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Recent developments and applications of Cadiot-Chodkiewicz reaction K. S. Sindhua, Amrutha P. Thankachana, P. S. Sajithaa, Gopinathan Anilkumara* Received 00th January 20xx,

Accepted 00th January 20xx The classical heterocoupling of a 1-haloalkyne with a terminal alkyne catalyzed by copper salts in the presence of a Manuscript base for the synthesis of unsymmetrical diynes is termed as Cadiot-Chodkiewicz coupling reaction. The diynes are of DOI: 10.1039/x0xx00000x great importance due to their biological, optical and electronic properties. A number of modifications were developed recently to improve the efficiency of Cadiot-Chodkiewicz coupling reactions in terms of selectivity and www.rsc.org/ yield. This is the first review on Cadiot-Chodkiewicz cross-coupling reaction which highlights the modern approaches and protocols developed for the synthesis and applications of unsymmetrical 1,3-diynes.

1. Introduction Chodkiewicz cross-coupling reaction, we outline the The transition metal catalyzed reactions have turned out to be developments, mechanism and modifications of the reaction the most powerful tools in organic synthesis during the past 1 along with its synthetic applications. several decades. The metal catalysts are widely used to Accepted

assemble carbon–carbon bonds between appropriately R 2 3 functionalized sp, sp , or sp centers. Alongside the vast 2 R R Glaser coupling developments in Pd-catalyzed cross coupling reactions, Cu(I) salt, Base 3 advances were being made in the arena of copper-mediated O2, solvent

catalysis also. Recently Cu salts have achieved particular R success in performing a number of transformations in good R R Glaser- Eglinton coupling Cu(OAc)2, pyridine yields, while maintaining low loading, mild reaction conditions R 1 and high functional group tolerance.2 Cu-promoted coupling R reactions have a longer history of about 150 years. Historically, Cu(I) salt, TMEDA R R Glaser- Hay coupling O2, solvent

it began in 1869 when Carl Glaser reported the air oxidation of Chemistry Cu(I)phenyl acetylide to diphenyldiacetylene via dimerization.3 Br R1 4 The most important methods towards the synthesis of R R1 Cadiot–Chodkiewicz coupling Cu(I) salt, Base 5 symmetrical diynes are still the Glaser oxidative acetylenic solvent 4 5 coupling , and its modified reactions such as the Eglinton and Scheme 1 The Glaser coupling modifications and Cadiot-Chodkiewicz coupling reaction the Hay coupling reactions.6 The synthesis of unsymmetrical diynes is more challenging than that of the symmetrical diynes in terms of reactivity and selectivity. These 1,3-diynes are very 2. The Classical Cadiot-Chodkiewicz coupling important in synthetic organic chemistry and are common reaction structural motifs of a large variety of biologically active molecules and supramolecular materials.7 The most commonly In 1955, Cadiot and Chodkiewicz reported the first copper(I)- used procedure for the preparation of unsymmetrical diyne catalyzed coupling of bromoalkyne 6 with 2-Methyl-but-3-yn- 8 and polyyne compounds is the Cadiot-Chodkiewicz reaction 2-ol 7 (Scheme 2). Later, the C(sp)-C(sp) coupling of (Scheme 1). The copper-catalyzed cross-coupling reaction haloalkynes with terminal alkynes for the synthesis of Biomolecular between terminal alkynes and haloalkynes is termed the unsymmetrical diynes is termed as the Cadiot-Chodkiewicz Cadiot-Chodkiewicz reaction.8 This reaction is known since the coupling reaction. Here, the procedure requires three & middle of the 1950s in which the terminal alkyne acts as the components to achieve a selective cross-coupling product, an nucleophile and the 1-haloalkyne acts as the electrophile in alkynyl halide, an alkyne and a copper source in stoichiometric the presence of an amine base. To the best of our knowledge, or catalytic quantities. Usually Cu catalysts along with an no review has so far been written specifically on this powerful amine, mostly, hydroxylamine, are used in this protocol and and traditional reaction.9 In this first review on Cadiot- the reaction is generally carried out at room temperature.

a. School of Chemical Sciences, Mahatma Gandhi University, PD Hills P O., Kottayam INDIA-686 560. Fax: +91-481-2731036 E-mail: [email protected] Organic

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OH (CH2)2OH Me H 10 Me 7 10 mol% CuI OH C5H11 Br C5H11 (CH2)2OH CuCl (1-2 mol%) Base, 20 oC Br Me 9 11 NH2OH.HCl Me EtNH2/H2O,RT 8 Base Time Isolated yield (%) 6 Et N 24h 20 Scheme 2 The classical Cadiot-Chodkiewicz coupling reaction 3 Et2NH 7h 35 BuNH2 6h 54 The relatively high yields, low cost of catalyst, wide substrate i-Pr2NH 3h 25 scope, and mild reaction conditions are the advantages of this pyrrolidine 15 min 95 reaction. Eventhough the reaction is successful in many Scheme 3 The Cadiot-Chodkiewicz coupling reaction in presence of different bases situations, the major limitation of this reaction is that sometimes the reaction suffers from reduced selectivity, yield As expected, chloroacetylenes in presence of pyrrolidine as Manuscript and the formation of a significant amount of homocoupling base showed lower reactivity and the corresponding iodides byproducts when the alkynes are bulky or when the electronic worked well. Even alkynols, which usually give the properties of the substituents attached to the reactants are homocoupled product, also worked smoothly. 10 similar. Excess of terminal alkynes are usually required to reduce the homocoupling and specific amines should be used b. Addition of co-catalysts as solvent. Often the coupling partners or precursors of The efficiency and scope of the hetero coupling reactions 11 bromoalkynes are not much stable also. The reactivity of were improved further using Palladium catalysts along with bromoalkynes can be enhanced by using oxygen substituted Cu(I) salts.14 Moreover, efficient heterocoupling of iodo and 12 bromoalkyne moieties. To overcome these challenges, many chloroalkynes took place in presence of Pd co-catalysts. In Accepted alternative methods have been explored. 1991, an improved CuI-catalyzed cross-coupling reaction of alkynyl iodides and terminal alkynes was reported by the 15 addition of a Pd(PPh3)2Cl2 co-catalyst. Thus, 3-Hydroxy-1- 3. Modification of Cadiot-Chodkiewicz coupling iodopropyne 12 when coupled with phenyl acetylene 13 in reaction presence of CuI, Pd(PPh3)2Cl2 and diisopropylamine in THF Due to the importance of unsymmetrical 1,3-diynes, several afforded the corresponding diyne 14 in 79% yield (Scheme 4). research groups worked on the coupling of acetylenic This procedure is catalytic in both Pd and Cu (3 mol %) and precursors and many attempts have been made to invent mild, provides high yields. Moreover, the homocoupling product efficient and highly selective methods for the cross-coupling of was obtained in negligible amount. alkynes and haloalkynes utilizing various catalytic systems and Pd(PPh3)2Cl2 (3 mol%) Chemistry solvents. HO CuI (3 mol%) Various factors such as nature of the base and the alkyne, I + Ph HO iPr2NH, THF Ph solvent, reaction time and temperature affect the efficiency of 12 13 RT, 1.5 h 14 heterocoupling reactions. A number of modifications are 79% reported for these coupling reactions. These variations are Scheme 4 Cu/Pd-catalyzed coupling of 3-hydroxy-1-iodopropyne with phenyl acetylene helpful in suppressing the formation of the unwanted homocoupled products. Later a similar protocol for the copper-catalyzed coupling a. Changing the base reaction of terminal alkynes with 1-bromo alkynes in pyrrolidine was reported using 10 mol% CuI and 5 mol% co- The amine base plays a crucial role for the improvement in the catalyst Pd(PPh ) Cl (Scheme 5).13 reaction rate and yield of the heterocoupling of alkynes and 3 2 2 haloalkynes. The cyclic secondary amines like pyrrolidine gave R quantitative yield for the cross coupling product 11 formed 16 Biomolecular from 1-bromo hept-1-yne 9 and 3-butyn-1-ol 10 (Scheme 3). 10 mol% CuI C5H11 Br C5H11 R The efficiency decreased when secondary amines (Et2NH,

