A novel and efficient stereo-controlled synthesis of hexahydroquinolinones via the diene-transmissive hetero-Diels-Alder reaction of cross-conjugated azatrienes with ketenes and electrophilic dienophiles

Article abstract of DOI:10.1016/j.tet.2008.10.090

The diene-transmissive hetero-Diels-Alder (DTHDA) reactions of cross-conjugated azatrienes (divinylimines or penta-1,4-dien-3-imines) having an N-aryl, N-alkyl, or N-dimethylamino substituent have been examined. The initial reaction of the azatrienes with diphenylketene at room temperature yielded β-lactams of [2+2] cycloadducts, which upon heating underwent [1,3]-sigmatropic rearrangement to produce the formal [4+2] cycloadducts. The reaction of N-phenylazatriene with dimethylketene or dichloroketene produced the [2+2] cycloadducts only, while the reaction of N-(dimethylamino)azatriene with dichloroketene gave the [4+2] cycloadduct without heating. When the [2+2] cycloadduct has two different vinyl substituents at C-4 of the β-lactam ring, the regioselectivity of the rearrangement depends on steric factors and the electronic demand of the substituents. The second Diels-Alder reaction of the initial [4+2] cycloadducts with electron-deficient dienophiles (TCNE, N-phenylmaleimide) stereoselectively yielded hexahydroquinolinone derivatives. Similarly, a tandem intermolecular-intramolecular mode of the aza-DTHDA reactions produced tetracyclic nitrogen-containing heterocycles in a regio- and stereoselective manner.

Full text of DOI:10.1016/j.tet.2008.10.090

Tetrahedron 65 (2009) 920–933
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and efficient stereo-controlled synthesis of hexahydroquinolinones
via the diene-transmissive hetero-Diels–Alder reaction of cross-conjugated
azatrienes with ketenes and electrophilic dienophiles
Satoru Kobayashi, Tomomi Semba, Taku Takahashi, Satoko Yoshida, Kotaro Dai,
*
Takashi Otani, Takao Saito
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2008
Received in revised form 25 October 2008
Accepted 28 October 2008
Available online 6 November 2008
The diene-transmissive hetero-Diels–Alder (DTHDA) reactions of cross-conjugated azatrienes (divinyl-
imines or penta-1,4-dien-3-imines) having an N-aryl, N-alkyl, or N-dimethylamino substituent have been
examined. The initial reaction of the azatrienes with diphenylketene at room temperature yielded
b
-lactams of [2þ2] cycloadducts, which upon heating underwent [1,3]-sigmatropic rearrangement to
produce the formal [4þ2] cycloadducts. The reaction of N-phenylazatriene with dimethylketene or di-
chloroketene produced the [2þ2] cycloadducts only, while the reaction of N-(dimethylamino)azatriene
with dichloroketene gave the [4þ2] cycloadduct without heating. When the [2þ2] cycloadduct has two
Keywords:
Tandem reaction
Diels–Alder
Diene-transmissive
Quinoline
Cycloaddition
different vinyl substituents at C-4 of the b-lactam ring, the regioselectivity of the rearrangement depends
on steric factors and the electronic demand of the substituents. The second Diels–Alder reaction of the
initial [4þ2] cycloadducts with electron-deficient dienophiles (TCNE, N-phenylmaleimide) stereo-
selectively yielded hexahydroquinolinone derivatives. Similarly,
a tandem intermolecular–intra-
molecular mode of the aza-DTHDA reactions produced tetracyclic nitrogen-containing heterocycles in
a regio- and stereoselective manner.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
an efficient synthesis of a variety of ring-fused oligocyclic com-
pounds using cross-conjugated carbotrienes.3 Recently, Fallis et al.
The diene-transmissive Diels–Alder (DTDA) reaction is one of
the sequential (so-called tandem, domino, cascade, etc.) trans-
formation methodologies1 and can usually be defined by two se-
quential cycloadditions that involve an initial Diels–Alder (DA)
reaction of a cross-conjugated triene (n¼1) (or its equivalents) with
a dienophile, followed by a second DA cycloaddition on the newly
formed, transmitted diene unit of the monoadduct with a dieno-
phile to give a bis-adduct (first reaction in Chart 1), although the
DTDA reaction is formally considered to be a set of multisequential
reported an application of this method for the construction of
a triterpenoid skeleton and tricyclic core of vinigrol.4a–e Sherburn
et al. reported the formal total synthesis of triptolide, a diterpenoid
natural product, using this methodology.4f,g Because the hetero-DA
reaction is among the most powerful and attractive methods of
obtaining six-membered heterocycles,5 it is promising that the
DTHDA methodology involving one or two hetero-DA reactions in
the sequence offers an efficient and attractive method for stereo-
selective synthesis of ring-fused heterocyclic systems. In this con-
text, our group previously reported the first example of the DTHDA
reaction using divinyl thioketones as cross-conjugated thiatrienes.6
Tsuge et al. reported the DTHDA reaction of divinyl ketones as
cross-conjugated oxatrienes.7 Spino et al. applied this oxatriene–
DTHDA methodology to construct the picrasane framework by use
of cyclic 2-formyl-1,3-diene.8 Very recently, the first report on the
DTHDA reaction using cross-conjugated dioxatrienes (1,1-difor-
mylethenes) has appeared.9 The DTHDA methodology involving
aza-DA reactions would be a valuable and attractive synthetic tool
for construction of a variety of ring-fused nitrogen-containing
heterocyclic systems because nitrogen heterocycles are found in
a wide range of natural and synthetic bioactive compounds.5,10
DA reactions of a,u-divinylpoly(vinylidene) in which the last two
steps involve the above-defined DTDA process (e.g., n¼2, 3, . in
Chart 1). The diene-transmissive hetero-Diels–Alder (DTHDA) re-
action is the special case of the DTDA reaction in which one or more
heteroatoms are contained within either a triene/polyene frame-
work or a dienophile skeleton or both in either DA process.
Since the early reports in 1955,2 the utility of this attractive
method has been shown by Tsuge, Kanemasa, Wada and others in
* Corresponding author. Tel.: þ81 3 5228 8254; fax: þ81 3 5261 4631.
E-mail address: tsaito@rs.kagu.tus.ac.jp (T. Saito).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.090

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
921
-divinylpoly(vinylidene)
n
DA 1
DA 2
n = 1
DA 1
DA 2
DA 3
n = 2
DA 3
DA 2
DA 3
DA 4
DA 1
DA 2
n = 3
DA 4
DA 3
DA 2
Chart 1. DTDA methodology of
a,
u
-divinylpoly(vinylidene).
Therefore, we started to investigate the DTHDA reaction using
divinyl imines A as cross-conjugated azatrienes in the initial DA
reaction with tosyl isocyanate and succeeded in stereoselective
synthesis of hexahydroquinazolinones B by the DTHDA method for
the first time (Scheme 1).11,12 We also examined ketenes as an
initial reactant with A to lead to hexahydroquinolinone derivatives
C, the results of which were partly given in a preliminary com-
munication.13 Herein, we report this aza-DTHDA reaction with
ketenes in detail and its application to an intramolecular version.
Et3N at 0 ꢀC for 1 h.14,15 Azatrienes 2a–h could be isolated,16 but
they were used without purification in the subsequent reaction
with ketenes, while N,N-dimethylaminoazatriene 2i is stable
enough to allow isolation. N-Phenylazatriene 2a reacted immedi-
ately (within 5 min) with diphenylketene17 at room temperature to
produce the [2þ2] cycloadduct 3a in 98% yield (Scheme 2, Table 1,
entry 1).18 Although 3a is an isolable crystalline compound, it un-
derwent [1,3]-sigmatropic rearrangement upon heating in toluene
under reflux for 1 h to yield the thermodynamically more stable
dihydropyridone 4a quantitatively, which corresponds to the for-
mal [4þ2] (DA) cycloadduct of azatriene 2a with diphenylketene
(Table 1, entry 1).19,20 Diphenylketene also reacted with azatrienes
2b–i having various substituents R1 (i.e., aryl, benzyl, alkyl, and
dimethylamino groups on the nitrogen atom) to produce the [2þ2]
cycloadducts 3b–i in good to excellent yields (entries 2–9). Simi-
larly, thermal rearrangement of 3b–i provided dihydropyridones
2. Results and discussion
2.1. Initial cycloaddition of azatrienes 2 with ketenes
Azatrienes 2 were prepared from the corresponding ketones 1
and a variety of primary amines by condensation using TiCl4 and
O
O
R
Ts
Ts
R
N
N
N
O
R
N
O
N
B
A
C
Scheme 1.
O
R2
O
R2
R2
Ph
R1
R2
R2
O
R1
O
R2
Ph
N
N
R1
Ph
R1NH2
N
Ph
Ph
TiCl4
Et3N
Ph
Ph
H4
Ph
CH2Cl2
1
2
3
4
Scheme 2.

922
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
Table 1
dienophile, tetracyanoethylene (TCNE) was carried out to examine
the diastereo -facial selectivity. The results are shown in Scheme 3
Initial cycloaddition of azatrienes 2 with ketenesa
p
Entry Azatriene R1
R2 Product Yield of 3 (%) Product Yield of 4 (%)
and Table 2. The reaction of 4a with TCNE proceeded at room
temperature for 10 min to produce [4þ2] cycloadduct 5a in 99%
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Ph
Ph 3a
98
84
80
96
96
76
90
72
91
16
20
96
de
4a
4b
4c
4d
4e
4f
4g
4h
4i
99
99
99
99
99
99
99
98
99
db
dc
99
23
4-MeOC6H4 Ph 3b
4-MeC6H4 Ph 3c
4-ClC6H4
yield with complete diastereo p-facial selectivity (Table 2, entry 1).
Similarly, the reactions of 4b–m with TCNE proceeded smoothly
within 10 min to produce 5b–m in nearly quantitative yield (entries
2–11). In all reactions, the dienophile (TCNE) added from the less
hindered back side (H4) to the diene moiety of 4, avoiding the more
bulky axial phenyl substituent at the 4-position (vide infra, Fig. 2).
Ph 3d
4-NO2C6H4 Ph 3e
Bn
Ph 3f
Ph 3g
Ph 3h
Ph 3i
Me 3j
Cl 3k
Me 3l
Cl 3m
7
8
9
2g
2h
2i
iPr
nPr
NMe2
Ph
Ph
NMe2
NMe2
10
11
12
13d
2a
2a
2i
4j
4k
4l
Table 2
Second cycloaddition of 4 with TCNE
2i
4m
Entry
Diene
R1
R2
Product
Yield (%)
a
Reaction of 2 with ketene was carried out in a one-pot procedure by generating 2
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Cl
5a
5b
5c
5d
5e
5f
5g
5h
5i
99
99
99
99
98
99
99
99
99
94
99
(1 (1.0 equiv), R1NH2 (2.0 equiv), Et3N (4.4 equiv), TiCl4 (1.0 equiv)). In the case of
R1¼NMe2 (entries 9, 12, 13), isolated azatriene 2i was used.
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
Bn
b
Compound 3j decomposed on heating to 200 ꢀC.
Compound 3k decomposed on heating to 140 ꢀC.
THF was used as solvent.
[2þ2] cycloadduct 3m was not obtained.
c
d
e
iPr
nPr
9
10
11
NMe2
NMe2
NMe2
4l
4m
5l
5m
4b–i in excellent yields (entries 2–9). The reaction of 2a with in situ
generated dimethylketene and dichloroketene produced the [2þ2]
cycloadducts 3j and 3k, respectively, albeit in low yield (entries 10
and 11). Unfortunately, both adducts 3j,k failed to give the expected
rearrangement products 4j,k under the thermal conditions tried
(entries 10 and 11). Similarly, the [2þ2] cycloadduct 3l was
obtained in 96% yield from the reaction of isolated azatriene 2i
(R1¼Me2N) with dimethylketene, and the cycloadduct 3l also un-
derwent the [1,3]-sigmatropic rearrangement to give the formal
[4þ2] cycloadduct 4l in 99% yield (entry 12). Meanwhile, the re-
action of 2i with dichloroketene directly gave the [4þ2] cyclo-
adduct 4m (23%) instead of the corresponding [2þ2] cycloadduct
3m even at room temperature (entry 13).18b,19c,d
2.3. Second cycloaddition with N-phenylmaleimide
The reaction of 4 with N-phenylmaleimide (N-PhMI) was carried
out to examine endo/exo selectivity as well as diastereo -facial
p
selectivity (Scheme 4 and Table 3). The reaction proceeded in
refluxing toluene to produce the single diastereomer 6 nearly
quantitatively. The sole exception is the case of 4l giving 6l (99%) in
a 69:31 ratio of a separable diastereomeric mixture of the exo- and
endo-isomers (entry 10). The p-facial selectivity of 4 for the N-PhMI
dienophile agreed with that observed in the reaction with TCNE.
2.2. Second cycloaddition with tetracyanoethylene
2.4. Determination of relative stereochemistry and proposed
transition-state structures
With the monocycloadducts 4 in hand, we performed the sec-
ond cycloaddition with some representative electron-deficient
dienophiles, because normal electron-demand DA reactions were
expected to proceed at the electron-rich 2-aminodiene moiety in 4.
Initially, the reaction of 4 with a symmetrical and reactive
The stereochemistry of bis-adducts 6 as well as 5 was de-
termined by inspection of the vicinal coupling constants of H9a
using 1H NMR spectroscopy (Fig. 1); a large vicinal coupling con-
stant (J¼ca. 12 Hz) between H9 and H9a indicated a trans diaxial
relationship, and a relatively large vicinal coupling constant (J¼ca.
8 Hz) between H9a and H9b suggested a pseudodiaxial relationship.
Additionally, the nuclear Overhauser effect (NOE) was observed
between H9 and H9b, and between H9a and H4 in a cis relationship.
Thus, the stereochemical outcome implied that the dienophile
attacked from the less hindered bottom H4-side of monoadduct 4 in
an exo mode (Fig. 2). The vicinal coupling constant between H4 and
the vinyl proton (H5) on the pyridone ring of 4 was ca. 7 Hz, sug-
gesting that H4 orients in a quasi-equatorial position, and hence the
O
R2
R1
O
N
R2
Ph
R2
R2
Ph
R1
H4a
TCNE
N
CH2Cl2
r.t., 10 min.
H4
NC
H7
Ph
Ph
H4
CN CN
CN
4
5
Scheme 3. Second cycloaddition with TCNE.
O
O
R2
R2
R2
R2
R1
R1
O
N
N
R2
R2
Ph
R1
H9a
H9b
H9a
H9b
N-PhMI
Toluene
reflux
N
+
Ph
O
Ph
O
H9
H4
Ph
H9
H4
Ph
H3a
H3a
Ph
H4
N
N
O
O
Ph
Ph
6 exo (H9a-H9b trans) 6 endo (H9a-H9b cis)
Scheme 4. Second cycloaddition with N-phenylmaleimide.
4

