Indoles via Palladium-Catalyzed Cyclization
Sandro Cacchi, Giancarlo Fabrizi, and Antonella Goggiamani
Department of Drug Chemistry and Technologies, Sapienza, University of Rome, 00185 Rome, Italy
CONTENTS
INTRODUCTION......
MECHANISMS......
Palladium(II)-Catalyzed Cyclizations......
Palladium(0)-Catalyzed Cyclizations......
SCOPE AND LIMITATIONS......
Indole Formation from Alkynes......
2-Substituted Indoles......
From 2-Alkynylanilid(n)es......
From 1,2-Dihaloarenes......
Under Copper-and/or Phosphine-Free Conditions......
Via Coupling/Cyclization Methods with Supported Palladium Catalysts......
From 2-Ethynylaniline......
From 3-(2-Trifluoroacetamidophenyl)-1-propargyl Carbonate Esters......
From 2-Halo-N-alkynylanilides......
3-Substituted Indoles ......
2,3-Disubstituted Indoles......
From Internal Alkynes and 2-Haloanilid(n)es ......
From 2-Alkynyltrifluoroacetanilides and Csp3, Csp2, and Csp Donors......
From 2-Alkynylanilid(n)es and Allylic Halides, Alkenes, and CO/MeOH......
From N-Alkynyl-2-haloanilides......
From 2-Alkynyl-N-alkylideneanilines......
From 2-Alkynylisocyanobenzenes......
From 2-(Alkynyl)phenylisocyanates......
From 2-Alkynylphenyl N,O-Acetals and from 2-Iodoanilides and 1-(Tributylstannyl)-1-substituted Allenes
Indole Formation from Alkenes......
Unsubstituted Indoles ......
2-Substituted Indoles......
3-Substituted Indoles......
2,3-Disubstituted Indoles......
Indoles via Arene Vinylation......
Indoles via N-Vinylation and N-Arylation......
Unsubstituted Indoles ......
2-Substituted Indoles......
3-Substituted Indoles......
2,3-Disubstituted Indoles......
Solid-Phase Synthesis......
Indole Formation from Alkynes......
Indole Formation from Alkenes......
Indole Formation via N-Vinylation and N-Arylation......
COMPARISON WITH OTHER METHODS......
Copper-Catalyzed Indole Formation ......
Indole Formation from Alkynes......
Indole Formation from Alkenes......
Indole Formation via N-Vinylation and N-Arylation......
Indole Formation via Arene Vinylation......
Gold-Catalyzed Indole Formation......
Indium-Catalyzed Indole Formation......
Iridium-Catalyzed Indole Formation......
Molybdenum-Catalyzed Indole Formation ......
Platinum-Catalyzed Indole Formation......
Rhodium-Catalyzed Indole Formation......
Ruthenium-Catalyzed Indole Formation......
Titanium-Catalyzed Indole Formation......
Zinc-Catalyzed Indole Formation......
EXPERIMENTAL CONDITIONS......
EXPERIMENTAL PROCEDURES......
2-(3-Acetoxyandrost-16-en-17-yl)-1H-indole [One-Flask Synthesis of a 2-Substituted Indole from 2-Ethynylaniline]
N-Acetyl-2-isopropyl-6-carbomethoxyindole [Preparation of a 2-Substituted Indole from a 2-Alkynylacetanilide]
2-[(4-Ethylpiperazin-1-yl)methyl]indole [Synthesis of a 2-Substituted Indole through an Intramolecular Heterocyclization/Intermolecular Nucleophilic Attack on a -Allylpalladium Intermediate]
3-(4-Acetylphenyl)indole [Synthesis of a 2-Unsubstituted 3-Arylindole via the Aminopalladation/Reductive Elimination Pathway]
2-Phenyl-3-(phenylethynyl)indole [Synthesis of a 2,3-Disubstituted Indole from a 2-Alkynyltrifluoroacetanilide and a 1-Bromoalkyne]
2-(Cyclooct-l-enyl)-3-(4-methoxybenzoyl)indole [Synthesis of a 2-Substituted-3-Carbonylated Indole via a Carbonylative Three-Component Cyclization]
2,3-Diphenylindole [Synthesis of a 2,3-Disubstituted Indole via a One-Pot Tandem Cross-Coupling/Aminopalladation/Reductive Elimination Process]
(2R,5S)-3,6-Diethoxy-2-isopropyl-5-[2-(trimethylsilyl)-3-indolyl]methyl-2,5-dihydropyrazine [Synthesis of a 2,3-Disubstituted Indole via Heteroannulation of an Internal Alkyne with 2-Iodoaniline]
N-Tosylindole [Synthesis of a 2,3-Unsubstituted Indole via Cyclization of a 2-Vinylanilide]......
