Palladium and Copper Catalyzed Sonogashira cross Coupling an Excellent Methodology for C-C Bond Formation over 17 Years: A Review

: Sonogashira coupling involves coupling of vinyl / aryl halides with terminal acetylenes catalyzed by transition metals, especially palladium and copper. This is a well known reaction in organic synthesis and plays a role in sp 2 -sp C-C bond formations. This cross coupling was used in synthesis of natural products, biologically active molecules, heterocycles, dendrimers, conjugated polymers and organic complexes. This review paper focuses on developments in the palladium and copper catalyzed Sonogashira cross coupling achieved in recent years concerning substrates, di ﬀ erent catalyst systems and reaction conditions. H


Introduction
The transition metal catalyzed cross-coupling reactions have played an important role in the field of organic synthesis [1,2]. Among them, the palladium catalyzed sp2-sp couplings between aryl or alkenyl halides or triflates and terminal alkynes in presence or absence of Copper (I) cocatalyst has become the most important method to prepare aryl-alkynes and conjugated enynes (Figure 1), which are precursors for pharmaceuticals, natural products and organic materials and this type of coupling commonly known as Sonogashira coupling [3][4][5]. This reaction was named after the scientists Sonogashira, Tohda, and Hagihara in 1975. This research came after Cassar [6] and Dieck and Heck [7] disclosed that it was possible to perform this coupling only under palladium catalyst at high temperatures. Sonogashira and Hagihara reported that addition of catalytic amount of Copper (I) iodide accelerates the C-C bond formations at room temperature [8]. However, addition of copper has many benefits, but it has some drawbacks associated with it, the main one being the necessity of avoiding the presence of oxygen in order to block the undesirable formation of alkyne homocoupling through a copper-mediated Hay/Glaser reaction [9] along with the main product and difficulty in recovery of reagents. To overcome this issue, elimination of the copper was a solution, so perhaps in this case the process may be called copper-free Sonogashira reaction, or Heck-Cassar reaction, Heck alkynylation or perhaps Sonogashira-Heck-Cassar coupling. Significant efforts were made to develop the coupling reaction and enhancement of reactivity of catalytic system in absence of copper sources. The copper free coupling process involves the use of excess amine which often acts as a solvent, but the environmental and economic advantages of the methodology end here. Thus, efforts were made to develop Sonogashira cross-coupling reaction in absence of both copper and amines [10]. In the Sonogashira process, different substrates have different reactivities as sp2 species reactivity order was found to be vinyl iodide > vinyl triflate > vinyl bromide > vinyl chloride > aryl iodide > aryl triflate > aryl bromide > aryl chloride. In organic halides, which are activated (electron-poor), the situation is even more promising [11]. The products obtained in Sonogashira reaction have various applications in the diverse areas of chemistry, such as electronics, dyes, polymers, sensors, natural products and in synthesis of heterocycles. Remarkable research on this topic has been going on for decades to search for more convenient reaction conditions and a better, efficient catalytic system and for synthesis of promising compounds. This review covers the developments in the Sonogashira cross-coupling reaction, as well as applications of this methodology from 2002 to 2018.

Scheme 2.
It was observed that Sonogashira cross coupling is a good methodology for the coupling of nitrogen containing heterocycles with terminal acetylenes. The 3-iodoindazoles were coupled with various propiolic or propargylic derivatives via palladium and copper catalyzed Sonogashira coupling to prepare the building blocks of interest in medicinal chemistry as tryptamine derivatives. As mentioned, in Scheme 3 the N-1 of the 3-iodo-1H-indazole 9 was protected and compound 12 was synthesized and 99% yield produced via this methodology. There was no coupling in position 3 of 9 without protection of N-1 [16]. Similarly, the 5-phenylpent-4-yn-1-ol 7 was synthesized via Sonogashira cross coupling without the protection of hydroxy group. The 7 was used as precursor for the synthesis of 2-aryl-2,5-dihydro-2H-pyrans 8. An aryl di-hydro-pyran precursor was synthesized via etherification of an aryl bishomoallylic alcohol. Sonogashira coupling of homo-propargylic alcohols with aryl bromides gave the (E)-arylhydroxyalkene cyclization precursors. The substituted acetylenes were reduced to the alkenols. The phenyl-selenenyl chloride in dichloromethane was used for synthesis of trans 2,3-disubstituted tetrahydropyrans. The oxidative-elimination proceeded by using 30% hydrogen peroxide and pyridine in THF giving 8 in good yield (Scheme 2) [15]. Similarly, the 5-phenylpent-4-yn-1-ol 7 was synthesized via Sonogashira cross coupling without the protection of hydroxy group. The 7 was used as precursor for the synthesis of 2-aryl-2,5-dihydro-2H-pyrans 8. An aryl di-hydro-pyran precursor was synthesized via etherification of an aryl bishomoallylic alcohol. Sonogashira coupling of homo-propargylic alcohols with aryl bromides gave the (E)-arylhydroxyalkene cyclization precursors. The substituted acetylenes were reduced to the alkenols. The phenyl-selenenyl chloride in dichloromethane was used for synthesis of trans 2,3disubstituted tetrahydropyrans. The oxidative-elimination proceeded by using 30% hydrogen peroxide and pyridine in THF giving 8 in good yield (Scheme 2) [15].

Scheme 2.
It was observed that Sonogashira cross coupling is a good methodology for the coupling of nitrogen containing heterocycles with terminal acetylenes. The 3-iodoindazoles were coupled with various propiolic or propargylic derivatives via palladium and copper catalyzed Sonogashira coupling to prepare the building blocks of interest in medicinal chemistry as tryptamine derivatives. As mentioned, in Scheme 3 the N-1 of the 3-iodo-1H-indazole 9 was protected and compound 12 was synthesized and 99% yield produced via this methodology. There was no coupling in position 3 of 9 without protection of N-1 [16]. It was observed that Sonogashira cross coupling is a good methodology for the coupling of nitrogen containing heterocycles with terminal acetylenes. The 3-iodoindazoles were coupled with various propiolic or propargylic derivatives via palladium and copper catalyzed Sonogashira coupling to prepare the building blocks of interest in medicinal chemistry as tryptamine derivatives. As mentioned, in Scheme 3 the N-1 of the 3-iodo-1H-indazole 9 was protected and compound 12 was synthesized and 99% yield produced via this methodology. There was no coupling in position 3 of 9 without protection of N-1 [16].
Similarly, the nitrogen containing heterocycles as in Scheme 4, 5-iodouracil PNA-residues was synthesized via Sonogashira cross coupling in solution and solid phase by reaction with different alkynes. In solution phase the yield was 38-53% and in solid phase, the yield was essentially quantitative. PNA is an oligonucleotide and it forms complexes with DNA and RNA [17]. Similarly, the nitrogen containing heterocycles as in Scheme 4, 5-iodouracil PNA-residues was synthesized via Sonogashira cross coupling in solution and solid phase by reaction with different alkynes. In solution phase the yield was 38-53% and in solid phase, the yield was essentially quantitative. PNA is an oligonucleotide and it forms complexes with DNA and RNA [17].
However, Grignard reaction is excellent methodology for the carbon-carbon formation [18,19]. The organic-halide with magnesium gives a Grignard reagent. The Grignard reagent is used for functional group transformation [20]. In addition, the Grignard Reagent was also used as an alternative source of aryl halide in Sonogashira Cross Coupling catalyzed by palladium and Copper iodide in Scheme 5. The different electron donating groups and electron with drawing groups were used with Grignard reagent. The -CF3 and -CH2-CH3 at ortho, meta and para position gave more than 99% yield. The Grignard-Sonogashira reaction was a facile and moderate method for the carboncarbon bond formation [21].
It was noted that the linear conjugated oligomers have attracted considerable attention of scientists due to their potential use in molecule-based electronics as molecular wires [22,23]. Kitamura and co-workers described the synthesis of a new class of linear conjugated oligomers by bi-directional method using Sonogashira cross coupling. The route for ethyne linked alternating π-donor and πacceptor system was developed as in Scheme 6. The change of substrate effects the yield and homocoupling yields 26%. The [2+1+2] method was used as a bi-directional method [24].
However, Grignard reaction is excellent methodology for the carbon-carbon formation [18,19]. The organic-halide with magnesium gives a Grignard reagent. The Grignard reagent is used for functional group transformation [20]. In addition, the Grignard Reagent was also used as an alternative source of aryl halide in Sonogashira Cross Coupling catalyzed by palladium and Copper iodide in Scheme 5. The different electron donating groups and electron with drawing groups were used with Grignard reagent. The -CF 3 and -CH 2 -CH 3 at ortho, meta and para position gave more than 99% yield. The Grignard-Sonogashira reaction was a facile and moderate method for the carbon-carbon bond formation [21].

Scheme 5.
It was also noted that Nucleophilic N-heterocyclic carbenes Pd (II) complex 35, especially imidazole-2-ylidene, was used as an alternative for phosphine ligands in homogeneous catalysis. In Sonogashira cross coupling, these Pd complexes were used as the palladium source and copper iodide was used as the co-catalyst for coupling of terminal acetylenes with aryl-halide Scheme 7. The palladium carbene complex alone produce 50% yield and with PPh3 yield was 97%. The aryl bromide derivatives with electron donating groups on the ring show less reactivity [25]. It was noted that the linear conjugated oligomers have attracted considerable attention of scientists due to their potential use in molecule-based electronics as molecular wires [22,23]. Kitamura and co-workers described the synthesis of a new class of linear conjugated oligomers by bi-directional method using Sonogashira cross coupling. The route for ethyne linked alternating π-donor and π-acceptor system was developed as in Scheme 6. The change of substrate effects the yield and homo-coupling yields 26%. The [2+1+2] method was used as a bi-directional method [24].
Catalysts 2020, 10 It was also noted that Nucleophilic N-heterocyclic carbenes Pd (II) complex 35, especially imidazole-2-ylidene, was used as an alternative for phosphine ligands in homogeneous catalysis. In Sonogashira cross coupling, these Pd complexes were used as the palladium source and copper iodide was used as the co-catalyst for coupling of terminal acetylenes with aryl-halide Scheme 7. The palladium carbene complex alone produce 50% yield and with PPh 3 yield was 97%. The aryl bromide derivatives with electron donating groups on the ring show less reactivity [25]. In addition, the synthesis of organic molecules on polymeric support was an excellent strategy for the identification of new organic compounds [26]. The palladium catalyzed cross coupling reaction on the solid support was developed for the synthesis of new drugs [27]. Duboc and co-worker reported the synthesis of new stable silylated polystyrene via palladium and copper mediated Sonogashira cross coupling. The mild conditions were used for cleaving of products from support and scavenger ionic resin was used for purification. The supported aryliodides were coupled with tri-methyl-silyl-acetylene via Pd (OAc) 2 (PPh 3 ) and copper iodide catalyzed Sonogashira cross coupling and the conversion was 100% (Scheme 8) [28].
Mostly, Benzo[b]furans exhibit diverse biological activities and used as the inhibitors of β-amyloid aggregation and cyclo-oxygenase-2 [29]. Thus, 4, 5 and 6-nitro-benzo[b]furans were synthesized by using 2-amino-nitro-phenols via coupling cyclization reaction. The 2-iodo-nitro-phenols were converted to corresponding acetates because the direct cross coupling gave low yield. The acetates were coupled with acetylene via Pd (PPh 3 ) 4 and CuI catalyzed Sonogashira cross coupling which were than reacted with KO t Bu, and the nitro-bezo[b]furan 45 was obtained (Scheme 9) [30].
It was observed that the nature of catalyst controls the Sonogashira cross coupling. Teply and co-workers reported that the copper as co-catalyst played important role for the formation of coupled product. The phenyl iodides were coupled with terminal acetylenes; in the absence copper co-catalyst, the cyclized product was formed (Scheme 10) [31]. reaction on the solid support was developed for the synthesis of new drugs [27]. Duboc and coworker reported the synthesis of new stable silylated polystyrene via palladium and copper mediated Sonogashira cross coupling. The mild conditions were used for cleaving of products from support and scavenger ionic resin was used for purification. The supported aryliodides were coupled with tri-methyl-silyl-acetylene via Pd (OAc)2(PPh3) and copper iodide catalyzed Sonogashira cross coupling and the conversion was 100% (Scheme 8) [28].

Scheme 8.
Mostly, Benzo[b]furans exhibit diverse biological activities and used as the inhibitors of βamyloid aggregation and cyclo-oxygenase-2 [29]. Thus, 4, 5 and 6-nitro-benzo[b]furans were synthesized by using 2-amino-nitro-phenols via coupling cyclization reaction. The 2-iodo-nitrophenols were converted to corresponding acetates because the direct cross coupling gave low yield. The acetates were coupled with acetylene via Pd (PPh3)4 and CuI catalyzed Sonogashira cross coupling which were than reacted with KO t Bu, and the nitro-bezo[b]furan 45 was obtained (Scheme 9) [30].
Catalysts 2020, 10, x FOR PEER REVIEW 8 of 48 It was observed that the nature of catalyst controls the Sonogashira cross coupling. Teply and co-workers reported that the copper as co-catalyst played important role for the formation of coupled product. The phenyl iodides were coupled with terminal acetylenes; in the absence copper cocatalyst, the cyclized product was formed (Scheme 10) [31].

