RSC Advances
Recent Advancements and Perspectives in Copper -catalysed Sonogashira Coupling Reactions
Journal: RSC Advances
Manuscript ID: RA-REV-03-2014-002529.R1
Article Type: Review Article
Date Submitted by the Author: 29-Apr-2014
Complete List of Authors: Thomas, Anns; Mahatma Gandhi University, School of Chemical Sciences Sujatha, Asha; Mahatma Gandhi University, School of Chemical Sciences Gopinathan, Anilkumar; Mahatma Gandhi University, School of Chemical Sciences
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Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE
Recent Advancements and Perspectives in Copper- catalyzed Sonogashira Coupling Reactions
Anns Maria Thomas, Asha Sujatha and Gopinathan Anilkumar*
5 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
C C bond formation using transition metal catalyzed Sonogashira coupling reaction is an indispensable tool in synthetic organic chemistry. Initially Pd complexes were used as catalyst; however advances in catalyst design fuelled the development of Cu catalysts, which are cheaper and more environmentally
10 benign than the Pd complexes. This is the first review reported so far dealing exclusively with Cu catalyzed Sonogashira coupling reaction. This review illustrates the current strategies and potentials of Cu catalyzed Sonogashira coupling reactions.
1. Introduction 40 Scheme 1. General representation of Pd/Cu-catalyzed Sonogashira coupling reaction Transition metal catalyzed reactions have evolved as a 15 versatile tool in organic chemistry during the last three decades The Sonogashira coupling reactions are carried out in a variety of because of easy carbon carbon bond formation which were used catalytic systems and reaction conditions. in the synthesis of many pharmaceuticals and agrochemicals. These reactions have many desirable features like mild reaction 2. Different catalytic systems for Sonogashira conditions, high efficiency and good functional group tolerance. 45 coupling 2 20 The Pd catalyzed cross coupling reactions between sp C halides Depending on the nature of the ligand present in the complex, the and terminal alkynes have been reported independently by Heck, catalyst systems are classified as discussed below. Cassar and Sonogashira in 1975. 1, 2 Heck and Cassar relied on Pd catalysts for coupling between sp 2 C halide and terminal alkyne, 2.1. Cu-Nitrogen complexes while Sonogashira utilized a combination of Pd and Cu catalysts. This is the most widely used catalytic system for Sonogashira 25 The Sonogashira Hagihara reaction involves the cross coupling 50 coupling reaction. Guo et al . in 2005 reported CuI reaction between an aryl halide (Cl, Br, I, OTf) and a terminal ethylenediamine catalyst system for the Sonogashira coupling of acetylene in presence of catalytic amounts of Pd complex, Cu I 3 7 aryl iodides and aryl bromides with aryl and alkyl acetylenes by salt and a base to form an aryl acetylene. A combination of 1 9 avoiding the use of toxic PPh 3. In the optimized reaction 10 mol% of Pd(PPh 3)2Cl 2 or Pd(PPh 3)4 and CuI as the catalyst condition, 10 mol% of CuI, 15 mol% of ethylenediamine and 2 30 system was generally used for the reaction. Owing to the high o 55 equivalents of K 2CO 3 were used in dioxane at 100 C (scheme 2). cost of Pd, the use of Sonogashira reaction in large scale Electron withdrawing and electron donating groups on the aryl production is restricted and consequently alternative catalyst 8 iodides and bromides were tolerated in the reaction affording systems are searched for. Thus replacing Pd with cheaper, more more than 80% yields for the iodides and 60 70% for the abundant and less toxic Cu has become an area of active research. bromides. 35 This review highlights the existing strategies and potentials of Sonogashira coupling reaction using Cu based catalysts as the sole catalyst system (without the use of Pd compounds) and covers literature from 2000 2013.
Pd-CuI catalyst R1X + HC CR2 R1C CR2 base
R1=aryl,vinyl; R2=aryl,alkyl
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CuI (10 mol%) Cu(OAc)2.H2O (10 mol%) NH 2 L (15 mol%) 2 2 L (20 mol%) PhN X + R R 2 2 K CO /dioxane X + R R 2 3 NH 1 TBAF, 14h 1 PhN 1 X = I, Br o 1 2 R R R 24h, 100 C R X = Br, I o L 130-135 C L
MeO (CH2)7CH3 O2N (CH2)7CH3 (CH2)5CH3 (X = I, 87%) (X = I, 95%) (X = I, 88%) (X = I, 94%) NO2
(X = Br, 62%) (X = I, 85%) (X = I, 93%) (X = I, 96%) O Scheme 2. Cu-catalyzed coupling reaction of aryl halides with terminal alkynes using ethylenediamine as ligand. (X = I, 85%) (X = Br, 57%) Venkataraman et al . utilized [Cu(phen)(PPh )Br] catalyzed 3 Scheme 5. Cu-catalyzed coupling reaction of aryl halides with terminal 5 coupling of electron rich and electron poor aryl iodides with alkynes using 1,4-diphenyl-1,4-diazabuta-1,3-diene . o phenyl acetylene in presence of K 2CO 3 in toluene at 110 C (scheme 3).10 They also used the methodology for the coupling of aryl acetylenes and ( Z) Methyl 3 iodoacrylate with complete 35 The deprotection of OAc group in propargylacetate was retention of stereochemistry using [Cu(bipy)(PPh 3)Br] as the observed during the coupling reaction (scheme 6). Although Cu II 10 catalyst. is a popular reagent for Glaser coupling of alkynes, no homo R1 coupling product was observed under the optimized reaction Cat. (10 mol%) conditions, arguably suppressing the oxidative homocoupling of 1 I R + K CO /toluene 40 alkynes. CO Me 2 3 2 o 8h, 110 C CO2Me Cu(OAc)2 (10 mol%) L (20 mol%) PhN R1 = Ph, 99% 1 I + R = 4-vinyl-Ph, 95% TBAF, 14h PhN 1 OAc OH R1 = 4-CN-Ph, 85% R = 2-CO Me-Ph, 77% 1 130-135 oC 1 2 R R L 1 1 N