Diene-transmissive hetero-Diels-Alder reaction of cross-conjugated azatrienes: A novel and efficient method for the synthesis of ring-fused nitrogen heterocycles

Article abstract of DOI:10.1039/a701575e

A diene-transmissive hetero-Diels-Alder reaction of cross-conjugated azatrienes, which provides a novel and efficient synthetic method for ring-fused, nitrogen-heterocyclic frameworks such as quinazolin-2-ones and pyrimido[5,4-c]-pyridazin-6-ones, is desc

Full text of DOI:10.1039/a701575e

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Diene-transmissive hetero-Diels–Alder reaction of cross-conjugated azatrienes:
a novel and efficient method for the synthesis of ring-fused nitrogen
heterocycles
Takao Saito,* Hiroaki Kimura, Tomomichi Chonan, Takayuki Soda and Takayuki Karakasa
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162, Japan
A diene-transmissive hetero-Diels–Alder reaction of cross-
conjugated azatrienes, which provides a novel and efficient
synthetic method for ring-fused, nitrogen-heterocyclic
frameworks such as quinazolin-2-ones and pyrimido[5,4-c]-
pyridazin-6-ones, is described for the first time.
investigated heterodienes in HDA cycloaddition reactions,7
there are no reports on the aza-DTHDA cycloaddition of cross-
conjugated azatrienes capable of 4p participation. We report
here for the first time on the aza-DTHDA reaction of such
azatrienes. The methodology constitutes a new facile access to
a variety of functionalized, ring-fused nitrogen heterocycles
with high efficiency and predictable stereoselectivity.
The diene-transmissive Diels–Alder (DTDA) reaction is de-
fined by two sequential (tandem) DA cycloadditions that
involve an initial DA reaction of a cross-conjugated triene (or its
equivalent) with a dienophile, followed by a second DA
reaction of the mono-adduct on the newly-formed diene unit to
give a bis-adduct (Scheme 1).1 Tsuge et al. have developed the
DTDA reactions.2 However, the diene-transmissive hetero-
Diels–Alder (DTHDA) reaction, in which one or more
heteroatoms are contained within either a triene framework or a
dienophile skeleton or both, has not been studied extensively,
despite its high potential for construction of a wide range of
ring-fused heterocycles; only a few reports have appeared so
far.3–6 In our previous reports, we disclosed the first examples
of the DTHDA reactions in both inter- and intra-molecular
modes of cycloadditions, in which divinyl thioketones were
used as cross-conjugated heterotrienes.3,4 Recently, Tsuge et al.
reported the aza-DTHDA reaction of carbotrienes with strong
diazo dienophiles such as azodicarboxylate and triazolinedione,
and the oxa-DTHDA reaction of divinyl ketones with an
enamine (initial cycloaddition) followed by tetracyanoethylene
or triazolinedione (second cycloaddition).5 Spino and Liu
showed that cyclic 2-formyl 1,3-dienes also took part in the oxa-
DTHDA reaction for the construction of a quassinoid frame-
work.6 Although azabutadienes constitute a class of widely
When the di-b-styrylmethanimine 1† (16 mmol) was allowed
to react with tosyl isocyanate (2–3 equiv.) at room temp. in
xylene (15 cm3) for 0.5–1 h, the 1:1 cycloadduct 2‡ was
obtained in good yield (Scheme 2, Table 1). Neither the
regioisomer nor the bis-adduct were detected in the reaction
mixture. A second DA cycloaddition of the diene 2 with
tetracyanoethylene (TCNE) proceeded smoothly at room
temp. to give a quantitative yield of the cycloadduct 3‡ with
complete stereoselectivity. The stereochemistry of the cycload-
