sequential addition and cyclization processes of α,β-ynones and α,β-ynoates containing proximate...

REVIEW ▌687

reviewSequential Addition and Cyclization Processes of α,β-Ynones and α,β-Ynoates Containing Proximate NucleophilesSequential Addition and Cyclization ProcessesGiorgio Abbiati,a Antonio Arcadi,*b Fabio Marinelli,b Elisabetta Rossia

a Dipartimento di Scienze Farmaceutiche – Sezione di Chimica Generale e Organica ‘A. Marchesini’, Università degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy

b Dipartimento di Scienze Fisiche e Chimiche, Università degli Studi dell’Aquila, Via Vetoio, 67010 Coppito, L’Aquila, ItalyFax +39(0862)433033; E-mail: [email protected]

Received: 02.10.2013; Accepted after revision: 06.11.2013

Abstract: This review examines sequential processes involvingα,β-ynones and α,β-ynoates containing proximate nucleophiles asuseful building blocks for the synthesis of heterocyclic derivativesthrough conjugate-addition-type, pericyclic and transition-metal-catalyzed transfer hydrogenation, hydroarylation, hydrovinylation,or hydroalkynylation reactions followed by heterocyclization.

1 Introduction

2 Conjugate Addition–Heterocyclization Processes of α,β-Ynones and α,β-Ynoates Containing Proximate Nucleo-philes

2.1 Conjugate Addition–Annulation Reactions of β-(2-Amino-aryl or Heteroaryl)-α,β-Ynones

2.2 Sequential Reactions of γ-Hydroxy-α,β-Acetylenic Esterswith Nucleophilic Reagents

2.3 Sequential Electrophilic Addition–Annulation Processes ofα,β-Ynones Containing Proximate Nucleophiles

3 Cycloaddition–Heterocyclization Processes of α,β-Ynonesand α,β-Ynoates Containing Proximate Nucleophiles

3.1 [2+2] and [4+2] Cycloaddition–Annulation Reactions

3.2 1,3-Dipolar Cycloaddition–Annulation Reactions

4 Transition-Metal-Catalyzed Addition–HeterocyclizationProcesses of α,β-Ynones and α,β-Ynoates Containing Prox-imate Nucleophiles

4.1 Palladium-Catalyzed Transfer Hydrogenation–Heterocycli-zation Processes

4.2 Palladium-Catalyzed Hydroarylation–HeterocyclizationProcesses

4.3 Rhodium-Catalyzed Hydroarylation–Heterocyclization Pro-cesses

4.4 Copper-Catalyzed Hydroarylation–Heterocyclization Pro-cesses

4.5 Transition-Metal-Catalyzed Hydrovinylation–Heterocycli-zation Processes

4.6 Transition-Metal-Catalyzed Hydroalkynylation–Heterocy-clization Processes

5 Conclusion

Key words: aminoalkynones, hydroxyalkynoates, sequential reac-tions, annulation, heterocycles

1 Introduction

α,β-Ynones and α,β-ynoates are prominently employed asvaluable building blocks in organic synthesis.1 A varietyof intramolecular 1a,2 and intermolecular3 reactions havebeen performed, taking advantage of their electronic prop-erties. Transition-metal-catalyzed processes have alsobeen described.4 α,β-Ynones and α,β-ynoates have foundwide application as versatile three-carbon building-blocksfor the development of new approaches to diversity-ori-ented syntheses of heterocycles through 1,3-dipolar cy-cloaddition reactions.5 Their reaction with bifunctionalnucleophiles presents a general strategy to the construc-tion of five-, six-, and seven-membered rings bysequential6 and consecutive6c,7 transformations. Catalyticgeneration of α,β-ynones compatible with subsequenttransformations have been developed, allowing new ap-proaches to the synthesis of heterocycles through multi-component coupling and cycloaddition sequences.8

Sequential addition to preformed or in situ generated α,β-ynones and α,β-ynoates of (hetero)nucleophiles and cy-clocondensation reactions have also been shown to haveconsiderable synthetic application.9

Based on the importance of α,β-ynones and α,β-ynoatesfor their crucial role as key intermediates in organic syn-thesis and for their key role as an interesting structuralmotif found in numerous biologically active molecules,we have been involved in the development of efficient ap-proaches to their formation10 and conversion into severalheterocyclic derivatives.11

This review summarizes investigations on sequential het-erocyclization processes involving conjugate-addition-type, cycloaddition and transition-metal-catalyzed trans-fer hydrogenation, hydroarylation, hydrovinylation andhydroalkynylation reactions of α,β-ynones and α,β-yno-ates containing proximate nucleophiles.

SYNTHESIS 2014, 46, 0687–0721Advanced online publication: 12.02.20140 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XDOI: 10.1055/s-0033-1338594; Art ID: SS-2013-E0656-R© Georg Thieme Verlag Stuttgart · New York

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688 G. Abbiati et al. REVIEW

Synthesis 2014, 46, 687–721 © Georg Thieme Verlag Stuttgart · New York

2 Conjugate Addition–Heterocyclization Pro-cesses of α,β-Ynones and α,β-Ynoates Con-taining Proximate Nucleophiles

2.1 Conjugate Addition–Annulation Reactions of β-(2-Aminoaryl or heteroaryl)-α,β-ynones

The palladium-catalyzed carbonylative Sonogashira reac-tion is an efficient methodology for the synthesis of con-

jugate ynones and the good functional-groupcompatibility of the procedure has been demonstrated.12

Interestingly, the carbonylative coupling of o-trimethylsi-lylethynylaniline with aryl iodides and the carbonylativecoupling of 2-ethynylaniline with vinyl triflates providedan easy entry to β-(2-aminophenyl)-α,β-ynones 1(Scheme 1).13

Biographical sketches█

Giorgio Abbiati receivedhis B.Sc. degree (Laurea) inchemistry and pharmaceuti-cal technology in 1997 andPh.D. in pharmaceutical sci-ences in 2000 from the Uni-versity of Milan under thesupervision of Prof. Elisa-

betta Rossi. In 2005 he wasappointed Assistant Profes-sor (Researcher) at the De-partment of MedicinalChemistry of the Universityof Milan. His scientific in-terests are mainly focusedon the study of novel syn-

thetic methodologies for thepreparation of heterocycliccompounds starting from al-kynes by homogeneous-metal-catalyzed domino andmulticomponent approach-es.

Antonio Arcadi obtainedhis B.Sc. degree (Laurea) inchemistry and pharmaceuti-cal technology at the Uni-versity ‘La Sapienza’ ofRome in 1978 under theguidance of Pr. S. Cacchi. In1979, he joined the Instituteof Chemistry at the Univer-sity of L’Aquila to under-take teaching fellowshipand research activities on

organometallic chemistrydirected towards organicsynthesis. He was appointedAssociate Professor of Or-ganic Chemistry in 1992 atthe University of Urbinoand as Full Professor of Or-ganic Chemistry in 2002 atthe University of L’Aquila.His current research inter-ests lie in the area of devel-oping new synthetic

methodologies throughtransition-metal catalysis.More recently, he has beenfocusing on the develop-ment of gold catalysis in or-ganic synthesis. Otherachievements are obtainedin the field of domino reac-tions as useful tools of greenchemistry.

Fabio Marinelli obtainedhis B.Sc. degree (Laurea) inchemistry at the University‘La Sapienza’ of Rome in1980. In 1983 he becameOrganic Chemistry Re-searcher at the University ofL’Aquila. Since 2001, hehas been Associate Profes-sor of Organic Chemistry atthe same university. His re-

search interests are centeredon the application of or-ganometallic complexes ascatalysts in organic synthe-sis. The main topics of hisscientific activity includethe synthesis of heterocycliccompounds from alkynesbearing proximate nucleo-philes in the presence of pal-ladium and gold salts or by

means of in situ generatedorganopalladium(II) inter-mediates, and hydroaryla-tion or hydrovinylation ofinternal alkynes with arylhalides and organoboron de-rivatives catalyzed by palla-dium and rhodiumcomplexes.

Elisabetta Rossi obtainedher B.Sc. degree (Laurea) inchemistry and pharmaceuti-cal technology at the Uni-versity of Milan in 1981. In1983 she obtained a Mas-ter’s degree in analyticaland chemical methodolo-gies for fine chemicals at thePolitecnico of Milan. In

1983 she became a Re-searcher (assistant profes-sor) and in 2001 she wasappointed Associate Profes-sor of Organic Chemistry atthe University of Milan. Herresearch activity is focusedon the study of novel syn-thetic methodologies for thepreparation of heterocyclic

compounds through dominoand multicomponent ap-proaches, intramolecularcyclizations and cycloaddi-tion reactions by means ofmetal catalysis of Lewis ac-ids and transition metals (In,B, Sc, Ti, Pd, Au, and Ag).

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REVIEW Sequential Addition and Cyclization Processes 689

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 687–721

Scheme 1

Work by our group has shown that the ynones 1, in thepresence of suitable nucleophiles, efficiently led to 2,4-di-substituted quinolines 2 through a tandem conjugate addi-tion and cyclization reaction (Scheme 2).14

Scheme 2

The reactions were generally carried out at 60–80 °C andaccomplished the isolation of 4-heterosubstituted 2-aryl-or 2-vinylquinoline derivatives in good to high yields asthe sole reaction products (Figure1).

Figure 1

Notably, the reaction of 1g with sodium iodide in aceticacid allowed the successful synthesis of 2-(4′-chlorophe-nyl)-4-iodoquinoline (2g) which was further elaboratedby means of palladium-catalyzed coupling reactions in avariety of two-step, one-pot procedures (Scheme 3).

R1

NH2

a or b

(a) (R1 = SiMe3, R2X = ArI): PdCl2, phosphine ligand; Et3N, n-Bu4F, THF, r.t(b) (R1 = H, R2X = vinyl triflates): Pd(OAc)2, dppp, Et3N, DMF, 60 °C

NH2

O

R2

1

+ R2X + CO

NH2

NuH

NH2

O

R

1

– H2Obase

Nu

H

CORN

Nu

H

R

2

N

OMe

2a (84%) OMe

N

OEt

2b (90%)

CF3N

OMe

2c (80%)

N

O(p-I-Ph)

2d (90%)

FN

Br

2f (60%)

CF3

N

I

2g (60%)Cl

N

SPh

2e (98%)

N

I

O

2h (60%)

Scheme 3

NH2

1g

NaI

AcOH

80 °C, o.n.N

Cl

I

2g

N

Cl

2i (72% from 1g)

Ph

Pd(OAc)2, Ph3P

CuI, Et3N, 60 °C

N

Cl

CO2Me

2k (60% from 1g)

EtO2CAc

K2CO3, Pd(PPh3)4

DMF, 60 °C

N

Cl

2l (48% from 1g)

N

Cl

2m (50% from 1g)

O

OEt

O

O OMe

NHAc

NHAc

CO2MeAcOK, Pd(OAc)2DMF, 60 °C

CO, MeOH, 60 °CPd(OAc)2,

dppf

O

Cl

Ph

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Following a similar strategy, a concise one-pot approachto the synthesis of 4-(1H-indol-3-yl)quinolines 4 wasachieved without any intermediate work-up and using eth-anol as solvent. The operationally simple procedure in-volved conjugate addition of sodium iodide to β-(2-aminophenyl)-α,β-ynones followed by cyclization andpalladium-catalyzed reaction with 2-alkynyltrifluoroacet-anilides 3 (Scheme 4).15

A variety of [1,8]naphthyridines 6 were obtained regiose-lectively and in high yield by reaction of the readily avail-able 3-(2-amino-5-methylpyridin-3-yl)-1-arylprop-2-yn-1-ones 5 at 80 °C in acetonitrile or alcoholic solvents inthe presence of a slight excess of a nitrogen, oxygen, sul-fur or selenium nucleophile or pronucleophile. The pres-ence of both electron-withdrawing and electron-donatinggroups in the 2-aryl moiety were tolerated. In the case ofamines, the solvent was omitted (Scheme 5).16

Surprisingly, the reaction of ynone 5a with the phospho-rus nucleophile diphenylphosphine afforded the 4-unsub-stituted [1,8]naphthyridine 7 through an unusualsequential reductive cycloamination (Scheme 6).

Scheme 6

2-Aryl- and 2-alkyl-4,9-bis(dialkylamino)benzo[h]quino-line-7,10-diones were prepared through the addition of asecondary amine to 6-acylethynyl-5-amino-3-diethylami-no-1,4-naphthoquinone followed by cyclization of the re-sulting adduct (Scheme 7).17

The reaction of β-(2-aminoaryl or heteroaryl)-α,β-ynonederivatives with nitrogen nucleophiles deserve a deeperinvestigation. Indeed, three major types of products havebeen observed, depending on the reaction conditions andon the nitrogen nucleophile employed.18 The reaction ofα,β-ynone 1e with benzylamine in boiling acetonitrilegave the (Z)-3-(2-aminophenyl)-3-benzylamino-1-naph-thalen-1-ylpropenone 8a as the main reaction product.Analogously, the α,β-ynone 1g reacted under the sameconditions with cyclohexylamine to lead to the (Z)-3-(2-

Scheme 4

NH2 N R

O

RR1

R2

R3

R1

R2

R3

NH

R4

R5

R6

NaI, TsOH, then

NHCOCF3

R5

R6R4

1 4

3 , Pd(PPh3)4, K2CO3

EtOH, reflux

12 examples (50–70%)

Scheme 5

N NH2

SiMe3

ArI, CO, PdCl2, dppf

N NH2

O

Ar

5

Nu– or NuH/K2CO3

N N R

Nu

6

(55–65%)

TBAF, Et3N, THF, r.t. solvent, 80 °C

N N

OEt

6a (90%)

N N

6b (95%)

N N

O

6c (92%)

N N

S

6d (84%)

N N

Se

6f (81%)

N N

N

6g (79%)

N N

S

6e (84%)

OMe

C6H4-4-I

O

OMe

O

N N

N

6e (65%)

O

O

C6H4-4-OMe

Phn-C12H25

N NH2

5a

N N

7 (60%)

Ph2PH

MeCN, 80 °C

O

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aminophenyl)-1-(4-chlorophenyl)-3-cyclohexylamino-propenone 8b in 75% yield (Scheme 8).

