LETTER
Synthesis of Highly Functionalized Oxindoles
separation may lead to considerable amounts of
decomposition products, specially from hydrolysis of the
terminal chloromethylene moiety.
2795
(3) Zaveri, N. T.; Jiang, F.; Olsen, C. M.; Deschamps, J. R.;
Parrish, D.; Polgar, W.; Toll, L. J. Med. Chem. 2004, 47,
2973.
(4) Alcaraz, M.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill,
D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.;
Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.;
Patel, Z. M.; Perkins, J.; Rowa, P.; Sadler, P.; Singleton, J.
T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Org. Process
Res. Dev. 2005, 9, 555.
(17) Data for Representative Compounds 8
Compound 8b: IR (film on NaCl): 1731.6 (C=O), 1112.9
(C–O) cm–1. 1H NMR (250 MHz, CDCl3): d = 7.73–7.67 (m,
4 H, H-2¢¢,6¢¢), 7.50–7.35 (m, 8 H, H-5,6,3¢¢,4¢¢,5¢¢), 6.77 (d,
1 H, J = 7.6 Hz, H-7), 5.07 (d, 1 H, J = 14.2 Hz, CH2O), 4.90
(d, 1 H, J = 14.2 Hz, CH2O), 3.31–3.13 (m, 2 H, H-3¢), 3.21
(s, 3 H, NCH3), 2.40–2.17 (m, 2 H, H-1¢), 1.43–1.28 (m, 2 H,
H-2¢), 1.12 [s, 9 H, C(CH3)3]. 13C NMR (62.9 MHz, CDCl3):
d = 173.2 (C-2), 142.4 (C-7a), 139.1 (C-4), 135.5 (C-2¢¢,6¢¢),
133.0 (C-1¢¢), 130.5 (C-6), 129.9 (C-4¢¢), 127.8 (C-3¢¢,5¢¢),
123.2 (C-3a), 121.6 (C-5), 107.4 (C-7), 64.4 (C-3), 60.9
(CH2O), 43.6 (C-3¢), 35.6 (C-1¢), 27.7 (C-2¢), 26.85 (NCH3),
26.75 [C(CH3)3], 19.3 [C(CH3)3]. Anal. Calcd for
(5) Kikuchi, C.; Hiranuma, T.; Koyama, M. Bioorg. Med. Chem.
Lett. 2002, 12, 2549.
(6) Gallagher, G.; Lavanchi, P. G.; Wilson, J. W.; Hieble, J. P.;
DeMarinis, R. M. J. Med. Chem. 1985, 28, 1533.
(7) For early surveys of oxindole alkaloids, see: (a) Cordell, G.
A. An Introduction to Alkaloids: A Biogenetic Approach;
Wiley-Interscience: New York, 1981. (b) Bindra, J. S.
Oxindole Alkaloids, In The Alkaloids – Chemistry and
Physiology, Vol. 14; Manske, R. H. F., Ed.; Academic Press:
New York, 1973, 83.
C29H33Cl2NO2Si: C, 66.15; H, 6.32; N, 2.66. Found: C,
65.97; H, 6.02; N, 2.36.
Compound 8d (major diastereomer, 8da; minor
(8) Abourriche, A.; Abboud, Y.; Maoufoud, S.; Mohou, H.;
Seffaj, T.; Charrouf, M.; Chaib, N.; Benamara, A.;
Bontemps, N.; Francisco, C. Farmaco 2003, 58, 1351.
(9) (a) Isolation: Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.;
Osada, H. J. Antibiot. 1996, 49, 527. (b) Structure: Cui, C.;
Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651. Total
syntheses: (c) Edmonson, S.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 1998, 37, 1138. (d) Wang, H.; Ganesan, A. J.
Org. Chem. 2000, 65, 4685. (e) Sebahar, P. R.; Williams, R.
M. J. Am. Chem. Soc. 2000, 122, 5666. (f) Von Nussbaum,
F.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2000, 39, 2175.
(g) Cytotoxic activity: Edmondson, S. E.; Danishefsky, S. J.;
Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121,
2147.
diastereomer, 8db): IR (film on NaCl): 1729.0 (C=O) cm–1.
1H NMR (250 MHz, CDCl3): d = 7.35–7.25 (m, 2 H, H-4,6),
7.07 (t, 1 H, J = 7.6 Hz, H-5), 6.80 (d, 1 H, J = 7.8 Hz, H-7),
3.75–3.60 (m, 1 H, H-3¢), 3.18 (m, 3 H, NCH3), 2.70–2.10
(m, 2 H, H-1¢), 1.80–1.35 (m, 4 H, H-2¢, CH2CH3), 0.95–
0.80 (m, 3 H, CH2CH3). 13C NMR (62.9 MHz, CDCl3): d =
174.1 (CO), 143.0 (C-7a, 8da), 142.9 (C-7a, 8db), 130.7 (C-
4), 129.7 (C-3a, 8da), 129.5 (C-3a, 8db), 124.6 (C-6), 124.0
(C-5, 8db), 123.9 (C-5, 8da), 109.1 (C-7), 65.1 (C-3¢, 8db),
64.9 (C-3¢, 8da), 64.7 (C-3), 36.8 (C-1¢, 8db), 36.3 (C-1¢,
8da), 33.1 (C-2¢, 8db), 32.7 (C-2¢, 8da), 31.8 (CH2, 8da),
31.5 (CH2, 8db), 27.1 (NCH3), 11.3 (CH2CH3). Anal. Calcd
for C14H17Cl2NO: C, 58.75; H, 5.99; N, 4.89. Found: C,
58.80; H, 5.91; N, 4.99.
