Palladium and Copper Catalyzed Sonogashira Cross Coupling an Excellent Methodology for C-C Bond Formation Over 17 Years: a Review

catalysts

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

Iram Kanwal 1, Aqsa Mujahid 1, Nasir Rasool 1,*, Komal Rizwan 1,2, Ayesha Malik 1, Gulraiz Ahmad 1, Syed Adnan Ali Shah 3,4, Umer Rashid 5,* and Nadiah Mad Nasir 6

1 Department of Chemistry, Government College University Faisalabad, Punjab 38000, Pakistan; [email protected] (I.K.); [email protected] (A.M.); [email protected] (K.R.); [email protected] (A.M.); [email protected] (G.A.) 2 Department of Chemistry, University of Sahiwal, Sahiwal 57000, Pakistan 3 Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam 42300, Selangor D. E., Malaysia; [email protected] 4 Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam 42300, Selangor D. E., Malaysia 5 Institute of Advanced Technology, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia 6 Department of Chemistry, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia; [email protected] * Correspondence: [email protected] (N.R.); [email protected] or [email protected] (U.R.); Tel.: +92-332-7491790 (N.R.); +60-3-9769-7393 (U.R.); Fax: +92-41-9201032 (N.R.); +60-3-9769-7006 (U.R.) Received: 12 December 2019; Accepted: 14 January 2020; Published: 20 April 2020

Abstract: 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 sp2-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, diﬀerent catalyst systems and reaction conditions.

Keywords: cross coupling; copper; palladium; transition; Sonogashira

1. 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 (Figure1), which are precursors for pharmaceuticals, natural products and organic materials and this type of coupling commonly known as Sonogashira coupling [3–5]. This reaction was named after the scientists Sonogashira, Tohda, and Hagihara in 1975.

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Figure 1. General schematic presentationFigure of 1. Sonogashira Cross Coupling reaction.

This research came after Cassar [[6]6] and DieckDieck and Heck [[7]7] discloseddisclosed that it waswas possiblepossible to performperform thisthis coupling coupling only only under under palladium palladium catalyst catalyst at high at temperatures. high temperatures. Sonogashira Sonogashira and Hagihara and reportedHagihara that reported addition that of addition catalytic of amount catalytic of Copper amount (I) of iodide Copper accelerates (I) iodide the accelerates C-C bond the formations C-C bond at roomformations temperature at room [ 8temperature]. However, [8]. addition However, of copper addition has of many copper benefits, has many but benefits, it has some but drawbacksit has some associateddrawbacks withassociated it, the with main it, one the beingmain theone necessitybeing the ofnecessity avoiding of theavoiding presence the presence of oxygen of in oxygen order toin blockorder theto block undesirable the undesirable formation formation of alkyne homocouplingof alkyne homocoupling through a copper-mediatedthrough a copper-mediated Hay/Glaser reactionHay/Glaser [9] alongreaction with [9] the along main productwith the and main diffi productculty in recoveryand difficulty of reagents. in recovery To overcome of reagents. this issue, To eliminationovercome this of theissue, copper elimination was a solution, of the copper so perhaps was a insolution, this case so the perhaps process in maythis case be called the process copper-free may Sonogashirabe called copper-free reaction, orSonogashira Heck-Cassar reaction, reaction, or Heck Heck-Cassar alkynylation reaction, or perhaps Heck Sonogashira-Heck-Cassar alkynylation or perhaps coupling.Sonogashira-Heck-Cassar Significant efforts coupling. were made Significant to develop effort the couplings were made reaction to develop and enhancement the coupling of reactivity reaction ofand catalytic enhancement system inof absencereactivity of copperof catalytic sources. system The in copper absence free of coupling copper process sources. involves The copper the use free of excesscoupling amine process which involves often the acts use as of asolvent, excess amine but the whic environmentalh often acts as and a solvent, economic but the advantages environmental of the methodologyand economic end advantages here. Thus, of ethefforts methodology were made toen developd here. SonogashiraThus, efforts cross-coupling were made to reaction develop in absenceSonogashira of both cross-coupling copper and amines reaction [10 in]. absence In the Sonogashira of both copper process, and di aminesfferent substrates[10]. In the have Sonogashira different reactivitiesprocess, different as sp2 speciessubstrates reactivity have different order was reactiviti found toes beas sp2 vinyl species iodide reactivity> vinyl triflate order >wasvinyl found bromide to be >vinylvinyl iodide chloride > vinyl> aryl triflate iodide > vinyl> aryl bromide triflate > vinylaryl bromide chloride >> aryl chloride.iodide > aryl In organic triflate > halides, aryl bromide which are> aryl activated chloride. (electron-poor), In organic halides, the situation which are is even activated more (electron-poor), promising [11]. the The situation products is obtainedeven more in Sonogashirapromising [11]. reaction The haveproducts various obtained applications in Sonogash in theira diverse reaction areas have of chemistry, various applications such as electronics, in the dyes,diverse polymers, areas of sensors,chemistry, natural such products as electronics, and in dyes, synthesis polymers, of heterocycles. sensors, natural Remarkable products research and onin thissynthesis topic of has heterocycles. been going Remarkable on for decades research to search on this for topic more has convenient been going reaction on for decades conditions to search and a better,for more effi convenientcient catalytic reaction system conditions and for synthesis and a bette ofr, promising efficient catalytic compounds. system This and review for synthesis covers the of developmentspromising compounds. in the Sonogashira This review cross-coupling covers the reaction, developments as well asin applicationsthe Sonogashira of this cross-coupling methodology fromreaction, 2002 as to well 2018. as applications of this methodology from 2002 to 2018.

2. Literature Review The palladiumpalladium catalyzed cross couplingcoupling betweenbetween carboncarbon halideshalides andand terminalterminal acetylenesacetylenes havehave been reported by variousvarious researchresearch groupsgroups [[12].12]. TheseThese cross couplings have used the formation of a carbon-carbon bond.bond. The copper as co-catalyst with palladium complexes were used for Sonogashira cross couplingcoupling [[13].13]. The Sonogashira cross coupling was also used for the preparation of compounds whichwhich areare pharmacologicallypharmacologically andand biologicallybiologically active.active. In this cross coupling, the various ligands with palladiumpalladium andand coppercopper co-catalystco-catalyst havehave beenbeen usedused byby variousvarious researchresearch groups.groups. 2.1. In 2002 2.1. In 2002 The Sonogashira cross coupling was used for synthesizes of diﬀerent organic compounds The Sonogashira cross coupling was used for synthesizes of different organic compounds which which are used as precursors for biologically active molecules. Earlier, the triple bond in C-9 and are used as precursors for biologically active molecules. Earlier, the triple bond in C-9 and C-10 of C-10 of Stereo-selective 9,10-didehydro retinoic acids 4 were formed “by Witting reaction” and by Stereo-selective 9,10-didehydro retinoic acids 4 were formed “by Witting reaction” and by addition addition reaction of 4-methyl-pyrylium tetra-ﬂuoro-borate on appropriate substrate, but protection reaction of 4-methyl-pyrylium tetra-fluoro-borate on appropriate substrate, but protection and de- and de-protection steps were used in these reactions. In 2002, the Sonogashira cross coupling was protection steps were used in these reactions. In 2002, the Sonogashira cross coupling was used by used by Abarbri and co-workers for the synthesis of 4 Stereo-selective 9,10-didehydro retinoic acids Abarbri and co-workers for the synthesis of 4 Stereo-selective 9,10-didehydro retinoic acids without without protection and de-protection of carboxylic acid. The dienyoic acid 3 was also synthesized via protection and de-protection of carboxylic acid. The dienyoic acid 3 was also synthesized via di- di-chloro-bis (tri-phenyl phosphine) palladium (II) and copper iodide catalyzed Sonogashira cross chloro-bis (tri-phenyl phosphine) palladium (II) and copper iodide catalyzed Sonogashira cross coupling (Scheme 1). The yield was 77% when the reagent 1 is (2Z,4E), R is Me and when R2 is Me3Si, the yield is 77% [14].

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2 coupling (Scheme1).The yield was 77% when the reagent 1 is (2Z,4E), R is Me and when R is Me3Si, theCatalysts yield 2020 is, 77%10, x FOR [14]. PEER REVIEW 3 of 48 Catalysts 2020, 10, x FOR PEER REVIEW 3 of 48

Scheme 1. Stereoselective Synthesis of 9,10-didehydro retinoic acids. Scheme 1. Similarly, the 5-phenylpent-4-yn-1-ol 7 was synthesized via Sonogashira cross coupling Similarly, the 5-phenylpent-4-yn-1-ol 7 was synthesized via Sonogashira cross coupling without without the protection of hydroxy group. The 7 was used as precursor for the synthesis of the protection of hydroxy group. The 7 was used as precursor for the synthesis of 2-aryl-2,5-dihydro- 2-aryl-2,5-dihydro-2H-pyrans 8. An aryl di-hydro-pyran precursor was synthesized via etheriﬁcation 2H-pyrans 8. An aryl di-hydro-pyran precursor was synthesized via etherification of an aryl of an aryl bishomoallylic alcohol. Sonogashira coupling of homo-propargylic alcohols with aryl bishomoallylic alcohol. Sonogashira coupling of homo-propargylic alcohols with aryl bromides gave bromides gave the (E)-arylhydroxyalkene cyclization precursors. The substituted acetylenes were the (E)-arylhydroxyalkene cyclization precursors. The substituted acetylenes were reduced to the reduced to the alkenols. The phenyl-selenenyl chloride in dichloromethane was used for synthesis of alkenols. The phenyl-selenenyl chloride in dichloromethane was used for synthesis of trans 2,3- trans 2,3-disubstituted tetrahydropyrans. The oxidative-elimination proceeded by using 30% hydrogen disubstituted tetrahydropyrans. The oxidative-elimination proceeded by using 30% hydrogen peroxide and pyridine in THF giving 8 in good yield (Scheme2)[15]. peroxide and pyridine in THF giving 8 in good yield (Scheme 2) [15].

Scheme 2. Sonogashira Cross Coupling ofScheme homo-propargylic 2. alcohols with bromobenzene.

It waswas observed observed that that Sonogashira Sonogashira cross cross coupling coupling is a goodis a methodologygood methodology for the couplingfor the coupling of nitrogen of containingnitrogen containing heterocycles heterocycles with terminal with terminal acetylenes. acetylenes. The 3-iodoindazoles The 3-iodoindazoles were coupled were coupled with various with propiolicvarious propiolic or propargylic or propargylic derivatives derivatives via palladium via palladium and copper and catalyzed copper Sonogashira catalyzed Sonogashira coupling to preparecoupling the to buildingprepare the blocks building of interest blocks in medicinalof interest chemistry in medicinal as tryptamine chemistry derivatives.as tryptamine As derivatives. mentioned, inAs Scheme mentioned,3 the in N-1 Scheme of the 3-iodo-1H-indazole3 the N-1 of the 3-iodo-1H-indazole9 was protected 9 and was compound protected12 andwas compound synthesized 12 was and 99%synthesized yield produced and 99% via yield this produced methodology. via this There method was noology. coupling There in was position no coupling 3 of 9 without in position protection 3 of 9 ofwithout N-1 [16 protection]. of N-1 [16]. Similarly, the nitrogen containing heterocycles as in Scheme4, 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].

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I I H (Boc)2O,DMAP,TEA, H CH3CN,3h (88%) N N + H (CH2)3NH(Tos) NH N 11 910Boc PdCl2(PPh3)2, (5mol%)Et3N, CuI,DMF,rt

(CH2)3NH(Tos) (CH2)3NH(Tos)

H MeONa,MeOH,rt H N N NH NBoc 13 12

Catalysts 2020, 10, x FORScheme PEER REVIEW3. SynthesisSynthesis of aza tryptamines via Sonogashira Cross Coupling. 5 of 48

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 carbon- carbon 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 π- acceptor 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].

Scheme 4. Synthesis of 4, 5-iodouracil PNA-residuesScheme via4. Sonogashira Cross Coupling in solution and solid phase.

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].

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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 carbon-carbon bond formation [21]. Scheme 4.

Scheme 5. Synthesis of trimethyl(phenylethynyl)silaneScheme 5. by Palladium and Copper catalyzed reaction.

It waswas noted also thatnoted the that linear Nucleophilic conjugated oligomersN-heterocyclic have attracted carbenes considerable Pd (II) complex attention 35, of especially scientists dueimidazole-2-ylidene, to their potential was use used in molecule-based as an alternative electronics for phosphine as molecular ligands in wires homogeneous [22,23]. Kitamura catalysis. and In co-workersSonogashira described cross coupling, the synthesis these Pd of acomplexes new class were of linear used conjugated as the palladium oligomers source by bi-directional and copper methodiodide was using used Sonogashira as the co-catalyst cross for coupling. coupling The of terminal route for acetylenes ethyne linked with aryl-halide alternating Schemeπ-donor 7. andThe π palladium-acceptor carbene system complex was developed alone produce as in Scheme 50% yield6. Theand changewith PPh of3 yield substrate was 97%. e ﬀects The the aryl yield bromide and homo-couplingderivativesCatalysts with 2020 yields, electron10, x FOR 26%. PEERdonating The REVIEW [2+ groups1+ 2] method on the wasring usedshow as less a bi-directional reactivity [25]. method [24]. 6 of 48

Scheme 6. Synthesis of Oligomers via SonogashiraScheme cross6. coupling followed by [2+1+2]bi- directional method.

Scheme 7.

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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 Scheme7. The palladium carbene complex alone produce 50% yield and with PPh3 yield was 97%. The aryl bromide derivatives with electron donating groupsScheme on 6. the ring show less reactivity [25].

Scheme 7. Sonogashira cross coupling ofScheme substituted 7. alkyl halide and terminal acetylene.

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(PPh3) and copper iodide catalyzed Sonogashira cross coupling and the conversion was 100% (Scheme8)[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 (PPh3)4 and CuI catalyzed Sonogashira cross coupling which were than reacted with KOtBu, and the nitro-bezo[b]furan 45 was obtained (Scheme9)[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]. Catalysts 2020, 10, x FOR PEER REVIEW 7 of 48

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-acetyleneCatalysts 2020, 10, x FOR PEER REVIEWvia Pd (OAc)2(PPh3) and copper iodide catalyzed Sonogashira 7cross of 48 coupling and the conversion was 100% (Scheme 8) [28]. 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 Catalyststri-methyl-silyl-acetylene2020, 10, 443 via Pd (OAc)2(PPh3) and copper iodide catalyzed Sonogashira 7cross of 48 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 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 (PPh3)4 and CuI catalyzed Sonogashira cross coupling which were than reacted with KOtBu, and the nitro-bezo[b]furan 45 was obtained (Scheme 9) [30]. Scheme 8. SynthesisScheme of Silylated 8. Polystyrene.

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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]. Scheme 9. Sonogashira cross coupling ofScheme substituted 9. iodo-acetates with terminal alkynes.

Scheme 9.

