**Miloslav Semler, Filip Horký and Petr Štˇepniˇcka \***

Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 40 Prague, Czech Republic; majkls@prepere.com (M.S.); filip.blud@seznam.cz (F.H.) **Miloslav Semler, Filip Horký and Petr Štěpnička \***  Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 40 Prague,

**\*** Correspondence: petr.stepnicka@natur.cuni.cz Czech Republic; majkls@prepere.com (M.S.); filip.blud@seznam.cz (F.H.) **\*** Correspondence: petr.stepnicka@natur.cuni.cz

Received: 25 September 2020; Accepted: 12 October 2020; Published: 15 October 2020 Received: 25 September 2020; Accepted: 12 October 2020; Published: 14 October 2020

**Abstract:** Palladium catalysts deposited over silica gel bearing simple amine (≡Si(CH2)3NH2) and composite functional amide pendants equipped with various donor groups in the terminal position (≡Si(CH2)3NHC(O)CH2Y, Y = SMe, NMe<sup>2</sup> and PPh2) were prepared and evaluated in Sonogashira-type cross-coupling of acyl chlorides with terminal alkynes to give 1,3-disubstituted prop-2-yn-1-ones. Generally, the catalysts showed good catalytic activity in the reactions of aroyl chlorides with aryl alkynes under relatively mild reaction conditions even without adding a copper co-catalyst. However, their repeated use was compromised by a significant loss of activity after the first catalytic run. **Abstract:** Palladium catalysts deposited over silica gel bearing simple amine (≡Si(CH2)3NH2) and composite functional amide pendants equipped with various donor groups in the terminal position (≡Si(CH2)3NHC(O)CH2Y, Y = SMe, NMe2 and PPh2) were prepared and evaluated in Sonogashiratype cross-coupling of acyl chlorides with terminal alkynes to give 1,3-disubstituted prop-2-yn-1 ones. Generally, the catalysts showed good catalytic activity in the reactions of aroyl chlorides with aryl alkynes under relatively mild reaction conditions even without adding a copper co-catalyst. However, their repeated use was compromised by a significant loss of activity after the first catalytic run.

**Keywords:** deposited catalysts; palladium; functional amides; Sonogashira reaction; alkynyl ketone synthesis **Keywords:** deposited catalysts; palladium; functional amides; Sonogashira reaction; alkynyl ketone synthesis

#### **1. Introduction 1. Introduction**

The first examples of Sonogashira-type cross-coupling of terminal alkynes with acyl chlorides to give alkynyl ketones (Scheme 1) were reported by Crisp and O'Donoghue in 1989 [1], who reacted furoyl chlorides with alkynes in the presence of [PdCl2(PhCN)2]/CuI and triethylamine to produce alkynyl furanyl ketones. With [PdCl2(PPh3)2]/CuI and similar catalysts, this reaction subsequently made it possible to synthesize a number of alkynyl ketones in organic solvents [2,3], in water (when adding sodium dodecyl sulfate as a phase transfer reagent) [4–7] and even in a flow reactor (when using unsupported Pd(OAc)<sup>2</sup> as the catalyst) [8]. The first examples of Sonogashira-type cross-coupling of terminal alkynes with acyl chlorides to give alkynyl ketones (Scheme 1) were reported by Crisp and O'Donoghue in 1989 [1], who reacted furoyl chlorides with alkynes in the presence of [PdCl2(PhCN)2]/CuI and triethylamine to produce alkynyl furanyl ketones. With [PdCl2(PPh3)2]/CuI and similar catalysts, this reaction subsequently made it possible to synthesize a number of alkynyl ketones in organic solvents [2,3], in water (when adding sodium dodecyl sulfate as a phase transfer reagent) [4–7] and even in a flow reactor (when using unsupported Pd(OAc)2 as the catalyst) [8].

Alongside the development of homogenous catalysts, various heterogeneous catalytic systems were devised for this cross-coupling reaction. Wang et al. [9] studied the coupling of aromatic chlorides and cinnamoyl chloride with ethynylbenzene mediated by [PdCl2(PPh3)2]/CuI deposited on KF-alumina under microwave irradiation. Subsequent reports described the use of conventional Pd/C [10], Pd nanoparticles supported by poly(1,4-phenylene sulfide) [11] or by functionalized polystyrene, PS-CH2NHC(S)NHN=C(Ph)C(Me)=N-OH (PS = polystyrene) (without a Cu co-catalyst) [12], and applications of Pd/BaSO4 with a ZnCl2 co-catalyst [13,14] in similar reactions. Alongside the development of homogenous catalysts, various heterogeneous catalytic systems were devised for this cross-coupling reaction. Wang et al. [9] studied the coupling of aromatic chlorides and cinnamoyl chloride with ethynylbenzene mediated by [PdCl2(PPh3)2]/CuI deposited on KF-alumina under microwave irradiation. Subsequent reports described the use of conventional Pd/C [10], Pd nanoparticles supported by poly(1,4-phenylene sulfide) [11] or by functionalized polystyrene, PS-CH2NHC(S)NHN=C(Ph)C(Me)=N-OH (PS = polystyrene) (without a Cu co-catalyst) [12], and applications of Pd/BaSO<sup>4</sup> with a ZnCl<sup>2</sup> co-catalyst [13,14] in similar reactions.

