Simple and efficient microwave assisted N-alkylation of isatin

Article abstract of DOI:10.3390/molecules13040831

We present herein the results of microwave promoted N-alkylations of isatin (1) with different alkyl, benzyl and functionalized alkyl halides. Reactions were carried out under different conditions, always employing methodologies compatible with MW assisted chemistry. Generation of isatin anion employing diverse bases and solvents or using the preformed isatin sodium salt was tested. The best results were achieved using K₂CO₃ or Cs ₂CO₃ and a few drops of N,N-dimethylformamide or N-methyl-2-pyrrolidinone. These reactions present noteworthy advantages over those carried out employing conventional heating.

Full text of DOI:10.3390/molecules13040831

Molecules 2008, 13, 831-840
molecules
ISSN 1420-3049
2008 by MDPI
www.mdpi.org/molecules
©
Full Paper
Simple and Efficient Microwave Assisted N-Alkylation of Isatin
María Sol Shmidt, Ana María Reverdito, Lautaro Kremenchuzky, Isabel Amalia Perillo* and
María Mercedes Blanco
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos
Aires, Junín 956 (1113) Buenos Aires, República Argentina
*
Author to whom correspondence should be addressed; e-mail: iperillo@ffyb.uba.ar
Received: 11 March 2008; in revised form: 9 April 2008 / Accepted: 9 April 2008 / Published: 10
April 2008
Abstract: We present herein the results of microwave promoted N-alkylations of isatin (1)
with different alkyl, benzyl and functionalized alkyl halides. Reactions were carried out
under different conditions, always employing methodologies compatible with MW assisted
chemistry. Generation of isatin anion employing diverse bases and solvents or using the
preformed isatin sodium salt was tested. The best results were achieved using K
2 3
CO or
Cs CO and a few drops of N,N-dimethylformamide or N-methyl-2-pyrrolidinone. These
2
3
reactions present noteworthy advantages over those carried out employing conventional
heating.
Keywords: Isatin, N-alkylation, microwave irradiation, conventional heating, isatin
sodium salt.
Introduction
N-alkylation of isatin (1, Scheme 1) reduces the lability of the isatin nucleus towards bases, while
maintaining its typical reactivity. Thus, N-substituted isatins 2 have been frequently used as
intermediates and synthetic precursors for the preparation of a wide variety of heterocyclic compounds
[
1, 2]. In addition, properly functionalized N-alkyl isatins present different biological activities [1], and
in recent years compounds showing potent cytotoxicity in vitro [3], antiviral activity [4] and potent
and selective caspase inhibition [5] have been reported, among others.

Molecules 2008, 13
832
As part of our ongoing investigations, we needed to use a series of isatinacetic acid derivatives.
This fact led us to explore synthetic methods to obtain N-alkylisatins 2 (Scheme 1). Literature
procedures include: a) direct synthesis from N-alkylanilines and b) N-alkylation of isatin. Direct
synthesis involves tedious multistep processes which usually give N-alkylisatins in low to moderate
overall yields [6]. N-Alkylation of isatin (1) is usually carried out generating the highly conjugated
-
isatin anion (1 ) [7] with different bases, followed by treatment with appropriate alkylating agents,
generally alkyl halides or sulphates (Scheme 1). These methods had been extensively reviewed [1,8]
2 2 3
and include the use of bases such as NaOH, NaH, CaH and K CO in different solvents. Synthesis of
N-functionalized isatins using a parallel synthesis employing a polymer supported strong base for the
deprotonation step has been recently reported [9].
Scheme 1. Synthetic route for N-substituted isatins 2.
O
O
O
base
RX
O
O
O
-
N
N
N
1-
2
R
H
1
Though some of the above mentioned methods provide good yields of N-alkylisatins, they generally
present drawbacks related to: a) the base lability of the isatin nucleus [10], b) use of hazardous
reagents such as metal hydrides, which require anhydrous solvents, c) use of aprotic organic solvents
with high water solubility and high boiling points, leading to complex workups, d) use of carcinogenic
solvents in some cases and e) side reactions due to the presence of keto-carbonyls (i.e. reductions
2 3
when metallic hydrides are used, aldolisation when K CO in acetone is employed). Besides, reaction
times are in general lenghty, with consequent formation of by-products, and hence low yields and
difficulties in product isolation.
Our interest in this type of reactions prompted us to test the use of microwave (MW) irradiation as
an alternative energy source. MW heating has gained popularity in the last decades as it remarkably
accelerates a wide variety of reactions and minimizes thermal decomposition of the products. Since the
initial work of Gedye [11] and Giguere [12], a rapidly increasing number of reports and reviews have
been published demonstrating the importance of such methodology [13]. However, to the best of our
knowledge, the potentialy of this method has not been exploited yet for the type of reactions of interest
in this case [14].
We present herein results of MW assisted synthesis of N-alkylisatins 2 by N-alkylation of isatin (1)
with different alkyl, benzyl and functionalized alkyl halides (Scheme 1, Table 1) and their comparison
with those obtained under conventional heating. Reactions were carried out under different conditions,
always employing methodologies compatible with MW assisted chemistry.

