Communication pubs.acs.org/Organometallics
Mechanistic Insight into the Regioselective Palladation of Indole Derivatives: Tetranuclear Indolyl Palladacycles with High C2−Pd or C3−Pd Bond Selectivity Yang Li,† Wen-Hua Wang,† Ke-Han He,† and Zhang-Jie Shi*,†,‡ †
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, People's Republic of China ‡ State Key Laboratory of Organometallic Chemistry, SIOC, CAS, Shanghai 200032, People's Republic of China S Supporting Information *
ABSTRACT: This research provides a straightforward understanding of the regioselective palladation of indole derivatives by capturing both C2−Pd and C3−Pd intermediates of N-phenylindole and N-methylindole. Those tetranuclear indolyl palladacycles suggest that the regioselectivity of palladation depends on the N-substituted protective groups of indoles as well as the acidity of the reaction medium.
A
studies. Herein, our research gives an understanding of the regioselective palladation of indole derivatives by capturing both C2−Pd and C3−Pd intermediates of N-phenylindole and N-methylindole. In accord with the reported PdII-catalyzed highly regioselective functionalization of indoles, it seems that basic conditions favor C3 selectivity.5 In contrast, C2 selectivity is mostly observed under acidic conditions.6 On the basis of these investigations, N-phenylindole (1a) was selected for our initial investigation due to its rigidity, proper electron density, and relatively lower reactivity. These characteristics of 1a may help to stabilize the desired intermediates. The unsubstituted C2 and C3 positions of 1a provided potential active sites to investigate the regioselectivity. To obtain the C3 palladation product, sodium pivalate was chosen as a proper base because of the following factors. First, in some cases of direct functionalization of indoles, the promoted efficiency was observed in the presence of pivalyl ligand.5b,7c,8a,b,9 Second, the bulky pivalyl ligand may play a key role in the stabilization of Pd−indole species. Third, the lipophilic pivalyl ligand might facilitate the precipitation of Pd−indole intermediates from a polar solvent.
s a ubiquitous heterocyclic structural unit, the indolyl scaffold exists in many natural products and pharmaceutical agents, and various methods have been developed to functionalize indole derivatives.1 Direct functionalization of the indolyl core by C−H transformation provides highly efficient access to complicated indolyl analogues.2 However, challenges still remain ,because both the chemo- and regioselectivities must be well controlled by avoiding the formation of intractable isomeric mixtures. Among the transition-metal-catalyzed direct functionalizations of indolyl derivatives, catalytic systems with Pd have shown excellent catalytic ability and regioselectivity.3−6 Particularly, in some cases, completely controllable C2 or C3 selectivity from the same substrate was observed by simple tuning the reaction parameters.7 Some mechanistic studies were investigated to understand the regioselectivity of the indolyl functionalization.7b,8 During this research, Sames and his co-workers have carried out comprehensive investigations on N-methylindolyl derivatives as model substrates.7b To provide a rationale for the observed C2 regioselectivity, they presented an electrophilic palladation pathway, accompanied by a 1,2-migration. After that, DeBoef and his co-workers also described a systematic concerted metalation deprotonation (CMD) process to approach the C2 regioselectivity by using the N-(2-(trimethylsilyl)ethoxy)methyl (SEM) indolyl derivatives as model substrates. However, no intermediates were isolated during these detailed mechanistic © 2012 American Chemical Society
Received: April 8, 2012 Published: June 6, 2012 4397
dx.doi.org/10.1021/om300284t | Organometallics 2012, 31, 4397−4400
Organometallics
Communication
Treatment of 1a with [Pd(OAc)2]3 (2a) in the presence of PivONa in MeOH at room temperature generated, as we predicted, the C3 palladation compound 10 as the major product in 58% isolated yield, accompanied by 7−9 as minor
