synthesis of heterocycles via palladium-catalyzed carbonylations...

Synthesis of Heterocycles via Palladium-Catalyzed CarbonylationsXiao-Feng Wu,*,†,‡ Helfried Neumann,‡ and Matthias Beller*,‡

†Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou, Zhejiang Province, P. R. China 310018‡Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany

CONTENTS

1. Introduction 12. Palladium-Catalyzed Carbonylative Synthesis of

Four-Membered Heterocycles 22.1. Palladium-Catalyzed Carbonylative Synthe-

sis of Four-Membered Lactones 22.2. Palladium-Catalyzed Carbonylative Synthe-

sis of Four-Membered Lactams 33. Palladium-Catalyzed Carbonylative Synthesis of

Five-Membered Heterocycles 43.1. Palladium-Catalyzed Carbonylative Synthe-

sis of Five-Membered Oxygen-ContainingHeterocycles 4

3.1.1. Palladium-Catalyzed Carbonylative Re-actions of Alkynols 4

3.1.2. Palladium-Catalyzed Carbonylative Re-actions of Alkenols 9

3.1.3. Palladium-Catalyzed Carbonylative Re-actions of 2-Halo-alke(y)nes 10

3.1.4. Other Palladium-Catalyzed Carbonyla-tions to Lactones 11

3.2. Palladium-Catalyzed Carbonylative Synthe-sis of Five-Membered Nitrogen-ContainingHeterocycles 13

3.3. Palladium-Catalyzed Carbonylative Synthe-sis of Other Five-Membered Heterocycles 18

4. Palladium-Catalyzed Carbonylative Synthesis ofSix-Membered Heterocycles 204.1. Palladium-Catalyzed Carbonylative Synthe-

sis of Six-Membered Oxygen-ContainingHeterocycles 20

4.2. Palladium-Catalyzed Carbonylative Synthe-sis of Six-Membered Nitrogen-ContainingHeterocycles 22

4.3. Palladium-Catalyzed Carbonylative Synthe-sis of Other Six-Membered Heterocycles 26

5. Palladium-Catalyzed Carbonylative Synthesis ofOther Heterocycles 28

6. Summary 28Author Information 29

Corresponding Author 29Notes 29Biographies 29

Acknowledgments 30References 30

1. INTRODUCTION

Palladium-catalyzed coupling reactions have become a powerfultool in organic synthesis.1 Today, there are numerousapplications of palladium catalysts in the preparation ofpharmaceuticals, agrochemicals, and also advanced materialsboth on laboratory and industrial scale. The importance ofpalladium catalysis was underlined by the 2010 Nobel Price toR. Heck, A. Suzuki, and E. Negishi for their pioneering work inthis field.2 Among all the palladium-catalyzed couplingreactions, carbonylation reactions also have experiencedimpressive improvements since the first work of R. Heck andco-workers in 1974.3 The advantages of carbonylations are (i) itis the most potent methodology in the synthesis of carbonyl-containing chemicals, which increases the carbon number at thesame time, and (ii) carbon monoxide (CO) can be used as aninexpensive and readily available C1 source, which is also inagreement with the green chemistry principles.4 The progressin carbonylation chemistry has been achieved not only inacademic laboratories but also in industry. Hence, it is notsurprising that there are many carbonylation reactions beingemployed on an industrial scale.5

Heterocyclic compounds are an integral part of manybiologically active molecules, and many currently marketeddrugs hold heterocycles as their core structure (Scheme 1).Numerous efforts in recent years focused on the developmentof improved methods for the synthesis of heterocycles.6

Considering the synthetic value of carbonylation reactionsand the preparation of heterocycles, the merging of these twotopics offers interesting possibilities for organic synthesis.Indeed, advancements in this area have been proven bynumerous publications. Although a number of reviews oncatalytic carbonylations7 as well as on the synthesis ofheterocycles already exist, no general summary on palladium-catalyzed carbonylative syntheses of heterocycles has beenpublished so far.8 Considering the importance of both topics,and the lack of a more general compilation, here we report a

Received: March 8, 2012Published: October 5, 2012

Review

pubs.acs.org/CR

© 2012 American Chemical Society 1 dx.doi.org/10.1021/cr300100s | Chem. Rev. 2013, 113, 1−35

pubs.acs.org/CR

summary of the main achievements in this area. To make iteasier for the reader to find the respective syntheticapplications, we organized this review with respect to the sizeand type of heterocycle. Hence, it was unavoidable thatpublications that focused primarily on methodology or catalystdevelopment will be mentioned in different subsections.

2. PALLADIUM-CATALYZED CARBONYLATIVESYNTHESIS OF FOUR-MEMBERED HETEROCYCLES

2.1. Palladium-Catalyzed Carbonylative Synthesis ofFour-Membered Lactones

Lactones, which occur widely in nature, are known to possesspotent biological activities.9 The application of palladium-catalyzed carbonylation reactions in the synthesis of four-membered lactones was first reported by Cowell and Stille in1980.10 They used PdCl2(PPh3)2 as catalyst, and the lactoneswere synthesized in high yields under mild conditions (1−4 barof CO; 25−60 °C) from the corresponding halo-substitutedalcohols (Scheme 2a). Not only four-membered rings but also

five- and six-membered lactones can be achieved. Later on,Qing and Jiang modified this methodology for the preparationof trifluoromethyl-substituted four- and five-membered lactones(Scheme 2b).11

In 1993, Shimizu et al. showed that lactones can also beformed using readily available allylic compounds as starting

materials.12 Lactones, together with esters, dienes, and allylicalcohols, were produced from alkenyloxiranes under theassistance of palladium catalysts. The selectivity of this reactiondepended on the nature of the alkenyloxiranes (Scheme 3).

Besides the mentioned processes, palladium-catalyzedcarbonylation of alkynols represents another powerful method-ology for the preparation of lactones. As early as in 1994,Gabriele and co-workers presented a PdI2/KI-catalyzedoxidative carbonylation of α-substituted hydroxyalkynes tofour-membered lactones in good yields under mild conditions.Later on, they extended this methodology to but-3-yn-1-ols forthe synthesis of five-membered lactones (Scheme 4a).13

Scheme 1. Selected Examples of Heterocyclic Drugs

Scheme 2. Palladium-Catalyzed Carbonylative Synthesis ofLactones

Scheme 3. Palladium-Catalyzed Carbonylative Synthesis ofLactones from Alkenyloxiranes

Scheme 4. Palladium-Catalyzed Carbonylative Synthesis ofLactones from Alkynols

Chemical Reviews Review

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Alternatively, Dupont and co-workers developed a Pd(OAc)2/2-PyPPh2 system for the production of various lactones fromalkynols (Scheme 4b).14 A mild and efficient methodology forthe PdCl2-catalyzed cyclocarbonylation of 2-alkynols withCuCl2 affording (Z)-α-chloroalkylidene-β-lactones was devel-oped by Ma and co-workers.15 Good regio- and stereo-selectivity were observed in the latter reaction. The opticallyactive (Z)-α-chloroalkylidene-β-lactones could be easily pre-pared from readily available optically active propargylicalcohols. The Pd(II)-catalyzed cyclocarbonylation of 2-alkynolswith CuBr2 was also studied. Although the yields of (Z)-α-bromoalkylidene-β-lactones were low, because of the relativelyhigher activity of the C−Br bond, the coupling reactions of (Z)-α-bromoalkylidene-β-lactones proceeded smoothly to affordthe corresponding products in high yields (Scheme 4c).2.2. Palladium-Catalyzed Carbonylative Synthesis ofFour-Membered Lactams

Lactams have a long and important history in the field ofmedicinal chemistry.16 Because of their importance, manymethodologies have been developed for their construction.Nevertheless, today still the Staudinger reaction is afundamental method for their production.17 Palladium-catalyzed carbonylation of aziridines represents anotherconvincing procedure for the synthesis of lactams. The firstreport in this area was published in 1981 by Alper and Perera.18

This novel methodology allowed the production of lactamsunder mild conditions, albeit in low yield. Furthermore, it wasused for the synthesis of hetero and carbon analogues ofpenicillin (Scheme 5a). The power of this procedure was also

proved by the carbonylation of methyleneaziridines to thecorresponding lactams in moderate yields (Scheme 5b).19

Ohfune and co-workers developed a highly stereoselectiveprocess for the synthesis of 3-vinyl-2-azetidinone via a ring-opening, carbonylation, and ring-closure sequence (Scheme5c).20 This methodology was also applied in the total synthesisof carbapenem (+)-PS-5.21 A mechanistic rationale for thisunusual reaction was proposed by Aggarwal and co-workers.22

Through their analysis, they have been able not only to switchfrom β-lactams to δ-lactams but also to switch the stereo-chemical outcome of the reaction by simply modifying thereaction parameters.Palladium-catalyzed carbonylative intramolecular cyclization

of 2-bromoamines provides an interesting alternative for thesynthesis of lactams. Ban and co-workers started from 2-bromo-3-aminopropene derivatives, which in the presence of Pd-(OAc)2 and PPh3 led to the corresponding α-methylene β-

lactams in good yields (Scheme 6a).23 Interestingly, Bricknerand co-workers modified the solvent [using N,N-dimethylfor-

mamide (DMF) instead of hexamethylphosphoramide(HMPA)] and made the methodology suitable for unprotectedprimary 2-bromoallylamines.24 In addition, Crisp and Meyersucceeded to produce lactams from the corresponding aminovinyl triflates by carrying out the reaction in CH3CN. Four-,five-, and six-membered lactams were produced in good toexcellent yields.25 Besides the mentioned starting materials, 4-amino-2-alkynyl carbonates were also applied for theproduction of lactams by Tsuji, Mandai, and co-workers.26 Inthe presence of palladium catalysts, lactams were produced inmoderate yields under mild conditions (Scheme 6b).The methodologies developed by Brickner and Tsuji and

their co-workers successfully avoid the use of aziridines in thepreparation of lactams,23−25 but the specificity of startingmaterials limited the scope. Notably, Torii and co-workerssucceeded to apply more easily available allyl phosphates andimines for the synthesis of lactams.27 3-Vinyl-β-lactams wereproduced in high yields from the corresponding imines andallylic compounds in a highly stereoselective manner (Scheme7a). Troisi and co-workers developed methodologies for the [2+ 2]-carbonylative cycloaddition of chiral imines with variousallyl halides. In the presence of a catalytic amount of Pd(OAc)2and PPh3, using NEt3 as base, under 27.5 bar of CO, chiralalkenyl-β-lactams were isolated in good yields.28 PdI2 and Pd/C−KI catalyst systems were also developed for β-lactamspreparation by Gabriele and co-workers.29 A new palladium-catalyzed synthesis of 3-amido-substituted β-lactams wasreported by Arndtsen and co-workers in 2006.30 This processinvolves the one-pot coupling of four components, two imines,CO, and an acid chloride, providing a flexible route to constructβ-lactams. Notably, two different imines can be used for thegeneration of lactams, making the independent control of allthe separate substituents possible (Scheme 7b). More recently,Wang and co-workers investigated the carbonylation of diazocompounds. Starting from diazo compounds, via ketenes as keyintermediates, β-lactams were formed after coupling withimines (Scheme 7c).31 Interestingly, neither base nor ligandwas needed in this methodology. Besides β-lactams, 1,3-dioxin-4-ones could also be synthesized by applying α-diazocarbonylcompounds and imines as substrates. The experiments weresupported by a density functional theory (DFT) study. Inaddition to typical imines, 1,3-thiazines were also used ascoupling partners with allyl compounds by Zhou and Alper.32

In their report, bicyclic β-lactams were synthesized by a

Scheme 5. Palladium-Catalyzed Carbonylative Synthesis ofLactams from Aziridines

Scheme 6. Palladium-Catalyzed Carbonylative Synthesis ofLactams



carbonylative coupling and cyclization reaction of 2-aryl-1,3-thiazines with allyl phosphates, catalyzed by bis(benzonitrile)-palladium dichloride, using N,N-diisopropylethylamine(DiPEA) as base in tetrahydrofuran (THF). Several rhodiumcomplexes were also effective for this process. These trans-formations are stereospecific, with the aryl and vinyl groups onthe β-lactam ring being cis to each other. This methodologyprovides a novel route for the preparation of the cephamanalogues, cis-7-vinyl-5-thia-1-azabicyclo[4.2.0]octan-8-ones(Scheme 7d).

