A novel and facile stereocontrolled synthetic method for polyhydro-quinolines and pyridopyridazines via a diene-transmissive Diels-Alder reaction involving inverse electron-demand hetero Diels-Alder cycloaddition of cross-conjugated azatrienes

Article abstract of DOI:10.1016/j.tet.2008.07.102

Cross-conjugated azatrienes bearing an electron-withdrawing sulfonyl or benzoyl group on the nitrogen atom underwent, on heating or in the presence of a Lewis acid (TMSOTf), an initial inverse electron-demand hetero Diels-Alder reaction with electron-rich dienophiles (vinyl ether, vinyl thioether, and allenyl ether) to produce 1:1 cycloadducts with high endo selectivity. The initial cycloadducts thus obtained underwent a second Diels-Alder reaction stereoselectively on the newly formed diene unit with electron-deficient dienophiles to give the crossed bis-cycloadducts, octahydroquinolines, with high diastereo-π-facial selectivity. The N-sulfonylazatrienes tethering an ortho-cinnamyloxyphenyl dienophile at the triene terminal underwent an initial intramolecular hetero Diels-Alder reaction of the inverse electron-demand type. The subsequent second Diels-Alder reaction of the formed mono-cycloadducts completed the diene-transmissive hetero Diels-Alder protocol to give benzopyrano[3,4-c]quinolines in a highly stereoselective manner.

Full text of DOI:10.1016/j.tet.2008.07.102

Tetrahedron 64 (2008) 9705–9716
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and facile stereocontrolled synthetic method for polyhydro-quinolines
and pyridopyridazines via a diene-transmissive Diels–Alder reaction
involving inverse electron-demand hetero Diels–Alder cycloaddition
of cross-conjugated azatrienes
*
Satoru Kobayashi, Tomoki Furuya, 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:
Cross-conjugated azatrienes bearing an electron-withdrawing sulfonyl or benzoyl group on the nitrogen
atom underwent, on heating or in the presence of a Lewis acid (TMSOTf), an initial inverse electron-
demand hetero Diels–Alder reaction with electron-rich dienophiles (vinyl ether, vinyl thioether, and
allenyl ether) to produce 1:1 cycloadducts with high endo selectivity. The initial cycloadducts thus ob-
tained underwent a second Diels–Alder reaction stereoselectively on the newly formed diene unit with
electron-deficient dienophiles to give the crossed bis-cycloadducts, octahydroquinolines, with high
Received 14 April 2008
Received in revised form 24 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Keywords:
Diels–Alder
Cycloaddition
Diene-transmissive
Heterocycle
diastereo-p-facial selectivity. The N-sulfonylazatrienes tethering an ortho-cinnamyloxyphenyl dienophile
at the triene terminal underwent an initial intramolecular hetero Diels–Alder reaction of the inverse
electron-demand type. The subsequent second Diels–Alder reaction of the formed mono-cycloadducts
completed the diene-transmissive hetero Diels–Alder protocol to give benzopyrano[3,4-c]quinolines in
a highly stereoselective manner.
Tandem reaction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
n
An efficient and convenient approach for the synthesis of
complex organic molecules often includes sequential reactions in
a set of multistep transformations, which is called a tandem, cas-
cade, or domino reaction.1 Any definition of these designations for
multistep processes seems to include some ambiguity, some arbi-
trary choice, and limitation of their usage because of the large
number of possible combinations of various transformations;
however, the application of certain sequential reactions has
emerged as one of the most effective and useful strategies in or-
ganic synthesis. The diene-transmissive Diels–Alder (DTDA) re-
action represents one of these methodologies. Although the DTDA
reaction is formally considered to be a set of multisequential Diels–
α,ω-divinylpoly(vinylidene)
second DA
initial DA
Chart 1. Diene-transmissive Diels–Alder methodology.
Schreiber, Sherburn, and others have developed this DTDA metho-
dology using cross-conjugated carbotrienes and equivalents.2,3
Fallis et al. reported the applications of the method for the
construction of oxygenated nor-steroid and triterpenoid skeletons,
and the tricyclic core of vinigrol.3 On the other hand, the hetero
Diels–Alder (HDA) methodology is among the most attractive and
important tool for the synthesis of a wide range of six-membered
heterocyclic compounds because of its potentially powerful and
straightforward construction of heterocycles with high control of
chemo-, regio-, and stereoselectivities.4
Alder (DA) reactions of
a,u-divinylpoly(vinylidene), the DTDA
reaction can usually be defined by the two final sequential cyclo-
additions that involve an initial DA reaction of a cross-conjugated
triene (n¼1) (or its equivalent) with a dienophile followed by
a second DA cycloaddition with a dienophile on the newly formed,
transmitted diene unit of the mono-adduct to give a bis-adduct
(Chart 1). The research groups of Tsuge and Kanemasa, Fallis,
Therefore, the diene-transmissive hetero Diels–Alder (DTHDA)
reaction, which is a special case of the DTDA reaction where one or
more heteroatoms are contained within either a triene framework
or a dienophile skeleton or both, should offer an efficient method
* 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.2008.07.102

9706
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
O
R1
Ts
R2
O
R1
N
H
N
Ts
R2
N
H
N
TsN
C O
R2
R2
R1
B
C
N
O
R3
R3
R2
R1
R2
R2
R3
O
R3
R3
R2
R1
O
N
R3
N
R32C
C
O
A
N
R2
R1
H
R2
R2
H
R2
D
E
F
Scheme 1.
for the synthesis of, in particular, ring-fused heterocycles by per-
forming tandem (hetero) DA reactions in a stereocontrolled man-
ner. In this context, our group has previously reported the first
examples of the DTHDA reaction,5 which involved cross-conjugated
thiatrienes.5,6 Tsuge et al. reported a cross-conjugated oxatriene
DTHDA reaction.7 Spino et al. also used the DTHDA method of cross-
conjugated oxatrienes for the construction of the picrasane
skeleton.8 The first representative of the DTHDA method using
cross-conjugated azatrienes has been reported.9 This process in-
volved the initial aza DA cycloaddition of A with a reactive dien-
ophile, tosyl isocyanate, followed by the second DA reaction of
application of method A to the preparation of 2d failed. These
N-sulfonyl- and acylazatrienes 2 could be readily purified through
extraction work-up and/or silica gel column chromatography in
contrast to labile N-alkyl analogs.
R
O
N
RNH2 (Method A)
RCl (Method B
)
Ph
Ph
Ph
Ph
1
2
Scheme 2.
mono-adducts
B with some representative electron-deficient
dienophiles stereoselectively to give ring-fused pyrimidinone
derivatives C as bis-adducts in good yields (Scheme 1).9 The cross-
conjugated azatrienes A also reacted with ketenes to furnish mono-
adducts E via [2þ2] adducts D.10 The mono-adducts E also
underwent the second DA reaction with electron-deficient dieno-
philes to give quinoline derivatives as bis-adducts with high regio-
and stereoselectivities. In certain cases, the intermediary [2þ2]
adducts could be isolated. Unfortunately, the azatrienes A having an
R1 group on nitrogen, such as Ph, p-Tol, PhCH2, i-Pr, and a quite
effective electron-releasing Me2N group, failed to undergo the
initial cycloaddition with the representative reactive dienophiles
such as tetracyanoethylene, N-phenylmaleimide, maleic anhydride,
dimethyl fumarate, dimethyl acetylene dicarboxylate, ethyl vinyl
ether, and styrene under, if necessary, harsh conditions and/or in
the presence of a Lewis acid promoter.9,10 To extend this DTHDA
methodology, we decided to investigate the DTHDA reaction of
cross-conjugated azatrienes G bearing an electron-withdrawing
group (EWG) on nitrogen, which involved an inverse electron-
demand aza Diels–Alder reaction in the initial cycloaddition. We
report the results here.
Table 1a
Entry
R
Method
Time (h)
Azatriene
Yieldb (%)
1
2
3
4
MeSO2
PhSO2
p-TolSO2
PhCO
A
A
A
B
7
7
7
2a
2b
2c
2d
82
87
65
46
6 (5þ1)
a
The reaction was carried out using method A or method B. Method A: 1
(1.0 equiv), RNH2 (2.0 equiv), Et3N (4.4 equiv), TiCl4 (1.0 equiv) in CH2Cl2, 0 ꢀCto rt.
Method B: 1 (1.0 equiv), LiHMDS (2.0 equiv) in THF, ꢁ78 ꢀC to rt, then add RCl
(3.0 equiv), ꢁ78 ꢀC to rt.
b
Isolated yield.
2.2. Initial cycloaddition of azatrienes 2 with ethyl vinyl ether
First, electron-deficient azatrienes 2 were allowed to react with
an electron-rich dienophile, ethyl vinyl ether (Scheme 3, Table 2).
Upon heating in toluene at 110 ꢀC for 23 h, N-mesylazatriene 2a
reacted with ethyl vinyl ether to afford cycloadduct 3a in 68% yield
with an endo/exo ratio of 90:10 (entry 1), while the reactions of
azatrienes 2b,c gave exclusively endo adducts 3b,c in 88% and 86%
yields, respectively (entries 2 and 3). In contrast, N-benzoylaza-
triene 2d did not react with ethyl vinyl ether under thermal re-
action conditions (entry 4). Then, the reactions were carried out in
the presence of a Lewis acid promoter. Common Lewis acids such as
AlCl3, TiCl4, SnCl4, Yb(OTf)3, and BF3$OEt2 did not effect the re-
actions of 2a–d leading to cycloadducts 3a–d, whereas the reaction
EWG
N
R
R
G
2. Results and discussion
OEt
OEt
2.1. Preparation of cross-conjugated azatrienes
H2
H2
OEt
R
R
R
N
N
N
+
The cross-conjugated N-sulfonylazatrienes 2a–c were prepared
in good yields by the condensation reaction between di-b-styryl
ketone 1 and sulfonamides (method A), as shown in Scheme 2 and
Table 1. N-Benzoylazatriene 2d was synthesized via the aza-Peter-
son reaction of 1 with lithium hexamethyldisilazide, followed by
acylation with benzoyl chloride (method B), because the
Ph
Ph
Ph
Ph
Ph
Ph
H4
3 (endo)
H4
3 (exo)
2
(H2-H4 cis)
Scheme 3.
(H2-H4 trans)

