Diene-transmissive hetero Diels-Alder reaction of cross-conjugated azatrienes with ketenes: A novel and efficient, stereo-controlled synthetic method for hexahydroquinolinones

Article abstract of DOI:10.1016/S0040-4039(02)00303-9

The cross-conjugated azatrienes, N-aryl-, N-alkyl- or N-dimethylamino-diβ-styrylmethanimines, reacted with diphenylketene and dimethylketene at room temperature to afford [2+2] cycloadducts, while the reaction with dichloroketene produced [4+2] cycloadducts. Upon heating, the [2+2] cycloadducts underwent a [1,3] sigmatropic rearrangement giving the formal [4+2] cycloadducts. The second Diels-Alder reaction of the [4+2] mono-adducts with electron-deficient dienophiles such as tetracyanoethylene, N-phenylmaleimide and methyl vinyl ketone gave hexahydroquinolinone derivatives stereoselectively. The cross-conjugated azatriene bearing different substituents at β- and β′-positions also underwent the diene-transmissive hetero Diels-Alder reaction in a highly site-, regio- and stereo-selective manner.

Full text of DOI:10.1016/S0040-4039(02)00303-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2627–2631
Diene-transmissive hetero Diels–Alder reaction of
cross-conjugated azatrienes with ketenes: a novel and efficient,
stereo-controlled synthetic method for hexahydroquinolinones
Takao Saito,* Satoru Kobayashi, Masato Ohgaki, Mari Wada and Chikako Nagahiro
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 26 December 2001; revised 4 February 2002; accepted 8 February 2002
Abstract—The cross-conjugated azatrienes, N-aryl-, N-alkyl- or N-dimethylamino-dib-styrylmethanimines, reacted with
diphenylketene and dimethylketene at room temperature to afford [2+2] cycloadducts, while the reaction with dichloroketene
produced [4+2] cycloadducts. Upon heating, the [2+2] cycloadducts underwent a [1,3] sigmatropic rearrangement giving the formal
[4+2] cycloadducts. The second Diels–Alder reaction of the [4+2] mono-adducts with electron-deficient dienophiles such as
tetracyanoethylene, N-phenylmaleimide and methyl vinyl ketone gave hexahydroquinolinone derivatives stereoselectively. The
cross-conjugated azatriene bearing different substituents at b- and b%-positions also underwent the diene-transmissive hetero
Diels–Alder reaction in a highly site-, regio- and stereo-selective manner. © 2002 Elsevier Science Ltd. All rights reserved.
The hetero Diels–Alder (HDA) methodology is among
the most attractive and important tools for the synthe-
sis of a wide range of six-membered heterocyclic com-
pounds because of their potentially powerful and
straightforward construction of heterocycles with high
control of regio- and stereochemistry.1 On the other
hand, the diene-transmissive hetero Diels–Alder
(DTHDA) reaction should offer an efficient method for
synthesis of, especially, ring-fused heterocycles by per-
forming multi-domino (hetero) DA reactions in a
stereo-controlled manner.2–4,†
In this context, we have recently reported the first
examples of the DTHDA reaction of cross-conjugated
azatrienes 2.5 This process involved the initial aza DA
cycloaddition of 2 with a reactive dienophile, tosyl
isocyanate, followed by the second DA reaction with
some representative dienophiles to give stereoselectively
ring-fused pyrimidinone derivatives as bis-adducts in
good yields.5 Unfortunately, the azatrienes 2 having an
R1 group on the nitrogen such as Ph, p-Tol, PhCH2,
i-Pr, and a quite effective electron-releasing Me2N
group, failed to react with representative dienophiles
Scheme 1.
Keywords: diene-transmissive Diels–Alder reaction; domino/tandem reactions; cycloaddition; quinoline; nitrogen heterocycle.
