Indium-promoted allylation reaction of imino-isatins in aqueous media: Synthesis of quaternary 3-aminooxindoles

Article abstract of DOI:10.1002/ejoc.201000141

Quaternary 3-amino-2-oxindoles have been obtained via allylation and propargylation reactions of imino-isatins in aqueous media promoted by In and Zn respectively, under Barbier conditions, in good to excellent yields. A quaternary new stereocenter has been formed without hydrolysis of the starting imino-isatin

Full text of DOI:10.1002/ejoc.201000141

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000141
Indium-Promoted Allylation Reaction of Imino-Isatins in Aqueous Media:
Synthesis of Quaternary 3-Aminooxindoles
Benito Alcaide,*[a] Pedro Almendros,*[b] and Cristina Aragoncillo[a]
Keywords: Synthetic methods / Indium / Allylation / Nitrogen heterocycles
Quaternary 3-amino-2-oxindoles have been obtained via
allylation and propargylation reactions of imino-isatins in
aqueous media promoted by In and Zn respectively, under
Barbier conditions, in good to excellent yields. A quaternary
new stereocenter has been formed without hydrolysis of the
starting imino-isatin.
amines,[6] from 3-ylideneoxindoles,[7] [2+2] cycloadditions
of isatin-derived azomethine ylides,[8] radical addition,[9]
amination of 2-oxindoles,[10] Grignard addition to
imines,[11] and oxidative intramolecular aza-spiroannu-
lation.[12]
Introduction
The presence of the 3,3-disubstituted oxindole skeleton
in various natural products and biologically active com-
pounds has stimulated considerable attention to the devel-
opment of novel strategies for their preparation.[1] In par-
ticular, the 3-substituted 3-amino-2-oxindole framework is
present in the potent gastrin/CCK-B receptor antagonist
AG-041R (1),[2] the vasopressin VIb receptor antagonist
SSR-149415 (2),[3] and the family of natural products chart-
ellines (e.g., chartelline C, 3)[4] (Figure 1), among others.
On the other hand, the appealing properties of organo-
metallic reactions in aqueous media include their synthetic
advantages (many reactive functional groups, such as hy-
droxy, amine, and carboxylic functions, do not require the
protection-deprotection protocol in such reactions, and
many water soluble compounds do not need to be con-
verted into their derivatives and can be reacted directly), its
potential as an environmentally benign chemical process
(the use of anhydrous flamable solvents can be avoided and
the burden of solvent disposal may be reduced), as well as
unique reactivity and selectivity that are not often attained
under dry conditions, making then profitable in many
cases.[13] Indium has emerged as the metal of choice to me-
diate a high number of transformations in aqueous media,
because of its enviromentally benign properties allied with
a high degree of chemo-, regio- and diastereoselectivity.[14]
In this context, addition to C=N[15] bonds offers an excel-
lent opportunity for the development of new carbon–car-
bon bond preparation of nitrogen-containing com-
pounds.[16]
Figure 1. Bioactive quaternary aminooxindoles.
Previously, we have reported the metal-mediated carb-
onyl-addition/cyclization reaction sequences in isatins.[17] In
connection with our current research interest in the prepa-
ration of biologically relevant nitrogenated compounds,[18]
Preparation of quaternary 3-aminooxindoles has been
achieved following several strategies including alkylation of
3-aminooxindoles,[5] substitution of 3-chlorooxindoles by
[a] Grupo de Lactamas y Heterociclos Bioactivos, Departamento we wish to describe herein the allylation of imines derived
de Química Orgánica I, Unidad Asociada al CSIC, Facultad de
from isatins in aqueous media promoted by indium.
Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
Fax: +34-91-39444103
Results and Discussion
E-mail: alcaideb@quim.ucm.es
[b] Instituto de Química Orgánica General, Consejo Superior de
The starting materials, imino compounds derived from
Investigaciones Científicas, CSIC,
isatins 4a–e, were efficiently prepared by condensation reac-
tion with tosylhydrazine, 1,1-diphenylhydrazine, benzoyl-
hydrazine and p-anisidine, respectively, following pro-
cedures described in the literature (Figure 2).[19]
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-91-5644853
E-mail: Palmendros@iqog.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000141.
Eur. J. Org. Chem. 2010, 2845–2848
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2845

