Indoles via palladium-catalyzed cyclization

Brought to you by the Organic Reactions Wiki, the online collection of organic reactions
Jump to: navigation, search

Indole synthesis via palladium-catalyzed cyclization involves the formation of the pyrrole moiety of the indole ring through palladium-catalyzed carbon-carbon or carbon-nitrogen bond formation. In the presence of either palladium(0) or palladium(II), appropriately substituted anilines and unsaturated substrates may react in either an intra- or intermolecular fashion to afford the indole skeleton.[1]


Transition-metal catalysts are commonly used to effect site-selective carbon-carbon and carbon-heteroatom bond formation. One synthetically attractive application of this idea concerns synthesis of the indole skeleton, which can be constructed through cross-coupling reactions of appropriately substituted 2-alkynyl, 2-alkenyl, and 2-allyl anilines. Palladium in particular has seen wide use as a transition-metal catalyst in this context, because of its versatility and effectiveness in establishing both C–C and C–X bonds. In the presence of a palladium catalyst, a variety of coupling partners combine to form aromatic indoles. Figure 1 outlines the known retrosynthetic disconnections one can envision based on the known coupling chemistry of alkenes and anilines.


Coupling reactions of alkynyl anilines are generally more versatile than reactions of alkenyl anilines. Equation 2 describes retrosynthetic disconnections of the indole skeleton that can be established through reactions of anilines bearing alkyne fragments, preformed or prepared in situ, in the presence of a palladium catalyst.


Although detailed mechanistic studies of palladium-catalyzed indole formation reactions are rare, some useful hypotheses have emerged about how these reactions proceed. Additionally, studies of palladium-catalyzed reactions have paved the way for the development of indole-forming reactions catalyzed by other transition metals.

Mechanism and Stereochemistry

Because the number of distinct, known palladium-catalyzed indole formation reactions is vast, mechanistic generalizations are difficult. Additionally, few detailed mechanistic studies have been made. Nonetheless, generalizations have been made about the likely mechanisms of these reactions. This section describes some of the dominant mechanistic paradigms that currently exist. Palladium-catalyzed indole-forming reactions not addressed here, such as the Heck-type coupling of enamines and aryl halides, follow mechanisms that have been well-established for related transformations.

Palladium(II)-catalyzed Reactions

Palladium(II) is a somewhat electrophilic species, and is able to coordinate to the π bonds of alkenes and alkynes. In the presence of a tethered amine, nucleophilic addition across the π bond may occur to establish new C–N and C–Pd bonds. When alkynes are used, protonolysis of the carbon-palladium bond yields the product and regenerates the catalyst (Eq. 3).[2] In the presence of alkenes, indolylpalladium complexes can react with carbon-carbon double bonds to afford intermediates from which indole derivatives are obtained via β-hydride elimination, and an external oxidant is required to regenerate palladium(II).


Palladium(0)-catalyzed Reactions

Palladium(0) is typically nucleophilic and susceptible to oxidative addition in the presence of carbon-halogen or -pseudohalogen bonds. Thus, the first step of most palladium(0)-catalyzed indole formation reactions involves oxidative addition into a C–X bond. Subsequent coordination of alkyne to the resulting palladium(II) species leads to migratory insertion of the alkyne into the carbon-palladium bond. Nucleophilic substitution of nitrogen for halide at palladium, followed by reductive elimination, affords the indole product and regenerates the palladium(0) catalyst (Eq. 4).[1] A mechanism involving aminopalladation and reductive elimination has been proposed to account for observations of certain palladium(0)-catalyzed reactions.[3]


Scope and Limitations

From a retrosynthetic point of view, palladium-catalyzed indole formation has extremely broad scope. Alkynyl anilines are most commonly used for indole formation, because they are easily constructed from o-haloanilines through Sonogashira coupling. In many cases, cyclization to form indoles is spontaneous under Sonogashira coupling conditions (Eq. 6).[4]


In the presence of a palladium(II) catalyst, internal alkynes react with o-haloanilines to form 2,3-disubstituted indoles. When internal, unsymmetrically substituted alkynes are used, the substitution pattern of the product is controlled primarily by steric and coordination factors in the carbopalladation step (Eq. 7).[5] Like other additions of heteroatoms and palladium across unsaturated carbon-carbon bonds, steric effects direct the nucleophile to the less hindered position and palladium to the more hindered position. In the presence of coordinating substituents, palladium prefers to reside at the position whose substituent has better coordinating ability.


When an aryl halide is combined with an o-alkynylaniline in the presence of a palladium(0) catalyst, aryl-substituted indoles are formed via an aminopalladation/reductive elimination process (Eq. 8).[6] This highly efficient reaction has been used to prepare 2-substituted, 3-substituted, and 2,3-disubstituted indoles.


