Stereoselective 1,3-dipolar cycloadditions to (s)-1-benzoyl-3- (cyanomethylidene)-5-(methoxycarbonyl)pyrrolidin-2-one

Article abstract of DOI:10.1002/(SICI)1522-2675(19981216)81:12<2332::AID-HLCA2332>3.0.CO;2-Q

(5S)-1-Benzoyl-3-[(E)-cyanomethylidene]-5-(methoxycarbonyl)pyrrolidin- 2-one (5) was prepared in four steps from L-pyroglutamic acid (1). 1,3- Dipolar cycloadditions of diazomethane (6) and 2,4,6-trimethoxybenzonitrile oxide (7) gave substituted 1,2,7-triazaspiro[4,4]non-1-en-6-one 12 and 1- oxa-2,7-diazaspiro[4,4]non-1-en-6-one 13 in 38 and 20% de, respectively. On the other hand, reaction of 5 with N-phenylbenzonitrile imines 8 and 9, generated in situ from the corresponding hydrazonoyl chlorides 10 and 11, respectively, and Et₃N, furnished racemic pyrrolo[3,4-c]pyrazoles 14 and 15 in 61 and 56% de, respectively. Cycloaddition of nitrile oxide 7, when performed in the presence of Et₃N, led to pyrrolo[3,4-d]isoxazole 16 in 85% de.

Full text of DOI:10.1002/(SICI)1522-2675(19981216)81:12<2332::AID-HLCA2332>3.0.CO;2-Q

2332
Helvetica Chimica Acta ± Vol. 81 (1998)
Stereoselective 1,3-Dipolar Cycloadditions to (S)-1-Benzoyl-3-
(cyanomethylidene)-5-(methoxycarbonyl)pyrrolidin-2-one
a
a
a
a
b
Ï
by Marko Skof ), Jurij Svete )*, Branko Stanovnik )*, Ljubo GolicÏ ), Simona GolicÏ-Grdadolnik ),
and Lovro SelicÏ a)
a) Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
b) National Institute of Chemistry, Ljubljana, Slovenia
(5S)-1-Benzoyl-3-[(E)-cyanomethylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (5) was prepared in four
steps from l-pyroglutamic acid (1). 1,3-Dipolar cycloadditions of diazomethane (6) and 2,4,6-trimethoxyben-
zonitrile oxide (7) gave substituted 1,2,7-triazaspiro[4.4]non-1-en-6-one 12 and 1-oxa-2,7-diazaspiro[4,4]non-1-
en-6-one 13 in 38 and 20% de, respectively. On the other hand, reaction of 5 with N-phenylbenzonitrile imines 8
and 9, generated in situ from the corresponding hydrazonoyl chlorides 10 and 11, respectively, and Et3N,
furnished racemic pyrrolo[3,4-c]pyrazoles 14 and 15 in 61 and 56% de, respectively. Cycloaddition of nitrile
oxide 7, when performed in the presence of Et3N, led to pyrrolo[3,4-d]isoxazole 16 in 85% de.
Introduction. ± 2-Substituted alkyl 3-(dimethylamino)prop-2-enoates as polyfunc-
tional compounds are very useful reagents for the preparation of a variety of
heterocyclic systems including those with a-amino and a-hydroxy acid structural
element [1][2]. Substitution of the Me2N group by a CN group leads to 2-substituted 3-
cyanoprop-2-enoates which we also found as versatile reagents for the preparation of
heterocyclic systems such as pyrroles, pyridazines, and pyrimidines [3]. 3-Cyanopro-
penoates can also act as dipolarophiles in 1,3-dipolar cycloaddition reactions [3]. In
continuation of our work in this field, we report on the preparation of (5S)-1-benzoyl-3-
[(E)-cyanomethylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (5) and stereoselectiv-
ity of cycloaddition reactions with 1,3-dipoles 6 ± 9, which resulted in the formation of
spiro and fused heterocyclic systems 12 ± 16. To our best knowledge, no 1,3-dipolar
cycloadditions to 5-substituted 3-(cyanomethylidene)pyrrolidin-2-ones has been pre-
viously reported in the literature. Just recently, regioselective 1,3-dipolar cycloadditions
of CH2N2 (6) and N-methyl-a-phenylnitrone to 3-(2,2,2-trifluoroethylidene)-g-lactams
were reported to give 6-oxo-1,2,7-triazaspiro[4.4]non-1-ene and 6-oxo-1-oxa-2,7-
diazaspiro[4.4]nonane, respectively [4], and, on the other hand, cycloaddition of
2,4,6-trimethylbenzonitrile oxide to (S)-1-(tert-butoxycarbonyl)-5-(ethoxycarbonyl)-3-
methylidenepyrrolidin-2-one was also reported to give (5S,8S)-7-(tert-butoxycarbon-
yl)-8-(ethoxycarbonyl)-3-(2,4,6-trimethylphenyl)-6-oxo-1-oxa-2,7-diazaspiro[4.4]non-
2-ene in a regiospecific and stereoselective manner [5].
