Synthesis of New Representatives of Push–Pull Enamines 5-Aryl-3-((dimethylamino)methylene)furan-2(3H)-Ones ^†

Abstract

The conditions for the synthesis of dimethylaminomethylene derivatives were selected based on the interaction of arylfuran-2(3H)-ones and dimethylformamide dimethylacetal (DMA-DMF), proceeding through the methylene active unit of the furanone ring. The influence of the used solvent and the type of activation on the reaction rate and product yields was established. Using NMR spectroscopy and the one-dimensional version of NOESY1D with selective excitation of protons, it was revealed that these systems exist in the form of an E-configuration.

1. Introduction

Furan-2(3H)-one is a promising heterocycle that has high chemical potential and acts as an easily accessible and platform-starting material for the synthesis of new series of compounds. The furan-2(3H)-one ring system is the main element of the skeleton of antitumor drugs [1,2,3,4], compounds with antioxidant [5] and antibacterial effects [6,7,8]. One of the most important tasks of organic chemistry is the development of new preparative methods for the synthesis of compounds that are capable of further modifications, leading to a variety of heterocyclic structures and containing pharmacophore fragments. Such compounds include dimethylaminomethylene derivatives, which have high prospects in the design of bioactive compounds that have antitumor [9], antioxidant [10] activity and are used as antibiotics [11].

Dimethylaminomethylenefuran-2(3H)-ones can be classified as highly effective synthons due to the presence of several active reaction centers, as well as the pronounced push–pull nature of the C=C bond, due to the presence of the carbonyl group of the furan-2(3H)-one fragment conjugated with the amino group. However, information on methods of preparation and properties of these systems is missing in the literature, which determines the relevance of searching for methods for synthesizing these compounds.

The most well-known synthetic reagent in the literature for the generation of enamine derivatives is dimethylformamide dimethyl acetal (DMF-DMA), the high reactivity of which is explained by the presence of methoxy groups that provide a partially positive charge on the carbon atom. Consequently, the DMF-DMA reagent can easily enter into condensation reactions with various functional groups of organic compounds, most common of which are methylene, methyl and amino groups, and it is also widely used as a one-carbon synthon for the construction of carbon skeletons [12,13,14,15,16,17,18,19,20].

2. Results and Discussion

2.1. Synthesis of 5-Aryl-substituted 3-((dimethylamino)methylene)furan-2(3H)-Ones

We investigated the possibility of introducing a dimethylaminomethylene fragment into the molecule of 5-arylfuran-2(3H)-ones. The conditions for the synthesis of dimethylaminomethylene derivatives of furan-2(3H)-one were optimized using the model reaction of 5-(4-chlorophenyl)-furan-2(3H)-one 1a with DMF-DMA 2 as an example (Scheme 1); the reagents were used in a molar ratio of 1:1 (

Table 1. Optimization of reaction conditions for the synthesis of 5-(4-chlorophenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3a.

Entry	Solvent	Temperature, °C	Time (min)	Yield, %
1	EtOH	78	180	50
2	i-PrOH	82	178	50
3	MeCN	81	150	50
4	1,4-Dioxane	101	160	61
5	Benzene	80	173	57
6	Toluene	110	110	70
7	Solvent-free	153	-	-
8	Toluene	115	25	75
9	Toluene	130	6	90
10	Toluene	150	-	-

).

When the reaction mixture is refluxed in an EtOH environment, it leads to the target product within 3 h with a yield of 50%; when using the more polar solvent acetonitrile, the reaction time is reduced to 2.5 h; however, the yield of the product does not change. Under these conditions, we tested non-polar solvents—benzene and toluene. The best results were obtained in toluene. Also, carrying out the reaction under solvent-free conditions in a twofold excess of DMF-DMA was not successful. Further attempts to increase the yield of the desired product and reduce the conversion time were conducted using a Monowave 50 pressurized vessel reactor (Anton Paar). When carrying out the transformation at 120 °C in toluene, the reaction time was reduced to 25 min with a yield of 75%; increasing the temperature to 130 °C allowed us the ability to carry out the reaction for 6 min with a yield of 90%. However, a subsequent increase in temperature did not provide the desired results and tarring of the reaction mixture was observed. Thus, these conditions were chosen as optimal for research (Scheme 2).

