1. Introduction
The Heck reaction has perpetuated its significance in synthetic organic chemistry for over half a century. Indeed, the introduction of this carbon-carbon bond-making cross-coupling reaction by Heck and Mizoroki has revolutionised synthetic methodology, thanks to its simplicity and effectiveness [1,2,3,4,5]. Since the first detailed mechanism was proposed by Heck and Nolley in 1972 [2], the elementary steps, reaction parameters and catalytic systems have counted among the major aspects attracting the interest of many researchers [4,6]. One crucial part of the Heck catalytic cycle, that sometimes receives little attention by synthetic chemists, is the β-hydride elimination elementary step. This process plays a key role in enantioselective versions of the reaction, for which it must proceed with suitable regioselectivity [7,8,9,10]. Control is also essential in so-called reductive Heck reactions for which, conversely, β-hydride elimination is to be avoided [11]. In relation to this context, the synthesis of 1,3-diarylpropene derivatives by the Heck reaction is especially worthy of study. Indeed, when the two aromatic groups differ, two possible regioisomers can be produced (Scheme 1).
Moreover, such compounds can be viewed as higher homologues of 1,2-diphenylethylene derivatives (stilbenes), as well as of dihydrostilbenes. In this respect, it is worth pointing out that hydroxylated stilbenes (stilbenoids) and hydroxylated dihydrostilbenes are of special biological importance. Indeed, stilbenoids are produced by various plants in response to stressors such as mechanical injury, e.g., resulting from attack by herbivores, or infection by pathogenic agents [12,13,14]. Most of these phytoalexin molecules are derived from trans-resveratrol, the presence of which in grape vines has been thought to be involved in the “French paradox” [15]. (E)-Resveratrol and other naturally occurring (E)-stilbene derivatives, such as piceatannol, oxyresveratrol or isorhapontigenin, have attracted much attention and have been the subject of extensive studies. Various interesting pharmacological properties have been disclosed, including antioxidant, anticancer, anti-inflammatory, cardioprotective, antifungal and antibacterial activities [14,15,16,17,18,19]. Interestingly, dihydrostilbenoids have been reported to exhibit a similar range of biological effects [20]. Some years ago, we studied the preparation of stilbenoid structural analogues having an amido substituent at the ortho position of one of the two aromatic parts, using the Heck reaction [21,22]. Some of these molecules were found to possess significant anticancer properties against HT-29, P388, DU-145, MCF-7 and BxPC-3 cancer cell lines, or chemopreventive action [21,22].
In our continuing efforts directed towards the discovery of novel biologically active derivatives, we decided to investigate the application of the Heck reaction to the synthesis of new compounds having a 1,3-diarylpropene skeleton, thus moving from a C6-C2-C6 to a C6-C3-C6 structure, but retaining the pharmacophores, i.e., an amido substituent on one of the phenyl rings and oxygen-based substituents on the other (Scheme 2). It is noteworthy that these new target molecules can be viewed not only as structural analogues of stilbenoids and dihydrostilbenoids, but, in fact, as hybrid compounds having characteristics of both types of molecules.
2. Results and Discussion
2.1. Synthesis of Amido-Substituted 1,3-Diarylpropene Derivatives
The synthesis of the targeted o-amido-substituted 1,3-diarylpropene products is illustrated in Scheme 2. First, the amido-substituted iodobenzene precursors 3a–j were prepared by N-acylation of 2-iodoaniline 1 with the respective acyl chlorides 2a–j. These compounds were then cross-coupled with estragole 4 or eugenol 5 using the Heck reaction, in the presence of palladium(II) acetate as a catalyst, affording the expected o-amido-substituted 1,3-diarylpropene products 6a–j–9a–j in 36–91% yields (Table 1). In each case, the formation of both possible regioisomers, 6/7 or 8/9, was observed [23,24,25].
2.2. Characterisation of the 1,3-Diarylpropene Heck Products
Compounds 6a–j–9a–j were characterised by FT-IR, 1D- and 2D-NMR spectroscopies as well as an HRMS analysis. Compounds 8b,9b were taken as an example to describe the obtained data. The FT-IR spectrum of the 8b/9b mixture exhibited characteristic absorptions at 3398 (broad, w), 3291 (broad, m), 2970–2873 (w), 1654 (s), 1509 (s) and 1371 (m) cm−1, corresponding to O-H stretching, N-H stretching, Csp3-H stretching, saturated amide C=O stretching, C=C aromatic stretching and CH3 bending, respectively. An out-of-plane C-H bending vibration at 753 cm−1 (s) indicated the presence of ortho-substituted aromatic rings in compound 8b/9b. On the other hand, a CH2 bending vibration was observed at 1446 cm−1 (m), indicating the presence of a methylene group (CH2). The para-substituted aromatic ring displayed out-of-plane C-H bending vibration bands at 812 (w) and 848 (m) cm−1.
Typically, the comprehensive description of all the 1H and 13C NMR signals of mixtures of isomers such as 8b/9b was not straightforward. However, it could be achieved by first carefully assigning the signals of the few Heck products for which we had managed to obtain samples of pure isomers, including 9b. This was done on the basis of 1D and 2D NMR experiments: COSY, DEPT135, HSQC and HMBC, as well as by comparison with reported NMR data of simpler compounds sharing structural subunits with our molecules, in particular 1-[(E)-cinnamyl]-4-methoxybenzene [23], 1-methoxy-4-[(E)-3-phenylprop-1-enyl]benzene [24], 4-[(E)-cinnamyl]-2-methoxyphenol [25], N-[2-[(E)-hex-1-enyl]phenyl]acetamide [26], N-(2-allylphenyl)acetamide [27] and N-[2-[(E)-cinnamyl]phenyl]prop-2-enamide [28]. Once this operation was completed, the corresponding descriptions were used as reference data for the remaining analyses.
The 1H NMR spectrum of the 8b/9b mixture exhibited important characteristic signals within the range δH 1.20–7.95 ppm. A downfield broad singlet for the amide proton (NH) of the major isomer 9b was observed at δH 7.35 ppm. The seven aromatic protons were distributed in two regions: 7.06−7.95 ppm and 6.72−6.85 ppm. The first area was assigned to the protons attached to the nitrogen-substituted aromatic ring. The doublet of the proton at the ortho position relative to the nitrogen atom was characteristic, with a particularly high chemical shift value: δH 7.95 ppm (J 8.0 Hz) for 9b and δH 7.84 ppm (J 7.6 Hz) for 8b. The somewhat lower value for the latter was a general observation in all the 6/7 and 8/9 series. The aromatic signals lying in the higher field region were assigned to the methoxyphenol part. They appeared as two sets of overlapping signals: a singlet, accounting for the proton located ortho to the methoxyl substituent; and an AB system for the other two protons, with a JAB coupling constant of 9.0 Hz. These signals were observed at a markedly lower field in the case of 9b (δH 6.81−6.87 ppm) than in the case of 8b (δH 6.72−6.74 ppm), which was a general trend for all 8/9 mixtures.
For each isomer and as expected, the propene unit bridging the two aromatic rings appeared as a doublet (one proton, J 16.0 Hz) for the vinylic CH directly attached to one of the aromatic rings (δH 6.38 ppm for 9b and 6.42 ppm for 8b), a doublet of triplets (one proton, J 16.0 and 6.0 Hz) for the central vinylic CH (δH 6.16 ppm for 9b and 6.27 ppm for 8b) and a doublet (two protons, J 6.0 Hz) for the allylic protons, in the aliphatic region (δH 3.53 ppm for 9b and 3.50 ppm for 8b). The high 3J coupling constant of 16.0 Hz confirmed the E configuration of the CH=CH double bond. The hydroxyl (OH) and methoxyl (OCH3) protons appeared as two singlets at δH 5.73 and 3.87 ppm, respectively, in the case of 9b. The OH proton of 8b came out at a somewhat higher field (δH 5.61 ppm), which was again a general trend in the 8/9 series.
The isopropyl group of 9b was characterised by an upfield doublet at δH 1.21 ppm (J 7.0 Hz), accounting for the magnetically equivalent six protons of the methyl groups. A septet (J 7.0 Hz) at δH 2.47 ppm was assigned to the neighbouring CH. It is worth mentioning that in the 1H NMR spectrum of the 8b/9b mixture, as well as in several other cases, traces of other products could be detected. Their isolation and characterisation were not attempted, but by analogy with related results reported in the literature [24,25,26], these were likely to be minor by-products of the Heck reaction, namely Z isomers of 8b and 9b and/or the vinylidene product resulting from alternative regioselectivity of the alkene 1,2-insertion step.
The 13C NMR spectrum of 8b/9b exhibited important characteristic signals within the range δc 19.6–175.1 ppm. A total of two sets of 19 carbon signals were observed, with different intensities, with the highest peaks accounting for the major isomer 9b. The presence of the carbonyl carbon was evidenced by a downfield signal at δc 175.1 ppm. The signals of the twelve aromatic ring carbon nuclei of 8b/9b were observed in the range δc 107.9−146.7 ppm. The peak of the CH located at the ortho position relative to the methoxyl substituent was especially characteristic, with a comparatively low chemical shift value due to the +M electron-donating effect of the substituents of this ring (δc 107.9 ppm for 9b and 111.2 ppm for 8b). The signals of the propene subunit also exhibited marked differences depending on the isomers. The CH2 group was clearly identifiable, with a chemical shift around 39 ppm for all compounds 8a–j (δc 39.2 ppm for 8b) and a value around 36 ppm for 9a–j (δc 36.1 ppm for 9b). The chemical shifts of the vinylic carbon atoms were also good markers. For instance, the central vinylic CH appeared at around 134 ppm in the 8 series (δc 134.2 ppm for 8b) and at around 125 ppm in the 9 series (δc 125.1 ppm for 9b). The methoxyl substituent (OMe) gave a signal at δc 55.9 ppm for 9b and 56.0 ppm for 8b; the isopropyl group was identified by two peaks at δc 36.7 (CH) and 19.6 ppm (Me) for both isomers.
2.3. Mechanistic Interpretation of the Results of the Heck Cross-Coupling Reactions
An examination of the literature reveals several examples of related Heck reactions giving mixtures of isomers [29,30,31,32,33,34,35,36]. In several cases, the ratios of isomers were not given and generally, the origin of the selectivities observed was not discussed. In a few instances, the observation of two main products having the same atom connections was interpreted as the formation of E and Z isomers [31,33], whereas those compounds are perhaps more likely to be regioisomers, as in the present work.
The mechanism of the Heck reaction and the exact nature of the intermediate palladium complexes involved have been extensively studied and discussed [3,4,5,6]. A simplified view is displayed in Scheme 3. A pre-activation step generated palladium(0), which then underwent the oxidative addition of the aryl iodide substrate 3. This produced the intermediate complex 10, where the palladium atom was attached to the ortho amido-substituted aryl group. Coordination of the allylbenzene reactant 4 or 5, followed by syn 1,2-insertion of the C=C bond, gave rise to the alkylpalladium species 11. The next step was a syn β-hydride elimination which, after de-coordination, delivered the product: 6 or 7 from 4 or 8 or 9 from 5, along with a palladium(II) hydride species. Finally, the palladium(0) catalyst was regenerated in a reductive elimination process.
The crucial elementary step with respect to the stereo- and regioselectivity of the formation of the products was the syn β-hydride elimination event taking place from intermediate 11. Indeed, the outcome was fully determined by which of the four neighbouring hydrogen atoms that are located at the β position relative to the metal centre participates in this process. In our reactions, little regioselectivity was observed when 1-allyl-4-methoxybenzene (estragole) 4 was employed, whereas with 1-allyl-3-methoxy-4-hydroxybenzene (eugenol) 5, selectivity in favour of product 9 was substantial, ranging from 62:38 to 81:19. In all cases, the (E) isomers were produced with high selectivity. The latter stereoselectivity is commonly observed in Heck reactions and it is generally considered that this is the result of kinetic control governed by the Curtin–Hammett principle [3,4,5].
Similarly, it appears that in the present examples, the observed regioselectivities cannot be explained by thermodynamic control. Products 7 and 9 were expected to be stabilised by conjugation of the C=C alkene fragment with the oxygen-substituted aromatic group, whereas in 6 and in 8, the presence of the ortho amido substituent forced the conformation of the neighbouring alkene out of the plane of the aromatic ring, thereby compromising a similar stabilising conjugation effect. Semi-empirical PM7 calculations, performed with R1 = Me or iPr, support this analysis: 7a, 7b, 9a and 9b were estimated to be more stable than their respective regioisomers 6a, 6b, 8a and 8b by 0.87 to 1.83 kcal.mol−1. Using estragole 4, thermodynamic control would thus result in significant 6/7 selectivity in favour of 7, in contrast to what was experimentally observed. More importantly, the energy difference between 8a and 9a was found to be lower than between 6a and 7a: 0.87 and 1.39 kcal.mol−1, respectively. The same situation was calculated in the case of 8b/9b vs. 6b/7b, with respective energy differences of 1.37 and 1.83 kcal.mol−1. Pure thermodynamic control would thus lead to lower selectivities with eugenol 5 than with estragole 4, which is the opposite of what is actually observed. Therefore, regioselectivity is most plausibly under kinetic control. In the reaction of intermediate 11, four possible transition states can be drawn, among which two, 12 and 13, account for the formation of the observed major (E) isomers (Scheme 4).
The higher selectivity observed using eugenol 5 indicates that the transition state 13 became comparatively more energetically accessible than 12 when the oxygen-substituted aromatic ring (displayed in blue) became more electron-rich. This was consistent with a partial positive charge being developed at the carbon atom of the C−H bond that was being broken in the process. This positive charge was best accommodated by the most electron-rich adjacent aromatic ring. This provides new support for a similar explanation that had been proposed by the group of Sigman to explain the regioselectivities of Heck cross-coupling reactions of allylbenzene with aryldiazonium salts having various electronic properties [34].
2.4. Cytotoxicity Activity
The MTT assay was used to evaluate the toxicity of N-(2-cinnamylphenyl)amides on the viability of two types of breast cancer cell lines, i.e., MCF-7 (with a receptor) and MDA-MB-231 (without a receptor). In this study, a normal breast cell line (MCF-10A) was used. MCF-7 is an ER-positive breast cancer cell, whereas MDA-MB-231 is an ER-negative breast cancer cell. These cancer cells have receptor sites that bind to oestrogen, promoting their growth and spread. Tamoxifen is a first-line anti-oestrogen therapy that is used to prevent the production or action of oestrogen.