Results and Discussion. ± Starting from l-pyroglutamic acid (1), (5S)-1-benzoyl-3-
[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (4) was pre-
pared by modified procedures described in the literature1), followed by treatment with
1
)
For the preparation of compound 2, see [6]; for the preparation of (S)-5-(alkoxycarbonyl)-3-
[(dimethylamino)methylidene]pyrrolidin-2-ones, see [7].

Helvetica Chimica Acta ± Vol. 81 (1998)
2333
Scheme 1
i) SOCl2/MeOH, 08 ± r.t. ii) MeCN, 4-(dimethylamino)pyridine, Et3N, PhCOCl. iii) (Me2N)2CHOtBu toluene,
1008. iv) KCN, AcOH, r.t.
KCN in AcOH to give (5S)-1-benzoyl-3-[(E)-cyanomethylidene]-5-(methoxycarbo-
nyl)pyrrolidin-2-one (5; Scheme 1). The configuration of the exocyclic CˆC bond in 4
and 5 was determined by NMR. Chemical shifts, coupling constants, and interatomic
distances, determined by NOESY experiments, are in agreement with the proposed
structure2) (Fig. 1).
d(H C(3')) [ppm]
d(H C(3')) [ppm]
Calculated [8]
Found
7.02
Calculated [8]
Found
6.53
6.75 (E)
6.26 (Z)
6.22 (E)
5.46 (Z)
Fig. 1. NMR Data for the determination of the configuration of the exocyclic CˆC bond
Cycloaddition reactions were performed with the following 1,3-dipoles: CH2N2 (6)
[9], 2,4,6-trimethoxybenzonitrile oxide (7) [10], N-phenylbenzonitrile imine 8, and N-
phenyl-4-chlorobenzonitrile imine 9. Both compounds, 8 and 9, were generated by
2
)
Calculated chemical-shift values (d [ppm]) for olefinic protons (H C(3')) in compounds 4 and 5 were
obtained by chemical-shift increments [8].

2334
Helvetica Chimica Acta ± Vol. 81 (1998)
Huisgenꢀs in situ method from the corresponding N-phenylbenzohydrazonoyl chloride
(10) and 4-chloro-N-phenylbenzohydrazonoyl chloride (11), respectively [11 ± 13].
Cycloadditions of 1,3-dipoles 6 ± 9 to pyrrolidinone 5 were regiospecific in all cases.
Regiochemistry, which was cofirmed by NMR characterization, is also in accordance
with regiochemistry of analogous reactions [4][5][14][15].