duct 3 was deduced from its 1H NMR spectrum based mainly on
the coupling constants, for example for 3a 3J4,4a 5.0, 4J4a,7 2.3,
3
4J4a,8 2.3 and J7,8 3.6 Hz, suggesting that, in the second
cycloaddition, the dienophile cycloadds from the less hindered
bottom side (anti to R2) of 2 in which the substituent R2 at C-4
occupies an axial arrangement in accord with the observed
coupling constant J4,5 (e.g. 6.9 Hz for 2a). Dimethyl azodi-
carboxylate (DAD) also afforded highly stereoselectively the
Table 1 Initial cycloaddition of 1 to afford mono-cycloadducts 2
Reaction
time/h
Cycloadduct
(% yield)a
Azatriene
1a
1b
1c
1
0.5
0.5
2a (90)
2b (91)
2c (93)
a
Isolated yield in a one-pot reaction from the divinyl ketones via method
A.†
Scheme 1
O
O
R2
Ts
R2
Ts
R1
Ts
Ts
R2
Ts
R2
R1
R1
O
N
H
N
Y
4
4
H
N
H
N
H
X
N
N
R1
H
N
O
O
H
i
ii
H
N
H
N
4a
R1
R1
4a H
1 N
R2
N
R2
E
4
5
N
H
8
H
7
R2
R2
H
8
7 R2
N
H
5
NC
NC
R2
R2
CN
E
R2
X
1
2
Y
CN
X
Y
2
3
4
a R1 = R2 = Ph
b R1 = p-Tol, R2 = Ph
c R1 = PhCH2, R2 = Ph
3 (NC)2C–C(CN)2
R2
R2
4
O
R1
H
4 EtO2CN–NCO2Et
H
N
Ts
H
Ts
R2
N
N
H
Ts
4a
O
H
O
H
O
N
H
R1
4
HC CH
4a
5
R1
E
H
H
O
N
N
5
6
H
O
O
5
6
8
N
8
Ph
H
7
N
Ph
H
H
R2
H
H
O
H
R2
E 7
H
R2
O
N
H
6 MeO2CHC–CCHCO2Me
Ph
5 (endo)
5 (exo)
6 (endo)
Scheme 2 Reagents and conditions: i, TsNCO, xylene, room temp., 0.5–1
h; ii, XNY, solvent, room temp. or heat
Fig. 1
Chem. Commun., 1997
1013

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Table 2 Second cycloaddition of 2 to afford bis-cycloadducts 3–6
Cycloadduct
(% yield)b
Run
Dienophilea
TCNE
Diene
Reaction conditions
Ratioc
1
2
3
4
5
6
7
8
9
2a
2b
2c
2a
2b
2c
2a
2b
2c
2a
2b
2c
Benzene, room temp., 5 min
Benzene, room temp., 5 min
Benzene, room temp., 5 min
Toluene, 110 °C, 10 min
Toluene, 110 °C, 10 min
Toluene, 110 °C, 10 min
Toluene, 110 °C, 7 h
Toluene, 110 °C, 17 h
Toluene, 110 °C, 4 h
Toluene, 110 °C, 9 h
3a (99)
3b (97)
3c (99)
4a (94)
4b (89)
4c (99)
5a (97)
5b (88)
5c (99)
6a (99)
6b (91)
6c (99)
—
—
—
—
—
—
56:44
70:30
38:62
57:43
59:41
53:47
DAD
NPMI
DMF
10
11
12
Toluene, 110 °C, 17 h
Toluene, 110 °C, 9 h
a
b
c
TCNE: tetracyanoethylene; DAD: diethyl azodicarboxylate; NPMI: N-phenylmaleimide; DMF: dimethyl fumarate. Isolated yield. Ratio (endo:exo)
determined by 1H NMR spectroscopy. The term endo refers to a cis-relationship between H4a and H5 and the term exo a trans-relationship.
(C), 135.4 (C), 137.0 (C), 139.3 (C), 139.4 (C), 141.5 (C), 144.4 (C), 150.7
(CO), 174.7 (CO) and 176.7 (CO).
cycloadduct 4‡ in good yield. With N-phenylmaleimide
(NPMI) and dimethyl fumarate (DMF) second cycloadditions
were effected upon heating in toluene for 4–17 h to produce
References
excellent yields of the cycloadducts 5 and 6 with complete
diastereoisoface selectivity but with almost no endo:exo-
selectivity. The results are summarised in Table 2. Fig. 1 shows
the most probable stereochemical (conformational and config-
urational) structures of the mono- (2) and bis-cycloadducts
(3–6) which were deduced from 1H NMR spectroscopic studies
and computational calculations using MOPAC 93, CONFLEX,
LAOCOON III and 3JHH2 programs.4,10,11
1 For excellent reviews and monographs on such sequential, multistep
processes (the so-called domino, tandem or cascade strategy) involving
a Diels–Alder reaction, see F. Fringuelli and A. Taticchi, Dienes in the
Diels–Alder Reaction, Wiley, New York, 1990; T.-L. Ho, Tandem
Organic Reactions, Wiley, New York, 1992; L. F. Tietze and
U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993, 32, 131; L. F. Tietze,
Chem. Rev., 1996, 96, 115; S. E. Denmark and A. Thorarensen, Chem.