Scheme 10. Sonogashira Cross Coupling of alkyne-substituted phenyl iodides with terminal alkynes. Scheme 10.

Furthermore, the phenyl iodides were coupled with terminal acetylenes via Palladium (0) and CopperFurthermore, (I) catalyzed the Sonogashiraphenyl iodides cross were coupling coupled and with 92% terminal yield of acetylenes coupled productvia Palladium was obtained (0) and Copper(Scheme (I) 11 )[catalyzed31]. Sonogashira cross coupling and 92% yield of coupled product was obtained (Scheme 11) [31].

Scheme 11.

2.2. 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].

Catalysts 2020, 10, x FOR PEER REVIEW 8 of 48 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-workersIt was reportedobserved that that the the copper nature as of co-catalyst catalyst co playedntrols importantthe Sonogashira role for cross the formation coupling. ofTeply coupled and product.co-workers The reported phenyl that iodides the copper were ascoupled co-catalyst with played terminal important acetylenes; role forin the formationabsence copper of coupled co- catalyst,product. the The cyclized phenyl product iodides was were formed coupled (Scheme with 10)terminal [31]. acetylenes; in the absence copper co- catalyst, the cyclized product was formed (Scheme 10) [31].

Scheme 10. Scheme 10. Furthermore, the phenyl iodides were coupled with terminal acetylenes via Palladium (0) and CatalystsCopperFurthermore,2020 (I) , catalyzed10, 443 the Sonogashira phenyl iodides cross were coupling coupled and wi 92%th terminal yield of acetylenes coupled product via Palladium was obtained (0)8 ofand 48 (SchemeCopper (I)11) catalyzed [31]. Sonogashira cross coupling and 92% yield of coupled product was obtained (Scheme 11) [31].

Scheme 11. Sonogashira Cross Coupling of alkyne-substitutedScheme 11. phenyl iodides with terminal alkynes via Palladium and Copper Catalyst. Scheme 11. 2.2. In 2003 2.2. In 2003 2.2. InIn 20032003, various scientists and researchers reported the Sonogashira reaction catalyzed via In 2003, various scientists and researchers reported the Sonogashira reaction catalyzed via palladiumIn 2003, and various copper scientists and different and researchers reaction reportedconditions. the As Sonogashira previously reaction discussed, catalyzed nitrogen via palladium and copper and diﬀerent reaction conditions. As previously discussed, nitrogen containing containingpalladium heterocyclesand copper showed and different many biological reaction activities conditions. such Asas anti-viralpreviously and discussed, anti-cancer nitrogen [32,33]. heterocycles showed many biological activities such as anti-viral and anti-cancer [32,33]. The alkynyl Thecontaining alkynyl heterocycles derivatives showed starting many from biological 5- iodinated activities pyrimidione such as anti-viral derivatives and wereanti-cancer obtained [32,33]. by derivatives starting from 5- iodinated pyrimidione derivatives were obtained by protecting the N-1 protectingThe alkynyl the derivatives N-1 or 2,4-position starting s fromof uracils. 5- iodinated Petricci andpyrimidione co-workers derivatives reported werethat the obtained 5-alkynyl by or 2,4-positions of uracils. Petricci and co-workers reported that the 5-alkynyl derivatives were derivativesprotecting thewere N-1 synthesized or 2,4-position froms ofpyrimidino uracils. Petriccines and and uridine co-workers via Sonogashira reported that cross the 5-alkynylcoupling synthesized from pyrimidinones and uridine via Sonogashira cross coupling reaction catalyzed by reactionderivatives catalyzed were synthesizedby palladium from and pyrimidinocopper. Thenes pyrimidinones and uridine andvia uridineSonogashira were coupledcross coupling in the palladium and copper. The pyrimidinones and uridine were coupled in the presence of DMF solution, presencereaction catalyzedof DMF solution, by palladium Et3N, PdCl and 2copper.(PPh3)2 andThe CuIpyrimidinones with propargyl and alcoholuridine at were room coupled temperature in the Et3N, PdCl2(PPh3)2 and CuI with propargyl alcohol at room temperature gave moderate yield and gavepresence moderate of DMF yield solution, and were Et3 N,not PdCl isolated.2(PPh It3) 2underwent and CuI with cyclization propargyl (Scheme alcohol 12) at [34]. room temperature were not isolated. It underwent cyclization (Scheme 12)[34]. gave moderate yield and were not isolated. It underwent cyclization (Scheme 12) [34].

Scheme 12. Scheme 12. Palladium and Copper catalyzedScheme coupling 12. of pyrimidinones and uridine with ethynol. Furthermore, Petricci and co-workers reported that the terminal alkynes irradiated with microwaveFurthermore,Furthermore, for 5 min Petricci Petricci at 45 and and°C co-workers were co-workers coupled reported reportedwith that pyrimidinones the that terminal the terminal alkynes via Sonogashirairradiated alkynes withirradiatedcross microwave coupling with forreactionmicrowave 5 min catalyzed at 45for◦ C5 were minby palladium coupledat 45 °C with wereand pyrimidinonescopper coupled gave with good via pyrimidinones Sonogashirayield as in Scheme crossvia Sonogashira coupling 13 [34]. reaction cross catalyzedcoupling byCatalystsreaction palladium 2020 catalyzed, 10,and x FOR copper by PEER palladium REVIEW gave good and yield copper as ingave Scheme good 13yield[34]. as in Scheme 13 [34]. 9 of 48

Scheme 13. MicrowaveScheme enhanced 13. Sonogashira coupling.

It cancan bebe additionally additionally noted noted that that the the nitrogen nitrogen containing containing heterocycles, heterocycles, especially especially pyridazinones, pyridazinones, show variousshow various biological biological activities activities and used and as used drugs as indrugs cardiovascular in cardiovascular system system and as and agrochemicals as agrochemicals [35,36]. [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 AlCl3 as in Scheme 14. The unprotected product 64 was synthesized [37].

O O O H N O N R O N Pd(PPh ) Cl /CuI N CH Cl /DMAP N 3 2 2 N Br + O 2 2 Br Cl o Et3N/DMF/60 C R

61 60 62 63 (60-90%)

Deprotecting agent

R=CH2OH,CH2CH2OH,Ph,TMS,H,CHOHCH3,CH 2OCOCH3 Deprotecting agent=AlCl ,HCl 3 O H N N

64 Scheme 14.

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].

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Scheme 13.

CatalystsIt can2020 ,be10 ,additionally 443 noted that the nitrogen containing heterocycles, especially pyridazinones,9 of 48 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 So,of great synthesis concern of thesefor vari nitrogen-containingous researchers. Thus, molecules Coelho with and shortco-workers and comprehensive synthesized the route 5-alkynyl is of greatpyridazinones concern forderiva varioustives. The researchers. NH group Thus, of pyridazinone Coelho and 60 co-workerswas protected synthesized with the methoxymethyl the 5-alkynyl pyridazinonesgroup to synthesized derivatives. protected The NH pyridazinone group of pyridazinone 62. The protected60 was pyridazinone protected with 62 the was methoxymethyl coupled with groupterminal to synthesizedalkyne by using protected bis (tri-phenyl-phosphin pyridazinone 62. Thee)-palladium protected pyridazinone chloride, copper62 was iodide coupled as a with co- terminalcatalyst, alkynetriethylamine by using as bis a base (tri-phenyl-phosphine)-palladium and DMF as a solvent. The 2-methoxymethyl-3-pyridazinone chloride, copper iodide as a co-catalyst, was triethylamine as a base and DMF as a solvent. The 2-methoxymethyl-3-pyridazinone was de-protected de-protected either with hydrochloric acid or AlCl3 as in Scheme 14. The unprotected product 64 was eithersynthesized with hydrochloric [37]. acid or AlCl3 as in Scheme 14. The unprotected product 64 was synthesized [37].

O O O H N O N R O N Pd(PPh ) Cl /CuI N CH Cl /DMAP N 3 2 2 N Br + O 2 2 Br Cl o Et3N/DMF/60 C R

61 60 62 63 (60-90%)

Deprotecting agent

R=CH2OH,CH2CH2OH,Ph,TMS,H,CHOHCH3,CH 2OCOCH3 Deprotecting agent=AlCl ,HCl 3 O H N N

64 Scheme 14. Sonogashira cross coupling of 5-bromo-2-Scheme 14. (methoxymethyl)- 6-phenyl pyridazin-3(2H) –one with chloro(methoxy)methane. In contrast, terminal acetylenes and 5-bromo-6-phenyl-3(2H)-pyridazinone without protection of NHIn contrast,group were terminal coupled acetylenes and andgave 5-bromo-6-phenyl-3(2 only around 5–10%H )-pyridazinoneof the 5-alkynyl without pyridazinones protection 67 of NHderivatives group were and more coupled than and 85% gave of reactant only around was recovered 5–10% of the(Scheme 5-alkynyl 15). The pyridazinones low reactivity 67 derivativeswas due to andthe acidity more than of the 85% NH of group reactant [37]. was recovered (Scheme 15). The low reactivity was due to the acidity of Catalyststhe NH 2020 group, 10, x [37 FOR]. PEER REVIEW 10 of 48

O O H H N N N N Pd(PPh3)2Cl2 /CuI Br + R o Et3N/DMF/60 C R

66 67 (5-10%) 65 Scheme 15. Sonogashira cross coupling of 5-bromo-6-phenylpyridazin-3(2H)-oneScheme 15. with terminal alkynes.

It waswas notednoted that thatπ -conjugatedπ-conjugated compounds compounds have have versatile versatile applications applications as in lightas in emitting light emitting diodes, diodes,carbohydrates carbohydrates sensing sensing and in and molecular in molecular electronics electronics [38]. The [38]. aryl The donors aryl donors were were coupled coupled with with aryl aryland heteroaryland heteroaryl acceptors acceptors via Sonogashiravia Sonogashira cross cross coupling coupling [39]. [39]. Elangovan Elangovan and and co-workers co-workers used used an anatmosphere atmosphere of Hydrogenof Hydrogen gas gas diluted diluted with with nitrogen nitrogen or argonor argon with with palladium palladium and and copper copper catalyst catalyst to tosynthesized synthesized terminal terminal aryl aryl ethynes ethynes and and aryl-pyridyl-ethynes aryl-pyridyl-ethynes with with donor donor substituentssubstituents inin veryvery good yields via a Sonogashira coupling reaction inin SchemeScheme 1616[ 40[40].].

Scheme 16.

Similarly, di-aryl-ethynes were synthesized via previously mentioned reaction conditions (Scheme 17) [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].

Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 10 of 48

O O H H N N Pd(PPh ) Cl /CuI N N Pd(PPh3)2Cl2 /CuI Br + R Et N/DMF/60 oC R Et3N/DMF/60 C R

67 (5-10%) 65 66 67 (5-10%) 65 Scheme 15.

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 Catalyststo synthesized2020, 10, 443 terminal aryl ethynes and aryl-pyridyl-ethynes with donor substituents in very10 good of 48 yields via a Sonogashira coupling reaction in Scheme 16 [40].

Scheme 16. Synthesis of internalScheme Ethynes 16. via Sonogashira cross coupling. Similarly, di-aryl-ethynes were synthesized via previously mentioned reaction conditions Similarly, di-aryl-ethynes were synthesizedsynthesized viavia previouslypreviously mementioned reaction conditions (Scheme 17)[40]. (Scheme 17) [40].

Scheme 17. Scheme 17. Synthesis of DiarylethynesScheme 17. via Sonogashira cross coupling.

InIn addition, addition, organotellurium organotellurium compounds compounds are a veryare a important very important class [41 ].class The 2-alkynyl[41]. The substituted 2-alkynyl hetero-aromaticsubstituted hetero-aromatic76 and similar 76 compounds andand similarsimilar were compoundscompounds synthesized werewere by synthesizedsynthesized coupling of vinylic byby couplingcoupling and hetero-aromatic ofof vinylicvinylic andand telluriumhetero-aromatic di-chlorides tellurium via palladium di-chlorides and via copper palladium catalyzed and Sonogashira copper catalyzed cross coupling Sonogashira (Scheme cross 18). Thecoupling various (Scheme palladium 18). The catalysts various with palladium CuI were catalysts used in with this CuI reaction. were used It was in noted this reaction. that the It same was noted that the same compounds show 82% yield when the reaction is applied with PdCl2 [42]. compoundsCatalystsnoted that2020 , the10 show, xsame FOR 82% PEER compounds yield REVIEW when show the reaction 82% yield is appliedwhen the with reaction PdCl2 is[ 42applied]. with PdCl2 [42].11 of 48

Scheme 18. Palladium and Copper catalyzedScheme Coupling 18. of substituted tellurium di-chlorides with prop-2-yn-1-ol. Moreover, the macrocyclic molecules are an important class of super molecular chemistry. So, SonogashiraMoreover, cross the coupling macrocyclic is an moleculesefficient method are anology important for synthesis class ofof supermacrocyclic molecular molecules. chemistry. The So,1,1′-Bi-2-naphthol Sonogashira cross (BINOL) coupling and their is an derivatives eﬃcient methodology were used in for asymmetric synthesis ofsynthesis macrocyclic [43]. molecules.Therefore, TheHarada 1,10-Bi-2-naphthol and co-workers (BINOL) reported and the their synthesis derivatives of were24- and used 26-membered in asymmetric macro-cyclic synthesis [43 ].bi-naphthol 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 dimersshown in80 Schemeand 81 were19 [44]. synthesized via Pd (PPh3)4 and CuI catalyzed Sonogashira Cross Coupling shownAs in discussed Scheme 19earlier,[44]. 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 system. Han and coworkers developed the Sonogashira cross coupling of fluorescein and rhodamine derivatives with 86 and 87 catalyzed by Pd (PAr3)4 and CuI (Scheme 21). Fluorescein and rhodamine derivatives were stable at high temperatures. The Sonogashira cross coupling worked well under microwave irradiation [46]. In addition, the 18F-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 18F chemistry. The coupled product was synthesized from Pd (PPh3)4 and CuI catalyzed Sonogashira cross coupling of 4-[18F] floro-iodo-benzene with terminal alkyne Scheme 22 [48].

2.3. 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].

Catalysts 2020, 10, 443 11 of 48 Catalysts 2020, 10, x FOR PEER REVIEW 12 of 48

Scheme 19. Synthesis of 24- and 26-membered macro-cyclicScheme 19. bi-naphthol dimmers via Palladium and Copper Catalyzed Coupling.

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 system. Han and coworkers developed the Sonogashira cross coupling of fluorescein and rhodamine derivatives with 86 and 87 catalyzed by Pd (PAr3)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, 443 12 of 48 Catalysts 2020, 10, x FOR PEER REVIEW 13 of 51

Catalysts 2020, 10, x FOR PEER REVIEW 13 of 48

(82)/clay, CuI (5 mol%) R' X + Ph H R Ph base(1.5eq),solvent(5 ml) 83 84 85 (64-99%)

X Base=Pyrr,Pip,Cs2CO3 Solv=Pyrr,Pip,DMA =I,Br, R'=H,NO ,CHO,MeCO, Clay=MK10,BA,BB 2 Scheme 20. Scheme 20. Synthesis of 4-(phenylethynyl)benzene derivativesderivatives via Pd and Cu catalyzed Coupling.Coupling.

