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Org. Synth. 2005, 81, 204

DOI: 10.15227/orgsyn.081.0204

METHYLTRIOXORHENIUM CATALYZED OXIDATION OF SECONDARY AMINES TO NITRONES: N-BENZYLIDENE-BENZYLAMINE N-OXIDE

[Benzenemethanamine, (N-phenylmethylene)-, N-oxide]

Submitted by Andrea Goti, ¹ Francesca Cardona, and Gianluca Soldaini.

Checked by Xiaowu Jiang and Marvin J. Miller.

1. Procedure

A 250-mL, two-necked, round-bottomed flask equipped with a magnetic stirbar, thermometer, and a reflux condenser fitted with a rubber septum and balloon of argon is charged with a solution of methyltrioxorhenium (MTO) (0.013 g, 0.05 mmol, 0.1% mol equiv) in 100 mL of methanol (Note 1). Urea hydrogen peroxide (UHP) (14.3 g, 152 mmol) is added (Notes 1, 2, 3, 4), the flask is cooled in an ice bath, and dibenzylamine (9.7 mL, 50.7 mmol) is then added dropwise via syringe over 10 min (Notes 1, 5). After completion of the addition, the ice bath is removed and the mixture is stirred at room temperature (Note 6). A white precipitate forms after approximately 5 min (Note 7) and the yellow color disappears within 20 min (Note 8). Another four portions of MTO (0.1% mol equiv, 0.013 g each) are added at 30-min intervals (2.5 hr total reaction time). After each addition, the reaction mixture develops a yellow color, which then disappears; only after the last addition does the mixture remain pale yellow (Note 9). The reaction flask is cooled in an ice bath and solid sodium thiosulfate pentahydrate (12.6 g, 50.7 mmol) is added in portions over 20 min in order to destroy excess hydrogen peroxide (Note 10). The cooled solution is stirred for 1 hr further, at which point a KI paper assay indicates that the excess oxidant has been completely consumed. The solution is decanted into a 500-mL flask to remove small amounts of undissolved thiosulfate. The solid is washed with 50 mL of MeOH and the methanol extract is added to the reaction solution which is then concentrated under reduced pressure by rotary evaporation. Dichloromethane (250 mL) is added to the residue and the urea is removed by filtration through cotton and celite. Concentration of the filtrate affords 10.3 g (97%) of the nitrone as a yellow solid (Note 11).

If desired, the nitrone can be recrystallized from diisopropyl ether (200 mL) (Notes 12, 13), affording 9.0 g (84%) of a white solid (Note 14). Concentration of the mother liquor and recrystallization of the residue from 40 mL of diisopropyl ether provides 0.600 g of additional nitrone. Total yield: 9.6 g (89%) of the nitrone as a white solid (Note 15).

2. Notes

1. Dibenzylamine, MTO, and UHP were purchased from Aldrich Chemical Company and used as received.

2. Caution: Potential hazards are associated with the use of the urea hydrogen peroxide complex (UHP). Due to the relatively high hydrogen peroxide content (ca. 36%) of this reagent, care should be exercised in its use. Additionally, concentrated solutions of H₂O₂ are potentially explosive, especially when contaminants such as metals are present. However, it has been reported that UHP is a safe source of hydrogen peroxide,² which makes it a good alternative to anhydrous or highly concentrated aqueous solutions of H₂O₂. UHP has been judged stable by negative impact and pressure-time tests for explosiveness on small samples² and the submitters have never experienced problems in its use.

3. Although the oxidation requires 2 mol equiv of oxidant with respect to amine, use of 3 mol equiv of UHP is advised in order to speed up the reaction and to reduce the amount of catalyst required. For example, use of a smaller excess of UHP (2.5 mol equiv) required an increase to 0.7% mol equiv of MTO and a 4 hr reaction time in order for the oxidation to proceed to completion.

4. Immediately upon addition of the urea-hydrogen peroxide adduct to the solution containing methyltrioxorhenium, a yellow color develops due to formation of the catalytically active rhenium peroxo complexes.³

5. The internal temperature of the solution rises from ca. 4°C to 12-13°C after all of the amine has been added.

6. The internal temperature varies from 24°C to 32°C during the whole reaction time, with the highest values being reached after each addition of the catalyst.

