Multicomponent Cascade Reactions Triggered by Cycloaddition of

Organometallics 2009, 28, 361–369

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Multicomponent Cascade Reactions Triggered by Cycloaddition of Fischer Alkoxy Alkynyl Carbene Complexes with Strained Bicyclic Olefins§ Manuel A. Fernańdez-Rodrı´guez, Facundo Andina,† Patricia Garcıá-Garcıá, Christian Rocaboy,‡ and Enrique Aguilar* Instituto UniVersitario de Quı´mica Organometa´lica “Enrique Moles”, Unidad Asociada al CSIC, UniVersidad de OViedo, Juliań ClaVerıá 8, 33006, OViedo, Spain ReceiVed October 6, 2008

A broad range of substituted 2-cyclopentenone derivatives are prepared by a multicomponent sequential reaction of chromium alkoxy alkynyl carbene complexes with strained bicyclic olefins. An unprecedented behavior of the carbene complexes, which react through the carbene carbon and both acetylenic carbons, in a [2+2+1]/[2+1] cascade sequence, allows the synthesis of multicomponent products, which (a) incorporate two units of the same strained bicyclic olefin, (b) incorporate two different olefins, and/or (c) involve intramolecular [2+1] reactions. Evidence of the formation of 2-cyclopentenone-derived Fischer carbene complexes as reaction intermediates is provided, as they are trapped with different types of olefins or undergo alkyne insertion. Introduction Multicomponent reactions (MCRs) have recently emerged as extremely powerful synthetic organic methods in terms of operational simplicity or atom economy and represent an important approach to diversity-oriented organic synthesis.1 In this regard, the extraordinary ability of group VI metal-derived Fischer carbene complexes (FCCs)2 to participate in such reactions has been extensively developed in the last decades and has allowed the selective construction of a wide range of highly functionalized structures through several selective processes, which include either hetero- or carbocyclizations.3

On the other hand, since the discovery of the carbene complexes by Fischer and Maasbo¨l in 1964,4 their behavior toward alkenes was one of the first and longest studied processes. In general, the reaction proceeds under thermal conditions by a formal [2+1] cycloaddition of the olefin to furnish a cyclopropane as the main product,5 although alkene metathesis and carbene ligand insertion into a olefinic β-C-H bond6 have also been observed as principal pathways in a few examples. The cyclopropanation reaction of FCCs with alkenes was first reported7 and developed for electron-deficient olefins8 and subsequently extended to electron-rich alkenes,9 1,3dienes,10 and more recently simple olefins.11 Besides the metal moiety and the electronic nature of the alkene, the process is

§

Dedicated to Prof. J. Barluenga on the occasion of his 69th birthday. * Corresponding author. E-mail: [email protected]. Current address: Ragactives, Parque Tecnolo´gico de Boecillo, Parcelas 2 y 3, 47151 Boecillo, Valladolid, Spain. ‡ Current address: Villapharma Research, Parque Tecnolo´gico de Fuente ´ lamo, Ctra. del Estrecho-Lobosillo, 30320 Fuente A ´ lamo, Murcia, Spain. A (1) For reviews about MCRs see: (a) Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: New York, 2005. (b) Ramoń, D.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634. (c) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144. (d) Hulme, C.; Core, V. Curr. Med. Chem. 2003, 10, 51–80. (e) Ugi, I. Pure Appl. Chem. 2001, 73, 187–191. (f) Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304–322. (g) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (h) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur. J. 2000, 6, 3321–3329. (i) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6, 255– 270. (j) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366–374. (k) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keting, T. A. Acc. Chem. Res. 1996, 29, 123–131. (l) Posner, G. H. Chem. ReV. 1986, 86, 831–844. (2) Selected reviews: (a) Herndon, J. W. Coord. Chem. ReV. 2007, 251, 1158–1258. (b) Go´mez-Gallego, M.; Manchenõ, M. J.; Sierra, M. A. Acc. Chem. Res. 2005, 38, 44–53. (c) Barluenga, J.; Santamarıá, J.; Toma´s, M. Chem. ReV. 2004, 104, 2259–2283. (d) Herndon, J. W. Coord. Chem. ReV. 2004, 248, 3–79. (e) Barluenga, J.; Flo´rez, J.; Fanãna´s, F. J. J. Organomet. Chem. 2001, 624, 5–17. (f) Do¨tz, K. H.; Ja¨kel, C.; Haase, W.-C. J. Organomet. Chem. 2001, 617-618, 119–132. (g) Sierra, M. A. Chem. ReV. 2000, 100, 3591–3638. (h) De Meijere, A.; Schirmer, H.; Duestsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964–4002. Recent books: (i) Metal Carbenes in Organic Synthesis; Do¨tz, K. H., Ed.; John Wiley & Sons: New York, 2004; Topics in Organometallic Chemistry Vol. 13. (j) Carbene Chemistry: from Fleeting Intermediates to Powerful Reagents; Bertrand, G., Ed.; Marcel Dekker, 2002. (k) Zaragoza Do¨rwald, F. In Metal Carbenes in Organic Synthesis; Wiley-VCH: New York, 1999. †