* Corresponding author. Tel.: +81-(0)3-5228-8254; fax: +81-(0)3-3235-2214; e-mail: tsaito@ch.kagu.sut.ac.jp
† Although the diene-transmissive Diels–Alder (DTDA) reaction is formally considered to be a set of multi-sequential DA reactions of
a,v-divinylpoly(vinylidene), the DTHDA reaction can usually be defined by two sequential (so-called tandem, domino, etc.) cycloadditions of
the two final processes that involve an initial DA reaction of a cross-conjugated triene (or its equivalents) with a dienophile, followed by a second
DA cycloaddition on the newly-formed, transmitted diene unit of the mono-adduct with a dienophile to give a bis-adduct, where one or more
heteroatoms are contained within either a triene framework or a dienophile skeleton or both. For DTDA reactions of carbotrienes, see the
literature in Ref. 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00303-9

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T. Saito et al. / Tetrahedron Letters 43 (2002) 2627–2631
such as tetracyanoethylene, N-phenylmaleimide, maleic
anhydride, dimethyl fumarate, dimethyl acetylenedicar-
boxylate, ethyl vinyl ether and styrene under, if neces-
sary, harsh conditions and/or in the presence of a Lewis
acid promoter.6,‡ In order to gain further insight into
the cycloaddition mechanism and to extend this
DTHDA methodology, we reasoned to utilize ketenes
as a useful carbonꢀcarbon dienophile in the initial
cycloaddition of 2 and a new variant 9 because of their
isoelectronic property with isocyanates.
[1,3] sigmatropic rearrangement with the cleavage of
the C(3)-C(4) bond of the azetidinone ring in 3a
(Scheme 2).12 Similarly, the [2+2] cycloadducts 3b–e
were converted exclusively to the [4+2] cycloadducts
4b–e (Table 1, runs 2–5). Dimethylketene generated in
situ from the acid chloride precursor also reacted with
the azatriene 2e, which is relatively stable and isolable,
to afford the [2+2] cycloadduct 5a in good yield, which
was similarly converted to the [4+2] cycloadduct 6a
quantitatively upon heating (run 6). However, the reac-
tion with dichloroketene generated gave 6b in low yield
instead of 5b even if performed at a low temperature
(run 7). The periselection outcome for the latter reac-
tion is in accord with the precedent observation that
generated haloketene tends to give [4+2] cycloadducts
in Diels–Alder reactions with 1-azadienes.9,13
When azatriene 2a (N-phenyldib-styrylmethanimine,
R1=Ph), generated in situ from the reaction of the
corresponding ketone 1 with aniline by the action of the
reagents TiCl4 and Et3N, was allowed to react with
diphenylketene at 0°C for 5 min, a 1:1-adduct was
obtained in 98% yield, the structure of which was
assigned to be a [2+2] cycloadduct 3a on the basis of
spectroscopic data (Scheme 1). The other aryl, benzyl,
alkyl and dimethylamino-substituted R1-azatrienes,
2b–e, also reacted with diphenylketene to give the [2+2]
cycloadducts 3b–e in good yields. The results are sum-
marized in Table 1. The formation of the [2+2] cycload-
ducts was not unexpected but, unfortunately, the
diene-transmissive Diels–Alder methodology would not
be applicable with the structure 3.
With the mono-cycloadducts (4 and 6) in hand, we
performed the second cycloaddition with some repre-
sentative electrophilic dienophiles, since the mono-
cycloadducts have an aminodiene unit and hence
normal electron-demanding DA reactions are antici-
pated to proceed smoothly. First, the reactions of 4
with
a
symmetrical, simple dienophile, tetra-
cyanoethylene (TCNE), were carried out to see the
p-facial selectivity. As expected, the reactions proceeded
rapidly (in 5–10 min) at room temperature in CH2Cl2 to
Many instances are available in the literature that kete-
nes reacted with imines, even with conjugated imines, to
afford azetidinones (b-lactams) as [2+2] cycloadducts,9
whereas it is also reported that selected 1-azadienes
(conjugated imines) underwent [4+2] cycloaddition with
ketenes.1,8,10,11 So, we subjected the cycloadduct 3a to
thermal reaction. When 3a was heated in refluxing
toluene for 2 h, it was found that the dihydropyridone
derivative 4a as the formal [4+2] cycloadduct was quan-
titatively obtained, which was presumably formed by a
O
O
Toluene
reflux
R2
R2
Ph
R1
R2
R2
N R1
Ph
N
3
4
or
Ph
H
CH2Cl2
r.t. for 5b
Ph
4, 6
3, 5
Scheme 2.