N R = 4-MeS-Ph, 91% R = 2-MeO-Ph, 98% Cu (R1 = 4-OMe, 68%) 1 1 1 R = 4-NH2-Ph, 90% R = n-Hex, 96% PPh3 Br (R = 4-NO2, 76%) Scheme 6. Deprotection of acetate group during Sonogashira coupling Catalyst. reaction. Scheme 3. Cu-catalyzed coupling reaction of terminal alkynes with (Z)- Methyl-3-iodoacrylate. Argon suppressed the Cu(II)acetate catalyzed reaction but I 45 favoured the Cu catalyzed reaction indicating that oxygen An inexpensive and environmentally friendly protocol for promotes the Cu(II)acetate catalyzed Sonogashira reaction. The 15 Sonogashira couplings of aryl halides with terminal alkynes was same authors then replaced the 1,4 diphenyl 1,4 diazabuta 1,3 introduced by Fu et al . in the presence of CuBr using 1,10 diene ligand with 4,6 dimethoxy 2 aminopyrimidine under phenanthroline as the ligand and tetrabutylammonium bromide essentially the same reaction condition used earlier (10 mol% of 11 (TBAB) as the phase transfer catalyst in water (scheme 4). o 50 Cu(OAc) 2 , 20 mol% of ligand, TBAF at 125 130 C without any solvent and in the presence of air) and observed that the coupling + CuBr/phen, TBAB X R2 R2 occurred in excellent yields for reaction between electron NaOH,H2O, 13 X=I,Br 120 oC,N , 24h deficient aryl iodides and aryl acetylenes. Aryl bromides and R1 2 R1 alkyl acetylenes afforded lower yields. The authors assume that 20 Scheme 4. CuBr/phen catalyzed Sonogashira coupling reaction. 55 the addition of pyrimidine ligand suppresses the oxidative 1,4 diphenyl 1,4 diazabuta 1,3 diene was used as a ligand in homocoupling of terminal alkynes. combination with catalytic Cu(OAc) 2 and TBAF for the Li and co workers further modified the catalyst system
Sonogashira coupling of aryl iodides and aryl bromides with (Cu(OAc) 2) by replacing the ligand with a coordinating solvent terminal alkynes without any solvent under aerobic conditions (Et 3N) and observed that aryl iodides and aryl bromides reacted 12 25 (scheme 5). Good yields of the products were obtained 60 with aryl and alkyl acetylenes in presence of 50 mol% of
irrespective of the nature of the substituents present in the Cu(OAc) 2 yielding good to excellent amounts of the cross substrates. Aryl bromides showed low reactivity, and a slight coupled products. 14 Electron donating and electron withdrawing increase in yield was observed when TBAF was replaced with groups in the aryl iodide component were used in the study. The TBAB or by increasing the catalyst loading. utility of this reaction is impeded by the requirement of 50 mol%
30 65 of Cu(OAc) 2 as the catalyst and the formation of homocoupling products from the terminal acetylene. Li and co workers applied the reaction conditions used by them in the CuI DABCO catalyzed Suzuki Miyaura coupling to Sonogashira reaction between aryl halide and a terminal alkyne,
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which afforded good to excellent yields of the coupling CuI (20 mol%) 15 L (20 mol%) products. Here 10 mol% of CuI, 20 mol% of DABCO and X + R2 R2 NHBn o K2CO3/DMF NHBn Cs 2CO 3 were used in DMF at 135 140 C (scheme 7). Substrates 1 R1 X = Br, I 140-145 oC R containing both electron donating and electron withdrawing L 5 groups were tolerated in the reaction. The protocol was successfully extended to alkyl acetylenes and vinyl halides.
CuI (10 mol%) (X = I, 2h, 75%) (X = I, 6h, 79%) DABCO (20 mol%) X + R2 R2 N OTHP N MeO Cs2CO3/DMF R1 X = Cl, Br, I R1 N o DABCO 20h,135-140 C (X = I, 20h, 75%) (X = I, 24h, 70%)
O2N MeO (CH2)7CH3 F3C
(X = I, 4h, 99%) (X = I, 9h, 94%) (X = I, 8h, 99%) (X = I, 8h, 85%)
NO2
O2N OMe
(X = I, 12h, 73%) (X = Br, 48h, 42%) (X = Br, 24h, 86%) (X = I, 20h, 99%)
OTHP Scheme 9. Cu-catalyzed Sonogashira coupling reaction using N,N’ - O2N MeO 25 dibenzyl BINAM as the ligand. (X = Cl, 18h, 55%) (X = I, 14h, 65%) Terminal alkynes containing heterocycles and sensitive groups (eg.OTHP) also gave the coupling product in good yields. Scheme 7. Cu catalyzed Sonogashira coupling reaction using DABCO as Aryl bromides also underwent the reaction; but their reactivity 10 the ligand. was found to be less compared to that of the iodo derivatives. 30 When the reaction condition was applied to o iodophenol, Two diphosphane ligands containing nitrogen donor groups Sonogashira coupling followed by intramolecular ring closure such as 2,5 bis(2 (diphenylphosphino)phenyl) 1,3,4 oxadiazole took place leading to benzofuran (scheme 8). However the (L 1) and 2,5 bis(2 (diphenylphosphino)5 methoxyphenyl) 1,3,4 corresponding aniline failed to undergo the ring formation and oxadiazole( L 2) were prepared and screened by Xu et al . for Cu 17 15 gave only the Sonogashira product. 35 catalyzed Sonogashira coupling reactions. They observed that ligands L 1 or L 2 in conjunction with Cu(MeCN) 4ClO 4 exihibit CuI (10 mol%) I better catalytic activity than the corresponding Cu(I) complexes 1 DABCO (20 mol%) 1 + R R L1Cu or L 2Cu (scheme 10). The reaction was found to be highly Cs2CO3/DMF O sensitive to the nature of substituents on aryl halides, alkynes and OH 24h,135-140 oC R1 = Ph (75%) 40 ligands. 1 R = C8H17 (82%) Ph O O CuI (10%) I DABCO (20%) + Ph O O Cs2CO3/DMF NH o 2 8h,135-140 C NH2 N N N N P P P P (89%) Scheme 8. Cu-catalyzed tandem Sonogashira-ring closure reaction using DABCO as the ligand. L1 L2 Sonogashira coupling between aryl iodides and terminal Cu(MeCN) ClO 20 alkynes was achieved by Sekar et al . using N,N ’ dibenzyl 4 4 16 X + BINAM CuI in the presence of K 2CO 3 (scheme 9). (5mol%) R1 R2 L1/L2 (5mol%) R1 R2 dioxane,K2CO3
Scheme 10. Sonogashira coupling reaction using diphosphane ligands.