Cycloaddition of CH2N2 (6) to pyrrolidinone 5 afforded (4S,5S,8S)-7-benzoyl-4-
cyano-8-(methoxycarbonyl)-1,2,7-triazaspiro[4.4]non-1-en-6-one (12) together with a
diastereoisomer in 38% de. Similarly, treatment with 7 gave (4S,5S,8S)-7-benzoyl-4-
cyano-8-(methoxycarbonyl)-1-oxa-2,7-diazaspiro[4.4]-2-en-6-one (13) together with a
diastereoisomer in 20% de. Isomerically pure compounds 12 and 13 were prepared by
crystallization of crude products (Scheme 2). The stereoselectivity of these cyclo-
additions was very poor, probably due to a large distance between the directing
stereocenter at C(5) and the reactive site. We also presume that N-benzoyl residue,
which could be preferably trans-oriented with respect to the 5-(methoxycarbonyl)
group, contributes to lower the stereoselectivity by directing the 1,3-dipole to approach
from the opposite side. However, the degree of stereoselectivity is in accordance with
Scheme 2
i) CH2N2 (6) Et2O, 108, 12 h. ii) 2,4,6-Trimethoxybenzonitrile oxide (7), CHCl3, reflux, 2 h; iii) N-phenyl-
benzohydrazonoyl chloride (10), Et3N, CH2Cl2, reflux, 0.5 h. iv) 4-Chloro-N-phenylbenzohydrazonoyl chloride
(11), Et3N, CH2Cl2, reflux, 0.5 h. v) 2,4,6-Trimethoxybenzonitrile oxide (7), Et3N, CH2Cl2, reflux, 0.5 h.
Compound
de [%]a)
Yieldb) [%]
12
13
14
15
16
38
20
61
56
85
42
44
36
47
58
a
) Determined by H-NMR. b) Yield of isolated compound after purification.
1

Helvetica Chimica Acta ± Vol. 81 (1998)
2335
that reported for an analogous reaction [5] (Scheme 3). The structure of compound 13
was also confirmed by X-ray structural analysis (Fig. 2 and Table).
On the other hand, cycloadditions of nitrile imines 8 and 9 gave racemic rel-
(3aR,4S,6aR)-3-aryl-5-benzoyl-6a-(cyanomethyl)-4-(methoxycarbonyl)-6-oxo-1-phe-
nyl-3a,6a,4,5-tetrahydro-1H,6H-pyrrolo[3,4-c]pyrazoles 14 and 15 in 61 and 56% de,
respectively. Cycloaddition of nitrile oxide 7, performed in the presence of Et3N, also
gave pyrrolo[3,4-d]isoxazole 16 in 85% de (Scheme 2). We first thought that Et3N, used
for in situ generation of N-phenylbenzonitrile imines 8 and 9 from the corresponding
N-phenylbenzohydrazonoyl chlorides 10 and 11, respectively, promoted isomerization
and racemization of 5 into endocyclic isomer 17. Consequently, this would explain the
formation of pyrrolo[3,4-c]pyrazoles 14 and 15. However, treatment of 5 with CH2N2 in
the presence of Et3N, or with Et3N itself, gave only inseparable mixtures of unidentified
products. Although at this moment we do not have a firm proof for the mechanism
leading to the formation of racemic fused compounds 14 ± 16, we assume that the
tautomeric form 17, which is in equilibrium with tautomer 18, might be responsible for
racemization and formation of fused compounds 14 ± 16. Preferential approach of 1,3-
Scheme 3
Fig. 2. ORTEP View of 13, showing the labeling of the non-H-atoms [16]. Ellipsoids at 40% probability level.

2336
Helvetica Chimica Acta ± Vol. 81 (1998)
Table. Crystallographic Data for Compounds 13 and 15
Compound
15
13
Crystal Data
Chemical formula
Chemical formula weight
C28H21N4O4Cl
512.95
C25H23N3O8
493.47
Cell setting
Space group
a [Š]
b [Š]
c [Š]
a [8]
b [8]
g [8]
V [Š3]
Monoclinic
C12/c1
22.5566(6)
7.6837(6)
30.0133(2)
90.0000
103.756(4)
90.0000
5052.65(43)
8
Orthorombic
P212121
0.445(1)
13.0551(8)
18.005(1)
90.0000
90.0000
90.0000
2455.2(3)
4
Z
3
Density [Mgm
Radiation type
Wavelength
]
1.349
MoKa
0.71069
75
1.335
MoKa
0.71069
50
No. of refl. for cell parameters
q Range [8]
7.9 ± 16.2
1.8878
10.0 ± 16.4
0.944
1
m [mm
]
Temp. [K]
293(1)
293(1)
Crystal form
Crystal size [mm]
Crystal color
Prism
0.65 Â 0.49 Â 0.21
Colorless
Colorless
Data Collection
Diffractometer
Enraf Nonius CAD-4 diffractometer
Data collection method
Absorption correction
No. of measured refl.
