An efficient methodology for the C-C bond forming radical cyclization of hydrophobic substrates in water: Effect of additive on radical reaction in water

Article abstract of DOI:10.1016/S0040-4020(02)01448-5

The combination of the water-soluble radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), water-soluble chain carrier, 1-ethylpiperidine hypophosphite (EPHP) and surfactant, cetyltrimethylammonium bromide (CTAB), was found to be the most

Full text of DOI:10.1016/S0040-4020(02)01448-5

Tetrahedron 59 (2003) 77–85
An efficient methodology for the C–C bond forming radical
cyclization of hydrophobic substrates in water: effect of additive
on radical reaction in water
*
Hisanori Nambu, Gopinathan Anilkumar, Masato Matsugi and Yasuyuki Kita
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received 7 November 2002; accepted 8 November 2002
Abstract—The combination of the water-soluble radical initiator, 2,20-azobis[2-(2-imidazolin-2-yl)propane] (VA-061), water-soluble chain
carrier, 1-ethylpiperidine hypophosphite (EPHP) and surfactant, cetyltrimethylammonium bromide (CTAB), was found to be the most
suitable condition for effective radical cyclization in water for a variety of hydrophobic substrates. The effect of additives and surfactant in
the radical cyclization reaction in water was also investigated. q 2002 Published by Elsevier Science Ltd.
1. Introduction
phobicity of the substrate tended to decrease the reactivity.
Recently, the same group has achieved an intermolecular
radical addition using a-bromocarbonyl compounds in
water.10 Naito et al. reported a radical addition reaction in
water by the use of highly polar imine compounds, which
can dissolve easily in water.11 We tried to develop a general
methodology for the C–C bond forming radical reaction
with an efficient chain carrier in water.
Water has many potential advantages as a solvent for
organic reactions from the vantage point of its cost, safety
and environmental concern. Therefore, the development of
an efficient and convenient synthetic methodology to
accomplish C–C bond formation in water is an important
subject. Recently, various C–C bond formations in aqueous
media have been reported.1 For instance: (i) Diels–Alder
reaction,2 (ii) Claisen rearrangement,3 (iii) Barbier-type
allylation,4 (iv) Mukaiyama aldol reaction,5 and so on were
successfully carried out in water.
Recently, some reports are available for the radical reactions
of hydrophobic substrates in water.12 We have developed an
unprecedented C–C bond forming radical reaction of
hydrophobic substrates in water using an efficient radical
reaction system. Our strategy is based upon the use of a
combination of a water-soluble radical initiator, water-
soluble chain carrier and surfactant. Recently, we have
reported the radical cyclization of hydrophobic substrates in
water using the combination of 2,20-azobis[2-(2-imidazolin-
2-yl)propane] (VA-061), 1-ethylpiperidine hypophosphite
(EPHP) and cetyltrimethylammonium bromide (CTAB).13
Here, we wish to report the full account of the studies on the
radical cyclization in water using the system we developed,
together with the effect of additives in these reactions.
Radical reaction6 is one of the most useful methods for
organic reaction in water, because most of the organic
radical species are stable in water, and they do not react with
water. In the last decade, some radical reactions in water
have been reported. These reactions in water can be
classified into two types. The first type utilizes a chain
carrier to carry out the reaction. For example, the radical
reductions in water have been reported using water-soluble
Sn compounds by Breslow et al.,7 and water-soluble Si
compounds by Togo and Yokoyama et al.8 In these
successful reports, the substrates always had hydrophilic
functional groups, which facilitated the solubility of
substrates in water. The second type makes use of some
radical reactions in water without any chain carrier. Thus, an
intramolecular radical cyclization in water has been
reported by Oshima et al.9 using a-iodocarbonyl com-
pounds as the substrate; however, increasing the hydro-
2. Results and discussion
Initially, we examined the radical cyclization of the
hydrophobic substrate, 2-iodo-1-aryl-1-prop-2-enyloxy-
ethane (1a) in water using conditions (i) and (ii) shown in
Scheme 1. When the reaction was carried out using Et3B in
water in the absence of a chain carrier, the reaction did not
proceed to completion. Consequently, we chose the
hypophosphorous acid derivatives (H3PO2þNaHCO3 and
Keywords: cetyltrimethylammonium bromide; C–C bond; radical
reactions.
*
Corresponding author. Tel.: þ81-668-798225; fax: þ81-668-798229;
e-mail: kita@phs.osaka-u.ac.jp
0040–4020/03/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01448-5

78
H. Nambu et al. / Tetrahedron 59 (2003) 77–85
Table 1. Radical cyclization reaction of 1a using water-soluble initiators
and chain carriers at 808C for 24 h
Entry Initiator (1 equiv.) Chain carrier (10 equiv.) Yield (trans/cis)a
1
2
3
4
5
VA-061
VA-061
VA-061
V-501
EPHP
64% (74:26) [24%]
33% (52:48) [37%]
41% (76:24) [43%]
62% (51:49) [3%]
63% (51:49) [13%]
b
H3PO2þNaHCO3
NaH2PO2
EPHP
V-50
EPHP
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
The ratio of the reagent: H3PO2/NaHCO3¼1:1.
b
Scheme 1. Radical cyclization reaction of 1a in water.
EPHP)14 as the chain carriers, and examined the reaction of
1a using the water-insoluble radical initiators (AIBN, Et3B
and V-70L15). Under these conditions, we observed that the
cyclization product (2a) was formed, albeit in low yields
(,15%). From these results, it is realized that the
cyclization of the hydrophobic substrate (1a) in water
using the above conditions is difficult.
azo-type initiators and hypophosphorous reagents for the
reaction of 1a in water (Table 1). As a result, we found that
the combinations of these water-soluble initiators (VA-061,
V-501 and V-50) and EPHP were more effective for the
radical cyclization of 1a than the former cases (cf.
Scheme 1).
To improve the yield of these radical reactions in water, we
decided to add an additive to our reaction system
comprising VA-061 and EPHP. Breslow et al. have already
reported that Diels–Alder reactions in water were acceler-
ated by the addition of the ‘salting out’ salt (e.g. LiCl) to the
system, and the rate of the reaction decreased by the
addition of the ‘salting in’ salt (e.g. guanidine hydro-
chloride).2,17 A ‘salting out’ salt is a material that increases
the hydrophobic effect of water and thereby decreases the
solubility of hydrocarbons, and a ‘salting in’ salt is a
material that decreases the association of hydrocarbon
residues in water and thus increases the water solubility of
hydrocarbons. With this background, we first examined the
additive effect of NaCl as a ‘salting out’ salt (Table 2).
When the cyclization was carried out in the presence of
1–10 equiv. of NaCl, the reaction of 1a proceeded more
effectively than that without any additive; however, the rate
of the reaction decreased when more than 50 equiv. of the
salt were added, and the starting material (1a) was
recovered. The side-reaction scarcely occurred. We guess
that this ‘salting out’ effect in the addition of the moderate
amount of the salt functioned to change the conformation of
the cyclization substrate. In other words, the addition of the
salt to the water system helps to increase the internal
pressure in water, thereby the cyclization substrate is
transformed from the non-compact forming Z-rotamer into
the compact forming E-rotamer, which is essential for the
cyclization (Scheme 2).1b,17 Therefore, the yield of the
cyclization reaction was found to be higher than that
observed without an additive. This kind of effect has
We presumed that a combination of water-soluble radical
initiators and water-soluble chain carriers would be an
effective system for radical reaction of 1a in water. We used
the water-soluble azo-type radical initiators for these
studies, which are shown in Figure 1.16 These water-soluble
azo-type compounds, which are efficient initiators in the
synthesis of polymers, are expected to generate radical
species effectively in water. The 10-hour half-life decompo-
sition temperatures of these initiators are included in
Figure 1. We presumed that water-soluble initiators are
more suitable for radical reactions in water since the
decomposition products from these initiators are easily
removable compared to those generated from water-
insoluble initiators (AIBN, Et3B and V-70L). We chose
the hypophosphorous reagent14 as a chain carrier, since this
reagent is less toxic than the commonly used Sn compounds.
