Reaction of 2-substituted-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes with electron-deficient olefins and acetylenes

Article abstract of DOI:10.1016/S0040-4020(03)00591-X

A facile oxime-nitrone isomerization through the 1,2-hydrogen shift in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes is discussed. The resultant NH-nitrones are trapped by maleimides to afford intermolecular cycloadducts. The reaction of the oximes with electron-deficient acetylenes undergoes via another path initiated by a nucleophilic attack of the oxime to acetylene moiety.

Full text of DOI:10.1016/S0040-4020(03)00591-X

Tetrahedron 59 (2003) 4113–4121
Reaction of 2-substituted-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde oximes with electron-deficient olefins and acetylenes
Masashi Shirai,a Hidekazu Kuwabara,a Satoshi Matsumoto,a Hidetoshi Yamamoto,a
Akikazu Kakehib and Michihiko Noguchia
,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwagdai, Ube 755-8611, Japan
bDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
Received 27 February 2003; accepted 7 April 2003
Abstract—A facile oxime–nitrone isomerization through the 1,2-hydrogen shift in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde
oximes is discussed. The resultant NH-nitrones are trapped by maleimides to afford intermolecular cycloadducts. The reaction of the oximes
with electron-deficient acetylenes undergoes via another path initiated by a nucleophilic attack of the oxime to acetylene moiety. q 2003
Published by Elsevier Science Ltd.
1. Introduction
intermolecular (1:1) cycloadduct D (Scheme 1). However,
other oximes including some a-keto oximes failed to give
any cycloadducts with NPMI even under more harsh
conditions.
Since the concept of the thermal isomerization of oxime to
nitrone through the 1,2-hydrogen shift was proposed by
Grigg and co-workers in 19841 and the existence of the
resultant NH-nitrone was elucidated by forming intra-
molecular cycloaddition products, extensive investigations
on the synthesis of highly functionalized isoxazolidine
derivatives have been developed by many groups.2 Never-
theless, the application of the resultant NH-nitrones to an
intermolecular cycloaddition reaction with dipolarophiles
has not been accomplished except for one report;1c only the
2-oxime A of 1,2,3-tricarbonyl system underwent 1,5-
proton transfer in refluxing toluene followed by 1,4-proton
transfer leading to the corresponding NH-nitrone C, which
was trapped by N-phenyl maleimide (NPMI) as an
As a part of our projects to generate the NH-1,3-dipoles
through the hydrogen shift and to perform the cycloaddition
reaction of the dipoles,3 we reported recently a facile
hydrazone–azomethine imine isomerization at the
periphery of a heterocyclic system and an intermolecular
cycloaddition reaction of the azomethine imine with
olefinic dipolarophiles.4 Therein, the formation of an
internal hydrogen bond between the NH in the dipole
moiety and the carbonyl oxygen in the heterocyclic system
would be essential for the facile isomerization process
(Scheme 2).
Scheme 1. Reactions. (1) 1,2-H shift; (2) 1,5-H shift; (3) proton transfer; (4) intermolecular cycloaddition reaction.
Keywords: oxime–nitrone isomerization; 1,3-dipolar cycloaddition; Michael addition.
*
Corresponding author. Tel.: þ81-836-85-9261; fax: þ81-836-85-9201; e-mail: noguchi@yamaguchi-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00591-X

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M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
Scheme 2.
In this paper, we want to report the facile oxime–nitrone
isomerization in the above system and the intermolecular
cycloaddition of the nitrone with NPMI. In the reaction of
the oxime with acetylenic dipolarophiles another reaction
pathway will be proposed.
as well as the coupling constants; for example, the relative
configurations among the three methine protons (3-H, 3a-H,
and 6a-H) in 4a were deduced to be all cis on the basis of the
coupling constants (J3–3a¼8.9 Hz, J3a–6a¼7.9 Hz). The
formation of 4a is easily explained by an endo-approaching
cycloadduct to the hydrogen-bonded NH-nitrone 6. While a
similar reaction of oximes 2b and 2c with 3 in benzene gave
two diastereomeric isoxazolidine derivatives (4b and 5b)
and (4c and 5c), respectively, the reaction of oxime 2d with
3 gave 4d as a single product. The relative configurations
among the three methine protons of 5b and 5c were deduced
to be trans–cis from the coupling constants (J3–3a¼6–
7 Hz, J3a – 6a¼7–8 Hz), and the formation of 5 was
responsible for an exo-approach of 3 to the NH-nitrone 6.
These stereochemical assignments were confirmed by
nuclear Overhauser effect (NOE) measurements of similar
systems as described later. A similar reaction of oxime 2a
with N-methyl maleimide (7) under same conditions gave
two diastereomeric isoxazolidine derivatives 8 and 9 in 68
and 4% yields, respectively (Table 1). The stereochemistries
2. Results and discussion
In order to elucidate the scope and features of the oxime–
nitrone isomerization in 4-oxo-4H-pyrido[1,2-a]pyrimi-
dine-3-carbaldehyde system, four oximes 2a–d were
prepared and examined the thermal behavior in the presence
of dipolarophiles (Scheme 3). The reaction of oxime 2a with
NPMI (3) in refluxing benzene for 36 h gave isoxazolidine
derivative 4a in 82% yield as a single product. A similar
reaction in refluxing ethanol or acetonitrile also gave 4a in
66 and 68% yields, respectively. The structure of 4a was
deduced on the basis of analytical and spectroscopic data. Its
stereochemistries were fully characterized by COSY spectra
Scheme 3.
Table 1. Reaction of oximes 2 with maleimides 3 and 7
Run
Oxime
Y
Maleimide
Solvent
Time (h)
Products (yield, %)
1
2
3
4
5
6
7
2a
2a
2a
2b
2c
2d
2a
Pyrrolidin-1-yl
Pyrrolidin-1-yl
Pyrrolidin-1-yl
Morpholino
NBn2
3
3
3
3
3
3
7
Benzene
Ethanol
36
36
24
24
24
24
36
4a (82)
4a (66)
4a (68)
4b (66), 5b (3)
4c (53), 5c (26)
4d (87)
Acetonitrile
Benzene
Benzene
Benzene
Benzene
OEt
Pyrrolidin-1-yl
8 (68), 9 (4)

M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
4115
Figure 1. Selected NOE signal enhancements and coupling constants among the isoxazolidine-ring protons of cycloadducts 8 and 9.
of 8 (endo-adduct) and 9 (exo-adduct) were also confirmed
by the coupling constants as well as NOE measurements
(Fig. 1).
