1 Tetrahedron

Development and applications of highly selective palladium- catalyzed monocoupling reactions of (cyclo) and 1,3- alkadienes bearing two or three electrophilic sites and bis(enol triflates) with terminal

Renzo Rossi,* Fabio Bellina,* Marco Lessi, and Chiara Manzini

Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy

ARTICLE INFO ABSTRACT

Article history: This review with 572 references illustrates the development of highly selective Pd/Cu- Received catalyzed and Cu-free Pd-catalyzed monoalkynylation reactions of (cyclo)alkenes and 1,3- Received in revised form bearing two or three identical or different electrophilic sites and bis(enol Accepted triflates) with terminal alkynes, highlighting the use of these reactions as key steps of the Available online syntheses of core structures and models of enediyne antitumor antibiotics, pharmacologically active compounds, and bioactive natural substances including insect Keywords pheromone components, and fungal and plant metabolites. A focus has also been set on Chemoselectivity efficient and powerful strategies involving the formation of substituted derivatives Site selectivity by one-pot site-selective Pd-catalyzed consecutive alkynylation reactions of Stereoselectivity di(pseudo)halogenated olefinic substrates with two different terminal alkynes. Finally, Carbon–carbon bond-forming reactions where appropriate, the reasons for the observed stereo-, site- and/or chemoselectivitites of Transition metal catalyst the illustrated monoalkynylation reactions have been mentioned and discussed.

Contents

1. Introduction ......

2. Monoalkynylation reactions of 1,2-di- and polyhalogenated ethenes and dihalogenated 1,3-

2.1. Monoalkynylation reactions of (E)- and (Z)-1,2-dichloroethene

2.2. Monoalkynylation reactions of stereodefined and (E)/(Z)-1,2-dibromo-1-alkenes and (E,E)-1,4-diiodo-1,3-

2.3. Monoalkynynation reactions of stereodefined 1-bromo-2-chloro-, 1-bromo-2-iodo-, 1-bromo-2- trifluoromethanesulfonyloxy-, 1-chloro-2-iodo-, and 1-fluoro-2-iodo-1-alkenes, and (1Z,3E)-1-chloro-3-iodo-1,3- butadiene

2 Tetrahedron

2.4 Monoalkynylation reactions of trihalogenated ethene derivatives bearing two different halogen atoms

3. Monoalkynylation reactions of 1,1-dihalogenated 1-alkenes

3.1. Monoalkynylation reactions of 1,1-dichloro-1-alkenes

3.2. Monoalkynylation reactions of 1,1-dibromo-1-alkenes

3.3. Monoalkynylation reactions of 1,1-dihalogenated 1-alkenes bearing different halogen atoms

4. Monoalkynylation reactions of stereodefined bis(enol triflates)

5. Conclusions

References and notes

Biographical sketch

Abbreviations: Ac, acetyl; Ar, aryl; Bn, benzyl; Boc, tert-butoxycarbonyl; n-Bu, n-butyl; t-Bu, tert-butyl; Cp, cyclopentadienyl; DABCO, 1,4-diazabicyclo[2.2.2]octane; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD, diethyl azodicarboxylate; DIBALH, diisobutylaluminum hydride; DMA, N,N-dimetylacetamide; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DME, dimethoxyethane; dppf, 1,1’-bis(diphenylphosphino)ferrocene; dppp, 1,3- bis(diphenylphosphino)propane; EDCI, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; Et, ethyl; Fm, 9- fluorenemethyl; HMPA, hexamethylphosphoramide; LDA, lithium diisopropylamide; LiHMDS, lithium bis(trimethylsilyl)amide; Me, methyl; MOM, methoxymethyl; NIS, N-iodosuccinimide; NBS, N-bromosuccinimide; o-NBS, ortho-nitrobenzenesulfonyl; Piv, pivaloyl; Ph, phenyl; i-Pr, iso-propyl; n-Pr, n-propyl; Red-Al, sodium bis(2- methoxyethoxy)aluminum hydride; rt, room temperature; TBAs, tetrabutylammonium hydrogen sulfate; TBDMS, tert- butyldimethylsilyl; TES, triethylsilyl; Tf, trifluoromethylsulfonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; THP, tetrahydropyranyl; TIPS, triisopropylsilyl; p-Tol, p-tolyl; Ts, p-toluenesulfonyl; Xantphos, 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene; Z(2-Cl), N-(2-chlorobenzyloxycarbonyloxy).

∗ Tel.: +39 050 2219282; fax: +39 050 2219260; e-mail: [email protected]; [email protected]

1. Introduction and Hagihara3a demonstrated that the cross-coupling of 1- alkynes with iodoarenes, bromoalkenes or bromopyridines Among the myriad of transition metal-catalyzed reactions, could be performed at room temperature in Et2NH in the 2 the Pd-catalyzed C(sp )–C(sp) bond-forming reactions presence of catalytic amounts of PdCl2(PPh3)2 and CuI from terminal alkynes and aryl and alkenyl halides or (Scheme 1). pseudohalides have emerged as a highly fascinating methodology of primary importance in synthetic organic PdCl2(PPh3)2 (5-10 mol%) CuI (10-20 mol%) chemistry. In fact, these cross-coupling reactions provide R1-X + H R2 R1 R2 Et NH, rt, 3-6 h an effective route for preparing arylacetylenes and 2 conjugated enynes which are precursors for natural (R1 = aryl, (cyclo)alkenyl, heteroaryl; R2 = alkyl, aryl; X = Br, I) compounds, pharmaceuticals, agrochemicals, and materials Scheme 1. Sonogashira reaction. with specialized electronic and optical properties.1 This protocol,3a in which CuI is thought to accelerate the These direct alkynylation reactions were introduced in 1 1975 by Cassar2a who reported the synthesis of aryl- and transfer of a 1-alkynyl group to an R -Pd-X⋅Ln complex through an alkynylcopper species,3b–d has become known as alkenyl-substituted acetylene derivatives by Pd(PPh3)4- 4 catalyzed reaction of aryl and alkenyl halides with 1- the Sonogashira reaction and has found wide application, alkynes in DMF at 50 °C in the presence of MeONa as especially in the preparation of intermediates for natural base. Simultaneously and independently, Dieck and Heck2b products, bioactive molecules and materials. showed that 1-alkynes are converted into 1,2-disubstituted There is still great interest in this reaction, due to its by treatment with aryl, heteroaryl and alkenyl technical simplicity, high yields, ability to tolerate a wide bromides and iodides at 100 °C in the presence of Et N or 3 variety of functional groups, and the fact that it does not piperidine as base and a catalytic amount of involve the use of preformed and expensive organometallic Pd(OAc) (PPh ) . A few months later Sonogashira, Tohda 2 3 2 reagents, as demonstrated by the impressive number of

3 Tetrahedron studies on the development of catalyst systems more of di(pseudo)halogenated olefinic substrates with two efficient and reactive than that formed by combining different terminal alkynes. Where appropriate, the reasons 5 PdCl2(PPh3)2 and CuI and by the efforts devoted to for the observed stereo-, site- and/or chemoselectivities of develop modifications to the original protocol. These the reported Sonogashira-type monoalkynylation reactions modifications include: (i) reactions carried out under phase- have been mentioned and discussed. transfer conditions;6 (ii) copper-free Pd-catalyzed couplings under conditions different from those of the Cassar-Heck For the sake of clarity, the scientific literature concerning alkynylations;7 (iii) copper- and amine-free Pd-catalyzed the topics covered in this review has been subdivided into alkynylation reactions;8 (iv) copper- and ligand-free Pd- three sections (interposed between the introduction and catalyzed alkynylations;9 (v) copper- and solvent-free conclusions): (i) monoalkynylation reactions of 1,2- Sonogashira couplings;10 (vi) copper-, amine-, and solvent- dihalogenated ethenes bearing identical or different halogen free Pd-catalyzed couplings;11 (vii) copper-catalyzed Pd- atoms; (ii) monoalkynylation reactions of 1,1- free Castro-Stephens-type reactions,12 and (viii) reactions dihalogenated-1-alkenes bearing identical or different carried out using Pd catalysts immobilized on various halogen atoms; and (iii) monoalkynylation reactions of support materials.13 stereodefined bis(enol triflates). In each of these sections, significant applications of the monoalkynylation reactions However, despite the great attention paid to this process have been reported and discussed. and its applications, as demonstrated by the fact that 5340 references can be found in the SciFinder data base for the 2. Monoalkynylation reactions of 1,2-di- and topic “Sonogashira” for the period 1975–September 2012, polyhalogenated ethenes and dihalogenated 1,3-dienes no comprehensive review summarizing and discussing the updated literature data on selective Sonogashira-type Among the various strategies that have been designed and 2 monocoupling reactions of substrates with two or more employed to form stereoselectively C(sp)–C(sp ) bonds of identical or different electrophilic sites on their sp2- stereodefined conjugated enynes, dienynes and enediynes hybridized carbon atoms has been published to date. The via Pd-catalyzed monoalkynylation reactions of 14 motivation for writing this review with 572 references, stereodefined 1,2-dihalogeno-1-alkenes, the Sonogashira which covers the literature up to the end of September protocol and its modifications are undoubtedly the most 2012, is to fill a part of this gap by illustrating highly useful and extensively used. selective Pd/Cu-catalyzed and Cu-free Pd-catalyzed monoalkynylation reactions of (cyclo)alkenes and 1,3- This section, which has been divided into four subsections, butadienes bearing two or three identical or different concerns Sonogashira-type monoalkynylation reactions of electrophilic sites and bis(enol triflates) with terminal 1,2-dihalogenated ethenes and dihalogenated conjugated alkynes. However, Pd-catalyzed selective monocoupling dienes. The first of these subsections has been devoted to reactions of 1-alkynes with (hetero)aryl halides or reviewing and commenting on the Sonogashira-type pseudohalides with two identical or different electrophilic reactions of (Z)- and (E)-1,2-dichloroethene, the second sites will not be covered. Moreover, Pd-catalyzed subsection discusses Sonogashira-type reactions of monocoupling reactions of 1-alkynes with non-conjugated stereoisomeric mixtures of 1,2-dibromoethenes and (E)-1,4- systems bearing an electrophilic site on each carbon- diiodo-1,3-butadienes, the third subsection concerns carbon double bond have also been considered to be monoalkynylation reactions of stereodefined 1-bromo-2- beyond the scope of this review. chloro-, 1-bromo-2-iodo-, 1-bromo-2- trifluoromethanesulfonyloxy-, 1-chloro-2-iodo-, and 1- In addition to describing and commenting on the fluoro-2-iodo-1-alkenes, and (1Z,3E)-1-chloro-3-iodo-1,3- aforementioned monoalkynylation reactions of butadienes, and the fourth subsection summarizes the (cyclo)alkenes and 1,3-dienes with two or three identical or monoalkynylation reactions of trihalogenated ethene different electrophilic sites and bis(enol triflates), emphasis derivatives bearing two different halogen atoms. Synthetic has been placed on the use of Pd-catalyzed applications of the cross-coupling products, which were monoalkynylations of (cyclo)alkenes and 1,3-butadienes obtained from the Pd-catalyzed reactions described in the bearing two or three identical or different electrophilic sites above-mentioned subsections, have also been reported. and bis(enol triflates) as key steps of the syntheses of core structures and models of enediyne antitumor antibiotics, 2.1 Monolkynylation reactions of (E)- and (Z)-1,2- pharmacologically active compounds, and bioactive dichloroethene naturally occurring compounds including insect sex pheromone components, and fungal and plant metabolites. In 1981, Ratovelomanana and Linstrumelle reported that Moreover, the review has been focused on the formation of the reaction of 1-alkynes with 5 equiv of (Z)-1,2- disubstituted acetylenic derivatives by one-pot site- dichloroethene (1) in at room temperature for 5 h selective Pd-catalyzed consecutive alkynylation reactions in the presence of 5 mol% Pd(PPh3)4, 5 mol% CuI and 1.5

4 Tetrahedron

equiv of n-BuNH2 provided stereospecifically (Z)-1-chloro- mol% PdCl2(PhCN)2, 10 mol% CuI and 20 equiv of 1-en-3-ynes 2a-d in high yields (Scheme 2).15 They also piperidine, i.e. using a protocol that allows the synthesis of found that the reaction of (E)-1,2-dichloroethene (3) with conjugated enynes in high yields from vinyl chlorides and 1-alkynes under experimental conditions very similar to 1-alkynes.18 those used to prepare compounds 2 gave stereospecifically and in high yields (E)-1-chloro-1-en-3-ynes 4a-d (Scheme 2).15 OH COOMe (1) (5 equiv) Cl (3) (5 equiv) Cl Cl Cl R1 H 3 Pd(PPh3)4 (5 mol%) Pd(PPh3)4 (5 mol%) HO OH CuI (5 mol %), PhH, CuI (5 mol %), PhH, 8 n-BuNH2 (1.5 equiv), rt, 5 h n-BuNH2 (1.5 equiv), rt, 5 h

OH OH C H COOMe 5 11 + I OH H 9

R1 Cl Cl 2 R1 OH 4 Cl Compound Yield C5H11 + R1 2 or 4 (%) OH H SiMe3 2a n-C5H11 95 10 4e 4a n-C5H11 98 2b CH2OTHP 95 4b CH2OTHP 95 2c CH2OAc 72 Scheme 4. Retrosynthesis of compound 8. 4c CH2OAc 65 2d CH2SMe 95 4d CH2SMe 100 Ratovelomanana and Linstrumelle also performed the synthesis of methyl ester 12 of (9Z,11E,13Z)-9,11,13- Scheme 2. Stereospecific synthesis of chloroenynes 2 and 4. octadecatrienoic acid (punicic acid), a polyunsaturated fatty acid isolated from the pomegranate,20 via a three-step However, more recently, the reaction between 2.2 equiv of reaction sequence (Scheme 5) in which the (E)-1-chloro-1- 3-(2-prop-2-ynyloxy)pyridine (5) with 1 equiv of 1 in ene-3-yne 4f, which was obtained in 98% yield by benzene at 40 °C, in the presence of 5.9 mol% Pd(PPh ) , 3 4 Pd(PPh3)4/CuI-catalyzed reaction of 3 with 1-, was a 21 12 mol% CuI and 5 equiv of n-BuNH2, was found to key intermediate. provide (Z)-3-(5-chloropent-4-en-2-ynyloxy)pyridine (6) in 16 Cl low yield. The main product of this Sonogashira-type Cl reaction was, in fact, the bisalkynylation derivative 7 3 (Scheme 3).16 H Pd(PPh3)4 / CuI (cat) n-BuNH2, PhH, rt (98%) O N

Cl H Cl Pd(PPh3)4 (5.9 mol %) 6 (12%) 4f O CuI (12 mol %) + + H Cl Cl n-BuNH (5 equiv), N 2 COOMe PhH, 40°C, 4 h O N 1 5 (2.2 equiv) Pd(PPh3)4 / CuI (cat) n-PrNH2, PhH, 10 h, rt (80%) O N

7 (51 %) COOMe 11 Scheme 3. Stereospecific synthesis of compounds 6 and 7. reduction with disiamyl borane In 1993, the Linstrumelle modification of the original protocol of the Sonogashira reaction was employed to COOMe prepare (E)-1-chloro-4-trimethylsilyl-1-en-3-yne (4e)17 in 12 82% yield, which was used as a building block in a Scheme 5. Synthesis of methyl ester 12 of punicic acid. stereocontrolled total synthesis of the methyl ester 8 of lipoxin LXB4.18 The convergent synthesis of this Compound 11, the direct precursor to 12, was synthesized metabolite of arachidonic acid, which was isolated by in 80% yield by Pd(PPh ) /CuI-catalyzed reaction of 4f Samuelson in 1984,19 was achieved on the basis of the 3 4 with methyl 9-decynoate, which was carried out according retrosynthetic analysis depicted in Scheme 4. The to a procedure previously employed for the alkynylation of homochiral diol 9 was prepared in 75% yield by the (E)-1-chloro-1-butene (13) with 9-decyn-1-yl acetate (14) reaction of 1- 10 with 4e in THF in the presence of 7 (Figure 1).21

5 Tetrahedron

H with methoxymethylacetylene. Compound 21 was then OAc Cl 8 used to prepare the stable bicycloenediyne 22 (Scheme 7) 13 14 possessing the core structure of esperamicin A1 (23), an antitumor enediyne antibiotic isolated from Actinomadura Figure 1. Structures of compounds 13 and 14. verrucosospora.28

Finally, reduction of the two triple bonds of 11 with OMe O Cl OMe H TBDMSO disiamylborane led to stereoisomerically pure 12 in 60% Pd(PPh3)4 (3 mol%) 21 overall yield. CuI (5 mol%) SiMe3 n-BuNH2, PhH, 25 °C, 4 h SiMe3 (71%) 2e 21 22 In 1985, an alkynylation sequence similar to that illustrated in Scheme 5 was employed for a three-step synthesis of HO Me O O S S macrolide 17 in 60.5% overall yield from (Z)-1,2- S Me O O Me dichloroethene (1), methyl 4-pentynoate (15) and 3-butyn- HO O O O O NH O O Me 23 O N H H 1-ol (16) (Figure 2). Me N O OH Me O O S O Me Me OH O O O HN Me Me 23 O Me H H esperamicin A1 O COOMe OH 15 16 17 Scheme 7. Synthesis of bicycloenediyne 22. Figure 2. Structures of compounds 15–17. Four years later, the Pd(PPh3)4/CuI-catalyzed reaction Three years later, (Z)-1-chloro-4-trimethylsilyl-1-buten-3- between 1.5 equiv of 2e and the highly crystalline alkyne yne (2e), which was prepared by coupling of 1 with 24 was used as a key step of the first enantioselective total trimethylsilylacetylene,15 was reacted with 1-alkyne 18 in synthesis of (-)-calicheamicinone (26), the naturally occurring antipode of the calicheamicin aglycone (Scheme the presence of n-BuNH2 and catalytic amounts of 8).29 Pd(PPh3)4 and CuI to give (Z)-1-trimethylsilyl-3-ene-1,5- diyne 19 in 59% yield (Scheme 6).24 O O Pd(PPh ) (10 mol%) O O N Cl 3 4 N CuI (20 mol%) O O O O Et3SiO + Et3SiO (18) n-BuNH2 (1.5 equiv) Me3Si H (1.0 equiv) OH Cl SiMe3 PhH, 0 °C, 2 h COOMe COOMe Pd(PPh3)4 (5 mol%) H (91%) Cl Cl H CuI (5 mol%) Pd(PPh3)4/CuI (cat) SiMe3 n-BuNH2 (1.5 equiv), PhH, rt SiMe3 n-BuNH2 24 2e (1.5 equiv) 25 1 (5 equiv) 2e 59% O HO O O NHCO Me O 2 O OH 20a: R1 = OH; R2 = H HO Scheme 6 R1 20b: R1 = H; R2 = OH MeSSS 26 R2

SiMe3 Scheme 8. Synthesis of enediyne 25, a precursor to compound 26. 19 As shown in Scheme 8, the alkynylation of 2e was carried Scheme 6. Synthesis of compound 19, a precursor to epimeric out at 0 °C in the presence of 1.5 equiv of n-BuNH to give carbinols 20a and 20b. 2 chemoselectively and stereospecifically enediyne 25 in 29 Compound 19 was then employed as a precursor to the 91% yield. epimeric carbinols 20a and 20b24 comprising a In 1994, the highly unstable model compounds 29 and 30 deoxyaglycone model for calicheamicins, a class of related to dynemicin A (31), an antitumor antibiotic isolated enediyne antibiotics derived from the bacterium 30,31 25 from Micromonospora chersina and M. globosa MG Micromonospora echinospora. 331-hF632 that is capable of cleaving double-stranded DNA Compound 2e and other (Z)-1-chloro-1-en-3-ynes 2, which in the presence of a reducing factor such as NADPH or glutathione, were synthesized using enediyne 28 as a were synthesized from (Z)-1,2-dichloroethene (1) (Scheme 33 2), were also used in the synthesis of simplified analogues precursor (Scheme 9). Compound 28 was of naturally occurring enediyne anticancer antibiotics and chemoselectively and stereospecifically synthesized in 63% intermediates of the core structure of natural enediynes.26 yield by Pd(PPh3)4/CuI-catalyzed cross coupling of 1- 27 alkyne 27 with 2e in at 25 °C in the presence of n- Thus, in 1989, Kadow and coworkers assembled enediyne 33 BuNH2 as base (Scheme 9). 21 by stereospecific Pd(PPh3)4/CuI-catalyzed reaction of 2e

6 Tetrahedron

Cl Pd(PPh3)4/CuI (cat) Scheme 11. Synthesis of enediyne 37, a precursor to aziridine 38. + N OTBDMS N OTBDMS n-BuNH2, PhMe, H COOEt SiMe3 25 °C, 8 h COOEt 27 2e (63%) 28 Compound 41, a further esperamicin core analog SiMe3 possessing an epoxide trigger similar to that found in dynemicin, was subsequently synthesized, as outlined in N 36 EtOOC (8% yield over Scheme 12, starting from acyclic (Z)-enediyne 40 which 4 steps) Me O was prepared in 81% yield by Pd(PPh3)4/CuI-catalyzed OH 37 29 OH O HN OH O reaction of the known 1-alkyne 39 with 2e followed by O deprotection of the tertiary alcohol. Surprisingly, compound Me 36 N OH O OH 41 proved to be relatively stable. 31 (9.6% over EtOOC dynemicin A 4 steps) Me Si H 3 OH 1) Pd(PPh3)4/CuI (cat) n-Bu N, THF, rt 30 Cl 3 + OH O 2) TBDMSOTf, 2,6-lutidine OTBDMS CH2Cl2, -78 °C to rt, then O O Scheme 9. Synthesis of enediyne 28, a precursor to compounds 29 SiMe3 35% aq TFA, CHCl3, rt 39 2e and 30. (81%) 40

HO In 1995, the dynemicin analogues 34 and 35 that lack the 10 steps nitrogen atom were synthesized from enediyne 33 which O OH was prepared in 62.9% overall yield by sequential Pd/Cu- catalyzed alkynylation of (Z)-1,2-dichlorethene with alkyne 41 H2N 32 and trimethylsilylacetylene (Scheme 10).34 Scheme 12. Synthesis of enediyne 40, a precursor to the OMe OMe esperamicin analogue 41. MeO MeO 1) 1, Pd(0)/Cu(I) (cat) (85% yield) SiMe3 2) Me3Si H O O Pd(0)/Cu(I) (cat) In 1997, (Z)-enediyne 43 was synthesized in 64% yield by Me (74% yield) Me OMe H OMe Pd2(dba)3/CuI-catalyzed coupling of alkyne 42 with a large 32 H OR 33 molar excess of chloroenyne 2e in benzene at 25 °C in the O 38 4 steps presence of n-BuNH2 and PPh3 (Scheme 13). MeO MeO H

34: R = SiMe3 (41% yield) + SiMe3 2e (4 equiv) 35: R = H (21% yield) O O Pd2(dba)3.•CHCl3 (2.5 mol%) PhO N CuI (10% mol) PhO N O O Me PPh3 (10% mol) Me Scheme 10. Synthesis of enediyne 33, a precursor to dynemycin n-BuNH (4 equiv), PhH O 2 O analogues 34 and 35. 25 °C, 1.5 h 42 (64%) 43

Again in 1995, (+)-(3S,4S,5S)-5-O-(t-butyldimethylsilyl)- 44a: R1 = Ph; R2 = H O 44b: R1 = Ph; R2 = Me 3,4-O-cyclohexylidene-1-carbomethoxy-5-[6- R1O S 1 2 2 O N 44c: R = Ph; R = SiMe3 O 44d: R1 = 4-ClC H ; R2 = H Me 6 4 (trimethylsilyl)-3-hexen-1,5-diynyl]-1-cyclohexene-3,4,5- 1 2 44e: R = Me; R = SiMe3 triol (37), which is a precursor to aziridine 38 possessing OR2 44f: R1 = Me; R2 = H the bicyclic core of the enediyne antibiotic esperamicin A1 (23), was prepared in 82% yield by Pd(PPh3)4/CuI- Scheme 13. Synthesis of enediyne 43, a precursor to the bioactive catalyzed reaction of chloroenyne 2e with 1-alkyne 36 in cyclic enediynes 44a-f. benzene at room temperature in the presence of 2 equiv of 35 n-BuNH2 and 24.3 mol% PPh3 (Scheme 11). Compound 43 was then used as an intermediate in the synthesis of the cyclic enediyne compounds 44a-f (Scheme Cl MeOOC MeOOC 13) related to dynemicin. Remarkably, compounds 44a-f, O (2e) (3.0 equiv) O

O SiMe3 O which are equipped with a 2-(arylsulfonyl)ethoxycarbonyl Me3Si OTBDMS Pd(OAc)2 (5.7 mol%), CuI (10.6 mol%) OTBDMS group or the 2-(methylsulfonyl)ethoxycarbonyl group as a PPh3 (24.3 mol%), n-BuNH2 (2 equiv) H PhH, rt, 12 h triggering device, showed both cytotoxicity against various 36 (82%) 37 tumor cell lines and potent DNA-cleaving activity.38 COOMe TBDMSO O 6 steps HO N The procedure used for the synthesis of (Z)-enediyne 43 (17% yield over 6 steps) was also employed to prepare analogues of this compound 38 39 40 40 MeO that included enediynes 45, 46 and 47 (Figure 3), H which were used as starting materials in the synthesis of a series of simple enediyne analogues of dynemycin A.39,40

7 Tetrahedron

R2 H (1.2-2 equiv) 1 R H (1 equiv) Pd(PPh3)4 (5 mol%) or SiMe3 Pd(PPh ) (5 mol%) Cl PdCl (PhCN) (5 mol%) O Cl 3 4 2 2 Cl CuI (10 mol%) R1 CuI (10 mol%) ArO N piperidine, 2 h, rt piperidine (2 equiv) O 3 (5 equiv) 4 20 °C, 9 h CH2OH

R2

45: [Ar = Ph; 2-FC6H4; 4-FC6H4; 2-ClC6H4; 3-ClC6H4; 4-ClC6H4; 1 2,4-Cl2C6H3; 4-MeOC6H4; 2-NO2C6H4; 4-NO2C6H4; 2-naphthyl] R 52

SiMe3 SiMe3 Compounds 4 Yield (%) Compounds 52 Yield (%) O O 1 1 2 4a: R = C5H11 92 52a: R = C5H11; R = SiMe3 95 1 1 2 PhO N Me PhO N 4e: R = SiMe3 76 52b: R = C5H11; R = (CH2)2COOMe 89 O O 1 1 2 4f: R = Bu 93 52c: R = Bu; R = C5H11 92 CH2OH 1 4g: R = C5H11CHOH 92 O 1 4h: R = CH2OH 88 OR 46 47 [R = Me, COt-Bu] R1 H (1 equiv) R2 H (1-2 equiv) Pd(PPh3)4 (5 mol%) Cl Pd(PPh3)4 (5-10 mol%) Cl Cl CuI (10 mol%) CuI (10-20 mol%) Figure 3. Structures of compounds 45–47. 1 n-BuNH (2 equiv) R n-BuNH (1-2 equiv) 1 (2 equiv) 2 2 2 PhH, 5 h, rt PhH, 4 h, rt In 1995 and in subsequent years, Banfi and Guanti synthesized a series of 10-membered cyclic enediynes of Scheme 15 general formula 49, trans-fused with N-protected and N- R1 R2 unprotected β-lactams, which were named lactenediynes, 53 via reaction schemes involving as a key step the reaction of Compounds 2 Yield (%) Compounds 53 Yield (%) 1 1 2 2a: R = C5H11 78 53a: R = Bu; R = (CH2)2OH 78 (Z)-chloroenyne 2e with 3-(prop-2-ynyl)azetidin-2-ones 48 1 1 2 2e: R = SiMe3 76 53b: R = Bu; R = (CH2)2COOMe 76 1 1 2 in a mixture of THF and piperidine at room temperature in 2f: R = Bu 86 53c: R = Bu; R = SiMe3 86 1 1 2 2g: R = CMe2NH2 95 53d: R = C5H11; R = CH2OH 95 1 (a) the presence of catalytic amounts of PdCl2(PhCN)2, CuI 2h: R = (CH2)3Cl 93 41–45 (a) and trimethylsilylacetylene (Scheme 14). by using Pd(PPh3)4 (5 mol%) without CuI

Cl H 2e Scheme 15. Synthesis of chloroenynes 4 and 2 and their SiMe3 SiMe3 conversion into enediynes 52 and 53, respectively. 1 OH 1 R PdCl2(PhCN)2 (10 mol%) R OH N CuI (10 mol%) N 1 1 O R Me3Si H (30 mol%) O R In particular, (E)-1-chloro-1-ene-3-ynes 4 were THF, piperidine 48 stereospecifically prepared in high yields by the reaction of 1-alkynes with 5 equiv of (E)-1,2-dichloroethene (3) in benzene at room temperature in the presence of 5 mol%

1 R R2 Pd(PPh3)4, 10 mol% CuI and 2 equiv of piperidine (Scheme N 47 O R1 15). Compounds 4 were then converted stereospecifically 49 in high yields into (E)-enediynes 52 by treatment with 1.2– 2.0 equiv of 1-alkynes in benzene at 20 °C in the presence Scheme 14. Synthesis of 10-membered cyclic enediynes 49. of 5 mol% Pd(PPh3)4 or PdCl2(PhCN)2, 10 mol% CuI and 2 equiv of piperidine. Noteworthy is that the use of n-BuNH2 Moreover, a protocol very similar to that employed to instead of piperidine proved to be preferable in the prepare compounds 49 was used to prepare lactenediynes synthesis of (Z)-1-chloro-1-ene-3-ynes 2 from (Z)-1,2- 46 51 from 2e and 1-alkyne 50 (Figure 4). dichloroethene (1) and 1-alkynes. It was also found that the molar ratio between 1 and 1-alkynes could be lowered from H 5 to 2 and that a further reaction of compounds 2 with 1-

OTBDMS OR alkynes under experimental conditions very similar to those N N employed for the monoalkynylation of 1 led O O stereospecifically to (Z)-enediynes 53 in excellent yields 50 51 (Scheme 15).47 Figure 4. Structures of compounds 50 and 51. A further demonstration of the synthetic usefulness of In 1994, Chemin and Linstrumelle reported several compounds 2 was given through their conversion to 1,3- examples of Pd/Cu-catalyzed sequential alkynylation diynes 54 by treatment with TBAF in THF at room 48 reactions of (Z)- and (E)-1,2-dichloroethene that provided temperature (Scheme 16). chloroenynes and then enediynes47 and described that both the nature of the catalyst and the amine were critical for the success of the couplings.

