M. Malacria, C. Courillon et al.
126.1 (III), 122.5 (IV), 109.4 (IV), 91.8 (IV), 50.1 ppm (II); IR (neat): n˜ =
3057, 2237, 1717, 1323 cmÀ1
elemental analysis: calcd (%) for
C16H10N2OF3I: C 44.67, H 2.34, N 6.51; found: C 44.57, H 2.32, N 6.38.
119.8 (III), 110.6 (IV), 107.7 (III), 56.4 (I), 49.9 ppm (II); IR (neat): n˜ =
2924, 2850, 1677 cmÀ1; HRMS (ES+): m/z: calcd for C16H12N2O2Na:
287.0796; found: 287.0785.
;
(E)-N-Cyano-N-(2-iodobenzyl)but-2-enamide (6k): Yield: 74% (meth-
od B); white solid; m.p. 628C; 1H NMR (400 MHz, CDCl3): d=7.86 (dd,
J=7.8, 1.0 Hz, 1H; Harom), 7.35 (td, J=7.6, 1.0 Hz, 1H; Harom), 7.29 (m,
9-Fluoroisoindolo
A
G
white solid; m.p. 2568C; 1H NMR (400 MHz, CDCl3): d=8.15 (d, J=
7.6 Hz, 1H; Harom), 7.6 (m, 5H; Harom), 7.12(m, 1H; H arom), 5.15 ppm (s,
2H; ArCH2); 13C NMR (100 MHz, CDCl3): d=163.1 (IV), 159.2(IV, d,
J=243 Hz), 157.9 (IV), 155.9 (IV), 151.9 (IV), 139.9 (IV), 134.7 (III, d,
J=10.3 Hz), 132.8 (III), 132.5 (IV), 129.1 (III), 123.8 (III), 123.7 (III),
123.4 (III, d, J=3.4 Hz), 113.1 (III), 50.0 ppm (II); 19F NMR (400 MHz,
CDCl3): d=À110.9 ppm (m); IR (neat): n˜ =1672, 1609, 730 cmÀ1; MS:
m/z: 253 [M+H]+; HRMS (ES+): m/z: calcd for C15H10N2OF: 253.0777;
found: 253.0765.
À
À
1H; Harom), 7.24 (m, 1H; CH3 CH=CH C=O), 7.02(td, J=7.6, 1.5 Hz,
À
À
1H; Harom), 6.59 (dd, J=14.9, 1.8 Hz, 1H; CH3 CH=CH C=O), 4.81 (s,
2H; ArCH2), 1.96 ppm (dd, J=7.1, 1.8 Hz, 3H; CH3); 13C NMR
(100 MHz, CDCl3): d=164.1 (IV), 149.9 (III), 139.9 (III), 135.9 (IV),
130.5 (III), 130.0 (III), 128.8 (III), 119.1 (III), 109.9 (IV), 99.1 (IV), 53.8
(II), 18.5 ppm (I); IR (neat): n˜ =3058, 2942, 2231, 1704 cmÀ1; HRMS
(ES+): m/z: calcd for C12H11N2ONaI: 348.9814; found: 348.9802.
Typical cyclization procedure: Tributyltin hydride (0.5 mmol, 2equiv)
and AIBN (0.25 mmol, 1 equiv) in benzene (4 mL) were added to a de-
gassed solution of N-acylcyanamide (0.25 mmol) in refluxing benzene
(11 mL) over 2h. The reflux was maintained until monitoring of the reac-
tion by TLC showed total consumption of the starting material. Once the
mixture was back to room temperature, aqueous NaOH (1m, 15 mL) was
added and the mixture was stirred for 30 min. The organic phase was ex-
tracted with ethyl acetate (220 mL), dried over MgSO 4, and concentrat-
ed under vacuum. Purification of the residue by silica-gel flash chroma-
tography afforded the cyclization products.
6-Fluoroisoindolo
A
N
white solid; m.p. 2488C; 1H NMR (400 MHz, CDCl3): d=8.25 (d, J=
7.6 Hz, 1H; Harom), 8.15 (d, J=7.8 Hz, 1H; Harom), 7.65 (m, 2H; Harom),
7.58 (m, 1H; Harom), 7.52(m, 1H; H arom), 7.43 (m, 1H; Harom), 5.17 ppm
(s, 2H; ArCH2); 13C NMR (100 MHz, CDCl3): d=159.9 (IV), 159.8 (IV),
157.4 (IV, d, J=253 Hz), 155.6 (IV), 139.8 (III), 139.1 (IV, d, J=12.0 Hz),
132.8 (III), 132.6 (IV), 129.1 (III), 126.4 (III, d, J=7.8 Hz), 124.2 (III),
123.6 (III), 122.7 (IV), 122.2 (III, d, J=4.3 Hz), 119.8 (III, d, J=19.8 Hz),
50.1 ppm (II); 19F NMR (400 MHz, CDCl3): d=À125.1 ppm (m); IR
(neat): n˜ =2955, 1677, 1625, 1613, 782 cmÀ1; HRMS (ES+): m/z: calcd
for C15H9N2OFNa: 275.0597; found: 275.0594.