Table 1. Reaction of azatrienes 2 with ketenes and thermal conversion of [2+2]cycloadducts 3 and 5 to [4+2]cycloadducts 4
and 6
Run
R1
R2
Azatriene
[2+2]Cycloadduct
Yield (%) (1“3)
[4+2]Cycloadduct
Yield (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Me
Cl
2a
2b
2c
2d
2e
2e
2e
3a
3b
3c
3d
3e
5a
5b
98
84
76
90
91
96
–
4a
4b
4c
4d
4e
6a
6b
99
99
99
99
p-CH3OC6H4
Benzyl
i-Pr
Me2N
Me2N
Me2N
99 (93)a
96
(23)a
a In parentheses, yield in a one-pot reaction from 2e.
‡ The results were not surprising because this would be the case as often encountered by such limitation that 1-aza-1,3-butadienes are usually
(inherently) less reactive as a 4p-component in DA reaction unless they bear sufficiently electron-donating or electron-withdrawing group(s) at
(a) suitable position(s) of the azadiene system.1,7 Moreover, semi-empirical calculations (AM1) have revealed that both of the coefficients on the
terminal nitrogen (1), carbon (4) and (4%) atoms in the HOMO of 2 (R1=Ph) are considerably small (N: −0.28 and C: 0.20, 0.06, respectively)
in the normal electron-demanding HOMO diene-LUMO dienophile DA reaction predicted by the magnitude differences of MOs energy level
separations and that the net atomic charges on the nitrogen atom (−0.16) of 2 and the cumulene carbon (0.49) of tosyl isocyanate were relatively
large in the negative and positive signs, respectively.6 These findings suggest that the reaction with tosyl isocyanate proceeds stepwise rather than
in a concerted manner.8 This assumption is consistent with the theoretical prediction that TCNE possessing lower LUMO energy than that of
TsNCO should have reacted with 2, if it is a concerted reaction, and with the fact that the reaction of 2 (particularly when R1=NMe2) with
TCNE did not give any cycloadducts.

T. Saito et al. / Tetrahedron Letters 43 (2002) 2627–2631
2629
give the [4+2] cycloadducts 714 in excellent yields with
complete p-facial selectivity (Scheme 3, Table 2). The
stereochemistry of 7 suggests that the dienophile should
cycloadd from the less hindered backside of the diene
4/6 (syn to H at the 4-position of the pyridone ring) due
to the steric reason (vide infra). Next, we carried out
the reactions with N-phenylmaleimide to examine the
endo–exo selectivity as well as the p-facial selectivity
(Scheme 4). The reactions proceeded upon heating in
toluene under reflux for 6–20 h to quantitatively yield
the [4+2] cycloadducts 8 with almost complete exo
selectivity except for the case of R2=Me. The results
are summarized in Table 3. The stereochemistry of 8
was determined 1H NMR spectroscopically (Fig. 1).
Table 3. DA Reaction of 4 and 6 with N-phenyl-
maleimide to give pyrroloquinolines 8
Run
Diene
Cycloadduct
exo:endoa
Yield (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
6a
6b
8a
8b
8c
8d
8e
8f
\95:5
\95:5
\95:5
\95:5
\95:5
69:31
99
99
99
99
99
94
99
8g
\95:5
a Ratio determined by 1H NMR (300 or 400 MHz) spectroscopy. No
endo isomers were detected for a ratio of >95:5.
Particularly, a large vicinal coupling constant (JH1–2
=
12.4 Hz) was observed between H1 and H2, which
indicates a trans-diaxial relationship between them, and
hence the attack of the dienophile from the bottom side
(Fig. 2). Nuclear Overhauser effect (NOE) was
observed notably between H1 and H3, and H2 and H5,
in a cis-relationship and no NOE between H2 and H3,
and H4 and H5, suggesting a trans (diaxial) relationship
and hence the exo addition of the dienophile. The exo
addition was also supported by a relatively large cou-
pling constant (8.12 Hz) between H4 and H5, implying
a trans-relationship. Fig. 2 shows the exo and endo
orientations. The fact that the observed vicinal coupling
NOE
H5
H2
H6
R2
O
Ph
NPh
N
R1
H4
H3
O
R2
O
Ph
H1
JH1-2 = 12.4 Hz
NOE
Figure 1. NOE measurement of 8a (exo).
Ph
Ph
H4
(Me)
4
(Me)
Ph
Ph
O
3
O
H1
3
R1
R1
O
R2
R2
H2
N
R1
H
N
O
(Me)
Ph
R2
R2
Ph
R1
(Me)
Ph
N
NC
NC
CN
CN
4, 6
H
J=7.0Hz
Ph
N
4, 6
J=7.0Hz
Ph
O
N
Ph
H
Ph
H
Ph
O
NC
NC
H
CH2Cl2 , r.t.
