"Syn effect" in nucleophilic addition of amines to 1,3-dienyl sulfone and ethyl (E)-2,4-pentadienoate

Article abstract of DOI:10.1246/bcsj.81.740

The stereochemistry of nucleophilic addition of amines to (E)-l-tosyl-l,3-butadiene was investigated. The Z/E ratios of the resulting allylic sulfones varied with amines, solvents, temperature, and concentration. When diethylamine was reacted in low conce

Full text of DOI:10.1246/bcsj.81.740

740 Bull. Chem. Soc. Jpn. Vol. 81, No. 6, 740–753 (2008)
Ó 2008 The Chemical Society of Japan
‘‘Syn Effect’’ in Nucleophilic Addition of Amines to
1,3-Dienyl Sulfone and Ethyl (E)-2,4-Pentadienoate
ꢀ
ꢀ
Masao Yamazaki, Samar Kumar Guha, Yutaka Ukaji, and Katsuhiko Inomata
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192
Received December 17, 2007; E-mail: inomata@cacheibm.s.kanazawa-u.ac.jp
The stereochemistry of nucleophilic addition of amines to (E)-1-tosyl-1,3-butadiene was investigated. The Z/E ra-
tios of the resulting allylic sulfones varied with amines, solvents, temperature, and concentration. When diethylamine
was reacted in low concentration at high temperature, the corresponding sterically unfavorable (Z)-4-amino-2-butenyl
sulfone was preferentially obtained. The stereochemistry of nucleophilic addition of amines to ethyl (E)-2,4-pentadi-
enoate, which possesses an ester group as a conjugated electron-withdrawing group instead of a p-toluenesulfonyl
(Ts) group, was also found to realize similar high Z selectivity. The predominant formation of Z isomers in both cases
ꢀ
was rationalized by a ‘‘syn effect,’’ which might be mainly due to n=ꢀ ! ꢁ interaction and/or 6ꢁ-electron homo-
aromaticity.
Allylic sulfones are versatile synthetic intermediates in or-
ganic synthesis.1 During the course of studies on the prepara-
tion of allylic sulfones,2 we investigated the stereochemistry of
isomerization of ꢂ-unsubstituted (E)-vinylic sulfones to the
corresponding allylic sulfones in the presence of a base and
found that the sterically unfavorable (Z)-allylic sulfones were
predominantly formed.3 This result was rationalized by a
conjugate addition to dienyl sulfones have been reported.6,7
A
nucleophilic addition of aniline derivatives to (E)-1-tosyl-1,3-
butadiene (1) in the presence of K2CO3 afforded the corre-
sponding (E)-allylic sulfones with good to complete stereose-
lectivity.6a Asymmetric conjugate addition of a ꢄ-ketoester
to (E)-1-(benzenesulfonyl)-1,3-butadiene in the presence of
K2HPO4 also gave the corresponding adduct with complete
E selectivity.6b Interestingly, it has been reported that addition
of a transition-metal reagent, lithium dibutylcuprate, to (E)-1-
(allylsulfonyl)-1,3-butadiene gave a 65/35 mixture of (Z)- and
(E)-allylic sulfones. Furthermore, the addition of the same lith-
ium dibutylcuprate to 1 was reported to give only (Z)-1-tosyl-
2-octene in 21% yield.6c However, both isomers were obtained
in 96% total yield with Z preference (Z/E = 65/35) in our re-
examination. This inconsistent result prompted us to investi-
gate the stereochemistry of the nucleophilic addition of vari-
ous nucleophiles. Among non-metallic compounds, amines
showed various stereoselectivities depending on the kinds of
amines and reaction conditions. Herein, we describe the results
of the stereochemistry of the nucleophilic addition of amines
to (E)-1-tosyl-1,3-butadiene (1)8 and to ethyl (E)-2,4-penta-
dienoate (4).
ꢀ
‘‘syn effect,’’4 which is primarily caused by ꢀ ! ꢁ interac-
tion and/or 6ꢁ-electron homoaromaticity (Figure 1).5 In stud-
ies related to allylic sulfones, the predominant formation of
(Z)-olefins, which could also be ascribed to the ‘‘syn effect,’’
was found in the desulfonylation reaction of ꢂ,ꢂ-dialkylated
(E)-allylic sulfones,5a the isomerization of (E)-ꢂ-fluorovinylic
sulfones to the corresponding allylic sulfones under basic con-
ditions,5b and the desilylation reaction of ꢃ-silylated allylic
and vinylic sulfones.5d Furthermore, we revealed that the
‘‘syn effect’’ works also in the conversion of (E)-ꢂ,ꢄ-unsatu-
rated esters and aldehydes into the corresponding ꢄ,ꢃ-unsatu-
rated esters and silyl enol ethers,5c,5e respectively, the elimina-
tion reaction of (E)-allylic acetates catalyzed by palladium un-
der specific conditions utilizing a base,5f and the 1,4-elimina-
tive ring-opening reaction of (E)-1-propenyloxirane deriva-
tives by treatment with metal amides.5g
Results and Discussion
For the preparation of allylic sulfones, nucleophilic addition
to dienyl sulfones is a useful method. A couple of reactions of
First, the nucleophilic addition of various amines 2a–2k to
β
α
π
*
π
π*
H
SO Ar
H
SO Ar
2
2
σ
Base
Base
H
Base
H
H
γ
H
H
α
σ
H
β
H
H
γ
δ
CH R
2
δ
R
←
σC-H
π
* interaction
6π-electron homoaromaticity
Figure 1. Proposed origin of the ‘‘syn effect’’ in the isomerization of ꢂ-unsubstituted (E)-vinylic sulfones to the corresponding
allylic sulfones.
Published on the web June 11, 2008; doi:10.1246/bcsj.81.740

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
741
(E)-1-tosyl-1,3-butadiene (1) was carried out in THF at 25 ꢁC
and the results are summarized in Table 1. The Z/E ratios of
the resulting allylic sulfones 3a–3k varied depending on the
kinds of amines. Primary amines such as propylamine and bu-
tylamine gave the corresponding (E)-allylic amines mainly
(Entries 1 and 2). To the contrary, acyclic secondary amines
preferentially formed (Z)-allylic amines (Entries 3–5 and 7–
9) as opposed to E isomers. Especially, n-Pr2NH and n-Bu2NH
showed relatively high Z preference although the reaction was
sluggish (Entries 5 and 7). Addition of cyclic secondary
amines gave almost equal amounts of (Z)- and (E)-allylic
amines (Entries 10 and 11).
and concentration; the results are summarized in Tables 2
and 3. Ethereal solvents generally afforded the (Z)-allylic
amine preferentially, but less polar benzene and highly polar
CH3CN and DMSO gave the E isomer mainly as shown in
Table 2. It was found that polar and less bulky ethers, such
as DME and THF, showed high Z selectivity (Entries 2 and
5). The time-course of the addition reaction checked by
1H NMR in THF-d8 revealed that the Z/E ratio was almost
constant as the reaction proceeded.9 It is noteworthy that the
Z selectivity was enhanced when the reaction was carried
Table 2. Stereochemistry of Nucleophilic Addition of
Et2NH (2d) to (E)-1-Tosyl-1,3-butadiene (1) in Various
SolventsaÞ
Next, the stereochemistry of the nucleophilic addition of
Et2NH (2d) to (E)-1-tosyl-1,3-butadiene (1) was examined in
detail, paying attention to the effect of solvents, temperature,
Et NH (2d)
2
Ts
(1.5 equiv.)
Table 1. Stereochemistry of Nucleophilic Addition of Var-
ious Amines 2a–2k to (E)-1-Tosyl-1,3-butadiene (1)aÞ
Ts
Solvent
Et N
2
1
3d
Temp., 18 h
RR'NH 2
(1.5 equiv.)
Ts
Entry
Solvent
DME
Temp/ꢁC 1/3dbÞ Yield/%cÞ Z/EdÞ
Ts
1
2
3
4
5
6
7
8
9
0
25
60
0
84/16
58/42
33/67
65/35
59/41
27/73
32/68
41/59
61/39
52/48
3/97
16
40
61
28
38
64
61
48
35
47
73
26
15
56
90
70
98
77
67/33
82/18
88/12
52/48
78/22
86/14
64/36
61/39
31/69
28/72
71/29
63/37
53/47
44/56
41/59
30/70
37/63
27/73
THF
RR'N
1
3
25 °C, Time
Entry
RR0NH 2
Time/h 1/3bÞ Yield/%cÞ Z/EdÞ
THF
1eÞ
2eÞ
3
4
5
6
7
8
9
n-PrNH2
n-BuNH2
Me2NHfÞ
Et2NH
n-Pr2NH
i-Pr2NH
n-Bu2NH
a
b
c
d
e
f
72
72
24
72
72
72
72
72
72
6
11/89
11/89
0/100
19/81
52/48
100/0
48/52
0/100
38/62
0/100
0/100
70
71
91
75
43
—
46
85
58
83
85
21/79
23/77
60/40
74/26
85/15
—
87/13
72/28
80/20
44/56
55/45
25
60
25
25
25
25
25
25
25
25
25
25
25
25
1,4-Dioxane
THP
Et2O
t-BuOMe
Pyridine
10
11
g
n-Bu(Me)NH h
12 N-Methylmorpholine
13 N-Methylpyrrolidine
14
15 Tetrahydrothiophene
16
17
18
71/29
81/19
44/56
0/100
27/73
0/100
0/100
i-Pr(Me)NH
Pyrrolidine
Piperidine
i
j
k
10
11
CHCl3
12
Benzene
MeCN
DMSO
a) Concentration of amines 2 was 150 mM (mmol dmꢂ3) in all
cases. b) The ratios were determined based on the isolated
yields. c) Isolated total yield of 3. d) The ratios were deter-
mined by 400 MHz 1H NMR spectra. e) Formation of
(TsCH2CH=CHCH2)2NR (R = n-Pr, 5%; n-Bu, 7%) was
observed. f) A commercially available 2.0 M (mol dmꢂ3) solu-
tion of Me2NH in THF was used.
a) Concentration of 2d was 150 mM in all cases. b) The ratios
were determined based on the isolated yields. c) Isolated total
yield of 3d. d) The ratios were determined by 400 MHz
1H NMR spectra.
Table 3. Effect of Concentration on Nucleophilic Addition of Et2NH (2d) to (E)-1-Tosyl-1,3-butadiene (1)
Ts
Et NH (2d)
2
Ts
THF
Et N
1
3d
2
Temp., 72 h
Concentrations
Entry
2d/1
Temp/ꢁC
1/3daÞ
Yield/%bÞ
Z/EcÞ
1/mM
2d/mM
1
2
3
4
5
6
100
50
25
25
3.1
10
150
75
37.5
37.5
37.5
15
1.5
1.5
1.5
1.5
12.0
1.5
25
25
25
60
60
25
19/81
51/49
64/36
38/62
28/72
86/14
75
48
33
50
72
12
74/26
93/7
96/4
96/4
98/2
94/6
a) The ratios were determined based on the isolated yields. b) Isolated total yield of 3d. c) The ratios were
1
determined by 400 MHz H NMR spectra.

