On water catalysis: An expeditious approach for the synthesis of quaternary centered 3-hydroxy-3-(nitromethyl)indolin-2-one derivatives

Article abstract of DOI:10.1039/c4gc02203c

A novel, efficient, eco-friendly on water method has been developed for the Henry reaction of isatins with nitromethane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in reaction rate was observed on water under mild and catalyst-free conditions. This reaction tolerated a wide range of substrates with good to excellent product yields and is even applicable at large scales. Moreover, this method is environmentally friendly as it reduces the waste generated by the use of toxic solvents.

Full text of DOI:10.1039/c4gc02203c

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ARTICLE TYPE
“On water” Catalysis: An expeditious approach for the synthesis of
Quaternary Centered 3-hydroxy-3-(nitromethyl)indolin-2-one
derivatives
Parvathaneni SaiPrathima*, Keesara Srinivas, Mandapati Mohan Rao*
5 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Oxindoles, with quaternary centre at C-3 position
constitute a common structural moiety for several drug candidates
and bioactive natural products.10 In particular 3-substituted-3-
hydroxyoxindoles is an emerging new scaffold for drug discovery
55 with a broad spectrum of biological activities.11 Several
pharmacologically active alkaloids such as dioxibrassinine, CPC-
1, Donaxaridine, Maremycin A and B, Horsfiline, spirobrassinin
in addition to several others contain 3-hydroxyoxindole moiety12
as shown in (Figure 1).
A novel efficient, eco-friendly method “on water” has been
developed for Henry reaction of isatins with nitro methane to
afford
3-hydroxy-3-nitromethylindolin-2-ones.
An
10 enhancement in reaction rate was observed “on water” under
mild and catalyst-free conditions. This reaction tolerated a
wide range of substrates with good to excellent yields of the
product and even applicable in large-scale. Moreover this
method is advantageous with regard to green aspects, in
15 terms of reducing the waste generated by using toxic solvents.
60
Water has a significant role as it is universal medium for all
chemical reactions of life.1 Organic reactions conceded ‘On-
water’ have become one of the most intriguing area of research in
20 green chemistry.2 Recent progress is initiated in developing
efficient catalytic processes in aqueous-phase which allows
insight into Nature’s way of chemical synthesis tend to be an
important challenge for organic chemists to be tackled.3 Indeed,
to maintain ecological factors there is a need to reduce the
25 amount of toxic and hazardous substances arising from constant
usage of solvents in synthetic pathways is of considerable
significance.4 In view of this, water as a solvent for catalysis is
desirable as it is economical, non-toxic and environmentally
attractive medium.5 The major breakthrough for water as a
30 reaction medium comes from the studies done by Breslow in
1980s.6 The subsequent exploration to describe the substantial
rate acceleration for insoluble reactants, termed as “on-water”
catalysis by Sharpless and co-workers, have attracted the
attension of organic chemists towards aqueous media.7 The
35 replacement of catalysts and hazardous solvents with relatively
benign solvents such as aqueous reaction medium, catalyst-free
and high atom economy, is one of the most essential
contributions for an ideal green synthesis.8 Recently, the
development of green protocols for the synthesis of highly
40 functionalized bio-active motifs has emerged as an attractive area
of research.9
Fig. 1 Natural products containing the 3-hydroxyindol-2-one
scaffold.
65 The nucleophilic addition reaction to isatins is the most
straightforward approach for direct entry of 3-substituted 3-
hydroxyoxindole framework (Scheme 1). Significant efforts has
been focussed on the development of efficient methods for the
construction of functionalized frameworks with this structure is
70 of considerable synthetic and biological importance.
Scheme 1 Synthesis of 3-substituted-3-hydroxyoxindoles
75 The nucleophilic addition of nitroalkanes to various electrophiles,
especially carbonyl compounds, is one of the most important
approaches to form C–C bonds.13 We explored Henry (nitroaldol)
reaction of isatins with nitroalkanes, affording β-nitroalcohols,
potential synthons for the synthesis of complex natural products.
80 The so obtained Henry adduct 3a can serve as synthetic precursor
for natural products like dioxibrassinin and spirobrassinin which
45 Inorganic & Physical Chemistry Division, Indian Institute of Chemical
Technology (IICT), Tarnaka, Hyderabad-500 607 (India)
Fax: (+)91 40 2716092, Tel: (+) 91 40 27193181
E-mail: mandapati@iict.res.in, saiprathimaiict@gmail.com
†Electronic Supplementary Information (ESI) available:
50 See DOI: 10.1039/b000000x/
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DOI: 10.1039/C4GC02P20a3gCe 2 of 5
