Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 15 OrganicPlease & doBiomolecular not adjust margins Chemistry Journal Name ARTICLE 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 3 1 Cu(I)phenyl acetylide to diphenyldiacetylene via dimerization. Br R 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 coupling reaction. Here, the procedure requires three This reaction is known since the & 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 9 and traditional reaction. 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 This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 1 Please do not adjust margins OrganicPlease & doBiomolecular not adjust margins Chemistry Page 2 of 15 COMMUNICATION Journal Name 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 14 bromoalkynes can be enhanced by using oxygen substituted Cu(I) salts. 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 addition of a Pd(PPh ) Cl co-catalyst.15 Thus, 3-Hydroxy-1- 3. Modification of Cadiot-Chodkiewicz coupling 3 2 2 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% 13 CH OH 80% as the base. 2 CH2NMe2 82% C8H17 61% C6H5 66% Scheme 5 Cu/Pd-catalyzed coupling of haloalkyne with terminal alkyne in pyrrolidine Organic 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 15 OrganicPlease & doBiomolecular not adjust margins Chemistry Journal Name COMMUNICATION 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.