(3) For a review of FCCs in MCRs see: Barluenga, J.; FernańdezRodrı´guez, M. A.; Aguilar, E. J. Organomet. Chem. 2005, 690, 539–587. (4) Fischer, E. O.; Maasbo¨l, A. Angew. Chem., Int. Ed. Engl. 1964, 3, 580. (5) Reviews: (a) Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96, 271–288. (b) Doyle, M. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 387-420. (c) Reissig, H.-U. In Organometallics in Organic Synthesis; Werner, H., Erker, G., Eds.; Springer: Berlin, 1989; Vol. 2, pp 311-322. (d) Brookhart, M.; Studabaker, W. B. Chem. ReV. 1987, 87, 411– 432. (6) (a) Harvey, D. F.; Brown, M. F. Tetrahedron Lett. 1990, 31, 2529– 2532. (b) Wienand, A.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1990, 29, 1129–1131. (c) For an example with an iron carbene complex: Semmelhack, M.; Tamura, R. J. Am. Chem. Soc. 1983, 105, 6570–6572. (7) (a) Cooke, M. D.; Fischer, E. O. J. Organomet. Chem. 1973, 56, 279–284. (b) Do¨tz, K. H.; Fischer, E. O. Chem. Ber. 1972, 105, 1356– 1367. (c) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1970, 103, 1273–1278. (8) (a) Barluenga, J.; Sua´rez-Sobrino, A. L.; Toma´s, M.; Garcıá-Granda, S.; Santiago-Garcıá, R. J. Am. Chem. Soc. 2001, 123, 10494–10501. (b) Barluenga, J.; Sua´rez-Sobrino, A. L.; Toma´s, M. Synthesis 2000, 935–940. (c) Hoffmann, M.; Reissig, H.-U. Synlett 1995, 625–627. (d) Wienand, A.; Reissig, H.-U. Chem. Ber. 1991, 124, 957–965. (e) Herdon, J. W.; Tumer, S. U. J. Org. Chem. 1991, 56, 286–294. (f) Wienand, A.; Reissig, H.-U. Organometallics 1990, 9, 3133–3142. (g) Herdon, J. W.; Tumer, S. U. Tetrahedron Lett. 1989, 30, 4771–4774. (h) Wienand, A.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2315–2318. (9) (a) Casey, C. P.; Cesa, M. C. Organometallics 1982, 1, 87–94. (b) Dorrer, B.; Fischer, E. O.; Kalbfus, W. J. Organomet. Chem. 1974, 81, C20-C22. (c) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1972, 105, 3966– 3973.

10.1021/om800958d CCC: $40.75  2009 American Chemical Society Publication on Web 11/26/2008

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highly dependent on the substitution of the carbene complex. Thus, alkyl and aryl FCCs are suitable reagents for the cyclopropanation of activated alkenes and 1,3-dienes, while simple olefins are cyclopropanated only with alkenyl- and heteroaryl-substituted complexes.11 Moreover, when electrondeficient olefins are used, the double bond of the alkenyl FCCs can also partake in the process, leading to a mixture of the expected cyclopropanes and cyclopentene derivatives as a result of a formal [3+2] cycloaddition, whose distribution can be controlled by the selection of the appropriate conditions.10b-10d In a particular case, conjugated enals or enones react with aryl or alkenyl FCCs to produce dihydrofurans, due to the spontaneous evolution, under the reaction conditions, of the initially formed cyclopropanes to the final formal [4+1] adducts.12 Cyclopentene derivatives are selectively obtained when neutral or silyloxy-substituded 1,3-dienes are employed.13 Furthermore, it has been established that, under suitable reaction conditions, alkenyl FCCs participate as dienophiles in Diels-Alder cycloadditions with 1,3-dienes and heterodienes.6a,14 In a similar manner, alkynyl FCCs display several patterns of reactivity depending on the nature of the alkene they are reacted with. In this way, they are known to react through the triple bond of the carbene ligand with electron-rich olefins to afford cyclobutene carbene complexes by a [2+2] cycloaddition15 (A, Scheme 1). When confronted with neutral and electron-rich 1,3-dienes and heterodienes, [4+2] cycloadditions result to afford cyclohexenyl carbene complexes (B, Scheme 1);16 in the latter case, when the acetylenic carbene ligand bears an aryl or an alkenyl substituent (R ) Ar or CdC), products can evolve, spontaneously or by warming, to form cyclopentadienes by the known cyclopentannulation process (B′, Scheme 1).17,18 Interestingly, by appropriate election of both the vinyl(10) Electron-deficient 1,3-dienes: (a) Barluenga, J.; Toma´s, M.; Lo´pezPelegrıń, J. A.; Rubio, E. J. Chem. Soc., Chem. Commun. 1995, 665–666. (b) Buchert, M.; Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1995, 128, 605– 614. (c) Buchert, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2723–2729. (d) Buchert, M.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2319–2320. Electron-rich 1,3-dienes: (e) Takeda, K.; Sakurama, K.; Yoshii, E. Tetrahedron Lett. 1997, 38, 3257–3260. (f) Wulff, W. D.; Yang, D. C.; Murray, C. K. J. Am. Chem. Soc. 1988, 110, 2653–2655. Nonactivated 1,3-dienes: (g) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 8916–8921. (h) See also refs 8e and 8i. (11) (a) Barluenga, J.; Lo´pez, S.; Flo´rez, J. Chem.-Eur. J. 2001, 7, 4723–4729. (b) Barluenga, J.; Lo´pez, S.; Trabanco, A. A.; FernańdezAcebes, A.; Flo´rez, J. J. Am. Chem. Soc. 2000, 122, 8145–8154. (c) Barluenga, J.; Fernańdez-Acebes, A.; Trabanco, A. A.; Flo´rez, J. J. Am. Chem. Soc. 1997, 119, 7591–7592. (12) Barluenga, J.; Fanlo, H.; Lo´pez, S.; Flo´rez, J. Angew. Chem., Int. Ed. 2007, 46, 4136–4140. (13) Neutral 1,3-dienes: (a) Barluenga, J.; Lo´pez, S.; Trabanco, A. A.; Flo´rez, J. Angew. Chem., Int. Ed. 2003, 42, 231–233. (b) Zaragoza Do¨rwald, F. Angew. Chem., Int. Ed. 2003, 42, 1332–1334. Sililoxy-substituted 1,3dienes: (c) Hoffmann, M.; Buchert, M.; Reissig, H.-U. Chem.-Eur. J. 1999, 5, 876–882. (d) Hoffmann, M.; Buchert, M.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1997, 36, 283–285. (14) Wulff, W. D. Organometallics 1998, 17, 3116–3134, and references therein. (15) (a) Barluenga, J.; Aznar, F.; Palomero, M. A.; Barluenga, S. Org. Lett. 1999, 1, 541–543. (b) Wulff, W. D.; Faron, K. L.; Su, J.; Springer, J. P.; Rheingold, A. L. J. Chem. Soc., Perkin Trans. 1 1999, 197–219, and references therein. (c) Faron, K. L.; Wulff, W. D. J. Am. Chem. Soc. 1988, 110, 8727–8729. (d) When the reaction of 2,3-dihydrofuran and alkynyl FCCs is carried out at tempereatures over 90 °C, a [2+2]/[2+1] tandem reaction sequence takes place: Pe´rez-Anes, A.; Garcıá-Garcıá, P.; Sua´rez´ . L.; Aguilar, E. Eur. J. Org. Chem. 2007, 3480–3487. Sobrino, A (16) (a) Barluenga, J.; Toma´s, M.; Lo´pez-Pelegrıń, J. A.; Rubio, E. Tetrahedron Lett. 1997, 38, 3981–3984, and references therein. (b) Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S. R. Tetrahedron 1985, 41, 5813–5832. (c) Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565–7567. (17) Barluenga, J.; Fernańdez-Rodrı´guez, M. A.; Aguilar, E. Org. Lett. 2002, 21, 3659–3662, and references therein.

