Generation of NH-azomethine imine intermediates through the 1,2-hydrogen shift of hydrazones and their intermolecular cycloaddition reaction with olefinic dipolarophiles

Article abstract of DOI:10.1016/S0040-4020(03)00593-3

The thermal 1,2-hydrogen shift of the hydrazone generates the NH-azomethine imine intermediate in the 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system under mild conditions. Therein, the resulting NH-azomethine imine should be stabilized by forming an internal hydrogen bond with the carbonyl oxygen at the 4-position. Its smooth stereoselective intermolecular cycloaddition reaction with olefinic dipolarophiles giving pyrazolidine derivatives is discussed.

Full text of DOI:10.1016/S0040-4020(03)00593-3

Tetrahedron 59 (2003) 4123–4133
Generation of NH-azomethine imine intermediates through the
1,2-hydrogen shift of hydrazones and their intermolecular
cycloaddition reaction with olefinic dipolarophiles
*
Michihiko Noguchi, Satoshi Matsumoto, Masashi Shirai and Hidetoshi Yamamoto
Department of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwadai, Ube, 755-8611, Japan
Received 24 December 2002; accepted 7 April 2003
Abstract—The thermal 1,2-hydrogen shift of the hydrazone generates the NH-azomethine imine intermediate in the 4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde system under mild conditions. Therein, the resulting NH-azomethine imine should be stabilized by forming an
internal hydrogen bond with the carbonyl oxygen at the 4-position. Its smooth stereoselective intermolecular cycloaddition reaction with
olefinic dipolarophiles giving pyrazolidine derivatives is discussed. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
internal hydrogen bond with the carbonyl oxygen
(Scheme 1).
The concept of the thermal isomerization of hydrazone to
NH-azomethine imine through the 1,2-hydrogen shift was
proposed by Grigg and co-workers in 19781 earlier than that
of oxime–nitrone.2 However, few reports3 on further
investigations concerning the synthetic and mechanistic
aspects have been accomplished in comparison with those
on acid-catalyzed hydrazone–azomethine imine isomeriza-
tion,4 or on the thermal oxime–nitrone one.5 As a reason,
the pyrazolidines obtained from NH-azomethine imines and
olefinic dipolarophiles were not very stable and dehydro-
genated to 2-pyrazoline derivatives under reaction con-
ditions and/or purification procedures. This provided an
ambiguity of the mechanism and stereochemistry of the 1,3-
dipolar cycloaddition process. As a part of our project to
develop 1,3-dipolar cycloaddition reactions at the periphery
of heterocyclic system, we reported that facile thermal
isomerizations of the oxime and hydrazone to the NH-
nitrone and -azomethine imine took place under neutral
conditions. The intramolecular cycloaddition reaction of the
dipoles with olefinic dipolarophiles provided isoxazolidine
and pyrazolidine derivatives fused by heterocycles,
respectively.6 Therein, we proposed that the 1,2-hydrogen
shift was assisted by the functional groups, e.g. carbonyl
and/or amino ones, occupied at the proper positions in the
same molecule and that the resulting NH-nitrone and
-azomethine imine should be stabilized by forming the
In order to obtain further information on the isomerization
process, we examined the thermal reaction of 2-substituted
4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde phenyl
hydrazones with olefinic dipolarophiles. We describe here
that the hydrogen bond formation between the resulting NH-
azomethine imine and the carbonyl oxygen at the 4-position
should be requisite for the facile thermal isomerization.
Also, the synthetic utility of the intermolecular cyclo-
addition reaction of the resulting NH-azomethine imine
with olefinic electron-deficient dipolarophiles will be
discussed.
2. Results and discussion
2.1. Thermal reaction of 2-substituted 4-oxo-4H-pyrido-
[1,2-a]pyrimidine-3-carbaldehyde phenyl hydrazones
with olefinic dipolarophiles
In order to elucidate the scope and features of the
hydrazone–azomethine imine isomerization in pyrido[1,2-
a]pyrimidin-4(4H)-one system, five phenyl hydrazones
3a–e were prepared and explored the thermal reaction
with olefinic dipolarophiles (Scheme 2).
Reaction of hydrazone 3a with N-phenylmaleimide (6) in
refluxing ethanol (EtOH) gave the desired NH-azomethine
imine cycloadduct 7a, dehydrogenated product 8a, 2-(pyr-
rolidin-1-yl)pyrido[1,2-a]pyrimidin-4(4H)-one (9a), and
2-pyrazoline 10 in 69%, trace, 27, and 30% yields,
respectively. The structures of 7a, 8a, and 10 were fully
Keywords: hydrazone; NH-azomethine imine; thermal 1,2-H shift;
cycloaddition; pyrazolidine.
*
Corresponding author. Tel.: þ81-836-85-9261, fax: þ81-836-85-9201;
e-mail: noguchi@po.cc.yamaguchi-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00593-3

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M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
Scheme 1. Reactions. (1) Protonation; (2) proton transfer to the imino nitrogen; (3) deprotonation; (4) endo-cycloaddition.
Scheme 2.
characterized by COSY and/or NOE experiments as well as
the coupling constants; for example, the relative configur-
ations among the three methine protons (Ha, Hb, and Hc) in
7a were assigned to be all cis on the basis of the NOE results
and the coupling constants demonstrated in Figure 1. This
means that the cycloaddition reaction proceeded in an endo-
approaching manner of maleimide 6 to the NH-azomethine
imine intermediate. Cycloadduct 7a was not very stable and
converted partially to 8a on long standing under air or on
treating with a column chromatography on silica gel.
Although the reaction path to 9a and 10 will be discussed
in a later section, these are secondary products from
cycloadduct 7a (Scheme 3).
To obtain further information of the reaction features, the
reaction of 3a with 6 at room temperature for 5 days gave 7a
(86%) and 8a (5%) together with trace amounts of 9a and
10. It should be noted that the hydrazone–azomethine imine
isomerization of 3a took place at room temperature. Similar
reactions in acetonitrile and benzene at reflux were also
examined; in both cases the four products 7a, 8a, 9a, and 10
were formed in excellent total yields, but the product ratios
were substantially different (Table 1; entries 3 and 4). The
formation of secondary products 9a and 10 was suppressed
perfectly by addition of 0.25 equiv. of triethylamine
Figure 1. Selected NOE signal enhancements and coupling constants
among the pyrazolidine-ring protons.
(entry 5).

M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4125
Scheme 3.
Table 1. Thermal reaction of hydrazone 3 with olefinic dipolarophiles 6, 11, 14, and 18
Entry
Hydrazone
Dipolarophile
Conditions
Et3N (equiv.)
