Catalytic imino Diels-Alder reaction by triflic imide and its application to one-pot synthesis from three components

Article abstract of DOI:10.1016/j.tet.2006.09.092

An imino Diels-Alder reaction of 2-siloxydienes with aldimines catalyzed by triflic imide (Tf₂NH; 0.1～10 mol % amount) has been developed leading to substituted piperidin-4-ones. Tf₂NH catalyst is compatible with basic functions, such as pyridine and indole rings in the imino Diels-Alder reaction. Furthermore, X-ray crystallographic analysis indicates that trans-2,6-diphenyl-4-piperidinone 4a obtained by this reaction has a unique conformation in the solid state.

Full text of DOI:10.1016/j.tet.2006.09.092

Tetrahedron 62 (2006) 11900–11907
Catalytic imino Diels–Alder reaction by triflic imide and its
application to one-pot synthesis from three components
y
*
Kiyosei Takasu, Naoya Shindoh, Hidetoshi Tokuyama and Masataka Ihara
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 28 August 2006; revised 22 September 2006; accepted 25 September 2006
Available online 27 October 2006
Abstract—An imino Diels–Alder reaction of 2-siloxydienes with aldimines catalyzed by triflic imide (Tf NH; 0.1w10 mol % amount) has
2
2
been developed leading to substituted piperidin-4-ones. Tf NH catalyst is compatible with basic functions, such as pyridine and indole rings in
the imino Diels–Alder reaction. Furthermore, X-ray crystallographic analysis indicates that trans-2,6-diphenyl-4-piperidinone 4a obtained by
this reaction has a unique conformation in the solid state.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2-siloxydienes, to the best of our knowledge, the Brønsted
acid-catalyzed reaction has not been reported yet. Sub-
9
The piperidine ring system is a ubiquitous structural motif of
naturally occurring alkaloids, biologically active synthetic
molecules, and organic fine chemicals. The imino Diels–
stituted piperidin-4-one produced in the above reaction
would be useful in medicinal chemistry.
1
0
1
Alder reaction is one of the most powerful and useful tools
used to prepare heterocycles containing the piperidine
nucleus. There have been many studies on the imino
Diels–Alder reaction, which is typically classified into two
variants. One is the reaction of all-carbon 1,3-dienes
TBSO
Ph
Tf NH (cat)
+
2
2
,3
N
CH Cl , 3 h
Ph
2
2
Ph
1a (1.2 eq)
2a (1 eq)
(
C]C–C]C synthon) with imines (C]N synthon). The
TBSO
Ph
TBSO
Ph
Ph
other is the cycloaddition of azadienes (C]N–C]C or
N]C–C]C synthons) with dienophilic alkenes (C]C
synthon). The former strategy has been more extensively
studied because a variety of imine dienophiles are readily
available by the reaction of corresponding aldehydes or ke-
tones with amines. The literature contains many studies of
the imino Diels–Alder reaction of imines with Danishefsky’s
dienes (1-alkoxy-3-siloxybutadienes) to give 2,3-dehydro-
piperidin-4-ones. Numerous kinds of Lewis acids, including
chiral catalysts and Brønsted acids have been developed in
the reaction of Danishefsky’s dienes. On the contrary, few
studies have focused on the reaction of less active 2-siloxy-
dienes with imines, which affords substituted piperidin-4-
ones (Scheme 1). Although several Lewis acids have
been found to activate the imino Diels–Alder reaction of
N
N
Ph
Ph
trans-3a
Ph
cis-3a
Scheme 1.
4
We have recently reported that triflic imide (Tf NH) works
2
as a good catalyst for (2+2)-cycloaddition of silyl enol ethers
with a,b-unsaturated esters even in low catalyst loading
5
6
11
(
w1 mol %). Furthermore, we have found that Tf NH
2
also catalyzes various cycloaddition reactions, such as
(2+2)-cycloaddition of allylsilane with acrylates, and the
Diels–Alder reaction of 2-siloxydiene and a,b-unsaturated
carbonyl compounds. In these contexts, silyl triflic
imides (R SiNTf ), which are generated from Tf NH and
12
7
,8
13,14
3
2
2
silyl enol ether substances, act as an active catalyst of the
Herein, we report the Tf NH-
2
catalyzed imino Diels–Alder reaction of 2-siloxydiene with
aldimine to give functionalized piperidin-4-one derivatives
and its application to the one-pot synthesis of piperidin-
4-ones from 2-siloxydiene, aldehyde, and amine.
1
0,11,14b
Keywords: Imino Diels–Alder reaction; Substituted piperidines; Triflic imide;
Three component reaction.
above cycloadditions.
*
Corresponding author. Tel.: +81 22 795 6878; fax: +81 22 795 6877;
e-mail: kay-t@mail.pharm.tohoku.ac.jp
Present address: Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo
y
142-8501, Japan.
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.092

K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
TBSO Ph
11901
2
. Results and discussion
O
Ph
Ph
TBAF (1.1 eq)
N
N
Ph
THF, -78 °C, 15 min
2.1. Imino Diels–Alder reaction of 2-siloxydienes with
aldimines
Ph
trans-3a
Ph
97%
trans-4a
At the outset of this study, the imino Diels–Alder reaction
of 2-siloxy-1,3-butadiene 1a (1.2 equiv) with benzaldimine
Scheme 2.
(
2a) (1.0 equiv) in the presence of Tf NH was examined
2
under various conditions (Scheme 1). With a 2 mol % of
Tf NH in CH Cl at ambient temperature, a diastereomeric
2
2
2
mixture of 2,6-diphenyl-4-siloxy-3,4-didehydropiperidine
a was obtained in 85% yield, and the diastereomeric ratio
3
1
was determined to be 4:1 (trans–cis) by H NMR (Table 1,
entry 1), whereas no reaction occurred in the absence of
the catalyst (entry 2). It is noteworthy that the reaction
proceeds smoothly even with 0.1 mol % catalyst loading
(
entry 3). However, when a stoichiometric amount of
Tf NH was used, decomposition of siloxydiene owing to
2
its protodesilylation was observed prior to promotion of
the desired cycloaddition (entry 4). The Tf NH-catalyzed
2
reaction can be successfully performed in various solvents,
such as toluene, THF, and acetonitrile (entries 5–7), and
the diastereomeric ratio of 3a was similar within a range
of 3:1–4:1 in these solvents. When the reaction of 1a with
2
a was conducted in CH CN, 3a, which is hardly soluble
3
in the solvent, precipitated. It is noteworthy that 3a can be
isolated with ease only by filtration even in a multi-gram
scale (entry 7). The reaction temperature does not affect
the diastereomeric ratio, and no desired product was ob-
Figure 1. Crystallographic structure of trans-4a (ORTEP drawing).
ꢀ
tained at high temperature (80 C in a sealed tube) (entries
8
and 9).