Molecules 2008, 13
833
Table 1. N-Substituted isatins 2.
O
O
N
R
2
Comp
.
R
Comp
R
.
2
a
Me
Et
2g
CH
2
CO
2
Et
Et)
CONHi-Pr
CON(Me)Ph
(CH CO
2
b
2h
2i
CH(CO
CH
CH
CH
2
2
2
c
n-Bu
2
2
d
CH
2
Ph
2j
2
2
e
CH
2
CH=CHP
h
2k
2
2
)
2
2
E
t
2
f
CH
2
CH
2
Br
2l
2
CH COPh
Results and Discussion
We initially examined reactions under “dry” conditions [16], irradiating the mixture of neat
-
reactants, either generating isatin anion (1 ) in situ (Method A) or employing the pre-formed sodium
+
-
isatin salt (Na 1 ) (Method B). In all cases decomposition of reactants or recovery of unreacted starting
material was observed. On the other hand, results improved notably when some drops of a polar
aprotic solvent, enough to humidify the reaction mixture, are added, giving a polar mixture that is
more prone to MW absorption [17]. This is a fundamental requirement in the case where the sodium
salt of isatin or alkylating agents with high melting point (i.e.: N-methyl-N-phenylchloroacetamide) are
used.
Using ethyl chloroacetate as alkylating agent, we optimized reaction conditions by testing several
parameters such as different bases and solvents. The best results were obtained employing K
2 3
CO or
Cs CO in N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP). Results obtained with
2
3
different alkyl halides are shown in Table 2. Employing low or medium power settings full
conversions are achieved in a few minutes and moderate to high yields of compounds 2 are obtained.
The use of NMP is specially important when poorly reactive halides are employed (see entry 19). We
also observed that, in general, the use of Cs CO as the base facilitates the workup, but yields are
2
3
lower in some cases (see entries 5 and 17).
In experiments carried out under conventional heating we encounter longer reaction times and
lower yields. As an example, using K CO /DMF, the cinnamyl derivative 2e was obtained in high
2
3
yield in two minutes, whereas under classical heating four hours were required (Entry 8). Furthermore,
to reach satisfactory yields high amounts of solvent are required, thus making product isolation most
difficult.

