Catalyst-free synthesis of 3-hydroxy-3-(alkyl/aryl)indolin-2-ones by addition of organoaluminum reagents to isatins

Article abstract of DOI:10.1016/j.tetlet.2013.07.027

An efficient synthesis of 3-hydroxy-3-(alkyl/aryl)indol-2-one derivatives has been described by the reactions of isatin with organoaluminum reagents. The reaction is very rapid and yields are high. The protocol is applicable for substituted isatins as well as a variety of organoaluminums.

Full text of DOI:10.1016/j.tetlet.2013.07.027

Tetrahedron Letters 54 (2013) 5048–5051
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst-free synthesis of 3-hydroxy-3-(alkyl/aryl)indolin-2-ones
by addition of organoaluminum reagents to isatins
⇑
G. Santosh Kumar, Palakuri Ramesh, A. Sanjeeva Kumar, A. Swetha, H. M. Meshram
Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 3-hydroxy-3-(alkyl/aryl)indol-2-one derivatives has been described by the reac-
tions of isatin with organoaluminum reagents. The reaction is very rapid and yields are high. The protocol
is applicable for substituted isatins as well as a variety of organoaluminums.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 May 2013
Revised 2 July 2013
Accepted 4 July 2013
Available online 11 July 2013
Keywords:
Isatin
Organoaluminum
Oxindoles
Catalyst-free conditions
The 3-hydroxyoxindole moiety is found in many biologically ac-
tive molecules such as convolutamydines.1 This is important struc-
tural motif in proteasome inhibitors like TMC-95A/B.2 The 3-
hydroxyoxindole moiety is also found in various alkaloids such
as donaxaridine, dioxibrassinine, welwitindolinone C, and 3-
hydroxyglucoisatisin.3 The carbon–carbon bond formation has
been one of the most studied reactions in the past 10 years.4 In
these studies, the additions of organozinc to aldehydes are one of
the most reliable processes and thus gain much attention from
chemists.5–9 Among alkylation reagents, trialkylaluminum
reagents are more interesting since they are inexpensive and com-
mercially available.10 Among the organometallic species, organo-
aluminum reagents stand out for practical applications. The
additional advantages of organoaluminum compounds include
low toxicities and considerable stabilities.11 The first example of
the asymmetric addition of AlEt3 to aldehydes, catalyzed by a
Ti(IV)–BINOL complex, was developed by Chan et al. in 1997.12d
Other reports include the titanium catalyzed addition of Me3Al,12b,c
Et3Al,12b (allyl)AlEt212b, and Ph3Al12a to aldehydes. In addition to
this some of the methods have been reported using nickel cata-
lyzed Me3Al11 or (Me3Al)2–DABCO11c to aldehydes (Fig. 1).
Grignard reagents (RMgX)14 or arylboronic acids (RB(OH)2).15
Following our recent interest in the synthesis of new 3-hydroxy-
S
NHMe
Br
HO
SMe
HO
HO
N
H
O
R
*
O
O
N
H
N
H
N
H
Br
convolutamydines A-E
dioxibrassinine
donoxaridine
A
: R = CH2COCH3
B: R = CH2CH2Cl
C: R = CH3
D: R = CH=CH2
E: R = CH2CH2OH
Figure 1. Representative examples of biologically active 3-hydroxy-indolin-2-ones.