8 Tetrahedron

(CH2)8 1) AgNO3 (2.59 equiv) Cl 1M TBAF (2.5 equiv) AcO H (CH ) OAc EtOH, H O R1 H Cl 2 8 2 THF, rt, 20 h R1 PdCl2(PhCN)2 (5 mol%) 2) KCN (12.2 equiv) (64-87%) SiMe SiMe 2 54 3 CuI (10 mol%) 3 H2O 4e piperidine, rt (76%) (71%) [R1 = C H ; Ph; (CH ) OH; CH(OH)Et; CH(OEt) ; CH NEt ; CH COOMe; CH SEt] 5 11 2 2 2 2 2 2 2 (CH ) AcO 2 8 activated Zn, H2O (CH ) AcO 2 8 MeOH Scheme 16. Synthesis of 1,3-diynes 54 from (Z)-12-chloro-1-en- H (67%) 56 3-ynes 2. Scheme 19. Synthesis of (9Z,11E)-9,11,13-tetradecadien-1-yl Stereoisomerically pure unsymmetrically substituted (E)- acetate (56). and (Z)-enediynes of general formula 52 and 53, respectively, were also prepared in good yields by a one- A year earlier, (Z,Z)-cyclodeca-3,9-diene-1,5,7,11-tetrayne pot procedure involving two sequential cross-coupling (57) was synthesized from compound 2e in 15.5% overall 54 reactions of alkynes with dichlorethenes 3 and 1, yield via a short reaction sequence (Scheme 20) in which respectively, in which the monoalkynylation reactions were 2e was coupled to 1,5-hexadiyne under standard Pd/Cu catalysis.24 carried out using a Pd(PPh3)4/CuI catalyst system and piperidine as the solvent and the alkynylation of the Cl 1) H (CH2)2 H resulting cross-coupling products was performed by the Pd(PPh3)4 / CuI (cat), n-BuNH2 addition of a catalytic amount of PdCl (PhCN) to the 2) K2CO3, MeOH 2 2 SiMe3 3) Cu(OAc)2, MeCN, 60 °C 49 (15.5% yield over 3 steps) crude reaction mixtures (Scheme 17). 2e 57

1) R1 H (1 equiv) Pd(PPh ) (5 mol%) 3 4 R2 Scheme 20. Synthesis of (Z,Z)-cyclodeca-1,5,7,11-tetrayne-3,9- CuI (10 mol%), piperidine, rt Cl Cl diene (57). 2) R2 H (1.2 equiv) 1 PdCl2(PhCN)2 (5 mol%) R 3 (2 equiv) piperidine, rt 52 The resulting bis-enediyne was deprotected with K2CO3 in Compounds 52 Yield (%) 1 2 MeOH to give the corresponding bis-terminal diyne which 52a: R = C5H11; R = SiMe3 75 1 2 52b: R = C5H11; R = (CH2)2OH 68 1 2 was immediately added to a solution of Cu(OAc)2 in MeCN 52c: R = C5H11CH(OH); R = (CH2)2OH 71 52d: R1 = Ph; R2 = Ph 62 at 60 °C to give compound 57 as a shock-sensitive dark 54 1) R1 H (1 equiv) solid (Scheme 20). Pd(PPh3)4 (5 mol%) CuI (10 mol%), piperidine, rt Cl Cl 2) R2 H (1.2 equiv) R1 R2 Again in 1995, sequential stereospecific alkynylation PdCl2(PhCN)2 (5 mol%) 1 piperidine, rt 53 reactions of (E)-1,2-dichloroethene were employed as key Compounds 53 Yield (%) steps of the synthesis of stereodefined polyenes, including 1 2 53a: R = (CH2)4OH; R = C5H11 78 55 1 2 53b: R = C5H11; R = SiMe3 73 tetraenes, pentaenes, and heptaenes. Thus, (2E,4Z,6E,8Z)- 1 2 53c: R = C5H11CHOH; R = CH2OH 72 1 2 2,4,6,8-tetradecadien-1-ol (59) was synthesized in 26.6% 53d: R = (CH2)2OH; R = CH2OH 62 1 2 53e: R = CMe2NH2; R = C5H11 71 overall yield by sequential alkynylation of 3 with 1-heptyne 1 2 53f: R = CMe2NH2; R = C5H11CHOH 64 and (E)-2-penten-4-yne followed by selective reduction56 of the triple bonds of the resulting coupling product 58 Scheme 17. One-pot synthesis of enediynes 52 and 53. (Scheme 21).55

1) C H H In 1995, compound 52a was used as a precursor to (3E,5Z)- 5 11 C H Pd(PPh ) /CuI (cat), piperidine 5 11 50 Cl 3 4 1,3,5-undecatriene (55) (Scheme 18), a compound Cl H 2) , piperidine OH isolated from the essential oil of galbanum.51 OH 3 PdCl2(PhCN)2/CuI (cat) 58

C5H11 Zn(Cu-Ag), MeOH, H2O C5H11 OH C5H11 (ref. 55) 59 SiMe3 (26.6% overall yield) 55 52a Scheme 21. Synthesis of (2E,4Z,6E,8Z)-2,4,6,8-tetradecadien-1-ol Scheme 18. Retrosynthesis of triene 55. (59). In addition, (E)-1-chloro-4-trimethylsilyl-1-butene-3-yne The stereoisomerically pure (3E,5Z,7E,9Z,11E)-pentaene (4e) was employed as a starting material in a three-step 55 64 was prepared in a similar way (Scheme 22). synthesis of (9Z,11E)-9,11,13-tetradecadien-1-yl acetate (56) (Scheme 19),50 a sex pheromone component of Stenoma cecropia,52 a serious defoliator of oil palm trees in South America.53

9 Tetrahedron

H Cl Cl (3) Me Cl PdCl (PPh ) (5 mol%) Red-Al, THF Cl R Cl 2 3 2 R C5H11 Cl (3) C5H11 OH CuI (10 mol%), piperidine -30 to 20 °C, 2 h OH H Pd(PPh3)4/CuI (cat) Cl PdCl2(PhCN)2/CuI (cat) (R = H: 88%; R = Me: 86%) OH piperidine piperidine 69a: R = H (67%) 60 61 (87%) (92%) 69b: R = Me (80%)

H MnO2 C5H11 R CH2Cl2 Zn(Cu-Ag) OH OH Cl R Me MeOH, H O 2 C5H11 Me (77%) 68a: R = H O OH 68b: R = Me 62 63 70a: R = H (87%) 70b: R = Me (81%)

Cl Cl (1) PdCl (PPh ) (5 mol%) Cl R Scheme 22. Synthesis of pentaene 63. 2 3 2 R Red-Al, THF Cl CuI (10 mol%), n-BuNH2, Et2O OH (R = H: 92%; R = Me: 88%) OH 71a: R = H (79%) 71b: R = Me (91%) Specifically, the Pd(PPh3)4/CuI-catalyzed MnO2 monoalkynylation of 3 with enyne 60 gave chlorodiene 61 CH2Cl2 R in 87% yield. This compound was reacted with (E)-3- Cl hexen-5-yn-2-ol in piperidine in the presence of catalytic O 72a: R = H (92%) quantities of PdCl2(PhCN)2 and CuI, affording the 72b: R = Me (98%) trienediyne 62 in 92% yield, which was reduced to 63 in 77% yield (Scheme 22).55 Scheme 24. Synthesis of compounds 70a, 70b, 72a, and 72b.

On the other hand, heptaene 67 was chemoselectively and Manganese dioxide oxidation of these compounds then led stereospecifically synthesized on the basis of the to (E,E)-chlorodienal 70a and (E,E)-chlorodienone 70b, 57 retrosynthetic analysis outlined in Scheme 23.55 A key step respectively (Scheme 24). On the other hand, (1Z,3E)-1- of this synthesis, which was performed without any chloro-5-hydroxy-1,3-dienols 71a and 71b were protection-deprotection sequence of the alcohol functions, synthesized by PdCl2(PPh3)2/CuI-catalyzed was the preparation of compound 66 by sequential monoalkynylation of (Z)-1,2-dichloroethene (1) with alkynylation of 3 with dieneynes 64 and 65. propargyl alcohols 69a and 69b, respectively, in Et2O in the presence of n-BuNH2 as the base, followed by selective C5H11 Me reduction of the resulting (Z)-1-chloro-1-en-3-ynes with OH 67 Red-Al. Manganese dioxide oxidation of 71a and 71b eventually led to dienals 72a and 72b, respectively (Scheme 57 C5H11 24).

Me 66 OH A similar protocol was employed to prepare chlorodienynols 74a and 74b from 1 and enynols 73a and H C H 5 11 Cl Me 73b, respectively, as well as chlorodienols 75a and 75b by + Cl + H 57 OH coupling of 3 with 73a and 73b, respectively (Figure 5). 64 3 65 Compounds 74a and 74b were then used as precursors to

C H Cl Me chlorotrienal 76a and chlorotrienone 76b, respectively, via 5 11 Cl + H SiMe3 H SiMe3 + OH a four-step reaction sequence involving their reduction by Red-Al into trienols, a rapid Pd(II)-catalyzed Scheme 23. Retrosynthesis of heptaene 67. rearrangement of the corresponding acetates, and hydrolysis of the resulting acetoxytrienes followed by MnO2 57 In 1996, the PdCl2(PPh3)2/CuI-catalyzed reactions of 3 with oxidation. Compounds 77a and 77b (Figure 5) were propargyl alcohols 68a and 68b in piperidine were similarly prepared from 75a and 75b, respectively.57 employed as key steps of the stereoselective synthesis of 57 H Cl Cl chlorodienols 69a and 69b, respectively (Scheme 24). R R R

OH OH OH 73a: R = H 74a: R = H 75a: R = H 73b: R = Me 74b: R = Me 75b: R = Me R Cl R Cl O O 76a: R = H 77a: R = H 76b: R = Me 77b: R = Me

Figure 5. Structures of compounds 73a,b, 74a,b, 75a,b, 76a,b, and 77a,b.

In 2001, (E)-1-chloro-1-nonen-3-yne (4a), which was prepared in 59% yield by treatment of 1-heptyne with 5 equiv of 3 in THF in the presence of catalytic amounts of

10 Tetrahedron

Pd(PPh3)4 and CuI and 2 equiv of piperidine, was used as was employed as a building block in the total synthesis of an intermediate in the synthesis of (10E,12Z)-[1-14C]- three polyacetylenic natural products, (S)-18- octadeca-10,12-dienoic acid (78) (Scheme 25).58 hydroxyminquartynoic acid (86), (S)-minquartynoic acid (87), and (E)-15,16-dihydrominquartynoic acid (88), which (1 equiv) Cl C H COOH Cl C5H11 H 5 11 Cl 7 was accomplished on the basis of the retrosynthetic analysis Pd(PPh3)4 (5 mol%) C5H11 CuI (10 mol%) 60 3 (5 equiv) piperidine (2 equiv) 4a 78 outlined in Scheme 29. Compounds 86–88 were isolated THF, rt, 5 h (59%) from a CHCl3 extract of the twigs of Ochanostachys H amantea from Southeast Asia61 and compound 87 was also THPO 6 Cl Cl 62 Cl Pd(PPh3)4 (5.2 mol%) Me COOH isolated from the stembark of Minquartia guianensis. CuI (11.9 mol%) THPO 6 5 7 piperidine (2.06 equiv) 3 (5.1 equiv) 79 80 THF, rt, 5 h H 1) n-BuLi/HMPA, -40 °C (82%) HO 2) (COCl) , DMSO, Et N, -78 °C Cl 8 Cl 2 3 Cl Pd(PPh3)4/CuI (cat) HO 3) NaClO2/NaH2PO4 8 Et2NH (2 equiv), DMSO Scheme 25. Synthesis of dienoic acids 78 and 80. 3 PhMe, 0.5 h 84 (76.5% over 3 steps)

1) CH2N2, Et2O, 0 °C 2) NBS, AgNO3, acetone, 0 °C to rt Moreover, (E)-1-chloro-1-en-3-yne 79, which was obtained H COOH Br COOH 6 3) LiOH, THF/MeOH/H2O 6 (61.5% over 3 steps) in 82% yield by Pd(PPh3)4/CuI-catalyzed reaction of 3 with 85 2-non-8-ynyloxy-tetrahydropyran in THF at room temperature using piperidine as base, was employed as the Scheme 28. Synthesis of bromodiyne 85. starting material in a convergent synthesis of (9Z,11E)-[1- 14C]-octadeca-9,11-dienoic acid (80) (Scheme 25).58 On the Cadiot-Chodkiewicz cross-coupling reactions63 were used other hand, (Z)-1-chloro-1-nonen-3-yne (2a), which was as key steps for the construction of the tetraene units of 86 60 prepared in 80% yield by Pd(PPh3)4/CuI-catalyzed reaction and 87 and the triyne unit of 88. of 1 with 1-heptyne in THF at room temperature using HO HO piperidine (2 equiv) as base, was employed as a precursor COOH COOH 14 HO 6 Me 6 to (10Z,12Z)-[1- C]-octadeca-10,12-dienoic acid (81) 86 87 (Scheme 26).58 HO MOMO 85 + H 85 + H BnO Me COOH Cl C5H11 7 C5H11 HO COOH 81 2a 6 Me 88 Scheme 26. Retrosynthesis of compound 81. MOMO H 85 + In 2004, (11Z,13E)-11,13,15-hexadecatrien-1-yl acetate Me (83), a sex pheromone component of oak processionary Scheme 29. Retrosynthesis of the naturally occurring polyynes moth, Thaumotopoea processionaria, was synthesized via a 86–88. seven-step reaction sequence in which (E)-1-chloro-5- hydroxy-1-tetradecen-3-yne (82), a key intermediate, was In 2003, a route involving sequential Pd/Cu-catalyzed prepared by PdCl2(PPh3)2/CuI-catalyzed reaction of 3 with alkynylation reactions of (E)-1,2-dichloroethene (3) was 11-dodecyn-1-ol in the presence of i-Pr2NH as base employed to prepare oligoenyne 90 (Scheme 30).64 59 (Scheme 27). Unfortunately, the experimental conditions Specifically, the reaction between 5 equiv of 3 with 1 equiv of the process were not reported. of t-butylacetylene in THF in the presence of 2 equiv of

H piperidine, 5 mol% Pd(PPh3)4 and 10 mol% CuI gave (E)-1- 5 steps HO Cl Cl 10 chloro-1-en-3-yne 4i in 85% yield. An analogous reaction Cl HO AcO PdCl2(PhCN)2/CuI (cat) 10 10 i-Pr2NH, THF between 3 and trimethylsilylacetylene produced compound 3 82 83 4e in 82% yield. Compound 4i was then converted into (E)- Scheme 27. Synthesis of the sex pheromone component 83 from enediyne 89 in 87% yield by coupling with 3. trimethylsilylacetylene in the presence of piperidine and a Pd(PPh3)4/CuI catalyst system. Finally, removal of the In 2006, (E)-1-chloro-1-en-3-yne 84 was synthesized in trimethylsilyl group in 89 and further Pd(PPh3)4/CuI- 80% yield by the reaction of equimolar amounts of 3 and catalyzed reaction of the resulting desilylated compound 64 10-hydroxy-1- in toluene in the presence of with 4e gave compound 90 in 12% yield (Scheme 30). catalytic quantitites of Pd(PPh3)4 and CuI and 2 equiv of 60 Et2NH (Scheme 28). Compound 84 was then converted into bromodiyne 85 in 47% overall yield via a six-step reaction sequence (Scheme 28).60 Finally, compound 85

11 Tetrahedron

R1 H (1 equiv) (Z)-stereoisomers of compound 91 in 63% yield (Scheme Pd(PPh ) (5 mol%) 1 (for 4i) H SiMe3 Cl 3 4 R Cl 67 CuI (10 mol%) Cl Pd(PPh3)4 (5 mol%) 33). piperidine (2 equiv) 3 (5 equiv) 4i: R1 = t-Bu (85%) CuI (10 mol%) THF, rt 1 piperidine (2 equiv) 4e: R = SiMe3 (82%) THF, rt piperidine (87%) Br PdCl2(PPh3)2 (5 mol%) Cl + Cl t-Bu NaH (cat), MeOH (1 equiv) t-Bu H Cl CuI (10 mol%) N SiMe3 then 4e (1 equiv) SiMe3 (63%) 3 1 + 3 (1:1) (5 equiv) 91 (E:Z = 9:1) Pd(PPh3)4 (5 mol%) 89 CuI (10 mol%), piperidine 90 (2 equiv), THF, rt (12%) Scheme 33. Stereoselective synthesis of compound 91.

Scheme 30. Synthesis of oligoenyne 90. Alami and coworkers also investigated some synthetic applications of (E)-1-chloro-1-en-3-ynes 4 involving Pd- A year earlier, Alami and coworkers had investigated the catalyzed reactions and, in this context, they found that Pd(PPh3)4/CuI-catalyzed monoalkynylation of a 1:1 treatment of (E)-1-chloro-4-phenyl-1-buten-3-yne (4i) with mixture of (Z)- and (E)-1,2-dichloroethene and found that, propargyl bromide in piperidine in the presence of 5 mol% when 5 equiv of (Z)/(E)-1,2-dichloroethene were reacted PdCl2(PPh3)2 and 10 mol% CuI provided (E)-enediyne 92 67 with 1-alkynes in Et2O at room temperature in the presence (Figure 6) in 76% yield. of 5 mol% Pd(PPh3)4, 10 mol% CuI and 2 equiv of Ph piperidine, (E)-1-chloro-1-en-3-ynes 4 were obtained in Ph high yields and with high stereoisomeric purity, except in Cl N the case of phenylacetylene (Scheme 31).65 They also 4i 92 observed that a change of the amine had no significant effect on the reaction. Figure 6. Structures of compounds 4i and 92.

R1 H (1 equiv) Moreover, they showed that the reaction of chloroenynes 4 Pd(PPh ) (5 mol%) Cl 3 4 R1 Cl CuI (10 mol%) Cl with Grignard reagents in the presence of PdCl2(PhCN)2 1 + 3 (1:1) (5 equiv) piperidine (2 equiv) 4 Et2O, rt and Et3N gave stereoisomerically pure cross-coupling 68,69 R1 Yield (%) E/Z products 93 in modest-to-excellent yields (Scheme 34).

4a n-C5H11 90 98/2 4i Ph 80 90/10 2 4j (CH2)9OH 85 97/3 R1 R MgCl (2 equiv) R1 4k CH2OH 90 98/2 2 Cl Et3N (8 equiv) R 4g C5H11CHOH 70 95/5 PdCl2(PPh3)2 (5 mol%), THF 4l CH2NMe2 75 95/5 4 93 4m CH2CH(C5H11)OH 71 98/2 4n (CH2)2OH 88 95/5 4o CHPhOH 78 95/5 93 R1 R2 Yield (%) a C5H11 4-MeC6H4 95 b C5H11 (Z)-Me-CH=CH 90 Scheme 31. Stereoselective synthesis of (E)-chloroenynes 4. c C5H11 CH2=CH 71 d C5H11 CH2=CMe 62 e C5H11 C8H17 15 f SiMe3 Ph 70 These results clearly demonstrated that (E)-1,2- g Ph Ph 93 dichloroethene (3) is remarkably more reactive than its Z- h C5H11CH(OTBDMS) Ph 76 i (CH)3Cl Ph 77 Ph stereoisomer. On the other hand, similar trends in j (CH)3COOEt 51 k 81 selectivity had already been observed in Pd-catalyzed 4-MeOC6H4-CH=CH Ph cross-coupling reactions of (E)- and (Z)-1-bromo-1- alkenes, where the (E)-stereoisomers were found to Scheme 34. Stereoselective synthesis of enynes 93. undergo preferentially intermolecular Pd-catalyzed cross- coupling reactions with organometallic compounds to give A stereocontrolled process involving the Pd-catalyzed Suzuki-type reaction between (E)- or (Z)-1-chloro-1-en-3- (E)-configured cross-coupling products having high 70 stereoisomeric purity (Scheme 32).66 ynes and boronic acids was also recently developed. The procedure (Scheme 35) proved to be general and allowed

1 2 1 2 R R Br Pdcat R R Br good access to several functionalized (E)- and (Z)-1-en-3- n Br + m + R2 M n R2 + m ynes 94 and 95, respectively, in good-to-excellent yields 70 Scheme 32. Stereoselective cross-coupling reactions involving with excellent stereoselectivities. (E)/(Z)-1-bromo-1-alkenes. Moreover, high yields of conjugated enynes 94 and 95 More recently, Alami and coworkers have reported a bearing a functional group were obtained with complete catalytic domino three-component process involving the stereoselectivity when chloroenynes 4 and 2, respectively, reaction of 1 equiv of propargyl bromide with 5 equiv of a were reacted under Pd catalysis with a molar excess of the 1:1 mixture of compounds 1 and 3 in piperidine at 80 °C in organozincate reagents generated in situ by the reaction of 67 alkyl and aryl Grignard compounds with less-than-molar the presence of 5 mol% PdCl2(PPh3)2 and 10 mol% CuI. 71 The reaction gave selectively a 9:1 mixture of the (E)- and amounts of ZnCl2 (Scheme 36).

12 Tetrahedron

2 PdCl (PPh ) (1 mol%) 1 R B(OH)2 (1.2 equiv) 1 2 3 2 R R CuI (10 mol%) 2 COOMe + Cl COOMe Cl Pd(PPh3)4 (5 mol%) R Cl H piperidine, THF Cl 4 K2CO3 (2 equiv) 94 (51%) PhMe/EtOH (2:1), 100 °C 96 3 97 MeN O 94 R1 R2 Yield (%) E/Z B O 98 a 2-MeOC6H4 4-MeOC6H4 94 100/0 O O COOMe b Ph 4-MeOC6H4 79 100/0 Pd(OAc)2 (2 mol%) c C5H11 4-MeOC6H4 81 100/0 SPhos (4 mol%), K3PO4⋅7H2O d 2-MeOC6H4 2-MeOC6H4 85 98/2 THF, PhMe, Δ 99 O (47%) e 2-MeOC6H4 3,4 -H C C H 88 98/2 2 O 6 3 f 2-MeOC6H4 2-naphthyl 81 97/3 Zn(Cu-Ag) COOMe g 2-MeOC6H4 4-ClC6H4 86 100/0 Me3SiCl (cat) MeOH, H O h 2-MeOC6H4 4-AcC H 84 97/3 2 6 4 (88%) 100 i 2-MeOC6H4 4-CHOC6H4 71 91/9 3-NO C H j 2-MeOC6H4 2 6 4 71 95/5 k 93 100/0 2-MeOC6H4 3-thienyl Scheme 37. Synthesis of the methyl ester 100 of bosseopentaenoic l 2-MeOC6H4 (E)-1-pentenyl 78 95/5 acid.

2 R1 R B(OH)2 (1.2 equiv) R1

Pd(PPh3)4 (5 mol%) 2 Compound 101, which was prepared in one step from 1 and Cl K2CO3 (2 equiv) R 2 PhMe/EtOH (2:1), 100 °C 95 3-butyn-1-ol according to the procedure of Kende and 24 95 R1 R2 Yield (%) E/Z Smith, was converted in two steps into the phosphonium a 2-MeOC6H4 4-MeOC6H4 76 0/100 salt 102. Compound 102 underwent a cis-selective Wittig b 2-EtOOCC6H4 4-MeOC6H4 83 3/97 c C5H11 4-MeOC6H4 83 0/100 reaction with aldehyde 103 to give chlorodiene 104 in 60% yield. Finally, treatment of 104 with n-BuLi in THF at -78 Scheme 35. Synthesis of enynes 94 and 95 from chloroenynes 4 °C followed by removal of the ketal protecting group with and 2, respectively, by Suzuki-type reactions. HCl provided ketone 105 in 24% overall yield (Scheme 38).77 2 R1 R MgBr (1.5 equiv) R1 2 Cl ZnCl2 (0.6 equiv), THF, reflux R 1) PPh , I , imidazole, CH Cl , rt 4 PdCl2(dppf) (5 mol%) 94 3 2 2 2 NaHMDS, THF OH PPh3I (60-95%) (10 examples) 2) PPh3, MeCN Cl Cl O O (quant.) OHC 103 (R1 = alkyl; R2 = (cyclo)alkyl; aryl) 102 Me 101 -78 °C to rt (60%)

2 H R1 R MgBr (1.5 equiv) R1 1) n-BuLi, THF, -78 °C O O ZnCl2 (0.6 equiv), THF, reflux Cl O 2) HCl Cl R2 PdCl2(dppf) (5 mol%) Me Me 2 (83-96%) 95 104 105 (3 examples) (R1 = alkyl; aryl; R2 = alkyl; aryl) Scheme 38. Synthesis of naturally occurring ketone 105. Scheme 36. Synthesis of enynes 94 and 95 from chloroenynes 4 and 2, respectively, by Pd-catalyzed reactions with organozincate Excellent site selectivity was unexpectedly observed by reagents. McGaffin and de Meijere in the Pd(PPh3)4/CuI-catalyzed reaction of 2-ethoxy-1-ethynylcyclopropane (106) with an Recently, the methyl ester 100 of bosseopentaenoic acid equimolar amount of (Z)-1,2-dichloroethene (1) in a 14:1 78 [(5Z,8Z,10E,12E,14Z)-5,8,19,12,14-eicosapentaenoic acid], mixture of benzene and i-Pr2NH at 20 °C. In fact, the a compound isolated from the red marine alga cross-coupling reaction (Scheme 39) provided (Z)-1-chloro- Lithothamnion corallioides,72 was synthesized via a route 1-en-3-yne 107 in 34% yield accompanied by 40% yield of involving, as the first step, the PdCl2(PPh3)2/CuI-catalyzed the homocoupled bisacetylene 108, without any detectable monoalkynylation of (E)-1,2-dichloroethene (3) with 1- amount of the bisalkynylation derivative of 1.78 According 73 79 alkyne 96 in piperidine (Scheme 37). A Pd(OAc)2/S- to a previous report, the formation of compound 108 was Phos-catalyzed Suzuki-Miyaura reaction of the resulting believed to be catalyzed by traces of oxygen. cross-coupling product 97 with the protected boronate ester 74 EtO Pd(PPh3)4 (5 mol%) Cl EtO 98 using Burke’s conditions yielded trienediyne 99 in CuI (10 mol%) EtO + + H Cl Cl PhH/i-Pr2NH (14:1) 47% yield. Finally, stereoselective reduction of the triple 20 °C OEt 56,75 106 1 107 108 bonds of 100, which was achieved with Zn(Cu/Ag) in (34%) (40%) aqueous MeOH in the presence of a catalytic quantity of 73 Me3SiCl, gave compound 101 in 88% yield (Scheme 37). Scheme 39. Site-selective synthesis of compound 108.

