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Article

A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters

by
Dezhi Lin
1,
Yunfang Liu
2,
Hongyu Yang
1,
Xiao Zhang
1,
Huaming Sun
1,
Yajun Jian
1,
Weiqiang Zhang
1,*,
Jianming Yang
3 and
Ziwei Gao
1
1
Key Laboratory of Applied Surface and Colloid Chemistry (MOE), Xi’an Key Laboratory of Organometallic Material Chemistry, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710119, China
2
South China Institute of Environmental Science, Ministry of Ecology and Environment, Guangzhou 510655, China
3
Xi’an Modern Chemistry Research Institute, Xi’an 710065, China
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(11), 4364; https://doi.org/10.3390/molecules28114364
Submission received: 19 April 2023 / Revised: 14 May 2023 / Accepted: 24 May 2023 / Published: 26 May 2023
(This article belongs to the Section Organometallic Chemistry)
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Versions Notes

Abstract

:
The palladium-catalyzed Sonogashira coupling of α, β-unsaturated acid derivatives offers a diversity-oriented synthetic strategy for cross-conjugated enynones. However, the susceptibility of the unsaturated C-C bonds adjacent to the carbonyl group toward Pd catalysts makes the direct conversion of α, β-unsaturated derivatives as acyl electrophiles to cross-conjugated ketones rare. This work presents a highly selective C-O activation approach to prepare cross-conjugated enynones using α, β-unsaturated triazine esters as acyl electrophiles. Under base and phosphine ligand-free conditions, NHC-Pd(II)-Allyl precatalyst alone catalyzed the cross-coupling of α, β-unsaturated triazine esters with terminal alkynes efficiently, yielding 31 cross-conjugated enynones with diverse functional groups. This method demonstrates the potential of triazine-mediated C-O activation for preparing highly functionalized ketones.

1. Introduction

Cross-conjugated enynones, or 1-en-4-yn-3-ones, play a crucial role in organic chemistry due to their unique reaction centers. These enynones consist of carbon–carbon double and triple bonds linked with a carbonyl group, which makes them valuable building blocks for synthesizing complex heterocycles and carbocycles [1,2,3,4]. The resulting compounds can contain oxygen, nitrogen, and sulfur and are used in pharmaceuticals and materials science, among other fields [5,6,7]. It is worth noting that the cross-conjugated enynone structure is not exclusive to synthetic compounds; it can also be found in nature in various plants, fungi, and sea organisms [8]. Researchers have even found Petroacetylene, a compound containing two enynone units, in the sea sponge Petrosia solida [9]. Broad application and occurrence highlight the importance of preparing these compounds’ synthetic potential and their role in nature.
Since there is limited access to cross-conjugated enynones from natural resources, considerable effort has been put into preparing conjugated acetylenic carbonyl compounds through various synthetic methods from commercially available starting materials. These methods include oxidatively dimerizing phenylacetylene [10], oxidizing secondary vinyl ethynyl alcohols [11,12,13,14,15], and aldol crotonic condensation of ethynyl methyl ketones with aromatic and heteroaromatic aldehydes [16]. Alternatively, transition metal-catalyzed coupling reactions offer a gentler approach for preparing acetylenic carbonyl derivatives avoiding the oxidation step. One such reaction is the palladium-catalyzed cross-coupling of terminal alkynes and metallated organic halide derivatives in the presence of carbon monoxide [17]. Copper(I) iodide in triethylamine catalyzed two components cross-coupling of cinnamoyl chloride and phenylacetylenes; however, the yield of 1-en-4-yn-3-one is lower in this case than in Pd-catalyzed reactions [18].
Pd-catalyzed cross-coupling reactions using carboxylic acid derivatives have been widely used in ketone synthesis since Milstein and Stille demonstrated the synthetic utility of acid chlorides as coupling partners decades ago [19]. Owing to the availability and structural diversity of carboxylic acids, various coupling partners of acyl halides [20,21,22,23,24], amides [25], thioesters [26], and esters [27], have been applied as acyl electrophiles in Pd-catalyzed cross-coupling reactions for drug discovery, natural product synthesis, and polymer synthesis [28]. In this context, Sonogashira cross-coupling of carboxylic acids derivatives represents a central strategy for 1-yn-3-ones’ synthesis. [29]. Despite aromatic and alkyl carboxylic acids derivatives’ success in 1,3-ynone synthesis, α, β-unsaturated carboxylic acid derivatives are rarely investigated as acyl electrophiles for the preparation of 1-en-4-yn-3-ones. Although few examples of palladium-catalyzed cross-coupling of cinnamic chlorides with terminal acetylenes provide a carbon monoxide-free protocol for preparing enynones, the catalyst systems were employed to selectively cleavage C(acyl)-O in the presence of C=C bond near the carbonyl group in acyl electrophile. The catalyst systems used for this reaction include Pd(PPh3)4 with ZnCl2 or ZnBr2 [30], Pd/BaSO4 [31], Pd/C [32], Pd(OAc)2 [33], Pd(PPh3)2Cl/CuI [34], and KF/Al2O3/Pd(PPh3)2Cl2/CuI with microwave activation [35], palladium nanoparticles embedded into the poly-1,4-phenylene sulfide polymer matrix [36], and even-more-complicated palladium-based catalyst systems [37,38]. To circumvent the complicated catalyst system, an α, β-unsaturated acyl electrophile with well-balanced stability and C(acyl)-O activity is highly demanding for the Pd-catalyzed preparation of cross-conjugated enynone.
To address this issue, we proposed that triazine esters are effective acylating reagents for Pd-catalyzed C-C coupling. Unlike traditional esters, the triazine ring is strongly electron-withdrawing to activate the C(acyl)-O bond. Meanwhile, the coordination ability of the triazine ring is advantageous for palladium-catalyzed carboxylate coupling reactions. Our group used acyl acid triazine esters as acylating reagents in Pd-catalyzed cross-coupling of C(acyl)-C(sp) bonds [27]. Using triazine as a core, we designed multifunctional phosphine ligands for Pd-catalyzed carbonylative reaction [39]. Recently, triazines as wingtips of NHC ligands accelerated the transmetallation of Pd-catalyzed carbonylative Sonogashira reactions [40]. Considering triazine’s unique ability to activate C(acyl)-O bonds and its catalytic implications, we envisioned triazine esters of α, β-unsaturated carboxylic acids as potent acyl electrophiles for Pd catalysis. Herein, we report Pd-catalyzed acyl Sonogashira reaction with bench-stable α, β-unsaturated carboxylic acids triazine esters as acyl electrophiles, by which cross-conjugated enynones were synthesized in a mild and selective manner.

