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. 2026 Jul 6;28(28):8952–8957. doi: 10.1021/acs.orglett.6c02359

Pd-Catalyzed De Novo Skeletal Editing of Bicyclic Carbamates Delivers 2‑Pyrimidinones

Wangyu Shi †,‡, Yue Ren †,‡, Jordi Benet-Buchholz †, Maria Vicent Morales †, Arjan W Kleij †,§,*
PMCID: PMC13386539  PMID: 42406643

Abstract

A newly designed Pd-catalyzed decarboxylative coupling between bicyclic carbamates and isocyanates allows to produce a wide range of 2-pyrimidinone mimics in good yields under user-friendly conditions and applying simple catalyst components. This catalytic transformation represents a formal and de novo skeletal editing that creates a novel and practical approach for potential 3D bioisosteric, nitrogen-based functionalized heterocycles. The utilization of these scaffolds is demonstrated in postsynthetic diversifications and through the design and construction of 3D drug-like analogues.

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Nitrogen-containing heterocycles are fundamental structural components in drug discovery. Among the 321 novel small-molecule drugs approved by the FDA between 2013 and 2023, 82% contain at least one nitrogen-containing heterocycle (Scheme a). In this regard, the pyrimidine scaffold ranks as the fifth most frequently occurring heterocycle and should thus be considered as a privileged scaffold in small-molecule drug design, offering key advantages such as favorable target engagement, good biocompatibility, and ease of functionalization. Consequently, pyrimidine-based compounds have been successfully employed across nearly all major therapeutic areas, giving rise to development and commercialization of numerous blockbuster drugs. , Therefore, the development of novel therapeutics toward the incorporation of a pyrimidine subunit is a major focus in medicinal chemistry.

1. (a) Importance of Pyrimidine Scaffolds for Drug Development, (b) State of the Art in the Development of 3D Bioisosteres, (c) Designing Pyrimidinone Analogues, (d) Use of BCB Chemistry to Access Bioisosteric Small Molecules, and (e) Our Approach Offering New Pyrimidinone Analogues Using a Newly Designed Substrate.

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The ″Escape from Flatland″ concept emphasizes to increase the proportion of sp3-hybridized carbon atoms in (drug) molecules to improve their aqueous solubility, membrane permeability, and metabolic stability. Based on this concept, in recent years the use of sp3-rich, three-dimensional bioisosteres such as bicyclo­[n.1.1]­alkanes (n = 1, 2, 3) as replacements for planar aromatic rings has become a mainstream strategy for improving the physicochemical properties and pharmacological performance of bioactive molecules. Significant success has been achieved in the advancement of benzene- and pyridine-isosteres as illustrated by the work from Stepan, Tan, Jiang, Mykhailiuk, , Tortosa, Anderson, Li, Glorius, Li and Wang, Zheng, Feng, Deng, Zhou, and others. , Despite these remarkable advances, little progress on the exploration of potential structural 3D-bioisosteres for pyrimidines (Scheme b) has been reported. , 2-Pyrimidinones represent highly important and relevant pyrimidine derivatives and actually constitute one of the most common forms of the pyrimidine scaffold in nature (Scheme c). Drugs based on this structure tend to exhibit superior biocompatibility. Therefore, developing 3D-bioisosteres reminiscent of pyrimidines is of great importance providing new directions and options for the optimization of new types of pyrimidine-containing drugs.

Bicyclic butanes (BCBs) are a highly versatile class of synthons employed for the construction of bicyclo­[n.1.1] scaffolds using photocatalysis, radical relay processes, boronyl radical catalysis, palladium catalysis, Lewis/Brønsted acid catalysis, and Lewis base catalysis (Scheme d). − Despite the versatility of BCBs, 2,4-dinitrogen-containing bicyclo[3.1.1]­heptanes cannot be easily accessed from them (Scheme d). Given the limited chemical space of such diaza-bicyclics, we present a novel approach that does not depend on BCB precursors, while using newly designed bicyclic carbamate precursors (Scheme e). We anticipated these to undergo facile decarboxylation under Pd-catalysis, − providing π-allyl Pd intermediates that should have the potential to undergo cycloaddition with readily available isocyanate reagents delivering pyrimidinones through a (formal) skeletal editing approach. − Together with the synthesis of the 3D diaza-bicycles, we also demonstrate downstream transformations providing access to a wider variety of synthons. The potential of these novel pyrimidinone derivatives is also illustrated by the creation of various drug analogues.

