Room temperature catalyst-free Knoevenagel condensation: Facile access to isatinylidenerhodanines

Article abstract of DOI:10.1016/j.tetlet.2013.01.069

A catalyst-free Knoevenagel type synthesis of isatinylidenerhodanines is reported starting from substituted isatins and rhodanines. The reaction proceeds spontaneously at room temperature in dimethyl sulfoxide (DMSO), employing a unique macrocyclic intermediate formed through an intramolecular H-bonding. Various substituted isatinylidenerhodanines could be synthesized in good yields.

Full text of DOI:10.1016/j.tetlet.2013.01.069

Tetrahedron Letters 54 (2013) 1700–1703
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Room temperature catalyst-free Knoevenagel condensation: facile access to
isatinylidenerhodanines
⇑
Fengtian Xue , Alexander D. MacKerell, Jr., Geoffrey Heinzl, Kellie Hom
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst-free Knoevenagel type synthesis of isatinylidenerhodanines is reported starting from substi-
tuted isatins and rhodanines. The reaction proceeds spontaneously at room temperature in dimethyl
sulfoxide (DMSO), employing a unique macrocyclic intermediate formed through an intramolecular
H-bonding. Various substituted isatinylidenerhodanines could be synthesized in good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 29 December 2012
Revised 10 January 2013
Accepted 14 January 2013
Available online 23 January 2013
Keywords:
Knoevenagel condensation
Isatinylidenerhodanines
BCL6 inhibitors
Bürgi–Dunitz trajectory
Catalyst-free
Isatinylidenerhodanine represents a privileged scaffold to the
drug discovery community.1 Isatinylidenerhodanine-containing
biologically active molecules exhibit intriguing anticancer proper-
ties.2 They have been evaluated to show activity against Gram-
positive and Gram-negative bacterial infections.3 Substituted
isatinylidenerhodanines can also be used as potential therapeutics
for the treatment of neurodegenerative diseases,4 diabetes,5 and
sleep and mood disorders.6 Moreover, they have been used in
developing molecular probes to evaluate activities of biological tar-
gets.7 While various applications of isatinylidenerhodanines have
been investigated, many efforts have been devoted to access func-
tionalized isatinylidenerhodanines in satisfactory yields under
mild conditions.
of 5-chloroisatin (2a) and 3-(4-oxo-2-thioxothiazolidin-3-yl)propa-
noic acid (3a). Using base catalysts such as ammonia, piperidine,
triethylamine (Et3N), K2CO3, and KOH in various solvents, the
substrate(s) decomposed quickly to give an insoluble dark brown
slurry. Without the base catalysts, on the other hand, no product
was detected even under elevated temperatures (Scheme 1).
Although none of the classical Knoevenagel conditions gave
encouraging results, a small amount (ꢀ5%) of a new product was
isolated when a catalytic amount of piperidine was used in CH2Cl2.
This new compound was characterized to be the intermediate alco-
hol 4a (Fig. 1a). The 1H NMR spectrum of 4a in DMSO-d6 showed
four unique sets of multiplet peaks at 1.5, 2.2, 3.6, and 3.9 ppm,
which represent the two methylene groups (C18 and C19,
Fig. 1a) of 4a. These results demonstrated that the two methylene
groups are involved in a ring system. We speculated that the
macrocyclic conformation was formed via an intramolecular
H-bonding between the carboxylic acid group and the tertiary
To date, various methods have been developed for the synthesis
of substituted isatinylidenerhodanines.
A common strategy
includes the Knoevenagel condensation, which has been utilized
to prepare a range of isatinylidenerhodanines.8 However, this
method often requires the use of base catalysts (e.g., amines9 and
alkoxides10), and the reactions are usually performed at elevated
temperature.11 Alternatively, base-free Knoevenagel conditions
have been reported, involving the use of ionic liquid as the reaction
media12 or microwave heating.13
During the course of our research in developing transcriptional
repressor B-cell lymphoma 6 (BCL6) inhibitors for human B-cell
lymphomas,2a we performed a series of reactions intended to synthe-
size isatinylidenerhodanine (1a) by the Knoevenagel condensation
H
N
O
S
Cl
H
N
S
O
N
S
bases
X
O
O
N
Cl
S
O
CO2
H
HO2C
2a
3a
1a
⇑
Corresponding author. Tel.: +1 410 706 8521.
E-mail address: fxue@rx.umaryland.edu (F. Xue).
Scheme 1. The Knoevenagel conditions attempt for the formation of 1a.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.069

