Pd(II)–Prolinate Prolinium and Pd(II)–LysGly Complexes Catalyzed the Enantioselective Aldol, Morita–Baylis–Hillman and Heck Reactions

TL;DR

This paper presents a new palladium-based catalyst that efficiently produces enantiopure compounds through multiple reactions, important for drug development.

Contribution

A novel Pd(II) complex with proline derivatives is shown to catalyze Aldol, Morita–Baylis–Hillman, and Heck reactions with high enantioselectivity and yield.

Findings

The catalyst achieved 80–95% yields with enantiomeric excesses over 99% in Aldol reactions.

Diastereoselectivities of up to 1:69 syn/anti were observed in Aldol reactions.

The catalyst also showed versatility in Morita–Baylis–Hillman and Heck coupling reactions.

Abstract

The induction of chirality to obtain enantiopure products of high synthetic value is of great importance across various scientific fields, particularly in the medical area, as it has been demonstrated that the different enantiomers of drugs interact differently with biological receptors. In this context, asymmetric catalysis focuses on the design of catalysts that are easy to synthesize, capable of efficiently and enantioselectively forming C–C bonds, and suitable for reuse in multiple catalytic processes. This work describes the application of a Pd(II) complex coordinated with the R and S forms of proline in direct Aldol, Morita–Baylis–Hillman, and Heck coupling reactions. The catalytic system efficiently promoted the aldol reaction, achieving yields of 80–95%, excellent diastereoselectivities (1:69 syn/anti), and enantiomeric excesses greater than 99%. From a mechanistic perspective, the formation of a transition state is proposed in which a proline molecule generates an enamine that, upon coordination with the metal center, is stabilized through interaction with the intermediate’s double bond. Moreover, the study of the Morita–Baylis–Hillman and Heck coupling reactions highlights the versatility of this type of catalyst.

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Full text

1. Introduction

Currently, asymmetric catalysis represents one of the most rapidly expanding areas in chemistry, as reflected by the increasing number of studies aimed at obtaining compounds with high enantiomeric excesses [1,2]. Such compounds are of great value in several fields, including agriculture, as the α-1 hormone originally produced by the oomycete Phytophthora, a pathogen of plant species [3]; natural products [4,5], with notable examples such as (−)-lingzhiol, a phytocompound isolated from the fungus Ganoderma lucidum [6]; and medicine, where widely used neuropharmaceuticals such as L-DOPA and (R)-selegiline represent outstanding examples [7,8,9,10,11].

A particularly significant milestone in asymmetric synthesis was marked by the seminal contributions of List et al. [12] and MacMillan et al. [13]. List reported the synthesis of aromatic aldol adducts in good yields and enantiomeric excesses approaching 80%, by catalyzing the reactions with L-proline (30 mol%). In parallel, MacMillan achieved Diels–Alder adducts with excellent yields and high enantioselectivity using imidazolidinone salts derived from L-proline as chiral catalysts. These pioneering studies not only established the foundations of organocatalysis as a powerful synthetic methodology [14,15], but also had such a profound impact that List and MacMillan were awarded the 2021 Nobel Prize in Chemistry [16].

Organocatalysis has been firmly established as a central strategy in asymmetric synthesis. In this context, proline has emerged as a privileged scaffold for the development of related chiral catalysts applied to a broad range of asymmetric transformations. Notably, proline-derived phosphoramide catalysts have been reported [17], along with proline-containing peptoid architectures enabling the highly enantioselective alkylation of amino acids [18] and proline-based tetrapeptides employed in nitro-olefin addition reactions [19]. In parallel, proline-derived catalysts have been extensively explored in classical asymmetric transformations, including aldol reactions [20], Michael additions [21,22,23], Mannich reactions [24], Henry reactions [25,26], Heck cross-coupling reactions [27] and allylic alkylations of ketones [28].

The latter study is particularly noteworthy, as it describes a dual catalytic system consisting of proline and [Pd(allyl)Cl]2. From a mechanistic perspective, the process is proposed to begin with the formation of an enamine intermediate between the ketone and proline. Subsequently, the carbonyl group of proline, assisted by the palladium-stabilized allyl fragment, promotes hydroxyl elimination with the concomitant formation of water. Finally, the enamine acts as a nucleophile toward the allyl moiety, completing the transformation.

Similar reactions in which Lewis acid-promoted catalysis has been explored include the asymmetric aldol reaction, where metals such as iron [29], gold [30], copper [31], silver [32], and d^10^ group metals such as nickel [33], platinum [34], and palladium [35,36] have been successfully employed. In particular, palladium has shown remarkable progress since the earliest reports, ranging from the efficient formation of C–C bonds to asymmetric versions of the reaction [35]. Furthermore, a noteworthy example involves the use of lithium-solvated ionic liquids, in which yields of up to 99% and outstanding enantiomeric excesses exceeding 99% have been achieved [37].

These catalytic systems, generated through the association of metals with ligands, have evolved considerably and are now widely employed [38]. They not only enhance the efficiency of catalytic processes but also enable one-pot reactions, providing more direct access to complex molecules. Among these systems, proline has been the organic fragment of choice in a significant number of research studies [39,40]. One notable example is the development of Fe_3_O_4_–L-proline/Pd nanocomposites, where a synergistic interaction between the organic fragment and the transition metals has been demonstrated in the synthesis of (±)-warfarin. A key step in this transformation involves the formation of a conjugated enone from aromatic aldehydes and acetone, leading to good yields [40]. Additionally, bifunctional catalysts have been reported for asymmetric sequential aldol/Suzuki reactions [41,42], as well as for the Morita–Baylis–Hillman reaction [43].

2. Results

As a starting point, the effect of proline as a ligand on the catalytic activity of the in situ generated Pd–Pro complex was evaluated in the aldol reaction between 4-nitrobenzaldehyde and cyclohexanone. Initially, the reaction was carried out using only PdCl_2_ in different solvents (Scheme 1), as expected, the reaction does not occur. This observation is consistent with previous reports indicating that the PdCl_2_-catalyzed aldol reaction proceeds only with activated enols and under harsh reaction conditions [44].

