C-C Forming Reactions with Palladium and Platinum : Lessons Learned in Our Group

This short paper details our experiences with Pdand Pt-catalyzed cross-coupling and cyclization reactions in investigations covering the years from 1997 until now. Pd-catalysed Suzuki-Miyaura-, Heckand Sonogashira-type cross coupling reactions in conjunction with other transformations in one pot, especially with the Wittig reaction, are highlighted. This is followed by a description of a combination of Heckand cyclization reactions. Finally, Pt-catalyzed diene-yne cyclization reactions are discussed.


INTRODUCTION
Our first contact with Pd-catalyzed cross-coupling reactions came when attempting to construct functionalized estradiol derivatives as potential diagnostic agents for estrogen receptor-positive breast cancer [1 -3].Initially, this involved Wittig olefination reactions of formylestrane derivatives with stabilized phosphoranes [4].In order to have a platform to diversify the molecules that could be prepared, a synthetic sequence was developed by constructing stabilized phosphoranes with a terminal haloaryl unit on a polymer backbone stemming from triphenylphosphinepolystyrene, derivatising the phosphoranes by C-C cross-coupling reaction and finally reacting the phosphoranes thus prepared with a steroidal carbaldehyde [5].This clearly showed that stabilized phosphoranes are compatible with reaction conditions needed to carry out many of the C-C cross-coupling reactions and would lead to the development of one-pot reactions involving Pd-catalyzed cross-coupling reactions and Wittig olefinations [6 -8].
Initially, Pd(PPh 3 ) 4 in a biphasic medium of aq.Na 2 CO 3 and 1,2-dimethoxyethane (DME) was found to be the catalyst of choice for many of the reactions detailed here.Later on, the slightly cheaper Pd(PPh 3 ) 2 Cl 2 was used as a pre-catalyst, in the presence of PPh 3 (3 equiv.).Interestingly, these were sufficiently active to catalyze Suzuki-Miyaura reactions with chloroarenes, where the chloro group was activated by a nitro substituent or as part of a quinoid system as in chloroanthraquinones [13] and 1-chloro-2,4-dinitrobenzene [14].Nevertheless, at a later time, other reaction systems were used.Reactions were run under Jeffery conditions [15 -17].Also, Pd freshly deposited on carbon nanofibers was used as catalyst [18] in Suzuki and Heck reactions.
The following gives a short overview of above reactions.At the end, a number of experimental procedures can be found as representative examples.