Scheme 8

One- and two-dimensional and dynamic NMR spectraanalysis showed that β-amino-α,β-unsaturated ketones 8are typical push–pull ethylenes, which can exist in differ-ent configurational and conformational isomeric forms(Scheme 9).18

Moreover, Z→E isomerization of derivatives 8 was exper-imentally observed by dynamic 1H NMR experimentsperformed in DMSO-d6 at 90 °C. As a consequence, theexpected 4-aminoquinolines 9a–d were isolated by carry-

ing out the reaction of ynone 1g with the correspondingprimary amines in toluene at reflux (Scheme 10).18

Scheme 10

These typical reaction conditions were ineffective in thepresence of primary amines bearing an electron-with-drawing group in the α-position, such as aminoacetonitrileand methyl esters of glycine, phenylglycine or valine. Thereaction of ynone 1g with secondary amines 11a–c underfairly acidic catalysis and with N,N-unsubstituted ami-dines 10a,b afforded the corresponding quinolines in ex-cellent yields (Scheme 11).18

Conversely, the divergent sequential reaction of 1g withN-alkyl- or N-aryl-substituted benzamidines 12a–c, N-im-idoylimino triphenylphosphorane 12d and N-methylimi-doylimino triphenylphosphorane 12e in the presence oftriethylamine hydrochloride led to the isolation of the vi-nylidenequinazolines 13a and 13b (Scheme 12).18

The formation of the vinylidenequinazolines 13 has beensuggested to be the result of the stereoselective trans-ad-

Scheme 7

O

O

H2N

NH2

O

R1

HNR2R3

O

O

H2N

NH2

O

N

R1

R3

R2

H+N

H2N

O

O

N

R1

R3

R2

NH2

O

+

NH2

MeCN

80 °C

N

OH

1e 8a (82%)

NH2

O

NH2

MeCN

80 °C

N

OH

1g 8b (75%)

Cl +Cl

H2N

H2N

Scheme 9

H2N

HH

NR H

O

Ar

(Z)-8

H2N N

H

Ar

HR

O

H2N

H

O Ar

NR H

(E)-8, s-cis

H2N

H

O

NR H

Ar

(E)-8, s-trans

–

+

NH2

O

Cl

1g

RNH2

toluene, reflux

(68–81%)

N

Cl

NHR

CH2

9a–d

R = Bn, p-Tol, n-Bu,

Scheme 11

1g

toluene, reflux

(85–90%)

N

Cl

NH

NH

NH2R

R

HN

10a,b

10a: R = Ph

10b: R = Me

toluene, refluxN

Cl

11a–c

R2NH

Et3N·HCl

NR2

11a = Et2NH

11b = NH

HN11c =

O

NH2

O

Cl

(70–97%)

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dition of the amidine moiety over the conjugate triplebond followed by a transamination reaction between theamino group and the amidine function of the intermediate14 (Scheme 13).18

Scheme 13

Torii and co-workers reported a palladium-catalyzed mul-ticomponent domino reaction giving rise to 2-aryl-4-dial-kylaminoquinolines in moderate to good yields throughtandem conjugate addition and cyclization reactions of thein situ generated β-(2-aminoaryl or heteroaryl)-α,β-ynones with amines (Scheme 14).19 The reaction was per-formed with 2-ethynylarylamines, aryl iodides, and dial-kylamines or dialkylamines with triethylamine, at 70 °Cunder a carbon monoxide atmosphere (18 bar) in the pres-ence of 5 mol% PdCl2(PPh3)2.

Scheme 14

Torii’s procedure was effective only with secondaryamines. In the presence of primary amines, a palladium-catalyzed carbonylative amidation reaction occurred, in-stead of a carbonylative cross-coupling reaction. Consid-ering that many factors are responsible of the outcome ofthe reaction of terminal alkynes with aryl iodides undercarbonylative conditions,11o further exploration has been

done in this field. Indeed, the carbonylative palladium-catalyzed coupling of 2-ethynylaniline derivatives witharyl iodides, in the presence of even a primary amine, re-sulted in an efficient multicomponent domino approach tothe preparation of the desired quinolines 9 and 2-aryl-4-amino[1,8]naphthyridines 15 through the appropriatechoice of catalyst, ligand, solvent, and reaction tempera-ture (Scheme 15).20

Scheme 15

Notably, this latter domino reaction allowed for the proce-dure to be extended to the use of primary amines bearingan electron-withdrawing group in the α-position (Scheme16).20

The palladium and phosphine system could play a rele-vant catalytic role in the intermolecular nucleophilic at-tack of the amine over the ynone. Indeed, the formation of9e was considered the result of the sequential palladium-catalyzed carbonylative coupling followed by the palladi-um-catalyzed aza-Michael addition of phenylalanine eth-yl ester to ynone 1g. The first part of the overall reactionrequires palladium(0) as catalyst, while the second needspalladium(II).21 Accordingly, by heating the β-(2-amino-phenyl)-α,β-ynone 1g and valine ethyl ester in dioxane at100 °C with 15 equivalents of triethylamine either with orwithout the standard catalytic system [Pd(OAc)2, (o-Tol)3P], quinoline 9f was isolated in 68% yield only in thecatalyzed reaction (Scheme 17). The experiments per-formed in the presence of either palladium(0), zinc(II) orgold(III) derivatives demonstrated that the sequential aza-Michael and cyclization reactions of primary amines bear-ing an electron-withdrawing group in the α-position occurin the presence of all of these catalysts. Several transition-

metal salts have been reported to efficiently catalyze aza-Michael reaction of enones by acting as powerful Lewisacids.22 Gold(I)-catalyzed highly efficient intermolecularhydroamination reactions have also been described.23 So,palladium acting simultaneously both as transition-metal

Scheme 12

N

NH

Ph

H

13a

O

Cl

N

NR

Ph

N

NPhH

13a,b

O

Cl

R

PPh3HN

+1g

toluene, reflux

(83–89%)

NH

NHRR

12a–c

12a: R = 4-ClC6H4

12b: R = 4-MeOC6H4

12c: R = Me

toluene, reflux

12d,e

NH2

O

Cl

(81–83%)

PPh3

12d: R = H

12e: R = Me

RNH2

+Et3N·HCl Et3N·HCl

N

NH

H

13

O

Cl

NH2

N

RHN

Ph

O

14

– RNH2

Cl

X

NH2

+

ZI

Y

CO (10 kg/cm2, 70 °C)

PdCl2(PPh3)2

N

X

NR2R1

11 examples, 43–86%

X

NH2

O

Z

Y

Z

Y

N

O

R2R1

XZ Y

NH

R1 R2

NH

R1 R2

NH2

X NH2 X N

NHR2

I

R1

R19: X = CH

15: X = N

X X

+

R2NH2, CO

Pd(OAc)2, (o-Tol)3P

THF (Et3N), 100 °C

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catalyst in the palladium(0) oxidation state and as Lewisacid catalyst in the palladium(II) oxidation state could bepresumed to achieve the formation of the quinoline deriv-ative in the multicomponent process.24

Scheme 17

The tandem addition and annulation reaction of carbonu-cleophiles with β-(2-aminophenyl)-α,β-ynones was alsoinvestigated.25 A sequential alkylation and heterocycliza-tion of β-(2-aminophenyl)-α,β-ynones 1 promoted byelectro-generated carbanions was reported to give a cleanand efficient entry to functionalized 4-alkylquinolines(Scheme 18).

Scheme 18

The exploitation of electrochemistry as a tool to generatecarbanions that can lead to the target heterocycles 16 ap-peared very attractive for the development of a more en-vironmentally friendly synthetic protocol.26 The directelectrolysis of pure nitroalkane was carried out at roomtemperature under an inert atmosphere and galvanostaticcontrol in a divided cell equipped with platinum elec-trodes. Then, after addition of a β-(2-aminophenyl)-α,β-ynone 1 to the cathode compartment at the end of the elec-trolysis, the formation of the corresponding 4-alkylquino-line 16 was observed. Cathodic (pure nitroalkane) andanodic [DMF, 0.1 M tetraethylammonium tetrafluorobo-rate (TEATFB)] compartments were separated by a G3-glass diaphragm filled with an agar gel [methyl cellulosein 0.1 M tetraethylammonium perchlorate (TEAP)–DMFsolution]. Moderate gas production was observed, at thecathodic compartment, during the electrolysis. The quin-oline derivatives 16 were isolated in the best yields whenthe amount of electricity (Q) supplied during the electrol-yses was 1.2 F·mol–1. Interestingly, the reaction workedwell even with sterically hindered nitroalkanes (Figure 2).

As illustrated in Scheme 19, the deprotonation of the start-ing nitroalkane under solvent-free conditions gives anionI that adds to the carbon–carbon triple bond to generate anew anion II. Then, the reaction of the starting nitroalkanewith the anion II affords the Michael adduct, regeneratingI. The relative basicity of anions I and II was of pivotalimportance for the reaction outcome. The more acidic ni-troalkanes (pKa = 8.5 and 7.7) favored the fast protonationof II leading to the corresponding quinolines in highyields (72–93%). In contrast, the least acidic nitromethane(pKa = 10.2) allowed the formation of the quinolines16d,e in only moderate yields (41–45%). It is very likelythat when the anion II is not basic enough, the resultingincrease in its concentration results in the formation ofside products.25

Scheme 16

NH2 N

+I

Pd(OAc)2 (0.05 equiv)

(o-Tol)3P (0.07 equiv)

THF–Et3N (15 equiv)

100 °C, CO (6 bar)Cl

Ph

NH2H

EtOOC

Cl

Ph

H

EtOOC

N NH2 N N

+I

Pd(OAc)2 (0.05 equiv)

(o-Tol)3P (0.07 equiv)


100 °C, CO (6 bar)

Cl

NH2H

EtOOC

Cl

NHH

EtOOC

NH

COOBzNH

COOBz

Ph

NH2H

EtOOCPh

H

EtOOC

9e (59%)

15a (48%)

NH


100 °C, CO (6 bar)

NH3H

EtOOC

NH2

O

1g

N

Cl

NHH

EtOOC

9f

catalyst

Catalyst-Pd(OAc)2 (5 mol%), P(o-Tol)3 (7 mol%)ZnCl2 (5 mol%)Pd(PPh3)4 (5 mol%)NaAuCl4 (5 mol%)

Yield068737578

Cl

NH2

R1

O

R2

R3

N

R3

R2

R

R1

1 16

R4

electrolysis

H

R4–

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Scheme 19

The solvent-free and supporting-electrolyte-free electrol-ysis protocol proved to be effective also for the directelectro-activation of methanol. Conversely, the electro-chemically promoted Michael reaction of active methy-lene compounds to β-(2-aminophenyl)-α,β-ynones 1 wasaccomplished in a solution of N,N-dimethylformamidecontaining TEATFB (0.1 M) as supporting electrolyte.

Interestingly, a potassium carbonate promoted intramo-lecular Michael addition, tautomerization and transesteri-fication cascade reaction accomplished the synthesis ofthe quinolone 18 in 80% yield from β-(2-malonylamido-4-methoxyphenyl)-α,β-ynone (17) (Scheme 20).14

Scheme 20

2.2 Sequential Reactions of γ-Hydroxy-α,β-Acet-ylenic Esters with Nucleophilic Reagents

γ-Hydroxy-α,β-acetylenic esters contain three adjacentfunctional groups, namely the alkoxycarbonyl group, theacetylenic unit and the alcoholic moiety, each displayingdifferent reactivity. They all undergo different types oftransformations.27 A variety of approaches to functional-ized α,β-unsaturated γ-lactones [Δ2-butenolides, furan-2(5H)-ones] starting from γ-hydroxy-α,β-acetylenic es-ters 19 and a wide range of nucleophiles have been ex-ploited.28 A series of natural compounds (alkaloids,steroids, tetronic and ascorbic acids, pheromones, and fra-grances) contain the Δ2-butenolide fragment29 and severalderivatives are known to act on enzymes and possess bac-tericidal, fungicidal, or antibacterial properties.30 4-Sub-stituted furan-2(5H)-ones have been found to be potentantibiotics and have shown cytotoxicity against humancolon carcinoma and human melanoma. 31

Some of the first studies performed with esters 19 in-volved their reactivity toward primary and secondaryamines. A conjugate addition and cyclization domino re-action leading to the 4-amino-substituted furan-2(5H)-ones 21 was prevalent. Under the reaction conditions, theinitially formed linear Michael adducts 20 underwent cy-clization to give the corresponding furan-2(5H)-one de-rivatives 21 (Scheme 21). Exothermic reactions occurredwhen the derivatives 19 were treated with secondary ali-phatic amines at room temperature; aniline was less reac-tive and in this case heating to 100 °C was necessary toinitiate reaction.28

Scheme 21

No products other than 4-aminolactones were isolatedfrom these addition reactions. This fact appears to supportthe hypothesis that the initial reaction of primary and sec-

Figure 2

N

NO2

16a (93%)

N

NO2

16b (72%)

N

NO2

F

F

OMe

16c (82%)

N

NO2

16d (45%)

N

NO2

OMe

N

NO2

N

NO2

F

F

OMe

N

NO2

OMe

16e (41%) 16f (90%)

16g (91%) 16h (89%)

NH2

O

R1

R2

R3

R4

R5O2N

I

NH2

R2

R3

R5R4

O2N

R1

O

II

NH2

R2

R3

R5R4

O2N

R1

O

R2

R3

N O

R1

H H

R4 NO2R5

R2

R3

N OH

R1

H

R4 NO2R5

R2

R3

N

R4 NO2R5

R1

1

R4

R5O2N

R4

R5O2N

I

H

–

–

–

+

NH

O

Ar

O O

OEt

17

K2CO3

DMF, 60 °C, 0.5 h

Ar = 4-MeOC6H4

NH

O

COOEt

Ar

O

NH

O

COOEt

NH

O

COOEt

Ar

O

NH

O

Ar

O

18 (80%)

Ar O

–

–

–

HO

R2

R1

O

OR3

19

NH

R5 R4H

N

R4

R5

OR3R1

O

R2 O

H

20

O

ON

R1R2

R4

R5

21

– R3OH

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ondary amines is a cis addition to the activated acetylenicbond, followed by lactone formation through eliminationof alcohol from the activated molecule. However, cis andtrans adducts could be in equilibrium through a commonzwitterionic resonance structure and the stabilization ofthe cis adduct by lactonization could be the driving forceshifting the reaction toward the formation of 21 as the solereaction product (Scheme 22).28

Analogously, the reaction of the methyl 5-hydroxyhex-2-ynoate (22) with diethylamine efficiently afforded the 4-(diethylamino)-5,6-dihydro-6-methylpyran-2-one (23),which is formally related to the naturally occurring δ-Δα,β-hexenolactone (Scheme 23).28

Scheme 23

The procedure was applied to the synthesis of a series offuran-2(5H)-one derivatives containing pharmacophoricsubstituents at the amine moiety.32 Thus, methyl (1-hy-droxycyclohexyl)propiolate (19a) was treated with vari-ous amines in anhydrous diethyl ether or in a 2:1 diethylether–methanol mixture at 20–60 °C to give desired ami-no derivatives 21 in high yields. The reactions with saltsof amines were performed in methanol at reflux for 15–20hours in the presence of sodium acetate. Under these con-ditions, both amino groups in 1,2-diaminopropane wereinvolved in the reaction leading to bislactone 24 (Scheme24).

