Download PDF
Synlett 2007(13): 2130-2132  
DOI: 10.1055/s-2007-984900
LETTER
© Georg Thieme Verlag Stuttgart · New York

Facile Synthesis of 1,1,3-Tetramethylisoindole N-Oxide from 2-Chlorobenzoic Acid Using Reverse-Cope Cyclization as a Key Step

Bunpei Hatano*, Haruna Sato, Tomohiro Ito, Tateaki Ogata
Department of Chemistry and Chemical Engineering, Faculty of Engineering, Yamagata University, 3-4-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
Fax: +81(238)263413; e-Mail: hatano@yz.yamagata-u.ac.jp;
Further Information

Publication History

Received 16 April 2007
Publication Date:
17 July 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

We have achieved an efficient alternative synthesis of 1,1,3-tetramethylisoindole N-oxide (1) using reverse-Cope cyclization as a key step, affording 1 in nine steps and 28% yield from 2-chlorobenzoic acid (2).

Key words

reverse-Cope cyclization - isoindole N-oxide - synthesis

    References and Notes

  • 1a Bandara BMR. Hinojosa O. Bernofsky C. J. Org. Chem.  1994,  59:  1642 
    Google Scholar
  • 1b Barasch D. Krishna MC. Russo A. Katzhendler J. Samuni A. J. Am. Chem. Soc.  1994,  116:  7319 
    Google Scholar
  • 1c Janzen EG. Zhang YK. Arimura M. Chem. Lett.  1993,  497 
    Google Scholar
  • 1d Janzen EG. Jandrisits LT. Shetty RV. Haire DL. Hilborn JW. Chem.-Biol. Interact.  1989,  70:  167 
    Google Scholar
  • 1e Makino K. Imaishi H. Morinishi S. Hagiwara T. Takeuchi T. Murakami A. Nishi M. Free Radical Res. Commun.  1989,  6:  19 
    Google Scholar
  • 2a Bottle SE. Micallef AS. Org. Biomol. Chem.  2003,  1:  2581 
    CrossrefGoogle Scholar
  • 2b Bottle SE. Hanson GR. Micallef AS. Org. Biomol. Chem.  2003,  1:  2585 
    CrossrefGoogle Scholar
  • Our synthetic strategy is based fundamentally upon the reported procedure for the N-hydroxyisoindole derivatives by Knight and co-workers. For references, see:
  • 3a Cooper NJ. Knight DW. Tetrahedron  2004,  60:  243 
    CrossrefGoogle Scholar
  • 3b Knight DW. Leese MP. De Kimpe N. Tetrahedron Lett.  2001,  42:  2597 
    CrossrefGoogle Scholar
  • 4 Dehydration using 20% H2SO4-AcOH, see: Garbisch EW. J. Org. Chem.  1961,  26:  4165.   Preparation of Olefin 4 To a solution of MeMgI in Et2O (3.56 M, 25 mL, 89 mmol) and Et2O (25 mL) was added dropwise ester 3 (5.0 g, 29.3 mmol) in Et2O (10 mL) at 20 °C under N2, and stirring was maintained overnight. The reaction mixture was poured into sat. NH4Cl (50 mL), and the mixture was extracted with Et2O (2 × 50 mL). The combined organic extracts were washed with sat. NaHCO3 and brine, and dried over anhyd Na2SO4. The crude alcohol was obtained after evaporation. Then the resulting crude alcohol was dissolved in freshly prepared 20% H2SO4-AcOH (6 mL), and stirring was maintained for 2 h. The reaction mixture was poured into H2O (50 mL), and extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with sat. NaHCO3 and brine, and dried over anhyd Na2SO4. After evaporation, almost pure olefin 4 (3.67 g, 24.1 mmol) was obtained in 82% yield
    CrossrefGoogle Scholar
  • 7 Broch RF. Bernstein MD. Durst HD. J. Am. Chem. Soc.  1971,  93:  2897 
    CrossrefGoogle Scholar
  • 8 Shibata T. Uemae K. Yamamoto Y. Tetrahedron: Asymmetry  2000,  11:  2339 
    CrossrefGoogle Scholar
  • 9 Oxidation of hydroxylamine using Cu(OAc)2, see ref. 8. Preparation of Nitrone 9 To a solution of oxime 6 (417 mg, 2.59 mmol) and NaBH3CN (260 mg, 4.14 mmol) in MeOH (5 mL) was added an aq 3 N HCl until ca. pH 3. After stirring for 1 h at r.t., the reaction mixture was neutralized with aq 1 N NaOH. The mixture was extracted with CH2Cl2 (3 × 20 mL), and the combined extracts were dried over anhyd Na2SO4, and the crude isoindole hydroxide 8 (337 mg) was obtained after evaporation. Crude 8 was dissolved in a mixture of MeOH (5 mL) and NH4OH (28%, 5 mL) in the presence of Cu(OAc)2·H2O (32 mg, 0.16 mmol), and air was bubbled into the solution until a persistent deep blue color was observed (2 h). After evaporation, sat. NaHCO3 (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined extracts were dried over anhyd Na2SO4, and evaporated to give crude nitrone 9. Pure 9 (318 mg, 1.97 mmol) was obtained by silica gel column chromatography in 76% yield (eluent EtOAc-MeOH = 100:0, 99:1, 98:2, 96:4, 92:8, 88:12, 86:14, 84:16, 100 mL each). The structure of 9 was assigned by the comparison of 1H NMR and 13C NMR data with those of an authentic sample. For reference, see: Fevig TL. Bowen SM. Janowick DA. Jones BK. Munson HR. Ohlweiler DF. Thomas CE. J. Med. Chem.  1996,  39:  4988 
    CrossrefGoogle Scholar
5

