Recent developments and applications of the Cadiot-Chodkiewicz reaction.

View Article Online

Organic & Biomolecular Chemistry

View Journal

Accepted Manuscript

This article can be cited before page numbers have been issued, to do this please use: K. S. Sindhu, A. P. Thankachan, S. P S and A. Gopinathan, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB00697J.

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

Please not adjust margins Organic & do Biomolecular Chemistry

View Article Online

Journal Name

DOI: 10.1039/C5OB00697J

ARTICLE Recent developments and applications of Cadiot-Chodkiewicz reaction

Published on 08 May 2015. Downloaded by Fudan University on 10/05/2015 15:01:19.

Received 00th January 20xx, Accepted 00th January 20xx DOI: 10.1039/x0xx00000x www.rsc.org/

K. S. Sindhua, Amrutha P. Thankachana, P. S. Sajithaa, Gopinathan Anilkumara* The classical heterocoupling of a 1-haloalkyne with a terminal alkyne catalyzed by copper salts in the presence of a base for the synthesis of unsymmetrical diynes is termed as Cadiot-Chodkiewicz coupling reaction. The diynes are of 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 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 The transition metal catalyzed reactions have turned out to be the most powerful tools in organic synthesis during the past 1 several decades. The metal catalysts are widely used to assemble carbon–carbon bonds between appropriately 2 3 functionalized sp, sp , or sp centers. Alongside the vast developments in Pd-catalyzed cross coupling reactions, advances were being made in the arena of copper-mediated catalysis also. Recently Cu salts have achieved particular success in performing a number of transformations in good yields, while maintaining low loading, mild reaction conditions 2 and high functional group tolerance. Cu-promoted coupling reactions have a longer history of about 150 years. Historically, it began in 1869 when Carl Glaser reported the air oxidation of 3 Cu(I)phenyl acetylide to diphenyldiacetylene via dimerization. The most important methods towards the synthesis of symmetrical diynes are still the Glaser oxidative acetylenic 4 5 coupling , and its modified reactions such as the Eglinton and 6 the Hay coupling reactions. 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 important in synthetic organic chemistry and are common structural motifs of a large variety of biologically active 7 molecules and supramolecular materials. The most commonly used procedure for the preparation of unsymmetrical diyne and polyyne compounds is the Cadiot-Chodkiewicz reaction (Scheme 1). The copper-catalyzed cross-coupling reaction between terminal alkynes and haloalkynes is termed the 8 Cadiot-Chodkiewicz reaction. This reaction is known since the middle of the 1950s in which the terminal alkyne acts as the nucleophile and the 1-haloalkyne acts as the electrophile in the presence of an amine base. To the best of our knowledge, no review has so far been written specifically on this powerful 9 and traditional reaction. In this first review on Cadiot-

a.

Chodkiewicz cross-coupling reaction, we outline the developments, mechanism and modifications of the reaction along with its synthetic applications. R 2 Glaser coupling

R

R Cu(I) salt, Base O2, solvent

3

R R

R

Glaser- Eglinton coupling

Cu(OAc)2, pyridine

R 1

R Cu(I) salt, TMEDA O2, solvent

R

R

Glaser- Hay coupling

R1

Br 4

Cu(I) salt, Base solvent

R1

R

Cadiot–Chodkiewicz coupling

5

Scheme 1 The Glaser coupling modifications and Cadiot-Chodkiewicz coupling reaction

2. The Classical Cadiot-Chodkiewicz coupling reaction In 1955, Cadiot and Chodkiewicz reported the first copper(I)catalyzed coupling of bromoalkyne 6 with 2-Methyl-but-3-yn8 2-ol 7 (Scheme 2). Later, the C(sp)-C(sp) coupling of haloalkynes with terminal alkynes for the synthesis of unsymmetrical diynes is termed as the Cadiot-Chodkiewicz coupling reaction. Here, the procedure requires three components to achieve a selective cross-coupling product, an alkynyl halide, an alkyne and a copper source in stoichiometric or catalytic quantities. Usually Cu catalysts along with an amine, mostly, hydroxylamine, are used in this protocol and the reaction is generally carried out at room temperature.

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

J. Name., 2013, 00, 1-3 | 1

This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins

Organic & Biomolecular Chemistry Accepted Manuscript

Page 1 of 15


Page 2 of 15

COMMUNICATION

Journal Name

7

OH Me Me OH

CuCl (1-2 mol%) Br 6

NH2OH.HCl EtNH2/H2O,RT

8

Br

C5H11 9

Me Me


3. Modification of Cadiot-Chodkiewicz coupling reaction Due to the importance of unsymmetrical 1,3-diynes, several research groups worked on the coupling of acetylenic precursors and many attempts have been made to invent mild, efficient and highly selective methods for the cross-coupling of alkynes and haloalkynes utilizing various catalytic systems and solvents. Various factors such as nature of the base and the alkyne, solvent, reaction time and temperature affect the efficiency of heterocoupling reactions. A number of modifications are reported for these coupling reactions. These variations are helpful in suppressing the formation of the unwanted homocoupled products. a. Changing the base The amine base plays a crucial role for the improvement in the reaction rate and yield of the heterocoupling of alkynes and haloalkynes. The cyclic secondary amines like pyrrolidine gave quantitative yield for the cross coupling product 11 formed from 1-bromo hept-1-yne 9 and 3-butyn-1-ol 10 (Scheme 3). The efficiency decreased when secondary amines (Et2NH, iPr2NH etc) were used as the base and very low yield of the desired product was obtained when tertiary amine was used 13 as the base.

Base, 20 oC

View Article Online

DOI: 10.1039/C5OB00697J

(CH2)2OH

C5H11 11

Base Time Isolated yield (%) 24h 20 Et3N 7h 35 Et2NH 6h 54 BuNH2 3h 25 i-Pr2NH pyrrolidine 15 min 95

Scheme 2 The classical Cadiot-Chodkiewicz coupling reaction

The relatively high yields, low cost of catalyst, wide substrate scope, and mild reaction conditions are the advantages of this reaction. Eventhough the reaction is successful in many situations, the major limitation of this reaction is that sometimes the reaction suffers from reduced selectivity, yield and the formation of a significant amount of homocoupling byproducts when the alkynes are bulky or when the electronic properties of the substituents attached to the reactants are 10 similar. Excess of terminal alkynes are usually required to reduce the homocoupling and specific amines should be used as solvent. Often the coupling partners or precursors of 11 bromoalkynes are not much stable also. The reactivity of bromoalkynes can be enhanced by using oxygen substituted 12 bromoalkyne moieties. To overcome these challenges, many alternative methods have been explored.

