Nitrilimine cycloaddition to 4-(pyrazol-5-yl)carbonyl-2-azetidinone and 4-(pyrazol-4-yl)carbonyl-2-azetidinone

Article abstract of DOI:10.1016/S0040-4039(02)02874-5

The higly stereoselective nitrilimine cycloaddition onto the novel 3(R*)-phenyl-4(S*)-cinnamoyl-2-azetidinone 2 gave 4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinone 5 as the major product and 4-(4,5-dihydropyrazol-4-yl)carbonyl-2-azetidinone 6 as the minor one. Ceric ammonium nitrate (CAN) oxidation of the cycloadducts gave the title compounds with good overall yield.

Full text of DOI:10.1016/S0040-4039(02)02874-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1425–1427
Nitrilimine cycloaddition to 4-(pyrazol-5-yl)carbonyl-2-
azetidinone and 4-(pyrazol-4-yl)carbonyl-2-azetidinone
Paola Del Buttero,a,* Giorgio Moltenia and Tullio Pilatib
aUniversita` degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, Via Golgi 19, 20133 Milano, Italy
bConsiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, 20133 Milano, Italy
Received 18 November 2002; revised 25 November 2002; accepted 18 December 2002
Abstract—The higly stereoselective nitrilimine cycloaddition onto the novel 3(R*)-phenyl-4(S*)-cinnamoyl-2-azetidinone 2 gave
4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinone 5 as the major product and 4-(4,5-dihydropyrazol-4-yl)carbonyl-2-azetidinone
6 as the minor one. Ceric ammonium nitrate (CAN) oxidation of the cycloadducts gave the title compounds with good overall
yield. © 2003 Elsevier Science Ltd. All rights reserved.
Due to their antibiotic or b-lactamase inhibitor activity,
methoxy aniline and (ii) Staudinger [2+2] cycloaddition
between imine 1 and phenylketene, which was gener-
ated in situ by base treatment of phenylacetyl chloride
(Scheme 1).
2-azetidinone-based heterocycles represent
a
very
attractive target of contemporary organic synthesis.1
Furthermore, the pyrazole and 4,5-dihydropyrazole
rings are found in several compounds which display
biological
activity
as
antiinflammatory2
and
Next, hydrazonoyl chloride 36 was treated with an
equimolecular amount of silver acetate in dry dioxane
in the presence of 2. Besides the recovery of unreacted
2 (15%), 1,3-dipolar cycloaddition of the labile nitril-
imine intermediate 4 gave regioisomeric (4R*,5%S*)-5
and (4R*,4%R*)-6 in the ratio 5:6=80:20 with a 70%
overall yield (Scheme 2). Product separation was
achieved on silica gel column chromatography with
tBuOMe–light petroleum 55:45 as eluent, while analyti-
cal and spectroscopic data of the cycloadducts are in
full agreement with the formulae depicted.7 The
regioselectivity of the cycloaddition is not surprising
and matches that usually observed in the reaction
anticoagulating3 factors. The present letter is concerned
with the first synthesis of 4-(pyrazol-5-yl)carbonyl-2-
azetidinone and 4-(pyrazol-4-yl)carbonyl-2-azetidinone,
which brings together the above-mentioned heterocyclic
fragments, by means of a nitrilimine 1,3-dipolar
cycloaddition.
First, we devised the novel 3(R*)-phenyl-4(S*)-cin-
namoyl-2-azetidinone 24 as a suitable starting building
block, which was readily obtained in good overall yield
from cinnamoylcarboxaldehyde.5 The two steps
involved were: (i) condensation of the latter with 4-
Scheme 1.
* Corresponding author. Fax: 0039-02-50314115; e-mail: paola.delbuttero@unimi.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02874-5

1426
P. Del Buttero et al. / Tetrahedron Letters 44 (2003) 1425–1427
Scheme 2.
Figure 1.
between nitrilimines and a,b-unsaturated carbonyl
derivatives.8 On the other hand, both major product
(4R*,5%S*)-5 and minor product (4R*,4%R*)-6 were
detected as single stereoisomers, the cycloaddition being
therefore fully stereoselective. Inspection of Dreiding
stereomodels of 2 showed that (i) the phenyl ring in the
3-position of the 2-azetidinone fragment effectively hin-
ders one of the two diastereofaces of the CꢀC dipolar-
ophile, and (ii) due to unavoidable steric crowding, a
free interchange between the four possible conforma-
tions of the cinnamoyl moiety in the 4-position is
precluded. A pictorial representation of these confor-
mations is given in Figure 1, while AM19 computed
distances HꢁHa and HꢁHb are summarised in Table 1.
In the light of the observed NOE enhancement (6%) of
Ha when irradiating H, it follows that the syn s-cis
arrangement is the only reasonable candidate describ-
ing the ground state conformation of 2, thus allowing
the stereoselective formation of (4R*,5%S*)-5 and
(4R*,4%R*)-6. As a further step of our work, we submit-
ted the latter cycloadducts to oxidation with ceric
ammonium nitrate (CAN), and obtained 4-(pyrazol-5-
yl)carbonyl-2-azetidinone 7 and 4-(pyrazol-4-yl)carbon-
yl-2-azetidinone 8, respectively (Scheme 3).10 These
compounds gave crystals suitable for X-ray diffracto-
metric analyses (Fig. 2),11 thus demonstrating unam-
biguously the regiochemical outcome of the nitrilimine
cycloaddition. In conclusion, the present study provides
the first insight into the regio- and stereoselectivity
involved in the nitrilimine cycloaddition to higly-func-
tionalised 2-azetidinones. Further developments are in
progress.
Table 1. AM1-calculated distances between HꢁHa and
a
HꢁHb
Entry
anti s-cis
anti s-trans
syn s-cis
syn s-trans
HꢁHa
HꢁHb
3.69
4.72
4.46
3.71
2.48
4.60
3.91
2.28
a
,
Distance in A.
Acknowledgements
We would like to thank MURST and CNR for finan-
cial support. We would also like to gratefully thank
student Dr. Paolo Anesa.
Scheme 3.