3. PALLADIUM-CATALYZED CARBONYLATIVESYNTHESIS OF FIVE-MEMBERED HETEROCYCLES

3.1. Palladium-Catalyzed Carbonylative Synthesis ofFive-Membered Oxygen-Containing Heterocycles

3.1.1. Palladium-Catalyzed Carbonylative Reactionsof Alkynols. The presence of a hydroxyl group and a triplebond in the same molecule makes alkynols suitable substratesfor the synthesis of heterocycles. As early as 1969, Nogi andTsuji reported the palladium-catalyzed carbonylation ofpropargyl alcohols in methanol to yield the correspondingfive-membered γ-lactones and also various esters. When 2,5-dimethyl-3-hexyn-2,5-diol was applied in benzene, diisopropy-lidenesuccinic acid was formed as the main product in 49%yield (Scheme 8).33

A general methodology for the carbonylative synthesis of α-methylene-γ-lactones was developed by Norton and co-workersin 1981.34 Ethynyl alcohols were prepared from epoxidationand ethynylation of olefins, which was followed by palladium-catalyzed carbonylation reaction, leading to α-methylene-γ-lactones in good yields (Scheme 9). In this methodologyvarious functional groups are tolerated, such as isolated doublebonds or bromine substituents. Another catalytic system,making use of a thiourea ligand, was developed by the samegroup. As with the first methodology, which proceeds in anasymmetric manner, the corresponding products were formed

in moderate yields.35 Drent and co-workers applied 2-pyridylphosphine as ligand for the carbonylation of propargylalcohols. In the presence of 2.5 mol % Pd(OAc)2, ligand, andmethanesulfonic acid, under 60 bar of CO and at 60−90 °C, α-methylene-γ-lactones were formed in good yields.36 Later on,Dupont and co-workers carried out the reaction in ionic liquids(1-n-butyl-3-methyl imidazolium).37 Quantitative yields oflactones were obtained, and with the possibility to reuse theionic catalyst system, this work constitutes an importantimprovement. Alternatively, a cationic palladium catalyst systemwas also developed.38 In this report, the cyclocarbonylation of3-butyn-1-ols was studied. Six-membered ring lactones wereproduced preferentially in acetonitrile using cationic palladiumcomplexes coordinated by certain chelating diphosphines(dppb) as catalyst. A triphenylphosphine-coordinated cationic

Scheme 7. Palladium-Catalyzed Carbonylative Synthesis of Lactams

Scheme 8. Palladium-Catalyzed Carbonylation Reactions ofPropargyl Alcohols



palladium complex, on the other hand, effected the formationof five-membered α-alkylidene lactones exclusively in DMF(N,N-dimethylformamide). A mechanism involving palladiumhydride species as active catalysts has been presumed for theformation of six-membered ring lactones.The palladium-catalyzed carbonylative preparation of α-

vinylidene-γ-lactones in good yields from 5-hydroxy-2-alkynylmethyl carbonates was described by Tsuji and co-workers.39

The reaction was particularly rapid with tertiary substitutedcarbonates and slower with secondary carbonates. However, theproduct could not be isolated selectively when a primarycarbonate group was used.In 1997, Yu and Alper succeeded in applying palladium

catalysts for the synthesis of 2(5H)-furanones from correspond-ing substituted alkynols under carbonylation conditions in 67−98% yield (Scheme 10).40 This reaction required catalyticamounts of Pd2(dba)3·CHCl3 (4 mol %) and 1,4-bis-(diphenylphosphino)butane (dppb) (8 mol %) in dichloro-methane under an atmosphere of CO (40 bar) at 95 °C. Inaddition, 14 bar of hydrogen were needed for this reaction.Other bidentate ligands, such as 1,3-bis(diphenylphosphino)-

propane (dppp), and monodentate ligands, such as PPh3 orPCy3, were equally effective for this reaction. Conjugatedenynols could also be carbonylated, affording 3-alkenyl-2(5H)-furanones in good yields. However, double-bond isomerization(cis−trans) occurred if the enynol containing a cis olefinicsubstituent was used as the substrate. The latter cyclo-carbonylation reaction is believed to proceed via anallenylpalladium intermediate, which is formed by initialinsertion of Pd(0) into the C−O bond of the alkynol followedby rearrangement. This methodology was applied for thecarbonylation of trifluoromethyl-substituted propargylic alco-hols to give the corresponding 3-trifluoromethyl-2-(5H)-furanones in high yields.41

The group of Gabriele succeeded in producing substitutedfurans from the corresponding alkynols under oxidativeconditions (Scheme 11a).42 4-Yn-1-ols bearing a terminal triple

bond undergo oxidative cyclization−alkoxycarbonylation inmethanol at 70 °C and 100 bar of a 9:1 mixture of carbonmonoxide and air in the presence of catalytic amounts of[PdI4]

2− in conjunction with an excess of KI to give 2E-[(methoxycarbonyl)methylene]tetrahydrofurans in good yields.A competing reaction, the cycloisomerization−hydromethox-ylation leading to 2-methoxy-2-methyltetrahydrofurans, couldbe easily prevented by increasing the KI excess. The latterproducts can be prepared from 4-yn-1-ols and methanol in highyields using the same catalytic system without KI excess in theabsence of carbon monoxide. Akita, Kato, and co-workersdeveloped another system that avoids the use of KI and highpressure and leads to different products (Scheme 11b).Following this, they succeeded in performing the reaction inan asymmetric manner by applying chiral bisoxazolines asligands.43

With respect to the reaction mechanism, the studies ofNorton and co-workers are noteworthy. It is proposed that thePd(II)-catalyzed cyclocarbonylation of acetylenic alcohols to α-methylene-γ-lactones proceeds through carboalkoxypalladiumintermediates, followed by intramolecular syn addition to thetriple bond (Scheme 12).44 Such intermediates have beenindependently synthesized, isolated, and found to undergoappropriate interconversions. A PdI2/Bu3P/CH3CN catalystsystem gave rates first-order in CO pressure, with the rate-determining step evidently being the uptake of CO by Pd. Theuse of a SnCl2 cocatalyst promoted ligand exchange on the

Scheme 9. Palladium-Catalyzed Carbonylative Synthesis ofMethylene Lactones

Scheme 10. Palladium-Catalyzed Carbonylative Synthesis of2(5H)-Furanones

Scheme 11. Palladium-Catalyzed Carbonylative Synthesis ofTetrahydrofurans

Scheme 12. Cyclocarbonylation of Deuterated Alkynol



palladium center, dissociating Cl− and forming a Pd cation,which is a much faster cyclocarbonylation catalyst. The rate isnow independent of CO pressure and first-order in Pd and insubstrate. The rate-determining step is coordination of thesubstrate, followed by rapid uptake of CO and completion ofthe cyclocarbonylation reaction. As the carboalkoxy intermedi-ates also react intermolecularly with terminal acetylenes, yieldsin the catalytic cyclocarbonylation reaction improved substan-tially when it was run at concentrations below 0.3 M.Besides the carbonylative cyclization of alkynols, the

carbonylative reaction of propargyl alcohols with additionalamines and thiols were also described. Ogawa and co-workersdeveloped the reaction of propargylic alcohols with diaryldisulfides and carbon monoxide. In the presence of tetrakis-(triphenylphosphine)palladium, a novel thiolative lactonizationreaction lead to β-(arylthio)- α,β-unsaturated lactones inmoderate to good yields (Scheme 13a).45 Similar conditions

can be employed with homopropargylic alcohols, giving thecorresponding δ-lactones with a β-arylthio group successfully.The reaction using diaryl diselenides in place of diaryl disulfidesalso led to a similar one-pot selenylation/lactonizationsequence to provide the corresponding β-selenobutenolides.Meanwhile, Xiao and Alper described the carbonylation ofpropargyl alcohols with thiols.46 By changing the reactionconditions, sulfur-containing furanones were produced in goodyields (Scheme 13b). In 2004, the group of Gabriele publishedthe carbonylative synthesis of 4-dialkylamino-5H-furan-2-ones.47 Starting from alkynols and dialkylamines, in thepresence of CO and air, the target products were producedin good yields by applying PdI2 and KI as the catalytic system(Scheme 13c).The mentioned developments of palladium-catalyzed carbon-

ylations of alkynols were also applied in the total synthesis ofbioactive molecules (Scheme 14).48 Examples constitute thesyntheses of Vernolepin, Germacranolide, (+)-Asimicin and(+)-Bullatacin, and so on.

As reported by Gabriele and co-workers, aside from lactones,furans can also be prepared by a similar process with differentsubstrates.49 Hence, a variety of (Z)-2-en-4-yn-1-ols have beencarbonylated under oxidative conditions to give substitutedfuran-2-acetic esters in good yields (Scheme 15a). The

cyclization−alkoxycarbonylation process occurred in alcoholicmedia at 50−70 °C under 100 bar pressure of a 9:1 mixture ofcarbon monoxide and air in the presence of catalytic amountsof PdI2 in conjunction with KI. The proposed reaction pathwayinvolves the in situ isomerization of the initially formed (E)-2-[(alkoxycarbonyl)methylene]-2,5-dihydrofuran species, whichin some cases have been isolated and shown to be theintermediates. Under similar reaction conditions, 3-yne-1,2-diols were transformed into the corresponding furan-3-carboxylic esters in good yields (Scheme 15b).50

The palladium-catalyzed carbonylation of alkynols resulted insynthetically interesting lactones and furans. Similarly, 2-hydroxy-substituted phenylacetylenes may give the correspond-ing benzofurans. Indeed, in 1994 Sakamoto and co-workersreported the palladium-catalyzed carbonylation reaction of 2-alkynylanilines and 2-alkynylphenols in methanol. As expected,the corresponding indoles and benzofurans are obtained inmoderate yields. The reaction of 2-alkynylbenzamides gave 3-alkylidenisoindoles (Scheme 16).51 A similar methodology was

reported by Lutjens and Scammells for the synthesis of XH-14and its derivatives, which contains a benzofuran as the mainskeleton.52 Efforts from Yang’s group improved the efficiency ofthis novel benzofuran process.53 By applying a PdI2−thioureacatalytic system and using CBr4 as oxidant, methyl benzofuran-3-carboxylates were produced in 78−84% yields from thecorresponding 2-hydroxyarylacetylenes. Both electron-rich andelectron-deficient groups were tolerated. Afterward, the samegroup developed palladium-mediated carbonylative annulations

Scheme 13. Palladium-Catalyzed Carbonylation of Alkynolswith Amines and Thiols

Scheme 14. Application of Palladium-CatalyzedCarbonylations of Alkynols in Total Synthesis

Scheme 15. Palladium-Catalyzed Carbonylative Synthesis ofFurans

Scheme 16. Palladium-Catalyzed Carbonylative Synthesis ofBenzofurans and Indoles



of o-alkynylphenols on silyl linker-based macrobeads andproduced 2,3-disubstituted benzofurans in good yields.54 Onthe basis of their continuing interest on this topic, they alsoreported the carbonylative annulation of o-alkynylphenols tobenzofuran-3-carboxylic acids and benzofuro[3,4-d]furan-1-ones. These five-membered heterocycles were synthesized ingood yields, but 1 equiv of palladium catalyst was needed forsuccessful coupling (Scheme 17).55

In 2002, a general methodology for the palladium-catalyzedcarbonylative annulation of o-alkynylphenol to construct 2-substituted-3-aroyl-benzofurans was reported by Yang, Fathi,and co-workers.56 Good yields of the desired products wereobtained (Scheme 18a). Interestingly, related to that work,Arcadi, Cacchi, and co-workers reported the synthesis of 3-alkylidene-2-coumaranones via carbonylative coupling of o-ethynylphenols and vinyl triflates (Scheme 18b).57 All threestudies showed that the presence of terminal alkynes and vinylcoupling partners negatively influences the selectivity. More-over, Chaplin and Flynn reported the synthesis of 3-alkylidene-2-coumaranones by multicomponent reaction using vinyliodide as the coupling partner (Scheme 18c).58 A simple andconvenient synthesis of 2-furan-2-ylacetamides starting from

readily available (Z)-2-en-4-yn-1-ols was reported by Gabrieleand co-workers.59 This method is based on the PdI2-catalyzedoxidative aminocarbonylation of alkynes to give the corre-sponding 2-ynamide intermediates, which undergo intra-molecular conjugate addition to give 2-(5H-furan-2-ylidene)-acetamide derivatives. Spontaneous or one-pot acid-promotedaromatization of 2-(5H-furan-2-ylidene)acetamides eventuallyleads to the final furanacetamide derivatives.Other carbonylation approaches toward 3-acyl-substituted

furans were also reported. For example, the palladium-catalyzedcarbonylative coupling of aryl iodides with 1-aryl-2-alkyn-1-ones led to furans in 36−75% yields (Scheme 19a).60 The

contribution from Li and Yu proved that furans can be preparedby carbonylative coupling of aryl iodides with γ-propynyl-1,3-diketones (Scheme 19b).61 The group of Kato, Akita, and co-workers developed a new type of PdII-catalyzed carbonylativedimerization of allenyl ketones.62 The resulting difuranylke-tones were obtained in moderate to good yields (Scheme 19c).

Scheme 17. Palladium-Mediated Annulation of o-Alkynylphenols

Scheme 18. Palladium-Catalyzed Carbonylative Coupling of o-Alkynylphenols

Scheme 19. Palladium-Catalyzed Carbonylative Synthesis ofFurans



The electrophilicity of the acylpalladium species was proposedto allow for the oxypalladation of an additional molecule ofallenyl ketones.Costa and Gabriele and co-workers presented a direct

synthesis of 1-(alkoxycarbonyl)methylene-1,3-dihydroisobenzo-furans and 4-(alkoxycarbonyl)benzo[c]-pyrans by oxidativepalladium-catalyzed cyclization/alkoxycarbonylation of 2-alky-nylbenzyl alcohols, and of 2-alkynylbenzaldehydes or 2-alkynylphenyl ketones.63 Reactions were carried out in ROHor CH3CN/ROH (R = Me, iPr) mixtures as the solvent at 70−105 °C in the presence of catalytic amounts of PdI2 inconjunction with KI under a 4:1 or 3:1 CO/air mixture (20 or32 bar total pressure at 25 °C). The reaction occurs throughintramolecular attack by the nucleophilic oxygen atom (eitheralready present in the starting material or generated in situ byROH attack on carbonyl group) on the triple bond coordinatedto PdII, followed by alkoxycarbonylation. The presence ofsubstituents at the alkyne terminal position and at the carbonatom α to the hydroxy group played a key role in the selectivityof the process toward the formation of a five- or six-memberedring (Scheme 20). Alternatively, the reaction of alkynyloxiranes

could also lead to 1,3-dihydroisobenzofurans and tetrahydro-furans.64 Moderate to good yields of the products wereproduced under similar reaction conditions (PdI2/KI/CO/O2).Because of the interesting biological properties of 3(2H)-

furanone derivatives, many methodologies have been developedfor their synthesis. In 1988, Inoue and co-workers synthesized3(2H)-furanones from the coupling of α-ethynyl tertiaryalcohols and acyl chlorides in the presence of a palladiumcatalyst and CO2.

