Thermal ene reactions of 3-(alk-2-enyl)benzylamino-2- (methoxycarbonyl)acrolein derivatives leading to 4,5-dihydro-1H-azepines

Article abstract of DOI:10.1016/S0040-4020(00)00029-6

Thermal reaction of 3-(alk-2-enyl)benzylamino-2- (methoxycarbonyl)acrolein derivatives 3 gave 4,5-dihydro-1H-azepines 4 stereoselectively in good yields via an intramolecular carbonyl-ene reaction. Conjugated diene compounds 10 from acroleins 3 also underwent olefin-ene reaction to give azepine derivatives 11. In these azepine-ring formation, the methoxycarbonyl group at the 2-position in 3 facilitated the progress of the reaction more effectively than the cyano group previously reported by us. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00029-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1299–1307
Thermal Ene Reactions of
3-(Alk-2-enyl)benzylamino-2-(methoxycarbonyl)acrolein
Derivatives Leading to 4,5-Dihydro-1H-azepines
a
a
a
b
Michihiko Noguchi,a, Hisashi Yamada, Shinji Takamura, Koichi Okada, Akikazu Kakehi and
*
Hidetoshi Yamamotoa
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 11 November 1999; accepted 6 January 2000
Abstract—Thermal reaction of 3-(alk-2-enyl)benzylamino-2-(methoxycarbonyl)acrolein derivatives 3 gave 4,5-dihydro-1H-azepines 4
stereoselectively in good yields via an intramolecular carbonyl-ene reaction. Conjugated diene compounds 10 from acroleins 3 also under-
went olefin-ene reaction to give azepine derivatives 11. In these azepine-ring formation, the methoxycarbonyl group at the 2-position in 3
facilitated the progress of the reaction more effectively than the cyano group previously reported by us. ᭧ 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
their imines bearing (alk-2-enyl)amino moieties at the
neighboring position. Although the cyclization could be
formally considered as 7 (1,4)-intramolecular carbonyl-5
and imine-ene reactions,6 the investigation on the mechan-
isms revealed that the azepine-ring formation consisted of
two consecutive orbital-allowed reactions. Firstly, the [1,6]
sigmatropic shift of the allylic hydrogen (TS 1) generates a
conjugated azomethine ylide (Intermediate), which bears
two 2p electron systems on the both carbon-termini of the
parent azomethine ylide. Secondly, its [1,7] electrocyclic
ring-closure (TS 2) gives the fused 4,5-cis-azepine stereo-
selectively (Scheme 1).4d–f
Among the methodologies for the stereoselective synthesis
of azepine derivatives from acyclic systems, much attention
has been focused on the 1,7-cyclization of conjugated
azomethine ylides totally bearing 8p electrons. The most
popular access to the conjugated azomethine ylide
substrates is concerned with the combination of an
azomethine ylide (4p) and conjugated diene systems (4p),
i.e. a,b,g,d-unsaturated azomethine ylides.1–3 In previous
papers,4 we also reported the stereoselective azepine-ring
formation by the cyclization of heterocyclic aldehydes and
Scheme 1.
Keywords: azepines; ene reactions; cyclization; aldehydes.
* Corresponding author. Tel. ϩ81-836-35-9423; fax: ϩ81-836-35-9933; e-mail: noguchi@po.cc.yamaguchi-u.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00029-6

1300
M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
Scheme 2.
On the other hand, only a few precedents of the thermally
induced cyclization of dialkylaminopolyenes such as
1-dimethylamino-1,3,4-pentatrienes7 and 1-morpholino-3-
vinylallenes8 leading to azepine derivatives were found in
the literatures, in which a,b,g,d-unsaturated azomethine
ylides were postulated as intermediates generated by the
sigmatropic shift of the hydrogen adjacent to the amino-
nitrogen. More recently, we successfully extended our
azepine-ring formation methodology to the imine and
conjugated diene derivatives of 3-(alk-2-enyl)amino-2-
cyanoacrolein, in which poly-functionalized 4,5-dihydro-
1H-azepine derivatives were obtained efficiently and stereo-
selectively (Scheme 2).9
Results and Discussion
Carbonyl-ene reaction of 3-(alk-2-enyl)amino-2-
(methoxycarbonyl)acrolein derivatives 3
A starting material 3-(N-allylbenzylamino)-2-(methoxy-
carbonyl)acrolein (3a) was prepared in a good yield in
the reaction of 2-(methoxycarbonyl)malonaldehyde (1)10
with N-allylbenzylamine (2a) in THF at room temperature.
Similarly, reaction with N-[(E)-but-2-enyl]-(2b), N-[(E)-
cinnamyl]- (2c), N-[(E)-3-(2-furyl)prop-2-enyl]-(2d), and
N-[(E)-3-(ethoxycarbonyl)prop-2-enyl]-benzylamine (2e)
gave also 3-(alk-2-enyl)benzylamino-2-(methoxycarbonyl)-
acroleins 3b–e as shown in Scheme 3. Acrolein derivatives
3 were obtained as ca (3:7) to (4:5) inseparable mixtures of
two geometric isomers and the mixtures were utilized for
the ene reaction without further purification.
In this paper, we describe the thermal reaction of 3-[N-(alk-
2-enyl)benzylamino]-2-(methoxycarbonyl)acrolein deriva-
tives in order to examine the effects of the substituent at
the 2-position of the acrolein derivatives on the azepine-ring
formation.
A reaction of acrolein derivative 3a in toluene heated under
Scheme 3.

M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
1301
Scheme 4.
Table 1. Carbonyl-ene reaction of 3-(alk-2-enyl)benzylamino-2-(methoxy-
carbonyl)acroleins 3b–e
quently, the structure of 7 was deduced to be the corre-
sponding 3,12-bis(methoxycarbonyl) derivative due to the
dimerization by coupling between the 2- and 20-carbons (7-
and 70-carbons) of two moles of 8. The formation of
products 6 and 7 is explained by the dimerization and its
mechanism of N-substituted 1H-azepine proposed by
Paquette and other groups.12
Run Substrate
R
Solvent Time (h) Products (Yield %)a
1
2
3
3b
3c
3d
3e
3e
Me
Ph
Toluene 24
Benzene 20
4b (62)
4c (66)
4d (71)
4e (88)
4e (72)
5b (12)
5c (9)
5d (19)
–
2-Furyl Benzene 12
CO2Et Benzene
CO2Et Toluene
4
6
2
5b
–
Similar thermal reaction of acrolein derivatives 3b–e gave
azepines 4b–e and [1,3]oxazines 5b–d in good to excellent
total yields (Scheme 4 and Table 1). 4,5-Cis relationship of
azepines 4b–e was supported by the small vicinal coupling
constants (ca 0 Hz) between the 4- and 5-H in comparison
with that of the azepine obtained by the ene reaction of
3-{N-benzyl[(E)-3-(ethoxycarbonyl)prop-2-enyl]amino}-2-
cyanoacrolein (ca 0 Hz).9 The structure of azepine 4e was
also confirmed unambiguously by its X-ray crystallographic
analysis.11 The treatment of azepines 4 with 1N hydrochloric
acid in THF gave [1,3]oxazines 5 in moderate to good
yields. The stereochemistry of the substituents at the 7-posi-
tion of 5b–d was deduced to be exo also from small vicinal
coupling constants between the bridge-head proton 6-H and
7-H (ca 0 Hz; 7-H: endo).4,9
a Based on isolated product.
b A mixture of unidentified products was also obtained.
reflux for 6 h gave the desired azepine 4a, [1,3]oxazine 5a
and two diastereomeric products 6 and 7 in 55, 15, 8, and
8% yields, respectively. Under more harsh conditions (in
refluxing xylene for 2 h), the corresponding yields of the
products were shifted to 28, 26, 15, and 12%. The structure
of 4a was deduced to be 1-benzyl-3-(methoxycarbonyl)-4-
hydroxy-4,5-dihydro-1H-azepine from its spectroscopic
data in comparison with those of related azepine derivatives
reported previously.4 In the IR spectrum of 4a the absorp-
tion at 3480 cmϪ1 was attributed to hydroxyl group and its
1H NMR spectrum showed three vinyl protons, 2-, 6-H, and
7-H, characteristic to the enamine moieties and individual
methylene and methine protons apart from methoxycarbonyl
and benzyl groups. On the other hand, the structure of 5a
was deduced to be 3-benzyl-5-(methoxycarbonyl)-3,6-
dihydro-2,6-ethano-2H-[1,3]oxazine, a secondary product
from azepine 4a, also on the basis of its spectroscopic data.
