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Article

Polyphosphoric Acid-Promoted Efficient Synthesis of Cinnamides via Aldol Condensation of Amide

by
Enhua Wang
1,†,
Lishou Yang
2,3,†,
Lanfeng He
2,3,
Qian Yang
1,
Xue Wang
1,
Yunlu Liu
1,
Manxiang Li
1,
Yang Lei
1,* and
Xiaosheng Yang
2,3,*
1
Department of Food and Medicine, Guizhou Vocational College of Agriculture, Qingzhen 551400, China
2
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
3
Natural Products Research Center of Guizhou Province, Guiyang 550014, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(19), 4632; https://doi.org/10.3390/molecules29194632 (registering DOI)
Submission received: 30 August 2024 / Revised: 19 September 2024 / Accepted: 27 September 2024 / Published: 29 September 2024
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Abstract

:
Cinnamides are common core structures that exist in a great number of pharmaceuticals and natural products. The development of efficient methods for preparing cinnamides is in great need. We report herein an efficient polyphosphoric acid (PPA)-promoted direct aldol condensation of an amide for the convenient and straightforward preparation of cinnamides. A variety of cinnamides were obtained in moderate-to-excellent yields (65–89%). This strategy features the use of equivalent amides and a short reaction time.

1. Introduction

Cinnamides have been used as building blocks for the construction of complex molecules, which commonly exist in pharmaceuticals and natural products [1,2,3,4,5,6]. Most of the cinnamides display varied bioactivities such as anti-tumor, anti-cancer, anti-depressant, and anti-convulsion effects (Figure 1) [7,8,9,10]. Very recently, Wu and co-workers reported that cinnamide derivatives exhibited neuroprotective activity and have potential for the treatment of cerebral ischemia [11,12]. Biersack and co-workers found that piperlongumine-type cinnamide derivatives showed good antiparasitic and antifungal activities [13]. Therefore, the development of efficient methods for preparing cinnamides is still a hot research topic in the field of organic chemistry. Commonly, cinnamides are synthesized from the acylation of amines with cinnamic acids [14,15,16], decarboxylative acylation of cinnamic acids [17], C-H bond functionalizations [18,19,20,21,22,23,24], and amidation of carboxylic acids [25]. However, the above-mentioned reactions suffer from limitations such as reliance on multisteps, the use of strong oxidants and special substrates, and catalyzation by transition metal or toxic metal salts.
Considering the limitations of the above approaches, the convenient preparations of cinnamides are highly desired. In 2010, the direct aldol condensation of unactivated amides catalyzed by dialkylcarbonates (DECs), as dehydrating agents, was reported (Scheme 1a) [26]. Later, Saito and co-workers reported a similar strategy for the preparation of cinnamides using 1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-hexachloride-based phosphorous (TAPC)/SO42− catalysis (Scheme 1b) [27]. Despite significant progress, the lowest acidity of the α-CH of amides results in major shortcomings such as the excessive use of dehydrating agents and amides, and the requirement of long reaction times (Scheme 1a,b). Recently, Cai and co-workers developed a visible light-promoted oxidative cross-coupling reaction of benzyl alcohols with N,N-dialkylacetamides for the construction of cinnamides; however, this strategy still needs excessive base and amides, as well as a long reaction time (Scheme 1c) [28]. Hence, the development of new synthetic strategies devoid of these disadvantages is still urgent.
The direct aldol condensation of unactivated amides is a straightforward and attractive methodology, but there is a need to develop an effective dehydrating agent to overcome the above disadvantages. PPA is commonly used as a dehydrating agent, and our group has developed several PPA-promoted condensation reactions for the synthesis of heterocycles [29,30,31]. Our previous studies indicated that PPA could activate the α-CH of the carbonyl group and efficiently promote aldol condensations. Inspired by our previous work and in continuation of our interest in PPA-promoted condensations, herein we wish to describe another direct aldol condensation of unactivated amides using PPA as an activator and dehydrating agent for the convenient and straightforward synthesis of cinnamides (Scheme 1d). This method features the use of equivalent amides and a short reaction time.