Ph
Ph
CN
N
O
NC
exo
endo
4, 6
O
7
Scheme 3.
trans adduct
cis adduct
(H2-H3, H4-H5)
Table 2. DA Reaction of 4 and 6 with TCNE to give
hexahydroquinolinones 7
Figure 2. exo and endo orientations.
Run
Diene
Cycloadduct
Yield (%)
constant between H1 and H2 in the diene 4/6 was ca. 7
Hz, suggests a quasi-equatorial arrangement of H1 and,
consequently, the phenyl group at the 4-position being
in quasi-axial orientation. The dienophile, therefore,
cycloadded exclusively from the bottom side to avoid
the steric hindrance between the phenyl group and the
dienophile in attacking from the topside. In the endo
addition, the steric repulsion with the CO moiety of the
dienophile exerted by the axial phenyl or chloro group
at the 3-position, would be large enough to surpass the
second orbital interaction, while the less bulky methyl
group would allow the endo addition by preference of
31% (Table 3, run 6). It is noteworthy that low exo–
endo selectivity was observed in the second cycloaddi-
tion of N-phenylmaleimide with the initial [4+2]
mono-cycloadducts of 2 with tosyl isocyanate.5 This is
probably due to the absence of an axial substituent on
the nitrogen at the 3-position in the initial
cycloadducts.
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
6a
6b
7a
7b
7c
7d
7e
7f
99
99
99
99
99
94
99
7g
Scheme 4.

2630
T. Saito et al. / Tetrahedron Letters 43 (2002) 2627–2631
Diego, 1987; (b) Boger, D. L. In Comprehensive
Organic Synthesis; Paquette, L. A.; Trost, B. M.; Flem-
ing, I., Eds.; Oxford: Pergamon, 1991; Vol. 5, p. 451;
(c) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1; (d) Buonora, P.; Olsen, J.-C.; Oh, T. Tetra-
hedron 2001, 57, 6099 and references cited therein.
2. For DT(H)DA of carbotrienes: (a) Blomquist, A. T.;
Verdol, J. A. J. Am. Chem. Soc. 1955, 77, 81; (b)
Tsuge, O.; Wada, E.; Kanemasa, S. Chem. Lett. 1983,
239; (c) Tsuge, O.; Kanemasa, S.; Wada, E.; Sakoh, H.
Yuki Gosei Kagaku Kyokaishi 1986, 44, 756 and refer-
ences cited therein; (d) Tsuge, O.; Hatta, T.; Yakata,
K.; Maeda, H. Chem. Lett. 1994, 1833; (e) Spino, C.;
Liu, G. J. Org. Chem. 1993, 58, 817; (f) Spino, C.; Tu,
N. Tetrahedron Lett. 1994, 35, 3683; (g) Hosomi, A.;
Masunari, T.; Tominaga, Y.; Yanagi, T.; Hojo, M.
Tetrahedron Lett. 1990, 31, 6201; (h) Adam, W.;
Deufel, T.; Finzel, R.; Griesbeck, A. G.; Hirt, J. J.
Org. Chem. 1992, 57, 3991; (i) Woo, S.; Legoupy, S.;
Parra, S.; Fallis, A. G. Org. Lett. 1999, 1, 1013; (j)
Woo, S.; Squire, N.; Fallis, A. G. Org. Lett. 1999, 1,
573.
3. For DTHDA of thiatrienes: (a) Motoki, S.; Matsuo,
Y.; Terauchi, Y. Bull. Chem. Soc. Jpn. 1990, 63, 284;
(b) Saito, T.; Kimura, H.; Sakamaki, K.; Karakasa, T.;
Moriyama, S. Chem. Commun. 1996, 811.
4. For DTHDA of oxatrienes: (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. Hete-
rocycles 1999, 50, 661; (c) Spino, C.; Liu, G.; Tu, N.;
Girard, S. J. Org. Chem. 1994, 59, 5596; (d) Spino, C.;
Liu, G. J. Org. Chem. 1993, 58, 817.
5. For DTHDA of azatrienes: Saito, T.; Kimura, H.;
Chonan, T.; Soda, T.; Karakasa, T. Chem. Commun.
1997, 1013.
Scheme 5. (i ) Bn–NH2 (2 equiv.), TiCl4 (100 mol%), Et3N
(4.4 equiv.), CH2Cl2, 0°C“rt.
