Regioselectivity, Stereoselectivity and Catalysis in Intermolecular Pauson

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Regioselectivity, Stereoselectivity and Catalysis in Intermolecular Pauson–Khand Reactions: Teaching an Old Dog New Tricks IntermolecularSabine Pauson–Khand Reactions Laschat,* Armand Becheanu, Thomas Bell, Angelika Baro Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany Fax +49(711)6854285; E-mail: [email protected] Received 18 July 2005 Dedicated to Prof. Henning Hopf on the occasion of his 65th birthday.

method in organic synthesis. Cyclopentenones are very Abstract: Since its discovery in the early seventies the inter- versatile building blocks for natural products, pharma- molecular Pauson–Khand reaction has made considerable progress 2 towards a powerful synthetic method. This account describes the ceuticals and fine chemicals such as prostaglandins 4, major accomplishments with respect to reactivity, stereoselectivity isocarbacyclins 6, sesquiterpenes 5, and jasmonates 7 and catalytic versions, which have been achieved over the last (Scheme 2). decade and summarizes mechanistic information being obtained by theoretical and experimental studies. H 1 Introduction CO2H 2 Reactivity: Improvement by Additives O HO CO2H 3 Regioselectivity: Some Mechanistic Struggles H 4 Stereoselectivity 4.1 Chiral Precursors 4.2 Chiral Auxiliaries HO OH C H 4.3 Chiral Cobalt Complexes 5 11 4 5 4.4 Chiral Amine N-Oxides 5 Catalysis H O 5.1 Cobalt-Catalyzed Reactions 5.2 Ruthenium-Catalyzed Reactions 5.3 Rhodium-Catalyzed Reactions H 5.4 Iridium-Catalyzed Reactions H CO2Me 6 Theoretical Studies and some Mechanistic Curiosities 6 7 7 Conclusions Scheme 2 Key words: Pauson–Khand reaction, metal-catalysis, stereoselectivity, theoretical studies The mechanism of the Pauson–Khand reaction, initially proposed by Magnus,3 has now been widely accepted (Scheme 3). In the presence of Co2(CO)8 the alkyne forms 1 Introduction the tetrahedral dicobalt complex 8. After loss of CO, the alkene is coordinated to give the alkene complex 9, which During their studies of cobalt–alkyne complexes in 1971 undergoes insertion of the alkene moiety into the sterical- Pauson and coworkers reported the formation of cyclo- ly least hindered Co–C bond. Subsequent CO insertion pentenone 3 by treating acetylene dicobalthexacarbonyl gives rise to the cobalt acyl complex 11. Extrusion of one 2a with ethylene (Scheme 1).1 Co(CO)3 fragment yields the cobaltacyclopropene complex 12, which is finally converted to the cyclopentenone O 13 by reductive cleavage of Co2(CO)6. Except the forma- −2 CO + 8 H H + Co (CO) tion of the stable and isolable cobalt–alkyne complex , 2 8 ∆ Co2(CO)6 however, there was no experimental evidence for this 1a 2a 3 mechanism until recently. Scheme 1 Since the early reports by Pauson it was found that several other complexes containing transition metals such Fe,4 5 6 7 8 9 10 11 Originally discovered by serendipity, the cobalt-mediated Ru, Rh, Ni, Cr, Mo, W, Ti, and Zr can be used for [2+2+1] cocyclization of an alkyne, an alkene and carbon this cocyclization. monoxide to cyclopentenone, commonly known as the In 1981 Schore reported the first example of an intra- Pauson–Khand reaction, has grown into a powerful molecular Pauson–Khand reaction (Scheme 4).12 Despite this initial delay the intramolecular variant made much more progress over the last two decades particularly with SYNLETT 2005, No. 17, pp 2547–2570 17.10.2005 regard to reactivity, stereoselectivity and catalysis as Advanced online publication: 05.10.2005 DOI: 10.1055/s-2005-918922; Art ID: A38505ST compared to the intermolecular counterpart. © Georg Thieme Verlag Stuttgart · New York 2548 S. Laschat et al. ACCOUNT

Based on our own research efforts in this area, the follow- gio- and stereoselectivity are often difficult to control. ing article will focus on the various above-mentioned And last but not least a catalytic version is out of sight. issues of the intermolecular Pauson–Khand reaction with some selected examples of the intramolecular version. Although the intermolecular Pauson–Khand reaction pro- 2 Reactivity: Improvement by Additives ceeds in a highly convergent fashion and tolerates a vari- ety of functional groups such as ethers, alcohols, tertiary One of the earliest attempts to improve the reactivity was amines, thioethers, ketones, acetals, esters, amides, aryl described by Smit13a (Scheme 5). By adsorption of the co- and alkyl halides, heterocycles, vinylethers and -esters, it balt–alkyne complex 16 to silica gel and performing the is limited to reactive alkenes such ethylene, allene and reaction without any solvent (dry state adsorption condi- strained cyclic alkenes. Sterically hindered alkenes are tions) reaction rate and yield of the intramolecular Pau- disfavored. In many cases, yields are only moderate. Re- son–Khand reaction could be dramatically increased.

Biographical Sketches

Sabine Laschat studied of Professor Larry Over- Technische Universität in chemistry at the Universität man, she finished her habil- Braunschweig from 1997– Würzburg from 1982–1987 itation at the Universität 2002. Since 2002 she holds and received her PhD at the Münster (mentor: Professor a Chair in Organic Chemis- Universität Mainz in 1991 Gerhard Erker) in 1996. try at the Universität under the supervision of Then she was appointed as Stuttgart. Professor Horst Kunz. After an Associate Professor of a postdoc year in the group Organic Chemistry at the

Armand G. Becheanu was his engineer diploma. He sität in Braunschweig, Ger- born in 1977 in Lipova, Ro- started his PhD on ‘Pauson– many, under the supervision mania. He studied at the Khand Reactions as Key of Professor Sabine Laschat ‘Politehnica’ University Steps for Pharmaceutically and currently continues Timisoara between 1995 Relevant Target Molecules’ work in Stuttgart after the and 2000, where he received at the Technische Univer- group moved there in 2002.

Thomas Bell was born in versität in Braunschweig, ‘Cellulose Modification London, UK, in February Germany, under the super- Using Ionic Liquids’ with 1981. He studied for a vision of Professor Sabine Professor A. P. Abbott and MChem (Europe) degree at Laschat. He graduated in Dr. S. Handa in cooperation the University of Leicester, 2003. He is currently study- with Procter and Gamble, UK, which included one ing at the University of Lei- UK. year at the Technische Uni- cester for his PhD on

Angelika Baro was born in she received her PhD in tific staff member at the Stadtoldendorf, Germany. 1987 in Clinical Biochemis- Institut für Organische Che- She studied chemistry at the try under the supervision of mie, Universität Stuttgart, Georg-August-Universität Professor H. D. Söling. Germany. Göttingen, Germany, where Since 1991 she is a scien-

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RL However, a disadvantage of the amine N-oxides is their

+ Co2(CO)8 need in large excess (3–6 equiv). A solution to this prob- S L R R (CO) Co Co(CO)3 – 2 CO 3 lem has been recently reported by Kerr, who developed a RS polymer-supported morpholine-N-oxide 21 which could 18be recycled up to five times by treatment with Davies re- 16 + R – CO agent (Scheme 7). This result is particularly relevant for the use and recycling of chiral amine N-oxides for stereo-

L RL R selective Pauson–Khand reactions (see chapter 4.4). + CO Co(CO) Co(CO)3 (CO)3Co 3 (CO)2Co RS + 21 R RS OH R + 10 9 OH THF, r.t., 0.5 h Co2(CO)6 O + CO 2b 20 22 1. cycle: 91% RL 5. cycle: 86% RL O O Co(CO)3–Co(CO)3 Co(CO)3 O O (OC)3Co N N S S R H O R O O R R = Agrogel 11 12 21 O

– Co2(CO)6 Scheme 7

RL A plethora of other Lewis bases such as dimethyl sulfox- O ide,17 cyclohexylamine,18,19 aqueous ammonium hydrox- RS ide (in dioxane),18 and sulfides20 has been developed in R 13 order to enhance Pauson–Khand reaction rates. Particular- ly n-butyl methyl sulfide turned out to be successful, Scheme 3 where other additives failed (Scheme 8).20

O Co2(CO)8 O Ph Ph ∆ + Co (CO) 14 15 (31%) 2 6 2c 23 24 Scheme 4 Scheme 8 Reagents and conditions: (i) Toluene, reflux, 3 d, 24: 23%; (ii) NMO (6 equiv), CH2Cl2, r.t., 10 min, 24: decomplexation;

Co2(CO)6 (iii) n-BuSMe (4 equiv), Cl(CH2)2Cl, 83 °C, 1.5 h, 24: 85% method O O O A or B In order to circumvent the major disadvantage of n-butyl

16 17 methyl sulfide, its unpleasant odor and high volatility, Kerr prepared a sulfide 25 tethered to a Merrifield resin Scheme 5 Reagents and conditions: Method A: isooctane, 24 h, (Scheme 9).21 Even with sterically hindered cobalt– 17 17 60 °C, : 29%; Method B: SiO2, O2, 0.5 h, 45 °C, : 75% alkyne complexes such as 2d high yields could be main- tained over at least five cycles. Later Schreiber,13b Krafft,14 and Chung15 discovered the accelerating effect of tertiary amine N-oxides, which is probably due to the oxidative removal of one CO ligand + 25 from the cobalt–alkyne complex (Scheme 6). + Cl(CH2)2Cl Co2(CO)6 83 °C, 0.5 h O 2d 20 26 Ph method SMe 1. cycle: 89% Ph + O 5. cycle: 88% A or B 25 1b 18 19 O = Merrifield resin Scheme 6 Reagents and conditions: Method A: DME, 4 h, 60–70 °C, 19: 45%; Method B: Me3NO (3 equiv), CH2Cl2, 2 h, Scheme 9 0 °C, 19: 80%