For the cytotoxicity assays, only pure isomers were submitted for evaluations. The cell lines were treated with different concentrations of the synthesized compounds, i.e., between 10 and 100 µM and incubated for 24−72 h. Table 2 displays the IC50 values, as well as the SI indexes. At 72 h, compound 6i exhibited weak cytotoxic activity against both MCF7 and MDA-MB-231 cells, with IC50 values of 91.78 µM and 73.79 µM, respectively. In addition, compounds 6d, 7d and 7e exhibited weak activity towards both MCF-7 and MCF-10A at 72 h. The IC50 values recorded were 65.83 µM, 47.92 µM, 88.46 µM and 92.89 µM, 71.19 µM and 69.18 µM, respectively. They were, however, inactive against MDA-MB-231 cells. All other compounds (i.e., isolated pure isomers) tested were inactive for cytotoxicity against all cell lines.
Tamoxifen, on the other hand, demonstrated strong activity against MCF-7, MDA-MB-231 and MCF-10A, with IC50 values at 72 h of 15.78 µM, 14.53 µM and 4.07 µM, respectively. The SI value was obtained by dividing the IC50 value for normal cell lines by the IC50 for cancerous cell lines. All compounds with SI values less than 2 were considered to have general toxicity, suggesting that they can cause cytotoxicity in normal cells as well [37].
3. Materials and Methods
3.1. General
All spectral data were procured using the following instruments: Fourier-transform Infrared (FTIR) spectra were obtained using a PerkinElmer 2000 FTIR Spectrum spectrometer (PerkinElmer, Waltham, MA, USA). Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AVN 500 MHz spectrometer (Bruker Bioscience, Billerica, MA, USA). Data were analysed with the Top Spin 3.6.1 software package (Bruker Bioscience, Billerica, MA, USA). Chemical shifts were internally calibrated using the residual CHCl3 solvent peak in CDCl3 (1H, δ 7.26), the CDCl3 solvent signal (13C, δ 77.0) or the tetramethylsilane (TMS) signal (1H or 13C, δ 0.00 ppm). Tetrahydrofuran (THF, QRëC, Grade AR) was freshly distilled from sodium benzophenone ketyl. Dimethylformamide (DMF, QRëC, Grade AR) was dried over 4 Å molecular sieves prior to use. All other commercially available chemicals and materials were used without further purification. Column chromatography was performed using Merck silica gel (0.040–0.063 mm) (Merck & Co., Kenilworth, NJ, USA). Thin Layer Chromatography (TLC) was completed with silica gel-coated aluminium sheets (silica gel 60 F254).
The procedure of intermediates and final compounds synthesis and their NMR; ATR-IR and HRMS spectra of the compounds are presented in Supplementary Materials.
3.2. Synthesis Procedures
3.2.1. General Procedure for the Preparation of the Ortho-Amido-Substituted Iodobenzene Precursors
A solution of 2-iodoaniline 1 (1.00 equiv.) and Et3N (1.00 equiv.) in dry THF (1.6–2.0 mL per mmol of 1) was cooled to 0–5 °C. The requisite acyl chloride 2 (1.00 equiv.) was then added dropwise, with stirring. The cold bath was removed, and the mixture was stirred vigorously overnight at room temperature. The white precipitate of Et3N.HCl was filtered off and rinsed with THF (3 × 5 mL). All the organic fractions were combined and concentrated under reduced pressure to afford the crude amide product 3, which was then purified by recrystallisation from n-hexane/chloroform. Full details and characterisation data for compounds 3a–3j are attached in the Supporting Information.
3.2.2. General Procedure for Preparing the Heck Cross-Coupling Reaction Products
In a dry three-necked flask equipped with a thermometer and a condenser, a solution of N-(2-iodophenyl) amide 3 (1.00 equiv.) in dry DMF (4.0 mL per mmol of substrate 3) was heated up to 120 °C and stirred for 20 min under nitrogen. Palladium(II) acetate (1.00% equiv.), triethylamine (3.50–5.00 equiv.) and the requisite allylbenzene derivative 4 or 5 (1.60 equiv.) were then added successively. The reaction mixture was stirred at 120 °C until the TLC analysis indicated complete consumption of 3 (3–6 h). After cooling, the saturated NH4Cl aqueous solution (6.0 mL per mmol of starting 3) was added and the mixture was extracted with EtOAc (three times, with portions of 2.0 mL per mmol of starting 3). The combined organic fractions were washed with H2O (6.0 mL per mmol of starting 3), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The ratio of product isomers was determined by 1H NMR spectroscopy of the crude product. Purification by gradient elution column chromatography (n-hexane/ethyl acetate, 95:5 to 50:50) then yielded the desired Heck reaction products. Some regioisomers could not be separated and reported as a mixture. Full details for compounds 6a–9j are attached in the Supporting Information.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)acetamide 6a. IR (neat) ν: 3286 (m, NH), 3004 (w), 2833 (w), 1653 (s, C=O), 1510 (s), 1453 (m), 1371 (m), 1273 (m), 1242 (s), 1179 (m), 1035 (m, C−O), 821 (m), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.76 (d, J = 8.0 Hz, H-2, 1H), 7.41 (br s, NH, 1H), 7.38 (d, J = 8.0 Hz, H-5, 1H), 7.22 (dd, J = 8.0, 7.5 Hz, H-3, 1H), 7.16 (br d, J = 8.5 Hz, H-11, 2H), 7.11 (dd, J = 8.0, 7.5 Hz, H-4, 1H), 6.87 (br d, J = 8.5 Hz, H-12, 2H), 6.45 (d, J = 15.5 Hz, H-7, 1H), 6.25 (dt, J = 15.5, 7.0 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.51 (d, J = 7.0 Hz, H-9, 2H), 2.14 (s, H-16, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 168.4 (C-15), 158.1 (C-13), 134.1 (C-1), 133.9 (C-8), 131.7 (C-10), 130.2 (C-6), 129.5 (C-11), 127.8 (C-3), 126.9 (C-5), 125.6 (C-7), 125.3 (C-4), 123.8 (C-2), 114.00 (C-12), 55.2 (C-14), 38.6 (C-9), 24.2 (C-16). HRMS (+ESI) [M + H]+: 282.1475, C18H20NO2 requires 282.1494.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)isobutyramide 6b. IR (neat) ν: 3268 (w, NH), 3032 (w), 2969 (w), 1651 (m, C=O), 1511 (s), 1452 (m), 1382 (w), 1287 (w), 1178 (w), 1033 (m, C−O), 834 (w), 746 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.86 (d, J = 8.0 Hz, H-2, 1H), 7.38 (br s, NH, 1H), 7.35 (d, J = 8.0 Hz, H-5, 1H), 7.22 (td, J = 8.0, 1.5 Hz, H-3, 1H), 7.15 (d, J = 8.5 Hz, H-11, 2H), 7.08–7.13 (m, H-4, 1H), 6.87 (d, J = 8.5 Hz, H-12, 2H), 6.40 (d, J = 15.0 Hz, H-7, 1H), 6.26 (dt, J = 15.0, 6.6 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.51 (d, J = 6.6 Hz, H-9, 2H), 2.47 (sept, J = 6.8 Hz, H-16, 1H), 1.21 (d, J = 6.8 Hz, H-17, 6H); 13C NMR (CDCl3, 125.8 MHz) δ: 175.0 (C-15), 158.2 (C-13), 134.5 (C-8), 134.2 (C-1), 131.5 (C-10), 129.8 (C-6), 129.6 (C-11), 127.8 (C-3), 127.1 (C-5), 125.5 (C-7), 124.9 (C-4), 123.2 (C-2), 114.0 (C-12), 55.3 (C-14), 38.6 (C-9), 36.6 (C-16), 19.6 (C-17). HRMS (+ESI) [M + H]+: 310.1823, C20H24NO2 requires 310.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)butyramide 6c. IR (neat) ν: 3290 (w, NH), 3005 (w), 2959 (w), 1648 (s, C=O), 1511 (s), 1453 (m), 1381 (w), 1291 (m), 1175 (m), 1159, 1037 (m, C−O), 829 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.84 (d, J = 7.6 Hz, H-2, 1H), 7.36 (d, J = 7.6 Hz, H-5, 1H), 7.34 (br s, NH, 1H), 7.16 (d, J = 8.2 Hz, H-11, 2H), 7.10–7.12 (m, H-3, H-4, 2H), 6.87 (d, J = 8.2 Hz, H-12, 2H), 6.41 (d, J = 15.3 Hz, H-7, 1H), 6.25 (dt, J = 15.3, 6.5 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.52 (d, J = 6.5 Hz, H-9, 2H), 2.30 (t, J = 7.4 Hz, H-16, 2H), 1.67–1.72 (m, H-17, 2H), 0.96 (t, J = 7.4 Hz, H-18, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.2 (C-15), 158.2 (C-13), 134.4 (C-8), 134.2 (C-1), 131.6 (C-10), 129.8 (C-6), 129.6 (C-11), 127.8 (C-3), 127.1 (C-5), 125.5 (C-7), 125.1 (C-4), 123.4 (C-2), 114.0 (C-12), 55.3 (C-14), 39.5 (C-16), 38.6 (C-9), 18.7 (C-17), 13.5 (C-18). HRMS (+ESI) [M + H]+: 310.1816, C20H24NO2 requires 310.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)pentanamide 6d. IR (neat) ν: 3262 (w, NH), 3002 (w), 2959 (w), 1652 (s, C=O), 1509 (s), 1450 (m), 1380 (w), 1292 (w), 1174 (m), 1037 (m, C−O), 813 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.88 (d, J = 7.8 Hz, H-2, 1H), 7.38 (br s, NH, 1H), 7.37 (d, J = 7.8 Hz, H-5, 1H), 7.27−7.31 (m, H-3, 1H), 7.18 (d, J = 8.5 Hz, H-11, 2H), 7.10−7.16 (m, H-4, 1H), 6.89 (d, J = 8.5 Hz, H-12, 2H), 6.44 (d, J = 15.2 Hz, H-7, 1H), 6.27 (dt, J = 15.2, 6.3 Hz, H-8, 1H), 3.82 (s, H-14, 3H), 3.54 (d, J = 6.3 Hz, H-9, 2H), 2.34 (t, J = 7.5 Hz, H-16, 2H), 1.64−1.73 (m, H-17, 2H), 1.40−1.46 (m, H-18, 2H), 0.97 (t, J = 7.5 Hz, H-19, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.3 (C-15), 158.2 (C-13), 134.3 (C-8), 134.2 (C-1), 131.6 (C-10), 129.8 (C-6), 129.5 (C-11), 127.8 (C-3), 127.1 (C-5), 125.6 (C-7), 125.0 (C-4), 123.4 (C-2), 114.0 (C-12), 55.3 (C-14), 38.7 (C-9), 37.4 (C-16), 27.8 (C-17), 22.3 (C-18), 13.7 (C-19). HRMS (+ESI) [M + H]+: 324.1958, C21H26NO2 requires 324.1964.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)hexanamide 6e. IR (neat) ν: 3278 (w, NH), 2952 (w), 2929 (w), 1651 (s, C=O), 1510 (s), 1451 (m), 1378 (w), 1296 (m), 1176 (m), 1037 (m, C−O), 824 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.85 (d, J = 7.5 Hz, H-2, 1H), 7.36 (br s, NH, 1H), 7.35 (d, J = 7.5 Hz, H-5, 1H), 7.27−7.30 (m, H-3, 1H), 7.16 (d, J = 8.5 Hz, H-11, 2H), 7.09−7.13 (m, H-4, 1H), 6.87 (d, J = 8.5 Hz, H-12, 2H), 6.43 (d, J = 15.0 Hz, H-7, 1H), 6.24 (dt, J = 15.0, 6.8 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.52 (d, J = 6.8 Hz, H-9, 2H), 2.29 (t, J = 7.2 Hz, H-16, 2H), 1.63−1.71 (m, H-17, 2H), 1.34−1.36 (m, H-18, 2H), 1.27−1.29 (m, H-19, 2H), 0.85 (t, J = 7.2 Hz, H-20, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.3 (C-15), 158.2 (C-13), 134.4 (C-8), 134.3 (C-1), 131.6 (C-10), 129.8 (C-6), 129.5 (C-11), 127.8 (C-3), 127.1 (C-5), 125.6 (C-7), 124.99 (C-4), 123.4 (C-2), 113.99 (C-12), 55.2 (C-14), 38.7 (C-9), 37.8 (C-16), 31.4 (C-18), 25.39 (C-17), 22.4 (C-19), 13.93 (C-20). HRMS (+ESI) [M + H]+: 338.2103, C22H28NO2 requires 338.2120.