No. of independent refl.
No. of observed refl.
Criterion of observed refl.
Rint
w/2q scans
None
24409
6530
3312
I > 2.5s(I)
0.0216
23740
3328
2464
I > 2.5s(I)
0.0251
qmax [8]
28
28
Range of h, k, l
29 ! h ! 29
10 ! k ! 10
39 ! l ! 39
13 ! h ! 13
17 ! k ! 17
23 ! l ! 23
No. of standard refl.
3
Frequency of standard refl.
Intensity decay [%]
Every 20000 s of scaning time
0.30
8.19
dipoles 7 ± 9 from the less hindered side of 17 should give 14 and 16 with rel-
(3aR,4S,6aR)-configuration. Diastereoselectivity of these reactions was much higher
because of the pronounced stereo-inductive effect of the MeOOC group, which is
adjacent to the reactive site (Scheme 4). The structure of compound 16 was also
confirmed by X-ray structural analysis3) (Fig. 3).
3
)
X-Ray data of structure analyses of the compounds 13 and 16 will be published elsewhere.

Helvetica Chimica Acta ± Vol. 81 (1998)
2337
Scheme 4
Fig. 3. ORTEP View of 15, showing the labeling of the non-H-atoms [16]. Ellipsoids at 35% probability level.

2338
Helvetica Chimica Acta ± Vol. 81 (1998)
Experimental Part
General. All starting materials were commercially available (in most cases from Fluka) and purified
following the standard techniques. The following compounds were prepared according to the procedures
described in the literature: (S)-5-(Methoxycarbonyl)pyrrolidin-2-one (2) [6], CH2N2 (6) [9], 2,4,6-trimethoxy-
benzonitrile oxide (7) [10], N-phenylbenzohydrazonoyl chloride 10, and 4-chloro-N-phenylbenzohydrazonoyl
chloride 11 [11 ± 13]. Product purifications were performed by flash chromatography (FC) on silica gel (Fluka;
Kieselgel 60). TLC: Merck, Alufolien Kieselgel 60 F 254, 0.2 mm. M.p.: Kofler micro hot stage. Optical
rotations: Perkin-Elmer 241 MC polarimeter. IR: Perkin-Elmer 1310 spectrophotometer. 1H- and 13C-NMR:
Bruker Avance DPX 300 spectrometer. Elemental analyses: Perkin-Elmer CHN Analyser 2400. Crude products
12 ± 16 were obtained as mixtures of two isomers: major isomers 12 ± 16 and the corresponding minor isomers.
Major isomers 12 ± 16 were isolated, purified, and fully characterized, while minor isomers were detected and
1
partially characterized by recording the H-NMR spectra of crude products. The following workup procedure
was applied for 1H-NMR determination of de of compounds 13 ± 16: After completion of reaction, volatile
components were evaporated in vacuo, and the residue purified by FC. The following eluents were used: CHCl3/
MeOH 25 :1 (14/minor isomer and 15/minor isomer), Et2O/petroleum ether 1 :1 (13/minor isomer and 16/minor
isomer). Fractions containing the product were combined, evaporated in vacuo, and 1H-NMR spectra of the
residue were recorded.
(S)-N-Benzoyl-5-(methoxycarbonyl)pyrrolidin-2-one (3). PhCOCl (7.266 g, 52 mmol) was added to a soln.
of (S)-5-(methoxycarbonyl)pyrrolidin-2-one (2; 7.300 g, 50 mmol) in pyridine (75 ml), and the mixture was
stirred at r.t. for 2 h. Volatile compounds were evaporated in vacuo, hexane (150 ml) was added to the residue,
the precipitate collected by filtration, and washed with MeOH (100 ml): 10.374 g (84%) of 3. M.p. 150 ± 1528
1
(MeOH). [a]2D3 ˆ‡ 30.1 (c ˆ 1.1, CH2Cl2). IR (KBr): 1770 ± 1740 (CˆO). H-NMR (300 MHz, (D6)DMSO):
2.00 ± 2.04 (m, H C(4)); 2.41 ± 2.47 (m, H C(4)); 2.57 ± 2.62 (m, H C(3)); 3.72 (s, MeO); 4.84 (dd, J ˆ 3.9,
8.7, H C(5)); 7.42 ± 7.47 (m, 2 H of Ph); 7.54 ± 7.61 (m, 3 H of Ph). 13C-NMR (75.5 MHz, CDCl3): 22.2; 32.1;
53.1; 59.1; 128.3; 129.5; 132.7; 134.1; 170.8; 172.0; 173.8. Anal. calc. for C13H13NO4 (247.25): C 63.15, H 5.30,
N 5.66; found: C 62.96, H 5.20, N 5.58.
