The “cesium effect” magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of β-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.


Introduction
Development of new synthetic methods that enable construction of divergent products from the same reactants by adjusting specic reaction parameters, reagents, and ligands has emerged as a powerful strategy that can facilitate rapid access to unexplored chemical space. 1 The benecial inuence of cesium salts on the rates of organic chemical reactions, leading to improved reaction efficiencies, is well known.Evidence from base-mediated ring closing reactions, 2 which demonstrated the exceptional suitability of cesium over other alkali metals, initiated reports of similar phenomenon in a large number of diverse chemical transformations, 3,4 commonly labeled as the "cesium effect" (Scheme 1A). 5 In the long history of these special effects, the cesium effect has been conned to the enhancement of a specic process, rather than replacement of one process by another.More generally, the effect of the metal cation in base-catalyzed and base-mediated reactions remains poorly understood, and the specic cation-mediated processes underlying experimentally observed changes in the selectivity and reactivity of various reactions have not been systematically investigated, precluding rational design of reactions and catalytic systems based on well-dened cationsubstrate interactions.
2-Pyridones possess a secondary amide moiety embedded in a 6-membered aromatic ring.They are a unique class of heterocycles that are more polar than their phenyl, pyridine, or phenol counterparts; and they are widely recognized in medicinal chemistry as bioisosteres for pyridine, phenol, and pyridine N-oxide groups, as well as bidentate hinge binding scaffolds, used as key design elements of diverse kinase inhibitors. 6Two main synthetic approaches have been used for their preparation: from other heterocyclic systems, mainly pyridines, and by condensation of acyclic systems. 7Notably, oligoheteroaryl systems containing pyridone units, e.g., pyridylpyridones, have key roles in drug discovery and materials science, 8 yet, they have remained synthetically challenging and are typically accessed by multistep synthetic sequences. 9Direct and modular methods of construction of pyridone-containing oligoheteroaryl systems that rely on simple precursors would facilitate rapid construction of libraries of structural analogues for structure-activity relationship studies.
We have been engaged in investigations of 1,2,3-triazine 1oxides, whose formation from vinyldiazo compounds and tertbutyl nitrite occurs in high yield under mild conditions without catalysis. 10Our recent report showed that these heterocyclic compounds undergo a facile oxadiaza excision cross coupling with b-ketocarbonyl compounds to form oligosubstituted pyridines in high yields. 11The oxadiaza excision cross coupling reactions were particularly efficient with b-ketoesters, producing oligosubstituted pyridine derivatives (Scheme 1B) at room temperature with DBU as the base.The same product was formed with potassium carbonate as the base.The pyridine ring formation takes place by a nucleophilic attack at the b-ketoester ketone group instead of the ester group, although the mechanistic effects that underpin the observed chemoselectivity were unclear.Additionally, the alternative pathway that proceeds via an attack at the ester group and unlocks new synthetic route to 2-pyridones remained unknown.
We report herein that the chemoselectivity of the oxadiaza excision cross-coupling can be controlled by the effect of the base metal cation, enabling the previously elusive construction of 2pyridones with cesium carbonate.We present evidence for this general, but unexpected, divergence in reactivity, including DFT calculations that point to the conformation-induced accommodation of the metal cation as the underlying cause of the switch in the reaction outcomes.Furthermore, we report the surprising in situ reaction between the cesium carbonate-formed pyridone with 1,2,3-triazine 1-oxides that enables facile access to a novel class of synthetically challenging pyridylpyridones by direct construction of up to four C-C/C-N bonds.