65 Later on, they did the same reaction underthe pressure of CO and CO2, but started from aryl halidesinstead of acyl chlorides.66 It was revealed that there was theintermediate formation of an acetylenic ketone from theacetylenic alcohol, CO, and the aryl halides and subsequentformation of a cyclic carbonate from the acetylenic ketone andCO2 and decarboxylation gave the 3(2H)-furanones (Scheme21).Alternatively, Kiji and co-workers succeeded to form the

same type of product in the absence of CO2, but with 3-isopropylidene-5-phenyl-2(2H)-furanone as the main prod-uct.67 Carbonylative coupling of iodobenzene and 2-methyl-3-butyn-2-ol in aqueous NaOH/benzene was carried out by usingPd(OAc)2/PPh3/Bu4PBr as catalyst. In sharp contrast to ahomogeneous Et3N solution, this biphasic solvent system gave3-isopropylidene-5-phenyl-2(2H)-furanone in moderate yieldand 2,2-dimethyl-5-phenyl-3(2H)-furanone and benzoic acid asbyproducts. The formation of 3-isopropylidene-5-phenyl-2(2H)-furanone is explained by the following sequential

reactions: carbonylative coupling of iodobenzene with 2-methyl-3-butyn-2-ol forms 4-hydroxy-4-methyl-1-phenyl-2-pen-tyn-1-one, which undergoes hydrogenolysis to yield 4-methyl-1-phenyl-2,3-pentadien-1-one. Subsequent cyclocarbonylation ofthe latter intermediate leads to the final product (Scheme 22).

Concerning the formation of 3-alkylidenefuran-2-ones, thegroup of Alper established a palladium catalyst system for thecarbonylative coupling of aryl iodides with benzyl acetylenes.68

More recently, our group developed a general and efficientmethod for the synthesis of these furanones. Starting from arylbromides and aryl triflates, after double carbonylation withbenzyl acetylenes, furanones were produced in good yields.Methylated BE-23372M, a kinase inhibitor, was also producedin a one-pot sequence with 65% yield (Scheme 23).69

The double carbonylation of benzyl acetylenes offers aninteresting pathway for furanone synthesis. By changing thereaction conditions, maleic anhydrides can be formed formterminal alkynes via insertion of two CO molecules (Scheme24a). The report from Alper’s group using PdCl2 and CuCl2 asthe catalytic system produced maleic anhydrides from thecorresponding terminal alkynes in the presence of formic acidor water.70 Afterward, several reported methods have been

Scheme 20. Palladium-Catalyzed Carbonylative Synthesis ofFurans and Pyrans

Scheme 21. Palladium-Catalyzed Synthesis of 3(2H)-Furanones

Scheme 22. Palladium-Catalyzed Carbonylative Synthesis ofFuranones

Scheme 23. Proposed Mechanism and the Synthesis ofMethylated BE-23372M



published from other groups with different oxidants.71 Notably,the study from Jiang’s group states that the reaction couldproceed smoothly in the absence of external oxidant by usingPdCl2 as the catalyst. Nevertheless, the presence of CuCl2 asoxidant can improve the yield from 76% to 99%.72 According tothe authors, traces of water in dioxane might play a role asoxidant. In addition to maleic anhydrides, 3-substituted furan-2(5H)-ones were also prepared from the carbonylation ofalkynes. Under oxidative reaction conditions, in the presence ofa suitable palladium catalyst, both terminal and internal alkynescan be transformed into the corresponding 3-substitutedfuranones (Scheme 24b).73

3.1.2. Palladium-Catalyzed Carbonylative Reactionsof Alkenols. In 1984, Semmelhack and co-workers studied theintramolecular alkoxycarbonylation/lactonization of allylicalcohols.74 The effects of solvents and remote substitutentson the stereoselectivity were carefully studied, and good yieldsof the corresponding lactones were achieved (Scheme 25).

Later, they studied the intramolecular alkoxycarbonylation ofhydroxyalkenes. Tetrahydrofurans were successfully producedin a stereoselective manner in moderate to excellent yields.75

In 1985, Alper and Leonard reported a palladium-catalyzedcarbonylation of alkenols into five- and six-memberedlactones.76 The reaction was conducted in acidic THF withPdCl2 as catalyst and CuCl2 as oxidant at room temperatureand under atmospheric pressure of CO. On the basis of thisachievement, they extended their methodology to secondaryand tertiary allylic alcohols.77 The reaction was also performedin an asymmetric manner by applying poly-L-leucine or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) as chiralligand.78 The use of CuCl2 as oxidant was avoided by usingPd(dba)2 as catalyst and dppb as ligand in 1,2-dimethoxyethane(DME) under 40 bar of CO and at 190 °C. The desiredlactones were isolated in 45−92% yields, and 2(5H)furanoneswere isolated in 60−80% yield in the case of alkynols.79

Notably, in this contribution the use of additional oxidant isavoided, but elevated temperature was needed. However, bycarrying out the reaction in dichloromethane (DCM) with amixture of 27 bar of H2 and 27 bar of CO, the reaction

temperature could be decreased to 110 °C. In the presence of(−)-BPPM [(2S,4S)-tert-butyl-4-(diphenylphosphino)-2-((diphenylphosphino)methyl)pyrrolidine-1-carboxylate], thereaction proceeded in an enantioselective manner (Scheme26a).80 Originally, the method was limited to only terminal

alkenes; however, by variation of palladium salts and ligands,internal alkynes could also be used as substrates in this reaction.In the presence of a catalytic amount of Pd(OAc)2 and dppb,α,β-substituted-γ-butyrolactones have been isolated in 42−85%yields (Scheme 26b).81 Depending on the structure of theallylic alcohol used, the formation of the corresponding alkeneor β,γ-unsaturated carboxylic acid as byproduct was observed.Interestingly, the group of Zhang developed a highly

enantioselective palladium-catalyzed asymmetric cyclocarbony-lation of geminally disubstituted allylic alcohols. Thereby theydemonstrated the first highly enantioselective cyclocarbonyla-tion of β,γ-substituted allylic alcohols lacking dialkyl sub-stituents at the α-position. These results demonstrate that theso-called BICP ligand is a unique chiral ligand for this kind ofpalladium-catalyzed asymmetric carbonylation (Scheme 27).82

Tamaru and co-workers reported the dialkoxycarbonylationof 3-butenols, to provide γ-butyrolactone 2-acetic acid esters inmoderate yields under 1 bar of CO (Scheme 28a).83 In thisstereospecific reaction, 1−50 mol % of PdCl2 and 3 equiv ofCuCl2 were needed as the catalyst system, and also propyleneoxide and ethyl ortho-acetate were required as additives. Besides

Scheme 24. Palladium-Catalyzed Synthesis of MaleicAnhydrides

Scheme 25. Palladium-Promoted Carbonylation of AllylicAlcohols

Scheme 26. Palladium-Catalyzed EnantioselectiveCarbonylation of Alkenols

Scheme 27. Palladium−BICP-Catalyzed Carbonylation ofAllylic Alcohols



3-butenols, 3-butyn-1-ols could also be used as startingmaterials and furnished α-methylene-γ-butyrolacetones inexcellent yields.84 The work from Inomata’s group excludedthe use of propylene oxide and ethyl ortho-acetate; instead, O2was applied as oxidant. In the presence of 10 mol % of PdCl2and 1.5 equiv of CuCl2, under CO/O2 (v/v 1:1; 1 bar),85 inmethanol at room temperature, 6 different γ-butyrolactone 2-acetic acid esters were formed in 76−94% yields.86 At the sametime, the palladium-catalyzed decarboxylative carbonylation of3-vinyl-1-oxo-2,6-dioxacyclohexanes to 2-vinyl-γ-butyrolactoneswas established by the same group.87 In the presence of acatalytic amount of Pd(PPh3)4, lactones were produced in highyields at room temperature under 1 bar of CO (Scheme 28b).On the basis of the carbonylation of allylic alcohols, the

related cyclocarbonylation of 2-allylphenols was also inves-tigated.88 Different catalytic systems, such as Pd-clays andPd(OAc)2/dppb, were developed, and ionic liquids (1-butyl-3-methylimidazolium (BMIM) PF6 and BMIM NTf2) anddimethyl carbonate (DMC) were applied as solvents besidesthe usual organic solvents. Five-, six- and even seven-memberedlactones were produced in good yields, and even in anasymmetric manner.The reaction of allylic alcohols allows for the construction of

one ring in one step. More interestingly, two conjugated five-membered rings can be easily formed by the palladium-catalyzed carbonylation of 4-penten-1,3-diols. The firstpalladium-promoted (stoichiometric) oxycarbonylation of 5-hexen-1,4-diols was reported by Semmelhack and co-work-ers.70,89 Later on, the group of Yoshida made the methodcatalytic in palladium by using CuCl2 as the reoxidant.90 cis-3-Hydroxytetrahydrofuran acetic acid lactones were synthesizedin good yields under 1 bar of CO at room temperature(Scheme 29). This methodology was applied by Kitching and

co-workers in the preparation of plakortone cores, a novel classof activators of cardiac SR-Ca2+-pumping ATPase.91 The groupof Gracza developed an asymmetric oxycarbonylation of pent-4-ene-1,3-diols.92 In the presence of palladium salts and chiralbis(oxazoline) ligands, 1,4-benzoquinone (BQ) in acetic acid,under 1 bar of CO, the desired product were produced in achiral manner in low yields. They also extended the substratesto 4-benzyloxyhepta-1,6-diene-3,5-diols. Besides the synthesisof plakortones, these methodologies were also applied in the

preparation of natural products such as Kumausyne, CrisamicinA, Deoxynojirimycin, and so on.93

The report from Dixneuf in 1996 demonstrated thecarbonylation of alkynyl carbonates to 5- or 6-memberedlactones in the presence of a palladium catalyst.94 It is assumedthat this reaction proceeded via an allenylpalladium inter-mediate. More recently, a mild and efficient methodology forthe PdCl2-catalyzed chlorocyclocarbonylation of 2,3- or 3,4-allenols with CuCl2 for the synthesis of 3-chloromethyl-2(5H)-furanones and 3-chloromethyl-5,6-dihydropyran-2-ones wasdeveloped by Ma and co-workers (Scheme 30a). Optically

active 3-chloromethyl-2(5H)-furanones could be prepared fromreadily available optically active 2,3-allenols.95 Meanwhile, Liand Shi reported the palladium-catalyzed cyclocarbonylation ofα-allenic alcohols to give the corresponding lactones (Scheme30b). The α-allenic alcohols were prepared from vinyl-bromohydrin derivatives under mild conditions.96

3.1.3. Palladium-Catalyzed Carbonylative Reactionsof 2-Halo-alke(y)nes. The works by Larock and co-workers inthe 1970s led to an efficient procedure for the synthesis ofchloro-substituted lactones.97 Here, the reaction of propargylicalcohols with mercuric chloride gave β-chloro-γ-hydroxyvinyl-mercuric chlorides as key intermediates. In the presence of astoichiometric amount of palladium chloride and 1 bar of CO,the corresponding products were synthesized in good yields(Scheme 31a). When applying CuCl2 as reoxidant and using

benzene as solvent, only catalytic amounts of palladiumchloride were needed. Kocovsky and co-workers obtainedorganomercurials from cyclopropyl alcohols, which wereconverted into lactones in the presence of a catalytic amountof palladium catalyst using BQ as oxidant (Scheme 31b). Thereaction was done in a stereoselective manner under 1 bar ofCO.98 These methodologies offer other choices for thesynthesis of functionalized lactones, but the main drawback ofthese protocols is the need for stoichiometric amounts of toxicmercury compounds. In this respect, the use of organic halidesas substrates, which avoids the need for mercury, is advanta-geous.

Scheme 28. Palladium-Catalyzed Carbonylative Synthesis ofLactones

Scheme 29. Palladium-Catalyzed Carbonylation of Diols

Scheme 30. Palladium-Catalyzed Cyclocarbonylation ofAllenols

Scheme 31. Palladium-Catalyzed Carbonylation ofOrganomercurials



In 1991, Shibasaki and co-workers reported the asymmetricsynthesis of α-methylene lactones starting from prochiralalkenyl halides.99 In the presence of 5 mol % of Pd(OAc)2and chiral ligand [(S,S)-chiraphos], under 1 bar of CO, thereaction was finished in 1 h at 80 °C in dimethylsulfoxide(DMSO) with K2CO3 as base. The group of Negishi reportedthe palladium-catalyzed cyclic carbometalation−carbonylationin 1994, and also the carbonylative cyclization of 1-iodo-2-alkenylbenzenes, 1-iodo-substituted 1,4-, 1,5-, and 1,6-dienes,and 5-iodo-1,5-dienes.100 Moderate yields of five- or six-membered heterocycles were achieved under CO pressure. 3-Iodohomoallylic alcohols were synthesized from 3,4-pentadien-2-one, tetra-n-butyl ammonium iodide, and aldehydes in thepresence of ZrCl4 as catalyst in good yields. These 3-iodohomoallylic alcohols can be further transformed into α,β-unsaturated γ-lactones by palladium-catalyzed cyclocarbonyla-tion (Scheme 32a).101 In a similar manner, allylic alcoholscould also be produced from aldehydes and acrylate via Baylis−Hillman reaction. Following the same idea, 3-alkenyl phthalideswere produced in good yields from the Baylis−Hillman adducts(Scheme 32b).102 With respect to the increasing importance oftrifluoromethyl-substituted compounds, the report of Qing andJiang on the cyclocarbonylation of 3-iodo-3-trifluoromethylallylic alcohols is noteworthy.103 Several 3-trifluoromethyl-2(5H)-furanones were isolated in good yields (Scheme 32c).Interestingly, Ryu and co-workers reported the influence oflight on the carbonylation of alkyl iodides.104 The reactionproceeds by a radical pathway (Scheme 32d). In the samereport, carboxylic acid esters and α-keto amides were alsosynthesized from the corresponding alkyl iodides under thesame reaction conditions. More recently, the same groupdescribed the Pd/light-induced carbonylation of alkenes toesters and lactones.In 1982, Larock and Fellows reported the thallation−

carbonylation of benzyl alcohols.105 Thallium(III) trifluoroace-tate was used for the ortho-thallation of arenes, which aresubsequently carbonylated with 10 mol % of PdCl2, 2 equiv ofLiCl, and MgO in either methanol or THF under 1 bar of CO.Moderate yields of phthalides were obtained (Scheme 33).Besides these two-step reactions, more efficient protocols

were also reported. For example, Crisp and Meyer reported thepalladium-catalyzed intramolecular coupling of hydroxyl vinyl

triflates.106 Here, α,β-butenolides were formed in good yields.Furthermore, the palladium-catalyzed cyclocarbonylation of 2-halobenzyl alcohols was also developed.107 The application ofMo(CO)6 as CO source, using microwave to promote thispalladium-catalyzed carbonylation system, has been reportedtoo.108 The usefulness of these methodologies was proven bynumerous applications in total synthesis, such as dihydroma-hubanolide B, (+)-homopumiliotoxin 233G, CP-263,114, andphomoidrides.109