Next, the imino Diels–Alder reactions of 1a with various
aldimines 2b–2l under optimal conditions (2 mol % Tf NH,
2
The major diastereomer of 3a was almost quantitatively con-
verted into piperidin-4-one 4a, which could be crystallized
CH Cl , rt) were examined (Scheme 3). Electron-poor (2b),
2
2
ꢀ
Scheme 2). Neither epimerization nor retro-Michael reac-
electron-rich aromatic (2c), and naphthyl substituted (2d)
aldimines also afforded desired adducts in good yields with
a similar stereoselectivity (Table 2, entries 1–3). Substrates
with a heterocyclic ring, such as pyridine (2e) and indole
from CH Cl –hexanes, by treatment with TBAF at ꢁ78 C
2
2
(
tion was observed in the process. X-ray crystallographic
analysis determined that compound 4a, derived from the
major diastereomer of 3a, possesses trans-oriented 2,6-sub-
stituents (Fig. 1). Fascinatingly, the crystallized form of
trans-4a exists as an unusual conformation. Namely, both
phenyl substituents at the C(2) and C(6) positions are
oriented axially, and the conformation of the six-membered
piperidine ring is a twist-boat form. Three continuous bulky
phenyl substituents at N(1), C(2), and C(6) of trans-4a
would prevent the chair-conformation with equatorially
oriented bulky substituents at C(2) and C(6).
(
Tf NH, but their reaction rates were decreased (entries 4, 5,
2f and 2l), underwent cycloaddition in the presence of
2
and 11). No protection is necessary for indole N–H in the
Tf NH-catalyzed reaction (entries 5 and 11). Further studies
2
revealed that aldimines obtained from benzylamine (2g) and
allylamine (2h) afforded the corresponding piperidinone de-
rivatives 3g and 3h in good yields, respectively (entries 6 and
7). On the contrary, electrophilic aldimines, which possess
an electron-withdrawing function on the nitrogen atom, af-
forded poor results. Reaction with acyl imine 2i and sulfonyl
imine 2j resulted in the formation of many side products al-
though trace amounts of cycloadducts 3i and 3j, respectively,
were produced (entries 8 and 9). The strongly electrophilic
imines, such as 2i and 2j, may be too reactive to selectively
promote the desired cycloaddition in the presence of the
Table 1. Imino Diels–Alder reaction of 1a with 2a
Entry
Cat. (mol %)
Solvent
Temp
ꢀ
Time
(h)
% Yield
(trans–cis)
b
(
C)
Tf NH catalyst. Phosphonyl imine 2k promoted the imino
2
Diels–Alder reaction. However, desilylated piperidinone 4k
was obtained in a moderate yield (entry 10) because of the
1
2
3
4
5
6
7
Tf NH (2.0)
None
2
CH
CH
CH
CH
THF
Toluene
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
rt
rt
rt
rt
rt
rt
rt
3
72
3
3
3
3
0.3
3
85 (80:20)
0 (—)
80 (75:25)
0 (—)
69 (63:37)
82 (67:33)
75 (82:18)
61 (79:21)
0 (—)
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
Tf
2
NH (0.1)
NH (100)
NH (2.0)
NH (2.0)
NH (2.0)
NH (2.0)
NH (2.0)
TBSO
R2
R1
R2
Tf NH (2 mol%)
2
CH
CH
CH
3
2
2
CN
1a
+
N
8
9
Cl
Cl
2
ꢁ78
N
CH Cl , rt, 3 h
2
2
R1
a
2
80
3
Ph
b-l
2
b-l
3
a
Reaction was carried out in a sealed tube. 1
Diastereomeric ratios were determined by H NMR.
b
Scheme 3.

11902
K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
Table 2. Imino Diels–Alder reaction of 1a with various aldimines
e
Entry
1
Imine 2
Product
% Yield (trans–cis)
NO2
TBSO
2b (Ph, p-NO
2
C
6
H
4
)
3b
85 (75:25)
N
Ph
Ph
OMe
TBSO
TBSO
2
3
2c (Ph, p-MeOC
6
H
4
)
3c
67 (77:23)
73 (84:16)
N
Ph
Ph
Ph
2d (Ph, 1-naphthyl)
3d
N
Ph
TBSO
TBSO
N
a
4
2e (Ph, 3-pyridyl)
2f (Ph, 3-indolyl)
61 (73:27)
35 (81:19)
N
3e
Ph
Ph
H
N
b
5
3f
N
Ph
Ph
N
3
g (R1 = Bn)
c
6
2g (Bn, Ph)
2h (Allyl, Ph)
2i (CO Et, Ph)
2
2j (Ts, Ph)
89 (85:15)
88 (80:20)
Trace (—)
32 (89:11)
TBSO
Ph
3h (R1 = allyl)
3i (R1 = CO Et)
c
7
8
9
R1
2
3j (R1 = Ts)
Ph
O
Ph
P
OEt
10
2k (PO(OEt)
2
, Ph)
N
4k
62 (63:37)
OEt
Ph O
N
Ph
N
N
H
d
3l
f
11
N
H
60 (60:40)
2l
OTBS
a
b
c
d
e
f
Cat. 5 mol %, 5 h.
Cat. 6 mol %, 24 h.
Cat. 5 mol %
Cat. 10 mol %, CH CN, 8 h.
3
Diastereomeric ratios were determined by H NMR.
Stereochemistry of each diastereomer was not assigned.
1
poor stability of the corresponding silyl enol ether 3k (the
reason is still unclear).
trans-3n was exclusively obtained as a sole diastereomer
in 69% yield, although a mixture of the geometrical isomer
(cis–trans¼ca. 5:2) of 1c was conducted in the reaction
Results of the imino Diels–Alder reaction of various 2-siloxy-
dienes 1b–1e and 2-methoxydiene 1f with aldimine 2a to
give avariety of substituted piperidin-4-ones are summarized
in Scheme 4 and Table 3. Whereas 3-methyl-2-siloxydiene
R1
R1
R2
R2
Ph
Ph
Ph
Tf NH (2 mol%)
2
+
R3
N
CH Cl , rt, 3 h
N
R3
Ph
2
2
1b efficiently reacted (86% yield, entry 1), reactions with
1-methyl-2-siloxydiene 1c and 2-tert-butyldimethylsiloxy-
1,3-butadiene (1d) required 5 mol % of catalyst for com-
R4
R4
3m-q
1
b-f
2a
plete consumption of aldimine 2a (entries 2 and 3). Notably,
Scheme 4.

K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
Table 3. Imino Diels–Alder reaction of 2a with various dienes
11903
7a (ca. 60% yield). The result suggests that the undesired
reaction of aldehyde 5 with silyl enol ether 1 (Mukaiyama-
aldol reaction) competes with imine formation of 5 with
amine 6. On the other hand, sequential addition of the sub-
strates as an alternative protocol was successful (Table 4,
entry 1). Namely, after pre-treatment with aldehyde 5a and
1
Entry Diene (R , R , R , R )
2
3
4
Cat.
mol %)
Product % Yield
(dr)
a
(
1
2
3
4
5
1b (H, OTBS, Me, H)
1c (Me, OTBS, H, H)
1d (H, OTBS, H, H)
1e (H, OTBS, H, OMe)
1f (H, OMe, H, Ph)
2
5
5
2
2
3m
3n
3o
3p
3q
86
69 (100:0)
69
0 (—)
48 (79:21)
b
c
˚
amine 6a in the presence of molecular sieves 4 A (MS4A)
in CH Cl for 20 min at ambient temperature, siloxydiene
2
2
a
1
Diastereomeric ratios were determined by H NMR.
