Cp2ZrCl2-induced Reformatsky and Barbier reactions on isatins: An efficient synthesis of 3-substituted-3-hydroxyindolin-2-ones

Article abstract of DOI:10.1002/aoc.1789

A mild and rapid one-pot process for Reformatsky and Barbier reactions using a catalytic quantity of zirconocene dichloride (Cp₂ZrCl ₂) as a promoter and zinc as a terminal reductant at room temperature in dimethyl formamide was developed. The protocol has wide substrate suitability and afforded the desired 3-substituted-3-hydroxyindolin-2-ones from istains in good yields and short reaction time.

Full text of DOI:10.1002/aoc.1789

Full Paper
Received: 30 November 2010
Revised: 21 January 2011
Accepted: 27 January 2011
Published online in Wiley Online Library: 26 April 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1789
Cp2ZrCl2-induced Reformatsky and Barbier
reactions on isatins: an efficient synthesis
of 3-substituted-3-hydroxyindolin-2-ones
Mangilal Chouhan, Ratnesh Sharma and Vipin A. Nair∗
A mild and rapid one-pot process for Reformatsky and Barbier reactions using a catalytic quantity of zirconocene dichloride
(Cp2ZrCl2) as a promoter and zinc as a terminal reductant at room temperature in dimethyl formamide was developed. The
protocol has wide substrate suitability and afforded the desired 3-substituted-3-hydroxyindolin-2-ones from istains in good
c
yields and short reaction time. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: zirconocene dichloride; zinc; α-bromoethylester; benzylbromide; isatin
Introduction
mediated reactions,[38,39] we have examined the feasibility of this
transition metal for the synthesis of 3-hydroxyindolin-2-ones.
3-Substituted-3-hydroxyindolin-2-ones have gained much atten-
tion because of their key structural resemblance to several drug
candidates and natural products, such as convolutamydines, di-
azonamide A, leptosin D, 3ꢁ-hydroxyglucoisatisin, witindolinone
C, TMC-95s, celogentin K and dioxibrassinine as well as several
other biologically active compounds (Fig. 1).[1–6] 3-Substituted-
3-hydroxyindolin-2-ones are known to possess antibacterial,
antiprotozoal and anti-inflammatory activities and have also
demonstrated agonistic activity with progesterone receptors, the
activities being influenced by the substituent at the C-3 position as
well as the absolute configuration at the stereogenic center.[7–9]
Among the reports available[10–13] on the synthesis of 3-
hydroxyindolin-2-ones from isatin derivatives, synthetic proce-
dures involving Baylis–Hillman reaction[10] or oxidation of 3-
Results and Discussion
For a detailed investigation, the Reformatsky reaction of ethyl
bromoacetate with 4-chlorobenzaldehyde was carried out. The
reaction mediated by zinc was tested in the presence of various
zirconium catalysts, viz. ZrOCl2, ZrCl4, Cp2ZrCl2 and CpZrCl3
(Table 1).WeobservedthatCp2ZrCl2 providedthemaximumyields
of the product, in a short time of 5 min, at an optimum catalytic
concentration of 10 mol%. The reaction was further attempted
with different metal reductants such as Fe, Mg, Sn, Mn and Zn
(Table 2). Poor yields and long reactions times decreased the
usefulness in the first three cases. A drastic improvement was
observed with Mn while Zn was found to be superior. Among
the various solvents tried, the polar aprotic solvent dimethyl
formamide (DMF) turned out to be the best (Table 3). The thermal
dependency of the reaction was analyzed at three different
temperatures of 0, 25 and 50 ◦C. At 0 ◦C, the reaction was sluggish
affordingonlytraceamountsofthedesiredproductalong withthe
starting material. Although the starting material was completely
consumed at 50 ◦C, the formation of only side products could be
observed. Maximum yield was obtained at 25 ◦C in 5 min. From
the above observations we inferred that reacting 0.1 equiv. of
Cp2ZrCl2, 2.0 equiv. of zinc and 1.5 equiv. of α-bromoester with
1.0 equiv. of the carbonyl compound in DMF as the solvent at
25 ◦C would be the ideal conditions for the reaction. The scope