As mentioned above, we have reported that the facile
oxime–nitrone isomerization in 4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde system 2 and the resulting
NH-nitrones 6 are allowed to react with maleimides 3 and 7
to give intermolecular cycloadducts. This is the second
example on the intermolecular cycloaddition of NH-
nitrones, but, unfortunately, other olefinic dipolarophiles
than maleimides 3 and 7 could not trap the NH-nitrone
intermediates similarly to the first example (Scheme 4).1c
To obtain further information on the reaction features, the
reaction of oxime 2a with other olefinic dipolarophiles
such as dimethyl fumarate, dimethyl maleate, and ethyl
acrylate under several conditions were examined; in the
reactions of 2a in benzene under reflux the unreacted 2a was
recovered in more than 90% yields. Similar reactions at
elevated temperature (e.g. in toluene under reflux) gave
mixtures of many products probably due to decomposition
of 2a.
Our next concern was focused on the reaction of NH-
nitrones 6 with acetylenic dipolarophiles; the reaction of
oxime 2a with dimethyl acetylenedicarboxylate (DMAD:
Scheme 4.

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M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
Scheme 5.
10) in benzene under reflux for 2 h gave a (1:1) adduct 11a
(84%) and a trace of 4-oxo-2-(pyrrolidin-1-yl)-4H-
pyrido[1,2-a]pyrimidine-3-carbonitrile (12a). A similar
reaction in ethanol or acetonitrile under reflux gave almost
same results. To obtain more information on the structure of
11a, some chemical conversions of 11a were examined; the
alkaline hydrolysis of 11a gave 3-amino-2-(pyrrolidin-1-
yl)pyrido[1,2-a]pyrimidin-4(4H)-one (13) in 80% yield.
The structure of 13 was also suggested on the basis of
analytical and spectroscopic data and confirmed finally by
an X-ray single crystal analysis. From these findings as well
as the results of the reaction of benzaldoxime and DMAD,5
the structure of 11a was deduced to be 3-oxo-3-[{4-oxo-2-
(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-3-yl}amino]-
methylenesuccinic acid dimethyl ester. The structure of 11a
was confirmed by an alternate synthesis from 13 and
2-ethoxymethylene-3-oxosuccinic acid dimethyl ester (15)
(Scheme 5).
The formation of 11, 18, and 19 was explained by assuming
a nucleophilic attack of oxime to acetylene moiety as shown
in Scheme 6. In the Michael type adduct 20, a Beckmann
type cleavage through path (a) gave carbocation 21 and
enolate 22. The enolate 22 performed a nucleophilic attack
to 21 to give imine 23, which was isomerized to enamine 24.
On the other hand, the elimination of ketone 25 from 20
[path (b)] gave nitrile derivative 12.
3. Conclusion
We have reported the facile oxime–nitrone isomerization
and the second example on the intermolecular cycloaddition
of the resultant NH-nitrones with maleimides. In the
reaction of the oximes with acetylenic dipolarophiles, a
nucleophilic addition of oxime to acetylene moiety was
preferable to the expecting 1,2-hydrogen shift leading to
NH-nitrones. Further investigations on the related chemistry
are under progress and the results will be reported
elsewhere.
The reaction of oxime 2a with dibenzoyl acetylene (16) and
methyl propiolate (17) in refluxing benzene gave 18 and 19,
respectively. A similar reaction of oxime 2b–d with DMAD
(10) also gave 11b–d and 12b–d, respectively. These
results are summarized in Table 2.
4. Experimental
4.1. General
Table 2. Reaction of oximes 2 with electron-deficient acetylenes 10, 16,
and 17
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. Tetramethylsilane was
used as internal standard, and J values are given in Hz.
Runa Oxime
Y
Acetylene Time
(h)
Products
(yield, %)
1
2
3
4
5
6
2a
2b
2c
2d
2a
2a
Pyrrolidin-1-yl 10
2
11a (84), 12a (trace)
Morpholino
NBn2
OEt
Pyrrolidin-1-yl 16
Pyrrolidin-1-yl 17
10
10
10
1.5 11b (79), 12b (trace)
11c (97), 12c (trace)
21 11d (20), 12d (52)
1.5 18 (98), 12a (trace)
2
4
19 (12), 12a (39)
a
Reaction conditions: benzene, reflux.
Scheme 6.

M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
4117
Splitting patterns are indicated as: s, singlet; d, doublet; t,
triplet; q, quadruplet, m, multiplet; br, broad signal; and ov,
overlapping signals. Mass spectra were determined on a
JEOL JMS-SX102A spectrometer. Elemental analyses were
performed on a Yanagimoto MT-5 CHN analyzer. All non-
aqueous reactions were run under positive pressure of argon
or nitrogen. All solvents were dried by standard methods
before use. The progress of reactions was monitored by TLC
(silica gel 60F-254, Merck). Chromatographic purification
was performed with Wakogel C-200 (100–200 mesh, Wako
Pure Chemical Industries) and/or silica gel 60 (230–400
mesh, Merck).
for C23H20N4O2 (384.4): C, 71.86; H, 5.24; N, 14.57.
Found: C, 71.95; H, 5.26; N, 14.47.
4.2.4. 2-Ethoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbaldehyde oxime (2d). 81%; Yellow prisms from
MeOH; mp 214–2168C; IR (KBr): 3240 (OH), 1660,
1620 (CO); 1H NMR (CDCl3): 1.45 (3H, t, J¼7.1 Hz,
OCH2CH3), 4.58 (2H, q, J¼7.1 Hz, OCH2CH3), 7.15 (1H,
ddd, J¼1.3, 6.9, 8.6 Hz, 7-H), 7.51 (1H, ddd, J¼0.7, 1.3,
6.9 Hz, 9-H), 7.79 (1H, ddd, J¼1.7, 6.9, 8.6 Hz, 8-H), 8.54
(1H, s, –CHvN–), 9.17 (1H, ddd, J¼0.7, 1.7, 6.9 Hz, 6-H),
9.79 (1H, br, OH); 13C NMR (CDCl3): 14.67, 63.40, 92.02,
115.17, 124.89, 128.70, 137.75, 143.58, 149.56, 155.90,
165.17. Anal. calcd for C11H12N3O3 (233.3): C, 56.65; H,
4.75; N, 18.02. Found: C, 56.58; H, 4.81; N, 17.95.
