Ortho-Palladation of (Z)-2-Aryl-4-Arylidene-5(4H ... - ACS Publications

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Organometallics 2010, 29, 1428–1435 DOI: 10.1021/om901068f

Ortho-Palladation of (Z)-2-Aryl-4-Arylidene-5(4H)-Oxazolones. Structure and Functionalization )

Gheorghe-Doru Roiban,†,‡ Elena Serrano,§ Tatiana Soler,^ Maria Contel, Ion Grosu,† Carlos Cativiela,‡ and Esteban P. Urriolabeitia*,§ †

)

Organic Chemistry Department, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, Arany Janos 11, 400028 Cluj-Napoca, Romania, ‡Departamento de Quı´mica Org
anica, Instituto de Ciencia de Materiales de Arag
on, CSIC-Universidad de Zaragoza, 50009 Zaragoza, Spain, §Departamento de Compuestos Organomet
alicos, Instituto de Ciencia de Materiales de Arag
on, CSIC-Universidad de Zaragoza, c/Pedro Cerbuna 12, 50009 Zaragoza, Spain, ^Servicios T
ecnicos de Investigaci
on, Facultad de Ciencias Fase II, 03690 San Vicente de Raspeig, Alicante, Spain, and Chemistry Department, Brooklyn College and The Graduate Center (CUNY), 2900 Bedford Avenue, Brooklyn, New York 11210 Received December 14, 2009

Ortho-palladated complexes of (Z)-2-aryl-4-arylidene-5(4H)-oxazolones have been prepared through oxidative addition. The reaction of (Z)-2-phenyl-4-(2-bromobenzylidene)-5(4H)-oxazolone (4) with Pd2(dba)3 3 CHCl3 gives the six-membered cyclopalladated dinuclear complex [Pd(μ-Br)(o-C6H4CHdCNC(O)OCPh)]2 (7). The reaction of 7 with PPh3 gives dinuclear 9, which incorporates one phosphine per Pd atom through cleavage of the Pd-N bond, and preserves the bromide bridging system. However, reaction with PPh2Me gives mononuclear 8, which incorporates two phosphines as a results of the cleavage of the μ-Br system and N displacement. In contrast, the reaction of 7 with pyridine gives complex 12 due to simple cleavage of the Br bridge, leaving the N-bonding intact. Therefore, three different reaction pathways have been characterized. The reactivity of the Pd-C bond in 7 has also been examined, and functionalized oxazolones can be obtained. The reaction of 7 with PhI(OAc)2 in acetic acid gives the starting oxazolone C6H4-2-Br-CHdCNC(O)OCPh (4), through the presumed oxidation of the Pd center and C-Br bond formation by reductive coupling. In contrast, the reaction of the acetate dimer 14 with PhI(OAc)2 in acetic acid gives C6H4-2-OAcCHdCNC(O)OCPh (20) through C-O coupling. When treatment of 7 with PhI(OAc)2 is performed in MeOH or EtOH, the oxazolones C6H4-2-OR-CHdCNC(O)OCPh (R = Me (18), Et (19)) are obtained. The reaction of 7 with CO in alcohols ROH gives cleanly the oxazolones C6H4-2-CO2RCHdCNC(O)OCPh (R = Me (21), iPr (22)) through CO migratory insertion into the Pd-C bond and further nucleophilic attack of the RO- fragment.

Introduction Ortho-palladated complexes1 are considered to be useful reagents in a variety of chemical transformations, most of them being Pd-mediated catalytic or stoichiometric organic *To whom correspondence should be addressed. Fax: (þ34) 976761187. E-mail: [email protected]. (1) Urriolabeitia, E. P. in Palladacycles: Synthesis, Characterization and Applications; Dupont, J., Pfeffer, M. Eds.; Wiley-VCH: Weinheim, Germany, 2008; Chapter 3: Oxidative Addition and Transmetallation. (2) Selected recent reviews on ortho palladation: (a) Dupont, J.; Consorti, C.; Spencer, J. Chem. Rev. 2005, 105, 2527. (b) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041. (c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036. (d) Omae, I. J. Organomet. Chem. 2007, 692, 2608. (e) Nishiyama, H. Chem. Soc. Rev. 2007, 36, 1133. (f) Gagliardo, M.; Snelders, D. J. M.; Chase, P. A.; Klein Gebbink, R. J. M.; van Klink, G. P. M.; van Koten, G. Angew. Chem., Int. Ed. 2007, 46, 8558. (g) Horino, Y. Angew. Chem., Int. Ed. 2007, 46, 2144. (h) Ma, L.; Wong, E. L.-M.; Che, C.-M. Dalton Trans. 2007, 4884. (i) Chatani, N. In Directed Metallation; Springer: New York, 2007; Topics in Organometallic Chemistry 24. (j) Leis, W.; Mayera, H. A.; Kaska, W. C. Coord. Chem. Rev. 2008, 252, 1787. (k) Djukic, J. P.; Hijazi, A.; Flack, H. D.; Bernardinelli, G. Chem. Soc. Rev. 2008, 37, 406. (l) Djukic, J. P.; Sortais, J. B.; Barloy, L.; Pfeffer, M. Eur. J. Inorg. Chem. 2009, 817. (m) Albrecht, M. Chem. Rev. 2010, 110, 576. (n) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. pubs.acs.org/Organometallics

Published on Web 02/22/2010

processes. Other applications have focused on their use in optical devices, biological applications, and other interesting properties.1 The most important method for the synthesis of ortho-palladated complexes is C-H bond activation,1-3 mainly at an aromatic ring. This reaction has been extensively studied, since it is a fundamental step in the catalytic or stoichiometric ortho functionalization of a large diversity of (3) Selected recent reviews on CH bond activation and applications: (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (c) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924. (d) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (e) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (f) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (g) Thansandote, P.; Lautens, M. Chem. Eur. J. 2009, 15, 5874. (h) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (i) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (j) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (k) Storr, T. E.; Baumann, C. G.; Thatcher, R. J.; De Ornellas, S.; Whitwood, A. C.; Fairlamb, I. J. S. J. Org. Chem. 2009, 74, 5810. (l) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243. (m) Vedernikov, A. N. Chem. Commun. 2009, 4781. (n) Mu~niz, K. Angew. Chem., Int. Ed. 2009, 48, 9412. (o) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20. (p) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (q) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. r 2010 American Chemical Society

Article

Organometallics, Vol. 29, No. 6, 2010 Scheme 1.a

a

R1 = Br, R2 = H (4), R1 = H, R2 = Br (5), R1 = H, R2 = I (6).

