Imino ene reaction catalyzed by Ytterbium(III) Triflate and TMSCl or TMSOTf

Article abstract of DOI:10.1021/jo0268153

A novel combined system of Yb(OTf)₃ with TMSCl or TMSOTf catalyzed an imino ene reaction. The reaction of N-tosylbenzaldimine (1) with α-methylstyrene (2) proceeded smoothly to give homoallylic amine 3 in the presence of a catalytic amount of Y

Full text of DOI:10.1021/jo0268153

Im in o En e Rea ction Ca ta lyzed by Ytter biu m (III) Tr ifla te a n d
TMSCl or TMSOTf
Masamichi Yamanaka, Atsushi Nishida, and Masako Nakagawa*,†
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522, J apan
nakagawa@chem.kanagawa-u.ac.jp.
Received December 6, 2002
A novel combined system of Yb(OTf)3 with TMSCl or TMSOTf catalyzed an imino ene reaction.
The reaction of N-tosylbenzaldimine (1) with R-methylstyrene (2) proceeded smoothly to give
homoallylic amine 3 in the presence of a catalytic amount of Yb(OTf)3 and TMSCl. This catalytic
system was successfully applied to the imino ene reactions of various aldimines with alkenes. This
new imino ene reaction provides a unique method for the three-component coupling reaction of an
aldehyde, tosylamide, and R-methylstyrene in the presence of Yb(OTf)3 and TMSOTf, to give the
corresponding homoallylic amine.
SCHEME 1. Im in o En e Rea ction
In tr od u ction
The development of new methods for the synthesis of
amines is one of the most important and attractive
subjects in synthetic organic chemistry, especially for the
synthesis of alkaloids and biologically active nitrogen-
containing compounds. Moreover, homoallylic amines are
frequently found in many naturally occurring nitrogen-
containing compounds, pharmaceuticals, and agrochemi-
cals and in substances with important biological activi-
ties. In addition, homoallylic amines are also a useful
building block for synthetic intermediates. Although
several methods exist for the synthesis of homoallylic
amines, two direct methods are the most well-known.
One of the most general procedures is the nucleophilic
addition of allylmetal reagents to imines, which is a
powerful method for selective C-C bond formation.1 As
part of our ongoing project along these lines, we previ-
ously reported the diastereo- and enantioselective addi-
tion of alkyllithium to chiral imines.2 The other method
is an imino ene reaction that involves a concerted
addition reaction of imines with alkenes to form a
homoallylic amine (Scheme 1).3
or those of reactive imines such as glyoxalate imines.3
Moreover, although a few excellent catalytic asymmetric
imino ene reactions have recently been reported, the
substrates were also limited to glyoxalate imine.4 There-
fore, we focused our attention on the use of Lewis acid
catalysts to increase the reactivities of the imine groups
in the imino ene reactions. For this purpose, we selected
lanthanide metals as a catalyst, since they have been
reported to have excellent catalytic activities as Lewis
acids for a variety of reactions, including catalytic enan-
tioselective reactions.5 In addition, lanthanide Lewis
acids have been shown to effectively activate imino
groups.6 Therefore, we envisioned that lanthanide metal
Lewis acids may be able to catalyze an imino ene
reaction. In fact, we recently found an imino ene reaction
catalyzed by a novel catalytic system: Yb(OTf)3 with
(4) (a) Druy, W. J ., III; Ferraris, D.; Cox, C.; Young, B.; Lectka, T.
J . Am. Chem. Soc. 1998, 120, 11006-11007. (b) Yao, S.; Fang, X.;
J ørgensen, K. A. Chem. Commun. 1998, 2547-2548.
Several recent reports have shown that imino ene
reactions are limited to either intramolecular reactions
(5) (a) Kobayashi, S. Synlett 1994, 689-701. (b) Inanaga, J .;
Sugimoto, Y.; Hanamoto, T. New J . Chem. 1995, 19, 707-712. (c)
Sibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1236-1256. (d) Sanchez-Blanco, A. I.; Gothelf, K. V.; J ørgensen,
K. A. Tetrahedron Lett. 1997, 38, 7923-7926. (e) Nishida, A.; Ya-
manaka, M.; Nakagawa, M. Tetrahedron Lett. 1999, 40, 1555-1558.
(f) Kobayashi, S.; Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett.
2001, 3, 165-167. (g) Nemoto, T.; Ohshima, T.; Shibasaki, M. J . Am.
Chem. Soc. 2001, 123, 9474-9475. (h) Yoshikawa, N.; Suzuki, T.;
Shibasaki, M. J . Org. Chem. 2002, 67, 2556-2565. (i) Shibasaki, M.;
Yoshikawa, N. Chem. Rev. 2002, 102, 2187-2209. (j) Inanaga, J .;
Furuno, H.; Hayano, T. Chem. Rev. 2002, 102, 2211-2225. (k)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev.
2002, 102, 2227-2302.
† Present address: Kanagawa University, Department of Chemistry,
Kanagawa University, 2946 Tsuchiya, Hiratsuka, Kanagawa 259-1293.
Phone: +81-463-59-4111. Fax: +81-463-58-9688.
(1) (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-2293.
(b) Bloch, R. Chem. Rev. 1998, 98, 1407-1438. (c) Kobayashi, S.;
Busujima, T.; Nagayama, S. Chem. Commun. 1998, 19-20. (d)
Nakamura, H.; Nakamura, K.; Yamamoto, Y. J . Am. Chem. Soc. 1998,
120, 4242-4243. (e) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.;
Shibasaki, M. J . Am. Chem. Soc. 2002, 124, 6536-6537.
(2) (a) Kawate, T.; Yamada, H.; Yamaguchi, K.; Nishida, A.; Naka-
gawa, M. Chem. Pharm. Bull. 1996, 44, 1776-1778. (b) Yamada, H.;
Kawate, T.; Nishida, A.; Nakagawa, M. J . Org. Chem. 1999, 64, 8821-
8828.
(3) (a) Achmatowicz, O., J r.; Pietraszkiewicz, M. J . Chem. Soc.,
Chem. Commun. 1976, 484. (b) Borzilleri, R. M.; Weinreb, S. M.
Synthesis 1995, 347-360. (c) Laschat, S.; Grehl, M. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 458-461. (d) Mikami, K.; Kaneko, M.; Yajima,
T. Tetrahedron Lett. 1993, 34, 4841-4842.
(6) (a) Kobayashi, S.; Nagayama, S. J . Am. Chem. Soc. 1997, 119,
10049-10053. (b) Gro¨ger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.;
Martens, J .; Shibasaki, M. J . Am. Chem. Soc. 1998, 120, 3089-3103.
(c) Schlemminger, I.; Saida, Y.; Gro¨ger, H.; Maison W.; Durot, N.; Sasai,
H.; Shibasaki, M.; Martens, J . J . Org. Chem. 2000, 65, 4818-4825.
10.1021/jo0268153 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/19/2003
3112
J . Org. Chem. 2003, 68, 3112-3120

Imino Ene Reaction
TABLE 2. Effects of Silyl Rea gen ts on th e Im in o En e
Rea ction betw een 1 a n d 2a
SCHEME 2
entry
silyl reagent
time (min)
3 (%)
1
2
3
4
5
6
7
TMSCl
15
15
240
15
15
240
60
94
92
0
94
89
53
79
TMSOTf
TMSImd
TESCl
TESOTf
TBDMSCl
TBDMSOTf
TABLE 1. Lew is Acid -Ca ta lyzed Im in o En e Rea ction
a
All reactions were carried out under 5 mol% Yb(OTf)3 and 5
mol% silyl reagent at room temperature.
entry
catalyst (mol %)
time
24 h
2 h
2 h
48 h
15 min
15 min
3 (%)
yield. These results suggested that the cationic nature
of the silyl group was an important factor in catalyzing
the reaction.
1a
2a
3a
4b
5b
6b
BF‚OEt2(25)
AlCl3 (25)
TiCl4 (25)
Yb(OTf)3 (25)
Yb(OTf)3 (5) and TMSCl (120)
Yb(OTf)3 (5) and TMSCl (5)
0
0
0
58
90
94
To shed light on the mechanism for the formation of 3
and on the nature of the reaction, we screened the
catalytic activities of other combinations of lanthanide
metal triflates [Ln(OTf)3] with TMSCl in the imino ene
reaction of 1 with 2. The catalytic activity profile of
Ln(OTf)3 and TMSCl is shown with an oxophilicity scale
(Figure 1). As illustrated, all of the Ln(OTf)3 with TMSCl
catalyzed the reaction with low to excellent yields. On
the other hand, without TMSCl, the reaction either did
not occur or only gave 3 in lower yields. Remarkably,
Yb(OTf)3-TMSCl and Sc(OTf)3-TMSCl each gave 3 in
higher yield and proved to be the catalysts of choice.
These results agreed well with the oxophilicity of lan-
thanide elements using tandem mass spectroscopy, as
reported by Yamaguchi and Imamoto, who concluded that
this oxophilicity reflects the relative Lewis acidity of
lanthanide elements.9 These observations suggest that
the oxophilicity, i.e., the Lewis acidity, of the lanthanide
metal may play an important role in the imino ene
reaction.
