Generation of functionalized azomethine ylides and their application to stereoselective heterocycle synthesis: an equivalent process of C-unsubstituted nitrile ylide cycloaddition reaction

Article abstract of DOI:10.1016/j.tet.2006.12.004

The synthetic process equivalent to C-unsubstituted (CH) nitrile ylides cycloaddition reaction is achieved via cycloaddition of NH-azomethine ylide and the following fission reaction of the cycloadducts under acidic conditions. Cycloaddition of NH-azometh

Full text of DOI:10.1016/j.tet.2006.12.004

Tetrahedron 63 (2007) 1630–1643
Generation of functionalized azomethine ylides and their
application to stereoselective heterocycle synthesis: an equivalent
process of C-unsubstituted nitrile ylide cycloaddition reaction
Keisuke Kawashima,a Akikazu Kakehib and Michihiko Noguchia,
*
aDepartment of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 11 October 2006; revised 5 December 2006; accepted 6 December 2006
Available online 29 December 2006
Abstract—The synthetic process equivalent to C-unsubstituted (CH) nitrile ylides cycloaddition reaction is achieved via cycloaddition of
NH-azomethine ylide and the following fission reaction of the cycloadducts under acidic conditions. Cycloaddition of NH-azomethine ylide
generated by a thermal 1,2-prototropy in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system with maleimides provides proline deriv-
atives under extremely mild conditions. Heating their adducts in AcOH at 85 ꢀC causes a cleavage of C–C bond between the proline and het-
erocyclic moiety to give the parent heterocyclic system and dehydroproline derivatives, which is regarded as a cycloadduct of C-unsubstituted
(CH) nitrile ylide. This cycloaddition–fission reaction sequences can be applied to one-pot three-component reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
approaches for the generation of NH-azomethine ylides are
constituted of three methodologies (Scheme 1). The first is
thermal and uncatalyzed isomerization of a-iminoester to
NH-azomethine ylide through a 1,2-prototropy, which was
first reported by Grigg and Kemp at 1977.2 They afterward
systematized the imine-azomethine ylide isomerization as
one of the general methodology of NH-1,3-dipole generation
from X¼Y–ZH system.3 The highly acidic hydrogen adja-
cent to the imine migrates to the nitrogen to produce the
The cycloaddition reaction of azomethine ylides with al-
kenes is a useful synthetic method for polysubstituted pyrro-
lidine derivatives, which are widely found in natural products
and biologically activecompounds.1 Among them, the chem-
istry of N-unsubstituted (NH) azomethine ylides has been
more attractive due to the biological and pharmacological as-
pects of N-unsubstituted (NH) pyrrolidines. Representative
H
H
R2
2
N
R1
R1
R1
A
B
1
CO2R3
R2
N
CO2R3
CO2R3
N
1,2-prototropy
A
B
R2
NH- Azomethine Ylide
H
Pyrrolidine
H
4
S
SnBu3
Ph
Bu3Sn
S
R1
SSnBu3
Ph
R1
N
N
A
B
Ph
R1
N
H
R1
N
H
Ph
1
1,4-stannatropy
A
B
A
B
B
Pyrrolidine
HSSnBu3
NH- Azomethine Ylide
O
M
N
O
M
N
O
H
N
R2
A
B
R1
R1
MX/Base
OR3
N
R1
R1
OR3
OR3
CO2R3
R2
R2
N-Metalated
R2
Chelated
A
Pyrrolidine
Azomethine Ylide
Ester Enolate
Scheme 1. Three representative methodologies for NH-azomethine ylide generation.
* 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 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.004

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1631
NH-azomethine ylide under neutral conditions, which takes
part in the cycloaddition reaction with various activated dipo-
larophiles. Formation of the NH-azomethine ylide is sensi-
tive to the pKa of a-hydrogen and the basicity of imine
nitrogen, and the equilibrium between imine and NH-azo-
methine ylide leans to the imine side. Therefore, very harsh
reaction conditions, i.e., benzene or toluene at reflux for long-
time, are required for generation of the species, which lead
to less-stereoselective cycloaddition reaction. The second
method is generation from a-metalloimines and a-metallo-
amides by utilizing 1,2- and 1,4-metallotropic strategy re-
ported by Komatsu and co-workers.4 For example, in the
reactions of a-stannylthioamides, the strong affinity between
Sn and sulfur causes a 1,4-stannatropy to afford the NH-
azomethine ylide. The reaction with dipolarophiles, such as
electron-deficient alkenes and alkynes, provided the corre-
sponding pyrrolidine and pyrrole derivatives in good to ex-
cellent yields. It should be noted that the cycloaddition
reaction of NH-azomethine ylides generated by 1,4-stanna-
tropy is regarded as nitrile ylide equivalents, because cyclo-
adducts of the corresponding nitrile ylides are obtained as the
results of cycloaddition of the azomethine ylide followed by
the elimination of Bu3SnSH. The production of highly toxic
Sn compound is the weak point of this methodology. The
third method is N-metalation of a-iminoesters.5 Treatment
of the a-iminoester possessing a coordinating group with
MX/base provides N-metalated azomethine ylide in situ,
which reactswithactivated alkenes at a low temperature. Var-
ious Lewis acids such as Ag, Cu, and Li salts can be used for
generation of the species in conjunction with various bases
such as Et3N, Hunig’s base, and DBU. The cycloaddition
reaction involving the N-metalated azomethine ylide can
overcome the less stereoselectivity, which is the disadvan-
tage point of 1,2-prototropic strategy, and recently the appli-
cation of this strategy to a catalytic enantioselective version
has been achieved by a number of research groups.6
dipoles and carbonyl oxygen in the heterocycles might facil-
itate the generation of the NH-dipoles. The fission reaction of
the cycloadduct made synthetic utility of our chemistry more
convenient, i.e., treatment of the pyrazolidines F obtained
from cycloaddition of NH-azomethine imines D with pyridi-
nium p-toluenesulfonate (PPTS) caused a cleavage of the
C–C bond between the pyrazolidine and heterocyclic moiety
to give 2-pyrazoline derivatives G in good yields, which can
be useful synthetic building block.
In this paper, we will report the generation of NH-azo-
methine ylide from aldimine in the same heterocyclic system
under extremely mild conditions and their stereoselective
cycloaddition reaction. Imines are derived from heterocyclic
aldehydes and amino acid methyl esters, and we expect
that the generated NH-azomethine ylides from the corre-
sponding imines are fixed only one configuration by double
internal hydrogen bond formations between the NH of re-
sulting dipoles and the carbonyl oxygen in the heterocycle
and ester carbonyl oxygen, which leads the stereoselective
cycloaddition reaction with maleimides. Fission reaction of
cycloadducts under acidic conditions accompanied by the
stereoselective cycloaddition will provide various dehydro-
proline derivatives. The application of the cycloaddition–
fission reaction sequences to a one-pot three-component
process will also be discussed.
2. Results and discussion
2.1. Optimization of reaction conditions and substrates
In order to elucidate the scope and features of the imine-
azomethine ylide isomerization in pyrido[1,2-a]pyrimi-
dine-4(4H)-one system, four aldehydes 1a–d, which have
N,N-dimethylamino (1a), N,N-dibenzylamino (1b), pyrroli-
dine-1-yl (1c), and morpholino (1d) groups at 2-position
of heterocyclic moiety were prepared and thermal reaction
was explored with NPMI.
As a part of our projects to develop 1,3-dipolar cycloaddi-
tions at the periphery of heterocyclic system, we reported
a facile generation of NH-nitrones C and NH-azomethine
imines D from oximes A and hydrazones B through the
1,2-prototropy under neutral conditions (Scheme 2).7,8 The
intermolecular cycloaddition reaction of the NH-azomethine
imines D with olefinic dipolarophiles such as N-phenylmale-
imide (NPMI), dimethyl maleate, and dimethyl fumarate in
benzene at reflux provided the corresponding pyrazolidine
derivatives F in moderate to good yields. Although the cyclo-
addition reaction of NH-nitrones C with dimethyl maleate
and dimethyl fumarate did not proceed, we succeeded in pro-
ceeding the cycloaddition reaction with NPMI in benzene at
reflux and offering the second example of intermolecular cy-
cloaddition reaction of NH-nitrone. We proposed that the in-
ternal hydrogen bond formation between the NH of resulting
At the outset, the cycloaddition reactions of imine 3a with
NPMI were carried out in various solvents at room tempera-
ture in order to determine the best reaction solvent (Table 1).
In all cases, imine 3a was generated only in situ and used for
reaction without isolation. Typical experimental procedure
was provided as following; aldehyde 1a (1.0 equiv) and
(DL)-phenylglycine methyl ester 2a (1.1 equiv) were com-
bined in solvent (0.5 M of 1a) and the mixture was stirred
for 1 h under an aerobic atmosphere, and then NPMI was
added. The mixture was stirred at room temperature for the
indicated time. Although the reaction in acetonitrile provided
proline derivatives 8a (93), 9a (5), and 10a (2) in a quantita-
tiveyield, it took about 30 h to complete the reaction (Table 1,
H
ZH
Z
O
Z
O
N
N
O
N
HN
H
B
A
O
N
N
N
A
2)
B
H
H
3)
H
Z
B
N
+
N
N
N
1)
A
N
NR2
NR2
NR2
NR2
A (Z = O; Oxime)
C (Z = O; NH-nitrone)
E (Z = O; Isoxazolidine)
B (Z = NPh; Hydrazone) D (Z = NPh; NH-azomethine imine) F (Z = NPh; Pyrazolidine)
G (Z = NPh; 2-Pyrazoline)
Scheme 2. Reaction modes: (1) 1,2-prototropy; (2) cycloaddition reaction; and (3) fission reaction.

1632
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
Table 1. Optimization of reaction solvent
Ph
Ph
Ph
N
O
O
O
H2N
CO2Me
O
N
N
CO2Me
CHO
2a
N
N
solvent, r.t., time
cycloaddition
solvent, r.t., 1 h
imine formation
N
NMe2
NMe2
Imine 3a
Aldehyde 1a
H3
H
N
2
H3
H
N
H
N
Ph
Ph
Ph
H3
1
6
P
CO2Me
P
CO2Me
CO2Me
P
H3a
O
H3a
O
O
H3a
O
H6a
O
H6a
O
H6a
+
+
6
5
N
4
5
7
O
4
N
N
N
3
P =
Ph
8a
Ph
9a
Ph
10a
8
9a
2
N
NMe2
9
Entry
Solvent
Time (h)
Products
Yielda (%)
Isomer ratiob
endo:exo
8a:9a:10a
1
2
3
4
MeCN
DME
Toluene
EtOH
32
27
1
Quant.
Quant.
Quant.
43
93:5:2
92:6:2
97:2:1
—
98:2
98:2
99:1
—
8a+9a+10a
45
8a
a
The yield is isolated yield.
Determined by 1H NMR.
b
entry 1). From the inspection of their spectroscopic data it
was found that, proline 8a was formed through the endo-
approach of NPMI to the kinetically favored (E,E)-dipole.
On the other hand, prolines 9a and 10a were deduced to
endo- and exo-approaches of NPMI to (E,Z)-dipole, respec-
tively, as discussed later. The reaction in 1,2-dimethoxy-
ethane (DME) also provided similar results (Table 1,
entry 2). The reaction in ethanol was very sluggish and led
to recovery of aldehyde 1a even after 45 h (entry 4). In the
case of toluene, the reaction proceeded on smoothly within
1 h together with a quantitative yield and high endo-selectiv-
ity. The reason why the reactions in acetonitrile, DME, and
ethanol were sluggish in comparison with the reaction in
toluene is that it would be hard to generate the imine 3a
in situ. In view of efficiency and selectivity, we chose toluene
as the best reaction solvent.
toluene. In all cases, the cycloaddition reactions gave excel-
lent yields and endo-selectivity. Although the reaction using
aldehyde 1a at 85 ꢀC proceeded within 10 min, the diastereo-
selectivity of proline 8a was moderate (entry 1). The reaction
using aldehyde 1a at room temperature provided the highest
diastereoselectivity (94% de) of 8a (entry 2). The reaction
using the other aldehydes (entries 3–5) at room temperature
afforded moderate diastereoselectivities (72–80% de) of the
corresponding prolines 8. It is worth noting that the corre-
sponding prolines 10 were not formed when aldehydes 1b
and 1d were used in the reaction. The bulky amino groups
would suppress the formation of cycloadducts 10b and
10d. In view of selectivity, N,N-dimethylamino group was
adopted as the best amino group of heterocyclic moiety.
2.2. Amino acid methyl ester scope
Next, we focused on the effect of amino groups at 2-position
of heterocyclic moiety on diastereoselectivity of the reaction
(Table 2). The cycloaddition reaction of imines 3a–d with
NPMI was performed at 85 ꢀC and room temperature, using
To investigate the scopes and limitations of imine-azo-
methine ylide isomerization and its intermolecular cycload-
dition reaction, a variety of amino acid methyl esters were
used to form imines 3e–i and these imines were subjected
Table 2. Influence of amino groups R on reaction selectivity
Ph
O
CHO
R
H2N
CO2Me
N
2a
NPMI
toluene, conditions
Imine 3a - d
Adducts
toluene, 1 h
N
Aldehydes 1a-d
Entry
Aldehyde
R
Cycloaddition conditions
Adducts
Yielda (%)
de (%) of 8
endo:exo
1
2
3
1a
N(Me)2
85 ꢀC, <10 min
rt, 60 min
rt, 90 min
8a+9a+10a
Quant.
Quant.
Quant.
74
94
80
98:2
99:1
100:0
1b
1c
N(Bn)2
8b+9b
4
rt, 60 min
rt, 60 min
8c+9c+10c
8d+9d
Quant.
94
72
76
97:3
N
5
1d
100:0
N
O
a
The yield is isolated yield.