N-(4-Bromobenzyl)-2-ethyl-3-(tert-butyldimethylsilyloxy)-5-methoxyindole [Synthesis of a 2,3-Substituted Indole via Cyclization of a 2-Allylaniline]
Indole [Cyclization of 2-Nitrostyrene]......
(l)-N,N-Di-tert-butoxycarbonyl Tryptophan Methyl Ester [Synthesis of a 3-Substituted Indole via Cyclization of an in Situ Generated 2-Haloanilinoenamine]
2,3-Diphenylindole [Synthesis of a 2,3-Disubstituted Indole through a One-Pot Hydroamination/Cyclization Process]
N-(4-Ethoxycarbonylphenyl)-2-ethoxycarbonyl-5-methoxyindole [Synthesis of a 2-Substituted Indole Based on an Intramolecular N-Arylation Process]
Methyl 2-(2-Methoxyquinolin-3-yl)indole-5-carboxylate [Synthesis of a 2-Substituted Indole through a Tandem Carbon–Nitrogen/Suzuki–Miyaura Coupling]
2-[1-[4-(Trifluoromethyl)benzyl]indol-3-yl]acetamide [A Solid-Phase Synthesis of a 3-Substituted Indole via Cyclization of a 2-Iodo-N-allylaniline]
Methyl 2-Indolecarboxylate [A Solid-Phase Synthesis of a 2-Substituted Indole via Tandem Heck Reaction/N-Arylation]
TABULAR SURVEY......
Table 1A. 2-Substituted Indoles from 2-Haloanilines and Alkynes......
Table 1B. 2-Substituted Indoles from 2-Haloanilides and Alkynes......
Table 1C. 2-Substituted Indoles from 1,2-Dihaloarenes and Alkynes......
Table 1D. 2-Substituted Indoles from 2-Alkynylanilines......
Table 1E. 2-Substituted Indoles from 2-Alkynylanilides......
Table 1F. 2-Substituted Indoles from 2-Alkynylhaloarenes......
Table 1G. 2-Substituted Indoles from 2-Halo-N-alkynylanilides......
Table 1H. 2-Substituted Indoles from 2-Alkynylisocyanatobenzenes......
Table 2A. 3-Substituted Indoles from 2-Haloanilines and Alkynes......
Table 2B. 3-Substituted Indoles from 2-Alkynylanilides......
Table 2C. 3-Substituted Indoles from 3-Iodo-N-allylaniline and Internal Alkynes......
Table 2D. 3-Substituted Indoles from 2-Halo-N-alkylanilines......
Table 2E. 3-Substituted Indoles from 2-Iodo-N-propargylanilides and N-2-(Halophenyl)allenamides
Table 3A. 2,3-Disubstituted Indoles from 2-Haloanilines, 2-Iodobenzoic Acids, or Anilines and Alkynes
Table 3B. 2,3-Disubstituted Indoles from 2-Haloanilides or N-Acyl Benzotriazoles and Alkynes..
Table 3C. 2,3-Disubstituted Indoles from 2-Alkynylanilines......
Table 3D. 2,3-Disubstituted Indoles from 2-Alkynylanilides......