3.1.4. Other Palladium-Catalyzed Carbonylations toLactones. There are many other procedures known forpalladium-catalyzed carbonylative lactone formation that weredeveloped besides the cyclocarbonylation of alkynols, alkenols,and 2-halo-alkens; for example, in 2003, Chatani’s groupreported the palladium-catalyzed carbonylation of 2-(propargyl)allyl phosphates.110 On the basis of this method,unsaturated γ-lactones were synthesized in good yields(Scheme 34). Two reaction mechanisms were proposed (aand b), and pathway a was developed further by Negishi’sgroup at the end of the 20th century.111 Starting from 2-haloaryl alkenyl ketones, in the presence of CO and palladiumcatalyst, the corresponding five- and six-membered heterocycleswere formed in good yields. Recently, Cho and Kim reportedthe palladium-catalyzed cyclocarbonylation of β-bromovinylaldehydes and ketones.112 The reactions of ketones neededhigher temperature compared to the aldehydes, and moderateto good yields were observed (Scheme 35). Palladium-catalyzedcyclocarbonylation was also applied in the total synthesis ofuncinine and its analogues.113

A convenient synthesis of 3-spiro-fused benzofuran-2(3H)-ones was reported by Arcadi’s group, and shortly after Grigg’sgroup extended this procedure toward 3-spiro-2-oxindoles.114

After palladium-catalyzed carbonylation of vinyl triflates with o-iodophenols (or o-iodoanilines), intramolecular Heck reactiongave the terminal products in good yields. Notably, the

Scheme 32. Palladium-Catalyzed Cyclocarbonylations

Scheme 33. Thallation−Carbonylation of Arenes



reactions were carried out under atmospheric pressure of COand at ambient temperature.Interestingly, the group of Miura developed the palladium-

catalyzed carbonylation reaction of naphthols and phenolshaving appropriate substituents with aldehydes in the presenceof CF3CO2H as cocatalyst.115 Hence, benzofuran-2(3H)-onederivatives were produced in good yields (Scheme 36). Thereaction mechanism is believed to start with the nucleophilicaddition of naphthol to the protonated aldehyde, which ispromoted by CF3CO2H, to give dihydroxy intermediate (2-hydroxybenzyl alcohols, for examples), followed by palladium-catalyzed carbonylation. Indeed, the reaction of 2-hydroxyben-zyl alcohols also took place effectively under similar conditions.Chatani and co-workers reported the carbonylation of yne

esters in 2005.116 Lactones were produced in good yields under1 bar of CO (Scheme 37a). The 2-pyridinyloxy group was a

good carbonyl leaving group among the groups tested.Following a similar concept, the cyclocarbonylation of 2-propynyl-1,3-dicarbonyls with organo halides or triflates lead tofurans in good yields (Scheme 37b).117 The oxidativecyclocarbonylation of 2-alkyl-2-propargylcyclohexane-1,3-dio-nes mediated by palladium catalysts was developed by Kato,Akita, and co-workers.118 Bicyclic-β-alkoxyacrylates wereproduced in 51−74% yields with 72−82% enantiomericexcesses (ee's) (Scheme 37c). The authors also extendedtheir palladium-catalyzed cyclocarbonylation to propargylicesters, propargylic acetates, 4-yn-1-ones, and allenyl ketones.This methodology was applied by Mukai and co-workers in thetotal synthesis of naturally occurring diacetylenic spiroacetalenol ethers.119 A related mechanistic study was also done byCarfagna and co-workers that was supported by bothexperiment and DFT study.120

The competition between a Pd(0)-promoted deallylationcatalytic cycle and a Pd(II)-promoted heterocyclizationcatalytic cycle (they have named this “sequential homobime-tallic catalysis”) has been shown to occur starting from 1-(2-allyloxyphenyl)-2-yn-1-ols to afford 2-benzofuran-2-ylaceticesters and β,γ-unsaturated esters in high yields undercarbonylative conditions by Gabriele’s group.121 In view ofthe conceptual as well as the synthetic importance of theprocess, the mechanistic aspects and the synthetic scope of thereaction were investigated in detail. All the experimentalevidence was in agreement with the sequential homobimetallicmechanism, and the reaction proved to be of general syntheticapplicability. Instead of esters, amides could also be producedin the presence of amines under the same conditions (Scheme38a).122 Applying similar reaction conditions, they also

Scheme 34. Palladium-Catalyzed Carbonylation of 2-(Propargyl)allyl Phosphates

Scheme 35. Palladium-Catalyzed Cyclocarbonylation of β-Bromovinyl Aldehydes and Ketones

Scheme 36. Palladium-Catalyzed Carbonylation of Naphthols with Aldehydes

Scheme 37. Palladium-Catalyzed Cyclocarbonylation ofAlkynones



succeeded to extend their methodology to the synthesis ofcoumarins (Scheme 38b).123 Starting from readily available 2-(1-hydroxyprop-2-ynyl)phenols, the reactions were carried outin the presence of catalytic amounts of PdI2 in conjunction withan excess of KI in MeOH at room temperature and under 90bar of CO to give 3-[(methoxycarbonyl)methyl]coumarins ingood isolated yields (62−87%).Grigg and co-workers reported palladium-catalyzed multi-

component reactions to interesting benzofurans and relatednitrogen heterocycles.124 Cyclocarboformylation can beachieved regioselectively and provides novel access to aldehydesby applying silane as hydride source. Alternatively, organo-stannanes and NaBPh4 were also used as coupling partners andgave the corresponding ketones in good yields (Scheme 39a).

They also described the multicomponent reaction ofbicyclopropylidene, CO, and aryl iodides or aryl thiols, leadingto different heterocycles in fair yields.125 The group of Larockdeveloped a palladium-catalyzed carbonylative annulation ofinternal alkynes. Five-, six-, seven-, and eight-membered ringlactones were synthesized by this procedure.126 This kind ofconcept was recently modified and used for total synthesis ofthe marine ascidian metabolite perophoramidine and othernatural products.127

The group of Gabriele developed also a novel carbonylationprocedure for the synthesis of indoles.128 Their multi-component cascade reaction is initiated by a nucleophilicattack to the imine moiety, which is followed by a palladium-

catalyzed heterocyclization−alkoxycarbonylation process. Anumber of indoles were prepared in good yields (Scheme 39b).3.2. Palladium-Catalyzed Carbonylative Synthesis ofFive-Membered Nitrogen-Containing Heterocycles

Nitrogen-containing heterocycles show a variety of biologicalactivities and represent privileged structures compared to othertypes of heterocycles. In this respect it is interesting that Arcadi,Cacchi, and co-workers reported the palladium-catalyzedcyclocarbonylation of 2-alkynyltrifluoroacetanilides with arylhalides and vinyl triflates.129 2-Substituted 3-acylindoles weresynthesized in fair to good yields (Scheme 40a). The

mechanism is believed to begin with the oxidative addition ofthe organohalide to active Pd(0) species, followed by thecoordination and insertion of CO to form the correspondingacylpalladium intermediate, which undergoes an intramolecularnucleophilic attack of the nitrogen atom after coordination ofthe triple bond to R−Pd−X. The final product is formed afterreductive elimination. Interestingly, 2-(1-alkynyl)benzenamineswere converted into 3-(halomethylene)indolin-2-ones in thepresence of PdX2 and CuX2 (X = Br, Cl).130 The products areachieved in moderate to good yields (Scheme 40b). The latterreaction mechanism is proposed to start with the coordinationof PdCl2 to the triple bond and nitrogen, followed by cis- andtrans-halopalladation to generate a vinylpalladium species.Afterward, the coordination and insertion of CO occurred,and the terminal product is formed after reductive elimination.The active Pd(II) species can be regenerated by the oxidationof Pd(0) with CuX2 to start a new catalytic cycle.Notably, when carrying out the reaction of 2-(1-alkynyl)-

benzenamines in methanol under oxidative conditions, (E)-3-(methoxycarbonyl)methylene-1,3-dihydroindol-2-ones wereproduced in 48−64% yields (Scheme 41a).131 1-(2-Amino-aryl)-2-yn-1-ols, which can be easily obtained by the Grignardreaction between 1-(2-aminoaryl)ketones and alkynylmagne-sium bromides, were carbonylated into quinoline-3-carboxylicesters or indol-2-acetic esters, depending on the reactionconditions (Scheme 41b).132 Using similar reaction conditions,the same authors also described the palladium-catalyzedcyclocarbonylations of 2-ynylamines to 4-dialkylamino-1,5-dihydropyrrol-2-ones (Scheme 41c)133 and (Z)-(2-en-4-ynyl)-amines to the corresponding pyrrols (Scheme 41d).134

A novel one-pot construction of pyrazoles and isoxazoles wasreported by Mori’s group in 2005, and later by Stonehous’sgroup. Starting form terminal alkynes, hydrazines or hydroxyl-amines, CO, and aryl iodides, the corresponding heterocycleswere formed in good yields under the assistance of a palladium

Scheme 38. Palladium-Catalyzed Carbonylative CascadeReaction

Scheme 39. Palladium-Catalyzed Cyclocarbonylation UsingSilanes or Borates As Coupling Partner and PdI2-CatalyzedCarbonylative Synthesis of Indoles

Scheme 40. Palladium-Catalyzed Cyclocarbonylation of 2-(1-Alkynyl)benzenamines



catalyst. The reaction was conducted at room temperatureusing ambient pressure of CO in an aqueous solvent system.Concerning the reaction mechanism, the first step is theoxidative addition of the aryl iodide to the palladium center,followed by coordination and insertion of CO to form theacylpalladium species. After reductive elimination, alkynonesare formed, which condensate with hydrazines or hydroxyl-amines to give pyrazoles or isoxazoles as the final products.135

Some one-pot, two-step procedures for generating pyrazoleswere also reported. Here, the alkynones were produced bycarbonylative coupling of aryl halides with terminal alkynes in

advance, followed by addition of hydrazine to furnish theproducts.136

As early as in 1983, Danishefsky and Taniyama reported thepalladium-mediated cyclization of acrylanilide (Scheme 42a).137

The group of Tamaru had a long-term interest in the relatedpalladium-catalyzed oxidative aminocarbonylation of unsatu-rated ureas and carbamates (Scheme 42b).138 The Pd(II)-catalyzed intramolecular aminocarbonylation of olefins bearingmany types of nitrogen nucleophiles has been examined indetail in their group. The cyclizations proceeded either underacidic conditions [A: typically PdCl2 (0.1 equiv) and CuCl2(3.0 equiv) under 1 atm of CO at room temperature inmethanol] or buffered conditions [B: typically PdCl2 (0.1equiv) and CuCl2 (2.3 equiv) under 1 atm of CO at 30 °C intrimethyl orthoacetate]. Among the different substrates tested,endocarbamates displayed distinctive reactivity: they smoothlyunderwent intramolecular aminocarbonylation under condi-tions B to furnish 4-[(methoxycarbonyl)methyl]-2-oxazolidi-nones in good yields. Other nitrogen-containing substrates(exoureas, endoureas, exocarbamates, and exotosylamides), onthe other hand, satisfactorily underwent aminocarbonylationonly under conditions A to give the corresponding products ingood yields. Under conditions B, they are unreactive andprovided the expected products either in poor yields or asintractable mixtures of products.Similar to the mentioned Wacker-type oxidation conditions,

N-tosylhomoallylamines furnished 3-methyl-2-pyrrolidones asproducts.139 In the presence of palladium and copper salts, thereactions were carried out at 1 bar of CO and at roomtemperature (Scheme 43a). Meanwhile, this reaction was alsorealized in an enantioselective manner by application of spirobis(isoxazoline) as chiral ligands. dppb and BINAP were alsoused as ligand under pressure of CO and H2 (Scheme 43b).