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1633
Table 3. Generality of amino acid esters
(DL)-amino acid
methyl ester
NPMI
toluene, conditions
Aldehyde 1a
Imine 3e - 3i
Adducts
toluene, 85 °C, 1h
Entry
(DL)-amino acid
methyl ester
Imine
Conditions
Products
Isomer ratioa
Yieldb (%)
endo:exo
8:9:10
1
2
3
4
5
6
7
8
9
Gly (R1¼H)
Ala (R1¼Me)
Val (R1¼i-Pr)
Phe (R1¼Bn)
3e
3f
3g
85 ꢀC, 21 h
85 ꢀC, 3 h
85 ꢀC, 2.5 h
rt, 22 h
8e+10e
8f+9f
8g+9g
82:0:18
94:6:0
43:57:0
38:62:0
90:10:0
97:3:0
100:0:0
86:14:0
94:6:0
67
76
72
98
85
88
88
94
77
82:18
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
3h
3i
85 ꢀC, 0.5 h
rt, 1 h
8h+9h
8h+9h
8h
ꢁ30 ꢀC, 20 h
85 ꢀC, 1 h
rt, 24 h
Met
8i+9i
(R1¼(CH2)2SMe)
Determined by 1H NMR.
The yield is isolated yield.
a
b
to react with NPMI without isolation (Table 3). In entries
2–9, the cycloaddition reaction with NPMI yielded the
corresponding proline derivatives in good to excellent yields
(72–98%) and the perfect endo-selectivity was achieved.
The simplest imine 3e derived from glycine methyl ester
reacted with NPMI at 85 ꢀC for 21 h to give the proline de-
rivatives 8e and 10e as a 82:18 ratio in 67% yield (entry
1). Why 10e was obtained as a minor product is unclear
yet. Imine 3f derived from (DL)-alanine methyl ester also un-
derwent the cycloaddition reaction with NPMI at 85 ꢀC for
3 h to give the corresponding proline derivatives 8f and 9f
as a 94:6 ratio in 76% yield (entry 2). Sterically hindered
imine 3g also reacted with NPMI at 85 ꢀC for 2.5 h, and the
corresponding proline derivatives 8g and 9g were isolated
as a 43:57 ratio in 72% yield (entry 3). Although the pro-
longed reaction time was required to complete the reaction,
the reaction of imine 3g with NPMI at room temperature pro-
vided proline derivatives 8g and 9g as a 38:62 ratio in 98%
yield (entry 4). We will discuss later in this paper why
adducts 8g and 9g were obtained almost even ratio in the
case of imine 3g. Aromatic-substituted imine 3h (R1¼Bn)
and heteroalkyl-substituted imine 3i (R1¼(CH2)2SMe) were
also good substrates for this reaction at both 85 ꢀC and room
temperature, and the corresponding proline derivatives were
isolated in 77–94% yields and good diastereoselectivities
(entries 5, 6, 8, and 9). In order to elucidate the scope and
features of the imine-azomethine ylide isomerization in
this system, imine 3h was subjected to react with NPMI
at ꢁ30 ꢀC. Surprisingly, the cycloaddition reaction of imine
3h with NPMI proceeded even at ꢁ30 ꢀC, although it took
about 20 h to complete the reaction, and the proline 8h
was obtained as a sole product in 88% yield (entry 7).
2.3. Structural determination
The structure of prolines 8a, 9a, and 10a was fully character-
ized by 13C NMR and COSY experiments as well as the
coupling constants of H NMR spectra. Since prolines 8a
1
and 9a have large coupling constants between H3 and H3a,
and H3a and H6a as shown in Figure 1, the relative con-
figurations among the three methine protons (H3, H3a, and
H6a) in the proline ring were assigned to be all cis. In the pro-
line 10a, the relative configuration between H3a and H6a was
assigned to be cis on the basis of large coupling constant
(JH3a–H6a¼10.6 Hz), while between H3 and H3a was as-
signed to be trans on the basis of small coupling constant
(JH3–H3a¼7.3 Hz) as showing in Figure 1. In view of the
shielding effect of phenyl group on H6a, the relative config-
urations between phenyl group and H6a in prolines 8a, 9a,
and 10a were determined. Since prolines 8a and 10a have
the chemical shift values of H6a in higher field, relative con-
figurations between phenyl group and H6a were assigned to
be cis. In the case of proline 9a, its correlation was trans
because it has the chemical shift value of H6a in lower field.
Shielding
Shielding
H3
H
N
H3
H
N
2
H3
H
N
Ph
Ph
Ph
CO2Me
O
N
1
6
CO2Me
P
CO2Me
P
P
N
H3a
H3a
O
H6a
O
H6a
O
H3a
O
H6a
P =
4
5
NMe2
O
O
N
N
N
Ph
Ph
Ph
8a
9a
10a
cycloadduct
J
3-3a (Hz)
J
3a-6a (Hz)
6a-H (ppm)
8a
9a
9.2 (cis)
9.2 (cis)
4.31 - 4.40
4.76
8.3 (cis)
7.9 (cis)
10a
7.3 (trans) 10.6 (cis)
4.12
Figure 1. Selected 1H NMR spectral data for prolines 8a, 9a, and 10a.

1634
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
H
N
H3
H
N
Finally, the structure of proline 8a was confirmed by its
single-crystal X-ray analysis.9 The structure of prolines
8b–d, 9b–d, and 10c was determined by the same consider-
ations as mentioned above. The structure of prolines 8e and
10e was also characterized by 13C NMR, COSY and NOE
CH3
CH3
14%
H3
5%
2.8%
Es = CO2Me
Es
H6a
O
P
Es
P
H3a
O
H3a
O
H6a
O
O
N
N
Ph
Ph
N
6%
10%
P =
1
experiments as well as the coupling constants of H NMR
N
NMe2
8f
9f
spectra. It was predicted that the relative configurations
among the four methine protons (H1, H3, H3a, and H6a) in
proline 8e were all cis on the basis of the coupling constants
(JH1–H6a¼8.9 Hz, JH3a–H6a¼8.6 Hz, and JH3–H3a¼7.3 Hz).
In the case of proline 10e, the correlations among four
methine protons (H1, H3, H3a, and H6a) predicted that H1
and H6a, and H3a and H6a were cis, while H3 and H3a was trans
on the basis of the coupling constants (JH1–H6a¼8.9 Hz,
JH3a–H6a¼8.6 Hz, and JH3–H3a¼1.0 Hz). NOE experiments
of prolines 8e and 10e made our predictions mentioned above
undoubted (Fig. 2). The structure of prolines 8f and 9f were
Cycloadduct 3-H (ppm) 3a-H (ppm) 6a-H (ppm) J3-3a (Hz) J3a-6a (Hz)
9.2 (cis)
9.2 (cis)
8.3 (cis)
8.3 (cis)
8f
9f
4.75
4.60
3.66
3.66
3.54
4.10
Figure 3. Selected 1H NMR spectral data and NOE signal enhancements for
prolines 8f and 9f.
formation between the NH and the carbonyl oxygen. The
severe steric repulsion exists in both Z,E-dipole 6 and Z,Z-
dipole 7 between heterocyclic moiety (P) and R groups (in
the dipole 6) or ester group (in the dipole 7); accordingly,
they would be excluded from reaction species involved in
cycloaddition reaction. The E,E-dipole 4 is stabilized by
double intramolecular hydrogen bonds, therefore, this is
kinetically predominant dipole. The E,Z-dipole 5 having
only one hydrogen bond is the second predominant dipole.
Prolines 8 were formed through the endo-approach of NPMI
to the kinetically favored E,E-dipole 4. Likewise, the endo-
approach of NPMI to the E,Z-dipole 5 would lead to prolines
9 and exo-approach of the one to the same dipole would
lead to prolines 10. The cycloaddition reaction of imine
3g, which was derived from the condensation of (DL)-
valine methyl ester and aldehyde 1a, exceptionally gave the
two diastereomers 8g and 9g in an almost 1:1 ratio. A likely
account for this result is suggested as follows; the dipole 4g
1
deduced on the basis of the coupling constants in H NMR
spectra and NOE experiments. The details are summarized
in Figure 3. The structure of the other prolines 8g–i and
9g–i was confirmed on comparison with H NMR spectral
1
data of prolines 8f and 9f. The structure of prolines 8f and
8g was confirmed by their single-crystal X-ray analysis.9
2.4. Reaction mechanism
Four geometrical isomers 4–7 are possible for the NH-azo-
methine ylides formed through the thermal 1,2-prototropy
of imines 3a–i and these ylides could be interconverted to
each other under the reaction conditions (Scheme 3). Rela-
tive stability among them could be evaluated on the grounds
of steric repulsion and intramolecular hydrogen bond
11 %
0 %
14 %
17 %
H3
H
N
H3
H
N
12 %
8 %
H1
H1
Es = CO2Me
Es
Es
P
P
H3a
O
H6a
O
H3a
O
H6a
O
O
N
N
N
Ph
Ph
P =
20 %
13 %
N
NMe2
8e
10e
J1-6a (Hz) J3a-6a (Hz) J3-3a (Hz)
Cycloadduct
8.9 (cis)
8.9 (cis)
8.6 (cis)
8.6 (cis)
7.3 (cis)
8e
1.0 (trans)
10e
Figure 2. Selected 1H NMR spectral data and NOE signal enhancements for prolines 8e and 10e.
O
R
OMe
H
H
O
P
R
OMe
O
N
N
H
O
N
N
CO2Me
H
R
N
>>
>>
N
N
CO2Me
N
R
R1
H
R1
H
P
N
N
R1
R1
E,Z-dipole 5
(S-shaped dipole Ι)
Z,Z-dipole 7
E,E-dipole 4
(W-shaped dipole)
Z,E-dipole 6
(S-shaped dipole ΙΙ)
(U-shaped dipole)
O
N
(E,E-4)
+
NPMI
(E,Z-5)
+
NPMI
(E,Z-5)
+
NPMI
8
9
10
P =
exo-
endo-
endo-
R1
approach
approach
approach
N
N
R1
Scheme 3. Four possible isomers 4–7 for NH-azomethine ylide.