2. Results and Discussion

We utilized a Pd-catalyzed Sonogashira reaction to synthesize cross-conjugated enynones from α, β-unsaturated carboxylic acid triazine esters as acylating reagents and alkynes. The triazine esters were prepared using Kamiński’s method in high yields from the α, β-unsaturated carboxylic acid using toluene as the solvent. The cross-coupling of cinnamic acid triazine ester 1a with phenylacetylene 3a was chosen to optimize palladium catalysts and solvents. Pd(OAc)2 alone catalyzed the reaction without ligand or base, yielding the desired enynone 3aa in various organic solvents (Table 1, Entries 1–5). The most suitable solvent for the reaction was MeCN, which yielded a 42% yield (Entry 6). The cinnamic acid anhydrous was detected in the raw product, which might be formed by the degradation of unconverted triazine esters due to the low activity of Pd(OAc)2. We screened palladium catalysts for the Sonogashira reactions and found that Pd(OAc)2 gave a promising 42% yield in MeCN (Entry 6), while PdCl2 and PdCl2(PPh)2 failed to catalyze the coupling reaction (Entries 7–8).
It is worth noting that allylic Pd(II) precatalysts, such as [Pd(cinnamyl)Cl]2, [(2-Methylallyl)PdCl]2, and [(allyl)PdCl]2 (Entries 9–11), substantially enhanced the activity of Pd, resulting in yields of 62–58%, respectively. NHC ligands further improved the allylic Pd(II) precatalysts Pd-1 and Pd-2, which yielded 75% and 78%, respectively (Entry 13). Remarkably, Pd-3, containing a less bulky NHC ligand, catalyzed the coupling reaction with 95% yields (Entry 14). The Pd-loading of Pd-3 as a precatalyst could be reduced to 1 mol% (Entry 16) without significantly impacting the reaction outcome. During optimization, low-yielding reactions generally showed the degradation of triazine ester into the corresponding anhydrous and no evidence of C(acyl)-O cleavage or decarbonylation pathways was observed.
Under mild optimal conditions, we evaluated the potential of triazine esters as acyl electrophiles in Pd-catalyzed Sonogashira coupling reactions. Without adding a base and phosphine ligand, Pd(II) efficiently catalyzed the coupling reactions at 50 °C in MeCN. As shown in Scheme 1, a broad range of triazine esters are compatible, converting into enynones with generally high to excellent yields. We began by exploring the coupling of cinnamic triazine esters with phenylacetylene 2a. Our findings revealed that several substitution patterns and types of cinnamic triazine esters 1a–1k provided satisfactory yields. For instance, both electron-rich and electron-poor cinnamic triazine esters, including those with para- (1b, 1c), meta- (1h), and sterically hindered ortho- (1i) substitution patterns, were effective in producing the desired enynone products. Additionally, the coupling reaction using 3,4,5-methoxyphenyl (1j), catecholyl (1k), and furanyl (1l) cinnamic triazine testers gave 96%, 78%, and 95% yields, respectively.
We have expanded the protocol to include acrylic triazine esters 1l–1r, which are significant in synthetic chemistry. It is important to note that acrylic triazine esters with methyl or n-propyl at both α- and β- positions can be coupled with phenylacetylene and converted to the corresponding unsaturated enynones (3ma–3oa) with high yields of 87–91%.
Sorbic triazine esters, which are challenging substrates, can be selectively activated at C(acyl)-O in the presence of the diene close to carbonyl groups to produce two α, β, γ, δ-dienynones (3qa, 3ra) with high yields of 94% and 88%, respectively. These extended conjugated systems would be difficult to be constructed using conventional nucleophilic addition methodologies, highlighting the practicality of these α, β-unsaturated carboxylic acid esters as acyl electrophiles.
Various functionalized alkynes reacted efficiently with cinnamic triazine ester (1a) to produce the desired cross-conjugated enynones in high yields (Scheme 2). Aryl alkynes with electron-donating groups at para- and meta-positions (2b–2f) and electron-withdrawing groups (2j–2k) provided satisfactory yields ranging from 60% to 95%. Sterically bulky ortho-chlorine in 2k was also fully compatible with Pd-catalyzed cross-couplings of cinnamic triazine (1a), producing the corresponding enynones with 93% yields. Enynones bearing biphenyl (3al) were isolated in 86% yields. Aliphatic alkynes (2m) also acted as good nucleophiles coupled with the triazine ester. On the other hand, alkynes with sterically hindered groups, such as i- butyl (3an), produced the corresponding enynones 3am with a 42% yield. These results highlight the advantages of using triazine ester as acyl electrophiles for synthesizing cross-conjugated enynones with broad applicability.