Results and discussion
Dropwise addition of 1,2,3-triazine 1-oxide 1a to a 50% molar excess of b-ketoester 2a using 2.0 equiv. of cesium carbonate, instead of DBU, in chloroform at room temperature resulted in the formation of pyridone 4a as the major product (Scheme 2).The structure of 4a was conrmed spectroscopically and from its X-ray crystal structure.This reaction was complete in less than 4 h, and pyridone 4a was easily separated from pyridine 3a by chromatography.Notably, when performed with K 2 CO 3 or Na 2 CO 3 as the base, the reactions required much longer reaction times to complete, and only pyridine 3a was formed, while no reaction was observed with Ag 2 CO 3 , pointing to a strong inuence of the metal on the reaction outcome and efficiency.In addition, only 3a was produced with cesium carbonate in the presence of an equivalent amount of 18-crown-6 that coordinates strongly with the cesium ion. 12Similarly, use of the polar protic solvent hexauoroisopropanol (HFIP) with cesium carbonate led to formation of pyridine 3a as the sole product, indicating that metal-substrate interactions that can be disrupted by solvent hydrogen bonding have an important role on reaction chemodivergence.Other aprotic solvents demonstrated similar preference for the pyridone formation with cesium carbonate as the base.On the other hand, less basic anions, e.g., uoride and acetate, failed to trigger the reaction, whereas cesium hydroxide proved to be a competent base, generating pyridone 4a.Pleasingly, increasing the reaction temperature in the cesium carbonate-promoted reactions caused an increase in the yield of pyridone 4a and a decrease in the amount of pyridine 3a.The optimum conditions for the reaction forming 4a used chloroform as the solvent with cesium carbonate as the base at 60 °C (Scheme 3).Importantly, the same substituted 1,2,3-triazine did not exhibit chemodivergence with this b-ketoester and, with cesium carbonate as the base, produced the pyridine derivative predominantly (91 : 9) at room temperature, suggesting involvement of a mechanistically distinct pathway in the 1,2,3-triazine-mediated reaction.
To evaluate the substrate scope and generality of this method for the formation of the pyridone scaffold under the developed conditions, we used representative 1,2,3-triazine 1oxides 1 with various ketoesters 2; and the results are summarized in Scheme 3. Reactions were performed under optimum conditions in chloroform with cesium carbonate as the base at Scheme 2 Influence of the reaction parameters on the oxadiaza excision cross-coupling of 1,2,3-triazine 1-oxide 1a with b-ketoester 2a.Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Cs 2 CO 3 or other base (0.2 mmol), chloroform or other solvent (2 mL), rt.For other details, see Table S1 in the ESI.† 60 °C.Yields of pyridones 4a-o are consistently high, and the alternative pyridine product was only detected in trace amount (<3%).A slight drop in yield was observed for triazine 1-oxides having an electron-withdrawing group on the aryl group at the 5-position (4b and 4c).Electronically neutral or donating groups provided the pyridone derivatives in very high yields (4a and 4d).Triazine 1-oxides with aliphatic substituents at the 5-position (except cyclopropyl, 4f) undergo ring opening through elimination of an a-proton attached to 1,2,3-triazine 1-oxide ring. 13A wide range of ketoesters were also examined, and there was no signicant difference in pyridone yields with alkyl or aryl substituted ketoesters (4f-o).When dimethyl malonate was used as the b-ketoester coupling partner, pyridone derivatives bearing the ester group were produced.Thus, pyridones 4p-4u featuring aryl and alkyl substituents were isolated in good yields, and the structure of pyridone 4p was conrmed by X-ray crystallographic analysis.
When the order of addition of 1,2,3-triazine 1-oxide and bketoester was reversed, a new compound was produced that was neither 2-pyridone 4 or pyridine 3.This new compound was identied to be pyridylpyridone 9, which is a combination of two molecules of 1,2,3-triazine 1-oxide and one molecule of bketoester with the loss of two molecules of N 2 O and one each of the b-ketoester alcohol and water.Indeed, when the amount of b-ketoester was made the limiting reagent and its amount reduced to 0.50 equiv., compound 9a was formed in 90% isolated yield (Scheme 4).This transformation takes advantage of the cesium effect to form pyridone 4 from the 1,2,3-triazine 1oxide that, because of the acyl group at its position 3, is now primed to form the enolate that undergoes oxadiaza excisionmediated formation of the pyridylpyridone by reaction with a second 1,2,3-triazine 1-oxide.Pyridylpyridones are a diverse classication of relatively unexplored heterocyclic compounds in which pyridine substituents are attached from positions 2-6 onto the 2-pyridone template positions 1, 3-6. 14 Most of these isomeric structures are unknown, but pyridine attachment from its position 2 to the 2-pyridone 1-position 15 and to its 4-and 6positions 16 are well known.
Pyridylpyridone 9 provides a template for a pyridine substituted from its 2-position to the 3-position of the pyridone (2-pyridyl-3-pyridones) that can be easily built upon by common variations in the substituents of the reactants.Indeed, changing the substituents of the 1,2,3-triazine 1-oxide gives the corresponding symmetrically substituted pyridylpyridones 9a-c in similar high yield.
In addition to the direct approach to symmetrically substituted 9a-c, a direct combination of 1,2,3-triazine 1-oxide with a 2-pyridone having different substituents allows the synthesis of unsymmetrically substituted pyridylpyridones 9d-i (Scheme 5).
Our prior reports established that carbon nucleophiles undergo addition to the 6-position of 5-substituted 4carboxylato-1,2,3-triazine 1-oxides, 11,17 and they point to the addition of the enolate to the 1,2,3-triazine N-oxide as the initial step in the reaction.With this information, we proceeded with the computational investigation of the divergent formation of pyridine and pyridone products in the presence of different bases (Fig. 1).To account for diastereomeric and conformational diversity, Boltzmann ensemble-averaged values were used for all intermediates and transition states.Consistent with previous computational studies of the reactions of 1,2,3triazines and amidines, 18 elimination of dinitrogen oxide from addition intermediate 5 proceeded over an accessible barrier TSA (DG s = 22.9 kcal mol −1 ), producing E-imine 6 that can undergo a thermodynamically favorable base-mediated isomerization to the more stable Z-imine 6b.In the absence of coordinating metals, the cyclization initiated by the nucleophilic addition of the imine nitrogen to the keto group is, kinetically, substantially more favorable (cf., TSB-K-T and TSB-E-T, DDG s = 7.8 kcal mol −1 ).The pathways that lead to the zwitterionic trans-intermediates 7-K-T and 7-E-T are more kinetically favorable over the cis-pathways (Scheme S1 †).Importantly, the kinetic preference for the nucleophilic attack at the keto group was also observed in the cis-pathways.Subsequent proton transfer produces hemiaminal 7b-K-T that is also more thermodynamically favored than the ester addition product 7b-E-T.Intermediates 7b-K-T and 7b-E-T can afford pyridine 8-E and pyridone 8-K by exergonic elimination of methanol (for 7b-K-T) and water (for 7b-E-T).These results are in agreement with the experimental data, indicating that pyridines are formed preferentially with organic bases.
To gain insight into the effects of metal ions on the reaction, calculations were conducted for the cyclization step with sodium and cesium ions bound to imine 6b (Fig. 2).Notably, nucleophilic addition of the imine nitrogen to the keto group is more kinetically favored in the sodium-mediated pathway (DDG s = 5.1 kcal mol −1 , TSB-Na-K-C vs. TSB-Na-E-C, Fig. 2A), leading to the pyridine product via a sequence of the cyclic zwitterion 7-Na-K-C and hemiaminal 7b-Na-K-C, in line with the experimental observations.The sodium coordination rendered the cis-cyclization the most kinetically favorable pathway, while the cyclization at the keto group remained kinetically favored in the trans-pathway (Scheme S2 †).By contrast, the imine addition to the ester group proceeds with a lower barrier in the cesiummediated cis-pathway (DDG s = 3.5 kcal mol −1 , TSB-Cs-E-C vs. TSB-Cs-K-C, Fig. 2B), generating cyclic hemiaminal 7b-Cs-E-C as a major product.The kinetic preference for the nucleophilic attack at the ester group was also observed in the less kinetically favorable trans-pathway (Fig. S3 †).These results point to a reversal of the reaction selectivity in favor of pyridone 8-E and are consistent with the selectivity observed experimentally.
To understand the effect of cesium ions that underlies the reversal of reaction selectivity, activation strain model (ASM) distortion/interaction analysis 19 was conducted on cyclization transition states TSB in the three reaction modalities (no metal, sodium, and cesium).The analysis of both the kinetically more favored pathways (Fig. 3) and the less kinetically favored ones (Fig. S2 †) in each modality indicates that the distortion in ketoester fragment F2 is substantially higher than in the smaller imine fragment F1 in all of the transition states, as it accommodates the proximal arrangement of the reacting carbonyl and imine nitrogen moieties.In the absence of a chelated metal ion, both transition states have similar interaction energies (Fig. 3A).However, the ester-centered transition state TSB-E-T has a signicantly higher distortion energy, predominantly in the ketoester fragment, as it necessitates a larger intraannular bond angle at the ketoester b-carbon (115.8°inTSB-E-T vs. 111.8°inTSB-K-T).Interestingly, sodium ion chelation leads to a signicant increase in the stabilizing interaction energies and a decrease in the distortion energies in both transition states (Fig. 3B).However, the stabilizing effect of sodium ion chelation does not change the kinetic preference for nucleophilic attack at the keto group, pointing to comparable inuence of sodium chelation on both transition states.Interestingly, the benecial effect of cesium ion chelation on interaction and distortion energies was less pronounced than for sodium (Fig. 3C) and commensurate with the lower charge density and larger ion radius of cesium. 20However, while the distortion energies were similar in TSB-Cs-E-C and TSB-Cs-K-C, the interaction energy was signicantly higher for TSB-Cs-E-C, reective of a more effective accommodation of the larger cation in TSB-Cs-E-C.The same trends were also observed in the less kinetically favored trans-pathway (Fig. S2C †).
These results indicate that divergent reaction outcomes can be achieved by exploiting differences in conformational accommodation of specically selected chelated metal ions, pointing to potential applications in other systems with competing cyclization processes.