5 mol% PdCl2(PPh3)2 & 15 17 iPr2NH etc) were used as the base and very low yield of the Pyrrolidine, 20 oC desired product was obtained when tertiary amine was used R = (CH2)2OH 91% as the base.13 CH2OH 80% CH2NMe2 82% C8H17 61% C6H5 66% Scheme 5 Cu/Pd-catalyzed coupling of haloalkyne with terminal alkyne in pyrrolidine Organic

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The yield of the coupling product 17 from 1-bromo alkyne 15 reaction.18 Cross-coupling of 4-bromo-2-methylbut-3-yn-2-ol was found to be increased in the presence of Palladium co- 25 with phenylacetylene 13 gave the diyne 26 in almost catalyst. As expected, 1-chloro alkynes showed lower reactivity quantitative yield (Scheme 8). under similar conditions. Another reaction in which Pd acts as a co-catalyst for the Pd(OAc)2 (0.01mol%) 16 OH CuI (0.2 mol%), OH formation of diynes was observed by Lee et al. The diyne 20 Br + Ph Ph was generated in quantitative yield when the Pd-Cu catalytic TBAB, iPr2NH, 25 13 o 26 system (5 mol% CuI and 5 mol% Pd(PPh3)2Cl2 ) in triethylamine N2, 70 C was used for the coupling of 1-iodo-5-phenyl-1-pentyne 18 99 % and (trimethylsilyl)acetylene 19 (Scheme 6). Scheme 8 Cross-coupling of 4-bromo-2-methylbut-3-yn-2-ol and phenylacetylene

By extensive kinetic studies, it was found that in the presence + TMS of TBAB, only 0.0001–0.01 mol% of Pd and less than 0.2 mol%

I Manuscript 18 19 of Cu were required for the coupling to afford the products in good to excellent yields. Pd(PPh3)2Cl2 (5 mol%) CuI (5 mol%) c. Use of Pd catalysts Et N, 25 oC 20 3 A few reports also illustrated that Cu salts are not mandatory TMS 100% for the coupling of the Cadiot-Chodkiewicz reactions. A water- soluble Pd catalytic system formed in situ from Pd(OAc)2 and Scheme 6 Coupling of 1-iodo-5- phenyl-1-pentyne and (trimethylsilyl)acetylene in the water-soluble ligand TPPTS presence of CuI and Pd co-catalyst (triphenylphosphinetrisulfonate sodium salt) was reported by

Amatore et al. for the heterocoupling reaction of alkynyl Accepted In 2008, Shi and co-workers developed another catalytic iodides 27 with terminal alkynes 28 in CH3CN/water system 19 system comprising of Pd(dba)2 and a phosphine ligand 23 for (Scheme 9). No Cu catalyst was used in this procedure. the synthesis of 1,3-conjugated diynes 24 with good yields (Scheme 7).17 Pd(OAc)2 (5 mol%) TPPTS (10 mol%), R1 I + R2 R1 R2 Pd(dba)2 (2 mol%)/23 Et3N, CH3CN/H2O (6:1) CuI (2 mol%) 27 28 29 R1 Br + R2 R1 R2 Et3N, DMF, OH 21 22 24 CH3(CH2)2 Ph RT, 9 h CH3(CH2)2 49% PPh2 60% Chemistry

Ph OH

Me3Si Me3Si CH(CH2)4CH3 23 O OH OH 57% 43% Ph Scheme 9 Pd-catalyzed coupling of haloalkyne with terminal alkyne in presence of Br TPPTS 82% 87% O O O The conditions are very mild and the reaction proceeded Ph smoothly for alkynyl iodides and alkynes that bear different 88% 87% functionalities like amines, alcohols etc. But the yield was moderate and homocoupled product was also formed. OH OH Br d. Use of Nickel catalysts Biomolecular 83% 94% Very recently Nickel-copper catalytic system (Ni(acac)2 and CuI) Scheme 7 Coupling of bromoalkynes with terminal alkynes in presence of Pd(dba)2 and was reported for the cross-coupling of alkynyl halides 21 with 20 & phosphine ligand alkynes 22 in the absence of any ligand (scheme 10). A number of functionalised diaryl, aryl–alkyl, aryl–heteroaryl and Here, the reaction was found to be independent of substrates diheteroaryl 1,3-diynes were produced with high yields. No in most cases, and even alkynes with similar substituents were product was observed when Ni or Cu catalyst was employed cross-coupled successfully with high yields. alone, and from the control experiments it was suggested that Recently, a highly selective Cu/Pd-catalyzed cross-coupling Ni is essential for initiation of the reaction and Cu acts in the reaction between terminal alkynes and 1-bromoacetylenes transmetallation step. However, the protocol failed in the using tetrabutyl ammonium bromide (TBAB) as an additive was coupling of aliphatic alkynes with aliphatic halides. developed and utilized effectively for the Cadiot-Chodkiewicz Organic

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Ni(acac)2 (5 mol%) Beneficial effects are reported for Cadiot-Chodkiewicz coupling CuI (5 mol%) reactions when co-solvents like methanol, ethanol, DMF and R1 Br + R2 R1 R2 Cs2CO3, NMP, THF are used. These co-solvents increase the solubility of 21 22 o 24 100 C, 10 h alkyne moieties. Supercritical CO2 (scCO2) has emerged as an environmentally benign and efficient solvent in organic O synthesis in recent days. A mild and environmentally friendly 89% 67% F3C approach was reported for the synthesis of unsymmetrical diynes 35 in which the scCO2 was used as the reaction medium 5 O and NaOAc as the base instead of the organic amine (Scheme S 88% 89% 12).23 This procedure was found to be highly efficient in the coupling of bromoalkynols with terminal alkynes using 67% S S catalytic CuCl in scCO2 and methanol co-solvent. Here, the CF3 74% reactions are limited to only bromoalkynols 33. O Manuscript Si Fe 79%* 88% 1.5 eq. NaOAc, HO CH3 HO CH3 5 mol% CuCl, R * corresponding iodide was used as the substrate Br + R MeOH, scCO2, H3C Scheme 10 Ni/Cu-catalyzed synthesis of unsymmetrical 1,3-diynes H3C 35 33 34 40 oC e. Use of ligands R = Ph, 91% R = Tol, 87% Another important modification employed for the R = CO2Et, 85% conventional Cadiot-Chodkiewicz coupling reaction is the use R = (CH2)5CH3, 81% of phosphine based ligands. Recently Wang and co-workers Scheme 12 Cadiot-Chodkiewicz coupling reaction carried out in supercritical CO2 reported that the Cadiot-Chodkiewicz reaction carried out in Accepted the presence of CuI and tris(o-tolyl)phosphine ligand afforded Some of the Pd-catalyzed hetero cross-coupling reactions are the unsymmetrical diynes 32 in excellent yields (Scheme 11).21 also carried out in presence of water. For example, a water-

Under the optimized reaction conditions, ethanol and soluble Pd catalytic system comprising of Pd(OAc)2 and the potassium carbonate were used as the solvent and the base water-soluble ligand TPPTS (triphenylphosphinetrisulfonate respectively. The coupling of terminal aliphatic alkynes with sodium salt) was used for Cadiot-Chodkiewicz coupling bromoalkynes was not successful with this protocol. reaction (Scheme 9).