3. Experimental

3.1. General Information

All reactions were performed using a 27.5 × 72.5 mm screw-caped vial under air without N2 protection. Glassware was dried in an oven before use. All reactions were stirred with magnetic followers. All stated temperatures refer to external bath/heating aluminum block temperatures. Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by thin-layer chromatography using silica gel. The thin-layer chromatography (TLC) employed glass 0.25 mm silica-gel plates. Flash chromatography columns were packed with 200–300 mesh silica-gel in petroleum (the boiling point was between 60–90 °C). Gradient flash chromatography was conducted eluting with a continuous gradient from petroleum to the indicated solvent, and they were listed as volume/volume ratios. 1H NMR and 13C NMR were recorded on a Bruker-400 MHz Spectrometer (1H: 400 MHz, 13C: 101 MHz), using Acetonitrile-d3 as the solvent at room temperature. The chemical shifts (δ) were expressed in ppm, and the coupling constants (J) were expressed in Hz. High-resolution mass spectra (HRMS) were recorded on a Bruker MAXIS spectrometer.

3.2. General Method for the Synthesis of α, β-Unsaturated Triazine Esters

Under an air atmosphere, a round-bottom flask of 150 mL equipped with a magnetic stir bar was charged successively with α-β unsaturated carboxylic acid (1sa–1sr 1.0 mmol), NMM (1.2 mmol) and 10 mL of toluene. The reaction mixture was stirred at room temperature to completely dissolve. Then, 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.2 mmol) was dissolved in 10 mL toluene into the reaction mixture dropwise. After the reaction, the resulting mixture was diluted with 20.0 mL of ethyl acetate and filtrated. The residue was washed with 1N citric acid solution, H2O, and 1N sodium bicarbonate, respectively. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel using the mixed solvent system of petroleum ether (PE) and ethyl acetate (EA) afforded the desired products (1a–1r).

