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Original Article
11 (
4
); 538-545
doi:
10.1016/j.arabjc.2015.11.013

Microwave-assisted intermolecular aldol condensation: Efficient one-step synthesis of 3-acetyl isocoumarin and optimization of different reaction conditions

, ,
a Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, 02040 Adıyaman, Turkey
b Department of Metallurgy and Material Engineering, Faculty of Engineering, Adıyaman University, 02040 Adıyaman, Turkey
c Department of Chemistry, Faculty of Art and Sciences, Adıyaman University, 02040 Adıyaman, Turkey

⁎Corresponding authors. Tel.: +90 (416) 223 3800/2808; fax: +90 (416) 223 3809 (M. Koca). Tel.: +90 (416) 223 3800/2760; fax: +90 (416) 223 3809 (A.S. Ertürk). mkoca@adiyaman.edu.tr (Murat Koca), aserturk@adiyaman.edu.tr (Ali S. Ertürk)

Received: , Accepted: ,
© The Author(s) 2015
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

This paper describes the optimization and comparison of conventional and microwave-assisted methods for efficient, cheap, one-pot, and straightforward synthesis of isocoumarins under mild reaction conditions. On this basis of this aim, synthesis of 3-acetyl isocoumarin from 2-formylbenzoic acid with mono-chloroacetone was chosen as a model reaction. Afterward, four different methods conventional (Method A), microwave open vessel (Method B), microwave sealed vessel (Method C), and microwave closed system (Method D) were used methodologically to determine best experimental conditions for each of these methods in this model reaction. The results revealed that developed Methods A, C and D could be used successfully under solvent-free conditions with good yields (84–87%) for the future efficient, one-pot synthesis of isocoumarins. This paper is also a first for characterizing 3-acetyl isocoumarin by using ATR, 1H NMR, 13C NMR and GC–MS.

Keywords

Isocoumarins
3-Acetyl isocoumarin
Microwave chemistry
Optimization
1

1 Introduction

Isocoumarins form an important part of natural lactones, many natural products, and pharmacological substances. They display a broad range of biological activities, including antifungal (Engelmeier et al., 2004; Hussain et al., 2009; Zhang et al., 2008), antimicrobial (Yoshikawa et al., 1994) anti-inflammatory, (Matsuda et al., 1999), antitumor (Agata et al., 2004; Kawano et al., 2007; Lim et al., 2003), anti-allergic (Kam et al., 1988), herbicidal (Kurume et al., 2008; Matsuda et al., 2008), and many others (Heynekamp et al., 2008; Kam et al., 1994). Depending on their broad range of biological activities, isocoumarins play a major role in the synthesis of various important pharmaceutical compounds as synthetic precursors and intermediates. Their such properties also make isocoumarins a focal point for inhibition studies such as DNA helicase inhibition (heliquinomycin) (Chino et al., 1998), β-amyloid peptide production inhibition (Bihel et al., 2003), and protease inhibition (Bihel et al., 2003; Harper and Powers, 1984). Due to these properties and wide range of applications, several synthetic routes and methods have been developed for the synthesis of isocoumarins and the attempts are still continuing. Consequently, isocoumarin synthesis has received much attention for developing efficient, more improved, and cheaper methods. Thus, a considerable scope for isocoumarin synthesis has emerged in time.

Microwave irradiation could be an alternative to many classical reactions with some advantages such as having better yields, shorter reaction times, and fewer by products (Kappe, 2004; Kim et al., 2009; Sinnwell and Ritter, 2007; Zhang et al., 2010). In addition, the amount of solvents, wasteful by products and reagents can also be minimized or even disappeared by microwave heating. These advantages of microwave irradiation are considered to be stemmed from microwave effect or thermal effect, which are the consequences of dielectric constant of used solvent. Thus, depending on the reaction conditions (ambient pressure, temperature, and superheating of solvent), reaction proceedings could be accelerated and the desired reactions, products, and yields that could not be succeeded by conventional synthesis methods, could be achieved by microwave (Iannelli et al., 2005; Kappe, 2004). However, it should be noticed that the microwave assisted synthesis is not a complete alternative for the conventional synthesis. In the last decade, 3-substituted isocoumarins with no substituent at the 4th position or substituent with halides (H, Br, I, etc.) were synthesized mainly by traditional (Bovicelli et al., 1999; Hussain et al., 2001; Mal et al., 2000) or transitional metal catalyzed reactions (Bellina et al., 2000; Liao and Cheng, 1995; Wang and Shen, 1998). Although these methods are useful and effective for the synthesis of isocoumarins, no method has been developed under solvent-free conditions for both microwave irradiation and conventional synthesis comparatively up to now.