Table 3E. 2,3-Disubstituted Indoles from 2-Halo-N-alkynylanilides and 2-Halo-N-alkylanilines...
Table 3F. 2,3-Disubstituted Indoles from 2-Alkynylisocyanobenzenes, -isocyanatobenzenes, and -N-alkylideneanilines
Table 3G. 2,3-Disubstituted Indoles from N-(2-Halophenyl)allenamides......
Table 3H. 2,3-Disubstituted Indoles from 2-Allenylanilides Prepared in Situ......
Table 4A. 2,3-Unsubstituted Indoles from 2-Vinylanilines and -anilides......
Table 4B. 2,3-Unsubstituted Indoles from 2-Nitrostyrenes......
Table 5A. 2-Substituted Indoles from 2-Allylanilines and -anilides......
Table 5B. 2-Substituted Indoles from 2-Haloarylenamines and -imines......
Table 5C. 2-Substituted Indoles from 2-Haroarylenamines and -imines Prepared in Situ......
Table 5D. 2-Substituted Indoles from 2-Nitrostyrenes......
Table 6A. 3-Substituted Indoles from 2-Halo- and 2-Pseudohalo-N-allylanilines and -anilides.....
Table 6B. 3-Substituted Indoles from 2-Halo-N-allylanilines and -anilides Prepared in Situ......
Table 6C. 3-Substituted Indoles from 2-Haloarylenamines......
Table 6D. 3-Substituted Indoles from 2-Haloarylenamines and -imines Prepared in Situ......
Table 6E. 3-Substituted Indoles from Arylenamines......
Table 6F. 3-Substituted Indoles from 2-Nitrostyrenes, Nitroalkenes, and Nitroarenes......
Table 7A. 2,3-Disubstituted Indoles from 2-Haloarylenamines and -imines......
Table 7B. 2,3-Disubstituted Indoles from 2-Haloarylenamines and -imines Prepared in Situ......
Table 7C. 2,3-Disubstituted Indoles from Arylenamines and -imines......
Table 7D. 2,3-Disubstituted Indoles from 2-Nitrostyrenes, 2-Isocyanostyrene, and 2-Allylanilines.
Table 8. Indoles via Arene Vinylation......
Table 9. 2,3-Unsubstituted Indoles via N-Vinylation and N-Arylation......
Table 10. 2-Substituted Indoles via N-Vinylation and N-Arylation......
Table 11. 3-Substituted Indoles via N-Vinylation and N-Arylation......
Table 12. 2,3-Disubstituted Indoles via N-Vinylation and N-Arylation......
Table 13. Solid-Phase Synthesis of Indoles from Alkynes......
Table 14. Solid-Phase Synthesis of Indoles from Alkenes......
Table 15. Solid-Phase Synthesis via N-Arylation......
Table 16. Miscellaneous......
REFERENCES......
INTRODUCTION
The palladium-catalyzed assembly of the functionalized pyrrole nucleus on a benzenoid scaffold is a widely used synthetic tool for the preparation of indole derivatives.1-10 This construction can be categorized into four main types: (1) cyclization of alkynes, (2) cyclization of alkenes, (3) cyclization via C-vinylation reactions, and (4) cyclization via N-arylation or N-vinylation reactions. The first approach is by the far the most versatile in terms of the range of the added functional groups and of the bonds that can be created in the construction of the pyrrole ring. This method is based on the utilization of precursors containing nitrogen nucleophiles and carbon–carbon triple bonds. The nitrogen nucleophile and alkyne moiety may be part of the same molecule or belong to two different molecules. Some of the most general and versatile alkyne-based cyclizations to indoles are summarized in Fig. 1.
(1)
Assembly of the pyrrole nucleus from precursors containing nitrogen nucleophiles and carbon–carbon double bonds entails only intramolecular cyclizations and, considering the bonds that can be created in the cyclization step, appears less versatile than the alkyne-based approach. Alkene-based cyclizations to give indoles are summarized in Fig. 2.