Scheme 24

As expected, the structure of the starting amine, the num-ber of substituents, and their size all played a key role onthe reaction rate. Benzylic amines were most reactive, astheir reactions proceeded readily in diethyl ether at roomtemperature. Arylhydrazines (о-nitro and о-methoxy-phenylhydrazines) did not react at room temperature,whereas refluxing of these compounds in methanol af-

forded complex mixtures of products. Nitrogen nucleo-philes, which are components of heterocycles, such aspiperidine, piperazine, and some other derivatives, react-ed under more drastic conditions. For example, refluxingof (–)-anabasine in butanol selectively afforded (in 74%yield) Δ2-butenolide 21a that possesses a chiral center inthe α-position with respect to the nitrogen atom (Scheme25).32

Scheme 25

It should be noted that the analogous reaction of anabasinewith 3-(1-hydroxycyclohexyl)propiolonitrile (25) in etha-nol at 40 °C gave only the linear adduct 26 (Scheme 26).32

Scheme 26

Significantly, optically active 4-amino-2(5H)-furanoneswere efficiently synthesized by combining an asymmetricalkyne addition to aldehydes with a subsequent aliphaticamine addition. Both steps were conducted at room tem-perature and the products were obtained with high enan-tioselectivity (84–90% ee) (Scheme 27).33

A useful direct, one-pot preparation of 4-dialkylamino-5H-furan-2-ones was also achieved starting from 2-yn-1-ols. The formation of the target 4-dialkylamino-5H-furan-2-ones occurred through an ordered sequence of steps,namely (a) palladium-catalyzed oxidative mono-amino-carbonylation of the starting 2-yn-1-ol to give an interme-diate 4-hydroxy-2-ynamide which is isolable underappropriate conditions; (b) stereoselective conjugate addi-tion of dialkylamine to the triple bond of 4-hydroxy-2-yn-amide with formation of (E)-3-dialkylamino-4-hydroxy-2-enamide (not isolated); (c) intramolecular alcoholysisof the amide function of the latter to give the final product(Scheme 28).34

Scheme 22

H

N

R4

R5

OR1

O

R2 O

H

cis-20

H

R1

ON

O

trans-20

R4 R5

R2

OH H

R1

ON

O

R5

R2

OH H

N

O

OR5

R4

R4 R1 OR2

H

R3

R3 R3R3

––

+

+

OH

O

OMe

O O

NEt2

22 23 (75%)

Et2O, r.t., 24 h

Et2NH

MeOH, 40 °C19a

H2N NH2·2 HCl

O

O

O

OHN

NH

24 (58%)

NaOAcHO O

OMe

+NH

H

NO O

NH

N

21a (74%)(–)-anabasine19a

HO O

OMe n-BuOH

reflux

+NH

H

NOH

NH

N

26(–)-anabasine25

HO

CN

CN

+

HH

25

MeOH

40 °C

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β-Hydroxybutenolides (tetronics acids) can be easily pre-pared in good yields by a protocol involving two consec-utive chemical events: a Michael addition of pyrrolidineon a secondary or tertiary γ-hydroxy-α,β-acetylenic esterto give the corresponding enamine, and the subsequentacid-catalyzed hydrolysis–lactonization of this intermedi-ate (Scheme 29).35. Tetronics acids are the subject of nu-merous studies owing to their wide array of biologicalproperties.

Scheme 29

The domino reaction between γ-hydroxy-α,β-acetylenicesters 19 and amines was significantly accelerated in re-cyclable ionic liquids.36 Commercial 1-butyl-3-methyl-imidazolium tetrafluoroborate [bmim][BF4] andhexafluorophosphate [bmim][PF6], 1-hexyl-3-methyl-imidazolium tris(pentafluoroethyl) trifluorophosphate[hmim][PF3(C2F5)3], 1-butyl-3-methylpyrrolidinium tri-flate [bmpl][OTf] and bis(triflyl)amide [bmpl][NTf2]were used as ionic liquids. The results of the reaction be-tween the alkyne 19a and piperidine in ionic liquids com-pared with those achieved earlier in diethyl ether andunder neat conditions showed that in all cases the 4-(pi-peridin-1-yl)-1-oxaspiro[4,5]dec-3-en-2-one (21b) wasformed much faster, at lower temperature, and in im-proved yield in ionic liquids than in diethyl ether or undersolvent-free conditions. As a rule, better results in termsof both the product yield and the reaction rate were ob-served with the less expensive ionic liquid [bmim][BF4](Scheme 30). Moreover, ionic liquids were recovered andreused at least five times without any decrease in reactionrates and product yields.

Scheme 30

Positive ionic liquid impact was attributed to ion–dipoleinteractions in the ionic liquid medium, which facilitatethe charge separation in compounds 19 and 20 and pro-mote the reaction (Figure 3).36

Figure 3

Another alternative procedure entailed the use of waterand ultrasound irradiation instead of ionic liquids.37 Verylikely, the sequential lactonization reaction observed un-der these latter reaction conditions is a consequence of therole played by water as a Brønsted acid catalyst both inMichael addition and in the transesterification step. Com-pared to traditional stirring, the application of ultrasoundirradiation significantly increased the reaction rate andyield. In order to show the general applicability of themethod, structurally diverse amines were used. Whilewith primary amines the corresponding 4-amino-2(5H)-furanones 21 were isolated as the main reaction products,with a secondary aliphatic amine, such as piperidine, lackof selectivity was observed due the competitive formationof the amide derivatives 27 (Scheme 31).

Inverse stereoselectivity was observed with thiols. When2-napthylthiol was added to a flask containing γ-hydroxy-4-(4-tolyl)but-2-ynoic acid ethyl ester (19d) in water, im-mersed in a room-temperature water bath and sonicated

Scheme 27

MeO2C

(1.2 equiv)

1. (S)-BINOL, Et2Zn

HMPA, CH2Cl2, 18 h

2. Ti(Oi-Pr)4, 1 h

3. RCHO

MeO2C

R

OHH

R = alkyl, aryl up to 76% (2 steps)

84–90% ee

O O

NH

H

R

Ph NH2

Ph

Scheme 28

OH

R2

R1PdI2 cat/KI

CO/air (20 atm)

R32NH, DME

100 °C

R1R2

HO O

NR32

R32N

R1R2

O O

NR32

R1

R2

O O

R32N

15 examples

(61–82%)

H

R1R2

HO O

OMe N

R1R2

O O

OMeR1

R2

O O

HONH HCl, H2O

i-PrOH, Δ

H

NH O O

N

21b

+

19a

HO O

OMe [bimin][BF4]

20 °C, 1 h

(85%)

O

R2

R1

O

OR3 H

N

R4

R5

OR3R1

O

R2 O

HHAn

Cat

An

Cat

19 20

–

–

++

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till completion of the reaction, only the formation, in 90%yield, of the (Z)-ethyl 4-hydroxy-3-(naphthalen-2-ylthio)-4-(4-tolyl)pent-2-enoate (28) was observed (Scheme 32).Conversely, it was reported that the nucleophilic additionreactions of a sulfur nucleophile to β-(2-amino-5-methyl-pyridin-3-yl)-α,β-ynones proceeded with high E stereose-lectivity and this stereochemical outcome accomplishedthe subsequent cyclization reaction. 16

Scheme 32

The domino conjugate addition and cyclization reactionof γ-hydroxy-α,β-acetylenic esters with alcohols or waterwas, also, extensively investigated. The ester 19b reactedvigorously with methanol containing sodium methoxide(30–50 mol%) to give the corresponding lactone 30a(Scheme 33).28

Scheme 33

The method was successfully applied to the synthesis ofbiologically active 4-spiro-2-hydrotetronic acids 30b,c(Scheme 34).38

Scheme 34

Analogously, the total synthesis of stenoma alkaloids,containing contiguous spirocyclic quaternary centers, wasachieved by treatment of suitable spiro γ-hydroxy-α,β-acetylenic ester derivatives with magnesium methoxide inboiling methanol. The corresponding methyl tetronates30d,e were isolated in 85% and 75% yields, respectively(Scheme 35).39 The formation of compounds 30d,e oc-curred in a stereocontrolled fashion through the interme-diacy of the corresponding (E)-3-methoxyacrylatederivatives.

Scheme 35

Lack of stereospecificity was observed in the preparationof lactone 30f, a key step in the synthesis of the aspertet-ronin group of natural products (Scheme 36).40

Scheme 31

H2O, r.t., )))

19b

21c–f

O

O

HN

O

O

HNPh

O

O

Ph

HNPh

O

O

HN

Ph

O

ON

NH

+

27 (16%)

N

HO

19b,c

21c (90%) 21d (91%) 21e (66%) 21f (60%)

21g (43%)

O

O

MeR1

HN

R2R2NH2

HO

R1

O

OMe

Me

HO O

OMe

H2O, r.t., ))) O

19d 28 (90%)

HO

O

OEt

+

SHH2O

r.t., 2.5 h

OH H

S O

OEt

OO

MeO

reflux, 45 min

30a (60%)19b

O

OMe

HO

NaOMe, MeOH

r.t.

NaOMe, MeOH

OH OEt

OO

O

OMe

30b: n = 1 (79%)

30c: n = 2 (85%)

nn

NO

HO

O

EtOPh

H

NO

O Ph

H

O

H3CO

NO

HO

O

EtOPh

HNO

O Ph

H

O

H3CO

Mg(OMe)2

NaOMe (cat.)

MeOH, reflux

Mg(OMe)2

NaOMe (cat.)

MeOH, reflux

30d (85%)

30e (75%)

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Scheme 36

Efficient catalytic systems for the synthesis of alkoxylatedlactones from γ- and δ-hydroxy-α,β-acetylenic esters havebeen developed as well. The mercuric oxide–boron triflu-oride catalyzed addition of alcohols to acetylenic bonds,not necessarily conjugated to carbonyl or similar groups,has been reported.41 It was successfully applied to thepreparation of β-methoxy-α,β-ethylenic-γ-lactones ingood yields.42 The boron trifluoride–mercuric oxide cata-lyst was also examined for the domino alkoxylation andlactonization reaction of δ-hydroxy ester derivatives. Theβ-methoxy-δ-Δα,β-hexenolactone 32 was obtained in 65%yield under the mercuric oxide–boron trifluoride cataly-sis, but the formation of 32 failed to occur when methano-lic sodium methoxide was used (Scheme 37). 28

Scheme 37

The polymeric reagent comprising mercury-impregnatedNafion-H was effective for the synthesis in good yield ofthe 4-ethoxy-1-oxaspiro[4,5]dec-3-en-2-one (30g) frommethyl (1-hydroxycyclohexyl)propiolate (19a) dissolvedin ethanol (Scheme 38). 43

Scheme 38

Teles and co-workers reported, in a seminal work, thehighly efficient gold-catalyzed alkoxylation of alkynes.44

Then, the potential of gold catalysis for the synthesis of 4-alkoxy-2(5H)-furanones was examined (Scheme 39).45

The gold-catalyzed tandem alkoxylation and lactonizationof γ-hydroxy-α,β-acetylenic esters was achieved by using2 mol% of [2,6-bis(diisopropylphenyl)imidazol-2-yli-dene]gold bis(trifluoromethanesulfonyl)imidate[Au(IPr)(NTf2)] catalyst. The procedure was applied to aseries of secondary propargylic alcohol derivatives allow-ing for yields of the desired products of up to 95%. In ad-dition, tertiary propargylic alcohols bearing mostly cyclicsubstituents were converted into the corresponding spiroderivatives. Both primary and secondary alcohols reactedwith the γ-hydroxy-α,β-acetylenic esters at moderate tem-peratures (65–80 °C), either under neat reactions or with1,2-dichloroethane as a reaction medium, allowing foryields of 23–95% of the desired products. Analysis of theintermediate 32 proved the exclusive formation of the E-isomer which allows for the subsequent lactonization.NOE experiments revealed that the initially envisionedisomerization of (possibly formed) Z-isomers does notneed to be invoked. This would represent a rare exampleof syn-addition in gold catalysis, which is however strong-ly related to the unique substrate properties.46

Scheme 39

Readily available optically active γ-hydroxy-α,β-acetyle-nic esters underwent regiospecific hydration in the pres-ence of Zeise’s dimer, [PtCl2(C2H4)]2, to afford thecorresponding optically active tetronic acids 33 (Scheme40).47

OH

O

OEt

O O

MeO

NaOMe

MeOH, r.t.