10 mol% CuI, g. Cadiot-Chodkiewicz coupling under solid support 20 mol% P(o-Tol)3 1 2 Kurth and coworkers demonstrated a polymer-supported R Br + R R1 R2 K CO ,EtOH, Cadiot-Chodkiewicz coupling to prevent the homocoupling of Chemistry 30 31 2 3 100 oC, 12h 32 haloalkyne.24 Copper (I) chloride catalyzed coupling reactions of polymer-bound bromo and iodo alkynes 36 with 1-octyne 37 were investigated. They observed that three- and four- MeO carbon alkynol (i.e., n=1, 2) derived haloalkynes performed well under the usual solution-phase Cadiot-Chodkiewicz 94% MeO 89% conditions in coupling reaction with 1-octyne 37 but when alkynols with n = 3 or 4 were used; approximately one third of Cl C6H13 C H 6 13 the isolated product was the homocoupled product. When 2% 78% 88% cross-linked PS-DVB (polystyrene-divinylbenzene) haloalkynyl- Cl esterified resin was used as the polymer support, the homocoupling was inhibited due to the diminished mutual 81% NO2 interaction between the haloalkynes, though lower yield of the 81% desired product was observed (Scheme 13). Biomolecular Scheme 11 Cadiot-Chodkiewicz coupling reaction of terminal alkynes with 1- bromoalkyne in presence of P(o-Tol)3 ligand. &

Very recently an amine-functionalized mesoporous silica SBA- 15-supported palladium was used for the cross-coupling of acetylenic bromides and terminal alkynes with high selectivity and good yields.22 Only minimal amounts of the homocoupling by-products were formed with this phosphine free ligand. f. Use of environmentally benign solvents Organic

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in presence of CuCl and EtNH2 at room temperature afforded the product 6,6-dimethyl-2,4-heptadiynyl hydrogen phthalate 37 46 in 65% yield (scheme 15).30 CuCl, NH2OH.HCl, R CO CH X 95%EtOH, n-PrNH , O 2 2 n 2 CuCl 36 KOH,THF, O R -polymer backbone H2O,n-Bu4NBr (CH3)3C Br + NH2OH.HCl EtNH RT HOOC 2, X: Br, I OH CH2 45 n 44 O

38 O

Scheme 13 Polymer supported Cadiot-Chodkiewicz coupling HOOC (CH ) C 3 3 Manuscript 46 65% Scheme 15 Reaction of 2-propynyl hydrogen phthalate with 1-bromo-3,3-dimethyl-1- 4. Scope of Cadiot-Chodkiewicz coupling reaction butyne under Cadiot-Chodkiewicz reaction conditions Cadiot-Chodkiewicz coupling reaction is extensively used for the synthesis of a wide range of aliphatic and aromatic Bromoacetylenes are used more frequently and the more diacetylenic compounds. The classical reaction work best for reactive acetylenic iodides are used sparsely. Usually the aromatic 1,3-butadienes, but the aliphatic counterparts are coupling of chloroalkynes with terminal alkynes furnishes the formed in lower yields. In general, less acidic alkynes have a diynes in poor yields. As expected, the low reactivity is tendency to undergo homocoupling rather than cross-coupling attributed to the inertness of chloroalkynes compared to their reactions. The Cadiot-Chodkiewicz coupling reaction has very bromo and iodo analogues obviously due to strong C-Cl bond. Accepted high functional group tolerance and it enables the coupling of As an exceptional case, Mori et al. reported a base free 25 26 27 acetylene moieties containing alcohols, epoxides, amines, procedure for the formation of unsymmetrical conjugated 28 29 30 31 amides, carboxylates, carboxylic esters, disulfides, silyl- diynes by the copper(I)-catalyzed cross-coupling reaction using 32 33 protected acetylenes and even nitroxyl radicals. alkynylsilanes and 1-chloroalkynes.4a,34 Cu-catalyzed cross- coupling reaction of alkynylsilanes 47 with 1-chloroalkyne 48 in a. Alcohols, amines and carboxylate esters presence of 10 mol% CuCl in DMF at 80 oC afforded excellent 1-bromoalkynes 39 were coupled with Propargyl alcohol 40 yield of the product 49. Alkynylsilanes bearing electron under normal Cadiot-Chodkiewicz reaction conditions at 50 oC donating groups afforded high yield of the coupled product affording the expected diacetylene in yields ranging from 23% (Scheme 16). The advantage of this method is that the reaction to 31%.25 The same group also reported the coupling of 1- can be carried out in neutral conditions, without any base and bromoalkynes 39 with prop-2-ynyl amine 42 under normal also moderate to good yields of the products were obtained. Chemistry 27 Cadiot-Chodkiewicz reaction conditions. Here also the yield CuCl (10 mol%) of the desired product 43 was quite low. 1 2 1 2 R SiMe3+ R Cl R R o 47 48 DMF, 80 C 48 h 49 OH CuCl (1 mol%) Br + CH3(CH2)n NH2OH.HCl MeO EtNH /H O, 50 oC 65% 39 40 2 2 OH CH3(CH2)n MeO COMe 35% 52% 41

MeOC Cl NH CuCl (1 mol%) 2 42%

CH (CH ) Br + Biomolecular 3 2 n NH2OH.HCl 42 EtNH /H O, 30 oC 39 2 2 NC COMe

NH2 & 40% CH3(CH2)n Scheme 16 Cadiot-Chodkiewicz coupling of alkynylsilane with 1-chloroalkyne 21 % 43 Scheme 14 Synthesis of unsymmetrically substituted diacetylenes containing alcohol b. Silylated alkynes and amine functionalities Silyl motifs are used as protective groups in the synthesis of terminal diynes. The protecting group is required because the Even carboxylic esters also successfully underwent Cadiot- cross-coupling products are more acidic than the coupling Chodkiewicz coupling reactions. The reaction of 1-bromo-3,3- partners. Thus silylation can be used as a preventive measure Organic dimethyl-1-butyne 44 with 2-propynyl hydrogen phthalate 45 to avoid the homo coupling in Cadiot-Chodkiewicz reaction.35

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Walton demonstrated that a triethylsilyl group is the suitable Copper acetylides are sometimes used instead of the terminal group for protection. The Cu(I) catalyzed reaction of alkyne as coupling partner in Cadiot–Chodkiewicz reactions. bromoethynyl(triethyl)silane 50 with aryl acetylene 13 Rubin and co-workers used such a copper acetylide for the 37 afforded the silylated diyne 51 in moderate yield. The reaction synthesis of acetylenic cyclophane C60H18. The copper was carried out using CuCl in presence of NH2OH.HCl and acetylide 57 was obtained by selectively deprotecting 1- o EtNH2 as the base in DMF at 25 C. (triisopropylsilyl)-6-(trimethylsilyl)-3-hexen-1,5-diyne with K2CO3/MeOH, and then deprotonation with LHMDS, followed CuCl,NH2OH.HCl by addition of CuBr. The copper acetylide 57 was coupled with Br SiEt3 SiEt3 EtNH2,DMF the tris(bromoalkyne) 56 at room temperature yielding the 51 50 stable protected triyne 58 (Scheme 19).