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 (PAr3)4 and CuI (Scheme 21). Fluorescein and rhodamine derivatives were stable at high temperatures. The Sonogashira cross coupling worked well under microwave irradiation [46].

Br AcO O OAc

O +

O N O N Cl 86 87 ii)K CO i) 5mol% Pd(PAr ) 2 3 3 4 1:1 MeOH/CH Cl 5mol% CuI,NEt 2 2 3, 25oC,12h iii)HCl DMF,microwave (aq) 120oC,25oC iv)NABARF,MeOH v)chloranil O N

Scheme 21. Sonogashira CrossO Coupling of bromorosamineScheme 21. with substitutedO isobenzofuran acetate.

In addition, the 18F-labelled aryl halides were used as the coupling partners in the palladium and O copper catalyzed Sonogashira cross-coupling.HO The 4-fluorophenyl group wasBHARF also present in drugs [47]. Wust and Kniess reported, forHO the first time, Sonogashira cross-coupling inN18F chemistry. The coupled 88 (45%) product was synthesized from Pd (PPh3)4 and CuI catalyzed Sonogashira cross coupling of 4-[18F] floro-iodo-benzene with terminal alkyne Scheme 22[48]. Scheme 21. Sonogashira Cross Coupling of bromorosamine with substituted isobenzofuran acetate.

Scheme 22.

Catalysts 2020, 10, x FOR PEER REVIEW 13 of 48

Scheme 20.

Catalysts 2020, 10, 443 13 of 48 Scheme 21.

Scheme 22. Palladium Cross Coupling of 18SchemeF-labelled 22. aryl halides with 1-ethynylcyclopentanol.

2.3. 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]. Catalysts 2020, 10, x FOR PEER REVIEW 14 of 48

. Scheme 23. Synthesis of Niphatesine and Norniphatesine via Sonogashira Coupling. Scheme 23. In addition, the nitrogen-containing heterocycles such as pyrimidines show many biological activesIn suchaddition, as adenosine the nitrogen-containing kinase inhibitors heterocycles [52], anti-tumor such andas pyrimidines antibiotics [ 53show]. The many tri-substituted biological pyrimidineactives such derivatives as adenosine were kinase synthesized inhibitors via [52], di-chloro-bis anti-tumor (tri-phenyl-phosphine) and antibiotics [53]. The palladium tri-substituted (II) and copperpyrimidine iodide derivatives catalyzed were Sonogashira synthesized cross via coupling, di-chloro-bis as shown (tri-pheny in Schemel-phosphine) 24[54]. palladium (II) and copper iodide catalyzed Sonogashira cross coupling, as shown in Scheme 24 [54]. 2.4. 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-phenyl-phosphine)

Scheme 24.

2.4. 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-phenyl- phosphine) 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].

Catalysts 2020, 10, x FOR PEER REVIEW 14 of 48

Catalysts 2020, 10, 443 Scheme 23. 14 of 48

In addition, the nitrogen-containing heterocycles such as pyrimidines show many biological palladiumactives such (II) as and adenosine copper iodidekinase catalyzedinhibitors Sonogashira [52], anti-tumor cross and coupling. antibiotics The iodo-[53]. βTheCCt tri-substituted intermediate waspyrimidine formed. derivatives The protection were and synthe deactivationsized via di-chloro-bis of N–H group (tri-pheny of indolel-phosphine) was necessary palladium for the synthesis (II) and ofcopper bivalent iodide ligands catalyzed of β-carboline-3-carboxylates Sonogashira cross coupling, (Scheme as shown 25)[56 in]. Scheme 24 [54].

CatalystsScheme 2020, 10 24., x FOR Synthesis PEER REVIEW of tri-substituted pyrimidineScheme 24. derivatives via Sonogashira cross coupling.15 of 48

Scheme 25. Scheme 25. Synthesis of bivalent analogues of β-carboline-3-carboxylates.

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-cyclo- propenyl-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 phenyl with electron withdrawing groups was higher [58].

Catalysts 2020, 10, 443 15 of 48

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-cyclo- propenyl-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 Catalystsphenyl 2020 with, 10 electron, x FOR PEER withdrawing REVIEW groups was higher [58]. 16 of 48 Catalysts 2020, 10, x FOR PEER REVIEW 16 of 48

Scheme 26. Palladium and Copper catalyzedScheme coupling 26. of iodo-di-ﬂuoro-cyclo-propenyl-alkene with terminal alkynes. Scheme 26. It was noted that thermally stable palladium catalysts were also used for Sonogashira reaction [59]. ItItIn waswas the noted notedliterature that that thermally survey,thermally (PPh) stable stable3 palladiumligand palladium was catalysts usedcatalysts for were werecoupling also also used ofused foraryl Sonogashirafor halides Sonogashira with reaction propiol-reaction [59]. aldehydeIn[59]. the In literature the diethyl literature survey, acetal survey,[60]. (PPh) Lemhadri3 (PPh)ligand3 and wasligand coworkers used was for used coupling used for the coupling oftetrapodal aryl halides of phosphinearyl with halides propiol-aldehyde ligand, with Tedicyppropiol- 113diethylaldehyde as a acetal palladium diethyl [60 ].acetal Lemhadri source [60]. withLemhadri and copper coworkers and for coworkers usedSonogashira the used tetrapodal thecross tetrapodal coupling phosphine phosphine of ligand,para-substituted ligand, Tedicyp Tedicyp113 arylas bromidesa113 palladium as a withpalladium source propiol-aldehydewith source copper with diethyl for copper Sonogashira acetal for Sonogashira(Scheme cross 27). coupling Thecross 0.01% ofcoupling para-substituted of catalyst of para-substituted with arylaryl bromides aryl waswithbromides used. propiol-aldehyde withAll functional propiol-aldehyde diethyl groups acetal an diethyld (Schemehetero-atomic acetal 27 (Scheme). The substrates 0.01% 27). The of were catalyst 0.01% used of with catalystin the aryl presence bromideswith aryl of wasbromides Tedicyp used. palladiumAllwas functional used. systemAll groupsfunctional [61]. and groups hetero-atomic and hetero-atomic substrates weresubstrates used inwere the us presenceed in the of presence Tedicyp palladiumof Tedicyp systempalladium [61]. system [61].

Scheme 27. Scheme 27. Synthesis of internalScheme Ethynes 27. via Sonogashira Cross Coupling. The same research group also reported that the product 119 was selectively obtained in 92% yieldThe Thein the samesame presence researchresearch of group0.1% group cata also alsolyst reported reported with 1,4-dibromobenzene that that the the product product119 119wassubstrate. was selectively selectively The obtainedmixtures obtained inof 92%products in yield 92% 119inyield the and in presence the120 presencewere of 0.1% obtained of catalyst 0.1% with cata with lyst1,2-di-bromo-benzene 1,4-dibromobenzene with 1,4-dibromobenzene when substrate. ratios substrate. The substrate/catalyst mixtures The mixtures of products of of 1000 products119 and 12010,000119 wereand were 120 obtained used,were withasobtained in 1,2-di-bromo-benzeneScheme with 28. 1,2-di-bromo-benzene The slower when reaction ratios whenrate substrate observed ratios/catalyst substrate/catalyst with of 1,2-di-bromo-benzene 1000 and 10,000of 1000 were and probablyused,10,000 as were in is Schemedue used, to steric 28as .in The reasonsScheme slower [61]. 28. reaction The slower rate observed reaction with rate 1,2-di-bromo-benzeneobserved with 1,2-di-bromo-benzene probably is due toprobably steric reasons is due [to61 steric]. reasons [61].

Scheme 28. Scheme 28.

Catalysts 2020, 10, x FOR PEER REVIEW 16 of 48

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 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].

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 Catalysts10,000 2020were, 10 used,, 443 as in Scheme 28. The slower reaction rate observed with 1,2-di-bromo-benzene16 of 48 probably is due to steric reasons [61].

Catalysts 2020, 10, x FOR PEER REVIEW 17 of 48 Catalysts 2020Scheme, 10, x 28.FORSonogashira PEER REVIEW cross coupling of 1,4-dibromobenzene with 3,3-diethoxyprop-1-yne. 17 of 48 Scheme 28. 2.5. In 2006 2.5. In 2006 2.5. In 2006 As previously described, palladium-N-heterocyclic carbene complexes were used for the As previously described, palladium-N-heterocyclic carbene complexes were used for the Sonogashira As previously cross coupling. described, Altenhoff palladium- and co-workersN-heterocyclic reported carbene the first complexes Sonogashira were cross used coupling for the Sonogashira cross coupling. Altenhoﬀ and co-workers reported the ﬁrst Sonogashira cross coupling of ofSonogashira alkynes with cross secondary coupling. alkyl Altenhoff bromides and co-workers in the presence reported of thepalladium- first SonogashiraN-heterocyclic cross couplingcarbene alkynes with secondary alkyl bromides in the presence of palladium-N-heterocyclic carbene complexes complexesof alkynes and with copper secondary iodide alkylwas used bromides as co-catalyst in the presencein Scheme of 29 palladium- [62]. N-heterocyclic carbene andcomplexes copper and iodide copper was usediodide as was co-catalyst used as inco-catalyst Scheme 29 in[62 Scheme]. 29 [62].

Scheme 29. Scheme 29. Sonogashira cross couplingScheme of Secondary 29. alkyl bromides with oct-1-yn-3-one. In addition, the 1,2-di-amino-cyclohexane was used with palladium-N-heterocyclic carbene complexInIn addition, addition,as in Scheme thethe 1,2-di-amino-cyclohexane301,2-di-amino-cyclohexane by the same research group. waswas usedItused improved withwith palladium-palladium- the yield ofNN-heterocyclic -heterocyclicthe coupled product carbenecarbene [62].complexcomplex as as in in Scheme Scheme 30 30 by by the the same same research research group. group. It improved It improved the the yield yield of the of coupledthe coupled product product [62]. [62].

Scheme 30. Palladium-N-heterocyclic carbeneScheme complex 30. and Copper Iodide Catalyzed Sonogashira Cross Coupling of disubstituted alkyl bromidesScheme with oct-1-yn-3-one..30. Moreover, the polymer supported palladium catalysts were also used for the Sonogashira cross coupling.Moreover,Moreover, In the thepast,the polymerpolymer the poly-styrene supportedsupported and palladiumpalladium silica supported catalystscatalysts phosphine werewere alsoalso palladium usedused forfor thethe catalysts SonogashiraSonogashira were used crosscross withcoupling.coupling. copper InIn theiodidethe past,past, for thethe coupling poly-styrene [63]. andandThe silicasilica[MCM-41-SH-Pd(0)] supportedsupported phosphinephosphine complex palladiumpalladium was used catalystscatalysts as a palladium werewere usedused sourcewithwith coppercopper with copper iodideiodide iodide forfor couplingcoupling in the Sonogashira [63[63].]. TheThe [MCM-41-SH-Pd(0)][MCM-41-SH-Pd(0)] cross coupling of aryl complexcomplex iodides waswas with usedused terminal asas aa palladiumpalladium alkynes Schemesourcesource with with31 [64]. coppercopper iodideiodide inin thethe SonogashiraSonogashira crosscross couplingcoupling ofof arylaryl iodidesiodides withwith terminalterminal alkynesalkynes SchemeScheme 31 31[ 64[64].].

Scheme 31. Scheme 31.

Catalysts 2020, 10, x FOR PEER REVIEW 17 of 48

2.5. 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

Catalystssource 2020with, 10 copper, 443 iodide in the Sonogashira cross coupling of aryl iodides with terminal alkynes17 of 48 Scheme 31 [64].

Catalysts 2020, 10Scheme, x FOR PEER 31. [MCM-41-SH-Pd(0)] REVIEW complexScheme and 31. CuI catalyzed Sonogashira coupling. 19 of 51

Moreover,Moreover, thethe bioorganometallicbioorganometallic chemistrychemistry has attractedattracted the attention of various chemists [65]. [65]. The The SonogashiraSonogashira crosscross couplingcoupling waswas aa goodgood methodologymethodology forfor thethe introductionintroduction ofof organometallicorganometallic compoundscompounds as labels. labels. The The bio-conj bio-conjugatesugates also also used used this this methodology. methodology. Hoffmann Hoﬀmann and and coworkers coworkers use usethe thePd Pdand and Cu Cu catalyzed catalyzed Sonogashira Sonogashira cross cross coupling coupling for for the the two-Step two-Step labeling labeling of phenyl-alaninephenyl-alanine peptidepeptide sideside chainschains withwith organo-metallicorgano-metallic compoundscompounds (Scheme(Scheme 3232).). TheThe ferroceneferrocene labeledlabeled derivativesderivatives werewere producedproduced inin goodgood yieldyield andand puritypurity byby reactionreaction ofof didifferentﬀerent ferrocene ferrocene alkyne alkyne [ 66[66].].

R O H Boc N N OMe H O

O H Pd(PPh3)2Cl2 N R CuI 1 R1 N H I THF/NEt3 O 131 6 h/r.t/Ar 133 O H R1 N OMe + Boc N H R O Pd(PPh3)2Cl2 CuI O R1 H 130 THF/NEt3 N OMe 132 Boc N 6 h/r.t/Ar H R O

134

R=CH3,CH(CH3)2,CH2-C6H5,CH2-C6H5 R1= Fe

SchemeScheme 32.32. Synthesis of ferrocene labeledlabeled derivativesderivatives viavia SonogashiraSonogashira CrossCross Coupling.Coupling.

2.6. In 2007 2.6. In 2007 It was observed that alkenyl nonaflates were easily available and stable but show reactivity as 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 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 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 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]. bicyclic nonaflate with phenyl acetylene in presence of Pd (OAc)2, PPh3 and CuI (Scheme 33) [68].

Scheme 33. Sonogashira cross coupling of bicyclic nonaflate with phenyl alkyne.

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-2H- chromene-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].

Catalysts 2020, 10, x FOR PEER REVIEW 18 of 48

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].

Scheme 32.

2.6. 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 Catalystsand as building2020, 10, 443 blocks [67]. Hogermeier and Co-workers reported the Sonogashira cross coupling18 of of 48 bicyclic nonaflate with phenyl acetylene in presence of Pd (OAc)2, PPh3 and CuI (Scheme 33) [68].

ONf

Nonaflation Pd(OAc)2,PPh3,CuI X X + Ph X Ph (i-Pr)2NH,DMF,rt ,17h

135 136 138 (78-86%) 137 X=O,S Scheme 33. Sonogashira cross couplingScheme of bicyclic33. nonaﬂate with phenyl alkyne.

