Bio-Organometallic Chemistry, ansa-Metallocenes, and Frustrated

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Organometallics 2011, 30, 358–368 DOI: 10.1021/om101118a

Bio-Organometallic Chemistry, ansa-Metallocenes, and Frustrated Lewis Pairs: Functional Group Chemistry at the Group 4 Bent Metallocenes Gerhard Erker* Organisch-Chemisches Institut der Universit€ at M€ unster, Corrensstrasse 40, 48149 M€ unster, Germany Received November 29, 2010

Functional group chemistry at the group 4 bent metallocenes is still a challenge, due to the special features of these early-metal systems. Nevertheless, an increasing number of reactions and protocols is being developed for attaching organic functional groups at the bent-metallocene frameworks and for carrying out reactions with them. Here some bio-organometallic bent metallocene systems are discussed. Chemical transformations are presented and discussed, including olefin metathesis and even variants of the Mannich reaction. It is shown that intramolecular [2 þ 2] cycloaddition reactions between alkenyl substituents at the Cp or indenyl rings under dynamic topochemical reaction control can lead to ansa-metallocenes. Frustrated Lewis pair chemistry provides tools, for example, for reduction reactions under very mild conditions.

Introduction The group 4 bent metallocenes have played a significant role in organometallic chemistry and catalysis and a variety of closely related adjacent fields for some time. This ranges from the use of zirconocene derivatives in organic synthesis1-3 to the essential role of titanocenes, zirconocenes, and hafnocenes in the development of homogeneous Ziegler-Natta olefin polymerization catalysis.4 It involves bio-organometallic applications such as the potential use of functionalized *E-mail: [email protected]. (1) (a) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24, 405– 411. (b) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115–8116. (c) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M. Tetrahedron Lett. 1987, 28, 3895–3898. (2) (a) Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi, T.; Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521–3523. (b) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124–130. (c) Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755–769. (3) (a) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771–10772. (b) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577–1578. (c) Knickmeier, M.; Erker, G.; Fox, T. J. Am. Chem. Soc. 1996, 118, 9623–9630. (d) Erker, G.; Aulbach, M.; Dreier, T.; Bergander, K.; Wegelius, E.; Fr€ ohlich, R.; Erker, G. Organometallics 2001, 20, 5067–5075. (e) Huo, S.; Shi, J.; Negishi, E. Angew. Chem. 2002, 114, 2245–2247; Angew. Chem., Int. Ed. 2002, 41, 2141-2143. (f) Negishi, E. In Organometallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 925-1002. (g) Negishi, E. Dalton Trans. 2005, 827–848. (4) (a) Brintzinger, H.; Fischer, D.; M€ ulhaupt, R.; Rieger, B.; Waymouth, R. M. Angew. Chem. 1995, 107, 1255-1283; Angew. Chem., Int. Ed. 1995, 34, 1143-1170. (b) You-Xian Chen, E.; Marks, T. J. Chem. Rev. 2000, 100, 1391–1434. (c) Chirik, P. J. Organometallics 2010, 29, 1500–1517. (5) (a) K€ opf, H.; K€ opf-Maier, P. Angew. Chem. 1979, 91, 509; Angew. Chem., Int. Ed. Engl. 1979, 18, 477-478 (b) K€ opf-Maier, P.; K€ opf, H. Chem. Rev. 1987, 87, 1137–1152. (c) Harding, M. M.; Mokdsi, G. Curr. Med. Chem. 2000, 7, 1289–1303. (6) (a) Petersen, J. L; Dahl, L. F. J. Am. Chem. Soc. 1975, 97, 6416–6422. (b) Lauher, J. W.; Hoffmann, R. J. Am. Chem. Soc. 1976, 98, 1729-1742, 6422-6433 (c) Green, J. C. Chem. Soc. Rev. 1998, 27, 263–272. (7) (a) R€ ottger, D.; Erker, G. Angew. Chem. 1997, 109, 840-856; Angew. Chem., Int. Ed. Engl. 1997, 36, 812-827. (b) Schottek, J.; R€ ottger, D.; Erker, G.; Fr€ ohlich, R. J. Am. Chem. Soc. 1998, 120, 5264–5273. See also: (c) Hoffmann, R.; Alder, R. W.; Wilcox, C. F., Jr. J. Am. Chem. Soc. 1970, 92, 4992–4993. pubs.acs.org/Organometallics

Published on Web 01/07/2011

titanocene dichlorides as antitumor agents.5 Moreover, the group 4 bent metallocenes possess very special stereoelectronic features6 that enable them ideally to stabilize very unusual bonding geometries at the element carbon.7 Over the years, my group has contributed to these and related aspects of metallocene chemistry. Much of this required the development of methods to deal with organic functional groups at the bent metallocenes and to design and develop a suitable organic functional group chemistry compatible with the special chemical features of sensitive titanocene, zirconocene, and hafnocene compounds.8 Some significant general developments will be described in this review. At the same time this compilation will be used to highlight some recent progress achieved by the M€ unster group in the areas of bio-organometallic chemistry,9 ansa-metallocenes8a and frustrated Lewis pair chemistry.10