4.2. General procedures for the preparation of oximes 2
A solution of 4-oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde (1a: 0.71 g, 2.9 mmol),
hydroxylamine hydrochloride (0.26 g, 1.3 equiv.), and
triethylamine (0.62 mL, 1.5 equiv.) in methanol (MeOH)
(10 mL) was stirred at room temperature for 8 h. The
solvent was evaporated to dryness, which was extracted
with dichloromethane (20 mL). The organic layer was dried
and the solvent was evaporated to give oxime 2a (0.62 g,
83%).
4.3. General procedures for the reaction of oximes 2 with
NPMI (3)
The solution of oxime 2a (0.26 g, 1.0 mmol) and NPMI (3:
0.19 g, 1.1 mmol) in benzene (3 mL) was heated under
reflux for 36 h. After cooling, the resulting crystals (4a:
0.29 g, 71%) were filtered off. The filtrate was evaporated to
dryness, which was subjected to a column chromatography
on silica gel to afford 4a (0.045 g, 11%) and the unreacted
oxime 2a (0.018 g, 7%) with hexane/ethyl acetate (1:1) as
an eluent.
4.2.1. 4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyri-
midine-3-carbaldehyde oxime (2a). Yellow plate from
MeOH; mp 209–2108C; IR (KBr): 3250 (OH), 1660, 1620
(CO); 1H NMR (CDCl3): 1.93 [4H, br, N(CH2CH2)2],
3.60 [4H, br, N(CH2CH2)2], 6.28 (1H, ddd, J¼1.2,
6.7, 7.6 Hz, 7-H), 7.27 (1H, ddd, J¼0.7, 1.2, 8.6 Hz, 9-H),
7.56 (1H, ddd, J¼1.7, 6.7, 8.6 Hz, 8-H), 8.17 (1H, s,
–CHvN–), 8.1–8.9 (1H, br, OH), 8.87 (1H, ddd, J¼0.7,
1.7, 7.6 Hz, 6-H); 13C NMR (CDCl3): 25.55, 50.84,
88.01, 112.27, 124.33, 127.80, 136.48, 146.42, 148.81,
157.75, 157.97. Anal. calcd for C13H14N4O2 (258.3):
C, 60.45; H, 5.46; N, 21.69. Found: C, 60.48; H, 5.39; N,
21.62.
4.3.1. (3R p,3aS p,6aS p)-(6)-3-[4-Oxo-2-(pyrrolidin-1-
yl)-4H-pyrido[1,2-a]pyrimidin-3-yl]-5-phenylperhydro-
pyrrolo[3,4-d]isoxazole-4,6-dione (4a). Colorless needles
from ethanol; mp 2248C; IR (KBr): 3200 (NH), 1730, 1710,
1620 (CO); 1H NMR (CDCl3): 1.96 [4H, br, N(CH2CH2)2],
3.73 [2H, m, N(CHHCH2)2], 3.80 [3H, ov, 3a-H and
N(CHHCH2)2], 4.97 (1H, dd, J¼8.9, 12.9 Hz, 3-H), 5.28
(1H, d, J¼7.9 Hz, 6a-H), 6.83 (1H, 0 J¼1.3, 6.9, 8.6 Hz,
70-H), 7.26 (1H, J¼0.7, 1.3, 6.9 Hz, 9 -H), 7.38–7.58 (6H,
ov, 80-H and Ph-H), 7.83 (1H, d, J¼12.9 Hz, exchanged
with D2O, NH), 8.64 (1H, J¼0.7, 1.7, 6.9 Hz, 60-H); 13C
[(CD3)2SO]: 25.23, 50.14, 51.94, 62.50, 82.13, 83.83,
113.89, 123.87, 126.36, 127.01, 128.27, 128.74, 132.54,
137.94, 147.89, 157.85, 160.23, 173.21, 174.92. Anal. calcd
for C23H21N4O5 (431.4): C, 64.04; H, 4.91; N, 16.23.
Found: C, 64.17; H, 5.01 N, 16.27.
4.2.2. 2-Morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carbaldehyde oxime (2b). 85%; Pale yellow prisms from
propan-2-ol (2-PrOH); mp 2058C; IR (KBr): 3260 (OH),
1660, 1620 (CO); 1H NMR (CDCl3): 3.62 [4H, br t,
J¼5.0 Hz, N(CH2CH2)2O], 3.81 [4H, br t, J¼5.0 Hz,
N(CH2CH2)2O], 6.99 (1H, dt, J¼1.3, 6.9 Hz, 7-H), 7.38
(1H, ddd, J¼0.7, 1.3, 8.6 Hz, 9-H), 7.67 (1H, ddd, J¼1.7,
6.9, 8.6 Hz, 8-H), 8.24 (1H, s, –CHvN–), 9.04 (1H, ddd,
J¼0.7, 1.7, 6.9 Hz, 6-H), 9.4–10.5 (1H, br, OH); 13C NMR
(CDCl3): 49.90, 66.88, 91.57, 113.87, 124.82, 128.18,
137.07, 144.89, 149.06, 156.84, 162.16. Anal. calcd for
C13H14N4O3 (274.3): C, 56.93; H, 5.14; N, 20.43. Found: C,
56.91; H, 5.20; N, 20.14.
While the reaction of oximes 2b and 2c with NPMI (3) and
usual work-up with a column chromatography gave (4b and
5b) and (4c and 5c), respectively, the reaction of oxime 2d
with 3 gave 4d.