In addition, Sn compounds have some disadvantages from
the standpoint of the purification process. On the other hand,
hypophosphorous reagent is water-soluble and is easily
removable from the product. In this point of view, we
investigated the optimum combination of the water-soluble
Table 2. Effect of the ‘salting out’ salt NaCl: radical cyclization reaction of
1a using VA-061 (1 equiv.) and EPHP (10 equiv.) at 808C for 24 h
Entry Equivalent of NaCl
Concentration (M)
Yield (trans/cis)a
1
2
3
4
5
6
None
1
5
10
50
Saturation
0
64% (74:26) [24%]
85% (60:40) [9%]
85% (58:42) [12%]
88% (60:40) [10%]
55% (67:33) [44%]
26% (70:30) [74%]
0.05
0.25
0.5
2.5
. 6
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
Figure 1. Various water-soluble azo-type radical initiators.

H. Nambu et al. / Tetrahedron 59 (2003) 77–85
79
We then investigated the additive effect of guanidine
hydrochloride as a ‘salting in’ salt (Table 4). The reaction
was accelerated by the addition of the salt, and it went to
completion furnishing higher yields when more than
50 equiv. of the salt were added to the system.
The characteristic effect of various ‘salting in’ salts in the
radical cyclization of 1a in water is apparent from Table 5.
Here also, we found that the rate of the reaction was
increased by the addition of salts. It should be mentioned
here that in the case of using ‘salting in’ salts, a large
quantity of the salt was necessary to facilitate the cyclization
reaction of 1a. To circumvent this disadvantage, we
searched for a more efficient additive for these reactions.
We planned the use of a surfactant18 to solubilize the
hydrophobic substrate in water. We examined the radical
cyclization of 1a using various surfactants in the presence of
VA-061 and EPHP (Table 6). As a result, we found that
surfactants functioned as the most efficient additive for the
radical cyclization of 1a from the viewpoint of its rate
acceleration effect. The concentration of cetyltrimethyl-
ammonium bromide (CTAB)18 used in our reactions is
within the range of micelle formation and therefore the
possibility of a micellar reaction cannot be ruled out. When
catalytic amount of the surfactants was used in the reaction,
the yield of the cyclization product (2a) was found to be
higher than the case of using other salts (‘salting in’ and
‘salting out’ agent). Our method is quite efficient, since a
highly toxic Sn compound is generally used as the chain
carrier19 despite the disadvantage from the environmental
point of view.
Scheme 2. The effect of the ‘salting out’ salt.
Table 3. Effect of various ‘salting out’ salts: radical cyclization reaction of
1a using VA-061 (1 equiv.) and EPHP (10 equiv.) at 808C for 24 h
Entry
Additive (1 equiv., 0.05 M)
Yield (trans/cis)a
1
2
3
NaF
NaBr
NaI
89% (65:35) [6%]
84% (60:40) [10%]
92% (68:32) [8%]
85% (74:26) [12%]
90% (58:42) [9%]
89% (63:37) [10%]
89% (52:48) [10%]
75% (64:36) [22%]
89% (57:43) [9%]
88% (58:42) [8%]
4
5
6
7
8
9
10
NaHCO3
Na2CO3
NaNO3
NaHSO4
Na2SO4
KBr
LiCl
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
Table 5. Effect of various ‘salting in’ salts: radical cyclization reaction of
1a using VA-061 (1 equiv.) and EPHP (10 equiv.) at 808C for 24 h
previously been reported by Oshima et al.9c in the radical
cyclization of allyl iodoacetate in water. In addition, when
excess amount of the ‘salting out’ salt is added, the substrate
1a is precipitated from the water system and the solubility of
the water-soluble initiators decreased in water, resulting in a
decrease in the rate of the reaction.
Entry
Additive (1 equiv., 0.05 M)
Yield (trans/cis)a
1
2
3
4
5
Et4NþBr2
NH4Cl
LiClO4
NaClO4
Urea
91% (56:44) [7%]
90% (60:40) [6%]
88% (58:42) [9%]
91% (58:42) [7%]
82% (64:36) [13%]
The characteristic effect of various ‘salting out’ salts in the
radical cyclization of 1a in water is apparent from Table 3.
From these observations, we found that all salts have similar
effect on the radical cyclization of 1a. This effect is useful
for the cyclization of 1a, however, the reaction did not reach
completion until 24 h.
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
Table 6. Effect of various surfactants: radical cyclization reaction of 1a
using VA-061 (1 equiv.) and EPHP (10 equiv.) at 808C
Table 4. Effect of the ‘salting in’ salt guanidine hydrochloride: radical
cyclization reaction of 1a using VA-061 (1 equiv.) and EPHP (10 equiv.) at
808C
Entry
Surfactant (0.2 equiv.)
Time (h)
Yield (trans/cis)a
1
2
3
4
5
None
CTAB
24
2
2
3.5
4
64% (74:26) [24%]
98% (55:45)
98% (62:38)
98% (51:49)
98% (62:38)
Entry
Equivalent
of guanidine·HCl
Concentration Time
(M)
Yield (trans/cis)a
(h)
CTACb
SDSc
1
2
3
4
5
6b
None
1
10
50
100
Saturation
0
24
24
24
20
5
64% (74:26) [24%]
93% (62:38) [5%]
94% (59:41) [3%]
96% (55:45)
97% (54:46)
97% (52:48)
Triton X-100d
0.05
0.5
2.5
5
6
7
KBr þ
24
24
82% (72:28) [17%]
85% (65:35) [7%]
Et4N Br2
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
CTAC: cetyl-trimethylammonium chloride.
SDS: sodium dodecyl sulfate.
Triton X-100: polyoxyethylene(10) isooctylphenyl ether.
.20
1
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
VA-061 (0.5 equiv.) was used.
b
c
d
b

80
H. Nambu et al. / Tetrahedron 59 (2003) 77–85
Table 7. Study of various initiators: radical cyclization reaction of 1a using
EPHP (10 equiv.) and CTAB (0.2 equiv.) at 808C
We again examined the various initiators in the presence of
EPHP and CTAB (Table 7). The reaction did not go to
completion when the typical radical initiator AIBN was
used (entry 7). While using Et3B, a known radical initiator at
low temperature, the yield of the desired product was found
to be low (entry 8). On the other hand, water-soluble
initiators were found to be quite effective in promoting the
intramolecular cyclization of 1a. Remarkably, VA-061 was
found to be the most suitable initiator under these conditions
(entry 1), and thus the use of VA-061 was explored further.
Entry
Initiator (1 equiv.)
Time (h)
Yield (trans/cis)a
1
2
3
4
5
6
VA-061
VA-044
VA-080
VA-082
V-501
2
2.5
5
24
24
4
98% (55:45)
95% (50:50)
76% (50:50)
71% (50:50)
72% (51:49)
92% (51:49)
V-50
7
8b
AIBN
Et3B
24
24
19% (57:43) [56%]
50% (67:33) [46%]
We next pursued for an expedient chain carrier for our
system containing VA-061 and CTAB (Table 8). After
screening a series of chain carriers such as hypo-
phosphorous acid derivatives (EPHP, H3PO2þEt3N,
etc.)14 and tris(trimethylsilyl)silane [(TMS)3SiH],20 we
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
Room temperature.
b
Table 8. Study of various chain carriers: radical cyclization reaction of 1a using VA-061 (1 equiv.) and CTAB (0.2 equiv.) at 808C
Entry
Chain carrier
Time (h)
Yield (trans/cis)a
1
2
3
4
5
6
7b
None
EPHP (10 equiv.)
EPHP (5 equiv.)
H3PO2 (10 equiv.)þEt3N (10 equiv.)