Bio-Organometallic Chemistry of Group 4 Metallocenes: Carbohydrate and Oligopeptide Derivatives Quite a number of metal complex/carbohydrate conjugates have been described in the literature. However, most of them contain electron-rich late transition metals.11 Carbohydrate derivatives of the air- and moisture-sensitive oxophilic group 4 metals are still quite rare.12 We treated, for (8) (a) Erker, G. Polyhedron 2005, 24, 1289–1297. (b) Erker, G. Coord. Chem. Rev. 2006, 250, 1056–1070. (9) Erker, G. J. Organomet. Chem. 2007, 692, 1187–1197. (10) Stephan, D. W.; Erker, G. Angew. Chem. 2010, 122, 50-81; Angew. Chem., Int. Ed. 2010, 49, 46-76. (11) (a) Steinborn, D.; Junicke, H. Chem. Rev. 2000, 100, 4283–4317. (b) Kl€ufers, P.; Kunte, T. Angew. Chem. 2001, 113, 4356-4358; Angew. Chem., Int. Ed. 2001, 40, 4210-4212. (c) M€ oker, J.; Thiem, J. Eur. J. Org. Chem. 2009, 4842–4847. (12) (a) Riediker, M.; Hafner, A.; Rish, G.; Togni, A. Angew. Chem. 1989, 101, 493-495; Angew. Chem., Int. Ed. Engl. 1989, 28, 499-500. (b) Vedsø, P.; Chauvin, R.; Li, Z.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1994, 77, 1631–1639. (c) Laï, R.; Martin, S. Tetrahedron: Asymmetry 1996, 7, 2783–2786. (d) K€untzer, D.; Jessen, L.; Heck, J. Chem. Commun. 2005, 5653–5655. (e) Schwidom, D.; Zeysing, D.; Schmidt, M.; Heck, J. Eur. J. Inorg. Chem. 2009, 5295–5298. r 2011 American Chemical Society

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359

Scheme 1

example, a methyltitanocene cation (2a, with [MeB(C6F5)3]anion) with the glucose derivative 3a, which was selectively deprotected at the 4-OH functionality (see Scheme 1). Rapid

Gerhard Erker was born on October 16, 1946. He studied chemistry at the Universities K€ oln and Bochum and received his doctoral degree from the Ruhr-Universit€ at Bochum in 1973. He was a postdoc at Princeton University. Back in Germany he did his Habilitation (Bochum 1981) and then became a Heisenberg fellow at the MaxPlanck-Institut f€ ur Kohlenforschung at M€ ulheim. He was a tenured “Associate Professor” at the Universit€ at W€ urzburg from 1985 to 1990, when he was appointed at his present position at the Universit€ at M€ unster. He had offers to join the chemistry faculties at the Universit€at Karlsruhe (1989) and the LMU M€ unchen (1994). Gerhard Erker is a member of the Nordrhein-Westf€ alische Akademie der Wissenschaften und der K€ unste, a member of Academia Europea, and a member of acatech. Among his awards are the Winnacker Scholarship, the Chemistry Award of the Akademie der Wissenschaften zu G€ ottingen, the Krupp Award, the Max-Planck-Research Award, the Otto-Bayer-Award, and, recently, the Adolf-von-Baeyer Medal of the German Chemical Society. Gerhard Erker served on the board of the GDCh (German Chemical Society) for two consecutive periods, and he was the GDCh President in 2000-2001. He was a member of the Senate of the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG). Gerhard Erker has a strong research interest in organometallic chemistry and catalysis. The chemistry of frustrated Lewis pairs and its application in small-molecule activation is currently a most actively pursued research area in the Erker group. Professor Erker and his co-workers have contributed a series of very reactive metal-free systems for activating dihydrogen, carbon dioxide or olefins, and alkynes to this new chemical field of high current interest. This new field is expanding rapidly, and the group is finding surprising new reactions. He has published >500 papers in refereed scientific journals and has been the supervisor of more than 100 doctoral students. He loves classical music and art.

Scheme 2

methane evolution was observed, and we isolated the product 4a in good yield. There is evidence that complex 4a contains a chelate carbohydrate coordination involving participation of the oxygen atom of the 6-OCH2Ph substituent in binding to the early transition metal.13 The reaction required activation of the titanocene system by cation formation; under our conditions the neutral dimethyltitanocene system did not react with the acidic 4-OH of the carbohydrate 3a. The respective zirconocenes are much more reactive. Dimethylzirconocene reacted readily with the carbohydrate reagent 3a with methane liberation. Subsequent removal of a methyl anion equivalent from zirconium by treatment with B(C6F5)3 then gave the analogous cationic chelate zirconocenecarbohydrate conjugate 4b by an “inverted” reaction sequence, as compared to the preparation of the analogous titanocene product 4a. Using a more basic σ-enolate metallocene reagent proved advantageous. Treatment of the bis(acetone-enolato)zirconocene complex 614 with the 6-deprotected glucopyranoside derivative 3b resulted in the liberation of 2 molar equiv of acetone with formation of the bis(carbohydrate)zirconocene complex 7 (see Scheme 2). Complex 7 was characterized by X-ray diffraction (see Figure 1). Similarly, the doubly deprotected glucofuranoside derivative 3c reacted cleanly with bis(propenolato)zirconocene to give the respective O,O-chelate carbohydrate zirconocene product 8, which was isolated as a (13) Meyer zu Berstenhorst, B.; Erker, G.; Kehr, G.; Wasilke, J.-C.; M€ uller, J.; Redlich, H.; Pyplo-Schnieders, J. Eur. J. Inorg. Chem. 2005, 92–99. (14) Sp€ather, W.; Klass, K.; Erker, G.; Zippel, F.; Fr€ ohlich, R. Chem. Eur. J. 1998, 4, 1411–1417.

