Synthesis and Reactivity of 2-Acetylthiophenes Derivatives ^†

Abstract

Thiophene is a five-membered sulfur containing a heteroaromatic ring. Its presence in compounds of therapeutic interest is remarkable, leading to various studies to develop strategies to synthesize new biologically active thiophene analogues. Due to the presence of a ketone function, 2-acetylthiophenes derivatives are good intermediates to prepare such important compounds. Since its discovery, the Vilsmeier–Haack reaction has always been a subject of great interest to organic chemists and continues to attract considerable attention. It is a powerful tool in organic chemistry. This reagent is widely used for the chloroformylation of ketones leading to 3-chloroacroleins, which are scaffolds to prepare 5-aryl-2-acetylthiophenes derivatives. Our team aimed to develop and functionalize heterocyclic compounds with promising biological and pharmacological activities, including some new concepts of green chemistry; as a part of our research, different derivatives of 5-aryl-2-acetylthiophenes were achieved in good yields and then used to prepare the new compounds.

1. Introduction

Highly substituted thiophenes form an internal part of numerous natural products and pharmaceuticals [1]; among the biological activities described in the literature are the following: anti-tumor [2], anti-inflammatory, anti-Alzheimer, antiviral, etc. [3].

Thiophene derivatives are prepared through several methods; for 5-aryl-2-acetyl thiophenes derivatives, we start with the preparation of β-chloroacroleins via the Vilsmeier–Haack reaction, followed by a cyclisation to reach our target molecules.

The research teams in our laboratory focused their efforts on the synthesis of new heterocyclic compounds with promising biological and pharmacological activities via modern and ecofriendly strategies [4,5,6,7,8]. As a part of our work, different derivatives of 5-aryl-2-acetylthiophenes (1) were achieved in good yields and were then used to prepare the new compounds (Figure 1).

2. Results and Discussion

In this communication, the retrosynthetic scheme that has been propounded is the following (Scheme 1).

The Vilsmeier–Haack reagent is used in several reactions, such as formylation [9], chlorination [10], chloroformylation [11], aromatization [12], cyclization [13], etc. In the present work, we focus on the chloroformylation of acetophenone derivatives to prepare β-aryl-β-chloroacrolein, followed by a cyclisation to obtain the corresponding thiopenes.

The Vilsmeier–Haack reagent is an iminium salt prepared by reacting phosphorusoxychloride (POCl₃) and DMF at 0 °C. The chloromethylene iminium salt interacts with the enolic form of acetophenone to form an iminium salt, which is rapidly hydrolyzed to isolate β-chloroacroleins (Scheme 2).

Different acetophenone derivatives (2) were used to prepare β-aryl-β-chloroacroleïn (3) with good yields (Scheme 3).

The obtained intermediates (3) react with sodium sulfide nonahydrate to form thiolate (I) as an intermediate, chloroacetone is then added, followed by potassium carbonate to result in 5-aryl-2-acetylthiophenes derivatives (4) in good yields (Scheme 4).

The structures of all the products were confirmed by ¹HNMR spectrum. The spectrum (Figure 2) of 1-(5-(4-methoxyphenyl)thiophen-2-yl)ethanone (R: OMe) shows the disappearance of the aldehyde (O=C-H) peak at around 10.18–10.25 ppm of the 3-chloro-3-(4-methoxyphenyl)acrylaldehyde and, of course, the presence of a single peak at 2.55 ppm corresponding to the protons (O=C-CH₃), in addition to the two protons of the thiophene ring at 7.63–7.47 ppm.

The presence of the ketone in the molecule (4) offers a multitude of interesting reactions such as the preparation of a second thiophene ring (5). Two suggestions are made as follows (Scheme 5):

(1)

Preparation of the corresponding alkene by a Knoevenagel condensation (II) followed by a Gewald reaction (5).

(2)

One-pot reaction using catalyst.

A reaction between 1-(5-(4-methoxyphenyl)thiophen-2-yl)ethanone and malononitrile in the presence of ammonium acetate was carried out; as the carbon chain increases in size, the Knoevenagel reaction becomes more difficult, requiring more than 72 h to reach the new product with low yield. An alternative way is under study to select the right catalyst for those types of reactions.

The general experimental procedure is as follows:

(1)

Synthesis of β-aryl-β-chloroacroleïne:

At 0 °C, 1.5 eq of POCl₃ was slowly added to 1.5 eq of DMF and the mixture was stirred for 10 min. Once the salt was ready, (0.7 g) of acetophenones (5) in DMF was added drop wise with stirring. The reaction mixture was heated at 60 °C. The evolution of the reaction was followed by TLC and, after the completion of the reaction, the solution was cooled at room temperature and then poured slowly into a sodium acetate aqueous solution (10%), pH = 4. The obtained solid was filtered and washed with water to obtain β-aryl-β-chloroacroleïn, which was used in the next step without further purification. For analysis, a small amount of the obtained solid was recrystallized from cyclohexane.

(2)

Synthesis of 5-aryl-2-acetylthiophenes derivatives:

To a solution of 1 eq of Na₂S.9H₂O in DMF, the previously prepared β-aryl-β-chloroacroleïn was added. The mixture was stirred at 60 °C, followed by TLC. After the completion of the reaction, 1 eq of chloroacetone was rapidly added and the reaction was stirred during 6 h at 60 °C. Then, 1 eq of K₂CO₃ dissolved in 1 mL of water was added to the reaction. The mixture was stirred for 30 min at 60 °C, cooled to room temperature and then poured in water. The solid obtained was filtered and the crude product was washed with water and then recrystallized from ethanol.

3. Conclusions

In the present communication, we have discussed the synthesis of 5-aryl-2-acetylthiophene derivatives (4). Future works will cover the preparation of a second thiophene ring using a simple and effective method.