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.tetlet.2008.05.054

The initial inverse electron-demand hetero-Diels-Alder reaction of N-sulfonyldivinylmethanimine with electron-rich dienophiles (ethyl vinyl ether and ethyl vinyl sulfide) affords [4+2] cycloadducts with high endo selectivity. The monocycloadducts then undergo a second Diels-Alder reaction on the newly formed diene unit with electron-deficient dienophiles (tetracyanoethylene, 4-phenyl-1,2,4-triazoline-3,5-dione, and N-phenylmaleimide) to give highly stereoselectively the crossed biscycloadducts, hexa- and octahydroquinolines, and octahydropyridopyridazines.

Full text of DOI:10.1016/j.tetlet.2008.05.054

Tetrahedron Letters 49 (2008) 4513–4515
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Tetrahedron Letters
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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:
The initial inverse electron-demand hetero-Diels–Alder reaction of N-sulfonyldivinylmethanimine with
electron-rich dienophiles (ethyl vinyl ether and ethyl vinyl sulfide) affords [4+2] cycloadducts with high
endo selectivity. The monocycloadducts then undergo a second Diels–Alder reaction on the newly formed
diene unit with electron-deficient dienophiles (tetracyanoethylene, 4-phenyl-1,2,4-triazoline-3,5-dione,
and N-phenylmaleimide) to give highly stereoselectively the crossed biscycloadducts, hexa- and octa-
hydroquinolines, and octahydropyridopyridazines.
Received 10 April 2008
Revised 6 May 2008
Accepted 12 May 2008
Available online 15 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The diene-transmissive Diels–Alder (DTDA) reaction is a useful
and attractive method for constructing polyring-fused cyclic com-
pounds, consisting of two sequential (tandem) Diels–Alder (DA)
reactions that involve an initial DA reaction of a cross-conjugated
triene (or its equivalent), followed by a second DA reaction of the
monoadduct using the newly formed diene unit. Many advances
and applications of this DTDA methodology of carbotrienes have
been reported.1 However, only a few examples of the diene-
transmissive hetero-Diels–Alder (DTHDA) reaction involving one
or more hetero-DA reactions in the tandem sequence have been
reported, despite its high potential for straightforward and
efficient construction of polyring-fused heterocyclic compounds
with high regio- and stereoselectivity.2–5
The first reported examples of the DTHDA reaction included
that of cross-conjugated thiatrienes.2,3 Tsuge et al.4 and Spino et
al.5 demonstrated the DTHDA reaction of cross-conjugated oxatri-
enes. Our group previously reported the first DTHDA reaction of
cross-conjugated azatrienes to produce hexa- and octahydroqui-
nazolinones with high regio- and stereoselectivities, which in-
cluded the initial aza-Diels–Alder reaction with tosyl isocyanate.6
We also succeeded in a stereoselective synthesis of hexahydro-
quinolinones by a DTHDA methodology using ketenes as a dieno-
phile in the initial aza-DA reaction.7 To extend this azatriene–
DTHDA methodology, we were prompted to use cross-conjugated
azatrienes bearing an electron-withdrawing sulfonyl group on
the nitrogen atom,8 which involved an inverse electron-demand
aza-DA reaction in the initial cycloaddition. We report the preli-
minary results here.
The cross-conjugated azatrienes 1 were prepared by condensa-
tion between di-b-styryl ketone and corresponding sulfonamides
using TiCl4 and Et3N; and they were stable enough to allow isola-
tion after aqueous workup and/or column chromatography. First,
the initial DA reaction of the azatrienes 1 with ethyl vinyl ether
was performed (Scheme 1, Table 1). When N-methanesulfonyl
azatriene 1a was heated in the presence of excess ethyl vinyl ether
in toluene for 23 h, the corresponding [4+2] cycloadduct 2a9 was
obtained in 68% yield with an endo:exo ratio of 90:10 (entry 1).
