ChemInform Abstract: Suzuki-Miyaura Cross-Coupling Catalyzed by Protein-Stabilized Palladium...

DOI: 10.1002/cssc.200900221

Suzuki–Miyaura Cross-Coupling Reactions in AqueousMedia: Green and Sustainable Syntheses of BiarylsVivek Polshettiwar,*[a] Audrey Decottignies,[b] Christophe Len,[b] and Aziz Fihri*[b]

Dedicated to Prof. James Clark for his pioneering work in green chemistry and to the memory of Yahia Mohammed.

502 � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 2010, 3, 502 – 522

1. Introduction

Transition-metal-catalyzed cross-coupling reactions are undeni-ably part of the key reactions of organic synthesis, becausethey allow the construction of highly complex molecules fromrelatively simple precursors.[1] In this context, the 1912 NobelPrize in Chemistry was awarded to Victor Grignard, known asthe “father” of organomagnesium reagents. These and otherorganometallic compounds rapidly found use in the formationof carbon–carbon bonds by many reactions (e.g. , nucleophilicsubstitution; addition of aldehydes, ketones, nitriles; and manyothers), facilitating access to a variety of products rangingfrom natural compounds to polymers.

Palladium has taken centre stage when it comes to the syn-thesis of complex and functionalized organic molecules byusing cross-coupling reactions. There are two main reasons forthe growing interest in this field. Firstly, the catalytic systemsprovide simple and practical methods for creating carbon–carbon and carbon–nitrogen bonds under sustainable condi-tions with excellent yields. Secondly, due to the mild reactionconditions the reactions are highly tolerant of many functionalgroups when the selective coupling of molecules at specificpositions without affecting other functional groups is required.

The Suzuki–Miyaura coupling reaction is one of the most im-portant synthetic transformations developed in the 20th centu-ry.[2–4] This reaction has profoundly changed chemistry, and it isuncommon to find a work in synthetic organic chemistry inwhich it does not feature. The reaction is generally catalyzedby soluble palladium complexes with various ligands, using ho-mogeneous catalytic systems because of their high reactivity,high turnover numbers, milder reaction conditions, and nota-bly the possibility to couple the widely available and low-costaryl chlorides.[5] A general reaction mechanism for the Suzuki–Miyaura reaction is shown in Scheme 1. Several excellent Re-views have been published in the literature.[6–14] Herein, wefocus on the use of water as a medium for Suzuki–Miyauracoupling reactions in homogenous and heterogeneous sys-tems, and its advantages towards green chemistry. The use oftoxic organic solvents remains a scientific challenge and anaspect of economical and ecological relevance, and water as abenign reaction medium has been found to be highly effectivein overcoming some of these issues.

2. Organic Chemistry in Water

Green Chemistry has emerged as an area that permeates all as-pects of chemical science and engineering. Among the mainobjectives of this methodology is the concurrent increase of

the proficient use of safer raw materials and trimming down ofwaste formed in the processes. The “Twelve Principles of GreenChemistry” address numerous concerns, such as the use oftoxic solvents, expensive reagents and catalysts, the number ofchemical steps and their reaction conditions, and the atom-economy of these synthetic protocols.[15–17] A diverse set of ap-proaches can be used to make a process green and sustaina-ble, reflecting the vastness and intricacy of this field.

Reaction solvents have a key influence on the environmentalimpact of chemical processes and also affect cost, safety, andhealth issues. They are essential during several steps, such assubstrate mixing and steady and homogeneous energy supplyfrom solvent to reactant molecules by heat transfer. They arealso known to control the regio- and chemoselectivity of trans-formations in a large number of synthetic processes. Becauseof their volatile and highly inflammable characteristics many ofthese organic solvents are at the central origin of ecologicalpollution. Thus, to make a protocol green and sustainable, pre-venting or minimizing the use of organic solvents is one of thebest ways to achieve this goal.[18–21] This can be achieved by re-placing hazardous solvents with ones that have superior eco-

[a] Dr. V. PolshettiwarKAUST Catalysis Center (KCC)King Abdullah University of Science and Technology,Thuwal 23955 (Saudi Arabia)Fax: (+ 966) 28-08-03-02E-mail : [email protected]

[b] A. Decottignies, Prof. C. Len, Dr. A. FihriTransformations Int�gr�es de la Mati�re RenouvelableESCOM-UTC1-All�e du R�seau Jean-Marie Buckmaster, 60200 Compi�gne (France)Fax: (+ 33) 3-44-97-15-91E-mail : [email protected]

Carbon–carbon cross-coupling reactions are among the mostimportant processes in organic chemistry, and Suzuki–Miyaurareactions are among the most widely used protocols for theformation of carbon–carbon bonds. These reactions are gener-ally catalyzed by soluble palladium complexes with various li-gands. However, the use of toxic organic solvents remains a

scientific challenge and an aspect of economical and ecologi-cal relevance. This Review will summarize various recently de-veloped significant methods by which the Suzuki–Miyaura cou-pling was conducted in aqueous media, and analyzes if theyare “real green” protocols.

Scheme 1. Catalytic cycle for the Suzuki–Miyaura cross-coupling.

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logical, health, and safety properties, such as supercriticalfluids, biosolvents, and ionic liquids. However, their costs, toxic-ity (in the case of ionic liquids) as well as challenging handlingare big concerns when using them as solvents.

Solvent-free processing is another solution, as one of theGreen Chemistry principles state that use of no (toxic) solventmakes a protocol green. However, this is not true in every caseand is in fact an example of how these principles can be misin-terpreted. The principle is only valid and really green if the de-veloped solvent-free protocol works at industry level, or atleast pilot-plant level. Only carrying out the reactions at asmall scale in a laboratory has little value, as at bench scalesuch small amounts of reactants can be mixed without solventwithout also being feasible at kilogram level, where the lack ofa reaction medium may lead to overheating of the reactionmixture because of inadequate heat- and mass-transfer. Natu-rally abundant water is one of the best choices as a reactionmedium because of its nontoxic, noncorrosive, and nonflam-

mable nature. Also, water can be contained because of its rela-tively high vapor pressure compared to organic solvents.These characteristics are encouraging for the use of water as agreen and sustainable alternative.[18–23]

The main difficulty with water as a solvent is that most or-ganic substrates are insoluble in it, making the reaction mix-ture heterogeneous. This can be overcome by using micro-waves as nonconventional heating technique. Under micro-wave irradiation, water (because of its high heat capacity) israpidly heated to high temperatures, enabling it to act as apseudo-organic solvent with precise control of the reactiontemperature.[22]

3. “Real Green” Protocols

Using water as a reaction medium is an excellent way to makea protocol greener. However, solvent replacement in itself maynot be enough. The entire process must be well planned, and

Dr. Vivek Polshettiwar was born in

Mangli (India) in 1979. He obtained his

Ph.D. (2005) under the supervision of

Prof. M. P. Kaushik from Jiwaji Universi-

ty and DRDE, Gwalior (India). He inves-

tigated nanostructured silica catalysis,

with Prof. J. J. E. Moreau and Prof. P.

Hesemann during his postdoctoral re-

search stay at ENSCM, Montpellier

(France) in 2006. He then went on to

research nanocatalysis and MW-assist-

ed new synthetic methods for green

chemistry with Prof. R. S. Varma at the EPA (USA) from 2007–2009.

Currently, he is working as a senior research scientist at the KAUST

catalysis center (Saudi Arabia) directed by Prof. J. M. Basset. His re-

search interests are in the area of advanced nanomaterials for cata-

lysts. He has over 50 publications including various review articles

and book chapters.

Audrey Decottignies was born in

France in 1985. She studied at Lille

University and at Lyon University,

where she obtained her M.Sc. in or-

ganic chemistry. She is currently a

Ph.D. student in the group of Prof. C.

Len, where she works on water-soluble

ligands and their use in catalyzed

cross-coupling reactions under the su-

pervision of Dr. A. Fihri.

Prof. Christophe Len was born in L’Isle

Adam (France) in 1966. He received his

Ph.D. in the field of carbohydrate

chemistry from the University of Picar-

die Jules Verne (UPJV) in Amiens

(France) under the supervision of Pro-

fessor P. Villa. In 1996, he joined Dr G.