742 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
Table 4. Stereochemistry of Nucleophilic Addition of
Et2NH (2d) to Ethyl (E)-2,4-Pentadienoate (4) in Various
SolventsaÞ
Table 5. Stereochemistry of Nucleophilic Addition of Var-
ious Amines 2 to 4aÞ
RR'NH 2
(1.5 equiv.)
CO2Et
Et2NH (2d)
(1.5 equiv.)
CO2Et
CO2Et
THF
CO2Et
RR'N
25 °C, 72 h
Solvent
25 °C, 120 h
4
5
Et N
2
4
5d
Yield/%cÞ
Entry
RR0NH 2
4/5bÞ
86/14
89/11
52/48
89/11
96/4
Yield/%cÞ
Z/EdÞ
4/5dbÞ
Z/EdÞ
1eÞ
2eÞ
3
4
5
6
7
8
9
10
n-PrNH2
n-BuNH2
Me2NHfÞ
Et2NH
n-Pr2NH
n-Bu2NH
n-Bu(Me)NH
i-Pr(Me)NH
Pyrrolidine
Piperidine
a
b
c
d
e
g
h
i
10
8
32
9
4
5
25
15
90
58
7/93
11/89
76/24
87/13
90/10
94/6
74/26
82/18
59/41
68/32
Entry
Solvent
1
2
3
4
5
6
7
8
9
10
DME
THF
1,4-Dioxane
THP
Et2O
Pyridine
CHCl3
Benzene
MeCN
EtOH
87/13
88/12
92/8
93/7
94/6
58/42
91/9
90/10
65/35
79/21
9
10
6
5
4
30
7
7
34
18
85/15
86/14
69/31
69/31
42/58
23/77eÞ
34/66
49/51
17/83eÞ
9/91
94/6
66/34
85/15
6/94
j
k
39/61
a) Concentration of amines 2 was 150 mM in all cases. b) The
ratios were determined based on the isolated yields. c) Isolated
total yield of 5 based on 4. d) The ratios were determined by
400 MHz 1H NMR spectra.11 e) Formation of 1-alkyl-1,6-di-
hydropyridin-2(3H)-one (alkyl = n-Pr, 5%; n-Bu, 6%) was
observed. f) A commercially available 2.0 M solution of
Me2NH in THF was used.
a) Concentration of Et2NH (2d) was 150 mM in all cases. b)
The ratios were determined based on the isolated yields. c)
Isolated total yield of 5d based on 4. d) The ratios were deter-
1
mined by 400 MHz H NMR spectra.11 e) Isomerization of Z
isomer to E isomer was observed during the reaction.
out at higher temperature (Entries 1–6).
The effect of concentration is shown in Table 3. The lower
concentration of Et2NH remarkably increased the Z selectivity
of 3d (Entries 1–3 and 6), though the reaction became slug-
gish. Finally, using excess Et2NH at 60 ꢁC, (Z)-allylic sulfone
3d was obtained in 72% yield with the highest Z selectivity
(Entry 5).
as THF and DME, to give the corresponding (Z)-5-amino-3-
pentenoate 5d selectively (Table 4, Entries 1 and 2).
In order to promote the addition reaction, several kinds of
proton sources were added to activate the ester carbonyl group
and/or to protonate to the anion developing at the ꢂ-position.
The reaction rate was remarkably accelerated by using proton
sources with lower pKa, however, Z selectivity of 5d was
decreased in contrast.12
Although the addition reaction of Et2NH (2d) proceeded
with higher stereoselectivity, the chemical yield was poor.
Next, we investigated the nucleophilic addition of various
amines 2 to 4 in THF at 25 ꢁC. The results are summarized
in Table 5. Similar tendency toward Z selectivity in the case
of (E)-1-tosyl-1,3-butadiene (1) was observed: Acyclic secon-
dary amines, especially n-Pr2NH (2e) and n-Bu2NH (2g),
showed relatively high Z selectivity although the chemical
yields were poorer (Entries 5 and 6). Pyrrolidine (2j), a cyclic
secondary amine, showed high chemical yield, but Z selectiv-
ity was not particularly good (Entry 9). The reaction rate of
nucleophilic addition of piperidine (2k) was moderate to afford
relatively good Z selectivity (Entry 10).
Thus, the reaction of piperidine (2k) to 4 was examined in
detail paying attention to the effect of temperature and concen-
tration, and the results are summarized in Table 6. It is note-
worthy that the Z selectivity of 5k was again enhanced when
the reaction was carried out at higher temperature (Entries
2–4, 7 and 8) and at lower concentration of piperidine (Entries
1 and 3, 5 and 6) up to 89/11 in 50% yield. On the other
hand, the concentration of 4 little affected the Z/E ratio of
5k (Entries 3 and 5, 6 and 7, and 8 and 9, respectively).
As described above, nucleophilic addition of secondary
amines to electron-deficient dienes 1 and 4 realized unprece-
dented high Z selectivity to give the corresponding sterically
As we described above, unprecedented Z selectivity in the
conjugate addition of amines to (E)-1-tosyl-1,3-butadiene (1)
was discovered. This phenomenon was suspected to be specific
to sulfonyl compounds. Therefore, nucleophilic addition of
amines to ethyl (E)-2,4-pentadienoate (4), which possesses
an ester group as a conjugated electron-withdrawing group in-
stead of a p-toluenesulfonyl (Ts) group, was next carried out.
Conjugate 1,6-addition reactions to (E)-2,4-pentadienoate
were reported to generally furnish the corresponding (E)-3-
pentenoate.10 For example, addition of nitroalkanes in the pres-
ence of Amberlyst A 27 or a lithium salt of a bislactim ether
afforded the exclusively E adducts.10a,10b Asymmetric conju-
gate addition of ꢄ-ketoesters to (E)-2,4-pentadienoate using
an inorganic base in the presence of cinchona alkaloids also
gave the corresponding adduct with complete E selectivity.6b
Nickel-catalyzed addition of morpholine has been reported to
give an (E)-allylic amine.10c Addition of organocopper reagents
afforded (E)-ꢄ,ꢃ-unsaturated esters.10d Only the transition-
metal-catalyzed addition reactions gave (Z)-ꢄ,ꢃ-unsaturated
esters.10e Thus, generally 1,6-conjugate addition to 2,4-penta-
dienoate has been believed to give the (E)-ꢄ,ꢃ-unsaturated
esters at least in the absence of transition-metal catalyst.
First, the stereochemistry of the nucleophilic addition of
Et2NH to 4 was investigated in various solvents as listed in
Table 4. Although the reactions were rather sluggish compared
with the reaction of (E)-1-tosyl-1,3-butadiene (1), similar high
Z selectivity was realized in polar and less bulky ethers, such

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
743
Table 6. Effect of Temperature and Concentration on Nucleophilic Addition of Piperidine (2k) to 4
NH
2k
CO2Et
CO2Et
THF
Temp., 72 h
N
4
5k
4/5kaÞ
Concentrations
Entry
2k/4
Temp/ꢁC
Yield/%bÞ
Z/EcÞ
4/mM
2k/mM
1
2
3
4
5
6
7
8
9
100
100
100
100
25
600
150
150
150
150
37.5
37.5
37.5
37.5
6.0
1.5
1.5
1.5
6.0
1.5
6.0
6.0
12.0
25
0
0/100
47/53
39/61
14/86
18/82
72/28
72/28
44/56
35/65
99
38
58
74
67
21
25
50
55
34/66
29/71
68/32
72/28
65/35
83/17
81/19
89/11
87/13
25
60
25
25
25
60
60
25
6.25
6.25
3.125
a) The ratios were determined based on the isolated yields. b) Isolated total yield of 5k based on 4. c) The
1
ratios were determined by 400 MHz H NMR spectra.
Ts
2
1
NH (1.5 equiv.)
3
CO2Et
X
2k
4
THF, 25 °C, 72 h
H
F
N
Et Et
8
33% (8/9 = 58/42)
A
F
CO2Et
N
CO2Et
(X = H or F)
F
N
Figure 2. Another possible origin of the ‘‘syn effect:’’ 1,4-
addition.
(E)-9
(Z)-9
E/Z = 1/99
ð2Þ
unfavorable (Z)-allylic compounds 3d and 5k. The mechanism
for predominant formation of (Z)-olefins is not yet clear.13 To
confirm the possibility of a concerted 1,4-addition mechanism
(Figure 2, A), nucleophilic addition of Et2NH (2d) (150 mM)
to (E)-3-fluoro-1-tosyl-1,3-butadiene (6) was investigated
(eq 1). Selective formation of (Z)-3-fluoro-2-butenyl sulfone
derivative (Z)-7 was observed. In addition, nucleophilic addi-
tion of piperidine (2k) (150 mM) to ethyl (E)-4-fluoro-2,4-
pentadienoate (8) (100 mM) also gave the corresponding Z
adduct, (Z)-9, selectively (eq 2). Selective formations of (Z)-
olefins, (Z)-7 and (Z)-9, could exclude the 1,4-addition mech-
anism A.
The elucidation of selective formation of (Z)-allylic sulfone
(Z)-3d and (Z)-3-pentenoate (Z)-5k and variation of Z/E ratios
by kinds of amines, solvents, temperature, and concentration
are quite difficult. The most favorable conformation of (E)-di-
enyl sulfone 1 and (E)-2,4-pentadienoate 4 might be s-trans
conformation.14 If the present addition reaction were kinetical-
ly controlled reflecting the initial conformation shown in C
(Scheme 1), it would be impossible to explain the Z selectiv-
ity. We try to rationalize the origin of the present ‘‘syn effect’’
ꢀ
in two ways, n=ꢀ ! ꢁ interaction and/or 6ꢁ-electron homo-
aromaticity in the following,15 taking into account the effects
of kinds of amines, solvents, temperature, and concentration.
The former is as follows (Scheme 1): When a pair of elec-
Et2NH (1.5 equiv.)
2d
Ts
ꢀ
trons on the amine nitrogen interacts with a ꢁ orbital of
C =C at the ꢅ-position of 1 and 4 via s-trans conformation
as shown in C, an anion would develop on the ꢃ-carbon which
might acquire sp3 character altering from sp2 character. The
nonbonding electron pair (n) of the ꢃ-carbanion can more ef-
THF, 25 °C, 72 h
24% (6/7 = 76/24)
F
ꢃ
ꢅ
6
F
Ts
Ts
Et2N
ꢀ
fectively interact with the ꢁ orbital of C =C in the eclipsed
ꢂ
conformations D and F, in both of which the n-orbital is
ꢄ
F
Et2N
(E)-7
(Z)-7
ꢀ
ꢀ
aligned with the ꢁ orbital (n ! ꢁ interaction), and confor-
E/Z = 5/95
mation E can be neglected.16 Further, the contribution of ꢀ !
ð1Þ
ꢀ
ꢁ
interaction might determine the preference of D or F,

744 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
H
R2N
H
EWG
H
H
NR2
β
α
H
H
or
γ
δ
H
THF
X
R2N
1,4 (X = H)
6,8 (X = F)
NR2
O
R2N
H
H
Hydrogen Bond
C
B
∗
∗
π
π
δ
π
∗
∗
∗
∗
π
π
π
π
π
π
H
EWG
H
H
EWG
H
H
EWG
H
δ
R2N
X
σC-X
n
H
σ
σC-X
C-Cγ
β
β
α
σC-C
α
α
β
X
n
γ
H
H
H
H
γ
n
X
δ
R2NH
R2NH
D
E
F
←
X = F
X = H
σC-X
π* interaction
X = H > C > F
H
β
EWG
H
α
H
β
EWG
H
γ
α
γ
H
δ
EWG = Ts or CO2Et
H
H
R2N
H
F
δ
R2NH
G
H
H
H
EWG
H
EWG
R2N
F
(Z )-7,9
(Z )-3,5
R2N
Scheme 1.
ꢀ
because ꢀ ! ꢁ interactions decrease in the order of
(Table 7, Entry 1), whereas Z selectivity was enhanced under
dilute conditions at higher temperature as shown in Table 7.20
Their syn intermediate forms 8ꢁ-electron system N, which has
no advantage compared with anti intermediate M leading to
(E)-allylic products. The fact that a considerable amount of
Z isomers were still produced might suggest the contribution
ꢀC{H ! ꢁ > ꢀC{C ! ꢁ > ꢀC{F ! ꢁ .17 Thus, (Z)-3 and
(Z)-5 were predominantly obtained in the case of 1 and 4 via
conformation F (X = H), whereas (Z)-7 and (Z)-9 were
formed in the case of 6 and 8 via D (X = F). Higher temper-
ature and lower concentration in coordinating solvent like THF
might dissociate the aggregation of bulkier dialkylamine (B)
via hydrogen bonding18 to generate the more nucleophilic
monomeric amine shown in C.19
ꢀ
ꢀ
ꢀ
ꢀ
of n=ꢀ ! ꢁ interaction discussed above, or that of a hydro-
gen bond between the ꢂ-fluorine atom and a proton of ammo-
nium ion as depicted in O.
In addition, 6ꢁ-electron homoaromaticity seems to also
contribute to the ‘‘syn effect’’ (Figure 3). When a monomeric
dialkylamine reacts with an electron deficient diene, the syn
intermediate J might be stabilized by 6ꢁ-electron homoaroma-
ticity, followed by protonation to afford the corresponding (Z)-
3 and (Z)-5. In the case of ꢃ-fluorinated dienes 6 and 8, the
participation of a lone pair of electrons on ꢃ-fluorine atom
to 6ꢁ-electron homoaromaticity, as depicted in L, may be
much more effective than that of methylene in K. As a result,
(Z)-7 and (Z)-9 were selectively obtained.
Furthermore, the reaction of Et2NH (2d) (150 mM) with
(E)-1-fluoro-1-tosyl-1,3-butadiene (10) was examined, and
(Z)-allylic sulfone 11 was mainly obtained (eq 3). Addition
of piperidine (150 mM) to octyl (Z)-2-fluoro-2,4-pentadienoate
(12) mainly gave (E)-2-fluoro-5-amino-3-pentenoate 13
Et2NH (1.5 equiv.)
2d
THF, 25 °C, 72 h
Ts
F
10
14% (10/11 = 80/20)
Ts
F
Ts
Et2N
F
Et2N
(Z)-11
(E)-11
Z/E = 62/38
ð3Þ
In conclusion, unprecedented Z selective conjugate addition
of amines to (E)-1-tosyl-1,3-butadiene (1) and ethyl (E)-2,4-
pentadienoate (4) was discovered. Especially, higher Z selec-

