Competitive thermal ene reaction and Diels-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones

Article abstract of DOI:10.1016/j.tet.2007.03.037

Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cyc

Full text of DOI:10.1016/j.tet.2007.03.037

Tetrahedron 63 (2007) 4548–4557
Competitive thermal ene reaction and Diels–Alder reactions of
2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-
4(4H)-ones
a
a
a
Michihiko Noguchi,a, Toshiya Sunagawa, Ryosuke Akao, Hisashi Yamada,
*
Hidetoshi Yamamotob and Akikazu Kakehic
aDepartment of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
bDepartment of Advanced Materials Science and Engineering, Graduate School of Science and Engineering,
Tokiwadai, Ube 755-8611, Japan
cDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 30 January 2007; revised 2 March 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-
ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cycloaddition
reaction between the a,b-unsaturated ester carbonyl moiety as a diene part and the alkenylamino moiety as an ene one. The reaction features
depended upon the kinds of substituents both on the vinyl and alkenyl counterparts; strongly electron-withdrawing substituents on the vinyl
moiety or an electron-donating substituent on the alkenyl one changed the reaction feature from the ene reaction to the hetero Diels–Alder
reaction.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
of the substituents both on the vinyl and alkenylamino parts;
when electron-withdrawing substituents such as cyano or
ethoxycarbonyl group resided on the vinyl moiety or an elec-
tron-donating substituent such as methyl or phenyl one did
on the alkenyl moiety, the hetero Diels–Alder reaction was
competing with or superior to the ene reaction. The scope
and limitations of these thermal reactions will be discussed.
Recently, we have reported on a facile and stereoselective
azepine-ring formation at the periphery of heterocyclic
systems via thermal imine- and carbonyl-ene reactions1 clas-
sified as a 7-(1,4) intramolecular ene reaction (Scheme 1).2
In order to develop the ene reaction, our next concern was
focused on the reaction of the similar substrates bearing
vinyl moiety as an enophile. The thermal reaction of 2-
(N-alk-2-enyl)-benzylamino-3-(2-substituted and 2,2-disub-
stituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave the
desired ene products and the hetero Diels–Alder adducts.
The latter products, therein, were formed by the [4+2] cyclo-
addition reaction of the a,b-unsaturated ester carbonyl moi-
ety of the substituted vinyl as a diene and the alkenyl moiety
as a dienophile. The reaction features depended on the kinds
2. Results and discussion
2.1. Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-
3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones
The starting 3-vinylpyridopyrimidines 2, 3, and 4 were
prepared by the reaction of 2-(N-allylbenzylamino)-3-for-
mylpyrido[1,2-a]pyrimidin-4(4H)-ones 1 with a Horner–
O
N
H
YH
O
O
6
R
7
CH=Y
1,7-Electrocyclization
N
YH
1,6-H Shift
antarafacial
N
N
H
7
N
Bn
conrotatory
N
Bn
R
N
1
N
N
Bn
R
1
Conjugated azomethine ylide
Y = O; NR'
Scheme 1. Reaction: (i) 7-(1,4) intramolecular ene reaction.
Keywords: Competitive reaction; Ene reaction; Diels–Alder reaction.
Y = O; NR'
* Corresponding author. Tel.: +81 836 85 9261; fax: +81 836 85 9201; e-mail: noguchi@yamaguchi-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.03.037

M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4549
Emmons reagent for 2, with diethyl malonate in refluxing
benzene in the presence of piperidine and acetic acid3 for
3, and with ethyl cyanoacetate in ethanol in the presence of
potassium carbonate for 4 (Scheme 2). Vinyl substrates 2a
and 4a were composed of inseparable mixtures of E- and
Z-isomers and the E/Z ratios were deduced to be >19:1 for
2 and >6:1 for 4 from their 1H NMR spectral data.
chromatographic purification on silica gel. The structure of
8 was also established by its spectroscopic data; the 1H–1H
COSY spectra of 8 elucidated two sets of alignment of meth-
ylene (d¼2.54 and 3.21; 5-H2)-methine (2.17; 4a-H)-me-
thine proton (4.34; 4-H) and methine (2.17; 4a-H)-methine
(4.15; 13b-H)-methylene ones (2.29 and 3.04; 1-H2). The
configurations among the 4-H, 4a-H, and 13b-H were
deduced to be trans (J4–4a¼9.9 Hz) and cis (J4a–13b: small)
also based on the coupling constants. The formation of 8
was explained by hydrolysis of ketene acetal moiety of 7.
The reaction of vinyl substrates 2a in refluxing xylene gave
the desired ene product, pyrido[10,20:1,2]pyrimido[4,5-
b]azepine 5a in good yields. The structure of 5a was estab-
lished by spectroscopic data in comparison with those of
the related azepine derivatives.1 In order to obtain further
information on the reaction features, substrates 2b and 2c
were allowed to react. While the thermal reaction of 2b in re-
fluxing xylene gave only azepine 5b, the similar reaction of
2c yielded a mixture of three isomeric products, azepine
5c, homo Diels–Alder adduct 6, and hetero Diels–Alder ad-
duct 7, in a good total yield (Scheme 3). The structure of 6
was also accomplished on the basis of its spectroscopic
These reaction features were explained by the frontier
molecular orbital (FMO) analysis5 using the model com-
pounds;6 the occupied p-electron energy level of the ene
moiety in 2c shifted upward and both Diels–Alder reactions
could be competitive with the ene reaction.
The thermal reaction of 4a gave the only product 11a in 76%
yield. In the 1H NMR spectrum of 11a, no signals assigned to
olefinic protons were shown and no absorption bands assign-
able to ester carbonyl were observed in its IR spectrum. The
13C NMR spectra including DEPT measurement of 11a
showed seven sp3-carbon signals; one methyl (d¼14.9),
four methylene (30.2, 50.1, 64.6, and 69.6), and two methine
ones (27.5 and 28.6). The 1H–13C and 1H–1H COSY spectra
of 11a elucidated two sets of the alignment of methylene
(d¼ca. 4.3; 4-H2)-methine (2.23; 4a-H)-methylene protons
(3.18 and 3.37; 5-H2) and methine (2.23; 4a-H)-methine
proton (ca. 4.3; 13b-H). The structure of 11a was deduced
to be 6-benzyl-1-cyano-2-ethoxy-4a,5,6,13b-tetrahydropyr-
ano[40,30:4,5]pyrido[2,3-d]pyrido[1,2-a]pyrimidin-13(4H)-
one comparing with the proton signal patterns of the similar
intramolecular hetero Diels–Alder adducts extensively stud-
ied by Tietze and other workers.7 Although the configuration
between the 4a-H and 13b-H in 11a could not be established
1
data; the H–1H COSY spectra of 6 elucidated two sets of
alignment of methylene (d¼ca. 3.0; 7-H2)-methine (2.49;
7a-H)-methylene protons (2.64 and 3.30; 8-H2) and methine
(2.49; 7a-H)-methine (4.01; 13a-H)-methine one (3.89;
13-H). This suggested that the framework of 6 was deduced
to be benzo[g]pyrido[10,20:1,2]pyrimido[4,5-c]isoquinoline
arising from the Diels–Alder reaction between the styrene
and vinyl moiety of 2c. The configurations among the
7a-H, 13a-H, and 13-H were deduced to be cis (J7a–13a
¼
4.6 Hz) and trans (J13a–13¼8.6 Hz) compared with the cou-
pling constants of the related ring systems obtained by the in-
tramolecular Diels–Alder reaction of the substrates bearing
styrene moiety as diene componentssuch as N-(E)-cinnamyl-
methyl fumaramic acid ethyl ester.4 On the other hand,
product 7 was not so stable and converted to 8 during the
O
O
N
O
N
O
CO2Et
CN
H
CO2Et
CO2Et
H
H
CO2Et
CHO
N
N
N
N
H
N
N
Bn
R
N
Bn
R
N
Bn
R
N
N
Bn
R
2a: R = H
2b: R = Me
2c: R = Ph
3a: R = H
3b: R = Me
1a: R = H
1b: R = Me
1c: R = Ph
4a: R = H
4b: R = Me
4c: R = Ph
Scheme 2. Mono(ethoxycarbonyl)- 2, bis(ethoxycarbonyl)- 3, and cyano(ethoxycarbonyl)-substituted vinyl substrates 4.
O
Es
O
N
O
N
O
O
H
CO2Et
H
R
H
13b
4
N
N
5
N
Ph
4
4a
H
N
Bn
R
N
Bn
N
N
Bn
Es = CO2Et
8
2a: R = H; 2b: R = Me
5a: R = H; 5b: R = Me
OEt
Es
13
Es
H
O
O
O
O
H
O
Ph
H
CO2Et
H
13a
7a
8
N
N
N
Ph
N
H
+
H
+
N
N
N
N
N
N
N
N
Ph
7
Bn
Bn
Bn
Bn
7
2c
5c
6
Scheme 3. Thermal reaction of 2 leading to ene products 5 and/or Diels–Alder products 6 and 7.

4550
M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
Table 1. Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-
substituted or 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones 2,
3, and 4
due to the signal overlapping of 4-H and 13b-H, it was tenta-
tively assigned to be cis from the similarity to the signal pat-
terns of other cis-annulated products and the results of X-ray
single crystal structure analysis of similar hetero Diels–Alder
cycloadducts as described later. Similar reaction of 3-[(2-
cyano-2-ethoxycarbonyl)vinyl] substrate 4b and 4c gave
only hetero Diels–Alder adducts 11b and 11c in good yields
(Scheme 4). Therein, addition of tertiary amines such as
triethylamine and diisopropylethylamine to the reaction
mixture accelerated the progress of the hetero Diels–Alder
reaction (Table 1, runs 7, 9, and 10). Probably, the isomeriza-
tion between E- and Z-isomers of 4a–4c could be catalyzed
by the tertiary amines and only the Z-isomers could perform
the hetero Diels–Alder reaction in an endo approaching man-
ner leading to products 11. Especially, the condensation of
aldehyde 1c and ethyl cyanoacetate in ethanol at room
temperature afforded an inseparable (1:4) mixture of hetero
Diels–Alder adduct 11c and the desired 4c.