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A completely different approach to rate enhancement uti- silanes for isoprostan synthesis (Scheme 12).27 Surpris- lizes solvent effects. Especially water has been identified ingly, the complete absence of water and additives, re- as a useful reaction medium for many organic reactions.22 spectively, turned out to be deleterious for the Pauson– In this respect recent results by Krafft should be men- Khand reaction. In the presence of additives only decom- tioned. Thermal intermolecular cocyclization in aqueous position products from enyne 31 were observed. How- solution in the presence of cetyltrimethylammonium bro- ever, when the reaction was carried out in acetonitrile with mide (CTAB) gave the desired enone 27 in good yield 1% of water, the cyclopentenone 32 was isolated, thus (Scheme 10).23 demonstrating the synthetic potential of silyloxy as a traceless linker. H O (0.1 M) Ph 2 + 20 O CTAB (0.5 equiv) 62% Co2(CO)8 Co2(CO)6 70 °C, 18 h Ph 1% H2O Ph O 2c Ph MeCN, reflux Me Si 2 30 min

27 O 31 32 (74%) Co (CO) 2 8 Scheme 12 NMO (6 equiv) 85% Ph + 20 MCH, [bmim]PF 1b 6 r.t., 0.5 h Simultaneously, Brummond developed Mo-promoted [2+2+1] cocyclizations of silicon-tethered allenes Scheme 10 (Scheme 13).28 Tethered allene-yne 33 was converted to the bicyclic enone 34. Subsequent E/Z isomerization with We have explored the scope and limitations of ionic liq- 1,3-propanedithiol provided the pure E-isomer, which uids as novel solvents for intermolecular Pauson–Khand was submitted to DIBAL reduction followed by fluoride- reactions.24,25 Although the amine N-oxide promoter induced cleavage of the vinyl–silicon bond to give the could be circumvented by a ionic liquid such as allylic alcohol 36. The latter was further converted to the [bmim]PF6, a biphasic system of [bmim]PF6/methyl- prostaglandin derivative 35. cyclohexane (MCH) not only made the use of low boiling CH2Cl2 obsolete, but also improved the work up, particu- O H larly the separation of the desired cyclopentenone from Mo(CO)6 C5H11 cobaltoxide and amine N-oxide residues, which remained · DMSO in the polar phase (Scheme 10). toluene Ph Si C H Ph2Si As mentioned in the introduction, the use of strained bi- 2 5 11 100 °C 33 34 (38%) cyclic alkenes and ethylene must be considered as serious E:Z = 33:67 limitation of substrates. Particularly, terminal alkynes 1) HS(CH2)3SH, BF3·OEt2 could not be used in intermolecular Pauson–Khand 2) DIBAL, Et2O, –78 °C reactions. Ogasawara presented a clever solution to this 3) BuNMe3F, HMPA/THF, pH 7.4 26 general problem (Scheme 11). O OH

4 steps OH O C5H11 O H H CO2H OH MOMO MOMO Si MOMO + Ph2 12,14 1) Co2(CO)8 35 (15-deoxy-∆ -PGJ2) 36 (13%) MOMO MOMO MOMO THF H H 2) method O O Scheme 13 28 29 30 A or B

Scheme 11 Reagents and conditions: Method A: Me3NO, THF, While looking for oxygenated cyclopentenone, Kerr and 30 –20 °C to r.t., 12 h, : 56%; Method B: cHexNH2, Cl(CH2)2Cl, Pauson studied vinyl esters and ethers as starting materi- reflux, 20 min, 29: 40% als.29 However, treatment of cobalt–alkyne complex with vinyl benzoate 37b29 in the presence of NMO did not give Alkene and alkyne were tethered via an ether moiety and the desired oxygenated product, but cyclopentenone 38 thus, the overall Pauson–Khand reaction occurred in- (Scheme 14). The reductive cleavage occurred only under tramolecularly. Careful choice of the reaction conditions inert conditions. After this unexpected outcome, Kerr and allowed to accomplish a reductive cleavage of the tether Pauson realized the potential of vinyl esters and even in the final step giving the bicyclo[3.3.0]octenone 29 in vinyl bromides as ethylene equivalents (Scheme 14). The 40% yield. strategy was applied in the total synthesis of (+)-taylori- In a related work Pagenkopf employed silicon-tethered one (39). enynes 31 derived from propargylic alcohols and vinyl

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O allene 41b resulted in the formation of cyclopentenones NMO·H2O 31 Ph X CH2Cl2 Ph 42 and 44 (47%, 70:30; Scheme 15). + r.t., 3 h Co2(CO)6 O O O 2c 37a X = OAc 38 (53%) 37b X = OBz (80%) H Y ++Y

O Y H H O O 42 43 44 OBz for 41a: 74%; 95% 5% – H H for 41b: 47%; 70% – 30%

39 37b 40 NMO (6 equiv) H 41a (Y = SiMe2Ph) CH2Cl2/THF 1:1 + · Scheme 14 –78 °C to r.t. 41b (Y = CO2Et) Y

While a great deal of experimental effort has been spent on modified reaction conditions in order to enhance the Co2(CO)6 rates, the observed large reactivity differences between 2e various alkenes in intermolecular Pauson–Khand reac- NMO (6 equiv) R tions still remained unclear. For example, in the intermo- CH2Cl2/THF 1:1 + 45a (R = H) 0 °C to r.t. 45b (R = Me) lecular thermal version the following reactivity order was CO2Me found: cyclohexene < cyclopentene < norbornene. Very O recently, Milet, Greene and Gimbert shed some light on R this important question by using DFT and ONIOM meth- CO2Me ods.30 They anticipated that the insertion of the alkene into 46a (59%) the Co–C bond (9 → 10, Scheme 3) is the rate-determin- 46b (0%) ing step and the LUMO (p* orbital) of the olefin plays an Scheme 15 important role in olefin–Co back-donation and creation of the new carbon bond by overlapping with the HOMO of In order to explain the results three competing pathways the alkyne Co2(CO)5 complex (Figure 1). Thus, transition were proposed (Scheme 16) starting from the allene com- states for cobaltacycle formation between propyne plex 9a. Allene insertion leads either to complex 48, 49 or Co2(CO)5 and cyclopentene, cyclohexene and nor- 50. Further insertion of CO, reductive elimination and bornene, respectively, were calculated and a strong decomplexation gave the products 42–44. correlation between HOMO/LUMO gaps and the relative reactivity of the olefin was found. Cazes also investigated the reaction of cobalt–alkyne complexes with electron-poor alkenes (Scheme 15).32 In contrast to previous observations Michael acceptors such dπ cobalt π* alkene as methyl acrylate 45a gave under NMO activation the desired cyclopentenone 46a in 59% yield. However, the re-

back-donation action was very sensitive to steric effects and the corresponding methyl methacrylate 45b did not give any π* alkyne σ − C C trace of product 46b. dσ cobalt π alkene A rather surprising discovery was made by Pericas and Riera33 regarding cyclopropene as a starting material for Pauson–Khand reactions (Scheme 17). While the NMO-

σ σ promoted Pauson–Khand reaction of cobalt–alkyne com- alkyne Co−alkyl plexes 2d proceeded eventless, the obtained bicyc- Figure 1 Schematic illustration of HOMO/LUMO orbital interac- lo[3.1.0]hex-3-en-2-one (51) underwent a photochemical tions in Co–C bonds rearrangement to an ortho-substituted phenol 52.

Although the majority of intermolecular Pauson–Khand reactions utilizes either cyclopentene, norbornene, nor- 3 Regioselectivity: Some Mechanistic bornadiene and derivatives thereof, Cazes31,32 and Struggles Pericas33 demonstrated that allenes, electron-poor alkenes and even cyclopropene are useful substrates for the inter- Whereas the intramolecular Pauson–Khand reaction re- molecular cocyclization. For example, treatment of co- sults in only one regioisomer, the corresponding inter- balt–alkyne complex 2e with moderately electron-rich molecular version always leads to product mixtures. A allene 41a gave 74% of a 95:5 mixture of cyclopenten- typical example is given in Scheme 18.34 ones 42 and 43, while the corresponding electron-poor

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R1 (CO)3 apical basal syn Co(CO) O Co 1 3 C OC R Y Co(CO)2 Co Co(CO)3 Co 42 H OC OC O basal syn C basal anti C R O H 48 O Co(CO)3 basal anti 55 apical Y Co(CO)2

R2 R Co(CO)3 47 R Co(CO)2 43 (CO)3 (CO)3 Co Co O O R1 O R1 Y C C 49 Co Co R2 C C O H O H Co(CO)3 R2 Co(CO)2 Co(CO)3 56a 56b H Co(CO) H 2 · 44 R Y Y O O 9a 50 R2 R1 R1 Scheme 16

R2 57 58 OH 1) NMO (6 equiv) O Scheme 19 CH2Cl2 hν CHCl 2) 3 Co2(CO)6 2d 51 (93%) 52 (98%) Upon treatment of norbornene diester 59a with various alkynes 1b–f in the presence of NMO we observed a de- Scheme 17 pendence of the regioselectivity on the steric hindrance (Scheme 20).37