Mackenzie’s group at the University of

Hull (UK) as a post-doctoral fellow to

work on the synthesis of nucleoside

analogues. In 1997, he became Ma�tre

de Conf�rences at UPJV and worked

on the chemistry of antiviral nucleoside analogues, specialising in

those with novel glycone systems. He received his habilitation in

2003 and was promoted to Full Professor at the University of Poiti-

ers (France) in 2004. During 2008, he had a secondment to the Uni-

versity of Compi�gne (France) to develop green chemistry. His cur-

rent research interests are the total synthesis of natural products

and bioactive molecules, including carbohydrates, and green

chemistry.

Dr. Aziz Fihri was born in Morocco in

1976. He received his Ph.D. from the

Burgundy University (France), where

he studied under the guidance of Prof.

J.-C. Hierso and Prof. Ph. Meunier. He

focused his efforts on the synthesis of

ferrocenylphosphines and their appli-

cation in catalyzed cross-coupling re-

actions. He then worked as a post-doc-

toral fellow, first with Prof. B. Coq

(ENSCM, France) and then in the

group of Prof. M. Fontecave (Atomic

Energy Center, France). Since 2008 he is a principal research scien-

tist at the ESCOM, and his current research interests include the or-

ganometallic chemistry of palladium, coordination chemistry, and

green chemistry.

504 www.chemsuschem.org � 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemSusChem 2010, 3, 502 – 522

V. Polshettiwar, A. Fihri et al.

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the solvent is only one part of this problem. The atom- andenergy-efficient use of renewable resources should also betaken into consideration. The above-mentioned solubility con-cerns can be overcome by phase-transfer catalysis, but this willmake the process more costly. Also, the isolation of productsfrom aqueous media is another issue. Evaporation of waterfrom the reaction mixture is one of the options, but is not anenergy-efficient procedure.

Although the use of water as reaction medium instead of anorganic solvent can make a protocol green, this is not necessa-rily true in every case. Most aqueous protocols described inpublished reports do use some amount of water as solvent,but also need excessive amounts of toxic organic solvents forworkup (e.g. , product extraction from the water medium). Thismakes the total relative amount of water used in the entireprocess much smaller, negating the main objective of usingwater as a solvent. Such processes can not be described asbeing “real green.” For example, Raines and co-workers carriedout an olefin metathesis in a homogeneous aqueous mediumusing a second-generation Hoveyda–Grubbs catalyst, andclaimed it as a green protocol.[24] However, they did not usepure water as a reaction medium but instead used organic sol-vents with small amounts of water in it, and very often expen-sive deuterated solvents. This does not justify a description ofthe protocol as truly environmentally friendly and sustainable.On the other hand, in a recently reported method, variousolefin ring-closing metathesis protocols proceeded in purewater without any additives or co-solvents.[25] This method canbe labeled as real green.

As a second example, Cadierno and co-workers have devel-oped a nitrile hydration protocol that uses pure water as a re-action medium. Although the protocol is good in terms of re-action conditions and product yield, it requires traditionalworkup procedures that use toxic organic solvents for isolationof the product, lessening the relative overall use of water assolvent.[26] They also made use of expensive ruthenium com-plexes as catalysts, which reduces the economy of the process.In comparison, a similar hydration protocol developed by Pol-shettiwar and Varma proceeds exclusively in aqueous mediawithout requiring any organic solvents, neither at the reactionnor at the workup stage.[27] The protocol also used inexpensivenanoferrite-supported ruthenium hydroxide, making it eco-nomical and sustainable. Thus, this protocol can be said to bereal green.

Organocatalysis has become a very significant area of re-search, and this metal-free approach to the synthesis of organ-ic molecules has attracted worldwide attention. Most of thesereactions are generally carried out in organic solvents, withsome aqueous-phase organocatalytic processes.[28] Althoughwater is an benign solvent and addition of water acceleratesthese reactions, the isolation of final product from the reactionmixture is cumbersome. Most published reports use excessiveamounts of toxic organic solvents for workup , and again thetotal relative amount of water used in the process is muchless. As clearly stated by Blackmond and co-workers :[28] “A ho-listic approach… that considers not only the reaction step butalso the economics and environmental impact of product

workup and reagent preparation provides the key to making aninformed decision on the benefits of water on a case-by-casebasis.” On this basis, a recently developed concept of nano-or-ganocatalysis in an aqueous medium can be described as areal green protocol.[29] The authors conducted the entire pro-cess in pure water, not using a single drop of organic solventfor either the reaction or workup . After completion of the re-action a phase separation occurred, separating the desiredproduct from the aqueous medium and facilitating the isola-tion of the crude product by simple decantation rather than atedious extraction process, thereby eliminating the use of vola-tile organic solvents during product workup . However, watercontaminated with organic materials presents its own signifi-cant environmental issues, which need to be overcome.

Kidwai and co-workers reported the synthesis of 2-amino-chromenes under aqueous microwave conditions. The reac-tions were carried out in saturated aqueous solutions of waterat 560 W for 2–4 min and after simple trituration by cold waterthe solid products were isolated. In this method only waterwas used in both the reaction and workup steps.[30] The samereaction was also studied by Pasha and Jayashankara, who re-placed potassium carbonate by tertabutylammonium bromide(TBAB).[31] Although the reaction rates and product yields weresimilar, their process required extraction with ethyl acetate toisolate the product and expensive TBAB instead of potassiumcarbonate. Thus, when comparing these two protocols onecan designate Kidwai et al.’s protocol as a real green.

In the case of the Suzuki–Miyaura reaction, which is thefocus of this Review, several aqueous protocols are known inthe literature. Very recently Eppinger et al. developed a novelprotocol in which this cross-coupling reaction was conductedat room temperature in pure aqueous buffer.[32] Importantly,they isolated a range of cross-coupling products by simple fil-tration in good yields and purity, and did not use organic sol-vent during the reaction or during the workup. Their methodis an excellent example of real green chemistry.

Thus, the merits of green chemistry process depend notonly on the reaction step but also on the product workupstage, which is of immense importance and a key aspect whendeciding on the greenness and sustainability of an aqueousprotocol.

4. Suzuki–Miyaura Coupling with Water-Solu-ble Phosphines as Ligand

Phosphines can be converted into water-soluble derivatives bythe introduction of polar groups, including carboxylates, sulfo-nates, and ammonium groups (Scheme 2). A large number ofdifferent strategies for Suzuki–Miyaura reactions in water is de-voted to these ligands. In this section we will focus on reac-tions conducted in aqueous media using water-soluble phos-phines combined with different salts.

Polyphenylene polymers can be prepared by Suzuki–Miyauracoupling. For example, Wallow and Novak have preparedpoly(p-quaterphenylene-2,2’-dicarboxylic acid by using thewater-soluble phosphine TPPMS associated with palladium.[33]

The reaction was carried out in a mixture of water/dimethylfor-


Green and Sustainable Syntheses of Biaryls

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mamide (7:3) at 85 8C by employing 1.5 mol % Pd(TPPMS)4

(Scheme 3).

More recently, Cho and co-workers developed a convenientand facile modification of cyclopenta[d][1,2]oxazines through aSuzuki–Miyaura cross-coupling reaction by using the water-soluble phosphine ligand tBu-Amphos.[34] The combination of15.6 mol % Pd(OAc)2 and 15.6 mol % ligand in the presence ofCs2CO3 as base proved to be an efficient system for the cou-pling of 7-iodocyclopenta[d][1,2]oxazines with several aryl bor-onic acids, and afforded a wide variety of 7-arylcyclopenta[d]-[1,2]oxazines in moderate to excellent yields (Scheme 4).

A new class of water-soluble triphenylphosphine analoguesbased on a dibenzofuran moiety was synthesized and tested inSuzuki–Miyaura reaction by Hiemstra and co-workers.[35] The re-actions were carried out in 1:1 or 1:2 H2O/MeCN mixtures with5 mol % Pd(OAc)2 and 15 mol % ligand 1 at temperatures rang-ing from 50–60 8C and Et3N as a base (Scheme 5). The additionof a ligand was essential for the progress of the reaction, asotherwise no product was obtained. However, the coupling ofaryl bromides and chlorides was not reported for this system.

A water-soluble monophosphine ligand, N-(4-diphenylphos-phino)phenylmethylgluconamide (abbreviated GLCAphos), wasintroduced by Miyaura and co-workers.[36] Palladium catalystsbased on this triarylphosphine are effective at low loadings forSuzuki–Miyaura couplings of activated aryl chlorides(Scheme 6). The catalyst prepared from GLCAphos revealed

higher activity than that synthesized from Ph2P(m-C6H4SO3Na)or P(m-C6H4SO3Na)3 for various haloarenes.