products (Scheme 1). The C3 palladation could be attributed to the high electron density at the C3 position of the indolyl derivatives. Meanwhile, no C2 palladation compound was observed. Gratifyingly, X-ray-quality crystals of 10 were obtained by slow volatilization of its DCM and acetone solution at 5 °C. Simultaneously, crystals of 7−9 were also obtained from the mother liquor of the above reaction mixture. Compound 10 is a novel tetranuclear palladacycle with 1a as bridges (Figure 1). Pd2 shows a typical σ sp2 Pd2−C3 bond. In comparison with Pd2, Pd1 engages in M−π interactions with the C2C3 moiety. This PdII−π (C2C3) interaction presents a η2 coordination with the deprotonated C3 atom and proton-bearing C2 atom. Meanwhile, C2−H is kept untouched during the electrophilic palladation of N-phenylindole. To the best of our knowledge, a structurally characterized PdII−indole complex including indole with unsubstituted C2 and C3 positions has not been reported.10,11 In addition, the coexistence of σ and π Pd−C bonding models in M−indole complexes was first observed in compound 10.12 On the basis of the X-ray structure characterization of compounds 7−10, the pathway to C3 palladation of 1 is proposed as follows (Figure 1): (1) 2a [Pd3(L1)6] (L1 = OAc−) initially undergoes a ligand exchange process to form the new trinuclear palladacycle 7 [Pd3(L2)6] (L2 = PivO−); (2) the tetranuclear palladacycle 8 [Pd4(L2)6(L3)2] (L2 = PivO−, L3 = MeO−) is derived from reorganization of the trinuclear palladacycle 7 in the presence of MeOH; (3) two carboxylate ligands of tetranuclear palladacycle 8 [Pd4(L2)6(L3)2] dissociate, followed by the electrophilic substitution of 8 with 1a at the C3 position. Then a proper base facilitated the deprotonation of indole derivatives to generate the sp2 C3− Pd species [Pd4(L1)2(L2)2(L3)2(indole)2] (10; L1 = L2 = PivO−, L3 = MeO−, indole = N-phenylindole). The formation of C3 palladation compound 9 is suggested by a similar pathway, in which an incomplete ligand exchange is involved. Subsequently, we focused our efforts to obtain Pd−indole complexes with metalation at the C2 position. After many trials
Scheme 1. Regioselective Electrophilic Palladation at the C3 Position of N-Phenylindolea
a
Gray spheres represent t-Bu.
Figure 1. Crystal structures of 7−10 and the possible pathway to 10 through C3 palladation of N-phenylindole (L1 = OAc, L2 = PivO, L3 = MeO−). Disordered atoms, some hydrogen atoms, and the solvent molecule are omitted for clarity. The crystal structure of 2a is based on CCDC 262708.13 4398
dx.doi.org/10.1021/om300284t | Organometallics 2012, 31, 4397−4400
Organometallics
Communication
Scheme 2. pH-Dependent Highly Regioselective Electrophilic Palladation at the C2 or C3 Position of N-Methylindole and X-ray Crystal Structures of Compounds 12 and 13a
a
Disordered atoms and some hydrogen atoms are omitted for clarity.
Pd black. After many trials, we found that, by treatment of 1b with 2a in PivOH at 45 °C in the presence of NaCl, a distinct red-brown solid could be isolated in 15% yield. To our delight, the structure of this red-brown solid was clearly identified as the C2 indolyl palladacycle 13 by X-ray crystal analysis (Scheme 2). No characteristic peak of a Pd−indole C3 complex (a single peak at about 9.2 ppm assigned to C2−H) was observed in the 1 H NMR spectrum of the remaining unidentified complexes. Under acidic conditions with N-methylindole as a substrate, complete inversion of the regioselectivity from C3 to C2 palladation was observed. In the crystal structure of complex 13, Pd1 presents a typical σ sp2 C2−Pd bond. Pd2 is engaged in T-shaped bonding to the C3 position. The Pd2−π(C3) interaction presents a η1 coordination with the proton-bearing C3 atom. The Pd2−H3 distance (1.89 Å) and Pd2−C3−H3 angle (66.5°) indicate some degree of η2 Pd2−H3−C3 agostic-type bonding, which is a meager compensation for the loss of Pd−C2 π bonding.14 Furthermore, comparison of 12 and 13 indicates the following. (1) Different T-shaped PdII−π interactions were discovered in 12 and 13. The C2C3 bond length (1.41(3) Å in 12) in a η2 PdII−π(C2C3) pattern is obviously elongated as compared with the observed value (1.38(2) Å in 13) in a η1 PdII−π(C3) pattern, and both of them are longer than that in free indole (1.365(9) Å).10 This may be a consequence of PdII−π interactions giving weak C2C3 bonds. (2) Pd2−C3 distances are shorter than Pd2−C2 distances in 12 and 13, which demonstrates that Pd2 atoms are engaged more with C3 than with C2. This effect probably results from the first contact of Pd with indole occurring at the “nucleophilic” C3 position. The productive C−H activation on the indole nucleus likely benefits from the T-shaped Pd−π interactions. (3) The squareplanar coordination structures of Pd ions are achieved with
