Inorganica Chimica Acta 363 (2010) 1903–1911

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Inorganica Chimica Acta

journal homepage: www.elsevier .com/locate / ica

Review

Taylor-made palladium–pincer complexes: A new source of more efficientcatalysts for sustainable organic synthesis

Isabel Moreno, Raul SanMartin *, Blanca Inés, Fátima Churruca, Esther Domínguez *

Kimika Organikoa II Saila, Zientzia eta Teknologia Fakultatea, Euskal Herriko Unibertsitatea, Sarriena Auzoa, z/g, 644 P.K., 48080 Bilbao, Spain

a r t i c l e i n f o

Article history:Received 24 November 2008Received in revised form 28 January 2009Accepted 4 March 2009Available online 13 March 2009

Dedicated to Prof. Umberto Belluco.

Keywords:PalladiumPincerCatalysisCross-couplingSustainable protocols

Isabel Moreno receivedPIFA in synthetic chemistr

Raul SanMartin is an Assthe supervision of Prof. T.Gallagher group at the Unappointed Associate Profearylation reactions applyi

0020-1693/$ - see front matter � 2009 Elsevier B.V. Adoi:10.1016/j.ica.2009.03.003

* Corresponding authors. Tel.: +34 946015435; fax:E-mail address: raul.sanmartin@ehu.es (R. SanMar

a b s t r a c t

The synthesis and catalytic activity of different pincer type palladium complexes synthesized in our lab-oratory are compiled in this report. The specific design of these palladacycles allows the employment ofsustainable protocols and the recycle of the catalytic systems.

The results obtained by our group in this context will be compared with other previously reported andnew advances in this field.

� 2009 Elsevier B.V. All rights reserved.

his Ph.D. from de University of the Basque Country in 2001 working on the applications of the hypervalent iodine reagenty. Since 2002, she is Assistant Professor in the same University.

ociate Professor with tenure at the University of the Basque Country. After a short predoctoral stay at Boston College underRoss Kelly, he obtained his Ph.D. in 1997. Then, granted a Doctorate Extraordinary Award, he joined Professor Timothy C.iversity of Bristol as a postdoctoral researcher, working on selective O- and C-glycosylations of 2-galactosamine, and wasssor in 2000. His research interests deal mainly with the development of new catalytic systems for arylation and hetero-ng sustainability criteria.

ll rights reserved.

+34 946012748.tin).

Blanca Inés received her degree in Chemistry from the University of the Basque Country in 2005. Currently she is a Ph.D. student in the sameUniversity under the supervision of Professors Raul SanMartin and Esther Domínguez. Her Thesis work is based on the synthesis and catalyticapplications in cross-coupling reactions in aqueous media of new palladium pincer complexes. She was in the University of Cologne (Germany) for hershort stay under the supervision of Dr. Bernd Goldfuss.

Fátima Churruca studied Organic Chemistry and received her Ph.D. degree, which was granted a Doctorate Extraordinary Award, from theUniversity of the Basque Country in 2003. After two years as Ph.D. lecturer and postdoctoral researcher in the field of Organometallic Chemistry at theUniversity of the Basque Country, she went on to Oxford, where she joined Timothy J. Donohoe’s group in a postdoctoral position for 2006–2007,working on the total synthesis of natural products. Since 2008, she is with the group of Professor A. Giannis (Germany), where she is currently workingas postdoctoral fellow of the international Human Frontier Science Program Network.

Esther Domínguez received her ph.D. in 1975 Supervised by Prof. L. Castedo. After a stay in 1976 at the London University College working at thegroup of Prof. P.J. Garratt, she occupied several academic positions at the University of the Basque Country until her appointment as Full Professor in1989. She has been Head of the Departments of Organic Chemistry and Organic Chemistry II in the periods 1992–1998 and 2001–2007, respectively,and presently is the Dean of the Faculty of Science and Technology and Vice-President of the Organic Chemistry group of the Spanish Royal Society ofChemistry. Her research interests are heterocyclic and natural products chemistry.