organic substrates.2-16 The C-H bond activationfunctionalization methodology allows the formation of a wide range of C-X bonds (X = C, O, N, S, P, halogen), and the regiospecific addition of a large number of functional groups to a given substrate has been achieved. In this context, methyl,4 acetate and/or methoxy,5 arylsulfonyl,6 ethoxycarbonyl,7 halogen,8 amide9 or amine,10 alkynyl,11 alkenyl,12 acyl,13 and aryl14 functional groups, as well as intramolecular cyclization processes15 and mechanistic studies,16 have been reported. (4) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (5) (a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. (b) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285. (c) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 17050. (6) Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466. (7) Yu, W. Y.; Sit, W. N.; Lai, K. M.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (8) (a) Wang, X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520. (b) Li, J. J.; Mei, T. S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452. (c) Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142. (d) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (e) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (9) (a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (b) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagn
e, M. R.; LloydJones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. (10) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S. Organometallics 2007, 26, 1365. (11) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (12) (a) Rauf, W.; Thompson, A. L.; Brown, J. M. Chem. Commun. 2009, 3874. (b) Lee, G. T.; Jiang, X.; Prasad, K.; Repic, O.; Blacklock, T. J. Adv. Synth. Catal. 2005, 347, 1921. (13) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120. (14) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651. (b) Li
egault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826. (c) Campeau, L. C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (d) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (e) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570. (f) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (g) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211. (h) Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947. (i) Daugulis, O.; Zaitsev, V. G.; Shavashov, D.; Pham, Q. N.; Lazareva, A. Synlett 2006, 3382. (j) Scarborough, C. C.; McDonald, R. I.; Hartmann, C.; Sazama, G. T.; Bergant, A.; Stahl, S. S. J. Org. Chem. 2009, 74, 2613. (k) Zhou, H.; Chung, W.-J.; Xu, Y.-H.; Loh, T.-P. Chem. Commun. 2009, 3472. (l) Zhou, H.; Xu, Y.-H.; Chung, W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 5355. (m) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 4720. (n) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (o) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047. (15) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Mu~niz, K. J. Am. Chem. Soc. 2007, 129, 14542. (c) Wu, L.; Qiu, S.; Liu, G. Org. Lett. 2009, 11, 2707. (d) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 2337. (e) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792. (f) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Chem. Eur. J. 2009, 15, 7292. (g) Murai, M.; Miki, K.; Ohe, K. Chem. Commun. 2009, 3466. (16) (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790. (b) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 10974. (c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651. (d) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234.

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We present here the synthesis of ortho-palladated unsaturated 5(4H)-oxazolones. These compounds are relevant organic precursors and intermediates in the preparation of heterocyclic compounds of pharmacological interest, more specifically in the synthesis of amino acids.17 Saturated 5(4H)-oxazolones are easily obtained from N-acylamino acids, and they have been used in coupling reactions as synthetic equivalents of R-amino acids in the synthesis of peptides. Asymmetric alkylation reactions have been reported in the enantioselective synthesis of acyclic R,R-quaternary amino acids.18 Unsaturated 5(4H)-oxazolones have been known for years. Many applications have been found for these compounds, and the reactivity of the exocyclic double bond makes them especially attractive intermediates for the asymmetric synthesis of non-proteinogenic amino acids.19 In spite of the extensive chemistry developed with 5(4H)-oxazolones, ortho-metalated complexes are restricted to Ir and Pd examples with saturated precursors,20 while metalated unsaturated 5(4H)-oxazolones are unknown. Only very recently have we reported21a the first example of ortho palladation of unsaturated 5(4H)-oxazolones. Due to the interest in unsaturated 5(4H)-oxazolones as strategic intermediates, we have studied the ortho palladation of a special class of oxazolones, namely the (Z)-2-aryl-4arylidene-5(4H)-oxazolones. Our aim was to provide an alternative synthetic route to their functionalization, complementary to classical organic methods. We have recently employed this strategy for the successful functionalization of R-amino acids.21b Gratifyingly, we have found in the present case that the regioselective modification of the ortho position of the arylidene ring in oxazolones is easily achievable. This fact could provide a selective reaction path to high added value modified amino acids that are not easily prepared by conventional methods.

Results and Discussion 1. Synthesis of the 5(4H)-Oxazolones. Our first step was to find the reactive positions of the oxazolones, since two aryl rings can be palladated. Surprisingly, the simplest case (Scheme 1, R1 = R2 = H)22 showed a total lack of reactivity (17) (a) Cativiela, C.; Dı´ az-de-Villegas, M. D. In The Chemistry of Heterocyclic Compounds; Palmer, D. C., Ed.; Wiley: New York, 2004; Vol. 60, p 129. (b) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev. 2007, 36, 1432. (c) Boyd, G. V. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.; Pergamon Press: Oxford, U.K., 1984; Vol. 6, pp 177-234. (d) Hartner, F. W., Jr. In Comprehensive Heterocyclic Chemistry II; Shinkai, I., Ed.; Pergamon Press: Oxford, U.K., 1996; Vol. 3, p 261. (e) Rao, Y. S.; Filler, R. Oxazoles. In The Chemistry of Heterocyclic Compounds; Turchi, I. J., Ed.; Wiley: New York, 1986; Vol. 45, p 363. (18) (a) Mosey, R. A.; Fisk, J. S.; Friebe, T. L.; Tepe, J. J. Org. Lett. 2008, 10, 825. (b) Cabrera, S.; Reyes, E.; Alem
an, J.; Milelli, A.; Kobbelgaard, S.; Joergensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031. (19) (a) Cativiela, C.; Dı´ az-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517. (b) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645. (c) Cativiela, C.; Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569. (d) Cativiela, C.; Ord
o~nez, M. Tetrahedron: Asymmetry 2009, 20, 1. (20) (a) Bauer, W.; Prem, M.; Polborn, K.; Suenkel, K.; Steglich, W.; Beck, W. Eur. J. Inorg. Chem. 1998, 485. (b) Bauer, W.; Polborn, K.; Beck, W. J. Organomet. Chem. 1999, 579, 269. (c) Skapski, A. C.; Smart, M. L. J. Chem. Soc., Chem. Commun. 1970, 658. (21) (a) Roiban, D.; Serrano, E.; Soler, T.; Grosu, I.; Cativiela, C.; Urriolabeitia, E. P. Chem. Commun. 2009, 4681. (b) Nieto, S.; Arnau, P.; Serrano, E.; Navarro, R.; Soler, T.; Cativiela, C.; Urriolabeitia, E. P. Inorg. Chem. 2009, 48, 11963. (22) (a) King, S. W.; Riordan, J. M.; Holt, E. M.; Stammer, C. H. J. Org. Chem. 1982, 47, 3270. (b) Hamidian, H.; Tikdari, A. M. Heterocycl. Commun. 2006, 12, 29.