Azatrienes 1b and 1c also reacted with ethyl vinyl ether under
the same reaction conditions to give highly endo selectively 2b
and 2c in 86% and 88% yields, respectively; no exo-isomers were
detected in the crude mixture (entries 2 and 3). Similarly, the reac-
tions of 1a and 1b with ethyl vinyl sulfide proceeded in refluxing
toluene to produce the monoadducts 3a and 3b in fair to good
yields with high endo selectivity (entries 4 and 5).
Because the obtained monoadducts 2 and 3 possess an electron-
rich aminodiene moiety, a second DA reaction could be performed
with electron-deficient dienophiles. First, the reactions of 2 and 3
with tetracyanoethylene (TCNE) were carried out to examine dia-
stereo-p-facial selectivity (Scheme 2 and Table 2). The reaction of
2a–c with TCNE proceeded at room temperature for 10 min to pro-
duce [4+2] cycloadducts 4a–c10 in 93–99% yields with complete
diastereo-p-facial selectivity (Table 2, entries 1–3). Similarly, the
reaction of 3a,b proceeded smoothly in refluxing dichloromethane
to give 5a,b in high yields (entries 4 and 5). A one-pot procedure
1b?2b?4b proved the DTHDA methodology to be even more
effective and viable (entry 6). In all cases, the dienophile added
from the less-hindered bottom H-4-side of the diene moiety, a con-
clusion that was supported by the fact that the large vicinal cou-
pling constant (ca. 12 Hz) between H-4 and H-4a in the
bisadducts (4 and 5) indicated a trans diaxial relationship. In the
* Corresponding author. Tel.: +81 3 5228 8254; fax: +81 3 5261 4631.
E-mail address: tsaito@rs.kagu.tus.ac.jp (T. Saito).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.054

4514
S. Kobayashi et al. / Tetrahedron Letters 49 (2008) 4513–4515
H2
H4
H2
X
X
X
SO2R
SO2R
SO2R
N
N
N
+
Toluene, 110 ºC
Ph
Ph
Ph
Ph
Ph
Ph
H4
1
2,3 (endo
)
2,3 (exo
)
(H2-H4 cis
)
(H2-H4 trans
)
Scheme 1.
Table 1
Ph
N
H7
H9
X
N
Initial cycloaddition of cross-conjugated azatrienes 1
SO2R
H2
H4
O
O
X
H9a
Entry
Azatriene
R
X
Time (h)
Adduct
Yield (%)
endo:exoa
SO2R
N
N
N
Ph
O
1
2
3
4
5
1a
1b
1c
1a
1b
Me
p-Tol
Ph
Me
p-Tol
OEt
OEt
OEt
SEt
SEt
23
15
13
48
37
2a
2b
2c
3a
3b
68
86
88
68
51
90:10
>95:5
>95:5
>95:5
>95:5
H
Ph
N
CH2Cl2 , r.t., 10 min
Ph
Ph
N
N
O
Ph
2,3 (H2-H4 cis
)
6,7 (H7-H9 cis
)
a
Endo:exo ratio determined based on 1H NMR integration of the endocyclic ole-
finic proton of 2 and 3. Ratio >95:5 denotes that no minor exo-isomer was detected.
Scheme 3.
Table 3
Second cycloaddition with PTAD
H2
H4
X
SO2R
H7
H2
H4
X
TCNE
N
SO2R
Entry
R
X
Diene
Adduct
Yield (%)
H4a
N
1
2
3
4
5
Me
p-Tol
Ph
Me
p-Tol
EtO
EtO
EtO
EtS
EtS
2a
2b
2c
3a
3b
6a
6b
6c
7a
7b
99
99
99
99
92
Ph
CH2Cl2
Ph
Ph
Ph
NC
NC
CN
CN
2, 3 (H2-H4 cis
)
4, 5 (H2-H4 cis
)
X
H2
H3'
X
SO2R
Ph
H3'
cycloadducts 6a–c and 7a,b, respectively, in quantitative yields.
