Conjugate addition reaction of THF-2-yl radical with α,β-unsaturated N-tosyl imines using a dimethylzinc-air initiator

Article abstract of DOI:10.1016/j.tet.2008.05.069

The reaction of tetrahydrofuran-2-yl radical, generated directly from THF by the action of dimethylzinc-air, with α,β-unsaturated N-tosyl aldimines was demonstrated to proceed preferentially in a conjugate addition manner to give 2-(3-hydroxyalkyl)- or 2-(3-aminoalkyl)tetrahydrofurans in good yield. The slow addition of the enimines and the use of dimethylzinc, rather than diethylzinc or triethylborane, were found to be the keys for the efficiency of the THF conjugate addition. The observed chemoselectivity could be rationalized by the larger coefficient of LUMO at the corresponding reaction site of the enimine.

Full text of DOI:10.1016/j.tet.2008.05.069

Tetrahedron 64 (2008) 7258–7265
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conjugate addition reaction of THF-2-yl radical with
imines using a dimethylzinc–air initiator
a,b-unsaturated N-tosyl
Ken-ichi Yamada, Hiroyuki Umeki, Masaru Maekawa, Yasutomo Yamamoto, Tito Akindele,
*
Mayu Nakano, Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2008
Received in revised form 10 May 2008
Accepted 15 May 2008
Available online 18 May 2008
The reaction of tetrahydrofuran-2-yl radical, generated directly from THF by the action of dimethylzinc–
air, with a,b-unsaturated N-tosyl aldimines was demonstrated to proceed preferentially in a conjugate
addition manner to give 2-(3-hydroxyalkyl)- or 2-(3-aminoalkyl)tetrahydrofurans in good yield. The slow
addition of the enimines and the use of dimethylzinc, rather than diethylzinc or triethylborane, were
found to be the keys for the efficiency of the THF conjugate addition. The observed chemoselectivity
could be rationalized by the larger coefficient of LUMO at the corresponding reaction site of the enimine.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
3.0 mmol) in THF (20 mL, 0.25 mol) was stirred at room tempera-
ture for 1 h under a constant introduction of air (0.5 mL/h) into the
Reactions involving radical species have led to synthetically
useful transformations that would have been otherwise impossible
or at least difficult to achieve.1 The development of new radical
initiators is one of the most important efforts for widening the ap-
plicability of radical reactions. We have studied dimethylzinc–air-
initiated radical reactions2 and have developed the directgeneration
solution (Scheme 1). Usual work-up gave a crude mixture, which
was then hydrolyzed with 10% HCl/THF (10:1). Sodium borohydride
reduction of the resulting mixture in methanol gave 1,4-adduct
alcohol 2a (24% yield), 1,2-adduct 3a (3% yield), and diene 4 (35%
yield). The diastereomeric ratio (dr) of 2–4 was 7:3, 3:2, and 7:3,
respectively, and E/Z ratio of the trisubstituted alkene moiety of 4
was 2:1 as shown in Scheme 1. The relative configuration of the 1,4-
adduct 2a was undoubtedly determined by the conversion of the
major isomer into the known compound with the established ste-
reochemistry (vide infra). The relative configuration of the 1,2-ad-
duct 3a was tentatively assigned by analogy to the corresponding
reaction of N-tosyl aldimines3a and the major isomers were
depicted in the scheme. The geometry of the trisubstituted alkene
was determined by NOE enhancement observed between the
of a-alkoxyalkyl radicals from ethers through hydrogen abstraction
and the direct functionalization of ethers by the reaction of the
resulting radicals with achiral imines,3 chiral imines,4 aldehydes,5
and amines.6 We also succeeded in the dimethylzinc–air-initiated
direct generation of cycloalkyl radicals and their aminoalkylation by
the reaction with N-tosyl imines.7 In these reactions, dimethylzinc
wasassumed to react withair-oxygen8 toinitiateradical reactions by
forming a methyl radical, which has a high ability in abstracting
a hydrogen atom due to the strong Me–H bond (the bond dissocia-
tion energy¼429 kJ/mol).9 As part of our continuing studies, we
describe a conjugate addition reaction10,11 of directlygenerated THF-
1. Me2Zn (3 equiv)
air (0.5 mL/h)
2. 10% HCl−THF (10:1)
Ts
+
O
2-yl radical with a,b-unsaturated N-tosyl aldimines.
Ph
N
3. NaBH4, MeOH
1a
250 equiv
O
H
2. Results and discussions
H
Ph
OH
O
H
O
H
2.1. Reaction of THF with N-tosyl cinnamaldimine (1a)
H
Ph
H
+
+
Ts
E:Z = 2:1
OH Ph
N
A solution of cinnamaldehyde N-tosyl imine 1a (285 mg,
1.0 mmol) and dimethylzinc (1.0 M hexane solution, 3.0 mL,
a
Ph
H
2a
3a
4
Method
24% (dr 7:3)
68% (dr 7:3)
3% (dr 3:2)
3% (dr 3:2)
35% (dr = 7:3)
3% (dr = 7:3)
A
B
Scheme 1. Addition of THF to 1a using Me2Zn–air initiator and formation of 2a, 3a,
and 4. aMethod A: Me2Zn was added to a THF solution of 1a within 1 min. Method B:
a THF solution of 1a was added to a THF solution of Me2Zn over 6 h.
* Corresponding author. Tel.: þ81 75 753 4553; fax: þ81 75 753 4604.
E-mail address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.069

K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
7259
olefinic CH of the trisubstituted alkene and carbinol CH2 or benzylic
CH. The production of undesirable 4 is probably ascribable to the
further reaction of 1,4-adduct intermediates 5 and/or 6 with 1a
(path A and/or path B in Scheme 2, respectively).
The presence of a Lewis acid as an additive did not affect this 1,4-
preference in the addition of THF-2-yl radical. Thus, in the presence
of 1 equiv of boron trifluoride diethyl etherate, under the condi-
tions corresponding to entry 1 in Table 1, the reaction still pro-
ceeded in 1,4-manner to give 7 in 32% yield along with 3 in 5% yield,
although the reaction efficacy significantly decreased by competi-
tive formation of unidentified byproducts. This is in contrast to the
reported triethylborane-mediated 1,2-selective addition of an ethyl
O
Me2Zn + O2
H
↓
radical to an
a,b-unsaturated oxime ether derived from cinna-
maldehyde in the presence of boron trifluoride diethyl etherate.12
Other approaches to high yield production of 2a by sterically and
electronically modified imines such as N-(2,4,6-triisopropylbenz-
enesulfonyl)-, N-(4-methoxyphenyl)-, and N-(2,6-diispropylphe-
nyl)imine failed to improve the yield of 2a. Direct use of
cinnamaldehyde as a Michael acceptor did not lead to any fruitful
results.
Me •
MeH
O
O
1a
1a
O
Ts
Ts
Ph
Ph
N
Ts
O
Ts
path A
Ph
N
N
N
5
Me2Zn
4
O
2.2. Reactions of other N-tosyl a,b-unsaturated aldimines
with THF
1a
Ts
Ph
N
Ph
Ph
N
Ts
path B
ZnMe
6
The reaction of THF with other b-aryl N-tosyl a,b-unsaturated
aldimines having an electron-withdrawing 4-chlorophenyl group
(1b), electron-donating 4-methoxy- and 4-methylphenyl groups
(1c, 1d), a sterically demanding 2-methylphenyl group (1e), and 2-
naphthyl group (1f) was proven to be promising under the slow
ZnMe
Scheme 2. Plausible mechanism for the production of 4.
addition protocol (Table 1). Whether the b-aryl group of imines had
Slow addition of 1a over 6 h to a mixture of dimethylzinc and
THF, under a constant introduction of air, was effective to improve
the production of 2a in 68% yield after imine hydrolysis and alde-
hyde reduction, and to suppress the formation of 4 in 3% yield. The
same slow addition conditions were followed by sodium borohy-
dride reduction (acidic hydrolysis step of imines into aldehydes was
omitted) to give 1,4-addition product tosylamide 7a with dr of 7:3
in 76% yield along with 1,2-adduct 3a (3:2 dr) in 3% yield (Table 1,
entry 1).
The suppressed production of 4 by the slow addition of 1a
clearly indicates the vital role of radical intermediate 5 in the
production of 4. Low concentration of 1a reduces the possibility of
the reaction of 5 with 1a (Scheme 2, path A), and hence 5 would be
converted to a zinc enamide 6. If path B is the main pathway to 4,
then 4 should not be suppressed in spite of the slow addition be-
cause reaction rates of both THF-2-yl radical and 6 are probably
first-order with respect to the concentration of 1a and should be
affected to the same degree: the slow addition would make the
whole reaction slow with no difference in the product ratio. Ac-
cordingly, the results indicate that the reaction of zinc enamide 6
with 1a, i.e., path B, should be negligible and path A is mainly re-
sponsible to the formation of 4.
an electron-withdrawing (entry 2) or an electron-donating sub-
stituent (entries 3 and 4), the 1,4-addition of THF-2-yl radical
mainly took place to give 2-(3-aminoalkyl)-THF 7 as a major
product in 55–70% yield, whilst 1,2-adducts 3 were minor products
(range of 7/3¼ca. 11:1 to 25:1). Even with sterically demanding
2-methylphenyl (entry 5) or 2-naphthyl group (entry 6), the 1,4-
addition was still preferred with a slightly increased amount of
1,2-adducts 3 (7/3¼17:2).
The relative configuration of major isomers of 7b–7f was
assigned to be the same as 7a based on 1H and 13C NMR chemical
shifts and coupling constants of the benzylic and adjacent methines
(Table 2). The coupling constants between these protons of the
major isomers of 7a and 7b were smaller (5.8 and 5.5 Hz) than
those of the minor isomers (9.2 and 8.8 Hz). This tendency of the
coupling constants was in good agreement with those calculated by
Karplus equation based on MMFF conformer distribution (2.6, 2.7,
9.6, and 8.2 Hz).13 Except for 7e, the peaks of these methine protons
of the major diastereomers appear at lower
the minor diastereomers, while those of the methine carbons of the
major diastereomers appear at higher ppm than those of
d ppm than those of
d
the minor diastereomers. Chemical shifts of methylene protons of
the tetrahydrofuran ring are also characteristic: those of the minor
diastereomers are better resolved and appear at higher
d ppm than
those of the major diastereomers. The peaks of the amide protons
Table 1
Radical addition of THF to unsaturated imines 1 using dimethylzinc–air initiatora
of minor diastereomers also appear at higher
the major diastereomers.
d ppm than those of
1. Me2Zn
The reaction of 4,4,5,5-tetramethyl-1,3-dioxolane14 with 1a
under 10 h slow addition conditions proceeded in 1,4-manner
to give 1,4-adduct 8 in 15% yield and 1,2-adduct 9 in 2% yield
(Scheme 3).