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1635
(R¼i-Pr) would still be kinetically favored dipole, in which
a severe steric repulsion between the isopropyl group and the
azomethine proton is there. Therefore, dipole 4g could be
easily converted to dipole 5g in order to release this steric re-
pulsion and the concentration of dipole 4g and 5g in situ
would become nearly even. Consequently, prolines 8g and
9g were obtained in an almost 1:1 ratio.
conditions was essentially independent of amino substituent
at the 2-position of heterocyclic moiety and gave the corre-
sponding heterocyclic moieties 11b–d and dehydroproline
12a in good yields (Table 4, entries 3–5). Prolines 8f–i
were also good substrates for this reaction to give the corre-
sponding heterocyclic moiety 11a and dehydroprolines 12f–i
in good yields (Table 4, entries 6–9). The fission reaction of
proline 8e (R2¼H) was also examined in AcOH solution at
50 ꢀC. Four products were detected on TLC analysis after
9 h and they were identified as 8e, aldehyde 1a, NPMI, and
11a by 1H NMR analysis of the crude mixture. This result in-
dicated that retro-cycloaddition reaction proceeded in this
case. A likely mechanism for this conversion is suggested
in Scheme 5. A reaction path similar to a retro-Mannich
addition process catalyzed by proton was proposed for
this conversion. A protonation at the 3-position of 8 affords
an iminium ion intermediate 14, which undergoes a retro-
Mannich type reaction to give the parent heterocyclic moiety
11 and dehydroproline 12.
2.5. Fission reaction of cycloadducts and its application
to one-pot three-component reaction
In the preceding paper,8 we reported that the fission reaction
of cycloadducts obtained from the cycloaddition reaction of
NH-azomethine imines with NPMI took place in the pres-
ence of PPTS, where a cleavage of C–C bond between pyr-
azolidine and heterocyclic moiety occurred to give the parent
heterocyclic system and 2-pyrazoline derivatives in high
yields. We expected that the treatment of prolines 8 with
acids would cause a similar fission reaction to give the parent
heterocyclic system and dehydroproline derivatives. The
treatment of proline 8a with PPTS in acetonitrile provided
2-(N,N-dimethylamino)pyrido[1,2-a]pyrimidin-4(4H)-one
11a in 90% yield and inseparable mixture of dehydroproline
12a and its dimer 13 as 4:1 ratio in 73% yield (Table 4,
entry 1). It was found that the dehydroproline 12a was easily
dimerized under acidic conditions, i.e., the treatment of 12a
with PPTS in refluxing methanol for 15 h gave the dimer 13
in 92% yield (Scheme 4). The structure of dimer 13 was char-
MeO2C
N
Ph
CO2Me
H3
H
2'
2
N
H3'
1
6
Ph
H
Ph
N
3a
H6a'
1'
6'
PPTS (1.0 eq.)
MeOH
CO2Me
H
H
4
5
H3a'
O
H6a'
O
O
O
N
4'
O
O
5'
N
Ph
N
Ph
Ph
12a
13
Scheme 4. Dimerization of dehydroproline 12a in the presence of PPTS.
1
acterized by H, 13C NMR, and mass spectra. Especially
mass spectra provided clear evidence of dimer 13 (FAB-
mass: m/z 697 (MH+), 637, 349 (1/2MH+, base peak), 289).
The dimer 13 existed as two isomeric mixture (1:1 ratio) in
CDCl3 solution. Although it is not clear in detail whether
those isomers are related as diastereomers or rotamers, we
suggest the latter on the basis of the sharp melting point
and molecular model considerations. The dimerization of
12a would proceed via acid-catalyzed Mannich type addi-
tion. Heating proline 8a in acetic acid (AcOH) at 85 ꢀC sup-
pressed the formation of dimer 13 and provided 11a in 67%
yield and dehydroproline 12a in 83% yield (Table 4, entry 2).
The fission reaction of prolines 8b–d under similar
CO2Me
R2
H
O
H
N
O
N
H
H
Proline 8
H
+ 12 +
11
NPh
N
H
H
O
NMe2
Iminium ion intermediate 14
Scheme 5. Plausible pathway for fission reaction of proline 8.
In order to make the cycloaddition–fission reaction se-
quences more efficient, these reaction sequences were
Table 4. Fission reaction of prolines 8
CO2Me
R2
CO2Me
H6a
R2
O
N
N
H
H3
O
2
1
6
H
O
N
HN
H
conditions
85 °C
N
H
+
3a
NPh
4
5
N
R1
O
O
N
H
Ph
O
R1
Prolines 8
11
12
Entry
Cycloadduct
R1
R2
Reaction conditions
Additive (equiv)
Product/yield (%)
Solv.
Time (h)
1
2
3
4
5
6
7
8
9
8a
NMe2
Ph
Ph
CH3CN
AcOH
PPTS (1.0)
None
None
None
None
None
3.0
0.5
4.5
0.75
3.0
1.5
0.5
1.0
0.5
11a/90
12a/73a
11a/67
11b/83
11c/90
11d/73
11a/quant.
11a/84
11a/70
11a/89
12a/83
12a/81
12a/82
12a/88
12f/quant.
12g/84
12h/84
12i/91
8b
8c
8d
8f
8g
8h
8i
NBn2
Pyrrolidin-1-yl
Morpholino
NMe2
AcOH
AcOH
Me
i-Pr
Bn
(CH2)2SMe
a
The yield included 15% of dimer 13.

1636
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
Table 5. Synthesis of dehydroprolines 12 via one-pot three-component reaction
R
N
H
O
R
O
N
CO2Me
H
CH3CN / AcOH (1/5)
85 °C, time
CHO
H
H
N
H2N
CO2Me
+
N
O
O
N
R'
N
NMe2
NMe2
Maleimide
12a, h-k
11a
Entry
R
R0
Maleimide
Time (h)
Product/yield (%)
12a/78
1a
2
Ph
Bn
Ph
Ph
Ph
3
1
1.5
11a/83
11a/89
11a/96
Ph
N
12h/94
12i/61
O
O
O
O
3
(CH2)2SMe
Me
N
4
5
Ph
Bn
Me
Me
5
3
11a/86
11a/94
12j/85
12k/78
a
Dehydroproline 12a0 was also obtained in 10% yield.
Ph
CO2Me
N
H
H
H
O
O
N
Ph
12a'
applied to one-pot three-component reaction. The results of
our survey for the one-pot reaction are compiled in Table 5.
The one-pot reaction of aldehyde 1, (DL)-phenylglycine
methyl ester, and NPMI in acetonitrile/acetic acid (¼1/5) so-
lution was examined at the outset, and dehydroproline 12a,
its isomer 12a0, and the parent heterocyclic system 11a was
obtained in 78%, 10%, and 83% yields, respectively (Table
5, entry 1). The progress of the one-pot reaction could be
traced out easily by TLC. On TLC, the formations of cyclo-
adducts 8a and its isomers were observed at first. When the
cycloadducts disappeared, the formation of 11a and 12a was
observed. Similar reactions of (DL)-phenylalanine methyl
ester and (DL)-methionine methyl ester gave the correspond-
ing dehydroproline 12h in 94% yield and 12i in 61% yield
(Table 5, entries 2 and 3). The one-pot reaction of N-methyl-
maleimide (NMMI) used as the dipolarophile also provided
the corresponding dehydroprolines 12j and 12k in good
yields (Table 5, entries 4 and 5). The dehydroprolines 12 cor-
respond to the cycloadducts of C-unsubstituted (CH) nitrile
ylides 15 and the maleimides. The C-unsubstituted nitrile
ylide chemistry as a synthetic tool has seldom been studied.
Although some examples for functionalized azomethine
ylides as synthetic equivalents of nitrile ylides are found in
the literature,10 there are few examples of C-unsubstituted
nitrile ylides.4g Therefore, in the present reaction sequences,
the cycloaddition of functionalized azomethine ylides 4 and
an acid fission reaction of the prolines 8, could be regarded
as an equivalent process of C-unsubstituted nitrile ylide
cycloaddition reaction. According to the procedure in the
literature,11 the parent heterocycle 11a could be easily for-
mylated to the starting aldehyde 1a in 80% yield.
selectivity. Heating cycloadducts in AcOH at 85 ꢀC provides
dehydroproline derivatives, which are regarded as cycload-
ducts of C-unsubstituted (CH) nitrile ylides and maleimides.
Our methodology is summarized in Scheme 6. Therein, the
parent heterocyclic system plays an important role in the fac-
ile generation of azomethine ylide and the fission reaction of
their cycloadducts. The cycloaddition–fission reaction se-
quences can be applied to one-pot three-component reaction.
It is worth noting that all of these reaction processes
described herein can be performed under an aerobic atmo-
sphere, using wet solvents. Further investigation on the
related chemistry is in progress and the results will be
reported elsewhere.
4. Experimental
4.1. General
Melting points were measured on a Yanagimoto micro melt-
ing point apparatus and are uncorrected. IR spectra were
measured on a HORIBA FT-200 spectrophotometer from
samples as pellets or NaCl discs. 1H NMR spectra were mea-
sured 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
deuteriochloroform (CDCl3) solutions unless otherwise
stated. Tetramethylsilane was used as an internal standard,
and J values are given in hertz. Splitting patterns are indi-
cated as: s, singlet; d, doublet; t, triplet; q, quadruplet; m,
multiplet; br, broad signals; and ov, overlapping signals.
Mass spectra were determined on a JEOL 700QQ spectro-
meter. Elemental analyses were performed on a Yanagimoto
MT-5 CHN analyzer. The progress of reactions was moni-
tored by TLC (silica gel 60F254, 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 imine to NH-
azomethine ylide under extremely mild conditions, e.g., at
ꢁ30 ꢀC to room temperature, and the resulting NH-azo-
methine ylide reacts with NPMI in high yield and endo-