S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
9707
Table 2
Initial cycloaddition with ethyl vinyl ether
Entry
Azatriene
R
Solvent
Temp (ꢀC)
TMSOTf (mol %)
Time (h)
Adduct
Yielda (%)
endo/exob
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2d
2d
2d
2d
2d
MeSO2
PhSO2
p-TolSO2
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
110
110
110
d
d
d
d
100
75
40
25
5
23
13
15
15
2
2
2
1
3
3a
3b
3c
d
68
88
86
d
90:10
>95:5
>95:5
d
110
ꢁ60
ꢁ60
ꢁ60
ꢁ60
ꢁ60
3d
3d
3d
3d
3d
30
63
72
86
37
83:17
>95:5
>95:5
>95:5
>95:5
a
Isolated yield.
endo/exo Ratio determined based on 1H NMR integration of the endo-cyclic olefinic proton of 3. Ratio >95:5 denotes that no minor exo-isomer was detected.
b
of 2d in the presence of Me3SiOSO2CF3 (TMSOTf) at ꢁ60 ꢀC in
dichloromethane afforded cycloadduct 3d in fair to good yield with
high endo selectivity (entries 5–8). Reducing the amounts of the
catalyst from 25 mol % to 5 mol % resulted in a decrease in the yield
(from 86% to 37%) of 2d (entries 8 and 9). It is noteworthy that
N-benzoyl-1-azadiene 2d underwent the TMSOTf-promoted
[4þ2]-cycloaddition with a vinyl ether, because reported examples
of a Lewis acid-catalyzed 1-azadiene DA reaction with electron-rich
dienophiles are rare.4l,11
dienophile as well.12 Allenyl methyl ether13 reacted with N-sulfo-
nylazatrienes 2a–c on heating at 110 ꢀC to produce cycloadducts
5a–c (Scheme 5, Table 4) having the exo-methylene dihydropyri-
dine structure. The reaction was highly exo selective, in contrast
to the reactions with ethyl vinyl ether and ethyl vinyl sulfide that
were highly endo selective. It is worth mentioning that the reaction
of N-sulfonyl-4-ethoxycarbonyl-1-azabuta-1,3-dienes with allenyl
ethers was reported to give the corresponding exo-methylene
cycloadducts with high endo selectivity.12
2.5. Second cycloaddition with tetracyanoethylene (TCNE)
2.3. Initial cycloaddition of azatrienes 2 with ethyl
vinyl sulfide
The mono-cycloadducts 3–5 formed by the initial inverse elec-
tron-demand aza DA cycloaddition of 2 possess a newly formed
amino diene unit, so that the dienes 3–5 are expected to undergo
a second DA cycloaddition with electron-deficient dienophiles in
a normal electron-demand mode. First, to examine the diastereo-
Vinyl sulfide is also an electron-rich dienophile with a suffi-
ciently high energy level of its HOMO to allow reaction with 2
(Scheme 4). In fact, N-sulfonylazatrienes 2a,c reacted with ethyl
vinyl sulfide in refluxing toluene to give cycloadducts 4a,c in
68% and 51% yields, respectively, with high endo selectivity (Table
3, entries 1 and 2). Similar to the reaction with ethyl vinyl ether,
N-benzoylazatriene 2d did not react with ethyl vinyl sulfide
under thermal conditions (entry 3); instead, the reaction of 2d
was promoted by TMSOTf at ꢁ60 ꢀC in CH2Cl2, producing 4d
in good yield with endo/exo ratios of 69:31 to 82:18 (entries 4
and 5).
p-facial selectivity of the second DA cycloaddition, a structurally
simple and reactive dienophile, TCNE, was used (Scheme 6,
Table 5).
In all cases, the reaction proceeded smoothly under mild re-
action conditions to give the cycloadducts, octahydroquinolines
6–7 or 60–80, in high yields with excellent diastereo-
p-facial
selectivity, regardless of the 2,4-cis (endo) or 2,4-trans (exo) isomers
of dienes 3–5. The stereochemical outcome would be ascribed to
the mechanism whereby the dienophile (TCNE) attacked from the
less hindered bottom H4 side of the diene (Scheme 6). A one-pot
procedure for the diene-transmissive HDA methodology 2c/3c/
6c was proved effective (entry 13). A toluene solution of azatriene
2c and ethyl vinyl ether was refluxed for 15 h (cf. Table 2, entry 3)
and cooled to room temperature. Addition of TCNE to the resultant
reaction mixture containing 3c with stirring (cf. Table 5, entry 3)
gave 6c in 76% yield. Clearly, the one-pot procedure is viable and
comparable to the stepwise procedure with regard to the total yield
and handling.
SEt
SEt
H2
H2
SEt
R
R
R
N
N
N
+
Ph
Ph
Ph
Ph
Ph
Ph
H4
4 (endo)
H4
4 (exo)
2
(H2-H4 cis)
Scheme 4.
(H2-H4 trans)
2.4. Initial cycloaddition of azatrienes 2 with allenyl
methyl ether
2.6. Second cycloaddition with 4-phenyl-1,2,4-triazoline-3,5-
dione (PTAD)
There are precedents for the inverse electron-demand Diels–
Alder reaction in which allenyl ethers react as an electron-rich
The reaction with an electrophilic dienophile, PTAD, was also
examined (Scheme 7, Table 6). The reaction of dienes 3 and 4
Table 3
Initial cycloaddition with ethyl vinyl sulfide
Entry
Azatriene
R
Solvent
Temp (ꢀC)
TMSOTf (mol %)
Time (h)
Adduct
Yielda (%)
endo/exob
1
2
3
4
5
2a
2c
2d
2d
2d
MeSO2
p-TolSO2
PhCO
PhCO
PhCO
Toluene
Toluene
Toluene
CH2Cl2
110
110
110
d
48
37
25
1
4a
4c
d
68
51
d
>95:5
>95:5
d
d
d
ꢁ60
100
25
4d
4d
64
84
69:31
82:18
CH2Cl2
ꢁ60
1
a
Isolated yield.
endo/exo Ratio determined based on 1H NMR integration of the endo-cyclic olefinic proton of 4. Ratio >95:5 denotes that no minor exo-isomer was detected.
b

9708
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
OMe
OMe
N
H2
H2
H4
R
R
R
OMe
+
N
N
.
Ph
Ph
Ph
Ph
Ph
Ph
H4
Toluene,110 °C
2
5 (endo)
5 (exo)
(H2-H4 cis)
(H2-H4 trans)
Scheme 5.
Table 4
Y
H
N
Ph
H7
H9
Initial cycloaddition with allenyl methyl ether
N
R
O
Y
N
N
O
H2
H4
Entry
2
R
Time (h)
Adduct
Yielda (%)
endo/exob
R
N
N
N
Ph
O
1
2
3
2a
2b
2c
MeSO2
PhSO2
p-TolSO2
29
41
20
5a
5b
5c
30
39
28
<5:95
<5:95
<5:95
H
Ph
CH2Cl2 , r.t., 10 min
Ph
Ph
N
a
O
Ph
Isolated yield.
b
endo/exo Ratio determined based on 1H NMR integration of the endo-cyclic
H2-H4 cis (endo)
H2-H4 trans (exo)
(H7-H9 cis)
9 - 10
3 - 4
olefinic proton of 5. Ratio <5:95 denotes that no minor endo-isomer was detected.
(H7-H9 trans)
9' - 10'
Scheme 7.
Z
Y
R
Y
X
Z
Table 6
N
H4a
R
X
TCNE
Second cycloaddition with PTAD
N
H7
Ph
CH2Cl2
Ph
Entry
R
Y
Diene
Adducta
Yieldb (%)
H4
Ph
Ph
H4
NC
1
2
3
4
5
6
7
8
9
MeSO2
PhSO2
p-TolSO2
PhCO
EtO
EtO
EtO
EtO
EtO
EtS
EtS
EtS
EtS
3a (cis)
3b (cis)
3c (cis)
3d (cis)
3d (trans)
4a (cis)
4c (cis)
4d (cis)
4d (trans)
9a
9b
9c
9d
90d
10a
10c
10d
100d
99
99
99
99
99
99
92
99
91
CN
CN
NC
H2(Z)-H4 cis (endo)
H2(Y)-H4 trans (exo)
6 - 7 (H2(Z)-H4 cis)
6' - 8' (H2(Y)-H4 trans)
3 - 5
PhCO
MeSO2
p-TolSO2
PhCO
R
N
Y
N
R
Y
X
H4a
X
PhCO
Z
Ph
H7
Ph
Z
a
A prime mark for the adducts (90, 100) denotes an H7–H9 trans relationship.
Isolated yield.
CN
CN
Ph
NC
H4
b
H4
Ph
NC
6 - 7
3 - 5
2.7. Second cycloaddition with dimethyl acetylene
dicarboxylate (DMAD)
Scheme 6.
With DMAD, the reaction of dienes 3 proceeded on heating at
110 ꢀC in toluene to produce compounds 12 in moderate yields
(Scheme 8, Table 7). Compounds 12 would be formed by the
elimination of ethanol and cis-stereoselective 1,3-H migration of
the initially formed 1:1 cycloadducts (11), the result of which
suggests that the H-migration would proceed in an ionic and
stepwise manner. The cis-selectivity would be ascribed to the
proceeded rapidly within 10 min at room temperature to produce
the cycloadducts 9/90 and 10/100, respectively, in quantitative yield
in all cases. The reaction was highly diastereo-p-facial selective, the
dienophile (PTAD) having attacked from the less congested H4 side
to the diene unit.
Table 5
Second cycloaddition with TCNE
Entry
R
X
Y
Z
Diene
Conditions
Adducta
Yieldb (%)
1
2
3
4
5
6
7
8
MeSO2
PhSO2
p-TolSO2
PhCO
H2
H2
H2
H2
H2
H2
H2
H2
EtO
EtO
EtO
EtO
H
EtS
EtS
EtS
H
H
H
H
EtO
H
H
H
H
EtO
H
H
3a (cis)
3b (cis)
3c (cis)
3d (cis)
3d (trans)
4a (cis)
4c (cis)
rt, 10 min
rt, 10 min
rt, 10 min
rt, 30 min
6a
6b
6c
6d
60d
7a
93
99
95
99
85
76
93
98
96
90
74
92
76
PhCO
rt, 60 min
MeSO2
p-TolSO2
PhCO
PhCO
MeSO2
PhSO2
40 ꢀC, 30 min
40 ꢀC, 60 min
rt, 30 min
7c
H
4d (cis)
7d
70d
80a
80b
80c
6c
9
H2
EtS
MeO
MeO
MeO
H
4d (trans)
5a (trans)
5b (trans)
5c (trans)
3c (cis)
rt, 30 min
rt, 40 min
rt, 50 min
rt, 55 min
110 ꢀC, 15 h/rt, 2 days
10
11
12
13
H2C
H2C
H2C
H2
p-TolSO2
p-TolSO2
a
A prime mark for the adducts (60–80) denotes an H2(Y)–H4 trans relationship. No minor isomer was detected by means of 1H NMR spectroscopy.
Isolated yield.
b