In 2009, Tsai et al. [15] reported the application of a Pd-bipyridyl complex grafted onto the mesoporous molecular sieve MCM-41.Coupling reactions of various substrates mediated by this catalyst in neat triethylamine, in the presence of CuI and triphenylphosphine, proceeded satisfactorily at low Pd loading (0.002–0.1 mol.%). More recently, Cai et al. [16] used a related Pd catalyst prepared by depositing Pd(OAc)<sup>2</sup> over an MCM-41 surface, modified by ≡Si(CH2)3NHCH2CH2NH<sup>2</sup> groups. At 0.2 mol.% Pd loading, and with 0.2 mol.% CuI as a co-catalyst, this material could be reused ten times with only a marginal loss of activity (reaction in triethylamine at 50 ◦C). Other authors evaluated the related catalysts obtained from supports bearing phosphine-donor groups, e.g., periodic mesoporous silica with ≡CH2CH2PPh<sup>2</sup> substituents [17] and polystyrene modified by the –CH2P <sup>+</sup>Ph2CH2CH2PPh<sup>2</sup> Cl− moieties at the surface [18]. In 2009, Tsai et al. [15] reported the application of a Pd-bipyridyl complex grafted onto the mesoporous molecular sieve MCM-41.Coupling reactions of various substrates mediated by this catalyst in neat triethylamine, in the presence of CuI and triphenylphosphine, proceeded satisfactorily at low Pd loading (0.002–0.1 mol.%). More recently, Cai et al. [16] used a related Pd catalyst prepared by depositing Pd(OAc)2 over an MCM-41 surface, modified by ≡Si(CH2)3NHCH2CH2NH2 groups. At 0.2 mol.% Pd loading, and with 0.2 mol.% CuI as a co-catalyst, this material could be reused ten times with only a marginal loss of activity (reaction in triethylamine at 50 °C). Other authors evaluated the related catalysts obtained from supports bearing phosphinedonor groups, e.g., periodic mesoporous silica with ≡CH2CH2PPh2 substituents [17] and polystyrene modified by the –CH2P+Ph2CH2CH2PPh2 Cl− moieties at the surface [18]. Alkynyl ketones are valuable synthetic building blocks, opening an access to a range of useful

Alkynyl ketones are valuable synthetic building blocks, opening an access to a range of useful compounds, such as intermediates for the synthesis of various heterocycles [19–23], biologically active compounds [24], naturally occurring compounds [25], liquid-crystalline materials [26], and ligands for transition metal ions [27]. In particular, the promising results achieved with deposited catalysts in the cross-coupling of acyl chlorides and alkynes and the wide range of applications of coupling products led us to consider using palladium catalysts deposited over the conventional silica gel bearing donor-substituted amide pendants [28] at the surface (Scheme 2) [29], which were already evaluated in Suzuki-Miyaura biaryl coupling [30]. The results from our study of these catalysts are presented in this contribution, with a particular focus on the reaction scope and a possible influence of the donor moieties within the functional supports that were varied. compounds, such as intermediates for the synthesis of various heterocycles [19–23], biologically active compounds [24], naturally occurring compounds [25], liquid-crystalline materials [26], and ligands for transition metal ions [27]. In particular, the promising results achieved with deposited catalysts in the cross-coupling of acyl chlorides and alkynes and the wide range of applications of coupling products led us to consider using palladium catalysts deposited over the conventional silica gel bearing donor-substituted amide pendants [28] at the surface (Scheme 2) [29], which were already evaluated in Suzuki-Miyaura biaryl coupling [30]. The results from our study of these catalysts are presented in this contribution, with a particular focus on the reaction scope and a possible influence of the donor moieties within the functional supports that were varied.

**Scheme 2.** Deposited catalysts used in this study. **Scheme 2.** Deposited catalysts used in this study.

### **2. Results**

#### **2. Results**  *2.1. Synthesis of the Catalysts*

*2.1. Synthesis of the Catalysts*  The deposited catalysts were prepared as reported previously (Scheme 3) [29]. In the first step, freshly calcined, commercial chromatography-grade silica gel (size fraction 63–200 µm) was mixed with (3-aminopropyl)trimethoxysilane in refluxing toluene to afford 3-aminopropylated support **1**. Material **1** was subsequently treated with α-functionalized acetic acids in the presence of peptide coupling agents [31,32], yielding the corresponding amide-functionalized supports **2–4**. In the final step, the resulting materials were treated with palladium(II) acetate in dichloromethane to produce the deposited Pd catalysts **5–7**. As an extension of our previous work, the parent aminopropylated The deposited catalysts were prepared as reported previously (Scheme 3) [29]. In the first step, freshly calcined, commercial chromatography-grade silica gel (size fraction 63–200 µm) was mixed with (3-aminopropyl)trimethoxysilane in refluxing toluene to afford 3-aminopropylated support **1**. Material **1** was subsequently treated with α-functionalized acetic acids in the presence of peptide coupling agents [31,32], yielding the corresponding amide-functionalized supports **2–4**. In the final step, the resulting materials were treated with palladium(II) acetate in dichloromethane to produce the deposited Pd catalysts **5–7**. As an extension of our previous work, the parent aminopropylated material **1** was also palladated to give material **8** containing only amine functional groups.

material **1** was also palladated to give material **8** containing only amine functional groups.