R1
R1
R3
R4
HO
O
R2
R2
Toluene
70°C
Al(R4)3
O
+
O
Owing to the significance of this organoaluminum reagent mo-
tif, the development of these reactions is highly valuable, and the
alkylation/arylation of isatins would be the most straightforward
approach to this end. Catalyst free reactions have received special
attention in recent years.13 There are two methods for the synthe-
sis of 3-hydroxy-3-alkyl/aryl-indolin-2-ones which involves using
N
N
R
R3
R
2
1
3
R
4 = Me, Et, Ph
R = H, CH3, Bn
R1 = H, Cl, Br
R2 = H, Cl, Br, I, F, OCF3, NO2
R3 = H, Cl, Br
⇑
Corresponding author. Tel.: +91 40 27191643; fax: +91 40 27193275.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Scheme 1. Synthesis of substituted 3-hydroxy-indolin-2-ones under catalyst-free
condition.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.027

G. S. Kumar et al. / Tetrahedron Letters 54 (2013) 5048–5051
5049
Table 1
We have initiated our investigation by examining the reaction
between free isatin 1 and triphenylaluminum 2 as a model. Initially
we have observed that the formation of desired product in
less yield when triphenylaluminum(1 mmol) reacted with free
isatin(1 mmol) in toluene at rt. Next we focused to examine the
reaction in detail to increase the reaction rate and yield. Surpris-
ingly, the extreme increase in the reaction rate and yield (90%) of
3a was observed when the temperature raised to 70 °C without
using any catalyst. And we also observed that there is no change
in yield even if the temperature is raised to 100 °C. The reaction
completed smoothly within 3 h at 70 °C to give 3-hydroxy-3-
(phenyl)indolin-2-one 3a which was confirmed by analyzing
spectral data (Table 2, entry 1). Though the reaction proceeds with
1:1 ratio of reactant, the best results were obtained by 2 equiv ratio
of AlPh3.
Screened solvents for the reaction of isatin with organoaluminum reagents
HO
O
Ph
O
Toluene
70°
+
AlPh3
O
N
H
N
H
Entry
Solvent
DMSO
Toluene
Xylene
Toluene
Dioxane
Acetonitrile
THF
Conditiona
Yieldb (%)
1
2
3
4
5
6
7
8
120 °C, 8 h
rt, 24 h
70 °C, 12 h
70 °C, 3 h
55
20
55
90
40
20
20
20
100 °C, 12 h
Reflux, 12 h
Reflux, 12 h
Reflux, 12 h
DCM
a
Reaction conditions: isatin (1 equiv) and organoaluminum (2 equiv) in solvent
Encouraged by these results, next we have studied the model
reaction in different solvents such as DMSO, toluene, xylene,
dioxane, acetonitrile, THF, and DCM. We have noticed that the
reaction proceeded in all the solvents with a different degree of
conversion (Table 1). However, toluene was the solvent of choice
in terms of reaction time and yield.
The scope of this catalyst-free protocol was investigated under
optimal condition17 and the results are summarized in Table 2.
Isatins bearing different substituents on the nitrogen atom and/
stirred at stipulated time.
b
Isolated yields.
3-substituted oxindole,16 herein, we wish to report the catalyst
free efficient synthesis of 3-hydroxy-3-(alkyl/aryl)indolin-2-one
derivatives by the organometallic reaction of isatins with trialkyl/
aryl aluminum in excellent yields. To the best of our knowledge,
however, there have been no examples reported to date that
employ this strategy (Scheme 1).
Table 2
3-Hydroxy-3-(alkyl/aryl)-indolin-2-one derivatives formation by using organoaluminum
Entry
1
Isatin
Al (Alky/Aryl)3
Producta
Time (h)
3
Yieldb(%)
90
HO
O
Ph
3a
O
O
AlPh3
N
H
N
H
HO
O
Ph
O
Br
I
Br
I
3b
O
2
3
4
AlPh3
AlPh3
AlPh3
3
3
3
93
92
93
N
H
N
H
O
HO
Ph
O
3c
O
N
N
H
H
HO
O
Ph
O
Cl
Cl
3d
O
N
N
H
H