(CH2)2OH 10 10 mol% CuI

Scheme 3 The Cadiot-Chodkiewicz coupling reaction in presence of different bases

As expected, chloroacetylenes in presence of pyrrolidine as base showed lower reactivity and the corresponding iodides worked well. Even alkynols, which usually give the homocoupled product, also worked smoothly. b. Addition of co-catalysts The efficiency and scope of the hetero coupling reactions were improved further using Palladium catalysts along with 14 Cu(I) salts. Moreover, efficient heterocoupling of iodo and chloroalkynes took place in presence of Pd co-catalysts. In 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-1iodopropyne 12 when coupled with phenyl acetylene 13 in presence of CuI, Pd(PPh3)2Cl2 and diisopropylamine in THF afforded the corresponding diyne 14 in 79% yield (Scheme 4). This procedure is catalytic in both Pd and Cu (3 mol %) and provides high yields. Moreover, the homocoupling product was obtained in negligible amount. Pd(PPh3)2Cl2 (3 mol%) CuI (3 mol%) HO Ph iPr2NH, THF 13 RT, 1.5 h

HO I+ 12

Ph 14 79%

Scheme 4 Cu/Pd-catalyzed coupling of 3-hydroxy-1-iodopropyne with phenyl acetylene

Later a similar protocol for the copper-catalyzed coupling reaction of terminal alkynes with 1-bromo alkynes in pyrrolidine was reported using 10 mol% CuI and 5 mol% co13 catalyst Pd(PPh3)2Cl2 (Scheme 5). R 16 Br

C5H11 15

10 mol% CuI

C5H11 5 mol% PdCl2(PPh3)2 17 Pyrrolidine, 20 oC R = (CH2)2OH CH2OH CH2NMe2 C8H17 C6H5

R 91% 80% 82% 61% 66%

Scheme 5 Cu/Pd-catalyzed coupling of haloalkyne with terminal alkyne in pyrrolidine

2 | J. Name., 2012, 00, 1-3




H

Organic & do Biomolecular Chemistry Please not adjust margins

Page 3 of 15 Journal Name

COMMUNICATION

I


18

19

Pd(PPh3)2Cl2 (5 mol%) CuI (5 mol%) Et3N, 25 oC

TMS

Scheme 6 Coupling of 1-iodo-5- phenyl-1-pentyne and (trimethylsilyl)acetylene in presence of CuI and Pd co-catalyst

In 2008, Shi and co-workers developed another catalytic system comprising of Pd(dba)2 and a phosphine ligand 23 for the synthesis of 1,3-conjugated diynes 24 with good yields 17 (Scheme 7).

R2

Br + 21

22

Br + 25

Pd(dba)2 (2 mol%)/23 CuI (2 mol%) R1 Et3N, DMF, RT, 9 h PPh2

26

Scheme 8 Cross-coupling of 4-bromo-2-methylbut-3-yn-2-ol and phenylacetylene

A few reports also illustrated that Cu salts are not mandatory for the coupling of the Cadiot-Chodkiewicz reactions. A watersoluble Pd catalytic system formed in situ from Pd(OAc)2 and the water-soluble ligand TPPTS (triphenylphosphinetrisulfonate sodium salt) was reported by Amatore et al. for the heterocoupling reaction of alkynyl iodides 27 with terminal alkynes 28 in CH3CN/water system 19 (Scheme 9). No Cu catalyst was used in this procedure. Pd(OAc)2 (5 mol%) TPPTS (10 mol%), R1

R2

I + 27

28

OH

24

CH3(CH2)2

R2 29

CH3(CH2)2

Ph 49%

60% OH Me3Si

Me3Si

O

57%

Ph

Br 87% O

R1 Et3N, CH3CN/H2O (6:1)

R2

OH

82%

Ph

99 %

Ph 23

OH

c. Use of Pd catalysts

20 100%

R1

Pd(OAc)2 (0.01mol%) CuI (0.2 mol%), Ph TBAB, iPr2NH, 13 N2, 70 oC

OH

By extensive kinetic studies, it was found that in the presence of TBAB, only 0.0001–0.01 mol% of Pd and less than 0.2 mol% of Cu were required for the coupling to afford the products in good to excellent yields.

TMS

+

18

reaction. Cross-coupling of 4-bromo-2-methylbut-3-yn-2-ol View Article Online 10.1039/C5OB00697J 25 with phenylacetylene 13 gave theDOI: diyne 26 in almost quantitative yield (Scheme 8).

O

CH(CH2)4CH3 43%

OH

Scheme 9 Pd-catalyzed coupling of haloalkyne with terminal alkyne in presence of TPPTS

The conditions are very mild and the reaction proceeded smoothly for alkynyl iodides and alkynes that bear different functionalities like amines, alcohols etc. But the yield was moderate and homocoupled product was also formed.

O

Ph 88% 87% OH

OH

Br 83%

94%

Scheme 7 Coupling of bromoalkynes with terminal alkynes in presence of Pd(dba)2 and phosphine ligand

Here, the reaction was found to be independent of substrates in most cases, and even alkynes with similar substituents were cross-coupled successfully with high yields. Recently, a highly selective Cu/Pd-catalyzed cross-coupling reaction between terminal alkynes and 1-bromoacetylenes using tetrabutyl ammonium bromide (TBAB) as an additive was developed and utilized effectively for the Cadiot-Chodkiewicz

d. Use of Nickel catalysts Very recently Nickel-copper catalytic system (Ni(acac)2 and CuI) was reported for the cross-coupling of alkynyl halides 21 with 20 alkynes 22 in the absence of any ligand (scheme 10). A

number of functionalised diaryl, aryl–alkyl, aryl–heteroaryl and diheteroaryl 1,3-diynes were produced with high yields. No product was observed when Ni or Cu catalyst was employed alone, and from the control experiments it was suggested that Ni is essential for initiation of the reaction and Cu acts in the transmetallation step. However, the protocol failed in the coupling of aliphatic alkynes with aliphatic halides.

J. Name., 2013, 00, 1-3 | 3




The yield of the coupling product 17 from 1-bromo alkyne 15 was found to be increased in the presence of Palladium cocatalyst. As expected, 1-chloro alkynes showed lower reactivity under similar conditions. Another reaction in which Pd acts as a co-catalyst for the 16 formation of diynes was observed by Lee et al. The diyne 20 was generated in quantitative yield when the Pd-Cu catalytic system (5 mol% CuI and 5 mol% Pd(PPh3)2Cl2 ) in triethylamine was used for the coupling of 1-iodo-5-phenyl-1-pentyne 18 and (trimethylsilyl)acetylene 19 (Scheme 6).