2. Results and Discussion

Initially, we set up the reaction benzaldehyde 1a and N,N-dimethylacetamide 2 as test substrates. A mixture of 1a (1 equiv.), 2 (1 equiv.), and PPA (2 equiv.) in DMF refluxed for 4 h under a nitrogen atmosphere produced the cinnamide 3a in a 46% yield (Table 1, entry 1). Screening of the amount of PPA showed that 1 equiv. was the best choice (Table 1, entries 2–4). Then, we investigated the influence of reaction temperature, and a decreased yield was observed upon decreasing the temperature to 140 °C (Table 1, entry 5 vs. 3). Subsequently, we tested the effect of the reaction time (Table 1, entries 6–8). To our delight, the reaction was found to be more effective when the reaction time increased to 6 h, which gave the desired product in a 79% yield (Table 1, entry 7). Next, we screened a serious of reaction media, such as 1,4-dioxane, THF, toluene, DCE, DMSO, and EtOH, and no improvement in the transformation was observed (Table 1, entries 9–14). Finally, the optimized reaction conditions were determined as 1a (1 equiv.), 2 (1 equiv.), and PPA (1 equiv.) in DMF refluxed for 6 h under a nitrogen atmosphere (Table 1, entry 7).
With the optimized reaction conditions in hand, we next examined the scope of aldehydes (Table 2). As shown in Table 2, the condensation proceeded well with a variety of benzaldehydes to yield desired products in moderate-to-good yields (3a–3i). Obviously, the electronic properties of the substituents had an effect on the yield. Benzaldehydes bearing electron-donating groups (OMe and Me) provided higher yields than those bearing electron-withdrawing groups, such as F, Cl, Br, CF3, and CN (3b–3g vs. 3h–3i). It was also found that this procedure was efficient for converting 2-naphthaldehyde, cyclohexanecarboxaldehyde, valeraldehyde, 2-thenaldehyde, 4-benzofurazancarboxaldehyde, and cinnamaldehyde to the corresponding cinnamides in good yields (3j–3o). Next, to demonstrate the synthetic potential of this protocol, we selected different types of aldehydes for gram-scale reactions (Scheme 2). To our delight, the gram-scale reactions also proceeded well to form the corresponding products in good yields.
Several control experiments were conducted in order to rationalize the reaction mechanism. As shown in Scheme 3a, the reaction was carried out in the presence of different dehydrating agent/acid catalysts and the desired product 3a was obtained in a 13% yield only in the case of using concentrated sulfuric acid, which demonstrated that this reaction underwent a dehydrating process. Then, the radical inhibitor 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) was employed in the reaction, yielding 3a in a high yield, suggesting that this procedure rules out the radical pathway (Scheme 3b).
Based on the mechanistic study and our previous reports [29,32], a plausible mechanism of the PPA-promoted aldol condensation of amides for the synthesis of cinnamides is depicted in Scheme 4. Firstly, amide 2 was activated through the formation of the phosphorylated adduct 4, followed by an enolization to produce intermediate 5. Then, intermediate 5 coupled with protonated benzaldehyde 1a formed intermediate 6, which was followed by a PPA-driven dehydration process to give intermediate 7. Finally, the carbocation is stabilized by removing a proton from the beta position yielding the desired product 3a.

3. Materials and Methods

3.1. General Information

All reagents, catalysts, and solvents were purchased from commercial suppliers and used without further purification unless otherwise noted. Column chromatography was carried out with silica gel (200–300 mesh). An X-4 melting point apparatus with a microscope (Dedu Precision Instrument Co., Ltd, Changzhou, China) was used for melting point determination. The IR spectra were recorded with Mattson FTIR spectrometer 5000 (Mattson, MA, USA). Absorption maxima were measured in cm−1. 1H NMR (600 MHz) and 13C NMR (150 MHz) spectra were achieved in CDCl3 on a Bruker AVANCE 600 MHz spectrometer (Bruker, Saarbrücken, Germany). High-resolution mass spectra were measured on a ThermoFisher QE Focus facility (Thermo Fisher Scientific, Waltham, MA, USA). The copies of the 1H NMR and 13C NMR spectra for all compounds see Supplementary Materials.

