Metal-Catalyzed Reactions in Water (Dixneuf/Metal-Catalyzed Reactions in Water) || Catalytic...

87

3Catalytic Nucleophilic Additions of Alkynes in WaterXiaoquan Yao and Chao-Jun Li

3.1Introduction

There has been an increasing interest in the development of efficient, economical,and environmentally friendly fundamental reactions for chemical synthesis overthe past two decades such as reactions working under ambient atmosphere withbenign solvents, maximizing atom utilization, and directly transforming naturalresources from their native states into useful chemical products [1]. One suchsubject is the development of the Grignard-type reactions in water [2], especiallycatalytic additions based on C–H bond activations, which would provide anatom-economical and greener approach to avoid the requirement for stoichiometricamounts of highly reactive metal intermediates in classical methodologies [3].

As an example of the Grignard-type reaction, the nucleophilic addition of terminalalkynes to various unsaturated electrophiles is of great interest because of gener-ating functionalized alkyne products that are amenable to further transformationsinto a wide range of structures [4, 5]. In the classical methodology, stoichio-metric amounts of highly reactive metal acetylides are required and are usuallygenerated beforehand from terminal alkynes and strongly basic organometallicreagents such as alkyl Grignard reagents, alkyl lithium reagents, or metal amides[6]. Furthermore, a protonic acid has to be added to quench the reaction. Therefore,the classical alkyne addition reactions suffer from low atom economy [7, 8], aresensitive toward air and moisture, do not tolerate various functional groups, andgenerate stoichiometric amounts of waste (Scheme 3.1, route A) [1].

Over the past two decades, to overcome the limitations of classical alkyne additionreactions, many excellent examples have been reported on the catalytic additionof terminal alkynes to unsaturated electrophiles, such as the palladium-catalyzeddirect conjugate addition of terminal alkynes to electron-deficient alkynes [9] andalkenes [10], direct addition of terminal alkyne to aldehyde by Yamaguchi et al.[11], Huang [12], and Carreira et al. [13], as well as many examples of the additionof terminal alkynes to C=N bonds [14–17]. However, among these examples,anhydrous conditions and an inert atmosphere are still needed, and few reactions

Metal-Catalyzed Reactions in Water, First Edition. Edited by Pierre H. Dixneuf and Victorio Cadierno. 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

88 3 Catalytic Nucleophilic Additions of Alkynes in Water

cat. [M], H2OC

XC HCR

C

X

XM

R

C MCRR′M

XH

R

H+

Route A

Route B

Scheme 3.1 Classical (A) and aqueous catalytic (B) nucleophilic addition of alkyne.

could be carried out in water or in the presence of other unprotected functionalgroups.

In contrast to the methods mentioned previously, an alternative approach involvesthe catalytic addition of terminal alkynes to unsaturated electrophiles in water(Scheme 3.1, route B). Studies from the authors’ and others’ laboratory in the pastdecade indicated that the terminal alkynes can react efficiently with a wide range ofelectrophiles in water by using various simple and readily available catalysts suchas copper, silver, gold, iron, and palladium. Furthermore, in many cases, waternot only functions as a solvent but also promotes the reaction, which is clearlydefying classical reactivities predicated on the relative acidities of water, alcohols,and terminal alkynes.

In this chapter, the development of catalytic direct nucleophilic additions ofterminal alkynes is described. For convenience, considering the structure ofelectrophilic substrates and their relative reactivities toward alkynes, the reactionsare classified into the following categories: (i) catalytic nucleophilic additions ofterminal alkynes with carbonyl derivatives (including acid chloride, aldehydes, andketones), (ii) catalytic addition of alkynes to C=N bonds, and (iii) catalytic conjugateadditions.

3.2Catalytic Nucleophilic Additions of Terminal Alkynes with Carbonyl Derivatives

On the basis of the results of the classical Grignard reaction, the relative reactivitiesof the carbonyl derivatives should have the order given in Scheme 3.2. However,among the carbonyl derivatives, most studies are focused on the addition ofterminal alkynes to aldehydes and only very limited examples involve the acid

R Cl

O

R H

O

Increased reactivity

R R′

O

R OR′

O

R NR2

O

Scheme 3.2 Relative reactivity of carbonyl derivatives toward alkyne.

3.2 Catalytic Nucleophilic Additions of Terminal Alkynes with Carbonyl Derivatives 89

chloride or ketones as electrophiles. There is no report on the catalytic reaction ofalkynes to ester or amide.

3.2.1Reaction with Acid Chlorides

Because of the high reactivity of acid chloride toward water, only very limitedstudies were performed on the reaction of terminal alkynes with acid chloridein water. In principle, such reactions are not the standard nucleophilic additionof terminal alkynes but the Sonogashira-type reaction and usually, the standardPd–Cu catalyst was used together with a surfactant to minimize hydrolysis.