Buchwald and co-workers reported that ligands based on di-alkylarylphosphines such as P(Cy)2(o-biphenyl) and P(tBu)2-(o-biphenyl) are very effective catalysts for palladium-catalyzedSuzuki–Miyaura reactions of aryl bromides and chlorides. Re-markably, these catalyst systems couple a broad spectrum ofaryl chlorides, such as electron-neutral and electron-rich sub-strates, at room temperature.[37–42] In this context, Miyaura andco-workers prepared the first hydrophilic gluconamide-modi-fied version of this class of ligands (Scheme 7).[43] The catalyst

Scheme 2. Water-soluble phosphine ligands employed in Suzuki–Miyaura re-actions.

Scheme 3. Synthesis of poly(p-quaterphenylene-2,2’-dicarboxylic acid) byusing Suzuki–Miyaura coupling.

Scheme 4. Suzuki-Miyaura coupling of 6-iodocyclopenta[d][1,2]oxazines witharyl boronic acids using tBu-Amphos.

Scheme 5. Suzuki–Miyaura reaction in the presence of a water-soluble sulfo-nated dibenzofuran-based phosphine ligand.

Scheme 6. Suzuki–Miyaura cross-couplings of activated aryl chlorides with 4-methylphenylboronic acid.



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formed in situ from Pd(OAc)2 and 3 exhibited a higher efficien-cy than with 4, TPPMS, or TPPTS. Interestingly, the Pd(OAc)2/3catalyst system gave comparable activity to a triphenylphos-phine gluconamide 2 catalyst for the Suzuki–Miyaura couplingof 4-bromoanisole at 80 8C, however at room temperature cat-alyst 2 was more active (Scheme 8). For the same reaction,

Pd(PPh3)4 yielded 74 % at 80 8C and was not active at roomtemperature. In addition, the 3/Pd catalyst also showed activitytowards 4-chlorobenzoic acid at 80 8C, while the catalyst de-rived from 2 was completely inactive. Due to the electron-withdrawing properties of the SO3

� group (sm = 0.30),[44] andstrong electron-donating abilities of alkylphosphines, the ob-served relative efficiency is in the order of the donating abili-ties of the ligands, except for 4.

In a similar way, Framery and co-workers reported the syn-thesis and catalytic activity of a new hydrosoluble glucosa-mine-based dicyclohexylarylphosphine 5.[45] Pd(OAc)2 com-bined with this phosphine (1 mol % Pd, 3:1 5/Pd) gave an ef-fective catalyst for the Suzuki–Miyaura coupling of activatedaryl chlorides at 80 8C in toluene/ethanol/water (3:2:2). Unacti-vated aryl chlorides did not couple in satisfactory yields underthese conditions (Scheme 9). These results are quite similar tothose published by Miyaura and co-workers using the glucona-

mide derivative of triphenylphosphine,[43] and similar activitieswere observed.

Tsai and co-workers developed a water-soluble palladium(II)/cationic 2,2’-bipyridyl catalyst, and evaluated its catalytic activi-ty in the Suzuki–Miyaura reaction in aqueous and aerobic con-ditions.[46] The catalyst showed good activity for activated anddeactivated aryl bromides at 100 8C using K2CO3 as base. In ad-dition, the recycling of the catalyst was briefly examined in thecoupling of phenylboronic acid with 4-bromoacetophenoneusing K2CO3 as the base and 0.1 mol % of catalyst. The recycledcatalyst was used without any appreciable loss of activity, al-though the reaction time increased with each cycle(Scheme 10). For the reactions of aryl chlorides, this systemgave satisfactory results in terms of yield; however, highertemperatures and longer reaction times were needed in addi-tion to the use of a phase-transfer agent.

Savignac and co-workers have examined the cross-couplingof 4-iodoanisole with phenylboronic acid in aqueous acetoni-trile (H2O/MeCN, 1:3) by employing a catalytic amount of hy-drosoluble catalyst (Pd:TPPTS, 2.5 mol %).[47] It is interesting tonote that inorganic bases such as K2CO3, Ba(OH)2, and Cs2CO3

were found to be inefficient while triethylamine and diisopro-pylamine led to the biphenyl products in good yield, and abetter yield was observed with diisopropylamine compared totriethylamine (Scheme 11). The principal drawback to this pro-tocol lies in its use of expensive aryl iodide electrophiles.

In a subsequent study, the same research group expandedthe initial results to aryl bromides. Suzuki–Miyaura cross-cou-pling reactions between a range of aryl bromides and boroniccompounds can be performed under mild conditions withhigh efficiencies and turnover numbers.[48] The process toler-

Scheme 7. Hydrophilic phosphines analogues of the (biaryl)dialkylphos-phines.

Scheme 8. Effect of ligands on the coupling of 4-methylphenylboronic acidwith 4-bromoanisole.

Scheme 9. Cross-couplings of unactivated aryl chlorides with 5/Pd(OAc)2.

Scheme 10. Coupling of phenylboronic acid and 4-bromoacetophenoneover five cycles.

Scheme 11. Cross-coupling of phenylboronic acid with 4-iodoanisole in thepresence of TPPTS.



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ates electron-rich and electron-poor substituents and providesan efficient access to sterically hindered biaryls (Scheme 12).This TPPTS/Pd(OAc)2 catalyst system has been applied to the

synthesis of Xenalipin, a potential cholesterol-reducing drug(Scheme 13).[48] The recycling of this catalyst system was ex-plored in the model coupling of 4-bromobenzaldehyde and

phenylboronic acid. The results obtained shown that the cata-lyst can be recycled three times without loss of activity. Thecross-coupling of aryl chlorides was unfortunately not reportedfor this catalytic system under these conditions.

The catalytic system TPPTS/PdCl2 was employed by Hoechstin the Suzuki–Miyaura cross-coupling of 2-chlorobenzonitrilewith 4-methylphenylboronic acid for the commercial produc-tion of 2-cyano-4’-methylbiphenyl, which is a key intermediatein the synthesis of angiotension II receptor antagonists thatare used for the treatment of hypertension (Scheme 14).[49, 50]

Shaughnessy and Booth have prepared two sterically de-manding, water-soluble alkylphosphines based on PtBu3 (tBu-Pip-phos and tBu-Amphos) and used them in Suzuki–Miyauracouplings of aryl bromides in aqueous acetonitrile (1:1) atroom temperature.[51] The authors disclosed that combinationsof Pd(OAc)2 and theses alkylphosphines are effective catalystsfor the coupling of a wide variety of aryl bromides with boron-ic acids (Scheme 15). Interestingly, cyclohexyl-substituted li-gands, such as Cy-Pip-phos and DCPES gave less-active cata-

lysts. In addition, the coupling of phenyl boronic acid with acti-vated aryl chlorides such as 4-chlorobenzonitrile in the pres-ence of tBu-Pip-phos/Pd(OAc)2 required high catalyst loadings(4 mol %) and higher temperatures (80 8C) to achieve goodyields (92 %), while tBu-Amphos/Pd(OAc)2 gave only 64 % yieldunder the same conditions. Both tBu-Amphos and tBu-Pip-phos gave low conversions (<30 %) with 4-chlorotoluene and4-chloroanisole under these conditions.

The water-soluble phosphines tBu-Amphos and tBu-Pip-phos combined with palladium(II) salts also gave highly activecatalysts for the Suzuki–Miyaura coupling of aryl bromides in amixture of water/toluene (1:1) or in neat water at room tem-perature.[52] Interestingly, the catalysts derived from these li-gands were found to be significantly more active than catalystsderived from TPPTS and DCPES. The recyclability of the tBu-Amphos/Na2PdCl4 catalyst was explored in the Suzuki–Miyauracoupling of 4-bromotoluene and phenylboronic acid in a 1:1water/toluene solvent system. The catalyst system was recy-cled three times before its activity began to drop appreciably;the reasons for the loss of activity are not known.

The authors have also prepared sterically demanding, water-soluble analogues of TPPTS such as TXPTS and TMAPTS. Theyfound that these ligands, when combined with palladium ace-tate, provide active catalysts for Suzuki–Miyaura couplings of avariety of aryl bromides with arylboronic acids in aqueous ace-tonitrile (H2O/MeCN, 1:1) at modest temperatures (50–80 8C;Scheme 16).[53]

In an independent study, the same group established thatwater-soluble phosphine TPPTS combined with Pd(OAc)2 is anefficient catalyst for the aqueous-phase modification of unpro-

Scheme 12. Cross-coupling of a variety of aryl bromides and boronic acidsusing Pd(OAc)2/TPPTS.