3.2. General Procedure for the Synthesis of Cinnamamides 3a–3o

Benzaldehyde (1 mmol), DMA (1 mmol), and PPA (1 mmol) were added to a 5 mL round-bottomed flask containing DMF (1 mL) solvent. Under the protection of nitrogen, the reaction mixture was refluxed for 6 h. The reaction liquid was quenched with water and extracted with ethyl acetate. The organic layer was dried by anhydrous Na2SO4 and evaporated under reduced pressure. The resulting crude compound was purified by silica gel column chromatography to yield the pure products 3a–3o.
  • (E)-N,N-Dimethylcinnamamide (3a). White solid; yield: 79%; m.p.: 100–104 °C. IR (KBr plate): νmax 1654 (C=O), 1648 (C=C), 1141 (C-N), 766 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.67–7.63 (dd, J = 15.4, 2.1 Hz, 1H, Ar-CH=), 7.52–7.49 (m, 2H, Ar-H), 7.36–7.32 (m, 3H, Ar-H), 6.89–6.86 (dd, J = 15.4, 2.1 Hz, 1H, CO-CH=), 3.14 (s, 3H, CH3), 3.04 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.7 (C=O), 142.3 (-CH=), 135.4 (Ar-C), 129.6 (Ar-C), 128.8 (Ar-C), 127.8 (Ar-C), 117.4 (-CH=), 37.4 (CH3), 35.9 (CH3). HRMS-ESI (m/z): calcd. for C11H13ONNa [M + Na]+: 198.0889; found: 198.0887.
  • (E)-3-(2-Fluorophenyl)-N,N-dimethylacrylamide (3b). White solid; yield: 78%; m.p.: 58–61 °C. IR (KBr plate): νmax 2941 (C-H), 1654 (C=O), 1597 (C=C), 1143 (C-N), 991 (Ar-H), 755 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.70 (dd, J = 15.8, 3.1 Hz, 1H, Ar-CH=), 7.49 (q, J = 6.3, 5.5 Hz, 1H, Ar-H), 7.31–7.26 (m, 1H, Ar-H), 7.12 (d, J = 7.3 Hz, 1H, Ar-H), 7.09–6.99 (m, 2H, Ar-H, CO-CH=), 3.14 (s, 3H, CH3), 3.05 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.6 (C=O), 161.3 (1JCF = 253.7, Ar-C), 135.3 (-CH=), 130.8 (3JCF = 9.1, Ar-C), 129.8, 124.3 (3JCF = 3.0, Ar-C), 123.3 (2JCF = 12.1, Ar-C), 120.5 (3JCF = 7.6, -CH=), 116.1 (2JCF = 21.1, Ar-C), 37.4 (CH3), 35.9 (CH3). HRMS-ESI (m/z): calcd. for C11H12ONF [M + Na]+: 216.0795; found: 216.0794.
  • (E)-3-(2-Chlorophenyl)-N,N-dimethylacrylamide (3c). White solid; yield: 80%; m.p.: 80–84 °C. IR (KBr plate): νmax 1648 (C=O), 1610 (C=C), 1143 (C-N), 759 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 15.5 Hz, 1H, Ar-CH=), 7.59–7.57 (m, 1H, Ar-H), 7.40–7.36 (m, 1H, Ar-H), 7.26–7.23 (m, 2H, Ar-H), 6.86 (d, J = 15.5 Hz, 1H, CO-CH=), 3.15 (s, 3H, CH3), 3.05 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.3 (C=O), 138.2 (-CH=), 134.6 (Ar-C), 133.7 (Ar-C), 130.3 (Ar-C), 130.1 (Ar-C), 127.7 (Ar-C), 126.9 (Ar-C), 120.6 (-CH=), 37.5 (CH3), 35.9 (CH3). HRMS-ESI (m/z): calcd. for C11H12NOClNa [M + Na]+: 232.0500; found: 232.0498.
