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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;
Further Information

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

    References and Notes

  • 1a Schröder M. Chem. Rev.  1980,  80:  187 
    Search in Google Scholar
  • 1b Haines AH. In Methods for the Oxidation of Organic Compounds   Academic Press; London: 1985.  p.75-84  
  • 1c Singh HS. In Organic Syntheses by Oxidation with Metal Compounds   Mijis WJ. de Jonge CRHI. Plenum Press; New York: 1986.  p.633-693.  
  • 2a Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
    Search in Google Scholar
  • 2b Waldmann H. In Organic Synthesis Highlights II   Wiley-VCH; Weinheim: 1995.  p.9-18  
  • 2c Kolb HC. Sharpless KB. In Transition Metals for Organic Synthesis   Vol. 2:  Beller M. Bolm C. Wiley-VCH; Weinheim: 2004.  p.275-307  
    Search in Google Scholar
  • 3a Maione AM. Romeo A. Synthesis  1984,  955 
  • 3b Coleman KS. Coppe M. Thomas C. Osborn JA. Tetrahedron Lett.  1999,  40:  3723 
    Search in Google Scholar
  • 3c Döbler C. Mehltretter GM. Sundermeier U. Eckert M. Militzer H.-C. Beller M. Tetrahedron Lett.  2001,  42:  8447 
    Search in Google Scholar
  • 3d Muldoon J. Brown SN. Org. Lett.  2002,  4:  1043 
    Search in Google Scholar
  • 4a Henbest HB. Khan SA. J. Chem. Soc., Chem. Commun.  1968,  1036 
  • 4b Hauser FM. Ellenberger SR. Clardy JC. Bass LS. J. Am. Chem. Soc.  1984,  106:  2458 
    Search in Google Scholar
  • 4c Solladié G. Fréchou C. Demailly G. Tetrahedron Lett.  1986,  27:  2867 
    Search in Google Scholar
  • 4d Kaldor SW. Hammond M. Tetrahedron Lett.  1991,  32:  5043 
    Search in Google Scholar
  • 4e Priebe W. Grynkiewicz G. Tetrahedron Lett.  1991,  32:  7353 
    Search in Google Scholar
  • 5a Schröder M. Griffith WP. J. Chem. Soc., Dalton Trans.  1978,  1599 
  • 5b Bassignani L. Brandt A. Caciagli V. Re L. J. Org. Chem.  1978,  43:  4245 
    Search in Google Scholar
  • 5c Hillis LR. Ronald RC. J. Org. Chem.  1985,  50:  470 
    Search in Google Scholar
  • 5d Armstrong A. Gethin DM. Wheelhouse CJ. Synlett  2004,  350 
  • 6 Gao S. Herzig D. Wang B. Synthesis  2001,  544 
    Thieme Connect
  • 6a Cook JW. Schoental R. J. Chem. Soc.  1948,  170 
  • 6b Okamoto A. Tainaka K. Kamei T. Org. Biomol. Chem.  2006,  4:  1638 
    Search in Google Scholar
  • 6c Tanaka K. Tainaka K. Okamoto A. Bioorg. Med. Chem.  2007,  15:  1615 
    Search in Google Scholar
  • 6d Umemoto T. Okamoto A. Org. Biomol. Chem.  2008,  6:  269 
    Search in Google Scholar
  • Compound 1a:
  • 8a Gates M. Montzka TA. J. Med. Chem.  1964,  7:  127 
    Search in Google Scholar
  • 8b Osa Y. Ida Y. Yano Y. Furuhata K. Nagase H. Heterocycles  2006,  69:  271 
    Search in Google Scholar
  • 8c Fujii H. Osa Y. Ishihara M. Hanamura S. Nemoto T. Nakajima M. Hasebe K. Mochizuki H. Nagase H. Bioorg. Med. Chem. Lett.  2008,  18:  4978 
    Search in Google Scholar
  • Compound 1b:
  • 9a Coop A. Janetka JW. Lewis JW. Rice KC. J. Org. Chem.  1998,  63:  4392 
    Search in Google Scholar
  • 9b Carroll RJ. Leisch H. Rochon L. Hudlicky T. Cox DP. J. Org. Chem.  2009,  74:  747 
    Search in Google Scholar
  • 10a Minato M. Yamamoto K. Tsuji J. J. Org. Chem.  1990,  55:  766 
    Search in Google Scholar
  • 10b Kwong H.-L. Sorato C. Ogino Y. Chen H. Sharpless KB. Tetrahedron Lett.  1990,  21:  2999 
