ORGANIC LETTERS
Fullerene-Sensitized [2 + 3] Cycloaddition between Maleimides and Iminodiacetic Ester: Formation of Pyrrolidine Derivatives
2000 Vol. 2, No. 5 667-669
Yaru Shi, Liangbing Gan,* Xiaolan Wei, Shi Jin, Sheng Zhang, Fanyu Meng, Zheming Wang, and Chunhua Yan State Key Laboratory of Rare Earth Materials Chemistry and Applications, Department of Chemistry, Peking UniVersity, Beijing 100871 China
[email protected] Received January 2, 2000
ABSTRACT
Fullerene catalyzes the cycloaddition of dimethyliminodiacetate to maleimides under photolysis to form 2,5-dimethoxycarbonylpyrrolidine derivatives.
The synthesis of substituted pyrrolidines is of great importance for pharmacological and biological studies. The classical [2 + 3] reaction of azomethane ylide with alkene is one of the most useful and frequently employed methods.1 Various other methods have also been developed, and the search for new routes continues to be an active field.2-4 In the investigation of the reaction between amino acid esters with C60, we have recently found that amino acid esters such as iminodiacetic esters add to a double bond of C60 photochemically to form a C60-incorporated 2,5-dicarboxylated pyrrolidine derivative (Scheme 1).5,6 The reaction is
Scheme 1
highly efficient. The yield can reach 80% on the basis of converted C60. 10.1021/ol005503o CCC: $19.00 Published on Web 02/11/2000
© 2000 American Chemical Society
Several other groups have also reported the photochemical reaction between C60 and amines, all forming fulleropyrrolidino derivatives.7-10 The reaction is formally a [2 + 3] cycloaddition reaction. This reaction is unprecedented for nonfullerene systems. We have now extended the reaction to other electron-deficient alkenes in place of C60. Here we report the fullerene-sensitized photolysis between dimethyliminodiacetate and maleimides yielding the 2,3,4,5-tetracarboxylated pyrrolidines (1). A mixture of dimethyliminodiacetate (80 mg, 0.5 mmol), N-phenylmaleimide (87 mg, 0.5 mmol), and C60 (5 mg, 0.007 (1) Huisgen, R.; Scheer, W.; Szeimies, G.; Huber, H. Tetrhedron Lett. 1966, 4, 397. (2) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235 (3) Grigg, R. Tetrhedron: Asymmetry 1995, 6, 2475v (4) Gothelf, K. V.; Jorgensen, K.A. Chem. ReV. 1998, 98, 863 (5) Gan, L. B.; Zhou D. J.; Luo, C. P.; Tan, H. S.; Huang, C. H.; Lu, M. J.; Pan, J. Q.; Wu, Y. J. Org. Chem. 1996, 61, 1954 (6) Gan, L. B.; Jiang, J. F.; Zhang, W.; Su, Y.; Shi, Y. R.; Huang, C. H.; Pan, J. Q.; Lu, M. J.; Wu, Y. J. Org. Chem. 1998, 63, 4240 (7) Lawson G. E.; Kitaygorodskiy, A.; Ma, B.; Bunker, C. E.; Sun Y.P. J. Chem. Soc., Chem. Commun. 1995, 2225 (8) Liou, K.; Cheng, C., J. Chem. Soc., Chem. Commun. 1996, 1423 (9) Ma, B.; Lawson, G. E.; Bunker, C. E.; Kitaygorodskiy, A.; Sun, Y.P. Chem. Phys. Lett. 1995, 247, 51 (10) Bernstein R.; Foote C. S. J. Phys. Chem. A 1999, 103, 7244
mmol) in toluene (80 mL) was irradiated for 1 h. The light source is an overhead projector light bulb kept in a watercooled jacket which is inserted in the reaction solution. During the photolysis the temperature of the solution is around 60 °C. Chromatography separation on silica gel afforded some unreacted C60 and compound 1a in 65% yield (110 mg). Reaction on an increased scale requires a longer reaction time. For example, when the starting materials are scaled up by 10, while keeping the solvent about the same, a 5 h irradiation is needed. In this case most of compound 1a could be collected as a precipitate from the concentrated reaction solution. A commercial mixture of C60/C70 (about 4:1 ratio) could also be used as the sensitizer with equal efficiency. The ethyl analogue 1b can be prepared by exactly the same procedure (Scheme 2).
Scheme 2 Figure 1. ORTEP plot of the molecular structure of 1a.