Another natural compound, (Z)-tetradeca-8-en-11,13-diyn- In 1996, (Z)-enediyne 110 was synthesized through a five- 2-one (105), a ketone isolated from Echinacea pallida step reaction sequence involving the PdCl2(PPh3)2/CuI- which exhibits a range of biological activitites,76 was catalyzed monoalkynylation of 1 with propargyl alcohol in recently synthesized using (Z)-1-chloro-6-hydroxy-1- Et2O in the presence of n-BuNH2 as the base and the 77 hexen-3-yne (101) as precursor (Scheme 38). subsequent Pd(PPh3)4/CuI-catalyzed cross coupling of the resulting stereoisomerically pure (Z)-1-chloro-1-en-3-yne

13 Tetrahedron

109 with THP-protected propargyl alcohol in Et2O in the 80 O O presence of n-BuNH2 (Scheme 40). Unfortunately, the 119 experimental details of the reactions summarized in Scheme 40 were not reported. It also deserves to be PPh3 + OHC mentioned that (Z)-enediyne 110 was found to exhibit O O DNA-cleaving properties at 37 °C in pH 8.0 as well as 116 118 potent cytotoxicity against human carcinoma cells.80 SnMe3 I OH COOH + HO Cl OH OH OTHP H H PdCl (PPh ) /CuI (cat) Pd(PPh ) /CuI (cat) 114 115 Cl 2 3 2 3 4 n-BuNH2, Et2O Cl n-BuNH2, Et2O 1 109 COOH + I OTHP OH SO2Ph Cl Me3Sn 113

OTHP OH

110 H COOH + Cl Cl Me3Si 1 Scheme 40. Synthesis of (Z)-enediyne 110. + Me Si H Br COOMe 3 In 1997, (Z)-3-en-1,5-diynes 111, which were prepared 117 according to the procedure reported in reference 46 by sequential alkynylation of 1 with trimethylsilylacetylene Scheme 42. Synthesis of dihydroxerulin (119). and a different 1-alkyne and subsequent desilylation, were converted into the corresponding poly(p-phenylene)s 112 Thus, (Z)-1-trimethylsilyl-6-phenyl-3-hexen-1,5-diyne by thermolysis in benzene (Scheme 41).81 No exogenous (120) was prepared in 63.8% yield by sequential chemical catalysts or reagents were required for the Pd(PPh3)4/CuI-catalyzed alkynylation of 1 with process. phenylacetylene and trimethylsilylacetylene in benzene at room temperature in the presence of n-BuNH2 as base R (Scheme 43). PhH H R Δ n 1) Ph C CH (1 equiv), 111 112 Pd(PPh3)4 (4 mol%) CuI (4 mol%), PhH, n-BuNH2 (5 equiv), 24 h, (76%) [R = n-C6H13; Ph; 4-C6H4-Ph; 2-C6H4-Ph; 4-C6H4-t-Bu; 1-naphthyl; 9-anthryl] Cl Cl 2) Me3Si H (1.3 equiv) Ph SiMe3 Pd(PPh3)4/CuI (cat), PhH, n-BuNH2 rt, 48 h (84%) 120 Scheme 41. Synthesis of poly(p-phenylene)s 112. 1 (2 equiv)

1) K2CO3, MeOH, H2O, rt, 6 h Ph

Cl Ph 2) (1.2 equiv) In 2000, dihydroxerulin (119), a noncytotoxic inhibitor of 121 Ph the biosynthesis of cholesterol which was isolated from Pd(PPh3)4/CuI (cat), PhH 82 n-BuNH2, rt, 24 h cultures of Xerula melanotricha, was stereoselectively (29% over 2 steps) synthesized according to the retrosynthetic analysis 83,84 outlined in Scheme 42. A key step of this approach was 1) K2CO3, MeOH, H2O, rt, 6 h Ph Ph 2) Cl Cl (1) (0.4 equiv) the Wittig reaction between aldehyde 118 and the Pd(PPh3)4/CuI (cat) 122 PhH, n-BuNH2, rt, 72 h phosphonium ylide 116. Compound 118 was prepared (6% over 2 steps) through a reaction sequence in which the first step was a PdCl2(PPh3)2/CuI-catalyzed Sonogashira reaction of methyl Scheme 43. Synthesis of cis-oligoenynes 121 and 122. (Z)-3-bromopropenoate (117) with trimethylsilylacetylene in acetonitrile in the presence of Et3N as base. On the other Compound 120 was then employed to prepare cis- hand, compound 116 was conveniently obtained via a short oligoenynes 121 and 122. Specifically, the Pd(PPh3)4/CuI- reaction sequence involving the synthesis of (Z)- catalyzed cross coupling between 1.2 equiv of (Z)-1-chloro- chloroenyne 113 in 90% yield from 1 and 1- and a 4-phenyl-1-buten-3-yne and the desilylation derivative of Stille reaction between (E)-3-iodo-2-propen-1-ol (115) and 120 gave compound 121 in modest yield (Scheme 43). On diynyltrimethylstannane 114 prepared from 113.83 the other hand, compound 122 was obtained in 6% overall yield by desilylation of 120 followed by a cross coupling In 2001, a strategy based on the Sonogashira reaction between the resulting 3-en-1,5-diyne with 0.4 2 Pd(PPh3)4/CuI-catalyzed C(sp)–C(sp ) coupling of 1- equiv of 1 in benzene at room temperature in the presence alkynes with (Z)-chlorovinyl chlorides was employed for of n-BuNH2 and catalytic amounts of Pd(PPh3)4 and CuI the construction of cis-dioligoacetylenes.85 (Scheme 43). It should be noted that 122 was found to undergo cis/trans stereomutation in solution,85 but this stereomutation could be avoided by incorporation of its ene

14 Tetrahedron

R1 O R2 H moiety into ring systems, as in the case of compounds 125 N 85 NHBoc N COOCHPh2 + H and 126 (Schemes 44 and 45). Scheme 44 illustrates the O H multistep stereocontrolled synthesis of configurationally Cl stable 125, starting from phenylacetylene and 1,2- 127 128 a: R1 = Me a: R2 = Me 85 1 2 dibromocyclopentene (123). b: R = CH2Ph b: R = CH2Ph 1 2 c: R = Me c: R = CH2OH

Ph H Me3Si H (4 equiv) Pd(PPh3)4 (3.7 mol%) CuI (2.0 mol%), n-BuNH (4 equiv) PdCl (PPh ) /CuI (cat) PdCl (PPh ) /CuI (cat) 2 Br 2 3 2 2 3 2 PhH, 40 °C, 3 h Br n-BuNH2, PhH, rt, 6 h Br n-BuNH2, PhH, rt, 24 h (80%) Ph (91%) (9%) 123 (0.3 equiv)

R1 H K2CO3, MeOH, H2O, rt, 16h Me3Si H (4 equiv) N NHBoc then 123 (1.2 equiv) PdCl2(PPh3)2/CuI (cat) Ph Ph O PdCl2(PPh3)2/CuI (cat) n-BuNH2, PhH, rt, 48 h n-BuNH2, PhH, rt, 20 h Br (99%) H SiMe3 (36%) N COOCHPh2 124 O R2 129 a: R1 = R2 = Me (60%) K2CO3, MeOH, H2O, rt, 16 h 1 2 b: R = R = CH2Ph (55%) Ph SiMe Ph 1 2 3 then 123 (1.2 equiv) c: R = Me; R = CH2OH (65%) PdCl (PPh ) /CuI (cat) 2 3 2 Br n-BuNH2, PhH, rt, 72 h (22%) Scheme 46. Synthesis of compounds 129a-c.

Me3Si H (6 equiv) Ph Finally, compound 131 was coupled to the required N-t- PdCl2(PPh3)2/CuI (cat) 88 n-BuNH2, PhH, rt, 72 h Boc-amino acids in the presence of EDCI to produce (81%) compounds 127a and 127b in 65% and 60% yield, 125 SiMe3 respectively (Scheme 47).86 Scheme 44. Synthesis of configurationally stable cis-oligoenyne OH N OH 3 125. H 1) MsCl, Et3N Cl Cl PdCl2(PPh3)2/CuI (cat) 2) NaN3, DMF n-BuNH2, PhH Cl Cl (70%) A key intermediate of this synthesis was enediyne 124, 1 101 130

1 1 R which was also employed to prepare compound 126 R H 85 NH2 N (Scheme 45) in 9% yield. PPh3, THF/H2O HOOC NHBoc NHBoc (65%) EDCI, DMAP, CH2Cl2 O

Cl Cl 131 127 K2CO3, MeOH, H2O, rt, 20 h a: R1 = Me (65%) b: R1 = CH Ph (60%) Ph then 123 (0.45 equiv) Ph 2 PdCl2(PPh3)2/CuI (cat) SiMe3 n-BuNH2, PhH, rt, 20 h (9%) Ph Scheme 47. Synthesis of of compounds 127a,b. 124 126 Interestingly, (Z)-chloroenyne 101 proved also to be a Scheme 45. Synthesis of configurationally stable cis-oligoenyne useful intermediate in the synthesis of 1-(p-tosyl)-1- 126. 89 azacyclodec-5-en-3,7-diyne (132), an N-substituted 10- membered monocyclic enediyne, which was found to In 2002, (Z)-enediynyl tripeptides 129a-c in fully protected undergo Bergman cyclization90 at 23 °C with a half life of form were synthesized without racemization by 72 h.89 Pd(PPh3)4/CuI-catalyzed reaction of (Z)-1-chloro-1-en-3-

Ts ynes 127a-c with acetylenic amides 128a-c in benzene at N 86 40 °C in the presence of n-BuNH2 (Scheme 46). 132 Compound 131, a precursor to compounds 127a,b, had been previously synthesized according to the reaction Figure 7. Structure of compound 132. sequence illustrated in Scheme 47 which began with the Moreover, in 2000, compound 133, a macrocyclic 18- PdCl2(PPh3)2/CuI-catalyzed monoalkynylation of 1 with 3- 87 membered bis(diazaenediyne), was efficiently synthesized butyn-1-ol. The resulting (Z)-1-chloro-1-en-3-yne 101 from (Z)-1-chloro-5-hydroxy-1-penten-3-yne (109)80 via was converted into azide 130 via mesylation followed by the eight-step reaction sequence illustrated in Scheme 48.89a treatment with NaN3. Subsequent reduction with PPh3 in 87 THF/H2O gave amine 131 in 65% yield.

15 Tetrahedron

Ts OH N 3 N NH3 1) MsCl, Et3N 1) PPh3, THF/H2O H 92 °C NH3 2) NaN3, DMF 2) p-TsCl, DMAP COO Cl Cl (55%) Cl 109 COO Ts Ts 137 N N H H 1) OTBDMS H MsCl, Et3N NH3 Pd(PPh3)4/CuI (cat) (81%) 99 °C NH3 n-BuNH2, PhH (72%) 2) CsF, MeOH (90%) OH OMs COO Ts COO N 139 K2CO3, DMF (90%) N Scheme 51. Thermal stability of 137 and 139 towards Bergman Ts

133 cyclization.

Scheme 48. Synthesis of macrocyclic compound 133. In 1997, as a part of another study on enediyne antitumor agents, the 3-keto-10-azabicyclo[7.3.1]enediyne core Compound 109 was also employed as the starting material structure 141 of dynemicin A (31) was synthesized, starting in the synthesis of enediynyl amino acid 137 (Scheme from (Z)-1,2-dichloroethene (1) (Scheme 52) via a reaction 49).91 Specifically, 109 was converted in three steps into sequence involving the preparation of stereoisomerically amine 134, which was immediately protected as the Boc pure 2b by highly selective monoalkynylation of 1 with derivative 135. A Pd(PPh3)4/CuI-catalyzed reaction THP propargyl ether, followed by the conversion of 2b into between 137 and benzyl 4-pentynoate gave the protected (Z)-3-en-1,5-diyne 140 by Pd(PPh3)4/CuI-catalyzed reaction enediynyl amino acid 136 in 72% yield. Removal of the with trimethylsilylacetylene. Finally, a six-step reaction benzyl ester of 136 by stirring in an alkaline MeOH sequence allowed the isolation of compound 141, which solution followed by final deprotection with trifluoroacetic was found to exhibit modest in vitro and in vivo antitumor acid gave 137 in 86.4% yield (Scheme 49).91 activity.92

1) MsCl, Et N OH 3 NH Cl OTHP OTHP 2 H SiMe 2) NaN3, DMF Boc2O, AcOEt H 3 3) PPh , THF/H O (96%) Pd(PPh ) (2.5 mol%) Pd(PPh ) (2.5 mol%) 3 2 Cl 3 4 3 4 Cl Cl CuI (5 mol%) Cl CuI (5 mol%) 109 134 1 n-BuNH2, THF 2b n-BuNH2, THF (72%) (90%) NHBoc NHBoc COOBn 1) KOH, MeOH NH3 H 2) TFA

Pd(PPh3)4/CuI (cat) (86.4%) O Cl n-BuNH2, PhH (72%) COOBn COO OTHP 135 136 137 6 steps HN

Scheme 49. Synthesis of amino acid 137. SiMe3 OMe 140 141 Amino acid 139, a higher homologue of 137, was synthesized by treatment of enediyne 138 with Scheme 52. Synthesis of enediyne 141. 86 trifluoroacetic acid in CH2Cl2 at 0 °C (Scheme 50). More recently, (Z)-enynylbenzofuran 142 was synthesized NHCOOt-Bu NH 93 3 in two steps from (Z)-enediyne 52c (Scheme 53), which TFA, CH2Cl2 0 °C, 1 h was prepared in 36.2% overall yield by sequential Pd/Cu- COOCHPh 2 COO catalyzed alkynylation of 1 with 1-hexyne and 138 139 trimethylsilylacetylene, according to the procedure of 46 Chemin and Linstrumelle. Desilylation of 52c with K2CO3 Scheme 50. Synthesis of amino acid 139 from compound 138. in MeOH gave compound 142, which was coupled with 2- iodophenol in Et O in the presence of n-BuNH and A comparison between the thermal stability of 137 and that 2 2 catalytic quantities of Pd(PPh ) and CuI to give 143 in 7% of 139 towards Bergman cyclization allowed a 3 4 yield (Scheme 53).93 The formation of the benzofuran ring demonstration for the first time of the effect of H-bonds presumably involved a cyclization process, catalyzed by the and electrostatic interactions in lowering the activation acidic phenol group, of the Sonogashira-type coupling energy of the Bergman cyclization (Scheme 51).91 derivative obtained from 142 and 2-iodophenol.93

16 Tetrahedron

I trimethylsilylacetylene in Et2O at 21°C in the presence of n- K2CO3, MeOH OH 95,96 (86%) Pd(PPh3)4 / CuI (cat) BuNH2 (Scheme 56). n-BuNH2, Et2O SiMe3 H (7%) 53c 142 1) t-BuPh2Si H , CuI (3 mol%) t-BuPh2Si Pd(PPh3)4 (2.9 mol%), n-BuNH2 (2 equiv) Et2O, 21 °C, 16 h Cl Cl then concentration and 2) Me3Si H (1.8 equiv), CuI (2.3 mol%) OH Me3Si Pd(PPh3)4 (2.3 mol%), n-BuNH2 (1.8 equiv) 1 (1.98 equiv) 149 Et2O, 16 h (64%) O 143 Scheme 56. Synthesis of 3-en-1,5-diyne 149. Scheme 53. Synthesis of compound 143. Enediyne 150 (Figure 8) was similarly prepared from 1, 95,96 5-Butylbenzofuran (145) was instead obtained in 34.2% triisopropylsilylacetylene and trimethylsilylacetylene. overall yield by a two-step reaction sequence in which the Compounds 149 and 150 were then used as building blocks in the preparation of enediyne 151 (Figure 8),95–97 a first step was the Pd(PPh3)4/CuI-catalyzed reaction of (Z)- 3-decen-1,5-diyne (142) with the t-butyldimethylsilyl ether substance that mimics the enediyne antibiotics, esperamicin of 2-iodophenol, which provided enediyne 144 in 57% and calicheamicin. Moreover, compound 152 (Figure 8), yield (Scheme 54).93 Anionic cycloaromatization of 144 which was obtained in high yield by desilylation of 150 with K2CO3 in a mixture of MeOH and benzene at room with sodium methoxide in MeOH under reflux then gave 96 compound 145 in 60% yield (Scheme 54).93 temperature, was employed as a building block in the synthesis of the bicyclo[7.3.1]trideca-4,9-dien-2,6-diyne 98 99 I 153 and racemic calicheamicinone (154) (Figure 8).

OTBDMS Na, MeOH Compound 153 is a calicheamicin-taxoid mimic that Pd(PPh3)4/CuI (cat) reflux, 16 h possesses the Taxotere side chain and an enediyne core. n-BuNH2, Et2O (60%)  H (57%) OTBDMS O On the other hand, compound 154 is the racemic form of 142 144 145 the aglycon of calicheamicin γ1, an antitumor antibiotic isolated from fermentations of Micromonospora Scheme 54. Synthesis of 5-butylbenzofuran (145). 100 echinospora sp.

In 2001, dehydro[14]annulene 148 was synthesized by OH PdCl2(PPh3)2/CuI-catalyzed bis-coupling of Vollhardt’s TIPS Me TIPS cyclobutadiene 146 to (Z)-chloroenyne 2e in piperidine.94a Me Me Me Si The reaction gave tetrayne 147 in 93% yield. Removal of 3 H H the C(sp)-silyl groups from 147 followed by ring closure OMOM 150 151 152 with Cu(OAc)2 in acetonitrile utilizing a procedure by AcO O 94b Me HO Vögtle then furnished 148 in 80% yield after NHCO2Me 94a BocHN O chromatography. (Scheme 55). O Ph OH OH MeSSS HO Me3Si 153 154

H Figure 8. Structures of compounds 150–154. Me3Si Me3Si Cl PdCl2(PPh3)2 (1 mol%) + CuI (3 mol%), piperidine SiMe Me3Si 3 rt, 18 h Me3Si In 1989, bicyclo[7.3.1]enediyne 158, possessing the core CoCp (93%) CoCp H structure of the esperamicin-calicheamicin class of 146 2e (3.04 equiv)

Me Si antitumor antibiotics, was synthesized in 9% overall yield 3 101 147 via an 8-step reaction sequence in which the key Me3Si 1) K2CO3, MeOH intermediate 157 was prepared by Pd(PPh3)4/CuI-catalyzed 2) Cu(OAc)2, MeOH (80%) Me3Si sequential alkynylation of 1 with 1-alkyne 155 and methyl CoCp propargyl ether (Scheme 57).88 The selective 148 Pd(PPh3)4/CuI-catalyzed monoalkynylation reaction of 1 with 155 was carried out at room temperature in benzene in Scheme 55. Synthesis of dehydro[14]annulene 148. the presence of i-Pr2NH as base. The resulting compound Some years before, (Z)-1-trimethylsilyl-6-t- 156, which was obtained in 79% yield, was then reacted butyldiphenylsilylhex-3-en-1,5-diyne (149) was obtained in with methyl propargyl ether in benzene at room temperature in the presence of n-BuNH2 and catalytic 64% yield by sequential Pd(PPh3)4/CuI-catalyzed alkynylation of 1 with t-butyldiphenylsilylacetylene and quantities of Pd(PPh3)4 and CuI to give 157 in 53% yield (Scheme 57).101

17 Tetrahedron

chloroperbenzoic acid (mCPBA) provided 168 in 45% yield TBDMSO OMe TBDMSO (1) O Cl Cl O H along with 32% of the deprotected compound 110 (Scheme Pd(PPh3)4/CuI (cat) Pd(PPh3)4/CuI (cat) i-Pr NH, PhH, rt, 1 h 103 2 n-BuNH2, PhH, rt, 12 h 59). H (79%) Cl (53%) 155 156 OH Cl OH OH OTHP (1.5 equiv) H H TBDMSO O PdCl (PPh ) (5 mol%) Pd(PPh ) (5 mol%) O Cl 2 3 2 3 4 TBDMSO CuI (15 mol%) Cl CuI (15 mol%) OTHP n-BuNH2 (5 equiv) n-BuNH2 (5 equiv), Et2O 1 (5 equiv) Et2O, 30 °C, 6 h 109 (50%) 166 (65%) OMe SPh SO2Ph SO2Ph 157 158 1) MeSO2Cl, Et3N, Cu2Cl2 m-CPBA (2.2 equiv) + 2) PhSH, NaOH, THF, H2O CH2Cl2 (44%) OTHP OTHP OH

Scheme 57. Synthesis of bicyclic enediyne 158. 167 168 110 (45%) (32%) Remarkably, bicyclic enediyne 158 proved to be stable at room temperature.101 Scheme 59. Synthesis of the unsymmetrically 1,8-functionalized (Z)-4-hexen-2,6-diyne 168. More recently, the polyamine-enediyne conjugates 165a–c were synthesized using (Z)-1-chloro-1-en-3-yne 161 as a Interestingly, the reaction of a degassed solution of 168 key intermediate, which was prepared in excellent yield by with 5 equiv of Et3N in the presence of 1,4-cyclohexadiene at 30 °C for 10 h provided the O-disubstituted benzene Pd(PPh3)4/CuI-catalyzed monoalkynylation of 1 with 1- 103 alkyne 160 obtained from the THP O-protected derivative 171 (Scheme 60). This result strongly cyanohydrin 159 (Scheme 58).102 Deprotection of 164 with suggested that the formation of 171 involved a base- catalyzed isomerization of 168 to the (Z)-enyne-allene- p-TsOH in methanol and acetylation of the resulting 104 alcohol gave 162, which was coupled with polyamine- sulfone 169 and the subsequent Myers cyclization of this alkynes 163a–c in benzene in the presence of Et NH and compound to give the biradical intermediate 170 (Scheme 2 60).103 catalytic quantities of Pd(PPh3)4 and CuI to give enediynes 164a–c. Finally, treatment of these compounds with HCl in dioxane yielded the required compounds 165a–c, which were found to exhibit potent DNA-damaging activity under physiological conditions.102

OTHP LDA, THF, HMPA, -78 °C OTHP Cl Cl (1) H Ph Ph CN then , -78 °C H CN Pd(PPh3)4/CuI (cat) Br n-BuNH2, PhH, rt 159 (43%) 160 (96%)

H R N N OTHP OAc Boc Boc Scheme 60. Synthesis of compound 171 from enediyne 168. 1) p-TsOH, MeOH, rt (163a-c) Ph CN Ph CN 2) EDCI, AcOH, Pd(PPh3)4/CuI (cat) Cl DMAP, CH2Cl2, 0 °C Cl Et2NH, PhH, rt In a very interesting paper, Myers and coworkers had (78%) 161 162 previously reported the synthesis of (Z)-1,2,4-heptatrien-6-

OAc OAc yne (174) via a stereospecific route which began with the Ph CN Ph HCl, dioxane, rt CN Pd/Cu-catalyzed sequential one-pot alkynylation of 1 with

R R propargyl alcohol and trimethylsilylacetylene (Scheme N N N N 105 Boc Boc H H H H Cl Cl 61).