of the optimized condition was tested on various aldehydes
and ketones (Scheme 2), which afforded β-hydroxyesters in good
yields (Table 4). Reactions with α-methyl α-bromoester afforded
•
alkylindolesbyCeCl3 7H2O/IBX[13] (Scheme 1)havedemonstrated
wider scope and applicability. Although unique, these methods
are considerably time-consuming and/or expensive, making it im-
portanttodevelopahighlyefficientmethodfortheirsynthesis;this
defines our interest. One of the most straightforward approaches
would be a carbon–carbon bond-forming reaction in which a
nucleophile adds to isatin in the presence of either a metal-
based catalyst[14–17] or an organocatalyst.[18] The Reformatsky
reaction[19] is a well-known method in which a metal, usually zinc,
is inserted between the carbon–halogen bond of an α-halo car-
bonyl compound under neutral conditions. It offers regioselective
enolate formation and upon reaction with carbonyl compounds
yield β-hydroxyesters. The nucleophilic character coupled with
low basicity makes the Reformatsky reaction a better alternative in
total synthesis where selectivity poses problems, but the classical
methodsuffersfromlimitationssuchaspre-activationofthemetal,
high reaction temperature, longer reaction time and formation of
undesired Claisen and homocoupled products.[20,21] To overcome
such issues, several approaches have been developed such as the
useofothermetals,[22–28] low-valentorganometallicspecies[29–32]
and in situ activation of metal by a sonochemical path.[33] Zirco-
nium is known to play a significant role in various synthetic
transformations.[34–37] In continuation of our work on zirconium-
∗
Correspondenceto:VipinA. Nair,DepartmentofMedicinalChemistry,National
Institute of PharmaceuticalEducation and Research, Sector 67, Mohali, Punjab
160062, India. E-mail: vn74nr@yahoo.com
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, Mohali, Punjab 160062, India
c
Appl. Organometal. Chem. 2011, 25, 470–475
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

Cp2ZrCl2-induced Reformatsky and Barbier reactions on isatins
Table 1. Effect of catalysts
Entry
Catalyst (mol%)
Time
Isolated yield (%)
1
2
3
4
5
6
7
ZrCl4 (15)
20 min
15 min
2 h
40
60
CpZrCl3(15)
ZrOCl2 (15)
Cp2ZrCl2 (15)
Cp2ZrCl2 (10)
Cp2ZrCl2 (5)
Cp2ZrCl2 (0)
35
5 min
5 min
15 min
12 h
87
85
62
Figure 1. Biologically active natural products with 3-substituted-3-
hydroxyindolin-2-ones as core unit.
Trace
Temperature, 25 ◦C; solvent, DMF.
diastereomers favoring the thermodynamically more stable anti
isomer (entries 6–8 and 13–16, Table 4).
Table 2. Effect of metals
Encouraged by the results obtained, our efforts were then
directed to obtain 3-substituted-3-hydroxyindolin-2-ones from
isatins (Scheme 3), employing this one-pot process. The reactions
were highly successful with satisfactory yields of the desired
products (entries 1–6, Table 5). The reaction tolerated both
electron-withdrawing and electron-donating groups alike. How-
ever, no diastereoselectivity could be observed in the reactions
when carried out with α-methyl α-bromoesters. The reaction con-
dition was further extended to the Barbier reaction on isatins with
benzyl halides to yield 3-benzyl-3-hydroxyindolin-2-one deriva-
tives (entries 7–15, Table 5). Based on this successful strategy, a
plausible mechanism was depicted, as illustrated in Fig. 2. It is well
known that, for all metal-mediated additions of organic halides,
the necessary condition is the ability of a metal in its active form to
insertintothecarbon–halogenbondtogenerateanorganometal-
lic species which can be trapped with various electrophiles.[27,28]
The Lewis acid Cp2ZrCl2 is expected to influence the course of
the reaction through dual activation. It can activate the organic
halide by coordination and increase the feasibility of insertion of
zinc between the carbon–halogen bond.[40] The activated organic
halide is thus easily reduced to the organozinc intermediate (A),
facilitatingthereactionswithisatinstoaffordthedesiredproducts.