S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
9709
formation of the more stable cis-fused tetrahydroquinoline struc-
ture (12) having a planar cyclohexa-1,3-diene moiety rather than
the less stable trans-fused one with a twisted planarity of the ring.
with TCNE and NPMI. Unexpectedly, however, the dienes 22 did not
react with these dienophiles at room temperature at all. The re-
actions with TCNE in refluxing dichloromethane and with NPMI in
refluxing toluene resulted in complex mixtures of products, any
adducts being obtained. It has previously been reported that exo-
isomers (H4a–H10b trans) of structurally similar sulfur analogs to
the dienes 22 (S instead of NR) are less reactive than the corre-
sponding endo-isomers in the reactions with these dienophiles.6
These facts suggest that relatively bulky dienophiles such as TCNE
and NPMI, which are reactive enough, do not react with 22 under
usual (thermal) conditions due to steric reasons encountered in the
transition states. In fact, the relatively less congested dienophiles,
DMAD and methyl acrylate, did react with the dienes 22, the results
of which are shown in Scheme 12/Table 10 and Scheme 13/Table 11.
The reaction of 22 with DMAD proceeded in refluxing toluene
for 11–16 h to produce chromeno[3,4-c]quinolines 24 in fair to
good yields with high stereoselectivity via 1,3-H migration of the
initially formed cycloadducts 23. DMAD probably attacked from the
2.8. Second cycloaddition with N-phenylmaleimide (NPMI)
N-Sulfonylated dienes 3a–c also reacted with N-phenyl-
maleimide (NPMI) in refluxing toluene to produce cycloadducts 14a
or 13b,c as final products (Scheme 9, Table 8, entries 1–3). The
reaction proceeded with high endo- and p-facial selectivities to give
initially 1:1 cycloadducts 15a–c, from which elimination of ethanol
occurred to furnish compounds 13b,c or the H-migration product
14a. However, the reaction of dienes 4a–c and 5a–c with NPMI
failed, no cycloadducts being obtained. In contrast to the reaction of
N-sulfonylated dienes 3a–c, the reaction of N-benzoylated dienes
3d and 4d produced the cycloadducts 15d/150d (entries 4 and 5)
and a 1:1 mixture of 16dþ17d/160dþ170d (entries 6 and 7), re-
spectively. In fact, the N-benzoylated cycloadducts (15d–17d, 150-
d–170d) are stable enough to allow isolation after being subjected
to heating conditions.
less congested bottom
(see Fig. 1).
p-face (from the H10b side) of the diene 22
With methyl acrylate, the dienes 22 also underwent a DA re-
action on heating to give single stereoisomers 25 of the 1:1 cyclo-
adducts in good yields, no other isomers being detected in a crude
mixture of the products. These facts suggest that the reaction
proceeded with high regio-, endo, and diastereo-p-facial selectiv-
ities, as illustrated in Figure 1.
2.9. By-product in the second thermal cycloaddition
The reactions of dienes 3–5 with TCNE and PTAD proceeded
smoothly at room temperature to give the corresponding cyclo-
adducts 6–10 quantitatively, whereas the reaction with DMAD and
NPMI required a long heating time, which, particularly in the cases
of sulfonylated dienes 3a–c, resulted in the formation of by-product
2.11. Structure determination
18, 4-phenyl-2-b-styrylpyridine, in 20–40% yield together with the
cycloadducts (12–14). This is probably due to the thermal instability
of 3 resulting from a cyclic N–O acetal structure in the competitive
elimination–aromatization leading to the pyridine nucleus. In fact,
when compound 3c was independently treated with a base on
heating, pyridine 18 was exclusively formed. Sulfinic acid and/or
pyridine 18 formed would catalytically accelerate the ethanol
elimination from 3/15a–c to give 18/13 as well as the proton mi-
gration from 13 to give 14.
2.11.1. Selected mono-cycloadducts
The obtained mono- and bis-cycloadducts were all character-
ized with the help of analytical data and spectral evidence (see
Section 4). Stereochemical assignments were mainly based on 1H
NMR spectroscopic studies and NOESY techniques, and X-ray
crystallographic analysis of bis-cycloadduct 160d. Figure 2 and Table
12 show configurational structures of an endo-isomer and an
exo-isomer with their most probable conformations of mono-
cycloadducts (3 and 4) and observed vicinal coupling constants of
H2–H5 around the tetrahydropyridine ring in the 1H NMR spectra
of 3 and 4. For the exo-isomers, characteristic large vicinal coupling
N
Ph
Ph
constants (J¼11–14 Hz) were observed with J3–4
, suggesting
18
a trans-diaxial relationship between H3 and H4. NOE was also
observed between H4 and the EtX (CH2) group. These facts confirm
that H4 and the EtX group both occupy a quasi-axial 1,3-position.
The preferred axial arrangement of the EtX group is ascribed to the
anomeric effect between the oxygen or sulfur atom (X) and the
nitrogen of the ring. As for the endo-isomers, large vicinal coupling
constants were not observed as a whole, and it was deduced that
H2 and H4 occupy a quasi-equatorial position and hence Ph and EtX
groups are both in a quasi-axial arrangement. The fact that NOE was
observed between the substituents (Ph and EtX) supports this ar-
rangement. The twist chair form of the endo-isomers is somewhat
deformed by the 1,3-diaxial repulsion between the substituents.
2.10. DTHDA methodology including an intramolecular aza
DA cycloaddition
Because the DTHDA methodology of N-sulfonyl or N-acyl cross-
conjugated azatrienes involving the inverse electron-demand aza
DA reaction in the initial cycloaddition was successful, we envis-
aged that its intramolecular version would be viable. Scheme 10
illustrates the preparation of the cross-conjugated azatrienes
tethering a dienophile.
The aldol reaction between TBS-protected salicylaldehyde and
4-phenylbut-3-en-2-one (a), dehydration (b), deprotection giving
the phenol 19 (c), followed by the dienophile tether introduction
(d), and imination of the carbonyl group in 20 (e) gave the desired
substrates 21a,b in total yields of 59% and 58%.
0
0
The values of J2–3, J2–3 , J3–4, J3 –4, and J4–5, listed in Table 12, agree
well with these arrangements of the exo- and endo-isomer.
2.11.2. Selected bis-cycloadducts
The azatriene 21 underwent an initial intramolecular aza DA
reaction upon heating to produce the H4a–H10b trans cycloadducts
22 with retention of the trans configuration of the dienophile (H4–
H4a). The stereochemical outcome of the adducts 22 suggests that
the reaction proceeded in a highly exo selective manner with regard
to the arrangement of the dienophile-connected tether relative to
the diene moiety (Scheme 11, Table 9).
The stereochemical arrangements and J values among H7, H8,
H80, and H9 of bis-cycloadducts 15d/16d (endo for initial cycload-
dition) and 150d/160d (exo for initial cycloaddition) are very similar
to those of the initial mono-cycloadducts, endo- and exo-3d/4d,
respectively. The observed large coupling constant values (11.6–
12.5 Hz) of J9–9a for all the cycloadducts (13, 15, 150, 16, and 160)
(Fig. 3, Table 13) suggest a trans-diaxial relationship between H9
and H9a, and hence the stereochemistry is ascribed to attack the
dienophile (NPMI) from the H4(9) side to the diene moiety of
As shown in Scheme 6/Table 5 and Scheme 9/Table 8, the dienes
3–5 were shown to undergo the second cycloaddition smoothly

9710
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
OEt
H2
R
OEt
R
N
H2
H4
H4a
N
H4a
H8
Ph
R
E
E
H8
H7
Ph
N
Ph
H4
E
Ph
H8a
H4
E
Toluene, 110 °C
Ph
Ph
E
E = CO2Me
E
3 H2-H4 cis (endo)
11
12
Scheme 8.
Table 7
4. Experimental
4.1. General
Second cycloaddition with DMAD
Entry
R
Diene
Time (h)
Adduct
Yielda (%)
1
2
3
MeSO2
PhSO2
p-TolSO2
3a (cis)
3b (cis)
3c (cis)
5
20
21
12a
12b
12c
59
31
31
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a
Isolated yield.
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
mono-cycloadducts 3/4 (see Scheme 6). A characteristic feature is
that the vicinal coupling constants J9a–9b in a trans relationship for
150d/160d were observed to be almost 0 Hz. X-ray crystallographic
analysis of compound 160d (Fig. 4) showed that the stereochemistry
of 160d as assigned in Figure 3 is correct and that the dihedral angle
H9a–C9a–C9b–H9b equals 91.9ꢀ, which supports the observed
J9a–9b value of zero. Similarly, the dihedral angle H3a–C3a–C4–H4
equals 144.3ꢀ, which is consistent with J3a–4¼7.5 Hz. That the ste-
reochemistry of 160d in solution (based on 1H NMR) and in crystals
(based on X-ray) is coincident with each other would be reasonable
for such a rigid molecular structure.
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
Table 8
Cycloaddition with NPMI
3. Conclusions
Entry
R
Y
Diene
Time (h)
Adducta
Yieldb (%)
1
2
3
4
5
6
7
MeSO2
PhSO2
p-TolSO2
PhCO
PhCO
PhCO
EtO
EtO
EtO
EtO
EtO
EtS
EtS
3a (cis)
3b (cis)
3c (cis)
3d (cis)
3d (trans)
4d (cis)
4d (trans)
3
18
18
32
75
53
70
14a
13b
13c
15d
150d
34
21
In conclusion, the diene-transmissive hetero Diels–Alder
methodology including an inverse electron-demand aza Diels–Al-
der reaction in the initial cycloaddition has been developed. The
protocol offers an attractive alternative to other methods for
accessing ring-fused nitrogen-containing heterocycles with high
regio- and stereoselectivities and atom efficiency, thus expanding
the potential of the diene-transmissive hetero Diels–Alder
methodology.
22
83
66
93c
70c
16dþ17d
PhCO
160dþ170d
a
b
c
A prime mark for the adducts (150–170) denotes an H7–H9 trans relationship.
Isolated yield.
1:1 Ratio of adducts in a mixture.
R
R
N
N
Ph
N
H
Y
H2
H4
Ph
O
Ph
O
H
O
O
H
H9
H
Ph
H9
H
Ph
or
R
N
H
H
Toluene
110 °C
N
N
Ph
Ph
O
O
Ph
Ph
3, 4 H2-H4 cis
13 (R = RSO2)
(endo)
14 (R = RSO2)
(endo)
H2-H4 trans
Y
Y
H7
Y
Y
H7
H7
H7
R
H
R
N
R
R
N
N
N
H9a
H9a
H9b
Ph
Ph
O
H9b
H9b
Ph
O
H9b
+
Ph
H9
H9
H
Ph
+
H9
H
Ph
H9
H
Ph
H
Ph
+
O
O
H
H
H
N
N
N
N
O
O
O
Ph
Ph
O
Ph
Ph
(R = RSO2)
(R = PhCO)
15a–c
(R = RSO2)
(R = PhCO)
15'a–c
17d (R = PhCO)
(cis-endo)
17'd (R = PhCO)
(trans-exo)
15d,16d
15'd,16'd
(cis-endo)
(trans-exo)
Scheme 9.

