A New Route to α-Carbolines Based on 6π-Electrocyclization of Indole-3-alkenyl Oximes

Indoles are converted into α-carbolines in four steps by acylation at C-3, Boc-protection, olefination of the resulting 3-indolyl aldehydes or ketones to give N-Boc-3-indolyl alkenyl oxime O-methyl ethers, which upon heating to 240 °C under microwave irradiation undergo loss of the Boc-group, and 6π-electrocyclization to α-carbolines, following aromatization by loss of methanol (11 examples, 30–90% yield).

In contrast to β-carbolines that are widely represented among natural products and synthetic bioactive compounds, 1À3 R-carbolines (pyrido[2,3-b]indoles) are considerably less well investigated. 4,5 Nevertheless there are some important examples such as the naturally occurring anticancer compounds grossularine-1 and -2 6À9 and the neuronal cell protective agent mescengricin ( Figure 1). 10 In the medicinal chemistry arena, R-carbolines such as the GABA modulator, 11 and the inhibitor of microsomal triglyceride transport protein implitapide, 12,13 have also been widely studied.
As a consequence, routes for the construction of the R-carboline nucleus are of interest, but unlike their β-carboline counterparts that are almost invariably prepared from tryptophan or tryptamine derivatives, there is no main synthetic access to the isomeric R-carbolines. Thus, R-carbolines have been obtained from 2-aminoindoles, 14À16 by a variation of the GraebeÀUllmann synthesis of Terms of Use CC-BY carbazoles, 17 by intramolecular DielsÀAlder reaction of pyrazinones, 18 from palladium-catalyzed reactions of anilines with 2,3-dihalopyridines, 19,20 by cyclization of 2-isocyanato-indoles, 6À8 and of iminyl radicals. 21À24 However, we were attracted by the possibility of developing a more general route based on a 6π-electrocyclic process, and we now report our initial results.
The projected precursors to R-carbolines were the 3-indolyl alkenyl oxime ethers 1, accessible from 3-acylindoles 2 (Scheme 1). 3-Acylindoles are readily available by exploiting the natural reactivity of indoles to undergo facile acylation at the 3-position. The participation of oxime ethers in 6π-electrocyclic processes is known from the work of Hibino, 25 and the possible intermediacy of imines related to 1 has been implicated in other work 23 and in a biomimetic synthesis of grossularine-1. 9 The precursors to the desired oxime ethers were 3-acylindoles 2 and phosphonates 3. The phosphonates were prepared by reaction of the corresponding carbonyl compound with O-methyl hydroxylamine, with the aldoxime precursor being prepared by acid hydrolysis of the commercially available diethyl (2,2-diethoxy)ethylphosphonate. The subsequent HornerÀWadsworthÀEmmons reaction with N-Boc-protected 3-indolyl aldehydes or ketones gave the required alkenyl oxime ethers 4 generally as mixtures of E/Z-alkene isomers that could be readily separated and characterized, apart from alkene 4g which was formed as the E-alkene.
In general only one oxime isomer was observed which, on the basis of the chemical shift of the oxime RCHd NOMe proton in the 1 H NMR spectrum, suggested that  the oximes have the (Z)-geometry. In the case of oxime 4a, removal of the Boc-protecting group gave the crystalline E-alkene-Z-oxime (Figure 2), confirming the Z-stereochemistry of the oxime double bond. The olefination reaction was then extended to indole-3-carbaldehydes bearing chloro-and alkoxy-groups, and indolyl ketones with methyl or ester groups (Table 1).
With a range of oxime ethers 4 in hand, their thermal cyclization reactions were studied. Initially, these were investigated leaving the Boc-group in place since it was assumed that it would be cleaved under the high temperature conditions. In the event, heating 4a, as a mixture of geometric isomers, to 180°C in 1,2-dichlorobenzene gave a mixture of the desired R-carboline 5a (12%) plus the Boc-deprotected starting material. Increasing the temperature to 240°C under microwave irradiation delivered the R-carboline 5a in 73% yield. We assume that the reaction involves initial thermal removal of the Boc-group to give the NH indole in which isomerization of the alkene into the cis-isomer required for electrocyclization is facilitated. In support of this, prior removal of the Boc-group in 4a under hydrolytic conditions (82%) gave the corresponding NH indole that cyclized to R-carboline 5a (54%) upon heating to 240°C. It would appear that the NH is essential for cyclization since the corresponding N-methyl compound does not give 9-methyl-R-carboline under the same conditions. Electrocyclization of the indolyl alkenyl oxime ethers 4bÀ4k, starting with either (Z)-or (E)-alkene isomers, proceeded similarly to give a range of R-carbolines 5 in 30À90% yield (Table 1). The structures of the carbolines 5f and 5h were confirmed by X-ray crystallography (Figure 3).
In conclusion, we have developed a new general route to R-carbolines that proceeds in just four steps from indoles.