As mentioned above, 2-(methoxycarbonyl)acrolein deriva-
tives 3 underwent an intramolecular carbonyl-ene reaction
to afford 4-hydroxy-4,5-dihydro-1H-azepines stereo-
selectively, while some 2-cyanoacrolein analogs except
for 3-{N-benzyl[(E)-3-(ethoxycarbonyl)prop-2-enyl]amino}-
2-cyanoacrolein, the most reactive one in the runs, did not
give any azepine derivatives under similar or more harsh
conditions. The methoxycarbonyl group at the 2-position of
acrolein derivatives 3, therefore, should facilitate the car-
bonyl-ene reaction more effectively than the cyano group.
The molecular formula (C30H30N2O4: Mw 482) of products 6
and 7 corresponds to that of dimeric products of the fully
conjugated azepine 8, which is formed by dehydration of 4a.
The 13C NMR spectra of 6 and 7 were almost identical with
each other over the whole region. The signal patterns in the
1H NMR spectra of both products 6 and 7 and their 2D-
NOESY spectra exhibited one set of alignment of protons;
olefin (dˆ7.39)-olefin (ca 6.2)-olefin (ca 6.2)-methine
(3.41)-methine proton (4.02) for 6 and olefin (dˆ7.32)-
olefin (6.25)-olefin (5.93)-methine (3.28)-methine proton
Stimulated by the above findings, we examine the reaction
of acrolein derivatives 3 with primary amines to form the
corresponding imines. Many efforts were made, yet
products obtained in good to excellent yields were vina-
midine derivatives 913 in which acrolein derivatives 3
predominantly reacted with two moles of the amines.
Utilizing N-(triphenylphosphoranylidene)aniline instead of
aniline for the imine preparation also gave a disappointing
result (Scheme 5). Therefore, our concern was turned
toward the thermal reaction of conjugated diene compounds
from acroleins 3.
(4.20) for 7. The simple signal patterns in the H and 13C
1
NMR spectra of 6 implied a symmetrical structure; the
benzylic methylene protons were observed as singlet. On
the other hand, the benzylic methylene protons of 7 were
AB quartet. The structure of crystalline 6 was speculated to
be the dimer coupled between the 2- and 70-carbons (7- and
20-carbons) of two moles of azepine 8 and confirmed
unambiguously to be 13,14-dibenzyl-3,9-bis(methoxy-
carbonyl)-13,14-diazatricyclo[6.4.1.12,7]tetradecan-3,5,9,
11-tetraene by the X-ray crystallographic analysis.11 Conse-
Olefin-ene reaction of conjugated diene compounds 10
from acroleins 3
Starting materials, methyl 5-N-(alk-2-enyl)benzylamino-

1302
M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
Scheme 5.
Scheme 6.
Table 2. Olefin-ene reaction of conjugated diene compounds 10 from acroleins 3
Run
Substrate
R
Solvent
Temp (ЊC)
Time (h)
Product (Yield %)a
1
2
10a
10b
10c
10e
10e
H
Me
Ph
CO2Et
CO2Et
Toluene
Toluene
Toluene
Toluene
Benzene
Reflux
Reflux
Reflux
90
12
20
12
6
11a (90)
11b (96)
11c (92)
11e (72)
11e (95)
3
4b
5
70
12
a Based on isolated product.
b A mixture of unidentified products was also obtained.
2,4-bis(methoxycarbonyl)penta-2,4-dienates (10a–c and
10e), were prepared in moderate yields by the condensation
of acroleins 3a–c and 3e and dimethyl malonate in the
presence of titanium tetrachloride and pyridine according
to the method reported by Lehnert.14 Conjugated diene
compounds 10 existed as almost single isomers in the
CDCl3 solutions, while the 4-cyano analogs did as mixtures
of E/Z isomers. The configuration of dienes 10, however,
could not be determined. Thermal reaction of diene
compounds 10a–c and 10e in toluene or benzene gave the
desired azepine derivatives 11a–c and 11e in almost quan-
titative yields (Scheme 6 and Table 2).
carbonyl- and imine-ene reactions of 2-(N-allylbenzyl-
amino)-3-formylpyrido[1,2-a]pyrimidine system.4e
Conclusion
We have described the stereoselective azepine-ring for-
mation via intramolecular ene reactions of 3-(alk-2-enyl)-
benzylamino-2-(methoxycarbonyl)acrolein derivatives
3
and 10. The methoxycarbonyl substituent at the 2-position
of 3 induced the reactivity with a nucleophile such as
primary amines; acroleins 3 reacted with two moles of the
amines to afford vinamidine derivatives. The substituent of
3 and 10 enhanced the reactivity toward the carbonyl- and
olefin-ene reaction in comparison with the corresponding
2-cyano analogs. Although the exact reason remains
unclear, we suggest that the electronic nature of the
methoxycarbonyl group does not so much influence the
rate of the thermal reaction, but its steric restriction may
align the N-attached olefinic configuration more favorably
toward the intramolecular ene reactions. Further details on
the mechanistic aspects and investigations on the effect of
the 2-position are in progress and will be reported
elsewhere.
Fortunately, the structure of 11e was confirmed to be 1-benzyl-
5-(ethoxycarbonyl)-3-(methoxycarbonyl)-4-bis(methoxy-
carbonyl)methyl-4,5-dihydro-1H-azepine by its X-ray
crystallographic analysis.11 The structures of 11a–c were
also determined on the basis of their spectroscopic data in
comparison with those of azepine 11e. The results in Table 2
showed that the olefin-ene reaction of dienes 10 proceeded
under milder conditions than that of the corresponding
2-cyano analogs.9
In order to obtain further understanding of the reaction
features, the solvent effect on the reaction rates of diene
10c was examined. Replacement of dioxane by more polar
solvents such as DMF, propionitrile, and butan-1-ol resulted
in reduced reaction rates [relative rates: dioxane (1.00),
DMF (0.65), propionitrile (0.51), and butan-1-ol (0.41);
see experimental section]. The same propensity for the
rate-decreasing in polar solvents was observed in the
Experimental
General
Melting points were measured on a Yanagimoto micro

M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
1303
melting point apparatus and are uncorrected. IR spectra
were measured on a JASCO IR-Report-100 spectro-
photometer from samples as KBr pellets or NaCl discs.
NMR spectra were measured on a JEOL EX-270 and/or
75.07; H, 6.43; N, 4.08%. This compound was a (2:3)
mixture of two geometric isomers in CDCl3. Major isomer:
1H NMR (CDCl3) dˆ3.75 (3H, s, OMe), 4.12 (2H, d,
Jˆ6.6 Hz, ϾNCH2CHy), 4.65 (2H, s, CH2Ph), 6.30 (1H,
td, Jˆ6.6 and 15.8 Hz, –CHyCH–Ph), 6.42 (1H, br d,
Jˆ15.8 Hz, yCH–Ph), 7.22–7.37 (10H, ov, Ph), 7.94 (1H,
s, 3-H), 9.77 (1H, s, 1-H). Assigned signals for minor
isomer: 1H NMR (CDCl3) dˆ3.74 (3H, s, OMe), 4.41
(2H, d, Jˆ6.0 Hz, ϾNCH2CHy), 5.05 (2H, s, CH2Ph),
6.51 (1H, br d, Jˆ15.8 Hz, yCH–Ph).