1904 I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19042. Symmetric pincers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1904

2.1. NCN-type complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19052.2. PCP-type complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19062.3. CNC-type complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1907

3. Unsymmetric PCN pincers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19084. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1910

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1910References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1910

1. Introduction

Palladium catalysts have become fundamental tools for a num-ber of organic reactions. In the last decade, the following three top-ics have attracted much attention: (i) minimizing the relativeamount of the metal containing catalyst, (ii) its recovery and recy-cling and (iii) the employment of environmentally more friendlymethodologies.

Among the plethora of procedures developed to reach the afore-mentioned goals, the use of pincer type palladium complexes, thatis, palladacycles containing tridentate ligands, has received specialattention not only because of the appropriate balance between sta-bility and reactivity but also for their high catalytic activity [1].Moreover, the specific design of this type of complexes allowsthe use of sustainable protocols such as aqueous media or eventheir anchorage to solid supports, which makes easier the isolationof the reaction products as well as the recovery and recycle of thecatalyst [2].

Following our research on the development of new catalyticsystems and their application in C–C bond formation processes,several palladium pincer complexes have been prepared in our lab-oratories and tested as catalysts in different reactions. In this re-port, we wish to summarize the results achieved by our group inthis context, with emphasis on the so-called ‘‘green chemistry”.In addition, a critical comparison with related complexes fromsources other than our own is also provided.

2. Symmetric pincers

Initially, on the basis of a much simpler synthetic sequence,we considered that pincer complexes with two identical donorgroups were more appropriate to start our research in thisfield. Taking into account the already existing examples of sym-metric pincer construction, we introduced slight modificationsin order to improve catalytic efficiency and/or sustainabilitycriteria.

I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911 1905

2.1. NCN-type complexes

Although the synthesis and properties of several NCN-pincerpalladium complexes were well documented [3], their applicationas catalysts in organic transformations was, in our opinion, scar-cely studied. To the best of our knowledge, when this researchwas started, no more than six of such complexes had beenapplied to cross-coupling reactions [4] and, only five of theseprecedents contained two heterocycle units as the source of bothN-donor atoms. Magil et al. had described the use of the cationicPd(II) complex A, which included a tridentate ligand composed ofa NHC moiety attached to two picolyl fragments, in the couplingof 4-bromoacetophenone with n-butyl acrylate recording TOFvalues slightly higher than 5000 h�1 [4a]. Better results were re-ported by Jung et al. with an unusual NCN pincer B. The presenceof additional N atoms, which probably provides it a less rigidcoordination to the metal, constitutes the principal feature of thispalladacycle. Complex B turned out to be exceptionally active ascatalyst in Heck reaction, since an outstanding TON value of4.3 � 106 was achieved [4b]. Another report pertinent to our caseis the work described by Díez-Barra et al., regarding the applica-tion of the triazolic complex C to the Heck vinylation of arylchlorides. Remarkable TON number values were achieved when18-crown-6 (86000) or TBAB (83000) were used as additives[4c]. Soro and co-workers prepared pincer D, in which twopyridines work as the source of N-donor atoms, and reported rel-atively good results in the Heck reaction between iodobenzeneand methyl acrylate [4e,4f]. Finally, Gupta et al. described thesynthesis of 1,3-phenylene-bis-(1H)-tetrazole pincer ligand E,and its employment along with Pd(OAc)2 in Suzuki cross-couplingreaction. It is noteworthy, however, that low TON values wereachieved in this case (20–100) [4d] (see Fig. 1).

Encouraged by the lack of literature about this type of com-pounds, we turned our attention on the design, preparation and

N

NO

O N

N

R

R2a: R= H2b: R= Me

NHN

R

R

Cs2CO3, MeCN

reflux

Br

BrO

O

1

Scheme 1. Synthesis of palladium

NN

N N

+

[BF4]-

PdN

NNN

NNI

PdNX

A

C D

PdMe

Fig. 1. Previous examples of NCN pincers empl

application as catalysts of new NCN pincer complexes [5]. So, weplanned the synthesis of the tridentate ligands 2a and 2b shownin Scheme 1, bearing an arene moiety flanked by two pyrazolylm-ethyl units capable of coordination to the metal. As a part of ourongoing research on the development of heterogeneous catalysts,and having in mind an ulterior anchoring to an insoluble support,a para-methoxycarbonylated arene moiety was employed for fur-ther functionalization.

