Aziridines, reactions with indoles

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.)... 

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]. 

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>. 

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. 

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. °... 

Indoles react with homochiral aryloxiranes at the benzylic carbon in high optical yield, under very mild conditions (1% InBrs, CH2CI2, rt). Reactions with A -Cbz aziridines are similarly catalysed by scandium triflate. ... 

Carbenoid ring-expansion of thiophen to a 2/f-thiopyran has been observed in the rhodium-catalysed reaction with (132), which gave (133) and (134). Evidence has been presented that the nitrene intermediate (135), obtained from the corresponding nitro- or azido-derivatives in the usual way, first gives the aziridine intermediate (136), which then leads to interesting heteropolycyclic systems such as 3-(2-thienyl)indole derivatives. ... 

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. 

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. 

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... 

Ruthenium-based catalysts display some utility for electrophilic amination of heteroaromatic substrates. Che and coworkers have found that [Ru(TTP)(CO)J in combination with PhI=NTs will oxidize arenes such as furan, indole, and pyrrole (Fig. 13) [68]. Reactions occur optimally under the action of ultrasound, a rather unusual addendum to the standard protocol for C-H amination. More intriguingly still, iV,A-ditosylated products are isolated in most instances, a finding that is not easily resolved mechanistically. As the substrate profile for this amination process involves only electron-rich heteroaromatics, aziridination of the arene nucleus would seem a likely step along the reaction coordinate. Interestingly, no amination product is observed when stoichiometric [Ru(TMP)(NTs)2] (TMP = tetra(2,4,-6-trimethylphenyl)porphyrin) is mixed with either furan or /V-phenylpyrrole. though a reduction of the starting Ru(VI) complex to a Ru(IV) species is noted... 

Indolyl A-Grignards, "" or even better their zinc analogues, undergo reaction predominantly at C-3 with a variety of carbon electrophiles such as aldehydes, ketones and acid halides, or reactive halo-hetero-cycles. Including aluminium chloride in the zinc reactions produces high yields of 3-acyl-indoles. The copper-catalysed reactions of indolyl-A-Grignards with A-t-butoxycarbonyl-aziridines also proceed well at C-3. ... 

In connection with the synthesis of pyrrolo[l,2-a]indoles, intramolecular carbene insertion reactions have been developed. Although strictly involving interactions between two substituents, they will be considered here because of their chemical similarity. Thermal decomposition of the sodium salt of the tosylhydrazone (219) gives intramolecular cycloaddition followed by loss of nitrogen to yield the fused indole (220) (Equation (66)) <89JCS(Pi)2449>. This technique can be extended to include oxime ethers (221) in place of alkenes and thus provide formation of an aziridine (222) insertion into alkynes could not be achieved (Equation (67)) <9iJCS(Pi)i72i>. 

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. 

This chapter deals with recent developments in "on-water" synthetic approaches to small (3-4) and medium (5-7) size aza-heterocycles of biological relevance. Selected examples of syntheses of aziridines, azetidines, 2-azetidinones, pyrroles, pyrazoles, imidazoles, benzimidazoles, indoles, pyridines, pyrimidines, quinolines, azu-lenes, and azepinones are described. A brief introductory paragraph on significance of each class of compoxmd is followed by its common S5mthetic methods. The role of water and mechanism of novel reactions will be discussed where applicable. 

Sc(OTf)3 in combination with 1 equivalent of TMSCl promoted the reaction of A -Me skatole 93 (2 equiv) and iV-Cbz aziridine 94 (1 equiv), which resulted stereoselectively in the formation of the desired pyrroloindoline 95 in high yield. In this case, a C3 attack of the indole onto the activated aziridine occurred followed by the addition of the nitrogen onto the resulting indolenium ion. Red-Al reduction allowed the authors to obtain ( )-desoxyeseroline 96, which was previously converted to ( )-physostigmine 97 by Fuji and co-workers. ... 

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