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K. Aksjonova et al.
PAPER
1H NMR (200 MHz, CDCl3): δ = 1.42 (t, J = 7.2 Hz, 3 H, CH3), 4.51
(q, J = 7.2 Hz, 2 H, OCH2), 7.54 (t, J = 7.7 Hz, 1 Harom), 7.67 (dd,
J = 7.7, 1.2 Hz, 1 Harom), 7.79 (dd, J = 7.7, 1.2 Hz, 1 Harom), 9.97 (s,
1 H, CHO).
HRMS (ESI): m/z [M + H]+ calcd for C8H6ClNO2: 184.0165; found:
184.0217.
Anal. Calcd for C8H6ClNO2: C, 52.34; H, 3.29; N, 7.63. Found: C,
51.57; H, 3.42; N, 6.97.
MS (EI, 70 eV): m/z (%) = 75.0 (90), 110.9 (40), 139.0 (100), 167.0
(95), 183.0 (100), 211.9 (10, [M]+).
7-Chloro-3-ethoxy-2-ethyl-2,3-dihydro-1H-isoindol-1-one (5f)
To a solution of 2f (115 mg, 0.45 mmol) in EtOH (3 mL) was added
aq 1 M HCl (2 mL) and the mixture was refluxed for 6 h. After cool-
ing to r.t., the mixture was neutralized with sat. aq NaHCO3. To the
mixture was added EtOAc (7 mL) and the organic layer was sepa-
rated, washed with H2O (2 × 5 mL) and brine (10 mL), and dried
(Na2SO4). The residue obtained after filtration and evaporation of
the solvent in vacuo was purified by flash chromatography on silica
gel (hexane–EtOAc, gradient from 2:1 to 1:1) to afford the products
5f (60 mg, 56%) as a yellowish oil and 4f (40 mg, 41%) as a white
powder.
2-Chloro-6-formyl-N,N-dimethylbenzamide (3e)
To a solution of 2e (810 mg, 3.17 mmol) in THF (15 mL) was added
aq 1 M HCl (15 mL) and the mixture was refluxed for 4 h. After
cooling to r.t., the mixture was neutralized with sat. aq NaHCO3. To
the mixture was added EtOAc (25 mL) and the organic layer was
separated, washed with H2O (2 × 20 mL) and brine (20 mL), and
dried (Na2SO4). The residue obtained after filtration and concentra-
tion of the solvent in vacuo was purified by flash chromatography
on silica gel (hexane–EtOAc, 6:1) to afford the product as a yellow-
ish oil; yield: 102 mg (15%).
IR (film): 3286, 3080, 2977, 1777, 1725, 1691, 1606, 1464–1385,
1202, 1085, 1063, 797 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H, CH3), 1.27
(t, J = 7.3 Hz, 3 H, CH3), 2.87–3.07 (m, 1 H, NCH), 3.11–3.26 (m,
1 H, NCH), 3.34 (sext, J = 7.3 Hz, 1 H, OCH), 3.82 (sext, J = 7.3
Hz, 1 H, OCH), 5.85 (s, 1 H, CH), 7.40–7.55 (m, 3 Harom).
IR (film): 3303, 3068, 2977, 1768, 1702, 1626, 1603, 1593, 1455,
1210, 1181, 1079, 909, 748 cm–1.
1H NMR (200 MHz, CDCl3): δ = 2.83 (s, 3 H, NCH3), 3.21 (s, 3 H,
NCH3), 7.50 (t, J = 7.8 Hz, 1 Harom), 7.67 (dd, J = 7.8, 1.1 Hz, 1
Harom), 7.85 (dd, J = 7.8, 1.1 Hz, 1 Harom), 9.98 (s, 1 H, CHO).
13C NMR (50 MHz, CDCl3): δ = 34.6, 37.6, 128.9, 130.1, 131.9,
13C NMR (50 MHz, CDCl3): δ = 8.5, 10.0, 29.8, 52.8, 79.5, 117.6,
134.2, 134.9, 137.5, 166.0, 189.6.
123.4, 127.8, 127.9, 128.0, 139.6, 160.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H10ClNO2: 212.0478;
HRMS (ESI): m/z [M + H]+ calcd for C12H14NClO2: 240.0791;
found: 212.0516.
found: 240.0773.
7-Chloro-2-ethyl-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (4f)
To a solution of 2f (128 mg, 0.50 mmol) in THF (2.5 mL) was added
aq 1 M HCl (2 mL) and the mixture was refluxed for 12 h. After
cooling to r.t., the mixture was neutralized with sat. aq NaHCO3. To
the mixture was added EtOAc (2 × 5 mL) and the organic layer was
separated, washed with H2O (2 × 5 mL) and brine (5 mL), and dried
(Na2SO4). The residue obtained after filtration and evaporation of
the solvent in vacuo was purified by flash chromatography on silica
gel (hexane–EtOAc, 5:1) to afford the product as a white powder;
yield: 66 mg (67%); mp 109–112 °C.