Molecules 2008, 13
834
MW promoted reaction of isatin and equimolecular amounts of ethylene bromide lead to a moderate
yield of N-(2-bromoethyl)isatin (2f, Entry 10), while when a three-fold ratio of isatin to ethylene
bromide is employed the bis derivative, 1,2-di(1-isatinyl)ethane, was obtained in acceptable yield
(
Entry 11).
Table 2. Reaction times and yields for isatin N-alkylation under MW irradiation and
conventional heating.
Microwave
Conventional
heating
Cpd. [a]
Reagents
Base
Solvent
min/watts Yield
h/ºC
yield
(%)
80
78
85
(
%)
1
2
3
4
5
6
7
2a
1
1
1
IMe [b]
K
K
K
2
2
2
CO
CO
CO
3
3
3
DMF
DMF
DMF
DMF
DMF [c]
DMF
-
3/300
3/300
95
90
1/70
1.30/70
2/70
2b
2c
2c
2d
2d
2d
IEt [b]
Br-nBu
Br-nBu
3/400
90
+
-
Na 1
5/500
5/200
5/400
4/700 [d]
69
96
66
62 [e]
1
ClCH
ClCH
ClCH
2
2
2
Ph
Ph
Ph
K
2
CO
3
1/120
82
+
-
-
Na 1
-
-
+
Na 1
/
2 3
Al O
8
9
2e
2e
2f
2f
2g
2h
2i
1
BrCH
BrCH
BrCH
BrCH CH
ClCH CO
BrCH(CO
ClCH
ClCH
ClCH
2
CH=CHPh
CH=CHPh
K
2
CO
-
3
DMF [c]
DMF
DMF
DMF
DMF [c]
DMF
DMF
DMF
-
2/200
3/300
2/200
3/300
3/200
3/200
4/200
4/300
86
67
50 [f]
15 [i]
76
55 [j]
86
58
4/70
2/70
62
+
-
Na 1
2
1
0
1
2
3
4
5
6
1
1
1
1
1
2
CH
Br [h]
Et
Et)
2
Br
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
-
3
3
3
3
3
40 [g]
1
1
1
1
1
1
2
2
2
2
2/85
4/70
2/90
68
25
81
2
2
2
CONHi-Pr
2
CONHi-Pr
2
CONHi-Pr
+
-
-
2i
2i
Na 1
+
Na 1
-
10/400 [d] 44 [e]
/
2 3
Al O
1
1
7
8
2j
2j
1
ClCH
ClCH
2
CON(Me)P
h
CON(Me)P
h
K
K
K
2
2
2
CO
-
3
3
3
NMP [k]
DMF
3/200
5/300
94
43
2/90
3/120
2/70
83
38
+
-
Na 1
2
1
2
2
9
0
1
2k
2k
2k
1
Cl(CH
Cl(CH
Cl(CH ) CO Et
2
)
)
3
CO
CO
2
Et
Et
CO
-
-
NMP
DMF
-
4/400
6/500
8/800 [d]
56 [l]
28
[m,e]
+
-
-
Na 1
2
3
2
+
Na 1
2
3
2
/
2 3
Al O
2
2
2
3
2l
2l
1
BrCH
BrCH
2
COPh
2
COPh
CO
-
DMF
DMF
7/160
4/320
53 [n]
62 [p]
22 [o]
+
-
Na 1
[
a] Melting points and literature data are presented in Experimental section; [b] a four-fold ratio of alkyl iodide to isatin
was used. [c] 93% when Cs CO is used as base; employing NMP as the solvent similar yields were obtained; [d] reactions
2
3
were conducted with intermittent heating alternating irradiation (1 min) and cooling (1 min) periods until the required
irradiation time was met; [e] yields do not improve employing tetrabutylammonium bromide as PTC. [f] 16% of 1,2-di(1-
isatinyl)ethane was also obtained; [g] 20% of 1,2-di(1-isatinyl)ethane was also obtained; [h] A three-fold ratio of isatin to
ethylene bromide was used; [i] 60% of 1,2-di(1-isatinyl)ethane was obtained; [j] 15% of isatin was recovered; when higher
powers or longer times are were used the yield of 2h diminished and important amounts of compound 2g were obtained;
[
k] 72% when Cs CO is used as base; [l] 35% when DMF is used as solvent; [m] traces of 2k, decomposition products and
2 3
unreacted isatin were detected by TLC; [n] 30% of epoxide 3 was obtained; [o] 45% of epoxide 3 was obtained; [p] 22% of
epoxide 3 was obtained.