As shown in Scheme 1, nucleophilic substitution in readilyavailable dibromide 1 provided ligands 2a–b. The key palladationstep leading to complexes 3a–b was performed by a proceduresimilar to that reported by Steel and co-worker [6].

Our attention was then focused on the evaluation of their cata-lytic activity in different organic reactions. Facing the enormoussynthetic potential, cross coupling methodologies in general, andHeck and co-workers [7] or Suzuki and co-workers [8] reactionsin particular, were initially chosen as model reactions to test thecatalytic ability of palladacycles 3a–b.

With regard to Heck reaction, different aryl bromides were cou-pled with styrene or methyl acrylate in the presence of catalyticamounts of 3a–b under standard conditions (Na2CO3, DMF,140 �C), providing in all cases good to excellent yields and moder-ate TON values up to 71000 (e.g. 71% yield of E-methyl cinnamatewhen 0.01 mol% Pd was employed). Interestingly, very similaryields and TON values were obtained from both catalysts 3, sug-gesting a low influence of the 3-methyl groups in the reactionoutcome.

Concerning Suzuki coupling, excellent results were achieved. Infact, several electronically dissimilar aryl bromides were efficientlycoupled with a number of arylboronic acids in quantitative yieldswhen minimal catalytic loadings of 3 were employed. A compari-son with the previously commented reports revealed that theTON values achieved with palladacycles 3a and 3b (up to8600000) were the highest described up to then for a Suzuki–

1) Pd(OAc)2,R

R

AcOH, reflux

2) LiCl,acetone, H2O

3a: R= H3b: R= Me

N

N

N

N

R

R

RPd Cl

R

O

O

NCN pincer complexes 3a–b.

PdN

N

N

N

N

NNN N

NNN N

E

B

X

oyed to promote cross-coupling reactions.

13 examplesYields ranging 92-100%TONs up to 8,600,000

8 examplesYields ranging 82-100%TONs up to 71,000

3pyrrolidine

100ºC

ArB(OH)2Ar-Ar

K2CO3, H2O 100ºC

3

K2CO3, DMF140°C

R2 R2Ar3

R1 H

Ar-X

ArR114 examplesYields ranging 77-100 %TONs up to 80000

N

N

N

N

R

R

RPd Cl

R

O

O

R= H 3aR= Me 3b

Scheme 2. Catalytic ability of NCN pincer complexes 3.

1906 I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911

Miyaura coupling catalyzed by a NCN pincer complex. Moreover, acomprehensive screening of different reaction conditions showedneat water as the optimal solvent with all the advantages impliednot only in terms of sustainability, safety and economy, but alsothose related to an easier work-up and purification procedures.

Sonogashira reaction, that is, the coupling of aryl halides withterminal acetylenes to produce aryl alkynes [9], had been a processscarcely explored with pincer complexes. To the best of our knowl-edge, only three reports had appeared in the literature and the re-sults achieved in this sense were just modest. Eberhard et al.described the application of a PCP phosphinite pincer complex inSonogashira reaction, but relatively high amounts of catalyst(5 mol%) and an additive (ZnCl2) were necessary [10]. Loch et al.evaluated the catalytic activity of a CNC pincer complex in differentreactions, and although excellent TON values were achieved inHeck coupling, the results obtained in Sonogashira were not good[11]. Finally it is noteworthy the report by Mas-Marzá et al. con-cerning the application of a clay supported CNC pincer in Sono-gashira reaction. In this case, once again, TON values were onlymoderate [12]. In addition, it should be pointed out that no NCNpincer complex had ever been applied to the coupling of aryl ha-lides with alkynes.

Accordingly, the evaluation of the catalytic potential of com-plexes 3 in this reaction became the next target. Again, both pin-cers 3a and 3b turned out to be adequate catalysts for thistransformation when optimized conditions were used (0.1 mol %of 3, pyrrolidine, 100 �C). It is noteworthy that the latter reactionconditions avoided the use of any copper co-catalyst or co-solvent(pyrrolidine was easily eliminated in vacuo) thus increasing the va-lue of the methodology. Concerning the TONs achieved, althoughinferior to the aforementioned ones in the Suzuki reaction withthese palladacycles, constituted a substantial improvement com-paring with the previously commented results, as an excellent va-lue of 80000 was obtained (see Scheme 2).