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
745
H
EWG
H
H
EWG
β
β
α
α
δ
(Z)-3,5
C
H
H
γ
γ
H
H
R2N
H
(X = H)
δ
H
R2N
H
I
J
6π
-electron
homoaromaticity
H
EWG
H
H
EWG
β
β
α
α
δ
F
H
(Z)-7,9
C
γ
γ
H
H
R2N
H
(X = F)
δ
F
R2N
H
K
L
6π-electron homoaromaticity
β
α
β
α
H
EWG
F
H
EWG
F
H
EWG
F
β
α
γ
H
H
γ
γ
H
H
R2N
H
δ
H
H
δ
δ
H
R2N
H
N
R2
H
M
N
O
6π
-electron
6π
-electron
8π-electron system
homoaromaticity
homoaromaticity
Figure 3. ‘‘Syn effect’’ based on 6ꢁ-electron homoaromaticity.
Table 7. Effect of Temperature and Concentration on Nucleophilic Addition of Piperidine (2k) to 12
NH
CO2Oct
CO2Oct
2k
THF
25 °C
72 h
F
F
N
13
12
Concentrations
Entry
2k/12
Temp/ꢁC
12/13aÞ
Yield/%bÞ
Z/EcÞ
12/mM
2k/mM
1
2
3
4
5
100
100
25
6.25
6.25
150
150
37.5
37.5
37.5
1.5
1.5
1.5
6.0
6.0
25
60
25
25
60
66/34
26/74
97/3
96/4
88/12
33
73
3
4
12
18/82
20/80
32/68
35/65
50/50
a) The ratios were determined based on the isolated yields. b) Isolated total yield of 13 based on 12. c) The
1
ratios were determined by 400 MHz H NMR spectra.
mass spectrometer. THF and Et2O were freshly distilled from so-
dium diphenylketyl. All other solvents were distilled and stored
over drying agents. Thin-layer chromatography (TLC), flash
column chromatography, and recycle HPLC were performed by
using Merck silica gel 60 PF254 (Art. 7749), Cica silica gel 60
(No. 37571), and JAIGL-SIL (s-043-15), respectively.
tivity could be realized when the reaction was carried out in
lower concentration of secondary amines at higher temperature
in polar ethereal solvent. The ‘‘syn effect’’ observed in the
ꢀ
present addition reaction was rationalized by n=ꢀ ! ꢁ inter-
action and/or 6ꢁ-electron homoaromaticity.
(E)-1-Tosyl-1,3-butadiene (1).21 To a solution of (E)-1-iodo-
4-tosyl-2-butene5a (758 mg, 2.25 mmol) in THF (7.0 mL) was
added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.370 mL,
2.48 mmol) under a nitrogen atmosphere. After 5 min, the reaction
mixture was treated with a saturated aqueous solution of NH4Cl,
and the solvent was evaporated. The organic substances were
extracted with EtOAc, followed by washing with H2O, brine,
and dried over Na2SO4. After evaporating the solvent, the residue
Experimental
1H and 19F NMR spectra were recorded on a JEOL Lambda
1
400 NMR spectrometer (400 MHz for H and 376 MHz for 19F).
Chemical shifts were determined in the ꢅ-scale relative to
Si(CH3)4 (ꢅ 0) and C6F6 (ꢅ ꢂ162:90) as internal standards, re-
spectively. IR spectra were measured on a JASCO FT/IR-230
spectrometer. MS spectra were recorded with a JEOL SX-102A

746 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
was purified by column chromatography (SiO2, hexane/
EtOAc = 5/1, v/v) to give 1 in 99% yield (465 mg) as an oil.
IR (neat) 3050, 2923, 2850, 1596, 1493, 1449, 1425, 1410,
7.81, 1.46 Hz), 5.88 (1H, dt, J ¼ 10:98, 6.83 Hz), 7.34 (2H, d,
J ¼ 7:81 Hz), 7.75 (2H, d, J ¼ 7:81 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 0.91 (3H, t, J ¼ 7:07 Hz), 1.31 (2H, sext, J ¼
7:07 Hz), 1.43 (2H, quint, J ¼ 7:07 Hz), 1.73 (1H, brs), 2.44
(3H, s), 2.51 (2H, t, J ¼ 7:07 Hz), 3.21 (2H, d, J ¼ 4:64 Hz),
3.77 (2H, d, J ¼ 6:34 Hz), 5.59 (1H, dt, J ¼ 15:61, 6.34 Hz),
5.64 (1H, dt, J ¼ 15:61, 4.64 Hz), 7.34 (2H, d, J ¼ 7:81 Hz),
7.74 (2H, d, J ¼ 7:81 Hz). HRMS (FABþ) ðM þ HÞþ, Found:
m=z 282.15262. Calcd for C15H24NO2S: 282.15277.
1303, 1182, 1147, 1087, 1020, 969, 890, 821, 728, 669 cmꢂ1
.
1H NMR (CDCl3) ꢅ 2.44 (3H, s), 5.59 (1H, d, J ¼ 10:25 Hz),
5.71 (1H, d, J ¼ 16:83 Hz), 6.37 (1H, ddd, J ¼ 16:83, 11.22,
10.25 Hz), 6.38 (1H, d, J ¼ 14:88 Hz), 7.23 (1H, dd, J ¼ 14:88,
11.22 Hz), 7.34 (2H, d, J ¼ 8:24 Hz), 7.78 (2H, d, J ¼ 8:24 Hz).
HRMS (FABþ) ðM þ HÞþ, Found: m=z 209.06386. Calcd for
C11H13O2S: 209.06363.
N-Butyl-4-tosyl-N-(4-tosyl-2-butenyl)-2-butenylamine: An
1
Representative Procedure for the Nucleophilic Addition Re-
action of Diethylamine (2d) to (E)-1-Tosyl-1,3-butadiene (1)
(Table 1, Entry 4). To a solution of (E)-1-tosyl-1,3-butadiene
(1) (94 mg, 0.45 mmol) in THF (4.5 mL) was added diethylamine
(2d) (0.070 mL, 0.68 mmol) at 25 ꢁC under a nitrogen atmosphere.
After stirring for 72 h, the reaction mixture was quenched by add-
ing silica gel (3.00 g), and the solvent was evaporated. The residue
was purified by column chromatography (SiO2, hexane/
EtOAc = 5/1, v/v, EtOAc, then EtOAc/MeOH = 3/1, v/v) to
give a mixture of (Z)- and (E)-3d (95 mg, 75%, Z/E = 74/26)
and to recover unreacted 1 (17 mg, 18%).
oil (a mixture of at least 3 isomers based on H NMR). IR (neat)
3030, 2955, 2927, 2871, 2813, 1597, 1494, 1455, 1403, 1316,
1303, 1237, 1142, 1087, 1018, 975, 882, 816, 728, 690,
664 cmꢂ1
.
1H NMR (CDCl3) ꢅ 0.85 (3H, t, J ¼ 7:08 Hz), [0.86
(3H, t, J ¼ 7:08 Hz), minor isomers], 1.14–1.34 (4H, m), 2.15–
2.23 (2H, m), 2.44 (6H, s), [2.46 (6H, s), minor isomers], 2.86
(2H, d, J ¼ 3:39 Hz), 2.91 (2H, d, J ¼ 3:17 Hz), [2.69–2.76
(4H, m), minor isomers], 3.72–3.79 (4H, m), [3.82–3.88 (4H,
m), minor isomers], 5.45–5.79 (4H, m), 7.32–7.36 (4H, m),
7.70–7.76 (4H, m). HRMS (FABþ) ðM þ HÞþ, Found: m=z
490.20833. Calcd for C26H36NO4S2: 490.20858.
In a similar way, addition reaction of amines 2a–2c and 2e–2k
was carried out to give the corresponding allylic amines 3a–3c
and 3e–3k. The physical and spectral data of 3a–3e and 3g–3k
and by-products are given in the following. Z/E ratios were deter-
N,N-Dimethyl-4-tosyl-2-butenylamine (3c):
An oil (Z/
E = 60/40). IR (neat) 3031, 2943, 2860, 2818, 2773, 1597,
1494, 1458, 1402, 1317, 1239, 1148, 1088, 1019, 977, 891, 852,
816, 713, 689, 663 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 2.07
(6H, s), 2.44 (3H, s), 2.67 (2H, dd, J ¼ 6:58, 1.46 Hz), 3.90
(2H, d, J ¼ 8:05 Hz), 5.54 (1H, dtt, J ¼ 10:98, 8.05, 1.46 Hz),
5.82 (1H, dt, J ¼ 10:98, 6.58 Hz), 7.34 (2H, d, J ¼ 8:29 Hz),
7.76 (2H, d, J ¼ 8:29 Hz). E isomer; 1H NMR (CDCl3) ꢅ 2.12
(6H, s), 2.44 (3H, s), 2.87 (2H, d, J ¼ 3:90 Hz), 3.79 (2H, d,
J ¼ 6:10 Hz), 5.52–5.60 (1H, m), 5.60 (1H, dt, J ¼ 15:34,
6.10 Hz), 7.33 (2H, d, J ¼ 8:29 Hz), 7.73 (2H, d, J ¼ 8:29 Hz).
HRMS (FABþ) ðM þ HÞþ, Found: m=z 254.12169. Calcd for
C13H20NO2S: 254.12147.
N,N-Diethyl-4-tosyl-2-butenylamine (3d): An oil (Z/E =
74/26). IR (neat) 3030, 2970, 2932, 2873, 2807, 1597, 1494,
1452, 1384, 1317, 1303, 1239, 1200, 1141, 1088, 1019, 976,
880, 816, 769, 712, 688 cmꢂ1. Z isomer; 1H NMR (CDCl3)
ꢅ 0.91 (6H, t, J ¼ 7:32 Hz), 2.31 (4H, q, J ¼ 7:32 Hz), 2.44
(3H, s), 2.76 (2H, d, J ¼ 6:59 Hz), 3.89 (2H, d, J ¼ 7:81 Hz),
5.53 (1H, dt, J ¼ 10:00, 7.81 Hz), 5.83 (1H, dt, J ¼ 10:00,
6.59 Hz), 7.34 (2H, d, J ¼ 8:05 Hz), 7.76 (2H, d, J ¼ 8:05 Hz).
1H NMR (C6D6) ꢅ 0.79 (6H, t, J ¼ 7:08 Hz), 1.86 (3H, s), 2.12
(4H, q, J ¼ 7:08 Hz), 2.58 (2H, d, J ¼ 6:34 Hz), 3.64 (2H, d,
J ¼ 7:81 Hz), 5.42 (1H, dt, J ¼ 10:98, 7.81 Hz), 5.65 (1H, dt,
J ¼ 10:98, 6.34 Hz), 6.74 (2H, d, J ¼ 8:05 Hz), 7.70 (2H, d,
J ¼ 8:05 Hz). E isomer; 1H NMR (CDCl3) ꢅ 0.95 (6H, t,
J ¼ 7:32 Hz), 2.37 (4H, q, J ¼ 7:32 Hz), 2.44 (3H, s), 3.02 (2H,
d, J ¼ 3:66 Hz), 3.79 (2H, d, J ¼ 5:12 Hz), 5.50–5.64 (2H, m),
7.34 (2H, d, J ¼ 8:05 Hz), 7.72 (2H, d, J ¼ 8:05 Hz). 1H NMR
(C6D6) ꢅ 0.83 (6H, t, J ¼ 7:08 Hz), 1.87 (3H, s), 2.21 (4H, q,
J ¼ 7:08 Hz), 2.75 (2H, d, J ¼ 5:86 Hz), 3.41 (2H, d, J ¼
7:32 Hz), 5.33 (1H, dt, J ¼ 15:61, 5.86 Hz), 5.48 (1H, dt, J ¼
15:61, 7.32 Hz), 6.76 (2H, d, J ¼ 7:81 Hz), 7.69 (2H, d, J ¼
7:81 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z 282.15198.
Calcd for C15H24NO2S: 282.15277.
1
mined by 400 MHz H NMR spectra.
N-Propyl-4-tosyl-2-butenylamine (3a): An oil (Z/E = 21/
79). IR (neat) 3321, 2958, 2929, 2874, 2810, 1597, 1495, 1455,
1403, 1381, 1317, 1303, 1238, 1145, 1088, 1018, 973, 816,
730, 665 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.87 (3H, t,
J ¼ 7:32 Hz), 1.41 (2H, sext, J ¼ 7:32 Hz), 1.56 (1H, brs), 2.40
(2H, t, J ¼ 7:32 Hz), 2.44 (3H, s), 3.00 (2H, dd, J ¼ 6:83,
1.46 Hz), 3.90 (2H, d, J ¼ 8:05 Hz), 5.49 (1H, dtt, J ¼ 10:73,
8.05, 1.46 Hz), 5.88 (1H, dt, J ¼ 10:73, 6.83 Hz), 7.34 (2H, d,
J ¼ 7:81 Hz), 7.75 (2H, d, J ¼ 7:81 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 0.89 (3H, t, J ¼ 7:32 Hz), 1.45 (2H, sext, J ¼
7:32 Hz), 1.56 (1H, brs), 2.44 (3H, s), 2.46 (2H, t, J ¼ 7:32 Hz),
3.19 (2H, d, J ¼ 4:64 Hz), 3.77 (2H, d, J ¼ 6:10 Hz), 5.58 (1H,
dt, J ¼ 15:37, 6.10 Hz), 5.63 (1H, dt, J ¼ 15:37, 4.64 Hz), 7.33
(2H, d, J ¼ 7:81 Hz), 7.73 (2H, d, J ¼ 7:81 Hz). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 268.13820. Calcd for C14H22NO2S:
268.13712.
N-Propyl-4-tosyl-N-(4-tosyl-2-butenyl)-2-butenylamine: An
1
oil (a mixture of at least 3 isomers based on H NMR). IR (neat)
2960, 2929, 2872, 1597, 1495, 1455, 1403, 1316, 1235, 1142,
1087, 1018, 976, 881, 815, 728, 666 cmꢂ1 1H NMR (CDCl3)
.
ꢅ 0.76–0.81 (2H, m), 0.79 (3H, t, J ¼ 7:32 Hz), [0.80 (3H, t,
J ¼ 7:32 Hz), minor isomers], 2.09–2.19 (2H, m), 2.44 (6H, s),
[2.46 (6H, s), minor isomers], 2.86 (2H, d, J ¼ 3:90 Hz), 2.91
(2H, d, J ¼ 3:42 Hz), [2.69–2.76 (4H, m), minor isomers], 3.74–
3.78 (4H, m), [3.83–3.87 (4H, m), minor isomers], 5.48–5.79
(4H, m), 7.32–7.36 (4H, m), 7.70–7.68 (4H, m). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 476.19165. Calcd for C25H34NO4S2:
476.19293.
N-Butyl-4-tosyl-2-butenylamine (3b): An oil (Z/E = 23/
77). IR (neat) 3323, 3030, 2956, 2927, 2871, 2810, 1597, 1493,
1457, 1402, 1377, 1318, 1303, 1240, 1146, 1088, 1045, 1018,
972, 917, 875, 816, 731, 695, 664 cmꢂ1. Z isomer; 1H NMR
(CDCl3) ꢅ 0.89 (3H, t, J ¼ 7:07 Hz), 1.31 (2H, sext, J ¼
7:07 Hz), 1.43 (2H, quint, J ¼ 7:07 Hz), 1.73 (1H, brs), 2.44
(3H, s), 2.51 (2H, t, J ¼ 7:07 Hz), 3.01 (2H, dd, J ¼ 6:83,
1.46 Hz), 3.89 (2H, d, J ¼ 7:81 Hz), 5.49 (1H, dtt, J ¼ 10:98,
N,N-Dipropyl-4-tosyl-2-butenylamine (3e): An oil (Z/E =
85/15). IR (neat) 3030, 2958, 2932, 2871, 2804, 1597, 1458,
1404, 1381, 1318, 1303, 1239, 1185, 1141, 1088, 1020, 976,
889, 816, 712, 688 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.81
(6H, t, J ¼ 7:32 Hz), 1.33 (4H, sext, J ¼ 7:32 Hz), 2.18 (4H, t,
J ¼ 7:32 Hz), 2.44 (3H, s), 2.74 (2H, dd, J ¼ 6:34, 1.71 Hz),