140

The combination of aminocarbonylation with Friedel−Craftsacylation was reported by Cernak and Lambert in 2009.141 Inthe presence of palladium and indium salts, α-pyrrolidinylketones were produced in good yields with CuCl2 as oxidant(Scheme 43c). This type of oxidative aminocarbonylation was

Scheme 41. PdI2-Catalyzed Carbonylations Leading toNitrogen Heterocycles

Scheme 42. Palladium-Catalyzed Oxidative Aminocarbonylation



also applied in the total synthesis of (±)-ferruginine,(±)-anatoxin-a, and 1,4-iminoglycitols.142

[Pd(CH3CN)4](BF4)2 is a strongly electrophilic complex,which can activate olefins to undergo nucleophilic attack bynitriles to give nitrilium salts. These nitrilium salts undergosubsequent reactions with a variety of nucleophiles, includingelectron-rich aromatics, alcohols, and amines, ultimatelyproducing a variety of heterocyclic ring systems.143 The reportfrom Alper’s group demonstrated that the use of 2-amino-styrenes as reactants in the presence of catalytic quantities ofpalladium acetate and tricyclohexylphosphine affords five-membered ring lactams in high yield and selectivity. Bicyclicand tricyclic heterocycles containing six-membered ring lactamscan be synthesized from the related reaction of 2-allylanilineswith CO/H2 using the catalytic system Pd(OAc)2/PPh3,whereas the use of 1,4-bis(diphenylphosphino)butane insteadof PPh3 in the latter process results in the formation of theseven-membered benzazepinones in good yield. The regiose-lectivity control depends on the nature of the palladiumcatalyst, the relative pressures of the gases, and the solvent.144

Beller and co-workers described the palladium-catalyzedcarbonylation of aldehydes with urea derivatives providing aremarkably simple, pharmacologically interesting method forthe preparation of 5-, 3,5-, and 1,3,5-substituted hydantoins ingood to very good yields.145

Besides the cyclocarbonylation of alkenyl and alkynyl amines,the palladium-catalyzed aminocarbonylation of allenic aminesconstitutes a versatile methodology for the construction ofnitrogen-containing heterocycles. The groups of Gallagher(Scheme 44a)146 and Tamaru (Scheme 44b)147 contributed

significantly to this area. In the presence of a palladium catalyst,allenic amines underwent cyclization under mild conditions inmethanol. Additional oxidation reagents were needed toreoxidize the intermediate Pd(0) species. This method wasalso used in the preparation of pumiliotoxin 251D by the samegroup.Palladium-catalyzed carbonylative C−H activation reactions

of aromatic rings have obvious advantages compared with thesimilar carbonylation reactions of aryl halides. Already in 1967,Takahashi and Tsuji published the palladium-mediated carbon-ylation of azobenzenes.148 They first prepared azobenzene−palladium chloride complexes, and then the complexes reactedunder an atmosphere of CO to indazolinones in excellentyields, which could be further carbonylated into quinazoline-dions in the presence of cobalt carbonyl (Scheme 45a). Benzyl

amine derivatives were also carbonylated by the formation ofthe corresponding palladium complexes in advance (Scheme45b).149 Palladium-catalyzed carbonylation of benzyl amines tobenzolactams were also reported. In the presence of catalyticamounts of palladium catalyst, and using Cu(II) and air asoxidants, N-monoalkylated benzyl amines or phenethylamineswere transformed into benzolactams in good yields, and N,N′-dialkylureas were obtained from primary amines (Scheme45c).150 More recently, Yu and co-workers reported thecarbonylation of C(sp3)−H bonds to succinimides. Notably,only a catalytic amount of palladium catalyst was neededtogether with 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO)as oxidant. However, the corresponding products were isolatedin moderate yields. The carbonylative C−H activation of arenesby using sulfonamide as directing group was also reported bythe same group (Scheme 45d).151

In addition to C−H activation reactions of arenes, thepalladium-catalyzed carbonylation of o-bromoaminoalkylben-zenes was reported by Ban and co-workers in 1978.152 In the

Scheme 43. Palladium-Catalyzed Aminocarbonylation

Scheme 44. Palladium-Catalyzed Cyclocarbonlyation ofAllenic Amines

Scheme 45. Palladium-Promoted Carbonylative C−HActivation



presence of catalytic amounts of Pd(OAc)2 and PPh3 underatmospheric pressure of CO, five-, six-, and even seven-membered benzolactams were prepared in good yields (Scheme46a). A similar sequential reaction was also developed by Grigg

and co-workers.153 Here, starting from 2-halobenzylamines,ethyl glyoxalates, and aryl boronic acids, the in situ-generatedcarbinolamines/imines reacted with CO to give isoindolones.Following this concept, Shim et al. developed a palladium-catalyzed coupling of o-bromobenzyl bromides with primaryamines. Initially, o-bromobenzyl amines are formed, which reactfurther via palladium-catalyzed aminocarbonylation in DMF.The final products were obtained in fair to moderate yields(Scheme 46b).154 The latter reaction was improved by Griggand co-workers,155 as well as in further studies by othergroups.156 Applying in situ-generated palladium nanoparticles,this three-component reaction proceeded even at roomtemperature under 1 bar of CO and gave the desired productsin good yields. Recently, the same group also described a novelpalladium-catalyzed carbonylative synthesis of isoindolin-1-ones.157

This three-component cascade process involved the carbon-ylation of substituted aryl iodides to generate the respective acylpalladium species, which reacted with a primary aliphatic/aromatic amine, amide, or sulfonamide followed by anintramolecular conjugate addition to afford 3-substitutedisoindolin-1-ones in good yields (Scheme 46c). Moreover,Shim and co-workers described the cyclocarbonylation of 2-(2-bromophenyl)-2-oxazolines by a palladium−nickel catalyst.158Under 3 bar of CO and in the presence of the bimetalliccatalyst, the corresponding isoindolinones were produced inhigh yields (Scheme 47a). Later on, they synthesized similarproducts by palladium-catalyzed coupling of 2-iodobenzoylchloride with imines.159 In the presence of Pd(PPh3)2Cl2/PPh3as the catalyst system and NEt3 as base, the correspondingisoindolinones were formed in moderate yields (Scheme 47b).More complex isoindolinones were produced by the samegroup through a palladium-catalyzed carbonylative coupling of2-bromobenzaldehydes with aminoalcohols or diamines.160

These multistep reactions provided the correspondingisoindolinones in good isolated yields (Scheme 47c). Thereactions of diamines were carried out under lower temperatureand with lower catalyst loading. Besides that, the palladium-catalyzed coupling of 2-bromobenzaldehydes and 2-bromocy-clohex-1-enecarbaldehydes with primary amines has also beendeveloped (Scheme 47d).161 Interestingly, no base was neededin these reactions. With respect to the mechanism, the reactionstarted with the formation of an imine by condensation of thealdehyde and the primary amine. Oxidative addition of thecarbon−bromide bond of the imine to the active palladium(0)catalyst produces the arylpalladium(II) complex. After coordi-nation of carbon monoxide to the metal center and subsequentinsertion into the C−Pd bond, an aroylpalladium(II)intermediate is formed. Then, an intramolecular acylpalladationto the imine gives the alkylpalladium(II) intermediate.Subsequent hydrogenolysis with molecular hydrogen leads tothe isoindolin-1-one. It is assumed that hydrogen is producedby the reaction of CO with H2O generated in the initialcondensation stage.The group of Mori and Shibasaki reported the use of a

special titanium−isocyanate complex for a novel one-step

Scheme 46. Palladium-Catalyzed Carbonylative Synthesis ofIsoindolin-1-ones

Scheme 47. Palladium-Catalyzed Carbonylative Synthesis Towards Isoindolin-1-ones



synthesis of isoindolinones and quinazolinones starting from o-halophenyl alkyl ketones.162 As shown in Scheme 48, thisreaction proceeds through the oxidative addition of the enollactone, generated by palladium-catalyzed carbonylation of o-halophenyl alkyl ketones, to the titanium−isocyanate complexA.Some other procedures for the preparation of isoindolinone

derivatives were also reported.163 Examples are the carbon-ylation of iodoanilines with phenylacetylenes (Scheme 49a), thereaction of 1-halo-2-alkynylbenzene with amines, and the one-pot reaction of 1,2-dihaloarenes, alkynes, and amines (Scheme49b).In addition to isoindolinones, several methods for the

preparation of phthalimides have been developed in the lasttwo decades. In 1991, Perry’s group reported the carbonylativecoupling of o-dihaloarenes with primary amines to phthali-mides.164 As shown in Scheme 50a, using PdCl2 as catalyst and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base, phthali-

mides were produced in good yields in dimethylacetamide(DMAc). The same group also succeeded in applying similarreaction conditions for the carbonylative synthesis of 2-arylbenzoxazoles and 2-arylbenzimidazoles.165 Here, arylhalides were coupled with o-fluoroanilines and o-phenylenedi-amines to give 2-arylbenzoxazoles and 2-arylbenzimidazoles,respectively. More recently, Cao and Alper extended thismethodology to 1,2-dibromobenzenes as substrates by usingphosphonium salt-based ionic liquids as solvent under 1 bar ofCO.166 This process showed a wide tolerance for functionalgroups, and excellent yields of products were obtained. Therecyclability of the catalytic system was also investigated. Thegroup of Larock developed the straightforward carbonylation ofo-halobenzoates and primary amines to phthalimides.167 Thismethod gave the corresponding products in good yields andtolerated different functional groups (Scheme 50b). Later on,the group of Queiroz showed that it is also possible to performsimilar reactions under CO-free conditions by using Mo(CO)6as CO source.168

The group of Arndtsen developed a number of elegantmulticomponent reactions that introduce one or two CO's intothe parent molecules.169 In the presence of a palladium catalyst,alkynes, imines, acid chlorides, and CO coupled together togive pyrroles as terminal products (Scheme 51a). Using α-amidoesters instead of imines and acid chlorides gave the sameproducts (Scheme 51b). Interestingly, when the reaction wascarried out with imines and acid chlorides, imidazoles wereformed as the final products. By simply changing the sequenceof addition of the substrates, imidazolinium salts andimidazolines were produced. In general, these methods offerconvenient pathways for the production of heterocycles fromeasily available substrates.

Scheme 48. Palladium-Catalyzed Carbonylative Synthesis of Isoindolin-1-ones

Scheme 49. Palladium-Catalyzed Carbonylative Synthesis of Isoindolinone Derivatives

Scheme 50. Palladium-Catalyzed Carbonylative Synthesis ofPhthalimides



In 2001, Kang and Kim demonstrated the cyclocarbonylationof allenic sulfonamides with aryl iodides.170 In their report, α-allenic sulfonamides underwent a carbonylation−coupling−endocyclization sequence with aryl iodides in the presence ofpalladium catalyst. Pyrrolines and pyrrolidines were producedin moderate yields under 20 bar of CO. The mechanism of thisreaction was proposed to start with oxidative addition of ArI toPd(0) followed by carbonylation to give acylpalladium species.This complex adds to the central carbon of the allene moiety toprovide a π-allylpalladium complex. Cyclization of the latterintermediate by endomode will give the terminal product(Scheme 52).

Under similar reaction conditions, 6-trifluoromethyl-12-acylindolo[1,2-c]quinazolines were prepared in high yieldsthrough palladium-catalyzed carbonylation of bis(o-trifluoroacetamidophenyl)acetylene with aryl or vinyl halidesand triflates.171

The reaction, which tolerated a variety of functional groups,probably involves the formation of a 3-acyl-2-(o-trifluoroacetamidophenyl)indole intermediate, followed bycyclization to the final products (Scheme 53). Recently, twonovel processes for the synthesis of carbonylated indole

derivatives were developed. Thus, Alper and co-workersreported a palladium-catalyzed N−C coupling/carbonylationsequence toward 2-carboxyindoles. The catalyst system showedgood functional group tolerance and gave the products in highyields (Scheme 54a). 2-Aroylindoles could also be producedfrom the same substrates in moderate yields (Scheme 54b).172

Finally, it is worth mentioning that in 2010 Staben andBlaquiere reported a four-component carbonylation reactionfor the synthesis of 1,2,4-triazoles.173 Under mild conditionsand low CO pressure, a wide substrate scope was achieved(Scheme 55). Notably, the pharmaceutically interesting productDeferasirox was also synthesized by this methodology.

3.3. Palladium-Catalyzed Carbonylative Synthesis of OtherFive-Membered Heterocycles

Besides the previously described five-membered oxygen- andnitrogen-containing heterocycles, the synthesis of five-mem-bered heterocycles with both oxygen and nitrogen as well asother heteroatoms will be summarized in this section.As early as 1992, Meyers and co-workers reported the

palladium-catalyzed carbonylative synthesis of oxazolines.174

Aryl or enol triflates made from the corresponding ketones andphenols, and also aryl halides, were used as starting materialsand coupled with amino alcohols to give chiral α,β-unsaturatedor aryl oxazolines in good yields. Later on, Perry’s groupperformed systematic studies on this one-pot, two-step processfor the preparation of oxazolines (Scheme 56).175

Young and DeVita developed a novel procedure for thesynthesis of oxadiazoles (Scheme 57a).176 In a one-potprocedure, oxadiazoles were prepared in moderate yieldsfrom aryl iodides and amidoximes under 1 bar of CO. Bothelectron-withdrawing and electron-donating substituents weretolerated. Afterward, Zhou and Chen reported a similarreaction with diaryliodonium salts as starting materials (Scheme57b).177

Oxazolidinones are another important class of heterocycles,and many of their derivatives show interesting biologicalactivities. Thus, in 1986 Tam reported the oxidative carbon-ylation of 2-aminoethanols to oxazolidinones.178 Using acombination of PdCl2 and CuCl2 as the catalytic system,reactions proceeded smoothly at 3 bar of CO. Diols andaminodiols were also used as substrates in this reaction.

Scheme 51. Palladium-Catalyzed Carbonylation of Imines

Scheme 52. Palladium-Catalyzed Carbonylative Coupling ofAllenic Sulfonamides with Aryl Iodides

Scheme 53. Palladium-Catalyzed Carbonylation of Bis(o-trifluoroacetamidophenyl)acetylene



Gabriele and co-workers also applied their PdI2/KI system forthe oxidative carbonylation of β-amino alcohols, but higherpressure was needed (20−60 bar of CO and air).179

Interestingly, Li and Xia reported that palladium on charcoalis a more efficient catalyst compared to the reportedhomogeneous catalyst systems.180 Albeit the catalyst could bereused for five times without losing activity and selectivity, it isvery likely that the “real” active catalyst in this heterogeneoussystem is leached palladium nanoparticles. In addition, Pd(II)complexes have been combined with anodic recycling at agraphite electrode.181 In this process, the reaction could becarried out at room temperature under atmospheric pressure ofcarbon monoxide. Good yields of oxazolidinones wereobtained. More recently, Troisi and co-workers developed thepalladium-catalyzed cyclocarbonylation of ortho-substitutedphenols, thiophenols, and anilines.182 Benzo-fused five- andsix-membered heterocycles are produced in excellent yields.Notably, no oxidation reagent was needed in this reaction.Apparently, the oxidative addition of Pd(0) to the N−H or O−H bond of the substrates regenerated the required Pd(II)species. Thus, this cyclocarbonylation of amino alcohols offers astraightforward process for the preparation of oxazolidinones.High yield and selectivity are easily achieved, with manypossibilities of catalytic systems available (Scheme 58).

