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Synlett 2009(14): 2341-2345  
DOI: 10.1055/s-0029-1217811
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel Oxidation Reaction of Tertiary Amines with Osmium Tetroxide

Hideaki Fujii, Ryo Ogawa, Eikichi Jinbo, Saori Tsumura, Toru Nemoto, Hiroshi Nagase*
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Fax: +81(3)34425707; e-Mail: nagaseh@pharm.kitasato-u.ac.jp;
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Publication History

Received 1 May 2009
Publication Date:
07 August 2009 (online)

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Abstract

Tertiary amines were oxidized with OsO4 to afford mixtures of lactams, hydroxylactams, and ketolactams. In contrast to RuO4, which was known to oxidize tertiary amines, amides, and N-carbamoylamines, OsO4 oxidized the tertiary amines exclusively and tolerated amides and N-carbamoylamines. A mechanism for the oxidation reaction is also proposed.

Key words

osmium tetroxide - oxidation - tertiary amine - 4,5-epoxymorphinan - opioid

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14

In the Supporting Information, the deprotonation of osmate ester is discussed in detail.

15

Plausible mechanisms to amide 2 and lactam 6 are described in the Supporting Information.

21

Oxidation of Amine with OsO 4 Stoichiometric Reaction Conditions: Conditions I
To the solution of amine in pyridine was added OsO4 (3 mol equiv) and stirred at r.t. for the time indicated in Tables  [¹] and  [²] . The aqueous solution of Na2SO3 was added to the reaction mixture and stirred vigorously at r.t. for several hours. The resulting mixture was evaporated under reduced pressure and extracted with CHCl3. The organic layer was washed with brine and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography and/or preparative TLC.
Catalytic Reaction Conditions: Conditions II
Amine was added to the solution of K3Fe(CN)6 (9 mol equiv), K2CO3 (9 mol equiv), and OsO4 (0.1 mol equiv) in t-BuOH and distilled H2O (1:1) and stirred at r.t. for the time indicated in Tables  [¹] and  [²] . To the reaction mixture was added the aqueous solution of Na2SO3 and stirred at r.t. for several hours. The resulting mixture was poured into distillated H2O and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and/or preparative TLC.

22

Amide 2a
¹H NMR (300 MHz, CDCl3): δ = 0.67-1.25 (m, 5 H), 1.44-1.86 (m, 6 H), 1.93-2.02 (m, 0.7 H), 2.07-2.15 (m, 0.3 H), 2.54-2.63 (m, 0.3 H), 2.62 (d, J = 18.3 Hz, 0.7 H), 2.76 (d, J = 18.0 Hz, 0.3 H), 2.90 (dd, J = 5.9, 18.3 Hz, 0.7 H), 3.00 (dd, J = 5.4, 18.0 Hz, 0.3 H), 3.05-3.18 (m, 0.7 H), 3.76-3.93 (m, 2 H), 3.89 (s, 3 H), 3.96-4.09 (m, 1.7 H), 4.14-4.24 (m, 1 H), 4.38-4.47 (m, 0.3 H), 4.49 (s, 1 H), 4.65 (br s, 0.3 H), 5.10-5.16 (m, 0.7 H), 6.64 (br d, J = 8.4 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H). IR (film): 3467, 2947, 1632, 1502, 1437, 1261, 1168, 1017 cm-¹. HRMS-FAB: m/z calcd for C23H28NO5 [M + H]+: 398.1962; found: 398.1976.