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
747
1
3.89 (2H, d, J ¼ 8:05 Hz), 5.52 (1H, dtt, J ¼ 10:98, 8.05,
1.71 Hz), 5.83 (1H, dt, J ¼ 10:98, 6.34 Hz), 7.34 (2H, d,
J ¼ 8:05 Hz), 7.75 (2H, d, J ¼ 8:05 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 0.83 (6H, t, J ¼ 7:32 Hz), 1.39 (4H, sext, J ¼
7:32 Hz), 2.27 (4H, t, J ¼ 7:32 Hz), 2.44 (3H, s), 3.02 (2H, d,
J ¼ 4:88 Hz), 3.78 (2H, d, J ¼ 6:10 Hz), 5.53–5.60 (1H, m),
5.61 (1H, dt, J ¼ 15:37, 4.88 Hz), 7.33 (2H, d, J ¼ 8:05 Hz),
7.73 (2H, d, J ¼ 8:05 Hz). HRMS (FABþ) ðM þ HÞþ, Found:
m=z 310.18535. Calcd for C17H28NO2S: 310.18407.
N,N-Dibutyl-4-tosyl-2-butenylamine (3g): An oil (Z/E =
87/13). IR (neat) 3030, 2955, 2930, 2871, 2803, 1598, 1495,
1457, 1404, 1378, 1318, 1303, 1234, 1140, 1088, 1019, 974,
887, 815, 712, 687 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.88
(6H, t, J ¼ 7:31 Hz), 1.20–1.40 (8H, m), 2.20 (4H, t, J ¼
7:81 Hz), 2.44 (3H, s), 2.72 (2H, dd, J ¼ 6:34, 1.71 Hz), 3.89
(2H, d, J ¼ 7:81 Hz), 5.52 (1H, dtt, J ¼ 10:98, 7.81, 1.71 Hz),
5.82 (1H, dt, J ¼ 10:98, 6.34 Hz), 7.33 (2H, d, J ¼ 8:05 Hz),
7.76 (2H, d, J ¼ 8:05 Hz). E isomer; 1H NMR (CDCl3) ꢅ 0.89
(6H, t, J ¼ 7:07 Hz), 1.20–1.40 (8H, m), 2.29 (4H, t, J ¼
7:56 Hz), 2.44 (3H, s), 3.01 (2H, d, J ¼ 4:64 Hz), 3.78 (2H, d,
J ¼ 6:10 Hz), 5.48–5.56 (1H, m), 5.61 (1H, dt, J ¼ 15:37,
4.64 Hz), 7.32 (2H, d, J ¼ 8:42 Hz), 7.73 (2H, d, J ¼ 8:42 Hz).
HRMS (FABþ) ðM þ HÞþ, Found: m=z 338.21518. Calcd for
C19H32NO2S: 338.21537.
8:29 Hz), 7.76 (2H, d, J ¼ 8:29 Hz). E isomer; H NMR (CDCl3)
ꢅ 1.65–1.80 (4H, m), 2.28–2.40 (4H, m), 2.44 (3H, s), 3.05 (2H, d,
J ¼ 4:88 Hz), 3.78 (2H, d, J ¼ 5:86 Hz), 5.60 (1H, dt, J ¼ 15:34,
5.86 Hz), 5.64 (1H, dt, J ¼ 15:34, 4.88 Hz), 7.33 (2H, d, J ¼
8:29 Hz), 7.73 (2H, d, J ¼ 8:29 Hz). HRMS (FABþ) ðM þ HÞþ,
Found: m=z 280.13644. Calcd for C15H22NO2S: 280.13712.
1-(4-Tosyl-2-butenyl)piperidine (3k): An oil (Z/E = 55/
45). IR (neat) 3030, 2933, 2853, 2795, 2754, 1597, 1494, 1467,
1453, 1402, 1372, 1318, 1303, 1242, 1141, 1118, 1088, 1041,
1019, 991, 901, 861, 816, 778, 734, 713, 690, 664 cmꢂ1. Z isomer;
1H NMR (CDCl3) ꢅ 1.30–1.45 (2H, m), 1.45–1.55 (4H, m), 2.10–
2.30 (4H, m), 2.44 (3H, s), 2.98 (2H, dd, J ¼ 6:59, 1.71 Hz), 3.90
(2H, d, J ¼ 7:81 Hz), 5.54 (1H, dtt, J ¼ 10:98, 7.81, 1.71 Hz),
5.84 (1H, dt, J ¼ 10:98, 6.59 Hz), 7.33 (2H, d, J ¼ 8:29 Hz),
7.72 (2H, d, J ¼ 8:29 Hz). E isomer; 1H NMR (CDCl3) ꢅ 1.30–
1.45 (2H, m), 1.40–1.55 (4H, m), 2.10–2.30 (4H, m), 2.44 (3H,
s), 2.88 (2H, d, J ¼ 4:64 Hz), 3.79 (2H, d, J ¼ 5:37 Hz), 5.50–
5.60 (1H, m), 5.58 (1H, dt, J ¼ 15:59, 5.37 Hz), 7.34 (2H,
d, J ¼ 8:29 Hz), 7.76 (2H, d, J ¼ 8:29 Hz). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 294.15420. Calcd for C16H24NO2S:
294.15277.
Nucleophilic Addition Reaction of Diethylamine (2d) to (E)-
1-Tosyl-1,3-butadiene (1) under Dilute Conditions at 60 ꢀC
(Table 3, Entry 5). To a solution of (E)-1-tosyl-1,3-butadiene
(1) (129 mg, 0.62 mmol) in THF (198 mL) was added diethyl-
amine (2d) (0.77 mL, 7.43 mmol) at 60 ꢁC under a nitrogen atmo-
sphere. After stirring for 72 h, the reaction mixture was quenched
by adding silica gel (3.34 g), and the solvent was evaporated. The
residue was purified by column chromatography (SiO2, hexane/
EtOAc = 5/1, v/v, EtOAc, then EtOAc/MeOH = 3/1, v/v) to
give a mixture of (Z)- and (E)-3d (125 mg, 72%, Z/E = 98/2)
and to recover unreacted 1 (36 mg, 28%).
A Representative Procedure for the Nucleophilic Addition
Reaction of Piperidine (2k) to Ethyl (E)-2,4-Pentadienoate
(4) (Table 5, Entry 10). To a solution of ethyl (E)-2,4-penta-
dienoate (4)22 (67 mg, 0.53 mmol) in THF (5.3 mL) was added
piperidine (2k) (0.079 mL, 0.80 mmol) at 25 ꢁC under a nitrogen
atmosphere. After stirring for 72 h, the reaction mixture was
quenched by adding silica gel (2.80 g), and the solvent was evapo-
rated. The residue was purified by column chromatography (SiO2,
hexane/EtOAc = 5/1, v/v, EtOAc, then EtOAc/MeOH = 3/1,
v/v) to give a mixture of (Z)- and (E)-5k (65 mg, 58%, Z/E =
68/32) and to recover unreacted 4 (25 mg, 37%).
N-Butyl-N-methyl-4-tosyl-2-butenylamine (3h):
An oil
(Z/E = 72/28). IR (neat) 3030, 2956, 2931, 2871, 2789, 1597,
1494, 1458, 1403, 1376, 1318, 1303, 1240, 1206, 1144, 1088,
1040, 1019, 976, 886, 859, 816, 782, 713, 688, 664 cmꢂ1. Z iso-
mer; 1H NMR (CDCl3) ꢅ 0.89 (3H, t, J ¼ 7:32 Hz), 1.22–1.44
(4H, m), 2.02 (3H, s), 2.16 (2H, t, J ¼ 7:81 Hz), 2.44 (3H, s),
2.70 (2H, dd, J ¼ 6:34, 1.46 Hz), 3.90 (2H, d, J ¼ 7:81 Hz),
5.54 (1H, dtt, J ¼ 10:98, 7.81, 1.46 Hz), 5.83 (1H, dt, J ¼
10:98, 6.34 Hz), 7.34 (2H, d, J ¼ 8:05 Hz), 7.75 (2H, d, J ¼
8:05 Hz). E isomer; 1H NMR (CDCl3) ꢅ 0.90 (3H, t, J ¼
7:32 Hz), 1.22–1.44 (4H, m), 2.08 (3H, s), 2.24 (2H, t, J ¼
7:81 Hz), 2.44 (3H, s), 2.94 (2H, d, J ¼ 4:64 Hz), 3.79 (2H, d,
J ¼ 5:37 Hz), 5.52–5.62 (1H, m), 5.61 (1H, dt, J ¼ 15:38,
5.37 Hz), 7.33 (2H, d, J ¼ 7:81 Hz), 7.73 (2H, d, J ¼ 7:81 Hz).
HRMS (FABþ) ðM þ HÞþ, Found: m=z 296.16882. Calcd for
C16H26NO2S: 296.16842.
N-Isopropyl-N-methyl-4-tosyl-2-butenylamine (3i): An oil
(Z/E = 80/20). IR (neat) 3030, 2966, 2792, 1597, 1453, 1402,
1383, 1362, 1317, 1304, 1236, 1143, 1088, 1018, 975, 876, 816,
769, 712, 688, 664 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.92
(6H, d, J ¼ 6:58 Hz), 1.99 (3H, s), 2.44 (3H, s), 2.68 (1H, sept,
J ¼ 6:58 Hz), 2.73 (2H, dd, J ¼ 6:34, 1.22 Hz), 3.91 (2H, d,
J ¼ 8:05 Hz), 5.52 (1H, dtt, J ¼ 10:98, 8.05, 1.22 Hz), 5.83 (1H,
dt, J ¼ 10:98, 6.34 Hz), 7.35 (2H, d, J ¼ 8:05 Hz), 7.76 (2H, d,
J ¼ 8:05 Hz). E isomer; 1H NMR (CDCl3) ꢅ 0.93 (6H, d, J ¼
6:58 Hz), 2.04 (3H, s), 2.44 (3H, s), 2.68 (1H, sept, J ¼
6:57 Hz), 2.98 (2H, d, J ¼ 4:15 Hz), 3.78 (2H, d, J ¼ 5:86 Hz),
5.56–5.62 (1H, m), 5.60 (1H, dt, J ¼ 15:14, 5.86 Hz), 7.32 (2H,
d, J ¼ 8:05 Hz), 7.73 (2H, d, J ¼ 8:05 Hz). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 282.15318. Calcd for C15H24NO2S:
282.15277.
In a similar way, reactions of amines 2a–2e and 2g–2j with
ethyl (E)-2,4-pentadienoate (4) were carried out to give the corre-
sponding addition products 5a–5e and 5g–5j. The physical and
spectral data of 5a–5e and 5g–5k and by-products are given in
1
the following. Z/E ratios were determined by 400 MHz H NMR
spectra. In the cases of Me2NH, Et2NH, n-Pr2NH, n-Bu2NH,
n-Bu(Me)NH, i-Pr(Me)NH, and pyrrolidine, the Z/E ratios were
measured in CDCl3 containing CF3CO2D in order to separate
1H NMR peaks, and no isomerization was observed for 24 h. Only
specific chemical shifts, which were measured in CDCl3 contain-
ing CF3CO2D and used for determination of Z/E ratios, are
shown.
1-(4-Tosyl-2-butenyl)pyrrolidine (3j): An oil (Z/E = 44/
56). IR (neat) 3030, 2963, 2875, 2789, 1597, 1494, 1459, 1402,
1347, 1317, 1304, 1291, 1236, 1142, 1088, 1018, 969, 929, 878,
816, 715, 669 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 1.65–1.78
(4H, m), 2.28–2.40 (4H, m), 2.44 (3H, s), 2.88 (2H, d, J ¼
6:59 Hz), 3.91 (2H, d, J ¼ 7:81 Hz), 5.51 (1H, dt, J ¼ 10:98,
7.81 Hz), 5.84 (1H, dt, J ¼ 10:98, 6.59 Hz), 7.34 (2H, d, J ¼
Ethyl 5-(Propylamino)-3-pentenoate (5a):
An oil (Z/
E = 7/93). IR (neat) 3317, 2960, 2933, 2874, 2816, 1738,
1652, 1462, 1408, 1369, 1330, 1301, 1256, 1175, 1096, 1029,
1
972, 937, 856, 808, 786, 751 cmꢂ1. Z isomer; H NMR (CDCl3)
ꢅ 0.92 (3H, t, J ¼ 7:32 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 1.52
(2H, sext, J ¼ 7:32 Hz), 2.10–2.25 (1H, m), 2.59 (2H, t, J ¼
7:32 Hz), 3.12 (2H, d, J ¼ 5:12 Hz), 3.30 (2H, d, J ¼ 4:64 Hz),