7-Methoxyisoindolo
N
E
white solid; m.p. 206–2088C; 1H NMR (400 MHz, CDCl3): d=8.26 (d,
J=8.8 Hz, 1H; Harom), 8.15 (d, J=7.3 Hz, 1H; Harom), 7.60 (m, 2H;
Harom), 7.58 (m, 1H; Harom), 7.21 (d, J=1.9 Hz, 1H; Harom), 7.05 (dd, J=
8.7, 1.9 Hz, 1H; Harom), 5.12(s, 2H; ArC H2), 3.94 ppm (s, 3H; OCH3);
13C NMR (100 MHz, CDCl3): d=164.7 (IV), 160.4 (IV), 155.8 (IV), 151.9
(IV), 139.9 (IV), 132.8 (IV), 132.4 (III), 128.9 (III), 128.0 (III), 123.7
(III), 123.5 (III), 116.7 (III), 114.3 (IV), 108.1 (III), 55.8 (I), 49.8 ppm
(II); IR (neat): n˜ =2926, 1664, 1608 cmÀ1; HRMS (ES+): m/z: calcd for
C16H12N2O2Na: 287.0796; found: 287.0806.
2-Methyl-2,3-dihydropyrimido[2,1-a]isoindol-4(6H)one (10r): Yield:
U
7.85 (m, 1H; Harom), 7.50 (m, 1H; Harom), 7.41 (m, 2H; Harom), 4.81, 4.73
À
À
À
(AB, d, J=16.7 Hz, 1H each; CH2Ar), 3.95 (m, 1H; CH3 CH CH2 C=
À
À
À
O), 2.61 (dd, J=16.9, 5.8 Hz, 1H; CH3 CH CHH C=O), 2.27 (dd, J=
À
À
À
16.9, 10.6 Hz, 1H; CH3 CH CHH C=O), 1.38 ppm (d, J=6.8 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3): d=168.6 (IV), 154.3 (IV), 139.8 (IV,
2C), 132.1 (III), 128.5 (III), 123.4 (III), 123.3 (III), 51.3 (III), 48.3 (II),
36.9 (II), 21.9 ppm (I); IR (neat): n˜ =2965, 2928, 1696, 1679, 1364 cmÀ1
HRMS (ES+): m/z: calcd for C12H13N2O: 201.1028; found: 201.1022.
;
2-Benzyl-3-iminoisoindolin-1-one (14n): Yield: 86%; pale-yellow solid;
1
m.p. 122–1238C; H NMR (400 MHz, CDCl3): d=8.30 (brs, 1H, C=NH),
CCDC-648622 contains the supplementary crystallographic data for
compound 10r. These data can be obtained free of charge from the
request/cif.
7.86 (m, 1H; Harom), 7.73 (m, 1H; Harom), 7.64 (m, 2H; Harom), 7.42(d, J=
7.1 Hz, 2H; Harom), 7.30 (t, J=7.1 Hz, 2H; Harom), 7.26 (d, J=7.3 Hz, 1H;
Harom), 5.02ppm (s, 2H, ArC H2); 13C NMR (100 MHz, CDCl3): d=167.9
(IV), 160.3 (IV), 136.8 (IV), 133.2 (III), 132.5 (III), 132.4 (IV), 131.1
(IV), 128.8 (III, 2C), 128.2 (III, 2C), 127.7 (III), 123.6 (III), 121.3 (III),
Ethyl 2-(3-hydroxy-5H-imidazo[2,1-a]isoindol-2-yl)acetate (10s): Yield:
G
51%; 1H NMR (400 MHz, CDCl3): d=7.75 (d, J=7.6 Hz, 1H; Harom),
7.49 (m, 2H; Harom), 7.34 (t, J=7.6 Hz, 1H; Harom), 4.73 (s, 2H; ArCH2),
3.96–3.84 (m, 3H; OCH2CH3, CHHC=O), 3.15 (d, J=15.9 Hz, 1H;
CHHC=O), 1.06 ppm (t, J=7.1 Hz, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=177.9 (IV), 169.5 (IV), 169.0 (IV), 145.9 (IV), 132.8 (III),
128.7 (III), 126.8 (IV), 124.6 (III), 123.9 (III), 80.6 (IV), 60.9 (II), 44.9
42.0 ppm (II); IR (neat): n˜ =3276, 1726, 1649 cmÀ1
; MS: m/z: 2 37
[M+H]+, 259 [M+Na]+; HRMS (ES+): m/z: calcd for C15H13N2O:
237.1028; found: 237.1017.