In 2003
In 2003, various scientists and researchers reported the Sonogashira reaction catalyzed via palladium and copper and different reaction conditions. As previously discussed, nitrogen containing heterocycles showed many biological activities such as anti-viral and anti-cancer [32,33]. The alkynyl derivatives starting from 5-iodinated pyrimidione derivatives were obtained by protecting the N-1 or 2,4-positions of uracils. Petricci and co-workers reported that the 5-alkynyl derivatives were synthesized from pyrimidinones and uridine via Sonogashira cross coupling reaction catalyzed by palladium and copper. The pyrimidinones and uridine were coupled in the presence of DMF solution, Et3N, PdCl2(PPh3)2 and CuI with propargyl alcohol at room temperature gave moderate yield and were not isolated. It underwent cyclization (Scheme 12) [34].

Scheme 12.
Furthermore, Petricci and co-workers reported that the terminal alkynes irradiated with microwave for 5 min at 45 °C were coupled with pyrimidinones via Sonogashira cross coupling reaction catalyzed by palladium and copper gave good yield as in Scheme 13 [34]. Scheme 11. Sonogashira Cross Coupling of alkyne-substituted phenyl iodides with terminal alkynes via Palladium and Copper Catalyst.

In 2003
In 2003, various scientists and researchers reported the Sonogashira reaction catalyzed via palladium and copper and different reaction conditions. As previously discussed, nitrogen containing heterocycles showed many biological activities such as anti-viral and anti-cancer [32,33]. The alkynyl derivatives starting from 5-iodinated pyrimidione derivatives were obtained by protecting the N-1 or 2,4-positions of uracils. Petricci and co-workers reported that the 5-alkynyl derivatives were synthesized from pyrimidinones and uridine via Sonogashira cross coupling reaction catalyzed by palladium and copper. The pyrimidinones and uridine were coupled in the presence of DMF solution, Et 3 N, PdCl 2 (PPh 3 ) 2 and CuI with propargyl alcohol at room temperature gave moderate yield and were not isolated. It underwent cyclization (Scheme 12) [34].

In 2003
In 2003, various scientists and researchers reported the Sonogashira reaction catalyzed via palladium and copper and different reaction conditions. As previously discussed, nitrogen containing heterocycles showed many biological activities such as anti-viral and anti-cancer [32,33]. The alkynyl derivatives starting from 5-iodinated pyrimidione derivatives were obtained by protecting the N-1 or 2,4-positions of uracils. Petricci and co-workers reported that the 5-alkynyl derivatives were synthesized from pyrimidinones and uridine via Sonogashira cross coupling reaction catalyzed by palladium and copper. The pyrimidinones and uridine were coupled in the presence of DMF solution, Et3N, PdCl2(PPh3)2 and CuI with propargyl alcohol at room temperature gave moderate yield and were not isolated. It underwent cyclization (Scheme 12) [34].

Scheme 12.
Furthermore, Petricci and co-workers reported that the terminal alkynes irradiated with microwave for 5 min at 45 °C were coupled with pyrimidinones via Sonogashira cross coupling reaction catalyzed by palladium and copper gave good yield as in Scheme 13 [34]. Furthermore, Petricci and co-workers reported that the terminal alkynes irradiated with microwave for 5 min at 45 • C were coupled with pyrimidinones via Sonogashira cross coupling reaction catalyzed by palladium and copper gave good yield as in Scheme 13 [34]. It can be additionally noted that the nitrogen containing heterocycles, especially pyridazinones, show various biological activities and used as drugs in cardiovascular system and as agrochemicals [35,36]. So, synthesis of these nitrogen-containing molecules with short and comprehensive route is of great concern for various researchers. Thus, Coelho and co-workers synthesized the 5-alkynyl pyridazinones derivatives. The NH group of pyridazinone 60 was protected with the methoxymethyl group to synthesized protected pyridazinone 62. The protected pyridazinone 62 was coupled with terminal alkyne by using bis (tri-phenyl-phosphine)-palladium chloride, copper iodide as a co-Scheme 13. Microwave enhanced Sonogashira coupling.
It can be additionally noted that the nitrogen containing heterocycles, especially pyridazinones, show various biological activities and used as drugs in cardiovascular system and as agrochemicals [35,36]. So, synthesis of these nitrogen-containing molecules with short and comprehensive route is of great concern for various researchers. Thus, Coelho and co-workers synthesized the 5-alkynyl pyridazinones derivatives. The NH group of pyridazinone 60 was protected with the methoxymethyl group to synthesized protected pyridazinone 62. The protected pyridazinone 62 was coupled with terminal alkyne by using bis (tri-phenyl-phosphine)-palladium chloride, copper iodide as a co-catalyst, triethylamine as a base and DMF as a solvent. The 2-methoxymethyl-3-pyridazinone was de-protected either with hydrochloric acid or AlCl 3 as in Scheme 14. The unprotected product 64 was synthesized [37].

Scheme 13.
It can be additionally noted that the nitrogen containing heterocycles, especially pyridazinones, show various biological activities and used as drugs in cardiovascular system and as agrochemicals [35,36]. So, synthesis of these nitrogen-containing molecules with short and comprehensive route is of great concern for various researchers. Thus, Coelho and co-workers synthesized the 5-alkynyl pyridazinones derivatives. The NH group of pyridazinone 60 was protected with the methoxymethyl group to synthesized protected pyridazinone 62. The protected pyridazinone 62 was coupled with terminal alkyne by using bis (tri-phenyl-phosphine)-palladium chloride, copper iodide as a cocatalyst, triethylamine as a base and DMF as a solvent. The 2-methoxymethyl-3-pyridazinone was de-protected either with hydrochloric acid or AlCl3 as in Scheme 14. The unprotected product 64 was synthesized [37]. In contrast, terminal acetylenes and 5-bromo-6-phenyl-3(2H)-pyridazinone without protection of NH group were coupled and gave only around 5-10% of the 5-alkynyl pyridazinones 67 derivatives and more than 85% of reactant was recovered (Scheme 15). The low reactivity was due to the acidity of the NH group [37]. In contrast, terminal acetylenes and 5-bromo-6-phenyl-3(2H)-pyridazinone without protection of NH group were coupled and gave only around 5-10% of the 5-alkynyl pyridazinones 67 derivatives and more than 85% of reactant was recovered (Scheme 15). The low reactivity was due to the acidity of the NH group [37]. It was noted that π-conjugated compounds have versatile applications as in light emitting diodes, carbohydrates sensing and in molecular electronics [38]. The aryl donors were coupled with aryl and heteroaryl acceptors via Sonogashira cross coupling [39]. Elangovan and co-workers used an atmosphere of Hydrogen gas diluted with nitrogen or argon with palladium and copper catalyst to synthesized terminal aryl ethynes and aryl-pyridyl-ethynes with donor substituents in very good yields via a Sonogashira coupling reaction in Scheme 16 [40]. It was noted that π-conjugated compounds have versatile applications as in light emitting diodes, carbohydrates sensing and in molecular electronics [38]. The aryl donors were coupled with aryl and heteroaryl acceptors via Sonogashira cross coupling [39]. Elangovan and co-workers used an atmosphere of Hydrogen gas diluted with nitrogen or argon with palladium and copper catalyst to synthesized terminal aryl ethynes and aryl-pyridyl-ethynes with donor substituents in very good yields via a Sonogashira coupling reaction in Scheme 16 [40].
It was noted that π-conjugated compounds have versatile applications as in light emitting diodes, carbohydrates sensing and in molecular electronics [38]. The aryl donors were coupled with aryl and heteroaryl acceptors via Sonogashira cross coupling [39]. Elangovan and co-workers used an atmosphere of Hydrogen gas diluted with nitrogen or argon with palladium and copper catalyst to synthesized terminal aryl ethynes and aryl-pyridyl-ethynes with donor substituents in very good yields via a Sonogashira coupling reaction in Scheme 16 [40].

Scheme 17.
In addition, organotellurium compounds are a very important class [41]. The 2-alkynyl substituted hetero-aromatic 76 and similar compounds were synthesized by coupling of vinylic and hetero-aromatic tellurium di-chlorides via palladium and copper catalyzed Sonogashira cross coupling (Scheme 18). The various palladium catalysts with CuI were used in this reaction. It was noted that the same compounds show 82% yield when the reaction is applied with PdCl2 [42]. Similarly, di-aryl-ethynes were synthesized via previously mentioned reaction conditions (Scheme 17) [40].
It was noted that π-conjugated compounds have versatile applications as in light emitting diodes, carbohydrates sensing and in molecular electronics [38]. The aryl donors were coupled with aryl and heteroaryl acceptors via Sonogashira cross coupling [39]. Elangovan and co-workers used an atmosphere of Hydrogen gas diluted with nitrogen or argon with palladium and copper catalyst to synthesized terminal aryl ethynes and aryl-pyridyl-ethynes with donor substituents in very good yields via a Sonogashira coupling reaction in Scheme 16 [40].

Scheme 17.
In addition, organotellurium compounds are a very important class [41]. The 2-alkynyl substituted hetero-aromatic 76 and similar compounds were synthesized by coupling of vinylic and hetero-aromatic tellurium di-chlorides via palladium and copper catalyzed Sonogashira cross coupling (Scheme 18). The various palladium catalysts with CuI were used in this reaction. It was noted that the same compounds show 82% yield when the reaction is applied with PdCl2 [42]. In addition, organotellurium compounds are a very important class [41]. The 2-alkynyl substituted hetero-aromatic 76 and similar compounds were synthesized by coupling of vinylic and hetero-aromatic tellurium di-chlorides via palladium and copper catalyzed Sonogashira cross coupling (Scheme 18). The various palladium catalysts with CuI were used in this reaction. It was noted that the same compounds show 82% yield when the reaction is applied with PdCl 2 [42]. Moreover, the macrocyclic molecules are an important class of super molecular chemistry. So, Sonogashira cross coupling is an efficient methodology for synthesis of macrocyclic molecules. The 1,1′-Bi-2-naphthol (BINOL) and their derivatives were used in asymmetric synthesis [43]. Therefore, Harada and co-workers reported the synthesis of 24-and 26-membered macro-cyclic bi-naphthol dimers 80 and 81 were synthesized via Pd (PPh3)4 and CuI catalyzed Sonogashira Cross Coupling shown in Scheme 19 [44].
As discussed earlier, the Nucleophilic N-heterocyclic carbenes was used as an alternative source for palladium phosphine ligands in organo-transition-metal catalysis. The CNC-pincer biscarbene ligand [PdBr (CNC-Bu2)]X (82) was used as a Pd catalytic source with copper iodide for the Sonogashira cross coupling of aryl-chlorides with alkynes as in Scheme 20. The piperidine used as base and DMF as solvent gave a good yield. It was noted that [PdBr (CNC-Bu2)]X (82) had great influence compared with commercially available palladium catalyst [45].
Similarly, the organometallic coupling was rarely used for fluorescein and rhodamime based Moreover, the macrocyclic molecules are an important class of super molecular chemistry. So, Sonogashira cross coupling is an efficient methodology for synthesis of macrocyclic molecules. The 1,1 -Bi-2-naphthol (BINOL) and their derivatives were used in asymmetric synthesis [43]. Therefore, Harada and co-workers reported the synthesis of 24-and 26-membered macro-cyclic bi-naphthol dimers 80 and 81 were synthesized via Pd (PPh 3 ) 4 and CuI catalyzed Sonogashira Cross Coupling shown in Scheme 19 [44]. As discussed earlier, the Nucleophilic N-heterocyclic carbenes was used as an alternative source for palladium phosphine ligands in organo-transition-metal catalysis. The CNC-pincer biscarbene ligand [PdBr (CNC-Bu 2 )]X (82) was used as a Pd catalytic source with copper iodide for the Sonogashira cross coupling of aryl-chlorides with alkynes as in Scheme 20. The piperidine used as base and DMF as solvent gave a good yield. It was noted that [PdBr (CNC-Bu 2 )]X (82) had great influence compared with commercially available palladium catalyst [45].
Similarly, the organometallic coupling was rarely used for fluorescein and rhodamime based system. Han and coworkers developed the Sonogashira cross coupling of fluorescein and rhodamine derivatives with 86 and 87 catalyzed by Pd (PAr 3 ) 4 and CuI (Scheme 21). Fluorescein and rhodamine derivatives were stable at high temperatures. The Sonogashira cross coupling worked well under microwave irradiation [46]. Catalysts 2020, 10,  In addition, the 18 F-labelled aryl halides were used as the coupling partners in the palladium and copper catalyzed Sonogashira cross-coupling. The 4-fluorophenyl group was also present in drugs [47]. Wust and Kniess reported, for the first time, Sonogashira cross-coupling in 18 F chemistry. The coupled product was synthesized from Pd (PPh 3 ) 4 and CuI catalyzed Sonogashira cross coupling of 4-[18F] floro-iodo-benzene with terminal alkyne Scheme 22 [48].