The group of Costa and Gabriele made comprehensivestudies on cyclocarbonylations of propargyl amines and relatedcompounds.183 In the presence of PdI2 and KI, oxazolidinonederivatives were synthesized in alcohols in the presence ofoxygen. In the case of prop-2-ynylamides, oxazolines wereprepared under similar reaction conditions (Scheme 59).

Related cyclocarbonylations of propargyl acetates and amideswere also studied by Kato and co-workers.184 They applied BQas oxidant and bisoxazoline ligands and obtained excellentyields of the cyclization products. The authors stated that theso-called box ligand enhanced the π-electrophilicity ofpalladium(II) and thus promoted the coordination of the triplebond of a second substrate molecule to the acyl palladiumintermediate to enable the dimerization reaction to take place.The cyclocarbonylation of o-alkenyl hydroxylamines under

oxidative conditions was reported by Bates and Sa-Ei.185

Treatment of o-homoallylhydroxylamines with palladium(II)and copper(II) in the presence of a base, methanol, and carbonmonoxide resulted in the formation of isoxazolidines (Scheme60). An electron-withdrawing group on the hydroxylaminenitrogen was essential for successful cyclization. Whencarbamate groups were used, the products were formedexclusively as their cis isomers.A facile and selective palladium-catalyzed domino synthesis

of carbonylated benzothiophenes was developed by Zeng andAlper in 2011.186 2-Carbonylbenzo[b]thiophene derivatives

Scheme 54. Palladium-Catalyzed Synthesis of Carbonylated Indoles

Scheme 55. Palladium-Catalyzed Carbonylative Synthesis ofTriazoles

Scheme 56. Palladium-Catalyzed Carbonylative Synthesis ofOxazolines

Scheme 57. Palladium-Catalyzed Carbonylative Synthesis ofOxadiazoles

Scheme 58. Palladium-Catalyzed Carbonylative Synthesis ofOxazolidinones

Scheme 59. Palladium-Catalyzed Carbonylation of PropargylAmines



were produced from 2-gem-dihalovinylthiophenols in 24−73%yields (Scheme 61). This protocol involved an intramolecular

C−S coupling/intermolecular carbonylation cascade sequenceand allowed for access to various highly functionalizedbenzo[b]thiophenes.

4. PALLADIUM-CATALYZED CARBONYLATIVESYNTHESIS OF SIX-MEMBERED HETEROCYCLES

In the previous section, we summarized the palladium-catalyzedcarbonylative synthesis of five-membered heterocycles. Someclosely related six-membered heterocycles have been men-tioned there and will not be further described in this section.4.1. Palladium-Catalyzed Carbonylative Synthesis ofSix-Membered Oxygen-Containing Heterocycles

Flavones are a major group of secondary metabolites foundthroughout plants and have shown a wide variety of biologicalactivities.187 Among all the known procedures, the palladium-catalyzed cyclocarbonylation of o-iodophenols with terminalacetylenes is one of the most straightforward processes. As earlyas in 1990, Kalinin and co-workers reported the first examplesof this type of reaction.188 They used 1 mol % of PdCl2(DPPF)(DPPF = diphenylphosphinoferrocene) as catalyst under 20 barof CO at 120 °C in Et2NH, which acted both as base andsolvent. About 50−81% of the corresponding flavones wereformed in the presence of 2 equiv of aromatic or aliphaticacetylenes. Applying the same reaction conditions, Torii,Kalinin, and co-workers used o-iodoanilines as substrates forthe preparation of quinolones.189 In this report, they showeddetailed studies on the catalyst system, solvent, base, temper-ature, and pressure. In the past decade, palladium-catalyzedcarbonylative syntheses of flavones have been carried out atroom temperature, under balloon pressure of CO, and evenusing water as solvent.190 Simple PdCl2 (5 mol %) and PPh3(10 mol %) were used as the catalyst system with NEt3 as baseand a slight excess of aliphatic acetylenes, and flavones wereproduced in 35−95% yields. Furthermore, Chen and co-workers described the reaction of o-iodophenols withethynylferrocene.191 Here, CuI (4 mol %) was used as additivetogether with 4 mol % of Pd(PPh3)4, using K2CO3 as base intoluene at 80 °C, giving the products in 74−80% yields. A one-pot Sonogashira-carbonylation annulation reaction of arylhalides, ethynyltrimethylsilane, and o-iodophenols was alsodeveloped by Awuah and Capretta.192 By applying microwaves,the products were isolated in 46−71%. The group of Alperperformed this reaction in phosphonium salt-based ionicliquids.193 No ligand was needed in this efficient and selective

reaction (Scheme 62). Huynh, Li, and co-workers tested aseries of palladium carbene complexes [PdBr2(iPr2-bimy)L]

with different types of coligands in the carbonylative annulationof 2-iodophenol with phenylacetylene to afford the respectiveflavone. Complexes with an N-phenylimidazole coligandshowed the best activity and also afforded high yields whenthe substrate scope was extended to other aryl or pyridylacetylenes. In addition, this catalyst was also efficient in thecarbonylative annulation of 2-iodoaniline with acid chlorides,giving 2-substituted 4H-3,1-benzoxazin-4-ones in good yields.Furthermore, this Pd−N-heterocyclic carbene (NHC) complexalso proved to be an efficient catalyst for the hydroxycarbony-lation of iodobenzenes at low catalyst loading and under lowCO pressure.194

Alternatively, Miao and Yang reported a novel method forthe preparation of flavones in 2000.195 Various flavones wereeasily synthesized via palladium-catalyzed carbonylative annu-lation of iodophenol acetates with terminal acetylenes in highyields (Scheme 63). This reaction provides also the possibility

for a combinatorial synthesis of flavones on solid supports.Following a similar concept, Martin and co-workers applied thecarbonylative Sonogashira reaction in the total synthesis ofluteolin as the key step.196

In addition to the palladium-catalyzed carbonylative couplingof o-iodophenols with acetylenes, its coupling with allenes wasalso developed. In 1997, Okuro and Alper reported such amethodology.197 In a regioselective process, benzopyranoneswere produced in fair to high yields (Scheme 64). The group ofGrigg improved this methodology to be performed atatmospheric CO pressure with Pd(PPh3)4 (5 mol %) ascatalyst and K2CO3 as base.

198 They also extended the substrate

Scheme 60. Palladium-Catalyzed Carbonylation of o-AlkenylHydroxylamines

Scheme 61. Palladium-Catalyzed Carbonylative Synthesis ofBenzothiophenes

Scheme 62. Palladium-Catalyzed Carbonylative Synthesis ofFlavones

Scheme 63. Palladium-Catalyzed Carbonylation ofIodophenol Acetates

Scheme 64. Palladium-Catalyzed Carbonylative Synthesis ofBenzopyranones



scope to o-iodoanilines. Meanwhile, the combination of thisreaction with Diels−Alder reactions and cyclocondensationswith hydrazine were also realized.199

As shown previously, the reaction of o-iodophenols withterminal acetylenes and CO gives flavones selectively. However,different products can be observed in the case of internalalkynes. In 2000, Kadnikov and Larock reported that thepalladium-catalyzed annulation of internal alkynes with o-iodophenols in the presence of CO resulted in exclusiveformation of coumarins.200 No isomeric chromones have beenobserved. The best reaction conditions utilized 2-iodophenol, 5equiv of alkyne under 1 atm of CO in the presence of 5 mol %Pd(OAc)2, 2 equiv of pyridine, and 1 equiv of n-Bu4NCl inDMF at 120 °C. The use of a sterically unhindered pyridinebase was essential to achieve high yields (Scheme 65). A variety

of 3,4-disubstituted coumarins containing alkyl, aryl, silyl,alkoxy, acyl, and ester groups were prepared in moderate togood yields. Moreover, mixtures of regioisomers were obtainedwhen unsymmetrical alkynes were employed. 2-Iodophenolswith electron-withdrawing and electron-donating substituentsand 3-iodo-2-pyridone are effective in this annulation process.The reaction is believed to proceed via oxidative addition of 2-iodophenol to Pd(0), insertion of the alkyne into the aryl−palladium bond, CO insertion into the resulting vinyliccarbon−palladium bond, and nucleophilic attack of thephenolic oxygen on the carbonyl carbon of the acylpalladiumcomplex with simultaneous regeneration of the Pd(0) catalyst.Notably, in this annulation process the intermolecular insertionof an alkyne into the aryl−C−Pd bond was preferred comparedto CO insertion. Afterward, Cao and Xiao described thisreaction under microwave irradiation, but the selectivityproblem was not resolved. Hence, coumarins and flavoneswere obtained.201

Li, Yu, and Alper developed also an efficient ionic liquid-based protocol for the preparation of highly substitutedendocyclic enol lactones via carbonylations of alkynes and1,3-diketones.202 The reactions proceeded in excellentregioselectivity and in reasonably good yields (Scheme 66a).The catalyst system could be recycled five times with onlymodest loss of catalytic activity. More recently, Wu and Huareported a similar reaction of 1,3-cyclohexanediones and

terminal alkynes.203 In the presence of a catalytic amount ofPd(PPh3)4, lactones were produced in good yields (Scheme66b). Similar products could also be synthesized by palladium-catalyzed carbonylation of iodoalkenes. This was demonstratedin the total synthesis of manoalide, a marine sesterterpenoidwith anti-inflammatory properties.204

For the synthesis of six-membered lactones, Kalck and co-workers described an interesting cyclocarbonylation of olefinicalcohols in 1993.205 By applying PdCl2(PPh3)2 orPdCl2(PPh3)2/SnCl2·2H2O as the catalytic system at 40 barof CO and 100 °C, lactones were produced from isopulegol.With the same catalyst, allylbenzenes, propenylbenzenes, andmonoterpenes were converted into the corresponding esters.Later on, they conducted this reaction in an asymmetricmanner and found that Pd(H)(SnCl3)L2 is the key activecatalyst species.206

Dong and Alper reported that the cyclocarbonylation of o-isopropenylphenols with CO (35 psi) and H2 (7 psi) usingPd(OAc)2 and (+)-DIOP [DIOP = (2,2-dimethyl-1,3-dioxo-lane-4,5-diylbismethylene)bisdiphenylphosphine] as the chiralcatalyst afforded 3,4-dihydro-4-methylcoumarins in 60−85%yield with up to 90% enantiomeric excess (Scheme67a).207They also used a PCP-type palladium(II) catalyst

immobilized on silica and silica-supported dendrimers for theproduction of five- or seven-membered ring lactones. From 2-allylphenols, the corresponding lactones were produced in goodselectivity and high yields. These immobilized catalysts werestable toward oxygen and moisture and could be recycled bysimple filtration in air. Apparently, they combine the advantagesof heterogeneous and homogeneous catalysts.208 Anotherefficient palladium-catalyzed domino reaction for the formation

Scheme 65. Palladium-Catalyzed Carbonylative Synthesis ofCoumarins

Scheme 66. Palladium-Catalyzed Carbonylation of 1,3-Diketones

Scheme 67. Palladium-Catalyzed IntramolecularCarbonylation of Hydroxyalkenes



of chromans and benzodioxins was described by Tietze and co-workers starting from the alkenes and allyl phenyl ethers(Scheme 67b).209 The same class of compounds was alsoprepared by intramolecular alkoxycarbonylations of alkenes,210

which was also applied in the total synthesis of leucascan-droolide A and polyketides.211

Already in 1978, the group of Norton reported thecyclocarbonylation of 2-exo-ethynyl-7-syn-norbornanol to α-methylene γ-lactone in moderate yield.212 Two decades later,Cao, Xiao, and Alper described a palladium-catalyzed doublecarbonylation and cyclization reaction of enynols with thiols toform thioester-containing 6-membered ring lactones withexcellent selectivity and in moderate to good yields (Scheme68a).213 They also conducted the reaction in ionic liquids, but

only monocarbonylated six-membered lactones were formed.Good selectivity and high yield were obtained, and therecyclability of the catalyst system was also tested (Scheme68b).214

Negishi and co-workers reported the reaction of aryl andalkenyl halides with acidic ketones.215 In the presence of CO(40−45 bar), NEt3 (1−2 equiv), and 5 mol % of PdCl2(PPh3)2in DMF at 100 °C, the corresponding enol carboxylates wereformed. In the case where alkenyl halides were used, theinitially formed products can cyclize to give the correspondinglactones.Ryu and co-workers reported the selective cyclocarbonyla-

tion of saturated alcohols to δ-lactones in which leadtetraacetate (LTA) was used as a one-electron oxidant togenerate highly reactive alkoxyl radicals.216 The mechanism ofthis remote carbonylation likely involves (i) alkoxyl radicalgeneration via LTA oxidation of the saturated alcohol, (ii)conversion of this alkoxyl radical to a δ-hydroxyalkyl radical by1,5-hydrogen-transfer reaction, (iii) CO trapping of the δ-hydroxyalkyl radical yielding an acyl radical, and (iv) oxidationand cyclization of the acyl radical to give the final δ-lactone.Carbonylations of five classes of saturated alcohols, namely,primary alcohols having primary δ-carbons, primary alcoholshaving secondary δ-carbons, primary alcohols having tertiary δ-carbons, secondary alcohols having primary δ-carbons, andsecondary alcohols having secondary δ-carbons, were carriedout to afford δ-lactones in moderate to good yields (Scheme69). A metal salt-free system was also tested for a specialsubstrate derived from a tertiary alcohol having a secondary δ-carbon. Here, the photolysis of the respective alkyl 4-

nitrobenzenesulfenate under CO pressure gave the δ-lactonein moderate yield.Zhou and co-workers demonstrated a regioselective borox-

arene formation from 2-hydroxybiphenyl and 2-methoxybi-phenyl under mild conditions.217 These synthetic intermediateswere converted further on to 3,4-benzocoumarins through COinsertion. Application of this chemistry to commerciallyavailable 3′-methyl-biphenyl-2-ylamine resulted in an efficienttwo-step synthesis of phenaglydon. However, in all thereactions described, 1 equiv of Pd(OAc)2 was needed foracceptable yields (Scheme 70).In 2009, Willis’s group demonstrated that in situ-generated

enolates can be employed as intramolecular nucleophiles inpalladium-catalyzed aryl-carbonylation reactions to give thecorresponding isocoumarins.218 At 1 bar of CO, good yieldswere achieved with both cyclic and acyclic ketones assubstrates. Later on, they also used this methodology in aconcise synthesis of the natural product thunberginol A(Scheme 71).Most recently, Yu and co-workers developed a palladium-

catalyzed carbonylation of phenethyl alcohols, which givesaccess to the related saturated isochromanones.219 Moderate toexcellent yields of the desired products were achieved via CHactivation by using amino acid ligands and overstoichiometricamounts of silver acetate (Scheme 72). The synthetic value ofthis method was proven by a short synthesis of a histamine-release inhibitor. Meanwhile, a comprehensive study of thesynthesis of isoquinoline and isocoumarin derivatives wasperformed. Intramolecular C−N and C−O reductive couplingtook place under relatively mild conditions.220

