Epoxides, reactions with indoles

The high-pressure-promoted (MeCN or CH2CI2, lOkbar, 42 or 65 °C, 1-3 d) and silica gel-catalyzed (rt, 2-10 d) reactions of epoxides with pyrroles and indoles have been demonstrated to be effective for the alkylation of these heterocycles (Scheme 113) <1996JOC984>. Nucleophilic epoxide-opening reaction with indoles 561 by adsorption on silica gel gave 2-(3-indolyl)-2-phenylethanols 562 in yield up to 88%. Indoles 562 were obtained also under high-pressure conditions in 13-61% yields. 

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]. 

Recently, Indian workers (61) reported that 2-naphthylmethylene triphenylarsorane reacted with substituted benzaldehydes to give the corresponding epoxides exclusively, whereas l-bromo-2-naphthylmethylene triphenylarsorane reacted with substituted benzaldehydes to give only olefins. In no case were both olefin and epoxide isolated and in all cases only fram-epoxides or trans-olefins were detected. It has also been reported that reaction of indole-3-carboxaldehyde with semistabilized ar-sonium ylides followed only the trans -carbonyl olefination (91). 

The Pd(0)-catalyzed allylation of 96 with acrolein dimethyl acetal gives exclusively compound 104. The 7j3-allylpalladium cationic complex (4, R = OMe) is attacked only at the center bearing the substituent MeO (80SC147), thus emphasizing the importance not only of steric effects in the electrophile but also of the electronic effects in the Tsuji-Trost reaction (92T1695). Indole 96 has been also allylated with epoxide 105 under Pd(0) catalysis by Trost and Molander (81JA5969). The intermediate cationic complex is attacked at the exocyclic position, 106 being formed, as shown in Scheme 22. 

Aromatic optically active epoxides 556 can be opened in a regioselective and clean way with indoles 555 in the presence of 1 mol% of InBr3. The reaction takes place with a Sn2 pathway affording the 2-aryl-2-(indol-3-yl)-l-ethanols 557 in good yield (up to 84%) with excellent enantioselectivity (ee up to 99%) (Equation 132) <2002JOC5386>. 

Depazay and co-workers have described the synthesis of a series of polyhydroxylated pyrrolidine, piperidine and azepanes derived from D-mannitol as novel mimetics of somatostatin [8]. The synthesis of one piperidine 116 is shown in O Scheme 9. The authors used reaction of tr) tamine with the D-mannitol derived bis-epoxide 112 followed by protection of the indole nitrogen with a Boc group to prepare the L-gulo-piperidine 113, the azepane 114 also being formed. Selective protection of the primary alcohol followed by reaction with hydrazoic acid... 

Epoxide ring-opening reactions with various nitrogen heterocycles (indoles, pyrroles, pyrazoles) have been efficiently promoted under mild conditions with high pressure or silica gel-catalysed conditions. 

Whereas the silica gel-catalysed reactions of epoxides with indoles 101 are more efficient than the high-pressure activated reactions for pyrrole 102, pyrazoles 103 and imidazoles 104, the best results were obtained with reactions carried out under high pressure. The reaction between epoxides 100 and indoles 101 occurred regioselectively and only 3-substituted indoles were produced (Scheme 7.26). 

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. °... 

Aza-indoles can be prepared from 2,6-dichloropyridin-3-yl-epoxides by reaction with primary amines " and 5-, 6-, and 7-azaindole-2-esters can be made" via the Hemetsberger-Knittel route. Note that 4-aza-indoles cannot be made this way since cyclisation of the appropriate precursor takes place preferentially onto the ring nitrogen generating a pyrazolo[l,5-fl]-pyridine. 

Moreover, catalytic asymmetric ring-opening reactions of me o-epoxides with indoles, alcohols, and thiols proceeded smoothly in the presence of catalytic amounts of Sc(DS)3 and chiral bipyridine ligand 3 in water to afford (3-amino alcohols in high yield and enantioselectivity (Scheme 15.19 and Scheme 15.20)." Note that an excellent hydrophobic, asymmetric environment has been created in water. 

The ring opening of epoxides with indole is accelerated by a combination of lanthanide catalysts and pressure, which was exploited in a synthesis of diolmycin A2 (35) (Scheme 7.8) [11]. Thus, reaction of epoxyalcohol 32 and indole (33) at 10 kbar in the presence of ytterbium(III) triflate and water gave rise to the adduct 34 in 51 % yield. Again, the application of pressure drastically decreased the reaction time. Subsequent debenzylation then provided the desired natural product 35. 

Compound 47 has been generated and used in the synthesis of a variety of 2-substituted indoles 48. Unlike lithiation of 77-(phenylsulfonyl)indole 3 [9,14], hthia-tion reactions of 4 have not been studied systematically. Nonetheless, selected examples including the corresponding reaction conditions used are given below (Table 7). Silanol 48g has been generated and exploited by Denmark in cross-coupling reactions [192, 193]. Kline used this chemistry to prepare 48b en route to a synthesis of 2-iodotryptamine [194]. Additional electrophiles used in reactions with 47 include epoxides (carbohydrates) [166], allyUc pivalates [195], and chlorodialkylphosphines [196]. 

To date, many electrophilic reagents, such as alkyl halides, alkenes, alkynes, carbonyl compounds, epoxides, alcohols, and ethers, have been investigated in AFC alkylation reactions. On the other hand, the reactive 5-membered heteroaromatic compounds, such as indole, pyrrole, furan, and thiophene derivatives, and electron-rich benzene derivatives have been successfully applied in AFC alkylation reactions. Indole and pyrrole derivatives are most popular substrates due to their high reactivity and account for almost 80% of the published methodologies. A variety of chiral organometal-lic catalysts and organocatalysts are employed in the catalytic AFC alkylation reactions with high enantiomeric control. 

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... 

Reversal of enantioselectivity in Cu-chiral bipyridine-catalyzed asymmetric ring-opening reactions of meso-epoxides with indole and aniline derivatives is observed compared to Sc-chiral bipyridine-catalyzed reactions, where the same chiral ligand is used (Scheme 32). " It was revealed from X-ray crystal structural analysis that a square pyramidal structure for the Cu° complex and a pentagonal bipyramidal... 

Catalytic asymmetric ring-opening reactions of meso epoxides with indole derivatives also proceeded smoothly, using the same chiral catalyst [173]. 

Traditionally, synthetic approaches toward this framework were charactoized by a lack of generality, involving poorly available starting material that require multistep synthetic transformations [22-25]. More recent approaches include tandem cleavage of hydrogenated / -and a-carbolines [26], ring closing metathesis [27], and metal-catalyzed Friedel-Crafts-type reactions of indole derivatives with several electrophiles (such as alkynes, alkenes or epoxides) (see Refs. [118] and [133] in Chap. 1 [28-32]). 

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