July 2011
Synthesis of Heterocyclic Substituted Norcantharidin Derivatives
811
CH3). Anal. Calcd. for C12H12N2O4S: C, 51.42; H, 4.32; N,
9.99. Found: C, 51.40; H, 4.33; N, 10.02.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(benzo[d][1,3]dioxol-5-yl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7
(1H,3aH)-dione (6e). This compound was obtained as beige
2-(Thiazol-2-yl)-4,7-epoxy-3a,4,7,7a-tetrahydro-1H-isoindole-
1,3(2H)-dione (6). This compound was obtained as beige crys-
tals, yield 15.8%, m.p.145ꢀC; 1H NMR(CDCl3) d: 7.80–7.79
(d, J ¼ 3.6 Hz, 1H, NACH), 7.34–7.33 (d, J ¼ 3.6, 1H, S-
CH), 6.59–6.57 (d, J ¼ 4.8, 2H, C5AH, C6AH), 5.44 (s, 2H,
C1AH, C4AH), 3.09 (s, 2H, C2AH, C3AH). Anal. Calcd. for
C11H8N2O3S: C, 53.22; H, 3.25; N, 11.28. Found: C, 53.23; H,
3.24; N, 11.30.
1
crystals, yield 40.6%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.47–
6.95 (m, 3H, Ar-H), 6.56–6.54 (d, J ¼ 12.38 Hz, 1H, NACH),
6.37–6.34 (d, J ¼ 12.77 Hz, 1H, S-CH), 6.07 (s, 2H, OCH2O),
5.27 (d, J ¼ 7.93 Hz, 1H, C5AH), 5.12 (s, 1H, C4AH), 4.81
(s, 1H, C1AH), 4.50 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.56 (d, J
¼ 7.92 Hz, 1H, C3-H), 3.41 (d, J ¼ 7.91 Hz, 1H, C2-H). Anal.
Calcd. for C19H13N3O6S: C, 55.47; H, 3.19; N, 10.21. Found:
C, 55.44; H, 3.17; N, 10.22.
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-fluorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (7a). This compound was obtained as
beige crystals, yield 54.7%, m.p. 287ꢀC; 1H NMR(CDCl3) d:
7.70–7.22(m, 4H, Ar-H), 6.75 (s, 1H, NACH), 5.18 (d, J ¼
7.91 Hz, 1H, C5AH), 4.95(s, 1H, C4AH), 4.74(s, 1H, C1AH),
4.47(d, J ¼ 7.92 Hz, 1H, C6AH), 3.59(d, J ¼ 7.94 Hz, 1H,
C3AH), 3.37(d, J ¼ 7.93 Hz, 1H, C2AH), 2.50 (s, 3H, CH3).
Anal. Calcd. for C19H14N3O4FS: C, 57.14; H, 3.53; N, 10.52.
Found: C, 57.15; H, 3.51; N, 10.54.
2-(5-Methylthiazol-2-yl)-4,7-epoxy-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione (7). This compound was obtained as
beige crystals, yield 76.8%, m.p.136ꢀC; 1H NMR (CDCl3) d:
7.43–7.42 (d, J ¼ 1.2, 1H, NACH), 6.57 (s, 2H, C5AH,
C6AH), 5.42 (s, 2H, C1AH, C4AH), 3.05 (s, 2H, C2AH,
C3AH), 2.48 (s, 3H, CH3). Anal. Calcd. for C12H10N2O3S: C,
54.95; H, 3.84; N, 10.68. Found: C, 54.97; H, 3.85; N, 10.65.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-fluorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7(1H,3aH)-
dione (6a). This compound was obtained as beige crystals,
1
yield 27.8%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.70–7.09 (m,
4H, Ar-H), 6.55–6.52 (d, J ¼ 12.41 Hz, 1H, NACH), 6.39–
6.36 (d, J ¼ 12.82 Hz, 1H, S-CH), 5.18 (d, J ¼ 7.92 Hz, 1H,
C5AH), 4.95(s, 1H, C4AH), 4.74(s, 1H, C1AH), 4.47(d, J ¼
7.92 Hz, 1H, C6AH), 3.59(d, J ¼ 7.94 Hz, 1H, C3AH),
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-chlorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (7b). This compound was obtained as beige
crystals, yield 35.4%, m.p. 268ꢀC; 1H NMR(CDCl3) d: 7.84–
7.46 (m, 4H, Ar-H), 6.74 (s, 1H, NACH), 5.18 (d, J ¼ 7.93
Hz, 1H, C5AH), 4.95 (s, 1H, C4AH), 4.73 (s, 1H, C1AH),
4.51 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60 (d, J ¼ 7.91 Hz, 1H,
C3AH), 3.36 (d, J ¼ 7.93 Hz, 1H, C2AH), 2.35 (s, 3H, CH3).
Anal. Calcd. for C19H14N3O4ClS: C, 54.88; H, 3.39; N, 10.10.
Found: C, 54.86; H, 3.41; N, 10.13.