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)decanamide 6f. IR (neat) ν: 3297 (w, NH), 2954 (w), 2920 (m), 1648 (m, C=O), 1509 (s), 1453 (m), 1378 (w), 1293 (m), 1174 (m), 1034 (m, C−O), 827 (w), 748 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.82 (d, J = 7.7 Hz, H-2, 1H), 7.42 (br s, NH, 1H), 7.36 (d, J = 7.7 Hz, H-5, 1H), 7.21−7.25 (m, H-3, 1H), 7.16 (d, J = 8.5 Hz, H-11, 2H), 7.08−7.13 (m, H-4, 1H), 6.87 (d, J = 8.5 Hz, H-12, 2H), 6.44 (d, J = 15.5 Hz, H-7, 1H), 6.24 (dt, J = 15.5, 6.5 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.51 (d, J = 6.5 Hz, H-9, 2H), 2.27−2.33 (m, H-16, 2H), 1.62−1.70 (m, H-17, 2H), 1.15−1.28 (m, H-18, H-19, H-20, H-21, H-22, H-23, 12H), 0.89 (t, J = 6.9 Hz, H-24, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-15), 158.2 (C-13), 134.3 (C-1), 134.1 (C-8), 131.6 (C-10), 130.1 (C-6), 129.5 (C-11), 127.8 (C-3), 127.0 (C-5), 125.6 (C-7), 125.0 (C-4), 123.5 (C-2), 113.97 (C-12), 55.2 (C-14), 38.6 (C-9), 37.8 (C-16), 31.81 (C-22), 29.4 (C-21), 29.3 (C-20), 29.2 (C-18, C-19), 25.75 (C-17), 22.6 (C-23), 14.0 (C-24). HRMS (+ESI) [M + H]+: 394.2741, C26H36NO2 requires 394.2746.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)cyclohexanecarboxamide 6g. IR (neat) ν: 3260 (w, NH), 3034 (w), 2931 (w), 1652 (s, C=O), 1511 (s), 1450 (m), 1384 (w), 1300 (w), 1175 (w), 1039 (m, C−O), 824 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.88 (d, J = 7.8 Hz, H-2, 1H), 7.38 (br s, NH, 1H), 7.34 (d, J = 7.8 Hz, H-5, 1H), 7.23 (t, J = 7.8 Hz, H-3, 1H), 7.16 (d, J = 8.6 Hz, H-11, 2H), 7.11 (t, J = 7.8 Hz, H-4, 1H), 6.88 (d, J = 8.6 Hz, H-12, 2H), 6.43 (d, J = 15.7 Hz, H-7, 1H), 6.27 (dt, J = 15.7, 5.8 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.53 (d, J = 5.8 Hz, H-9, 2H), 2.18 (td, J = 11.7, 2.7 Hz, H-16, 1H), 1.92 (d, J = 12.6 Hz, H-17α, 2H), 1.75−1.83 (m, H-17β, 2H), 1.65–1.72 (m, H-19β, 1H), 1.40−1.49 (m, H-18α, 2H), 1.15−1.34 (m, H-18β, H-19α, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 174.1 (C-15), 158.2 (C-13), 134.5 (C-8), 134.3 (C-1), 131.5 (C-10), 130.1 (C-6), 129.7 (C-11), 127.8 (C-3), 127.1 (C-5), 125.6 (C-7), 124.8 (C-4), 123.1 (C-2), 114.0 (C-12), 55.2 (C-14), 46.4 (C-16), 38.6 (C-9), 29.7 (C-17), 25.7 (C-18, C-19). HRMS (+ESI) [M + H]+: 350.2123, C23H28NO2 requires 350.2120.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)benzamide 6h. IR (neat) ν: 3259 (w, NH), 3030 (w), 2834 (w), 1647 (s, C=O), 1512 (s), 1483 (s), 1440 (w), 1300 (m), 1176 (m), 1037 (m, C−O), 815 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.98 (d, J = 7.9 Hz, H-2, 1H), 7.75 (br s, NH, 1H), 7.70 (d, J = 7.4 Hz, H-17, 2H), 7.49 (t, J = 7.4 Hz, H-19, 1H), 7.41 (d, J = 7.9 Hz, H-5, 1H), 7.29 (t, J = 7.4 Hz, H-18, 2H), 7.26–7.33 (m, H-3, 1H), 7.08 (d, J = 8.7 Hz, H-11, 2H), 7.06–7.09 (m, H-4, 1H), 6.78 (d, J = 8.7 Hz, H-12, 2H), 6.39 (d, J = 15.7 Hz, H-7, 1H), 6.26 (dt, J = 15.7, 6.0 Hz, H-8, 1H), 3.72 (s, H-14, 3H), 3.45 (d, J = 6.0 Hz, H-9, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 165.4 (C-15), 158.1 (C-13), 134.9 (C-8, C-16), 134.3 (C-1), 131.8 (C-19), 131.4 (C-10), 130.02 (C-6), 129.7 (C-11), 128.8 (C-18), 127.9 (C-3), 127.3 (C-5), 127.1 (C-17), 125.6 (C-7), 125.1 (C-4), 123.1 (C-2), 114.0 (C-12), 55.3 (C-14), 38.6 (C-9). HRMS (+ESI) [M + H]+: 344.1674, C23H22NO2 requires 344.1651.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)-2-methylbenzamide 6i. IR (neat) ν: 3275 (w, NH), 3027 (w), 2997 (w), 1646 (s, C=O), 1514 (s), 1444 (m), 1306 (m), 1271 (m), 1249, 1177 (m), 1037 (m, C−O), 827 (w), 748 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.02 (d, J = 7.5 Hz, H-2, 1H), 7.76 (br s, NH, 1H), 7.43−7.35 (m, H-5, H-19, H-21, 3H), 7.31−7.26 (m, H-3, H-18, 2H), 7.18−7.13 (m, H-4, H-20, 2H), 7.11 (d, J = 8.5 Hz, H-11, 2H), 6.82 (d, J = 8.5 Hz, H-12, 2H), 6.44 (br d, J = 15.5 Hz, H-7, 1H), 6.29 (dt, J = 15.5, 6.5 Hz, H-8, 1H), 3.79 (s, H-14, 3H), 3.50 (br d, J = 6.5 Hz, H-9, 2H), 2.51 (s, H-22, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 168.0 (C-15), 158.1 (C-13), 136.54 (C-16), 136.3 (C-17), 134.6 (C-8), 134.2 (C-1), 131.36 (C-10), 131.28 (C-19), 130.3 (C-6), 130.20 (C-18), 129.6 (C-11), 127.9 (C-3), 127.2 (C-5), 126.57 (C-21), 125.9 (C-20), 125.5, 125.4 (C-4, C-7), 123.3 (C-2), 114.0 (C12), 55.2 (C-14), 38.5 (C-9), 19.9 (C-22). HRMS (+ESI) [M + H]+: 358.1801, C24H24NO2 requires 358.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)prop-1-en-1-yl)phenyl)furan-2-carboxamide 6j. IR (neat) ν: 3355 (w, NH), 3126 (w), 2934 (w), 1669 (m, C=O), 1510 (s), 1450 (m), 1301 (m), 1164 (m), 1010 (m, C−O), 835 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.44 (br s, NH, 1H), 8.10 (d, J = 8.2 Hz, H-19, 1H), 7.26–7.31 (m, H-2, H-3, H-5, 3H), 7.18 (d, J = 7.5 Hz, H-11, 2H), 7.12–7.15 (m, H-4, H-17, 2H), 6.86 (d, J = 7.5 Hz, H-12, 2H), 6.58 (d, J = 15.8 Hz, H-7, 1H), 6.54–6.57 (m, H-18, 1H), 6.31 (dt, J = 15.8, 6.2 Hz, H-8, 1H), 3.80 (s, H-14, 3H), 3.55 (d, J = 6.2 Hz, H-7, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 158.1 (C-13), 156.1 (C-15), 148.0 (C-16), 144.2 (C-19), 134.8 (C-8), 133.7 (C-1), 131.5 (C-10), 129.7 (C-11), 129.48 (C-6), 127.9 (C-3), 125.5 (C-5), 125.1 (C-7), 125.0 (C-4), 122.6 (C-2), 115.12 (C-17), 114.0 (C-12), 112.5 (C-18), 55.2 (C-14), 38.7 (C-9). HRMS (+ESI) [M + H]+: 334.1445, C21H20NO3 requires 334.1443.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)acetamide 7a. IR (neat) ν: 3286 (m, NH), 3004 (w), 2833 (w), 1653 (s, C=O), 1510 (s), 1453 (m), 1371 (m), 1273 (m), 1242 (s), 1179 (m), 1035 (m, C−O), 821 (m), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.82 (d, J = 8.0 Hz, H-2′, 1H), 7.28 (br d, J = 8.5 Hz, H-11′, 2H), 7.27 (dd, J = 8.0, 7.5 Hz, H-3′, 1H), 7.26–7.29 (m, NH, 1H), 7.23 (d, J = 8.0 Hz, H-5′, 1H), 7.13 (dd, J = 8.0, 7.5 Hz, H-4′, 1H), 6.84 (br d, J = 8.5 Hz, H-12′, 2H), 6.40 (d, J = 16.0 Hz, H-9′, 1H), 6.17 (dt, J = 16.0, 6.5 Hz, H-8′, 1H), 3.80 (s, H-14′, 3H), 3.51 (d, J = 6.5 Hz, H-7′, 2H), 2.11 (s, H-16′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 168.3 (C-15′), 159.2 (C-13′), 136.0 (C-1′), 131.1 (C-9′), 130.6 (C-6′), 130.1 (C-5′), 129.4 (C-10′), 127.4 (C-3′), 127.3 (C-11′), 125.4 (C-8′), 125.3 (C-4′), 123.9 (C-2′), 113.96 (C-12′), 55.2 (C-14′), 36.0 (C-7′), 24.3 (C-16′). HRMS (+ESI) [M + H]+: 282.1475, C18H20NO2 requires 282.1494.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)isobutyramide 7b. IR (neat) ν: 3268 (w, NH), 3032 (w), 2969 (w), 1651 (m, C=O), 1511 (s), 1452 (m), 1382 (w), 1287 (w), 1178 (w), 1033 (m, C−O), 834 (w), 746 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.94 (d, J = 7.5 Hz, H-2′, 1H), 7.38 (br s, NH, 1H), 7.24–7.27 (m, H-3′, H-11′, 3H), 7.23 (d, J = 7.5 Hz, H-5′, 1H), 7.08–7.13 (m, H-4′, 1H), 6.84 (d, J = 8.7 Hz, H-12′, 2H), 6.38 (d, J = 15.8 Hz, H-9′, 1H), 6.18 (dt, J = 15.8, 6.5 Hz, H-8′, 1H), 3.80 (s, H-14′, 3H), 3.52 (d, J = 6.5 Hz, H-7′, 2H), 2.47 (sept, J = 6.8 Hz, H-16′, 1H), 1.20 (d, J = 6.8 Hz, H-17′, 6H); 13C NMR (CDCl3, 125.8 MHz) δ: 175.1 (C-15′), 159.2 (C-13′), 135.6 (C-1′), 131.2 (C-9′), 130.2 (C-5′), 130.1 (C-6′), 129.4 (C-10′), 127.5 (C-3′), 127.3 (C-11′), 125.3 (C-8′), 125.0 (C-4′), 123.3 (C-2′), 114.0 (C-12′), 55.3 (C-14′), 36.5 (C-16′), 36.1 (C-7′), 19.6 (C-17′). HRMS (+ESI) [M + H]+: 310.1823, C20H24NO2 requires 310.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)butyramide 7c. IR (neat) ν: 3290 (w, NH), 3005 (w), 2959 (w), 1648 (s, C=O), 1511 (s), 1453 (m), 1381 (w), 1291 (m), 1175 (m), 1159, 1037 (m, C−O), 829 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.91 (d, J = 8.0 Hz, H-2′, 1H), 7.34 (br s, NH, 1H), 7.28 (br dd, J = 8.0, 7.5 Hz, H-3′, 1H), 7.27 (br d, J = 8.5 Hz H-11′, 2H), 7.23 (d, J = 7.5 Hz, H-5′, 1H), 7.12 (t, J = 7.5 Hz, H-4′, 1H), 6.85 (br d, J = 8.5 Hz H-12′, 2H), 6.41 (br d, J = 16.0 Hz, H-9′, 1H), 6.18 (dt, J = 16.0, 6.0 Hz, H-8′, 1H), 3.80 (s, H-14′, 3H), 3.52 (br d, J = 6.0 Hz, H-7′, 2H), 2.28 (t, J = 7.5 Hz, H-16′, 2H), 1.70 (sext, J = 7.5 Hz, H-17′, 2H), 0.95 (t, J = 7.5 Hz, H-18′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.2 (C-15′), 159.2 (C-13′), 136.2 (C-1′), 131.2 (C-9′), 130.2 (C-5′), 130.0 (C-6′), 129.4 (C-10′), 127.5 (C-3′), 127.3 (C-11′), 125.3 (C-8′), 125.0 (C-4′), 123.5 (C-2′), 114.0 (C-12′), 55.3 (C-14′), 39.7 (C-16′), 36.2 (C-7′), 19.2 (C-17′), 13.7 (C-18′). HRMS (+ESI) [M + H]+: 310.1816, C20H24NO2 requires 310.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)pentanamide 7d. IR (neat) ν: 3262 (w, NH), 3002 (w), 2959 (w), 1652 (s, C=O), 1509 (s), 1450 (m), 1380 (w), 1292 (w), 1174 (m), 1037 (m, C−O), 813 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.94 (d, J = 7.7 Hz, H-2′, 1H), 7.38 (br s, NH, 1H), 7.30 (d, J = 8.8 Hz, H-11′, 2H), 7.27–7.31 (m, H-3′, 1H), 7.25 (d, J = 7.7 Hz, H-5′, 1H), 7.10−7.16 (m, H-4′, 1H), 6.87 (d, J = 8.8 Hz, H-12′, 2H), 6.42 (d, J = 15.8 Hz, H-9′, 1H), 6.20 (dt, J = 15.8, 6.0 Hz, H-8′, 1H), 3.82 (s, H-14′, 3H), 3.54 (d, J = 6.0 Hz, H-7′, 2H), 2.32 (t, J = 7.5 Hz, H-16′, 2H), 1.64−1.73 (m, H-17′, 2H), 1.34−1.39 (m, H-18′, 2H), 0.90 (t, J = 7.5 Hz, H-19′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.3 (C-15′), 159.2 (C-13′), 136.3 (C-1′), 131.2 (C-9′), 130.2 (C-5′), 129.9 (C-6′), 129.4 (C-10′), 127.5 (C-3′), 127.3 (C-11′), 125.3 (C-8′), 125.0 (C-4′), 123.3 (C-2′), 114.0 (C-12′), 55.3 (C-14′), 37.6 (C-16′), 36.2 (C-7′), 27.8 (C-17′), 22.4 (C-18′), 13.8 (C-19′). HRMS (+ESI) [M + H]+: 324.1958, C21H26NO2 requires 324.1964.