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Roiban et al.

Scheme 2. Synthesis of 7a

Scheme 3.a

a Reagents and conditions: CH2Cl2 or toluene, room temperature, 24 h, Ar.

toward the most usual palladating reagents (Pd(OAc)2, Li2[PdCl4], etc.) under standard conditions.21a Looking for alternative methods, we focused our attention on oxidative addition processes,1 for which halogen-substituted (Z)-2aryl-4-arylidene-5(4H)-oxazolones had to be prepared (Scheme 1, 4-6). Compounds 4-6 were synthesized by the Erlenmeyer reaction.23 This method involves the condensation of N-benzoylglycine with a carbonyl compound, in the presence of a cyclodehydrating agent such as acetic anhydride. While 1 is commercially available, N-2-bromobenzoylglycine24 (2) and N-2-iodobenzoylglycine25 (3) had to be prepared (Supporting Information). Although two geometric isomers are possible for 4-6, the Erlenmeyer synthesis proceeds stereoselectively, favoring the thermodynamically more stable Z isomer, which is easily isolated by recrystallization.26a,b Additional arguments are referenced to mass spectra26c and to previous determinations of X-ray molecular structures of related oxazolones.27 2. Synthesis of Six-Membered Palladacycles. The reaction of 4 with Pd2(dba)3 3 CHCl328 gives the dinuclear complex 7, as depicted in Scheme 2. The reaction occurs under very mild conditions, affording high yields of 7, which is isolated as a greenish yellow solid. The mass spectrum of 7 is in good agreement with a dimeric structure, the most abundant ion being the protonated molecule which loses a bromide [M - Br]þ at m/z 788.9. The lack of solubility of 7 precludes its characterization in solution by NMR methods, but the evidence of its dimeric nature was obtained from its reactivity, shown in Schemes 3 and 4. The reaction of 7 with PPh2Me (1:2 molar ratio) failed to give a unique reaction product. An increase in the molar ratio 7:PPh2Me (1:4.5) gives a single compound, characterized as 8 (Scheme 3). The 1H NMR spectrum of 8 suggests a monomeric structure in which the two phosphine ligands are (23) Erlenmeyer, E. Ber. Dtsch. Chem. Ges. 1900, 33, 2036. (24) (a) Raiford, L. C.; Buurman, C. H. J. Org. Chem. 1943, 8, 466. (b) Novello, N. J.; Miriam, S. R.; Sherwin, C. P. J. Biol. Chem. 1926, 67, 555. (25) (a) Barcelo-Oliver, M.; Terr
on, A.; Garcia-Raso, A.; Molins, E. Polyhedron 2007, 26, 1417. (b) Barcelo-Oliver, M.; Garcia-Raso, A.; Terr
on, A.; Molins, E.; Prieto, M. J.; Moreno, V.; Martinez, J.; Llad
o, V.; L
opez, I.; Guti
errez, A.; Escriba, P. V. J. Inorg. Biochem. 2007, 101, 649. (c) BarceloOliver, M.; Terr
on, A.; Garcia-Raso, A.; Fiol, J. J.; Molins, E.; Miravitlles, C. J. Inorg. Biochem. 2004, 98, 1703. (26) (a) Kumar, K.; Phelps, D. J.; Careg, P. R. Can. J. Chem. 1978, 56, 232. (b) Prokofev, E. P.; Kapeiskaya, E. I. Tetrahedron Lett. 1979, 20, 737. (c) Curcuruto, O.; Traldi, P.; Cativiela, C.; Díaz-de-Villegas, M. D.; Garcia, J. I.; Mayoral, J. A.; Ajo, D. J. J. Heterocycl. Chem. 1990, 27, 1495. (27) (a) Haasbroek, P. P.; Oliver, D. W.; Carpy, A. M. J. J. Mol. Struct. 2003, 648, 61. (b) Busetti, V.; Mayoral, J. A.; Cativiela, C.; Díaz-deVillegas, M. D.; Ajo, D. Z. Kristallogr. 1989, 189, 65. (c) Bowden, K.; Perjessy, A.; Benko, J.; Fabian, W. M. F.; Kolehmainen, E.; Melikian, G. S.; Hritzova, O.; Laihia, K.; Vollarova, O.; Tapuzian, V. O.; Kiriakossian, N.; Nissinen, M. J. Chem. Res. (S) 2002, 7, 309. (28) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J. Organomet. Chem. 1974, 65, 253.

a

Reagents and conditions: (i) PPh2Me, CH2Cl2, room temperature; (ii) PPh3, CHCl3, room temperature; (iii) PPh3, MeOH, Δ; (iv) PPh3, MeOH, Δ; (v) Tl(acac), CHCl3, room temperature, 2 h.

Scheme 4.a

a

Reagents and conditions: (i) py, CH2Cl2, room temperature; (ii) py, MeOH, room temperature; (iii) CH3COOAg, CH2Cl2, 12 h, room temperature; (iv) AgClO4, CH3CN.

mutually trans, since the methyl protons appear as triplets, due to virtual coupling (JPH = 3.4 Hz), and the oxazolone is η1-coordinated. However, the reaction of 7 with PPh3 in a 1:2

Article

Figure 1. Molecular drawing of 9. Selected bond distances (A˚) and angles (deg): Pd(1)-C(1), 2.007(6); Pd(1)-P(1), 2.249(5); Pd(1)-Br(1A), 2.522(6); Pd(1)-Br(1), 2.5582(15); C(1)Pd(1)-P(1), 88.52(19); C(1)-Pd(1)-Br(1A), 87.72(18); P(1)Pd(1)-Br(1A), 175.28(5); C(1)-Pd(1)-Br(1), 173.01(17); P(1)-Pd(1)-Br(1), 96.52(10); Br(1A)1-Pd(1)-Br(1), 87.47(8); Pd(1A)1-Br(1)-Pd(1), 92.53(8).