  • (E)-3-(2,4-Dichlorophenyl)-N,N-dimethylacrylamide (3d). White solid; yield: 67%; m.p.: 138–141 °C. IR (KBr plate): νmax 2935 (C-H), 1650 (C=O), 1602 (C=C), 1141 (C-N), 768 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 15.4 Hz, 1H, Ar-CH=), 7.53 (d, J = 8.4 Hz, 1H, Ar-H), 7.42 (d, J = 2.1 Hz, 1H, Ar-H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H, Ar-H), 6.86 (d, J = 15.4 Hz, 1H, CO-CH=), 3.17 (s, 3H, CH3), 3.07 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.1 (C=O), 137.1 (-CH=), 135.4 (Ar-C), 135.2 (Ar-C), 132.4 (Ar-C), 129.9 (Ar-C), 128.4 (Ar-C), 127.4 (Ar-C), 121.0 (-CH=), 37.5 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C11H11ONCl2Na [M + Na]+: 266.0110; found: 266.0108.
  • (E)-3-(4-Bromophenyl)-N,N-dimethylacrylamide (3e). White solid; yield: 69%; m.p.: 127–130 °C. IR (KBr plate): νmax 1648 (C=O), 1595 (C=C), 1147 (C-N), 751 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 15.4 Hz, 1H, Ar-CH=), 7.49 (d, J = 8.3 Hz, 2H, Ar-H), 7.38 (d, J = 8.4 Hz, 2H, Ar-H), 6.87 (d, J = 15.4 Hz, 1H, CO-CH=), 3.16 (s, 3H, CH3), 3.06 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.4 (C=O), 141.1 (-CH=), 134.3 (Ar-C), 132.0 (Ar-C), 129.2 (Ar-C), 123.6 (Ar-C), 118.1 (-CH=), 37.4 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C11H13ONBr [M + H]+: 254.0175; found: 254.0173.
  • (E)-N,N-Dimethyl-3-(4-(trifluoromethyl)phenyl)acrylamide (3f). White solid; yield: 66%; m.p.: 110–112 °C. IR (KBr plate): νmax 2935 (C-H), 1656 (C=O), 1607 (C=C), 818 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.63–7.57 (m, 1H, Ar-CH=), 7.56–7.50 (m, 4H, Ar-H), 6.92 (dd, J = 15.5, 3.7 Hz, 1H, CO-CH=), 3.13–3.08 (m, 3H, CH3), 3.02–2.97 (m, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.0 (C=O), 140.5 (-CH=), 138.7 (Ar-C), 130.9(2JCF = 30.2, Ar-C), 127.9 (Ar-C), 125.6 (Ar-C), 123.9 (1CF = 271.8, CF3), 120.0 (-CH=), 37.3 (CH3), 35.9 (CH3). HRMS-ESI (m/z): calcd. for C12H12ONF3Na [M + Na]+: 266.0763; found: 266.0762.
  • (E)-3-(4-Cyanophenyl)-N,N-dimethylacrylamide (3g). White solid; yield: 77%; m.p.: 149–154 °C. IR (KBr plate): νmax 1650 (C=O), 1608 (C=C), 1143 (C-N), 834 (Ar-H), 824 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.63 (m, 2H, Ar-CH=, Ar-H), 7.58 (d, J = 8.1 Hz, 3H, Ar-H), 6.96 (d, J = 15.4 Hz, 1H, CO-CH=), 3.16 (d, J = 4.8 Hz, 3H, CH3), 3.05–3.03 (m, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 165.8 (C=O), 140.1 (-CH=), 139.7 (Ar-C), 132.6 (Ar-C), 128.20 (Ar-C), 121.1 (CN), 118.6 (-CH=), 112.6 (Ar-C), 37.5 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C12H12ON2Na [M + Na]+: 223.0842; found: 223.0840.