HO
O
Ph
3e
O
O
5
6
AlPh3
AlPh3
3
3
95
94
N
N
H
H
Br
Cl
Br
Cl
O
HO
Ph
3f
O
O
N
N
H
H
Cl
F3CO
Cl
HO
O
Ph
F3CO
3g
O
O
7
8
AlPh3
AlEt3
3.5
3.5
80
85
N
N
H
H
HO
O
3h
O
O
N
N
H
H
Br
Br
HO
O
3i
9
AlEt3
O
3.5
84
75
O
N
N
H
H
HO
O
F3CO
Cl
F3CO
Cl
3j
O
O
10
11
AlEt3
AlEt3
3.5
3.5
N
N
H
H
HO
O
3k
O
O
80
N
H
N
H
(continued on next page)

5050
G. S. Kumar et al. / Tetrahedron Letters 54 (2013) 5048–5051
Table 2 (continued)
Entry
Isatin
Al (Alky/Aryl)3
AlEt3
Producta
Time (h)
3.5
Yieldb(%)
78
HO
O
O2N
O2N
3l
O
O
12
13
14
N
H
N
H
HO
O
I
I
3m
O
O
AlEt3
AlEt3
3.5
3.5
78
80
N
N
H
H
HO
O
F
F
3n
O
O
N
H
N
H
Cl
Cl
HO
O
Cl
Cl
3o
O
15
16
17
AlEt3
AlEt3
AlEt3
3.5
3.5
3
78
76
76
O
N
N
H
H
HO
O
3p
3q
O
O
N
N
HO
O
O
O
N
N
Bn
Bn
HO
O
O
O
3r
O
18
19
AlMe3
AlMe3
3
3
90
89
N
N
H
H
HO
O
Br
I
Br
I
3s
O
N
H
O
N
H
HO
O
O
20
21
AlMe3
AlMe3
3t
3
3
89
88
N
N
H
H
HO
HO
O
O
O
3u
3v
N
N
N
O
O
O
22
AlMe3
3
88
N
Bn
Bn
a
Reaction conditions: isatin (1 equiv) and organoaluminum (2 equiv) at 70 °C.
Isolated yields.
b
or the aromatic ring could also be alkylated/arylated effectively
under this condition. The addition of AlPh3 2 to various isatins 1
proceeded readily and resulted into expected product in high yield.
Further, we extended this protocol to different substituted isatins.
For example, 5-halo isatins reacted with AlPh3 in the optimized
condition and resulted into high yields of the expected product
(Table 2, entries 2–4). Other 5-substituted, 7-substituted, and
4,7-substituted isatins also afforded comparatively good yields of
products (Table 2, entries 5–7). Then we extended this protocol
for the AlMe3/AlEt3 addition to different substituted isatins which
gave good yield of the products. For example, simple isatin reacted
with AlMe3/AlEt3 to afford high yield of desired products (Table 2,
entries 8 and 18). In addition to this N-substituted isatins (Table 2,
entries 16 and 17) were subjected to the AlMe3/AlEt3 reaction in an
identical condition which resulted in the expected product in less
yield. Similarly, 4-substituted, 5-substituted and also 5,7-disubsti-
tuted isatins (Table 2, entries 11–13 and 15) participated in the
reaction and gave comparatively less yields. During the experiment
we observed the reactivity profile of alkyl/aryl Al is as follows
AlPh3 > AlMe3 > AlEt3.
synthesis of new novel compounds which are not prepared earlier
(Table 2, entries 6–15 and 20). A wide variety of isatins having dif-
ferent substituents were examined. Isatins bearing either an
electron-donating or an electron-withdrawing substituent at 40-,
50-, and 70-position gave excellent yield of products. More impor-
tantly, aluminum reagents with different aryl nucleophiles can
be easily prepared for additions to isatins, furnishing tertiary alco-
hols. The present method provides direct access for the synthesis of
a large number of 3-alkyl/aryl-3-hyroxy indole-2-ones molecules
which may be useful in search of lead molecules.
Acknowledgments
G.S.K., P.R., A.S.K. and A.S. thank CSIR for the award of a fellow-
ship and to Dr. Ahmed Kamal, HOD, MCP Division, IICT, for his sup-
port and encouragement.
References and notes
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In summary, we have developed a novel method for the
alkylation/arylation of isatin at 3 position, using tri alkyl/aryl alu-
minum. This method is applicable for substituted isatins and yields
are high. Moreover the present protocol is also amenable for the
4. Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994.