1a and Tf NH (4 mol %) were added to the resulting mixture
2
at 0 C to give the desired product 3a selectively in 78%
b
ꢀ
The relative configuration of the major diastereomer was assigned as
trans-3n because both protons at C(5) and C(6) exist on an equatorial
yield (no formation of 7a was observed). After completion
of the above three component reaction, successive treatment
with tetrabutylammonium fluoride (TBAF) in one-pot fur-
nished piperidinone 4b in a good yield (entry 2). The MCR
using aliphatic amine 6b instead of aromatic amine 6a also
successfully afforded 3g in good yield (entry 3). On the
contrary, the reaction of aliphatic aldehyde 5b resulted in
1
position (J[H(C5)–H(C6)]¼3.1 Hz in H NMR).
c
The relative configuration of major diastereomer was tentatively assigned
as trans-3q by an analogy to 3a.
(entry 3). The mechanistic detail including the stereochem-
ical outcome is under investigation. Danishefsky diene 1e
was evaluated as a more electron-rich diene partner, but
only decomposition of 1e by Tf NH was observed (entry 4).
7
a
a poor yield of 3r under similar conditions (entries 4 and
). This is possibly due to the instability of the corresponding
imine derived from 5b and 6b in the presence of Tf NH
2
5
2
We initially considered that the actual catalyst of the imino
Diels–Alder reaction would be R SiNTf , which is formed
from Tf NH and siloxydiene in situ. However, the reaction
1
7
(
Scheme 6).
3
2
1
1
2
of 2-methoxydiene 1f occurred in the presence of 2 mol % of
catalyst to give 3q in moderate yield (entry 5). This observa-
Table 4. Three component syntheses of 3 and 4
Entry
Aldehyde
Amine
Product
% Yield
(trans–cis)
1
5
c
tion indicates that Tf NH (pK ¼1.7 in water) directly acti-
2
a
vates aldimines as a Brønsted acid in the imino Diels–Alder
reaction. The action of the Tf NH catalyst in the reaction is
1
2
5a (PhCHO)
5a (PhCHO)
5a (PhCHO)
6a (PhNH
6a (PhNH
6b (BnNH
6b (BnNH
6b (BnNH
2
)
)
3a
4a
3g
3r
4r
78 (80:20)
72 (82:18)
74 (80:20)
a
2
2
different from that in the (2+2)-cycloaddition, which was
recently established by our group. The following experi-
3
2
)
)
)
1
1
b
i
d
4
5b ( PrCHO)
5b ( PrCHO)
2
2
16 (ND )
15 (68:32)
a,b
i
5
ment also suggests the catalytic role of Tf NH. Thus, when
2
the mixture of 1a and 2a was treated with pre-organized
TBSTf (50 mol %), which was prepared from TBSCl and
a
One-pot process involving three component reaction and desilylation was
carried out.
2
b
c
d
AgNTf in CH Cl , decomposition of silyl enol ether 1a
2
Cat. 6 mol %, 24 h.
Diastereomeric ratios were determined by H NMR.
ND means ‘not determined’.
2
2
1
quickly occurred prior to imino Diels–Alder reaction with 2a.
2
.2. Application to multicomponent reaction
3. Conclusion
We have further assessed the one-pot multicomponent reac-
tion (MCR) for the formation of substituted piperidin-4-ones
derivatives starting from three components: siloxydiene 1,
aldehyde 5, and amine 6 (Scheme 5). When a mixture of
the whole substrates, 1a, benzaldehyde (5a), and aniline
In summary, we have demonstrated that triflic imide (Tf NH)
2
works as an effective catalyst for the imino Diels–Alder
reaction of 2-siloxydienes and aldimines as well as the three
component reaction. Tf NH catalyst is compatible for basic
1
6
2
functions, such as pyridine and indole rings in the imino
Diels–Alder reaction. In the reaction, Tf NH would directly
(
Tf NH (2 mol %), the desired MCR product 3a was isolated
6a) (molar ratio: 1a:5a:6a¼1.2:1:1), was treated with
2
2
activate the imine partner as a Brønsted acid to promote
the imino Diels–Alder reaction. It is clearly different from
catalytic (2+2)-cycloaddition, in which Lewis acidic silyl
in ca. 20% yield, but the major product was an aldol adduct
TBSO
Tf NH (2 mol%), MS 4Å
triflic imides, generated from Tf NH and silylated substrates,
2
2
+
R CHO
1
+
R NH
2
2
CH Cl , 0 °C, 4 h
act as a real catalyst. Furthermore, X-ray crystallographic
analysis indicates that the obtained trans-2,6-diphenyl-
piperidin-4-one 4a has a unique conformation in the solid
state.
2
2
Ph
5 (1.0 eq) 6 (1.0 eq)
1a (1.2 eq)
TBSO
R1
O
R1
R2
TBAF
N
N
R2
CH Cl ,
2
2
4. Experimental
0
°C,10 min
Ph
Ph
for entry 2 & 5
4.1. General
3
4
All reactions were carried out under an inert atmosphere.
Anhydrous THF and CH Cl were purchased from the Kanto
Chemical Co., Inc. Unless otherwise described, other mate-
rials were obtained from commercial suppliers and used
without further purification. Column chromatography was
O
Ph
OH
2
2
Ph
7
a
Scheme 5.

11904
K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
ꢁ
1 1
performed on Merck silica gel 60 N (230–400 mesh), and
flash column chromatography was performed on Cica silica
gel 60 (spherical/40–100 mm). Reactions and chromato-
graphy fractions were analyzed employing precoated silica
gel plate (Merck silica gel 60F254). All melting points
were determined on Yanaco micro melting point apparatus
and are uncorrected. IR spectra were measured on Shimadzu
1681, 1597, 1518, 1346, 1207 cm ; H NMR (400 MHz,
CDCl ) d 8.09 (d, J¼8.5 Hz, 2H), 7.35 (d, J¼8.8 Hz, 2H),
3
7.29–7.25 (m, 4H), 7.21–7.17 (m, 1H), 7.01 (t, J¼7.8 Hz,
2H), 6.69 (t, J¼7.1 Hz, 1H), 6.58 (d, J¼8.5 Hz, 2H), 5.27–
5.22 (m, 2H), 5.18 (dd, J¼4.9, 1.5 Hz, 1H), 3.06 (dd,
J¼16.1, 5.4 Hz, 1H), 2.43 (dd, J¼16.6, 4.1 Hz, 1H), 0.81
1
3
(s, 9H), 0.00 (s, 3H), ꢁ0.07 (s, 3H); C NMR (75 MHz,
1
13
FTIR-8300 spectrometer. The H and C NMR spectra were
recorded on JEOL AL 400 (400 and 100 MHz) and Varian
Gemini 2000 (300 and 75 MHz), respectively, as CDCl3
solutions, and were reported in parts per million downfield
CDCl ) d 150.7, 146.8, 143.6, 128.8, 128.7, 128.6, 128.5,
3
128.2, 128.1, 127.9, 126.8, 126.4, 126.1, 123.5, 119.2,
118.0, 106.7, 60.3, 57.9, 37.0, 25.5, 17.9, ꢁ4.4, ꢁ4.5;
+
LRMS m/z 486 (M ); Anal. Calcd for C H N O Si: C,
2
9 34 2 3
1
from TMS (d¼0) for the H NMR and relative to the central
71.57; H, 7.04; N, 5.76. Found: C, 71.40; H, 7.14; N, 5.59.