Products (yield, %)
Recovered 3
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3b
3b
3d
3e
3e
3e
3a
3a
3a
6
6
6
6
6
6
6
6
6
6
6
11
14
18
EtOH, reflux, 20 h
None
None
None
None
0.25
7a (69), 8a (trace), 9a (27), 10 (30)
7a (86), 8a (5), 9a (trace), 10 (trace)
7a (48), 8a (32), 9a (17), 10 (10)
7a (72), 8a (trace), 9a (23), 10 (26)
7a (87), 8a (13)
7b (73), 8b (8), 9b (17), 10 (14)
7b (91), 8b (9)
7d (82), 8d (12)
EtOH, room temperature, 5 d
Benzene, reflux, 20 h
MeCN, reflux, 20 h
Benzene, reflux, 20 h
EtOH, reflux, 20 h
Benzene, reflux, 20 h
EtOH, reflux, 4 h
EtOH, reflux, 48 h
Benzene, reflux, 30 h
1,2-DCE, reflux, 30 h
Benzene, reflux, 20 h
Benzene, reflux, 3 d
Benzene, reflux, 3 d
None
0.25
None
None
None
None
0.25
9
endo-7e (50), 8e (trace)
3e (22)
3e (15)
10
11
12
13
14
endo-7e (60), exo-7e0 (10), 8e (9)
endo-7e (74), exo-7e0 (14), 8e (5)
12 (82), 13 (12)
0.25
0.25
15 (45), 16 (29)
15 (34), 16 (trace), 19 (28)
3a (17)
3a (22)
2-Amino-substituted hydrazones 3b and 3c, 2-ethoxy-
substituted 3d, and 2-methyl-substituted 3e were allowed
to react with 6 in aprotic and protic solvents with and/or
without triethylamine. The thermal reaction of 3b with 6 in
EtOH gave 7b, 8b, 9b, and 10 in an excellent total yield,
while a similar reaction in benzene in the presence of
triethylamine (0.25 equiv.) gave 7b and 8b in a quantitative
total yield. A similar thermal reaction of 3d with 6 in EtOH
in the presence of triethylamine also gave 7d and 8d. The
reaction of 3e with 6 in EtOH and benzene at reflux for 48 h
gave an inseparable mixture of diastereomers endo-7e and
exo-7e0 (see Section 4) in moderate yields together with the
recovered hydrazone 3e probably due to the poor solubility
of 3e in these solvents. To solve this problem, the reaction of
3e with 6 in dichloroethane (1,2-DCE) at reflux for 28 h
gave endo-7e, exo-7e0, and 8e in 74, 14, and 5% yields,
respectively. On the other hand, hydrazone 3c (E-isomer)
did not take place the conversion to the NH-azomethine
imine in EtOH, butan-1-ol (n-BuOH), and toluene at reflux.
The hydrazone 3c was recovered quantitatively and existed
as a mixture of E/Z isomers.
with 6 gave 7a and 8a and the reaction with N-methyl-
maleimide (11) gave also cycloadduct 12 and dehydro-
genated 13. In the thermal reaction with dimethyl fumarate
(14) for 3 days, cycloadduct 15 and dehydrogenated 16 (see
Section 4) were formed together with the recovered
hydrazone 3a. A similar reaction with dimethyl maleate
(18) gave three products 15 (34%), 16 (trace), and 19 (28%)
and the recovered hydrazone 3a (22%). This suggested that
under the reaction conditions maleate 18 was isomerized
into fumarate 14,7 both of which reacted with the resulting
NH-azomethine imine. Finally, the reaction with ethyl
acrylate (20) in refluxing benzene for 5 days was examined;
hydrazone 3a was consumed out, but an inseparable mixture
of products probably containing regio- and stereo-isomeric
cycloadducts was obtained. The assignment of the stereo-
chemistries of the cycloadducts 15 and 19 was also shown in
Figure 1. The results of the isomerization of hydrazones 3
and cycloaddition with diporaophiles are summarized in
Table 1 (Scheme 4).
The thermal isomerization of hydrazones 3 to the NH-
azomethine imine intermediates took place under mild
conditions and the intermolecular cycloaddition reaction of
the resulting NH-azomethine imines with olefinic
dipolarophile proceeded in a stereoselective manner to
give pyrazolidine derivatives in good yields. Since the
isomerization of 2-ethoxy- 3d and 2-methyl-substituted
To elucidate the scope and limitations of this isomerization
of hydrazones 3 and the cycloaddition reaction of the
azomethine imine, the thermal reaction of 3a with 6 and
other dipolarophiles in benzene in the presence of
triethylamine (0.25 equiv.) was also examined; the reaction

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M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
Scheme 4.
hydrazones 3e also took place under similar mild con-
ditions, the facile generation of NH-azomethine imines in
this system should require the existence of carbonyl group at
the 4-position. The carbonyl oxygen is possible to form an
internal hydrogen bond with the NH of the resulting
azomethine imine, which stabilizes the azomethine imine
and leans the equilibrium between hydrazone and
NH-azomethine imine toward the 1,3-dipole side.
60% yields, respectively, together with the recovered 7a
(33%) (Table 2).
A similar fission reaction of cycloadduct 7b into 9b and 10
was observed. On the other hand, cycloadducts 7d and 7e
did not exhibit any change under similar acidic conditions
(Scheme 3). Although details are still unclear, a reaction
path similar to a retro-Michael type addition process
catalyzed by proton is proposed for the fission reaction
of7a,b (Scheme 5).
2.2. Reaction of 2-(pyrrolidin-1-yl)-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde phenyl hydrazones with
olefinic dipolarophiles under acidic conditions
Table 2. Fission reaction of cycloadducts 7 in the presence of additives
Entrya Adduct 7 Additive (equiv.) Products (yield, %) Recovered 7
As shortly mentioned above, the reaction of NH-azomethine
imine cycloadduct 7a with basic and acidic reagents was
examined to elucidate the reaction path leading to 9a and
10. Heating 7a in benzene with or without 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU; 1.0 equiv.) gave no change and
7a was recovered in high yields. On the other hand, a
solution of 7a and pyridinium p-toluenesulfonate (PPTS;
1.0 equiv.) in benzene was heated at reflux for 20 h to give
9a and 10 in both 90% yields. The amount of PPTS required
for the fission reaction of 7a was also explored; in the
presence of 5 mol% of PPTS, 7a gave 9a and 10 in 63 and
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7b
7d
7e
None
–
–
7a (100)
7a (100)
–
7a (22)
7a (33)
–
DBU (1.0)
PTTS (1.0)
PTTS (0.2)
PTTS (0.05)
PTTS (1.0)
PTTS (1.0)
PTTS (1.0)
9a (90), 10 (90)
9a (77), 10 (67)
9a (63), 10 (60)
9b (90), 10 (93)
–
7d (100)
7e (100)
–
a
Reaction conditions: benzene, reflux, 20 h.

M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4127
Scheme 5.
Pyrrolidinylpyridopyrimidine 9a was also converted into
the starting aldehyde 2a in 77% yield by the reaction with
Vilsmeier reagent.
the presence of PPTS (1.0 equiv.) gave 9a and 10 in 90%
yield and quantitatively, respectively. Similar good results
were obtained in the reaction with maleimide 11; the desired
25 and 9a were formed in 80 and 84% yields, respectively.
2-Pyrazoline 26, pyrazole 27, and 9a were obtained in 51,
28, and 75% yields, respectively, in a similar reaction of 3a
with fumarate 14. Reducing the amount of PPTS utilized to
0.2 equiv. in the above reaction provided an essentially
same results; the yield of aromatized product 27 was
decreased, while that of 2-pyrazoline 26 was improved.
Unfortunately, the reaction with maleate 18 under similar
conditions gave 2-pyrazoline 26, 27 and 5a, which were also
formed by reaction of 3a and fumarate 14. As mentioned
above, the reaction with acrylate 20 in the presence of
triethylamine gave an inseparable mixture of many
products. The reaction with 20 in the presence of PPTS
(0.2 equiv.) gave simplified results; two regioisomeric
2-pyrazolines 28 and 29, pyrazole 30, and 9a were obtained
in 52, 16, 14 and 82% yields, respectively (Table 3,
Scheme 7).