Page 4 of 15

R1

Journal Name

R2

Br + 21

22

Ni(acac)2 (5 mol%) CuI (5 mol%) R1 Cs2CO3, NMP, 100 oC, 10 h

R2 24

O 67%

89%

O

5 89% 67%

CF3

F3C

S

88%

S

74%

S

O


Fe

Beneficial effects are reported for Cadiot-Chodkiewicz coupling View Article Online DOI:ethanol, 10.1039/C5OB00697J reactions when co-solvents like methanol, DMF and THF are used. These co-solvents increase the solubility of alkyne moieties. Supercritical CO2 (scCO2) has emerged as an environmentally benign and efficient solvent in organic synthesis in recent days. A mild and environmentally friendly approach was reported for the synthesis of unsymmetrical diynes 35 in which the scCO2 was used as the reaction medium and NaOAc as the base instead of the organic amine (Scheme 23 12). This procedure was found to be highly efficient in the coupling of bromoalkynols with terminal alkynes using catalytic CuCl in scCO2 and methanol co-solvent. Here, the reactions are limited to only bromoalkynols 33.

Si

79%*

88%

1.5 eq. NaOAc, HO CH3 5 mol% CuCl,

HO CH3 Br +

* corresponding iodide was used as the substrate

Scheme 10 Ni/Cu-catalyzed synthesis of unsymmetrical 1,3-diynes

H3C

33

1

R2

Br +

R

30

10 mol% CuI, 20 mol% P(o-Tol)3 K2CO3,EtOH, 100 oC, 12h

31

Cl

MeO C6H13

R2

R1 32

89%

C6H13 88%

78% Cl

NO2

H3C

35 91% 87% 85% 81%

Scheme 12 Cadiot-Chodkiewicz coupling reaction carried out in supercritical CO2

Some of the Pd-catalyzed hetero cross-coupling reactions are also carried out in presence of water. For example, a watersoluble Pd catalytic system comprising of Pd(OAc)2 and the water-soluble ligand TPPTS (triphenylphosphinetrisulfonate sodium salt) was used for Cadiot-Chodkiewicz coupling reaction (Scheme 9). g. Cadiot-Chodkiewicz coupling under solid support

MeO 94%

34

MeOH, scCO2, 40 oC

R = Ph, R = Tol, R = CO2Et, R = (CH2)5CH3,

e. Use of ligands Another important modification employed for the conventional Cadiot-Chodkiewicz coupling reaction is the use of phosphine based ligands. Recently Wang and co-workers reported that the Cadiot-Chodkiewicz reaction carried out in the presence of CuI and tris(o-tolyl)phosphine ligand afforded 21 the unsymmetrical diynes 32 in excellent yields (Scheme 11). Under the optimized reaction conditions, ethanol and potassium carbonate were used as the solvent and the base respectively. The coupling of terminal aliphatic alkynes with bromoalkynes was not successful with this protocol.

R

R

81% 81%

Scheme 11 Cadiot-Chodkiewicz coupling reaction of terminal alkynes with 1bromoalkyne in presence of P(o-Tol)3 ligand.

Kurth and coworkers demonstrated a polymer-supported Cadiot-Chodkiewicz coupling to prevent the homocoupling of 24 haloalkyne. 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 fourcarbon alkynol (i.e., n=1, 2) derived haloalkynes performed well under the usual solution-phase Cadiot-Chodkiewicz conditions in coupling reaction with 1-octyne 37 but when alkynols with n = 3 or 4 were used; approximately one third of the isolated product was the homocoupled product. When 2% cross-linked PS-DVB (polystyrene-divinylbenzene) haloalkynylesterified resin was used as the polymer support, the homocoupling was inhibited due to the diminished mutual interaction between the haloalkynes, though lower yield of the desired product was observed (Scheme 13).

Very recently an amine-functionalized mesoporous silica SBA15-supported palladium was used for the cross-coupling of acetylenic bromides and terminal alkynes with high selectivity 22 and good yields. Only minimal amounts of the homocoupling by-products were formed with this phosphine free ligand. f. Use of environmentally benign solvents

4 | J. Name., 2012, 00, 1-3




COMMUNICATION


Page 5 of 15

COMMUNICATION in presence of CuCl and EtNH2 at room temperature afforded View Article Online DOI: 10.1039/C5OB00697J the product 6,6-dimethyl-2,4-heptadiynyl hydrogen phthalate 30 46 in 65% yield (scheme 15).

37 CO2CH2

R

CuCl, NH2OH.HCl, X 95%EtOH, n-PrNH2,

n

O CuCl

KOH,THF, H2O,n-Bu4NBr

36 R -polymer backbone X: Br, I

OH CH2

O

Br +

(CH3)3C

HOOC 45

44

n

NH2OH.HCl EtNH2, RT O

38

O

Scheme 13 Polymer supported Cadiot-Chodkiewicz coupling


(CH3)3C

4. Scope of Cadiot-Chodkiewicz coupling reaction Cadiot-Chodkiewicz coupling reaction is extensively used for the synthesis of a wide range of aliphatic and aromatic diacetylenic compounds. The classical reaction work best for aromatic 1,3-butadienes, but the aliphatic counterparts are formed in lower yields. In general, less acidic alkynes have a tendency to undergo homocoupling rather than cross-coupling reactions. The Cadiot-Chodkiewicz coupling reaction has very high functional group tolerance and it enables the coupling of 25 26 27 acetylene moieties containing alcohols, epoxides, amines, 28 29 30 31 amides, carboxylates, carboxylic esters, disulfides, silyl32 33 protected acetylenes and even nitroxyl radicals. a. Alcohols, amines and carboxylate esters 1-bromoalkynes 39 were coupled with Propargyl alcohol 40 o under normal Cadiot-Chodkiewicz reaction conditions at 50 C affording the expected diacetylene in yields ranging from 23% 25 to 31%. The same group also reported the coupling of 1bromoalkynes 39 with prop-2-ynyl amine 42 under normal 27 Cadiot-Chodkiewicz reaction conditions. Here also the yield of the desired product 43 was quite low. OH Br +

CH3(CH2)n 39

65%

Scheme 15 Reaction of 2-propynyl hydrogen phthalate with 1-bromo-3,3-dimethyl-1butyne under Cadiot-Chodkiewicz reaction conditions

Bromoacetylenes are used more frequently and the more reactive acetylenic iodides are used sparsely. Usually the coupling of chloroalkynes with terminal alkynes furnishes the diynes in poor yields. As expected, the low reactivity is attributed to the inertness of chloroalkynes compared to their bromo and iodo analogues obviously due to strong C-Cl bond. As an exceptional case, Mori et al. reported a base free procedure for the formation of unsymmetrical conjugated diynes by the copper(I)-catalyzed cross-coupling reaction using 4a,34 alkynylsilanes and 1-chloroalkynes. Cu-catalyzed crosscoupling reaction of alkynylsilanes 47 with 1-chloroalkyne 48 in o presence of 10 mol% CuCl in DMF at 80 C afforded excellent yield of the product 49. Alkynylsilanes bearing electron donating groups afforded high yield of the coupled product (Scheme 16). The advantage of this method is that the reaction can be carried out in neutral conditions, without any base and also moderate to good yields of the products were obtained. SiMe3 + R2

R1 47

CuCl (1 mol%)

