An unusual by-product from a non-synchronous reaction between ethyl 1,2,4-triazine-3-carboxylate and an enamine

Abstract

The main product from the reaction of ethyl 1,2,4-triazine-3-carboxylate 3 and the pyrrolidine enamine of N-tert-butoxycarbonylpiperidone 2 was an azabicyclo[3.2.1]octane 4 which resulted not from a Diels–Alder reaction, but from a series of non-synchronous steps, demonstrating a heretofore unknown reaction pathway for the electron-deficient diene 3 and electron-rich dienophile 2.

References

1. D. L. Boger and M. Patel, Prog. Heterocycl. Chem., 1989, 1, 30 and references cited therein.
2. E. C. Taylor, Bull. Soc. Chim. Belg., 1988, 97, 599 and references cited therein.
3. S. C. Benson, L. Lee and J. K. Snyder, Tetrahedron Lett., 1996, 37, 5061 and references cited therein W.-H. Fan, M. Parikh and J. K. Snyder, Tetrahedron Lett., 1995, 36, 6591 and references cited therein.
4. (a) D. L. Boger, J. S. Panek and M. M. Meier, J. Org. Chem., 1982, 47, 895; (b) D. L. Boger and J. S. Panek, J. Am. Chem. Soc., 1985, 107, 5745.
5. W. Paudler and K. Kraus, Synthesis, 1974, 351 and references cited therein.
6. Selected data for 1: δ_H(CDCl₃, 200 MHz) 8.50 (d, J 4.9, 1 H), 7.19 (d, J 4.9, 1 H), 4.63 (s, 2 H), 4.46 (q, J 7.1, 2 H), 3.66 (br t, J 5.9, 2 H), 3.17 (br t, J 5.9, 2 H), 1.50 (s, 9 H), 1.44 (t, J 7.1, 3 H); m/z(FAB LRMS) 308 (18%), 307 ([MH]⁺, 96), 251 (100), 207 (8), 57 (71).
7. Selected data for 4: white solid; mp 187.5–189.5 °C with effervescence; ν_max(KBr)/cm^–1 3359 (br), 1759, 1701, 1640; δ_H(DMSO, 500 MHz, 340 K) 6.66 (br m, NH), 6.48 (d, J 4.0, NH), 4.27 (br dd, J 12.7 and 12.9, 2 H), 4.19 (q, J 7.0, 2 H), 3.85 (t, J 5.0, 1 H), 3.39 (d, J 5.6, 1 H), 3.28 (d, J 12.7, 1 H), 3.19 (d, J12.9, 1 H), 2.33 (s, 1 H), 2.26 (s, 1 H), 1.43 (s, 9 H), 1.24 (t, J 7.0, 3 H); δ_C(DMSO, 500 MHz, 340 K) 215.1, 161.3, 154.1, 137.4, 79.8, 60.7, 53.8, 53.2, 52.6, 52.4, 51.8, 50.3, 28.0, 14.0; m/z(FAB LRMS) 354 (19%), 353 ([MH]⁺, 100), 297 (27). Calc. for C₁₆H₂₄N₄O₅: C 54.54; H, 6.87; N, 15.90. Found: C, 54.29; H, 6.93; N, 15.73%).
8. Crystals of 4 were grown in a concentrated EtOAc–benzene solution, and benzene was incorporated into the crystalline lattice in a ratio of 1∶1 with 4. A small single crystal was mounted on glass fiber under Paratone-8277 and placed on the X-ray diffractometer in a cold N₂ogen stream supplied by a Siemens LT-2A low temperature device. The X-ray intensity data were collected on a standard Siemens SMART CCD Area Detector System equipped with a normal focus molybdenum target X-ray tube operated at 2.0 kW (50 kV, 40 mA). A quadrant of data were collected using a narrow frame method with scan widths of 0.3° in w, and an exposure time of 30 s per frame. Frames were integrated to 40° with the Siemens SAINT program yielding a total of 3416 reflections, of which 1832 were independent reflections [R(int)= 0.0700]. The unit cell parameters were based upon the least-squares refinement of three dimensional centroids of 857 reflections at –80 °C, giving a monoclinic cell with a= 15.038(1), b= 13.967(1), c= 10.777(1)Å, β= 99.594(4)°, V= 2232.0(2)ų. The space group was assigned as P2₁/c(Z= 4 and D_c= 1.281 g cm^–3) on the basis of systematic absences using the XPREP program (Siemens, SHELXTL 5.04). The absorption coefficient was 0.092 mm^–1. The structure was solved by direct methods and refined by full-matrix least-squares on F². All nonhydrogen atoms were refined with anisotropic thermal parameters, with H atoms included in idealized positions. The empirical formula is C₁₆H₂₄N₄O₅·C₆H₆ giving a formula weight of 430.50 g mol^–1. Final R indices [1143 data having I > 2σ(I)]; R₁(%)= 7.90 [R₁= 0.0790; wR₂= 0.1481]. CCDC 182/810.
9. D. L. Boger, R. S. Coleman, J. S. Panek and D. Yohannes, J. Org. Chem., 1984, 49, 4405.
10. J. E. Macor, PhD Thesis, Princeton University, 1986, pp. 21–23 and 66–68.