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)hexanamide 7e. IR (neat) ν: 3278 (w, NH), 2952 (w), 2929 (w), 1651 (s, C=O), 1510 (s), 1451 (m), 1378 (w), 1296 (m), 1176 (m), 1037 (m, C−O), 824 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.92 (d, J = 7.8 Hz, H-2′, 1H), 7.36 (br s, NH, 1H), 7.27−7.30 (m, H-3′, 1H), 7.27 (d, J = 8.8 Hz, H-11′, 2H), 7.22 (d, J = 7.8 Hz, H-5′, 1H), 7.09−7.13 (m, H-4′, 1H), 6.84 (d, J = 8.5 Hz, H-12′, 2H), 6.40 (d, J = 15.5 Hz, H-9′, 1H), 6.18 (dt, J = 15.5, 6.5 Hz, H-8′, 1H), 3.80 (s, H-14′, 3H), 3.52 (d, J = 6.5 Hz, H-7′, 2H), 2.29 (t, J = 7.2 Hz, H-16′, 2H), 1.63−1.71 (m, H-17′, 2H), 1.34−1.36 (m, H-18′, 2H), 1.27−1.29 (m, H-19′, 2H), 0.85 (t, J = 7.2 Hz, H-20′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.3 (C-15′), 159.2 (C-13′), 136.3 (C-1′), 131.2 (C-9′), 130.3 (C-5′), 130.2 (C-6′), 129.4 (C-10′), 127.5 (C-3′), 127.3 (C-11′), 125.3 (C-8′), 125.01 (C-4′), 123.3 (C-2′), 114.02 (C-12′), 55.3 (C-14′), 37.6 (C-16′), 36.2 (C-7′), 31.4 (C-18′), 25.43 (C-17′), 22.3 (C-19′), 13.87 (C-20′). HRMS (+ESI) [M + H]+: 338.2103, C22H28NO2 requires 338.2120.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)decanamide 7f. IR (neat) ν: 3297 (w, NH), 2954 (w), 2920 (m), 1648 (m, C=O), 1509 (s), 1453 (m), 1378 (w), 1293 (m), 1174 (m), 1034 (m, C−O), 827 (w), 748 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.90 (d, J = 7.5 Hz, H-2′, 1H), 7.42 (br s, NH, 1H), 7.27 (d, J = 8.6 Hz, H-11′, 2H), 7.23 (d, J = 7.5 Hz, H-5′, 1H), 7.21−7.25 (m, H-3′, 1H), 7.08−7.13 (m, H-4′, 1H), 6.84 (d, J = 8.5 Hz, H-12′, 2H), 6.41 (d, J = 16.0 Hz, H-9′, 1H), 6.18 (dt, J = 16.0, 6.6 Hz, H-8′, 1H), 3.80 (s, H-14′, 3H), 3.51 (d, J = 6.6 Hz, H-7′, 2H), 2.27−2.33 (m, H-16′, 2H), 1.62−1.70 (m, H-17′, 2H), 1.15−1.28 (m, H-18′, H-19′, H-20′, H-21′, H-22′, H-23′, 12H), 0.89 (t, J = 6.9 Hz, H-24′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-15′), 159.2 (C-13′), 136.2 (C-1′), 131.2 (C-9′), 130.1 (C-5′), 129.9 (C-6′), 129.4 (C-10′), 127.4 (C-3′), 127.2 (C-11′), 125.3 (C-8′), 125.0 (C-4′), 123.5 (C-2′), 113.99 (C-12′), 55.2 (C-14′), 37.5 (C-16′), 36.1 (C-7′), 31.79 (C-22′), 29.4 (C-21′), 29.3 (C-20′), 29.2 (C-18′, C-19′), 25.70 (C-17′), 22.6 (C-23′), 14.0 (C-24′). HRMS (+ESI) [M + H]+: 394.2741, C26H36NO2 requires 394.2746.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)cyclohexanecarboxamide 7g. IR (neat) ν: 3260 (w, NH), 3034 (w), 2931 (w), 1652 (s, C=O), 1511 (s), 1450 (m), 1384 (w), 1300 (w), 1175 (w), 1039 (m, C−O), 824 (w), 747 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.97 (d, J = 7.6 Hz, H-2′, 1H), 7.38 (br s, NH, 1H), 7.28 (d, J = 8.8 Hz, H-11′, 2H), 7.24−7.28 (m, H-3′, 1H), 7.21−7.24 (m, H-5′, 1H), 7.09 (t, J = 7.6 Hz, H-4′, 1H), 6.85 (d, J = 8.8 Hz, H-12′, 2H), 6.36 (d, J = 15.8 Hz, H-9′, 1H), 6.18 (dt, J = 15.8, 6.0 Hz, H-8′, 1H), 3.81 (s, H-14′, 3H), 3.52 (d, J = 6.0 Hz, H-7′, 2H), 2.18 (td, J = 11.7, 2.7 Hz, H-16′, 1H), 1.92 (d, J = 12.6 Hz, H-17α′, 2H), 1.75−1.83 (m, H-17β′, 2H), 1.65–1.72 (m, H-19β′, 1H), 1.40−1.49 (m, H-18α′, 2H), 1.15−1.34 (m, H-18β′, H-19α′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 174.1 (C-15′), 159.2 (C-13′), 136.4 (C-1′), 131.4 (C-9′), 130.2 (C-5′), 130.1 (C-6′), 129.3 (C-10′), 127.5 (C-3′), 127.3 (C-11′), 125.3 (C-8′), 124.8 (C-4′), 123.2 (C-2′), 114.1 (C-12′), 55.3 (C-14′), 46.5 (C-16′), 36.3 (C-7′), 29.8 (C-17′), 25.7 (C-18′, C-19′). HRMS (+ESI) [M + H]+: 350.2123, C23H28NO2 requires 350.2120.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)benzamide 7h. IR (neat) ν: 3259 (w, NH), 3030 (w), 2834 (w), 1647 (s, C=O), 1512 (s), 1483 (s), 1440 (w), 1300 (m), 1176 (m), 1037 (m, C−O), 815 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.16 (br s, NH, 1H), 8.04 (d, J = 7.7 Hz, H-2′, 1H), 7.70 (d, J = 7.4 Hz, H-17′, 2H), 7.43 (t, J = 7.4 Hz, H-19′, 1H), 7.29 (t, J = 7.4 Hz, H-18′, 2H), 7.26–7.33 (m, H-3′, 1H), 7.22 (d, J = 8.7 Hz, H-11′, 2H), 7.20–7.23 (m, H-5′, 1H), 7.10 (td, J = 7.7, 1.2 Hz, H-4′, 1H), 6.80 (d, J = 8.7 Hz, H-12′, 2H), 6.42 (d, J = 16.0 Hz, H-9′, 1H), 6.17 (dt, J = 16.0, 6.0 Hz, H-8′, 1H), 3.76 (s, H-14′, 3H), 3.53 (d, J = 6.0 Hz, H-7′, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 165.4 (C-15′), 159.3 (C-13′), 136.6 (C-1′), 134.8 (C-16′), 134.8 (C-8′), 131.7 (C-9′, C-19′), 130.3 (C-5′), 129.99 (C-6′), 129.1 (C-10′), 128.7 (C-18′), 127.7 (C-3′), 127.4 (C-11′), 127.0 (C-17′), 125.2 (C-8′), 125.1 (C-4′), 123.1 (C-2′), 114.1 (C12′), 55.2 (C-14′), 36.8 (C-7′). HRMS (+ESI) [M + H]+: 344.1674, C23H22NO2 requires 344.1651.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)-2-methylbenzamide 7i. IR (neat) ν: 3275 (w, NH), 3027 (w), 2997 (w), 1646 (s, C=O), 1514 (s), 1444 (m), 1306 (m), 1271 (m), 1249, 1177 (m), 1037 (m, C−O), 827 (w), 748 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.16 (d, J = 7.5 Hz, H-2′, 1H), 7.75 (br s, NH, 1H), 7.37 (br d, J = 8.0 Hz, H-21′, 1H), 7.34 (dd, J = 7.5, 7.0 Hz, H-19′, 1H), 7.33 (td, J = 7.5, 1.0 Hz, H-3′, 1H), 7.27 (dd, J = 7.5, 1.0 Hz, H-5′, 1H), 7.23 (d, J = 7.5 Hz, H-18′, 1H), 7.17 (br d, J = 8.5 Hz, H-11′, 2H), 7.16 (ddd, J = 8.0, 7.0, 1.0, H-20′, 1H), 7.08 (t, J = 7.5 Hz, H-4′, 1H), 6.82 (br d, J = 8.5 Hz, H-12′, 2H), 6.30 (dt, J = 16.0, 1.5 Hz, H-9′, 1H), 6.16 (dt, J = 16.0, 6.5 Hz, H-8′, 1H), 3.81 (s, H-14′, 3H), 3.55 (dd, J = 6.5, 1.5 Hz, H-7′, 2H), 2.48 (s, H-22′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 167.9 (C-15′), 159.2 (C-13′), 136.7 (C-1′), 136.48 (C-16′), 136.2 (C-17′), 131.5 (C-19′), 131.33 (C-9′), 130.3, 130.17 (C-5′, C18′), 129.9 (C-6′), 129.3 (C-10′), 127.6 (C-3′), 127.3 (C-11′), 126.65 (C-21′), 125.8 (C-20′), 125.2 (C-8′), 125.0 (C-4′), 122.9 (C-2′), 113.9 (C12′), 55.3 (C-14′), 36.3 (C-7′), 19.9 (C-22′). HRMS (+ESI) [M + H]+: 358.1801, C24H24NO2 requires 358.1807.
(E)-N-(2-(3-(4-Methoxyphenyl)allyl)phenyl)furan-2-carboxamide 7j. IR (neat) ν: 3355 (w, NH), 3126 (w), 2934 (w), 1669 (m, C=O), 1510 (s), 1450 (m), 1301 (m), 1164 (m), 1010 (m, C−O), 835 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.15 (br s, NH, 1H), 8.10 (d, J = 8.2 Hz, H-19′, 1H), 7.39 (d, J = 7.5 Hz, H-2′, 1H), 7.29 (d, J = 7.6 Hz, H-11′, 2H), 7.26–7.31 (m, H-3′, H-5′, 2H), 7.12–7.15 (m, H-4′, H-17′, 2H), 6.85 (d, J = 7.6 Hz, H-12′, 2H), 6.54–6.57 (m, H-18′, 1H), 6.52 (d, J = 15.5 Hz, H-9′, 1H), 6.20 (dt, J = 15.5, 6.1 Hz, H-8′, 1H), 3.80 (s, H-14, 3H), 3.61 (d, J = 6.1 Hz, H-7′, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 159.2 (C-13′), 156.0 (C-15′), 148.0 (C-16′), 144.2 (C-19′), 135.9 (C-1′), 131.9 (C-9′), 130.2 (C-5′), 130.0 (C-6′), 129.54 (C-10′), 127.6 (C-3′), 127.3 (C-11′), 125.0 (C-8′), 124.8 (C-4′), 122.9 (C-2′), 115.08 (C-17′), 114.0 (C-12′), 112.4 (C-18′), 55.2 (C-14′), 36.6 (C-7′). HRMS (+ESI) [M + H]+: 334.1445, C21H20NO3 requires 334.1443.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)acetamide 8a. IR (neat) ν: 3348 (w, OH), 3229 (w, NH), 3125 (w), 2965 (w), 1636 (m, C=O), 1517 (s), 1460 (w), 1374 (w), 1273 (s), 1236 (m), 1175 (m), 1033 (m, C−O), 868 (w), 822 (w), 797 (w), 756 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.77 (d, J = 8.0 Hz, H-2, 1H), 7.38 (d, J = 7.5 Hz, H-5, 1H), 7.29 (br s, NH, 1H), 6.64–7.17 (m, H-3, H-4, H-11, H-14, H-15, 5H), 6.45 (br d, J = 15.5 Hz, H-7, 1H), 6.26 (dt, J = 15.5, 7.0 Hz, H-8, 1H), 5.56 (s, OH, 1H), 3.89 (s, H-16, 3H), 3.51 (d, J = 7.0 Hz, H-9, 2H), 2.15 (s, H-18, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 168.3 (C-17), 146.6 (C-12), 144.2 (C-13), 134.2 (C-1), 134.0 (C-8), 131.5 (C-10), 130.5 (C-6), 127.9 (C-3), 127.0 (C-5), 125.7 (C-7), 125.4 (C-4), 123.8 (C-2), 121.2 (C-15), 114.43 (C-14), 111.2 (C-11), 55.95 (C-16), 39.2 (C-9), 24.2 (C-18). HRMS (+ESI) [M + H]+: 298.1435, C18H20NO3 requires 298.1443.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)isobutyramide 8b. IR (neat) ν: 3398 (w, OH), 3291 (m, NH), 3016 (w), 2970 (w), 1654 (s, C=O), 1509 (s), 1446 (m), 1371 (w), 1273 (s), 1236 (s), 1155 (m), 1038 (m, C−O), 848 (m), 812 (w), 798 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.84 (d, J = 7.6 Hz, H-2, 1H), 7.43 (d, J = 7.6 Hz, H-5, 1H), 7.36 (br s, NH, 1H), 7.21 (td, J = 7.6, 1.7 Hz, H-3, 1H), 7.06 (t, J = 7.6 Hz, H-4, 1H), 6.72–6.74 (m, H-11, H-14, H-15, 3H), 6.42 (d, J = 15.8 Hz, H-7, 1H), 6.27 (dt, J = 15.8, 6.5 Hz, H-8, 1H), 5.61 (br s, OH, 1H), 3.88 (s, H-16, 3H), 3.50 (d, J = 6.5 Hz, H-9, 2H), 2.47 (sept, J = 7.0 Hz, H-18, 1H), 1.20 (d, J = 7.0 Hz, H-19, 6H); 13C NMR (CDCl3, 125.8 MHz) δ: 175.1 (C-17), 146.7 (C-13), 144.2 (C-12), 135.7 (C-1), 134.2 (C-8), 131.4 (C-10), 130.0 (C-6), 127.9 (C-3), 127.0 (C-5), 125.6 (C-7), 124.9 (C-4), 122.8 (C-2), 121.3 (C-15), 114.7 (C-14), 111.2 (C-11), 55.9 (C-16), 39.2 (C-9), 36.7 (C-18), 19.6 (C-19). HRMS (+ESI) [M + H]+: 326.1755, C20H24NO3 requires 326.