Conclusions
In summary, chemodivergent outcomes of the oxadiaza excision cross-coupling of 1,2,3-triazine 1-oxides and b-ketoesters can be encoded by alkali metal ions, unlocking an efficient and direct construction of synthetically challenging oligosubstituted pyridones and pyridylpyridones from abundant precursors, requiring only cesium carbonate as a base.Notably, cesium carbonate almost exclusively generated pyridones, while other inorganic and organic bases provided the pyridine scaffold.The key difference in formation of pyridines and pyridones lies in the cyclization of the imine intermediate.The computational study comparing the effect of cesium and sodium ions in reactions with ketoesters reveals that the cesium-coordinated species is selective for attack of the ester carbon that gives rise to the pyridone derivative.In contrast, the sodiumcoordinated species was selective for attack of the ketone carbon that favored formation of pyridine product.Further analysis pointed to key differences in the conformational accommodation of the metal ions, suggesting that new divergent outcomes can be systematically harnessed by exploiting differences in conformational accommodation of specically selected chelated metal ions and underscoring potential applications in other systems with competing cyclization processes.

Fig. 1
Fig. 1 Computed Gibbs free energy profile of the chemodivergent formation of pyridine and pyridone products, DG, kcal mol −1 .

Fig. 3
Fig. 3 Distortion/interaction analysis of the cyclization transition states for the cyclization processes in the absence of metal ions (A), and with sodium (B) or cesium (C) chelation, DE, kcal mol −1 .