7. The white precipitate is presumably N,N-dibenzylhydroxylamine, an intermediate oxidation product, which disappears after the third catalyst addition.

8. The disappearance of the yellow color indicates a low concentration of the active catalytic species due to loss in efficiency of the cycle.

9. Monitoring of the reaction by TLC on silica gel showed complete consumption of the starting amine (elution with 20:1 CH₂Cl₂/CH₃OH, visualization by UV and by iodine; dibenzylamine: R_f = 0.4, nitrone: R_f = 0.7).

10. The submitters found that on small scale (1 mmol) this treatment is unnecessary. On a larger scale, it is recommended to destroy excess hydrogen peroxide for safety, although oxidations on larger scale without this treatment have been carried out without experiencing any problem. It was also observed that product of higher purity is obtained when hydrogen peroxide is destroyed.

11. The crude nitrone has the following physical data: mp 75-77°C; Anal. Calcd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.39; H, 6.18; N, 6.78.

12. Caution: Use of diisopropyl ether from a freshly opened bottle is advised, due to possible formation of peroxides in aged ethereal solvents. Other solvents were less effective for this recrystallization.

13. The crude solid is readily dissolved in a smaller amount of solvent, but employing the indicated volumes is recommended in order to achieve better yields of recrystallization. With this volume of solvent, heating at 74°C is sufficient to have complete solubilization of the solid.

14. The nitrone exhibits the following spectral and physical data: mp (uncorr.) 79-81°C (lit.⁴ 81-83°C); ¹H NMR pdf (300 MHz, CDCl₃) δ: 5.09 (s, 2 H), 7.38-7.49 (m, 9 H), 8.17-8.20 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ: 71.29, 128.41, 128.57, 128.93, 129.17, 130.35, 130.51, 133.35, 134.11; IR (KBr) cm⁻¹: 3061, 3030, 2995, 1581, 1497, 1459, 1153; MS (EI, 70 eV) m/z (%): 211 (M^+., 27), 195 (7), 181 (16), 91 (100), 83 (78), 66 (70), 65 (52); exact mass (FAB): Calcd (M+H)⁺ 212.1075, found 212.1064. Anal. Calcd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.57; H, 5.92; N, 6.51.

15. The submitters report a yield of 86% and the checkers obtained the product in 85-90% yield in several runs.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Nitrones are very useful tools in the construction of structurally complex molecules and particularly nitrogen-containing biologically active compounds, usually allowing a high degree of diastereocontrol. In this context, both the [3+2] cycloaddition of nitrones to alkenes⁵^,⁶ and the alkylation of nitrones by organometallic reagents⁷ have been extensively developed and have become extremely reliable synthetic procedures. In addition, nitrones are useful spin trap reagents, widely employed in biological systems.⁸

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with N-hydroxylamines⁵ and the oxidation of N,N-disubstituted hydroxylamines.⁵^,⁹ Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.¹⁰^,¹¹^,¹²^,¹³. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane¹⁰ or N-phenylsulfonyl-C-phenyloxaziridine,¹¹ and oxidations with hydrogen peroxide catalyzed by Na₂WO₄⁴^,¹² or SeO₂.¹³ All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give somewhat erratic and unreproducible results in some cases. Particularly, functionalized pyrrolidines and piperidines behaved as capricious substrates in those protocols. For example, a chiral optically active pyrrolidine underwent racemization to variable degrees upon oxidation to the corresponding nitrone with H₂O₂ catalyzed by Na₂WO₄¹⁴ and oxidation with dimethyldioxirane of a chiral 2-morpholinone gave scarcely reproducible results.¹⁵ In these cases, the described oxidation method using methyltrioxorhenium/urea. H₂O₂ complex was demonstrated to be a better alternative, furnishing consistently good and reproducible yields (see Table, entries 9 and 11, respectively), without loss of enantiomeric purity, also on multi-gram scale. The examples reported in the Table are illustrative of the scope of the oxidation method described here. Most of the reactions reported in the Table have been carried out on a 0.5-1 mmol scale and are unoptimized, with a 2% mol equiv of MTO being employed. The procedure described above has been scaled-up and optimized, also in terms of minimal catalyst use. The amount of catalyst to be used in order to achieve complete conversion is not greatly influenced by the reaction scale. Indeed, essentially the same results as those reported above have been obtained on a 10 mmol scale with 0.4% mol equiv of MTO and in a further scale-up of the process on 0.1 mol of dibenzylamine with a minimal increase to 0.6% mol equiv of MTO. On a 10-12 mmol scale, 0.7% mol equiv of MTO were necessary for oxidizing completely dibutylamine and 1% mol equiv was sufficient to oxidize the more sterically congested N-(tert-butyl)-N-benzylhydroxylamine.