The new azatriene 9, generated in situ from the corre-
sponding ketone, reacted with diphenylketene rapidly
to afford the [2+2] cycloadduct 10 in an 83% yield
(Scheme 5). Heating the adduct 10 at 111°C for 5 min
caused the [1,3] rearrangement to give a mixture of two
pyridones 11 and 12 in 97% yield with a ratio of 18:82,
which are formally the [4+2] cycloadducts of the aza-
triene 9 reacting at both cross-conjugated diene sites. It
should be pointed out that the [4+2] cycloadduct 12
arising from the reaction at the electron-rich diene
moiety of 9 is the major product. When the mixture of
11 and 12 was allowed to react with TCNE at room
temp. for 10 min, the quinolone derivative 13 was
obtained only as the [4+2] cycloadduct from 11 in 91%
yield together with the unreacted 12 in 97% yield.
Interestingly, the recovered 12 reacted with methyl
vinyl ketone in refluxing xylene for 7 h giving com-
pound 14 in 86% yield with a cis:trans ratio of 80:20
which was presumably formed by 1,3-H-migration of
the preformed endo and exo [4+2] cycloadducts,
respectively.
6. Saito, T.; Kobayashi, S.; Chonan, T.; Yoshida, S.;
Wada, M. 30th Congress of Heterocyclic Chemistry,
Hachioji, Abstr. 1L-06, P. 22, 1999; unpublished
results.
7. (a) Boger, D. L.; Corbett, W. L.; Curran, T. T.;
Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713; (b)
Trione, C.; Toledo, L. M.; Kuduk, S. D.; Fowler, F.
W.; Grierson, D. S. J. Org. Chem. 1993, 58, 2075; (c)
Serckx-Poncin, B.; Hesbain-Frisque, A.-M.; Ghosez, L.
Tetrahedron Lett. 1982, 23, 3261; (d) Beaudegnies, R.;
Ghosez, L. Tetrahedron: Asymmetry 1994, 5, 557; (e)
Sakamoto, M.; Satoh, K.; Nagano, M.; Nagano, M.;
Tamura, O. J. Chem. Soc., Perkin Trans. 1 1998, 3389;
(f) Sakamoto, M.; Nagano, M.; Suzuki, Y.; Tamura, O.
Tetrahedron 1996, 52, 733; (g) Blanco, M. M.; Alonso,
M. A.; Avendan˜o, C.; Mene´ndez, J. C. Tetrahedron
1996, 52, 5933 and references cited therein.
In conclusion, the diene-transmissive hetero Diels–
Alder methodology of cross-conjugated azatrienes with
ketenes provides a new entry to stereoselective synthesis
of quinoline derivatives.
8. (a) Tietze, L. F.; Fennen, J.; Geissler, H.; Schulz, G.;
Anders, E. Liebigs Ann. Chem. 1995, 1681; (b) Fabian,
W. M. F.; Kollenz, G. J. Phys. Org. Chem. 1994, 7, 1;
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hedron Lett. 1998, 39, 8911.
9. Ghosez, L.; Marchand-Brynaert, J. In Comprehensive
Organic Synthesis; Paquette, L. A.; Trost, B. M.; Flem-
ing, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p. 85
and references cited therein.
References
1. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San

T. Saito et al. / Tetrahedron Letters 43 (2002) 2627–2631
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10. (a) Elliott, M. C.; Monk, A. E.; Kruiswijk, E.; Hibbs, D.
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11. For a recent, excellent paper on the cycloaddition mecha-
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[4+2]- or [2+2]cycloadducts, see: Machiguchi, T.;
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14. Compound 7a: colorless crystals, mp 195–197°C; IR
(KBr):1696, 1650, 1496, 1280, 700 cm−1 1H NMR (400
;
MHz/CDCl3) l 4.10 (ddd, J=1.9, 2.1, 10.9, 1H, H-2),
4.29 (dd, J=1.9, 4.8, 1H, H-3), 4.92 (d, J=10.9, 1H,
H-1), 5.10 (dd, J=2.1, 4.8, 1H, H-4), 6.67–7.74 (m, 25H,
Ar); FABMS 632 (M++H, 6), 246 (17), 185 (60), 93 (100).
FABHRMS calcd for C43H30N5O [M++H]: 632.2450.
Found: 632.2443.