Fernańdez-Rodrı´guez et al. Scheme 1. Reaction of Alkynyl FCCs toward Activated Olefins and 1,3-Dienes

substituted alkynyl FCC and the diene, the initially formed cycloadducts are able to undergo a double or triple cascade [4+2] cycloaddition/cyclopentannulation process, furnishing highly functionalized polycyclic compounds.18 On the other hand, the cyclopropanation of alkynyl FCCs with olefins has remained unknown until recently. Aumann was the first one to propose the formation of an alkynyl cyclopropane from a FCC as an intermediate in a cascade reaction;19 the cyclopropane adducts were shortly isolated for the first time, using specially reactive olefins such as fulvenes (C, Scheme 1).20 More recently, we have also disclosed a general procedure for the diastereoselective cyclopropanation of electron-deficient olefins with chromium alkynyl FCCs (D, Scheme 1).21 Having in mind the high dependence of the process on the alkene employed, we decided to explore the behavior of highly reactive strained olefins. In a previous communication, we described the initial results of MCRs of alkynyl FCCs with strained and hindered bicyclic olefins such as norbornene derivatives.22 The major products, obtained in a single operation, incorporate up to four different components, generating a cyclopentenone and cyclopropane rings through the formation of five new σ C-C bonds in a formal [2+2+1]/[2+1] cycloaddition. Herein, we report a thorough study of the scope and limitations of both inter- and intramolecular multicomponent processes. In addition, we report a formal [2+2+1]/[3+2] cycloaddition by using an internal alkyne as the fourth component.

Results and Discussion 1. Reaction with Norbornene: Preliminary Results and Process Optimization. The initial studies were carried out with methoxy phenylethynyl chromium carbene complex 1a and norbornene 2a (Scheme 2). (18) (a) Barluenga, J.; Aznar, F.; Barluenga, S.; Fernańdez, M.; Martıń, A.; Garcıá-Granda, S.; Pin˜era-Nicola´s, A. Chem.-Eur. J. 1998, 4, 2280– 2298. (b) Barluenga, J.; Aznar, F.; Barluenga, S.; Martıń, A.; Garcıá-Granda, S.; Martıń, E. Synlett 1998, 473–474. (19) Wu, H.-P.; Aumann, R.; Fro¨hlich, R.; Saarenko, P. Chem.-Eur. J. 2001, 7, 700–710. (20) Barluenga, J.; Martıńez, S.; Sua´rez-Sobrino, A. L.; Toma´s, M. J. Am. Chem. Soc. 2002, 124, 5948–5949. (21) Barluenga, J.; Fernańdez-Rodrı´guez, M. A.; Garcıá-Garcıá, P.; Aguilar, E.; Merino, I. Chem.-Eur. J. 2006, 12, 303–313. (22) Barluenga, J.; Fernańdez-Rodrı´guez, M. A.; Andina, F.; Aguilar, E. J. Am. Chem. Soc. 2002, 124, 10978–10979.

