The Regio-and Stereoselective Synthesis of 1,4-Diarylbut-1-en-3-ynes Having Aryl Groups at the Mutual Syn Positions

: (E)-1-aryl-2,4-bis(trimethylsilyl)but-1-en-3-ynes readily undergo protodesilylation and subsequent aerobic, copper-free Sonogashira cross-coupling with aryl halides to form (E)-1,4-diaryl- 2-(trimethylsilyl)but-1-en-3-ynes. The proposed one-pot, two-step approach allows access to the isomers containing aryl substituents in mutual syn positions. The resulting 2-silyl enynes can be further converted by proto-or halodesilylation.


Introduction
Conjugated enynes are valuable moieties in organic chemistry, providing convenient starting materials for constructing aromatic and heteroaromatic molecules [1][2][3][4][5][6]. Their structural motif is present in numerous biologically active molecules [7][8][9][10] and some functional materials [11,12]. A general method for the synthesis of enynes must ensure the regio-and stereoselective formation of the target compounds. The substitution pattern and stereoelectronic properties of the substituents significantly influence the reactivity, making a single and general synthetic route difficult to achieve. State-of-the-art catalytic methods for the synthesis of conjugated enynes have been reported in several reviews [9,13,14] and there has been significant progress in recent years. Several new examples of the synthesis and reactivity of conjugated enynes have been described [14]. The number of applications of conjugated enynes in the synthesis of organic compounds is steadily increasing [2][3][4]15,16].
The selective synthesis of 1,4-diarylbut-1-ene-3-ynes with the same substituents in positions 1 and 4 can be conveniently performed via selective alkyne homo-dimerization. However, if the substituents at positions 1 and 4 are different (Figure 1a), alkyne crossdimerisation may not always be applicable due to low selectivity. In this case, other procedures may need to be applied (Scheme 1).

Introduction
Conjugated enynes are valuable moieties in organic chemistry, providing con starting materials for constructing aromatic and heteroaromatic molecules [1-6 structural motif is present in numerous biologically active molecules [7][8][9][10] an functional materials [11,12]. A general method for the synthesis of enynes must en regio-and stereoselective formation of the target compounds. The substitution and stereoelectronic properties of the substituents significantly influence the rea making a single and general synthetic route difficult to achieve. State-of-the-art c methods for the synthesis of conjugated enynes have been reported in several [9,13,14] and there has been significant progress in recent years. Several new exam the synthesis and reactivity of conjugated enynes have been described [14]. The of applications of conjugated enynes in the synthesis of organic compounds is increasing [2][3][4]15,16].
In addition, we describe preliminary studies on using the reactivity of the silyl group in position 2 for the modification of the synthesised enynes.
We started the study by treatment of a methanolic solution of bissilylated 1,3-enyne 1a with an excess (5 equivalents) of KF. The reaction was carried out in air at 65 °C and led to the formation of the new compound in good yield after 3 h. GC-MS and NMR analyses showed the exclusive formation of the product 2a, selectively desilylated at the acetylene moiety.
The protodesilylation procedure has been adapted for convenient use application in a one-pot sequence. The optimization research included the selection of the solvent, the base, and the reaction conditions. Of the bases tested, TBAF, KOt-Bu, and KOH resulted in the decomposition of 1a and the formation of a mixture of unidentified compounds. In contrast, the reaction with KF, CsF, NaF, and K2CO3 in the MeOH solution was efficient even at room temperature. Raising the temperature to 65 °C reduced the reaction time required for complete conversion from 3 h to 1 h. Under these conditions, the silyl group at the Csp 2 carbon atom remained untouched. Solvents commonly used for Sonogashira connections, such as THF, DMF, and toluene, resulted in reduced conversion and yield. The results are summarised in Table 1. In addition, we describe preliminary studies on using the reactivity of the silyl group in position 2 for the modification of the synthesised enynes.
In addition, we describe preliminary studies on using the reactivity of the sily in position 2 for the modification of the synthesised enynes.