The reaction was highly diastereo-p-face selective, the same as
the reaction with TCNE.
N
H3
H4a
H4
2, 3
H2
H3
CN
Ph
N
SO2R
H7
The second DA reaction with N-phenylmaleimide (N-PhMI) was
carried out to examine endo/exo selectivity in addition to diaste-
reo-p-facial selectivity (Scheme 4, Table 4). The monoadducts
2a–c reacted with N-PhMI in refluxing toluene to produce cycload-
ducts 9a or 8b,c as final products. The reaction proceeded with
high endo and p-facial selectivities to give initially the 1:1-cycload-
duct, from which elimination of ethanol occurred to furnish com-
pounds 8b,c or, in the case of entry 1, 9a after H-migration from 8a.
In conclusion, the diene-transmissive hetero-Diels–Alder reac-
tion of N-sulfonylated cross-conjugated azatrienes including an
inverse electron-demand aza-Diels–Alder reaction in the initial
H4
NC
Ph
CN
CN
NC
CN
Ph
NC
4, 5
NC
Scheme 2.
Table 2
Second cycloaddition with TCNE
Entry
R
X
Diene
Conditions
Adduct
Yield (%)
1
2
3
4
5
6
Me
p-Tol
Ph
Me
p-Tol
p-Tol
EtO
EtO
EtO
EtS
EtS
EtO
2a
2b
2c
3a
3b
2b
rt, 10 min
rt, 10 min
rt, 10 min
40 °C, 30 min
40 °C, 60 min
4a
4b
4c
5a
5b
4b
93
95
99
76
93
76
Ph
N
H2
OEt
SO2R
O
O
N
110 °C, 15 h?rt, 2 d
Ph
Ph
Toluene
110 ºC
H4
2, 3 H2-H4 cis
endo-monoadduct, the vicinal coupling constants between H-30
and H-4 and between H-3 and H-4 were observed to be ca. 8 Hz
and 5–6 Hz, respectively, suggesting that H-4 orients in a quasi-
equatorial position, and hence the phenyl substituent takes a qua-
si-axial position. Therefore, the top side of the tetrahydropyridine
ring was blocked by the more bulky phenyl group from attack by
the dienophile.
The reactions of 2 and 3 with 4-phenyl-1,2,4-triazoline-3,5-
dione (PTAD) were also examined to confirm diastereo-p-facial
selectivity (Scheme 3, Table 3). Dienes 2a–c and 3a,b reacted
rapidly within 10 min at room temperature to produce the
SO2R
H
SO2R
N
N
H9a
H9b
Ph
H9
O
Ph
O
H
H9
H
or
Ph
Ph
H
H
N
N
O
O
Ph
Ph
8 (endo
)
9 (endo)
Scheme 4.

S. Kobayashi et al. / Tetrahedron Letters 49 (2008) 4513–4515
4515
Table 4
5601; (e) Spino, C. Synlett 2006, 23; (f) Perreault, S.; Spino, C. Org. Lett. 2006, 8,
4385.
Second cycloaddition with N-PhMI
6. Saito, T.; Kimura, H.; Chonan, T.; Soda, T.; Karakasa, T. Chem. Commun. 1997,
1013.
Entry
R
Diene
Time (h)
Adduct
Yield (%)
7. Saito, T.; Kobayashi, S.; Ohgaki, M.; Wada, M.; Nagahiro, C. Tetrahedron Lett.
2002, 43, 2627.
1
2
3
Me
p-Tol
Ph
2a
2b
2c
3
18
18
9a
8b
8c
34
22
21
8. Boger et al. showed that an N-sulfonyl group on an azadiene was a quite
effective substituent for an inverse electron-demand aza-DA reaction: (a)
Boger, D. L.; Curran, T. T. J. Org. Chem. 1990, 55, 5439; (b) Boger, D. L.; Corbett,
W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713; (c) Boger, D.
