The term “net-zero carbon” is becoming increasingly common as we consider a future marked by a rising global temperature and severe weather patterns – a result of human-induced greenhouse gas emissions. The principle of net-zero revolves around the idea of using Earth’s carbon resources at a rate that does not exceed their natural replenishment. In 2015, the United Nations introduced the Sustainable Development Goals (SDGs), wherein the 7th goal focuses on ensuring access to affordable, renewable and clean energy . Moreover, the European Union has committed to ambitious environmental targets as part of the European Green Deal .

Advancements in C1 chemistry are pivotal to achieving this equilibrium. As such, it is becoming increasingly essential for synthetic methods to align with a net-zero carbon future . Therefore, advancing C1 chemistry remains a crucial endeavor for our group . In synthetic organic chemistry, C1 compounds are usually installed using CO, CO2, HCO2H, CH3OH and CH4, which is mostly due to their presence in greenhouse emissions . Although abundant and inexpensive, their valorization still remains problematic due to their thermodynamic stability and chemical inertness . Multicomponent reaction (MCR) chemistry is a type of convergent chemistry characterized by diversity, complexity and efficiency. MCRs are compatible with C1 chemistry due to the generally great tolerance of different functional groups. They have been mostly employed in the synthesis of oxazolidinones and oxazinanones utilizing CO2 and CO . In addition, carbonyldiimidazole-based heteroannulations via MCRs have been reported, giving access to drug like scaffolds . However, their employment in C1 chemistry should and could be advanced.

Figure 1: Heteroannulated pyrimidones in drug discovery: blockbuster drugs that are based on the privileged pyrimidine scaffold.

Scheme 1: Strategies towards targeted adducts: A) Niementowski quinazoline synthesis utilizing anthranilic acid and B) access to heteroannulated pyrimidones by MCRs of suitably substituted heterocycles and formamide as C1 source.

Scheme 2: Access to the key building blocks 2–4 by employing three different nonisocyanide-based MCRs. Diversity and complexity were the essential features of our library of starting materials. The colored frames indicate the different scaffold types.

To our great delight, the heterocycles 2–4 could successfully be subjected to refluxing formamide under neat conditions, instantly yielding the desired thienopyrimidones 5a–e, quinolinopyrimidones 6a–e and indolopyrimidones 7a–e, respectively, as reported in the literature . In accordance with the reported mechanism, after the initial formylation of the amino group at position 2, an intramolecular nucleophilic attack by the NH moiety of the amide group resulted in pyrimidone annulation . This was observed for the first time and completed the reported heteroannulation landscape utilizing the Niementowski reaction . In general, the reactions had a rather broad scope as a great range of cyanoacetamides was compatible. The synthesis was efficient and rapid as the final adducts could be isolated only by precipitation. In addition, the reactions were performed in a parallel setup using custom-made metal blocks.

Scheme 3: Synthesis of N-substituted thienopyrimidones 5a–e by a Gewald three-component reaction employing 2-aminothiophenes 2a–e and formamide as C1 source. A characteristic fluorescence for compound 5a was reported (365 nm in DMSO). The reported yield refers to the overall two-step synthesis.

Scheme 4: Synthesis of N-substituted quinolinopyrimidones 6a–e from 2-aminoindoles 3a–e and formamide as C1 source. A characteristic fluorescence for compound 6c was reported (365 nm in DMSO). The reported yields refer to the overall two-step synthesis.

Scheme 5: Synthesis of N-substituted indolopyrimidones 7a–e from 2-aminoindoles 4a–e and formamide as C1 source. A characteristic fluorescence for compound 7b was reported (365 nm in DMSO). The reported yield refers to the overall two-step synthesis.

Figure 2: Representative fluorescence spectrum of compounds 5b (λex = 330 nm) and 6e (λex = 430 nm) at 0.2 M in DMSO.

Figure 3: Molecular geometry observed within the crystal structure of compound 7b (CCDC 2376493).

In conclusion, we successfully combined the Niementowski quinazoline synthesis with nonisocyanide-based chemistry, thereby expanding and enhancing the scope of C1 MCR chemistry. That way, we obtained 15 diversely substituted heteroannulated pyrimidones, employing privileged thiophene, quinoline and indole scaffolds in a rapid fashion, without the need of column chromatography, in a parallel setup.