(10) For reviews of the chemistry of the welwitindolinones, see:
(a) Avendaño, C.; Menéndez, J. C. Curr. Org. Synth. 2004,
1, 65. (b) Menéndez, J. C. In Bioactive Heterocycles V, In
Topics in Heterocyclic Chemistry, Vol. 11; Springer: Berlin/
Heidelberg, 2007, 63.
(11) (a) Szabo-Pusztay, K.; Szabo, L. Synthesis 1979, 276.
(b) Underwood, R.; Prasad, K.; Repic, O.; Hardtmann, G.
Synth. Commun. 1992, 22, 343. (c) Cushing, T. D.; Sanz-
Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115,
9323.
(12) For a review of the synthesis of 2-oxindoles, see: Karp, G.
M. Org. Prep. Proced. Int. 1993, 25, 481.
(13) Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.;
Pearson, D. P. J.; Veal, K. T. Tetrahedron Lett. 1999, 40,
4593.
Compound 8g (major diastereomer, 8ga; minor
diastereomer, 8gb): IR (film on NaCl): 3296.0 (NH), 1718.7
(C=O) cm–1. 1H NMR (250 MHz, CDCl3): d = 8.96 (s, 1 H,
NH, 8ga), 8.90 (s, 1 H, NH, 8gb), 6.96 (d, 1 H, J = 2.4 Hz,
H-4), 6.88 (d, 1 H, J = 8.5 Hz, H-6), 6.82 (dd, 1 H, J = 8.5,
2.4 Hz, H-7), 4.05–3.85 (m, 1 H, H-3¢), 3.81 (s, 3 H, OCH3),
2.60–2.40 (m, 2 H, H-1¢), 2.40–2.20 (m, 2 H, H-2¢), 1.48 (d,
3 H, J = 6.5 Hz, CH3, 8ga), 1.46 (d, 3 H, J = 6.3 Hz, CH3,
8gb). 13C NMR (62.9 MHz, CDCl3): d = 177.1 (CO), 156.3
(C-5), 141.1 (C-7a), 134.1 (C-3a, 8gb), 133.8 (C-3a, 8ga),
115.7 (C-7, 8gb), 115.5 (C-7, 8ga), 111.8 (C-4, 8ga), 111.5
(C-4, 8gb), 111.3 (C-6), 68.0 (C-3), 58.2 (C-3¢, 8gb), 58.0
(C-3¢, 8ga), 56.2 (OCH3), 36.9 (C-1¢, 8gb), 36.5 (C-1¢, 8ga),
35.1 (C-2¢, 8gb), 34.8 (C-2¢, 8ga), 25.7 (CH3, 8gb), 25.5
(CH3, 8ga). Anal. Calcd for C13H15Cl2NO2: C, 54.18; H,
5.25; N, 4.86. Found: C, 53.95; H, 5.12; N, 4.75.
(14) Some of these compounds are known in the literature. See:
Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047.
(15) Wuest, F. R.; Kniess, T. J. Labelled Compd. Radiopharm.
2005, 48, 31.
(18) Compound 8a has been previously obtained in 7% yield by
treatment of alcohol 6a with NCS in CH2Cl2 followed by
addition of aq NH4Cl. See: (a) Hino, T.; Miura, H.;
Nakagawa, T.; Murata, R.; Nakagawa, M. Heterocycles
1975, 3, 805. (b) Hino, T.; Miura, H.; Murata, R.;
Nakagawa, M. Chem. Pharm. Bull. 1978, 26, 3695.
(19) Data for 3-Chloro-1-methyl-3-(3-oxobutyl)oxindole
IR (film on NaCl): 1728.2, 1717.0 (C=O) cm–1. 1H NMR
(250 MHz, CDCl3): d = 7.39 (d, 1 H, J = 7.6 Hz, H-4), 7.37
(t, 1 H, J = 7.6 Hz, H-6), 7.15 (t, 1 H, J = 7.6 Hz, H-5), 6.87
(d, 1 H, J = 7.6 Hz, H-7), 3.25 (s, 3 H, NCH3), 2.65–2.40 (m,
4 H, H-1¢,2¢), 2.11 (s, 3 H, COCH3). 13C NMR (62.9 MHz,
CDCl3): d = 206.9 (C-3¢), 173.9 (C-2), 142.7 (C-7a), 130.8
(C-4), 129.8 (C-3a), 124.5 (C-6), 123.9 (C-5), 109.2 (C-7),
64.4 (C-3), 38.4 (C-2¢), 33.2 (C-1¢), 30.4 (COCH3), 27.0
(NCH3). MS: m/z = 251 [M+]. Anal. Calcd for C13H14ClNO2:
C, 62.03; H, 5.61; N, 5.56. Found: C, 62.35; H, 5.81; N, 5.62.
(16) Representative Experimental Procedure
To a solution of oxalyl chloride (5 equiv) in anhyd CH2Cl2
(10 mL), at –78 °C under an argon atmophere, was added
DMSO (7 equiv). The solution was stirred for ca. 10 min,
until effervescence ceased. A solution of alcohol 6b (350
mg, 0.77 mmol) in anhyd CH2Cl2 (3 mL) was added
dropwise via cannula, and the red solution was stirred for 10
min at –78 °C. Then, Et3N (10 equiv) was added and the
solution was left to warm to r.t. for 20 min, while stirred. The
reaction mixture was diluted with CH2Cl2 (20 mL) and
washed with sat. aq NH4Cl (3 × 20 mL). The organic layer
was dried (Na2SO4) and evaporated, and the residue was
purified by rapid chromatography on silica gel, eluting with
PE–EtOAc mixtures (gradient from 20:1 to 5:1), to yield
compound 8b (357 mg, 90%). Slower chromatographic
Synlett 2007, No. 18, 2792–2796 © Thieme Stuttgart · New York