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**Scheme 3.** Preparation of catalysts **5**-**8**. Legend: *i*. (3-aminopropyl)trimethoxysilane in toluene, refluxing; *ii*. amidation with **Y**CH2CO2H in the presence of peptide coupling agents (1 hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) or the corresponding hydrochloride (EDC⋅HCl)); *iii*. treatment with Pd(OAc)2 in dichloromethane. **Scheme 3.** Preparation of catalysts **5**–**8**. Legend: *i*. (3-aminopropyl)trimethoxysilane in toluene, refluxing; *ii*. amidation with **Y**CH2CO2H in the presence of peptide coupling agents (1-hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) or the corresponding hydrochloride (EDC·HCl)); *iii*. treatment with Pd(OAc)<sup>2</sup> in dichloromethane. **Scheme 3.** Preparation of catalysts **5**-**8**. Legend: *i*. (3-aminopropyl)trimethoxysilane in toluene, refluxing; *ii*. amidation with **Y**CH2CO2H in the presence of peptide coupling agents (1 hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC) or the corresponding hydrochloride (EDC⋅HCl)); *iii*. treatment with Pd(OAc)2 in dichloromethane.

Materials **1**–**8** were characterized by elemental analysis and infrared (IR) spectroscopy, and the data on **1**–**7** were compared with those on the previously studied catalysts. While the IR spectra of the newly synthesized materials were virtually identical to those previously reported (see ref. [29]), elemental analysis revealed differences, most likely reflecting the amount of residual adsorbed matter (mostly water). Full characterization data are presented in the Experimental Section. Materials **1**–**8** were characterized by elemental analysis and infrared (IR) spectroscopy, and the data on **1**–**7** were compared with those on the previously studied catalysts. While the IR spectra of the newly synthesized materials were virtually identical to those previously reported (see ref. [29]), elemental analysis revealed differences, most likely reflecting the amount of residual adsorbed matter (mostly water). Full characterization data are presented in the Experimental Section. Materials **1**–**8** were characterized by elemental analysis and infrared (IR) spectroscopy, and the data on **1**–**7** were compared with those on the previously studied catalysts. While the IR spectra of the newly synthesized materials were virtually identical to those previously reported (see ref. [29]), elemental analysis revealed differences, most likely reflecting the amount of residual adsorbed matter (mostly water). Full characterization data are presented in the Experimental Section.

#### *2.2. Catalytic Assessment 2.2. Catalytic Assessment 2.2. Catalytic Assessment*

Applications of deposited Pd catalysts to Sonogashira-type coupling of terminal alkynes with acyl chlorides (see Introduction) has been studied considerably less than their use in conventional Sonogashira cross-coupling between alkynes and organic halides [33]. Hence, our initial experiments with catalysts **5**–**8** aimed to find the optimal reaction conditions for these catalysts and to compare their performance with regard to influence of the varied functional groups modifying the support's surface. As a model reaction, we chose the coupling between equimolar amounts of ethynylbenzene (**9a**) and 4-methylbenzoyl chloride (**10d**), producing 1-(4-methylphenyl)-3-phenyl-2-propyn-1-one (**11ad**, see Scheme 4). The influence of the solvent and base, which are known to strongly affect these reactions (see references in the Introduction), were evaluated first. The screening experiments were performed with 0.5 mol.% of catalyst **5** and 5 mol.% of CuI in neat amines and in mixtures of triethylamine with an organic solvent as well. When using neat morpholine and pyridine, the coupling reaction did not proceed in any appreciable extent. However, when replacing these bases with *N*-methylmorpholine and *N*,*N*-diisopropylethylamine (Figure 1), the yields determined by gas chromatography (GC yields) of the coupling product **11ad** after 8 h at 50 °C were 2% and 10%, respectively. The best (albeit still rather low) yield of 21% after 8 h was achieved in neat triethylamine. Applications of deposited Pd catalysts to Sonogashira-type coupling of terminal alkynes with acyl chlorides (see Introduction) has been studied considerably less than their use in conventional Sonogashira cross-coupling between alkynes and organic halides [33]. Hence, our initial experiments with catalysts **5**–**8** aimed to find the optimal reaction conditions for these catalysts and to compare their performance with regard to influence of the varied functional groups modifying the support's surface. As a model reaction, we chose the coupling between equimolar amounts of ethynylbenzene (**9a**) and 4-methylbenzoyl chloride (**10d**), producing 1-(4-methylphenyl)-3-phenyl-2-propyn-1-one (**11ad**, see Scheme 4). The influence of the solvent and base, which are known to strongly affect these reactions (see references in the Introduction), were evaluated first. The screening experiments were performed with 0.5 mol.% of catalyst **5** and 5 mol.% of CuI in neat amines and in mixtures of triethylamine with an organic solvent as well. When using neat morpholine and pyridine, the coupling reaction did not proceed in any appreciable extent. However, when replacing these bases with *N*-methylmorpholine and *N*,*N*-diisopropylethylamine (Figure 1), the yields determined by gas chromatography (GC yields) of the coupling product **11ad** after 8 h at 50 ◦C were 2% and 10%, respectively. The best (albeit still rather low) yield of 21% after 8 h was achieved in neat triethylamine. Applications of deposited Pd catalysts to Sonogashira-type coupling of terminal alkynes with acyl chlorides (see Introduction) has been studied considerably less than their use in conventional Sonogashira cross-coupling between alkynes and organic halides [33]. Hence, our initial experiments with catalysts **5**–**8** aimed to find the optimal reaction conditions for these catalysts and to compare their performance with regard to influence of the varied functional groups modifying the support's surface. As a model reaction, we chose the coupling between equimolar amounts of ethynylbenzene (**9a**) and 4-methylbenzoyl chloride (**10d**), producing 1-(4-methylphenyl)-3-phenyl-2-propyn-1-one (**11ad**, see Scheme 4). The influence of the solvent and base, which are known to strongly affect these reactions (see references in the Introduction), were evaluated first. The screening experiments were performed with 0.5 mol.% of catalyst **5** and 5 mol.% of CuI in neat amines and in mixtures of triethylamine with an organic solvent as well. When using neat morpholine and pyridine, the coupling reaction did not proceed in any appreciable extent. However, when replacing these bases with *N*-methylmorpholine and *N*,*N*-diisopropylethylamine (Figure 1), the yields determined by gas chromatography (GC yields) of the coupling product **11ad** after 8 h at 50 °C were 2% and 10%, respectively. The best (albeit still rather low) yield of 21% after 8 h was achieved in neat triethylamine.