The purpose of this study was to develop and compare efficient, cheap, one-pot and straightforward various microwave and conventional synthesis methods for isocoumarins under mild reaction conditions. For this aim, the reaction of starting material 2-formylbenzoic acid with monochloro acetone for the synthesis of 3-acetyl isocoumarin, which is the product of an intermolecular aldol condensation, was chosen as model reaction. Indeed, the main deterministic reason behind this selection was the insufficient number of present work and synthetic approach available in the literature for this molecule.

The first attempt to develop a synthetic method for 3-acetyl isocoumarin was pioneered by Kanevskaya et al. (1953), Kanevskaya and Shemyakin (1932) in the beginning of 1930s. This study reported the two-step synthesis of 3-acetyl isocoumarin. The first step is the condensation of the 2-formylbenzoic acid potassium salt (alkali metal salt) with mono-chloroacetone (halogenated methyl ketone) to give esters. These esters are cyclized when heated with an organic base piperidine yielding 3-acetyl isocoumarin. Several decades later, in 2008, this attempt was followed by using a different method just by Ishchenko et al. (2008) for 3-substituted isocoumarin derivatives. In their study, a convenient one-step method for the synthesis of 3-oxohetarylisocoumarins, by cyclization of 2-formylbenzoic acid and heterocyclic α-haloketones with triethylamine as a base was developed. Afterward, a little effort has been conducted in the literature for the synthesis of 3-acetyl isocoumarin. It seems to be synthesized on demand from only one commercial source (http://www.daybiochem.com, 2015) with no explicit synthetic route. In this point, lack of sufficient and validated synthesis methods for 3-acetyl isocoumarin in the literature has attracted our interest. Thus, we have canalized our method development studies on the synthesis of isocoumarins by selecting this molecule as a model.

Methodologically, four different methods were used for the model synthesis of 3-acetyl isocoumarin. These were conventional (Method A), microwave open vessel (Method B), microwave sealed vessel (Method C), and microwave closed system (Method D) methods. Factors affecting the reaction conditions for all the methods were considered as solvent type, temperature, used base and reaction time except for heating sources, which are microwave and conventional. Therefore, reactions were optimized under different series of experimental trials, and best reaction conditions were determined. Interestingly, solvent-free conditions have been considered for both conventional and microwave methods, as well. In this way, the source of microwave effect was investigated.

In this study, we have presented mild and efficient novel synthesis methods using microwave and conventional methods comparatively for the synthesis of 3-acetyl isocoumarin. In this way, the best synthetic conditions for the 3-acetyl isocoumarin, which could be used as a backbone in the role of precursor or reaction intermediate in the synthesis of numerous pharmaceutically active agents, were optimized. These methods can also be used as general synthetic routes leading to the synthesis of substitute isocoumarins and derivatives in future studies.

2

2 Result and discussion

Our aim was to develop one-step, efficient, cheap methods for the synthesis of 3-substituted isocoumarins using conventional and microwave conditions comparatively. To perform this aim, reaction of 2-formylbenzoic acid (1) with mono-chloroacetone (2) was chosen as a model reaction to synthesize 3-acetyl isocoumarin (3) (Scheme 1). For this model reaction, four different types of methods were used. These methods were Methods A, B, C and D. Indeed, Method A was conventional and the other methods B, C and D were the microwave-assisted synthesis methods. While factors affecting the reaction conditions were considered as the presence or absence (solvent-free) of any solvent, type of solvent, base, temperature, time for Method A, power (watt) at different temperatures was also regarded as a significant influential parameter for Methods B, C and D.

