30 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 1
Kaila et al.
an additional 10 min and then cooled to room temperature, poured
onto 225 mL of crushed ice, and allowed to stand for 30 min. The
precipitate was collected by filtration, washing three times with
water, and dried under vacuum to yield isatin that was usually of
sufficient purity to be used directly in the next step. Occasionally,
the first step produced an oil or sludge rather than an isolable solid.
In these cases, the hydroxyiminoacetanilide was obtained by ethyl
acetate extraction of the cooled reaction mixture; the ethyl acetate
solution was washed with brine, dried (MgSO4), filtered, and
evaporated to give a viscous oil. Cold concentrated sulfuric acid
was added to this oil in a 250 mL round-bottomed flask, and the
mixture was heated to 80 °C for 30 min (open to the atmosphere).
The reaction was then cooled to room temperature and worked up,
as described above. The following isatins were commercially
available 19, 25, 40, 42, 44, 48, 51, 55, 57, 73, and 92.
7-Methylindoline-2,3-dione (21): Orange powder, yield 40%.
1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 6.99 (t, J ) 7.6
Hz, 1H), 7.34 (d, J ) 7.6 Hz, 1H), 7.43 (d, J ) 7.6 Hz, 1H), 11.09
(s, 1H). MS (electrospray): 162 (M + H)+.
6-Methylindoline-2,3-dione (23) and 4-Methylindoline-2,3-
dione (3-5): Orange powder, inseparable 1:1 mixture, yield 26%.
1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 1.5H), 2.44 (s, 1.5H),
6.71 (m, 1H), 6.87 (t, 1H), 7.42 (m, 1H), 10.99 (s, 1H). MS
(electrospray), 162 (M + H)+.
7-Isopropylindoline-2,3-dione (29): Brown powder, yield 46%.
1H NMR (400 MHz, DMSO-d6) δ 1.18 (d, J ) 6.8 Hz, 6H), 3.04
(sep, 1H), 7.06 (t, J ) 7.7 Hz, 1H), 7.35 (d, J ) 7.3 Hz, 1H), 7.54
(d, J ) 7.3 Hz, 1H), 11.09 (s, 1H). MS (electrospray): 188 (M -
H)-.
Hz, 1H), 9.46 (s, 1H), 12.45 (s, 1H). MS (electrospray): 241 (M
- H)-. Isatin: Reddish-brown powder, yield 77%. 1H NMR (400
MHz, DMSO-d6): δ 7.02 (t, J ) 7.8 Hz, 1H), 7.52 (d, J ) 6.6 Hz,
1H), 7.79 (d, J ) 8.1 Hz, 1H), 11.32 (s, 1H).
7-Methoxyindoline-2,3-dione41 (59): 1H NMR (400 MHz,
DMF): δ 4.13 (s, 3H), 7.24-7.33 (m, 1H), 7.34-7.41 (m, 1H),
7.60 (dd, J ) 8.08, 1.01 Hz, 1H), 11.38 (s, 1H).
7-Ethoxyindoline-2,3-dione (61): Purified by flash chromatog-
raphy over silica gel (20% ethyl acetate in cyclohexane), yield 9.7%.
1H NMR (400 MHz, DMSO-d6): δ 1.33 (t, J ) 6.95 Hz, 3H),
4.10 (q, J ) 6.91 Hz, 2H), 6.82-7.01 (m, 1H), 7.02-7.18 (m,
1H), 7.56 (d, J ) 7.33 Hz, 1H), 10.68 (s, 1H).
N-(2,3-Dioxoindolin-5-yl)acetamide (76): Purified by tituration
with ethyl acetate, yield 50%. 1H NMR (400 MHz, DMSO-d6): δ
2.03 (s, 3H), 6.87 (d, J ) 8.84 Hz, 1H), 7.64 (dd, J ) 8.34, 2.27
Hz, 1H), 7.80 (d, J ) 2.27 Hz, 1H), 10.01 (s, 1H), 10.93 (s, 1H).
2,3-Dioxoindoline-5-carboxylic Acid (78): Purified by crystal-
lization from ethyl acetate and methanol, yield 45%. 1H NMR (400
MHz, DMSO-d6): δ 7.01 (d, J ) 8.34 Hz, 1H), 7.92 (d, J ) 1.77
Hz, 1H), 8.15 (dd, J ) 8.08, 1.77 Hz, 1H), 11.38 (s, 1H).