O O

Ph Ph Ph + R + + MeO2C Co2(CO)6 MeO2C 59a 1b–f1c R = CH2CH2OH 2c 37c 53 (53%) 54 (47%) 1d R = n-C5H11 NMO (6 equiv) 1e R = C(CH3)2OH Co2(CO)8 1f R = t-Bu Scheme 18 CH2Cl2, r.t. O When we started our investigations on the regioselectivity R R of intermolecular Pauson–Khand reactions employing + MeO C 2 O MeO2C norbornenes, surprisingly little work has been done on MeO C MeO C 35 2 2 unsymmetrically substituted bridged bicyclic alkenes. 60 61 According to the commonly accepted mechanism36 the cocyclization is initiated by the formation of cobalt– R Yield (%) 60 61 Ph 56 a 61 39 alkyne complex 55 with a tetrahedral Co2C2 core (Scheme 19). CH2CH2OH 28 b 85 15 n-C5H11 49 c 65 35 Under thermal conditions or in the presence of amine N- C(CH3)2OH 42 d 48 52 oxide promoters complex 55 is assumed to undergo decar- t-Bu 49 e 6 94 bonylation at the basal (equatorial) carbon monoxide, Scheme 20 which is oriented anti relative to R1 followed by coordination of an alkene to give alkene complexes 56a and 56b. While linear unbranched alkynes yielded preferably re- The regioselectivity with respect to the alkene is due to gioisomer 60, the ratio was reverted in favor of regioiso- steric hindrance in the insertion step 56a → 57 versus 56b mer 61, when tert-butyl-substituted acetylene 1f was → 58. The less hindered face of the alkene is inserted into employed. During these experiments an unexpected tem- the less hindered Co–C bond. For alkenes with sufficient- perature effect was found (Scheme 21). For example, the ly large substituents R2, conformation 56a and thus, cy- Pauson–Khand reaction of norbornene diester 59a with clopentenone 57 is preferred. However, with most alkenes propargylic alcohol 1e yielded at low temperature regio- mixtures of regioisomers 57, 58 are obtained. isomer 60d as the major product, whereas at elevated temperatures regioisomer 61d was favored. This reversal of

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(toluene, CH2Cl2, THF), albeit at different temperature X + R ranges. X 59a 1 59b X = N–CO Et O 2 NMO 59c X = CH2 (6 equiv) OH OH Co (CO) , NMO (6 equiv), toluene 59a + 1e + 2 8 Co (CO) 2 8 E E R R O E E 60d 61d OC X CO E = CO Me Co Co X Co Co 2 Solvent T (°C) Yield (%) 60d 61d X OC H CO X OC H CO CH Cl –20 24 90 10 C C C C 2 2 O O O O CH2Cl2 0 25 88 12 exo-Si exo-Re CH2Cl2 20 34 81 19 CH2Cl2 40 42 48 52 H R R H Toluene –25 61 95 5 Co Co Toluene 20 59 23 77 Toluene 120 48 12 88 OOC C OC CO

Scheme 21 CH3 CH3 XX XX

From these results we have developed the following mechanistic rationale (Scheme 22). In contrast to the liter- O O ature proposal we assumed removal of an axial CO ligand R R X X from the prochiral cobalt–alkyne complex resulting in the X X formation of diastereomeric alkene complexes exo-Si and 60 61 exo-Re. Newman perspectives of these two complexes rationalize that due to the preference to insert the olefin into Scheme 22 the least hindered alkyne carbon atom at low temperatures and with alkynes bearing small substituents R complex exo-Si should be favored, leading to product 60. However, R O OAc at elevated temperatures and with bulky substituents R Ph Ph 62 complex exo-Re should be preferred giving product 61. + Our experimental results were further supported by Co2(CO)8 OAc OAc (a) Cazes,38 who studied the regioselectivity of 7-oxanor- O 64R 65 bornenes. However, the question axial versus equatorial 1b: 29%, 57 : 43 R Ph alkene complex still remained open. 1g: 77%, 66 : 34 1b R = H 39 40 Almost simultaneously, Arjona, Plumet and Tam dis- 1g R = CO2Et covered remote substituent effects on the regioselectivity R O O O in Pauson–Khand reactions of 2-substituted norbornenes, (b) Ph Ph Co2(CO)8 7-aza- and 7-oxanorbornenes. Moderate levels of regiose- + O CN CN 40 lectivity were observed for norbornenes (Scheme 23), O R while the regioisomeric ratio increased considerably for CN OAc OAc 7-oxanorbornenes 63.39a 66 67 63 OAc 1b: 75%, 70 : 30 Moreover, the regioselectivity increases with increasing 1g: 60%, 70 : 30 electron withdrawal by the remote substituent. Semi-em- Scheme 23 Reagents and conditions: (a) CyNH , Cl(CH ) Cl, pirical calculations indicated a polarization of the alkene 2 2 2 80 °C; (b) NMO, CH2Cl2, r.t. which is controlled by the remote substituent.40 Remark- ably, the presence of a bromine atom in the alkene moiety of 7-oxa- and 7-azanorbornenes not only could be used to alkyne complex 71b gave exclusively regioisomer 73 revert the regioisomeric ratio, but also a reductive dehalo- (Scheme 25). genation step leads to removal of the bromine atom from Concerning allene cocyclization Cazes proposed coordi- the product during the progress of reaction. The bromine nation of the allene on an axial vacant ligand site of the atom is thus acting as a traceless controller (Scheme 24). cobalt atom.42 For Pauson–Khand reactions with vi- According to Cazes41 silyl groups at the alkyne are useful nylethenes the regioselectivity turned out to be strongly to control the regioselectivity in Pauson–Khand reactions dependent on the reaction conditions.43 Under thermal employing allenes. While the cobalt–alkyne complex 71a conditions dihydrofuran 76 gave a mixture of regioiso- with one silyl group yielded a mixture of cyclopentenones mers 77, 78, whereas the NMO-promoted reaction yielded 73–75, the corresponding disilyl-substituted cobalt– exclusively compound 77 as a single regioisomer (Scheme 26).

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Boc Pauson–Khand reaction of substituted acetylenes with N 45 X norbornene. The experimentally observed regioisomeric 2c + H preference shown in Scheme 27 cannot be explained simply by steric arguments. SO2Tol 68a X = H 68b X = Br O 2 O R 2 NMO, CH Cl Me R 2 2 for 1m 20 + O Boc Boc CO Et R1 2 R1 Ph N Ph N 79g 179R1 R2 + H H b HPh a h H CO Et b O 2 i H CH2OH c SO2Tol SO2Tol 69 70 j H Me d k Me TMS e 68a: 45%, 65 : 35 l Me Ph f 68b: 60%, 100 : 0 m Me CO2Et g Scheme 24 Scheme 27

Me3Si R + · For example, while ethyl propiolate 1h gave preferably C6H13 isomer 79b, ethyl butynoate 1m afforded regioisomer 79g Co (CO) 2 6 as the major product. Therefore, Milet, Gimbert and 71a R = n-Bu 72 71b R = SiMe3 Greene used DFT to examine whether electronic differ- NMO ences in the acetylenic substituents are involved in con- CH2Cl2/THF, –78 °C–20 °C, 4 h trolling the regioselectivity.45 From calculations of atomic

O O O charges of the alkyne carbon atoms by natural population analysis it became evident that indeed propyne is strongly Me3Si Me3Si C6H13 R polarized, with the terminal alkyne carbon carrying a + + C6H13 C6H13 higher charge density as compared to the internal alkyne R R Me3Si 73 74 75 carbon. Ethyl propiolate 1h is only weakly polarized and 38% a 45% (100:0) a 10% a 45% (88:12) thus, steric effects are becoming predominant. In contrast,

22% b 100% (82:18) b – b – ethyl butynoate 1m is strongly polarized in the opposite direction, resulting in a large charge density at the a-car- Scheme 25 bon relative to the ester group. In addition, electronegative substituents on the alkyne should strengthen the acceptor properties of the bridging ligand, which would result in re- O O duced back-donation from the metal into the p* orbitals of O Ph Ph the CO ligands. This proposal could be verified by exam- 2c + O + ination of the CO absorptions in the IR spectra of the co- O 76 77 78 balt–alkyne complexes. The trans-effect together with the difference in electron density on the two acetylenic car- Scheme 26 Reagents and conditions: (a) Toluene, 70 °C, 20% yield bons in the complex should therefore be responsible for a (77: 78%, 78: 22%); (b) NMO, CH Cl , US, 43% yield (77: 100%) 2 2 discriminate loss of CO. The mechanism could be elegantly verified by employing an alkyne with two aryl sub- While the above-mentioned experimental work was in stituents of similar size but with different electronic progress, Milet, Gimbert and Greene published two theo- properties. As suggested by the calculations regioisomer 44,45 retical studies. From DFT calculations of cobalt–prog- 81 was obtained as the sole product (Scheme 28). yne complexes bearing the alkene moiety either at an axial position or at one of the two equatorial positions it was CH3 concluded that the initial position of ethylene (and other OC CO OC CO O olefins when pseudorotation is relatively facile) does not Co toluene determine the regiochemistry in the Pauson–Khand reac- 80 °C tion, because the barrier for pseudorotation of CO and eth- 6 h 44 C ylene can easily be overcome at room temperature. O However, for the insertion step the complex with the axi- H3C CO2Et CO2Et ally coordinated alkene runs through the lowest lying tran- 80 81 (65%) sition state and thus, must be considered seriously. The Scheme 28 second study dealt with the regiochemical outcome of the

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4 Stereoselectivity R R In order to differentiate between the enantiotopic faces of Co2(CO)8 (2 equiv) O H CH2Cl2 H the prochiral cobalt–alkyne complex (Scheme 29), four HH different strategies are conceivable: i) chiral precursors H NMO (12 equiv), 0 °C H O (ex chiral pool), ii) chiral auxiliaries, iii) chiral cobalt R complexes, and iv) chiral additives. 86 87 R

R HR O Re Si O axial O axial C C OC C R Co Co equatorial cis Co Co equatorial cis C CO C C O C O O – C C C O H O O O H equatorial trans equatorial trans H Scheme 29 –