Multicomponent Cascade Reactions Scheme 2. Reaction of Methoxy Phenylethynyl Chromium Carbene Complex 1a with Norbornene 2a

Organometallics, Vol. 28, No. 1, 2009 363 Table 1. Optimization of the Tandem [2+2+1]/[2+1] Cycloaddition

entry N equiv solvent

First, we performed the reaction using an excess of olefin (5 equiv) in refluxing toluene for 30 min, which resulted in the isolation of compound 4a in 38% yield as a 3:1 mixture of diastereomers, which could be separated by semipreparative HPLC using hexane/2-propanol as eluent. The structure of 4a was tentatively proposed based on NMR studies (COSY, HMQC, HMBC, NOESY) and confirmed by X-ray diffraction of the major diastereomer (4a maj),23 which was crystallized from hexane/dichloromethane (90/10) (Figure 1). In addition, cyclopropyl derivative 3a was isolated as a minor product (10% yield) in a 3:1 diastereomeric ratio. The diastereomers could be separated by semipreparative HPLC using hexane as eluent; their relative stereochemistry was determined by a NOESY experiment. A close examination of both the global reaction to furnish compound 4a and the proper structure of 4a displays several interesting features: (a) it has incorporated two units of norbornene, one unit of carbene ligand, and a CO moiety as a result of a formal tandem [2+2+1]/[2+1] cycloaddition process; (b) the alkynyl carbene complex reacts in an unprecedented manner through the carbene carbon and both acetylenic carbons and allows the incorporation of a carbonyl ligand into a cyclopentenone ring; (c) five σ C-C new bonds have been formed and two rings have been created; and (d) it represents a highly functionalized compound that should be amenable to further transformations. With the structure of both cycloadducts identified, we proceeded to optimize the reaction conditions with a double objective: to improve the global yield and to direct the process toward the cascade [2+2+1]/[2+1] adduct 4a. Temperature, number of equivalents of olefin, solvent, and nature of the metal of the carbene complex were the variables considered. In all cases, the consumption of the starting material and, therefore, the completion of the reaction were indicated by a color change and monitored by TLC. It was observed that the reaction required temperatures higher than 70 °C to proceed; however, experiments conducted in the range of 70 to 160 °C mainly differed in the reaction time (Table 1, entry 1), with 110 °C

Figure 1. ORTEP drawing of 4a maj. Ellipsoids are shown at the 50% level.

1 2 3 4 5c 6 7d 8e 9e,f 10e,g 11e,g

5 5 5 5 5 10 10 10 10 10 10

toluene toluene DME hexane CH2Cl2 toluene toluene toluene toluene toluene toluene

T (°C)a 70-160 110 90 80 90 110 80-110 110 110 110 110

reaction time (t) 3a (%)b 4a (%)b 10 min-7 h 30 min 12 h 1h 5h 30 min 30 min-24 h 55 min 55 min 55 min 45 min

∼10 10 12 5 11 12 12 18 7 4h

∼40 38 24 30 35 43 ∼50 60 61 70 75

a Bath temperature. b Isolated yield based on the starting carbene complex 1a. c Reaction conducted in a sealed tube. d Reaction performed under CO pressure in a sealed tube (initially 1 atm, reaction pressure not quantified). e Slow addition of the carbene complex 1a to the reaction mixture (addition time: entries 8-10, 45 min; entry 11, 35 min). f Conducted with continuous N2 bubbling. g Performed under 1 atm of CO. h dr ) 4:1.

being the temperature of choice (entry 2). The polarity of the solvent played a decisive role in the reaction: solvents such as DMF or THF (not listed in Table 1) resulted in only carbene decomposition, whereas reactions conducted in DME (1,2dimethoxyethane), hexane, or dichloromethane either provided lower yields, required longer reaction times, or both (entries 3-5 vs 2). Toluene was then considered the solvent of choice for the reaction. The process was also sensitive to the nature of the metal, as the analogous tungsten carbene complex decomposed instead of adding to olefin 2a. Regarding the number of equivalents of norbornene, better results were achieved when 10 equiv were employed instead of the initial 5 equiv (entries 2 vs 6); a greater excess of the alkene (20 equiv) did not increase the yield. Interestingly, cycloadduct 4a was selectively obtained when the reaction was performed under a moderate pressure of CO (entry 7); however, the tandem cycloaddition was also inhibited under high CO pressures. After such initial screening only a slight enhancement in the yield was achieved (entry 7 vs 1). Considering that it was probably due to thermal decomposition of the starting carbene complex 1a, the reaction was performed by slow addition of the carbene complex to the reaction mixture, leading to an improved combined 72% yield (entry 8). Moreover, while the proportion of the cyclopropane 3a was increased by bubbling N2 through the reaction mixture (entry 9), it was diminished to 4-7% when the reaction was performed under CO atmosphere (entries 10, 11). Therefore, the highest yield of the desired [2+2+1]/[2+1] cycloadduct 4a (75%) was reached when the reaction was performed under CO atmosphere and the carbene addition time was kept at 35 min (entry 11). 2. Scope of the Reaction. Reactions of a series of strained and sterically hindered bicyclic olefins 2a-g, structurally related to norbornene, and methoxy alkynyl FCCs 1a-f were evaluated under the optimized reaction conditions; the results are summarized in Table 2. Moderate to good yields of tandem adducts 4 were selectively or exclusively obtained with all the alkenes employed, 2a-f, with the exception of endo-2g, which led to decomposition of (23) See Supporting Information.


Fernańdez-Rodrı´guez et al.