Saito et al . reported a convenient method for the synthesis of 45 mechanically interlocked [2]rotaxanes by Sonogashira coupling mediated by a macrocyclic phenanthroline Cu(I) complex (scheme 11).25 Here the bond formation occurred selectively inside the macrocyclic ring. Phenyl acetylenes and aryl halides
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having bulky substituents were used as the substrate for CuI (5 mol%) PPh3 (15 mol%) synthesising the rotaxanes I + R2 R2 KOH/H2O o 1 K2CO3,Xylene R1 4-6h,140 C R + I 120 oC Macrocyclic ligand complex O2N MeO (4h, 95%) (4h, 93%) O
O2N (CH2)5CH3 O (6h, 94%) N S (6h, 47%) CuI N (4h, 89%)
O 35 Scheme 13. Cu-catalyzed coupling reaction of aryl halides with terminal alkynes in water. O Macrocyclic phenanthroline-Cu(I) catalyst Nishihara et al. introduced a direct method for the cross coupling reaction of alkynylsilanes with aryl halides using inexpensive and Scheme 11. Sonogashira coupling reaction using Macrocyclic readily available CuCl/PPh catalytic system in the presence of 5 phenanthroline-Cu(I) catalyst. 3 24 40 PhCO 2K additive (scheme 14). This protocol was found to be 2.2. Cu-Phosphorus complexes very useful for a broad range of targets including aryl , Phosphines are used as efficient ligands in combination with heteroaryl , and alkyl substituted alkynylsilanes and various many transition metals and are widely used in C C bond electron rich and electron deficient aryl iodides formation. This is particularly true in the case of Pd catalyzed CuCl (5 mol%) 18 PPh (5mol%) 10 coupling reactions. In 1993 Miura et al . reported a combination 3 R R R1 SiMe3 + R2 I 1 2 of CuI PPh system to achieve the coupling between aryl and PhCO2K (1 equiv) 3 o vinyl iodides with terminal alkynes .19 Another example where DMI,120 C,12 h 45 CuCl/PPh catalyzed Sonogashira coupling reaction. copper catalyst along with phosphorus ligand used in the Scheme 14. 3 Sonogashira coupling was reported by Venkataraman et al . Another unprecedented protocol for Sonogashira coupling I 15 wherein premade Cu complexes of the type Cu(phen)(PPh )Br 3 reaction was reported by Lee et al . employing Cu 2O/xantphos and Cu(neocup)(PPh 3)Br were used for aryl acetylene coupling catalytic system which tolerates a broad range of functional 20 reactions to afford excellent yields of the product (scheme 12). groups like enolizable ketones, esters,nitro groups, unprotected 40 50 amines, halides etc (scheme 15) . They have also demonstrated I for the first time that di ortho substituted aryl iodides can be used Cat (10 mol%) N N + Cu as a coupling partner in the presence of this catalytic system K CO /toluene 2 3 1 PPh3 Br o R R1 24h, 110 C Cu2O (1 mol%) Cat Xantphos (1 mol%) R H + Ar-I OMe R1 Ar O Cs2CO3,Dioxane R=aryl,alkyl 135 oC,
(71%) (85%)
MeO2C (89%) Scheme 12. Cu-catalyzed cross-coupling reaction of aryl iodides and O 20 phenyl acetylene using [Cu(phen)(PPh 3)Br ]. PPh2 PPh2 xantphos Venkataraman et al . further extended the work to o iodophenols and terminal acetylenes using [Cu(phen)(PPh 3)2]NO 3 Scheme 15. Sonogashira coupling reaction in the presence of Xantphos as the copper source which led to the formation of benzofuran 55 ligand derivatives via a tandem Sonogashira cyclization reaction. 21 The 2.3. Cu-Oxygen complexes 25 use of Cu(II) PPh 3 in Sonogashira reaction has also been reported. 22 Oxygen containing ligands together with transition metals Interestingly, simple Sonogashira coupling in water has been were also used in catalysis for coupling reactions.26 In particular, reported by Liu et al . using CuI and PPh 3 using KOH as the base o 23 Cu oxygen complexes found application in C C bond at 140 C (scheme 13). This procedure was found to be 27 60 formation. Sonogashira coupling using Cu(acac) 2 and 1,3 30 compatible with both electron donating and electron withdrawing diphenylpropane 1,3 dione as the ligand in DMF was reported by groups on the aryl iodide. Aliphatic terminal alkynes were also Taillefer et al (scheme 16).28 Aryl iodides having electron found to be suitable for this reaction. withdrawing groups on reaction with phenyl acetylene or hexyl
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acetylene afforded good to excellent yields of the product at 90 40 iodide. Aliphatic alkynes are also suitable substrates for this oC while iodobenzene and aryl iodides containing electron transformation. donating substituents required higher temperature (120 oC) to get CuI (10 mol%) O moderate to excellent yields . L (30 mol%) X + R2 R2 OH 1 N R K2CO3/DMF R1 o HCl Cu(acac)2 (10 mol%) 24h, 100 C L L (30 mol%) O OMe I + R2 R2 K2CO3/DMF O Cl 1 R1 90-120 oC R (X = Br, 94%) (X = I, 82%)a L O NC O N (CH ) CH Cl 2 2 5 3 N (X = Br, 70%) (24h, 96%)a (30h, 83%)a (X = Br, 60%) F H (CH2)4CH3 MeO (CH2)5CH3
(40h, 63%)b (40h, 65%)b (X = I, 75%) (X = Br, 64%) a: reaction temp. 90 oC. a: reaction time 36h. o 5 b: reaction temp. 120 C.