Entry Substrate Solvent/under reflux Time (h) Products/Yielda (%)
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
3a
3b
4a
4a
4b
4b
4ce
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylenec
Xylene
Benzened
Benzened
80
70
26
45
28
24
24
24
30
15
5a/75
5b/80
5c/35; 6/35; 8/11
9a/73
9b/ca. 35; 10/42b
11a/76
11a/88
11b/80
11b/92
11c/86
a
Based on isolated products.
b
c
d
e
Two other unidentified products were also obtained.
EtN(i-Pr)2 (1.0 equiv) was added.
NEt3 (1.0 equiv) was added.
A (4:1) mixture of 4c and 11c was used.
The competition between the hetero Diels–Alder reaction
and the ene reaction similar to that of substrates 2 was also
observed in the thermal reaction of 3-[2,2-bis(ethoxycarbo-
nyl)]vinyl substrates 3a and 3b; the thermal reaction of 3a
gave azepine 9a, while the reaction of 3b gave 9b and hetero
Diels–Alder adduct 10 in ca. 35 and 42% yields, respec-
tively. The configurations of the 4- and 5-position of the aze-
pine ring of 5b, 5c, and 9b could not be established only by
their coupling constants, we assigned them to be cis on the
basis of the stereochemical strictness of the imine- and car-
bonyl-ene reactions in this system.1b These results are sum-
marized in Schemes 3 and 4 and Table 1.
2–4 would change from the ene reaction to the hetero Diels–
Alder reaction.6
2.2. The competitive thermal ene and hetero Diels–Alder
reactions in other heterocyclic systems
In order to obtain further information on the reaction
features, we examined the similar reactions in other two
systems;
4-(N-allylbenzylamino)-3-vinyl[1]benzopyran-
2(2H)-ones 12 and 6-(N-allylbenzylamino)-1,3-dimethyl-
5-vinylpyrimidine-2,4(1H,3H)-diones 13 were prepared.
The reaction of 2-(ethoxycarbonyl)vinyl 12a and 2,2-[bis-
(ethoxycarbonyl)]vinyl 12b in refluxing xylene gave the ex-
pected ene products 14a and 14b. On the other hand, a similar
reaction of [2-cyano-2-(ethoxycarbonyl)]vinyl 12c gave het-
ero Diels–Alder adduct 15 in a moderate yield along with the
unreacted 12c. Addition of 1,8-diazabicyclo[2.2.2]octane
(DABCOÔ) as a tertiary amine to the reaction mixture did
not provide any improvement of the yield of 15. Fortunately,
X-ray single crystal structure analysis9 was accomplished
As described above, strongly electron-withdrawing substitu-
ents on the vinyl moiety and an electron-donating one on the
alkenylamino moiety changed the reaction feature from the
ene reaction to the hetero Diels–Alder reaction. These re-
sults suggest that the hetero Diels–Alder reaction proceeds
in an inverse electron-demanded manner.8 The reaction fea-
tures were also explained by the FMO analysis; the calcula-
tion results showed that the frontier p-electron energy levels
(p*) of a,b-unsaturated ester carbonyl moieties of 2a, 3a,
and 4a were expected to shift downward in the order. The
frontier p*-level becomes closer to the frontier p-level
and the interaction between the frontier orbitals would be
predominantly operated. The reaction features of substrates
1
for products 15 and 1610 and, consequently, the H NMR
spectral assignments concerning the pyran and pyridine
ring of the hetero Diels–Alder adducts 15 and 16 were fully
accomplished. Finally, the reaction of 13a and 13b in reflux-
ing o-dichlorobenzene (ODCB) gave ene products 17a and
17b in moderate to good yields together with a small amount
OEt
CHEs2
N
O
O
N
Es
H
H
CO2Et
CO2Et
CHEs2
O
O
O
Me
13b
4a
4
N
N
5
4
N
N
Me
+
H
N
N
Bn
R
N
N
Bn
N
N
Bn
Bn
9a
3a: R = H; 3b: R = Me
Es: CO2Et
9b
10b
OEt
NC
H
O
O
O
H
CO2Et
13b
4a
4
N
R
N
CN
R
H
N
N
N
N
Bn
Bn
a: R = H; b: R = Me; c: R = Ph
11
4
Scheme 4. Thermal reaction of 3 and 4 leading to ene products 9 and/or Diels–Alder products 10b and 11.

M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4551
OEt
OEt
O
NC
H
CHZEs
N
O
H
CO2Et
Z
NC
H
O
O
H
O
O
12b
4a
12b
4a
O
4
Ph
O
O
1)
2)
O
H
N
Bn
N
Bn
N
Bn
Bn
16
12a: Z = H
12b: Z = CO2Et
12c: Z = CN
15 (50%)
14a: Z = H (79%)
14b: Z = CO2Et (83%)
Es = CO2Et
OEt
NC
H
CHZEs
CHZEs
N
O
O
O
O
H
O
H
CO2Et
Z
10a
4a
Me
O
Me
N
Me
O
Me
N
N
3)
3)
N
+
N
Me
O
N
N
N
Bn
N
Me
O
N
N
Me Bn
Me Bn
Bn
13a: Z = H
13b: Z = CO2Et
13c: Z = CN
17c: Z = CN (51%)
18 (41%)
17a: Z = H (69%)
17b: Z = CO2Et (78%)
Scheme 5. Reaction of 12 and 13 leading to ene products 14 and 17 and/or hetero Diels–Alder products 15 and 18. Reaction conditions: (1) xylene, reflux, 20 h;
(2) xylene, reflux, 36 h; (3) ODCB, reflux, 25 h.
of polymeric products. On the other hand, the similar reac-
tion of 13c gave ene product 17c and hetero Diels–Alder
adduct 18 (Scheme 5).
dimethylpyrimidin-2,4(1H,3H)-dione in this study were
known.1
4.2. Preparation of mono(ethoxycarbonyl)-substituted
vinyl compounds 2, 12a, and 13a
3. Conclusions
Typical procedures. To a solution of aldehyde 1a (0.32 g,
1.0 mmol) and ethyl (diethylphosphono)acetate (0.27 g,
1.0 mmol) in THF (5 ml), 0.12 g of sodium hydride (50%
in mineral oil; 2.5 mmol) was added, and the resultant mix-
ture was stirred at room temperature for 2 h. The solvent was
evaporated and the residue was extracted with dichloro-
methane (2ꢀ20 ml). The dichloromethane was evaporated
to dryness. The residue was subjected to silica-gel column
chromatography to afford 2a (0.18 g, 46%) with hexane/
ethyl acetate (3/1) as an eluent.
2-(Ethoxycarbonyl)- and[2-(ethoxycarbonyl)-2-substituted]-
vinyl heterocyclic compounds bearing the (alk-2-enyl)amino
moiety at the adjacent position performed a competitive
7-(1,4) intramolecular ene reaction and hetero Diels–Alder
reaction. The reaction features depended upon the electronic
nature of both the substituents of the alkenylamino and the
vinyl moieties and we suggested the the FMO analysis should
be useful for their understandings.
4. Experimental section
4.1. General
4.2.1. 2-(N-Allylbenzylamino)-3-(2-ethoxycarbonyl)-
vinylpyrido[1,2-a]pyrimidin-4(4H)-one (2a). Yellow crys-
tals from EtOH; mp 155–156 ꢁC; IR (KBr): 1700,
1680 cmꢂ1
;
1H NMR (CDCl3): 1.25 (3H, t, J¼7.3 Hz,
Melting points were measured on a Yamagimoto micro melt-
ing point apparatus and are uncorrected. IR spectra were
measured on JASCO IR-Report-100 or HORIBA FT-200
spectrophotometer from samples as KBr pellets or NaCl
discs. NMR spectra were measured on a JEOL EX-270
CH2CH3), 4.06 (2H, d, J¼5.6 Hz, –CH2CH]), 4.18 (2H,
q, J¼7.3 Hz, CH2CH3), 4.82 (2H, s, CH2Ph), 5.20–5.31 (2H,
ov, ]CH2), 5.99 (1H, m, –CH2CH]), 6.95 (1H, dd, J¼6.6,
7.3 Hz, 7-H), 7.16 (1H, d, J¼15.5 Hz, –CH]CH–Es), 7.26–
7.33 (6H, ov, Ph–H and 9-H), 7.62 (1H, dd, J¼6.6, 7.0 Hz,
8-H), 7.72 (1H, d, J¼15.5 Hz, –CH]CH–Es), 8.93 (1H, d,
J¼7.3 Hz, 6-H). Anal. Calcd for C23H23N3O3 (389.4): C,
70.93; H, 5.95; N, 10.79%; found: C, 70.89; H, 5.96; N,
10.74%. This compound was a (19:1) mixture of E- and Z-
isomer; 1H NMR spectral signals due to the Z-isomer: 6.76
(d, J¼11.5 Hz, –CH]CH–Es), 6.88 (7-H), 9.91 (6-H).
1
spectrometer (270 MHz for H and 67.8 MHz for 13C) in
deuteriochloroform solutions. Tetramethylsilane was used
as internal standard and J values are given in hertz. Splitting
patterns are indicated as: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad signal; and ov, overlapping
signals. Elemental analyses were performed on a Hitachi
026 CHN analyser. All non-aqueous reactions were run under
positivepressure of argon or nitrogen. All solventsweredried
by standard methods before use. The progress of reactions
was monitored by TLC (silica gel 60 F254, Merck). Chroma-
tographic purification was performed with Wakogel C-200
(100–200 mesh, Wako Pure Chemical Industries) and/or
silica gel 60 (230–400 mesh, Merck). The starting aldehydes
4.2.2. 2-[N-Benzyl-(E)-(but-2-enyl)amino]-3-(2-ethoxy-
carbonyl)vinylpyrido[1,2-a]pyrimidin-4(4H)-one (2b).