Cl 48

CuCl (10 mol%) DMF, 80 oC 48 h

R1

R2 49

MeO

NH2OH.HCl EtNH2/H2O, 50 oC

40

HOOC 46

65%

OH CH3(CH2)n

52%

41 MeOC

NH2 CuCl (1 mol%) Br +

CH3(CH2)n 39

42

COMe

MeO

35%

Cl 42%

NH2OH.HCl EtNH2/H2O, 30 oC NH2

COMe

NC 40%

CH3(CH2)n 21 % 43 Scheme 14 Synthesis of unsymmetrically substituted diacetylenes containing alcohol and amine functionalities

Even carboxylic esters also successfully underwent CadiotChodkiewicz coupling reactions. The reaction of 1-bromo-3,3dimethyl-1-butyne 44 with 2-propynyl hydrogen phthalate 45

Scheme 16 Cadiot-Chodkiewicz coupling of alkynylsilane with 1-chloroalkyne

b. Silylated alkynes Silyl motifs are used as protective groups in the synthesis of terminal diynes. The protecting group is required because the cross-coupling products are more acidic than the coupling partners. Thus silylation can be used as a preventive measure 35 to avoid the homo coupling in Cadiot-Chodkiewicz reaction.

J. Name., 2013, 00, 1-3 | 5




Journal Name



Walton demonstrated that a triethylsilyl group is the suitable group for protection. The Cu(I) catalyzed reaction of bromoethynyl(triethyl)silane 50 with aryl acetylene 13 afforded the silylated diyne 51 in moderate yield. The reaction was carried out using CuCl in presence of NH2OH.HCl and o EtNH2 as the base in DMF at 25 C. Br

SiEt3 50

CuCl,NH2OH.HCl

SiEt3

EtNH2,DMF

51 MeOH,H2O, NaOH

13

Copper acetylides are sometimes used instead ofView theArticle terminal Online DOI: 10.1039/C5OB00697J alkyne as coupling partner in Cadiot–Chodkiewicz reactions. Rubin and co-workers used such a copper acetylide for the 37 synthesis of acetylenic cyclophane C60H18. The copper acetylide 57 was obtained by selectively deprotecting 1(triisopropylsilyl)-6-(trimethylsilyl)-3-hexen-1,5-diyne with K2CO3/MeOH, and then deprotonation with LHMDS, followed by addition of CuBr. The copper acetylide 57 was coupled with the tris(bromoalkyne) 56 at room temperature yielding the stable protected triyne 58 (Scheme 19). Br

TIPS

Cu


57 52

Br

Scheme 17 Cadiot-Chodkiewicz coupling of aryl acetylene with bromoethynyl(triethyl)silane.

56

Since the silyl group can be easily deprotected with aqueous methanolic alkali, such type of cross-coupling reactions can be 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 in terms of both yields and easy handling was described by 36 Marino et al. The cross-coupling reaction between bromoalkyne 53 and trialkylsilyl acetylene 54 was catalyzed by CuCl and NH2OH.HCl in 30% n-butyl amine in water system affording excellent yields of the diyne 55 which is a useful synthon for polyynes possessing excellent electronic and optical properties (Scheme 18).

1

R

R2

Br +

53

54

CuCl (60 mol%) NH2OH.HCl n-BuNH2:H2O, RT

R1

R2 55

HO Br Br Br

pyridine, RT, 4h

TES

95%

TES

92%

TES

87%

TIPS

91%

TIPS

75%

TBS

91%

Br TIPS

43% TIPS TIPS

58

Scheme 19 The coupling of copper acetylide with tris(bromoalkyne) in presence of pyridine

The reaction is usually carried out in pyridine and is promising, but because of its exothermic nature, the metal acetylides are less preferred compared to terminal alkynes. Another modification to this reaction involves the use of n-BuLi for metal exchange process. The diyne 59 was coupled with silyl protected 1-bromo-1,3-butadiyne 60 to form the phenylhexatriyne synthon 61 which could be used as a precursor for the synthesis of dehydrobenzoannulenes 38 (scheme 20).

HO Br Br

TMS H

Br

TMS 60

n-BuLi, THF, - 78 oC

HO Br Me2N Br

TBS

90%

Scheme 18 Cadiot-Chodkiewicz coupling of trialkyl silane with bromoalkyne

Bromoalkynes containing polar functional groups such as hydroxyl and amino groups afforded good yield of the product within 5 minutes. c. Use of metal acetylides

59

CuBr (0.5 mol%), TIPS pyridine 62%

TIPS

61 Scheme 20 Modified Cadiot-Chodkiewicz coupling of 1-bromo-1,3-butadiyne and alkyne with n-BuLi

This modification makes Cadiot-Chodkiewicz reaction one of the most efficient active template cross-coupling reactions and this strategy is used for active metal template synthesis of rotaxanes and catananes (see section 5.c).

6 | J. Name., 2012, 00, 1-3




COMMUNICATION



COMMUNICATION


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 diiodoacetylene 63 under Cadiot-Chodkiewicz reaction 39 condition (Scheme 21). The reaction using diiodoacetylenes simplifies the synthetic route to long polyyne chains with tailor-made end caps, thus making this procedure applicable for the general synthesis of α,ω-diarylpolyynes. The unusual photophysical and spectroscopic properties of the dinaphthyl polyynes 64 make them promising building blocks in electronic devices.

63 I

I

CuCl,NH2OH.HCl

Cu

aq.NH3, RT, 2days

62

64

e. Decarboxylative Cross-coupling A copper-catalyzed decarboxylative cross-coupling reaction of propiolic acids with terminal alkynes was reported in 2010 by Yu et al. which is considered as an extension of the classical 40 Cadiot-Chodkiewicz reaction. Substituted arylpropiolic acids 65 reacted with arylacetylenes 66 in presence of CuI, 1,10o phenanthroline and Et3N at 120 C in DMF under air affording the unsymmetrical conjugated diynes 67 in moderate yields (Scheme 22). Only a slight excess of the propiolic acid was used in this method. Since only carbon dioxide is produced as the by-product instead of organic halides, the process can be considered as a green variant of the Cadiot-Chodkiewicz coupling reaction. However the reaction temperature is high and the yields are not satisfactory. R2 66 CuI (10 mol%) R1

CO2H

1,10-phenanthroline (10 mol%) Et3N, DMF,120 oC air, 20h

65

The Cadiot-Chodkiewicz coupling of terminal alkynes and 1haloalkynes has been regarded as a key step for the carboncarbon bond-formation in many of the processes in polymer and supramolecular chemistry. The reaction together with the modified processes are used in the synthesis of natural products, natural and synthetic polyynes, interlocked compounds, highly conjugated molecules for use in electronic and as optical materials. An attempt is made to provide a flavour of the generality and functional group tolerance of this reaction. a. Generation of precursors for macrocyclic and dendrimeric polyynes 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 yield 70 in good yield which is used for the synthesis of longer 41 sp carbon chains (Scheme 23).