Scheme 13. Synthesis of Xenalipin by Suzuki–Miyaura reaction.

Scheme 14. Synthesis of 2-cyano-4’-methylbiphenyl by Suzuki–Miyaura reac-tion.

Scheme 15. Suzuki–Miyaura couplings using tBu-Pip-phos or tBu-Amphos/Pd(OAc)2.



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tected halonucleosides.[54] The combination of 2.5 mol %Pd(OAc)2 and 6.25 mol % TPPTS in the presence of Na2CO3 asthe base proved to be an efficient system for the coupling of8-bromo-2’-deoxyguanosine with arylboronic acids to give 8-aryl-2’-deoxy-guanosine adducts in excellent yield in a mixtureof water/acetonitrile (2:1) (Scheme 17). Importantly, the TPPTS

ligand was found to be superior to water-soluble alkylphos-phines for this coupling reaction. The coupling chemistry hasbeen extended to 5-iodo-2’-deoxyuridine and 8-bromo-2’-de-oxyadenosine as well as the ribonucleosides 8-bromoguano-sine and 8-bromoadenosine (Scheme 18).

Despite being out of the main scope of the present Review,the first example of the use of porphyrins as catalysts inSuzuki–Miyaura reactions by Kostas and co-workers is worthmentioning.[55] They synthesized a palladium complex with a

phosphine-free and water-soluble potassium carboxylate saltof a porphyrin, which served as an efficient precatalyst for theSuzuki–Miyaura cross-coupling of electron-poor or -rich arylbromides with phenylboronic acid under mild reaction condi-tions, in neat water and in air (Scheme 19). The feasibility of re-

cycling and reusing the catalyst was explored for the couplingof phenylboronic acid with 4-bromobenzonitrile as a model re-action. The reaction was repeated at 100 8C for 4 h, for up tothree cycles, but unfortunately the catalyst exhibited a loss inactivity (cycle 3: 53 % yield).

Plenio and co-workers synthesized a disulfonated stericallydemanding and electron-rich fluorenylphosphine 8 in threesteps, from simple and commercially available starting materi-als.[56] The authors disclosed that the combination of 0.02–0.1 mol % Pd and two equivalents of the triply protonatedligand in the presence of K2CO3 as base was an effective cata-lyst for aqueous Suzuki–Miyaura coupling reactions of N-heter-ocyclic chlorides with a broad range of aryl boronic acids(Scheme 20). The authors extended the procedure to also in-

Scheme 16. Suzuki–Miyaura coupling using TXPTS or TMAPTS/Pd(OAc)2.

Scheme 17. Synthesis of 8-aryl-2’-deoxyguanosine adducts.

Scheme 18. Suzuki–Miyaura coupling of 8-bromo-2’-deoxyadenosine witharyl boronic acids.

Scheme 19. Suzuki–Miyaura cross-coupling in water, catalyzed by a palladi-um–porphyrin complex.

Scheme 20. Suzuki–Miyaura reaction of N-heteroaryl chlorides in water.



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clude the coupling of 2-chloropyridines and 2-chloroquinolineswith 3-pyridine boronic acid. Accordingly, quantitative forma-tion of the respective coupling products was achieved using0.1 mol % catalyst leading at 100 8C in pure water as solvent.

In a very recent study, Plenio and co-workers also reportedan efficient protocol for the Suzuki–Miyaura coupling of unpro-tected 6-chloropurines with various aryl boronic acids in awater/n-butanol mixture or in water alone, using the highlywater-soluble fluorenylphosphine 9 as the ligand.[57] Catalystloadings between 0.5 and 2 mol % Na2PdCl4 and twice as muchphosphine was sufficient to obtain good isolated yields(Scheme 21)

Uridine diphosphate-sugars are the natural donor substratesfor a large number of carbohydrateactive enzymes, includingglycosyltransferases and epimerases.[58] In this regard, the syn-thesis of novel 5-substituted uridine diphosphate-glucose de-rivatives with interesting fluorescent properties and potentialapplications as sensors for carbohydrate-active enzymes wasreported by Wagner and Pesnot.[59] They were synthesized bySuzuki–Miyaura coupling reactions between arylboronic acidsand 5-iodo uridine diphosphate-glucose in neat water usingNa2Cl4Pd/TPPTS as catalytic system (Scheme 22). Interestingly,the optimized cross-coupling conditions could also be applied

successfully to 5-bromo uridine monophosphate, but not to 5-bromo uridine diphosphate-glucose. No examples were report-ed with 5-chloro uridine monophosphate and 5-chloro uridinediphosphate-glucose.

5. Suzuki–Miyaura Coupling with Palladacyclesas Catalyst

Palladacycles are compounds that contain one palladium–carbon bond intramolecularly stabilized by one or two neutraldonor atoms. Since their discovery in the mid-1960s, thesecompounds are of great interest today because of their easyaccessibility, which makes it possible to modulate both theirsteric and electronic properties and their catalytic efficiency incarbon–carbon cross-coupling reactions.[60, 61]

To date, there are relatively few examples of water-solublepalladium catalysts used in Suzuki–Miyaura coupling. N�jeraand co-workers have used an oxime-derived palladacyclic com-plex as a catalyst for couplings of aryl bromides and chloridesin aqueous media under aerobic conditions using the TBAB asadditive.[62] The coupling of various aryl bromides with phenyl-boronic acid at catalyst loadings as low as 0.001 mol % oc-curred in excellent yields, whereas aryl chlorides requiredhigher reaction temperatures and higher catalyst loadings(Scheme 23). The catalyst was thermally stable, not sensitive toair or moisture, and readily accessible from inexpensive start-ing materials.

In related work, Botella and N�jera have reported that air-and water-stable oxime palladacycles such as 11 represent an-other class of non-phosphorus-based ligands for Suzuki–Miyaura couplings of unactivated aryl chlorides in neat water(Scheme 24). They observed that 11 catalyzes cross-couplings

Scheme 21. Suzuki–Miyaura coupling of 6-chloropurine nucleosides with Pd/ligand 9.

Scheme 22. Suzuki–Miyaura coupling of 5-iodo uridine diphosphate-glucosewith various arylboronic acids.

Scheme 23. Suzuki–Miyaura coupling of aryl chlorides using palladacycle 10.

Scheme 24. Suzuki–Miyaura coupling of unactivated aryl chlorides and phe-nylboronic acid in water using palladacycle 11.



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of a range of aryl and heteroaryl chlorides, including electron-rich substrates, in water in variable yields.[63] The recycling ofthe catalyst has been briefly examined in the coupling of p-chloroacetophenone with phenylboronic acid. Unfortunately,the catalytic activity and the recyclability dropped significantlyin the fourth cycle.

In their study in 2005, Liu and co-workers have reported thesynthesis of benzylic palladacyles and its catalytic activitytoward Suzuki–Miyaura coupling in neat water under aerobicatmosphere.[64] This catalyst prepared from an imine precursorshowed high catalytic activity in the coupling of aryl bromideswith phenylboronic acid, with turnover numbers reaching upto 106. However, the coupling of aryl chlorides required longertimes, higher catalyst loadings, and gave significantly loweryields as compared to aryl bromides (Scheme 25). It is interest-ing to note that for the chloride substrates, the addition of tet-rabutylammonium bromide was required for the better conver-sion.[64]

More recently, Shaughnessy and co-workers have synthe-sized two water-soluble palladacycles from benzylamine orbenzaldehyde imine ligands bearing hydrophilic functionalgroups (13 and 14 ; Scheme 26.[65] These hydrophilic palladacy-

cles gave active catalysts for the Suzuki–Miyaura coupling ofactivated and deactivated bromides substrates in combinationwith tBu-Amphos at 80 8C after 4 h with catalyst loadings aslow as 0.02 mol % Pd in neat water. Under the same condi-tions, both catalysts gave modest yields in the coupling ofphenylboronic acid with 4-chlorobenzonitrile

The recycling of catalysts derived from tBu-Amphos and pal-ladacycles 13 and 14 was explored in the cross-coupling of 4-bromotoluene with phenylboronic acid. The reaction was car-ried out in water at 80 8C for 1 h. The catalyst derived from pal-

ladacycle 13 worked well up to four cycles of quantitativeyield, before the efficiency of the catalyst began to degrade.The catalyst derived from 14 could be used 12 times before asignificant loss of catalyst activity was observed. This degree ofrecyclability is one of the highest reported in the literature fora Suzuki–Miyaura coupling of an aryl bromide using a homo-geneous catalyst.