One-pot synthesis of 3-acetyl isocoumarin with Methods A, B, C, and D.
Scheme 1
One-pot synthesis of 3-acetyl isocoumarin with Methods A, B, C, and D.

In the experiments, ethanol (EtOH) was used as polar protic solvent whereas acetone and dimethylformamide (DMF) were used as polar aprotic solvents. In addition, solvent-free conditions and influence of the type of used base on the reactions were also investigated. Thus, potassium carbonate (K2CO3), potassium phosphate (K3PO4), and Trimethylamine (TEA) were used as different types of bases during experiments. In this way, polar and nonpolar reaction conditions for Methods A, B, C and D were optimized by performing different series of experimental trials for each factor. As a result, optimum reaction conditions for the methods were determined and described in detail as follows.

2.1

2.1 Conventional synthesis of 3-acetyl isocoumarin

2.1.1

2.1.1 Method A: conventional synthesis

We started to investigate optimum reaction conditions for the synthesis of 3-acetyl isocoumarin with the traditional approach, Method A, comprising of conventional heating. Primarily, pre-experiments were conducted and repeated under different series of trials for various temperatures, time, base, and solvents. The optimization results for Method A are summarized in Table 1. As shown in Table 1, compound 3 could be prepared in good yield in the presence of TEA at 130 °C (entries 1–10), and solvent-free condition was found to be the best reaction medium (entries 10–13). Under the solvent-free conditions and TEA, the yields increased consistently as the temperature increased from 110 °C to 130 °C and maintained up to 87%. However, further increase in temperature to 140 °C led to a decrease in the yield, and the decrease was almost stable up to 150 °C (entries 14–19). On the other hand, the yields increased with time, i.e., from 77% (30 min) to maximum 87% (180 min). Extending the reaction time longer than 60 min did not change the yield significantly (entries 15 and 14–17). Taking all these findings into consideration, we concluded that 130 °C, 60 min, TEA, and solvent-free with 84% yield were the optimal conditions (entry 15).

Table 1 Optimization of the reaction conditions of compound 3 with Method A (conventional) and Method B (microwave open vessel).
Entry Solvent Base Temp. (°C) Time (min) Yield (%)
Method Method Method
A B A B A B
1 Acetone K2CO3 Reflux Reflux 720 120 Trace <1
2 Acetone K3PO4 Reflux Reflux 720 120 Trace <1
3 DMF K2CO3 Reflux Reflux 720 120 Trace <1
4 DMF K3PO4 Reflux Reflux 720 120 Trace Trace
5 EtOH K2CO3 Reflux Reflux 720 120 Trace Trace
6 EtOH K3PO4 Reflux Reflux 720 120 Trace Trace
7 Solvent-free K2CO3 Reflux Reflux 720 120 Trace Trace
8 Solvent-free K3PO4 Reflux Reflux 720 120 Trace Trace
9 Solvent-free TEA 110 Reflux 10 10 48 <1
10 Solvent-free TEA 130 Reflux 10 10 62 <1
11 Acetone TEA Reflux Reflux 720 120 <1 <1
12 DMF TEA Reflux Reflux 720 120 <1 <1
13 EtOH TEA Reflux Reflux 720 120 10 <1
14 Solvent-free TEA 130 Reflux 30 30 77 <1
15 Solvent-free TEA 130 Reflux 60 60 84 <1
16 Solvent-free TEA 130 Reflux 120 120 86 <1
17 Solvent-free TEA 130 Reflux 180 180 87 <1
18 Solvent-free TEA 140 Reflux 60 60 85 <1
19 Solvent-free TEA 150 Reflux 120 60 86 <1

2.2

2.2 Microwave-assisted synthesis of 3-acetyl isocoumarin

2.2.1

2.2.1 Method B: microwave open vessel

Method B was examined as an alternative to the conventional synthesis Method A. In Method B, our aim was to investigate whether there exists a microwave effect, including microwave heating, under atmospheric open vessel conditions for the synthesis of compound 3. For this purpose, under a series of power and time trials between 0–300 W and 0–120 min, pre-experiments were performed, and the optimum reaction conditions were determined as 300 W and 120 min.