Key to our investigation was the access to a precursor that would enable an easy entry to 2,4-diazabicyclo[3.1.1]­heptan-3-ones (2-pyrimidinone analogues), and commercially available tert-butyl (3-oxocyclobutyl)­carbamate A (a Boc-protected aminocyclobutanone) provided such a starting point allowing to prepare the initial target in just two steps (see SI for details). Treatment of A with vinyl magnesium bromide (giving intermediate B) followed by NaH-assisted annulation afforded the free NH-version of a bicyclic carbamate in typical yields around 60% in repeated experiments. N-protection (≥85% yield, repeated experiments) gave access to vinyl N-tosyl bicyclic carbamate 1a. Next, 1a was subjected to 4-chloro-arylisocyanate 2a under Pd catalysis and varying conditions optimizing the solvent, Pd precursor and ancillary ligand (Figure , Table S1). Based on previous experience, − we surmised that a Pd­(allyl) intermediate would easily form that engages with the isocyanate through the basic N-atom of the pi-allyl fragment (see the scheme to Table S1). Attack on the electrophilic carbon center of the isocyanate and subsequent ring-closure should then deliver the target 2,4-diazabicyclo[3.1.1]­heptan-3-one 3a.

1.

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Optimized process conditions for the formation of 2,4-diazabicyclo[3.1.1]­heptan-3-one 3a. Optimized conditions: Pd2(dba)3·CHCl3 (2.5 mol%), dppb (5 mol%), 1.0 mL CH2Cl2, N2 atmosphere, 15 min. Conv. (1a) >99%, NMR yield of 3a is 90% (88% isolated).

Initially, we screened a few N- and P-based bidentate ligands (Table S1, entries 1–3) and found that these reactions provided access to product 3a in different amounts (10–67%) and varying chemo-selectivities. A disubstituted cyclobutene derivative 4 was identified as the major byproduct in these experiments, whose formation can be rationalized by an undesired β-hydride elimination reaction occurring from the Pd­(allyl) intermediate favored by the conjugated nature of the 1,3-diene in 4. The use of simple and cheap triphenylphosphine (Table S1, entry 4) was also productive leading to product 3a in 51% yield with a relatively low amount of byproduct 4 (6%). To further increase the chemo-selectivity toward 3a and improving its yield, various less and more flexible bidentate diphosphines were examined (Table S1, entries 5–8), which led to the identification of dppb [1,4-bis­(diphenylphosphino)­butane] as a ligand favoring the rapid formation 3a in high yield (Table S1, entry 5:15 min reaction time, conversion of 1a > 99%, yield of 3a 90% determined by 1H NMR, 88% isolated) with only trace amounts of byproduct 4 being observed. At this stage, we believe that the relative large bite angle in the Pd-dppb complex results in less stable and thus more reactive Pd intermediates propelling the formation of 3a.

The presence of a ligand is crucial, as without it (Table S1, entry 9) even after 24 h (1440 min) hardly any conversion of 1a was noted. In the absence of the isocyanate 2a, conversion of 1a takes place (entry 10, > 99%) but under these conditions the major identified product was 4 (26%). The presence of [Pd] is also required as virtually no conversion without it (Table S1, entry 11) occurs. Different solvents were scrutinized (Table S1, entries 12–15, vs entry 5) showing rather similar results when using DCM, DCE and THF and a somewhat inferior product yield in the case of ACN. The final experiments (Table S1, entries 16–18) were dedicated to revealing the influence of the reaction stoichiometry and the amount/type of Pd precursor. When inverting the ratio between 1a and 2a (from 1:1.2 to 1.2:1, Table S1, entry 16 vs entry 5), product 3a was formed with a very similar yield of 88%. Lowering the amount of [Pd] and dppb to 1.0 and 2.0 mol %, respectively, effectively produced 3a in high selectivity but with a reduced yield (Table S1, entry 17, 71%). Finally, replacing Pd2dba3·CHCl3 by Pd­(PPh3)4 as the metal precursor was not beneficial as it did not lead to any observable amounts of 3a. While product 3a can be easily assigned on the basis of specific 1H/13C NMR and IR spectroscopic signatures, an X-ray diffraction study of a single crystal obtained for 3a (see insert in the scheme to Table S1; SI for details) unambiguously confirmed the proposed atom connectivity.