For the formation of the Pd–amino acid complex, L-proline was employed, and the metal precursor was pre-activated by stirring PdCl_2_ in the solvent for 2 or 24 h, with the aim of generating coordination vacancies. Subsequently, the amino acid was added, and the reaction mixture was stirred 4 h before introducing the aldehyde and the ketone. The best results were obtained when the metal was stirred with the solvent for 24 h (Table 1, entries 2 and 6). The effect of the solvent was also evaluated, revealing that the optimal reaction conditions were achieved using DMF (Table 1, entry 6).

Given that the results obtained with proline were modest, it was decided to explore the effect of replacing Pro with a bulkier ligand, such as a dipeptide, and to assess the influence of introducing a second amino group—specifically, a primary amine derived from an S-Lys N-terminal—on the yield and stereoselectivity of the reaction.

In this context and based on the results obtained for the aldol reaction catalyzed by the in situ generated complex, dichlorido(κ^2^-Nα,Nε-(S)-lysylglycine methyl ester)palladium(II) complex [(S)-3] was previously prepared via the reaction of the methyl ester of the dipeptide (S)-Lys-Gly (2) with PdCl_2_ under reflux in CH_3_CN, as illustrated in Scheme 2 [45,46,47].

The structure of the complex (S)-3 was confirmed based on the changes in chemical shifts and signal broadening of the lysine side chain observed in the ^1^H NMR spectrum (Figure 1a), particularly for the β-, γ-, δ-, and ε-methylene protons. These observations suggest that Pd coordination occurs through the α- and ε-amino groups. This coordination mode is further supported by fast atom bombardment mass spectrometry (FAB^+^) and the fragmentation signals detected at m/z 289 and 307 are consistent with metal coordination with S-Lys fragment (see Figure S4). It is noteworthy that the presence of chlorine atoms, detected in the EDS spectrum (Kα emission) at 2.622 keV, and of palladium at 3.382 keV, further confirms the formation of the Pd complex.

The aldol reaction catalyzed by complex (S)-3 was carried out using 4-nitrobenzaldehyde and cyclohexanone as a model system (Table 2). A comparative evaluation revealed that the reaction did not proceed in water, whereas in solvents such as EtOH, THF, DMF, and DMSO, the reaction occurred after 48 h, affording low to moderate yields with a 1:1 diastereomeric ratio (syn/anti) (Table 2, entries 2, 3, 4 and 7). An increase in the enantioselectivity of the reaction was also observed with increasing solvent polarity, with the best results obtained in DMSO (Table 2, entry 4).

In this regard, the low catalytic activity and stereochemical induction exhibited by complex (S)-3 may arise from several factors, including its limited solubility even in polar solvents and the relatively large size of the catalyst, which may impart greater conformational flexibility, leading to less reactive catalytic species or less stable transition states. Furthermore, steric hindrance may impede the formation of stable intermediates capable of promoting the formation of the desired product. In this context, it has been reported that (S)-lysine, in its free amino acid form, catalyzes the aldol reaction with good yields and high enantiomeric excesses [48]. However, when this amino acid is coordinated to a transition metal such as zinc, although it retains good catalytic activity, its ability to induce asymmetry is considerably diminished. This behavior can be attributed to steric effects associated with the coordination complex, which result in the catalytic site being positioned away from the α-amino group adjacent to the chiral center of the amino acid [49].

This was a significant finding, as it has been reported that in solvents such as DMF or DMSO, glycine-derived complexes can generate species through dynamic exchange with the solvent, which is reflected in the stability of the intermediate species involved in the catalytic process [45].

To improve the stereoselectivity of the process, the reaction was conducted in DMSO at 4 °C. Under these conditions, a significant enhancement in catalytic performance was observed, suggesting that the reaction is thermodynamically favored toward product formation at lower temperatures. A 39% yield and an enantiomeric excess (ee) of 32% were obtained under these optimized conditions (Table 2, entry 7).

Once the optimal conditions were established, the aldol reaction was carried out using substituted aromatic aldehydes and cyclic ketones. The reaction was catalyzed by both the (S)-Lys-Gly·PdCl_2_ complex [(S)-3] and the (S)-prolinium dichloro((S)-prolinate−κ^2^N,O)palladium(II) complex [(S)-4], which were obtained and characterized in a previous study (Figure 2) [46,47]. The results are summarized in Table 3.

The Pd catalyst (S)-3 exhibited lower efficiency in C–C bond formation, affording poor enantiomeric excesses and a 1:1 diastereomeric ratio in most cases (Table 3, entries 2, 4, 6). In contrast, the catalyst containing proline as the ligand (complex (S)-4) efficiently promoted the reaction, achieving yields above 85% and enantiomeric excesses greater than 95% (Table 3, entries 1, 3, 5, 7, 9 and 10). An increase in enantioselectivity was also observed when the aldehyde substituent with the most electron-withdrawing group was located at the meta or ortho position, suggesting that the steric hindrance generated by this substituent in proximity to the Pd center plays a key role in chiral induction (Table 3, entries 1 and 3). This observation is further supported by the fact that aldehydes with para-substituents afforded the highest yields but lower stereoselectivities (Table 3, entries 5, 8, 10). Similarly, a syn/anti diastereomeric ratio of up to 1:69 was obtained (Table 3, entry 3). In all cases, the anti diastereoisomer was formed preferentially.

Based on the above results, a plausible reaction mechanism can be proposed according to the model described by Houk and List [50]. In this case, the coordination complex (S)-4, previously reported by Aviña-Verduzco et al., corresponds to a neutral complex composed of an N,O-bidentate prolinate anion coordinated to Pd, with its coordination sphere completed by a prolinium cation [46,47].