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Figure 1. View of the molecular structure of the zirconocene-carbohydrate conjugate 7. Scheme 3

dimer (also characterized by an X-ray crystal structure analysis) in 90% yield.15 Since the discovery of the cytotoxic properties of the organometallic titanocene dichloride system by K€ opf et al.,5 many functionalized titanocene derivatives have been investigated for their cancerostatic potential.16 Titanocenes modified by carbohydrates seemed to be good candidates in that development. Some σ-carbohydrate titanocenes, such as 4, were too hydrolytically sensitive; we prepared a series of titanocene dichloride complexes bearing the carbohydrate-derived functional groups attached at their Cp rings.12 We synthesized a series of ribosyl-substituted titanocene derivatives by means of the synthetic route depicted in Scheme 3, among them the complex 13a. This turned out to exhibit a remarkable cytotoxic activity. In cell tests against a series of different cancer lines it showed IC50 values in the range of ca. 5 μM.17 (15) Meyer zu Berstenhorst, B.; Erker, G.; Kehr, G.; Fr€ ohlich, R. Dalton Trans. 2006, 3200–3203. (16) (a) Strohfeldt, K.; Tacke, M. Chem. Soc. Rev. 2008, 37, 1174– 1187. (b) Pampill on, C.; Claffey, J.; Strohfeldt, K.; Tacke, M. Eur. J. Med. Chem. 2008, 43, 122–128. (c) Eger, S.; Immel, T. A.; Claffey, J.; M€ullerBunz, H.; Tacke, M.; Groth, U.; Huhn, T. Inorg. Chem. 2010, 49, 1292–1294. (17) (a) Meyer zu Berstenhorst, B. Dissertation; WWU M€ unster, 2006. (b) Sasse, F.; Erker, G.; Kehr, G.; Meyer zu Berstenhorst, B.; Redlich, H. Ger. Offen. GWXXBX DE 102006053690 A1 20080515 CAN 148:562124 AN 2008:587667, 2008. (18) Lippert, B. Cisplatin-Chemistry and Biochemistry of a Leading Anticancer Drug; Wiley-VCH: Weinheim, Germany, 1999.

Scheme 4

Titanocene dichlorides seem to follow a different action pathway in the cell as compared to, for example, cisplatin.18 There might be titanocene-protein interactions involved, at least at the transport stage.19 We tried to learn about potential titanocene/peptide contacts by using a special model system. Since it was not clear to us initially whether reactive titanocene or zirconocene complexes would tolerate interactions with the multifunctional peptide backbones at all, we (19) (a) Sun, H.; Li, H.; Weir, R. A.; Sadler, P. Angew. Chem. 1998, 110, 1622-1625; Angew. Chem., Int. Ed. 1998, 37, 1577-1579. (b) Sun, H.; Li, H.; Sadler, P. J. Chem. Rev. 1999, 99, 2817–2842.

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Scheme 5

methane at room temperature to yield the κ3O,O,N-chelate complex 15c. This zirconocene product was characterized by an X-ray crystal structure analysis (see Scheme 5 and Figure 2).21b Treatment of the isocyanide 16, derived from the dipeptide H-Val-Val-OCH3, with [Cp2ZrCH3(THF)þ] [BPh4-] (2d) gave the related cationic peptide κ3O,O,Nchelate zirconocene product 15d (see Scheme 5), which was also characterized by X-ray diffraction.21a

ansa-Metallocene Formation: A Case of Dynamic Topochemical Reaction Control

Figure 2. Projection of the molecular structure of the peptide chelate zirconocene cation 15c (only the cation is depicted).

used a series of di-, tri-, and tetrapeptides derived from the non-polar amino acids alanine, valine, and (in some cases) glycine for the reaction with suitable metallocene derivatives. Usually, the oligopeptides were esterified at the C terminus and Boc or Z protected at the N terminus. We treated the respective peptides with the methyl-metallocene cations, employed as their THF-stabilized derivatives (Ti, 2c; Zr, 2d; both with BPh4- anion) at low temperature. NMR analysis revealed the formation of the κO adducts (e.g., 14a (M = Ti)). In some cases we were able to monitor an equilibration with a second κO isomer (14b), formally derived from migration of the titanocene moiety along the chain. Eventually, internal deprotonation of the peptide backbone took place with methane evolution to yield the chelate-peptide titanocene cation products 15 (see Scheme 4).20,21 The essential structural features of the κ3O,O,N-chelate coordination of the peptide to the metallocene unit in the 15 type products were determined from separate experiments in the zirconocene series. Treatment of the dipeptide derivative Boc-Ala-Val-OMe with [Cp2ZrCH3(THF)þ][BPh4-] (2d) at -15 °C in dichloromethane gave the adduct 14c, which lost (20) Harmsen, D.; Erker, G.; Fr€ ohlich, R.; Kehr, G. Eur. J. Inorg. Chem. 2002, 3156–3171. (21) (a) Oberhoff, M.; Erker, G.; Fr€ ohlich, R. Chem. Eur. J. 1997, 3, 1521–1525. (b) Wonnemann, J.; Oberhoff, M.; Erker, G.; Fr€ohlich, R.; Bergander, K. Eur. J. Inorg. Chem. 1999, 1111–1120.