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
923
Table 3
Table 4
Second cycloaddition of 4 with N-phenylmaleimide
Initial cycloaddition of azatrienes 8 with ketenes
Entry Diene R1
R2
Time (h) Product Yield (%) exo/endoa
Entry Azatriene R1
R2 Product Yield of Product Yield of
Ratio
9 (%)
10þ11 (%) (10/11)a
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
7.0
8.0
7.0
6a
6b
6c
6d
6e
6f
99
99
99
99
98
99
99
99
99
99
99
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
>95/5
69/31
>95/5
4-MeOC6H4 Ph
1
2
3
4
8a
8b
8c
8d
8e
8e
Ph
Ph 9a
66
57
83
53
57
89
10a, 11a 99
81/19
82/18
82/18
83/17
87/13
82/18
4-MeC6H4
4-ClC6H4
4-NO2C6H4
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4 Ph 9b
10b, 11b 99
10c, 11c 97
10d, 11d 97
10e, 11e 97
10f, 11f 77
7.0
8.0
7.0
Bn
Ph 9c
Ph 9d
Ph 9e
Me 9f
iPr
5
NMe2
NMe2
iPr
13.0
9.5
6.0
6g
6h
6i
6b
nPr
a
Ratio was determined based on integration of the 1H NMR signals of the methyl
9
NMe2
NMe2
NMe2
protons of the Et ester group.
10
11
4l
4m
Me 40.0
Cl 7.0
6l
6m
b
Reaction was carried out from isolated azatriene 8e.
a
Ratio was determined by 1H NMR spectroscopy. Ratio >95:5 denotes that no
dienophile over the second orbital interaction in the endo transi-
tion-state. However, the endo addition was partially observed in the
reaction of monoadduct 4l bearing a relatively small methyl sub-
stituent at the C3 position (Table 3, entry 10).
endo-isomer was detected.
phenyl group at C4 occupies a quasi-axial position. Therefore, the
dienophiles attacked from the bottom H4 side of the diene unit
avoiding steric repulsion between the phenyl group at C4 and the
dienophile. The observed exo-selectivity is explained in terms of
the steric repulsion exerted between the bulky axial phenyl or
chloro substituent at the C3 position and the imido moiety of the
2.5. DTHDA reaction of azatrienes 8, 14, and 15 bearing two
different vinyl groups
2.5.1. Initial cycloaddition of azatrienes 8, 14, and 15 with ketenes
We performed the DTHDA reaction of cross-conjugated aza-
trienes (8, 14, and 15) bearing different substituents at the diene
termini to examine electronic and/or steric effects in the DTHDA
cycloaddition involving the [1,3]-sigmatropic rearrangement. Aza-
triene 8a generated in situ from the corresponding ketone 7 and
aniline also reacted with diphenylketene to afford the [2þ2]
cycloadduct 9a in 66% yield (Scheme 5, Table 4, entry 1). The adduct
9a underwent [1,3]-sigmatropic rearrangement upon heating in
toluene for 2 h to afford the two formal [4þ2] cycloadducts, dihy-
dropyridones 10a and 11a, in 99% yield in a ratio of 81:19 (Table 4,
entry 1). Similarly, azatrienes 8b–e reacted with diphenylketene or
dimethylketene to produce the [2þ2] cycloadducts 9b–f in 53–89%
yields, and their thermal isomerization provided mixtures of pyr-
idones 10b–f and 11b–f in good yields in ratios of 82–87:18–13. The
predominant formation of 10 over 11 is attributed to the stabilizing
ability difference due mainly to the substituents (Ph, CO2Et) in the
canonical resonance structures of the zwitterionic intermediates
(Fig. 3).
NOE
H4
H9a
O
H5
R2
Ph
NPh
N
R
H3a
O
R2
H9b
O
Ph
H9
J
H
9–9a = 12 Hz
NOE
Figure 1. Stereochemistry of compound 6.
Ph
Ph
Ph
O
Ph
O
H4 4
3
H4
H5
R
R
H5
N
Azatrienes 14 and 15 were also subjected to reaction with
diphenylketene and dimethylketene to produce again the [2þ2]
N
Ph
Ph
J
4–5 = 7.0 Hz
O
H
O
Ph
Ph
N
O
+
O
+
Ph
-
R2
R2
R1
R2
R2
-
R1
N
9
Figure 3.
O
11
Ph
N
10
N
O
O
Ph
Ph
COOEt
EtOOC
endo TS
exo TS
Figure 2. exo and endo transition-state models.
R2
R2
R1
O
R2
O
R1
N
N
R1NH2
R2
Ph
COOEt
Ph
O
COOEt
TiCl4
Et3N
CH2Cl2
Ph
COOEt
8
9
7
O
R2
R2
Ph
R2
R2
R1
R1
+
N
N
COOEt
Ph
COOEt
H4
H4
10
11
Scheme 5.

924
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
R2
R2
O
O
R1
O
R2
R2
R2
R2
R3
R1
R1NH2
TiCl4
Et3N
CH2Cl2
N
R1
O
N
N
R3
R3
H4
18, 19
R3
12, 13
14, 15
16, 17
Scheme 6.
Table 5
Initial cycloaddition of azatrienes 14 and 15 with ketenes
Entry
Azatriene
R1
R2
R3
Product
Yield of 16/17 (%)
Conditions (16/17/18/19)
Product
Yield of 18/19 (%)
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
14f
14f
15a
15b
15c
15d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Cl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et
CO2Et
CO2Et
CO2Et
16a
16b
16c
16d
16e
16f
16g
16h
17a
17b
17c
17d
43
57
71
61
89
83
82
d
Xylene, 140 ꢀC, 5.0 h
Xylene, 140 ꢀC, 2.5 h
Toluene, 110 ꢀC, 1.0 h
Toluene, 110 ꢀC, 2.5 h
Toluene, 110 ꢀC, 1.0 h
Toluene, 110 ꢀC, 5.0 h
Toluene, 110 ꢀC, 12 h
rt, 5 min.
Xylene, 140 ꢀC, 3.0 h
Toluene, 110 ꢀC, 1.0 h
Xylene, 140 ꢀC, 5.5 h
Toluene, 110 ꢀC, 4.0 h
18a
18b
18c
18d
18e
18f
18g
18h
19a
19b
19c
19d
77
90
95
50
48
57
70
70
88
91
93
94
4-MeOC6H4
Bn
iPr
nPr
NMe2
NMe2
NMe2
Ph
9
50
52
50
33
10
11
12
Bn
iPr
NMe2
cycloadducts 16 and 17, respectively, both of which underwent
[1,3]-sigmatropic rearrangement upon heating to give 18 and 19 as
sole products, respectively (Scheme 6 and Table 5). The reaction of
14f with dichloroketene proceeded at room temperature for 5 min
to give the [4þ2] cycloadduct 18h instead of the [2þ2] cycloadduct
16h (entry 8). It is noteworthy to mention that although 18 and 19
were formed as the formal DA products of azatrienes with ketenes
via the rearrangement, the reaction took place at the mono-
substituted diene C-terminus, even for the case that the substituent
is an electron-withdrawing ethoxycarbonyl group for 15/17 (Table
5). These results suggest that steric factors played the predominant
role rather than electronic factors in the overall process
([2þ2]þrearrangement). In fact, 1-dimethylamino-4,4-bis-(2-methyl-
1-propenyl)-3,3-diphenylazetidin-2-one derived from 2,6-dimethyl-
2,5-heptadien-4-one (phorone) did not undergo [1,3]-sigmatropic
rearrangement even under the severe thermal conditions tried
until its retro [2þ2] reaction along with partial decomposition
occurred.
TCNE of 10 and 11 as a mixture (Scheme 7). When a mixture of 10a
and 11a (ratio, 81:19) was treated with TCNE at room temperature
for10 min, wefortunatelyfound thatonly 11a reactedto provide bis-
adduct 20a in 95% yield along with 10a in almost quantitative re-
covery yield (96%)(Table 6, entry1). Similarly, bis-adducts 20b–f and
unreacted 10b–f were both successfully obtained separately in good
yields (entries 2–6). The trans relationship between H4 and H4a of 20
indicated that TCNE attacked from the less hindered H4-side,
avoiding the more bulky ester substituent at the 4-position of the
pyridone ring of 11 in agreement with the reaction of 4 (vide supra).
Thus, separated monoadduct 10a reacted with an excess
amount of methyl vinyl ketone (MVK) in refluxing xylene for 23 h
to give hexahydroquinolinones 21a and 22a in 74% yield in a ratio of
17:83 (Scheme 8, Table 7, entry 1). The latter compound 22a could
be produced from the initially formed DA endo-adduct 21a via [1,3]-
H-migration under thermal reaction conditions because the sepa-
rated compound 21d (entry 3) was converted to 22d by prolonged
heating in xylene [21d (major isomer) was used instead of 21a].
Similarly, the reactions of 10c–e with MVK afforded 21c–e and 22c–
e (entries 2–4). In the case of 10d, the formation of small amounts
of exo isomers was variably detected (exo-210d and exo-220d).
2.5.2. Second cycloaddition of monoadducts 10 and 11
The monoadduct dienes 10 and 11 were inseparable by column
chromatography. Thus, we attempted the second DA reaction with
2.5.3. Second cycloaddition of monoadducts 18 and 19
Initially, the DA reaction with TCNE was carried out (Scheme 9
and Table 8). Monoadducts 18 and 19 were considered to be less
reactive than monoadducts 4 and 11 because of steric hindrance
between the two methyl substituents at the diene terminus and the
attacking dienophile. Actually, these reactions required heating at
a somewhat higher temperature and/or longer reaction time
O
O
R2
R2
Ph
R2
R2
Ph
R1
R1
N
N
COOEt
COOEt
H4
H4
10
10
TCNE
CH2Cl2
r.t., 10 min.
+
+
Table 6
O
R2
R2
COOEt
Second cycloaddition of 10/11 with tetracyanoethylene
R1
O
N
R2
R2
H4a
H4
CN
R1
10a, 11a Ph
10b, 11b 4-MeOC6H4 Ph 20b
R2
Product Yield of 20 (%) Recovered 10 (%)
R1
Entry Diene
N
1
2
Ph 20a
95
93
91
92
94
99
96
93
97
96
97
98
H7
Ph
Ph
COOEt
H4
3
4
10c, 11c Bn
10d, 11d iPr
10e, 11e NMe2
Ph 20c
Ph 20d
Ph 20e
Me 20f
NC
CN
CN
5
6a
10f, 11f
NMe2
11
20
a
Reaction was carried out for 3.5 h (monitored by 1H NMR spectroscopy).
Scheme 7. Second cycloaddition of 10/11 with tetracyanoethylene.