1
3
CDCl resonance (d¼77.00) for the C NMR. Mass spectra
3
were recorded on JEOL DX-303 or AX-500 spectrometer.
Elemental analyses were performed on Yanagimoto MT-3
or YANACO CHN CORDER MT-6, and the results (C, H)
were within ꢂ0.4% of theoretical values. X-ray crystallo-
graphic analysis was performed on Rigaku R-AXIX RAPID.
4.2.4. cis-4-(tert-Butyldimethylsiloxy)-6-(p-nitrophenyl)-
1,2-diphenyl-3,4-didehydropiperidine (cis-3b). Pale yel-
low oil. IR (neat) 2930, 1680, 1597, 1521, 1346,
ꢁ
1
1
1207 cm
;
H NMR (400 MHz, CDCl ) d 8.00 (d,
3
J¼8.7 Hz, 2H), 7.48 (d, J¼8.7 Hz, 2H), 7.25–7.15 (m,
5
H), 6.96 (t, J¼8.0 Hz, 2H), 6.82 (t, J¼7.5 Hz, 1H), 6.77
4.2. General procedure for imino Diels–Alder reaction
in the presence of Tf NH
(d, J¼8.0 Hz, 2H), 5.02 (t, J¼2.4 Hz, 1H), 4.81 (dd,
J¼9.9, 3.9 Hz, 1H), 4.72 (d, J¼1.9 Hz, 1H), 2.69 (ddt,
J¼16.4, 9.4, 2.4 Hz, 1H), 2.42 (dd, J¼16.4, 3.6 Hz, 1H),
0.96 (s, 9H), 0.21 (s, 3H), 0.03 (s, 3H); LRMS m/z 486
2
To a solution of 2-siloxydiene 1 (1.2 equiv) and aldimine 2
1.0 equiv) in CH Cl (1.0 M) was added Tf NH (0.08 M
+
(
(M ); HRMS m/z 486.2316 (calcd for C H N O Si:
29 34 2 3
2
2
2
toluene solution, 2–10 mol %) dropwise at ambient temper-
ature. The reaction mixture was stirred for an appropriate
time, and then was quenched with saturated NaHCO aq.
The mixture was extracted with CHCl . The combined
3
organic layers were dried over MgSO , filtered, and concen-
4
486.2339).
4.2.5. trans-4-(tert-Butyldimethylsiloxy)-6-(p-methoxy-
phenyl)-1,2-diphenyl-3,4-didehydropiperidine (trans-
3c). Colorless oil. IR (neat) 2930, 1681, 1597, 1510,
3
ꢁ
1 1
trated in vacuo. The residue was purified by flash column
chromatography on silica gel using hexane–AcOEt (includ-
ing 1% NEt ) as an eluent to give 3 as a diastereomeric mix-
1250 cm ; H NMR (400 MHz, CDCl ) d 7.18–7.09 (m,
3
4H), 7.04–6.99 (m, 3H), 6.92 (d, J¼8.8 Hz, 2H), 6.84 (t,
J¼8.8 Hz, 2H), 6.60 (d, J¼8.8 Hz, 2H), 6.48 (t, J¼6.3 Hz,
1H), 5.02–4.99 (m, 2H), 4.96 (t, J¼4.6 Hz, 1H), 3.59 (s,
3H), 2.82 (dd, J¼16.3, 5.6 Hz, 1H), 2.27 (dd, J¼16.3,
3
ture. Several compounds were recrystallized from MeOH to
give its trans-3 as a single diastereomer.
3
.9 Hz, 1H), 0.67 (s, 9H), ꢁ0.16 (s, 3H), ꢁ0.22 (s, 3H);
1
3
4
3
.2.1. trans-4-(tert-Butyldimethylsiloxy)-1,2,6-triphenyl-
,4-didehydropiperidine (trans-3a). Colorless needles.
C NMR (75 MHz, CDCl ) d 158.3, 147.9, 147.5, 144.4,
3
129.0, 128.5, 128.4, 127.9, 127.8, 126.5, 126.4, 118.6,
113.5, 113.3, 106.9, 60.2, 57.7, 55.2, 37.2, 25.6, 14.7,
ꢀ
H NMR (400 MHz, CDCl ) d 7.36–7.14 (m, 10H), 6.99
ꢁ1
Mp 125–127 C; IR (KBr) 2930, 1680, 1599, 1502 cm
;
1
+
ꢁ4.5; LRMS m/z 471 (M ); HRMS m/z 471.2580 (calcd
3
(
1
2
dd, J¼8.7, 7.5 Hz, 2H), 6.63 (m, 3H), 5.24 (d, J¼5.3 Hz,
for C H NO Si: 471.2594).
3
0
37
2
H), 5.19 (m, 2H), 3.02 (ddt, J¼16.2, 5.8, 1.9 Hz, 1H),
.45 (dd, J¼16.2, 3.6 Hz, 1H), 0.80 (s, 9H), ꢁ0.03 (s, 3H),
4.2.6. trans-4-(tert-Butyldimethylsiloxy)-6-(1-naphthyl)-
1,2-diphenyl-3,4-didehydropiperidine (trans-3d). Color-
1
3
ꢁ
0.12 (s, 3H); C NMR (75 MHz, CDCl ) d 147.8, 147.4,
3
ꢀ
1502, 1207 cm ; H NMR (400 MHz, CDCl ) d 7.94–
1
1
44.6, 142.8, 128.6, 128.5, 128.2, 127.3, 126.7, 126.6,
26.4, 118.4, 117.8, 106.9, 60.3, 58.0, 37.1, 25.4, 17.8,
less crystals. Mp 159–160 C; IR (KBr) 2928, 1686, 1597,
ꢁ1
1
3
+
ꢁ
4.7, ꢁ4.9; LRMS m/z 441 (M ); Anal. Calcd for
7.92 (m, 1H), 7.88–7.85 (m, 1H), 7.70 (d, J¼8.2 Hz, 1H),
7.49–7.45 (m, 2H), 7.42 (d, J¼7.0 Hz, 2H), 7.36 (t,
J¼7.5 Hz, 2H), 7.30–7.25 (m, 2H), 7.08 (d, J¼7.0 Hz, 1H),
C H NOSi: C, 78.86; H, 7.99; N, 3.17. Found: C, 78.59;
9 35
2
H, 8.00; N, 3.07.