To explore the generality of this imino ene reaction,
we next applied Yb(OTf)3-TMSX catalyst in the reaction
of various aldimines with R-methylstyrene 2 under
optimized conditions. As shown in Table 3, homoallylic
amines were exclusively formed in the reaction of 2 with
benzaldimine with an electron-withdrawing group at the
benzene ring (entries 1 and 2), whereas an electron-
donating substituent reduced the yield (entry 3). 2-Furyl-
aldimine 10 also reacted with 2 to give 11 in moderate
yield, but only if the reaction temperature was kept at
-15 °C due to its high reactivity (entry 4). The nature of
the substituents on the nitrogen had a profound effect.
The reaction of N-benzenesulfonyl and N-4-nitro-
benzenesulfonyl (p-Ns) derivatives, 12 and 14 respec-
tively, with 2 proceeded as smoothly as that of 1 (entries
5 and 6). However, an N-methoxycarbonyl group deac-
tivated the imino ene reaction with 2. A combination of
Yb(OTf)3 with TMSCl (10 mol %) in the reaction of 16
gave 17 in moderate yield (entry 7). TMSOTf was more
effective than TMSCl with a less-reactive substrate like
16. The yield of 17 increased up to 74% when TMSOTf
(10 mol %) was used instead of TMSCl (entry 8). Phos-
phinoyl imine 18 also gave the corresponding homoallylic
amine 19, but in low yield, even when 25 mol % Yb(OTf)3
and TMSOTf were used (entry 9). Interestingly, when
a
b
CH2Cl2 was used as a solvent. CH2Cl2-THF (4:1) was used
as a solvent.
TMSCl (Scheme 2).7 In this report, we describe in detail
Yb(OTf)3-catalyzed imino ene reactions in the presence
of TMSCl or TMSOTf.
Resu lts a n d Discu ssion
We initiated the reaction of N-tosylbenzaldimine (1)
with R-methylstyrene (2) under various conditions. Typi-
cal Lewis acids such as BF3‚OEt2, AlCl3, and TiCl4 did
not catalyze the reaction, even though unidentified
products were formed with AlCl3 and TiCl4 (Table 1,
entries 1-3). On the other hand, to our delight, 25 mol
% Yb(OTf)3 was found to catalyze the imino ene reaction
of 1 with 2, and after 48 h of stirring at room tempera-
ture, the expected homoallylic amine 3 was obtained in
58% yield (entry 4). We anticipated that under this
condition, Yb(OTf)3 may coordinate with the amine
produced, which required a prolonged reaction time.
Therefore, it was assumed that the reaction would
proceed much faster if this coordination of the amine with
Yb(OTf)3 could be prevented. Accordingly, we examined
the effect of a stoichiometric amount of TMSCl on the
reaction.8 As expected, the reaction of 1 and 2 was indeed
accelerated and 3 was obtained in 90% yield after 15 min
of stirring at room temperature (entry 5). To our surprise,
a catalytic amount of TMSCl was sufficient to accelerate
the reaction. Even 5 mol % Yb(OTf)3 and 5 mol % TMSCl
gave almost a quantitative isolated yield (94%) of imino
ene product 3 in only 15 min (entry 6).
We next turned our attention to the effect of a silyl
reagent in this reaction (Table 2). TMSOTf, triethylsilyl
chloride (TESCl), and TESOTf were found to be as
effective as TMSCl (entries 2, 4, and 5). However, the
reaction did not take place with 1-(trimethylsilyl)imid-
azole (TMSImd) (entry 3). Other silyl reagents with bulky
alkyl groups such as TBDMSCl or TBDMSOTf also
catalyzed the imino ene reaction to give 3 in moderate
(7) Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2,
159-161.
(8) Reaction rate in the nucleophilic addition of diethyl zinc to imine
was accelerated by R3SiCl: J imeno, C.; Vidal-Ferran, A.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1999, 40, 777-780.
(9) Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun. 1999,
1703-1704.
J . Org. Chem, Vol. 68, No. 8, 2003 3113

Yamanaka et al.
F IGURE 1. Lanthanide metal effects.
TABLE 3. Im in o En e Rea ction s of Va r iou s Ald im in es Ca ta lyzed by Yb(OTf)3-TMSX
aldimine
entry
R1
R2
X
catalyst (mol%)
time (h)
yield (%)
1
2
4
6
8
o-ClC6H4
p-NO2C6H4
p-MeOC6H4
2-furyl
Ph
Ph
Ph
Ph
Ph
Ts
Ts
Ts
Ts
Cl
OTf
Cl
Cl
Cl
OTf
Cl
OTf
OTf
Cl
5
10
5
5
5
0.5
1
2
3
0.5
2
1
1
1.5
5
48
5 (92)
7 (86)
9 (54)
3
4a
5
10
12
14
16
16
18
20
22
11 (66)
13 (91)
15 (81)
17 (44)
17 (74)
19 (38)
21 (0)b
23 (0)
SO2Ph
SO2p-NO2C6H4
CO2Me
CO2Me
P(O)Ph2
Ph
6
7
8
9
10
11
5
10
10
25
25
25
Ph
Ph
Bn
OTf
a
b
Reaction was carried out at -15 °C. Aza-Diels-Alder adduct (24) was obtained in 63% yield.
SCHEME 3
SCHEME 4
an N-alkylaldimine such as 22 was inert in a similar
reaction with 2 (entry 11). These results indicate that
the electron-withdrawing nature of the N-substituent is
necessary for a successful imino ene reaction. Although
a direct imino ene reaction of an N-alkylaldimine such
as 22 did not take place, N-alkylated homoallylic amines
were readily accessible by using Fukuyama’s p-Ns pro-
tecting group.11 Thus, benzylation of 15 with benzyl
bromide under usual conditions gave N-benzyl derivative
25, which was in turn treated with PhSH in the presence
N-phenylaldimine 20 was subjected to similar reaction
conditions, the aza Diels-Alder reaction proceeded ex-
clusively to give 24, and no imino ene product 21 was
obtained (entry 10 and Scheme 3).10 On the other hand,
(10) Aza Diels-Alder reaction of N-arylaldimine with alkene: (a)
Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y.
Synthesis 1995, 801-804. (b) Kobayashi, S.; Ishitani, H.; Nagayama,
S. Synthesis 1995, 1195-1202. (c) Batey, R. A.; Simoncic, P. D.; Lin,
D.; Smyj, R. P.; Lough, A. J . Chem. Commun. 1999, 651-652.
(11) (a) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373-6374. (b) Fukuyama, T.; Cheung, M.; J ow, C.-K.; Hidai,
Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831-5834.
3114 J . Org. Chem., Vol. 68, No. 8, 2003

Imino Ene Reaction
TABLE 4. Im in o En e Rea ction s of Va r iou s Alk en es
Ca ta lyzed by Yb(OTf)3-TMSX
SCHEME 5
SCHEME 6
(Table 5, entries 1 and 2). Furthermore, 38 was a mixture
1
of (E)- and (Z)-isomers (nearly 9:1) as determined by H
NMR spectroscopy ((E)-isomer, δCH3 1.56 ppm; (Z)-isomer,
δCH3 1.50 ppm). Remarkably, raising the temperature to
reflux improved the product yield to 60% and 38 became
the major product (entry 4), whereas lowering the tem-
perature to -10 °C hampered the reaction (entry 3).
When 1,2-dichloroethane (DCE)-THF was used, the
reaction occurred more rapidly and 38 was obtained as
almost a single product (entries 5 and 6). The reaction
of (E)-36 with 1 under identical conditions gave results
quite similar to those with (Z)-36 and produced 38 as the
major product along with minor amounts of 37 (entry 7).
To examine the fate of the C-H at the methyl group
of 36, we carried out the reaction of deuterated alkene
(Z)-39 (D content ) 96%) with 1. Subjecting (Z)-39 to
similar conditions led to a uniquely labeled product 40,
although the reaction was sluggish and gave a low yield
(30%). The 1H NMR spectra of 40 showed that deuterium
was incorporated into the allylic and olefinic positions,
as shown in Scheme 5, suggesting that isomerization of
the double bond in 36 occurred prior to the imino ene
reaction. In fact, when (Z)-39 was treated with Yb(OTf)3
and TMSOTf in the absence of 1, isomerization of (Z)-39
to the (E)-isomer was observed along with an imbalance
of deuterium (Scheme 6). These results suggested that
Yb(OTf)3-TMSX catalyzed the isomerization of the double
bond more rapidly than the imino ene reaction, and 1,1-
disubstituted isomer 41 generated in situ reacted with 1
more rapidly than other isomers such as (E)- or (Z)-36
to give 38. Supporting evidence was obtained by the
reaction of R-ethylstyrene 41 with 1, which produced the
of K2CO3 to deprotect the p-Ns group to give 23 in high
yield (Scheme 4).
Next, we examined the similar reaction of 1 with
various 1,1-disubstituted alkenes (Table 4). Sterically
hindered alkene 26 reacted somewhat more slowly to give
27 in 68% yield when TMSOTf was used (entry 1).