In 2004, Li’s group [18] reported a highly effective direct coupling of acid chloridewith terminal alkynes catalyzed by PdCl2(PPh3)2/CuI to produce ynones with upto 99% yield in water (Equation 3.1). In this reaction, a catalytic amount of sodiumlauryl sulfate was necessary as the surfactant for the success of this transformation,possibly by temporarily stabilizing the acid chloride.

R1O

ClR

O

R

R1

+Cat. Pd(PPh3)2Cl2/CuI

K2CO3, surfactant, H2O

51−99% yield (3.1)

To develop an even greener approach to the coupling, immobilized Pd catalystsinstead of the homogeneous palladium catalyst were also used recently. Twokinds of silica-based supports were used for such studies: mesoporous silica withchamber cavities [19] and ethyl-bridged periodic mesoporous organosilicas (PMOs)[20]. The catalysts could be recycled effectively (Equation 3.2).

PhO

ClPh

O

Ph

Ph

+Dodecyl sodium sulfate, K2CO3,Solid-supported Pd cat., CuI (cat.)

H2O, 4h, 65 °C77−94% yield

(3.2)

3.2.2Reaction with Aldehydes

In the earlier research of Li’s group, a bis-metal strategy through dual activationfor the direct addition of terminal alkynes to aldehydes was developed in water(Equation 3.3) [21]. Considering neither alkynes nor aldehydes are reactive enough,they postulated that two different catalysts should be required to activate eachof the reaction partners. As RuCl3 precursor shows high catalytic activity inpolymerization of terminal alkynes in water, it was selected to activate terminalalkynes, whereas In3+ was used to activate aldehdyes based on the nature of its


water-tolerant Lewis acidity [22, 23].

+ H C C R2 Cat. RuCl3, cat In(OAc)3, base

60−90 °C, H2O R1

OH

R2

R1CHO

27−94% yield (3.3)

In this combination, In(OAc)3 was proposed to work as a Lewis acid and activate thecarbonyl to react with alkynylruthenium that was formed in situ from rutheniumchloride and terminal alkynes via C–H bond activation with the promotion ofa catalytic amount of base. Through proton exchange with water, the alkyneaddition product is formed while regenerating the base and the two metal catalysts(Scheme 3.3).

It is well known that the salts of coinage metals such as Cu(I), Ag(I), andAu(I) can activate the C–H bond of terminal alkynes to form metal acetylidesvery easily. However, it is also widely accepted that these simple metal acetylidesare only reactive toward imines, but fail to participate in the nucleophilic C=Oaddition because of the strong and covalent nature of C–M bonds [24, 25]. In2005, Yao and Li found that if a catalytic amount of phosphine ligand, especially astrongly coordinating and π-acidic phosphine ligand, was added, the reaction couldproceed very well in water. By using a single metal catalyst (Cy3PAgCl) togetherwith 0.2 equiv of i-Pr2NEt in water, a highly efficient alkynylation of aldehydes

Ru(II)/In(III)

H R′ Base

[Ru] R′

[Ru] R′

OH

R

O

R

R′

[Ru]

OH

R

R′

Base-H+

O

HR

+

In(III)

Ru(III)

Reduced in situ

Base-H+

Scheme 3.3 Proposed mechanism of the alkynylation catalyzed by Ru/In in water.


was succeeded in up to 98% yield (Equation 3.4) [26]. With this method, even ahydroxyl-containing aldehyde could be alkynylated without the need of a protectinggroup (Equation 3.5).

R H

O+ H R′

Cat. Cy3PAgCl

Water, rt to 100 °C R

OH

R′35−98% yield (3.4)

HO

O

H

HO

OH

Ph+ PhH

10 mol% Cy3PAgCl20 mol% i -Pr2NEt

Water, 80 °C, 1.5 d

73%

(3.5)The ligand was proposed to serve two purposes in the reaction: (i) to weaken theC–Ag bond and (ii) to increase the Lewis acidity of [Ag] center (to coordinate andactivate C=O bonds). In fact, the reaction shows the best results in water aloneas solvent. In toluene or under neat conditions, no reaction was observed at all.The introduction of an organic solvent resulted in an obvious decrease in yield.These studies suggested that the silver acetylide was dually activated by both theelectron-donating (but π-acidic) phosphine ligand and water (Scheme 3.4), and themechanism was proposed in Scheme 3.5.

