4920
C. Altug˘ et al. / Tetrahedron Letters 50 (2009) 4919–4921
CO Et
2
2c
1
N
OH
2
N
NH
CO Et
2
ON
CO Et
2
N
CO Et
2
ON
CO Et
2
HO
NO
N
OH
HNO
Ar
2
NH
NH
N
benzene, reflux
2 h
NH
NO
2
2a
1
4 (observed)
Scheme 3.
5, 35%
4
N
CO Et
2
N
C
HO
rich double-bond of the alkylidenepyrrolidine clearly renders this
a ‘special case’, although we would anticipate many other in-
stances in which the nitrous acid would be trapped. This may
therefore limit the applicability of nitrolic acids as nitrile oxide
precursors.
N
N
5
6
7
Ar
Ar
C
N
O
Acknowledgements
7
N
O
Ar
C N O
_
Ar
N
We are extremely grateful to the Abant Izzet Baysal University,
N
N
Directorate of Research Projects Commission (BAP Grant
2007.03.03.260) and TUBITAK (The Scientific and Technological
Research Council of Turkey, Grant 106T645) for financial support
and to Mr. Robin Hicks for technical assistance. We would also like
to thank Dr Robert Richardson (School of Chemistry, Cardiff
University) for helpful discussions.
O
N
O
N
Ar
N
8
3a
Scheme 2.
References and notes
ing to provide similar products in good yields (Table 1). In all cases,
complete consumption of the alkylidenepyrrolidine reagent 1 was
observed.
1. Feuer, H. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; John Wiley
& Sons: New Jersey, 2008; Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John
Wiley & Sons: New York, 1984; Easton, C. J.; Hughes, C. M. M.; Savage, G. P.;
Simpson, G. W. Adv. Heterocycl. Chem. 1994, 60, 261–327; Houk, K. N.; Sims, J.;
Duke, R. E., Jr.; Strozier, R. W.; George, J. K. J. Am. Chem. Soc. 1973, 95, 7287–
7301; Wagner, G.; Danks, T. N.; Vullo, V. Tetrahedron 2007, 63, 5251–5260;
Vullo, V.; Danks, T. N.; Wagner, G. Eur. J. Org. Chem. 2004, 2046–2052.
2. Matt, C.; Gissot, A.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 2000, 41,
1191–1194.
Variable amounts of a by-product were observed in the 1H NMR
data of the crude reaction mixtures. Under milder conditions than
those shown in Table 1, this became a significant side-product, and
appeared to be consistent with either structure 4 or 5. Upon chro-
matography, compound 5 was obtained (1H NMR, 13C NMR, IR,
MS).10 This was similar, but not identical to the compound that
we had observed in the crude reaction mixtures, which we would
therefore attribute to compound 4 (Scheme 3). In particular, the
oxime carbon in compound 5 resonates at 143.2 ppm, whereas
the corresponding carbon in alkylidenepyrrolidine 1 resonates at
76.5 ppm. Nitrosation of the alkene, as in compound 4, is unlikely
3. Elliott, M. C.; Wood, J. L.; Wordingham, S. V. Trends Heterocycl. Chem. 2005, 10,
73–95; Elliott, M. C.; Wordingham, S. V. Synthesis 2006, 1162–1170; Davies, C.
D.; Elliott, M. C.; Wood, J. L. Tetrahedron 2006, 62, 11158–11164.
4. Altug˘, C.; Dürüst, Y.
A new route for the synthesis of phenyl sulfonyl
substituted isoxazoles, International Conference on Organic Chemistry, June
5–9, 2007, Erzurum, Turkey.