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)butyramide 8c. IR (neat) ν: 3399 (w, OH), 3269 (w, NH), 3053 (w), 2936 (w), 1646 (s, C=O), 1510 (s), 1453 (m), 1376 (w), 1271 (s), 1229 (s), 1155 (m), 1034 (m, C−O), 849 (w), 806 (w), 794 (w), 756 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.82 (d, J = 7.7 Hz, H-2, 1H), 7.32 (br s, NH, 1H), 7.37 (d, J = 7.7 Hz, H-5, 1H), 7.08–7.09 (m, H-3, 1H), 7.01 (t, J = 7.7 Hz, H-4, 1H), 6.73–6.75 (m, H-11, H-14, H-15, 3H), 6.42 (d, J = 15.3 Hz, H-7, 1H), 6.26 (dt, J = 15.3, 7.1 Hz, H-8, 1H), 5.57 (s, OH, 1H), 3.88 (s, H-16, 3H), 3.50 (d, J = 7.1 Hz, H-9, 2H), 2.29 (t, J = 7.3 Hz, H-18, 2H), 1.71 (sext, J = 7.3 Hz, H-19, 2H), 0.96 (t, J = 7.3 Hz, H-20, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.2 (C-17), 146.6 (C-13), 144.2 (C-12), 134.2 (C-1), 134.1 (C-8), 131.4 (C-10), 130.0 (C-6), 127.9 (C-3), 127.0 (C-5), 125.6 (C-7), 125.1 (C-4), 123.5 (C-2), 121.2 (C-15), 114.4 (C-14), 111.2 (C-11), 56.0 (C-16), 39.7 (C-18), 39.2 (C-9), 19.2 (C-19), 13.7 (C-20). HRMS (+ESI) [M + H]+: 326.1768, C20H24NO3 requires 326.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)pentanamide 8d. IR (neat) ν: 3302 (w, OH), 3270 (w, NH), 3027 (w), 2961 (w), 1647 (s, C=O), 1510 (s), 1452 (m), 1377 (w), 1272 (m), 1229 (s), 1155 (m), 1039 (m, C−O), 850 (w), 818 (w), 782 (w), 755 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.80 (d, J = 7.5 Hz, H-2, 1H), 7.09–7.41 (m, NH, H-3, H-4, H-5, 4H), 6.72–6.73 (m, H-11, H-14, H-15, 3H), 6.43 (d, J = 15.3 Hz, H-7, 1H), 6.26 (dt, J = 15.3, 6.9 Hz, H-8, 1H), 5.64 (s, OH, 1H), 3.88 (s, H-16, 3H), 3.50 (d, J = 6.9 Hz, H-9, 2H), 2.30 (t, J = 7.5 Hz, H-18, 2H), 1.63–1.66 (m, H-19, 2H), 1.32–1.37 (m, H-20, 2H), 0.94 (t, J = 7.5 Hz, H-21, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17), 146.6 (C-13), 144.2 (C-12), 134.2 (C-1), 134.0 (C-8), 131.4 (C-10), 130.1 (C-6), 127.8 (C-3), 127.0 (C-5), 125.7 (C-7), 125.1 (C-4), 123.5 (C-2), 121.2 (C-15), 114.4 (C-14), 111.2 (C-11), 55.9 (C-16), 39.2 (C-9), 37.3 (C-18), 27.8 (C-19), 22.31 (C-20), 13.72 (C-21). HRMS (+ESI) [M + H]+: 340.1908, C21H26NO3 requires 340.1913.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)hexanamide 8e. IR (neat) ν: 3394 (w, OH), 3292 (w, NH), 3027 (w), 2955 (w), 1648 (s, C=O), 1511 (s), 1450 (m), 1372 (w), 1274 (s), 1236 (s), 1154 (m), 1038 (m, C−O), 851 (w), 817 (w), 785 (w), 754 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.81 (d, J = 8.1 Hz, H-2, 1H), 7.09–7.38 (m, NH, H-3, H-4, H-5, 4H), 6.72–6.73 (m, H-11, H-14, H-15, 3H), 6.44 (d, J = 15.6 Hz, H-7, 1H), 6.25 (dt, J = 15.6, 6.9 Hz, H-8, 1H), 5.60 (s, OH, 1H), 3.88 (s, H-16, 3H), 3.50 (d, J = 6.9 Hz, H-9, 2H), 2.30 (t, J = 7.2 Hz, H-18, 2H), 1.65–1.68 (m, H-19, 2H), 1.34–1.36 (m, H-20, H-21, 4H), 0.92 (t, J = 7.2 Hz, H-22, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17), 146.6 (C-13), 144.2 (C-12), 134.3 (C-1), 134.1 (C-8), 131.5 (C-10), 130.0 (C-6), 127.9 (C-3), 127.0 (C-5), 125.7 (C-7), 125.1 (C-4), 123.5 (C-2), 121.2 (C-15), 114.4 (C-14), 111.2 (C-11), 55.91 (C-16), 39.2 (C-9), 37.5 (C-18), 31.4 (C-20), 25.4 (C-19), 22.4 (C-21), 13.9 (C-22). HRMS (+ESI) [M + H]+: 354.2060, C22H28NO3 requires 354.2069.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)decanamide 8f. IR (neat) ν: 3399 (w, OH), 3271 (w, NH), 3068 (w), 2923 (m), 2853 (m), 1650 (s, C=O), 1510 (s), 1452 (m), 1377 (w), 1270 (m), 1226 (s), 1155 (m), 1039 (m, C−O), 850 (w), 822 (w), 787 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.83 (d, J = 7.9 Hz, H-2, 1H), 7.37 (d, J = 7.9 Hz, H-5, 1H), 7.32 (br s, NH, 1H), 7.30–7.32 (m, H-3, 1H), 7.07–7.09 (m, H-4, 1H), 6.73–6.74 (m, H-11, H-14, H-15, 3H), 6.44 (d, J = 15.4 Hz, H-7, 1H), 6.25 (dt, J = 15.4, 6.8 Hz, H-8, 1H), 5.54 (s, OH, 1H), 3.89 (s, H-16, 3H), 3.50 (d, J = 6.8 Hz, H-9, 2H), 2.30 (t, J = 7.3 Hz, H-18, 2H), 1.62–1.70 (m, H-19, 2H), 1.23–1.29 (m, H-20, H-21, H-22, H-23, H-24, H-25, 12H), 0.87 (t, J = 7.3 Hz, H-26, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17), 146.6 (C-13), 144.2 (C-12), 134.1 (C-1), 134.1 (C-8), 131.5 (C-10), 129.9 (C-6), 127.9 (C-3), 127.1 (C-5), 125.1 (C-7, C-4), 123.5 (C-2), 121.2 (C-15), 114.4 (C-14), 111.1 (C-11), 55.9 (C-16, OCH3), 39.3 (C-9), 37.7 (C-18), 31.8 (C-24), 29.5 (C-23), 29.4 (C-22), 29.34 (C-20), 29.27 (C-21), 25.8 (C-19), 22.6 (C-25), 14.1 (C-26). HRMS (+ESI) [M + H]+: 410.2691, C26H36NO3 requires 410.2695.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)cyclohexanecarboxamide 8g. IR (neat) ν: 3394 (w, OH), 3290 (m, NH), 3030 (w), 2928 (m), 1649 (s, C=O), 1512 (s), 1447 (m), 1386 (w), 1280 (m), 1226 (s), 1156 (m), 1039 (m, C−O), 859 (w), 830 (w), 783 (w), 750 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.84 (d, J = 8.0 Hz, H-2, 1H), 7.39 (br s, NH, 1H), 7.37 (t, J = 8.0 Hz, H-5, 1H), 7.25–7.29 (m, H-3, 1H), 7.08–7.11 (m, H-4, 1H), 6.73–6.74 (m, H-11, H-14, H-15, 3H), 6.38 (d, J = 15.3 Hz, H-7, 1H), 6.27 (dt, J = 15.3, 6.4 Hz, H-8, 1H), 5.57 (s, OH, 1H), 3.89 (s, H-16, 3H), 3.50 (d, J = 6.4 Hz, H-9, 2H), 2.15–2.21 (m, H-18, 1H), 1.92 (d, J = 11.5 Hz, H-19α, 2H), 1.75–1.77 (m, H-19β, 2H), 1.42–1.49 (m, H-20α, 2H), 1.16–1.28 (m, H-20β, H-21, 4H); 13C NMR (CDCl3, 125.8 MHz) δ: 174.2 (C-17), 146.6 (C-13), 144.2 (C-12), 134.3 (C-1), 134.2 (C-8), 131.3 (C-10), 129.4 (C-6), 127.8 (C-3), 127.0 (C-5), 125.6 (C-4), 125.0 (C-7), 123.4 (C-2), 121.3 (C-15), 114.4 (C-14), 111.3 (C-11), 55.92 (C-16), 46.3 (C-18), 39.2 (C-9), 29.8 (C-19), 25.7 (C-20, C-21). HRMS (+ESI) [M + H]+: 366.2065, C23H28NO3 requires 366.2069.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)benzamide 8h. IR (neat) ν: 3528 (w, OH), 3225 (w, NH), 3062 (w), 3027, 2965 (w), 1649 (m, C=O), 1516 (s), 1484 (m), 1372 (w), 1272 (s), 1247 (m), 1157 (m), 1026 (m, C−O), 866 (w), 819 (w), 793 (w), 754 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 6.68–8.22 (m, NH, H-3, H-4, H-5, H-11, H-14, H-15, H-19, H-20, H-21, 12H), 8.04 (d, J = 7.5 Hz, H-2, 1H), 6.47–6.50 (m, H-7, 1H), 6.30–6.37 (m, H-8, 1H), 5.50 (s, OH, 1H), 3.88 (s, H-16, 3H), 3.51 (d, J = 6.0 Hz, H-9, 2H); 13C NMR (CDCl3, 125.8 MHz), characteristic signals, δ: 134.7 (C-8), 134.3 (C-1), 128.8 (C-20), 127.9 (C-3), 125.0 (C-4), 123.2 (C-2), 121.3 (C-15), 114.3 (C-14), 111.2 (C-11), 55.85 (C-16), 39.2 (C-9). HRMS (+ESI) [M + H]+: 360.1596, C23H22NO3 requires 360.1600.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)-2-methylbenzamide 8i. IR (neat) ν: 3388 (w, OH), 3271 (w, NH), 3024 (w), 2965 (w), 1646 (s, C=O), 1515 (s), 1451 (m), 1379 (w), 1267 (s), 1236 (s), 1157 (w), 1032 (m, C−O), 866 (w), 834 (w), 790 (w), 751 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.00 (d, J = 8.0 Hz, H-2, 1H), 7.74 (br s, NH, 1H), 7.42 (d, J = 8.0 Hz, H-5, 1H), 7.36–7.40 (m, H-20, H-21, 2H), 7.35 (d, J = 7.5 Hz, H-23, 1H), 7.28 (t, J = 8.0 Hz, H-3, 1H), 7.15–7.21 (m, H-4, H-22, 2H), 6.68 (s, H-11, 1H), 6.72 (d, J = 8.2 Hz, H-14, H-15, 2H), 6.46 (d, J = 15.9 Hz, H-7, 1H), 6.30 (dt, J = 15.9, 6.3 Hz, H-8, 1H), 5.50 (s, OH, 1H), 3.80 (s, H-16, 3H), 3.48 (d, J = 6.3 Hz, H-9, 2H), 2.50 (s, H-24, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 167.9 (C-17), 146.3 (C-12), 144.3 (C-13), 136.7 (C-18), 136.4 (C-19), 134.3 (C-8), 134.1 (C-1), 131.3 (C-21), 131.2 (C-10), 130.24 (C-20), 130.0 (C-6), 127.9 (C-3), 127.1 (C-5), 126.5 (C-23), 126.1 (C-22), 125.8 (C-7), 125.4 (C-4), 125.0 (C-2), 121.2 (C-15), 114.37 (C-14), 111.2 (C-11), 55.7 (C-16), 39.1 (C-9), 19.9 (C-24). HRMS (+ESI) [M + H]+: 374.1743, C24H24NO3 requires 374.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)prop-1-en-1-yl)phenyl)furan-2-carboxamide 8j. IR (neat) ν: 3416 (w, OH), 3216 (w, NH), 3039 (w), 2954 (w), 1617 (m, C=O), 1511 (m), 1460 (m), 1350 (m), 1266 (m), 1227 (m), 1153 (m), 1035 (m, C−O), 885 (w), 826 (w), 785 (w), 758 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.43 (br s, NH, 1H), 8.12 (d, J = 7.9 Hz, H-21, 1H), 7.39 (d, J = 7.0 Hz, H-2, 1H), 7.29–7.33 (m, H-3, H-5, 2H), 7.15–7.20 (m, H-4, H-19, 2H), 6.78 (s, H-11, 1H), 6.75–6.77 (m, H-14, H-15, 2H), 6.55–6.58 (m, H-7, 1H), 6.54 (d, J = 7.9 Hz, H-20, 1H), 6.30–6.34 (m, H-8, 1H), 5.52 (s, OH, 1H), 3.88 (s, H-16, 3H), 3.54 (d, J = 6.0 Hz, H-9, 2H). HRMS (-ESI) [M-H]−: 348.1245, C21H19NO4 requires 348.1236.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)acetamide 9a. IR (neat) ν: 3348 (w, OH), 3229 (w, NH), 3125 (w), 2965 (w), 1636 (m, C=O), 1517 (s), 1460 (w), 1374 (w), 1273 (s), 1236 (m), 1175 (m), 1033 (m, C−O), 868 (w), 822 (w), 797 (w), 756 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.86 (d, J = 8.0 Hz, H-2′, 1H), 7.29 (br s, NH, 1H), 7.29 (ddd, J = 8.0, 7.5, 1.0 Hz, H-3′, 1H), 7.24 (d, J = 8.0 Hz, H-5′, 1H), 7.15 (dd, J = 8.0, 7.5 Hz, H-4′, 1H), 6.89−6.82 (m, H11′, H14′, H15′, 3H), 6.38 (dt, J = 16.0, 1.5 Hz, H-9′, 1H), 6.16 (dt, J = 16.0, 6.5 Hz, H-8′, 1H), 5.64 (s, OH, 1H), 3.89 (s, H-16′, 3H), 3.53 (dd, J = 6.5, 1.5 Hz, H-7′, 2H), 2.12 (s, H-18′, 3H); 13C NMR (CDCl3, 125 MHz) δ: 168.2 (C-17′), 146.7 (C-12′), 145.6 (C-13′), 136.1 (C-1′), 131.5 (C-9′), 130.4 (C-6′), 130.3 (C-5′), 129.2 (C-10′), 127.6 (C-3′), 125.4, 125.3 (C-4′, C-8′), 123.8 (C-2′), 120.0 (C-15′), 114.5 (C-14′), 108.0 (C-11′), 55.90 (C-16′), 36.1 (C-7′), 24.4 (C-18′). HRMS (+ESI) [M + H]+: 298.1435, C18H20NO3 requires 298.1443.