Multicomponent synthesis via acceptorless alcohol dehydrogenation: an easy access to tri-substituted pyridines

Abstract

Herein, we report palladium supported on a hydroxyapatite catalyst for synthesizing tri-substituted pyridines using ammonium acetate as the nitrogen source via acceptorless alcohol dehydrogenation strategy. The strategy offers a broad substrate scope using inexpensive and readily available alcohols as the starting material. The catalyst was prepared using a simple method and analyzed by several techniques, including FE-SEM, EDS, HR-TEM, BET, XRD, FT-IR, UV-visible spectroscopy, and XPS, demonstrating the anchoring of Pd nanoparticles on hydroxyapatite in the zero oxidation state. Moreover, several controlled experiments were carried out to understand the reaction pathway and a suitable mechanism has been proposed.

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The synthesis of N-heterocycles has attracted incredible attention considering their inevitable role in natural products,¹ pharmaceuticals,² agrochemicals,³ and functional materials.⁴ Among other N-heterocycles, pyridine-containing compounds have high significance owing to their numerous applications as biomolecules, organocatalysts, ligands, linkers, and sensors (Fig. 1).⁵ Thus, functionalizing the pyridine moiety offers an attractive method for synthesizing interesting compounds with diverse applications.⁶ Several methods have been reported for synthesizing pyridine derivatives, including classical condensation reactions,⁷ C–H annulation reactions,⁸ and multi-component approaches.⁹ However, most of these methods have drawbacks, such as poor atom economy,¹⁰ generation of large amounts of waste,¹¹ and harsh reaction conditions.¹²

Fig. 1 Selected examples of pyridine-containing molecules having a wide range of applications.

Since the last decade, acceptorless dehydrogenative coupling (ADC) reactions have emerged as an efficient methodology for synthesizing diverse heterocyclic compounds from relatively inexpensive and readily available starting materials.¹³ In this strategy, the by-products generated are hydrogen and water, which make these methods environmentally benign with a high atom economy.¹⁴ Acceptorless alcohol dehydrogenation has garnered attention because of the easy availability of inexpensive and less toxic alcohols as the starting material.¹⁵ Thus, several research groups are engaged in exploring acceptorless alcohol dehydrogenation strategies for the synthesis of various heterocyclic compounds.¹⁶ In 2013, Milstein and co-workers reported on the ruthenium-catalyzed synthesis of 2,6-disubstituted pyridines using γ-amino-alcohols with secondary alcohols.¹⁷

Later, Kempe and his group synthesized 3-aminopyridines via the Ir-catalyzed dehydrogenative coupling of γ-amino alcohols and β-amino alcohols.¹⁸ These methods were found to be very interesting and remarkable. However, the use of air-sensitive phosphine-based ligands limited their applications.

An interesting report by Deng et al. revealed a strategy for synthesizing tri-substituted pyridine through the condensation of aldehyde, methyl ketone, and ammonium salts under air (Scheme 1a).¹⁹ Recently, Paul and co-workers reported a similar approach using alcohols as the primary feedstock catalyzed by an air-stable Zn(II)-catalyst, featuring a redox-active tridentate azo-aromatic pincer, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline, for synthesizing 2,4,6-trisubstituted pyridine (Scheme 1b).²⁰ The aforesaid method works well under homogeneous reaction conditions.

Scheme 1 Context of the study.

Heterogeneous catalysis plays a pivotal role in numerous chemical and industrial processes²¹ and has gained wide attention considering its remarkable ability to accelerate reaction rates, low cost, higher stability, and selectivity.²² Moreover, their ease of separation, reusable nature, and benign character make heterogeneous catalysts an appropriate choice for the sustainable synthesis of organic compounds.²³ In this regard, hydroxyapatite, a biomaterial, has received significant importance for its utility as a heterogeneous support.²⁴ Transition metals supported on the hydroxyapatite surface show efficient catalytic performances in a variety of organic transformations.²⁵ Among others, hydroxyapatite-supported metal nano-catalysts have been less explored for the synthesis of heterocycles via acceptorless alcohol dehydrogenation methodology.²⁶

Recently, our group reported on a hydroxyapatite-supported copper nano-catalyst for direct C(sp³)-S coupling between alcohols and dithiocarbamate anions via the borrowing hydrogen strategy.^27a With our continued interest in exploring the novel applications of acceptorless dehydrogenation reactions,²⁷ we report here palladium supported on a hydroxyapatite catalyst for the synthesis of tri-substituted pyridines using ammonium acetate as the nitrogen source via an acceptorless alcohol dehydrogenation strategy.