In 2004
It was noted that Nitrogen-containing heterocycles as pyridine alkaloids were used as precursors for the synthesis of bis-pyridine alkaloids like cyclostellettamine B [49]. These alkaloids showed antimicrobial and cytotoxic activities [50]. The di-chloro-bis (tri-phenyl-phosphine) palladium (II) and copper bromide catalyzed Sonogashira cross coupling was a key step for the synthesis of Niphatesine C 94 and Norniphatesine C 95 (Scheme 23) [51]. In addition, the nitrogen-containing heterocycles such as pyrimidines show many biological actives such as adenosine kinase inhibitors [52], anti-tumor and antibiotics [53]. The tri-substituted pyrimidine derivatives were synthesized via di-chloro-bis (tri-phenyl-phosphine) palladium (II) and copper iodide catalyzed Sonogashira cross coupling, as shown in Scheme 24 [54]. In addition, the nitrogen-containing heterocycles such as pyrimidines show many biological actives such as adenosine kinase inhibitors [52], anti-tumor and antibiotics [53]. The tri-substituted pyrimidine derivatives were synthesized via di-chloro-bis (tri-phenyl-phosphine) palladium (II) and copper iodide catalyzed Sonogashira cross coupling, as shown in Scheme 24 [54].

In 2005
As previously discussed, the nitrogen containing heterocycles are biologically active. The bivalent ligands of β-carboline-3-carboxylate derivatives were used to treat human alcoholics [55]. The bivalent analogues of β-carboline-3-carboxylates were synthesized via di-chloro-bis (tri-phenylphosphine) palladium (II) and copper iodide catalyzed Sonogashira cross coupling. The iodo-β CCt intermediate was formed. The protection and deactivation of N-H group of indole was necessary for the synthesis of bivalent ligands of β-carboline-3-carboxylates (Scheme 25) [56]. However, the insertion of di-fluorocarbene into carbon-carbon triple bonds is one of the most convenient methods for synthesizing of organic fluoride compounds [57]. The gem-di-fluoro-cyclopropenyl-alkynes were synthesized by using Sonogashira cross coupling catalyzed via copper iodide and different ligands with palladium Scheme 26. The amine as base gave poor yield and the use of Cs2CO3 gave 70% yield. The phenyl with electron donating groups gave lower yield and the yield of However, the insertion of di-fluorocarbene into carbon-carbon triple bonds is one of the most convenient methods for synthesizing of organic fluoride compounds [57]. The gem-di-fluoro-cyclopropenyl-alkynes were synthesized by using Sonogashira cross coupling catalyzed via copper iodide and different ligands with palladium Scheme 26. The amine as base gave poor yield and the use of Cs 2 CO 3 gave 70% yield. The phenyl with electron donating groups gave lower yield and the yield of phenyl with electron withdrawing groups was higher [58].

Scheme 26.
It was noted that thermally stable palladium catalysts were also used for Sonogashira reaction [59]. In the literature survey, (PPh)3 ligand was used for coupling of aryl halides with propiolaldehyde diethyl acetal [60]. Lemhadri and coworkers used the tetrapodal phosphine ligand, Tedicyp 113 as a palladium source with copper for Sonogashira cross coupling of para-substituted aryl bromides with propiol-aldehyde diethyl acetal (Scheme 27). The 0.01% of catalyst with aryl bromides was used. All functional groups and hetero-atomic substrates were used in the presence of Tedicyp palladium system [61].

Scheme 27.
The same research group also reported that the product 119 was selectively obtained in 92% yield in the presence of 0.1% catalyst with 1,4-dibromobenzene substrate. The mixtures of products 119 and 120 were obtained with 1,2-di-bromo-benzene when ratios substrate/catalyst of 1000 and 10,000 were used, as in Scheme 28. The slower reaction rate observed with 1,2-di-bromo-benzene probably is due to steric reasons [61]. It was noted that thermally stable palladium catalysts were also used for Sonogashira reaction [59]. In the literature survey, (PPh) 3 ligand was used for coupling of aryl halides with propiol-aldehyde diethyl acetal [60]. Lemhadri and coworkers used the tetrapodal phosphine ligand, Tedicyp 113 as a palladium source with copper for Sonogashira cross coupling of para-substituted aryl bromides with propiol-aldehyde diethyl acetal (Scheme 27). The 0.01% of catalyst with aryl bromides was used. All functional groups and hetero-atomic substrates were used in the presence of Tedicyp palladium system [61]. It was noted that thermally stable palladium catalysts were also used for Sonogashira reaction [59]. In the literature survey, (PPh)3 ligand was used for coupling of aryl halides with propiolaldehyde diethyl acetal [60]. Lemhadri and coworkers used the tetrapodal phosphine ligand, Tedicyp 113 as a palladium source with copper for Sonogashira cross coupling of para-substituted aryl bromides with propiol-aldehyde diethyl acetal (Scheme 27). The 0.01% of catalyst with aryl bromides was used. All functional groups and hetero-atomic substrates were used in the presence of Tedicyp palladium system [61].

Scheme 27.
The same research group also reported that the product 119 was selectively obtained in 92% yield in the presence of 0.1% catalyst with 1,4-dibromobenzene substrate. The mixtures of products 119 and 120 were obtained with 1,2-di-bromo-benzene when ratios substrate/catalyst of 1000 and 10,000 were used, as in Scheme 28. The slower reaction rate observed with 1,2-di-bromo-benzene probably is due to steric reasons [61]. The same research group also reported that the product 119 was selectively obtained in 92% yield in the presence of 0.1% catalyst with 1,4-dibromobenzene substrate. The mixtures of products 119 and 120 were obtained with 1,2-di-bromo-benzene when ratios substrate/catalyst of 1000 and 10,000 were used, as in Scheme 28. The slower reaction rate observed with 1,2-di-bromo-benzene probably is due to steric reasons [61].

Scheme 27.
The same research group also reported that the product 119 was selectively obtained in 92% yield in the presence of 0.1% catalyst with 1,4-dibromobenzene substrate. The mixtures of products 119 and 120 were obtained with 1,2-di-bromo-benzene when ratios substrate/catalyst of 1000 and 10,000 were used, as in Scheme 28. The slower reaction rate observed with 1,2-di-bromo-benzene probably is due to steric reasons [61].

In 2006
As previously described, palladium-N-heterocyclic carbene complexes were used for the Sonogashira cross coupling. Altenhoff and co-workers reported the first Sonogashira cross coupling of alkynes with secondary alkyl bromides in the presence of palladium-N-heterocyclic carbene complexes and copper iodide was used as co-catalyst in Scheme 29 [62].

In 2006
As previously described, palladium-N-heterocyclic carbene complexes were used for the Sonogashira cross coupling. Altenhoff and co-workers reported the first Sonogashira cross coupling of alkynes with secondary alkyl bromides in the presence of palladium-N-heterocyclic carbene complexes and copper iodide was used as co-catalyst in Scheme 29 [62].

Scheme 29.
In addition, the 1,2-di-amino-cyclohexane was used with palladium-N-heterocyclic carbene complex as in Scheme 30 by the same research group. It improved the yield of the coupled product [62].

Scheme 30.
Moreover, the polymer supported palladium catalysts were also used for the Sonogashira cross coupling. In the past, the poly-styrene and silica supported phosphine palladium catalysts were used with copper iodide for coupling [63]. The [MCM-41-SH-Pd(0)] complex was used as a palladium source with copper iodide in the Sonogashira cross coupling of aryl iodides with terminal alkynes Scheme 31 [64]. Scheme 29. Sonogashira cross coupling of Secondary alkyl bromides with oct-1-yn-3-one.
In addition, the 1,2-di-amino-cyclohexane was used with palladium-N-heterocyclic carbene complex as in Scheme 30 by the same research group. It improved the yield of the coupled product [62].

In 2006
As previously described, palladium-N-heterocyclic carbene complexes were used for the Sonogashira cross coupling. Altenhoff and co-workers reported the first Sonogashira cross coupling of alkynes with secondary alkyl bromides in the presence of palladium-N-heterocyclic carbene complexes and copper iodide was used as co-catalyst in Scheme 29 [62].

Scheme 29.
In addition, the 1,2-di-amino-cyclohexane was used with palladium-N-heterocyclic carbene complex as in Scheme 30 by the same research group. It improved the yield of the coupled product [62].

Scheme 30.
Moreover, the polymer supported palladium catalysts were also used for the Sonogashira cross coupling. In the past, the poly-styrene and silica supported phosphine palladium catalysts were used with copper iodide for coupling [63]. The [MCM-41-SH-Pd(0)] complex was used as a palladium source with copper iodide in the Sonogashira cross coupling of aryl iodides with terminal alkynes Scheme 31 [64]. Moreover, the polymer supported palladium catalysts were also used for the Sonogashira cross coupling. In the past, the poly-styrene and silica supported phosphine palladium catalysts were used with copper iodide for coupling [63]. The [MCM-41-SH-Pd(0)] complex was used as a palladium source with copper iodide in the Sonogashira cross coupling of aryl iodides with terminal alkynes Scheme 31 [64].
Moreover, the polymer supported palladium catalysts were also used for the Sonogashira cross coupling. In the past, the poly-styrene and silica supported phosphine palladium catalysts were used with copper iodide for coupling [63]. The [MCM-41-SH-Pd(0)] complex was used as a palladium source with copper iodide in the Sonogashira cross coupling of aryl iodides with terminal alkynes Scheme 31 [64]. Moreover, the bioorganometallic chemistry has attracted the attention of various chemists [65]. The Sonogashira cross coupling was a good methodology for the introduction of organometallic compounds as labels. The bio-conjugates also used this methodology. Hoffmann and coworkers use the Pd and Cu catalyzed Sonogashira cross coupling for the two-Step labeling of phenyl-alanine peptide side chains with organo-metallic compounds (Scheme 32). The ferrocene labeled derivatives were produced in good yield and purity by reaction of different ferrocene alkyne [66].
Catalysts 2020, 10, x FOR PEER REVIEW 19 of 51 Moreover, the bioorganometallic chemistry has attracted the attention of various chemists [65]. The Sonogashira cross coupling was a good methodology for the introduction of organometallic compounds as labels. The bio-conjugates also used this methodology. Hoffmann and coworkers use the Pd and Cu catalyzed Sonogashira cross coupling for the two-Step labeling of phenyl-alanine peptide side chains with organo-metallic compounds (Scheme 32). The ferrocene labeled derivatives were produced in good yield and purity by reaction of different ferrocene alkyne [66].

In 2007
It was observed that alkenyl nonaflates were easily available and stable but show reactivity as the alkenyl triflates. Furthermore, the generally employed sulfonylating reagents (nonafluoro-butane sulfonyl fluoride) were less expensive than other triflating reagents. These were used in synthesis and as building blocks [67]. Hogermeier and Co-workers reported the Sonogashira cross coupling of bicyclic nonaflate with phenyl acetylene in presence of Pd (OAc)2, PPh3 and CuI (Scheme 33) [68].

In 2007
It was observed that alkenyl nonaflates were easily available and stable but show reactivity as the alkenyl triflates. Furthermore, the generally employed sulfonylating reagents (nonafluoro-butane sulfonyl fluoride) were less expensive than other triflating reagents. These were used in synthesis and as building blocks [67]. Hogermeier and Co-workers reported the Sonogashira cross coupling of bicyclic nonaflate with phenyl acetylene in presence of Pd (OAc) 2 , PPh 3 and CuI (Scheme 33) [68].

In 2007
It was observed that alkenyl nonaflates were easily available and stable but show reactivity as the alkenyl triflates. Furthermore, the generally employed sulfonylating reagents (nonafluoro-butane sulfonyl fluoride) were less expensive than other triflating reagents. These were used in synthesis and as building blocks [67]. Hogermeier and Co-workers reported the Sonogashira cross coupling of bicyclic nonaflate with phenyl acetylene in presence of Pd (OAc)2, PPh3 and CuI (Scheme 33) [68]. In addition, the vinyl chloride was least reactive while used in the synthesis of natural products and biologically active compounds [69]. Bera and coworkers used the Pd/C-CuI-PPh3 catalyzed Sonogashira cross coupling for alkynylation of β-chloroacroleins (-CCl=CCHO-). The 4-alkynyl-2Hchromene-3-carbaldehydes and 5-alkynyl-2,3-dihydro benzo[b] oxepine-4-carbaldehydes were synthesized via Cu and Pd/C-mediated Sonogashira cross coupling Scheme 34. The Pd/C-CuI-PPh3 catalytic system was efficient for this coupling [70]. In addition, the vinyl chloride was least reactive while used in the synthesis of natural products and biologically active compounds [69].
It was noted that N-Carbamoyl heterocyclic carbene complex of palladium was developed as palladium source in 2002 while in 2008 it was used in base free Sonogashira cross coupling. The base sensitive substrates were used and catalyzed by palladium complex 148 and copper. The iodobenzene was coupled with terminal acetylenes in absence of base and catalyzed via N-Carbamoyl heterocyclic carbene complex of palladium and copper iodide Scheme 37. A good yield of the coupled product was obtained [73].

