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Alternative Oxidation
« on: December 11, 2001, 02:06:00 PM »
J. Org. Chem. 66:7907(2001)

A Mild and Effcient Alternative to the Classical Swern Oxidation

Lidia De Luca, Gianpaolo Giacomelli* and Andrea Porcheddu
Dipartimento di Chimica, University degli Studi di Sassari, Italy
Received July 17, 2001

Carbonyl compounds are of great importance as intermediates to prepare other functional groups in organic synthesis. In particular, aldehydes and N-protected alpha-amino aldehydesl are important and versatile compounds.
Oxidation of alcohols to the corresponding carbonyl compounds is one of the most important synthetic procedures, and the development of selective and extent reagents for that conversion, especially when other oxidizable functional groups are also present, has interested organic chemists for a long time. In this context, notwithstanding the availability of many preparative methods, the restrictions that accompany some of them make new, mild, and selective procedures highly desirable. Most of the methods for the oxidation of alcohols utilize dimethyl sulfoxide as a reagent via dimethyl alkoxysulfonioum salts that react with a base to give the carbonyl compound and dimethyl sulfide. The electrophilic reagents that have been used to activate dimethyl sulfoxide include acetic anhydride2, methanesulfonic anhydride3 tosyl chloride4, sulfur trioxide/pyridine5, phosphorus pentoxide6, thionyl chloride7; and oxalyl chloride7,8 among others. Generally, the activation of DMSO can be violent and exothermic, and successful activation requires low temperatures, usually -60°C. Of all the activators, the highest yields of carbonyl compounds, with minimal byproduct formation, were obtained with thionyl chlonde and oxalyl chloride, especially the latter. Unfortunately, oxalyl chloride is moisture sensitive and dangerously toxic, and its vapor is a powerful irritant, particularly to the respiratory system and to the eyes. On this basis and following our interest in the use of [1,3,5]triazine derivatives in organic synthesis9, herein we report a mild and efficient alternative procedure for the quantitative conversion of alcohols into the corresponding carbonyl compounds. The method uses dimethyl sulfoxide (DMSO), activated by 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride, TCT), under the so-called Swern oxidation conditions10.
We have observed that the activation of DMSO can be conveniently conducted with the very cheap cyanuric chloride, which can be used even for large-scale work, simply using THF as solvent. The procedure is based on treatment of TCT with 5 equiv of DMSO in THF at -30°C for 30 min, followed by addition of the alcohol. After an additional 30 min, triethylamine (TEA, 4 equiv) was added (Scheme 1). The reaction mixture was then quenched with water and worked up to yield the carbonyl compound. Although formation of the dimethyl alkoxysulfonium salt occurred even at 0°C without any apparent decomposition, the reactions were carried out at -30°C to prevent eventual formation of undesirable byproducts, such as chloro derivatives or thiomethyl ethers11.
As shown in Tables 1 and 2, a variety of carbonyl compounds and N-protected amino aldehydes were prepared from commercially available alcohols. The yields were quantitative (>99%), and the conversions12 was very high in most of the cases. The oxidation proceeds with satisfactory rates even when the alcohol has steric constrains. Only in the case of 9-fluorenemethanol was the reaction found to be very slow (20% conversion after 8 h). The oxidation of 2-phenylthioethanol is very slow too, possibly due to the competition of sulfur atom of the alcohol in the coordination with the TCT.
The methodology is cleanly applicable to N-protected beta-amino alcohols13: the corresponding aldehydes are recovered as pure products and in good conversions even if the reaction requires a longer time (90 min after the addition of TEA). Only N-Boc beta-amino alcohols seem to react more slowly and in some cases may deprotect partially under the reaction conditions (e.g., Table 2, run 3)
On these results, alpha-amino aldehydes could be efficiently prepared in total good yield by using TCT/NABH4 reduction9a of N-protected alpha-amino acid followed by oxidation according to the present procedure. Thus, (S)-N-benzyloxycarbonyl-2-amino-3-phenylpropionaldehyde, [alpha]20D -52.3 (c 0.7, Me0H) was recovered, without significant racemization of the chiral center14, from (S)-N-benzyloxycarbonylphenylalanine. This method could avoid some problems encountered in the synthesis of the aldehydes by controlled DIBAL reduction of alpha-amino esters15 or in the reduction of N-protected alpha-amino acids by H2 and Pd/C9b.
In conclusion, the method presented in this report is operationally simple and can be used as a valid alternative to the classical Swern oxidation, requiring milder conditions and cheaper reagents.