Table 2. Scope of Tandem [2+2+1]/[2+1] Cycloaddition of FCCs 1 with Bicyclic Olefins 2

a All the experiments were conducted by slow addition of carbene complex 1 (1 equiv) to olefin 2 (10 equiv) in refluxing toluene under CO atmosphere unless otherwise stated. b Isolated yield based on the starting carbene complex 1. c Diastereomeric ratio determined by 1H NMR (300 MHz) of the isolated products. d Performed by slow addition of 1a (1 equiv) to 2b (10 equiv) and BHT (4%) in refluxing toluene with N2 bubbling; polymerized norbornadiene of undetermined molecular weight was also isolated. e Mixture of eight isomers. f Obtained as a mixture of isomers in a 3:1 ratio. g Obtained as a mixture of three diastereomers in a 56:20:24 ratio.

the starting carbene complex (entries 1-7). The reaction with norbornadiene 2b had to be conducted in the presence of 2,6di-tert-butyl-4-methylphenol (BHT, 4%) and with nitrogen bubbling to minimize undesired polymerization of the olefin (entry 2). While double-bond chemoselectivity was observed for bis-cyclopentadiene 2c, the reaction led to a mixture of eight isomers (entry 3). The [2+2+1]/[2+1] sequence tolerated the presence of heteroatoms (olefins 2d-f, entries 4-6), as well as amide or carbamate groups in the olefin (i.e., 2d, 2f, entries 4, 6) but not an anhydride moiety (2g, entry 7). Noteworthy, the influence of the substitution in the alkynyl carbene complex is significant, and as a result, variable mixtures of cycloadducts 3 and 4 were obtained. Thus, reactions of aryl(entries 1-7), alkenyl- (entry 8), or alkyl- (entry 9) substituted

Figure 2. Other alkoxy alkynyl FCCs tested.

alkynyl FCCs selectively formed the multicomponent adducts 4; however, bulky alkyl- or silyl-substituted alkynyl carbene complexes increased the amount of cyclopropane adducts 3 (entries 10, 11). In this regard, reaction of FCC 1f, which bears an extraordinarily bulky substitutent that totally blocks the triple bond,17 resulted in the complete inhibition of the multicomponent process (entry 12). The MCR was also suppressed when a sterically more demanding group is placed in the alkoxy moiety

Multicomponent Cascade Reactions Scheme 3. Reaction of Methoxy Phenylethynyl Chromium Carbene Complex 1a with (E)-Cyclooctene

of the alkynyl FCC (i.e., FCC 5a, Figure 2); carbene decomposition was observed instead. Considering that the large strain energy exhibited by bicyclic olefins 2 was highly responsible for this new reactivity pattern of FCCs, we explored the behavior of other strained olefins such as (E)-cyclooctene. However, the reaction of 1a with (E)-cyclooctene following method A conditions [1a: (E)-cyclooctene 1:10, toluene, reflux] resulted in the direct cyclopropanation of the double bond, while 10% of four-component cycloadduct 7 was obtained under method B reaction conditions [slow addition of 1a (1 equiv) to (E)cyclooctene (10 equiv) in refluxing toluene under a CO atmosphere], as an almost equimolecular 1:1:1 mixture of three diastereomers (Scheme 3). Once more, the yield of the [2+2+1]/[2+1] MCR sequence adduct increases when the process is performed under a CO atmosphere, as it has been previously observed for olefins 2. Other tested olefins, structurally related to norbornene, include cyclopentene or bicycle[2,2,2]oct-2-ene; however, under the reaction conditions only carbene decomposition was observed. These results pointed out that, in addition to the ring strain, which seems to be necessary to initiate the reaction, steric hindrance appears to play an important role to direct the reaction toward the four-component adducts in acceptable yields. With all these considerations, we thought that 3,4-disubstituted cyclobutenes would display the necessary requirements for the reaction; however, a wide range of experiments performed with FCC 1a and several rather accessible cyclobutenes24 [such as trans-3,4-dichloro-1cyclobutene, cis-3,4-dichloro-1-cyclobutene, bicyclo[5.2.0]non8-ene, or bicyclo[4.2.0]oct-7-ene] were unsuccessful; only intractable mixtures of carbene and cyclobutene decomposition compounds were detected. 3. Mechanism of the [2+2+1]/[2+1] Tandem Cycloaddition. With all these results in hand, we propose the mechanism depicted in Scheme 4. An initial CO ligand decoordination from carbene complexes 1 could occur, thus generating a tetracarbonyl species I; bicyclic olefins 2 will probably add to 1 or I in a 1,2-fashion or by a [2+2] cycloaddition, leading to the dipolar addition product II or metallacyclobutane III, respectively, which may be in equilibrium. Intermediate III may evolve to the formation of cyclopropanes 3, this pathway being enhanced in the absence of CO; however, when the reaction is carried out in the presence of CO, the alternative route shown could be highly preferred. Then, a CO insertion should take place to generate IV, followed by a 1,3-metal migration,25 which could be promoted by the electron pair of the methoxy group of IV. The resulting metallacyclobutane V would evolve to form a vinylogous methoxy-stabilized (24) (a) Hoberg, H.; Fro¨lich, C. Synthesis 1981, 830–831. (b) Leigh, W. J.; Zheng, K.; Clark, K. B. J. Org. Chem. 1991, 56, 1574–1580. (c) Liu, R. S. J. Am. Chem. Soc. 1967, 89, 112–114. (25) 1,3-Metal group migrations have previously been observed in FCC chemistry: Barluenga, J.; Trabanco, A. A.; Flo´rez, J.; Garcıá-Granda, S.; Llorca, M. A. J. Am. Chem. Soc. 1998, 120, 12129-12130.