In addition, addition, the the vinyl vinyl chloride chloride was least was reactive least while reactive used while in the synthesis used in of the natural synthesis products of naturaland biologically products active and compounds biologically [69]. active Bera compounds and coworkers [69]. used Bera the andPd/C–CuI–PPh coworkers3 usedcatalyzed the PdSonogashira/C–CuI–PPh cross3 catalyzed coupling for Sonogashira alkynylation cross of β-chloroacroleins coupling for alkynylation(–CCl=CCHO–). of Theβ-chloroacroleins 4-alkynyl-2H- (–CClchromene-3-carbaldehydes=CCHO–). The 4-alkynyl-2H-chromene-3-carbaldehydes and 5-alkynyl-2,3-dihydro benzo[b] and oxepine-4-carbaldehydes 5-alkynyl-2,3-dihydro benzo[b] were oxepine-4-carbaldehydessynthesized via Cu and Pd/C-mediated were synthesized Sonogashira via Cu and cross Pd coupling/C-mediated Scheme Sonogashira 34. The Pd/C–CuI–PPh cross coupling3 Schemecatalytic 34 system. The Pdwas/C–CuI–PPh efficient for3 catalyticthis coupling system [70]. was eﬃcient for this coupling [70]. Catalysts 2020, 10, x FOR PEER REVIEW 19 of 48

Scheme 34. Sonogashira cross coupling of β-chloroacroleinsScheme 34. under Pd/C–CuI–PPh3 catalytic system. 2.7. In 2008 2.7. In 2008 Moreover, Buta-1,3-diynes were present in natural products and bioactive molecules, and found Moreover, Buta-1,3-diynes were present in natural products and bioactive molecules, and found to be intermediate in synthesis [71]. The (E)-1,2-di-iodoalkenes were used as building blocks for to be intermediate in synthesis [71]. The (E)-1,2-di-iodoalkenes were used as building blocks for the the synthesis of unsymmetrical buta-1,3-diynes and 2-ethynyl-benzo-furans. The unsymmetrical synthesis of unsymmetrical buta-1,3-diynes and 2-ethynyl-benzo-furans. The unsymmetrical buta- buta-1,3-diynes were synthesized via palladium and copper catalyzed Sonogashira cross coupling in 1,3-diynes were synthesized via palladium and copper catalyzed Sonogashira cross coupling in good good yields (Scheme 35)[72]. yields (Scheme 35) [72].

Scheme 35. Synthesis of unsymmetrical buta-1,3-diynesScheme 35. via Palladium and Copper Catalyzed Coupling.

Furthermore,Furthermore, 2-ethynylbenzo-furans were were synt synthesizedhesized by by Sonogashira Sonogashira cross cross coupling coupling of of2- 2-ethynyl-phenolethynyl-phenol with with (E)-1,2-di-iodo-alkenes (E)-1,2-di-iodo-alkenes catalyzed catalyzed via via Pd Pd (II) (II) acetate, acetate, and and CuI CuI Scheme Scheme 36 36 [72].[72].

Scheme 36.

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].

Catalysts 2020, 10, x FOR PEER REVIEW 20 of 51

Scheme 34. Sonogashira cross coupling of β-chloroacroleins under Pd/C–CuI–PPh3 catalytic system.

2.7. In 2008 Moreover, Buta-1,3-diynes were present in natural products and bioactive molecules, and found to be intermediate in synthesis [71]. The (E)-1,2-di-iodoalkenes were used as building blocks for the synthesis of unsymmetrical buta-1,3-diynes and 2-ethynyl-benzo-furans. The unsymmetrical buta- 1,3-diynes were synthesized via palladium and copper catalyzed Sonogashira cross coupling in good yields (Scheme 35) [72].

Scheme 35. Synthesis of unsymmetrical buta-1,3-diynes via Palladium and Copper Catalyzed Coupling .

CatalystsFurthermore,2020, 10, 443 2-ethynylbenzo-furans were synthesized by Sonogashira cross coupling19 of of 482- ethynyl-phenol with (E)-1,2-di-iodo-alkenes catalyzed via Pd (II) acetate, and CuI Scheme 36 [72].

OH I 2 Pd(OAc)2,CuI O 1 R R + R1 R2 I Et3N-THF,r.t 147 145 146 (32-91%) 1 n t R =H,CO 2Me,OH,NH2,NHAc, C8H17, Bu 2 n R =CO2Et,CH2OH,Ph, C8H17,C6H11OH

SchemeScheme 36.36. CouplingCoupling ofof (E)-1,2-di-iodo-alkenes(E)-1,2-di-iodo-alkenes withwith 2-ethynyl-phenol.2-ethynyl-phenol.

It was noted that N-Carbamoyl heterocyclic carbene complex of palladium was developed as 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 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 sensitive substrates were used and catalyzed by palladium complex 148 and copper. The was coupled with terminal acetylenes in absence of base and catalyzed via N-Carbamoyl heterocyclic iodobenzene was coupled with terminal acetylenes in absence of base and catalyzed via N- carbene complex of palladium and copper iodide Scheme 37. A good yield of the coupled product was Carbamoyl heterocyclic carbene complex of palladium and copper iodide Scheme 37. A good yield obtained [73]. Catalystsof the coupled2020, 10, x productFOR PEER was REVIEW obtained [73]. 20 of 48

N NN

O Pd N N

148

Scheme 37. Base free Sonogashira crossScheme coupling 37. of phenyl iodide and phenyl alkyne. 2.8. In 2009 2.8. In 2009 Usually, the Sonogashira reaction is performed by using Pd–phosphine complex and CuI in Usually, the Sonogashira reaction is performed by using Pd–phosphine complex and CuI in the the presence of secondary or tertiary amine or various simple bases. Many of these complexes are 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, 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 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 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 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 pyridyl-azetidine based Pd (II) complexes (154, 155, 156) for the Sonogashira reaction [74]. Various bromides and aryl chlorides efficiently coupled with 153 under different catalyst loadings. The addition aryl bromides and aryl chlorides efficiently coupled with 153 under different catalyst loadings. The of Copper Iodide increased the rate of reaction (Scheme 38). 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]

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

Catalysts 2020, 10, x FOR PEER REVIEW 20 of 48

N NN

O Pd N N

148

Scheme 37.

2.8. 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

Catalystsof these2020 catalysts., 10, 443 Thus, the search for coupling catalysts that show excellent activity and 20broad of 48 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 asaryl shown bromides in (Scheme and aryl 39 ).chlorides Diﬀerent efficiently alkyl and coupled aryl terminal with 153 alkynes, under as different well as propargyl catalyst loadings. alcohols andThe protectedaddition of propargyl Copper Iodide alcohols increased were used. the rate of reaction (Scheme 38).

Catalysts 2020, 10, x FOR PEER REVIEW 21 of 48 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, asScheme well as 38.propargylSonogashira alcohols cross and coupling protectedScheme of bromobenzene 38.propargyl withalcohols terminal were phenyl used. alkyne.

Scheme 39. Sonogashira Cross CouplingScheme of 3-Iodobenzo[ 39. b]furans with phenyl alkyne.

Similarly, in in organic organic synthesis, synthesis, alkynes alkynes are areof gr ofeat great interest interest because because of their of use their in the use synthesis in the synthesisof heterocyclic of heterocyclic compounds compounds via intra-molecular via intra-molecular hetero-annulation hetero-annulation of amines, ofalcohols, amines, carboxylic alcohols, carboxylicacids and amides acids andto a C–C amides triple to bond. a C–C Thus, triple Salas bond. and Coworkers Thus, Salas reported and Coworkersa nitro-group reported mediated a nitro-groupregio-controlled mediated hetero-annulation regio-controlled hetero-annulationof 2-[2-(phenylethynyl)phenyl] of 2-[2-(phenylethynyl)phenyl] acetic acids aceticto (Z)-1-(2- acids to (Z)-1-(2-nitrobenzylidene)iso-chroman-3-onesnitrobenzylidene)iso-chroman-3-ones (Scheme (Scheme 40) [81] 40. Cross)[81]. coupling Cross coupling of ester of of ester o-iodophenyl of o-iodophenyl acetic aceticacid with acid Trimethylsilyl-acetylene with Trimethylsilyl-acetylene and then and Trimethylsilyl then Trimethylsilyl group groupwas deprotected was deprotected by using by TBAF, using TBAF,which whichprovided provided the derivati the derivativeve of phenyl-acetylene of phenyl-acetylene 163,163 which, which was was then then subjected subjected to to a a secondsecond Sonogashira crosscross couplingcoupling withwith o-bromoo-bromo nitrobenzene.nitrobenzene. ThisThis resultedresulted inin thethe formationformation ofof 164164.. Phenyl acetate derivatives formed by basic hydrolysis of 164 underwent cyclo-isomerization, resulting in the formation of expected lactone, which on reactionreaction withwith NaOMeNaOMe inin CH3OH,CH3OH, furnishedfurnished thethe requiredrequired nitrophenyl-naphthoquinone, whichwhich waswas thenthen easilyeasily convertedconverted intointo 165165..

Scheme 40.

Catalysts 2020, 10, x FOR PEER REVIEW 21 of 48 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.

Scheme 39.

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 Catalystsformation2020 ,of10 ,expected 443 lactone, which on reaction with NaOMe in CH3OH, furnished the required21 of 48 nitrophenyl-naphthoquinone, which was then easily converted into 165.

Scheme 40. Synthesis of 5H-benzo[bScheme]carbazole-6,11-dione 40. via Palladium and Copper CatalystsCatalyzed 2020, 10, x Coupling. FOR PEER REVIEW 22 of 48 2.9. In 2010 2.9. In 2010 Among heterocycles, pyrans are the most common common st structuralructural moieties present in various various natural natural products. In In particular, particular, 2 H-benzopyrans-benzopyrans are are present present in in a various compounds that exhibit important biological and and pharmaceutical pharmaceutical activities activities such such as coutareagenin as coutareagenin and anddauri-chromenic dauri-chromenic acid show acid showanti- diabeticanti-diabetic properties properties [82] [and82] andanti-HIV anti-HIV activity activity [83] [respectively.83] respectively. The The applicability applicability of the of theselectivity selectivity of alkyneof alkyne at at3-position 3-position and and chalcogen chalcogen at at4-position 4-position of of benzopyran benzopyran can can constitu constitutete a a synthetic synthetic approach approach toto the the synthesis synthesis of of biological biological active active compounds. compounds. Thus, Thus, Speranca Speranca and and coworkers coworkers reported reported the the synthesis synthesis of 3-alkynyl-4-chalcogen-2 HH-benzopyrans-benzopyrans (as (as shown shown in in Scheme Scheme 41)41) via via Sonogashira Sonogashira reaction reaction of of 166 with various terminal-alkynes in in the the presence presence of of Pd Pdand and Cu catalystcatalyst [[84].84]. The obtained product was effectiveeffective for Successive hydro-telluration at the trip triplele bond. They They compare compare the the influence influence of of different different catalysts such such as as Pd(PhCN) Pd(PhCN)2Cl2Cl2, 2PdCl, PdCl2, Pd(OAc)2, Pd(OAc)2, Pd(PPh2, Pd(PPh3)2Cl3)22 andCl2 andPd(PPh Pd(PPh3)4. Pd(PPh3)4. Pd(PPh3)2Cl2 was3)2Cl found2 was tofound be the to most be the efficient most effi catalyst.cient catalyst. It was Italso was noted also notedthat in that the inabsence the absence of CuI, of no CuI, coupling no coupling product product was formed.was formed. In addition In addition to using to using Et3N Et3N as base as baseand solvent, and solvent, we tried we triedother other solvents solvents and bases. and bases.

Scheme 41. Scheme 41. Synthesis of 3-alkynyl-4-chalcogen-2H-benzopyrans via sonogashira reaction. 2.10. In In 2011 2011 As an an extension extension of of our our study study of of preparation preparation of of heterocycles, heterocycles, in in 2011, 2011, Gupta Gupta et et al. al. synthesized synthesized a highlya highly diverse diverse pyrimido[1,2-a]indoles pyrimido[1,2-a]indoles through through subsequent subsequent Sonogashira Sonogashira reaction reaction and [3+3] and cyclo- [3+3] condensationcyclo-condensation reaction reaction [85]. They [85]. synthesized They synthesized 1-(4-methy 1-(4-methylphenyl)-3-phenylprop-2-yn-1-onelphenyl)-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

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 48

2.9. 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.

Scheme 41.

2.10. In 2011

CatalystsAs2020 an, extension10, 443 of our study of preparation of heterocycles, in 2011, Gupta et al. synthesized22 of 48 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 bycoupling cross coupling of 169 and of 169 terminaland terminal acetylene acetylene in thein presence the presence of Pd/Cu of Pd /andCu andtriethyl triethyl amine, amine, as asshown shown in inScheme Scheme 42. 42 The. The resulting resulting product product was was then then treated treated with with 171171 atat 90 90 °C◦C in the presencepresence ofof SodiumSodium carbonatecarbonate andand acetonitrileacetonitrile toto furnishfurnish 172172 asas aa singlesingle regio-isomerregio-isomer throughthrough [3[3+3]+3] cyclo-condensation.cyclo-condensation. ThisThis approachapproach failedfailed toto yieldyield thethe requiredrequired product,product, whenwhen bothboth thesethese conditionsconditions werewere combinedcombined inin multicomponentmulticomponent tandemtandem formatformat inin one-pot.one-pot. Therefore,Therefore, theythey optimizedoptimized thethe conditionsconditions ofof reactionreaction byby usingusing variousvarious didifferentfferent bases,bases, solventssolvents andand PdPd catalysts.catalysts. However, afterafter investigatinginvestigating variousvarious solventssolvents andand bases,bases, thethe useuse ofof Pd(PPhPd(PPh33))22Cl2,, CuI CuI and and triethyl amine, followed byby additionaddition ofof 171171 andand 1.51.5 equivequiv ofof CsCs22CO33 under reflux reflux for 6 h were found to be eefficientfficient reactionreaction conditions.conditions.

Scheme 42. Synthesis of pyrimido-indoles viaScheme Sonogashira 42. Coupling and [3+3] Cyclocondensation.