The fission product 10 corresponds to the cycloadduct of
maleimide 6 with C-unsubstituted N-phenyl nitrile imine
intermediate 21, which was formed by photolysis of
2-phenyltetrazole and characterized by the spectroscopic
properties.8 However, it has not been applied to organic
synthesis except for a few example9 to our best knowledge.
Buzykin et al.9b reported that a C-unsubstituted nitrile imine
23, generated from imidoyl chloride 22 and triethylamine,
performed a dimerization to give tetrazine 24 in only 5%
yield (Scheme 6). However, further intermolecular cyclo-
addition of 21 with dipolarophiles have not been well
documented. Therefore, our next concern was focused on
the reaction of 3a with olefinic dipolarophiles under the
acidic conditions.
The reaction of 3a with maleimide 6 in refluxing benzene in
Scheme 6.

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M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
Table 3. Reaction of hydrazone 3a with dipolarophiles 6, 11, 14, 18, and 20 in the presence of PPTS
Entrya
Dipolarophile (equiv.)
PPTS (equiv.)
Time
Products (yield, %)
9a (100), 10 (90)
9a (84), 25 (80)
9a (75), 26 (51), 27 (28)
9a (85), 26 (64), 27 (15)
9a (65), 26 (59), 27 (7)
9a (82), 28 (52), 29 (14), 30 (16)
1
2
3
4
5
6
6 (1.0)
1.0
1.0
1.0
0.2
1.0
0.2
20 h
20 h
3 d
3 d
3 d
11 (1.0)
14 (1.0)
14 (1.0)
18 (1.5)
20 (3.0)
2 d
a
Reaction conditions: benzene, reflux.
Scheme 7.
It was generally known that acid catalysts accelerated the
isomerization of hydrazone to azomethine imine.4 The
intervention of a protonated NH-azomethine imine species
was postulated, when strong protic acids such as conc.
hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid
were used as catalysts. In the present case, the PPTS is a
weak acid and a catalytic amount of PPTS is effective for the
formation of fission products (entries 4 and 6). Thus, we
suggest that the intermediates in these reactions under both
neutral and acidic conditions are not protonated but ordinary
NH-azomethine imines and that the PPTS facilitates the
hydrazone–azomethine imine isomerization3b as well as the
fission reaction of the NH-azomethine imine cycloadducts
from hydrazones 3a and 3b, which afforded 3-unsubstituted
2-pyrazoline derivatives and 2-(substituted amino)-
pyrido[1,2-a]pyrimidin-4(4H)-one (5a,b).
4. Experimental
4.1. General
Melting points were measured on a Yanagimoto micro
melting point apparatus and are uncorrected. IR spectra
were measured on a JASCO IR Report-100 spectro-
photometer from samples as pellets or NaCl discs. 1H
NMR spectra were measured on JEOL EX-270 and/or
EX-400 spectrometers (270 and 400 MHz, respectively)
and 13C NMR spectra were measured on a JEOL EX-270
spectrometer (67.8 MHz) in deuterated-chloroform
(CDCl3) solutions unless otherwise stated. Tetramethyl-
silane was used as internal standard, and J values are
given in Hz. Splitting patterns are indicated as: s, singlet;
d, doublet; t, triplet; q, quadruplet, m, mutiplet; 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. Conclusion
We have reported a facile isomerization of hydrazone to
azomethine imine under extremely mild conditions, e.g. at
room temperature, in this system, in which the resulting
NH-azomethine imine should be stabilized by forming an
internal hydrogen bond. Further investigations on the
related chemistry are under progress and the results will
be reported elsewhere.

M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4129
4.2. Preparation of starting materials
(1 mL) was added and the resulting mixture was warmed to
room temperature. The reaction mixture was poured into
saturated 1 M aqueous Rochelle salt solution (20 mL) and
stirred for 1 h. After extraction and evaporation, the residue
was subjected to a column chromatography on silica gel
with EtOAc and EtOAc/MeOH (5/1) as eluents to afford the
desired aldehyde (5: 0.86 g, 46%) and alcohol (0.24 g,
12%), respectively.
4.2.1. General procedures for the preparation of 2-
substituted 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehydes 2. A solution of 2-chloro-4-oxo-4H-
pyrido[1,2-a]-pyrimidine-3-carbaldehyde (1)10 (5.2 g,
25 mmol), pyrrolidine (2.7 g, 38 mmol) and triethylamine
(6.9 mL, 50 mmol) in THF (25 mL) was stirred at room
temperature for 3 h. The solvent was evaporated to dryness,
which was extracted with dichloromethane (CH2Cl2)/5%
aqueous sodium hydrogencarbonate. The organic layer was
dried on anhydrous magnesium sulfate and the solvent was
evaporated. The residue was subjected to a column
chromatography on silica gel with ethyl acetate (EtOAc)
as an eluent to afford 2-(pyrrolidin-1-yl)-4-oxo-4H-
pyrido[1,2-a]pyrimidine-3-carbaldehyde (2a: 4.4 g, 73%).
Aldehyde 2a was used for the next procedure without
further purification.
4.2.8. 2-Methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde (5). 1H NMR (CDCl3): 2.83 (3H, s, 2-
CH3), 7.33 (1H, m, 7-H), 7.71 (1H, d, J¼8.9 Hz, 9-H), 7.99
(1H, m, 8-H), 10.59 (1H, s, CHO).
4.3. General procedures for the preparation of 2-substi-
tuted 4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbalde-
hyde phenyl hydrazones 3
A solution of aldehyde (2a: 2.52 g, 10.4 mmol) and phenyl
hydrazine (1.23 g, 11.4 mmol) in MeOH (15 mL) was
stirred at room temperature for 12 h. The desired hydrazone
3a (3.19 g, 92%) was obtained as precipitates from the
MeOH solution and collected by filtration.
4.2.2. 4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyri-
midine-3-carbaldehyde (2a). 1H NMR (CDCl3): 1.95
(4H, br t, J¼6.8 Hz, N(CH2CH2)2), 3.4–3.8 (4H, br,
N(CH2CH2)2), 6.38 (1H, td, J¼7.0, 1.7 Hz, 7-H), 7.21
(1H, d, J¼8.9 Hz, 9-H), 7.62 (1H, m, 8-H), 8.81 (1H, dd,
J¼7.0, 1.0 Hz, 6-H), 10.27 (1H, s, CHO).
4.3.1. 4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyri-
midine-3-carbaldehyde phenyl hydrazone (3a). Yellow
needles from hexane/EtOAc mp 159–1608C; IR (KBr):
4.2.3. 2-(N-Benzylmethylamino)-4-oxo-4H-pyrido[1,2-
1
a]pyrimidine-3-carbaldehyde (2b). Yield 85%. H NMR
1
3220 (NH), 1650 (CvO); H NMR (CDCl3): 1.85–1.94
(CDCl3): 3.02 (3H, s, NCH3), 5.30 (2H, s, NCH2Ph), 6.88
(1H, m, 7-H), 7.20–7.36 (6H, ov, 9-H and Ph-H), 7.65 (1H,
m, 8-H), 8.70 (1H, m, 6-H), 10.27 (1H, s, CHO).