We started the study by treatment of a methanolic solution of bissilylated 1, 1a with an excess (5 equivalents) of KF. The reaction was carried out in air at 65 led to the formation of the new compound in good yield after 3 h. GC-MS and NM yses showed the exclusive formation of the product 2a, selectively desilylated at ylene moiety.
The protodesilylation procedure has been adapted for convenient use applic a one-pot sequence. The optimization research included the selection of the solv base, and the reaction conditions. Of the bases tested, TBAF, KOt-Bu, and KOH resulted in the decomposition o the formation of a mixture of unidentified compounds. In contrast, the reaction w CsF, NaF, and K2CO3 in the MeOH solution was efficient even at room temperatu ing the temperature to 65 °C reduced the reaction time required for complete con from 3 h to 1 h. Under these conditions, the silyl group at the Csp 2 carbon atom re untouched. Solvents commonly used for Sonogashira connections, such as TH and toluene, resulted in reduced conversion and yield. The results are summarise ble 1. We started the study by treatment of a methanolic solution of bissilylated 1,3-enyne 1a with an excess (5 equivalents) of KF. The reaction was carried out in air at 65 • C and led to the formation of the new compound in good yield after 3 h. GC-MS and NMR analyses showed the exclusive formation of the product 2a, selectively desilylated at the acetylene moiety.
The protodesilylation procedure has been adapted for convenient use application in a one-pot sequence. The optimization research included the selection of the solvent, the base, and the reaction conditions.
Of the bases tested, TBAF, KOt-Bu, and KOH resulted in the decomposition of 1a and the formation of a mixture of unidentified compounds. In contrast, the reaction with KF, CsF, NaF, and K 2 CO 3 in the MeOH solution was efficient even at room temperature. Raising the temperature to 65 • C reduced the reaction time required for complete conversion from 3 h to 1 h. Under these conditions, the silyl group at the Csp 2 carbon atom remained untouched. Solvents commonly used for Sonogashira connections, such as THF, DMF, and toluene, resulted in reduced conversion and yield. The results are summarised in Table 1.
After establishing the protodesilylation conditions, we investigated the Sonogashira coupling of terminal enyne with aryl bromides (or iodides) to find a convenient and efficient procedure. To find the optimum catalyst, base, and reaction conditions, studies were carried out using the cross-coupling of (E)-1-(4-methoxyphenyl)-2-trimethylsilylbut-1-en-3-yne (2a) with iodobenzene (Scheme 4) as a test reaction. After establishing the protodesilylation conditions, we investigated the Sonogashira coupling of terminal enyne with aryl bromides (or iodides) to find a convenient and effi cient procedure. To find the optimum catalyst, base, and reaction conditions, studies were carried out using the cross-coupling of (E)-1-(4-methoxyphenyl)-2-trimethylsilylbut-1-en 3-yne (2a) with iodobenzene (Scheme 4) as a test reaction.  Table 2). The greates yields were observed for the phosphine-based catalysts [Pd(PPh3)4] and [PdCl2(PPh3)2] The other palladium complexes exhibited lower activity. Among the bases tested, KF and NEt3 gave the best performance. Finally, the high yields of Sonogashira cross-coupling under copper-free conditions prompted us to investigate the effect of the copper salt on the course of the reaction. Regardless of the amount of CuI used (1, 2, or 5 equivalents in relation to the catalyst), the course of the reaction was unaffected.  2 ]. The other palladium complexes exhibited lower activity. Among the bases tested, KF and NEt 3 gave the best performance. Finally, the high yields of Sonogashira cross-coupling under copper-free conditions prompted us to investigate the effect of the copper salt on the course of the reaction. Regardless of the amount of CuI used (1, 2, or 5 equivalents in relation to the catalyst), the course of the reaction was unaffected.