H3PO2 (10 equiv.)þNaHCO3 (10 equiv.)
NaH2PO2 (10 equiv.)
24
2
4
2
6
No reaction
98% (55:45)
87% (64:36)
98% (52:48)
84% (78:22)
58% (78:22) [8%]
94% (67:33)
24
0.5
(TMS)3SiH (2 equiv.)
a
1
The ratios were determined by H NMR. The recovered yield of starting material is shown in brackets.
VA-061 (0.5 equiv.) was used.
b
Table 9. Radical cyclization reaction of various hydrophobic substrates (1a–j) using the combination of VA-061 (1 equiv.), EPHP (10 equiv.) and CTAB
(0.2 equiv.) at 808C
Entry
Substrate
R1
R2
R3
R4
R5
Time (h)
Product
Yield (trans/cis)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
MeO
MeO
MeO
MeO
MeO
MeO
H
H
H
H
H
H
H
H
H
H
H
Me
H
2
4
3
4
3
2
2
2a
2b
2c
2d
2e
2f
98% (55:45) [64% (74:26)]b
88% (66:34) [53% (62:38)]b
94% (61:39)
Me
Me
H
H
CO2Et
H
Me
H
–(CH2)3–
H
H
86%
94%c
96% (75:25)
87% (78:22)
H
H
H
H
1g
2g
8d
1h
1i
0.5
2h
2i
98%e [21%]f
9g
2
99% (74:26) [9% (67:33)]b
10h
1j
18
2j
64% [22%]b
a
1
The ratios were determined by H NMR.
b
c
d
e
f
When CTAB was not used; reaction time: 24 h.
Obtained as a mixture of endo and exo (53:47).
VA-061 (0.5 equiv.) was used.
Obtained as a mixture of endo and exo (76:24).
Obtained as a mixture of endo and exo (75:25) when CTAB was not used; reaction time: 0.5 h.
NaHCO3 (10 equiv.) was added.
VA-061 (1.5 equiv.) was used.
g
h

H. Nambu et al. / Tetrahedron 59 (2003) 77–85
81
found that EPHP and the combination of hypophosphorous
acid and triethylamine are suitable for our system. The role
of these reagents can be explained as follows. The organic
bases (1-ethylpiperidine and triethylamine) used in the
reaction are incorporated in the formation of micellar
system, and the hypophosphorous reagent is efficiently
incorporated in micellar system with the organic bases. The
radical cyclization of 1a using 5 equiv. of EPHP proceeded
slowly and in lower yield than that using 10 equiv. of EPHP.
When (TMS)3SiH was used as the chain carrier, the target
product was obtained in good yield within a short period of
time, however, it required a tedious procedure for the
isolation of the desired product from the by-product derived
from (TMS)3SiH. Thus, we discovered that the combination
of VA-061, EPHP and CTAB is the most appropriate
condition for the radical reactions of the substrate 1a in
water.
apparent effectiveness of the surfactant CTAB (entries
4–6). By tuning the amount of CTAB, the reactivity can be
greatly enhanced. The yield of the cyclization product (2l)
was found to be lower when other surfactants (SDS or
Triton X-100) were used. Thus, it is concluded that CTAB is
the most effective surfactant for our system.
3. Conclusion
In summary, we have discovered that a combination of
water-soluble azo-type radical initiator (VA-061), water-
soluble chain carrier (hypophosphorous acid derivative,
EPHP) and surfactant (CTAB) is an ideal reaction system to
accomplish radical cyclization in water. This method is an
elegant way to achieve C–C bond forming radical reactions
in water for various hydrophobic substrates. In addition, we
found that the yield of the radical cyclization reaction in
water was increased by the addition of the ‘salting out and
salting in’ salts. Therefore, we believe that the addition of
additives (surfactant and other salts) would be applied to
various other cyclization reactions in water.
The utility and generality of this method was confirmed by
applying to a series of hydrophobic substrates (1a–j). In all
cases, the intramolecular cyclization proceeded with high
efficiency and yield (Table 9). Notable is the fact that the
reaction showed low reactivity when the surfactant (CTAB)
was not used. The present method using the iodides (1a–j)
was tried to extend to bromides, and we found that bromides
were unsuitable as the substrate. Thus, when the bromide of
1a was used as the substrate, the cyclic compound (2a) was
produced in only 4% yield and the starting material was
recovered in 25% yield.
4. Experimental
4.1. General
All melting points are uncorrected. Infrared (IR) absorption
spectra were recorded on a Shimadzu FTIR-8100 spec-
1
trometer using KBr pellets. H and 13C NMR spectra were
In order to test the scope and limitations of our
methodology, we subsequently tried the radical cyclization
strategy to yield pyrrolidines, which are often present in
natural products. Thus, the allyl amine 1k was subjected to
the radical reaction conditions in water at 808C to give the
corresponding pyrrolidine 2k in 90% yield. The results are
obtained for other substrates and are summarized in
Table 10. As a consequence, we found that our method is
also effective for the radical cyclization in water to afford
pyrrolidines (entry 2). As expected, in the absence of the
surfactant, the reaction proceeded with decrease in
reactivity (entries 1, 3). The following experimental results
using a more hydrophobic substrate (1l) supported the
measured in CDCl3 on VARIAN VXR-200, JEOL JNM-EX
270, JEOL JNM-AL 300 and JEOL JNM-LA 500
spectrometers with TMS or CHCl3 as the internal standard.
E. Merck silica gel 60 (70–230 mesh ASTM) and Fuji
Silysia Chemical silica gel BW-300 were used for column
chromatography and flash column chromatography. Anhy-
drous CH2Cl2 was distilled from P2O5. Anhydrous THF was
distilled from sodium/benzophenone under nitrogen. The
assignment of stereochemistry of the cyclization product
was based on NOE difference. cis–trans (or exo–endo)
ratios were determined from the integration in the 1H NMR
spectra of the diastereomeric mixture.
Table 10. Application to highly hydrophobic substrates
4.2. General procedure for the preparation of allyl ether
1a–i and allyl amine 1k–l
Under nitrogen atmosphere, the allyl alcohol or amine
(7.52 mmol) was added to a solution of the olefin
(3.76 mmol) in dry CH2Cl2 (25 ml) at room temperature.
After 5 min, the reaction mixture was cooled to 2788C,
added N-iodosuccinimide (5.64 mmol) and allowed to reach
08C in about 1–6 h. To the reaction mixture, a saturated
aqueous solution of Na2S2O3 was added, and stirred
vigorously for 5 min. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2. The
combined organic layer was dried with Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silicagel using hexane/Et2O (20:1–1:1)
to give the products 1a–i, k and l.
Entry
R
Surfactant
Time (h)
Yield (trans/cis)a
1
2
3
4
5
6
7
8
Ms None
Ms CTAB (0.2 equiv.)
24
8
24
24
24
6
90% (72:28)
99% (72:28)
8% (53:47) [23%]
46% (75:25) [21%]
65% (75:25) [14%]
87% (75:25)
Ts
Ts
Ts
Ts
Ts
Ts
None
CTAB (0.2 equiv.)
CTAB (1 equiv.)
CTAB (2 equiv.)
SDS (2 equiv.)
Triton X-100 (2 equiv.)
24
24
33% (75:25) [11%]
49% (75:25) [39%]
a
The ratios were determined by 1H NMR. The recovered yield of starting
material is shown in brackets.