It should be mentioned that after the publication of our work,Luo et al. described the synthesis of a series of NCN-type pincercomplexes based on a bis(oxazole) ligand. These palladacycles

PR2

Pd

PR2

X

O PR2

Pd

O PR2

X

G

O P(OR)2

Pd

O P(OR)2

X

O PR2

Pd

PR2

X

F H I

Fig. 2. Typical structures of PCP pincers complexes.

proved to be adequate catalysts in the Suzuki couplings but provid-ing TON values slightly lower than those achieved with our NCNpincer complex [13].

2.2. PCP-type complexes

In contrast to NCN pincer complexes, the synthesis and applica-tion as catalysts or catalyst precursors [14] of PCP palladacycleshad been studied by several research groups. In fact, palladatedbis(alkylphosphine) pincers F [15,16], bis(phosphinite) complexesG [17], bis(phosphite) complexes H [18], or even unsymmetricalderivatives I [14,19] had exhibited excellent catalytic propertiesin a wide variety of metal-mediated organic transformations(Fig. 2).

Three aspects were considered on designing our PCP complexes.First, the easier synthesis of phosphinite ligands from commer-cially available and inexpensive precursors, in contrast with theusually tedious preparation of phosphine derivatives [18b]. Sec-ond, the higher catalytic activity of phosphinite complexes [20],and finally, once again the insertion of an ester group that couldfacilitate the subsequent immobilization of the palladacycles to asolid support [21].

On the basis of these premises, complexes 5 were easily pre-pared by slight modifications of procedures described in the liter-ature [18a,b]. As can be seen in Scheme 3, a one-potphosphorylation/palladation sequence was carried out startingfrom commercially available ethyl 3,5-dihydroxybenzoate 4. Pin-cers 5a–b were found to be air- and thermally stable.

To our delight, when the catalytic activity of PCP complexes 5aand 5b was tested in Heck, Suzuki and Sonogashira cross-couplingreactions employing the previously optimized conditions for NCNpincers, good yields and TON values were achieved.

Encouraged by the fact that PCP complexes had shown promis-ing results as catalysts in other Pd-catalyzed organic transforma-tions [22], and taking into account our previous experience in a-arylation of ketone enolates [23], we next envisaged the use of pin-cers 5 in this reaction. It is noteworthy that our work would consti-tute the first report regarding the application of a pincerpalladacycle to promote the arylation of enolates.

According to our experience, deoxybenzoins were challengingsubstrates to accomplish initial assays. In view of the results sum-marized in Scheme 4, a series of electronically dissimilar deoxy-benzoins were successfully arylated, when relatively low catalystloadings (0.1 mol%) were employed. This methodology was alsoefficiently applied to the a-arylation of a symmetric dialkyl ketone,cyclohexanone, with several arylbromides. Moreover, a-mono- ordiarylation of methyl aryl ketones were performed selectively.

OR1

R2

+ ArBr OR1

R2Ar

O + ArBr O

Ar

O

R1

+ 2 ArBr

O

R1Ar

Ar

6 examples78-96%

3 examples78-88%

6 examples88-99%

5 examples84-88%

i

i

i

i

i. 5 (0.1 mol%), Cs2CO3, DMF

Scheme 4. Enolate arylation reactions catalyzed by PCP pincer complexes 5.

OH

OH

EtOOC

1. PClR2, Et3N, PhMe, reflux

2. PdCl2COD, PhMe, reflux (5a)EtOOC

O

O

Pd

PR2

PR2

X

5a R=iPr, X=Cl (92%)

5b R=Ph, X=OCOCF3 (56%)

4

or2. Pd(OCOCF3)2, THF, rt (5b)

Scheme 3. Synthesis of PCP pincer complexes 5.

I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911 1907

Therefore, we demonstrated that PCP pincer complexes 5a and 5bare effective catalysts not only for standard cross-coupling reac-tions but also for a-arylation of ketones.

It should be pointed out that as a consequence of the excellentresults achieved with this type of palladacycles, several groupshave continued designing and employing as catalytic systems no-vel PCP pincer ligands. For instance, Ogo et al. prepared a seriesof water soluble palladacyclic aqua complexes, and tested theircatalytic ability in Heck, Suzuki, and Stille reactions in water[24]. Kirchner and co-workers have reported a new generation ofPCP ligands based on 1,3-diaminobenzenes, which upon phosphor-ylation and metallation provide phosphinoamide complexes[25,26].