InIn addition,addition, inin thethe lastlast fewfew years,years, inin thethe fieldfield ofof syntheticsynthetic chemistry,chemistry, H H22OO hashas gainedgained significantsignificant attentionattention duedue toto itsits uniqueunique characteristiccharacteristic properties,properties, especiallyespecially atat highhigh pressurepressure andand highhigh temperaturetemperature conditionsconditions [[86].86]. Various organicorganic reactionsreactions includingincluding C–CC–C coupling,coupling, de-hydrationsde-hydrations andand rearrangementrearrangement Catalysts 2020, 10, x FOR PEER REVIEW 23 of 48 reactionsreactions have been been carried carried out out in in H H2O2 O[[87,88].87,88 Thus,]. Thus, Javaid Javaid and andcoworkers coworkers studied studied Sonogashira Sonogashira cross cross coupling reaction in high-pressure and high-temperature (HPHT) water using tubular reactors coupling reaction in high-pressure and high-temperature (HPHT) water using tubular reactors coated withwith PalladiumPalladium and and Palladium-Copper Palladium-Copper alloy alloy [89 [89].]. The The reaction reaction was was dependent dependent on pressureon pressure and temperature.and temperature. Under Under optimized optimized conditions conditions of reaction, of reaction, 16 MPa of16 pressure MPa of and pressure 250 ◦C temperatureand 250 °C andtemperature alkaline aqueousand alkaline medium, aqueous cross medium, coupling cross of iodo-benzene coupling of iodo-benzene and 173 was investigatedand 173 was byinvestigated using this system,by using and this diphenyl system, and ethyne diphenyl was obtained ethyne was with obta 100%ined selectivity. with 100% The selectivity. freshly Palladium The freshly plated Palladium reactor gaveplated very reactor poor gave conversion. very poor Therefore, conversion. for Sonogashira Therefore, for coupling, Sonogashira the catalytic coupling, activity the ofcatalytic Palladium activity was increasedof Palladium by using was Pd-Cuincreased alloy, by which using enhanced Pd-Cu alloy, the effi whichciency enhanced of the reaction the efficiency because of of the the co-catalytic reaction ebecauseffect that of facilitated the co-catalytic the transfer effect of that electron facilitated between the two-metals.transfer of electron This catalytic between system two-metals. offers various This advantagescatalytic system such offers as shortest various reaction advantages time. reusablesuch as shortest and leaching reaction free time. process, reusable and high-selectivityand leaching free of theprocess, required and producthigh-selectivity (Scheme of 43 the). required product (Scheme 43).

Scheme 43. Pd-Cu Catalyzed SonogashiraScheme cross coupling 43. of phenyl iodide and phenyl acetylene.

In 2011, KawasokoKawasoko synthesized (E)-telluro(silyl)ketene acetals acetals and and used them as a substrate in Pd and Cu catalyzed catalyzed Sonogashira Sonogashira reactions(Scheme reactions (Scheme 44) 44 [90].)[90 (Z)-1,4-diorganyl-2-(triorganyl)–silyl-1-]. (Z)-1,4-diorganyl-2-(triorganyl)-silyl -1-buten-3-ynesbuten-3-ynes was was obtained obtained via viacross cross coupling coupling 1.0 equiv 1.0 equiv of (E)-telluro(silyl) of (E)-telluro(silyl) ketene ketene acetal ( acetal176) with (176) 2 withequivalents 2 equivalents of 177 by of 177usingby 20 using mol 20 % molof both % of PdCl both2 PdCland CuI2 and and CuI CH and3OH/Et CH33OHN as/Et solvent3N as solvent under undersonication. sonication.

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.

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 43.

In 2011, Kawasoko synthesized (E)-telluro(silyl)ketene acetals and used them as a substrate in Pd and Cu catalyzed Sonogashira reactions(Scheme 44) [90]. (Z)-1,4-diorganyl-2-(triorganyl)–silyl-1- buten-3-ynes was obtained via cross coupling 1.0 equiv of (E)-telluro(silyl) ketene acetal (176) with 2 Catalysts 2020, 10, 443 23 of 48 equivalents of 177 by using 20 mol % of both PdCl2 and CuI and CH3OH/Et3N as solvent under sonication.

Scheme 44. Synthesis of (Z)-1,4-diorganyl-2-tri(organyl)silyl-1-buten-3-ynesScheme 44. via Cross Coupling.

Recently, aa wide wide variety variety of crossof cross coupling coupling reactions reactions catalyzed catalyzed by Palladium by Palladium complexes complexes containing containingN-heterocyclic N-heterocyclic carbene (NHC) carbene as a (NHC) ligand haveas a beenligand reported. have been NHC reported. derived NHC from derived disubstituted from disubstitutedimidazolium saltimidazolium engaged the salt attention engaged of the researchers attention [91 of]. N-heterocyclicresearchers [91]. carbene N-heterocyclic formed a strongercarbene formedbond with a stronger most ofbond the with metals most than of the phosphine metals than ligands phosphine due to ligands theirgood due toσ their-donating good σ ability-donating [92]. abilityIndeed, [92]. in many Indeed, catalytic in many reactions catalytic metal reactions complexes metal containing complexes NHC containing ligand NHC have beenligand proved have been to be provedmore eﬃ tocient be more catalysts efficient as compared catalysts to as phosphine-containing compared to phosphine-containing metal-complexes metal-complexes [93]. Thus, Luo [93]. and Thus,coworkers Luo synthesizedand coworkers a new synthesized bis-N-heterocyclic a new carbene-PdIbis-N-heterocyclic2 catalyst carbene-PdI179 from ca2 ﬀcatalysteine, as 179 shown from in caffeine,Scheme 45 as. Undershown various in Scheme conditions 45. Under Palladium various Catalyst conditions179 was Palladium used in SonogashiraCatalyst 179 cross was couplingused in Sonogashiraof para-bromo cross nitrobenzene coupling of180 para-bromoand phenylacetylene nitrobenzene181 180. The and reaction phenylacetylene did not proceed 181. The very reaction well in didH2O, not even proceed at 90 ◦veryC[94 well]. The in 1 H equivalent2O, even at of 90 Brij °C 30 [94]. was The added 1 equivalent in the reaction of Brij mixture 30 was as added the non-ionic in the reactionsurfactant mixture and NaO-t-Bu as the non-ionic and KOH surfactant as the base, and and NaO-t-Bu it improved and yieldKOH asas thethe temperature base, and it wasimproved raised yieldfromCatalysts 25as 2020the◦C ,totemperature 10 90, x FOR◦C. PEER was REVIEW raised from 25 °C to 90 °C. 24 of 48

Scheme 45. Copper and bis-NHC-PdI2 catalyzedScheme 45. Sonogashira Cross Coupling of para-bromo nitrobenzene with phenylacetylene. 2.11. In 2012 2.11. In 2012 Khera and coworkers reported Pd catalyzed reactions and synthesis of bis(triflates) of 2,4′- bis(hydroxy)Khera and diphenyl coworkers sulfone reported [95]. PdIn medicina catalyzedl chemistry, reactions andarylated synthesis sulfones of bis(triﬂates)are important of 2,4structural0-bis(hydroxy) moieties diphenyl because sulfoneof their [various95]. In medicinalbiological activities chemistry, such arylated as anti-bacterial sulfones are activity important [96], structuralantiHIV [97] moieties and anti-cholesteremic because of their various[98]. The biological Sonogashira activities cross such coupling as anti-bacterial of 183 with activityalkynes [ 96184], antiHIVgave 2,4 [′97-bis(alkynyl)diphenyl] and anti-cholesteremic sulfones [98]. The185 Sonogashiracontaining two cross different coupling ar ofyl183 groupswith (Scheme alkynes 184 46).gave The 2,4reaction0-bis(alkynyl)diphenyl was carried out by sulfones using 185Coppercontaining Iodide twoand di[Pd(PPhﬀerent3 aryl)2Cl2 groups] as a catalyst, (Scheme triethyl 46). The amine reaction as a wasbase carried and DMF out as by the using solvent. 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).

Scheme 47.

CatalystsCatalysts 2020 2020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 2424 ofof 4848

SchemeScheme 45. 45.

2.11.2.11. In In 2012 2012 KheraKhera andand coworkerscoworkers reportedreported PdPd catalyzedcatalyzed reactionsreactions andand synthesissynthesis ofof bis(triflates)bis(triflates) ofof 2,42,4′-′- bis(hydroxy)bis(hydroxy) diphenyldiphenyl sulfonesulfone [95].[95]. InIn medicinamedicinal l chemistry,chemistry, arylatedarylated sulfonessulfones areare importantimportant structuralstructural moietiesmoieties becausebecause ofof theitheirr variousvarious biologicalbiological activitiesactivities suchsuch asas anti-bacterialanti-bacterial activityactivity [96],[96], antiHIVantiHIV [97][97] andand anti-cholesteremicanti-cholesteremic [[98].98]. TheThe SonogashiraSonogashira crosscross couplingcoupling ofof 183183 withwith alkynesalkynes 184184 gavegave 2,42,4′-bis(alkynyl)diphenyl′-bis(alkynyl)diphenyl sulfonessulfones 185185 containingcontaining twotwo differentdifferent ararylyl groupsgroups (Scheme(Scheme 46).46). TheThe reactionCatalystsreaction2020 was was, 10 carried ,carried 443 out out by by using using Copper Copper Iodide Iodide and and [Pd(PPh [Pd(PPh3)3)2Cl2Cl2]2] as as a a catalyst, catalyst, triethyl triethyl amine amine24 as ofas 48a a basebase and and DMF DMF as as the the solvent. solvent.

Scheme 46. Synthesis of 2,4’-bis(alkynyl)diphenylSchemeScheme 46. 46. sulfones via Sonogashira Reaction.

Similarly,Similarly,Similarly, Nishihara Nishihara and and coworkers coworkers synthesized synthesized unsymmetrically unsymmetrically disubsti disubstituteddisubstitutedtuted ethynes ethynesethynes by byby the thethe Pd-Cu(I)Pd-Cu(I)Pd-Cu(I) co-catalyzedco-catalyzedco-catalyzed Sonogashira-Hagihara Sonogashira-HagiharaSonogashira-Hagihara cross crosscross coupling couplingcoupling reactions reactionsreactions of 1-aryl-2-trimethylsilyl ofof 1-aryl-2-trimethylsilyl1-aryl-2-trimethylsilyl ethynes ethyneswithethynes aryl withwith iodides, arylaryl iodides,bromides,iodides, bromides,bromides, and chlorides andand chloridechloride [99]. Unsymmetricalss [99].[99]. UnsymmetricalUnsymmetrical diarylethyne diarylethynediarylethyne moieties moietiesaremoieties common areare commonincommon the pharmaceutical inin thethe pharmaceuticalpharmaceutical industry, natural industry,industry, products naturalnatural and productsproducts materials and science.and materialsmaterials Compounds science.science. containing CompoundsCompounds this containingmoietycontaining can this this easily moiety moiety be synthesized can can easily easily be be by synthesized synthesized using of the by by Sonogashira-Hagiharausing using of of the the Sonogashira-Hagihara Sonogashira-Hagihara cross coupling cross cross reaction coupling coupling of reactionterminalreaction of of alkynes terminal terminal with alkynes alkynes aryl halides, with with aryl aryl or halides, pseudo-halideshalides, or or pseudo-halides pseudo-halides (Scheme 47 (Scheme ).(Scheme 47). 47).

CatalystsScheme 2020, 10, 47. x FORSynthesis PEER REVIEW of unsymmetrically disubstitutedSchemeScheme 47. 47. ethynes by the Pd-Cu catalyzed coupling.25 of 48

2.12. In 2013 2.12. In 2013 Ahammed used the Sonogashira reaction for the sy synthesisnthesis of of 2-(2-nitroph 2-(2-nitrophenyl)-1-arylenyl)-1-aryl ethanones, ethanones,

a valuablevaluable precursor precursor for for the the synthesis synthesis of indolesof indoles [100 ].[100]. In the In presence the pres ofence pyrrolidine, of pyrrolidine, the alkyne the formedalkyne viaformed Palladium via Palladium and Copper and catalyzed Copper couplingcatalyzed of coupling190 with 1-ethynyl-4-methoxybenzeneof 190 with 1-ethynyl-4-methoxybenzene continue with simultaneouscontinue with regio-selective simultaneous hydration, regio-selective which resulted hydration, in the which formation resulted of corresponding in the formation aryl-ketone of (Schemecorresponding 48). Thisaryl-ketone method (Scheme has various 48). This signiﬁcant method features has various such assignificant high yields, features reaction such inas Hhigh2O, andyields, magniﬁcent reaction in regio-selectivity. H2O, and magnificent regio-selectivity.

Scheme 48. Synthesis of 2-(2-nitrophenyl)-1-arylScheme ethanones 48. via Sonogashira cross coupling followed by hydration reaction. The Phenylene-ethynylene oligomers and polymers are of great interest, because of their use for fabricationThe Phenylene-ethynylene of optoelectronic and oligomers electronic and devices polymers [101,102]. areof In great recent interest, years, great because progress of their has use been for fabricationmade in the of optoelectronicsynthesis of andnume electronicrous triple devices bond [101 containing,102]. In recent oligomers years, greatand rod progress like hasrigid been p- madearylacetylene in the synthesis polymers; of numerous however, triple because bond of containing intrinsic oligomerslimitations and of rod ma likeny rigidsynthetic p-arylacetylene methods, polymers;synthesis of however, highly becauseconjugated of intrinsic arylene-ethynyle limitationsne of polymers many synthetic and large methods, oligomers synthesis is impossible. of highly conjugatedDefects in the arylene-ethynylene conjugated system polymers restrict and their large use oligomers in photonics is impossible. and molecular Defects electronics. in the conjugated For the systempreparation restrict of triple their usebond in containing photonics andπ-conjugated molecular systems electronics. Sonogashira For the preparationcross coupling of triple is the bond only containingeffective methodπ-conjugated [103]. systemsHetero-coupling Sonogashira of te crossrminal coupling alkynes is theand onlyiodo e ﬀsubstitutedective method aromatic [103]. Hetero-couplingcompounds is more of terminal difficult alkynesthan the and homo iodo coupling substituted of the aromatic two terminal compounds alkynes is [104]. more The diﬃ synthesiscult than theof arylene homo couplingethynylene of theoligomers two terminal via Sonogashira alkynes [104 re].action The synthesisis also complicated of arylene ethynylenebecause of competing oligomers 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 formation of 196. This was then reacted with excess 1,4-diiodobenzene to yield dimer substituted 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). Iaroshenko described an effective method for the synthesis of thieno[3,2-b]-, [2,3-c]-, and [3,2-c] pyridones via Sonogashira cross coupling of thienyl acetylenes with bromo thiophenes using Et3N or di-isopropyl amine, followed by subsequent addition of amines/ammonium to the thienyl acetylenes intermediate [106]. The suitable substrate for the synthesis of 204 is 1-(3-bromothiophen-2-yl)-3- arylprop-2-yn-1-ones (203). Compound 203 was achieved by Sonogashira reaction of 202 with terminal aryl acetylenes using Pd and Copper in the presence of Et3N in Tetrahydrofuran as shown in Scheme 50. Then the reactions of ketone with amines in the presence of Pd2(dba)3, BINAP, 1.4 equivalent of Cs2CO3 and toluene as a base and solvent, respectively, resulted in the formation of thieno[3,2-b] pyridones 204.

Catalysts 2020, 10, 443 25 of 48 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 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). Catalysts 2020, 10, x FOR PEER REVIEW 26 of 48

Scheme 49. Synthesis of dimer viaScheme oxygen-free 49. Sonogashira Cross Coupling.