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)isobutyramide 9b. IR (neat) ν: 3398 (w, OH), 3291 (m, NH), 3016 (w), 2970 (w), 1654 (s, C=O), 1509 (s), 1446 (m), 1371 (w), 1273 (s), 1236 (s), 1155 (m), 1038 (m, C−O), 848 (m), 812 (w), 798 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.95 (d, J = 8.0 Hz, H-2′, 1H), 7.35 (br s, NH, 1H), 7.29 (ddd, J = 8.0, 7.5, 1.0 Hz, H-3′, 1H), 7.23 (br d, J = 7.5 Hz, H-5′, 1H), 7.13 (t, J = 7.5 Hz, H-4′, 1H), 6.85 (s, H-11′, 1H), 6.84 (AB system, δA = 6.84, δB = 6.85, JAB = 9.0 Hz, H15′, H14′, 2H), 6.38 (br d, J = 16.0 Hz, H-9′, 1H), 6.16 (dt, J = 16.0, 6.0 Hz, H-8′, 1H), 5.73 (br s, OH, 1H), 3.87 (s, H-16′, 3H), 3.53 (br d, J = 6.0 Hz, H-7′, 2H), 2.47 (sept, J = 7.0 Hz, H-18′, 1H), 1.21 (d, J = 7.0 Hz, H-19′, 6H); 13C NMR (CDCl3, 125.8 MHz) δ: 175.1 (C-17′), 146.6 (C-12′), 145.5 (C-13′), 136.3 (C-1′), 131.6 (C-9′), 130.2 (C-5′), 130.0 (C-6′), 129.2 (C-10′), 127.5 (C-3′), 125.1, 125.0 (C-4′, C-8′), 123.4 (C-2′), 119.9 (C-15′), 114.4 (C-14′), 108.0 (C-11′), 55.9 (C-16′), 36.7 (C-18′), 36.0 (C-7′), 19.6 (C-19′). HRMS (+ESI) [M + H]+: 326.1755, C20H24NO3 requires 326.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)butyramide 9c. IR (neat) ν: 3399 (w, OH), 3269 (w, NH), 3053 (w), 2936 (w), 1646 (s, C=O), 1510 (s), 1453 (m), 1376 (w), 1271 (s), 1229 (s), 1155 (m), 1034 (m, C−O), 849 (w), 806 (w), 794 (w), 756 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.92 (d, J = 7.7 Hz, H-2′, 1H), 7.32 (br s, NH, 1H), 7.28 (t, J = 7.7 Hz, H-3′, 1H), 7.23 (d, J = 7.7 Hz, H-5′, 1H), 7.13 (t, J = 7.7 Hz, H-4′, 1H), 6.88 (s, H-11′, 1H), 6.84 (d, J = 8.2 Hz, H-15′, 1H), 6.82 (d, J = 8.2 Hz, H-14′, 1H), 6.38 (d, J = 15.9 Hz, H-9′, 1H), 6.16 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.69 (s, OH, 1H), 3.88 (s, H-16′, 3H), 3.52 (d, J = 6.2 Hz, H-7′, 2H), 2.29 (t, J = 7.3 Hz, H-18′, 2H), 1.71 (sext, J = 7.3 Hz, H-19′, 2H), 0.96 (t, J = 7.3 Hz, H-20′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.2 (C-17′), 146.7 (C-12′), 145.5 (C-13′), 136.3 (C-1′), 131.6 (C-9′), 130.2 (C-5′), 130.0 (C-6′), 129.2 (C-10′), 127.5 (C-3′), 125.2, 125.1 (C-4′, C-8′), 123.5 (C-2′), 119.9 (C-15′), 114.4 (C-14′), 108.0 (C-11′), 55.9 (C-16′), 39.7 (C-18′), 36.1 (C-7′), 19.2 (C-19′), 13.7 (C-20′). HRMS (+ESI) [M + H]+: 326.1768, C20H24NO3 requires 326.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)pentanamide 9d. IR (neat) ν: 3302 (w, OH), 3270 (w, NH), 3027 (w), 2961 (w), 1647 (s, C=O), 1510 (s), 1452 (m), 1377 (w), 1272 (m), 1229 (s), 1155 (m), 1039 (m, C−O), 850 (w), 818 (w), 782 (w), 755 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.91 (d, J = 7.8 Hz, H-2′, 1H), 7.37 (br s, NH, 1H), 7.28 (t, J = 7.8 Hz, H-3′, 1H), 7.23 (d, J = 7.8 Hz, H-5′, 1H), 7.13 (t, J = 7.8 Hz, H-4′, 1H), 6.86 (s, H-11′, 1H), 6.85 (d, J = 8.2 Hz, H-15′, 1H), 6.83 (d, J = 8.2 Hz, H-14′, 1H), 6.38 (d, J = 15.9 Hz, H-9′, 1H), 6.16 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.77 (s, OH, 1H), 3.87 (s, H-16′, 3H), 3.52 (d, J = 6.2 Hz, H-7′, 2H), 2.30 (t, J = 7.4 Hz, H-18′, 2H), 1.63–1.66 (m, H-19′, 2H), 1.32–1.37 (m, H-20′, 2H), 0.88 (t, J = 7.4 Hz, H-21′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17′), 146.7 (C-12′), 145.5 (C-13′), 136.2 (C-1′), 131.6 (C-9′), 130.2 (C-5′), 130.1 (C-6′), 129.2 (C-10′), 127.5 (C-3′), 125.2, 125.1 (C-4′, C-8′), 123.5 (C-2′), 119.9 (C-15′), 114.5 (C-14′), 108.0 (C-11′), 55.8 (C-16′), 37.5 (C-18′), 36.1 (C-7′), 27.8 (C-19′), 22.34 (C-20′), 13.68 (C-21′). HRMS (+ESI) [M + H]+: 340.1908, C21H26NO3 requires 340.1913.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)hexanamide 9e. IR (neat) ν: 3394 (w, OH), 3292 (w, NH), 3027 (w), 2955 (w), 1648 (s, C=O), 1511 (s), 1450 (m), 1372 (w), 1274 (s), 1236 (s), 1154 (m), 1038 (m, C−O), 851 (w), 817 (w), 785 (w), 754 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.92 (d, J = 7.7 Hz, H-2′, 1H), 7.36 (br s, NH, 1H), 7.28 (t, J = 7.7 Hz, H-3′, 1H), 7.24 (d, J = 7.7 Hz, H-5′, 1H), 7.13 (t, J = 7.7 Hz, H-4′, 1H), 6.86 (s, H-11′, 1H), 6.85 (d, J = 8.2 Hz, H-15′, 1H), 6.84 (d, J = 8.2 Hz, H-14′, 1H), 6.38 (d, J = 15.9 Hz, H-9′, 1H), 6.15 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.73 (s, OH, 1H), 3.87 (s, H-16′, 3H), 3.52 (d, J = 6.2 Hz, H-7′, 2H), 2.30 (t, J = 7.5 Hz, H-18′, 2H), 1.65–1.68 (m, H-19′, 2H), 1.28–1.29 (m, H-20′, H-21′, 4H), 0.86 (t, J = 7.5 Hz, H-22′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17′), 146.7 (C-12′), 145.6 (C-13′), 136.3 (C-1′), 131.6 (C-9′), 130.2 (C-5′), 130.0 (C-6′), 129.2 (C-10′), 127.5 (C-3′), 125.2, 125.1 (C-4′, C-8′), 123.5 (C-2′), 119.9 (C-15′), 114.5 (C-14′), 108.0 (C-11′), 55.86 (C-16′), 37.8 (C-18′), 36.1 (C-7′), 31.4 (C-20′), 25.4 (C-19′), 22.3 (C-21′), 13.8 (C-22′). HRMS (+ESI) [M + H]+: 354.2060, C22H28NO3 requires 354.2069.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)decanamide 9f. IR (neat) ν: 3399 (w, OH), 3271 (w, NH), 3068 (w), 2923 (m), 2853 (m), 1650 (s, C=O), 1510 (s), 1452 (m), 1377 (w), 1270 (m), 1226 (s), 1155 (m), 1039 (m, C−O), 850 (w), 822 (w), 787 (w), 753 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.93 (d, J = 6.8 Hz, H-2′, 1H), 7.32 (br s, NH, 1H), 7.29 (t, J = 6.8 Hz, H-3′, 1H), 7.23 (d, J = 6.8 Hz, H-5′, 1H), 7.13 (t, J = 6.8 Hz, H-4′, 1H), 6.86 (s, H-11′, 1H), 6.85 (d, J = 8.2 Hz, H-15′, 1H), 6.83 (d, J = 8.2 Hz, H-14′, 1H), 6.38 (d, J = 15.9 Hz, H-9′, 1H), 6.16 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.65 (s, OH, 1H), 3.88 (s, H-16′, 3H), 3.52 (d, J = 6.2 Hz, H-7′, 2H), 2.30 (t, J = 7.3 Hz, H-18′, 2H), 1.62–1.70 (m, H-19′, 2H), 1.23–1.29 (m, H-20′, H-21′, H-22′, H-23′, H-24′, H-25′, 12H), 0.87 (t, J = 7.3 Hz, H-26′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 171.4 (C-17′), 146.7 (C-12′), 145.5 (C-13′), 136.3 (C-1′), 131.6 (C-9′), 130.2 (C-5′), 129.9 (C-6′), 129.2 (C-10′), 127.6 (C-3′), 125.2 (C-4′, C-8′), 123.45 (C-2′), 120.0 (C-15′), 114.5 (C-14′), 107.9 (C-11′), 55.87 (C-16′), 37.9 (C-18′), 36.2 (C-7′), 31.8 (C-24′), 29.4 (C-23′), 29.32 (C-22′), 29.29 (C-20′), 29.2 (C-21′), 25.8 (C-19′), 22.6 (C-25′), 14.1 (C-26′). HRMS (+ESI) [M + H]+: 410.2691, C26H36NO3 requires 410.2695.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)cyclohexanecarboxamide 9g. IR (neat) ν: 3394 (w, OH), 3290 (m, NH), 3030 (w), 2928 (m), 1649 (s, C=O), 1512 (s), 1447 (m), 1386 (w), 1280 (m), 1226 (s), 1156 (m), 1039 (m, C−O), 859 (w), 830 (w), 783 (w), 750 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 7.96 (d, J = 7.6 Hz, H-2′, 1H), 7.39 (br s, NH, 1H), 7.28 (t, J = 7.6 Hz, H-3′, 1H), 7.23 (d, J = 7.6 Hz, H-5′, 1H), 7.11 (t, J = 7.6 Hz, H-4′, 1H), 6.87 (d, J = 8.2 Hz, H-15′, 1H), 6.85 (s, H-11′, 1H), 6.84 (d, J = 8.2 Hz, H-14′, 1H), 6.41 (d, J = 15.9 Hz, H-9′, 1H), 6.16 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.69 (s, OH, 1H), 3.88 (s, H-16′, 3H), 3.53 (d, J = 6.2 Hz, H-7′, 2H), 2.15–2.21 (m, H-18′, 1H), 1.92 (d, J = 11.5 Hz, H-19α′, 2H), 1.75–1.77 (m, H-19β′, 2H), 1.42–1.49 (m, H-20α′, 2H), 1.16–1.28 (m, H-20β′, H-21′, 4H); 13C NMR (CDCl3, 125.8 MHz) δ: 174.2 (C-17′), 146.7 (C-12′), 145.5 (C-13′), 136.4 (C-1′), 131.8 (C-9′), 130.2 (C-5′), 129.8 (C-6′), 129.2 (C-10′), 127.5 (C-3′), 125.2 (C-8′), 124.9 (C-4′), 123.3 (C-2′), 120.0 (C-15′), 114.5 (C-14′), 107.9 (C-11′), 55.87 (C-16′), 46.5 (C-18′), 36.2 (C-7′), 29.8 (C-19′,), 25.7 (C-20′, C-21′). HRMS (+ESI) [M + H]+: 366.2065, C23H28NO3 requires 366.2069.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)benzamide 9h. IR (neat) ν: 3528 (w, OH), 3225 (w, NH), 3062 (w), 3027, 2965 (w), 1649 (m, C=O), 1516 (s), 1484 (m), 1372 (w), 1272 (s), 1247 (m), 1157 (m), 1026 (m, C−O), 866 (w), 819 (w), 793 (w), 754 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.22 (s, NH, 1H), 8.12 (d, J = 7.5 Hz, H-2′, 1H), 7.77 (d, J = 7.5 Hz, H-19′, 2H), 7.51 (t, J = 7.5 Hz, H-21′, 1H), 7.36 (t, J = 7.5 Hz, H-3′, H-20′, 3H), 7.29 (d, J = 7.5 Hz, H-5′, 1H), 7.18 (t, J = 7.5 Hz, H-4′, 1H), 6.87 (s, H-11′, 1H), 6.86 (AB system, δA = 6.84, δB = 6.88, JAB = 8.5 Hz, H15′, H14′, 2H), 6.46 (br d, J = 16.0 Hz, H-9′, 1H), 6.22 (dt, J = 16.0, 5.5 Hz, H-8′, 1H), 5.66 (s, OH, 1H), 3.88 (s, H-16′, 3H), 3.61 (d, J = 5.5 Hz, H-7′, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 165.4 (C-17′), 146.7 (C-12′), 145.6 (C-13′), 136.7 (C-1′), 134.8 (C-18′), 132.2 (C-9′), 131.8 (C-21′), 130.4 (C-5′), 129.9 (C-6′), 128.9 (C-10′), 128.8 (C-20′), 127.8 (C-3′), 127.1 (C-19′), 125.2 (C-8′), 125.0 (C-4′), 123.2 (C-2′), 120.2 (C-15′), 114.5 (C-14′), 107.9 (C-11′), 55.87 (C-16′), 36.8 (C-7′). HRMS (+ESI) [M + H]+: 360.1596, C23H22NO3 requires 360.1600.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)-2-methylbenzamide 9i. IR (neat) ν: 3388 (w, OH), 3271 (w, NH), 3024 (w), 2965 (w), 1646 (s, C=O), 1515 (s), 1451 (m), 1379 (w), 1267 (s), 1236 (s), 1157 (w), 1032 (m, C−O), 866 (w), 834 (w), 790 (w), 751 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.16 (d, J = 7.9 Hz, H-2′, 1H), 7.74 (br s, NH, 1H), 7.36–7.40 (m, H-20′, H-21′, 2H), 7.32 (d, J = 7.5 Hz, H-23′, 1H), 7.28 (t, J = 7.9 Hz, H-3′, 1H), 7.23 (d, J = 7.9 Hz, H-5′, 1H), 7.17 (t, J = 7.5 Hz, H-22′, 1H), 7.09 (t, J = 7.9 Hz, H-4′, 1H), 6.76 (s, H-11′, 1H), 6.83 (d, J = 8.2 Hz, H-14′, H-15′, 2H), 6.28 (d, J = 15.9 Hz, H-9′, 1H), 6.14 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.61 (s, OH, 1H), 3.86 (s, H-16′, 3H), 3.56 (d, J = 6.2 Hz, H-7′, 2H), 2.47 (s, H-24′, 3H); 13C NMR (CDCl3, 125.8 MHz) δ: 167.9 (C-17′), 146.6 (C-12′), 145.5 (C-13′), 136.7 (C-18′), 136.5 (C-19′), 136.2 (C-1′), 131.8 (C-9′), 131.3 (C-21′), 130.3 (C-5′), 130.15 (C-20′), 130.0 (C-6′), 129.0 (C-10′), 127.6 (C-3′), 126.7 (C-23′), 125.9 (C-22′), 125.5 (C-4′), 125.2 (C-8′), 124.8 (C-2′), 119.9 (C-15′), 114.39 (C-14′), 108.0 (C-11′), 55.8 (C-16′), 36.3 (C-7′), 19.9 (C-24′). HRMS (+ESI) [M + H]+: 374.1743, C24H24NO3 requires 374.1756.