In 2009
Usually, the Sonogashira reaction is performed by using Pd-phosphine complex and CuI in the presence of secondary or tertiary amine or various simple bases. Many of these complexes are sensitive to both moisture and air. Previously, non-phosphine Sonogashira cross coupling was used, as discussed earlier in this review. However, only activated aryl-chlorides can couple in the presence of these catalysts. Thus, the search for coupling catalysts that show excellent activity and broad applicability continues. In 2009, Lee and Coworkers synthesized efficient water stable phosphine free pyridyl-azetidine based Pd (II) complexes (154, 155, 156) for the Sonogashira reaction [74]. Various aryl bromides and aryl chlorides efficiently coupled with 153 under different catalyst loadings. The addition of Copper Iodide increased the rate of reaction (Scheme 38). Scheme 37. Base free Sonogashira cross coupling of phenyl iodide and phenyl alkyne.

In 2009
Usually, the Sonogashira reaction is performed by using Pd-phosphine complex and CuI in the presence of secondary or tertiary amine or various simple bases. Many of these complexes are sensitive to both moisture and air. Previously, non-phosphine Sonogashira cross coupling was used, as discussed earlier in this review. However, only activated aryl-chlorides can couple in the presence of these catalysts. Thus, the search for coupling catalysts that show excellent activity and broad applicability continues. In 2009, Lee and Coworkers synthesized efficient water stable phosphine free pyridyl-azetidine based Pd (II) complexes (154, 155, 156) for the Sonogashira reaction [74]. Various aryl bromides and aryl chlorides efficiently coupled with 153 under different catalyst loadings. The addition of Copper Iodide increased the rate of reaction (Scheme 38).
Oxygen containing heterocycles possess many biological activities, such as anti-inflammatory [75], anticancer [76], antioxidative [77], antiviral [78] and antifungal activity [79]. It was a major challenge for organic chemists to synthesize heterocyclic compounds with a high degree of selectivity, specially the benzo[b]furan from a simple synthon. The typical structure of these compounds has a substituent at the C-2 and C-3 of benzofuran skeleton. Thus, Manarin and coworkers reported the preparation of 160 through the Sonogashira reaction of compound 158 in the presence of Palladium and Copper [80] as shown in (Scheme 39). Different alkyl and aryl terminal alkynes, as well as propargyl alcohols and protected propargyl alcohols were used.
Usually, the Sonogashira reaction is performed by using Pd-phosphine complex and CuI in the presence of secondary or tertiary amine or various simple bases. Many of these complexes are sensitive to both moisture and air. Previously, non-phosphine Sonogashira cross coupling was used, as discussed earlier in this review. However, only activated aryl-chlorides can couple in the presence of these catalysts. Thus, the search for coupling catalysts that show excellent activity and broad applicability continues. In 2009, Lee and Coworkers synthesized efficient water stable phosphine free pyridyl-azetidine based Pd (II) complexes (154, 155, 156) for the Sonogashira reaction [74]. Various aryl bromides and aryl chlorides efficiently coupled with 153 under different catalyst loadings. The addition of Copper Iodide increased the rate of reaction (Scheme 38).

Scheme 38.
Oxygen containing heterocycles possess many biological activities, such as anti-inflammatory [75], anticancer [76], antioxidative [77], antiviral [78] and antifungal activity [79]. It was a major challenge for organic chemists to synthesize heterocyclic compounds with a high degree of selectivity, specially the benzo[b]furan from a simple synthon. The typical structure of these compounds has a substituent at the C-2 and C-3 of benzofuran skeleton. Thus, Manarin and Similarly, in organic synthesis, alkynes are of great interest because of their use in the synthesis of heterocyclic compounds via intra-molecular hetero-annulation of amines, alcohols, carboxylic acids and amides to a C-C triple bond. Thus, Salas and Coworkers reported a nitro-group mediated regio-controlled hetero-annulation of 2-[2-(phenylethynyl)phenyl] acetic acids to (Z)-1-(2nitrobenzylidene)iso-chroman-3-ones (Scheme 40) [81]. Cross coupling of ester of o-iodophenyl acetic acid with Trimethylsilyl-acetylene and then Trimethylsilyl group was deprotected by using TBAF, which provided the derivative of phenyl-acetylene 163, which was then subjected to a second Sonogashira cross coupling with o-bromo nitrobenzene. This resulted in the formation of 164. Phenyl acetate derivatives formed by basic hydrolysis of 164 underwent cyclo-isomerization, resulting in the formation of expected lactone, which on reaction with NaOMe in CH3OH, furnished the required nitrophenyl-naphthoquinone, which was then easily converted into 165. Similarly, in organic synthesis, alkynes are of great interest because of their use in the synthesis of heterocyclic compounds via intra-molecular hetero-annulation of amines, alcohols, carboxylic acids and amides to a C-C triple bond. Thus, Salas and Coworkers reported a nitro-group mediated regio-controlled hetero-annulation of 2-[2-(phenylethynyl)phenyl] acetic acids to (Z)-1-(2-nitrobenzylidene)iso-chroman-3-ones (Scheme 40) [81]. Cross coupling of ester of o-iodophenyl acetic acid with Trimethylsilyl-acetylene and then Trimethylsilyl group was deprotected by using TBAF, which provided the derivative of phenyl-acetylene 163, which was then subjected to a second Sonogashira cross coupling with o-bromo nitrobenzene. This resulted in the formation of 164. Phenyl acetate derivatives formed by basic hydrolysis of 164 underwent cyclo-isomerization, resulting in the formation of expected lactone, which on reaction with NaOMe in CH3OH, furnished the required nitrophenyl-naphthoquinone, which was then easily converted into 165. acid with Trimethylsilyl-acetylene and then Trimethylsilyl group was deprotected by using TBAF, which provided the derivative of phenyl-acetylene 163, which was then subjected to a second Sonogashira cross coupling with o-bromo nitrobenzene. This resulted in the formation of 164. Phenyl acetate derivatives formed by basic hydrolysis of 164 underwent cyclo-isomerization, resulting in the formation of expected lactone, which on reaction with NaOMe in CH3OH, furnished the required nitrophenyl-naphthoquinone, which was then easily converted into 165.

In 2010
Among heterocycles, pyrans are the most common structural moieties present in various natural products. In particular, 2H-benzopyrans are present in a various compounds that exhibit important biological and pharmaceutical activities such as coutareagenin and dauri-chromenic acid show anti-diabetic properties [82] and anti-HIV activity [83] respectively. The applicability of the selectivity of alkyne at 3-position and chalcogen at 4-position of benzopyran can constitute a synthetic approach to the synthesis of biological active compounds. Thus, Speranca and coworkers reported the synthesis of 3-alkynyl-4-chalcogen-2H-benzopyrans (as shown in Scheme 41) via Sonogashira reaction of 166 with various terminal-alkynes in the presence of Pdand Cu catalyst [84]. The obtained product was effective for Successive hydro-telluration at the triple bond. They compare the influence of different catalysts such as Pd(PhCN) 2 Cl 2 , PdCl 2 , Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 and Pd(PPh 3 ) 4 . Pd(PPh 3 ) 2 Cl 2 was found to be the most efficient catalyst. It was also noted that in the absence of CuI, no coupling product was formed. In addition to using Et3N as base and solvent, we tried other solvents and bases.

In 2010
Among heterocycles, pyrans are the most common structural moieties present in various natural products. In particular, 2H-benzopyrans are present in a various compounds that exhibit important biological and pharmaceutical activities such as coutareagenin and dauri-chromenic acid show antidiabetic properties [82] and anti-HIV activity [83] respectively. The applicability of the selectivity of alkyne at 3-position and chalcogen at 4-position of benzopyran can constitute a synthetic approach to the synthesis of biological active compounds. Thus, Speranca and coworkers reported the synthesis of 3-alkynyl-4-chalcogen-2H-benzopyrans (as shown in Scheme 41) via Sonogashira reaction of 166 with various terminal-alkynes in the presence of Pd and Cu catalyst [84]. The obtained product was effective for Successive hydro-telluration at the triple bond. They compare the influence of different catalysts such as Pd(PhCN)2Cl2, PdCl2, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd(PPh3)4. Pd(PPh3)2Cl2 was found to be the most efficient catalyst. It was also noted that in the absence of CuI, no coupling product was formed. In addition to using Et3N as base and solvent, we tried other solvents and bases.

In 2011
As an extension of our study of preparation of heterocycles, in 2011, Gupta et al. synthesized a highly diverse pyrimido[1,2-a]indoles through subsequent Sonogashira reaction and [3+3] cyclocondensation reaction [85]. They synthesized 1-(4-methylphenyl)-3-phenylprop-2-yn-1-one by cross coupling of 169 and terminal acetylene in the presence of Pd/Cu and triethyl amine, as shown in Scheme 42. The resulting product was then treated with 171 at 90 °C in the presence of Sodium carbonate and acetonitrile to furnish 172 as a single regio-isomer through [3+3] cyclo-condensation. This approach failed to yield the required product, when both these conditions were combined in multicomponent tandem format in one-pot. Therefore, they optimized the conditions of reaction by

In 2011
As an extension of our study of preparation of heterocycles, in 2011, Gupta et al. synthesized a highly diverse pyrimido[1,2-a]indoles through subsequent Sonogashira reaction and [3+3] cyclo-condensation reaction [85]. They synthesized 1-(4-methylphenyl)-3-phenylprop-2-yn-1-one by cross coupling of 169 and terminal acetylene in the presence of Pd/Cu and triethyl amine, as shown in Scheme 42. The resulting product was then treated with 171 at 90 • C in the presence of Sodium carbonate and acetonitrile to furnish 172 as a single regio-isomer through [3+3] cyclo-condensation. This approach failed to yield the required product, when both these conditions were combined in multicomponent tandem format in one-pot. Therefore, they optimized the conditions of reaction by using various different bases, solvents and Pd catalysts. However, after investigating various solvents and bases, the use of Pd(PPh 3 ) 2 Cl 2 , CuI and triethyl amine, followed by addition of 171 and 1.5 equiv of Cs 2 CO 3 under reflux for 6 h were found to be efficient reaction conditions. Scheme 41.

In 2011
As an extension of our study of preparation of heterocycles, in 2011, Gupta et al. synthesized a highly diverse pyrimido[1,2-a]indoles through subsequent Sonogashira reaction and [3+3] cyclocondensation reaction [85]. They synthesized 1-(4-methylphenyl)-3-phenylprop-2-yn-1-one by cross coupling of 169 and terminal acetylene in the presence of Pd/Cu and triethyl amine, as shown in Scheme 42. The resulting product was then treated with 171 at 90 °C in the presence of Sodium carbonate and acetonitrile to furnish 172 as a single regio-isomer through [3+3] cyclo-condensation. This approach failed to yield the required product, when both these conditions were combined in multicomponent tandem format in one-pot. Therefore, they optimized the conditions of reaction by using various different bases, solvents and Pd catalysts. However, after investigating various solvents and bases, the use of Pd(PPh3)2Cl2, CuI and triethyl amine, followed by addition of 171 and 1.5 equiv of Cs2CO3 under reflux for 6 h were found to be efficient reaction conditions.

Scheme 42.
In addition, in the last few years, in the field of synthetic chemistry, H2O has gained significant attention due to its unique characteristic properties, especially at high pressure and high temperature conditions [86]. Various organic reactions including C-C coupling, de-hydrations and rearrangement reactions have been carried out in H2O [87,88]. Thus, Javaid and coworkers studied Sonogashira cross In addition, in the last few years, in the field of synthetic chemistry, H 2 O has gained significant attention due to its unique characteristic properties, especially at high pressure and high temperature conditions [86]. Various organic reactions including C-C coupling, de-hydrations and rearrangement reactions have been carried out in H 2 O [87,88]. Thus, Javaid and coworkers studied Sonogashira cross coupling reaction in high-pressure and high-temperature (HPHT) water using tubular reactors coated with Palladium and Palladium-Copper alloy [89]. The reaction was dependent on pressure and temperature. Under optimized conditions of reaction, 16 MPa of pressure and 250 • C temperature and alkaline aqueous medium, cross coupling of iodo-benzene and 173 was investigated by using this system, and diphenyl ethyne was obtained with 100% selectivity. The freshly Palladium plated reactor gave very poor conversion. Therefore, for Sonogashira coupling, the catalytic activity of Palladium was increased by using Pd-Cu alloy, which enhanced the efficiency of the reaction because of the co-catalytic effect that facilitated the transfer of electron between two-metals. This catalytic system offers various advantages such as shortest reaction time. reusable and leaching free process, and high-selectivity of the required product (Scheme 43).
Catalysts 2020, 10, x FOR PEER REVIEW 23 of 48 coupling reaction in high-pressure and high-temperature (HPHT) water using tubular reactors coated with Palladium and Palladium-Copper alloy [89]. The reaction was dependent on pressure and temperature. Under optimized conditions of reaction, 16 MPa of pressure and 250 °C temperature and alkaline aqueous medium, cross coupling of iodo-benzene and 173 was investigated by using this system, and diphenyl ethyne was obtained with 100% selectivity. The freshly Palladium plated reactor gave very poor conversion. Therefore, for Sonogashira coupling, the catalytic activity of Palladium was increased by using Pd-Cu alloy, which enhanced the efficiency of the reaction because of the co-catalytic effect that facilitated the transfer of electron between two-metals. This catalytic system offers various advantages such as shortest reaction time. reusable and leaching free process, and high-selectivity of the required product (Scheme 43).