In a very recent research, even silver nanoparticles (Ag NPs) were found tobe a highly efficient catalyst for the nucleophilic additions of terminal alkynes toaldehydes, with the promotion of ligand. In the past decade, much attention hasbeen paid to the use of nanoparticles as catalysts in organic reactions. Becauseof their easy preparation and relatively high stability in air, the nanoparticles ofcoinage metals were widely reported, including many excellent examples of theirapplications as catalysts in organic reactions. Compared with many examples ofusing copper or gold nanoparticles as catalysts, there are only a few reports onusing Ag NPs as catalysts, and in most cases, for dehydrogenation reactions [27]. AgNPs were rarely used in the construction of carbon-carbon bonds or carbon-heterobonds. Very recently, Yao reported a highly efficient addition of alkynes to aldehydescatalyzed by TiO2-supported Ag NPs (Ag/TiO2), in which significant effects of boththe support and the ligand were observed [28]. The catalyst showed much highercatalytic activities than the reported Ag(I)–phosphine complex [26], and gave goodexcellent yields for a variety of aldehydes and terminal alkynes. Furthermore, thesupported catalyst could be separated and recovered conveniently by centrifugationfrom the reaction mixture and reused effectively, no obvious reduction of catalytic


CHOAg Ph

OH

Ph+

Additives, solvent

0.1mmol1.0 mmol

Entry Conditions Resulta

1

2

3

4

Water, 95 °C, overnight

Toluene, 95 °C, overnight

+ 0.11 mmol PCy3water, 35 °C, overnight

+ 0.11 mmol PCy3toluene, 35 °C, 10 h

80 °C, overnight

No reaction

68%

c

No reaction

No reactiontrace

5 + 0.11 mmol PCy3,1.5 mmol phenylacetylene,2 ml H2O, 95 °C, overnight

ba

432%

+ 0.11 mmol PCy3,1.5 mmol phenylacetylene,0.2 mmol i-Pr2NEt,2 ml H2O, 95 °C, overnight

86%

6

a the yield was calculated based on substrate b

Scheme 3.4 The effect of phosphine ligand and water dually activation.

Cy3PAgCl

H R′ i -Pr2NEt

Cy3PAg R′

Cy3PAg R′

O

HR

O

R

R′

AgPCy3

OH

R

R′

i -Pr2NEtH+Cl−

i -Pr2NEtH+Cl−

O

HR

+

Scheme 3.5 Proposed mechanism of the alkynylation catalyzed by silver in water.


activity was observed after several recycles (Equation 3.6).

CHO+

CHHO

Ag/TiO2−10PPh3, Et3N

Water, 60 °CUp to 98% yield

RRR′

R′

(3.6)The nature of the support materials proved to be an important influential factoron the catalytic activities of nanoparticles in the reaction. The Ag NPs supportedon TiO2, which has suitable acidic sites, showed the highest catalytic activity, whilesupports with strong basic character (CeO2) or with weak acidic character (SiO2)are not suitable for the reaction. The use of Al2O3 as the support, which has bothacidic and basic sites, also resulted in a low activity. The suitable acidic sites on thesilver–TiO2 surface might have facilitated the binding of aldehydes and acceleratedthe addition of silver acetylide to carbonyl groups.

To further understand the nature of the Ag-NP-catalyzed reaction, a ‘‘hot sep-aration’’ [29] experiment was designed and carried out, and the results indicatedthat the reaction should occur on the surface of the solid catalysts rather than insolution due to the soluble silver–phosphine complex (Scheme 3.6).

Br

OH

+CHO

Br

Ag/TiO2–10 (5 mol%)PPh3 (10 mol%)Et3N (40 mol%)

H2O, 60 °C

2 h, 38% conv. After hot separation: 10 h, 37% conv.

Scheme 3.6 The hot separation experiment for the Ag NPs/TiO2-catalyzed direct couplingof aldehydes and alkynes.

On the basis of the ligand-promoted, silver(I)-catalyzed nucleophilic additionsof terminal alkynes, a highly efficient, water-triggered, counteranion-controlled,and silver/phosphine-complex-catalyzed stereoselective cascade alkynylation/cyclization of terminal alkynes with salicylaldehydes leading to substituted2,3-dihydrobenzofuran-3-ol derivatives was developed by using Cy3P–silvercomplex as catalyst in water (Scheme 3.7, route A) [30]. Compared with thetraditional method (Scheme 3.7, route B) [31, 32], this reaction provides analternative and greener approach for the syntheses of aurones, which haveexhibited a wide range of biological activities and been used as antifungal agents,tyrosinase inhibitors, antioxidant, and others [33].

Interestingly, counteranions in the silver complex proved to be the key factorto control Z/E stereoselectivity: (Z)-2-benzylidene-2,3-dihydrobenzofuran-3-ol wasachieved as a single isomer by using Cy3PAgCl as catalyst in water, while theE-isomers can also be obtained stereoselectively with AgF/Cy3P as the in situcatalyst. Furthermore, aurones can also be obtained effectively from the cascadereaction followed by oxidation without further purification.