88 R

4.1 Chiral Precursors Scheme 31 Marco-Contelles used an ex chiral pool strategy to obtain the iridoid aglycon 85 (Scheme 30).46 Starting from the excellent diastereoselectivities for amine N-oxide-pro- carbohydrate-derived enol ether 82 the enyne 83 was moted cocyclizations of cobalt complexes and arylvinyl- prepared, which underwent amine N-oxide-promoted co- sulfoxides such as (R)-89 (Scheme 32). cyclization to the tricyclic cyclopentenone 84, which was further converted to the target compound 85. O NMe2 S + OAc OAc OTIPS Co2(CO)6 AcO 2f (R)-89 O O NMO, MeCN, 0 °C O O 1) OsO , TMEDA O O 82 83 4 CH2Cl2, –78 °C S 1) Co2(CO)8, CH2Cl2 HO TIPSO Ar HO 2) toluene, reflux H 2) NMO, 0 °C, 40% 3) HCl, r.t. HO HO OAc H O H 91 (44%, >99% ee) 90 (62%, dr 93:7)

HO H Scheme 32 O O H H O O Treatment of alkyne complex 2f with arylvinylsulfoxide 85 84 (R)-89 yielded the cyclopentenone 90 in 62% as a diaste- Scheme 30 reomeric mixture (dr 93:7), which was converted in three steps into the antibiotic (–)-pentenomycin (91, 44% yield, >99% ee). Presumably the N,N-dimethylamino group 47 As described by Grossman the chiral C2-symmetric chelates the cobalt atom which coordinates the alkene, bisenyne 86 was converted by a twofold Pauson–Khand thus increasing the steric bias in favor of one diastereo- reaction to the tethered pentalenedione 87, which was fur- mer. This hypothesis is supported by observations that ther converted to the chiral cyclopentadienyl ligand 88 arylvinylsulfoxides without an amino anchor gave lower (Scheme 31). diastereoselectivities. In contrast, attaching the sulfoxide auxiliary to the alkyne 4.2 Chiral Auxiliaries gave rather disappointing results. Pericas and Riera unex- pectedly found an easy racemization of alkynyl sulfoxide cobalt complex 2g resulting in low diastereoselectivities The vast majority of stereoselective intermolecular 49 Pauson–Khand reactions is based on chiral auxiliaries, of the corresponding cyclopentenone 92 (Scheme 33). which are either attached to the alkene or the alkyne. For Chiral oxazolidin-2-ones proved to be very useful auxilia- example, chiral sulfoxides have been successfully used ries for alkynes, as was shown by Moyano and Pericas for both alkenes and alkynes. Carretero48 reported good to (Scheme 34).50

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Tol O alkyne complexes the corresponding cyclopentenones 99 S O toluene, 65 °C were obtained even at –21 °C with good diastereoselectiv- 27 h Bu ities (Scheme 36). S Bu + 20 Tol 34%

Co2(CO)6 O OBn

2g 92 (dr 64:36) NR2* toluene Scheme 33 N + 18 O

O 99 O O Ph OBn 22 °C, 0.17 h, 24%, dr 71:29 98 1) Co2(CO)8 0 °C, 1.5 h, 32%, dr 82:18 N O –21 °C, 12 h, 32%, dr 88:12 2) + 18 O Ph Ph X* H H O O 93a 94a C OC C O O OC C C Ph Co Co Co C Co C H OC OC O O O O C C O H C C O N R O N R OC Co Co CO 94a R R C O Ph Scheme 36 O X* O N DFT calculations suggest that the dialkylamino substitu- H ent is assisting and directing the dissociative loss of CO through a trans-effect (Scheme 36). Scheme 34 Reagents and conditions: (i) Toluene, r.t., 21 h, 94a: 91%, dr 84:16; (ii) NMO, CH Cl , –20 °C, 94a: 100%, dr 79:21 Oppolzer’s bornane-2,10-sultam (100, Scheme 37) 2 2 proved to be a highly efficient auxiliary for intermolecular Pauson–Khand reactions giving exceptional diastereose- Semiempirical calculations (PM3) of the cobalt–alkyne lectivities.54 Based on DFT calculations it was assumed complexes clearly indicate that the S-configured chiral that the extremely efficient chirality transfer is due to che- auxiliary effectively shields the Re face of the tetrahedral lation of one of the cobalt atoms by the sulfoxide moiety cobalt cluster, therefore directing the alkene to an equato- and subsequent rate-determining formation of the alkene rial anti-position of the Si face as depicted in Scheme 34. complex at this specific coordination site. Subsequent insertion of the alkene, CO insertion and cleavage of the cobalt fragment gives the major diastereo- O mer 94a. It should be noted that similar yields and dia- O Ph stereoselectivities were obtained under both thermal and 1) Co2(CO)8 N amine N-oxide-promoted conditions. When Hsung reex- 2) + 18 O Ph 51 O2S CH2Cl2, amined the Pauson–Khand reaction of chiral ynamides, X* NMO·H2O endo-products were observed as mixtures together with 100 0 °C to r.t., 1 h 94b the expected exo-products. By careful optimization of the 93%, dr >99.9:0.1 reaction conditions he was able to obtain either endo- or Scheme 37 exo-products (Scheme 35). This result was later confirmed by Riera and Verdaguer.52 Unfortunately, no clear Although previous studies by several groups have sug- mechanistic rationale could be drawn. gested that chelating effects of the chiral auxiliary might contribute to enhanced diastereoselectivity, this issue has O R O H X* not been thoroughly investigated until Pericas, Riera and O 55 1) Co2(CO)8 Greene reported their results in a series of papers. They N O H + 2) + 18 H R anticipated that an additional thioether moiety at the chiral NMO (6 equiv) X* H auxiliary would serve as an internal promoter which re- Ph CH2Cl2, –10 °C R places one CO ligand and is further substituted by the 95a R = Ph 96a 30% 97a 0% alkene. When complex 101 bearing a camphor-derived 95b R = H 96b 0% 97b 16% (dr 66:34) auxiliary (Scheme 38) was generated at typical thermal Scheme 35 conditions minimizing conversion to complex 102 and further treated with norbornene the desired cyclopentenones 103, 104 were obtained with excellent yields albeit By using chiral C2-symmetric ynamines 98 Pericas improved the reactivity in thermal Pauson–Khand reactions with a meager diastereoselectivity of 60:40 in favor of dramatically.53 Despite the high instability of the cobalt– compound 103.

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4.3 Chiral Cobalt Complexes

∆ Chiral heterobimetallic alkyne complexes provide an ad- O or NMO O – CO ditional tool to accomplish stereoselective intermolecular SMe MeS OC CO CO Pauson–Khand reactions, as was demonstrated first by Co + CO Co Co Co C C 9,57 C O C O Christie (Scheme 40). O C O C C O C O O H O H 101 102 + 18 hexane, 20 °C CH2Cl2, –20 °C

HO O O O OR* O O *RO O C O C + C menthol C Co Co C Co Co OC O C CO C HBF , Et O O C C O 4 2 C O 103 104 O H O H from 101: 95%, 60 : 40 55a 108 (72%) from 102: 82%, 96 : 4 1) Na[CpMo(CO) ], THF 3 78% 2) chromatography Scheme 38

In contrast, conversion of complex 101 to the chelated complex 102 by treatment with NMO and subsequent O O addition of alkene resulted even at –20 °C in exceptional OR* + 18 diastereoselectivities.55a From detailed studies, NMR in- OC toluene Mo C Co CO vestigations of the equilibrium between the two complex- O C C O es 101, 102 and DFT calculations a mechanistic picture O H emerges in which chelation of the axial position at the Re 110 (61%, 100% de) 109 face is preferred and formation of the major diastereomer Scheme 40 103 occurs through a sequence of the most stable inter- 55b–f,56 mediates. Because even a slight excess of NMO had The cobalt–alkyne complex 55a was etherified with a deleterious influence on the diastereoselectivity, Pericas menthol to give complex 108. Subsequent treatment with and Riera developed an amine N-oxide free method,55f in Na[CpMo(CO)3] gave a 1:1 mixture of heterobimetallic which the chelated complex 102 is formed under purely complex 109 and its diastereomeric counterpart which thermal conditions by simply heating to 55 °C prior to could be separated by chromatography. When complex alkene addition and insertion at subambient temperatures. 109 was heated with norbornadiene (18) the cyclopenten- The chiral auxiliary could be further used for a stereocon- 55d one 110 was obtained as a single diastereomer. Control trolled conjugate addition. The auxiliary was removed experiments with the corresponding bis-cobalt–alkyne by treatment with SmI2 and subsequent tandem retro complex showed only a slight diastereomeric excess in the Diels–Alder/Lewis acid catalyzed Diels–Alder reaction cyclopentenone product 110. with maleic anhydride afforded the cyclopentenone 107 58 (Scheme 39). When studying heterobimetallic W–Co and Mo–Co complexes59 of alkynoates, Pericas and Moyano were surprised to find endo-adducts (Scheme 41).59 O 1) n-Bu2CuCNLi2 TMSCl H 103 OH + H 2) SmI2 O O O 1) Co2(CO)8 H THF, MeOH Bu THF, r.t. 0 °C SMe N O O 105 (99%) 106 (88%, dr >99:1) 2) Na[CpMo(CO) ] Me 3 O THF, reflux, 80 min Me Bu X* 3) + 18 (10 equiv) , MeAlCl , CH Cl , 55 °C O 2 2 2 93b 111 75%, dr 88:12 O O Scheme 41

Bu The chirality of the tetrahedral C2CoMo core appears to 107 (88%) control the diastereoselectivity of the endo-products such Scheme 39 as 111. The analogous [MoCp(CO)2]2 complexes did not react with norbornadiene (18) to the cyclopentenone, thus indicating that the cobalt atom is the ‘active’ species in these heterobimetallic complexes.