B. Alcaide, P. Almendros, C. Aragoncillo
SHORT COMMUNICATION
Figure 2. Starting imines 4a–f derived from isatins (PMP =
4-MeO-C6H4).
Scheme 2. Allylation reaction of tosylhydrazone 4b and 4c in aque-
Initially we explored the allylation reaction of tosyl-
hydrazone derived isatin 4a in aqueous media promoted by
indium. Treatment of a THF/NH4Cl (aq. saturated) solu-
tion of compound 4a with allyl bromide in the presence of
indium, using the same optimum conditions that we de-
scribed previously for allylation reactions of isatins and β-
lactams,[17,20] afforded compound 5 derived from hydrolysis
of the starting tosylhydrazone 4a followed by carbonyl-
allylation (Scheme 1). Several attempts to obtain the al-
lylation reaction of the C=N bond in aqueous media, in-
cluding addition of additives (HfCl4 or InCl3), without hy-
drolysis of the tosylhydrazone group were unsuccessful.
Fortunatelly, imino-allylation of tosylhydrazone 4a was
achieved when the reaction was performed in MeOH as sol-
vent, affording 3-amino-2-oxindole 6a in 55% yield
(Scheme 1).
ous media.
Lewis acid which activates both the imine group as well as
the softness of the allylmetal reagents. A transmetallation of
the initially formed organometallic reagent with indium(III)
chloride as Lewis acid may be involved. Due to the impor-
tance of the presence of a catalytic amount of additive in
the reaction, allylation of imine 4d was investigated using
different additives (silver trifate, zinc iodide, silver acetate
and bismuth trichloride). In the event, the expected al-
lylated product 6d was obtained in good to excellent yields
in all cases (Table 1, entries 5–9, 11, and 14). Analogous
results were obtained for the indium-mediated allylation re-
actions on using imino-isatins 4d–f in the presence of prenyl
bromide or 3,3-dimethylallyl bromide (Table 1, entries 10–
14).
Table 1. Allylation reaction of imino-isatins 4d–f under aqueous
conditions.
Scheme 1. Allylation reaction of tosylhydrazone 4a in anhydrous
and aqueous media.
We then turned our attention to hydrazones 4b and 4c.
Thus, treatment of compounds 4b and 4c under the condi-
tions described above afforded products 6b and 6c, respec-
tively, in good yields (Scheme 2).
Entry Imine R2 R3
R4 R5 Additive
(2 mol-%) [h]
t
Product Yield
[%][a]
These preliminary results encouraged us to screen the in-
dium-promoted allylation of imines 4d–f derived from p-
anisidine. Under the optimized conditions, allylation prod-
uct 6d was obtained in 54% yield (see Table 1, entry 1).
Since the incorporation of water stable additives could im-
prove both yield and conversion rate, we explored further
the indium-promoted allylation of imine 4d in the presence
of different additives. The addition of catalytic quantity of
hafnium(IV) chloride afforded compound 6d in very low
yield (Table 1, entry 2). Fortunately, the addition of in-
dium(III) chloride (cat.) accelerated the process, affording
the 3-amino-3-allyl-2-oxindoles 6d and 6e in fair yields
(85% and 54%, respectivelly) after 1 h (Table 1, entries 3
and 4). Although the role of the InCl3 as additive is not
1
2
3
4
5
6
7
8
4d
4d
4d
4e
4d
4d
4d
4d
4f
4d
4f
4d
4e
4f
H
H
H
Br
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
Bn
H
Bn
H
H
Bn
H
H
H
H
H
H
H
H
H
H
–
24
3
1
1
1
1
1
3
1
3
1
2
1
1
6d
6d
6d
6e
6d
6d
6d
6d
6f
54
17
85
54
90
82
78
75
87
40
72
87
61
77
H
H
H
H
HfCl4
InCl3
InCl3
TfOAg
ZnI2
H
H
H
H
AcOAg
BiCl3
AcOAg
9
10
11
12
13
14
H
Me InCl3
6g
6h
6i
H
Me AcOAg
Me
Me
Me
H
H
H
InCl3
InCl3
AcOAg
6j
6k
[a] Yield of pure, isolated product with correct analytical and spec-
completely understood, it may be explained in terms of troscopic data. [b] PMP = 4-MeO-C6H4.
2846 Eur. J. Org. Chem. 2010, 2845–2848
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Indium-Promoted Allylation of Imino-Isatins
Having established the optimal reaction conditions to Table 2. Propargylation reaction of imino-isatins 4d and 4f under
aqueous conditions.
carry out the allylation reaction, our next aim was to evalu-
ate the feasibility of other related metal-mediated Barbier-
type reactions in imino-isatins, studying the regiochemistry
of the connection (e.g., allenylation vs. propargylation).
However, it is not easy to control selectivity between
Barbier-type propargylation and allenylation with propar-
gyl halides. The reaction of propargyl bromide with metals
has been proposed to generate an equilibrium between the
Entry Imine R1
M
Additive
(2 mol-%)
t
[h]
Ratio Product
7/8
Yield
[%][a]
allenyl and propargyl organometallics. Both organometallic
species can react with the C=N bond affording a mixture
of two regioisomers, namely, homopropargyl and allenyla-
mines. The regioselectivity of the carbon–carbon bond for-
mation was initially investigated through the metal-pro-
moted reaction between tosylhydrazone 4a and propargyl