4.3.2. (3R p,3aS p,6aS p)-(6)-3-(2-Morpholino-4-oxo-4H-
pyrido[1,2-a]pyrimidin-3-yl)-5-phenylperhydro-
pyrrolo[3,4-d]isoxazole-4,6-dione (4b). Colorless needles
from 2-PrOH; mp 186–1878C; IR (KBr): 3240 (NH), 1740,
1710, 1630 (CO); 1H NMR (CDCl3): 3.47 [4H, m,
N(CH2CH2)2O], 3.77–3.85 [5H, ov, 3a-H and
N(CH2CH2)2O], 4.79 (1H, dd, J¼9.2, 13.5 Hz, 3-H), 5.31
(1H, d, J¼7.9 Hz, 6a-H), 7.00 (1H, dt, J¼1.3, 6.9 Hz, 70-H),
7.39–7.49 (6H, ov, 90-H and Ph-H), 7.57 (1H, d, J¼13.5 Hz,
exchanged with D2O, NH), 7.68 (1H, ddd, J¼1.2, 6.6,
4.2.3. 2-(N,N-Dibenzylamino)-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbaldehyde oxime (2c). 55%; Pale
yellow prisms from 2-PrOH; mp 208–2108C; IR (KBr):
3260 (OH), 1660, 1620 (CO); 1H NMR (CDCl3): 4.72 (4H,
s, 2£CH2Ph), 6.94 (1H, dt, J¼1.3, 6.9 Hz, 7-H), 7.16–7.35
(11H, ov, Ph-H and 9-H), 7.60 (1H, ddd, J¼1.3, 6.9, 8.6 Hz,
8-H), 8.30 (1H, s, –CHvN–), 9.00 (1H, br d, J¼6.9 Hz,
6-H), 9.7–10.4 (1H, br, OH); 13C NMR (CDCl3): 53.51,
91.18, 113.46, 124.73, 127.33, 127.85, 128.14, 128.54,
136.82, 137.47, 145.16, 148.75, 156.96, 162.25. Anal. calcd
8.3 Hz, 80-H), 8.72 (1H, ddd, J¼0.7, 1.2, 6.9 Hz, 60-H); 13
C
NMR (CDCl3): 50.32, 51.21, 63.97, 66.85, 81.82, 89.27,
114.57, 125.07, 126.72, 126.81, 128.66, 128.97, 132.00,

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M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
137.09, 149.07, 159.25, 165.32, 172.74, 174.16. Anal. calcd
for C23H21N5O5 (447.4): C, 61.74; H, 4.73; N, 15.65.
Found: C, 61.68; H, 4.79; N, 15.30.
63.12, 81.42, 87.82, 115.27, 124.91, 126.69, 127.37, 128.30,
128.70, 129.00, 131.84, 134.17, 137.66, 149.90, 158.42,
165.86, 172.88, 173.94. Anal. calcd for C21H18N4O5
(406.4): C, 62.06; H, 4.46; N, 13.79. Found: C, 62.16; H,
4.48; N, 13.62.
4.3.3. (3R p,3aR p,6aR p)-(6)-3-(2-Morpholino-4-oxo-4H-
pyrido[1,2-a]pyrimidin-3-yl)-5-phenylperhydropyr-
rolo[3,4-d]isoxazole-4,6-dione (5b). Although this
compound could not be isolated as a pure form, the
structure was elucidated by its 1H NMR spectroscopic data
(CDCl3): 3.59 [2H, br, N(CHHCH2)2O], 3.71–3.85 [6H, ov,
N(CHHCH2)2O], 4.52 (1H, dd, J¼5.9, 7.3 Hz, 3a-H), 4.68
(1H, dd, J¼5.9, 12.5 Hz, 3-H), 5.33 (1H, d, J¼7.3 Hz,
6a-H), 6.078 (1H, d, J¼12.5 Hz, NH), 7.05 (1H, dt, J¼1.3,
6.9 Hz, 7 -H), 7.31–7.53 (6H, ov, 90-H and Ph-H), 7.72 (1H,
ddd, J¼1.7, 6.9, 8.6 Hz, 80-H), 8.85 (1H, ddd, J¼0.7, 1.7,
6.9 Hz, 60-H).
Similarly, the reaction of oxime 2a with 7 gave 8 and 9 in 68
and 4% yields, respectively.
4.3.7. (3R p,3aS p,6aS p)-(6)-5-Methyl-3-{4-oxo-2-(pyrro-
lidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-3-yl}perhydro-
pyrrolo[3,4-d]isoxazole-4,6-dione (8). Colorless crystals
without recrystallization; mp 200–2018C; IR (KBr): 3190
(NH), 1710, 1700, 1640 (CO); 1H NMR (CDCl3): 1.96 [4H,
br, N(CH2CH2)2], 3.04 (3H, s, 5-Me), 3.61 (1H, dd, J¼7.3,
8.9 Hz, 3a-H), 3.68, 3.77 [each 2H, each m, N(CH2CH2)2],
4.86 (1H, dd, J¼8.9, 12.5 Hz, 3-H), 5.12 (1H, d, J¼7.3 Hz,
6a-H), 6.83 (1H, J¼1.7, 6.9, 7.3 Hz, 70-H), 7.27 (1H, J¼1.0,
1.7, 8.9 Hz, 90-H), 7.055 (2H, ov, 80-H and NH), 8.61 (1H,
ddd, J¼1.0, 7.3 Hz, 6 -H); 13C NMR (CDCl3): 25.23, 25.70,
50.46, 51.57, 63.63, 81.98, 83.85, 112.65, 124.35, 126.72,
136.39, 148.46, 158.51, 161.13, 174.14, 175.35. Anal. calcd
for C18H19N5O4 (369.4): C, 58.53; H, 5.18; N, 18.96.
Found: C, 58.77; H, 5.30; N, 18.78.
4.3.4. (3R p,3aS p,6aS p)-(6)-3-{2-(N,N-Dibenzylamino)-
4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-5-phenylper-
hydropyrrolo[3,4-d]isoxazole-4,6-dione (4c). Colorless
needles from 2-PrOH; mp 1708C; IR (KBr): 3200 (NH),
1
1720, 1660, 1630 (CO); H NMR (CDCl3): 3.66 (1H, dd,
J¼7.9, 8.9 Hz, 3a-H), 4.59, 4.77 (each 2H, each d,
J¼15.8 Hz, 2£CH2Ph), 4.91 (1H, dd, J¼8.9, 13.2 Hz,
3-H), 5.15 (1H, d, J¼7.9 Hz, 6a-H), 6.97 (1H, ddd, J¼1.0,
6.9, 8.3 Hz, 70-H), 7.26–7.48 (16H, ov, 90-H and Ph-H),
7.63 (1H, ddd, J¼1.7, 6.6, 8.3 Hz, 80-H), 7.77 (1H, d,
J¼13.2 Hz, exchanged with D2O, NH), 8.74 (1H, br d,
J¼6.9 Hz, 60-H); 13C NMR (CDCl3): 51.20, 53.68, 63.83,
81.76, 88.52, 114.12, 124.85, 126.76, 126.86, 127.48,
127.80, 128.63, 128.73, 128.97, 132.02, 136.93, 137.11,
148.48, 159.17, 165.21, 172.87, 174.32. Anal. calcd for
C33H27N5O4 (557.6): C, 71.08; H, 4.88; N, 12.56. Found: C,
70.83; H, 5.10; N, 12.51.