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1637
O
OMe
H
O
N
N
R2
N
Cycloaddition
Thermal
1,2-H Shift
Reaction
NMe2
NH-Azomethine Ylide 4
CO2Me
R2
R2
H
O
O
N
N
CO2Me
O
N
HN
N
R1
N
N
H
H
O
NMe2
NMe2
Proline 8
Imine 3
R2
H +
R2
CO2Me
Imine Formation
H
C N
Fission Reaction
O
N
Reaction
H
CO2Me
H
H
C-Unsubstituted nitrile ylide 15
O
+
O
O
Formylation
CHO
H
N
N
N
R1
O
O
N
N
NMe2
N
NMe2
R1
Aldehyde 1a
Scheme 6. Functionalized NH-azomethine ylide 4 as C-unsubstituted nitrile ylide equivalent.
4.2. General procedure for the preparation of 2-amino-
4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehydes 1
prepared and its physical and spectroscopic data are pro-
vided in the literature.12
A solution of 2-chloro-4-oxo-4H-pyrido[1,2-a]-pyrimidine-
3-carbaldehyde11 (1.04 g, 5 mmol), dimethylamine (2.0 M
solution in methanol, 5 mL, 10 mmol), and triethylamine
(3.5 mL, 25 mmol) was stirred at room temperature for
5 h. The solvent was evaporated to dryness to give solid resi-
due, which was extracted with dichloromethane (CH2Cl2)/
5% aqueous sodium hydrogencarbonate. The organic layer
was dried on anhydrous magnesium sulfate and the solvent
was evaporated to give aldehyde 1a (0.945 g, 87%). Alde-
hyde 1a was used for the next procedure without further
purification.
4.2.4. 2-Morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carbaldehyde (1d). Yellow crystals from benzene; mp
175.5–176.5 ꢀC; 1H NMR (CDCl3): 3.74–3.77 (4H, m,
N(CH2CH2)2O), 3.81–3.85 (4H, m, N(CH2CH2)2O), 6.93
(1H, ddd, J¼1.3, 6.9, 6.9 Hz, 7-H), 7.25 (1H, dd, J¼1.3,
8.6 Hz, 9-H), 7.71 (1H, ddd, J¼1.3, 6.9, 8.6 Hz, 8-H), 8.85
(1H, ddd, J¼1.3, 6.9, 6.9 Hz, 6-H), 10.13 (1H, s, CHO);
13C NMR (CDCl3): 50.1, 67.6, 96.4, 113.7, 125.1, 128.4,
139.9, 151.6, 159.6, 162.5, 186.6. Anal. calcd for
C13H13N3O3 (259.26): C, 60.22; H, 5.05; N, 16.21. Found:
C, 60.11; H, 5.10; N, 16.13.
4.2.1. 2-(N,N-Dimethylamino)-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde (1a). Yellow prisms from
4.3. General procedure for reaction of imines 3a–d and
3g–i with NPMI
1
hexane/benzene; mp 165.7–166.3 ꢀC; H NMR (CDCl3):
3.12 (6H, s, N(CH3)2), 6.86 (1H, ddd, J¼1.0, 6.9, 6.9 Hz,
7-H), 7.22 (1H, dd, J¼1.0, 8.2 Hz, 9-H), 7.63 (1H, ddd,
J¼1.7, 6.9, 8.2 Hz, 8-H), 8.81 (1H, ddd, J¼1.0, 1.7,
6.9 Hz, 6-H), 10.12 (1H, s, CHO); 13C NMR (CDCl3):
41.2, 95.7, 112.5, 124.5, 127.8, 138.8, 150.6, 159.9, 161.7,
186.5. Anal. calcd for C11H11N3O2 (217.22): C, 60.82; H,
5.10; N, 19.34. Found: C, 60.63; H, 5.15; N, 19.20.
A solution of aldehyde 1a (0.217 g, 1.0 mmol) and (DL)-
phenylglycine methyl ester 2a (0.182 g, 1.1 mmol) in tolu-
ene (2 mL) was stirred at room temperature for 1 h under
an aerobic atmosphere. To the solution N-phenylmaleimide
(0.19 g, 1.1 mmol) was added and the mixture was allowed
to react at the same temperature for additional 1 h. The mix-
ture was evaporated to dryness to give solid residue, which
was crystallized from methanol to give proline 8a (97%).
The filtrate methanol solution was evaporated to dryness to
give solid residue, which was subjected to a column chroma-
tography on silica gel to give 9a (2%) and 10a (1%) with
hexane/ethyl acetate (1:2) as an eluent.
4.2.2. 2-(N,N-Dibenzylamino)-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde (1b). Colorless prisms from
1
hexane/benzene; mp 128.5–129.5 ꢀC; H NMR (CDCl3):
4.80 (4H, s, N(CH2Ph)2), 6.93 (1H, ddd, J¼1.0, 6.9,
6.9 Hz, 7-H), 7.16 (4H, m, Ph–H), 7.22–7.33 (7H, ov,
Ph–H and 9-H), 7.68 (1H, ddd, J¼1.3, 6.9, 8.6 Hz, 8-H),
8.87 (1H, dd, J¼1.3, 6.9 Hz, 6-H), 10.20 (1H, s, CHO);
13C NMR (CDCl3): 53.8, 96.9, 113.2, 124.9, 127.4, 127.8,
128.0, 128.6, 136.9, 139.2, 151.0, 160.6, 161.9, 186.7.
Anal. calcd for C23H19N3O2 (369.42): C, 74.78; H, 5.18;
N, 11.37. Found: C, 74.82; H, 5.15; N, 11.45.
4.4. General procedure for reaction of imines 3e–f
with NPMI
A solution of aldehyde 1a (0.217 g, 1.0 mmol), glycine
methyl ester hydrochloride 2e (0.188 g, 1.5 mmol), and tri-
ethylamine (0.21 mL, 1.5 mmol) in toluene (2 mL) was
heated at 85 ꢀC for 1 h under an aerobic atmosphere. To the
solution N-phenylmaleimide (0.19 g, 1.1 mmol) was added
and the mixture was allowed to react at the same temperature
4.2.3. 4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimi-
dine-3-carbaldehyde (1c). This compound has been already

1638
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
for 21 h. The mixture was evaporated to dryness to give
solid residue, which was extracted with dichloromethane
(CH2Cl2)/5% aqueous sodium hydrogencarbonate. The
organic layer was dried over anhydrous magnesium sulfate
and the solvent was evaporated. The residue was crystal-
lized from methanol to give proline 8e (55%). The filtrate
methanol solution was evaporated to dryness to give solid
residue, which was subjected to a column chromatography
on silica gel to give 10e (12%) with ethyl acetate as an eluent.
4.4.4. (1R*,3R*,3aS*,6aR*)-( )-Methyl 3-[2-(N,N-di-
benzylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (8b). White powders from i-PrOH/benzene; mp
221–222 ꢀC; IR (KBr): 3290 (NH), 1743, 1707, 1655, 1633
(CO); 1H NMR (CDCl3): 3.29 (1H, dd, J¼7.9, 9.6 Hz,
3a-H), 3.76 (3H, s, CO2CH3), 4.25 (1H, d, J¼7.9 Hz,
6a-H), 4.37 (1H, d, J¼15.5 Hz, CH2Ph), 4.60 (1H, d,
J¼15.5 Hz, CH2Ph), 4.68 (1H, dd, J¼9.6, 13.2 Hz, 3-H),
5.62 (1H, d, J¼13.2 Hz, exchanged with D2O, NH), 6.95
(1H, t, J¼6.9 Hz, 70-H), 7.08–7.18 (10H, ov, CH2Ph–H,
Ph–H, and NPh–H), 7.32–7.49 (9H, ov, CH2Ph–H, Ph–H,
NPh–H, and 90-H), 7.60 (1H, ddd, J¼1.7, 6.9, 8.6 Hz,
80-H), 7.72 (2H, m, Ph–H), 8.89 (1H, br d, J¼6.9 Hz,
60-H); 13C NMR (CDCl3): 49.3, 53.0, 54.1, 56.7, 59.1,
73.8, 95.8, 113.9, 124.9, 127.0, 127.2, 127.24, 127.5,
128.1, 128.45, 128.5, 128.9, 132.5, 136.4, 137.5, 138.9,
148.4, 159.2, 165.2, 170.5, 175.1, 175.6. Anal. calcd for
C42H35N5O5 (689.76): C, 73.13; H, 5.11; N, 10.15. Found:
C, 72.95; H, 5.23; N, 9.98.
4.4.1. (1R*,3R*,3aS*,6aR*)-( )-Methyl 3-[2-(N,N-di-
methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (8a). Colorless prisms from hexane/benzene;
mp 211–212 ꢀC; IR (KBr): 3280 (NH), 1745, 1709, 1655,
1632 (CO); 1H NMR (CDCl3): 2.98 (6H, s, N(CH3)2), 3.47
(1H, dd, J¼8.3, 9.2 Hz, 3a-H), 3.78 (3H, s, CO2CH3),
4.31–4.4 (2H, ov, 3-H, 6a-H), 5.59 (1H, br d, J¼13.2 Hz, ex-
changed with D2O, NH), 6.86 (1H, ddd, J¼1.0, 7.3, 7.3 Hz,
70-H), 7.27–7.58 (10H, ov, 80-H, 90-H, Ph–H, and NPh–H),
7.78 (2H, dd, J¼1.7, 6.6 Hz, Ph–H), 8.79 (1H, dd, J¼1.0,
7.3 Hz, 60-H); 13C NMR (CDCl3): 41.5, 49.8, 53.0, 56.5,
59.6, 74.0, 91.3, 113.1, 124.5, 126.9, 127.0, 127.3, 128.1,
128.3, 128.4, 128.8, 132.5, 136.2, 139.3, 148.3, 159.1,
164.5, 170.7, 175.0, 175.5. Anal. calcd for C30H27N5O5
(537.57): C, 67.03; H, 5.06; N, 13.03. Found: C, 67.01; H,
5.10; N, 12.89.
4.4.5. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-[2-(N,N-di-
benzylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (9b). White powders from hexane/i-PrOH; mp
191–192 ꢀC; 1H NMR (CDCl3): 3.54 (3H, s, CO2CH3),
3.55 (1H, dd, J¼7.9, 9.2 Hz, 3a-H), 4.59–4.62 (2H, ov, 3-H
and 6a-H), 4.68 (1H, d, J¼16.2 Hz, CH2Ph), 4.75 (1H, d,
J¼16.2 Hz, CH2Ph), 5.60 (1H, br s, exchanged with D2O,
NH), 6.96 (1H, ddd, J¼1.3, 6.9, 6.9 Hz, 70-H), 7.24–7.37
(19H, ov, CH2Ph–H, Ph–H, NPh–H, and 90-H), 7.48 (2H,
dd, J¼1.3, 8.3 Hz, Ph–H), 7.63 (1H, ddd, J¼2.0, 6.9,
8.6 Hz, 80-H), 8.85 (1H, br d, J¼6.9 Hz, 60-H); 13C NMR
(CDCl3): 49.9, 53.35, 53.44, 53.8, 59.9, 76.2, 93.7, 113.8,
124.7, 126.1, 126.7, 126.8, 127.3, 127.7, 128.1, 128.6,
132.3, 134.9, 136.4, 137.3, 148.1, 159.4, 164.6, 173.3,
174.0, 174.9. Anal. calcd for C42H35N5O5 (689.76):
C, 73.13; H, 5.11; N, 10.15. Found: C, 72.84; H, 5.12;
N, 10.10.
4.4.2. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-[2-(N,N-di-
methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (9a). White crystals from hexane/ethyl acetate;
mp 229–230 ꢀC; 1H NMR (CDCl3): 3.17 (6H, s, N(CH3)2),
3.71–3.79 (4H, ov, 3a-H and CO2CH3), 4.51 (1H, dd,
J¼9.2, 12.2 Hz, 3-H), 4.76 (1H, d, J¼7.9 Hz, 6a-H), 5.55
(1H, br d, J¼12.2 Hz, exchanged with D2O, NH), 6.91
(1H, ddd, J¼1.3, 6.9, 6.9 Hz, 70-H), 7.28–7.40 (9H, ov,
90-H, Ph–H, and NPh–H), 7.51–7.65 (3H, ov, 80-H and
Ph–H), 8.79 (1H, dd, J¼1.0, 6.9 Hz, 60–H); 13C NMR
(CDCl3): 41.5, 49.9, 53.5, 53.9, 60.4, 76.4, 91.6, 113.2,
124.5, 126.1, 126.6, 126.7, 128.0, 128.1, 128.5, 132.3,
134.8, 136.2, 148.2, 159.1, 164.6, 173.9, 174.7. Anal. calcd
for C30H27N5O5 (537.57): C, 67.03; H, 5.06; N, 13.03.
Found: C, 67.01; H, 5.19; N, 12.89.
4.4.6. (1R*,3R*,3aS*,6aR*)-( )-Methyl 3-[2-(pyrrolidin-
1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-4,6-dioxo-
1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-carboxyl-
ate (8c). This compound was obtained as a (1:1) molecular
complex with ethyl acetate after recrystallization. White
crystals from hexane/ethyl acetate; mp 223–224 ꢀC; IR
(KBr): 3296 (NH), 1740, 1709, 1655, 1630 (CO); 1H
NMR (CDCl3): 1.26 (3H, t, J¼7.3 Hz, CH3CO2CH2CH3),
1.77–1.85 (4H, br m, N(CH2CH2)2), 2.04 (3H, s,
CH3CO2CH2CH3), 3.42 (1H, dd, J¼8.3, 9.2 Hz, 3a-H),
3.51–3.52 (4H, br m, N(CH2CH2)2), 3.78 (3H, s,
CO2CH3), 4.12 (2H, q, J¼7.3 Hz, CH3CO2CH2CH3), 4.36
(1H, d, J¼8.3 Hz, 6a-H), 4.48 (1H, dd, J¼9.2, 12.9 Hz,
3-H), 5.76 (1H, br d, J¼12.9 Hz, exchanged with D2O,
NH), 6.80 (1H, ddd, J¼1.3, 6.9, 6.9 Hz, 70-H), 7.21–7.54
(10H, ov, 80-H, 90-H, Ph–H, and NPh–H), 7.78 (2H, dd,
J¼1.0, 7.9 Hz, Ph–H), 8.78 (1H, dd, J¼1.0, 6.9 Hz, 60-H);
13C NMR (CDCl3): 14.2, 21.1, 25.6, 50.28, 50.33, 53.0,
56.7, 59.1, 60.4, 74.0, 89.1, 112.4, 124.3, 127.0, 127.4,
128.1, 128.3, 128.4, 128.9, 132.6, 136.0, 139.5, 148.3,
158.8, 160.5, 170.7, 171.2, 175.1, 175.6. Anal. calcd for
C36H37N5O7 (651.71): C, 66.35; H, 5.72; N, 10.75. Found:
C, 66.30; H, 5.79; N, 10.67.
4.4.3. (1R*,3S*,3aS*,6aR*)-( )-Methyl 3-[2-(N,N-di-
methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (10a). Although this compound could not be
isolated in a pure form, the structure was estimated on com-
parison with 1H and 13C NMR spectroscopic data of prolines
8a and 9a. Colorless prisms from hexane/benzene; mp 231–
232 ꢀC; 1H NMR (CDCl3): 3.23 (6H, s, N(CH3)2), 3.62 (3H,
s, CO2CH3), 4.12 (1H, d, J¼10.6 Hz, 6a-H), 4.23 (1H, br d,
J¼11.9 Hz, exchanged with D2O, NH), 4.47 (1H, dd, J¼7.3,
10.6 Hz, 3a-H), 4.85 (1H, dd, J¼7.3, 11.9 Hz, 3-H), 6.88
(1H, ddd, J¼1.0, 6.6, 7.9 Hz, 70-H), 7.32–7.48 (9H, ov,
90-H, Ph–H, and NPh–H), 7.57 (1H, ddd, J¼1.2, 6.6,
8.9 Hz, 80-H), 7.88 (2H, d, J¼6.93 Hz, Ph–H), 8.74 (1H,
dd, J¼1.2, 7.9 Hz, 60-H); 13C NMR (CDCl3): 41.3, 51.4,
53.1, 58.4, 59.9, 77.2, 92.7, 113.0, 124.8, 126.5, 126.7,
127.1, 128.1, 128.3, 128.5, 129.0, 132.5, 136.2, 140.3,
148.5, 158.6, 163.7, 172.4, 175.4, 177.2.