S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
9711
OTBS
Ph
H6a
O
H7
N
OH
O
Ph
CHO
R
a, b,c
H4
N
H4a
+
O
CO2Me
H12a
Ph
R
Ph
O
H12b
H11
H10
Ph
Ph
H10b
19
CO2Me
Ph
Ph
R
25
O
O
22
O
N
e
d
Scheme 13.
Ph
Ph
20
21
Table 11
Second cycloaddition with methyl acrylate
Scheme 10. (a) LDA (1.2 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, 93%; (d) cinnamyl
bromide (2.0 equiv), K2CO3 (2.0 equiv), acetone, reflux, 3 h, 95%; (e) RNH2 (2.0 equiv),
TiCl4 (2.0 equiv), Et3N (8.8 equiv), 0 ꢀC, rt, overnight; 21a (R¼Ms): 72%, 21b (R¼Ts):
71%.
Entry
Diene
Solvent
Temp (ꢀC)
Time (h)
Adduct
Yielda (%)
1
2
23a
23b
Toluene
Benzene
110
80
9
16
25a
25b
59
54
a
Isolated yield.
Ph
H4
N
Merck Co. Ltd). PTLC was performed on Wakogel B5F. All reactions
were performed under argon.
H4a
Ph
R
R
N
O
O
Ph
Ph
H10b
H4a
N
R
Ph
H4
H10b
H6a
N
R
Ph
H7
H12a
21
22
H10
O
H11
Ph
O
Scheme 11.
H12b
Ph
MeO2C
Me
O
O
22
25
Table 9
Intramolecular aza DA reaction
Figure 1.
Entry
R
Solvent
Temp (ꢀC)
Time (h)
Adduct
Yielda (%)
1
2
MeSO2
p-TolSO2
Xylene
Toluene
140
110
3
8
22a
22b
57
60
H2
H2
Y
N
Y
N
H3
H3'
H3'
H3
R
R
a
Isolated yield.
Ph
Ph
Ph
Ph
H4
H4
H5
H5
exo-isomer
endo-isomer
(H2-H4 cis)
Ph
H7
Ph
H6a
(H2-H4 trans)
H4
H4a
N
R
O
H12a
N
R
O
E
E
H3
NOE
H5
XEt
Toluene
110 °C
H12b
E
H10
Ph
Ph
H3'
H10b
H2
Ph
H4
Ph
R
N
H2
H5
R
N
E
H4
H3'
22
23
NOE
XEt
E = CO2Me
H3
Ph
H6a
H7
Figure 2.
N
R
O
H12b
E
H10
Ph
Table 12
Vicinal coupling constants
E
Diene
R
XEt
J (Hz)
24
2–3
2–30
3–4
30–4
4–5
Scheme 12.
3a (endo)
3a (exo)
3b (endo)
3c (endo)
3d (endo)
3d (exo)
4a (endo)
4c (endo)
4d (endo)
4d (exo)
Ms
Ms
Bsa
Ts
Bz
Bz
Ms
Ts
OEt
OEt
OEt
OEt
OEt
OEt
SEt
SEt
SEt
SEt
3.5
2.4
3.7
3.6
7.0
1.6
4.2
4.0
8.0
4.0
4.8
2.4
5.5
5.3
3.4
1.6
7.0
7.1
5.7
1.1
4.5
12.6
6.5
6.3
7.0
11.2
6.0
7.0
6.5
11.6
8.3
6.6
7.8
7.9
7.5
7.0
7.4
7.5
10.0
7.3
3.7
1.5
3.6
3.6
3.6
3.5
3.7
3.4
3.8
3.5
Table 10
Second cycloaddition with DMAD
Entry
Diene
R
Time (h)
Adduct
Yielda (%)
1
2
23a
23b
MeSO2
p-TolSO2
11
16
24a
24b
62
57
Bz
Bz
a
a
Isolated yield.
Benzenesulfonyl.

9712
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
and brine, dried over MgSO4, and concentrated in vacuo. Re-
crystallization from CH2Cl2/hexane (1:2, v/v) yielded N-(3-phenyl-
1- -styryl-2-propenylidene)-4-p-toluenesulfonamide (2c) (2.53 g,
65%) as yellow needles; mp 184–185 ꢀC; IR (KBr): 1632, 1512, 1340,
H7
H7
H7
H9
Y
Y
H8
H8
H8
R
R
R
N
N
N
H9a
H9b
b
H8
Ph
H9a
H9a
H9b
H8'
Ph
O
Ph
H9
H4
Ph
H4
Ph
H9 H9b H4
Ph
1282, 1146, 1092 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 2.42 (s, 3H, Ts),
7.26–7.59 (m, 16H, Ar, olefin), 7.93 (d, J¼8.2 Hz, 2H, Ar); 13C NMR
O
O
H3a
H3a
O
H3a
O
N
N
Ph
N
(126 MHz, CDCl3)
d 21.5 (CH3), 123.3 (C), 127.1 (3CH), 128.5 (4CH),
O
Ph
Ph
129.0 (4CH), 129.4 (3CH), 130.7 (2CH), 134.7 (C), 138.9 (C), 143.3 (C),
144.2 (2CH), 172.6 (C). LRMS-EI m/z (%): 387 (Mþ, 1), 232 (MþꢁTs,
100). Anal. Calcd for C24H21NO2S: C, 74.39; H, 5.46; N, 3.61. Found:
C, 74.53; H, 5.63; N, 3.60.
13 (R = RSO2)
(endo)
15d,16d (R = Bz)
(cis-endo)
15'd,16'd (R = Bz)
(trans-exo)
Figure 3.
4.3. Preparation of cross-conjugated azatriene 2d: method B
(Table 1, entry 4)
Table 13
Vicinal coupling constants
A solution of 1 (234 mg, 1.0 mmol) in THF (10 mL) was cooled to
–78 ꢀC and lithium bis(trimethylsilyl)amide (2.0 mL, 1.0 M solution
in THF, 2.0 mmol) was added dropwise. The reaction mixture was
gradually warmed to room temperature with stirring for 5 h and
then cooled to ꢁ78 ꢀC again. After the addition of benzoyl chloride
(0.348 mL, 3.0 mmol), the reaction mixture was warmed to room
temperature with stirring for 1 h, after which the reaction was
quenched with 10% aqueous K2CO3 and the mixture was extracted
with EtOAc (10 mLꢂ2). The combined extracts were washed with
10% aqueous K2CO3 and brine, dried over Na2SO4, and concentrated
in vacuo. Purification by flash chromatography [SiO2: EtOAc/hexane
(1:9, v/v)] followed by recrystallization from CH2Cl2/Et2O (1:4, v/v)
Bis-adduct
R
Y
J (Hz)
9–9a
9a–9b
9b–3a
3a–4
4–5
13b
13c
15 (endo)
150 (exo)
16 (endo)
160 (exo)
Bs
Ts
Bz
Bz
Bz
Bz
d
11.6
11.6
12.3
11.8
12.6
12.2
2.0
2.0
4.4
0
2.5
0
8.3
8.3
8.5
8.4
8.8
8.0
6.7
6.5
8.9
6.9
4.6
7.5
3.2
3.2
2.2
0
0
0
d
OEt
OEt
SEt
SEt
yielded N-(3-phenyl-1-
(155 mg, 46%) as pale yellow crystals; mp 162–163 ꢀC; IR (KBr):
1643, 1581 cmꢁ1; 1H NMR (600 MHz, DMSO-d6)
b-styryl-2-propenylidene)benzamide (2d)
d
7.18 (d, J¼16.1 Hz,
2H, olefin), 7.39–7.45 (m, 6H, Ar), 7.54 (t, J¼7.6 Hz, 2H, Ar), 7.65 (t,
J¼7.4 Hz, 1H, Ar), 7.70–7.71 (m, 4H, Ar), 7.75 (d, J¼16.1 Hz, 2H,
olefin), 7.92 (d, J¼7.6 Hz, 2H, Ar); 13C NMR (151 MHz, DMSO-d6)
d
122.2 (2CH), 128.1 (4CH), 128.86 (2CH), 128.91 (2CH), 128.93
(4CH), 130.0 (2CH), 133.2 (CH), 133.3 (C), 135.0 (2C), 140.6 (2CH),
161.1 (C), 179.6 (C). Anal. Calcd for C24H19NO: C, 85.43; H, 5.68; N,
4.15. Found: C, 85.22; H, 5.71; N, 4.21.
4.4. Typical procedure for the initial [4D2] cycloaddition
reaction of cross-conjugated azatriene 2 with ethyl vinyl
ether under thermal conditions (Table 2, entry 3)
A mixture of 2c (388 mg, 1.0 mmol) and ethyl vinyl ether
(1.0 mL, 10 mmol) in toluene (30 mL) was heated at 110 ꢀC for 15 h,
additional ethyl vinyl ether (1.0 mL, 10 mmol) being added every
2 h during that time. After being cooled to room temperature, the
reaction mixture was concentrated in vacuo. Purification of the
residue by flash chromatography [SiO2: EtOAc/hexane (1:9, v/v)]
yielded 2-ethoxy-4-phenyl-6-
tetrahydropyridine (3c (endo), H2–H4 cis) (395 mg, 86%) as a yel-
low oil; IR (neat): 1354, 1166 cmꢁ1; 1H NMR (300 MHz, CDCl3)
1.18
(t, J¼7.1 Hz, 3H, OCH2CH3), 1.91 (ddd, J¼3.6, 6.3, 14.0 Hz, 1H, H-3),
2.09 (ddd, J¼5.3, 7.9, 14.0 Hz, 1H, H-30), 2.46 (s, 3H, Ts), 2.65 (ddd,
J¼3.6, 6.3, 7.9 Hz, 1H, H-4), 3.60 (dq, J¼7.1, 9.6 Hz, 1H, OCH2CH3),
3.90 (dq, J¼7.1, 9.6 Hz, 1H, OCH2CH3), 5.54 (dd, J¼3.6, 5.3 Hz, 1H, H-
2), 5.96 (d, J¼3.6 Hz, 1H, H-5), 6.84 (s, 2H, H-7, H-8), 7.06–7.08 (m,
2H, Ar), 7.14–7.18 (m, 1H, Ar), 7.21–7.34 (m, 7H, Ar), 7.43–7.45 (m,
b-styryl-1-p-toluenesulfonyl-1,2,3,4-
d
Figure 4. ORTEP drawing of 160d.
4.2. Typical procedure for the preparation of cross-
conjugated azatriene 2: method A (Table 1, entry 3)
A mixture of 1,5-diphenyl-1,4-pentadien-3-one (1) (2.34 g,
10 mmol), Et3N (6.13 mL, 44 mmol), and p-toluenesulfonamide
(3.4 g, 20 mmol) in CH2Cl2 (50 mL) was cooled to 0 ꢀC, and titanium
tetrachloride (10 mL, 1.0 M solution in CH2Cl2, 10 mmol) was added
dropwise. The reaction mixture was warmed to room temperature
with stirring for 7 h, after which the reaction was quenched with
saturated aqueous NaHCO3 and the mixture was extracted with
CH2Cl2 (30 mLꢂ2). The combined extracts were washed with water
2H, Ar), 7.72 (d, J¼8.3 Hz, 2H, Ar); 13C NMR (126 MHz, CDCl3)
d 14.9
(CH3), 21.6 (CH3), 37.0 (CH), 38.0 (CH2), 63.4 (CH2), 84.4 (CH), 125.3
(CH), 126.5 (CH), 126.8 (2CH), 127.3 (CH), 127.5 (2CH), 127.7 (CH),
128.0 (2CH),128.3 (2CH),128.6 (2CH),129.3 (CH), 129.7 (2CH), 135.0
(C), 136.7 (C), 136.9 (C), 143.9 (C), 144.4 (C). LRMS-EI m/z (%): 459
(Mþ, 2), 304 (13), 258 (61), 256 (100). HRMS-EI m/z [M]þ calcd for
C28H29O3NS: 459.1868, found: 459.1860.

