G. P. Luke, D. A. Holt / Tetrahedron: Asymmetry 10 (1999) 4393–4403
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4.18. (S)-5-[1-(1,3-Dioxoisoindolin-2-yl)ethyl]-2-(cyclohexylmethoxy)benzaldehyde 17
To a mixture of salicylaldehyde 16 (1.395 g, 4.72 mmol) in MeOH (40 mL)–H2O (1 mL) at rt
was added Cs2CO3 (1.62 g, 4.96 mmol). After stirring for 30 min, the resulting yellow solution was
concentrated in vacuo. Toluene was added to the residue and then removed in vacuo in order to
azeotropically remove the H2O. This was repeated once more. The residue was then suspended in DMF
(20 mL) and treated with (bromomethyl)cyclohexane (0.79 mL, 5.67 mmol). The mixture was stirred at
90°C for 2 h. After cooling to rt, the reaction mixture was diluted with H2O (50 mL) and extracted
with EtOAc. The extract was washed with additional H2O (2×50 mL) and brine (1×50 mL). The
aqueous washes were re-extracted once with EtOAc, and the combined extracts were dried over MgSO4
and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with
7:1 hexanes:EtOAc followed by 6:1 hexanes:EtOAc afforded 1.05 g (57%) of ether 17. Some impure
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fractions were not collected. H NMR (300 MHz, CDCl3) δ 10.49 (s, 1H), 7.92 (d, J=2.4 Hz, 1H),
7.81–7.77 (m, 2H), 7.71–7.66 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 5.54 (q, J=7.3 Hz, 1H), 3.85 (d, J=5.8
Hz, 2H), 1.94–1.69 (m, 6H), 1.89 (d, J=7.3 Hz, 3H), 1.32–1.03 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
189.5, 167.9, 161.0, 134.9, 133.9, 132.3, 131.9, 127.1, 124.5, 123.2, 112.6, 73.9, 48.5, 37.6, 29.7, 26.3,
25.7, 17.4. Electrospray mass spectrum (50:50 acetonitrile:water + 0.1% NH4OH): m/z 392 [M+H].
4.19. (S)-5-[1-(1,3-Dioxoisoindolin-2-yl)ethyl]-2-(cyclohexylmethoxy)benzoic acid 18
A solution of aldehyde 17 (222 mg, 0.567 mmol) in CH3CN (1.2 mL) was diluted with a solution of
NaH2PO4·2H2O (24 mg, 0.153 mmol) in H2O (0.5 mL). The mixture was cooled to 0°C and treated with
50% H2O2 (34 µL, 0.595 mmol) followed by a solution of NaClO2 (90 mg, 0.794 mmol) in H2O (1.6
mL). The mixture was then stirred at rt for 20 h. Next, some solid NaHSO3 was added to the reaction
mixture to destroy the unreacted HOCl and H2O2. The mixture was acidified with 1.0 M aq HCl and
extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, and concentrated
to 230 mg (100%) of acid 18 as a foam. 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=2.4 Hz, 1H), 7.82–7.78
(m, 2H), 7.72–7.68 (m, 3H), 7.00 (d, J=8.7 Hz, 1H), 5.57 (q, J=7.3 Hz, 1H), 4.02 (d, J=6.0 Hz, 2H),
1.96–1.71 (m, 6H), 1.90 (d, J=7.3 Hz, 3H), 1.39–1.03 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 167.8,
165.1, 157.0, 134.0, 133.9, 132.6, 131.8, 123.2, 117.4, 112.6, 75.6, 48.3, 37.2, 29.7, 26.1, 25.5, 17.4.
Electrospray mass spectrum (50:50 acetonitrile:water + 0.1% NH4OH): m/z 406 [M−H].
4.20. (S)-5-[1-(1,3-Dioxoisoindolin-2-yl)ethyl]-2-(cyclohexylmethoxy)benzamide 19
To a solution of acid 18 (223 mg, 0.547 mmol) and NMM (0.09 mL, 0.821 mmol) in THF (5 mL)
at 0°C was added HOBt·H2O (126 mg, 0.821 mmol) followed by EDC (157 mg, 0.821 mmol). The
reaction mixture was stirred at 0°C for 44 min and then treated with 14 drops of concentrated NH4OH.
The reaction mixture was stirred overnight while slowly warming to rt. The mixture was then diluted with
EtOAc and washed with 1.0 M aq HCl (2×10 mL), half saturated aq NaHCO3 (2×10 mL), H2O (1×10
mL), and brine (1×10 mL). The EtOAc extract was dried over MgSO4 and concentrated. The crude
material was purified by flash chromatography on silica gel. Elution with 1:1 EtOAc:hexanes followed
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by 2:1 EtOAc:hexanes afforded 208 mg (94%) of amide 19 as a colorless solid. H NMR (300 MHz,
CDCl3) δ 8.28 (d, J=2.4 Hz, 1H), 7.81–7.74 (m, 3H), 7.71–7.65 (m, 2H), 7.62 (dd, J=8.6, 2.5 Hz, 1H),
6.93 (d, J=8.7 Hz, 1H), 5.96 (br, 1H), 5.57 (q, J=7.3 Hz, 1H), 3.91 (d, J=5.9 Hz, 2H), 1.90 (d, J=7.3 Hz,
3H), 1.86–1.71 (m, 6H), 1.37–1.02 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 167.9, 167.0, 156.8, 133.8,