6
.92 (dd, J¼7.5, 7.2 Hz, 2H), 6.62 (t, J¼7.2 Hz, 1H), 6.49
4
3
.2.2. cis-4-(tert-Butyldimethylsiloxy)-1,2,6-triphenyl-
,4-didehydropiperidine (cis-3a). The compound could
(d, J¼8.0 Hz, 2H), 5.87 (t, J¼5.1 Hz, 1H), 5.43 (d, J¼
5.8 Hz, 1H), 5.34 (dd, J¼5.8, 1.9 Hz, 1H), 2.96 (dd, J¼15.9,
13
1
not be isolated in a pure form. The H NMR spectrum was
assigned from a mixture of trans-3a and cis-3a. H NMR
5.8 Hz, 1H), 2.60 (dd, J¼15.9, 4.3 Hz, 1H), 0.71 (s, 9H),
1
ꢁ0.11 (s, 3H), ꢁ0.26 (s, 3H); C NMR (75 MHz, CDCl )
3
(
400 MHz, CDCl ) d 7.41–7.02 (m, 10H), 6.89 (t,
3
d 148.4, 147.1, 144.5, 137.7, 133.9, 131.0, 129.0, 128.7,
128.3, 127.6, 126.7, 126.5, 126.0, 125.3, 125.2, 122.9,
118.3, 117.3, 105.9, 61.3, 54.0, 35.0, 25.5, 17.8, ꢁ4.5, ꢁ4.8;
J¼8.3 Hz, 2H), 6.76 (d, J¼8.3 Hz, 2H), 6.72 (d, J¼8.3 Hz,
H), 4.98 (t, J¼1.9 Hz, 1H), 4.71 (d, J¼1.9 Hz, 1H), 4.66
dd, J¼9.8, 3.9 Hz, 1H), 2.71 (ddt, J¼16.8, 9.8, 1.9 Hz,
H), 2.40 (ddt, J¼16.8, 3.9, 1.7 Hz, 1H), 0.91 (s, 9H),
0.15 (s, 6H).
1
(
1
ꢁ
+
LRMS m/z 491 (M ); Anal. Calcd for C H NOSi: C,
3
3 37
80.60; H, 7.58; N, 2.85. Found: C, 80.55; H, 7.62; N, 2.80.
4.2.7. trans-4-(tert-Butyldimethylsiloxy)-1,2-diphenyl-6-
(3-pyridyl)-3,4-didehydropiperidine (trans-3e). Colorless
4.2.3. trans-4-(tert-Butyldimethylsiloxy)-6-(p-nitro-
phenyl)-1,2-diphenyl-3,4-didehydropiperidine (trans-
ꢀ
ꢁ1
crystals. Mp 116–117 C; IR (KBr) 2945, 1678, 1597,
1504, 1371, 1196 cm
ꢀ
1
3
b). Colorless needles. Mp 139–140 C; IR (KBr) 2955,
;
H NMR (400 MHz, CDCl3)

K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
11905
1
3
d 8.45 (d, J¼2.2 Hz, 1H), 8.42 (dd, J¼4.6, 1.4 Hz, 1H), 7.46
(s, 3H), ꢁ0.01 (s, 3H); C NMR (75 MHz, CDCl3)
d 148.4, 143.3, 140.3, 138.4, 138.1, 129.9, 129.8, 128.2,
127.8, 127.5, 127.1, 102.8, 55.2, 52.8, 28.7, 25.7, 25.6,
(
dt, J¼8.0, 1.9 Hz, 1H), 7.30–7.24 (m, 4H), 7.19–7.12 (m,
2
6
H), 7.00 (dd, J¼8.7, 7.2 Hz, 2H), 6.67 (t, J¼7.2 Hz, 1H),
.61 (d, J¼8.9 Hz, 2H), 5.20 (dd, J¼5.6, 4.1 Hz, 1H), 5.17
+
18.0, ꢁ4.6; LRMS m/z 519 (M ); HRMS m/z 519.2233
(
s, 2H), 3.05 (dd, J¼16.4, 5.8 Hz, 1H), 2.42 (dd, J¼16.4,
(calcd for C H NO SSi: 519.2263).
3
0
37
3
1
3
3
NMR (75 MHz, CDCl ) d 149.0, 148.1, 147.2, 146.9,
.9 Hz, 1H), 0.81(s, 9H), 0.00 (s, 3H), ꢁ0.06 (s, 3H);
C
4.2.12. trans-1-(Diethoxyphosphonyl)-2,6-diphenyl-4-
piperidone (trans-4k). Colorless needles (from hexane–
3
1
1
43.7, 137.8, 134.9, 128.5, 126.7, 126.4, 123.0, 119.3,
18.5, 106.9, 60.1, 56.4, 36.9, 25.5, 17.9, ꢁ4.4, ꢁ4.6;
ꢀ
1227 cm ; H NMR (400 MHz, CDCl ) d 7.51–7.45 (m,
AcOEt). Mp 92–94 C; IR (neat) 3206, 1686, 1649, 1613,
+
ꢁ1
1
LRMS m/z 442 (M ); HRMS m/z 442.2440 (calcd for
C H N OSi: 442.2440).
3
3H), 7.39–7.21 (m, 7H), 6.64 (d, J¼16.2 Hz, 1H), 4.79–
2
8 34 2
4
.71 (m, 1H), 4.06–3.92 (m, 4H), 3.79–3.70 (m, 2H), 3.27
4
1
.2.8. trans-4-(tert-Butyldimethylsiloxy)-6-(3-indolyl)-
,2-diphenyl-3,4-didehydropiperidine (trans-3f). Color-
(ds, J¼16.2, 6.0 Hz, 1H), 3.15 (dd, J¼16.2, 6.0 Hz, 1H),
1
3
1.28 (t, J¼7.1 Hz, 3H), 1.11 (t, J¼7.1 Hz, 3H); C NMR
ꢀ
373, 1223 cm ; H NMR (400 MHz, CDCl ) d 7.84 (br
less crystals. Mp 144–145 C; IR (KBr) 1684, 1595, 1502,
1
(75 MHz, CDCl ) d 197.8, 143.4, 142.7, 134.2, 130.7,
3
ꢁ1 1
128.9, 128.5, 128.3, 127.3, 126.4, 126.1, 62.5, 62.3, 52.5,
48.4, 16.3, 15.9; LRMS m/z 388 (M +H); Anal. Calcd for
3
+
s, 1H), 7.33 (d, J¼7.1 Hz, 2H), 7.27–7.04 (m, 6H), 6.95–
6
5
2
9
.87 (m, 4H), 6.67–6.61 (m, 3H), 5.29 (t, J¼4.9 Hz, 1H),
.11 (dd, J¼4.1, 1.7 Hz, 1H), 5.02 (d, J¼4.1 Hz, 1H),
.87–2.82 (m, 1H), 2.48 (dd, J¼16.6, 4.9 Hz, 1H), 0.77 (s,
C H NO P: C, 65.11; H, 6.76; N, 3.62. Found: C, 65.15;
26
2
1
4
H, 6.64; N, 3.60.