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1639
4.4.7. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-[2-(pyrrolidin-
1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-4,6-dioxo-
1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-carboxyl-
ate (9c). Colorless crystals from i-PrOH/benzene; mp
223–224 ꢀC; 1H NMR (CDCl3): 1.87–2.04 (4H, br m,
N(CH2CH2)2), 3.67–3.79 (8H, ov, CO2CH3, 3a-H, and
N(CH2CH2)2), 4.64 (1H, dd, J¼9.2, 12.2 Hz, 3-H), 4.74
(1H, d, J¼7.9 Hz, 6a-H), 5.76 (1H, br d, J¼12.2 Hz, ex-
changed with D2O, NH), 6.84 (1H, ddd, J¼1.3, 6.9, 6.9 Hz,
70-H), 7.24–7.40 (9H, ov, 90-H, Ph–H, and NPh–H), 7.51–
7.58 (3H, ov, 80-H and Ph–H), 8.76 (1H, dd, J¼1.0, 6.9 Hz,
60-H); 13C NMR (CDCl3): 25.8, 50.4, 50.7, 53.6, 54.1,
60.0, 89.3, 112.6, 124.4, 126.3, 126.8, 128.1, 128.2, 128.6,
132.5, 135.0, 136.0, 148.3, 158.9, 160.9, 174.0, 174.2,
174.9. Anal. calcd for C32H29N5O5 (563.60): C, 68.19; H,
5.19; N, 12.43. Found: C, 68.03; H, 5.33; N, 12.71.
(1H, br d, J¼12.2 Hz, exchanged with D2O, NH), 7.01
(1H, ddd, J¼1.0, 6.9, 7.1 Hz, 70-H), 7.25–7.45 (9H, ov,
90-H, NPh–H, and Ph–H), 7.53 (2H, dd, J¼1.7, 7.9 Hz,
Ph–H), 7.67 (1H, ddd, J¼1.3, 7.1, 8.3 Hz, 80-H), 8.83 (1H,
dd, J¼1.3, 6.9 Hz, 60-H); 13C NMR (CDCl3): 49.9, 50.4,
53.7, 53.9, 59.9, 66.9, 95.0, 114.4, 125.1, 126.2, 126.7,
128.2, 128.3, 128.34, 128.7, 132.3, 134.6, 136.6, 148.9,
159.5, 164.7, 173.8, 174.7. Anal. calcd for C32H29N5O6
(579.60): C, 66.31; H, 5.04; N, 12.08. Found: C, 66.32;
H, 5.13; N, 11.95.
4.4.11. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-[2-(N,N-dime-
thylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-4,6-
dioxo-5-phenylperhydropyrrolo[3,4-c]-pyrrole-1-carb-
oxylate (8e). White crystals from CH2Cl2/benzene; mp
246–247 ꢀC; IR (KBr): 3298 (NH), 1740, 1701, 1651,
1630 (CO); 1H NMR (CDCl3): 3.14 (6H, s, N(CH3)2), 3.59
(1H, dd, J¼8.6, 8.9 Hz, 6a-H), 3.83–3.89 (4H, ov,
CO2CH3 and 3a-H), 4.08 (1H, dd, J¼7.3, 13.2 Hz, 3-H),
4.57 (1H, dd, J¼8.9, 13.2 Hz, 1-H), 4.79 (1H, dd, J¼13.2,
13.2 Hz, exchanged with D2O, NH), 6.89 (1H, ddd, J¼1.3,
6.6, 6.6 Hz, 70-H), 7.31–7.45 (6H, ov, 90-H and NPh–H),
7.58 (1H, ddd, J¼1.7, 6.6, 7.8 Hz, 80-H), 8.79 (1H, br d,
J¼6.6 Hz, 60-H); 13C NMR (CDCl3): 41.7, 49.3, 51.4,
52.4, 61.9, 63.1, 91.6, 113.2, 124.6, 126.9, 127.0, 128.4,
128.9, 132.5, 136.3, 148.4, 159.0, 164.7, 169.8, 175.0,
175.4. Anal. calcd for C24H23N5O5 (461.47): C, 62.46; H,
5.02; N, 15.18. Found: C, 62.35; H, 4.92; N, 15.16.
4.4.8. (1R*,3S*,3aS*,6aR*)-( )-Methyl 3-[2-(pyrrolidin-
1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-4,6-dioxo-
1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-carboxyl-
ate (10c). Colorless crystals from i-PrOH/benzene; mp 217–
218 ꢀC; 1H NMR (CDCl3): 1.86–1.96 (4H, br m,
N(CH2CH2)2), 3.61 (3H, s, CO2CH3), 3.80–3.83 (4H, br m,
N(CH2CH2)2), 4.15 (1H, d, J¼10.2 Hz, 6a-H), 4.37 (1H, br
d, J¼8.3 Hz, exchanged with D2O, NH), 4.55 (1H, dd,
J¼6.9, 10.2 Hz, 3a-H), 5.15 (1H, br s, 3-H), 6.81 (1H, ddd,
J¼1.3, 7.3, 7.3 Hz, 70-H), 7.25–7.57 (10H, ov, 80-H, 90-H,
Ph–H, and NPh–H), 7.88 (2H, d, J¼6.9 Hz, Ph–H), 8.70
(1H, br d, J¼7.3 Hz, 60-H); 13C NMR (CDCl3): 26.2, 50.8,
52.1, 53.5, 58.9, 59.3, 91.5, 112.8, 125.0, 126.2, 127.1,
127.6, 128.5, 128.8, 129.0, 129.5, 132.9, 136.4, 140.8,
148.9, 158.8, 160.0, 173.1, 175.9, 177.9. Anal. calcd for
C32H29N5O5 (563.60): C, 68.19; H, 5.19; N, 12.43. Found:
C, 68.09; H, 5.33; N, 12.24.
4.4.12. (1R*,3R*,3aR*,6aS*)-( )-Methyl 3-[2-(N,N-di-
methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-
4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyrrole-1-
carboxylate (10e). Colorless crystals from benzene/i-PrOH;
mp 226–227 ꢀC; 1H NMR (CDCl3): 3.16 (6H, s, N(CH3)2),
3.65 (1H, dd, J¼8.6, 8.9 Hz, 6a-H), 3.82 (3H, s, CO2CH3),
3.99 (1H, dd, J¼1.0, 8.6 Hz, 3a-H), 4.63 (1H, br s, 3-H),
4.74–4.77 (2H, ov, NH and 1-H), 6.87 (1H, ddd, J¼1.3,
6.9, 6.9 Hz, 70-H), 7.30–7.48 (6H, ov, 90-H and NPh–H),
7.57 (1H, ddd, J¼1.7, 6.9, 6.9 Hz, 80-H), 8.71 (1H, br d,
J¼6.9 Hz, 60-H); 13C NMR (CDCl3): 41.6, 48.9, 52.1,
52.7, 62.0, 63.4, 90.9, 113.2, 124.6, 126.6, 126.8, 128.3,
128.9, 132.6, 136.2, 148.3, 159.0, 164.5, 172.7, 175.5,
177.1. Anal. calcd for C24H23N5O5 (461.47): C, 62.46; H,
5.02; N, 15.18. Found: C, 62.51; H, 4.96; N, 14.88.
4.4.9. (1R*,3R*,3aS*,6aR*)-( )-Methyl 3-(2-morpholino-
4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-4,6-dioxo-1,5-di-
phenylperhydropyrrolo[3,4-c]pyrrole-1-carboxylate
(8d). This compound was obtained as a (2:1) molecular com-
plex with benzene after recrystallization. White powders
from hexane/benzene; mp 196–197 ꢀC; IR (KBr): 3267
1
(NH), 1734, 1714, 1659, 1632 (CO); H NMR (CDCl3):
3.28–3.59 (9H, ov, N(CH2CH2)2O and 3a-H), 3.79 (3H, s,
CO2CH3), 4.29 (1H, dd, J¼9.2, 13.2 Hz, 3-H), 4.39 (1H, d,
J¼7.9 Hz, 6a-H), 5.36 (1H, d, J¼13.2 Hz, exchanged with
D2O, NH), 6.98 (1H, ddd, J¼1.0, 6.9, 6.9 Hz, 70-H), 7.33–
7.50 (12H, ov, 90-H, NPh–H, Ph–H, and 1/2C6H6), 7.64
(1H, ddd, J¼1.7, 6.6, 6.6 Hz, 80-H), 7.75 (2H, dd, J¼1.3,
7.6 Hz, Ph–H), 8.82 (1H, br d, J¼6.9 Hz, 60-H); 13C NMR
(CDCl3): 49.7, 50.4, 53.1, 55.9, 59.0, 66.7, 94.6, 114.3,
125.0, 126.9, 127.0, 127.1, 128.3, 128.46, 128.54, 128.9,
132.5, 136.5, 139.2, 149.0, 159.4, 164.7, 170.6, 175.0,
175.4. Anal. calcd for C35H32N5O6 (618.66): C, 67.95; H,
5.21; N, 11.32. Found: C, 67.98; H, 5.23; N, 11.23.
4.4.13. (1R*,3S*,3aR*,6aS*)-( )-Methyl 1-methyl-3-[2-
(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-
3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyrrole-
1-carboxylate (8f). Colorless crystals from i-PrOH/benz-
ene; mp 245–246 ꢀC; IR (KBr): 3286 (NH), 1736, 1705,
1
1655, 1630 (CO); H NMR (CDCl3): 1.62 (3H, s, CH3),
3.12 (6H, s, N(CH3)2), 3.54 (1H, d, J¼8.3 Hz, 6a-H), 3.66
(1H, dd, J¼8.3, 9.2 Hz, 3a-H), 3.85 (3H, s, CO2CH3), 4.75
(1H, dd, J¼9.2, 13.2 Hz, 3-H), 5.29 (1H, br d, J¼13.2 Hz,
exchanged with D2O, NH), 6.86 (1H, ddd, J¼1.3, 6.6,
6.9 Hz, 70-H), 7.26–7.44 (7H, ov, 90-H and NPh–H), 7.56
(1H, ddd, J¼1.0, 6.9, 8.2 Hz, 80-H), 8.78 (1H, dd, J¼1.0,
6.6 Hz, 60-H); 13C NMR (CDCl3): 24.2, 41.6, 49.3,
52.7, 57.9, 60.2, 68.3, 91.6, 113.1, 124.5, 126.9, 127.0,
128.3, 128.8, 132.5, 136.2, 148.3, 159.0, 164.7, 172.1,
175.0, 175.3. Anal. calcd for C25H25N5O5 (475.50):
C, 63.15; H, 5.30; N, 14.73. Found: C, 63.39; H, 5.32;
N, 14.68.
4.4.10. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-(2-morpho-
lino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-4,6-dioxo-
1,5-diphenylperhydropyrrolo[3,4-c]pyrrole-1-carboxyl-
ate (9d). Colorless crystals from i-PrOH/benzene; mp
213–214 ꢀC; 1H NMR (CDCl3): 3.46–3.60 (4H, ov,
N(CH2CH2)2O), 3.67 (1H, dd, J¼7.9, 8.9 Hz, 3a-H), 3.77–
3.83 (7H, ov, CO2CH3 and N(CH2CH2)2O), 4.53 (1H, dd,
J¼8.9, 12.2 Hz, 3-H), 4.76 (1H, d, J¼7.9 Hz, 6a-H), 5.34