under different pH conditions, we failed to isolate our expected indolyl C-2 palladacycles. Interestingly, the unexpected C3 palladation compound 11 was observed and isolated in 34% yield when compound 1a was treated with 2a in the presence of PivOH at 45 °C (Scheme 1). Its structure shows a similarity with compound 10 by an analysis of the single-crystal structure (see the Supporting Information). The difference is that the indole molecules are bridged by the chlorides. At the same time, no C2 palladation compound was detected. Thus, we failed to detect the expected C2−Pd indolyl palladacycles under acidic conditions. Possibly, this result is due to the electronic characteristics of the phenyl group, which induces the lower reactivity of N-phenylindole (1a). The steric hindrance of the N-phenyl group might be another factor inhibiting the C2 palladation. To prove the regioselectivity based on the pH of the reaction medium in many reactions by the Pd intermediates, we changed the substrate from N-phenylindole (1a) to N-methylindole (1b), due to its high reactivity.2 By treatment of 1b with 2a in the presence of PivONa as a base in MeOH, C3 indolyl palladacycle 12 was obtained as a dark red solid smoothly in 34% isolated yield (Scheme 2). Crystals of 12 suitable for X-ray analysis were also obtained by slow volatilization of its DCM and acetone solution at 5 °C. X-ray crystallography of 12 shows a tetranuclear palladacycle similar to compound 10. No characteristic peak of a C2 indolyl palladacycle (a single peak at about 6.2 ppm assigned to C3−H) was observed in the remaining unidentified complexes and the original reaction mixture. We further tried to obtain the Pd−indole complex with palladation at the C2 position with 1b under acidic conditions. First, the reaction was conducted in AcOH; compound 1b was quickly consumed, accompanied by the precipitation of 4399
dx.doi.org/10.1021/om300284t | Organometallics 2012, 31, 4397−4400
Organometallics
Communication
Chem. 2007, 72, 1476. (e) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 2006, 1379. (f) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990. (4) For palladium-catalyzed direct C3 functionalizations, see: (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull. 1989, 37, 1477. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (c) Djakovitch, L.; Dufaud, V.; Zaidi, R. Adv. Synth. Catal. 2006, 348, 715. (d) Djakovitch, L.; Rouge, P.; Zaidi, R. Catal. Commun. 2007, 8, 1561. (e) Villar, A.; Kaspar, L. T.; Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506. (f) Li, Y.; Wang, W.-H.; Yang, S.-D.; Li, B.-J.; Feng, C.; Shi, Z.-J. Chem. Commun. 2010, 46, 4553. (5) For palladium-catalyzed direct C3 functionalizations under basic conditions, see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199. (b) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (c) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415. (d) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529. (e) Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49, 2499. (f) Gu, Y.; Wang, X.-M. Tetrahedron Lett. 2009, 50, 763. (g) Ackermann, L.; Barfusser, S. Synlett 2009, 808. (h) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052. (i) Choy, P. Y.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2011, 76, 80. (j) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365. (k) Yamaguchi, A. D.; Mandal, D.; Yamaguchi, J.; Itami, K. Chem. Lett. 2011, 40, 555. (6) For palladium-catalyzed direct C2 functionalizations under acidic conditions, see: (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (b) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (c) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (d) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428. (e) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.- Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009, 47, 1473. (f) Zhou, J.; Hu, P.; Zhang, M.; Huang, S.; Wang, M.; Su, W. Chem. Eur. J. 2010, 16, 5876. (g) Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010, 12, 3185. (h) Yang, L.; Zhao, L.; Li, C.-J. Chem. Commun. 