Synthesizing indoles

A classical method for synthesizing indoles is by the Fischer indolization, which involves the cyclization of arylhydrazones in the presence of strong acids. Lipinska... 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(II) species. Pleixats and coworkers treated iodophenylsulfide 151, obtained from o-iodoaniline and crotyl bromide in two steps, with... 

Adapting Gribble s method for synthesizing indol-3-yl triflate [37], Mdrour et al converted 2-formyl- l-(phenylsulfonyl)- l//-indole (31) to indol-2-yl triflate 32 in two steps. 32 was subsequently coupled with benzofuryl-2-boronic acid to furnish 2-benzofurylindole 33 [38, 39]. In another case, 2-bromoacetaniline was coupled with 2-formyl-3-furylboronic acid 35 [40]. The resulting Suzuki coupling adduct underwent a spontaneous cyclization, forming tricyclic furo[2,3-c]quinoline 36. 

Unfortunately, the reaction fails with acetaldehyde and cannot, therefore, be used to synthesize indole... 

The absolute configuration of 1 was established in 1967.4 Since then, l5 and 2a6 have been the subject of several syntheses. A challenge in both cases was the stereochemistry at the three stereogenic centers of the quinolizidine subunit. Tietze and co-workers have previously synthesized indole alkaloids of the corynanthe group,7 this problem is based on the recent enantioselective total synthesis of 1.2,8,12... 

HELMLINGER, J., RAUSCH, T HILGENBERG, W., Localization of newly synthesized indole-3-methyl-3-glucosinolate (= glucobrassicin) in vacuoles from horseradish (Armoracia msticana)., Physiol. Plant., 1983,58, 302-310. 

The first relationship between members of the indole group and simpler benzene derivatives was that established by Baeyer and Emmerling, 1869, in synthesizing indole from ortho-mtro cinnamic acid by fusion with potassium hydroxide and iron filings. The steps in the synthesis are probably as follows ... 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(ll) species. Pleixats and coworkers treated iodophenylsulfide 276, obtained from o-iodoaniline and crotyl bromide in two steps, with Pd(Ph,P)4 and EtjN in refluxing acetonitrile to form the intramolecular Heck cychzation product 277 [175]. The mechanism is akin to that of the Mori-Ban indole synthesis (see page 27). In another case, the intramolecular Heck cyclization of enamidone 278 with a pendant thienylbromide moiety furnished the 6-endo-trig product, indolizine 279, in 63% yield, along with the debrominated enamidone 280 in 37% yield [179]. 

Anilinosulfonium compounds of type 17 can also be used to synthesize indol-2(3. 0 Ones 19 starting from A -chloroanilines and (methylsulfanyl)acetic ester. The (o-aminophenyl)acetic esters 18 obtained via the S-ylide lead to indol-2(3//)-ones 19 after cyclization and reductive desulfurization. 

This reaction has been applied for synthesizing indoles with substitutents in the benzene ring rather than the pyrrole moiety of the indole ring. In addition, this method has been adapted for synthesizing amides and esters via solid-support synthesis. ... 

This reaction was first reported by Nenitzescu in 1929. It is the synthesis of a 5-hydroxyindoie derivative involving the condensation between a 1,4-benzoquinone and a /3-amino-a ,/3-unsaturated compound and subsequent cyclization. Therefore, this reaction is generally known as the Nenitzescu indole synthesis, Nenitzescu reaction, j or Nenitzescu synthesis.Occasionally, it is also referred to as the Nenitzescu cyclization, Nenitzescu condensation, s.2i qj. Nenitzescu process. It should be pointed out that the synthesized indole derivatives by this reaction are restricted to those with an electron-withdrawing group at position 3, such as an ester or a carbonyl group. In addition, the completion of this reaction requires an appropriate oxidizing agent to convert the initial adduct into the indole derivative. i From monosubstituted quinone, 4-, 6- and 7-substituted 5-hydroxyindole derivatives all are possible products, but 6-substituted isomer is the one normally obtained. ... 