MeOH,H O, 13 2 Br NaOH TIPS Cu 57 Manuscript

52 Br Scheme 17 Cadiot-Chodkiewicz coupling of aryl acetylene with pyridine, RT, 4h bromoethynyl(triethyl)silane. 56

Since the silyl group can be easily deprotected with aqueous Br methanolic alkali, such type of cross-coupling reactions can be TIPS envisaged for the synthesis of unique linear conjugated polyynes. Under the similar conditions, the advantage of bulky trialkylsilyl groups such as triethylsilyl or triisopropylsilyl group Accepted in terms of both yields and easy handling was described by Marino et al.36 The cross-coupling reaction between 43% bromoalkyne 53 and trialkylsilyl acetylene 54 was catalyzed by TIPS CuCl and NH2OH.HCl in 30% n-butyl amine in water system TIPS 58 affording excellent yields of the diyne 55 which is a useful synthon for polyynes possessing excellent electronic and optical properties (Scheme 18). Scheme 19 The coupling of copper acetylide with tris(bromoalkyne) in presence of pyridine CuCl (60 mol%)

1 NH2OH.HCl The reaction is usually carried out in pyridine and is promising, R Br R2 1 2 Chemistry + R R but because of its exothermic nature, the metal acetylides are n-BuNH2:H2O, RT 53 54 55 less preferred compared to terminal alkynes. HO Another modification to this reaction involves the use of n-BuLi Br TES 95% for metal exchange process. The diyne 59 was coupled with silyl protected 1-bromo-1,3-butadiyne 60 to form the Br TES 92% phenylhexatriyne synthon 61 which could be used as a precursor for the synthesis of dehydrobenzoannulenes Br TES 87% (scheme 20).38 HO Br TMS TIPS 91% H Br TMS Br TIPS 75% 60 n-BuLi, THF, - 78 oC

HO Biomolecular TBS 91% Br CuBr (0.5 mol%), TIPS pyridine 59

Me N & 2 TBS 90% 62% TIPS Br

61 Scheme 18 Cadiot-Chodkiewicz coupling of trialkyl silane with bromoalkyne Scheme 20 Modified Cadiot-Chodkiewicz coupling of 1-bromo-1,3-butadiyne and alkyne with n-BuLi Bromoalkynes containing polar functional groups such as hydroxyl and amino groups afforded good yield of the product This modification makes Cadiot-Chodkiewicz reaction one of within 5 minutes. the most efficient active template cross-coupling reactions and this strategy is used for active metal template synthesis of c. Use of metal acetylides rotaxanes and catananes (see section 5.c). Organic

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Scheme 22 Decarboxylative cross-coupling reaction of propiolic acids with terminal d. Use of diiodoacetylenes alkynes A series of sp hybridised carbon chains terminated by naphthyl groups (dinaphthyl polyynes) were synthesized through a new route by the reaction of copper (I) ethynyl naphthalide 62 with 5. Applications of Cadiot-Chodkiewicz coupling diiodoacetylene 63 under Cadiot-Chodkiewicz reaction reactions in diverse fields 39 condition (Scheme 21). The reaction using diiodoacetylenes The Cadiot-Chodkiewicz coupling of terminal alkynes and 1- simplifies the synthetic route to long polyyne chains with haloalkynes has been regarded as a key step for the carbon- tailor-made end caps, thus making this procedure applicable carbon bond-formation in many of the processes in polymer for the general synthesis of α,ω-diarylpolyynes. The unusual and supramolecular chemistry. The reaction together with the photophysical and spectroscopic properties of the dinaphthyl modified processes are used in the synthesis of natural polyynes 64 make them promising building blocks in electronic products, natural and synthetic polyynes, interlocked devices.

compounds, highly conjugated molecules for use in electronic Manuscript and as optical materials. An attempt is made to provide a 63 flavour of the generality and functional group tolerance of this I I reaction. CuCl,NH2OH.HCl Cu a. Generation of precursors for macrocyclic and dendrimeric aq.NH3, RT, 2days polyynes 62 Many precursors for the generation of dendrimeric polyynes containing odd number of acetylene units were prepared by Cadiot-Chodkiewicz reaction. An example of this type of reaction is given below. The coupling of alkyne 68 and alkynyl bromide 69 was carried out in the presence of CuI/n-BuLi to Accepted 64 Scheme 21 Synthesis of dinaphthyl polyyne using Cadiot-Chodkiewicz coupling yield 70 in good yield which is used for the synthesis of longer sp carbon chains (Scheme 23).41 e. Decarboxylative Cross-coupling TBDMSO o A copper-catalyzed decarboxylative cross-coupling reaction of n-BuLi, 0 C CuCl (6 mol%) propiolic acids with terminal alkynes was reported in 2010 by Br TMS + o Yu et al. which is considered as an extension of the classical pyridine, 0 C, 1 h 40 68 69 Cadiot-Chodkiewicz reaction. Substituted arylpropiolic acids TBDMSO 65 reacted with arylacetylenes 66 in presence of CuI, 1,10- TBDMSO o phenanthroline and Et3N at 120 C in DMF under air affording the unsymmetrical conjugated diynes 67 in moderate yields TMS Chemistry (Scheme 22). Only a slight excess of the propiolic acid was used 70 TBDMSO in this method. Since only carbon dioxide is produced as the 50% by-product instead of organic halides, the process can be considered as a green variant of the Cadiot-Chodkiewicz Scheme 23 Cu-catalyzed Cadiot-Chodkiewicz coupling of dendrimer-bound alkynes coupling reaction. However the reaction temperature is high and the yields are not satisfactory. An efficient method for the synthesis of tub shaped cyclohexadiene-based acetylenic macrocycles was reported by 42 R2 66 Sankararaman et al. Synthesis of a mixture of acetylenic macrocycles 73 ranging from dimer to octamer was performed CuI (10 mol%) using the coupling of cis-1,4-diethynyl-1,4-dimethoxy 1 R1 R2 R CO2H cyclohexa-2,5-diene 71 and the corresponding ethynyl 65 1,10-phenanthroline (10 mol%) 67 o bromide 72 (Scheme 24). It is found that the tetrameric Et3N, DMF,120 C air, 20h

macrocycle (n=3) was obtained as the major product in 33% Biomolecular yield followed by the hexameric macrocycle (n=5) in 13% yield. OMe