(5S)-1-Benzoyl-3-[(E)-(dimethylamino)methylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (4). A mix-
ture of 3 (2.473 g, 10 mmol), toluene (20 ml), and tert-butyl/bis(dimethylamino)methyl ether (2.610 g,
15 mmol) was heated at 90 ± 1008 for 2 h, volatile components were evaporated in vacuo, and solid residue
was crystallized from AcOEt/hexane 2 :1 (15 ml). The precipitate was collected by filtration to give 2.237 g
(74%) of 4. M.p. 133 ± 1348 (AcOEt). [a]D23
ˆ
36.0 (c ˆ 1.25, CHCl3). IR (KBr): 1745, 1720 ± 1700 (CˆO).
1H-NMR (300 MHz, (D6)DMSO): 2.94 (dd, J ˆ 3.1, 14.8, H C(4)); 3.02 (s, Me2N); 3.37 (dd, J ˆ 10.7, 14.6,
H
C(4)); 3.69 (s, MeO); 4.73 (dd, J ˆ 3.7, 10.2, H C(5)); 7.02 (s, CHNMe2); 7.35 ± 7.40 (m, 2 H of Ph); 7.45 ±
7.51 (m, 3 H of Ph). 13C-NMR (75.5 MHz, CDCl3): 27.3; 43.0; 53.3; 56.6; 91.7; 128.3; 129.5; 131.9; 136.1;
148.1; 170.2; 171.7; 172.8. Anal. calc. for C16H18N2O4 (302.33): C 63.56, H 6.00, N 9.27; found: C 63.34, H 6.35,
N 9.13.
(5S)-1-Benzoyl-3-[(E)-cyanomethylidene]-5-(methoxycarbonyl)pyrrolidin-2-one (5). A soln. of 4 (2.983 g,
10 mmol) and KCN (0.715 g, 11 mmol) in AcOH (100%, 20 ml) was left at r.t. for 2 d. Then, the soln. was
concentrated to one half of the original volume (ca. 10 ml) by careful evaporation in vacuo (T< 408). H2O
(50 ml) was added to residue and the product extracted with Et2O (2 Â 50 ml). Org. phases were combined and
volatile components evaporated in vacuo at 208. H2O (10 ml) and MeOH (2 ml) were added to the residue, the
mixture was cooled (08), and the precipitate was collected by filtration and crystallized again from MeOH/H2O
1 : 2 to give 2.075 g (73%) of 5. M.p. 119 ± 1218 (MeOH/H2O 1 : 2). [a]2D3 ˆ‡ 71.5 (c ˆ 0.85, CHCl3). IR (KBr):
1
2240 (CN), 1750, 1680 (CˆO). H-NMR (300 MHz, (D6)DMSO): 3.20 (dt, J ˆ 2.7, 2.9, 19.2, H C(4)); 3.49
(ddd, J ˆ 3.4, 9.4, 19.2, H C(4)); 3.73 (s, MeO); 5.01 (dd, J ˆ 3.4, 9.4, H C(5)); 6.53 (dd, J ˆ 2.6, 3.4, CHCN);
7.45 ± 7.51 (m, 2 H of Ph); 7.58 ± 7.67 (m, 3 H of Ph). 13C-NMR (75.5 MHz, CDCl3): 28.7; 53.7; 55.8; 104.2;
115.2; 128.5; 129.6; 133.1; 133.4; 151.6; 163.4; 170.4; 170.7. Anal. calc. for C15H12N2O4 (284.27): C 63.38, H 4.26,
N 9.85; found: C 63.39, H 4.50, N 9.70.