O
H
O
H
O
air
+
+
H
H
2. NaBH4
MeOH
Ts
Ts
Ts
Ar
N
Ar
7 (dr 7:3)
N
H
Ar
3 (dr 3:2)
N
H
1
Entry
1
Ar
Yield of 7 (%)
Yield of 3 (%)
2.3. Reactions initiated by diethylzinc and triethylborane
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
76
55
59
70
60
51
3
5
4
5
7
6
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-MeC6H4
2-Naphthyl
The reaction of 1a with THF was performed using other estab-
lished radical initiators, diethylzinc,15,16 and triethylborane,17 to
compare the reaction efficiency (Scheme 4). The reaction initiated
by diethylzinc gave 7a in slightly lower yield of 65%, while a sig-
nificant amount (12%) of ethyl-adduct 10 was produced. Using
triethylborane initiator, the production of 10 increased to 20% yield
and 1,4-adducts 7a and 2a were obtained in 33% and 9% yields,
a
The reaction was conducted in 250 equiv of THF with 6 equiv of Me2Zn under
continuous introduction of air (0.5 mL/h). Imines 1 (1 mmol) were added over 6 h as
a THF solution.

7260
K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
Table 2
Coupling constant (J, Hz) and chemical shift (
d
, ppm) values of 1H and 13C NMR of methines, 1H of oxygenated methylene, and amide NH of adduct 7
3JH–H
d
ArCH
d
OCH
d
OCH2
d NH
a
1H
13C
1H
13C
1H
1H
7a
7b
7c
7d
7e
7f
Major
Minor
Major
Minor
Major
Minor
Major
Minor
Major
Minor
Major
Minor
5.8
9.2
5.5
8.8
2.68
2.49
2.67
2.53
2.63
2.45
2.63
2.45
32.2
33.6
32.5
33.3
46.7
48.1
47.3
48.8
41.6
41.7
47.7
49.5
3.95
3.88
3.91
3.84
3.91
3.84
3.92
3.85
3.90
3.94
4.04
4.00
82.3
83.0
82.0
82.7
82.3
83.1
82.4
83.0
82.2
82.2
82.3
82.9
3.66, 3.71
3.76, 3.84
3.64, 3.67
3.76, 3.84
3.65, 3.70
3.75, 3.84
3.65, 3.71
3.76, 3.84
3.66, 3.70
3.77, 3.88
3.66, 3.70
3.78, 3.87
4.44
4.87
4.72
4.75
4.45
4.76
4.41
4.75
4.67
4.99
4.75
4.98
2.76
2.68
a
The coupling constants between the benzylic and the adjacent methine protons.
1) (COCl)2, DMSO; Et3N
2) NaClO2, NaH2PO4
O
H
O
H
O
AlCl3
1. Me2Zn
air
Ts 2. NaBH4
N
MeOH
O
O
H
Ph
H
Ph
O
O
O
O
3) (COCl)2
+
OH
Cl
+
Ts
Ts
major 2a
11
Ph
added over 10 h
Ph
N
H
Ph
N
H
1a
8
9
15%
2%
Cl−
Scheme 3. Attempted reaction of C1 unit ether to 1a using Me2Zn–air initiator.
O
H
O+
H
H
O+
O
Ph
Ph
1. initiator, air
Ts
+
O
O
O
Ph
N
Cl
1) NaI
2. NaBH4, MeOH
O
O
1a
2) Bu3SnH, Et3B
49%
Ph
40% (4 steps)
Ph
12
13
O
H
O
Et
+
+
H
H
H
Scheme 5. Conversion of major isomer of 2a into lactones 12 and 13.
Ts
Ts
Ts
Ph
N
H
Ph
N
Ph
N
H
H
initiator
Et2Zn
Et3B
7a
3a
3%
9%
10
65%
33% + 2a (9%)
12%
20%
optimized geometries and the energy and MO coefficients of the
LUMO were calculated by the B3LYP/6-31G level DFT method for s-
Scheme 4. Radical reaction of THF with 1a using Et2Zn or Et3B–air initiator.
*
cis and s-trans conformers of N-(3-phenylprop-2-enylidene)-
benzenesulfonamide (14) (Fig. 1). The LUMO energy of the s-cis
conformer was found to be lower than that of the s-trans conformer
(ꢀ2.45 vs ꢀ2.38 eV), although the population of the conformers at
respectively.18,19 These results suggest that the addition of ethyl
radical to 1a is competing with the hydrogen atom abstraction from
THF by the ethyl radical, indicating the privilege of dimethylzinc for
the efficient generation of THF-2-yl radical from THF.
27 ꢁC was calculated to be trans/cis¼97.5:2.5 (
D
G0¼9.14 kJ/mol). In
the s-cis conformer, the
b-carbon C3 was found to have largest
coefficient (jLUMOj¼0.4477) and the azomethine carbon C1 has the
second largest coefficient (jLUMOj¼0.3817), apparently suggesting
that 1,4-conjugate addition is much more favorable than 1,2-addi-
tion.23 Qualitatively the same results (0.4341 at C3 and 0.3622 at
C1) were obtained for the s-trans conformer.
2.4. Acylative tetrahydrofuran ring opening to convert 1,4-
adduct 2a into lactones 12 and 13, and determination of the
relative configuration of 2a
The THF moiety of the adduct is convertible into an a,u-func-
C1
0.3622
Ph
S
tionalized C4 chain unit as shown in Scheme 5. Sequential Swern
and Pinnick oxidations of the major isomer of 2a gave the corre-
sponding carboxylic acid, which was then converted into acyl
chloride 11. Treatment of 11 with aluminum chloride at room
temperature provided lactone 12 via the known acylative tetrahy-
drofuran ring opening.20 Dehalogenation of 12 gave the known
lactone 1321 to establish the relative stereochemistry of 2a.
C3
C3
O
O
0.4477
0.4341
N
O
S
O
Ph
Ph
s-cis-14
Ph
s-trans-14
LUMO = −2.38 eV
N
C1
0.3817
E
LUMO = −2.45 eV
E
Figure 1. LUMO energy and coefficients on
of s-cis and s-trans conformers of -unsaturated N-benzensulfonyl imine 14 by
B3LYP/6–31G
b-carbon (C3) and azomethine carbon (C1)
a,b
*
.
2.5. MO calculation rationale for selective 1,4-conjugate
addition reaction22
Because
radicals having relatively high energy SOMOs, the most important
MO interaction between the radicals and the -unsaturated imine
(1a) should be the SOMO of the radicals and LUMO of the imine. The
a
-alkoxyalkyl radicals are classified as nucleophilic
3. Conclusions
a,
b
We have shown that THF-2-yl radical, directly generated from
THF by dimethylzinc–air, undergoes addition to -unsaturated N-
a,b

K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
7261
tosyl aldimines preferentially in 1,4-manner to give 2-(3-hydroxy-
alkyl)- or 2-(3-aminoalkyl)-tetrahydrofurans in good yield. The use
of dimethylzinc, rather than diethylzinc or triethylborane, was the
key for the efficiency of the THF addition. The slow addition of the
enimines 1 efficiently improved the production of the desired ad-
duct 2 or 7, by suppressing the formation of 4, which suggests that 4
was produced through the reaction of 1a and intermediate radical
5, and not zinc amide 6. The adduct 2 was converted into lactones
12 and 13. The observed selective 1,4-conjugate addition was
rationalized by the larger LUMO coefficient at the corresponding
reaction site of the enimine.
1H), 7.45 (d, J¼7.9, 2H), 7.34 (d, J¼8.3, 2H), 7.34 (d, J¼7.9, 2H), 6.95
(dd, J¼9.5, 15.9, 1H), 2.44 (s, 3H), 2.40 (s, 3H). 13C NMR: 171.1 (CH),
154.0 (CH), 144.4 (C), 142.6 (C), 135.6 (C), 131.6 (C), 130.0 (CH), 129.8
(CH), 128.7 (CH), 127.9 (CH), 123.8 (CH), 21.5 (CH3ꢂ2). FABMS m/z:
300 (MþH). FABMS m/z: 300.1056 (calcd for
C17H18NO2S:
300.1058).
4.1.5. 4-Methyl-N-[3-(2-methylphenyl)propenylidene]-
benzenesulfonamide (1e)
Yield: 49%, mp 126–128 ꢁC. IR (KBr): 3040, 2924, 1612, 1582,
1319, 1157, 1088. 1H NMR: 8.82 (d, J¼9.5, 1H), 7.87 (d, J¼8.3, 2H),
7.79 (d, J¼15.6, 1H), 7.59 (d, J¼7.7, 1H), 7.36–7.32 (m, 3H), 7.26–7.23
(m, 2H), 6.94 (dd, J¼9.5,15.6,1H), 2.46 (s, 3H), 2.44 (s, 3H). 13C NMR:
171.2, 151.5, 144.5, 138.3, 135.4, 133.0, 131.5, 131.2, 129.8, 128.0,
126.8, 126.7, 125.5, 21.6, 19.7. FABMS m/z: 300 (MþH). FABMS m/z:
300.1056 (calcd for C17H18NO2S: 300.1058).
4. Experimental section
4.1. General
All melting points were uncorrected. IR spectra were expressed
in cmꢀ1
.
1H and 13C NMR spectra were measured in CDCl3 at 500
4.1.6. 4-Methyl-N-(3-naphth-2-ylpropenylidene)-
and 125 MHz, respectively. 13C NMR peak multiplicity assignments
were made based on DEPT. Chemical shift values are expressed in
parts per million relative to internal TMS. J values were presented in
hertz. Abbreviations are as follows: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. Column chromatography was
performed using silica gel. A hexane solution of dimethylzinc,
diethylzinc, and triethylborane was purchased from Kanto chemical
co., Inc. 4,4,5,5-Tetramethyl-1,3-dioxolane was prepared according
benzenesulfonamide (1f)
Yield: 61%, mp 167–170 ꢁC. IR (KBr): 3047, 3009, 2916, 1612,
1582, 1312, 1157, 1088. 1H NMR: 8.83 (d, J¼9.5, 1H), 7.97 (s, 1H),
7.89–7.84 (m, 5H), 7.66 (m, 1H), 7.65 (d, J¼15.6, 1H), 7.58–7.53 (m,
2H), 7.35 (d, J¼8.2, 2H), 7.10 (dd, J¼9.5, 15.6, 1H), 2.44 (s, 3H). 13
C
NMR: 170.9, 153.9, 144.5, 135.4, 134.8, 133.2, 131.7, 131.3, 129.8,
129.2, 128.9, 128.1, 128.0, 127.9, 127.1, 124.9, 123.3, 21.6. FABMS m/z:
336 (MþH). FABMS m/z: 336.1060 (calcd for C20H18NO2S, 336.1058).
to the reported procedure.14
a,b-Unsaturated N-tosyl aldimines 1
were prepared by the reported procedure24 from the corresponding
aldehydes.25 Before introduction to a reaction mixture, air was
passed through a drying tube filled with NaOH.