4.3.8. (3R p,3aR p,6aR p)-(6)-5-Methyl-3-{4-oxo-2-(pyro-
lidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-3-yl}perhydro-
pyrrolo[3,4-d]isoxazole-4,6-dione (9). Colorless needles
from 2-PrOH; mp 202–2038C; IR (KBr): 3180 (NH), 1690,
1
1640, 1620 (CO); H NMR (CDCl3): 1.85, 1.98 [each 2H,
each m, N(CH2CH2)2], 3.01 (3H, s, 5-Me), 3.77 [4H, m,
N(CH2CH2)2], 4.45 (1H, dd, J¼5.9, 7.3 Hz, 3a-H), 4.80
(1H, dd, J¼5.9, 12.5 Hz, 3-H), 5.20 (1H, d, J¼7.3 Hz,
6a-H), 6.81 (1H, d, J¼12.5 Hz, NH), 6.87 (1H, ddd, J¼0 1.5,
6.9, 7.3 Hz, 70-H), 7.28 (1H, ddd,0J¼0.6, 1.5, 8.9 Hz, 9 -H),
7.59 (1H,0br dd, J¼6.9, 8.9 Hz, 8 -H), 8.74 (1H, dd, J¼0.6,
7.3 Hz, 6 -H); 13C NMR (CDCl3): 24.92, 25.66, 50.57,
53.69, 63.32, 83.22, 86.21, 112.63, 124.58, 126.49, 136.51,
148.71, 158.29, 159.04, 171.87, 177.00. Anal. calcd for
C18H19N5O4 (369.4): C, 58.53; H, 5.18; N, 18.96. Found: C,
58.23; H, 5.22; N, 18.67.
4.3.5. (3R p,3aR p,6aR p)-(6)-3-{2-(N,N-Dibenzylamino)-
4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-5-phenylper-
hydropyrrolo[3,4-d]isoxazole-4,6-dione (5c). Colorless
needles from 2-PrOH; mp 119–1208C; IR (KBr): 3210
(NH), 1720, 1650, 1620 (CO); 1H NMR (CDCl3): 4.54 (1H,
dd, J¼6.6, 7.9 Hz, 3a-H), 4.73 (3H, ov, 3-H and 2£CHHPh),
4.89 (2H, d, J¼16.2 Hz, 2£CHHPh), 5.24 (1H, d, J¼7.9 Hz,
6a-H), 6.96 (1H, br t, J¼6.9 Hz, 70-H), 7.13–7.49 (17H, ov,
900-H and Ph-H and NH), 7.62 (1H, br dd, J¼6.9, 7.3 Hz,
8 -H), 8.82 (1H, br d, J¼6.9 Hz, 60-H); 13C NMR (CDCl3):
52.85, 53.07, 64.15, 82.75, 88.39, 113.71, 124.85, 126.54,
127.17, 127.53, 128.25, 128.59, 128.70, 128.95, 131.14,
136.96, 137.30, 148.63, 158.76, 163.99, 170.48, 174.81.
HRMS (EI) m/z: 557.2045 (calcd for C33H27N5O4:
557.2063). Anal. calcd for C33H27N5O4 (557.6): C, 71.08;
H, 4.88; N, 12.56. Found: C, 70.53; H, 5.10 N, 12.51.
4.4. Reaction of oximes 2 with electron-deficient
acetylenes 10, 16, and 17
General procedures for the reaction of oximes 2 with
DMAD (10). A solution of oxime 2a (0.135 g, 0.52 mmol)
and DMAD (10; 0.066 mL, 1.0 equiv.) in benzene (3 mL)
was heated under reflux for 2 h. The solvent was evaporated
to dryness, which was subjected to a column chromato-
graphy on silica gel to afford 11a (0.173 g, 84%) and 12a
(trace) with hexane/ethyl acetate (1:2) and (2:3) as eluents,
respectively.
4.3.6. (3R p,3aS p,6aS p)-(6)-3-(2-Ethoxy-4-oxo-4H-
pyrido[1,2-a]pyrimidin-3-yl)-5-phenylperhydro-
pyrrolo[3,4-d]isoxazole-4,6-dione (4d). Colorless crystals
without recrystallization; mp 181–1828C; IR (KBr): 3200
(NH), 1700, 1660, 1620 (CO); 1H NMR (CDCl3): 1.43 (3H,
t, J¼7.1 Hz, OCH2CH3), 3.83 (1H, dd, J¼7.6, 8.9 Hz,
3a-H), 4.55 (2H, q, J¼7.1 Hz, OCH2CH3), 5.17 (1H, dd,
J¼8.9, 13.5 Hz, 3-H), 5.29 (1H, d, J¼7.6 Hz, 6a-H), 70.13
(1H, ddd, J¼1.0, 6.9, 8.3 Hz, 70-H), 7.35–7.51 (6H, ov, 9 -H
and Ph-H), 7.71–7.80 (2H, ov, 80-H and NH), 8.89 (1H, br
d, J¼6.9 Hz, 60-H); 13C NMR (CDCl3): 14.63, 51.43, 60.77,
4.4.1. 3-Oxo-2-{3-[4-oxo-2-(pyrrolidin-1-yl)-4H-
pyrido[1,2-a]pyrimidin-3-yl]aminomethylene}succinic
acid dimethyl ester (11a). Pale yellow needles from
2-PrOH; mp 2058C; IR (KBr): 3120 (NH), 1740, 1700,
1660 (CO); 1H NMR (CDCl3): 1.96 [4H, br, N(CH2CH2)2],
3.76 [4H, br, N(CH2CH2)2], 3.80, 3.92 (each 3H, each s,
OMe), 6.94 0(1H, dt, J¼1.3, 6.9 Hz, 70-H), 7.31 (1H, br d,
J¼8.9 Hz, 9 -H), 7.61 (1H, ddd, J¼1.7, 6.9, 8.9 Hz, 80-H),
8.83–8.56 (2H, ov, 60-H and –NH–CHv), 11.81 (1H, d,

M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
4119
J¼13.9 Hz, exchanged with D2O, –NH–CHv); 13C NMR
(CDCl3): 25.47, 49.81, 51.43, 52.31, 97.65, 97.84, 113.17,
124.40, 127.64, 136.51, 147.89, 153.84, 154.93, 160.27,
165.93, 166.31, 186.88. Anal. calcd for C19H20N4O6
(400.4): C, 56.99; H, 5.04; N, 13.99. Found: C, 56.78; H,
5.11; N, 14.08.