Wacker and Kasireddy described a solid-phase synthesis of 2,3-disubstituted indoles (Scheme 5) [37] via the modified Madelung synthesis reported by Reinhoudt [34, 35]. The basic approach is shown in equation 1, and several synthesized indoles are posted. 

Schirok also employed dimethyl sulfonium ylide to synthesize indoles, but where the indole nitrogen is derived from an intermolecular reaction of the styrene epoxide 34 with a primary amine (Scheme 5) [15]. The reaction proceeds by amination of the epoxide 34 to give amino... 

Kruse also reported that the intervention of a semicarba-zone derivative prepared from the p-dimethylaminostyrene often led to superior yields of the resulting indole. This modification is illustrated in Scheme 6 (equation 1). Kruse s rationale is that the low solubility of the semicar-bazone minimizes polymerization reactions and effectively increases the catalyst loading [55]. This modification was employed by the groups of Leonard [57], Corrie [58], and Harada [59] to synthesize indoles 47, 48, and 49, respectively. 4-Aminoindole (47) was prepared from 2,6-dinitro-toluene, 4-A,A-dimethylaminoindole (48) started from... 

Aqueous hydrolysis furnishes the aldehyde and then indole by cyclodehydration. Walker first used catalytic hydrogenation in the Pschorr-Hoppe indolization to prepare 5,6-dimethoxyindoles (Scheme 2, equations 2-4) [3]. With four moles of H, ammonia is liberated (equations 2,3), but with three moles of H the product retains the 2-amino group (equations 4, 5) [3]. Independently from Walker, Plieninger and Ndgradi synthesized indole and 5,6-dimeth-oxyindole from the respective o-nitrophenylacetonitriles using Raney nickel hydrogenation and/or sodium in amyl alcohol [4]. 

The leading figure in the discovery and early chemistry of indole is Adolf Baeyer, who first synthesized indole by heating oxindole with zinc powder [1] and by reducing 2,3-dichloroindole with zinc/KOH [2], For an excellent review of the early indole chemistry, see Sumpter and Miller [3], Given Baeyer s seminal history with indole, it was fitting that he and Jackson discovered in 1880 the first practical synthesis of indoles the Baeyer-Jackson indole synthesis (Scheme 1, equation 1) [4, 5], which entails the reductive cyclization of o-nitrobenzyl carbonyl compounds. Since 1880, this simple indolization has been used extensively, as seen both in this chapter and in previous chapters. Scheme 1 includes some additional early indole syntheses of this type (equations 2-4) [6-8]. For a discussion of the early syntheses of indoloindoles (cf. equation 4), see Samsoniya and Trapaidze [9]. 

In one of the first significant modifications of the Watanabe ruthenium catalyst for indolization, Zhang, Ding, and coworkers used [Ru(CO)jXantphos]j (1) to synthesize indoles from anilines and vicinal symmetrical and unsymmetrical diols both (Scheme 4) [26]. Madsen and his colleagues employed a RuCyphosphine catalyst to prepare 2,3-disubstituted indoles from anilines and 1,2-diols, and they also found that a [Cp IrCl2l2/MsOH catalyst is equally effective in this reaction [27], Iridium-based... 

Antonchick and colleagues made use of PIDA to craft a series of 1-arylcarbazoles (Scheme 7, equation 1) [17], and Muniz s team employed iodosobenzene and 2,4,5-tris-isopropybenzene sulfonic acid (TIPBSA) as a modified Koser reagent to synthesize indoles (equation 2) [18],... 

In similar Heck-type reactions, commercially available palladium acetate is used as a catalyst, providing a new route for synthesizing indoles, benzofurans, 1,2-dihydroisoquinolines and other interesting derivatives, quite gratifyingly with regioselectivities often matching those reported in our chemistry. ... 

The mercuration of atenes followed by transmetallation to BH3 or BCI3 is advantageous over the lithiation route in synthesizing indole-... 

SCHRODER. 1984. The T-region of Ti plasmids codes for an enzyme synthesizing indole-3-acetic acid. 

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