1
3
H), ꢁ0.03 (s, 3H), ꢁ0.09 (s, 3H); C NMR (75 MHz,
4.2.13. 2-(tert-Butyldimethylsiloxy)-4-phenyl-1,4,6,7,12,12b-
hexahydroindolo[2,3a]quinolizine (3l). Pale brown solids
(major diastereomer). Mp 155–157 C; IR (neat) 2930,
CDCl ) d 148.6, 144.4, 136.0, 128.3, 128.1, 127.1, 126.5,
3
1
1
ꢀ
22.5, 121.8, 120.3, 119.6, 119.3, 119.2, 116.7, 110.8,
06.6, 60.0, 51.9, 35.3, 25.6, 18.0, ꢁ4.4; LRMS m/z 480
ꢁ
1 1
1674, 1454, 1201, 837 cm ; H NMR (400 MHz, CDCl )
3
+
(
M ); Anal. Calcd for C H N OSi: C, 77.45; H, 7.55; N,
3
d 7.54 (br s, 1H), 7.35–7.15 (m, 7H), 7.03–6.94 (m, 2H),
4.91 (d, J¼3.4 Hz, 1H), 4.52 (d, J¼5.0 Hz, 1H), 4.13 (q,
J¼5.0 Hz, 1H), 3.06 (m, 1H), 2.83 (m, 1H), 2.59 (d,
J¼14.5 Hz, 1H), 2.43 (dd, J¼16.4, 4.8 Hz, 1H), 2.36–2.24
1 36 2
5
.83. Found: C, 77.64; H, 7.59; N, 5.71.
4.2.9. trans-1-Benzyl-4-(tert-butyldimethylsiloxy)-2,6-di-
phenyl-3,4-didehydropiperidine (trans-3g). Colorless oil.
1
3
(m, 2H), 0.85 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); C NMR
ꢁ
1
1
IR (neat) 2928, 1665, 1371, 1256, 891 cm ; H NMR
400 MHz, CDCl ) d 7.20–6.92 (m, 15H), 4.83 (d,
(75 MHz, CDCl ) d 148.4, 139.9, 136.3, 135.0, 129.9,
3
(
128.0, 127.7, 127.5, 121.6, 119.5, 118.2, 110.7, 108.3,
105.2, 63.1, 48.2, 35.5, 25.7, 21.3, 18.0, ꢁ4.1, ꢁ4.2;
3
J¼3.9 Hz, 1H), 4.02 (d, J¼3.9 Hz, 1H), 3.83 (dd, J¼8.5,
+
5
1
3
1
1
.6 Hz, 1H), 3.22 (d, J¼13.6 Hz, 1H), 3.11 (d, J¼13.6 Hz,
LRMS m/z 430 (M ); HRMS m/z 430.2455 (calcd for
C H N OSi: 430.2440).
H), 2.25 (m, 2H), 0.74 (s, 9H), ꢁ0.21 (s, 3H), ꢁ0.25 (s,
2
7 34 2
1
3
H); C NMR (75 MHz, CDCl ) d 149.6, 144.1, 141.5,
3
40.3, 128.9, 128.7, 128.4, 128.2, 128.0, 127.9, 127.0,
26.8, 104.5, 59.3, 54.8, 50.8, 31.3, 25.9, 25.7, 18.2, ꢁ4.0,
Colorless oil (minor diastereomer). IR (neat) 3418, 2972,
1672, 1452, 1163, 835 cm ; H NMR (400 MHz, CDCl )
ꢁ
1 1
3
+
ꢁ4.1; LRMS m/z 379 (M ); HRMS m/z 455.2656 (calcd
for C H NOSi: 455.2644).
d 7.73 (br s, 1H), 7.46–7.06 (m, 9H), 4.77 (s, 1H), 4.03 (s,
1H), 3.90 (d, J¼10.1 Hz, 1H), 2.97 (dd, J¼11.4, 4.8 Hz,
30 37
1
H), 2.77–2.68 (m, 1H), 2.63–2.46 (m, 3H), 2.37 (td,
1
3
4.2.10. trans-1-Allyl-4-(tert-butyldimethylsiloxy)-2,6-di-
phenyl-3,4-didehydropiperidine (trans-3h). Colorless oil.
J¼11.4, 3.9 Hz, 1H), 0.92 (s, 9H), 0.11 (s, 6H); C NMR
(100 MHz, CDCl ) d 148.0, 144.4, 136.6, 134.7, 128.7,
3
ꢁ
1
1
IR (neat) 2928, 1666, 1362, 1171 cm
(
;
400 MHz, CDCl ) d 7.50–7.20 (m, 10H), 5.90–5.83 (m,
H NMR
128.4, 128.3, 127.7, 127.2, 126.8, 121.5, 119.5, 118.2,
110.7, 109.0, 67.1, 55.7, 48.7, 35.9, 25.6, 21.7, 18.0, ꢁ4.2;
3
+
1
1
H), 5.14 (dd, J¼17.1, 1.7 Hz, 1H), 5.09 (dd, J¼7.5,
LRMS m/z 431 (M +H); HRMS m/z 430.2467 (calcd for
C H N OSi: 430.2440).
.7 Hz, 1H), 4.39 (br s, 1H), 4.06 (t, J¼7.2 Hz, 1H), 2.92
2
7 34 2
(
dd, J¼14.0, 7.0 Hz, 1H), 2.84 (dd, J¼14.0, 5.3 Hz, 1H),
2
0
1
1
.43 (d, J¼7.2 Hz, 1H), 1.28–1.26 (m, 2H), 0.98 (s, 9H),
4.2.14. 4-(tert-Butyldimethylsiloxy)-4-methyl-1,2-di-
phenyl-4,5-didehydropiperidine (3m). Colorless oil. IR
(neat) 2928, 1709, 1597, 1504, 1253 (br) cm ; H NMR
1
3
.23 (s, 6H); C NMR (75 MHz, CDCl ) d 149.5, 144.1,
3
ꢁ1 1
41.5, 137.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.6,
26.7, 126.6, 116.6, 104.4, 59.1, 54.7, 49.8, 31.1, 25.8,
(400 MHz, CDCl ) d 7.26–7.15 (m, 7H), 6.83 (d,
3
+
ꢁ
4.3; LRMS m/z 405 (M ); Anal. Calcd for C H NOSi:
2
J¼7.9 Hz, 2H), 6.74 (t, J¼7.2 Hz, 1H), 5.12 (dd, J¼6.0,
6 35
C, 76.98; H, 8.70; N, 3.45. Found: C, 76.78; H, 8.69; N, 3.21.
1.9 Hz, 1H), 3.84 (d, J¼15.5 Hz, 1H), 3.55 (d, J¼15.0 Hz,
1
H), 2.92 (m, 1H), 2.40 (d, J¼16.2 Hz, 1H), 1.65 (s, 3H),
1
3
4
.2.11. trans-4-(tert-Butyldimethylsiloxy)-2,6-diphenyl-1-
p-toluenesulfonyl)-3,4-didehydropiperidine (trans-3j).