Additionally, the electrophilicity of isatins may also be enhanced
by Cp2ZrCl2, which makes the carbonyl group more suscepti-
ble to a nucleophilic attack by the in situ-generated organozinc
intermediate.
Entry
Solvent
Time
Isolated yield (%)
1
2
3
4
5
Fe dust
Mg dust
Sn dust
Mn dust
Zn dust
12 h
5 h
40
48
32
70
85
8 h
30 min
5 min
Cp2ZrCl2, 10 mol%; temperature, 25 ◦C; solvent, DMF.
Table 3. Effect of solvents
Entry
Solvent
Time
Isolated yield (%)
1
2
3
4
5
6
7
THF
2.0 h
3.5 h
2.5 h
5 min
5.0 h
8.0 h
5.0 h
40
28
32
85
32
10
18
DME
DEE
DMF
Acetonitrile
Toluene
DCE
Cp2ZrCl2, 10 mol%; temperature, 25 ◦C.
Experimental
In conclusion, we report a highly efficient catalytic one-
pot process for Reformatsky and Barbier reactions, which was
conveniently extended to the synthesis of 3-substituted-3-
hydroxyindolin-2-ones from isatins.
All isatin derivatives were synthesized according to the litera-
ture procedure.[41] Zirconium compounds, α-bromoester, benzyl
bromides and metals (Fe, Mg, Sn, Mn, Zn) were purchased from
Scheme 1. Some of the reported methods for synthesis of 3-hydroxyindolin-2-ones.
c
Appl. Organometal. Chem. 2011, 25, 470–475
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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M. Chouhan, R. Sharma and V. A. Nair
Scheme 2. Cp2ZrCl2-catalyzed Reformatsky reaction.
Ethyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (6a)
Table 4. Reactions of aldehydes and ketones with α-haloesters
White solid. M.p. 97–99 ◦C. 1H NMR (400 MHz, CDCl3): δ 7.39–7.41
(d, J = 7.4 Hz, 1H, Ar–H), 7.32–7.36 (m, 1H, Ar–H), 7.07–7.11
(m, 1H, Ar–H), 6.83–6.85 (d, J = 7.8 Hz, 1H, Ar–H), 4.43 (s, 1H,
-OH), 4.09–4.15 (m, 2H, -OCH2-), 3.20 (s, 3H, N–CH3), 2.93 (s, 2H,
-CH2-), 1.17–1.20 (t, J = 7.1 Hz, 3H, C–CH3). 13C NMR (100 MHz,
CDCl3): δ 176.1 (N–C O), 170.3 (O–C O), 143.5 (Ar–C), 130.1
(Ar–C), 129.2 (Ar–C), 123.8 (Ar–C), 123.1 (Ar–C), 108.5 (Ar–C), 73.5
(C–OH), 61.1(-OCH2-), 41.2 (-CH2-), 26.2 (N–CH3), 13.9 (C–CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NO4Na: 272.0899;
found: 272.0917.
Entry
R
R1
R2 Producta Isolated yield (%) Anti/Synb
1
H
H
H
3a
3b
3c
3d
3e
3f
86
85
79
82
78
84
80
85
76
78
75
70
73
80
77
72
–
2
H
Cl
H
–
–
3
H
CN
CH3
OCH3
H
H
4
H
H
–
5
H
H
–
6
H
CH3
CH3
CH3
H
65/35
67/33
67/33
–
7
H
Cl
3g
3h
3i
8
H
CH3
H
9
CH3
10
11
12
13
14
15
16
CH3 Cl
CH3 Br
CH3 CH3
H
3j
–
Ethyl 2-(5-fluoro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate(6b)
H
3k
3l
–
White solid. M.p. 105–108 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.16–7.19 (m, 1H, Ar–H), 7.01–7.07 (m, 1H, Ar–H), 6.75–6.78
(m, 1H, Ar–H), 4.62 (s, 1H, -OH), 4.10–4.16 (m, 2H, -OCH2-), 3.19
(s, 3H, N–CH3), 2.93 (s, 2H, -CH2-), 1.18–1.22 (t, J = 7.1 Hz, 3H,
C–CH3). 13C NMR (100 MHz, CDCl3) : δ 176.0 (N–C O), 170.2
(O–C O), 160.6 (Ar–C), 158.2 (Ar–C), 139.4 (Ar–C), 130.8 (Ar–C),
116.1 (Ar–C), 116.3 (Ar–C), 112.2 (Ar–C), 112.4 (Ar–C), 109.2
(Ar–C), 73.6 (C–OH), 61.2 (-OCH2-), 41.1 (-CH2-), 26.4 (N–CH3),
13.9 (C–CH3). HRMS (ESI): m/z [M + Na]+ calcd for C13H14FNO4Na:
290.0805; found: 290.0799.