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
925
O
O
O
R2
R2
Ph
R2
R2
Ph
R1
R1
R2
R2
Ph
R1
N
N
N
H4a
H4 H6 H7
COOEt
COMe
MVK
+
Xylene
reflux
COOEt
H4 H6 H7
COOEt
COMe
H4
10
21 endo (H6-H7 cis)
22 (endo isomer derivative)
Scheme 8. Second cycloaddition of 10 with methyl vinyl ketone.
O
Table 7
Second cycloaddition of 10 with methyl vinyl ketone
R2
R2
R3
O
R1
R2
R1
N
H9a
H9b
N
R2
R3
N-PhMI
Entry
Diene
R1
R2
Time (h)
Product
Yield (%)
Ratio (21/22)a
H9
H3a
1
2
3
4
10a
10c
10d
10e
Ph
Ph
Ph
Ph
Ph
23
24
26
75
21a, 22a
21c, 22c
21d, 22d
21e, 22e
74
66
65
57
17/83
19/81
80/20
9/91
H4
O
Bn
iPr
N
O
NMe2
Ph
a
Ratio was determined based on integration of the 1H NMR signals of the methyl
18, 19
25, 26
exo
protons of the Et ester group.
Scheme 10. Second cycloaddition of 18/19 with N-phenylmaleimide.
compared with those of 4 and 11; however, they provided clean
reactions to give bis-adducts 23 and 24 in good to excellent yields
with complete
p-facial selectivity.
Table 9
Second cycloaddition of 18/19 with N-phenylmaleimide
O
R2
R2
R3
R1
O
R2
R2
R1
Entry Diene R1 R2 R3
Solvent Temp Time Product Yield
N
H4a
N
(ꢀC)
(h)
(%)
TCNE
CH2Cl2
H4
NC
R3
1
2
3
4
18f
NMe2 Ph Ph
Mesitylene 166
110
30
25f
56
98
93
98
H4
19a
19b
19d
Ph
Ph COOEt Toluene
65
20
24
26a
26b
26d
CN
CN
Bn
Ph COOEt Xylene
140
110
CN
NMe2 Ph COOEt Toluene
18, 19
23, 24
Scheme 9. Second cycloaddition of 18/19 with tetracyanoethylene.
cycloadded from the less hindered back H4-side to the diene (18,19)
in the exo arrangement (cf. Fig. 2).
Table 8
Second cycloaddition of 18/19 with tetracyanoethylene
2.6. Intramolecular DTHDA reaction
Entry Diene R1
R2 R3
Temp (ꢀC) Time (h) Product Yield of
Synthesis of more highly ring-fused nitrogen heterocycles
prompted us to incorporate an intramolecular mode in this DTHDA
methodology, because we have succeeded in the intramolecular
DTHDA reaction of N-sulfonyl azatrienes to give benzopyrano[3,4-
c]quinolines with high regio- and stereoselectivities.12b
23/24 (%)
1a
2a
3
4
5
18a
18b
18c
18d
18e
18f
18g
18h
19a
19b
19c
19d
Ph
Ph Ph
83
83
40
40
40
rt.
6.5
4.5
30
8.0
4.0
1.0
63
9.0
0.5
2.0
2.0
0.5
23a
23b
23c
23d
23e
23f
23g
23h
24a
24b
24c
24d
99
99
99
98
99
99
99
62
99
91
94
99
4-MeOC6H4 Ph Ph
Bn
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Me Ph
Cl Ph
Ph COOEt 40
Ph COOEt rt.
Ph COOEt rt.
Ph COOEt rt.
iPr
nPr
When an intramolecular version is used as the second DA re-
action in this DTHDA methodology, the site selectivity in the initial
cycloaddition with ketene is of particular importance for the sec-
ond intramolecular DA reaction. Encouraged by the successful re-
sults in the intermolecular version (see azatrienes 14, 15 in Scheme
6), we designed a new azatriene 29 to overcome these difficulties.
Ketone 28, the precursor of imine 29, was synthesized as outlined
in Scheme 11. Aldol reaction of mesityl oxide with TBS-protected
salicylaldehyde (a) followed by dehydration with methanesulfonyl
chloride/triethylamine (b) and deprotection of the TBS group by
treatment with TBAF (c) gave ketone 27 in 86% yield in three steps
(Scheme 11). Acylation of the hydroxyl group of 27 with fumaric
acid monomethyl ester using DCC produced the tethered ketone 28
in 86% yield (d).
As illustrated in Scheme 12, the azatriene 29 generated from
ketone 28 and benzylamine (a) reacted with diphenylketene to
produce the expected [2þ2] cycloadduct 30 in 34% yield (b). The
[1,3]-sigmatropic rearrangement worked cleanly upon heating 30
in toluene for 2 h to give diene 31 as the sole product in 88% yield
(c). The intramolecular DA reaction of 31 required prolonged
6
NMe2
NMe2
NMe2
Ph
7a
8
83
rt.
9
10
11
12
Bn
iPr
NMe2
a
1,2-Dichloroethane was used as solvent.
Next, the reaction with N-PhMI was performed to observe endo/
exo selectivity and -facial selectivity as well (Scheme 10, Table 9).
p
The monoadduct 18f reacted with N-PhMI in refluxing mesitylene
for 30 h to produce a bis-adduct, hexahydroquinolinone 25f, in 56%
yield (entry 1), while the other compounds 18a–e and 18g,h only
decomposed without giving any adducts under the reaction con-
ditions. On the other hand, the reactions of monoadducts 19a,b,d
with N-PhMI proceeded under milder thermal conditions to give
hexahydroquinolinones 26a,b,d in excellent yields (entries 2–4). All
of the reactions proceeded with complete
selectivities to give single diastereomers. Namely, N-PhMI
p-facial and endo/exo

926
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
O
COOMe
O
O
OTBS
CHO
OH
O
O
d
a, b, c
+
27
28
Scheme 11. (a) LDA (1.1 equiv), THF, ꢁ78 ꢀC, 1 h, 99%; (b) MsCl (1.2 equiv), Et3N (2.4 equiv), CH2Cl2, rt, overnight, 93%; (c) TBAF (1.0 equiv), THF, rt, 1 h, 93%; (d) mono-
methylfumarate (1.1 equiv), DCC (2.0 equiv), DMAP (cat.), toluene, 10 min, 86%.
O
O
O
Ph
Ph
N
Bn
O
COOMe
O
O
COOMe
Bn
a
b
N
O
O
COOMe
28
29
30
O
O
O
Ph
Ph
Ph
Ph
Ph
Bn
Bn
N
Bn
Ph
N
N
H12c
H12b
H12c
H12b H6
H6a
d
c
+
H6
H4
O
O
O
H6a
O
COOMe
COOMe
COOMe
O
O
31
32 endo
32' exo
(H6a-H12c cis)
(H6a-H12c trans)
Scheme 12. (a) BnNH2 (2.0 equiv), TiCl4 (1.0 equiv), Et3N (4.4 equiv), CH2Cl2, 0 ꢀC, 1.5 h; (b) Ph2CCO (2.0 equiv), rt, 2 h, 34%; (c) toluene, reflux, 2 h, 88%; (d) xylene, reflux, 31 h, 63%
(48:52).
heating at a higher temperature (in refluxing xylene for 31 h) to
proceed, giving mixture of 8-oxa-3-azabenzo[4,5]cyclo-
p-facial selectivities of the cycloaddition by means of 2D NMR
a
spectroscopy (NOESY) alone because of overlapping of several es-
sential peaks. Finally, X-ray crystal structure analyses unequivocally
established the structures of 32 and 320 (Fig. 4), proving that both
cycloadducts (32 and 320) were formed by the tethered dienophile
hepta[1,2,3-de]naphthalenes 32 (endo) and 320 (exo) in 63% yield in
a ratio of 48:52. Compound 320 was assigned as an exo-cycloadduct,
based on its vicinal coupling constant between H6a and H12c
(J¼10.5 Hz), which indicated a trans diaxial relationship between
them. However, we could not clearly determine the endo/exo and
attacking from the
modes with respect to the chain, respectively.
b
-face (anti to H4) to the diene 31 in endo and exo
Figure 4. X-ray crystal structure analysis of 32 (left) and 320 (right).

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
927
3. Conclusion
(0.152 mL, 2.0 mmol) in CH2Cl2 (25 mL) was cooled to 0 ꢀC, and
titanium tetrachloride (1.0 mL, 1.0 M solution in CH2Cl2, 1.0 mmol)
was added dropwise. The reaction mixture was stirred at room
temperature for 30 min, quenched with saturated aqueous NaHCO3
and extracted with CH2Cl2 (10 mLꢂ2). The combined extracts were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:9, v/v)] followed by recrystallization from CH2Cl2/
The DTHDA methodology of cross-conjugated azatrienes bear-
ing electron-donating N-substituents reacting with ketenes fol-
lowed by electrophilic dienophiles has been shown to be an
efficient method for construction of hexahydroquinolinones with
high regio- and stereoselectivities. The intermolecular–intra-
molecular DTHDA reaction mode was also successfully applied for
the stereoselective synthesis of 8-oxa-3-azabenzo[4,5]cyclo-
hepta[1,2,3-de]naphthalene. Further studies on the DTHDA reaction
using cross-conjugated heterotrienes are currently under way in
our laboratory.
hexane (1:9, v/v) yielded N,N-dimethyl-N0-(3-phenyl-1-
ylallylidene)hydrazine (2i) (214 mg, 77%) as orange crystals. Mp
122–123 ꢀC; IR (KBr): 1738, 1498, 1376, 752, 692 cmꢁ1 1H NMR
(300 MHz, CDCl3)
2.68 (s, 6H, Me(NMe2)), 6.96 (d, J¼16.1 Hz, 1H,
olefin), 7.00 (d, J¼16.8 Hz, 1H, olefin), 7.16–7.55 (m, 12H, olefin, Ar);
13C NMR (75 MHz, CDCl3)
47.8 (2CH3), 121.2 (CH), 125.8 (CH), 127.1
b-styr-
;
d
4. Experimental
4.1. General
d
(4CH), 128.3 (CH), 128.6 (2CH), 128.8 (3CH), 134.8 (CH), 135.5 (CH),
136.4 (C), 136.6 (C), 159.1 (C). HRMS-ESI m/z [MþNa]þ calcd for
C19H21N2: 277.1699, found: 277.1699.
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. Infrared spectra were recorded on
Et3N (0.033 mL, 0.24 mmol) was added to a solution of azatriene
2i (55 mg, 0.2 mmol) in CH2Cl2 (10 mL) at 0 ꢀC followed by iso-
butyryl chloride (0.025 mL, 0.24 mmol). After 10 min, the reaction
was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (10 mLꢂ2). The combined extracts were washed with water
and brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography [SiO2: EtOAc/hexane
(1:4, v/v)] followed by recrystallization from CH2Cl2/hexane (1:4,
a Hitachi 270-30 or a Horiba FT-710 spectrophotometer. 1H and 13
C
NMR spectral data were obtained with a Bruker AV 600, a JEOL
JNM-EX 500, a JEOL JNM-LA 400, a Bruker DPX 300, a JEOL JNM-EX
300, or a JEOL JNM-EX 270 instrument. Chemical shifts (d) are
quoted in parts per million using tetramethylsilane (
d
¼0) for 1H
NMR and CDCl3 (
d
¼77.0) for 13C NMR. Mass spectra were measured
on a Bruker Daltonics microTOF, a Hitachi double-focusing M-80B,
or a JEOL JMS-SX 102 spectrometer. Elemental analyses were per-
formed with a YANACO CHN-CODER MT-6 model analyzer. Column
chromatography was conducted on silica gel (Kanto Chemical Co. or
Merck Co. Ltd). HPLC was performed on a JASCO UV-970 equipped
with a detector (254 nm) using a Pegasil silica, 60–5, 20ꢂ250 mm
column and EtOAc/hexane as eluent. All reactions were performed
under argon.
v/v) yielded 1-(N,N-dimethylamino)-3,3-dimethyl-4,4-di-
ylazetidin-2-one (3l) (67 mg, 96%) as colorless crystals. Mp 123–
124 ꢀC; IR (KBr): 1756, 1498, 1450, 1332, 976, 750, 698 cmꢁ1 1H
NMR (270 MHz, CDCl3) 1.28 (s, 6H, 2Me), 2.98 (s, 6H, 2Me(NMe2)),
6.44 (d, J¼16.2 Hz, 2H, -H(styryl)), 6.77 (d, J¼16.2 Hz, 2H,
-H(styryl)), 7.23–7.45 (m,10H, Ar); 13C NMR (68 MHz, CDCl3)
19.8
b-styr-
;
d
a
b
d
(2CH3), 46.6 (2CH3), 56.1 (C), 72.8 (C), 126.5 (4CH), 127.6 (2CH),
127.9 (2CH), 128.6 (4CH), 133.6 (2CH), 136.5 (2C), 172.8 (C). HRMS-
ESI m/z [MþNa]þ calcd for C23H26N2NaO: 369.1937, found:
369.1940.
4.2. Typical procedure for preparation of azatriene 2 and its
sequential [2D2] cycloaddition with diphenylketene
(Table 1, entry 1)
4.4. Typical procedure for [1,3]-sigmatropic rearrangement of
the [2D2] cycloadduct 3 (Table 1, entry 1)
A mixture of 1,5-diphenyl-1,4-pentadiene-3-one (1) (234 mg,
1.0 mmol), Et3N (0.612 mL, 4.4 mmol), and aniline (0.182 mL,
2.0 mmol) in CH2Cl2 (25 mL) was cooled to 0 ꢀC, and titanium tet-
rachloride (1.0 mL, 1.0 M solution in CH2Cl2, 1.0 mmol) was added
dropwise. The reaction mixture was stirred at room temperature
for 30 min, then a solution of diphenylketene12 (388 mg, 2.0 mmol)
in CH2Cl2 (5 mL) was added dropwise. After 5 min, the reaction
mixture was quenched with water (5 mL) and extracted with
CH2Cl2 (10 mLꢂ2). The combined extracts were washed with water
and brine, dried over MgSO4, and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography [SiO2: EtOAc/hexane
(1:4, v/v)] followed by recrystallization from CH2Cl2/hexane (1:4,
A solution of 3a (252 mg, 0.5 mmol) in toluene (20 mL) was
heated at 110 ꢀC for 2 h and then concentrated in vacuo. Purification
of the residue by flash chromatography [SiO2: EtOAc/hexane (1:4,
v/v)] followed by recrystallization from CH2Cl2/hexane (1:4, v/v)
yielded 1,3,3,4-tetraphenyl-6-b-styryl-3,4-dihydro-1H-pyridin-2-
one (4a) (249 mg, 99%) as colorless crystals. Mp 216–217 ꢀC; IR
(KBr): 1682, 1496, 1336, 750, 698 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
4.27 (d, J¼7.1 Hz, 1H, H-4), 5.85 (d, J¼15.9 Hz, 1H, H-8), 6.10 (d,
J¼7.1 Hz, 1H, H-5), 6.59–6.61 (m, 2H, Ar), 6.65 (d, J¼15.9 Hz, 1H, H-
7), 6.86–6.97 (m, 5H, Ar), 7.03–7.45 (m, 16H, Ar), 7.69–7.72 (m, 2H,
Ar); 13C NMR (126 MHz, CDCl3)
d 48.7 (CH), 60.7 (C), 109.1 (CH),
v/v) yielded 1,3,3-triphenyl-4,4-di-
(494 mg, 98%) as colorless crystals. Mp 158–159 ꢀC; IR (KBr): 1738,
1498, 1376, 752, 692 cmꢁ1 1H NMR (300 MHz, CDCl3)
6.28 (d,
J¼16.3 Hz, 2H, -H(styryl)), 6.58 (d, J¼16.3 Hz, 2H, -H (styryl)),
7.02–7.28 (m, 19H, Ar), 7.63 (d, J¼7.4 Hz, 4H, Ar), 7.75 (d, J¼7.7 Hz,
2H, Ar); 13C NMR (75 MHz, CDCl3)
72.8 (C), 77.9 (C), 118.4 (2CH),
b
-styrylazetidin-2-one (3a)
123.3 (CH), 125.8 (CH), 126.5 (4CH), 127.1 (CH), 127.55 (CH), 127.60
(CH), 127.9 (CH), 128.17 (2CH), 128.23 (2CH), 128.5 (4CH), 128.8
(2CH), 129.0 (2CH), 129.2 (2CH), 130.4 (CH), 130.5 (2CH), 136.4 (C),
138.3 (C),138.79 (C),138.81 (C),141.2 (C),142.0 (C),170.8 (C). HRMS-
ESI m/z [MþNa]þ calcd for C37H29NNaO: 526.2141, found: 526.2152.
;
d
a
b
d
124.0 (CH), 126.5 (4CH), 127.2 (2CH), 128.0 (3CH), 128.2 (4CH), 128.3
(3CH), 128.5 (4CH), 128.8 (4CH), 133.2 (2CH), 136.2 (2C), 137.6 (2C),
137.7 (C), 167.0 (C). HRMS-ESI m/z [MþNa]þ calcd for C37H29NNaO:
526.2141, found: 526.2145.
4.5. Typical procedure for the [4D2] cycloaddition of
azatriene with dichloroketene (Table 1, entry 13)
Dichloroacetyl chloride (0.56 mL, 6.0 mmol) was added drop-
wise to a solution of Et3N (0.84 mL 6.0 mmol) in THF (40 mL) at 0 ꢀC
followed by a solution of azatriene 2i (552 mg, 2.0 mmol) in THF
(15 mL), and the mixture was stirred for 1 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 and extracted with
EtOAc (30 mLꢂ2). The combined extracts were washed with water
and brine, dried over MgSO4, and concentrated in vacuo.
4.3. Preparation of azatriene 2i and successive [2D2]
cycloaddition with dimethylketene (Table 1, entry 12)
A mixture of 1,5-diphenyl-1,4-pentadiene-3-one (1) (234 mg,
1.0 mmol), Et3N (0.612 mL, 4.4 mmol), and 1,1-dimethylhydrazine