164a: R = H (58%) 165a: R = H (77%) 164b: R = (CH2)4NHBoc (73%) OH 164c: R = (CH ) NBoc(CH ) NHBoc (68%) 165b: R = (CH ) NH Cl (65%) Cl OH OH 2 4 2 3 2 4 3 H Me3Si H (14 equiv) PdCl (PPh ) (5 mol%) Pd(PPh ) (5 mol%) 165c: R = (CH2)4NH2(CH2)3NH3 (66%) Cl 2 3 2 3 4 Cl Cl CuI (15 mol%) Cl CuI (20 mol%) SiMe i-PrNH2 (5 equiv), Et2O, i-PrNH2 (14 equiv), 3 1 (5 equiv) 23 °C, 6 h 109 Et2O, 0 °C, 1 h 172 (65%) (83%)

Scheme 58. Synthesis of the polyamine-enediyne conjugates NH2 1) KF 2H O (2 equiv) N ⋅ 2 ⋅ 165a–c. MeOH, 0 °C, 2.5h (96%) H MTAD (1.3 equiv)

2) MeSO2Cl (3 equiv), C6D6, 23 °C, 20 min. Et3N (5 equiv), CH2Cl2, 0 °C, 20 min (31.2% yield based on 172) H H In 1994, Wu and coworkers synthesized the then NH2-NH2 (14.3 equiv), CH2Cl2/MeOH (8:1), 0 °C, 2 h 173 174 unsymmetrically 1,8-functionalized (Z)-4-hexen-2,6-diyne 168 via Pd(PPh3)4/CuI-catalyzed reaction of (Z)-1-chloro- Scheme 61. Synthesis of (Z)-1,2,4-heptatrien-6-yne (174). 1-en-3-yne 109 with tetrahydropyranyl propargyl ether (Scheme 59).103 The resulting compound 166 was then Desilylation of the resulting dialkynylated derivative 172 converted into the corresponding mesylate, which was followed by mesylation of the hydroxyl group and reacted with thiophenol under alkaline conditions to give subsequent treatment with a large molar excess of the sulfide 167. Finally, oxidation of 167 with m- hydrazine in methanol at 0 °C gave compound 173. Finally,

18 Tetrahedron treatment of this crude compound with 4-methyl-1,2,4- Scheme 63. Synthesis of enediyne 180. triazoline-3,5-dione (MTAD) under anaerobic conditions produced compound 174 containing the (Z)-allene-ene-yne However, the alkynylation of the resulting coupling functional group, which was found to undergo a mild compound 178 was carried out in the presence of catalytic 109 thermal reaction to form aromatic compounds in the quantities of Pd(PPh3)4 and CuI. presence of 1,4-cyclohexadiene.105 The initial step in the formation of the aromatic compounds was supposed to be Pd/Cu-catalyzed sequential alkynylation reactions of (Z)- an electrocyclization reaction forming α,3-dehydrotoluene 1,2-dichloroethene (1) were also used by Shibuya and (175) (Scheme 62), which might function as a DNA- coworkers for the synthesis of the 10-membered 110 damaging agent.105 heterocyclic enediyne 184 (Scheme 64). Monocoupling of 1 with 3-butyn-1-ol in benzene at 25 °C in the presence

CH ⋅ Δ 2 Me of n-BuNH2 and catalytic quantitites of Pd(PPh3)4 and CuI + + gave (Z)-vinyl chloride 101 in 90% yield. A second H 174 175 coupling of 101 with t-butyldimethylsilyl propargyl ether under analogous reaction conditions provided enediyne 181 Scheme 62. Thermal conversion of compound 174 into aromatic in 87% yield. Mesylation of 181 followed by nucleophilic compounds. substitution with potassium thioacetate gave thioacetate 182 in 81% yield, which by desilylation and subsequent In 2010, (Z)-enediyne 172, which was prepared in 72.3% mesylation of the resulting alcohol provided compound 183 yield by Myers’ route,105 was employed as an intermediate in 87% yield. Finally, simultaneous slow addition of in the synthesis of compound 176, a building block in a solutions of 183 and sodium methoxide in MeOH via a synthesis of the labile cis-cis-trans unit of fosfotriecin syringe pump into a large amount of MeOH at room (177) (Figure 9).106 This secondary metabolite, isolated temperature gave the enediyne 184 in 61% yield (Scheme from Streptomyces pulvuraceus,107 was shown to be active 64).110 against leukemia, lung cancer, breast cancer, and ovarian 108a,b OH OH cancer and to be a strong inhibitor of type 2A and a Cl OH OTBDMS H Me3Si weak inhibitor of type 1 serine/threonine protein Pd(PPh ) /CuI (cat) Pd(PPh ) /CuI (cat) Cl 3 4 3 4 108c n-BuNH2, PhH, 25 °C, 4 h Cl n-BuNH2, PhH, 25 °C, OTBDMS phosphatase. (90%) 12 h 1 101 (87%) 181

OPO3HNa H OH S OMe OH 1) MsCl, Et N, CH Cl 0 °C, 0.5 h OTBDMS O O 3 2 2, O 1) 1 N HCl, acetone Me OH 2) KSCOMe, acetone, reflux, 2 h 2) MsCl, Et3N (81%) 176 177 OTBDMS CH2Cl2, 0 °C, 0.5 h (87%) 182

Figure 9. Structures of compounds 176 and 177. S OMe

O MeONa, MeOH 25 °C, 36h S (61%) Some years earlier, Myers and coworkers, in the context of OMs an enantioselective synthesis of (+)-dynemicin A (31) and 183 184 its analogues, carried out the synthesis of enediyne 180 in 51.3% overall yield by sequential Pd/Cu-catalyzed Scheme 64. Synthesis of the 10-membered heterocyclic enediyne monocoupling reactions of 1 with t- 184. butyldimethylsilylacetylene and trimethylsilylacetylene and subsequent cleavage of the trimethylsilyl-protected group Compound 184 was then converted into isothiochromanone of the resulting dialkynylated derivative 179 (Scheme (186) in 58% yield by heating in benzene (2 mM solution) 63).109 As in the case of other Pd/Cu-catalyzed sequential in the presence of 1,4-cyclohexadiene at 80 °C.110 As Sonogashira reactions of 1,103,105 the monoalkynylation shown in Scheme 65, the reaction very likely involved the reaction of this substrate was conveniently performed using formation of intermediate 185 via the Bergman reaction.90 air-stable and inexpensive PdCl2(PPh3)2 as the Pd 109 derivative. 80 °C S S S TBDMS TBDMS Cl 184 185 186 TBDMS H Me3Si H (1.4 equiv) PdCl (PPh ) (5 mol%) Pd(PPh ) (4.8 mol%) Cl 2 3 2 3 4 CuI (5 mol%) Cl CuI (15 mol%) n-PrNH2, 23 °C, 3 h n-PrNH2 (3.9 equiv), SiMe3 Scheme 65. Synthesis of isothiochromanone (186). (60%) Et2O, 0 °C, 3 h, then 23 °C, 1 h 1 (4 equiv) 178 (90%) 179 TBDMS In 1993, Grissom and coworkers synthesized K2CO3 (1.1 equiv) MeOH, 23 °C, 1 h unsymmetrical enediynes 187a–c by sequential (95%) 111 H alkynylation of 1 (Scheme 66). Thus, 4-pentyn-1-ol was 180

19 Tetrahedron coupled to 1 under standard conditions22 to yield the Scheme 67. Synthesis of compounds 191 and 192. required monocoupling product in 95% yield. The second coupling was achieved under the same conditions with the On the other hand, enediyne 194 was synthesized from 4- required 1-alkynes to yield enediynes 187a–c in 62, 88 and benzoylazetidinone (193)116 by the three-step reaction 99% yields, respectively, which were used as precursors to sequence shown in Scheme 68.113 enediynes 188a–e with one olefinic tether. It was then H found that thermolysis of compounds 188a–e at 170–245 OCOPh OH , Zn(OAc) O OH (109) °C in the presence of 1,4-cyclohexadiene gave 2,3- H 2 Cl

NH (80%) NH Pd(PPh3)4/CuI (cat) dihydroindenes 189a–e in moderate isolated yields O O n-BuNH 111 2 (Scheme 66). 193 (65%)

1) H , Pd(PPh3)4/CuI (cat) OH Cl OH p-TsCl, DMAP n-BuNH2 O O 2) 3 , Pd(PPh ) (1.7 mol%) (63%) Cl R H 3 4 OH Cl CuI (4 mol%), n-BuNH (1.7 equiv) NH (Ref. 114) NH 2 R3 O O PhH, rt 187a: R3 = SiMe (62%) 1 3 187b: R3 = n-Bu (88%) 194 3 R1 187c: R = CH2OTBDMS (99%) R1 2 R 170 °C-230 °C, R2 Scheme 68. Synthesis of enediyne 194.

C6H4Cl2

4 R3 R It should be noted that attempted Pd(PPh3)4/CuI-catalyzed 1 2 3 1 2 4 188a: R = COOMe; R = H; R = CH2OTBDMS 189a: R = COOMe; R = H; R = H (45%) alkynylation reactions of 109 with terminal alkynes 188b: R1 = COOMe; R2 = H; R3 = n-Bu 189b: R1 = COOMe; R2 = H; R4 = CH=CH-Et (47%) 188c: R1 = COOMe; R2 = H; R3 = H 189c: R1 = COOMe; R2 = H; R4 = H (11%) possessing a β-lactam functionality in the presence of an 188d: R1 = COOi-Pr; R2 = Me; R3 = H 189d: R1 = COOi-Pr; R2 = Me; R4 = H (13%) 1 2 3 1 2 4 188e: R = CH2OH; R = H, R = n-Bu 189e: R = CH2OH; R = H; R = CH=CH-Et + CH2CH=CH- excess of Et3N instead of n-BuNH2 failed to produce any of Me (54%) the desired product.113

Scheme 66. Synthesis of 2,3-dihydroindenes 189a–e. In 1996, chloroenyne 109 was also employed as electrophilic partner in a Pd(PPh ) /CuI-catalyzed reaction Remarkably, the cyclization reactions of the nonaromatic 3 4 with alkyne 195 in Et O in the presence of n-BuNH as enediynes 188a–e proceeded at lower temperature than 2 2 base, which provided enediyne 196 (Figure 10) in 40% those of the corresponding aromatic enediynes.112 yield.117

Monocyclic enediynes 191, 192 and 194 possessing a β- HO O O lactam functionality were synthesized by Basak and Khamrai using stereospecific Pd(PPh3)4/CuI-catalyzed N N alkynylation reactions of (Z)-1-chloro-5-hydroxy-1-penten- COOEt H COOEt 195 196 3-yne (109) as key steps (Schemes 67 and 68).113 The reaction sequences employed to prepare compounds 191 Figure 10. Structures of compounds 195 and 196. and 192 from 4-phenylsulfonylazetidinone (190)114 are outlined in Scheme 67. Interestingly, compounds 191 and In 1996, Jones and coworkers performed a six-step 192 proved to exhibit significant activity against synthesis of enediyne 198 involving the sequential 113 ampicillin-resistant E. coli. Pd(PPh3)4/CuI-catalyzed reaction of dichloroethene 1 with homopropargyl alcohol and trimethylsilyl O-protected H propargyl alcohol (Scheme 69).118 SO Ph OH (109) 2 1) EtMgBr, Me3Si H (70%) Cl

2) CsF, MeCN (90%) Pd(PPh3)4/CuI (cat) NH NH OH O O n-BuNH2 1) TBDMSCl, imidazole (65%) 2) 1, Pd(PPh ) /CuI (cat) 1) CBr4, PPh3 190 OH 3 4 H n-BuNH2, Et2O 2) Amberlyst 15, OSiMe PhH, Et2O 3) 3 OTBDMS H (82% over 2 steps) p-TsCl, DMAP Pd(PPh3)4/CuI (cat) 197 n-BuNH2, Et2O (55%) 4) K2CO3, MeOH NH OH (Ref. 101) NH Cl O O (58% over 4 steps) 191 (30 equiv) Br NaOH, TBAS O 37 °C O SO2Ph MgBr OH (109) H H Cl (71%) (> 90%) NH THF NH Pd(PPh3)4/CuI (cat) OH O O n-BuNH 2 198 199 200 190 (61%)

Scheme 69. Synthesis of isochromone 200. NH p-TsCl, DMAP NH O O (60%) (Ref. 114) The resulting cross-coupling product was reacted with OH Cl K2CO3 in MeOH to give compound 197, which was reacted 192

20 Tetrahedron

Me Me with CBr4 and PPh3 and subsequently with Amberlyst 15 in Cl COOMe NH2 (2 equiv) H COOMe H benzene and Et2O providing 198 in 82% yield from 197. Pd(PPh3)4 (5 mol%) Pd(PPh ) (5 mol%) Cl 3 4 CuI (10 mol%) Cl CuI (10 mol%) Finally, a Williamson-type ring closure of 198 furnished 1 n-BuNH2 (2 equiv), n-BuNH2 (1 equiv), (1.5 equiv) PhH, rt, 6 h PhH, rt, 6 h compound 199 in 71% yield, which was incubated with a (89.9%) (97%) large excess of 1,4-cyclohexadiene at 37 °C to give a nearly COOMe O quantitative yield of isochromone (200) via a Bergman 1) Me3Al (2.1 equiv) NH 118 CH2Cl2, reflux, 6 h NH2 2) H+ cyclization reaction (Scheme 69). Me Me Me Me (72%) 204 205 Four years later, Jones and coworkers attempted to prepare the monocyclic enediyne 201 according to the exocyclic Scheme 72. Synthesis of the stable enediyne lactam 205. enolate ring-closure strategy outlined in Scheme 70.119 Ring closure of compound 204 by treatment with trimethylalane in refluxing CH2Cl2 provided after OMe COOMe acidification the stable enediyne lactam 205 in 72% yield OMe 120 201 (Scheme 72). X In many of the examples reported in this subsection, it has Scheme 70. Exocyclic enolate ring-closure strategy. been shown that several Pd/Cu-catalyzed reactions of (Z)-1- chloro-1-en-3-ynes with terminal alkynes were successfully The synthesis of the requisite acyclic enediyne substrates 203 was achieved by the reaction sequence illustrated in carried out using n-BuNH2 as the solvent or base. However, Scheme 71. Specifically, they prepared compound 2b in the Pd(PPh3)4/CuI-catalyzed cross coupling of (Z)- 69% yield by selective monocoupling of 1 with THP O- chloroenyne 2e with 4-ethynyl-4-methylcyclohex-2-en-1- protected propargyl alcohol according to a modification of one (206), which was performed in the context of a study the procedure of Ratovelomanana and Linstrumelle15 in on arene diradical formation in calicheamicin-esperamicin which 1.1 equiv instead of 5 equiv of 1 were used.119 The analogues, was instead carried out using Et2NH as the base and the solvent (Scheme 73).121 Nevertheless, the result of Pd(PPh3)4/CuI-catalyzed reaction of 2b with an equimolar amount of methyl 5-hexynoate in Et O in the presence of the reaction was not entirely satisfactory, since the coupling 2 provided 91% pure compound 207 in 50% yield.121 n-BuNH2 followed by deprotection of the THP-protected hydroxyl group of the resulting compound furnished (Z)- O O SiMe 3 Pd(PPh3)4 (5 mol%) SiMe enediyne 202 in 61% yield. Compound 202 was then CuI (20 mol%) 3 + converted into a variety of functional-group analogues of Et2NH, 20 °C, 20 min. Me Cl (50%) Me general formula 203 (Scheme 71), but attempts to obtain H monocyclic enediyne 201 by intramolecular cyclization of 206 2e 207 compounds 203 failed.119 Scheme 73. Synthesis of compound 207.

1) H (1 equiv) Cl OTHP OTHP COOMe H Pd(PPh3)4 (3 mol%) Instead, as regards the Pd/Cu-catalyzed monoalkynylation Pd(PPh ) (3 mol%) CuI (6 mol%), n-BuNH (1.5 equiv) Cl 3 4 2 reactions of 1 with terminal alkynes, it should be noted that, CuI (6 mol%) Cl Et2O, 12 h, 25 °C 1 n-BuNH2 (1.5 equiv), Et2O, 2b 2) TsOH, MeOH in many of the examples discussed so far, the required (Z)- (1.1 equiv) 25 °C, 4 h (69%) (61% over 2 steps) 1-chloro-1-en-3-ynes were obtained in high yields using

OH X molar ratios between 1 and 1-alkynes that were higher than 1 and performing the Sonogashira reactions at room (59-97%) temperature. Nevertheless, (Z)-1-chloro-1-en-3-ynes 2b and COOMe COOMe 202 203 208 were recently obtained in satisfactory yields by the reaction of 1 equiv of 1 with 1 equiv of THP O-protected Scheme 71. Synthesis of compounds 203. propargyl alcohol and 3-phenoxy-1-, respectively, in the presence of 5 equiv of n-BuNH2, 3.1 mol% In 1995, (Z)-enediyne 204 was prepared in high yield by Pd(PPh3)4, and 20 mol% CuI in benzene under microwave 122,123 highly selective sequential Pd(PPh3)4/CuI-catalyzed irradiation for 3-5 min (Scheme 74). reactions of 1 with methyl 5-hexynoate and 1,1-dimethyl-2- propynylamine (Scheme 72).120

21 Tetrahedron

OR1 H PdCl (PPh ) (5 mol%) Ar H H (1 equiv) OR1 OR1 Cl MeO 2 3 2 MeO Cl CuI (10 mol%) Cl PdCl2(PhCN)2 (5 mol%) Pd(PPh3)4 (3.1 mol%) + + n-BuNH (2 equiv) CuI (10 mol%) Cl MeO 2 MeO CuI (20 mol%) Et2O, 20 °C piperidine (2 equiv) Cl n-BuNH (5 equiv), PhH, Cl OMe (77%) OMe THF, 12 h 2 OR1 µW, 3-5 min. 1 215 216 (2 equiv) 1 (1 equiv) 2b: R1 = THP (60%) 209: R1 = THP (9%) 208: R1 = Ph (62%) 210: R1 = Ph (13%) MeO MeO MeO OMe OR1 MeO OH OR1 Ar OMe R2 H (1.1 equiv) OMe 218 217a: Ar = 4-MeOC6H4 (86%) combretastatin A4 Pd(PPh3)4 (5 mol%) 217b: Ar = 2-naphthyl (71%) Cl CuI (19.7 mol%) 217c: Ar = 2-quinolinyl (38%) R2 n-BuNH2 (5 equiv), PhH, 217d: Ar = 3-HO,4-MeOC6H3 (73%) 2b, 208 µW, 3-5 min 211 217e: Ar = 3-NH2,4-MeOC6H3 (61%) (52-66%) Scheme 76. Synthesis of (Z)-enediynes 217a-e. Scheme 74. Synthesis of compounds 2b, 208 and 211. The two-step synthesis of compounds 217a–e began with a Compounds 2b and 208 were in fact obtained in 60 and PdCl2(PPh3)2/CuI-catalyzed reaction of 3,4,5- 62% yield, respectively, but the reactions also furnished trimethoxyphenylacetylene (215) with 2 equiv of 1 in Et O significant amounts of the symmetrically substituted (Z)-3- 2 122 at 20 °C in the presence of 2 equiv of n-BuNH2 (Scheme en-1,5-diynes 209 and 210, respectively (Scheme 74). It 76).125 The reaction produced (Z)-chloroenyne 216 in 77% was also shown that very short reaction times were yield, which was reacted with the required necessary to prepare unsymmetrically substituted enediynes (hetero)arylacetylenes using PdCl2(PhCN)2 associated with of general formula 211 in satisfactory yields by CuI as the catalyst and piperidine as base.125 The cross Pd(PPh3)4/CuI-catalyzed alkynylation of 2b and 208 under 122 couplings gave (Z)-enediynes 217a–e in 38–86% yield microwave irradiation (Scheme 74). (Scheme 76).125,130

In 2004, two conjugated (Z)-enediyne-carrying chlorophyll In 2007, the enediyne-bridged amino acid 223 was derivatives, 214a and 214b were synthesized by synthesized via a low-yielding route in which the first step Pd(PPh3)4/CuI-catalyzed coupling of the zinc-chlorin 212 was the reaction of alkyne 219 with 2 equiv of 1 in Et2NH with (Z)-chloroenynes 213a and 213b, respectively, at room temperature in the presence of 10 mol% followed by removal of zinc from the resulting cross- PdCl2(PPh3)2 and 10 mol% CuI, which provided the (Z)- coupling products by treatment with TFA in CH2Cl2 124 chloroenyne derivative of lysine 220 in 47% yield (Scheme (Scheme 75). 131 77). The Pd(PPh3)4/CuI-catalyzed cross coupling of 220

R1 with 1-alkyne 221a (see also Scheme 78) in Et2NH at room temperature furnished (Z)-enediyne 222 in 25% yield. HO H HO Finally, a three-step reaction sequence allowed the Me Me 1) Pd(PPh ) (19.4 mol%) conversion of 222 into compound 223 in 30% yield Me 1 3 4 Me N R CuI (2.42 equiv), n-BuNH2 N 131 (1.5 equiv), rt, 8 h H (Scheme 77). Me Zn N + Me N N Et N Et 2) 30% TFA, CH2Cl2, rt, 4 h H N Cl N Cl Me Me H MeOOC O MeOOC O 212 1 1 213a: R = Pr (1.5 equiv) 214a: R = Pr (nr) Cl N COOEt PdCl2(PPh3)2 (10 mol%) 1 1 213b: R = (CH2)2OH (1.5 equiv) 214b: R = (CH2)2OH (64% over 2 steps) o-Nbs CuI (10 mol%) N COOEt + o-Nbs Et NH, rt, 3 h Cl 2 (47%) Scheme 75. Synthesis of compounds 214a and 214b. 1 219 NHZ(2-Cl) 220 (2 equiv) NHZ(2-Cl) A year later, Provot, Alami and coworkers achieved the O BocHN synthesis of unsymmetrically substituted (Z)-enediynes N (221a) O NH N COOEt 3 steps H 125 Bn H o-Nbs 217a–e, which can be considered analogues of (30%) Pd(PPh3)4 (10 mol%) Bn NHBoc CuI (10 mol%) combretastin A4 (218), a compound isolated from the Et2NH, 5 h, rt 126 (25%) South African willow Combretum caffrum, which NHZ(2-Cl) exhibits strong antitubulin activity by binding to the 222 colchicine binding site of tubulin,127 shows potent O NH HN COOH cytotoxicity against a variety of human cancer cells,128 and has demonstrated powerful antiangiogenesis properties.129 Bn NH2

223 NH2

Scheme 77. Synthesis of the enediyne-bridged amino acid 223.

22 Tetrahedron

In 2008, Jeric and coworkers focused their attention on the catalyzed Sonogashira-type reaction of 229a–e with 1 gave synthesis of (Z)-chloroenyne-substituted amino acids compounds 230a–e in modest-to-satisfactory yields suitable for the construction of enediyne-related peptide (Scheme 79).132 derivatives.132 Two groups of chloroenyne-modified amino acids, 224a-e and 226a-e were synthesized as illustrated in In 2009, (Z)-enediynols 233a, 233b and 233c were Scheme 78. Specifically, compounds 224a-e were prepared synthesized in 39, 77 and 75% yield, respectively, by the in satisfactory yields by the coupling of alkynes 221a-e PdCl2(PPh3)2/CuI-catalyzed reaction of the with 2 equiv of 1 in THF at room temperature in the propargylglycine derivative 231 with (Z)-haloenynols 109, 133 presence of 2 equiv of n-BuNH2, 10 mol% PdCl2(PhCN)2 101 and 232, respectively (Scheme 80). It was then found and 10 mol% CuI. A similar protocol was used in the that subjecting of 233b to Mitsunobu conditions134 led to synthesis of compounds 226a-e from 1 and alkynes 225a– the elimination product 234 in 34% yield, while 233c under e, which were prepared by deprotection of the Boc group of these conditions was transformed into the 12-membered compounds 221a-e under acidic conditions followed by the heterocycle derivative 235 in 61% yield. However, no introduction of the o-Nbs group. The yields of 226a-e were enediyne could be isolated when 233a was reacted in found to be lower than those of compounds 224a-e.132 experimental conditions similar to those employed to prepare 234 and 235. In this case, the O O BocHN 1) TFA / H2O (9:1) o-Nbs HN tetrahydroisoquinoline derivative 236 was obtained in 16% N N 133 H 2) o-Nbs-Cl, Et3N H H H yield (Scheme 80). R CH2Cl2 R 221a-e 225a-e H Cl PdCl2(PPh3)2 (4.5-5.2 mol%) CuI (9.8-10.3 mol%) + Cl PdCl (PhCN) (10 mol%) Cl PdCl (PhCN) (10 mol%) n-BuNH2 (4.9-5.1 equiv) 2 2 2 2 OH (1) (1) TsHN COOMe Et2O, rt, 4-5 h CuI (10 mol%) CuI (10 mol%) n Cl Cl n-BuNH2 (2 equiv) n-BuNH2 (2 equiv) (2 equiv) THF, rt, 0.5 h (2 equiv) THF, rt 231 109: n = 1 101: n = 2 232: n = 3

COOMe (for 233a) PPh (1.49 equiv) O O 3 COOMe DEAD (1.53 equiv) BocHN o-Nbs HN NHTs N N PhMe, THF, rt, 3 h NTs H H R R OH (16%) n Cl Cl 233a: n = 1 (39%) Bergman 224a-e 226a-e (for 233c) cyclization a: R = Bn (40%) a: R = Bn (44%) 233b: n = 2 (77%) 233c: n = 3 (75%) PPh3 (1.52 equiv) b: R = CH2C6H4OBoc (57%) b: R = CH2C6H4OBoc (54%) DEAD (1.48 equiv) c: R = i-Pr (52%) c: R = i-Pr (35%) PhMe, THF COOMe d: R = H (41%) d: R = H (38%) (for 233b) rt, 0.5 h e: R = (CH ) NH[Z(2-Cl)] (40%) e: R = (CH ) NH[Z(2-Cl)] (30%) (61%) 2 4 2 4 PPh3 (1.51 equiv) N DEAD (1.52 equiv), PhMe Ts THF, rt, 1 h (34%) 236 Scheme 78. Synthesis of compounds 224a-e and 226a-e. NTs

COOMe A third group of (Z)-chloroenyne-modified amino acids COOMe NHTs 235 230a–e was prepared from the ethyl esters of N-Boc- protected amino acids 227a–e, which were converted into 234 compounds 228a–e possessing the amino group activated 132 through the o-Nbs moiety (Scheme 79). Scheme 80. Synthesis of compounds 234–236.

O O Br BocHN 1) TFA/H2O (9:1) o-Nbs HN H OEt OEt It was also found that the homochiral 11-membered cyclic 2) o-Nbs-Cl, Et3N K2CO3, DMF R R CH2Cl2 enediyne 239 was obtained in 70% yield by cyclization, 227a-e 228a-e under high-dilution Mitsunobu conditions, of acyclic (Z)- Cl H enediyne 238, which was prepared in 84% yield by Cl (1) (2 equiv) coupling of alkyne 237 with (Z)-chloroenyne 109 in Et O at O Cl O 2 o-Nbs N o-Nbs N OEt PdCl2(PhCN)2 (10 mol%) OEt room temperature in the presence of n-BuNH2 and a R CuI (10 mol%) R n-BuNH2 (2 equiv), THF, rt combination of Pd(PPh3)4 and CuI as catalyst (Scheme 229a-e 230a-e 133 a: R = Bn (48%) 81). b: R = CH2C6H4OBoc (30%) c: R = i-Pr (32%) Scheme 79 d: R = H (50%) e: R = (CH2)4NH[Z(2-Cl)] (n.r.)

Scheme 79. Synthesis of (Z)-chloroenyne-modified amino acids 230a–e.