30f (43%)

+

OH

MeO

31 (34%)

OEt

O

OH

O

OMe

HgO, BF3·OEt2

MeOH, 30 °C, 24 h

CCl3CO2H

O O

OMe

32 (65%)

OH

O

OMe O O

EtO

19a

Hg/Nafion-H

EtOH, 40 °C, 50 h

30g (85%)

R1

OH

O

OEtO

O

R1

R2O

[Au(IPr)(NTf2)] (2 mol%)

R2OH, 65 °C, 2 h

OR2

H

OH

R1

O OEt

32

Scheme 40

O

OMe

(4 equiv)

1. (S)-BINOL (40 mol%), Et2Zn (4 equiv)

HMPA (2 equiv), CH2Cl2, r.t., 16 h

2. Ti(Oi-Pr)4 (1 equiv), 1 h

3. RCHO, 4 h

MeO

O

HHO

R

O

OH

O

H

R

tetronic acidR = alkyl, aryl

Zeise's dimer(2 mol%)

MeOH–H2Oreflux

PtCl

Cl

ClPt

Cl

33

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In the catalytic hydration, 2 mol% of the Zeise dimer wasused. The resulting product 33 was then treated with ace-tic anhydride and pyridine, which quantitatively convert-ed both the enol and keto tautomers of 33 into the acetate34 (Scheme 41).47 The enantiomeric purities of the tetron-ic acid products were very similar to those of the startingaliphatic γ-hydroxy-α,β-acetylenic esters.

Scheme 41

The electron-withdrawing effect of the ester group, theLewis acidity of the platinum(II) center, and the chelatingeffect in the coordination of the acetylenic ester to theplatinum(II) center might contribute to the observed re-giospecific hydration (Figure 4).47

Figure 4

The conjugate addition of water to the triple bond tookplace efficiently with complete regioselectivity. The hy-dration reaction of γ-hydroxy-α,β-ynones 35 afforded thecorresponding 3(2H)-furanones 36 in excellent yields inthe presence of mercury-impregnated Nafion-H and fiveequivalents of water in ethanol at 40 °C (Scheme 42).43

The process was applied to the synthesis of the naturallyoccurring bullatenone (36a).

Scheme 42

2.3 Sequential Electrophilic Addition–Annula-tion Processes of α,β-Ynones Containing Proximate Nucleophiles

α,β-Ynones may undergo electrophilic addition, and suit-ably substituted acetylenic ketones were found to be ver-satile synthetic precursors of various heterocycles throughsequential reactions promoted by electrophilic reagents.48

Hydroxy acetylenic acetals and hydroxy acetylenic ke-tones led to substituted 3-halofurans (Scheme 43, a), fla-vones (Scheme 43, b), and styrylchromones in good toexcellent yields.49

Scheme 43

Hydroxy acetylenic aldehydes derived from hydrolysis ofhydroxy acetylenic acetals and hydroxy acetylenic ke-tones can undergo regioselective addition of HX or H2Ogiving rise to a mixture of E- and Z-adducts. Then rapidinterconversion of the E- and Z-adducts under the reactionconditions achieves the formation of the target product af-ter cyclization and dehydration (Scheme 44).49

Scheme 44

In this way, the reaction of 1k with hydrogen iodide gavethe expected 4-iodoquinoline derivative in a moderateyield of 40% (Scheme 45).14

O

O

O

H

R O

OH

O

H

R

pyridine

Ac2OO

OAc

O

H

R

34

O

OAc

O

H

34a (61%, 74% ee)

O

OAc

O

H

34b (78%, 82% ee)

O

OAc

O

H

34c (41%, 92% ee)

O

OAc

O

H

34d (46%, 90% ee)

O

MeO

R

OH

H2O

Pt

HO

R2

R1O

R3O

O

35

Hg/Nafion-H

36

Hg/Nafion-H, H2O

EtOH, 40 °C, 14 hHO

O

Ph

35a

R3R2

R1

O

O

36a (100%)

Ph

OR2

OR2

HO

R1

HX

(X = Cl, Br, I) O

X

R1a)

O

R2

HO

R1

HX

(X = Cl, Br, I) OR1

R2

X

b) R1

O

OH

R2

R3concd H2SO4

aq EtOHO

O

R1 R2

R3

c)

R OH

O

R1

R O

O

R1

HBr

1,4-dioxane

O

R2

HO

R1

OR1

R2

X

X HHX

R1 O

R2OH

H

O

R2X

HO

R1

– H2O

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Scheme 45

Moreover, acid-assisted Michael addition of HX over thein situ generated γ-hydroxy alkynones played a key role inthe one-pot three-component synthesis of 3-halofurans(Scheme 46).8k The palladium-catalyzed cross-couplingof acyl chlorides with the tetrahydropyranyl propargylether was followed by acid-catalyzed deprotection of thetetrahydropyranyl ether with concomitant Brønsted acidmediated Michael addition of the halide to the alkynoneintermediate. Hence, the E-configured enone derivativesubsequently underwent a cyclocondensation to give the3-halofuran.

Scheme 46

Analogoulsy, 2-substituted N-Boc-4-iodopyrroles wereisolated in a one-pot fashion by the palladium-catalyzedcross-coupling of (hetero)aryl-, alkenyl-, and selectedalkyl-substituted acid chlorides with N-Boc-protectedpropargylamine followed by Michael addition of hydro-gen iodide and cyclocondensation (Scheme 47). Interest-ingly, upon addition of a further alkyne, another couplingcan be carried out in a one-pot fashion. 50

Scheme 47

The reactions of various substituted but-2-yn-1-ones bear-ing hydroxy, tosylamine, and thioacetate functionalgroups at the C4-position with iodine or bromoiodine atroom temperature afforded the corresponding 3,4-diiodo-and 3-bromo-4-iodo-substituted furans, pyrroles, andthiophenes in good to high yields (Scheme 48).51

Scheme 48

The solvent plays a critical role in the selective formationof the desired dihalogenated heterocycles (Scheme 49).51

Scheme 49

The results above indicate that the formation of the thio-phene derivative in nitromethane takes place through a se-quential process involving: a) addition of iodine to thetriple bond of the starting ynone derivative to give the E-configured diodinated enone; b) isomerization of the E-configured enone to the Z-configured enone; and c) intra-molecular condensation under Lewis acidic iodine condi-tions. A different sequence was suggested to occur inmethanol to lead to furan and pyrrole formation through apathway involving a ketal intermediate (Scheme 50).51

Scheme 50

The methoxy-incorporated dihydrofuran derivativeshown in Scheme 51 was isolated by starting from a suit-able ynone without a proton at the propargylic carbon.

NH2

O

HI

1,4-dioxane

1k

I

R1 Cl

O

+

R2

OTHP1) Pd(PPh2)2Cl2, CuI

Et3N, THF, r.t.

2) NaX, PTSA·H2O

MeOH, r.t.O

X

R1

R2

R1

O

R2

OTHP

R1

O

R2

OHH+, MeOH

– THPOMe NaX

X

R1

HO

R2

O

HX

– H2O

R1

Cl

O

+

N Boc

H PdCl2(PPh3)2

CuI

Et3N, THF, r.t.

R1

O

N

H

Boc

N

BocR1

IR2

Cs2CO3, 70 °CNR1

Boc

R2

NaI, PTSA·H2Ot-BuOH, r.t.

R2

ONu

R1 solvent, r.t.

OR1

R2

IX

X = I, BrNu = OH, NTs, SAc

IX

Ph

OAcS SPh

II

I2

(83%)

I2

I

I

AcSPh

O

(91 %)

I

I

AcSPh

O SPh

II

I2

(87 %)

CH2Cl2r.t., 5 h

MeNO2r.t., 5 h

MeNO2r.t., 5 h

R2

OHNu

R1

Nu = O, NTs

MeOH

I+

OMe

OIHNu

R1

R2 HI

OMe

HNu

R1R2

+

OMe

HNu

R1

R2.

.

I OMe

R2

NuH

R1I Nu

II

H R2

OMe

R1

NuR1

R2

II

– IOH

– MeOH

I–

+

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Scheme 51

The dihalogenated furan derivatives underwent furtherelaboration to provide useful organic electronics bymeans of palladium-catalyzed cross-coupling reactions.Moreover, sequential Sonogashira, addition, cyclocon-densation and Suzuki reactions achieved a diversity-ori-ented multicomponent access to substituted 3-arylfurans(Scheme 52). 52

Scheme 52

3 Cycloaddition–Heterocyclization Processes of α,β-Ynones and α,β-Ynoates Containing Proximate Nucleophiles

3.1 [2+2] and [4+2] Cycloaddition–Annulation Reactions

The [2+2] cycloadditions of enamines with electrophilicacetylenes in apolar solvents are well documented andrepresent an important strategy for the synthesis of cy-clobutene derivatives.53 However, while the behavior inthese reactions of acetylene mono- and dicarboxylates aswell as methyl propiolate has received significant atten-tion both from the theoretical and applied points of view,less attention has been paid to the cycloaddition reactions

with α,β-ynones and related compounds. When β-(2-ami-nophenyl)-α,β-ynones 1 were treated in toluene under re-flux for four to six hours with three equivalents of 1-(cyclohexen-1-yl)pyrrolidine, the 1-(1-pyrrolidino)bicyc-lo[4.2.0]octane[7,8-c]-2-arylquinolines 37a–c were iso-lated in moderate yields (Scheme 53).54

Thermal rearrangement of this type of cyclobutene deriv-ative represents a useful method for ring enlargement withtwo carbon atoms and has been widely used in the synthe-sis of medium-sized carbo- and heterocycles.55 Indeed,37c was quantitatively converted into the thermodynami-cally favored tricyclic quinoline 38a by heating under re-flux in xylene (Scheme 54).

Scheme 54

Interestingly, c-fused quinolines 38b–e were directlyisolated, in toluene at reflux, from the reaction of β-(2-aminophenyl)-α,β-ynones 1 with cyclopentanone- orcyclohexanone-derived enamines (Scheme 55).54

Scheme 55

β,β-Disubstituted enamines failed to give cycloadditionreactions and, instead, 4-aminoquinolines were isolatedafter prolonged reaction times of 24 hours (Scheme 56).54

Very likely, the 4-aminoquinolines were formed by a

Ph

OHO I2 (3 equiv)

MeOH, r.t., 2.5 hO

OMe

Ph

II

(83%)

ClO

+

OTHP1) Pd(PPh2)2Cl2, CuI

Et3N, THF, r.t., 2 h

PTSA·H2O

MeOH, r.t., 4 hOMe OMe

2) ICl, NaCl O

ICl

MeO

OMe

O

Cl

MeO

OMe

OMe

Pd(PPh3)2Cl24-MeOC6H4B(OH)2

Na2CO3, H2OTHF–MeOH 90 °C, 24 h

Scheme 53

NH2

O

R1

R2

+N

NH2

H N

ArO

N

R1

R2

H

37a–c

R1 R2 Yield (%)

37a Cl H 5637b H CF3 5837c COMe H 52

1

N

38a

N

O

N

N

H

37c O

NH2

O

R1 +N

N

38b–e

R1 n Y Yield (%)

38b Cl 1 - 5838c COMe 1 - 5538d Cl 1 O 5238e Cl 2 - 45

Y

R1

n

N Y

n

1

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domino Michael addition and annulation reaction of theamine, which might be generated in situ by the hydrolysisof the starting enamine.

Scheme 56

β-Monosubstituted enamines gave rise not only to the 4-amino derivative but also to a new 3,4-disubstituted quin-oline derivative, probably through a nucleophilic attack,annulation, isomerization and elimination cascade(Scheme 57).54 The lack of reactivity of these latter en-amines towards cycloaddition was attributed to electroniceffects.56

Although the intramolecular [4+2]-cycloaddition reac-tions of conjugated ynones have been extensively ex-plored,57 the domino Diels–Alder and annulationreactions of α,β-ynones and α,β-ynoates containing prox-imate nucleophiles have been less investigated. To thebest of our knowledge only two examples of this reactionhave been reported. Methyl 2-(1′-hydroxycyclohexyl)pro-piolate (19a) underwent, in anhydrous xylene at 170 °C,the domino Diels–Alder and lactonization reaction with2,3-dimethylbutadiene to give 5,6-dimethyl-3-spirocyclo-hexyldihydrophthalide (39a).58 The same alkyne 19a re-acted with butadiene in benzene at 200 °C giving rise tothe lactone 39b in good yield (Scheme 58).59

3.2 1,3-Dipolar Cycloaddition–Annulation Reac-tions

The sequential 1,3-dipolar cycloaddition and annulationreaction of conjugate ynone 1e with 4-nitrophenylazidegave the triazolo[4,5-c]quinoline 40a (Scheme 59).14

Scheme 59

Analogously, the sequential 1,3-dipolar cycloaddition andannulation reaction of conjugate ynone 1g with a benzoni-trile oxide achieved the synthesis of isoxazolo[4,5-c]quin-oline 41a (Scheme 60).14

Scheme 60

The synthetic and medicinal importance of isoxazole-annulated ring systems provided enough incentive to de-vise simple strategies for the generation of these molecu-

NH2

O

Cl

+H

N

N

Cl

N

(76%)

Scheme 57

NH2

O

Ar+

H

N

Ph

HN Ar

N

(36%)

+

N

(32%)

NH2

Ar

O

Ph

N NH

N

Ph

Ar

O

Ph

Ar

O

Ar = 4-ClC6H4

–

+

Scheme 58

OH O

OMe

O O

19a

xylene

39a170 °C, 18 h

O O

39b

benzene

200 °C, 15 h

NH2

O

+

N

NO2

N3

Cl2CHCHCl2

reflux, 6 h

N

NNNO2

40a (63%)1e

NH2

O

Cl

+N

N

Ph

Cl

Cl

41a (71%)

Cl2CHCHCl2

Et3N, reflux, 6 h

NO

HO

1g

Dow

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lar frameworks.60 A number of isoxazoloquinolines havebeen identified as MRP1 inhibitors61 and a class of isoxa-zoloquinoline derivatives showed anxiolytic activity.62

For getting through the bottleneck for further studies anddevelopments in medicinal chemistry, the reactivity of β-(2-aminophenyl)-α,β-ynones 1 towards nitrile oxides de-rived from differently substituted aldehydes was investi-gated, and provided a clean, mild, and general synthesis offunctionalized isoxazolo[4,5-c]quinolines. Products 41were easily prepared by slow dropwise addition of a solu-tion of the appropriate α-chlorooxime (1.2 mmol) in anhy-drous xylene to a boiling solution of β-(2-aminophenyl)-α,β-ynone 1 (1.0 mmol) and triethylamine (1.5 mmol) inanhydrous xylene (Scheme 61).63

Scheme 61

However, under these standard conditions, the alkaneni-trile oxides, generated in situ from the corresponding α-chlorooximes, underwent dimerization to furoxanes.64