3.3. General Procedure for the Coupling of α, β-Unsaturated Triazine Esters and Alkyne

The general procedure for the optimization reactions: an oven-dried 30-mL screw-cap vial equipped with a magnetic stirring bar was charged with the corresponding α, β-unsaturated triazine esters (0.25 mmol, 1.0 equiv.), alkyne (0.5 mmol, 2 equiv.), Pd-3 (3.0 mol%). Then, MeCN (2.0 mL) was added. The reaction mixture was stirred at 50 °C. The conversion was monitored by TLC analysis, and unless otherwise noted, the triazine esters were fully converted within 12 h. The reaction mixture was diluted with 20.0 mL of ethyl acetate, filtrated, and concentrated under reduced pressure. Purification of the crude product by flash chromatography on silica gel using the mixed-solvent system of petroleum ether (PE) and ethyl acetate (EA) afforded the desired products.
(E)-1,5-diphenylpent-1-en-4-yn-3-one (3aa) [12], the general method using Triazine Ester 1a and Phenylacetylene 2a gave the title compound 3aa in 95% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.02 (d, J = 16.2 Hz, 1H), 7.73 (d, J = 7.3 Hz, 5H), 7.58–7.45 (m, 7H), 6.92 (d, J = 16.2 Hz, 1H). 13C NMR (101 MHz, Acetonitrile-d3): δ/ppm = 177.94, 148.62, 134.26, 133.04, 131.32, 131.02, 129.17, 128.97, 128.93, 128.55, 119.93, 90.75, 86.05.
(E)-5-phenyl-1-(p-tolyl)pent-1-en-4-yn-3-one (3ba) [41], the general method using Triazine Ester 1b and Phenylacetylene 2a gave the title compound 3ba in 94% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.97 (d, J = 16.1 Hz, 1H), 7.74–7.69 (m, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.55–7.43 (m, 3H), 7.27 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 16.1 Hz), 2.37 (s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.93, 148.77, 142.19, 133.00, 131.49, 130.94, 129.81, 128.98, 127.60, 119.98, 90.56, 86.10, 20.69.
(E)-1-(4-methoxyphenyl)-5-phenylpent-1-en-4-yn-3-one (3ca) [41], the general method using Triazine Ester 1c and Phenylacetylene 2a gave the title compound 3ca in 90% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.97 (d, J = 16.1 Hz, 1H), 7.75–7.65 (m, 4H), 7.58–7.51 (m, 1H), 7.48 (m, 2H), 7.04–6.97 (m, 2H), 6.79 (d, J = 16.1 Hz, 1H), 3.84(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.83, 162.43, 148.66, 132.96, 130.90, 128.94, 126.79, 126.33, 120.07, 114.61, 90.28, 86.13, 55.32.
(E)-1-(4-fluorophenyl)-5-phenylpent-1-en-4-yn-3-one (3da) [41], the general method using Triazine Ester 1d and Phenylacetylene 2a gave the title compound 3da in 85% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.97 (d, J = 16.0 Hz, 1H), 7.79–7.69 (m, 4H), 7.58–7.44 (m, 3H), 7.24–7.15 (m, 2H), 6.84 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.80, 164.39 (d, J = 251.6 Hz), 147.26, 133.04, 131.22 (d, J = 8.8 Hz), 131.02, 130.76 (d, J = 12.6 Hz), 128.96, 128.38, 119.89, 116.14 (d, J = 22.3 Hz), 90.77, 85.99.
(E)-5-phenyl-1-(4-(trifluoromethyl)phenyl)pent-1-en-4-yn-3-one (3ea) [42], the general method using Triazine Ester 1e and Phenylacetylene 2a gave the title compound 3ea in 85% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 8.03 (d, J = 16.0 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.78–7.71 (m, 4H), 7.58–7.53 (m, 1H), 7.49 (m, 2H), 6.98 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ/ppm = 177.71, 146.32, 138.04, 133.13, 131.16, 130.70, 129.32, 128.98, 125.93 (d, J = 17.2 Hz), 119.73, 91.30, 85.94.
(E)-1-(4-chlorophenyl)-5-phenylpent-1-en-4-yn-3-one (3fa) [41], the general method using Triazine Ester 1f and Phenylacetylene 2a gave the title compound 3fa in 80% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.95 (d, J = 16.1 Hz, 1H), 7.75–7.66 (m, 4H), 7.61–7.38 (m, 5H), 6.88 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.76, 146.98, 136.55, 133.07, 131.06, 130.39, 129.25, 129.07, 128.96, 119.84, 90.95, 85.99.
(E)-1-(4-bromophenyl)-5-phenylpent-1-en-4-yn-3-one (3ga) [43], the general method using Triazine Ester 1g and Phenylacetylene 2a gave the title compound 3ga in 82% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.95 (d, J = 16.0 Hz, 1H), 7.78–7.70 (m, 2H), 7.65–7.45 (m, 7H), 6.90 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.78, 147.08, 133.43, 133.07, 132.26, 131.07, 130.56, 129.14, 128.97, 125.01, 119.83, 90.98, 85.98.