7-Ethylindoline-2,3-dione (80): Orange-brown powder, yield
1
27%, recrystallization from ethanol gave orange-red needles. H
NMR (400 MHz, DMSO-d6): δ 1.14 (t, J ) 7.5 Hz, 3H), 2.56 (q,
J ) 7.6 Hz, 2H), 7.03 (t, J ) 7.5 Hz, 1H), 7.35 (d, J ) 7.3 Hz,
1H), 7.46 (d, J ) 7.6 Hz, 1H), 11.11 (s, 1H). MS (electrospray):
176 (M + H)+.
7-sec-Butylindoline-2,3-dione (82). Hydroxyiminoacetanilide:
Sticky dark brown oil. 1H NMR (400 MHz, DMSO-d6): δ 0.75 (t,
J ) 7.3 Hz, 3H), 1.14 (d, J ) 6.8 Hz, 3H), 1.51 (m, 2H), 2.86 (m,
1H), 7.24 (m, 4H), 7.68 (s, 1H), 9.57 (s, 1H), 12.16 (s, 1H). MS
6-Isopropylindoline-2,3-dione (31) and 4-Isopropylindoline-
2,3-dione. Hydroxyiminoacetanilide: Pale golden yellow powder,
1
(electrospray): 219 (M - H)-. Isatin: Yield 52%. H NMR (400
1
yield 72%. H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J ) 7.1
MHz, DMSO-d6): δ 0.81 (t, J ) 7.3 Hz, 3H), 1.17 (d, J ) 6.8 Hz,
3H), 1.55 (m, 2H), 2.83 (m, 1H), 7.06 (t, J ) 7.6 Hz, 1H), 7.36 (d,
J ) 7.1 Hz, 1H), 7.51 (d, J ) 7.6 Hz, 1H), 11.09 (s, 1H). MS
(electrospray): 202 (M - H)-.
Hz, 6H), 2.85 (sept, 1H), 6.98 (d, J ) 7.8 Hz, 1H), 7.24 (t, J ) 7.8
Hz, 1H), 7.53 (d, J ) 8.1 Hz, 1H), 7.56 (s, 1H), 7.66 (s, 1H), 10.10
(s, 1H), 12.15 (s, 1H). MS (electrospray): 205 (M - H)-. Isatin:
Dark brown solid, inseparable 8:2 mixture, yield 78%. 6-Isopro-
pylisatin: 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J ) 6.8 Hz,
6H), 2.94 (sept, 1H), 6.76 (s, 1H), 6.96 (d, J ) 7.8 Hz, 1H), 7.43
7-tert-Butylindoline-2,3-dione (84): Isatin was isolated by ethyl
acetate extraction of the solution obtained by pouring the cooled
reaction mixture onto ice, yield 55%. 1H NMR (400 MHz, DMSO-
d6) δ 1.32 (s, 9H), 7.04 (t, 1H), 7.39 (d, J ) 7.3 Hz, 1H), 7.55 (dd,
J ) 7.8, 1.3 Hz, 1H), 10.76 (s, 1H). MS (electrospray): 204 (M +
H)+.
1
(d, J ) 7.8 Hz, 1H), 10.98 (s, 1H). 4-Isopropylisatin: H NMR
(400 MHz, DMSO-d6): δ 1.18 (d, J ) 7.3 Hz, 6H), 3.69 (sept,
1H), 6.72 (d, J ) 7.8 Hz, 1H), 7.00 (d, J ) 7.8 Hz, 1H), 7.50 (t,
J ) 7.8 Hz, 1H), 10.98 (s, 1H). MS (electrospray): 188 (M -
H)-.
7-Fluoroindoline-2,3-dione (88). Hydroxyiminoacetanilide:
Yield 71%. 1H NMR (400 MHz, DMSO-d6): δ 7.20 (m, 2H), 7.29
(m, 1H), 7.74 (s, 1H), 7.86 (m, 1H), 9.81 (s, 1H), 12.30 (s, 1H).
Isatin: Yield 65%. 1H NMR (400 MHz, DMSO-d6): δ 7.08 (ddd,
1H), 7.38 (dt, J ) 7.5, 0.8 Hz, 1H), 7.54 (ddd, J ) 10.4, 8.3, 1.0
Hz, 1H), 11.56 (s, 1H). MS (electrospray): 164 (M - H)-.
5-Isopropylindoline-2,3-dione (33): Purified by tituration with
ethyl acetate, yield 71%. 1H NMR (400 MHz, DMSO-d6): δ 1.18
(d, J ) 7.07 Hz, 6H), 2.77-2.95 (m, 1H), 6.84 (d, J ) 8.08 Hz,
1H), 7.38 (d, J ) 1.77 Hz, 1H), 7.49 (dd, J ) 8.08, 2.02 Hz, 1H),
10.94 (s, 1H). MS (electrospray): 188 (M - H)-.