dt, J¼1.3, 6.9 Hz, 7-H), 7.24–7.39 (11H, ov, 9-H and
Ph-H), 7.70 (1H, ddd, J¼1.7, 6.9, 8.9 Hz, 8-H), 8.85 (1H,
ddd, J¼0.7, 1.7, 6.9 Hz, 6-H). Anal. calcd for C23H18N4O
(366.4): C, 75.36; H, 4.95; N, 15.29. Found: C, 75.25; H,
5.10; N, 15.12.
4.4.7. 3-Oxo-2-{3-[2-ethoxy-4-oxo-4H-pyrido[1,2-a]pyri-
midin-3-yl]aminomethylene}succinic acid dimethyl ester
(11d). Pale yellow needles from 2-PrOH; mp 1818C; IR
(KBr): 3200 (NH), 1740, 1700, 1680 (CO); 1H NMR
(CDCl3): 1.53 (3H, t, J¼6.9 Hz, OCH2CH3), 3.80. 3.92
(each 3H, each s, OMe), 4.65 (2H, q, J¼6.9 Hz, OCH2CH3),
7.26 (1H, ddd, J¼1.0, 6.9, 7.3 Hz, 70-H), 7.60 (1H, br d,
J¼7.3 Hz, 90-H), 7.83 (1H, ddd, J¼1.0, 6.9, 7.3 Hz, 80-H),
9.10 (1H, br d, J¼7.3 Hz, 60-H), 9.70 (1H, d, J¼13.5 Hz,
–NH–CHv), 12.67 (1H,d, J¼13.5 Hz, –NH–CHv);
13C NMR (CDCl3): 14.59, 51.47, 52.26, 64.33, 98.06,
100.72, 115.90, 125.05, 127.55, 136.82, 146.85, 152.38,
154.73, 157.83, 165.95, 166.50, 186.58; MS (EI) m/z: 375
(Mþ, 27), 316 (100). Anal. calcd for C17H17N3O7 (375.3):
C, 54.40; H, 4.57; N, 11.20. Found: C, 54.27; H, 4.66; N,
10.92.
4.4.2. 4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyri-
midine-3-carbonitrile (12a). Colorless prisms from
2-PrOH; mp 250–2518C; IR (KBr): 2200 (CN), 1670
1
(CO); H NMR (CDCl3): 2.00 [4H, br, N(CH2CH2)2], 3.90
[4H, br, N(CH2CH2)2], 6.87 (1H, ddd, J¼1.0, 6.6, 7.3 Hz,
7-H), 7.24 (1H, br d, J¼8.6 Hz, 9-H), 7.64 (1H, ddd, J¼1.7,
6.6, 8.6 Hz, 8-H), 8.80 (1H, br d, J¼7.3 Hz, 6-H). Anal.
calcd for C13H12N4O (240.3): C, 64.99; H, 5.03; N; 23.32.
Found: C, 64.73; H, 5.07; N, 23.24.
4.4.3. 3-Oxo-2-{3-(2-morpholino-4-oxo-4H-pyrido[1,2-
a]pyrimidin-3-yl)aminomethylene}succinic acid
dimethyl ester (11b). Yellow prisms from MeOH; mp
1
2128C; IR (KBr): 3100 (NH), 1740, 1705, 1660 (CO); H
NMR (CDCl3): 3.45 [4H, t, J¼4.6 Hz, N(CH2CH2)2O], 3.79
(3H, s, OMe), 3.90 [7H, ov, N(CH2CH2)2O and OMe], 7.14
(1H, ddd, J¼1.3, 6.6, 7.3 Hz, 70-H), 7.52 (1H, br d,
J¼8.9 Hz, 90-H), 7.74 (1H, ddd, J¼1.7,0 6.6, 8.9 Hz, 80-H),
8.99 (1H, ddd, J¼1.0, 1.7, 7.3 Hz, 6 -H), 9.65 (1H, d,
J¼13.5 Hz, –NH–CHv), 12.32 (1H, d, J¼13.5 Hz, –NH–
CHv); 13C (CDCl3): 48.97. 51.52, 52.23, 66.54, 98.13,
102.91, 115.15, 125.34, 127.33, 136.42, 147.19, 153.67,
156.08, 157.57, 165.79, 166.25, 186.85. Anal. calcd for
C19H20N4O7 (416.4): C, 54.81; H, 4.84; N, 13.46. Found: C,
54.41; H, 4.87; N, 13.20.
4.4.8. 2-Ethoxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-
carbonitrile (12d). Colorless needles from 2-PrOH; mp
1538C; IR (KBr): 2220 (CN), 1670 (CO); 1H NMR (CDCl3):
1.46 (3H, t, J¼7.0 Hz, OCH2CH3), 4.60 (2H, q, J¼7.0 Hz,
OCH2CH3), 7.32 (1H, dt, J¼1.3, 6.9 Hz, 7-H), 7.61 (1H, br
d, J¼8.6 Hz, 9-H), 8.03 (1H, ddd, J¼1.7, 6.9, 8.6 Hz, 8-H),
9.00 (1H, ddd, J¼1.0, 1.7, 6.9 Hz, 6-H). Anal. calcd for
C11H9N3O2 (215.2): C, 61.39; H, 4.22; N, 19.53. Found: C,
61.32; H, 4.19; N, 19.09.
4.4.4. 2-Morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carbonitrile (12b). Colorless prisms from 2-PrOH; mp
1808C; IR (KBr): 2200 (CN), 1680 (CO); 1H NMR (CDCl3):
3.81 [4H, t, J¼4.6 Hz, N(CH2CH2)2O], 4.06 [4H,t,
J¼4.6 Hz, N(CH2CH2)2O], 6.69 (1H, ddd, J¼1.7, 6.6,
7.3 Hz, 7-H), 7.30 (1H, br d, J¼8.6 Hz, 9-H), 7.73 (1H, ddd,
J¼1.7, 6.6, 8.6 Hz, 8-H), 8.84 (1H, ddd, J¼1.0, 1.7, 7.3 Hz,
6-H). Anal. calcd for C13H12N4O2 (256.3): C, 60.93; H,
4.72; N, 21.86. Found: C, 60.68; H, 4.85; N, 21.87.