928
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
Purification of the residue by flash chromatography [SiO2: EtOAc/
hexane (1:19, v/v)] yielded 3,3-dichloro-1-(N,N-dimethylamino)-4-
(30 mL) was added dropwise to the mixture. The reaction mixture
was stirred for 5 min at the same temperature, quenched with
saturated aqueous NH4Cl and extracted with EtOAc (150 mLꢂ2).
The combined extracts were washed with water and brine, dried
over MgSO4, and concentrated in vacuo. Purification of the residue
by flash chromatography (SiO2: EtOAc) yielded (2-oxo-4-phenyl-
but-3-enyl)phosphonic acid dimethyl ester (4.9 g, 98%) as a color-
less oil. IR (neat): 1736, 1690, 1658, 1610, 1262, 1048, 1030, 836,
phenyl-6-
b
-styryl-3,4-dihydro-1H-pyridin-2-one (4m) (178 mg,
23%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
d
2.94 (s, 3H,
Me(NMe2)), 2.97 (s, 3H, Me(NMe2)), 4.27 (d, J¼4.3 Hz,1H, H-4), 5.64
(d, J¼4.3 Hz, 1H, H-5), 6.87 (d, J¼16.2 Hz, 1H, H-8), 6.94 (d,
J¼16.2 Hz, 1H, H-7), 7.27–7.47 (m, 10H, Ar); 13C NMR (126 MHz,
CDCl3) d 42.5 (CH3), 43.1 (CH3), 54.4 (CH), 86.7 (C), 104.8 (CH), 121.4
(CH), 126.8 (2CH), 128.3 (3CH), 128.5 (CH), 128.7 (2CH), 130.0 (2CH),
131.2 (CH), 135.8 (C), 136.4 (C), 141.9 (C), 160.9 (C).
800 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 3.31 (s, 1H, H-1), 3.38 (s, 1H,
H-10), 3.79 (d, J¼0.8 Hz, 3H, Me(OMe)), 3.82 (d, J¼0.8 Hz, 3H,
Me(OMe)), 6.88 (d, J¼16.1 Hz, 1H, H-3), 7.39–7.59 (m, 5H, Ar), 7.64
4.6. Typical procedure for the DA reaction of monoadducts 4
with tetracyanoethylene (Table 2, entry 1)
(d, J¼16.1 Hz, 1H, H-4); 13C NMR (75 MHz, CDCl3)
d 39.7 (CH2, d,
J¼129.1 Hz), 52.9 (CH3), 53.1 (CH3), 125.5 (CH), 128.5 (2CH), 128.9
(2CH), 130.9 (CH), 133.9 (C), 144.9 (CH), 190.7 (C, d, J¼6.1 Hz).
A solution of (2-oxo-4-phenylbut-3-enyl)phosphonic acid di-
methyl ester (1.3 g, 5.0 mmol) in DMF (50 mL) was added dropwise
to a suspension of K2CO3 (1.1 g, 8.0 mmol) in DMF (200 mL) at
ꢁ20 ꢀC. After 5 min, a solution of ethyl glyoxylate (1.0 g, 10 mmol)
in DMF (20 mL) was added dropwise at the same temperature, and
the reaction mixture was stirred for an additional 5 min. The re-
action mixture was quenched with saturated aqueous NH4Cl and
extracted with EtOAc (50 mLꢂ2). The combined extracts were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:9, v/v)] followed by recrystallization from CH2Cl2/
hexane (1:8, v/v) yielded 7 (737 mg, 64%) as yellow crystals and its
cis-isomer (70) (334 mg, 29%) as a yellow oil, respectively.
TCNE (29 mg, 0.225 mmol) was added to a solution of 4a (75 mg,
0.15 mol) in CH2Cl2 (10 mL). The reaction mixture was stirred at
room temperature for 10 min and then concentrated in vacuo.
Purification of the residue by flash chromatography [SiO2: EtOAc/
hexane (3:7, v/v)] followed by recrystallization from CH2Cl2/hexane
(1:3, v/v) yielded 2-oxo-1,3,3,4,7-pentaphenyl-1,2,3,4,4a,7-hexa-
hydroquinoline-5,5,6,6-tetracarbonitrile (5a) (94 mg, 99%) as col-
orless crystals. Mp 195–197 ꢀC; IR (KBr): 1696, 1650, 1496, 1280,
700 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.10 (ddd, J¼1.9, 2.1, 10.9 Hz,
1H, H-4a), 4.29 (dd, J¼1.9, 4.8 Hz, 1H, H-7), 4.92 (d, J¼10.9 Hz, 1H,
H-4), 5.10 (dd, J¼2.1, 4.8 Hz, 1H, H-8), 6.67–7.74 (m, 25H, Ar); 13C
NMR (100 MHz, CDCl3) d 42.9 (C), 43.8 (CH), 46.8 (CH), 48.7 (CH, C),
62.8 (C), 108.3 (CH), 109.1 (C), 109.8 (C), 110.0 (C), 111.5 (C), 127.5
(2CH), 127.8 (3CH), 128.0 (2CH), 128.2 (3CH), 128.8 (3CH), 128.9
(CH), 129.5 (CH), 129.8 (2CH), 130.2 (CH), 130.3 (3CH), 130.5 (2CH),
131.2 (2CH), 132.2 (C), 133.6 (C), 137.7 (C), 138.0 (C), 139.0 (C), 139.3
(C), 170.6 (C). LRMS-FAB m/z (ion, % relative intensity): 632 (MþþH,
6), 246 (17), 185 (60), 93 (100). HRMS-FAB m/z [MþH]þ calcd for
C43H30N5O: 632.2450, found: 632.2443.
4.8.1. (2E,5E)-4-Oxo-6-phenylhexa-2,5-dienoic acid ethyꢁl 1ester (7)
;
1H NMR
Yellow crystals; mp 39 ꢀC; IR (KBr): 1720, 1684 cm
(300 MHz, CDCl3)
d
1.34 (t, J¼7.1 Hz, 3H, Me(COOEt)), 4.29 (q,
J¼7.1 Hz, 2H, CH2(COOEt)), 6.83 (d, J¼15.7 Hz, 1H, H-3), 6.98 (d,
J¼16.1 Hz, 1H, H-5), 7.39–7.45 (m, 3H, Ar), 7.49 (d, J¼15.7 Hz, 1H, H-
2), 7.57–7.62 (m, 2H, Ar), 7.72 (d, J¼16.1 Hz, 1H, H-6); 13C NMR
4.7. Typical procedure for DA reaction of monoadducts 4 with
(68 MHz, CDCl3) d 14.1 (CH3), 61.3 (CH2), 124.9 (CH), 128.5 (2CH),
N-phenylmaleimide (Table 3, entry 1)
129.0 (2CH), 131.1 (CH), 131.2 (CH), 134.1 (C), 138.4 (CH), 145.4 (CH),
165.6 (C), 188.3 (C). HRMS-ESI m/z [MþNa]þ calcd for C14H14NaO3:
253.0835, found: 253.0839.
A mixture of 4a (101 mg, 0.2 mmol) and N-phenylmaleimide
(52 mg, 0.3 mmol) in toluene (20 mL) was heated at 110 ꢀC for 7 h,
and then concentrated in vacuo. Purification of the residue by flash
chromatography [SiO2: EtOAc/hexane (3:7, v/v)] followed by re-
crystallization CH2Cl2/hexane (1:3, v/v) yielded 2,4,6,8,8,9-hexa-
phenyl-4,6,8,9,9a,9b-hexahydro-3aH-pyrrolo[3,4-f]quinoline-1,3,
7-trione (6a) (134 mg, 99%) as colorless crystals. Mp 198–200 ꢀC; IR
(KBr): 1710, 1628, 1496, 1382, 696 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.8.2. (2Z,5E)-4-Oxo-6-phenyl-hexa-2,5-dienoic acid ethyl
ester (70)
Yellow oil; IR (neat): 1714, 1654, 1626 cmꢁ1; 1H NMR (300 MHz,
CDCl3)
d
1.23 (t, J¼7.1 Hz, 3H, Me(COOEt)), 4.17 (q, J¼7.1 Hz, 2H,
CH2(COOEt)), 6.22 (d, J¼12.1 Hz, 1H, H-3), 6.70 (d, J¼12.1 Hz, 1H, H-
2), 6.84 (d, J¼16.4 Hz, 1H, H-5), 7.27–7.56 (m, 6H, H-6, Ar); 13C NMR
d
3.02 (br d, J¼12.4 Hz, 1H, H-9a), 3.11 (dd, J¼4.1, 8.2 Hz, 1H, H-9b),
(68 MHz, CDCl3) d 13.9 (CH3), 61.1 (CH2), 126.2 (CH), 126.3 (CH),
3.23 (dd, J¼8.1, 8.2 Hz, 1H, H-3a), 3.65 (dd, J¼3.4, 8.1 Hz, 1H, H-4),
5.03 (dd, J¼2.9, 3.4 Hz,1H, H-5), 5.93 (d, J¼12.4 Hz,1H, H-9), 6.99 (d,
J¼7.1 Hz, 2H, Ar), 7.10–7.48 (m, 28H, Ar); 13C NMR (100 MHz, CDCl3)
128.4 (2CH), 128.9 (2CH), 130.8 (CH), 134.2 (C), 140.3 (CH), 145.4
(CH), 165.0 (C), 193.6 (C). HRMS-ESI m/z [MþNa]þ calcd for
C14H14NaO3: 253.0835, found: 253.0838.
d
38.1 (CH), 42.3 (CH), 42.5 (CH), 44.5 (CH), 47.4 (CH), 63.4 (C), 106.9
(CH), 126.4 (3CH), 126.9 (CH), 127.25 (CH), 127.31 (2CH), 127.6 (CH),
127.66 (3CH),127.69 (2CH),127.9 (CH),128.4 (4CH),128.5 (CH),128.8
(CH), 129.3 (3CH), 129.7 (2CH), 130.4 (2CH), 130.9 (2CH), 131.6 (CH),
131.7 (C),136.17 (C),136.23 (C),138.49 (C),138.52 (C),141.1 (C),142.8
(C), 172.3 (C), 174.1 (C), 176.3 (C). LRMS-EI m/z (ion, % relative in-
tensity): 676 (Mþ, 71), 503 (MþꢁN-PhMI, 14), 481 (26), 309 (Mþ
ꢁN-PhMI, Ph2CCO, 100). HRMS-EI m/z [M]þ calcd for C47H36N2O3:
676.2726, found: 676.2729.
4.9. Typical procedure for preparation of azatriene 8 and its
sequential [2D2] cycloaddition with diphenylketene
(Table 4, entry 1)
A mixture of 7 (230 mg, 1.0 mmol), Et3N (0.612 mL, 4.4 mmol),
and aniline (0.182 mL, 2.0 mmol) in CH2Cl2 (25 mL) was cooled to
0 ꢀC, and titanium tetrachloride (1.0 mL, 1.0 M solution in CH2Cl2,
1.0 mmol) was added dropwise. The reaction mixture was stirred at
room temperature for 2 h, then a solution of diphenylketene
(388 mg, 2.0 mmol) in CH2Cl2 (5 mL) was added dropwise. After
5 min, the reaction mixture was quenched with water (5 mL) and
extracted with CH2Cl2 (10 mLꢂ2). The combined extracts were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:4, v/v)] followed by recrystallization from CH2Cl2/
4.8. Preparation of 4-oxo-6-phenylhexa-2,5-dienoic acid ethyl
ester (7)
n-BuLi (38 mL, 1.6 M solution in hexane, 60 mmol) was added
dropwise to a solution of dimethyl methylphosphonate (6.5 mL,
60 mmol) in THF (200 mL) at ꢁ65 ꢀC, and the mixture was stirred
for 30 min. A solution of methyl cinnamate (3.2 g, 20 mmol) in THF
hexane (1:4, v/v) yielded 3-(4-oxo-1,3,3-triphenyl-2-b-styrylazetidin-2-