Tetrahydro-1-naphthylidene 28 also reacted with 1 to
give 29 in 59% yield (entry 2). The effect of a dimethoxy
group was remarkable. The reaction of 30, in contrast to
28, was complete within 15 min, and the yield increased
to 82% (entry 3), implying that the nucleophilic nature
of the alkene favors the imino ene reaction. Tryptamine
derivative 35 was obtained by the reaction of 1 with
indolidene 34, which was readily prepared by selective
allylic bromination with Yb(OTf)3-TMSCl followed by
cyclization (entry 5).12
We encountered an unexpected phenomenon in the
reaction with trisubstituted olefin (36). The reaction of
1 with (Z)-36 using Yb(OTf)3-TMSCl or TMSOTf at room
temperature gave a mixture of imino ene product 37 and
unexpected product 38 in a ratio of 3:2 or 1:1, respectively
TABLE 5. Rea ction of 1 w ith Tr isu bstitu ted Olefin (36)
yield of
37 + 38 (%)
entry
36a
X
catalyst (mol %)
solventb
temp
rt
time (h)
37c:38
E:Z (38)
1
2
3
4
5
6
7
(Z)-36
(Z)-36
(Z)-36
(Z)-36
(Z)-36
(Z)-36
(E)-36
Cl
OTf
Cl
Cl
Cl
5
5
10
10
5
CH2Cl2-THF
CH2Cl2-THF
CH2Cl2-THF
CH2Cl2-THF
DCE-THF
30
30
7 days
6
2
3
2
31
41
0
60
55
73
76
3:2
1:1
90:10
88:12
rt
-10 °C
reflux
reflux
reflux
reflux
1:7
91:9
<1:10
<1:10
<1:10
82:18
82:18
84:16
OTf
OTf
5
5
DCE-THF
DCE-THF
a
b
(Z)-36 ) 96% Z; (E)-36 ) 85% E. DCE ) 1,2-dichloroethane. c About 1:1 mixture of syn and anti adducts.
J . Org. Chem, Vol. 68, No. 8, 2003 3115

Yamanaka et al.
SCHEME 7
SCHEME 8
used, the reaction gave imino ene product 47 in 66%
yield, together with homoallylic alcohol derived from the
carbonyl ene reaction in 13% yield (entry 7).
In summary, we have demonstrated for the first time
the utility of a Yb(OTf)3-TMSX catalyst, which is experi-
mentally simple and inexpensive, for the imino ene
reaction of aldimines with 1,1-disubstituted alkenes. This
process proceeds under mild conditions and provides
efficient access to synthetically useful homoallylic amines.
These procedures can now be conducted in a single
preparative coupling step. Further application of these
reactions to the synthesis of heterocyclic natural products
is now in progress.
TABLE 6. Yb(OTf)3-TMSOTf-Ca ta lyzed
Th r ee-Com p on en t Rea ction of Ald eh yd e, Tosyla m id e,
a n d r-Meth ylstyr en ea
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reactions were carried out
under an argon atmosphere. Tetrahydrofuran was distilled
from sodium/benzophenone prior to use. Dichloromethane was
distilled from P2O5 and redistilled from CaH2 prior to use.
Dimethylformamide and 1,2-dichloroethane were distilled from
1
CaH2. H NMR spectra were recorded at 400 MHz. 13C NMR
spectra were recorded at 100 MHz.
P r ep a r a tion of Im in es. The N-sulfonyl imines were
prepared by known methods.15 For example, in preparation
of 1, benzaldehyde (2.0 mL, 20 mmol), p-toluenesulfonamide
(3.42 g, 20 mmol), and Si(OEt)4 (4.7 mL, 21 mmol) were placed
in a flask and heated at 160 °C for 5 h. On cooling, the reaction
mixture was crystallized with EtOAc and n-pentane. The
resulting crystals were collected by filtration and gave pure 1
(3.67 g, 71%). The other compounds, 4, 6, 8, 10, 12, and 14,16
were prepared using a similar procedure. N-Methoxycarbonyl
imine (16),17 N-phosphynoyl imine (18),18 N-phenyl imine
(20),19 and N-benzyl imine (22)20 were also synthesized by
known procedures.
P r ep a r a tion of Alk en es. 2, 26, and 32 were purchased
from commercial sources and used without purification. 28,21
30,22 and 41 were prepared from the corresponding ketones
by Wittig methylenation. 34 was synthesized by Mizoroki-
Heck reaction23 or allylic bromination and cyclization.12 36 was
prepared by the ethylenation of acetophenone.24
entry
R
yield (%)
1
Ph
3 (92)
42 (79)
43 (71)
44 (45)
45 (76)
46 (85)
47 (66)
2b
3
CH3
iPr
4
5
6
7
t-Bu
c-C3H5
c-C6H11
CO2Et
a
All reactions were carried out with 5 mol% Yb(OTf)3 and 120
b
mol% TMSOTf at room temperature. Used 2 equiv of acetalde-
hyde. c Carbonyl ene product (13%) was also obtained.
expected compound 38 (Scheme 7).13 The geometric
isomer ratio of the trisubstituted olefin of 38 was 89:11
(E:Z), as determined by the H NMR spectrum. Interest-
1
Gen er a l P r oced u r e for th e Im in o En e Rea ction . A
dichloromethane (4 mL) solution of imine (0.5 mmol) was
added to a tetrahydrofuran (1 mL) solution of Yb(OTf)3. TMSX
and alkene (1.0 mmol) were then added successively. The
reaction mixture was stirred at room temperature for the
specified time. The mixture was diluted with H2O and ex-
tracted with CH2Cl2. The combined organic layers were washed
with brine and dried over MgSO4. Concentration under
reduced pressure gave a crude residue, which was chromato-
graphed on silica gel.
ingly, the ratio of (E)- and (Z)-isomers of 38 obtained from
41 was quite similar to that in the reaction of 36 with 1
(Scheme 8).
Having developed a unique imino ene reaction, we next
examined the three-component coupling reaction14 of
aldehyde, amine, and alkene, since the direct isolation
and purification of some imines can be difficult due to
their instability. First, we investigated the reaction
between benzaldehyde, tosylamide, and R-methylstyrene
under various conditions.7 In three-component coupling
reactions, the addition of TMSOTf was found to give
better results. Accordingly, when 5 mol % Yb(OTf)3 was
used along with 120 mol % TMSOTf, the reaction
proceeded rapidly to give 3 in 92% yield (Table 6, entry
1). These conditions were applied to various aldehydes,
and in all cases the corresponding imino ene products
(42-46) were obtained in moderate to good yields (entries
2-6). The anticipated carbonyl ene products were not
observed, except with glyoxalate. When glyoxalate was
N-(1,3-Dip h en ylb u t -3-en yl)-4-m et h ylb en zen esu lfon -
a m id e (3). According to the general procedure, imine 1 (130
mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol) were reacted in the
(15) Love, B. E.; Raje, P. S.; Williams, T. C., III. Synlett 1994, 493-
494.
(16) Na¨geli, I.; Baud, C.; Bernardinelli, G.; J acquier, Y.; Moran, M.;
Mu¨ller, P. Helv. Chim Acta 1997, 80, 1087-1105.
(17) Kupfer, R.; Meier, S.; Wu¨rthwein, E. U. Synthesis 1984, 688-
690.
(18) J ennings, W. B.; Lovely, C. J . Tetrahedron 1991, 47, 5561-
5568.
(19) Bigelow, L. A.; Eatough, H. Org. Synth. 1941, 1, 80-81.
(20) Texier-Boullet, F. Synthesis 1985, 679-681.
(21) Vanhessche, K. P. M.; Sharpless, K. B. J . Org. Chem. 1996,
61, 7978-7979.
(22) van der Meer, F. T.; Feringa, B. L. Tetrahedron Lett. 1992, 33,
6695-6696.
(23) Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J .
Chem. Soc., Perkin Trans. 1 1993, 1941-1942.
(24) Vedejs, E.; Cabaj, J .; Peterson, M. J . J . Org. Chem. 1993, 58,
8, 6509-6512.
(12) Yamanaka, M.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron Lett. 2002, 43, 2403-2406.
(13) However, 36 could not be detected in the reaction mixture of
41 and 1.
(14) (a) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Commun.
1998, 19-20. (b) Manabe, K.; Kobayashi, S. Chem. Commun. 2000,
669-670.
3116 J . Org. Chem., Vol. 68, No. 8, 2003

Imino Ene Reaction
presence of Yb(OTf)3 (16 mg, 0.025 mmol) and TMSCl (2.7 mg,
0.025 mmol) at room temperature for 15 min. Column chro-
matography on silica gel (n-hexane/acetone ) 8/1) gave rise
to pure 3 (177 mg, 94%) as a pale yellow oil: IR (neat) 3278,
2925, 1599, 1495, 1443, 1323, 1158, 698 cm-1; 1H NMR (CDCl3)
δ 2.33 (3H, s), 2.89 (2H, m), 4.23 (1H, dd, J ) 7.0, 13.0 Hz),
4.94 (1H, d, J ) 1.0 Hz), 5.17 (1H, brs), 5.22 (1H, d, J ) 1.0
Hz), 7.02-7.05 (4H, m), 7.13-7.26 (8H, m), 7.44 (2H, d, J )
8.0 Hz); 13C NMR (CDCl3) δ 21.4, 44.1, 56.4, 111.3, 126.1, 126.6,
127.0, 127.4, 127.7, 128.3, 128.4, 129.2, 136.9, 139.3, 140.7,
142.9, 143.7; LRMS (FAB) m/ z 376 [5, M+ - H], 260 [100];
HRMS (C23H22NO2S) found 376.1371, calcd 376.1371.