1
EX-400 spectrometers (270 and 400 MHz of H and 67.8
and for 13C) in deuteriochloroform solutions unless other-
wise stated. Tetramethylsilane was used as internal standard
and J values are given in Hz. Splitting patterns are indicated
as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad signal; and ov, overlapping signals. Mass spectra
were determined on a JEOL JMS-SX102A spectrometer.
Elemental analyses were performed on a Yanagimoto
MT-5 CHN analyzer. All non-aqueous reactions were run
under positive pressure of argon or nitrogen. All solvents
were dried by standard methods before use. The progress of
reactions was monitored by TLC (silica gel 60F-254,
Merck). Chromatographic purification was performed with
Wakogel C-200 (100–200 mesh, Wako Pure Chemical
Industries) and/or silica-gel 60 (230–400 mesh, Merck).
3-{N-Benzyl[(E)-3-(2-furyl)prop-2-enyl]amino}-2-
(methoxycarbonyl)acrolein (3d). Yield: 83%; yellow oil.
C19H19NO4 (325.4): calcd C, 70.14; H, 5.89; N, 4.31%;
found C, 70.11; H, 5.92; N, 4.29%. This compound was a
(4:5) mixture of two geometric isomers in CDCl3. Major
isomer: 1H NMR (CDCl3) dˆ3.75 (3H, s, OMe), 4.05
(2H, d, Jˆ6.3 Hz, ϾNCH2CHy), 4.65 (2H, s, CH2Ph),
6.04 (1H, m, furyl 3-H), 6.34 (3H, ov, –CHyCH– and
furyl 4-H), 7.22–7.37 (6H, ov, Ph and furyl 5-H), 7.92
(1H, s, 3-H), 9.77 (1H, s, 1-H). Assigned signals for minor
isomer: 1H NMR (CDCl3) dˆ3.77 (3H, s, OMe), 4.38 (2H,
d, Jˆ6.7 Hz, ϾNCH2CHy), 5.02 (2H, s, CH2Ph).
Starting materials
Preparation of 3-(N-allylbenzylamino)-2-(methoxycar-
bonyl)acrolein (3a). Typical procedures. To a solution
of 2-(methoxycarbonyl)malonaldehyde (1;10 0.81 g,
6.2 mmol) in THF (10 ml) added N-allylbenzylamine (2a;
1.00 g, 6.8 mmol) and the mixture was stirred at room
temperature for 9 h. The solvent was evaporated and the
residue was subjected to column chromatography on
silica-gel to afford 3-(N-allylbenzylamino)-2-(methoxy-
carbonyl)acrolein (3a; 1.44 g, 90%) with hexane/ethyl
acetate (5/1).
3-{N-Benzyl[(E)-3-(ethoxycarbonyl)prop-2-enyl]-
amino}-2-(methoxycarbonyl)acrolein (3e). Yield: 64%;
yellow oil. C18H21NO5 (331.4): calcd C, 65.24; H, 6.39;
N, 4.23%; found C, 65.33; H, 6.42; N, 4.28%. This
compound was a (2:3) mixture of two geometric isomers
1
in CDCl3. Major isomer: H NMR (CDCl3) dˆ1.26 (3H, t,
Jˆ7.3 Hz, CH2CH3), 3.75 (3H, s, OMe), 4.07 (2H, d,
Jˆ6.7 Hz, ϾNCH2CHy), 4.11–4.23 (2H, ov, CH2CH3),
4.60 (2H, s, CH2Ph), 5.77 (1H, ov, yCH–Es), 6.70–6.88
(1H, ov, –CHyCH–Es), 7.21–7.37 (5H, ov, Ph), 7.95
(1H, br s, 3-H), 9.77 (1H, br s, 1-H). Assigned signals for
minor isomer: 1H NMR (CDCl3) dˆ3.78 (3H, s, OMe), 4.62
(2H, s, CH2Ph), 7.79 (1H, br s, 3-H).
3-(N-Allylbenzylamino)-2-(methoxycarbonyl)acrolein
(3a). Pale yellow oil. C15H17NO3 (259.3): calcd C, 69.48; H,
6.61; N, 5.40%; found C, 69.18; H, 6.77; N, 5.61%. This
compound was a (4:5) mixture of two geometric isomers in
1
CDCl3. Major isomer: H NMR (CDCl3) dˆ3.77 (3H, s,
Preparation of Methyl 5-(N-allylbenzylamino)-2,4-
bis(methoxycarbonyl)penta-2,4-penta-2,4-dienate (10a).
Typical procedures. To a solution of TiCl4 (0.22 ml,
2 mmol) in THF (7 ml) cooled at 0ЊC added acrolein 3a
(0.267 g, 1 mmol) and dimethyl malonate (0.198 g,
1.5 mmol) in THF (1 ml), and the mixture was stirred at
the same temperature for 1 h. Pyridine (0.32 ml,
4.0 mmol) was added to the mixture and the reaction
mixture was allowed to stand at room temperature for 8 h.
After quenching the reaction with water, the mixture was
extracted with ethyl acetate (3×10 ml) and the organic layer
was evaporated to give a residue. The residue was subjected
with column chromatography on silica-gel to afford conju-
gated diene 10a (0.177 g, 47%) with hexane/ethyl acetate
(2/1).
OMe), 3.93 (2H, br d, Jˆ5.3 Hz, ϾNCH2CHy), 4.61 (2H,
s, CH2Ph), 5.09–5.35 (2H, ov, yCH2), 5.75 (1H, m,
–CHyCH2), 7.16–7.39 (5H, ov, Ph), 7.90 (1H, br s, 3-H),
1
9.75 (1H, s, 1-H). Assigned signals for minor isomer: H
NMR (CDCl3) dˆ4.26 (2H, br d, Jˆ5.7 Hz, ϾNCH2CHy),
4.97 (2H, s, CH2Ph).
Similarly, acrolein derivatives 3b–e were obtained.
3-{N-Benzyl[(E)-but-2-enyl]amino}-2-(methoxycarbonyl)-
acrolein (3b). Yield: 76%; pale yellow oil. C16H19NO3
(273.3): calcd C, 70.31; H, 7.01; N, 5.12%; found C,
70.56; H, 7.16; N, 5.12%. This compound was a (4:5)
mixture of two geometric isomers in CDCl3. Major isomer:
1H NMR (CDCl3) dˆ1.71 (3H, d, Jˆ6.3 Hz, yCHMe), 3.76
(3H, s, OMe), 3.86 (2H, d, Jˆ6.0 Hz, ϾNCH2CHy), 4.59
(2H, s, CH2Ph), 5.43, 5.63 (each 1H, each m, –CHyCH–),
7.15–7.38 (5H, ov, Ph), 7.88 (1H, br s, 3-H), 9.74 (1H, s,
1-H). Assigned signals for minor isomer: 1H NMR (CDCl3)
dˆ4.15 (2H, br d, Jˆ5.7 Hz, ϾNCH2CHy), 4.99 (2H, s,
CH2Ph).