**Scheme 4.** Coupling reaction used to screen for reaction conditions. **Scheme 4.** Coupling reaction used to screen for reaction conditions. **Scheme 4.** Coupling reaction used to screen for reaction conditions.

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**Figure 1.** Kinetic profiles for the model coupling reaction performed in neat amines (0.5 mol.% catalyst **5**, 5 mol.% CuI) at 50 °C. Solid lines are added as a visual guide. **Figure 1.** Kinetic profiles for the model coupling reaction performed in neat amines (0.5 mol.% catalyst **5**, 5 mol.% CuI) at 50 ◦C. Solid lines are added as a visual guide. **5**, 5 mol.% CuI) at 50 °C. Solid lines are added as a visual guide.

Reaction tests performed in organic solvents in the presence of 5 equiv. of triethylamine (Figure

Reaction tests performed in organic solvents in the presence of 5 equiv. of triethylamine (Figure 2) revealed a marked acceleration of the coupling reaction in acetonitrile (ca. 60% yield of **11ad** within 3 h at 50 °C). In contrast, reactions in other tested solvents, viz. toluene, 1,4-dioxane, acetone and *N,N*dimethylformamide, proceeded less efficiently, achieving lower yields than the aforementioned reaction in neat triethylamine (below 15% after 8 h; Figure 2); no reaction was observed in methanol. Reaction tests performed in organic solvents in the presence of 5 equiv. of triethylamine (Figure 2) revealed a marked acceleration of the coupling reaction in acetonitrile (ca. 60% yield of **11ad** within 3 h at 50 ◦C). In contrast, reactions in other tested solvents, viz. toluene, 1,4-dioxane, acetone and *N*,*N*-dimethylformamide, proceeded less efficiently, achieving lower yields than the aforementioned reaction in neat triethylamine (below 15% after 8 h; Figure 2); no reaction was observed in methanol. 2) revealed a marked acceleration of the coupling reaction in acetonitrile (ca. 60% yield of **11ad** within 3 h at 50 °C). In contrast, reactions in other tested solvents, viz. toluene, 1,4-dioxane, acetone and *N,N*dimethylformamide, proceeded less efficiently, achieving lower yields than the aforementioned reaction in neat triethylamine (below 15% after 8 h; Figure 2); no reaction was observed in methanol.

**Figure 2.** Kinetic profiles for the model coupling reaction performed in organic solvents with added triethylamine (5 equiv. NEt3, 0.5 mol.% catalyst **5**, 5 mol.% CuI) at 50 °C. Legend: MeCN (), DMF **Figure 2.** Kinetic profiles for the model coupling reaction performed in organic solvents with added triethylamine (5 equiv. NEt3, 0.5 mol.% catalyst **5**, 5 mol.% CuI) at 50 °C. Legend: MeCN (), DMF (), acetone (), dioxane (), toluene (). The solid lines connecting the experimental points are a visual guide and do not represent any fit of the data. **Figure 2.** Kinetic profiles for the model coupling reaction performed in organic solvents with added triethylamine (5 equiv. NEt<sup>3</sup> , 0.5 mol.% catalyst **<sup>5</sup>**, 5 mol.% CuI) at 50 ◦C. Legend: MeCN (#), DMF (), acetone (H), dioxane (•), toluene (4). The solid lines connecting the experimental points are a visual guide and do not represent any fit of the data.