    Search in Google Scholar
  • 11a Nan Y. Xu W. Zaw K. Hughes KE. Huang L.-F. Dunn WJ. Bauer L. Bhargava HN. J. Heterocycl. Chem.  1997,  34:  1195 
    Search in Google Scholar
  • 11b Meredith W. Nemeth GA. Boucher R. Carney R. Haas M. Sigvardson K. Teleha CA. Tetrahedron Lett.  2003,  44:  73814 
    Search in Google Scholar
  • 11c Fujii H. Imaide S. Watanabe A. Nemoto T. Nagase H. Tetrahedron Lett.  2008,  49:  6293 
    Search in Google Scholar
  • Dihydroxylation of enamines by OsO4 oxidation was reported to occur:
  • 12a Kutney JP. Bylsma F. J. Am. Chem. Soc.  1970,  92:  6090 
    Search in Google Scholar
  • 12b LaLonde RT. Auer E. Wong CF. Muralidharan VP. J. Am. Chem. Soc.  1971,  93:  2501 
    Search in Google Scholar
  • 12c Mangeney P. Andriamialisoa RZ. Lanlois N. Langlois N. Langlois Y. Potier P. J. Am. Chem. Soc.  1979,  101:  2243 
    Search in Google Scholar
  • Enamine moieties in indoles were reportedly oxidized with OsO4 to indolinones via dihydroindolines:
  • 13a For recent examples, see: Sundberg RJ. In The Chemistry of Indoles   Academic Press; London: 1970.  p.298 
  • 13b Kitajima M. Takayama H. Sakai S. J. Chem. Soc., Perkin Trans. 1  1994,  1573 
  • 13c Takayama H. Tominaga Y. Kitajima M. Aimi N. Sakai S. J. Org. Chem.  1994,  59:  4381 
    Search in Google Scholar
  • 13d Peterson AC. Cook JM. J. Org. Chem.  1995,  60:  120 
    Search in Google Scholar
  • 13e Wearing XZ. Cook JM. Org. Lett.  2002,  4:  4237 
    Search in Google Scholar
  • 16 Nagase H. Abe A. Portoghese PS. J. Org. Chem.  1989,  54:  4120 
    CrossrefSearch in Google Scholar
  • 17a Carlsen PHJ. Katsuki T. Martin VS. Sharpless KB. J. Org. Chem.  1981,  46:  3936 
    Search in Google Scholar
  • 17b Courtney JL. In Organic Syntheses by Oxidation with Metal Compounds   Mijis WJ. de Jonge CRHI. Plenum Press; New York: 1986.  p.445-467  
  • 17c Murahashi S. Komiya N. In Ruthenium in Organic Synthesis   Murahashi S. Wiley-VCH; Weinheim: 2004.  p.53-93  
  • 17d Bernd P. Synthesis  2005,  2453 
  • TPAP (tetra-n-propylammonium perruthenate) was also used in organic synthesis. See the following reviews:
  • 18a Ley SV. In Comprehensive in Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.305-327  
    Search in Google Scholar
  • 18b Griffith WP. Chem. Soc. Rev.  1992,  21:  179 
    Search in Google Scholar
  • 18c Ley SV. Norman J. Griffith WP. Synthesis  1994,  639 
  • 19a Sheehan JC. Tulis RW. J. Org. Chem.  1974,  39:  2264 
    Search in Google Scholar
  • 19b Bettoni G. Franchini C. Morlacchi F. Tangari N. Tortorella V. J. Org. Chem.  1976,  41:  2780 
    Search in Google Scholar
  • 19c Yoshifuji S. Tanaka K. Nitta Y. Chem. Pharm. Bull.  1985,  33:  1749 
    Search in Google Scholar
  • 19d Yoshifuji S. Arakawa Y. Nitta Y. Chem. Pharm. Bull.  1985,  33:  5042 
    Search in Google Scholar
  • 19e Yoshifuji S. Tanaka K. Kawai T. Nitta Y. Chem. Pharm. Bull.  1985,  33:  5515 
    Search in Google Scholar
  • 19f Yoshifuji S. Tanaka K. Kawai T. Nitta Y. Chem. Pharm. Bull.  1986,  34:  3873 
    Search in Google Scholar
  • 19g Kaname M. Yoshifuji S. Sashida H. Tetrahedron Lett.  2008,  49:  2786 
    Search in Google Scholar
  • 20 Compound 1f: Horikiri H. Kawamura K. Heterocycles  2004,  63:  865 
    CrossrefSearch in Google Scholar
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.