Table 1 presents the optimization results for Method B in comparison with Method A. The same experimental conditions in Method A were used to perform the reactions of compound 3 with Method B at 300 W and for 120 min. However, as detailed in Table 1, compound 3 only could be prepared at lower yields less than 1% (entries 1–3, 9–19). Nevertheless, the optimum conditions for moderate or higher yield synthesis of compound 3 could not be determined by using Method B. Instead, only the trace amount or lower than 1% yield of compound 3 was obtained for all the trials (entries 1–19).

Table 1 also indicates that results obtained by using Method B are distant from optimum even in the solvent-free and TEA based experimental conditions, which are the optimum conditions for Method A. Thus, it could be inferred that there was no explicit microwave heating effect to accelerate and obtain good yields with Method B. Due to these limitations of Method B, a need for the investigation of optimum reaction conditions by using Method C emerged.

2.2.2

2.2.2 Method C: microwave sealed vessel

Not only the weakness of Method B but also the optimum conditions obtained by Method A, which were solvent-free, 60 min and 130 °C, led to search for an alternative method. For this reason, microwave sealed vessel method (Method C) was conducted. In Method C, a fixed power microwave irradiation was applied to a sealed microwave vessel containing the stoichiometric mixture of compounds 1 and 2 at the optimum conditions obtained with the Method A. The aim of Method C was to see and compare whether there is a difference between the conventional heating and microwave heating. Optimization parameters except for types of solvent and used base were applied power (watt) and yield. Pre-experiments were conducted in a series of powers between 0 and 200 W for repeated times.

Table 2 shows the optimization of the reaction conditions of compound 3 with Method C. As shown in Table 2, compound 3 could be synthesized in moderate or good yields under the conditions of solvent-free and TEA (entries 1–9). No dramatic change in yield was observed with an increase in time 10 min (50%) to 30 min (58%) at 100 W (entries 1–3). In contrast, it was almost remained constant after 15 min (57%) until reaching 30 min (58%) (entries 2 and 3). Increase in power from 100 W to 200 W and maintenance at 200 W led to increase in yield constantly from 69% (5 min) to 87% (180 min) (entries 4–9). However, it should be noted that a considerable increase in yield 84% (60 min) was not observed (entry 7). Thus, it could be concluded that 200 W, 130 °C, TEA and solvent-free, and 60 min with 84% yield were the optimum reaction conditions under microwave sealed vessel conditions (entry 7).

Table 2 Optimization of the reaction conditions of compound 3 with Method C.
Entry Solvent Base Power (W) Temp. (°C) Time (min) Yield (%)
1 Solvent-free TEA 100 130 10 50
2 Solvent-free TEA 100 130 15 57
3 Solvent-free TEA 100 130 30 58
4 Solvent-free TEA 200 130 5 69
5 Solvent-free TEA 200 130 10 72
6 Solvent-free TEA 200 130 30 77
7 Solvent-free TEA 200 130 60 84
8 Solvent-free TEA 200 130 120 87
9 Solvent-free TEA 200 130 180 88

Comparison of the optimization results obtained with Method A (entry 15, Table 1) and Method C (entry 7, Table 2) revealed that the optimum yields in these two methods were same as 130 °C, TEA and solvent-free, and 60 min with 84% yield. We concluded that we could not observe an explicit microwave heating effect as the optimal conditions of Methods A and C. In addition, it could be inferred from the results for Methods A and C that these two methods validated each other.

2.2.3

2.2.3 Method D: microwave closed system

Good yield obtained from the optimization of compound 3 with Method C showed that further research on the microwave-assisted synthesis of compound 3 should be performed (Table 2). Thus, the closed system method was chosen to analyze microwave effect on the model synthesis reaction of compound 3. For this purpose, the effect of solvents, used bases, temperature, and reaction time under microwave irradiation and the closed system were investigated. The results are summarized in Table 3.