(E)-N-(2-(3-(4-Hydroxy-3-methoxyphenyl)allyl)phenyl)furan-2-carboxamide 9j. IR (neat) ν: 3416 (w, OH), 3216 (w, NH), 3039 (w), 2954 (w), 1617 (m, C=O), 1511 (m), 1460 (m), 1350 (m), 1266 (m), 1227 (m), 1153 (m), 1035 (m, C−O), 885 (w), 826 (w), 785 (w), 758 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ: 8.43 (br s, NH, 1H), 8.12 (d, J = 7.9 Hz, H-21′, 1H), 7.29–7.33 (m, H-2′, H-3′, H-5′, 3H), 7.15–7.20 (m, H-4′, H-19′, 2H), 6.89 (s, H-11′, 1H), 6.87 (d, J = 8.2 Hz, H-15′, 1H), 6.86 (d, J = 8.2 Hz, H-14′, 1H), 6.55 (d, J = 15.9 Hz, H-9′, 1H), 6.54 (d, J = 7.9 Hz, H-20′, 1H), 6.18 (dt, J = 15.9, 6.2 Hz, H-8′, 1H), 5.62 (s, OH, 1H), 3.88 (s, H-16′, 3H), 3.62 (d, J = 6.2 Hz, H-7′, 2H); 13C NMR (CDCl3, 125.8 MHz) δ: 156.1 (C-17′), 148.0 (C-18′), 146.7 (C-12′), 145.5 (C-13′), 144.1 (C-21′), 136.0 (C-1′), 132.3 (C-9′), 130.3 (C-5′), 130.0 (C-6′), 129.4 (C-10′), 127.7 (C-3′), 125.1 (C-4′), 124.7 (C-8′), 122.9 (C-2′), 120.2 (C-15′), 115.1 (C-19′), 114.3 (C-14′), 112.5 (C-20′), 107.7 (C-11′), 55.9 (C-16′), 36.6 (C-7′). HRMS (-ESI) [M-H]−: 348.1245, C21H19NO4 requires 348.1236.
3.3. Bioassay Assessment
3.3.1. Cell Cultures
MCF-7 and MDA-MB-231 human breast cancer cell lines, as well as MCF-10A human normal breast cell lines, were used in this study. These cells were acquired from the American Type Culture Collection (Manassas, VA, USA). MCF-7 and MDAMB-231 cells were regularly cultured in Dulbecco’s Modified Eagle’s Medium (DMEM; Gibco, Waltham, MA, USA), and supplemented with 10% (v/v) foetal bovine serum (FBS; Gibco, Waltham, MA, USA) and 100 U/mL penicillin-streptomycin (PenStrep; Gibco, Waltham, MA, USA). MCF-10A cells were routinely cultured in DMEM/F12 (Gibco, Waltham, MA, USA) medium supplemented with 5% horse serum (Sigma-Aldrich, Burlington, MA, USA), 10 μg/mL of insulin (Sigma-Aldrich, Burlington, MA, USA), 20 ng/mL of human epidermal growth factor (hEGF; ThermoFisher, Waltham, MA, USA), 0.5 μg/mL of hydrocortisone (Sigma-Aldrich, Burlington, MA, USA) and 1 U/mL PenStrep. All cell lines were maintained in a humidified atmosphere with 5% CO2 at 37 °C.
3.3.2. Semi-Empirical Calculations
Molecular modelling was performed on compounds 6a, 7a, 8a, 9a, 6b, 7b, 8b and 9b. In each case, the most stable conformer was located and its geometry pre-optimised using the molecular mechanics MMFF94 force field [38], with the Avogadro 1.2.0 software [39,40]. Semi-empirical geometry optimisation was then performed using the PM7 method [41], with the MOPAC2016 software [42].
3.3.3. Cytotoxicity Assays
The effects of the N-(2-cinnamylphenyl)amide products (i.e., isolated pure isomers) on MCF-7, MDA-MB-231 and MCF-10A were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation assay. The cell lines were seeded in 96-well plates at a density of 1 × 104 cells/well and allowed to grow overnight for cell attachment. The cell lines were then treated with fresh assay medium, supplemented with increasing concentrations of tested compounds (10–100 µM) and incubated for 24–72 h at 37 °C. For this assay, the blank and negative controls used were the culture medium alone (without cells) and cells with culture medium only (untreated cells), respectively. For the positive control, MCF-10A cells were treated with 30 μM tamoxifen. At each incubation period (24, 48 and 72 h), 10 μL of MTT solution (5 mg/mL) was added to each well, and cells were further incubated for 4 h at 37 °C in 5% CO2. The solution mixture in each well was replaced with 100 μL of dimethyl sulfoxide (DMSO) to solubilise the MTT crystalline products. The optical density (O.D.) of each well was measured using a microplate reader (PowerWave-XS; Bio-Tek Instruments, Winooski, Vermont, USA) at 570 nm. The experiments were conducted in triplicate for each cell line.
A plot of % cell proliferation versus sample concentration was used to show the 50% inhibitory concentration (IC50). The selectivity index (SI) was used to indicate the cytotoxic selectivity of the samples against cancer cells and normal cells. It was calculated from the IC50 of the samples in normal cells versus cancer cells. An SI of less than 2 suggests the general toxicity of the drug/sample in cells, while an SI of more than 2 is an indication of the sample selectively targeting cancer cells [37]. All data were analysed and presented as means standard deviation (±SD). Comparisons between each concentration of 18 samples were evaluated using Student’s t-test, where p < 0.05, p < 0.01 or p < 0.001 were considered as statistically significant relative to the untreated control cells.
4. Conclusions
A series of new bio-inspired (E)-1,3-diarylpropene derivatives were synthesised using palladium-catalysed Heck cross-coupling reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol, in 36–91% yields. In each case, two regioisomers were obtained, differing by the position of the (E) C=C double bond in the central propene subunit. Higher selectivities were obtained with eugenol, which was rationalised by the β-hydride elimination step being kinetically favoured at the position adjacent to the most electron-rich aromatic substituent. The products could be considered as stilbenoid and dihydrostilbenoid structural analogues, as well as hybrid molecules, and their cytotoxicities were evaluated using MTT proliferation assays against several cancer cell lines. However, only compounds 6d, 6e, 7d, 7i and 7e exhibited low growth inhibition against MCF-7 and MDA-MB-231, respectively. Hence, no promising effects were disclosed, in comparison with the reference drug tamoxifen.
Conceptualization, M.N.A.; methodology, A.S.T., J.S., M.M., N.N.S.N.M.K., Y.S. and M.N.A.; validation, N.S.R., N.N.S.N.M.K., Y.S. and M.N.A.; formal analysis, A.S.T., J.S. and M.M.; investigation, A.S.T., J.S. and M.M.; resources, M.N.A.; data curation, A.S.T., J.S. and M.M.; writing—original draft preparation, A.S.T., J.S., M.M. and M.N.A.; writing—review and editing, N.S.R., N.N.S.N.M.K., Y.S. and M.N.A.; visualization, A.S.T., Y.S. and M.N.A.; supervision, N.S.R., Y.S. and M.N.A.; project administration, M.N.A.; funding acquisition, M.N.A. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
Not applicable.
This work was carried out in the frame of a collaboration between NPSO, SCS, Universiti Sains Malaysia and LSO, Ecole Polytechnique. The authors wish to thank the Universiti Sains Malaysia Fellowship Scheme (A.S.T.). We are also grateful to Awang K. and Abd. Rahim N. A. for their assistance.
The authors declare no conflict of interest.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Enlarge this image.Scheme 1. Synthesis of 1,3-diarylpropene derivatives by the Heck reaction. Comparison of the structures of the products with those of stilbenes and dihydrostilbenes.
Enlarge this image.Scheme 2. Synthesis of amido-substituted 1,3-diarylpropene compounds by the Heck cross-coupling reaction.
Enlarge this image.Scheme 3. Simplify mechanism of the Heck cross-coupling reaction of 2-amidoiodobenzenes 3 with allylbenzene derivatives 4 or 5.
Enlarge this image.Scheme 4. Proposed transition states of the β-hydride elimination step from 11, leading either to regioisomers (E)-6/8 or (E)-7/9.
Synthesis of o-amido-substituted 1,3-diarylpropene products 6a–j–9a–j.
| Compounds | R1 | R2 | R3 | Yield * | 6/7 or 8/9 Ratio # |
|---|---|---|---|---|---|
| 6a, 7a | Me | H | OMe | 75% | 51:49 |
| 6b, 7b | iPr | H | OMe | 86% | 54:46 |
| 6c, 7c | nPr | H | OMe | 80% | 48:52 |
| 6d, 7d | nBu | H | OMe | 78% | 47:53 |
| 6e, 7e | nC5H11 | H | OMe | 91% | 49:51 |
| 6f, 7f | nC9H19 | H | OMe | 72% | 45:55 |
| 6g, 7g | cC6H11 | H | OMe | 69% | 49:51 |
| 6h, 7h | Ph | H | OMe | 78% | 47:53 |
| 6i, 7i | 2-MePh | H | OMe | 58% | 49:51 |
| 6j, 7j | 2-furyl | H | OMe | 36% | 47:53 |
| 8a, 9a | Me | OMe | OH | 49% | 38:62 |
| 8b, 9b | iPr | OMe | OH | 75% | 21:79 |
| 8c, 9c | nPr | OMe | OH | 79% | 26:74 |
| 8d, 9d | nBu | OMe | OH | 82% | 22:78 |
| 8e, 9e | nC5H11 | OMe | OH | 56% | 21:79 |
| 8f, 9f | nC9H19 | OMe | OH | 57% | 28:72 |
| 8g, 9g | cC6H11 | OMe | OH | 62% | 19:81 |
| 8h, 9h | Ph | OMe | OH | 81% | 29:71 |
| 8i, 9i | 2-MePh | OMe | OH | 79% | 22:78 |
| 8j, 9j | 2-furyl | OMe | OH | 83% | 26:74 |
* solated yields of unseparated regioisomers. # The ratios were determined by 1H-NMR spectroscopy of the crude products.
Cytotoxicities (IC50 values) and selectivity indexes (SI) of the most active bio-inspired 1,3-diarylpropene Heck reaction products.
| Compounds | Time | IC50 Value (µM) | ||||
|---|---|---|---|---|---|---|
| MCF-7 | SI | MDA-MB-231 | SI | MCF-10A | ||
| 6d | 24 h | 94.05 ± 1.26 | 1.06 | >100 ± 0.01 | - | >100 ± 0.01 |
| 48 h | 93.34 ± 2.15 | 1.01 | >100 ± 0.01 | 0.94 | 94.39 ± 9.71 | |
| 72 h | 65.83 ± 7.33 | 1.41 | >100 ± 0.01 | 0.93 | 92.89 ± 8.71 | |
| 6e | 24 h | >100 ± 0.01 | 0.81 | >100 ± 0.01 | 0.81 | 80.91 ± 7.58 |
| 48 h | >100 ± 0.01 | 0.90 | >100 ± 0.01 | 0.90 | 90.09 ± 8.80 | |
| 72 h | >100 ± 0.01 | 0.99 | >100 ± 0.01 | 0.99 | 98.50 ± 2.60 | |
| 6i | 24 h | >100 ± 0.01 | - | >100 ± 0.01 | - | >100 ± 0.01 |
| 48 h | >100 ± 0.01 | - | >100 ± 0.01 | - | >100 ± 0.01 | |
| 72 h | 91.78 ± 7.95 | 1.09 | 73.79 ± 6.92 | 1.36 | >100 ± 0.01 | |
| 7d | 24 h | 58.90 ± 1.81 | 1.70 | >100 ± 0.01 | 1.00 | >100 ± 0.01 |
| 48 h | 48.68 ± 3.46 | 1.54 | >100 ± 0.01 | 0.75 | 75.03 ± 8.58 | |
| 72 h | 47.92 ± 2.96 | 1.49 | >100 ± 0.01 | 0.71 | 71.19 ± 9.25 | |
| 7e | 24 h | >100 ± 0.01 | - | >100 ± 0.01 | - | >100 ± 0.01 |
| 48 h | >100 ± 0.01 | 0.70 | >100 ± 0.01 | 0.70 | 70.27 ± 1.88 | |
| 72 h | 88.46 ± 2.37 | 0.78 | >100 ± 0.01 | 0.69 | 69.18 ± 0.01 | |
| Tamoxifen | 24 h | 16.22 ± 0.37 | 0.20 | 13.62 ± 0.95 | 0.24 | 3.24 ± 0.01 |
| 48 h | 15.36 ± 1.42 | 0.22 | 15.86 ± 0.73 | 0.21 | 3.33 ± 0.02 | |
| 72 h | 15.78 ± 0.10 | 0.26 | 14.53 ± 0.08 | 0.28 | 4.07 ± 0.09 | |
Supplementary Materials
The following are available online at
References
1. Mizoroki, T.; Mori, K.; Ozaki, A. Arylation of olefin with aryl iodide catalyzed by palladium. Bull. Chem. Soc. Jpn.; 1971; 44, 581. [DOI: https://dx.doi.org/10.1246/bcsj.44.581]
2. Heck, R.F.; Nolley, J.P., Jr. Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides. J. Org. Chem.; 1972; 37, pp. 2320-2322. [DOI: https://dx.doi.org/10.1021/jo00979a024]
3. De Meijere, A.; Meyer, F.E. Fine feathers make fine birds: The Heck reaction in modern garb. Angew. Chem. Int.; 1994; 33, pp. 2379-2411. [DOI: https://dx.doi.org/10.1002/anie.199423791]
4. Beletskaya, I.P.; Cheprakov, A.V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev.; 2000; 100, pp. 3009-3066. [DOI: https://dx.doi.org/10.1021/cr9903048]
5. Jonathan, P.K.; Andrew, W. The Heck–Mizoroki cross-coupling reaction: A mechanistic perspective. Org. Biomol. Chem.; 2007; 5, pp. 31-44.