Scheme 21 Synthesis of dinaphthyl polyyne using Cadiot-Chodkiewicz coupling

R1

5. Applications of Cadiot-Chodkiewicz coupling reactions in diverse fields

R2 67

OMe 51%

TBDMSO + Br TBDMSO

TMS 69

68

n-BuLi, 0 oC CuCl (6 mol%) pyridine, 0 oC, 1 h

TBDMSO TMS TBDMSO

70 50%

Scheme 23 Cu-catalyzed Cadiot-Chodkiewicz coupling of dendrimer-bound alkynes

An efficient method for the synthesis of tub shaped cyclohexadiene-based acetylenic macrocycles was reported by 42 Sankararaman et al. Synthesis of a mixture of acetylenic macrocycles 73 ranging from dimer to octamer was performed using the coupling of cis-1,4-diethynyl-1,4-dimethoxy cyclohexa-2,5-diene 71 and the corresponding ethynyl bromide 72 (Scheme 24). It is found that the tetrameric macrocycle (n=3) was obtained as the major product in 33% yield followed by the hexameric macrocycle (n=5) in 13% yield. These macrocycles find application in the areas of molecular recognition and guest-host chemistry.

OMe

Me 53% Et

MeO 46%

Cl

MeO 40%

J. Name., 2013, 00, 1-3 | 7




Scheme 22 Decarboxylative cross-coupling reaction of propiolic acids with terminal View Article Online alkynes DOI: 10.1039/C5OB00697J

d. Use of diiodoacetylenes


Page 8 of 15

COMMUNICATION OMe

MeO

Br

+

MeO MeO

OMe

OMe

n = 1-7

72

n

One of the active components of red Ginseng, the Panaxytriol 82, mostly found in North America which is used as a traditional medicine, was synthesized by Cu-catalyzed Cadiot46 Chodkiewicz coupling (Scheme 26). It acts as analeptic and erythropoietic.

73

OH

Scheme 24 Cu-catalyzed synthesis of macrocycles via Cadiot-Chodkiewicz reaction


b. Natural polyacetylenes

CuCl (7 mol%), EtNH2, NH2OH.HCl,

Br

80

A large number of polyynes have been isolated from fungi and higher plants. They exhibit excellent biological properties including antimicrobial, cytotoxic, antitumor, antiviral, and enzyme inhibitory activity. Their synthetic routes are based primarily on Cu-catalyzed heterocoupling reactions especially Cadiot-Chodkiewicz reaction to assemble the polyyne skeleton. In 2006, Tykwinski et al. reviewed the total syntheses of these challenging natural polyynes, including the copper-mediated 43 diyne bond formation reactions. Cadiot-Chodkiewicz reaction was used in the synthesis of the marine natural product, Siphonodiol 77 which is a C23 44 polyacetylene diol (Scheme 25). Siphonodiol shows antimicrobial, cytotoxic, antiviral and enzyme inhibitory activity. It also acts as an environmentally harmless antifoulant.

+

MeOH, 0

HO

OH

OH

1h 82

HO

OH

Panaxytriol (63%)

Scheme 26 Cu-catalyzed synthesis of panaxytriol via Cadiot-Chodkiewicz reaction.

The synthesis of similar chiral polyacetylenic alcohols such as (S)-and (R)-Falcarinol and Panaxjapyne A 85 also includes the linkage between a chiral bromoalkynol 83 and an enyne 84 which is accomplished by Cadiot-Chodkiewicz cross-coupling 47 reaction (scheme 27). Br R

+

CuCl, n-BuNH2 H2O, THF 84

NH2OH.HCl MeOH, 0oC

85 R OH

76

CuI (20 mol%) piperidine, RT, 6 h

(CH2)5CH3

81

I

75

oC,

(CH2)5CH3

OH 83 TIPS

View Article Online

DOI: 10.1039/C5OB00697J

CuBr (10 mol%) NH2OH.HCl piperidine MeOH, RT

71 Br

Fig 1 Callyberyne A and Callyberyne B

OMe

40%

OH

TIPS

R= vinyl R= ethyl

OH

Falcarinol Panaxjapyne

Scheme 27 Cu-catalyzed synthesis of Falcarinol and Panaxjapyne A via CadiotChodkiewicz reaction. HO OH

74 OH

77 OH

Siphonodiol

Scheme 25 Synthesis of Siphonodiol via Cadiot-Chodkiewicz coupling

The preparation of a key intermediate in the synthesis of Callyberynes 78 and 79 (Figure 1) which are C21 hydrocarbon polyacetylenes and structurally related to Siphonodiols was 45 also achieved by Cadiot-Chodkiewicz reaction. These Callyberynes show biological activity and play ecological role such as (1) induce metamorphosis of sessile marine animals (2) act as antifoulant and (3) inhibit fertilization of starfish gametes.

The synthesis of (3R,8S)-Falcarindiol 89 was also achieved using Cadiot-Chodkiewicz coupling conditions by the reaction between (3S,4Z)-1-bromododec-4-en-1-yn-3-ol 86 and 3(R)48 (tert-butyldiphenylsilyloxy)-1-pentene-4-yne 87 (Scheme 28). Falcarindiol shows antifungal and antitumor activity.

Br

86

78 Callyberyne A

aq.EtNH2,MeOH 0 oC, 30 min.

OTBDPS TBAF, THF

OH

OH

OH

0 oC, 3 h 89 Falcarindiol

4 3

87

+

88 4

OTBDPS

CuCl (2 mol%) NH2OH.HCl

OH

3

79 Callyberyne B

Scheme 28 Synthesis of Falcarindiol via Cadiot-Chodkiewicz coupling

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

8 | J. Name., 2012, 00, 1-3




MeO

Journal Name



COMMUNICATION

induces morphological and physiological differentiation of certain tumor cell lines and also exhibits antibacterial and antifungal activities.

O

NH2OH.HCl,TMP DMF, 0 oC, 24 h

O

90

6

O

O

O Ivorenolide B 95

O

O

OH OH

91

Br


CH2Cl2,t-BuOOH

O

OH

6

6

O

CH2OH (+)-diethyl tartate, Ti(o-iPr)4

Oplopandiol 96

OH

O

OMe

HO

Oploxyne A 97

Oploxyne B 98

OH

OH

92

H

O

(-)-Nitidon H

Virol C 99

CH2OH Scheme 29 Synthesis of (-)-Nitidon via Cu-catalyzed Cadiot-Chodkiewicz coupling

OH

HO 50

Synthesis of anticancer agents like Minquartynoic acid 93 12 and (S)-(-)-(E)-15,16-dihydrominquartynoic acid 94, was also achieved using Cadiot-Chodkiewicz procedure (Figure 2). The key step in the synthesis of these compounds is the one-pot Cadiot-Chodkiewicz coupling to construct the tetrayne unit, which on further modifications yielded the products in good yields and selectivity.