(2)
Cyclization to indoles via arene vinylation has limited synthetic scope. However, it is interesting that, unlike the above alkyne- and alkene-based procedures where the site of the oxidative addition of carbon–X bond to the palladium(0) species is located on the benzenoid ring (Figures 1 and 2), the oxidative addition site is located in a vinylic fragment tethered to the benzenoid ring in this type of cyclization. Furthermore, it is the sole example of the construction of the pyrrole ring via palladium-catalyzed vinylation of an ortho-unfunctionalized aromatic ring (Fig. 3). Such direct arene vinylation and arylation processes are of great current interest.11-14
(3)
Finally, indoles can be prepared via cyclizations proceeding through N-arylation and N-vinylation reactions (Fig. 4) that are based on the pioneering work15-22 on palladium-catalyzed carbon–nitrogen bond forming reactions from aryl halides or triflates with amines, amides, and carbamates.
(4)
In general, only synthetic procedures where palladium catalysis is involved in the pyrrole ring construction event are discussed herein. Palladium-catalyzed reactions producing indole-related compounds, such as azaindoles, indazoles, indolines, oxindoles, bis(indolyl)methanes, and related systems, or condensed polycyclic compounds, such as carbolines, carbazoles, indoloquinolines, indoloquinazolines, and related systems, are not discussed. Indoles are classified as 2-substituted, 3-substituted, and 2,3-disubstituted derivatives without considering the functionalization of the nitrogen atom.
MECHANISMS
A variety of reaction parameters such as solvents, temperature, the nature of the substrates and ligands, bases, and additives, and sometimes even their combination can influence the mechanism operating in this reaction. In addition, catalytic cycles usually consist of several consecutive steps and the chemical nature as well as the reactivity of each intermediate can differ depending on reaction conditions. Some reaction parameters can also exhibit opposing effects on different steps of a catalytic cycle. In view of this complexity, it is not surprisingthat the literature contains few detailed mechanistic studies. Therefore, the word mechanism is used in this section to indicate a plausible rationalization of how products are formed rather than an experimentally supported mechanism. These plausible rationalizations are categorized into two main types corresponding to two main sections: palladium(II)- and palladium(0)-catalyzed reactions. The two main sections are subclassified by the proposed reaction mechanisms. Since the palladium-catalyzed cyclization to indoles is an extremely diverse class of reactions from a mechanistic point of view, only the main mechanistic proposals are discussed below.
Palladium(II)-Catalyzed Cyclizations
Most of the syntheses of indoles catalyzed by Pd(II) salts involve cyclizations of aryl alkynes containing ortho-nitrogen nucleophiles (Fig. 1, disconnections a and a+d) or allylic and vinylic arenes containing ortho-nitrogen nucleophiles (Fig. 2, disconnection a).”
Palladium(II) salts are fairly electrophilic species. For that reason, the first event leading to cyclization in palladium(II)-catalyzed reactions is usually considered to be the coordination of acetylenic or olefinic -electrons to a palladium(II) species. As shown in Schemes 1 and 2 for 2-alkynylanilides23 and 2-allylanilines,24 the resultant -palladium complexes 1 and 3 subsequently undergo an intramolecular nucleophilic attack of a nitrogen nucleophile across the activated carbon–carbon multiple bond to give the aminopalladation adducts 2 and 4, respectively. With acetylenic precursors, protonolysis of the carbon–palladium bond of 2 forms 2-substituted indoles andregenerates the active catalytic species. This approach to the construction of the pyrrole ring, which ultimately allows for the addition of nitrogen–hydrogen bonds across carbon–carbon multiple bonds, is frequently described as a hydroamination reaction. With alkene precursors, the conversion of aminopalladation adducts 4 into indole derivatives involves a -elimination step that ultimately leads to the formation of palladium(0) species. Consequently, for the reaction to be catalytic with respect to palladium(II), the presence of stoichiometric amounts of oxidants such as CuCl2, Cu(OAc)2, benzoquinone, tert-butyl hydroperoxide (TBHP), or MnO2 is required to allow for the in situ conversion of palladium(0) into palladium(II).