molar ratio affords the unique soluble product 9, characterized by X-ray methods. A drawing of the molecular structure and selected bond distances and angles of 9 are shown in Figure 1. The structure shows a dimeric skeleton in which two Pd atoms are bridged by two bromides, forming a Pd2(μ-Br)2 moiety. Each Pd center completes its coordination sphere by bonding to a phosphine and to a η1-aryl ligand. The connectivity in this structure is noteworthy, since it contains simultaneously a bromide bridging system and a potential C, N-chelating ligand. This means that the incoming phosphine promotes the displacement of the N atom of the oxazolone instead to the cleavage of the Pd(μ-Br)2Pd bridge. Consequently, the stabilization by chelating effect of the palladated oxazolone should be small, probably indicating a weak bonding of the N to the Pd atom. This reactivity of ortho-palladated dimers toward L ligands (1:2 molar ratio) is unprecedented, since it is well established that the reaction of ortho-palladated halide-bridged dimers [Pd(μ-X)(C∧N)]2 with neutral monodentate ligands L affords mononuclear [PdX(C∧N)L] species, through symmetrical cleavage of the bridge, where the L ligand is trans to the N atom.29 The oxazolone ligand is normal to the coordination plane, this fact being shown by the dihedral angle between the best least-squares planes defined by the Pd(1)P(1)-Br(1) atoms and all atoms contained in the oxazolone (89.53(15)). Other parameters do not show deviations with respect to reported values in similar structures.30 The cleavage of the bromide bridge in 7, affording monomer 10, occurred under harsher conditions, when excess PPh3 was added to 7 (1:4 molar ratio) and the mixture was refluxed in methanol for 1 h. Complex 10 can also be obtained in two steps by further treatment of 9 with PPh3 (1:2 molar ratio) in refluxing methanol. While the chelation of the palladated oxazolone is not retained with the addition of soft phosphine ligands, we have (29) Deeming, A. J.; Rothwell, I. P.; Hursthouse, M. B.; New, L. J. Chem. Soc., Dalton Trans. 1978, 1490. (30) (a) Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D. G.; Taylor, R. J. Chem. Soc., Dalton Trans. 1989, S1. (b) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1.

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Figure 2. Molecular drawing of 14. Selected bond distances (A˚) and angles (deg): Pd(1)-C(1), 1.9741(16); Pd(1)-N(1), 2.0378(14); Pd(1)-O(3), 2.0455(11); Pd(1)-O(4), 2.1268(11); C(1)-Pd(1)N(1), 91.71(6); C(1)-Pd(1)-O(3), 90.49(6); N(1)-Pd(1)-O(3), 177.42(5); C(1)-Pd(1)-O(4), 172.16(5); N(1)-Pd(1)-O(4), 95.54(5); O(3)-Pd(1)-O(4), 82.34(5).

found that it is stable toward the bonding of harder ligands, such as acetylacetonate (acac), acetate, acetonitrile, and pyridine. Therefore, 7 reacts with Tl(acac) (1:2 molar ratio) to give the acetylacetonate 11 (Scheme 3). On the other hand, the reaction of 7 with pyridine (1:2 molar ratio) produces the clean cleavage of the bromide bridge affording 12 (Scheme 4). The py bonding trans to the N atom of the oxazolone is inferred from the anisotropic shielding of the H60 0 signal, this only being possible if the oxazolone acts as a chelate ligand and, therefore, lies in the molecular plane. An additional argument in favor of the mononuclear structure of 12 comes from a comparison of the diffusion coefficients of 11 and 12. Diffusion ordered spectroscopy (DOSY) has proved to be a valuable tool for the determination of relative molecular sizes in solution.32 The D (m2 s-1) value for 11 (acac as ancillary ligand, assumed as mononuclear) is 8.94  10-10 (2 mM, CDCl3, 300 K, δ = 2.3 ms, Δ = 100 ms). This value fits very well with that determined for complex 12 (8.59  10-10 m2 s-1), measured under the same experimental conditions, suggesting the same nuclearity in both cases. 7 reacts with excess py under harsher conditions (MeOH, Δ), giving 13 through dimer cleavage, bonding of two pyridines to each Pd, and opening of the oxazolone ring through methanolysis. The metathesis of the bromide ligands by acetate, achieved by reaction of 7 with AgOAc (1:2 molar ratio), gives the dimer 14, characterized by X-ray diffraction. Figure 2 shows a molecular drawing of 14 and the most relevant bond distances and angles. As is clear from the structure shown in Figure 2, each Pd atom is bonded to the N(1) atom and to the ortho benzylidenic C(1) atom of the oxazolone, and two ortho-palladated oxazolones are connected by two bridging acetate ligands in an “open-book” arrangement.33 (31) Forni
es, J.; Martı´ nez, F.; Navarro, R.; Urriolabeitia, E. P. J. Organomet. Chem. 1995, 495, 185. (32) (a) Pregosin, P. S.; Anil Kumar, P. G.; Fern
andez, I. Chem. Rev. 2005, 105, 2977. (b) Antalek, B. Concepts Magn. Reson. 2002, 14, 225. (c) Hodge, P.; Monvisade, P.; Morris, G. A.; Preece, I. Chem. Commun. 2001, 239. (33) Gorunova, O. N.; Keuseman, K. J.; Goebel, B. M.; Kataeva, N. A.; Churakov, A. V.; Kuz’mina, L. G.; Dunina, V. V.; Smoliakova, I. P. J. Organomet. Chem. 2004, 689, 2382.

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Figure 3. Molecular drawing for 15. Selected bond distances (A˚) and angles (deg): Pd(1)-C(1), 1.991(3); Pd(1)-N(2), 2.000(2); Pd(1)-N(1), 2.024(2); Pd(1)-N(3), 2.120(2); C(1)Pd(1)-N(1), 90.27(10); C(1)-Pd(1)-N(2), 89.06(10); N(2)Pd(1)-N(1), 175.30(9); C(1)-Pd(1)-N(3), 173.48(9); N(2)Pd(1)-N(3), 87.72(9); N(1)-Pd(1)-N(3), 92.46(8).

The relative disposition of the two palladated oxazolones is anti, in order to minimize intramolecular interactions. The open-book structure forces the two Pd centers to be in close proximity, and the Pd(1)-Pd(1A) distance in 14 is 2.9357(8) A˚, a value shorter than the sum of the van der Waals radii (3.26 A˚).34 Other parameters fall in the usual ranges found in the literature.30 Finally, the reaction of 7 with AgClO4 (1:2 molar ratio) in NCMe gives the unstable bis-solvate 15, as depicted in Scheme 4. The spectroscopic data obtained for 15 are consistent with the proposed formula,35 and additional information is provided by its X-ray structure determination. A molecular drawing and selected bond distances and angles for 15 are shown in Figure 3. The structure shows a mononuclear complex in which the Pd atom is bonded to a C,Nchelated oxazolone and to two acetonitriles. The oxazolone shows a boat conformation, with a dihedral angle between the best least-squares planes defined by N(1)-Pd(1)-C(1) and C(6)-C(7)-C(8) of 34.71(3). The Pd(1)-N(2) (2.000(2) A˚) and Pd(1)-N(3) bond lengths (2.120(2) A˚) are quite different, due to the large trans influence of the aryl carbon, compared with that of the iminic N(1), although both of them are within the range reported for related situations.30,36 Other internal parameters of the ligand are as expected. 3. Attempts To Prepare Five-Membered Palladacycles. We have shown that the oxidative addition is an efficient method to prepare ortho-palladated derivatives from oxazolones incorporating the metal at the benzylidene ring. Therefore, we have also attempted the preparation of fivemembered rings using the same strategy. Initial treatment of (Z)-2-(2-bromophenyl)-4-benzylidene-5(4H)-oxazolone (5) with [Pd2(dba)3 3 CHCl3] gave unreacted oxazolone and black Pd. This was somewhat unexpected, since the oxidative addition products of 4 were successfully prepared. Therefore, we modified slightly our strategy by changing the starting Pd source to [Pd(PPh3)4] and the starting oxazolone (34) Bondi, A. J. Phys. Chem. 1964, 68, 441. (35) Jensen, R. S.; Umeda, K.; Okazaki, M.; Ozawa, F.; Yoshifuji, M. J. Organomet. Chem. 2007, 692, 286. (36) Adrian, R. A.; Broker, G. A.; Tiekink, E. R. T.; Walmsley, J. A. Inorg. Chim. Acta 2008, 361, 1261.