As a first step, it is proposed that the catalytic process is controlled entirely by the prolinate–PdCl_2_ anion (S)-4, since the prolinium cation, being protonated (R–NH_2_^+^), is unable to form the enamine intermediate (Scheme 3). In this context, it is suggested that the coordination complex, in polar aprotic solvents such as DMSO, undergoes dynamic ligand exchange, thereby allowing the release of the amino lone pair and the formation of the enamine a derived from the ketone through a dual mechanism, similar to that submitted for proline–Zn^2+^ complexes [51]. This process generates a molecule of water and establishes an interaction between the enamine C=C bond and the vacant p orbital of the palladium center A. A similar mechanism has been proposed for the aldol reaction [52] as well as for carbocyclization reactions catalyzed by chiral amines and Pd species [53].

Subsequently, after incorporation of the aldehyde into the catalytic cycle, it is proposed that its coordination to the Pd center occurs through the carbonyl oxygen atom and from the less sterically hindered side. Concomitantly, at this stage, the transfer of the hydrogen from the NH_3_^+^ group of the prolinium cation to the prolinate is suggested. Once this complex is established, and considering the electrophilic nature of the aldehyde carbonyl carbon, nucleophilic attack of the enamine on the aldehyde takes place through the Si face of the aldehyde relative to the enamine (B vs. C), thereby facilitating C–C bond formation with a preference for generation of the anti-isomer D. Finally, the resulting intermediate is hydrolyzed by a water molecule, leading to formation of the aldol adduct and regeneration of the catalyst, thus completing a new catalytic cycle.

This information is supported by the results obtained from DFT calculations, particularly through the transition-state search, which was performed starting from intermediate C. The calculations revealed that, following hydrogen transfer from the prolinium cation leading to the formation of proline, as well as the generation of the PdCl_2_–proline–OH complex from the proline carboxylate, and once the aldehyde becomes coordinated to the Pd center, it undergoes a nucleophilic attack by the enamine, resulting in the formation of a new carbon–carbon bond (Figure 3).

The relative free energies associated with the proposed reaction pathway are summarized in Table 4. In both the gas phase and DMSO, the reaction proceeds through a low-energy transition state, with activation barriers of 7.1 and 6.7 kcal/mol, respectively. Notably, the intermediate formed after C–C bond formation is slightly endothermic in the gas phase (+0.4 kcal/mol), whereas in DMSO it is significantly stabilized.

Catalyst Scope

To determine the extent to which Pd complexes (S)-3 and (S)-4 act as chiral catalysts in the stereoselective formation of C–C bonds, they were evaluated in the Morita–Baylis–Hillman (MBH) reaction, a catalytic process that does not involve the formation of an enamine but does activate the vinyl group. For this purpose, the reaction was carried out between 2-cyclohexen-1-one and a series of substituted aromatic aldehydes according to the conditions shown in Table 4.

It is noteworthy that the reaction proceeded with the complexes evaluated giving good yields (Table 5, entries 2, 4 and 8). Furthermore, a preference for condensation with the vinyl group was observed. This lead exclusively to the formation of the Morita–Baylis–Hillman (MBH) adduct, rather than the aldol adduct that would have been expected had condensation occurred at the saturated position of the ketone. However, despite the good yields, HPLC analysis revealed that asymmetry induction was not achieved in any of the cases. Consequently, each MBH adduct was obtained as a racemic mixture in all cases.

However, although the stereoselectivity was not as expected, this reaction supports the hypothesis that chirality in the aldol reaction is probably due to the formation of enamine intermediates that involve direct covalent interactions with the catalyst, and not to electronic factors or non-covalent interactions such as those observed in MBH processes for the induction of chirality, such as thiourea catalysis [54].

On the other hand, it is proposed that, given the good yields, palladium could be activating the carbonyl or vinyl group of the α,β-unsaturated ketone, in accordance with the mechanism proposed for Pd-catalyzed MBH reactions [55]. This condition would favor catalysis promoted by DIPEA, a tertiary amine that is inefficient in the MBH reaction, unlike DABCO or DBU [56]. It should be noted that poor yields were obtained when using aldehydes deactivated with electron-donating groups within the aromatic ring, for example 2-, 3- and 4-anisaldehyde.

Nevertheless, catalysts 3 and 4 were also evaluated in the Heck cross-coupling. For this purpose, the alkene 2-cyclohexen-1-one was again used against some 4-substituted aryl halides (Table 6).

The reaction was carried out under reflux conditions and with microwave energy (60 W). It was observed that the yields were significantly higher when the process was carried out by microwave irradiation (Table 6, entries 2 to 9). In this context, it is important to highlight that complexes 3 and 4 efficiently promoted the formation of the carbon-carbon (C–C) bond, with the best results obtained when the reaction was catalyzed by the Pd complex 4, reaching yields of up to 90% when 4-iodophenol was used as the aryl halide (Table 6, entry 3).

On the other hand, complex 3 also allowed the successful formation of Heck adducts, with lower yields compared to catalyst 4 (Table 6, entries 2, 4, 6, 8). Obtaining these products is of particular importance, as they act as direct precursors of 3-aryl substituted phenols, compounds of high synthetic value [57]. Furthermore, it should be noted that Heck couplings with conjugated enones are particularly difficult to achieve, which further highlights the relevance of these results [58].

In addition to evaluating the catalytic capacity, the interaction of the complexes with the π-conjugated system was examined, a crucial interaction for the formation of C–C bonds described as one of the most consistent reaction mechanisms for this process [52].

3. Materials and Methods

3.1. General

Column chromatography was carried out with Merck Sigma-Aldrich (Milwaukee, WI, USA) Silica Gel (70–230 mesh). TLC was performed with Merck 60-F254 plates (Darmstadt, Germany), and spots were visualized using UV light and iodine vapor. Infrared (IR) spectra were recorded on a Thermo Scientific Nicolet iS10 spectrometer (Madison, WI, USA). ^1^H and ^13^C NMR spectra were acquired on a Varian Mercury Plus spectrometer (Palo Alto, CA, USA) operating at 100 and 400 MHz. Mass spectra (MS) were obtained via electron impact (EI) using a Thermo Scientific ISQ CT instrument. High-resolution mass spectrometry (HRMS) data were collected using a Bruker Maxis Impact ESI-QTOF-MS (Bremen, Germany). The chromatograms were obtained using a Thermo Fisher Scientific UltiMate 3000 high-performance equipped with a UV detector (Germering, Germany).

