A facile synthesis of isoindoline and Δ1-pyrrolines from chalcone and glycine by a cascade of process involving addition, in situ decarboxylation, and cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.05.119

In this Letter, we report a rapid one-step entry into isoindoline and Δ¹-pyrrolines from chalcone. The key step in the synthesis is the addition of glycine to chalcone. In acidic medium the reaction presumably goes through aza-Michael addition,

Full text of DOI:10.1016/j.tetlet.2014.05.119

Accepted Manuscript
A facile synthesis of isoindoline and Δ 1-pyrrolines from chalcone and glycine
by a cascade of process involving addition, in situ decarboxylation and cycli-
zation
Elangovan Elamparuthi, Subramaniayan Sarathkumar, Swaminathan Girija,
Veerappan Anbazhagan
PII:
S0040-4039(14)00952-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.119
TETL 44710
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2014
28 May 2014
29 May 2014
Please cite this article as: Elamparuthi, E., Sarathkumar, S., Girija, S., Anbazhagan, V., A facile synthesis of
1
isoindoline and Δ -pyrrolines from chalcone and glycine by a cascade of process involving addition, in situ
decarboxylation and cyclization, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.119
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Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
A facile synthesis of isoindoline and ∆1-pyrrolines from chalcone and glycine by a
cascade of process involving addition, in situ decarboxylation and cyclization
Elangovan Elamparuthi*, Subramaniayan Sarathkumar, Swaminathan Girija, Veerappan Anbazhagan*
a Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur – 613 401, Tamil Nadu, India
Tel: (+) 91-4362-264101-3689; Fax: (+) 91-4362-26120, E-mail: elamparuthi@scbt.sastra.edu; anbazhagan@scbt.sastra.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
In this paper, we report a rapid one- step entry into isoindoline and ∆1-pyrrolines from chalcone.
The key step in the synthesis is the addition of glycine to chalcone. In acidic medium the
reaction presumably goes through aza-Michael addition, whereas in basic medium the reaction
proceeds through condensation followed by cyclization.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Chalcone, isoindoline, ∆1-pyrrolines, aza-Michael
addition, intramolecular electrocyclization
Isoindolines, ∆1-pyrrolines and their derivatives are of interest
as antitumor,1 diuretic agents, selective serotonin uptake
inhibitors and herbicides.2 Hence, intensive research efforts are
being continued to develop new and efficient synthetic methods.3
Traditionally, the syntheses of isoindolines involve the use of
metal or organocatalyst.3c,4 Very recently, Zu et al,5 reported the
synthesis of polycyclic isoindolines using palladium catalyst.3f,3h,
acetic acid would involve in sequence of steps: activation of
chalcone α,β-unsaturated ketone as Michael acceptor which
Table 1 Synthesis of isoindolin-1-phenylethanone using
acetic acid.
O
O
,6
The expensive and moisture sensitive nature of the metal
catalyst would restrict the use of the metal catalyzed reactions in
large scale.
H2N
CO2H
2
AcOH, xylene
110 °C, 30 min
NH
3a-i
R2
R1
R1
R2
1a-i
In search of simple methods to synthesize isoindolines, we
turned our attention to chalcones. With α,β-unsaturated ketone as
part of the chalcones substrate, it should be possible to introduce
aza-Michael addition7 more readily by employing acid and amino
acids as the amine component. Decarboxylation would give
carbanion and allow electro cyclization and give fused bicyclic
amine product in one step. To test this desired chemistry, the
investigation was initiated using 1 equiv. of chalcone 1a and 1
equiv. of glycine 2 with 0.3 equiv. of acetic acid in xylene at 110
°C, and isoindoline product 3a was obtained in good yield (Table
1). The starting material 1 was prepared by the Claisen-Schmidt
condensation between ketones and aldehydes in the presence of
sodium hydroxide in ethanol (see ESI for details).
O
O
O
NH
NH
NH
Cl
NO2
MeO
3c, 86%
3b, 62%
3a, 89%
O
O
O
NH
NH
NH
OMe
Cl
F
Cl
Cl
3f, 78%
3d, 83%
3e, 72%
O
O
O
NH
NH
NH
The reaction with 1 equiv of glycine for 30 minutes afforded
isoindoline 3a in poorer yield (28 %). While adding 3 equiv of
glycine, the reaction afforded the expected product 3a in good
F
NO2
Cl
Cl
3g, 82%
3h, 69%
3i, 86%
°
AcOH = acetic acid, yields are calculated by after column purification.
yield. On decreasing the reaction temperature to 80 C, the yields
were considerably decreased. The use of strong acid like
trifluoroacetic acid, trichloroacetic acid instead of acetic acid
largely produces decomposed product. The desired product 3a
was not obtained in the absence of acetic acid. We reasoned that
directs aza-Michael addition with glycine to form the
intermediate a. Then, it would mediate acid catalyzed
decarboxylation to produce the carbanion intermediate b, which
may preferentially undergo nucleophilic addition to aromatic