Methyl 5-(N-allylbenzylamino)-2,4-bis(methoxycarbonyl)-
penta-2,4-dienate (10a). Pale yellow prisms from hexane-
ethyl acetate; mp 64–65ЊC; 1H NMR (CDCl3) dˆ3.63, 3.68,
3.74 (each 3H, each s, OMe), 3.93 (2H, dd, Jˆ0.7 and
5.7 Hz, ϾNCH2CHy), 4.55 (2H, s, CH2Ph), 5.25 (1H, br
dd, Jˆ1.0 and 17.2 Hz, yCHH), 5.35 (1H, br d, Jˆ9.2 Hz,
yCHH), 5.86 (1H, m, –CHyCH2), 7.21–7.43 (5H, ov, Ph),
7.71 (1H, s, 3-H), 7.81 (1H, s, 5-H); 13C NMR (CDCl3)
dˆ51.2, 51.6, 52.0 (OMe), 55.3 (CH2Ph), 58.6
3-{N-Benzyl[(E)-cinnamyl]amino}-2-(methoxycarbonyl)-
acrolein (3c). Yield: 72%; pale yellow oil. C21H21NO3
(335.4): calcd C, 75.20; H, 6.31; N, 4.18%; found C,

1304
M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
(ϾNCH2CHy), 95.8 (2-C), 119.2 (4-C), 120.6 (yCH2),
127.4, 128.3, 129.0, 135.4 (Ph–C), 132.1 (–CHyCH2),
140.6 (3-C), 154.3 (5-C), 165.7, 166.6, 167.7 (CO2).
C20H23NO6 (373.3): calcd C, 64.33; H, 6.28; N, 3.75%;
found C, 64.16; H, 6.33; N, 3.79%.
evaporating the toluene, the residue was subjected to
column chromatography on silica-gel to afford 6 (0.019 g,
8%) and 7 (0.019 g, 8%) with hexane/ethyl acetate (10/1),
5a (0.035 g, 15%) with hexane/ethyl acetate (5/1), and
4a (0.128 g, 55%) with hexane/ethyl acetate (3/1),
respectively.
Similarly, diene compounds 10b,c,e were obtained.
1-Benzyl-4-hydroxy-3-(methoxycarbonyl)-4,5-dihydro-
Methyl 5-{N-benzyl[(E)-but-2-enyl]amino}-2,4-bis-
(methoxycarbonyl)penta-2,4-dienate (10b). Yield: 55%;
pale yellow needles from hexane–benzene; mp 78–79ЊC;
1H NMR (CDCl3) dˆ1.75 (3H, dd, Jˆ1.3 and 6.3 Hz,
yCH–Me), 2×3.66, 3.74 (total 9H, each s, OMe), 3.86
(2H, dd, Jˆ0.7 and 5.7 Hz, ϾNCH2CHy), 4.55 (2H, s,
CH2Ph), 5.48, 5.66 (each 1H, each m, –CHyCH–), 7.20–
7.42 (5H, ov, Ph), 7.71 (1H, s, 3-H), 7.79 (1H, s, 5-H); 13C
NMR (CDCl3) dˆ17.7 (yCH–Me), 51.1, 51.6, 51.9 (OMe),
54–60 (br, CH2Ph and ϾNCH2CHy), 95.5 (2-C), 120.0
(4-C), 124.8 (yCH–Me), 127.2, 128.1, 128.9, 135.6
(Ph–C), 131.4 (–CHyCH–Me), 140.8 (3-C), 154.3 (5-C),
165.7, 166.6, 167.8 (CO2). C21H25NO6 (387.4): calcd C,
65.10; H, 6.50; N, 3.62%; found C, 65.10; H, 6.54; N,
3.65%.
1H-azepine (4a). Pale yellow oil; IR (NaCl) v~ ˆ 3480;
1
1710, 1600 cmϪ1; H NMR (CDCl3) dˆ2.36 (1H, dddd,
Jˆ1.7, 4.3, 8.3, and 14.1 Hz, 5-H), 2.47–2.58 (2H, ov,
5-H and OH), 3.72 (3H, s, OMe), 4.57 (2H, s, CH2Ph),
5.10 (1H, ddd, Jˆ5.3, 8.3, and 8.6 Hz, 6-H), 5.20 (1H, br
dd, Jˆ4.3 and 5.3 Hz, 4-H), 5.94 (1H, ddd, Jˆ1.2, 1.7, and
8.6 Hz, 7-H), 7.21–7.40 (5H, ov, Ph), 7.59 (1H, d,
Jˆ1.2 Hz, 2-H); 13C NMR (CDCl3) dˆ33.4 (5-C), 51.4
(OMe), 62.6 (CH2Ph), 66.7 (4-C), 107.5 (3-C), 109.9
(6-C), 126.7, 127.9, 128.9, 136.8 (Ph–C), 132.4 (7-C),
145.7 (2-C), 169.0 (CO2). C15H17NO3: calcd 259.1200;
observed m/z (EI) 259.1208.
3-Benzyl-5-(methoxycarbonyl)-3,6-dihydro-2,6-ethano-
2H-[1,3]oxazine (5a). Pale yellow oil; IR (NaCl) v~ ˆ 1700;
1
1600 cmϪ1; H NMR (CDCl3) dˆ1.99–2.17 (4H, ov, 7-H2
Methyl 5-{N-benzyl[(E)-cinnamyl]amino}-2,4-bis-
(methoxycarbonyl)penta-2,4-dienate (10c). Yield: 43%;
pale yellow oil; 1H NMR (CDCl3) dˆ3.63, 3.66, 3.74
(each 3H, each s, OMe), 4.09 (2H, d, Jˆ5.3 Hz,
ϾNCH2CHy), 4.61 (2H, s, CH2Ph), 6.17 (1H, td, Jˆ5.3
and 15.8 Hz, –CHyCH–Ph), 6.51 (1H, d, Jˆ15.8 Hz,
yCH–Ph), 7.24–7.44 (10H, ov, Ph), 7.74 (1H, s, 3-H),
7.86 (1H, s, 5-H); 13C NMR (CDCl3) dˆ51.2, 51.6, 52.0
(OMe), 54–60 (br, CH2Ph and ϾNCH2CHy), 95.9 (2-C),
120.7 (4-C), 123.1 (yCH–Ph), 126.5, 127.3, 128.2, 128.6,
129.0, 134.5, 135.5, 135.7 (Ph–C and –CHyCH–Ph), 140.7
(3-C), 154.2 (5-C), 165.6, 166.5, 167.7 (CO2). C26H27NO6
(449.5): calcd C, 69.47; H, 6.05; N, 3.12%; found C, 69.99;
H, 6.24; N, 3.25%. C26H27NO6: calcd 449.1839; observed
m/z (EI) 449.1826.
and 8-H2), 3.67 (3H, s, OMe), 4.33 (2H, s, CH2Ph), 4.99
(1H, dd, Jˆ1.0 and 2.3 Hz, 2-H), 5.03 (1H, d, Jˆ2.0 Hz,
6-H), 7.21(1H, d, Jˆ1.0 Hz, 4-H), 7.25–7.39 (5H, ov, Ph);
13C NMR (CDCl3) dˆ35.7, 37.3 (7- and 8-C), 50.5 (OMe),
56.6 (CH2Ph), 74.3 (6-C), 87.1 (2-C), 103.9 (5-C), 127.6,
127.9, 128.8, 136.5 (Ph–C), 142.7 (4-C), 166.3 (CO2).
C15H17NO3 (259.3): calcd C, 69.48; H, 6.61; N, 5.40%;
found C, 70.24; H, 6.72; N, 5.52%. C15H17NO3: calcd
259.1199; observed m/z (EI) 259.1208.
13,14-Dibenzyl-3,9-bis(methoxycarbonyl)-13,14-diaza-
tricyclo[6.4.1.12,7]tetradecan-3,5,9,11-tetraene (6). Color-
less prisms from hexane–propan-2-ol; mp 183–184ЊC; IR
1
(KBr) v~ ˆ 1700; 1600 cmϪ1; H NMR (CDCl3) dˆ3.41
(2H, dd, Jˆ4.3 and 4.9 Hz, 1- and 7-H), 3.47 (4H, s,
2×CH2Ph), 3.66 (6H, s, 2×OMe), 4.02 (2H, t, Jˆ1.3 Hz,
2- and 8-H), 6.15–6.28 (4H, ov, 5-, 6-, 11-, and 12-H),
7.13–7.23 (10H, ov, Ph), 7.39 (2H, dd, Jˆ1.6 and 6.9 Hz,
4- and 10-H); 13C NMR (CDCl3) dˆ51.8 (MeO), 56.8
(CH2Ph), 59.6 (1- and 7-C), 60.9 (2- and 8-C), 124.1 (5-
and 11-C), 126.8, 128.0, 128.1, 135.0 (Ph–C), 134.8 (6- and
12-C), 138.7 (3- and 9-C), 143.4 (4- and 10-C), 168.1 (CO2).