Iaroshenko described an eﬀective method for the synthesis of thieno[3,2-b]-, [2,3-c]-,Br and [3,2-c] NH2 Br Ph pyridones via Sonogashira cross coupling of thienyl acetylenesPh with bromo thiophenes using OMe Cl Et3N or di-isopropyl amine, followed by subsequentPdCl addition2(PPh3)2,CuI, of amines/ammonium to the S S S thienyl acetylenesO intermediate [106]. TheO suitableEt3N, substrate THF, Ar,rt, for 2 hthe synthesisO of 204 is 1-(3-bromothiophen-2-yl)-3-arylprop-2-yn-1-ones (203). Compound 203 was achieved203 by Sonogashira 201 reaction of 202 with terminal aryl acetylenes202 using Pd and Copper in the presence of Et3N in Tetrahydrofuran as shown in Scheme 50. Then the reactions of ketone with amines in the presence of Pd2(dba)3, BINAP, 1.4 equivalent of Cs2CO3 and toluene as a base and solvent, respectively, resulted in the formation of thieno[3,2-b] pyridones 204. OMe

CH2 N Ph

S O 204 (92%) Scheme 50.

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].

Catalysts 2020, 10, x FOR PEER REVIEW 26 of 48

Catalysts 2020, 10, 443 26 of 48 Scheme 49.

Br NH2 Br Ph Ph OMe Cl PdCl2(PPh3)2,CuI, S S S O O Et3N, THF, Ar, rt, 2 h O 203 201 202

OMe

CH2 N Ph

S O 204 (92%)

Scheme 50. Synthesis of 4-(3-methoxybenzyl)-5-phenylthieno[3,2-b]pyridin-7(4H)-one.Scheme 50.

TheyThey synthesizedsynthesized thieno[2,3-c]pyridonesthieno[2,3-c]pyridones by SonogashiraSonogashira reaction ofof 205205 withwith terminalterminal alkynealkyne followedfollowed byby aa basebase mediatedmediated intra-molecularintra-molecular C-NC-N bondbond formingforming reactionreaction (Scheme(Scheme 5151).). ItIt waswas foundfound thatthat inin thethe presencepresence ofof PdPd/Cu,/Cu, reactionreaction ofof 205205 withwith 206206 resultedresulted inin thethe formation of thieny alkyne 207. ReactionReaction ofof 207207 withwith aq.NHaq.NH33 atat heatingheating producedproduced amidesamides whichwhich reactreact withwith sodiumsodium methoxidemethoxide inin CHCH3OH at reﬂuxreflux furnishedfurnished thieno[2,3-c]thieno[2,3-c] pyridonespyridones 208208 byby intramolecularintramolecular cyclizationcyclization reactionreaction [[106].106]. Catalysts3 2020, 10, x FOR PEER REVIEW 27 of 48

Scheme 51. Synthesis of 5-(4-methoxyphenyl)thieno[2,3-c]pyridin-7(6H)-one.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.

2.13. 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

Catalysts 2020, 10, x FOR PEER REVIEW 27 of 48

Catalysts 2020, 10, 443 27 of 48 Scheme 51.

Thieno[3,2-c]pyridines was also synthesized by PdPd/Cu/Cu catalyzedcatalyzed Sonogashira reaction of thethe correspondingcorresponding alkyne with with 209209,, followed followed by by hydrolysis hydrolysis of of CN CN group group of of the the 211211 underunder the the action action of of Triﬂuoroacetic acid-H SO system to amides and their intramolecular cyclization with sodium Trifluoroacetic acid-H2SO2 4 system4 to amides and their intramolecular cyclization with sodium methoxidemethoxide [[106]106] (Scheme(Scheme 5252).).

Scheme 52. Synthesis of 3-(4-propylphenyl)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-c]pyridin-1Scheme 52. (2H)-one. 2.13. In 2014 2.13. In 2014 Korzec and coworkers developed a less costly and more efficient bimetallic nano Pd/PdO/Cu catalyticKorzec system and for coworkers Sonogashira developed cross coupling a less costly as shown and more in Scheme efficient 53. bimetallic They checked nano the Pd/ PdOcatalytic/Cu catalyticactivity of system different for Sonogashirabimetallic catalysts cross coupling during cross as shown coupling in Scheme reaction 53. of They 213 checkedwith tri-methyl the catalytic silyl activityacetylene. of Catalysts different differ bimetallic in their catalysts metal loadings, during cross type couplingof carrier reactionmetal and of Concentration213 with tri-methyl of Pd [107]. silyl acetylene.CatalystsThe carrier metals played differ ina role their both metal as cocatalyst loadings, typeto help of carrierthe trans-metalation metal and Concentration step in the Sonogashira of Pd [107]. Thereaction carrier and metals the playedPd support a role bothfor the as cocatalystheterogenous to help catalysis. the trans-metalation Among all the step checked in the Sonogashira bimetallic Catalystsreactioncomposition, 2020 and, 10 ,onlythe x FOR Pd Palladium/Copper PEER support REVIEW for the composite heterogenous were catalysis. found to be Among active. all The the catalytic checked ability bimetallic28 of of the 48 composition, only Palladium/Copper composite were found to be active. The catalytic ability of Palladium/Copperthe Palladium/Copper catalytic catalytic system system was was affected affected by by the the conditions conditions of of the the reaction, reaction, especially especially the temperature and concentration of phosphine ligands.ligands.

Scheme 53. Palladium and Copper catalyzedScheme Sonogashira 53. cross coupling of tri-methyl silyl acetylene.

A newnew heterogeneous heterogeneous Pd-Cu Pd-Cu/C/C catalytic catalytic system forsy Sonogashirastem for Sonogashira alkynylation-[3 alkynylation-[3+2]-+2]-cyclo addition cycloadditionleading to triazoles leading was to developed triazoles bywas Rossy developed and coworkers by Rossy (Scheme and coworkers 54)[108]. (Scheme The Sonogashira 54) [108]. step The is Sonogashirasuitable for both step electron-donating is suitable for andboth with-drawing electron-donating substituents and onwith-drawing the iodoaryl. substituents This protocol on allows the iodoaryl.the synthesis This of protocol various usefulallows heterocycles the synthesis with of various an inexpensive useful hetero base andcycles ligand with in an hydrophilic inexpensive solvents. base and ligandThe same in hydrophilic authors also solvents. 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 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.

Catalysts 2020, 10, x FOR PEER REVIEW 28 of 48

Palladium/Copper catalytic system was affected by the conditions of the reaction, especially the temperature and concentration of phosphine ligands. Catalysts 2020, 10, x FOR PEER REVIEW 28 of 48

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 electronScheme-donating 53. and with-drawing substituents on the iodoaryl. This protocol allows the synthesis of various useful heterocycles with an inexpensive base and ligandA new in hydrophilicheterogeneous solvents. 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 Catalystsiodoaryl.2020 This, 10, 443protocol allows the synthesis of various useful heterocycles with an inexpensive28 base of 48 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 twoScheme pathways. 54. Synthesis In path of triazolesI, the series Sonogashira involvesScheme alkynylation-[3 firstly 54. Click+ 2]-cycloand then addition Heck catalyzed reaction via while Pd and Path II involvesCu supported Sonogashira on charcoal. and then Click transformations (Scheme 55). 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. Pd-Cu supported on CharcoalScheme catalyzed 55. sequential Sonogashira-Click reaction.

In another another study, study, Pd–bis(oxazoline) Pd–bis(oxazoline) (Pd–BOX) (Pd–BOX) A Aand and B complexes B complexes was wassynthesized synthesized and their and theircatalytic catalytic activities activities was checked was checked in Sonogashira in Sonogashira cross coupling cross coupling by Hussain by Hussainand coworkers and coworkers (Scheme (Scheme56) [109]. 56 The)[109 reaction]. The reactionof phenyl of acetylene phenyl acetylene andScheme iodo-benzene and 55. iodo-benzene in the presence in the presence of Pd-BOX of Pd-BOX (A) or (A)(B) orand (B) CuI and and CuI Et and3N as Et 3aN base as a at base 70 at°C. 70 The◦C. results The results showed showed good good conversion conversion of iodo-benzene of iodo-benzene (77%) (77%) in inthe the presenceIn presence another of ofPalladium-BOXstudy, Palladium-BOX Pd–bis(oxazoline) (A) (A) and and slightly(Pd–BOX) slightly lower lower A and conversion conversion B complexes (57%) (57%) was with with synthesized Palladium-BOX Palladium-BOX and their (B), (B), aaffordingcatalyticﬀordingCatalysts activities2020 thethe ,di-phenylacetylene di-phenylacetylene10, x FOR was PEER checked REVIEW in as as Sonogashira thethe onlyonly product.product. cross coupling by Hussain and coworkers 29(Scheme of 48 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.

Scheme 56. Sonogashira coupling reactionScheme of 56. iodobenzene with phenyl acetylene.

It wasIt was observed observed that enolsthat enols of cyclic of 3-alkynylcyclic 3-alkynyl substituted substituted 1,2-diones 1,2-diones can be achieved can be viaachieved Sonogashira via reaction.Sonogashira As shown reaction. in Scheme As shown 57, anin eSchemeﬃcient 57, Sonogashira an efficient reaction Sonogashira of substituted reaction acetylenesof substituted with enolateacetylenes of 3-bromocyclopentane with enolate of 3-bromocyclopent and 3-bromocyclohexane-1,2-diketonesane and 3-bromocyclohexane-1,2-diketones was developed by Paju was and 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 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).

Catalysts 2020, 10, x FOR PEER REVIEW 29 of 48

Scheme 56.

Catalysts It2020 was, 10 , 443observed that enols of cyclic 3-alkynyl substituted 1,2-diones can be achieved 29via of 48 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 coworkersdeveloped [110 by]. Paju In and a short coworkers reaction [110]. time, In thea short protocol reaction aff ordstime,enols the protoc of 1,2-diketonescyclohexaneol affords enols of 1,2- anddiketonescyclohexane 3-alkynylsubstituted and cyclopentane 3-alkynylsubstituted with good cycl yield.opentane In order with togood find yield. favorable In order conditions to find for Sonogashirafavorable conditions reaction of for cyclic Sonogashira 3-bromo-1,2-diones reaction of they cyclic investigated 3-bromo-1,2-diones the reaction they of 3-bromo-1,2-dionesinvestigated the withreaction Phenyl of acetylene 3-bromo-1,2-diones and trimethylsilyl with Phenyl acetylene acetylene (TMSA). and trimethylsilyl Phenyl acetylene acetylene reaction (TMSA). in the Phenyl presence ofacetylene Pd and Cu reaction and TMSA in the with presence unprotected of Pd and 3-bromo Cu and Cyclopentane-1,2-diketonesTMSA with unprotected 3-bromo gave Cyclopentane- a low yield 13% of1,2-diketones Phenyl acetylenic gave and a low 15% yield for Trimethylsilyl 13% of Phenyl acetylenic acetylenic compound. and 15% Infor the Trimethylsilyl same reaction acetylenic conditions, thecompound. bromide of In silyl the enolsame etherreaction reacted conditions, smoothly the withbromide phenylacetylene of silyl enol ether and reacted TMSA atsmoothly the same with time, affphenylacetyleneording the corresponding and TMSA productsat the same in time, 90% andaffording 83% yieldthe corresponding respectively. products Therefore, in 90% only and protected 83% cyclicyield 3-bromo-1,2-diones respectively. Therefore,227 onlywere protected used in cyclic Sonogashira. 3-bromo-1,2-diones A medium 227presence were used of in CuISonogashira. supported theA reaction. medium presence of CuI supported the reaction.

Scheme 57. Cross Coupling of cyclicScheme 3-bromo-1,2-diketones 57. with terminal acetylene.

DoubleDouble Sonogashira Sonogashira reaction reaction is anis excellentan excellent method method for thefor synthesisthe synthesis of calix-arenes of calix-arenes with electronwith richelectron cavities. rich Due cavities. to unique Due and to tunableunique three-dimensionaland tunable three-dimensional structure, Calix[4]arene structure, Calix[4]arene is broadly used is in thebroadly design used of fluorescent in the design receptors of fluorescent as a molecular receptors sca ffasold a molecular [111,112]. scaffold Thus, Sun [111,112]. and coworkers Thus, Sun reported and synthesiscoworkers of derivatives reported ofsynthesis calix[4]arene of derivatives through Palladium of calix[4]arene catalyzed Sonogashirathrough Palladium reaction fromcatalyzed231 and 25,27-dipropargyl-calix[4]areneSonogashira reaction from 231[ 113and]. 25,27-dipropargyl-calix[4]arene Calix[4]arene derivatives show [113]. different Calix[4]arene fluorescent derivatives properties dueshow to the different different fluorescent nature of substituents properties Calixarenesdue to the containingdifferent nature the electron-donating of substituents groupsCalixarenes such as methoxycontaining enhanced the electron-donating the intensity of groups fluorescence, such as while methoxy in a-protic enhanced solvents, the inte thensity electron-withdrawing of fluorescence, groupswhile containing in a-protic Calixarenes solvents, arethe notelectron-withdrawing apparently fluorescent. groups This econtainingffect was estimatedCalixarenes mainly are duenot to apparently fluorescent. This effect was estimated mainly due to the increase of delocalization of the theCatalysts increase 2020 of, 10 delocalization, x FOR PEER REVIEW of the p-π electron (Scheme 58). 30 of 48 p-π electron (Scheme 58).

Scheme 58. Synthesis of calix[4]arene derivativesScheme via 58. Palladium and Copper catalyzed Coupling.

2.14.2.14. In In 2015 2015 BellinaBellina and and coworkers coworkers in in 2015 2015 developed developed substituted alkynyl alkynyl imidazoles imidazoles via via a aone one pot pot sequential sequential reactionreaction involving involving a a highly highly regio-selective regio-selective electrophilicelectrophilic C-5 C-5 bromination bromination of of substituted substituted imidazoles, 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.

Catalysts 2020, 10, x FOR PEER REVIEW 30 of 48

Scheme 58.

2.14. In 2015 Catalysts 2020, 10, 443 30 of 48 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 eefficientﬃcient Sonogashira Coupling [[114].114]. They They observed observed that that the the use of piperidine as a base instead of Et3NN increased increased the yield (Scheme 59).59). The The typica typicall approach approach for for the the synthesis synthesis of of hetero 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].115,116].

Scheme 59. One-pot sequential brominationScheme of substituted 59. imidazoles via Sonogashira Coupling.