Scheme 18. Cu catalyzed Sonogashira coupling reaction using N,N Cu(acac) -catalyzed Sonogashira coupling reaction using 1,3- Scheme 16. 2 45 dimethylglycine as ligand . diphenylpropane-1,3-dione as the ligand.
Mao et al . reported CuBr catalyzed Sonogashira cross Later the same group succeeded in extending the above protocol 10 coupling reaction of aryl iodides with aryl and alkyl acetylenes in the presence of rac BINOL and Cs CO to afford low to to vinyl iodides leading to the synthesis of conjugated enynes at a 2 3 32 moderate yields. 29 lower temperature (scheme 19). They also found that the geometry of the olefin part was preserved during coupling. An efficient, and inexpensive CuCl 2/salicylic acid catalytic system for Sonogashira coupling reaction was developed by Chen R 15 et al. for the cross coupling reaction of haloarenes and R I iodoheteroarenes with terminal alkynes under mild reaction 1 CuI/N,N-dimethylglycine R1 conditions to products in 18 95% yields (scheme 17).30 Here, + R H CS CO ,dioxane, 80 oC R R 2 3 R R Salicylic acid acts as a bidentate donor ligand to activate the 50 2 3 R=alkyl, aryl 2 3 catalytic reactivity of copper chloride in the coupling reaction. Scheme 19. Aminoacid catalyzed Sonogashira coupling reaction 20 Substituted aryl iodides and heteroaryl iodides reacted effectively with terminal alkynes affording the corresponding aryl alkynes in Cu catalyzed Sonogashira reaction of o iodoacetanilide with high yields. alkynes at RT was achieved using N methylpyrrolidine 2 carboxamide ligand. 33 Here 30 mol% of CuI and one equivalent CuCl2(20mol%) Ar' Ar Ar' 55 of ligand were used along with 2.5 equivalents of Cs 2CO 3 in ArX + Salicylic acid(20mol%) or DMF at RT (scheme 20). or Cs2CO3,DMF Ar=aryl,or heteroaryl o Ar R R 130 C H X=I,Br 2 CuI (30 mol%) H N R N R2 L (100 mol%) NHMe.HCl O + R3 Cs CO O N 1 X 2 3 H O 25 Scheme 17. CuCl 2/salicylic acid-catalyzed Sonogashira-type cross- R R1 X = I, Br DMF, RT 3 L coupling reaction . 2 R R = CF3, Me CO Me H 2 H 2.4 Cu-N and O bidentate ligand Complexes N CF H N CH 3 N CF 3 3 O O O The CuI/ N,N dimethylglycine catalyst system developed by I (CH ) CH Ph 30 Ma et al . has been successfully applied in the Sonogashira 2 5 3 Ph coupling in the absence of palladium and phosphine. 31 Thus a (X = I, 71%) (X = I, 83%) (X = I, 93%) H H variety of aryl bromides/iodides reacted with terminal alkynes in N Me H N CF3 N CF the presence of CuI, N,N dimethylglycine:hydrochloride and 3 O O O K2CO 3 affording products with yields ranging from 60 99% Et 35 (scheme 18). Both electron rich and electron deficient aryl Ph OH iodides gave excellent yields while aryl bromides required a (X = I, 60%) (X = I, 78%) (X = Br, 27%) higher catalyst loading (20 mol% of CuI, 60 mol% of N,N Scheme 20. Cu-catalyzed Sonogashira coupling reaction of o- dimethylglycine). Functional groups such as –Cl, F, NO 2, iodoacetanilides using N-methylpyrrolidine-2-carboxamide as ligand. alkoxy, ester, ketone and pyridyl were tolerated on the aryl 60 In the case of o diiodoacetanilide, both the o positions could be
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substituted with alkynes. The o bromoacetanilides showed lower inexpensive and moisture stable catalytic system for Sonogashira reactivity towards coupling with alkynes under this condition. coupling (scheme 23).36 Besides acting as an OH functionalised Reusable sulfonato Cu(II) (salen) complex was reported as a new 35 ligand, choline chloride also acted as a tetraalkylammonium salt, catalytic system for the alkynylation of aryl iodides with terminal that supported and stabilised the Cu(I) species during the 5 alkynes in water under aerobic conditions by Zhou et al (scheme reaction. This catalytic system was found to be effective in the 21) .34 It was demonstrated that aryl halides with electron reaction of phenylacetylenes with a variety of aryl halides. Very withdrawing groups gave excellent yields of the product good yields were obtained when aryl halides substituted with compared to electron rich aryl iodides and the reaction was also 40 electron withdrawing groups were used. found to be sensitive to steric effects. 20 mol%[ChCl][CuCl] I X + TBAB (20 mol%) R1 o DMF,KOH,140 C,N2 catalyst (10mol%) R R + R2 R2 R1 X NaOH(1 .0 equiv) X + H O, 100 oC,24 h X=C,N 2 N - HO CuCl2