Organometallics, Vol. 28, No. 1, 2009 365 Scheme 4. Proposed Mechanism for the [2+2+1]/[2+1] Tandem Cycloaddition

Scheme 5. Alternative Mechanism for the Formation of Carbene Complex VI via FCC Isomerization Followed by a Pauson-Khand Reaction

carbene species VI,26 which will account for the formation of compounds 4 in the final steps. An alternative mechanism that involves an initial rearrangement of FCCs 1 followed by a Pauson-Khand-type [2+2+1] cyclization reaction (PKR)27 would also explain the formation of intermediate VI. However, this possibility was completely ruled out due to the following facts: (a) such rearrangement is not thermodynamically favored for heteroatom-stabilized chro(26) The transformation of IV into VI could follow a mechanism involving even more steps (“less concerted”) via the methoxy-induced ringopening of the metallacyclopentanone moiety on IV to form VII and the subsequent intramolecular alkyne insertion via metallacycle V:



Scheme 6. Cross-Reaction Attempted between FCC 1a, Olefin 2e, and Cyclopropane 3e

mium FCCs,28,29 and (b) neither the participation of the rearranged carbene 1′ in the reaction nor the formation of cyclopropanes 3′ has been detected (Scheme 5). On the contrary, a very clear signal in the HMBC spectra between the methoxy group and the quaternary carbon of the cyclopropanes corroborates the proposed structure for cyclopropanes 3. The option that 3 could be an intermediate for the formation of 4 was discarded by performing a cross-reaction. Considering that the corresponding cyclopropane 3 was not observed in the coupling of 2e and 1a (Table 1, entry 5), a cross-reaction was attempted by slow addition of 1a (0.2 mmol, 1 equiv) to a solution of 2e (3 equiv) and 3e (1 equiv) in refluxing toluene under CO atmosphere (Scheme 6). The carbene 1a disappeared in 30 min (TLC), and no cross-type products were detected either in the NMR spectrum of the crude residue or after column chromatography (in fact, unreacted cyclopropane 3e was almost completely recovered). Such result, therefore, evidenced that, once it was formed, cyclopropane 3e did not evolve under the reaction conditions. 4. [2+2+1]/[2+1] Coupling Reaction Sequence Involving Two Different Olefins. The [2+2+1]/[2+1] tandem cycloaddition process presented above allows a rapid access to highly functionalyzed polycyclic compounds that incorporate up to four components, among which two are the same bicyclic olefin. Obviously, 1 equiv of the strained bicyclic olefin 2 is required to initiate the reaction sequence; however, we questioned if a second and different olefin may be used to provide the fourth and final component, therefore introducing an extra element of diversity30 into the reaction products. Ethyl vinyl ether 8a was initially chosen as fourth component for the [2+2+1]/[2+1] reaction sequence. After optimization of the stoichiometric ratio of the reactants, polycyclic compounds 9a and 10a were isolated in 7% and 25% yields (together with some amount of 3a and 4a) in a reaction carried out with FCC 1a, norbornene 2a, and ethyl vinyl ether 8a in a 1:5:15 (27) Selected recent reviews on the Pauson-Khand reaction: (a) Pe´rezCastells, J. Top. Organomet. Chem. 2006, 19, 207–257. (b) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022–3037. (c) BlancoUrgoiti, J.; Anõrbe, L.; Pe´rez-Serrano, L.; Domıńguez, G.; Pe´rez-Castells, J. Chem. Soc. ReV. 2004, 33, 32–42. (d) Bonãga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795–9833. (e) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004, 3377–3383. (f) Gibson, S. E.; Stevanazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800–1810. (28) Metallotropic [1,3]-carbene shifts have been reported for alkynylcarbene complexes of several metals: (a) Lee, D.; Kim, M. Org. Biomol. Chem. 2007, 5, 3418–3427. Also, for a chromium-manganese exchange: (b) Ortin, Y.; Coppel, Y.; Lugan, N.; Mathieu, R.; McGlinchey, M. Chem. Commun. 2001, 1690–1691. (29) For chromium (and also for molybdenum and tungsten) alkynylcarbene complexes the metallotropic [1,3]-shift equilibrium is displaced toward the formation of the corresponding heteroatom-stabilized FCC: (a) Barluenga, J.; Garcıá-Garcıá, P.; de Saá, D.; Fernańdez-Rodrı´guez, M. A.; Bernardo de la Ruá, R.; Ballesteros, A.; Aguilar, E.; Toma´s, M. Angew. Chem., Int. Ed. 2007, 46, 2610–2612. (b) Barluenga, J.; Bernardo de la Ruá, R.; de Saá, D.; Ballesteros, A.; Toma´s, M. Angew. Chem., Int. Ed. 2005, 44, 4981–4983. (30) Schreiber, S. L. Science 2000, 287, 1964–1969.

Scheme 7.