3.2. Catalyst Synthesis

Dichlorido(κ^2^-Nα,Nε-L-lysylglycine methyl ester)palladium(II) (S)-3

Complex (S)-3 was obtained by dissolving palladium chloride (PdCl_2_) (0.024 g, 0.137 mmol) in CH_3_CN, and 0.136 g of the peptide L-lysine-glycine-OMe (0.270 mmol) was added to the resulting mixture. Following the reaction, 0.042 g of complex (S)-3 was obtained as a black solid in 51% yield. m.p. 216–218 °C (decomposition). ^1^H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 3.73 (m, 1H, CH), 3.71 (dd, J = 19.7, 17.4, 2.4 Hz, 2H, CH_2_), 3.46 (t, J = 6.2 Hz, 2H, NH_2_), 3.40 (s, 3H, CH_3_), 2.38 (dd, J = 14.1, 7.1 Hz, 2H, CH_2_), 1.62 (m, 2H, CH_2_), 1.30 (m, 2H, CH_2_). ^13^C NMR (100 MHz, DMSO-d6, TMS) δ (ppm): 168.0, 166.2, 54.0, 44.3, 43.9, 32.5, 30.1, 21.4. FTIR ν_max/cm^−1^: 3246, 3211, 2960, 2924, 2860, 1581, 1468, 1085, 1011, 758. MS (FAB) m/z: [M + 2] = 613. EDS (keV): S 0.09, Cl 0.1, Pd 0.25, O 0.5, S 2.3, Cl 2.6, Pd 2.8.

(S)-prolinium dichloro((S)-prolinate-κ^2^N,O)palladate(II) (S)-4

Complex 4 was obtained by dissolving palladium chloride (PdCl_2_) (0.100 g, 0.56 mmol) in CH_3_CN; subsequently, L-proline (0.136 g, 1.18 mmol) was added to the resulting mixture. After the reaction, 0.166 g of compound (S)-4 was isolated as an orange solid (73% yield) m.p. 177–179 °C (decomposition). ^1^H NMR (400 MHz, CD_3_OD) δ (ppm): 5.69 (s), 4.41 (dd, J = 8.4, 6.9 Hz, 1H), 3.80 (dd, J = 14.5, 8.5 Hz, 1H), 3.39 (t, J = 7.1 Hz, 2H), 3.28–2.94 (m, 2H), 2.43 (m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 2.00 (m, 1H), 2.01 (m, 1H), 1.67 (m, 1H). ^13^C NMR (100 MHz, CD_3_OD) δ (ppm): 171.5, 60.70, 53.52, 47.20, 31.16, 29.53, 25.30, 24.60. MS: 284.12 (M+, 3%), 251 (14), 186 (6), 111 (8), 97 (24). IR ν_max/cm^−1^: 3449, 3182, 2966, 1720, 1574, 1299, 1223, 1032, 743. HRMS: calcd for C_10_H_17_Cl_2_N_2_O_4_Pd [M + H] 405.9678; found 405.9783.

3.3. General Procedure for the Aldol Reaction

In a magnetically stirred flask, 1 equivalent of the corresponding aldehyde and 5 equivalents of cyclohexanone were placed in 0.3 mL of DMSO. 10 mol% catalyst was added to the mixture, and the reaction was allowed to proceed at 4 °C for 48 h. After the reaction time, a supersaturated ammonium chloride solution was added, and the mixture was extracted with EtOAc (3 × 40 mL) and distilled water (20 mL). The organic phases were combined, dried with Na_2_SO_4_, filtered, and evaporated under reduced pressure. The crude product was analyzed by ^1^H NMR to determine diastereoselectivity and purified by column chromatography (hexane/EtOAc 80:20).

2-(hydroxy(2-nitrophenyl)methyl)cyclohexan-1-one 1a [59]

Following the methodology, 0.030 g (0.198 mmol) of 2-nitrobenzaldehyde, 0.10 mL (0.097 g, 0.992 mmol) of cyclohexanone, and 0.008 g (0.019 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.042 g of compound 1a, corresponding to a 86% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.85 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.44 (dd, J = 11.2, 4.3 Hz, 1H), 5.45 (d, J = 7.1 Hz, 1H), 2.76 (dt, J = 12.7, 6.5 Hz, 1H), 2.45 (d, J = 13.6 Hz, 1H), 2.34 (td, J = 13.3, 6.2 Hz, 1H), 2.10 (ddd, J = 9.0, 5.7, 2.8 Hz, 1H), 1.85 (dd, J = 13.1, 2.5 Hz, 1H), 1.79–1.54 (m, 4H); ^13^C NMR (101 MHz, CD_3_OD) δ (ppm): 214.8, 148.6, 136.5, 133.0, 128.9, 128.3, 124.0, 69.7, 57.2, 42.7, 31.0, 27.7, 24.9. HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10): t_R = 21.62 min (major) and 23.23 min (minor), 99% ee.

2-(hydroxy(3-nitrophenyl)methyl)cyclohexan-1-one 1b [59]

0.030 g (1.198 mmol) of 3-nitrobenzaldehyde, 0.10 mL (0.097 g, 0.992 mmol) of cyclohexanone, and 0.008 g (0.019 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.040 g of compound 1b, corresponding to a 84% isolated yield ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 8.22 (s, 1H), 8.16 (dd, J = 8.2, 1.2 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 4.90 (dd, J = 8.5, 2.2 Hz, 1H), 4.15 (d, J = 2.8 Hz, 1H), 2.69–2.58 (m, 1H), 2.55–2.46 (m, 1H), 2.43–2.33 (m, 1H), 2.12 (ddd, J = 12.6, 5.8, 2.9 Hz, 1H), 1.84 (d, J = 13.5 Hz, 1H); ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 214.7, 148.1, 143.21, 133.1, 129.2, 122.7, 121.9, 73.9, 57.0, 42.5, 30.6, 27.5, 24.5. HPLC (Chiralpak AD-H, hexane/i-PrOH 95:5): t_R = 51.62 min (major) y 66.86 min (minor), 99% ee.

