Synthesis of indoles

Indoles are usually prepared from non-heterocyclic precursors by cyclisation reactions on suitably substituted benzenes they can also be prepared from pyrroles by construction of the homocyclic aromatic ring, and from indolines by dehydrogenation. 

Because of the importance of indoles in natural products synthesis and pharmaceutical chemistry, many new routes to indoles and improvements of older reactions have been developed since the last edition of this book. This section discusses the most important methods now available, often those which have been used most frequently and are the most adaptable.  

Still the most widely used route, the Fischer synthesis consists of heating an arylhydrazone, usually with acid, sometimes in an inert solvent ammonia is lost and an indole formed. 

The Fischer synthesis,first discovered in 1883, involves the acid- or Lewis acid-catalysed rearrangement of a phenylhydrazone with the elimination of ammonia. The preparation of 2-phenylindole illustrates the process in its simplest form.  

The full mechanistic details of the multi-step Fischer sequence are still not completely sure, but there is considerable evidence that the sequence shown below operates, for example labelling studies proved the loss of the /3-nitrogen as ammonia, and in some cases intermediates have been detected by C and N NMR spectroscopy. The most important step - the one in which a carbon-carbon bond is made - is electrocyclic in character and analogous to the Claisen rearrangement of phenyl allyl ethers. 

1 Synthesis of Interesting Indole Structures through Asymmetric Catalysis 

Organocatalysis (See Chapter 2) MacMillan s group applied multiple asymmetric catalytic strategies to develop 

As a remarkable fact, the induction in the enamine addition step (second cycle) is believed to arise from catalyst control that would provide high levels of diastereo-selectivity for the overall process. As represented, a single imidazolidinone catalyst could enable both activation cycles, modulating control of the enforced sense of enantio-and diastereoinduction. 

SCHEME 6.12 Cascade reaction through iminium-enamine catalysis. 

SCHEME 6.14 One-pot cascade catalysis with star polymer catalysts. 

This reaction can be considered to proceed via arylation of the enamine tautomer of 1. In the presence of bulky, electron-rich phosphine ligands such as 2, the indole products are obtained in good yields. In addition to hydrazones, presynthesized 

PdCl2(PPh3)2 PPhs (10 mol%) DIPEA, THE MeOH, reflux 

Recently, Newman and Lautens reported a strategy for the synthesis of 2-bromoindoles incorporating a reversible oxidation addition process [32]. A catalyst system using the tetrafluoroborate salt of electron-rich and bulky tri-t-butylphosphine was used which allowed access to 2-bromo-5-iodoindole 10 in 68% yield, noteworthy for its potential for further synthetic elaboration. 

Kaspar and Ackermann also reported that the process could be performed as a three-component system, featuring in situ generation of the key o-alkynylhaloarenes via the incorporation of a tandem Sonogashira reaction [35]. Related chemistries have been reported for the synthesis of 2-aminoindoles from ynamide-based substrates [36], A-aminoindoles from hydrazine-based nucleophiles [37], and N-unsubstituted indoles via the use of ammonia as the coupling partner [38,39], 

The utility of this route was demonstrated with a synthesis of the natural product demethylasterriquinone A [44], -(Reverse prenyl)indole 15 was utilized as a key intermediate in this synthesis, which also demonstrates that sterically demanding N-nucleophiles can be incorporated. Willis and co-workers have also reported a copper-catalyzed version. In general, this variant was more limited however, greater 

The Batcho indole synthesis involves the conversion of an o-nitrotoluene to a (3-dialkyl-amino-o-nitrostyrene with dimethylformamide acetal, followed by reductive cyclization to indoles. This provides a useful strategy for synthesis of substituted indoles (Eq. 10.49).63 

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-arylindoles (Eq. 10.50).64 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole65 and 5-amino-7-ethoxycarbonylindole for use in synthesis of l//-pyrrolo[3,2-g]quinazoline ring system (Eq. 10.51)66 have been prepared from the appropriate o-nitrotoluene. 

Recently, synthesis of the 4-arylindole portion of the antitumor agent diazonamide has been achieved starling from 3-bromo-2-methylnitrobenzene via Suzuki coupling and the Batcho reaction.67b 

The 2-aminophenethyl alcohols resulting from condensation of ort/io-nitrotoluenes are good precursors for preparation of indoles. Watanabe and coworkers have developed ruthenium-catalyzed dehydrogenative iV-heterocyclization for synthesis of indoles and other heterocycles from 2-aminophenethyl alcohols or 2-nitrophenylethyl alcohols (Eq. 10.52). 69a The oxidative cycli-zation of 2-aminophenethyl alcohols are also catalyzed by Pd-based catalysts.69 

A neat synthesis of 4-nitroindole depends on an acylation-deacylation sequence from 2-methyl-3-nitroaniline, as shown in Eq. 10.53.70 On the other hand, treatment of /V-protected indoles with acetyl nitrate generated in situ at low temperature gives the corresponding 

In 2014, Rh(III)-catalyzed intramolecular annulation of alkyne-tethered acetanilides for the synthesis of fused tricyclic indoles 3 via C-H activation was developed by the groups of Liu, Jia, and Li [6a-c]. The reactions have a good substrate scope, utilize molecular oxygen as the cooxidant, and proceed with complete regioselectivity. It is interesting to note that only the sterically hindered ortho-C-H bond of the arene moiety participated in C-C bond formation (Eq. (5.3)). Similarly, the cyclization of anilides with allyl carbonates also proceeded to form 2-substituted indoles 4 (Eq. (5.4)) [6d]. 