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
929
yl)-acrylic acid ethyl ester (9a) (330 mg, 66%) as colorless crystals.
(100 mL) at ꢁ65 ꢀC, and the mixture was warmed to 0 ꢀC and
stirred for 1 h. The solution was cooled to ꢁ65 ꢀC, before mesityl
oxide (2.0 mL, 18 mmol) was added dropwise, and the reaction
mixture was stirred for an additional 1 h. A solution of ethyl
glyoxylate (3.6 g, 36 mmol) in THF (10 mL) was added dropwise to
the mixture at ꢁ65 ꢀC, and the resulting mixture was stirred for an
additional 1 h at the same temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl and extracted with EtOAc
(100 mLꢂ2). The combined extracts were washed with water and
brine, dried over MgSO4, and concentrated in vacuo. Purification of
the residue by flash chromatography [SiO2: EtOAc/hexane (1:4,
v/v)] yielded 2-hydroxy-6-methyl-4-oxo-hept-5-enoic acid ethyl
Mp 169–171 ꢀC; IR (KBr): 1750, 1708, 1500, 1376, 1308, 1188, 754,
708 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.17 (t, J¼7.0 Hz, 3H,
Me(COOEt)), 4.07 (dq, J¼1.8, 7.0 Hz, 2H, CH2(COOEt)), 5.81 (d,
J¼15.9 Hz, 1H, H-2), 6.08 (d, J¼16.5 Hz, 1H, H-6), 6.63 (d, J¼16.5 Hz,
1H, H-5), 7.06–7.10 (m, 3H, Ar), 7.18–7.31 (m, 11H, Ar), 7.29 (d,
J¼15.9 Hz,1H, H-3), 7.50–7.52 (m, 2H, Ar), 7.63–7.66 (m, 4H, Ar); 13C
NMR (126 MHz, CDCl3)
d 14.1 (CH3), 60.6 (CH2), 72.1 (C), 78.5 (C),
118.2 (2CH), 123.9 (CH), 124.3 (CH), 126.6 (2CH), 127.5 (2CH), 127.8
(CH), 128.3 (2CH), 128.4 (3CH), 128.5 (2CH), 128.6 (2CH), 128.8
(2CH), 129.0 (2CH), 134.0 (CH), 135.8 (C), 136.7 (C), 137.0 (C), 137.1
(C), 144.2 (CH), 165.1 (C), 166.4 (C). HRMS-ESI m/z [MþNa]þ calcd
for C34H29NNaO3: 522.2040, found: 522.2040.
ester (2.0 g, 54%) as a colorless oil. IR (neat): 3448, 1736 cmꢁ1
;
1H
1.29 (t, J¼7.0 Hz, 3H, Me(COOEt)), 1.91 (d,
NMR (500 MHz, CDCl3)
d
4.10. Typical procedure for [1,3]-sigmatropic rearrangement
of [2D2] cycloadduct 9 (Table 4, entry 1)
J¼1.2 Hz, 3H, Me), 2.16 (d, J¼1.2 Hz, 3H, Me), 2.90 (dd, J¼6.1, 17.1 Hz,
1H, H-3), 2.96 (dd, J¼4.0, 17.1 Hz, 1H, H-3), 3.39 (d, J¼5.8 Hz, 1H,
OH), 4.25 (dq, J¼1.8, 7.3 Hz, 2H, CH2(COOEt)), 4.49 (ddd, J¼4.0, 5.8,
6.1 Hz, 1H, H-2), 6.07 (dd, J¼1.2, 1.2 Hz, 1H, H-5); 13C NMR
A solution of 9a (250 mg, 0.5 mmol) in toluene (20 mL) was
heated at 110 ꢀC for 2 h and then concentrated in vacuo. Purification
of the residue by flash chromatography [SiO2: EtOAc/hexane (1:4,
v/v)] yielded a mixture of 10a and 11a (247 mg, 99%, 81:19) as a pale
yellow solid.
(126 MHz, CDCl3)
d 13.2 (CH3), 19.9 (CH3), 26.7 (CH3), 46.6 (CH2),
60.5 (CH2), 66.5 (CH), 122.8 (CH), 155.8 (C), 173.1 (C), 196.6 (C).
HRMS-ESI m/z [MþNa]þ calcd for C10H16NaO4: 223.0941, found:
223.0935.
Methanesulfonyl chloride (0.88 mL, 11.4 mmol) was added to
a solution of 2-hydroxy-6-methyl-4-oxo-hept-5-enoic acid ethyl
ester (1.9 g, 9.5 mmol) and Et3N (3.2 mL, 22.8 mmol) in CH2Cl2
(50 mL) at 0 ꢀC. The reaction mixture was stirred at room temper-
ature overnight, diluted with saturated aqueous NaHCO3, and
extracted with CH2Cl2 (30 mLꢂ2). The combined extracts were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:4, v/v)] yielded 13 (1.6 g, 94%) as a yellow oil. IR
4.11. Preparation of (E)-5-methyl-1-phenylhexa-1,4-dien-3-
one (12)
n-BuLi (11.3 mL, 1.6 M in hexane, 18 mmol) was added dropwise
to a solution of diisopropylamine (2.5 mL, 18 mmol) in THF
(100 mL) at ꢁ65 ꢀC, and the mixture was warmed to 0 ꢀC and
stirred for 1 h. The solution was recooled to ꢁ65 ꢀC, and mesityl
oxide (2.0 mL, 18 mmol) was added dropwise. After being stirred
for 1 h, benzaldehyde (1.53 mL, 15 mmol) was added dropwise to
the mixture. The reaction mixture was stirred for an additional
10 min at the same temperature, quenched with saturated aqueous
NH4Cl, and extracted with EtOAc (100 mLꢂ2). The combined ex-
tracts were washed with water and brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by flash chro-
matography [SiO2: EtOAc/hexane (1:4, v/v)] yielded 1-hydroxy-5-
methyl-1-phenylhex-4-en-3-one (2.72 g, 89%) as a yellow oil. 1H
(neat): 1720, 1612 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.25 (t, J¼
7.1 Hz, 3H, Me(COOEt)), 1.90 (d, J¼1.1 Hz, 3H, Me), 2.14 (d, J¼1.0 Hz,
3H, Me), 4.18 (q, J¼7.1 Hz, 2H, CH2(COOEt)), 6.24 (dd, J¼1.0, 1.1 Hz,
1H, H-5), 6.60 (d, J¼15.9 Hz, 1H, H-3), 7.05 (d, J¼15.9 Hz, 1H, H-2);
13C NMR (75 MHz, CDCl3)
d 14.0 (CH3), 21.3 (CH3), 28.0 (CH3), 61.1
(CH2), 122.6 (CH), 130.0 (CH), 141.7 (CH), 160.0 (C), 165.8 (C), 188.5
(C). HRMS-ESI m/z [MþNa]þ calcd for C10H14NaO3: 205.0835,
found: 205.0829.
NMR (300 MHz, CDCl3)
d
1.91 (d, J¼1.2 Hz, 3H, Me), 2.19 (d, J¼1.1 Hz,
3H, Me), 2.82 (d, J¼5.7 Hz, 2H, H-2, H-2), 3.72 (d, J¼2.7 Hz, 1H, OH),
4.13. Typical procedure for preparation of azatriene 14 and its
sequential [2D2] cycloaddition with diphenylketene (Table 5,
entry 1)
5.13–5.20 (m, 1H, H-1), 6.03–6.05 (m, 1H, H-4), 7.28–7.41 (m, 5H,
Ar); 13C NMR (100 MHz, CDCl3)
d 21.0 (CH3), 27.8 (CH3), 52.1 (CH2),
70.1 (CH), 123.6 (CH), 125.6 (2CH), 127.4 (CH), 128.4 (2CH), 143.0 (C),
157.6 (C), 200.6 (C).
A mixture of 12 (559 mg, 3.0 mmol), Et3N (1.8 mL,13 mmol), and
aniline (0.55 mL, 6.0 mmol) in CH2Cl2 (50 mL) was cooled to 0 ꢀC,
and titanium tetrachloride (3.0 mL, 1.0 M solution in CH2Cl2,
3.0 mmol) was added dropwise. The reaction mixture was stirred at
room temperature for 1 h, then cooled to 0 ꢀC. A solution of
diphenylketene (1.2 g, 6.0 mmol) in CH2Cl2 (10 mL) was added
dropwise. After 5 min, the reaction mixture was quenched with
water and extracted with CH2Cl2 (30 mLꢂ2). The combined extracts
were washed with water and brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by flash chro-
matography [SiO2: EtOAc/hexane (1:9, v/v)] yielded 4-(2-methyl-
Methanesulfonyl chloride (0.84 mL, 10.9 mmol) was added to
a
solution of 1-hydroxy-5-methyl-1-phenyl-hex-4-en-3-one
(1.85 g, 9.08 mmol) and Et3N (3.1 mL, 21.8 mmol) in CH2Cl2 (50 mL)
at 0 ꢀC. The reaction mixture was warmed to room temperature
with stirring overnight, diluted with saturated aqueous NaHCO3,
and extracted with CH2Cl2 (30 mLꢂ2). The combined extracts were
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:4, v/v)] afforded 12 (1.44 g, 85%) as a yellow oil. IR
(neat): 1658, 1628, 1600, 1450, 1114 cmꢁ1
CDCl3)
1.97 (d, J¼1.2 Hz, 3H, Me), 2.22 (d, J¼1.1 Hz, 3H, Me), 6.34–
6.36 (m, 1H, H-4), 6.78 (d, J¼16.1 Hz, 1H, H-2), 7.34–7.41 (m, 3H, Ar),
7.50–7.60 (m, 3H, Ar, H-1); 13C NMR (100 MHz, CDCl3)
21.1 (CH3),
;
1H NMR (400 MHz,
d
propenyl)-1,3,3-triphenyl-4-
43%) as a yellow oil. IR (neat): 1748, 1664, 1600, 1380 cmꢁ1; 1H NMR
(400 MHz, CDCl3) 1.19 (s, 3H, Me), 1.58 (s, 3H, Me), 5.59 (d,
b-styrylazetidin-2-one (16a) (589 mg,
d
d
27.9 (CH3), 123.6 (CH), 128.2 (2CH), 128.3 (CH), 128.9 (2CH), 130.1
(CH), 135.0 (C), 142.0 (CH), 156.4 (C), 190.2 (C).
J¼1.2 Hz, 1H, H-3), 6.03 (d, J¼16.1 Hz, 1H, H-6), 6.56 (d, J¼16.1 Hz,
1H, H-5), 7.04–7.08 (m, 3H, Ar), 7.17–7.37 (m, 11H, Ar), 7.47 (dd,
J¼1.2, 7.1 Hz, 2H, Ar), 7.66–7.71 (m, 4H, Ar); 13C NMR (100 MHz,
4.12. Preparation of (E)-6-methyl-4-oxo-hepta-2,5-dienoic
CDCl3) d 19.7 (CH3), 27.3 (CH3), 72.7 (C), 78.1 (C), 118.2 (3CH), 120.4
acid ethyl ester (13)
(CH), 124.0 (CH), 126.6 (3CH), 126.8 (CH), 127.1 (CH), 127.3 (CH),
127.8 (CH), 128.2 (2CH), 128.5 (2CH), 128.9 (CH), 129.1 (2CH), 129.3
(2CH), 131.0 (CH), 132.2 (CH), 136.5 (C), 137.4 (C), 137.5 (C), 138.6 (C),
139.6 (C), 167.5 (C). LRMS-FAB m/z (ion, % relative intensity): 456
n-BuLi (11.3 mL, 1.6 M in hexane, 18 mmol) was added dropwise
to a solution of diisopropylamine (2.5 mL, 18 mmol) in THF

