Synthesis of 3 , 4-dihydropyrazino [ 1 , 2-a ]-indol-1 ( 2 H )-ones by cascade addition-cyclization reactions from vinyl selenones

In recent years much attention has been placed on domino reactions that entail the stepwise transformation of a single starting material forming multiple bonds in one ordered sequence without isolating intermediates. This minimizes waste production, solvents employment and energy consumption addressing most of the green chemistry issues. [1] Our research group investigated such cascade reactions using, as valuable reagents vinyl selenones for the synthesis of different heterocyclic compounds. [2]


INTRODUCTION
In recent years much attention has been placed on domino reactions that entail the stepwise transformation of a single starting material forming multiple bonds in one ordered sequence without isolating intermediates.This minimizes waste production, solvents employment and energy consumption addressing most of the green chemistry issues.[1] Our research group investigated such cascade reactions using, as valuable reagents vinyl selenones for the synthesis of different heterocyclic compounds. [2] Here we report the synthesis of 3,4-dihydropyrazino[1,2-a]-indol-1(2H)-ones reacting differently functionalized indoles with vinyl selenones.The pyrazino-indole scaffold is very attractive from a medicinal chemistry point of view given its multiple biological activities.For example they have been investigated for their antifungal activity, anti-Candida and anti-Aspergillus activity.

RESULTS AND DISCUSSION
The vinyl selenones were easily synthesized through oxidation of the corresponding vinyl selenides (Figure 2).As a result of the domino process, the 3,4-dihydropyrazino[1,2-a]indol-1(2H)-one 3a, was obtained as single product and in a excellent yields (Scheme 1).

Scheme 1 -Synthesis of the variously substituted 3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones starting from vinyl selenone 2a
To test the versatility of the method the vinyl selenone 2a was used in a series of reactions employing indole-amides variously decorated at the phenyl ring (1b-d) as well as indoles carrying aliphatic or aromatic groups at the amidic nitrogen (1e, f).As shown in Scheme 1, in every cases the cascade process has proved successful with all the compounds isolated in good to excellent yields after chromatographic purification.Both the mono (1b, c) and the di-substitution (1d) of the indole phenyl ring permitted the domino reaction to occur providing the target molecules.Also different substitutions at the amide functionality (1e-1f) lead to the formation of the products, thus demonstrating that the positive outcome of the reaction is not influenced by the steric hindrance at the level of the amidic nucleophile.
With these encouraging results in hands, the reaction was investigated from a mechanistic point of view.In particular indoles 1a and 1b were reacted with selenone 2b, that carries an alkylic chain in β position (Scheme 2).

Scheme 2 -Synthesis of the variously substituted 4-hexyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones starting from vinyl selenone 2b
From these reactions, the sole products isolated were 4-hexyl-3,4-dihydropyrazino[1,2a]indol-1(2H)-ones bearing the alkylic chain close to the indole nitrogen, leading us to hypothesize the following reaction mechanism (Scheme 3): even though there are two distinct nucleophile on the starting material, only the indolic nitrogen is the donor of the aza-Michael reaction that attach the vinylic position of the selenone.After a proton exchange reaction the amidic anion acts as nucleophile displacing the selenone moiety and affording the target compounds (4a-4b).The structure of the final derivatives were confirmed by comparing the 1 H and 13 C NMR spectra with that reported for similar compounds [4].

CONCLUSION
In conclusion, we have developed a quick and simple method to synthesize 3,4dihydropyrazino[1,2-a]indol-1(2H)-ones in excellent yields, with an efficient and eco-friendly Michael cascade reaction.We have also tested that changes in the starting materials does not modify the result of the reaction, confirming the broad applicability of the proposed protocol.Studies are in progress to shed a light into the biological activities of the compounds reported herein.In particular, the whole set of derivatives is still under investigation to evaluate their antiviral capability.

Figure 2 -
Figure 2 -Preparation of the vinyl selenones