6-Phenylindoline-2,3-dione (37) and 4-Phenylindoline-2,3-
dione. Hydroxyiminoacetanilide: Yellow powder, yield 88%. 1H
NMR (400 MHz, DMSO-d6): δ 7.39 (m, 1H), 7.48 (m, 1H), 7.62
(dd, J ) 8.3, 7.3 Hz, 1H), 7.70 (m, 1H), 8.02 (s, 1H), 10.27 (s,
1H), 12.20 (s, 1H). Isatin: Dark red powder, inseparable mixture
of uncertain isomeric ratio, yield 59%. 1H NMR (400 MHz, DMSO-
d6): δ 6.90 (d, J ) 7.1 Hz), 7.02 (d, J ) 7.1 Hz), 7.12 (s), 7.35
(m), 7.50 (m), 7.61 (m), 7.73 (m), 11.13 (s), 11.14 (s). MS
(electrospray): 222 (M - H)-.
1
6,7-Dimethylindoline-2,3-dione42 (90): H NMR (400 MHz,
DMSO-d6): δ 2.09 (s, 3H), 2.28 (s, 3H), 6.90 (d, J ) 7.83 Hz,
1H), 7.25 (d, J ) 7.58 Hz, 1H), 11.01 (s, 1H).
7-Methyl-5-(trifluoromethoxy)indoline-2,3-dione (96). Purified
1
by tituration with ethyl acetate, yield 70%. H NMR (400 MHz,
DMSO-d6): δ 2.23 (s, 3H), 7.35 (s, 1H), 7.50 (s, 1H), 11.26 (s,
1H).
7-Aryl Indoline-2,3-dione (7-Arylisatins). 7-Iodoindoline-2,3-
dione. Hydroxyiminoacetanilide: Beige solid, yield 83%. 1H NMR
(400 MHz, DMSO-d6): δ 6.99 (t, J ) 7.7 Hz, 1H), 7.41 (t, 1H),
7.63 (s, 1H), 7.76 (dd, J ) 8.1, 1.3 Hz, 1H), 7.90 (dd, J ) 7.8, 1.3
Hz, 1H), 9.38 (s, 1H), 12.42 (s, 1H). MS (electrospray): 289 (M
- H)-. Isatin: Dark red powder, yield 80%. 1H NMR (400 MHz,
DMSO-d6): δ 6.89 (t, J ) 7.7 Hz, 1H), 7.50 (d, J ) 7.3 Hz, 1H),
7.95 (d, J ) 6.8 Hz, 1H), 11.01 (s, 1H). MS (electrospray): 272
(M - H)-.
General Procedure. To a 1-L three-necked round-bottomed flask
fitted with a reflux condenser were added 7-iodoindoline-2,3-dione
(2.0 g, 7.33 mmol) and tetrakis[triphenylphosphine]palladium (0.424
g, 0.367 mmol), followed by 225 mL of 1,2-dimethoxyethane. The
atmosphere in the reaction vessel was made inert by opening to
vacuum, then to a positive pressure of nitrogen (3×). Arylboronic
acid (8.06 mmol) and a solution of sodium bicarbonate (1.23 g,
14.7 mmol) in 225 mL of water were added, and the evacuation/
7-(Trifluoromethoxy)indoline-2,3-dione (46). Hydroxyimi-
noacetanilide: Lumpy brown solid, yield 85%. 1H NMR (400 MHz,
DMSO-d6): δ 7.31 (m, 1H), 7.42 (m, 2H), 7.75 (s, 1H), 7.97 (dd,
J ) 7.8, 1.3 Hz, 1H), 9.71 (s, 1H), 12.39 (s, 1H). Isatin: Yield
70%. 1H NMR (400 MHz, DMSO-d6): δ 7.15 (t, J ) 7.8 Hz, 1H),
7.56 (d, J ) 7.3 Hz, 1H), 7.64 (d, J ) 8.3 Hz, 1H), 11.71 (s, 1H).
MS (electrospray): 230 (M - H)-.
7-(Trifluoromethyl)indoline-2,3-dione (50): Yield 61%. 1H
NMR (400 MHz, DMSO-d6): δ 7.23 (t, J ) 7.7 Hz, 1H), 7.78 (d,
J ) 7.3 Hz, 1H), 7.85 (d, J ) 8.1 Hz, 1H), 11.46 (s, 1H). MS
(electrospray): 214 (M - H)-.
7-Bromoindoline-2,3-dione (53). Hydroxyiminoacetanilide:
Brown solid, yield 85%. 1H NMR (400 MHz, DMSO-d6): δ 7.16
(t, 1H), 7.41 (t, J ) 7.7 Hz, 1H), 7.69 (m, 2H), 7.91 (d, J ) 8.1