4.2.1. 2-Iodo-1-(4-methoxyphenyl)-1-prop-2-enyloxy-
1
ethane (1a). Obtained in 98% as colorless oil: H NMR

82
H. Nambu et al. / Tetrahedron 59 (2003) 77–85
(CDCl3) d: 3.27–3.41 (m, 2H), 3.81 (s, 3H), 3.81 (dd, 1H,
J¼12.5, 5.0 Hz), 3.98 (dd, 1H, J¼12.5, 5.0 Hz), 4.43
(dd, 1H, J¼8.0, 5.0 Hz), 5.18 (dd, 1H, J¼10.0, 1.0 Hz),
5.27 (dd, 1H, J¼17.0, 1.0 Hz), 5.85–5.98 (m, 1H), 6.89
(d, 2H, J¼9.0 Hz), 7.24 (d, 2H, J¼9.0 Hz). 13C NMR
(CDCl3) d: 10.9, 55.3, 69.9, 80.5, 114.0, 117.4, 127.8, 131.9,
134.4, 159.6. HRMS (EI) calcd for C12H15O2I (Mþ):
318.0117. Found: 318.0113. Anal. calcd for C12H15O2I: C,
45.30; H, 4.75; I, 39.89. Found: C, 45.50; H, 4.74; I,
39.73.
131.3, 143.8, 159.8, 166.3. HRMS (EI) calcd for C15H19O4I
(Mþ): 390.0328. Found: 390.0323.
4.2.7. 2-Iodo-1-phenyl-1-prop-2-enyloxyethane (1g).21
Obtained in 14% as colorless oil: 1H NMR (CDCl3) d:
3.30–3.42 (m, 2H), 3.85 (dd, 1H, J¼12.5, 6.0 Hz), 3.99 (dd,
1H, J¼12.5, 5.5 Hz), 4.48 (dd, 1H, J¼8.0, 5.0 Hz), 5.20 (dd,
1H, J¼10.0, 1.5 Hz), 5.29 (dd, 1H, J¼17.0, 1.5 Hz),
5.88–5.94 (m, 1H), 7.30–7.40 (m, 5H). 13C NMR
(CDCl3) d: 10.6, 70.1, 80.9, 117.5, 126.6, 128.4, 128.7,
134.3, 140.0.
4.2.2. 1-But-2-enyloxy-2-iodo-1-(4-methoxyphenyl)-
1
ethane (1b). Obtained in 86% as colorless oil: H NMR
4.2.8. 6-Hex-2-enyloxy-5-iodooxane (1h). Obtained in
1
98% as colorless oil: H NMR (CDCl3) d: 0.91 (t, 3H,
(CDCl3) d: 1.70 (d, 3H, J¼6.0 Hz), 3.26–3.40 (m, 2H), 3.82
(s, 3H), 3.72–3.98 (m, 2H), 4.41 (dd, 1H, J¼8.0, 5.0 Hz),
5.53–5.71 (m, 2H), 6.85–6.92 (m, 2H), 7.22–7.25 (m, 2H).
13C NMR (CDCl3) d: 11.1, 17.8, 55.2, 69.7, 80.3, 114.0,
127.2, 127.9, 129.9, 132.1, 159.5. HRMS (EI) calcd for
C13H17O2I (Mþ): 332.0273. Found: 332.0268.
J¼7.0 Hz), 1.35–1.48 (m, 2H), 1.52–1.64 (m, 1H), 1.71–
1.83 (m, 1H), 1.96–2.08 (m, 3H), 2.33–2.43 (m, 1H), 3.58
(ddd, 1H, J¼11.0, 7.0, 3.5 Hz), 3.95–4.03 (m, 2H), 4.08–
4.14 (m, 1H), 4.20 (dd, 1H, J¼12.0, 5.5 Hz), 4.68 (d, 1H,
J¼5.5 Hz), 5.52–5.61 (m, 1H), 5.69–5.78 (m, 1H). 13C
NMR (CDCl3) d: 13.7, 22.1, 25.5, 29.5, 32.7, 34.3, 63.4,
68.9, 101.2, 125.4, 135.3. HRMS (FAB) calcd for
C11H19O2NaI (MþþNa): 333.0327. Found: 333.0329.
4.2.3. 2-Iodo-1-(3-methylbut-2-enyloxy)1-(4-methoxy-
1
phenyl)ethane (1c). Obtained in 99% as colorless oil: H
NMR (CDCl3) d: 1.57 (s, 3H), 1.74 (s, 3H), 3.25–3.39 (m,
2H), 3.81 (s, 3H), 3.87 (t, 2H, J¼8.5 Hz), 4.40 (dd, 1H,
J¼8.0, 5.0 Hz), 5.38 (t, 1H, J¼6.0 Hz), 6.89 (d, 2H,
J¼8.0 Hz), 7.24 (d, 2H, J¼8.0 Hz). 13C NMR (CDCl3) d:
11.2, 18.1, 25.8, 55.3, 65.5, 80.5, 114.0, 120.6, 127.9, 132.3,
137.9, 159.6. HRMS (EI) calcd for C14H19O2I (Mþ):
346.0430. Found: 346.0432.
4.2.9.
1-Butoxy-1-hex-2-enyloxy-2-iodoethane
(1i).
Obtained in 99% as colorless oil: 1H NMR (CDCl3) d:
0.91 (t, 3H, J¼7.5 Hz), 0.93 (t, 3H, J¼7.5 Hz), 1.35–1.47
(m, 4H), 1.53–1.63 (m, 2H), 2.03 (td, 2H, J¼7.0, 6.5 Hz),
3.23 (d, 2H, J¼5.5 Hz), 3.48 (td, 1H, J¼9.0, 6.5 Hz), 3.60
(td, 1H, J¼9.0, 6.5 Hz), 4.00 (ddd, 1H, J¼11.5, 6.5, 2.0 Hz),
4.10 (ddd, 1H, J¼11.5, 6.5, 2.0 Hz), 4.64 (t, 1H, J¼5.5 Hz),
5.53–5.60 (m, 1H), 5.68–5.75 (m, 1H). 13C NMR (CDCl3)
d: 5.5, 13.7, 13.9, 19.3, 22.2, 31.7, 34.3, 66.2, 67.4, 101.0,
125.7, 135.2. HRMS (FAB) calcd for C12H23O2NaI
(MþþNa): 349.0640. Found: 349.0648.
4.2.4. 2-Iodo-1-(4-methoxyphenyl)-1-(2-methylprop-2-
1
enyloxy)ethane (1d). Obtained in 70% as colorless oil: H
NMR (CDCl3) d: 1.79 (s, 3H), 3.27–3.42 (m, 2H), 3.69 (d,
1H, J¼12.5 Hz), 3.82 (s, 3H), 3.86 (d, 1H, J¼12.5 Hz), 4.40
(dd, 1H, J¼8.5, 4.5 Hz), 4.90 (s, 1H), 4.95 (s, 1H), 6.90 (d,
2H, J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3)
d: 10.8, 19.9, 55.3, 72.9, 80.3, 112.9, 114.0, 127.9, 132.0,
141.8, 159.6. HRMS (EI) calcd for C13H17O2I (Mþ):
332.0273. Found: 332.0292.
4.2.10. Z-1-But-2-enyloxy-2-iodobenzene (1j).22 Under
nitrogen atmosphere, DEAD (40% solution in toluene,
2.16 ml, 4.77 mmol) was added to a mixture of 2-iodo-
phenol (500 mg, 2.27 mmol), triphenylphosphine (1.25 g,
4.77 mmol) and crotyl alcohol (0.407 ml, 4.77 mmol) in dry
THF (20 ml) and stirred at room temperature for 3 h. The
reaction was then quenched with saturated aqueous
NaHCO3 and extracted with AcOEt. The organic layer
was washed with brine, dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatography
on silicagel using hexane/AcOEt (20:1) to give 1j (615 mg,
4.2.5. 1-Cyclohex-2-enyloxy-2-iodo-1-(4-methoxyphenyl)-
ethane (1e). Obtained in 75% as diastereomeric mixture.