930
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
(MþþH, 68), 455 (Mþ, 22), 261 (100), 170 (44), 167 (33), 77 (Ph, 35).
HRMS-EI m/z [M]þ calcd for C33H29NO: 455.2249, found: 455.2250.
Ar), 7.60–7.63 (m, 2H, Ar); 13C NMR (126 MHz, CDCl3)
d 14.1 (CH3),
48.7 (CH), 60.47 (CH2), 60.53 (C), 115.7 (CH), 120.1 (CH), 125.9 (CH),
126.5 (2CH), 127.4 (CH), 127.7 (CH), 127.9 (CH), 128.30 (2CH), 128.32
(4CH), 128.5 (2CH), 129.1 (2CH), 129.2 (2CH), 130.4 (2CH), 136.9 (C),
137.2 (C), 138.2 (C), 138.6 (CH), 140.7 (C), 141.4 (C), 166.0 (C), 170.6
(C). HRMS-ESI m/z [MþNa]þ calcd for C34H29NNaO3: 522.2040,
found: 522.2045.
4.14. Typical procedure for [1,3]-sigmatropic rearrangement
of [2D2] cycloadduct 16 (Table 5, entry 1)
A solution of 16a (300 mg, 0.66 mmol) in xylene (30 mL) was
heated 140 ꢀC for 5 h, and then concentrated in vacuo. Purification
of the residue by flash chromatography [SiO2: EtOAc/hexane (1:4,
v/v)] followed by recrystallization from CH2Cl2/hexane (1:4, v/v)
4.16. Typical procedure for the second cycloaddition of
monoadducts 10 with methyl vinyl ketone (Table 7, entry 1)
yielded
6-(2-methyl-propenyl)-1,3,3,4-tetraphenyl-3,4-dihydro-
1H-pyridin-2-one (18a) (231 mg, 77%) as colorless crystals. Mp
Methyl vinyl ketone (0.06 mL, 0.7 mmol) was added to a xylene
(10 mL) solution of 10a (72 mg, 0.15 mmol) and heated at 140 ꢀC for
14 h. After being cooled to room temperature, the reaction mixture
was concentrated in vacuo. Purification of the residue by flash
chromatography [SiO2: EtOAc/hexane (1:4, v/v)] yielded a mixture
of 21a and 22a (61 mg, 74%, 17:83) as a colorless solid. Analytically
pure 22a was obtained by preparative HPLC [EtOAc/hexane (1:4,
v/v)].
192–193 ꢀC; IR (KBr): 3032, 2360, 1634, 1496, 1327, 1265, 756,
694 cmꢁ1
;
1H NMR (600 MHz, CDCl3)
d
1.45 (d, J¼1.1 Hz, 3H, Me),
1.55 (d, J¼1.1 Hz, 3H, Me), 4.22 (d, J¼6.8 Hz, 1H, H-4), 4.94–4.96 (m,
1H, H-7), 5.57 (dd, J¼1.1, 6.8 Hz, 1H, H-5), 5.58–6.61 (m, 2H, Ar),
6.85–6.90 (m, 2H, Ar), 6.93–6.97 (m, 3H, Ar), 7.05–7.15 (m, 5H,
Ar), 7.24–7.29 (m, 1H, Ar), 7.33–7.38 (m, 3H, Ar), 7.40–7.43 (m, 2H,
Ar), 7.67–7.77 (m, 2H, Ar); 13C NMR (150 MHz, CDCl3)
d 19.5 (CH3),
25.6 (CH3), 48.9 (CH), 60.7 (C), 111.0 (CH), 120.1 (CH), 125.6 (CH),
126.4 (2CH), 127.0 (CH), 127.3 (CH), 127.4 (CH), 128.08 (2CH), 128.09
(2CH), 128.3 (2CH), 128.6 (2CH), 128.9 (2CH), 129.2 (2CH), 130.5
(2CH), 137.0 (C), 138.0 (C), 138.6 (C), 139.1 (C), 141.3 (C), 142.0 (C),
170.9 (C). LRMS-EI m/z (ion, % relative intensity): 455 (Mþ, 42), 261
(100), 170 (54), 165 (22), 77 (Ph, 11). HRMS-ESI m/z [MþNa]þ calcd
for C33H29NNaO: 478.2141, found: 478.2141. Anal. Calcd for
C33H29NO: C, 87.00; H, 6.42; N, 3.07. Found: C, 87.12; H, 6.66; N,
3.05.
6-Acetyl-2-oxo-1,3,3,4-tetraphenyl-1,2,3,4,5,6,7,8-octahydro-
quinoline-7-carboxylic acid ethyl ester (22a): colorless crystaꢁls1; mp
;
1H
202–204 ꢀC; IR (KBr): 1732, 1716, 1680, 1496, 1346, 700 cm
NMR (600 MHz, C6D6)
d
0.70 (t, J¼7.2 Hz, 3H, Me(COOEt)), 1.73–1.78
(m, 2H, H-6, H-8), 1.80 (s, 3H, Me(COMe)), 2.02 (d, J¼17.4 Hz, 1H, H-
8), 2.24 (dd, J¼6.1, 17.4 Hz, 1H, H-5), 2.82 (ddd, J¼2.6, 2.6, 6.2 Hz,
1H, H-7), 2.86–2.92 (m, 1H, H-5), 3.66 (dq, J¼7.2, 10.5 Hz, 1H,
CH2(COOEt)), 3.74 (dq, J¼7.2, 10.5 Hz, 1H, CH2(COOEt)), 3.75 (s, 1H,
H-4), 6.84–6.88 (m, 3H, Ar), 6.94–7.09 (m, 11H, Ar), 7.21–7.24 (m,
3H, Ar), 7.29–7.34 (m, 1H, Ar), 7.62 (d, J¼7.7 Hz, 2H, Ar); 13C NMR
4.15. Typical procedure for the second cycloaddition of
monoadduct 11 with tetracyanoethylene (Table 6, entry 1)
(150 MHz, CDCl3)
d 13.8 (CH3), 26.6 (CH2), 27.4 (CH3), 29.3 (CH2),
39.5 (CH), 47.2 (CH), 53.8 (CH), 60.66 (C), 60.70 (CH2), 115.2 (C),
125.7 (CH), 126.4 (2CH), 127.2 (CH), 127.3 (CH), 127.8 (CH), 128.0
(CH), 128.1 (2CH), 128.2 (4CH), 129.1 (3CH), 129.3 (CH), 129.6 (CH),
130.0 (C), 130.3 (2CH), 138.0 (C), 138.3 (C), 141.2 (C), 141.9 (C), 170.5
(C), 171.4 (C), 207.6 (C). HRMS-ESI m/z: [MþNa]þ calcd for
C38H35NNaO4: 592.2458, found: 592.2457.
TCNE (10 mg, 0.08 mmol) was added to a solution of a mixture
of 10a and 11a (175 mg, 0.35 mol, 81:19) in CH2Cl2 (10 mL). The
reaction mixture was stirred at room temperature for 10 min and
then concentrated in vacuo. Purification of the residue by flash
chromatography [SiO2: EtOAc/hexane (3:7, v/v)] followed by
recrystallization from CH2Cl2/hexane (1:3, v/v) yielded 5,5,6,6-tetra-
cyano-2-oxo-1,3,3,7-tetraphenyl-1,2,3,4,4a,5,6,7-octahydroquinoline-
4-carboxylic acid ethyl ester (20a) (40 mg, 95% yield based on 11a)
as colorless crystals along with 3-(6-oxo-1,4,5,5-tetraphenyl-
1,4,5,6-tetrahydropyridin-2-yl)-acrylic acid ethyl ester (10a)
(136 mg, 96% recovery) as colorless crystals.
Compound 21a: 1H NMR (500 MHz, CDCl3)
Me(COOEt)).
d
1.18 (t, J¼7.1 Hz, 3H,
4.17. Typical procedure for the second cycloaddition of
monoadduct 18 with tetracyanoethylene (Table 8, entry 1)
Compound 20a: colorless crystals; mp 115–117 ꢀC; IR (KBr):
TCNE (17 mg, 0.13 mmol) was added to a solution of 18a (50 mg,
0.11 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was
heated at 83 ꢀC for 6.5 h, and then concentrated in vacuo. Purifi-
cation of the residue by flash chromatography [SiO2: EtOAc/hexane
(3:7, v/v)] followed by recrystallization from CH2Cl2/hexane (1:4,
v/v) yielded 7,7-dimethyl-2-oxo-1,3,3,4-tetraphenyl-1,2,3,4,4a,7-
hexahydroquinoline-5,5,6,6-tetracarbonitrile (23a) (64 mg, 99%) as
colorless crystals. Mp 200–201 ꢀC; IR (KBr): 3024, 1689, 1651, 1311,
1732, 1706, 1670, 1496, 1322, 1280, 1250, 1196, 702 cmꢁ1 1H NMR
;
(500 MHz, CDCl3)
d
0.89 (t, J¼7.0 Hz, 3H, Me(COOEt)), 3.62 (dq,
J¼7.0, 10.7 Hz, 1H, CH2(COOEt)), 3.94 (dq, J¼7.0, 10.7 Hz, 1H,
CH2(COOEt)), 4.17 (dd, J¼1.8, 3.4 Hz, 1H, H-7), 4.49 (ddd, J¼1.8, 1.8,
11.0 Hz, 1H, H-4a), 4.54 (d, J¼11.0 Hz, 1H, H-4), 4.94 (dd, J¼1.8,
3.4 Hz, 1H, H-8), 7.07–7.08 (d, J¼7.3 Hz, 2H, Ar), 7.19–7.21 (d,
J¼7.3 Hz, 2H, Ar), 7.26–7.48 (m, 14H, Ar), 7.53–7.54 (d, J¼7.3 Hz, 2H,
Ar); 13C NMR (126 MHz, CDCl3)
d
13.2 (CH3), 42.9 (CH), 43.5 (C), 46.4
748, 702 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 1.41 (s, 3H, Me), 1.59 (s,
(C), 46.9 (CH), 50.8 (CH), 61.1 (C), 62.8 (CH2), 109.4 (C), 109.8 (C),
109.9 (CH), 110.4 (C), 110.9 (C), 127.4 (2CH), 128.1 (2CH), 128.2 (CH),
128.3 (CH), 128.5 (2CH), 128.9 (CH), 129.3 (2CH), 129.4 (2CH), 129.5
(2CH), 130.20 (2CH), 130.26 (2CH), 130.30 (CH), 132.7 (C), 137.4 (C),
137.5 (C), 138.6 (C), 138.7 (C), 169.3 (C), 169.9 (C). LRMS-FAB m/z
(ion, % relative intensity): 628 (MþþH, 100), 500 (MþþHꢁTCNE,
37), 499 (MþꢁTCNE, 29), 165 (32). HRMS-FAB m/z [MþH]þ calcd for
C40H30N5O3: 628.2348, found: 628.2359.
3H, Me), 4.15 (dd, J¼1.8, 10.8 Hz, 1H, H-4a), 4.63 (d, J¼1.8 Hz, 1H, H-
8), 4.81 (d, J¼10.8 Hz, 1H, H-4), 6.44 (d, J¼6.4 Hz, 1H, Ar), 6.99 (d,
J¼7.7 Hz, 2H, Ar), 7.04–7.12 (m, 1H, Ar), 7.16–7.23 (m, 5H, Ar), 7.23–
7.32 (m, 4H, Ar), 7.35 (dd, J¼7.2, 7.9 Hz, 2H, Ar), 7.40 (dd, J¼7.4,
7.5 Hz, 1H, Ar), 7.49 (dd, J¼7.6, 7.9 Hz, 2H, Ar), 7.69 (d, J¼7.6 Hz, 2H,
Ar); 13C NMR (126 MHz, CDCl3)
d 26.0 (CH3), 30.1 (CH3), 39.7 (C),
43.1 (CH), 43.2 (C), 49.1 (CH), 51.4 (C), 62.4 (C), 109.7 (C), 110.2 (C),
110.46 (C), 110.53 (C), 115.1 (CH), 127.5 (3CH), 127.85 (3CH), 127.90
(CH), 127.93 (3CH), 128.0 (CH), 128.7 (CH), 129.6 (CH), 129.7 (2CH),
130.2 (3CH), 131.4 (2CH), 132.9 (C), 134.1 (C), 139.0 (C), 139.4 (C),
139.7 (C), 170.5 (C). LRMS-EI m/z (ion, % relative intensity): 583 (Mþ,
28), 455 (MþꢁTCNE, 5), 284 (41), 261 (25), 194 (Ph2CCO, 100), 166
(30), 165 (29), 77 (Ph, 10). HRMS-ESI m/z [MþNa]þ calcd for
C39H29N5NaO: 606.2264, found: 606.2236.
Compound 10a: colorless crystals; mp 171–173 ꢀC; IR (KBr):
1714, 1680, 1496, 1182, 698 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.16
(t, J¼7.1 Hz, 3H, Me(COOEt)), 4.05 (q, J¼7.1 Hz, 2H, CH2(COOEt)),
4.28 (d, J¼7.1 Hz, 1H, H-4), 5.73 (d, J¼15.9 Hz, 1H, H-2), 6.26 (d,
J¼7.1 Hz, 1H, H-3), 6.57–6.61 (m, 3H, Ar), 6.66–6.99 (m, 5H, Ar),
7.08–7.29 (m, 4H, Ar), 7.13 (d, J¼15.9 Hz, 1H, H-3), 7.32–7.43 (m, 6H,