0.92 (s, 9H), 0.00 (s, 3H), ꢁ0.01 (s, 3H); C NMR
(
Colorless crystals. Mp 124–126 C; IR (neat) 1346, 1159,
(75 MHz, CDCl ) d 149.0, 142.0, 140.1, 129.0, 128.1,
3
ꢀ
126.8, 126.7, 117.9, 114.7, 108.5, 60.3, 57.1, 49.3, 35.7,
25.7, 13.8, ꢁ3.9, ꢁ4.1; LRMS m/z 379 (M ); Anal. Calcd
ꢁ
1
1
+
1
093 cm
;
H NMR (400 MHz, CDCl ) d 7.84 (d,
3
J¼8.1 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 7.10 (t, J¼3.9 Hz,
for C H NOSi$0.2H O: C, 75.22; H, 8.78; N, 3.66. Found:
2
4
33
2
2
5
H), 7.00 (dd, J¼8.0, 2.2 Hz, 2H), 6.95–6.89 (m, 6H),
.69 (t, J¼2.4 Hz, 1H), 5.31 (d, J¼6.8 Hz, 1H), 4.99 (dd,
C, 75.37; H, 8.72; N, 3.56.
J¼4.1, 2.4 Hz, 1H), 2.45 (s, 3H), 2.40 (dd, J¼17.4 Hz,
4.2.15. trans-4-(tert-Butyldimethylsiloxy)-3-methyl-1,2-
diphenyl-4,5-didehydropiperidine (trans-3n). Colorless
1
H), 2.04 (ddt, J¼17.4, 7.2, 2.4 Hz, 1H), 0.88 (s, 9H), 0.09

11906
K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
ꢁ
1 1
oil. IR (neat) 2930, 1668, 1595, 1495, 1254 cm ; H NMR
400 MHz, CDCl ) d 7.25–7.13 (m, 7H), 6.81 (d, J¼8.1 Hz,
4.3.1. Typical procedure for three component reaction
starting from 1a, 5a, and 6a (Table 4, entry 1). To a schlenk
(
2
3
˚
round-bottom flask was introduced molecular sieves (4 A,
H), 6.70 (t, J¼7.1 Hz, 1H), 4.99 (q, J¼3.1 Hz, 1H), 4.92
(
d, J¼5.8 Hz, 1H), 3.93 (dt, J¼15.0, 3.1 Hz, 1H), 3.76 (dt,
crushed), 5a (0.40 mmol) and 6a (0.40 mmol). Small
amount of CH Cl was used to wash the wall. The mixture
J¼15.0, 3.1 Hz, 1H), 3.11–3.04 (m, 1H), 0.91 (s, 9H), 0.88
2
2
1
3
(
(
d, J¼7.3 Hz, 3H), 0.20 (s, 3H), 0.14 (s, 3H); C NMR
was stirred for 30 min at room temperature, then cooled
to 0 C in an ice bath. To the solution were added 1a
ꢀ
(0.48 mmol) and Tf NH (0.08 M toluene solution, 200 mL,
75 MHz, CDCl ) d 151.2, 138.9, 137.3, 129.4, 129.1,
3
1
3
(
28.9, 128.7, 128.6, 127.9, 127.8, 117.9, 115.0, 99.2, 63.7,
7.6, 25.7, 18.2, 13.9, 11.2, ꢁ3.5, ꢁ4.3; LRMS m/z 379
2
16 mmol, 4 mol %) dropwise. The reaction mixture was
stirred for 4 h, and then was quenched with saturated
NaHCO aq. The mixture was extracted twice with CHCl .
+
M ); Anal. Calcd for C H NOSi: C, 75.93; H, 8.76; N,
2
4 33
3
.69. Found: C, 75.92; H, 8.85; N, 3.67.
3
3
The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel using hexane–
4.2.16. 4-(tert-Butyldimethylsiloxy)-1,2-diphenyl-4,5-di-
dehydropiperidine (3o). Colorless oil. IR (neat) 2856,
ꢁ
1 1
1
688, 1597, 1201, 876 cm ; H NMR (400 MHz, CDCl )
3
AcOEt with 1% NEt to give 3a.
3
d 7.23–7.15 (m, 7H), 6.84 (d, J¼8.0 Hz, 2H), 6.75 (t,
J¼7.4 Hz, 1H), 5.15 (dd, J¼6.3, 1.9 Hz, 1H), 4.96 (dd,
J¼3.3, 1.6 Hz, 1H), 3.96 (dt, J¼15.9, 2.7 Hz, 1H), 3.64
4
.3.2. Typical procedure for three component reaction,
starting from 1a, 5a, and 6a followed by desilylation
Table 4, entry 2). To a schlenk round-bottom flask was in-
(
ddd, J¼15.7, 3.0, 1.6 Hz, 1H), 2.89 (m, 1H), 2.42 (dd,
(
J¼16.5, 1.4 Hz, 1H), 0.88 (s, 9H), 0.09 (s, 3H), 0.03 (s,
˚
troduced molecular sieves (4 A, crushed), 5a (0.40 mmol)
and 6a (0.40 mmol). Small amount of CH Cl was used to
wash the wall. The mixture was stirred for 30 min at room
temperature, then cooled to 0 C in an ice bath. To the solu-
tion were added 1a (0.48 mmol) and Tf NH (0.08 M toluene
1
3
3
1
2
H); C NMR (75 MHz, CDCl ) d 149.3, 147.6, 141.7,
3
2
2
29.1, 128.1, 126.9, 118.0, 114.9, 100.8, 56.6, 44.1, 35.4,
5.7, 18.0, ꢁ4.4, ꢁ4.5; LRMS m/z 365 (M ); Anal. Calcd
+
ꢀ
for C H NOSi$0.3H O: C, 74.46; H, 8.59; N, 3.78. Found:
2
3
31
2
2
C, 74.23; H, 8.72; N, 3.73.
solution, 200 mL, 16 mmol, 4 mol %) dropwise. After the
reaction mixture was stirred for 4 h, to the resulting solution
4.2.17. trans-4-Methoxy-1,2,6-triphenyl-3,4-didehydro-
piperidine (trans-3q). Colorless oil. IR (neat) 1682, 1599,
was added tetra-n-butylammonium fluoride (1.0 M in THF,
0
ꢀ
10 min at the same temperature, and then was quenched
.48 mmol) at 0 C. The reaction mixture was stirred for
ꢁ
1
1
1
502, 1371, 1221 cm
;
H NMR (400 MHz, CDCl3)
d 7.34–7.15 (m, 10H), 7.00 (dd, J¼8.8, 7.3 Hz, 2H), 6.66–
with saturated NaHCO aq. Work-up and purification was
3
followed as above.
6
1
.59 (m, 3H), 5.29 (d, J¼5.1 Hz, 1H), 5.22 (t, J¼5.1 Hz,
H), 4.99 (dd, J¼5.1, 1.2 Hz, 1H), 3.44 (s, 3H), 3.08 (dd,
1
3
J¼15.8, 5.1 Hz, 1H), 2.53 (dd, J¼15.8, 3.7 Hz, 1H); C
NMR (75 MHz, CDCl ) d 152.2, 147.6, 144.8, 128.5,
3
Acknowledgements
1
9
28.4, 128.0, 127.1, 126.6, 126.5, 126.3, 118.2, 117.6,
7.1, 59.7, 58.1, 54.4, 35.0; LRMS m/z 341 (M ); HRMS
+
This work was financially supported by Grants-in-Aid from
the Mitsubishi Chemical Corporation Fund and the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
m/z 341.1785 (calcd for C H NO: 341.1780).