bromide in anhydrous methanol, however, in the event only
starting material was recovered. Unfortunately, the same
behavior was observed when hydrazones 4b and 4c were
treated under both aqueous and anhydrous conditions.
Thus, we turned our attention to the indium-promoted re-
action between imino-isatin 4d and propargyl bromide in
THF/NH4Cl (aq. saturated) in the presence of HfCl4 at
room temperature. In the event, the 3-substituted 3-amino-
oxindole moiety was obtained after 2 days of reaction; how-
ever, the observed regioselectivity was poor (75:25) in favor
of the propargylic product. The use of other additives
(TfOAg, SnCl2·H2O/LiI or AcOAg) increased the amount
of the ratio 7/8 in favor of the propargylated product
(Table 2, entries 2, 4 and 5). Only, when the indium-pro-
moted propargylation of imino-isatin 4d was tested using
a small amount of ZnI2 the corresponding propargylated
product 7a was obtained as a single regioisomer (Table 2,
entry 3). Interestingly, the zinc-induced reaction, using a
catalytic amount of additive (HfCl4) afforded after 18 h 3-
amino-3-propargyl-2-oxindole (7a) as single isomer in good
yield (86%). The use of other additives has been tested for
the propargylation reaction. Among all additives studied,
the use of a catalytic amount of ZnI2, AcOAg or BiCl3 did
not improve the reaction time and/or the yield (see Table 2,
entries 8–10). However, when a small amount of TfOAg
was added to the reaction mixture, the propargylated prod-
uct 7a was obtained in just one hour in excellent yield
(90%) (Table 2, entry 7).
Unfortunately, attempted experiments to find an efficient
allenylation method by the use of 3-substituted 2-propynyl
bromides (1-bromo-2-butyne and 3-bromo-1-phenyl-
propyne) did not provide the corresponding 3-allenyl-3-
aminooxyindoles of type 8. The metal promoters used were
indium or zinc in presence of a small amount of additive
(HfCl4, InCl3, BiCl3, ZnI2, TfOAg, SnCl2·H2O/LiI or
AcOAg), obtaining in all cases a complex mixture of reac-
tion. Interestingly, treatment of imino-isatin 4d with 1-
bromo-2-butyne, indium powder (1.56 mmol), InCl3
(0.03 mmol) and CuI (1.04 mmol) in methanol/water (1:1),[21]
cleanly afforded the propargylated compound 9 in 45% yield
(Scheme 3). However, when the same reactions conditions
were applied to the reaction of imino-isatin 4d with 3-bromo-
1-phenylpropyne, only a complex crude was obtained.
1
2
3
4
5
4d
4d
4d
4d
4d
H
H
H
H
H
In HfCl4
In TfOAg
In ZnI2
In AcOAg
In SnCl2·2H2O 18 90:10
48 75:25
18 90:10
18 100:0
18 90:10
7a
7a
7a
7a
7a
75
87
40
72
77
LiI
6
7
8
9
10
11
4d
4d
4d
4d
4d
4f
H
H
H
H
H
Zn HfCl4
Zn TfOAg
Zn ZnI2
Zn AcOAg
Zn BiCl3
18 100:0
100:0
7a
7a
7a
7a
7a
7b
86
90
85
83
78
85
1
18 100:0
18 100:0
18 100:0
100:0
Bn Zn AcOAg
[a] Yield of pure, isolated product with correct analytical and spec-
troscopic data. [b] PMP = 4-MeO-C6H4; M = metal promoter.
Scheme 3. Propargylation reaction of imino-isatin 4d in aqueous
media.
Conclusions
In conclusion, we have achieved an efficient protocol for
the preparation of quaternary 3-amino-2-oxindoles from
imino-isatins. The Barbier-type allylation and propargyl-
ation reactions proceeds in aqueous environment under
mild conditions promoted by indium and zinc respectively.
In addition, it has been shown the importance of the use of
additives in the reaction time, yield and the selectivity of
the addition reactions.
Experimental Section
General Procedure for the Allylation Reaction of Isatins 4 Promoted
by Indium in Aqueous Medium. Preparation of Compounds 6: Allyl
bromide (2 mmol) was added to a well-stirred suspension of the
corresponding isatin (1.0 mmol) and indium powder (229 mg,
2 mmol) in THF/NH4Cl (aq. saturated) (1:1, 5 mL) at room tem-
perature. After disappearance of the starting material (TLC), the
mixture was extracted with ethyl acetate (3ϫ5 mL). The organic
extract was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Chromatography of the residue using ethyl
acetate/hexanes mixtures gave analytically pure compounds 6.
Eur. J. Org. Chem. 2010, 2845–2848
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2847

B. Alcaide, P. Almendros, C. Aragoncillo
SHORT COMMUNICATION
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Acknowledgments
We would like to thank the Dirección General de Investigación –
Ministerio de Ciencia e Innovación (DGI-MICINN) (Projects
CTQ2006-10292 and CTQ2009-09318), Universidad Complutense-
Banco Santander Central Hispano (UCM-BSCH) (Grant GR58/
08) and Comunidad Autónoma de Madrid (CAM) (Project S2009/
PPQ-1752) for financial support. C. A. thanks Consejo Superior
de Investigaciones Científicas (CSIC) for an I3P contract and Min-
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Received: February 2, 2010
Published Online: April 9, 2010
2848
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Eur. J. Org. Chem. 2010, 2845–2848