Development of five membered heterocyclic frameworks via [3+2] cycloaddition reaction in an aqueous micellar system

Article abstract of DOI:10.1039/c4nj00325j

A series of novel dihydropyrrolo[2,1-a]isoquinolines and dihydropyrrolo[1,2-a]quinolines have been synthesized from isoquinolines/ quinolines, various substituted phenacyl bromides and substituted dialkylacetylenedicarboxylates via [3+2] cycloaddition reaction. The reaction proceeds in aqueous micellar medium with DBU as a catalyst. The present protocol offers a simple one pot sequential reaction affording products in excellent yields. the Partner Organisations 2014.

Full text of DOI:10.1039/c4nj00325j

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LETTER
Development of five membered heterocyclic
frameworks via [3+2] cycloaddition reaction in an
aqueous micellar system†
Cite this: New J. Chem., 2014,
38, 2756
Received (in Montpellier, France)
4th March 2014,
Accepted 3rd April 2014
Mandavi Singh, Shyam Babu Singh, Shahin Fatma, Preyas Ankit and
Jagdamba Singh*
DOI: 10.1039/c4nj00325j
www.rsc.org/njc
A series of novel dihydropyrrolo[2,1-a]isoquinolines and dihydropyrrolo- efficient one-pot synthesis of novel dihydropyrroloisoquinolines
[1,2-a]quinolines have been synthesized from isoquinolines/quinolines, via reaction of isoquinolines and various phenacyl bromides
various substituted phenacyl bromides and substituted dialkylacetylene- followed by addition of substituted dialkylacetylenedicarboxylates
dicarboxylates via [3+2] cycloaddition reaction. The reaction proceeds in under various conditions.
aqueous micellar medium with DBU as a catalyst. The present protocol
The proposed multicomponent synthesis is very appealing
offers a simple one pot sequential reaction affording products in due to its numerous advantages over conventional linear syn-
excellent yields.
thesis, such as the reduced number of synthetic steps, shorter
reaction times, a high degree of atom economy, etc., which allow
the preparation of diverse structures in a rapid and cost-effective
manner.9 In the present work, we also found that 1,3-dipolar
ylide cycloaddition reaction is an efficient and very powerful tool
for the construction of dihydropyrroloisoquinolines.
Bridgehead nitrogen heterocycles, especially pyrroloisoquinolines,
are of great interest because they constitute a major class of natural
products, many of which exhibit useful biological activities.1
Pyrrolo[2,1-a]isoquinolines, an important series of this class,
have received much attention in the last few years due to their
antidepressant,2 muscarinic agonist, cardiotonic3 and anti-
cancer activities. These compounds also serve as intermediates
for the synthesis of various bioactive alkaloids.4 Additionally,
these compounds can also be used as positron emission tomo-
graphy (PET) radiotracers for imaging serotonin uptake sites.5
The various biological activities and applications of pyrrolo[2,1-a]-
isoquinoline derivatives have attracted the attention of organic
chemists and a number of synthetic methodologies have been
developed for these systems.6 However, most of these methods
are multistep processes and require a long reaction time. A
common protocol for the synthesis of pyrrolo[2,1-a] isoquinoline
is 1,3-dipolar cycloaddition of isoquinolinium ylides with alkynes.