2.3. CNC-type complexes

The first palladium pincer carbene complex which revealed tobe an active catalyst for the Heck reaction was described by Crab-

NPd

N N

NR

NRBr

Br-

J: R= MeK: R= Bu

NN N

N N

Pd

R R

L

Br

Fig. 3. CNC pincers complexes emplo

tree and co-workers (Fig. 3J) [27]. In spite of the relatively good re-sults obtained, the principal disadvantage of this catalytic systemwas the relatively high temperatures required and its low solubil-ity in solvents commonly used to perform Heck couplings [28]. Dif-ferent structural changes were proposed in order to solve thesolubility issue and further explore the catalytic potential of theframework. For example, the introduction of methylene spacersbetween the rings (Fig. 3 L) [29], or the replacement of N-methylgroups by larger alkyl substituents in imidazole rings (K) [11,30].More recently, Hahn et al. [31] prepared the lutidine-brigdedbis(benzimidazolium) dibromides and the corresponding palla-dium pincer complexes M and observed a catalytic behaviour inHeck reaction similar to that reported by Crabtree et al.

As mentioned in the introduction, the easy recovery and recy-cling of the catalytic systems is one of the most important aimsof the researches carried out in this field. In this context, the immo-bilisation of active homogeneous catalysts to insoluble supportshas become a popular strategy to facilitate their reuse. With regard

Br-

NN N

N N

Pd

Br-

R R

M

Br

yed in cross-coupling reactions.

1908 I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911

to CNC pincer complexes, this type of palladacycles has been an-chored to different clays [12,32] or solid polymers [33]. The princi-pal advantage of this methodology is the easier separation of thecatalyst from the reaction products with equal or even higher cat-alytic activity comparing with the corresponding homogeneouscounterparts. However, the recyclability of these heterogeneoussystems is strongly dependent on the nature of the immobilisation,and most of them require multistep synthesis. So, when wedecided to design a CNC pincer complex capable of catalyzingcross-coupling reactions and easy to be reused/recycled, we ex-plored a simpler strategy [34]. Thus, the projected structure in-cluded a functional group hydrophilic enough to work in aqueousmedia. Once the reaction is finished, after separation by simpleextraction with a suitable organic solvent, the aqueous phase,and consequently the catalytic system, could be reused. If our pre-mise was fulfilled, this methodology would combine the advanta-ges of homogeneous and heterogeneous catalysts.

Treatment of readily available 6 with n-butylimidazole pro-vided intermediate 7, which was palladated with Pd(OAc)2/DMSOin a similar way to the work by Carbtree et al. [11] providing targetcomplex 8 in a 93% overall yield (Scheme 5). It should be pointedout that concomitant hydrolysis occurred in the transformationof 6 into 7.

Following our protocol, to test the catalytic activity of the pre-pared CNC pincer complex, we selected Suzuki–Miyaura reaction.Thus, a series of electronically dissimilar arylboronic acids werequantitatively coupled with several bromoarenes, employingK2CO3 as base, and neat water as solvent (Scheme 6). To our delightthe catalytic activity of this CNC pincer complex was outstanding,reaching TON values of 109 which constituted, as far as we know,the best ones ever achieved in Suzuki coupling not only with pincercomplexes but also with any other palladium catalyst.

With these excellent results in hands, our attention was then fo-cussed on catalyst separation and reuse. In fact, as expected, a sim-ple extraction with dietylether allowed a ready separation of theproducts from the hydrophilic catalyst 8. The resulting aqueouslayer was employed without further treatment in successive runs,with just addition of substrates and base. The recyclability of the

NHOOC

N

N

Br

R1+ K2CO3, H

100º C

B(OH)2

R2

Scheme 6. Suzuki reaction in water ca

NHOOC

N

N

NEtOOC

Br

Br

NN nBu

DMF

6

Scheme 5. Synthesis

catalyst was confirmed since the reaction was repeated up to 5times without observing any loss of catalytic activity.