Yellow prisms from EtOH; mp 148–149 ꢁC; IR (KBr):
1720, 1660 cmꢂ1
;
1H NMR (CDCl3): 1.27 (3H, t,
J¼7.3 Hz, CH2CH3), 1.74 (3H, br d, J¼4.3 Hz, ]CH–
Me), 3.99 (2H, d, J¼4.0 Hz, pNCH2CH]), 4.18 (2H, q, J¼
7.3 Hz, CH2CH3), 4.81 (2H, s, CH2Ph), 5.56–5.65 (2H, ov,
–CH]CH–Me), 6.94 (1H, dd, J¼7.0, 7.3 Hz, 7-H), 7.15
1a–1c,
2(2H)-one
4-(N-allylbenzylamino)-3-formyl[1]benzopyran-
and 6-(N-allylbenzylamino)-5-formyl-1,3-

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M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
(1H, d, J¼15.5 Hz, –CH]CH–Es), 7.26–7.32 (6H, ov, Ph–H
and 9-H), 7.62 (1H, dd, J¼5.3, 7.0 Hz, 8-H), 7.70 (1H, d,
J¼15.5 Hz, –CH]CH–Es), 8.94 (1H, br d, J¼7.3 Hz,
6-H). Anal. Calcd for C24H25N3O3 (403.5): C, 71.44; H,
6.24; N, 10.41%; found: C, 71.87; H, 6.37; N, 10.38%.
(6H, ov, Ph–H and 9-H), 7.58 (1H, –CH]CEs2), 7.70
(1H, dd, J¼6.0, 6.6 Hz, 8-H), 8.89 (1H, br d, J¼7.3 Hz, 6-
H). Anal. Calcd for C26H27N3O5 (461.5): C, 67.66; H,
5.90; N, 9.11%; found: C, 67.75; H, 5.89; N, 9.14%.
4.3.2. 2-[N-Benzyl-(E)-(but-2-enyl)amino]-3-[2,2-bis-
(ethoxycarbonyl)vinyl]pyrido[1,2-a]pyrimidin-4(4H)-
one (3b). Yellow prisms from hexane/benzꢂen1e; mp 132–
4.2.3. 2-[N-Benzyl-(E)-cinnamylamino]-3-(2-ethoxy-
carbonyl)vinylpyrido[1,2-a]pyrimidin-4(4H)-one (2c).
Yellow crystals from EtOH; mp 162–163 ꢁC; IR (KBr):
1700, 1660 cmꢂ1; 1H NMR (CDCl3): 1.22 (3H, t, J¼7.1 Hz,
CH2CH3), 4.15 (2H, q, J¼7.1 Hz, CH2CH3), 4.29 (2H, d,
J¼6.3 Hz, pNCH2CH]), 4.86 (2H, s, CH2Ph), 6.34 (1H,
td, J¼6.3, 15.8 Hz, –CH]CH–Ph), 6.49 (1H, d, J¼15.8 Hz,
–CH]CH–Ph), 6.97 (1H, dd, J¼6.6, 7.3 Hz, 7-H), 7.17
(1H, d, J¼15.5 Hz, –CH]CH–Es), 7.20–7.40 (11H, ov,
Ph–H and 9-H), 7.67 (1H, dd, J¼6.6, 7.0 Hz, 8-H), 7.75 (1H,
d, J¼15.5 Hz, –CH]CH–Es), 8.97 (1H, br d, J¼7.3 Hz,
6-H). Anal. Calcd for C29H27N3O3 (465.5): C, 74.82; H,
5.85; N, 9.03%; found: C, 74.66; H, 6.05; N, 9.01%.
133 ꢁC; IR (KBr): 1710, 1700, 1660 cm
;
1H NMR
(CDCl3): 1.24, 1.33 (each 3H, each t, J¼7.3 Hz, CH2CH3),
1.73 (3H, d, J¼4.3 Hz, –CH]CH–Me), 4.02 (2H, d,
J¼4.6 Hz, –CH2CH]), 4.16, 4.35 (each 2H, each q, J¼
7.3 Hz, CH2CH3), 4.82 (2H, s, CH2Ph), 5.59–5.64 (2H, ov,
–CH]CH–Me), 6.90 (1H, dd, J¼7.0, 7.3 Hz, 7-H), 7.23–
7.36 (6H, ov, Ph–H and 9-H), 7.56 (1H, s, –CH]CEs2),
7.62 (1H, dd, J¼5.3, 7.0 Hz, 8-H), 8.88 (1H, d, J¼7.3 Hz,
6-H). Anal. Calcd for C27H29N3O5 (475.3): C, 68.19; H,
6.15; N, 8.84%; found: C, 68.02; H, 6.15; N, 8.83%.
4.3.3. 4-(N-Allylbenzylamino)-3-[2,2-bis(ethoxycarbo-
nyl)vinyl][1]benzopyran-2(2H)-one (12b). Pale yellow
crystals from hexane/benzene; mp 108–109 ꢁC; IR (KBr):
4.2.4. 4-(N-Allylbenzylamino)-3-(2-ethoxycarbonyl)-
vinyl[1]benzopyran-2(2H)-one (12a). Yellow prisms from
1
EtOH; mp 119–120 ꢁC; IR (KBr): 1720, 1670 cmꢂ1; H
1740, 1710, 1660 cmꢂ1 1H NMR (CDCl3): 1.29, 1.30
;
NMR (CDCl3): 1.30 (3H, t, J¼7.3 Hz, CH2CH3), 3.88 (2H,
d, J¼6.9 Hz, pNCH2CH]), 4.23 (2H, q, J¼7.3 Hz,
CH2CH3), 4.56 (2H, s, CH2Ph), 5.25 (1H, dd, J¼1.3,
17.1 Hz, –CH]CHH), 5.36 (1H, dd, J¼1.3, 10.2 Hz,
–CH]CHH), 5.85 (1H, m, –CH2CH]CH2), 7.06 (1H, d,
J¼15.8 Hz, –CH]CH–Es), 7.18–7.64 (10H, ov, Ar–H and
–CH]CH–Es). Anal. Calcd for C24H23NO4 (389.4): C,
74.02; H, 5.95; N, 3.60%; found: C, 73.82; H, 6.21; N, 3.83%.
(each 3H, each t, J¼7.3 Hz, CH2CH3), 3.89 (2H, d,
J¼6.6 Hz, pNCH2CH]), 4.22–4.34 (4H, ov, CH2CH3),
4.58 (2H, s, CH2Ph), 5.26 (1H, dd, J¼1.3, 17.2 Hz,
–CH]CHH), 5.36 (1H, dd, J¼1.3, 10.2 Hz, –CH]CHH),
5.85 (1H, m, –CH2CH]CH2), 7.19–7.39 (7H, ov, Ar–H),
7.40 (1H, s, 3-CH]CEs2), 7.52–7.62 (2H, ov, Ar–H).
Anal. Calcd for C27H27NO6 (461.5): C, 70.27; H, 5.90; N,
3.04%; found: C, 69.82; H, 6.12; N, 3.32%.
4.2.5. 6-(N-Allylbenzylamino)-5-(2-ethoxycarbonyl)-
vinyl-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (13a).
Colorless crystals from EtOH; mp 124–125 ꢁC; IR (KBr):
4.3.4. 6-(N-Allylbenzylamino)-5-[2,2-bis(ethoxycarbo-
nyl)vinyl]-1,3-dimethylpyrimidin-2,4(1H,3H)-dione
(13b). Colorless crystals from EtOH; mp 151–152 ꢁC; IR
1
1
1700, 1670, 1660 cmꢂ1; H NMR (CDCl3): 1.27 (3H, t,
(KBr): 1720, 1710, 1670 cmꢂ1; H NMR (CDCl3): 1.26,
J¼7.3 Hz, CH2CH3), 3.34 (3H, s, 1-Me), 3.38 (3H, s,
3-Me), 4.06 (2H, d, J¼6.9 Hz, pNCH2CH]), 4.19 (2H, q,
J¼7.3 Hz, CH2CH3), 4.28 (2H, s, CH2Ph), 5.27–5.40 (2H,
ov, –CH]CH2), 5.84 (1H, m, –CH]CH2), 7.05 (1H, d,
J¼15.5 Hz, –CH]CH–Es), 7.17–7.40 (6H, ov, Ph–H and
–CH]CH–Es). Anal. Calcd for C21H25N3O4 (383.4): C,
65.78; H, 6.57; N, 10.96%; found: C, 66.10; H, 6.39; N,
10.69%.
1.27 (each 3H, each t, J¼7.3 Hz, CH2CH3), 3.31 (3H, s,
1-Me), 3.33 (3H, s, 3-Me), 3.63 (2H, d, J¼6.9 Hz,
pNCH2CH]), 4.17–4.34 (6H, ov, CH2CH3 and CH2Ph),
5.27–5.40 (2H, ov, –CH]CH2), 5.83 (1H, m, –CH]CH2),
7.12 (1H, s, –CH]CEs2), 7.19–7.39 (5H, ov, Ph–H). Anal.
Calcd for C24H29N3O6 (455.5): C, 63.28; H, 6.42; N,
9.22%; found: C, 63.12; H, 6.29; N, 9.23%.
4.4. Preparation of [cyano(ethoxycarbonyl)]-substituted
vinyl compounds 4, 12c, and 13c
4.3. Preparation of bis(ethoxycarbonyl)-substituted
vinyl compounds 3, 12b, and 13b
Typical procedures. A solution of aldehyde 1a (0.64 g,
2.0 mmol), ethyl cyanoacetate (3 ml, 15.6 mmol), potassium
acetate (0.41 g, 4.2 mmol) in EtOH (10 ml) was stirred at
room temperature for 6 h. Usual work-up using silica-gel col-
umn gave 4a (0.80 g, 96%) with hexane/ethyl acetate (3/1).
Typical procedures. A solution of aldehyde 1a (0.64 g,
2.0 mmol), diethyl malonate (0.30 ml, 2.2 mmol), piperidine
(0.40 ml, 4.0 mmol), and acetic acid (0.23 ml, 4.0 mmol) in
benzene (10 ml) was refluxed for 12 h. Usual work-up using
silica-gel column gave 3a (0.27 g, 31%) with hexane/ethyl
acetate (4/1).