Cat. Cy3PAgClin water

Cat. Cy3P/AgF

In water

R1

O

OH

R2

R3

Z -isomer

E -isomer

OH

OH

R′R O

OH

R

R′

O

O

R

R′

Catalyticcyclization

Oxidation

OH

CHO

+ Ar H

Route ARoute B

R

Aurones

Stoichiometricreaction with2 equiv. ofLiBu-n

Scheme 3.7 Synthesis of 2,3-dihydrobenzofuran-3-ol and aurone derivatives.

The dual activation effect on metal acetylides from phosphine ligand and waterwas also observed in the gold-catalyzed addition. By using the same strategy withthe silver-catalyzed cascade reaction, a cascade addition/cyclization of terminalalkynes with ortho-alkynylaryl aldehydes catalyzed by phosphine–gold(I) complexwas achieved, leading to 1-alkynyl-1H-isochromenes in water (Equation 3.7) [34].

H

O

R

R′H+Cat Me3PAuCl O

R′

RWater/toluene

up to 89% yield (3.7)

The reaction was dually promoted by an electron-donating phosphine ligandand water, as well as chelation-controlled (Scheme 3.8). Under the standardconditions, no catalytic activity was observed in the reaction of phenylacetylenewith benzaldehydes, which suggested that the o-alkynyl in the substrate mightfunction as a chelating–activating group. The chelating model also provides anexplanation to the result of the reaction being sensitive to the size of phosphineligand. Thus, the smaller ligand, Me3P, gives the best results [35].

On the other hand, a Zn(OTf)2-promoted addition of terminal alkynes to aldehy-des was carried out in wet toluene (containing 80–1000 ppm water) [36]. However,in this case, stoichiometric Zn(OTf)2 has to be used. The intermediate in thereaction was studied by ReactIR, and the formation of π-complex of alkynes withZn(II) and the subsequent generation of Zn-acetylides were believed to be the keysteps in the reaction [37].

Besides the examples of the formation of propargyl alcohols, α, β-unsaturatedcarbonyl compound was obtained in low yield from the addition of 1-phenylpropyneto valeraldehyde catalyzed by indium triflate in the mixed solvent of water andTFA (Equation 3.8) [38]. The product may be formed via a cross aldol reaction of


AuL

LAuCl

R H

AuL R

O

R′

RO

R

R′

AuL

O

R

R′AuL

O

R

R′H

O

H

R

H+, Cl−

H+, Cl−

Scheme 3.8 Tentative mechanism for the gold(I)-catalyzed cascade alkynylation/cyclization.

pentanal and propiophenone that was prepared in situ from the Lewis-acid-catalyzedhydration of 1-phenylpropyne.

MeMe

Bu-n

HO

In(OTf)3 (2 mol%)+ n -BuCHO

TFA/H2O = 1 : 1

30% yield (3.8)

3.2.3Reaction with Ketones

Ketones are much less reactive than aldehydes and imines for both steric andelectronic reasons, and aldol-type reaction is usually found to be predominant forketones with α-Hs in the presence of both Lewis acid and base. Until now, only twotypes of ketone, trifluoromethyl ketone and isatins, were active toward the reaction.

By using the same strategy of the phosphine-activated silver acetylide, a highlyeffective direct alkynylation of trifluoromethyl ketone in water or in organic solvents


was successfully developed with AgF/PCy3 as the catalyst (Equation 3.9) [39]. In thisreaction, trifluoropyruvate was one of the most reactive substrates and reacted withterminal alkynes very well in water at room temperature. Trifluoroacetophenoneshowed a lower reactivity toward terminal alkynes, and the reaction temperaturehad to be increased to 100 ◦C. It is noteworthy that both phosphine ligandand counterions played important roles in the reaction: PCy3-AgF is the bestcombination of choices while only a trace amount of the alkynylation product wasobserved with AgBr or AgI as catalyst, or when other phosphine ligands were used.Interestingly, the reaction proceeded well in water, in common organic solvents,or under neat conditions, but failed completely in ethanol or methanol.

F3C CO2Et

O

+ PhCat. AgF/PCy3

H2O, rt

OH

CO2Et

CF3

Ph

93% (3.9)

A copper-catalyzed enantioselective alkynylation of activated trifluoromethylketones was reported recently by Shibasaki and coworkers [40] in combinationwith either chiral bidentate phosphine or pybox ligands in an anhydrous solvent.

Very recently, the direct alkynylation of isatins catalyzed by N-heterocyclic carbene(NHC)–Ag complexes via the activation of alkyne C–H bond on water was devel-oped by Li’s group for the efficient synthesis of 3-hydroxy-3-ethynylindolin-2-onesunder an air atmosphere. In this reaction, a remarkable rate enhancement by waterin the aqueous heterogeneous system was observed (Equation 3.10) [41].