Further purification of the diastereomers using column
1
chromatography was unsuccessful; colorless oil: H NMR
(CDCl3) d: 1.39–1.75 (m, 3H), 1.87–2.13 (m, 3H), 3.25–
3.35 (m, 2H), 3.81 (s, 3H), 3.68–3.76, 3.82–3.93 (each m,
total 1H), 4.52–4.57 (m, 1H), 5.56–5.59, 5.84–5.87 (each
m, total 1H), 5.87–5.89 (m, 1H), 6.89 (d, 2H, J¼8.5 Hz),
7.28 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3) d: 11.7. 12.0,
18.8, 19.3, 25.2, 27.2, 29.6, 55.3, 70.4, 72.5, 79.5, 79.9,
113.9, 114.0, 127.2, 127.6, 127.7, 127.8, 131.0, 131.5,
133.1, 133.4, 159.4. HRMS (EI) calcd for C15H19O2I (Mþ):
358.0430. Found: 358.0436.
1
99%) as colorless oil: H NMR (CDCl3) d: 1.76 (d, 3H,
J¼5.0 Hz), 4.52 (d, 2H, J¼4.0 Hz), 5.70–5.94 (m, 2H),
6.71 (d, 1H, J¼8.0 Hz), 6.87 (d, 1H, J¼8.0 Hz), 7.24–7.30
(m, 1H), 7.77 (d, 1H, J¼8.0 Hz). 13C NMR (CDCl3) d: 17.9,
69.8, 86.8, 112.6, 122.5, 125.5, 129.3, 130.1, 139.5, 157.3.
HRMS (EI) calcd for C10H11OI (Mþ): 273.9855. Found:
273.9830.
4.2.6. Ethyl 4-[2-iodo-1-(4-methoxyphenyl)ethoxy]but-2-
enoate (1f). Obtained in 56% as colorless oil: IR
(KBr) cm21: 1717. 1H NMR (CDCl3) d: 1.30 (t, 3H,
J¼7.0 Hz), 3.31 (dd, 1H, J¼10.0, 5.0 Hz), 3.39 (dd, 1H,
J¼10.0, 8.5 Hz), 3.82 (s, 3H), 3.96–4.12 (m, 2H), 4.21 (q,
2H, J¼7.0 Hz), 4.43 (dd, 1H, J¼8.5, 4.5 Hz), 6.19 (td, 1H,
J¼15.5, 2.0 Hz), 6.90 (d, 2H, J¼8.5 Hz), 6.92 (td, 1H,
J¼15.5, 4.0 Hz), 7.23 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3)
d: 10.3, 14.3, 55.3, 60.4, 67.5, 81.5, 114.2, 121.5, 127.8,
4.2.11. [2-Iodo-1-(4-methoxyphenyl)ethyl](methylsul-
fonyl)prop-2-enylamine (1k). Obtained in 34% as color-
1
less oil: IR (KBr) cm21: 1329, 1150. H NMR (CDCl3) d:
2.79 (s, 3H), 3.64 (dd, 1H, J¼16.0, 7.0 Hz), 3.72–3.89 (m,
3H), 3.83 (s, 3H), 5.11 (t, 1H, J¼8.0 Hz), 5.18–5.28 (m,
2H), 5.72–5.85 (m, 1H), 6.92 (d, 2H, J¼8.5 Hz), 7.29 (d,
2H, J¼8.5 Hz). 13C NMR (CDCl3) d: 6.1, 41.1, 48.0, 55.3,
62.9, 114.1, 118.9, 127.8, 129.7, 134.7, 159.7. HRMS (EI)
calcd for C13H18NO3SI (Mþ): 395.0052. Found: 395.0066.

H. Nambu et al. / Tetrahedron 59 (2003) 77–85
83
Anal. calcd for C13H18NO3SI: C, 39.50; H, 4.59; N, 3.54.
Found: C, 39.62; H, 4.54; N, 3.51.
40.8, 55.2, 73.9, 79.8, 113.6, 126.8, 135.9, 158.7. 1H NMR
(CDCl3) cis-2b d: 0.93 (t, 3H, J¼7.5 Hz), 1.40–1.50 (m,
3H), 2.19–2.47 (m, 2H), 3.64 (t, 1H, J¼7.5 Hz), 3.79 (s,
3H), 4.07 (t, 1H, J¼8.0 Hz), 4.83 (dd, 1H, J¼10.5, 5.5 Hz),
6.86 (d, 2H, J¼8.5 Hz), 7.27 (d, 2H, J¼8.5 Hz). 13C NMR
(CDCl3) cis-2b d: 12.9, 26.1, 41.7, 42.2, 55.2, 73.7, 81.2,
113.7, 127.0, 135.1, 158.8. HRMS (EI) calcd for C13H18O2
(Mþ): 206.1307. Found: 206.1309.
4.2.12. [2-Iodo-1-(4-methoxyphenyl)ethyl][(4-methyl-
phenyl)sulfonyl]prop-2-enylamine (1l). Obtained in 30%
as colorless columnar crystals: mp 104–1058C: IR
(KBr) cm21: 1336, 1159. 1H NMR (CDCl3) d: 2.44 (s,
3H), 3.35 (dd, 1H, J¼16.5, 8.0 Hz), 3.59–3.71 (m, 2H),
3.79 (s, 3H), 3.89 (dd, 1H, J¼16.5, 4.0 Hz), 5.05 (d, 2H,
J¼12.0 Hz), 5.14 (dd, 1H, J¼10.5, 5.5 Hz), 5.58–5.72 (m,
1H), 6.80 (d, 2H, J¼8.5 Hz), 6.97 (d, 2H, J¼8.5 Hz), 7.30
(d, 2H, J¼8.0 Hz), 7.70 (d, 2H, J¼8.0 Hz). 13C NMR
(CDCl3) d: 5.1, 21.6, 47.1, 55.2, 62.0, 113.8, 117.7, 126.8,
127.2, 129.7, 130.0, 135.8, 137.7, 143.5, 159.5. HRMS (EI)
calcd for C19H22NO3SI (Mþ): 471.0365. Found: 471.0377.
Anal. calcd for C19H22NO3SI: C, 48.41; H, 4.70; N, 2.97.
Found: C, 48.32; H, 4.69; N, 2.95.
4.3.3. 1-Methoxy-4-[4-(methylethyl)-2-oxolanyl]benzene
(2c). Obtained in 94% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
1
graphy was unsuccessful; colorless oil: H NMR (CDCl3)
trans-2c d: 0.89–0.96 (m, 6H), 1.41–1.60 (m, 1H), 1.93–
2.20 (m, 3H), 3.52 (t, 1H, J¼8.5 Hz), 3.80 (s, 3H), 4.21 (t,
1H, J¼7.0 Hz), 4.96 (t, 1H, J¼6.0 Hz), 6.87 (d, 2H,
J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3)
trans-2c d: 21.6, 31.7, 39.1, 46.3, 55.2, 73.0, 80.2, 113.6,
126.7, 136.1, 158.6. 1H NMR (CDCl3) cis-2c d: 0.89–0.96
(m, 6H), 1.41–1.60 (m, 2H), 1.93–2.20 (m, 1H), 2.31–2.40
(m, 1H), 3.71 (t, 1H, J¼8.5 Hz), 3.80 (s, 3H), 4.08 (t, 1H,
J¼8.0 Hz), 4.84 (dd, 1H, J¼10.5, 5.5 Hz), 6.87 (d, 2H,
J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3) cis-
2c d: 21.5, 32.1, 40.6, 48.1, 55.2, 72.7, 81.5, 113.7, 126.9,
135.1, 158.8. HRMS (EI) calcd for C14H20O2 (Mþ):
220.1463. Found: 220.1463.
4.3. General procedure for the preparation of
tetrahydrofuran 2a–g, j–l and pyrrolidine 2h, i using
VA-061
VA-061 (37.6 mg, 0.15 mmol) was added to a solution of
1a–l (0.30 mmol), CTAB (21.9 mg, 0.060 mmol) and
aqueous EPHP (538 mg, 3.0 mmol; H2O solution, 3 ml) in
H2O (3 ml) at room temperature. The reaction mixture was
then stirred and heated to 808C. The progress of the reaction
was monitored by TLC. An additional amount of the
initiator VA-061 (37.6 mg, 0.15 mmol) was added to the
reaction mixture, when the reaction showed slow conver-
sion. The reaction mixture was then extracted with AcOEt,
and the organic layer was dried using Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography on silicagel using hexane/Et2O (20:1–1:1)
to give the products 2a–l (64–99%).