More recently, Li and Wu developed a palladacyclic complexderived from sulfonated naphthoxazole ligand that can be em-ployed for Suzuki–Miyaura reactions in neat water under aero-bic conditions.[66] The system is very efficient for the couplingof aryl bromides and moderate to good yields were obtained(Scheme 27). Unfortunately, the catalyst gave little or no yieldswith aryl chlorides.

6. Microwave-Assisted Suzuki–Miyaura cou-pling reactions

Microwave irradiation has become very important in organicreactions in the last decade, and it is reasonable to assert thatthere are now very few areas of organic chemistry that havenot been shown to be enhanced by using microwave heating.In their study in 1996, Larhed and Hallberg were the first toreport general conditions for the enhancement of the Suzuki–Miyaura cross-coupling reaction by microwave irradiation.[67]

Phenylboronic acid was coupled with 4-methylphenyl bromideto give a modest yield of coupling product accompanied bybiphenyl formation (Scheme 28).

Leadbeater and Marco have also developed a methodologyfor the ligand-free microwave-mediated Suzuki–Miyaura cou-pling in aqueous media.[68] A wide range biaryls can be pre-pared from phenylboronic acid and aryl iodides, bromides, andchlorides (Scheme 29). This methodology has the advantage oflow catalyst loadings (0.4 mol %), short reaction times (5–10 min), and ease of reaction. Applying the same protocol, a10-fold scale-up was possible under microwave-assisted open-vessel reflux conditions for 10 min at 110 8C, achieving yieldsnearly identical to the closed-vessel runs. Importantly, the com-

Scheme 25. Coupling of aryl chlorides with phenylboronic acid using palla-dacycle 12.

Scheme 26. Cross-couplings of phenylboronic acid with 4-chlorobenzo-ni-trile using 13 and 14/tBu-Amphos.

Scheme 27. Coupling of aryl bromides with phenylboronic acid catalyzed by15 in water.

Scheme 28. Coupling of phenylboronic acid with 4-bromotoluene.



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parison of the reactions performed using microwave heatingwith those using conventional thermal heating showed thatusing these conditions probably no non-thermal microwave ef-fects were associated with the impressive speed of the reac-tion.[69]

In another study, the same research group also showed thatby using low catalyst concentrations, Suzuki–Miyaura couplingscan be performed in open reaction vessels under microwaveheating (Scheme 30). This is particularly noteworthy because

an open vessel reaction is a much safer option for scale-uppurposes. This technology is also an excellent substitute for re-actions running in continuous-flow microwaves, when the han-dling of solids as well as highly viscous liquids or heterogene-ous reaction mixtures is often problematic. The reaction is scal-able from the millimol to the mol scale with no need for re-op-timization, and it can be performed in aqueous ethanol using1–5 ppm Pd as the catalyst.[70]

Arvela and Leadbeater have recently developed a methodol-ogy for the Suzuki–Miyaura coupling of aryl chlorides withphenylboronic acid in the presence of palladium on carbon asa catalyst using water as a solvent, and using of simultaneouscooling in conjunction with microwave heating.[71] They dem-onstrated that the cooling can significantly prolong the life-time of the aryl chloride substrates during the course of the re-action and increased the product yield as well as overall recov-ery of material (Scheme 31).

Buchwald and Anderson have reported the synthesis andthe catalytic activity of sodium 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl-3’-sulfonate, which incorporates a water-solubilizing sulfonate group, for the Suzuki–Miyaura couplingof aryl chlorides with arylboronic acids in water.[72] A large vari-

ety of both hydrophobic and hydrophilic substrates, includingheterocyclic compounds, could be coupled in excellent yieldsand even at room temperature (in some cases). Microwave ac-tivation (150 8C) allowed substantial shortening of reactiontimes and reducing of the catalyst loading, from 2 to0.1 mol %, without any decreases in activity (Scheme 32).

Using similar reaction conditions, Shaughnessy et al.’smethod for Suzuki–Miyaura reactions in aqueous media wasfurther optimized and applied to the synthesis of novel purine-amino acid conjugates.[54, 73] An efficient single-step synthesis ofoptically pure (adenin-8-yl)phenylalanines and (purin-6-yl)phe-nylalanines was elaborated using both classical heating andmicrowave irradiations. Classical heating was more efficient forthe synthesis of 8-substituted nucleosides and more labile nu-cleotides, while microwave heating was more efficient forpurine bases and 6-substituted nucleosides (Scheme 33). Thereactions were fast under microwave irradiation in the pres-ence of 13 mol % of TPPTS and 5 mol % of Pd(OAc)2 in a water/acetonitrile mixture.[74]

A new air- and moisture-stable palladium complex contain-ing salicylaldehyde N(4)-hexamethyleneiminylthiosemicarba-zone has been designed by Loupy and co-workers.[75] Thiscomplex was inactive towards Suzuki–Miyaura coupling underaerobic conditions, by conventional heating. On the otherhand, microwave irradiation promoted the effective catalyticactivity of the complex for the coupling of aryl bromides withphenylboronic acid in DMF/H2O, under conditions strictly simi-lar to those used under conventional heating, with turnovernumbers of up to 37 000 (Scheme 34). The coupling of the acti-vated 1-chloro-4-nitrobenzene with phenylboronic acid yieldedonly 25 % of coupling product after 1 h at 155 8C. These resultsled the authors to propose that specific microwave effects

Scheme 29. Microwave-mediated Suzuki–Miyaura coupling in water usingPd(OAc)2.

Scheme 30. Suzuki–Miyaura reactions in open vessels with ultralow catalystloadings.

Scheme 31. Suzuki–Miyaura coupling using microwave heating with simulta-neous cooling.

Scheme 32. Suzuki–Miyaura coupling of aryl chlorides using microwaveheating

Scheme 33. Synthesis of (adenin-8-yl)phenylalanines.



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rather than thermal effects may be responsible for the acceler-ation of this reaction.

Another example of a simple, but potentially valuable, trans-formation was described by L�pine and Zhu.[76] They investi-gated a concise and efficient total synthesis of Biphenomycin B(Scheme 35), which is a cyclic tripeptide and displays potent

activity against Gram-positive, b-lactam-resistant bacteria, suchas Streptococcus aureus, Enterococcus faecalis, or Streptococcus.The authors performed the macrocyclization to furnish the 15-membered ring system of the molecule in a yield of 50 % by amicrowave-assisted, intramolecular Suzuki–Miyaura reaction. Itis particularly noteworthy that the microwave-assisted proce-dure gave a rewarding 33 % yield when simple Pd(OAc)2 wasused in the absence of any ligands, whereas the use of muchmore specific catalytic systems met with failure or furnishedvery low yields of the target biaryl compound when performedunder conventional heating conditions.

In another example of microwave-enhanced palladium cata-lyzed transformations, the Larhed group demonstrated theprospect for functionalization of peptides from an aryl iodide(Scheme 36).[77] They developed the rapid syntheses of 24novel C2-symmetric HIV-1 protease inhibitors by using of a vari-ety of palladium-catalyzed carbon–carbon reactions, includingSuzuki–Miyaura cross-couplings under microwave-assisted con-ditions. The combination of 10 mol % Pd(OAc)2 and 20 mol %[(tBu)3PH]BF4 in the presence of K2CO3 as base proved to be an

efficient system for Suzuki–Miyaura reactions in a mixture ofwater/1,2-dimethoxyethane (1:3) at 120 8C. The prospect forprotein functionalization in the future is very clear from thisvery interesting piece of work.

In 2005, the research group of Van der Eycken developed anovel microwave-enhanced, transition-metal-mediated proto-col for the synthesis of N-shifted buflavine analogues.[78] Thekey biaryl-generating step was performed by using a palladi-um-catalyzed Suzuki–Miyaura reaction upon focused micro-wave irradiation. Ring-closing metathesis (RCM) reactions weresuccessfully employed to generate the rigid, medium-sizedring systems of the target molecules. Again, microwave irradia-tion was found to be highly beneficial in overcoming the highactivation barrier of the reaction. The reactions were per-formed with 5 mol % of tetrakis(triphenylphosphine)palladi-um(0) as catalyst and NaHCO3 as base in a mixture of DMF/H2O (1:1) at 150 8C (Scheme 37).