H
–
CH3
H
CH3
CH3
CH3
CH3
3m
3n
3o
3p
54/46
53/47
56/44
52/48
CH3 Cl
CH3 Br
CH3 CH3
a Spectral data compared with literature reports;[19–30] b Anti/Syn ratio
was determined by 1H NMR.
a commercial source and used as received. Solvents were dis-
tilled and dried before use. The 1H and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively on a Bruker Avance
DPX 400 (400 MHz) spectrometer in CDCl3/(CD3)2SO using tetram-
ethyl silane as an internal standard. The chemical shifts (δ) for
1H and 13C are given in ppm relative to residual signals of the
solvent. Coupling constants are given in Hz. The following abbre-
viations are used to indicate the multiplicity: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; bs, broad signal. High resolution
mass spectra were recorded on a Bruker Maxix mass spectrometer.
Melting points are uncorrected.
Ethyl 2-(5-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetate (6c)
White solid. M.p. 109–112 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.39–7.40 (d, J = 2.0 Hz, 1H, Ar–H), 7.30–7.33 (dd, J = 2.0 Hz,
8.3 Hz, 1H, Ar–H), 6.76–6.78 (d, J = 8.3 Hz, 1H, Ar–H), 4.57 (s, 1H,
-OH), 4.10–4.16 (m, 2H, -OCH2-), 3.19 (s, 3H, N–CH3), 2.93 (s, 2H,
-CH2-), 1.19–1.22 (t, J = 7.2 Hz, 3H, C–CH3). 13C NMR (100 MHz,
CDCl3): δ 175.8 (N–C O), 170.1 (O–C O), 142.1 (Ar–C), 130.8
(Ar–C), 130.0 (Ar–C), 128.5 (Ar–C), 124.6 (Ar–C), 109.5 (Ar–C), 73.4
(C–OH), 61.3 (-OCH2-), 41.0 (-CH2-), 26.4 (N–CH3), 13.9 (C–CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H14ClNO4Na: 306.0509;
found: 306.0504.
General Procedure
To a stirred solution of Cp2ZrCl2 (0.1 equiv.) and zinc (2.0
equiv.) in anhydrous DMF (5 ml) was added a solution of α-
bromoester or benzyl bromide (1.5 equiv.) and N-methyl isatin (1.0
equiv.) in anhydrous DMF (5 ml) under nitrogen atmosphere at
room temperature (25 ◦C) in a dropwise manner. After complete
consumption of isatin as monitored by TLC, the reaction mixture
was quenched with cold hydrochloric acid (20 ml, 1 M) and
extracted with ethyl acetate. The organic layer was washed
with water, then with aqueous solution of Na2CO3, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product obtained was purified by column chromatography
on neutral alumina using a mixture of ethyl acetate and hexane
(1 : 4) as the eluent to get the desired product.
Ethyl 2-(1-benzyl-3-hydroxy-2-oxoindolin-3-yl)acetate (6d)
White solid. M.p. 118–120 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.40–7.41 (d, J = 7.3 Hz, 1H, Ar–H), 7.17–7.39 (m, 6H, Ar–H),
7.01–7.05 (m, 1H, Ar–H), 6.69–6.71 (d, J = 7.8 Hz, 1H, Ar–H),
4.84–4.89 (m, 3H, N–CH2 –Ar, -OH), 4.06–4.09 (m, 2H, -OCH2-),
2.98–3.09 (m, 2H, -CH2-), 1.10–1.14 (t, J = 7.1 Hz, 3H, C–CH3). 13
C
NMR (100 MHz, CDCl3): δ 176.5 (N–C O), 170.1 (O–C O), 142.7
(Ar–C), 135.4 (Ar–C), 130.0 (Ar–C), 129.4 (Ar–C), 128.8 (Ar–C),
127.7 (Ar–C), 127.3 (Ar–C), 123.9 (Ar–C), 123.2 (Ar–C), 109.6
(Ar–C), 73.5 (C–OH), 61.1 (-OCH2-), 43.8 (N–CH2 –Ar), 41.4 (-CH2-),
13.9 (C–CH3). HRMS (ESI): m/z [M + Na]+ calcd for C19H19NO4Na:
348.1212; found: 348.1206.