The conditions reported in entry 5 of Table S1 were then utilized to investigate the scope of this catalytic and formal skeletal editing process (Scheme ), and we first varied the isocyanate reagent 2. With product 3a isolated in good yield (88%), we further varied the aryl-substituent R2 in the reagent 2, allowing to introduce potentially useful functionalities including aryl halide (Br, I; synthesis of 3c and 3d), nitrile (3g), ester (3h), and acyl (3i) groups. Notably, within the series of products 3a–3l, good-to-excellent yields of 61–97% were achieved with R2 having an electron-withdrawing character, while isocyanates with a (more) donating R2 ability gave rise to 2,4-diazabicyclo[3.1.1]­heptan-3-one products in much lower yields (3j–3l; 39–55%; note that in these cases, 4 was observed as a major side-product). This can be rationalized by assuming a lower electrophilic nature of the carbon atom of the isocyanate group, thereby attenuating the reactivity of it in the presence of the Pd­(allyl) species.

2. Product Scope for 3 Varying the Isocyanate Reagent 2 .

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Positional variation of the aryl-substituents (3m–3r; ortho, meta and meta,para) was feasible and the use of these isocyanate reagents 2 resulted in the formation of the desired 2,4-diazabicyclo[3.1.1]­heptan-3-one products in high yields (73–94%). Product 3p could be easily scaled up 10 times with a slightly improved yield (72 vs 66%). Products with more complex aryl groups having multiple electron-donating substituents could also be prepared (3s: 36%, and 3t: 42%) but in modest yield as noted for 3j–3l. In the case of 3s, the NTs product could not be purified well-enough by column chromatography and, therefore, the initial 2,4-diazabicyclo[3.1.1]­heptan-3-one was deprotected by magnesium powder in MeOH at 60 °C. The yield presented is thus of the two-step sequence without isolating the NTs intermediate. Larger aromatic (3u, 61%), heteroaromatic (3v, 94%) and an aryl acyl (3w, 83%; 85% when scaled up) in 2 were successfully probed providing the products in good to excellent yield. The use of aryl isocyanate reagents with a nitro-aryl, tosyl or alkyl group proved to be unproductive.

Second, we varied the substituent on the N-atom of the bicyclic carbamate precursor and combined it with two different isocyanates having either a p-chloro-aryl or a benzoyl substituent (Scheme ). Compared to 3a (88%), 2,4-diazabicyclo[3.1.1]­heptan-3-one 5a (63%) and 5b (40%) feature other aryl sulfonyl groups. In the case of 5c, the lower yield is a result of a lower reactivity of the starting bicyclic carbamate (5b) as much lower conversion was noted for it even after 24 h. Larger aryl sulfonyl groups as those present in 5c (2-naphthyl sulfonyl, 55%) and alkyl sulfonyls (5d–f; 75–92%) were also endorsed, with the synthesis of compound 5f successfully scaled up ten times with a slightly improved yield of 80%. More complex heteroaryl sulfonyl fragments (products 5g–i) are also tolerated in this protocol allowing to isolate the corresponding 2,4-diazabicyclo[3.1.1]­heptan-3-ones in 60–70% yield. Lastly, when we subjected bicyclic carbamates with N-Bz (Bz = benzoyl) or N-PMB (p-methoxy-benzyl) fragments to the optimized conditions, (hardly) no substrate conversion was observed indicating a privileged nature of N-aryl sulfonyl groups in the bicyclic carbamate substrate.

3. Product Scope for 3 while Varying the N-Substituent of the Bicyclic Carbamate Precursor 1 .

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The synthetic utility of various 2,4-diazabicyclo[3.1.1]­heptan-3-one was then examined (Scheme ). Compound 3p undergoes a deaminative borylation under Cu-catalysis in the presence of B2pin2 affording cyclobutane 6 in 58% yield (Scheme a). When 3a is treated with Mg powder at 60 °C in MeOH, clean N-deprotection takes place delivering the free NH-based 2,4-diazabicyclo[3.1.1]­heptan-3-one 7 in 84% (Scheme b). Combining both N-deprotection and N-alkylation using BnBr (Scheme c) in a one-pot sequence provides access to 8 in an 80% overall yield.