S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
931
4.18. Typical procedure for the second cycloaddition of
Methanesulfonyl chloride (0.34 mL, 4.4 mmol) was added to
monoadduct 19 with N-phenylmaleimide (Table 9, entry 2)
a
solution of 1-[2-(tert-butyldimethylsilanyloxy)phenyl]-1-
hydroxy-5-methylhex-4-en-3-one (1.2 g, 3.7 mmol) and Et3N
(1.2 mL, 8.9 mmol) in CH2Cl2 (40 mL) at 0 ꢀC. The reaction mix-
ture was warmed to room temperature with stirring overnight,
diluted with saturated aqueous NaHCO3, and extracted with
CH2Cl2 (20 mLꢂ2). The combined extracts were washed with
water and brine, dried over MgSO4, and concentrated in vacuo.
Purification of the residue by flash chromatography [SiO2: EtOAc/
hexane (1:9, v/v)] yielded (E)-1-[2-(tert-butyldimethylsilyloxy)-
phenyl]-5-methylhexa-1,4-dien-3-one (860 mg, 74%) as a yellow
oil. IR (neat): 2939, 2862, 1658, 1620, 1481, 1304, 1257, 1111, 1049,
A mixture of 19a (80 mg, 0.19 mmol) and N-phenylmaleimide
(66 mg, 0.38 mmol) in toluene (30 mL) was heated at 110 ꢀC for
65 h, and then concentrated in vacuo. Purification of the residue
by flash chromatography [SiO2: EtOAc/hexane (3:7, v/v)] followed
by recrystallization from CH2Cl2/hexane (1:3, v/v) yielded 4,4-di-
methyl-1,3,7-trioxo-2,6,8,8-tetraphenyl-2,3,3a,4,6,7,8,9,9a,9b-deca-
hydro-1H-pyrrolo[3,4-f]quinoline-9-carboxylic acid ethyl ester
(26a) (116 mg, 98%) as a colorless solid. Mp 60–62 ꢀC; IR (KBr):
1724, 1708, 1394, 1196, 698 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 0.80
(t, J¼7.3 Hz, 3H, Me(COOEt)), 0.96 (s, 3H, Me), 1.07 (s, 3H, Me), 2.94
(d, J¼7.9 Hz, 1H, H-3a), 3.52 (ddd, J¼2.1, 4.0, 12.2 Hz, 1H, H-9a), 3.63
(dd, J¼4.0, 7.9 Hz, 1H, H-9b), 3.88 (dq, J¼7.3, 10.7 Hz, 1H,
CH2(COOEt)), 3.96 (dq, J¼7.3, 10.7 Hz, 1H, CH2(COOEt)), 4.33 (d,
J¼2.1 Hz, 1H, H-5), 5.23 (d, J¼12.2 Hz, 1H, H-9), 7.10–7.21 (m, 9H,
Ar), 7.33–7.50 (m, 9H, Ar), 7.55 (d, J¼7.6 Hz, 2H, Ar); 13C NMR
987, 918, 841, 779, 447 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 0.24 (s,
6H, 2Me(OTBS)), 1.06 (s, 9H, 3Me(OTBS, tBu)), 1.95 (d, J¼1.1 Hz,
3H, Me), 2.18 (d, J¼1.1 Hz, 3H, Me), 6.40–6.42 (m, 1H, H-4), 6.71
(d, J¼16.4 Hz, 1H, H-2), 6.84 (dd, J¼1.0, 8.1 Hz, 1H, Ar), 6.99 (dd,
J¼7.5, 7.5 Hz, 1H, Ar), 7.22–7.26 (m, 1H, Ar), 7.58 (dd, J¼1.6, 7.8 Hz,
1H, Ar), 7.96 (d, J¼16.4 Hz, 1H, H-1); 13C NMR (126 MHz, CDCl3)
(126 MHz, CDCl3)
d
13.3 (CH3), 29.8 (CH3), 29.9 (CH3), 33.8 (CH), 34.4
d
ꢁ4.3 (2CH3), 18.3 (C), 20.9 (CH3), 25.8 (3CH3), 27.7 (CH3), 119.9
(C), 45.0 (CH), 46.9 (CH), 51.6 (CH), 61.1 (CH2), 61.3 (C), 115.8 (CH),
126.5 (2CH), 126.9 (CH), 127.0 (2CH), 128.0 (CH), 128.2 (CH), 128.4
(CH), 128.5 (3CH), 128.8 (CH), 129.2 (3CH), 129.3 (2CH), 129.6 (CH),
130.2 (2CH), 131.6 (C), 136.2 (C), 138.7 (C), 139.7 (C), 140.6 (C), 170.8
(C), 171.9 (C), 175.7 (C), 177.0 (C). HRMS-ESI m/z [MþNa]þ calcd for
C40H36N2NaO5: 647.2516, found: 647.2506.
(CH), 121.6 (CH), 122.8 (CH), 126.4 (C), 127.3 (CH), 128.6 (CH),
131.2 (CH), 137.5 (CH), 154.7 (C), 154.7 (C), 191.2 (C). HRMS-
ESI m/z [MþNa]þ calcd for C19H28NaO2Si: 339.1751, found:
339.1759.
TBAF (2.7 mL, 1.0 M solution in THF, 2.7 mmol) was added to
a
solution of (E)-1-[2-(tert-butyldimethylsilanyloxy)phenyl]-5-
methylhexa-1,4-dien-3-one (850 mg, 2.7 mmol) in THF (60 mL) at
0 ꢀC. The reaction mixture was stirred for 25 min, diluted with
saturated aqueous NH4Cl, and extracted with EtOAc (20 mLꢂ2). The
combined extracts were washed with water and brine, dried over
MgSO4, and concentrated in vacuo. Purification of the residue by
flash chromatography [SiO2: EtOAc/hexane (1:4, v/v)] followed by
recrystallization from CH2Cl2/hexane (1:9, v/v) yielded (E)-1-(2-
hydroxyphenyl)-5-methylhexa-1,4-dien-3-one (27) (495 mg, 91%)
as yellow needles. Mp 142–143 ꢀC; IR (KBr): 3132, 1620, 1566, 1450,
4.19. Preparation of methyl 2-((E)-5-methyl-3-oxohexa-1,4-
dienyl)phenyl fumarate (28)
A
mixture of salicylaldehyde (0.533 mL, 5.0 mmol), Et3N
(0.835 mL, 6.0 mmol), and 4-(dimethylamino)pyridine (10 mg,
0.08 mmol) in CH2Cl2 (40 mL) was cooled to 0 ꢀC, and a solution of
tert-butyldimethylsilyl chloride (904 mg, 6.0 mmol) in CH2Cl2
(20 mL) was added dropwise. The reaction mixture was stirred at
room temperature for 1 h, quenched with saturated aqueous
NaHCO3 and extracted with CH2Cl2 (20 mLꢂ2). The combined ex-
tracts were washed with brine, dried over MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography [SiO2:
EtOAc/hexane (1:9, v/v)] yielded 2-(tert-butyldimethylsilanyloxy)-
benzaldehyde as a colorless oil (1.18 g, quant.).
1373, 1257, 1126, 979, 748, 455 cmꢁ1 1H NMR (500 MHz, DMSO)
;
d
1.93 (s, 3H, Me), 2.13 (s, 3H, Me), 6.43 (s, 1H, H-4), 6.83 (dd, J¼7.6,
7.6 Hz, 1H, Ar), 6.90 (d, J¼8.4 Hz, 1H, Ar), 6.95 (d, J¼16.1 Hz, 1H, H-
2), 7.23 (dt, J¼1.6, 7.8 Hz, 1H, Ar), 7.60 (dd, J¼1.5, 7.7 Hz, 1H, Ar), 7.77
(d, J¼16.1 Hz, 1H, H-1), 10.18 (s, 1H, OH); 13C NMR (126 MHz, CDCl3)
d
21.2 (CH3), 28.0 (CH3), 116.7 (CH), 120.4 (CH), 122.1 (C), 123.3 (CH),
128.5 (CH), 129.2 (CH), 131.5 (CH), 139.2 (CH), 156.3 (C), 156.8 (C),
192.4 (C). HRMS-ESI m/z [MþNa]þ calcd for C13H14NaO2: 225.0886,
found: 225.0890.
Mesityl oxide (3.2 mL, 27.6 mmol) was added dropwise to a so-
lution of lithium diisopropylamide (15.3 mL, 1.8 M in THF,
27.6 mmol) in THF (250 mL) at ꢁ65 ꢀC. The reaction mixture was
stirred for 1 h, and a solution of 2-(tert-butyldimethylsilanyloxy)-
benzaldehyde (5.5 g, 23.0 mmol) in THF (30 mL) was added
dropwise. The reaction mixture was stirred for an additional
50 min, quenched with saturated aqueous NH4Cl and extracted
with EtOAc (100 mLꢂ2). The combined extracts were washed with
water and brine, dried over MgSO4, and concentrated in vacuo.
Purification of the residue by flash chromatography [SiO2: EtOAc/
hexane (3:97, v/v)] yielded 1-[2-(tert-butyldimethylsilanyloxy)-
phenyl]-1-hydroxy-5-methylhex-4-en-3-one (6.9 g, 90%) as a pale
yellow oil. IR (neat): 3479, 2939, 2900, 2862, 1736, 1682, 1619, 1481,
Dicyclohexyl carbodiimide (2.7 g, 12.9 mmol) was added to
a solution of 27 (1.3 g, 6.4 mmol), fumaric acid monomethyl ester
(920 mg, 7.1 mmol) and 4-dimethylaminopyridine (64 mg,
0.52 mmol) in toluene (200 mL). The reaction mixture was stirred
for 3 h, quenched with water and extracted with EtOAc (50 mLꢂ2).
The combined organic layers were washed with water and brine,
dried over MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography [SiO2: EtOAc/hexane (1:4, v/v)]
followed by recrystallization from CH2Cl2/hexane (1:9, v/v) yielded
methyl 2-((E)-5-methyl-3-oxohexa-1,4-dienyl)phenyl fumarate
(28) (1.59 g, 78%) as pale yellow needles. Mp 73–75 ꢀC; IR (KBr):
1450, 1381, 1257, 1111, 1049, 918, 833, 771, 447 cmꢁ1
;
1H NMR
2908, 1728, 1628, 1257, 1173, 980, 756 cmꢁ1
CDCl3)
;
1H NMR (600 MHz,
1.96 (d, J¼1.1 Hz, 3H, Me), 2.22 (d, J¼1.1 Hz, 3H, Me), 3.87
(500 MHz, CDCl3) 0.23 (s, 3H, Me(OTBS)), 0.27 (s, 3H, Me(OTBS)),
d
d
t
0.98 (s, 9H, 3Me(OTBS, Bu)), 1.89 (d, J¼1.1 Hz, 3H, Me), 2.17 (d,
J¼1.0 Hz, 3H, Me), 2.66 (dd, J¼9.5, 17.3 Hz, 1H, H-2), 2.95 (dd, J¼2.4,
17.3 Hz, 1H, H-2), 3.77 (d, J¼3.2 Hz, 1H, OH), 5.44 (dt, J¼2.8, 9.5 Hz,
1H, H-1), 6.02–6.04 (m, 1H, H-4), 6.77 (dd, J¼1.0, 8.0 Hz, 1H, Ar),
6.98 (ddd, J¼0.9, 7.5, 7.5 Hz, 1H, Ar), 7.13 (ddd, J¼1.8, 7.7, 7.7 Hz, 1H,
Ar), 7.50 (dd, J¼1.7, 7.6 Hz, 1H, Ar); 13C NMR (126 MHz, CDCl3)
(s, 3H, Me(COOMe)), 6.26–6.29 (m, 1H, H-3), 6.79 (d, J¼16.1 Hz, 1H,
H-2), 7.08 (d, J¼15.9 Hz, 1H, H-4 or H-5), 7.12 (d, J¼15.9 Hz, 1H, H-4
or H-5), 7.17 (dd, J¼1.1, 8.2 Hz, 1H, Ar), 7.30 (dd, J¼7.5, 7.5 Hz, 1H,
Ar), 7.42 (ddd, J¼1.5, 7.7, 7.7 Hz, 1H, Ar), 7.61 (d, J¼16.1 Hz, 1H, H-
1), 7.70 (dd, J¼1.5, 7.8 Hz, 1H, Ar); 13C NMR (126 MHz, CDCl3)
d 21.1
(CH3), 27.9 (CH3), 52.4 (CH3), 122.7 (CH), 123.7 (CH), 126.7 (CH),
127.5 (CH), 127.6 (C), 130.1 (CH), 130.9 (CH), 132.3 (CH), 134.5 (CH),
135.4 (CH), 148.9 (C), 157.4 (C), 163.1 (C), 164.9 (C), 189.3 (C).
HRMS-ESI m/z [MþNa]þ calcd for C18H18NaO5: 337.1046, found:
337.1046.
d
ꢁ4.4 (CH3), ꢁ4.0 (CH3), 18.1 (C), 20.9 (CH3), 25.7 (3CH3), 27.7
(CH3), 50.6 (CH2), 65.4 (CH), 117.9 (CH), 121.3 (CH), 123.7 (CH), 126.5
(CH), 127.8 (CH), 133.5 (C), 151.7 (C), 156.6 (C), 201.1 (C). HRMS-ESI
m/z [MþNa]þ calcd for C19H30NaO3Si: 357.1856, found: 357.1864.