4.2. 3-Phenyl-3-(tetrahydrofuran-2-yl)propane-1-ol (2a), and
(2Z,4E)- and (2E,4E)-5-phenyl-2-(phenyl(tetrahydrofuran-2-
yl)methyl)penta-2,4-dien-1-ol (4) (Scheme 1)
4.1.1. 4-Methyl-N-(3-phenylpropenylidene)benzenesulfon-
amide (1a)
THF (18.5 mL, 0.23 mol) and 1.0 M solution of Me2Zn in hexane
(6.0 mL, 6.0 mmol) were placed in a three-neck flask attached with
NaOH tube. A solution of cinnamaldehyde imine 1a (285 mg,
1.0 mmol) in 1.5 mL of THF was added (0.25 mL/h) over 6 h to the
stirred mixture at room temperature, while air was injected to the
solution (0.5 mL/h), using a syringe pump. After the addition of 1a,
the mixture was stirred for additional 0.5 h and quenched with
NH4Cl (15 mL). The mixture was diluted with EtOAc and the organic
layer was separated. The aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The resulting pale-yellow oil was dis-
solved in EtOAc and passed through Al2O3 (10 g), which was suc-
cessively eluted with EtOAc. After concentration, the resulting pale-
yellow solid was dissolved in methanol (3 mL) and then NaBH4
(39 mg, 1.0 mmol) was added to the solution. After 15 min, the re-
action was quenched with water (3 mL) and the resulting aqueous
layer was extracted with EtOAc. The organic layer was washed with
brine and dried over Na2SO4. Concentration and column chroma-
tography (hexane/EtOAc¼1:1) gave a 7:3 diastereomeric mixture of
2a (139.7 mg, 68%) as colorless oil, and a 7:3 diastereomeric mix-
ture of a 2:1 mixture of (E,E)- and (E,Z)-4 (1.1 mg, 3%) as pale-yellow
oil.
Yield: 63%, 119–121 ꢁC. IR (KBr): 1624, 1582, 1315, 1153, 1091. 1H
NMR: 8.59 (d, J¼9.5, 1H), 7.86 (d, J¼8.3, 2H), 7.56–7.53 (m, 2H), 7.48
(d, J¼15.9,1H), 7.44–7.39 (m, 3H), 7.33 (d, J¼7.9, 2H), 6.97 (dd, J¼9.5,
15.9, 1H), 2.42 (s, 3H). 13C NMR: 170.9, 153.8, 144.5, 135.3, 134.1,
131.6, 129.8, 129.2, 128.6, 127.9, 124.6, 21.5. EIMS m/z: 284 (Mþ), 155
(Ts), 130 (MꢀTs), 91. These spectroscopic data were identical to
those reported.26
4.1.2. N-[3-(4-Chlorophenyl)propenylidene]-4-methylbenzene-
sulfonamide (1b)
Yield: 83%, mp 178–180 ꢁC. IR (KBr): 1620,1574,1319,1173,1088.
1H NMR: 8.76 (d, J¼9.5, 1H), 7.85 (d, J¼8.3, 2H), 7.48 (d, J¼8.6, 2H),
7.42 (d, J¼15.8, 1H), 7.40 (d, J¼8.6, 2H), 7.34 (d, J¼8.3, 2H), 6.95 (dd,
J¼9.5, 15.8, 1H), 2.44 (s, 3H). 13C NMR: 170.5, 152.0, 144.6, 137.6,
135.2, 132.6, 129.8, 129.7, 129.5, 128.0, 125.2, 21.5. FABMS m/z: 322
(Mþ2þH), 320 (MþH). FABMS m/z: 320.0506 (calcd for
C
16H15ClNO2S: 320.0512).
4.1.3. N-[3-(4-Methoxyphenyl)propenylidene]-4-
methylbenzenesulfonamide (1c)
Yield: 82%, mp 105–106.5 ꢁC. IR (KBr): 1624, 1601, 1574, 1512,
1315, 1245, 1157, 1091. 1H NMR: 8.74 (d, J¼9.8, 1H), 7.85 (d, J¼8.5,
2H), 7.51 (d, J¼8.5, 2H), 7.44 (d, J¼15.6, 1H), 7.33 (d, J¼8.5, 2H), 6.93
A 7:3 diastereomeric mixture of 2a. IR (neat): 3382, 1064. 1H
NMR: 7.31–7.16 (m, 5H), 4.08–4.04 (m, 0.7H), 4.03–3.97 (m, 0.3H),
3.94–3.89 (m, 0.3H), 3.85–3.80 (m, 0.3H), 3.80–3.75 (m, 0.7H),
3.72–3.68 (m, 0.7H), 3.61–3.57 (m, 1H), 3.49–3.45 (m, 1H), 2.91–
2.86 (m, 0.7H), 2.72–2.65 (m, 0.3H), 2.20–1.40 (m, 6H). 13C NMR:
major 141.8, 128.5, 128.2, 126.4, 82.7, 68.2, 60.9, 47.2, 35.4, 29.2,
25.8; minor 143.0, 128.4, 127.8, 126.4, 83.4, 68.2, 61.5, 49.6, 37.9,
30.8, 25.5. MS m/z: 206 (Mþ). Anal. Calcd for C13H18O2: C, 75.69; H,
8.80. Found: C, 75.94; H, 8.92. The diastereomers were separated by
column chromatography (hexane/EtOAc¼3:2).
(d, J¼8.5, 2H), 6.86 (dd, J¼9.8, 15.6, 1H), 3.86 (s, 3H), 2.43 (s, 3H). 13
C
NMR: 171.1,162.6,153.9,144.2,135.7,130.6,129.7,127.8,127.0,122.2,
114.6, 55.4, 21.4. FABMS m/z: 316 (MþH). Anal. Calcd for
C
17H17NO3S: C, 64.74; H, 5.43; N, 4.44. Found: C, 64.77; H, 5.45; N,
4.38.
4.1.4. 4-Methyl-N-[3-(4-methylphenyl)propenylidene]-
benzenesulfonamide (1d)
Yield: 25%, mp 153–155 ꢁC. IR (KBr): 2924,1612,1574,1312,1150,
1088. 1H NMR: 8.76 (d, J¼9.5,1H), 7.85 (d, J¼8.3, 2H), 7.48 (d, J¼15.9,
The minor less polar diastereomer of 2a. Colorless oil. IR (neat):
3387, 2955, 2870, 1597, 1458, 1404, 1119, 1057, 918, 864, 764, 702. 1H
NMR: 7.29 (dd, J¼7.3, 7.4, 2H), 7.21 (dt, J¼7.4, 1.5, 1H), 7.17 (dd, J¼1.5,

7262
K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
7.3, 2H), 4.00 (ddd, J¼6.4, 8.3, 8.9, 1H), 3.91 (ddd, J¼6.7, 6.7, 8.3, 1H),
3.82 (ddd, J¼5.8, 8.0, 8.3, 1H), 3.64 (ddd, J¼5.3, 5.3, 11.0, 1H), 3.54
(ddd, J¼4.6, 8.6, 11.0, 1H), 2.83 (br s, 1H), 2.68 (ddd, J¼7.0, 7.0, 8.9,
1H), 2.21 (m, 1H), 1.73–1.94 (m, 3H), 1.60 (m, 1H), 1.40 (dddd, J¼8.5,
8.5, 8.5, 12.5, 1H). 13C NMR: 143.2 (C), 128.6 (CH), 128.0 (CH), 126.6
(CH), 83.4 (CH), 68.1 (CH2), 61.5 (CH2), 49.6 (CH), 37.9 (CH2), 30.7
(CH2), 25.4 (CH2). FABMS m/z: 207 (MþH). FABMS m/z: 207.1390
(calcd for C13H19O2: 207.1385).
J¼5.8, 6.4, 8.2, 1H), 3.71 (ddd, J¼6.8, 6.8, 8.3, 1H), 3.66 (ddd, J¼5.8,
7.6, 8.3, 1H), 2.87 (m, 1H), 2.79 (m, 1H), 2.68 (ddd, J¼5.2, 5.2, 10.1,
1H), 2.42 (s, 3H), 1.82–1.96 (m, 3H), 1.44 (dddd, J¼8.2, 8.2, 8.2, 12.2,
1H); minor 7.66 (d, J¼7.0, 2H), 7.19–7.28 (m, 5H), 7.03 (d, J¼7.0, 2H),
4.87 (t, J¼5.7, 1H), 3.88 (ddd, J¼6.4, 7.6, 9.2, 1H), 3.84 (ddd J¼7.0, 7.0,
8.3, 1H), 3.76 (ddd, J¼6.1, 8.0, 8.3, 1H), 2.91 (m, 1H), 2.84 (m, 1H),
2.49 (ddd, J¼5.2, 8.8, 9.2, 1H), 2.42 (s, 3H), 2.11 (m, 1H), 1.71–1.84
(m, 3H), 1.56 (m, 1H), 1.32 (dddd, J¼8.2, 8.2, 8.2, 12.5, 1H). 13C NMR:
major 143.3 (C), 140.9 (C), 137.0 (C), 129.64 (CH), 128.64 (CH), 128.4
(CH), 127.10 (CH), 126.78 (CH), 82.3 (CH), 68.1 (CH2), 47.7 (CH), 41.4
(CH2), 32.2 (CH2), 29.0 (CH2), 25.7 (CH2), 21.4 (CH3); minor 143.2
(C), 142.0 (C), 137.1 (C), 129.60 (CH), 128.65 (CH), 128.0 (CH), 127.11
(CH), 126.83 (CH), 83.0 (CH), 68.0 (CH2), 49.3 (CH), 41.7 (CH2), 33.6
(CH2), 30.6 (CH2), 25.4 (CH2), 21.4 (CH3). FABMS m/z: 360 (MþH).
FABMS m/z: 360.1632 (calcd for C20H26NO3S: 360.1633).