Table 3 Optimization of the reaction conditions for compound 3 with Method D.
Entry Solvent Base Temp (°C) Time (min) Yield (%)
1 Acetone K2CO3 120 15 Trace
2 Acetone K3PO4 120 15 Trace
3 Acetone KOH 120 15 Mixture
4 Acetone TEA 120 15 10
5 EtOH TEA 120 15 48
6 Solvent-free TEA 120 15 50
7 Acetone TEA 120 30 76
8 Acetone TEA 150 30 77
9 Acetone TEA 180 30 86
10 Acetone TEA 200 30 78
11 Acetone TEA 180 45 84
12 Acetone TEA 180 60 83
13 EtOH TEA 150 15 66
14 EtOH TEA 200 15 66
15 EtOH TEA 150 30 66
16 EtOH TEA 180 30 78
17 EtOH TEA 200 30 87
18 EtOH TEA 220 30 86
19 EtOH TEA 200 45 71
20 EtOH TEA 200 60 69
21 Solvent-free TEA 130 15 76
22 Solvent-free TEA 140 15 72
23 Solvent-free TEA 150 15 78
24 Solvent-free TEA 120 30 77
25 Solvent-free TEA 130 30 84
26 Solvent-free TEA 140 30 82
27 Solvent-free TEA 150 30 77
28 Solvent-free TEA 130 45 82
29 Solvent-free TEA 130 60 72

Table 3 shows the optimized reaction conditions for Method D. A yield can just be observed when TEA was used as base (entries 1–4). Also, it could be observable that acetone, EtOH and solvent-free conditions could be the desired conditions for the moderate or higher yield production of compound 3 (entries 4–6). Therefore, we focused on the optimization of the reaction conditions under these solvents.

As shown in Table 3, the yields increased consistently with an increase of the temperature from 120 °C to 180 °C in the presence of TEA and acetone (entries 7–9). Further increase in temperature to 200 °C, however, caused a sudden decrease in the yield (entries 7–10). On the other hand, considerable change in the amount of yield was not observed over time from 86% (30 min) to 83% (60 min) (entries 9 and 11, 12). In fact, the yield almost maintained the same with an increase in time from 30 min to 60 min. Thus, we concluded that TEA, 180 °C, and 30 min with 86% yield were the optimum conditions under the closed system in the presence of acetone as solvent (entry 9).

Under the conditions of EtOH and TEA, a small amount of an increase in the yield was observed with an increase in temperature from 120 °C to 200 °C (entries 5, 13, 14). Increasing the reaction time from 15 min to 30 min resulted with no proper change in the yield (entries 13–15). The yields increased consistently with an increase in temperature from 150 °C (66%) to 200 °C (87%) (15–17). Further increasing the temperature did not change the yield significantly (entry 18). However, a decrease in the yield after increasing reaction time from 87% (30 min) to 69% (60 min) (entries 17–20) was observed. Therefore, we concluded that TEA, 200 °C, and 30 min with 87% yield were the optimum conditions under the closed system in the presence of EtOH as solvent (entry 17).

Solvent recovery or waste products are important as much as obtaining moderate and higher yields. Under solvent-free conditions of Methods A and C, we observed good yields. We also investigated the effect of solvent-free microwave closed system conditions for the synthesis of compound 3. As explained in Table 3, a significant increase in yield was not observed with an increase of temperature from 130 °C to 150 °C (entries 21, 25–27). On the other hand, a remarkable increase in yield from 50% (15 min) to 77% (30 min) was observed with an increase in time (entries 6 and 24). Increasing the temperature a little from 120 °C to 130 °C improved the yield from 77% to 84% (entries 24 and 25). Further increase in temperature led to decrease in yield from 84% (130 °C) to 77% (150 °C) (entries 25–27). Increasing the reaction time, however, resulted in a decrease in yield from 84% (30 min) to 72% (60 min) (entries 25, 28, and 29). As a result, we concluded that TEA, 130 °C, and 30 min with 84% yield were the optimum conditions under closed solvent-free media (entry 25).