Using similar reaction conditions, the same authors havealso developed the synthesis of ring-expanded buflavine ana-logues possessing a 9-membered medium-sized ring system(Scheme 38).[79] Microwave-enhanced Suzuki–Miyaura cross-coupling and ring-closing metathesis reactions were used askey steps. The Suzuki–Miyaura reaction, which is often prob-lematic in case of cross-coupling between an electron-rich aryl

Scheme 34. Microwave-promoted Suzuki–Miyaura cross-coupling of aryl bro-mides with phenylboronic acid catalyzed by palladium complex 16 in air.

Scheme 35. Microwave-assisted synthesis of Biphenomycin B.

Scheme 36. Microwave-assisted synthesis of HIV-1 protease inhibitors.

Scheme 37. Microwave-assisted synthesis of N-shifted buflavine analogues.



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halide and an electron-poor boronic acid, has been successfullyapplied under microwave irradiation conditions. The combina-tion of a second-generation Grubbs catalyst and microwave ir-radiation has proved to be highly useful in generating the oth-erwise difficult to synthesize 8- and 9-membered ring systems.

Dawood evaluated the catalytic activity of benzothiazole-based PdII-complexes 17 and 18 in Suzuki–Miyaura cross-cou-pling reactions of aryl bromides and chlorides with phenylbor-onic acid both under thermal as well as microwave irradiationconditions in water. These precatalysts were found to be effi-cient and highly active for activated aryl bromides and hetero-cyclic bromides, with very high TONs, under thermal heatingas well as microwave irradiation conditions. Deactivated arylbromides were more effective than their chloride analogs. Theimmobilized catalyst 18 anchored to a glass/polymer compo-site material shaped as Raschig rings was found to have highdurability compared to the mobilized catalyst 17. The highTONs associated with these catalysts is highly important formass production on industrial scale (Scheme 39).[80]

Nucleoside derivatives occupy a pivotal position in the ar-senal of drug candidates for combating various viruses.[81, 82] 5-Aryltriazole acyclonucleosides with various aromatic groups onthe triazole ring belong to an important class of biologicallyactive nucleosides. They were synthesized via a simple and effi-cient one-step procedure involving the direct Suzuki–Miyauracoupling of the unprotected 5-bromotriazole acyclonucleosidein aqueous solution under microwave irradiation(Scheme 40).[83] This coupling method directly afforded the cor-

responding product in good to excellent yield and involved noprotection and deprotection steps.

7. Suzuki–Miyaura Couplings by Using Alterna-tive Nucleophilic Partners

Generally, Suzuki–Miyaura reactions are carried out utilizingboronic acids or esters, however, more recently alternativeboron reagents have been developed for use in Suzuki–Miyaura reactions. Among these, potassium organotrifluorobo-rate salts are easier to prepare, store, and handle compared toboronic acids or esters.[84, 85] In 2006, the group of Leadbeaterdeveloped a protocol for coupling a wide range of aryl iodidesand bromides in good yields using low catalyst loading(Scheme 41). However, these conditions were not effective for

the widely available, low-cost aryl chlorides.[86] Another inter-esting report parallel to the Leadbeater protocol, investigatingthe microwave-assisted Suzuki–Miyaura reactions of variousaryl halides with potassium organotrifluoroborates, has recent-ly appeared.[87] The method does not require the use of phos-phine ligands or phase-transfer catalysts. The authors indicatethat the reactions can be carried out using PdCl2 as the cata-lyst and K2CO3 as the base in aqueous methanol, and all reac-tions are complete in 20 min (Scheme 42).

Aryl triflates can be utilized as substrates to substitute thearyl halide in Suzuki–Miyaura couplings.[88] These coupling re-actions can be conducted in aqueous ethanol in the absence

Scheme 38. Microwave-assisted synthesis of ring-expanded buflavine ana-logues.

Scheme 39. Suzuki–Miyaura reactions under thermal and microwave heatingusing benzothiazole-based PdII complexes.

Scheme 40. Suzuki–Miyaura coupling between 5-bromotriazole acyclonu-cleoside and various boronic acids.

Scheme 41. Suzuki–Miyaura coupling reactions of aryl halides with potassi-um organotrifluoroborates.



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of a base and ligand under microwave irradiation, and the de-sired products were obtained in good to excellent yieldswithin 15 min at 90 8C (Scheme 43).

8. Suzuki–Miyaura Couplings in Non-Ionic Am-phiphilic Water

One recent innovation, introduced by Lipshutz and co-workersas a contribution to green chemistry, concerns the use ofdilute aqueous solutions containing nonionic amphiphiles inwater as the only solvent, promoting different carbon–carboncoupling reactions.[89, 90] They disclosed that inexpensive andcommercially available nonionic amphiphiles such as Triton X-100 or the vitamin E-derived polyoxyethanyl a-tocopheryl se-bacate (PTS; Scheme 44) form nanometer-sized particles in

water and promote Heck cross-couplings of non-water-solublepartners at ambient temperatures.[91] Concerning the Suzuki–Miyaura reaction, the authors established that the coupling ofaryl iodide with arylboronic acids requires only 1–2 wt % PTS inwater in presence of 2 mol % of the PdCl2{1,1’-bis(di-tert-butyl-phosphino)ferrocene} (abbreviated Pd(dtbpf)Cl2) at ambienttemperature.[92] Lower amounts of PTS gave higher levels ofconversion more rapidly than did solutions containing 5, 10, or15 wt % in water. The coupling of electron-rich, electron-poor,and sterically congested aryl bromides was equally possible inexcellent yields above 76 % at room temperature (Scheme 45).

Other surfactants such as TRITON X-100, TPGS, and Brij 30served in a similar capacity to varying extents. However, PTSwas the carrier of choice for a wide range of aryl bromides andboronic acids. As the authors noted, a decisive advantage ofPd(dtbpf)Cl2 is its robustness towards air and moisture, whichallows its use in water.

Reactions in PTS/H2O with aryl chlorides showed the expect-ed drop in reactivity compared to iodides and bromides. It wasfound that the N-heterocyclic carbine containing complex 19(Scheme 46) led to efficient cross-coupling between arylboron-

ic acids and aryl chlorides at ambient temperatures. For exam-ple, in presence of complex 19, the reaction of 2-chloro-1,3-di-methylbenzene with 2,3-dimethylphenylboronic acid gave asatisfactory yield of up to 98 % after only 4 h at ambient tem-perature, whereas the Pd(dtbpf)Cl2 was less effective and only28 % of coupling product was obtained after 24 h at 50 8C. Sur-prisingly, under otherwise identical conditions, Pd(dtbpf)Cl2 didnot satisfactorily mediate reactions between aryl bromides andarylboronic acids.

In a subsequent study, the same research group expandedthe initial results by the application of the Pd(dtbpf)Cl2 toSuzuki–Miyaura coupling reactions of several water-insoluble

Scheme 42. Microwave-accelerated Suzuki–Miyaura coupling reactions usingpotassium aryltrifluoroborates.

Scheme 43. Suzuki–Miyaura reactions of potassium aryltrifluoroborates saltswith aryl triflates.

Scheme 44. Structural comparisons between PTS, TPGS, TRITON X-100, andBrij 30.

Scheme 45. Suzuki–Miyaura reactions of aryl bromides using Pd(dtbpf)Cl2 inPTS-water.

Scheme 46. Catalyst complexes used in Suzuki–Miyaura cross-couplings inPTS-H2O.



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aryl/heteroaryl bromides with aryl/heteroaryl boronic acids.[93]

The good conversions obtained with 2 mol % Pd(dtbpf)Cl2 and2 mol % PTS in water in the presence of 3 equiv of triethyla-mine as base in 4 to 20 h at room temperature or 40 8C(Scheme 47).

In an extension to this work, the authors found that PdCl2-{PtBu2(Ph-p-NMe2)}2 20 also gave a higher yield for the cou-pling of heteroaromatic chlorides with non-heteroaromaticboronic acids (Scheme 48).[93] PTS was the best surfactantamong those surveyed, but the authors did not explain thecause of this reactivity difference. They only indicated that PTSappeared to provide a hydrophilic lipophilic balance and parti-cle size that best accommodated both educts and catalysts.