Yield of 3 (F igu r e 1). Reactions were carried out in the
presence of 5 mol % Ln(OTf)3 and 5 mol % TMSCl at room
temperature for 1 h. Sc(OTf)3, 88%; Y(OTf)3, 67%; La(OTf)3,
17%; Ce(OTf)3, 21%; Pr(OTf)3, 34%; Nd(OTf)3, 25%; Sm(OTf)3,
26%; Eu(OTf)3, 42%; Gd(OTf)3, 30%; Tb(OTf)3, 34%; Dy(OTf)3,
37%; Ho(OTf)3, 47%; Er(OTf)3, 53%; Tm(OTf)3, 58%; Yb(OTf)3,
93%; Lu(OTf)3, 63%. Reactions were carried out in the presence
of 25 mol % Ln(OTf)3 at room temperature for 24 h. Sc(OTf)3,
42%; Y(OTf)3, 14%; La(OTf)3, 1%; Ce(OTf)3, 0%; Pr(OTf)3, 0%;
Nd(OTf)3, 0%; Sm(OTf)3, 0%; Eu(OTf)3, 0%; Gd(OTf)3, 2%;
Tb(OTf)3, 14%; Dy(OTf)3, 12%; Ho(OTf)3, 5%; Er(OTf)3, 11%;
Tm(OTf)3, 19%; Yb(OTf)3, 52%; Lu(OTf)3, 25%.
N-[1-(2-Ch lor op h en yl)-3-p h en ylb u t -3-en yl]-4-m et h yl-
ben zen esu lfon a m id e (5). According to the general proce-
dure, imine 4 (147 mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol)
were reacted in the presence of Yb(OTf)3 (16 mg, 0.025 mmol)
and TMSCl (2.7 mg, 0.025 mmol) at room temperature for 30
min. Column chromatography on silica gel (n-hexane/acetone
) 8/1) gave rise to pure 5 (190 mg, 92%) as a colorless oil: IR
(neat) 3280, 2924, 1598, 1444, 1325, 1160, 759 cm-1; 1H NMR
(CDCl3) δ 2.32 (3H, s), 2.64 (1H, dd, J ) 10.0, 14.0 Hz), 3.07
(1H, dd, J ) 5.0, 14.0 Hz), 4.64 (1H, ddd, 5.0, 5.0, 10.0 Hz),
4.92 (1H, brs), 5.06 (1H, s), 5.34 (1H, s), 7.01 (2H, d, J ) 8.0
Hz), 7.10-7.24 (9H, m), 7.42 (2H, d, J ) 8.5 Hz); 13C NMR
(CDCl3) δ 21.4. 42.1, 53.3, 116.7, 126.0, 126.9, 127.0, 127.7,
128.3, 128.4, 128.8, 129.2, 129.4, 131.9, 136.0, 138.4, 138.5,
143.0, 143.5; (FAB) m/ z 410 [20, M+ - H], 294 [100]; HRMS
(C23H21ClNO2S) found 410.1001, calcd 410.0981.
55.2, 55.8, 113.7, 116.3, 126.1, 127.1, 127.7, 127.8, 128.4, 129.2,
132.6, 133.7, 136.9, 139.3, 142.8, 143.9; LRMS (FAB) m/ z 406
[2, M+ - H], 260 [100]; HRMS (C24H24NO3S) found 406.1446,
calcd 406.1477.
N-(1-F u r a n -2-yl-3-p h en ylbu t-3-en yl)-4-m eth ylben zen e-
su lfon a m id e (11). According to the general procedure, imine
10 (125 mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol) were reacted
in the presence of Yb(OTf)3 (16 mg, 0.025 mmol) and TMSCl
(2.7 mg, 0.025 mmol) at -15 °C for 3 h. Column chromatog-
raphy on silica gel (n-hexane/acetone ) 5/1) gave rise to pure
11 (121 mg, 66%) as a brown oil: IR (neat) 3276, 2926, 1599,
1496, 1444, 1328, 1160, 701 cm-1; 1H NMR (CDCl3) δ 2.16 (3H,
s), 2.96 (1H, dd, J ) 7.5, 14.0 Hz), 3.02 (1H, dd, J ) 7.0, 14.0
Hz), 4.43 (1H, ddd, J ) 7.0, 7.5, 7.5 Hz), 4.98 (1H, d, J ) 1.0
Hz), 5.05 (1H, d, J ) 7.5 Hz), 5.24 (1H, d, J ) 1.0 Hz), 5.86
(1H, d, J ) 3.0 Hz), 6.08 (1H, dd, J ) 2.0, 3.0 Hz), 7.08-7.15
(4H, m), 7.20-7.29 (4H, m), 7.53 (2H, d, J ) 8.0 Hz); 13C NMR
(CDCl3) δ 21.4, 40.9, 50.3, 107.5, 109.9, 116.3, 126.1, 127.0,
127.7, 128.4, 129.3, 137.3, 139.4, 141.8, 143.0, 143.3, 152.2;
LRMS (EI) m/ z 367 [1, M+], 91 [100]; HRMS (C21H22NO3S)
found 368.1303, calcd 368.1320.
N-(1,3-Dip h en ylbu t-3-en yl)-ben zen esu lfon a m id e (13).
According to the general procedure, imine 12 (123 mg, 0.5
mmol) and 2 (0.13 mL, 1.0 mmol) were reacted in the presence
of Yb(OTf)3 (16 mg, 0.025 mmol) and TMSCl (2.7 mg, 0.025
mmol) at room temperature for 15 min. Column chromatog-
raphy on silica gel (n-hexane/EtOAc ) 4/1) gave rise to pure
13 (165 mg, 91%) as a colorless oil: IR (neat) 3278, 2938, 1600,
1495, 1447, 1323, 1159, 754, 690 cm-1; 1H NMR (CDCl3) δ 2.90
(2H, m), 4.28 (1H, dd, J ) 7.5, 13.0 Hz), 4.95 (1H, s), 5.16 (1H,
brs), 5.23 (1H, s), 6.99-7.01 (2H, m), 7.12-7.42 (11H, m), 7.55
(2H, dd, J ) 1.0, 7.5 Hz); 13C NMR (CDCl3) δ 44.1, 56.5, 116.4,
126.1, 126.6, 127.0, 127.5, 127.8, 128.3, 128.5, 128.6, 132.2,
139.4, 140.0, 140.4, 143.8; LRMS (FAB) m/ z 363 [5, M+], 246
[100]; HRMS (C22H21NO2S) found 363.1306, calcd 363.1293.
N -(1,3-Dip h e n ylb u t -3-e n yl)-4-n it r ob e n ze n e su lfon -
a m id e (15). According to the general procedure, imine 14 (290
mg, 1.0 mmol) and 2 (0.26 mL, 2.0 mmol) were reacted in the
presence of Yb(OTf)3 (31 mg, 0.05 mmol) and TMSOTf (11 mg,
0.05 mmol) at room temperature for 2 h. Column chromatog-
raphy on silica gel (n-hexane/acetone ) 6/1) gave rise to pure
15 (329 mg, 81%) as a pale green solid: mp ) 147-148 °C
(n-hexane/EtOAc); IR (KBr) 3251, 1604, 1523, 1350, 1312,
1161, 703 cm-1; 1H NMR (CDCl3) δ 2.83 (1H, dd, J ) 9.5, 14.5
Hz), 2.99 (1H, ddd, J ) 1.0, 5.5, 14.5 Hz), 4.34 (1H, ddd, J )
5.0, 5.5, 9.5 Hz), 4.97 (1H, d, J ) 5.0 Hz), 5.07 (1H, d, J ) 1.0
Hz), 5.35 (1H, d, J ) 1.0 Hz), 7.04-7.06 (2H, m), 7.15-7.18
(3H, m), 7.23-7.30 (5H, m), 7.60 (2H, d, J ) 9.0 Hz), 8.01 (2H,
d, J ) 9.0 Hz); 13C NMR (CDCl3) δ 44.1, 56.6, 116.8, 123.7,
126.0, 126.6, 127.9, 128.2, 128.5, 128.7, 129.4, 131.7, 138.7,
139.9, 143.5, 145.7; LRMS (FAB, negative) m/ z 407 [100, M
- H-]. Anal. Calcd for C22H20N2O4S: C, 64.69; H, 4.93; N, 6.86.
Found: C, 64.44; H, 4.92; N, 6.99.
4-Meth yl-N-[1-(4-n itr oph en yl)-3-ph en ylbu t-3-en yl]-ben -
zen esu lfon a m id e (7). According to the general procedure,
imine 6 (152 mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol) were
reacted in the presence of Yb(OTf)3 (16 mg, 0.025 mmol) and
TMSCl (2.7 mg, 0.025 mmol) at room temperature for 2 h.