These macrocycles find application in the areas of molecular & 51% recognition and guest-host chemistry. Me OMe

53% MeO Et

46% MeO Cl Organic 40%

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Fig 1 Callyberyne A and Callyberyne B MeO OMe MeO OMe

CuBr (10 mol%) One of the active components of red Ginseng, the Panaxytriol 71 NH2OH.HCl 82, mostly found in North America which is used as a Br + Br piperidine MeOH, RT traditional medicine, was synthesized by Cu-catalyzed Cadiot- 46 MeO OMe Chodkiewicz coupling (Scheme 26). It acts as analeptic and n MeO OMe n = 1-7 erythropoietic. 72 73 OH Scheme 24 Cu-catalyzed synthesis of macrocycles via Cadiot-Chodkiewicz reaction CuCl (7 mol%), (CH2)5CH3 Br EtNH2, NH2OH.HCl, b. Natural polyacetylenes 80 OH OH A large number of polyynes have been isolated from fungi and + MeOH, 0oC, 1 h higher plants. They exhibit excellent biological properties (CH ) CH 82 Manuscript including antimicrobial, cytotoxic, antitumor, antiviral, and 2 5 3 HO HO OH Panaxytriol enzyme inhibitory activity. Their synthetic routes are based (63%) primarily on Cu-catalyzed heterocoupling reactions especially 81 Cadiot-Chodkiewicz reaction to assemble the polyyne skeleton. Scheme 26 Cu-catalyzed synthesis of panaxytriol via Cadiot-Chodkiewicz reaction. In 2006, Tykwinski et al. reviewed the total syntheses of these challenging natural polyynes, including the copper-mediated The synthesis of similar chiral polyacetylenic alcohols such as diyne bond formation reactions.43 (S)-and (R)-Falcarinol and Panaxjapyne A 85 also includes the Cadiot-Chodkiewicz reaction was used in the synthesis of the linkage between a chiral bromoalkynol 83 and an enyne 84 marine natural product, Siphonodiol 77 which is a C23 which is accomplished by Cadiot-Chodkiewicz cross-coupling 44 47 polyacetylene diol (Scheme 25). Siphonodiol shows reaction (scheme 27). Accepted antimicrobial, cytotoxic, antiviral and enzyme inhibitory activity. It also acts as an environmentally harmless Br + CuCl, n-BuNH antifoulant. R 2 H2O, THF OH 83 84 NH2OH.HCl o 85 TIPS I MeOH, 0 C R 75 76 OH 40% OH R= vinyl Falcarinol CuI (20 mol%) TIPS R= ethyl Panaxjapyne piperidine, RT, 6 h OH

Scheme 27 Cu-catalyzed synthesis of Falcarinol and Panaxjapyne A via Cadiot- Chemistry Chodkiewicz reaction. HO OH The synthesis of (3R,8S)-Falcarindiol 89 was also achieved 74 using Cadiot-Chodkiewicz coupling conditions by the reaction 77 OH between (3S,4Z)-1-bromododec-4-en-1-yn-3-ol 86 and 3(R)- 48 Siphonodiol OH (tert-butyldiphenylsilyloxy)-1-pentene-4-yne 87 (Scheme 28). Scheme 25 Synthesis of Siphonodiol via Cadiot-Chodkiewicz coupling Falcarindiol shows antifungal and antitumor activity.

The preparation of a key intermediate in the synthesis of OH CuCl (2 mol%) NH OH.HCl Callyberynes 78 and 79 (Figure 1) which are C21 hydrocarbon Br OTBDPS 2 polyacetylenes and structurally related to Siphonodiols was + also achieved by Cadiot-Chodkiewicz reaction.45 These aq.EtNH2,MeOH 87 0 oC, 30 min. Callyberynes show biological activity and play ecological role 86 Biomolecular such as (1) induce metamorphosis of sessile marine animals (2) OH OTBDPS OH OH act as antifoulant and (3) inhibit fertilization of starfish TBAF, THF & gametes. 0 oC, 3 h

88 89

4 Falcarindiol 4 Scheme 28 Synthesis of Falcarindiol via Cadiot-Chodkiewicz coupling 3 3

78 79 Cu-catalyzed Cadiot-Chodkiewicz coupling is also used in the Callyberyne A Callyberyne B synthesis of naturally occurring and highly unsaturated pyranone derivative (-)-Nitidon 92 (Scheme 29).49 (-)-Nitidon Organic

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induces morphological and physiological differentiation of certain tumor cell lines and also exhibits antibacterial and OH OH antifungal activities. 6 O O (E)-penten-2-yn-ol CuCl (10 mol%), O Oplopandiol OH 96 NH OH.HCl,TMP Ivorenolide B O O 2 O O DMF, 0 oC, 24 h 95 OH OH 6 90 Br 91 6

CH OH O 2 HO OMe Oploxyne A Oploxyne B (+)-diethyl tartate, OH 97 O O OH 98 Ti(o-iPr)4 OH Manuscript 92 CH2Cl2,t-BuOOH H (-)-Nitidon O H CH2OH Virol C OH Scheme 29 Synthesis of (-)-Nitidon via Cu-catalyzed Cadiot-Chodkiewicz coupling 99 HO Synthesis of anticancer agents like Minquartynoic acid50 93 12 and (S)-(-)-(E)-15,16-dihydrominquartynoic acid 94, was also OH H achieved using Cadiot-Chodkiewicz procedure (Figure 2). The (+)-Gymnasterkoreayne F key step in the synthesis of these compounds is the one-pot Accepted 100 Cadiot-Chodkiewicz coupling to construct the tetrayne unit, O O which on further modifications yielded the products in good OAc yields and selectivity. (-)-Gummiferol HO HO COOH 101 OH OH H C 6 O 3 93 7 Minquartynoic acid OH O HO 7 (-)-Petrosiol D HO CO2H 102 94 6 O OH Chemistry (S)-(-)-(E)-15,16-Dihydrominquartynoic Acid O Fig 2 Minquarynoic acid and dihydrominquartynoic acid Peyssonenyne B OH 103 Fig 3 Some natural products prepared using Cadiot-Chodkiewicz reaction The following biologically active natural products, Ivorenolide B 95 51, Oplopandiol 96 52, Oploxyne A 97, Oploxyne B 98 53, Virol C 99, 54 (+)-Gymnasterkoreayne F 100,55 (-)-Gummiferol The synthesis of conjugated dienic pheromone components 101,56 (-)-Petrosiol D 10257 and Peyssonenyne B 10358 were was achieved by a route which involves the Cadiot- prepared following a strategy featuring the Cadiot- Chodkiewicz coupling reaction and successive dialkylborane Chodkiewicz reaction (Figure 3). reduction as the key steps. Yadav et al. prepared (3E,5Z)-3,5-tetradecadienoic acid (Megatomic acid) 109, the sex attractant of the black carpet beetle, following the customary procedure of the Cadiot- Chodkiewicz cross-coupling reaction of 1-decyne 104 and 4-

bromo-3-butyn-1-ol 105 in the presence of CuCl affording 3,5- Biomolecular tetradecadiyn-1-ol 106 in 90% yield (Scheme 30). 59 Reduction

of 106 with lithium aluminium hydride gave (E)-tetradeca-3- & en-5-yn-1-ol 107 which on stereoselective hydrogenation with disiamylborane yielded the dienol 108 with 99% stereoselectivity and 85% yield. Oxidation of dienol 108 with Jones reagent gave Megatomic acid 109 in 83% yield. The reaction was carried out at room temperature or a little higher to achieve a reasonable reaction rate.