(4H, m, N(CH2CH2)2), 3.56–3.61 (4H, m, N(CH2CH2)2),
6.81 (2H, ov, 7-H and Ph-H), 6.97 (2H, d, J¼7.6 Hz, Ph-H),
7.19–7.27 (3H, ov, 9-H and Ph-H), 7.47–7.54 (1H, m, 8-H),
8.05 (1H, br, NH), 8.35 (1H, s, CHvN), 8.85 (1H, m, 6-H);
13C NMR (CDCl3): 26.1, 51.4, 91.5, 112.5, 112.8, 119.5,
124.7, 127.7, 129.7, 135.8, 136.2, 145.8, 148.5, 156.8,
159.5. Anal. calcd for C19H19N5O (333.4): C, 68.45; H,
5.74; N, 21.01. Found: C, 68.34; H, 5.69; N, 20.88.
4.2.4. 2-(N-Benzylamino)-4-oxo-4H-pyrido[1,2-a]pyri-
midine-3-carbaldehyde (2c). Yield 75%. 1H NMR
(CDCl3): 4.84 (2H, m, NCH2Ph), 6.90 (1H, m, 7-H), 7.27
(6H, ov, 9-H and Ph-H), 7.57, 7.70 (total 1H, each m, 8-H),
9.04, 10.30 (total 1H, s, CHO), 10.02, 11.21 (total 1H, br,
NH).
4.3.2. 2-(N-Benzylmethylamino)-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde phenyl hydrazone (3b).
Yield 96%. Orange crystals from hexane/EtOAc; mp
4.2.5. 2-Ethoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde (2d). A solution of sodium ethoxide,
prepared from 0.20 g (8.7 mmol) of sodium metal and dry
EtOH (20 mL), and aldehyde (1: 1.04 g, 5.0 mmol) was
stirred at room temperature for 22 h. After similar
evaporation and extraction, the residue was subjected to a
column chromatography on silica gel with chloroform/
methanol (MeOH) (1/1) to afford the desired aldehyde (2d:
0.42 g, 39%).
1
186–1888C; IR (KBr): 3240 (NH), 1590 (CO); H NMR
(CDCl3): 2.95 (3H, s, NCH3), 5.05 (2H, s, NCH2Ph), 6.76–
6.91 (4H, ov, 7-H and Ph-H), 7.16–7.42 (8H, ov, 9-H and
Ph-H), 7.51–7.57 (1H, m, 8-H), 7.77 (1H, br, NH), 8.34
(1H, s, CHvN), 8.85 (1H, m, 6-H); 13C NMR (CDCl3):
41.3, 55.0, 91.8, 112.4, 112.6, 119.1, 124.4, 127.2, 127.4,
128.0, 128.6, 129.2, 135.0, 136.0, 138.0, 145.2, 147.7,
158.8, 159.6. Anal. calcd for C23H21N5O (383.5): C,
72.04; H, 5.52; N, 18.26. Found: C, 72.10; H, 5.51; N,
18.20.
4.2.6. 2-Ethoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde (2d). 1H NMR (CDCl3): 1.48 (3H, t,
J¼7.2 Hz, OCH2CH3), 4.63 (2H, q, J¼7.2 Hz,
OCH2CH3), 7.23 (1H, m, 7-H), 7.54 (1H, d, J¼4.5 Hz,
9-H), 7.92 (1H, m, 8-H), 9.17 (1H, m, 6-H), 10.39 (1H, s,
CHO).
4.3.3. 2-(N-Benzylamino)-4-oxo-4H-pyrido[1,2-a]pyri-
midine-3-carbaldehyde phenyl hydrazone (3c). Y. 77%.
Yellow crystals from hexane/EtOAc; mp 216–2188C; IR
(KBr): 3240 (NH), 1630 (CO); 1H NMR (CDCl3): 4.86 (2H,
d, J¼5.0 Hz, NCH2Ph), 6.60 (1H, m, Ph-H), 6.76, 6.90 (total
1H, m, 7-H), 7.06 (1H, m, Ph-H), 7.32–7.69 (10H, ov, 8-H,
9-H and Ph-H), 8.48 (1H, s, CHvN), 8.93 (1H, m, 6-H),
9.37 (1H, br, NH); 13C NMR (CDCl3): 45.6, 90.2, 112.0,
112.8, 119.3, 124.4, 127.5, 127.6, 128.5, 128.8, 129.2,
136.4, 137.1, 138.4, 144.5, 149.8, 157.0, 157.3. Anal. calcd
for C22H19N5O (369.4): C, 71.53; H, 5.18; N, 18.96. Found:
C, 71.60; H, 5.21; N, 18.88.
4.2.7. 2-Methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde (5). To a solution cooled at 2508C of ethyl
2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate
(4:11 2.32 g, 10.0 mmol) in CH2Cl2 (50 mL) diisobutyl-
aluminium hydride (20 mL of 1.0 M toluene solution,
20.0 mmol) was added slowly. The reaction mixture was
stirred for additional 2 h at the same temperature and MeOH

4130
M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4.3.4. 2-Ethoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde phenyl hydrazone (3d). Yield 87%. Orange
crystals from hexane/EtOAc; mp 184–1868C; IR (KBr):
3230 (NH), 1680, 1670 (CO); 1H NMR (CDCl3): 1.55 (3H,
t, J¼7.3 Hz, OCH2CH3), 4.62 (2H, q, J¼7.3 Hz,
OCH2CH3), 6.83 (1H, br t, J¼7.3 Hz, 8-H), 7.11–7.16
(3H, ov, Ph-H), 7.24–7.29 (2H, m, Ph-H), 7.50 (1H, m,
9-H), 7.63 (1H, br, NH), 7.74 (1H, m, 7-H), 8.15 (1H, s,
CHvN), 9.13 (1H, br d, J¼6.9 Hz, 6-H); 13C NMR
(CDCl3): 14.7, 63.2, 95.1, 112.6, 115.0, 119.5, 124.9,
128.0, 129.1, 132.1, 136.7, 145.1, 148.4, 157.1, 164.2. Anal.
calcd for C17H16N4O2 (308.3): C, 66.22; H, 5.23; N, 18.17.
Found: C, 66.29; H, 5.23; N, 18.12.
173.5. Anal. calcd for C29H24N6O3 (504.6): C, 69.04; H,
4.79; N, 16.66. Found: C, 69.16; H, 4.87; N, 16.58.
4.4.3. 2-(Pyrrolidin-1-yl)pyrido[1,2-a]pyrimidin-4(4H)-
one (9a). Although this compound is known in the
literature,12 none of physical and spectroscopic data were
found therein. Colorless needles from hexane/benzene; IR
(KBr): 1650 (CO); 1H NMR (CDCl3): 1.98 (4H, br,
N(CH2CH2)2), 3.50 (4H, br, N(CH2CH2)2), 5.37 (1H, s,
3-H), 6.80 (1H, m, 7-H), 7.26 (1H, m, 9-H), 7.52 (1H, m,
8-H), 8.87 (1H, m, 6-H); 13C NMR (CDCl3): 24.6, 46.4,
80.7, 111.7, 124.0, 127.5, 135.9, 150.5, 157.7, 159.0. Anal.
calcd for C12H13N3O (215.3): C, 66.96; H, 6.09; N, 19.52.
Found: C, 66.88; H, 6.13; N, 19.40.