The Synthesis of 7-azaindoles having triazole and quinoxaline substituents at C-5, via double Sonogashira crosscross coupling coupling of di-halogenatedof di-halogenated amino amino pyridines pyridines was reported was reported by Leboho by and Leboho coworkers and coworkersin 2015 (Scheme in 2015 60 (Scheme)[117]. 60) A [117]. double A double Sonogashira Sonogashira coupling coupling of 3,5-diiodoaminopyridine of 3,5-diiodoaminopyridine with TMS-acetylenewith TMS-acetylene gave gave compound compound237. 237 Removal. Removal of of TMS TMS with with TBAF TBAF resulted resulted in in thethe formationformation of 238 which ononfurther further double double Sonogashira Sonogashira with with 4-methoxy 4-methoxy iodobenzene iodobenzene gave gave compound compound239. 239 After. After that, that,compound compound239 on239treatment on treatment with with TFAA TFAA was was converted converted into into triﬂuoroacetamide trifluoroacetamide and andthen then itit was subjected to the Cacchi-reaction and 2,3,5-trisubstituted2,3,5-trisubstituted 7-azaindoles7-azaindoles waswas achieved.achieved. Catalysts 2020, 10, x FOR PEER REVIEW 31 of 48

Scheme 60. Synthesis of 3,5-bis((4-methoxyphenyl)ethynyl)pyridin-2-amineScheme 60. via Pd and Cu catalyzed Cross Coupling. The same authors also reported that when 240 was exposed to acetylene under Sonogashira conditions,The same coupling authors occurred also reported at the position that when of io240dine.was Then, exposed the azaindole to acetylene nucleus under was Sonogashira formed by conditions,using KOtBu coupling in a mixture occurred of atDi-methyl the position formamide of iodine. and Then, tetra-hydro the azaindole furan, followed nucleus wasby another formed bySonogashira using KOtBu cross in coupling a mixture reaction of Di-methyl at the bromo formamide substituted and tetra-hydro site of azaindoles, furan, which followed resulted by another in the Sonogashiraformation of cross243. This coupling was then reaction subjected at the to bromo tetra-n-butylammonium substituted site of azaindoles, fluoride (TBAF) which for resulted the removal in the formationof the trimethylsilyl. of 243. This Then was then7-azaindoles subjected having to tetra-n-butylammonium quinoxaline and triazole ﬂuoride substituents (TBAF) for at the C-5 removal 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 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.

Catalysts 2020, 10, x FOR PEER REVIEW 31 of 48

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 Catalystsusing KOtBu2020, 10, 443in a mixture of Di-methyl formamide and tetra-hydro furan, followed by another31 of 48 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 of the trimethylsilyl. Then 7-azaindoles having quinoxaline and triazole substituents at C-5 were accomplished through an alkyne-azide cycloaddition (Scheme 61). easily accomplished through an alkyne-azide cycloaddition (Scheme 61).

Scheme 61. Synthesis of 5-ethynyl-2-phenyl-1H-pyrrolo[2,3-b]pyridineScheme 61. via Sonogashira reaction.

Similarly, derivatives of of 2-alkynyl 2-alkynyl benzoxazole benzoxazole and and 2-alkynyl 2-alkynyl benzothiazole benzothiazole was was synthesized synthesized via viaSonogashira Sonogashira of the of theterminal terminal alkynes alkynes and and thio-e thio-ethersthers under under aerobic aerobic conditions, conditions, using using Pd(dppf)Cl Pd(dppf)Cl2 and2 andCuI by CuI Paun by Paun and coworkers and coworkers as shown as shown in Scheme in Scheme 62 [118]. 62[ The118]. nature The natureof benzoxazoles of benzoxazoles and benzo- and benzo-thiazolesthiazoles were also were checked also checked in the de-sulfitative in the de-sulﬁtative Sonogashira. Sonogashira. The reaction The occurred reaction better occurred in aerobic better inconditions aerobic conditions than inert than atmosphere, inert atmosphere, although although increased increased amounts amounts of the diyne of the diyneside product side product were wereCatalystsformed. formed. 2020 , 10, x FOR PEER REVIEW 32 of 48

Scheme 62. Synthesis of 2-alkynyl benzoxazoleScheme and 62. –thiazole via Sonogashira Cross Coupling.

In aerobic conditions,conditions, the authors also coupled 248 with phenylphenyl acetylene,acetylene, which showed C–S and C–Br couplingcoupling ofof thethe alkyne.alkyne. Under aerobicaerobic conditions,conditions, methylmethyl thio-benzoxazolesthio-benzoxazoles brominatedbrominated analog gave product 249 (Scheme 6363).). Increasing the equivale equivalentsnts of alkyne did not improve the yield of coupling reaction. Under Under inert inert atmosphere, atmosphere, an an attempt attempt to to selective selective Sonogashira Sonogashira cross cross coupling coupling of of5-bromo-2-(methylthio) 5-bromo-2-(methylthio) benzoxazol benzoxazolee surprisingly surprisingly gave gave compound compound 250250, ,with with preservation preservation of of the bromine substituent which allowed the opportunity to further functionalize the benzoxazole nucleus through reactionsreactions ofof thethe C–BrC–Br bond.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 [121–123]. 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).

Scheme 63.

Catalysts 2020, 10, x FOR PEER REVIEW 32 of 48

Scheme 62.

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

Catalystsbromine2020 substituent, 10, 443 which allowed the opportunity to further functionalize the benzoxazole nucleus32 of 48 through reactions of the C–Br bond.

CatalystsScheme 2020, 10 63., x SonogashiraFOR PEER REVIEW Cross Coupling of 5-bromo-2-(methylthio)benzoxazoleScheme 63. with phenylacetylene.33 of 48

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 [121-123]. 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). Scheme 64. Synthesis of arylethynyl linked triarylamine with substituted phenylacetylene. Scheme 64. Pd-pincer complexes havehave beenbeen widelywidely usedused asas a catalyst in a various C-C or carbon-hetero bond formation [[125].125]. In In past past decades, decades, due due to to low costscosts and widewide scopescope applications,applications, NCN-PdNCN-Pd pincerpincer complexes have attracted much attention. Thus, in 2015, Zhang and coworkers coworkers synthesized PdII- 257,, 258 and 259 pincerpincer complexescomplexes and checked their activity in Sonogashira reaction (Scheme 65)65)[ [126].126]. In the Sonogashira reaction, reaction, 258b258b waswas used used as as a aprecatalyst precatalyst to to optimize optimize the the conditions conditions of ofreaction, reaction, in inorder order to tocheck check the the catalytic catalytic activity activity of of these these comple complexes.xes. Different Diﬀerent solvent solvent and and bases bases were were used, and it waswas found that the cross-coupling reaction gave excellent yield of products, when KOAc and DMAC werewere usedused asas thethe basebase and solvent respectively. Similarly,Similarly, thethe otherother itemsitems suchsuch asas loadingloading of catalystcatalyst 1mmol%,1 mmol %, temperature temperature of of reaction reaction 90 ◦90C as°C wellas well as reaction as reaction time time of 12h of are12 h also are optimized. also optimized. Using Using these optimizedthese optimized conditions conditions of reactions, of reactions, they checked they chec the catalyticked the abilitycatalytic of ability the other of Pdthe pincer other complexesPd pincer incomplexes the same in cross the same coupling cross reaction.coupling reaction. Their catalyzed Their catalyzed results showed results showed that 259a thatwas 259a the was most the active most catalystactive catalyst and the and general the general order of order catalytic of catalytic ability wasability as follows,was as follows,259 >258 259>257 > 258. Furthermore, > 257. Furthermore, varying t Zvarying from Bu Z tofrom NO 2Busuggestt to NO that2 suggest presence that of presence the electron-withdrawing of the electron-withdrawing groups at the groups 4th position at the of 4th Pd enhancedposition of its Pd catalytic enhanced activity. its catalytic activity.

2.15. 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-20-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

Scheme 65.

Catalysts 2020, 10, x FOR PEER REVIEW 33 of 48

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

Catalyststhese optimized2020, 10, 443 conditions of reactions, they checked the catalytic ability of the other Pd 33pincer of 48 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, deprotectedvarying Z from in the Bu presencet to NO2 of suggest K2CO3 ,that MeOH presence/H2Oto of a ﬀtheord elec thetron-withdrawing desired product 261 groupsand 262 at ,the which 4th areposition highly of ﬂuorescent Pd enhanced (Scheme its catalytic 66). activity.

Catalysts 2020, 10, x FOR PEER REVIEW 34 of 48 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 K2CO3, MeOH/H2O to afford the desired product 261 and 262, which are highly fluorescent (Scheme 66). 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 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 yellowScheme compound 65. Sonogashira 266 was obtained Cross Coupling instead of underScheme the expected Copper 65. and product NCN 265 Palladium due to pincer1,2-Pd complexe migration in an intermediatecatalytic system. complex (Scheme 67). 2.15. 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

Scheme 66. Synthesis of rigid perylene nucleosides via Sonogashira cross coupling. Scheme 66.

Catalysts 2020, 10, 443 34 of 48

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 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 intermediateCatalysts 2020, 10 complex, x FOR PEER (Scheme REVIEW 67 ). 35 of 48

Scheme 67. Cross coupling of 4,6,7,9-tetrabromo-1,3-dimethyl-1H-perimidin-2(3H)-oneScheme 67. with TMSA.

In 2016, Gholinejad and coworkers synthesized and characterized an eefficientﬃcient heterogenous catalyst PdPd andand Cu Cu nanoparticles nanoparticles supported supported on phosphiniteon phosphinite functionalized functionaliz Agaroseed Agarose biopolymer biopolymer [129]. The[129]. activity The activity of this catalyticof this catalytic system wassystem checked was inchecked Sonogashira in Sonogashira reaction of reaction aryl-iodide of aryl-iodide and substituted and phenylacetylenesubstituted phenylacetylene at room temperature at room temperature by using DABCO by using as aDABCO base and as Dimethylacetamide a base and Dimethylacetamide (DMA) as a solvent(DMA) as and a solvent 0.05%mol and Pd 0.05%mol (Scheme Pd68). (Scheme 68).

Scheme 68. Agarose Functionalized PhosphorusScheme containing 68. Palladium and Copper Nanoparticles catalyzed Sonogashira reaction of aryl-iodide and substituted phenylacetylene. The synthesis of a marine brominated poly-unsaturated lipid xestospongenyne 272 having pancreaticThe synthesis lipase inhibitory of a marine activity brominated through Sonogashira poly-unsaturated cross coupling lipid xestospongenyne of 270 with E/Z272 isomerhaving of pancreatic1,2-dibromoethene lipase inhibitory in the presence activity of throughPd and Copper Sonogashira Catalyst cross in triethylamine couplingof 270 waswith reported E/Z isomer by Gong of 1,2-dibromoethene(Scheme 69) [130]. The in the resulting presence moderate of Pd and yield Copper might Catalyst be because in triethylamine of the lower wasreactivity reported of 271 by GongIn Pd (Schemecatalyzed 69 reactions.)[130]. The Generally, resulting moderatethe (E) isomer yield mightof 1,2-dibromoethene be because of the is lower more reactivity reactive ofthan271 theIn Pd Z catalyzedisomer. 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[1,2- b]benzofuran derivatives by the means of Sonogashira cross coupling and intra-molecular alkyne

Catalysts 2020, 10, x FOR PEER REVIEW 35 of 48

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).

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 Catalystscatalyzed2020, 10 reactions., 443 Generally, the (E) isomer of 1,2-dibromoethene is more reactive than the35 ofZ 48 isomer.

Scheme 69. Synthesis of xestospongenyne pancreaticScheme 69. lipase inhibitor via Palladium and Copper catalyzed reaction. In 2016, Nayak and coworkers reported the preparation of 5 and 6-acylated naptho[1,2- b]benzofuranIn 2016, derivatives Nayak and by the coworkers means of Sonogashira reported thecross preparationcoupling and ofintra-molecular 5 and 6-acylated alkyne naptho[1,2-b]benzofuran derivatives by the means of Sonogashira cross coupling and intra-molecularCatalysts 2020, 10 alkyne, x FOR PEER carbonyl REVIEW metathesis (Scheme 70)[131]. Sonogashira coupling of36 273of 48 with 1-ethynyl-4-methylbenzenecarbonyl metathesis(Scheme (274 70)) in [131]. the presence Sonogashira of Pdcoupling and Cu of resulted273 with 1-ethynyl-4-methylbenzene in the formation of 275 in 96% yield( which,274) in the upon presence heating of inPd Triﬂuoroacetic and Cu resulted acid in the/DCE formation at 80 ◦ Cof for275 1h,in 96% produced yield which, desired upon product heating276 in excellentin Trifluoroacetic yield. acid/DCE at 80 °C for 1 h, produced desired product 276 in excellent yield.

Scheme 70. Synthesis of naphtho[1,2-b]benzofuran-5-yl(p-tolyl)methanoneScheme 70. (276) by Sonogashira reaction. Similarly, they performed Palladium and Copper catalyzed Sonogashira of 277 with hex-1-yne Similarly,(278) in the they presence performed of Et3N Palladiumat 70 °C, and and produced Copper Compound catalyzed 279 Sonogashira in 96% yield. of Subjection277 with of hex-1-yne 279 in TFA/DCE for 1 h at 80 °C produced 6-acylaed product 280 in 97% yield (Scheme 71). (278) in the presence of Et3N at 70 ◦C, and produced Compound 279 in 96% yield. Subjection of 279 in TFA/DCE for 1 h at 80 ◦C produced 6-acylaed product 280 in 97% 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 derivatives that are helpful as electron transporting components in the preparation of OLEDs (Scheme 72).

2.16. In 2017

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

Catalysts 2020, 10, x FOR PEER REVIEW 36 of 48

carbonyl metathesis(Scheme 70) [131]. Sonogashira coupling of 273 with 1-ethynyl-4-methylbenzene (274) in the presence of Pd and Cu resulted in the formation of 275 in 96% yield which, upon heating in Trifluoroacetic acid/DCE at 80 °C for 1 h, produced desired product 276 in excellent yield.

Catalysts 2020, 10, 443 36 of 48 Scheme 70. syntheticSimilarly, method they they performed performed Palladium derivatization and Copper reaction catalyzed of iodo-3 SonogashiraH-pyrazole, of as 277 shown with in hex-1-yne Scheme 73 . Pd( and278) Cuin the catalyzed presence Sonogashira of Et3N at 70 cross °C, and coupling produced of iodo-3CompoundH-pyrazole 279 in 96% proceeded yield. Subjection smoothly of and 279 the resultingin TFA/DCE product for 2861 h atwas 80 formed°C produced in 85% 6-acylaed yield. product 280 in 97% yield (Scheme 71).

Catalysts 2020, 10, x FOR PEER REVIEW 37 of 48

derivatives that are helpful as electron transporting components in the preparation of OLEDs (Scheme 72).

N N

N N O Pd(dppf)Cl2 (5mol%) Br + O CuI (10mol%), Et3N THF,12h, Ar Catalysts 2020, 10, x FOR PEER REVIEW (1.5 equiv) 37 of 48 283 (91%) 281 282 derivativesScheme 71. thatSynthesis are helpful of 1-(naphtho[1,2-b]benzofuran-6-yl)pentan-1-one as electron transpSchemeorting 71. components in the via Pdpreparation and Cu mediayted of OLEDs Scheme 72. (SchemeCross Coupling.72). An efficient synthesis of 2,5-disubstituted Alkynyl bridged 1,3,4-Oxadiazole through 2.16.Sonogashira In 2017 cross coupling between arylacetylene and oxadiazole substitutedN N phenyl bromides in

the presenceN N of Palladium and Copper3 was reported by Paun and coworkersO [132]. This strategy is Liu and coworkers reported FeCl catalyzedPd(dppf)Cl synthesis2 (5mol%) of iodo-3H-pyrazoles derivatives [133]. 3veryH-pyrazoles suitable derivativesfor the synthesisBr are+ important of Luminescent heterocyclic small compounds molecules because or precursor of their of extensive other complex use in O CuI (10mol%), Et3N cyclopropenes, carbene intermediates, and diazoalkeneTHF,12h,s Ar synthesis. To signify the effectiveness of the (1.5 equiv) synthetic method they performed derivatization reaction of iodo-3H-pyrazole, as shown283 (91%) in Scheme 282 73. Pd and 281Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and the resultingScheme product 72. Synthesis 286 was of 2-naphthalen formed in 85% substitutedScheme yield. 72. oxadiazole via Sonogashira Cross Coupling.