Next, reactions were carried out in the air, using commercially available solvents and reagents without further purification. Performing the reaction in MeOH at 65 • C in the presence of [PdCl 2 (PPh 3 ) 2 ] (1 mol%) and NEt 3 proved to be optimal. Under these conditions, product yields of up to 99% were obtained at a relatively low reaction temperature (65 • C) and catalyst loading (1 mol%). Following the optimisation studies, the one-pot syntheses of the 1,4-diarylbut-1-en-3-ynes were assessed according to Scheme 5. Next, reactions were carried out in the air, using commercially available solvents and reagents without further purification. Performing the reaction in MeOH at 65 °C in the presence of [PdCl2(PPh3)2] (1 mol%) and NEt3 proved to be optimal. Under these conditions, product yields of up to 99% were obtained at a relatively low reaction temperature (65 °C) and catalyst loading (1 mol%). Following the optimisation studies, the one-pot syntheses of the 1,4-diarylbut-1-en-3-ynes were assessed according to Scheme 5.
The silylated 1,3-enynes were found to undergo efficient protodesilylation/Sonogashira coupling with a wide range of aromatic bromides and iodides ( Figure 2). Products 4a-o were obtained by treating, in the first step, a methanolic solution of bissilylated 1,3-enynes (1a-e) with 5 equivalents of K2CO3 at 65 °C. The reaction was carried out for 1 h and the progress was monitored by GC-MS. After completion of the protodesilylation, the corresponding aromatic bromide or iodide was added together with NEt3 and palladium catalyst [PdCl2(PPh3)2] (1 mol%) and the reaction was continued for a further 23 h. It was possible to obtain 1,3-enynes with overall isolated yields in the range of 60% to 92% (Figure 2). Scheme 5. The one-pot procedure of protodesilylation/Sonogashira coupling sequence.
The silylated 1,3-enynes were found to undergo efficient protodesilylation/Sonogashira coupling with a wide range of aromatic bromides and iodides ( Figure 2). Products 4a-o were obtained by treating, in the first step, a methanolic solution of bissilylated 1,3-enynes (1a-e) with 5 equivalents of K 2 CO 3 at 65 • C. The reaction was carried out for 1 h and the progress was monitored by GC-MS. After completion of the protodesilylation, the corresponding aromatic bromide or iodide was added together with NEt 3 and palladium catalyst [PdCl 2 (PPh 3 ) 2 ] (1 mol%) and the reaction was continued for a further 23 h. It was possible to obtain 1,3-enynes with overall isolated yields in the range of 60% to 92% (Figure 2).
Isomers with aryl groups in mutual syn positions were selectively formed. This method allows for the efficient conversion of reagents containing amine, nitro, methyl, methoxy, trifluoromethyl, and thiophenyl groups. Aryl halides containing conjugated aromatic rings, such as naphthyl and phenanthryl, were efficiently converted. Meta-substituted phenyl halides were also proved to be suitable reagents (see products 4d and 4e, Figure 2).
The reported method is not free from limitations. Reagents containing aldehyde, nitrile, and hydroxide groups could not be efficiently converted under the conditions used and generated products with yields below 15%. Furthermore, ortho-nitro and orthomethyl substituted phenylacetylenes did not undergo Sonogashira cross-coupling with protodesilylated 1a and trace amounts of the products were obtained. Nearly no conversion of aryl halides was observed. Other limitations relate to the optimisation of the one-pot process. For instance, THF and DMF are not suitable solvents in the proposed method. Isomers with aryl groups in mutual syn positions were selectively formed. This method allows for the efficient conversion of reagents containing amine, nitro, methyl, methoxy, trifluoromethyl, and thiophenyl groups. Aryl halides containing conjugated aromatic rings, such as naphthyl and phenanthryl, were efficiently converted. Meta-substituted phenyl halides were also proved to be suitable reagents (see products 4d and 4e, Figure 2).
The reported method is not free from limitations. Reagents containing aldehyde, nitrile, and hydroxide groups could not be efficiently converted under the conditions used and generated products with yields below 15%. Furthermore, ortho-nitro and ortho-methyl substituted phenylacetylenes did not undergo Sonogashira cross-coupling with protodesilylated 1a and trace amounts of the products were obtained. Nearly no conversion of  Moreover, the reactivity of the silyl group attached to the enyne double bond allows further transformations. Treatment of 4l with KOt-Bu or KOH resulted in a mixture of unidentified products, and using KF as a desilylation agent had no effect. In contrast, desilylation with TBAF in CH 2 Cl 2 solution at room temperature yielded 89% of the protodesilylated product (5) (Scheme 6). aryl halides was observed. Other limitations relate to the optimisation of the one-pot process. For instance, THF and DMF are not suitable solvents in the proposed method.
