Arch. Pharm. Chem. Life Sci. 2011, 11, 372–385
Spiro-oxazolidinone-benzopyrans as ARL2 inhibitors
383
2-(2,4-Dichlorophenyl)-2,3-dihydro-2 0H-spiro[chromene-
4,5 0-[1,3]oxazolidin]-2 0-one 45a
Yield: 80%; 1H-NMR (CDCl3) d 2.23–2.39 (m, 1H, CH2); 2.58–
2.69 (m, 1H, CH2); 3.85–3.95 (m, 2H, CH2); 5.40–5.54 (m, 1H,
CH); 6.93–6.99 (m, 1H, Ar); 7.02–7.11 (m, 1H, Ar); 7.25–7.50
(m, 4H, Ar); 7.65–7.76 (m, 1H, Ar) ppm.
Ethyl[6-bromo-2-(4-methoxyphenyl)-2-methyl-2 0-oxo-2,3-
dihydro-3 0H-spiro[chromene-4,5 0-[1,3]oxazolidin]-3 0-yl]
acetate 19b
Yield: 88%; 1H-NMR (CDCl3) d 1.21–1.35 (m, 3H, Me); 1.72
(s, 3H, Me); 2.67 (s, 2H, CH2); 3.16 (d, 1H, J ¼ 9.0 Hz, CH2);
3.29 (d, 1H, J ¼ 9.0 Hz, CH2); 3.79 (s, 3H, OMe); 3.97 (s, 2H,
CH2); 4.18–4.29 (m, 2H, CH2); 6.84 (d, 2H, J ¼ 8.6 Hz, Ar); 6.91
(d, 1H, J ¼ 8.8 Hz, Ar); 7.22–7.27 (m, 2H); 7.40 (dd, 1H, J ¼ 2.4,
8.6 Hz, Ar); 7.58 (d, 1H, J ¼ 2.4 Hz, Ar) ppm.
6-Bromo-2-(2,4-dichlorophenyl)-2,3-dihydro-2 0H-
spiro[chromene-4,5 0-[1,3]oxazolidin]-2 0-one 45b
The crude product was purified by crystallization from EtOH.
Yield: 44%; 1H-NMR (CDCl3) d 2.20–2.33 (m, 1H, CH2); 2.61
(dd, 1H, J ¼ 1.4, 13.6 Hz, CH2); 3.87 (s, 2H, CH2); 5.41 (dd, 1H,
J ¼ 1.4, 12.3 Hz, CH); 6.85 (d, 1H, J ¼ 8.9 Hz, Ar); 7.35–7.44
(m, 3H, Ar); 7.60 (d, 1H, J ¼ 2.4 Hz, Ar); 7.63 (d, 1H, J ¼ 8.4 Hz,
Ar) ppm.
Ethyl[2-(4-chlorophenyl)-2-methyl-2 0-oxo-2,3-dihydro-
3 0H-spiro[chromene-4,5 0-[1,3]oxazolidin]-3 0-yl]acetate
20a
Yield: 63%; 1H-NMR (CDCl3) d 1.20–1.37 (m, 3H, Me); 1.73 (s, 3H,
Me); 2.61 (d, 1H, J ¼ 14.5 Hz, CH2); 2.73 (d, 1H, J ¼ 14.5 Hz,
CH2); 3.24 (d, 1H, J ¼ 8.9 Hz, CH2); 3.49 (d, 1H, J ¼ 8.9 Hz, CH2);
4.01 (s, 2H, CH2); 4.22 (q, 2H, J ¼ 7.2 Hz, CH2); 6.99–7.06 (m, 2H,
Ar); 7.27–7.39 (m, 5H, Ar); 7.50–7.55 (m, 1H, Ar) ppm.
6-Bromo-2-(2,4-difluorophenyl)-2,3-dihydro-2 0H-
spiro[chromene-4,5 0-[1,3]oxazolidin]-2 0-one 46b
Yield: 66%; 1H-NMR (CDCl3) d 2.45–2.54 (m, 2H, CH2); 3.79
(d, 1H, J ¼ 8.9 Hz, CH2); 3.86 (d, 1H, J ¼ 8.9 Hz, CH2); 5.26–
5.45 (m, 1H, CH); 6.74–7.14 (m, 3H, Ar); 7.21–7.67 (m, 3H, Ar)
ppm.
Ethyl[6-bromo-2-(4-chlorophenyl)-2-methyl-2 0-oxo-2,3-
dihydro-3 0H-spiro[chromene-4,5 0-[1,3]oxazolidin]-3 0-yl]
acetate 20b
Yield: 76%; 1H-NMR (CDCl3) d 1.21–1.34 (m, 3H, Me); 1.73
(s, 3H, Me); 2.40–2.73 (m, 2H, CH2); 3.12–3.52 (m, 2H, CH2);
4.01 (s, 2H, CH2); 4.10–4.30 (m, 2H, CH2); 6.90–7.05 (m, 1H, Ar);
7.25–7.45 (m, 5H, Ar); 7.54 (d, 1H, J ¼ 2.4 Hz, Ar) ppm.