2.16. In 2017

73. Pd and Cu catalyzed Sonogashira cross coupling of iodo-3H-pyrazole proceeded smoothly and theScheme resulting 73. productPd-Cu catalyzed 286 was Sonogashiraformed in 85% cross Schemeyield. coupling 73. of 4-iodo-3,3-dimethyl-5-phenyl-3H- pyrazole with phenyl acetylene. The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2- DihydropyridineThe silver catalyzed from ketene synthesis N,N-acetals of derivativeswas reported of by AzepineS. Nayak and fused coworkers. with Cyclobutene They enlarged and 1,2-Dihydropyridinethe Dihydropyridine from ring ketene by SonogashiraN,N-acetals cross was coupling reported of by alkenyl S. Nayak iodo and moiety coworkers. [134]. Sonogashira They enlarged theCoupling Dihydropyridine of 287 yield ring extended by Sonogashira π conjugated cross System coupling 289 (Scheme of alkenyl 74). 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 Scheme 73. the synthesis of various structurally diverse molecules [136,137]. A range of reactions, including organometallicThe silver coupling catalyzed protocols, synthesis of have derivative been applieds of Azepine on these fused newlywith Cyclobutene obtained halogenated and 1,2- cyclohexa-2,4-dienones.Dihydropyridine from keteneα-halo-dienones N,N-acetals was were reported subjected by S. to Nayak Sonogashira and coworkers. cross coupling They enlarged reaction. 2-bromo-5,6,6-trimethoxycyclohexa-2,4-dienonethe Dihydropyridine ring by Sonogashira cross coupling undergoes of alkenyl Pd-Cu catalyzediodo moiety Sonogashira [134]. Sonogashira coupling withCoupling compound of 287290 yieldand extended formed theπ conjugated adduct (292 System) in 74% 289yield (Scheme (Scheme 74). 75). Surprisingly, under same

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. 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 Scheme 74. 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 A facile synthetic approach to functionalize cyclohexa-2,4-dienones was developed by to give an intermediate, which is then aromatized to give the 2-methoxy-3-methyl-6-(phenylethynyl) 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-(phenylethynyl)

Catalysts 2020, 10, x FOR PEER REVIEW 37 of 48

derivatives that are helpful as electron transporting components in the preparation of OLEDs (Scheme 72).

N N

N N O Pd(dppf)Cl2 (5mol%) Br + O CuI (10mol%), Et3N THF,12h, Ar (1.5 equiv) 283 (91%) 281 282 Scheme 72.

2.16. 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. Catalysts 2020, 10, 443 37 of 48 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 1H-NMR analysis − ◦ showed 3 products; 293, 294 and 296, which indicatesScheme 73. that in this reaction Sonogashira Coupling was followed by aromatization reaction. To avoid the generation of hydrido-Pd intermediate they used an The silver catalyzed synthesis of derivatives of Azepine fused with Cyclobutene and 1,2- alternative Sonogashira coupling procedure. In this procedure, Pre-synthesized Pd(PPh3)4 was used DihydropyridineCatalysts 2020, 10, x FORfrom PEER ketene REVIEW N,N -acetals was reported by S. Nayak and coworkers. They 40enlarged of 51 asthe a catalyst, Dihydropyridine Cu(I)-Phenylethyne ring by Sonogashira was used ascross a reactant, coupling and of pyridinealkenyl iodo was moiety used as [134]. a base. Sonogashira Under these reactionCouplingcyclohexa-2,4-dienones. conditions, of 287 yield Sonogashira extended α-halo-dienones π coupled conjugated productwere System subjected294 289was to(Scheme obtainedSonogashira 74). in 93%cross yield.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 30min of reaction, thin layer chromatography and 1H-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(PPh3)4 was usedScheme as a 74. catalyst,Synthesis Cu(I)-Phenylethyne of derivatives of was Azepine usedScheme fusedas a reactant, 74. with Cyclobutene and pyridine and was 1,2-Dihydropyridine used as a base. Under via theseSonogashira reaction cross conditions, Coupling. Sonogashira coupled product 294 was obtained in 93% yield. A facile synthetic approach to functionalize cyclohexa-2,4-dienones was developed by Chittimalla andO coworkers [135]. Cyclohexa-2,4-dienones are important synthetic precursors in the H CO synthesis3 of variousBr structurally diverse molecules [136,137]. A rangeH3CO of reactions,O including H3CO PdCl2(PPh3) H CO organometallic coupling+ protocols, have been applied on these newly3 obtained halogenated cyclohexa-2,4-dienones.H3CO α-halo-dienones wereCuI, subjected DIPEA to SonogashiraH3CO cross coupling reaction. 2- THF, r.t, 1h bromo-5,6,6-trimethoxycyclohexa-2,4-dienone undergoes Pd-Cu catalyzed Sonogashira coupling 290 291 292 (74%) 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)

SchemeScheme 75. 75.Sonagashira Sonagashira coupling coupling ofof substitutedsubstituted o- o-benzoquinoneswithbenzoquinoneswith phenyl phenyl acetylene. 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 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 MnO2 (Scheme 76).

Catalysts 2020, 10, 443 38 of 48

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 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 Catalysts 2020, 10, x FOR PEER REVIEW 41 of 51 withCatalysts MnO 20202, (Scheme10, x FOR PEER 76). REVIEW 41 of 51

Scheme 76. SonogashiraSonogashira reaction reaction of 5-chloro-2-iodoaniline with hydroxyl-pheylacetylene.

In organic synthesis, silyl groups areare widelywidely used.used. Deprotection of silyl-ethynl intermediate is typically donedone by by using using a a Fluoride Fluoride source. source. However, However, the the use use of a of Fluoride a Fluoride source source is not is suitable not suitable due to due the tohigh the price high of price fluoride of fluoride salts and salts low and fluoride low contentfluoride mass, content and mass, another and issue another is the issue origin is ofthe fluorinated origin of fluorinatedreagent. Due reagent. to these Due issues, to these Sinai issues, and coworkers Sinai and coworkers developed developed a cheap, nontoxic a cheap,and nontoxic easily and available easily deprotecting agent H SiF for the deprotection of ethynyl-trimethyl silane to form terminal acetylenes available deprotecting2 agent6 H2SiF6 for the deprotection of ethynyl-trimethyl silane to form terminal (Schemeacetylenes 77 (Scheme)[139]. This 77) reagent[139]. This was reagent used in was Sonogashira used in reactionSonogashira for the reaction synthesis for ofthe derivatives synthesis of derivativesarylethynylpivalanilides of arylethynylpivalanilides and amines, 2-arylbenzofurans, and amines, 2-arylbenzofurans, and N-benzyltriazole. and TransformationN-benzyltriazole. of Transformationterminal acetylenes of terminal catalyzed acetylenes by transition catalyzed metal isby one transition of the most metal frequently is one of used the most methods frequently for the synthesis of heterocycles and internal-acetylenes. H SiF showed efficient reactivity and its presence used methods for the synthesis of heterocycles and2 internal-acetylenes.6 H2SiF6 showed efficient reactivityhad no deleterious and its presence effect on had Sonogashira no deleterious cross effect coupling. on Sonogashira cross coupling.

Scheme 77. SynthesisSynthesis of arylethynyl pivalanilides via Pd and Cu Coupling. Similarly, 1-iodo-4-methoxybenzene (305) coupled with protected terminal acetylene in the Similarly, 1-iodo-4-methoxybenzene (305) coupled with protected terminal acetylene in the presence of DIPA solvent and Pd/Cu catalyst. The desired intermediate 307 is formed in 30 min and presence of DIPA solvent and Pd/Cu catalyst. The desired intermediate 307 is formed in 30minutes then the Silyl protecting group is removed by adding Hexaﬂuoro silicic Acid. After deprotection, and then the Silyl protecting group is removed by adding Hexafluoro silicic Acid. After deprotection, the intermediate coupled readily with 2-iodoaniline and resulted in the formation of 308 in 89% yield the intermediate coupled readily with 2-iodoaniline and resulted in the formation of 308 in 89% yield (Scheme 78). (Scheme 78). 2.17. 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

Catalysts 2020, 10, x FOR PEER REVIEW 42 of 51

Catalysts 2020, 10, 443 39 of 48 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. BothCatalysts the 2020 electron, 10, x FOR donating PEER REVIEW and electron withdrawing substrates gave good yield [142]. 42 of 51

Scheme 78. Synthesis of 2-((4-methoxyphenyl)ethynyl)aniline via sonogashira Cross Coupling.

2.17. 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 2,3- 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]. Scheme 79.79.Synthesized Synthesized the the 2,3-di-hydro-pyrrole 2,3-di-hydro-pyrrole derivatives derivatives via Pd via and Pd Cu and catalyzed Cu catalyzed Cross Coupling. Cross Coupling. It was also noted that isocoumarins are naturally occurring lactones and are biologically active. TheyIt are was used also as noted a precursor that isocoumarins for synthesis are ofnaturally bio active occurring complex lactones compounds and are [143 biologically]. The 3-alkynyl active. Theyisocoumarins are used were as a synthesizedprecursor for via synthesis palladium of bio and active copper complex catalyzed compounds Sonogashira [143]. cross The coupling 3-alkynyl of isocoumarinsmethyl 2-(20,2 0were-dibromo synthesized vinyl) benzoate via palladium with terminal and copper alkyne catalyzed by Liu andSonogashira co-workers. cross The coupling naturally of methyloccurring 2-(2 compounds′,2′-dibromo 30 -hydroxycorﬁnvinyl) benzoate and with gymnopalyne terminal alkyne A were by alsoLiu and synthesized co-workers. via palladiumThe naturally and occurringcopper catalyzed compounds Sonogashira 3′-hydroxycorfin cross coupling and asgymnopalyne a key step (Scheme A were 80 also)[144 synthesized]. via palladium and copperIn addition, catalyzed N-Heterocyclic Sonogashira cross carbenes coupling are widely as a key used step (Scheme as ligands 80)[144]. 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 (SchemeScheme 81)[ 14679. ].Synthesized the 2,3-di-hydro-pyrrole derivatives via Pd and Cu catalyzed Cross Coupling.

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].

Catalysts 2020, 10, x FOR PEER REVIEW 43 of 51

Catalysts 2020, 10, 443 40 of 48 Catalysts 2020, 10, x FOR PEER REVIEW 43 of 51

Scheme 80. Sonogashira cross coupling of methyl 2-(2′,2′-dibromo vinyl) benzoate with substituted terminal alkyne.

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 80. Sonogashira cross coupling of methyl 2-(20,20-dibromo vinyl) benzoate with substituted Scheme 80. Sonogashira cross coupling of methyl 2-(2′,2′-dibromo vinyl) benzoate with substituted (Schemeterminal 81) [146]. alkyne. terminal alkyne.

Catalysts 2020, 10, x FOR PEER REVIEW 44 of 51

OMe 317 or 318 (0.01 mol %) 319 or 320 (1 mol %) + OMe Br Base, Solvent,120oC

321 322 323 (8-86%)

Base=K3PO 4,CsF,Na2CO3,CsCO3 Solvent=DMSO,THF SchemeScheme 81. SonogashiraSonogashira cross cross coupling coupling of of bulky bulky and and heterocyclic heterocyclic halides with heteroaryl alkynes.

3. Conclusions In summary, Sonogashira cross-coupling is used for the synthesis of different organic bioactive and pharmacologically important compounds. This review article highlighted the palladium and copper-based catalysts for Sonogashira cross-coupling. The Pd-Cu-catalyzed cross-coupling of terminal acetylenes with sp2-C halides is a broadly useful method for conjugated acetylenes. In particular, the search for more reactive and long-living catalysts for the aryl chlorides remains a challenging object for future research.

Funding: This research received no external funding

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Zapf, A.; Beller, M. Fine chemical synthesis with homogeneous palladium catalysts: Examples, status and trends. Top. Catal. 2002, 19, 101–109. 2. Bolm, C.; Beller, M. Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2004; Volume 1. 3. Brandsma, L. Synthesis of Acetylenes, Allenes and Cumulenes; Elsevier Academic Press: Amsterdam, The Netherlands, 2004. 4. Meijere, A.D.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim, Germany, 2004. 5. Tykwinski, R.R. Evolution in the Palladium-catalyzed cross-coupling of sp-and sp2-hybridized carbon atoms. Angew. Chem. Int. Ed. 2003, 42, 1566–1568. 6. Cassar, L. Synthesis of aryl-and vinyl-substituted acetylene derivatives by the use of nickel and palladium complexes. J. Organomet. Chem. 1975, 93, 253–257. 7. Dieck, H.; Heck, F. Palladium catalyzed synthesis of aryl, heterocyclic and vinylic acetylene derivatives. J. Organomet. Chem. 1975, 93, 259–263. 8. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett. 1975, 16, 4467– 4470. 9. Evano, G.; Blanchard, N.; Toumi, M. Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis. Chem. Rev. 2008, 108, 3054–3131. 10. Chinchilla, R.; Nájera, C. Recent advances in Sonogashira reactions. Chem. Soc. Rev. 2011, 40, 5084–5121. 11. Thorand, S.; Krause, N. Improved procedures for the palladium-catalyzed coupling of terminal alkynes with aryl bromides (Sonogashira coupling). J. Org. Chem. 1998, 63, 8551–8553. 12. Dieck, H.A.; Heck, F.R. Improved procedures for the palladium-catalyzed coupling of terminal alkynes with aryl bromides (Sonogashira coupling). J. Organomet. Chem. 1975, 93, 259–263.

Catalysts 2020, 10, 443 41 of 48

3. Conclusions In summary, Sonogashira cross-coupling is used for the synthesis of diﬀerent organic bioactive and pharmacologically important compounds. This review article highlighted the palladium and copper-based catalysts for Sonogashira cross-coupling. The Pd-Cu-catalyzed cross-coupling of terminal acetylenes with sp2-C halides is a broadly useful method for conjugated acetylenes. In particular, the search for more reactive and long-living catalysts for the aryl chlorides remains a challenging object for future research.

Author Contributions: Conceptualization, N.R. K.R., I.K.; Data curation, G.A., Ayesha Malik (A.M.), U.R.; software, I.K., S.A.A.S., K.R., N.M.N. writing—original draft preparation, I.K., Aqsa Mujahid (A.M).; U.R. K.R., N.R.; writing—review and editing, K.R., G.A., S.A.A.S.; visualization, N.R., U.R; supervision, N.R.; project administration, N.R. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

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