Compounds 228a–e were converted into alkynes 229a–e by treatment with propargyl bromide in DMF in the presence of K2CO3. Finally, the PdCl2(PhCN)2/CuI-

23 Tetrahedron

H Cl cycloaromatization by treatment with sodium methoxide in (109) (1.02 equiv) 136 OH OH refluxing MeOH. Pd(PPh3)4 (5.1 mol%) CuI (11.4 mol%) n-BuNH (6.1 equiv), Et O 1 TsHN COOMe 2 2 R rt, 5 h TsHN COOMe 237 (84%) 238 H R1 Pd(PPh3)4 (5 mlo%) PPh3 (1.38 equiv) CuI (1.5 mol%) DEAD (1.19) + n-BuNH (5 mol%) PhMe, THF CN 2 CN COOMe Cl Et O, 6 h, 25 °C rt, 15 min 2 (70%) NTs 1 2 242 243a: R = CH2OTHP (52%) 1 239 243b: R = (CH2)4Me (22%) 1 243c: R = (CH2)3Me (17%) 1 243d: R = (CH2)3OTHP (33%) Scheme 81. Synthesis of the 11-membered cyclic enediyne 239. Scheme 83. Synthesis of 2-(6-substituted-3-hexen-1,5- In 2009, the group of Ley successfully employed the diynyl)benzonitriles 243a–d. commercially available easily-handled encapsulated Pd species Pd-EnCat TPP30 as a catalyst component of the Specifically, treatment of 243a with 5 equiv of sodium microwave-mediated reaction of 1 with 0.5 equiv of 3,3- methoxide in refluxing MeOH for 6 h gave phenanthridine diethoxy-1-propyne, which was carried out in toluene, in 244a in 4% yield along with phenathridinone 245a in 7% the presence of 6 mol% CuI and 0.5 equiv of DBU yield. The reaction of 243b with sodium methoxide under (Scheme 82).135 The resulting chloroenyne 240 was the same reaction conditions gave 244b in 12% yield, 245b obtained in 89% yield. A similar procedure was then in 6% yield, and the biphenyl derivative 246b in 4% yield employed for the stereospecific synthesis of the (E)- (Scheme 84). Similarly, cycloaromatization of 243c configured compounds 241a and 241b in 67% yield from provided biphenyl 246c in 9% yield along with compounds (E)-1,2-dichloroethene (3) and 0.5 equiv of 3,3-diethoxy- 244c and 245c in 1 and 17% yield, respectively. Under the 1-propyne and 1 equiv of 3-methoxyphenylacetylene, same reaction conditions, 243d gave phenanthridine 244d respectively (Scheme 82).135 Remarkably, Pd-EnCat in 26% yield and isoquinoline 247 in 12% yield (Scheme 136 TPP30, containing co-encapsulated PPh3 ligand, could be 84). recovered and recycled by simple filtration of the reaction 135 R1 1 mixtures. R1 R

+ OEt Cl N NH Cl H (0.5 equiv) MeONa (5 equiv) OEt OMe O MeOH, reflux, 12 h OEt PhMe, DBU (0.5 equiv) CN 245a: 7% Cl 244a: 4% Pd-EnCat TPP30 (4 mol%) 245b: 6% CuI (6 mol%), 100 °C, 10 min OEt 244b: 12% 1 245c: 17% µW 243a: R = CH2OTHP 244c: 1% 1 240 1 (89%) 243b: R = (CH2)4Me 244d: 26% 1 243c: R = (CH2)3Me R1 1 243d: R = (CH2)3OTHP R1

Cl + Cl + N 1 (0.5-1 equiv) OMe R H CN PhMe, DBU (0.5 equiv) OMe Cl Pd-EnCat TPP30 (4 mol%) R1 246a: 0% 247: 12% CuI (6 mol%), 100 °C, 10 min 246b: 4% 1 3 µW 241a: R = CH(OEt)2 (67%) 246c: 9% 1 241b: R = 3-MeOC6H4 (67%) Scheme 84. Cycloaromatization of compounds 243a–d. Scheme 82. Synthesis of compounds 240, 241a and 241b. A plausible mechanism for the formation of compounds An extensive use of (Z)-1-chloro-1-en-3-ynes was made by 244, 245 and 247, involving methoxide addition to the Wu and coworkers in the synthesis of unsymmetrically cyano group of compounds 243, was proposed. The anionic substituted acyclic (Z)-3-en-1,5-diynes (used) as precursors cycloaromatization of (Z)-enediynes 243 and the product to heterocycles.93,136–140 As previously mentioned (Scheme formation in this mechanism were suggested to be 53), enediyne 52a was employed as a starting material in dependent upon the regiochemistry of the nucleophilic the synthesis of the 2-substituted benzofuran 143.93 addition reaction.136 Moreover, 2-(6-substituted-3-hexen-1,5- diynyl)benzonitriles 243a–d were prepared in 17–52% In 2004, Wu and coworkers synthesized 4-butyl-9H- yields by treatment of 2 equiv of 2-ethynylbenzonitrile carbazole (252a) in 58% yield by treatment of 2-(6-butyl- (242) with 1 equiv of the required (Z)-1-chloro-1-en-3-ynes 3(Z)-hexen-1,5-diynyl)aniline (251a) with t-BuOK in NMP 2 in Et O containing 5 mol% Pd(PPh ) , 15 mol% CuI, and 137 2 3 4 at 60 °C for 2 h (Scheme 85). The synthesis of compound 5 equiv of n-BuNH (Scheme 83).136 As shown in Scheme 2 251a from 1 was accomplished according to a reaction 84, compounds 243a–d were found to undergo sequence that involved the efficient conversion of 1 into

24 Tetrahedron unsymmetrically substituted (Z)-3-en-1,5-diyne 248 by followed by anionic cyclization and subsequent sigmatropic 138 sequential Pd(PPh3)4/CuI-catalyzed alkynylation reactions. rearrangement of the resulting compounds. The reaction of 248 with K2CO3 in MeOH provided compound 249 in 79% yield, which was coupled with 2- iodoaniline (250) in Et2O in the presence of n-BuNH2 and a SiMe3 1) n-Bu H n-Bu catalyst system consisting of a mixture of Pd(PPh3)4 and Pd(PPh3)4/CuI(cat) 137 n-BuNH2, Et2O Ar-I CuI to give 251a in 39% yield. Noteworthy, the 2) K2CO3, MeOH Cl H Pd(PPh3)4/CuI (cat) intramolecular anionic cyclization of 251a gave 252a along (53% over 2 steps) n-BuNH2, Et2O 2e (52-84%) n-Bu with the indole derivative 253a in 21% yield. n-Bu NaN3 n-Bu DMF, 80 °C, 12 h + N N Ar N Cl Me3Si H Ar N N N C4H9 H Ar Pd(PPh3)4/CuI(cat) Pd(PPh ) /CuI 254 255 256 Cl 3 4 (cat) Cl n-BuNH , Et O n-BuNH , Et O 2 2 SiMe 2 2 2f (91%) 3 1 (50%) 248 Scheme 87. Synthesis of triazoles 255 and 256. I (250) K2CO3, MeOH NH2 t-BuOK (2.5 equiv) n-Bu n-Bu (79%) Pd(PPh3)4/CuI(cat) NMP, 60 °C, 2 h N3 n-Bu H n-BuNH Et O 1,5 aryl shift 2, 2 NH Ar (39%) 2 [3+2] Ar 249 251a N Ar N N N N N 254 1, 5 aryl shift + N N n-Bu n-Bu H H 1,5 aryl shift protonation protonation 252a (58%) 253a (21%) N Ar N N n-Bu N N N Ar N Ar Scheme 85. Synthesis of compounds 252a and 253a. 255 N N 256 Various (Z)-2-(6-substituted 3-hexen-1,5-diynyl)anilines 251 were then prepared using the procedure employed for Scheme 88. Proposed mechanism for the formation of compounds the synthesis of 251a. Treatment of compounds 251 with t- 255 and 256. BuOK resulted in the formation of carbazoles 252 in 36– 60% yields along with indoles 253 in 21–40% yield In 2008, several (Z)-2-(6-substituted-3-hexen-1,5- (Scheme 86).136 diynyl)benzoates 258 were prepared in 62–89% yields by the reaction of (Z)-1-chloro-1-en-3-ynes 2 with methyl 2- R1 R1 ethynylbenzoate (257) in Et2O at room temperature for 6 h R1 t-BuOK, NMP in the presence of n-BuNH2 as base, 5 mol% Pd(PPh3)4 and + 139 60 °C 5 mol% CuI (Scheme 89). Compounds 258 were then N N H H reacted with 3 equiv of CuCl and 5 mol% PdCl in NH2 2 2 251 252 253 refluxing acetonitrile to give dibenzo[b,d]pyran-6-ones 259 in modest-to-good yields. However, the one-step tandem Scheme 86. Intramolecular anionic cyclization of enediynes 255. cyclization reaction of enediynes 258 bearing an electron- donating group on the aryl ring in the 6-position of the In 2005, several 1-aryl-1H-benzotriazoles were prepared in enediyne system gave compounds 259 as the major high yields from (Z)-3-en-1,5-diynes 254, which were products along with the minor trichloro derivatives 260 synthesized from (Z)-1-chloro-4-trimethylsilyl-1-buten-3- (Scheme 89).139 yne (2e) as outlined in Scheme 87.138 Treatment of R1 compounds 254 with sodium azide in DMF at 80 °C for 12 H PdCl (5 mol%) Pd(PPh ) (5 mol%) 2 3 4 CuCl (3 equiv) h provided 1-aryl-4-butyl-1H-benzo[d][1,2,3]-triazoles 255 CuI (5 mol%) 2 + MeCN, reflux, 1 h n-BuNH Et O Cl COOMe 2, 2 in 54-70% yields along with 7-butyl-1-aryl-1H- rt, 6 h 2 257 (62 - 89%) benzo[d][1,2,3]-triazoles 256 in 18–20% yields. COOMe Cl Cl Interestingly, when DMSO was employed as the solvent Cl 258 R1 R1 instead of DMF, compounds 255 were obtained in 24–64% Cl + yields and the yields of compounds 256 ranged from 43 to O O 138 67%. O O 260 A mechanism for the formation of compounds 255 and 256 was proposed (Scheme 88),138 involving a 1,3-dipolar Scheme 89. Synthesis of compounds 259 and 260. cycloaddition reaction of the azide anion to enediynes 254

25 Tetrahedron

More recently, several (Z)-enediynones 262 were mixture of 1,2-dibromoethene with terminal alkynes.143 In synthesized in high yields by of particular, they found that the reaction of 1,2- chloroenynes 2 with propargyl alcohol 261 followed by isopropylidenetetradeca-3,5,13-triyne (267) with 4 equiv of oxidation of the resulting cross-coupling products with a stereoisomeric mixture of 1,2-dibromoethene in Et3N at 140 MnO2 (Scheme 90). Compounds 262 were then treated room temperature for 12 h in the presence of 5 mol% with 2 equiv of hydrazine in acetonitrile at 60 °C for 1 h Pd(PPh3)4 and 11.9 mol% CuI gave 98% stereoisomerically and subsequently with 1 equiv of CuCl to provide 2,7- pure (E)-1-bromo-1-en-3-yne 268 in 62% yield (Scheme disubstituted pyrazolo[1,5-a]pyridines 263 in good yields 92). (Scheme 90). Noteworthy is that the cascade cyclization reaction leading to compounds 263 was able to tolerate O 140,141 O Br Pd(PPh3)4 (5.9 mol%) many functional groups. CuI (11.9 mol %) + H Et N, rt, 12 h Br 5 3 O (62%) R1 264 267 OH 1) Pd(PPh3)4/CuI(cat) Ph n-BuNH2 , Et2O (68 -88%) + Ph O OH 2) MnO , CH Cl (85 -98%) Cl H 2 2 2 O OH 1 2 261 R TsOH (cat), MeOH Ph 262 5 (74%) 5 Br Br 268 269 NH -NH (2 equiv) 2 2 N MeOH, 60 °C, 1h N

then CuCl (1 equiv) 1 Scheme 92. Synthesis of compounds 268 and (+)-diplyne A (269). reflux, 30 h R (45 -80%) 263 (R1 = alkyl , aryl) Removal of the acetonide protecting group from 268 using Scheme 90. Synthesis of pyrazolo[1,5-a]pyridines 263. a catalytic amount of TsOH in MeOH gave (+)-diplyne A (269) (Scheme 92).143 The enantiomer of 269, which was It is also worth mentioning that the copper-catalyzed isolated from the crude extract of the Philippine sponge cyclization of the enediynone 262 in which R1 = t-butyl Diplastrella sp., was found to inhibit the activity of the gave the expected pyrazolo[1,5-a]pyridine in 13% yield HIV-1 integrase,144 a 32-kDa protein produced from the C- along with 72% yield of an (η2-alkyne)copper complex, terminal portion of the Pol gene product, which is an which was apparently the intermediate to the final attractive target for new anti-HIV drugs. cyclization derivative.140 Gung and coworkers also reported that the reaction of 2.2 Monoalkynylation reactions of stereodefined and tetradeca-3,5,11,13-tetrayn-1,2-diol (270) with (E)/(Z)-1,2- (E)/(Z)-1,2-dibromo-1-alkenes and (E, E)-1,4-diiodo-1,3- dibromoethene (264) under experimental conditions very butadiene similar to those employed in the synthesis of 268 provided stereoselectively (+)-diplyne D in 56% yield (271) (Scheme In 2004, Organ and coworkers investigated the Sonogashira 93),143 which is the enantiomer of a second brominated reaction of a 1:1 mixture of (Z)- and (E)-1,2-dibromoethene polyacetylene isolated from Diplastrella sp.144 (264) and found that the reaction of 1.5 equiv of 1-hexyne with 1 equiv of 264 in THF at 60 °C in the presence of 2 OH Br OH equiv of piperidine, 5 mol% Pd(PPh3)4 and 5 mol% CuI + Pd(PPh3)4 (6.1 mol%) 142 Br H CuI (12.2 mol%) gave diyne 265 in 42% yield (Scheme 91). Surprisingly, 3 142 Et3N, rt, 6.5 h the monocoupling product 266 was not detected. On the 264 270 (56%) contrary, the formation of 265 was not a surprise since OH homocoupling products of 1-alkynes are common side OH products of Pd/Cu-catalyzed Sonogashira reactions.4b 3

Br n-Bu H (1.5 equiv) Br 271 n-Bu n-Bu + n-Bu Br Br Pd(PPh3)4 (5 mol%) CuI (5 mol%) 264 piperidine (2 equiv) 265 (42%) 266 (0%) THF, 60 °C, 5 h Scheme 93. Synthesis (+)-diplyne D (271).

Scheme 91. Synthesis of diyne 265 by Pd/Cu-catalyzed reaction Moreover, these authors prepared compound 273, the (+)- of 1-hexyne with (E)/(Z)-1,2-dibromoethene (264). enantiomer of diplyne E, in 42% yield by the Pd(PPh3)4/CuI-catalyzed reaction of tetradec-11-en-3,5,13- Again in 2004, and in contrast to these results, Gung and triyn-1,2-diol (272) with 4 equiv of 264 in Et3N (Scheme coworkers achieved successful stereoselective Sonogashira- 94).145 Diplyne E is another brominated polyacetylene type monoalkynylation reactions of a stereoisomeric isolated from Diplastrella sp.144

26 Tetrahedron

OH terminal alkynes, 3 mol% Pd(PPh ) , 10 mol% CuI, and 1.5 Br OH 3 4 Pd(PPh3)4 (6.1 mol%) + H CuI (12 mol%) equiv of Et3N in toluene at room temperature. Noteworthy Br 3 Et3N, rt, 16 h is that the reactions gave compounds 276 in good-to- (42%) 264 272 excellent yields when carried out within a dry box under 147 OH argon. OH

Table 1. Synthesis of monocoupling enynes 277 from 2,3- 3 Br 273 dibromonorbornadiene (275).

R1 R1 Scheme 94. Synthesis of (+)-diplyne E (273). Br R1 H + Pd(PPh3)4 (2 -3 mol%) However, compound 273 proved to be contaminated by ca. Br CuI (10 mol%) Br 144 275 Et3N (1.5 equiv) 277 276 THF, rt 10% of its stereoisomer 274 (Figure 11), a brominated R1 polyacetylene originating from the Takai olefination 146 277 276 reaction which was employed to prepare a precursor to Entry Equiv of 275 R1 Yield (%) Yield (%) 272.145 1 2 Ph a 45 a 39 2 5 a 48 47 OH Ph a OH 3 5 Me3Si b 47 b 50

4 2 n-Bu c 51 c 33 4 Br 274 5 5 n-Bu c 63 c 35 6 5 CH2OH d 49 polymeric material

Figure 11. Structure of compound 274. 7 5 (CH2)2OH e 70 polimeryc material

It is also worth noting that the stereochemical results of the Sonogashira-type reactions that provided stereoselectively In 2006, Buchwald and coworkers found that the reaction compounds 268, 271 and 273 were consistent with previous of 5-chloro-1-pentyne (278) with 2.5 equiv of 1,2- reports that (E)-1,2-dibromoethene is more reactive than dibromocyclopentene (279) in toluene at room temperature the corresponding (Z)-stereoisomer in Pd-catalyzed cross- in the presence of 3 mol% PdCl2(PPh3)2, 4 mol% CuI and 5 coupling reactions.66f equiv of n-hexylamine gave 1-bromo-2-(5-chloropent-1- ynyl)cyclopent-1-ene (280) in 85% yield (Scheme 95).148 In 2002, in order to synthesize unsymmetrically substituted H Pd(PPh3)4 (3 mol%) Br norbornadiene-2,3-diynes 276, Tranmer and Tam CuI (4 mol%) Cl + Br investigated the Sonogashira monoalkynylation of 2,3- n-C6H13NH2 (5 equiv) 147 Br PhMe, rt, overnight Cl (85%) dibromonorbornadiene (275) (Figure 12). 278 279 280

R1 I Br 1) n-BuLi

2) I2 Br Cl 275 276 281 2 R

Figure 12. Structures of compounds 275 and 276. Scheme 95. Synthesis of 1-bromo-1-en-3-yne 280.

The best results in the synthesis of 2-(1-alkynyl)-3- Compound 280 was then chemoselectively converted into bromonorbornadienes 277 were obtained when 1-alkynes iodoenyne 281 by treatment with n-BuLi followed by the addition of iodine.148 were reacted with 2–5 equiv of 275, 2–3 mol% Pd(PPh3)4, 10 mol% CuI, and 1.5 equiv of Et3N in THF at room 147 1-Bromo-2-(phenylethynyl)cyclopent-1-ene (282) and the temperature (Table 1). Unfortunately, unsatisfactory corresponding 1-iodo derivative 283 (Figure 13) were selectivity was observed for the reactions reported in Table similarly prepared from phenylacetylene and 1,2- 1, except for the one (entry 7) that provided compound dibromocyclopentene (279).148 277e in 70% yield. Nevertheless, in all cases examined, the required monocoupling products 277 were readily Br I separated from the corresponding dialkynylation derivatives 276 by column chromatography. Compounds Ph Ph 282 283 277 could then be employed in the synthesis of unsymmetrically substituted norbornadien-2,3-diynes 276 Figure 13. Structures of compounds 282 and 283. by a second Sonogashira coupling with 1.2 equiv of

27 Tetrahedron

Some interesting examples of the syntheses of In fact, the reaction produced the (Z)-coupling product 286 stereodefined highly functionalized 3-en-1,5-diynes via (Scheme 97).149a Unfortunately, the yield of the reaction regio- and stereospecific Sonogashira monoalkylation and the stereoisomeric purity of the cross-coupling product reactions of alkyl (Z)-2,3-dibromopropenoates with 1- were not reported. alkynes have also been reported in the literature. Myers and coworkers described the treatment of ethyl (Z)-2,3- In 2002, bromoenyne 290 was regioselectively synthesized dibromopropenoate (285) with 1.7 equiv of in 63.7% yield by monoalkynylation of 285 with methyl trimethylsilylacetylene, 5 mol% Pd(PPh3)4, 20 mol% CuI, propargyl ether according to the protocol described by and 1.7 equiv of i-Pr2NH in DMF at 0 °C for 10 h to give Myers, followed by reduction of the resulting 87–94% pure (Z)-bromoenyne 286 in 48–86% yields monocoupling compounds with DIBALH in THF at -78 °C (Scheme 96).149a,150 (Scheme 98). Compound 290 further participated in a Sonogashira reaction with alkyne 292 possessing a

Me3Si H Br (1.05 equiv) EtOOC Pd(PPh3)4 (5 mol%) cyanohydrin moiety to give compound 293, which upon H COOEt 2 Br CuI (20 mol%) CCl4 , 70 °C, 0.5 h Br treatment with Et N in MeOH produced efficiently the i-Pr NH (1.7 equiv) 3 284 (99%) 285 2 DMF, 0 °C, 10 h (86%) enyne-allenyl ketone 294. The reaction of 294 with 1.2 OTBDMS (287) equiv of Et3N in the presence of 50 equiv of 1,4- EtOOC CH(OEt)2 EtOOC Br SiMe cyclohexadiene gave the cycloaromatized derivative 296 3 PdCl2(PPh3)2 (5 mol%) SiMe3 CuI (20 mol%) and the adduct 297 via the biradical 295 (Scheme 98).151 286 n-PrNH2 (4 equiv), PhMe OTBDS 60 °C, 2 h CH(OEt)2 (83%) Interestingly, in basic buffer solution, biradical 295 showed 151 288 potent DNA-cleaving ability.

Scheme 96. Synthesis of (Z)-bromoenyne 286 and enediyne 288. In 2007, crude compound 286, which was obtained from ethyl (Z)-2,3-dibromopropenoate (285) according to the 149a,150 Moreover, the PdCl2(PPh3)2/CuI-catalyzed reaction of procedure reported by Myers and coworkers. was alkyne 287 with 1.2 equiv of 286 in toluene at 60 °C in the reduced with DIBALH in toluene at -78°C and the resulting presence of 4 equiv of n-PrNH2 produced enediyne 288 in alcohol was dissolved in benzene and treated with 3-(t- 83% yield (Scheme 96).149a Compound 285 was readily butylsimethylsilyloxy)-1- and n-BuNH2 in the available in quantitative yield by the reaction of ethyl presence of catalytic amounts of Pd(PPh3)4 and CuI at 60 152 propiolate (284) with 1.05 equiv of bromine in CCl4 at 70 °C for 6 h (Scheme 99). °C for 0.5 h (Scheme 96).149a OMe 1) Pd(PPh ) / CuI Br EtOOC Br 3 4 (cat) HO As regards the regioselectivity observed in the Pd/Cu- n-BuNH2, DMF, 0 °C MOMCl, i-Pr2NH CH Cl , reflux Br 2) DIBALH, THF, - 78 °C 2 2 OMe (93%) catalyzed monoalkynylation reaction of 285, it should be (98%) noted that the result illustrated in Scheme 96 could be 285 290 R1 R1 expected taking into account that the C–Br bond in the β- (292) Br Et3N MOM Pd(PPh3)4/CuI(cat) MOM MeOH position of 285, due to the conjugative effect in this α,β- n-PrNH2 , PhMe, 60 °C unsaturated ester, is more electrophilic than the C–Br bond OMe (34%) OMe 291 293 in the α-position and, therefore, undergoes preferentially the oxidative addition reaction with the catalytically active Ph O Ph MOMO MOMO C Pd(0) species. MOM O Ph O OMe OMe OMe An unexpected stereochemical result was, however, 294 295 observed when stereoisomerically pure ethyl (E)-2,3- Ph Ph dibromopropenoate (289), readily available in 81% yield by MOMO MOMO treatment of ethyl propiolate (284) with a suspension of 1.3 O + O OMe OMe equiv of pyridinium bromide perbromide in CH2Cl2 at 20 296 297 O 149a,b R1 = OMe °C for 40 h, was reacted with trimethylsilylacetylene NC Ph O under the same conditions employed in the synthesis of 286 from 285. Scheme 98. Synthesis of compounds 296 and 297 from 285.

Me3Si H N Br The resulting (E)-configured enediyne 298, which was Br3 EtOOC H Pd(PPh3)4 (1.7 equiv) H COOEt EtOOC CH2Cl2 , 23 °C, 40 h CuI (20 mol%) Br SiMe obtained in 40% yield over 3 steps, was then employed as Br 3 (97%) i-Pr2NH (1.7 equiv) 152 284 289 DMF, 0 °C 286 precursor to the racemic form 299 of (+)-estrone, an estrogenic hormone secreted by ovary as well as adipose Scheme 97. Synthesis of (Z)-bromoenyne 286 from ethyl (E)-2,3- tissue. dibromopropenoate (289).

28 Tetrahedron

R2 1) DIBALH, THF, - 78 °C 1) Cp2ZrEt2 EtOOC Br OTBDMS R1 EtOOC Br 2) R2 Br SiMe3 2) R1 R1 3) NBS Pd(PPh ) /CuI (cat) 1 Br Pd(PPh3)4/CuI 3 4 R Br n-BuNH , PhH, 50 °C i-Pr2NEt, DMF SiMe3 2 307 305 (40% over e steps) 285 286

O Scheme 102. Synthesis of (Z)-1-bromo-1-en-3-ynes 305.

OTBDMS H HOH2C H H We would also like to point out that, as far as we know, no HO protocol has been reported to date for the successful SiMe3 298 299 synthesis of stereodefined 1-iodo-1-en-3-ynes by Sonogashira reaction of stereodefined 1,2-diiodoalkenes Scheme 99. Synthesis of racemic estrone (299) from ethyl (Z)- with terminal alkynes.156 In the only study carried out so far 2,3-dibromopropenoate (285). on this type of reaction, Organ and coworkers found that treatment of (E)-1,2-diiodoethene (308) with 1-hexyne in Myers’ protocol149a,150 was also employed for the synthesis THF at 60 °C in the presence of 2 equiv of piperidine, 5 of methyl (Z)-2-bromo-2-en-4-ynoates 302 and 303 in 56% mol% Pd(PPh ) , and 5 mol% CuI gave 1,3-diyne 309 in and 63% yield, respectively, from methyl (Z)-2,3- 3 4 51% yield and did not produce the required (E)-1-iodo-1- dibromopropenoate (301) and the required terminal alkynes en-3-yne (Scheme 103).142 (Scheme 100).148 Scheme 100 illustrates the synthesis of compound 301 in 90% yield, which was carried out by the n-C4H9 n-C4H9 H (1.5 equiv) I Pd(PPh3)4 (5 mol%) dropwise addition of bromine to a CCl4 solution of methyl I CuI (5 mol%) n-C4H9 propiolate (300) heated at 70 °C, its conversion into enynes 308 piperidine (2 equiv) 309 THF, 60 °C, 5 h 302 and 303, and the three-step synthesis of iodoenyne 304 (51%) from 302.148 Scheme 103. Formation of diyne 309 from 1-hexyne and (E)-1,2- MeOOC Br R1 (1.65 equiv) Br2 (1.05 equiv) diiodoethene (308). H COOMe CCl , 70 °C, 0.5 h Pd(PPh3)4 (5 mol%) 4 Br (90%) CuI (20 mol%) 301 300 i-Pr2NEt (1.65 equiv) DMF, 0 °C Nevertheless, in 2009, Gong and Omollo succeeded in (for 302) Br MeOOC Br 1) DIBALH, Et O, rt TIPSO performing the Sonogashira monoalkynylation of (E,E)-1,4- 2 157 2) TIPSOTf, lutidine diiodo-1,3-butadiene (311). In fact, the reaction of 2 CH Cl ,0 °C to rt 2 2 n-C5H11 R1 (70% over 2 steps) equiv of 311 with 1 equiv of enantiomerically pure (R)-1- 1 302: R = n-C5H11 hexyn-3-ol (310) in a 5:1 mixture of benzene and pyridine 303: R1= at room temperature for 1 h, in the presence of 16.8 mol% I TIPSO PdCl (PPh ) and 13 mol% CuI, gave iodoenyne 312 in NaI (1.49 mol%), CuI (5 mol%) 2 3 2 MeNH(CH2)2NHMe ( 10 mol%) 63% yield (Scheme 104). The subsequent Sonogashira n-BuOH, 120 °C n-C5H11 (68%) 304 reaction between 312 and 1.34 equiv of 1,3-diyne 313 produced (R) (7E,9E)-10-dodeca-7,9-dien-5-yn-1-ol (314) Scheme 100. Synthesis of iodoenyne 304 from methyl propiolate in 73% yield, which was then employed as a precursor to (300). (R)-cicutoxin (315) (Scheme 104),157 a major toxic component of the water hemlocks, Cicuta virosa and C. Recently, 2,3,5-trisubstituted thiophenes 306 were maculata.158–160 synthesized from (Z)-1-bromo-1-en-3-ynes 305 according 153 OH OH to the procedure illustrated in Scheme 101. PdCl2(PPh3)2 (16.8 mol%) CuI (13.0 mol%) + I I PhH/piperidine (5:1) I 2 H R 1) i-Pr3SiSH (1.2 equiv) 310 311 rt, 2 h 312 1 R1 Pd2(dba)3 (2.5 mol%) R (63%) Xantphos (5 mol%) R1 Br LiHMDS (1.2 equiv) R1 S R2 OTHP (313) OH 2) TBAF (3 equiv), rt, 2 h 305 306 PdCl2(PPh3)2 (6.25 mol%) 2 steps CuI (12.5 mol%) PhH/Et N (4:1), rt, 1 h 3 314 (38% for 2 steps) Scheme 101. Synthesis of 2,3,5-trisubstituted thiophenes 306. (73%) OH OTHP

However, compounds 305 were not obtained by 315 OH Sonogashira monoalkynylation of the corresponding (Z)- 1,2-dibromoalkenes, but their synthesis was performed by Scheme 104. Synthesis of (R)-cicutoxin (315). stereocontrolled alkynylzirconation of alkynes 307 with

Cp2ZrEt2 and 1-bromo-1-alkynes and subsequent addition of N-bromosuccinimide (Scheme 102).154,155 2.3 Monoalkynylation reactions of stereodefined 1- bromo-2-chloro-, 1-bromo-2-iodo-, 1-bromo-2-