Rev., 1996, 96, 137; J. D. Winkler, Chem. Rev., 1996, 96, 167. For recent
publications, see ‘Cascade Reactions’, Tetrahedron Symposia-in-Print,
1996, 52, 11 385; K. H. Ang, S. Brase, A. G. Steinig, F. E. Meyer,
A. Llebaria, K. Voigt and A. de Meijere, Tetrahedron, 1996, 52, 11 503;
S. E. Denmark and C. B. W. Senanayake, Tetrahedron, 1996, 52,
11 579; A. Franz, P.-Y. Eschler, M. Thrin and R. Neier, Tetrahedron,
1996, 52, 11 643; A. Hosomi, T. Masunari, Y. Tominaga, T. Yanagi and
M. Hojo, Tetrahedron Lett., 1990, 31, 6201.
2 O. Tsuge, S. Kanemasa, E. Wada and H. Sakoh, Yuki Gosei Kagaku
Kyokaishi, 1986, 44, 756; O. Tsuge, E. Wada and S. Kanemasa, Chem.
Lett., 1983, 239; O. Tsuge, E. Wada, S. Kanemasa and H. Sakoh, Bull.
Chem. Soc. Jpn., 1984, 57, 3221; O. Tsuge, S. Kanemasa, H. Sakoh and
E. Wada, Bull. Chem. Soc. Jpn., 1984, 57, 3234; S. Kanemasa,
H. Sakoh, E. Wada and O. Tsuge, Bull. Chem. Soc. Jpn., 1985, 58, 3312;
S. Kanemasa, H. Sakoh, E. Wada and O. Tsuge, Bull. Chem. Soc. Jpn.,
1986, 59, 1869.
Thus, it has been shown that the DTHDA methodology of
cross-conjugated azatrienes is successfully applied to a synthe-
sis of ring-fused nitrogen heterocycles.
Footnotes
† The imine 1 was prepared by Barluenga’s method involving the reaction
of iminophosphorane with prop-2-ynyltriphenylphosphonium salt, fol-
lowed by successive treatment with an aldehyde, butyllithium and an
aldehyde (Method B, 60–70% yield).8 Otherwise, the imine 1 was more
conveniently prepared by the condensation reaction of di-b-styryl ketone
with an amine in the presence of TiCl4 and triethylamine (method A,
90–95% yield).9
‡ Selected data for 2a: mp 132–133 °C; m/z 506 (M+, 0.5%) and 309 (M+
2 TsNCO, 100%); nmax (KBr)/cm21 1170, 1362 (SO2) and 1698 (CO); dH
(270 MHz, CDCl3) 2.19 [s, 3 H, CH3 (Ts)], 5.73 (d, 1 H, J 6.9 Hz, 5-H), 5.85
(d, 1 H, J 16.2 Hz, 7-H), 6.09 (d, 1 H, J 6.9 Hz, 4-H), 6.57 (d, 1 H, J 16.2
Hz, 8-H), 6.90 (d, 2 H, J 8.58 Hz, ArH), 6.97–7.02 (m, 2 H, ArH) and
7.08–7.31 (m, 15 H, ArH); dC (DEPT, CDCl3) 21.5 (CH3), 56.9 (CH), 103.8
(CH, C-5), 120.5 (CH), 125.6 (2CH), 125.8 (2CH), 127.0 (CH), 127.4 (CH),
127.5 (CH), 127.6 (2CH), 127.7 (2CH), 127.8 (2CH), 128.0 (2CH), 128.06
(2CH), 128.10 (2CH), 131.3 (CH), 135.8 (C), 136.0 (C), 137.1 (C), 137.5
(C), 140.3 (C), 140.0 (C) and 150.0 (CO). For 3a: mp 160–163 °C; m/z
(FAB) 635 (M+ + 1, 2%), 309 (M+ 2 TCNE 2 TsNCO, 98%) and 308
(100%); HRMS (FAB) found M+ + 1 635.1860 C37H27O3N6S requires M +
1, 635.1868; nmax (KBr)/cm21 1174, 1364, 1718 (CO) and 2256 (CN); dH
(270 MHz, CDCl3, [H,H]-COSY) 2.31 [s, 3 H, CH3 (Ts)], 3.92 (dd, 1 H,
J 5.0, 2.3 and 2.3 Hz, 4a-H), 4.32 (dd, 1 H, J 3.6 and 2.3 Hz, 7-H), 5.29 (dd,