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 470–475

Cp2ZrCl2-induced Reformatsky and Barbier reactions on isatins
Scheme 3. Cp2ZrCl2-catalyzed reactions of isatins with organic halides.
Table 5. Reactionsofisatinswithα-bromoestersandbenzylbromides
Ethyl 2-(1-benzyl-5-chloro-3-hydroxy-2-oxoindolin-3-yl)acetate (6f)
White solid. M.p. 110–112 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.40–7.41 (d, J = 1.4 Hz, 1H, Ar–H), 7.27–7.35 (m, 5H, Ar–H),
7.17–7.20 (d, J = 8.3 Hz, 1H, Ar–H), 6.62–6.64 (d, J = 8.3 Hz,
1H, Ar–H), 4.84–4.94 (dd, J = 15.7 Hz, 24.7 Hz, 2H, N–CH2 –Ar),
4.57 (s, 1H, -OH), 4.11–4.22 (m, 2H, -OCH2-), 2.99 (s, 2H, -CH2-),
1.20–1.23 (t, J = 7.1 Hz, 3H, C–CH3). 13C NMR (100 MHz, CDCl3):
δ 175.9 (N–C O), 170.1 (O–C O), 141.2 (Ar–C), 134.8 (Ar–C),
130.9 (Ar–C), 129.9 (Ar–C), 128.9 (Ar–C), 128.6 (Ar–C), 127.8
(Ar–C), 127.2 (Ar–C), 124.6 (Ar–C), 110.7 (Ar–C), 73.5 (C–OH),
61.4 (-OCH2-), 44.0 (N–CH2 –Ar), 41.1 (-CH2-), 13.9 (C–CH3). HRMS
(ESI): m/z [M + Na]+ calcd for C19H18ClNO4Na: 382.0822; found:
382.0842.
Entry
R
R1
R2
Product Isolated yield (%)
1
H
F
CH3
CH3
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
CO2C2H5
C6H5
6a
6b
6c
6d
6e
6f
80
73
82
75
80
73
75
72
83
80
82
82
77
76
80
2
3
Cl CH3
4
H
F
CH2C6H5
CH2C6H5
5
6
Cl CH2C6H5
7
H
H
H
H
H
H
H
6g
6h
6i
8
H
p-ClC6H4
p-CH3C6H4
C6H5
9
H
10
11
12
13
14
15
CH3
CH3
CH3
6j
p-ClC6H4
p-CH3C6H4
C6H5
6k
6l
3-Benzyl-3-hydroxyindolin-2-one (6g)
White solid. M.p. 172–175 ◦C. 1H NMR (400 MHz, DMSO-d6): δ
10.05 (bs, 1H, -NH-C O), 7.05–7.14 (m, 5H, Ar–H), 6.88–6.93 (m,
3H, Ar–H), 6.59–6.65 (m, 1H, Ar–H), 6.14 (s, 1H, -OH), 3.14–3.17
(d, J = 12.6 Hz, 1H, C–CH2 –Ar), 2.99–3.02 (d, J = 12.6 Hz, 1H,
C–CH2 –Ar). 13C NMR (100 MHz, DMSO-d6): δ 179.2 (N–C O),
142.0 (Ar–C), 135.4 (Ar–C), 131.3 (Ar–C), 130.5 (Ar–C), 129.4
(Ar–C), 127.9 (Ar–C), 126.8 (Ar–C), 125.0 (Ar–C), 121.7 (Ar–C),
109.7 (Ar–C), 77.1 (C–OH), 43.8 (C–CH2 –Ar). HRMS (ESI): m/z [M
+ Na]+ calcd for C15H13NO2Na: 262.0844; found: 262.0857.