5. 3-(6-Chloropyridin-3-yl)-7a-[3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-
5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazole (3a). 6-Chloropyridin-3-
nitrolic acid (2a) (2.0 equiv, 201 mg, 1.0 mmol) was added to ethyl
(2-pyrrolidin-2-ylidene acetate (1) (77.5 mg, 0.5 mmol) in dry benzene
(10 mL) and the mixture was heated at reflux for 2 h. The reaction mixture
was concentrated in vacuo, and the crude residue was purified by flash column
to lead to such a dramatic increase, whereas related a-oximinoest-
ers show almost identical chemical shifts.11 Reaction of phenylnitr-
olic acid only gave compounds 4/5, with compound 3 not observed
even under forcing conditions.
chromatography (1:
1 petroleum ether–ethyl acetate) to give the title
compound (154 mg, 76%) as a yellow solid, m.p. 162–163 °C; mmax. (Nujol)
1582, 1555, 1141, 1114, 967, 933, 893, 838, 722 cmÀ1; dH (400 MHz; CDCl3)
9.03 (1H, d, J 1.8 Hz), 8.71 (1H, d, J 1.8 Hz), 8.27 (1H, dd, 8.3, 2.4 Hz), 8.02 (1H,
dd, J 8.4, 2.4 Hz), 7.41–7.36 (2H, m), 3.43–3.40 (2H, m), 2.88 (1H, ddd, J 14.2,
10.7, 6.9 Hz), 2.72 (1H, ddd, J 14.2, 7.1, 3.3 Hz), 2.15–2.07 (1H, m), 2.05–1.98
(1H, m); dC (100 MHz; CDCl3) 178.2 (C), 166.3 (C), 156.8 (C), 154.7 (C), 154.5
(C), 149.3 (CH), 149.2 (CH), 138.3 (CH), 137.9 (CH), 125.2 (CH), 125.1 (CH),
122.0 (C), 121.1 (C), 104.4 (C), 54.1 (CH2), 37.7 (CH2), 25.6 (CH2); m/z (TOF ES+)
This reaction represents, to the best of our knowledge, the first
example of the chemical trapping of nitrous acid liberated from a
nitrolic acid, although there are reports of biological studies in
which nitrolic acids are used as NO2/NO sources.12 The electron-
444.1 (MH+
+
CH3CN, 100%), 405.0 (M+, 16), 403.0 (M+, 25). Selected
Table 1
crystallographic data: C17H12Cl2N6O2, FW = 403.23, T = 150(2) K, k = 0.71073 Å,
Formation of adducts 3
2
monoclinic,
P21/c,
a = 6.8900(3) Å,
b = 13.7810(5) Å,
c = 18.1120(9),
b = 94.5030(10)°, V = 1714.45(13) Å3, Z = 4,
q
(calc) = 1.562 Mg/m3, crystal
N
OH
size = 0.50 Â 0.12 Â 0.12 mm3, reflections collected = 6624, independent
R
N
R
CO Et
2
reflections = 3885, R(int) = 0.0569, parameters = 244, R1 [I > 2r(I)] = 0.085, wR2
N
NO
2
O
N
[I > 2r(I)] = 0.19, R1 (all data) = 0.12, wR2 (all data) = 0.21. Full crystallographic
O
data for this compound have been deposited with the CCDC, reference number
NH
R
N
1
3
6. Kim, H. Y.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2001, 3, 2137–2140.
7. Fetizon, M.; Golfier, M.; Milcent, R.; Papadakis, I. Tetrahedron 1975, 31, 165–
170.
Compound
R
Conditions
Yield (%)
3a
3b
3c
3d
6-Chloro-3-pyridyl
3-Pyridyl
4-Pyridyl
Me
Benzene, reflux, 2 h
110 °C, 100 W, 10 mina
110 °C, 100 W, 10 mina
Toluene, reflux, 2 h
76
66
58
65
8. Diaz-Ortiz, A.; de la Hoz, A.; Alcazar, J.; Carrillo, J. R.; Herrero, M. A.; Fontana, A.;
de Mata Munoz, J. Comb. Chem. High Throughput Screening 2007, 10, 163–169.
9. Risitano, F.; Grassi, G.; Foti, F.; Rotondo, A. Tetrahedron 2001, 57, 7391–7393;
Miller, D. J.; Scrowston, R. M.; Kennewell, P. D.; Westwood, R. Tetrahedron 1994,
50, 5159–5168; Malamidou-Xenikaki, E.; Coutouli-Argyropoulou, E.
Tetrahedron 1990, 46, 7865–7872.
a
CEM discover microwave reactor.