Preparation of Aldehyde 5
To a solution of Grignard reagent obtained from olefin 4 (12.5 g, 82.0 mmol), Mg turnings (2.6 g, 106.6 mmol, activated by small amount of MeI), and anhyd THF (100 mL) was added dropwise DMF (12.7 mL, 164 mmol) at 20 °C under N2, and stirring was maintained overnight. The reaction mixture was then poured into aq 3 N HCl (100 mL). The mixture was extracted with Et2O (3 × 50 mL), and the combined organic extracts were washed with sat. NaHCO3, H2O, and brine. After drying over anhyd Na2SO4 and evaporation, the pure aldehyde 5 (8.9 g, 61.0 mmol) was obtained by Kugelrohr distillation in 74% yield.

6

Preparation of Oxime 6
To a suspension of aldehyde 5 (450 mg, 3.08 mmol) and NH2OH·HCl (834 mg, 12.0 mmol) in CH2Cl2 (5 mL) was added an aq NaOH (1 N, 22.5 mL) in an ice-bath. The two-phase clear solution was vigorously stirred for 5 h at r.t. The solid NaCl was added to the resulting emulsion, and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined extracts were washed with sat. NaHCO3 and brine, and dried over anhyd Na2SO4. After evaporation, oxime 6 (423 mg, 2.62 mmol) was obtained in 85% yield in almost pure grade. An analytic sample was purified by silica gel chromatography.
Data for Oxime 6
Mp 68.6-70.1 °C. IR (mull): νmax = 3184, 1630, 1597, 1489, 1315, 1281, 1203, 978, 924, 876, 769, 756 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.35 (s, 1 H), 8.23 (br, 1 H), 7.79 (dd, 1 H, J = 8.0, 1.5 Hz), 7.37-7.34 (m, 1 H), 7.28-7.26 (m, 1 H), 7.23 (dd, 1 H, J = 8.0, 1.5 Hz), 5.32-5.31 (m, 1 H), 4.88 (m, 1 H), 2.08 (dd, 1 H, J = 1.5, 1.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 149.6, 144.0, 143.2, 129.6, 128.7, 128.1, 127.2, 126.0, 117.4, 25.0. MS (EI): m/z (%) = 160 (9) [M - H], 145 (9), 144 (100) [M - OH], 143 (28), 129 (9), 128 (18), 116 (18), 115 (45), 103 (8), 91 (12), 89 (10), 77 (13). Anal. Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.60; H, 6.97; N, 8.57.