9. Suzuki–Miyaura Coupling Using Silica-Sup-ported Palladium Catalysts

The Suzuki–Miyaura reactions is generally carried out in a ho-mogeneous phase, because of the higher reactivity, higherturnover numbers, milder reaction conditions, and notably thepossibility of coupling the widely available and low-cost arylchlorides.[94, 95] Homogeneous catalysis, most notably in water,offers unique opportunities to minimize solvent waste; howev-

er, separation of the catalyst from the product continues topose difficulties and recycling is often troublesome and costly.Heterogeneous Pd catalyst systems have been found highly ef-fective in overcoming some of these challenges, because theycan be easily separated from a reaction mixture by simple fil-tration or magnetic attraction and reused in successive reac-tions provided that the active sites have not become deactivat-ed.[96–98] Simplification of workup protocols and handling ofcatalysts are especially important factors for the industrial ap-plications of catalysts. Importantly, because metal contamina-tion is highly regulated by the pharmaceutical industry, with-out any further purification these leach-proof catalysts leaveno metal remnants in the end products. The chemical stabilityof the inorganic supports is important, especially under oxidiz-ing conditions. This is why the majority of heterogeneous cata-lysts are based on silica supports, primarily because silica dis-plays some advantageous properties, such as excellent stabili-ty, good accessibility, and porosity, and because organicgroups can be robustly anchored to the surface to provide cat-alytic centers.

An example of a Suzuki–Miyaura coupling using water-solu-ble ligands on MCM-41 support was described by Kosslick andco-workers, designing the MCM-41-supported Pd starting fromsurfaces functionalized propylsulfonic groups. The alkylsulfo-nated support was prepared by bi- or tridentate anchoring ofmercaptopropyltriethoxysilane on the walls of Al-MCM-41, fol-lowed by oxidation with hydrogen peroxide to the corre-sponding sulfonic acid. These functionalized supports werethen coated with a mixture of Pd(OAc)2 and a water-solublephosphine ligand, such as Ph2P(CH2)2S(CH2)3SO3Na or PdCl2-[Ph2P(CH2)4SO3K]2 (catalyst 21 a, Scheme 49). Moreover, the al-kylsulfonated Al-MCM-41 material was made amphiphilic bythe adsorption of the surfactant cetyltrimethylammonium bro-mide (CTAB; catalyst 21 b), followed by exposure to the sameprecursor complex. The quaternary ammonium ion not onlychanged the surface polarity, but also served as phase-transferagent in the Suzuki–Miyaura reaction.[99, 100]

The resulting heterogeneous catalysts were tested for thecoupling of p-iodoanisole with phenylboronic acid in a bipha-sic toluene/ethanol/water mixture in the presence of Na2CO3

as base and the amphiphile CTAB as phase transfer reagent(Scheme 50). The catalyst 21 b displayed a much-enhanced ac-tivity in comparison to the parent catalyst 21 a (90 % vs. 2 % in

Scheme 47. Cross-couplings of aryl/heteroaryl bromides with aryl/heteroarylboronic acids using Pd(dtbpf)Cl2 in 2 % PTS/water.

Scheme 48. Couplings of heteroaryl chlorides with non-heteroaromatic bor-onic acids using catalyst 20 in different surfactants.

Scheme 49. Propylsulfonic-functionalized MCM-41-supported Pd catalysts.



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10 min). This was ascribed to a micellar effect, with the amphi-philic solid improving the mixing of the two liquid phases.However, a subsequent run with 21 b revealed a decreased ac-tivity, possibly due to loss of the quaternary ammonium com-pound from the support. The authors indicated that the activespecies may not only be the anchored PdII complexes, but alsodeposited Pd0 clusters, formed by decomposition of PdII reac-tion intermediates.

Corma and co-workers have established that an oxime-car-bapalladacycle complex covalently anchored onto mercapto-propyl-modified silica (Scheme 51) catalyzed cross-couplings of

halobenzenes with phenylboronic acid in aqueousmedia.[101, 102] This catalyst was found to be very active in thecoupling of 4-chloroacetophenone and 4-bromoacetophenonewith phenylboronic acid in refluxing water, whereas the samesubstrates were converted in only moderate yields in refluxingwater in the presence of TBAB. The authors indicated that afterfiltration and washing with ethanol and ether, the silica-sup-ported Pd was recovered and was used eight times without anoticeable decrease in the activity. The catalyst was shown tobe superior when supported on silica in comparison with mes-oporous MCM-41 or polymeric supports derived from styreneor methyl acrylate. The authors attributed this to an easieraccess to the surface active sites in silica support.

Corma and co-workers have also prepared a periodic meso-porous organosilicas (PdL@PMO) incorporating a carbapallada-cycle (Scheme 52).[103] The resulting materials showed the or-dering and structure expected for an MCM-41 silica. The cata-lytic activity of these mesoporous catalyst been examined inthe Suzuki–Miyaura cross-coupling of aryl bromides and chlor-ides with phenylboronic acid in water in the presence of K2CO3

as base. These catalysts showed significantly higher activity foraryl bromides than that of a related amorphous silica catalystcontaining the same complex, but this mesoporous solid wasinefficient in catalyzing the coupling of chlorosubstituted de-

rivatives. The solid can be reused although a progressive deac-tivation caused by decomposition of the initial oxime carbapal-ladacycle. The authors believe that this catalyst transformationcould be responsible for the progressive decrease in the con-version upon reuse. Importantly, the X-ray diffraction of theused catalyst after the sixth use showed that the structure ofperiodic mesoporous organosilica was completely collapsed,and the material has become an amorphous solid.

More recently, Xiao and co-workers have described the syn-thesis and the catalytic activity of a new palladium catalystsupported on PEG-modified mesoporous silica. This mesopo-rous catalyst was obtained from coated mesoporous materialswhich contained a layer of readily available PEG with a labilecoordinating ability for palladium (Scheme 53).[104] Under the

various conditions explored, the prepared catalysts proved ef-fective in Suzuki–Miyaura couplings of a variety of aryl bro-mides, aryl iodides, and chlorobenzene with different aryl bor-onic acids (Scheme 54).

The catalyst was recycled several times with no detectabledeactivation and no leaching of the catalyst to the organiclayer. The authors indicated that the catalyst remained activeafter exposure to air for up to six weeks, and they attributedthe high activity and stability of the mesoporous structure ofmaterial. A study on a more diverse array of substrates wouldbe necessary to determine the scope of this catalyst.

Crudden and co-workers have shown that thiol-functional-ized mesoporous silicate leads to an effective catalyst for

Scheme 50. Cross-coupling of p-iodanisole with phenylboronic acid usingcatalyst 21 b.

Scheme 51. Results of the Suzuki–Miyaura cross-coupling reaction of halo-benzenes with phenylboronic acid in aqueous media using supported cata-lyst 22.

Scheme 52. Synthesis of periodic mesoporous silica through co-condensa-tion of a carbapalladacycle complex and tetraethoxysilane.

Scheme 53. Synthesis of a mesoporous silica-supported catalyst.



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Suzuki–Miyaura reactions of 4-chloroacetophenone and arylbromides with phenylboronic acid in aqueous media(Scheme 55). Fairly good to excellent yields of the coupling

products were obtained at 90–100 8C in the presence of1 mol % SBA-15-SH-Pd. The SBA-15-SH-Pd catalyst was reusedfour times with virtually no loss of activity. Heterogeneity tests,such as hot filtration experiments and three-phase tests,showed that the reaction occurred predominantly via surface-bound Pd.[105]

Bannwarth and co-workers originally developed the first ap-plication of a precatalyst supported on a fluorous solid supportin catalytic cross-coupling.[106, 107] The Suzuki–Miyaura couplingreaction of phenylboronic acid with 4-bromo-a-hydroxybenze-neacetic acid was examined using water as the sole reactionsolvent and a complete conversion of expected product wasobtained with 0.1 mol % of 23 a–d (Scheme 56). The perform-ances of Pd-complex 23 a on fluorous reversed phase silica gel(FRPSG) 23 in water of water-soluble aryl bromides with sever-al phenylboronic acids have been evaluated. Fairly good to ex-cellent yields of the coupling products were obtained exceptin the case of 2-bromobenzoic acid, which is probably due tosteric hindrance of the o-carboxyl group (Scheme 57). TheFRPSG-supported catalysts were separated by simple filtration,and the catalysts could be reused several times without signifi-cant loss of efficiency. An advantage of this strategy comparedto conventional covalent catalyst immobilization is that thesame support can be used for different catalysts, without theneed for a separate linker unit.