Column chromatography on silica gel (n-hexane/acetone ) 6/1)
gave rise to pure 7 (181 mg, 86%) as a pale green solid: mp )
154-156 °C (n-hexane/EtOAc); IR (KBr) 3248, 2910, 1597,
1
1514, 1346, 1157, 700 cm-1; H NMR (CDCl3) δ 2.36 (3H, s),
2.83-2.86 (2H, m), 4.31 (1H, ddd, J ) 2.5, 7.5, 15.0 Hz), 4.97
(1H, d, J ) 1.0 Hz), 5.28 (1H, d, J ) 1.0 Hz), 5.29 (1H, brs),
7.08 (2H, d, J ) 8.0 Hz), 7.12 (2H, dd, J ) 1.5, 8.0 Hz), 7.24-
7.27 (5H, m), 7.44 (2H, d, J ) 8.5 Hz), 8.02 (2H, d, J ) 8.5
Hz); 13C NMR (CDCl3) δ 21.4, 43.8, 55.6, 117.2, 123.5, 126.0,
127.0, 127.6, 128.0, 128.6, 129.4, 136.3, 138.5, 142.9, 143.6,
147.1, 148.3; LRMS (FAB) m/ z 423 [3, M+ - H], 154 [100];
Anal. Calcd for C23H22N2O4S: C, 65.39; H, 5.25; N, 6.63.
Found: C, 65.49; H, 5.30; N, 6.43.
N-(1,3-Dip h en ylbu t-3-en yl)-ca r ba m ic Acid Meth yl Es-
ter (17). According to the general procedure, imine 16 (82 mg,
0.5 mmol) and 2 (0.13 mL, 1.0 mmol) were reacted in the
presence of Yb(OTf)3 (31 mg, 0.05 mmol) and TMSOTf (11 mg,
0.05 mmol) at room temperature for 1 h. Column chromatog-
raphy on silica gel (n-hexane/EtOAc ) 6/1) gave rise to pure
17 (103 mg, 74%) as a colorless oil: IR (neat) 3328, 1718, 1701,
N-[1-(4-Meth oxyp h en yl)-3-p h en ylbu t-3-en yl]-4-m eth yl-
ben zen esu lfon a m id e (9). According to the general proce-
dure, imine 8 (145 mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol)
were reacted in the presence of Yb(OTf)3 (31 mg, 0.05 mmol)
and TMSOTf (11 mg, 0.05 mmol) at room temperature for 1
h. Column chromatography on silica gel (n-hexane/acetone )
5/1) gave rise to pure 9 (111 mg, 54%) as a colorless oil: IR
(neat) 3276, 2933, 1612, 1512, 1442, 1321, 1250, 1159, 1034,
1
1543, 1509, 1458, 1363, 1193, 699 cm-1; H NMR (CDCl3) δ
2.95 (2H, d, J ) 7.0 Hz), 3.57 (3H, s), 4.72 (1H, brs), 4.94 (1H,
brs), 5.00 (1H, d, J ) 1.0 Hz), 5.27 (1H, d, J ) 1.0 Hz), 7.18-
7.37 (10H, m); 13C NMR (CDCl3) δ 43.2, 51.9, 54.2, 115.6, 126.3,
127.3, 127.7, 128.4, 128.5, 140.5, 142.4, 144.9, 156.2; LRMS
(FAB) m/ z 282 [7, M+ + H], 164 [100]; HRMS (C18H20NO2)
found 282.1504, calcd 282.1494.
1
706 cm-1; H NMR (CDCl3) δ 2.34 (3H, s), 2.85 (1H, dd, J )
7.0, 14.5 Hz), 2.92 (1H, dd, J ) 8.0, 14.5 Hz), 3.74 (3H, s),
4.17 (1H, ddd, 5.0, 7.0, 8.0 Hz), 4.95 (2H, brs), 5.23 (1H, d, J
) 1.0 Hz), 6.69 (2H, d, J ) 9.0 Hz), 6.94 (2H, d, J ) 8.5 Hz),
7.06 (2H, d, J ) 8.0 Hz), 7.18-7.20 (2H, m), 7.25-7.27 (3H,
m), 7.44 (2H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 21.4, 44.1,
N-(1,3-Dip h en ylb u t -3-en yl)-P ,P -d ip h en ylp h osp h in ic-
a m id e (19). According to the general procedure, imine 18 (306
mg, 1.0 mmol) and 2 (0.26 mL, 2.0 mmol) were reacted in the
presence of Yb(OTf)3 (155 mg, 0.25 mmol) and TMSOTf (56
mg, 0.25 mmol) at room temperature for 1.5 h. Column
J . Org. Chem, Vol. 68, No. 8, 2003 3117

Yamanaka et al.
chromatography on silica gel (n-hexane/EtOAc ) 2/1) gave rise
to pure 19 (163 mg, 38%) as a white powder. IR (KBr) 3446,
chromatography on silica gel (n-hexane/acetone ) 6/1) gave
rise to pure 23 (86 mg, 92%) as a yellow oil: IR (neat) 3325,
2924, 1626, 1601, 1493, 1453, 1116, 699 cm-1; 1H NMR (CDCl3)
δ 1.72 (1H, brs), 2.76 (1H, dd, J ) 9.5, 14.0 Hz), 2.89 (1H, dd,
J ) 5.0, 14.0 Hz), 3.37 (1H, d, J ) 13.5 Hz), 3.60 (1H, d, J )
13.5 Hz), 3.68 (1H, dd, J ) 5.0, 9.5 Hz), 5.07 (1H, s), 5.29 (1H,
s), 7.11-7.37 (15H, m); 13C NMR (CDCl3) δ 45.2, 51.4, 60.0,
115.4, 126.3, 126.7, 127.0, 127.2, 127.6, 127.9, 128.2, 128.4,
140.5, 144.0, 145.7; LRMS (EI) m/ z 313 [6, M+], 197 [100];
HRMS (C23H24N) found 314.1917, calcd 314.1909.
1
2918, 1437, 1187, 694 cm-1; H NMR (CDCl3) δ 2.99 (1H, dd,
J ) 8.0, 14.0 Hz), 3.24 (1H, dd, J ) 6.5, 14.0 Hz), 3.35 (1H,
brs), 4.27 (1H, dd, J ) 6.5, 8.5 Hz), 4.87 (1H, d, J ) 1.0 Hz),
5.21 (1H, d, J ) 1.0 Hz), 7.06 (2H, d, J ) 6.5 Hz), 7.16-7.75
(18H, m); 13C NMR (CDCl3) δ 45.5, 54.8, 116.0, 126.2, 126.6,
127.2, 127.5, 128.3, 128.4, 128.5, 131.8, 131.9, 132.0, 132.2,
132.3, 140.0, 142.9, 144.4; LRMS (FAB) m/ z 424 [20, M+
H], 306 [100]; HRMS (C28H27NOP) found 424.1817, calcd
424.1830.
+
N-[3-(2,2-Dim eth ylpr opyl)-1-ph en ylbu t-3-en yl]-4-m eth yl-
ben zen esu lfon a m id e (27). According to the general proce-
dure, imine 1 (130 mg, 0.5 mmol) and 26 (0.16 mL, 1.0 mmol)
were reacted in the presence of Yb(OTf)3 (31 mg, 0.05 mmol)
and TMSOTf (11 mg, 0.05 mmol) at room temperature for 4
h. Column chromatography on silica gel (n-hexane/ EtOAc )
8/1) gave rise to pure 27 (125 mg, 68%) as a pale yellow solid:
mp ) 70-73 °C (n-hexane/EtOAc); IR (KBr) 3278, 2952, 1599,
4-Meth yl-2,4-diph en yl-1,2,3,4-tetr ah ydr oqu in olin e (24).25
According to the general procedure of imino ene reaction, imine
20 (91 mg, 0.5 mmol) and 2 (0.13 mL, 1.0 mmol) were reacted
in the presence of Yb(OTf)3 (77 mg, 0.13 mmol) and TMSCl
(14 mg, 0.13 mmol) at room temperature for 5 h. Column
chromatography on silica gel (n-hexane/EtOAc ) 10/1) gave
rise to aza Diels-Alder cycloadduct 24 (95 mg, 63%) as a
mixture of two diastereomers. Further purification with flash
column chromatography on silica gel (n-hexane/EtOAc ) 10/
1) could separate these two isomers. Major diastereomer:
yellow solid; IR (KBr) 3383, 2966, 1602, 1495, 1474, 1345,
1
1456, 1327, 1159, 700 cm-1; H NMR (CDCl3) δ 0.82 (9H, s),
1.54 (1H, d, J ) 13.5 Hz), 1.60 (1H, d, J ) 13.5 Hz), 2.33 (1H,
dd, J ) 9.5, 14.0 Hz), 2.36 (3H, s), 2.44 (1H, dd, J ) 5.5, 14.0
Hz), 4.33 (1H, ddd, 5.0, 5.5, 9.5 Hz), 4.77 (1H, s), 4.85 (1H, s),
5.00 (1H, d, J ) 5.0 Hz), 7.11-7.19 (7H, m), 7.54 (2H, J ) 8.5
Hz); 13C NMR (CDCl3) δ 21.4, 29.8, 30.8, 46.8, 47.8, 56.0, 117.9,
126.6, 127.2, 127.3, 128.1, 128.2, 129.2, 137.1, 141.1, 143.0;
LRMS (FAB) m/ z 370 [3, M+ - H], 260 [100]. Anal. Calcd for
1
1311, 1256, 1113, 702 cm-1; H NMR (CDCl3) δ 1.82 (3H, s),
1.95 (1H, dd, J ) 2.5, 13.0 Hz), 2.26 (1H, dd, J ) 12.0, 13.0
Hz), 4.01 (1H, dd, J ) 2.5, 12.0 Hz), 6.58 (1H, d, J ) 8.5 Hz),
7.00 (1H, ddd, J ) 1.5, 7.5, 7.5 hz), 7.14-7.37 (10H, m), 7.44
(2H, d, J ) 7.5 Hz); 13C NMR (CDCl3) δ 29.7, 42.3, 48.3, 54.0,
114.5, 117.6, 125.8, 126.7, 126.9, 127.2, 127.3, 127.5, 127.6,
128.0, 128.6, 143.9, 144.7, 150.2; LRMS (FAB) m/ z 299 [100,
M+]; HRMS (C22H21N) found 299.1659, calcd 299.1674. Minor
diastereomer: yellow solid; IR (KBr) 3385, 2958, 1602, 1482,
C
22H29NO2S: C, 71.12; H, 7.87; N, 3.77. Found: C, 71.19; H,
7.94; N, 3.72.
