Indoles with aziridines

The most convenient syntheses of tryptamines involve treatment of indole with aziridines. The reaction of indole (143) with aziridinium tetrafluoro-borate (144) afforded tryptamine (145) in 40% yield (Scheme 29). However, lack of regioselectivity in this reaction gives l-(2-aminoethyl)indole (146) as a by-product. 

Epoxides and aziridines are also capable of electrophilic subsitution of indoles. Indolylmagncsium bromide and cyclohexene oxide react to give 3-(lrans-2-hydroxycyclohexyl)indole[14]. Reaction of indoles with epoxides also occurs in the presence of Lewis acids. For example, indole reacts with methyl 2S,3R-epoxybutanoate at C3 with inversion of configuration[15]. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

IV-sulfonated aziridines have also been used in Friedel-Ciafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with aziridines has also been reported ... 

An efficient and economical new approach toward the synthesis of 7-aminoaziridinomitosenes, as represented by compound 96, has been developed in less than 15 total operations from commercially available chemicals. Overall our scheme represents the second total synthesis of a fully functionalized aziridinomitosene. At one stage, new insights into the mechanistic details involving the reaction of l,2-epoxypyrrolo[l,2-c]indoles with nucleophiles are provided. Notably, the route presented has the advantage of accessing both the aziridine and 7-amino substituents in deprotected form. Further application of this synthetic approach to additional C-9-substituted mitosenes can be anticipated. 

The condensation of indoles with epoxides or aziridines can also be conducted on the surface of silica <2005JOC3490>. 

Indole and several indoles functionalized at C-2 were condensed with aziridines, vinylaziridines, oxiranes, and vinyloxiranes in the solid state on the surface of silica (Equations 134 and 135) <2005JOC3490>. 

The indole 1211 was converted to quinone 1212 by a convenient procedure involving reduction to the indoline followed by Fremy oxidation (Scheme 233) <1998B15199>. The indoline is an aminobenzene derivative, a class of compounds known to undergo Fremy oxidations readily. The Fremy s salt also converts the indoline back to the indole resulting in quinone 1212 as the final product. Aziridination of quinone 1212 to afford compound 1213 was carried out with aziridine under aerobic conditions (reductive addition of aziridine followed by air oxidation to the quinone). 

The treatment of the magnesium derivative of indole (147) with aziridine in refluxing xylene led to tryptamine (145) (46%) (Scheme 30). ... 

Indoles react with epoxides and aziridines in the presence of Lewis acids (see 20.4.1 for reaction of indolyl anions with such reactants) with opening of the three-membered ring and consequent 3-(2-hydroxyethylation) and 3-(2-aminoethylation) of the heterocycle. Both ytterbium triflate and phenylboronic acid are good catalysts for reaction with epoxides under high pressure silica gel is also an effective catalyst, but reactions are slow at normal pressure and temperature. Reaction with aziridines can be catalysed by zinc triflate or boron trifluoride. °... 

The expansion of smaller rings into the heterocyclic ring of the benzazepines has been achieved with aziridine, indole, quinoline, and isoquinoline systems, usually in high yields, and benzazepines with the highest degree... 

An interesting intramolecular cycloaddition reaction of indoles with azides has also been reported. Heating solutions of l-(D-azidoalkylindoles 199, which bear an electron-attracting substituent (e.g., CHO, COMe, C02Me, CN) at C-3, has led to the formation of tricyclic indoles 201 as products [87] (Scheme 55). The authors suggest that after the initial 1,3-dipolar cycloaddition, the intermediate triazoline 200 loses nitrogen (perhaps via an aziridine intermediate) to produce the tricyclic products 201. 

The direct functionalization reaction of 2,3-disubstituted indoles with various N-Ts aziridines was catalyzed by Sc(OTf)3 (eq 35). The reaction proceeds in mild conditions using various 2,3-disubstituted indoles and aziridines, leading to the Ce-functionalized indole as the major regioisomer. 