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An alternative approach towards chiral cobalt–alkyne It was known from Bonnet,62 Bird,63 and Cullen64 that complexes utilized chiral phosphine ligands. This access monophosphines such as PPh3 usually coordinate at the dates back to 1988 when Pauson and Brunner60 employed apical position, diphosphines with small bite angles such (R)-(+)-glyphos (112) to prepare a 60:40 diastereomeric as f6fos prefer the basal chelated geometry, while the basal mixture of the cobalt complexes 113a,b which could be bridged orientation was obtained for diphosphines with an separated by chromatography (Scheme 42). Subsequent increased bite angle and a more flexible tether such as reaction with norbornene (20) yielded the enantiomerical- dppm or dppe. Diphosphines with a very large bite angle ly pure cyclopentenone 27. Kerr modified the original (e.g. dppb) gave apical bridged complexes. At the outset methodology by using mild decarbonylation with amine of our experiments we anticipated that a chiral C2-sym- N-oxides61 and thus, obtaining the chiral complexes in metrical diphosphine such as BINAP should prefer a basal high yields. bridged coordination mode.65 By treating (3,3-dimethylbutyne)Co2(CO)6 and (R)-BINAP in refluxing THF Ph followed by recrystallization from diethyl ether the corre- toluene, 60 °C R* O O 170 min Ph P C sponding (3,3-dimethylbutyne)[(R)-BINAP]Co2(CO)4 2c + O 2 Co PPh2 Co C complex was obtained as a crystalline solid, which fortu- 55% C O O C C nately was suitable for X-ray crystal structure determina- 112 O H O (R)-(+)-glyphos 113a tion. As shown in Figure 2 indeed a basal anti-bridged 60:40 + coordination mode was found. Further work with achiral Ph R* diphosphines confirmed that, for example, (phenylacetyl- 1) chromatography OC PPh2 ene)(dppm)Co2(CO)4 also contains a basal anti-bridged Ph Co Co 2) + 20 CO diphosphine ligand (Figure 3). OC C C O O O H 27 (31%, 100% ee) 113b Scheme 42

However, even under these very mild conditions two serious limitations could not be overcome. First no enantio- facial differentiation of the two enantiotopic cobalt atoms in the prochiral cobalt–alkyne complex could be achieved and secondly the diastereomeric cobalt–alkyne phosphine complexes required tedious chromatographic separations. Because in some cases, even preparative HPLC is necessary, this route is not accessible to large-scale synthesis.

RL RL RL O O O O C C C P OC C Co Co P Co Co P Co Co C OC OC OC O P CO P C S C S P O R O R RS basal basal-apical basal anti chelated chelated bridged

L L R O R OC C P P Co Co P Co P C Co CO C O C Figure 2 X-ray crystal structure of (3,3-dimethylbutyne)[(R)- C O C O O S S R O R BINAP]Co2(CO)4 basal syn apical bridged bridged Surprisingly, upon treatment with norbornene (20) both Scheme 43 the (R)-BINAP and the dppm complex turned out to be completely unreactive, and neither thermal conditions nor Encouraged by the promising stereoselectivities of amine N-oxides resulted in the formation of the desired cobalt–alkyne complexes bearing chiral phosphines we cyclopentenone. In order to get a deeper insight we carried initiated a study of various diphosphines. Depending on out some qualitative rate experiments (Scheme 44). the distance of the two P atoms and the flexibility of the (3,3-Dimethylbutyne)Co2(CO)6 (114a) and the corre- tether bidentate phosphines should give access to five sponding complex 114b, where one CO ligand has been different cobalt–alkyne complexes, i.e. basal chelated, replaced by PPh3, were submitted to thermal and amine N- basal-apical chelated, basal anti-bridged, basal syn- oxide-promoted Pauson–Khand reactions. The rate-deter- bridged, and apical bridged (Scheme 43). mining influence of PPh3 is clearly visible. The effect is

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consequence, the shutdown of the cocyclization pathway is caused by the decrease of the reaction rate due to the phosphine and the coordination of the bidentate ligand at the ‘wrong’ position, i.e. basal anti instead of basal syn. Another implication of these results is that in the Pauson– Khand reaction of (alkyne)[(R)-glyphos]Co2(CO)6 the coordination and insertion step presumably takes place at the phosphine-free cobalt atom. The Co(CO)2glyphos moiety is thus acting as a chiral neighbour that directs the stereoselectivity. The results obtained so far with (R)-BINAP prompted us to look for chiral diphosphine ligands which would meet the following requirements: a) diastereoselective com- plexation and b) formation of a chelated complex instead of a bridged one in order to overcome the limitation with (R)-BINAP. We anticipated that the phosphine phosphinite ligand 117 might serve this purpose (Scheme 45).66

DABCO 6 steps (4 equiv) Figure 3 X-ray crystal structure of (phenylacetylene)- O O 28% PPh2 THF, 85 °C PPh2 (dppm)Co2(CO)4 O 18 h, quant. SO3H PPh2 BH3 PPh2

115BH3 116 117 O O Ph C O C C L toluene, 80 °C or Co Co Co Co + 20 C CO C O C C O CH2Cl2, NMO, r.t. Ph O C O C O C Ph2 O C O H C O O H H O P Ph Co Co 118 114a L = CO 26 OC 114b L = PPh C Ph2P 3 O THF, 60 °C, 6 h O Ph Scheme 44 119a O O Ph + C C Co Co O Ph OC CO even more pronounced when two CO ligands were re- C PPh2 Ph P PPh2 2 Ph placed by PPh3 or a diphosphine such as dppm. In this Co Co + P O O case, less than 1% conversion was observed. The de- OC C Ph2 C O creased reaction rate of the phosphine complex is proba- O Ph bly due to the replacement of carbon monoxide by a 119b 119c poorer p-acceptor ligand thus increasing back-donation between cobalt and the remaining carbon monoxide. This Scheme 45 should lead to a retardation of the initial decarbonylation step in the Pauson–Khand reaction. According to the Ligand 116 can be prepared in 6 steps followed by depro- mechanistic scheme proposed for the cocyclization the tection from (S)-(+)-camphorsulfonic acid (115). Heating carbon monoxides in the basal position anti to the larger of phosphine phosphinite 117 in the presence of tolane co- substituent are usually supposed to be most prone to un- balt complex 118 yielded two cobalt complexes 119a,b dergo decarbonylation and subsequent coordination of the (20%) and 119c (21%) with a chelated and bridged geom- alkene. The inertness of the (R)-BINAP complex and the etry. Unfortunately, the spectroscopic data gave no evi- corresponding dppm (and dppe) complexes towards the dence for either apical-basal chelated (119a,b) or basal reaction conditions support this mechanism. The only car- chelated (119c) geometry and subsequent Pauson–Khand bon monoxide that might be accessible for the cocycliza- reactions were therefore expected to be of less mechanis- tion is the basal coordinated C1–O1 and C3–O3. tic value. Nevertheless, these bidentate ligands proved to However, the insertion step is very sensitive to steric hin- be useful in catalytic asymmetric hydrogenation of meth- drance and thus, insertion from a basal position such as ylacetamidocinnamates reaching complete conversion C3–O3 is disfavored due to steric interactions with the with up to 89% ee.67 Our mechanistic assumptions were tert-butyl group. In contrast, the other two basal positions further supported by very recent results by Gibson,68 who are occupied by the phosphine ligand and thus, the found conditions to obtain the chelated BINAP cobalt– Pauson–Khand reaction is completely suppressed. As a alkyne complexes, which indeed could be used for enan-

Synlett 2005, No. 17, 2547–2570 © Thieme Stuttgart · New York 2560 S. Laschat et al. ACCOUNT tioselective Pauson–Khand reactions. While our above- The problems associated with phosphine ligands motivat- mentioned basal anti-bridged BINAP cobalt–alkyne com- ed two other groups to put further efforts in this issue. plex was obtained by mixing the cobalt–alkyne complex Christie prepared diastereomeric cobalt–alkyne complex- with (R)-BINAP,65 Gibson first prepared a precatalyst es 109b with menthyl auxiliary and N-heterocyclic car- 72 from either Co2(CO)8 or Co4(CO)12 and (R)-BINAP and bene ligand (NHC, Scheme 48). The obtained yields and then added the alkyne68 in order to get the chelated diastereoselectivities of the Pauson–Khand product 110 complex. Thus, the order of addition seems to play an were excellent, however, the presence of a chiral auxiliary important role. Gibson speculated that the bridged com- was still necessary. In addition, partial migration of the plex might be an intermediate during epimerization of the NHC ligand was observed creating some loss of stereo- chelated complex. chemical integrity. To overcome the deleterious effect of phosphine ligands R*O on the reactivity of the cobalt center Gimbert and Greene i-Pr i-Pr pursued a different approach maintaining the excellent O CO N N 69,70 C NHC stereocontrol. The reactivity in Pauson–Khand reac- Co + C Co CO O C tions of cobalt–alkyne complexes 120 bearing bidentate C O i-Pr i-Pr O H BF4 diphosphinoamine ligands with norbornene (20) in- 108 creased with increasing electron-withdrawal from the K Amylate hexane, 65 °C phosphorus atoms (Scheme 46).69 The replacement of the R* = menthyl bridging N-methyl group by (+)-a-methylbenzylamine O R*O yielded the cyclopentenone 27 with 16% ee. OR* CO + 18 NHC Co Co CO Ph H 70 °C, 1 h OC O C O H C O OC C O H Co Co C + 20 110 (95%, 87% de) 109b (dr 75:25) C O Ph O P P toluene, 80 °C X H X X 3–5 d Scheme 48 X E 120a–f 27 120 E X 27, Yield (%) Moyano, Pericas and Riera reexamined the possibilities of bidentate phosphinooxazoline ligands on the cobalt atoms a CH2 Ph 24 73 b NMe Ph 65 (Scheme 49). Depending on the steric bulkiness of the c NMe F 92 substituents at the alkyne and at the oxazoline moiety d NMe (CF3)2CHO >98 either chelated complex 122 or complex 123 with mono- e NMe Pyrrolyl 90 f Pyrrolyl 98, 16% ee dentate phosphine was observed, which could be inter- N Ph converted under certain conditions. However, the non- chelated complexes such as 123 gave much better enantio- Scheme 46 selectivities than the corresponding chelated species (Scheme 49). By using circular dichroism the absolute X-ray crystal structures reveal that the bridging diphos- configuration of the non-chelate complex 123 could be phinoamine ligand occupies the basal anti-position. This correlated with the absolute configuration of the cyclo- strongly suggests that the apical (axial) CO ligand is re- pentenone product 19. Coordination of the phosphine to placed by the alkene. Although later work by Moyano and the Re face of 123 resulted in 2R-configured cyclopenten- Pericas71 confirmed the high reactivity of trispyrro- one 19. lylphosphine containing cobalt–alkyne complexes, the enantioselectivity of the diphosphinoamine ligand could Ph 70 not be improved. After considerable experimentation, Ph2 O P C Co + 20 two equivalents of (R)-BINOL-derived phosphoramidite Co C C O 27 (quant., 51% ee) 121 were found to increase the enantiomeric excess of the O C toluene, 80 °C N H O reaction with norbornene (20) up to 38% (Scheme 47). Ph O 122