6-Bromo-2-(4-bromo-2-fluorophenyl)-2,3-dihydro-2 0H-
spiro[chromene-4,5 0-[1,3]oxazolidin]-2 0-one 47b
The crude product was purified by crystallization from
EtOH. Yield: 77%; 1H-NMR (CDCl3) d 2.31–2.56 (m, 2H,
CH2); 3.79 (d, 1H, J ¼ 9.1 Hz, CH2); 3.86 (d, 1H,
J ¼ 9.1 Hz, CH2); 5.35 (dd, 1H, J ¼ 3.3, 10.7 Hz, CH); 6.82
(d, 1H, J ¼ 8.8 Hz, Ar); 7.28–7.53 (m, 4H, Ar); 7.59 (d, 1H,
J ¼ 2.4 Hz, Ar) ppm.
Ethyl[2-(4-methoxyphenyl)-2 0-oxo-2,3-dihydro-3 0H-
spiro[chromene-4,5 0-[1,3]oxazolidin]-3 0-yl]acetate 48a
Yield: 63%; 1H-NMR (CDCl3) d 1.22–1.33 (m, 3H, Me); 2.47–2.69
(m, 2H, CH2); 3.78–3.94 (m, 5H, CH2, OMe); 4.06–4.29 (m, 4H,
CH2); 4.99–5.07 (m, 1H, CH); 6.88–7.07 (m, 4H, Ar); 7.23–7.30
(m, 1H, Ar); 7.39 (d, 2H, J ¼ 8.4 Hz, Ar); 7.49–7.53 (m, 1H, Ar)
ppm.
General procedure for preparation of compounds 19a,b,
20a,b, 48a,b–50a,b, 51b, 52b
A solution of (1.50 mmol) in dry THF (7 mL) was added
dropwise, at ꢀ788C, under N2 atmosphere to a solution
of n-BuLi (1.05 mL, 1.70 mmol, 1.6 M in hexane) and
the reaction mixture was stirred for 1 h. Then, ethyl
bromoacetate (0.25 g, 1.50 mmol) was added dropwise at
ꢀ788C and the resulting mixture was allowed to warm
to room temperature and was stirred overnight. The
mixture was quenched with NH4Cl and then the
solvent was evaporated. The aqueous phase was extracted
with AcOEt and the organic layer was dried and
evaporated.
Ethyl[6-bromo-2-(4-methoxyphenyl)-20-oxo-2,3-dihydro-
3 0H-spiro[chromene-4,50-[1,3]oxazolidin]-30-yl]acetate 48b
Yield: 70%; 1H-NMR (CDCl3) d 1.25–1.58 (m, 3H, Me); 2.83–2.86
(m, 2H, CH2); 3.79–3.89 (m, 5H, CH2, OMe); 3.97–4.26 (m, 4H,
CH2); 5.46–5.50 (m, 1H, CH); 6.88–6.96 (m, 3H, Ar); 7.51–7.74
(m, 3H, Ar) 7.92–7.97 (m, 1H, Ar) ppm.
Ethyl[2-(4-chlorophenyl)-2 0-oxo-2,3-dihydro-3 0H-
spiro[chromene-4,5 0-[1,3]oxazolidin]-3 0-yl]acetate 49a
The crude product was purified by flash column chromatog-
raphy eluted with AcOEt/hexane 2:3. Yield: 60%; 1H-NMR
(CDCl3) d 1.30 (t, 3H, J ¼ 7.1 Hz, Me); 2.45–2.62 (m, 2H,
CH2); 3.83 (d, 1H, J ¼ 8.5 Hz, CH2); 3.91 (d, 1H, J ¼ 8.5 Hz,
CH2); 4.05 (d, 1H, J ¼ 18.1 Hz, CH2); 4.15 (d, 1H, J ¼ 18.1 Hz,
CH2); 4.24 (q, 2H, J ¼ 7.1 Hz, CH2); 5.00–5.15 (m, 1H, CH); 6.90–
6.94 (m, 1H, Ar); 7.00–7.09 (m, 1H, Ar); 7.24–7.33 (m, 1H, Ar);
7.36–7.47 (m, 4H, Ar); 7.51 (dd, 1H, J ¼ 1.5, 7.8 Hz, Ar) ppm.
Ethyl[2-(4-methoxyphenyl)-2-methyl-2 0-oxo-2,3-dihydro-
3 0H-spiro[chromene-4,5 0[1,3]oxazolidin]-3 0-yl]acetate 19a
Yield: 38%; 1H-NMR (CDCl3) d 1.20–1.32 (m, 3H, Me); 1.66
(s, 3H, Me); 2.04–2.32 (m, 2H, CH2); 2.51–2.83 (m, 2H, CH2);
3.14–3.40 (m, 2H, CH2); 3.77 (s, OMe); 4.08–4.24 (m, 2H, CH2);
6.75–7.05 (m, 4H, Ar); 7.19–7.43 (m, 4H, Ar) ppm.
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