Scheme 44.
Recently, a wide variety of cross coupling reactions catalyzed by Palladium complexes containing N-heterocyclic carbene (NHC) as a ligand have been reported. NHC derived from disubstituted imidazolium salt engaged the attention of researchers [91]. N-heterocyclic carbene formed a stronger bond with most of the metals than phosphine ligands due to their good σ-donating ability [92]. Indeed, in many catalytic reactions metal complexes containing NHC ligand have been proved to be more efficient catalysts as compared to phosphine-containing metal-complexes [93]. Thus, Luo and coworkers synthesized a new bis-N-heterocyclic carbene-PdI2 catalyst 179 from caffeine, as shown in Scheme 45. Under various conditions Palladium Catalyst 179 was used in Sonogashira cross coupling of para-bromo nitrobenzene 180 and phenylacetylene 181. The reaction did not proceed very well in H2O, even at 90 °C [94]. The 1 equivalent of Brij 30 was added in the reaction mixture as the non-ionic surfactant and NaO-t-Bu and KOH as the base, and it improved yield as the temperature was raised from 25 °C to 90 °C. Scheme 44. Synthesis of (Z)-1,4-diorganyl-2-tri(organyl)silyl-1-buten-3-ynes via Cross Coupling.
Recently, a wide variety of cross coupling reactions catalyzed by Palladium complexes containing N-heterocyclic carbene (NHC) as a ligand have been reported. NHC derived from disubstituted imidazolium salt engaged the attention of researchers [91]. N-heterocyclic carbene formed a stronger bond with most of the metals than phosphine ligands due to their good σ-donating ability [92]. Indeed, in many catalytic reactions metal complexes containing NHC ligand have been proved to be more efficient catalysts as compared to phosphine-containing metal-complexes [93]. Thus, Luo and coworkers synthesized a new bis-N-heterocyclic carbene-PdI 2 catalyst 179 from caffeine, as shown in Scheme 45. Under various conditions Palladium Catalyst 179 was used in Sonogashira cross coupling of para-bromo nitrobenzene 180 and phenylacetylene 181. The reaction did not proceed very well in H 2 O, even at 90 • C [94]. The 1 equivalent of Brij 30 was added in the reaction mixture as the non-ionic surfactant and NaO-t-Bu and KOH as the base, and it improved yield as the temperature was raised from 25 • C to 90 • C.

Scheme 46.
Similarly, Nishihara and coworkers synthesized unsymmetrically disubstituted ethynes by the Pd-Cu(I) co-catalyzed Sonogashira-Hagihara cross coupling reactions of 1-aryl-2-trimethylsilyl ethynes with aryl iodides, bromides, and chlorides [99]. Unsymmetrical diarylethyne moieties are common in the pharmaceutical industry, natural products and materials science. Compounds containing this moiety can easily be synthesized by using of the Sonogashira-Hagihara cross coupling reaction of terminal alkynes with aryl halides, or pseudo-halides (Scheme 47). Similarly, Nishihara and coworkers synthesized unsymmetrically disubstituted ethynes by the Pd-Cu(I) co-catalyzed Sonogashira-Hagihara cross coupling reactions of 1-aryl-2-trimethylsilyl ethynes with aryl iodides, bromides, and chlorides [99]. Unsymmetrical diarylethyne moieties are common in the pharmaceutical industry, natural products and materials science. Compounds containing this moiety can easily be synthesized by using of the Sonogashira-Hagihara cross coupling reaction of terminal alkynes with aryl halides, or pseudo-halides (Scheme 47). bis(hydroxy) diphenyl sulfone [95]. In medicinal chemistry, arylated sulfones are important structural moieties because of their various biological activities such as anti-bacterial activity [96], antiHIV [97] and anti-cholesteremic [98]. The Sonogashira cross coupling of 183 with alkynes 184 gave 2,4′-bis(alkynyl)diphenyl sulfones 185 containing two different aryl groups (Scheme 46). The reaction was carried out by using Copper Iodide and [Pd(PPh3)2Cl2] as a catalyst, triethyl amine as a base and DMF as the solvent.

Scheme 46.
Similarly, Nishihara and coworkers synthesized unsymmetrically disubstituted ethynes by the Pd-Cu(I) co-catalyzed Sonogashira-Hagihara cross coupling reactions of 1-aryl-2-trimethylsilyl ethynes with aryl iodides, bromides, and chlorides [99]. Unsymmetrical diarylethyne moieties are common in the pharmaceutical industry, natural products and materials science. Compounds containing this moiety can easily be synthesized by using of the Sonogashira-Hagihara cross coupling reaction of terminal alkynes with aryl halides, or pseudo-halides (Scheme 47).

In 2013
Ahammed used the Sonogashira reaction for the synthesis of 2-(2-nitrophenyl)-1-aryl ethanones, a valuable precursor for the synthesis of indoles [100]. In the presence of pyrrolidine, the alkyne formed via Palladium and Copper catalyzed coupling of 190 with 1-ethynyl-4-methoxybenzene continue with simultaneous regio-selective hydration, which resulted in the formation of corresponding aryl-ketone (Scheme 48). This method has various significant features such as high yields, reaction in H 2 O, and magnificent regio-selectivity.

In 2013
Ahammed used the Sonogashira reaction for the synthesis of 2-(2-nitrophenyl)-1-aryl ethanones, a valuable precursor for the synthesis of indoles [100]. In the presence of pyrrolidine, the alkyne formed via Palladium and Copper catalyzed coupling of 190 with 1-ethynyl-4-methoxybenzene continue with simultaneous regio-selective hydration, which resulted in the formation of corresponding aryl-ketone (Scheme 48). This method has various significant features such as high yields, reaction in H2O, and magnificent regio-selectivity.

Scheme 48.
The Phenylene-ethynylene oligomers and polymers are of great interest, because of their use for fabrication of optoelectronic and electronic devices [101,102]. In recent years, great progress has been made in the synthesis of numerous triple bond containing oligomers and rod like rigid parylacetylene polymers; however, because of intrinsic limitations of many synthetic methods, synthesis of highly conjugated arylene-ethynylene polymers and large oligomers is impossible. Defects in the conjugated system restrict their use in photonics and molecular electronics. For the preparation of triple bond containing π-conjugated systems Sonogashira cross coupling is the only effective method [103]. Hetero-coupling of terminal alkynes and iodo substituted aromatic compounds is more difficult than the homo coupling of the two terminal alkynes [104]. The synthesis of arylene ethynylene oligomers via Sonogashira reaction is also complicated because of competing homo coupling induced by the oxidizing agent (O2) and Copper iodide. Thus, under oxygen-free conditions Bai and coworkers synthesized 193 monomer by methylation of 2,6-di-tert-butylphenol, followed by iodination. It was then coupled with Trimethylsilyl acetylene (TMSA) under the conditions of Sonogashira cross coupling reaction to furnish the monomer protected with Trimethylsilyl, followed by deprotection by using tera-n-butyl ammonium fluoride resulted in the The Phenylene-ethynylene oligomers and polymers are of great interest, because of their use for fabrication of optoelectronic and electronic devices [101,102]. In recent years, great progress has been made in the synthesis of numerous triple bond containing oligomers and rod like rigid p-arylacetylene polymers; however, because of intrinsic limitations of many synthetic methods, synthesis of highly conjugated arylene-ethynylene polymers and large oligomers is impossible. Defects in the conjugated system restrict their use in photonics and molecular electronics. For the preparation of triple bond containing π-conjugated systems Sonogashira cross coupling is the only effective method [103]. Hetero-coupling of terminal alkynes and iodo substituted aromatic compounds is more difficult than the homo coupling of the two terminal alkynes [104]. The synthesis of arylene ethynylene oligomers via Sonogashira reaction is also complicated because of competing homo coupling induced by the oxidizing agent (O 2 ) and Copper iodide. Thus, under oxygen-free conditions Bai and coworkers synthesized 193 monomer by methylation of 2,6-di-tert-butylphenol, followed by iodination. It was then coupled with Trimethylsilyl acetylene (TMSA) under the conditions of Sonogashira cross coupling reaction to furnish the monomer protected with Trimethylsilyl, followed by deprotection by using tera-n-butyl ammonium fluoride resulted in the formation of 196. This was then reacted with excess 1,4-diiodobenzene to yield dimersubstituted with iodo [105]. A small amount of side product formed by homo-coupling was also obtained. Repeating this cycle of mono-alkynylation of diiodo-phenylene, coupling with Trimethylsilyl acetylene (TMSA) and then deprotection of TMS, resulted in the formation of tri, tetra and pentamer along with homo coupling side products. Efficiency of the Sonogashira reaction decreases as the size of coupling partners increases, even if there is no steric hinderance at the reaction site (Scheme 49). They synthesized thieno [2,3-c]pyridones by Sonogashira reaction of 205 with terminal alkyne followed by a base mediated intra-molecular C-N bond forming reaction (Scheme 51). It was found that in the presence of Pd/Cu, reaction of 205 with 206 resulted in the formation of thieny alkyne 207. Reaction of 207 with aq.NH3 at heating produced amides which react with sodium methoxide in CH3OH at reflux furnished thieno [2,3-c] pyridones 208 by intramolecular cyclization reaction [106]. They synthesized thieno [2,3-c]pyridones by Sonogashira reaction of 205 with terminal alkyne followed by a base mediated intra-molecular C-N bond forming reaction (Scheme 51). It was found that in the presence of Pd/Cu, reaction of 205 with 206 resulted in the formation of thieny alkyne 207. Reaction of 207 with aq.NH 3 at heating produced amides which react with sodium methoxide in CH 3 OH at reflux furnished thieno [2,3-c] pyridones 208 by intramolecular cyclization reaction [106]. Thieno [3,2-c]pyridines was also synthesized by Pd/Cu catalyzed Sonogashira reaction of the corresponding alkyne with 209, followed by hydrolysis of CN group of the 211 under the action of Trifluoroacetic acid-H 2 SO 4 system to amides and their intramolecular cyclization with sodium methoxide [106] (Scheme 52).

Scheme 51.
Thieno [3,2-c]pyridines was also synthesized by Pd/Cu catalyzed Sonogashira reaction of the corresponding alkyne with 209, followed by hydrolysis of CN group of the 211 under the action of Trifluoroacetic acid-H2SO4 system to amides and their intramolecular cyclization with sodium methoxide [106] (Scheme 52). Scheme 52.

In 2014
Korzec and coworkers developed a less costly and more efficient bimetallic nano Pd/PdO/Cu catalytic system for Sonogashira cross coupling as shown in Scheme 53. They checked the catalytic activity of different bimetallic catalysts during cross coupling reaction of 213 with tri-methyl silyl acetylene. Catalysts differ in their metal loadings, type of carrier metal and Concentration of Pd [107]. The carrier metals played a role both as cocatalyst to help the trans-metalation step in the Sonogashira reaction and the Pd support for the heterogenous catalysis. Among all the checked bimetallic composition, only Palladium/Copper composite were found to be active. The catalytic ability of the Scheme 52. Synthesis of 3-(4-propylphenyl)- 6,7,8,9-tetrahydrobenzo[4,5]thieno [3,2-c]pyridin-1 (2H)-one.

In 2014
Korzec and coworkers developed a less costly and more efficient bimetallic nano Pd/PdO/Cu catalytic system for Sonogashira cross coupling as shown in Scheme 53. They checked the catalytic activity of different bimetallic catalysts during cross coupling reaction of 213 with tri-methyl silyl acetylene.Catalysts differ in their metal loadings, type of carrier metal and Concentration of Pd [107]. The carrier metals played a role both as cocatalyst to help the trans-metalation step in the Sonogashira reaction and the Pd support for the heterogenous catalysis. Among all the checked bimetallic composition, only Palladium/Copper composite were found to be active. The catalytic ability of the Palladium/Copper catalytic system was affected by the conditions of the reaction, especially the temperature and concentration of phosphine ligands. Palladium/Copper catalytic system was affected by the conditions of the reaction, especially the temperature and concentration of phosphine ligands.

Scheme 53.
A new heterogeneous Pd-Cu/C catalytic system for Sonogashira alkynylation-[3+2]cycloaddition leading to triazoles was developed by Rossy and coworkers (Scheme 54) [108]. The Sonogashira step is suitable for both electron-donating and with-drawing substituents on the iodoaryl. This protocol allows the synthesis of various useful heterocycles with an inexpensive base and ligand in hydrophilic solvents. A new heterogeneous Pd-Cu/C catalytic system for Sonogashira alkynylation-[3+2]-cyclo addition leading to triazoles was developed by Rossy and coworkers (Scheme 54) [108]. The Sonogashira step is suitable for both electron-donating and with-drawing substituents on the iodoaryl. This protocol allows the synthesis of various useful heterocycles with an inexpensive base and ligand in hydrophilic solvents.
The same authors also studied the chances of intra-molecular reaction in order to get structurally intriguing iso-indolines fused triazoles. According to the kinetic of reactions, the reaction can proceed by two pathways. In path I, the series involves firstly Click and then Heck reaction while Path II involves Sonogashira and then Click transformations (Scheme 55).
A new heterogeneous Pd-Cu/C catalytic system for Sonogashira alkynylation-[3+2]cycloaddition leading to triazoles was developed by Rossy and coworkers (Scheme 54) [108]. The Sonogashira step is suitable for both electron-donating and with-drawing substituents on the iodoaryl. This protocol allows the synthesis of various useful heterocycles with an inexpensive base and ligand in hydrophilic solvents.