Cl CH3
Cl CH3
Cl CH3
6m
6n
6o
p-ClC6H4
p-CH3C6H4
Ethyl 2-(1-benzyl-5-fluoro-3-hydroxy-2-oxoindolin-3-yl)acetate(6e)
White solid. M.p. 119–122 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.25–7.35 (m, 5H, Ar–H), 7.17–7.19 (m, 1H, Ar–H), 6.88–6.94 (m,
1H, Ar–H), 6.61–6.64 (m, 1H, Ar–H), 4.84–4.95 (dd, J = 15.7 Hz,
23.5 Hz, 2H, N–CH2 –Ar), 4.68 (s, 1H, -OH), 4.11–4.19 (m, 2H, -
3-(4-Chlorobenzyl)-3-hydroxyindolin-2-one (6h)
White solid. M.p. 224–226 ◦C. 1H NMR (400 MHz, DMSO-d6): δ
10.08 (bs, 1H, -NH-C O), 7.08–7.15 (m, 4H, Ar–H), 6.88–6.92
(m, 3H, Ar–H), 6.60–6.62 (d, J = 7.6 Hz, 1H, Ar–H), 6.18 (s, 1H,
-OH), 3.11–3.14 (d, J = 12.6 Hz, 1H, C–CH2 –Ar), 2.95–2.98 (d,
J = 12.6 Hz, 1H, C–CH2 –Ar). 13C NMR (100 MHz, DMSO-d6): δ
178.5 (N–C O), 141.4 (Ar–C), 134.0 (Ar–C), 131.8 (Ar–C), 131.0
(Ar–C), 130.6 (Ar–C), 128.9 (Ar–C), 127.4 (Ar–C), 124.4 (Ar–C),
121.3 (Ar–C), 109.3 (Ar–C), 76.3 (C–OH), 42.5 (C–CH2 –Ar). HRMS
(ESI): m/z [M + Na]+ calcd for C15H12ClNO2Na: 296.0454; found:
296.0452.
OCH2-), 3.01 (s, 2H, -CH2-), 1.18–1.21 (t, J = 7.1 Hz, 3H, C–CH3). 13
C
NMR (100 MHz, CDCl3): δ 176.2 (N–C O), 170.1 (O–C O), 160.6
(Ar–C), 158.2 (Ar–C), 138.5 (Ar–C), 135.0 (Ar–C), 130.9 (Ar–C),
130.8 (Ar–C), 128.8 (Ar–C), 127.8 (Ar–C), 127.2 (Ar–C), 116.3
(Ar–C), 116.1 (Ar–C), 112.4 (Ar–C), 112.1 (Ar–C), 110.3 (Ar–C),
73.7 (C–OH), 61.3 (-OCH2-), 44.0 (N–CH2 –Ar), 41.2 (-CH2-), 13.9
(C–CH3). HRMS (ESI): m/z [M + Na]+ calcd for C19H18FNO4Na:
366.1118; found: 366.1112.
Figure 2. Plausible mechanism for Cp2ZrCl2-catalysed reaction.
c
Appl. Organometal. Chem. 2011, 25, 470–475
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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M. Chouhan, R. Sharma and V. A. Nair
3-Hydroxy-3-(4-methylbenzyl)indolin-2-one (6i)
3H, N–CH3). 13C NMR (100 MHz, CDCl3): δ 177.6 (N–C O), 141.6
(Ar–C), 133.5 (Ar–C), 131.0 (Ar–C), 130.1 (Ar–C), 129.4 (Ar–C),
128.3 (Ar–C), 127.8 (Ar–C), 127.0 (Ar–C), 124.9 (Ar–C), 109.1
(Ar–C), 76.71 (C–OH), 44.9 (C–CH2 –Ar), 26.0 (N–CH3). HRMS
(ESI): m/z [M + Na]+ calcd for C16H14ClNO2Na: 310.0611; found:
310.0616.