(), acetone (), dioxane (), toluene (). The solid lines connecting the experimental points are a

visual guide and do not represent any fit of the data. A subsequent series of experiments was designed to assess the effect of the CuI additive and relative amounts of the starting materials. Rather surprisingly, the reaction performed in neat triethylamine with 0.5 mol.% of catalyst **5** *without* adding CuI at 50 °C ensued in a higher yield of the coupling product than the similar reaction in the presence of the CuI co-catalyst (5 mol.%; 39% vs. 21%). Consistently, when using acetonitrile as the solvent (with added NEt3, 5 equiv.), the reaction without CuI produced **11ad** in a 78% yield after 8 h, which is a higher yield than that of the reaction performed in the absence of CuI (63%). Subsequently, we determined whether the coupling reaction is affected by the amount of acyl chloride when gradually increasing the amount of 4-toulyl chloride (**10d**) up to 1.5 equiv. As shown in Figure 3, the yield of **11ad** significantly increased with the amount A subsequent series of experiments was designed to assess the effect of the CuI additive and relative amounts of the starting materials. Rather surprisingly, the reaction performed in neat triethylamine with 0.5 mol.% of catalyst **5** *without* adding CuI at 50 °C ensued in a higher yield of the coupling product than the similar reaction in the presence of the CuI co-catalyst (5 mol.%; 39% vs. 21%). Consistently, when using acetonitrile as the solvent (with added NEt3, 5 equiv.), the reaction without CuI produced **11ad** in a 78% yield after 8 h, which is a higher yield than that of the reaction performed in the absence of CuI (63%). Subsequently, we determined whether the coupling reaction is affected by the amount of acyl chloride when gradually increasing the amount of 4-toulyl chloride (**10d**) up to 1.5 equiv. As shown in Figure 3, the yield of **11ad** significantly increased with the amount A subsequent series of experiments was designed to assess the effect of the CuI additive and relative amounts of the starting materials. Rather surprisingly, the reaction performed in neat triethylamine with 0.5 mol.% of catalyst **5** without adding CuI at 50 ◦C ensued in a higher yield of the coupling product than the similar reaction in the presence of the CuI co-catalyst (5 mol.%; 39% vs. 21%). Consistently, when using acetonitrile as the solvent (with added NEt3, 5 equiv.), the reaction without CuI produced **11ad** in a 78% yield after 8 h, which is a higher yield than that of the reaction performed in the absence of CuI (63%). Subsequently, we determined whether the coupling reaction is affected by the amount of acyl chloride when gradually increasing the amount of 4-toulyl chloride (**10d**) up to 1.5 equiv. As shown in Figure 3, the yield of **11ad** significantly increased with the amount of acyl chloride. With only 1.3 equiv. of **10d**, the GC yields of the coupling product were already virtually quantitative within 1 h of the reaction time.

of acyl chloride. With only 1.3 equiv. of **10d**, the GC yields of the coupling product were already

of acyl chloride. With only 1.3 equiv. of **10d**, the GC yields of the coupling product were already

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**Figure 3.** Variation in the gas chromatography (GC) yields of **11ad** observed when changing the amount of acyl chloride in the reaction mixture. Conditions: catalyst **5** (0.5 mol.%), alkyne **9a** (1 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 50 °C. Reaction time: 1 h (white bars), 3 h (grey bars), and 8 h (black bars). **Figure 3.** Variation in the gas chromatography (GC) yields of **11ad** observed when changing the amount of acyl chloride in the reaction mixture. Conditions: catalyst **5** (0.5 mol.%), alkyne **9a** (1 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 50 ◦C. Reaction time: 1 h (white bars), 3 h (grey bars), and 8 h (black bars). amount of acyl chloride in the reaction mixture. Conditions: catalyst **5** (0.5 mol.%), alkyne **9a** (1 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 50 °C. Reaction time: 1 h (white bars), 3 h (grey bars), and 8 h (black bars).

**Figure 3.** Variation in the gas chromatography (GC) yields of **11ad** observed when changing the

Using 1.5 equiv. of **10d**, we subsequently tried to reduce the catalyst loading. Under these conditions, the reaction proceeded satisfactorily, even in the presence of 0.1 and 0.2 mol.% of the selected model catalyst **5** and at short reaction times, as shown in Figure 4, which compares the GC yields of the coupling product **11ad** achieved over different periods of time. When decreasing the reaction temperature, however, the yield of the coupling product dramatically decreased (100% at 50 °C, 67% at 40 °C and ≈14% at 30 °C after 30 min of the reaction with catalyst **5** and 0.5 mol.% Pd in the reaction mixture). Using 1.5 equiv. of **10d**, we subsequently tried to reduce the catalyst loading. Under these conditions, the reaction proceeded satisfactorily, even in the presence of 0.1 and 0.2 mol.% of the selected model catalyst **5** and at short reaction times, as shown in Figure 4, which compares the GC yields of the coupling product **11ad** achieved over different periods of time. When decreasing the reaction temperature, however, the yield of the coupling product dramatically decreased (100% at 50 ◦C, 67% at 40 ◦C and ≈14% at 30 ◦C after 30 min of the reaction with catalyst **5** and 0.5 mol.% Pd in the reaction mixture). Using 1.5 equiv. of **10d**, we subsequently tried to reduce the catalyst loading. Under these conditions, the reaction proceeded satisfactorily, even in the presence of 0.1 and 0.2 mol.% of the selected model catalyst **5** and at short reaction times, as shown in Figure 4, which compares the GC yields of the coupling product **11ad** achieved over different periods of time. When decreasing the reaction temperature, however, the yield of the coupling product dramatically decreased (100% at 50 °C, 67% at 40 °C and ≈14% at 30 °C after 30 min of the reaction with catalyst **5** and 0.5 mol.% Pd in the reaction mixture).