748 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
1
4.15 (2H, q, J ¼ 7:07 Hz), 5.72–5.78 (2H, m). E isomer; 1H NMR
(CDCl3) ꢅ 0.92 (3H, t, J ¼ 7:32 Hz), 1.26 (3H, t, J ¼ 7:07 Hz),
1.52 (2H, sext, J ¼ 7:32 Hz), 2.10–2.25 (1H, m), 2.59 (2H, t, J ¼
7:32 Hz), 3.06 (2H, d, J ¼ 5:85 Hz), 3.26 (2H, d, J ¼ 5:37 Hz),
4.14 (2H, q, J ¼ 7:07 Hz), 5.67 (1H, dt, J ¼ 15:61, 5.37 Hz),
5.74 (1H, dt, J ¼ 15:61, 5.85 Hz). HRMS (FABþ) ðM þ HÞþ,
Found: m=z 186.14923. Calcd for C10H20NO2: 186.14940.
1-Propyl-3,6-dihydro-1H-pyridin-2-one: An oil. IR (neat)
2964, 2931, 2872, 1637, 1497, 1458, 1411, 1267, 1164, 979,
dtt, J ¼ 15:37, 6.83, 1.22 Hz). H NMR (CDCl3 with CF3CO2D)
ꢅ 2.83 (2H, d, J ¼ 7:07 Hz). HRMS (FABþ) ðM þ HÞþ, Found:
m=z 200.16450. Calcd for C11H22NO2: 200.16505.
Ethyl 5-(Dipropylamino)-3-pentenoate (5e):
An oil (Z/
E = 90/10). IR (neat) 3030, 2959, 2934, 2873, 2800, 1740,
1458, 1367, 1319, 1254, 1163, 1095, 1075, 1033, 973, 848, 748,
676 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.87 (6H, t, J ¼
7:32 Hz), 1.26 (3H, t, J ¼ 7:32 Hz), 1.47 (4H, sext, J ¼
7:32 Hz), 2.39 (4H, t, J ¼ 7:32 Hz), 3.12 (2H, d, J ¼ 5:61 Hz),
3.13 (2H, d, J ¼ 4:64 Hz), 4.15 (2H, q, J ¼ 7:32 Hz), 5.68 (1H,
dt, J ¼ 10:98, 4.64 Hz), 5.73 (1H, dt, J ¼ 10:98, 5.61 Hz).
1H NMR (CDCl3 with CF3CO2D) ꢅ 3.84 (2H, d, J ¼ 4:64 Hz).
E isomer; 1H NMR (CDCl3) ꢅ 0.87 (6H, t, J ¼ 7:32 Hz), 1.26
(3H, t, J ¼ 7:32 Hz), 1.47 (4H, sext, J ¼ 7:32 Hz), 2.42 (4H, t,
J ¼ 7:32 Hz), 3.07 (4H, d, J ¼ 6:34 Hz), 4.14 (2H, q, J ¼
7:32 Hz), 5.63 (1H, dt, J ¼ 15:61, 6.34 Hz), 5.66 (1H, dt, J ¼
15:61, 6.34 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 3.75
(2H, d, J ¼ 6:34 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z
228.19671. Calcd for C13H26NO2: 228.19635.
Ethyl 5-(Dibutylamino)-3-pentenoate (5g): An oil (Z/E =
94/6). IR (neat) 3030, 2957, 2932, 2871, 2798, 1740, 1652,
1456, 1367, 1318, 1252, 1162, 1096, 1034, 973, 937, 852, 735,
668 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.90 (6H, t, J ¼
7:07 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 1.29 (4H, sext, J ¼
7:07 Hz), 1.43 (4H, tt, J ¼ 7:56, 7.07 Hz), 2.41 (4H, t, J ¼
7:56 Hz), 3.09 (2H, d, J ¼ 5:86 Hz), 3.12 (2H, d, J ¼ 5:61 Hz),
4.15 (2H, q, J ¼ 7:07 Hz), 5.68 (1H, dt, J ¼ 10:73, 5.86 Hz),
5.72 (1H, dt, J ¼ 10:73, 5.61 Hz). 1H NMR (CDCl3 with
CF3CO2D) ꢅ 3.85 (2H, d, J ¼ 5:61 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 0.90 (6H, t, J ¼ 7:07 Hz), 1.26 (3H, t, J ¼ 7:07 Hz),
1.27 (4H, sext, J ¼ 7:07 Hz), 1.43 (4H, tt, J ¼ 7:32, 7.07 Hz),
2.40 (4H, t, J ¼ 7:32 Hz), 3.06 (4H, d, J ¼ 5:61 Hz), 4.13 (2H,
q, J ¼ 7:07 Hz), 5.62 (1H, dt, J ¼ 15:61, 5.61 Hz), 5.68 (1H, dt,
J ¼ 15:61, 5.61 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 3.76
(2H, d, J ¼ 5:61 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z
256.22696. Calcd for C15H30NO2: 256.22765.
900, 675 cmꢂ1
.
1H NMR (CDCl3) ꢅ 0.92 (3H, t, J ¼ 7:32 Hz),
1.61 (2H, sext, J ¼ 7:32 Hz), 2.90–2.98 (2H, m), 3.39 (2H, t,
J ¼ 7:32 Hz), 3.88–3.93 (2H, m), 5.66–5.80 (2H, m). HRMS
(FABþ) ðM þ HÞþ, Found: m=z 140.10772. Calcd for C8H14NO:
140.10754.
Ethyl 5-(Butylamino)-3-pentenoate (5b): An oil (Z/E =
11/89). IR (neat) 3391, 2959, 2931, 2872, 2821, 1736, 1652,
1540, 1465, 1409, 1370, 1303, 1254, 1174, 1096, 1029, 973,
940, 856, 810, 736 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.91
(3H, t, J ¼ 7:32 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 1.34 (2H, sext,
J ¼ 7:32 Hz), 1.48 (2H, quint, J ¼ 7:32 Hz), 1.90–2.02 (1H, m),
2.62 (2H, t, J ¼ 7:32 Hz), 3.12 (2H, d, J ¼ 5:37 Hz), 3.30 (2H,
d, J ¼ 4:88 Hz), 4.15 (2H, q, J ¼ 7:07 Hz), 5.66–5.77 (2H, m).
E isomer; 1H NMR (CDCl3) ꢅ 0.91 (3H, t, J ¼ 7:32 Hz), 1.26
(3H, t, J ¼ 7:07 Hz), 1.34 (2H, sext, J ¼ 7:32 Hz), 1.48 (2H,
quint, J ¼ 7:32 Hz), 1.90–2.02 (1H, m), 2.61 (2H, t, J ¼
7:32 Hz), 3.06 (2H, d, J ¼ 5:61 Hz), 3.25 (2H, d, J ¼ 5:12 Hz),
4.14 (2H, q, J ¼ 7:07 Hz), 5.67 (1H, dt, J ¼ 15:61, 5.12 Hz),
5.73 (1H, dt, J ¼ 15:61, 5.61 Hz). HRMS (FABþ) ðM þ HÞþ,
Found: m=z 200.16450. Calcd for C11H22NO2: 200.16505.
1-Butyl-3,6-dihydro-1H-pyridin-2-one:
An oil. IR (neat)
3047, 2958, 2931, 2871, 1634, 1496, 1456, 1411, 1375, 1326,
1298, 1251, 1197, 1165, 1131, 1112, 1083, 984, 854, 734,
677 cmꢂ1
.
1H NMR (CDCl3) ꢅ 0.94 (3H, t, J ¼ 7:56 Hz), 1.34
(2H, sext, J ¼ 7:56 Hz), 1.56 (2H, quint, J ¼ 7:56 Hz), 2.93–
2.97 (2H, m), 3.42 (2H, t, J ¼ 7:56 Hz), 3.88–3.94 (2H, m),
5.69–5.80 (2H, m). HRMS (FABþ) ðM þ HÞþ, Found: m=z
154.12298. Calcd for C9H16NO: 154.12319.
Ethyl 5-(Butylmethylamino)-3-pentenoate (5h):
An oil,
Ethyl 5-(Dimethylamino)-3-pentenoate (5c): An oil (Z/E =
76/24). IR (neat) 2979, 2941, 2857, 2817, 2772, 1737, 1652,
1457, 1367, 1320, 1259, 1175, 1096, 1031, 975, 853 cmꢂ1. Z iso-
(Z/E = 74/26). IR (neat) 3028, 2957, 2933, 2872, 2840, 2787,
1739, 1652, 1462, 1367, 1319, 1255, 1164, 1096, 1063, 1033,
973, 858, 736 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 0.91 (3H, t,
J ¼ 7:32 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 1.31 (2H, sext, J ¼
7:32 Hz), 1.46 (2H, quint, J ¼ 7:32 Hz), 2.21 (3H, s), 2.33 (2H,
t, J ¼ 7:32 Hz), 3.02 (2H, d, J ¼ 5:86 Hz), 3.12 (2H, d, J ¼
6:34 Hz), 4.15 (2H, q, J ¼ 7:07 Hz), 5.68 (1H, dt, J ¼ 10:73,
6.34 Hz), 5.74 (1H, dt, J ¼ 10:73, 5.86 Hz). 1H NMR (CDCl3 with
CF3CO2D) ꢅ 3.10–3.25 (4H, m). E isomer; 1H NMR (CDCl3) ꢅ
0.91 (3H, t, J ¼ 7:32 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 1.31 (2H,
sext, J ¼ 7:32 Hz), 1.45 (2H, quint, J ¼ 7:32 Hz), 2.21 (3H, s),
2.34 (2H, t, J ¼ 7:32 Hz), 2.99 (2H, d, J ¼ 6:59 Hz), 3.07 (2H,
d, J ¼ 6:34 Hz), 4.14 (2H, q, J ¼ 7:07 Hz), 5.63 (1H, dt,
1
mer; H NMR (CDCl3) ꢅ 1.26 (3H, t, J ¼ 7:07 Hz), 2.24 (6H, s),
2.96 (2H, d, J ¼ 6:34 Hz), 3.13 (2H, d, J ¼ 6:42 Hz), 4.15 (2H, q,
J ¼ 7:07 Hz), 5.67 (1H, dt, J ¼ 10:98, 6.34 Hz), 5.75 (1H, dt,
J ¼ 10:98, 6.42 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 3.74–
3.82 (2H, m). E isomer; 1H NMR (CDCl3) ꢅ 1.26 (3H, t,
J ¼ 7:07 Hz), 2.23 (6H, s), 2.92 (2H, d, J ¼ 6:34 Hz), 3.07 (2H,
d, J ¼ 6:59 Hz), 4.14 (2H, q, J ¼ 7:07 Hz), 5.61 (1H, dt,
1
J ¼ 15:37, 6.34 Hz), 5.72 (1H, dt, J ¼ 15:37, 6.59 Hz). H NMR
(CDCl3 with CF3CO2D) ꢅ 3.63–3.71 (2H, m). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 172.13432. Calcd for C9H18NO2:
172.13375.
1
J ¼ 15:86, 6.34 Hz), 5.71 (1H, dt, J ¼ 15:86, 6.59 Hz). H NMR
Ethyl 5-(Diethylamino)-3-pentenoate (5d): An oil (Z/E =
87/13). IR (neat) 2960, 2923, 2853, 1732, 1457, 1367, 1280,
1260, 1181, 1033, 850, 705, 670 cmꢂ1. Z isomer; 1H NMR (C6D6)
ꢅ 0.90 (6H, t, J ¼ 7:08 Hz), 0.93 (3H, t, J ¼ 7:07 Hz), 2.35 (4H, q,
J ¼ 7:08 Hz), 2.95–2.98 (4H, m), 3.92 (2H, q, J ¼ 7:07 Hz), 5.66
(1H, dtt, J ¼ 10:98, 6.59, 1.46 Hz), 5.78 (1H, dtt, J ¼ 10:98, 7.32,
1.46 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 2.97 (2H, d,
J ¼ 6:59 Hz). E isomer; 1H NMR (C6D6) ꢅ 0.94 (9H, t, J ¼
7:08 Hz), 2.39 (4H, q, J ¼ 7:08 Hz), 2.87 (2H, dd, J ¼ 6:83,
1.22 Hz), 2.94 (2H, dd, J ¼ 6:34, 1.22 Hz), 3.92 (2H, q,
J ¼ 7:08 Hz), 5.56 (1H, dtt, J ¼ 15:37, 6.34, 1.22 Hz), 5.73 (1H,
(CDCl3 with CF3CO2D) ꢅ 2.95–3.05 (4H, m). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 214.18101. Calcd for C12H24NO2:
214.18070.
Ethyl 5-(Isopropylmethylamino)-3-pentenoate (5i): An oil
(Z/E = 82/18). IR (neat) 3030, 2966, 2930, 2880, 2840, 2789,
1739, 1652, 1456, 1366, 1320, 1258, 1176, 1094, 1034, 974,
1
874, 796, 688 cmꢂ1. Z isomer; H NMR (CDCl3) ꢅ 1.05 (6H, d,
J ¼ 6:59 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 2.21 (3H, s), 2.90 (1H,
sept, J ¼ 6:59 Hz), 3.10 (2H, d, J ¼ 6:10 Hz), 3.13 (2H, d, J ¼
5:85 Hz), 4.15 (2H, q, J ¼ 7:07 Hz), 5.70 (1H, dt, J ¼ 10:98,
6.10 Hz), 5.74 (1H, dt, J ¼ 10:98, 5.85 Hz). 1H NMR (CDCl3 with