[ChCl][CuCl] N N Cu Scheme 23. Choline chloride/CuCl catalyzed Sonogashira coupling. NaO3S O O SO3Na 2.5. Cu nanoparticles
10 Catalyst 45 Cu nanoparticles show remarkable catalytic activity due to Scheme 21. Sonogashira coupling catalyzed by reusable sulfonato-Cu(II) (salen) complex. their high surface to volume ratios. Rothenberg et al . utilised heterogeneous copper nanoclusters for the palladium and Mao and co workers developed an interesting bifunctional phosphine free Sonogashira coupling of phenyl acetylene and aryl catalyst systems using 8 hydroxyquinoline which could attach halides. 37 High yields were obtained when tetrabutylammonium o 15 both the electrophilic and nucleophilic substrates through two 50 acetate (TBAA) was used as the base in DMF at 110 C. Electron different parts. 35 They found that this catalytic system is deficient aryl halides afforded excellent yields.
applicable for the coupling of a broad range aryl halides and Li et al . developed a reusable Cu 2O/PPh 3/TBAB system for heteroaryl halides with terminal alkynes (scheme 22). A variety the cross coupling reaction of aryl and heteroaryl halides with of aryl iodides can be successfully used in this reaction and for terminal acetylenes under neat conditions (scheme 24).38 Among
20 aryl bromides a higher reaction temperature and a longer reaction 55 the four different types of Cu 2O used, the Cu 2O nanoparticles time is required to get satisfactory results. They succeeded in were found to be the best when used in presence of PPh 3 and extending the protocol to arylchlorides by adding TBAB as an TBAB. Both electron rich and electron poor aryl halides reacted additive. Furthermore when 1,4 dibromobenzene was used as the with alkynes having aryl, hetero aryl and alkyl groups in the
substrate only mono substituted product was formed. presence of octahedral Cu 2O nanoparticles without loss of 60 activity for 4 runs. For aryl bromides and chlorides, octahedral CuI (10 mol%) 8-hydroxyquinoline (20 mol%) Cu 2O afforded the coupling products; albeit in low yields. Ar-X + Ph Ph Ar o Heteroaryl bromides and chlorides also gave moderate yields Cs2CO3,DMF, 110-130 C,Ar X=I,Br,Cl with alkynes. Ar=aryl, heteroaryl
N O Cu N O
Cu-8-hydroxyquinoline bifunctional catalyst system 25 Scheme 22. Sonogashira coupling using bifunctional catalyst system
They also designed another bifunctional catalytic system by combining 1,10 phenanthroline with BINOL and applied for the coupling between 4 iodoanisole and phenylacetylene giving good 30 yields of the product.
Very recently Choline Chloride/CuCl has been reported as an
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Cu O (10 mol%) 2 35 catalyzed Sonogashira coupling of aryl iodides and aryl X + R2 PPh3 (20 mol%) R2 acetylenes under microwave irradiation was reported by He et al .
TBAB/K CO 1 wherein the substrates were subjected to MW irradiation in R1 X = I,Br,Cl 2 3 R 135-140 oC presence of Cs 2CO 3 and in the absence of any ligands affording 42 OH 43 87% yields of the products (scheme 26). O N 2 CuI (10 mol%) Cs CO /NMP (X = I, 20h, 95%) (X = I, 24h, 88%) I + 2 3
1 2 MW, 2-6h 1 2 NH2 R R R R N N MeO t-Bu OMe (X = I, 24h, 50%) (X = Br, 36h, 40%) (4h, 76%) NC OMe N N O N (2h, 71%) 2 EtO2C OMe (X = Br, 24h, 83%) (X = Cl, 30h, 83%) (2h, 54%) t-Bu NH2 N N F a OMe OMe (2h, 78%) N S t-Bu N (X = Br, 24h, 46%) (X = Br, 36h, 43%) t-Bu (2.5h, 87%)
(4h, 79%) a: N-arylation product was also formed in 10%. Scheme 24. Cu catalyzed Sonogashira coupling reaction using Cu 2O 40 nanoparticles
Scheme 26. Cu-catalyzed Sonogashira coupling reaction under 5 3. Sonogashira coupling under ligandless conditions. microwave irradiation.