4.3.4. 1-Methoxy-4-(4,4-dimethyl-2-oxolanyl)benzene
1
(2d). Obtained in 86% as colorless oil: H NMR (CDCl3)
d: 1.14 (s, 3H), 1.19 (s, 3H), 1.67 (dd, 1H, J¼12.5, 9.5 Hz),
2.07 (dd, 1H, J¼12.5, 6.5 Hz), 3.63 (d, 1H, J¼8.0 Hz), 3.74
(d, 1H, J¼8.0 Hz), 3.79 (s, 3H), 4.98 (dd, 1H, J¼9.5,
6.5 Hz), 6.87 (d, 2H, J¼7.0 Hz), 7.27 (d, 2H, J¼7.0 Hz).
13C NMR (CDCl3) d: 26.5, 26.7, 40.1, 49.7, 55.2, 80.5, 80.8,
113.7, 126.9, 135.6, 158.7. HRMS (EI) calcd for C13H18O2
(Mþ): 206.1307. Found: 206.1316.
4.3.1. 1-Methoxy-4-(4-methyl-2-oxolanyl)benzene (2a).
Obtained in 98% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
4.3.5. 1-Methoxy-4-(7-oxabicyclo[4.3.0]non-8-yl)benzene
(2e). Obtained in 94% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
1
graphy was unsuccessful; colorless oil: H NMR (CDCl3)
1
trans-2a d: 1.09 (d, 3H, J¼6.5 Hz), 1.86–2.01 (m, 2H),
2.37–2.54 (m, 1H), 3.44 (dd, 1H, J¼8.0, 7.0 Hz), 3.79 (s,
3H), 4.20 (dd, 1H, J¼8.0, 7.0 Hz), 4.97 (t, 1H, J¼7.0 Hz),
6.86 (d, 2H, J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz). 13C NMR
(CDCl3) trans-2a d: 17.8, 33.3, 42.6, 55.3, 75.6, 79.8, 113.6,
126.8, 135.8, 158.7. 1H NMR (CDCl3) cis-2a d: 1.10 (d, 3H,
J¼6.5 Hz), 1.38–1.49 (m, 1H), 2.37–2.54 (m, 2H), 3.56
(t, 1H, J¼8.0 Hz), 3.79 (s, 3H), 4.06 (t, 1H, J¼8.0 Hz), 4.85
(dd, 1H, J¼10.0, 5.5 Hz), 6.86 (d, 2H, J¼8.5 Hz), 7.24
(d, 2H, J¼8.5 Hz). 13C NMR (CDCl3) cis-2a d: 17.5,
34.9, 43.8, 55.3, 75.3, 81.4, 113.7, 127.0, 135.3, 158.8.
HRMS (EI) calcd for C12H16O2 (Mþ): 192.1150. Found:
192.1166.
graphy was unsuccessful; colorless oil: H NMR (CDCl3)
endo-2e d: 1.22–1.79 (m, 7H), 1.86–2.30 (m, 4H), 3.80 (s,
3H), 4.23 (d, 1H, J¼3.5 Hz), 5.13 (t, 1H, J¼7.5 Hz), 6.84–
6.89 (m, 2H), 7.24–7.33 (m, 2H). 1H NMR (CDCl3) exo-2e
d: 1.22–1.79 (m, 8H), 1.86–2.30 (m, 2H), 2.33–2.42 (m,
1H), 3.80 (s, 3H), 3.99 (d, 1H, J¼5.0 Hz), 4.90 (t, 1H,
J¼7.5 Hz), 6.84–6.89 (m, 2H), 7.24–7.33 (m, 2H). 13C
NMR (CDCl3) endoþexo-2e d: 20.5, 21.5, 23.8, 24.1, 27.3,
28.5, 28.6, 28.9, 38.1, 38.7, 40.4, 41.9, 55.2, 77.8, 78.5,
79.3, 113.6, 113.7, 126.7, 126.9, 136.3, 137.3, 158.5, 158.6.
HRMS (EI) calcd for C15H20O2 (Mþ): 232.1463. Found:
232.1465.
4.3.6. Ethyl 2-[4-(4-methoxyphenyl)-3-oxolanyl]acetate
(2f). Obtained in 96% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
4.3.2. 4-(4-Ethyl-2-oxolanyl)-1-methoxybenzene (2b).
Obtained in 88% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
graphy was unsuccessful; colorless oil: IR (KBr) cm21
:
1
graphy was unsuccessful; colorless oil: H NMR (CDCl3)
1732. 1H NMR (CDCl3) trans-2f d: 1.26 (t, 3H, J¼7.0 Hz),
1.97–2.12 (m, 2H), 2.45–2.56 (m, 2H), 2.72–2.85 (m, 1H),
3.55 (dd, 1H, J¼8.5, 7.0 Hz), 3.79 (s, 3H), 4.14 (q, 2H,
J¼7.0 Hz), 4.28 (dd, 1H, J¼8.5, 7.0 Hz), 4.94 (t, 1H,
J¼7.0 Hz), 6.87 (d, 2H, J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz).
13C NMR (CDCl3) trans-2f d: 14.2, 35.4, 37.8, 40.2, 55.2,
trans-2b d: 0.93 (t, 3H, J¼7.5 Hz), 1.40–1.50 (m, 2H),
1.93–1.99 (m, 2H), 2.19–2.47 (m, 1H), 3.50 (t, 1H,
J¼8.0 Hz), 3.79 (s, 3H), 4.21 (dd, 1H, J¼8.0, 7.0 Hz),
4.93 (t, 1H, J¼7.0 Hz), 6.86 (d, 2H, J¼8.5 Hz), 7.27 (d, 2H,
J¼8.5 Hz). 13C NMR (CDCl3) trans-2b d: 12.8, 26.4, 40.5,

84
H. Nambu et al. / Tetrahedron 59 (2003) 77–85
60.5, 73.5, 79.6, 113.7, 126.8, 135.0, 158.8, 172.3. 1H NMR
(CDCl3) cis-2f d: 1.26 (t, 3H, J¼7.0 Hz), 1.43–1.55 (m,
1H), 2.45–2.56 (m, 3H), 2.72–2.85 (m, 1H), 3.68–3.74 (m,
1H), 3.79 (s, 3H), 4.10–4.18 (m, 1H), 4.14 (q, 2H,
J¼7.0 Hz), 4.84 (dd, 1H, J¼6.5, 6.0 Hz), 6.87 (d, 2H,
J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3) cis-
2f d: 14.2, 36.4, 38.1, 41.3, 55.2, 60.5, 73.1, 80.9, 113.7,
127.0, 135.0, 158.8, 172.3. HRMS (EI) calcd for C15H20O4
(Mþ): 264.1361. Found: 264.1368.
11.4, 27.6, 43.3, 76.5, 109.4, 120.2, 124.3, 128.0, 130.9,
159.9.