Studies of Heck reactions of 2-halonitrobenzenes revealed that in the presence of triphenylphosphine and carbon monoxide, 2-nitrostyrenes, product of the Heck coupling, cyclize to form indoles as a side product of Heck coupling.[7] Since that initial discovery, the reaction has been optimized and is now a useful synthesis of indoles (Eq. 9).[8]


Bond c (Eq. 2) may be established through the coupling of a nucleophilic enamine and electrophilic aryl halide. Enamines generated in situ from aldehydes and 2-haloanilines couple smoothly to give indoles (Eq. 10).[9]


Likewise, the coupling of the nucleophilic nitrogen of a tethered enamine and an electrophilic aryl halide is a natural approach to establish bond g. Buchwald-Hartwig coupling conditions are useful in this context (Eq. 11).[10]


Vinylation of the nitrogen atom of an aniline with a tethered vinyl halide establishes bond a. When a dihalide is used, a second coupling reaction is possible to functionalize the 2-position of the indole.[11][12][13] When further coupling is undesirable, care must be taken to avoid catalyst inhibition through oxidative addition into the product's C–X bond. Use of the fluoroboric acid salt of tri(tert-butyl)phosphine is useful for avoiding this problem (Eq. 12).[14]


Solid-phase synthesis has been applied to the palladium-catalyzed formation of indoles, usually by anchoring the aromatic substrate to resin before the introduction of palladium and any other substrates (Eq. 13).[15]


Comparison to Other Methods

Although a number of other metals have been applied to the synthesis of indoles, none match the versatility and substrate scope of palladium. The majority of indole-formation reactions that employ other metals use 2-alkynyl anilines, which typically must be prepared through Sonogashira coupling with palladium anyway. In a few cases, however, other metals are useful to accomplish couplings that are not possible with palladium.

Copper, like palladium, can be used to effect a domino coupling/cyclization process (Eq. 14).[16]


Gold-catalyzed hydroamination has been applied to the synthesis of indoles. In the presence of electrophiles, the organogold intermediates of this reaction may react further to establish substituents at the 3-position of the indole ring (Eq. 15).[17]


Platinum-catalyzed methods are sometimes complementary to palladium-based methods. For instance, the platinum(II)-catalyzed indole formation and acyl migration in Eq. 16 cannot be accomplished with palladium.[18]


Rhodium has also been used to effect indole formation; however, only terminal alkynes may be used. It has been suggested that this reaction involves a rhodium vinylidene intermediate (Eq. 17).[19]


Zinc is useful for the formation of indoles from anilines and propargylic alcohols, via a mechanism involving a unique 1,2-nitrogen shift (Eq. 18).[20]


Experimental Conditions and Procedure

Typical Conditions

The most common palladium(0) sources used in these reactions are Pd(PPh3)4 and Pd2dba3, and the most common palladium(II) sources are PdCl2 and Pd(OAc)2. Reduction of palladium(II) with a variety of reagents (alkenes, alkynes, phosphines, etc.) provides a convenient route to catalytically active palladium(0). Additionally, unique palladium-phosphine complexes may be generated in situ through ligand exchange reactions. Importantly, the efficiency of indole formation often depends on the coordination number of the palladium pre-catalyst, because unsaturated complexes are required for oxidative addition. Additives such as lithium chloride may be necessary to stabilize catalytic intermediates or prevent undesired side reactions.[5] In general, a variety of solvents, ligands, bases, and additives should be screened when searching for optimized conditions.

Example Procedure[21]


To a solution of of N-acetyl-2-(3-methylbutyn-l-yl)-5-carbomethoxyaniline (0.107 g, 0.413 mmol) in MeCN (4 mL) was added PdCl2(MeCN)2 (11 mg, 0.041 mmol) and the mixture was heated at 80 °C for 1.5 h. The solvent was removed in vacuo and the resulting oil was purified by column chromatography on silica gel (17% EtOAc/n-hexane) to yield 0.088 g (82%) of the product shown as a white, crystalline solid: mp 67.5–68.5 °C; IR (CHC13) 1711, 1554, 1462, 1313, 1304, 1297, 1255, 1108 cm–1; 1H NMR (CDC13) δ 8.41 (d, J = 1.4 Hz, 1H), 7.89 (dd, J = 1.4, 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 6.50 (s, 1H), 3.92 (s, 3H), 3.72 (hept, 1H), 2.84 (s, 3H), 1.30 (d, J = 6.8 Hz, 6H). Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61. Found: C, 69.40; H, 6.61.


  1. a b Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. React. 2012, 76, 281. doi: (10.1002/0471264180.or076.03)
  2. Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A. Tetrahedron Lett. 1985, 26, 5963.
  3. Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671.
  4. Ackermann, L. Org. Lett. 2005, 7, 439.
  5. a b Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652.
  6. Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363.
  7. Kasahara, A.; Izumi, T.; Murakami, S.; Miyamoto, K.; Hino, T. J. Heterocycl. Chem. 1989, 26, 1405.
  8. Söderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838.
  9. Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826.
  10. Brown, J. A. Tetrahedron Lett. 2000, 41, 1623.
  11. Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907.
  12. Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549.
  13. Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955.
  14. Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416.
  15. Fagnola, M. C.; Candiani, I.; Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.; Bedeschi, A. Tetrahedron Lett. 1997, 38, 2307.
  16. Cacchi, S; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
  17. Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.
  18. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546.
  19. Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074.
  20. Kumar, M. P.; Liu, R.-S. J. Org. Chem. 2006, 71, 4951.
  21. Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.