  • (E)-N,N-Dimethyl-3-(3-phenoxyphenyl)acrylamide (3h). White solid; yield: 81%; m.p.: 71–73 °C. IR (KBr plate): νmax 3024 (C-H), 2927 (C-H), 1651 (C=O), 1607 (C=C), 1164 (C-N), 754 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 15.4 Hz, 1H, Ar-CH=), 7.35 (dt, J = 14.8, 7.9 Hz, 3H, Ar-H), 7.27 (d, J = 7.8 Hz, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 7.13 (t, J = 7.4 Hz, 1H, Ar-H), 7.03 (d, J = 8.4 Hz, 2H, Ar-H), 6.99 (dd, J = 8.1, 2.5 Hz, 1H, Ar-H), 6.86 (d, J = 15.4 Hz, 1H, CO-CH=), 3.16 (s, 3H, CH3), 3.07 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.5 (C=O), 157.6 (Ar-C), 156.9 (Ar-C), 141.7 (-CH=), 137.2 (Ar-C), 130.1 (Ar-C), 129.9 (Ar-C), 123.5 (Ar-C), 123.0 (Ar-C), 119.8 (Ar-C), 118.9 (Ar-C), 118.2 (-CH=), 117.7 (Ar-C), 37.5 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C17H17O2NNa [M + Na]+: 290.1152; found: 290.1148.
  • (E)-N,N-Dimethyl-3-(p-tolyl)acrylamide (3i). White solid; yield: 85%; m.p.: 112–117 °C. IR (KBr plate): νmax 2935 (C-H), 1650 (C=O), 1602 (C=C), 1141 (C-N), 768 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 15.4 Hz, 1H, Ar-CH=), 7.42 (d, J = 8.0 Hz, 2H, Ar-H), 7.17 (d, J = 7.8 Hz, 2H, Ar-H), 6.84 (d, J = 15.4 Hz, 1H, CO-CH=), 3.15 (s, 3H, CH3), 3.05 (s, 3H, CH3), 2.35 (s, 3H, Ar-CH3). 13C NMR (150 MHz, CDCl3) δ 166.9 (C=O), 142.3 (-CH=), 139.8 (Ar-C), 132.6 (Ar-C), 129.5 (Ar-C), 127.8 (Ar-C), 116.3 (-CH=), 37.4 (CH3), 35.9 (CH3), 21.4 (CH3). HRMS-ESI (m/z): calcd. for C12H15ONNa [M + Na]+: 212.1046; found: 212.1044.
  • (E)-N,N-Dimethyl-3-(naphthalen-2-yl)acrylamide (3j). Light yellow solid; yield: 78%; m.p.: 158–161 °C. IR (KBr plate): νmax 2934 (C-H), 1648 (C=O), 1601 (C=C), 1138 (C-N), 822 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.91 (s, 1H, Ar-H), 7.82 (m, 4H, Ar-CH=, Ar-H), 7.67 (d, J = 8.6 Hz, 1H, Ar-H), 7.48 (dd, J = 6.2, 3.2 Hz, 2H, Ar-H), 6.99 (d, J = 15.4 Hz, 1H, CO-CH=), 3.19 (s, 3H, CH3), 3.08 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.6 (C=O), 142.4 (-CH=), 133.9 (Ar-C), 133.4 (Ar-C), 132.8 (Ar-C), 129.2 (Ar-C), 128.5 (Ar-C), 128.5 (Ar-C), 127.7 (Ar-C), 126.9 (Ar-C), 126.6 (Ar-C), 123.7 (Ar-C), 117.6 (-CH=), 37.5 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C15H15ONNa [M + Na]+: 248.1046; found: 248.1045.
  • (E)-3-Cyclohexyl-N,N-dimethylacrylamide (3k). Light yellow solid; yield: 89%; m.p.: 96–100 °C. IR (KBr plate): νmax 1647 (C=O), 1602 (C=C), 1140 (C-N). 1H NMR (600 MHz, CDCl3) δ 6.80 (dd, J = 15.2, 7.0 Hz, 1H, Ar-CH=), 6.17 (d, J = 15.2 Hz, 1H, CO-CH=), 3.05 (s, 3H, CH3), 2.98 (s, 3H, CH3), 2.14–2.08 (m, 1H, Cy-H), 1.76–1.71 (m, 4H, Cy-H), 1.65 (m, 1H, Cy-H), 1.26 (m, 2H, Cy-H), 1.14 (m, 3H, Cy-H). 13C NMR (150 MHz, CDCl3) δ 167.2 (C=O), 151.3 (-CH=), 117.6 (-CH=), 40.7 (Cy-C), 37.3 (CH3), 35.7 (CH3), 32.0 (Cy-C), 25.9 (Cy-C), 25.7 (Cy-C). HRMS-ESI (m/z): calcd. for C11H20ON [M + H]+: 182.1539; found: 182.1539.