O OAc

(-)-Gummiferol

COOH

OH OH

101 O

6

93 Minquartynoic acid

OH

(+)-Gymnasterkoreayne F 100 O

HO

HO H3C

H

7

O

OH

HO

(-)-Petrosiol D

HO 94

6

7

102

CO2H

O

(S)-(-)-(E)-15,16-Dihydrominquartynoic Acid

Peyssonenyne B

Fig 2 Minquarynoic acid and dihydrominquartynoic acid

O

OH OH

103

The following biologically active natural products, Ivorenolide 51 52 53 B 95 , Oplopandiol 96 , Oploxyne A 97, Oploxyne B 98 , 54 55 Virol C 99, (+)-Gymnasterkoreayne F 100, (-)-Gummiferol 56 57 58 101, (-)-Petrosiol D 102 and Peyssonenyne B 103 were prepared following a strategy featuring the CadiotChodkiewicz reaction (Figure 3).

Fig 3 Some natural products prepared using Cadiot-Chodkiewicz reaction

The synthesis of conjugated dienic pheromone components was achieved by a route which involves the CadiotChodkiewicz coupling reaction and successive dialkylborane 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 CadiotChodkiewicz cross-coupling reaction of 1-decyne 104 and 4bromo-3-butyn-1-ol 105 in the presence of CuCl affording 3,559 tetradecadiyn-1-ol 106 in 90% yield (Scheme 30). Reduction of 106 with lithium aluminium hydride gave (E)-tetradeca-3en-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.

J. Name., 2013, 00, 1-3 | 9




(E)-penten-2-yn-ol CuCl (10 mol%),

View Article Online

DOI: 10.1039/C5OB00697J OH

OH


Page 10 of 15

COMMUNICATION

Journal Name OH

104

HO

105

110

CuCl (60 mol%), NH2OH.HCl ethylamine, MeOH, H2O. 30 oC, 1 h

(8Z,10Z)-8,10-Dodecadien-1-ol

OAc

OH

111 AcO

106

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


LiAlH4, Diethyl ether OH

112 (3Z,5Z)-3,5-dodecadienyl acetate

OAc 113

107

(8Z,10Z)-8,10-tetradecadienyl acetate

disiamylborane, THF, 30% H2O2

Fig 4 Some dienic pheromones synthesized using Cadiot-Chodkiewicz reaction

OH

108 CrO3, H2SO4 COOH

c. Catenanes and rotaxanes The synthesis of interlocked compounds especially catenanes and rotaxanes was revolutionalized by active metal template synthesis using the Cadiot-Chodkiewicz reaction. Rotaxanes and catenanes were used to create molecular electronic 61 devices and molecular sensors. Leigh et al. reported a new rotaxane forming reaction with unsymmetrical threads using Cadiot-Chodkiewicz reaction utilizing n-BuLi as the base 62 (Scheme 31).

Megatomic acid 109

RO

X 114

Scheme30 Synthesis of Megatomic acid using Cadiot-Chodkiewicz reaction

X: I,Br

+

N

RO

Several other Z,Z- and Z,E-dienic pheromone compounds such as (8Z,10Z)-8,10-dodecadien-1-ol 110, (Z,E)-3,5tetradecadienyl acetate 111, (3Z,5Z)-3,5-dodecadienyl and (8Z,10Z)-8,10-tetradecadienyl acetates 112 and 113 were 60 prepared following a related strategy (Figure 4).

CuI 115 +

N

RO

N O

O

OR

n-BuLi,THF

N

O

O O

O

117 84% O

O

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.

10 | J. Name., 2012, 00, 1-3




+

View Article Online

DOI: 10.1039/C5OB00697J

Br



COMMUNICATION View Article Online

N

N

N

N Cu-L O

O

O

O

O

O 118 O

O


N

L= I or THF

116

O

O

RO O

Cu L

N O

OR

II O

O

119 Fig 5 [2]Catenane from bipyridyl macrocycle and bromoalkyne.

d. Buckminsterfullerene conjugates

N

OR

N

RO

OR

O

O

An efficient synthetic protocol for making covalently linked dihydroazulene-Buckminsterfullerene conjugates 122 using 64 Cadiot-Chodkiewicz reaction was developed by Nielsen et al. These conjugates are used as light-triggered conductance switches in single-molecule devices. The coupling of fulleropyrrolidine aryl-ethynyl alkyne 120 with dihydroazulene (DHA) 121 using Pd(PPh3)4/CuI catalyst system under microwave heating (70 °C) resulted in the formation of the product 122 in moderate yields (Scheme 33).

114

oxidative addition Br

O

O reductive elimination 117

-CuBr O

RO

N III N Cu Br

OPr NC CN 121

O N

Br

OR O

III

Pd(PPh3)4 (6 mol%), CuI (10 mol%) NEt3, THF, MW, 70 oC. 10 h

O

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]

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

OPr

120 CN CN

N

122 (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

J. Name., 2013, 00, 1-3 | 11




DOI: 10.1039/C5OB00697J


Page 12 of 15

COMMUNICATION

Journal Name 66

the Online Cu(I) C-C bond to give the 1,3-diyne VIII, regenerating View Article DOI: 10.1039/C5OB00697J species and thus the catalytic cycle continues. R1

H IV

R1


4 123

Cu V

R1

CuX

R2

Cu X VII

reductive elimination

N-n-Bu2

R1

R2

Br 124

VIII

Pd(PPh3)2Cl2, CuI, Et3N, THF, Heat

Scheme 35 Mechanism of Cu-catalyzed Cadiot-Chodkiewicz coupling reaction

Pd(PhCN)2Cl2, P(t-Bu)3. 17h n-Bu2-N

N-n-Bu2

n-Bu2-N

N-n-Bu2

The mechanism of palladium-catalyzed Cadiot-Chodkiewicz 17 coupling reactions was proposed by Lei et al. At first the 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 homocoupled side product is formed. R1

125

X VI

H I

R2

oxidative addition

-

H

n-Bu2-N

R1

X-

Base -BH

Scheme 34 Formation of an acetylenic 60-carbon atom macrocyclic cyclophane

Synthesis of poly(triacetylene)-derived oligomers with very high fluorescence intensities also utilized Cadiot-Chodkiewicz 68 cross-coupling reactions on solid support.