Ketolactam 3
¹H NMR (300 MHz, CDCl3): δ = 1.31-1.58 (m, 2 H), 1.66-1.82 (m, 2 H), 2.63-2.73 (m, 1 H), 2.78-2.96 (m, 2 H), 3.71-4.03 (m, 4 H), 3.87 (s, 3 H), 4.20-4.29 (m, 1 H), 5.42 (s, 1 H), 6.67 (d, J = 8.1 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 7.74 (br s, 1 H). IR (film): 1736, 1694 cm-¹. HRMS-FAB: m/z calcd for C19H20NO6 [M + H]+: 358.1291; found: 358.1300.
Ketolactam 4a
¹H NMR (300 MHz, CDCl3): δ = 0.28-0.40 (m, 2 H), 0.49-0.69 (m, 2 H), 1.03-1.18 (m, 1 H), 1.35-1.61 (m, 2 H), 1.66-1.86 (m, 2 H), 2.67-2.76 (m, 1 H), 2.78 (dd, J = 4.2, 17.7 Hz, 1 H), 2.93 (dd, J = 6.9, 14.1 Hz, 1 H), 3.04 (dd, J = 1.2, 17.7 Hz, 1 H), 3.75-4.10 (m, 5 H), 3.86 (s, 3 H), 4.21-4.29 (m, 1 H), 5.40 (s, 1 H), 6.65 (d, J = 8.1 Hz, 1 H), 6.84 (d, J = 8.1 Hz, 1 H). IR (film): 2923, 1733, 1670 cm-¹. HRMS-FAB: m/z calcd for C23H26NO6 [M + H]+: 412.1760; found: 412.1776.
Hydroxylactam 5a
¹H NMR (300 MHz, CDCl3): δ = 0.21-0.36 (m, 2 H), 0.45-0.65 (m, 2 H), 0.99-1.13 (m, 1 H), 1.17-1.35 (m, 1 H), 1.51-1.77 (m, 3 H), 2.60-2.71 (m, 2 H), 2.76 (dd, J = 7.1, 14.0 Hz, 1 H), 2.89 (br d, J = 17.4 Hz, 1 H), 3.71-4.00 (m, 6 H), 3.87 (s, 3 H), 4.17-4.25 (m, 1 H), 5.17 (s, 1 H), 6.59 (d, J = 8.1 Hz, 1 H), 6.79 (d, J = 8.1 Hz, 1 H). One proton of the OH group was not observed. IR (film): 3294, 2928, 1623, 1503, 1439, 1276, 1194, 1055 cm-¹. HRMS-FAB: m/z calcd for C23H28NO6 [M + H]+: 414.1917; found: 414.1896.
Lactam 6a
¹H NMR (300 MHz, CDCl3): δ = 0.21-0.34 (m, 2 H), 0.45-0.63 (m, 2 H), 0.98-1.12 (m, 1 H), 1.18-1.35 (m, 1 H), 1.52-1.77 (m, 3 H), 2.35 (dt, J = 12.7, 3.7 Hz, 1 H), 2.61 (d, J = 17.1 Hz, 1 H), 2.60-2.77 (m, 2 H), 2.72 (d, J = 17.4 Hz, 1 H), 2.93 (dd, J = 1.2, 17.4 Hz, 1 H), 3.73-3.81 (m, 1 H), 3.84-4.02 (m, 4 H), 3.87 (s, 3 H), 4.20 (dt, J = 5.2, 6.8 Hz, 1 H), 4.49 (s, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H). IR (film): 2923, 1635, 1504, 1440 cm-¹. HRMS-FAB: m/z calcd for C23H28NO5 [M + H]+: 398.1967; found: 398.1962.
Iminoketone 7
¹H NMR (400 MHz, CDCl3): δ = 1.28-1.41 (m, 1 H), 1.44-1.54 (m, 1 H), 1.68-1.78 (m, 2 H), 2.45 (ddd, J = 3.2, 4.3, 12.3 Hz, 1 H), 2.91 (ddd, J = 0.8, 5.4, 17.9 Hz, 1 H), 2.96 (ddd, J = 0.7, 2.0, 17.8 Hz, 1 H), 3.77-3.82 (m, 1 H), 3.86 (s, 3 H), 3.91 (dt, J = 7.3, 6.5 Hz, 1 H), 4.00 (q, J = 6.6 Hz, 1 H), 4.24 (ddd, J = 5.4, 6.8, 7.1 Hz, 1 H), 4.54 (ddd, J = 1.8, 3.3, 6.7 Hz, 1 H), 5.32 (s, 1 H), 6.66 (d, J = 8.2 Hz, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 1.5 Hz, 1 H). IR (film): 2928, 1710, 1606, 1503, 1440, 1279, 1187, 1061 cm-¹. HRMS-FAB: m/z calcd for C19H20NO5 [M + H]+: 342.1341; found: 342.1335.