Proposed Mechanism for the Formation of Compounds 9 and 10

ratio in toluene at 110 °C (Table 3, entry 1). Cyclopropane 9a is the expected product, and it may be explained as the result of the cyclopropanation of the double bond of 8a by carbene intermediate VI; on the other hand, compound 10a is an acyclic adduct that also incorporates electron-rich olefin 8a as the fourth component. Two plausible routes may explain its formation: (1) a rearrangement of 9a, similar to the one previously proposed for other cyclopropanations involving chromium carbene complexes with electron-deficient olefins,8f or (2) an alternative mechanism that does not imply the formation of the cyclopropane (Scheme 7).6b Gratifyingly, the formation of such reaction products supports the role of carbene complex VI as an intermediate of the proposed reaction mechanism. The stereochemistry of adduct 10a was determined by a NOESY experiment. The reaction was also tested at 80 °C, and although much longer reaction times were required (5 h vs 30 min), it provided a notable increase in the combined amount of compounds 9a and 10a (entry 2). Interestingly, the reaction with benzooxanorbornadiene 2e resulted in a considerable (80%) combined yield of adducts 9b and 10b (entry 3). Other significant results obtained are listed in Table 3. The reactions were carried out with FCC 1a and bicyclic olefins 2a and 2e, in toluene, at the two temperatures indicated in Table 3. In general, the reactions at 110 °C were completed in 30 min, while at 80 °C they required 3-6 h, although higher selectivity and combined yields were achieved. Other nonbicyclic olefins tested were 1-hexene 8b (entries 4-6) and styrene 8c (entries 7-10) as simple monosubstituted olefins and methyl acrylate 8d, an electron-deficient olefin, which underwent incorporation into the four-component adducts 9g and 10g at 80 °C (entry 11); remarkably, 8d undergoes direct cyclopropanation21 by FCC 1a at 110 °C, even in the presence of norbornene 2a. Terminal monosubstituted dienes were also employed, such as trans-1,3-pentadiene 8e and isoprene 8f, to find that the incorporation into the four-component adducts took place through the less hindered double bond (entries 12, 13); in these reactions cyclohexenes, which came from a [4+2]

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Table 3. Scope of [2+2+1]/[2+1] Cycloaddition Reactions Involving Four Different Components

a Reactions were conducted in a sealed tube using a 1:5:15 ratio of carbene complex 1a and olefins 2 and 8, heated at the given temperature for 30 min to 6 h before completion. b Bath temperature. c Isolated yield based on the starting carbene complex 1a. d Obtained as mixtures of diastereoisomers; for the diastereomeric ratio [estimated by 1H NMR (300 MHz) of the isolated products], see the Supporting Information. e Cyclopropane 3a was also isolated (entry 1, 6%; entry 4, 4%; entry 7, 5%). f Compounds 9c and 10c could not be separated; the yield was estimated by NMR from a 56% combined isolated yield. g Obtained as an undetermined mixture of isomers. h The corresponding [4+2] Diels-Alder cyclohexenes, formed by reaction between olefin 2e and dienes 8e,f, were also isolated (entry 12, 13%; entry 13, 19%; yields based on olefin 2e). i Not isolated; estimated yield, from a mixture with 10i.

Diels-Alder reaction between 2e and the dienes, were also isolated as byproducts. Nonactivated disubstituted olefins were also checked. No coupling was observed for (Z)-cyclooctene or 2-ethyl-1-butene, but it occurred with a more reactive olefin such as cyclopentene 8g. Again, the reaction outcome was highly dependent on the temperature: four-different-component cyclopropane 9j was the major product at 80 °C (52%, dr ) 1.5:1, entry 15), while 4e was the main product at 110 °C (40%, entry 14). Finally, other unsaturated systems such as imines, enamines, or aldehydes were also tested; however, they were not compatible with the reaction sequence, as they readily reacted with alkynyl FCCs 1, inhibiting the tandem cycloaddition sequence. Complex reaction mixtures were formed in all these reactions. 5. [2+2+1]/Intramolecular [2+1] Reaction Sequence. Considering the lack of selectivity of the four different component coupling reaction, which led to mixtures of three or four products, we turned to study the intramolecular cyclopropanation version of this reaction. However, no evidence of coupling was detected in the complex mixtures formed by reaction between bicyclic olefins 2a,e and FCCs 5b,c (Figure 2), which present a double bond in the alkoxy moiety but a bulky substituent in

Scheme 8. Intermolecular [2+2+1]/[2+1] Sequence with Allyloxy FCC 5d

the triple bond. Only FCC 5d, with a less bulky substituent in the triple bond, was able to undergo an [2+2+1]/[2+1] intermolecular coupling with two molecules of 2e to render a low yield (20%) of product 11 (which, in fact, is a compound of type 4) in Scheme 8; therefore, the expected final intramolecular cyclopropanation step did not take place for the reaction of FCC 5d and alkene 2e. Then, we decided to place the double bond in the carbon skeleton linked to the triple bond. Thus, FCC 1g (Scheme 9), which presents an ortho-vinyl group, was prepared23 and reacted with 2a in toluene at 110 °C under CO atmosphere, to give a mixture of cyclopropanation product 3h, the intermolecular fourcomponent adduct 4k, and cycloadduct 12a, which proceeds