Subsequently, a competitive nucleophilic addition and an-nulation reaction promoted by the chloride ion led mainlyto the corresponding 4-chloroquinoline derivatives(Scheme 62).63

The dimerization of labile nitrile oxides to furoxanes wasminimized by carrying out the reactions in toluene at40 °C. Under these milder conditions, the isoxazolo[4,5-c]quinolines 41h,i were isolated in 23 and 73% yield, re-spectively (Scheme 63).63

Scheme 63

Further improvement was accomplished by the develop-ment of a one-pot procedure starting from β-(2-amino-aryl)-α,β-ynones and generating the α-chlorooxime fromthe corresponding oxime, and subsequently the nitrile ox-ide, in the same reaction step. A solution of the crude α-chlorooxime, obtained by treating the appropriate oximewith N-chlorosuccinimide (NCS) at 0 °C in chloroformand in the presence of a catalytic amount of pyridine, wasadded dropwise at 40 °C, over a period of 30 minutes, toa solution of conjugate ynone 1h and triethylamine in tol-uene. Under these conditions, the isoxazolo[4,5-c]quino-line 41j was isolated in 41% yield (Scheme 64).63

Scheme 64

The suggested reaction mechanism involves a regioselec-tive [3+2]-cycloaddition reaction of the ynone with the ni-trile oxide, generated in situ from the corresponding α-chlorooxime, followed by an intramolecular addition andelimination reaction between the amino and carbonylgroup, with loss of water. The observed regioselectivity isin agreement with the results obtained in the cycloaddi-tions of disubstituted electron-deficient alkynes with ni-

NH2

O

ArN

N

R1

Cl

41

Et3N, xylene, reflux

NOHO

1

R1

Ar

N

41b (63%)

NO

OMe

Cl

N

41c (69%)

NO

F

O

N

41d (77%)

NO

Cl

NO2

N

41e (45%)

NO

Cl

N

41f (55%)

NO

ON

41g (48%)

NO

CO2Et

NO2

CO2Et

Scheme 62

NH2

ON

N

R1

Cl 42

Et3N, xylene, reflux

HO

R1 = Et, (Et)2CH

Cl

N ON

O

R1R1

Cl

Cl(87%)

+

1g

+–

NH2

O N

N

R

Cl

Et3N, toluene, 40 °C, 24 h

HO

Cl

Cl

41h: R = Et (23%)

41i: R = CHEt2 (73%)

NO

R

1g

NH2

O

CO2Et

N Et

NCS, CHCl3

HO

N Et

Cl

HO

toluene, Et3N N

CO2Et41j (41%)

NO

Et

1h

N

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trile oxides that generate isoxazoles carrying electron-withdrawing group in the 4-position (Scheme 65).65

Scheme 65

Nitrones, too, behave as 1,3-dipoles in cycloadditionreactions66 and are particularly suitable for the construc-tion of structurally complex molecules such as nitrogen-containing biologically active compounds and fused- orbridged-ring structures.67 Alkynes undergo facile cyclo-addition reactions with nitrones under thermal conditionsto give isoxazolines and the regioselectivity is strongly af-fected by steric and electronic factors.68 Monosubstitutedelectron-rich alkynes give 5-substituted 4-isoxazolines asthe main products, whereas electron-poor monosubstitut-ed alkynes show a strong tendency to afford 4-substituteddihydroisoxazoles 43 with high regioselectivity.69 This isalso the case for internal alkynes such as ethyl phenylpro-piolate (Scheme 66).70 This inversion of regioselectivityhas been rationalized by frontier molecular orbital theo-ry.71

Scheme 66

On the basis of this knowledge, it was envisaged that thecycloaddition reaction of β-(2-aminophenyl)-α,β-ynones1 with nitrones could provide a straightforward entry intoisoxazolino[4,5-c]quinolines 44 through a sequential one-pot protocol according to Scheme 67.72

Scheme 67

The isoxazolino[4,5-c]quinolines 44 were isolated inmoderate to high yields as single regioisomers.72 Asshown in Figure 5, the reaction tolerates various function-al groups, such as keto (44a,b), nitrile (44d), and ester(44h) groups; vinyl (44a–c) and heteroaryl (44f) substitu-

ents are also allowed on the isoxazoline moiety. Moreoverthe isoxazolino[4,5-c]quinoline 44i, substituted on thebenzene ring of the quinoline, was also obtained in goodyield.

Figure 5

4 Transition-Metal-Catalyzed Addition–Het-erocyclization Processes of α,β-Ynones and α,β-Ynoates Containing Proximate Nucleo-philes

4.1 Palladium-Catalyzed Transfer Hydrogena-tion–Heterocyclization Processes

The transition-metal-catalyzed hydrogenation of alkynesis one of the most important reactions in organic chemis-try.73 This transformation is accomplished by using hy-drogen gas in the presence of either a heterogeneouscatalyst74 such as Raney nickel, Lindlar’s catalyst or pal-ladium on carbon, or a homogeneous catalyst based on arhodium, ruthenium or iridium complex. 75 However,these methods often suffer from a lack of chemo- and ste-

NO R1

R1CNO

– H2ONH2

O

Ar

N Ar

41

NO

R1

NH2

O

Ar

1

HOH

N

Me

R1

+ R2 EWG ON

EWG

R1

R2

EWG = CO2Me, CNR2 = H, Ph

Me

43

+–

NH2

O

R3 N

N

H

toluene, Δ

O

R3

44

NO

R4R1

R2

R4

Me

R2

R1

Me

1

+–

N

44a (81%)

NO

Me

Ph

Ac

N

44b (60%)

NO

Me

Ac

N

44c (86%)

NO

Me

Ph

Cl

O

N

44d (61%)

NO

Me

CN

N

44e (84%)

NO

Me

Cl

N

44f (43%)

NO

Me

OMe

N

44g (87%)

NO

Me

F3C

N

44h (50%)

NO

Me

CO2Et

O

N

44i (68%)

NO

Me

MeOF

F

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reoselectivity, arising from the cis/trans interconversionof the alkenes, and an over-reduction of the resulting al-kenes to alkanes. Low tolerance with respect to functionalgroups such as carbonyl, formyl, and nitro groups, and toC–X bonds (where X = O, N, Cl, etc.) due to competitivehydrogenolysis, also narrows its generality. Alkynescould also be hydrogenated by using ammonium formate,instead of hydrogen gas, in the presence of a palladiumcatalyst.76 A variety of γ-hydroxy-α,β-acetylenic esterswith a tertiary hydroxy group reacted selectively with for-mic acid and tri-n-butylamine in the presence ofPd(OAc)2(PPh3)2 to give the corresponding butenolides45 in good to high yields through a sequential cis-hydro-genation and cyclization process. The reactions were car-ried out at 60 °C with the following molar ratio: γ-hydroxy-α,β-acetylenic ester–formic acid–tri-n-butyl-amine–Pd(OAc)2(PPh3)2 = 1:2.6:3.4:0.02 (Scheme 68).77

A 85:15 mixture of butenolide 45g and saturated γ-lactone46g was isolated (65% total yield), starting from the cor-responding γ-hydroxy-α,β-acetylenic ester that possesseda secondary hydroxy group under the same reaction con-ditions. When formic acid was reduced to about 50% ex-cess, it was possible to isolate 45g in 69% yield, and anincrease in the amount of formic acid to about 300% ex-cess gave 46g in 64% yield (Scheme 69).77

Scheme 69

Additional evidence showed that the nature of the formatesalt and of the reaction medium can significantly affectthe reaction course.78 Moreover, it was reported that, de-pending on the character of the starting γ-hydroxy-α,β-acetylenic ester, the 1,4-dicarbonyl compound 49 couldbe isolated under the usual hydrogenation conditions, in-stead of the expected cyclic derivative, through a differentisomerization and hydrogenation sequence. In the pres-ence of aryl, heteroaryl or vinyl groups in the starting al-

kyne, the formation of an E/Z mixture of alkenes 48 viathe intermediacy of allenyl alcohol 47 occurs more rapidlythan the palladium-catalyzed hydrogenation of the car-bon–carbon triple bond (Scheme 70).79

Scheme 70

Further elaboration of ethyl γ-aryl orheteroaryl-γ-hy-droxy-2-butynoates with (S)-amino acid benzyl esters inethanol or dimethylformamide in the presence of triethyl-amine provided a general, regioselective entry to N-(3-aryl or heteroaryl-1-ethoxycarbonyl-3-oxopropyl)-(S)-amino acid esters, useful intermediates for the synthesis ofangiotensin converting enzyme inhibitors.80 Examples ofselective trans reduction of carbon–carbon triple bonds ofγ-hydroxy-α,β-acetylenic esters were also described.81

The palladium-catalyzed transfer hydrogenation andcyclization of β-(2-aminoaryl)-α,β-ynones 1 afforded2-aryl- and 2-vinylquinolines 51 in good yields.13 Hetero-geneous conditions [3 equiv of HCOONH4, 10 mol%Pd/C in MeOH (58 mL/mmol) at 70 °C] gave 51 in goodyield. However, significant amounts of over-reduction de-rivatives, the tetrahydroquinolines 54, were sometimesisolated. No attempts were made to establish whether 54is generated via transfer hydrogenation of 51 or by reduc-tion of intermediate 50 and cyclization of saturated inter-mediate 52 followed by reduction of the resultant 3,4-dihydroquinoline 53. Higher product selectivity has beenobserved under homogeneous conditions (Scheme 71).

Scheme 68

R1R2

HO O

OR3H

R1R2

OH O

OR3

R1R2

OO

H

45

Pd(OAc)2(PPh3)2

n-Bu3N, HCO2H

DMF, 60 °C

OH

O

45a (73%)

O

O

45b (85%)

O

O

O

O

O

O

O

45d (78%) 45e (55%) 45f (65%)

O O

H15C7

HO O

OEt

OH15C7

OOH15C7

O +

45g 46g

Pd(OAc)2(PPh3)2

n-Bu3N, HCO2H

DMF, 60 °C

R

HO O

OEt

Pd(OAc)2(PPh3)2

n-Bu3N, HCO2H

R

O

OEt

O

O

OEt

R

O

O

OEt +R

OEtO

O

R = aryl, heteroaryl, vinyl

49

47 48

R

HO

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Scheme 71

4.2 Palladium-Catalyzed Hydroarylation–Heterocyclization Processes

The reaction of aryl iodides with acetylenic systems in thepresence of a palladium catalyst, formic acid, and a sec-ondary or tertiary amine, results in the formation of sub-stituted olefinic derivatives.82 This hydroarylationreaction, which can tolerate various common functionalgroups, occurs with high stereoselectivity and, dependingon the nature of the substituents on the sp carbon atoms,with good regioselectivity. Since the syn stereochemistryof addition drives the substituents to the same side of thecarbon–carbon double bond, it was speculated that the re-action could provide easy access to a variety of cyclic de-rivatives by starting from suitable precursors. Thehydroarylative lactonization reaction of γ-hydroxy-α,β-acetylenic esters with aryl iodides was applied to the syn-thesis of functionalized butenolides 55. The regioselectiv-ity of the reaction was good and appeared to bedetermined mainly by steric and coordinating factors(Scheme 72).77

Scheme 72

Accordingly, the isomeric butenolides 56 were isolated inlow yield. As expected, when γ-hydroxy-α,β-acetylenicesters containing a less hindered secondary alcoholicgroup were allowed to react under the usual conditions, alack of regiochemistry was observed (Scheme 73).77

Scheme 73

The sequential hydroarylation and cyclization processmost probably proceeds through the following steps: a) re-gioselective syn addition of the s-arylpalladium interme-diate [generated in situ via oxidative addition of the aryliodide to Pd(0)] over the starting γ-hydroxy-α,β-acetyle-nic ester; b) reductive decarboxylative elimination of theresultant s-alkenylpalladium formate intermediate andcondensation to give the butenolide 55 together with re-generation of the active palladium catalyst (Scheme 74).77

Scheme 74

Highly regioselective syn hydroarylation and cyclizationsequences were also achieved via palladium-catalyzed ad-dition of arylboronic acids to γ-hydroxy-α,β-acetylenicesters. The hydroarylation of simple unsymmetrical al-kynes with a variety of organoboronic acids, under palla-dium catalysis, was reported to give a mixture of thecorresponding regioisomeric alkenes.83 However, it wasfound that incorporation of a specific functional group,such as a keto, hydroxy, or 2-pyridyl group, could play arole in controlling the site of addition. Mechanistically, itis expected that oxygen or nitrogen atoms present in thealkyne substrate would bind the Lewis acidic boronic acidand thereby direct the addition site.84 On the other hand,bulky substituents might block addition to one end of thealkyne. The regioselectivity can also be controlled by em-ploying particular types of ligands.85 Hence, it was report-ed that the palladium-catalyzed arylative lactonization ofγ-hydroxy-α,β-acetylenic esters with boronic acids could

NH2

O

R

1

R = aryl, vinyl

[Pd], HCO2H

N R

N R NH

R– H2O

– H2O

[H]

50 51

52 53 54

NH2

O R

NH2

O R

[H][H]

R1R2

OO

55

Pd(OAc)2(PPh3)2

n-Bu3N, HCO2H

DMF, 60 °CR2

HO

R1 O

OR3

PhO

O

55a (66%)

Ar

OMe

O O

55c (41%)

Cl

HO

O

O

55b (84%)

+ ArI

F

C7H15

HO

O

OEt

OC7H15 O

OC7H15 O

+

55d (32%)

56d (31%)

Pd(OAc)2(PPh3)2

n-Bu3N, HCO2H

DMF, 60 °C

OMe

MeO

I

OMe

+

Pd(0)L2

Pd(OAc)2L2

HCO2H, Bu3N

ArI

Ar

L

Pd

L

I

R2

HO

R1

O

OR3

ArPd

R1

OHR2

OR3

O

L

O

L

HCO2H + Bu3N

Bu3NH+ I– + CO2

R3OH

OR1

R2

O

Ar

55

O

H

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be achieved with a high control of regioselectivity andsyn-stereoselectivity under two different sets of reactionconditions (Scheme 75).86

The palladium-catalyzed hydroarylation and cyclizationreactions of β-(2-aminoaryl)-α,β-ynones 1 with organobo-ron derivatives were also investigated (Scheme 76).87 Theprocess led to the regioselective formation of quinolines58 under all of the reaction conditions tested.