2-(hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one 1c [59]

0.030 g (1.198 mmol) of 4-nitrobenzaldehyde, 0.10 mL (0.097 g, 0.992 mmol) of cyclohexanone, and 0.008 g (0.019 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.048 g of compound 1c, corresponding to a 98% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 8.21 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.90 (d, J = 8.4 Hz, 1H), 4.10 (s, 1H), 2.66–2.30 (m, 1H), 2.19–2.06 (m, 1H), 1.84 (d, J = 13.5 Hz, 1H), 1.77–1.51 (m, 2H), 1.47–1.30 (m, 1H); ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 214.7, 148.3, 147.4, 127.8, 126.5, 123.3, 73.9, 57.1, 42.6, 30.7, 27.5, 24.6; HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10): flow 1 mL/min, t_R = 27.13 min (minor) y 30.03 min (major), 92% ee.

2-((3-chlorophenyl)(hydroxy)methyl)cyclohexan-1-one 1d [59]

0.024 mL (0.030 g, 0.213 mmol) of 3-chlorobenzaldehyde, 0.11 mL (0.104 g, 1.067 mmol) of cyclohexanone and 0.008 g (0.021 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.045 g of compound 1d, corresponding to a 90% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.33 (s, 1H), 7.27 (d, J = 3.4 Hz, 2H), 7.19 (d, J = 3.1 Hz, 1H), 4.75 (d, J = 8.1 Hz, 1H), 4.02 (s, 1H), 2.65–2.53 (m, 1H), 2.48 (d, J = 13.6 Hz, 1H), 2.35 (td, J = 13.1, 6.0 Hz, 1H), 2.13–1.77 (m, 2H), 1.81 (d, J = 11.9 Hz, 1H), 1.73–1.49 (m, 4H), 1.31 (dd, J = 25.9, 15.7 Hz, 1H); ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 215.1, 143.0, 134.2, 129.5, 128.0, 127.1, 125.2, 74.2, 57.2, 42.6, 30.7, 27.6, 24.6. HPLC: Diacel Chiralpak AD-H, hexane/i-PrOH 90:10, flow 1 mL/min., 99% ee.

2-((4-chlorophenyl)(hydroxy)methyl)cyclohexan-1-one 1e [59]

0.025 mL (0.030 g, 0.213 mmol) of 4-chlorobenzaldehyde, 0.11 mL (0.104, 1.067 mmol) of cyclohexanone and 0.008 g (0.021 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.032 g of compound 1e, corresponding to a 63% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.33–7.28 (m, 1H), 7.28–7.19 (m, 1H), 5.32 (d, J = 19.9 Hz, 1H), 4.76 (dd, J = 8.7, 2.6 Hz, 1H), 4.02 (d, J = 2.8 Hz, 1H), 2.61–2.50 (m, 1H), 2.51–2.42 (m, 1H), 2.41–2.27 (m, 1H), 2.13–2.03 (m, 1H), 1.89–1.74 (m, 1H), 1.74–1.48 (m, 2H), 1.35–1.22 (m, 1H). ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 215.2, 139.4, 133.4, 128.4, 128.3, 74.0, 57.2, 42.5, 30.6, 27.6, 24.6. HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10) flow 0.5 mL/min, t_R = 30.5 min (minor) y 35.86 min (major), 93% ee.

2-((3-bromophenyl)(hydroxy)methyl)cyclohexan-1-one 1f [59]

0.018 mL (0.030 g, 0.162 mmol) of 3-bromobenzaldehyde, 0.060 mL (0.079 g, 0.909 mmol) of cyclohexanone, and 0.006 g (0.016 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.040 g of compound 1f, corresponding to a 88% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.49 (s, 1H), 7.45–7.34 (m, 1H), 7.28–7.10 (m, 2H), 4.69 (t, J = 29.5 Hz, 1H), 4.03 (s, 1H), 2.57 (s, 1H), 2.47 (d, J = 12.7 Hz, 1H), 2.42–2.28 (m, 1H), 2.06 (d, J = 14.4 Hz, 1H), 1.88–1.73 (m, 1H), 1.66 (dd, J = 25.0, 10.2 Hz, 2H), 1.58 (d, J = 12.2 Hz, 2H), 1.30 (dd, J = 25.3, 13.9 Hz, 1H); ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 143.28, 130.9, 129.9 129.8, 125.7, 124.3, 122.5, 74.1, 57.2, 42.6, 30.7, 27.6, 24.6, HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10) flow 0.5 mL/min, t_R = 31.99 min (minor) y 35.46 min (major), 98% ee.

2-((4-bromophenyl)(hydroxy)methyl)cyclohexan-1-one 1g [59]

0.030 g (0.162 mmol) of 4-bromobenzaldehyde, 0.084 mL (0.079 g, 0.32 mmol) of cyclohexanone, and 0.006 g (0.016 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.041 g of compound 1g, corresponding to a 91% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.46 (dd, J = 7.5, 5.8 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 4.75 (dd, J = 8.7, 2.6 Hz, 1H), 4.02 (d, J = 2.8 Hz, 1H), 2.59–2.51 (m, 1H), 2.47 (dt, J = 13.7, 4.3 Hz, 1H), 2.35 (td, J = 13.3, 6.6 Hz, 1H), 2.08 (ddd, J = 12.1, 5.9, 2.9 Hz, 1H), 1.84–1.73 (m, 1H), 1.73–1.47 (m, 2H), 1.36–1.20 (m, 1H). ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 215.1, 139.9, 131.3, 128.6, 121.5, 74.0, 57.2, 42.5, 30.6, 27.6, 24.5. HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10) flow 0.5 mL/min, t_R = 31.99 min (minor) and 35.46 min (major), 98% ee.