Scheme 54.
The same authors also studied the chances of intra-molecular reaction in order to get structurally intriguing iso-indolines fused triazoles. According to the kinetic of reactions, the reaction can proceed by two pathways. In path I, the series involves firstly Click and then Heck reaction while Path II involves Sonogashira and then Click transformations (Scheme 55).

Scheme 55.
In another study, Pd-bis(oxazoline) (Pd-BOX) A and B complexes was synthesized and their catalytic activities was checked in Sonogashira cross coupling by Hussain and coworkers (Scheme 56) [109]. The reaction of phenyl acetylene and iodo-benzene in the presence of Pd-BOX (A) or (B) and CuI and Et3N as a base at 70 °C. The results showed good conversion of iodo-benzene (77%) in the presence of Palladium-BOX (A) and slightly lower conversion (57%) with Palladium-BOX (B), affording the di-phenylacetylene as the only product. iodoaryl. This protocol allows the synthesis of various useful heterocycles with an inexpensive base and ligand in hydrophilic solvents.

Scheme 54.
The same authors also studied the chances of intra-molecular reaction in order to get structurally intriguing iso-indolines fused triazoles. According to the kinetic of reactions, the reaction can proceed by two pathways. In path I, the series involves firstly Click and then Heck reaction while Path II involves Sonogashira and then Click transformations (Scheme 55).

Scheme 55.
In another study, Pd-bis(oxazoline) (Pd-BOX) A and B complexes was synthesized and their catalytic activities was checked in Sonogashira cross coupling by Hussain  It was observed that enols of cyclic 3-alkynyl substituted 1,2-diones can be achieved via Sonogashira reaction. As shown in Scheme 57, an efficient Sonogashira reaction of substituted acetylenes with enolate of 3-bromocyclopentane and 3-bromocyclohexane-1,2-diketones was developed by Paju and coworkers [110]. In a short reaction time, the protocol affords enols of 1,2diketonescyclohexane and 3-alkynylsubstituted cyclopentane with good yield. In order to find favorable conditions for Sonogashira reaction of cyclic 3-bromo-1,2-diones they investigated the reaction of 3-bromo-1,2-diones with Phenyl acetylene and trimethylsilyl acetylene (TMSA). Phenyl acetylene reaction in the presence of Pd and Cu and TMSA with unprotected 3-bromo Cyclopentane-1,2-diketones gave a low yield 13% of Phenyl acetylenic and 15% for Trimethylsilyl acetylenic Scheme 56. Sonogashira coupling reaction of iodobenzene with phenyl acetylene.
It was observed that enols of cyclic 3-alkynyl substituted 1,2-diones can be achieved via Sonogashira reaction. As shown in Scheme 57, an efficient Sonogashira reaction of substituted acetylenes with enolate of 3-bromocyclopentane and 3-bromocyclohexane-1,2-diketones was developed by Paju and coworkers [110]. In a short reaction time, the protocol affords enols of 1,2-diketonescyclohexane and 3-alkynylsubstituted cyclopentane with good yield. In order to find favorable conditions for Sonogashira reaction of cyclic 3-bromo-1,2-diones they investigated the reaction of 3-bromo-1,2-diones with Phenyl acetylene and trimethylsilyl acetylene (TMSA). Phenyl acetylene reaction in the presence of Pd and Cu and TMSA with unprotected 3-bromo Cyclopentane-1,2-diketones gave a low yield 13% of Phenyl acetylenic and 15% for Trimethylsilyl acetylenic compound. In the same reaction conditions, the bromide of silyl enol ether reacted smoothly with phenylacetylene and TMSA at the same time, affording the corresponding products in 90% and 83% yield respectively. Therefore, only protected cyclic 3-bromo-1,2-diones 227 were used in Sonogashira. A medium presence of CuI supported the reaction.

Scheme 56.
It was observed that enols of cyclic 3-alkynyl substituted 1,2-diones can be achieved via Sonogashira reaction. As shown in Scheme 57, an efficient Sonogashira reaction of substituted acetylenes with enolate of 3-bromocyclopentane and 3-bromocyclohexane-1,2-diketones was developed by Paju and coworkers [110]. In a short reaction time, the protocol affords enols of 1,2diketonescyclohexane and 3-alkynylsubstituted cyclopentane with good yield. In order to find favorable conditions for Sonogashira reaction of cyclic 3-bromo-1,2-diones they investigated the reaction of 3-bromo-1,2-diones with Phenyl acetylene and trimethylsilyl acetylene (TMSA). Phenyl acetylene reaction in the presence of Pd and Cu and TMSA with unprotected 3-bromo Cyclopentane-1,2-diketones gave a low yield 13% of Phenyl acetylenic and 15% for Trimethylsilyl acetylenic compound. In the same reaction conditions, the bromide of silyl enol ether reacted smoothly with phenylacetylene and TMSA at the same time, affording the corresponding products in 90% and 83% yield respectively. Therefore, only protected cyclic 3-bromo-1,2-diones 227 were used in Sonogashira. A medium presence of CuI supported the reaction.

Scheme 57.
Double Sonogashira reaction is an excellent method for the synthesis of calix-arenes with electron rich cavities. Due to unique and tunable three-dimensional structure, Calix [4]arene is broadly used in the design of fluorescent receptors as a molecular scaffold [111,112]. Thus, Sun and coworkers reported synthesis of derivatives of calix [4]arene through Palladium catalyzed Sonogashira reaction from 231 and 25,27-dipropargyl-calix [4]arene [113]. Calix [4]arene derivatives show different fluorescent properties due to the different nature of substituents Calixarenes containing the electron-donating groups such as methoxy enhanced the intensity of fluorescence, while in a-protic solvents, the electron-withdrawing groups containing Calixarenes are not apparently fluorescent. This effect was estimated mainly due to the increase of delocalization of the p-π electron (Scheme 58).

Scheme 57. Cross Coupling of cyclic 3-bromo-1,2-diketones with terminal acetylene.
Double Sonogashira reaction is an excellent method for the synthesis of calix-arenes with electron rich cavities. Due to unique and tunable three-dimensional structure, Calix [4]arene is broadly used in the design of fluorescent receptors as a molecular scaffold [111,112]. Thus, Sun and coworkers reported synthesis of derivatives of calix [4]arene through Palladium catalyzed Sonogashira reaction from 231 and 25,27-dipropargyl-calix [4]arene [113]. Calix [4]arene derivatives show different fluorescent properties due to the different nature of substituents Calixarenes containing the electron-donating groups such as methoxy enhanced the intensity of fluorescence, while in a-protic solvents, the electron-withdrawing groups containing Calixarenes are not apparently fluorescent. This effect was estimated mainly due to the increase of delocalization of the p-π electron (Scheme 58).

In 2015
Bellina and coworkers in 2015 developed substituted alkynyl imidazoles via a one pot sequential reaction involving a highly regio-selective electrophilic C-5 bromination of substituted imidazoles, followed by an efficient Sonogashira Coupling [114]. They observed that the use of piperidine as a base instead of Et3N increased the yield (Scheme 59). The typical approach for the synthesis of hetero aryl alkynes relies on the Sonogashira reaction, in which terminal-alkynes and hetero-aryl halides are cross coupled in the presence of Palladium-Copper [115,116]. Scheme 58. Synthesis of calix [4]arene derivatives via Palladium and Copper catalyzed Coupling.

In 2015
Bellina and coworkers in 2015 developed substituted alkynyl imidazoles via a one pot sequential reaction involving a highly regio-selective electrophilic C-5 bromination of substituted imidazoles, followed by an efficient Sonogashira Coupling [114]. They observed that the use of piperidine as a base instead of Et 3 N increased the yield (Scheme 59). The typical approach for the synthesis of hetero aryl alkynes relies on the Sonogashira reaction, in which terminal-alkynes and hetero-aryl halides are cross coupled in the presence of Palladium-Copper [115,116]. Scheme 58.

In 2015
Bellina and coworkers in 2015 developed substituted alkynyl imidazoles via a one pot sequential reaction involving a highly regio-selective electrophilic C-5 bromination of substituted imidazoles, followed by an efficient Sonogashira Coupling [114]. They observed that the use of piperidine as a base instead of Et3N increased the yield (Scheme 59). The typical approach for the synthesis of hetero aryl alkynes relies on the Sonogashira reaction, in which terminal-alkynes and hetero-aryl halides are cross coupled in the presence of Palladium-Copper [115,116].

Scheme 59.
The Synthesis of 7-azaindoles having triazole and quinoxaline substituents at C-5, via double Sonogashira cross coupling of di-halogenated amino pyridines was reported by Leboho and coworkers in 2015 (Scheme 60) [117]. A double Sonogashira coupling of 3,5-diiodoaminopyridine with TMS-acetylene gave compound 237. Removal of TMS with TBAF resulted in the formation of 238 which on further double Sonogashira with 4-methoxy iodobenzene gave compound 239. After that, compound 239 on treatment with TFAA was converted into trifluoroacetamide and then it was subjected to the Cacchi-reaction and 2,3,5-trisubstituted 7-azaindoles was achieved. Scheme 59. One-pot sequential bromination of substituted imidazoles via Sonogashira Coupling.
The Synthesis of 7-azaindoles having triazole and quinoxaline substituents at C-5, via double Sonogashira cross coupling of di-halogenated amino pyridines was reported by Leboho and coworkers in 2015 (Scheme 60) [117]. A double Sonogashira coupling of 3,5-diiodoaminopyridine with TMS-acetylene gave compound 237. Removal of TMS with TBAF resulted in the formation of 238 which on further double Sonogashira with 4-methoxy iodobenzene gave compound 239. After that, compound 239 on treatment with TFAA was converted into trifluoroacetamide and then it was subjected to the Cacchi-reaction and 2,3,5-trisubstituted 7-azaindoles was achieved. The same authors also reported that when 240 was exposed to acetylene under Sonogashira conditions, coupling occurred at the position of iodine. Then, the azaindole nucleus was formed by using KOtBu in a mixture of Di-methyl formamide and tetra-hydro furan, followed by another Sonogashira cross coupling reaction at the bromo substituted site of azaindoles, which resulted in the formation of 243. This was then subjected to tetra-n-butylammonium fluoride (TBAF) for the removal of the trimethylsilyl. Then 7-azaindoles having quinoxaline and triazole substituents at C-5 were easily accomplished through an alkyne-azide cycloaddition (Scheme 61). The same authors also reported that when 240 was exposed to acetylene under Sonogashira conditions, coupling occurred at the position of iodine. Then, the azaindole nucleus was formed by using KOtBu in a mixture of Di-methyl formamide and tetra-hydro furan, followed by another Sonogashira cross coupling reaction at the bromo substituted site of azaindoles, which resulted in the formation of 243. This was then subjected to tetra-n-butylammonium fluoride (TBAF) for the removal of the trimethylsilyl. Then 7-azaindoles having quinoxaline and triazole substituents at C-5 were easily accomplished through an alkyne-azide cycloaddition (Scheme 61).

Scheme 60.
The same authors also reported that when 240 was exposed to acetylene under Sonogashira conditions, coupling occurred at the position of iodine. Then, the azaindole nucleus was formed by using KOtBu in a mixture of Di-methyl formamide and tetra-hydro furan, followed by another Sonogashira cross coupling reaction at the bromo substituted site of azaindoles, which resulted in the formation of 243. This was then subjected to tetra-n-butylammonium fluoride (TBAF) for the removal of the trimethylsilyl. Then 7-azaindoles having quinoxaline and triazole substituents at C-5 were easily accomplished through an alkyne-azide cycloaddition (Scheme 61).