4.3.11. 1-(Methylsulfonyl)-4-methyl-2-(4-methoxy-
phenyl)pyrrolidine (2k). Obtained in 98% as diastereo-
meric mixture. Further purification of the diastereomers
using column chromatography was unsuccessful; colorless
1
needles: mp 105–1068C: IR (KBr) cm21: 1337, 1149. H
NMR (CDCl3) cis-2k d: 1.08 (d, 3H, J¼6.5 Hz), 1.55–1.67
(m, 1H), 2.24–2.38 (m, 1H), 2.44–2.58 (m, 1H), 2.54 (s,
3H), 3.04 (t, 1H, J¼10.5 Hz), 3.80 (s, 3H), 3.97 (dd, 1H,
J¼10.5, 8.5 Hz), 4.77 (dd, 1H, J¼10.0, 7.0 Hz), 6.88 (d, 2H,
J¼8.5 Hz), 7.28 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3) cis-
2k d: 16.4, 33.8, 39.2, 45.7, 55.2, 55.8, 63.9, 114.0, 128.0,
4.3.7. 3-Methyl-5-phenyloxolane (2g).23 Obtained in 87%
as diastereomeric mixture. Further purification of the
diastereomers using column chromatography was
1
unsuccessful; colorless oil: H NMR (CDCl3) trans-2g d:
1
1.09 (d, 3H, J¼7.0 Hz), 1.90–2.05 (m, 2H), 2.37–2.49 (m,
1H), 3.47 (dd, 1H, J¼8.0, 7.0 Hz), 4.22 (dd, 1H, J¼8.0,
7.0 Hz), 5.03 (t, 1H, J¼7.0 Hz), 7.20–7.36 (m, 5H). 13C
NMR (CDCl3) trans-2g d: 17.7, 33.2, 42.6, 75.7, 80.0,
125.5, 127.0, 128.2, 154.1. 1H NMR (CDCl3) cis-2g d: 1.09
(d, 3H, J¼7.0 Hz), 1.45 (dd, 1H, J¼9.5, 2.0 Hz), 2.40–2.55
(m, 2H), 3.58 (t, 1H, J¼8.0 Hz), 4.09 (t, 1H, J¼8.0 Hz),
4.92 (dd, 1H, J¼9.5, 6.0 Hz), 7.20–7.36 (m, 5H). 13C NMR
(CDCl3) cis-2g d: 17.3, 35.0, 43.9, 75.4, 81.6, 125.9, 127.0,
128.3, 154.1.
134.2, 159.0. H NMR (CDCl3) trans-2k d: 1.09 (d, 3H,
J¼6.5 Hz), 1.96–2.05 (m, 2H), 2.44–2.58 (m, 1H), 2.67 (s,
3H), 3.15 (t, 1H, J¼9.0 Hz), 3.70 (dd, 1H, J¼9.0, 6.5 Hz),
3.80 (s, 3H), 4.90 (dd, 1H, J¼6.5, 4.5 Hz), 6.88 (d, 2H,
J¼8.5 Hz), 7.28 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3)
trans-2k d: 17.1, 31.7, 38.1, 43.8, 55.2, 55.5, 62.3, 113.9,
127.4, 134.9, 158.8. HRMS (EI) calcd for C13H19NO3S
(Mþ): 269.1085. Found: 269.1091. Anal. calcd for
C13H19NO3S: C, 57.97; H, 7.11; N, 5.20; S, 11.90. Found:
C, 57.74; H, 6.96; N, 5.14; S, 11.80.
4.3.8.
7-Butyl-2,9-dioxabicyclo[4.3.0]nonane
(2h).
4.3.12. 4-Methyl-1-[(4-methylphenyl)sulfonyl]-2-(4-
methoxyphenyl)pyrrolidine (2l). Obtained in 88% as
diastereomeric mixture. Further purification of the dia-
stereomers using column chromatography was unsuccess-
Obtained in 98% as diastereomeric mixture. Further
purification of the diastereomers using column chromato-
graphy was unsuccessful; colorless oil: H NMR (CDCl3)
1
endo-2h d: 0.90 (t, 3H, J¼7.0 Hz), 1.10–1.50 (m, 6H),
1.50–1.99 (m, 5H), 2.20–2.39 (m, 1H), 3.38–3.56 (m, 1H),
3.57–3.79 (m, 2H), 3.94 (t, 1H, J¼8.0 Hz), 5.28 (d, 1H,
J¼3.0 Hz). 13C NMR (CDCl3) endo-2h d: 14.0, 19.2, 22.9,
ful; colorless needles: mp 103–1048C: IR (KBr) cm21
:
1346, 1159. 1H NMR (CDCl3) cis-2l d: 0.95 (d, 3H,
J¼6.5 Hz), 1.41–1.52 (m, 1H), 1.77–1.87 (m, 1H),
2.29–2.36 (m, 1H), 2.41 (s, 3H), 3.07 (t, 1H, J¼11.0 Hz),
3.78–3.84 (m, 1H), 3.79 (s, 3H), 4.58 (dd, 1H, J¼9.5,
7.0 Hz), 6.81 (d, 2H, J¼8.0 Hz), 7.22 (d, 2H, J¼8.0 Hz),
7.24 (d, 2H, J¼8.0 Hz), 7.59 (d, 2H, J¼8.0 Hz). 13C NMR
(CDCl3) cis-2l d: 16.5, 21.5, 33.2, 45.6, 55.3, 56.6, 64.2,
1
23.3, 26.7, 30.5, 36.5, 41.0, 61.0, 70.2, 102.1. H NMR
(CDCl3) exo-2h d: 0.90 (t, 3H, J¼7.0 Hz), 1.10–1.50 (m,
6H), 1.50–1.99 (m, 5H), 2.20–2.39 (m, 1H), 3.38–3.56 (m,
1H), 3.57–3.79 (m, 1H), 3.82–3.92 (m, 1H), 4.28 (t, 1H,
J¼8.0 Hz), 4.99 (d, 1H, J¼3.0 Hz). 13C NMR (CDCl3) exo-
2h d: 14.0, 20.8, 22.4, 22.9, 30.8, 32.4, 37.8, 44.2, 64.5,
74.3, 102.2. HRMS (FAB) calcd for C14H20O2 (MþþH):
185.1542. Found: 185.1525.
1
113.7, 127.4, 127.5, 129.5, 135.0, 135.7, 143.1, 158.7. H
NMR (CDCl3) trans-2l d: 0.87 (d, 3H, J¼6.5 Hz),
1.48–1.60 (m, 1H), 1.77–1.87 (m, 1H), 2.29–2.36 (m,
1H), 2.42 (s, 3H), 2.85 (t, 1H, J¼9.0 Hz), 3.72 (dd, 1H,
J¼9.0, 7.0 Hz), 3.79 (s, 3H), 4.79 (dd, 1H, J¼8.0, 2.5 Hz),
6.83 (d, 2H, J¼8.0 Hz), 7.22 (d, 2H, J¼8.0 Hz), 7.28 (d, 2H,
J¼8.0 Hz), 7.66 (d, 2H, J¼8.0 Hz). 13C NMR (CDCl3)
trans-2l d: 16.9, 21.5, 31.3, 43.5, 55.3, 55.8, 62.7, 113.6,
127.2, 127.5, 129.5, 135.0, 135.5, 143.2, 158.6. HRMS (EI)
calcd for C19H23NO3S (Mþ): 345.1398. Found: 345.1396.
Anal. calcd for C19H23NO3S: C, 66.06; H, 6.71; N, 4.05; S,
9.28. Found: C, 66.06; H, 6.72; N, 4.00; S, 9.21.
4.3.9. 3-Butyl-5-butoxyoxolane (2i).24 Obtained in 99% as
diastereomeric mixture. Further purification of the
diastereomers using column chromatography was
1
unsuccessful; colorless oil: H NMR (CDCl3) trans-2i d:
0.89 (t, 3H, J¼7.5 Hz), 0.92 (t, 3H, J¼7.5 Hz), 1.21–1.60
(m, 11H), 1.98–2.45 (m, 2H), 3.31–3.47 (m, 2H), 3.62–
3.71 (m, 1H), 3.94 (t, 1H, J¼7.5 Hz), 5.10 (dd, 1H, J¼5.5,
3.0 Hz). 13C NMR (CDCl3) trans-2i d: 13.9, 14.0, 19.4,
22.8, 30.9, 31.9, 32.8, 38.6, 39.1, 67.5, 71.9, 104.5. 1H NMR
(CDCl3) cis-2i d: 0.89 (t, 3H, J¼7.5 Hz), 0.92 (t, 3H,
J¼7.5 Hz), 1.21–1.60 (m, 11H), 1.98–2.45 (m, 2H), 3.31–
3.47 (m, 2H), 3.62–3.71 (m, 1H), 4.04 (t, 1H, J¼8.0 Hz),
5.10 (dd, 1H, J¼5.5, 3.0 Hz). 13C NMR (CDCl3) cis-2i d:
13.9, 14.0, 19.4, 22.8, 30.7, 31.8, 33.7, 37.0, 39.3, 67.0,
72.6, 104.1.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific
Research (S) (No. 13853010), for Scientific Research on
Priority Area (A) (No. 13029062) from the Ministry of
Education, Science, Sports, and Culture, Japan and the
Takeda Science Foundation, Japan. We thank Wako Pure
Chemical Industries, Ltd., for the generous supply of several
water-soluble azo-type initiators. G. A. thanks the Japan
Society for the Promotion of Science (JSPS) for a
postdoctoral fellowship.