  • (E)-N,N-Dimethylhept-2-enamide (3l). White oil; yield: 74%; IR (KBr plate): νmax 2938 (C-H), 1654 (C=O), 1611 (C=C), 1143 (C-N). 1H NMR (600 MHz, CDCl3) δ 6.88 (dt, J = 14.5, 7.0 Hz, 1H, Ar-CH=), 6.25 (d, J = 15.1 Hz, 1H, CO-CH=), 3.09 (s, 3H, CH3), 3.01 (s, 3H, CH3), 2.22 (q, J = 7.4 Hz, 2H, CH2), 1.46 (t, J = 7.7 Hz, 2H, CH2), 1.36 (q, J = 7.4 Hz, 2H, CH2), 0.92 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 167.0 (C=O), 146.4 (-CH=), 120.1 (-CH=), 37.4 (CH3), 35.7 (CH3), 32.2 (CH2), 30.5 (CH2), 22.3 (CH2), 13.9 (CH3). HRMS-ESI (m/z): calcd. for C9H17ONNa [M + Na]+: 178.1202; found: 178.1200.
  • (E)-N,N-Dimethyl-3-(thiophen-2-yl)acrylamide (3m). Light yellow solid; yield: 71%; m.p.: 98–101 °C. IR (KBr plate): νmax 2930 (C-H), 1643 (C=O), 1601 (C=C), 1140 (C-N), 705 (Th-H). 1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 15.1 Hz, 1H, Ar-CH=), 7.31 (d, J = 5.1 Hz, 1H, CO-CH=), 7.22 (d, J = 3.6 Hz, 1H, Th-H), 7.03 (dd, J = 5.0, 3.6 Hz, 1H, Th-H), 6.69 (d, J = 15.1 Hz, 1H, Th-H), 3.15 (s, 3H, CH3), 3.06 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.4 (C=O), 140.5 (-CH=), 135.2 (Th-C), 130.3 (Th-C), 128.0 (Th-C), 127.2 (Th-C), 116.1 (-CH=), 37.4 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C9H11ONNaS [M + Na]+: 204.0454; found: 204.0453.
  • (E)-3-(Benzo[c][1,2,5]oxadiazol-4-yl)-N,N-dimethylacrylamide (3n). Light yellow solid; yield: 65%; m.p.: 154–160 °C. IR (KBr plate): νmax 2931 (C-H), 1651 (C=O), 1612 (C=C), 1143 (C-N), 812 (Ar-H), 766 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 15.3 Hz, 1H, Ar-CH=), 7.82 (d, J = 8.6 Hz, 1H, Ar-H), 7.76 (d, J = 15.2 Hz, 1H, CO-CH=), 7.49–7.44 (m, 2H, Ar-H), 3.28 (s, 3H, CH3), 3.12 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.2 (C=O), 149.6 (Ar-C), 147.5 (-CH=), 136.5 (Ar-C), 133.7 (Ar-C), 131.7 (Ar-C), 126.2 (Ar-C), 125.3 (Ar-C), 117.0 (-CH=), 37.5 (CH3), 36.0 (CH3). HRMS-ESI (m/z): calcd. for C11H11O2N3Na [M + Na]+: 240.0743; found: 240.0741.
  • (2E, 4E)-N,N-Dimethyl-5-phenylpenta-2,4-dienamide (3o). White solid; yield: 74%; m.p.: 108–113 °C. IR (KBr plate): νmax 1643 (C=O), 1624 (C=C), 1125 (C-N), 812 (Ar-H), 758 (Ar-H). 1H NMR (600 MHz, CDCl3) δ 7.46–7.41 (m, 3H, Ar-CH=, Ar-H, -CH=), 7.33 (t, J = 7.6 Hz, 2H, Ar-H), 7.27 (d, J = 7.3 Hz, 1H, -CH=), 6.92–6.83 (m, 2H, Ar-H), 6.45 (d, J = 14.7 Hz, 1H, CO-CH=), 3.10 (s, 3H, CH3), 3.03 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ 166.8 (C=O), 142.5 (-CH=), 139.0 (-CH=), 136.4 (Ar-C), 128.8 (Ar-C), 128.7 (Ar-C), 127.0 (Ar-C), 126.9 (-CH=), 120.6 (-CH=), 37.4 (CH3), 35.9 (CH3). HRMS-ESI (m/z): calcd. for C13H16ON [M + H]+: 202.1226; found: 202.1224.