(E)-5-phenyl-1-(m-tolyl)pent-1-en-4-yn-3-one (3ha), the general method using Triazine Ester 1h and Phenylacetylene 2a gave the title compound 3ha in 93% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.97 (d, J = 16.1 Hz, 1H), 7.80–7.65 (m, 2H), 7.63–7.41 (m, 5H), 7.41–7.19 (m, 2H), 6.89 (d, J = 16.1 Hz, 1H), 2.37(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.95, 148.87, 139.04, 134.19, 133.03, 132.09, 131.00, 129.47, 129.05, 128.97, 128.35, 126.15, 119.93, 86.05, 20.38. IR(KBr): ν(C≡C): 2212 cm−1; ν(C=O): 1627 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C18H15O: 247.1117; Found: 247.1114.
(E)-5-phenyl-1-(o-tolyl)pent-1-en-4-yn-3-one (3ia), the general method using Triazine Ester 1i and Phenylacetylene 2a gave the title compound 3ia in 85% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.03 (d, J = 16.1 Hz, 1H), 7.74–7.64 (m, 3H), 7.50–7.40 (m, 4H), 7.36 (d, J = 5.7 Hz, 1H), 7.28 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 16.1 Hz, 1H), 2.57(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.99, 148.51, 142.20, 134.21, 133.53, 131.31, 131.05, 130.03, 129.17, 128.88, 128.61, 126.18, 119.78, 90.04, 89.74. IR(KBr): ν(C≡C): 2212 cm−1; ν(C=O): 1626 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C18H15O: 247.1117; Found: 247.1112.
(E)-5-phenyl-1-(3,4,5-trimethoxyphenyl)pent-1-en-4-yn-3-one (3ja), the general method using Triazine Ester 1j and Phenylacetylene 2a gave the title compound 3ja in 96% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.92 (d, J = 16.1 Hz, 1H), 7.75–7.71 (m, 2H), 7.58–7.45 (m, 3H), 7.01(s, 2H), 6.89 (d, J = 16.0 Hz, 1H), 3.86(s, 6H), 3.77(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.82, 153.67, 148.82, 140.80, 132.99, 130.94, 129.76, 128.95, 127.92, 119.97, 106.43, 90.49, 86.11, 60.07, 55.94. IR(KBr): ν(C≡C): 2210 cm−1; ν(C=O): 1626 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C20H19O4: 323.1277; Found: 323.1270.
(E)-1-(benzo[d][1,3]dioxol-5-yl)-5-phenylpent-1-en-4-yn-3-one (3la) [44], the general method using Triazine Ester 1k and Phenylacetylene 2a gave the title compound 3ka in 91% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.91 (d, J = 16.0 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.55–7.44 (m, 3H), 7.24 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 16.0 Hz, 1H), 6.04 (s, 2H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.76, 150.73, 148.58, 132.97, 130.90, 128.94, 128.61, 126.72, 126.12, 120.02, 108.60, 106.76, 102.32, 90.39, 86.10. IR(KBr): ν(C≡C): 2211 cm−1; ν(C=O): 1622 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C15H11O2: 223.0753; Found: 223.0747.
(E)-1-(furan-2-yl)-5-phenylpent-1-en-4-yn-3-one (3ka), the general method using Triazine Ester 1l and Phenylacetylene 2a gave the title compound 3la in 95% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.75 (d, J = 15.9 Hz, 1H), 7.70–7.65 (m, 3H), 7.55–7.41 (m,3H), 6.95 (d, J = 3.6 Hz, 1H), 6.71–6.56 (m, 2H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.22, 150.64, 146.68, 146.62, 134.30, 132.99, 130.96, 128.95, 125.55, 119.91, 118.03, 113.30, 90.43, 85.94. IR(KBr): ν(C≡C): 2210 cm−1; ν(C=O): 1624 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C18H13O3: 277.0859; Found: 277.0855.
(E)-2-methyl-1,5-diphenylpent-1-en-4-yn-3-one (3ma) [45], the general method using Triazine Ester 1m and Phenylacetylene 2a gave the title compound 3ma in 78% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.15(s, 1H), 7.71–7.67 (m, 2H), 7.60 (d, J = 7.3 Hz, 2H), 7.54–7.40 (m, 6H), 2.10 (d, J = 1.1 Hz, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 180.31, 145.48, 138.09, 135.50, 132.90, 130.86, 130.33, 129.47, 128.93, 128.71, 120.11, 91.37, 85.81, 11.61.
(E)-4-methyl-1-phenylhex-4-en-1-yn-3-one (3na) [12], the general method using Triazine Ester 1n and Phenylacetylene 2a gave the title compound 3na in 91% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.66–7.59 (m, 2H), 7.52–7.49 (m, 1H), 7.47–7.37 (m, 3H), 1.96 (d, J = 6.9 Hz, 3H), 1.81(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 179.71, 146.18, 139.19, 132.70, 130.71, 128.92, 120.16, 90.22, 85.66, 14.51, 9.44.
5-methyl-1-phenylhex-4-en-1-yn-3-one (3oa) [46], the general method using Triazine Ester 1o and Phenylacetylene 2a gave the title compound 3oa in 87% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.59–7.55 (m, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 2H), 6.28(s, 1H), 2.28(s, 3H), 1.97(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 176.69, 158.34, 132.96, 130.46, 128.65, 126.26, 120.57, 90.42, 89.21, 28.06, 21.33.