3.1. Inside-out core–shell architectures (Cu 2O@Cu) No specific influence of electronic effects on the reactivity Catalytic species with a Cu O core and a Cu shell, which are 2 45 of acetylenes or aryl iodides was noticed in this reaction. Ester in contrast to the normally reported Cu 2O outside structure and acetyl groups on the aryl iodide gave lower yields of the 39 (Cu@Cu 2O), were reported by Varma et al . in 2012. They coupling product presumably due to decomposition under the 10 successfully employed the Cu 2O@Cu composite in Sonogashira basic reaction condition. The reaction was found to be sluggish coupling reaction of aryl iodides with phenyl acetylenes and for aryl bromides. Phenyl acetylene containing an NH 2 group found that biaryl acetylenes could be produced with excellent 50 gave in addition to the Sonogashira coupling product, an N yields (85–94%) in the absence of Pd and ligand (scheme 25). arylated product as well in small amount. Alkyl alkynes are inert Moreover, different functional groups such as –COMe, –NO 2, to this reaction. 15 and –OMe were found to be compatible with the reaction In 2002 Wang et al . reported a Cu catalyzed microwave conditions. The recovered Cu 2O@Cu after reaction still could assisted Sonogashira coupling between electron rich/electron keep the core–shell structure, implying the good stability of the 55 deficient aryl acetylenes and aryl iodides in presence of CuI, PPh 3 composition. The recovered catalyst could also be reused. 43 and K 2CO 3 in DMF.
Cu2O@Cu Cu catalyzed Sonogashira reaction in polyethyleneglycol 44 K2CO3 (PEG) under microwave irradiation has also been reported. ArI Ph + Ar Ph PEGs of different molecular weight were studied in presence of DMF,110 oC 60 CuI to produce low to moderate yields of the products. 20 Scheme 25. Sonogashira coupling reaction using Cu 2O@Cu composite Sonogashira cross coupling reaction catalyzed by Cu salt 3.2. Supported Cu catalysts under microwave irradiation in water was recently reported by An interesting ligand free supported copper precatalysts for Chen and co workers; however a stoichiometric amount of Sonogashira coupling reaction was reported by Biffis et al .41 tetrabutylammonium bromide was required for achieving 45 They developed Cu(II) oxide and Cu metal highly dispersed on 65 satisfactory yields. The synergic effect of Fe and Cu salts was 25 alumina, which can be used as a precatalyst for Sonogashira utilised by Vogel et al. in Sonogashira coupling wherein aryl coupling reaction of aryl iodides with electron rich alkynes like iodides reacted with terminal alkynes in the presence of
arylacetylenes. Eventhogh the substrate scope of the reaction is Fe(acac) 3, CuI and Cs 2CO 3 in DMF or NMP affording good to limited, it represent a novel class of solid easy to handle catalytic excellent yields. 46 Microwave irradiation of the reaction mixture system that allows a simpler product recovery. 70 reduced the reaction time manifold.
30 4. Sonogashira coupling under microwave irradiation 5. Mechanism In recent years, microwave assisted rate acceleration technology has evolved as a powerful tool in organic synthesis, Although a great deal of progress has been achieved in because of the manifold advantages such as milder reaction improving the reaction conditions and designing ligands for the conditions, faster reaction and enhanced selectivity. Copper Cu catalyzed C C bond forming reactions, the mechanistic 75 aspects on the intricate details with which the reactants and
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catalysts go through still remains elusive and lacks sufficient [Cu(DMEDA)2]Cl2.H2O I R R R1 experimental proof. Based on different mechanistic studies it is R1 DMEDA, Cs2CO3 o assumed that the Cu(I) salts first reacts with terminal alkynes to 35 dioxane, Ar, 135 C Sonogashira coupling using Cu-DMEDA complex form a Cu(I) acetylide species which then undergoes oxidative Scheme 28. 5 addition with aryl halide followed by decomposition to give the required product. A mechanism was proposed for this reaction based on Wang et al . in 2002 put forward a catalytic cycle for kinetic measurements and DFT calculations (scheme 29).48 Sonogashira coupling reaction under microwave irradiation. 43 In N the first step, the terminal acetylene reacts with CuI PPh 3 in the 10 presence of a base to form the organometallic compound. The N Cu highly reactive organometallic compound then enters the cross N N [ Cu R']n R' coupling reaction with iodoarene to give aryl alkynyl derivative Resting state R2X of Cu PPh 3. This derivative is unstable and can easily regenerate the CuI and PPh 3 through reductive elimination. Cs-X 15 The mechanism of Cu catalyzed Sonogashira coupling in presence of 1,3 diphenylpropane 1,3 dione ligand was reported R1 by Taillefer et al. 28 They proposed that the ligand coordinated to
copper salt forms the catalytic species in this reaction (scheme N R2 27). In the first step the deprotonated alkyne reacts with Cu(I) H R' N Cu X 20 diketone ligand complex to generate the Cu(I) acetylide + Cs CO intermediate. This then undergoes oxidative addition with aryl 40 2 3 iodide to form a four coordinated Cu III complex, which may exist Scheme 29. Mechanism proposed by Bolm et al. for Cu-catalyzed Sonogashira coupling reaction. either as neutral or cationic form. Then reductive elimination occurs expelling the cross coupled product. The resting state of the catalyst is assumed to be a polymeric [Cu] precursor complex [Cu(phenylacetylene)] n that is in equilibrium with an 45 active monomeric catalyst. The DMEDA ligand activates the
Ph resting state by dissolving the [Cu(phenylacetylene)] n polymer O and forming a soluble [Cu (DMEDA)(phenylacetylene)] Ph - =LX complex. This complex reacts with the aryl halide, which results
O O K2CO3 in coupling leading to C C bond formation and generation of I + Ph Cu 50 [Cu(DMEDA)(I)] complex. The R H O S Ph S [Cu(DMEDA)(phenylacetylene)] complex, which is proposed to Ph R be the active state of the catalyst, is regenerated through KHCO3 + KI transmetallation with Cesium phenyl acetylenate. + S Saito et al . proposed a mechanism for the formation of 25 Ph 55 [2]rotaxanes by Sonogashira coupling . Alkynes in the presence - K+ of base form a Cu(I) acetylide complex upon which aryl iodide O I gets added oxidatively and forms a Cu(III) complex (scheme 30). Cu S The oxidative addition is accelerated by the presence of a ortho III O S Cu Ph R carbonyl group. Finally reductive elimination occurs and a new I KLX+S 60 C C bond is formed. Ph R or PhI+ S KI + - + S I + K2CO3 III KLX KHCO Cu 3 I S 25 Ph R CuI Cu Scheme 27. Mechanism of Sonogashira coupling reaction proposed by Taillefer et al .