2-(hydroxy(2-methoxyphenyl)methyl)cyclohexan-1-one 1h [60]

0.030 g (0.220 mmol) of 2-methoxybenzaldehyde, 0.114 mL (0.108 g, 1.101 mmol) of cyclohexanone and 0.009 g (0.01 mmol) of catalyst were placed in 0.3 mL of DMSO. The reaction afforded 0.031 g of compound 1h, corresponding to a 61% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.40 (dd, J = 7.5, 1.4 Hz, 1H), 7.33–7.17 (m, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.26 (dd, J = 8.4, 4.1 Hz, 1H), 3.81 (s, 3H), 2.78–2.68 (m, 1H), 2.47 (dt, J = 13.4, 3.2 Hz, 1H), 2.34 (td, J = 12.9, 6.0 Hz, 1H), 2.09–1.98 (m, 1H); ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 215.5, 156.6, 129.5, 128.5, 127.7, 120.8, 110.4, 68.5, 57.2, 55.3, 42.5, 30.4, 27.9, 24.6; HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10) flow 1 mL/min, t_R = 27.90 min (minor) and 30.14 min (major), 97% ee.

2-(hydroxy(3-(trifluoromethyl)phenyl)methyl)cyclohexan-1-one 1i

0.030 g (0.022 mL, 0.172 mmol) of 2-trifluoromethylbenzene, 0.089 mL (0.084 g, 0.861 mmol) of cyclohexanone and 0.008 g (0.01 mmol) of catalyst were placed in 0.3 mL of DMF. The reaction afforded 0.041 g of compound 1i, corresponding to a 89% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.65–7.39 (m, 1H), 4.85 (dd, J = 8.7, 2.4 Hz, 1H), 4.10 (d, J = 2.7 Hz, 1H), 2.66–2.55 (m, 1H), 2.47 (t, J = 16.1 Hz, 1H), 2.44–2.33 (m, 1H), 2.11 (ddd, J = 9.4, 5.9, 2.9 Hz, 1H), 1.92–1.48 (m, 1H), 1.32 (qd, J = 13.6, 7.4 Hz, 1H). ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 215.1, 141.9, 130.4, 128.7, 74.3, 57.2, 42.6, 30.7, 27.6, 24.6. HPLC, ee not resolved by HPLC.

2-(hydroxy(4-nitrophenyl)methyl)cyclopentan-1-one 1j [61]

0.030 g (0.198 mmol) of 4-nitrobenzaldehyde, 0.088 mL (0.083 g, 0.992 mmol) of cyclopentanone, and 0.008 g (0.01 mmol) of catalyst were placed in 0.3 mL of DMF. The reaction afforded 0.027 g of compound 1j, corresponding to a 59% isolated yield. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 8.29–8.11 (m, 1H), 7.58–7.49 (m, 1H), 5.43 (s, 1H), 4.85 (d, J = 9.2 Hz, 1H), 2.63 (d, J = 8.4 Hz, 1H), 2.54–2.34 (m, 1H), 2.33–2.11 (m, 1H), 2.08–1.92 (m, 1H), 1.81–1.60 (m, 1H). ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 150.0, 127.3, 126.3, 123.7, 123.6, 74.4, 70.4, 56.0, 55.0, 38.9, 38.5, 26.8, 22.4, 20.2; HPLC (Chiralpak AD-H, hexane/i-PrOH 90:10) flow 0.8 mL/min, t_R = 32.90 min (minor) y 35.76 min (major), 86% ee.

3.4. General Procedure for the Morita-Baylis-Hillman Reaction

In a flask equipped with magnetic stirring, 1 equivalent of the corresponding aldehyde and 5 equivalents of cyclohexen-1-one were placed in 1 mL of ethylene glycol. To the resulting reaction mixture, 10 mol% of catalyst was added, and the mixture was treated with 3 equivalents of diisopropylethylamine (DIPEA) and 0.01 mL of acetic acid. The reaction was allowed to proceed in an oil bath for 24 h. After the reaction time, the mixture was extracted with ethyl acetate (3 × 40 mL) and distilled water (50 mL). The organic phases were combined and dried with sodium chloride (Na_2_SO_4_), filtered by gravity, and evaporated under reduced pressure. The crude reaction product was purified by column chromatography using a mixture of hexane/EtOAc as the eluent.

2-((2-chlorophenyl)(hydroxy)methyl)cyclohex-2-en-1-one 5a

According to the MBH reaction, a mixture of 0.024 mL (0.030 g, 0.213 mmol) of 2-chlorobenzaldehyde and 0.107 mL (0.102 g, 1.07 mmol) of 2-cyclohexen-1-one in 1 mL of ethylene glycol was treated with 0.111 mL (0.082 g, 0.640 mmol) of DIPEA, 0.01 mL of acetic acid, and 0.008 g (0.01 mmol) of catalyst (S)-3 was added. From this reaction, 0.045 g of a white solid was obtained with a yield of 90%; m.p. 92–84 °C. ^1^H NMR (400 MHz; CDCl_3_, TMS) δ (ppm): 7.62 (m, 1H), 7.21–7.35 (m, 3H). 6.48 (t, J = 4.2 Hz, 1H), 5.95 (s, 1H), 3.76, (s, 1H), 2.48–2.52 (m, 2H), 2.32–2.35 (m, 2H), 1.96–2.04 (m, 2H) ^13^C NMR (100 MHz; CDCl_3_; TMS) δ (ppm): 200.0, 149.9, 139.0, 138.4, 129.2, 128.6, 128.2, 126.9, 68.6, 38.4, 25.7, 22.4. MS (IE) m/z: 235(M-1, 4%), 201(26), 183(100), 165(17), 115(18), 77(25).