7-Chloro-3-ethoxy-2,3-dihydro-1H-isoindol-1-one (5h)
To a solution of 2h (114 mg, 0.50 mmol) in EtOH (3 mL) was added
aq 1 M HCl (2 mL) and the mixture was refluxed for 6 h. After cool-
ing to r.t., the mixture was neutralized with sat. aq NaHCO3. To the
mixture was added EtOAc (7 mL) and the organic layer was sepa-
rated, washed with H2O (2 × 5 mL) and brine (10 mL), and dried
(Na2SO4). The colorless oil obtained after filtration and evaporation
of the solvent in vacuo was purified by flash chromatography on sil-
ica gel (hexane–EtOAc, gradient from 2:1 to 1:1) to afford products
5h (17 mg, 16%) and 4h (20 mg, 22%) as white powders.
IR (Nujol): 3346, 2977, 1683, 1674, 1608, 1461, 1419, 1203, 1064,
780, 732 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 3 H, CH3),
3.26–3.51 (m, 2 H, NCH2), 3.53–3.74 (m, 1 H, CH), 5.72 (d, J =
11.2 Hz, 1 H, OH), 7.33 (dd, J = 7.4, 1.5 Hz, 1 Harom), 7.42–7.57 (m,
2 Harom).
Mp 116–120 °C.
IR (Nujol): 3284, 1720, 1606, 1463, 1202, 1120, 1091, 768 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3 H, CH3),
3.31–3.39 (m, 1 H, OCH), 3.51–3.60 (m, 1 H, OCH), 5.92 (s, 1 H,
CHN), 7.19 (s, 1 H, NH), 7.43–7.56 (m, 3 Harom).
13C NMR (50 MHz, CDCl3): δ = 15.2, 60.7, 82.5, 122.3, 127.9,
131.5, 131.6, 133.4, 145.8, 167.8.
HRMS (ESI): m/z [M + H]+ calcd for C10H10ClNO2: 212.0478;
found: 212.0511.
13C NMR (50 MHz, CDCl3): δ = 8.1, 28.7, 74.9, 116.9, 122.3, 125.5,
126.1, 127.8, 141.3, 160.0.
Anal. Calcd for C10H10ClNO2·0.5H2O: C, 54.43; H, 5.03; N, 6.35.
Found: C, 54.51; H, 5.00; N, 6.25.
Anal. Calcd for C10H10ClNO2: C, 56.75; H, 4.76; N, 6.62. Found: C,
56.21; H, 4.52; N, 6.17.
7-Chloro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (4h)
To a solution of 2h (114 mg, 0.50 mmol) in THF (2.5 mL) was add-
ed aq 1 M HCl (2 mL) and the mixture was refluxed for 12 h. After
cooling to r.t., the mixture was neutralized with sat. aq NaHCO3. To
the mixture was added EtOAc (2 × 5 mL) and the organic layer was
separated, washed with H2O (2 × 5 mL) and brine (5 mL), and dried
(Na2SO4). The residue obtained after filtration and evaporation of
the solvent in vacuo was purified by flash chromatography on silica
gel (hexane–EtOAc, gradient from 2:1 to 1:2) to afford the product
as a white powder; yield: 54 mg (59%); mp 164–168 °C.
7-Chloro-2-ethyl-3-methoxy-2,3-dihydro-1H-isoindol-1-one
(6f)
Compound 2f (2.00 g, 7.80 mmol) was dissolved in 3.75 M AcCl–
MeOH (15 mL) and the mixture was refluxed for 8 h. After cooling
to r.t., the mixture was neutralized with sat. aq NaHCO3. To the
mixture was added EtOAc (2 × 35 mL) and the organic layer was
separated, washed with H2O (2 × 35 mL) and brine (35 mL), and
dried (Na2SO4). The yellow oil obtained after filtration and evapo-
ration of the solvent in vacuo was purified by flash chromatography
on silica gel (hexane–EtOAc, gradient from 5:1 to 5:3) to afford the
product 6f as a white powder; yield: 1.34 g (76%); mp 80–82 °C.
IR (Nujol): 3345, 3287, 1683, 1465, 1087 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 5.82 (d, J = 9.2 Hz, 1 H,
CHOH), 6.37 (d, J = 9.2 Hz, 1 H, OH), 7.47–7.53 (m, 2 H, H-5, 7),
7.56–7.63 (m, 1 H, H-6), 8.99 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 77.2, 123.2, 127.9, 129.5,
130.9, 133.9, 150.2, 166.5.
IR (Nujol): 2960–2840, 1780, 1460, 1380, 1355, 1310, 1070, 930
cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H, CH3), 2.90
(s, 3 H, OCH3), 3.25–3.35 (m, 1 H, NCH), 3.75–3.90 (m, 1 H,
NCH), 5.85 (s, 1 H, CH), 7.45–7.55 (m, 3 Harom).
Synthesis 2012, 44, 2200–2208
© Georg Thieme Verlag Stuttgart · New York