1 H, J 3.6 and 2.3 Hz, 8-H), 6.14 (d, 1 H, J 5.0 Hz, 4-H), 6.99 (d, 2 H, J 8.6
Hz, ArH) and 7.29–7.48 (m, 17 H, ArH); dC (DEPT, CDCl3) 21.5 (CH3),
42.7 (C), 45.5 (C), 47.7 (CH), 49.1 (CH), 59.4 (CH), 108.0 (CN), 109.1
(CN), 110.3 (CN), 111.2 (CN), 111.7 (CH), 127.4 (2CH), 128.0 (2CH),
128.8 (2CH), 129.1 (CH), 129.3 (4CH), 129.76 (2CH), 129.81 (CH), 130.1
(2CH), 130.3 (2CH), 130.6 (CH), 131.0 (C), 135.0 (C), 135.4 (C), 137.1 (C),
137.2 (C), 144.9 (C) and 149.4 (CO). For 5a (exo): mp 151–152 °C; m/z 679
(M+ + 1, 24%), 525 (M+ 2 TsH, 32%) and 481 (100%); nmax (KBr)/cm21
1170, 1386 and 1716 (CO); dH (270 MHz, [2H]10- p-xylene, [H,H]- and
[C,H]-COSY in CDCl3) 1.86 [s, 3 H, CH3 (Ts)], 2.21 (dd, 1 H, J 10.6 and
10.6 Hz, 5-H), 2.66 (br d, 1 H, J 10.6 Hz, 4a-H), 3.13 (br d, 1 H, J 10.6 Hz,
7-H), 3.34 (dd, 1 H, J 10.6 and 10.6 Hz, 6-H), 4.83 (br s, 1 H, 8-H), 6.90 (br
s, 1 H, 4-H) and 6.58–7.82 (m, 24 H, ArH); dC (DEPT, CDCl3) 21.5 (CH3),
43.2 (CH), 43.6 (CH), 46.1 (CH), 48.2 (CH), 58.7 (CH), 115.8 (CH), 126.1
(2CH), 126.3 (2CH), 127.4 (CH), 127.8 (CH), 128.3 (2CH), 128.5 (2CH),
128.68 (CH), 128.75 (2CH), 128.9 (3CH), 129.1 (6CH), 129.6 (CH), 131.3
3 S. Motoki, Y. Matsuo and Y. Terauchi, Bull. Chem. Soc. Jpn., 1990, 63,
284.
4 T. Saito, H. Kimura, K. Sakamaki, T. Karakasa and S. Moriyama, Chem.
Commun., 1996, 811.
5 O. Tsuge, T. Hatta, K. Yakata and H. Maeda, Chem. Lett., 1994, 1833;
O. Tsuge, T. Hatta, H. Yoshitomi, K. Kurosaka, T. Fujiwara, H. Maeda
and A. Kakehi, Heterocycles, 1995, 41, 225.
6 G. Spino and G. Liu, J. Org. Chem., 1993, 58, 817.
7 D. L. Boger and S. M. Weinreb, Hetero Diels–Alder Methodology in
Organic Synthesis, Academic, New York, 1987; D. L. Boger, in
Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and L. A.
Paquett, Pergamon, Oxford, 1991, vol. 5, p. 451; J. Barluenga, Adv.
Heterocycl. Chem., 1993, 57, 1.
8 J. Barluenga, I. Merino and F. Palacios, J. Chem. Soc., Perkin Trans. 1,
1991, 341; K. Eiter and H. Oediger, Justus Liebigs Ann. Chem., 1965,
682, 62.
9 D. L. Boger, W. L. Cobett, T. T. Curran and A. M. Kasper, J. Am. Chem.
Soc., 1991, 113, 1713.
10 S. Moriyama, T. Karakasa, T. Inoue, K. Kurashima, S. Satsumabayashi
and T. Saito, Synlett, 1996, 72.
11 LAOCOON III, D. F. Detar, Computer Programs for Chemistry, W. A.
Benjamin, Inc., New York 1968, vol. 1, p 10; Chemistry and Software
No. 8007 program was used. The following JCPE (Japan Chemistry
Program Exchange) programs were used: CONFLEX (program No.
P040), MOPAC 93 (program No. P081), and 3JHH2 (program No.
P012).
Received in Cambridge, UK, 6th March 1997; Com.
7/01575E
1014
Chem. Commun., 1997