6. Jagtap, S. Heck reaction—State of the art. Catalysts; 2017; 7, 267. [DOI: https://dx.doi.org/10.3390/catal7090267]
7. Dounay, A.B.; Overman, L.E. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev.; 2003; 103, pp. 2945-2963. [DOI: https://dx.doi.org/10.1021/cr020039h] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12914487]
8. Shibasaki, M.; Vogl, E.M.; Ohshima, T. Asymmetric Heck reaction. Adv. Synth. Catal.; 2004; 346, pp. 1533-1552. [DOI: https://dx.doi.org/10.1002/adsc.200404203]
9. Mc Cartney, D.; Guiry, P.J. The asymmetric Heck and related reactions. Chem. Soc. Rev.; 2011; 40, pp. 5122-5150. [DOI: https://dx.doi.org/10.1039/c1cs15101k]
10. Reznikov, A.N.; Ashatkina, M.A.; Klimochkin, Y.N. Recent developments in asymmetric Heck type cyclization reactions for constructions of complex molecules. Org. Biomol. Chem.; 2021; 19, pp. 5673-5701. [DOI: https://dx.doi.org/10.1039/D1OB00496D]
11. Xie, J.-Q.; Liang, R.-X.; Jia, Y.-X. Recent advances of catalytic enantioselective Heck reactions and reductive-Heck reactions. Chin. J. Chem.; 2021; 39, pp. 710-728. [DOI: https://dx.doi.org/10.1002/cjoc.202000464]
12. Chong, J.; Poutaraud, A.; Hugueney, P. Metabolism and roles of stilbenes in plants. Plant Sci.; 2009; 177, pp. 143-155. [DOI: https://dx.doi.org/10.1016/j.plantsci.2009.05.012]
13. Rivière, C.; Pawlusa, A.D.; Mérillon, J.-M. Natural stilbenoids: Distribution in the plant kingdom and chemotaxonomic interest in Vitaceae. Nat. Prod. Rep.; 2012; 29, pp. 1317-1333. [DOI: https://dx.doi.org/10.1039/c2np20049j]
14. Morabito, G.; Miglio, C.; Peluso, I.; Serafini, M. Fruit polyphenols and postprandial inflammatory stress. Polyphenols in Human Health and Disease; 1st ed. Watson, R.R.; Preedy, V.R.; Zibadi, S. Academic Press: Cambridge, UK, 2014; pp. 1107-1126.
15. Siemann, E.H.; Creasy, L. Concentration of the phytoalexin resveratrol in wine. Am. J. Enol. Vitic.; 1992; 43, pp. 49-52.
16. Babich, H.; Reisbaum, A.G.; Zuckerbraun, H.L. In vitro response of human gingival epithelial SG cells to resveratrol. Toxicol. Lett.; 2000; 114, pp. 143-153. [DOI: https://dx.doi.org/10.1016/S0378-4274(99)00288-X]
17. De Filippis, B.; Ammazzalorso, A.; Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Amoroso, R. Anticancer activity of stilbene-based derivatives. Chem. Med. Chem.; 2017; 12, pp. 558-570. [DOI: https://dx.doi.org/10.1002/cmdc.201700045]
18. Teplova, V.; Isakova, E.; Klein, O.; Dergachova, D.; Gessler, N.; Deryabina, Y.I. Natural polyphenols: Biological activity, pharmacological potential, means of metabolic engineering. Appl. Biochem. Microbiol.; 2018; 54, pp. 221-237. [DOI: https://dx.doi.org/10.1134/S0003683818030146]
19. De Filippis, B.; Ammazzalorso, A.; Amoroso, R.; Giampietro, L. Stilbene derivatives as new perspective in antifungal medicinal chemistry. Drug Dev. Res.; 2019; 80, pp. 285-293. [DOI: https://dx.doi.org/10.1002/ddr.21525]
20. Vitalini, S.; Cicek, S.S.; Granica, S.; Zidorn, C. Dihydroresveratrol type dihydrostilbenoids: Chemical diversity, chemosystematics, and bioactivity. Curr. Med. Chem.; 2018; 25, pp. 1194-1240. [DOI: https://dx.doi.org/10.2174/0929867324666170830112343]
21. Kee, C.H.; Ariffin, A.; Awang, K.; Takeya, K.; Morita, H.; Hussain, S.I.; Chan, K.M.; Wood, P.J.; Threadgill, M.D.; Lim, C.G. Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications. Org. Biomol. Chem.; 2010; 8, pp. 5646-5660. [DOI: https://dx.doi.org/10.1039/c0ob00296h]
22. Azmi, M.N.; Din, M.F.M.; Kee, C.H.; Suhaimi, M.; Ping, A.K.; Ahmad, K.; Nafiah, M.A.; Thomas, N.F.; Mohamad, K.; Hoong, L.K. Design, synthesis and cytotoxic evaluation of o-carboxamido stilbene analogues. Int. J. Mol. Sci.; 2013; 14, pp. 23369-23389. [DOI: https://dx.doi.org/10.3390/ijms141223369] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24287912]
23. Malkov, A.V.; Davis, S.L.; Baxendale, I.R.; Mitchell, W.L.; Kočovský, P. Molybdenum (II)-catalyzed allylation of electron-rich aromatics and heteroaromatics. J. Org. Chem.; 1999; 64, pp. 2751-2764. [DOI: https://dx.doi.org/10.1021/jo982178y] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11674344]
24. Frye, E.C.; O’Connor, C.J.; Twigg, D.G.; Elbert, B.; Laraia, L.; Hulcoop, D.G.; Venkitaraman, A.R.; Spring, D.R. Palladium-catalysed cross-coupling of vinyldisiloxanes with benzylic and allylic halides and sulfonates. Chem. Eur. J.; 2012; 18, pp. 8774-8779. [DOI: https://dx.doi.org/10.1002/chem.201200431] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22678946]
25. Watanabe, K.; Mino, T.; Abe, T.; Kogure, T.; Sakamoto, M. Hydrazone–Palladium-catalyzed allylic arylation of cinnamyloxyphenylboronic acid pinacol esters. J. Org. Chem.; 2014; 79, pp. 6695-6702. [DOI: https://dx.doi.org/10.1021/jo501235w]
26. Falcou, A.; Marsacq, D.; Hourquebie, P.; Duchêne, A. General access to ortho-and meta-alkylanilines for the synthesis of polyanilines and poly (anilines-co-substituted anilines). Tetrahedron; 2000; 56, pp. 225-231. [DOI: https://dx.doi.org/10.1016/S0040-4020(99)00934-5]
27. Bender, C.F.; Widenhoefer, R.A. Gold(I)-catalyzed intramolecular hydroamination of unactivated alkenes with carboxamides. Chem. Commun.; 2006; 39, pp. 4143-4144. [DOI: https://dx.doi.org/10.1039/b608638a]
28. He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Pd(II)/tBu-quinolineoxazoline: An air-stable and modular chiral catalyst system for enantioselective oxidative cascade cyclization. Org. Lett.; 2009; 11, pp. 5626-5628. [DOI: https://dx.doi.org/10.1021/ol902348t]
29. Berthiol, F.; Doucet, H.; Santelli, M. Heck reaction of aryl halides with linear or cyclic alkenes catalysed by a tetraphosphine/palladium catalyst. Tetrahedron Lett.; 2003; 44, pp. 1221-1225. [DOI: https://dx.doi.org/10.1016/S0040-4039(02)02788-0]
30. Bar, F.M.A.; Khanfar, M.A.; Elnagar, A.Y.; Badria, F.A.; Zaghloul, A.M.; Ahmad, K.F.; Sylvester, P.W.; El Sayed, K.A. Anti-amoebic activity of eugenol derivatives against Acanthamoeba castellanii. Bioog. Med. Chem.; 2010; 18, pp. 496-507.
31. Tarnowicz-Ligus, S.; Trzeciak, A.M. Heck transformations of biological compounds catalyzed by phosphine-free palladium. Molecules; 2018; 23, 2227. [DOI: https://dx.doi.org/10.3390/molecules23092227]
32. Belley, M.; Gallant, M.; Roy, B.; Houde, K.; Lachance, N.; Labelle, M.; Trimble, L.A.; Chauret, N.; Li, C.; Sawye, N. et al. Structure–activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP3 antagonists. Bioorg. Med. Chem. Lett.; 2005; 15, pp. 527-530. [DOI: https://dx.doi.org/10.1016/j.bmcl.2004.11.051]
33. Lyaskovskyy, V.; Fröhlich, R.; Würthwein, E.-U. Mechanistic study on rearrangement cascades starting from annulated 2-aza-hepta-2, 4-dienyl-6-ynyl anions: Formation of aniline and azepine derivatives. Chem. Eur. J.; 2007; 13, pp. 3113-3119. [DOI: https://dx.doi.org/10.1002/chem.200601491]
34. Werner, E.W.; Sigman, M.S. Operationally simple and highly (E)-styrenyl-selective Heck reactions of electronically nonbiased olefins. J. Am. Chem. Soc.; 2011; 133, pp. 9692-9695. [DOI: https://dx.doi.org/10.1021/ja203164p]
35. Tomasch, M.; Schwed, J.S.; Kuczka, K.; Meyer dos Santos, S.; Harder, S.; Nüsing, R.M.; Paulke, A.; Stark, H. Fluorescent human EP3 receptor antagonists. ACS Med. Chem. Lett.; 2012; 3, pp. 774-779. [DOI: https://dx.doi.org/10.1021/ml300191g]
36. Fukuda, M.; Sasaki, T.; Hashimoto, T.; Miyachi, H.; Waki, M.; Asai, A.; Takikawa, O.; Ohno, O.; Matsuno, K. Cyclic analogue of S-benzylisothiourea that suppresses kynurenine production without inhibiting indoleamine 2, 3-dioxygenase activity. Bioorg. Med. Chem. Lett.; 2018; 28, pp. 2846-2849. [DOI: https://dx.doi.org/10.1016/j.bmcl.2018.07.034]
37. Badisa, R.B.; Darling-Reed, S.F.; Joseph, P.; Cooperwood, J.S.; Latinwo, L.M.; Goodman, C.B. Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells. Anticancer Res.; 2009; 29, pp. 2993-2996.
38. Halgren, T.A. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J. Comput. Chem.; 1996; 17, pp. 490-519. [DOI: https://dx.doi.org/10.1002/(SICI)1096-987X(199604)17:5/6<490::AID-JCC1>3.0.CO;2-P]
39. Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminf.; 2012; 4, 17. [DOI: https://dx.doi.org/10.1186/1758-2946-4-17]
40. Avogadro Home Page. Available online: https://avogadro.cc/ (accessed on 10 September 2021).
41. Stewart, J.J.P. Optimization of parameters for semiempirical methods VI: More modifications to the NDDO approximations and re-optimization of parameters. J. Mol. Mod.; 2013; 19, pp. 1-32. [DOI: https://dx.doi.org/10.1007/s00894-012-1667-x]
42. Stewart, J.J.P. MOPAC2016. Stewart Computational Chemistry: Colorado Springs, CO, USA. Available online: http://openmopac.net/ (accessed on 10 September 2021).
43. Ladziata, U.; Koposov, A.Y.; Lo, K.Y.; Willging, J.; Nemykin, V.N.; Zhdankin, V.V. Synthesis, structure, and chemoselective reactivity of N-(2-iodylphenyl)acylamides: Hypervalent iodine reagents bearing a pseudo-six-membered ring scaffold. Angew. Chem. Int. Ed.; 2015; 44, pp. 7127-7131. [DOI: https://dx.doi.org/10.1002/anie.200502707]
44. Curran, D.P.; Yu, H.; Liu, H. Amide-based protecting/radical translocating (PRT) groups. Generation of radicals adjacent to carbonyls by 1,5-hydrogen transfer reactions of o-iodoanilides. Tetrahedron; 1994; 50, pp. 7343-7366. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)90466-1]
45. Prasad, D.J.C.; Sekar, G. Cu-catalyzed in situ generation of thiol using xanthate as a thiol surrogate for the one-pot synthesis of benzothiazoles and benzothiophenes. Org. Biomol. Chem.; 2013; 11, pp. 1659-1665. [DOI: https://dx.doi.org/10.1039/C3OB26915A]
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; Singh, Jaymeer 1 ; Rezali, Nurul Syafiqah 2
; Musthahimah Muhamad 3 ; Nik Nur Syazni Nik Mohamed Kamal 3
; Six, Yvan 4
; Mohamad Nurul Azmi 1
1 School of Chemical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
2 Chemical Sciences Programme, School of Distance Education, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia
3 Integrative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Penang, Malaysia
4 Laboratoire de Synthèse Organique (LSO), École Polytechnique, CNRS, Institut Polytechnique de Paris, CEDEX, 91128 Palaiseau, France