ansa-Metallocenes of the group 4 metals have significantly contributed to the development of homogeneous ZieglerNatta olefin polymerization catalysis.4 Initially the construction of the ansa bridge between the pair of Cp or indenyl rings was carried out at the pure ligand precursor stage and the assembled doubly deprotonated ligand framework was then attached to the group 4 metal in a final transmetalation step. We and others have subsequently developed various methods of forming the ansa bridge at the bent-metallocene stage by using a small series of carbon-carbon bond forming protocols that were compatible with the special requirements governed by the specific properties of the sensitive group 4 metallocenes. Ring-closing olefin metathesis was an option.22 Substituted bis(allyl-Cp)zirconocene dichlorides, such as the complex rac-18, readily underwent metathetical CdC coupling with loss of ethylene to yield the C4-bridged unsaturated ansa-zirconocene rac-19 (Figure 3). rac-19 gives an active ethylene polymerization catalyst upon activation with excess MAO, but it is less active than the catalyst derived from the starting material 18.23 [Cl2(PCy3)2RudCHPh] (17)-catalyzed intramolecular olefin metathesis turned out to be well suited to prepare the “large ansa-metallocene” 21. Complex 21 contains a trans carbon-carbon double bond inside the (22) (a) Bielawski, C. W.; Grubbs, R. H. Prog. Polym. Sci. 2007, 32, 1–29. (b) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746– 1787. (23) Tumay, T. A.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Dalton Trans. 2009, 8923–8928. (24) H€ uerl€ander, D.; Kleigrewe, N.; Kehr, G.; Erker, G.; Fr€ ohlich, R. Eur. J. Inorg. Chem. 2002, 2633–2642.

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Figure 3. Views of the molecular structures of the unsaturated ansa-metallocenes rac-19 (left) and trans-21 (right) obtained by catalytic ring-closing olefin metathesis. Scheme 6

Scheme 7

medium-sized metallacyclic ring system24,25 (see Scheme 6 and Figure 3). ansa-Metallocenes of the group 4 metals can even be prepared by a Mannich reaction. Deprotonation of various 6-(dialkylamino)fulvenes (22)26 gave the respective (enaminoCp)Li reagents 23. Their reaction with the group 4 metal tetrahalides MCl4 (M = Ti, Zr, Hf) in a 2:1 stoichiometry gave the bis(enamino-Cp)MCl2 compounds 24, which readily underwent an intramolecular Mannich C-C coupling reaction. This reaction is Lewis acid or Brønsted acid catalyzed. In (25) (a) See also ref 15. (b) Ogasawara, M.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2002, 124, 9068–9069. (c) Cano Sierra, J.; H€uerl€ander, D.; Hill, D.; Kehr, G.; Erker, G.; Fr€ohlich, R. Chem. Eur. J. 2003, 9, 3618–3622. (26) Hafner, K.; Voepel, K. H.; Ploss, G.; Koenig, C. Org. Synth. 1967, 47, 52–54.

Figure 4. View of the molecular structure of the C3-bridged ansa-zirconocene dichloride complex 25a (-NR2 = -NMe2).

some cases the subsequent Mannich condensation reaction takes place so rapidly that it is hard to stop the reaction at the stage of the bis(enamino-Cp)MCl2 stage (24) unless special precautions are taken.27,28 Therefore, the C3-bridged ansametallocenes can often be obtained in good yield directly from the reaction of the (enamino-Cp)lithium reagent with the respective Lewis acidic metal tetrachloride in a one-pot reaction (see Scheme 7 and Figure 4).29-31 This type of an acid-catalyzed Mannich condensation reaction has successfully been applied also to ferrocene chemistry. It has made the respective [3]ferrocenophanes easily available.32 These systems have provided a suitable basis for (27) Venne-Dunker, S.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Organometallics 2003, 22, 948–958. (28) Tumay, T. A.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Organometallics 2009, 28, 4513–4518. (29) Kn€ uppel, S.; Erker, G.; Fr€ ohlich, R. Angew. Chem. 1999, 111, 2048-2051; Angew. Chem., Int. Ed. Engl. 1999, 38, 1923-1926. (30) Kn€ uppel, S.; Wang, C.; Kehr, G.; Fr€ ohlich, R.; Erker, G. J. Organomet. Chem. 2005, 690, 14–32. (31) Bai, S.-D.; Wei, X.-H.; Guo, J.-P.; Liu, D.-S.; Zhou, Z.-Y. Angew. Chem. 1999, 111, 2051-2054; Angew. Chem., Int. Ed. Engl. 1999, 38, 1926-1928. (32) Liptau, P.; Kn€ uppel, S.; Kehr, G.; Kataeva, O.; Fr€ ohlich, R.; Erker, G. J. Organomet. Chem. 2001, 637-639, 621–630.

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Organometallics, Vol. 30, No. 3, 2011 Scheme 8