Williams and co-workers have reported the use of reverse-phase silica in the in the Suzuki–Miyaura reaction of severalboronic acids with a large range of water-soluble aryl iodidesand bromides in neat water.[108] The reverse-phase catalyst wasprepared by treatment of derivatized silica (reverse-phasesilica) with palladium acetate and triphenylphosphine in cyclo-hexane. In general, the reactions were completed in 1.5–4 hwith low levels of palladium leaching, even though theselevels were higher than for ordinary-phase glass beads. In addi-tion, the recycling of the reverse-phase glass beads was brieflyinvestigated in the coupling of 3-bromophthalic acid with 4-carboxyphenyl boronic acid, and the initial results showed thatthe catalyst could be recycled at least once without any loss ofactivity. Unfortunately, a very low yield or no product was ob-tained in the coupling of aryl chlorides. Nonetheless, thismethodology could be extended to a larger-scale synthesis(Scheme 58).

More recently, Wang and Cai have shown that perfluoro-tagged palladium nanoparticles can be successfully immobi-lized onto a fluorous silica gel (Scheme 59), and the resultingcatalyst could efficiently catalyze the Suzuki–Miyaura reaction

Scheme 54. The SBA-Si-PEG-Pd(PPh3)n-catalyzed Suzuki–Miyaura coupling ofvarious substrates.

Scheme 55. SBA-15-SH-Pd-catalyzed Suzuki–Miyaura reactions.

Scheme 56. Suzuki–Miyaura reactions performed with 0.1 mol % of 23 a–dimmobilized on support 23.

Scheme 57. Suzuki–Miyaura reactions with different substrates in the pres-ence of 23 a on support 23.

Scheme 58. Cross-coupling of 4-formylphenylboronic acid with 5-bromo-pyridine-3-carboxylic acid using a reverse-phase silica-supported catalyst ona larger scale.



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in refluxing water in the presence of TBAB and K2CO3.[109]

Under the optimized conditions the performance of this cata-lyst, Pd-24/FSG, was evaluated for a wide range of aryl bro-mides. As shown in Scheme 60, aryl bromides bearing either

electron-donating or electron-withdrawing substituents at theortho and para positions, afforded the corresponding biphen-yls in good to excellent yields. Aryl trifluoromethanesulfonateand aryl perfluorooctanesulfonate were more active than bro-mobenzene in terms of yield as well as the time. However,chlorobenzene was not active for the reaction and an onlymoderate yield was obtained, even when the catalyst loadingwas increased to 1 mol %. The recycling of this catalyst was ex-amined in the coupling of aryl trifluoromethanesulfonate, arylperfluorooctanesulfonate, and bromobenzene with phenylbor-onic acid, and the results obtained showed that the catalystcould be recycled at least once without any loss of activity.

The group of Pleixats prepared a surface hybrid silica materi-al containing di(2-pyridyl)methylamine–palladium dichloridecomplex covalently bound to the silica matrix by using a sol-gel process (Scheme 61). This material was very active in thecoupling of 4-bromoacetophenone with phenylboronic acid,even after 10 consecutive cycles.[110, 111] They were also activefor the coupling of 3-chlorobenzonitrile with phenylboronicacid. However, a study on a more diverse array of substrateswould be necessary to determine the scope of these catalysts.

More recently, the same research groups have also describedthe synthesis of organic–inorganic hybrid silica materials frommonosilylated imidazolium and disilylated dihydroimidazoliumsalts in acidic conditions, using NaBF4 and 1-cetyl-3-methylimi-dazolium chloride as cationic surfactant (Scheme 62).[112] Theauthors explored the catalytic activity of systems formed byPd(OAc)2 and this hybrid silica material in Suzuki–Miyaura reac-tions of aryl chlorides. They observed that the catalytic systemsserved as efficient and versatile catalysts for aryl bromides with

phenylbornic acid in a mixture of H2O/DMF at 110 8C(Scheme 63). The recycling was successfully conducted on arylbromides. However, activity and recyclability with aryl chlorideswas modest. Also, in situ formation of palladium nanoparticleswas observed in recycling experiments.

The research group of Zhang developed a highly effectivesilica-supported N-heterocyclic carbene (NHC)–palladium cata-lyst for the cross-coupling of aryl bromides with phenylboronicacid in neat water under air without a phase-transfer re-agent.[113] By using this solid support, cross-coupling of highlyelectron-rich substrates, such as methoxy-substituted aryl bro-mides, as well as several nitrogenated heteroaryl bromides wasrealized and the desired products was obtained in moderateto excellent yield (Scheme 64). Unfortunately, the coupling of

Scheme 59. Preparation of fluorous nanoparticle stabilizers and fluoroussilica gel-supported Pd catalyst.

Scheme 60. Pd-24/FSG-catalyzed Suzuki–Miyaura reactions.

Scheme 61. Reusability of catalysts 25 a–c for the Suzuki–Miyaura reactionof 4-bromoacetophenone with phenylboronic acid over ten consecutive re-cycling experiments.

Scheme 62. Synthesis of hybrid silica materials M1–M3.

Scheme 63. Suzuki–Miyaura cross-couplings between phenylboronic acidsand aryl bromides using Pd(OAc)2/M systems.



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aryl chlorides was not reported using this system in water andtheir couplings were achieved only in refluxing n-butanol. Thesolid-support-based NHC–palladium complex could be storedfor more than two months without significant loss of activity,and could be reused 2–3 times in the coupling of aryl bro-mides and phenylboronic acid. The authors indicated that nopalladium black formation was observed during the catalyticprocess.

Finally, in a sequential approach, Jin and co-workers used animmobilized NHC–Pd complex prepared by reaction of silica-supported imidazolium chloride with Pd(OAc)2 for Suzuki–Miyaura cross-couplings.[114] High catalytic activity was ob-served in the coupling of deactivated aryl iodides such as 2-io-doanisole, 4-iodo-anisole, 2-iodotoluene, and 4-iodophenol aswell as activated 1-iodo-4-nitrobenzene and 1-iodo-3-nitroben-zene with phenylboronic acid. Deactivated aryl iodides pos-sessing an electron-donating group showed a slight drop in re-activity compared to those possessing an electron-withdrawinggroup. However, only a slightly longer reaction time was re-quired to reach almost quantitative conversion. Electron-rich,electron-neutral, and electron-poor aryl bromides were also ef-ficiently coupled with arylboronic acids containing electron-do-nating and electron-withdrawing substituents in an aqueousmedium (Scheme 65).

The authors also tested the coupling of several aryl chloridesin the presence of 1 mol % catalyist. The reaction of chloroben-

zene with phenylboronic acid proceeded smoothly to affordthe desired product with high yields. However, low yields wereobserved in the coupling of substituted aryl chlorides. The cat-alyst was easily recoverable and reusable, without a significantloss of catalytic activity, as well as air-stable to allow easy use.

10. Summary and Outlook

During the past decade, many reactions that were convention-ally believed to occur only in organic solvents have been de-veloped in water as a solvent, because reactions in aqueousmedia offer many advantages, particularly the environmentalfriendliness and low cost of naturally abundant water. Amongthe various reactions developed, we have found that theSuzuki–Miyaura coupling protocol is an excellent example ofthis development and has strongly benefited from aqueouschemistry. However, despite this impressive progress, anumber of challenges remain untapped: the coupling of thereadily available and low-cost aryl chlorides continues to posedifficulties and the difference between their activity in homo-geneous and heterogeneous phases is very high. Future re-search will also certainly be aimed at the determination of re-action mechanisms, to help to design economical and high-performance catalysts.

As a final note, despite the fact that water is the cheapestand safest solvent, its presence is generally avoided throughthe dehydrative drying of substrates and solvents for moisture-sensitive reactions. Thus, the use of water as a medium whenreplacing these organic reactions is one of the latest challeng-es for modern organic chemists.

Acknowledgements

We thank G. Santini for his support of this work and the R�gionPicardie for their financial support.

Keywords: cross coupling · green chemistry · microwavechemistry · palladium · sustainable chemistry · water chemistry

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Scheme 64. Cross-coupling mediated by a solid support-based NHC-palladi-um complex in neat water.

Scheme 65. Suzuki–Miyaura coupling of various aryl bromides and iodideswith arylboronic acids.



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