For comparison, compound 1a was also prepared by the classical [2 + 3] thermal reaction (Scheme 2). Thus, heating a mixture of N-phenylmaleimide, glycine methyl ester, and methyl glyoxylate gave 1a. The yield of this thermal reaction is 56% in our hands. Both the 1H and 13C NMR spectra of the sample from this thermal reaction are exactly the same as those from the fullerene-sensitized photoreaction. Spectroscopic data of 1a agree with the structure as depicted.11 Several stereoisomers such as the cis and trans isomer could be envisioned for the compound. Both 1H and 13C NMR indicate that the isolated compound is isomerically pure and just one stereoisomer is present. But these data cannot distinguish whether 1a has C2 symmetry or Cs symmetry, both of which should have the same NMR pattern. In other words, relative stereo positions of the two carboxylates and the four pyrrolidine ring protons cannot be assigned from these data alone. To obtain a conclusive assignment of the structure of 1, we obtained single crystals of 1a by slow evaporation from a CHCl3 solution and determined its crystal structure by X-ray analysis.12 The X-ray molecular structure (Figure 1) (11) Selected data for 1a: 1H NMR (200 MHz, CDCl3) 3.72 (m, 2H), 3.84 (s, 6H), 4.11 (m, 2H), 7.21 (m, 2H), 7.43 (m, 3H); 13C NMR (50 MHz, CDCl3) 49.89, 52.77, 63.35, 126.42, 128.98, 129.25, 169.44, 174.12 (the phenyl C attached to the N is too weak to be assigned unambiguously). 1b: 1H NMR (400 MHz, CDCl3) 1.13 (t, 7.2 Hz, 3H), 3.49 (q, 7.2 Hz, 2H), 3.55 (m, 2H), 3.85 (s, 6H), 4.02 (m, 2H), 4.16 (d, 7.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) 12.91, 34.22, 49.83, 52.47, 62.79, 169.28, 174.65; EI-MS 285 (M+ + 1, 0.3%), 225 (M+ - COOMe, 55%), 94 (100%). 668
indicates a Cs symmetry for 1a. All four protons on the pyrrolidine ring are shown to be on the same side, and the two methoxycarbonyl groups at the 2,5-positions are in the cis-relative position. This stereo arrangement is similar to that of the pyrrolidine derivatives reported by Cossion and co-workers,13 who used metalating reagents in their 1,3dipole cycloadditions. The trans-2,5-dicarboxylated pyrrolidine derivatives have been reported by Harwood 14 and Risch15 also via controlled diastereoselective 1,3-dipole cycloadditions. Compound 2 was detected occasionally from the above fullerene-sensitized reaction from different runs. The isolated yield of 2 is less than 5%. It does not contain the maleimide moiety and corresponds to the oxygenation of a methylene carbon in the iminodiacetic ester. When cyclohexene is used in the place of maleimide, 2 is the only isolated product in the photochemical reaction of Scheme 2. Therefore, the cycloaddition reaction does not take place with this relatively electron-rich alkene. Compound 2 can also be prepared by photolysis of iminodiacetic methyl ester alone in the presence of C60/C70 (Scheme 3). Compound 2 has been shown to be an effective inhibitor of prolyl 4-hydroxylase.16 (12) The X-ray diffraction experiment for 1a was performed on a CAD4 Mach3 diffaractometer with graphite-monochromatized Mo KR radiation (n ) 0.710 73 Å). A total of 4220 reflection data, of which 3420 unique (Rint ) 0.023), were collected in a θ range of 2.25-26.970°. The data were corrected by Lp factors and decay (1.0%) but not absorption. The structure was solved by direct method and refined anisotropicly for all non-hydrogen atoms by full-matrix least squares. All hydrogen atoms were located by difference Fourier synthesis and refined isotropically. All calculations were carried out with Shelex97 on a 586 PC. Crystal data: space group P21/c, a ) 8.7139(4) Å, b ) 16.7814(8) Å, c ) 1.7419(7) Å, β ) 90.406(5)°, V ) 1570.76(15) Å3, Z ) 4, Dc ) 1.405 g cm-3, F(000))696, size 0.40 × 0.35 × 0.24 mm, µ ) 0.109 mm-1, R1 ) 0.053 (wR2 ) 0.113) for 2614 observed reflections with I g 2σ(I), GOF ) 1.192, max/min ∆F ) 0.22/0.17 e Å-3. (13) Ayerbe, M.; Arrieta, A.; Cossio, F. P.; Linden, A. J. Org. Chem. 1998, 63, 1795 (14) Harwood: L. M.; Lilley, I. A. Tetrhedron: Asymmetry 1995, 6, 1557 (15) Wittland, C.; Florke, U.; Risch, N. Synthesis 1997, 1291 Org. Lett., Vol. 2, No. 5, 2000
Scheme 3
A radical mechanism, in which oxygen in the air is suggested as the oxidant, has been proposed previously for the reaction between C60 and dimethyliminodiacetate.5,6 Foote et al. have recently established that singlet oxygen is involved in the photochemical reaction of C60 and amines.10 According to their mechanism, C60 sensitizes the formation of singlet oxygen in the first step, and this singlet oxygen then interacts with the amine to form an R carbon-centered radical, which adds to fullerene and opens a double bond on the spherical surface. When the same set of steps is repeated, a second R carbon of the attached amine is added to the other fullerene carbon of the already opened double bond, yielding a pyrrolidinofullerene derivative. Their study is extensive and the conclusion is well supported. The reaction here should follow the same mechanism as in Scheme 4. Because of the combined action of the electrondonating imino group and the electron-withdrawing carboxyl group, the R carbon-centered radical is more stable than the nitrogen-centered radical. Such a “push-pull” stabilized radical is the most stable for amino acids.17 In agreement with this fact, no product corresponding to nitrogen addition could be detected from the photochemical reaction. The formation of 2 further supports the presence of the R carboncentered radical. Blank experiment indicates that the presence of fullerene is essential for the reaction. No cycloaddition product could be detected when the reaction was carried out without the addition of fullerene. In summary, fullerene serves as an effective sensitizer for the formation of the iminodiacetic ester radical and the radical
Scheme 4
adds to maleimides in a 2 + 3 pattern to form a pyrrolidine derivative. Acknowledgment. L.G. thanks Dr. David R. M. Walton at the University of Sussex for helpful discussions. The project is supported by the National Natural Science Foundation of China (29825102). Supporting Information Available: Details of the X-ray diffraction data of compound 1a. This material is available free of charge via the Internet at http://pubs.acs.org. OL005503O
(16) Cunliffe C. J.; Franklin T. J.; Hales N. J.; Hill G. B. J. Med. Chem. 1992, 35, 2652
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(17) Easton, C. J. Chem. ReV. 1997, 97, 53
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