Similarly, the reaction of oxime 2a with acetylenes 16 and
17 gave (18 and 12a) and (19 and 12a), respectively.
4.4.9. 2-{3-[4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-
a]pyrimidin-3-yl]aminomethylene}-1,4-diphenylbutane-
1,2,4-trione (18). Yellow prisms from benzene; mp 232–
2338C; this compound was obtained as a (1:1) molecular
complex with benzene. Anal. calcd for C35H30N4O4
(C29H24N4O4þC6H6: 570.6): C, 73.67; H, 5.30; N, 9.82.
Found: C, 73.79; H, 5.30; N, 9.82; IR (KBr): 3220 (NH),
1
4.4.5. 3-Oxo-2-{3-[2-(N,N-dibenzylamino)-4-oxo-4H-
pyrido[1,2-a]pyrimidin-3-yl]aminomethylene}succinic
acid dimethyl ester (11c). Yellow prisms from 2-PrOH; mp
158–1598C; IR (KBr): 3120 (NH), 1740, 1700, 1660 (CO);
1H NMR (CDCl3): 3.71, 3.91 (each 3H, each s, OMe), 4.77
(4H, s, 2£CH2Ph), 7.04 (1H, ddd, J¼1.3, 6.6, 7.3 Hz, 70-H),
7.18–7.33 (10H, ov, Ph-H), 7.43 (1H, br0d, J¼8.6 Hz, 90-H),
7.68 (1H, ddd, J¼1.7, 6.6, 8.6 Hz, 8 -H), 8.65 (1H, d,
J¼13.5 Hz, –NH–CHv), 8.87 (1H, ddd, J¼0.6, 1.3,
7.3 Hz, 60-H), 11.94 (1H, d, J¼13.5 Hz, –NH–CHv);
13C NMR (CDCl3): 51.36, 52.29, 53.73, 98.08, 101.18,
114.27, 125.01, 127.46, 127.51, 127.58, 128.73, 136.64,
136.98, 147.42, 155.18, 156.13, 159.30, 165.84, 166.13,
186.97. Anal. calcd for C29H26N4O6 (526.5): C, 66.15; H,
4.98; N, 10.64. Found: C, 66.19; H, 5.05; N, 10.56.
1660, 1620; H (CDCl3): 1.98 [4H, br, N(CH2CH2)2], 3.74
[4H, br, N(CH2CH2)2], 6.91 (1H, ddd, J¼1.3, 6.9, 7.3 Hz,
70-H), 7.23–7.63 (8H, ov, 80- and 90-H and Ph-H), 7.73 (2H,
dd, J¼1.7, 7.9 Hz, Ph-H), 7.92 (2H, dd, J¼0.7, 8.2 Hz, Ph-
H), 8.55 (1H, d, J¼13.2 Hz, –NH–CHv), 8.70 (1H, dd,
J¼0.7, 7.3 Hz, 60-H), 12.09 (1H, d, J¼13.2 Hz, –NH–
CHv); 13C NMR (CDCl3): 25.53, 49.85, 98.06, 109.06,
113.12, 124.45, 127.65, 127.99, 128.57, 129.25, 129.36,
131.57, 133.21, 133.92, 136.49, 137.97, 147.87, 153.91,
155.04, 161.18, 192.67, 193.17, 197.16.
4.4.10. 2-{3-[4-Oxo-2-(pyrrolidin-1-yl)-4H-pyrido[1,2-
a]pyrimidin-3-yl]aminomethylene}malonaldehydric
acid methyl ester (19). Pale yellow needles from benzene;
mp 231–2328C; IR (KBr): 3100 (NH), 1700, 1650, 1630
(CO); 1H NMR (CDCl3): 1.95 [4H, br, N(CH2CH2)2], 3.65–
3.85 [7H, ov, N(CH2CH2)2 and OMe], 6.92 (1H, dt, J¼1.3,
6.6 Hz, 70-H), 7.30 (1H, br d, J¼8.3 Hz, 90-H), 7.61 (1H,
ddd, J¼1.7, 6.6, 8.3 Hz, 80-H), 8.53 (1H, dd, J¼3.6,
13.5 Hz, –NH–CHv), 8.84 (1H, ddd, J¼0.7, 1.7, 6.6 Hz,
4.4.6. 2-(N,N-Dibenzyl)amino-4-oxo-4H-pyrido[1,2-
a]pyrimidine-3-carbonitrile (12c). Colorless needles
from 2-PrOH; mp 1808C; IR (KBr): 2200 (CN), 1680
(CO); 1H NMR (CDCl3): 5.07 (4H, s, 2£CH2Ph), 6.97 (1H,

4120
M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
60-H), 9.93 (1H, d, J¼3.6 Hz, –CHO), 11.90 (1H, d,
J¼13.5 Hz, –NH–CHv); 13C NMR (CDCl3): 25.43,
49.63, 51.04, 98.08, 101.56, 112.96, 124.35, 127.76,
136.28, 147.85, 154.03, 155.24, 158.78, 167.58, 191.10.
Anal. calcd for C17H18N4O4 (342.4): C, 59.64; H, 5.30; N,
16.37. Found: C, 59.46; H, 5.41; N, 16.30.
by direct method (SIR88)8 and refined by least-squares to R
0.059 (Rw 0.051).
4.8. Preparation of 11a by the reaction of 13 and 15
A mixture of 2-oxosuccinic acid dimethyl ester (14: 7.77 g,
48.5 mmol), prepared accordingly to the literature by
Sucrow and Grosz,9 triethyl orthoformate (7.19 g,
1.0 equiv.), and acetic anhydride (9.90 g, 2 equiv.) was
stirred at 1008C for 1 h. The reaction mixture was
evaporated in vacuo to afford 2-ethoxymethylene-3-oxo-
succinic acid dimethyl ester (15: 9.77 g, 93%). Ester 15 was
used for the next reaction without further purification.