29 Tetrahedron

trifluoromethanesulfonyloxy-, 1-chloro-2-iodo-, and 1- PdCl2(PPh3)2, 15 mol% CuI, and 3 equiv of i-Pr2NEt fluoro-2-iodo-1-alkenes, and (1Z,3E)-1-chloro-3-iodo- produced chemoselectively and stereospecifically ethyl (Z)- 1,3-butadiene 2-(1-alkynyl)-3-chloro-2-alkenoates 322a-h in good yields (Scheme 106).162 Before presenting and commenting on the results of the title reactions, we feel it is worth mentioning that, although R1 R2 (3 equiv) 1 n-Bu4NI (1 equiv) I PdCl (PPh ) (10 mol%) R COOEt Cl 2 3 2 Cl(CH2)2Cl, reflux, 18 h CuI (15 mol%) the exact mechanism of the Pd/Cu-catalyzed Sonogashira (62 -91%) COOEt 1 i-Pr2NEt ( 3 equiv) 320a: R = Me CH Cl , 0 °C or rt, 2 h 1 2 2 reactions is still at present unknown, it is generally believed 320b: R = c-C6H11 321a: R1= Me 320c: R1= TBDMSO(CH ) 1 2 2 321b: R = c-C6H11 that (i) the catalytic cycle of the reactions involving alkenyl 1 321c: R = TBDMSO(CH2)2 (pseudo)halides is initiated by the oxidative addition of R2 ( for 322a and 322c) R1 R2 these electrophiles to a catalytically active Pd(0) 1 4d,5d R Ph (6 equiv) PdCl (PPh ) (10 mol%) species, and that (ii) this addition, which is considered COOEt 2 3 2 Cl CuI (15 mol%) Ph COOEt to be the rate-determining step, is the main source of the i-Pr2NEt (3 equiv) 322a-h dioxane, rt, 18 h selectivity observed in Pd/Cu-catalyzed monoalkynylation 323a,b 2 Compounds 322 Compounds 323 Yield(%) Yield(%) reactions of alkenes bearing two different C(sp ) R1 R2 R1 R2 electrophilic sites. The observed order of reactivity of these a Me Ph 78 a Me Ph 79 2 2 2 77 b Me SiMe 42 sites is as follows: C(sp )–I > C(sp )–OTf > C(sp )–Br > b Me 4-FC6H4 3 2 2 c 68 C(sp )–Cl >> C(sp )–F. This order is related to the relative Me Me3Si 74 2 d Me n-C6H13 bond-dissociation energies of the C(sp )–(pseudo)halogen 72 e Me (CH2)2OTBDMS bonds. 76 f Me CH2OTBDMS 68 g c-C6H11 Ph 79 In accordance with the foregoing, in 2004, Organ and h TBDMSO(CH2)2 SiMe3 coworkers found that the reaction of (E)-1-chloro-2- iodoethene (316) with 1.5 equiv of 1-hexyne in THF at 60 Scheme 106. Synthesis of chloroenynes 322 and enediynes 323. °C in the presence of 5 mol% Pd(PPh3)4, 5 mol% CuI, and 2 equiv of piperidine gave (E)-1-chloro-1-octen-3-yne (317) in 42% yield along with a trace amount of (E)- Notably, the alkynylation reaction occurred exclusively at enediyne 318 (Scheme 105).142 the 2-position of compounds 321, which in principle is less activated than the 3-position towards oxidative addition to a n-Bu (1.5 equiv) catalytically active Pd(0) species. Thus, the coupling was I n-Bu n-Bu Cl + Pd(PPh3)4 (5 mol%) halogen selective and this result can be explained taking Cl n-Bu 316 CuI (5 mol%) 317 318 2 piperidine (2 equiv) into account the higher reactivity of the C(sp )–I bond over THF, 60 °C, 5 h the C(sp2)–Cl bond. Scheme 105. Synthesis of (E)-1-chloro-1-en-3-yne 317. As shown in Scheme 106, compounds 322a and 322c On the contrary, the reaction of (E)-1-bromo-2-iodoethene proved to be able to undergo a Sonogashira reaction with a (319) (Figure 14) with 1-hexyne under similar experimental large molar excess of phenylacetylene to give the sterically 162 conditions provided 5,5-dodecadiyne in 62% yield142 and crowded enediynes 323a and 323b in satisfactory yields. the required 1-bromo-1-en-3-yne could not be detected. In 2011, Zhu and coworkers reported that the I Br PdCl2(PPh3)2/CuI-catalyzed reaction of (Z)-4-chloro-5- 319 iodo-5-phenyl-4-pentenal (326) with 2 equiv of phenylacetylene in toluene at 40 °C in the presence of 3 Figure 14. Structure of compound 319. equiv of Et3N occurred with halogen selectivity similar to that observed for the Sonogashira reaction of compounds Compound 316 was synthesized in 59% yield by bubbling 321162 to give chloroenyne 327 in 65% yield (Scheme acetylene gas through a solution of ICl in HCl at -10 °C161 107).163 and (E)-1-bromo-2-iodoethene (319) was obtained in 56% yield by bubbling acetylene gas through a solution of IBr in Pd(OAc)2 (5 mol%) 142 LiI (2 equiv) Cl CHO Ph Cl + CHO 48% HBr at 0 °C. AcOH, rt, 1 h I Ph 324 325 (65%) Ph 326 In 2006, Ogilvie and coworkers synthesized ethyl (E)-3- Ph (2 equiv) PdCl2(PPh3)2 (5 mol%) Cl chloro-2-iodo-2-alkenoates 321a-c by exposure of the CuI (15 mol%) CHO Et3N (3 equiv), PhMe Ph corresponding ethyl 2-alkynoates 320a-c to n-Bu4NI in 40 °C, overnight (65%) 327 refluxing dichloroethane and found that the reaction of compounds 321a-c with 3 equiv of 1-alkynes in CH2Cl2 at Scheme 107. Synthesis of chloroenyne 327. room temperature in the presence of 10 mol%

30 Tetrahedron

Compound 326 was prepared in 65% yield by treatment of Figure 15. Structure of enediyne 333 (FAUC 88). 1-chloro-2-phenylacetylene (324) with a solution of 5 equiv of acrolein (325), 2 equiv of LiI, and 5 mol% Pd(OAc)2 in Very recently, Zhu and coworkers reported the first AcOH at room temperature (Scheme 107).163 example of chemo-, regio- and stereoselective Sonogashira monoalkynylation of a stereodefined 1-bromo-2-chloro-1- More recently, efforts by Koester and Werz to react .166 They prepared (Z)-1-bromo-2-chloro-2- perbenzylated 2-chloro-1-iodoglucal 328 with phenylethene (335) in 87% yield by treatment of 1-bromo- phenylacetylene resulted in a halogen-selective 2-phenylacetylene (334) with 2 equiv of LiCl, 2.6 mol% 3 monoalkynylation of the pseudoanomeric position that [(η -C3H5)PdCl]2 and 10 mol% cis,cis-1,5-cyclooctadiene provided 1-phenylethynyl-3,4,6-tri-O-benzyl-2- in AcOH at 80 °C for 6 h. Compound 335 was then reacted chloroglucal (329) in quantitative yield (Scheme 108). The with 1.5 equiv of phenylacetylene, 3 equiv of Et3N, 5 mol% reaction was carried out in refluxing Et3N for 12 h in the PdCl2(PPh3)2 and 15 mol% CuI in toluene at 80 °C to give presence of 5 mol% PdCl2(PPh3)2 and 10 mol% CuI. Even (Z)-chloroenyne 336 in 81% yield with complete halogen the use of an elevated temperature did not lead to the selectivity (Scheme 110).166 formation of the required enediyne.164

(10 mol%) Cl Ph (1.5 equiv) OBn Ph (2 -3 equiv) OBn LiCl (2 equiv) Br PdCl2(PPh3)2 (5 mol%) O PdCl (PPh ) (5 mol%) BnO Ph Br Ph BnO 2 3 2 3 I [(η -C3H5)PdCl2] (2.6 mol%) CuI (15 mol%) BnO CuI (10 mol%) BnO Ph H Et N (3 equiv) Cl 334 AcOH, 80 °C, 6 h 335 3 Cl Et3N, reflux PhMe, 80 °C (81%) 328 (99%) 329 (81%) Cl Ph p-Tolyl Ph p-TolylB(OH)2 (1.5 equiv) Pd(OAc) (5 mol%) Ph 2 Ph Scheme 108. Halogen-selective synthesis of compound 329. H PPh3 (10 mol%) H Cs2CO3 (2 equiv) 336 PhMe, dioxane, 90 °C 337 (70%) The first and only example of chemoselective Sonogashira monocoupling of a 2-bromo-1-enyl triflate was reported by Scheme 110. Synthesis of enynes 336 and 337. Gmeiner and coworkers in 2005.165 They found that the reaction of 2-bromocyclohex-1-en-1-yl triflate (330) with Moreover, the Pd(OAc)2/PPh3-catalyzed Suzuki-Miyaura 4.4 equiv of trimethylsilylacetylene in THF at 40 °C for 3.5 reaction167 of 336 with p-tolylboronic acid gave the 166 h in the presence of 15.2 mol% Pd(PPh3)4, 16.9 mol% CuI trisubstituted enyne 337 in 70% yield (Scheme 110). and 12.9 equiv of piperidine gave dipropyl-[3-bromo-4- (trimethylsilylethynyl)-cyclohex-3-en-1-yl]amine (331) in In 1991, Eddarir and coworkers reported some examples of 67% yield along with the 1,2-dialkynylation derivative 332 chemo-and regioselective copper-free Sonogashira in 7% yield (Scheme 109).165 monocoupling reactions of 1-bromo-2-fluoro-1-alkenes. 168,169 As expected on the basis of the significant difference NPr2 NPr2 2 2 NPr2 Me3Si (4 equiv) in reactivity between C(sp )–F and C(sp )–Br bonds in Pd-

PdCl2(PPh3)2 (5mol%) Br + catalyzed reactions, the Sonogashira reactions produced 1- Br CuI (16.9 mol%) piperidine (12.5 equiv) SiMe3 fluoro-1-en-3-ynes. On the other hand, it should also be OTf THF, 40 °C, 3.5 h

SiMe3 SiMe3 taken into account that successful Sonogashira reactions of 330 331 332 alkenyl fluorides have not been described to date.

Scheme 109. Synthesis of compounds 331 and 332. Eddarir and coworkers found that the reaction of stereoisomeric mixtures of 1-bromo-2-fluoro-1-alkenes As expected, a lower selectivity was observed when 330 338a-d with 2 equiv of phenylacetylene, 2 mol% Pd(OAc)2 was reacted with 5.9 equiv of trimethylsilylacetylene at 95 and 4 mol% PPh3 in refluxing Et3N for 3 h gave °C in the presence of 10 mol% Pd(PPh ) , 11.1 mol% CuI 3 4 fluoroenynes 339a-d in satisfactory-to-good yields. and 9.5 equiv of piperidine. The reaction gave 324 in 42% (Scheme 111).168 However, unexpectedly, not all couplings 165 yield along with 332 in 24% yield. Interestingly, proved to be stereoselective. For example, the Pd/Cu- cleavage of the C(sp)–SiMe3 groups of 332 with TBAF led catalyzed reaction between phenylacetylene and an E/Z to the neuroceptor-active enediyne 333 (FAUC 88) (Figure mixture of compound 338d in a 2:98 ratio, respectively, 15), which displayed a highly selective dopamine D3 provided in 63% yield an E/Z mixture of 339d in a 45:55 165 receptor affinity. ratio, respectively (Scheme 111).

NPr2

333

31 Tetrahedron

Ph F 2 Ph ( 2 equiv) R (1.2 equiv) H F H F 1 Br CuI, KI Pd(OAc) (5 mol%) R Pd(OAc)2 (2 mol%) 2 1 1 1 H R FC C R FC C 1 DMF R 2 PPh ( 4 mol%) 2 R IFp-Tol CuI (16 mol%) R 3 R I Et3N, relfux, 3 h Et3NH, rt, overnight 338 339 R2 342 343 344

Compounds 339 Compounds 338 E/Z E/Z Compounds 344 R1 R2 Yield (%) Yield% 1 a(i) 83 92/8 R R2 a(i) Ph H 92/8 MeOOC(CH ) n-Bu 85 b 74 90/10 a 2 8 b n-C5H11 H 90/10 c 68 40/60 b MeOOC(CH2)8 SiMe3 80 c COOEt Ph 5/95 d 63 45/ 5 c MeOOC(CH2)8 Ph 84 d COOEt 2-AcO -3-MeOC6H3 2/98 d MeOOC(CH2)8 THPOCH2 88 (i) Reaction run in n-BuNH instead of Et N. 2 3 e MeOOC(CH2)8 EtOOC-CMe2CH2 77

f Cl(CH ) SiMe 92 Scheme 111. Synthesis of fluoroenynes 339. 2 9 3 g Cl(CH2)9 AcO(CH2)9 78 84 Compounds 338 were not commercially available and those h Cl(CH2)9 Ph i AcO(CH ) cyclohexenyl 78 with R2 = H, i.e. 338a and 338b, were prepared from the 2 9 j AcO(CH2)9 Ph 84 corresponding 1-alkynes by treatment with 1,3-dibromo- 85 k Ph THPOCH2 5,5-dimethylhydantoin (340) and pyridine⋅HF complex in 67 l Ph EtOOC-CMe2CH2 sulfolane at 0–20 °C (Scheme 112).168 m Ph MeOOC(CH2)8 90

n n-C10H21 THPOCH2 90 MeO Me • HF Br N o n-C10H21 n-Bu 78 R1 H + N Br CFR1 C sulfolane H Br 0 °C to 20 °C O 340 338 a, b Scheme 114. Stereoselective synthesis of (E)-fluoroenynes 344.

Scheme 112. Synthesis of 1-bromo-2-fluoro-1-alkenes 338a and Compounds 344 included polyfunctional derivatives such 338b. as 344d, 344e and 344g.

C H On the other hand, compounds 338c and 338d were F 5 11 F COOMe H OH 6 synthesized in 100 and 74% yield, respectively, by the MeOOC(CH2)7 Pd(OAc) /CuI I 2 (cat) Et NH, rt n-C5H11 addition of 1.5 equiv of bromine to (Z)-unsaturated esters 343p 3 345 (91%) 341170 followed by dehydrobromination with 2 equiv of OH DBU in THF at 20 °C (Scheme 113).168 Scheme 115. Stereoselective synthesis of compound 345.

1) Br (1.5 equiv), CCl 60 °C, 3 h Br 2 2 4, (EtOOC)FC CHR (EtOOC)FC C 2) DBU (2 equiv), THF, 20 °C, 10 min R2 It should be noted that the carboxylic acid corresponding to 341 338c: R2 = Ph(100%) methyl ester 345 is a fluorinated analogue of 11,12- 2 338d: R = 2-AcO-3-MeOC6H4(74%) dehydrocoriolic acid (346) (Figure 16), a polyunsaturated carboxylic acid, which was found to exhibit a stronger Scheme 113. Synthesis of compounds 338c and 338d. inhibitory activity than the naturally occurring coriolic acid 174,175 It is worth noting that the use of a copper-free protocol for (347) (Figure 16) against rice blast fungus. the Sonogashira reaction between phenylacetylene and COOH 1 COOH R 6 compounds 338 allowed the phenylacetylene dimerization 6 R n-C H Cl 171 n-C H 5 11 via copper-mediated to be avoided, thus 5 11 R2 I OH 3 making it easier to isolate compounds 339. OH R 346 347 348 349

172 In 2001, Yoshida and coworkers synthesized chemo- and Figure 16. Structures of compounds 346–349. stereoselectively (E)-1-fluoro-1-en-3-ynes 344a-o, in high yields by Pd(OAc)2/CuI-catalyzed reaction of 1-alkynes In concluding this subsection, we wish to mention the with β-fluoroalkenyl iodides 343a-o, which were obtained results obtained by Alami and coworkers in the context of a by treatment of (E)-(β-fluoroalkenyl)iodonium salts 342a- study on the synthesis of dienediynes of general formula o173 with CuI and KI in DMF (Scheme 114). 348 by sequential chemoselective Sonogashira reactions of 1-chloro-3-iodo-1,3-butadienes 349 (Figure 16).176 They The usefulness of the method for preparing compounds 344 found that the Pd(PPh3)4/CuI-catalyzed reaction of 349a was then illustrated by the synthesis of 9- with propargyl alcohol in piperidine provided chemo- and fluorodehydrocoriolic acid methyl ester (345) in 91% yield regioselectively 3-(1-alkynyl)-1,3-butadiene 350 in 82% from methyl (E)-10-iodo-9-fluoro-9-decenoate (343p) and yield (Scheme 116). Treatment of this compound with 3- 172 racemic 1-octyn-3-ol (Scheme 115). hydroxy-1-butyne in piperidine in the presence of a

32 Tetrahedron

PdCl (PhCN) /CuI catalyst system gave compound 348a in 2 2 R1 (1.56 equiv) 176 F N F Li (1.47 equiv) 55% yield (Scheme 116). However, during the F PdCl2(PPh3)2 (2.2 mol%) CFBr2 THF, - 98 °C, 12 min CuI (2.2 mol%) purification step, compound 348a underwent a partial (87%) Br Et3N, rt, 8 -16 h 176 354 stereomutation of its trisubstituted double bond. 355

F OH F OH Ph Ph Me Ph Cl Pd(PPh3)4/CuI(cat) PdCl (PhCN) /CuI Cl 2 2 (cat) HO 1 I piperidine piperidine R (82%) (55%) Me 1 OH 356a: R = Ph (30%) 349a 350 OH 348a 1 356b: R = HO(CH2)2 (64%)

Scheme 116. Synthesis of compounds 350 and 348a from 1- Scheme 118. Synthesis of (Z)-1,2-difluoro-1-en-3-ynes 356a,b. chloro-3-iodo-1,3-butadiene 349a. More recently, a tandem process involving a 2.4 Monoalkynylation reactions of trihalogenated chemoselective Pd/Cu-catalyzed Sonogashira ethene derivatives bearing two different halogen atoms monoalkynylation reaction followed by a 6-endo-dig cyclization reaction was employed to prepare in satisfactory A few examples of Sonogashira monoalkynylation yields 3,4-difluoro-6-substituted-2-pyrones 358a–f as the reactions of trihalogenated ethene derivatives bearing two sole products from (E)-2,3-difluoro-3-iodoacrylic acid different halogen atoms have ben reported in the literature (357), 1.1 equiv of the required terminal alkyne, 2 mol% to date. In 1990, Löffler and Himbert177 described that the PdCl2(PPh3)2, 5 mol% CuI, and 4 equiv of acetonitrile at reaction of arylacetylenes with 1.57 equiv of 2-bromo-1,1- 180 178 room temperature (Scheme 119). dichloroethene (351) and catalytic amounts of PdCl (PPh ) and CuI in refluxing Et N occurred chemo- F 2 3 2 3 R1 (1.2 equiv) F F F and stereoselectively to give 1,1-dichloro-1-buten-3-ynes PdCl2(PPh3)2 (2 mol%) CuI (5 mol%) 1 I COOH R O O 1 352a-c in modest-to-satisfactory yields, which could be Et3N (4 equiv), MeCN a: R = Ph (62% 1 357 rt, 12 -24 h 358 b: R = n-C5H11 (59%) 1 converted to (1,3-butadiynyl)amines 353 by treatment with c: R = Ph(CH2)2 (64%) 1 d: R = 4-CF3C6H4 (69%) 2.6 equiv of lithium amides in Et O at room temperature 1 2 e: R = 4-MeOC6H4 (71%) 177 1 (Scheme 117). f: R = 2-pyridyl C C (43%)

H Ar (1 equiv) R1R2NLi (2.6 equiv) Scheme 119. Synthesis of 3,4-difluoro-6-substituted-2-pyrones H Cl PdCl2(PPh3)2 (0.4 mol%) Et2O, rt, 4 h Br Ar Cl CuI (0.75 mol%) Cl 358a–f. Et3N, reflux, 4 h 351 Cl 352a: Ar = Ph (68%) 352b: Ar = 4-MeC6H4 The mechanism which was proposed to explain the R1 352c: Ar = 4-MeOC6H4 Ar N formation of compounds 358 (Scheme 120) involved two R2 353 catalytic cycles.180 In the first of these (cycle A), (Z)-2,3- difluoro-2-en-4-ynoic acids 359 were formed by a typical Scheme 117. Synthesis of 1,1-dichloro-1-en-3-ynes 352 and Pd/Cu-catalyzed Sonogashira reaction. In the second diynes 353. catalytic cycle (cycle B), compounds 359 were transformed into the final products 358 by a Pd(II)-catalyzed 6-endo-dig Eight years later, it was found that 1-bromo-1,2-difluoro-2- cyclization reaction. It should be noted, however, that this (1-naphthyl)ethene (355), which was obtained by treatment mechanism does not take into account that the Pd(II)- of 1,1-dibromo-1,2-difluoro-2-(1-naphthyl)ethane (354) catalyzed cyclization reactions of (Z)-2-en-3-ynoic acids with 1.47 equiv of lithium 2,2,6,6-tetramethylpiperidide in generally occur with poor regioselectivity, affording THF at -98 °C, was able to react with 1.56 equiv of mixtures of 2-pyrones and γ-alkylidenebutenolides.181 terminal alkynes, such as phenylacetylene or 1-butyn-3-ol, 2.2 mol% PdCl2(PPh3)2 and 2.2 mol% CuI in Et3N at room temperature to give (Z)-1,2-difluoro-1-en-3-ynes 356a,b in modest yields and with retention of configuration (Scheme 118).179

33 Tetrahedron

PdCl2(PPh3)2 F with 2.2 equiv of 1-alkynes different from those employed R1 , CuI, Et N F 3 for their synthesis to give unsymmetrical enediynes 363 Et3NHI 183 R1 O O R1 (Figure 17) in 70–75% yield. F 358

HPd F (Ph3P)2Pd 184 R1 R1 O O In 2003, Qian and Negishi employed the valuable HX 183 R1 R1 F F protocol developed by Linstrumelle to prepare HX Pd(0) B I COOH compounds 361d, 361e and 2-chloro-1-decen-3-yne (361f) HPdX (Figure 17) in 82, 69 and 66% yield, respectively. These F F H F F substances were formed along with 5, < 1 and 4%, X Pd COOH A IPd COOH respectively, of the symmetrical enediynes 364d, 364e and R1 364f (Figure 17).183 Interestingly, the selectivity of the 1 R , CuI, Et3N reaction that produced 361f proved to be significantly F F F F Et3NHI higher than that of the Pd(t-Bu P) -catalyzed cross-coupling COOH Pd COOH 3 2 reaction between 1-octynylzinc bromide and 5 equiv of 360 R1 359 R1 which provided 361f in 33% yield along with 364f in 22% yield (Scheme 122).184 Scheme 120. Proposed mechanism for synthesis of compounds

358. n-C6H13 ZnBr + Cl Cl Pd(t-Bu3P)2 (5 mol%) Cl n-C6H13 THF, 23 °C, 6 h n-C6H13 n-C6H13 3. Monoalkynylation reactions of 1,1-dihalogenated 1- 360 361f 364f alkenes Scheme 122. Synthesis of compounds 361f and 364f via Negishi 3.1 Monoalkynylation reactions of 1,1-dichloro-1- cross-coupling reaction. alkenes182 Compounds 361 were then found to be useful precursors to 184–186 The first examples of Sonogashira monoalkynylation terminal 1,3-diynes 54 and unsymmetrically 1,4- 184,187 reactions of 1,1-dichloroethene (360) were described in disubstituted 1,3-diynes 365 (Scheme 123). 1987 by Linstrumelle and coworkers.183 They reported that 1) LDA (2 equiv) THF, - 78 °C the reaction of 5 equiv of 360 with 1 equiv of 1-alkynes, 5 R1 H 2) H2O 54 mol% Pd(PPh3)4, 5 mol% CuI, and 1.5 equiv of n-BuNH2 in Cl 1) LDA (2 equiv), THF, - 78 °C benzene at room temperature gave 2-chloro-1-en-3-ynes R1 2) ZnBr2 (1.1 equiv), 0 °C 1 361 R Ar 361 in excellent yields and with high selectivity. The 3) ArX, Pd(PPh3)4 (5 mol%) 0 - 23 °C, 3 h 365 synthesis of compounds 361a–e is depicted in Scheme (67 - 93%) 121. Scheme 123. Synthesis of 1,3-diynes 54 and 365.

R1 Pd(PPh3)4 (5 mol%) 188 Cl 1 Cl Cl CuI (5 mol%) a: R = C5H11 (81%) Again in 2003, Negishi and coworkers carried out the 1 1 n-BuNH2 (1.5 equiv) R b: R = (CH2)3Cl (82%) PhH, rt 1 360 361 c: R = (CH2)2OAc (72%) Sonogashira-type monoalkynylation reaction of 1,1- d: R1 = Ph (90%) 1 dichloro-1-alkenes 366 under experimental conditions e: R = SiMe3 (82%) significantly different from those used in the synthesis of 187 Scheme 121. Synthesis of compounds 361a–e. compounds 361. Specifically, compounds 366a–c were reacted with 1.5 equiv of trimethylsilylacetylene, 5 mol% In the case of the synthesis of compound 361a, less than PdCl2(DPEphos), 5 mol% CuI, and 6 equiv of i-Pr2NH in 4% of the symmetrically 1,1-disubstituted dialkynyl benzene at room temperature. The resulting (Z)-configured derivative 362a (Figure 17) was in fact detected in the monocoupling products 367a–c, which were obtained in crude reaction mixture. 56–90% yields, were, however, accompanied by significant amounts of the corresponding bis-alkynylation derivatives

Cl 369a–c and, in the case of the reactions involving 366a and 1 2 1 1 C5H11 C5H11 R R n-C6H13 R R 366b, by the (E)-configured derivatives 368a and 368b, 362a 363 361f 364 respectively, in 3% yield, and by compound 368c in less d: R1 = Ph 188 1 e: R = SiMe3 than 1% yield (Scheme 124). 1 f: R = n-C6H13

Figure 17. Structures of compounds 362a, 363 361f, and 364d-f.

It was also found that compounds 361, under conditions similar to those reported in Scheme 121, were able to react

34 Tetrahedron

Cl R1 reactions of (E)- and (Z)-1-bromo-1-alkenes are Cl 366a: R1 = Ph substantially different and that (E)-bromides undergo 1 366b: R = Me3SiC C 366c: R1 = TBDSOCH CH(Me)CH preferentially intermolecular Pd-catalyzed cross-coupling 2 2 66 Me3Si reactions. PdCl2(DPEphos) (5 mol%) CuI (5 mol%) i-Pr2NH (6 equiv), PhH N Me Me rt, 0.5 h Cl H O O Pd(PPh3)4 (10 mol%) Cl SiMe3 O Br SiMe3 CuI (30 mol%) 1 + OTBDMS R + Et N (2 equiv), 23 °C + Br 3 HO (61%) SiMe3 1 Me Si R R1 TBDMS 3 371 372 N 367a (84%) 368a (3%) SiMe3 Me Me 367b (56%) 369a (12%) 368b (3%) Cl O O 367c (90%) 368c (<1%) 369b (4%) 369c (10%) O H OTBDMS HO Br

Scheme 124. Sonogashira-type reactions of 1,1-dichloro-1- TBDMS 373 alkenes 366a–c. Me3Si

Interestingly, compounds 367, which could also be Scheme 126. Synthesis of bromoenyne 373. obtained stereoselectively and in good yields by In 2002, Myers and coworkers described the first PdCl2(DPEphos)-catalyzed reaction of dichloroalkenes 366 with trimethylsilylethynylzinc chloride or bromide, proved enantioselective synthesis of the kedarcidin chromophore aglycon in a differentially protected form 377.193 2-Bromo- to be able to undergo stereospecific Pd(t-Bu3P)2-catalyzed methylation with dimethylzinc or methylzinc halides to 1-en-3-yne 376, which was prepared in 61% yield by 188 give the (E)-configured derivatives 370 (Scheme 125). Pd(PPh3)4/CuI-catalyzed reaction of 1,1-dibromo-1-alkene 374 with alkyne 375 in t-BuOMe at 23 °C in the presence Cl Me Me Zn or MeZnX 1 of 2.2 equiv of Et3N (Scheme 127), was a key intermediate R1 2 R Pd((Pt-Bu3)2 (cat) SiMe of this appealing route, which was 25 steps in the longest SiMe3 THF, 0- 50 °C 3 367 370 193 (91-99%) linear sequence.