4.4.1. 2-(N-Allylbenzylamino)-3-(2-cyano-2-ethoxycar-
bonyl)vinylpyrido[1,2-a]pyrimidin-4(4H)-one (4a). Yel-
1
4.3.1. 2-(N-Allylbenzylamino)-3-[2,2-bis(ethoxycarbo-
nyl)vinyl]pyrido[1,2-a]pyrimidin-4(4H)-one (3a). Yellow
prisms from EtOH; mp 114–116 ꢁC; IR (KBr): 1710, 1700,
1680 cmꢂ1; 1H NMR (CDCl3): 1.23, 1.36 (each 3H, each t,
J¼7.3 Hz, CH2CH3), 4.09 (2H, d, J¼5.6 Hz, pNCH2CH]),
4.16, 4.36 (each 2H, each d, J¼7.3 Hz, CH2CH3), 4.84 (2H,
s, CH2Ph), 5.19–5.32 (2H, ov, –CH]CH2), 5.94 (1H, m,
–CH]CH2), 6.92 (1H, dd, J¼6.6, 7.3 Hz, 7-H), 7.24–7.36
low paste; IR (KBr): 2200, 1710, 1680, 1660 cmꢂ1; H
NMR (CDCl3): 1.33 (3H, t, J¼7.3 Hz, CH2CH3), 4.11 (2H,
d, J¼5.6 Hz, pNCH2CH]), 4.29 (2H, q, J¼7.3 Hz,
CH2CH3), 4.85 (2H, s, CH2Ph), 5.16–5.31 (2H, ov, –CH]
CH2), 5.91 (1H, m, –CH]CH2), 6.98 (1H, dd, J¼6.6,
7.3 Hz, 7-H), 7.26–7.37 (6H, ov, Ph–H and 9-H), 7.70 (1H,
dd, J¼6.6, 7.0 Hz, 8-H), 8.26 (1H, s, –CH]C(CN)Es),
8.96 (1H, br d, J¼7.3 Hz, 6-H). Anal. Calcd for

M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4553
C23H22N4O3 (414.5): C, 69.55; H, 5.35; N, 13.52%; found:
C, 69.92; H, 5.51; N, 13.32%. This compound was a (6:1)
mixture of E- and Z-isomer; 1H NMR spectral signal due to
the Z-isomer: 8.87 (br d, J¼7.3 Hz, 6-H).
silica-gel column chromatography with hexane/ethyl acetate
(3/1) as an eluent to afford 5a (0.12 g, 75%).
4.5.1. 1-Benzyl-5-(ethoxycarbonyl)methyl-4,5-dihydro-
pyrido[10,20:1,2]pyrimido[4,5-b]azepin-6(1H)-one (5a).
4.4.2. 2-[N-Benzyl-(E)-(but-2-enyl)amino]-3-(2-cyano-2-
ethoxycarbonyl)vinylpyrido[1,2-a]pyrimidin-4(4H)-one
Yellow paste; IR (NaCl): 1730, 1650 cmꢂ1 1H NMR
;
(CDCl3): 1.16 (3H, t, J¼7.3 Hz, CH2CH3), 2.32–2.62 (4H,
ov, 4-H2 and 5-CH2Es), 4.07 (2H, q, J¼7.3 Hz, CH2CH3),
4.52 (1H, m, 5-H), 4.90 (1H, m, 3-H), 5.10, 5.20 (each 1H,
each d, J¼15.8 Hz, CH2Ph), 6.04 (1H, dd, J¼2.3, 9.9 Hz,
2-H), 6.86 (1H, dd, J¼6.6, 7.3 Hz, 9-H), 7.21–7.37 (6H,
ov, Ph–H and 11-H), 7.49 (1H, dd, J¼5.0, 7.3 Hz, 10-H),
8.86 (1H, br d, J¼6.6 Hz, 8-H); 13C NMR (CDCl3): 14.0
(CH2CH3), 31.1 (4-C), 31.6 (5-C), 37.8 (5-CH2CO–), 55.5
(CH2Ph), 60.0 (OCH2CH3), 103.2 (5a-C), 107.1 (3-C),
113.0 (10-C), 124.7 (9-C), 127.0, 127.5, 128.6, 138.8 (Ph–
C), 128.3 (8-C), 130.6 (2-C), 135.0 (11-C), 147.1 (12a-C),
157.6, 158.3 (6- and 11a-C), 172.3 (CO2). Anal. Calcd for
C23H23N3O3 (389.4): C, 70.93; H, 5.95; N, 10.79%; found:
C, 70.48; H, 6.12; N, 10.43%.
1
(4b). Yellow paste; IR (KBr): 2200, 1720, 1670 cmꢂ1; H
NMR (CDCl3): 1.35 (3H, t, J¼7.3 Hz, CH2CH3), 1.71
(3H, d, J¼5.0 Hz, ]CH–Me), 4.02 (2H, d, J¼4.6 Hz,
pNCH2CH]), 4.30 (2H, q, J¼7.3 Hz, CH2CH3), 4.83 (2H,
s, CH2Ph), 5.52–5.60 (2H, ov, –CH]CH–), 6.95 (1H, dd, J¼
7.0, 7.3 Hz, 7-H), 7.24–7.36 (6H, ov, Ph–H and 9-H), 7.72
(1H, dd, J¼5.3, 7.0 Hz, 8-H), 8.25 (1H, s, –CH]C(CN)Es),
8.94 (1H, br d, J¼7.3 Hz, 6-H). Anal. Calcd for C25H24N4O3
(428.5): C, 70.07; H, 5.65; N, 13.08%; found: C, 69.65; H,
5.81; N, 12.71%. This compound was a (7:1) mixture of E-
and Z-isomer; 1H NMR spectral signal due to the Z-isomer:
8.85 (br d, J¼7.3 Hz, 6-H).
4.4.3. 2-[N-Benzyl-(E)-cinnamylamino]-3-(2-cyano-2-
ethoxycarbonyl)vinylpyrido[1,2-a]pyrimidin-4(4H)-one
(4c). This was obtained as an inseparable (4:1) mixture with
4.5.2. (4R*,5S*)-( )-1-Benzyl-5-(ethoxycarbonyl)methyl-
4-methyl-4,5-dihydropyrido[10,20:1,2]pyrimido[4,5-
b]azepin-6(1H)-one (5b). Pale yellow paste; IR (NaCl):
1
hetero Diels–Alder product 11c. Compound 4c: H NMR
(CDCl3): 1.28 (3H, t, J¼7.3 Hz, CH2CH3), 4.22 (2H, q,
J¼7.3 Hz, CH2CH3), 4.31 (2H, d, J¼6.2 Hz, pNCH2CH]),
4.85 (2H, s, CH2Ph), 6.30 (1H, td, J¼6.2, 15.5 Hz,
–CH]CHPh), 6.55 (1H, d, J¼15.5 Hz, –CH]CHPh),
6.95 (1H, dd, J¼7.0, 7.3 Hz, 7-H), 7.24–7.37 (11H, ov,
Ph–H and 9-H), 7.72 (1H, dd, J¼5.3, 7.0 Hz, 8-H), 8.28
(1H, s, –CH]C(CN)Es), 8.94 (1H, br d, J¼7.3 Hz, 6-H).
1720, 1660 cmꢂ1 1H NMR (CDCl3): 1.05 (3H, d,
;
J¼6.9 Hz, CH2CH3), 1.15 (3H, d, J¼7.3 Hz, 4-Me), 2.42
(1H, dd, J¼10.2, 14.5 Hz, pNCHHCO–), 2.53 (1H, dd,
J¼4.6, 14.5 Hz, pNCHHCO–), 2.82 (1H, m, 4-H), 3.97
(2H, q, J¼6.9 Hz, CH2CH3), 4.33 (1H, m, 5-H), 4.54 (1H,
br td, J¼2.1, 10.2 Hz, 3-H), 5.09, 5.26 (each 1H, each d,
J¼15.5 Hz, CH2Ph), 5.93 (1H, dd, J¼3.0, 10.2 Hz, 2-H),
6.87 (1H, dd, J¼6.6, 7.3 Hz, 9-H), 7.23–7.38 (6H, ov, Ph–
H and 11-H), 7.50 (1H, dd, J¼5.0, 7.3 Hz, 10-H), 8.88
(1H, d, J¼6.6 Hz, 8-H); 13C NMR (CDCl3): 14.0
(CH2CH3), 21.2 (4-Me), 33.7 (5-CH2Es), 35.8 (4-C), 37.1
(5-C), 55.5 (CH2Ph), 60.0 (OCH2CH3), 103.9 (5a-C),
112.4 (3-C), 113.0 (10-C), 124.9 (9-C), 127.1, 127.8,
128.6, 139.0 (Ph–C), 128.0 (8-C), 128.5 (2-C), 135.0 (11-
C), 147.3 (12a-C), 157.3 (11a-C), 158.5 (6-C), 173.2
(CO2). Anal. Calcd for C24H25N3O3 (403.5): C, 71.44; H,
6.24; N, 10.41%; found: C, 71.08; H, 6.00; N, 10.22%.
4.4.4. 4-(N-Allylbenzylamino)-3-(2-cyano-2-ethoxy-
carbonyl)vinyl[1]benzopyran-2(2H)-one (12c). Yellow
prisms from EtOH; mp 151–152 ꢁC; IR (KBr): 2225,
1740, 1660 cmꢂ1
;
1H NMR (CDCl3): 1.37 (3H, t, J¼
7.3 Hz, CH2CH3), 3.98 (2H, d, J¼5.6 Hz, pNCH2CH]),
4.34 (2H, q, J¼7.3 Hz, CH2CH3), 4.62 (2H, s, CH2Ph),
5.25–5.42 (2H, ov, –CH]CH2), 5.85 (1H, m, –CH]
CH2), 7.16–7.67 (9H, ov, Ar–H), 7.95 (1H, s, –CH]
C(CN)Es). Anal. Calcd for C25H22N2O4 (414.4): C, 72.45;
H, 5.35; N, 6.76%; found: C, 72.23; H, 5.36; N, 6.80%.
4.5.3. (4R*,5S*)-( )-1-Benzyl-5-(ethoxycarbonyl)methyl-
4-phenyl-4,5-dihydropyrido[10,20:1,2]pyrimido[4,5-
b]azepin-6(1H)-one (5c). Pale yellow prisms from hexane/
benzene; mp 157–158 ꢁC; IR (KBr): 1725, 1665,
4.4.5. 6-(N-Allylbenzylamino)-5-(2-cyano-2-ethoxycar-
bonyl)vinyl-1,3-dimethylpyrimidin-2,4(1H,3H)-dione
(13c). Pale yellow needles from EtOH; mp 146–147 ꢁC; IR
(KBr): 2200, 1710, 1660 cmꢂ1; 1H NMR (CDCl3): 1.33 (3H,
t, J¼7.3 Hz, CH2CH3), 3.41 (3H, s, 1-Me), 3.41 (3H, s, 3-Me),
3.64 (2H, d, J¼6.9 Hz, pNCH2CH]), 4.28, 4.31 (each 1H,
each d, J¼13.3 Hz, CH2Ph), 5.33 (1H, br d, J¼17.2 Hz,
]CHH), 5.43 (1H, br d, J¼10.2 Hz, ]CHH), 5.82 (1H, m,
–CH]CH2), 7.20–7.39 (5H, ov, Ph–H), 7.62 (1H, s, –CH]
C(CN)Es). Anal. Calcd for C22H24N4O4 (408.4): C, 64.69;
H, 5.92; N, 13.72%; found: C, 64.75; H, 5.88; N, 13.51%.