Scheme 61.
Similarly, derivatives of 2-alkynyl benzoxazole and 2-alkynyl benzothiazole was synthesized via Sonogashira of the terminal alkynes and thio-ethers under aerobic conditions, using Pd(dppf)Cl2 and CuI by Paun and coworkers as shown in Scheme 62 [118]. The nature of benzoxazoles and benzothiazoles were also checked in the de-sulfitative Sonogashira. The reaction occurred better in aerobic conditions than inert atmosphere, although increased amounts of the diyne side product were formed. Similarly, derivatives of 2-alkynyl benzoxazole and 2-alkynyl benzothiazole was synthesized via Sonogashira of the terminal alkynes and thio-ethers under aerobic conditions, using Pd(dppf)Cl 2 and CuI by Paun and coworkers as shown in Scheme 62 [118]. The nature of benzoxazoles and benzo-thiazoles were also checked in the de-sulfitative Sonogashira. The reaction occurred better in aerobic conditions than inert atmosphere, although increased amounts of the diyne side product were formed. In aerobic conditions, the authors also coupled 248 with phenyl acetylene, which showed C-S and C-Br coupling of the alkyne. Under aerobic conditions, methyl thio-benzoxazoles brominated analog gave product 249 (Scheme 63). Increasing the equivalents of alkyne did not improve the yield of coupling reaction. Under inert atmosphere, an attempt to selective Sonogashira cross coupling of 5-bromo-2-(methylthio) benzoxazole surprisingly gave compound 250, with preservation of the bromine substituent which allowed the opportunity to further functionalize the benzoxazole nucleus through reactions of the C-Br bond. In aerobic conditions, the authors also coupled 248 with phenyl acetylene, which showed C-S and C-Br coupling of the alkyne. Under aerobic conditions, methyl thio-benzoxazoles brominated analog gave product 249 (Scheme 63). Increasing the equivalents of alkyne did not improve the yield of coupling reaction. Under inert atmosphere, an attempt to selective Sonogashira cross coupling of 5-bromo-2-(methylthio) benzoxazole surprisingly gave compound 250, with preservation of the bromine substituent which allowed the opportunity to further functionalize the benzoxazole nucleus through reactions of the C-Br bond.
Triarylamines linked with aryl-ethynyl (Ar-ethynyl-TAA) are of great interest because of their wide use in the synthesis of various natural products [119,120] and polymers [121][122][123]. Numerous methods have been reported for the synthesis of Ar-ethynyl-TAA by Sonogashira coupling using Pd and Cu which were applied in low yields of products at long reaction times. Thus, Safaei-Ghomi and coworkers developed an efficient method for the preparation of various derivatives of Aryl ethynyl linked triarylamines via Sonogashira cross coupling using Pd/Cu nanoparticles under ultrasonic irradiation [124]. This solvent-free method offers several advantages such as high yields, green procedure, short reaction times. Behaviors of different catalytic systems were checked, among which Pd (PPh 3 ) 2 Cl 2 /CuI nanoparticle showed excellent catalytic activity (Scheme 64). and C-Br coupling of the alkyne. Under aerobic conditions, methyl thio-benzoxazoles brominated analog gave product 249 (Scheme 63). Increasing the equivalents of alkyne did not improve the yield of coupling reaction. Under inert atmosphere, an attempt to selective Sonogashira cross coupling of 5-bromo-2-(methylthio) benzoxazole surprisingly gave compound 250, with preservation of the bromine substituent which allowed the opportunity to further functionalize the benzoxazole nucleus through reactions of the C-Br bond.

Scheme 63.
Triarylamines linked with aryl-ethynyl (Ar-ethynyl-TAA) are of great interest because of their wide use in the synthesis of various natural products [119,120] and polymers [121][122][123]. Numerous methods have been reported for the synthesis of Ar-ethynyl-TAA by Sonogashira coupling using Pd and Cu which were applied in low yields of products at long reaction times. Thus, Safaei-Ghomi and coworkers developed an efficient method for the preparation of various derivatives of Aryl ethynyl linked triarylamines via Sonogashira cross coupling using Pd/Cu nanoparticles under ultrasonic irradiation [124]. This solvent-free method offers several advantages such as high yields, green procedure, short reaction times. Behaviors of different catalytic systems were checked, among which Pd (PPh3)2Cl2/CuI nanoparticle showed excellent catalytic activity (Scheme 64). Pd-pincer complexes have been widely used as a catalyst in a various C-C or carbon-hetero bond formation [125]. In past decades, due to low costs and wide scope applications, NCN-Pd pincer complexes have attracted much attention. Thus, in 2015, Zhang and coworkers synthesized PdII-257, 258 and 259 pincer complexes and checked their activity in Sonogashira reaction (Scheme 65) [126]. In the Sonogashira reaction, 258b was used as a precatalyst to optimize the conditions of reaction, in order to check the catalytic activity of these complexes. Different solvent and bases were used, and it was found that the cross-coupling reaction gave excellent yield of products, when KOAc and DMAC were used as the base and solvent respectively. Similarly, the other items such as loading of catalyst 1 mmol %, temperature of reaction 90 °C as well as reaction time of 12 h are also optimized. Using these optimized conditions of reactions, they checked the catalytic ability of the other Pd pincer complexes in the same cross coupling reaction. Their catalyzed results showed that 259a was the most active catalyst and the general order of catalytic ability was as follows, 259 > 258 > 257. Furthermore, varying Z from Bu t to NO2 suggest that presence of the electron-withdrawing groups at the 4th position of Pd enhanced its catalytic activity. Pd-pincer complexes have been widely used as a catalyst in a various C-C or carbon-hetero bond formation [125]. In past decades, due to low costs and wide scope applications, NCN-Pd pincer complexes have attracted much attention. Thus, in 2015, Zhang and coworkers synthesized PdII-257, 258 and 259 pincer complexes and checked their activity in Sonogashira reaction (Scheme 65) [126]. In the Sonogashira reaction, 258b was used as a precatalyst to optimize the conditions of reaction, in order to check the catalytic activity of these complexes. Different solvent and bases were used, and it was found that the cross-coupling reaction gave excellent yield of products, when KOAc and DMAC were used as the base and solvent respectively. Similarly, the other items such as loading of catalyst 1mmol%, temperature of reaction 90 • C as well as reaction time of 12h are also optimized. Using these optimized conditions of reactions, they checked the catalytic ability of the other Pd pincer complexes in the same cross coupling reaction. Their catalyzed results showed that 259a was the most active catalyst and the general order of catalytic ability was as follows, 259 >258 >257. Furthermore, varying Z from Bu t to NO 2 suggest that presence of the electron-withdrawing groups at the 4th position of Pd enhanced its catalytic activity.

In 2016
A synthetic strategy for the formation of perylene nucleoside containing elongated rigid link between hydrocarbon and nucleobase through Sonogashira cross coupling was developed by Chistov and coworkers in 2016 [127]. 5-iodo-2 -deoxyuridine 260 was protected by Propinaylation and then coupled with Trimethysilyl. Alkynes were added in the presence of Pd and Cu and TBAF in the reaction which promote Silyl deprotection. Propinyl protection of both OH groups make both coupling products soluble enough to be purified by column chromatography. Both the OH groups are then deprotected in the presence of K 2 CO 3 , MeOH/H 2 O to afford the desired product 261 and 262, which are highly fluorescent (Scheme 66). order to check the catalytic activity of these complexes. Different solvent and bases were used, and it was found that the cross-coupling reaction gave excellent yield of products, when KOAc and DMAC were used as the base and solvent respectively. Similarly, the other items such as loading of catalyst 1 mmol %, temperature of reaction 90 °C as well as reaction time of 12 h are also optimized. Using these optimized conditions of reactions, they checked the catalytic ability of the other Pd pincer complexes in the same cross coupling reaction. Their catalyzed results showed that 259a was the most active catalyst and the general order of catalytic ability was as follows, 259 > 258 > 257. Furthermore, varying Z from Bu t to NO2 suggest that presence of the electron-withdrawing groups at the 4th position of Pd enhanced its catalytic activity. Scheme 65.

In 2016
A synthetic strategy for the formation of perylene nucleoside containing elongated rigid link between hydrocarbon and nucleobase through Sonogashira cross coupling was developed by Chistov and coworkers in 2016 [127]. 5-iodo-2′-deoxyuridine 260 was protected by Propinaylation The synthesis of a series of mono, di, tri and tetra-alkynyl derivatives of 1,3-dimethyl-and 1,3diethyl-1H-perimidine-2(3H)-ones from the corresponding bromides via the Sonogashira cross coupling was reported by Filatova, as shown in Scheme 66 [128] . It was found that placing two Trimethylsilyl-ethynyl groups at 6 and 7 positions of the primidone made a sterically hindered system and, sometimes, is accompanied by a previously unknown 1,2-migration of the Pd(II)-X group in the intermediate complex. When tetrabromide 263 was coupled with Trimethylsilyl acetylene 264 an unexpected result was observed. The reaction was slow when carried out in ordinary conditions, and inseparable products were obtained. However, when Trimethylsilyl acetylene was used in the presence of Pd2dba3/PPh3, CuI, triethylamine, and the system was heated for 12 h, a crystalline bright yellow compound 266 was obtained instead of the expected product 265 due to 1,2-Pd migration in an intermediate complex (Scheme 67). The synthesis of a series of mono, di, tri and tetra-alkynyl derivatives of 1,3-dimethyl-and 1,3-diethyl-1H-perimidine-2(3H)-ones from the corresponding bromides via the Sonogashira cross coupling was reported by Filatova, as shown in Scheme 67 [128]. It was found that placing two Trimethylsilyl-ethynyl groups at 6 and 7 positions of the primidone made a sterically hindered system and, sometimes, is accompanied by a previously unknown 1,2-migration of the Pd(II)-X group in the intermediate complex. When tetrabromide 263 was coupled with Trimethylsilyl acetylene 264 an unexpected result was observed. The reaction was slow when carried out in ordinary conditions, and inseparable products were obtained. However, when Trimethylsilyl acetylene was used in the presence of Pd 2 dba 3 /PPh 3 , CuI, triethylamine, and the system was heated for 12 h, a crystalline bright yellow compound 266 was obtained instead of the expected product 265 due to 1,2-Pd migration in an intermediate complex (Scheme 67). In 2016, Gholinejad and coworkers synthesized and characterized an efficient heterogenous catalyst Pd and Cu nanoparticles supported on phosphinite functionalized Agarose biopolymer [129]. The activity of this catalytic system was checked in Sonogashira reaction of aryl-iodide and substituted phenylacetylene at room temperature by using DABCO as a base and Dimethylacetamide (DMA) as a solvent and 0.05%mol Pd (Scheme 68).
In 2016, Gholinejad and coworkers synthesized and characterized an efficient heterogenous catalyst Pd and Cu nanoparticles supported on phosphinite functionalized Agarose biopolymer [129]. The activity of this catalytic system was checked in Sonogashira reaction of aryl-iodide and substituted phenylacetylene at room temperature by using DABCO as a base and Dimethylacetamide (DMA) as a solvent and 0.05%mol Pd (Scheme 68). In 2016, Gholinejad and coworkers synthesized and characterized an efficient heterogenous catalyst Pd and Cu nanoparticles supported on phosphinite functionalized Agarose biopolymer [129]. The activity of this catalytic system was checked in Sonogashira reaction of aryl-iodide and substituted phenylacetylene at room temperature by using DABCO as a base and Dimethylacetamide (DMA) as a solvent and 0.05%mol Pd (Scheme 68).

Scheme 68.
The synthesis of a marine brominated poly-unsaturated lipid xestospongenyne 272 having pancreatic lipase inhibitory activity through Sonogashira cross coupling of 270 with E/Z isomer of 1,2-dibromoethene in the presence of Pd and Copper Catalyst in triethylamine was reported by Gong (Scheme 69) [130]. The resulting moderate yield might be because of the lower reactivity of 271 In Pd catalyzed reactions. Generally, the (E) isomer of 1,2-dibromoethene is more reactive than the Z isomer. The synthesis of a marine brominated poly-unsaturated lipid xestospongenyne 272 having pancreatic lipase inhibitory activity through Sonogashira cross couplingof 270with E/Z isomer of 1,2-dibromoethene in the presence of Pd and Copper Catalyst in triethylamine was reported by Gong (Scheme 69) [130]. The resulting moderate yield might be because of the lower reactivity of 271 In Pd catalyzed reactions. Generally, the (E) isomer of 1,2-dibromoethene is more reactive than the Z isomer.
The synthesis of a marine brominated poly-unsaturated lipid xestospongenyne 272 having pancreatic lipase inhibitory activity through Sonogashira cross coupling of 270 with E/Z isomer of 1,2-dibromoethene in the presence of Pd and Copper Catalyst in triethylamine was reported by Gong (Scheme 69) [130]. The resulting moderate yield might be because of the lower reactivity of 271 In Pd catalyzed reactions. Generally, the (E) isomer of 1,2-dibromoethene is more reactive than the Z isomer.

Scheme 69.
In 2016, Nayak and coworkers reported the preparation of 5 and 6-acylated naptho [1,2b]benzofuran derivatives by the means of Sonogashira cross coupling and intra-molecular alkyne An efficient synthesis of 2,5-disubstituted Alkynyl bridged 1,3,4-Oxadiazole through Sonogashira cross coupling between arylacetylene and oxadiazole substituted phenyl bromides in the presence of Palladium and Copper was reported by Paun and coworkers [132]. This strategy is very suitable for the synthesis of Luminescent small molecules or precursor of other complex derivatives that are helpful as electron transporting components in the preparation of OLEDs (Scheme 72).

In 2017
Liu and coworkers reported FeCl 3 catalyzed synthesis of iodo-3H-pyrazoles derivatives [133]. 3H-pyrazoles derivatives are important heterocyclic compounds because of their extensive use in cyclopropenes, carbene intermediates, and diazoalkenes synthesis. To signify the effectiveness of the synthetic method they performed derivatization reaction of iodo-3H-pyrazole, as shown in Scheme 73. Pd and Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and the resulting product 286 was formed in 85% yield.

