Tuneable access to indole, indolone, and cinnoline derivatives from a common 1,4-diketone Michael acceptor

A convergent strategy is reported for the construction of nitrogen-containing heterocycles from common substrates: 1,4-diketones and primary amines. Indeed, by just varying the substrates, the substituents, or the heating mode, it is possible to selectively synthesize indole, indolone (1,5,6,7-tetrahydroindol-4-one), or cinnoline (5,6,7,8-tetrahydrocinnoline) derivatives in moderate to excellent yields.

Indeed, indole ring-containing compounds have various biological and pharmacological activities and are part of many marketed drugs used as anticancer, antiemetic, antihypertensive, antidepressant, anti-inflammatory, or anti-HIV agents, among others [9]. In contrast, concerning indolone and cinnoline derivatives, there are very few marketed drugs, but many molecules are under investigations for their activities as antibacterial, antifungal, anticancer, or anti-inflammatory agents or even on the central nervous system [7,12,13].
From the state-of-the-art, a strategy that promotes the synthesis of indole, indolone, or cinnoline derivatives from the same starting material is not yet available. To reach this goal, the Michael reaction between 1,4-diketones and primary amines seems particularly attractive because of its straightforward and metal-free properties, and because they can be performed under air. Herein, we report our investigations on this reaction, and we have shown that it can be selectively directed towards the synthesis of indole, indolone, or cinnoline derivatives by just changing the substrates, substituents, or heating mode (Scheme 1).

Results and Discussion
The synthesis of the target compounds required the prior preparation of a panel of variously substituted 1,4-diketones 5. The 1,4-diketones 5 have been prepared either by a Nef reaction [56] from the corresponding nitroenone 3 or a Wittig reaction [57] from 1,2-cyclohexanedione and the corresponding ylide 4 (Scheme 2).
sponding Baylis-Hillman alcohols 1a/b in good yield [58], followed by a DMAP-catalyzed acetylation of these alcohols, which gave the corresponding acetates 2a-d [59]. The nitrenones 3a-d were finally obtained in an acceptable yield by reacting the acetate derivatives with the appropriate nitroalkanes [60]. The next step was the transformation of the nitro group of 3a-d via the Nef reaction, using sodium ethoxide in ethanol, followed by the hydrolysis with concentrated sulfuric acid at a low temperature [56], leading to the corresponding new γ-diketones 5a-d in 61-87% yield (Scheme 2).
Despite the efficiency of the Nef reaction, the diversity at the R 1 position via this synthetic route remains limited in terms of chemical diversity as it depends on the availability of the corresponding nitro derivative. It was thus decided to move on to the Wittig reaction [57], offering a much more straightforward and efficient route to a panel of new diketones, 5e-k, from 1,2cyclohexanedione and the corresponding Wittig ylides 4a-g (readily accessible from the corresponding halogenated derivatives, Scheme 2). Indeed, the Wittig reaction leads exclusively to the isomerized products 5.
With the 1,4-diketones 5 in hand, we first investigated the synthesis of indole and indolone derivatives. The reaction mechanism shown in Scheme 3 involves the formation of an imine upon the reaction of the primary amine with the most reactive carbonyl moiety (nonconjugated and exocyclic carbonyl function). Then, depending on the reaction conditions, the imine can react following a 1,2-or 1,4-addition process, leading respectively to an indole 6 (after dehydration and aromatization) or an    Table 1, entry 5, these conditions were applied to several amines, producing the corresponding substituted indoles 6a and 6c-f in 41-54% yield (Scheme 4). The yield of the indolones 7a and 7c-f was found almost constant (10-14%) with all amines involved. It is worthy of note that the two compounds were easily separated using usual chromatographic techniques.
The reaction was also applied to a diamine (Scheme 5). When 1,3-diaminopropane was used, the bisindole 6g was isolated in 46% yield. Interestingly, the mixed indolone/indole compound 9 was also obtained as a side product. However, no traces of the bisindolone derivative were detected.
We then succeeded in directing the reaction exclusively towards indole formation by reacting the diketone with appropriate substrates, combining a primary amine with a tertiary amine or a pyridine separated by several spacer arms (Scheme 6).
Under these conditions, the functional indoles 6h-l were obtained exclusively in 45-55% yield. We assume that the tertiary amine would interact with the protonated intermediate, and thus promoting the 1,2-addition (Scheme 6). However, for the pyridine substituent (compounds 6k and 6l), another intermediate may be involved as the shape of this diamine does not allow enough flexibility to achieve the conformation of the proposed intermediate.