4.3.5. 2-Methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde phenyl hydrazone (3e). Yield 82%. Orange
crystals from hexane/EtOAc; mp 184–1868C; IR (KBr):
4.4.4. 2-Pyrazoline 10. Colorless needles from hexane/
1
EtOAc; mp 1588C; IR (KBr): 1770, 1740 (CO); H NMR
1
3240 (NH), 1680 (CO); H NMR (CDCl3): 2.95 (3H, s,
(CDCl3): 4.65 (1H, dd, J¼10.9, 1.6 Hz, 3a-H), 5.07 (1H, d,
J¼10.9 Hz, 6a-H), 6.92 (1H, d, J¼1.6 Hz, 3-H), 6.98–7.52
(10H, ov, Ph-H); 13C NMR (CDCl3): 55.4, 63.3, 114.3,
121.7, 126.3, 129.1, 129.2, 129.3, 131.1, 133.5, 144.4,
171.1, 172.1. Anal. calcd for C17H13N3O2 (291.3): C, 70.09;
H, 4.50; N, 14.42. Found: C, 70.08; H, 4.41; N, 14.38.
2-CH3), 6.88 (1H, m, 7-H), 7.05–7.28 (3H, ov, Ph-H),
7.29–7.36 (2H, m, Ph-H), 7.74 (1H, m, 8-H), 7.81 (1H, m,
Ph-H), 8.15 (1H, s, CHvN), 9.20 (1H, br d, J¼6.9 Hz, 6-H).
Anal. calcd for C16H14N4O2 (278.3): calcd C, 69.03; H,
5.07; N, 20.13. Found: C, 69.16; H, 5.10; N, 20.28.
4.4. General procedures for the reaction of hydrazone 3
with dipolarophiles
4.4.5. NH-Azomethine imine cycloadduct 7b. Colorless
crystals without recrystallization; mp 1778C; IR (KBr):
3240 (NH), 1775, 1710, 1700, 1630 (CO), 1H NMR
(CDCl3): 3.07 (3H, s, NCH3), 3.61 (1H, dd, J¼9.2,
8.2 Hz, 3a0-H), 4.60 (1H, dd, J¼12.5, 9.2 Hz, 3-H), 4.64,
4.85 (each 1H, each d, J¼15.8 Hz, NCH2Ph), 4.96 (1H, d,
J¼9.2 Hz, 6a0-H), 6.35 (1H, d, J¼12.5 Hz, exchangeable
with D2O, 20-NH), 6.88–6.97 (2H, ov, Ph-H and 7-H),
7.19–7.29 (9H, ov, Ph-H), 7.31–7.42 (2H, ov, Ph-H and
9-H), 7.45–7.55 (4H, ov, Ph-H), 7.62 (1H, br t, J¼6.9 Hz,
8-H), 8.77 (1H, m, 6-H); 13C NMR (CDCl3): 39.5, 50.8,
56.8, 61.4, 70.8, 89.7, 113.6, 114.7, 120.7, 124.7, 126.9,
127.3, 127.4, 128.5, 128.6, 128.9, 129.0, 129.1, 132.4,
136.6, 137.4, 148.5, 150.9, 159.1, 165.0, 173.9, 175.1. Anal.
calcd for C33H28N6O3 (556.6): C, 71.21; H, 5.07; N, 15.10.
Found: C, 71.09; H, 5.07; N, 15.15.
A solution of hydrazone 3a (0.20 g, 0.60 mmol) and
maleimide 6 (0.10 g, 0.60 mmol) in EtOH was heated at
reflux for 20 h. After cooling, the precipitates 7a (0.21 g,
69%) was filtered off and the filtrate was evaporated to
dryness. The residue was subjected to a column chroma-
tography on silica gel with hexane/EtOAc (6/1), (1/1) and
(1/2) as eluents to afford 2-pyrazoline 10 (0.050 g, 30%),
dehydrogenated 8a (trace) and pyridopyrimidine 9a
(0.040 g, 27%), respectively.
4.4.1. NH-Azomethine imine cycloadduct 7a. Yellow
crystals without recrystallization; mp 217–2188C; IR
(KBr): 3240 (NH), 1775, 1710, 1700, 1650 (CO); 1H
NMR (CDCl3): 1.91 (4H, br, N(CH2CH2)2), 3.71 (5H, ov,
N(CH2CH2)2 and 3a0-H), 4.70 (1H, dd, J¼12.2, 8.9 Hz,
30-H), 5.02 (1H, d, J¼7.9 Hz, 6a0-H), 6.51 (1H, d,
J¼12.2 Hz, exchangeable with D2O, 20-NH), 6.82 (1H, m,
7-H), 6.92 (1H, m, Ph-H), 7.25–7.57 (11H, ov, Ph-H, 8-H
and 9-H), 8.73 (1H, m, 6-H); 13C NMR (CDCl3): 26.1, 50.9,
52.2, 61.6, 71.0, 87.0, 113.2, 115.0, 120.9, 124.8, 127.3,
127.4, 127.5, 128.9, 129.0, 129.4, 129.6, 133.0, 136.7,
148.9, 151.5, 159.1, 161.6, 174.3, 175.6. Anal. calcd for
C29H26N6O3 (506.6): C, 68.76; H, 5.17; N, 16.59. Found: C,
68.62; H, 5.17; N, 16.40.
4.4.6. Dehydrogenated product 8b. Orange crystals from
EtOH; mp 280–2818C; IR (KBr): 1770, 1700, 1650 (CO);
1H NMR (CDCl3): 2.76 (3H, s, NCH3), 4.75, 5.27 (each 1H,
each d, J¼15.2 Hz, NCH2Ph), 5.20 (1H, d, J¼11.2 Hz,
3a0-H), 6.09 (1H, d, J¼11.2 Hz, 6a0-H), 6.86–7.00 (2H, ov,
7-H and Ph-H), 7.18 (2H, m, Ph-H), 7.30–7.62 (10H, ov,
8-H, 9-H and Ph-H) and 8.86 (1H, br d, J¼7.3 Hz, 6-H); 13C
NMR (CDCl3) 39.6, 54.8, 55.7, 64.6, 86.8. 112.7, 114.4,
121.0, 124.4, 126.1, 127.2, 127.4, 127.6, 128.5, 128.8,
129.1, 129.1, 131.3, 136.7, 137.7, 141.9, 145.1, 148.6,
158.8, 160.6, 171.5, 172.7. Anal. calcd for C33H26N6O3
(554.6): C, 71.47; H, 4.73; N, 15.15. Found: C, 71.56; H,
4.80; N, 15.11.
4.4.2. Dehydrogenated product 8a. Yellow crystals from
MeOH; mp 280–2818C; IR (KBr): 1770, 1710, 1700, 1650
(CO); 1H NMR (CDCl3): 1.74–1.84 (2H, br,
N(CH2CHH)2), 1.95–1.96 (2H, br, N(CH2CHH)2) 3.22
(2H, br, N(CHHCH2)2), 3.58–3.68 (2H, br, N(CHHCH2)2),
5.23 (1H, d, J¼11.2 Hz, 3a0-H), 6.06 (1H, d, J¼11.2 Hz,
6a0-H), 6.84 (1H, m, 7-H), 6.97 (1H, t, J¼7.6 Hz, Ph-H),
7.23–7.59 (11H, ov, Ph-H, 8-H and 9-H), 8.83 (1H, m,
6-H); 13C NMR (CDCl3): 25.5, 50.4, 56.0, 65.3, 86.4, 112.7,
115.0, 121.6, 124.7, 126.6, 127.7, 129.3, 129.5, 129.6,
131.9, 136.9, 142.5, 145.7, 149.4, 158.0, 158.7, 172.1,
4.4.7. 2-(N-Methylbenzylamino)pyrido[1,2-a]pyrimidin-
4(4H)-one (9b). Colorless crystals from hexane/EtOAc; mp
118–1198C; IR (KBr): 1650 (CO); 1H NMR (CDCl3): 3.06
(3H, s, NCH3), 4.90 (2H, br s, NCH2Ph), 5.60 (1H, s, 3-H),
6.86 (1H, m, 8-H), 7.22–7.36 (6H, ov, Ph-H and 9-H), 7.57
(1H, m, 7-H), 8.90 (1H, br d, J¼6.9 Hz, 6-H); 13C NMR
(CDCl3) 35.7, 52.6, 80.6, 112.2, 124.3, 127.2, 127.2, 127.4,
128.6, 136.2, 137.7, 150.5, 158.5, 161.2. Anal. calcd for

M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4131
C16H15N3O (265.3): C, 72.43, H, 5.70; N, 15.84. Found: C,
72.35; H, 5.66; N, 15.70.