Considering the results achieved with this type of catalytic sys-tems, currently, CNC pincer complexes continue attracting greatattention. For example, Wei et al. have described the synthesisand catalytic utility in Suzuki reaction of a new CNC pincer com-plex, but relatively high loadings (1%) were necessary [35]. Onthe other hand, Tu et al. have reported a microwave-assisted syn-thesis of a novel CNC pincer complex. This palladacycle constitutesan excellent catalyst in Heck and Suzuki reactions in NMP, provid-ing TONs up to 8.8 � 106 and 1.5 � 108, respectively [36].

3. Unsymmetric PCN pincers

Although the presence of two different donor groups can pro-vide unique properties and reactivity, relatively few reports onthe synthesis and applications of this type of palladacycles haveappeared in the literature. As far as we know, only four PCN com-plexes have been described as catalysts in cross-coupling reactions[37,38]. So, DuPont and co-workers designed unsymmetrical palla-dacycles N and O bearing a central vinyl anion (Fig. 4). The study ofthe catalytic behaviour of the latter compounds revealed that bothof them were efficient promoting Suzuki and Heck reactions, but interms of catalytic activity, the phosphine containing complex O re-sulted to be more active than the phosphinite analogue N, provid-ing good TON values in the alkenylation of aryl iodides (up to 106)[39].

More recently Gong et al. have reported the synthesis and appli-cation in Suzuki coupling of palladacycles P and Q (Fig. 4) that fea-ture a phenyl backbone, a phosphinito and amino (P) or pyrazolyl(Q) groups [26].

The above-mentioned scarcity encouraged us to explore the de-sign, synthesis and catalytic activity of a new PCN palladacycle 12as part of our ongoing research on the development of new cata-lysts based on pincer complex structures [40].

Following the synthetic sequence depicted in Scheme 7, the keyintermediate amine 10 was prepared by reduction of readily avail-

N

N

nBu

nBu

Pd Br

Br-

19 examplesyields ranging 92-99%

TON up to 109

reusable 5 runs without loss of activity

2OR1 R2

talyzed by CNC reusable pincer 8.

NHOOC

N

N

N

N

nBu

nBu

Br-

8

N

N

nBu

nBu

2 Br-Pd(OAc)2

DMSO

7

Pd Br

+

+

of NCN pincer 8.

PdPR2

O

NMe2

Cl

Cl NMe2

Pd

Cl

ClPR2

N O P

PdN

NO

R'2P R

RCl

Q

Pd NEt2O

Ph2PCl

Fig. 4. Unsymmetrical PNC pincers complexes employed in cross-couplingreactions.

I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911 1909

able pyrazol 9. After treatment with ClPPh2, the so-obtained unsta-ble ligand 11 was palladated in situ, providing the target PCN pin-cer complex 12 [41].

Having fully characterized this unusually structured palladacy-cle, a number of different assays was set in order to evaluate itscatalytic profile.

Initially, we focused our attention on Hiyama coupling, anemerging process in Pd–pincer catalysis [42]. Instead of using fluo-ride additives to promote the transmetallation step, the recentmodification using hydroxide anion was preferred as it allowedaqueous media [43].

Thus, a several aryl bromides were coupled with (trimethoxysi-lyl)benzene, in the presence of sodium hydroxide and employingneat water as solvent. Although in some cases the yields obtainedwere only moderate (Scheme 8), and the catalytic loadings rela-tively high (2 mol%) [44], it should be noted that this constituted,as far as we known, the first example of a Hiyama coupling per-formed by a pincer complex.

Copper-free Sonogashira coupling was the next process cho-sen to examine the catalytic activity of PCN complex 12. Accord-ingly, arylation of phenylacetylene with a range of aryl iodideswas performed providing moderate to good yields in most cases

9 10

reflux

EtOH, AcOH ClPPh2, NEt3

PhMe:hexane 9:1

N N

NO2

N N

NH2

Fe

Scheme 7. Synthesis of unsym

X

R1+ K2CO3

100º

B(OH)2

R2

12 (0.01

X= Cl, Br, I

Scheme 9. Biaryl synthesis by Suzuki cou

R1PyrrolidineH2O, 50º C

PhCCH12 (2 mol%)

R1

7 examplesyields ranging 16-83%

Ph

Scheme 8. Sonogashira and Hiyama reac

[40]. In comparison with NCN palladacycles 3, this nonsymmet-ric PCN pincer produced a catalyst of lower efficiency but al-lowed the reaction to be run in aqueous solution with therelevant advantages: safety, non-toxicity, environmental benigni-ty and economy.