O 1) toluene, 80 °C 2c + P NEt2 27 O Ph O 2) + 20, toluene + 18 80 °C O 70%, 38% ee N Ph P C (2R)-19 (85%, 94% ee) 2 Co 121 Co C NMO, CH2Cl2 t-Bu O OC C 0 °C, 24 h C O Scheme 47 O H 123

Scheme 49

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The epimerization rate of complexes such as 123 is ligand must be considered as major limitation. In a com- strongly dependent on the alkyne substituent and the rate pletely different approach the prochiral cobalt–alkyne increases in the order Ph < n-Bu < SiMe3 << t-Bu. Further complex 8 is desymmetrized by a chiral amine N-oxide experiments showed that the intermolecular Pauson– which should lead to the preferred decarbonylation of ei- Khand reaction of the pure diastereomeric complexes is ther Re face or Si face ultimately resulting in the formation stereospecific.73b The only requisite for obtaining high of one of the two enantiomeric cyclopentenones 128 enantioselectivities is that the rate of the cocyclization (Scheme 51). must be higher as compared to the epimerization. Further- more, the use of amine N-oxides allowed convenient recy- R1 O cling of the ligand as phosphine oxide. Based on their OC C Co Co ground-breaking results with camphor-derived auxiliaries C OC O with a tethered thioether promoter Pericas and Riera de- C C O H O veloped new hemilabile (P,S) ligands named PuPHOS 8 (124)74 and CamPHOS (126)75,76 which are generated from (+)-pulegone (125) and (+)-camphorsulfonic acid R*3N–O (112), respectively (Scheme 50). The authors assumed a R1 R1 O O coordination pathway, which is also depicted in C C Co Scheme 50. The incoming ligand preferably coordinates Co Co Co C C CO OC C O O C via P at the axial position. The phosphine then undergoes C C O O H O O H migration to the equatorial position yielding complex Re Si 127b. Final replacement of an equatorial CO at the second cobalt atom should give bridged complex 127c. R2 R2

O R2 R1 R2 R1

O O O O for TMS 128 ent-128 Ph S P 93%, up to 97% ee Scheme 51 124Ph 125

O In a seminal paper Kerr demonstrated for the first time that brucine N-oxide could be used for this purpose giving Ph O for TMS 72–78% ee for the reaction of (1,1-dimethyl-prop-2- S P 77 Ph O ynol)Co2(CO)6 with norbornene (20). Because nothing SO3H 72%, up to 79% ee was known about the scope and limitation of Pauson– 126 115 Khand reactions in the presence of chiral amine N-oxides, P we investigated the intermolecular cocyclization of S * DABCO S R O norbornene (20) with terminal alkynes 1 in the presence toluene P C of various chiral amine N-oxides in more detail 65 °C 78,79 R Co Co (Scheme 52). C CO O C C Co (CO) O As shown in Table 1, (–)-sparteine N16-oxide (130), (+)- 2 6 O H 2 127a sparteine N1-oxide (131), (–)-17-oxosparteine N-oxide (132), (–)-nicotine N1-oxide (133) as well as (–)-nicotine N1,N1¢-bisoxide (134) resulted only in low enantioselec- R O R O tivities (up to 16% ee) regardless of the alkyne. Remark- O O C C C C ably, the enantioselectivities could be considerably Co Co Co Co improved up to 42% ee by using amine N-oxides with ad- C CO C CO O S O C P P O ditional donor functionalities such as (–)-quinine N-oxide H H S (136), the tetracyclic N-oxide (135) and (–)-brucine N- * * 127c 127b oxide (137).

Scheme 50 Sterically hindered alkynes (e.g. 1f) and alkynes with hydroxy groups (1c,e) gave higher enantioselectivities. Therefore, hydrogen bonding between the alkyne and the 4.4 Chiral Amine N-Oxides N-oxide seems to play an important role in controlling the enantioselectivity. In order to rationalize the stereochem- Despite the progress in stereoselective Pauson–Khand ical results, we assumed hydrogen bonding between the reactions utilizing chiral auxiliaries or chiral P-ligands, in- alkyne hydroxy group and the N-oxide preferably at the Si troduction, removal and/or recycling of the auxiliary or

O tion of complex 138, which undergoes CO insertion and

Co2(CO)8 decomplexation to give cyclopentenone 22. Although this 20 + R H R mechanistic proposal caused controverse discussions, R*3NO (6 equiv) 1THF, –78 °C to r.t. 129 DFT calculations by Gimbert, Milet and Greene strongly supported this suggested scheme.44 Despite the modest O enantioselectivities obtained with amine N-oxides, Nicholas80 and Kerr81 independently pushed the desym- N N N N N N O O O metrization of cobalt–alkyne complexes with chiral amine 130 131 132 N-oxides one step further. Remarkably, both enantiomers of cyclopentenone 22 could be received by using a single source of chirality. That means, while brucine N-oxide N O (137) resulted in decarbonylation at the Si face, sub- O N N N N sequent alkene insertion should give enantiomer 22. O H N OH However, if PPh3 is added to the mixture directly after de- 133 134 135 carbonylation, the empty coordination site is immediately occupied by PPh3 and the opposite cobalt complex results. Further treatment with NMO leads to decarbonylation at H N O the more reactive phosphine-free Re cobalt giving the N opposite enantiomer ent-22 after alkene insertion. H O MeO OH MeO MeO N O NR*3 O O N O H 136 137 OH O CO O C – R*3N C Co Co Scheme 52 Co C Co O – CO2 CO OC C OC C O C C O H O H O Si attack face due to the steric bias provided by the amine N-oxide

(Scheme 53). X = CH2, CHCO2Et, N–CO2Et X X The complex undergoes decarbonylation of the axial CO H X ligand assisted by the hydroxy group of the alkyne moiety OH OH acting as a labile ligand, which is replaced by norbornene, X Co O norbornene ester or aza-norbornenes. As can be seen from C OC CO Co Co CO the Newman perspective insertion preferably takes place OC C C at the least hindered Co–C-bond, resulting in the forma- XX O H O

Table 1 Amine N-Oxide-Promoted Pauson–Khand Reaction of – CO Various Terminal Alkynes 1 H H OH OH N-Oxide Alkyne 1 R Product Yield (%) ee (%) + CO X X Co Co 129 X X CO CO 130 1n Pr a 46 13 138 O

131 1f t-Bu b 62 12 – Co2(CO)6 O 132 1b Ph c 73 16 X X X 133 1f t-Bu b 47 10 X OH OH 22 O 134 1f t-Bu b 48 10 Scheme 53 135 1e CMe2OH e 57 18 1f t-Bu b 37 33 5 Catalysis 1n Pr a 42 12

136 1n Pr a 28 2 One of the earliest examples of catalytic intermolecular cocyclizations was developed by Pauson (Scheme 54).82 1c (CH2)2OH d 68 30 While treating norbornadiene (18) with 10 mol% of 137 1e CMe OH e 67 42 (acetylene)Co2(CO)6 (2a) in the presence of acetylene and 2 carbon monoxide at 60–70 °C the corresponding cyclo- 1n Pr a 75 0 pentenone 19c was isolated in 14% yield.

O complex 143, which undergoes CO insertion and reduc- HC CH/CO 1:1 tive elimination to yield the final cyclopentenone 15b. H H + 18 60–70 °C Unfortunately, chiral metallocenes were not amenable to Co2(CO)6 catalytic intermolecular Pauson–Khand reactions. At this 2a (10 mol%) 19c (14%) point further improvement in catalytic intramolecular 2b Scheme 54 reactions are reported continuously, while the intermolecular reactions are still lagging behind. Nevertheless, various attempts towards a catalytic intermolecular Almost 20 years later a truly catalytic system was reported 83 reaction have been performed, which can be categorized by Rautenstrauch (Scheme 55), in which a TON of 220 according to the metal, i.e. reactions employing i) cobalt, for Co2(CO)8 was realized in the preparation of 2-pentyl- ii) ruthenium, iii) rhodium and iv) iridium. cyclopent-2-en-1-one (139) as a precursor for methyl dihydrojasmonate. Rautenstrauch proposed that the formation of cobalt clusters such as Co4(CO)12 might induce a shutdown of the catalytic cycle. Despite the high turn- O X 15b over the scope of this catalytic version was rather limited.

