Synthesis of an assembly of structurally important
Acridine and its derivatives are important structural motifs possessing antimalarial, antiviral, and antiallergic properties [
Synthesis of acridines under sonic condition.
Synthesis of
Sonic reactions are viewed as green and contemporary methods in synthetic organic chemistry. Sonochemical reactions are classified into three types based on their chemical effects induced by cavitation; they are homogeneous sonochemistry of liquids, heterogeneous sonochemistry of liquid-liquid or solid-liquid, and sonocatalysis (which overlaps the first two) and other mechanical effects. Study of chemical reactions under the mechanical effects sonic conditions is also called “false sonochemistry” which is also an important component of regular sonochemistry. In addition, the use of an inexpensive and versatile catalyst, CAN, in conjunction with ultrasound is considered to be economical and beneficiary in organic synthesis [
All starting materials were commercial products and were used without further purification except liquid aldehydes and amines which were distilled before use. Melting points were measured on a Raaga make melting point apparatus. Nuclear magnetic resonance spectra were obtained on 400 MHz and 100 MHz Bruker AMX instruments in CDCl3 using TMS as a standard. ESI-Mass spectra were recorded using ESI-Q TOF instrument. All the reactions were carried out using SIDILU make sonic bath working at 35 kHz (constant frequency: 120 W) maintained at 26°C by circulating water without mechanical stirring. Yields refer to yield of the isolated products.
Dimedone/cyclohexa-1,3-dione (2 mmol), aromatic aldehyde (1 mmol), and substituted aniline (1 mmol) were taken in acetonitrile (0.5 mL) and mixed well, and to this CAN (5 mol%) was added. The reaction was subjected to ultrasonic irradiation in a bath working at 26°C (35 kHz). The course of the reaction was monitored on TLC (3 : 7: EtOAc : hexane). After completion of the reaction, water (10 mL) was added and the separated solid was filtered. The crude product was then subjected to silica gel column chromatography (3 : 7: EtOAc : hexane) to get the pure products. The same procedure was followed for the reactions carried out with ammonium acetate or 2-aminopyridine.
13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
To begin with, we planned to work with highly electron deficient 2-chloro-4-fluoroaniline (1 mmol), dimedone (2 mmol), and an electron deficient 4-fluorobenzaldehyde (1 mmol) in 3–5 mL acetonitrile as a solvent. We studied the reaction using various Lewis acid catalysts such as ZnCl2, ZnBr2, SnCl4, AlCl3, CuCl, and CAN under sonic condition (26°C, 35 kHz) and found that CAN (5 mole%) catalysed the reaction effectively and gave very high yield (90%, 1 h) of the product under sonic condition, and with other catalysts the yield was below 40% after 2 h.
To understand the effect of ultrasound on the present reaction, we carried out a comparative study on the CAN catalysed reaction under sonic and silent condition. Under silent condition, the reaction was carried out using dimedone (2 mmol), 2-chloro-4-fluoroaniline (1 mmol), and 4-fluorobenzaldehyde (1 mmol) in acetonitrile (3–5 mL) as a solvent at 70°C for 4 h, and we observed the formation of acridine-1,8-dione in 50% yield (Table
Comparison between CAN catalysed silent and sonic reactions.
Entry | Reactions | Silent conditiona | Sonic conditionb | ||
---|---|---|---|---|---|
Time | Yieldc | Time | Yieldc | ||
1 | Dimedone (1 mmol) and 2-chloro-4-fluoroaniline (1 mmol) to form |
45 min | 75% | 20 min | 95% |
2 | Reaction between intermediates |
4 h | 50% | 1 h | 90% |
3 | Mixing all the reactants ( |
5 h | 50% | 1 h | 90% |
Formation of
In order to understand the role of ultrasound and the catalyst we decided to study the mechanism of formation of acridines in detail. From the literature, it is clear that formation of acridines involves the condensation of
Formation of Knoevenagel adduct.
Formation of
After optimizing the reaction conditions, we applied the optimized condition to a range of other aromatic aldehydes and aromatic amines, ammonium acetate, and a heterocyclic amine; the results of this study are presented in Table
A small library of acridines synthesized under sonic conditiona.
Entry | ( |
( |
Amines ( |
Product | Yieldb % | Time (min) |
---|---|---|---|---|---|---|
1 | R1 = CH3 | 4-Methoxy |
4-Chloro, 2-fluoroaniline ( |
|
90 | 40 |
2 | R1 = CH3 | 2-Fluoro |
( |
|
95 | 45 |
3 | R1 = CH3 | Thiophene-2-aldehdye | ( |
|
95 | 45 |
4 | R1 = CH3 | 4-Chloro |
( |
|
93 | 45 |
5 | R1 = CH3 | Benzaldehyde | ( |
|
95 | 45 |
6 | R1 = CH3 | 4-Hydroxy |
( |
|
90 | 40 |
7 | R1 = CH3 | Benzaldehyde | Aniline ( |
|
95 | 40 |
8 | R1 = CH3 | 4-Chloro |
( |
|
93 | 40 |
9 | R1 = H | 4-Chloro |
( |
|
90 | 40 |
10 | R1 = H | Benzaldehyde | NH4Ac |
|
90 | 20 |
11 | Dimedone | 4-Chloro |
NH4Ac |
|
95 | 20 |
12 | R1 = CH3 | Benzaldehyde | 2-Aminopyridine |
|
90 | 50 |
13 | Dimedone and cyclohexa-1,3-dione | Benzaldehyde | 2-Aminopyridine |
|
85 | 50 |
A plausible mechanism for the formation of acridines from
The noteworthy qualities of the sonication are improved reaction rates and formation of pure products in high yields. Additionally, sonication allows benefits like easier manipulation, improved energy conservation, and low waste generation as compared to the traditional methods; in recent years, the sonochemical energy delivery has been used as an excellent alternative to thermal energy in promoting organic reactions. The origin of the energy lies in the “cavitation” phenomenon which involves formation, growth, and collapse of several millions of tiny vapour bubbles in the liquid medium [
We have applied the effective combination of suitable solvents and ultrasound in the synthesis of heterocyclic and other important compounds through one-pot multicomponent reaction strategies under sonic condition earlier [
To conclude, we have developed a general, practical, and high yielding procedure to construct different
The authors declare that there is no conflict of interests; that is, the authors of the paper do not have a direct financial relation that might lead to a conflict of interests for any of the authors.
The authors express their sincere thanks to the University Grants Commission, New Delhi, India, for the financial assistance and a fellowship under the UGC major research project (F. no. 37-71/2009(SR)).