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18. Spectral data for new compounds:
4-Bromo-3-ethyl-3-hydroxyindolin-2-one (Table 2, 3f): White solid; Mp 160–
162 °C; 1HNMR (300 MHz, CDCl3 + DMSO-d6):
d 3.68 (s, 1H), 6.98 (d,
J = 8.98 Hz, 1H), 7.26 (d, J = 8.98 Hz, 1H), 7.33–7.42 (m, 5H), 8.02(s, 1H) ppm;
C13 NMR (75 MHz, CDCl3 + DMSO-d6): d 93.3, 109.5, 125.8, 126.1, 126.4, 127.1,
129.3, 129.6, 136.4 139.2, 143.0, 163.0 ppm; IR (KBr):
m = 3374, 3195, 1718,
1611, 1467, 1422, 1303, 1160, 1063, 810, 768, 700 cmꢁ1; MS (EI): m/z = 295
(M+1).
4-Bromo-3-ethyl-3-hydroxyindolin-2-one (Table 2, 3i): White solid; Mp 162–
164 °C; 1HNMR (300 MHz, CDCl3 + DMSO-d6): d 0.59 (t, J = 7.32 Hz, 3H), 1.83 (q,
J = 7.32 Hz, 2H), 5.50 (s, 1H), 6.79 (dd, J = 1.97, 5.93 Hz, 1H), 7.00–7.04 (m, 2H),
10.12 (s, 1H) ppm; C13 NMR (75 MHz, CDCl3 + DMSO-d6): d 4.3, 31.2, 82.1,
113.8, 123.3, 127.3, 128.4, 130.6, 141.8, 177.8 ppm; IR (KBr):
m = 3246, 3177,
1706, 1619, 1472, 1440, 1182, 1082, 930, 826, 730 cmꢁ1; MS (EI): m/z = 279
(M+Na).
3-Ethyl-3-hydroxy-5-(trifluoromethoxy)indolin-2-one (Table 2, 3j): White solid;
Mp 158–160 °C; 1H NMR (300 MHz, CDCl3 + DMSO-d6): d 0.74 (t, J = 7.66 Hz,
3H), 1.92 (q, J = 7.66 Hz, 2H), 5.79 (s, 1H), 6.86 (d, J = 8.20 Hz, 1H), 7.06 (d,
J = 8.20 Hz, 1H), 7.17 (s, 1H), 10.06 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3 + DMSO-d6):
d 4.3, 31.9, 86.2, 111.1, 111.8, 112.4, 121, 131.8, 133,
156.3, 177.8 ppm; IR (KBr)
m = 3346, 3157, 1709, 1629, 1462, 1240, 1182, 1082,
11. (a) Alegre, S.; Diéguez, M.; Pàmies, O. Tetrahedron: Asymmetry 2011, 22, 834;
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2005, 44, 2232.
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Chem. Soc. 1997, 119, 4080.
920, 816 cmꢁ1; MS (EI): m/z = 262 (M+1).
5-Chloro-3-ethyl-3-hydroxyindolin-2-one (Table 2, 3k): White solid; Mp 204-
2060C; 1H NMR (300 MHz, CDCl3+ DMSO-d6): d 0.72 (t, J = 7.32 Hz, 3H), 1.84 (q,
J = 7.32 Hz, 2H), 5.72 (s, 1H), 6.78 (t, J = 8.54 Hz, 1H), 7.12 (d, J = 8.54 Hz, 1H),
7.19 (s, 1H), 10.10 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3+ DMSO-d6): d 4.3,
31.9, 85.4, 110.9, 125.9, 126.3, 126.6, 132.2, 139.0, 177.8 ppm; IR (KBr):
m =
3256, 2942, 1703, 1605, 1490, 1423, 1325, 1185, 1070, 985, 924, 798 cm-1; MS
(ESI): m/z = 234 (M+Na).
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17. General procedure: To a solution of isatin 1 (1 mmol) in toluene (5 mL) was
added the solution of trialkyl/aryl Al 2 (2 mmol, 2 M in toluene) dropwise at
RT. Then the mixture was heated at 70 °C and stirred for additional 3–3.5 h (see
Table 2). The reaction was monitored by TLC. After completion of the reaction,
toluene was evaporated and extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic layer was washed with brine solution, dried over anhydrous
Na2SO4, and concentrated under reduced pressure (rotary evaporator). The
3-Ethyl-3-hydroxy-5-nitroindolin-2-one (Table 2, 3l): White solid; Mp 209–
211 °C; 1H NMR (300 MHz, CDCl3 + DMSO-d6): d 0.76 (d, J = 7.00 Hz, 3H), 1.92
(q, J = 7.00 Hz, 2H), 5.92 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 8.09–8.14 (m, 2H), 10.6
(s, 1H); 13C NMR (75 MHz, CDCl3 + DMSO-d6): d 4.3, 31.9, 84.9, 108.9, 121.4,
124.7, 131.7, 143.6, 147, 177.8; IR (KBr):
m = 3285, 2927, 2856, 1714, 1624,
1524, 1338, 1177, 1089, 840, 734 cmꢁ1; MS (EI): m/z = 223 (M+1).