Molecules 2008, 13
835
Reaction of isatin with phenacyl bromide, either under conventional heating or in the MW
promoted reaction, leads to N-substituted derivative 2l in acceptable yields, although the MW
procedure provided the best results (Entry 22). Variable amounts of epoxide 3 (Scheme 2), resulting
from addition of the halometylketone anion (A) onto the isatin β-carbonyl and further cyclization were
obtained as a side product [18].
+
-
MW promoted N-alkylation of isatin using the preformed sodium salt (Na 1 ) requires higher power
to complete the reactions, but the yields do not surpass 70% (entries 4, 6, 9, 15, 18 and 20). In the
reaction with phenacyl bromide, the method facilitates work up and improves yields by minimizing
epoxide formation (Entry 23). Absence of an excess of base which would make carbanion A formation
difficult, accounts for such results (Scheme 2).
As an alternative, techniques combining MW irradiation with the use of isatin sodium salt
supported on mineral surfaces under solvent free conditions were used (Method C), an eco-friendly
methodology which had received attention in recent years [16]. Under such conditions, high powers
were required. In order to avoid reactant and product decomposition, reactions were conducted with
intermittent heating. This method was designed to avoid overheating of reactants, according to Varma
et al., when a household microwave oven is employed. [19] However, yields did not exceed 62 %, and
could not be improved using phase transfer catalysis (Entries 7, 16 and 21).
Scheme 2. Probable mechanism for the synthesis of epoxide 3.
O
H
O
Cl
-
-
O
ClCH-CO-C H
O
6
5
- Cl-
(
A)
O
O
O
N
O
N
N
H
H
1
3
H
Conclusions
We have developed a simple and efficient MW assisted synthesis of N-alkylisatins 2 by N-
alkylation of isatin (1) using a household oven. The procedure involves the use of K CO or Cs CO
2
3
2
3
and a few drops of DMF or NMP, and is a general one for reactions with alkyl, benzyl and
functionalized alkyl halides of different reactivity. The use of MW irradiation offers many advantages
over conventional heating: it remarkably decreases reaction times, requires less solvent, thus
facilitating reaction workups, and increases yields.
Experimental
General
1
13
Melting points were taken on a Büchi capillary apparatus and are uncorrected. The H- and C-
NMR spectra were recorded on a Bruker MSL 300 MHz spectrometer. DMSO-d was used as the
6