Roiban et al.

Figure 4. Molecular drawing for 17. Selected bond distances (A˚) and angles (deg): Pd(1)-C(1), 1.994(5); Pd(1)-P(1), 2.3306(13); Pd(1)-P(2), 2.3389(12); Pd(1)-I(1), 2.6682(5); C(1)-Pd(1)-P(1), 85.51(13); C(1)-Pd(1)-P(2), 88.56(13); P(1)-Pd(1)-I(1), 90.54(3); P(2)-Pd(1)-I(1), 94.41(3). Scheme 5.a

a Reagents and conditions: (i) Pd2(dba)3 3 CHCl3, PPh3, CHCl3, room temperature, 2 h; (ii) PPh3, CHCl3, room temperature, 10 min.

to iodide 6 (Scheme 1). Iodide-containing substrates are the best choice to attempt an oxidative addition, as has been previously outlined.37 Under these conditions, 6 reacts with Pd2dba3 and PPh3 (2:1:8 molar ratio), giving the insoluble yellow greenish solid 16, whose plausible structure is shown in Scheme 5. Complex 16 was insoluble in common solvents, making its solution characterization unfeasible. Therefore, the structure is proposed by analogy with 9 (the N atom is not bonded in the presence of phosphines) and by subsequent reactivity. In fact, treatment of 16 with PPh3 (1:4 molar ratio) in CHCl3 affords soluble 17 through a typical cleavage of a halide bridging system. The X-ray structure determination of 17 confirmed the proposal shown in Scheme 5. Figure 4 gives a molecular drawing and collects selected bond distances and angles. The structure shows the usual distorted-squareplanar environment for the Pd(II) center. The Pd atom is (37) (a) Roy, A. M.; Hartwig, J. F. Organometallics 2004, 23, 194. (b) Alc
azar-Roman, L. M.; Hartwig, J. F. Organometallics 2002, 21, 491.

Article

bonded to the C(1) of the 2-phenyl group of the oxazolone, to the terminal iodine I(1), and to the phosphorus P(1) and P(2) atoms, the last two atoms being mutually trans. The distribution of the ligands is in good agreement with the antisymbiotic effect shown by the Pd atom38 and with the reluctance of the phosphines to be coordinated trans to the aryl group or transphobia.39 4. Functionalization Processes: Formation of C-C, C-O, and C-Br Bonds. As has been described in the Introduction, a wide prospect of synthetic tools based on ortho palladation can be used to regioselectively functionalize organic substrates. One of the most successful methods is based on oxidative coupling processes, which have been extensively studied. There is at the present time an exciting controversy about the mechanism of some of these reactions, namely halogenation, acetoxylation, and alkoxylation processes, due to the plausible involvement of transient species of Pd(III)5c,8e and/or Pd(IV)3h,n as active species. These studies involve detailed mechanistic determinations,16b-d and these processes have still not shown all their chemical potentiality. One of the most popular oxidants used in these oxidative couplings are iodine(III) reagents, due to their low toxicity and milder reaction conditions in comparison with other oxidants,40 characteristics which confer them a great potential for the functionalization of cyclometalated complexes.3b,c,5,41 We have successfully used these reagents on the functionalization of R-amino acids.21b With the aim of introducing acetate groups at the ortho position of the oxazolone, and in accord with previous observations,5 complex 7 was reacted with excess PhI(OAc)2 in acetic acid as solvent. Surprisingly, the reaction takes a different path and the o-bromobenzylidene compound 4 was obtained instead in 50% yield after the usual workup (see Scheme 6). The characterization of 4 as the reaction product was performed by comparison with an authentic sample prepared through conventional Erlenmeyer methods.42 The formation of 4 from 7 cannot be the result of direct reductive elimination on the Pd(II) derivative 7, since that would mean that the reverse of oxidative addition has occurred. This reaction is not possible on thermodynamic grounds, since the spontaneous reaction is the formation of 7 from Pd(0). Moreover, Pd(0) should be formed and we did not detect the presence of black palladium. Therefore, the presence of the oxidant is critical in this process. In order to explain the formation of 4 from 7, it is sensible to assume that the reaction starts by oxidation of the Pd(II) center to (38) (a) Pearson, R. G. Inorg. Chem. 1973, 12, 712. (b) Pearson, R. G. J. Chem. Educ. 1968, 45, 581. (c) Davies, J. A.; Hartley, F. R. Chem. Rev. 1981, 81, 79. (39) (a) Vicente, J.; Abad, J. A.; Frankland, A. D.; Ramı´ rez de Arellano, M. C. J. Chem. Soc., Chem. Commun. 1997, 959. (b) Vicente, J.; Arcas, A.; Bautista, D.; Jones, P. G. Organometallics 1997, 16, 2127. (c) Vicente, J.; Abad, J. A.; Frankland, A. D.; Ramírez de Arellano, M. C. Chem. Eur. J. 1999, 5, 3066. (d) Vicente, J.; Abad, J. A.; Martínez-Viviente, E.; Jones, P. G. Organometallics 2002, 21, 4454. (e) Vicente, J.; Arcas, A.; Bautista, D.; Ramírez de Arellano, M. C. J. Organomet. Chem. 2002, 663, 164. (f) Bartolom
e, C.; Espinet, P.; Vicente, L.; Villafa~ne, F.; Charmant, J. P. H.; Orpen, A. G. Organometallics 2002, 21, 3536. (g) Vicente, J.; Arcas, A.; G
alvez-L
opez, M. D.; Juli
a-Hern
andez, F.; Bautista, D.; Jones, P. G. Organometallics 2008, 27, 1582. (40) (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. (41) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 5836. (42) Mesaik, M. A.; Rahat, S.; Khan, K. M.; Zia-Ullah, C.; Muhammad, I.; Murad, S.; Ismail, Z.; Rahman, A.; Aqeel, A. Bioorg. Med. Chem. 2004, 12, 2049.