(KBr): 1770, 1710, 1660 (CO); 1H NMR (CDCl3): 2.72 (3H,
s, 2-CH3), 5.29 (1H, d, J¼11.1 Hz, 3a0-H), 6.00 (1H, d,
J¼11.1 Hz, 6a0-H), 7.01 (1H, td, J¼7.4, 1.3 Hz, 7-H), 7.19
(1H, td, J¼6.9, 1.0 Hz, Ph-H), 7.26–7.35 (3H, ov, Ph-H and
9-H), 7.49–7.56 (3H, ov, Ph-H and 8-H), 7.80 (1H, m, 8-H),
8.83 (1H, d, J¼6.6 Hz, 6-H); 13C NMR (CDCl3): 24.9, 54.6,
64.6, 106.2, 114.4, 115.9, 121.6, 126.1, 126.2, 127.3, 128.8,
131.3, 136.9, 140.8, 144.5, 149.4, 164.9, 171.2, 172.3. Anal.
calcd for C26H19N5O3 (449.5): C, 69.48; H, 4.26; N, 15.58.
Found: C, 69.32; H, 4.52; N, 15.59.
4.4.8. NH-Azomethine imine cycloadduct 7d. Colorless
needles from hexane/EtOAc; mp 2268C; IR (KBr): 3260
1
(NH), 1775, 1720, 1710, 1630 (CO); H NMR (CDCl3):
1.38 (3H, t, J¼7.3 Hz, OCH2CH3), 3.73 (1H, dd, J¼8.9,
7.9 Hz, 3a0-H), 4.53 (2H, m, OCH2CH3), 4.91 (1H, dd,
J¼12.9, 8.9 Hz, 30-H), 5.00 (1H, d, J¼7.9 Hz, 6a0-H), 6.59
(1H, d, J¼12.5 Hz, exchangeable with D2O, 20-NH), 6.94
(1H, t, J¼6.9 Hz, Ph-H), 7.06 (1H, m, 7-H), 7.25–7.48
(10H, ov, Ph-H and 5-H), 7.71 (1H, m, 8-H), 8.92 (1H, br d,
J¼6.9 Hz, 6-H); 13C NMR (CDCl3) 14.7, 51.4, 57.9,
63.2, 69.9, 90.0, 114.6, 115.0, 120.5, 124.8, 126.7, 127.3,
128.5, 128.9, 129.1, 132.1, 137.3, 149.7, 150.9, 158.5,
165.5, 173.8, 174.8. Anal. calcd for C27H23N5O4 (481.5):
C, 67.35; H, 4.81; N, 14.54; found C, 67.46; H, 4.86; N,
14.47.
4.4.12. NH-Azomethine imine cycloadduct 12. Colorless
crystals without recrystallization; mp 199–2008C; IR
(KBr): 3240 (NH), 1770, 1720, 1710, 1660 (CO); 1H
NMR (CDCl3): 1.91 (4H, ov, N(CH2CH2)2), 3.06 (3H, s,
NCH3), 3.50 (1H, dd, J¼9.2, 7.6 Hz, 3a0-H), 3.67 (4H, ov,
N(CH2CH2)2), 4.60 (1H, dd, J¼12.2, 9.2 Hz, 30-H), 4.89
(1H, d, J¼7.6 Hz, 6a0-H), 6.25 (1H, d, J¼12.2 Hz,
exchangeable with D2O, 20-NH), 6.83 (1H, m, 7-H), 6.90
(1H, m, Ph-H), 7.27 (5H, ov, 9-H and Ph-H), 7.55 (1H, m,
8-H), 8.68 (1H, m, 6-H); 13C NMR (CDCl3): 25.3, 25.7,
50.4, 51.4, 60.9, 70.4, 86.6, 112.6, 114.5, 120.4, 124.4,
126.8, 129.1, 136.2, 148.4, 150.8, 158.6, 161.1, 175.1,
176.1. Anal. calcd for C24H24N6O3 (444.5): C, 64.85; H,
5.44; N, 18.91. Found: C, 64.58; H, 5.54; N, 18.80.
4.4.9. Dehydrogenated product 8d. Yellow needles from
propan-2-ol; mp 134–1368C; IR (KBr): 1770, 1720, 1710,
1640 (CO); 1H NMR (CDCl3) 1.42 (3H, t, J¼7.2 Hz,
CH2CH3), 4.49–4.66 (2H, m, CH2CH3), 5.25 (1H, d,
J¼11.2 Hz, 3a0-H), 5.72 (1H, J¼11.2 Hz, 6a0-H), 6.97 (1H,
br t, J¼7.4 Hz, Ph-H), 7.15 (1H, td, J¼6.9, 1.3 Hz, 7-H),
7.26–7.74 (10H, ov, Ph-H and 9-H), 7.79 (1H, m, 8-H), 9.12
(1H, dd, J¼6.6, 1.0 Hz, 6-H); 13C NMR (CDCl3): 16.1,
56.1, 64.9, 65.4, 91.1, 115.8, 116.5, 122.5, 126.3, 126.9,
127.7, 129.7, 130.1, 130.4, 130.7, 132.8, 139.5, 146.1,
151.1, 158.7, 166.8, 172.7, 173.8. Anal. calcd for
C27H21N5O4 (479.5): C, 67.63; H, 4.41; N, 14.61. Found:
C, 67.55; H, 4.51; N, 14.44.
4.4.13. Dehydrogenated product 13. Yellow prisms from
EtOH; mp 260–2638C (with decomposition); IR (KBr):
1770, 1720, 1660 (CO); 1H NMR (CDCl3): 1.75–1.82,
1.82–2.02 (each 2H, each br, N(CH2CH2)2), 2.8–3.2, 3.53–
3.59 (each 2H, each br, N(CH2CH2)2), 6.83 (1H, td, J¼7.0,
1.3 Hz, Ph-H), 6.96 (1H, t, J¼7.3 Hz, 7-H), 7.26–7.59 (6H,
ov, Ph-H and 9-H), 8.83 (1H, dd, J¼7.3, 0.7 Hz, 6-H); 13C
NMR (CDCl3): 25.3, 25.4, 49.9, 55.7, 64.9, 86.1, 112.2,
114.4, 121.1, 123.8, 124.4, 127.3, 129.1, 136.4, 141.9,
145.3, 148.9, 157.5, 172.9, 174.1. Anal. calcd for
C24H22N6O3 (442.5): C, 65.14; H, 5.01; N, 19.00. Found:
C, 65.22; H, 5.21; N, 18.91.