A similar mechanism was suggested by Nishihara et al . for the 24 CuI coupling between alkynylsilanes with aryl halides. Cu 30 Bolm et al . reported an efficient catalytic system for Sonogashira Hagihara type reactions. 47 They were successful in carrying out the coupling reactions between various aryl iodides -CuI and terminal aryl alkynes using [Cu(DMEDA) 2]Cl 2.H 2O as a demetallation catalyst precursor and Cs 2CO 3 as base in dioxane (scheme 28). Rotaxane Scheme 30. Mechanism for the synthesis of rotaxane proposed by Saito et al .
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A mechanism for Cu II catalyzed Sonogashira coupling under I aerobic condition was proposed by Li et al .13 based on Miura 19 Ph and Rothenberg 37 involving a four centered transition state for OH O active Cu catalyst. Subsequent consecutive oxidative addition and 5 reductive elimination afford the required arylacetylenes as the Cu2O (1 mol%) product. Xantphos (1 mol%)
Cs2CO3,Dioxane 6. Applications 135 oC, 8h Ph
I C C bond formation using transition metal catalysis finds O OH application in a wide variety of areas such as pharmaceuticals, R 49 R 10 agrochemicals, organic synthesis etc. Most of these coupling R 45 R reactions were achieved by Pd catalysis. Sonogashira coupling Scheme 32. Synthesis of benzofurans and isobenzofuran derivatives reaction using Pd and Cu catalyst were used for the synthesis of aryl acetylenes. Now a days Sonogashira coupling using Cu Another interesting one pot method for the synthesis of catalyst alone is an emerging field. Some cascade reactions biologically active nitrogen heterocycles like isoquinoline and 15 combining Sonogashira coupling leading to heterocycles has also pyridine was developed by Ray et al. employing 1,10 53 been reported. Thus Venkataraman et.al reported an interesting 50 phenanthroline as the ligand. Here the reaction between one pot synthesis of 2 arylbenzo[ b]furans 21 ; the core structure is terminal alkyne and substituted aromatic o-bromoaldehyde prevalent in some natural products and the compounds show afforded isoquinoline derivatives as the product while the important biological activities, 50 like anticancerous, 51 antifungal 52 reaction between terminal alkynes and non aromatic β- 20 etc. The traditional methods for the synthesis of benzo[ b]furans bromoaldehyde gave pyridines and dihydro isoquinoline have limited functional group tolerance and require multistep 55 derivatives (scheme 33). reactions. In Venkataraman’s method benzo[ b]furan derivatives
were prepared from o iodophenols and aryl acetylenes using
R1 [Cu(Phen)(PPh 3)2]NO 3 as the catalyst and Cs 2CO 3 as the base in R1 R 25 toluene (scheme 31) . R2 Br 4 CuI/1,10-Phenanthroline R2 R4 + 10mol%[Cu(Phen)(PPh3)2]NO3 o I Et3N, NH3, DMF, 95 C N Cs2CO3(2equiv) R3 CHO R3 + HO o Toluene,110 C O R Br R4 R R' R' CuI/1,10-Phenanthroline + N N C Et N, NH , DMF, 95 oC CHO 3 3 O O O Scheme 33. Synthesis of isoquinoline and pyridine derivatives. 91% O 96% Ma et al. utilized CuI/L Proline catalytic system for the
60 Scheme 31. Synthesis of 2-arylbenzofurans using [Cu(Phen)(PPh3)2]NO 3 synthesis of indole derivatives which are prevalent in biologically as the catalyst. active natural products from 2 bromotrifluoroacetanilides and terminal alkynes. 32 The ortho substituent effect directed by – 30 Here both electron rich and electron deficient arylacetylenes NHCOCF group plays a key role in this transformation and o iodophenols reacted effectively affording the 3 corresponding benzo[ b]furans in excellent yields. This procedure (scheme 34). The reaction was applied to substrates having avoids the use of expensive and air sensitive additives. It was also 65 both electron rich and electron deficient functional groups found that arylacetylenes containing alkene as the substituent and aromatic and aliphatic alkynes; however with simple 35 gave the coupling products in good yields without the formation aliphatic alkynes, only low yields were obtained. of Heck coupling products, which would be observed if a Pd catalyst was used. Mao et al reported that bifunctional Cu catalyst can also be used for this reaction, but it require slightly higher temperature. 35 40 Benzofurans and isobenzofurans can also be synthesized through a 5 exo-dig cyclization in one pot method introduced by Lee et al (scheme 32).40
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CuI (2 mol%) Scheme 35. Application of Sonogashira coupling in natural product Br R L-Proline (6 mol%) R + R' synthesis R' K CO , DMF, 80 oC N 2 3 H NHCOCF3 7. Summary and Outlook R=alkyl, aryl Sonogashira coupling reaction is an important Et Cl 20 transformation in organic synthesis for the production of