Molecules 2008, 13
836
solvent, and the standard concentration of the samples was 20 mg/mL. Chemical shifts are reported in
ppm (δ) relative to TMS as an internal standard. Splitting multiplicities are reported as singlet (s),
broad signal (bs), doublet (d), double doublet (dd), triplet (t), double triplet (dt), quartet (q), and
multiplet (m). MS (electron impact) were performed on a MS Shimadzu QP-1000 instrument at 70 eV.
High resolution spectra were obtained with a model VG AutoSpec three sector (EBE) mass
spectrometer (Waters, Milford, MA, USA) at a scan rate of 1 scan/4 sec, operating with variable
magnetic field at 8000 resolving power (10% valley definition) using perfluorokerosene (PFK) as
reference compound. TLC analyses were carried out on Silica gel 60 F254 using chloroform:methanol
(
9:1) as solvent. Preparative thin layer separations (PLC) were carried out by centrifugally accelerated
radial chromatography using a Chromatotron model 7924T. The rotors were coated with Silica Gel 60
PF254 and the layer thickness was 2 mm. Chloroform and increasing percentages of methanol were
used as eluent. Reagents, solvents and starting materials were purchased from standard sources and
purified according to literature procedures. Reactions with reagents solid or high boiling point under
MW irradiation were conducted in a domestic MW oven (BGH 16260) employing open vessels.
Adaptation for reflux heating [20] was used when volatile alkylating agents were employed.
General procedure for synthesis of compounds 2 employing conventional heating
A mixture of isatin (1, 147 mg, 1 mmol), potassium carbonate (1.82 mg, 1.3 mmol), the
corresponding alkyl halide (1.1 mmol) and DMF (5 mL) was heated in an oil bath at appropriate
temperature and monitored by TLC. When the reaction was completed, the reaction mixture was
poured into ice-water. If the product crystallized, the resulting solid was filtered, washed with water
and purified by recrystallization or by chromatographic methods. If not, the suspension was extracted
with chloroform and the organic layer was washed with water, and then dried and concentrated in
vacuo affording compounds 2. Details of the reactions (temperature, times and yields) are listed in
Table 2. Using either higher temperatures or smaller amounts of solvent, the yields diminish.
General procedures for synthesis of compounds 2 employing MW irradiation
-
Method A: Generating the isatin anion (1 ) in situ
Reaction conditions were selected using ethyl chloroacetate as alkylating agent. Na CO , K CO
3,
2
3
2
2 2
Cs CO3, CaH , TEA, LiOH, NMM, NaOEt were tested as bases. The following polar aprotic solvents
were evaluated: DMF, DMA, HMPT, MeCN, DMSO and NMP. The best results were obtained using
K CO or Cs CO and a few drops of DMF or NMP. The following general procedure was employed:
2
3
2
3
an intimate mixture of isatin (1, 147 mg, 1 mmol), the appropriate alkyl halide (1.1 mmol), base (1.3
mmol) and some drops of the corresponding solvent (giving a slurry at room temperature) was exposed
to MW irradiation. The reaction mixture was cooled to room temperature and mixed thoroughly with
ice-water. Compounds 2 were isolated following the procedure indicated above. Solvents, powers,
times and yields are listed in Table 2 (entries 1-3, 5, 8, 10-14, 17, 19 and 22).

Molecules 2008, 13
837
Method B: Employing preformed isatin sodium salt
A solution of sodium (0.8 g) in absolute ethanol (16 mL) was added to isatin (6 g) suspended in
absolute ethanol (24 mL), the mixture being well shaken to avoid caking. The violet-black isatin
+
-
sodium salt (Na 1 ) was collected, well washed with alcohol and finally with benzene until the
+
-
washings were colourless and then dried. An intimate mixture of isatin sodium salt (Na 1 ) (169 mg, 1
mmol), the appropriate alkyl halide (1.1 mmol) and some drops of the corresponding solvent was
exposed to MW irradiation and the reaction products isolated as was indicated in the method A.
Solvents, powers, times and yields are given in Table 2 (entries 4, 6, 9, 15, 18, 20 and 23).
Method C: Employing supported reagents
+
-
To a solution of isatin sodium salt (Na 1 , 169 mg, 1 mmol) in the minimum amount of water,
neutral alumina (400 mg) was added. The mixture was evaporated with a rotary evaporator and the
solid was dried 1 h at 110ºC. The corresponding alkyl halide (1.1 mmol) was adsorbed onto isatin on
alumina and the mixture was irradiated by microwave in a Pyrex beaker (15 mL). After cooling at
room temperature, the mixture was extracted with dichloromethane. The product was purified after
evaporation of the solvent. Powers, times and yields are listed in Table 2 (Entries 7, 16 and 21).
Physical properties of compounds 2
Compounds 2a-j and 2l are described in literature. Melting points for these and other compounds
are as follows: 1a, 131ºC, lit. [21] 129-130ºC; 2b, 86ºC, lit. [21] 86-87ºC; 2c, isolated as an oil, lit.
[
22] 36ºC; 2d, 131ºC, lit. [23] 132ºC; 2e, 137ºC, lit. [24] 137-139ºC; 2f, 131ºC, lit. [22] 131ºC; 2g,
17ºC, lit. [25]116-118ºC; 2h, 96ºC, lit. [21] 95-96ºC; 2i, 193ºC, lit. [26] 193-195ºC; 2j, 188ºC, lit.
26] 188-189ºC; 2l, 140-142, lit. [27] 144-145ºC. Spectral properties of compounds 2a, 2b, 2d, 2f-j
1
[
and 2l were similar to those reported in literature indicated above. Data that was not found in the
literature was as follows:
1
N-(n-Butyl)isatin (2c): H-NMR δ: 7.60 (d, H-4, 7.4 Hz), 7.55 (t, H-6, 7.4 Hz), 7.10 (t, H-5, 7.4 Hz),
6
.89 (d, H-7, 7.4 Hz), 3.71 (t, NCH , 7.3 Hz), 1.67 and 1.40 (m, CH -CH ) and 0.95 (t, CH , 7.1 Hz);
2 2 2 3
1
3
C-NMR δ: 188.0 (C-3), 158.9 (C-2), 148.9 (C-7a), 138.0 (C-6), 126.3 and 123.6 (C-4,5), 121.0 (C-
a), 116.3 (C-7), 48.1 (NCH ), 29.2 (N-CH -CH ), 19.4 (CH -CH ) and 13.6 (CH ); EIMS m/z: 203
3
2
2
2
2
3
3
+.
(
M , 41%), 132 (100%).
1
N-Cinnamylisatin (2e): H-NMR δ: 7.63 (d, H-4, 7.7 Hz), 7.56 (t, H-6, 7.7 Hz), 7.37-7.24 (m, HC6H5),
7
1
.12 (t, H-5, 7.7 Hz), 6.96 (d, H-7, 7.7 Hz), 7.68 (d, CH=CH-C
6
H
5
, 15.9 Hz), 6.18 (td, CH
, 6.2 Hz); C-NMR δ: 190.0 (C-3), 158.3 (C-2), 150.7 (C-7a), 138.3
), 134.0 (CH -CH=CH), 128.7 (Cm-C ), 128.2 (Cp-C ), 126.5 (Co-
), 125.4 and 123.8 (C-4,5), 121.4 (CH=CH-C ), 118.6 (C-3a), 110.8 (C-7) and 42.2 (NCH );
2
-CH=CH,
1
3
5.9 and 6.2 Hz), 4.5 (d, NCH
2
(
C-6), 135.7 (Cipso-C
6
H
5
2
6
H
5
6 5
H
C
6
H
5
6
H
5
2
+.
EIMS m/z: 263 (M , 26%), 146 (100%).