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
749
NBS
EWG
EWG
Br
t-BuOH / H2O
OH
1; EWG = Ts
4; EWG = CO2Et
14; EWG = Ts, 52%
16; EWG = CO2Et, 56%
EWG
EWG
DAST
CH2Cl2
DBU
THF
Br
F
F
15; EWG = Ts, 94%
6; EWG = Ts, 95%
17; EWG = CO2Et, 90%
8; EWG = CO2Et, 76%
1) n-BuLi
1) LDA
2) CH2=CHCH2Br
2) MeSSMe
Ts
Ts
Ts
THF-HMPA
THF-HMPA
MeS
F
F
F
19; 77%
18
20; 71%
Ts
F
Ts
∆
mCPBA
CH2Cl2
THF
MeS
O
F
21; 87%
10; 99%
1) ClCO2i-Bu, Et3N
2) OctOH
I2
CO2H
CO2Oct
F
+
THF
CH2Cl2
F
CO2Oct
F
22
12; 43%
(E)-isomer
Scheme 2.
CF3CO2D) ꢅ 2.75 (3H, s). E isomer; 1H NMR (CDCl3) ꢅ 1.06
(6H, d, J ¼ 6:59 Hz), 1.26 (3H, t, J ¼ 7:07 Hz), 2.23 (3H, s),
2.91 (1H, sept, J ¼ 6:59 Hz), 3.08 (2H, d, J ¼ 6:83 Hz), 3.10
(2H, d, J ¼ 6:10 Hz), 4.14 (2H, q, J ¼ 7:07 Hz), 5.67 (1H, dt,
J ¼ 10:25, 5.12 Hz). E isomer; 1H NMR (CDCl3) ꢅ 1.26 (3H, t,
J ¼ 7:08 Hz), 1.38–1.50 (2H, m), 1.59 (4H, quint, J ¼ 5:61 Hz),
2.31–2.44 (4H, m), 2.95 (2H, d, J ¼ 5:37 Hz), 3.07 (2H, d,
J ¼ 5:61 Hz), 4.13 (2H, q, J ¼ 7:08 Hz), 5.65 (1H, dt, J ¼
15:39, 5.61 Hz), 5.68 (1H, dt, J ¼ 15:39, 5.37 Hz). HRMS
(FABþ) ðM þ HÞþ, Found: m=z 212.16534. Calcd for C12H22NO2:
212.16505.
Nucleophilic Addition Reaction of Piperidine (2k) to Ethyl
(E)-2,4-Pentadienoate (4) under Dilute Conditions at 60 ꢀC
(Table 6, Entry 8). To a solution of ethyl (E)-2,4-pentadienoate
(4) (65 mg, 0.52 mmol) in THF (83 mL) was added piperidine (2k)
(0.306 mL, 3.09 mmol) at 60 ꢁC under a nitrogen atmosphere. Af-
ter stirring for 72 h, the reaction mixture was quenched by adding
silica gel (3.02 g), and the solvent was evaporated. The residue
was purified by column chromatography (SiO2, hexane/EtOAc =
5/1, v/v, EtOAc, then EtOAc/MeOH = 3/1, v/v) to give a mix-
ture of (Z)- and (E)-5k (54 mg, 50%, Z/E = 89/11) and to recov-
er unreacted 4 (26 mg, 40%).
1
J ¼ 15:37, 6.83 Hz), 5.71 (1H, dt, J ¼ 15:37, 6.10 Hz). H NMR
(CDCl3 with CF3CO2D) ꢅ 2.72 (3H, s). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 200.16542. Calcd for C11H22NO2:
200.16505.
Ethyl 5-(Pyrrolidin-1-yl)-3-pentenoate (5j): An oil (Z/E =
59/41). IR (neat) 3029, 2967, 2908, 2875, 2787, 1739, 1655,
1461, 1445, 1407, 1368, 1345, 1320, 1256, 1173, 1096, 1033,
940, 902, 879, 858 cmꢂ1. Z isomer; 1H NMR (CDCl3) ꢅ 1.26
(3H, t, J ¼ 7:07 Hz), 1.72–1.82 (4H, m), 2.50–2.57 (4H, m),
3.14 (2H, d, J ¼ 6:34 Hz), 3.15 (2H, d, J ¼ 5:86 Hz), 4.15 (2H,
q, J ¼ 7:07 Hz), 5.70 (1H, dt, J ¼ 10:98, 6.34 Hz), 5.73 (1H, dt,
J ¼ 10:98, 5.86 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 3.73
1
(2H, d, J ¼ 5:86 Hz). E isomer; H NMR (CDCl3) ꢅ 1.26 (3H, t,
J ¼ 7:07 Hz), 1.72–1.82 (4H, m), 2.50–2.57 (4H, m), 3.06 (2H,
d, J ¼ 5:61 Hz), 3.10 (2H, d, J ¼ 5:37 Hz), 4.15 (2H, q,
J ¼ 7:07 Hz), 5.69 (1H, dt, J ¼ 15:39, 5.61 Hz), 5.75 (1H, dt,
J ¼ 15:39, 5.37 Hz). 1H NMR (CDCl3 with CF3CO2D) ꢅ 3.66
(2H, d, J ¼ 5:37 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z
198.14951. Calcd for C11H20NO2: 198.14940.
Fluorine-substituted dienes 6, 8, 10, and 12 were prepared as
shown in Scheme 2.
(E)-1-Bromo-4-tosylbut-3-en-2-ol (14): To a solution of 1
(198 mg, 0.951 mmol) in t-BuOH (10 mL) and H2O (12 mL) was
added NBS (254 mg, 1.43 mmol). After 48 h, the reaction mixture
was quenched with a saturated solution of NaHSO3, and the sol-
vent was evaporated. The organic substances were extracted with
Et2O, followed by washing with H2O, brine, and dried over
Na2SO4. After evaporating the solvent, the residue was separated
by preparative TLC (SiO2, hexane/EtOAc = 5/1, v/v) to give 14
in 52% yield (152 mg). Mp 119.5–120.0 ꢁC (from hexane/
EtOAc). IR (KBr) 3481, 3054, 2980, 2940, 2870, 1630, 1596,
Ethyl 5-(Piperidin-1-yl)-3-pentenoate (5k): An oil (Z/E =
68/32). IR (neat) 3030, 2935, 2854, 2790, 1739, 1651, 1455,
1367, 1319, 1254, 1160, 1115, 1037, 999, 861, 792 cmꢂ1. Z iso-
mre; 1H NMR (CDCl3) ꢅ 1.26 (3H, t, J ¼ 7:08 Hz), 1.38–1.50
(2H, m), 1.59 (4H, quint, J ¼ 5:61 Hz), 2.31–2.44 (4H, m), 2.98
(2H, d, J ¼ 5:12 Hz), 3.12 (2H, d, J ¼ 5:37 Hz), 4.14 (2H, q,
J ¼ 7:08 Hz), 5.70 (1H, dt, J ¼ 10:25, 5.37 Hz), 5.72 (1H, dt,