4.4.10. NH-Azomethine cycloadduct endo-7e and exo-7e0.
Although these two compounds were not attained to isolate
to each other as pure forms, the structures were assigned to
be endo- and exo-cycloadduct, respectively, on the basis of
1
their H NMR spectroscopic data as well as a chemical
conversion. Elementary analysis of the 5:1 mixture of endo-
7e and exo-7e0 provided good results. Anal. calcd for
C26H21N5O3 (451.5): C, 69.17; H, 4.69; N, 15.51. Found: C,
69.22; H, 4.82; N, 15.66.
4.4.14. NH-Azomethine imine cycloadduct 15. Yellow
needles from hexane/EtOAc; mp 187–1888C; IR (KBr):
3210 (NH), 1730, 1720, 1650 (CvO); H NMR (CDCl3):
1
1.79–1.84 (4H, ov, N(CH2CH2)2), 1.94–1.99 (4H, ov,
N(CH2CH2)2), 3.57, 3.89 (each 3H, each s, OCH3), 4.46
(1H, dd, J¼12.5, 8.9 Hz, 30-H), 4.71 (1H, dd, J¼8.9, 6.3 Hz,
40-H), 4.82 (1H, d, J¼6.3 Hz, 50-H), 5.66 (1H, d, J¼12.5 Hz,
exchangeable with D2O, 20-NH), 6.81–6.86 (2H, m, Ph-H
and 7-H), 7.15 (2H, m, Ph-H), 7.22–7.28 (3H, ov, Ph-H and
9-H), 7.55 (1H, m, 8-H), 8.86 (1H, m, 6-H); 13C NMR
(CDCl3): 25.6, 50.4, 52.2, 52.8, 53.0, 61.4, 70.4, 87.2, 112.2,
113.5, 119.3, 124.3, 127.0, 128.9, 136.1, 148.5, 150.6,
158.1, 160.6, 172.6, 172.8. Anal. calcd for C25H27N5O5
(477.5): C, 62.88; H, 5.70; N, 14.67. Found: C, 62.83; H,
5.76; N, 14.56.
1H NMR (CDCl3): assigned signals for major isomer endo-
0
0
7e: 2.59 (3H, s, 2-CH3),03.75 (1H, dd, J3a –3 ¼8.9 Hz [cis],
0
0
0
0
J3a –6a ¼7.9 Hz [cis], 3a -H), 4.68 (1H, dd, J3 –2 ¼12.5 Hz,
0
0
0
0
0
0
J3 –3a ¼8.9 Hz, 3 -H), 5.06 (1H, d, J6a –3a ¼7.9 Hz, 6a -H),
0
0
6.63 (1H, d, J2 –3 ¼12.5 Hz, exchangeable with D2O,
20-NH), 6.98 (1H, m, Ph-H), 7.16 (1H, m, 7-H), 7.28–
7.79 (11H, ov, 8-H, 9-H, Ph-H), 8.92 (1H, m, 6-H); assigned
signals for minor isomer exo-7e0: 2.70 (3H, s, 2-CH3), 4.49
0
0
0
0 0
(1H, dd, J3a –3 ¼7.3 Hz [trans], J3a – 6a ¼7.9 Hz [cis],
3a0-H), 4.84 (1H, d, J6a –3a ¼7.9 Hz, 6a -H), 4.94 (1H, dd,
0
0
J3 – 2 ¼12.2 Hz, J3 – 3a¼7.3 Hz, 30-H), 5.66 (1H, d,
0
0
0
0
0
J2 –3 ¼12.2 Hz, exchangeable with D2O, 2 -NH).
4.4.15. Dehydrogenated product 16. Although this
compound was not attained to isolate as a pure form, the
The treatment of the 5:1 mixture of endo-7e and exo-7e0
(0.15 g, 0.33 mmol) with 10% palladium/carbon (0.050 g)
in refluxing 1,4-dioxane (5 mL) for 8 h gave dehydro-
genated product 8e (0.14 g, 94%).
1
structure was assigned on the basis of its H NMR spectra:
1H NMR (CDCl3): 1.61, 1.83 (each 2H, each m,
N(CH2CH2)2), 3.38, 3.62 (each 2H, each m,
N(CH2CH2)2), 3.71, 3.78 (each 3H, each s, OCH3), 5.17
(1H, d, J¼6.6 Hz, 40-H), 5.47 (1H, d, J¼6.6 Hz, 50-H),
6.77–6.97 (2H, ov, Ph-H and 7-H), 7.03 (2H, br d,
4.4.11. Dehydrogenated product 8e. Yellow prisms from
EtOH/hexane; mp 142–1448C (with decomposition); IR

4132
M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
J¼7.6 Hz, Ph-H), 7.247.30 (3H, ov, Ph-H and 9-H), 7.53
(1H, m, 8-H), 8.79 (1H, dd, J¼6.3, 0.7 Hz, 6-H).
m, Ph-H), 7.34 (2H, m, Ph-H), 7.44 (2H, m, Ph-H); 13C
NMR (CDCl3): 25.4, 55.4, 63.2, 114.2, 114.6, 121.5, 129.2,
133.3, 144.4, 172.1, 173.1. Anal. calcd for C12H11N3O2
(229.2): C, 62.87; H, 4.84; N, 18.33. Found: C, 62.85; H,
4.88; N, 18.17.
In order to obtain product 16, adduct 15 (0.10 g, 0.21 mmol)
was treated with 10% palladium/carbon (0.040 g) in
refluxing 1,4-dioxane (5 mL) for 2 h. Usual work-up did
not give the desired 16 but a further dehydrogenated product
pyrazole 17 (0.077g, 78%).
4.6.2. Dimethyl 1-phenyl-2-pyrazoline-4,5-dicarboxylate
(26). Yellow oil; IR (NaCl): 1725 (CO); 1H NMR (CDCl3):
3.78, 3.81 (each 3H, each s, OCH3£2), 4.32 (1H, dd, J¼7.3,
2.0 Hz, 4-H), 5.05 (1H, d, J¼2.0 Hz, 3-H), 6.92 (1H, t,
J¼7.3 Hz, Ph-H), 7.09 (2H, m, Ph-H), 7.28 (2H, m, Ph-H);
13C NMR (CDCl3): 53.2, 57.3, 62.7, 113.5, 120.6, 123.8,
129.1, 134.1, 144.3, 168.0, 170.7; HRMS (EI):
m/z¼262.0938. Calcd for C13H14N2O4: 262.0953. Anal.
calcd for C13H14N2O4 (262.3): C, 59.54; H, 5.38; N, 10.68.
Found: C, 59.87; H, 5.10; N, 10.72.
4.4.16. Pyrazole 17. Colorless prisms from propan-2-ol; mp
1
194–1958C; IR (KBr): 1720, 1715, 1670 (CO); H NMR
(CDCl3): 1.81 (4H, br, N(CH2CH2)2), 3.35 (4H, br,
N(CH2CH2)2), 3.79, 3.86 (each 3H, each s, OCH3), 6.81
(1H, t, J¼6.9 Hz, 7-H), 7.27 (1H, m, Ph-H), 7.14–7.57 (6H,
ov, Ph-H and 7- and 9-H), 8.86 (1H, J¼7.3 Hz, 6-H); 13C
NMR (CDCl3): 25.4, 49.1, 51.9, 53.1, 86.5, 111.9, 117.3,
124.2, 124.3, 127.8, 128.7, 129.1, 136.1, 136.4, 139.1,
149.2, 149.4, 157.5, 157.9, 161.3, 162.7. Anal. calcd for
C25H23N5O5 (473.5): C, 63.41; H, 4.90; N, 14.79. Found: C,
63.50; H, 4.79; N, 14.70.