N-[2-(3,4-Dih yd r on a p h t h a len -1-yl)-1-p h en ylet h yl]-4-
m eth ylben zen esu lfon a m id e (29). According to the general
procedure, imine 1 (130 mg, 0.5 mmol) and 28 (144 mg, 1.0
mmol) were reacted in the presence of Yb(OTf)3 (16 mg, 0.025
mmol) and TMSCl (2.7 mg, 0.025 mmol) at room temperature
for 1 h. Column chromatography on silica gel (n-hexane/
acetone ) 8/1) gave rise to pure 29 (238 mg, 59%) as a pale
yellow solid: mp ) 49-51 °C (n-hexane/acetone); IR (KBr)
3282, 2931, 1599, 1491, 1448, 1323, 1157, 1093, 700 cm-1; 1H
NMR (CDCl3) δ 2.05-2.21 (2H, m), 2.28 (3H, s), 2.55 (1H, d,
J ) 8.0 Hz), 2.57 (1H, d, J ) 8.0 Hz), 2.66 (1H, dd, J ) 9.5,
14.0 Hz), 2.83 (1H, dd, J ) 6.0, 14.0 Hz), 4.31 (1H, ddd, J )
4.5, 5.5, 9.0 Hz), 4.97 (1H, d, J ) 4.0 Hz), 5.73 (1H, t, J ) 4.5
Hz), 6.96 (2H, d, J ) 8.5 Hz), 7.05-7.12 (4H, m), 7.16-7.26
(5H, m), 7.43 (2H, d, J ) 8.0 Hz); 13C NMR (CDCl3) δ 21.4,
23.0, 28.0, 42.2, 56.0, 122.4, 126.4, 126.5, 126.8, 126.9, 127.4,
127.7, 128.3, 129.1, 129.5, 132.1, 133.0, 136.4, 136.6, 141.5,
142.9; LRMS (FAB) m/ z 404 [10, M+ + H], 260 [100]; HRMS
(C25H25NO2S) found 403.1579, calcd 403.1606.
N-[2-(6,7-Dim et h oxy-3,4-d ih yd r on a p h t h a len -1-yl)-1-
p h en yleth yl]-4-m eth ylben zen esu lfon a m id e (31). Accord-
ing to the general procedure, imine 1 (259 mg, 1.0 mmol) and
30 (409 mg, 2.0 mmol) were reacted in the presence of Yb(OTf)3
(31 mg, 0.05 mmol) and TMSCl (5 mg, 0.05 mmol) at room
temperature for 15 min. Column chromatography on silica gel
(n-hexane/acetone ) 5/1) gave rise to pure 31 (379 mg, 82%)
as an orange powder: mp ) 62-63 °C (n-hexane/CH2Cl2); IR
(KBr) 3284, 2935, 1603, 1510, 1458, 1327, 1267, 1159, 700
cm-1; 1H NMR (CDCl3) δ 2.07-2.19 (2H, m), 2.30 (3H, s), 2.49-
2.55 (2H, m), 2.73 (1H, dd, J ) 8.5, 14.5 Hz), 2.80 (1H, dd, J
) 6.5, 14.5 Hz), 3.85 (3H, s), 3.91 (3H, s), 4.28 (1H, ddd, J )
4.0, 6.5, 8.5 Hz), 4.89 (1H, brs), 5.62 (1H, t, J ) 4.5 Hz), 6.63
(1H, s), 6.66 (1H, s), 6.98 (2H, d, J ) 7.5 Hz), 7.13 (2H, dd, J
) 2.0, 7.5 Hz), 7.21-7.24 (3H, m), 7.41 (2H, d, J ) 8.5 Hz);
13C NMR (CDCl3) δ 21.3, 23.1, 27.8, 42.6, 55.8, 56.0, 56.2, 106.9,
111.3, 125.8, 126.4, 126.8, 127.3, 127.4, 128.4, 129.1, 129.3,
131.6, 136.2, 141.2, 143.0, 147.1, 147.8; LRMS (EI) m/ z 463
[13, M+], 260 [100]. Anal. Calcd for C27H29NO4S: C, 69.95; H,
6.30; N, 3.02. Found: C, 69.74; H, 6.07; N, 2.75.
1
1444, 1338, 1312, 1259, 1119, 702 cm-1; H NMR (CDCl3) δ
1.75 (3H, s), 2.14 (1H, dd, J ) 11.5, 13.0 Hz), 2.26 (1H, dd, J
) 3.0, 13.0 Hz), 4.01 (1H, dd, J ) 3.0, 11.5 Hz), 6.60 (1H, dd,
J ) 1.0, 8.5 Hz), 6.75 (1H, ddd, J ) 1.0, 7.5, 8.0 Hz), 7.09-
7.13 (3H, m), 7.16-7.32 (9H, m); 13C NMR (CDCl3) δ 29.6, 41.6,
47.9, 53.1, 114.2, 117.3, 125.8, 126.4, 126.6, 127.1, 127.5, 127.6,
128.2, 128.5, 144.3, 144.6, 150.4; LRMS (FAB) m/ z 299 [100,
M+]; HRMS (C22H21N) found 299.1672, calcd 299.1674.
N-Ben zyl-N-(1,3-d ip h en ylbu t-3-en yl)-4-n itr oben zen e-
su lfon a m id e (25). To a solution of 15 (327 mg, 0.8 mmol) in
DMF (8 mL) were added K2CO3 (553 mg, 4.0 mmol) and BnBr
(0.14 mL, 1.2 mmol) in sequence. The reaction mixture was
stirred for 2.5 h at ambient temperature, and the disappear-
ance of 15 was monitored by TLC analysis. Then, the mixture
was diluted with H2O and extracted with Et2O. Combined
organic layers were washed with brine and dried over MgSO4.
Concentration in vacuo afforded a yellow crude residue.
Column chromatography on silica gel (n-hexane/acetone ) 7/1)
gave rise to pure 25 (357 mg, 90%) as a yellow caramel: IR
(neat) 3100, 2932, 1605, 1528, 1496, 1455, 1348, 1161, 698
cm-1; 1H NMR (CDCl3) δ 3.17 (1H, dd, J ) 9.5, 14.0 Hz), 3.22
(1H, dd, J ) 6.0, 14.0 Hz), 4.19 (1H, d, J ) 15.5 Hz), 4.54 (1H,
d, J ) 15.5 Hz), 4.92 (1H, s), 4.98 (1H, dd, J ) 6.0, 9.5 Hz),
5.16 (1H, s), 6.91 (2H, d, J ) 7.0 Hz), 7.07-7.29 (11H, m),
7.54 (2H, d, J ) 9.0 Hz), 7.91 (1H, d, J ) 9.0 Hz), 8.09 (2H, d,
J ) 9.0 Hz), 8.27 (1H, d, J ) 9.0 Hz); 13C NMR (CDCl3) δ 49.7,
50.7, 60.8, 116.2, 123.8, 124.2, 126.3, 127.7, 127.9, 128.2, 128.4,
128.5, 128.6, 129.0, 134.8, 140.0, 144.3, 146.9, 149.4; LRMS
(FAB) m/ z 499 [5, M+ + H], 291 [100]; HRMS (C29H27N2O4S)
found 499.1707, calcd 499.1691.