2-((4-chlorophenyl)(hydroxy)ethyl)cyclohex-2-en-1-one 5b

According to the MBH reaction, a mixture of 0.030 g (0.213 mmol) of 4-chlorobenzaldehyde and 0.107 mL (0.102 g, 1.07 mmol) of 2-cyclohexen-1-one in 1 mL of ethylene glycol, were treated with 0.111 mL (0.082 g, 0.640 mmol) of DIEA and 0.01 mL of acetic acid and 0.008 g (0.01 mmol) of catalyst (S)-3 was added. From this reaction, 0.046 g of white solid was obtained with a yield of 91%; m.p. 83–85 °C. ^1^H RMN (400 MHz, CDCl_3_, TMS) δ (ppm): 7.36–7.27 (m, 5H), 6.74 (t, J = 4.1 Hz, 1H), 5.52 (d, J = 4.9 Hz), 3.47 (d, J = 5.4 Hz, 1H), 2.49–2.43 (m, 2H), 2.40 (dd, J = 10.7, 5.2 Hz, 2H), 2.06–1.94 (m, 2H).^13^C RMN (100 MHz, CDCl_3_, TMS) δ (ppm): 200.4, 147.5, 140.6, 141, 133.1, 128.4, 127.8, 72.0, 38.4, 25.7, 22.4; MS (IE) m/z: 236(M^+^, 31%), 201(95), 155(38), 96(39), 77(100).

2-(hydroxy(3-nitrophenyl)methyl)cyclohex-2-en-1-one 5c

According to the MBH reaction, a mixture of 0.030 g (0.198 mmol) of 2-nitrobenzaldehyde and 0.100 mL (0.095 g, 0.992 mmol) of 2-cyclohexen-1-one in 1 mL of ethylene glycol was treated with 0.102 mL (0.076 g, 0.595 mmol) of DIEA and 0.01 mL of acetic acid. To this mixture, 0.008 g (0.01 mmol) of catalyst (S)-3 was added. 0.039 g of a light yellow solid was obtained in an 81% yield; m.p. 82–85 °C. ^1^H NMR (400 MHz; CDCl_3_, TMS) δ (ppm): 8.22 (m, 1H), 8.16–8.02 (m, 1H), 8.11 (m, 1H), 7.72 (m, 1H), 7.52 (m, 1H), 6.89 (t, J = 4.1 Hz, 1H), 5.61 (s, 1H), 3.78 (s, 1H), 2.45 (m, 4H), 2.02 (m, 2H). ^13^C NMR (100 MHz; CDCl_3_; TMS) δ (ppm): 199.9, 148.0, 144.2, 140.1, 132.5, 129.1, 122.3, 121.2, 71.5, 38.3, 25.6, 22.3. MS (IE) m/z: 246(M-1, 4%), 230(100), 200(38), 123(20).

2-(hydroxy(4-nitrophenyl)methyl)cyclohex-2-en-1-one 5d

According to the MBH reaction, a mixture of 0.030 g (0.198 mmol) of 4-nitrobenzaldehyde, 0.100 mL (0.095 g, 0.992 mmol) of 2-cyclohexen-1-one in 1 mL of ethylene glycol was treated with 0.102 mL (0.076 g, 0.595 mmol) of DIEA and 0.01 mL of acetic acid. To this mixture, 0.008 g (0.01 mmol) of catalyst (S)-3 was added. From this reaction, 0.043 g of a white solid was obtained with a yield of 89%; m.p. 135–137 °C. ^1^H NMR (400 MHz; CDCl_3_, TMS) δ (ppm): 8.19 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 6.85 (t, J = 4.0 Hz, 1H), 5.61 (s, 1H), 3.66 (s, 1H), 2.45 (dt, J = 7.9, 6.1 Hz, 4H), 2.01 (m, 2H). ^13^C NMR (100 MHz; CDCl_3_; TMS) δ (ppm): 200.0, 149.3, 148.14, 147.1, 140.1, 127.0, 123.4, 71.8, 38.3, 25.7, 22.3. MS (IE) m/z: 246(M-1, 25%), 230(100), 200(81), 128(15).

3.5. General Procedure for the Heck Cross-Coupling

In a round-bottom flask equipped with magnetic stirring, 1 equivalent of aryl halide, 5 equivalents of 2-cyclohexen-1-one, and 10 mol% of catalyst were placed in a 1:1 H_2_O/DMF mixture. This mixture was treated with 3 equivalents of DIEA and subsequently heated in a CEM microwave reactor at 60 W for 30 minutes. After the reaction time, the product was extracted with EtOAc (3 × 30 mL), the organic phases were combined and dried with anhydrous Na_2_SO_4_, and then dried using a rotary evaporator under reduced pressure. The products were purified by column chromatography using a mixture of hexane/EtOAc as the eluent (90:10).

3-(4-hydroxyphenyl)cyclohex-2-en-1-one 6a

Following the general methodology for the Heck reaction, 0.040 g (0.181 mmol) of 4-iodophenol and 0.092 mL (0.087 g, 0.909 mmol) of 2-cyclohexen-1-one and 0.095 mL (0.070 g, 0.541 mmol) of DIEA were reacted; to this mixture, 0.007 g (0.017 mmol) of catalyst was added in 3 mL of the water/DMF solvent mixture (1:1), from this reaction, 0.030 g of a white solid was obtained in a yield of 90%; m.p. of 150–152 °C. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.47 (d, J = 8.7 Hz, 2H, H-Ar), 7.06 (s, 1H, OH), 6.91 (d, J = 8.7 Hz, 1H, H-Ar), 6.42 (s, 1H, CH), 2.76 (t, J = 5.6 Hz, 2H, CH_2_), 2.55–2.43 (m, 2H, CH_2_), 2.19–2.05 (m, 1H, CH_2_). ^13^C NMR (100 MHz, CDCl_3_) δ (ppm): 201.0, 160.5, 158.3, 130.2, 127.9, 123.0, 115.8, 37.0, 27.8, 22.6. MS (IE) m/z: 188(M^+^, 94%), 160(100), 132(65), 131(60).