(E)-1-phenyloct-4-en-1-yn-3-one (3pa) [47], the general method using Triazine Ester 1p and Phenylacetylene 2a gave the title compound 3pa in 90% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.67–7.62 (m, 2H), 7.56–7.49 (m, 1H), 7.49–7.43 (m, 2H), 7.36 (dt, J = 16.0, 6.9 Hz, 1H), 6.25–6.19 (m, 1H), 2.36–2.28 (m, 2H), 1.56 (h, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 178.16, 155.11, 132.88, 132.14, 130.92, 128.95, 119.89, 90.28, 85.76, 34.27, 20.96, 13.08.
(4E,6E)-1-phenylocta-4,6-dien-1-yn-3-one (3qa), the general method using Triazine Ester 1q and Phenylacetylene 2a gave the title compound 3qa in 94% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.70–7.65 (m, 2H), 7.64–7.50 (m,2H), 7.46 (t, J = 7.3 Hz, 2H), 6.53–6.33 (m, 2H), 6.20 (d, J = 15.6 Hz, 1H), 1.90 (d, J = 6.3 Hz, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 178.05, 149.21, 143.26, 132.90, 130.87, 129.93, 129.70, 128.93, 119.99, 90.15, 86.02, 18.28. IR(KBr): ν(C≡C): 2210 cm−1; ν(C=O): 1619 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C14H13O: 197.0961; Found: 197.0967.
(4E,6E)-1,7-diphenylhepta-4,6-dien-1-yn-3-one (3ra) [48], the general method using Triazine Ester 1r and Phenylacetylene 2a gave the title compound 3ra in 88% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.78 (dd, J = 11.3, 10.5 Hz, 1H), 7.73–7.68 (m, 2H), 7.59–7.52 (m, 3H), 7.51–7.45 (m, 2H), 7.43–7.35 (m, 3H), 7.26–7.09 (m, 2H), 6.41 (d, J = 15.3 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.68, 148.79, 143.06, 136.10, 132.96, 131.66, 130.94, 129.68, 129.06, 128.96, 127.61, 126.52, 120.00, 90.48, 86.18.
(E)-5-(4-methoxyphenyl)-1-phenylpent-1-en-4-yn-3-one (3ab) [7], the general method using Triazine Ester 1a and 1-ethynyl-4-methoxybenzene 2b gave the title compound 3ab in 60% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.97 (d, J = 16.1 Hz, 1H), 7.72 (dd, J = 6.5, 2.9 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.50–7.43 (m, 3H), 7.00 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 16.1 Hz, 1H), 3.84(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.90, 161.94, 147.97, 135.16, 134.33, 131.17, 129.14, 128.85, 128.64, 114.64, 111.51, 91.92, 85.96, 55.38.
(E)-1-phenyl-5-(p-tolyl)pent-1-en-4-yn-3-one (3ac) [41], the general method using Triazine Ester 1a and 4-ethynyltoluene 2c gave the title compound 3ac in 95% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.99 (d, J = 16.2 Hz, 1H), 7.72 (dd, J = 6.7, 2.9 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 5.2, 2.0 Hz, 3H), 7.29 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 16.1 Hz, 1H), 2.39(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.93, 148.33, 141.96, 134.27, 133.08, 131.25, 129.66, 129.15, 128.89, 128.59, 116.79, 91.38, 85.91, 20.84.
(E)-5-(4-ethylphenyl)-1-phenylpent-1-en-4-yn-3-one (3ad), the general method using Triazine Ester 1a and 4-Ethylphenylacetylene 2d gave the title compound 3ad in 61% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.00 (d, J = 16.2 Hz, 1H), 7.72 (dd, J = 6.5, 2.9 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.47 (dd, J = 5.1, 1.7 Hz, 3H), 7.32 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 16.2 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.94, 148.35, 148.13, 134.28, 133.21, 131.25, 129.15, 128.89, 128.59, 128.53, 117.04, 91.39, 85.90, 28.64, 14.73. IR(KBr): ν(C≡C): 2208 cm−1; ν(C=O): 1625 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C19H17O: 261.1274; Found: 261.1277.
(E)-5-(4-butylphenyl)-1-phenylpent-1-en-4-yn-3-one (3ae), the general method using Triazine Ester 1a and 1-Butyl-4-eth-1-ynylbenzene 2e gave the title compound 3ae in 90% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 7.91 (d, J = 16.1 Hz, 1H), 7.63–7.54 (m, 4H), 7.46–7.41 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 16.1 Hz, 1H), 2.65 (t, J = 7.7 Hz, 2H), 1.61 (p, J = 7.3 Hz, 2H), 1.37 (hept, J = 6.8 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (400 MHz, CDCl3): δ/ppm = 178.45, 148.20, 146.41, 134.21, 133.12, 131.21, 129.18, 128.93, 128.78, 128.72, 117.33, 92.42, 86.55, 35.87, 33.35, 22.40, 14.02. IR(KBr): ν(C≡C): 2194 cm−1; ν(C=O): 1627 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C21H21O: 289.1587; Found: 289.1585.
(E)-1-phenyl-5-(m-tolyl)pent-1-en-4-yn-3-one (3af) [4], the general method using Triazine Ester 1a and 1-Ethynyl-3-methylbenzene 2f gave the title compound 3af in 87% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.00 (d, J = 16.1 Hz, 1H), 7.72 (dd, J = 6.5, 2.9 Hz, 2H), 7.56–7.44 (m, 5H), 7.38–7.34 (m, 2H), 6.90 (d, J = 16.1 Hz, 1H), 2.37(s, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.93, 148.51, 139.02, 134.25, 133.43, 131.85, 131.29, 130.15, 129.16, 128.91, 128.86, 128.57, 119.74, 91.09, 85.82, 20.28.