Organic

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OH Br + HO 105 104 110 CuCl (60 mol%), (8Z,10Z)-8,10-Dodecadien-1-ol NH2OH.HCl ethylamine, MeOH, o H2O. 30 C, 1 h OAc OH 111

AcO 106 (Z,E)-3,5-tetradecadienyl acetate

LiAlH , Diethyl ether Manuscript 4 112 OH (3Z,5Z)-3,5-dodecadienyl acetate OAc

113 107 (8Z,10Z)-8,10-tetradecadienyl acetate disiamylborane, Fig 4 Some dienic pheromones synthesized using Cadiot-Chodkiewicz reaction THF, 30% H2O2 OH c. Catenanes and rotaxanes The synthesis of interlocked compounds especially catenanes and rotaxanes was revolutionalized by active metal template Accepted synthesis using the Cadiot-Chodkiewicz reaction. Rotaxanes 108 and catenanes were used to create molecular electronic 61 CrO3, H2SO4 devices and molecular sensors. Leigh et al. reported a new rotaxane forming reaction with unsymmetrical threads using COOH Cadiot-Chodkiewicz reaction utilizing n-BuLi as the base (Scheme 31).62

Megatomic acid RO X 109 114 X: I,Br

Chemistry + Scheme30 Synthesis of Megatomic acid using Cadiot-Chodkiewicz reaction RO N N RO Several other Z,Z- and Z,E-dienic pheromone compounds such CuI O O OR 115 as (8Z,10Z)-8,10-dodecadien-1-ol 110, (Z,E)-3,5- + n-BuLi,THF tetradecadienyl acetate 111, (3Z,5Z)-3,5-dodecadienyl and (8Z,10Z)-8,10-tetradecadienyl acetates 112 and 113 were N N prepared following a related strategy (Figure 4).60 O O O O

117 84% O O Biomolecular

116 & Scheme 31 Synthesis of [2] rotaxane using Cadiot-Chodkiewicz coupling

Here, the copper (I) acetylide 118 generated from the terminal acetylene 115 was captured by the bipyridine macrocycle 116 (Scheme 32). Oxidative addition of bromoacetylene 114 to the opposite face of the macrocycle produces Cu(III) intermediate III and subsequent reductive elimination furnishes the

heterocoupled [2]rotaxane 117. Organic

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N N N N Cu-L O O O O

O O

118 O O O O RO N N Cu 116 L= I or THF L O O Manuscript

119 OR II Fig 5 [2]Catenane from bipyridyl macrocycle and bromoalkyne. O O d. Buckminsterfullerene conjugates An efficient synthetic protocol for making covalently linked dihydroazulene-Buckminsterfullerene conjugates 122 using N N OR Cadiot-Chodkiewicz reaction was developed by Nielsen et al.64 RO OR 114 These conjugates are used as light-triggered conductance O O oxidative

addition switches in single-molecule devices. The coupling of Accepted fulleropyrrolidine aryl-ethynyl alkyne 120 with dihydroazulene

Br (DHA) 121 using Pd(PPh3)4/CuI catalyst system under O O microwave heating (70 °C) resulted in the formation of the product 122 in moderate yields (Scheme 33). reductive elimination III OPr N N 117 -CuBr Cu 121 Br NC CN RO O O N Br

OR Chemistry Pd(PPh ) (6 mol%), III 3 4 O O CuI (10 mol%) NEt3, THF, MW, 70 oC. 10 h

Scheme 32 Mechanism of Cadiot-Chodkiewicz active metal template synthesis of [2]rotaxane proposed by Liegh et al. [Reproduced with permission from Angew. Chem. Int. Ed., 2008, 47, 4392] OPr 120

Cadiot-Chodkiewicz reaction has also been applied in the CN CN synthesis of [2]Catenanes 119 using [Cu(CH3CN)4]PF6 in N dichloromethane in acceptable yield (Figure 5).63

122 Biomolecular (38%) &

Scheme 33 Synthesis of DHA-C60 conjugate by Pd-catalyzed Cadiot-Chodkiewicz reaction

e. Cyclophanes Modified Cadiot-Chodkiewicz cross-coupling plays a crucial

role in the design and synthesis of suitable building blocks of Organic

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COMMUNICATION Journal Name novel cyclophanes,65 dihydroazulenes66 and C-C bond to give the 1,3-diyne VIII, regenerating the Cu(I) dehydrobenzo[n]annulenes ([n]DBAs) (in which n denotes the species and thus the catalytic cycle continues. number of π electrons in the cyclic pathway).67 The dehydroannulenes annelated by propellatriene units exist in R1 H different shapes and supramolecular geometries. The IV preparation of an acetylenic 60-carbon atom macrocyclic 1 - R Cu cyclophanes with para- and meta-substituted capping groups Base -BH X 65 V was reported by Fallis et al. The key step in the synthesis is R2 X 1 - oxidative addition the Cadiot-Chodkiewicz coupling of an aminosubstituted R VI acetylenic precursor 123 and a substituted bromide 124. The structure of the cyclophane 125 is shown in scheme 34. R1 Cu R2 CuX H X VII Manuscript reductive elimination n-Bu2-N N-n-Bu2 4 123 H R1 R2 I Br 124 VIII

Pd(PPh3)2Cl2, CuI, Scheme 35 Mechanism of Cu-catalyzed Cadiot-Chodkiewicz coupling reaction Et3N, THF, Heat

Pd(PhCN)2Cl2, Accepted P(t-Bu)3. 17h The mechanism of palladium-catalyzed Cadiot-Chodkiewicz coupling reactions was proposed by Lei et al.17 At first the n-Bu2-N N-n-Bu2 bromoalkyne IX undergoes oxidative addition to Pd(0) species to form an intermediate X followed by transmetallation with alkynylcopper XI to afford XIII (Scheme 36). The alkynylcopper XI is generated from the Cu(I) salt and terminal alkyne XII in presence of a base. Finally, reductive elimination takes place and the target diyne XIV is formed along with the regeneration of the Pd(0) species. If the reductive elimination is slow, the intermediate will react with another alkynylcopper and the Chemistry homocoupled side product is formed.