Scheme 76

Higher yields were observed in the presence of an excessof the organoboron reagent. Interestingly, the environ-mentally benign ethanol was a suitable reaction mediumand this solvent was used when the process was extendedto the reaction of various ynones 1 and boron derivativesto afford quinolines 58 in good to excellent yields (Figure6).87 Various substituents were tolerated, both on the bo-ron derivative and on the alkynone. Aryltrifluoroboratesalts gave results comparable with those obtained with ar-ylboronic acids. Moreover, the reaction of 1a with the ar-yltrifluoroborate salts could proceed without the additionof acetic acid. Although these reaction conditions wereless effective than the standard protocol that required 0.15equivalent of acetic acid, the possibility of carrying outthe palladium-catalyzed hydroarylation under neutralconditions is undoubtedly worthy of interest. Palladi-um(II) acetate with 1,2-bis(diphenylphosphino)ethane(dppe) was generally used as the catalytic system. Slightlybetter yields were observed in some examples when theamount of 1,2-bis(diphenylphosphino)ethane was in-creased to 0.1 equivalent (Pd/P = 1:2); however, no sys-tematic investigation was carried out in this regard. Whenpalladium(II) acetate alone or a combination of palladi-um(II) acetate and tri(tert-butyl)phosphine were tested inplace of the palladium(II) acetate and 1,2-bis(diphe-nylphosphino)ethane system, a dramatic loss of efficiencywas observed, together with a less pronounced decrease inthe selectivity. Conversely, the catalytic system compris-ing palladium(II) acetate and tricyclohexylphosphinegave good results, showing that the use of a bidentate li-

gand is not compulsory. The hydroarylation was also cat-alyzed by palladium(0) precatalysts. The catalytic systemcomprising tris(dibenzylideneacetone)dipalladium(0) and1,2-bis(diphenylphosphino)ethane gave nearly the sameyield as palladium(II) acetate with 1,2-bis(diphe-nylphosphino)ethane, while tetrakis(triphenylphos-phine)palladium(0) was much less effective.

Figure 6

A plausible catalytic cycle for the hydroarylation is de-picted in Scheme 77. The active palladium(0) catalyst canbe generated in situ from palladium(II) species in severalways, including oxidation of 1,2-bis(diphenylphosphi-no)ethane88 and homocoupling of arylboronic acid.89 Theoxidative addition of palladium(0) to acetic acid affordsthe hydride complex 59 [it is likely that, under neutralconditions, this step can take place through the insertionof palladium(0) into the O–H bond of ethanol].90 Then, 59coordinates the ynone 1 to give the π-complex 60. Subse-quent hydropalladation followed by transmetallation witharylboronic acid (or potassium trifluoroborate) generates

Scheme 75

R1

HO

R2

O

OR3

OR2

R1

O

Ar

55

OR2

R1

O

56

Ar

ArB(OH)2

Pd(OAc)2 (3 mol%)

dppe (3 mol%)

ArB(OH)2

Pd(OAc)2 (3 mol%)

(t-Bu)3P (6 mol%)

AcOH (10 mol%) AcOH (10 mol%)

R1 = H, MeR2 = H, Me, i-Pr, t-Bu, PhAr = 4-MeOC6H4, Tol

NH2

Ar1

O

Ar2B(OH)2 orAr2BF3

–K+

Pd cat.

Y

– H2O N

Ar1

Ar2

YNH2

Y

Ar2

O Ar1

581

N

Ph

OMe58a (76%)

N

OMe58b (93%)

N

Ph

58c (78%)

N

SMe

58d (70%)

N

F

N

F

FOMe

COMe

N

OMe

CN

F3CN

SMe

58e (90%) 58f (60%)

58g (70%) 58h (74%)

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the species 62, from which the hydroarylation product 63is obtained through reductive elimination of palladium(0).Subsequent sequential cycloamination results in the for-mation of the quinoline ring 58. A similar catalytic cyclewas probed by ESI-FTMS in the related hydroarylation ofallenes with arylboronic acids in the presence of aceticacid.91

An alternative pathway for the hydroarylation could alsobe considered. Initial transmetallation of palladium(II)acetate with boron derivatives generates an ArPdOAccomplex; carbopalladation92 of 1 by this species gives theintermediate 64; protonolysis of 64 affords the alkene 63and regenerates the catalyst (Scheme 78).

Scheme 78

This latter cycle can, however, be ruled out when the re-action is carried out using a palladium(0) precatalyst. Theregiochemical outcome of this reaction also suggests thatthe formation of the product via ArPdOAc is unlikely. In-deed, on the basis of experimental93 and theoretical94 re-sults concerning the insertion of α,β-alkynones andalkynals into an aryl–palladium, the isolation of 3-aryl-quinolines as the main product should be expected. Athird possibility, involving the initial oxidative addition ofarylboronic acid to palladium(0) to give an Ar-Pd-B(OH)2

species that then carbopalladates the triple bond, seems incontrast with the results that show that such oxidative ad-dition does not take place.95 Assuming, therefore, that thecatalytic cycle depicted in Scheme 77 is operating, in or-der to shed some light on the observed regioselectivity,quantum-chemical calculations in the framework of den-

sity functional theory were carried out, leading to the con-clusion that electronic factors provide the mainexplanation for the observed regioselectivity, since themore electrophilic β-carbon atom conceivably showsgreater affinity for the palladium.

4.3 Rhodium-Catalyzed Hydroarylation–Heterocyclization Processes

The rhodium-catalyzed hydroarylation of alkynes with ar-ylboronic acids is a well-established functionalizationmethodology. The reaction shows the same stereochemi-cal outcome of the palladium-catalyzed process (syn addi-tion), but electronic factors seem to play a more importantrole in determining the regioselectivity. In particular,methyl trimethylsilylpropynoate was selectively arylatedat the C3 carbon atom, despite the presence of a bulky tri-methylsilyl group on that position.96 The same regiochem-ical outcome was observed in the sequential reaction ofα,β-ynones 1 with arylboronic acids giving rise to the cor-responding 2,4-diarylquinolines 58 through a rhodium-catalyzed hydroarylative cycloamination process(Scheme 79).97

Scheme 79

The reaction of phenylboronic acid with ynone 1j waschosen as a model system to screen the best reaction con-ditions for the synthesis of 2,4-diarylquinolines (Scheme80).97

Scheme 77

O

R1

NH2

R2 H

– H2O AcOH

HPdOAc

O

R1

NH2

AcOPd H

R2B(OH)2

NH2

R1

OHPdOAc

Pd0

59

61

62

63

(ligands omitted for simplicity)

60

58

1

O

R1

NH2

Pd H

R2

NH2

R1O

N

R2

R1

Pd(OAc)2 ArPdOAcO

R1

NH2

Ar PdOAc

H+

64

57

63

ArB(OH)2

1

O

R1

NH2

Ar H

– Pd(II)

NH2

Ar1

O

Ar2B(OH)2 orAr2BF3

–K+

Rh(I) cat.

YO

Ar1

Ar2

Y – H2O

N

Ar2

Ar1

Y

NH2

1 58

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Scheme 80

With Rh(acac)(C2H4) and 1,1′-bis(diphenylphosphi-no)ferrocene (dppf) as catalyst, 58j was always isolated asthe main reaction product in good to high yield. The regi-oselectivity, determined by way of 1H NMR and GC-MSanalysis, was shown to be higher than 96%. The highestyields were obtained with a fivefold excess of boronic ac-id. The use of a 2:1 ratio of rhodium to 1,1′-bis(diphe-nylphosphino)ferrocene seemed preferable to a 1:1 ratio.The replacement of dioxane with a greener solvent such asaqueous ethanol was also possible, although the formergave better yields. With regard to the ligand, 1,3-bis(di-phenylphosphino)propane (dppp) was slightly less effec-tive than 1,1′-bis(diphenylphosphino)ferrocene indioxane–water, whereas in ethanol the two ligands gavesimilar yields. When the methodology was extended todifferent α,β-ynones and different boron derivatives, thequinolines 58 were isolated in moderate to high yields.The process tolerated electron-withdrawing as well aselectron-donating substituents on the α,β-ynone and aryl-boronic acid moieties. Substituents on the benzene ring ofthe quinoline could also be introduced, and heteroarylbo-ronic acids were used as well.

Furthermore, rhodium(I) complexes were efficient cata-lysts for the regioselective synthesis of 4-substituted2(5H)-furanones 56 (Scheme 81).98

Scheme 81

The reaction selectivity was strongly influenced by the re-action medium, the temperature and the precatalyst’scharacter. Indeed, in the reaction of one equivalent of 4-hydroxy-4-methylpent-2-ynoic acid ethyl ester (19b) withfive equivalents of phenylboronic acid, the 5,5-dimethyl-4-phenyl-5H-furan-2-one (56h) was isolated in 69% yieldtogether with the regioisomer 55h in 10% yield in thepresence of [Rh(cod)(OH)]2 with 1,1′-bis(diphe-nylphosphino)ferrocene as the catalytic system in 1,4-di-oxane–water (10:1, v/v). The formation of 65a (20%yield) as by-product was also observed (Scheme 82).98

Scheme 82

The use of [Rh(cod)OH]2/dppf resulted in a more activecatalytic system with respect to [Rh(cod)Cl]2/dppf andRh(acac)(C2H4)2/dppf even though the latter combinationwas highly selective. The use of [Rh(cod)OH]2 withoutthe addition of phosphine ligands also promoted the reac-tion, but with no improvement in terms of selectivity. Thecombination of [Rh(cod)OH]2 with triphenylphosphineproved to be unsuitable and generally resulted in low se-lectivity. The choice of the bulky, electron-rich 2-(di-tert-butylphosphino)biphenyl as ligand (67; Figure 7), whichwas reported to have beneficial effects on the rhodium-catalyzed addition of alkynes to 1,2-diketones, 1,2-ketoesters and aldehydes,99 did not ensure improved selectivi-ty. Chelating bisphosphine ligands gave inconsistent re-sults. The features of the bisphosphine ligands played apivotal role in determining the outcome of the reaction.Although it has been reported that excellent catalytic ac-tivities could arise from diphosphine ligands on a xan-thene backbone,100 experiments performed under theusual reaction conditions in the presence of [Rh(cod)OH]2

and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene(68; Figure 7) led to a complex reaction mixture. Whereasthe formation of 65a (53% yield) prevailed with 1,2-bis(diphenylphosphino)ethane, improved yields of thetarget 56h were observed by increasing the distancebetween the two phosphorus atoms in the series 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphi-no)propane (dppp) and 1,4-bis(diphenylphosphino)bu-tane (dppb). Among the bisphosphine ligands examined,1,4-bis(diphenylphosphino)butane was significantly moreeffective.

Figure 7

NH2

O

solvent, 80–100 °C N

Rh(acac)(C2H4)

58j (55–80%)1j

PhB(OH)2

R2R1

HO

O

OR3 OO

R1R2

Ar

56

Rh(I) catalyst

ArBX2

19

HO

O

19b

catalyst

PhB(OH)2

O

Ph

OO

Ph

O

O

O

55h 56h 65a

+ +OEt O

O

Ph

P

67

SO3–Na+

PPh2

69

PP

SO3–Na+

SO3–Na+SO3

–Na+

+Na–O3S

71

O

PPh2PPh2

68

SO3–Na+

PPh2

70

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The screening of the solvent system resulted in the obser-vation that the use of ethanol instead of 1,4-dioxane wasdetrimental to the reaction selectivity. The reaction wasalso carried out in neat water and in a biphasic water/tol-uene system by associating the [Rh(cod)OH]2 with water-soluble ligands 69–71 (Figure 7). Surprisingly, eventhough disappointing results were observed from a syn-thetic point of view, the reaction in water led to the forma-tion of 56h as a single regioisomer. Conversely, in thebiphasic water/toluene system, a lack of regioselectivitywas observed.

The role played by the phenylboroxine in the reaction out-come was explored (Scheme 83).101 It is presumed that, insolution, arylboronic acids are in equilibrium with the cor-responding arylboroxines and water. This equilibriumshould influence the reaction stoichiometry and preventthe coupling process. Moreover, the ratio of 19b to triphe-nylboroxine, the nature of the ligand, and the reactiontemperature all had an effect on the reaction outcome. In-deed the reaction of an equimolar amount of 19b withphenylboroxine, in the presence of a rhodium–1,2-bis(di-phenylphosphino)ethane catalytic system in 1,4-dioxaneand water at 100 °C for two hours gave a 45% yield of thedibutenolide derivative 65a together with the derivative56h. The formation of 65a in a better yield was observedby reacting the boroxine with excess alkyne 19b. A simi-lar effect of the boron reagent has also been reported in thenickel-catalyzed 1,2-addition of arylboroxines to aromat-ic aldehydes.102 The formation of the tributenolide deriv-ative 66a was observed when the excess of 19b wasincreased, or when the reaction was conducted in anhy-drous solvent, using 1,4-dioxane (dried with molecularsieves).

The subsequent investigation into the scope and limita-tions of the rhodium-catalyzed alkylative lactonizationshowed that the reaction of the -hydroxy-,-acetylenicester bearing a tertiary propargylic group resulted in a re-versal of the regioselectivity compared to that observed inthe palladium-catalyzed process. Moreover, in contrastwith the results obtained in the palladium-catalyzed alkyl-ative lactonization of 19 with organoboronic acids, thebulkiness of groups near the triple bond did not affect theregioselectivity of the rhodium-catalyzed reaction whichwas directed by the ester group.77,85 According to the re-sults observed with the model system, the use of[RhOH(cod)]2/dppb as the catalytic system accomplishedthe formation of the target 4-substituted 2(5H)-furanonesin good yield with excellent regioselectivity. Multiple ad-dition derivatives were detected as by-products. The best

selectivity was observed with the use ofRh(acac)(C2H4)2/dppf. As far as organoboron derivativesare concerned, the process was tolerant of aryl- and het-eroarylboronic acids, their corresponding pinacol esters,and aryl and vinyl trifluoroborate salts. The latter deriva-tives have emerged as promising compounds that canovercome certain limitations of other organoboron deriv-atives.103 According to the literature,104 the yield of 4-aryl-or 4-heteroaryl-2(5H)-furanones starting from pinacol es-ters derivatives was lower than that observed starting fromboronic acids.

