GRIESBECK ET AL.
3 of 8
reduced pressure and 4.6 g (22.1 mmol, 99%) of the anhy-
dride 7 were obtained as a beige solid. m.p: 164°C. H‐
ESI‐MS: 340 [M + H+]. FT‐IR: [cm–1] = 3931 (w), 3902
(w), 3778(m), 3648 (m), 3566 (m), 3081 (w), 2923 (w),
2387 (w), 2337 (w), 1733 (m), 1697 (s), 1616 (m), 1506
(m), 1473 (m), 1419 (w), 1370 (s), 1311 (s), 1225 (m),
1163 (m), 1087 (m), 998 (m), 891 (w), 861 (w), 751 (s),
667 (w). UV (CH3CN, 10–5 M): λmax = 347 nm, ε
(347 nm) = 2440 L mol–1 cm–1.
1
NMR (300 MHz, DMSO): δ [ppm] = 7.18 (s, 2H), 3.82 (s,
6H). 13C‐NMR (75 MHz, DMSO): δ [ppm] = 165.0, 157.4,
126.5, 111.7, 56.2. GC‐MS (EtOAc, EI): τR: 13.21 min; m/
z: [%] = 208 [M] (17%), 165 (4%), 164 (66%), 137 (7%),
136 (100%), 121 (12%), 93 (39%), 62 (9%), 50 (27%). FT‐
IR: [cm–1] = 3900 (w), 3851(w), 3749 (w), 3734 (w),
3689 (w), 3648 (w), 3586 (w), 3566 (w), 2925 (w), 2853
(w), 2368 (w), 2337 (w), 1868 (w), 1843 (m), 1772 (s),
1732 (w), 1716 (w), 1589 (m), 1506 (m), 1456 (w), 1423
(w), 1321 (s), 1231 (m), 1134 (w), 1090 (m), 983 (m), 888
(s), 817 (m), 817 (m), 700 (w).
2.7 | 2‐(5,6‐Dimethoxy‐1,3‐dioxoisoindolin‐2‐
yl)acetic acid (8)
Yield 0.84 g (3.16 mmol, 44%). Colorless solid. m.p.
289.5°C. 1H‐NMR (300 MHz, DMSO) δ [ppm] = 7.43
(s, 2H), 4.26 (s, 2H), 3.93 (s, 6H). 13C‐NMR (75 MHz,
DMSO) δ [ppm] = 169.6, 167.8, 154.3, 125.1, 106.3, 56.9.
FT‐IR: [cm–1] = 3293 (w), 2330 (w), 1749 (m), 1710.0
(s), 1599 (m), 1506 (m), 1458 (w), 1423 (m), 1393 (m),
1306 (m), 1306 (m), 1289 (w), 1221 (m), 1190 (w), 1161
(m), 1120 (w), 1088 (m), 995 (s), 930 (w), 903 (m).
2.4 | Synthesis of the dimethoxyphthalimides
1a, 1b, 8
A mixture of 1 eq. of the phthalic anhydride (7) and 1.05 eq.
of the amine was dissolved in acetic acid (0.05 mM) and
stirred for 4 hours under reflux. After cooling, the reaction
mixture was diluted with water and a precipitate was formed,
which was collected by suction filtration.
2.8 | Methyl 2‐(2‐(5,6‐dimethoxy‐1,3‐
dioxoisoindolin‐2‐yl)acetamido)‐4‐(methylthio)
butanoate (3)
2.5 | 5,6‐Dimethoxy‐2‐(3‐(methylthio)propyl)
isoindoline‐1,3‐dione (1a)
Yield 1.2 g (4.1 mmol, 82%). Colorless solid. m.p. 179°C.