Pyrrolo[2,1-a]isoquinolines are generally synthesized by 1,3-dipolar
addition of isoquinolium ylide to limited commercially available
alkynes. Active alkenes have also been used as alternatives to
alkynes with some disadvantages such as long reaction time, low
yield and use of metallic catalysts.7
Initially, we investigated optimization conditions with respect to
both the catalyst and the solvent. For this purpose, isoquinoline (1),
4-chlorophenacylbromide (2) and diethylacetylenedicarboxylate (3)
were chosen as model substrates for the synthesis of a representa-
tive compound (4a) (Scheme 1). We performed this reaction using
DBU (10%) as a catalyst and water as the preferred solvent because
it is the best green solvent for solution phase chemistry and
cyclization reactions occur more easily in polar solvents.10 The
main obstacle in this procedure is related to the solubility
problem which led to the formation of the product in traces even
after 10 h. The key issue is the insolubility of 4-chlorophenacyl
bromide in water. To overcome this problem, we used cetyltri-
methylammonium bromide (CTAB: cmc value 0.92 mM)11 as a
surfactant, which contributes significantly to the promotion of
the reaction,12 since it acts as an emulsifying agent when mixed
with an organic reagent to form colloidal dispersion. It can be easily
removed after completion of the reaction using the powdered
activated carbon method13 or the potassium ferrate method.14 As
a trial, we performed the reaction with 5 mol% of CTAB in water but
no significant change was observed. An encouraging change was
noticed when the reaction was carried out with 8 mol% of CTAB in
50 mL of water. This gave only 25% yield of the product (Table 1,
entry 3). Surprisingly, the reaction afforded a maximum yield of
70% (Table 1, entry 4) when performed with 10 mol% of CTAB. No
change in yield was noticed when the concentration of CTAB was
As part of our interest in the development of new molecules
and novel strategies in heterocyclic synthesis,8 we herein report an
Environmentally Benign Synthesis Lab, Department of Chemistry, University of
Allahabad, Allahabad-211002, India. E-mail: dr.jdsau@gmail.com;
Tel: +91 9415218507
† Electronic supplementary information (ESI) available: Spectral data for synthe-
sized compounds. See DOI: 10.1039/c4nj00325j
2756 | New J. Chem., 2014, 38, 2756--2759
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Scheme 1 Synthesis of diethyl 3-(4-chlorobenzoyl)-3,10b-dihydropyrrolo[2,1-a] isoquinoline-1,2-dicarboxylate in an aqueous micellar system.
Table 1 Effect of different surfactants on the yield of the reaction
Table 3 Effect of different solvents on the yield of the reaction
Entry
Surfactant
Conc. (mol%)
Time (min)
Yield (%) Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
—
—
5
8
10
10
15
10
10
180
180
180
30
50
30
Traces
Traces
25
70
70
70
30
45
1
2
3
4
5
6
Hexane
CH3CN
THF
Toluene
1,4-Dioxane
Water
30
30
30
30
30
30
25
75
50
35
55
95
CTAB
CTAB
CTAB
CTAB
CTAB
SDS
30
30
TTAB
With the hope of increasing the yield of the product, we
performed a series of reactions by changing the concentration
of the base, i.e., DBU, and found that 20% DBU afforded a
maximum yield (95%) in 30 minutes. Further increment of the
catalyst amount (DBU) did not affect the yield of the product.
We have also performed the reaction in the presence of other
bases like Et3N, DABCO, DMAP and K2CO3 and the results are
summarized in Table 2, which clearly shows that DBU is the
best catalyst for the proposed synthesis.
Lastly, to study the effect of solvents, we replaced water by
other organic solvents but the results were not as good as in the
case of water (Table 3). It was also noticed that a higher reaction
temperature (instead of room temperature) had no effect on
Table 2 Optimization of base
Entry
Base
Conc. (mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
DBU
DBU
DBU
DBU
DBU
Et3N
DABCO
DMAP
K2CO3
10
15
20
30
40
20
20
20
20
30
30
30
30
30
30
30
30
30
70
72
95
95
95
40
Traces
Traces
52
further increased. Besides CTAB, other surface active reagents like the yield.
sodium dodecylsulfate (SDS: cmc value 8.1 mM)15 and tetradecyl-
With the encouraging results we employed different derivatives
trimethylammonium bromide (TTAB: cmc value 3.8 mM)16 were of phenacyl bromide and acetylenedicarboxylate to prepare a series
also used to perform the reaction (Table 1, entries 7 and 8), but no of dihydropyrroloisoquinolines (Table 4). This protocol well tolerates
satisfactory results were obtained as compared to CTAB.