(4S,5S,8S)-7-Benzoyl-4-cyano-8-(methoxycarbonyl)-1,2,7-triazaspiro[4.4]non-1-en-6-one (12). A soln. of
CH2N2 (6) in Et2O (ca. 0.67m, 7.5 ml, 5 mmol) was added to a soln. of 5 (0.284 g, 1 mmol) in Et2O (5 ml). The
mixture was left at 108 for 12 h and the precipitate collected by filtration to give a mixture of 12 and its isomer
in a ratio of 69 : 31 (the same ratio of isomers was also obtained after evaporation of the reaction mixture).
Yield: 95% (0.30 g). [a]2D3 ˆ‡ 350 (c ˆ 0.42, CH2Cl2). Anal. calc. for C16H14N4O4 (326.31): C 58.89, H 4.32,
N 17.17; found: C 58.65, H 4.29, N 17.09.
Crystallization from CH2Cl2/Et2O 3 :1 gave 0.136 g (42%) of isomerically pure 12. M.p. 171 ± 1738 (CH2Cl2/
Et2O 3 :1). [a]2D3 ˆ‡ 433 (c ˆ 0.42, CH2Cl2). IR (KBr): 2240 (CN), 1760 ± 1730, 1700 ± 1680 (CˆO). 1H-NMR

Helvetica Chimica Acta ± Vol. 81 (1998)
2339
(300 MHz, (D6)DMSO): 2.63 (dd, J ˆ 5.6, 14.0, H C(9)); 3.24 (dd, J ˆ 8.2, 13.9, H C(9)); 3.73 (dd, J ˆ 4.9,
9.4, H C(4)); 3.78 (s, MeO); 4.97 (dd, J ˆ 9.4, 18.5, H C(3)); 5.19 (dd, J ˆ 5.3, 18.5, H C(3)); 5.32 (dd, J ˆ
5.8, 8.5, H C(8)); 7.49 (t, J ˆ 7.6, 2 H of Ph); 7.62 (t, J ˆ 7.5, 2 H of Ph); 7.75 (d, J ˆ 7.2, 1 H of Ph). 13C-NMR
(75.5 MHz, (D6)DMSO): 28.8; 29.3; 52.8; 56.5; 82.2; 98.2; 117.8; 127.9; 129.3; 132.5; 132.9; 167.9; 169.3; 170.2.
Anal. calc. for C16H14N4O4 (326.31): C 58.89, H 4.32, N 17.17; found: C 58.43, H 4.41, N 17.24. Minor isomer:
1H-NMR (300 MHz, (D6)DMSO): 2.72 (dd, J ˆ 2.6, 14.3, H C(9)); 3.12 (dd, J ˆ 10.2, 14.3, H C(9)); 3.69
(dd, J ˆ 4.9, 9.4, H C(4)); 3.78 (s, MeO); 4.94 (dd, J ˆ 9.4, 18.5, H C(3)); 5.19 (dd, J ˆ 4.9, 18.5, H C(3));
5.32 (dd, J ˆ 2.6, 10.2, H C(8)).
(4S,5S,8S)-7-Benzoyl-4-cyano-8-(methoxycarbonyl)-3-(2,4,6-trimethoxyphenyl)-1-oxa-2,7-diazaspiro[4.4]-
non-2-en-6-one (13). A mixture of 5 (0.284 g, 1 mmol), 2,4,6-trimethoxybenzonitrile oxide (7; 0.209 g, 1 mmol),
and CHCl3 (10 ml) was heated under reflux for 2 h, cooled, and volatile compounds were evaporated in vacuo.