A 6:4 diastereomeric mixture of 3a. IR (neat): 3271, 2870, 1327,
1157, 1065. 1H NMR: 7.71–7.68 (m, 2H), 7.27–7.07 (m, 7H), 6.24 (d,
J¼15.9, 0.4H), 6.22 (d, J¼15.9, 0.6H), 5.77 (dd, J¼7.9, 15.9, 0.6H), 5.75
(dd, J¼8.4, 16, 0.4H), 5.00 (br d, J¼6.4, 1H), 4.02–3.94 (m, 0.8H),
3.92–3.70 (m, 3.2H), 2.28 (s, 1.8H), 2.27 (s, 1.2H), 1.95–1.79 (m,
3.6H), 1.70 (m, 0.4H). 13C NMR: major 143.2 (C), 136.2 (C), 133.8 (C),
132.7 (CH), 129.4 (CH), 128.36 (CH), 127.8 (CH), 127.5 (CH), 126.4
(CH), 124.4 (CH), 80.7 (CH), 68.7 (CH2), 59.44 (CH), 28.0 (CH2), 25.7
(CH2), 21.3 (CH3); minor 143.3 (C), 136.2 (C), 133.8 (C), 132.7 (CH),
129.5 (CH), 128.42 (CH), 127.9 (CH), 127.4 (CH), 126.6 (CH), 124.4
(CH), 80.8 (CH), 68.8 (CH2), 59.45 (CH), 28.0 (CH2), 25.7 (CH2), 21.3
(CH3). MS m/z: 286 (MꢀC4H8O). Anal. Calcd for C20H23O3NS: C,
67.20; H, 6.49; N, 3.92. Found: C, 66.91; H, 6.51; N, 3.74.
The major more polar diastereomer of 2a. Colorless oil. IR (neat):
3387, 2947, 2870, 1597, 1450, 1057, 918, 733, 702. 1H NMR: 7.20–7.31
(m, 5H), 4.06 (ddd, J¼6.1, 6.1, 8.6, 1H), 3.76 (ddd, J¼7.1, 7.1, 7.8, 1H),
3.69 (ddd, J¼6.1, 7.8, 7.8, 1H), 3.58 (ddd, J¼5.8, 5.8, 10.7, 1H), 3.47
(ddd, J¼6.1, 7.9, 10.7, 1H), 2.88 (ddd, J¼5.5, 5.5, 9.8, 1H), 1.90–2.06
(m, 3H), 1.65–1.84 (m, 3H), 1.57 (dddd, J¼8.4, 8.4, 8.4, 12.2, 1H). 13
C
NMR: 141.9 (C), 128.7 (CH), 128.3 (CH), 126.6 (CH), 82.7 (CH), 68.1
(CH2), 60.9 (CH2), 47.1 (CH), 35.3 (CH2), 29.0 (CH2), 25.7 (CH2).
FABMS m/z: 207 (MþH). FABMS m/z: 207.1396 (calcd for C13H19O2:
207.1385).
A 2:1 mixture of (2Z,4E)- and (2E,2E)-4. IR (neat): 3406, 1061. 1H
NMR: 7.44–7.06 (m, 10H), 6.67–6.60 (m, 0.87H), 6.57 (d, J¼15.9,
0.13H), 6.46 (d, J¼11.3, 0.27H), 6.39 (d, J¼11.3, 0.48H), 6.35 (d, J¼11.3,
0.12H), 6.27 (d, J¼11.6, 0.13H), 4.55 (m, 0.75H), 4.46 (m, 0.25H), 4.37
(d, J¼11.9, 0.13H), 4.28 (d, J¼12.2, 0.12H), 4.25–4.19 (m, 1.27H), 4.09
(d, J¼13.5, 0.48H), 3.99–3.90(m,1.63H), 3.82 (m,1H), 3.77(m, 0.12H),
3.65 (d, J¼6.4, 0.12H), 3.58 (d, J¼8.9, 0.13H), 2.06–1.75 (m, 3H),1.70–
1.60 (m, 1H). 13C NMR: 142.0, 141.3, 141.2, 140.3, 137.5, 137.4, 134.6,
134.5,128.8,128.73,128.69,128.68,128.6,128.5,128.2,127.84,127.77,
126.7, 126.61, 126.55, 124.0, 123.8, 80.1, 79.7, 68.5, 68.3, 65.5, 64.9,
50.5, 50.4, 30.8, 30.1, 25.6, 25.3. MS m/z: 320 (Mþ).
The major diastereomer of (2Z,4E)-4 was isolated as pale-yellow
oil by preparative silica gel TLC (hexane/acetone¼6:1). The (2Z)-
geometry was determined by NOE (8% between benzylic CH at
3.58 ppm and C3 olefinic CH at 6.28 ppm). IR (neat): 3359, 1045. 1H
NMR: 7.39 (d, J¼7.3, 2H), 7.33–719 (m, 8H), 7.14 (dd, J¼11.0, 15.6,
1H), 6.57 (d, J¼15.6, 1H), 6.28 (d, J¼11.0, 1H), 4.46 (dt, J¼9.15, 12.9,
1H), 4.37 (d, J¼13.9, 1H), 4.24 (d, J¼11.4, 1H), 3.99 (dd, J¼7.8, 14.6,
1H), 3.85 (dd, J¼7.8, 14.6, 1H), 3.58 (d, J¼8.9, 1H), 2.30–2.36 (m, 2H),
2.01–1.97 (m, 2H). 13C NMR: 142.4, 141.4, 137.5, 133.9, 131.2, 128.74,
128.67, 128.4, 127.7, 126.9, 126.6, 124.4, 81.4, 68.4, 60.1, 57.1, 29.7,
25.5. MS m/z: 320 (Mþ). EIMS m/z: 320.1783 (calcd for C22H24O2:
320.1176).
4.3.2. N-(3-(4-Chlorophenyl)-3-(tetrahydrofuran-2-yl)propyl)-4-
methylbenzenesulfonamide (7b) and (E)-N-(3-(4-chlorophenyl)-1-
(tetrahydrofuran-2-yl)allyl)-4-methylbenzenesulfonamide (3b)
(entry 2)
The same procedure except for the addition of 1b (320 mg,
1.0 mmol) as a solution in THF (9.0 mL, 1.5 mL/h) gave 7b (216.2 mg,
55%) as white solid and 3b (19.5 mg, 5%) as white solid.
A 7:3 diastereomeric mixture of 7b. Mp 98–99 ꢁC. IR (neat): 3278,
1327, 1157, 1088. 1H NMR: major 7.66 (d, J¼7.0, 2H), 7.27 (d, J¼7.0,
1H), 7.20 (d, J¼8.0, 2H), 7.06 (d, J¼8.0, 2H), 4.72 (t, J¼6.0, 1H), 3.91
(ddd, J¼5.5, 7.3, 7.3, 1H), 3.67 (m, 1H), 3.64 (m, 1H), 2.82 (m, 1H),
2.71 (m, 1H), 2.67 (m, 1H), 2.42 (s, 3H), 1.92–1.80 (m, 3H), 1.75 (m,
1H), 1.61 (m, 1H), 1.38 (m, 1H); minor 7.67 (d, J¼8.0, 2H), 7.28 (d,
J¼8.0, 2H), 7.22 (d, J¼8.3, 2H), 6.98 (d, J¼8.3, 2H), 4.75 (t, J¼6.0, 1H),
3.87–3.81 (m, 2H), 3.76 (ddd, J¼6.0, 8.0, 8.0, 1H), 2.89 (m, 1H), 2.81
(m, 1H), 2.53 (ddd, J¼5.2, 8.8, 8.9, 1H), 2.43 (s, 3H), 2.09 (m, 1H),
1.82–1.72 (m, 3H), 1.58 (m, 1H), 1.30 (m, 1H). 13C NMR: major 143.4
(C), 139.4 (C), 136.8 (C), 132.5 (C), 130.0 (CH), 129.7 (CH), 128.5 (CH),
127.1 (CH), 82.0 (CH), 68.1 (CH2), 46.9 (CH), 41.1 (CH2), 32.5 (CH2),
29.2 (CH2), 25.6 (CH2), 21.4 (CH3); minor 143.3 (C), 140.3 (C), 136.9
(C), 132.5 (C), 129.6 (CH), 129.3 (CH), 128.8 (CH), 127.7 (CH), 82.7
(CH), 68.1 (CH2), 48.3 (CH), 41.3 (CH2), 33.3 (CH2), 30.4 (CH2), 25.4
(CH2), 21.4 (CH3). MS m/z: 395 (Mþ2), 393 (Mþ). Anal. Calcd for
4.3. General procedure of the reaction of
a,b-unsaturated N-tosyl imines 1
4.3.1. 4-Methyl-N-(3-phenyl-3-(tetrahydrofuran-2-yl)propyl)-
benzenesulfonamide (7a) and (E)-4-methyl-N-(3-phenyl-1-(tetra-
hydrofuran-2-yl)allyl)benzenesulfonamide (3a) (Table 1, entry 1)
THF (20.0 mL, 0.25 mol) and 1.0 M solution of Me2Zn in hexane
(6.0 mL, 6.0 mmol) were placed in a three-neck flask attached with
NaOH in a drying tube. THF solution (4.7 mL) of 1a (289 mg,
1.0 mmol) was added (0.78 mL/h) over 6 h to the stirred solution at
room temperature, while air was injected to the solution (0.5 mL/h)
using a syringe pump. After the addition of 1a, the mixture was
stirred for additional 0.5 h and quenched with methanol (20 mL),
and then NaBH4 (47 mg, 1.2 mmol) was added. After 15 min, the
whole was quenched with water (20 mL). The resulting aqueous
solution was extracted with EtOAc three times. The combined or-
ganic layers were washed with brine and dried over Na2SO4. Con-
centration and column chromatography (hexane/EtOAc¼2:1) gave
a 7:3 diastereomeric mixture of 7a (273.0 mg, 76%) as white solid of
mp 108–110 ꢁC and a 6:4 diastereomeric mixture of 3a (10.7 mg,
3%) as white solid of mp 85–88 ꢁC.
C
20H24O3NS: C, 60.98; H, 6.14; N, 3.56. Found: C, 60.79; H, 6.17; N,
3.57.