O
HO
exhibits various biological properties including antifungal,
NO2
antitumor as well as oviposition stimulation (Figure 2).14
Solvent
rt
+
CH3NO2
O
O
N
H
N
SCH3
N
H
S
HO
HO
NO2
O
2
1a
3a
S
N
H
SMe
N
H
O
N
H
O
60 Scheme 2. Henry reaction of isatin with nitroalkane.
N
3a
H
Dioxibrassinin
Table 1. Solvent effect on the yield of Henry reaction of isatina
Spirobrassinin
5
Fig:2 Representative examples showing the synthetic importance
of Henry adduct 3a
Conversion [%]
Entry
1
Solvent
Time (h)
0.5
65
70
75
98
-
water
neat
The condensation of nitromethane with isatin has been
reported using diethylamine ethanol solution, DBU (1,8-
72
72
60
2
3
4
10
40
IPA
Diazabicyclo[5.4.0]undec-7-ene)
and
DABCO
(1,4-
10 Diazabicyclo[2.2.2]octane) as bases for the formation of adduct.15
All the existing methods for Henry reaction with cyclic ketones
such as isatins inevitably required a base, by which there will be a
great difficulty in the recovery of pure product as under strong
basic conditions there is a every possibility of rearrangement of
15 the product. The developed methods suffer from limitations such
as tedious work-up, longer reaction time, unsatisfactory yields
and narrow scope of substrates. In view of this, there is still need
to develop a generally applicable method for the synthesis of
DMF
72
60
72
72
5
6
7
20
30
THF
MEOH
DCM
10
30
8
9
DMSO
CHCl3
72
30
10
11
72
72
CH3CN
Toluene
20
-
functionalized
3-hydroxy-3-(nitromethyl)indolin-2-ones.
aAll reactions were performed using isatin (0.5 mmol), nitro
80 methane (2 equiv) and solvent (2 mL) at room temperature
20 Nevertheless, organic synthesis involving nucleophilic addition
of nitromethane to isatins under the “on water” conditions
remains elusive.
The rate of acceleration of reaction “on-water’’ is due to the
formation of hydrogen bonds on the interface.18 Also the amount
of water is found to be crucial in determining the rates of reaction
85 and yields of the product. When 0.5, 1.0, 2.0, 3.0, 4.0 and 5.0 mL
of water was taken, 3a was obtained in 60%, 96%, 98%, 99%,
92% and 90% yields within 72h, 3h, 1h, 0.5h, 6h and 6h
successively. With 4 mL of water the yield slightly decreased to
92%. Further increase in water content, there is considerable
90 reduction in yield due to dispersion of the reagents. The best
result was obtained in the presence of 3.0 mL of water with 99%
yield, within 0.5 h of reaction time (Fig. 3).
In continuation of our interest to develop green synthesis
25 protocols for C3 functionalisation of isatins with quaternary
centres,16 we reported the enantioselective synthesis of 3-
hydroxy-3-nitromethyl indolin-2-ones.17 During our work for
preparation of their respective racemic products we observed the
formation of henry adducts by Click-chemistry approach under
30 on-water conditions due to the fact that the highly reactive β-
carbonyl group of the isatin derivatives is very susceptible to
nucleophilic attack. Herein, we report a clean, an atom
economical, catalyst-free, very simple and highly efficient
strategy for henry reaction of isatins to give the addition products
35 in excellent yields at room temperature. In practical terms, the
catalytic “on water” process through the activation of alkane C–H
bond provided an environmentally benign and highly efficient
approach for the synthesis of 3-hydroxy-3-nitromethyl indolin-2-
ones.
40
To investigate the feasibility of “on water” catalytic route for
synthesis of 3-hydroxy-3-nitromethyl indolin-2-one, sequence of
experiments were carried out using 1a with 2 as a model reaction.
Subsequently, the solvent effect on the reaction was examined
45 using various organic solvents (Table 1). When the reaction was
performed in DMF, MeOH, DMSO and CHCl3 lower yields of
Henry product (3a) were obtained (entry 4, 6, 8 and 9). Whereas
in iso-propanol, THF, DCM and acetonitrile, only trace amounts
of Henry adduct (3a) was formed (entry 3, 5, 7 and 10). However,
50 when the reaction was carried out without any solvent and
toluene, product formation was not observed (entries 2 and 11).
All the solvents screened gave low yields of the desired product
albeit in long reaction times. In contrast, water showed significant
improvement over the other solvents in terms of yield and
55 reaction time (entry 1). To our delight water found to be the best
system to afford Henry adduct in excellent yields within 30 min
at room temperature under vigorous stirring.