F. Xue et al. / Tetrahedron Letters 54 (2013) 1700–1703
1701
Figure 1. (a) 1H NMR spectrum of 4a in DMSO-d6. (b) Probability distribution of selected distance from Langevin dynamic simulations of 4a in the gas phase. The simulation
was performed at 600 K with a friction coefficient of 5 psÀ1, SHAKE of all covalent bonds involving hydrogens, with an integration timestep of 0.002 ps, no truncation of the
nonbond interactions and with coordinates saved every 20 ps for analysis. The use of the higher temperature and gas phase was designed to simply check if the carboxylate
moiety could assume a confirmation that could allow it to hydrogen bond with the O2 hydroxyl moiety.
hydroxyl group (Fig. 1a). To investigate if such a macrocyclic
conformation of the system was accessible, a Langevin dynamics
simulation of 4a was performed using the program CHARMM14
with the CHARMM General force field.15 Probability distributions
of select atom pairs from the simulation (Fig. 1b) showed that
the acid moiety of 4a could indeed form an intramolecular hydro-
gen bond with the O2 hydroxyl. Interestingly, 4a was not stable in
DMSO-d6, as it eliminated a water molecule spontaneously under
room temperature to yield 1a in quantitative yield within 6 h.
To further investigate the condensation reaction using DMSO as
the solvent, equal molar of 2a and 3a were mixed in DMSO-d6. Sur-
prisingly, the Knoevenagel condensation took place spontaneously
(Fig. 2a). The starting materials disappeared gradually (red,
Fig. 2b), generating product 1a (blue, Fig. 2b), along with a striking
color change from bright orange to dark red. The intermediate 4a
was generated quickly after mixing the starting materials and
peaked around 4 h (green, Fig. 2b). Over 85% of the starting mate-
rials were converted into 1a in 48 h. After 72 h, both starting mate-
rials (2a and 3a) and intermediate 4a disappeared with
quantitative generation of 1a.
conversion (80%, Fig. 2b). Under similar conditions the N-methyl
rhodanine 3b, a compound with the carboxylic acid group removed
from 3a, showed almost no formation of the corresponding inter-
mediate (4b) and product 1b (Table 1, entry 2). This result high-
lighted the importance of the carboxylic acid group in catalyzing
the reaction, possibly as an intrinsic Brønsted–Lowry acid. With
the carboxylic acid group of 3a replaced by an ester group,
compound 3c still showed a significant reactivity toward 2a in
the condensation (Table 1, entry 3). However, the corresponding
intermediate (4c) peaked at 16 h after mixing the starting materi-
als (Fig. S2), which is 4 times longer than that of 3a. The rate
constant of the first step was 2.5 MÀ1 hÀ1, which is more than
fivefolds slower than that of 3a, which was calculated to be
15.8 MÀ1 hÀ1. These results indicated that, without the assistance
of the Brønsted–Lowry acid, the rate of the first step of the conden-
sation is much slower. However, the dehydration of intermediate
4c showed a similar rate to that of 4a.
Next, substitution effect on the reaction was studied by testing
the conversion of 10 analogs of 2a with substituent(s) at the 5- and
7-positions of the isatin moiety (Fig. 3). When 2a was used, 80% of
the starting material was consumed in 24 h to generate the inter-
mediate alcohol 4a (13%) and product 1a (67%). Without substitu-
tion (2l, R1 = R2 = H), the reaction went on slowly with more than
90% of starting material left in the reaction mixture after 24 h.
Small halogens (e.g., F, Cl, and Br) at the 5-position of the isatin ring
The role of the carboxylic acid group of 3a in the spontaneous
condensation was studied. We compared the reaction outcome of
2a with three N-substituted rhodanines (3a–c) by following the
conversion of both starting materials in 24 h (Table 1). Using 3a
as
a
starting material, the condensation indicated a high
(a)
(b)
Figure 2. (a) Time course of the condensation of 2a and 3a in DMSO-d6. (b) Concentration of 2a/3a (red), intermediate 4a (green), and isatinylidenerhodanine product (1a,
blue) versus time.