C30H30N2O4 (482.6): calcd C, 74.67; H, 6.27; N, 5.81%;
found C, 74.56; H, 6.32; N, 5.82%. The structure of
this compound was confirmed by X-ray crystal structure
analysis.11
Methyl 5-{N-benzyl[(E)-3-(ethoxycarbonyl)prop-2-enyl]-
amino}-2,4-bis(methoxycarbonyl)penta-2,4-dienate (10e).
1
Yield: 53%; yellow oil; H NMR (CDCl3) dˆ1.31 (3H, t,
Jˆ7.3 Hz, CH2CH3), 3.66, 3.68, 3.75 (each 3H, each s,
OMe), 4.06 (2H, dd, Jˆ1.7 and 5.0 Hz, ϾNCH2CHy),
4.22 (2H, q, Jˆ7.3 Hz, CH2CH3), 4.55 (2H, s, CH2Ph),
5.95 (1H, td, Jˆ1.7 and 15.8 Hz, yCH–Es), 6.87 (1H, td,
Jˆ5.0 and 15.8, ϾNCH2CHy), 7.21–7.43 (5H, ov, Ph),
7.63 (1H, s, 3-H), 7.63 (1H, s, 5-H); 13C NMR (CDCl3)
dˆ14.1 (CH2CH3), 51.3, 52.1, 52.4 (OMe), 54.5 (br,
CH2Ph), 56–59 (br, ϾNCH2CHy), 60.8 (CH2CH3), 96.5 (2-
C), 122.0 (4-C), 124.2 (yCH–Es), 127.4, 128.5, 129.1, 136.0
(Ph–C), 140.1 (3-C), 141.2 (–CHyCH–Es), 165.2, 165.3,
166.2, 167.4 (CO2). C23H27NO8 (445.5): calcd C, 62.01; H,
6.58; N, 3.14%; found C, 62.44; H, 6.29; N, 3.25%.
C23H27NO8: calcd 445.1737; observed m/z (EI) 445.1730.
13,14-Dibenzyl-3,12-bis(methoxycarbonyl)-13,14-diaza-
tricyclo[6.4.1.12,7]tetradecan-3,5,9,11-tetraene (7).
Yellow oil. We did not succeed in isolating this compound
as a pure form and, however, its structure was deduced by
the spectroscopic data as follows. 1H NMR (CDCl3) dˆ3.28
(1H, d, Jˆ5.9 Hz, 7- and 8-H), 3.41, 3.51 (each 2H, each d,
Jˆ13.5 Hz, 2×CH2Ph), 3.74 (6H, s, 2×OMe), 4.20 (2H, br s,
1- and 2-H), 5.93 (2H, dd, Jˆ5.9 and 11.2 Hz, 6- and 12-H),
6.25 (1H, dd, Jˆ7.9 and 11.2 Hz, 5- and 11-H), 7.17–7.25
(10H, ov, Ph), 7.32 (2H, d, Jˆ7.9 Hz, 4- and 10-H); 13C
NMR (CDCl3) dˆ51.9 (MeO), 56.8 (CH2Ph), 58.1 (1- and
2-C), 61.2 (7- and 8-C), 124.7 (5 and 11-C), 126.8, 127.9,
Carbonyl-ene reaction of 3-(alk-2-enyl)amino-2-(meth-
oxycarbonyl)acrolein derivatives 3
Thermal Reaction of Acrolein Derivative 3a. Typical
procedures. A solution of 3a (0.232 g, 0.896 mmol) in
toluene (10 ml) was heated under reflux for 6 h. After

M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
1305
128.3, 135.8 (Ph–C), 133.9 (6- and 12-C), 138.6 (3- and
9-C), 141.7 (4- and 10-C), 168.3 (CO2); MS (EI) m/z: 482
(Mϩ), 364, 241.
144.9 (4-C), 166.1 (CO2). C21H21NO3 (335.4): calcd C,
75.20; H, 6.31; N, 4.18%; found C, 75.37; H, 6.28; N,
4.22%.
Similarly, thermal reaction of acrolein derivatives 3b–e
gave azepine 4b–e and/or [1,3]oxazines 5b–d and the
results are demonstrated in Table 1.
(4Sء,5Rء)-(^)-1-Benzyl-5-(2-furyl)-4-hydroxy-3-(methoxy-
carbonyl)-4,5-dihydro-1H-azepine (4d). Colorless prisms
from hexane–propan-2-ol; mp 116–117ЊC; IR (KBr) v~ ˆ
1
3480; 1710, 1600 cmϪ1; H NMR (CDCl3) dˆ2.05 (1H,
4Sء,5Sء)-(^)-1-Benzyl-4-hydroxy-3-(methoxycarbonyl)-
5-methyl-4,5-dihydro-1H-azepine (4b). Pale yellow oil;
br, OH), 3.78 (3H, s, OMe), 3.80 (1H, br, 5-H), 4.62 (2H,
s, CH2Ph), 5.21 (1H, ddd, Jˆ1.0, 4.3, and 8.9 Hz, 6-H), 5.49
(1H, s, 4-H), 6.02 (1H, td, Jˆ1.7 and 8.9 Hz, 7-H), 6.25 (1H,
d, Jˆ3.3 Hz, furyl 3-H), 6.34 (1H, dd, Jˆ2.0 and 3.3, furyl
4-H), 7.23–7.41 (6H, ov, Ph and furyl 5-H), 7.60 (1H, s,
1
IR (NaCl) v~ ˆ 3480; 1710, 1600 cmϪ1; H NMR (CDCl3)
dˆ1.22 (3H, d, Jˆ6.9 Hz, 5-Me), 1.77 (1H, br s, OH), 2.58
(1H, m, 5-H), 3.72 (3H, s, OMe), 4.56 (2H, s, CH2Ph), 4.75
(1H, ddd, Jˆ1.0, 4.3, and 8.9 Hz, 6-H), 4.98 (1H, s, 4-H),
5.86 (1H, td, Jˆ1.7 and 8.9 Hz, 7-H), 7.21–7.40 (5H, ov,
Ph), 7.60 (1H, d, Jˆ1.0 Hz, 2-H); 13C NMR (CDCl3)
dˆ19.5 (5-Me), 37.7 (5-C), 51.4 (OMe), 62.6 (CH2Ph),
71.7 (4-C), 107.7 (3-C), 115.5 (6-C), 126.8, 128.0, 128.9,
136.9 (Ph–C), 130.0 (7-C), 145.7 (2-C), 168.8 (CO2).
C16H19NO3 (273.3): calcd C, 70.31; H, 7.01; N, 5.12%;
found C, 70.38; H, 7.06; N, 5.13%.
1
2-H); H NMR (CDCl3) dˆ43.6 (3-C), 51.6 (OMe), 62.7
(CH2Ph), 69.9 (4-C), 105.5, 110.3, 141.4, 155.8 (furyl-C),
106.9 (3-C), 110.0 (6-C), 126.8, 128.1, 129.0, 136.6 (Ph–C),
130.6 (7-C), 146.0 (2-C), 168.3 (CO2). C19H19NO4 (325.4):
calcd 70.14; H, 5.89; N, 4.31%; found C, 70.15; H, 5.93; N,
4.36%.
(2Rء,6Sء,7Rء)-(^)-3-Benzyl-7-(2-furyl)-5-(methoxycar-
bonyl)-3,6-dihydro-2,6-ethano-2H-[1,3]oxazine
(5d).