One-Pot Cross-Coupling Reaction: Wittig Olefination Procedures
We realized that haloaroylmethylidenetriphenylphosphoranes such as 1 and 8 would be stable under conditions necessary for Suzuki- [5,19], Sonogashira [5,19,20] and Heck [5,21] reactions and hence it was possible to derivatize 1 and 8 to a plethora of phosphoranes, such as 3, 5, 7, and 10 (Scheme 1).These could be reacted subsequently with carbaldehydes in a Wittig olefination [5,19,21].The reactions proceed with the corresponding phosphonium salts also [5].Here, even Na 2 CO 3 has been found to be a base strong enough to convert the phosphonium salts into the respective phosphoranes.For the most part, Suzuki-Wittig reactions were run with Pd(PPh 3 ) 4 as the catalyst in a solvent mixture of aq.Na 2 CO 3 and DME [22], and Sonogashira coupling-Wittig reactions were carried out with Pd(PPh 3 ) 4 /CuI as catalysts and diisopropylamine (DIPA) as base in toluene [5].For Heck-Wittig reactions various conditions were used with Pd(OAc) 2 or Pd(Cl 2 )dppe [23] as the catalyst and with Et 3 N or K 2 CO 3 as base in DMF at 100 °C.However, here Jefferytype PTC conditions in aq.Na 2 CO 3 /CHCl 3 and either Bu 4 NCl or BnMe 3 NCl as PTC catalyst were found to be favorable, where the reactions were run at room temperature (rt).Haloaroylmethylidenetriphenylphosphoranes such as 1 could also be reacted with a boronic acid, and a carbaldehyde in a one-pot Suzuki-Wittig reaction (eg. to 13 Scheme 2) [5].   .In this type of reaction, there is a choice of phosphoranes, both stabilized and semistabilized, that can be used.In contrast to above transformations, where the Wittig olefination with the rather sparingly reactive phosphoranes 1, 8 and 24 is more sluggish than the concomitant Suzuki reaction, reactions with semi-stabilized phosphoranes and with the stabilized alkoxycarbonylmethylideenetriphenylphosphoranes 16 are rapid [24] and the Suzuki transformation determines the completion of the process.Lastly, in the case of Suzuki-Wittig reactions in one pot, the boronic acids can act as the central building block, that is when formylarylboronic acids (e.g.19) are employed [25,26].When dihaloarenes (e.g.26) are utilized in these reactions, p-terphenyl derivatives 28 can be prepared easily (Scheme 3) [25].Instead of the phosphoranes, phosphonium salts 20 also can be used as the starting material (Scheme 2).An easy method of separation was found for those reactions in which the Wittig-Suzuki coupling was run in a mixture of hexane/ether (10:1) aq.2M Na 2 CO 3 in the presence of either Pd(OAc) 2 -PPh 3 (eg., Scheme 2, to 21) or Pd 2 (dba) 3 as catalyst, under ultrasonication.After completion of the reaction the products are found in the organic phase, which is separated from the aq.phase and concentrated in vacuo to give the products in sufficient purity to be used in further transformations [26].
The one-pot Suzuki-Wittig procedure with 16 can be run with a concomitant hydrolysis step (see Experimental Part).Previously, it has been noted that Wittig reaction of aldehydes with 16 can be performed in 10w% aq.NaOH, which leads to the hydrolysis of the acrylates formed and makes a simple work-up possible.In the case of solid products, simple filtration of triphenylphosphine oxide and acidification followed by a second filtration are enough to obtain the acrylic acids [27].In the case of combining the hydrolysis step with the Suzuki-Wittig procedure, the presence of unreacted boronic acid and the metal catalyst makes a chromatographic separation of the product 30 necessary (Scheme 3).
A further reaction that the authors have carried out with the Suzuki cross-coupling reaction in one pot is a Williamson-type ether synthesis, eg., to 34 (Scheme 3).This procedure was run as a PTC reaction with solid KOH and benzyltributylammonium chloride (BTABC) as the PT catalyst and with Pd/C as the coupling catalyst (Scheme 3) [28].
3-O-Methylestra-1,3,5 (10),16-tetraen-17-one (51) could be converted to the respective chromiumtricarbonyl complex 52 easily by reaction with chromium hexacarbonyl [Cr(CO) 6 ] in a mixture of dibutyl ether-THF.The complexation proceeds stereoselectively to give the β-facial complex 52 exclusively.The stereochemistry was established by single crystal X-ray crystallography of the complex [9].The stereochemistry can be explained by the directing effect of the alkene-moiety at C6/C7 [9].When the steroidal chromium complex 52 is reacted with iodobenzene under Pd(OAc) 2 catalysis under PTC conditions, a triarylation happens with a concomitant ring-closure reaction and 53 is obtained after decomplexation (Scheme 7) [10].The transformation also works with other η 6 -dihydronaphthalene tricarbonylchromium(0) complexes, e.g. with 54 (Scheme 7).The reason for this reaction pathway over the common Heck-type arylation of the alkene moiety can be envisaged to be the difficulty in cyclic alkenes for a single bond rotation to occur after the syn-addition of the arylpalladium halide species to the double bond.This rotation is needed in most cases for a subsequent syn-hydridopalladium elimination to occur, a pathway that can easily be followed by non-cyclic alkenes.Interestingly, this has been found to lead to cascade reactions also in selected other, non-complexed cyclic alkenes, as was shown by de Meijere [32,33], Catellani [34 -36] and Carretero [37].We believe that a possible mechanism in our case starts with a standard syn-addition of the arylpalladium iodide to the double bond of the η 6 -dihydronaphthalene tricarbonylchromium(0).As there is no possibility for a synhydridopalladium elimination, the Pd inserts into the neighboring aryl C-H bond leading to a palladacycle, e.g. to 61 (Scheme 8).Then, follows an oxidative addition to the Pd of the palladacyle, followed by the first aryl-aryl coupling.This step is repeated after a C-C single bond rotation linking the aryl unit to the tetrahydronaphthalene system.A reductive elimination on the Pd leads to the final ring closure.The exact intermediates and the oxidation states of Pd in these intermediates still need to be ascertained.The chromium complexes, e.g.66, can be purified by column chromatography under inert atmosphere.In the solid state, they are fairly stable over a short period of time.They can be decomplexed by exposing the substances in solution to air and light, eg., to UV irradiation.The regiochemistry of the arylations was determined by single crystal X-ray crystallography of the chromium complexes of type 66 [10].