EtOH (10 ml) was added to the residue, the mixture was cooled ( 158), and the precipitate was collected by
filtration to give 0.217 g (44%) of 13. M.p. 213 ± 2158. [a]2D3 ˆ‡ 400 (c ˆ 0.60, CH2Cl2). IR (KBr): 2260 (CN),
1760, 1690 (CˆO). 1H-NMR (300 MHz, CDCl3): 2.73 (dd, J ˆ 14.7, 5.3, H C(9)); 3.00 (dd, J ˆ 14.6, 8.3,
H
C(9)); 3.82 (s, MeO); 3.84 (s, MeO); 3.86 (s, MeO); 5.01 (dd, J ˆ 5.5, 8.1, H C(8)); 5.28 (s, H C(4)); 6.15
(s, 2 H of Ar); 7.44 ± 7.49 (m, 2 H of Ph); 7.57 ± 7.62 (m, 1 H of Ph); 7.72 ± 7.75 (m, 1 H of Ph). 13C-NMR
(75.5 MHz, CDCl3): 33.1; 48.4; 53.7; 55.86; 55.93; 56.5; 88.2; 91.4; 96.5; 113.8; 128.5; 129.9; 132.8; 133.5; 147.6;
160.7; 164.2; 169.1; 170.0; 171.0. Anal. calc. for C25H23N3O8 (493.47): C 60.84, H 4.69; N 8.51; found: C 60.62;
H 5.04; N 8.42. Minor isomer: 1H-NMR (300 MHz, CDCl3): 5.37 (s, H C(4)).
General Procedure for the Preparation of rel-(3aR,4S,6aR)-3-Aryl-5-benzoyl-6a-(cyanomethyl)-4-(methoxy-
carbonyl)-6-oxo-1-phenyl-3a,6a,4,5-tetrahydro-1H,6H-pyrrolo[3,4-c]pyrazoles 14 and 15. A hydrazonoyl chlor-
ide 10 or 11 (1.0 mmol) and Et3N (0.2 ml, 1.5 mmol) were added to a soln. of 5 (0.284 g, 1.0 mmol) in CH2Cl2
(5 ml), and the mixture was heated at reflux temp. for 30 min, cooled, and volatile components were evaporated
in vacuo. EtOH (10 ml) was added to the residue, the mixture was cooled ( 158), and the precipitate was
collected by filtration to give a pyrrolo[3,4-c]pyrazole (14 or 15).
rel-(3aR,4S,6aR)-5-Benzoyl-6a-(cyanomethyl)-1,3-diphenyl-4-(methoxycarbonyl)-6-oxo-3a,4,5,6a-tetrahy-
dro-1H,6H-pyrrolo[3,4-c]pyrazole (14). Compound 14 was prepared from 5 (0.284 g, 1.0 mmol), N-phenyl-
benzohydrazonoyl chloride (10; 0.231 g, 1.0 mmol), and Et3N (0.2 ml, 1.5 mmol). Yield: 47% (0.225 g). M.p.
203 ± 2058 (EtOH/DMF 20 :1). [a]D23
ˆ
10.3 (c ˆ 0.4, CH2Cl2). IR (KBr): 2240 (CN), 1750, 1690 (CˆO).
1H-NMR (300 MHz, (D6)DMSO): 3.12 (d, J ˆ 17.3, CH2); 3.59 (d, J ˆ 17.3, CH2); 3.86 (s, MeO); 4.91 (d, J ˆ
3.0, H C(3a)); 5.02 (d, J ˆ 3.0, H C(4)); 7.08 ± 7.13 (m, 1 H of Ph); 7.33 ± 7.59 (m, 12 H of Ph); 7.89 ± 7.92
(m, 2 H of Ph). 13C-NMR (75.5 MHz, (D6)DMSO): 22.5; 52.0; 54.1; 61.0; 75.1; 116.8; 119.3; 123.9; 127.3; 129.0;
129.6; 129.8; 129.9; 130.6; 130.6; 133.2; 133.7; 142.9; 148.9; 169.2; 170.1; 170.9. Anal. calc. for C28H2N4O4
(478.51): C 70.28, H 4.63, N 11.71; found: C 70.21, H 4.63, N 11.68. Minor isomer: 1H-NMR (300 MHz,
(D6)DMSO): 5.09 (d, J ˆ 10.2, H C(3a)); 5.49 (d, J ˆ 10.2, H C(4)).