(2Rء,6Sء,7Sء)-(^)-3-Benzyl-5-(methoxycarbonyl)-7-
methyl-3,6-dihydro-2,6-ethano-2H-[1,3]oxazine (5b).
Colorless prisms from hexane; mp 82–83ЊC; IR (KBr) v~ ˆ
Colorless prisms from hexane, mp 93–94ЊC; IR (KBr) v~ ˆ
1
1710; 1600 cmϪ1; H NMR (CDCl3) dˆ2.28 (1H, ddd,
Jˆ3.3, 5.9, and 13.5 Hz, 8-H), 2.43 (1H, dd, Jˆ8.9 and
13.2 Hz, 8-H), 3.70 (3H, s, OMe), 3.74 (1H, dd, Jˆ3.3
and 8.6 Hz, 7-H), 4.37 (2H, s, CH2Ph), 5.08 (1H, s, 6-H),
5.15 (1H, br d, Jˆ5.9 Hz, 2-H), 6.03 (1H, d, Jˆ3.3 Hz, furyl
3-H), 6.25 (1H, dd, Jˆ2.0 and 3.3 Hz, furyl 4-H), 7.26–7.37
(7H, ov, furyl 5-H and Ph and 4-H); 13C NMR (CDCl3)
dˆ41.7 (8-C), 49.7 (7-C), 50.7 (OMe), 56.8 (CH2Ph),
78.3 (6-C), 87.3 (2-C), 102.8 (5-C), 104.3, 110.0, 141.1,
156.0 (furyl-C), 127.6, 128.0, 128.9, 136.4 (Ph–C), 142.5
(4-C), 156.7 (CO2). C19H19NO4 (325.4): calcd C, 70.14; H,
5.89; N, 4.31%; found C, 70.14; H, 5.90; N, 4.31%.
1710; 1600 cmϪ1
;
1H NMR (CDCl3) dˆ1.01 (3H, d,
Jˆ7.3 Hz, 7-Me), 1.59 (1H, ddd, Jˆ2.6, 6.3, and 13.2 Hz,
8-H), 2.22 (1H, dd, Jˆ8.3 and 13.2 Hz, 8-H), 2.57 (1H, m,
7-H), 3.67 (3H, s, OMe), 4.31 (2H, s, CH2Ph), 4.60 (1H, s,
6-H), 5.01 (1H, d, Jˆ5.9 Hz, 2-H), 7.19 (1H, s, 4-H), 7.24–
7.39 (5H, ov, Ph); 13C NMR (CDCl3) dˆ21.2 (7-Me), 44.1,
45.6 (7- and 8-C), 50.5 (OMe), 56.6 (CH2Ph), 79.9 (6-C),
87.6 (2-C), 103.3 (5-C), 127.5 (5-C), 127.5, 127.9, 128.8,
136.6 (Ph–C), 142.1 (4-C), 166.2 (CO2). C16H19NO3
(273.3): calcd C, 70.31; H, 7.01; N, 5.12%; found C,
70.38; H, 7.06; N, 5.13%.
(4Sء,5Sء)-(^)-1-Benzyl-5-ethoxycarbonyl-4-hydroxy-3-
(methoxycarbonyl)-4,5-dihydro-1H-azepine (4e). Color-
less prisms from hexane–ethyl acetate; mp 126–127ЊC;
(4Sء,5Sء)-(^)-1-Benzyl-4-hydroxy-3-(methoxycarbonyl)-
5-phenyl-4,5-dihydro-1H-azepine (4c). Colorless prisms
from hexane; mp 128–129ЊC; IR (KBr) v~ ˆ 3490; 1710,
IR (KBr) v~ ˆ 3480; 1725, 1700, 1600 cmϪ1
;
1H NMR
1600 cmϪ1
;
1H NMR (CDCl3) dˆ1.92 (1H, br d,
(CDCl3) dˆ1.30 (3H, t, Jˆ7.3 Hz, CH2CH3), 2.22 (1H, br
s, OH), 3.29 (1H, br d, Jˆ5.6 Hz, 5-H), 3.74 (3H, s, OMe),
4.23 (2H, q, Jˆ7.3 Hz, CH2CH3), 4.59 (2H, s, CH2Ph), 5.42
(1H, dd, Jˆ5.6 and 8.9 Hz, 6-H), 5.69 (1H, s, 4-H), 6.03
(1H, br d, Jˆ8.9 Hz, 7-H), 7.21–7.39 (5H, ov, Ph), 7.66
(1H, s, 2-H); 13C NMR (CDCl3) dˆ14.5 (CH2CH3), 49.0
(5-C), 51.6 (OMe), 61.3 (CH2CH3), 62.7 (CH2Ph), 68.5
(4-C), 106.4 (3-C), 107.3 (6-C), 126.8, 128.1, 129.0, 136.5
(Ph–C), 130.9 (7-C), 146.0 (2-C), 168.2, 171.9 (CO2).
C18H21NO5 (331.36): calcd C, 65.24; H, 6.39; N, 4.23%;
found C, 64.99; H, 6.40; N, 4.30%. The structure of
this compound was confirmed by X-ray crystal structure
analysis.11
Jˆ5.6 Hz, OH), 3.70 (4H, ov, OMe and 5-H), 4.63 (2H, s,
CH2Ph), 5.16 (1H, ddd, Jˆ1.3, 4.9, and 8.9 Hz, 6-H), 5.28
(1H, br d, Jˆ5.6 Hz, 4-H), 6.02 (1H, ddd, Jˆ1.3, 2.3, and
8.9 Hz, 7-H), 7.25–7.43 (10H, ov, Ph), 7.70 (1H, s, 2-H);
13C NMR (CDCl3) dˆ49.5 (5-C), 51.6 (OMe), 62.8
(CH2Ph), 71.6 (4-C), 108.2 (3-C), 113.2 (6-C), 126.7,
126.9, 128.1, 128.3, 128.5, 129.0, 136.8, 143.6 (Ph–C),
130.1 (7-C), 145.2 (2-C), 168.4 (CO2). C21H21NO3
(335.4): calcd C, 75.20; H, 6.31; N, 4.18%; found C,
75.22; H, 6.48; N, 4.29%.
(2Rء,6Sء,7Rء)-(^)-3-Benzyl-5-(methoxycarbonyl)-7-
phenyl-3,6-dihydro-2,6-ethano-2H-[1,3]oxazine
(5c).
Colorless prisms from hexane; mp 121–123ЊC; IR (KBr)
v~ ˆ 1710; 1600 cmϪ1
;
1H NMR (CDCl3) dˆ2.17 (1H,
Olefin-ene reaction of conjugated diene compounds 10
from 3-(alk-2-enyl)amino-2-(methoxycarbonyl)acrolein
derivatives 3
ddd, Jˆ3.3, 6.3, and 13.5 Hz, 8-H), 2.58 (1H, dd, Jˆ8.9
and 13.5 Hz, 8-H), 3.65–3.68 (4H, ov, OMe and 7-H),
4.39 (2H, s, CH2Ph), 4.96 (1H, s, 6-H), 5.19 (1H, d,
Jˆ5.9 Hz, 2-H), 7.18–7.38 (11H, ov, Ph and 4-H); 13C
NMR (CDCl3) dˆ45.3 (8-C), 50.6 (OMe), 56.6 (CH2Ph),
56.8 (7-C), 80.5 (6-C), 87.6 (2-C), 103.5 (5-C), 126.3,
126.7, 127.8, 128.0, 128.4, 128.9, 136.5, 142.3 (Ph–C),
Thermal Reaction of Diene 10a. Typical procedures. A
solution of diene 10a (0.102 g, 0.27 mmol) in toluene (5 ml)
was heated under reflux for 12 h and the solvent was evapo-
rated. The residue was subjected to column chromatography

1306
M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
on silica-gel to afford azepine 11a (0.092 g, 90%) with
hexane/ethyl acetate (1/1).