**Figure 4.** Variation in the GC yields of **11ad** observed upon changing the amount of catalyst **5**. Catalyst loading: 0.1 mol.% (white bars), 0.2 mol.% (grey bars), and 0.5 mol.% (black bars). Conditions: alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal **Figure 4.** Variation in the GC yields of **11ad** observed upon changing the amount of catalyst **5**. Catalyst loading: 0.1 mol.% (white bars), 0.2 mol.% (grey bars), and 0.5 mol.% (black bars). Conditions: alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 50 °C. **Figure 4.** Variation in the GC yields of **11ad** observed upon changing the amount of catalyst **5**. Catalyst loading: 0.1 mol.% (white bars), 0.2 mol.% (grey bars), and 0.5 mol.% (black bars). Conditions: alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 50 ◦C.

standard) in acetonitrile solvent at 50 °C. Lastly, we compared all prepared catalysts and palladium(II) acetate under rather harsh reaction conditions (0.1 mol.% Pd, 30 °C reaction temperature). Regrettably, the kinetic profiles presented in Figure 5 clearly indicate that unsupported palladium(II) acetate outperforms all deposited catalysts. Among the deposited catalysts, the lowest efficiency exerted catalyst **7** bearing phosphine groups, Lastly, we compared all prepared catalysts and palladium(II) acetate under rather harsh reaction conditions (0.1 mol.% Pd, 30 °C reaction temperature). Regrettably, the kinetic profiles presented in Figure 5 clearly indicate that unsupported palladium(II) acetate outperforms all deposited catalysts. Among the deposited catalysts, the lowest efficiency exerted catalyst **7** bearing phosphine groups, Lastly, we compared all prepared catalysts and palladium(II) acetate under rather harsh reaction conditions (0.1 mol.% Pd, 30 ◦C reaction temperature). Regrettably, the kinetic profiles presented in Figure 5 clearly indicate that unsupported palladium(II) acetate outperforms all deposited catalysts. Among the deposited catalysts, the lowest efficiency exerted catalyst **7** bearing phosphine groups, whereas the performance of catalysts bearing the S- and N-donor groups (**5** and **6**) was quite similar and slightly better than that of catalyst **8** obtained from the amine-functionalized support.

whereas the performance of catalysts bearing the S- and N-donor groups (**5** and **6**) was quite similar

and slightly better than that of catalyst **8** obtained from the amine-functionalized support.

whereas the performance of catalysts bearing the S- and N-donor groups (**5** and **6**) was quite similar

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**Figure 5.** Kinetic profiles for the model coupling reaction performed in the presence of different catalysts: Pd(OAc)2 (), catalyst **5** (), catalyst **6** (), catalyst **7** (), and catalyst **8** (). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 30 °C. The solid lines connecting the experimental points serve as a visual guide and do not represent any fit of the data. **Figure 5.** Kinetic profiles for the model coupling reaction performed in the presence of different catalysts: Pd(OAc)<sup>2</sup> (N), catalyst **<sup>5</sup>** (•), catalyst **<sup>6</sup>** (5), catalyst **<sup>7</sup>** (), and catalyst **<sup>8</sup>** (3). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 30 ◦C. The solid lines connecting the experimental points serve as a visual guide and do not represent any fit of the data. catalysts: Pd(OAc)2 (), catalyst **5** (), catalyst **6** (), catalyst **7** (), and catalyst **8** (). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile solvent at 30 °C. The solid lines connecting the experimental points serve as a visual guide and do not represent any fit of the data.

Recycled catalysts **5–8** significantly lost their activity (Figure 6), presumably due to leaching of

Recycled catalysts **5–8** significantly lost their activity (Figure 6), presumably due to leaching of the deposited metal and to overall catalyst deactivation (the amount of Pd leached out during the first run was only 1%–4% of the initial amount). Notably, CuI (5 mol.%) addition to the reaction mixture increased the stability of the catalysts and even led to an activation of the phosphinefunctionalized catalyst **7**, whereas the amount of leached-out Pd remained approximately the same (2%–4% during the first run; see the Supporting Information, Table S1). However, the yields of **11ad** obtained with recycled deposited catalysts **5–8**/CuI were still considerably lower than the yields achieved during the first runs and further decreased upon catalyst reuse. Recycled catalysts **5–8** significantly lost their activity (Figure 6), presumably due to leaching of the deposited metal and to overall catalyst deactivation (the amount of Pd leached out during the first run was only 1%–4% of the initial amount). Notably, CuI (5 mol.%) addition to the reaction mixture increased the stability of the catalysts and even led to an activation of the phosphine-functionalized catalyst **7**, whereas the amount of leached-out Pd remained approximately the same (2–4% during the first run; see the Supporting Information, Table S1). However, the yields of **11ad** obtained with recycled deposited catalysts **5–8**/CuI were still considerably lower than the yields achieved during the first runs and further decreased upon catalyst reuse. the deposited metal and to overall catalyst deactivation (the amount of Pd leached out during the first run was only 1%–4% of the initial amount). Notably, CuI (5 mol.%) addition to the reaction mixture increased the stability of the catalysts and even led to an activation of the phosphinefunctionalized catalyst **7**, whereas the amount of leached-out Pd remained approximately the same (2%–4% during the first run; see the Supporting Information, Table S1). However, the yields of **11ad** obtained with recycled deposited catalysts **5–8**/CuI were still considerably lower than the yields achieved during the first runs and further decreased upon catalyst reuse.