phenacyl bromides containing both electron-withdrawing and
Table 4 Synthesis of dihydropyrroloisoquinoline derivatives
Entry
R1
R2/R3/R4
Time (min)
Producta
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
H/H/Cl
Cl/H/H
30
30
40
35
40
15
30
40
20
35
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
94
90
92
88
95
95
92
96
94
H/H/OMe
OH/H/H
H/OH/OMe
H/H/NO2
H/H/Cl
H/H/OMe
H/H/NO2
OH/H/H
4j
a
Reaction conditions: isoquinoline (1 mmol), phenacyl bromides (1.1 mmol), DBU (20 mol%), dialkyl acetylenedicarboxylate (1 mmol), CTAB
b
(10 mol%); RT. Isolated yield.
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Table 5 Synthesis of dihydropyrroloquinoline derivatives
phenacyl bromides and dialkylacetylenedicarboxylates under
optimized conditions to obtain several dihydropyrroloquino-
lines (5a–j). We got almost the same results as compared to
isoquinolines. The results are summarized in Table 5.
Mechanistically, the first step of the reaction is a nucleophilic
substitution reaction between isoquinoline and 4-chlorophenacyl
bromide under micellar conditions, leading to the formation of
a quaternary ammonium salt. This salt is then converted into
nitrogen ylide in the presence of the base DBU. This inter-
mediate behaves as a carbon nucleophile in cycloaddition
reaction with diethylacetylenedicarboxylate giving the desired
product (Scheme 2). This is a good example of (3+2) coupling of
nitrogen ylide and diethylacetylenedicarboxylate. This mecha-
nism is also supported by Dekamin et al.17
We have synthesized a number of novel dihydropyrrolo[2,1-a]-
isoquinolines and dihydropyrrolo[1,2-a]quinolines via 1,3-dipolar
ylide cycloaddition reaction. The reaction is one pot sequential
addition, which operates in basic aqueous micellar medium under
mild conditions. The method described here is simple and efficient
involving green protocols to obtain five membered ring systems.
The yield of the products obtained is also excellent.
Entry
R1
R2/R3/R4
Time (min)
Producta
Yieldb (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
H/H/Cl
Cl/H/H
40
40
60
50
50
30
45
50
45
50
5a
5b
5c
5d
5e
5f
5g
5h
5i
85
85
75
80
80
88
86
82
86
80
H/H/OMe
OH/H/H
H/OH/OMe
H/H/NO2
H/H/Cl
H/H/OMe
H/H/NO2
OH/H/H
10
5j
a
Reaction conditions: quinoline (1 mmol), phenacyl bromides
(1.1 mmol), DBU (20 mol%), dialkyl acetylenedicarboxylate (1 mmol),
b
CTAB (10 mol%); RT. Isolated yield.
electron donating substituents. The electronic effect and the
nature of the substituents in phenacyl bromide show some
obvious effects in terms of the yield of the reaction. Phenacyl
bromide with electron-withdrawing groups gives better results
as compared to electron-donating groups.
Experimental
General procedure for synthesis
To a homogeneous solution of CTAB (10 mol%) in water,
To explore the scope and generality of the reaction with the isoquinolines/quinolines (1 mmol) and phenacyl bromides
optimized conditions, we also employed quinolines with different (1.1 mmol) were added and stirred at room temperature for
Scheme 2 Plausible mechanism for the synthesis of diethyl-3-(4-chlorobenzoyl)-3,10b-dihydropyrrolo[2,1-a]isoquinoline-1,2-dicarboxylate in
aqueous micellar medium.
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dicarboxylate (1 mmol) were added to the reaction mixture
and stirred at room temperature for appropriate time periods
mentioned in Tables 4 and 5. Progress of the reaction was
monitored by TLC. Upon completion of the reaction, the
product was extracted with ethyl acetate. The organic layer
was washed thoroughly with water until free from CTAB and
base and then dried under reduced pressure. The products
were isolated by column chromatography.
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