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

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.


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

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 PdCl 2 and PdCl 2 (PPh) 2 failed to catalyze the coupling reaction (Entries 7-8). 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  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.
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%. 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.
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 Scheme 1. Scope and limitation of α, βtriazine 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.
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 orthochlorine 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 ibutyl (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.
Molecules 2023, 28, x FOR PEER REVIEW 5 of 12 with a 42% yield. These results highlight the advantages of using triazine ester as acyl electrophiles for synthesizing cross-conjugated enynones with broad applicability.

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.

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 silicagel 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. 1 H NMR and 13 C NMR were recorded on a Bruker-400 MHz Spectrometer ( 1 H: 400 MHz, 13 C: 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.

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).

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.

General Information
All reactions were performed using a 27.5 × 72.5 mm screw-caped vial under air without N 2 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. 1 H NMR and 13 C NMR were recorded on a Bruker-400 MHz Spectrometer ( 1 H: 400 MHz, 13 C: 101 MHz), using Acetonitrile-d 3 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.

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, H 2 O, and 1N sodium bicarbonate, respectively. The organic layer was dried over anhydrous MgSO 4 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).

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 screwcap 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.
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.