5-H), 3.37 (1H, d, Jˆ9.6 Hz, 4-CHEs2), 3.56, 3.66, 3.71
(each 3H, each s, OMe), 4.10–4.27 (2H, ov, CH2CH3),
4.58 (2H, s, CH2Ph), 4.83 (1H, d, Jˆ9.6 Hz, 4-H), 5.33
(1H, ddd, Jˆ1.0, 4.3, and 9.2 Hz, 6-H), 5.99 (1H, td,
Jˆ2.0 and 9.2 Hz, 7-H), 7.23–7.42 (5H, ov, Ph), 7.56
(1H, br s, 2-H); 13C NMR (CDCl3) dˆ14.1 (CH2CH3),
47.2 (5-C), 51.6 (4-C), 51.7, 52.2, 52.5 (OMe), 57.5
(4-CHEs2), 61.4 (CH2CH3), 62.8 (CH2Ph), 105.5 (3-C),
106.6 (6-C), 126.9, 128.1, 129.0, 136.8 (Ph–C), 130.5
(7-C), 144.8 (2-C), 167.8, 168.5, 168.6, 172.2 (CO2).
C23H27NO8 (445.5): calcd C, 62.01; H, 5.75; N, 3.14%;
found C, 61.97; H, 6.09; N, 3.20%. The structure of this
compound was confirmed by X-ray crystal structure
analysis.11
1-Benzyl-3-methoxycarbonyl-4-{[bis(methoxycarbonyl)]-
methyl}-4,5-dihydro-1H-azepine (11a). Pale yellow oil;
;
IR (NaCl) v~ ˆ 1700; 1600 cmϪ1 1H NMR (CDCl3)
dˆ2.39 (1H, br d, Jˆ15.5 Hz, 5-H), 2.53 (1H, ddd,
Jˆ4.6, 8.9, and 15.5 Hz, 5-H), 3.43 (1H, d, Jˆ10.6 Hz,
4-CHEs2), 3.63, 3.67, 3.71 (each 3H, each s, OMe), 4.20
(1H, ddd, Jˆ4.0, 4.6, and 10.6 Hz, 4-H), 4.54 (2H, s,
CH2Ph), 4.84 (1H, td, Jˆ8.9 and 9.2 Hz, 6-H), 5.85 (1H,
br td, Jˆ4.3 and 9.2 Hz, 7-H), 7.24–7.40 (5H, ov, Ph), 7.53
(1H, dd, Jˆ1.0 and 1.6 Hz, 2-H); 13C NMR (CDCl3) dˆ30.9
(5-C), 38.5 (4-C), 51.5, 52.2, 52.3 (OMe), 57.6 (4-CHEs2),
62.8 (CH2Ph), 105.8 (3-C), 108.5 (6-C), 126.8, 127.9, 128.9,
137.2 (Ph–C), 131.6 (7-C), 145.2 (2-C), 168.7, 168.8 (CO2).
C20H23NO6 (373.4): calcd C, 64.33; H, 6.21; N, 3.75%;
found C, 64.69; H, 6.29; N, 3.69%. C20H23NO6: calcd
373.1526; observed m/z (EI) 373.1518.
Single-crystal X-Ray structure analyses of diazatri-
cyclotetradecantriene 6 and azepines 4e and 11e11
Single crystals of compounds 6 (C30H30N2O4: 482.52) as
prisms from hexane–propan-2-ol, 4e (C18H21NO5: 331.37)
as prisms from hexane, and 11e (C23H27NO8: 445.47)
as prisms from hexane were obtained. A crystal of
approximate dimensions 0.24×0.32×0.38 mm3 for 6,
0.28×0.42×0.64 mm3 for 4e, and 0.16×0.48×0.68 mm3 for
11e were used for data collection, respectively. All measure-
ments were made on a Rigaku AFC5S diffractometer by
employing graphite-monochromated Mo–Ka radiation.
The unit-cell dimensions were obtained by least-squares
analysis of 25 reflections within the range of
39.09Ͻ2uϽ39.94Њ for 6, 18 reflections within the range of
20.10 Ͻ2uϽ22.48Њ for 4e, and 13 reflections within the
range of 12.39 Ͻ2uϽ23.74Њ for 11e, respectively. The
crystal data for compound 6 are given: crystal system: tri-
Similarly, thermal reaction of conjugated dienes 10b,c,e
gave azepine 11b,c,e and the results are demonstrated in
Table 2.
(4Rء,5Sء)-(^)-1-Benzyl-3-methoxycarbonyl-4-{[bis-
(methoxycarbonyl)]methyl}-5-methyl-4,5-dihydro-1H-
azepine (11b). Yellow oil; IR (NaCl) v~ ˆ 1700; 1600 cmϪ1
;
1H NMR (CDCl3) dˆ1.03 (3H, d, Jˆ7.6 Hz, 5-Me), 2.75
(1H, m, 5-H), 3.32 (1H, d, Jˆ8.3 Hz, 4-CHEs2), 3.54, 3.69.
3.74 (each 3H, each s, OMe), 4.29 (1H, br d, Jˆ8.3 Hz,
4-H), 4.53 (2H, s, CH2Ph), 4.63 (1H, ddd, Jˆ1.0, 4.0, and
9.2 Hz, 6-H), 5.81 (1H, ddd, Jˆ1.6, 2.3, and 9.2 Hz, 7-H),
7.20–7.41 (5H, ov, Ph), 7.51 (1H, dd, Jˆ1.0 and 1.6 Hz,
2-H); 13C NMR (CDCl3) dˆ21.0 (5-Me), 37.4 (5-C), 44.4
(4-C), 51.5, 52.0, 52.4 (OMe), 57.6 (4-CHEs2), 62.4
(CH2Ph), 106.2 (3-C), 114.5 (6-C), 126.8, 127.9, 128.8,
137.0 (Ph–C), 129.4 (7-C), 144.9 (2-C), 168.7, 168.9,
169.3 (CO2). C21H25NO6 (387.4): calcd C, 65.10; H, 6.50;
N, 3.62%; found C, 64.71; H, 6.54; N, 3.35%. C21H25NO6:
calcd 387.1682; observed m/z (EI) 387.1672.