R1 Br n-Bu -N N-n-Bu IX 2 2 R1 Pd(L) 125 Pd(L) Scheme 34 Formation of an acetylenic 60-carbon atom macrocyclic cyclophane Oxidative addition X Br R1

Synthesis of poly(triacetylene)-derived oligomers with very Transmetallation high fluorescence intensities also utilized Cadiot-Chodkiewicz XIV CuBr R2 cross-coupling reactions on solid support.68 R2 Cu XI Reductive R1 Pd(L) R2 6. Mechanistic study of Cadiot-Chodkiewicz elimination XIII [Cu], Base reaction Biomolecular 2 Only a few mechanistic studies have been conducted on the H R & process of C(sp)-C(sp) bond formation of the Cadiot- XII

Chodkiewicz coupling. The reaction mechanism involves Scheme 36 Mechanism of Pd-catalyzed Cadiot-Chodkiewicz coupling reaction deprotonation of the acetylenic proton from the terminal alkyne IV by a base followed by formation of a copper 69 acetylide V (Scheme 35). The ability of deprotonation of 7. Conclusion terminal acetylene is believed to be due to the high proportion of s character of carbon atom. Oxidative addition of copper 1,3-Diynes serve as building blocks and intermediates for the acetylide on haloalkyne VI affords a bis alkynyl copper species synthesis of a large variety of compounds in different fields like VII which undergoes reductive elimination producing the new supramolecular chemistry, organic synthesis and material Organic

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science. These unsymmetrical diynes can be easily synthesized 8 W. Chodkiewicz and P. Cadiot, C. C. R. Hebd. Seances Acad. using Cadiot-Chodkiewicz reaction. Cadiot-Chodkiewicz Sci., 1955, 241, 1055. coupling reaction can also be successfully applied as the key 9 (a) R. Hua, in Copper-Mediated Cross-Coupling Reactions, step in the synthesis of natural products, many of which John Wiley & Sons, Inc., 2013, 455; (b) W. Shi and A. Lei, exhibit excellent biological activities, and in the synthesis of Tetrahedron Lett., 2014, 55, 2763; (c) T. A. Schaub and M. electronic and optical materials as well as in molecular Kivala, in Metal-Catalyzed Cross-Coupling Reactions and recognition systems. This is an old but very useful reaction and More, Wiley-VCH Verlag GmbH & Co. KGaA, 2014, 665; (d) H. attempts to improve the yield are still under investigation. This Li, S. Liu and L. S. Liebeskind, in Copper-Mediated Cross- review gives an overview of recent developments in the Coupling Reactions, John Wiley & Sons, Inc., 2013, 485. coupling reactions of terminal alkynes with haloalkynes 10 E.-i. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979. particularly focused on the exploration of the modified 11 H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. strategies and their applications. The advantage of the Chem. Int. Ed., 1984, 23, 727. coupling reaction includes the relatively good yields, low cost 12 B. W. Gung and G. Kumi, J. Org. Chem., 2003, 68, 5956. Manuscript of catalyst and mild reaction conditions. The reaction will 13 M. Alami and F. Ferri, Tetrahedron Lett., 1996, 37, 2763. increasingly find advantages by the use of Pd co-catalysts. This 14 S. A. Nye and K. T. Potts, Synthesis, 1988, 375. protocol tolerates numerous functionalized starting materials 15 J. Wityak and J. B. Chan, Syn. Commun., 1991, 21, 977. including alcohols, carboxylates, acetals etc. Despite the many 16 G. C. M. Lee, B. Tobias, J. M. Holmes, D. A. Harcourt and M. significant discoveries and developments in Cadiot- E. Garst, J. Am. Chem. Soc., 1990, 112, 9330. Chodkiewicz reaction, there still remain the issues of selectivity 17 W. Shi, Y. Luo, X. Luo, L. Chao, H. Zhang, J. Wang and A. Lei, J. and formation of considerable amounts of homocoupling by- Am. Chem. Soc. , 2008, 130, 14713. products. In addition, in many cases the precursors of this 18 Y. Weng, B. Cheng, C. He and A. Lei, Angew. Chem. Int. Ed., reaction are less stable. It is presumed that the next 2012, 51, 9547.

breakthroughs in this area will be the improvement in the 19 C. Amatore, E. Blart, J. P. Genet, A. Jutand, S. Lemaire- Accepted efficiency of the catalyst at lower catalyst loading, Audoire and M. Savignac, J. Org. Chem., 1995, 60, 6829. enhancement of the selectivity and yields by fine tuning of the 20 N. Mukherjee, D. Kundu and B. C. Ranu, Chem. Commun., reaction conditions, and further insight into the mechanism of 2014, 50, 15784. Cadiot-Chodkiewicz reaction. This reaction also awaits the 21 S. Wang, L. Yu, P. Li, L. Meng and L. Wang, Synthesis, 2011, development of more practical and economical conditions and 1541. procedures for application in large-scale syntheses. 22 H. Li, L. Wang, M. Yang and Y. Qi, Catalysis Commun., 2012, 17, 179. 23 H.-F. Jiang and A. Z. Wang, Synthesis, 2007, 1649. Acknowledgements 24 J. M. Montierth, D. R. DeMario, M. J. Kurth and N. E. Schore, Tetrahedron, 1998, 54, 11741. The authors are thankful to the Kerala State Council for Chemistry Science, Technology and Environment (KSCSTE), Trivandrum 25 E. Barbu and J. Tsibouklis, Tetrahedron Lett., 1996, 37, 5023. for a research grant (Order No. 341/2013/KSCSTE dated 26 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1992, 15.03.2013). KSS and APT thank the University Grants 33, 5355. Commission (UGC), New Delhi and KSCSTE, Trivandrum for 27 R. Rodriguez-Abad and J. Tsibouklis, Syn. Commun., 1998, 28, junior research fellowships. 4333. 28 L. Fomina, A. Vega, S. Fomine, R. Gaviño and T. Ogawa, Macromol. Chem. Phys., 1996, 197, 2653. References 29 F. Babudri, L. Di Nunno and S. Florio, Synthesis, 1983, 230. 30 M. Rösner and G. Köbrich, Angew. Chem. Int. Ed., 1975, 14,

708. 1 M. Beller and C. Bolm, Transition metals for organic 31 M. D. Mowery and C. E. Evans, Tetrahedron Lett., 1997, 38, synthesis: building blocks and fine chemicals, Wiley-VCH, 11. 1998. 32 L. Blanco, H. E. Helson, M. Hirthammer, H. Mestdagh, S.

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Anilkumar, RSC Adv., 2014, 4, 21688. & 33 D. W. Wiley, J. C. Calabrese, R. L. Harlow and J. S. Miller, 3 C. Glaser, Ber. Dtsch. Chem. Ges., 1869, 2, 422. Angew. Chem. Int. Ed., 1991, 30, 450. 4 (a) P. Siemsen, R. C. Livingston and F. Diederich, Angew. 34 Y. Nishihara, K. Ikegashira, A. Mori and T. Hiyama, Chem. Int. Ed., 2000, 39, 2632; (b) K. S. Sindhu and G. Tetrahedron Lett., 1998, 39, 4075. Anilkumar, RSC Adv., 2014, 4, 27867. 35 R. Eastmond and D. R. M. Walton, Tetrahedron, 1972, 28, 5 G. Eglinton and A. R. Galbraith, Chem. Ind., 1956, 737. 4591. 6 A. S. Hay, J. Org. Chem., 1962, 27, 3320. 36 J. P. Marino and H. N. Nguyen, J. Org. Chem., 2002, 67, 6841. 7 C. Zhang and C. F. Chen, J. Org. Chem., 2007, 72, 9339. 37 Y. Rubin, T. C. Parker, S. I. Khan, C. L. Holliman and S. W. McElvany, J. Am. Chem. Soc., 1996, 118, 5308. Organic