Br IX

R1

Pd(L) Oxidative addition

Pd(L) X

Transmetallation CuBr

XIV

R2 Cu

R2

6. Mechanistic study of Cadiot-Chodkiewicz reaction Only a few mechanistic studies have been conducted on the process of C(sp)-C(sp) bond formation of the CadiotChodkiewicz coupling. The reaction mechanism involves 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 terminal acetylene is believed to be due to the high proportion of s character of carbon atom. Oxidative addition of copper acetylide on haloalkyne VI affords a bis alkynyl copper species VII which undergoes reductive elimination producing the new

Br

R1

Reductive elimination

1

R

Pd(L)

XI

2

R

XIII

[Cu], Base R2

H XII Scheme 36 Mechanism of Pd-catalyzed Cadiot-Chodkiewicz coupling reaction

7. Conclusion 1,3-Diynes serve as building blocks and intermediates for the synthesis of a large variety of compounds in different fields like supramolecular chemistry, organic synthesis and material

12 | J. Name., 2012, 00, 1-3




65

novel cyclophanes, dihydroazulenes and dehydrobenzo[n]annulenes ([n]DBAs) (in which n denotes the 67 number of π electrons in the cyclic pathway). The dehydroannulenes annelated by propellatriene units exist in different shapes and supramolecular geometries. The preparation of an acetylenic 60-carbon atom macrocyclic cyclophanes with para- and meta-substituted capping groups 65 was reported by Fallis et al. The key step in the synthesis is the Cadiot-Chodkiewicz coupling of an aminosubstituted acetylenic precursor 123 and a substituted bromide 124. The structure of the cyclophane 125 is shown in scheme 34.



Journal Name

COMMUNICATION

science. These unsymmetrical diynes can be easily synthesized using Cadiot-Chodkiewicz reaction. Cadiot-Chodkiewicz coupling reaction can also be successfully applied as the key step in the synthesis of natural products, many of which exhibit excellent biological activities, and in the synthesis of electronic and optical materials as well as in molecular recognition systems. This is an old but very useful reaction and attempts to improve the yield are still under investigation. This review gives an overview of recent developments in the coupling reactions of terminal alkynes with haloalkynes particularly focused on the exploration of the modified strategies and their applications. The advantage of the coupling reaction includes the relatively good yields, low cost of catalyst and mild reaction conditions. The reaction will increasingly find advantages by the use of Pd co-catalysts. This protocol tolerates numerous functionalized starting materials including alcohols, carboxylates, acetals etc. Despite the many significant discoveries and developments in CadiotChodkiewicz reaction, there still remain the issues of selectivity and formation of considerable amounts of homocoupling byproducts. In addition, in many cases the precursors of this reaction are less stable. It is presumed that the next breakthroughs in this area will be the improvement in the efficiency of the catalyst at lower catalyst loading, enhancement of the selectivity and yields by fine tuning of the reaction conditions, and further insight into the mechanism of Cadiot-Chodkiewicz reaction. This reaction also awaits the development of more practical and economical conditions and procedures for application in large-scale syntheses.

The authors are thankful to the Kerala State Council for Science, Technology and Environment (KSCSTE), Trivandrum for a research grant (Order No. 341/2013/KSCSTE dated 15.03.2013). KSS and APT thank the University Grants Commission (UGC), New Delhi and KSCSTE, Trivandrum for junior research fellowships.

References

2

3 4

5 6 7

9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Acknowledgements

1

8

25 26 27 28 29 30

M. Beller and C. Bolm, Transition metals for organic synthesis: building blocks and fine chemicals, Wiley-VCH, 1998. (a) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337; (b) A. M. Thomas, A. Sujatha and G. Anilkumar, RSC Adv., 2014, 4, 21688. C. Glaser, Ber. Dtsch. Chem. Ges., 1869, 2, 422. (a) P. Siemsen, R. C. Livingston and F. Diederich, Angew. Chem. Int. Ed., 2000, 39, 2632; (b) K. S. Sindhu and G. Anilkumar, RSC Adv., 2014, 4, 27867. G. Eglinton and A. R. Galbraith, Chem. Ind., 1956, 737. A. S. Hay, J. Org. Chem., 1962, 27, 3320. C. Zhang and C. F. Chen, J. Org. Chem., 2007, 72, 9339.

31 32

33 34 35 36 37

W. Chodkiewicz and P. Cadiot, C. C. R. Hebd. Seances View ArticleAcad. Online DOI: 10.1039/C5OB00697J Sci., 1955, 241, 1055. (a) R. Hua, in Copper-Mediated Cross-Coupling Reactions, John Wiley & Sons, Inc., 2013, 455; (b) W. Shi and A. Lei, Tetrahedron Lett., 2014, 55, 2763; (c) T. A. Schaub and M. Kivala, in Metal-Catalyzed Cross-Coupling Reactions and More, Wiley-VCH Verlag GmbH & Co. KGaA, 2014, 665; (d) H. Li, S. Liu and L. S. Liebeskind, in Copper-Mediated CrossCoupling Reactions, John Wiley & Sons, Inc., 2013, 485. E.-i. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979. H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. Chem. Int. Ed., 1984, 23, 727. B. W. Gung and G. Kumi, J. Org. Chem., 2003, 68, 5956. M. Alami and F. Ferri, Tetrahedron Lett., 1996, 37, 2763. S. A. Nye and K. T. Potts, Synthesis, 1988, 375. J. Wityak and J. B. Chan, Syn. Commun., 1991, 21, 977. G. C. M. Lee, B. Tobias, J. M. Holmes, D. A. Harcourt and M. E. Garst, J. Am. Chem. Soc., 1990, 112, 9330. W. Shi, Y. Luo, X. Luo, L. Chao, H. Zhang, J. Wang and A. Lei, J. Am. Chem. Soc. , 2008, 130, 14713. Y. Weng, B. Cheng, C. He and A. Lei, Angew. Chem. Int. Ed., 2012, 51, 9547. C. Amatore, E. Blart, J. P. Genet, A. Jutand, S. LemaireAudoire and M. Savignac, J. Org. Chem., 1995, 60, 6829. N. Mukherjee, D. Kundu and B. C. Ranu, Chem. Commun., 2014, 50, 15784. S. Wang, L. Yu, P. Li, L. Meng and L. Wang, Synthesis, 2011, 1541. H. Li, L. Wang, M. Yang and Y. Qi, Catalysis Commun., 2012, 17, 179. H.-F. Jiang and A. Z. Wang, Synthesis, 2007, 1649. J. M. Montierth, D. R. DeMario, M. J. Kurth and N. E. Schore, Tetrahedron, 1998, 54, 11741. E. Barbu and J. Tsibouklis, Tetrahedron Lett., 1996, 37, 5023. D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1992, 33, 5355. R. Rodriguez-Abad and J. Tsibouklis, Syn. Commun., 1998, 28, 4333. L. Fomina, A. Vega, S. Fomine, R. Gaviño and T. Ogawa, Macromol. Chem. Phys., 1996, 197, 2653. F. Babudri, L. Di Nunno and S. Florio, Synthesis, 1983, 230. M. Rösner and G. Köbrich, Angew. Chem. Int. Ed., 1975, 14, 708. M. D. Mowery and C. E. Evans, Tetrahedron Lett., 1997, 38, 11. L. Blanco, H. E. Helson, M. Hirthammer, H. Mestdagh, S. Spyroudis and K. P. C. Vollhardt, Angew. Chem. Int. Ed., 1987, 26, 1246. D. W. Wiley, J. C. Calabrese, R. L. Harlow and J. S. Miller, Angew. Chem. Int. Ed., 1991, 30, 450. Y. Nishihara, K. Ikegashira, A. Mori and T. Hiyama, Tetrahedron Lett., 1998, 39, 4075. R. Eastmond and D. R. M. Walton, Tetrahedron, 1972, 28, 4591. J. P. Marino and H. N. Nguyen, J. Org. Chem., 2002, 67, 6841. Y. Rubin, T. C. Parker, S. I. Khan, C. L. Holliman and S. W. McElvany, J. Am. Chem. Soc., 1996, 118, 5308.