10

Preparation of 1
To a solution of MeMgI in Et2O (3.56 M, 3.5 mL, 12 mmol) and Et2O (10 mL) was added dropwise nitrone 9 (777 mg, 4.82 mmol) in Et2O (5 mL) at 0 °C under N2, and the reaction mixture was stirred at r.t. overnight. The reaction mixture was then poured into sat. NH4Cl (30 mL), and the mixture was extracted with Et2O (2 × 30 mL). The combined organic extracts were dried over anhyd Na2SO4, and the crude three-substituted isoindole hydroxide (663 mg) was obtained after evaporation. The crude residue was dissolved in a mixture of MeOH (5 mL) and NH4OH (28%, 5 mL) in the presence of Cu(OAc)2·H2O (132 mg, 0.663 mmol), and air was bubbled into the solution until a persistent deep blue color was observed (10 min). After evaporation, sat. NaHCO3 (20 mL) was added to the residue, and the mixture was extracted with CH2Cl2 (2 × 20 mL). The combined extracts were dried over anhyd Na2SO4, and evaporated to give crude TMINO(1). Pure TMINO (1, 567 mg, 3.52 mmol, overall yield of 28% from 2) was obtained by silica gel column chromatography (eluent EtOAc-MeOH = 90:10, 85:15, 80:20, 75:25, 70:30, 100 mL each) in 73% yield. The structure of 1 was assigned by the comparison of 1H NMR and 13C NMR data with those of an authentic sample in ref. 2a.

11

Other N-oxide derivatives 10 were obtained according to the same procedure for TMINO(1) using the corresponding Grignard reagent. The analytical data were as follows.
Data for Oxime 10a
Light brown solid; mp 73.6-76.0 °C. IR (neat): νmax = 2972, 1694, 1534, 1461, 1349, 1271, 1219, 1112, 993, 762, 687, cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.54-7.53 (m, 1 H), 7.37-7.32 (m, 2 H), 7.30-7.28 (m, 1 H), 3.69 (sept, 1 H, J = 7.0 Hz), 1.54 (s, 6 H), 1.42 (d, 6 H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3): δ = 147.3, 145.1, 132.6, 127.9, 127.1, 120.5, 120.1, 75.7, 24.8, 24.5, 18.4. MS (EI): m/z (%) = 203 (23) [M], 188 (20), 175 (23), 160 (100) [M - i-Pr], 128 (28), 115 (22). Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.55; H, 8.37; N, 6.73.
Data for Oxime 10b
Light brown solid; mp 116.2-118.2 °C. IR (neat): νmax = 2968, 1692, 1510, 1447, 1354, 1325, 1278, 1207, 1090, 981, 757, 675 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.79-7.76 (m, 1 H), 7.31-7.28 (m, 2 H), 7.26-7.24 (m, 1 H), 1.61 (s, 9 H), 1.50 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 147.6, 145.6, 134.0, 127.8, 126.7, 121.9, 120.6, 75.9, 35.3, 26.8, 25.1. MS (EI): m/z (%) = 217 (12) [M], 175 (30), 161 (12), 160 (100) [M - t-Bu], 144 (16), 128 (10), 115 (12). Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.13; H, 8.61; N, 6.31.
Data for Oxime 10c
Light brown solid; mp 105.3-108.4 °C. IR (neat): νmax = 2960, 1600, 1529, 1463, 1445, 1388, 1332, 1270, 1154, 751, 688, 627 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.11 (dd, 2 H, J = 1.2, 8.3 Hz), 7.64-7.63 (m, 1 H), 7.56-7.53 (m, 2 H), 7.49-7.45 (m, 1 H), 7.41-7.37 (m, 2 H), 7.36-7.33 (m, 1 H), 1.65 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 1447, 139.0, 133.1, 130.0, 128.6, 128.6, 128.5, 128.2, 127.5, 120.7, 120.5, 76.9, 24.9. MS (EI): m/z (%) = 237 (100) [M], 236 (26), 222 (66), 221 (25), 220 (76), 165 (23), 128 (24), 115 (24), 95 (28), 91 (23), 82 (21). Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.15; H, 6.44; N, 5.87.