(E)-5-(4-bromophenyl)-1-phenylpent-1-en-4-yn-3-one (3ag) [49], the general method using Triazine Ester 1a and 1-bromo-4-ethynylbenzene 2g gave the title compound 3ag in 75% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 7.89 (d, J = 16.1 Hz, 1H), 7.61 (dd, J = 6.5, 2.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 5.1, 1.7 Hz, 3H), 6.87 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ/ppm = 178.08, 148.65, 134.32, 134.04, 132.17, 131.41, 129.22, 128.84, 128.45, 125.49, 119.21, 90.23, 87.51.
(E)-5-(4-chlorophenyl)-1-phenylpent-1-en-4-yn-3-one (3ah) [49], the general method using Triazine Ester 1a and 1-chloro-4-ethynylbenzene 2h gave the title compound 3ag in 90% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 7.89 (d, J = 16.1 Hz, 1H), 7.64–7.56 (m, 4H), 7.47–7.38 (m, 5H), 6.87 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ/ppm = 178.09, 148.62, 137.09, 134.22, 134.05, 131.39, 129.55–129.09 (m), 128.83, 128.47, 118.75, 90.20, 87.40.
(E)-1-phenyl-5-(4-(trifluoromethyl)phenyl)pent-1-en-4-yn-3-one (3ai) [4], the general method using Triazine Ester 1a and 1-Ethynyl-4-(trifluoromethyl)benzene 2i gave the title compound 3ai in 86% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.03 (d, J = 16.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.73 (m, 2H), 7.50–7.43 (m, 3H), 6.93 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.65, 149.26, 134.14, 133.53, 131.46, 129.18, 128.99, 128.33, 125.74 (d, J = 11.5 Hz), 124.16, 88.39, 87.30.
(E)-5-(4-fluorophenyl)-1-phenylpent-1-en-4-yn-3-one (3aj) [49], the general method using Triazine Ester 1a and 1-fluoro-4-ethynylbenzene 2j gave the title compound 3aj in 76% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 8.00 (d, J = 16.1 Hz, 1H), 7.80–7.71 (m, 4H), 7.47 (m, 3H), 7.26–7.19 (m, 2H), 6.90 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 177.83, 164.02 (d, J = 249.8 Hz), 148.64, 135.64 (d, J = 9.1 Hz), 134.23, 131.32, 129.16, 128.92, 128.47, 116.27 (d, J = 22.6 Hz), 89.72, 85.92.
(E)-5-(2-chlorophenyl)-1-phenylpent-1-en-4-yn-3-one (3ak), the general method using Triazine Ester 1a and 1-chloro-2-ethynylbenzene 2k gave the title compound 3ak in 93% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 8.14 (d, J = 16.1 Hz, 1H), 7.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.60 (dd, J = 6.5, 2.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.46–7.38 (m, 4H), 7.34–7.29 (m, 1H), 6.88 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ/ppm = 178.38, 149.90, 137.47, 135.06, 134.19, 131.80, 131.41, 129.75, 129.22, 128.84, 128.65, 127.01, 120.58, 90.61, 87.77. IR(KBr): ν(C≡C): 2213 cm−1; ν(C=O): 1630 cm−1. HRMS(ESI) m/z: [M+H]+ calcd. for C17H11OCl: 267.0571; Found: 267.0568.
(E)-5-([1,1′-biphenyl]-4-yl)-1-phenylpent-1-en-4-yn-3-one (3al) [4], the general method using Triazine Ester 1a and 4-ethynyl-1,1′-biphenyl 2l gave the title compound 3al in 86% yield; 1H NMR (400 MHz, CDCl3): δ/ppm = 7.94 (d, J = 16.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.68–7.60 (m, 6H), 7.51–7.37 (m, 6H), 6.90 (d, J = 16.1 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ/ppm = 178.33, 148.41, 143.54, 139.89, 134.18, 133.58, 131.30, 129.21, 129.10, 128.83, 128.66, 128.29, 127.43, 127.24, 119.00, 91.76, 87.42.
(E)-1-phenylnon-1-en-4-yn-3-one (3am) [50], the general method using Triazine Ester 1a and hex-1-yne 2m gave the title compound 3am in 80% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.87 (d, J = 16.1 Hz, 1H), 7.73–7.60 (m, 2H), 7.45 (dd, J = 5.1, 2.0 Hz, 3H), 6.79 (d, J = 16.1 Hz, 1H), 2.50 (t, J = 7.1 Hz, 2H), 1.63 (dt, J = 14.8, 7.1 Hz, 2H), 1.49 (dq, J = 14.4, 7.2 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 174.23, 170.70, 162.38, 149.11, 133.75, 131.40, 129.17, 128.68, 115.88, 56.01.
(E)-6,6-dimethyl-1-phenylhept-1-en-4-yn-3-one (3an) [51], the general method using Triazine Ester 1a and 3,3-dimethylbut-1-yne 2n gave the title compound 3an in 42% yield; 1H NMR (400 MHz, Acetonitrile-d3): δ/ppm = 7.84 (d, J = 16.1 Hz, 1H), 7.70–7.65 (m, 2H), 7.46 (dd, J = 5.1, 1.7 Hz, 3H), 6.79 (d, J = 16.1 Hz, 1H), 1.36 (s, 9H). 13C NMR (400 MHz, Acetonitrile-d3): δ/ppm = 178.36, 148.16, 134.22, 131.15, 129.13, 128.79, 128.69, 102.04, 77.23, 29.38, 27.69.