1640
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
4.4.14. (1R*,3R*,3aS*,6aR*)-( )-Methyl 1-methyl-3-[2-
(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-
3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyrrole-
1-carboxylate (9f). Although this compound could not be
isolated in a pure form, the structure was elucidated from
its H NMR spectroscopic data. H NMR (CDCl3): 1.78
(3H, s, CH3), 3.14 (6H, s, N(CH3)2), 3.66 (1H, dd, J¼8.3,
9.2 Hz, 3a-H), 3.83 (3H, s, CO2CH3), 4.10 (1H, d,
J¼8.3 Hz, 6a-H), 4.60 (1H, d, J¼9.2 Hz, 3-H), 6.88 (1H,
ddd, J¼1.3, 6.9, 6.9 Hz, 70-H), 7.30–7.47 (6H, ov, 90-H
and Ph–H), 7.57 (1H, ddd, J¼1.3, 6.9, 8.6 Hz, 80-H), 8.72
(1H, br d, J¼6.9 Hz, 60-H).
with D2O, NH), 6.83 (1H, ddd, J¼1.3, 7.3, 7.3 Hz, 70-H),
7.23–7.42 (11H, ov, 90-H, NPh–H, and CH2Ph–H), 7.54
(1H, ddd, J¼1.3, 7.3, 8.6 Hz, 80-H), 8.76 (1H, dd, J¼1.3,
7.3 Hz, 60-H); 13C NMR (CDCl3): 41.7, 42.4, 49.8, 52.6,
57.7, 60.3, 72.8, 92.4, 113.1, 124.5, 126.95, 127.0, 128.2,
128.3, 128.8, 130.3, 132.5, 136.2, 136.6, 148.4, 158.7,
165.0, 171.2, 175.0, 175.4. Anal. calcd for C31H29N5O5
(551.59): C, 67.50; H, 5.30; N, 12.70. Found: C, 67.49; H,
5.28; N, 12.72.
1
1
4.4.18. (1R*,3R*,3aS*,6aR*)-( )-Methyl 1-benzyl-3-[2-
(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-
3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyrrole-
1-carboxylate (9h). Colorless crystals from i-PrOH/benz-
ene; mp 229–230 ꢀC; 1H NMR (CDCl3): 3.12 (7H, ov,
N(CH3)2 and CH2Ph), 3.59–3.67 (4H, ov, CO2CH3 and
3a-H), 3.93 (1H, d, J¼14.2 Hz, CH2Ph), 4.22 (1H, d,
J¼8.3 Hz, 6a-H), 4.56 (1H, dd, J¼9.2, 12.2 Hz, 3-H), 4.78
(1H, br d, J¼12.2 Hz, exchanged with D2O, NH), 6.90
(1H, ddd, J¼1.0, 7.3, 7.3 Hz, 70-H), 7.18–7.62 (12H, ov,
80-H, 90-H, NPh–H, and CH2Ph–H), 8.75 (1H, br d,
J¼7.3 Hz, 60-H); 13C NMR (CDCl3): 40.7, 41.4, 49.9, 52.4,
53.9, 60.9, 74.5, 91.8, 113.1, 124.6, 126.7, 126.8, 126.9,
128.3, 128.4, 128.9, 129.8, 132.5, 136.1, 136.5, 148.1,
158.9, 164.4, 173.6, 175.1, 175.13. Anal. calcd for
C31H29N5O5 (551.59): C, 67.50; H, 5.30; N, 12.70. Found:
C, 67.33; H, 5.18; N, 12.60.
4.4.15. (1R*,3S*,3aR*,6aS*)-( )-Methyl 1-isopropyl-3-
[2-(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyr-
role-1-carboxylate (8g). White powders from hexane/
i-PrOH; mp 205–206 ꢀC; IR (KBr): 3307 (NH), 1736,
1701, 1655, 1630 (CO); 1H NMR (CDCl3): 1.15 (6H, br d,
J¼6.6 Hz, CH(CH3)2), 2.38 (1H, br m, CH(CH3)2), 3.17
(6H, s, N(CH3)2), 3.70–3.79 (2H, ov, 3a-H and 6a-H), 3.86
(3H, s, CO2CH3), 4.82 (1H, dd, J¼8.9, 12.2 Hz, 3-H), 4.99
(1H, br d, J¼12.2 Hz, exchanged with D2O, NH), 6.84
(1H, ddd, J¼1.0, 6.9, 6.9 Hz, 70-H), 7.23–7.41 (6H, ov,
90-H and NPh–H), 7.55 (1H, ddd, J¼1.7, 6.9, 8.6 Hz, 80-H),
8.79 (1H, br d, J¼6.9 Hz, 60-H); 13C NMR (CDCl3): 17.9,
18.5, 35.0, 41.6, 50.7, 52.5, 55.2, 61.1, 75.6, 92.3, 113.0,
124.5, 127.0, 128.25, 128.28, 128.8, 132.5, 136.1, 148.3,
158.6, 164.6, 172.1, 175.1, 176.0. Anal. calcd for
C27H29N5O5 (503.55): C, 64.40; H, 5.80; N, 13.91. Found:
C, 64.09; H, 5.83; N, 13.86.
4.4.19. (1R*,3S*,3aR*,6aS*)-( )-Methyl 3-[2-(N,N-dime-
thylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-1-(2-
methylthio)ethyl-4,6-dioxo-5-phenylperhydropyr-
rolo[3,4-c]pyrrole-1-carboxylate (8i). Colorless crystals
from i-PrOH/benzene; mp 240–241 ꢀC; IR (KBr): 3298
4.4.16. (1R*,3R*,3aS*,6aR*)-( )-Methyl 1-isopropyl-3-
[2-(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyr-
role-1-carboxylate (9g). This compound was obtained as
a (1:1) molecular complex with benzene after recrystalliza-
tion. Colorless crystals from hexane/benzene; mp 122–
123 ꢀC; IR (KBr): 3278 (NH), 1747, 1704, 1650, 1625
(CO); 1H NMR (CDCl3): 1.13 (3H, d, J¼6.6 Hz,
CH(CH3)2), 1.20 (3H, d, J¼6.6 Hz, CH(CH3)2), 2.68 (1H,
m, CH(CH3)2), 3.13 (6H, s, N(CH3)2), 3.63 (1H, dd, J¼8.6,
8.6 Hz, 3a-H), 3.84 (3H, s, CO2CH3), 4.37–4.44 (2H, ov,
3-H and 6a-H), 4.63 (1H, br s, exchanged with D2O, NH),
6.85 (1H, dd, J¼6.9, 6.9 Hz, 70-H), 7.26–7.46 (12H, ov,
90-H, NPh–H, and C6H6), 7.54 (1H, ddd, J¼0.7, 6.9,
8.3 Hz, 80-H), 8.73 (1H, br d, J¼6.9 Hz, 60-H); 13C NMR
(CDCl3): 19.0, 20.0, 32.2, 41.5, 50.0, 52.6, 53.2, 60.6, 78.1,
91.9, 113.1, 124.5, 126.7, 126.9, 128.3, 128.8, 132.6,
136.1, 148.2, 158.9, 164.5, 173.6, 175.1, 175.3. Anal. calcd
for C33H35N5O5 (581.66): C, 68.14; H, 6.07; N, 12.04.
Found: C, 68.04; H, 6.00; N, 12.19.
1
(NH), 1734, 1701, 1653, 1630 (CO); H NMR (CDCl3):
1.96 (1H, m, CH2CH2SCH3), 2.14 (3H, s, SCH3), 2.39 (1H,
m, CH2CH2SCH3), 2.54 (1H, m, CH2CH2SCH3), 2.68 (1H,
m, CH2CH2SCH3), 3.16 (6H, s, N(CH3)2), 3.52 (1H, d,
J¼8.3 Hz, 6a-H), 3.63 (1H, dd, J¼8.3, 8.9 Hz, 3a-H), 3.87
(3H, s, CO2CH3), 4.64 (1H, dd, J¼8.9, 12.5 Hz, 3-H), 5.15
(1H, br d, J¼12.5 Hz, exchanged with D2O, NH), 6.87
(1H, ddd, J¼1.0, 6.9, 6.9 Hz, 70-H), 7.31–7.43 (6H, ov,
90-H and NPh–H), 7.56 (1H, ddd, J¼1.0, 6.9, 8.3 Hz, 80-H),
8.78 (1H, dd, J¼1.0, 6.9 Hz, 60-H); 13C NMR (CDCl3):
15.7, 29.0, 35.9, 41.7, 49.2, 52.9, 57.8, 60.0, 71.7, 91.6,
113.2, 124.6, 127.0, 128.4, 128.9, 132.5, 136.3, 148.4,
159.0, 164.9, 171.0, 174.9, 175.0. Anal. calcd for
C27H29N5O5S (535.62): C, 60.55; H, 5.46; N, 13.08. Found:
C, 60.74; H, 5.39; N, 13.09.
4.4.20. (1R*,3R*,3aS*,6aR*)-( )-Methyl 3-[2-(N,N-dime-
thylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-1-(2-
methylthio)ethyl-4,6-dioxo-5-phenylperhydropyr-
rolo[3,4-c]pyrrole-1-carboxylate (9i). Colorless needle
1
4.4.17. (1R*,3S*,3aR*,6aS*)-( )-Methyl 1-benzyl-3-[2-
(N,N-dimethylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-
3-yl]-4,6-dioxo-5-phenylperhydropyrrolo[3,4-c]pyrrole-
1-carboxylate (8h). White crystals from benzene/i-PrOH;
mp 215–216 ꢀC; IR (KBr): 3298 (NH), 1741, 1701, 1649,
1630 (CO); 1H NMR (CDCl3): 3.09 (6H, s, N(CH3)2), 3.19
(1H, d, J¼13.9 Hz, CH2Ph), 3.36 (1H, d, J¼13.9 Hz,
CH2Ph), 3.61 (1H, dd, J¼8.6, 9.2 Hz, 3a-H), 3.74 (1H, d,
J¼8.6 Hz, 6a-H), 3.84 (3H, s, CO2CH3), 4.67 (1H, dd,
J¼9.2, 12.5 Hz, 3-H), 5.12 (1H, br d, J¼12.5 Hz, exchanged
crystals from i-PrOH/benzene; mp 175–176 ꢀC; H NMR
(CDCl3): 2.12 (3H, s, SCH3), 2.34 (1H, m, CH2CH2SCH3),
2.46–2.66 (2H, ov, CH2CH2SCH3), 2.88 (1H, m,
CH2CH2SCH3), 3.14 (6H, s, N(CH3)2), 3.67 (1H, dd,
J¼8.2, 9.2 Hz, 3a-H), 3.85 (3H, s, CO2CH3), 4.17 (1H, d,
J¼8.2 Hz, 6a-H), 4.53 (1H, d, J¼9.2 Hz, 3-H), 4.65 (1H,
br s, exchanged with D2O, NH), 6.88 (1H, ddd, J¼1.3,
6.6, 6.6 Hz, 70-H), 7.30–7.46 (6H, ov, 90-H and NPh–H),
7.57 (1H, ddd, J¼2.0, 6.6, 8.6 Hz, 80-H), 8.72 (1H, br
d, J¼6.6 Hz, 60-H); 13C NMR (CDCl3): 15.4, 29.8, 34.5,