4. Conclusions

In conclusion, we have developed an efficient PPA-promoted direct aldol condensation of amides for the straightforward synthesis of cinnamides. A range of cinnamides have been prepared in moderate-to-good yields. Compared to previous approaches, the methodology was characterized by the use of equivalent amides and a short reaction time.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29194632/s1, copies of the 1H NMR and 13C NMR spectra for all compounds.

Author Contributions

E.W.: investigation, methodology; L.Y.: methodology; L.H. and Q.Y.: data curation, formal analysis; X.W. and Y.L. (Yunlu Liu): data curation; M.L.: formal analysis; Y.L. (Yang Lei) and X.Y.: funding acquisition, project administration, writing—original draft, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

The work here was supported by the Guizhou Provincial Natural Science Foundation (No. QKHJC-ZK[2024] General 643), the Project of Natural Science Research of the Guizhou Vocational College of Agriculture (No. yk230109), the Innovation Capacity Construction of Scientific Research Institutions in Guizhou Province (No. QKHFQ[2024]005) and the Project of Key Laboratory for Characteristics of Colleges and Universities of the Guizhou Provincial Department of Education (No. QJHKYZ[2020]018).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

The authors are grateful for the help provided by the staff at the Guizhou Vocational College of Agriculture and the Natural Products Research Center of Guizhou Province.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Molecules 29 04632 g001
Figure 1. Selected bioactive cinnamide derivatives.
Figure 1. Selected bioactive cinnamide derivatives.
Molecules 29 04632 g001
Molecules 29 04632 sch001
Scheme 1. Previous reported strategies for the synthesis of cinnamides and this work. (a) Previous work: DEC-promoted aldol condensation of unactivated amides for the synthesis of cinnamides. (b) Previous work: TAPC and H2SO4 catalyzed aldol condensation of unactivated amides for the synthesis of cinnamides. (c) Visible light-promoted oxidation/condensation of benzyl alcohols with amides to cinnamides. (d) This work: PPA-promoted direct aldol condensation of unactivated amides for the convenient and straightforward synthesis of cinnamides.
Scheme 1. Previous reported strategies for the synthesis of cinnamides and this work. (a) Previous work: DEC-promoted aldol condensation of unactivated amides for the synthesis of cinnamides. (b) Previous work: TAPC and H2SO4 catalyzed aldol condensation of unactivated amides for the synthesis of cinnamides. (c) Visible light-promoted oxidation/condensation of benzyl alcohols with amides to cinnamides. (d) This work: PPA-promoted direct aldol condensation of unactivated amides for the convenient and straightforward synthesis of cinnamides.