In 2008, Giri and Yu reported a selective palladium-catalyzedC−H activation of aromatic carboxylic acids too.221 In thepresence of a catalytic amount of Pd(OAc)2, benzoic andphenylacetic acid derivatives were converted into ortho-substituted dicarboxylic acids in good yields (Scheme 73).The authors were also able to characterize the initially formedcyclometalation complex by X-ray. It should be noted thatrelated carbonylation products can be produced from 1,8-diiodonaphthalene.222

Cyclic carbonates represent an important class of carbonylcompounds with interesting potential applications in thechemical industry.223 Hence, Gabriele’s group reported anefficient method for the oxidative carbonylation of 1,2- and 1,3-diols to five- and six-membered cyclic carbonates (Scheme74).224 In the presence of their previously described PdI2-basedsystem, 1,2-diols underwent an oxidative carbonylation processto afford 5-membered cyclic carbonates in high yields (84−94%) and with good efficiency for this kind of reaction (up toca. 190 mol of product per mol of PdI2). Under similarconditions, 6-membered cyclic carbonates were obtained forthe first time through a direct catalytic oxidative carbonylationof 1,3-diols (66−74% yields). Obviously in this work nooxidative addition of the active palladium complex to a C−Xbond takes place. Instead, activation of carbon monoxidefollowed by nucleophilic attack of the alcohol and subsequentreductive elimination provides the cyclic carbonates.

4.2. Palladium-Catalyzed Carbonylative Synthesis ofSix-Membered Nitrogen-Containing Heterocycles

For the preparation of various quinoline derivatives, thepalladium-catalyzed carbonylative coupling of 2-haloanilineswith terminal alkynes offers straightforward access. Thus, asearly as in 1991, Torii and co-workers reported this type of

Scheme 68. Palladium-Catalyzed Carbonylation of Enynols

Scheme 69. Cyclocarbonlyation of Aliphatic Alcohols



carbonylation process.225 In the presence of 5 mol % ofpalladium catalyst and under 20 bar of CO at 120 °C, 2-substituted 1,4-dihydro-4-oxo-quinolines were produced ingood yields (Scheme 75). Shortly after, Kalinin and co-workers

reported the same process by using 10 mol % of PdCl2(DPPF)in Et2NH under 20 bar of CO at 120 °C,226 which was laterapplied by Haddad et al. in the synthesis of BILN 2061derivatives (Scheme 75a).227 Alternatively, the palladium-catalyzed reaction of 3-(2-haloarylamino)prop-2-enoates leadsto quinoline derivatives.228 A similar concept was used byMuller and co-workers in their elegant synthesis ofmeridianins.229 On the basis of a carbonylative Sonogashirareaction and a subsequent cyclocondensation process, 2,4,6-trisubstituted pyrimidines were produced that were furtherconverted into meridianins. In 1990, Torii’s group developedthe palladium-catalyzed carbonylation of 3-substituted 3-(2-haloarylamino)prop-2-enoates. Various 2-substituted 1,4-dihy-dro-4-oxo-quinoline-3-carboxylates were produced in goodyields from the corresponding enoates (Scheme 75b). Astudy from Ye and Alper showed that 2-iodoanilines and allenesgave similar quinoline derivatives under carbonylation con-ditions.230 This palladium-catalyzed cyclocarbonylation reactionof o-iodoanilines with allenes and CO in 1-butyl-3-methyl-imidazolium hexafluorophosphate afforded 3-methylene-2,3-dihydro-1H-quinolin-4-ones in moderate to excellent yieldsunder a low pressure (5 bar) of CO (Scheme 75c). As shownby the authors previously, the ionic liquid enhanced theefficiency of the cyclocarbonylation reaction. The recyclabilityof the system of ionic liquid/catalyst/ligand was alsodemonstrated.Quinazolines as another class of important six-membered

nitrogen-containing heterocycles find numerous applications indrugs. In 1987, Tilley and co-workers reported an interestingprotocol for their synthesis.231 Starting from 5-substituted 2-(2-bromoanilino)-pyridine, pyrido[2,1-b]quinazolines were pro-duced under carbonylative conditions. The reaction mechanismwas believed to proceed through an acyl palladium species,which undergoes nucleophilic attack by the pyridine nitrogen,leading to ring-closure with loss of palladium(0) and a proton.The methodology has been shown to be compatible with avariety of functional groups including amides, primary alcohols,aromatic amines, and heteroaromatic rings. Hence, it allows fora flexible selection of substituents on the ultimate pyrido[2,1-b]-quinazoline ring (Scheme 76a).Larksarp and Alper developed a catalytic system for the

cyclocarbonylation of o-iodoanilines with heterocumulenes.232

By applying a palladium acetate−bidentate phosphine catalystsystem at 70−100 °C, the corresponding 4(3H)-quinazolinonederivatives were obtained in good yields (Scheme 76b). Byutilizing o-iodoaniline with isocyanates, carbodiimides, andketenimines, 2,4-(1H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones, and 2-alkyl-4(3H)-quinazolinones were ob-tained, respectively. The nature of the substrates and theelectrophilicity of the carbon center of the carbodiimide, as wellas the stability of the ketenimine, influenced the product yieldsof this reaction. Urea-type intermediates are believed to begenerated first in situ from the reaction of o-iodoanilines withheterocumulenes. Then, palladium-catalyzed carbonylation andintramolecular cyclization give the products. The same group

Scheme 70. Palladium-Mediated Synthesis of 3,4-Benzocoumarins

Scheme 71. Palladium-Catalyzed Carbonylative Synthesis ofIsocumarins

Scheme 72. Palladium-Catalyzed Carbonylative C−HActivation of Phenethyl Alcohols

Scheme 73. Selective Palladium-Catalyzed Carbonylative C−H Activation of Phenylacetic Acids

Scheme 74. Palladium-Catalyzed Oxidative Carbonylation ofDiols



also developed carbonylation reactions of N-(2-iodophenyl)-N′-phenyl-carbodiimides (Scheme 76c)233 and N,N′-di-o-iodophenyl carbodiimides (Scheme 76d)234 to yield thecorresponding quinazolines under similar reaction conditions.They also proved that quinazolines could be synthesized fromo-iodoanilines, imidoyl chlorides, and CO (Scheme 76e).235

The latter reaction was proposed to proceed via in situformation of an amidine, followed by oxidative addition, COinsertion, and intramolecular cyclization to give the substitutedquinazolin-4(3H)-ones.More recently, Zhu and co-workers developed a palladium-

catalyzed intramolecular C−H carboxamidation of N-arylami-

dines to the corresponding quinazolines.236 The reactions werecarried out in the presence of 1.0 equiv of CuO as oxidantunder atmospheric pressure of CO and provided diversified 2-aryl(alkyl)-quinazolin-4(3H)-ones in reasonable to good yieldsfrom N-arylamidines, which are readily derived from anilinesand nitriles (Scheme 76f).In 2000, Knight and co-workers developed the palladium-

catalyzed decarboxylative carbonylation of 5-vinyloxazolidin-2-ones.237 Good yields of 3,6-dihydro-1H-pyridin-2-ones wereobtained from the corresponding 5-vinyloxazolidin-2-ones,which are readily prepared from amino acid precursors, by a

Scheme 75. Palladium-Catalyzed Carbonylative Synthesis of Quinolinones

Scheme 76. Palladium-Catalyzed Carbonylative Synthesis of Quinazolines



palladium-catalyzed decarboxylative carbonylation process(Scheme 77).

In 1997, Alper and co-workers reported the cyclocarbony-lation of 2-vinylanilines.238 In the presence of chiral phosphinesas ligands, quinolinones were produced in a stereoselectivemanner (Scheme 78a). Moderate to excellent yields ofquinolinones with 20−54% of ee were achieved. Recently,they developed a new route to ring-fused substituted oxazolo-and pyrazoloisoquinolinones via a three-component cascadeprocess through a one-pot carboxamidation/aldol-type con-densation reaction sequence.239 A range of ring-fusedoxazoloisoquinolinones and pyrazoloisoquinolinones wereobtained from a variety of active methylene compounds(Scheme 78b). The products of these cascade reactions containdifferent functional groups that can be further functionalized.Hence, this methodology enables further molecular manipu-

lation of these interesting nitrogen-containing heterocycles.Alternatively, isoquinolinones can also be prepared viapalladium-catalyzed carbonylation of diethyl(2-iodoaryl)-malonates and imidoyl chlorides.240 Fair to good yields of thecorresponding products were obtained using tris(2,6-dimethoxyphenyl)phosphine (TDMPP) as ligand (Scheme78c). In addition, Broggini and co-workers developed thepalladium-catalyzed cyclocarbonylation of N-allylamides and 2-iodobenzoic acids.241 At high pressure (100 bar of CO),isoquinolinones were produced in good yields (Scheme 78d).The group of Larock developed a palladium-catalyzed

annulation of internal alkynes with N-substituted o-iodoanilinesunder 1 bar of carbon monoxide, which resulted in theformation of 3,4-disubstituted 2-quinolones (Scheme 79a).242

In this reaction the nature of the substituent on the nitrogen iscrucial for obtaining high yields of the 2-quinolones. The bestresults are obtained using alkoxycarbonyl, p-tolylsulfonyl, andtrifluoroacetyl substituents. Notably, the N-protecting group islost during the course of the reaction. A variety of internalalkynes, bearing alkyl, aryl, heteroaryl, hydroxyl, and alkoxylsubstituents, were effective in this process. Electron-rich andelectron-poor N-substituted o-iodoanilines, as well as hetero-cyclic analogues, could be employed as annulating agents.Related 2-iodophenols were also tested under the reactionconditions; however, the corresponding coumarins wereformed in low yields. Willis and co-workers developed apalladium-catalyzed carbonylative coupling of 2-(2-haloalkenyl)aryl halides with primary amines.243 Quinoloneswere produced in good yields under atmospheric pressure ofCO (Scheme 79b). More recently, a palladium-catalyzedannulation of benzamides with [60]fullerene was alsoreported.244 This reaction proceeded through direct sp2 C−Hbond activation to form a 7-membered palladacycle inter-media te , which led to the format ion of [60]-fulleroisoquinolinones in moderate yields (8−64% based onrecovered C60). At the same time, palladium-catalyzedcyclocarbonylations of arylethylamines were also reported(Scheme 79c and 79d),245 and the total synthesis of teleocidin

Scheme 77. Palladium-Catalyzed Carbonylative Synthesis ofPyridinones

Scheme 78. Palladium-Catalyzed Carbonylative Synthesis of Isoquinolinones



B4 was achieved (Scheme 79e).246 Mechanistic studies on thiskind of carbonylation were performed by the group of Vicenteand Saura-Llamas.247

In 2002, Dai and Larock reported the palladium-catalyzedcyclocarbonylation of o-(1-alkynyl)benzaldimines.248 A numberof 3-substituted 4-aroylisoquinolines have been prepared ingood yields by treating N-tert-butyl-2-(1-alkynyl)benzaldimineswith aryl halides in the presence of CO and a palladium catalyst(Scheme 80a). Synthetically this methodology provides a

simple and convenient route to isoquinolines containing aryl,alkyl, or vinyl substituents at C-3 and an aroyl group at C-4 ofthe isoquinoline ring. The reaction is believed to proceed viacyclization of the alkyne containing a proximate nucleophiliccenter promoted by an acylpalladium complex. More recently,Gabriele and co-workers applied the same substrates in the

carbonylative synthesis of isoquinoline-4-carboxylic esters andisochromene-4-carboxylic esters. Again they used PdI2 ascatalyst and performed the reactions in alcohols (Scheme80b).249 The group of Rossi developed a palladium-catalyzedcarbonylative synthesis of 2-aryl-4-aminoquinolines and 2-aryl-4-amino[1,8]naphthyridines.250 This palladium-catalyzed dom-ino reaction started from aryl iodides and amines leading to 2-aryl-4-amino-quinolines and 2-aryl-4-amino[1,8]naphthyridines(Scheme 80c). The scope of the reaction was examined usingtwo 2-ethynylarylamines, four aryl iodides, and 10 primaryamines as substrates. The selection of the appropriate catalyticsystem was achieved by testing several palladium/phosphinesystems and allowed researchers to override previously reporteddrawbacks associated with the use of primary amines in relatedreactions.An enantioselective synthesis of tetrahydropyrrolo[1,2-c]-

pyrimidine-1,3-diones via palladium-catalyzed intramolecularoxidative aminocarbonylation was described by Sasai and co-workers.251 The carbon−carbon double bond of suitablesubstituted N-alkenylureas reacted intramolecularly with oneof the nitrogen atoms in the presence of a palladium catalystunder a carbon monoxide atmosphere (Scheme 81). Notably,

the use of a chiral spiro bis(isoxazoline) ligand (SPRIX) wasessential to obtain the desired products in optically activeforms. In comparison with the coordination ability of otherknown ligands, the peculiar character of SPRIX originates fromtwo structural characteristics: low σ-donor ability of theisoxazoline coordination site and rigidity of the spiro skeleton.4.3. Palladium-Catalyzed Carbonylative Synthesis of OtherSix-Membered Heterocycles