Ring-opening reactions with 3-alkylaziridine esters 36 take a similar course. The reactions are in practically all cases regio- and stereospecific with attack at C-3. An important difference is that the aziridine ring needs to be activated by an electron-withdrawing substituent, such as a tosyl or a benzyloxycarbonyl group. In addition, for benzenethiol, indole, and DMF, catalysis with BF3 was necessary (Scheme 22) [31]. 

In vivo studies were carried on the aziridinated cyclopent[Z ]indole quinone out before it was discovered that the aziridinyl ring did not participate in DNA alkylation. The results in Fig. 7.22 for the B16 melanoma syngraft model reveal that there was substantial reduction of tumor mass at 3 mg/kg. However, toxicity (animal deaths) became apparent at 5 mg/kg. On the other hand, human lung cancer xenografts in SCID (severe combined immunodeficient) mice were reduced to 50% mass with 3x1 mg/kg doses without any animal deaths. 

Nakagawa devised a concise synthetic route to physostigimine (169) where the key step involves the alkylative cyclization of 1,3-dimethylindole (167) with (Z)-aziridine catalyzed by Sc(OTf)3 and TMSC1 to give 168, which, in turn, can be converted into 169 . A similar asymmetric approach to this natural product was also developed by these authors via treatment of tryptophan carbamates with the Corey-Kim reagent so as to induce intramolecular cyclization to the pyrrolo-indole skeleton . 

Various N-protected aziridines have been reacted with N-lithiated indoles to afford N-alkylated and 3-alkylated products, the exact ratios depending on the reaction solvent and the nature of the N-protecting group <1989CB2397>. Indoles and V-alkyl indoles afford tryptamine derivatives on reaction of aziridines under Lewis acid catalysis <1998SL754>. An improved technical process for the efficient N-alkylation of indoles 119 using the N-protected homochiral aziridine 123 has been developed (Equation 20) <20030PD22>. 

Compounds whose structures include a quinone moiety have been intensively investigated as potential antitumor agents. At least two quinones, mitomycin C and diaziquone, that have found their way to the clinic. These compounds in addition include a reactive aziridine ring. A recent entry that incorporates both those features, apaziquone (135), also known as E09, may be viewed as an oxidized indole. In the key reaction of a succinct synthesis to this agent, quinone 129 is allowed to react with... 

Radical centers can also be generated on the aziridine ring itself, which can then take part in further reaction with preservation of the heterocyclic entity. This process is demonstrated by the radical cyclization of the highly functionalized indole 289 to give the tetracyclic aziridine 290 in fair overall yield (Scheme 75) <1998TL2455>. 

A second approach to this type of ring formation is shown in Scheme 57 and uses a radical cyclization to form the tetracyclic nucleus <1998TL2455>. Indole 301 was alkylated with the aziridinyl triflate 302 and then the carboxy-late was hydrolyzed, activated, and irradiated to prepare bromoaziridine 303 in 62% yield. This is remarkable series of tranformations, especially for an activated aziridine. The aldehyde is then reduced and -Bu3SnH is used to initiate a stereoselective radical cyclization to form the tetracycle 304. A series of functional group transformations then converts 304 into (-f)-9a-desmethoxymitomycin A. 

The nitrene adducts 7, obtained by the addition of phthalimidonitrene to 2-methyl-l//-indole and 2-phenyl-1//-indole (cf. Houben-Weyl, Vol. E6b, Part 2, p 1227), afford, on treatment with dimsyl anion. 2-methylquinazoline and 2-phenylquinazoline, respectively. The aziridine 7 obtained by the addition of phthalimidonitrene to l-(phenylsulfonyl)-l//-indole gives quinazo-line on treatment with methanolic potassium hydroxide. 

As mentioned above, aryl azides normally react with olefins to form 1,2,3-A -triazolines or aziridines with concerted nitrogen evolution. Pyrolysis of o-azidostyrenes leads to good yields of the 2-substituted indoles 177 instead For example, with R = n-Pr in 176, the... 

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