Figure 1: Fused heterocycles containing the piperazine and diazepine core.

In recent years, multicomponent reactions have become a useful tool for the synthesis of complex structures which overcome many of these problems, with the Ugi reaction leading these strategies. The scope of the Ugi reaction further increases when coupled with post-condensation reactions, which usually require the use of starting reagents that bear two functional groups. In order to avoid competitive reactions, these groups need to be compatible with the components of the Ugi reaction or the intermediates generated during the reaction. Thus, an amine can rarely be directly incorporated as an additional functional group, because of different competitive reactions triggered by it, such as the interrupted Ugi reaction resulting from the competitive addition over the nitrilium intermediate or the split-Ugi reaction arising from a competitive O,N-acyl transference on the imidate intermediate, through a remote Mumm rearrangement .

Different strategies have been developed to avoid these competitive reactions, the most common ones being the use of protecting groups (Ugi/deprotection/cyclization strategy) or of surrogates of amines . However, direct incorporation of the second amine without derivatization is the most desirable strategy from the point-of view of sustainability. This has been achieved following two different approaches: the blockage of the amine group throughout the reaction by the incorporation of an additional group on the carbonyl component or the use of amine groups with a limited reactivity, modulated by their substitution .

As part of our continued interest in developing new and efficient strategies for synthesizing complex fused nitrogen heterocycles, we decided to evaluate the use of amine groups with a reduced reactivity in the synthesis of 3H-benzo[e][1,4]diazepin-5-ones, heterocycles previously synthesized by our research group through Ugi/Staudinger/aza-Wittig and Ugi/reduction/cyclization sequences, using 2-azidobenzoic and 2-nitrobenzoic acids, respectively. The first methodology has several drawbacks, as the need to synthesise the 2-azidobenzoic acid from anthranilic acid and sodium azide, the requirement of anhydrous conditions to perform the Staudinger/aza-Wittig sequence or the generation of large quantities of triphenylphosphine oxide which needs to be removed by chromatography column, while the more eco-friendly second strategy needs an additional stage for the reduction of the nitro group on the Ugi adduct.

Scheme 1: Synthesis of benzodiazepinones 5 from anthranilic acid derivatives.

Table 1: Results obtained in the synthesis of benzodiazepinones 5 from anthranilic acid derivatives.

Scheme 2: Diastereoselective one-pot synthesis of benzodiazepinones 6.

Table 2: Results obtained in the diastereoselective one-pot synthesis of benzodiazepinones 6.

aYield referred to the major diastereomer after purification; bdetermined by 1H NMR of the reaction mixture; cconfiguration l(αS,3S):u(αS,3R) .

Scheme 3: Synthesis of bis-1,4-benzodiazepines 7.

Scheme 4: Synthesis of benzodiazepinone 5c and pyrrolobenzodiazepinone 8 from anthranilic acid and 3-bromopropanamine.

Scheme 5: Synthesis of pyrrolopiperazinones 9 from pyrrole and indole carboxylic acids.

Table 3: Results obtained in the synthesis of pyrrolopiperazinones 9 from pyrrole and indole carboxylic acids.

Scheme 6: Synthesis of pyrrolopiperazinones 10 from N-phenylglicine.

Table 4: Results obtained in the synthesis of pyrrolopiperazinones 10 from N-phenylglycine.

aYield after purification; bunstable; cused in the following step without purification.

Figure 2: X-ray diffraction structures of pyrrolopiperazinones 9a (left) and 10a (right). The thermal ellipsoid plot (Olex2) is at the 40% probability level.

Scheme 7: Synthesis of pyrrolopiperazinone 11 using (S)-α-methylbenzylamine.

Scheme 8: Proposed mechanism in the spontaneous cyclization of Ugi adducts obtained from arylglyoxals and deactivated amines.

Moreover, we envisaged the possibility of obtaining piperazinoquinazoline derivatives, a core found in fungal metabolites , systems with promising antitumour activity , as well as dipyrrolopiperazinone derivatives, substructure found in some alkaloids such as dibromophakellin or the palau’amine , which possess immunosuppressive and cytotoxic properties , through post-condensation reactions.

Scheme 9: Synthesis of pyrrolopiperazinoquinazolines 13.

Table 5: Results obtained in the synthesis of pyrrolopiperazinoquinazolines 13.