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1641
41.5, 50.0, 52.9, 53.1, 60.5, 73.1, 91.4, 113.2, 124.6,
126.6, 126.9, 128.4, 128.9, 132.5, 136.2, 148.2, 158.9,
164.5, 173.9, 174.9, 175.1. Anal. calcd for C27H29N5O5S
(535.62): C, 60.55; H, 5.46; N, 13.08. Found: C, 60.55; H,
5.50; N, 12.76.
4.6.3. (1R*,3aR*,6aS*)-( )-Methyl 1,3a,4,5,6,6a-hexa-
hydro-1-isopropyl-4,6-dioxo-5-phenylpyrrolo[3,4-c]pyr-
role-1-carboxylate (12g). Colorless crystals from hexane/
benzene; mp 140–141 ꢀC; IR (KBr): 1749, 1713, 1622
1
(CO), 1597 (CH]N–); H NMR (CDCl3): 0.97 (3H, d,
J¼6.3 Hz, CH(CH3)2), 0.99 (3H, d, J¼5.9 Hz, CH(CH3)2),
2.75 (1H, m, CH(CH3)2), 3.48 (1H, d, J¼8.9 Hz, 6a-H),
3.70 (3H, s, CO2CH3), 4.29 (1H, dd, J¼0.7, 8.9 Hz, 3a-H),
7.24 (2H, m, NPh–H), 7.36–7.60 (3H, ov, NPh–H), 7.84
(1H, d, J¼0.7 Hz, CH]N–); 13C NMR (CDCl3): 16.8,
17.7, 34.1, 47.6, 52.8, 59.8, 91.8, 126.4, 128.9, 129.3, 131.5,
160.7, 170.0, 171.1, 174.7. Anal. calcd for C17H18N2O4
(314.34): C, 64.96; H, 5.77; N, 8.91. Found: C, 64.99; H,
5.77; N, 8.98.
4.5. General procedure for fission reaction of prolines
8a–d and 8f–i
A solution of proline 8a (0.161 g, 0.3 mmol) in acetic acid
(3 mL) was heated at 85 ꢀC for 0.5 h under an aerobic atmo-
sphere. After cooling to room temperature, the mixture was
diluted with dichloromethane (10 mL) and pH was adjusted
to 6–7 with 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 to give 12a
(83%) with hexane/ethyl acetate (1:3) as an eluent and
then 11a (67%) with ethyl acetate as an eluent.
4.6.4. (1R*,3aR*,6aS*)-( )-Methyl 1-benzyl-1,3a,4,5,
6,6a-hexahydro-4,6-dioxo-5-phenylpyrrolo[3,4-c]pyr-
role-1-carboxylate (12h). Colorless crystals from hexane/
benzene; mp 186–187 ꢀC; IR (KBr): 1745, 1716, 1624
1
(CO), 1597 (CH]N–); H NMR (CDCl3): 3.30 (1H, dd,
4.6. General procedure for one-pot three-component
reaction
J¼1.3, 8.7 Hz, 3a-H), 3.51 (2H, s, CH2Ph), 3.57 (1H, d,
J¼8.7 Hz, 6a-H), 3.76 (3H, s, CO2CH3), 7.13–7.50 (10H,
ov, CH2Ph–H and NPh–H), 7.65 (1H, d, J¼1.3 Hz,
CH]N–); 13C NMR (CDCl3): 42.3, 48.8, 53.1, 59.5, 86.9,
126.3, 127.4, 128.3, 129.0, 129.2, 131.1, 131.2, 134.3,
161.8, 170.1, 170.8, 174.5. Anal. calcd for C21H18N2O4
(302.38): C, 69.60; H, 5.01; N, 7.73. Found: C, 69.54; H,
4.98; N, 7.77.
Aldehyde1a(0.109 g,0.5 mmol),(DL)-phenylglycinemethyl
ester 2a (0.107 g, 0.65 mmol), and N-phenylmaleimide
(0.095 g, 0.55 mmol) were combined in acetic acid (5 mL)/
acetonitrile (1 mL) and the mixture was heated at 85 ꢀC
for 3 h. The mixture was evaporated to dryness to give an
oily residue, which was extracted with dichloromethane
(CH2Cl2)/5% aqueous sodium hydrogencarbonate. The
organic layer was dried over anhydrous magnesium sulfate
and the solvent was evaporated. The residue was subjected
to a column chromatography on silica gel to give 12a
(78%) and its diastereomer 12a0 (10%) with hexane/ethyl
acetate (1:1) as an eluent, and then 11a (83%) with ethyl
acetate as an eluent.
4.6.5. (1R*,3aR*,6aS*)-( )-Methyl 1,3a,4,5,6,6a-hexa-
hydro-1-(2-methylthio)ethyl-4,6-dioxo-5-phenylpyr-
rolo[3,4-c]pyrrole-1-carboxylate (12i). Colorless needles
from i-PrOH; mp 132–133 ꢀC; IR (KBr): 1741, 1705,
1618 (CO), 1597 (CH]N–); 1H NMR (CDCl3): 2.04–2.17
(5H, ov, SCH3 and CH2CH2SMe), 2.53–2.65 (2H, ov,
CH2CH2SMe), 3.55 (1H, d, J¼8.9 Hz, 6a-H), 3.70 (3H, s,
CO2CH3), 4.43 (1H, dd, J¼1.3, 8.9 Hz, 3a-H), 7.24 (2H, m,
NPh–H), 7.40–7.58 (3H, ov, NPh–H), 7.82 (1H, d,
J¼1.3 Hz, CH]N–); 13C NMR (CDCl3): 15.6, 28.5, 38.7,
50.6, 53.0, 59.4, 86.8, 126.3, 129.0, 129.3, 131.2, 161.3,
169.5, 170.8, 173.9. Anal. calcd for C17H18N2O4S
(346.40): C, 58.94; H, 5.24; N, 8.09. Found: C, 58.93; H,
5.28; N, 8.08.
4.6.1. (1R*,3aS*,6aR*)-( )-Methyl 1,3a,4,5,6,6a-hexa-
hydro-4,6-dioxo-1,5-diphenylpyrrolo[3,4-c]pyrrole-1-
carboxylate (12a). Colorless needles from i-PrOH; mp 191–
192 ꢀC; IR (KBr): 1747, 1716, 1628 (CO), 1597 (CH]N–);
1H NMR (CDCl3): 3.54 (3H, s, CO2CH3), 3.77 (1H, d,
J¼9.2 Hz, 6a-H), 4.26 (1H, dd, J¼1.3, 9.2 Hz, 3a-H),
7.17–7.42 (8H, ov, Ph–H and NPh–H), 7.52 (2H, dd,
J¼1.3, 7.9 Hz, Ph–H), 7.89 (1H, d, J¼1.3 Hz, CH]N–);
13C NMR (CDCl3): 53.6, 54.0, 59.8, 90.3, 126.5, 126.9,
128.1, 128.4, 128.9, 129.2, 131.5, 140.6, 161.7, 170.0,
171.0, 174.3. Anal. calcd for C20H16N2O4 (348.35):
C, 68.96; H, 4.63; N, 8.04. Found: C, 68.68; H, 4.60;
N, 7.86.
4.6.6. (1R*,3aS*,6aR*)-( )-Methyl 1,3a,4,5,6,6a-hexa-
hydro-5-methyl-4,6-dioxo-1-phenylpyrrolo[3,4-c]pyr-
role-1-carboxylate (12j). Colorless crystals from hexane/
benzene; mp 186–187 ꢀC; IR (KBr): 1738, 1697, 1630
1
(CO), 1603 (CH]N–); H NMR (CDCl3): 3.02 (3H, s,
NCH3), 3.64 (3H, s, CO2CH3), 3.79 (1H, d, J¼8.9 Hz,
6a-H), 4.25 (1H, dd, J¼1.3, 8.9 Hz, 3a-H), 7.34–7.41 (3H,
ov, Ph–H), 7.56–7.59 (2H, m, Ph–H), 7.93 (1H, d, J¼
1.3 Hz, CH]N–); 13C NMR (CDCl3): 25.3, 53.5, 54.0,
59.8, 89.5, 127.0, 128.1, 128.4, 140.5, 161.7, 169.7, 172.0,
175.2. Anal. calcd for C15H14N2O4 (286.28): C, 62.93; H,
4.93; N, 9.79. Found: C, 62.89; H, 4.94; N, 9.76.
4.6.2. (1R*,3aR*,6aS*)-( )-Methyl 1,3a,4,5,6,6a-hexa-
hydro-1-methyl-4,6-dioxo-5-phenylpyrrolo[3,4-c]pyr-
role-1-carboxylate (12f). White powders from ether; mp
138–139 ꢀC; IR (KBr): 1743, 1707, 1620 (CO), 1597
(CH]N–); 1H NMR (CDCl3): 1.68 (3H, s, CH3), 3.39
(1H, d, J¼8.6 Hz, 6a-H), 3.69 (3H, s, CO2CH3), 4.42 (1H,
dd, J¼1.3, 8.6 Hz, 3a-H), 7.21 (2H, m, NPh–H), 7.40–7.50
(3H, ov, NPh–H), 7.73 (1H, d, J¼1.3 Hz, CH]N–);
13C NMR (CDCl3): 25.8, 51.9, 52.9, 59.3, 83.9, 126.3,
128.9, 129.2, 131.2, 160.1, 170.3, 171.0, 174.1. Anal. calcd
for C15H14N2O4 (286.28): C, 62.93; H, 4.93; N, 9.79. Found:
C, 63.12; H, 4.85; N, 9.88.
4.6.7. (1R*,3aR*,6aS*)-( )-Methyl 1-benzyl-1,3a,4,
5,6,6a-hexahydro-5-methyl-4,6-dioxopyrrolo[3,4-c]-
pyrrole-1-carboxylate (12k). Colorless needles from pen-
tane/ethyl ether; mp 104–105 ꢀC; IR (KBr): 1741, 1703,
1
1647 (CO), 1612 (CH]N–); H NMR (CDCl3): 2.89 (3H,
s, NCH3), 3.10 (1H, dd, J¼1.3, 8.3 Hz, 3a-H), 3.41 (1H, d,