the synthesis of a variety of [3]ferrocenophane-based ligand systems33 and of related bio-organometallics.34 In view of the general sensitivity of the group 4 bent metallocenes, we thought that it might be advantageous to aim at achieving the formation of the ansa bridge by reagentor catalyst-free carbon-carbon coupling on the bent-metallocene stage. Photochemical [2 þ 2] cycloaddition of the olefinic substituents was a viable option. It is well-known that cyclobutane formation by photochemical [2 þ 2] cycloaddition can readily be achieved in the crystal in a variety of cases by topochemical reaction control.35,36 Attaching a pair of vinylic substituents at the Cp or indenyl groups of the bent metallocenes might create a situation where conformational control37 brings the alkenyl units in close proximity to allow for their photochemical coupling reaction (see Scheme 8). This principle of “dynamic topochemical reaction control”38 in solution worked beautifully. Here is an example:28 the (enamino-Cp)2ZrCl2 complex 24a was isolated under carefully selected acid-free reaction conditions and characterized by X-ray diffraction. This revealed that the system attains a bent-metallocene conformation where both enamino substituents are oriented toward the open front side of the bent-metallocene wedge. In this favored structure the olefinic units have a maximum separation from each other, too far for any direct interaction, let alone C-C bond formation. Nevertheless, photolysis of (33) (a) Liptau, P.; Seki, T.; Kehr, G.; Abele, A.; Fr€ ohlich, R.; Erker, G.; Grimme, S. Organometallics 2003, 22, 2226–2232. (b) Liptau, P.; Tebben, L.; Kehr, G.; Wibbeling, B.; Fr€ohlich, R.; Erker, G. Eur. J. Inorg. Chem. 2003, 3590-3600, 4261. (c) Liptau, P.; Tebben, L.; Kehr, G.; Fr€ ohlich, R.; Erker, G.; Hollmann, F.; Rieger, B. Eur. J. Org. Chem. 2005, 9, 1909–1918. (34) (a) Tebben, L.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Eur. J. Inorg. Chem. 2008, 2654–2658. (b) Tebben, L.; Bussmann, K.; Hegemann, M.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Organometallics 2008, 27, 4269–4272. (35) (a) Kohlsch€ utter, V. Z. Anorg. Allg. Chem. 1918, 105, 1–25. Reviews: (b) Morawetz, H. Science 1966, 152, 705–711. (c) Green, B. S.; Lahav, M.; Rabinovich, D. Acc. Chem. Res. 1979, 12, 191–197. (d) Ramamurthy, V.; Venkatesan, K. Chem. Rev. 1987, 87, 433–481. (e) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074. (f) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1483. (g) Nagarathinam, M.; Peedikakkal, A. M. P.; Vittal, J. J. Chem. Commun. 2008, 5277–5288. For a general overview see also: (h) Hopf, H. Angew. Chem. 2003, 115, 2928-2931; Angew. Chem., Int. Ed. 2003, 42, 2822-2825. (i) Toda, F. Top. Curr. Chem. 2005, 254, 1–40. (j) Trask, A. V.; Jones, W. Top. Curr. Chem. 2005, 254, 41–70. (k) Kaupp, G. Top. Curr. Chem. 2005, 254, 95– 183. (l) Sakamoto, M. Top. Curr. Chem. 2005, 254, 207–232. (m) Scheffer, J. R.; Xia, W. Top. Curr. Chem. 2005, 254, 233–262. (n) Matsumoto, A. Top. Curr. Chem. 2005, 254, 263–305. (36) (a) Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 1996– 2000. (b) Cohen, M. D.; Schmidt, G. M. J.; Sonntag, F. I. J. Chem. Soc. 1964, 2000–2013. (c) Schmidt, G. M. J. J. Chem. Soc. 1964, 2014–2021. (d) Bregman, J.; Osaki, K.; Schmidt, G. M. J.; Sonntag, F. I. J. Chem. Soc. 1964, 2021–2030. (e) Rabinovich, D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 2030–2040. (f) Cohen, M. D.; Schmidt, G. M. J.; Flavian, S. J. Chem. Soc. 1964, 2041–2051. (g) Bregman, J.; Leiserowitz, L.; Schmidt, G. M. J. J. Chem. Soc. 1964, 2068–2085. (h) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647–678. (37) (a) Kr€ uger, C.; Nolte, M.; Erker, G.; Thiele, S. Z. Naturforsch., B 1992, 47, 995–999. (b) Knickmeyer, M.; Erker, G.; Fox, T. J. Am. Chem. Soc. 1996, 118, 9623–9630. (c) J€odicke, T.; Menges, F.; Kehr, G.; H€oweler, U.; Fr€ ohlich, R. Eur. J. Inorg. Chem. 2001, 2097–2106. (38) Greger, I.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Organometallics 2010, 29, 3210–3221.

363

Scheme 9

Scheme 10

24a in solution at ambient temperature resulted in a rapid ansa-metallocene formation by intramolecular [2 þ 2] cycloaddition. Eventually we reached a photostationary equilibrium favoring the bis(dimethylamino)cyclobutylene-bridged ansa-zirconocene dichloride isomer (26a:24a = 70:30). Complex 26a was also characterized by X-ray diffraction (the molecular structures of both of the isomers 24a and 26a are depicted on the cover of this issue of Organometallics). It features the cyclobutylene ansa bridge at the narrow back side of the bent-metallocene wedge, as would be expected from a [2 þ 2] cycloaddition of a respective local minimum conformational structure under “dynamic topochemical reaction control” (see Scheme 9). Photochemical ansa-metallocene formation by intramolecular photochemical [2 þ 2] cycloaddition under “dynamic topochemical control” is even more efficient in the case of zirconocene and hafnocene complexes bearing pairs of alkenyl groups at their Cp or indenyl rings. In these cases the nature of the R-substituents at the alkenyl groups is essential: small alkyl groups (CH3) and hydrogen lead to practically complete conversion to the respective ansa-metallocenes, whereas larger groups (e.g., cyclohexyl and aryl) may result in unfavorable photostationary equilibria.39 Typical examples for complete conversion to the ansa-zirconocenes are the systems 27 f 28 depicted in Scheme 10 and Figure 5.40 The photochemical cyclization of the corresponding (2alkenyl-indenyl)2ZrCl2 systems (29) to yield the ansa-bis(indenyl)ZrCl2 isomers (30) is even favorable for alkenyl R-substituents such as methyl, phenyl, and cyclohexyl (see Scheme 11). Interestingly, the system 30a (R = CH3) reacts with butadiene-magnesium to give a single (s-trans-η4-butadiene)-ansa-zirconocene isomer. From its 1H NMR spectrum it seems that it is stabilized by a pair of C-H/π-arene interactions between the butadiene “meso” hydrogen atoms and the covering phenylene units at the front side of the bentmetallocene wedge.41,42 (39) (a) Erker, G.; Wilker, S.; Kr€ uger, C.; Goddard, R. J. Am. Chem. Soc. 1992, 114, 10983–10984. (b) Erker, G.; Wilker, S.; Kr€uger, C.; Nolte, M. Organometallics 1993, 12, 2140–2151. (40) (a) Paradies, J.; Fr€ ohlich, R.; Kehr, G.; Erker, G. Organometallics 2006, 25, 3920–3925. (b) Paradies, J.; Kehr, G.; Fr€ohlich, R.; Erker, G. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 15333–15337. (c) Greger, I.; Kehr, G.; Fr€ohlich, R.; Erker, G. Organometallics 2010, 29, 860–866. (41) (a) Nie, W.-L.; Erker, G.; Kehr, G.; Fr€ ohlich, R. Angew. Chem. 2004, 116, 313-317; Angew. Chem., Int. Ed. 2004, 43, 310-313. (b) Chen, L.; Nie, W.-L.; Paradies, J.; Kehr, G.; Fr€ ohlich, R.; Wedeking, K.; Erker, G. Organometallics 2006, 25, 5333–5344.