The advantages of this type of activation of the reaction mixture are new reaction pathways, i.e., by varying the heating time and temperature, one can observe the formation of various intermediate reaction products; significant reduction in transformation time; increased product yields; minimized solvent consumption and the ability to carry out reactions without the use of catalysts, which meets the principles of “green chemistry”. The literature provides isolated information on the study of the features of carrying out various chemical transformations using a reactor of this type, which determines the relevance of research in this area.

The use of a sealed vessel reactor allowed us the possibility to monitor and analyze conditions inside the vial (Figure 1).

The temperature curve smoothly increased to 50 °C, which corresponds to the process of dissolution of the initial components, followed by a sharp increase to 191 °C, significantly exceeding the initially set temperature value. This indicates an exothermic reaction occurring with the formation of 5-(4-chlorophenyl)-3-((dimethylamino)methylene)furan-2(3H)-one. An increase in temperature above the boiling point of toluene (130 °C versus 110 °C) offered us the opportunity to enhance the interaction due to the formation of a gaseous water–toluene azeotrope, which is shown by an increase in pressure up to 10 bar (Figure 1).

2.2. Structure of 3-Dimethylaminomethylene Derivatives of Furan-2(3H)-Ones 3a–f

The structures of the new compounds were determined by spectroscopic methods (¹H, ¹³C NMR, HMBC, HSQC, NOESY1D) and elemental analysis data. Phenyldimethylaminomethylenefuran-2(3H)-ones showed ¹H and ¹³C NMR data sets consistent with the proposed structures. Compounds 3a–f showed ¹H NMR chemical shifts for the protons of the methyl group NMe₂ in the form of one singlet in the range of 3.30–3.33 ppm. Signals of vinyl protons of the furan-2(3H)-one ring were observed in the range of 6.83–7.09 ppm; protons belonging to the exocyclic double bond C=C appeared at 7.19–7.28 ppm. The resulting structures were found to exist as the E-isomer, the configuration of which around the C=C bond was confirmed using a one-dimensional variant of NOESY1D under selective excitation. It was shown that there is no spatial correlation between the vinyl proton of the furan-2(3H)-one fragment and the proton at the C=C bond, which indicates data in favor of the E-configuration.

3. Material and Methods

3.1. Physical Measurements

¹H (400 MHz) and ¹³C NMR (100 MHz) spectra in acetone-d₆ were recorded with a Varian (Agilent) 400 spectrometer (Agilent Technologies, Santa Clara, CA, USA), and the internal standard was TMS. Chemical shifts (δ) are reported in ppm. Elemental analysis was performed on a CHNS analyzer “Elementar Vario MICRO cube” (Elementar Analysensysteme GmbH, Hanau, Germany). Melting points were determined on a Stuart™ SMP10 melting point apparatus (Cole-Parmer, Beacon Road, Stone, Staffordshire, ST15 OSA, UK). The progress of the reaction and the purity of the synthesized compounds were monitored by TLC on ALUGRAM^®® SIL G UV254 plates (MACHEREY-NAGEL GmbH and Co. KG, Düren, Germany), a hexane–ethyl acetate–acetone (2:2:1) mixture was the eluent.

3.2. Synthesis and Characterization of Compounds 3a–f

A mixture of 1 mmol of the corresponding 5-arylfuran-2(3H)-one 1a–f and 1 mmol of DMF-DMA 2 in 5 mL of toluene was placed in a Monowave 50 Anton Paar sealed vessel reactor and heated at 130 °C for 6 min. The crystals that precipitated during cooling were washed with cold toluene, recrystallized from ethanol, and dried.

• 5-(4-(Chlorophenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3a

Yellow crystals (ethanol), yield 0.33 g (90%), mp 210–211 °C; ¹H NMR (400 MHz, acetone-d₆): δ 3.33 (s, 6H, CH₃), 7.07 (s, 1H, Fu), 7.28 (s, 1H, =CH), 7.38 (d, J = 8.0 Hz, 2H, Ar), 7.60 (d, J = 8 Hz, 2H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 45.67, 95.22, 101.45, 124.53, 128.61, 131.48, 143.67, 147.56, 170.03 (C=O). Anal. calcd. for C₁₃H₁₂ClNO₂: C: 62.53%; H: 4.84%; N: 5.61%; Cl: 14.20%; Found: C: 62.75%; H: 4.98%; N: 5.82%; Cl: 14.06%.