A 6:4 diastereomeric mixture of 3b. Mp 87–90. IR (neat): 3271,
2970, 2870, 1327, 1157, 1088. 1H NMR: 7.70–7.67 (m, 2H), 7.23–7.20
(m, 2H), 7.17–7.14 (m, 2H), 7.04 (d, J¼8.6, 0.8H), 7.01 (d, J¼8.2, 1.2H),
6.21 (d, J¼15.9, 0.4H), 6.18 (d, J¼15.9, 0.6H), 5.76 (dd, J¼15.9, 8.0,
0.6H), 5.74 (dd, J¼15.9, 8.3, 0.4H), 5.04 (br d, J¼7.7, 0.4H), 5.02 (br d,
J¼6.8, 0.6H), 3.99–3.93 (m, 0.8H), 3.91–3.76 (m, 2.2H), 3.75–3.70
(m, 1H), 2.30 (s, 1.8H), 2.29 (s, 1.2H), 1.94–1.64 (m, 4H). 13C NMR:
major 143.25 (C), 138.03 (C), 134.7 (C), 133.4 (C), 131.4 (CH), 129.45
(CH), 128.5 (CH), 127.6 (CH), 127.40 (CH), 125.3 (CH), 80.6 (CH),
68.77 (CH2), 59.2 (CH), 28.0 (CH2), 25.7 (CH2), 21.3 (CH3); minor
143.26 (C), 138.02 (C), 134.7 (C), 133.4 (C), 132.5 (CH), 129.48 (CH),
128.57 (CH), 127.6 (CH), 127.36 (CH), 125.3 (CH), 80.9 (CH), 68.83
A 7:3 diastereomeric mixture of 7a. IR (neat): 3279, 1320, 1150,
1072. 1H NMR: major 7.65 (d, J¼7.0, 2H), 7.20–7.29 (m, 5H), 7.13 (d,
J¼7.0, 2H), 1.64 (m, 1H), 4.44 (t, 6.0, 1H), 1.76 (m, 1H), 3.95 (ddd,

K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
7263
(CH2), 59.5 (CH), 29.2 (CH2), 27.3 (CH2), 21.3 (CH3). FABMS m/z: 392
(Mþ2ꢀH), 390 (MꢀH). FABMS m/z: 390.0936 (calcd for
1H), 4.99 (br d, J¼6, 1H), 4.01–3.69 (m, 4H), 2.32 (s, 1.2H), 2.31 (s,
1.8H), 2.29 (s, 1.8H), 2.28 (s, 1.2H), 1.94–1.68 (m, 4H). 13C NMR:
major 143.2 (C), 138.0 (C), 137.6 (C), 133.4 (C), 132.6 (CH), 129.42
(CH), 129.0 (CH), 127.43 (CH), 126.4 (CH), 125.5 (CH), 80.7 (CH), 68.7
(CH2), 59.5 (CH), 28.0 (CH2), 25.7 (CH2), 21.1 (CH3), 14.1 (CH3); mi-
nor 143.1 (C), 138.0 (C), 137.6 (C), 133.7 (CH), 133.4 (C), 129.43 (CH),
129.1 (CH),127.39 (CH), 126.4 (CH), 123.3 (CH), 81.1 (CH), 68.8 (CH2),
59.7 (CH), 27.2 (CH2), 25.7 (CH2), 21.3 (CH3), 14.1 (CH3). FABMS m/z:
370 (MꢀH). FABMS m/z: 370.1472 (calcd for C21H24O3NS: 370.1482).
C
20H21O3ClNS: 390.0936).
4.3.3. N-(3-(4-Methoxyphenyl)-3-(tetrahydrofuran-2-yl)propyl)-4-
methylbenzenesulfonamide (7c) and (E)-4-methyl-N-[1-
(tetrahydrofuran-2-yl)-3-(4-methoxyphenyl)allyl]-
benzenesulfonamide (3c) (entry 3)
The general procedure gave a 7:3 diastereomeric mixture of 7c
(229.6 mg, 59%) as white solid and 6:4 diastereomeric mixture of 3c
(16.3 mg, 4%) as pale-yellow oil.
4.3.5. 4-Methyl-N-[3-(tetrahydrofuran-2-yl)-3-(2-tolyl)propyl]-
benzenesulfonamide (7e) and (E)-4-methyl-N-[1-(tetrahydrofuran-
2-yl)-3-(2-tolyl)allyl]benzenesulfonamide (3e) (entry 5)
The general procedure gave 7e (224.1 mg, 60%) and 3e (26.0 mg,
7%) as colorless oil.
A 7:3 diastereomeric mixture of 7c. Mp 94–96 ꢁC. IR (KBr): 3279,
1612, 1512, 1327, 1250, 1157, 1065. 1H NMR: 7.67–7.64 (m, 2H), 7.28–
7.26 (m, 2H), 7.05–7.03 (m,1.4H), 6.96–6.94 (m, 0.6H), 6.81–6.78 (m,
2H), 4.74–4.73 (t, 0.3H), 4.42–4.40 (t, 0.7H), 3.93–3.89 (m, 0.7H),
3.87–3.81 (m, 0.6H), 3.77–3.75 (m, 0.3H), 3.78 (s, 3H), 3.72–3.63 (m,
1.4H), 2.94–2.74 (m, 2H), 2.65–2.61 (m, 0.7H), 2.47–2.44 (m, 0.3H),
2.42 (s, 3H), 2.11–2.04 (m, 0.3H), 1.93–1.70 (m, 3.7H), 1.68–1.60 (m,
1H), 1.48–1.39 (m, 0.7H), 1.34–1.25 (m, 0.3H). 13C NMR: major 158.2
(C),143.2 (C),136.9 (C),132.8 (C),129.6 (CH),129.47 (CH),127.0 (CH),
113.7 (CH), 82.3 (CH), 68.0 (CH2), 55.0 (CH3), 46.7 (CH), 41.3 (CH2),
32.3 (CH2), 29.0 (CH2), 25.6 (CH2), 21.3 (CH3); minor 158.3 (C), 143.1
(C), 137.0 (C), 133.8 (C), 129.52 (CH), 128.8 (CH), 127.0 (CH), 113.9
(CH), 83.1 (CH), 68.0 (CH2), 55.0 (CH3), 48.1 (CH), 41.5 (CH2), 33.4
(CH2), 30.4 (CH2), 25.3 (CH2), 21.3 (CH3). MS m/z: 389 (Mþ). Anal.
Calcd for C21H27O4NS: C, 64.75; H, 6.99; N, 3.60. Found: C, 64.68; H,
6.95; N, 3.60.
A 7:3 diastereomeric mixture of 7e. IR (neat): 3279, 2947, 1327,
1157, 1065. 1H NMR: 7.67–7.64 (m, 2H), 7.28–7.25 (m, 2H), 7.17 (d,
J¼7.3, 0.7H), 7.14–7.07 (m, 3H), 6.99 (d, J¼7.0, 0.3H), 4.99 (br s,
0.3H), 4.67 (br t, J¼6, 0.7H), 3.95–3.86 (m, 1.3H), 3.77 (m, 0.3H),
3.72–3.64 (m, 1.4H), 3.07 (m, 0.7H), 2.90–2.85 (m, 0.6H), 2.83–2.76
(m, 1.7H), 2.42 (s, 0.9H), 2.41 (s, 2.1H), 2.25 (s, 3H), 2.07 (m, 0.3H),
1.97–1.70 (m, 4.4H), 1.62–1.58 (m, 0.3H), 1.42 (m, 0.7H), 1.24 (m,
0.3H). 13C NMR: major 143.2 (C), 139.4 (C), 136.8 (C), 136.7 (C), 130.3
(CH), 129.6 (CH), 127.0 (CH), 126.31 (CH), 126.2 (CH), 82.2 (CH), 67.9
(CH2), 41.6 (CH and CH2 overlapping), 31.7 (CH2), 28.7 (CH2), 25.8
(CH2), 21.4 (CH3), 20.0 (CH3); minor 143.1 (C), 140.7 (C), 136.93 (C),
136.91 (C), 130.6 (CH), 129.55 (CH), 126.8 (CH), 126.4 (CH), 126.27
(CH), 82.2 (CH), 68.1 (CH2), 41.8 (CH2), 41.7 (CH), 30.8 (CH2), 30.3
(CH2), 25.4 (CH2), 21.4 (CH3), 20.1 (CH3). MS m/z: 374 (Mþ). FABMS
m/z: 373.1707 (calcd for C21H27O3NS: 373.1712).
A 6:4 diastereomeric mixture of 3e. IR (neat): 3271, 2970, 1443,
1327, 1157, 1065. 1H NMR: 7.73–7.70 (m, 2H), 7.19–7.01 (m, 6H), 6.50
(d, J¼15.9, 0.6H), 6.49 (d, J¼15.9, 0.4H), 5.70 (dd, J¼8.0, 15.9, 0.6H),
5.65 (dd, J¼8.3, 15.9, 0.4H), 5.10–5.07 (m, 1H), 4.03–3.96 (m, 0.8H),
3.93–3.70 (m, 3.2H), 2.305 (s, 1.8H), 2.297 (s, 1.2H), 2.22 (s, 1.2H),
2.20 (s, 1.8H), 1.96–1.80 (m, 3.6H), 1.73 (m, 0.4H). 13C NMR: major
143.2 (C), 138.0 (C), 135.29 (C), 135.25 (C), 130.5 (CH), 130.09 (CH),
129.5 (CH), 128.0 (CH), 127.65 (CH), 127.35 (CH), 125.9 (CH), 125.7
(CH), 80.8 (CH), 68.7 (CH2), 59.7 (CH), 28.0 (CH2), 25.7 (CH2), 21.3
(CH3), 19.5 (CH3); minor 143.20 (C), 138.0 (C), 135.30 (C), 135.29 (C),
131.6 (CH), 130.1 (CH), 129.5 (CH), 128.0 (CH), 127.7 (CH), 127.31
(CH), 125.8 (CH), 125.7 (CH), 81.2 (CH), 68.8 (CH2), 59.7 (CH), 27.1
(CH2), 25.7 (CH2), 21.3 (CH3), 19.6 (CH3). MS m/z: 371 (Mþ). Anal.
Calcd for C21H25O3NS: C, 67.89; H, 6.78; N, 3.77. Found: C, 67.62; H,
6.82; N, 3.48.