4.4 Copper-Catalyzed Hydroarylation–Hetero-cyclization Processes

The copper-catalyzed conjugate addition of arylboronatesto alkynoates proceeded in methanol under mild condi-tions to yield trisubstituted cinnamates with precise synselectivity (Scheme 84).105

Scheme 84

A variety of copper salts were examined but none of themwere superior to the acetates. Copper(I) chloride and cop-per(I) bromide gave the desired products in comparableyields, although their reactions were only complete afterprolonged reaction time. In contrast, copper(I) iodide,copper(II) chloride and copper(II) bromide exhibitedbarely any catalytic activity. Electron-donating ligandssuch as 2,2′-bipyridine (bipy) and the N-heterocyclic car-benes 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-yli-dene (IPr) and 1,3-dimesitylimidazol-2-ylidene (IMes)did not show any positive effect. The protocol was, how-ever, compatible with phenylboronic acids bearing car-bon–halogen bonds as well as carbonyl functional groups.To obtain further insight into the reaction mechanism, thereaction was carried out in methanol-d1. As a result,mono-deuterated product was obtained, indicating that themethanolic hydroxy group behaved as a proton donor. In-sufficient deuteration might be attributed to the hydro-gen–deuterium exchange between methanol-d1 andphenylboronic acid or direct proton transfer from phenyl-boronic acid to an alkenylcopper intermediate (Scheme85).105

Scheme 83

BO

BO

B

O

Ph

PhPh

+ +

OPh

OO

O

O

66a

HO

O

19b

O

Ph

O

O

O

56h 65a

+

OEt OO

Ph[Rh(cod)OH]2

(3 mol%)ligand

1,4-dioxane–H2O

(10:1)

O

n-C5H11

O

OMe

Ph-B(OH)2 (1.5 equiv)

CuOAc (1 mol%)

MeOH (0.5 M), 28 °C, 6 h n-C5H11

Ph

O

MeO

(95%)

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Scheme 85

Scheme 86 outlines a plausible mechanism of the copper-catalyzed conjugate addition of arylboronic acids to al-kynoates.105 Transmetallation from the arylboronic acidsto copper methoxide (or acetate) proceeds via a four-centered transition state to yield reactive arylcopper spe-cies. Subsequent carbocupration of the alkynoates pro-duces vinylcopper intermediates, which then undergoprotonolysis106 by methanol to yield the final cinnamateswith concomitant restoration of copper methoxide. Be-cause the protocol employs methanol as a solvent, thevinylcopper intermediates undergo facile protonolysis be-fore isomerization, resulting in the stereoselective forma-tion of the syn-hydroarylation products even at ambienttemperature. In previous cuprate-based methods, a low re-action temperature was required to prevent the isomeriza-tion of the initially formed syn-carbocupration adducts toanti-isomers via allenolate intermediates.107

Scheme 86

The efficient copper-catalyzed addition reaction of bis(pi-nacolato)diboron to α,β-acetylenic esters has been alsodeveloped to give corresponding β-borylated α,β-ethyl-enic esters in high yields under mild reaction condi-tions.108 On the basis of the success of above studies, itwas envisaged that applying the carbocupration procedureto alkynoate substrates with a hydroxy terminus should al-low an easy approach to unsaturated lactones via concom-itant cyclization between the hydroxy group and the estercarbonyl. The copper-catalyzed hydroarylation of methyl4-hydroxybut-2-ynoate with phenylboronic acid gave 3-phenylbutenolide in 61% yield. When the reaction wascarried out using the phenyl-substituted butynoate deriva-

tive, the corresponding 4,5-diphenylbutenolide was ob-tained in similar yield (Scheme 87).105

Scheme 87

Moreover, as an extension of this sequential hydroaryla-tion and lactonization process, a synthetic approach wasdeveloped for 4-arylcoumarins, which constitute a sub-group of flavonoids.109 When the building block 72 wasfirst subjected to hydroarylation conditions, 4-phenylcou-marin (73a) was obtained in 54% yield; however, unex-pectedly, 4-methoxycoumarin (74) was also formed in37% yield (Scheme 88).109

Scheme 88

It was reasonable to assume that the ortho hydroxy groupplayed a key role in facilitating the addition of methanol.In fact, the methoxymethyl-protected derivative under-went smooth hydroarylation within six hours under thesame conditions, and upon treatment with 6 M hydrochlo-ric acid in refluxing methanol in the same pot, the desiredcoumarin 73a was formed in 89% yield as the exclusiveproduct (Scheme 89).109

Scheme 89

The scope of the method in terms of arylboronic acidswas checked. Neither electron-donating nor electron-withdrawing groups had a deleterious effect on the forma-tion of coumarins 73 (Figure 8).109

More importantly, the protocol was applied to arylboronicacids having a labile functional group, efficiently afford-ing the corresponding coumarins 73g,h without the loss ofthe reactive carbon–iodine bond or the formyl group.These functional groups are useful synthetic handles forfurther derivatizations (Scheme 90).109

n-C5H11

O

OMe

PhB(OH)2 (1.5 equiv)

CuOAc (1 mol%)

CH3OD (0.5 M), 28 °C, 24 h n-C5H11

Ph

O

MeO

(74%, 86% D)

D

LnCuOMe

(LnCuOAc)

ArB(OH)2

RO

LnCu Ar

B(OH)2

ROB(OH)2LnCuAr

R1

O

OR2

CuLn

R1 O

R2O

Ar

R1

CuLnAr

O

R2O

MeOH

R1

HAr

O

R2O

CO2Me

RPhB(OH)2 (3 equiv)CuOAc (2 mol%)

MeOH, 28 °C OO

Ph

R

R = H, 2 h (61%)

R = Ph, 24 h (59%)

HO

OH

O

OMe

72

PhB(OH)2 (3 equiv)

CuOAc (2 mol%)

MeOH (0.5 M), 28 °C

12 h

O O

Ph

O O

OMe

+

73a (54%) 74 (37%)

OMOM

O

OMe 1. PhB(OH)2 (3 equiv)

CuOAc (2 mol%)

MeOH (0.5 M), 28 °C

O O

Ph

73a (89 %)

2. 6 M HCl, 3 h

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Scheme 90

The application of the method to the synthesis of naturalproducts isolated from the Dalbergia plant family high-lights its utility (Figure 9).109 The plants in this familyhave been known to possess unique medicinal properties.

In order to examine the effect of the tether length betweenthe alkyne and hydroxy moieties, the copper-catalyzedhydroarylation of methyl 5-hydroxypent-2-ynoate (75)was carried out. In contrast to the result obtained from 3-(2-hydroxyethyl)propiolate, only the 4-phenylpentenolide76a was isolated; the corresponding 4-methoxypenteno-lide was not formed from 75 (Scheme 91).110

Scheme 91

Very likely, the product selectivity depends on the dis-tance of the hydroxy group from the carbomethoxy moi-ety. Nevertheless, the use of the tert-butyldimethylsilyl(TBS) as protecting group increased the overall yield ofproducts 76 (Scheme 92).110

Figure 8

O O

73b (90%)

O O O O O O

OMe

O

Cl

O O

I

O O

CHO

O O

NO2

O O

73c (93%) 73d (89%) 73e (89%) 73f (88%)

73g (89%) 73h (87%) 73i (87%) 73j (85%)

O O

R

(73h: R = CHO)

NH

CuI (5 mol%)

dmeda (20 mol%)

K3PO4, toluene

140 °C, 24 h

O O

N

(98%)

O O

(58%)

N

C5H11

Bz

73

(73g: R = I)

Figure 9

MOMO OMOM

O

OMe

MeO OMOM

O

OMe

MeO OMOM

O

OMe

MOMO

MeO

B(OH)2

OTBS

OMe

B(OH)2

H

OTBS

B(OH)2

OO

O O

OO

MeO

MeO

(78%)

O OMeO

(98%)

HO

OH

O OHO

OMe

OH(93%)

OH

O

PhB(OH)2 (3 equiv)CuOAc (2 mol%)

MeOH, 28 °C, 2 h O

Ph

O

75 76a (55%)

OMe

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Scheme 92

4.5 Transition-Metal-Catalyzed Hydrovinyl-ation–Heterocyclization Processes

Vinyl halides reacted with disubstituted acetylenes in thepresence of the palladium–formate reducing system togive stereoselective formation of functionalized 1,2,4-tri-substituted 1,3-dienes in good to high yields.111 The na-ture of the base and the temperature affected theregiochemical outcome of the reaction. A high degree ofregioselectivity was observed in the hydrovinylation ofsteroidal γ-hydroxy-α,β-ynoates. In these cases, sequen-tial hydrovinylation and heteroannulation occurred togive the corresponding 3-alkenyl spirobutenolides 77a,bin good yields (Scheme 93).

Based on the concept of sequential hydrovinylation andcyclization of γ-hydroxy-α,β-acetylenic ester 19, a gener-al regioselective synthesis of 3-vinylfuran-2(5H)-ones 77from vinyl triflates was also explored.112 The reactionswere carried out in N,N-dimethylformamide at 40 °C us-ing the following molar ratios: vinyltriflate–19–potassiumformate–palladium(II) acetate = 1:1.2:2:0.05. The omis-sion of the phosphine ligands was the key to directing theoutcome of the reaction towards the desired hydrovinyl-ation product by hampering the competitive palladium-catalyzed reduction of triflates to the corresponding al-kenes (Scheme 94).

The regioisomeric 4-vinylfuran-2(5H)-ones 78 can bereadily accessed from vinyl organoboron derivatives andalkyl 4-hydroxy-2-alkynoates by means of sequentialrhodium-catalyzed stereo- and regioselective addition andlactonization reactions. The formation of the derivative

78a occurred by reaction of ynoate 19a with an excess (5equiv) of the potassium β-styryltrifluoroborate in the pres-ence of the catalytic system Rh(acac)(C2H4) (0.03equiv)/dppf (0.06 equiv) in 1,4-dioxane–water (10:1) at100 °C for two hours (Scheme 95).98

OTBS

1. CuOAc (2 mol%)

MeOH, 28 °C

O

O

76a–d

2. HCl (6 M), r.t., 1 h

R

B(OH)2

+

76a R = H (86%); 76b R = Me (88%); 76c R = OMe (86%); 76d R = Cl (78%)

O

OMe

R

Scheme 93

MeO

OH

O

OEt

MeO

O

On-Bu

O

OH

O

OEt

O

O

OPh

PhBr

n-Bu3N, DMF, 60 °C

77a (72%)

77b (80%)

n-BuI

Pd(OAc)2, o-Tol3P

n-Bu3N, DMF, 60 °C

Pd(OAc)2, o-Tol3P

Scheme 94

R2R1

HO

O

OR3 OO

R1

R2Pd(OAc)2, HCO2K

DMF, 40 °C

OTf

77

OO

Ph

OO

t-Bu

OO

OO

OO

O

EtO

O

O

H3CO

O

OO

77c (74%) 77d (80%) 77e (68%) 77f (71%)

77g (82%) 77h (70%) 77i (91%)

19

+

Scheme 95

19a

O

O

Ph

HO O

OMe

+

Ph

BF3K

1,4-dioxane–H2O

100 °C, 2 h

Rh(acac)(C2H4)2

dppf

78a (79%)

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The rhodium-catalyzed process was also applied to the re-gioselective preparation of 4-vinylquinolines, such as thatshown in Scheme 96.97

4.6 Transition-Metal-Catalyzed Hydroalkynyl-ation–Heterocyclization Processes

While the Michael reaction of stabilized carbon nucleo-philes constitutes one of the fundamental carbon–carbonbond-forming processes, it does not generally extend tothe acetylide anion. Effecting such additions by use of atransition-metal catalyst may have the advantage of (a)extending the reaction to acceptors that may not otherwiseparticipate, (b) controlling stereochemistry (geometry)where applicable, (c) promoting further useful transfor-mations of the initial adducts, and (d) enhancing syntheticefficiency by not requiring stoichiometric amounts of re-agents like bases or metals. Trost reported that the addi-tion of terminal alkynes to γ-hydroxy ynoates may bereadily directed to form either furans 79 in two tandempalladium-catalyzed reactions or butenolides 80 in apalladium-and-tin co-catalyzed event (Scheme 97).113

Scheme 97

Addition of one equivalent each of the alkyne and the al-kynoate to 2 mol% tris(2,6-dimethoxyphenyl)phosphine

(TDMPP) and 5 mol% palladium(II) acetate in benzene atroom temperature followed by 0.75–1.5 equivalents of1,8-diazabicyclo[5.4.0]undec-7-ene gave furan 79a in87% yield after direct column chromatography of the re-action mixture (Scheme 98).113

Scheme 98

The effect of the ratio of the rather basic tris(2,6-dimeth-oxyphenyl)phosphine relative to palladium acetate in pro-moting furan formation was investigated. Increasing theamount of palladium acetate relative to the ligand dramat-ically improved the extent of furan formation. Thus, theuse of a 1:2, or preferably 2:5, ratio of tris(2,6-dimethoxy-phenyl)phosphine to palladium(II) acetate effected com-plete addition and cyclization to the isofuran derivative.The subsequent tautomerization reaches completion uponaddition of 1,8-diazabicyclo[5.4.0]undec-7-ene at thispoint (Scheme 99).113

Since uncomplexed palladium acetate enhances furan for-mation, it was thought that the addition of a base like tri-ethylamine may reduce the Lewis acidity of palladiumacetate as well as serve as a general base catalyst for lac-tonization. Indeed, furan formation was completely sup-pressed and butenolide 80a was isolated in 81% yield byusing a 1:1 mixture of tetrahydrofuran and triethylamineas solvent (Scheme 100).113

Scheme 100

Scheme 96

+

Ph

BF3K

1,4-dioxane–H2O

100 °C, 7 h

Rh(acac)(C2H4)2

dppf

NH2

O

t-Bu N

t-Bu

Ph

(60%)

HO O

OEt

R

Pd(OAc)2

P

MeO

MeO

TDMPP

TDMPP =

R

path B

path A

O

OEt

OR

O

OEt

OR

O

OEt

77

78 79

80

OH

path B3

O

O

R

HO O

OEt

Ph

Pd(OAc)2

TDMPPOPh

O

OEt

79a (87%)