Molecules 29 04632 sch001
Molecules 29 04632 sch002
Scheme 2. Gram-scale reactions. Gram-scale reactions of benzaldehyde 1a (a), cyclohexanecarboxaldehyde 1k (b), and 2-thenaldehyde 1m (c). Reaction conditions: PPA (10 mmol) and DMF (10 mL).
Scheme 2. Gram-scale reactions. Gram-scale reactions of benzaldehyde 1a (a), cyclohexanecarboxaldehyde 1k (b), and 2-thenaldehyde 1m (c). Reaction conditions: PPA (10 mmol) and DMF (10 mL).
Molecules 29 04632 sch002
Molecules 29 04632 sch003
Scheme 3. Control experiments. (a) Effect of catalyst on the reaction. (b) Investigation of free radical mechanism. Reaction conditions: 1a (1 mmol), 2 (1 mmol), PPA (1 mmol), catalyst (1 mmol), and DMF (1 mL).
Scheme 3. Control experiments. (a) Effect of catalyst on the reaction. (b) Investigation of free radical mechanism. Reaction conditions: 1a (1 mmol), 2 (1 mmol), PPA (1 mmol), catalyst (1 mmol), and DMF (1 mL).
Molecules 29 04632 sch003
Molecules 29 04632 sch004
Scheme 4. Plausible mechanism.
Scheme 4. Plausible mechanism.
Molecules 29 04632 sch004
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 29 04632 i001
EntryPPA (Equiv.)T (°C)t (h)Solvent3a (%) b
12reflux4DMF46
21.5reflux4DMF45
31reflux4DMF50
40.5reflux4DMF22
511404DMF13
61reflux5DMF64
71reflux6DMF79
81reflux7DMF77
91reflux61,4-Dioxane6
101reflux6THF/
111reflux6Toluene15
121reflux6DCE/
131reflux6DMSO/
141reflux6EtOH/
a Reaction conditions: 1a (1 mmol), 2 (1 mmol), and solvent (1 mL). The boiling point of DMF is 153 °C. b Isolated yield.
Table 2. Evaluation of substrate scope a.
Table 2. Evaluation of substrate scope a.
Molecules 29 04632 i002
Molecules 29 04632 i003
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), PPA (1 mmol), and DMF (1 mL). Isolated yield.
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MDPI and ACS Style

Wang, E.; Yang, L.; He, L.; Yang, Q.; Wang, X.; Liu, Y.; Li, M.; Lei, Y.; Yang, X. Polyphosphoric Acid-Promoted Efficient Synthesis of Cinnamides via Aldol Condensation of Amide. Molecules 2024, 29, 4632. https://doi.org/10.3390/molecules29194632

AMA Style

Wang E, Yang L, He L, Yang Q, Wang X, Liu Y, Li M, Lei Y, Yang X. Polyphosphoric Acid-Promoted Efficient Synthesis of Cinnamides via Aldol Condensation of Amide. Molecules. 2024; 29(19):4632. https://doi.org/10.3390/molecules29194632

Chicago/Turabian Style

Wang, Enhua, Lishou Yang, Lanfeng He, Qian Yang, Xue Wang, Yunlu Liu, Manxiang Li, Yang Lei, and Xiaosheng Yang. 2024. "Polyphosphoric Acid-Promoted Efficient Synthesis of Cinnamides via Aldol Condensation of Amide" Molecules 29, no. 19: 4632. https://doi.org/10.3390/molecules29194632

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