Due to its broad scope, as well as to its favorable features (commercial availability of the catalyst, use of a "green" oxidant, economy, extremely simple procedure and work-up), this method has been rapidly accepted, as demonstrated by its use by several different research groups, despite its recent disclosure.¹⁶^,¹⁷ This procedure employing CH₃ReO₃ and UHP appears to be the method of choice when optically active nitrones are prepared by oxidation of the corresponding amines.¹⁴^,¹⁵^,¹⁸

References and Notes

Dipartimento di Chimica Organica "Ugo Schiff", Polo Scientifico, Università degli Studi di Firenze, via della Lastruccia 13, I-50019 Sesto Fiorentino, Firenze, Italy.
Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990, 533.
(a) Herrmann, W. A.; Fischer, R. W.; Scherer, W.; Rauch, M. U. Angew. Chem. Int. Ed. Engl. 1993, 32, 1157; (b) Espenson, J. H. Chem. Commun. 1999, 479.
Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736.
(a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.; Ed.; John Wiley & Sons: New York, 1984; (b) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1; (c) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; Feuer, H., Ed.; VCH Publishers: New York, 1988; (d) Frederickson, M. Tetrahedron 1997, 53, 403.
For a recent use of nitrones in a different [3+2] cycloaddition, see: Hanessian, S.; Bayrakdarian, M. Tetrahedron Lett. 2002, 43, 967.
(a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895; (c) Lombardo, M.; Trombini, C. Synthesis 2000, 759; (d) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442.
(a) Janzen, E. G. In Free Radicals in Biology; Pryor, W. A., Ed.; Academic Press: New York, 1980; vol. 4, pp. 115-154; (b) Rosen, G. M.; Finkelstein, E. Adv. Free Rad. Biol. Med. 1985, 1, 345-375; (c) Janzen, E. G.; Haire, D. L. In Advances in Free Radical Chemistry; Tanner, D. D., Ed.; Jai Press: Greenwich, CT, 1990.
(a) Cicchi, S.; Corsi, M.; Goti, A. J. Org. Chem. 1999, 64, 7243; (b) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42, 6503.
Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954.
Zajac, W. W., Jr.; Walters, T. R.; Darcy, M. G. J. Org. Chem. 1988, 53, 5856.
Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth., Coll. Vol. IX 1998. 632.
Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383.
Einhorn, J.; Einhorn, C.; Ratajczak, F.; Gautier-Luneau, I.; Pierre, J.-L. J. Org. Chem. 1997, 62, 9385.
Long, A.; Baldwin, S. W. Tetrahedron Lett. 2001, 42, 5343.
Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025.
Related methods employing H₂O₂ instead of UHP have been published: (a) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. J. Org. Chem. 1996, 61, 8099; (b) Yamazaki, S. Bull. Chem. Soc. Jpn. 1997, 70, 877.
(a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Durif, A.; Averbuch, M.-T.; Pierre, J.-L. Tetrahedron Lett. 1998, 39, 2565; (b) Shibata, T.; Uemae, K.; Yamamoto, Y. Tetrahedron: Asymmetry 2000, 11, 2339; (c) Okue, M.; Kobayashi, H.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Watanabe, H. Kitahara, T. Tetrahedron Lett. 2002, 43, 857; (d) Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Synthesis 2007, 485
It has been recently discovered that imines also undergo oxidation to nitrones under similar conditions: Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

N-Benzylidene-benzylamine N-oxide;
Benzenemethanamine, N-(phenylmethylene)-, N-oxide; (3376-26-9)

Methyltrioxorhenium:
Rhenium, methyltrioxo-, (T-4); (70197-13-6)

Urea hydrogen peroxide:
Urea, compd. with
hydrogen peroxide (H₂O₂) (1:1); (124-43-6)

Dibenzylamine:
Benzenemethanamine, N-(phenylmethyl)-; (103-49-1)

Notes

References/EndNotes

Article Compounds

Authors