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Scheme 6.a

a Reagents: (i) PhI(OAc)2/AcOH; (ii) PhI(OAc)2/ROH; (iii) CO/ ROH, -Pd0.

Scheme 7. Synthesis of Compound 20

Pd(IV),19b-d with concomitant incoporation of the acetate fragments (structure A; Scheme S1 in the Supporting Information). What is important in structure A is that there are simultaneously a bromide and at least one acetate cis to the Pd-C bond, both ligands being able to undergo reductive elimination. The final synthesis of 4 means that C-Br reductive elimination is favored over C-O bond formation. Since the only source of bromine in the starting reagents consists of the bromide bridges present in 7, we reasoned that the simple change of bromide bridges to acetate bridges should lead, under the same reaction conditions, to the oxazolone being incorporated ortho to the acetate group. In fact, reaction of 14 with excess PhI(OAc)2 in acetic acid gives the ortho-functionalized oxazolone [C6H4-2-OAcCHdCNC(O)OCPh] (20) through oxidation of Pd(II) to Pd(IV) and subsequent reductive elimination by C-O coupling (Scheme 7). Compound 20 has been previously reported,43 but it was not fully characterized (see the Supporting Information). It is also worthy of note that the resulting functionalized oxazolones (4 and 20) do not remain bonded to the Pd center after the reductive coupling step, as occurs in other substrates previously reported.21b Therefore, the isolation of the pure free compounds is considerably simpler. This fact could be related to the low bonding ability of the iminic N atom, as has been stated in preceding paragraphs (sections 2 and 3), and avoids the use of phenanthroline to liberate the modified materials.21b Using the same experimental methodology, the reaction of 7 with excess PhI(OAc)2 in MeOH or EtOH gives the oxazolones [C6H4-2-OR-CHdCNC(O)OCPh] (OR = OMe (18), (43) (a) Kirby, G. W.; Michael, J.; Narayanaswami, S. J. Chem. Soc., Perkin Trans. 1 1972, 2003. (b) Neuberger, A. Biochem. J. 1948, 43, 599. (c) Erlenmeyer, E.; Stadlin, W. Justus Liebigs Ann. Chem. 1904, 337, 283.

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OEt (19)), respectively.44 In these cases, the expected products derived from the incorporation of the methoxide or the ethoxide fragments are obtained, in spite of the competing presence of bromide and acetate groups. The lower yield of 19 (about 9%) compared with that of 18 (42%) is probably related to the ease of formation of the methoxide anion and its incorporation in the putative Pd(IV) intermediate, in comparison with the ethoxide anion, due to the slightly higher acidity of methanol. An additional proof is that 2-propanol does not react at all with 7 and excess PhI(OAc)2 at room temperature, and again, compound 4 is obtained due to oxidation of the Pd(II) center in 7 and subsequent competing reductive elimination and formation of the C-Br bond. Once we had seen that oxazolones could be ortho-functionalized by formation of new C-Br and C-O bonds, we attempted the formation of new C-C bonds. The reaction of 7 with CO (1 atm) in the alcoholic medium ROH (methanol or 2-propanol) results in the synthesis of [C6H4-2-CO2RCHdCNC(O)OCPh] (CO2R = CO2Me (21), CO2iPr (22)) by incorporation of the CO2R functional group at the ortho position of the oxazolone. This carbonylation process occurs under very mild reaction conditions, avoiding the use of high pressure or special devices, and represents an easy way to introduce the carboxylate moiety, which is a useful synthetic building block.7 The mechanism of this reaction is completely different from that proposed for the synthesis of 18-20, since Pd(II)/Pd(0) species are involved in this case. It is assumed (Supporting Information, Scheme S2) that the initial step is the coordination of the CO ligand which, once bonded, undergoes nucleophilic attack of the methoxide anion, forming an acyl species. The final reductive elimination by C-C coupling gives the free modified oxazolones 21 and 22. Interestingly, the acidity of 2-propanol is enough to promote the formation of the acyl intermediate. This fact suggests that a broad scope of carboxylates, coming from alcohols with similar acidity, is accessible through this method.

Conclusion A series of new ortho-metalated palladium complexes of (Z)-2-aryl-4-arylidene-5(4H)-oxazolones were prepared through oxidative addition. Palladation has been achieved at both the 4-benzylidene and the 2-phenyl rings, the former giving six-membered rings. The stability of these palladacycles is strongly dependent on the neighboring ligands. Soft ligands such as phosphines afford η1(C) bonding for the 4-benzylidene ring, while with hard (acetate, acetylacetonate) or borderline ligands (pyridine, NCMe) the 4-benzylidene group can coordinate in an stable C,N-chelating fashion. However, palladation at the 2-phenyl ring only affords η1-aryl complexes. The reactivity of oxazolones metalated at the 4-benzylidene ring toward soft oxidants [PhI(OAc)2] affords the ortho-functionalized free oxazolones [C6H4-2-FG-CHdCNC(O)OCPh] (FG = functional group) under mild conditions. Different functional groups can be introduced at the oxazolone skeleton by modification of the solvent, the ancillary ligands at the Pd center, or the reaction conditions. Then, the methodology presented here allowing the introduction of the substituent at the ortho (44) (a) Rao, I. S. J. Org. Chem. 1976, 41, 722. (b) Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M. Synthesis 1995, 671. (c) Buck, J. S.; Baltzly, R.; Richard, W. S. J. Am. Chem. Soc. 1938, 60, 1789.

Roiban et al.

position of the aromatic ring involves an advantageous alternative to the direct synthesis of the oxazolone ring using an ortho-substituted benzaldeyhde. This is due to the sometimes difficult availability of the appropriate ortho-substituted benzaldehyde and to the evident low yields in the condensation reaction due to steric reasons. The synthesis of the modified 5(4H)-oxazolones open the way to the synthesis of new families of interesting compounds and, in particular, of modified phenylalanines with a great variety of substituents in the ortho position of the phenyl ring.