1650 cmꢂ1
;
1H NMR (CDCl3): 0.93 (3H, t, J¼7.3 Hz,
CH2CH3), 2.33 (1H, dd, J¼4.6, 15.2 Hz, 5-CHHCO2–),
2.57 (1H, dd, J¼13.6, 15.2 Hz, 5-CHHCO2–), 3.71–3.86
(2H, ov, CH2CH3), 4.05 (1H, br dd, J¼2.6, 5.9 Hz, 4-H),
4.59 (1H, m, 5-H), 4.96 (1H, td, J¼2.3, 10.6 Hz, 3-H),
5.04, 5.44 (each 1H, each d, J¼15.2 Hz, CH2Ph), 6.20
(1H, dd, J¼3.0, 10.6 Hz, 2-H), 6.92 (1H, ddd, J¼1.3, 6.6,
7.0 Hz, 9-H), 7.21–7.51 (11H, ov, Ph–H and 11-H), 7.54
(1H, ddd, J¼1.0, 7.0, 8.9 Hz, 10-H), 8.93 (1H, dd, J¼1.0,
6.6 Hz, 8-H); 13C NMR (CDCl3): 13.8 (CH2CH3), 32.7 (5-
C), 37.8 (5-CH2CO2–), 45.6 (6-C), 55.4 (CH2Ph), 59.9
(OCH2CH3), 103.1 (5a-C), 108.5 (3-C), 113.2, 125.0,
126.5, 127.4, 127.8, 128.1, 128.3, 128.5, 130.5, 130.5,
135.2, 138.8, 143.6 (Ph–C and 2-, 8-, 9-, 10- and 11-C),
147.5 (12a-C), 157.9, 158.7 (6- and 11a-C), 172.5 (CO2).
Anal. Calcd for C29H27N3O3 (465.5): C, 74.82; H, 5.85; N,
8.91%; found: C, 74.52; H, 5.90; N, 8.91%.
4.5. Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-
3-(2-ethoxycarbonyl)vinylpyrido[1,2-a]pyrimidin-
4(4H)-ones 2
Typical procedures. A solution of 2a (0.16 g, 0.4 mmol) in
dry xylene (10 ml) was deoxygenated by flushing of argon
stream for 30 min and refluxed for 80 h. The solvent was
evaporated to dryness and the residue was subjected to

4554
M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4.5.4. (7aR*,13S*,13aR*)-( )-6-Benzyl-13-(ethoxycar-
bonyl)-6,7,7a,8,13,13a-hexahydrobenzo[g]pyrido[10,20:
1,2]-pyrimido[4,5-c]isoquinolin-14(14H)-one (6). Color-
less prisms from hexane/benzene; mp 84–86 ꢁC; IR (KBr):
ov, 5-CHEs2 and CH2CH3), 4.22 (2H, q, J¼7.3 Hz,
CH2CH3), 4.76–4.86 (2H, ov, 3- and 5-H), 5.10, 5.23 (each
1H, each d, J¼15.2 Hz, CH2Ph), 6.02 (1H, dd, J¼1.3,
9.6 Hz, 2-H), 6.89 (1H, dd, J¼6.6, 8.3 Hz, 9-H), 7.23–7.42
(6H, ov, Ph–H and 11-H), 7.53 (1H, dd, J¼5.0, 8.3 Hz,
10-H), 8.88 (1H, br d, J¼6.6 Hz, 8-H); 13C NMR (CDCl3):
13.6, 14.1 (CH2CH3), 30.2 (4-C), 33.9 (5-C), 53.8
(5-CHEs2), 55.6 (CH2Ph), 60.9, 61.2 (OCH2CH3), 101.5
(5a-C), 105.6 (3-C), 113.1 (10-C), 124.9 (9-C), 127.1,
127.8ꢀ2, 138.8 (Ph–C), 128.4 (8-C), 130.3 (2-C), 135.4
(11-C), 147.5 (12a-C), 158.5 (11a-C), 158.5 (6-C), 168.4,
168.5 (CO2). Anal. Calcd for C26H27N3O5 (461.5): C,
67.67; H, 5.90; N, 9.10%; found: C, 67.86; H, 6.07; N, 8.75%.
1720, 1660 cmꢂ1
;
1H NMR (CDCl3): 1.22 (3H, t, J¼
7.3 Hz, CH2CH3), 2.49 (1H, m, 7a-H), 2.64 (1H, dd, J¼2.5,
16.6 Hz, 8-H), 3.01–3.14 (2H, ov, 7-H2), 3.30 (1H, dd,
J¼5.6, 16.6 Hz, 8-H), 3.89 (1H, d, J¼8.9 Hz [trans], 13-H),
4.01 (1H, ddd, J¼1.3, 4.6 [cis], 8.9 Hz [trans], 13a-H), 4.23
(2H, q, J¼7.3 Hz, CH2CH3), 4.57, 5.29 (each 1H, each d,
J¼15.2 Hz, CH2Ph), 6.82 (1H, dt, J¼1.3, 6.9 Hz, 4-H),
7.04–7.33 (10H, ov, Ar–H and 3-H), 7.50 (1H, ddd, J¼1.3,
6.6, 6.8 Hz, 2-H), 8.89 (1H, dd, J¼0.7, 6.8 Hz, 1-H); 13C
NMR (CDCl3): 14.1 (CH2CH3), 29.4 (7a-C), 31.7 (8-C),
33.3 (13a-C), 47.7 (7-C), 49.8 (13-C), 51.1 (CH2Ph), 61.2
(OCH2CH3), 93.4 (13b-C), 112.0 (3-C), 124.2, 126.6,
126.9, 127.2, 127.5, 127.7, 128.6, 128.8, 129.2, 131.6, 133.7,
135.5, 138.2 (Ar–C), 149.5 (5a-C), 156.1, 156.4 (7a- and 14-
C), 174.9 (CO2). Anal. Calcd for C29H27N3O3 (465.5): C,
74.66; H, 6.05; N, 9.01%; found: C, 74.73; H, 5.89; N, 9.03%.
4.6.2. (4R*,5R*)-( )-1-Benzyl-5-[2,2-bis(ethoxycarbo-
nyl)methyl]-4-methyl-4,5-dihydropyrido[10,20:1,2]pyr-
imido[4,5-b]azepin-6(1H)-one (9b). This compound was
contaminated by other unidentified products and could not
be isolated as a pure form. The structure was speculated on
1
1
the basis of its H NMR spectral data; H NMR (CDCl3):
1.08 (3H, d, J¼7.3 Hz, 4-Me), 1.29 (6H, t, J¼7.2 Hz,
CH2CH3), 2.89 (1H, m, 4-H), 3.80–3.85 (2H, ov, 5-CHEs2
and 5-H), 4.22 (4H, q, J¼7.2 Hz, CH2CH3), 4.58 (1H, br d,
J¼9.9 Hz, 3-H), 4.81, 5.43 (each 1H, each d, J¼15.5 Hz,
CH2Ph), 5.99 (1H, dd, J¼0.5, 9.9 Hz, 2-H), 6.88 (1H, dt,
J¼0.7, 7.3 Hz, 9-H), 7.21–7.54 (7H, ov, Ph–H and 10- and
11-H), 8.88 (1H, dd, J¼0.6, 7.3 Hz, 8-H).
4.5.5. (4R*,4aS*,13bS*)-( )-6-Benzyl-2-ethoxy-4-phenyl-
4a,5,6,13b-tetrahydropyrano[40,30:4,5]pyrido[2,3-d]pyr-
ido[1,2-a]pyrimidin-13(4H)-one (7). This compound could
not be isolated as a pure form from the reaction mixture and
was converted to 8 during column chromatography on silica
gel; 1H NMR (CDCl3): 1.34 (t, J¼7.1 Hz, CH2CH3), 3.78 (s,
1-H), 4.15 (q, J¼7.1 Hz, CH2CH3).
4.6.3. (4R*,4aR*,13bS*)-( )-6-Benzyl-2-ethoxy-1-(ethoxy-
carbonyl)-4-methyl-4a,5,6,13b-tetrahydropyrano[40,30:
4,5]-pyrido[2,3-d]pyrido[1,2-a]pyrimidin-13(4H)-one
4.5.6. (4R*,4aS*,13bR*)-( )-6-Benzyl-4-phenyl-4a,5,6,
13b-tetrahydropyrano[40,30:4,5]pyrido[2,3-d]pyrido[1,2-
a]pyrimidine-2,13(1H,4H)-dione (8). Yellow prisms from
1
(10b). Colorless paste; IR (NaCl): 1720, 1660 cmꢂ1; H
ethyl acetate; mp 72–73 ꢁC; IR (KBr): 1720, 1660 cmꢂ1
;
NMR (CDCl3): 1.16 (6H, t, J¼7.3 Hz, CH2CH3), 1.65
(3H, J¼6.3 Hz, 4-Me), 2.22 (1H, dddd, J¼2.0, 4.0, 7.6,
10.3 Hz, 4a-H), 3.31 (1H, dd, J¼3.6, 13.9 Hz, 5-H), 3.71–
3.81 (2H, ov, 5- and 13b-H), 3.99–4.15 (5H, ov, 4-H and
CH2CH3), 4.65, 5.33 (each 1H, each d, J¼14.8 Hz,
CH2Ph), 6.84 (1H, dd, J¼7.3, 8.0 Hz, 10-H), 7.25–7.36
(6H, ov, Ph–H and 8-H), 7.54 (1H, dd, J¼6.6, 8.0 Hz, 9-
H), 8.81 (1H, d, J¼7.3 Hz, 11-H); 13C NMR (CDCl3):
13.8, 13.9 (CH2CH3), 23.2 (4-Me), 33.4 (13b-C), 41.4
(4a-C), 44.7 (5-C), 51.5 (CH2Ph), 55.5 (1-C), 58.7 (4-C),
61.2, 61.5 (OCH2CH3), 87.0 (13a-C), 112.3 (10-C), 124.3
(8-C), 127.3 (11-C), 127.4, 127.9, 128.5, 137.8 (Ph–C),
135.9 (9-C), 149.5 (6a-C), 156.6, 156.7 (7a- and 13-C),
168.0 (2-C), 168.3 (CO2). Anal. Calcd for C27H29N3O5
(475.3): C, 68.19; H, 6.15; N, 8.84%; found: C, 67.89; H,
6.01; N, 8.60%.