2.3

2.3 Comparison of the optimized Methods A, B, C and D

Several entries of experiments were conducted with different bases, solvents, temperatures and reaction time for Methods A, B, C, and D in order to optimize the reaction conditions of compound 3 (Tables 1–3). We compared in Table 4 the best synthetic conditions for each method. It could be easily seen from Table 4 that the best yield (87%) was obtained with Method D at 200 °C when EtOH and TEA were used as solvent and base, respectively (No. 4). The closest second best yield was observed in the presence of acetone, TEA at 180 °C (86%) (No. 2).

Table 4 Comparison of the optimization results of Methods A, B, C and D.
No Solvent Base Temp (°C) Time (min) Yield (%)
Methods Method Method
A B C D A B C D A B C D
1 Acetone K2CO3 Rfa. Rf. – 140 720 120 – <1 <1 – Trace
2 Acetone TEA Rf. Rf. – 180 720 180 – 30 <1 <1 – 86
3 EtOH K2CO3 Rf. Rf. – 150 720 120 – 30 Trace Trace – Trace
4 EtOH TEA Rf. Rf. – 200 720 120 – 30 10 <1 – 87
5 S.f. TEA 130 Rf. 130 130 60 120 60 30 84 Trace 84 84
a Reflux.

However, the yield was not the only parameter one can consider while optimizing the reaction conditions of a reaction. Time, solvent use, recovery and waste products are the other factors to be taken into consideration while deciding the optimum reaction conditions. From this viewpoint, it could be observable from Table 4 that the best yields could be obtained under solvent-free conditions when TEA was used as base for Methods A and C (No. 5). In both methods, the best reaction conditions were common as 130 °C, 60 min, TEA with 84% (No. 5). The same yield was observed with Method D under solvent-free conditions. Significantly, the Method D improved two times the reaction time (30 min) under solvent-free conditions when compared to Methods A and C (60 min) (No. 5).

The effect of base was one of the factors we investigated on the final product yield. Only trace amount of yields was observed for all the methods when K2CO3 was used as base (No. 1, 3), while TEA produced moderate or higher yields (No. 2, 4, 5). On the other hand, Method D differed from the other methods on one significant point that the reactions that could not be performed by using a kind of solvent with even low yields were conducted with higher yields under acetone, TEA (86%) (No. 2), and EtOH, TEA (87%) (No. 4) conditions in 30 min. In conclusion, it could be inferred from these findings that the beneficial effect of using microwave heating could be observable obviously when Method D is applied.

3

3 Experimental

3.1

3.1 Materials

2-carboxybenzaldehyde, mono-chloroacetone, potassium carbonate, potassium phosphate, triethylamine, acetone, ethanol, and dimethylformamide were purchased from Sigma-Aldrich. Unless otherwise stated all chemicals were of analytical grade and used without further purification. Microwave reactions were performed in sealed heavy-walled 10 mL Pyrex tubes (CEM Corporation, North Carolina, USA). CDCl3 and TMS (internal reference) were used in the measurements of 1H NMR and 13C NMR spectra.

3.2

3.2 Instrumentation

Melting point was measured with Stuart SMP30 melting point apparatus (Serial No: R000100112). IR (ATR) spectra (4000–650 cm−1, resolution 4 cm−1) were recorded on PerkinElmer Spectrum 100 FT-IR Spectrometer (Serial No: LR64912C). 1H NMR and 13C NMR spectra were recorded in Bruker Avance 500 MHz Spectrometer. MS spectra were measured with an Agilent 19091 N-136 GC–MS instrument.

Microwave-irradiated reactions were carried out with a CEM Focused Microwave™ Synthesis System, Model Discover (CEM Corporation, North Carolina, USA) with a continuous microwave power delivery system with operator selectable power output from 0 to 300 W (±30 W) programmable in 1-watt increments, infrared temperature control system programmable from 25 to 250 °C, pressure controlled and 5 to 125 mL vessel capacity was used as microwave reactor (Serial Number DU9472).