2
ring, subsequent oxidation to produce 3a (Scheme 1). The
proposed mechanism is based on the metal arene complex
nucleophilic addition. The major difference in our methodology
is the metal-free environment.8 The required nucleophile was
generated by acid-catalyzed decarboxyation.
Scheme 1 Proposed mechanism for the formation of isoindoline
and ∆1-pyrrolines, respectively.
H
H
O
HO2C
NH
O
N
N
O
Ph
O
AcOH
Ph
3a
O
Ph
-CO2
Ph
Table 2 Effect of solvent in the preparation of isoindoline.
b
a
2
Ph
6π
cyclization
Entry
Solvent
Time
(h)
12
12
8
Temperature
Yield 3a[a ]
N
1
HO2C
Ph
N
N
Py
4a
(°C)
80
-CO2
Ph
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7
CH3CN
THF
0
c
d
e
70
0
DMF
110
110
0
DMSO
Toluene
Xylene
Benzene
5
32
58
89
52
Table 4 Synthesis of isoindoline and ∆1-pyrrolines employing
other amino acids.
4
110
110
80
0.5
1.5
O
R
R
R
O
Ph
N
[a]yields are calculated after column purification.
H2N
CO2H
H2N
CO2H
Ph
Ph
Ph
NH
Py, 110 °C
45 min
Ph
AcOH, 110 °C
30 min
1
The viability of the reaction was tested in different high
boiling solvents. The best yield was obtained with xylene. The
R
5a, b
6a, b
°
reactions carried out at 110 C in polar solvents resulted in
O
OH
decomposition of starting materials. Similarly, changes in the
solvent polarity also affected the yield (Table 2). These results
suggest that the less polar solvents are more suitable to produce
the product 3a in good yield. Using the optimized conditions, we
next examined the reaction scope. Typical results are summarized
in Table 1.
N
6a, 82%
NH
5a, 79%
OH
O
Table 3 Synthesis of ∆1-pyrrolines using pyridine.
NH
NH
N
O
5b, 74%
6b, 79%
N
H
N
H2N
CO2H
2
R2
Py, 110 °C, 45 min
R1
R2
R1
4a-i
1a-i
yields are calculated by after column purification.
N
N
N
Subsequently, the scope of the reaction was explored with
other bases like sodium hydroxide, sodium methoxide and
triethylamine, but the best result was obtained with pyridine (pKa
5.25). As an alternate to pyridine, we tested the reaction in
lutidine, a moderate base with pKa 6.6. The reaction offered the
desired products in good yield as similar to pyridine. So, further
studies have been performed with pyridine considering the cost-
effectiveness. To test the scope of the method, a series of
chalcone 1a-i and glycine 2 were subjected to the conditions
described above. The reaction of 1a-i with glycine 2 proceeded
smoothly, affording the corresponding substituted ∆1-pyrrolines
4a-i, within 45 minutes, in good yields (Table 3). As summarized
in Table 4, the proposed methodology is indeed possible with
amino acids, such as tyrosine and tryptophan.
OMe
Cl
O2N
4b, 77%
4c, 81%
4a, 89%
N
N
N
Cl
OMe
Cl
F
Cl
4d, 79%
4e, 85%
4f, 88%
N
N
N
Cl
Cl
O2N
F
4g, 86%
4h, 74%
4i, 92%
In conclusion, we have developed a rapid single- step method
to prepare isoindoline and ∆1-pyrrolines from chalcone. The
Py= pyridine, yields are calculated after column purification.
The success of the synthetic strategy encouraged us to test our
methodology in the presence of base instead of acetic acid.
acetic acid initiates
a
sequential azaMichael addition,
decarboxylation and electrocyclization reaction, leading to
efficient synthesis of isoindoline. On the other hand, pyridine
Strikingly, the investigation initiated using chalcone 1a and
°
glycine 2 in pyridine at 110 C yields ∆1-pyrroline 4a. We
initiates
a
sequential iminization, decarboxylation and
electrocyclization reaction, leading to efficient synthesis of ∆1-
pyrrolines. To the best of our knowledge in chalcone chemistry,
for the first time an amino acid was employed to generate
carbanion and electrocyclization to form new carbon-carbon
bond. Further, the simple manipulation of the reaction conditions
to obtain two different products from the same chalcone makes
our method very attractive. Further studies on the expansion of
the substrate scope and the application of this methodology with
other amino acids are currently underway in our laboratory and
will be reported in due course.
reasoned that the reaction proceeded by the formation of imine.
The reactions of amine to carbonyl group have been extensively
studied. Thus, the condensation would give an imine c9 and
decarboxylation would generate carbanion intermediate d. This
intermediate undergoes thermal electrocyclization with the
alkene and produces an intermediate e, which preferentially
yields 4a via 6π intramolecularcyclization (Scheme 1).10 So far
the available methods to synthesis ∆1-pyrrolines involve multiple
steps. Recently, ∆1-pyrrolines were synthesized by Michael
addition reaction of nitromethane to chalcone with subsequent
reductive cyclization with Zn/HCl.11 For the first time, we
showed a single step approach involving imine formation and
thermal electrocyclization12 to get the desired ∆1-pyrrolines
product in good yield.

3
Acknowledgments
Tetrahedron Letters
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217/2012)..
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A facile synthesis of isoindoline and ∆1-pyrrolines from chalcone and glycine
by a cascade of process involving addition, in situ decarboxylation and
cyclization
Elangovan Elamparuthi*, Subramaniayan Sarathkumar, Swaminathan Girija, Veerappan Anbazhagan*
O
O
N
Py, 110 °C
45 min
AcOH, 110 °C
30 min
R2
NH
R1
R1
R2
R2
1a-i
2
R1
H2N
CO2H
3a-i
62-89% yield
4a-i
74-89% yield