24 23
4.3. Typical procedure for desilylation of trans-3a into
trans-4a
1
9
To a solution of trans-3a (0.30 mmol) in dry THF (0.5 M)
was added tetra-n-butylammonium fluoride (1.0 M in THF,
0.33 mL, 0.33 mmol) dropwise at ꢁ78 C. The reaction
mixture was stirred for 15 min at the same temperature,
References and notes
ꢀ
1. (a) Elbein, D. A.; Molyneux, R. Alkaloids; Chemical and
Biological Perspectives; Palletier, S. W., Ed.; Wiley: New
York, NY, 1987; Vol. 57; (b) O’Hagan, D. Nat. Prod. Rep.
2000, 17, 435–446.
2. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic: San Diego,
1987; (b) Heintzelman, G. R.; Meigh, I. R.; Mehajan, Y. R.;
Weinreb, S. M. Org. React. 2005, 65, 141–599.
3. (a) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57,
6099–6138; (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379–471; (c) Takasu, K.; Nishida, N.;
Tomimura, A.; Ihara, M. J. Org. Chem. 2005, 70, 3957–3962.
4. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96,
7807–7808.
. For selected examples: (a) Hermitage, S.; Howard, J. A. K.; Jay,
D.; Pritchard, R. G.; Probert, M. R.; Whiting, A. Org. Biomol.
Chem. 2004, 2, 2451–2460; (b) Badorrey, R.; Cativiela, C.;
Dfaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron 1999, 55,
7601–7612.
and then diluted with CHCl . The solution was poured into
3
water, and the mixture was extracted twice with CHCl3.
The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel using
hexane–AcOEt (6:1) with 1% NEt as an eluent to afford
3
trans-4a as white solids. An analytical sample for X-ray
crystallography was prepared by recrystallization from
ꢀ
H NMR (400 MHz, CDCl ) d 7.35–7.22 (m, 10H), 7.10
dichloromethane–hexane as pillars, mp 206–207 C;
1
3
(
dd, J¼8.9, 7.5 Hz, 2H), 6.71 (t, J¼7.2 Hz, 1H), 6.50 (d,
J¼8.0 Hz, 2H), 5.48 (dd, J¼6.3, 2.1 Hz, 2H), 3.24 (dd,
J¼17.5, 6.3 Hz, 2H), 2.99 (dd, J¼17.5, 2.1 Hz, 2H).
5
1
6
Crystal data for trans-4a. C H NO, monoclinic, space
2
3 21
˚
˚
group P2 /n, a¼13.21(2) A, b¼8.586(13) A, c¼
1
˚
ꢀ
˚
3
1
1
6.02(3) A, b¼106.91(7) , V¼1738.7(50) A , Z¼4, D¼
3
.251 g/cm , R¼0.1635, R ¼0.1035, GOF¼1.419.
w

K. Takasu et al. / Tetrahedron 62 (2006) 11900–11907
11907
6
. For selected examples: (a) Akiyama, T.; Takaya, J.; Kagoshima,
H. Tetrahedron Lett. 1999, 40, 7831–7834; (b) Itoh, J.; Fuchibe,
K.; Akiyama, T. Angew. Chem., Int. Ed. 2006, 45, 4796–4798.
. (a) Akiba, K.; Motoshima, T.; Ishimaru, K.; Yabuta, K.; Hirota,
H.; Yamamoto, Y. Synlett 1993, 657–658; (b) Stanetty, P.;
Mihovilovic, M. D.; Mereiter, K.; V €o llenkle, H.; Renz, F.
Tetrahedron 1998, 54, 875–894; (c) Ishimaru, K.; Kojima, T.
J. Chem. Soc., Perkin Trans. 1 2000, 2105–2108; (d)
Ishimaru, K.; Kojima, T. Heterocycles 2001, 55, 1591–1597.
. For a related study using 2-amino-1,3-siloxybutadiene instead
of 1-siloxy-1,3-butadiene; Barluenga, J.; Alejandro, F.; Aznar,
F.; Vald ꢀe s, C. Tetrahedron Lett. 2002, 43, 8159–8163.
Soc. 2006, 128, 48–49; (c) Sweis, R. F.; Schramm, S. A.;
Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 7442–7443;
(d) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett 2001,
1851–1854.
7
15. Foropoulos, J., Jr.; DesMarteau, D. D. Inorg. Chem. 1984, 23,
3720–3723.
16. For examples of three component synthesis, see: (a)
Kobayashi, S.; Ishitani, H.; Nagayama, S. Chem. Lett. 1995,
423–424; (b) Sisko, J.; Weinreb, S. M. Tetrahedron Lett.
1989, 30, 3037–3040.
8
9
17. Based on our recent finding of the multicomponent (4+2)-
1
(2+2)-cascade cycloaddition of siloxydienes and acrylates,
8
. Ishimaru et al. reported the reaction of aldimines with
2
we attempted the imino Diels–Alder variant starting from
siloxydienes 1, imines 2, and acrylates (Scheme 6). Unfortu-
nately, the desired MCR adduct 8 could not be obtained under
various reaction conditions.
-siloxybutadienes in the presence of triflic acid (TfOH) as
a Brønsted acid catalyst furnished Mannich adduct. On the
other hand, in our case using triflic imide, no Mannich adduct
was observed. Ishimaru, K.; Kojima, T. Tetrahedron Lett.
2003, 44, 5441–5444.
0. (a) Rameshkumar, N.; Veena, A.; Ilavarasan, R.; Adirai, M.;
Shanmugapandivan, P.; Sridhar, S. K. Biol. Pharm. Bull.
TBSO
Ar
CO Me
2
Tf2NH
N
1
+
+
R2
R1
2
003, 26, 188–193; (b) Ramalingan, C.; Balasubramanian, S.;
Kabilan, S.; Vasudevan, A. Eur. J. Med. Chem. 2004, 39,
27–533; (c) Soldatenkov, A. T.; Lenov, A. N.; Mamybekova,
1
2
7
CO Me
2
5
CO Me
2
OTBS
Z. A.; Kolyadina, N. M.; Mobio, I. G.; Naumov, Y. I.;
Kumarova, A. O.; An, L. T. Pharm. Chem. J. 2004, 38, 361–
OTBS
OTBS
R2
3
63; (d) Aridoss, G.; Balasubtamanian, S.; Parthiban, D.;
Kabilan, S. Eur. J. Med. Chem. 2006, 41, 268–275.
R1
R2
R1
N
Ar
R2
R1
N
Ar
Ar
N
1
1. Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005, 127,
668–3669.
imino Diels-Alder
Scheme 6.
(2 + 2)-cycloaddition
8
3
1
2. Takasu, K.; Hosokawa, N.; Inanaga, K.; Ihara, M. Tetrahedron
Lett. 2006, 47, 6053–6056.
3. Takasu, K.; Inanaga, K.; Ihara, M. unpublished results.
1
1
4. Recent reports for Tf
R. B.; Bousquet, T.; Othman, M.; Della, V. Org. Lett. 2005,
, 5335–5337; (b) Boxer, M.; Yamamoto, H. J. Am. Chem.
2
NH-catalyzed reactions; (a) Athman,
18. Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004, 126,
1352–1353.
19. Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292–9295.
7