N N important compounds including heterocycles, natural products H H and pharmaceuticals. Since its discovery in 1975, significant 94% Cl 76% improvements have been made in the reaction conditions. The pioneering work used Pd as catalyst, which is toxic and MeO 25 expensive, and consequently initiated the search for an alternative catalytic system. In this context Cu emerged as a new catalyst, N OTHP MeO C N OTHP H 2 H which is abundant and cheap. Today Cu catalyzed Sonogashira 84% 72% coupling reaction is an indispensible tool in synthetic organic Scheme 34.Synthesis of indole derivatives via Sonogashira coupling chemistry. The recent advances discussed herein illustrate the reaction 30 potential of this chemistry. The common catalytic system uses I The catalyst system developed by Zhou et al. 34 was Cu in the presence of P, N and O ligands. However scant reports are available using Cu II salts and reactions in solvent free, ligand 5 successfully applied in the synthesis of biologically active 2 –aryl indoles by a cascade process with 2 iodoanilines and terminal free and in aerobic conditions. Limited reports are available dealing with the mechanistic aspects of this reaction. Further alkynes.The recycled catalyst was reused giving excellent yields 35 efforts to study the mechanism and to extend the application of of the product. this protocol are still going on. Sonogashira coupling has also been used for the total Acknowledgement: GA thanks the Kerala State Council for 10 synthesis of naturally occurring phthalides (±) herbaric acid and (±) (4 methoxybenzyl) 5,7 dimethoxyphthalide from terminal Science, Technology and Environment, Trivandrum (Order No. alkynes and 2 iodobenzoic acid derivatives via 5 exo dig 341/2013/KSCSTE dated 15.03.2013) for financial support. cyclisation with high stereo , regio and chemoselectivities 40 School of Chemical Sciences, Mahatma Gandhi University (scheme 35).54 Kottayam, Kerala, India, 686560 MeO COOH Tel: +91481 2731036, Fax: (+91 481 2731009) E-mail: [email protected] MeO I . 45 OEt CuI(20 mol%) or OTHP OEt K2CO3(3equiv), DMF OMe 80 oC,16h O O MeO MeO O O MeO MeO 50 OH OMe
O O HO MeO O O HO OH MeO (±)-herbaric acid OMe (±)-(4-methoxybenzyl)-5,7- 15 dimethoxyphthalide
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Am. Chem. 2011. Currently she is doing her doctoral research in Cu-catalyzed Soc. , 1999, 121 , 669 685. coupling reaction under the guidance of Dr. G. Anilkumar in School 28. F. Monnier, F. Turtaut, L. Duroure and M. Taillefer, Org. Lett. , 2008, 10 , 3203 3206. of Chemical Sciences, Mahatma Gandhi University 30 29. J. Mao, J. Guo and S. J. Ji, J. Mol. Catal. A: Chemical , 2008, 284 , 85 88. 30. H. J. Chen, Z. Y. Lin, M. Y. Li, R. J. Lian, Q. W. Xue, J. L. Chung, S. C. Chen and Y. J. Chen, Tetrahedron , 2010, 66 , 7755 7761. 35 31. D. Ma and F. Liu, Chem. Commun. , 2004, 1934 1935. 32. F. Liu and D. Ma, J. Org. Chem. , 2007, 72 , 4844 4850. 33. H. Jiang, H. Fu, R. Qiao, Y. Jiang and Y. Zhao, Synthesis , 2008, 2417 2426. 34. L. Yu, X. Jiang, L. Wang, Z. Li, D. Wu and X. Zhou, Eur. J. 90 Asha Sujatha was born in Kerala, India, in 1988. She received her 40 Org. Chem. , 2010, 5560 5562. B.Sc. degree from Mahatma Gandhi University (Assumption 35. M. Wu, J. Mao, J. Guo and S. Ji, Eur. J. 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Liu, Y. Hu, B. Wei and L. Kang, Synth. Commun. , 2002, 32, 1937 1945. 44. E. Colacino, L. Daïch, J. Martinez and F. Lamaty, Synlett , Gopinathan Anilkumar was born in Kerala, India and took his Ph. D 2007, 1279 1283. 100 in 1996 from Regional Research Laboratory, Trivandrum with Dr. 60 45. G. Chen, X. Zhu, J. Cai and Y. Wan, Synth. Commun. , 2007, Vijay Nair. He did postdoctoral studies at University of Nijmegen, 37, 1355 1361. Netherlands, Osaka University, Japan, Temple University, USA 46. C. M. Rao Volla and P. Vogel, Tetrahedron Lett. , 2008, 49, 5961 5964. and Leibniz-institüt für Katalyse, Rostock, Germany. He was a 47. E. Zuidema and C. Bolm, Chem. Eur. J. , 2010, 16, 4181 4185. senior scientist at AstraZeneca (India). Currently he is an 65 48. L. H. Zou, A. J. Johansson, E. Zuidema and C. Bolm, Chem. 105 Associate Professor in Organic Chemistry at the School of Eur. J. , 2013, 19, 8144 8152. Chemical Sciences, Mahatma Gandhi University in Kerala, India. 49. J. Tsuji, Transition Metal Reagents and Catalysts: Innovations His research interests are in the areas of organic synthesis, in Organic Synthesis , John Wiley & Sons, 2002. medicinal chemistry and catalysis, particularly on Ruthenium, Iron, 50. D. M. X. M. Donnelly, M. J, in Comprehensive Heterocyclic Zinc and Copper catalyzed reactions. 70 Chemistry , ed. A. R. Katritzky, Rees, C. W, Pergamon Press: Oxford, 1984, vol. 4, pp. 657 712. 110
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Recent Advancements and Perspectives in Copper-catalyzed Sonogashira Coupling Reactions
Anns Maria Thomas, Asha Sujatha and Gopinathan Anilkumar*
The review highlights the orgin, development, mechanistic insights and recent applications of Cu- catalyzed Sonogashira coupling reactions.