• 5-Phenyl-3-((dimethylamino)methylene)furan-2(3H)-one 3b

Yellow crystals (ethanol), yield 0.29 g (85%), mp 206–207 °C; ¹H NMR (400 MHz, acetone-d₆): δ 3.32 (s, 6H, CH₃), 7.01 (s, 1H, Fu), 7.21–7.25 (m, 2H, Ar+1H, =CH), 7.34–7.38 (t, 2H, Ar), 7.61 d, (J = 8.0 Hz, 2H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 95.24, 100.49, 123.07, 127.05, 128.51, 130.53, 131.09, 144.89, 147.15, 171.09 (C=O). Anal. calcd. for C₁₃H₁₃NO₂: C: 72.54%; H: 6.09%; N: 6.51%; Found: C: 71.99%; H: 5.87%; N: 6.02%.

• 5-(4-(Bromophenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3c

Red crystals (ethanol), yield 0.32 g (92%), mp 224–225 °C; ¹H NMR (400 MHz, acetone-d₆): δ 3.32 (s, 6H, CH₃), 7.09 (s, 1H, Fu), 7.28 (s, 1H, =CH), 7.50–7.55 (m, 4H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 38.90, 45.92, 95.08, 101.62, 119.87, 124.80, 129.73, 131.59, 143.68, 147.59, 170.83 (C=O). Anal. calcd. for C₁₃H₁₂BrNO₂: C: 53.08%; H: 4.11%; N: 4.76%; Br: 27.16%; Found: C: 53.43%; H: 4.28%; N: 4.31%; Br: 27.66%.

• 5-(4-(Methylphenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3d

Yellow crystals (ethanol), yield 0.32 g (91%), mp 215–216 °C; ¹H NMR (400 MHz, acetone-d₆): δ 2.31 (s, 3H, CH₃), 3.31 (s, 6H, CH₃), 6.93 (s, 1H, Fu), 7.22 (s, 1H, =CH), 7.18 (d, J = 8 Hz, 2H, Ar), 7.69 (d, J = 8 Hz, 2H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 20.54, 38.73, 45.70, 95.39, 99.61, 123.10, 127.83, 129.15, 136.6, 145.08, 146.78, 171.16 (C=O). Anal. calcd. for C₁₄H₁₅NO₂: C: 73.34%; H: 6.59%; N: 6.11%; Found: C: 73.72%; H: 6.92%; N: 6.65%.

• 5-(3,4-(Dimethylphenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3e

Yellow crystals (ethanol), yield 0.33 g (89%), mp 207–209 °C; ¹H NMR (400 HMz, acetone-d₆): δ 2.24 (d, J = 4 Hz, 6H, CH₃), 3.30 (s, 6H, CH₃), 6.90 (s, 1H, Fu), 7.21 (s, 1H, =CH), 7.11 (d, J = 8 Hz, 1H, Ar), 7.33 (d, J = 8 Hz, 1H, Ar), 7.40 (s, 1H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 18.66, 18.90, 38.73, 45.70, 95.40, 99.31, 120.74, 124.80, 128.21, 129.70, 135.61, 136.52, 145.35, 146.56, 171.18 (C=O). Anal. calcd. for C₁₅H₁₇NO₂: C: 74.05%; H: 7.04%; N: 5.76%; Found: C: 74.45%; H: 7.42%; N: 5.82%.

• 5-(4-(Methoxyphenyl)-3-((dimethylamino)methylene)furan-2(3H)-one 3f

Brown crystals (ethanol), yield 0.35 g (88%), mp 186–187 °C; ¹H NMR (400 MHz, acetone-d₆): δ 3.30 (s, 6H, CH₃), 3.81 (s, 6H, OCH₃), 6.83 (s, 1H, Fu), 6.94 (d, J = 8 Hz, 2H, Ar), 7.19 (s, 1H, =CH), 7.55 (d, J = 8 Hz, 2H, Ar); ¹³C NMR (100 MHz, acetone-d₆): δ 38.73, 45.70, 54.68, 95.46, 98.30, 114.01, 123.32, 124.59, 159.22, 145.16, 146.33, 171.20 (C=O). Anal. calcd. for C₁₄H₁₅NO₃: C: 68.56%; H: 6.16%; N: 5.71%; Found: C: 69.01%; H: 6.13%; N: 5.99%.

4. Conclusions

We developed optimal conditions for the synthesis of aryl-substituted dimethylaminomethylenefuran-2(3H)-ones, where arylfuran-2(3H)-ones and a reactive one-carbon synthone, DMF-DMA, were used as starting components. It was found that the highest yields and shorter transformation times were achieved when using a MW50 sealed vessel reactor and a non-polar solvent—toluene.