˚
clinic; space group: P1 (#2); cell constants: a: 8.530(3) A, b:
3
˚
˚
˚
9.586(4) A, c: 8.162(7) A, V: 636.8(3) A ; aˆ98.56(5)Њ,
bˆ100.78(6)Њ, gˆ77.86(3)Њ; Z value: 2; Dc: 2.517
g cmϪ3. Similarly, the crystal data for compound 4e are
given: crystal system: triclinic; space group: P1 (#2); cell
˚
˚
˚
constants: a: 10.37(3) A, b: 10.42(1) A, c: 9.40(2) A, V:
3
˚
865(3) A ; aˆ109.5(1)Њ, bˆ108.1(2)Њ, gˆ67.5(1)Њ; Z
value: 2; Dc: 1.272 g cmϪ3. The crystal data for compound
(4Rء,5Sء)-(^)-1-Benzyl-3-methoxycarbonyl-4-{[bis-
(methoxycarbonyl)]methyl}-5-phenyl-4,5-dihydro-1H-
11e are given: crystal system: monoclinic; space group: P21/
˚
˚
n (#14); cell constants: a: 8.12(1) A, b: 11.27(3) A, c:
azepine (11c). Yellow oil; IR (NaCl) v~ ˆ 1700; 1600 cmϪ1
;
3
˚
˚
25.11(2) A, V: 2275(4) A ; bˆ97.9(1)Њ; Z value: 4; Dc:
1.300 g cmϪ3. The v –2u scan technique to a maximum
2u-value of 54.9Њ was used and scans of (1.63ϩ
0.30 tan u)Њ were made at a speed 16Њ minϪ1 for 6. The
v –2u scan technique to a maximum 2u-value of 55.1Њ
was used and scans of (1.10ϩ0.30 tan u)Њ were made at a
speed 16Њ minϪ1 for 4e. The v-2u scan technique to a
maximum 2u-value of 55.1Њ was used and scans of
(0.97ϩ0.30 tan u)Њ were made at a speed 16Њ minϪ1 for
11e. A total of 3111 observed reflections (unique: 2914;
Rintˆ0.029) for 6, 4190 observed reflections (unique:
3968; Rintˆ0.083) for 4e, and 4873 observed reflection
(unique: 4491; Rintˆ0.083) was collected for 11e, respec-
tively. All calculations were performed using t exan
program.15 Atoms other than hydrogen were refined aniso-
tropically. The structure of compound 6 was solved by
direct methods (SIR)16 and refined by least-squares to R
0.048 (Rw 0.051). The structure of compound 4e was
solved by direct methods (MITHRIL)17 and refined by
least-squares to R 0.106 (Rw 0.106). The structure of
1H NMR (CDCl3) dˆ3.20, 3.51, 3.72 (each 3H, each s,
OMe), 3.52 (1H, d, Jˆ8.6 Hz, 4-CHEs2), 3.97 (1H, m,
5-H), 4.59 (2H, s, CH2Ph), 4.61 (1H, br d, Jˆ8.6 Hz,
4-H), 5.23 (1H, ddd, Jˆ1.3, 3.6, and 9.9 Hz, 6-H), 6.04
(1H, ddd, Jˆ0.6, 2.6, and 9.9 Hz, 7-H), 7.17–7.42 (10H,
ov, Ph), 7.59 (1H, d, Jˆ0.6 Hz, 2-H); 13C NMR (CDCl3)
dˆ45.7 (5-C), 47.1 (4-C), 51.4, 51.6, 52.0 (OMe), 57.3
(4-CHEs2), 62.5 (CH2Ph), 106.6 (3-C), 110.0 (6-C), 126.6,
127.0, 127.8, 127.9, 128.3, 128.8, 136.8, 142.3 (Ph-C),
130.5 (C-7), 145.0 (2-C), 167.8, 168.5, 168.6 (CO2).
C26H27NO6 (449.5): calcd C, 69.47; H, 6.05; N, 3.12%;
found C, 68.94; H, 6.25; N, 3.07%. C26H27NO6: calcd
449.1839; observed m/z (EI) 449.1818.
(4Rء,5Sء)-(^)-1-Benzyl-5-ethoxycarbonyl-3-methoxy-
carbonyl-4-{[bis(methoxycarbonyl)]methyl}-4,5-dihydro-
1H-azepine (11e). Colorless prisms from hexane–benzene;
1
mp 112–123ЊC; IR (KBr) v~ ˆ 1700; 1600 cmϪ1; H NMR
(CDCl3) dˆ1.32 (3H, t, Jˆ7.3 Hz, CH2CH3), 3.34 (1H, m,

M. Noguchi et al. / Tetrahedron 56 (2000) 1299–1307
1307
compound 11e was solved by direct methods (MITHRIL)17
and refined by least-squares to R 0.073 (Rw 0.070).
Kakehi, A. Tetrahedron 1996, 52, 13081; (d) Kuroki, Y.; Akao,
R.; Inazumi, T.; Noguchi, M. Tetrahedron 1994, 50, 1063; (e)
Noguchi, M.; Mizukoshi, T.; Uchida, T.; Kuroki, Y. Tetrahedron
1996, 52, 13097; (f) Noguchi, M.; Mizukoshi, T.; Nakagawa, S.;
Kakehi, A. Tetrahedron 1996, 52, 13111.
Kinetics on thermal reaction of conjugated Diene 10c
The apparatus and procedures for the measurement of the
conversion rates are same as those in the previous paper.4e
To measure the rates of the disappearance of the diene 10c,
dichlorobenzene was utilized as internal standard. A
Wakosil-II5C18HG (id 4.6×250 mm2) column was used
and the flow rate of the elution was 1 ml minϪ1 and the
component of the elution was acetonitrile–H2O (1:1). All
rates of conversion of 10c in several solvents were first-
order with respect to the diene concentration. The obtained
rate constants [k (sϪ1)×105] at 97ЊC were as bellows: 2.78
(relative rate: 1.00) in dioxane, 1.79 (0.39) in DMF, 1.42
(0.51) in propionitrile, and 1.13 (0.41) in butan-1-ol.
5. As recent reviews on carbonyl-ene reactions: Mikami, K.;
Shimizu, M. Chem. Rev. 1992, 92, 1021; Mikami, K.; Terada,
M.; Narisawa, S.; Nakai, T. Synlett 1992, 255.
6. Aa a review on imine-ene reactions: Borzilleri, R. M.; Weinreb,
S. M. Synthesis 1995, 347.
7. Klop, W.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1983,
988.
8. Mayer, T.; Maas, G. Tetrahedron Lett. 1992, 33, 205; Reinhard,
R.; Glaser, M.; Neumann, R.; Maas, G. J. Org. Chem. 1997, 62
7744.
9. Noguchi, M.; Yamada, H.; Takamura, S.; Uchida, T.; Hironaka,
M.; Kakehi, A.; Yamamoto, H.; Eur. J. Org. Chem. 2000, in press.
10. Bu¨chi, G.; Carlson, J. A.; Powell, J. E.; Tietze, L. F. J. Am.
Chem. Soc. 1973, 95, 540.
11. Crystallographic data for the structures of diazatricyclotetra-
decatetraene 6 and azepines 4e and 11e have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. 136 764 for 6, 136 766 for 4e, and 136 765 for
11e.
Acknowledgements
We thank Mr. Tetsuhiro Maeda for his experimental
assistance. The author (M. N.) is also grateful for the
financial support by the Grant-in-Aid for Scientific Research
No. 09650940 from the Ministry of Education, Science,
Sports and Culture of Japan.
12. Hafner, K.; Mondt, J. Angew. Chem. Int. Ed. Engl. 1966, 5,
¨
839; Habermehl, G.; Gottlicher, S. Angew. Chem., Int. Ed. Engl.
1967, 6, 805; Johnson, A. L.; Simmons, H. E. J. Am. Chem. Soc.
1967, 89, 3191; Paquette, L. A.; Barrett, J. H.; Kuhla, D. E. J. Am.
Chem. Soc. 1969, 91, 3616.
References
13. Preparation and physical properties of vinamidine derivatives
including 9: Kamimura, A.; Sato, E.; Kanayama, D.; Noguchi, M.,
unpublished data.
1. As a review: Zecchi, G. Synthesis 1991, 181.
2. Hu¨bner, T. Dissertation, University of Freiburg, 1987; Marx,
K.; Eberbach, W. Tetrahedron 1997, 53, 14687.
14. Lehnert, W. Tetrahedron 1972, 28, 663; Lehnert, W. Tetrahedron
1973, 29, 635.
15. t exan –t exr ay, Structure Analysis Package, Molecular
Structures Corporation, 1985.
3. Arany, A.; Groundwater, P. W.; Nyerges, M. Tetrahedron Lett.
1998, 39, 3267; Arany, A.; Bendell, D.; Groundwater, P. W.;
Garnett, T.; Nyerges, M. J. Chem. Soc., Perkin Trans. 1 1999,
2605.
16. Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.;
Polidori, G.; Spagna, R.; Viterbo, D. J. Appl. Crystallogr. 1989,
22, 389.
4. (a) Inazumi, T.; Yamada, K.; Kuroki, Y.; Kakehi, A.; Noguchi,
M. J. Chem. Soc., Perkin Trans. 1, 1994, 557; (b) Ianazumi, T.;
Harada, E.; Mizukoshi, T.; Kakehi, A.; Noguchi, M. J. Chem. Soc.,
Perkin Trans. 1, 1994, 565; (c) Noguchi, M.; Mizukoshi, T.;
17. Gilmore, C. J. J. Appl. Crystallogr. 1984, 17, 42.