NHBoc Scheme 125. Synthesis of compounds 370. Cl N HO Pd(PPh ) (10 mol%) COOCH2CF3 3 4 O O CuI (32 mol%) H Me In concluding this subsection, it also seems appropriate to O Et N (2.2 equiv) TBDMSO 3 Br + Me t-BuOMe, 23 °C mention that, as far as we know, selective Sonogashira Br (61%) TES monoalkynylation reactions of 2,2-disubstituted 1,1- TBDSMS dichloroethenes have not been reported to date. 374 375

NHBoc i-Pr O OMOM 3.2 Monoalkynylation reactions of 1,1-dibromo-1- Cl N COOCH CF 2 3 O 189 MeO OH alkenes O OMe HN O O TBDMSO Me N Cl O The Sonogashira-type monoalkynylation reactions of 1,1- Br Me OTIPS 190 TBDMS O dibromo-1-alkenes, in contrast to those of 1,1-dichloro- TES 1-alkenes, have received considerable attention. The first 376 377 example of these coupling reactions was reported in 2000 TESO O 191 by Myers and Goldberg. In the context of a study on the Scheme 127. Stereoselective synthesis of compound 377. synthesis of the core structure of the chromoprotein 192 enediyne antibiotic, kedarcidin, they found that the Five years later, Myers and coworkers performed the Pd(PPh3)4/CuI-catalyzed reaction of dibromoalkene 371 synthesis of the proposed structure of the kedarcidin with monoprotected diyne 372 in Et2O in the presence of 194 chromophore. A step of this route was the Sonogashira- Et3N proceeded optimally to give stereoselectively (Z)- type stereoselective monoalkynylation of 1,1-dibromo-1- alkenyl bromide 373 in 61% yield (Scheme 126).191 alkene 378 with 1-alkyne 379 in Et2O at 23 °C in the presence of 2.5 equiv of Et3N and a high loading of Such a stereoselectivity can be explained by taking into 191 Pd(PPh3)4 (30 mol%) and CuI (30 mol%) (Scheme 128). account that it is presumably of steric origin and involves The reaction provided bromotrienyne 380 in 61% yield.195 the oxidative addition of a Pd(0) species to the less It is noteworthy that the results of this investigation allowed hindered C–Br bond in the E-position of 371. Moreover, the proposal of a stereochemical revised structure for the the stereochemical result of the alkynylation reaction chromophore component of kedarcidin.194 shown in Scheme 126 could be anticipated by taking into account that the rates of the Pd-catalyzed cross-coupling

35 Tetrahedron

i-PrO OPiv the PdCl2(dppf)⋅CH2Cl2/CuI-catalyzed reaction between O MeO 1,1-dibromoalkene 384 and trimethylsilylacetylene gave OMe HN H NMe2 Me compound 385 in 81% yield (Scheme 130). Subsequent Cl N OH O NiCl2(dppp)-catalyzed reaction of 385 with OSiEt i-Pr O O OFm O 2 H ethylmagnesium bromide, followed by treatment of the TBDMSO OH Br Br resulting cross-coupling product with TBAF in THF at -20 379 378 TES TES °C, gave the branched enyne 386 in 58% yield. Finally, Pd(PPh3)4 (3.0 mol%) CuI (30 mol%) iodination of 386 in the presence of morpholine and cis- Et3N (2.5 equiv), Et2O 23 °C, 2 h 198 (61%) reduction of the resulting 1-iodo-1-alkyne with diimide 19 i-PrO OPiv led to compound 387 in 58% yield (Scheme 130).

O MeO SiMe OMe HN 3 Br Me Si H NMe 3 2 H PdCl (dppf) CH Cl / CuI N COOFm Me Br 2 2 2 (cat) O H OH i-Pr2NEt, PhH, rt Br OSit-BuPh2 (81%) O OSiEt2i-Pr O 384 OSit-BuPh TBDMSO H 385 2 OH Br 1) EtMgBr, NiCl (dppp) 380 2 (cat) I THF, rt 1) I2 , morpholine, PhH, 50 °C TES H H TES 2) TBAF, THF, - 20 °C Et 2) diimide, THF, rt Et (80%) (58%) OSit-BuPh2 OSit-BuPh2 Scheme 128. Stereoselective synthesis of compound 380. 386 387

Me In the early 2000s, a catalyst system consisting of a mixture of 5 mol% PdCl (dppf) and 4 mol% CuI was used by Me 2 388 CHO Uenishi and Matsui for the reactions of (11-Z)-retinal trimethylsilylacetylene with 1,1-dibromo-1-alkenes 381a,b in benzene at room temperature in the presence of 2–3 Scheme 130. Synthesis of (2E,4Z)-3-ethyl-5-iodopentadienyl silyl 195,196 equiv of i-Pr2NEt (Scheme 129). ether (387).

SiMe Me3Si (1.5 equiv) 3 In 2001, Kim and coworkers investigated the influence of Br PdCl (dppf) (5 mol%) Ph 2 Ph n n the amine solvents and the molar ratio between 1-alkyne Br CuI (5 mol%) Br i-Pr2NEt (2 -3 equiv) 381a : n = 0 PhH, rt, 10 -20min 382a : n = 0 (87%) and 1,1-dibromo-1-alkene on the ratio of the products of the 381b : n = 1 382b : n = 1 (79%) PdCl2(PPh3)2/CuI/PPh3-catalyzed reaction of 2-[(E)-4- 199 SiMe3 stilbenyl]-1,1-dibromoethene (389) and 3-butyn-1-ol. Ph n They found that bromoenyne 390 was the main product only when 389 was reacted with 2.2 equiv of 3-butyn-1-ol SiMe3 in i-Pr NH for 8 h and that, under these conditions, the 383a : n = 0 (< 10%) 2 383b : n = 1(15%) reaction (Scheme 131) provided 390 in 68% yield along with enediyne 391 in 20% yield. Scheme 129. Synthesis of compounds 382a,b and 383a,b.

OH (2.2 equiv) The coupling reactions occurred stereoselectively and that OH Br Br involving 381a gave the monocoupling compound 382a in PdCl2(PPh3)2 (10 mol%) Ph Br PPh (20 mol%) Ph 3 390 87% yield along with the bis-alkynylation derivative 383a CuI (20 mol%) OH i-Pr2NH, rt, 8 h in less than 10% yield. On the other hand, the reaction 389 involving 381b provided compound 382b in 79% yield Ph along with compound 383b in 15% yield (Scheme OH 195,196 129). It should be noted that the use of PdCl2(dppf) as 391 component of the catalyst system largely improved the selectivity of the couplings. In fact, other Pd complexes Scheme 131. Synthesis of compounds 390 and 391. such as Pd(PPh3)4, PdCl2(PPh3)2 and Pd(dppe)2 provided mixtures of bromoenynes, enediynes and the starting 1,1- However, when the same Sonogashira reaction was carried dibromoalkenes with poor selectivity.195,196 out in piperidine, 1,3-diyne 392 (Figure 18) was obtained in 56% yield.199,200 The protocol illustrated in Scheme 129 was then used in a Ph key step of the synthesis of (2E,4Z)-3-ethyl-5- iodopentadienyl silyl ether (387), a C11–C15 part of a 13- 197 ethyl-substituted analogue of (11Z)-retinal (388) which is 392 an important chromophore for the visual system. Indeed, Ph

36 Tetrahedron

Figure 18. Structure of compound 392. gave 2-(1-alkynyl)indoles 398a-i in high yields (Scheme 133). Moreover, 2-(1-alkynyl)benzofurans 400a-f were More recently, Gómez, López and coworkers investigated obtained from o-gem-dibromovinylphenol (399) and 1- the Sonogashira reactions of 1’,1’-dibromo-exo-glucal 393 alkynes using a protocol similar to that employed to prepare with 1,1 equiv of phenylacetylene, trimethylsilylacetylene compounds 394. However, the use of a 2:1 mixture of and 1-dodecyne in Et2NH, in the presence of catalytic toluene and water instead of toluene as the solvent provided 201 202 quantitites of Pd(PPh3)4 and CuI. Unexpectedly, the better yields of compounds 400 (Scheme 134). reaction involving phenylacetylene gave a stereoisomeric R1 (1.5 equiv) mixture of 2-bromo-1-en-3-yne 394a in 39% yield along 10% Pd/C (2-5 mol%) Br with the bis-alkynylation derivative 395a in 24% yield CuI(4-5 mol%) Br P(p-MeOPh)3 (8 mol%) N NH H (Scheme 132). 2 i-Pr2Nh (2.5 equiv) R1 PhMe, 1.5 -48 h, 100 °C 397 398 R1 a : R1 = Ph (85%) b : R1 = n-C H (70%) Me O Me O 6 13 1 Br 1 (1.1 equiv) c : R = (CH2)3OH (65%) Me O R Me O O O 1 Pd(PPh3)4 (5 mol%) d : R = (CH2)3OTHP (71%) Br Br 1 CuI (10 mol%) e : R = CH2OH (40%) f : R1 = SiMe (57%) O O Et2NH O O 3 1 Me Me g : R = (CH2)3CN (80%) Me Me 1 h : R = (CH2)4Cl (70%) 1 393 394a: R = Ph (39%) i : R1 = 3-Pyridyl (81%) 1 394b: R = SiMe3 (37%) 1 394c: R = n-C10H21 (35%) + R1 Scheme 133. Synthesis of compounds 398. Me O Me 1 (1.5 equiv) O O R 10% Pd/C (2-5 mol%) Br CuI (4 mol%) O O R1 Br P(p-MeOPh)3 (8 mol%) O OH Me Me i-Pr2NH (2.5 equiv) R1 PhMe/H2O (2:1), 100 °C, 12 h 399 400 395a: R1 = Ph (24%) 1 a : R1 = n-C H (80%) 395b: R = SiMe3 (37%) 6 13 1 b : R = CH2OH (49%) 1 c : R = CH2OTBDMS (80%) 1 d : R = (CH2)2OH (63%) Scheme 132. Sonogashira reaction of compound 393. 1 e : R = (CH2)3CN (80%) f : R1 = Me OH Bromoenyne 394b was also obtained as a stereoisomeric HO mixture in 37% yield along with compound 395b in 37% yield from the reaction of 393 with trimethylsilylacetylene Scheme 134. Synthesis of compounds 400. (Scheme 132). However, the Sonogashira reaction of 393 with 1-dodecyne could be stopped at the monoalkynylation 3.3 Monoalkynylation reactions of 1,1-dihalogenated derivative 394c, but this compound was still obtained as a 1-alkenes bearing different halogen atoms stereoisomeric mixture in 35% yield (Scheme 132).202 In 1995, Linstrumelle and coworkers reported that Me O Cl Me metalation of (E)-1-chloro-1-en-3-ynes 4 with n-BuLi (1 O O Cl equiv) at -100°C followed by treatment with iodine gave O O (Z)-1-chloro-1-iodo-1-en-3-ynes 401 in good yields Me Me 203 396 (Scheme 135). Coupling of 401a and 401b with 2 equiv of 1-alkynes in the presence of 2 equiv of piperidine, 5 Figure 19. Structure of dichloro-exo-glucal 396. mol% Pd(PPh3)4 and 10 mol% CuI gave chemoselectively and stereospecifically chloroenediynes 402a-i in excellent Interestingly, dichloro-exo-glucal 396 (Figure 19) did not yields (Scheme 135).203 undergo a Sonogashira reaction under the various conditions attempted.

In concluding this subsection, we wish to mention the rapid access to a variety of 2-(1-alkynyl)-substituted indoles and benzofurans by Pd/C-CuI-P(p-MeOPh)3-catalyzed tandem stereoselective Sonogashira-Ullman coupling of geminal dibromovinyl substrates with terminal alkynes.202 In 2007, Lautens and coworkers found that treatment of o-gem- dibromovinylaniline (397) with 1.5 equiv of 1-alkynes, 2–5 mol% of 10% Pd/C, 4–5 mol% CuI, 8 mol% P(p-MeOPh)3, and 2.5 equiv of i-Pr2NH in toluene at 100 °C for 1.5–48 h

37 Tetrahedron

2 (2 equiv) Ph I (1.5 equiv) R Ph H 1) n-BuLi, THF, Et O, - 100°C n-C10H21 Cl Cl 2 1) n-BuLi, THF, Et2O, pentane, - 100 °C Pd(PPh3)4 (5 mol%) PdCl (PPh ) (4 mol% 2) I2, THF, - 100°C F F 2 3 2 R1 1 F F 2) I2 R I CuI (10 mol%) CuI (0.25 mol%) 4 piperidine (4 equiv) 408 409 Et3N, rt 401a: n-C5H11 (84%) PhH, 50 -60 °C (73%) 401b: R1= Ph (60%) n-C10H21 n-C10H21

R3 Ph DABCO (6 equiv) Cl R3 (2 equiv) NMP, reflux, 10 h F F F PdCl2(PhCN)2 (5 mol%) (66%) 410 411 F R1 CuI (10 mol%) piperidine, 25 -60 °C R1 R2 2 402 403 R Scheme 137. Synthesis of compounds 409–411 from (Z)-1,2- Compound 402 Compound 403 Reaction Yield (%) Temp (°C) Yield (%) 1 R2 R3 difluorostyrene (408). R1 R2 R a n-C5H11 (CH2)2OH Ph 25 72 a n-C5H11 CH2OH 79 b n-C5H11 Ph (CH2)2OH 60 44 b n-C H (CH ) OH 87 5 11 2 2 c n-C5H11 SiMe3 CH2OH 25 45 Moreover, it was discovered that 410 underwent cyclization c n-C5H11 Ph 90 d n-C5H11 n-C5H11 Ph 60 64 d n-C5H11 SiMe3 72 e Ph (CH2)2OH Ph 25 78 e n-C5H11 n-C5H11 85 f Ph Ph Ph 25 59 to produce 4-decyl-1,2-difluoronaphthalene (411) in 66%

f Ph SiMe3 75 g Ph CH OH 71 yield when treated with 6 equiv of DABCO in refluxing 2 205 h Ph (CH2)2OH 90 NMP for 10 h (Scheme 137). i Ph Ph 81

Scheme 135. Synthesis of chloroenediynes 402 and enetriynes As far as we know, examples of Sonogashira 403. monoalkynylation reactions of 1-iodo-1-bromo-, 1-bromo- 1-chloro-, and 1-chloro-1-fluoro-1-alkenes have not been Compounds 402 were then converted to stereoisomerically reported in the literature to date. On the contrary, pure enetriynes 403a-f in moderate-to-good yields by significant attention has been directed to Pd/Cu-catalyzed or Cu-free Pd-catalyzed reactions of stereodefined and PdCl2(PhCN)2/CuI-catalyzed coupling with 1-alkynes in 203 206,207 piperidine at 25–60 °C (Scheme 135). (E/Z)-mixtures of 1-bromo-1-fluoro-1-alkenes with 1- alkynes. In 2001, Zhang and Burton synthesized a stereoisomeric mixture of 1-fluoro-1-iodostyrene (406) (E/Z = 1:1) by a In 1990, Eddarir and coworkers synthesized (E)-2-fluoro-1- Wittig-Horner reaction of diethyl en-3-ynes 414a–e by Pd(OAc)2/PPh3-catalyzed fluoroiodomethylphosphate (404) with benzaldehyde (405) chemoselective and stereospecific crosscoupling of 1- and showed that the coupling of 406 with phenylacetylene alkynes with the required (Z)-1-bromo-1-fluoroalkenes 413 in refluxing n-BuNH or Et N (Scheme 138).206a in Et3N at room temperature for 16 h, in the presence of 2 3 Compounds 413 were prepared by bromination of the catalytic quantities of PdCl2(PPh3)2 and CuI, gave a 1:1 mixture of (Z)- and (E)-1,4-diphenyl-2-fluoro-1-buten-3- corresponding (E)-2-fluoro-2-alkenoic acids 412 followed 206a yne (407) in 38% yield after chromatographic purification by debromocarboxylation (Scheme 138). of the resulting crude reaction mixture (Scheme 136).204 1) Br CCl or CH Cl R2 (1 -2 equiv) 1 2, 4 2 1 R F reflux, 5 h R Br Interestingly, the 1:1 Z/E ratio for 407 improved to 7:3 after Pd(OAc)2 ( 2 mol%) 204 COOH 2) NaHCO3 or n-Bu4NOH F PPh3 ( 4 mol%) a modest reaction time. acetone, reflux n-BuNH or Et N 413 2 3 412 (59 -83%) reflux 2 Ph R Ph F LDA, THF, - 78 °C PdCl2(PPh3)2 (cat) (EtO)2P(O)CFHI + PhCHO R1 (54%) H I CuI (cat) 404 405 406 (Z/E= 1:1) Et3N, rt, 16 h F 1 2 414 a: R =R = Ph (71%) 1 2 Ph F b: R = Ph; R = n-C5H11 (63%) 1 2 c: R = Ph; R = CMe2OH (40%) 1 2 H d: R = 4-Cl-C6H4; R = Ph (71%) 1 2 e: R = 4-NO2-C6H4; R = Ph (73%) Ph 407 (Z/E= 1:1) Scheme 138. Synthesis of fluoroenynes 414a-e. Scheme 136. Synthesis of compound 407. Notably, compound 414e could not be synthesized in n-

An example of a chemoselective and stereospecific BuNH2. In fact, the Sonogashira reaction in n-BuNH2 gave Sonogashira monoalkynylation reaction of a stereodefined carboxyamide 415 (Figure 20) of instead the expected 1-fluoro-1-iodo-1-alkene was described in 2006 by Burton enyne.206a Nevertheless, 414e was prepared in 72% yield by and coworkers.205 They prepared (E)-1,2-difluoro-1-iodo-2- a copper-free Pd-catalyzed reaction of (Z)-1-bromo-1- phenylethene (409) in 83% yield by the reaction of (Z)-1,2- fluoro-2-(4-nitrophenyl)ethene (413c) with phenylacetylene difluorostyrene (408) with n-BuLi in THF/Et2O at -100 °C in Et3N. for 0.5 h followed by the addition of a THF solution of X O N 2 O iodine. Compound 409 was subsequently reacted with 1.5 Br NHn-Bu equiv of 1-dodecyne, 4 mol% PdCl2(PPh3)2 and 0.25 mol% F 413a: X = H 415 CuI in Et3N at room temperature to give (Z)-1,2-difluoro-1- 413e: X = NO2 phenyl-1-tetradecen-3-yne (410) in 73% yield.

38 Tetrahedron

R3 Figure 20. Structures of compounds 413a, 413e and 415. R2 Br 2 3 PdCl2(PPh3)2 (0.7 mol%) R R F CuI (2 mol%), Et3N 416 rt, 16 -24 h 417 F It was also observed that (Z)-1-bromo-1-fluorostyrene Compounds 416 Compounds 417 Entry Yield (%) (413a) (Figure 20) underwent stereomutation by heating at R1 E/Z R2 R3 E/Z 1 Ph 6/5 Ph Ph 100:0 38 60 °C in the presence of 0.1 equiv of Pd(OAc)2 and that the 46 2 Ph 1/1 Ph n-C5H11 98:2

Sonogashira reaction of the resulting 90:10 E/Z 3 Ph 3/2 Ph CH2OCH(OEt)Me 95:5 54 stereoisomeric mixture with phenylacetylene, according to 4 Ph 6/5 Ph SiMe3 99:1 23 5 Ph 1/1 Ph CH(OH)Me 95:5 49 the protocol used to prepare stereoisomerically pure 414a, OH provided a 90:10 Z/E mixture of this fluoroenyne (Scheme 6 Ph 1/1 Ph 99:1 45 206a 139). 7 4-ClC6H4 1/1 4-ClC6H4 CH(OH)Me 99:1 48 8 n-C7H15 7/3 n-C7H15 Ph 90:10 64 9 PhHMe 7/3 PhCHMe CH(OH)Me 92:8 53 Ph 10 n-C H 1/1 n-C H CH OCH(OEt)Me 93:7 46 Ph 7 15 7 15 2 3/97 Ph Br 11 Ph Ph Ph 3:97 88 Pd(PPh3)4 (2 mol%) Ph 12 Ph 0/100 Ph n-C5H11 0:100 87 PPh (4 mol%) F 3 F n-BuNH reflux 13 Ph >2/98 Ph CH2OCH(OEt)Me >2:98 89 413a (90:10 E/Z mixture) 2, (81%) 414a (90:10 E/Z mixture) 14 Ph 0/100 Ph CH(OH)Me >1:99 89 15 4-ClC6H4 0/100 4-ClC6H4 CH(OH)Me 0:100 77 Scheme 139. Synthesis of 90:10 mixture of (Z)- and (E)-414a. 16 PhCHMe 0/100 PhCHMe CH(OH)Me 0:100 78

R2 Br R2 Br R2 F PdCl2(PPh3)2 In 2001, Zhang and Burton reported that the reaction of E/Z + H F HCOOH, n-Bu3N H F H H mixtures of 1-bromo-1-fluoro-1-alkenes 416 with DMF, 35 °C 416 (Z)-416 418 equimolar amounts of 1-alkynes in Et3N at room R3 (Z)-417 R2 R3 Yield (%) PdCl (PPh ) /CuI temperature in the presence of 0.7 mol% PdCl2(PPh3)2 and 2 3 2 92 Et3N, rt a 2-ClC6H4 n-C5H11 2 mol% CuI occurred stereoselectively to give R3 b 2-ClC6H4 n-C5H11 72 predominantly (Z)-2-fluoro-1-en-3-ynes 417 in satisfactory 2 c 4-MeOC6H4 n-C5H11 82 R 204 yields (Table 2, entries 1–10). On the other hand, the H F coupling reactions involving Z-configured compounds 416 (E)-417 were found to produce fluoroenynes (E)-417 in high yields Scheme 140. Stereoselective synthesis of (E)-2-fluoro-1-en-3- (entries 11–16, Table 2).204 ynes (E)-417. In 2002, Burton and coworker described a new protocol for It was also found that some compounds obtained as the synthesis of (E)-2-fluoro-1-en-3-ynes 410 from described above, i.e. (E)-1-aryl-2-fluoro-1-en-3-ynes 419, stereoisomeric mixtures of 1-bromo-1-fluoro-1-alkenes.208 underwent cyclization by treatment with DABCO or DBU They reported that 1:1 mixtures of (E)- and (Z)-configured in refluxing NMP to give 3-fluoro-1-substituted compounds 416 could be stereoselectively reduced using 420 in good-to-excellent yields (Scheme 141). the HCOOH/n-Bu N/PdCl (PPh ) /DMF system to give 209 3 2 3 2 mixtures of (Z)-1-bromo-1-fluoro-1-alkenes, (Z)-416,206

X R2 R2 and (E)/(Z)-1-fluoro-1-alkenes 418 (Scheme 140). It was DBU (2 equiv) or X subsequently reported that, when these mixtures were DABCO (6 equiv) treated with terminal alkynes, 4 mol% PdCl2(PPh3)2, and 1 H F NMP, reflux F 420 419 Compounds 420 mol% CuI in Et3N at room temperature, stereoisomerically 2 X R CH2 Yield% pure compounds (E)-417 were obtained in high yields a 4-F n-Pr 77 (Scheme 140).209 b 4-F n-Bu 77 c 4-CF3 n-Pr 89 d 4-CF3 n-Bu 82 e 4-CF3 n-C9H19 74 Table 2. Stereoselective PdCl2(PPh3)2/CuI-catalyzed coupling of f 4-CF3 Bn 69 (E/Z)-1-bromo-1-fluoro-1-alkenes 416 with 1-alkynes. g 3,5-F2 n-Pr 55 h 3,5-F2 n-Bu 66

Scheme 141. Synthesis of 3-fluoro-1-substituted naphthalenes 420.

The mechanism of the cyclization (Scheme 142) was thought to involve a base-catalyzed isomerization of the 1,3-enyne system of compounds 419 to the corresponding allene and a subsequent 6π-cyclization to form a two-ring system.205,209

39 Tetrahedron

2 R base 2 R1 X R2 R X H R1 H pool Br PPh3, CFCBr3 and/or CHO Ph PdCl2(PPh3)2(cat) Ph THF, reflux, 5 h F H F F [1,7]-H shift CuI , Et N Ph 419 H F 426 (49%) 427 (cat) 3 F R2 428 X R1

1 DABCO (6 equiv) Ph 429a : R = n-Pr (72%) 1 F NMP, reflux 429b : R = n-Bu (71%) 420 1 F 429c : R = Bn (85%)

Scheme 142. Proposed mechanism for synthesis of naphthalenes Scheme 144. Synthesis of fluorobiphenyls 429a-c. 420. The cyclization mechanism (Scheme 145), which is similar Compounds 420 might then be formed from a [1,7]-H shift to that illustrated for the synthesis of compounds 420, was without assistance of the base or from the abstraction of H proposed to involve the DABCO-catalyzed isomerization of from C-9 by the base, followed by acquisition of H from the dienyne system of compounds 428 to a diene-allene the proton pool (a trace of moisture in the system or the system, followed by the formation of intermediates 430 by 205,209 protonated base) (Scheme 142). a 6π-cyclization reaction, and, finally, isomerization of these cyclized intermediates to the aromatic derivatives 429 In 2006, Burton and coworkers also described a facile (Scheme 145).210 procedure for the site-specific preparation of fluorinated

R1 1 1 derivatives from 1-bromo-1-fluoro-1- 1 R R Ph CH2 R Ph 209 Base • Ph alkenes. Specifically, a stereoisomeric mixture of 1- 6 π cyclization Ph bromo-1-fluoro-2-(2-naphthyl)ethene (422), which was F F H F H F prepared in 42% yield from 2-naphthaldehyde (421), was 428 430 429 reacted with 1.2 equiv of 1-alkynes, 5.7 mol% PdCl2(PPh3)2 Scheme 145. Proposed mechanism for synthesis of compounds and 5 mol% CuI in Et3N at room temperature to afford 2- fluoro-1-en-3-ynes 423 as stereoisomeric mixtures. Finally, 429. treatment of the crude compounds 423 with 0.2 equiv of DBU in NMP under reflux for 2 h was found to provide site 4. Monoalkynylation reactions of stereodefined bis(enol selectively the fluorinated phenanthrene derivatives 424a, b triflates) in good yields (Scheme 143).209 Noteworthy is that no In the last three decades, enol triflates, due to their facile derivatives 425 were obtained. preparation from carbonyl compounds,211 have been widely

R1 (1.2 equiv) used as electrophiles in transition metal-catalyzed cross- PPh , CFBr PdCl (PPh ) (5.7 mol%) 212 3 3 Br 2 3 2 coupling reactions. The first examples of Pd-catalyzed CHO THF, reflux CuI (5.0 mol%) (42%) 421 H F Et3N, rt, 48 h coupling reactions of enol triflates with terminal alkynes 422 were described in 1986 by Cacchi and coworkers.213 The R1 R1 DBU (2 equiv) reactions, which were carried out at 60 °C in the presence + NMP, reflux, 3 h of a base and Pd(OAc)2 as catalyst, were found to give 1 F H F R F conjugated enynes in good yields. It was also observed that 423 424a : R1 = n-Bu (77%) 425 (0%) 1 424b : R = n-C10H21 (78%) the addition of CuI as co-catalyst allowed the reactions to proceed at room temperature.213 Scheme 143. Synthesis of 424a,b. A few years later, site-selective Pd/Cu-catalyzed Again in 2006, Wang and Burton synthesized Sonogashira couplings of 1-alkynes with bis(enol triflates) 214,215a,b 214,216a,b 217a–d fluorodienynes 428 by PdCl2(PPh3)2/CuI-catalyzed (Z)-431, (E)-431, (Z)-432, and (E)- chemoselective Sonogashira reaction of 1-alkynes with a 432217c (Figure 21) were extensively used by the research mixture of (1E,3E)- and (1Z,3E)-1-bromo-1-fluoro-4- teams of Terashima and Brückner to construct monocyclic phenyl-1,3-butadiene (427), which was prepared in 49% dienediyne models of the neocarzinostatin chromophore.218 yield from trans-cinnamaldehyde (426) (Scheme 144).210 OTf TfO They also described that the reaction of crude compounds OTf OTf OTf OTf OTf 428 with 6 equiv of DABCO in refluxing NMP yielded 2- OTf substituted-4-fluorobiphenyls 429a-c in high yields (Z)-431 (E)-431 (Z)-432 (E)-432 (Scheme 144).210 Figure 21. Structures of compounds (Z)- and (E)-431 and (Z)- and (E)-432.

