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

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).

reverse-Cope cyclization - isoindole N-oxide - synthesis

References and Notes

1a Bandara BMR. Hinojosa O. Bernofsky C. J. Org. Chem.  1994,  59:  1642 

1b Barasch D. Krishna MC. Russo A. Katzhendler J. Samuni A. J. Am. Chem. Soc.  1994,  116:  7319 

1c Janzen EG. Zhang YK. Arimura M. Chem. Lett.  1993,  497 

1d Janzen EG. Jandrisits LT. Shetty RV. Haire DL. Hilborn JW. Chem.-Biol. Interact.  1989,  70:  167 

1e Makino K. Imaishi H. Morinishi S. Hagiwara T. Takeuchi T. Murakami A. Nishi M. Free Radical Res. Commun.  1989,  6:  19 

2a Bottle SE. Micallef AS. Org. Biomol. Chem.  2003,  1:  2581 

2b Bottle SE. Hanson GR. Micallef AS. Org. Biomol. Chem.  2003,  1:  2585 

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 

3b Knight DW. Leese MP. De Kimpe N. Tetrahedron Lett.  2001,  42:  2597 

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

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): ν_max = 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.

7 Broch RF. Bernstein MD. Durst HD. J. Am. Chem. Soc.  1971,  93:  2897 

8 Shibata T. Uemae K. Yamamoto Y. Tetrahedron: Asymmetry  2000,  11:  2339 

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 

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): ν_max = 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): ν_max = 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): ν_max = 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.