1642
K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
J¼8.3 Hz, 6a-H), 3.42 (1H, d, J¼13.9 Hz, CH2Ph), 3.48
(1H, d, J¼13.9 Hz, CH2Ph), 3.75 (3H, s, CO2CH3), 7.12
(2H, m, CH2Ph–H), 7.24–7.29 (3H, ov, CH2Ph–H), 7.56
(1H, d, J¼1.3 Hz, CH]N–); 13C NMR (CDCl3): 25.1, 42.4,
49.0, 52.9, 59.5, 86.0, 127.3, 128.3, 131.1, 134.2, 161.8,
170.1, 171.8, 175.3. Anal. calcd for C16H16N2O4 (300.31):
C, 63.99; H, 5.37; N, 9.33. Found: C, 63.89; H, 5.19; N, 9.45.
47.26 (CH), 47.53 (CH), 53.48 (CO2CH3), 53.68 (CH),
53.71 (CO2CH3), 53.80 (CO2CH3), 53.93 (CO2CH3), 54.22
(CH), 56.34 (CH), 56.73 (CH), 59.89 (CH), 60.88 (CH),
72.38 (quaternary C), 73.59 (quaternary C), 73.87 (quater-
nary C), 75.10 (quaternary C), 89.78 (quaternary C), 90.89
(quaternary C), 163.58 (CH]N–), 163.77 (CH]N–),
169.65 (C]O), 169.88 (C]O), 171.81 (C]O), 172.18
(C]O), 173.10 (C]O), 173.31 (C]O), 173.37 (C]O),
173.60 (C]O), 173.66 (C]O), 174.23 (C]O), 174.54
(C]O). Anal. calcd for C40H32N4O8 (696.70): C, 68.96;
H, 4.63; N, 8.04. Found: C, 68.90; H, 4.47; N, 7.91. MS
(FAB): m/z 697 (MH+), 637, 349 (1/2MH+, base peak), 289.
4.6.8. 2-(N,N-Dimethylamino)pyrido[1,2-a]pyrimidin-
4(4H)-one (11a). This compound has been already prepared
and its physical and spectroscopic data are provided in the
literature.13
4.6.9. 2-(N,N-Dibenzylamino)pyrido[1,2-a]pyrimidin-
4(4H)-one (11b). Colorless needles from hexane/i-PrOH;
mp 152–153 ꢀC; 1H NMR (CDCl3): 4.80 (4H, br s, CH2Ph),
5.62 (1H, s, 3-H), 6.83 (1H, ddd, J¼1.3, 6.9, 6.9 Hz, 7-H),
7.17–7.34 (11H, ov, 9-H and CH2Ph–H), 7.54 (1H, ddd,
J¼1.7, 6.9, 8.6 Hz, 8-H), 8.88 (1H, br d, J¼6.9 Hz, 6-H);
13C NMR (CDCl3): 50.5, 81.2, 112.4, 124.5, 127.2, 127.4,
127.6, 128.7, 136.3, 137.3, 150.6, 158.6, 161.3. Anal. calcd
for C22H19N3O (341.41): C, 77.40; H, 5.61; N, 12.31. Found:
C, 77.52; H, 5.59; N, 12.34.
References and notes
1. (a) Obst, U.; Betschmann, P.; Lemer, C.; Seiler, P.; Diederich,
€
F.; Gramilich, V.; Weber, L.; Banner, D. W.; Schonholzer, P.
Helv. Chim. Acta 2000, 83, 855–909; (b) Pearson, W. H.
Studies in Natural Products Chemistry; Atta-Rahman, Ed.;
Elsevier: New York, NY, 1998; Vol. 1, pp 322–358; (c)
Gribble, G. W. Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, UK, 1996; Vol. 2, pp 207–257.
4.6.10. 2-(Pyrrolidin-1-yl)pyrido[1,2-a]pyrimidin-4(4H)-
one (11c). This compound has already been prepared and
its physical and spectroscopic data are provided in our pre-
vious paper.8
2. (a) Grigg, R.; Kemp, J. J. Chem. Soc., Chem. Commun. 1977,
125–126; (b) Grigg, R.; Kemp, J. J. Chem. Soc., Chem.
Commun. 1978, 109–111; (c) Grigg, R.; Kemp, J.
Tetrahedron Lett. 1978, 19, 2823–2826.
3. (a) Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. J. Chem. Soc.,
Perkin Trans. 1 1984, 41–46; (b) For a review, see: Grigg, R.
Chem. Soc. Rev. 1987, 16, 89–121; (c) Grigg, R.; Donegan,
G.; Gunaratne, H. Q. N.; Kennedy, D. A.; Malone, J. F.;
Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45,
1723–1746; (d) Grigg, R.; Malone, J. F.; Mongkolaussa-
varatana, T.; Thianpatanagul, S. Tetrahedron 1989, 45, 3849–
3862; (e) Grigg, R.; Armstrong, P. Tetrahedron 1989, 45,
7581–7586; (f) Ardill, H.; Dorrity, M. J. R.; Grigg, R.; Leon-
Ling, M.-S.; Malone, J. F.; Sridharan, V.; Thianpatanagul, S.
Tetrahedron 1990, 46, 6433–6448; (g) Grigg, R.; Rankovic,
Z.; Thornton-Pett, M.; Somasunderam, A. Tetrahedron 1993,
49, 8679–8690; (h) Grigg, R.; McMeekin, P.; Sridharan, V.
Tetrahedron 1995, 51, 13331–13346; (i) Grigg, R.; McMeekin,
P.; Sridharan, V. Tetrahedron 1995, 51, 13347–13356. Also see
references cited therein.
4. (a) For a recent review, see: Komatsu, M.; Minakata, S.;
Oderaotoshi, Y. ARKIVOC 2006, 7, 370–389; (b) Komatsu,
M.; Ohno, M.; Tsuno, S.; Ohshiro, Y. Chem. Lett. 1990, 19,
575–576; (c) Ohno, M.; Komatsu, M.; Miyata, H.; Ohshiro,
Y. Tetrahedron Lett. 1991, 32, 5813–5816; (d) Komatsu, M.;
Okada, H.; Akaki, T.; Oderaotoshi, Y.; Minakata, S. Org.
Lett. 2002, 4, 3505–3508; (e) Okada, H.; Akaki, T.;
Oderaotoshi, Y.; Minakata, S.; Komatsu, M. Tetrahedron
2003, 59, 197–205; (f) Komatsu, M.; Okada, H.; Yokoi, S.;
Minakata, S. Tetrahedron Lett. 2003, 44, 1603–1606; (g)
Komatsu, M.; Kasano, Y.; Yonemori, J.; Oderaotoshi, Y.;
Minakata, S. Chem. Commun. 2006, 526–528. Also see refer-
ences cited therein.
4.6.11. 2-Morpholinopyrido[1,2-a]pyrimidin-4(4H)-one
(11d). Colorless needles from i-PrOH; mp 188–189 ꢀC; 1H
NMR (CDCl3): 3.65–3.68 (4H, ov, N(CH2CH2)2O), 3.78–
3.81 (4H, ov, N(CH2CH2)2O), 5.62 (1H, s, 3-H), 6.89 (1H,
ddd, J¼1.3, 6.9, 6.9 Hz, 7-H), 7.28 (1H, m, 9-H), 7.59
(1H, ddd, J¼2.0, 6.9, 8.9 Hz, 8-H), 8.90 (1H, br d,
J¼6.9 Hz, 6-H); 13C NMR (CDCl3): 44.6, 66.6, 81.3,
112.7, 124.4, 127.6, 136.5, 150.6, 158.7, 161.1. Anal. calcd
for C12H13N3O2 (231.25): C, 62.33; H, 5.67; N, 18.17.
Found: C, 62.13; H, 5.80; N, 18.06.
4.7. Procedure for dimerization of dehydroproline 12a
A solution of dehydroproline 12a (0.174 g, 0.5 mmol) and
pyridinium p-toluenesulfonate (0.126 g, 0.5 mmol) in meth-
anol (5 mL) was heated under reflux for 15 h. The resulting
precipitates were filtrated to give dimer 13 (0.165 g, 92%).
This compound existed in two isomeric mixture (1:1 ratio) in
1
CDCl3 solution. Their selected H and 13C NMR spectral
data are provided as following.
4.7.1. Methyl 3a-(1-methoxycarbonyl-4,6-dioxo-1,5-di-
phenylperhydropyrrolo[3,4-c]pyrrol-3-yl)-1,3a,4,5,6,6a-
hexahydro-4,6-dioxo-1,5-diphenylpyrrolo[3,4-c]pyrrole-
1-carboxylate (13). Colorless crystals from acetonitrile/
1
MeOH; mp 284–285 ꢀC; H NMR (CDCl3): 2.47 (1H, dd,
J¼6.6, 9.9 Hz, 3a0-H), 3.04–3.11 (2H, ov, NH and 3a0-H),
3.26–3.31 (2H, ov, NH and 6a-H), 3.38 (1H, d, J¼10.9 Hz,
6a-H), 3.60 (1H, s, 6a-H), 3.62 (3H, s, CO2CH3), 3.63
(3H, s, CO2CH3), 3.64 (3H, s, CO2CH3), 3.66 (3H, s,
CO2CH3), 4.09 (1H, dd, J¼3.9, 6.6 Hz, 30-H), 4.41 (1H,
s, 6a-H), 4.62 (1H, t, J¼6.6 Hz, 30-H), 8.07 (1H, s,
CH]N–), 8.26 (1H, s, CH]N–); 13C NMR (CDCl3):
5. (a) A recent review: Kanemasa, S. Synlett 2002, 1371–1387;
(b) Grigg, R.; Gunaratne, H. Q. N. J. Chem. Soc., Chem.
Commun. 1982, 384–386; (c) Amornraksa, K.; Barr, D.;
Donegan, G.; Grigg, R.; Ratananukul, P.; Sridharan, V.
Tetrahedron 1989, 45, 4649–4668; (d) Tsuge, O.; Kanemasa,
S.; Yoshioka, M. J. Org. Chem. 1988, 53, 1384–1391;

K. Kawashima et al. / Tetrahedron 63 (2007) 1630–1643
1643
(e) Grigg, R.; Montgomery, J.; Somasunderam, A. Tetrahedron
ꢀ
1992, 48, 10431–10442; (f) Ayerbe, M.; Arrieta, A.; Cossıo,
F. P. J. Org. Chem. 1998, 63, 1795–1805; (g) Vivanco, S.;
8. Noguchi, M.; Matsumoto, S.; Shirai, M.; Yamamoto, H.
Tetrahedron 2003, 59, 4123–4133.
9. Structures of prolines 8a, 8f, and 8g were confirmed by single-
crystal X-ray structure analysis and their crystallographic data
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 604568
for 8a, CCDC 604569 for 8f, and CCDC 604570 for 8g.
Copies of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
10. (a) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem.
Soc. Jpn. 1986, 59, 1809–1824; (b) Fraga-Dubreuil, J.;
Cherouvrier, J. R.; Bazureau, J. P. Green Chem. 2000, 2,
226–229; (c) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc.
2004, 126, 12776–12777; (d) Bowman, R. K.; Johnson, J. S.
J. Org. Chem. 2004, 69, 8537–8540.
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