O +4 +2 CO Co2(CO)8 (0.0022 equiv) reductive Cp2Ti elimination Cp2Ti CO (100 bar) X CO X C5H11 + toluene, 150 °C, 16 h O 14b TON 220 144 2h 139 (47–49%) oxidative – CO + CO insertion addition Scheme 55

+4 +4 Cp Ti Cp2Ti X 2 A remarkable breakthrough was achieved, when Buch- OC X wald demonstrated in 1996 that titanocene complexes are 143 insertion – CO 141 capable of catalyzing the intramolecular Pauson–Khand +4 Cp Ti reaction of enynes such as 14b.84 Shortly after that 2 X Buchwald developed an enantioselective version by utilizing a chiral ansa-titanocene 140 (Scheme 56) which 142 has previously been used for stereoselective Ziegler– Scheme 57 Natta polymerization.85,86

Cp2Ti(CO)2 5.1 Cobalt-Catalyzed Reactions (0.05 equiv) EtO2C O CO (1.22 atm) EtO2C It should be noted that Livinghouse discovered a catalytic toluene, 90 °C intramolecular version of the Pauson–Khand reaction em- 12–48 h 15b (91%) 87 ploying Co2(CO)8 under ultrapure conditions. In order to EtO2C avoid the use of Co2(CO)8 which decomposes upon pro- EtO2C CO (1 atm) H toluene, 90 °C longed storage, Chung developed an in situ method, 14b 12 h EtO2C where the cobalt carbonyl is formed from Co(acac) and O 2 EtO C 88 2 NaBH4 under CO pressure, and by reacting norbornadiene (18) the desired cyclopentenone 19 was obtained al- 15b (90%, 87% ee) most quantitatively. A related substoichiometric system 89 Me Ti Me was described by Periasamy utilizing CoBr2 and Zn. Sugihara reported that methylidenetricobalt nonacarbonyl (145) catalyzed intra- and intermolecular Pauson–Khand 140 [(S,S)-(ebthi)Ti(Me2)] reactions (Scheme 58).90 (0.05 equiv) Even Co2(CO)8 can be used as a catalyst under suitable Scheme 56 conditions. For example, Jeong used supercritical CO2 as a solvent for catalytic Pauson–Khand reactions of nor- The following catalytic cycle was proposed bornene (20) with terminal alkynes in the presence of 3 91 (Scheme 57).86 Oxidative addition of the enyne 14b to the mol% of Co2(CO)8. However, when employing ethylene titanocene dicarbonyl complex which may be either instead of norbornene (20) these conditions gave less than directly used or in situ formed from titanocenedimethyl 10% of the cyclopentenone.92 Fortunately, by running the complex under CO pressure, gave the titanacyclopropene reaction of 1b in supercritical ethylene in the presence of complex 141. Decarbonylation to 142 followed by inser- Co4(CO)11[P(OPh)3] or Co4(CO)12, 2-phenylcyclopenten- tion of the alkene should give the titanocyclopentene one was obtained in good yield without any alkyne

Synlett 2005, No. 17, 2547–2570 © Thieme Stuttgart · New York 2564 S. Laschat et al. ACCOUNT trimerization as the by-product. The results by Jeong also afforded under similar conditions the unsaturated g-lac- 103 disproved Rautenstrauch’s notion that Co4(CO)12 poisons tam 151. the catalytic cycle.

H N N O O

Co(CO)3 O (OC)3Co Ph O O O Co 148 + (CO) Ph 3 76% Py Py 145 (1 mol%) Ph 1b + 20 for 1o Py Py toluene, 120 °C, 10 h H 149a 94:6 149b 7 atm CO H R Ph (a) 27 (98%) 1o R = Me O 1p R = Ph for 1p Ph Ar Scheme 58 99% N

Ph Py Both Co2(CO)8- and Co4(CO)12-catalyzed reactions are N 151 promoted by Lewis basic solvents (e.g. DMF, H2O) or ad- N ditives (e.g. cyclohexylamine, tributylphosphanesulfide) as was independently reported by Sugihara,93 Krafft,94 and 150 OMe 95 Hashimoto. Catalytic reactions were also possible by Scheme 60 Reagents and conditions: (a) Ru3(CO)12 (2.5 mol%), 96,97 microwave irradiation according to results by Groth. P(4-CF3C6H4)3 (7.5 mol%), 5 atm CO, toluene, 160 °C, 20 h Very recently, the cyclobutadiene equivalent 146 was successfully employed in catalytic cocyclizations by Gibson According to Mitsudo Ru3(CO)12 could also be employed (Scheme 59).98 in the catalytic cocondensation of squaric acid derivatives such as 152 and norbornene (20) to yield the cyclopenten- 104 O one 153 as a single regioisomer (Scheme 61). Co2(CO)8 (7 mol%) CO2Me 1 atm CO Ph 1b + Ru3(CO)12 O DME, 75 °C, 4 h; (5 mol%) CO2Me 205 °C, 6 Torr, 1.5 h O OEt 146 147 (75%) PEt3 (15 mol%) 20 + THF, 3 atm CO Scheme 59 O 160 °C, 20 h OEt 152 153 (47%)

When considering the decreased reactivity of cobalt– Scheme 61 alkyne complexes bearing phosphine ligands, it was quite surprising that (PPh3)Co2(CO)7 catalyzed the Pauson– 99 Mitsudo also showed that alkynes could be replaced by Khand reaction without any problems. Moreover, this allylic carbonates in intermolecular Pauson–Khand monophosphine complex turned out to be much more reactions catalyzed by [RuCl2(CO)3]2 in the presence of stable than Co2(CO)8. 105 Et3N. Hiroi studied catalytic reactions of phenylacetylene (1b) and norbornene (20) in the presence of Co2(CO)8 and chiral ligands such as (S)-BINAP, (R,R)-DIOP, (S,R)- 5.3 Rhodium-Catalyzed Reactions BPPFOH and (S,R)-PPFA.100 However, with neither ligand an enantiomeric excess exceeding 10% could be With [RhCl(CO)2]2 as a catalyst, Narasaka was able to achieved. With regard to immobilization a very promising perform intramolecular Pauson–Khand reactions with ex- result was obtained by Chung.101 Although the yields for cellent yields.106 In contrast, yields for intermolecular re- intermolecular cocyclizations were much lower as actions were much lower, and unstrained terminal alkenes compared to the corresponding intramolecular reactions, 156a,b only resulted in the formation of quinones 157 and cobalt on mesoporous silica proved to be a suitable 158 (Scheme 62). heterogeneous catalyst. In order to explore the scope of [RhCl(CO)2]2 in more detail, we studied intermolecular reactions of norbornadiene (18) and terminal alkynes such as phenylacetylene (1b). 5.2 Ruthenium-Catalyzed Reactions While the use of [RhCl(CO)2]2 alone did not give any conversion, the presence of the chelating diphosphine dppe The use of Ru catalysts allowed access to unusual sub- and a Ag(I) salt resulted in the formation of the conjugated strates. A hetero Pauson–Khand reaction was described 102 diene 159 accompanied by some polymeric by-products by Murai. Dipyridylketone 148 reacted with alkyne 1o (Scheme 63). No trace of the desired cyclopentenone was to give the (5H)-furanones 149a,b (Scheme 60). The found. Obviously the CO insertion step is somewhat conversion of the corresponding imine 150 with alkyne 1p

O O erobimetallic nanoparticles derived from Co2Rh2(CO)12 Ph were used as catalysts (Scheme 65). The nanoparticles + 20 + could be recycled at least five times without any loss of (a) 69% Ph activity. Surprisingly, this catalytic system was complete- 154a 53:47 154b ly unreactive towards enynes. O O + Ph O 1o + O (a) 38% Co2Rh2 (0.3 mol%) Ph + 1b H THF, 130 °C, 18 h 155a50:50 155b Ph 163 164 (77%) R O O 156a R = Ph or Ph Ph Ph Scheme 65 156b R = Ph(CH2)2

(a) Ph A further modification employing Ru/Co nanoparticles O O immobilized on charcoal and 2-pyridyl formate as a CO 157 158 source allowed both inter- and intramolecular cocyclization in excellent yields.110 For intermolecular reactions Scheme 62 Reagents and conditions: (a) [RhCl(CO)2]2 (5 mol%), 1 atm CO, Bu2O, 130 °C, 60 h Chung proposed a mechanism involving a Co-catalyzed Pauson–Khand cycle coupled with a Ru-catalyzed decarbonylation cycle (Scheme 66).