750 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
1494, 1399, 1375, 1316, 1303, 1145, 1086, 1044, 1018, 971, 915,
1
tion of 16 (125 mg, 0.560 mmol) in CH2Cl2 (4.0 mL) was added
DAST (0.111 mL, 0.841 mmol) at 0 ꢁC under a nitrogen atmo-
sphere. After 70 min, the reaction mixture was quenched with cool
water, and the solvent was evaporated. The organic substances
were extracted with EtOAc, followed by washing with H2O, brine,
and dried over Na2SO4. After evaporating the solvent, the residue
was purified by preparative TLC (SiO2, hexane/EtOAc = 5/1,
v/v) to give 17 in 90% yield (114 mg) as an oil. IR (neat) 2983,
2940, 2906, 2875, 1722, 1665, 1467, 1446, 1420, 1392, 1370,
1347, 1308, 1274, 1183, 1095, 1065, 1044, 979, 902, 876, 857,
813, 733, 706, 662 cmꢂ1. H NMR (CDCl3) ꢅ 2.43 (3H, s), 3.25
(1H, d, J ¼ 5:37 Hz), 3.43 (1H, dd, J ¼ 10:49, 6.10 Hz), 3.53
(1H, dd, J ¼ 10:49, 4.39 Hz), 4.58–4.63 (1H, m), 6.71 (1H, dd,
J ¼ 15:37, 2.44 Hz), 6.92 (1H, dd, J ¼ 15:37, 3.66 Hz), 7.33
(2H, d, J ¼ 7:81 Hz), 7.75 (2H, d, J ¼ 7:81 Hz). Found: C,
43.34; H, 4.24%. Calcd for C11H13O3SBr: C, 43.29; H, 4.29%.
(E)-4-Bromo-3-fluoro-1-tosyl-1-butene (15): To a solution
of 14 (92 mg, 0.301 mmol) in CH2Cl2 (4 mL) was added DAST
(0.060 mL, 0.452 mmol) at 0 ꢁC under a nitrogen atmosphere. Af-
ter 4 h, the reaction mixture was quenched with cool water, and
the solvent was evaporated. The organic substances were extract-
ed with EtOAc, followed by washing with H2O, brine, and dried
over Na2SO4. After evaporating the solvent, the residue was puri-
fied by preparative TLC (SiO2, hexane/EtOAc = 3/1, v/v) to
give 15 in 94% yield (87 mg). Mp 94.5–95.0 ꢁC (from hexane/
EtOAc). IR (KBr) 3075, 3030, 2970, 2920, 1596, 1422, 1315,
1304, 1280, 1210, 1149, 1086, 1019, 964, 934, 841, 812, 795,
825, 720, 687 cmꢂ1
.
1H NMR (CDCl3) ꢅ 1.31 (3H, t, J ¼ 7:07
Hz), 3.51 (1H, ddd, J ¼ 24:15, 9.27, 5.86 Hz), 3.54 (1H, ddd,
J ¼ 24:15, 9.27, 5.86 Hz), 4.23 (2H, q, J ¼ 7:07 Hz), 5.29 (1H,
dddt, J ¼ 47:08, 4.39, 1.71, 5.86 Hz), 6.17 (1H, dt, J ¼ 15:61,
1.71 Hz), 6.88 (1H, ddd, J ¼ 19:27, 15.61, 4.39 Hz). 19F NMR
(CDCl3) ꢅ ꢂ181:1 (1F, ddt, J ¼ 47:08, 19.27, 24.15 Hz). HRMS
(FABþ) ðM þ HÞþ, Found: m=z 224.99253, 226.99238. Calcd
for C7H11O2F79Br: 224.99264. Calcd for C7H11O2FB81Br:
226.99060.
1
708, 696, 666 cmꢂ1. H NMR (CDCl3) ꢅ 2.45 (3H, s), 3.55 (1H,
ddd, J ¼ 20:91, 11.37, 5.50 Hz), 3.58 (1H, ddd, J ¼ 17:79,
11.37, 4.95 Hz), 5.37 (1H, ddddd, J ¼ 46:95, 5.50, 4.95, 3.30,
1.83 Hz), 6.69 (1H, dd, J ¼ 15:04, 1.83 Hz), 6.92 (1H, ddd,
J ¼ 20:72, 15.04, 3.30 Hz), 7.36 (2H, d, J ¼ 7:89 Hz), 7.78 (2H,
d, J ¼ 7:89 Hz). 19F NMR (CDCl3) ꢅ ꢂ182:2 (1F, ddt, J ¼
46:95, 17.79, 20.91 Hz). Found: C, 42.81; H, 3.90%. Calcd for
C11H12O2SFBr: C, 43.01; H, 3.94%.
Ethyl (E)-4-Fluoro-2,4-pentadienoate (8): To a solution of
17 (76 mg, 0.338 mmol) in THF (3.0 mL) was added DBU
(0.056 mL, 0.371 mmol) under a nitrogen atmosphere. After
5 min, the reaction mixture was quenched with a saturated solution
of NH4Cl, and the solvent was evaporated. The organic substances
were extracted with EtOAc, followed by washing with H2O, brine,
and dried over Na2SO4. After evaporating the solvent, the residue
was separated by column chromatography (SiO2, hexane/
EtOAc = 5/1, v/v) to give 8 in 76% yield (37 mg) as an oil. IR
(neat) 3050, 2984, 2940, 2906, 1719, 1653, 1618, 1467, 1447,
1395, 1367, 1307, 1258, 1230, 1177, 1096, 1036, 973, 953, 891,
(E)-3-Fluoro-1-tosyl-1,3-butadiene (6): To a solution of 15
(129 mg, 0.420 mmol) in THF (4.0 mL) was added DBU
(0.069 mL, 0.462 mmol) under a nitrogen atmosphere. After
5 min, the reaction mixture was quenched with a saturated solution
of NH4Cl, and the solvent was evaporated. The organic substances
were extracted with EtOAc, followed by washing with H2O, brine,
and dried over Na2SO4. After evaporating the solvent, the residue
was purified by column chromatography (SiO2, hexane/
EtOAc = 5/1, v/v) to give 6 in 95% yield (90 mg). Mp 90.3–
90.5 ꢁC (from hexane/EtOAc). IR (KBr) 3060, 1649, 1593,
1312, 1291, 1269, 1205, 1146, 1086, 1018, 971, 950, 885, 844,
866, 737 cmꢂ1
.
1H NMR (CDCl3) ꢅ 1.31 (3H, t, J ¼ 7:08 Hz),
4.23 (2H, q, J ¼ 7:08 Hz), 4.84 (1H, dd, J ¼ 46:35, 2.93 Hz),
5.04 (1H, dd, J ¼ 14:64, 2.93 Hz), 6.20 (1H, d, J ¼ 15:61 Hz),
7.05 (1H, dd, J ¼ 26:10, 15.61 Hz). 19F NMR (CDCl3) ꢅ
ꢂ112:99 (1F, ddd, J ¼ 46:35, 26.10, 14.64 Hz). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 145.06616. Calcd for C7H10O2F:
145.06648.
1
831, 816, 705, 670 cmꢂ1. H NMR (CDCl3) ꢅ 2.45 (3H, s), 4.96
4-Fluoro-4-tosyl-1-butene (19): To a mixed solution of 185b
(300 mg, 1.59 mmol) and HMPA (0.415 mL, 2.39 mmol) in THF
(15.9 mL) was added a solution of n-BuLi in hexane (1.14 mL,
1.75 mmol, 1.54 M) at ꢂ72 ꢁC under a nitrogen atmosphere, fol-
lowed by addition of allyl bromide (0.165 mL, 1.91 mmol) after
30 min. The reaction mixture was stirred for 10 min at ꢂ72 ꢁC
and for 3 h at room temperature, and then quenched by addition
of a saturated NH4Cl solution. After removing the solvent under
reduced pressure, the organic substances were extracted with
EtOAc, followed by washing with H2O, brine, and drying over
Na2SO4. After evaporating the solvent, the residue was separated
by preparative TLC (SiO2, hexane/EtOAc = 5/1, v/v) to give
19 in 77% yield (278 mg) as an oil. IR (neat) 3084, 2983, 2925,
1644, 1597, 1494, 1431, 1375, 1330, 1305, 1245, 1221, 1185,
1155, 1090, 1078, 1044, 1018, 989, 928, 867, 816, 737, 705,
663 cmꢂ1. 1H NMR (CDCl3) ꢅ 2.47 (3H, s), 2.63 (1H, ddddt, J ¼
20:00, 15.37, 9.76, 6.83, 1.22 Hz), 2.88 (1H, ddddt, J ¼ 36:10,
15.37, 6.83, 2.93, 1.22 Hz), 5.10 (1H, ddd, J ¼ 48:30, 9.76,
2.93 Hz), 5.22 (1H, dd, J ¼ 10:02, 1.22 Hz), 5.24 (1H, dd, J ¼
17:08, 1.22 Hz), 5.80 (1H, ddt, J ¼ 17:08, 10.02, 6.83 Hz), 7.39
(2H, d, J ¼ 8:29 Hz), 7.82 (2H, d, J ¼ 8:29 Hz). 19F NMR
(CDCl3) ꢅ ꢂ179:7 (1F, ddd, J ¼ 48:30, 36.10, 20.00 Hz). HRMS
(FABþ) ðM þ HÞþ, Found: m=z 229.06941. Calcd for
C11H14O2FS: 229.06985.
(1H, dd, J ¼ 45:86, 3.17 Hz), 5.13 (1H, dd, J ¼ 14:39, 3.17 Hz),
6.66 (1H, d, J ¼ 14:88 Hz), 7.05 (1H, dd, J ¼ 25:13, 14.88 Hz),
7.35 (2H, d, J ¼ 8:05 Hz), 7.78 (2H, d, J ¼ 8:05 Hz). 19F NMR
(CDCl3) ꢅ ꢂ111:8 (1F, ddd, J ¼ 45:86, 25.13, 14.39 Hz). Found:
C, 58.68; H, 5.00%. Calcd for C11H11FO2S: C, 58.39; H, 4.90%.
Ethyl (E)-5-Bromo-4-hydroxy-2-pentenoate (16): To a solu-
tion of 4 (252 mg, 2.00 mmol) in t-BuOH (5.0 mL) and H2O
(6.0 mL) was added NBS (534 g, 3.00 mmol). After 20 h, the reac-
tion mixture was quenched with a saturated solution of NaHSO3,
and the solvent was evaporated. The organic substances were ex-
tracted with Et2O, followed by washing with H2O, brine, and
dried over Na2SO4. After evaporating the solvent, the residue
was purified by preparative TLC (SiO2, hexane/EtOAc = 3/1,
v/v) to give 16 in 56% yield (252 mg) as an oil. IR (neat) 3443,
2982, 2939, 2904, 2874, 1716, 1659, 1467, 1445, 1420, 1393,
1370, 1307, 1276, 1220, 1182, 1096, 1040, 982, 900, 877, 858,
722, 655 cmꢂ1
.
1H NMR (CDCl3) ꢅ 1.30 (3H, t, J ¼ 7:08 Hz),
3.15 (1H, brs), 3.44 (1H, dd, J ¼ 10:49, 6.59 Hz), 3.56 (1H, dd,
J ¼ 10:49, 4.15 Hz), 4.21 (2H, q, J ¼ 7:08 Hz), 4.52–4.60 (1H,
m), 6.16 (1H, dd, J ¼ 15:61, 1.71 Hz), 6.90 (1H, dd, J ¼ 15:61,
4.65 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z 222.99672,
224.99452. Calcd for C7H12O379Br: 222.99698, Calcd for
C7H12O381Br: 224.99494.
Ethyl (E)-5-Bromo-4-fluoro-2-pentenoate (17): To a solu-
(E)-4-Fluoro-4-methylsulfanyl-4-tosyl-1-butene (20): In a

M. Yamazaki et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
751
dry flask, n-BuLi in hexane (0.740 mL, 1.14 mmol, 1.54 M) was
added to a solution of i-Pr2NH (115 mL, 1.14 mmol) in THF
(9.4 mL) at ꢂ72 ꢁC and the mixture was stirred for 30 min,
followed by dropwise addition of a solution of 19 (220 mg,
0.964 mmol) in THF (2.0 mL). After stirring for 30 min at
ꢂ72 ꢁC, MeSSMe (0.154 mL, 1.71 mmol) was added to the reac-
tion mixture and the mixture was stirred for 90 min at room tem-
perature. Then, the reaction mixture was quenched with phosphate-
buffer (pH 7.2). After evaporating the organic solvent, the product
was extracted with EtOAc, followed by washing with H2O, brine,
and drying over Na2SO4. After evaporating the solvent, the resi-
due was separated by preparative TLC (hexane/EtOAc = 9/1,
v/v) to afford 20 in 71% yield (188 mg) as an oil. IR (neat)
3083, 3027, 2983, 2935, 1642, 1597, 1493, 1428, 1333, 1306,
1292, 1244, 1212, 1185, 1155, 1087, 1040, 1018, 984, 970, 928,
lowed by washing with a saturated solution of NaHSO3, brine,
and drying over Na2SO4. The solvent was evaporated and the re-
sulting residue was purified by recycle HPLC (SiO2, hexane/
EtOAc = 40/1, v/v) to give (Z)-ester 12 in 43% yield (214 mg)
as an oil. IR (neat) 3094, 2957, 2927, 2857, 1824, 1729, 1646,
1598, 1468, 1421, 1391, 1380, 1338, 1288, 1227, 1189, 1140,
1100, 1000, 923, 774, 723, 658 cmꢂ1 1H NMR (CDCl3) ꢅ 0.89
.
(3H, t, J ¼ 7:08 Hz), 1.30–1.40 (10H, m), 1.70 (2H, quint, J ¼
6:83 Hz), 4.23 (2H, t, J ¼ 6:83 Hz), 5.44 (1H, d, J ¼ 10:25 Hz),
5.58 (1H, d, J ¼ 16:59 Hz), 6.58 (1H, dd, J ¼ 29:76, 10.98 Hz),
6.68 (1H, ddd, J ¼ 16:59, 10.98, 10.25 Hz). 19F NMR (CDCl3)
ꢅ ꢂ128:48 (1F, d, J ¼ 29:78 Hz). HRMS (FABþ) ðM þ HÞþ,
Found: m=z 229.15848. Calcd for C13H22O2F: 229.16038.
The addition reaction of amines 2d and 2k to the synthesized
fluorine-substituted dienes 6, 8, 10, and 12 was carried out in a
similar manner described for the addition to 1 and 4. The physical
and spectral data of the corresponding allylic products are given in
the following.
873, 815, 762, 706 cmꢂ1 1H NMR (CDCl3) ꢅ 2.34 (3H, d,
.
J ¼ 1:46 Hz), 2.48 (3H, s), 2.73–2.81 (2H, m), 5.14 (1H, dd,
J ¼ 17:08, 1.46 Hz), 5.21 (1H, dd, J ¼ 10:00, 1.46 Hz), 5.79
(1H, ddt, J ¼ 17:08, 10.00, 6.83 Hz), 7.39 (2H, d, J ¼ 8:05 Hz),
7.85 (2H, d, J ¼ 8:05 Hz). 19F NMR (CDCl3) ꢅ ꢂ141:3 (1F, dd,
J ¼ 20:65, 18.36 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z
275.05846. Calcd for C12H16O2FS2: 275.05758.
N,N-Diethyl-2-fluoro-4-tosyl-2-butenylamine (7):
An oil
(Z/E = 95/5). IR (neat) 2970, 2927, 2873, 1705, 1597, 1455,
1385, 1318, 1303, 1147, 1087, 920, 817, 753, 669 cmꢂ1. Z isomer;
1H NMR (CDCl3) ꢅ 0.96 (6H, t, J ¼ 7:08 Hz), 2.44 (3H, s), 2.44
(4H, q, J ¼ 7:08 Hz), 3.08 (2H, d, J ¼ 14:88 Hz), 3.89 (2H, d,
J ¼ 7:81 Hz), 4.95 (1H, dt, J ¼ 33:42, 7.81 Hz), 7.33 (2H, d,
J ¼ 8:05 Hz), 7.76 (2H, d, J ¼ 8:05 Hz). 19F NMR (CDCl3) ꢅ
ꢂ104:9 (1F, dt, J ¼ 33:42, 14.88 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 0.96 (6H, t, J ¼ 7:08 Hz), 2.44 (3H, s), 2.44 (4H, q,
J ¼ 7:08 Hz), 2.98 (2H, d, J ¼ 17:81 Hz), 3.92 (2H, d, J ¼
8:78 Hz), 5.22 (1H, dt, J ¼ 18:78, 8.78 Hz), 7.33 (2H, d, J ¼
8:05 Hz), 7.76 (2H, d, J ¼ 8:05 Hz). 19F NMR (CDCl3) ꢅ ꢂ92:0
(1F, dt, J ¼ 18:78, 17.81 Hz). HRMS (FABþ) ðM þ HÞþ, Found:
m=z 300.14305. Calcd for C15H23NO2SF: 300.14335. The stereo-
chemistry of (Z)- and (E)-7 was assigned based on JH{F through
the double bond.24 Furthermore, NOE analysis between methylene
protons and a vinylic proton in (Z)-7 supported the assignment
(Figure 4).
Ethyl 4-Fluoro-5-(piperidin-1-yl)-3-pentenoate (9): An oil
(Z/E = 99/1). IR (neat) 2970, 2937, 2856, 2807, 1739, 1371,
1343, 1308, 1248, 1183, 1029, 993, 949, 864, 669 cmꢂ1. Z isomer;
1H NMR (CDCl3) ꢅ 1.26 (3H, t, J ¼ 7:07 Hz), 1.40–1.48 (2H, m),
1.60 (4H, quint, J ¼ 5:61 Hz), 2.40–2.48 (4H, m), 3.05 (2H, d,
J ¼ 18:54 Hz), 3.16 (2H, dd, J ¼ 7:31, 0.98 Hz), 4.15 (2H, q,
J ¼ 7:07 Hz), 4.97 (1H, dt, J ¼ 35:62, 7.32 Hz). E isomer;
1H NMR (CDCl3) ꢅ 1.26 (3H, t, J ¼ 7:07 Hz), 1.40–1.48
(2H, m), 1.60 (4H, quint, J ¼ 5:61 Hz), 2.40–2.48 (4H, m), 2.88
(2H, d, J ¼ 18:05 Hz), 3.32 (2H, d, J ¼ 8:05 Hz), 4.15 (2H, q,
J ¼ 7:07 Hz), 5.44 (1H, dt, J ¼ 20:25, 8.05 Hz). 19F NMR
(CDCl3) ꢅ ꢂ100:2 (1F, dt, J ¼ 20:25, 18.05 Hz). HRMS (FABþ)
ðM þ HÞþ, Found: m=z 230.15619. Calcd for C12H21NO2F:
230.15563. The stereochemistry of (Z)- and (E)-9 was assigned
based on JH{F through the double bond.24
(E)-1-Fluoro-1-tosyl-1,3-butadiene (10):
Compound 20
(156 mg, 0.569 mmol) was treated with mCPBA (ca. 65%,
151 mg, 0.569 mmol) in the presence of NaHCO3 (96 mg,
1.14 mmol) in CH2Cl2 (6.0 mL) for 30 min at room temperature.
Then, the reaction mixture was quenched with a saturated aqueous
solution of NaHSO3. After evaporating the organic solvent, the
product was extracted with EtOAc, followed by washing with a
saturated solution of NaHCO3, H2O, brine, and drying over
Na2SO4. After removal of solvent, the residue was purified by pre-
parative TLC (hexane/EtOAc = 5/1, v/v) to afford 21 in 87%
yield (144 mg). A THF (4.0 mL) solution of the obtained sulfoxide
21 (65 mg, 0.224 mmol) was refluxed for 2 h. The reaction mixture
was condensed in vacuo to afford 10 in 99% yield (50 mg) as an
oil. The obtained 10 was used for the reaction with diethylamine
without further purification. IR (neat) 3050, 2925, 2854, 1812,
1724, 1651, 1596, 1492, 1457, 1333, 1305, 1212, 1154, 1087,
1
984, 930, 815, 706, 666 cmꢂ1. H NMR (CDCl3) ꢅ 2.46 (3H, s),
5.51 (1H, d, J ¼ 10:25 Hz), 5.65 (1H, d, J ¼ 17:08 Hz), 6.49
(1H, ddd, J ¼ 17:08, 10.98, 10.25 Hz), 6.70 (1H, dd, J ¼ 30:74,
10.98 Hz), 7.38 (2H, d, J ¼ 8:05 Hz), 7.83 (2H, d, J ¼ 8:05 Hz).
19F NMR (CDCl3) ꢅ ꢂ126:9 (1F, d, J ¼ 30:74 Hz). HRMS
(FABþ) ðM þ HÞþ, Found: m=z 227.05495. Calcd for
C11H12O2FS: 227.05420.
Octyl (Z)-2-Fluoro-2,4-pentadienoate (12):
To a mixed
solution of (Z)- and (E)-2-fluoro-2,4-pentadienoic acid (22)23
(252 mg, 2.17 mmol) in THF (5.0 mL) was added triethylamine
(0.303 mL, 2.17 mmol) and isobutyl chloroformate (0.282 mL,
2.17 mmol) at ꢂ15 ꢁC under a nitrogen atmosphere, followed by
addition of octanol (0.684 mL, 4.34 mmol) after 30 min. The reac-
tion mixture was stirred at room temperature overnight, and then
quenched by adding a saturated NH4Cl solution, and the solvent
was evaporated. The organic substances were extracted with
EtOAc, followed by washing with brine, and dried over Na2SO4.
After evaporating the solvent, the residue was purified by prepar-
ative TLC (SiO2, hexane/EtOAc = 30/1, v/v) to give a mixture
of (Z)-ester 12 and the corresponding E isomer. Then, the mixture
of esters (291 mg, 1.27 mmol) was treated with iodide (49 mg,
0.191 mmol) in CH2Cl2 (5.0 mL) at room temperature overnight
to isomerize (E)-ester to (Z)-ester 12. To the reaction mixture
was added H2O and the product was extracted with EtOAc, fol-
7.65%
8.10%
H
H H
H
H
Ts
Et2N
F
(Z)-7
Figure 4.