N

O

O

R2

R1 + R3 H“On water”

IMesAgCli -Pr2NEt

NO

R2

R1

HOR3

30−99%

(3.10)

3.3Addition of Terminal Alkyne to Imine, Tosylimine, Iminium Ion, and Acyl Iminium Ion

Among the C=N bond-containing electrophiles in Scheme 3.9, imine and iminiumion have been studied most extensively. Considering the difference in reactivitiestoward nucleophilic addition for different C=N bonds, several strategies have beenused. In these reactions, the catalysts from coinage metals prove to be the mosteffective.

3.3 Addition of Terminal Alkyne to Imine, Tosylimine, Iminium Ion, and Acyl Iminium Ion 97

R H

NCOR″R′

R H

NR″(H)R′

R H

NR′


R H

NOR′

Scheme 3.9 Relative reactivity of C=N bonds toward alkynes.

3.3.1Reaction with Imines

Generally speaking, among all of C=N bonds, simple imines have the leastreactivity toward alkynes. In early 2001, as the first attempt, the dual-activatingstrategy was employed by Li and coworkers [42] for a highly efficient A3-coupling(aldehyde-alkyne-amine) in water or under solvent-free conditions with a combinedRu/Cu catalyst (Equation 3.11). It was found that phenylacetylene can react with anarylimine in the presence of a catalytic amount of Cu(I) in aqueous media to givethe desired adducts in low conversions. When RuCl3 was used as a cocatalyst, thereaction was more efficient. No desired product was found when RuCl3 alone wasused as the catalyst. A broad range of substituted aromatic and aliphatic imineswere converted into propargylamines by this method. The additions were found tobe also highly effective under solvent-free conditions.

RCHO + ArNH2 +

NHAr

RR′

Cat. RuCl3Cat. CuBr

H2O or neat

R: aromatic, aliphaticAr: PhR′: aromatic, aliphatic

57−95%

R′

(3.11)

The ruthenium/copper cocatalyst system also provides an opportunity torun a multiple and tandem additions of terminal alkynes to C=N bonds.A five-component double aldehyde-alkyne-amine coupling was developed tosynthesize various dipropargyl amines from a range of simple amines, aldehydes,and alkynes in one pot under mild conditions in water and an atmosphere of air(Equation 3.12) [43].

R1NH2 +H H

O+2 2 R2 NR1

R2

R2Cat. RuCl3Cat. CuBr

H2O, rt

15−84%

(3.12)Interestingly, at high temperature, toluene is a better solvent than water for thenucleophilic addition of alkynes, whereas at room temperature, with extendedreaction time, the opposite result is observed. Furthermore, oxygen in air does notinhibit the reaction at all.


By using a combined copper/rhodium catalyst instead of the combination ofcopper/ruthenium, tetrasubstituted isoindolines can be synthesized readily fromthree alkyne units, two aqueous formaldehyde units, and a primary amine in asingle synthetic operation (Equation 3.13) [44].

N

Ph

Ph

Ph

R1

R2

NH2R1

R2

H H

OH Ph2 3+ +

3 mol% RhCl(PPh3)330 mol% CuBr

Neat, 40−80 °C 8 h15−86% yield

(3.13)Independent from Li’s work, an [Ir]-catalyzed addition of trimethylsilylacetyleneto imines was also reported by Ishii [45, 46] and Carreira [47, 48] at almostthe same time. However, the alkyne substrates in the reactions were limited totrimethylsilylacetylene and the reaction gave only moderate yields under anhydrousconditions and inert atmosphere.

On the basis of the fact that CuBr alone as catalyst did lead to a trace amountof the product in the A3 addition of primary amines, aldehydes, and terminalalkynes, ligand was introduced to activate the Cu-C bond in copper acetylideintermediate and to achieve an A3 addition with enantioselectivity. In 2002, Liand coworkers reported the first AA3-coupling (asymmetric aldehyde-alkyne-aminecoupling) in water and in organic solvents (Equation 3.14). The use of the tridentatebis(oxazolinyl)pyridines (pybox) with Cu(OTf) afforded the product with both highyield and enantioselectivity (up to 99.6% ee in organic solvent [49] and 84% ee inwater) [50]. In most cases, imines were formed in situ, and the operation was verysimple: mixing an aldehyde, an aniline, and an alkyne with the catalyst in one pot.Subsequently, many modifications for the copper(I)-complex-catalyzed reactionhave been reported [16, 17].

R1 CHO Ar NH2 R2Cu(OTf) / ligand

+ +R1

HN

R2

Ar

NO

N N

O

Ph Ph

Water or organic solvent

48−93% yield,78−99% eeligand =

(3.14)The success of the A3 addition provides opportunities to access various propargylamines and further functionalizations. Interestingly, with CO2 introduced intothe copper-catalyzed A3 reactions, the ligand can be eliminated and an efficient


four-component tandem A3-coupling/carboxylative cyclization between aldehydes,amines, terminal alkynes, and CO2 was thus developed. The best yields wereobtained in EtOAc and EtOH (Equation 3.15) [51]. Furthermore, the reaction alsoproceeded well under solvent-free conditions or in water. Various oxazolidinoneproducts were readily synthesized by this procedure.