4.3.10. 3-Ethyloxaindane (2j).22 Obtained in 64% as
1
colorless oil: H NMR (CDCl3) d: 0.99 (t, 3H, J¼7.5 Hz),
1.56–1.69 (m, 1H), 1.75–1.86 (m, 1H), 3.33–3.43 (m, 1H),
4.23 (dd, 1H, J¼9.0, 6.5 Hz), 4.64 (t, 1H, J¼9.0 Hz), 6.78–
6.89 (m, 2H), 7.10–7.19 (m, 2H). 13C NMR (CDCl3) d:

H. Nambu et al. / Tetrahedron 59 (2003) 77–85
85
Cho, D. H. Synlett 2002, 1523. (d) Nambu, H.; Hata, K.;
Matsugi, M.; Kita, Y. Chem. Commun. 2002, 1082.
13. Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi,
M. Org. Lett. 2001, 3, 1157.
References
1. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous
Media. Wiley: New York, 1997. (b) Grieco, P. A. Organic
Synthesis in Water. Blackie: London, 1998.
14. (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C.
Tetrahedron Lett. 1992, 33, 5709. (b) Barton, D. H. R.;
Jang, D. O.; Jaszberenyi, J. C. J. Org. Chem. 1993, 58, 6838.
(c) Jang, D. O. Tetrahedron Lett. 1996, 37, 5367. (d) Jang,
D. O.; Cho, D. H.; Chung, C.-M. Synlett 2001, 1923.
15. (a) Kita, Y.; Gotanda, K.; Fujimori, C.; Murata, K.;
Wakayama, R.; Matsugi, M. Tetrahedron Lett. 1997, 38,
3549. (b) Kita, Y.; Gotanda, K.; Murata, K.; Suemura, M.;
Sano, A.; Yamaguchi, T.; Oka, M.; Matsugi, M. Org. Process
Res. Dev. 1998, 2, 250. (c) Kita, Y.; Gotanda, K.; Ohira, C.;
Suemura, M.; Sano, A.; Matsugi, M. J. Org. Chem. 1999, 64,
6928. and references cited therein.
2. (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816. (b) Breslow, R.; Maitra, U.; Rideout, D. C. Tetrahedron
Lett. 1983, 24, 1901. (c) Breslow, R. Acc. Chem. Res. 1991, 24,
159.
3. (a) Ponaras, A. A. J. Org. Chem. 1983, 48, 3866. (b) Coates,
R. M.; Roger, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P.
J. Am. Chem. Soc. 1987, 109, 1160. (c) Gajewski, J. J.; Jurayj,
J.; Kimbrough, D. R.; Gande, M. E.; Ganem, B.; Carpenter,
B. K. J. Am. Chem. Soc. 1987, 109, 1170. (d) Copley, S. D.;
Knowles, J. R. J. Am. Chem. Soc. 1987, 109, 5008. (e) Brandes,
E. B.; Grieco, P. A.; Gajewski, J. J. J. Org. Chem. 1989, 54,
515.
16. Kita, Y.; Matsugi, M. In Radical Initiators. Radicals in
Organic Synthesis, Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vol. 1, pp 1–10. The water-soluble azo type
radical initiators used in our studies are available from Wako
Pure Chemical Industries, Ltd. Osaka, Japan.
4. (a) Li, C.-J. Tetrahedron 1996, 52, 5643. (b) Li, C.-J.; Chan,
T.-H. Tetrahedron 1999, 55, 11149.
5. (a) Lubineau, A. J. Org. Chem. 1986, 51, 2142. (b) Lubineau,
A.; Meyer, E. Tetrahedron 1988, 44, 6065. (c) Kobayashi, S.;
Hachiya, I. J. Org. Chem. 1994, 59, 3590.
17. (a) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239.
(b) Kool, E. T.; Breslow, R. J. Am. Chem. Soc. 1988, 110,
1596. (c) Breslow, R.; Rizzo, C. J. J. Am. Chem. Soc. 1991,
113, 4340.
6. (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds. Pergamon: Oxford, 1986. (b) Curran,
D. P. Synthesis 1988, 489. (c) Motherwell, W. B.; Crich, D.
Free-Radical Reactions in Organic Synthesis. Academic:
London, 1992. (d) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. Rev. 1991, 91, 1237. (e) Molander, G. A.; Harris, C. R.
Chem. Rev. 1996, 96, 307. (f) Snider, B. B. Chem. Rev. 1996,
96, 339. (g) Renaud, P.; Sibi, M. P. Radicals in Organic
Synthesis. Wiley-VCH: Weinheim, 2001.
18. (a) In Catalysis in Micellar and Macromolecular Systems.
Fendler, J. H., Ed.; Academic: New York, 1998. (b) Tascioglu,
S. Tetrahedron 1996, 52, 11113. (c) Tohma, H.; Takizawa, S.;
Watanabe, H.; Kita, Y. Tetrahedron Lett. 1998, 39, 4547.
(d) Tohma, H.; Takizawa, S.; Watanabe, H.; Fukuoka, Y.;
Maegawa, T.; Kita, Y. J. Org. Chem. 1999, 64, 3519.
19. Maitra has already reported a radical reduction using
surfactants and Sn compound in water; Maitra, U.; Sarma,
K. D. Tetrahedron Lett. 1994, 35, 7861.
7. (a) Light, J.; Breslow, R. Tetrahedron Lett. 1990, 31, 2957.
(b) Rai, R.; Collum, D. B. Tetrahedron Lett. 1994, 35, 6221.
8. Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. Bull.
Chem. Soc. Jpn 1997, 70, 2519.
20. (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(b) Baguley, P. A.; Walton, J. C. Angew. Chem. Int. Ed.
1998, 37, 3072.
9. (a) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 1998, 63, 8604. (b) Wakabayashi, K.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Bull. Chem. Soc.
Jpn 2000, 73, 2377. (c) Yorimitsu, H.; Nakamura, T.;
Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Am.
Chem. Soc. 2000, 122, 11041.
21. (a) Okabe, M.; Tada, M. Bull. Chem. Soc. Jpn 1982, 55, 1498.
(b) Nakamura, E.; Machii, D.; Inubushi, T. J. Am. Chem. Soc.
1989, 111, 6849.
22. Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114,
6050.
10. Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima, K.
J. Org. Chem. 2001, 66, 7776.
23. Rawal, V. H.; Singh, S. P.; Dufour, C.; Michoud, C. J. Org.
Chem. 1993, 58, 7718.
11. (a) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65,
5043. (b) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org.
Lett. 2002, 4, 131.
24. (a) Ueno, Y.; Moriya, O.; Chino, K.; Watanabe, M.; Okawara,
M. J. Chem. Soc., Perkin Trans. 1 1986, 1351. (b) Tang, J.;
Shinokubo, H.; Oshima, K. Tetrahedron 1999, 55, 1893.
12. (a) Jang, D. O.; Cho, D. H. Synlett 2002, 631. (b) Jang, D. O.;
Cho, D. H. Tetrahedron Lett. 2002, 43, 5921. (c) Jang, D. O.;