White solid. M.p. 185–188 ◦C. 1H NMR (400 MHz, DMSO-d6): δ
10.08 (bs, 1H, -NH-C O), 7.21–7.23 (d, J = 7.2 Hz, 1H, Ar–H),
7.15–7.19 (m, 1H, Ar–H), 6.90–7.00 (m, 3H, Ar–H), 6.80–6.82
(d, J = 8.0 Hz, 2H, Ar–H), 6.65–6.67 (d, J = 7.6 Hz, 1H, Ar–H),
6.18 (s, 1H, -OH), 3.15–3.18 (d, J = 12.6 Hz, 1H, C–CH2 –Ar),
3.02–3.05 (d, J = 12.6 Hz, 1H, C–CH2 –Ar), 2.22 (s, 3H, Ar–CH3).
13C NMR (100 MHz, DMSO-d6): δ 179.2 (N–C O), 142.0 (Ar–C),
135.7 (Ar–C), 132.2 (Ar–C), 131.4 (Ar–C), 130.3 (Ar–C), 129.3
(Ar–C), 128.5 (Ar–C), 124.9 (Ar–C), 121.7 (Ar–C), 109.7 (Ar–C), 77.1
(C–OH), 43.4 (C–CH2 –Ar), 20.9 (Ar–CH3). HRMS (ESI): m/z [M +
Na]+ calcd for C16H15NO2Na: 276.1000; found: 276.1015.
5-Chloro-3-(4-chlorobenzyl)-3-hydroxy-1-methylindolin-2-one(6n)
White solid. M.p. 179–181 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.08–7.12 (d, J = 8.4 Hz, 2H, Ar–H), 6.85–6.87 (d, J = 8.4 Hz,
2H, Ar–H), 6.57–6.59 (d, J = 8.2 Hz, 1H, Ar–H), 7.21–7.26 (m, 2H,
Ar–H), 3.92 (s, 1H, -OH), 3.23–3.26 (d, J = 12.9 Hz, 1H, C–CH2 –Ar),
3.14–3.17 (d, J = 12.9 Hz, 1H, C–CH2 –Ar), 2.98 (s, 3H, N–CH3).
13C NMR (100 MHz, CDCl3): δ 177.3 (N–C O), 141.5 (Ar–C), 133.0
(Ar–C), 131.9 (Ar–C), 131.4 (Ar–C), 130.7 (Ar–C), 129.6 (Ar–C),
128.5 (Ar–C), 128.0 (Ar–C), 124.8 (Ar–C), 109.3 (Ar–C), 76.70
(C–OH), 44.1 (C–CH2 –Ar), 26.1 (N–CH3). HRMS (ESI): m/z [M +
Na]+ calcd for C16H13Cl2NO2Na: 344.0221; found: 344.0222.
3-Benzyl-3-hydroxy-1-methylindolin-2-one (6j)
White solid. M.p. 162–165 ◦C. 1H NMR (400 MHz, DMSO-d6): δ
7.20–7.21 (t, J = 1.3 Hz, 1H, Ar–H), 7.13–7.14 (d, J = 0.8 Hz,
1H, Ar–H), 7.06–7.07 (m, 3H, Ar–H), 6.98–6.99 (t, J = 0.8 Hz, 1H,
Ar–H), 6.83–6.86 (m, 2H, Ar–H), 6.74–6.76 (d, J = 7.7 Hz, 1H,
Ar–H), 6.21 (s, 1H, -OH), 3.15–3.18 (d, J = 7.6 Hz, 1H, C–CH2 –Ar),
3.00–3.03 (d, J = 7.6 Hz, 1H, C–CH2 –Ar), 2.89 (s, 3H, N–CH3).
13C NMR (100 MHz, DMSO-d6): δ 182.2 (N–C O), 148.1 (Ar–C),
140.0 (Ar–C), 135.4 (Ar–C), 135.1 (Ar–C), 134.1 (Ar–C), 132.6
(Ar–C), 131.6 (Ar–C), 129.3 (Ar–C), 127.1 (Ar–C), 113.2 (Ar–C), 81.7
(C–OH), 48.8 (C–CH2 –Ar), 30.7 (N–CH3). HRMS (ESI): m/z [M +
Na]+ calcd for C16H15NO2Na: 276.1000; found: 276.1025.