Experimental Section

All the solvents and the reagents were used in the commercially available grade of purity. The N-protected alpha-amino alcohols were prepared from the corresponding alpha-amino acids according to the literature9b and their purity was established before utilization by melting point and optical rotation. Cyanuric chloride was purchased from Avocado. Elemental analyses were performed on a Perkin-Elmer 420 B analyzer, optical rotations ware measured with a Perlrin-Elmer 241 automatic polarimeter in a 1 dm tube. The 1H NMR (300 MHz) and 13C NMR (75.4 MHz) were obtained with a Varian VXR-300 spectrometer from CDCl3 solutions.
General Procedure for the Synthesis of Aldehydes and Ketones. The procedure for the preparation of N-benzyloxycarbonyl-2-amino-3-phenylpropionaldehyde is representative. DMSO (1.25 mL, 17.6 mmol) was added to a solution of TCT (0.66 g, 3.6 mmol) in THF (20 mL) stirred and maintained at -30°C. After 30 min, N-benzyloxycarbonyl-2-amino-3-phenylpropan-1-ol, [alpha]20D -41.0 (c 1, MeOH) (0.86 g, 3 mmol), in THF (10 mL) was added slowly at -30°C with stirring, followed by TEA (2 mL, 14.3 mmol) after an additional, 30 min. After 15 min, the mixture was warmed to room temperature, the solvent evaporated under vacuum, and Et2O (50 mL) added to the solid formed. The mixture was quenched with 1N HCI, and the organic phase washed with 15 mL of a saturated solution of NaHCO3, followed by brine. The organic layer was dried (Na2SO4) and the solvent evaporated to yield pure N-benzyloxycarbonyl-2-amino-3-phenylpropionaldehyde (0.77 g, 90%): mp 79°C; [alpha]20D -52.3 (c 0.7 MeOH)14; 1H-NMR delta 9.63 (s 1H), 7.37 (m, 10H), 5.31 (s, 1H), 5.11 (s, 2H), 4.50 (m, 1H), 3.15 (d, 2H).
Simple aldehydes and ketones obtained were characterized by usual spectral data and compared with authentical samples, when commercial, or with the literature values. The following alpha-amino aldehydes were already described: N-benzyloxycarbonylglycinal16, N-tert-butoxycarbonyl-L-phenylalaninal14b,17, N-tert-butoxycarbonyl-L-isoleucinal17, N-benzyloxycarbonyl-L-valinal16, N-(9-fluorenylmethoxycarbonyl)-L-phenylalaninal18, N- benzyloxycarbonyl-L-prolinal14.
N-(9-fluorenylmethoxycarbonyl)-L-prolinal (0.83 g, 86%): 1H-NMR delta 9.44 (s, 0.6H), 9.13 (s, 0.4H), 7.82-7.23 (m, 8H) 4.47-3.98 (m, 3H), 3.89 (m, 1H), 3.40 (m, 2H), 2.03-1.60 (m, 4H); 13C-NMR delta 199.4, 157.4, 140.1, 132.6, 128.2, 124.9, 120.8, 67.0, 64.8, 47.2, 46.3, 27.6, 23.5. Anal. Calcd for C20H19NO3 (321.14): C, 74.75; H, 5.96; N, 4.36. Found: C, 74.75; H, 5.99; N 4.34.


(1) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149.
(2) Albright, J. D.; Goldman, L. J. Org. Chem. 1967, 32, 2416.
(3) Murray, R. W.; Gu, D. J. Chem. Soc., Perkin Trans. 2 1994, 451.
(4) Albright, J. D. J. Org. Chem. 1974, 39, 1977.
(5) Parikh, J. R.; Doering, W. Von E. J. Am. Chem. Soc. 1967, 89, 5507.
(6) Taber; D. F.; Amedio, J. C., Jr.; Jung, K. J. Org. Chem.[/i] 1987, 52, 5621.
(7) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(8) Marx, M.; Tidwell, T. T. J. Org. Chem. 1984, 49, 788. Liu, Y.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856.
(9) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999, 40, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem. 1999, 64, 8962. (c) Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000, 275. (d) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 1519.
(10) The use of TCT was already cited but the author reported only two examples, where TCT was used dissolved in a very toxic, possibly carcinogenic solvent such as HMPA4.
(11) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(12) Determined by NMR analysis of the crude product after 30 min of the addition of TEA.
(13) In the case of N-Fmoc alpha-amino alcohol, diisopropylethylamine (DIPEA) was used instead of TEA.
(14) (a) Sharma, R. P.; Gore, M. G.; Akhtar, M. J. Chem. Soc, Chem. Commun. 1979, 875. (b) Soucek, M.; Urban, J. Collect. Czech. Chem. Commun. 1995, 60, 693.
(15) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18. Roush, W. R.; Hunt, J. A. J. Org. Chem. 1995, 60, 798.
(16) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J. Org. Chem. 1987, 52, 1252.
(17) Castro, B.; Fehrentz, J. A. Synthesis 1983, 676.
(18) Wen, J. J.; Crews, C. M. Tetrahedron: Asymmetry 1998, 9, 1855.


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Re: Alternative Oxidation
« Reply #1 on: December 11, 2001, 02:34:00 PM »
Great, It goes right on to my page!


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Re: Alternative Oxidation
« Reply #2 on: December 12, 2001, 05:41:00 AM »
Always at your service, Chief!  8)