Scheme 71.
An efficient synthesis of 2,5-disubstituted Alkynyl bridged 1,3,4-Oxadiazole through Sonogashira cross coupling between arylacetylene and oxadiazole substituted phenyl bromides in the presence of Palladium and Copper was reported by Paun and coworkers [132]. This strategy is very suitable for the synthesis of Luminescent small molecules or precursor of other complex

In 2017
Liu and coworkers reported FeCl3 catalyzed synthesis of iodo-3H-pyrazoles derivatives [133]. 3H-pyrazoles derivatives are important heterocyclic compounds because of their extensive use in cyclopropenes, carbene intermediates, and diazoalkenes synthesis. To signify the effectiveness of the synthetic method they performed derivatization reaction of iodo-3H-pyrazole, as shown in Scheme 73. Pd and Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and the resulting product 286 was formed in 85% yield.

Scheme 73.
The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2-Dihydropyridine from ketene N,N-acetals was reported by S. Nayak and coworkers. They enlarged the Dihydropyridine ring by Sonogashira cross coupling of alkenyl iodo moiety [134]. Sonogashira Coupling of 287 yield extended π conjugated System 289 (Scheme 74).

In 2017
Liu and coworkers reported FeCl3 catalyzed synthesis of iodo-3H-pyrazoles derivatives [133]. 3H-pyrazoles derivatives are important heterocyclic compounds because of their extensive use in cyclopropenes, carbene intermediates, and diazoalkenes synthesis. To signify the effectiveness of the synthetic method they performed derivatization reaction of iodo-3H-pyrazole, as shown in Scheme 73. Pd and Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and the resulting product 286 was formed in 85% yield.

Scheme 73.
The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2-Dihydropyridine from ketene N,N-acetals was reported by S. Nayak and coworkers. They enlarged the Dihydropyridine ring by Sonogashira cross coupling of alkenyl iodo moiety [134]. Sonogashira Coupling of 287 yield extended π conjugated System 289 (Scheme 74).
The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2-Dihydropyridine from ketene N,N-acetals was reported by S. Nayak and coworkers. They enlarged the Dihydropyridine ring by Sonogashira cross coupling of alkenyl iodo moiety [134]. Sonogashira Coupling of 287 yield extended π conjugated System 289 (Scheme 74).
A facilesynthetic approach to functionalize cyclohexa-2,4-dienones was developed by Chittimalla and coworkers [135]. Cyclohexa-2,4-dienones are important synthetic precursors in the synthesis of various structurally diverse molecules [136,137]. A range of reactions, including organometallic coupling protocols, have been applied on these newly obtained halogenated cyclohexa-2,4-dienones. α-halo-dienones were subjected to Sonogashira cross coupling reaction. 2-bromo-5,6,6-trimethoxycyclohexa-2,4-dienone undergoes Pd-Cu catalyzed Sonogashira coupling with compound 290 and formed the adduct (292) in 74% yield (Scheme 75). Surprisingly, under same conditions, compound 293 and phenylacetylene gave product 294 in 80% yield. They guess that hydrido-Pd intermediate formed from Pd (0) and DIPEA could reduce the conjugated-double bond to give an intermediate, which is then aromatized to give the 2-methoxy-3-methyl-6-(phenyl ethynyl) phenol (294). To check whether aromatization or Sonogashira Coupling occurred first, a reaction was performed at −10 • C. After 30 min of reaction, thin layer chromatography and 1 H-NMR analysis showed 3 products; 293, 294 and 296, which indicates that in this reaction Sonogashira Coupling was followed by aromatization reaction. To avoid the generation of hydrido-Pd intermediate they used an alternative Sonogashira coupling procedure. In this procedure, Pre-synthesized Pd(PPh 3 ) 4 was used as a catalyst, Cu(I)-Phenylethyne was used as a reactant, and pyridine was used as a base. Under these reaction conditions, Sonogashira coupled product 294 was obtained in 93% yield.
3H-pyrazoles derivatives are important heterocyclic compounds because of their extensive use in cyclopropenes, carbene intermediates, and diazoalkenes synthesis. To signify the effectiveness of the synthetic method they performed derivatization reaction of iodo-3H-pyrazole, as shown in Scheme 73. Pd and Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and the resulting product 286 was formed in 85% yield.

Scheme 73.
The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2-Dihydropyridine from ketene N,N-acetals was reported by S. Nayak and coworkers. They enlarged the Dihydropyridine ring by Sonogashira cross coupling of alkenyl iodo moiety [134]. Sonogashira Coupling of 287 yield extended π conjugated System 289 (Scheme 74).

Scheme 74.
A facile synthetic approach to functionalize cyclohexa-2,4-dienones was developed by Chittimalla and coworkers [135]. Cyclohexa-2,4-dienones are important synthetic precursors in the synthesis of various structurally diverse molecules [136,137]. A range of reactions, including organometallic coupling protocols, have been applied on these newly obtained halogenated cyclohexa-2,4-dienones. α-halo-dienones were subjected to Sonogashira cross coupling reaction. 2bromo-5,6,6-trimethoxycyclohexa-2,4-dienone undergoes Pd-Cu catalyzed Sonogashira coupling with compound 290 and formed the adduct (292) in 74% yield (Scheme 75). Surprisingly, under same conditions, compound 293 and phenylacetylene gave product 294 in 80% yield. They guess that hydrido-Pd intermediate formed from Pd (0) and DIPEA could reduce the conjugated-double bond to give an intermediate, which is then aromatized to give the 2-methoxy-3-methyl-6-(phenylethynyl) Sonogashira cross coupling reaction can also be used for the synthesis of ynones that are important building blocks for the synthesis of quinoline. In 2017, Rode and coworkers synthesized 4nitroquinolinesand 4-sulfonylquinolinesvia reaction of ynones with nitrite and sulfinate anions in the presence of NH4Cl as a proton source [138]. Starting ynones was prepared by using Sonogashira cross coupling of substituted iodoaniline with 298 and then oxides caused the resulting product 299 with Scheme 75. Sonagashira coupling of substituted o-benzoquinoneswith phenyl acetylene. Sonogashira cross coupling reaction can also be used for the synthesis of ynones that are important building blocks for the synthesis of quinoline. In 2017, Rode and coworkers synthesized 4-nitroquinolinesand 4-sulfonylquinolinesvia reaction of ynones with nitrite and sulfinate anions in the presence of NH 4 Cl as a proton source [138]. Starting ynones was prepared by using Sonogashira cross coupling of substituted iodoaniline with 298 and then oxides caused the resulting product 299 with MnO 2 (Scheme 76). In organic synthesis, silyl groups are widely used. Deprotection of silyl-ethynl intermediate is typically done by using a Fluoride source. However, the use of a Fluoride source is not suitable due to the high price of fluoride salts and low fluoride content mass, and another issue is the origin of fluorinated reagent. Due to these issues, Sinai and coworkers developed a cheap, nontoxic and easily available deprotecting agent H2SiF6 for the deprotection of ethynyl-trimethyl silane to form terminal acetylenes (Scheme 77) [139]. This reagent was used in Sonogashira reaction for the synthesis of derivatives of arylethynylpivalanilides and amines, 2-arylbenzofurans, and N-benzyltriazole. Transformation of terminal acetylenes catalyzed by transition metal is one of the most frequently used methods for the synthesis of heterocycles and internal-acetylenes. H2SiF6 showed efficient reactivity and its presence had no deleterious effect on Sonogashira cross coupling. In organic synthesis, silyl groups are widely used. Deprotection of silyl-ethynl intermediate is typically done by using a Fluoride source. However, the use of a Fluoride source is not suitable due to the high price of fluoride salts and low fluoride content mass, and another issue is the origin of fluorinated reagent. Due to these issues, Sinai and coworkers developed a cheap, nontoxic and easily available deprotecting agent H 2 SiF 6 for the deprotection of ethynyl-trimethyl silane to form terminal acetylenes (Scheme 77) [139]. This reagent was used in Sonogashira reaction for the synthesis of derivatives of arylethynylpivalanilides and amines, 2-arylbenzofurans, and N-benzyltriazole. Transformation of terminal acetylenes catalyzed by transition metal is one of the most frequently used methods for the synthesis of heterocycles and internal-acetylenes. H 2 SiF 6 showed efficient reactivity and its presence had no deleterious effect on Sonogashira cross coupling. In organic synthesis, silyl groups are widely used. Deprotection of silyl-ethynl intermediate is typically done by using a Fluoride source. However, the use of a Fluoride source is not suitable due to the high price of fluoride salts and low fluoride content mass, and another issue is the origin of fluorinated reagent. Due to these issues, Sinai and coworkers developed a cheap, nontoxic and easily available deprotecting agent H2SiF6 for the deprotection of ethynyl-trimethyl silane to form terminal acetylenes (Scheme 77) [139]. This reagent was used in Sonogashira reaction for the synthesis of derivatives of arylethynylpivalanilides and amines, 2-arylbenzofurans, and N-benzyltriazole. Transformation of terminal acetylenes catalyzed by transition metal is one of the most frequently used methods for the synthesis of heterocycles and internal-acetylenes. H2SiF6 showed efficient reactivity and its presence had no deleterious effect on Sonogashira cross coupling.

In 2018
As previously mentioned, the nitrogen containing heterocycles have attracted the attention of many research groups. The Poly-functional pyrroles are present in many naturally occurring compounds as vitamin B 12 , Chlorins and Porphins [140]. The Poly-functional pyrroles are used as precursor for synthesizing many biologically active drugs and N-methyl-pyrrole-carboxylic acid is used as building block in pharmaceutical chemistry [141]. Liang and coworkers synthesized the 2,3-di-hydro-pyrrole derivatives by using terminal alkyne and allenamide allyl acetate via palladium and copper catalyzed Sonogashira reaction (Scheme 79). The different ligands were used with palladium and copper catalysts. Both the electron donating and electron withdrawing substrates gave good yield [142].

In 2018
As previously mentioned, the nitrogen containing heterocycles have attracted the attention of many research groups. The Poly-functional pyrroles are present in many naturally occurring compounds as vitamin B12, Chlorins and Porphins [140]. The Poly-functional pyrroles are used as precursor for synthesizing many biologically active drugs and N-methyl-pyrrole-carboxylic acid is used as building block in pharmaceutical chemistry [141]. Liang and coworkers synthesized the 2,3di-hydro-pyrrole derivatives by using terminal alkyne and allenamide allyl acetate via palladium and copper catalyzed Sonogashira reaction (Scheme 79). The different ligands were used with palladium and copper catalysts. Both the electron donating and electron withdrawing substrates gave good yield [142]. It was also noted that isocoumarins are naturally occurring lactones and are biologically active. They are used as a precursor for synthesis of bio active complex compounds [143]. The 3-alkynyl isocoumarins were synthesized via palladium and copper catalyzed Sonogashira cross coupling of methyl 2-(2′,2′-dibromo vinyl) benzoate with terminal alkyne by Liu and co-workers. The naturally occurring compounds 3′-hydroxycorfin and gymnopalyne A were also synthesized via palladium and copper catalyzed Sonogashira cross coupling as a key step (Scheme 80) [144].

In 2018
As previously mentioned, the nitrogen containing heterocycles have attracted the attention of many research groups. The Poly-functional pyrroles are present in many naturally occurring compounds as vitamin B12, Chlorins and Porphins [140]. The Poly-functional pyrroles are used as precursor for synthesizing many biologically active drugs and N-methyl-pyrrole-carboxylic acid is used as building block in pharmaceutical chemistry [141]. Liang and coworkers synthesized the 2,3di-hydro-pyrrole derivatives by using terminal alkyne and allenamide allyl acetate via palladium and copper catalyzed Sonogashira reaction (Scheme 79). The different ligands were used with palladium and copper catalysts. Both the electron donating and electron withdrawing substrates gave good yield [142]. It was also noted that isocoumarins are naturally occurring lactones and are biologically active. They are used as a precursor for synthesis of bio active complex compounds [143]. The 3-alkynyl isocoumarins were synthesized via palladium and copper catalyzed Sonogashira cross coupling of methyl 2-(2′,2′-dibromo vinyl) benzoate with terminal alkyne by Liu and co-workers. The naturally occurring compounds 3′-hydroxycorfin and gymnopalyne A were also synthesized via palladium and copper catalyzed Sonogashira cross coupling as a key step (Scheme 80) [144]. It was also noted that isocoumarins are naturally occurring lactones and are biologically active. They are used as a precursor for synthesis of bio active complex compounds [143]. The 3-alkynyl isocoumarins were synthesized via palladium and copper catalyzed Sonogashira cross coupling of methyl 2-(2 ,2 -dibromo vinyl) benzoate with terminal alkyne by Liu and co-workers. The naturally occurring compounds 3 -hydroxycorfin and gymnopalyne A were also synthesized via palladium and copper catalyzed Sonogashira cross coupling as a key step (Scheme 80) [144].
In addition, N-Heterocyclic carbenes are widely used as ligands with palladium catalyst and are important for Sonogashira cross coupling [145]. Shen and co-workers reported that the acenaphthoimidazolylidene palladium complex and copper co catalyst showed high catalytic activity for the Sonogashira Cross Coupling of bulky and heterocyclic halides with heteroaryl alkynes (Scheme 81) [146].