J. Name., 2013, 00, 1-3 | 13




Page 13 of 15


Journal Name

38 M. L. Bell, R. C. Chiechi, C. A. Johnson, D. B. Kimball, A. J. Matzger, W. Brad Wan, T. J. R. Weakley and M. M. Haley, Tetrahedron, 2001, 57, 3507. 39 F. Cataldo, L. Ravagnan, E. Cinquanta, I. E. Castelli, N. Manini, G. Onida and P. Milani, J. Phy. Chem. B, 2010, 114, 14834. 40 M. Yu, D. Pan, W. Jia, W. Chen and N. Jiao, Tetrahedron Lett., 2010, 51, 1287. 41 T. Gibtner, F. Hampel, J. P. Gisselbrecht and A. Hirsch, Chem. Eur. J., 2002, 8, 408. 42 A. Bandyopadhyay, B. Varghese and S. Sankararaman, J. Org. Chem., 2006, 71, 4544. 43 A. L. K. Shi Shun and R. R. Tykwinski, Angew. Chem. Int. Ed., 2006, 45, 1034. 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. 48 G. Zheng, W. Lu and J. Cai, J. Nat. Prod., 1999, 62, 626. 49 F. Bellina, A. Carpita, L. Mannocci and R. Rossi, Eur. J. Org. Chem., 2004, 2610. 50 B. W. Gung and H. Dickson, Org. Lett., 2002, 4, 2517. 51 Y. Wang, Q.-F. Liu, J.-J. Xue, Y. Zhou, H.-C. Yu, S.-P. Yang, B. 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. Petragnani, Synlett, 2002, 2002, 1335. 55 A. Carpita, S. Braconi and R. Rossi, Tetrahedron Asymmetry, 2005, 16, 2501. 56 H. Takamura, H. Wada, N. Lu, O. Ohno, K. Suenaga and I. Kadota, J. Org. Chem., 2013, 78, 2443. 57 A. Sathish Reddy and P. Srihari, Tetrahedron Lett., 2013, 54, 6370. 58 P. García-Domínguez, R. Alvarez and Á. R. de Lera, Eur. J. Org. 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. 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. Symes and J. Wu, J. Am. Chem. Soc., 2009, 131, 15924. 64 M. Santella, V. Mazzanti, M. Jevric, C. R. Parker, S. L. Broman, A. D. Bond and M. B. Nielsen, J. Org. Chem., 2012, 77, 8922. 65 M. A. Heuft, S. K. Collins and A. G. Fallis, Org. Lett., 2003, 5, 1911.

66 S. L. Broman, M. Jevric, A. D. Bond and M. B. Nielsen, J. Online Org. View Article DOI: 10.1039/C5OB00697J Chem., 2014, 79, 41. 67 (a) D. B. Kimball, M. M. Haley, R. H. Mitchell, T. R. Ward, S. Bandyopadhyay, R. V. Williams and J. R. Armantrout, J. Org. Chem., 2002, 67, 8798; (b) S.I. Kato, N. Takahashi and Y. Nakamura, J. Org. Chem., 2013, 78, 7658. 68 N. F. Utesch and F. Diederich, Org. Biomol. Chem., 2003, 1, 237. 69 P. C. Cadiot, W. Chem. Acetylenes, 1969, 597. Biographical sketch of authors

K.S Sindhu was born in Kerala, India, in 1983. She received her B.Sc. degree from Mahatma Gandhi University (St. Xaviers College, Aluva) in 2003 and her M.Sc. degree from School of Chemical Sciences, Mahatma Gandhi University in 2007. She earned National Eligibility test (NET) with a scholarship. Currently she is doing her doctoral research under the guidance of Dr. G. Anilkumar in the School of Chemical Sciences, Mahatma Gandhi University.

Amrutha P Thankachan was born in Kerala, India, in 1988. She obtained her B.Sc. degree from Mahatma Gandhi University (C M S College, Kottayam) in 2009 and her M.Sc. degree from School of Chemical Sciences, Mahatma Gandhi University in 2011. Currently she is doing her doctoral research under the guidance of Dr. G. Anilkumar in School of Chemical Sciences, Mahatma Gandhi University.

P S. Sajitha was born in Kerala, India in 1991. She obtained her B.Sc. degree from St.Theresa’s College ,Ernakulam in 2011 and her M.Sc. degree from Union Christian College, Aluva in 2013 (Mahatma Gandhi University).In 2014, she joined the group of Dr. G. Anilkumar as a project fellow working in the area of Cadiot-Chodkiewicz reaction.

14 | J. Name., 2012, 00, 1-3





COMMUNICATION

Page 14 of 15

Page 15 of 15


Journal Name

COMMUNICATION View Article Online



DOI: 10.1039/C5OB00697J

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 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.

J. Name., 2013, 00, 1-3 | 15



RECENT SYNTHETIC DEVELOPMENTS AND APPLICATIONS OF THE ULLMANN REACTION. A REVIEW.

Recent developments in the chemistry and biological applications of benzoxaboroles.

Acoustic black holes: recent developments in the theory and applications.

The reductive decyanation reaction: an overview and recent developments.

Recent developments on sequence spaces and compact operators with applications.

Recent developments in sweat analysis and its applications.

Mass-spectrometry-based microbial metabolomics: recent developments and applications.

Split-luciferase complementary assay: applications, recent developments, and future perspectives.

Recent developments in the Suzuki-Miyaura reaction: 2010-2014.

Recent developments in β-C-glycosides: synthesis and applications.

Recent Developments of Magnetoresistive Sensors for Industrial Applications.

Recent Developments of Liposomes as Nanocarriers for Theranostic Applications.

Recent developments in methods for identifying reaction coordinates.

Recent developments and applications of hyperspectral imaging for quality evaluation of agricultural products: a review.

From structure to catalysis: recent developments in the biotechnological applications of lipases.

stereology in lung research.

Cobalamin and folate: recent developments.

Coalescence 2.0: a multiple branching of recent theoretical developments and their applications.

Recent developments and applications of electron transfer dissociation mass spectrometry in proteomics.

Recent developments in dystonia.

Helix mimetics: Recent developments.

Neuroglobin - recent developments.

Oxidative folding: recent developments.

Recent developments in CrystFEL.