A 6:4 diastereomeric mixture of 3c. IR (neat): 3279, 2939, 2862,
1604, 1512, 1327, 1157, 1096. 1H NMR: 7.69 (d, J¼8.6, 1.2H), 7.68 (d,
J¼8.6, 0.8H), 7.15 (d, J¼8.6, 1.2H), 7.14 (d, J¼8.6, 0.8H), 7.05 (d, J¼8.6,
0.8H), 7.02 (d, J¼8.6,1.2H), 6.79 (d, J¼8.6, 0.8H), 6.77 (d, J¼8.6,1.2H),
6.18 (d, J¼15.9, 0.4H), 6.17 (d, J¼15.9, 0.6H), 5.62 (dd, J¼7.9, 15.9,
0.6H), 5.61 (dd, J¼8.6, 15.9, 0.4H), 5.03–5.01 (m, 1H), 4.00–3.69 (m,
4H), 3.80 (s, 1.2H), 3.79 (s, 1.8H), 2.30 (s, 1.8H), 2.29 (s, 1.2H), 1.95–
1.67 (m, 4H). 13C NMR: major 159.38 (C), 143.13 (C), 138.2 (C), 132.3
(CH), 129.40 (CH), 129.01 (C), 127.7 (CH), 127.47 (CH), 124.3 (CH),
113.8 (CH), 80.8 (CH), 68.7 (CH2), 59.6 (CH), 55.2 (CH3), 28.0 (CH2),
25.7 (CH2), 21.3 (CH3); minor 159.44 (C), 143.10 (C), 138.2 (C), 132.3
(CH), 129.42 (CH), 129.04 (C), 127.7 (CH), 127.4 (CH), 122.2 (CH),
113.8 (CH), 31.2 (CH), 68.8 (CH2), 59.7 (CH), 55.26 (CH2), 27.3 (CH2),
25.7 (CH2), 21.3 (CH3). FABMS m/z: 386 (MꢀH). FABMS m/z:
386.1429 (calcd for C21H24O4NS: 386.1426).
4.3.4. 4-Methyl-N-[3-(tetrahydrofuran-2-yl)-3-(4-tolyl)propyl]-
benzenesulfonamide (7d) and (E)-4-methyl-N-[1-(tetrahydrofuran-
2-yl)-3-(4-tolyl)allyl]benzenesulfonamide (3d) (entry 4)
The general procedure gave 7d (261.4 mg, 70%) as white solid
and 3d (18.6 mg, 5%) as colorless oil.
4.3.6. 4-Methyl-N-[3-(naphthalen-2-yl)-3-(tetrahydrofuran-2-
yl)propyl]benzenesulfonamide (7f) and (E)-4-methyl-N-[3-
(naphthalen-2-yl)-1-(tetrahydrofuran-2-yl)allyl]-
A 7:3 diastereomeric mixture of 7d. Mp 80–81 ꢁC. IR (KBr): 3279,
2970, 2862, 1319, 1150, 1072. 1H NMR: 7.67–7.64 (m, 2H), 7.29–7.26
(m, 2H), 7.06 (d, J¼8.0, 2H), 7.01 (d, J¼8.0,1.4H), 6.91 (d, J¼8.0, 0.6H),
4.75 (br t, J¼6, 0.3H), 4.41 (br t, J¼6, 0.7H), 3.92 (m, 0.7H), 3.88–3.82
(m, 0.6H), 3.76 (m, 0.3H), 3.73–3.63 (m, 1.4H), 2.93–2.74 (m, 2.3H),
2.63 (m, 0.7H), 2.43 (s, 0.9H), 2.42 (s, 2.1H), 2.312 (s, 0.9H), 2.306 (s,
2.1H), 2.8 (m, 0.3H),1.93–1.71 (m, 4H),1.65 (m, 0.7H),1.44 (m, 0.7H),
1.31 (m, 0.3H). 13C NMR: major 143.2 (C), 137.8 (C), 136.9 (C), 136.2
(C), 129.59 (CH), 129.1 (CH), 128.4 (CH), 127.07 (CH), 82.4 (CH), 68.0
(CH2), 47.3 (CH), 41.4 (CH2), 32.2 (CH2), 29.0 (CH2), 25.6 (CH2), 21.4
(CH3), 20.9 (CH3); minor 143.2 (C), 138.8 (C), 137.1 (C), 136.3 (C),
129.55 (CH), 129.3 (CH), 127.8 (CH), 127.08 (CH), 83.0 (CH), 68.0
(CH2), 48.8 (CH), 41.6 (CH2), 33.5 (CH2), 30.5 (CH2), 25.4 (CH2), 21.4
(CH3), 20.9 (CH3). MS m/z: 373 (Mþ). Anal. Calcd for C21H27O3NS: C,
67.53; H, 7.29; N, 3.75. Found: C, 67.36; H, 7.36; N, 3.73.
benzenesulfonamide (3f) (entry 6)
The same procedure except for the addition of 1f as a THF so-
lution (9.4 mL, 1.57 mL/h) gave 7f (225.2 mg, 51%) and 3f (24.4 mg,
6%) as white solid.
A 7:3diastereomeric mixture of 7f. IR (neat): 3279, 2947,1327,1157,
1072. 1H NMR: 7.81–7.76 (m, 1H), 7.75–7.72 (m, 2H), 7.63–7.59 (m,
2H), 7.56 (s, 0.7H), 7.49 (s, 0.3H), 7.47–7.40 (m, 2H), 7.31–7.28 (m,1H),
7.19 (d, J¼8.2, 0.6H), 7.16 (d, J¼8.3, 1.4H), 4.98 (m, 0.3H), 4.75 (m,
0.7H), 4.05–3.97 (m, 1H), 3.85 (m, 0.3H), 3.77 (m, 0.3H), 3.72–3.63
(m,1.4H), 2.94–2.79 (m, 2H), 2.77–2.66 (m,1H), 2.38 (s, 0.9H), 2.35 (s,
2.1H), 2.22–2.17 (m, 0.3H), 2.01–1.97 (m, 1.4H), 1.92–1.85 (m, 1H),
1.80–1.71 (m, 1.3H), 1.65–1.52 (m, 1H), 1.47 (m, 0.7H), 1.37 (m, 0.3H).
13C NMR: major 143.2 (C), 138.4 (C), 136.7 (C), 133.36 (C), 132.51 (C),
129.6 (CH), 128.1 (CH), 127.69 (CH), 127.65 (CH), 127.56 (CH), 127.0
(CH), 126.5 (CH), 125.92 (CH), 125.5 (CH), 82.3 (CH), 68.1 (CH2), 47.7
(CH), 41.3 (CH2), 32.3 (CH2), 29.2 (CH2), 25.6 (CH2), 21.4 (CH3); minor
143.1 (C),139.3 (C),136.7 (C),133.42 (C),132.46 (C),129.6 (CH),128.4
A 6:4 diastereomeric mixture of 3d. IR (neat): 3279, 2924, 1327,
1157, 1065. 1H NMR: 7.70–7.67 (m, 2H), 7.17–7.14 (m, 2H), 7.07–6.97
(m, 4H), 6.20 (d, J¼15.9, 0.4H), 6.18 (d, J¼15.9, 0.6H), 5.74–5.67 (m,

7264
K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
(CH), 127.63 (CH), 127.1 (CH), 126.9 (CH), 126.1 (CH), 125.87 (CH),
125.6 (CH), 82.9 (CH), 68.1 (CH2), 49.2 (CH), 41.6 (CH2), 33.4 (CH2),
30.6 (CH2), 25.4 (CH2), 21.4 (CH3). MS m/z: 409 (Mþ). FABMS m/z:
409.1718 (calcd for C24H27O3NS: 409.1712).
bath was added DMSO (0.06 mL, 0.9 mmol) and the mixture was
stirred for 2 min at the same temperature. To the mixture was
added a solution of (RS,SR)-alcohol 2a (44.5 mg, 0.216 mmol) in
CH2Cl2 (0.2 mLþ0.1 mL washing twice) at the same temperature,
and the whole was stirred for 15 min at the same temperature
before the addition of Et3N (0.15 mL, 1.1 mmol) at the same tem-
perature. After stirring for 5 min, the cooling bath was removed to
allow the reaction mixture warm up to room temperature. After
4.5 h, water was added to the mixture and the whole was
extracted with CHCl3 three times. The combined organic layers
were washed with water and brine, dried over Na2SO4, and con-
centrated to give pale-yellow oil (49.5 mg) including mainly
(RS,SR)-3-phenyl-3-tetrahydrofuran-2-yl-propanal. 1H NMR: 1.53
(m, 1H), 1.66 (m, 1H), 1.72–1.83 (m, 2H), 2.82 (ddd, J¼1.7, 7.5, 16.6,
1H), 2.89 (ddd, J¼2.3, 6.9, 16.6, 1H), 3.48 (ddd, J¼4.6, 7.5, 7.5, 1H),
3.68–3.71 (m, 2H), 4.11 (m, 1H), 7.21–7.26 (m, 3H), 7.29–7.31 (m,
2H), 9.67 (dd, J¼1.7, 2.3, 1H). 13C NMR: 25.8 (CH2), 28.2 (CH2), 43.8
(CH), 45.6 (CH2), 68.1 (CH2), 81.9 (CH), 126.9 (CH), 128.4 (CH), 128.5
(CH), 140.3 (C), 201.2 (CH). IR (neat): 2970, 2870, 2723, 1960, 1720,
1489, 1450, 1381, 1180, 1057, 934, 764, 702, 532. EIMS m/z: 204
(Mþ), 160 (MꢀCH2CHOH), 71 (C4H7O). The crude aldehyde
(49.5 mg) was placed in a 10 mL round-bottom flask cooled in an
ice–water bath, to which was added a 2 M solution of 2-methyl-
but-2-ene in THF (2.2 mL, 4.4 mmol), and then a mixture of
NaH2PO4 and NaClO2 in water (2.7 M each, 0.80 mL, 2.2 mmol
each). The cooling bath was removed and the mixture was stirred
for 1 h before addition of 5% HCl. The whole was extracted with
CHCl3 five times. The combined organic layers were extracted with
10% NaOH five times and the combined aqueous layers were
washed with CHCl3. The basic extract was acidified by addition of
concd HCl and extracted with CHCl3 five times. The combined
organic layers were dried over MgSO4 and concentrated to give
colorless oil (44.9 mg) including mainly (RS,SR)-3-phenyl-3-tetra-
hydrofuran-2-yl-propanoic acid. 1H NMR: 1.43–1.62 (m, 2H), 1.70–
1.88 (m, 2H), 2.76 (dd, J¼8.5, 16.0, 1H), 2.89 (dd, J¼6.4, 16.0, 1H),
3.79 (m, 1H), 3.70 (t, J¼6.7, 2H), 4.11 (m, 1H), 7.19–7.29 (m, 5H),
10.4 (br s, 1H). 13C NMR: 25.7 (CH2), 28.6 (CH2), 36.9 (CH2), 45.6
(CH), 68.3 (CH2), 81.6 (CH), 126.9 (CH), 128.3 (CH), 128.7 (CH),
140.3 (C), 178.1 (CH). IR (neat): 3032, 2978, 2878, 2684, 1713, 1450,
1412, 1265, 1165, 1072, 918, 733, 710, 617. EIMS m/z: 220 (Mþ), 203
(MꢀOH), 160 (MꢀCH2C(OH)2), 71 (C4H7O). The crude carboxylic
acid (44.9 mg) was stirred with oxalyl chloride (0.17 mL, 2.0 mmol)
for 30 min and the mixture was concentrated under reduced
pressure to give pale-yellow oil (46.7 mg) including mainly
(RS,SR)-3-phenyl-3-tetrahydrofuran-2-yl-propanoyl chloride. 1H
NMR: 1.48 (m, 1H), 1.56 (m, 1H), 1.75 (m, 1H), 1.84 (m, 1H), 3.34
(dd, J¼6.6, 13.9, 1H), 3.40 (m, 1H), 3.44 (dd, J¼5.2, 13.9, 1H), 3.68–
3.75 (m, 2H), 4.12 (ddd, J¼4.0, 6.9, 7.4, 1H), 7.24–7.28 (m, 3H), 7.3
(m, 2H). EIMS m/z: 240 (Mþ2), 238 (Mþ), 203 (MꢀCl), 71 (C4H7O).