932
S. Kobayashi et al. / Tetrahedron 65 (2009) 920–933
4.20. Preparation of the azatriene 29 and its sequential
[2D2]-cycloaddition with diphenylketene
acid methyl ester (32 and 320) (99 mg, 63%) in a ratio of 48:52.
Analytically pure 32 and 320 were obtained by preparative HPLC
[SiO2: EtOAc/hexane (1:19 to 1:8, v/v)].
A mixture of 28 (285 mg, 0.9 mmol), Et3N (0.56 mL, 4.0 mmol),
and benzylamine (0.25 mL, 1.8 mmol) in CH2Cl2 (25 mL) was cooled
to 0 ꢀC, and titanium tetrachloride (0.9 mL,1.0 M solution in CH2Cl2,
0.9 mmol) was added dropwise. The reaction mixture was stirred at
the same temperature for 1.5 h, then a solution of diphenylketene
(353 mg,1.8 mmol) in CH2Cl2 (5 mL) was added dropwise. After 2 h,
the reaction mixture was quenched with water and passed through
a short CeliteÒ pad eluting with CH2Cl2. The filtrate was extracted
with CH2Cl2 (10 mLꢂ2), and the combined extracts were washed
with water and brine, dried over MgSO4, and concentrated in vacuo.
Purification of the residue by flash chromatography [SiO2: EtOAc/
hexane (1:4, v/v)] afforded 2-{(E)-2-[1-benzyl-2-(2-methylprop-1-
enyl)-4-oxo-3,3-diphenylazetidin-2-yl]vinyl}phenyl methyl fuma-
rate (30) (183 mg, 34%) as a yellow oil. IR (neat): 3023, 1743, 1142,
Compound 32: colorless crystals; mp 217–219 ꢀC; IR (KBr):
2924, 1751, 1660, 1643, 1173, 702 cmꢁ1 1H NMR (600 MHz, CDCl3)
;
d
0.76 (s, 3H, Me), 0.81 (s, 3H, Me), 2.00 (d, J¼14.0 Hz, 1H, H-6), 3.44
(ddd, J¼2.2, 3.5, 10.6 Hz, 1H, H-12c), 3.70 (dd, J¼10.6, 14.0 Hz, 1H, H-
6a), 3.71 (s, 3H, Me(COOMe)), 4.60 (d, J¼3.5 Hz, 1H, H-12b), 5.03 (d,
J¼2.2 Hz, 1H, H-4), 5.04 (d, J¼13.6 Hz, 1H, benzyl), 5.22 (d,
J¼13.6 Hz, 1H, benzyl), 6.89–6.95 (m, 2H, Ar), 7.02–7.10 (m, 3H, Ar),
7.17–7.25 (m, 7H, Ar), 7.26–7.33 (m, 5H, Ar), 7.34–7.38 (m, 2H, Ar);
13C NMR (150 MHz, CDCl3)
d 23.3 (CH3), 30.0 (CH3), 33.9 (C), 36.4
(CH), 44.5 (CH), 46.2 (CH), 48.5 (CH2), 48.7 (CH), 52.0 (CH3), 56.8 (C),
119.0 (CH), 119.2 (CH), 125.0 (CH), 126.4 (CH), 126.7 (2CH), 127.0
(CH), 127.09 (2CH), 127.17 (2CH), 127.24 (CH), 128.1 (C), 128.4 (2CH),
129.2 (CH), 129.3 (2CH), 129.4 (CH), 130.8 (2CH), 133.1 (C), 137.1 (C),
140.0 (C),145.3 (C),150.4 (C),169.46 (C),169.51 (C),171.4 (C). HRMS-
ESI m/z: [MþNa]þ calcd for C39H35NNaO5: 620.2407, found:
620.2408.
1295, 1211, 1180, 1142, 980, 756, 702, 524, 478 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
d
1.25 (s, 3H, Me), 1.41 (d, J¼1.0 Hz, 3H, Me), 3.85
(s, 3H, Me(COOMe)), 4.32 (d, J¼15.1 Hz, 1H, benzyl), 4.47 (d,
J¼15.1 Hz, 1H, benzyl), 5.06–5.09 (m, 1H, H-3), 5.80 (d, J¼16.2 Hz,
1H, H-2), 6.41 (d, J¼16.2 Hz,1H, H-1), 6.85 (dd, J¼1.4, 7.8 Hz,1H, Ar),
6.98 (s, 2H, H-4, H-5), 7.00–7.39 (m, 16H, Ar), 7.69 (dd, J¼1.4, 7.3 Hz,
Compound 320: colorless crystals; mp 152–154 ꢀC; IR (KBr):
2924, 1774, 1736, 1450, 1219, 702 cmꢁ1 1H NMR (600 MHz, CDCl3)
;
d
0.56 (s, 3H, Me), 1.10 (s, 3H, Me), 2.74 (d, J¼10.7 Hz, 1H, H-6), 2.78
(dd, J¼10.5,10.7 Hz,1H, H-6a), 2.80–2.84 (m, 1H, H-12c), 3.67 (s, 3H,
Me(COOMe)), 4.51 (d, J¼6.1 Hz, 1H, H-12b), 4.67 (d, J¼1.8 Hz, 1H, H-
4), 4.91 (d, J¼16.1 Hz, 1H, benzyl), 5.42 (d, J¼16.1 Hz, 1H, benzyl),
6.99 (ddd, J¼0.9, 7.4, 7.7 Hz, 1H, Ar), 7.01–7.11 (m, 6H, Ar), 7.15–7.37
2H, Ar); 13C NMR (126 MHz, CDCl3)
d 20.5 (CH3), 26.4 (CH3), 43.8
(CH2), 52.4 (CH3), 73.0 (C), 78.0 (C), 121.3 (CH), 121.9 (CH), 125.2
(CH), 126.4 (CH), 126.7 (CH), 126.9 (CH), 127.0 (CH), 127.28 (2CH),
127.31 (2CH), 128.2 (2CH), 128.5 (2CH), 128.6 (2CH), 128.8 (C), 129.1
(2CH), 129.2 (2CH), 132.4 (CH), 132.9 (CH), 134.8 (CH), 137.05 (C),
137.10 (C), 138.6 (C), 138.8 (C), 147.3 (C), 162.9 (C), 164.8 (C), 169.6
(C). HRMS-EI m/z [M]þ calcd for C39H35NO5: 597.2515, found:
597.2517.
(m, 12H, Ar); 13C NMR (150 MHz, CDCl3)
d 26.9 (CH3), 30.2 (CH3),
35.3 (C), 41.6 (CH), 41.9 (CH), 43.4 (CH), 47.0 (CH2), 51.8 (CH), 51.9
(CH3), 56.4 (C), 116.6 (CH), 120.2 (CH), 126.0 (CH), 126.3 (2CH), 126.4
(CH),127.05 (2CH),127.07 (CH), 127.2 (CH), 127.4 (2CH),128.4 (2CH),
128.5 (C), 129.06 (CH), 129.07 (CH), 129.3 (2CH), 130.8 (2CH), 133.2
(C), 136.6 (C), 139.8 (C), 144.0 (C), 150.9 (C), 169.7 (C), 170.8 (C), 172.5
(C). HRMS-ESI m/z: [MþNa]þ calcd for C39H35NNaO5: 620.2407,
found: 620.2386.
4.21. [1,3]-Sigmatropic rearrangement of the [2D2]
cycloadduct 30
4.23. X-ray crystallographic data for compounds 32 and 320
A solution of 30 (180 mg, 0.3 mmol) in toluene (20 mL) was
heated at 110 ꢀC for 2 h, and then concentrated in vacuo. Purifica-
tion of the residue by flash chromatography [SiO2: EtOAc/hexane
(1:9, v/v)] followed by recrystallization from CH2Cl2/hexane (1:8,
v/v) yielded 2-[1-benzyl-6-(2-methylprop-1-enyl)-2-oxo-3,3-
diphenyl-1,2,3,4-tetrahydropyridin-4-yl]phenyl methyl fumarate
(31) (158 mg, 88%) as pale yellow crystals. Mp 84–85 ꢀC; IR (KBr):
2962, 2924, 2360, 1736, 1658, 1442, 1304, 1242, 1173, 756,
Crystallographic data (excluding structure factors) for 32 and 320
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 701491 and
682526, respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, (fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
702 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
1.42 (d, J¼0.8 Hz, 3H, Me),
1.71 (d, J¼0.8 Hz, 3H, Me), 3.82 (s, 3H, Me(COOMe)), 4.41 (d,
J¼6.9 Hz, 1H, H-1), 4.71 (d, J¼14.7 Hz, 1H, benzyl), 5.03 (d,
J¼14.7 Hz, 1H, benzyl), 5.32 (d, J¼6.9 Hz, 1H, H-2), 5.49 (br s, 1H, H-
3), 6.54 (d, J¼7.9 Hz, 2H, Ar), 6.75 (s, 2H, H-4, H-5), 6.77 (dd, J¼1.1,
8.2 Hz, 1H, Ar), 6.88–7.03 (m, 4H, Ar), 7.10–7.29 (m, 7H, Ar), 7.30–
7.37 (m, 3H, Ar), 7.46–7.52 (m, 2H, Ar); 13C NMR (126 MHz, CDCl3)
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.10.090.
References and notes
d
19.3 (CH3), 25.6 (CH3), 40.0 (CH), 46.9 (CH2), 52.4 (CH3), 60.2 (C),
110.4 (CH), 119.1 (CH), 121.3 (CH), 126.0 (CH), 126.1 (CH), 126.3
(2CH), 127.1 (CH), 127.4 (CH), 128.0 (2CH), 128.1 (CH), 128.2 (2CH),
128.3 (2CH), 128.8 (2CH), 129.9 (CH), 130.2 (C), 130.4 (2CH), 132.7
(CH), 134.7 (CH), 137.5 (C), 138.0 (C), 140.2 (C), 140.9 (C), 141.9 (C),
148.2 (C), 162.4 (C), 165.1 (C), 170.6 (C). HRMS-ESI m/z [MþNa]þ
calcd for C39H35NNaO5: 620.2407, found: 620.2415.
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