3.3

3.3 General experimental

Various entries of experimental procedures were conducted for the one-pot, efficient synthesis of compound 3 by using Methods A–D, and results are summarized in Tables 1–3. Conventional synthesis was carried out using oil bath while microwave reactions were performed in sealed heavy-walled 10 mL Pyrex tubes (CEM Corporation, North Carolina, USA) under controlled conditions in a safe and reproducible manner with CEM Focused Microwave™ Synthesis System. During microwave reaction, single mode microwave irradiation was used at a fixed temperature, pressure, and irradiation power by automatic power control. All closed system reactions were carried out at an adjustable microwave power range 30–100 W under pressure control, open vessel reactions were carried out between 0 and 300 W and microwave sealed vessel reactions were conducted between 0 and 200 W. Both in conventional and microwave reactions performed in the presence of a solvent, the used amount of solvent was identical and 5 mL. Experimental procedures of these methods for best or optimal conditions are as in the flowing parts. Full characterizations of compound 3 with ATR, MS and NMR (1H and 13C) were explained in Supporting Information (Figs. S1–S4).

3.4

3.4 Synthesis procedure for Method A

A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloroacetone (0.62 g, 6.67 mmol) was added over (0.67 g, 6.67 mmol) TEA. The resulting mixture was mixed at 130 °C oil bath temperature for 60 min under solvent-free conditions as indicated in Table 1. Afterward, the product was precipitated in distilled water, filtered and washed with 3 mL acetone. The pure product was obtained by recrystallization from EtOH. The end product was light orange solid and yield was 84% (entry 15, Table 1) (1.05 g, 5.60 mmol).

3.5

3.5 Synthesis procedure for Method B

A simple synthetic route for Method B is as follows. A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloroacetone (0.62 g, 6.67 mmol) was added over a 50 mL reaction vessel. Then, equimolar amount of related base and 5 mL of related solvent (in the presence of solvent) were added to vessel. The reactions were conducted for appropriate base, solvent, time by refluxing under 0–200 W power intervals (Table 1.). Afterward, the product was precipitated in distilled water and filtered. The pure product was obtained by recrystallization from EtOH. The crude product was light orange solid and yields were trace or below 1% under microwave open vessel conditions.

3.6

3.6 Synthesis procedure for Method C

A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloroacetone (0.62 g, 6.67 mmol) was added over (0.67 g, 6.67 mmol) TEA. Then the sealed 10 mL microwave tube was irradiated at 200 W, 130 °C for 60 min. Then, the product was precipitated in distilled water, filtered and washed with acetone. The pure product was obtained by recrystallization from EtOH. The resulted product was light orange solid and yield was 84% (1.05 g, 5.60 mmol) (entry 7, Table 2).

3.7

3.7 Synthesis procedure for Method D

3.7.1

3.7.1 Synthesis procedure for Method D while acetone used as solvent

A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloroacetone (0.62 g, 6.67 mmol) was added to a stirred solution of (0.67 g, 6.67 mmol) TEA in 5 mL acetone. Then the closed, pressure controlled, 10 mL, microwave tube was treated at 180 °C for 30 min. After removal of the excess acetone under vacuum at 60 °C bath temperature, the product was precipitated in distilled water, filtered and washed with acetone. The pure product was obtained by recrystallization from EtOH. The resulted product was light orange solid and yield was 86% (1.08 g, 5.73 mmol) (entry 9, Table 3).

3.7.2

3.7.2 Synthesis procedure for Method D while EtOH used as solvent

A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloroacetone (0.62 g, 6.67 mmol) was added to a stirred solution of (0.67 g, 6.67 mmol) TEA in 5 mL EtOH solution mixture. Then the closed, pressure controlled, 10 mL, microwave tube was treated at 200 °C for 30 min. After removal of the excess EtOH under vacuum at 60 °C bath temperature, the product was precipitated in distilled water, filtered and washed with acetone. The pure product was obtained by recrystallization from EtOH. The resulted product was light orange solid and yield was 87% (entry 17, Table 3) (1.09 g, 5.80 mmol).