The crude chloride (46.7 mg) was dissolved in benzene (2 mL) and
cooled in an ice–water bath. To the solution was added AlCl3
(41 mg, 0.31 mmol) and the cooling bath was removed to allow
the reaction mixture warm up to room temperature. The mixture
was stirred for 3 h at the same temperature and then 10% HCl was
added. The whole was extracted with CHCl3 five times, and the
combined organic layers were dried over MgSO4 and concentrated
to give pale-purple oil (43.1 mg). Purification of the crude material
by column chromatography (hexane/EtOAc¼4:1) gave the titled
chloro lactone 12 (19.3 mg, 40% over four steps) as colorless oil. 1H
NMR: 1.30–1.43 (m, 2H), 1.76 (m, 1H), 1.94 (m, 1H), 2.79 (dd, J¼4.9,
17.5, 1H), 2.89 (dd, J¼8.6, 17.5, 1H), 3.42 (ddd, J¼5.8, 7.3, 11.0, 1H),
3.49 (ddd, J¼5.8, 6.9, 11.0, 1H), 3.76 (ddd, J¼4.9, 6.4, 8.6, 1H), 4.74
A 6:4 diastereomeric mixture of 3f. IR (neat): 3279, 3055, 1327,
1157, 1065. 1H NMR: 7.80–7.68 (m, 3H), 7.49–7.43 (m, 3H), 7.29–7.24
(m, 2H), 7.18–7.11 (m, 3H), 6.41–6.36 (m, 1H), 5.91–5.83 (m, 1H),
5.04 (d, J¼6.1, 1H), 4.06–4.00 (m, 1H), 3.96–3.91 (m, 1H), 3.88–3.72
(m, 2H), 2.21 (s, 1.5H), 2.19 (s, 1.5H), 1.97–1.81 (m, 3H), 1.77–1.70 (m,
1H); 13C NMR: major 143.23 (C), 138.0 (C), 133.6 (C), 133.4 (C),
133.05 (C), 132.8 (CH), 129.47 (CH), 127.95 (CH), 127.7 (CH), 127.4
(CH), 127.0 (CH), 126.50 (CH), 126.3 (CH), 126.1 (CH), 124.8 (CH),
123.50 (CH), 80.8 (CH), 68.9 (CH2), 59.5 (CH), 28.0 (CH2), 25.7 (CH2),
21.26 (CH3); minor 143.26 (C), 138.1 (C), 133.9 (CH), 133.6 (C), 133.4
(C),133.04 (C),129.46 (CH),128.00 (CH),127.7 (CH),127.5 (CH),127.0
(CH), 126.51 (CH), 126.4 (CH), 126.0 (CH), 124.8 (CH), 123.47 (CH),
81.1 (CH), 68.8 (CH2), 59.7 (CH), 27.3 (CH2), 25.7 (CH2), 21.24 (CH3).
FABMS m/z: 406 (MþH). FABMS m/z: 406.1483 (calcd for
C
24H24O3NS: 406.1482).
4.3.7. 4-Methyl-N-[3-phenyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-
2-yl)propyl]benzenesulfonamide (8) and (E)-4-methyl-N-[3-phenyl-
1-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)allyl]benzenesulfonamide
(9) (Scheme 2)
The general procedure except for the use of 4,4,5,5-tetramethyl-
1,3-dioxolane (36.5 mL, 0.25 mol) and 1a (1.0 mmol, 0.45 mL/h) in
4.5 mL of benzene gave 8 (62.6 mg, 15%) as a white solid and 9
(8.3 mg, 2%) as a white solid by column chromatography (toluene/
Et2O¼19:1).
Compound 8: mp 107–110 ꢁC. IR (KBr): 3279, 2978, 1435, 1327,
1157. 1H NMR: 7.66 (d, J¼8.3, 2H), 7.27–7.19 (m, 5H), 7.09 (d, J¼7.4,
2H), 5.03 (d, J¼5.5, 1H), 4.48 (br s, 1H), 2.94–2.81 (m, 2H), 2.68 (ddd,
J¼4.9, 5.5, 9.8, 1H), 2.42 (s, 3H), 2.02 (m, 1H), 1.81 (m, 1H), 1.15 (s,
3H), 1.11 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H); 13C NMR: 143.2 (C), 139.7
(C), 137.0 (C), 129.6 (CH), 128.8 (CH), 128.4 (CH), 127.1 (CH), 126.9
(CH), 102.6 (CH), 82.1 (C), 81.8 (C), 48.8 (CH), 41.5 (CH2), 30.6 (CH2),
24.06 (CH3), 24.02 (CH3), 22.2 (CH3), 22.0 (CH3), 21.4 (CH3). FABMS
m/z: 416 (MꢀH). FABMS m/z: 416.1889 (calcd for C23H30O4NS:
416.1901).
Compound 9: mp 120–122 ꢁC. IR (KBr): 3302, 2978, 1412, 1327,
1157. 1H NMR: 7.73 (d, J¼8.3, 2H), 7.27–7.16 (m, 7H), 6.36 (d, J¼15.9,
1H), 5.86 (dd, J¼7.4, 15.9, 1H), 4.99 (d, J¼3.4, 1H), 4.84 (d, J¼7.6, 1H),
4.03 (m, 1H), 2.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H), 1.11 (s, 6H). 13
C
NMR: 143.2 (C), 138.1 (C), 136.3 (C), 133.6 (CH), 129.4 (CH), 128.4
(CH), 127.8 (CH), 127.5 (CH), 126.5 (CH), 124.3 (CH), 100.2 (CH), 82.9
(C), 82.6 (C), 58.7 (CH), 24.2 (CH3), 24.1 (CH3), 22.2 (CH3), 22.1 (CH3),
21.3 (CH3). MS m/z: 415 (Mþ). Anal. Calcd for C23H29O4NS: C, 66.48;
H, 7.03; N, 3.37. Found: C, 66.42; H, 7.21; N, 3.09.
4.3.8. 4-Methyl-N-(3-phenylpentyl)benzenesulfonamide (10)
(Scheme 4)
The same procedure except for the use of diethylzinc instead of
dimethylzinc gave 7a (235 mg, 65%), 3a (13.9 mg, 3%), and 10
(36.9 mg, 12%) as pale-yellow oil. Compound 10: IR (neat): 3279,
2924, 1327, 1157. 1H NMR: 7.65–7.64 (d, J¼8.2, 2H), 7.27–7.17 (m,
5H), 7.04–7.03 (m, 2H), 4.22 (br s, 1H), 2.84–2.74 (m, 2H), 2.44–2.31
(m, 1H), 2.42 (s, 3H), 1.87–1.81 (m, 1H), 1.72–1.64 (m, 1H), 1.63 (m,
2H), 0.73–0.70 (t, J¼7.3, 3H). 13C NMR: 144.0 (Cꢂ2), 143.3 (C), 129.6
(CH), 128.6 (CH), 127.6 (CH), 127.1 (CH), 126.4 (CH), 45.0 (CH), 41.5
(CH2), 36.1 (CH2), 29.6 (CH2), 21.4 (CH3), 11.9 (CH3). FABMS m/z: 318
(MþH). FABMS m/z: 318.1533 (calcd for C18H24O2NS: 318.1528).
4.3.9. (RS,SR)-5-(3-Chloropropyl)-4-phenyldihydrofuran-2(3H)-
one (12) (Scheme 5)
To a solution of oxalyl chloride (0.04 mL, 0.4 mmol) in CH2Cl2
(1 mL) in a 10 mL round-bottom flask cooled in a dry ice–ethanol
(ddd, J¼3.8, 6.4, 10.0, 1H), 7.15 (d, J¼7.1, 2H), 7.29–7.38 (m, 3H). 13
C
NMR: 28.6 (CH2), 29.0 (CH2), 35.6 (CH2), 44.2 (CH2), 44.4 (CH), 83.2
(CH), 127.75 (CH), 127.82 (CH), 129.0 (CH), 137.7 (C), 176.5 (CH). IR
(neat): 2955, 1774, 1450, 1412, 1180, 756, 702. EIMS m/z: 240

K. Yamada et al. / Tetrahedron 64 (2008) 7258–7265
7265
(Mþ2), 238 (Mþ), 149, 104. FABMS m/z: 239.0831 (calcd for
5. Yamamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004, 45, 795–797.
6. Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.; Tomioka, K. Tetrahedron
2005, 61, 379–384.
C
13H16ClO2: 239.0839).
7. Yamada, K.; Yamamoto, Y.; Maekawa, M.; Chen, J.; Tomioka, K. Tetrahedron Lett.
2004, 45, 6595–6597.
4.3.10. (RS,SR)-4-Phenyl-5-propyldihydrofuran-2(3H)-one (13)
(Scheme 5)
8. (a) Lewinski, J.; Marciniak, W.; Lipkowski, J.; Justyniak, I. J. Am. Chem. Soc.
2003, 125, 12698–12699; (b) Lewinski, J.; Sliwinski, W.; Dranka, M.; Justyniak,
I.; Lipkowski, J. Angew. Chem., Int. Ed. 2006, 45, 4826–4829; (c) Jana, S.;
Berger, R. J. F.; Fro¨hlich, R.; Pape, T.; Mitzel, N. W. Inorg. Chem. 2007, 46,
4293–4297.