1H NMR (CDCl3): 2.17 (1H, m, 4a-H), 2.29 (1H, dd,
J¼10.9, 15.5 Hz, 1-H), 2.57 (1H, dd, J¼2.0, 13.5 Hz, 5-
H), 3.04 (1H, dd, J¼4.0, 15.5 Hz, 1-H), 4.12–4.18 (2H, ov,
CHHPh and 13b-H), 4.34 (1H, d, J¼9.9 Hz, 4-H), 5.33
(1H, d, J¼14.9 Hz, CHHPh), 6.89 (1H, dt, J¼1.7, 6.9 Hz,
10-H), 7.11–7.32 (11H, ov, Ph–H and 8-H), 7.56 (1H, ddd,
J¼1.7, 6.9, 8.9 Hz, 9-H), 8.91 (1H, br d, J¼6.9 Hz, 11-H);
13C NMR (CDCl3): 29.7 (13b-C), 38.8 (1-C), 42.4 (4a-C),
43.7 (5-C), 51.7 (CH2Ph), 74.2 (4-C), 90.9 (13a-C), 112.31
(10-C), 126.7, 127.3, 127.4, 127.9, 128.2, 128.4, 128.5,
128.7, 135.5 (Ph–C and 8- and 9-C), 135.6 (11-C), 142.9
(6a-C), 149.3 (7a-C), 156.8 (13-C), 172.8 (2-C). Anal. Calcd
for C27H23N3O3 (437.5): C, 74.12; H, 5.30; N, 9.61%; found:
C, 74.33; H, 5.18; N, 9.78%.
4.6. Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-
3-[2,2-bis(ethoxycarbonyl)vinyl]pyrido[1,2-a]pyrimi-
din-4(4H)-ones 3
4.7. Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-
3-[2-cyano-2-(ethoxycarbonyl)vinyl]pyrido[1,2-a]pyri-
midin-4(4H)-ones 4
Typical procedures. A deoxygenated solution of 3a (0.18 g,
0.4 mmol) in xylene (10 ml) was refluxed for 40 h. The sol-
vent was evaporated to dryness and the residue was sub-
jected to silica-gel column chromatography with hexane/
ethyl acetate (3/1) as an eluent to afford 9a (0.16 g, 89%).
Typical procedures. A deoxygenated solution of 4a (0.26 g,
0.6 mmol) in xylene (10 ml) was refluxed for 24 h. The sol-
vent was evaporated to dryness and the residue was sub-
jected to silica-gel column chromatography with hexane/
ethyl acetate (3/1) as an eluent to afford 11a (0.20 g, 77%).
4.6.1. 1-Benzyl-5-[2,2-bis(ethoxycarbonyl)methyl]-4,5-
dihydropyrido[10,20:1,2]pyrimido[4,5-b]azepin-6(1H)-
one (9a). Pale yellow paste; IR (NaCl): 1740, 1720,
1660 cmꢂ1; 1H NMR (CDCl3): 0.91, 1.27 (each 3H, each t,
J¼7.3 Hz, CH2CH3), 2.57 (2H, ov, 4-H2), 3.80–3.97 (3H,
4.7.1. (4aR*,13bR*)-( )-6-Benzyl-1-cyano-2-ethoxy-
4a,5,6,13b-tetrahydropyrano[40,30:4,5]pyrido[2,3-d]pyr-
ido[1,2-a]-pyrimidin-13(4H)-one (11a). Yellow plaꢂte1s
from EtOH; mp 211–212 ꢁC; IR (KBr): 2250, 1670 cm
;

M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4555
1H NMR (CDCl3): 1.25 (3H, t, J¼7.3 Hz, CH2CH3), 2.23
(1H, m, 4a-H), 3.18 (1H, ddd, J¼1.3, 5.0, 12.5 Hz, 5-H),
3.37 (1H, dd, J¼12.2, 12.5 Hz, 5-H), 4.12 (2H, q,
J¼7.3 Hz, CH2CH3), 4.25–4.39 (3H, ov, 4-H2 and 13b-H),
4.70, 5.27 (each 1H, each d, J¼15.2 Hz, CH2Ph), 6.85
(1H, dd, J¼5.6, 7.0 Hz, 10-H), 7.20–7.37 (6H, ov, Ph–H
and 8-H), 7.54 (1H, dd, J¼5.6, 7.2 Hz, 9-H), 8.95 (1H, d,
J¼7.0 Hz, 11-H); 13C NMR (CDCl3): 14.9 (CH2CH3),
27.5 (13b-C), 28.6 (4a-C), 43.8 (5-C), 51.0 (CH2Ph), 64.6
(OCH2CH3), 65.2 (1-C), 69.6 (4-C), 89.4 (13a-C), 112.4
(9-C), 118.5 (CN), 124.1 (10-C), 127.4, 127.6, 128.7,
137.8 (Ph–C), 128.2 (11-C), 136.1 (8-C), 149.8 (6a-C),
156.2 (7a-C), 157.2 (13-C), 165.4 (2-C). Anal. Calcd for
C24H22N4O3 (414.5): C, 69.55; H, 5.35; N, 13.52%; found:
C, 69.78; H, 5.43; N, 13.52%.
4.8.1. 1-Benzyl-5-(ethoxycarbonyl)methyl-6-oxo-4,5-
dihydro[1]benzopyrano[4,3-b]azepin-6(1H)-one (14a).
Yellow needles from EtOH; mp 146–147 ꢁC; IR (KBr):
1720, 1680 cmꢂ1
;
1H NMR (CDCl3): 1.21 (3H, t, J¼
7.3 Hz, CH2CH3), 2.02–2.08 (2H, ov, 5-CH2Es), 2.22 (1H,
ddd, J¼4.3, 7.6, 17.2 Hz, 4-H), 2.45 (1H, ddd, J¼2.9, 5.6,
17.2 Hz, 4-H), 4.07 (2H, q, J¼7.3 Hz, CH2CH3), 4.13 (1H,
m, 5-H), 4.59, 4.87 (each 1H, each d, J¼14.5 Hz, CH2Ph),
4.71 (1H, ddd, J¼2.9, 4.3, 9.9 Hz, 3-H), 6.11 (1H, dd,
J¼2.0, 9.9 Hz, 2-H), 7.19–7.73 (9H, ov, Ph–H); 13C NMR
(CDCl3): 14.1 (CH2CH3), 30.8 (4-C), 33.1 (5-C), 36.9 (5-
CH2Es), 60.1, 60.2 (CH2Ph and OCH2CH3), 105.8 (5a-C),
117.4 (11b-C), 117.7, 121.6, 123.5ꢀ2, 125.2, 128.3,
128.8ꢀ2, 130.7, 136.4, 152.4, 152.9 (Ar–C), 162.7 (6-C),
172.1 (CO2). Anal. Calcd for C24H23NO4 (389.4): C, 74.02;
H, 5.95; N, 3.60%; found: C, 74.28; H, 6.03; N, 3.49%.
4.7.2. (4R*,4aR*,13bR*)-( )-6-Benzyl-1-cyano-2-ethoxy-4-
methyl-4a,5,6,13b-tetrahydropyrano[40,30:4,5]pyrido[2,3-
d]-pyrido[1,2-a]pyrimidin-13(4H)-one (11b). Yellow
needles from EtOH; mp 203–204 ꢁC; IR (KBr): 2200,
4.8.2. 1-Benzyl-5-[bis(ethoxycarbonyl)methyl]-4,5-di-
hydro[1]benzopyrano[4,3-b]azepin-6(1H)-one (14b). Yel-
low needles from EtOH; mp 178–179 ꢁC; IR (KBr): 1740,
1
1670 cmꢂ1
;
1H NMR (CDCl3): 1.25 (3H, t, J¼7.3 Hz,
1710, 1700 cmꢂ1; H NMR (CDCl3): 1.19, 1.22 (each 3H,
CH2CH3), 1.44 (3H, d, J¼6.6 Hz, 4-Me), 1.98 (1H, m,
4a-H), 3.12 (1H, dd, J¼5.0, 12.5 Hz, 5-H), 3.25 (1H, br t,
J¼12.5 Hz, 5-H), 4.10 (2H, q, J¼7.3 Hz, CH2CH3), 4.30
(1H, d, J¼5.0 Hz [cis], 13b-H), 4.46 (1H, dq, J¼1.3,
6.6 Hz, 4-H), 4.68, 5.27 (each 1H, each d, J¼15.2 Hz,
CH2Ph), 6.86 (1H, dd, J¼5.6, 7.3 Hz, 10-H), 6.83–7.37
(6H, ov, Ph–H and 8-H), 7.54 (1H, br dd, J¼5.6, 7.6 Hz,
9-H), 8.97 (1H, br d, J¼7.3 Hz, 11-H); 13C NMR (CDCl3):
14.8 (CH2CH3), 18.8 (4-Me), 25.1 (13b-C), 31.7 (4a-C),
45.2 (5-C), 50.9 (CH2Ph), 63.9 (1-C), 64.3 (OCH2CH3),
75.9 (4-C), 89.0 (13a-C), 112.3 (9-C), 118.5 (CN), 124.1
(10-C), 127.3, 127.5, 128.6, 137.8 (Ph–C), 128.1 (11-C),
136.0 (8-C), 149.8 (6a-C), 156.4 (7a-C), 157.2 (13-C),
161.9 (2-C). Anal. Calcd for C25H24N4O3 (428.5): C,
70.07; H, 5.65; N, 13.08%; found: C, 70.00; H, 5.71; N,
13.02%.
each t, J¼7.3 Hz, CH2CH3), 2.35 (1H, ddd, J¼4.6, 6.6,
17.5 Hz, 4-H), 2.50 (1H, dd, J¼3.0, 17.5 Hz, 4-H), 3.63
(1H, d, J¼12.2 Hz, 5-CHEs2), 4.00–4.20 (4H, ov,
CH2CH3), 4.46 (1H, m, 5-H), 4.69 (1H, dd, J¼3.0, 9.9 Hz,
3-H), 4.76, 4.82 (each 1H, each d, J¼14.5 Hz, CH2Ph),
6.13 (1H, dd, J¼1.3, 9.9 Hz, 2-H), 7.15–7.75 (9H, ov, Ar–
H); 13C NMR (CDCl3): 13.9, 14.1 (CH2CH3), 29.5 (4-C),
36.2 (5-C), 53.5 (5-CHEs2), 59.5 (CH2Ph), 61.2, 61.4
(OCH2CH3), 105.4 (5a-C), 117.6 (11b-C), 117.7, 119.7,
123.5, 124.7, 128.1, 129.0, 130.9, 136.3, 152.8, 152.9 (Ar–
C), 162.6 (6-C), 168.1, 168.5 (CO2). Anal. Calcd for
C27H27NO6 (389.4): C, 70.27; H, 5.90; N, 3.03%; found:
C, 70.15; H, 5.99; N, 2.78%.