4. Conclusions

This report presents a diversity-oriented synthesis of cross-conjugated enynones through Pd-catalyzed Sonogashira coupling using triazine esters as acyl electrophiles. The study demonstrates that many triazine esters can produce cross-conjugated enynones with high-to-excellent yields under base- and phosphine-ligand-free conditions. The proposed mechanism for the reaction provides a better understanding of the reaction pathway and highlights the significance of triazine-stabilized intermediates in the Pd-catalyzed Sonogashira coupling reaction.
Overall, this method can potentially expand the possibilities of triazine-mediated C-O activation in various fields. Further research is needed to investigate the full potential of this Pd-catalyzed transformation of triazine ester electrophiles, with possible future studies focusing on more challenging substrates and the development of new earth-abundant metal–catalyst systems.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28114364/s1. This file contains details about the spectrum of the product.

Author Contributions

Conceptualization, W.Z. and J.Y.; methodology, D.L. and Y.L.; validation, Y.L., H.Y. and X.Z.; writing—original draft preparation, D.L., H.Y. and X.Z.; writing—review and editing, Y.L., Y.J., W.Z., H.S. and J.Y.; supervision, W.Z., J.Y. and Z.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by a grant from the National Natural Science Foundation of China (22171173), the 111 Project (B14041), Key Research and Development Project of Shaanxi Science and Technology Department (2017SF-064).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article. The data can be found in the Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 28 04364 sch001 550
Scheme 1. Scope and limitation of α, β- triazine esters in of Pd catalyzed Sonogashira coupling reaction. All reactions were performed with 0.25 mmol of triazine esters (1a–1r) and 0.5 mmol of terminal alkynes 2a. Yields are of isolated products after purification by flash chromatography on silica gel.
Scheme 1. Scope and limitation of α, β- triazine esters in of Pd catalyzed Sonogashira coupling reaction. All reactions were performed with 0.25 mmol of triazine esters (1a–1r) and 0.5 mmol of terminal alkynes 2a. Yields are of isolated products after purification by flash chromatography on silica gel.
Molecules 28 04364 sch001
Molecules 28 04364 sch002 550
Scheme 2. Scope and limitation of terminal alkynes of Pd catalyzed Sonogashira coupling reaction. All reactions were performed with 0.25 mmol of cinnamic triazine ester (1a) and 0.5 mmol of terminal alkynes (2b–2n). Yields are of isolated products after purification by flash chromatography on silica gel.
Scheme 2. Scope and limitation of terminal alkynes of Pd catalyzed Sonogashira coupling reaction. All reactions were performed with 0.25 mmol of cinnamic triazine ester (1a) and 0.5 mmol of terminal alkynes (2b–2n). Yields are of isolated products after purification by flash chromatography on silica gel.
Molecules 28 04364 sch002
Table
Table 1. The optimization of the palladium-catalyzed cross-coupling of cinnamic triazine ester 1a and phenylacetylene 3a.
Table 1. The optimization of the palladium-catalyzed cross-coupling of cinnamic triazine ester 1a and phenylacetylene 3a.
Molecules 28 04364 i001
EntryCatalystSolventYield [%] a
1Pd(OAc)2Toluene10
2Pd(OAc)21,4-Dioxane16
3Pd(OAc)2THF13
4Pd(OAc)2DMFN.D.
5Pd(OAc)2Anisole6
6Pd(OAc)2MeCN42
7PdCl2MeCN2
8PdCl2(PPh)2MeCNN.D.
9[(Cinnamyl)PdCl]2MeCN62
10[(2-Methylallyl)PdCl]2MeCN60
11[(allyl)PdCl]2MeCN58
12Pd-1MeCN75
13Pd-2MeCN78
14Pd-3MeCN96
15 bPd-3MeCN95
16 cPd-3MeCN95
a All reactions were performed on a 0.25 mmol scale in 2 mL of solvent, and yields were determined by calibrated GC analysis with biphenyl as an internal standard. b catalyst (3% mol) was used. c catalyst (1% mol) was used, 24 h.
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MDPI and ACS Style

Lin, D.; Liu, Y.; Yang, H.; Zhang, X.; Sun, H.; Jian, Y.; Zhang, W.; Yang, J.; Gao, Z. A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters. Molecules 2023, 28, 4364. https://doi.org/10.3390/molecules28114364

AMA Style

Lin D, Liu Y, Yang H, Zhang X, Sun H, Jian Y, Zhang W, Yang J, Gao Z. A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters. Molecules. 2023; 28(11):4364. https://doi.org/10.3390/molecules28114364

Chicago/Turabian Style

Lin, Dezhi, Yunfang Liu, Hongyu Yang, Xiao Zhang, Huaming Sun, Yajun Jian, Weiqiang Zhang, Jianming Yang, and Ziwei Gao. 2023. "A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters" Molecules 28, no. 11: 4364. https://doi.org/10.3390/molecules28114364

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