752 Bull. Chem. Soc. Jpn. Vol. 81, No. 6 (2008)
‘‘Syn Effect’’ in Addition of Amines to Dienes
´
68, 2223. b) L. Bernardi, J. Lopez-Cantarero, B. Niess, K. A.
N,N-Diethyl-4-fluoro-4-tosyl-2-butenylamine (11): An oil
(Z/E = 62/38). IR (neat) 2970, 2933, 2808, 1596, 1492, 1458,
Jørgensen, J. Am. Chem. Soc. 2007, 129, 5772. c) F. Naf, R.
¨
1384, 1330, 1305, 1200, 1153, 1088, 1045, 816, 712, 669 cmꢂ1
.
Decorzant, S. D. Escher, Tetrahedron Lett. 1982, 23, 5043.
A conjugate addition reaction of piperidine to an ꢂ-substi-
Z isomer; 1H NMR (CDCl3) ꢅ 1.02 (6H, t, J ¼ 7:08 Hz), 2.48
(3H, s), 2.50 (4H, q, J ¼ 7:08 Hz), 3.19–3.23 (2H, m), 5.48 (1H,
ddd, J ¼ 13:91, 11.47, 8.54 Hz), 6.05 (1H, dd, J ¼ 47:33,
8.54 Hz), 6.18 (1H, dt, J ¼ 11:47, 5.61 Hz), 7.39 (2H, d,
J ¼ 8:05 Hz), 7.81 (2H, d, J ¼ 8:05 Hz). 19F NMR (CDCl3) ꢅ
ꢂ171:3 (1F, dd, J ¼ 47:33, 13.91 Hz). E isomer; 1H NMR
(CDCl3) ꢅ 1.00 (6H, t, J ¼ 7:08 Hz), 2.47 (3H, s), 2.47 (4H, q,
J ¼ 7:08 Hz), 3.11–3.21 (2H, m), 5.50 (1H, dd, J ¼ 47:08,
6.34 Hz), 5.77 (1H, ddd, J ¼ 15:37, 15.12, 6.34 Hz), 6.10 (1H,
dt, J ¼ 15:12, 6.10 Hz), 7.37 (2H, d, J ¼ 8:05 Hz), 7.79 (2H, d,
J ¼ 8:05 Hz). 19F NMR (CDCl3) ꢅ ꢂ174:7 (1F, dd, J ¼ 47:08,
15.37 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z 300.14327.
Calcd for C15H23NO2SF: 300.14335.
7
tuted dienyl sulfone, (2E)-2-tosyl-2,4-pentadiene, produced the
corresponding (E)-allylic sulfones stereoselectively: T. Cuvigny,
C. Herve du Penhoat, M. Julia, Tetrahedron 1986, 42, 5321.
8
Preliminary results have been reported: M. Yamazaki,
S. K. Guha, Y. Ukaji, K. Inomata, Chem. Lett. 2006, 35, 514.
By 1H NMR measurement of the addition reaction of
9
Et2NH (2d) (150 mM) to 1 at 25 ꢁC, Z/E ratios of 3d were found
to be almost constant (between 75/25 and 73/27) in a period of
92 h.
10 a) R. Ballini, G. Bosica, D. Fiorini, Tetrahedron Lett. 2001,
42, 8471. b) D. Pettig, U. Schollkopf, Synthesis 1988, 173. c)
¨
U. M. Dzhemilev, A. Z. Yakupova, S. K. Minsker, G. A.
Tolstikov, J. Org. Chem. USSR. 1979, 15, 1041. d) E. J. Corey,
C. U. Kim, R. H. K. Chen, M. Takeda, J. Am. Chem. Soc. 1972,
Octyl 2-Fluoro-5-(piperidin-1-yl)-3-pentenoate (13): An oil
(Z/E = 50/50). IR (neat) 2931, 2856, 2799, 2760, 1764, 1742,
1467, 1278, 1197, 1156, 1119, 1039, 991, 862 cmꢂ1. Z isomer;
1H NMR (CDCl3) ꢅ 0.88 (3H, t, J ¼ 6:83 Hz), 1.20–1.40 (10H,
m), 1.40–1.50 (2H, m), 1.58 (4H, quint, J ¼ 5:61 Hz), 1.64 (2H,
quint, J ¼ 6:83 Hz), 2.30–2.50 (4H, m), 3.10–3.25 (2H, m), 4.19
(2H, dt, J ¼ 6:83, 1.46 Hz), 5.62 (1H, ddd, J ¼ 46:59, 9.27,
1.78 Hz), 5.68 (1H, dtt, J ¼ 10:98, 9.27, 1.46 Hz), 5.91 (1H, dt,
J ¼ 10:98, 6.83 Hz). 19F NMR (CDCl3) ꢅ ꢂ182:9 (1F, dd,
J ¼ 46:59, 9.27 Hz). E isomer; 1H NMR (CDCl3) ꢅ 0.88 (3H, t,
J ¼ 6:83 Hz), 1.20–1.40 (10H, m), 1.40–1.50 (2H, m), 1.58 (4H,
quint, J ¼ 5:61 Hz), 1.64 (2H, quint, J ¼ 6:83 Hz), 2.30–2.50
(4H, m), 2.98–3.03 (2H, m), 4.19 (2H, dt, J ¼ 1:22, 6.83 Hz),
5.26 (1H, ddd, J ¼ 48:81, 6.34, 1.78 Hz), 5.77 (1H, dtt,
J ¼ 6:34, 15.37, 1.46 Hz), 6.08 (1H, dddt, J ¼ 15:37, 3.42, 1.22,
6.59 Hz). 19F NMR (CDCl3) ꢅ ꢂ184:8 (1F, dd, J ¼ 48:81,
15.37 Hz). HRMS (FABþ) ðM þ HÞþ, Found: m=z 314.24791.
Calcd for C18H33NO2F: 314.24953.
´
´
94, 4395. e) G. de la Herran, C. Murcia, A. G. Csaky, Org. Lett.
¨
2005, 7, 5629.
11 In the cases of 5c–5e and 5g–5j, the Z/E ratios were deter-
mined by the spectra measured in CDCl3 containing CF3CO2D to
separate 1H NMR peaks, and no isomerization was observed for
24 h. Specific chemical shifts used for determination of Z/E ratios,
which were measured in CDCl3 containing CF3CO2D, are shown
in Experimental Section.
12 Reaction conditions: 4 (100 mM), Et2NH (300 mM), pro-
ton source (150 mM), THF, 25 ꢁC, 24 h. Without proton source
(4% yield; Z/E = 83/17), CF3CO2H (pKa ¼ 0;25a 42%; 7/93),
HCO2H (3.7;25a 14%; 12/88), 2,4,6-tri(t-butyl)phenol (12.19;25c
10%; 66/34), EtOH (17;25a 6%; 73/27), i-PrOH (18;25b 5%;
82/18), t-BuOH (19;25a 5%; 83/17).
13 Radical mechanism could be ruled out because the pres-
ence of TEMPO, N-hydroxyphthalimide, or galvinoxyl free radi-
cal did not affect the Z/E ratios.
14 Crystal structure of an (E)-1,3-butadienyl sulfone revealed
the conformation of its diene moiety to be s-trans: M. Zeller,
A. D. Hunter, P. Sampson, N. Chumachenko, Acta Crystallogr.,
Sect. E 2006, 62, o1369; An X-ray analysis of (E)-2,4-pentan-
dienoic acid also proved to be s-trans conformation: F. A. Cotton,
J. P. Donahue, C. A. Murillo, J. Am. Chem. Soc. 2003, 125, 5436;
Furthermore, methyl (E)-2,4-pentadienoate was reported to be
predominantly in the planar s-trans conformation in solution:
T. Fueno, K. Yamaguchi, J. Am. Chem. Soc. 1972, 94, 1119.
15 a) S. Winstein, J. Am. Chem. Soc. 1959, 81, 6524. b)
P. v. R. Schleyer, J. D. Dill, J. A. Pople, W. J. Hehre, Tetrahedron
1977, 33, 2497. c) L. A. Paquette, Angew. Chem., Int. Ed. Engl.
1978, 17, 106. d) D. Cremer, J. Am. Chem. Soc. 1979, 101,
7199. e) K. N. Houk, R. W. Strozier, N. G. Rondan, R. R. Fraser,
N. Chuaqui-Offermanns, J. Am. Chem. Soc. 1980, 102, 1426. f)
J. D. Fenske, K. T. Kuwata, K. N. Houk, S. E. Paulson, J. Phys.
Chem. A 2000, 104, 7246. g) S. Mangelinckx, N. Giubellina,
N. D. Kimpe, Chem. Rev. 2004, 104, 2353, and references cited
therein.
The present work was financially supported in part by
Grant-in-Aid for Scientific Research from Japan Society for
the Promotion of Science (JSPS).
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The ‘‘syn effect’’ is herein defined as an effect which stabil-
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ꢀ
16 An effective n ! ꢁ interaction cannot occur in the con-
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the ethyl ester and the octyl ester.5c,5e
´
´
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