2010, 46, 4184. (7) For transition-metal-catalyzed direct regioselective C2 and C3 functionalizations, see: (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (c) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (d) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e) Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929. (f) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908. (g) Liang, Z.; Zhao, J.; Zhang, Y. J. Org . Chem. 2010, 75, 170. (8) (a) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B J. Am. Chem. Soc. 2010, 132, 14676. (b) Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047. (c) Meir, R; Kozuch, S.; Uhe, A.; Shaik, S. Chem. Eur. J. 2011, 17, 7623. (9) (a) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (10) Onitsuka, K.; Yamamoto, M.; Suzuki, S.; Takahashi, S. Organometallics 2002, 21, 581. (11) (a) Shimazaki, Y.; Yokoyama, H.; Yamauchi, O. Angew. Chem., Int. Ed. 1999, 38, 2401. (b) Conway, B.; Hevia, E.; Kennedy, A. R.; Mulvey, R. E. Chem. Commun. 2007, 2864. (12) Shimazaki, Y.; Yajima, T.; Takani, M.; Yamauchi, O. Coord. Chem. Rev. 2009, 479. (13) Bakhmutov, V. I.; Berry, J. F.; Cotton, F. A.; Ibragimov, S.; Murillo, C. A. Dalton Trans. 2005, 1989. (14) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreño, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336.
bridging carboxyl and methoxy ligands in 12 and bridging carboxyl and chlorine in 13, respectively. In addition, the methoxy bridges two Pd ions which are connected to the same indole in compound 12, whereas the chloride bridges two Pd ions which are connected with different indole molecules in 13. (4) Compound 12 shows a structure characterized by Ci symmetry, which has a tetranuclear palladacycle scaffold with two trans N-methylindole groups as bridging units. 13 shows a structure characterized by C2 symmetry, which has a tetranuclear palladacycle scaffold with two cis N-methylindoles as bridging units. These studies are consistent with the previous reports on direct functionalization of N-methylindoles via Pd catalysis. In summary, to unveil the mechanism of the regioselectivity in the direct functionalization of indole and its derivatives, several novel tetranuclear indolyl palladacycles were synthesized and structurally determined by X-ray crystallography. These Pd−indole complexes provide a straightforward understanding of the regioselective palladation. Our studies also suggest that the regioselectivity of palladation depends on not only the N-substituted protective groups of indoles but also the pH of the medium. These observations are beneficial for an understanding of previously developed direct functionalization of indole derivatives via Pd catalysis. Meanwhile, it is also important to design new transformations toward the direct C−H functionalization of indolyl derivatives. Hopefully, this investigation also offers helpful insights into the regio- and chemoselectivity of electrophilic metalation of indolyl compounds with other metals and the electrophilic activation of C−H bonds of a normal aromatic system.
■
ASSOCIATED CONTENT
S Supporting Information *
Text, figures, tables, and CIF files giving experimental details, characterization data, and X-ray crystal structure data. This material is available free of charge via the Internet at http:// pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*Tel and fax: (+86) 10-6276-0890. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Support of this work by the “973” Project from the MOST of China (2009CB825300) and the NSFC (Nos. 20902006, 21002001) is gratefully acknowledged.
■
REFERENCES
(1) For selected reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; 2011, 111, PR215 (update 1). (b) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153. (c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449. (2) For reviews of direct functionalization of indolyl core by C−H activation, see: (a) Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (b) Beck, E. M.; Gaunt, M. J. Top. Curr. Chem. 2010, 292, 85. (3) For palladium-catalyzed direct C2 functionalizations, see: (a) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A.; Kurihara, T.; Shimizu, M. Heterocycles 1985, 23, 2327. (b) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (c) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979. (d) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. 4400
dx.doi.org/10.1021/om300284t | Organometallics 2012, 31, 4397−4400