L. J. Am. Chem. Soc. 2006, 128, 2587 and references cited therein.
9. Compound 2a (endo, H2–H4 cis): Colorless crystals; mp 111–113 °C; IR (KBr):
cycloaddition step has been developed. The protocol provides a
new entry to the highly stereoselective synthesis of octahydro-
quinolines and pyridopyridazines. Further work to extend the
scope of this methodology is currently under way.
2970, 1335, 1157, 1119 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.14 (t, J = 7.1 Hz,
;
3H, OCH2CH3), 2.22 (ddd, J = 3.5, 4.5, 14.2 Hz, 1H, H-3), 2.51 (ddd, J = 4.8, 8.3,
14.2 Hz, 1 H, H-30), 3.02 (s, 3H, Ms), 3.50 (dq, J = 7.1, 9.3 Hz, 1H, OCH2CH3), 3.54
(ddd, J = 3.7, 4.5, 8.3 Hz, 1H, H-4), 3.78 (dq, J = 7.1, 9.3 Hz, 1H, OCH2CH3), 5.54
(dd, J = 3.5, 4.8 Hz, 1H, H-2), 6.02 (d, J = 3.7 Hz, 1H, H-5), 6.88 (s, 2H, H-7, H-8),
7.18–7.36 (m, 8H, Ar), 7.42–7.45 (m, 2H, Ar); 13C NMR (126 MHz, CDCl3) d 14.8
(CH3), 30.9 (CH3), 37.2 (CH), 37.6 (CH2), 40.6 (CH2), 63.4 (CH), 83.9 (CH), 122.0
(CH), 126.5 (2CH), 126.7 (2CH), 127.9 (CH), 128.2 (2CH), 128.3 (2CH), 128.6
(CH), 129.9 (CH), 134.8 (C), 136.6 (C), 144.5 (C). HRMS-ESI m/z: [M+Na]+ calcd
for C22H25NNaO3S: 406.1447, found: 406.1461. Anal. Calcd for C22H25NO3S: C,
68.90; H, 6.57; N, 3.65. Found: C, 69.11; H, 6.79; N, 3.67. Compound 2a (exo,
References and notes
1. 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. Yuki Gosei Kagaku Kyokaishi 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) Woo, S.; Squire, N.;
Fallis, A. G. Org. Lett. 1999, 1, 573; (i) Woo, S.; Legoupy, S.; Parra, S.; Fallis, A. G.
Org. Lett. 1999, 1, 1013; (j) Kwon, O.; Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc.
2002, 124, 13402; (k) Payne, A. D.; Willis, A. C.; Sherburn, M. S. J. Am. Chem. Soc.
2005, 127, 12188; (l) Brummond, K. M.; You, L. Tetrahedron 2005, 61, 6180; (m)
Mitasev, B.; Yan, B.; Brummond, K. M. Heterocycles 2006, 70, 367; (n) Bradford,
T. A.; Payne, A. D.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S. Org. Lett.
2007, 9, 4861; (o) Miller, N. A.; Willis, A. C.; Paddon-Row, M. N.; Sherburn, M. S.
Angew. Chem., Int. Ed. 2007, 46, 937; (p) Souweha, M. S.; Arab, A.; ApSimon, M.;
Fallis, A. G. Org. Lett. 2007, 9, 615; (q) Souweha, M. S.; Enright, G. D.; Fallis, A. G.
Org. Lett. 2007, 9, 5163.
2. Motoki, S.; Matsuo, Y.; Terauchi, Y. Bull. Chem. Soc. Jpn. 1990, 63, 284.
3. Saito, T.; Kimura, H.; Sakamaki, K.; Karakasa, T.; Moriyama, S. Chem. Commun.
1996, 811.
4. (a) Tsuge, O.; Hatta, T.; Yoshitomi, H.; Kurosaka, K.; Fujiwara, T.; Maeda, H.;
Kakehi, A. Heterocycles 1995, 41, 225; (b) Tsuge, O.; Hatta, T.; Fujiwara, T.;
Yokohari, T.; Tsuge, A. Heterocycles 1999, 50, 661.