N-Ben zyl-(1,3-d ip h en ylbu t-3-en yl)-a m in e (23). To a so-
lution of 25 (150 mg, 0.3 mmol) in DMF (3 mL) were added
K2CO3 (124 mg, 0.9 mmol) and PhSH (0.04 mL, 0.4 mmol) in
sequence. The reaction mixture was stirred for 2.5 h at
ambient temperature, and the disappearance of 25 was
monitored by TLC analysis. Then, the mixture was quenched
with 1 N NaOH and extracted with Et2O. Combined organic
layers were washed with brine and dried over MgSO4. Con-
centration in vacuo afforded a yellow crude residue. Column
N-[2-(Cycloh ex-1-en yl)-1-ph en yleth yl]-4-m eth ylben zen e-
su lfon a m id e (33). According to the general procedure, imine
1 (259 mg, 1.0 mmol) and 32 (0.24 mL, 2.0 mmol) were reacted
in the presence of Yb(OTf)3 (62 mg, 0.10 mmol) and TMSOTf
(22 mg, 0.10 mmol) at room temperature for 20 h. Column
(25) Hesse, K.-D. Liebigs Ann. Chem. 1970, 741, 117-123.
3118 J . Org. Chem., Vol. 68, No. 8, 2003

Imino Ene Reaction
chromatography on silica gel (n-hexane/acetone ) 8/1) gave
rise to pure 33 (86 mg, 24%) as a pale yellow solid: IR (KBr)
CH3CHO (0.12 mL, 2.0 mmol), TsNH2 (171 mg, 1.0 mmol), and
2 (0.26 mL, 1.0 mmol) were reacted in the presence of Yb(OTf)3
(31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2 mmol). Column
chromatography on silica gel (n-hexane/acetone ) 6/1) gave
rise to pure 42 (248 mg, 79%) as a pale yellow oil: IR (neat)
3278, 2973, 1599, 1495, 1426, 1323, 1161, 706 cm-1; 1H NMR
(CDCl3) δ 0.98 (3H, d, J ) 6.5 Hz), 2.31 (3H, s), 2.40 (1H, dd,
J ) 7.5, 14.0 Hz), 2.65 (1H, dd, J ) 6.5, 14.0 Hz), 3.18 (1H,
ddq, J ) 6.5, 6.5, 7.0 Hz), 4.66 (1H, brs), 4.95 (1H, s), 5.20
(1H, s), 7.08-7.17 (7H, m), 7.56-7.58 (2H, m); 13C NMR
(CDCl3) δ 21.2, 21.4, 43.4, 48.1, 115.7, 126.0, 127.0, 127.6,
128.3, 129.5, 137.5, 139.4, 143.1, 144.3; LRMS (FAB) m/ z 315
[40, M+], 198 [100]; HRMS (C18H21NO2S) found 315.1301, calcd
315.1293.
1
3271, 2941, 1458, 1323, 1161, 706 cm-1; H NMR (CDCl3) δ
1.23-1.40 (2H, m), 1.47 (2H, s like), 1.58-1.66 (2H, m), 1.95
(2H, brs like), 2.30-2.37 (6H, m), 4.67-4.69 (2H, m), 5.67 (1H,
m), 7.05-7.14 (7H, m), 7.50 (2H, d, J ) 8.0 Hz); 13C NMR
(CDCl3) δ 20.9, 21.2, 21.4, 23.2, 25.3, 45.7, 58.1, 111.9, 126.7,
127.2, 127.3, 127.7, 128.3, 129.1, 132.6, 137.0, 139.4, 143.1;
LRMS (FAB) m/ z 356 [5, M+ + H], 260 [100]; HRMS (C21H26
NO2S) found 356.1662, calcd 356.1684.
-
4-Meth yl-N-{1-p h en yl-2-[1-(tolu en e-4-su lfon yl)-1H-in -
d ol-3-yl]eth yl}-ben zen esu lfon a m id e (35). According to the
general procedure, imine 1 (130 mg, 0.5 mmol) and 34 (285
mg, 1.0 mmol) were reacted in the presence of Yb(OTf)3 (16
mg, 0.025 mmol) and TMSCl (2.7 mg, 0.025 mmol) at room
temperature for 30 min. Column chromatography on silica gel
(n-hexane/acetone ) 4/1) gave rise to pure 35 (198 mg, 73%)
as an orange powder: mp ) 176 °C (Et2O); IR (KBr) 3278,
2924, 1599, 1495, 1448, 1365, 1325, 1173, 1122, 702 cm-1; 1H
NMR (CDCl3) δ 2.30 (6H, s), 3.03 (1H, dd, J ) 6.5, 14.5 Hz),
3.09 (1H, dd, J ) 7.5, 14.5 Hz), 4.50 (1H, ddd, J ) 6.5, 7.0, 7.5
Hz), 5.23 (1H, d, J ) 6.5 Hz), 6.94 (2H, d, J ) 8.0 Hz), 7.06-
7.28 (11H, m), 7.36 (2H, d, J ) 8.0 Hz), 7.63 (2H, d, J ) 8.5
Hz), 7.89 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 21.4, 21.5,
33.6, 57.4, 113.6, 117.5, 119,1, 123.1, 124.6, 126.5, 126.7, 127.6,
128.5, 129.2, 129.8, 130.3, 134.9, 135.0, 136.6, 140.6, 143.1,
144.9; LRMS (FAB) m/ z 545 [7, M+ + H], 260 [100]. Anal.
Calcd for C30H28N2O4S2: C, 66.15; H, 5.18; N, 5.14. Found: C,
65.89; H, 5.18; N, 5.04.
N -(1,3-D ip h e n y lp e n t -(3E )-e n y l)-4-m e t h y lb e n ze n e -
su lfon a m id e ((E)-38). Dichloroethane (4 mL) solution of
imine 1 (130 mg, 0.5 mmol) was added to the tetrahydrofuran
(1 mL) solution of Yb(OTf)3 (16 mg, 0.025 mmol). Then,
TMSOTf (6 mg, 0.025 mmol) and (Z)-36 (132 mg, 1.0 mmol)
were added successively. The reaction mixture was refluxed
for 3 h. After cooling to room temperature, the reaction mixture
was diluted with H2O and extracted with CH2Cl2. Combined
organic layers were washed with brine and dried over MgSO4.
Concentration under reduced pressure afforded a crude resi-
dure. The residure was chromatographed on silica gel (n-
hexane/EtOAc ) 7/1) to give a mixture of 37 and 38 (143 mg,
73%). Further purification with flash column chromatography
on silica gel (n-hexane/EtOAc ) 8/1) gave rise to pure (E)-38
as a pale yellow oil: IR (neat) 3277, 2924, 1599, 1495, 1454,
1325, 1159, 700 cm-1; 1H NMR (CDCl3) δ 1.56 (3H, d, J ) 7.0
Hz), 2.35 (3H, s), 2.87 (1H, dd, J ) 7.5, 14.0 Hz), 3.01 (1H, dd,
J ) 7.5, 14.0 Hz), 4.13 (1H, m), 4.74 (1H, d, J ) 4.5 Hz), 5.71
(1H, q, J ) 7.0 Hz), 6.99-7.01 (2H, m), 7.07 (2H, d, J ) 8.0
Hz), 7.10-7.28 (9H, m), 7.42 (2H, d, J ) 8.0 Hz); 13C NMR
(CDCl3) δ 14.2, 21.4, 37.7, 56.9, 126.4, 126.6, 126.9, 127.1,
127.5, 127.9, 128.2, 128.7, 129.2, 129.7, 136.1, 140.6, 141.8,
143.0; LRMS (FAB, negative) m/ z 390 [100, M - H-]; HRMS
(C24H24NO2S) found 390.1532, calcd 390.1527.
N-(1-Isop r op yl-3-p h en ylbu t-3-en yl)-4-m eth ylben zen e-
su lfon a m id e (43). According to the general procedure,
iPrCHO (0.09 mL, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol), and
2 (0.26 mL, 1.0 mmol) were reacted in the presence of Yb(OTf)3
(31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2 mmol). Column
chromatography on silica gel (n-hexane/acetone ) 8/1) gave
rise to pure 43 (244 mg, 71%) as a colorless solid: mp ) 104-
105 °C (n-hexane/acetone); IR (KBr) 3290, 2952, 1629, 1602,
1464, 1420, 1319, 1162, 715 cm-1; 1H NMR (CDCl3) δ 0.72 (3H,
d, J ) 7.0 Hz), 0.82 (3H, d, J ) 7.0 Hz), 1.86 (1H, m), 2.40,
(3H, s), 2.54 (1H, ddd, J ) 1.0, 7.5, 14.5 Hz), 2.60 (1H, ddd, J
) 1.0, 7.5, 14.5 Hz), 3.10 (1H, dddd, J ) 3.5, 7.5, 7.5, 7.5 Hz),
4.57 (1H, d, J ) 7.5 Hz), 5.01 (1H, d, J ) 1.5 Hz), 5.22 (1H, d,
J ) 1.5 Hz), 7.11-7.27 (7H, m), 7.64 (2H, d, J ) 8.5 Hz); 13C
NMR (CDCl3) δ 16.3, 18.3, 21.5, 29.5, 37.8, 56.8, 115.6, 126.1,
127.2, 127.6, 128.3, 129.4, 137.7, 139.4, 143.0, 144.6; LRMS
(FAB) m/ z 343 [35, M+], 226 [100]. Anal. Calcd for C20H25
-
NO2S: C, 69.94; H, 7.34; N, 4.08. Found: C, 69.64; H, 7.34;
N, 4.00.