4. Post-Synthetic Utility Studies.

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2,4-Diazabicyclo­[3.1.1]­heptan-3-one 3a was further subjected to several different oxidation and/or reduction conditions (Scheme d). Treatment of 3a under adapted Sharpless dihydroxylation conditions followed by reduction of the mixture in the presence of (excess) LiAlH4 produces both diol 9a (26% yield, X-ray structure provided below under Scheme d), and monoalcohol 9b (46% yield). When LiAlH4 is replaced by NaBH4 following a similar sequence, 9b is isolated in 71% with only traces of diol 9a being formed. Finally, addition of (excess) of LiAlH4 to 9b yielded syn-1,3-diaminated cyclobutane derivative 10 in 61% yield. Finally, product 5f was converted into syn-1,3-diaminated cyclobutane 11 (82%, Scheme e) featuring a primary amine by basic hydrolysis, and the latter product could be further advanced to N-cyanated 12 (56%, in 2 steps from 3w) by combining it with cyanogen bromide.

To demonstrate that 2,4-diazabicyclo[3.1.1]­heptan-3-ones can be readily introduced into more relevant scaffolds, three multistep sequences were performed (Figure S1, Scheme ). Similar to the synthesis of 11 (Scheme e), 2,4-diazabicyclo[3.1.1]­heptan-3-one 5f was converted into a diaminated cyclobutane (isolated but not purified) and subsequently reduced in the presence of LiAlH4 to provide 13 in 63% overall yield (Figure S1, top). The latter was then coupled to chlorinated heterocycle X at the more nucleophilic N-center of 13 to afford, in two steps, a structural mimic of Abrocitinib (a compound used against eczema) with a diversification handle through the presence of a vinyl group. A second example is shown in Scheme and starts with 2,4-diazabicyclo[3.1.1]­heptan-3-one 3p. An intramolecular Heck reaction in 3p under suitable Pd catalysis conditions furnished tetracyclic 15 in 70% yield. N-deprotection similar to 7 (Scheme b) gave access to 16 in 92% yield. Finally, treatment of 16 with imidazole Y under basic conditions provided a 3D drug analogue (17: 48%, 2 steps) of a 5-HT3 receptor antagonist after removal of the trityl N-protecting group. In a third case, 2,4-diazabicyclo[3.1.1]­heptan-3-one 3a was first converted into hydroxymethylene derivative 9b (71%), then transformed into the mesyl-compound 18 (95%), and finally coupled to piperidine Z via nucleophilic substitution to give a Rupatadine mimic (19) in 52% yield (Figure S1, below). These combined examples (Figure S1, and Scheme ) demonstrate the versatile synthetic nature of the 2,4-diazabicyclo[3.1.1]­heptan-3-one synthons that are available through skeletal editing of bicyclic carbamate precursors.

5. Synthesis of Potential 3D Bioisosteres.

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In summary, we present an effective strategy to prepare 2,4-diazabicyclo[3.1.1]­heptan-3-ones from carbamate precursors via a formal Pd-catalyzed skeletal editing approach using modular bicyclic carbamates as de novo substrates for bioisosteric development. The process combines fast reaction times, user-friendly reaction conditions, structural diversity in the products and application potential in the synthesis of structural pyrimidine/2-pyrimidinone drug mimics.

Supplementary Material

ol6c02359_si_001.pdf (13.6MB, pdf)

Acknowledgments

This work was supported by the Spanish Government (Ministerio de Ciencia e Innovación Severo Ochoa Excellence Accreditation CEX2024-001469-S funded by MCIU/AEI/ 10.13039/501100011033 and PID2023-149295NB-I00). We further thank the Cerca program/Generalitat de Catalunya and ICREA for support. W.S. and Y.R. thank the Chinese Research Council for predoctoral fellowships (2021-06350046 and 2024-06350035).

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.6c02359.

  • Experimental procedures, full spectroscopic data for all new compounds, and copies of NMR and IR spectra, and X-ray crystal structure data (PDF)

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

ol6c02359_si_001.pdf (13.6MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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