1H‐NMR (300 MHz, CDCl3): δ [ppm] = 7.30 (s, 2H), 4.00
(s, 6H), 3.75 (t, J = 7.0 Hz, 2H), 2.53 (t, J = 7.4 Hz, 2H),
2.10 (s, 3H), 2.03‐1.90 (m, 2H). 13C‐NMR (75 MHz,
CDCl3): δ [ppm] = 168.5, 153.8, 125.5, 105.3, 56.6, 37.1,
31.4, 28.1, 15.4. GC‐MS (EtOAc, EI): τR: 13.79 min; m/z:
[%] = 295.26 [M] (22%), 248.19 (100%), 220.24 (70%),
207.17 (20%), 190.09 (24%), 177.17 (22%), 164.16 (32%),
136.19 (29%), 121.12 (34%), 93.13 (31%), 75.13 (38%),
61.05 (36%). FT‐IR: [cm–1] = 3081 (w), 1763 (w), 1733
(m), 1697 (m), 1598 (w), 1504 (m), 1475 (w), 1460 (w),
1422 (w), 1390 (s), 1339 (s), 1311 (s), 1278 (w), 1225 (m),
1210 (m), 1190 (m), 1163 (m), 1137 (m), 1131 (m), 1115
(m), 1104 (m), 1088 (m), 1027 (m), 1015 (m), 994 (m),
947 (w), 910 (w), 891 (w), 861 (w), 842 (m), 835 (m),
797 (s), 778 (w), 751 (s), 714 (w), 702 (w), 662 (w), 652
A solution of 8 (0.53 g, 2 mmol) in dry THF (4 ml) was
cooled to –25°C. A total of 0.28 ml (2 mmol, 1 eq.) of
NEt3 and 0.28 ml (2.2 mmol, 1.1 eq.) of
isobutylchloroformate were added and stirred 30 minutes at
–25°C. A total of 0.40 g (2 mmol, 1 eq.) L‐methionine methyl
ester hydrochloride were suspended in 4 ml chloroform and
added to reaction and stirred 90 minutes at –25°C. The reac-
tion was diluted with 5% NaHCO3‐solution and extracted.
The organic phase was washed with 10% HCl‐solution, brine
and dried over MgSO4. The solvent was evaporated under
reduced pressure and 0.82 g (1.99 mmol, quant.) of 3 were
observed as colorless solid. m.p. 227°C. 1H‐NMR
(300 MHz, DMSO) δ [ppm] = 8.67 (d, J = 7.7 Hz, 1H;
NH), 7.41 (s, 2H), 4.39 (m, 1H), 4.21 (d, J = 1.7 Hz, 2H),
3.93 (s, 6H), 3.64 (s, 3H), 2.50 (s, 2H), 2.04 (s, 3H), 0.91
(d, J = 6.7 Hz, 2H), 0.83 (dd, J = 9.3, 6.7 Hz, 2H). 13C‐
NMR (75 MHz, DMSO) δ [ppm] = 172.4, 167.9, 167.1,
154.1, 125.3, 106.2, 75.9, 56.9, 52.5, 51.4, 31.1, 29.8, 15.0.
FT‐IR: [cm–1] = 3294 (w), 2947 (w), 2358 (w), 1747 (m),
1716 (s), 1705 (s), 1662 (w), 1597 (w), 1558 (w), 1506
(w), 1474 (w), 1463 (w), 1417 (s), 1394 (m), 1381 (w),
1310 (s), 1224 (m), 1211 (m), 1116 (w), 1090 (m), 1000
(s), 926 (w), 891 (w), 870 (w). HR‐MS: [M + H]+:
411.12205 (calc.), 411.12191 (measured). Elemental analy-
sis: calc.: 52.67% C, 5.40% H, 6.83 % N, measured:
52.66% C, 5.86% H, 5.77% N. UV (CH3CN, 10–5 M):
λmax = 345 nm, ε (345 nm) = 1940 L mol–1 cm–1.
(w). UV (CH3CN, 10–5 M): λmax
= 347 nm, ε
(347 nm) = 1700 L mol–1 cm–1.
2.6 | 2‐(5,6‐Dimethoxy‐1,3‐dioxoisoindolin‐2‐
yl)‐4‐(methylthio)butanoic acid (1b)
Yield 7.25 g (21.4 mmol, 89%). Colorless solid. m.p. 236°C.
1H‐NMR (300 MHz, DMSO): δ [ppm] = 7.41 (s, 2H), 4.86
(t, J = 7.3 Hz, 1H), 3.93 (s, 6H), 2.39‐2.30 (m, 4H), 2.01
(s, 3H). 13C‐NMR (300 MHz, DMSO): δ [ppm] = 171.0,
168.1, 154.1, 124.8, 106.2, 56.7, 50.8, 30.42, 28.0, 14.8.