Molecules 2008, 13
838
1
N-(3-Ethoxycarbonylpropyl)isatin (2k): isolated as an oil; H-NMR δ: 7.67 (d, H-4, 7.3 Hz), 7.57 (t,
H-6, 7.3 Hz), 7.14 (t, H-5, 7.3 Hz), 6.98 (d, H-7, 7.3 Hz), 4.10 (q, OCH , 7.1 Hz), 3.77 (t, NCH , 7.3
Hz), 2.40 (t, COCH , 7.3 Hz), 2.00 (m, CH2, 7.3 Hz) and 1.25 (t, CH , 7.1 Hz); C-NMR δ: 186.5 (C-
), 156.9 (C-2), 149.1 (C-7a), 136.4 (C-6), 125.9 and 124.3 (C-4,5), 122.2 (C-3a), 118.6 (C-7), 59.6
2
2
1
3
2
3
3
+.
(OCH ), 46.1 (NCH ), 31.5 (CH -CO), 22.6 (N-CH -CH ), and 13.9 (CH ); EIMS m/z: 261 (M ,
2 2 2 2 2 3
5
4
2%), 132 (100%); HMRS: Calcd. for C14H15NO : 261.100108; Experimental: 261.100452.
Acknowledgements
This work was financially supported by the Universidad de Buenos Aires.
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1
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[
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2
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.
For some examples: (a) Baiocchi, L.; Giannangeli, M.; Rossi, V.; Ambrogi, V.; Grandolini, G.;
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3
[
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1
1
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1
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2
2
2
2
3. Majumdar, K.C.; Kundu, A. K.; Chatterjee, P. 1-Alkylisatins via Aldol-Retro-aldol
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Sample Availability: Samples of the compounds are available from the authors.
2008 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.
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