Experimental Section Safety Note. Caution! Perchlorate salts of metal complexes with organic ligands are potentially explosive. Only small amounts of these materials should be prepared, and they should be handled with great caution.46 General Methods. Details are as previously reported (Supporting Information).21b Pd2(dba)3 3 CHCl3 was prepared by following literature methods.28 The starting amides 2 and 3 were synthesized by previously described methods.24,25 Oxazolone 4 was synthesized as reported,42 while 547 and 647b were mentioned in the literature but their characterization data were not provided. Synthesis of 7. Pd2(dba)3 3 CHCl3 (0.300 g, 0.328 mmol) and 4 (0.163 g, 0.655 mmol) were suspended in toluene or CH2Cl2 (30 mL) under an Ar atmosphere, and this deep violet mixture was stirred at 25 C for 24 h. The resulting suspension was centrifugated, and the solid obtained was washed two times with CH2Cl2 (20 mL) and Et2O (10 mL) to afford 7 as a green solid (yield 0.248 g, 87%). IR: ν 1784 cm-1 vs (CdO), 1633 cm-1 vs (CdN). MS (MALDIþ) m/z (relative intensity, %): 788.9 (100%) [M - Br]þ. Anal. Calcd for C32H20Br2N2O4Pd2: C, 44.22; H, 2.32; N, 3.22. Found C, 44.48; H, 2.65; N, 3.67. Synthesis of 8. To a stirred suspension of 7 (0.231 g, 0.266 mmol) in CH2Cl2 (10 mL), under an Ar atmosphere, was added PPh2Me (0.212 g, 1.058 mmol). The initial suspension gradually dissolved. After it was stirred for 1 h at 25 C, the resulting solution was filtered through Celite and evaporated to afford 8 as a yellow solid (yield 0.256 g, 76%). 1H NMR (400 MHz, CDCl3) δ: 1.80 (t, J = 3.4 Hz, 6H, 2CH3), 6.60 (t, 3J = 7.3 Hz, 1H, H50 0 ), 6.75 (t, 3J = 7.5 Hz, 1H, H40 0 ), 7.09 (d, 3J = 6.4 Hz, 1H, H60 0 ), 7.19-7.34 (m, 12H, 4Ho-PPh2Me, 8Hm-PPh2Me), 7.40-7.44 (m, 8H, Ho,Hp-PPh2Me), 7.50 (t, 3J = 7.5 Hz, 2H, H30 , H50 ), 7.54-7.59 (m, 1H, H40 ) 7.72 (s, 1H, H70 0 ), 8.10 (d, 3J = 7.2 Hz, 2H, H20 , H60 ), 8.18 (d, 3J = 8.0 Hz, 1H, H30 0 ). 31P NMR (162 MHz, CDCl3) δ: 7.29 (s, 2P, 2PPh2CH3). Synthesis of 9. Complex 9 was prepared by following the same procedure as was reported for 8. Therefore, 7 (0.159 g, 0.183 mmol) was reacted with PPh3 (0.096 g, 0.366 mmol) in CH2Cl2 (10 mL) to give 9 as a yellow solid (yield 0.217 g, 85%). 1H NMR (400 MHz, CDCl3) δ: 6.78-6.89 (m, 2H, H40 0 , H50 0 ), 7.10-7.39 (m, 6H, Hm-PPh3), 7.37-7.65 (m, 13H, 6Ho-PPh3, 3Hp-PPh3, H60 0 , H30 , H40 , H50 ), 8.12-8.16 (m, 2H, H20 , H60 ), 8.30 (d, 3J = 7.30 Hz, 1H, H30 0 ), 8.58 (s, 1H, H70 0 ). 31P NMR (162 MHz, CDCl3) δ: 24.04 (s, PPh3). Synthesis of 14. To a suspension of 7 (0.258 g, 0.297 mmol) in 10 mL of CH2Cl2 was added silver acetate (0.149 g, 0.893 mmol). The suspension changed from greenish to reddish brown. This suspension was stirred overnight at 25 C with exclusion of light. After the reaction time the suspension was filtered through Celite and the reddish solution was evaporated to dryness,

(45) Nagase, S. Nippon Kagaku Zasshi 1960, 81, 309. (46) Wolsey, W. C. J. Chem. Educ. 1973, 50, A335. (47) (a) Grimshaw, J.; Hamilton, R.; Trocha-Grimshaw, J. J. Chem. Soc., Perkin Trans. 1 1982, 229. (b) Palcut, M.; Benko, J.; Mueller, N.; Hritzova, O.; Vollarova, O.; Melikian, G. S. J. Chem. Res. Synop. 2004, 10, 649.

Article affording 14 as a red solid (yield 0.204 g, 83%). 1H NMR (400 MHz, CDCl3) δ: 1.04 (s, 3H, CH3), 7.15-7.25 (m, 2H, H40 0 , H50 0 ), 7.31 (dd, 3J = 7.3 Hz, 4J = 2.0 Hz, 1H, H60 0 ), 7.38-7.45 (m, 3H, H30 0 , H30 , H50 ), 7.49 (s, 1H, H70 0 ), 7.55 (t, 3J = 7.2 Hz, 1H, H40 ), 7.85 (d, 3J = 7.3 Hz, 2H, H20 , H60 ). Reactivity of 7 with PhI(OAc)2. Synthesis of 4. To a suspension of 7 (0.160 g, 0.185 mmol) in AcOH (10 mL) was added PhI(OAc)2 (0.248 g, 0.74 mmol). The resulting brown mixture was stirred for 16 h at room temperature, affording an orange suspension which was filtered, giving a solid and a solution which were treated separately. The solid obtained is a mixture in which 4 can be identified. This solid was dissolved in CH2Cl2 (3 mL), the solution was washed with H2O (5 mL), and the organic phase was dried on anhydrous MgSO4, filtered, and evaporated to dryness to afford 4 was as a pale yellow solid (30.1 mg). On the other hand, the orange solution was evaporated to dryness. The residue was dissolved in chloroform (17 mL) and the solution washed with 10% Na2SO3 (4  10 mL) and with saturated NaCl solution (3  10 mL). The organic phase was dried on anhydrous MgSO4, filtered, and evaporated to dryness. The yellow residue was purified by silica gel chromatography using ethyl acetate/hexane (2:8) as eluent. The yellow band was collected and evaporated to dryness, yielding 4 as a pale yellow solid (29.8 mg) (total yield 50%). These solids were characterized as 4 by comparison of their spectral data with those of an authentic sample. Synthesis of 18. The synthesis and characterization of 18 have been reported previously.44a,b PhI(OAc)2 (0.229 g, 0.693 mmol) was added to a suspension of 7 (0.152 g, 0.173 mmol) in MeOH (15 mL), and the mixture was stirred for 18 h at room temperature. After the reaction time the brown-orange solution was evaporated to dryness. The brown-yellow residue was purified by as described for 4 by CHCl3 solution, washing with Na2SO3 and brine, and silica gel chromatography using ethyl acetate/ hexane (1:9) as eluent. The yellow band was collected and evaporated to dryness, giving 18 as a yellow solid (yield 41.2 mg, 42%). Synthesis of 19. The synthesis of 19 has been reported,44c but a complete characterization was not reported (Supporting Information). Compound 19 was prepared similarly to 18, starting from 7 (0.152 g, 0.173 mmol) and PhI(OAc)2 (0.231 g, 0.717 mmol) in ethanol (25 mL). The orange-brown residue was purified by silica gel chromatography using ethyl acetate/ hexane (2:8) as eluent. The yellow band was collected and evaporated to dryness, giving compound 19 as a yellow solid (yield 10.7 mg, 9.2%). 1H NMR (400 MHz, CDCl3): δ 1.50 (t, 3H, 3J = 7.0 Hz, CH3), 4.14 (q, 2H, OCH2), 6.92 (d, 1H, 2J = 8.4 Hz, H30 0 ), 7.09 (t, 1H, 2J = 8.1 Hz, H50 0 ), 7.42 (td, 1H, 4J = 1.6 Hz, H40 0 ), 7.54 (t, 2H, 2J = 7.8 Hz, H30 , H50 ), 7.68 (t, 1H, H40 ), 7.90 (s, 1H, H70 0 ), 8.17 (dd, 2H, 4J = 1.4 Hz, H20 , H60 ), 8.89 (dd, 1H, 4J = 1.7 Hz, H60 0 ). Synthesis of 20. The synthesis of 20 has been reported previously, but it was not fully characterized (Supporting Information).43 PhI(OAc)2 (0.191 g, 0.58 mmol) was added to a suspension of 14 (0.191 g, 0.58 mmol) in AcOH (6 mL). The resulting mixture was stirred for 18 h at room temperature, and the brown-orange solution was evaporated to dryness. The resulting residue was dissolved in chloroform (17 mL) and washed with Na2SO3 10% (4  10 mL) and with saturated NaCl solution (3  10 mL). The organic phase was dried on anhydrous MgSO4, filtered, and evaporated to dryness. The yellow residue was purified by silica gel chromatography using ethyl acetate/hexane (3:8) as eluent. The yellow band was collected and evaporated to dryness, giving 20 as a yellow solid (yield 50.2 mg, 56.5%). 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 3H, CH3), 7.18 (dd, 1H, 2J = 8.1 Hz, 3J = 1.2 Hz, H30 0 ), 7.36