[RhCl(CO) ] (10 mol%) 2 2 [Co] 18 + 1b R dppe, 1 atm CO, AgOTf X O R 159 (60%) Ph R N H O X O Scheme 63 X Co [Ru]

Pauson–Khand reaction decarbony- blocked. Change of stoichiometry and CO pressure did R lation R not change the outcome of the reaction. O X [Ru] The different catalytic activity of Rh complexes in intra- X C HO Co N versus intermolecular reactions was also noticed by O Chung,107 when treating norbornene (20) and phenylacet- Scheme 66 ylene (1b) with entrapped [Rh(COD)Cl]2. Only 6% of the desired cyclopentenone 27 could be isolated, whereas intramolecular reactions yielded 79–93% of the product. 5.4 Iridium-Catalyzed Reactions Recently, Wender investigated Rh-catalyzed competing 108 Based on Shibata’s promising results with Ir catalysts in [2+2+1], [4+2], and [2+2+2] cycloadditions. The prod- 111 uct ratio turned out to be strongly temperature dependent. intramolecular Pauson–Khand reactions we investigat- By simply decreasing the temperature from 80 °C to ed intermolecular Pauson–Khand reactions of alkyne 1b 60 °C the reaction of alkyne 160 and 2,3-dimethylbuta- and 1o with norbornadiene (18) and norbornene (20). For diene (161) gave 98% of the cyclopentenone 162 as com- example, the reaction of phenylpropyne (1o) and nor- pared to meager 11% at 80 °C (Scheme 64). bornene (20) in the presence of catalytic amounts of [Ir(COD)Cl]2 and tol-BINAP in toluene under 1 atm CO gave only 0.3% of the cyclopentenone 154. Mainly unre- O OMe OMe acted phenylpropyne was recovered after work up. When [RhCl(CO)2]2 (5 mol%) norbornadiene (18) was used instead, no conversion was + 1 atm CO, Cl(CH2)2Cl, 4.5 h observed. As shown in Scheme 67, the situation changed when phe- OMe OMe 160 161 60 °C: 162 (98%) nylacetylene (1b) was employed. The reaction of 1b with 80 °C: 162 (11%) 20 gave 15% of the cyclopentenone 27 together with the Scheme 64 regioisomeric alkyne trimerization products 165, 166 in 16% and 10% yield, respectively. Employing 18 under the same conditions, the conjugated diene 159 was isolated in A major limitation of the above-mentioned catalytic pro- 74% yield. Although Ir-catalyzed C–C coupling between cesses is the need of carbon monoxide. Chung elegantly alkyne and alkene is obviously much faster for norborna- addressed this problem by using an a,b-unsaturated alde- diene (18) as compared to norbornene (20) and even the 109 hyde instead of an alkene and CO. For this purpose het- competing alkyne trimerization is completely suppressed,

Ph Ph getically favored over competing/alternative pathways. Ph The most important mechanistic finding was that, while + 20 27 (15%) + + (A) the bond-forming events occur only on one metal atom, Ph Ph the other metal atom acts as an anchor and also exerts 165 166 Ph electronic influences on the other through the metal–metal + 18 1b 159 (74%) bond. (A) Shortly after that, theoretical studies by Milet, Gimbert O O and Greene44,45 emphasized the importance of the trans- + 20 Ph + effect in govering the regioselectivity. Koch and Schmalz (B) investigated the configurational stabilities of cationic, Ph 27a 27b radical and anionic Co2(CO)6 complexed propargylic spe- 1) BINAP, AgOTf, 90 °C 13% – cies by DFT and found a surprisingly high racemization 2) dppe, AgOTf, 90 °C 12% 6% barrier for the anionic intermediate.115 However, experi- 3) dppe, AgOTf, 90 °C 2% 18% 4) dppe, AgOTf, reflux 32% – mental evidence was still sparse until Gimbert, Greene and Milet116 were able to detect the decarbonylated inter- Scheme 67 Reagents and conditions : Method A: [Ir(COD)Cl]2, mediate 166 by tandem mass spectrometry using negative BINAP, toluene, 1 atm CO, 110 °C, 12 h; Method B: [Ir(COD)Cl]2, THF, 1 atm CO, 12 h ion electrospray ionization. Subsequent collision-activat- ed reaction (CAR) with norbornene (20) yielded a molecular ion with m/z = 781, i.e. the corresponding alkene the final CO insertion is too slow. In order to improve the complex (Scheme 68). Complementary DFT calculations catalytic activity of the Ir catalyst, AgOTf was added to revealed the chronology of the early events of the Pauson– the reaction mixture.112 In addition, the coordination prop- Khand reaction in the gas phase. The results perfectly sup- erties of the solvent were improved by using THF instead port Nakamura’s calculations and the original Magnus of toluene. It turned out that the quality of the Ag(I) salt mechanism. and the solvent was very critical. In the presence of BINAP and AgOTf the Ir-catalyzed reaction of phenyl- Ph Ph acetylene with norbornene (20) gave cyclopentenone 27a O O OC C OC C Co ESI Co CAR in 13% as a single regioisomer. Use of dppe instead of Co C Co C m/z = 781 OC O OC O BINAP gave a mixture of the regioisomers 27a and 27b in PPh2 PPh2 + 20 Ph P Ph2P 18–20% overall yield. Upon lowering the reaction tem- 2 H H m/z = 94 perature from 90 °C to reflux the yield of cyclopentenone 27a could be further improved to 32%. Unfortunately, the 165 166 (m/z = 687) use of BINAP or tol-BINAP under these modified condi- Ph CH2Ph tions did not give the desired cyclopentenone. Both Rh O O OC C OC C and Ir catalysts appeared to be not suitable to promote C– Co HOAc Co Co C Co C OC O OC Co O C coupling and CO insertion efficiently and thus, allow a C C C O C (CO)3 O full catalytic cycle for the intermolecular Pauson–Khand O H O 167 168 reaction. Scheme 68

6 Theoretical Studies and Some Mechanistic Another combined theoretical and experimental mecha- Curiosities nistic study by McGlinchey dealt with the acid-catalyzed rearrangement of cobalt–alkyne complexes such as 167 to As discussed earlier the original mechanism for the stoi- alkylidene nonacarbonyl tricobalt clusters 168 chiometric Pauson–Khand reaction which was proposed (Scheme 68).117 by Magnus in 19853 was commonly accepted despite While tandem catalysis employing intramolecular some disputes about the coordination mode of the alkene. Pauson–Khand reactions has been recently explored in Surprisingly, little theoretical and experimental mecha- several cases,118 only little information was known about nistic information existed until 2001 a very detailed DFT intermolecular tandem processes. Towards this goal we study by Nakamura appeared.113 The results from DFT investigated the sequential Pauson–Khand reaction/trans- calculations clearly indicated, for example, that the initial fer hydrogenation outlined in Scheme 69. We anticipated CO loss is rather energy consuming and thus, that the transfer hydrogenation with RuCl (PPh ) should irradiation87,114 or promoters (Lewis bases, tethered donor 2 3 3 be compatible with the preceeding Pauson–Khand reac- ligands, etc.) acting as weak ligands enhance the rate of tion conditions.119 While the two-step process yielded this step. It was also found that the alkene insertion step is 54% of the diastereomeric ketones 169a,b (dr 81:19) to- the critical stereo- and regiochemistry determining step of gether with 5% of the saturated alcohol 170, the corre- the Pauson–Khand reaction. Another result was that sponding one-pot reaction was only successful when the migratory insertion of CO at the alkene terminus is ener- base KOH was added after a certain induction period of 2

Synlett 2005, No. 17, 2547–2570 © Thieme Stuttgart · New York ACCOUNT Intermolecular Pauson–Khand Reactions 2567 hours. Monitoring by GC indicated clean conversion to 7 Conclusions the cyclopentenone 27 within two hours. Subsequent addition of KOH resulted in the formation of diastereomeric During the last couple of years the intermolecular ketone 169a,b (dr 58:42) in 57%. The results indicated Pauson–Khand reaction has seen tremendous achieve- that in accordance with observations by Sasson120 and ments concerning reactivity, novel substrates, regio- and 121 Wilkinson Ru(H)Cl(PPh3)3 as the major active species stereoselectivity. In particular, theoretical studies using preferably adds to the C=C bond rather than to the ketone. DFT methods have provided very detailed insight into the mechanism, which not long ago appeared more or less like O a black box. However, one of the most urgent problems, Co2(CO)8 toluene or i-PrOH, ∆ i.e. a catalytic and hopefully enantioselective version has 20 + 1b Ph not yet been solved to fully satisfy synthetic chemist re- 78% 27 quirements. From the preliminary results it seems that co- 1) RuCl2(PPh3)3 balt–carbonyl complexes are still much better suited to RuCl (PPh ) Co2(CO)8 2 3 3 promote both C–C coupling of alkyne and alkene, and CO ∆ i-PrOH, ∆, 2 h KOH, i-PrOH, insertion as compared to other transition metal catalysts. 2) KOH, ∆, 2 h But maybe we and others have not yet looked carefully O O H OH enough. So, there is still plenty of work to do in the future. H Ph H + + Ph H Ph Acknowledgment 169a 169b 170 two-step81:19 54% 5% This work would not have been possible without the dedicated work one-pot 58:42 57% – and controversial discussions of our former coworker Volker Derdau whom we would like to thank very much. General financial Scheme 69 support by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, the Deutscher Akademischer Austausch- In contrast, the outcome of this sequential reaction might dienst (DAAD award for A. Becheanu), the European Community (ERASMUS/SOKRATES fellowship for T. Bell) and the Ministe- be also due to an intermediate cobalt hydride species, rium für Wissenschaft, Forschung und Kunst des Landes Baden- which is acting as a reducing agent. In the intramolecular Württemberg are gratefully acknowledged. Special thanks belong Pauson–Khand reactions of enyne 14c in the presence of to Yves Gimbert, Anne Milet and Andrew Greene from the Co4(CO)12 Krafft isolated in acetonitrile the desired bi- University of Grenoble for their stimulating discussions and great cyclic enone 171 in 69% yield.122 However, in i-PrOH hospitality. only the saturated ketone 172 was obtained in 56% (Scheme 70). Deuterium-labeling experiments demon- References strate that a hydridocobalt species was involved and that the hydride comes from the solvent isopropanol. (1) Pauson, P. L.; Khand, I. U.; Knox, G. R.; Watts, W. E. J. Chem. Soc. D 1971, 36. (2) Reviews: (a) Park, K. H.; Chung, Y. K. Synlett 2005, 545. EtO2C (b) Rodriguez Rivero, M.; Adrio, J.; Carretero, J. C. Synlett 2005, 26. (c) Gibson, S. E.; Mainolfi, N. Angew. Chem. Int. EtO2C Ed. 2005, 44, 3022; Angew. Chem. 2005, 117, 3082. 14c (d) Bonaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795. (e) Gibson, S. E.; Stevenazzi, A. Angew. Chem. Int. Co (CO) 4 12 solvent, 70 °C, 24 h Ed. 2003, 42, 1800; Angew. Chem. 2003, 115, 1844. (f) Hanson, B. E. Comments Inorg. Chem. 2002, 23, 289.

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