N-(1-ter t-Bu tyl-3-p h en ylbu t-3-en yl)-4-m eth ylben zen e-
su lfon a m id e (44). According to the general procedure, t-
BuCHO (0.11 mL, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol), and
2 (0.26 mL, 1.0 mmol) were reacted in the presence of Yb(OTf)3
(31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2 mmol). Column
chromatography on silica gel (n-hexane/acetone ) 8/1) gave
rise to pure 44 (160 mg, 45%) as a white solid: mp ) 132-
133 °C (n-hexane/EtOAc); IR (KBr) 3288, 2962, 1448, 1369,
1317, 1151, 704 cm-1 1H NMR (CDCl3) δ 0.87 (9H, s), 2.32
;
(1H, dd, J ) 9.0, 14.5 Hz), 2.39 (3H, s), 2.93 (1H, dd, J ) 3.5,
14.5 Hz), 3.25 (1H, ddd, J ) 4.0, 9.0, 9.0 Hz), 4.46 (1H, d, J )
9.0 Hz), 4.98 (1H, d, J ) 1.0 Hz), 5.10 (1H, d, J ) 1.0 Hz),
7.15-7.32 (7H, m), 7.59 (2H, d, J ) 8.5 Hz); 13C NMR (CDCl3)
δ 21.5, 26.8, 35.6, 38.0, 61.6, 115.9, 126.2, 127.1, 127.5, 128.2,
129.1, 139.1, 139.8, 142.6, 144.6; LRMS (FAB) m/ z 357 [4, M+],
240 [100]. Anal. Calcd for C21H27NO2S: C, 70.55; H, 7.61; N,
3.92. Found: C, 70.69; H, 7.66; N, 4.02.
N-(1-Cyclopr opyl-3-ph en ylbu t-3-en yl)-4-m eth ylben zen e-
su lfon a m id e (45). According to the general procedure,
c-C3H5CHO (0.07 mL, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol),
and 2 (0.26 mL, 1.0 mmol) were reacted in the presence of
Yb(OTf)3 (31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2
mmol). Column chromatography on silica gel (n-hexane/
acetone ) 7/1) gave rise to pure 45 (260 mg, 76%) as a colorless
oil: IR (neat) 3277, 2925, 1710, 1599, 1495, 1443, 1327, 1160,
708 cm-1; 1H NMR (CDCl3) δ -0.14 (1H, m), 0.01 (1H, m), 0.22
(1H, m), 0.34 (1H, m), 0.69 (1H, m), 2.41 (3H, s), 2.57 (1H, m),
2.68 (1H, ddd, J ) 1.0, 7.5, 14.0 Hz), 2.91 (1H, ddd, J ) 1.0,
6.0, 14.0 Hz), 4.48 (1H, d, J ) 6.0 Hz), 5.09 (1H, d, J ) 1.0
Hz), 5.31 (1H, d, J ) 1.0 Hz), 7.16-7.30 (7H, m), 7.65 (2H, d,
J ) 8.0 Hz); 13C NMR (CDCl3) δ 3.1, 4.3, 16.3, 21.5, 42.3, 57.1,
116.0, 126.2, 127.2, 127.6, 128.4, 129.4, 137.8, 140.0, 143.1,
Gen er a l P r oced u r e for th e Th r ee-Com p on en t Cou -
p lin g. Aldehyde (1.0 mmol) was added to the dichloromethane
(8 mL) and tetrahydrofuran (2 mL) solution of Yb(OTf)3 (0.05
mmol) and TsNH2 (1.0 mmol). Then, TMSOTf (1.2 mmol) and
2 (2.0 mmol) were added successively. The reaction mixture
was stirred at room temperature for 1 h. The mixture was
diluted with H2O and extracted with CH2Cl2. Combined
organic layers were washed with brine and dried over MgSO4.
Concentration under reduced pressure afforded a crude resi-
due. The residue was chromatographed on silica gel.
N-(1,3-Dip h en ylb u t -3-en yl)-4-m et h ylb en zen esu lfon -
a m id e (3). According to the general procedure, PhCHO (0.1
mL, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol), and 2 (0.26 mL,
1.0 mmol) were reacted in the presence of Yb(OTf)3 (31 mg,
0.05 mmol) and TMSOTf (0.22 mL, 1.2 mmol). Column
chromatography on silica gel (n-hexane/acetone ) 8/1) gave
rise to pure 3 (347 mg, 92%) as a pale yellow oil.
144.4; LRMS (FAB) m/ z 341 [3, M+], 224 [100]; HRMS (C20H23
-
NO2SNa) found 364.1317, calcd 364.1347.
N-(1-Cycloh exyl-3-ph en ylbu t-3-en yl)-4-m eth ylben zen e-
su lfon a m id e (46). According to the general procedure,
c-C6H11CHO (0.12 mL, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol),
and 2 (0.26 mL, 1.0 mmol) were reacted in the presence of
Yb(OTf)3 (31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2
4-Met h yl-N-(1-m et h yl-3-p h en ylb u t -3-en yl)-b en zen e-
su lfon a m id e (42). According to the general procedure,
J . Org. Chem, Vol. 68, No. 8, 2003 3119

Yamanaka et al.
mmol). Column chromatography on silica gel (n-hexane/
acetone ) 7/1) gave rise to pure 46 (326 mg, 85%) as a white
solid: mp ) 93 °C (n-hexane/Et2O); IR (KBr) 3338, 2925, 1497,
1409, 1319, 1157, 712 cm-1; 1H NMR (CDCl3) δ 0.90-1.08 (5H,
m), 1.35 (1H, d, J ) 11.0 Hz), 1.45-1.52 (1H, m), 1.62-1.64
(2H, m), 1.73 (1H, d, J ) 11.0 Hz), 2.40 (3H, s), 2.51 (1H, dd,
J ) 7.5, 14.0 Hz), 2.64 (1H, dd, J ) 7.5, 14.0 Hz), 3.09 (1H,
dddd, J ) 3.5, 7.5, 7.5, 7.5 Hz), 4.24 (1H, d, J ) 7.5 Hz), 4.98
(1H, d, J ) 1.0 Hz), 5.23 (1H, d, J ) 1.0 Hz), 7.12-7.15 (2H,
m), 7.20 (2H, d, J ) 8.5 Hz), 7.25-7.26 (3H, m), 7.61 (2H, d,
J ) 8.5 Hz); 13C NMR (CDCl3) δ 21.5, 26.2, 26.2, 26.4, 27.1,
28.8, 37.7, 40.0, 56.6, 115.6, 126.1, 127.2, 127.6, 128.3, 129.4,
137.7, 139.5, 143.0, 144.6; LRMS (FAB) m/ z 383 [5, M+], 266
[100]. Anal. Calcd for C23H24NO2S: C, 72.03; H, 7.62; N, 3.65.
Found: C, 72.02; H, 7.75; N, 3.63.
4-P h en yl-2-(tolu en e-4-su lfon ylam in o)-pen t-4-en oic Acid
Eth yl Ester (47).4 According to the general procedure, EtO2-
CCHO (102 mg, 1.0 mmol), TsNH2 (171 mg, 1.0 mmol) and 2
(0.26 mL, 1.0 mmol) were reacted in the presence of Yb(OTf)3
(31 mg, 0.05 mmol) and TMSOTf (0.22 mL, 1.2 mmol). Column
chromatography on silica gel (n-hexane/EtOAc ) 5/1) gave rise
to pure 47 (246 mg, 66%) as a colorless solid: mp ) 90-91 °C
(Et2O); IR (KBr) 3269, 2981, 1736, 1599, 1495, 1448, 1340,
1
1213, 1163, 708 cm-1; H NMR (CDCl3) δ 1.03 (3H, t, J ) 7.0
Hz), 2.38 (3H, s), 2.90 (1H, d, J ) 6.5 Hz), 2.92 (1H, d, J ) 7.0
Hz), 3.68-3.78 (2H, m), 3.98 (1H, ddd, J ) 6.5, 7.0, 9.0 Hz),
5.11 (1H, s), 5.18 (1H, d, J ) 9.0 Hz), 5.32 (1H, s), 7.21 (2H, d,
J ) 8.5 Hz), 7.25-7.31 (5H, m), 7.62 (2H, d, J ) 8.5 Hz); 13C
NMR (CDCl3) δ 13.7, 21.4, 39.3, 54.5, 61.5, 117.1, 126.3, 127.2,
127.8, 128.3, 129.5, 136.7, 139.4, 142.6, 143.5, 171.0; LRMS
(EI) m/ z 373 [3, M+], 218 [100].
Ack n ow led gm en t. We thank the Ministry of Edu-
cation, Culture, Sports, Science and Technology, J apan,
and the Uehara Memorial Foundation for supporting
our research program. We also thank Ms. Hara and Ms.
Seki at the Analytical Center, Chiba University, for
performing mass spectroscopy and elemental analysis.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0268153
3120 J . Org. Chem., Vol. 68, No. 8, 2003