+ R′′ CHO + R′′′ NH2R′

O

NR′′′ O

R′R′′

Cat.CuI

CO2

38–91% yield (3.15)

The copper(I)–pybox complex was also used as a catalyst in a three-componenttandem coupling-annulation of terminal alkynes, amines, and ortho-alkynylarylaldehydes, in which 1-(arylethynyl)-1,2-dihydroisoquinolines were achieved withexcellent to moderate yields. In some examples, water was found to be an additiveto activate the reaction with or without pybox ligand. Compared with the methodsin which imine had to be pre-prepared and purified, the process provides a greenerchoice (Equation 3.16) [52].

H

O

R1

+N

R1

Cat.CuOTf/Pybox

CH2Cl2 or CH2Cl2−H2O+NH2R2 R3

R3

R2

Up to >99% of yield

(3.16)

3.3.2Reaction with Iminium Ions

In principle, compared with imines, the increased reactivity of iminium ionsrenders the opportunity to explore catalysts for catalytic direct nucleophilic additionof terminal alkynes. In 1997, Dax and Youngman [53] reported a stoichiometricresin-supported copper reagent employed in the condensation of secondary amines,aldehydes, and alkynes via the formation of iminium ion. Stoichiometric Cu(I)supported on Al2O3 for the reaction of terminal alkynes, amines, and formaldehydewas then reported by Pagni [54] with the assistance of microwave.

Li and coworkers [55] found that the reaction is highly efficient and generalwith gold as the catalyst (Equation 3.17). No cocatalyst or activator is needed forthe gold-catalyzed reaction. Less than 1 mol% of catalyst is enough to generatean excellent yield of the corresponding propargylamine products. Dialkylaminesare good for the reaction, whereas anilines gave the corresponding products in


lower yields. N-alkylanilines did not form the desired products. Aromatic aldehydesreacted more efficiently, and nearly quantitative yields were obtained in most cases.Aliphatic aldehydes can also be used; however, some trimerizations of aldehydeswere observed, which decreased the yields of the propargylamine products. Theproperties of solvents significantly affect the reaction: water is the best solvent, andthe reaction process is very clean with almost quantitative yield, whereas the use oforganic solvents such as THF, toluene, and DMF resulted in low conversions andmore by-products.

RCHO + +N

R

R′

Cat. AuCl

H2O/70 °C

R : aromatic, aliphaticR′ : aromatic, aliphatic, SiMe3

Amines : piperidine, HN(allyl)2, HN(Bn)2

NH

53–99%

R′

(3.17)

Gold complexes were also used to catalyze the reaction by using a tetradentateN,O-ligand. Che et al. [56, 57] reported a gold-catalyzed three-component couplingof aldehyde, alkyne, and amine in water using gold(III)–salen complexes asprecursor. With chiral prolinol derivatives as the amine component, up to 99 : 1diastereoselectivities were attained (Equation 3.18). This coupling reaction has beenapplied to the synthesis of propargylamine-modified artemisinin derivatives withthe delicate endoperoxide moieties remaining intact.

R1 H

O

R3NH

NR2

R2

R1

R3

+ +Salen−Au(III)

Water, N2, 40 °C, 24 h

O

N N

OAu

R R

+

R′ O

N N

OAu

R R

+

R′ Cl−

67–99% yield, up to 99 : 1 dr

Cl−

(3.18)Subsequently, water-soluble Au(I) complexes of the type [AuCl(PR3)] withalkylbis(m-sulfonated-phenyl) (mC6H4SO3Na)2 and dialkyl-(m-sulfonated-phenyl)(mC6H4SO3Na) phosphanes have been evaluated as catalysts in the synthesisof propargylamines by the A3-coupling of aldehydes, amines, and alkynes inwater [58].


Very recently, a combination of AuCl3-CuCl2-TEMPO (tetramethylpiperidinoxyl)was also reported as catalyst in the coupling of piperidine, phenylacetylene, andbenzaldehyde. The addition of TEMPO and copper(II) chloride to reactions withgold(III) chloride maintained the catalytic activity of gold for up to 33 cycles [59].

Recently, the A3-coupling of phenylacetylene, benzaldehyde, and piperidine inwater has been employed as a standard prototype reaction to evaluate the catalyticactivities of the supported gold nanoparticles. Various solid supports, such asnanoparticulated ceria [60], styrene copolymer [60], mesoporous carbon nitride[61], and HS/SO3H functionalized PMOs [62] were used in the reaction, andusually good to excellent yields were achieved.