Moreover, the reactivity of the silyl group attached to the enyne double bond allows further transformations. Treatment of 4l with KOt-Bu or KOH resulted in a mixture of unidentified products, and using KF as a desilylation agent had no effect. In contrast, desilylation with TBAF in CH2Cl2 solution at room temperature yielded 89% of the protodesilylated product (5) (Scheme 6). Scheme 6. Protodesilylation of 2-silylsubstituted 1,4-(diaryl)but-1-en-3-yne.
cess. For instance, THF and DMF are not suitable solvents in the proposed method.
Moreover, the reactivity of the silyl group attached to the enyne double bond allows further transformations. Treatment of 4l with KOt-Bu or KOH resulted in a mixture of unidentified products, and using KF as a desilylation agent had no effect. In contrast, desilylation with TBAF in CH2Cl2 solution at room temperature yielded 89% of the protodesilylated product (5) (Scheme 6). Scheme 6. Protodesilylation of 2-silylsubstituted 1,4-(diaryl)but-1-en-3-yne.
Optimisation of protodesilylation. A 10 mL two-neck round bottom flask, equipped with a magnetic stirring bar, was charged with 0.069 g (0.225 mmol) of representative (E)-1-(4-methoxyphenyl)-2,4-bis(trimethylsilyl)but-1-en-3-yne, 5 mL of MeOH, 0.2 g of K 2 CO 3 , and 0.03 mL of dodecane (internal standard). The vial was closed under air and then stirred and heated at temperatures ranging from 25 to 65 • C in an oil bath for a given reaction time. The reaction course was monitored by gas chromatography.
Optimisation of Sonogashira coupling. First, 25 µL (0.225 mmol) of iodobenzene, 0.15 mL of NEt 3, and 0.0045 mmol of Pd catalyst were added to the methanol solution of desilylated 1,3-enyne. The reaction mixture was heated at various temperatures ranging from 25 to 65 • C in an oil bath for a given reaction time. The reaction course was monitored by gas chromatography.
Representative one-pot synthesis. The synthesis was carried out in a two-neck round bottom flask with a capacity of 100 mL and equipped with a magnetic stirring bar under a closed system. The flask was charged with 0.25 g (0.817 mmol) of (E)-1-(4-methoxyphenyl)-2,4-bis(trimethylsilyl)but-1-en-3-yne, 20 mL of MeOH, and 0.58 g of K 2 CO 3 (4.09 mmol). The reaction mixture was stirred and heated at 65 • C in an oil bath for 1 h. Afterwards, 0.9 mL (0.817 mmol) of iodobenzene, 0.5 mL of NEt 3 , and 0.006 g (0.0817 mmol) of [PdCl 2 (PPh 3 ) 2 ] were added to the reaction mixture, and the heating was continued for an additional 23 h. Then, the solvent was removed under vacuum, and the solid residue was purified by column chromatography over silica gel and using hexane/ethyl acetate (25:1) as an eluent. Products characterisation 4a. Isolated as a yellow oil, 225 mg (92% yield). Spectroscopic characterisation:  Protodesilylation of 4l. A 10 mL two-neck round bottom flask, which was equipped with a magnetic stirring bar, was charged with 0.082 g (0.225 mmol) of (E)-1-(4-methylphenyl)-2-(trimethylsilyl)-4-biphenylbut-1-en-3-yne (4l), 5 mL of CH 2 Cl 2 , 0.18 g (0.675 mmol) of TBAF and 5 mL of CH 2 Cl 2 . The mixture was stirred at room temperature for 24 h. The solvent was then removed under vacuum, and the solid residue was purified by column chromatography on silica gel with hexane/ethyl acetate (25:1).