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38 M. L. Bell, R. C. Chiechi, C. A. Johnson, D. B. Kimball, A. J. 66 S. L. Broman, M. Jevric, A. D. Bond and M. B. Nielsen, J. Org. Matzger, W. Brad Wan, T. J. R. Weakley and M. M. Haley, Chem., 2014, 79, 41. Tetrahedron, 2001, 57, 3507. 67 (a) D. B. Kimball, M. M. Haley, R. H. Mitchell, T. R. Ward, S. 39 F. Cataldo, L. Ravagnan, E. Cinquanta, I. E. Castelli, N. Manini, Bandyopadhyay, R. V. Williams and J. R. Armantrout, J. Org. G. Onida and P. Milani, J. Phy. Chem. B, 2010, 114, 14834. Chem., 2002, 67, 8798; (b) S.I. Kato, N. Takahashi and Y. 40 M. Yu, D. Pan, W. Jia, W. Chen and N. Jiao, Tetrahedron Lett., Nakamura, J. Org. Chem., 2013, 78, 7658. 2010, 51, 1287. 68 N. F. Utesch and F. Diederich, Org. Biomol. Chem., 2003, 1, 41 T. Gibtner, F. Hampel, J. P. Gisselbrecht and A. Hirsch, Chem. 237. Eur. J., 2002, 8, 408. 69 P. C. Cadiot, W. Chem. Acetylenes, 1969, 597. 42 A. Bandyopadhyay, B. Varghese and S. Sankararaman, J. Org. Chem., 2006, 71, 4544. Biographical sketch of authors 43 A. L. K. Shi Shun and R. R. Tykwinski, Angew. Chem. Int. Ed., 2006, 45, 1034. Manuscript 44 S. López, F. Fernández-Trillo, P. Midón, L. Castedo and C. Saá, J. Org. Chem., 2005, 70, 6346. 45 S. López, F. Fernández-Trillo, L. Castedo and C. Saá, Org. Lett., 2003, 5, 3725. 46 H. Yun and S. J. Danishefsky, J. Org. Chem., 2003, 68, 4519. 47 Y.-Q. Yang, S.-N. Li, J.-C. Zhong, Y. Zhou, H.-Z. Zeng, H.-J. Duan, Q.-H. Bian and M. Wang, Tetrahedron: Asymmetry, 2015, 26, 361. K.S Sindhu was born in Kerala, India, in 1983. She received her B.Sc. 48 G. Zheng, W. Lu and J. Cai, J. Nat. Prod., 1999, 62, 626. degree from Mahatma Gandhi University (St. Xaviers College, Aluva)

49 F. Bellina, A. Carpita, L. Mannocci and R. Rossi, Eur. J. Org. in 2003 and her M.Sc. degree from School of Chemical Sciences, Accepted Chem., 2004, 2610. Mahatma Gandhi University in 2007. She earned National Eligibility 50 B. W. Gung and H. Dickson, Org. Lett., 2002, 4, 2517. test (NET) with a scholarship. Currently she is doing her doctoral research under the guidance of Dr. G. Anilkumar in the School of 51 Y. Wang, Q.-F. Liu, J.-J. Xue, Y. Zhou, H.-C. Yu, S.-P. Yang, B. Chemical Sciences, Mahatma Gandhi University. Zhang, J.-P. Zuo, Y. Li and J.-M. Yue, Org. Lett., 2014, 16, 2062. 52 N. Kumar Bejjanki, A. Venkatesham, K. Balraju and K. Nagaiah, Helv. Chim. Acta, 2013, 96, 1571. 53 B. V. S. Reddy, R. Nageshwar Rao, B. Kumaraswamy and J. S. Yadav, Tetrahedron Lett., 2014, 55, 4590. 54 H. A. Stefani, P. H. Menezes, I. M. Costa, D. O. Silva and N. Chemistry Petragnani, Synlett, 2002, 2002, 1335. 55 A. Carpita, S. Braconi and R. Rossi, Tetrahedron Asymmetry, 2005, 16, 2501. Amrutha P Thankachan was born in Kerala, India, in 1988. She 56 H. Takamura, H. Wada, N. Lu, O. Ohno, K. Suenaga and I. obtained her B.Sc. degree from Mahatma Gandhi University (C M S Kadota, J. Org. Chem., 2013, 78, 2443. College, Kottayam) in 2009 and her M.Sc. degree from School of 57 A. Sathish Reddy and P. Srihari, Tetrahedron Lett., 2013, 54, Chemical Sciences, Mahatma Gandhi University in 2011. Currently 6370. she is doing her doctoral research under the guidance of Dr. G. Anilkumar in School of Chemical Sciences, Mahatma Gandhi 58 P. García-Domínguez, R. Alvarez and Á. R. de Lera, Eur. J. Org. University. Chem., 2012, 2012, 4762. 59 Jhillu S. Yadav, E. J. Reddy and T. Ramalingam, New J. Chem., 2001, 25, 223. 60 R. Mozuraitis, V. Buda, I. Liblikas, C. R. Unelius and A. K. B. Karlson, J. Chem. Ecol., 2002, 28, 1191. 61 M. J. Chmielewski, J. J. Davis and P. D. Beer, Org. Biomol. Biomolecular Chem., 2009, 7, 415. 62 J. Berná, S. M. Goldup, A. L. Lee, D. A. Leigh, M. D. Symes, G. & Teobaldi and F. Zerbetto, Angew. Chem. Int. Ed., 2008, 47, 4392. 63 S. M. Goldup, D. A. Leigh, T. Long, P. R. McGonigal, M. D. P S. Sajitha was born in Kerala, India in 1991. She obtained her Symes and J. Wu, J. Am. Chem. Soc., 2009, 131, 15924. B.Sc. degree from St.Theresa’s College ,Ernakulam in 2011 and her M.Sc. degree from Union Christian College, Aluva in 2013 (Mahatma 64 M. Santella, V. Mazzanti, M. Jevric, C. R. Parker, S. L. Broman, Gandhi University).In 2014, she joined the group of Dr. G. Anilkumar A. D. Bond and M. B. Nielsen, J. Org. Chem., 2012, 77, 8922. as a project fellow working in the area of Cadiot-Chodkiewicz reaction. 65 M. A. Heuft, S. K. Collins and A. G. Fallis, Org. Lett., 2003, 5, 1911. Organic

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Gopinathan Anilkumar was born in Kerala, India and took his Ph.D in 1996 from Regional Research Laboratory, Trivandrum with Dr. Vijay Nair. He did postdoctoral studies at University of Nijmegen, Netherlands (with Professor Binne Zwanenburg), Osaka University, Japan (with Professor Yasuyuki Kita), Temple University, USA (with Professor Franklin Davis) and Leibniz-institüt für Katalyse, Rostock, Germany (with Professor Matthias Beller). He was a senior scientist at AstraZeneca (India). Currently he is Associate Professor in Organic Manuscript Chemistry at the School of Chemical Sciences, Mahatma Gandhi University in Kerala, India. His research interests are in the areas of organic synthesis, medicinal chemistry and catalysis, particularly on Ruthenium, Iron, Zinc and Copper catalyzed reactions.

Accepted Chemistry Biomolecular & Organic

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