Scheme 9. Inter- and Intramolecular [2+2+1]/[2+1] Sequences with FCC 1g

Scheme 10. [2+2+1]/Intramolecular [2+1] Sequences with Olefin 2e and FCCs 1h,i

from the intramolecular cyclopropanation of the vinyl group, in a 75% combined yield. Lowering the temperature to 80 °C and performing the reaction in the absence of CO resulted basically in a decrease of the yield of cyclopropane 3h. However, the direct cyclopropanation was suppressed when olefin 2e was employed; only the sequentially formed adducts 4l and indene 12b were isolated in moderate combined yields. Again, slightly lower yields were reached in the absence of CO at 80 °C. The [2+2+1] reaction followed by an intramolecular cyclopropanation, starting from FCC 1g, would lead to a nondetected highly strained structure 13 (Scheme 9), which should be relatively unstable and would evolve toward the formation of indenyl adducts 12. On the other hand, the formation of strained [2.1.0] structure 13 would be relatively disfavored, which may explain the production of mixtures of both inter- and intramolecular [2+2+1]/[2+1] adducts.31 Therefore, if the FCC incorporates a 1,6-enyne unit, the final intramolecular cycloaddition should be the major reaction pathway because the [3.1.0] bicyclic system would certainly be less strained than the [2.1.0] system. To prove this hypothesis, FCCs 1h and 1i were reacted with bicyclic olefin 2e in toluene at 80 °C in the absence of CO (Scheme 10). Under these conditions, cycloadducts 14a and 14b, which were formed exclusively by a [2+2+1]/intramolecular cyclopropanation sequence, were isolated (31) A nucleophilic mechanism has been proposed for the indene formation from structurally similar intermediates, based on the correlation between the efficiency of the process and the nucleophilicity of the olefin: Zhang, L.; Herndon, J. W. Organometallics 2004, 23, 1231–1235.

Scheme 11. Alkyne Insertion in VI (R ) Ph) and Possible Evolution Patterns

in good yields as mixtures of diastereomers. As expected and contrary to what occurs for adducts 13, [3.1.0] bicyclic compounds 14 formed via intramolecular cyclopropanation do not undergo ring expansion. 6. Internal Alkynes as Fourth Partner in the Four-Component Coupling. Taking into account the previously proposed mechanism (Scheme 4), we next hypothesized that the intermediate vinylogous methoxy-stabilized carbene complex VI (R ) Ph) should be able to insert an alkyne unit to form VIII, which may evolve either by a cyclopentannulation or by a Do¨tz benzannulation processes32 to generate new and highly functionalized indenes 15 or naphthols 16 (Scheme 11). However, the presence of terminal alkynes inhibits the cascade reaction by promoting a Pauson-Khand reaction leading to cyclopentenones. This result has allowed the development of a substoichiometric tungsten-catalyzed intermolecular PKR, although of limited scope.33 On the other hand, the insertion of an alkyne as the fourth component could be achieved indeed using an internal alkyne, such as 3-hexyne 17a, which reacted with FCC 1a and bicyclic olefin 2e in toluene (Scheme (32) (a) Do¨tz, K. H.; Tomuschat, P. Chem. Soc. ReV. 1999, 28, 187. (b) Minatti, A.; Do¨tz, K. H. Top. Organomet. Chem. 2004, 13, 123–156, and references therein. (33) Garcıá-Garcıá, P.; Fernańdez-Rodrı´guez, M. A.; Rocaboy, C.; Andina, F.; Aguilar, E. J. Organomet. Chem. 2008, 693, 3092–3096.

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Scheme 12. Internal Alkynes as Fourth Component in the Tandem Reaction

12). Indene 19a was obtained as major product, although minor quantities of both 4e and Pauson-Khand adduct 18 were also isolated. Other internal alkynes, such as 4-octyne 17b, were also incorporated as fourth partner, although to a slightly lesser extent since a 29% yield of indene 19b was produced. Alkyne insertion was also observed when the more stable FCC 1d was employed. Note that 1d bears a t-Bu group, and therefore, it cannot undergo annulation reaction; instead, the intermediate carbene complex 22 evolved to cyclobutenone 21, through the insertion of a second carbonyl unit to form 23 and after a final electrocyclization step. Compound 21 is a fivecomponent adduct, which presents a quaternary carbon and was isolated as a 1:1 diastereomer mixture. A 7% yield of 18 and a 6% yield of [2+2] adduct 20 were isolated as byproducts. Finally, the results displayed in Scheme 12 also support the role of carbene complex VI as an intermediate in the proposed reaction mechanism of Scheme 4.

Conclusions In summary, alkoxy alkynyl Fischer carbene complexes react in an unprecedented manner through a [2+2+1]/[2+1] sequence with strained and hindered olefins (i.e., bicyclo[2.2.1]heptene derivatives), yielding highly functionalized polycycles that incorporate up to four different components (two of them may be identical). This cascade sequence is initiated by an interaction between the bicyclic olefin and the FCC, which takes part through its three reactive positions: the carbene and both acetylenic carbons. Two new rings and five σ C-C bonds are created in the process. Either electron-rich, neutral, or electron-

deficient olefins may act as the fourth component in the reaction sequence, which would lead to the final products by being trapped by intermediate carbene complex VI. The presence of an extra double bond in the appropriate position of the FCC considerably increases the selectivity of the reaction and allows the formation of the [2+2+1]/intramolecular [2+1] adducts as the sole reaction products. Terminal alkynes inhibit the cascade reaction, while internal alkynes are also suitable reagents to act as the fourth component in the reaction sequence: when the FCC bears an aromatic group, indenes are obtained in a [2+2+1]/ [3+2] cascade; otherwise cyclobutenones, which result from the further insertion of a carbonyl group, are formed.

Acknowledgment. We are very grateful to Prof. Barluenga for helpful discussions and, especially, for encouraging us to pursue this research. We thank the Ministerio de Ciencia y Tecnologıá (Spain) (grant CTQ2004-08077-C02-01, predoctoral fellowships to P.G.-G. and F.A., postdoctoral fellowship to C.R.), Principado de Asturias (project IB05136), and the Fundacioń Ramoń Areces for the financial support received. F.A. thanks the Universidad de Oviedo and CSIC for undergraduate fellowships. Supporting Information Available: Complete Experimental Section including detailed experimental procedures, spectroscopic data for all new compounds, and crystallographic information files (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. OM800958D

Multicomponent Cascade Reactions Triggered by Cycloaddition of

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