3.7.3

3.7.3 Synthesis procedure for Method D in solvent-free conditions

A mixture of 2-carboxybenzaldehyde (1.00 g, 6.67 mmol) and mono-chloro acetone (0.62 g, 6.67 mmol) was added over (0.67 g, 6.67 mmol) TEA. Then under solvent-free conditions, the closed, pressure controlled, 10 mL, microwave tube was treated at 130 °C for 30 min. After removal of the excess EtOH under vacuum at 60 °C bath temperature, the product was precipitated in distilled water, filtered and washed with acetone. The pure product was obtained by recrystallization using EtOH. The resulted product was light orange solid and yield was 84% (1.05 g, 5.60 mmol) (entry 25, Table 3).

3.8

3.8 Characterization data of 3-acetyl isocoumarin (3)

Melting Point: 130 ± 0.1 °C; GC–MS: m/z = 188.10 (M+, %89), 145,1 (100), 117.1 (29), 89,1 (95), 63,1 (16); 1H NMR (500 MHz, CDCl3): δ = 2.56 (s, 3 H, -CH3), 7.37 (s, 1 H, H-4), 7.60–7.68 (m, 2 H, H-5, H-7), 7.74–7.82 (td, J = 7.6, 1.3 Hz, 1 H, H-6), 8.3 (d, J = 7.9 Hz, 1 H, H-8); 13C NMR (400 MHz, CDCl3): 26.1 (C-10), 109.0 (C-4), 122.8 (C-8a), 128.3 (C-8), 130.0 (C-5), 130.8 (C-7), 135.0 (C-6), 135.3 (C-4a), 148.9 (C-3), 160.9 (C-1), 192.2 (C-9).

4

4 Conclusion

The aim of this study was to develop and compare efficient, cheap, one-pot and straightforward various microwave and conventional synthesis methods for isocoumarins under mild reaction conditions. For this aim, we chose the model reaction of 2-formylbenzoic acid with mono-chloroacetone for the synthesis of 3-acetyl isocoumarin. Synthesis of 3-acetyl isocoumarin was accomplished by the developed new methods. These methods were Methods A, C and D, which are conventional, microwave sealed vessel, and microwave closed system methods, respectively. The best yields obtained by these methods were 84% (solvent-free, TEA) for Method A, 84% (solvent-free, TEA) for Method C, and 87% (EtOH, TEA) for Method D. These results were followed with the yields 86% (acetone, TEA) and 84% (solvent-free, TEA) for Method D.

Under solvent-free conditions, both in conventional synthesis Method A and microwave assisted synthesis methods C and D, the reactions, in which the TEA was used as the base, proceeded two times faster in Method D (30 min) than others (60 min) (No. 5, Table 4) with the same 84% yield. On the other hand, in the presence of a solvent, a yield was observed only at the reactions, where acetone and EtOH were used as solvent together with TEA, when Method D was used. The yields were 86% and 87% for acetone and EtOH for these reactions, respectively (No. 2, 4, Table 4). Taken together, observation of the results obtained from Methods A, C and D that only beneficial microwave heating effect was observed at Method D as it accelerated the reaction time two times (30 min) in comparison with those of Methods A and C (60 min) with the same product yield 84% (No. 5, Table 4).

In conclusion, we developed three different novel methods for the first efficient, one-pot synthesis of 3-acetyl isocoumarin after comparing the conventional and the microwave conditions. The developed novel methods could be used as general synthetic routes leading to the synthesis of substitute isocoumarins and derivatives, which are considered as the backbone in the role of precursor or reaction intermediate for the synthesis of numerous pharmaceutically active agents, in future studies. Furthermore, the developed methods offer several significant advantages such as solvent-free, high conversions, clean reaction procedure, no wasteful of by-products and solvents, which make them also important for prospective studies.

Acknowledgments

This research was supported by Adıyaman University Scientific Research Projects Coordination Department. Project Number: FEFMAP/2015-0006. Authors declare that there is no conflict of interest.

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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2015.11.013.

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 1


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