Following the success of gold catalysts in A3 reaction, it was found that AgX(X = Cl, Br, and I) also showed good catalytic activities to the three-componentcoupling in water, among which the highest lipophilic silver precursor, AgI, gavethe best results (Equation 3.19) [63]. Surprisingly, the water-soluble or partiallysoluble salts such as AgNO3, Ag2O, AgOAc, Ag2SO4, AgOTf, and AgBF4 were allfound to catalyze the reaction in low conversions (about 25–45%). In contrast tothe gold-catalyzed reaction, aromatic aldehydes show less reactivities than aliphaticaldehydes, which displayed higher reactivity and gave cleaner reactions, in thesilver-catalyzed additions. Acyclic amines (such as diallyl amine) were less effectivein the reaction and only a trace amount of the product was observed, whereascyclic amines reacted very well under these conditions. The reaction proceededvery well in water as well as in organic solvents such as toluene and DMF. Up to92% yield was achieved even with or by using 0.2 mol% of AgI catalyst in water.

RCHO + R′2NH +

N

RR′′

Cat.Ag(I)

H2O

53–99% yield

R′ R′

R′′

(3.19)

Other modifications for the A3 reaction have also been reported: ionic liquid[Bmim]BF4 is found to be a viable solvent for this reaction, and the catalystcan be recycled effectively with the solvent together for several times [64]; AgNPs are also used as an effective and recyclable catalyst for the reaction in PEGaqueous solution [65]. Subsequently, Rueping and coworkers [66] reported theasymmetric silver-catalyzed alkyne-iminium addition reaction catalyzed by chiralprotonic acids.

Shortly after the asymmetric addition of terminal alkynes to imines catalyzed bythe pybox–Cu(I) complex, a N,P-bidenate ligand, QUINAP, was used with CuBr ascatalyst by Knochel and coworkers [67] to succeed in a highly efficient asymmetricaddition of terminal alkynes to enamines (Equation 3.20). Their further researchextends the scope of the reaction to a wide range including a one-pot A3 reaction[68, 69]. Carreira and coworkers [70] developed a Cu-PINAP catalyst for the same


reaction and a higher enantiomeric excess was achieved.

R1CHO + C CH R2

R1

R2

N

Toluene+

R4

CuBr / ligandR3

N

PPh2

43–99% yield, 32–96% ee

ligand =

R3NHR4

(3.20)Secondary amine-aldehyde-alkyne additions can also be catalyzed by CuI in waterunder microwave irradiations. By using (S)-proline methyl ester as a chiral source,a highly diastereoselective method for constructing chiral propargylamines wasdeveloped [71]. Almost at the same time, Li’s group [72] reported their new versionfor the three-component addition of aldehyde, alkyne, and secondary amines, inwhich CuI was also used as catalyst as well as with microwave irradiation undersolvent-free conditions. In ionic liquids, the A3 addition also works very well withcopper catalyst [73].

With CuI as catalyst in aqueous solution, the A3-coupling of formaldehyde,secondary amines, and a variety of terminal alkynes such as aromatic, aliphatic,and silylated acetylenes as well as alkynols proceeded effectively [74]. The useof ultrasound is equally successful for such reactions in water with coppercatalyst [75].

Gold-, silver-, and copper-catalyzed A3-couplings of α-oxyaldehydes, alkynes,and amines in water have also been investigated. In these reactions, gold andsilver catalysts provide complementary results between catalyzing α-oxyaldehydesand α-alkyl aldehydes, respectively. With protected glyceraldehydes as substrate,the gold-catalyzed reaction provides an efficient access to a variety of α-oxylatedpropargylamines (Equation 3.21) [76].

R2O

OR1

+NH

+AuI (5 mol%)

H2O, N2, rt R2

N

OR1 35–93% yield

(3.21)

3.3.3Reaction with Acylimine and Acyliminium Ions

In previous studies on alkyne-imine additions, aliphatic primary amines wereineffective. One possible reason might be due to the low stability of aliphatic iminestoward water. Considering the reactivity of C=N bond and their stability toward

3.4 Direct Conjugate Addition of Terminal Alkynes 103

R1O N SO2Ph

O

H

R2R1

O N

O

H

R2

R3 /CuBr

H2O/40–50 °C

R3

N

O OR

OMe Ph /CuBr

H2O/40–50 °C N

O OR

Ph

R1O N

O

H

R2

N

O OR

10–72% yield

58–81% yield

Scheme 3.10 Addition of alkynes to acylimine and acyliminium ions.

water, N-acylimine and N-acyliminium ions generated in situ from the aminescontaining a good leaving group at the α-position were used as substrates instead.Under ultrasonic irradiations, CuBr (10–30 mol%) can catalyze the addition ofterminal alkynes to both acylimine and acyliminium ions in water to give moderateyields. By using a stoichiometric amount of CuBr, the reaction led to good yields ofthe corresponding products (Scheme 3.10) [77].