40 Tetrahedron

In 1992, Terashima and coworkers prepared (E)-5- Again in 1992, bis(enol triflate) (Z)-431 was synthesized by [(trifluoromethanesulfonyloxy)methylene]-1-cyclopenten- Brückner, Suffert and coworkers215a from 2- 1-yl trifluoromethanesulfonate [(E)-431] and its (Z)- formylcyclopentanone (433) using a procedure different stereoisomer, (Z)-431, as follows.214 from that illustrated in Scheme 146. Specifically, 433 was reacted with 1 equiv of t-BuLi in hexane and THF at -65 °C O H O O OTf for 15 min and the resulting lithium enolate was treated CHO Tf2O (excess) with 1 equiv of triflic anhydride for a few minutes to give 2,6-di-t-Bu-4-Me-pyridine OTf CH Cl rt, 1 d 433 2 2, (E)-431 the unstable monotriflate 440 (Scheme 148). This (63 %) SiMe3 OTf compound was then converted without purification into (Z)- OTf Me Si 3 OTf h acetone υ, Pd(PPh3)4 (5 mol%) 431 in 29% overall yield by deprotonation with lithium

CuI (10 mol%) SiMe3 (Z)-431 hexamethylsilazide at -65 °C followed by reaction with Et2NH (2 equiv), DMF, rt (56%) (Z)-434 + OTf triflic anhydride. Remarkably, N,N- OEt 216b OEt bis(trifluoromethanesulfonyl)aniline, which had (Z)-435 Pd(PPh3)4 (5 mol%) previously been employed instead of triflic anhydride, CuI (10 mol%) Et2NH (2 equiv), DMF, rt secured a 36% overall yield of (Z)-431 but at higher costs.

O OTf OTf CH(OEt)2 CH(OEt)2 H 1) t-BuLi (1 equiv), hexane 1) LiHMDS (1.2 equiv) OTf O THF, - 65 °C, 15 min O THF, - 65 °C, 5 min OTf OTf 2) Tf O ( 1 equiv) 2) Tf2O , - 65 °C 2 ≈ + ca. 5 min 433 440 (29 % overall yield) (Z)-431 (Z)-436 (Z)-437 Scheme 148. Synthesis of (Z)-431 according to Brückner, Suffert Scheme 146. Synthesis of compounds (Z)-434, (Z)-435, (Z)-436, and coworkers.215a and (Z)-437. In complete agreement with the results reported by The reaction of 2-formylcyclopentanone (433) with a molar Terashima,214 Brückner, Suffert and coworkers observed excess of triflic anhydride in the presence of 2,6-di-t-butyl- that the exocyclic triflate moiety of (Z)-431 underwent 4-methylpyridine afforded (E)-431 in 63% yield, which, by faster Pd/Cu-catalyzed Sonogashira coupling than its irradiation in acetone with a high-pressure mercury lamp, endocyclic counterpart.215 In fact, when (Z)-431 was produced stereomutation of the exo-cyclic double bond to reacted with 1.1 equiv of trimethylsilylacetylene, 10 mol% give (Z)-431 in 37% yield along with (E)-431 in 48% PdCl (PPh ) and 30 mol% CuI in a 3:1 mixture of THF recovery (Scheme 146). The site-selective 2 3 2 and i-Pr NH, an inseparable 4:1 mixture of compounds (Z)- monoalkynylation of (Z)-431 was then investigated and it 2 434 and (Z)-435 was isolated in 76% yield.215b was found that the reaction of equimolar amounts of trimethylsilylacetylene and (Z)-431 in DMF at room Brückner and coworkers also developed a procedure for the temperature in the presence of 5 mol% Pd(PPh ) , 10 mol% 3 4 isolation of the major components (Z)-441 of the mixtures CuI and 2 equiv of Et NH produced an inseparable mixture 2 of regioisomeric compounds (Z)-441 and 442, which were of regioisomeric compounds (Z)-434 and (Z)-435 in a ca. obtained by PdCl (PPh ) /CuI-catalyzed Sonogashira 4:1 molar ratio, respectively (Scheme 146).183 However, 2 3 2 monoalkynylation reactions of bis(enol triflate) (Z)-431 treatment of (Z)-431 with 3,3-diethoxy-1-propyne under the with terminal alkynes.215a These mixtures, still containing same conditions as mentioned above resulted in the the catalytically active Pd(0) species, could be resolved formation of the regioisomeric compounds (Z)-436 and (Z)- kinetically by the addition of another terminal alkyne in 437, which could be separated in 50 and 10% yield, substoichiometric amounts (0.3–0.4 equiv), which reacted respectively (Scheme 146). Interestingly, compound (Z)- preferentially with the minor components 442 of the 436 proved to be suitable to undergo a coupling reaction mixtures by converting them into the biscoupling with 1-alkyne 438 in the presence of 2 equiv of Et NH and 2 derivatives (Z)-443 and (Z)-444 (Scheme 149).215a high loadings of Pd(PPh ) and CuI to give the (Z)- 3 4 Compounds (Z)-441 now proved to be separable and were dienediyne diol acetal 439 in 92% yield (Scheme 147).214 obtained in 37–52% yields based on (Z)-431.215a

Me O CH(OEt)2 Me Me O O OTf Me Pd(PPh3)4 (20 mol%) OH O CuI ( 50 mol%) OH OH + Et2NH (2 equiv), DMF CH(OEt)2 OH (92%) H (Z)-436 438 439

Scheme 147. Synthesis of dienediyne 439.

41 Tetrahedron

R1 OTf OTf 1) CsF (2.3 equiv), MeOH R1 20 °C, 30 h, (75%) 1 OTf PdCl (PPh ) (5 mol%) R 2 3 2 OTf OH 2) TBDMSCl (1.5 equiv) OTBDMS + OTf OTf CuI (15 mol%) imidazole (3 equiv) THF/i-Pr2NH (3:1) DMF, rt, 4 h (83%) (Z)-431 rt, 5.5 h (Z)-441 442 Me3Si H (Z)-445 446 1 R R1 R1 R2 (0.3 -0.4 equiv) PdCl2(PPh3)2 (5 mol%) camphorsulforic acid (0.3 equiv) 1 2 2- 4.5 h, rt R R CuCl (57 mol%) EtSH (12 equiv) OTf + OTBDMS + LiCl (3 equiv) (28 equiv) PhH/i-Pr2NH (3:1) (degassed) (Z)-441 (Z)-443 (Z)-444 rt, 6 h (33%) 447 37 °C (0.03 M in PhH), 6 h

Compounds (Z)-441

R1 Yield (%)

a CH2OTHP 47 + b CH2OSiMePh2 35 c (CH2)2OH 36 SEt d (CH2)3OH 37 448 449 e CH2SiMe3 37 f SiMe3 52 Scheme 151. Synthesis of compounds 448 and 449. Scheme 149. Procedure for synthesis and separation of compounds (Z)-441. Intramolecular PdCl2(PPh3)2/CuCl/LiCl-catalyzed alkynylation of (Z)-446 led to dienediyne 447 in 33% yield, It was also found that dienediynes (Z)-444 containing which could be stored at -30 °C for several days (Scheme 217b,219 differentiated alkynyl groups could be accessed in modest 151). It was also established that treatment of 446 to good yields by PdCl2(PPh3)2/CuI-catalyzed coupling of with 0.3 equiv of camphorsulfonic acid, 28 equiv of 1,4- enol triflates (Z)-441 with a molar excess of 1-alkynes in a cyclohexadiene and 12 equiv of ethylthiol in benzene at 37 3:1 mixture of THF and i-Pr2NH at room temperature °C furnished the cyclopenta[b]phenanthrene 448 in 31% (Scheme 150).215a yield through cycloaromatization along with compound 449 in 6% yield (Scheme 151).217b,219 Remarkably, when the R1 R1 Sonogashira-type intramolecular reaction of (Z)-445 was R2 (2 -5 equiv) R2 performed using a typical PdCl2(PPh3)2/CuI catalyst OTf PdCl2(PPh3)2 (10 -30 mol%) 219 CuI (30 mol%) system, compound 448 was obtained in only 10% yield. THF/i-Pr2NH (3:1) (Z)-441 3-73 h, rt (Z)-444 Surprisingly, bis(enol triflate) (E)-431 proved to be able to Compounds (Z)-444 Yield% undergo Pd(PPh3)4/CuI-catalyzed coupling with terminal R1 R2 alkynes in a 3:1 mixture of THF and i-Pr2NH preferentially a CH2OTHP SiMe3 77

b CH2OTHP CH2SiMe3 52 at the endocyclic more sterically hindered triflate site. In c CH2OSiMePh2 CH2SiMe3 55 fact, consecutive additions of two different terminal alkynes d CH2OTHP n-C4H9 29 furnished dienediynes (E)-450 and (E)-451 as 87:13÷68:32 e (CH2)2OH SiMe3 73 f (CH2)2OH CH2SiMe3 65 mixtures in 48–91% yields after flash chromatography on g (CH ) OH SiMe 72 216b 2 3 3 silica (Scheme 152). h CH2SiMe3 (CH2)2OH 60

e SiMe3 (CH2)2OH 60 R2 R1 j SiMe3 (CH2)3OH 57 TfO 1) R1 (1.1 equiv) Pd(PPh ) (5 mol%), CuI (15 mol%) OTf 3 4 R1 R2 THF/i-Pr2NH (3:1), rt, 0.5-16 h + no work up Scheme 150. Synthesis of dienediynes (Z)-444. 2) R2 (2.5 equiv) (E)-431 1-48 h, rt (E)-450 (E)-451

Total 219 1 2 In 1994, Suffert and Brückner synthesized enynyl triflate R R Yield(%) (E)-450 (E)-451 (E)-450/(E)451 215a (Z)-445 using their earlier-developed protocol and then 4-ClC6H4OTBDMS CH2SiMe3 48 a a 75:25 CH2SiMe3 4-ClC6H4OTBDMS 55 b b 68:32 converted this compound into the terminal acetylene SiMe3 CH2OTBDMS 83 c c 80:20 derivative (Z)-446, which was found to decompose readily CH2OTBDMS SiMe3 91 d d 80:20 CH2OTHP CH2OTBDMS 63 e e 77:23 in the absence of solvent (Scheme 151). CH2OTBDMS CH2OTHP 74 f f 81:19

CH2OTHP CH2OSit-BuPh2 72 g g 82:18

CH2OSit-BuPh2 CH2OTHP 62 h h 87:13

CH2OSit-BuPh2 SiMe3 53 i i 80:20

CH2SiMe3 4-ClC6H4COTBDMS 68 j j 75:25

4-ClC6H4OTBDMS CH2SiMe3 54 k k 80:20 SiMe3 CH2OTBDMS 68 l l 80:20

42 Tetrahedron

Scheme 152. Selective synthesis of dienediynes (E)-450 and (E)- in particular, when n-PrNH2 was used as base (Scheme 451. 155).217a

SiMe OTf 3 More recently, in the context of a study on the synthesis of OTf Me3Si SiMe3 polycyclic substructures present in several natural products, OTf PdCl2(PPh3)2/CuI(cat) OTf Suffert and coworkers found that the reaction of bis(enol THF, amine + triflate) (Z)-431 with 1.1 equiv of alkyne 452 in a 3:1 (Z)-432 457 (major) 458 (minor) mixture of benzene and i-Pr2NH at room temperature, in the presence of 4 mol% PdCl2(PPh3)2 and 10 mol% CuI, 457/458 Amine Total Yield (%) produced chemoselectively a 9:1 mixture of compounds molar ratio 453 and 454 (Scheme 153) from which the required n-PrNH2 >99:1 49 220 PhCH2NH2 98:2 66 monotriflate 453 was isolated in 79% yield. Et3N 94:4 62

i-Pr2NH 91:9 73 Me Me piperidine 98:2 54 O O piperidine 96:4 75 OTf PdCl2(PPh3)2 (4 mol%) morpholine 95:5 64 + CuI (10 mol%) OTf H PhH/i-Pr2NH (3:1), rt SnBu (Z)-431 452 3 Scheme 155. Selective synthesis of compound 457.

SnBu3 SnBu3 However, in a subsequent study, the monoalkynylation TfO derivative (Z)-460 was synthesized in 66% yield by + treatment of (Z)-432 with 1.1 equiv of diyne 459 in a O O TfO Me Me O O degassed mixture of i-Pr2NH and Et2O at 0 °C using a Me Me 453 (453/454 = 9:1) 454 mixture of 5 mol% PdCl2(PPh3)2 and 10 mol% CuI as catalyst (Scheme 156).217c Desilylation of (Z)-460 followed Scheme 153. Selective synthesis of monotriflate 453. by intramolecular coupling by the catalytic action of 5 mol% PdCl2(PPh3)2, 30 mol% CuCl, 3 equiv of LiCl in i- Compound 453 was separated from 454 by applying a Pr2NH and degassed benzene at 5–10 °C provided the 10- previously described procedure,215a i.e. the addition of a membered dienediyne 461 in 27.4% yield (Scheme 156).217c substoichiometric amount of a terminal alkyne different from 452, which reacted preferentially with 454 by OTf OTf PdCl2(PPh3)2 (5 mol%) converting this compound into a bis-coupling derivative OTf CuI (10 mol%) + OMe 220 H that was readily separated from 453. OMe i-Pr2NH, Et2O (degassed) 0 °C, 4 h Me3Si Me3Si (66%) (Z)-432 459 (Z)-460 The research group of Brückner also paid significant OMe 1) 45% aq NH4F, n-BuNHSO4 (0.25 equiv) attention to site-selective Sonogashira monoalkynylation CH2Cl2, rt, 0.5 h reactions of the six-membered bis(enol triflate) (Z)- 2) PdCl2(PPh3)2 (5 mol%) 217a,217b,217d,221–223 CuCl (30 mol%) 432, which, as shown in Scheme 154, was LiCl (3 equiv), i-Pr2NH PhH (degassed), 5-10 °C, 110 min stereoselectively prepared in two steps from 2- (27.4 % over 2 steps) 461 formylcyclohexanone (455) via the Z-configured monotriflate 456 in 42.2% yield.217a Scheme 156. Synthesis of dienediyne 461.

H O OTf OTf Site selectivity analogous to that observed for the O LiHMDS (1.1 equiv) O OTf Sonogashira reaction between (Z)-432 and 459 was t-BuLi, THF, -78 °C, 10-15 min THF, - 65 to - 78 °C, 1.1 h then Tf2O, - 78 °C, 15 min then Tf2O (1.1 equiv) observed for the PdCl2(PPh3)2/CuI-catalyzed reaction (57%) 20 min 455 (Z)-456 (74%) (Z)-432 between bis(enol triflate) (E)-432 and alkyne 459 (Scheme 157).217c Scheme 154. Synthesis of bis(enol triflate) (Z)-432.

TfO TfO Surprisingly, the PdCl2(PPh3)2/CuI-catalyzed PdCl2(PPh3)2 (5 mol%) OTf CuI (10 mol%) OMe monocoupling reaction of (Z)-432 with + H Et O (degassed) OMe 2 i-Pr2NH, 0 °C, 3 h Me3Si trimethylsilylacetylene was shown to occur with site Me3Si (87%) (E)-432 459 (E)-460 selectivity opposite to that observed for the analogous reaction of the five-membered bis(enol triflate) (Z)-431 to Scheme 157. Synthesis of compound (E)-460. give compound 457 as the major product and 458 as the 217a minor component. Interestingly, this monotriflate was Compound (Z)-432 proved also to be capable of undergoing best obtained when the Sonogashira reaction was a one-pot/two-component PdCl2(PPh3)2/CuI-catalyzed bis- performed in THF in the presence of a primary amine and,

43 Tetrahedron coupling reaction with two different terminal alkynes.221 Scheme 158. Selective synthesis of compound 462 and conversion The first coupling partner was o-ethynylbenzyl alcohol and into dienediyne 465. the second was trimethylsilylacetylene. The reaction HO (Scheme 158) provided a 96:4 mixture of the C-silylated OTf SiMe3 221 (1.3 equiv) 1) NH4F ( 50 mol%) OH n-BuNHSO4 (0.25 equiv) dienediyne 462 and its regioisomer 463 in 81% yield. SiMe3 CH2Cl2, rt, 1 h Compound 462 was then converted into the unstable 6-/10- PdCl2(PPh3)2 (5 mol%) CuI (12 mol%) 2) I2 (2.5 equiv) 457 morpholine (5.9 equiv) membered ring dienediyne 465 by a four-step route THF/i-Pr2NH (3:1), rt, 4 h (82%) 466 THF, 40 °C, 4 h O 3) Dess-Martin reagent involving cyclization of the iodinated dienediyne aldehyde (2.0 equiv), CH2Cl2 224 221 H rt, 1 h 464 by a Nozaki-Hiyama reaction (Scheme 158). (66 % over 3 steps) I CrCl2 (3 equiv) OH

On the other hand, the synthesis of compound 468, an NiCl2 (1 equiv) THF, - 10 to - 5 °C, 5 h isomer of 465, was accomplished via a reaction sequence in 467 (53%) 468 which dienediyne 466 was obtained in 82% yield by treatment of monotriflate 457 with o-ethynylbenzyl Scheme 159. Synthesis of compound 468. alcohol, 5 mol% PdCl2(PPh3)2 and 12 mol% CuI in a 3:1 OH mixture of THF and i-Pr2NH at room temperature (Scheme OTf 221 Et2O/i-Pr2NH (3:1) OH 159). Desilylation of 466 and iodination of the resulting OTf PdCl2(PPh3)2 (5 mol%) CuI (12 mol%) Me 1-alkyne with iodine and morpholine, followed by butyn-2-ol (1.15 equiv), 3 h 225 then 4-pentyn-1-ol (1.0 equiv) oxidation with the Dess-Martin reagent, delivered the (Z)-432 469 O H desired iodinated aldehyde 467. Finally, a Nozaki-Hiyama- O 1) Zn/Cu couple (45 equiv) type cyclization of 467 provided compound 468 in 53% (COCl)2 (2.3 equiv) DME, 5 h, then DMSO (4.8 equiv) TICl3 (15 equiv) yield, which proved to be less prone to decomposition 2) addition of 470 in DME Et3N (10 equiv), CH2Cl2 during flash chromatography than its isomer 465 (Scheme - 78 °C to rt by syringe pump at - 5 °C (59%) over 6 h 159).221 470

OH

Compound (Z)-432 was also used to prepare dienediyne Me OH Me + 469 in 73% yield by a one-pot, two-step PdCl2(PPh3)2/CuI- catalyzed coupling reaction with 3-butyn-2-ol and 4- 471 472 pentyn-1-ol (Scheme 160).222 A double Swern oxidation of 469 provided the keto-aldehyde 470 in 59% yield, which Scheme 160. Synthesis of dienediyne 469 and conversion into 226 underwent an intramolecular McMurry coupling using compounds 471 and 472. the reagent prepared from TiCl3⋅1.5 DME and a Zn/Cu couple, to give trienediyne 471 in 47% yield (Scheme Finally, the strategy used for the synthesis of trienediyne 160).222 Compound 471 was formed along with the 471 from (Z)-432 was extended to generate the dienediyne diastereomeric dienediyne pinacols 472, which were epoxycarbonate 476223 possessing a structure more closely isolated in 23% yield.222 related to the neocarzinostatin chromophore than that of earlier analogues prepared by the Brückner team. In OTf particular, bis(enol triflate) (Z)-432 was coupled at its OTf endocyclic carbon–carbon double bond with alkyne 473

(Z)-432 and subsequently at its semicyclic carbon-carbon double bond with alkyne 474 to give dienediyne 475 in 39% yield (1.15 equiv) 223 OH (Scheme 161). PdCl2(PPh3)2 (5 mol%) CuI ( 12 mol%) Et2O/i-Pr2NH (3:1), rt, 2 h thenMe3Si (1.5 mol%) Dess-Martin oxidation of 465 led to the keto-aldehyde 476 17 h (81%) in 39% yield, which was subjected to a McMurry ring- SiMe 3 closure reaction that yielded trienediyne 477 in 43% yield. + OH Finally, a five-step reaction sequence allowed the SiMe3 HO convertsion of 477 into the required 6-/10-membered 462 463 dienediyne epoxycarbonate 478 (Scheme 161).223 3 steps

OH I

CrCl2 (3 equiv)

NiCl2 (1 equiv) CHO THF, - 10 to -5 °C, 5 h (26%) 464 465

44 Tetrahedron

OTf Me Me solution of (Z)-432 in OH two or more electrophilic sites using low or ultra-low Et O/i-Pr NH (3:1) at 0 °C OTf 2 2 227 successive additions of OH loadings of Pd, a very expensive and toxic metal. In fact, PdCl2(PPh3)2 ( 5 mol%) CuI (10 mol%), 473 (1.1 equiv), 3 h then O numerous investigations have been performed on couplings (Z)-432 addition of 474 (1 equiv), 0 °C, 15 h 475 O (39%) Me Me of terminal alkynes with aryl halides that involve the use of very high substrate/Pd catalyst molar ratios,228 but, to our Me Me knowledge, no similar studies have been carried out to date CHO Zn/Cu couple (45 equiv) Dess-Martin periodinane O DME, 5 h, reflux, then on alkynylation reactions of alkenyl halides or CH2Cl2, rt, 50 min TiCl3 (15 equiv), 35 °C (49%) O DME over 3 h pseudohalides and, in particular, of olefinic substrates O (42%) Me bearing two or three different electrophilic sites. 476 Me Me Me Me Me However, in our view, one of the major goals to be O achieved is the development and application of highly O O O O (14.9% yield) selective transition-metal-free Sonogashira monocoupling Me Me Me Me 477 478 reactions involving (cyclo)alkenes bearing two or more identical or different electrophilic sites. These couplings OH Me Me should be inexpensive and simple to perform by eliminating H OH O the need to remove trace transition metals. Unfortunately, O H Me Me 473 474 little attention has so far been devoted to the study of transition-metal-free Sonogashira couplings.229

Scheme 161. Synthesis of dienediyne 475 and conversion into Finally, we can expect that a significant expansion of the dienediyne epoxycarbonate 478. synthetic potential of the alkynylation reactions summarized and discussed in this review will result from 5. Conclusions their use in one-pot multicomponent processes able to 230 This review has illustrated how highly selective produce highly sophisticated complex structures. Sonogashira-type single couplings of terminal alkynes with

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Biographical sketch

Renzo Rossi was born in Pisa (Italy) and graduated in Organic Chemistry with first-class honours at the

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University of Pisa defending a thesis performed under the initially mainly devoted to the total synthesis of guidance of Professor Piero Pino. In 1969, he became naturally occurring compounds of biological and/or Assistant Professor and in 1971 he earned the libera pharmacological interest and to the synthesis of docenza in Organic Chemistry. After holding other structural analogues of naturally occurring fungicidal intermediate positions at the University of Pisa and the derivatives of agrochemical interest. More recently, Scuola Normale Superiore of Pisa, in 1980 he became Full Prof. Bellina focused his attention on new and efficient Professor of Organic Chemistry at the University of protocols for regioselective transition-metal-mediated Calabria. In 1982, he again joined the University of Pisa carbon-carbon and carbon-heteroatom bond-forming where he has held the Chair of Chemistry of Naturally reactions, with a particular interest in the selective functionalization of oxygen-containing unsaturated Occurring Compounds. In 1999, the University of Pisa heterocycles such as 2(5H)-furanones and 2(2H)- awarded him the Ordine del Cherubino. His current pyranones. Currently, he is working on the research interests include: i) new catalytic methods for the development of novel and efficient protocols for the synthesis of oxygen-containing heterocycles; ii) the transition metal-catalyzed direct C–H and N–H bond preparation of substances which exhibit significant arylation of heteroarenes, the direct functionalization cytotoxicity against human tumor cell lines and of active C(sp3)-H bonds, the alkynylation of antivascular properties; iii) the study of new methodologies (hetero)aromatic scaffolds, and on the application of for carbon–carbon bond formation that involve the use of these new procedures to the selective preparation of organometallic reagents; iv) transition metal-catalyzed bioactive natural and synthetic compounds and to new 3 direct arylation reactions of substrates with activated sp - organic chromophores. hybridized C–H bonds with aryl halides and pseudohalides; v) the design, development and applications of new, highly chemo- and regioselective methods for the transition metal- catalyzed direct C- and N-arylation reactions of electron- rich heteroaromatic systems, including free (NH)-azoles, with aryl halides and pseudohalides. In recent years, several successful studies have also been performed by his research group in the field of the synthesis and evaluation of the biological properties of insect sex pheromone components, Marco Lessi was born in Livorno (Italy) in 1979. He insecticidal carboxyamides, natural phototoxins, and studied Chemistry at the University of Pisa and received his naturally-occurring compounds of marine origin and their Laurea Degree with first-class honours in June 2004 structural analogues which are characterized by the 2(5H)- defending a thesis performed under the guidance of furanone ring. Professor Rossi, who has coauthored over Professor Dario Pini. In January 2005, he began his PhD 230 research publications and a number of highly cited fellowship in the laboratory of Professor Pini and received review articles and patents, is a fellow of the Royal Society his PhD degree in 2008, submitting a thesis on the of Chemistry, the American Chemical Society, and the preparation and applications of new insoluble polymer- Società Chimica Italiana. He is a reviewer for several bound (IPB) enantioselective catalytic systems. These international journals dealing with synthetic organic studies were focused on the synthesis of transition-metal chemistry and organometallics. complexes obtained from bisoxazoline and BINOL ligands. In the period January 2008–March 2009, Dr. Lessi worked for Solvay Solexis S.p.A. on the development of new routes for the preparation of high-fluorinated low-molecular- weight molecules and oligomers. In March 2009, he re- joined the University of Pisa where he currently cooperates with Professor Bellina. The current research interests of Dr. Lessi involve the development of novel and efficient protocols for highly selective transition metal-catalyzed 3 2 direct C(sp )-H and C(sp )-H arylation reactions, and the Fabio Bellina was born in Catania (Italy) in 1964. He discovery of new synthetic routes and applications of studied Chemistry at the University of Pisa and functionalized ionic liquids obtained from naturally received his Laurea Degree with first-class honours in occurring building blocks. 1990. In 1992, he joined the University of Pisa as an Organic Chemistry Researcher in the Department of Chemistry and Industrial Chemistry. In October 2003, he was appointed by the Faculty of Science of the University of Pisa as an Associate Professor of Organic Chemistry. His research interests were

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University of Pisa in 2011 defending a thesis performed under the guidance of Professor Anna Iuliano. Currently, she holds a position as PhD student at the Department of Chemistry and Industrial Chemistry of the University of Pisa under the guidance of Professor Fabio Bellina. She is currently working on the development and application of new protocols for the selective arylation of N-containing heteroaromatics.

Chiara Manzini was born in Lucca (Italy) in 1986 and graduated in Chemistry with first-class honours at the