3-(4-methoxyphenyl)cyclohex-2-en-1-one 6b

Following the general methodology for the Heck reaction, 0.040 g (0.170 mmol) of 1-methoxy-4-iodobenzene and 0.086 mL (0.082 g, 0.854 mmol) of 2-cyclohexen-1-one and 0.089 mL (0.066 g, 0.512 mmol) of DIEA were reacted; to this mixture, 0.007 g (0.017 mmol) of catalyst was added in 3 mL of the water/DMF solvent mixture (1:1). From this reaction, 0.027 g of a white solid was obtained with a yield of 80%; melting point of 73–75 °C. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.47 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 9.7 Hz, 2H), 6.40 (t, J = 1.2 Hz, 1H), 3.85 (s, 3H), 2.75 (td, J = 6.3, 1.2 Hz, 2H), 2.47 (td, J = 6.3, 1.2 Hz, 2H), 2.14 (m, 2H). ^13^C NMR (100 MHz, CDCl_3_) δ (ppm): 199.8, 161.1, 159.0, 130.7, 127.5, 123.6, 114.0, 55.3, 37.1, 27.7, 22.7; MS (IE) m/z: 202(M^+^, 96%), 174(100), 146(70), 131(47), 131(59).

3-(4-ethoxyphenyl)cyclohex-2-en-1-one 6c

Following the general methodology for the Heck reaction, 0.040 g (1.6 mmol) of 1-ethoxy-4-iodobenzene, 0.081 mL (0.077 g, 0.806 mmol), of 2-cyclohexen-1-one and 0.084 mL (0.062 g, 0.483 mmol) of DIEA were reacted. To this mixture, 0.007 g (0.017 mmol) of catalyst was added in 3 mL of a water/DMF solvent mixture (1:1). This reaction yielded 0.026 g of a white solid with a 76% yield and a melting point of 57–59 °C. ^1^H NMR (400 MHz, CDCl_3_) δ (ppm): 7.51 (d, J = 8.8 Hz, 2H), 6.92 (d, J = Hz, 2H), 6.40 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 2.75 (t, J = 5.6 Hz, 2H), 7.47 (m, 2H), 2.14 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H). ^13^C NMR (101 MHz, CDCl_3_) δ (ppm): 197.2, 160.6, 159.1, 130.5, 127.5, 123.55, 114.5, 63.5, 37.1, 27.8, 22.7, 14.7; MS (IE) m/z: 216(M^+^, 100%), 188(88), 160(68), 131(58).

3-(4-benzyloxyphenyl)ciclohex-2-en-1-ona 6d

Following the general methodology for the Heck reaction, 0.040 g (0.128 mmol) of 1-iodo-4-phenylmethoxybenzene, 0.065 mL (0.061 g, 0.063 mmol) of 2-cyclohexen-1-one and 0.067 mL (0.050 g, 0.386 mmol) of DIEA were placed in a mixture. To this mixture, 0.005 g (0.012 mmol) of catalyst was added to 2 mL of a water/DMF solvent mixture (1:1). This reaction yielded 0.025 g of a white solid in a 71% yield; melting point 60–62 °C. ^1^H NMR (400 MHz, CDCl_3_, TMS) δ (ppm): 7.52 (d, J = 8.9 Hz, 2H), 7.38 (m, 5H), 7.00 (d, J = 8.9 Hz, 2H), 6.40 (s, 1H), 5.11 (s, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.47 (m, 2H), 2.14 (m, 2H). ^13^C NMR (100 MHz, CDCl_3_, TMS) δ (ppm): 199.9, 160.3, 159.0, 136.4, 131.0, 128.6, 128.1, 127.6, 127.41, 123.7, 70.0, 37.1, 27.8, 22.7.

3.6. Computational Details

All electronic structure calculations were performed using Density Functional Theory (DFT) in Gaussian16 [62] employing the global-hybrid, meta-GGA density functional M08-HX developed by Zhao and Truhlar [63]. The molecular orbitals were described using the def2-SVP basis set for all atoms, which corresponds to a double-ζ quality basis with polarization functions, designed to provide a balance between computational efficiency and accuracy [64]. For palladium, the def2 effective core potential (def2-ECP) was employed to replace the inner-core electrons of the metal and implicitly account for scalar relativistic effects [65]. Thus M08HX/def2-SVP theory level was employed in the scans along the reaction coordinate, and from the energy profiles obtained, the transition state and intermediate were located.

The geometries selected for these stationary points were optimized at the same level of theory. Each stationary point was characterized by calculating harmonic vibrational frequencies. The intermediate was characterized by the absence of imaginary frequencies, whereas the transition state exhibits a single imaginary frequency, associated with the vibrational mode corresponding to the reaction coordinate.

Gibbs free energy was calculated for the thermal corrections obtained in the frequency analysis, considering standard conditions of 298.15 K and 1 atm. The relative energies are reported with respect to the Gibbs free energy of the reactants. The calculations were performed in the gas phase, and then the solvent effects were considered employing the polarizable continuum model (PCM) [66] using DMSO by the single point calculations at the same level of theory.

4. Conclusions

The Pd catalysts (S)-3 and (S)-4 are readily available and easily synthesized complexes that have been shown to promote the aldol reaction efficiently. These catalysts allowed for the production of aldol adducts in good yields and with high diastereoselectivity (r.d. up to 1:69), favoring the formation of the anti diastereomer in all cases. Furthermore, the complexes (S)-3 and (S)-4 demonstrated the ability to induce high enantioselectivity and achieving enantiomeric excesses greater than 99%.

Additionally, a plausible reaction mechanism based on the Houk–List model is proposed, in which the initial formation of an enamine that interacts with the palladium atom is envisaged. Subsequently, the metal center facilitates the approach of the aldehyde through a coordination interaction, thereby promoting the nucleophilic attack of the enamine. The feasibility of this mechanism is supported by the DFT calculations of the corresponding transition state.

Finally, it is worth noting that these catalysts also efficiently promote other processes, such as the Morita–Baylis–Hillman (MBH) reaction and the Heck cross-coupling, which opens up the possibility of their use in sequential or one-pot reactions for obtaining molecules of greater complexity and high synthetic value.