1702
F. Xue et al. / Tetrahedron Letters 54 (2013) 1700–1703
Table 1
Condensation of 2a with N-substituted rhodanines 3a–c
H
N
H
N
H
N
O
O
OH
O
Cl
S
O
Cl
-H2O
Cl
S
O
O
N
DMSO-d6, r.t.
S
O
S
R
N
N
R
S
R
S
3a-c
4a-c
1a-c
Compound
R
[3a–c] (mM)a
[4a–c] (mM)
[1a–c] (mM)
Conv.b (%)
3a
3b
3c
CH2CH2CO2H
CH3
CH2CH2CO2Et
6.7
31.7
13.0
4.3
<0.6
7.7
22.0
<0.6
13.0
81
<4
60
a
For each reaction, equal molar (0.10 mmol) of starting materials were mixed in 3.0 mL DMSO-d6 at room temperature. The concentration of each compound was
calculated directly based on the time-course of the 1H NMR spectra.
b
The conversion was calculated based on the 1H NMR spectra in 24 h.
R2
H
N
O
R2
S
N
H
N
R1
S
O
DMSO-d6, r.t.
-H2O
O
S
O
R1
N
O
S
CO2H
HO2C
2a, 2d-l
3a
1a, 1d-l
Figure 3. Conversion of reactions containing substituted isatins initiated with equal molar isatin and 3a in DMSO-d6. Each bar represents the concentration of a compound
calculated based on a 1H NMR spectrum 24 h after mixing the starting materials. The data represent the average of three measurements with the error approximately 2%.
were favorable for reactivity, with the conversions of over 60%. On
the other hand, iodine at the 5-position impaired the reaction rate
significantly, probably due to the diminished electronegativity of
iodine. Compared to those of other halogens (3.98 of F, 3.16 of Cl,
and 2.96 of Br in Pauling scale), the Pauling scale of iodine (2.66)
is close to that of carbon (2.55 in Pauling scale). When R1 = CH3
(2g), the reaction showed low conversion similar to that of the
non-substituted isatin (2l), indicating that the introduction of a
slightly electron-donating CH3 group at the 5-position is unfavor-
able for reactivity. Additional F (5k) or Cl (5j) substituent at the
7-position is detrimental to the reactivity of isatins, which can be
explained by the Bürgi–Dunitz trajectory.16 The additional halogen
substituents are adjacent to the p⁄ orbital of the electronphilic
carbonyl group of the isatins and, as a result, block the attack of
the incoming nucleophiles. However, we also noticed that addi-
tional CH3 at the 7-position of the isatin ring did not change the
rate dramatically (2h vs 2a). This result indicated that in addition
to the steric factor, the electronic characteristics of the 7-position
substituent might also play a role.
The proposed mechanism for the observed reaction is shown in
Scheme 2. The enol form of 3a attacks the keto group of substi-
tuted isatin to give an intermediate alcohol 4a, which is stabilized
by the carbonyl oxygen atom of the terminal carboxylic acid of
rhodanine 3a. Elimination of water molecule from 4a generates
isatinylidenerhodanine.
In summary, we have presented a room temperature catalyst-
free synthesis of substituted isatinylidenerhodanines using DMSO
as the solvent. This reaction protocol provides a facile complemen-
tary to the classical Knoevenagel condensation.
S
S
OH
O
N
S
N
S
R2
HO2C
HO2C
H
N
O
Supplementary data
R1
O
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.069.
R2
R2
H
N
H
N
O
O
O
R1
-H2O
R1
H
H
O
References and notes
S
O
S
O
N
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S
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HO2C
Scheme 2. Proposed reaction mechanism.

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