Scheme 5:
Reaction of 5b with a diamine.

Scheme 6: Synthesis of the indoles 6h-l.
We next examined the preparation of a set of indolones under the microwave conditions determined in Table 1, entry 13. These conditions were applied to several amines, producing exclusively the corresponding substituted indolones 7d and 7g-k in 48-56% yield (Scheme 7).
Here again, the amount of indolone was found to be almost constant, whatever the amine involved was, suggesting that the reaction is not dependent on the nature of the amine. It is worth to notice that, for a substrate combining a primary amine with a pyridine separated by a spacer arm, only the indolone derivative is obtained in those conditions as well (compound 7i, Scheme 7). Based on these results, we found it important to check whether the indole 6b resulted from a 1,2-addition and not from a degradation of the indolone 7b. For this purpose, the indolone 7b was refluxed overnight with acetic acid in toluene, under these conditions producing mainly the indole (Table 1, entry 5). The indolone 7b was found unchanged, with no trace of the indole 6b being detected (see Supporting Information File 1, chapter I), indicating that the indole was formed intramolecularly by a 1,2-addition of the intermediately formed imine to the Michael acceptor (Scheme 3).
We then investigated the synthesis of cinnoline derivatives by mixing the diketone 5a and hydrazine monohydrate under various conditions (Table 2). We first investigated the reactivity in ethanol, as a protic solvent, at room temperature ( Table 2, entry 1). Under these conditions, the expected cinnoline 8a Scheme 7: Synthesis of the indolone derivatives 7b, 7d, and 7g-k. was obtained in a low yield of 20% that could be increased up to 40% upon refluxing the mixture ( These optimized conditions were then applied to the previously synthesized 1,4-diketones 5a-k (Scheme 8). As a general obser-vation, the reaction was found to be efficient for producing the expected cinnoline derivatives 8a-k in good to excellent yield (77-94%) and tolerated alkyl, aromatic, and heteroaromatic groups as R 1 .
The success of our convergent strategy here can be explained through the mechanism suggested in Scheme 9. The synthetic pathway leading to the formation of the indolone 7 starts with an imine formation between the secondary amine and the nonconjugated carbonyl from the 1,4-diketone. After an Scheme 8: Synthesis of the cinnoline derivatives 8a-k.

Scheme 9:
Proposed mechanism for the preparation of the compounds 6, 7, and 8.
imine-enamine equilibrium, an intramolecular 1,4-addition to the Michael acceptor part of the molecule occurs, followed by a prototropy, leading to an intermediate enol that, after a keto-enol equilibrium and aromatization, gives the indolone 7.
For the indole 6 and the cinnoline 8, the synthesis starts with the protonation of the oxygen atom of the conjugated carbonyl group of the 1,4-diketone, followed by an imine formation between the secondary amine and the nonconjugated carbonyl unit. Next, an intramolecular 1,2-addition to the Michael acceptor part of the molecule, previously activated by acid catalysis, takes place (after an imine-enamine equilibrium for the indole pathway), followed by a prototropy, the release of a water molecule, the recovery of the proton catalyst, and atmospheric oxygen aromatization, leading to the indole 6 or the cinnoline 8.

Conclusion
In summary, we have successfully developed a straightforward and metal-free strategy for the synthesis of nitrogen-containing heterocyclic moieties of biological interest; indoles 6, indolones 7, and cinnolines 8, starting from common substrates 1,4-diketones 5 and primary amines. The protocols developed here used mild conditions, were functional-group tolerant, transition-metal-free, proceeded in moderate to good yield, and could therefore easily be used in medicinal chemistry projects for the rapid access to a wide range of variously substituted compounds for structure-activity relationship studies. The biological activity of the molecules is currently being studied.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data, and copies of the spectra of all compounds.