3-Imino-2-(4-(trifluoromethyl)benzyl)isoindolin-1-one
(14m):
Yield:
90%; off-white solid; m.p. 1368C; 1H NMR (400 MHz, CDCl3): d=7.6
(m, 1H; Harom), 7.25 (m, 4H; Harom), 6.90 (m, 2H; Harom), 6.82(m, 1H;
Harom), 4.75 ppm (s, 2H; ArCH2); 13C NMR (100 MHz, CDCl3): d=167.2
(IV), 159.7 (IV), 141.5 (IV), 134.9 (IV), 132.6 (III), 132.1 (IV), 132.0
(III), 131.3 (IV), 128.9 (III, 2C), 125.6 (III), 125.5 (III), 123.5 (IV), 123.2
(III), 120.8 (III), 41.3 ppm (II); IR (neat): n˜ =3281, 2925, 1722,
1653 cmÀ1; HRMS (ES+): m/z: calcd for C16H12N2OF3: 305.0902; found:
305.0910; elemental analysis: calcd (%) for C16H11N2OF3: C 63.16, H
3.64, N 9.21; found: C 62.84, H 3.63, N 9.02.
(II), 35.6 (II), 14.0 ppm (I); IR (neat): n˜ =2926, 2854, 1735, 1658 cmÀ1
Ethyl 4-hydroxy-2,6-dihydropyrimido[2,1-a]isoindole-3-carboxylate
.
AHCTREUNG
(10s’): Yield: 28%; 1H NMR (400 MHz, CDCl3): d=7.99 (d, J=7.6 Hz,
1H; Harom), 7.64 (m, 1H; Harom), 7.52(m, 2H; H arom), 4.74, 4.65 (AB d,
J=16.4 Hz, 1H each; ArCH2), 4.12–4.04 (m, 2H; OCH2CH3), 3.12(s,
2H; CH2N=C), 1.15 ppm (t, J=7.1 Hz, 3H; OCH2CH3); 13C NMR
(100 MHz, CDCl3): d=169.8 (IV), 168.9 (IV), 145.9 (IV, 2C), 133.9 (III),
129.2 (III), 126.3 (IV), 124.6 (III, 2C), 97.4 (IV), 61.1 (II), 45.2 (II), 42.1
(II), 14 ppm (I); HRMS (ES+): m/z: calcd for C14H15N2O3: 259.1083;
found: 259.1071.
9-Methylisoindolo
N
N
white solid; m.p. 236–2378C; 1H NMR (400 MHz, CDCl3): d=8.11 (d,
J=7.6 Hz, 1H; Harom), 7.64–7.53 (m, 5H; Harom), 7.19 (d, J=7.3 Hz, 1H;
Harom), 5.06 (s, 2H; ArCH2), 2.92 ppm (s, 3H, ArCH3); 13C NMR
(100 MHz, CDCl3): d=161.4 (IV), 154.7 (IV), 151.2(IV), 141.2(IV),
139.8 (IV), 133.4 (III), 132.8 (IV), 132.2 (III), 129.2 (III), 128.9 (III),
125.8 (III, IV), 123.5 (III), 49.9 (II), 23.2 ppm (I); IR (neat): n˜ =2924,
1668, 1629, 1594 cmÀ1; MS: m/z: 249 [M+H]+.
Tin-free radical cyclization of 6o to yield luotonin A: A solution of N-
acylcyanamide 6o (100 mg, 0.24 mmol) and pyridine (98 mL, 5 equiv) in
benzene (14 mL) was refluxed under air and irradiated with a sun lamp
(300 W) until monitoring of the reaction by TLC showed total consump-
tion of the starting material. The reaction mixture was concentrated and
purified on silica gel (pentane/ethyl acetate 5:5) to give luotonin A
(37 mg, 54%).
9-Methoxyisoindolo
N
N
white solid; m.p. 2548C; 1H NMR (400 MHz, CDCl3): d=8.12(d, J=
7.6 Hz, 1H; Harom), 7.65 (t, J=8.1 Hz, 1H; Harom), 7.59 (m, 2H; Harom),
7.55 (m, 1H; Harom), 7.38 (d, J=8.1 Hz, 1H; Harom), 6.89 (d, J=8.1 Hz,
1H; Harom), 5.09 (s, 2H; ArCH2), 4.0 ppm (s, 3H; ArOCH3); 13C NMR
(100 MHz, CDCl3): d=160.5 (IV), 159.2(IV), 155.4 (IV), 15.24 (IV),
140.1 (IV), 134.6 (III), 132.8 (IV), 132.4 (III), 128.9 (III), 123.6 (III, 2C),
1250
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1238 – 1252