95 Figure. 3 Effect of volume of water on the yield and reaction
time of 3-hydroxy-3-nitromethyl indolin-2-one (3a)
The reaction was examined with distilled, HPLC grade as well as
in tap water. However similar results were obtained as obtained
100 with tap water (entry 1, Table 1). No considerable difference was
observed in terms of yield. Paying attention to the need to
develop economical sustainable methods we carried out all
reactions in tap water. As the reaction proceeds in tap water also
we examined the role of pH of water for product formation. The
2
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maximum yield of the product was obtained at a pH of 7.95 and
low yield at pH of 6.0 (Fig. 4).
20
5
Figure. 4 Effect of pH on the yield of 3-hydroxy-3-nitromethyl indolin-
2-one (3a)
10 Having established the optimal reaction conditions, the scope of
the reaction was extended to isatin bearing different substituents
at 5-position and methyl, allyl, benzyl substituents at the N-1
position. The results are summarized in Table 2. All the
substrates afforded the desired products with excellent yields (74-
15 99%) at room temperature in aqueous medium.
Table 2. Catalyst-free Henry reaction of isatin on water.a
aReaction conditions: Isatin (0.5 mmol), nitromethane (2.0 mmol) and
water (3 ml) at room temperature. bTime in hours, cOverall yield of
adducts.
25
Several N-alkylated isatins with substituents (methyl, benzyl,
allyl, halo substituted benzyl) at N-1 position are synthesized by
adapting the reported procedure and subjected to
30 functionalisation at C-3 position. The reaction is fast with high
yields with unsubstituted isatin when compared to substituted
halogens at C-5 position (Table 2). In case of benzyl substituent
at the N-1 position, the reaction proceeded faster with good yields
than that of methyl and allyl group at the N-1 position (entries 3i,
35 3j and 3k). When N-allyl isatin is employed the reaction is
comparatively slow with 74% yield of the product (entry 3k). In
case of N-methyl isatin and 5-methyl isatin, the reaction was slow
with 80 and 88% yields respectively (entries 3i and 3h). All
examples of isatins with electron withdrawing groups at C-5
40 position, C-7 position and substituents at N-1 position lead to
equally satisfying results.
The developed protocol was found to be successful not only with
isatin having electron withdrawing but also with electron
45 donating substituents. All the screened structurally varied N-
substituted oxindole derivatives underwent efficient nitroaldol
addition with good yields of Henry adducts in an aqueous
reaction medium (Table 2). One of the most unique features of
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this nitroaldol reaction is that, it works “on water” under catalyst-
free or additive-free reaction conditions.
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55
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Scheme 3. Henry reaction of isatin with nitroethane.
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65
In order to demonstrate the scale-up potential of this efficient
transformation, we conducted a gram-scale synthesis of 3a
15 (Scheme 2), wherein isatin 1a (30 mmol, 4.41 g), nitromethane 2
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70
6.
7.
1
products were characterized by H NMR,13C NMR and mass
spectroscopy.
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20 rationalize this transformation is illustrated in Scheme 4. The
distinctive basicity, polarity and hydrogen bonding capacity of
water makes it efficient for stabilizing isatin as well as nitroalkyl
anion. We reasoned that, water work as a solvent as well as a
mild base which abstract acidic α-hydrogen of nitroalkane and
25 efficiently form nitroalkyl anion C. This nitroalkyl anion
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and form desired 3-hydroxy-3-(nitroalkyl)-2-oxindole product in
high yield 3a.
8.
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30
Scheme 4. Possible Reaction Mechanism
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Conclusions
35 An eco-friendly and efficient method “on-water” has been
developed for synthesis of 3-hydroxy-3-nitromethylindolin-2-one
frameworks under catalyst-free conditions. It serves as invincible
system for the production of Henry adducts from isatin, which
involves water as solvent, no base, room temperature, with
40 excellent yields of the desired products. The method has good
level of generality and applicable for various substituted isatins
under “on-water” conditions. The water after the reaction (after
the filtration) contains only trace amount of nitromethane. The
advantage of our reaction is base free reaction, as most of the
45 bases are water soluble, which decreases the effort for the
100
105
110
115
purification as water has high energy of evaporation. The new
compounds reported herein could find potential application in
synthetic chemistry.
50 Acknowledgements
Dr.SaiPrathima gratefully acknowledge to the financial assistance
provided by the ORIGIN Project (CSC-0108) and special thanks
to the Director (IICT) India, for the fellowship.
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5492.
4
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DOI: 10.1039/C4GC02203C
GRAPHICAL ABSTRACT
An efficient, eco-friendly method “on water” has been developed for Henry reaction of isatins
with nitro methane to afford 3-hydroxy-3-nitromethylindolin-2-ones. An enhancement in
reaction rate was observed “on water” under mild and catalyst-free conditions. This reaction
tolerated a wide range of substrates with good to excellent yields of the product and even
applicable in large-scale. Moreover this method is advantageous with regard to green aspects, in
terms of reducing the waste generated by using toxic solvents.
H2O