P. Del Buttero et al. / Tetrahedron Letters 44 (2003) 1425–1427
1427
Figure 2.
References
6.6, C3-H
J=6.6, C4-H
6: mp 207°C (from iPr2O); IR (Nujol): wmax 1760, 1730,
6
), 5.32 (1H, d, J=4.2, C%-H
6
), 5.80 (1H, d,
5
6
), 6.8–7.5 (18 H, m, aromatics). (4R*,4%R*)-
1. (a) Southgate, R. Contemp. Org. Synth. 1994, 1, 417; (b)
The Organic Chemistry of i-Lactams; Georg, G. I., Ed.;
VCH: New York, 1993; (c) Sammes, P. G. Chem. Rev.
1976, 76, 113.
2. (a) Copp, F. C.; Islip, P. J.; Tateson, J. E. Biochem.
Pharmacol. 1984, 33, 339; (b) Fr´ıgola, J.; Colombo, A.;
Pare´s, J.; Mart´ınez, L.; Sagarra, R.; Roser, R. Eur. J.
Med. Chem. 1989, 24, 435.
1700 cm−1; H NMR (CDCl3): l 2.35 (3H, s, CH3
6 C6H4-),
1
3.70 (3H, s, CH3OC6H4-), 3.77 (3H, s, CH3OOC-), 4.10
(1H, d, J=3.2, C%4-H), 4.57 (1H, d, J=3.2, C5%-H), 4.79
(1H, d, J=6.3, C3-H), 5.07 (1H, d, J=6.3, C4-H), 6.7–7.4
(18 H, m, aromatics).
6
6
6
6
6
6
8. Shimizu, T.; Hayashi, T.; Nishi, T.; Teramura, K. Bull.
Chem. Soc. Jpn. 1984, 57, 787.
3. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.;
Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.;
Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.;
Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem.
2001, 44, 566.
9. As implemented in the HyperChem Professional 6.03
version, 2000.
10. Selected data for 7 and 8. 7: mp 183°C (from iPr2O); IR
(Nujol): wmax 1750, 1730, 1685 cm−1; 1H NMR (CDCl3): l
2.32 (3H, s, CH3
(3H, s, CH3OOC-), 4.42 (1H, d, J=6.5, C3-H
d, J=6.5, C4-H), 6.3–7.7 (18 H, m, aromatics). 8: mp
209°C (from iPr2O); IR (Nujol): wmax 1740, 1715, 1685
6
C6H4-), 3.74 (3H, s, CH3
6
OC6H4-), 3.79
6
6
), 4.78 (1H,
4. Selected data for 2: mp 202°C (from ethanol); IR (Nujol):
6
1
wmax 1740, 1690 cm−1; H NMR (CDCl3): l 3.72 (3H, s),
4.93 (1H, d, J=6.5), 5.07 (1H, d, J=6.5), 6.46 (1H, d,
J=16.0), 6.8–7.2 (15 H, m).
1
cm−1; H NMR (CDCl3): l 2.28 (3H, s, CH3
(3H, s, CH3OC6H4-), 4.08 (3H, s, CH3OOC-), 4.82 (1H,
d, J=6.6, C3-H), 6.07 (1H, d, J=6.6, C4-H), 6.9–7.5 (18
H, m, aromatics).
6 C6H4-), 3.77
6
6
5. Le Corre´, M. Bull. Soc. Chim. Fr. 1974, 1951.
6. El-Abadelah, M. M.; Hussein, A. Q.; Kamal, M. R.;
Al-Adhami, K. H. Heterocycles 1988, 27, 917.
6
6
11. Crystallographic data (excluding structure factors) for
structures 7 and 8 have been deposited with the Cam-
bridge Crystallographic data Centre as supplementary
publication numbers CCDC 197536 and CCDC 197535,
respectively.
7. Selected data for (4R*,5%S*)-5 and (4R*,4%R*)-6.
(4R*,5%S*)-5: mp 200°C (from iPr2O); IR (Nujol): wmax
1
1745, 1730, 1685 cm−1; H NMR (CDCl3): l 2.14 (3H, s,
CH
6
3C6H4-), 3.67 (1H, d, J=4.2, C%-H
6
), 3.71 (3H, s,
4
CH3OC6H4-), 3.90 (3H, s, CH3
6
6 OOC-), 4.89 (1H, d, J=