4.5. General procedures for the preparation of nitriles 12
from aldehydes 1
To a solution cooled at 58C of aldehyde 1a (1.00 g,
4.1 mmol) in water (5 mL), hydroxylamine O-sulfonic
acid (HOS in 81% purity: 0.75 g, 1.3 equiv.) was added.
The reaction mixture was stirred at the same temperature for
1 h, heated at 508C for 3 h, and made basic (pH 8.05) with
1N NaOH. The mixture was extracted with dichloromethane
(3£10 mL). The organic layer was dried and the solvent was
evaporated to afford nitrile 12a (0.836 g, 85%). Similarly,
nitriles 12b–d were obtained from aldehydes 1b–d in
70–89% yields.
4.8.1. 2-Ethoxymethylene-3-oxosuccinic acid dimethyl
ester (15). Colorless oil. This compound was obtained as a
(1:1) mixture of two diastereomers. 1H NMR (CDCl3): 1.46,
1.44 (each 3H, each t, J¼7.1 Hz, OCH2CH3), 3.77, 3.79,
3.87, 3.88 (each 3H, each s, OMe), 4.35, 4.39 (each 2H, q,
J¼7.1 Hz, OCH2CH3), 7.93, 7.95 (each 1H, each s, vCH–
OEt). HRMS (EI) m/z 216.0584 (calcd for C12H14N4O:
216.0634).
4.6. Alkaline hydrolysis of 11a
A solution of 11a (0.080 g, 0.18 mmol) in 1N NaOH (2 mL)
was stirred at room temperature for 1 h. The reaction
mixture was extracted with dichloromethane (20 mL£2).
The organic layer was dried and the solvent was evaporated.
The residue was subjected to a column chromatography on
silica gel to afford 13 (0.034 g, 80%) with dicholoro-
methane/MeOH (25:1) as an eluent.
To a stirred solution of 3-amino-2-(pyrrolidin-1-
yl)pyrido[1,2-a]pyrimidin-4(4H)-one (13: 0.046 g,
0.20 mmol) in THF (0.5 mL), ester 15 (0.058 g,
0.27 mmol) was added at room temperature. The mixture
was stirred for 1 h and the solvent was evaporated. The
residue was subjected to a preparative TLC with dichloro-
methane/MeOH (25:1) as an eluent to afford the desired 11a
(0.064 g, 80%).
4.6.1. 3-Amino-2-(pyrrolidin-1-yl)pyrido[1,2-a]pyrimi-
din-4(4H)-one (13). Yellow prisms from 2-PrOH; mp
1228C; 1H NMR (CDCl3): 1.95 [4H, br, N(CH2CH2)2], 3.0–
3.7 (2H, br, NH2), 3.79 [4H, br, N(CH2CH2)2], 6.86 (1H, dt,
J¼1.5, 6.8 Hz, 7-H), 7.29 (1H, dd, J¼1.0, 7.8 Hz, 9-H), 7.39
(1H, m, 8-H), 8.83 (1H, dd, J¼1.0, 6.4 Hz, 6-H); 13C NMR
(CDCl3): 25.5, 48.8, 108.5, 112.7, 124.2, 126.6, 131.8,
143.1, 150.6, 153.6; MS (FAB) m/z: 230 (Mþ). Anal. calcd
for C12H14N4O (230.3): C, 62.59; H, 6.13; N, 24.33. Found:
C, 62.55; H, 6.19; N, 24.28. HRMS (EI) m/z: 230.1147
(calcd for C12H14N4O: 230.1168).
Acknowledgements
The present work was partially supported by Grant-in-Aid
for Scientific Researches on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ (13029082 and
14044073) and Grant-in-Aid for Scientific Research
(C-13650905) from the Ministry of Education, Science,
Sports and Culture, Japan. We are also thankful to Ube
Industries LTD for a gift of hydroxylamine O-sulfonic acid
(HOS).
4.7. Single-crystal X-ray structure determination of 136
Single crystals (prisms) of compound 13 for X-ray
diffraction studies were obtained by recrystallization from
References
2-PrOH
(crystal
of
approximate
dimensions,
0.16£0.38£0.72 mm3). All measurements were made on a
Rigaku AFC55 diffractometer by employing graphite-
monochromated Mo Ka radiation. The unit-cell dimensions
were obtained by least-squares analysis of 22 reflections
within the range of 25.64,2u,27.788. The crystal data for
13 are given: crystal system: monoclinic; space group: P21/c
1. (a) Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. J. Chem. Soc.,
Perkin Trans. 1 1984, 41. (b) Grigg, R.; Jordan, M.;
Tangthongkum, A. J. Chem. Soc., Perkin Trans. 1 1984, 47.
(c) Grigg, R.; Thianpantagul, S. J. Chem. Soc., Perkin Trans. 1
1984, 653. (d) Also, see: Grigg, R. Chem. Soc. Rev. 1987, 16,
89.
˚
˚
(#14); cell constants: a: 15.008(7) A, b: 4.823(5) A, c:
2. (a) Norman, M. H.; Heathcock, C. H. J. Org. Chem. 1987, 52,
226. (b) Grigg, R.; Heaney, F.; Markandu, J.; Surendrakumar,
S.; Thornton-Pett, M.; Warnock, W. J. Tetrahedron 1991, 47,
4007. (c) Grigg, R.; Dorrity, M. J.; Heaney, F.; Malone, J. F.;
Rajviroongit, S.; Sridharan, V.; Surendrakumar, S. Tetrahedron
1991, 47, 8297. (d) Hassner, A.; Mauya, R. Tetrahedron Lett.
1989, 30, 5803. (e) Hassner, A.; Maurya, R.; Padwa, A.;
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3
˚
˚
16.351(5) A, V: 1085(1) A , b: 113.51(2)8; Z value: 4; Dc:
1.41 g cm23. The v–2u scan technique to a maximum 2u-
value of 55.08 was used and scans of (1.63þ0.30 tan u)8
were made at a speed of 168 min21 13. A total of 2896
observed reflections (unique: 2794; Rint¼0.020) was
collected. All calculations were performed using TEXAN
program.7 Atoms other than hydrogen were refined
anisotropically. The structure of compound 13 was solved

M. Shirai et al. / Tetrahedron 59 (2003) 4113–4121
4121
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`
(k) Chiacchio, U.; Corsaro, A.; Pistara, V.; Rescifina, A.;
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6. Crystallographic data for 13 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 203 080. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
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