Indoles, synthesis from azides

The Rh-catalyzed annulation of triazoles has been explored by several investigators as a novel indole synthesis. Fokin s team generated azavinyl carbenes with rhodium and parlayed this reaction into an indole synthesis (equation 3) [54], Davies and colleagues described a one-pot indole synthesis from tosyl azide and cyclohexenyl derivatives involving an in situ triazole formation (equation 4) [55], and Lin reported a synthesis of 3-indolylimines using a similar approach (equation 5) [56]. Miura and coworkers effected the Rh-cat-alyzed intramolecular synthesis of 3,4-fused indoles... 

SCHEME 537 Rh-catalyzed cascade synthesis of indoles 55 from azides 54. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

The most reliable method for generating nitrenes is the thermal or photochemical elimination of nitrogen from azides. An alternative method which is useful for indole and carbazole synthesis is the deoxygenation of aromatic nitro compounds with trivalent phosphorus compounds. Triethyl phosphite is the most commonly used reagent, though more reactive compounds may be useful in special cases (B-79MI30600). 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Curtius rearrangement of the heteroaroyl azides, obtained from the reaction of the carboxylic acid chlorides with sodium azide, provides a route to the amino-pyrroles and -indoles (e.g. B-70MI30504, B-77MI30506, 78CPB1054), which, because of the ease of synthesis of the carboxylic acids, is frequently preferable to reduction of the nitro compounds. 

Amidines are also formed from less stable 1-hetaryl-220 and l-styryl-5-aminotriazolines.222,492,493 Thermolysis of the latter provides a method of synthesis of novel l-amino-2-azabutadienes (Scheme 176)492,493 Whereas cyanogen azide addition to dihydropyridines leads to bicycloazir-idines,241-243 addition of ethyl azidoformate yields the corresponding amidine 494 Likewise, indoles (103) react with picryl and sulfonyl azides to give... 

The base-catalyzed condensation of a-azido esters and ketones with aromatic aldehydes has recently been developed as a new vinyl azide synthesis.42,43 The yields range from moderate to excellent in some cases. The thermal decomposition of ethyl a-azidocinnamate (87) in xylene gives only 2-ethoxycarbonylindole (88).44 The unstable 2-ethoxycarbonyl-3-phenyl-l-azirine could be detected if the thermolysis was carried out at a lower temperature. This fact indicates that the 1-azirine is probably an intermediate leading to the indole, although the intermediacy of the vinyl nitrene could not be established. This result is similar to that observed by Isomura et al. on the pyrolysis of terminal vinyl azides.27,28... 

We have used the reaction extensively to prepare the indole moiety of several natural products. For example, the key step in the synthesis of the bacterial coenzyme methoxatin (36) is the formation of the indole (35) by intramolecular nitrene insertion from the azide (34), readily prepared from commercially available 4-aminosalicyclic acid. The third ring was annelated onto the indole (35) using conventional chemistry to give, after oxidation to the orrho-quinone, the natural product (36). 

It is sometimes desirable to avoid the use of alkoxide during the formation of C—C double bonds in the synthesis of / -lactams [3324]. An iminophosphorane (formed in situ from an azide and triphenylphosphine) reacts with a carboxylic ester group in a neighbouring malonylidene side-chain to form this ring [3792]. The classic Wittig reaction has been extended to the synthesis of 2-vinylindoles [3603], and other indoles have been obtained from isothiocyanato phosphoranes [3297]. 

The preparation of an indole (nitrene generated from an azide - the Hemetsberger-Knittel synthesis) and of carbazole ° (nitrene generated by deoxygenation of a nitro group) illustrate the power of the method. 

Scheme 10. Synthesis of indoles from o-alkynyl aryl azides...

A key step in a synthesis of the carbazole alkaloid murraya-quinone-B (132) is the concomitant indole ring formation and regio-selective Claisen rearrangement from the azide (129), which on... 

In 2009, Chiba s group reported a manganese-mediated synthesis of pyridines from cyclopropanols with vinyl azides [70]. In the presence of 1.7 equivalents of Mn(AcAc)3, a variety of pyridine derivatives have been prepared in good yields at room temperature. In their further studies, they realized this transformation in a catalytic manner [71]. In their mechanistic studies, they found the reactions were initiated by a radical addition of /3-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give imi-nyl radicals, which cyclized with the intramolecular carbonyl groups. Additionally, the application of this newly developed methodology in the synthesis of quaternary indole alkaloid, melinonine-E, was accomplished as well (Scheme 3.33). 

---