(5)
(6)
Palladium(0)-Catalyzed Cyclizations
Cyclizations to indoles catalyzed by a palladium(0) species provide a wider variety of applications than palladium(II)-catalyzed cyclizations, and some are among the most efficient and generally applicable methods. They include a range of alkyne-based syntheses (Fig. 1, disconnections a+d, c+e, a+c, c, b, and a+f), alkene-based syntheses (Fig. 2, disconnection c), cyclization to indoles via arene vinylation (Fig. 3), and cyclizations based on N-vinylation and N-arylation reactions (Fig. 4).
Palladium(0) complexes are usually nucleophilic and the initial step of the vast majority of palladium(0)-catalyzed cyclizations to indoles involves an oxidative addition of carbon–X bonds (X = I, Br, Cl, OTf) to coordinatively unsaturated palladium(0) species to give carbon–palladium(II)–X intermediates that contain an electrophilic palladium. In general, the oxidative addition step is favored by increasing the electron density on palladium. The observed rate of oxidative addition with carbonaryl–halogen bonds increases in the order C–F < C–Cl < C–Br < C–I (aryl fluorides are almost inert).25 The reactivity of aryl triflates is approximately between that of aryl iodides and aryl bromides. In the presence of monodentate ligands, a cis-complex is likely to be the initial product of the oxidative addition. Subsequently,isomerization gives rise to the thermodynamically more stable trans-complex. With bidentate ligands, the cis-complex is the usual intermediate.
The aminopalladation/reductive elimination mechanism has been suggested to account for the cyclization to indoles of 2-alkynyltrifluoroacetanilides,7 2-alkynylisocyanobenzenes,26 2-alkynylisocyanatobenzenes27,28 (Fig. 1, disconnection a+d) and 2-halo-N-alkynylanilides29 (Fig. 1, disconnection c+e). Although some differences exist in the details of the mechanistic proposals for the cyclization of these compounds, the general features of the aminopalladation/reductive elimination pathway are well described by the example shown in Scheme 3 for the synthesis of free (NH)2,3-disubstituted indoles from 2-alkynyltrifluoroacetanilides 5. In this mechanism, coordination of -acetylenic electrons to organopalladium complexes, generated in situthrough oxidative addition of organic precursors to palladium(0) species, afford -alkyne-organopalladium complexes 6 that subsequently undergo nucleophilic attack of the nitrogen atom across the activated carbon–carbon triple bond to give the -indolylpalladium intermediates 7 (the aminopalladation adduct). The free indole product (NH) is formed by hydrolysis of the amide bond and a reductive elimination step (not necessarily in this order) that produces a new carbon–carbon bondand regenerates the active palladium(0) catalyst.
(7)
The palladium-catalyzed reaction of aryl halides with alkynes not containing nucleophiles close to the carbon–carbon triple bond may form -alkyne--arylpalladium complexesthat, unable to undergo an intramolecular nucleophilic attack across the carbon–carbon triple bond, afford carbopalladation adducts 8 (Eq. 1). These adducts, depending on reaction conditions, can be converted into a variety of products via an intermolecular process, as exemplified in Eq. 1.
(8)
When the aryl moiety added to palladium(0) contains a nitrogen nucleophile adjacent to the oxidative addition site, as shown in Scheme 4, the carbopalladation adduct 10 can undergo anintramolecular halide displacement from the palladium to give a nitrogen-containing palladacycle 11 that subsequently affords the indole product via a reductive elimination step.30,31 This carbopalladation route (Fig. 1, disconnection a+c) is one of the most versatile and efficient indole syntheses.
