8
76% (36:64)
O
N
I
N
9
61% (39:61)
88% (45:55)
O
N
O
O
O
N
O
O
O
Br
10
O
I
10
O
O
O
11
12
99% (27:73)
95% (31:69)
Br
O
11
12
98% (22:78)
90% (44:56)
I
O
Br
O
I
N
O
N
Ts
Ts
N
N
Ts
a The yields were determined after chromatographic purifications.
b The cis/trans ratio is determined by 1H NMR analysis.
Ts
a The yields were determined after chromatographic purifications.
b The cis/trans ratio is determined by 1H NMR spectral analysis.
OH
(1.0 mmol) and I2 (3.0 mmol) in THF at 0 ꢀC was added
L-proline (0.2 mmol) and the reaction mixture was stir-
red at 0 ꢀC for 10 min. The mixture was quenched with
saturated Na2S2O7 (10 mL), extracted with ether
(20 mL · 3). The organic layer was washed with brine
(30 mL), dried with MgSO4, and then removed under re-
duced pressure. Further purification was achieved on a
flash chromatograph with silica gel and ethyl acetate/
hexanes.
O
Ph
I
Ph
1.1 I2, 2 mL CH2Cl2, 0oC, 24 h
N. R.
*
*
*
1.1 IBr, 5 mL CH2Cl2, 0 oC, 2 h
68%
2.0 I2, 1.0 KI, 5 mLTHF, 0oC, 24 h
54% + S.M.
3.0 I2, 1.5 KI, 5 mL THF, 0 oC, 3.5 h
91%
*
*
3.0 I2, 20 mol%
L
-Proline, 5 mL THF, 0 oC, 10 min
99%
Scheme 4.
The experimental results showed that the formation
yield of b-iodotetrahydrofuran was nearly as high
as the yield of b-bromotetrahydrofuran obtained under
the reaction condition. The stereoselectivity (cis/trans)
of proline-catalyzed bromocyclization reaction gener-
ally is better than its corresponding iodocyclization
reaction.
when a base KI was introduced into the reaction mix-
ture. The yield can be increased to 91% when an amount
of I2 and KI were introduced to 3 and 1.5 equiv. An
excellent yield (99%) was achieved when a catalytic
amount of L-proline was introduced to the iodocycliza-
tion reaction condition.
In conclusion, this natural proline-catalyzed reaction
provides a simple and highly efficient method for the
preparation of b-halogenated (b-bromo or b-iodo) tetra-
hydrofuranyl compound from 5-hydroxypentene via an
intramolecular cyclization (5-exo-trig) under either
acidic or basic reaction condition.
A series of 5-hydroxypentenes was investigated under
this proline-catalyzed iodocyclization reaction condition
and the results are shown in Table 3. The typical proce-
dure for synthesis of a b-iodonated tetrahydrofuran is as
follows: To a reaction mixture of 5-hydroxypentene

A. S.-Y. Lee et al. / Tetrahedron Letters 48 (2007) 6790–6793
6793
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