S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
9713
4.5. Typical procedure for the initial [4D2] cycloaddition
reaction of cross-conjugated azatriene 2d with ethyl vinyl
ether promoted by TMSOTf (Table 2, entry 8)
cooled to ꢁ60 ꢀC. Trimethylsilyltrifluoromethanesulfonate (1.0 M
solution in CH2Cl2, 0.1 mL, 0.1 mmol) was added dropwise to the
mixture at a rate of 0.6 mL/h by syringe pump. After the addition,
the reaction mixture was stirred at the same temperature for
50 min and then diluted with MeOH and water and extracted with
CH2Cl2 (10 mLꢂ2). The combined extracts 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)]
A mixture of 2d (675 mg, 2.0 mmol) and ethyl vinyl ether
(0.57 mL, 6.0 mmol) in CH2Cl2 (30 mL) was cooled to ꢁ60 ꢀC. Tri-
methylsilyltrifluoromethanesulfonate (1.0 M solution in CH2Cl2,
0.5 mL, 0.5 mmol) was added dropwise to the mixture at a rate of
0.5 mL/h by syringe pump with stirring. After the addition was
completed, the reaction mixture was diluted with MeOH and water,
and then extracted with CH2Cl2 (10 mLꢂ2). The combined extracts
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)] followed by recrystallization from CH2Cl2/
yielded (2-ethylthio-4-phenyl-6-b-styryl-3,4-dihydro-2H-pyridin-
1-yl)phenylmethanones (4d (endo) and 4d (exo)) as a mixture
(143 mg, 84%). Further purification performed by PTLC [SiO2:
EtOAc/hexane (1:9, v/v)] followed by recrystallization from CH2Cl2/
Et2O (1:4, v/v) yielded pure 4d (endo) and 4d (exo), respectively.
Compound 4d (endo): colorless crystals; mp 150–151 ꢀC; IR (KBr):
Et2O (1:4, v/v) yielded (2-ethoxy-4-phenyl-6-
b
-styryl-3,4-dihydro-
1635, 1350, 694 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
1.38 (t, J¼7.4 Hz,
2H-pyridin-1-yl)phenylmethanone (3d (endo), H2–H4 cis) (702 mg,
86%) as colorless crystals; mp 133–134 ꢀC; IR (KBr): 1635,1358,1065,
3H, SCH2CH3), 1.90 (ddd, J¼5.7, 10.0, 13.7 Hz, 1H, H-30), 2.76 (dq,
J¼7.4, 12.9 Hz, 1H, SCH2CH3), 2.99–3.07 (m, 2H, H-3, SCH2CH3), 3.60
(ddd, J¼3.8, 6.5, 10.0 Hz, 1H, H-4), 6.16 (d, J¼3.8 Hz, 1H, H-5), 6.26
(dd, J¼5.7, 8.0 Hz, 1H, H-2), 6.30 (d, J¼16.0 Hz, 1H, H-8), 6.39 (d,
J¼16.0 Hz, 1H, H-7), 7.10–7.11 (m, 2H, Ar), 7.15–7.31 (m, 7H, Ar),
7.34–7.40 (m, 4H, Ar), 7.54–7.55 (m, 2H, Ar); 13C NMR (126 MHz,
1026, 694 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
1.19 (d, J¼7.0 Hz, 1H,
OCH2CH3), 2.13 (ddd, J¼3.4, 7.5, 13.9 Hz, 1H, H-30), 2.75 (ddd, J¼7.0,
7.0, 13.9 Hz, 1H, H-3), 3.62 (ddd, J¼3.6, 7.0, 7.5 Hz, 1H, H-4), 3.78 (m,
2H, OCH2CH3), 6.01 (d, J¼3.6 Hz,1H, H-5), 6.11 (br s,1H, H-2), 6.28 (d,
J¼16.0 Hz,1H, H-8), 6.41 (d, J¼16.0 Hz,1H, H-7), 7.11 (d, J¼7.4 Hz, 2H,
Ar), 7.14–7.39 (m,11H, Ar), 7.58–7.61 (m, 2H, Ar); 13C NMR (126 MHz,
CDCl3)
d 15.1 (CH3), 26.2 (CH2), 39.9 (CH), 43.2 (CH2), 56.1 (CH),
125.7 (CH), 126.3 (2CH), 126.6 (CH), 126.8 (CH), 127.4 (2CH), 127.6
(CH), 127.7 (2CH), 127.9 (2CH), 128.3 (2CH), 128.7 (2CH), 129.7 (CH),
130.6 (CH), 136.3 (C), 136.8 (C), 138.9 (C), 143.0 (C), 169.7 (C). HRMS-
ESI m/z [MþNa]þ calcd for C28H27NNaOS: 448.1706, found:
448.1702. Anal. Calcd for C28H27NOS: C, 79.02; H, 6.39; N, 3.29.
Found: C, 79.26; H, 6.52; N, 3.27. Compound 4d (exo): colorless
CDCl3) d 15.1 (CH3), 38.7 (CH), 40.6 (CH2), 64.0 (CH2), 81.1 (CH),125.0
(CH), 126.1 (CH), 126.3 (2CH), 126.6 (CH), 127.5 (CH), 127.6 (2CH),
128.1 (4CH), 128.4 (2CH), 128.5 (2CH), 128.8 (CH), 130.8 (CH), 136.6
(C), 136.8 (C), 137.2 (C), 144.2 (C), 170.5 (C). HRMS-ESI m/z [MþNa]þ
calcd for C28H27NNaO2: 432.1934, found: 432.1954. Anal. Calcd for
C28H27NO2:C, 82.12;H, 6.65;N, 3.42. Found:C, 82.20;H, 6.94;N, 3.40.
crystals; mp 110–111 ꢀC; IR (KBr): 1635, 1350, 694 cmꢁ1
(500 MHz, CDCl3)
;
1H NMR
d
1.43 (t, J¼7.5 Hz, 3H, SCH2CH3), 2.35 (ddd, J¼4.0,
4.6. Typical procedure for the initial [4D2] cycloaddition
reaction of cross-conjugated azatriene 2 with ethyl vinyl
sulfide under thermal conditions (Table 3, entry 2)
11.6, 13.9 Hz, 1H, H-3), 2.47 (ddd, J¼1.1, 7.3, 13.9 Hz, 1H, H-30), 2.83
(dq, J¼7.5, 12.8 Hz, 1H, SCH2CH3), 2.99 (dq, J¼7.5, 12.8 Hz, 1H,
SCH2CH3), 3.96 (ddd, J¼3.5, 7.3, 11.6 Hz, 1H, H-4), 5.67 (d, J¼3.5 Hz,
1H, H-5), 6.08 (d, J¼15.7 Hz, 1H, H-8), 6.23 (br s, 1H, H-2), 6.38 (d,
J¼15.7 Hz, 1H, H-7), 7.00 (d, J¼7.1 Hz, 2H, Ar), 7.12–7.19 (m, 3H, Ar),
Ethyl vinyl sulfide (0.5 mL, 5.0 mmol) and 4 Å MS (1.0 g,
100 wt %) were added to a solution of 2c (1.0 g, 2.6 mmol) in tolu-
ene (30 mL). The reaction mixture was heated at 110 ꢀC for 37 h in
a sealed tube, during which time additional ethyl vinyl sulfide
(0.1 mL, 1.0 mmol) was added every 2 h. After being cooled to room
temperature, the reaction mixture was concentrated in vacuo. Pu-
rification of the residue by flash chromatography [SiO2: EtOAc/
hexane (1:9, v/v)] followed by recrystallization from CH2Cl2/Et2O
7.31–7.36 (m, 6H, Ar), 7.40–7.43 (m, 2H, Ar), 7.67–7.68 (m, 2H, Ar); 13
C
NMR (126 MHz, CDCl3) d 15.3 (CH3), 25.6 (CH2), 39.1 (CH2), 39.2 (CH),
59.4 (CH),117.8 (CH),126.1 (2CH),127.0 (CH),127.3 (CH),127.47 (CH),
127.54 (2CH), 128.1 (2CH), 128.2 (2CH), 128.3 (2CH), 128.8 (CH),
128.9 (2CH),130.9 (CH),136.1 (C),136.5 (C),136.8 (C),143.5 (C),170.2
(C). HRMS-ESI m/z [MþNa]þ calcd for C28H27NNaOS: 448.1706,
found: 448.1706. Anal. Calcd for C28H27NOS: C, 79.02; H, 6.39;
N, 3.29. Found: C, 79.12; H, 6.60; N, 3.24.
(1:4, v/v) yielded 2-ethylthio-4-phenyl-6-b-styryl-1-p-toluene-
sulfonyl-1,2,3,4-tetrahydropyridine (4c (endo), H2–H4 cis) (635 mg,
51%) as colorless crystals; mp 157–158 ꢀC; IR (KBr): 2924, 1358,
4.8. Typical procedure for the initial [4D2] cycloaddition
reaction of cross-conjugated azatriene 2 with methyl
allenyl ether (Table 4, entry 3)
1165, 1088 cmꢁ1; 1H NMR (600 MHz, CDCl3)
d
1.35 (t, J¼7.5 Hz, 3H,
SCH2CH3), 1.69 (ddd, J¼4.5, 7.0, 13.6 Hz, 1H, H-3), 2.38 (ddd, J¼7.1,
7.5, 13.6 Hz, 1H, H-30), 2.42 (ddd, J¼3.4, 7.0, 7.5 Hz, 1H, H-4), 2.47 (s,
3H, Ts), 2.72 (dq, J¼7.5, 13.4 Hz, 1H, SCH2CH3), 2.93 (dq, J¼7.5,
13.4 Hz, 1H, SCH2CH3), 5.57 (dd, J¼4.5, 7.1 Hz, 1H, H-2), 6.11 (d,
J¼3.4 Hz, 1H, H-5), 6.86 (d, J¼16.1 Hz, 1H, H-8), 6.91 (d, J¼16.1 Hz,
1H, H-7), 6.99 (d, J¼7.2 Hz, 2H, Ar), 7.17–7.20 (m, 1H, Ar), 7.23–7.26
(m, 3H, Ar), 7.32–7.34 (m, 4H, Ar), 7.47 (d, J¼7.2 Hz, 2H, Ar), 7.76 (d,
A mixture of 2c (194 mg, 0.5 mmol) and methyl allenyl ether13
(350 mg, 5.0 mmol) was heated in toluene (15 mL) at 110 ꢀC for
20 h; additional methyl allenyl ether (70 mg, 1.0 mmol) being
added every 2 h during this time. After being cooled, the reaction
mixture was concentrated in vacuo. Purification of the residue by
flash chromatography [SiO2: EtOAc/hexane (1:9, v/v)] followed by
recrystallization from CH2Cl2/hexane (1:9, v/v) yielded 2-methoxy-
J¼8.2 Hz, 2H, Ar); 13C NMR (151 MHz, CDCl3)
d 14.6 (CH3), 21.6
(CH3), 26.2 (CH2), 37.4 (CH), 39.7 (CH2), 59.6 (CH), 126.5 (CH), 126.7
(CH), 126.8 (2CH), 127.2 (CH), 127.6 (2CH), 127.7 (2CH), 127.8 (CH),
128.5 (2CH), 128.6 (2CH), 129.8 (2CH), 129.9 (CH), 136.3 (C), 136.5
(C), 136.8 (C), 143.6 (C), 144.1 (C). HRMS-ESI m/z [MþH]þ calcd for
3-methylene-4-phenyl-6-
rahydropyridine (5c) (64 mg, 28%) as colorless crystals; mp
142–144 ꢀC; IR (KBr): 1356, 1168 cmꢁ1 1H NMR (500 MHz, CDCl3)
2.87 (s, 3H, Ts), 3.43 (s, 3H, OMe), 4.20 (br s, 1H, H-4), 5.29 (s, 1H,
b-styryl-1-p-toluenesulfonyl-1,2,3,4-tet-
;
C
28H30NO2S2: 476.1712, found: 476.1710.
d
H-10), 5.38 (s, 1H, H-9), 5.52 (s, 1H, H-2), 5.98 (d, J¼2.8 Hz, 1H, H-5),
6.95 (d, J¼15.9 Hz, 1H, H-8), 6.83 (d, J¼15.9 Hz, 1H, H-7), 7.16–7.36
(m, 12H, Ar), 7.43 (d, J¼7.9 Hz, 2H, Ar); 13C NMR (126 MHz, CDCl3)
4.7. Typical procedure for the first [4D2] cycloaddition
reaction of cross-conjugated azatriene 2d with ethyl
vinyl sulfide promoted by TMSOTf (Table 3, entry 5)
d
21.6 (CH3), 44.5 (CH), 55.7 (CH3), 89.5 (CH), 117.3 (CH2), 122.8 (CH),
126.7 (CH), 126.8 (3CH), 127.8 (CH), 128.0 (2CH), 128.3 (2CH), 128.5
(2CH), 128.6 (2CH), 129.2 (2CH), 130.0 (CH), 134.1 (C), 135.5 (C),
136.8 (C), 143.4 (CH), 143.8 (C), 144.2 (C). LRMS-EI m/z (%) 457 (Mþ,
Ethyl vinyl sulfide (0.081 mL, 0.8 mmol) was added to a solution
of 2d (135 mg, 0.4 mmol) in CH2Cl2 (10 mL) and the mixture was