Scheme 99

OR

O

OEtR

O

OEt OR

O

OEtPd

AcO OAcAcOPd

– [Pd(OAc)2]

79

OH – AcOH OR

O

OEt

HO

O

OEt+

Pd(OAc)2

TDMPP

THF, Et3N

OH

O

OHO

80a (81%)

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A much more effective approach involved the addition ofa catalytic amount (10–40 mol%) of tri-n-butyltin acetateas a transesterification catalyst. The addition of 20 mol%of tri-n-butyltin acetate to 3 mol% palladium(II) acetateand 3 mol% tris(2,6-dimethoxyphenyl)phosphine in tetra-hydrofuran, followed by 1 equivalent each of hydroxyynoate and terminal alkyne, led, after 16 hours at roomtemperature, to the formation of the butenolide derivative,which was isolated after direct column chromatography ofthe reaction mixture. The utility of this protocol was ex-amined in the synthesis of the natural product cleviolide(81b) which, by virtue of the sensitivity of the polyunsat-uration within a small molecular framework, demandsvery mild methods. Interestingly, a 92% yield of a 14:1 ra-tio of cleviolide (81b) to isocleviolide (81c), from whichpure cleviolide can be crystallized, was isolated by react-ing an excess of a 4:1 ratio of the conjugated and uncon-jugated enynes with ethyl 4-hydroxybutynoate (Scheme101).113

Strategies based upon the 6-endo-dig cyclization of inter-mediate adducts 83 derived by palladium-catalyzed addi-tion of terminal alkynes onto ynoates 82 have beenexplored with the aim of accessing the synthesis of bryo-statins and other natural products showing promising an-titumor activity (Scheme 102).114

Scheme 102

Two potential competing processes to the 6-endo-dig cy-clization were immediately evident: a lactonization to δ-

pentanolactone 85 (Scheme 103, path B) or a 5-exo-digcyclization to diene 86 (Scheme 103, path A).114

Scheme 103

The reaction of hept-1-yne and methyl 5-hydroxypent-2-ynoate (82a) catalyzed by palladium acetate with tris(2,6-dimethoxyphenyl)phosphine as ligand gave the dihydro-pyran 84a in satisfactory yield as the only detectable prod-uct (Scheme 104). Following the reaction by thin-layerchromatography revealed that formation of the simple ad-duct 83a occurred completely within 24 hours, but cycli-zation proceeded very slowly. Increasing the reactiontemperature to 50 °C when the formation of adduct 83awas complete, or simply running the reaction at 50 °Cfrom the beginning, led to a significant reduction in reac-tion time with about the same yield but gave rise to com-petitive formation of lactone 85a. A workable solutionwas found by increasing the catalyst loading whereby a61% isolated yield of dihydropyran 84a was isolated asthe only product.

The trans-hydroxyalkynoate 82b, on the other hand, gavethe expected adduct within two days (50% isolated yield).Use of more forcing conditions gave no dihydropyran butonly lactone 85b, which was isolated in 58% overall yield(Scheme 105).114

Based on the previously observed dramatic rate enhance-ment in the formation of π-allylpalladium complexes fromless nucleophilic alkenes upon using palladium trifluoro-acetate, a one-pot protocol was used to achieve the rapid

Scheme 101

HO O

OEt

O

O+O

O+

81b 81cratio = 14:1

(overall 92%)

ratio = 4:1Pd(OAc)2 (3 mol%)

TDMPP (3 mol%)

(n-Bu)3SnOAc (20 mol%)

OH

R1

O

OEt

R2

[Pd]

O OEt

R1

R2

OOH

R2

R1

82 83 84

O

EtO

O OEt

R2

R1

OH

83

O

O

85

R1

R2

O

R2

R1

86

O

OEt

A

B

path Apath B

Scheme 104

OH

O

OEt

O OEt

OH

C5H11

O

82a 83a

C5H11

Pd(OAc)2 (10 mol%)

TDMPP (4 mol%)

benzene, r.t., 2.5 d O

O

85a84a (61%)

C5H11

C5H11

O

EtO+

Dow

nloa

ded

by: U

nive

rsity

of S

outh

ern

Cal

iforn

ia. C

opyr

ight

ed m

ater

ial.



conversion of the two alkyne 82c,d directly into the dihy-dropyran. A 1:1 mixture of palladium acetate and tris(2,6-dimethoxyphenyl)phosphine (TDMPP) for the initial ad-dition (stage one) followed by addition of palladium tri-fluoroacetate for the cyclization (stage two) were used.The effectiveness of this protocol was highlighted by thesuccessful synthesis of the dihydropyrans 83c,d (Scheme106).114 Placing a conjugating substituent like phenyl onthe terminal alkyne allows the 5-exo-dig cyclization tocompete with the 6-endo-dig product.

The two-stage one-pot catalytic system employing thecombination of palladium acetate and palladium trifluoro-acetate allowed the reaction to be extended to the forma-tion of seven-membered rings, a cyclization that failscompletely in the absence of the palladium trifluoroace-tate (Scheme 107).

The addition of a terminal aromatic alkyne to a suitablyactivated propargyl amine 86 resulted in ynenoates 87(77–97% isolated yield), the isomerization of which via a

5-endo-dig cyclization and tautomerization then providedpyrroles 89 (Scheme 108). 115

Initial investigations employing phenyl acetylene as thedonor alkyne with toluene as the solvent revealed thatproduct distributions depend on the ratio of palladium(II)acetate to the tris(2,6-dimethoxyphenyl)phosphine ligand.Accordingly, an equimolar amount of ligand and metalcleanly afforded ynenoate 87a as a single geometrical iso-mer, whereas decreasing the amount of the ligand resultedin competitive formation of isopyrrole 88a (Scheme 109).

Scheme 109

Importantly, pyrrole formation was not observed underthe reaction conditions, and increasing either the reactiontime or temperature resulted in complex mixtures andpoor mass recovery. While both free and phosphine-ligat-ed palladium(II) acetate were ineffective at promotingisomerization to the pyrrole product, palladium trifluoro-acetate resulted in clean formation of pyrrole 89b fromynenoate 87b. In this case, neither acetonitrile nor benzo-nitrile complexes of palladium(II) chloride were as effec-tive as palladium trifluoroacetate, which promoted thedesired cyclization and tautomerization in near quantita-tive yield. Once again, tris(2,6-dimethoxyphenyl)phos-phine was found to inhibit both of these transformations,suggesting that a nonphosphine-ligated palladium speciesis responsible for catalysis (Scheme 110).115

Thus, treatment of 86 with a variety of aromatic alkynesin the presence of palladium(II) acetate (0.75 mol%) andtris(2,6-dimethoxyphenyl)phosphine (0.75 mol%) in tolu-ene at room temperature afforded the correspondingynenoate 87 in 77–97% isolated yields after six hours(Scheme 111, conditions A).115 Non-aromatic donor al-kynes generally required slightly longer reaction times(12–24 h), and provided ynenoates 87 in 64–97% isolated

Scheme 105

O

OEt

H

OHH

C5H11

Pd(OAc)2 (10 mol%)

TDMPP (4 mol%)

benzene, r.t., 60 h

82b

H

OHH

83b (62%)

C5H11

OEt

O

H

HO

C5H11

D

85b (58%)

O

Scheme 106

OH

O

OEt

O

RO

1. Pd(OAc)2, TDMPP

2. Pd(TFA)2

OR

82c: R = TBDMS

82d: R = PMB83c (55%)

83d (61%)

+

EtO

O

Scheme 107

2. Pd(TFA)2O

C5H11O

C5H11

(56%)

OH

OEt

+

1. Pd(OAc)2 (10 mol%) TDMPP (4 mol%)

O

EtO

Scheme 108

HN

Boc

O

OMe R

[Pd]

MeO2C H

NHBoc

RN

R

MeO2C

H

Boc

N

Boc

R

86 87 88 89

MeO2C

HN

Boc

O

OMe

PhMeO2C H

NHBoc

PhN

Ph

MeO2C

H

Boc

86 87a 88a

+

Pd(OAc)2/TDMPP

toluene, 18 h, r.t.

Entry

1

2

3

Pd(OAc)2(mol%)

TDMPP(mol%)

Ratio 87a/88a

Conversion(%)

3.0

3.0

3.0

3.0

1.5

0.8

20:1

3:2

1:5

100

100

100

Dow

nloa

ded

by: U

nive

rsity

of S

outh

ern

Cal

iforn

ia. C

opyr

ight

ed m

ater

ial.



yields. Alternatively, pyrroles 89 could be obtained inyields ranging from 60 to 99% in a two-stage, one-potprocess (Scheme 111, conditions B).115 For aromatic do-nors, addition of palladium trifluoroacetate (1.5 mol%),following complete conversion into the ynenoate, resultedin the cyclized and isomerized product after only sixhours. Once again, non-aromatic donors required slightlylonger reaction times and higher catalyst loadings [5mol% Pd(OTFA)2] but nevertheless returned good to ex-cellent yields of the desired products after 24 hours. Im-portantly, these reactions were performed in screw-capvials under an ambient atmosphere, with commercial-grade alkynes and benchtop solvents. Furthermore, theyields remained consistent upon scale-up. The methodwas tolerant of a wide range of substituted donor alkynes:ortho-, meta-, and para-substituted aromatic alkynes with

both electron-donating and electron-withdrawing groupsparticipated effectively. Given the involvement of palladi-um(II) species throughout both the coupling and the isom-erization steps, aryl bromides did not interfere with thereaction. The basic nitrogen of an unprotected aniline wasalso tolerated in the coupling portion of the cascade. In ad-dition to aromatic donors, aliphatic alkynes underwent ef-ficient coupling and isomerization. Importantly, both freeand acetylated propargyl alcohols reacted smoothly underthe standard conditions. Interestingly, the use of a 1,3-enyne as a donor provided an efficient synthesis of desir-able C-vinyl pyrroles.

Scheme 111

The use of palladium catalysis to effect the cyclization of87 offered additional avenues for substitution of the pyr-role nucleus. The ynenoate 87b was cyclized to isopyrrole88b in quantitative yield in the presence of palladium(II)acetate (3 mol%) in tetrahydrofuran. Gratifyingly, 88bunderwent addition to both Eschenmoser’s salt (90) anddiazene 91, affording products of carbon–carbon and car-bon–nitrogen bond formation, 92a and 92b, respectively.In addition, oxygenation affording the hydroxy derivative92c could be effected by simply stirring 88b overnight,open to the atmosphere and in the presence of silica gel(Scheme 112).115

Scheme 110

MeO2C H

NHBoc

Nn-Bu

MeO2C

H

Boc

87b 88b

Pd(II) (0.75 mol%)

toluene (1.0 M)r.t., 3 h

Entry

1

2

3

TDMPP(mol%)

Ratio88b/89b

Conversion(%)

– 1:20

1:20

100

95

n-BuN n-Bu

MeO2C

Boc

89b

Pd(II)

Pd(OTFA)2

Pd(OTFA)2 0.4

4

5

Pd(OTFA)2 0.8 1:2 72

PdCl2(MeCN)2 – 1:1 47

PdCl2(PhCN)2 – 1:20 52

+

HN

Boc

O

OMe

R

MeO2C H

H

NHBoc

RN

Boc

R

8687 89

conditions Bconditions A

R

MeO2C

Scheme 112

Nn-Bu

MeO2C

H

Boc

87b 88b

MeO2C H

NHBoc

Pd(OAc)2 (3 mol%)

THF (1.0 M), r.t., 3 hn-Bu

Nn-Bu

MeO2C

Boc

92

NMe

MeI–

90

Nn-Bu

MeO2C

Boc

N

92a (70% from 87b)

Me

MeNN

Troc

Troc 91

Nn-Bu

MeO2C

N

Boc

N

92b (70% from 87b)

Troc

H

Troc

1. air, SiO2

2. NaBH4

Nn-Bu

MeO2C

OH

Boc

92c (72% from 87b)

A B

A B

H

Nn-Bu

MeO2C

H

Boc

88b

+

Dow

nloa

ded

by: U

nive

rsity

of S

outh

ern

Cal

iforn

ia. C

opyr

ight

ed m

ater

ial.



The ability to intercept isopyrrole 88 provided an attrac-tive, atom-economical avenue for further derivatizationsof the pyrrole side chain. The palladium-catalyzed cycli-zation of 87b in the presence of acrolein and lithium bro-mide afforded 93a via a reductive Heck-type additionreaction. Alternatively, allylation in the 3-position was ef-fected with allyl chloride in the presence of bis(acetoni-trile)dichloropalladium(II) and propylene oxide as asuitable acid scavenger (Scheme 113).115

5 Conclusion

Research activities aimed to the use of valuable syntheticbuilding blocks for the development of increasingly effi-cient synthetic processes have demonstrated that additionreactions to α,β-ynones and α,β-ynoates containing prox-imate nucleophiles can be interfaced with subsequent cy-clizations to generate more complex functionalmolecules. The synthetic approaches to heterocyclic de-rivatives from these starting building blocks based on se-quential processes involving conjugate addition-type,pericyclic and transition-metal-catalyzed transfer hydro-genation, hyroarylation, hydrovinylation, or hy-droalkynylation reactions followed by annulation havebeen summarized. These methodologies benefit from theability to conduct multiple chemical transformations in asingle reaction vessel, providing their intended targetswhile minimizing waste associated with traditional isola-tion and purification protocols.

Acknowledgment

The authors are grateful for financial support from the Universitàdegli Studi dell’Aquila and Università degli Studi di Milano.

References

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Scheme 113

Nn-Bu

MeO2C

H

Boc

Pd(II)

Nn-Bu

MeO2C

Boc

93a (60% from 87b)

O

LiBr, Pd(OAc)2

Cl

O

PdCl2(MeCN)2 N n-Bu

MeO2C

Boc

93b (63% from 87b)

87b

MeO2C H

NHBoc

n-Bu

+

O

Dow

nloa

ded

by: U

nive

rsity

of S

outh

ern

Cal

iforn

ia. C

opyr

ight

ed m

ater

ial.



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sequential addition and cyclization processes of α,β-ynones and α,β-ynoates containing proximate...

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