Various convenient methods for the synthesis of protected indoles have been reported by several groups [7a-e]. Interesting C-H oxidative coupling reactions of various arenes with alkynes are shown in Eqs. (5.5)-(5.9). These methods allow quick access to a number of functional molecules in good yields via an N-N bond oxidative cleavage or use of an external oxidant. Excellent regioselectivity was achieved by using asymmetrically substituted alkynes. 

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles, 

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There are a number of other sources of information available about the synthesis of indoles. The most comprehensive entree to the older literature is through Volume 25, Parts I-IIl, of The Chemistry of Heterocyclic Compounds, which were published between 1972 and 1979[23]. Work to the early 1980s is reviewed in Comprehensive Heterocyclic Chemistry[24 and a second edition is forthcoming[25]. Other reviews emphasizing recent developments are also availablc[26-28]. 

A two-step synthesis of indoles from o-nitrobenzaldehydes proceeds by condensation with nitromcthanc followed by reductive cyclization. Like the Leim-gruber Batcho method, the principal application of the reaction is to indoles with only carbocyclic substituents. The forniation of the o,p-dinitrostyrenes is usually done under classical Henry condensation conditions but KF/18-crown-6 in propanol was found to be an advantageous reaction medium for acetoxy-substituted compounds[1]. The o,p-dinitrostyrenes can also be obtained by nitration of p-nitrostyrenes[2]. 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

Phenylhydrazine has been used in the synthesis of indole derivatives. The hydrazones of aldehydes and ketones contain-... 

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

Anisole and mixtures of diethyl ether with aromatic hydrocarbons have both been widely employed as solvents for these reactions. Ethers other than diethyl ether and anisole have also been successfully used (cf. refs. 14-17). Hcxamethylphosphorotriamide has recently been used as a solvent for indole Grignard reactions. Young and Mizianty have recently described the use of an aromatic magnesium halide (phenylmagnesium bromide) for the synthesis of indole magnesium bromide. 

The combination of silyl enol ethers and fluoride ion provides more reactive anions to give alkylated nitre compounds in good yields after oxidation v/ith DDQ, as shovm in Eq. 9.22. This process provides a new method for synthesis of indoles and oxyindoles fsee Chapter 10, Symhesis of Hatarocydic Compoioids). 

The nonaromatic lactones from cis-13, and trcyclohexaneacetic acid14 were important intermediates in the synthesis of indole alkaloids. 

Fig. 26 Solid-phase synthesis of indol-2-ones by microwave-assisted radical cyclization. Reagents and conditions a NaH, DMF b BusSnH, AIBN, DMF, MW 170 °C, 45 min, sealed vessel c 10% TFA in CH2CI2. R = H, F, Me, OCF3 R = Phe, 3-OMe - Phe, 4-Me - Phe, 3,4-0CH20-Ph, (CH2)4, diMe R" = H, Me R " = H, Me...

Thus far, we have discovered and demonstrated a new and effident method for the synthesis of indoles from various carbonyl compounds. This, in conjunction with the use of alkyries in the palladium-catalyzed indolization, widens the spectrum of indoles that can be prepared by these means. The simple procedure, mild reaction conditions, and ready availability of the starting materials render these methods valuable additions to indole chemistry. We next extended this method to the synthesis of the indole core of a PGD2 receptor antagonist, laropiprant 3. 

Scheme 2.123. Synthesis of indols via a domino carbolithiation/addition/cyclization process.

In continuation of the aforementioned reaction, Hiroya and coworkers used cop-per(II) acetate for the synthesis of indoles 2-943 in reasonable yields from the corresponding ethynylanilines 2-941 by a domino intermolecular Michael addition/cop-per-assisted nucleophilic tosylate displacement reaction via 2-942 (Scheme 2.211) [482],... 

The sequence could even be prolonged by including a Pummerer reaction. Thus, treatment of 4-103 with trifluoroacetic acid (TFA) gave the furan 4-104, which underwent a cycloaddition to furnish 4-105 the erythryna skeleton 4-109 was obtained after subsequent addition of a Lewis acid such as BF3- Et20 (Scheme 4.23) [33]. It can be assumed that 4-106, 4-107 and 4-108 act as intermediates. In a more recent example, these authors also used the procedure for the synthesis of indole alkaloids of the Aspidosperma type [34]. 

Yamazaki, Kondo and coworkers [78] reported on a combination of a Heck reaction and an animation on solid phase for the synthesis of indole carboxylate 6/1-148, employing an acetylated immobilized enamide 6/1-145 and a bifunctionalized... 

Pal and coworkers described a Pd°-catalyzed water-based synthesis of indoles 6/1-224 using iodoanilines as 6/1-222 and alkynes 6/1-223 in up to 89% yield (Scheme 6/1.57) [112],... 

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