Indole ring preparing

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

The material in the succeeding chapters describes both the synthesis of the indole ring and means of substituent modification which are especially important in indole chemistry. The first seven chapters describe the preparation of indoles from benzenoid precursors. Chapter 8 describes preparation of indoles from pyrroles by annelation reactions. These syntheses can be categorized by using the concept of bond disconnection to specify the bond(s) formed in the synthesis. The categories are indicated by the number and identity of the bond(s) formed. This classification is given in Scheme 1.1. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20"C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

On saponification l-(2-methoxycarbonylphenyl)pyrrole yields l-(2-carboxyphenyl)pyrrole, m.p. 106-107°, which on reaction with polyphosphoric acid at 70° is cyclized to 9-keto-9H-pyrrolo-(l,2-a)indole in 28-32% yield. Through the choice of the appropriate amine and acetal components, the substituted l-(2-meth-oxycarbonylphenyl)pyrroles become readily available intermediates in the preparation of a variety of derivatives of the pyrrolo( 1,2-a) indole ring system. 

Palladium-catalyzed reactions of arylboronic acids have been utilized to craft precursors for constructing indole rings. Suzuki found that tris(2-ethoxyethenyl)borane (149) and catechol-derived boranes 150 readily couple with o-iodoanilines to yield 151, which easily cyclize to indoles 152 with acid [158]. Kumar and co-workers used this method to prepare 5-(4-pyridinyl)-7-azaindoles from 6-amino-5-iodo-2-methyl-3,4 -bipyridyl [159], A similar scheme with catechol-vinyl sulfide boranes also leads to indoles [160]. A Suzuki protocol has been employed by Sun and co-workers to synthesize a series of 6-aryloxindoles [161]. 

Palmisano and Santagostino first reported Stille reactions of indole-ring stannylindoles with their detailed studies of 1V-SEM stannane 159 [170], Thus 159, which is readily prepared by C-2 lithiation of A-SEM indole and quenching with Bu3SnCl (88%), couples under optimized Pd(0)-catalyzed conditions to give an array of cross-coupled products 160. Some other examples and... 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cyclizations of 254 and 255 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 254 and the IV-benzylindole 256 [271,272]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 257, and they prepared a series of peripheral-type benzodiazepine receptors 258 using this chemistry. For example, 258 (n = 3, R = n-Pr) is obtained in 81% yield. 

In a synthetic route to the E-azaebumane series, an intramolecular heteroaryl Heck reaction was the major cyclization strategy [140], Under Jeffery s ligand-free conditions, E-azaebumane skeleton 182 was prepared from bromopyridine 181. The migratory insertion occurred at C(2) of the indole ring. 

In spite of its formal similarity to the above mentioned annulation processes, the reaction shown in 4.37. includes a unique migration step. Oxidative insertion of the palladium into the phenyl-iodine bond is followed by the migration of the palladium onto the more electron rich indole ring. The 2-indolylpalladium complex than carbopalladates the pendant alkync moiety and the process ends by the formal activation of a C-H bond of the phenyl substituent and subsequent reductive elimination, furnishing the pentacyclic product.48 The same strategy has been utilised in the preparation of the indoloindolone framework from /V-bcnzoyl-3-(o-iodophcnyl)-indolc in an oxidative addition - palladium migration - C-H activation sequence.49... 

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