In 1996, Cacchi, Fabrizi, and Marinelli reported a novelsynthesis of benzoxazinones.252 Starting from 2-iodoaniline andunsaturated halides or triflates in the presence of K2CO3 andPd(PPh3)4 under atmospheric pressure of CO, 2-aryl- and 2-vinyl-4H-3,1-benzoxazin-4-ones were produced in good yields(Scheme 82a). This methodology was later applied in thesynthesis of a new potent inhibitor of human leukocyteelastase.253 Three years later, Larksarp and Alper developed therelated palladium-catalyzed carbonylative coupling of 2-iodoani-lines with acid chlorides to benzoxazinones.254 In their work 2-substituted-4H-3,1-benzoxazin-4-ones were produced in goodto excellent yields (Scheme 82b). The reaction is believed toproceed via in situ amide formation followed by oxidativeaddition to Pd(0), CO insertion, and intramolecular cyclizationto form the 2-substituted-4H-3,1-benzoxazin-4-one derivatives.The same reaction was done under the assistance ofmicrowaves, applying Pd/C as catalyst.255 In addition, it wasproved that benzoxazinone derivatives can be prepared from 2-

Scheme 79. Palladium-Catalyzed Carbonylative Synthesis ofQuinolinone Derivatives

Scheme 80. Palladium-Catalyzed Carbonylative Synthesis ofQuinolines

Scheme 81. Palladium-Catalyzed Carbonylation ofAlkenylureas



iodoanilines directly (Scheme 82c).256 More interestingly, thisclass of compounds was produced from the correspondinganiline derivatives as well, via C−H activation, and even atroom temperature (Scheme 82d and 82e).257 Recently, ourgroup developed a convenient and general palladium-catalyzedcarbonylative synthesis of 2-arylbenzoxazinones.258 Startingfrom 2-bromoanilines and aryl bromides, the correspondingproducts were isolated in good yields (65−91%; Scheme 82f).Moreover, a one-pot synthesis of 2,3-diarylquinazolinones wasalso demonstrated.Xiao and Alper reported an efficient procedure for the

synthesis of thiochromanones.259 Here, the desired productswere obtained by palladium-catalyzed carbonylative ring-forming reactions of 2-iodothiophenol derivatives with allenesand carbon monoxide. These reactions afforded thiochroman-4-ones in good to excellent isolated yields with fairly highregioselectivity (Scheme 83). This catalytic heteroannulationmay involve regioselective addition of the sulfur moiety on themore electrophilic carbon center of the allene, arylpalladiumformation, CO insertion, subsequent intramolecular cyclization,and then reductive elimination. The regioselectivity is proposedto be governed by electronic effects.A novel synthesis of 3-substituted-3,4-dihydro-2H-1,3-

benzothiazin-2-ones was described by Alper and co-workers

in 2008. The strategy relied on an unusual palladium-catalyzedcarbonylation of 2-substituted-2,3-dihydro-1,2-benzisothiazolesto give the corresponding 3,4-dihydro-2H-1,3-benzothiazin-2-one derivatives in general in good yields (Scheme 84a).Finally it is worth mentioning that the group of Gabriele

described a one-step synthesis of 2-[(dialkylcarbamoyl)-methylene]-2,3-dihydrobenzo[1,4]-dioxines and (Z)-3-[(dialkylcarbamoyl)methylene]-3,4-dihydro-2H-benzo[1,4]-oxazines.260 Starting from readily available 2-prop-2-ynylox-yphenols and 2-prop-2-ynyloxyanilines, the correspondingproducts were obtained in good yields via tandem PdI2-catalyzed oxidative aminocarbonylation and intramolecularconjugate addition (Scheme 84b).

Scheme 82. Palladium-Catalyzed Carbonylative Synthesis of Benzoxazinones

Scheme 83. Palladium-Catalyzed Carbonylative Synthesis ofThiochromanones



5. PALLADIUM-CATALYZED CARBONYLATIVESYNTHESIS OF OTHER HETEROCYCLES

Although most of the carbonylative cyclizations focused on theformation of five- and six-membered rings, there are also a fewexamples known for the preparation of larger rings; forexample, in 1999, the palladium-catalyzed synthesis of a2,3,4,5-tetrahydro-1H-2,4-benzodiazepine-1,3-dione derivativewas reported by Bocelli et al.261 Using 1-butyl-1(o-iodoben-zyl)-3-phenylurea as starting material at 80 °C under COpressure, 91% of the desired product was isolated (Scheme 85).

Lu and Alper developed a more general and efficient methodfor the synthesis of oxygen-, nitrogen-, or sulfur-containingmedium ring-fused heterocycles with recyclable palladium-complexed dendrimers on silica as catalysts.262 Their processtolerates a wide array of functional groups, including halide,ether, nitrile, ketone, and ester. The dendritic catalysts showedhigh activity, affording the heterocycles in excellent yields(Scheme 86). Importantly, these catalysts were easily recovered

by simple filtration in air and could be reused up to the eightcycles with only a slight loss of activity. Recently, the sameauthors used PdI2 and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phospha-adamantane (Cytop 292) as an in situ-formedpalladium complex for the intramolecular carbonylation ofsubstituted 2-(2-iodophenoxy)anilines.263 A series of substi-tuted dibenzo[b,f ][1,4]oxazepin-11(10H)-ones were preparedin good yields under mild reaction conditions. This type of

aminocarbonylation was also applied in the synthesis of C-14-labeled heterocycles.264

More recently, Alper and co-workers described a convenientprotocol for the synthesis of substituted benzazepine derivatives(Scheme 87).265 This protocol is based on the sequential

palladium-catalyzed allylic amination and a subsequent intra-molecular carbonylation reaction. The substrates were obtainedby Baylis−Hillman reaction.The success of the latter palladium-catalyzed one-pot

reaction opened the possibility of a new synthetic route forthe formation of a number of biologically interesting productscontaining the benzazepine ring system.Recently, an efficient method for the synthesis of 1,4-benzo-

and pyrido-oxazepinones was also disclosed.266 This reactionproceeds via a domino process through one-pot ring-opening/carboxamidation reaction sequences of N-tosylaziridines with 2-halophenols/pyridinol under phase-transfer conditions (benzyl-triethylammonium chloride, TEBA). The method worked witha range of N-tosylaziridines and 2-halophenols/pyridinol toprovide facile access to a variety of 1,4-benzo- and pyrido-oxazepinones (Scheme 88a). The authors also performed thereaction with 2-iodothiophenols, which led to 1,4-benzothiaze-pin-5-ones in good yields (Scheme 88b).267

The group of Kalck reported a chemo- and regioselectiveprocedure for the production of a nine-membered lactone.268

Starting from dihydromyrcenol in the presence ofPdCl2(PPh3)2/SnCl2·2H2O and molecular sieves, cyclocarbo-nylation occurred and gave the lactone as final product(Scheme 89).Cho and Larock developed a palladium-catalyzed intra-

molecular cyclocarbonylation of hydroxyl-substituted 3-iodofur-ans, leading to the corresponding lactone-containing furans.269

The 3-iodofurans are readily prepared by iodocyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of various diols.Meanwhile, a neat one-pot synthesis of a cryptand wasdeveloped by using a palladium-catalyzed carbonylationreaction (Scheme 90).270 Finally, the group of Takahashi andDoi also applied elegantly carbonylations for the preparation ofmacrosphelide and related macrolactams.271

6. SUMMARYWe have tried to summarize in this review the majordevelopments of palladium-catalyzed carbonylative synthesesof heterocycles in the last two decades. In general, in thesereactions inexpensive carbon monoxide is incorporated into theparent substrate by insertion of CO into an activated C−Xbond (X = Cl, Br, I) in the presence of palladium catalysts. Theresulting acyl palladium complexes will react further both inter-

Scheme 84. Palladium-Catalyzed Carbonylative Synthesis ofBenzothiazinone, Benzodioxine, And BenzoxazineDerivatives

Scheme 85. Palladium-Catalyzed Carbonylative Synthesis ofBenzodiazepinedione

Scheme 86. Palladium-Catalyzed Carbonylative Synthesis ofBenzodiazepinediones

Scheme 87. Palladium-Catalyzed Carbonylative Synthesis ofSeven-Membered Lactams



and intramolecularly with a variety of O-, N-, C-, and S-nucleophiles. Advantageously, such processes allow for asubstantial increase in molecular complexity of the substrate.The basis for most of today’s known methodologies was laid byR. F. Heck and co-workers already in the mid-1970s in his workon amino- and alkoxycarbonylations of simple aryl bromides,and therefore the term Heck carbonylation is sometimes usedfor them.Although most synthetic organic chemists are somewhat

reluctant to use carbon monoxide in coupling reactions becauseof the necessity to use high-pressure equipment, the ongoingsuccess of palladium-catalyzed carbonylations is documented byan increasing number of synthetic applications and publicationsin the past years. Clearly, the main focus of the work in mostacademic laboratories in the past was to increase the tool box ofsynthetic methodologies. Hence, today a range of carbonylativecyclizations is available. Notably, some of the procedures allowfor an efficient assembly toward potentially bioactive hetero-cycles, which are otherwise significantly more difficult to access.Despite an extensive amount of ligands and catalysts

nowadays (commercially) available as well as substantialknow-how in catalyst optimization strategies, for mostcarbonylation reactions the catalytic efficiency (total catalystturnover numbers and turnover frequencies) is still relativelylow. Here, further improvements are desired, and it is mostlikely that the recent advances in the development of ligandsand their improved synthetic abilities on the lab scale will resultin improved processes also for kg-syntheses in the processdevelopment of the pharmaceutical industry. Apart from furthercatalyst improvements (improved efficiencies; replacing noble

palladium by other metals), what are the goals for the future inthis area? From a synthetic point of view, advancements ofcarbonylative CH-activation processes are highly desirable.Here, more environmentally benign procedures can be foreseenif the regioselectivity can be controlled. Moreover, an importantissue would be to replace the toxic and gaseous carbonmonoxide by more benign and practical analogues. In thisrespect the use of carbon dioxide in the presence of a benignreductant would be a very interesting option. We encouragesynthetic chemists to address these challenging goals.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; [email protected].

Notes

The authors declare no competing financial interest.

Biographies

Xiao-Feng Wu was born in 1985 in China. He studied chemistry inZhejiang Sci-Tech University (China), where he got his Bachelor’sdegree in science (2007). In the same year, he went to Rennes 1University (France) and worked with Prof C. Darcel on iron-catalyzed

Scheme 88. Palladium-Catalyzed Carbonylation of N-Tosyl Aziridines

Scheme 89. Palladium-Catalyzed Carbonylative Synthesis ofa Nine-Membered Lactone

Scheme 90. Palladium-Catalyzed Carbonylative Synthesis of H3L



mailto:[email protected]



reactions. After he earned his Master’s degree in 2009, he joinedMatthias Beller’s group in Leibniz-Institute for Catalysis (Germany),where he completed his Ph.D. thesis in January 2012. Then he startedhis independent research at ZSTU and LIKAT. His research interestsinclude carbonylation reactions, heterocycles synthesis, and thecatalytic application of cheap metals. He also was a fellow of theMax-Buchner-Forschungsstiftung.

Helfried Neumann studied chemistry at the University of Wurzburg,Germany. He then moved to the group of Priv.-Doz. Dr. Herges/Prof.Schleyer at the University of ErlangenNurnberg, where he obtainedhis Ph.D. in 1995 working on the synthesis of tetradehydrodian-thracene. In 1996, he became an associate researcher at the Institutefor Organic Catalysis, Rostock (IfOK), and the TU Darmstadt. Since1998 he has been a project leader in the group of Matthias Beller. Hisresearch interests include multicomponent reactions, carbonylations,and transition metal-catalyzed synthesis of fine chemicals.

Matthias Beller, born in 1962, studied chemistry in Gottingen,Germany, where he completed his Ph.D. thesis in 1989 in the group ofProf. Tietze. Then, he spent 1 year in the group of Prof. Sharpless atMIT, U.S.A. From 1991 to 1995, Beller was an employee of HoechstAG in Frankfurt, Germany. In 1996, he moved to the TechnicalUniversity of Munich as Professor for Inorganic Chemistry. In 1998,he relocated to Rostock to head the Institute for Organic Catalysis(IfOK). Since 2006 Matthias Beller is director of the Leibniz-Institutefor Catalysis. His scientific work has been published in around 530publications, and >90 patent applications have been filed in the lastdecade. Matthias Beller has received several awards including the Otto-Roelen Medal, the Leibniz-Price, and the German Federal Cross ofMerit. Most recently, he received the first “European Price forSustainable Chemistry” and the “Paul-Rylander Award” of the OrganicReaction Catalysis Society, U.S.A. Matthias Beller is a member of theAssociation for Technical Sciences of the Union of German Academiesof Sciences and Humanities, as well as the German National Academia

of Science. He is married to Dr. Anja Fischer-Beller, and they have twosons.

ACKNOWLEDGMENTS

The authors thank the state of Mecklenburg−Vorpommern andthe Bundesministerium fur Bildung und Forschung (BMBF)for financial support. The authors also thank Drs. MartinNielsen and Marko Hapke (both LIKAT) for valuable adviceon this review.

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