Finally, the catalytic effectiveness of unsymmetrical pincer 12in Suzuki–Miyaura reaction was thoroughly tested and the opti-mized reaction conditions were set as shown in Scheme 9. Dueto the hydrophilicity of the pincer pincer ligand [41], the reactionswere best performed in water, where an array of arylboronic acidsreacted with the suitable aryl halides affording the correspondingbiaryls in good to excellent yields. Moreover an outstanding TONvalue of 8.2 � 106, the highest in a Suzuki coupling performed withan unsymmetrical pincer palladacycle, was achieved in this envi-ronmentally friendly process [40].

Having demonstrated that unsymmetrical complex 12 was asuitable catalyst to promote Suzuki–Miyaura arylation betweentypical arylboronic acids and aryl halides, next, we attempted toexpand the methodology to include several non-usual substrates[45] such as alkylboronic acids or non-aryl halides. Even if the Su-zuki-like coupling of these substrates has been much less investi-gated, some recent papers have shown that PCP or NCNcomplexes are feasible catalysts for these reactions [46–49].

The PCN complex was an active catalyst even towards theseuncommon substrates and promoted efficiently the relevant cou-plings. While the reaction with n-butylboronic acid failed to pro-ceed in water but gave good results only in xylene, a-bromoenones and benzyl halides reacted smoothly as electrophileswith aryl boronic acids, providing the expected coupling productswith complete retention of stereochemistry, where the case[50,51]. This is the first unsymmetrical pincer Pd-complex whichdisplays a substantial catalytic activity in these unusual Suzukicouplings (see Scheme 10).

12

N PPh2

NN

Pd Cl

H

N N

NPPh2H

rt PhMe, reflux

11

Pd(COD)Cl2

metrical PCN pincer 12.

, H2OC

R1 R2mol%)

18 examplesyields ranging: 72-99%

TONs up to 8.2 106

pling catalyzed by PCN complex 12.

X

NaOH, H2O140º C

PhSi(OMe)3Ph

R1

12 (2 mol%)

3 examplesyields ranging 13-82%

tions catalyzed by PCN complex 12.

X

R

Ar

R

R

12

Ph

BrO

ArB(OH)212 (4 mol%)

+

Ph

ArO

Br

R

+ nBuB(OH)2K2CO3, o-xylene

130oC

12 (2 mol%)

Na2CO3, H2O100oC

12 (0.1 mol%)ArB(OH)2+

N PPh2

NN

Pd Cl

H

3 examples38-90%

22 examples35-99%

4 examples61-94%

X= Cl, Br

Na2CO3, H2O100oC

Scheme 10. Suzuki coupling of uncommon substrates catalyzed by PCN complex 12.

1910 I. Moreno et al. / Inorganica Chimica Acta 363 (2010) 1903–1911

4. Conclusions

It is clear that palladium pincer complexes can provide uniquecatalytic properties in cross-coupling reactions and many organictransformations. Excellent yields, incredibly high TON and TOFsand applicability to a wide range of substrates regardless theirelectronic or steric properties. Moreover, a precise design of thistype of palladacycles allows the employment of environmentallybenign methodologies and/or the easy reuse of the catalytic sys-tem, even in the case of homogeneous catalysts.

Acknowledgments

This research was supported by the University of the BasqueCountry/Regional Government of Biscay/Basque Government (Pro-jects DIPE 06/10, UNESCO07/08 and GIU06/87/IT-349-07) and theSpanish Ministry of Education and Science (MEC CTQ2007-64501). B.I. thanks the University of the Basque Country (UPV/EHU) for a predoctoral scholarship. The authors also thank Petro-nor, S.A. for generous donation of hexane.

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[50] All of our efforts to accomplishing the reaction in neat water wereunsuccessful and in all cases the starting materials were recovered.

[51] A PCP palladium pincer has been used in a Suzuki coupling withbromoundecane as electrophilic partner. See Ref. [25].