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Alkynes or allenes containing a tethered aryl halide fragment such as 2-iodo-N-propargylanilides or N-2-halophenylallenamides can form carbopalladation adducts intramolecularly (Fig. 1, disconnection c). The addition intermediates derived from alkynes have been trapped by norbornene to give indoles containing polycyclic substituents at C(3).32 Palladium acetate and (n-Bu)3P catalyze the cyclization of 2-alkynyl-N-alkylidene-anilines to indoles (Fig. 1, disconnection b).33
The formation of 2-aminomethylindoles 17 from 3-(2-trifluoroacetamidophenyl)-1-propargyl carbonate ester 1234 (Fig. 1, disconnection a+f) is likely to proceed through the following basic steps (Scheme 5): (a) initial formation of the -allenylpalladium complex 13—via an SN2’ reaction of the palladium complex with ester 12—that is in equilibrium with the -propargylpalladium intermediate 14;35 (b) intramolecular nucleophilic attack of the nitrogen at the central carbon of the allenyl/propargylpalladium complex;36-42 (c) protonation of the resultant carbene complex 15 to give the -allylpalladium complex 16; (d) site selective intermolecular nucleophilic attack of the nitrogen nucleophile at the less-hindered allylic terminus of 16. A similar mechanism is most probably operating for the conversion of ester 12 into 2-alkylindoles.43
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The intramolecular version of the Heck reaction has been used for the construction of the indole ring44 (Fig. 2, disconnection c) and an intramolecularhalide displacement within arylpalladium intermediates by carbon nucleophiles has been proposed to account for the cyclizationof 2-haloanilino enamines to indoles (Fig. 2, disconnection c).45,46Phenolic carbamates containing a bromovinylic fragment bound to the nitrogen atom are thought to give indole carbamates through an arene vinylation mechanism (Fig. 3).47
The general features of the N-arylation and N-vinylation method (Fig. 4) are shown in Scheme 6 for the cyclization of 2-chlorophenylacetaldehyde N,N-dimethylhydrazone (18) to 1-dimethylaminoindole (21)48 and entail (a) an oxidative addition of the aryl chloride fragment to a palladium(0) species to afford the -arylpalladium intermediate 19,(b) an intramolecular chloride displacement by nitrogen to give the palladacycle 20, and (c) a subsequent reductive elimination leading to the formation of 1-dimethylaminoindole (21).
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SCOPE AND LIMITATIONS
Indole Formation from Alkynes
2-Substituted Indoles.From 2-Alkynylanilid(n)es.The majority of the examples describing the alkyne-based synthesis of 2-substituted indoles originate from the observation that these indole derivatives can be prepared via palladium(II)-catalyzed cyclization of 2-alkynylanilides (Fig. 1, disconnection a; Scheme 1). The main variations of this method involve the synthesis of the starting 2-alkynylanilides. In early examples, the preparation of 2-alkynylanilides features the coupling of preformed copper(I) salts of terminal alkynes with 2-thallated anilides in acetonitrile.23 This procedure has rarely found applications in indole synthesis, very likely because of the toxicity of the metal used. 2-Bromoacetanilides have subsequently been used in the coupling reaction,49but the2-alkynylacetanilides are prepared through palladium(0)-catalyzed reaction of2-bromoacetanilides with alkynylstannanes, a procedure that still uses toxic reagents. A significant improvement came with the discovery50 that treatment of terminal alkynes with 2-haloanilides under Sonogashira conditions51,52 can directly afford indole products in a single step through a tandem coupling–cyclization process (Eq. 2; Fig. 1, disconnection a+c).
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The palladium-catalyzed coupling of terminal alkynes with aryl halides or triflates containing a nitrogen nucleophile in theortho position followed by a palladium-catalyzed cyclization step has been extensively applied, providing stepwise and tandem syntheses of 2-substituted indoles. The cyclization of the coupling products can also be performed using base-mediated50,53-64 and copper-catalyzed protocols.50,65-69 The involvement of both palladium and copper catalysis in the cyclization of 2-alkynylanilines or their N-substituted derivatives has also been reported.50,68 In some cases, particularly when indole products are obtained through tandem processes based on Sonogashira cross-coupling followed by a cyclization reaction, the specific role of the palladium catalyst and/or the base and/or copper in the formation of the pyrrole ring are not clearly established.