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Figure 5. Views of the molecular structures of the open bis(vinyl-Cp)zirconium dichloride complex 27a (left) and its ansa-zirconocene isomer 28a (right). Scheme 11

Scheme 12

Figure 6. View of the cyclooctadienylene-bridged ansa-zirconocene complex 32.

The bis(butadienyl-Cp)ZrCl2 complex 31 shows a similar photolytic behavior. UV irradiation of the organometallic conjugated diene derivative in toluene at ambient temperature rapidly resulted in a clean conversion to the ansa-metallocene complex 32, formally by a [4 þ 4] cycloaddition reaction (see Scheme 12 and Figure 6).43 Photolysis of 31 at -80 °C (HPK 125, quartz filter) in dichloromethane gave slightly more complex product mixtures but allowed for a partial mechanistic clarification of the pathway taken in the formation of the eight-membered-ring product 32. Irradiation under these conditions gave two new products that were stable even at room temperature once they were formed. These are the organometallic ladderane 33 (see Scheme 13) and its isomer 34. Compound 33 always made ca. 35% of the total product mixture, but the amount of 34 varied (usually 90% at -95 °C in d8-THF). At this temperature a close to 1:1 mixture of the meso- and rac-42 diastereomers is present, according to the 7Li NMR spectrum. Photolysis of the solution of 42 at -90 °C (HPK125, quartz filter) resulted in a slow [2 þ 2] cycloaddition reaction to give a ca. 95% conversion to the carbon-carbon coupling product 43 after 3 days. This coupling reaction apparently takes place under dynamic topochemical reaction control. It is synthetically useful. Transmetalation by treatment with TiCl3 followed by oxidative chlorination eventually gave the cyclobutylenebridged ansa-titanocene dichloride product 44 as a mixture of the rac isomer (major) with one of the two meso-44 isomers (see Scheme 15 and Figure 7). This is a system that is not directly available photolytically at the bent-metallocene stage.

Frustrated Lewis Pairs in Metallocene Chemistry Frustrated Lewis pair (FLP) chemistry has seen a steep ascent in its development recently.10 It was shown that, for example, phosphorus or nitrogen bases46,47 bearing sufficiently bulky substituents in combination with, for example, bulky boron Lewis acids bearing strongly electron withdrawing C6F5 substituents often gave rise to very special situations of non-quenched coexisting Lewis base/Lewis acid (45) (a) Paquette, L. A.; Bauer, W.; Sivik, M. R.; B€ uhl, M.; Feigel, M.; von R. Schleyer, P. J. Am. Chem. Soc. 1990, 112, 8776–8789. (b) Kunz, K.; Pflug, J.; Bertuleit, A.; Fr€ohlich, R.; Wegelius, E.; Erker, G.; W€urthwein, E.-U. Organometallics 2001, 20, 392–400. (46) (a) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W. Science 2006, 314, 1124–1126. (b) Welch, G. C.; Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880–1881. (c) Spies, P.; Erker, G.; Bergander, K.; Fr€ohlich, R.; Grimme, S.; Stephan, D. W. Chem. Commun. 2007, 5072– 5074. (47) (a) Sumerin, V.; Schulz, F.; Nieger, M.; Leskel€a, M.; Repo, T.; Rieger, B. Angew. Chem. 2008, 120, 6090-6092; Angew. Chem., Int. Ed. 2008, 47, 6001-6003. (b) Sumerin, V.; Schulz, F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskel€a, M.; Repo, T.; Pyykk€ o, P.; Rieger, B. J. Am. Chem. Soc. 2008, 130, 14117–14119. (48) (a) Stephan, D. W. Org. Biomol. Chem. 2008, 6, 1535–1539. (b) Kenward, A. L.; Piers, W. E. Angew. Chem. 2008, 120, 38-42; Angew. Chem., Int. Ed. 2008, 47, 38-41.

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Organometallics, Vol. 30, No. 3, 2011 Scheme 16