**Figure 6.** Results of catalytic experiments with fresh and reused catalysts without (left) and with (right) added CuI (5 mol.%): catalyst **5** (white bars), catalyst **6** (grey bars), catalyst **7** (black bars), and catalyst **8** (hatched bars). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), **Figure 6.** Results of catalytic experiments with fresh and reused catalysts without (left) and with (right) added CuI (5 mol.%): catalyst **5** (white bars), catalyst **6** (grey bars), catalyst **7** (black bars), and catalyst **8** (hatched bars). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile at 50 °C for 2 h. **Figure 6.** Results of catalytic experiments with fresh and reused catalysts without (left) and with (right) added CuI (5 mol.%): catalyst **5** (white bars), catalyst **6** (grey bars), catalyst **7** (black bars), and catalyst **8** (hatched bars). Conditions: 0.1 mol.% Pd, alkyne **9a** (1 equiv.), acyl chloride **10d** (1.5 equiv.), triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile at 50 ◦C for 2 h.

triethylamine (5 equiv.), dodecane (1 equiv.; internal standard) in acetonitrile at 50 °C for 2 h. Using catalyst **5** (0.5 mol.% Pd), we also performed reaction scope tests, which are summarized in Table 1. Initially, we focused on the reactions of ethynylbenzene (**9a**) with substituted benzoyl chlorides. In the case of methyl-substituted acyl chlorides, the yields of the coupling products Using catalyst **5** (0.5 mol.% Pd), we also performed reaction scope tests, which are summarized in Table 1. Initially, we focused on the reactions of ethynylbenzene (**9a**) with substituted benzoyl chlorides. In the case of methyl-substituted acyl chlorides, the yields of the coupling products Using catalyst **5** (0.5 mol.% Pd), we also performed reaction scope tests, which are summarized in Table 1. Initially, we focused on the reactions of ethynylbenzene (**9a**) with substituted benzoyl chlorides. In the case of methyl-substituted acyl chlorides, the yields of the coupling products increased with the decrease in steric hindrance. Similar reactions with isomeric nitrobenzoyl chlorides proceeded generally less efficiently and required longer reaction times to achieve isolated yields of the coupling products higher than 50%; the reaction of **9a** with 2-nitrobenzoyl chloride, the most sterically crowded and deactivated acyl chloride, did not proceed. For the acyl chlorides, the substituents with a positive

inductive (+*I*) or a mesomeric (+*M*) effect (4-Me, 4-Cl and 4-MeO) apparently facilitated the reaction (isolated yields 85% or higher), whereas the nitro group, with a strong −*M* effect, hampered the cross-coupling. Conversely, the outcome of the coupling reactions between benzoyl chloride (**10a**) and substituted phenylacetylenes (4-Me, 4-MeO and 4-CF3) all proceeded with high isolated yields, in line with the long distance between the substituents in position 4 of the benzene ring and the reaction site, which inevitably minimizes their influence.


**Table 1.** Summary of the reaction scope tests <sup>a</sup> .

<sup>a</sup> Conditions: alkyne (1.0 mmol), acyl chloride (1.5 mmol) and triethylamine (5 mmol) were mixed in the presence of catalyst **5** (0.5 mol.% Pd) in acetonitrile (5 mL) at 50 ◦C for 2 h. <sup>b</sup> Isolated yield after column chromatography. An average of two independent runs is given. <sup>c</sup> Fc = ferrocenyl. <sup>d</sup> Reaction time was extended to 24 h. <sup>e</sup> n.d. = the product was not detected. <sup>f</sup> The reaction was performed with 1.0 mmol of acyl chloride, and the reaction time was extended to 4 h.

The coupling of **9a** with cinnamoyl chloride also proceeded satisfactorily, producing **11ak** in an 87% isolated yield. In contrast, 3-phenylpropanoyl chloride (as a representative of aliphatic acyl chlorides bearing an sp<sup>3</sup> substituent at the acyl group) did not produce any coupling product under analogous conditions. Conversely, pivaloyl chloride was converted into **11am** with an acceptable 51% isolated yield. A similar yield was obtained with 2-furoyl chloride, whereas the reaction with 2-thiophenecarbonyl chloride had a lower yield. The ethynylferrocene/benzoyl chloride pair also displayed a rather sluggish reaction, associated with side processes that were partly suppressed by lowering the amount of the acyl chloride.

In addition to spectroscopic characterization, the structure of **11af** was determined by single-crystal X-ray diffraction analysis. Figure 7 shows the corresponding molecular structure along with selected interatomic distances and angles.

C8-C9 177.0(3), C8-C9C-10 175.5(3).