Subsequently, under anhydrous conditions, CuBr [78], ZnCl2 [79], and AuX3 [80]were also reported as high efficient catalysts for addition of the similar acyliminiumions and terminal alkynes.

3.4Direct Conjugate Addition of Terminal Alkynes

For the conjugate addition of terminal alkynes to unsaturated carbonyl compoundsin water, there are only a few examples reported in recent years, which might bedue to the less electrophilic nature of C=C double bonds than C=N or C=O bonds(Scheme 3.11).

In 2003, Carreira and Knopfel [81] reported that alkynyl copper reagents, gen-erated from terminal alkynes and catalytic Cu(OAc)2 in the presence of sodiumascorbate, undergo additions to alkylidene Meldrum’s acid at room temperature inaqueous media to give the corresponding adducts (Equation 3.22). The restriction

R

O

R

O

OR′

RR′

O

R O

O

R′RR′

O

R

O R′


Scheme 3.11 Relative reactivity of unsaturated carbonyl compounds toward alkyne.


to this methodology is that it is limited to highly activated alkylidene Meldrum’sacid.

O O

O O

Ph

O O

O O

Ph

Ph

Ph

20% Cu(OAc)2

40% Na-Ascorbate

10 : 1 H2O-tBuOH, 0.25 M, rt

85%

(3.22)

Later, with chiral PINAP as ligand, the enantioselective conjugate addition ofterminal alkynes was developed and 82–97% ee were achieved with good yields(Equation 3.23) [82, 83].

NN

MeO PPh2

HNEtEt

Ph

L

O O

O O

R

O O

O O

R

Ar

5–20 mol% Cu(OAc)2

10–40 mol% Na-AscorbateAr

64–94% yield82–97% ee

+H2O

5–7 mol% L

(3.23)On the other hand, Chen and Li [84] reported a facile and selective copper/palladiumcocatalyzed addition of terminal alkynes to activated alkynes in water without thecompetition of the homocoupling of the terminal alkynes (Equation 3.24). In thiscase, water was found to be the best solvent of choice.

H

+ CO2CH3

5 mol% CuBr2.5 mol% PdCl2(PPh3)2

Water, 60 °C 88%

CO2CH3

(3.24)By adjusting the activity of metal acetylide with ligand, Li and coworkers alsoreported a simple and highly efficient Pd-catalyzed addition of a terminal alkyneto conjugated enone, either in water or in acetone under an air atmosphere(Equation 3.25) [85]. The use of a more electron-rich phosphine ligand,trimethylphosphine, is the key in the reaction. However, any substituenton the C=C double bond would prevent the reaction. The same reactioncan also be carried out using Rh(acac)(CO)2 as catalyst in the presence oftris(o-methoxylphenyl)phosphine in aqueous dioxane solutions [86].

3.5 Conclusions 105

HR +

O

R′R

O

R′Pd(OAc)2/Me3P in water

51–91% yield (3.25)

When a highly electron-donating NHCs ligand was introduced to combine withpalladium species as catalyst, acrylate esters could react with terminal alkynes inacetone (Equation 3.26) [87]. However, it does not work as effectively in water, andthe same substrate restriction (without any substituent on the C=C) was observed.

The conjugate addition of terminal alkynes to unsaturated carbonyl compoundsprovides an alterative, simple, efficient method to prepare γ, δ-alkynyl-β-amino acidderivatives. Zhou and Li [88] also reported a copper-catalyzed three-componentamine-alkyne-alkyne addition reaction (Equation 3.27). Excellent diastereoselectiv-ities (up to >99 : 1) were achieved when chiral prolinol derivatives was employedas the amine component.

R1 + COOR2

Pd(OAc)2/NHCs

Acetone, 60 °C R1

COOR2

(3.26)

CO2R5+ +R35 mol% CuBr

R3

CO2R5

NR1 R2

R4

R4100 °C, tolueneR1R2NH

46–82% yield

(3.27)

3.5Conclusions

The development of catalytic direct additions of terminal alkynes to unsaturatedelectrophiles in water in the past decade provides an efficient and atom-economicalalternative to the classical alkyne reactions, by avoiding the pregeneration ofmetal acetylides with stoichiometric and highly basic reagents, the requirement ofpredried anhydrous organic solvent and inert atmosphere, the preprotection of sen-sitive functional groups, and the generation of stoichiometric wastes. Thus, thesenovel synthetic methodologies have greatly enhanced overall synthetic efficienciesand furthered the long-term objective of developing the Grignard-type reactions inwater.

Acknowledgments

We thank the NSFC (21172107 to XY), NSERC, FQRNT, and Canada ResearchChair (to CJL) for financial support.


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