4.8.3. (4aR*,12bR*)-( )-6-Benzyl-1-cyano-2-ethoxy-
4a,5,6,12b-tetrahydro[1]benzopyrano[4,3-b]pyrano[4,3-
d]pyridin-12(4H)-one (15). Yellow prisms from EtOH; mp
4.7.3. (4R*,4aS*,13bS*)-( )-6-Benzyl-1-cyano-2-ethoxy-4-
phenyl-4a,5,6,13b-tetrahydropyrano[40,30:4,5]pyrido[2,3-
d]pyrido[1,2-a]pyrimidin-13(4H)-one (11c). Yellow
prisms from EtOH; mp 220–221 ꢁC; IR (KBr): 2200,
231–232 ꢁC; IR (KBr): 2200, 1700 cmꢂ1 1H NMR
;
(CDCl3): 1.27 (3H, t, J¼7.3 Hz, CH2CH3), 2.14 (1H, m,
4a-H), 3.14 (1H, dd, J¼4.0, 12.2 Hz, 5-H), 3.26 (1H, br t,
J¼12.2 Hz, 5-H), 4.01–4.18 (3H, ov, 12b-H and CH2CH3),
4.29 (1H, dd, J¼1.7, 11.6 Hz, 4-H), 4.42 (1H, dd, J¼2.6,
11.6 Hz, 4-H), 4.62, 4.82 (each 1H, each d, J¼16.8 Hz,
CH2Ph), 7.05–7.57 (9H, ov, Ar–H); 13C NMR (CDCl3):
14.9 (CH2CH3), 26.1 (12b-C), 29.3 (4a-C), 46.7 (5-C),
59.0 (CH2Ph), 64.6, 64.7 (1-C and OCH2CH3), 69.5 (4-C),
104.4 (12a-C), 115.8 (6a-C), 118.0 (CN), 118.2, 123.4,
124.3, 126.8, 128.0, 129.3, 131.3, 136.4, 153.3, 153.6 (Ar–
C), 161.8 (12-C), 163.7 (2-C). Anal. Calcd for
C25H22N2O4 (414.4): C, 72.45; H, 5.35; N, 6.76%; found:
C, 72.27; H, 5.46; N, 6.44%. The structure of 15 was con-
firmed by X-ray single crystal structure analysis.9
1660 cmꢂ1
;
1H NMR (CDCl3): 1.23 (3H, t, J¼7.3 Hz,
CH2CH3), 2.36 (1H, m, 4a-H), 3.30–3.46 (2H, ov, 5-H2),
3.97 (1H, d, J¼4.6 Hz [cis], 13b-H), 4.24 (2H, q, J¼7.3 Hz,
CH2CH3), 4.75, 5.28 (each 1H, each d, J¼15.2 Hz, CH2Ph),
5.36 (1H, br s, 4-H), 6.83 (1H, dd, J¼6.6, 7.2 Hz, 10-H),
7.19–7.42 (11H, ov, Ph–H and 8-H), 7.52 (1H, dd, J¼5.0,
7.2 Hz, 9-H), 8.90 (1H, d, J¼6.6 Hz, 11-H); 13C NMR
(CDCl3): 15.0 (CH2CH3), 25.1 (13b-C), 33.4 (4a-C), 45.8
(5-C), 51.1 (CH2Ph), 64.7 (OCH2CH3), 65.3 (1-C), 80.6
(4-C), 89.3 (13a-C), 112.4 (9-C), 118.3 (CN), 124.1 (10-
C), 124.6, 124.7, 127.4, 127.6, 128.5, 128.7, 129.0, 137.8,
137.9 (Ph–C), 128.1 (11-C), 136.1 (8-C), 149.8 (6a-C),
156.5 (7a-C), 157.0 (13-C), 162.7 (2-C). Anal. Calcd for
C30H26N4O3 (490.5): C, 73.45; H, 5.34; N, 11.42%; found:
C, 73.11; H, 5.20; N, 11.36%.
4.9. Compounds 17a, 17b, 17c, and 18
Thermal reaction of 13a and 13b gave ene products 17a and
17b, on the other hand 13c gave ene product 17c and hetero
Diels–Alder product 18.
4.8. Compounds 14a, 14b, and 15
Thermal reaction of 12a and 12b gave ene products 14a and
14b, while reaction of 12c afforded hetero Diels–Alder
product 15.
4.9.1. 9-Benzyl-5-(ethoxycarbonyl)methyl-1,3-dimethyl-
6,9-dihydro-1H-pyrimido[4,5-b]azepin-2,4(3H,5H)-di-
one (17a). Colorless needles from EtOH; mp 146–147 ꢁC;

4556
M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
IR (KBr): 1730, 1640, 1620 cmꢂ1; 1H NMR (CDCl3): 1.18
(3H, t, J¼7.3 Hz, CH2CH3), 1.80 (2H, br s, 5-CH2Es),
2.13 (1H, ddd, J¼4.3, 5.6, 17.2 Hz, 6-H), 2.32 (1H, br d,
J¼17.2 Hz, 6-H), 3.37 (3H, s, 1-Me), 3.46 (3H, s, 3-Me),
3.94–4.03 (3H, ov, 5-H and CH2CH3), 4.23, 4.34 (each
1H, each d, J¼14.2 Hz, CH2Ph), 4.71 (1H, m, 7-H), 5.90
(1H, br d, J¼9.9 Hz, 8-H), 7.22–7.38 (5H, ov, Ph–H); 13C
NMR (CDCl3): 14.1 (CH2CH3), 28.6 (1-Me), 29.0 (6-C),
31.1 (5-C), 35.5 (3-Me), 36.5 (5-CH2Es), 58.4 (CH2Ph),
60.0 (OCH2CH3), 107.6 (4a-C), 108.9 (7-C), 128.7, 128.9,
129.3, 135.1 (Ph–C), 129.0 (2-C), 151.0 (9a-C), 153.2 (2-
C), 162.9 (4-C), 172.3 (CO2). Anal. Calcd for C21H25N3O4
(383.4): C, 65.78; H, 6.57; N, 10.96%; found: C, 65.57; H,
6.65; N, 10.63%.
10a-H), 4.04–4.37 (6H, ov, 4-H and CH2CH3 and CH2Ph),
7.26–7.45 (5H, ov, Ph–H); 13C NMR (CDCl3): 14.9
(CH2CH3), 25.2 (4-Me), 28.2 (10a-C), 28.6 (6a-C), 34.3
(2-Me), 46.3 (6-C), 57.2 (CH2Ph), 64.6 (OCH2CH3), 64.8
(10-C), 69.3 (7-C), 96.6 (10b-C), 118.5 (CN), 126.9, 128.2,
129.2, 135.2 (Ph–C), 152.6 (4a-C), 154.0 (3-C), 162.2
(1-C), 163.9 (CO2). Anal. Calcd for C22H24N4O4 (408.4):
C, 64.69; H, 5.92; N, 13.72%; found: C, 64.41; H, 5.86; N,
13.47%.
References and notes
1. (a) Inazumi, T.; Yamada, K.; Kuroki, R.; Kakehi, A.; Noguchi,
M. J. Chem. Soc., Perkin Trans. 1 1994, 557–564; Inazumi, T.;
Harada, E.; Mizukoshi, T.; Kakehi, A.; Noguchi, M. J. Chem.
Soc., Perkin Trans. 1 1994, 565–570; Kuroki, Y.; Akao, R.;
Inazumi, T.; Noguchi, M. Tetrahedron 1994, 50, 1063–1072;
Noguchi, M.; Mizukoshi, T.; Kakehi, A. Tetrahedron 1996,
52, 13081–13096; (b) Noguchi, M.; Mizukoshi, T.; Uchida,
T.; Kuroki, Y. Tetrahedron 1996, 52, 13097–13110; Noguchi,
M.; Mizukoshi, T.; Nakagawa, S.; Kakehi, A. Tetrahedron
1996, 52, 13111–13120.
2. For reviews: Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92,
1021–1050; Oppolzer, W.; Sniekus, V. Angew. Chem., Int.
Ed. Engl. 1978, 17, 476–486.
3. The desired vinyl compounds 3a, 3b, 12b, and 13b in this study
were also obtained by utilizing other dehydrating conditions,
such as in THF at room temperature in the presence of titanium
tetrachloride or in acetic anhydride in the presence of zinc di-
chloride at 80 ꢁC. In some cases, however, tetrahydropyridine
derivatives were formed as major products. Details of the tetra-
hydropyridine synthesis will be described elsewhere.