5-Chloro-3-hydroxy-1-methyl-3-(4-methylbenzyl)indolin-2-one(6o)
White solid. M.p. 181–183 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.22–7.25 (dd, J = 2.0 Hz, 8.2 Hz, 1H, Ar–H), 7.18–7.19 (d,
J = 2.0 Hz, 1H, Ar–H), 6.95–6.97 (d, J = 7.8 Hz, 2H, Ar–H),
6.84–6.86 (d, J = 7.8 Hz, 2H, Ar–H), 6.58–6.60 (d, J = 8.3 Hz, 1H,
Ar–H), 3.34 (s, 1H, -OH), 3.23–3.26 (d, J = 13.0 Hz, 1H, C–CH2 –Ar),
3.11–3.14 (d, J = 13.0 Hz, 1H, C–CH2 –Ar), 3.01 (s, 3H, N–CH3),
2.30 (s, 3H, Ar–CH3). 13C NMR (100 MHz, CDCl3): δ 177.4 (N–C O),
141.7 (Ar–C), 136.6 (Ar–C), 131.0 (Ar–C), 130.2 (Ar–C), 130.0
(Ar–C), 129.4 (Ar–C), 128.6 (Ar–C), 128.2 (Ar–C), 124.9 (Ar–C),
109.1 (Ar–C), 76.69 (C–OH), 44.4 (C–CH2 –Ar), 26.0 (N–CH3), 21.0
(Ar–CH3). HRMS (ESI): m/z [M + Na]+ calcd for C17H16ClNO2Na:
324.0767; found: 324.0762.
3-(4-Chlorobenzyl)-3-hydroxy-1-methylindolin-2-one(6k)
White solid. M.p. 182–183 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.21–7.31 (m, 1H, Ar–H), 7.18–7.19 (d, J = 0.8 Hz, 1H, Ar–H),
7.06–7.12 (m, 3H, Ar–H), 6.87–6.90 (m, 2H, Ar–H), 6.67–6.69 (d,
J = 7.8 Hz, 1H, Ar–H), 3.38 (s, 1H, -OH), 3.27–3.30 (d, J = 13.0 Hz,
1H, C–CH2 –Ar), 3.11–3.15 (d, J = 13.0 Hz, 1H, C–CH2 –Ar), 3.03 (s,
3H, N–CH3). 13C NMR (100 MHz, CDCl3): δ 177.5 (N–C O), 143.1
(Ar–C), 132.8 (Ar–C), 132.5 (Ar–C), 131.5 (Ar–C), 129.8 (Ar–C),
128.9 (Ar–C), 127.9 (Ar–C), 124.3 (Ar–C), 122.9 (Ar–C), 108.4
(Ar–C), 76.69 (C–OH), 44.1 (C–CH2 –Ar), 26.0 (N–CH3). HRMS
(ESI): m/z [M + Na]+ calcd For C16H14ClNO2Na: 310.0611; found:
310.0632.
Acknowledgment
We are thankful to the Council of Scientific and Industrial Research,
Government of India and the National Institute of Pharmaceutical
Education and Research for research funding.
3-Hydroxy-1-methyl-3-(4-methylbenzyl)indolin-2-one(6l)
References
White solid. M.p. 149–151 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.25–7.29 (m, 1H, Ar–H), 7.19–7.21 (m, 1H, Ar–H), 7.04–7.08
(m, 1H, Ar–H), 6.93–6.95 (d, J = 8.0 Hz, 2H, Ar–H), 6.83–6.86
(d, J = 8.0 Hz, 2H, Ar–H), 6.66–6.68 (d, J = 7.8 Hz, 1H, Ar–H),
3.43 (s, 1H, -OH), 3.27–3.30 (d, J = 13.0 Hz, 1H, C–CH2 –Ar),
3.11–3.14 (d, J = 13.0 Hz, 1H, C–CH2 –Ar), 3.03 (s, 3H, N–CH3),
2.26 (s, 3H, Ar–CH3). 13C NMR (100 MHz, CDCl3): δ 177.9 (N–C O),
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108.1 (Ar–C), 76.7 (C–OH), 44.3 (C–CH2 –Ar), 25.9 (N–CH3), 21.0
(Ar–CH3). HRMS (ESI): m/z [M + Na]+ calcd for C17H17NO2Na:
290.1157; found: 290.1181.
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