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(s, 1H, H70 0 ), 7.40 (t, 1H, 2J = 8.1 Hz, H50 0 ), 7.48 (td, 1H, 3J = 1.7 Hz, H40 0 ), 7.54 (t, 2H, 2J = 7.8 Hz, H30 , H50 ), 7.63 (tt, 1H, 4 J = 1.3 Hz, H40 ), 8.18 (dd, 2H, H20 , H60 ), 8.93 (dd, 1H, H60 0 ). Synthesis of 21. The synthesis of 21 has been reported previously, but it was not fully characterized (Supporting Information).45 A suspension of 7 (0.130 g, 0.150 mmol) in methanol (10 mL) was stirred under a CO atmosphere for 14 h. During this time, a clear decomposition was observed. After the reaction time the black suspension was filtered through a plug of Celite to remove Pd(0), and the resulting yellow solution was evaporated to dryness. The residue was dissolved in dichloromethane (15 mL), the light suspension was filtered through a pad of Celite, and the resulting yellow solution was evaporated to dryness in vacuo to afford 21 as a pale yellow solid (yield 39.1 mg, 43.1%). 1H NMR (400 MHz, CDCl3): δ 3.47 (s, 3H, OMe), 7.40-7.42 (m, 3H, H40 , H30 , H50 ), 7.44 (s, 1H, H70 0 ), 7.61-7.68 (m, 3H, H20 , H60 , H50 0 ), 7.79 (d, 2H, 2J = 4.7 Hz, H4 0 0 , H30 0 ), 8.42 (d, 1H, 2J = 8.0 Hz, H60 0 ). Synthesis of 22. Compound 22 was prepared similarly to 21, starting from 7 (0.138 g, 0.160 mmol) and CO (1 atm) in 2-propanol (12 mL). The mixture was stirred for 16 h at room temperature and filtered through a plug of Celite, and the resulting orange solution was evaporated to dryness. The residue was purified by silica gel chromatography using ethyl acetate/hexane (3:8) as eluent. The colorless band was collected and evaporated to dryness, affording the compound 22 as a white solid (yield 40.1 mg, 37.4%). 1H NMR (400 MHz, CDCl3): δ 1.24 (d, 3H, 3J = 6.2 Hz, CH3), 1.38 (d, 3H, 3J = 6.1 Hz CH3), 3.99 (m, CH), 7.39-7.40 (m, 3H, H40 , H30 , H50 ), 7.42 (s, 1H, H70 0 ), 7.61-7.67 (m, 3H, H20 , H60 , H50 0 ), 7.78 (m, 2H, H40 0 , H30 0 ), 8.41 (dd, 1H, 3J = 8.0 Hz, 4J = 0.7 Hz, H60 0 ). X-ray Crystallography. Crystals of adequate quality for X-ray measurements were grown by slow diffusion of Et2O into CH2Cl2 (14, 17) or CHCl3 solutions (9, 15) of the crude products at 25 C. A single crystal of each compound (dimensions in Table 1 in the Supporting Information) was mounted at the end of a quartz fiber in a random orientation, covered with magic oil, and placed under the cold stream of nitrogen. Data collection was performed at room temperature or low temperature (150 K) on an Oxford Diffraction Xcalibur2 diffractometer using graphite-monochromated Mo KR radiation (λ = 0.710 73 A˚). A hemisphere of data was collected on the basis of three ω-scan or j-scan runs. The diffraction frames were integrated using the program CrysAlis RED,48 and the integrated intensities were corrected for absorption with SADABS.49 The structures were solved and developed by Patterson and Fourier methods.50 The structures were refined to Fo2, and all reflections were used in the least-squares calculations.51

Acknowledgment. Funding from CNCSIS 92/2004, PNII Idei 515, and Idei 570 (Romania), the Ministerio de Ciencia e Innovaci
on (Projects CTQ2008-01784 and CTQ2007-62245, Spain), and Gobierno de Arag
on (PI071-09) is gratefully acknowledged. Supporting Information Available: Figures and text giving a complete experimental section with all preparative details and tables and CIF files giving complete data collection parameters for 9, 14, 15, and 17. This material is available free of charge via the Internet at http://pubs.acs.org. (48) CrysAlis RED, Version 1.171.27p8; Oxford Diffraction Ltd., 2005. (49) Sheldrick, G. M. SADABS: Empirical Absorption Correction Program; University of G€ottingen, G€ottingen, Germany, 1996. (50) Sheldrick, G. M. SHELXS-86. Acta Crystallogr. 1990, A46, 467. (51) Sheldrick, G. M. SHELXL-97. Acta Crystallogr. 2008, A64, 112.