4.9.2. 9-Benzyl-5-[bis(ethoxycarbonyl)methyl]-1,3-
dimethyl-6,9-dihydro-1H-pyrimido[4,5-b]azepin-
2,4(3H,5H)-dione (17b). Colorless needles from hexane/
benzene; mp 159–160 ꢁC; IR (KBr): 1740, 1715,
1645 cmꢂ1
;
1H NMR (CDCl3): 1.14–1.21 (6H, ov,
CH2CH3), 2.21 (1H, br td, J¼4.6, 17.8 Hz, 6-H), 2.30 (1H,
br d, J¼17.8 Hz, 6-H), 3.29 (1H, m, 5-H), 3.35 (3H, s,
1-Me), 3.44 (3H, s, 3-Me), 3.99–4.13 (5H, ov, CH2CH3
and 5-CHEs2), 4.32, 4.40 (each 1H, each d, J¼14.2 Hz,
9-CH2Ph), 4.71 (1H, m, 7-H), 5.92 (1H, br d, J¼9.9 Hz,
8-H), 7.36 (5H, ov, Ph–H); 13C NMR (CDCl3): 13.8, 14.0
(CH2CH3), 28.6 (1-Me), 29.5 (6-C), 32.2 (5-C), 35.4 (3-
Me), 52.9 (5-CHEs2), 57.8 (CH2Ph), 61.0, 61.1 (OCH2CH3),
106.9 (4a- and 7-C), 128.4, 128.8, 128.9, 129.1, 135.0 (Ph–C
and 8-C), 151.2 (9a-C), 153.1 (2-C), 162.9 (4-C), 168.3
(CO2). Anal. Calcd for C24H29N3O6 (383.4): C, 63.28; H,
6.37; N, 9.21%; found: C, 63.19; H, 6.37; N, 9.21%.
4.9.3. 9-Benzyl-5-[cyano(ethoxycarbonyl)methyl]-1,3-
dimethyl-6,9-dihydro-1H-pyrimido[4,5-b]azepin-
2,4(3H,5H)-dione (17c). Colorless needles from EtOH; mp
4. Cox, M. T. J. Chem. Soc., Chem. Commun. 1975, 903–905;
Oppolzer, W.; Achini, R.; Pfenninger, E.; Weber, H. P. Helv.
Chim. Acta 1976, 59, 1186–1202.
5. Fukui, K. Acc. Chem. Res. 1974, 4, 57–64; Fleming, I. Frontier
Orbitals and Organic Chemical Reactions; Wiley: New York,
NY, 1976.
1
166–167 ꢁC; IR (KBr): 2250, 1730, 1650 cmꢂ1; H NMR
(CDCl3): 1.34 (3H, t, J¼6.9 Hz, CH2CH3), 2.16 (1H, dd,
J¼8.9, 14.9 Hz, 6-H), 2.56 (1H, d, J¼13.9 Hz, 5-H), 2.90
(1H, ddd, J¼1.3, 8.6, 14.9 Hz, 6-H), 3.25 (1H, d,
J¼13.9 Hz, 5-CH(CN)Es), 3.30 (3H, s, 1-Me), 3.52 (3H, s,
3-Me), 4.11–4.39 (5H, ov, 7-H and CH2CH3 and CH2Ph),
6.12 (1H, d, J¼9.9 Hz, 8-H), 7.13–7.36 (5H, ov, Ph–H);
13C NMR (CDCl3): 13.8 (CH2CH3), 27.5 (6-C), 28.5 (1-
Me), 31.5 (5-C), 34.0 (3-Me), 38.4 (5-CH(CN)Es), 59.7
(CH2Ph), 63.1 (OCH2CH3), 95.6 (7-C), 101.3 (4a-C),
119.9 (CN), 128.3, 129.0, 129.3, 135.0 (Ph–C), 135.5 (8-
C), 151.4 (9a-C), 152.3 (2-C), 162.1 (4-C), 167.7 (CO2).
Anal. Calcd for C16H24N4O4 (408.5): C, 64.69; H, 5.92; N,
6. Preliminary calculations were made using the N-methyl sub-
strates instead of N-benzyl ones 2, 3, 4, 12, and 13 in order to
avoid conformational and computational complexities by
PM3 method11 with the standard parameters as implemented
in a MOPAC program12 (version 6.00) on the VAX 4000 sys-
tem. p-Electron energy levels were examined downward
from the HOMO and the levels possessing the coefficients at
both the carbon atoms of the ene moieties were adopted as
the frontier orbitals (p). The similar treatments (examination
of the p*-electron levels upward from LUMO) were performed
for the a,b-unsaturated ester carbonyl moieties and adopted as
the frontier orbitals (p*). Although the substituents on the ene
and the a,b-unsaturated ester moieties effected on the both
frontier orbitals (p and p*), the substituents on the ene moie-
ties effected predominantly on p and the substituents on the
vinyl moieties did on p* as expected. When the energy
differences (DE) between the frontier orbitals (p* and p) of
the model substrates became less than 9.7 eV, the reaction fea-
tures of the actual substrates 2, 3, 4, 12, and 13 changed from
the ene reactions to the hetero Diels–Alder reactions. In order
to perform further discussion on the reaction mechanism,
more precise calculations on the energy levels and the transi-
tion states are now under progress and the details will be
reported elsewhere.
1
13.72%; found: C, 64.58; H, 6.01; N, 13.64%. In the H
NMR spectrum of the crude reaction mixture, signals due
to another diastereomer were observed, however, the isomer
could not be isolated by chromatographic purification: 1.29
(t, J¼7.3 Hz, CH2CH3), 6.03 (d, J¼9.9 Hz, 8-H).
4.9.4. (6aR*,10aR*)-( )-5-Benzyl-10-cyano-9-ethoxy-2,4-
dimethyl-4,5,6,6a,7,10a-hexahydropyrano[30,40:6,5]pyr-
ido[3,4-d]pyrimidin-1,3(2H)-dione (18). Yellow prisms
from EtOH; mp 115–116 ꢁC; IR (KBr): 2200, 1690,
1640 cmꢂ1
;
1H NMR (CDCl3): 1.27 (3H, t, J¼6.9 Hz,
CH2CH3), 1.86 (1H, m, 6a-H), 3.03 (1H, dd, J¼2.3, 13.5 Hz,
6-H), 3.18 (1H, dd, J¼12.5, 13.5 Hz, 6-H), 3.38, 3.39 (each
3H, each s, 2- and 4-Me), 3.94 (1H, d, J¼4.6 Hz [cis],

M. Noguchi et al. / Tetrahedron 63 (2007) 4548–4557
4557
7. Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131–163; Tietze, L. F.; Geissler, H.; Fennen, J.; Brumby, T.;
Brand, S.; Schulz, G. J. Org. Chem. 1994, 59, 182–191;
Tietze, L. T.; Montenbruck, A.; Schneider, C. Synlett 1994,
509–510; Tietze, L. F.; Heubsch, T.; Ott, C.; Kuchta, G.;
Buback, M. Liebigs Ann. 1995, 1–7; Tietze, L. F. Chem. Ind.
(London) 1995, 453–457 and references cited therein;
Also see: Snider, B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065–
8070; Snider, B. B.; Lu, Q. Tetrahedron Lett. 1994, 35, 531–
534; J. Org. Chem. 1996, 61, 2839–2844; Desimoni, G.; Faita,
G.; Righetti, P.-P. Tetrahedron Lett. 1995, 36, 2855–2858;
Takano, S.; Satoh, S.; Ogasawara, K. Chem. Commun. 1998,
59–60.
8. Bachmann, W. E.; Deno, N. C. J. Am. Chem. Soc. 1949, 71,
3062–3072; Carboni, R. A.; Rindsey, R. V. J. Am. Chem. Soc.
1959, 81, 4342–4346; Sauer, J.; Wiest, H. Angew. Chem., Int.
Ed. Engl. 1962, 1, 269; Sauer, J. Angew. Chem., Int. Ed.
Engl. 1966, 5, 211–230; Sauer, J. Angew. Chem., Int. Ed.
Engl. 1967, 6, 16–33; Houk, K. N. J. Am. Chem. Soc. 1973,
95, 4092–4094; Houk, K. N.; Strozier, R. W. J. Am. Chem.
Soc. 1973, 95, 4094–4096; Sauer, J.; Sustmann, R. Angew.
Chem., Int. Ed. Engl. 1980, 19, 779–807.
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
10. Similar condensation of 4-[N-benzyl-(E)-cinnamylamino]-3-
formyl[1]benzopyran-2(2H)-one with ethyl cyanoacetate in
EtOH at room temperature for 5 h gave not the desired vinyl
compound but hetero Diels–Alder product 16 (86%).
(4R*,4aS*,12bS*)-(ꢃ)-6-Benzyl-1-cyano-2-ethoxy-4-phenyl-
4a,5,6,12b-tetrahydro[1]benzopyrano[4,3-b]pyrano[4,3-d]-
pyridin-12(4H)-one (16): yellow prisms from EtOH; mp 223–
1
224 ꢁC; IR (KBr): 2190, 1690 cmꢂ1; H NMR (CDCl3): 1.34
(3H, t, J¼6.9 Hz, CH2CH3), 2.20 (1H, m, 4a-H), 3.28–3.34
(2H, ov, 5-H2), 3.72 (1H, d, J¼4.3 Hz [cis], 12b-H), 4.23
(2H, q, J¼6.9 Hz, CH2CH3), 4.71, 4.80 (each 1H, each d,
J¼16.8 Hz, CH2Ph), 5.37 (1H, br s, 4-H), 7.07–7.65 (9H, ov,
Ar–H); 13C NMR (CDCl3): 15.0 (CH2CH3), 25.7 (12b-C),
32.1 (4a-C), 48.5 (5-C), 59.0 (CH2Ph), 64.8 (1-C), 64.9
(OCH2CH3), 80.8 (4-C), 104.3 (12a-C), 115.6 (6a-C), 118.0
(CN), 118.1, 123.4, 124.3, 124.4, 127.0, 128.1, 128.7, 129.2,
129.3, 131.3, 136.3, 137.9, 153.3 (Ar–C), 154.1ꢀ2 (6b- and
10a-C), 161.7 (12-C), 162.8 (2-C); m/z: 490 (M+). Anal.
Calcd for C31H26N2O4 (490.5): C, 75.90; H, 5.34; N, 5.71%;
found: C, 76.12; H, 5.32; N, 5.76%. The structure of 16 was
confirmed by X-ray single crystal structure analysis.9
9. Crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC-101213 for compound
15 and CCDC-101214 for compound 16. Copies of the data
can be obtained, free of charge, on application to CCDC,
11. Stewart, J. J. J. Comput. Chem. 1989, 10, 209–220 and 221–264.
12. Stewart, J. J.; Frank, J. MOPAC program, version 6.00; on the
VAX 4000 system; Research Laboratory, U.S. Airforce
Academy: Colorado Springs, CO 80840.