Erker Scheme 17

Scheme 18

pairs in solution. Such frustrated Lewis pairs, as they were termed,48 may possess the ability to react cooperatively with a variety of substrates. This is extensively being used for small-molecule activation. Often quite unusual reactions are encountered. We have developed the chemistry of the intramolecular frustrated P/B Lewis pair (46).46c,49 It is readily obtained by anti-Markovnikov hydroboration of dimesitylvinylphosphine (45) with “Piers’ borane” [HB(C6F5)2].50 The system features a weakly interacting phosphine/borane pair49,51 that reacts with a variety of unsaturated substrates such as aldehydes, alkenes, conjugated enynes and diynes, and even with carbon dioxide to yield the adducts 47-51 (see Scheme 16).52 The FLP 46 splits dihydrogen heterolytically under ambient conditions to yield the zwitterionic phosphonium/hydridoborate system (52).49 The P/B pair currently is one of the most active metal-free hydrogen activation systems. It is able to transfer the Hþ/H- pair to a variety of substrates53 and has, consequently, been shown to be an active catalyst for the hydrogenation of, for example, enamines or imines.53,54 This can very favorably be used for applications in organmetallic chemistry, especially in cases where the use of appropriate reagents is prohibited due to the high sensitivity of the metal-containing substrates. The 46/52 system has been shown to be a good catalyst for the hydrogenation of the conformationally constrained conjugated dienamine units in a variety of metallocene systems. With sufficiently (49) Spies, P.; Kehr, G.; Bergander, K.; Wibbeling, B.; Fr€ ohlich, R.; Erker, G. Dalton Trans. 2009, 1534–1541. (50) (a) Parks, D. J.; Spence, R. E. v H.; Piers, W. E. Angew. Chem. 1995, 107, 895-897; Angew. Chem., Int. Ed. 1995, 34, 809-811. (b) Parks, D. J.; Piers, W. E.; Yap, G. P. A. Organometallics 1998, 17, 5492–5503. (51) See for a comparison: Axenov, K.; M€ omming, C. M.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Chem. Eur. J. 2010, 16, 14069-14073. (52) (a) M€ omming, C. M.; Fr€ omel, S.; Kehr, G.; Fr€ ohlich, R.; Grimme, S.; Erker, G. J. Am. Chem. Soc. 2009, 131, 12280–12289. (b) M€ omming, C. M.; Otten, E.; Kehr, G.; Fr€ohlich, R.; Grimme, S.; Stephan, D. W.; Erker, G. Angew. Chem. 2009, 121, 6770-6773; Angew. Chem., Int. Ed. 2009, 48, 6643-6646. (c) M€ omming, C. M.; Kehr, G.; Wibbeling, B.; Fr€ ohlich, R.; Schirmer, B.; Grimme, S.; Erker, G. Angew. Chem. 2010, 122, 2464-2467; Angew. Chem., Int. Ed. 2010, 49, 2414-2417. ohlich, R.; (53) Spies, P.; Schwendemann, S.; Lange, S.; Kehr, G.; Fr€ Erker, G. Angew. Chem. 2008, 120, 7654-7657; Angew. Chem., Int. Ed. 2008, 47, 7543-7546. (54) Wang, H.; Fr€ ohlich, R.; Kehr, G.; Erker, G. Chem. Commun. 2008, 5966–5968.

bulky amine groups present, we observed selective 1,4hydrogenation of the bridge in the [3]ferrocenophanes 53 to give the respective organometallic allylamines 54 in excellent yield under mild conditions.55 Even the dienamine bridge of the sensitive ansa-zirconocene complex 25a was selectively hydrogenated under nearly ambient conditions using this FLP catalyst system (see Scheme 17). It had been shown that bulky imines can serve both as Lewis base components in frustrated Lewis pairs and as substrates in FLP-catalyzed hydrogenation reactions.56 We have used this for an application in organometallic chemistry, where a quasi-autocatalytic reduction of imine units attached at a zirconocene dichloride framework was effected by addition of the strong and bulky B(C6F5)3 Lewis acid and dihydrogen.57 The group 4 bent metallocene imine 57 was synthesized by in situ deprotonation of the 6-aminofulvene reagent 56 with Cl2Zr(NMe2)2(THF)2. Liberation of dimethylamine furnished the doubly imine functionalized (55) Schwendemann, S.; Tumay, A. T.; Axenov, K. V.; Peuser, I.; Kehr, G.; Fr€ ohlich, R.; Erker, G. Organometallics 2010, 29, 1067–1069. (56) (a) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008, 1701–1703. (b) Chen, D.; Klankermayer, J. Chem. Commun. 2008, 2130– 2131. (c) Geier, S. J.; Chase, P. A.; Stephan, D. W. Chem. Commun. 2010, 46, 4884–4886. (57) (a) Axenov, K. V.; Kehr, G.; Fr€ ohlich, R.; Erker, G. J. Am. Chem. Soc. 2009, 131, 3454–3455. (b) Axenov, K. V.; Kehr, G.; Fr€ohlich, G.; Erker, G. Organometallics 2009, 28, 5148–5158.

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Organometallics, Vol. 30, No. 3, 2011

Figure 8. View of the molecular structure of the product 58. Scheme 19

Scheme 20

zirconocene complex 57 in >60% yield. Addition of a substoichiometric quantity of B(C6F5)3 gave a frustrated Lewis pair. Exposure of the system to dihydrogen (2 bar, room temperature, toluene) resulted in catalytic imine hydrogenation to yield the zirconocene-amine product 58 in good yield (see Scheme 18 and Figure 8). Under the applied reaction conditions the remaining B(C6F5)3 Lewis acid reacted further with the product 58, which now served as a bulky FLP Lewis base, and hydrogen to yield the salt 59. Total addition of 2 mol equiv of the B(C6F5)3 Lewis acid (plus dihydrogen) eventually gave the zirconocene bisammonium dication product 60 (with [HB(C6F5)3-] counteranions). The salt 60 itself turned out to be a suitable catalyst for the catalytic reduction of bulky imines and of sufficiently bulky silyl enol ethers. We recently started to explore the limits of frustrated Lewis pair behavior. For that reason we needed to attach the strongly Lewis acidic -B(C6F5)2 functionality to group 4

367

Figure 9. Molecular structure of the zirconocene-based P/B Lewis pair 68.