4.6.3. Dimethyl 1-phenylpyrazole-4,5-dicarboxylate (27).
Colorless needles from hexane/EtOAc; mp 73–758C; IR
(KBr): 1720 (CO); 1H NMR (CDCl3): 3.87, 3.88 (each 3H,
each s, OCH3£2), 7.45–7.51 (5H, ov, Ph-H), 8.05 (1H, s,
3-H); 13C NMR (CDCl3): 51.9, 53.4, 115.6, 123.8, 129.0,
129.1, 129.3, 136.7, 141.3, 161.3, 162.2. Anal. calcd for
C13H12N2O4 (260.2): C, 60.00; H, 4.61; N, 10.76. Found C,
59.90; H, 4.61; N, 10.74.
4.4.17. NH-Azomethine imine cycloadduct 19. Pale
yellow crystals from hexane/EtOAc; mp 185–1878C; IR
(KBr): 3230 (NH), 1730, 1720, 1650 (CO); 1H NMR
(CDCl3): 1.90 (4H, br, N(CH2CH2)2), 3.60 (4H, br,
N(CH2CH2)2), 3.66, 3.84 (each 3H, each s, OCH3), 3.99
(1H, dd, J¼7.3, 5.9 Hz, 40-H), 4.27 (1H, dd, J¼12.9, 5.9 Hz,
30-H), 4.42 (1H, d, J¼7.3 Hz, 50-H), 6.81–6.88 (3H, ov,
Ph-H, 20-NH and 7-H), 7.09 (2H, m, Ph-H), 7.24 (3H, ov,
Ph-H and 9-H), 7.55 (1H, m, 8-H), 8.90 (1H, m, 6-H); 13C
NMR (CDCl3): 25.6, 50.6, 52.5, 55.8, 61.5, 70.2, 87.9, 112.5,
114.3, 119.6, 124.3, 127.1, 128.7, 136.2, 148.4, 152.1, 158.3,
161.6, 170.1, 171.6. Anal. calcd for C25H27N5O5 (477.5): C,
62.88; H, 5.70; N, 14.67. Found: C, 62.85; H, 5.78; N, 14.61.
4.6.4. Ethyl 1-phenyl-2-pyrazoline-4-carboxylate (28).
1
Pale yellow oil; IR (NaCl): 1720 (CO); H NMR (CDCl3):
1.30 (3H, t, J¼7.1 Hz, CH2CH3), 3.88 (1H, dd, Jgem¼11.5
Hz, J4–5¼8.9 Hz, 5-H), 3.95–4.15 (2H, ov, 4- and 5-H),
4.23 (2H, q, J¼7.1 Hz, CH2CH3), 6.79 (1H, d,
J3–4¼1.7 Hz), 6.87 (1H, t, J¼7.3 Hz, Ph-H), 7.05 (2H, d,
J¼7.3 Hz, Ph-H), 7.24–7.31 (2H, m, Ph-H); 13C NMR
(CDCl3): 14.1, 49.0, 51.6, 61.8, 113.0, 119.7, 129.1, 136.0,
145.2, 169.1; HRMS (EI): m/z¼218.1061. Calcd for
C12H14N2O2: 218.1055.
4.5. General procedures for the reaction of hydrazone 3
with dipolarophiles in the presence of PPTS
4.6.5. Ethyl 1-phenylpyrazole-4-carboxylate (29). Color-
less needles from hexane/EtOAc; mp 96–998C; IR (KBr):
1720 (CO); 1H NMR (CDCl3): 1.38 (3H, t, J¼7.3 Hz,
OCH2CH3), 4.34 (2H, q, J¼7.3 Hz, OCH2CH3), 7.36 (1H,
m, Ph-H), 7.48 (2H, m, Ph-H), 7.71 (2H, m, Ph-H), 8.10
(1H, s, 3-H), 8.41 (1H, s, 5-H); 13C NMR (CDCl3): 14.4,
60.4, 116.9, 119.6, 127.5, 129.6, 130.0, 139.4, 142.1, 162.8.
Anal. calcd for C12H12N2O4 (216.1): C, 66.65; H, 5.59; N,
12.96. Found C, 66.44; H, 5.67; N, 12.91.
A solution of hydrazone 3a (0.20 g, 0.60 mmol), maleimide
6 (0.10 g, 0.60 mmol) and PPTS (0.15 g, 0.60 mmol) in
benzene (3 mL) was heated at reflux for 20 h. Usual work-
up with silica-gel chromatography with hexane/EtOAc (6/1)
as an eluent afforded 2-pyrazoline 10 (0.16 g, 90%) and
pyridopyrimidine 9a (0.13 g, 90%), respectively.
4.6. Conversion of 9a into the starting aldehyde 2a
To a dry dimethyl formamide (2.7 mL, 35.1 mmol) cooled
below 108C was added phosphorous oxychloride (2.02 g,
13.7 mmol) for 10 min. To the resultant solution was added
pyrrolidinylpyridopyrimidine 9a (0.86 g, 4.0 mmol) and the
mixture was heated at 908C for 1 h. After cooling, the
solution was poured into ice-water (40 mL) and basified to
8.5 with 2N NaOH aq. The solution was extracted with
toluene (50 mL£2), the organic layer was washed with brine
(50 mL£3), dried over anhydrous sodium sulfate, and the
solvent was removed under reduced pressure to give
aldehyde 2a (0.86 g, 77%).
4.6.6. Ethyl 1-phenyl-2-pyrazoline-5-carboxylate (30).
Yellow oil; IR (NaCl): 1720 (CO); 1H NMR (CDCl3): 1.22
(3H, t, J¼7.3 Hz, OCH2CH3), 3.11 (1H, ddd, J¼17.8, 7.3,
1.7 Hz, 4-H), 3.35 (1H, ddd, J¼17.8, 12.5, 1.7 Hz, 4-H),
4.21 (2H, q, J¼7.3 Hz, OCH2CH3), 4.59 (1H, dd, J¼12.5,
7.3 Hz, 5-H), 6.71 (1H, t, J¼1.7 Hz, 3-H), 6.87 (1H, m,
Ph-H), 7.03 (2H, m, Ph-H), 7.26 (2H, m, Ph-H); 13C NMR
(CDCl3): 14.1, 39.7, 60.2, 61.7, 113.1, 119.9, 129.1, 138.5,
145.0, 171.6; HRMS (EI): m/z¼218.1065. Calcd for
C12H14N2O2: 218.1055.
4.6.1. 2-Pyrazoline 25. Colorless needles from hexane/
EtOAc; mp 168–1698C; IR (KBr): 1770, 1720, 1650 (CO);
1H NMR (CDCl3): 3.04 (3H, s, 5-CH3), 4.50 (1H, dd,
J¼10.9 Hz, 6a-H), 6.84 (1H, d, J¼2.0 Hz, 3-H), 6.99 (1H,
Acknowledgements
The present work was partially supported by Grant-in-Aid
for Scientific Research on Priority Areas (A) ‘Exploitation

M. Noguchi et al. / Tetrahedron 59 (2003) 4123–4133
4133
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