5. (a) Spino, C.; Liu, G. J. Org. Chem. 1993, 58, 817; (b) Spino, C.; Liu, G.; Tu, N.;
Girard, S. J. Org. Chem. 1994, 59, 5596; (c) Spino, C.; Hill, B.; Dubé, P.; Gingras, S.
Can. J. Chem. 2003, 81, 81; (d) Dion, A.; Dubé, P.; Spino, C. Org. Lett. 2005, 7,
H2–H4 trans): Yellow oil; IR (neat): 1335, 1157, 1119 cmꢀ1 1H NMR (600 MHz,
;
CDCl3) d 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.77 (ddd, J = 2.4, 12.6, 13.9 Hz, 1H,
H-3), 2.37 (dddd, J = 1.5, 2.4, 6.6, 13.9 Hz, 1H, H-30), 3.01 (s, 3H, Ms), 3.68 (dq,
J = 7.1, 9.6 Hz, 1H, OCH2CH3), 3.86 (dq, J = 7.1, 9.6 Hz, 1H, OCH2CH3), 3.88 (m,
J = 1.5, 6.6, 12.6 Hz, 1H, H-4), 5.54 (dd, J = 2.4, 2.4 Hz, 1H, H-2), 5.67 (dd, J = 1.5,
1.5 Hz, 1H, H-5), 6.81 (d, J = 15.6 Hz, 1H, H-8), 7.01 (d, J = 15.6 Hz, 1H, H-7),
7.23–7.44 (m, 10H, Ar); 13C NMR (151 MHz, CDCl3) d 15.0 (CH3), 36.1 (CH2),
36.3 (CH), 40.5 (CH), 63.5 (CH2), 84.3 (CH3), 116.6 (CH), 126.6 (CH), 126.8
(2CH), 126.9 (CH), 127.5 (2CH), 127.9 (CH), 128.6 (2CH), 128.9 (2CH), 129.9
(CH), 134.1 (C), 136.6 (C), 143.7 (C). HRMS-ESI m/z: [M+Na]+ calcd for
C
22H25NNaO3S: 406.1447, found: 406.1465.
10. Compound 4a: Colorless crystals; mp 176–177 °C; IR (KBr): 1350, 1165 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3), 2.31 (ddd, J = 2.9,
2.9, 15.1 Hz, 1H, H-3), 2.56 (ddd, J = 2.9, 9.7, 15.1 Hz, 1H, H-30), 3.19 (s, 3H, Ms),
3.38 (dq, J = 7.1, 8.9 Hz, 1H, OCH2CH3), 3.53 (dq, J = 7.1, 8.9 Hz, 1H, OCH2CH3),
3.9 (ddd, J = 2.9, 9.7, 11.5 Hz, 1H, H-4), 4.19 (ddd, J = 1.8, 1.8, 11.5 Hz, 1H, H-4a),
4.5 (dd, J = 1.8, 2.8 Hz, 1H, H-7), 5.44 (dd, J = 2.9, 2.9 Hz, 1H, H-2), 6.50 (dd,
J = 1.8, 2.8 Hz, 1H, H-8), 7.26–7.53 (m, 10H, Ar); 13C NMR (126 MHz, CDCl3) d
14.9 (CH3), 35.1 (CH2), 40.2 (CH), 40.9 (CH3), 41.3 (C), 43.2 (CH), 43.8 (C), 46.8
(CH), 64.7 (CH2), 85.3 (CH), 108.3 (C), 109.7 (C), 111.1 (C), 111.3 (C), 114.2 (CH),
128.4 (CH), 128.6 (CH), 129.2 (2CH), 129.3 (3CH), 130.0 (2CH), 130.4 (CH),
132.1 (C), 132.5 (C), 139.7 (C). HRMS-ESI m/z: [M+Na]+ calcd for
C
28H25N5NaO3S: 534.1570, found: 534.1546.