**3. Experimental** 

*3.1. Methods and Materials* 

**3. Experimental** 

*3.1. Methods and Materials* 

**Figure 7.** PLATON [34] plot of the molecular structure of **11af** showing the atomic labels and displacement ellipsoids at 50% probability level. Selected distances and angles (in Å and deg): N1=O1 1.224(4), N1=O2 1.229(3), C3-N1 1.468(4), C7=O3 1.223(4), C1-C7 1.492(4), C7-C8 1.447(4), C8-C9 1.205(4), C9-C10 1.433(4); O1=N1=O2 123.4(2), C1-C7-C8 116.7(3), O3=C7-C1/C8 121.6(2)/121.7(2), C7- **Figure 7.** PLATON [34] plot of the molecular structure of **11af** showing the atomic labels and displacement ellipsoids at 50% probability level. Selected distances and angles (in Å and deg): N1=O1 1.224(4), N1=O2 1.229(3), C3-N1 1.468(4), C7=O3 1.223(4), C1-C7 1.492(4), C7-C8 1.447(4), C8-C9 1.205(4), C9-C10 1.433(4); O1=N1=O2 123.4(2), C1-C7-C8 116.7(3), O3=C7-C1/C8 121.6(2)/121.7(2), C7-C8-C9 177.0(3), C8-C9C-10 175.5(3). **Figure 7.** PLATON [34] plot of the molecular structure of **11af** showing the atomic labels and displacement ellipsoids at 50% probability level. Selected distances and angles (in Å and deg): N1=O1 1.224(4), N1=O2 1.229(3), C3-N1 1.468(4), C7=O3 1.223(4), C1-C7 1.492(4), C7-C8 1.447(4), C8-C9 1.205(4), C9-C10 1.433(4); O1=N1=O2 123.4(2), C1-C7-C8 116.7(3), O3=C7-C1/C8 121.6(2)/121.7(2), C7- C8-C9 177.0(3), C8-C9C-10 175.5(3).

The compound crystallizes with the symmetry of the triclinic space group *P–*1 and with one molecule in the asymmetric unit. Parameters describing the molecular geometry of **11af** are unexceptional and in line with the corresponding parameters reported for 1-(4-nitrophenyl)-3 phenylprop-2-yn-1-one (4-O2NC6H4C(O)C≡CPh) [2,35] and 3-(4-methoxyphenyl)-1-phenylprop-2 yn-1-one (PhC(O)C≡CC6H4OMe-4) [36]. The planes of the benzene rings C(1-6) and C(10-15) in **11af** are essentially coplanar (dihedral angle: 0.4(1)°), and even the nitro group is twisted by only 4.1(3)° with respect to its bonding benzene ring. In the crystal, the individual molecules assemble into columnar stacks of inversion-related molecules (Figure 8) via offset π···π stacking interactions of their parallel aromatic rings. These stacks, oriented along the crystallographic *b* axis, are further The compound crystallizes with the symmetry of the triclinic space group *P*–1 and with one molecule in the asymmetric unit. Parameters describing the molecular geometry of **11af** are unexceptional and in line with the corresponding parameters reported for 1-(4-nitrophenyl)- 3-phenylprop-2-yn-1-one (4-O2NC6H4C(O)C≡CPh) [2,35] and 3-(4-methoxyphenyl)- 1-phenylprop-2-yn-1-one (PhC(O)C≡CC6H4OMe-4) [36]. The planes of the benzene rings C(1-6) and C(10-15) in **11af** are essentially coplanar (dihedral angle: 0.4(1)◦ ), and even the nitro group is twisted by only 4.1(3)◦ with respect to its bonding benzene ring. In the crystal, the individual molecules assemble into columnar stacks of inversion-related molecules (Figure 8) via offset π···π stacking interactions of their parallel aromatic rings. These stacks, oriented along the crystallographic *b* axis, are further interconnected in the direction of the crystallographic *a* axis by the C11-H11···O3 soft hydrogen bonds (C11···O3 = 3.327(3) Å, angle at H11 = 158◦ ). The compound crystallizes with the symmetry of the triclinic space group *P–*1 and with one molecule in the asymmetric unit. Parameters describing the molecular geometry of **11af** are unexceptional and in line with the corresponding parameters reported for 1-(4-nitrophenyl)-3 phenylprop-2-yn-1-one (4-O2NC6H4C(O)C≡CPh) [2,35] and 3-(4-methoxyphenyl)-1-phenylprop-2 yn-1-one (PhC(O)C≡CC6H4OMe-4) [36]. The planes of the benzene rings C(1-6) and C(10-15) in **11af** are essentially coplanar (dihedral angle: 0.4(1)°), and even the nitro group is twisted by only 4.1(3)° with respect to its bonding benzene ring. In the crystal, the individual molecules assemble into columnar stacks of inversion-related molecules (Figure 8) via offset π···π stacking interactions of their parallel aromatic rings. These stacks, oriented along the crystallographic *b* axis, are further interconnected in the direction of the crystallographic *a* axis by the C11-H11···O3 soft hydrogen bonds (C11···O3 = 3.327(3) Å, angle at H11 = 158°).

interconnected in the direction of the crystallographic *a* axis by the C11-H11···O3 soft hydrogen bonds

**Figure 8.** Section of the columnar stacks in the structure of **11af**. The π···π interactions of the parallel benzene rings are indicated by red dotted lines, and the centroid···centroid separation is given in Å. **Figure 8.** Section of the columnar stacks in the structure of **11af**. The π···π interactions of the parallel benzene rings are indicated by red dotted lines, and the centroid···centroid separation is given in Å.

**Figure 8.** Section of the columnar stacks in the structure of **11af**. The π···π interactions of the parallel benzene rings are indicated by red dotted lines, and the centroid···centroid separation is given in Å.

Infrared spectra were recorded in diffuse reflectance mode using a Fourier-transform infrared spectrometer FTIR Nicolet 6700 (Thermo Fisher Scientific, Waltham, MA, USA; (scan range 400–4000
