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,[1−3] α-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[6−9] and the neuronal cell protective agent mescengricin (Figure 1).[10] In the medicinal chemistry arena, α-carbolines such as the GABA modulator,[11] and the inhibitor of microsomal triglyceride transport protein implitapide,[12,13] have also been widely studied.

Figure 1

Structures of naturally occurring and bioactive α-carbolines.

As a consequence, routes for the construction of the α-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 α-carbolines. Thus, α-carbolines have been obtained from 2-aminoindoles,[14−16] by a variation of the Graebe–Ullmann synthesis of carbazoles,[17] by intramolecular Diels–Alder reaction of pyrazinones,[18] from palladium-catalyzed reactions of anilines with 2,3-dihalopyridines,[19,20] by cyclization of 2-isocyanato-indoles,[6−8] and of iminyl radicals.[21−24] 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 α-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]

Scheme 1

Projected Route to α-Carbolines by 6π-Electrocyclization of 3-Indolyl Alkenyl Oxime Ethers

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 Horner–Wadsworth–Emmons 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 RCH=NOMe proton in the 1H 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).

Figure 2

X-ray crystal structure of (E)-3-(1-methyl-1H-indol-3-yl)propenal (Z)-methyl oxime.

Table 1

Preparation of Indolyl Alkenyl Oxime Ethers 4 [Indoles, Phosphonates, 3a, R2 = H; 3b, R2 = Me] and Their Conversion into α-Carbolines 5 by 6π-Electrocyclization

entry	2	Xa	R4	3	R2	4	E yield/%	Z yield/%	Xb	5	yield/%
1	a	H	H	a	H	a	46	38	H	a	73
2	b	5-OMe	H	a	H	b	37	25	6-OMe	b	36
3	c	6-OMe	H	a	H	c	38	60	7-OMe	c	30
4	d	5-Cl	H	a	H	d	49	42	6-Cl	d	55
5	a	H	H	b	Me	e	11	22	H	e	90
6	c	6-OMe	H	b	Me	f	28	62	7-OMe	f	77
7	b	5-OMe	H	b	Me	g	34c	–	6-OMe	g	41
8	e	H	CO2Me	a	H	h	38c	49	H	h	52
9	f	H	Me	a	H	i	49	16c	H	i	62
10	f	H	Me	b	Me	j	45	23	H	j	65
11	e	H	CO2Me	b	Me	k	52	29	H	k	51

Indole numbering.

α-Carboline numbering.

Mixture of oxime geometric isomers.

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 α-carboline 5a (12%) plus the Boc-deprotected starting material. Increasing the temperature to 240 °C under microwave irradiation delivered the α-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 α-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-α-carboline under the same conditions. Electrocyclization of the indolyl alkenyl oxime ethers 4b–4k, starting with either (Z)- or (E)-alkene isomers, proceeded similarly to give a range of α-carbolines 5 in 30–90% yield (Table 1). The structures of the carbolines 5f and 5h were confirmed by X-ray crystallography (Figure 3).

Figure 3

X-ray crystal structures of α-carbolines 5f and 5h.

In conclusion, we have developed a new general route to α-carbolines that proceeds in just four steps from indoles.