A short Word on Pd-Catalysts
Many Pd-and Pt-catalysts have been developed [39 -41] for C-C cross-coupling reactions.Recyclability of the catalyst, low catalyst loading and high turnover frequencies are some important characteristics of the catalyst.Equally important, however, are versatility, cost, and ease of preparation.Many of the reactions above were run with commercially available Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 and Pt(PPh 3 ) 4 or with Pd(OAc) 2 under Jeffery [15 -17] conditions.It must be noted that the commonly used reaction system with the commercially available Pd(PPh 3 ) 4 in DME/aq.Na 2 CO 3 satisfactorily facilitates the Suzuki cross-coupling of chloroarenes with differently substituted arylboronic acids, when the chloro-substituent is activated as in 1-chloro-2,4-dinitrobenzene (70b) [14] and chloroanthraquinones [13] such as in 67 (Scheme 9).It must be noted that 1-chloro-2,4-dinitrobenzene (70b) is often used as a substrate to test the activity of new Pd-catalysts in Suzuki reactions and thus it must be realized that 70b undergoes cross-coupling reactions with ease and other substrates would put the new catalyst to a more rigorous test.70% [13] 72-84% [14] Lastly, we studied the catalytic activity of Pd immobilized as nanoparticles on carbon nanofibers (CNFs) [42].These vapor-grown carbons over different catalysts [eg., with reactant gases CO/H 2 (4:1) or ethylene/H 2 (4:1) over [reduced] Co-Mo (9:1) cat., prepared from (NH 4 ) 6 Mo 7 O 24 and Co(NO 3 ) 2 .6H 2 O, carbon nanofibers grown in a flow reactor at 480-600 °C are made of graphene layers, formed into stacked cones, cups or plates.The positioning of the stacks in relation to each other then leads to platelet-type and herring (fish-bone)-type CNFs.In addition, there are the tubular-type CNFs (Fig. 1).

Fig. (1). Schematic representation of different types of carbon nanofibers (CNFs).
With these CNFs in hand, Pd was immobilized on them by reduction, starting out from either PdCl 2 [microwave irradiation, 650 W, 2 min.(free-running temperature), CNF, in ethylene glycol with or without the surfactant polyvinylpyrrolidone K-30 (PVP)], from H 2 PdCl 4 prepared from PdCl 2 and 1.5 N aq.HCl solution [immobilization of Pd on CNF using sodium formate, hydrazine or NaBH 4 as reductant in H 2 O with and without the surfactant PVP] or from Pd 2 (dba) 3 . CHCl 3 [reduction: CNF, H 2 [1 atm], toluene].Good results in the Heck reaction of 4-bromobenzaldehyde and tert-butyl acrylate were obtained with Pd on tubular CNF, which had been prepared by the permeation technique described above, starting out from PdCl 2 in aq.HCl, reducing the Pd(II) with hydrazine in H 2 O in the presence of surfactant PVP.This Pd-doped tubular CNF was found to carry 4.6-5.6wt%Pd with a Pd-particle size of 10-15 nm.For the Heck reaction, this catalyst gave a turnover frequency of 44.6 h -1 in DMF at 100 °C, where solid K 2 CO 3 was used as the base.This compared well with pre-catalysts PdCl 2 (TOF 1.9 h -1 ), Pd(OAc) 2 (TOF >10.8 h -1 ), and Pd(PPh 3 ) 2 Cl 2 (TOF 29.0 h -1 ) [18,43].Also, Pd immobilized on tubular CNF served as a satisfactory catalyst for the Suzuki reaction of 4methoxyphenylboronic acid and 4-bromobenzaldehyde (Scheme 10), providing 4-methoxy-4'-formylbiphenyl in more than 98% yield, when the reaction was run with a catalyst loading of 0.02 mol% in Pd at rt for 4h, utilizing ethanol as solvent and Na 2 CO 3 as base.The Pd@CNF catalysts could be recycled.The chemical shifts are relative to tetramethylsilane (TMS) (solvent CDCl 3 , unless otherwise noted).Mass spectra were measured with a JMS-01-SG-2 or with an Agilent QTOF 6540 UHD.Column chromatography, when necessary, was performed on silica gel (S, 0.063 mm -0.1 mm, Riedel de Haen and Merck grade 9385 or on Wakogel 300).

CONCLUSION
This was a short tour-de-force of some of the work on Pd-and Pt-catalysis that we have carried out over the years.The focus has been to develop strategies of combining various reactions with Pd-or Pt-catalyzed C-C cross coupling reactions in one pot.Furthermore, diene-yne cyclizations were studied under Pt-catalysis that led either to arenes or fulvenes.A triarylation of η 6 -dihydronaphthalene tricarbonylchromium complexes with concomitant ring closure was more of a serendipitous discovery.

Scheme 10 .
Heck and Suzuki reactions with Pd-doped carbon nanofibers.MHz).The assignments of the carbon signals were aided by DEPT 90 and DEPT 135 experiments (DEPT = Distortionless Enhancement by Polarisation Transfer).