3-Ethyl-3-hydroxy-5-iodoindolin-2-one (Table 2, 3m): White solid; Mp 220–
227 °C; 1H NMR (300 MHz, CDCl3 + DMSO-d6): d 0.71 (t, J = 7.62 Hz, 3H), 1.82 (t,
J = 7.62 Hz, 2H), 5.74 (s, 1H), 6.62 (d, J = 8.71 Hz, 1H), 7.45 (d, J = 7.62 Hz, 1H),
7.49 (s, 1H), 10.14 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): d 4.3,
31.9, 85., 90.0, 123.3, 132.4, 135.1, 139.2, 139.8, 177.8 ppm; IR (KBr)
m = 3258,
3184, 2920, 1701, 1626, 1489, 1157, 927, 817, 733 cmꢁ1; MS (EI): m/z = 326
(M+Na).
3-Ethyl-5-fluoro-3-hydroxyindolin-2-one (Table 2, 3n): White solid; Mp 158–
160 °C; 1H NMR (300 MHz, CDCl3 + DMSO-d6): d 0.72 (t, J = 7.55 Hz, 3H), 1.90
(q, J = 7.55 Hz, 2H), 5.86 (s, 1H), 6.81 (d, J = 8.30 Hz, 1H), 6.86–6.93 (m, 1H),
7.02 (dd, J = 7.93, 8.30 Hz, 1H), 10.06 (s, 1H) ppm; 13C NMR (75 MHz,
CDCl3 + DMSO-d6): d 6.7, 30.3, 84.4, 110.7, 111.0, 114.1, 132.5, 136.9, 159.5,
179.5 ppm; IR (KBr):
m = 3267, 2933, 1698, 1610, 1485, 1435, 1343, 1175, 1095,
993, 805, 704 cmꢁ1; MS (EI): m/z = 218 (M+Na).
4,5-Dichloro-3-ethyl-3-hydroxyindolin-2-one (Table 2, 3o): Yellow solid; Mp
228–230 °C; 1HNMR (300 MHz, CDCl3 + DMSO-d6): d 0.59 (t, J = 7.00 Hz, 3H),
1.90 (q, J = 7.00 Hz, 2H), 5.79 (s, 1H), 6.73 (d, J = 8.00 Hz, 1H), 7.29 (d,
J = 8.00 Hz, 1H), 10.10 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3 + DMSO-d6): d 4.3,
31.4, 80.3, 109.0, 125.8, 129.1, 129.1, 132.5, 139.1, 177.8 ppm; IR (KBr):
m
= 3256, 2942, 1703, 1605, 1490, 1423, 1325, 1185, 1070, 985, 924, 798 cmꢁ1
;
MS (EI): m/z = 247 (M+1).
3-Hydroxy-5-iodo-3-methylindolin-2-one (Table 2, 3t): Yellow solid; Mp 248–
250 °C; 1HNMR (300 MHz, CDCl3 + DMSO-d6): d 1.48 (s, 3H), 5.82 (s, 1H), 6.67
(d, J = 8.60 Hz, 1H), 7.48 (s, 1H), 7.58 (s, 1H), 10.03 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3 + DMSO-d6): d 23.2, 77.4, 90.4, 123.7, 129.5, 136.7, 140.7,
141.3, 177.5 ppm; IR (KBr):
m = 3258, 3184, 2920, 1701, 1626, 1489, 1157, 927,
817, 733 cmꢁ1; MS (ESI): m/z = 312 (M+Na).