9714
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
14), 426 (5). HRMS-EI m/z [M]þ calcd for C28H27NO3S: 457.1712,
found: 457.1710.
at 110 ꢀC for 21 h and then concentrated in vacuo. Purification of
the residue by flash chromatography [SiO2: EtOAc/hexane (1:2, v/
v)] followed by recrystallization from CH2Cl2/hexane (1:9, v/v)
yielded dimethyl-4,7-diphenyl-1-p-toluenesulfonyl-1,4,4a,8a-tet-
rahydroquinoline-5,6-dicarboxylate (12c) (60 mg, 31%) as color-
less crystals; mp 185–186 ꢀC; IR (KBr): 1728, 1257, 1358,
4.9. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 3 with TCNE (Table 5, entry 3)
TCNE (56 mg, 0.44 mmol) was added to a solution of 3c (endo)
(101 mg, 0.22 mmol) in CH2Cl2 (5 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 (1:2, v/v)] followed by recrystallization from CH2Cl2/
diethyl ether (1:4, v/v) yielded 2-ethoxy-4,7-diphenyl-1-p-tolue-
nesulfonyl-1,2,3,4,4a,7-hexahydroquinoline-5,5,6,6-tetracarboni-
trile (6c) (123 mg, 95%) as colorless crystals; mp 198–199 ꢀC; IR
1165 cmꢁ1 1H NMR (600 MHz, CDCl3)
; d 2.49 (s, 3H, Ts), 2.69 (dd,
J¼5.3, 10.8 Hz, 1H, H-4a), 2.86 (s, 3H, COOMe), 3.44 (ddd, J¼2.0,
2.0, 10.8 Hz, 1H, H-4), 3.52 (s, 3H, COOMe), 4.51 (dd, J¼5.3, 5.3 Hz,
1H, H-8a), 4.93 (dd, J¼2.0, 7.9 Hz, 1H, H-3), 6.23 (d, J¼5.3 Hz, 1H,
H-8), 6.73 (dd, J¼2.0, 7.9 Hz, 1H, H-2), 6.83 (d, J¼6.1 Hz, 2H, Ar),
7.17–7.29 (m, 6H, Ar), 7.37 (t, J¼7.6 Hz, 2H, Ar), 7.42 (d, J¼8.2 Hz,
2H, Ar), 7.76 (d, J¼8.2 Hz, 2H, Ar); 13C NMR (151 MHz, CDCl3)
d
21.6 (CH3), 39.1 (CH), 44.7 (CH), 50.0 (CH), 51.4 (CH3), 52.1 (CH3),
(KBr): 1342, 1165 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
1.23 (t,
115.1 (CH), 125.2 (CH), 125.5 (CH), 127.3 (CH), 127.4 (3CH), 128.1
(2CH), 128.2 (4CH), 128.9 (2CH), 129.9 (2CH), 130.2 (C), 133.9 (C),
134.6 (C), 136.5 (C), 140.1 (C), 140.2 (C), 144.5 (C), 166.80 (C),
166.82 (C). HRMS-ESI m/z [MþNa]þ calcd for C32H29NNaO6S:
578.1608, found: 578.1630.
J¼7.0 Hz, 3H, OCH2CH3), 2.28 (ddd, J¼1.8, 6.1, 15.0 Hz, 1H, H-30),
2.51 (s, 3H, Ts), 2.56 (ddd, J¼4.9, 9.2, 15.0 Hz, 1H, H-3), 3.28 (ddd,
J¼6.1, 9.2, 11.6 Hz, 1H, H-4), 3.44 (dq, J¼7.0, 9.2 Hz, 1H, OCH2CH3),
3.67 (dq, J¼7.0, 9.2 Hz, 1H, OCH2CH3), 3.80 (ddd, J¼2.1, 2.1, 11.6 Hz,
1H, H-4a), 4.38 (dd, J¼2.1, 3.6 Hz, 1H, H-7), 5.64 (dd, J¼1.8, 4.9 Hz,
1H, H-2), 6.38 (dd, J¼2.1, 3.6 Hz, 1H, H-8), 7.31–7.49 (m, 12H, Ar),
4.12. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 3 with N-phenylmaleimide
(Table 8, entry 3)
7.86 (ddd, J¼1.8,1.8, 8.6 Hz, 2H, Ar); 13C NMR (68 MHz, CDCl3)
d 14.8
(CH3), 21.7 (CH3), 36.7 (CH2), 39.7 (CH), 40.5 (C), 42.6 (CH), 44.5 (C),
46.8 (CH), 64.1 (CH2), 83.9 (CH), 108.4 (C), 109.7 (C), 110.1 (C), 111.3
(C), 112.9 (CH), 127.8 (3CH), 128.8 (2CH), 129.0 (2CH), 129.3 (2CH),
130.17 (2CH), 130.21 (CH), 130.6 (2CH), 131.7 (C), 132.5 (C), 135.8 (C),
138.2 (C), 145.3 (C). LRMS-FAB m/z (%): 610 (MþþNa, 29), 482 (17),
176 (100). HRMS-FAB m/z [MþNa]þ calcd for C34H29N5O3SNa:
610.1889, found: 610.1900.
A mixture of 3c (151 mg, 0.33 mmol) and N-phenylmaleimide
(114 mg, 0.66 mmol) in toluene (5 mL) was heated at 110 ꢀC for 18 h
and then concentrated in vacuo. Purification of the residue by flash
chromatography [SiO2: EtOAc/hexane (1:2, v/v)] followed by re-
crystallization from CH2Cl2/hexane (1:9, v/v) yielded 2,4,9-tri-
phenyl-6-p-toluenesulfonyl-3a,4,6,9,9a,9b-hexahydropyrrolo[3,4-f]
quinoline-1,3-dione (13c) (43 mg, 22%) as a colorless crystals; mp
4.10. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 3 with 4-phenyl-1,2,4-triazoline-
3,5-dione (Table 6, entry 3)
246–247 ꢀC; IR (KBr): 1713, 1381, 1350, 1173 cmꢁ1
(300 MHz, CDCl3)
;
1H NMR
d
2.28 (br dd, J¼1.9, 11.6 Hz, 1H, H-9), 2.40 (s, 3H,
Ts), 2.88 (dd, J¼2.0, 8.3 Hz, 1H, H-9b), 3.02 (dd, J¼6.5, 8.3 Hz, 1H,
H-3a), 3.30 (ddd, J¼1.5, 2.0, 11.6 Hz, 1H, H-9a), 3.92 (br dd, J¼3.2,
6.5 Hz, 1H, H-4), 5.06 (dd, J¼1.9, 8.0 Hz, 1H, H-8), 6.36 (dd, J¼1.5,
3.2 Hz, 1H, H-5), 6.81 (dd, J¼2.2, 8.0 Hz, 1H, H-7), 6.90 (dd, J¼2.1,
4-Phenyl-1,2,4-triazoline-3,5-dione (110 mg, 0.65 mmol) was
added to a solution of 3c (endo) (250 mg, 0.54 mmol) 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 (1:2, v/v)]
followed by recrystallization from CH2Cl2/hexane (1:6, v/v) yiel-
ded 7-ethoxy-2,4,9-triphenyl-6-p-toluenesulfonyl-4,6,7,8,9,9a-hexa-
hydro-2,3a,6,9b-tetraazacyclopenta[a]naphthalene-1,3-dione (9c)
(341 mg, 99%) as colorless crystals; mp 222–223 ꢀC; IR (KBr): 1720,
7.8 Hz, 2H, Ar), 7.20–7.50 (m, 15H, Ar), 7.68 (d, J¼8.3 Hz, 2H, Ar); 13
C
NMR (151 MHz, CDCl3)
d 21.6 (CH3), 33.1 (CH), 41.7 (CH), 42.0 (CH),
43.7 (CH), 48.6 (CH), 114.4 (CH), 125.2 (CH), 125.4 (CH), 125.8 (2CH),
127.3 (2CH), 127.7 (CH), 127.7 (CH), 127.9 (2CH), 128.1 (2CH), 128.3
(CH),129.0 (2CH),129.0 (4CH),130.0 (2CH),131.7 (C),133.3 (C),134.2
(C), 140.0 (C), 141.8 (C), 144.6 (C), 175.3 (C), 176.1 (C). HRMS-ESI m/z
[MþNa]þ calcd for C36H30N2NaO4S: 609.1818, found: 609.1789.
1350, 1165 cmꢁ1; 1H NMR (600 MHz, CDCl3)
d
1.40 (t, J¼7.0 Hz, 3H,
OCH2CH3), 2.39 (ddd, J¼2.6, 3.1, 15.2 Hz, 1H, H-80), 2.44 (s, 3H, Ts),
2.48 (m, 1H, H-8), 3.41 (ddd, J¼3.1, 11.0, 11.0 Hz, 1H, H-9), 3.82 (dq,
J¼7.0, 9.3 Hz, 1H, OCH2CH3), 3.99 (dq, J¼7.0, 9.3 Hz, 1H, OCH2CH3),
5.24 (dd, J¼2.0, 2.0 Hz,1H, H-4), 5.36 (ddd, J¼0.8, 2.0,11.0 Hz,1H, H-
9a), 5.71 (dd, J¼2.6, 3.2 Hz, 1H, H-7), 5.89 (dd, J¼0.8, 2.0 Hz, 1H, H-
5), 7.14–7.15 (m, 2H, Ar), 7.22–7.24 (m, 3H, Ar), 7.25–7.30 (m, 5H, Ar),
7.33–7.39 (m, 7H, Ar), 7.69–7.70 (m, 2H, Ar); 13C NMR (151 MHz,
4.13. Preparation of ketone 20
A solution of tert-butyldimethylsilylchloride (904 mg, 6.0 mmol)
in CH2Cl2 (20 mL) was added dropwise at 0 ꢀC to a solution 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). The reaction mixture was warmed to room temperature
with stirring for an additional 1 h and then diluted with saturated
aqueous NaHCO3 and extracted with CH2Cl2 (20 mLꢂ2). The com-
bined extracts were washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification of the residue by flash chroma-
tography [SiO2: EtOAc/hexane (1:9, v/v)] yielded 2-(tert-butyl-
dimethylsilanyloxy)benzaldehyde as a colorless oil (1.18 g, quant.).
n-Butyllithium (1.5 M solution in hexane, 2.4 mL, 3.6 mmol) was
added dropwise to a solution of diisopropylamine (0.63 mL,
3.6 mmol) in THF (40 mL) at ꢁ65 ꢀC, and the mixture was warmed
to room temperature and stirred for an additional 1 h. The solution
was cooled to ꢁ65 ꢀC before a solution of benzalacetone (526 mg,
3.6 mmol) in THF (15 mL) was added dropwise and the reaction
mixture was stirred for 1 h at the same temperature. A solution of
2-(tert-butyldimethylsilanyloxy)benzaldehyde (709 mg, 3.0 mmol)
CDCl3) d 15.1 (CH3), 21.6 (CH3), 35.2 (CH2), 44.4 (CH), 54.2 (CH), 61.4
(CH), 64.8 (CH2), 85.8 (CH), 110.0 (CH), 125.1 (2CH), 127.57 (2CH),
127.60 (2CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 128.6 (2CH), 128.72
(2CH), 128.73 (2CH), 128.8 (2CH), 129.8 (2CH), 131.0 (C), 131.8 (C),
135.7 (C), 138.5 (C), 141.4 (C), 144.5 (C), 148.5 (C), 155.0 (C). HRMS-
ESI m/z [MþNa]þ calcd for C36H34N4NaO5S: 657.2142, found:
657.2175. Anal. Calcd for C36H34N4O5S: C, 68.12; H, 5.40; N, 8.83.
Found: C, 67.76; H, 5.53; N, 8.77.
4.11. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 3 with dimethyl acetylene
dicarboxylate (Table 7, entry 3)
A mixture of 3c (162 mg, 0.35 mmol) and dimethyl acetylene
dicarboxylate (99 mg, 0.70 mmol) in toluene (5 mL) was heated