3.37(d,
J
¼
7.93 Hz, 1H, C2AH). Anal. Calcd. for
C18H12N3O4FS: C, 56.10; H, 3.14; N, 10.90. Found: C, 56.08;
H, 3.15; N, 10.87.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-chlorophenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7(1H,3aH)-
dione (6b). This compound was obtained as beige crystals,
1
yield 22.5%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.74–7.06 (m,
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(4-(methylsulfinyl)phenyl)-pyrrolo[3,4-f]-1,2-benzi-
soxazole-5,7(1H,3aH)-dione (7c). This compound was obtained
4H, Ar-H), 6.55–6.52 (d, J ¼ 12.42 Hz, 1H, NACH), 6.38–
6.36 (d, J ¼ 12.78 Hz, 1H, S-CH), 5.18 (d, J ¼ 7.93 Hz, 1H,
C5AH), 4.95 (s, 1H, C4AH), 4.73 (s, 1H, C1AH), 4.48 (d, J ¼
7.92 Hz, 1H, C6AH), 3.59 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.36
1
as beige crystals, yield 27.4%, m.p. >300ꢀC; H NMR(CDCl3)
d: 8.05–7.74 (m, 4H, Ar-H), 6.74 (s, 1H, NACH), 5.24–5.22
(d, J ¼ 7.91 Hz, 1H, C5AH), 4.99 (s, 1H, C4AH), 4.76 (s, 1H,
C1AH), 4.51–4.49 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60–3.58 (d,
J ¼ 7.92 Hz, 1H, C3AH), 3.38–3.36 (d, J ¼ 7.90 Hz, 1H,
C2AH), 2.64 (s, 3H, CH3), 2.40 (s, 3H, CH3). Anal. Calcd. for
C20H17N3O5S2: C, 54.12; H, 3.86; N, 9.47. Found: C, 54.09;
H, 3.88; N, 9.50.
(d,
J
¼
7.93 Hz, 1H, C2AH). Anal. Calcd. for
C18H12N3O4ClS: C, 53.80; H, 3.01; N, 10.46. Found: C,
53.81; H, 3.04; N, 10.42.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(4-(methylsulfinyl)phenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-5,7
(1H,3aH)-dione (6c). This compound was obtained as beige
1
crystals, yield 24.3%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.81–
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(3-hydroxy-4-methoxyphenyl)-pyrrolo[3,4-f]-1,2-
benzisoxazole-5,7(1H,3aH)-dione (7d). This compound was
obtained as beige crystals, yield 33.4%, m.p. >300ꢀC; 1H
NMR(CDCl3) d: 7.47–6.89 (m, 3H, Ar-H), 6.47 (s, 1H, NACH),
5.24 (d, J ¼ 7.90 Hz, 1H, C5AH), 4.98 (s, 1H, C4AH), 4.75 (s,
1H, C1AH), 4.52 (d, J ¼ 7.93 Hz, 1H, C6AH), 3.83 (s, 3H,
OCH3), 3.59 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.38 (d, J ¼ 7.92 Hz,
1H, C2AH), 2.30 (s, 3H, CH3). Anal. Calcd. for C20H17N3O6S:
C, 56.20; H, 4.01; N, 9.83. Found: C, 56.17; H, 3.98; N, 9.85.
exo,exo-6-(5-Methylthiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-
hexahydro-3-(benzo[d][1,3]dioxol-5-yl)-pyrrolo[3,4-f]-1,2-ben-
zisoxazole-5,7(1H,3aH)-dione (7e). This compound was
obtained as beige crystals, yield 53.7%, m.p. 282ꢀC; 1H
NMR(CDCl3) d: 7.47–6.95 (m, 3H, Ar-H), 6.70 (d, 1H,
NACH), 6.12 (s, 2H, OCH2O), 5.27 (d, J ¼ 7.93 Hz, 1H,
C5AH), 5.12 (s, 1H, C4AH), 4.81 (s, 1H, C1AH), 4.50 (d, J ¼
7.90 Hz, 1H, C6AH), 3.58 (d, J ¼ 7.92 Hz, 1H, C3AH), 3.41
(d, J ¼ 7.92 Hz, 1H, C2AH), 2.30 (s, 3H, CH3). Anal. Calcd.
6.96 (m, 4H, Ar-H), 6.55–6.52 (d, J ¼ 12.40 Hz, 1H, NACH),
6.38–6.35 (d, J ¼ 12.80 Hz, 1H, S-CH), 5.24–5.22 (d, J ¼
7.92 Hz, 1H, C5AH), 4.99 (s, 1H, C4AH), 4.76 (s, 1H,
C1AH), 4.51–4.49 (d, J ¼ 7.92 Hz, 1H, C6AH), 3.60–3.58 (d,
J ¼ 7.92 Hz, 1H, C3AH), 3.38–3.36 (d, J ¼ 7.92 Hz, 1H,
C2AH), 2.64 (s, 3H, CH3). Anal. Calcd. for C18H12N3O5S2: C,
53.14; H, 3.52; N, 9.78. Found: C, 53.11; H, 3.55; N, 9.79.
exo,exo-6-(Thiazol-2-yl)-4,8-epoxy-3a,4,4a,7a,8,8a-hexahydro-
3-(3-hydroxy-4-methoxyphenyl)-pyrrolo[3,4-f]-1,2-benzisoxazole-
5,7(1H,3aH)-dione (6d). This compound was obtained as beige
1
crystals, yield 31.2%, m.p. >300ꢀC; H NMR(CDCl3) d: 7.83–
7.19 (m, 3H, Ar-H), 6.55–6.52 (d, J ¼ 12.44 Hz, 1H, NACH),
6.38–6.36 (d, J ¼ 12.75 Hz, 1H, S-CH), 5.24 (d, J ¼ 7.90 Hz,
1H, C5AH), 4.98 (s, 1H, C4AH), 4.75 (s, 1H, C1AH), 4.52 (d,
J ¼ 7.93 Hz, 1H, C6AH), 3.77 (s, 3H, OCH3), 3.59 (d, J ¼
7.92 Hz, 1H, C3AH), 3.38 (d, J ¼ 7.92 Hz, 1H, C2AH). Anal.
Calcd. for C19H15N3O6S: C, 55.20; H, 3.66; N, 10.16. Found:
C, 55.18; H, 3.64; N, 10.15.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet