Chiang Mai Journal of Science

Mechanistic Investigation of Copper-Catalyzed Three-Component Synthesis of Quinazoline Derivative: A DFT Study

1. INTRODUCTION

Quinazoline is a prominent heterocyclic scaffold present in a wide range of pharmacologically active compounds [1-4]. Quinazoline derivatives display diverse and potent biological activities, which has driven extensive research into developing synthetic methodologies that expand structural diversity and enhance pharmacological efficacy. Consequently, the design of efficient, sustainable, and environmentally benign synthetic strategies remains a central objective in contemporary organic synthesis.

Conventional strategies to build fused aromatic N-heterocycles often rely on stepwise sequences and conditions that can limit functional-group tolerance, increase solvent and reagent use, and reduce overall efficiency. Historically, quinazoline derivatives have been prepared through several classical synthetic approaches:

1. Conrad–Limpach Synthesis—condensation of anilines with β-ketoesters to form 4-hydroxyquinolines via Schiff base intermediates, followed by cyclization and dehydration [5-7].

2. Gould–Jacobs Reaction—condensation of anilines with ethoxymethylenemalonic esters, followed by cyclization and decarboxylation to afford 4-hydroxyquinolines [8-11].

3. Bischler–Napieralski Reaction—cyclodehydration of β-phenylethylamines in the presence of phosphoryl chloride to form dihydroisoquinolines, which can be aromatized to isoquinolines, structural analogs of quinazolines [12-15].

Although these traditional methods have been instrumental in constructing quinazoline frameworks, they often require harsh reaction conditions—such as elevated temperatures and strong acids or bases—that limit functional-group compatibility and reduce yields. In addition, they typically involve multiple steps, lowering the overall efficiency of the synthetic process.

To overcome these limitations, contemporary organic synthesis increasingly employs metal-catalyzed multicomponent reactions (MCRs) to construct complex heterocyclic structures in a single operational step. By combining three or more reactants, MCRs enable the simultaneous formation of multiple bonds, thereby enhancing atom economy and reducing waste [16-20]. Among the various metals employed, copper has emerged as a particularly versatile and cost-effective catalyst for facilitating these transformations [21-25]. Copper-catalyzed MCRs have been widely applied to the synthesis of nitrogen-containing heterocycles, including quinazolines [21, 26, 27]. Copper’s ability to cycle between Cu(I) and Cu(II) oxidation states, combined with its low toxicity and abundance, makes it an attractive catalyst for such transformations. In particular, copper-catalyzed three-component reactions efficiently construct quinazoline derivatives from readily available starting materials under mild conditions, with excellent functional-group tolerance.

In particular, Xu and co-workers [26] reported a copper-catalyzed three-component domino reaction for the synthesis of quinazoline derivatives under aerobic conditions from 2-bromoaldehydes, benzylamines, and sodium azide, demonstrating high efficiency and functional-group tolerance under mild conditions. Their mechanistic proposal suggested that copper plays a dual catalytic role by facilitating (a) nucleophilic aromatic substitution (S_NAr) and (b) intramolecular C–N bond formation. However, the sequence of elementary steps and the specific catalytic contributions of copper—substrate activation, stabilization of charged intermediates, and/or redox mediation—remain incompletely defined.

Density functional theory (DFT) is a powerful tool for elucidating reaction mechanisms, having been widely applied to rationalize the reactivity and electronic properties of heterocycles [28], and to probe the structural and catalytic behavior of transition-metal systems [29-31]. Such studies bridge the gap between experimental observations and mechanistic hypotheses, making DFT particularly suited for investigating the copper-catalyzed quinazoline synthesis reported by Xu et al. In this work, we present a detailed DFT analysis to: (i) evaluate competing pathways for the CuI/L-proline-catalyzed quinazoline formation reported by Xu et al., and (ii) clarify the specific catalytic contributions of copper to the overall reaction process.

2. COMPUTATIONAL METHODS

The computational model was constructed to reflect the CuI/L-proline catalytic system employed by Xu et al., which provided the highest reported yields for quinazoline formation. All calculations were conducted using the Gaussian 16 software package [32]. Geometry optimizations were carried out using the M06 exchange-correlation functional, employing the 6-31G* basis set for C, H, N, and O atoms. Heavier atoms (I, Br, and Cu) were treated using the def2-QZVP basis set. Single-point energy (ΔE_sp) calculations were subsequently performed using the 6-311++G** basis set for light atoms and the def2-QZVP basis set for I, Br, and Cu to improve energetic accuracy. Solvent effects were incorporated via the polarizable continuum model (PCM), with dimethyl sulfoxide (DMSO) as the solvent, applied in both geometry optimizations and single-point energy calculations. Thermal corrections were computed at 298.15 K. Stationary points were characterized through vibrational frequency analysis, where minima exhibited exclusively positive eigenvalues, and transition states displayed a single imaginary frequency corresponding to the intended reaction coordinate. Free energy-corrected single-point energies (ΔG_sp) were found to be consistent with other computed thermodynamic values and are thus reported exclusively throughout the study.

3. RESULTS AND DISCUSSION

The reaction mechanism for the copper-catalyzed synthesis of quinazoline derivatives from 2-bromoaldehydes, benzylamides, and sodium azide, as proposed by Xu et al. [26], involves an initial copper-assisted nucleophilic aromatic substitution (S_NAr) followed by dehydration, cyclization, and denitrogenation . To evaluate the feasibility of this pathway, we examined whether the S_NAr step of 2-bromo-benzaldehyde occurs before or after Schiff base formation between benzylamine and 2-bromo-benzaldehyde, using computed free-energy profiles as a guide. In addition, we also investigated whether ring closure proceeds through a direct Cu–C bond formation, as suggested by Xu et al. [26], or via a more conventional intramolecular cyclization. The optimized geometries of all stationary points are illustrated in Figure 1, and the corresponding relative free energies are summarized in Table 1. The overall mechanistic sequence derived from our DFT analysis is depicted in Scheme 1.

3.1 Pathway A
The initial step in Pathway A involves the nucleophilic aromatic substitution (S_NAr) reaction between the 2-bromobenzaldehyde and azide anion. In this step, the terminal nitrogen of azide attacks the electrophilic aromatic carbon bearing the bromine substituent, leading to displacement of bromide via TS1. This step results in formation of a new C–N bond and generation of the azido-substituted aldehyde intermediate (INT1), accompanied by liberation of Br⁻. The N–C bond length decreases from 5.44 Å in the reactant (REACT) to 1.87 Å at the transition state (TS1), signifying the progression of the nucleophilic attack. TS1 exhibits characteristic features of an S_NAr transition state, with partial C–N bond formation and concomitant C–Br bond cleavage. The activation energy for this step is calculated to be 23.8 kcal/mol, while the resulting intermediate (INT1) is stabilized at –23.0 kcal/mol relative to REACT. The electron-withdrawing aldehyde group enhances the susceptibility of the aromatic ring toward nucleophilic attack, thereby facilitating this transformation. The formation of INT1 establishes the key azide functionality required for subsequent intramolecular cyclization steps later in the pathway. These findings align with previously reported literature [33, 34], which indicates that such S_NAr processes benefit from the electron-withdrawing nature of the aldehyde substituent, enhancing aromatic reactivity. In the second step, benzylamine engages in nucleophilic addition to the aldehyde group of INT1 to generate the corresponding carbinolamine intermediate (INT2). This transformation proceeds through TS2 and involves simultaneous C–N bond formation and proton transfer. At TS2, the C–N distance decreases from 2.87 Å in the reactant complex to 1.56 Å, indicating substantial bond formation. Benzylamine serves as the sole nucleophile. The calculated activation free energy for this step is 15.0 kcal/mol, a relatively low barrier consistent with facile amination under the experimental conditions. The transition state is product-like in character, with the benzylamine nitrogen nearly fully bonded to the carbonyl carbon. Closer inspection of the optimized TS2 geometry reveals the participation of a second benzylamine molecule functioning as a proton shuttle. The imaginary frequency vector corresponds to proton transfer from the N–H group of one benzylamine to the NH₂ group of another, producing a six-membered cyclic transition state. This arrangement is considerably more favorable than the strained four-membered alternative that would result if only one benzylamine molecule were present. Comparable bimolecular proton-transfer mechanisms have been reported in related systems. For example, a study on Schiff base synthesis from aromatic amines demonstrated that, in the absence of acid catalysts or polar solvents, an additional amine molecule can mediate proton transfer and markedly reduce the activation barrier [35]. Likewise, recent theoretical studies of Schiff base formation from hexoses have shown that explicit water molecules can serve as proton-transfer mediators, generating six-membered cyclic transition states that significantly reduce the barrier of the dehydration step, which is often rate-determining [36]. These precedents strongly support our interpretation that the bimolecular arrangement in TS2 represents a realistic and energetically accessible proton-transfer pathway. The overall mechanistic picture is consistent with previous experimental and theoretical reports [26, 36, 37], further confirming the feasibility of this step even in the absence of a copper catalyst. The resulting carbinolamine intermediate (INT2) is highly stabilized, lying 23.3 kcal/mol below the reactants in relatively free energy.

Cyclization occurs via intramolecular nucleophilic attack of the terminal azide nitrogen onto the carbocation center. This step proceeds through TS5 and leads to formation of the quinazoline framework bound to the copper center (INT5). At TS5, the C–N bond distance decreases from 3.35 Å in INT4 to 2.38 Å, indicating substantial bond formation. The activation energy for this step is only 5.2 kcal/mol, reflecting a highly favorable process that effectively drives the reaction toward completion. The transition state is product-like in nature, with the azide nitrogen nearly fully bonded to carbocation. The low energetic demand of this step reflects the strong driving force associated with ring closure and aromatization of the heterocyclic core, as well as the efficiency of the copper catalyst in promoting ring closure [40] and is consistent with the mechanistic pathway proposed by Xu et al.[26].

In the final step, proton transfer and copper dissociation occur through TS6, resulting in release of the neutral quinazoline product (PROD) and regeneration of the catalytically active copper species. The hydroperoxy abstracts a proton from the carbon adjacent to the imine group and restores aromaticity within the quinazoline ring system. At TS6, the O–H bond contracts from 2.38 Å to 1.35 Å, while the adjacent C–N bond shortens from 1.46 Å to 1.42 Å, with partial proton transfer and almost fully established imine bond. The associated activation energy is 18.3 kcal/mol, moderate compared to earlier steps such as dehydration. The overall reaction culminates in the quinazoline product (PROD), which is highly stabilized at –126.1 kcal/mol relative to the starting materials, confirming the strong thermodynamic preference for product formation under the reaction conditions.

3.2 Pathway B
Pathway B represents an alternative mechanistic scenario in which benzylamine attacks the aldehyde group of the starting o-bromobenzaldehyde prior to azide substitution. In this pathway, nucleophilic addition of benzylamine occurs directly from REACT through TS7 to form the hemiaminal intermediate INT6. The transition state TS7 involves concerted C–N bond formation and proton transfer, yielding INT6 with retention of the bromine substituent on the aromatic ring. At the transition state, the C---N bond distance contracts from 2.88 Å in the reactant complex to 1.57 Å, reflecting substantial bond formation. As in Pathway A, the optimized TS7 also involves two benzylamine molecules, with one acting as a proton shuttle. The imaginary frequency vector corresponds to proton transfer within a six-membered cyclic transition state, which is mechanistically consistent with prior computational studies of Schiff base formation that highlight the role of auxiliary amine or solvent molecules in stabilizing proton transfer. From TS7, nucleophilic addition leads to the hemiaminal intermediate INT6. The computed activation free energy for this step is 19.6 kcal/mol, which is slightly higher than that of the corresponding step in Pathway A (15.0 kcal/mol, TS2). The resulting hemiaminal intermediate (INT6) is only marginally stabilized, lying at 0.3 kcal/mol below the reactants in relative free energy.

Subsequent dehydration of INT6 proceeds via TS8, leading to formation of the imine intermediate INT7. As illustrated in Scheme 1, this dehydration step requires elimination of water and reorganization of the C–N bonding framework. The relatively high energetic demand of TS8 reflects the absence of stabilizing copper coordination at this stage, rendering dehydration less favorable than in Pathway A, making it the rate-determining step of Pathway B. At the transition state (TS8), the C−O bond between the benzaldehyde carbon and hydroxyl oxygen elongates from 1.42 Å in INT6 to 1.73 Å, while the H–O bond of the departing water molecule shortens, indicating bond cleavage. The resulting INT7 is stabilized by only –4.0 kcal/mol relative to REACT, further reflecting the inefficiency of this pathway. From INT7, coordination to the CuI/L-proline/O₂ system which then undergoes azide-assisted transformations produces INT7*. After that, two possible pathways via TS11 and TS9 are investigated with two-step sequences as the nucleophilic attack followed by the loss of leaving group. Both routes are energetically demanding and require sequential bond reorganization steps, as indicated by the “2 steps” notation in Scheme 1. In one branch, the system may proceed through TS9, involving the catalytically active copper complex-assisted substitution with bromide departure. This pathway is consistent with the proposed mechanism from Xu et al. [26] that cyclization might proceed via formation of a Cu–C bonded intermediate (INT8) through TS9. Our calculations, however, show that this structure is not viable: the optimized Cu–C distance is far too long to represent covalent bonding, and the corresponding species lies at very high energy, indicating pronounced instability. The associated barrier of 44.8 kcal·mol⁻¹ renders this step kinetically prohibitive under the studied conditions. Further progression from INT8 requires additional rearrangement through TS10 to converge toward the same copper-bound quinazoline-type intermediate observed in Pathway A. Instead, our results favor an alternative route in which the azide nitrogen directly attacks the aromatic ring, displacing bromide via TS11. At this transition state, the C–N bond contracts from 4.89 Å to 1.87 Å, with an activation free energy of 28.1 kcal·mol⁻¹. While this barrier is somewhat lower than that predicted for Cu–C bond formation, it remains significantly higher than the S_NAr step in Pathway A (15.0 kcal·mol⁻¹). Consequently, the accumulation of multiple high-energy intermediates and the necessity for sequential transformations render Pathway B both kinetically and thermodynamically less favorable than Pathway A. Overall, these findings strongly support Pathway A as the most accessible mechanism for quinazoline formation.

3.3 Rate Determining Step
Overall, Pathway A is characterized by a well-orchestrated sequence of copper-assisted steps with moderate activation barriers and efficient stabilization of charged intermediates (Figure 2). The initial S_NAr step (TS1) emerges as the rate-determining step, while the subsequent nucleophilic addition (TS2), dehydration (TS3), hydride abstraction (TS4), cyclization (TS5), and proton transfer (TS6) proceed smoothly toward product formation.

In contrast, Pathway B begins with nucleophilic addition (TS7) then suffers from a high-energy dehydration step (TS8), and multiple energetically costly two-step transformations involving azide coordination and bromide displacement (TS9-TS11). These features collectively render Pathway B mechanistically unfavorable under the studied conditions.

4. CONCLUSIONS

This DFT investigation clarifies the operating mechanism of the CuI/L-proline–catalyzed three-component synthesis of quinazoline derivatives from 2-bromobenzaldehyde, benzylamine, and sodium azide under aerobic conditions. Among the two mechanistic scenarios evaluated, the calculations consistently support an azide-first pathway (Pathway A) as the dominant route. The reaction is initiated by an S_NAr displacement of bromide by azide, and this step is predicted to be turnover-limiting (ΔG_sp ≈ 23.8 kcal/mol). Subsequent benzylamine addition to the aldehyde is comparatively facile (ΔG_sp ≈ 15.0 kcal/mol) and is best described by an amine-assisted proton-shuttle arrangement that stabilizes proton transfer during C–N bond formation. After the carbinolamine forms, coordination to the copper/ligand system in the presence of O₂ enables a sequence of productive transformations. Copper coordination and aerobic redox participation reduce the energetic penalty for dehydration and for the key hydride abstraction event (each ΔG_sp ≈ 19.7 kcal/mol), generating a highly stabilized cationic intermediate that undergoes rapid intramolecular closure to the quinazoline framework (ΔG_sp ≈ 5.2 kcal/mol). Product release and re-aromatization proceed with a moderate barrier (ΔG_sp ≈ 18.3 kcal/mol), and the overall transformation is strongly exergonic, consistent with the experimentally observed efficiency of the process when both catalyst and oxygen are present.

In contrast, Pathway B is disfavored due to an energetically demanding dehydration step (ΔG_sp ≈ 34.3 kcal/mol) and additional high-barrier events associated with bromide displacement and proposed copper–carbon bonding (computed barriers up to ~44.8 kcal/mol), making this sequence kinetically implausible under the reported conditions. Collectively, these results provide a coherent explanation for the experimentally observed dependence on the CuI/L-proline system and on molecular oxygen, and they offer a mechanistic foundation for future catalyst/ligand tuning and substrate-scope expansion in related quinazoline-forming multicomponent reactions.

Overall, this work provides mechanistic clarity on the copper-catalyzed quinazoline synthesis and identifies the factors governing selectivity and efficiency. These insights not only rationalize the experimentally observed reactivity but also offer guidance for the rational design of improved catalytic systems and optimized conditions for the efficient synthesis of quinazoline derivatives.

ACKNOWLEDGEMENTS

The authors would like to thank King Mongkut's Institute of Technology Ladkrabang, Thailand, for research support.

AUTHOR CONTRIBUTIONS

Phanupong Phokakul: Writing – Original draft preparation, Investigation, Formal analysis. Duangkamol Gleeson: Formal analysis. Pichayapa Limluan: Review & editing. Matthew Paul Gleeson: Methodology, Investigation, Formal analysis. Kanokthip Boonyarattanakalin: Project instigation, Supervision, Writing – Original draft, review & editing, Methodology, Formal analysis.

CONFLICT OF INTEREST STATEMENT

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

DECLARATION OF USE OF GENERATIVE AI

During the preparation of this manuscript, the authors used OpenAI's ChatGPT to assist with improving the clarity, grammar, and readability of the English language. The authors carefully reviewed and edited all generated text and take full responsibility for the content of this publication. No generative AI tool was used for data analysis, interpretation of results, scientific conclusions, or the generation of research findings.

FUNDING

This research received no external funding.

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