1-Pyrroline 1-Oxide1

[24423-88-9]  · C4H7NO  · 1-Pyrroline 1-Oxide  · (MW 85.12)

(prototypical cyclic nitrone for intermolecular 1,3-dipolar cycloadditions1,2)

Physical Data: bp 74-76 °C/0.1 mmHg.

Solubility: sol dichloromethane, chloroform, ether, aromatic hydrocarbons, water.

Form Supplied in: not commercially available.

Preparative Methods: usually prepared by oxidation of 1-hydroxypyrrolidine with two equivalents of yellow Mercury(II) Oxide (HgO) in dichloromethane or chloroform at 0-10 °C.3 After 4 h, the mixture is filtered to remove mercury salts and the nitrone is most often used without further purification, with or without solvent exchange. An alternative procedure is the direct oxidation of pyrrolidine with 30% aqueous Hydrogen Peroxide catalyzed by Na2WO4.H2O in water, followed by extraction with dichloromethane and chromatographic purification.4 Although the yield is lower, this method has the advantages of pyrrolidine as the starting material and of avoiding the use and disposal of large quantities of mercury(II) salts.

A regiospecific oxidative decarboxylation of N-alkyl-a-amino acids under phase transfer conditions using H2O2 and Na2WO4 catalyst has been used successfully with proline to afford 1-pyrroline 1-oxide in 55% yield.10 The method appears to be efficient and convenient for other cyclic as well as acyclic nitrones.

1,3-Dipolar Cycloadditions.

One of the more recent reviews cites 20 examples of cycloaddition between 1-pyrroline 1-oxide and acyclic and cyclic alkenes to give bicyclic (or tricyclic) isoxazolidines.1a These reactions are carried out in toluene at reflux or neat at 100 °C; however, a,b-unsaturated esters often react smoothly at room temperature. Numerous substituted 1-pyrroline 1-oxides have been studied, and intramolecular examples are known. The six-membered ring analog, 2,3,4,5-tetrahydropyridine 1-oxide, is also useful.1a,4 The cycloadditions are both stereoselective and regioselective. Terminal alkenes give exclusively 5-substituted isoxazolidines with the substituent cis to the hydrogen at the ring fusion (exo transition state) (eq 1).5 This is the expected regiochemistry for a nitrone LU-controlled process. When methyl crotonate was the educt alkene, the methoxycarbonyl group showed a preference for an endo transition state, as well as being positioned at C-4 in the isoxazolidine under conditions of kinetic control (eq 2).6

Electron-rich alkenes, i.e. vinyl ethers and enamines, undergo cycloaddition at slow rates and often give poor yields because of decomposition of the nitrone. High pressure conditions can obviate the problem (eq 3).7

One of the two syntheses of (±)-cocaine by Tufariello and co-workers3 involved both an intermolecular and an intramolecular cycloaddition, and it utilized some of the numerous further transformations of the isoxazolidine ring that enhance the versatility of 1,3-dipolar cycloadditions of nitrones in synthesis (eq 4). A similar approach was taken to synthesize anatoxin-a.8 The oxidative ring opening with m-Chloroperbenzoic Acid to generate an intermediate nitrone, the key to the success of this strategy, has recently been carried out on other polycyclic isoxazolidines with magnesium monoperoxyphthalate hexahydrate (MMPP).9

Other Reactions.

Like other nitrones, 1-pyrroline 1-oxide undergoes reactions with nucleophiles, electrophiles, and radicals, addition of organometallic reagents,4 reduction, oxidation, etc.2a However, these reactions have their greatest utility with substituted analogs such as 5,5-dimethyl-1-pyrroline 1-oxide (DMPO), a useful spin trapping reagent for biologically generated radicals.


1. For reviews primarily concerned with 1,3-dipolar cycloadditions: (a) Confalone, P. N.; Huie, E. M. OR 1988, 36, 1. (b) Little, R. D. COS 1991, 5, 247. (c) Padwa, A.; Schoffstall, A. M. Adv. Cycloaddition 1990, 2, 1. (d) DeShong, P.; Lander, S. W.; Leginus, J. M.; Dicken, C. M. Adv. Cycloaddition 1988, 1, 87. (e) Balasubramanian, N. OPP 1985, 17, 23. (f) Black, D. St. C.; Crozier, R. S.; Davis, V. C. S 1975, 205. (g) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, p 83. (h) Tufariello, J. J. ACR 1979, 12, 396.
2. For reviews of the synthesis and chemistry of nitrones, including 1,3-dipolar cycloadditions: (a) Breuer, E. In Nitrones, Nitronates, and Nitroxides; Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1989, pp 139, 245. (b) Tarrant, G. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 2, p 500. (c) Sandler, S. R.; Karo, W. In Organic Functional Group Preparations; Wasserman, H., Ed.; Academic: San Diego, 1983; Vol. 3, p 301. (d) Delpierre, G. R.; Lamchen, M. QR 1965, 329.
3. Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.; Wong, S. C.; Ali, Sk. A. JACS 1979, 101, 2435.
4. Murahashi, S.-I.; Mitsui, H.; Shiota, T; Tsuda, T.; Watanabe, S. JOC 1990, 55, 1736.
5. Iida, H.; Watanabe, Y.; Kibayashi, C. JCS(P1) 1985, 261.
6. Tufariello, J. J.; Tette, J. P. JOC 1979, 40, 3866. Tufariello, J. J.; Lee, G. E.; Senaratne, P. A.; Al-Nuri, M. TL 1979, 101, 4359.
7. Dicken, C. M.; DeShong, P. JOC 1982, 47, 2047.
8. (a) Tufariello, J. J.; Meckler, H.; Senaratne, K. P. A. JACS 1984, 106, 7979. (b) Tufariello, J. J.; Meckler, H.; Senaratne, K. P. A. T 1985, 41, 3447.
9. Holmes, A. B.; Hughes, A. B.; Smith, A. L. SL 1991, 47.
10. Murahashi, S.-I.; Imada, Y.; Ohtake, H. JOC 1994, 59, 6170.

Norman A. LeBel

Wayne State University, Detroit, MI, USA



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