S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
9715
in THF (10 mL) was added dropwise to the mixture at ꢁ65 ꢀC and
the reaction mixture was stirred for an additional 10 min. The re-
action mixture was 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)] yielded 1-[2-(tert-butyldimethylsilanyl-
oxy)phenyl]-1-hydroxy-5-phenylpent-4-en-3-one as a colorless
oil (1.14 g, 99%).
hexane (1:9, v/v) yielded 4-methyl-N-(3-phenyl-1-{2-[2-(3-phenyl-
2-propenoxy)phenyl]vinyl}allylidene)benzenesulfonamide (21b)
(738 mg, 71%) as yellow needles; mp 156–157 ꢀC; IR (KBr): 1622,
1344, 1284, 1152 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 2.38 (s, 3H, Ts),
4.77 (d, J¼5.8 Hz, 2H, H-5, H-6), 6.34 (dt, J¼5.8, 15.9 Hz, 1H, H-7),
6.73 (d, J¼15.9 Hz, 1H, H8), 6.97 (d, J¼8.3 Hz, 1H, Ar), 7.01 (t,
J¼7.6 Hz, 1H, Ar), 7.11–7.43 (m, 13H, olefin, Ar), 7.50 (d, J¼7.3 Hz, 2H,
Ar), 7.63 (br s, 1H, olefin), 7.89–7.99 (m, 4H, olefin, Ar); 13C NMR
(126 MHz, CDCl3)
d 21.5 (CH3), 69.2 (CH2), 112.5 (CH), 121.2 (2CH),
Methane sulfonyl chloride (0.23 mL, 3.0 mmol) was added to
solution of 1-[2-(tert-butyldimethylsilanyloxy)phenyl]-1-hy-
123.6 (CH), 123.8 (CH), 124.1 (C), 126.6 (2CH), 127.0 (2CH), 128.0
(CH), 128.4 (2CH), 128.6 (2CH), 128.9 (2CH), 129.3 (2CH), 130.44
(2CH), 132.0 (CH), 133.3 (CH), 134.9 (C), 136.2 (C), 139.1 (C), 140.0
(CH), 143.1 (C), 144.0 (CH), 157.6 (C), 173.3 (C). LRMS-EI m/z (%): 519
(Mþ, 1), 455 (44), 363 (100), 91 (92). HRMS-ESI m/z [MþNa]þ calcd
for C33H29NNaO3S: 542.1760, found: 542.1771.
a
droxy-5-phenylpent-4-en-3-one (957 mg, 2.5 mmol) and Et3N
(0.84 mL, 6.0 mmol) in CH2Cl2 (25 mL) at 0 ꢀC. The reaction mixture
was warmed to room temperature with stirring overnight, diluted
with saturated aqueous NaHCO3, 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 (1:9,
v/v)] yielded 1-[2-(tert-butyldimethylsilanyloxy)phenyl]-5-phe-
nylpenta-1,4-dien-3-one as a yellow oil (838 mg, 93%).
4.15. Typical procedure for the intramolecular aza Diels–
Alder reaction (Table 9, entry 2)
A toluene (30 mL) solution of 21b (520 mg, 1.0 mmol) was
heated at 110 ꢀC for 8.0 h. After being cooled to room temperature,
the reaction mixture was concentrated in vacuo. Purification of the
residue by flash chromatography [SiO2: EtOAc/hexane (1:9, v/v)]
TBAF (1.0 M solution in THF, 1.0 mL, 1.0 mmol) was added to
solution of 1-[2-(tert-butyldimethylsilanyloxy)phenyl]-5-phe-
a
nylpent-1,4-dien-3-one (365 mg, 1.0 mmol) in THF (30 mL) at 0 ꢀC.
The reaction mixture was stirred for 10 min and then 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 (1:2, v/v)] followed by
recrystallization from CH2Cl2/hexane (1:9, v/v) yielded 1-(2-
hydroxyphenyl)-5-phenylpent-1,4-dien-3-one (19) (233 mg, 93%)
as yellow needles.
yielded 4-phenyl-2-
hydro-2H-chromeno[3,4-c]pyridine (22b) (312 mg, 60%) as an or-
ange oil; IR (neat): 1319, 1142 cmꢁ1 1H NMR (500 MHz, CDCl3)
b-styryl-3-p-toluenesulfonyl-3,4,4a,10b-tetra-
;
d
2.21 (dddd, J¼3.4,10.4,10.7,11.0 Hz,1H, H-4a), 2.37 (s, 3H, Ts), 2.60
(dd, J¼4.0, 11.0 Hz, 1H, H-10b), 3.81 (dd, J¼10.4, 10.4 Hz, 1H, H-50),
4.06 (dd, J¼3.4, 10.4 Hz, 1H, H-5), 4.72 (d, J¼10.7 Hz, 1H, H-4), 6.63
(d, J¼4.0 Hz, 1H, H-1), 6.74 (dd, J¼7.9, 7.9 Hz, 1H, Ar), 6.77 (d,
J¼15.9 Hz, 1H, H-12), 6.86 (d, J¼15.9 Hz, 1H, H-11), 6.92 (dd, J¼7.3,
K2CO3 (276 mg, 2.0 mmol) and cinnamyl bromide (0.30 mL,
2.0 mmol) were added to a solution of 19 (250 mg, 1.0 mmol) in
acetone (40 mL). The mixture was heated under reflux for 2 h. After
being cooled to room temperature, the reaction mixture was di-
luted with saturated aqueous NH4Cl and extracted with EtOAc
(20 mLꢂ2). The combined extracts 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)] followed
by recrystallization from CH2Cl2/hexane (1:9, v/v) yielded 1-phe-
nyl-5-[2-(3-phenyl-2-propenoxy)phenyl]penta-1,4-dien-3-one (20)
(273 mg, 94%) as yellow needles; mp 100–101 ꢀC; IR (KBr): 1652,
7.3 Hz, 1H, Ar), 7.09–7.38 (m, 14H, Ar), 7.62 (d, J¼8.2 Hz, 2H, Ar); 13
C
NMR (126 MHz, CDCl3) d 21.6 (CH3), 35.7 (CH), 48.5 (CH), 63.5 (CH),
67.6 (CH2), 116.8 (CH), 121.1 (CH), 122.3 (C), 125.8 (CH), 126.8 (2CH),
127.0 (3CH), 127.5 (CH), 127.5 (2CH), 127.9 (CH), 128.0 (CH), 128.1
(CH), 128.6 (2CH), 128.9 (2CH), 129.5 (2CH), 130.8 (C), 136.3 (C),
136.6 (C), 140.4 (C), 141.9 (C), 143.9 (C), 154.0 (C). LRMS-EI m/z (%):
519 (Mþ, 1), 455 (22), 360 (97), 91 (100). HRMS-ESI m/z [MþNa]þ
calcd for C33H29NNaO3S: 542.1760, found: 542.1759.
4.16. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 23 with dimethyl acetylene
dicarboxylate (Table 10, entry 2)
1588, 1572, 996, 688 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 4.79 (d,
J¼5.5 Hz, 2H, H-5, H-6), 6.47 (dt, J¼5.5, 15.9 Hz, 1H, H-7), 6.78 (d,
J¼15.9 Hz, 1H, H-8), 6.98 (d, J¼7.9 Hz, 1H, Ar), 7.01 (d, J¼7.9 Hz, 1H,
Ar), 7.08 (d, J¼16.2 Hz, 1H, H-2), 7.24 (d, J¼15.9 Hz, 1H, H-3),
7.24–7.36 (m, 7H, Ar), 7.42 (d, J¼7.3 Hz, 2H, Ar), 7.51 (d, J¼6.7 Hz,
2H, Ar), 7.62 (d, J¼7.3 Hz, 1H, Ar), 7.69 (d, J¼15.9 Hz, 1H, H-4), 8.12
A toluene (10 mL) solution of 22b (104 mg, 0.2 mmol) and di-
methyl acetylene dicarboxylate (0.049 mL, 0.4 mmol) was heated at
110 ꢀC for 16 h. After being cooled to room temperature, the re-
action mixture was concentrated in vacuo. Purification of the res-
idue by flash chromatography [SiO2: EtOAc/hexane (1:4, v/v)]
followed by recrystallization from CH2Cl2/hexane (1:5, v/v) yielded
dimethyl 7,10-diphenyl-8-p-toluenesulfonyl-6a,7,8,9,10,12b-hexahy-
dro-6H-chromeno[3,4-c]quinoline-11,12-carboxylate (24b) (75 mg,
57%) as colorless crystals; mp 230–232 ꢀC; IR (KBr): 1732, 1362,
(d, J¼16.2 Hz, 1H, H-1); 13C NMR (126 MHz, CDCl3)
d 69.0 (CH2),
112.6 (CH), 121.0 (CH), 123.9 (CH), 124.0 (C), 125.6 (CH), 126.1 (CH),
126.6 (2CH), 128.0 (CH), 128.3 (2CH), 128.6 (2CH), 128.8 (2CH),
129.3 (CH), 130.2 (CH), 131.6 (CH), 133.3 (CH), 134.8 (C), 136.2 (C),
138.8 (CH), 142.8 (CH), 157.7 (C), 189.5 (C). HRMS-ESI m/z [MþNa]þ
calcd for C26H22NaO2: 389.1512, found: 389.1513.
1166 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
2.11 (br dd, J¼3.1, 11.3 Hz,
1H, H-12b), 2.24 (s, 3H, Ts), 2.61 (dddd, J¼4.0, 10.1, 11.0, 11.3 Hz, 1H,
H-6a), 2.92 (ddd, J¼3.1, 6.7, 18.3 Hz, 1H, H-90), 3.02 (s, 3H, COOMe),
3.41 (dd, J¼10.7, 11.0 Hz, 1H, H-60), 3.69 (s, 3H, COOMe), 4.02 (dd,
J¼4.0, 10.7 Hz, 1H, H-6), 4.10 (dd, J¼1.2, 18.3 Hz, 1H, H-9), 4.18 (br d,
J¼6.7 Hz, 1H, H-10), 4.41 (d, J¼10.1 Hz, 1H, H-7), 6.69–6.76 (m, 4H,
Ar), 6.85 (dd, J¼7.3, 7.3 Hz, 1H, Ar), 6.95 (d, J¼8.2 Hz, 2H, Ar), 7.07
(dd, J¼6.7, 8.2 Hz, 1H, Ar), 7.24–7.43 (m, 6H, Ar), 7.51–7.56 (m, 4H,
4.14. Typical procedure for the preparation of cross-
conjugated azatriene 21
Titanium tetrachloride (1.0 M solution in CH2Cl2, 4.0 mL,
4.0 mmol) was added dropwise at 0 ꢀC to a solution of 20 (733 mg,
2.0 mmol), Et3N (2.45 mL, 17.6 mmol), and p-toluenesulfonamide
(685 mg, 4.0 mmol) in CH2Cl2 (40 mL). The mixture was warmed to
room temperature with stirring overnight, diluted with saturated
aqueous NaHCO3, and extracted with CH2Cl2 (40 mLꢂ2). The
combined extracts were washed with water and brine, dried over
MgSO4, and concentrated in vacuo. Recrystallization from CH2Cl2/
Ar); 13C NMR (100 MHz, CDCl3)
d 21.5 (CH3), 37.2 (CH), 37.6 (CH2),
39.0 (CH), 50.0 (CH), 51.6 (CH3), 52.3 (CH3), 65.7 (CH), 67.9 (CH2),
117.1 (CH),120.0 (C),121.0 (CH),126.3 (2CH),126.8 (2CH),127.2 (CH),
127.9 (CH), 127.9 (2CH), 128.1 (CH), 128.6 (2CH), 128.9 (2CH), 129.1
(C), 129.3 (CH), 129.4 (C), 129.7 (2CH), 135.5 (C), 137.6 (C), 138.7 (C),