9. McMillen, D. F.; Golden, D. M. Annu. Rev. Phys. Chem. 1982, 33, 493–532.
10. Review: Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377–10441.
11. (a) Jacobs, R. L.; Ecke, G. G. J. Org. Chem. 1963, 28, 3036–3038; (b) Muramatsu,
H.; Inukai, K.; Ueda, T. J. Org. Chem. 1964, 29, 2220–2223; (c) Fraser-Reid, B.;
Anderson, R. C.; Hicks, D. R.; Walker, D. L. Can. J. Chem. 1977, 55, 3986–3995; (d)
Gevorgyan, V.; Priede, E.; Liepins, E.; Gavars, M.; Lukevics, E. J. Organomet. Chem.
1990, 393, 333–338; (e) Fontana, F.; Minisci, F.; Yan, Y. M.; Zhao, L. Tetrahedron
Lett. 1993, 34, 2517–2520; (f) Clark, A. J.; Rooke, S.; Sparey, T. J.; Taylor, P. C.
Tetrahedron Lett. 1996, 37, 909–912; (g) Gong, J.; Fuchs, P. L. J. Am. Chem. Soc.
1996, 118, 4486–4487; (h) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118,
Chloro lactone 12 (17.8 mg, 74.6 mmol) was placed in a 10 mL
round-bottom flask and dissolved in dry acetone (0.4 mL). To the
solution was added NaI (56 mg, 0.37 mmol) and the mixture was
stirred for 36 h at 50 ꢁC. To the mixture cooled to room temperature
was added 10% Na2S2O3. The mixture was extracted with CHCl3
three times, and the combined organic layers were dried over
Na2SO4 and concentrated to give pale-yellow oil (17.6 mg). Purifi-
cation of the crude material by column chromatography (hexane/
EtOAc¼4:1) gave pale-yellow oil (17.1 mg) including chloro lactone
12 and iodo lactone in a ratio of 3:7 (23% and 53%, respectively). 1H
NMR (iodo lactone): 1.30–1.36 (m, 2H), 1.81 (m, 1H), 1.96 (m, 1H),
2.79 (dd, J¼5.1, 17.6, 1H), 2.99 (dd, J¼8.7, 17.6, 1H), 3.06 (ddd, J¼6.9,
6.9, 9.8, 1H), 3.49 (ddd, J¼6.9, 6.9, 9.8, 1H), 3.76 (m, 1H), 4.73 (ddd,
´
´
¨
11986–11987; (i) Peleta, O.; Cırkva, V.; Buskova, Z.; Bohm, S. J. Fluorine Chem.
1997, 86, 155–171; (j) Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc.
1997, 119, 4123–4129; (k) Xiang, J.; Jiang, W.; Fuchs, P. L. Tetrahedron Lett. 1997,
38, 6635–6638; (l) Xiang, J.; Evarts, J.; Rivkin, A.; Curran, D. P.; Fuchs, P. L.
Tetrahedron Lett. 1998, 39, 4163–4166; (m) Kim, S.; Kim, N.; Chung, W.-J.; Cho,
C. H. Synlett 2001, 937–940; (n) Jang, Y.-J.; Shih, Y.-K.; Liu, J.-Y.; Kuo, W.-Y.; Yao,
C.-F. Chem.dEur. J. 2003, 9, 2123–2128; (o) Oka, R.; Nakayama, M.; Sakaguchi,
S.; Ishii, Y. Chem. Lett. 2006, 35, 1104–1105; (p) Bagal, S. K.; Tournier, L.; Zard, S.
Z. Synlett 2006, 1485–1490; (q) Geraghty, N. W. A.; Lally, A. Chem. Commun.
2006, 4300–4302; (r) Ferna´ndez, M.; Alonso, R. Org. Lett. 2005, 7, 11–14.
12. (a) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron Lett. 1998, 39, 631–
634; (b) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T. Tetrahedron
1998, 54, 11431–11444.
J¼6.4, 6.4, 7.7, 1H), 7.14 (d, J¼8.0, 2H), 7.31 (m, 1H), 7.37 (m, 2H). 13
C
NMR (iodo lactone): 5.5 (CH2), 29.7 (CH2), 32.1 (CH2), 35.5 (CH2),
44.4 (CH), 82.8 (CH), 127.75 (CH), 127.83 (CH), 129.0 (CH), 137.7 (C),
176.5 (CH). The mixture was dissolved in benzene (0.1 mL). To the
solution at room temperature were added Bu3SnH (0.10 mL,
0.38 mmol) and then a 1.0 M solution of Et3B in hexane (0.01 mL,
0.01 mmol). The mixture was stirred for 1 h at the same tempera-
ture and concentrated. The resulting residue was dissolved in EtOAc
(2 mL), and KF (0.1 g) and satd. KF (0.2 mL) were added. The whole
was vigorously stirred for 2.5 h and filtered through Celite pad. The
filtrate was concentrated and purified by column chromatography
(hexane/EtOAc¼4:1) to give the titled lactone 13 (7.4 mg, 49% over
two steps) as pale-yellow oil along with the recovered 12 (3.7 mg,
21%) as pale-yellow oil. The spectroscopic data of 13 were in good
agreement with those reported.21 1H NMR: 0.82 (t, J¼7.2, 3H), 1.11
(m, 1H), 1.24–1.32 (m, 2H), 1.46 (m, 1H), 2.78 (dd, J¼4.9, 11.2, 1H),
2.96 (dd, J¼8.6, 11.2, 1H), 3.73 (ddd, J¼4.9, 6.3, 8.6, 1H), 4.72 (ddd,
J¼4.1, 6.3, 9.5, 1H), 7.15 (d, J¼7.0, 2H), 7.30 (t, J¼7.0, 1H), 7.35 (dd,
J¼7.0, 7.0, 2H). 13C NMR: 13.6 (CH3), 19.1 (CH2), 33.2 (CH2), 35.7
(CH2), 44.6 (CH), 84.0 (CH), 127.6 (CH), 127.8 (CH), 128.8 (CH), 138.1
(C), 176.9 (C). IR (neat): 3963, 1774, 1180, 957, 748, 702. EIMS m/z:
205 (Mþ1), 204 (Mþ).
13. The MMFF conformer distributions were calculated using Spartan ’06:
Wavefunction, Inc., Irvine, CA. Coupling constants of the adjacent methines of
the conformers were calculated by a modified Karplus equation, J¼5.25ꢀ
0.5cos
4
þ5.25cos 2
4. The calculated coupling constants shown here are
weight-average of those of the conformers based on Boltzmann distribution at
27 ꢁC.
14. Willy, W. E.; Binsch, G.; Eliel, E. L. J. Am. Chem. Soc. 1970, 92, 5394–5402.
15. Reviews: (a) Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P. Tetra-
hedron 2007, 63, 77–85; (b) Bazin, S.; Feray, L.; Bertrand, M. P. Chimia 2006, 60,
260–265.
16. (a) Miyano, S.; Hashimoto, H. J. Chem. Soc., Chem. Commun. 1971, 1418–1419; (b)
Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998, 39, 6335–
6336; (c) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148–
1150; (d) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999,
64, 9189–9193; (e) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T.
J. Org. Chem. 2000, 65, 176–185; (f) Miyabe, H.; Konishi, C.; Naito, T. Org. Lett.
2000, 2, 1443–1445; (g) Feringa, B. L.; Kellog, R. M.; van der Deen, H. Org. Lett.
2000, 2, 1593–1595; (h) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.;
Perfetti, P. Tetrahedron 2000, 56, 3951–3961; (i) Bazin, S.; Feray, L.; Siri, D.;
Naubron, J.-V.; Bertrand, M. P. Chem. Commun. 2002, 2506–2507; (j) Denes, F.;
Chemla, F.; Normant, J. F. Angew. Chem., Int. Ed. 2003, 42, 4043–4046; (k)
Miyabe, H.; Asada, R.; Yoshida, K.; Takemoto, Y. Synlett 2004, 540–542; (l)
Miyabe, H.; Asada, R.; Takemoto, Y. Tetrahedron 2005, 61, 385–393; (m) Bazin,
S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. Tetrahedron 2005, 61, 4261–4274; (n)
Denes, F.; Cutri, S.; Perez-Luna, A.; Chemla, F. Chem.dEur. J. 2006, 12, 6506–
6513.
Acknowledgements
This research was partially supported by the 21st Century COE
(Center of excellence) Program ‘Knowledge Information In-
frastructure for Genome Science’, a Grant-in-Aid for Young Scien-
tists (B), a Grant-in-Aid for Scientific Research on Priority Areas
‘Advanced Molecular Transformations’, and Targeted Proteins Re-
search Program from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
17. Reviews: (a) Olliver, C.; Renaud, P. Chem. Rev. 2001, 101, 3415–3434; (b) Yor-
imitsu, H.; Oshima, K. Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 1; Chapter 1.2, pp 11–27.
18. In the reactions involving diethylzinc or triethylborane, the diastereomeric
ratios of the products were identical to those in the reaction involving
dimethylzinc.
19. Highly diastereoselective conjugate addition of an ethyl radical to
a,b-un-
saturated oxime ethers using Et3B was reported, where Et2Zn failed to give the
product: Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem.,
Int. Ed. 2005, 44, 6190–6193.
References and notes
´
20. Grayson, D. H.; McCarthy, U.; Roycroft, E. D. Org. Biomol. Chem. 2003, 1, 1930–
1. (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vols. 1 and 2; (b) Radicals in Synthesis I & II; Gansa¨uer, A., Ed.;
Topics in Current Chemistry; Springer: Berlin, Heidelberg, 2006; Vols. 263 and
264.
2. Review: Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth. Org. Chem. Jpn. 2004,
62, 1158–1165.
3. (a) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org.
Lett. 2002, 4, 3509–3511; (b) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org. Lett.
2003, 5, 1797–1799; (c) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K.
J. Org. Chem. 2004, 64, 1531–1534.
4. Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada, K.; Tomioka, K.
Org. Lett. 2006, 8, 5729–5732.
1937.
21. Ohno, T.; Ishino, Y.; Tsumagari, Y.; Nishiguchi, I. J. Org. Chem. 1995, 60, 458–460.
22. The final geometry optimization, the energy, and the vibrational frequency
calculations were performed using Gaussian 03W: Gaussian, Inc., Wallingford
CT, 2004, for initial geometries optimized by Spartan ’06: Wavefunction, Inc.,
Irvine, CA. All the ground states were verified by vibrational frequency analysis.
23. These LUMO coefficients were the root mean squares of the MO coefficients of
the atomic orbitals belonging to each carbon atom.
24. Brian, E. L.; Prasad, S. R.; Thomas, C. W. Synlett 1994, 493–494.
25. Gianfranco, B.; Sandro, C.; Giancarlo, F. Org. Lett. 2003, 5, 777–780.
26. Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742–2753.