bent-metallocene frameworks. Initial experiments employing alkynyl substituents at the metallocene frameworks as starting points were met with selectivity problems. As a typical example the hydroboration of the bis(propynylindenyl)-ZrCl2 complex 61 with HB(C6F5)2 was rapid but not sufficiently regioselective to be useful for our purposes.58 The formation of a substantial amount of the Markovnikov oriented addition products was a serious complication (see Scheme 19). Hydroboration of pendant allyl substituents attached at the Cp ring was regioselective. Thus, treatment of the alkenyl-functionalized zirconium complex 63 with 9-BBN furnished the anti-Markovnikov product 64. At 90 °C complex 64 reacted further by intramolecular alkyl abstraction/ readdition to yield the product 66, with cleavage of Me-BBN (see Scheme 20).59 We then prepared the doubly functionalized zirconocene complex 67 by treatment of (allyl-Cp)ZrCl3 3 dme with the [Cp-PtBu2]Li reagent. Subsequent hydroboration with Piers’ borane went smoothly to yield the respective anti-Markovnikov product 68. This is a frustrated Lewis pair devoid of any measurable P/B interaction. In the crystal the bulky -PtBu2 and -B(C6F5)2 groups are found separated from each other at an almost maximum distance (see Figure 9).60 Here we have arrived at an extreme situation of a frustrated Lewis pair. The P/B pair does not show the usual cooperative behavior when treated with a terminal acetylene. The reaction of 68 with 1-pentyne took place exclusively at the -B(C6F5)2 functionality. We observed a rapidly proceeding 1,1-carboboration reaction to take place at room temperature in toluene. It is selectively the boron-bound alkyl group that undergoes migration from boron to carbon. The reaction is not stereoselective, and we have obtained a close to equimolar mixture of the products (Z)-69 and (E)-69 (see Scheme 21). Participation of the phosphine was excluded by the observation that the related phosphine-free borylzirconocene system 70 underwent the analogous 1,1-carboboration reaction with 1-pentyne under similar conditions to give a (Z)-71 þ (E)-71 product mixture in good yield.60 (58) Chen, L.; Kehr, G.; Fr€ ohlich, G.; Erker, G. Eur. J. Inorg. Chem. 2008, 73–83. (59) Emmert, M.; Kehr, G.; Fr€ ohlich, G.; Erker, G. Chem. Eur. J. 2009, 15, 8124–8127. (60) Chen, C.; Eweiner, F.; Wibbeling, B.; Fr€ ohlich, R.; Senda, S.; Ohki, Y.; Tatsumi, K.; Grimme, S.; Kehr, G.; Erker, G. Chem. Asian J. 2010, 5, 2199–2208. (61) (a) Wrackmeyer, B. Coord. Chem. Rev. 1995, 145, 125–156. (b) Wrackmeyer, B. Heteroat. Chem. 2006, 17, 188–208 and references cited therein.

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Organometallics, Vol. 30, No. 3, 2011 Scheme 21

Erker

boration reaction with tolane under forcing conditions (125 °C, 9 days) to give the product 73 in good yield.63 During this process a non-activated C-C bond is broken64 and we have observed exclusively methyl migration from boron to carbon. The product 73 was employed in crosscoupling to yield a tetrasubstituted alkene.

Conclusions

Scheme 22

We used this new variant of the 1,1-carboboration reaction61 to prepare trisubstituted alkenes from terminal alkynes. As a typical example, simple stirring of phenylacetylene with B(C6F5)3 in pentane at room temperature gave a mixture of (E)- and (Z)-72 in good yield (Scheme 22).60,62 We employed the alkenyl boranes as reagents in Pd-catalyzed SuzukiMiyaura type cross-coupling reactions. This reaction type could even be developed into a novel type of carbon-carbon bond activation process. Typically, the borane CH3-B(C6F5)2 underwent a selective 1,1-carbo(62) See also: (a) Binnewirtz, R.-J.; Klingenberger, H.; Welte, R.; Paetzold, P. Chem. Ber. 1983, 116, 1271–1284. (b) Jiang, C.; Blacque, O.; Berke, H. Organometallics 2010, 29, 125–133.

Organic functional group chemistry at the group 4 bent metallocenes is difficult. Many classical reagents and reaction conditions are not compatible with the typical features of these early d-metal compounds. Aqueous conditions lead to attack at the metal (often with μ-oxo-bis(metallocene) complex formation), and a variety of other nucleophiles attack the weakly electrophilic metal center in these complexes as well. Protic reagents as well as radicals tend to induce Cp-M cleavage. From this background the variety of successful methods described here had to be adapted, and it was shown that there is a good chance to carry out useful organic functional group conversions at the bent-metallocene stage. This has opened easy systematic access to a variety of useful organometallic systems but at the same time has led to the discovery of a variety of new reactions or new and useful variants, something we had hoped for but which was difficult to plan in detail.

Acknowledgment. The work described in this article was carried out by a group of very talented and dedicated co-workers and collaborators. Their names are listed in the respective literature references. We all have enjoyed tremendously working together on these projects in the nice and stimulating atmosphere in the Organic Chemistry Institute of the Universit€at M€ unster. I cordially thank all of them for their great contributions. Special thanks goes to Dr. Roland Fr€ ohlich (X-ray) and Dr. Gerald Kehr (NMR and much more), who were extensively involved in most of the work. Financial support from the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Alexander von Humboldt-Stiftung is gratefully acknowledged. I thank the Gesellschaft Deutscher Chemiker for their appreciation of the research carried out by my group over many years by awarding me the Adolf-von-Baeyer-Denkm€ unze; this event eventually led to the writing of this article. (63) Chen, C.; Kehr, G.; Fr€ ohlich, R.; Erker, G. J. Am. Chem. Soc. 2010, 132, 13594–13595. (64) See also: Fan, C.; Piers, W. E.; Parvez, M.; McDonald, R. Organometallics 2010, 29, 5132–5139.