rel-(3a,4,5-6aR)-5-Benzoyl-3-(4-chlorophenyl)-6a-(cyanomethyl)-4-(methoxycarbonyl)-6-oxo-1-phenyl-3a,
4,5,6a-tetrahydro-1H,6H-pyrrolo[3,4-c]pyrazole (15). Compound 15 was prepared from 5 (0.284 g, 1.0 mmol),
4-chloro-N-phenylbenzohydrazonoyl chloride (11; 0.265 g, 1.0 mmol), and Et3N (0.2 ml, 1.5 mmol). Yield: 36%
(0.184 g). M.p. 187 ± 1898 (EtOH/DMF 20 :1). [a]D23 ˆ 1.3 (c ˆ 0.30, CH2Cl2). IR (KBr): 2260 (CN), 1770 ± 1730,
1690 ± 1670 (CˆO). 1H-NMR (300 MHz, (D6)DMSO): 3.13 (d, J ˆ 17.7, CH2); 3.57 (d, J ˆ 17.3, CH2); 3.86
(s, MeO); 4.92 (d, J ˆ 3.0, H C(3a)); 5.03 (d, J ˆ 3.0, H C(4)); 7.11 (t, J ˆ 7.2, 1 H of Ph); 7.33 ± 7.42 (m, 6 H
of Ph); 7.46 (m, 2 H of Ph); 7.54 ± 7.59 (m, 1 H of Ph); 7.64 (d, J ˆ 6.8, 2 H of Ar); 7.90 (d, J ˆ 6.8, 2 H or Ar).
13C-NMR (75.5 MHz, (D6)DMSO): 22.4; 51.8; 54.1; 60.9; 75.4; 116.8; 119.3; 124.0; 128.9; 129.0; 129.5; 129.6;
129.8; 129.9; 133.2; 133.7; 135.1; 142.8; 148.0; 169.1; 170.1; 170.8. Anal. calc. for C28H21N4O4Cl (512.95): C 65.56,
H 4.13, N 10.92; found: C 65.74, H 4.18, N 10.98. Minor isomer: 1H-NMR (300 MHz, (D6)DMSO): 5.08 (d, J ˆ
10.2, H C(3a)); 5.48 (d, J ˆ 10.2, H C(4)).
rel-(3aR,4S,6aR)-5-Benzoyl-6a-(cyanomethyl)-4-(methoxycarbonyl)-6-oxo-3-(2,4,6-trimethoxyphenyl)-3a,
4,5,6a-tetrahydro-1H,6H-pyrrolo[3,4-d]isoxazole (16). 2,4,6-Trimethoxybenzonitrile oxide (7; 0.209 g, 1.0 mmol),
and Et3N (0.2 ml, 1.5 mmol) were added to a soln. of 5 (0.284 g, 1.0 mmol) in CHCl3 (5 ml), and the mixture was
heated at reflux temp. for 2 h, cooled, and volatile components were evaporated in vacuo. EtOH (10 ml) was
added to the residue, the mixture was cooled ( 158), and the precipitate was collected by filtration to give
0.286 g (58%) of 16. M.p. 226 ± 2288 (EtOH/DMF 20 : 1). [a]2D3 ˆ‡ 0.4 (c ˆ 0.98, CH2Cl2). 1H-NMR (300 MHz,
(D6)DMSO): 3.26 (d, J ˆ 17.3, CH2); 3.42 (d, J ˆ 17.3, CH2); 3.71 (s,MeO); 3.74 (s, MeO); 3.85 (s, MeO); 4.46
(d, J ˆ 0.9, H C(3a)); 4.65 (d, J ˆ 1.0, H C(4)); 6.37 (s, 2 H of Ar); 7.53 ± 7.60 (m, 4 H of Ar); 7.64 ± 7.72
(m, 1 H of Ar). 13C-NMR (75.5 MHz, (D6)DMSO): 22.1; 54.3; 54.5; 56.5; 57.0; 58.8; 86.9; 92.2; 96.2; 116.5;

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Helvetica Chimica Acta ± Vol. 81 (1998)
129.4; 129.5; 132.9; 134.3; 154.6; 160.2; 169.6; 169.9; 170.2. Anal. calc. for C25H23N3O8 (493.47): C 60.84, H 4.69,
N 8.51; found: C 60.47, H 4.81, N 8.44. Minor isomer: 1H-NMR (300 MHz, (D6)DMSO): 4.75 (d, J ˆ 4.9,
H
C(3a)).
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Received October 1, 1998