9716
S. Kobayashi et al. / Tetrahedron 64 (2008) 9705–9716
141.0 (C), 141.4 (C), 143.8 (C), 155.1 (C), 166.3 (C), 167.0 (C). LRMS-EI
m/z (%): 661 (Mþ, 59), 595 (19), 506 (MþꢁTs, 94), 505 (MþꢁTs, H,
89), 474 (73), 117 (93), 91 (100). HRMS-EI m/z [M]þ calcd for
References and notes
1. (a) Hall, N. Science 1994, 266, 32; (b) Ho, T.-L. Tandem Organic Reactions; Wiley:
New York, NY, 1992; (for domino reactions); (c) Tietze, L. F.; Brasche, G.; Ger-
icke, K. M. Domino Reactions in Organic Synthesis; Wiley: Weinheim, 2006; (d)
Tietze, L. F. Chem. Rev. 1996, 96, 115; (e) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; (f) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996,
96, 137; (g) Winkler, J. D. Chem. Rev. 1996, 96, 167; (h) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. Rev. 1996, 96, 177; (i) Parsons, P. J.; Penkett, C. S.; Shell, A. J.
Chem. Rev. 1996, 96, 195 (for cascade processes); (j) Padwa, A.; Weingarten, M.
D. Chem. Rev. 1996, 96, 223; (k) Neuschu¨tz, K.; Velker, J.; Neier, R. Synthesis
1998, 227.
C
39H35NO7S: 661.2134, found: 661.2145.
4.17. Typical procedure for the second [4D2] cycloaddition
reaction of mono-adduct 23 with methyl acrylate (Table 11,
entry 2)
Methyl acrylate (0.14 mL, 1.54 mmol) was added to a benzene
(10 mL) solution of 22b (40 mg, 0.077 mmol) and heated at 80 ꢀC
for 16 h. After being cooled to room temperature, the reaction
mixture was concentrated in vacuo. Purification of the residue by
PTLC [SiO2: EtOAc/hexane (1:2, v/v)] followed by recrystallization
from CH2Cl2/hexane (1:5, v/v) yielded 7,10-diphenyl-8-p-toluene-
sulfonyl-6a,7,8,10,11,12,12a,12b-octahydro-6H-5-oxa-8-aza-benzo[c]-
phenanthrene-11-carboxylic acid methyl ester (25b) (31 mg, 54%) as
colorless crystals; mp 99–101 ꢀC; IR (KBr): 1738, 1494, 1338,
2. For DT(H)DA of carbotrienes: (a) Blomquist, A. T.; Verdol, J. A. J. Am. Chem.
Soc. 1955, 77, 81; (b) Bailey, W. J.; Economy, J. J. Am. Chem. Soc. 1955, 77, 1133;
(c) Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983, 239; (d) Tsuge, O.;
Kanemasa, S.; Wada, E.; Sakoh, H. J. Synth. Org. Chem. Jpn. 1986, 44, 756 and
references cited therein; (e) Tsuge, O.; Hatta, T.; Yakata, K.; Maeda, H. Chem.
Lett. 1994, 1833; (f) Hosomi, A.; Masunari, T.; Tominaga, Y.; Yanagi, T.; Hojo,
M. Tetrahedron Lett. 1990, 31, 6201; (g) Adam, W.; Deufel, T.; Finzel, R.;
Griesbeck, A. G.; Hirt, J. J. Org. Chem. 1992, 57, 3991; (h) Kwon, O.; Park, S. B.;
Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 13402; (i) Payne, A. D.; Willis,
A. C.; Sherburn, M. S. J. Am. Chem. Soc. 2005, 127, 12188; (j) Brummond, K. M.;
You, L. Tetrahedron 2005, 61, 6180; (k) Mitasev, B.; Yan, B.; Brummond, K. M.
Heterocycles 2006, 70, 367; (l) Bradford, T. A.; Payne, A. D.; Willis, A. C.;
Paddon-Row, M. N.; Sherburn, M. S. Org. Lett. 2007, 9, 4861; (m) Miller, N. A.;
Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. Angew. Chem., Int. Ed. 2007,
46, 937.
1164 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
1.54 (ddd, J¼9.5, 13.1,
13.1 Hz, 1H, H-120), 2.29 (dddd, J¼3.7, 10.7, 10.7, 11.3 Hz, 1H, H-6a),
2.38 (s, 3H, Ts), 2.47 (ddd, J¼4.9, 9.2, 9.5 Hz,1H, H-11), 2.51–2.55 (m,
2H, H-12, H-12a), 2.59 (dd, J¼10.7, 10.7 Hz, 1H, H-12b), 3.47 (s, 3H,
COOMe), 3.54 (dd, J¼3.7, 9.2 Hz, 1H, H-10), 3.72 (dd, J¼10.7, 10.7 Hz,
1H, H-60), 4.09 (dd, J¼3.7, 10.7 Hz, 1H, H-6), 4.91 (d, J¼11.3 Hz, 1H,
H-7), 6.09 (dd, J¼1.2, 3.7 Hz, 1H, H-9), 6.85 (d, J¼7.9 Hz, 1H, Ar), 6.90
(dd, J¼7.6, 7.6 Hz, 1H, Ar), 7.14 (dd, J¼7.9, 7.9 Hz, 1H, Ar), 7.19–7.37
(m, 13H, Ar), 7.52 (d, J¼7.9 Hz, 2H, Ar); 13C NMR (126 MHz, CDCl3)
3. (a) Woo, S.; Squire, N.; Fallis, A. G. Org. Lett. 1999, 1, 573; (b) Woo, S.; Legoupy, S.;
Parra, S.; Fallis, A. G. Org. Lett. 1999, 1, 1013; (c) Souweha, M. S.; Arab, A.; Ap-
Simon, M.; Fallis, A. G. Org. Lett. 2007, 9, 615; (d) Souweha, M. S.; Enright, G. D.;
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Synthesis; Academic: San Diego, CA, 1987; (b) Boger, D. L. In Comprehensive
Organic Synthesis; Paquette, L. A., Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, p 451; (c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1; (d) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131; (e) Buonora, P.; Olsen,
J.-C.; Oh, T. Tetrahedron 2001, 57, 6099; (f) Behforouz, M.; Ahmadian, M. Tet-
rahedron 2000, 56, 5259; (g) Jayakumar, S.; Ishar, M. P. S.; Mhajan, M. P. Tet-
rahedron 2002, 58, 379; (h) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39,
3558 and references cited therein. For recent reports on HDA of 1-azadienes,
see: (i) Berry, C. R.; Hsung, R. P. Tetrahedron 2004, 60, 7629; (j) Clark, R. C.;
Pfeiffer, S. S.; He, M.; Strube, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418;
d
21.5 (CH3), 31.6 (CH2), 37.9 (CH), 43.7 (CH), 44.0 (CH), 45.3 (CH),
48.9 (CH), 51.7 (CH3), 63.0 (CH), 67.4 (CH2), 117.7 (CH), 120.9 (CH),
123.5 (C), 125.5 (CH), 127.0 (CH), 127.2 (2CH), 127.7 (2CH), 128.0
(CH), 128.1 (2CH), 128.2 (CH), 128.6 (2CH), 128.7 (2CH), 129.0 (CH),
129.4 (2CH), 137.8 (C), 138.1 (C), 141.2 (C), 142.8 (C), 143.8 (C), 155.7
(C), 175.5 (C). LRMS-EI m/z (%): 605 (Mþ, 9), 541 (30), 540 (18), 450
(100), 221 (43), 117 (51), 91 (81). HRMS-EI m/z [M]þ calcd for
´
´
(k) Boger, D. L. J. Am. Chem. Soc. 2006, 128, 2587; (l) Esquivias, J.; Gomez Arrayas,
R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480.
5. For DTHDA of thiatrienes, see: Motoki, S.; Matsuo, Y.; Terauchi, Y. Bull. Chem.
Soc. Jpn. 1990, 63, 284.
C
37H35NO5S: 605.2236, found: 605.2220.
6. Saito, T.; Kimura, H.; Sakamaki, K.; Karakasa, T.; Moriyama, S. Chem. Commun.
1996, 811.
7. (a) Tsuge, O.; Hatta, T.; Yoshitomi, H.; Kurosaka, K.; Fujiwara, T.; Maeda, H.;
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Yokohari, T.; Tsuge, A. Heterocycles 1999, 50, 661.
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4385.
4.18. X-ray data for compound 160d
Crystallographic data (excluding structure factors) for 160d have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 679645. 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).
9. Saito, T.; Kimura, H.; Chonan, T.; Soda, T.; Karakasa, T. Chem. Commun. 1997,
1013.
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2002, 43, 2627.
11. Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999, 40, 7215.
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W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713.
13. Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1985, 50, 5308.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.07.102.