Result and discussion

The catalyst was prepared using the wet impregnation method. Initially, PdCl₂ was dissolved in 5 mL of aqueous NaCl (0.2 M) solution, resulting in a brown coloration, and was added dropwise into a stirring slurry of hydroxyapatite at room temperature. Then, the pH was adjusted to 11 using a concentrated ammonia solution, and the mixture was stirred for 24 h at room temperature.

At this time, the aqueous supernatant becomes colorless, indicating the complete anchoring of Pd(II) onto the support. The light brown Pd(II) HAP is then reduced by NaBH₄ and results in a solid black residue. The black residue is then washed with distilled water thoroughly and dried at 70 °C overnight to give the grey-black powder Pd NPs@HAP with metal loading (0.6 wt%) found by ICP-MS analysis, and labelled as Pd NPs@HAP (Scheme S1 and S3 in ESI†).

The synthesized Pd NPs@HAP was then characterized using various spectroscopic and analytical techniques, including FE-SEM, HR-TEM, XPS, p-XRD, FT-IR, UV-visible spectroscopy, and BET analysis. The nitrogen adsorption–desorption isotherm plot was classified as type IV, and the surface area calculated by the BET method was 86.496 m² g⁻¹ (Fig. S1, ESI†). Moreover, the pore size and pore volume were found to be 30.004 nm and 0.6488 cm³ g⁻¹, respectively (Table S1, ESI†). The energy-dispersive spectroscopy (EDS) analysis of Pd NPs@HAP was performed along with SEM analysis in different selected zones of the Pd NPs@HAP surface, confirming the presence of elemental Ca, Cu, P, O and Pd (Fig. S2, ESI†).

TEM images show the presence of homogeneously distributed palladium nanoparticles on the HAP surface (Fig. 2a–c). The sizes of the particles are in the range of 10–20 nm. The high-resolution TEM image of Pd NPs@HAP shows the high crystallinity of the palladium (0) nanoparticles, and the crystalline spacing of 0.2 nm agrees with the [111] lattice spacing of palladium.²⁸ The crystallinity and structural composition of the synthesized materials were ensured by X-ray diffraction (XRD) analysis at room temperature (Fig. S4a, ESI†). Powder XRD diffraction patterns of Pd NPs@HAP exhibited a broad reflection, corresponding to the hydroxyapatite support. Three additional reflections were found in the XRD pattern (2θ = 39°, 46° and 65°), which could be attributed to Pd(0).²⁹ The FTIR spectra of HAP and Pd NPs@HAP show the characteristic tetrahedral PO₄³⁻ peaks, which are at 472–600 cm⁻¹ and 1032–1090 cm⁻¹ (Fig. S4b, ESI†).³⁰

Fig. 2 (a) SAED patterns of Pd NPs@HAP. (b) HR-TEM image of Pd NPs@HAP. (c) High-magnification HR-TEM image of Pd NPs@HAP showing the palladium nanoparticle with an average size of 10–20 nm and lattice plane of 0.2 nm, which corresponds to the palladium of the (111) plane. (d) XPS elemental analysis of Pd NPs@HAP shows the support hydroxyapatite composed of calcium, phosphorous, and oxygen. (e) Binding energy value for Pd in Pd NPs@HAP.

The elemental analysis and chemical states of palladium on the surface of the Pd NPs@HAP catalyst were determined by XPS analysis (Fig. 2d and e). The XPS spectra of Ca 2p, P 2p, and O 1s are characteristic of phosphorus, calcium, and oxygen in hydroxyapatite. The 2p peaks at 133.8 eV and 132.9 eV are assigned to the phosphorus in hydroxyapatite. The Ca 2p spectra are composed of two peaks corresponding to Ca 2p_1/2 and Ca 2p_3/2. The binding energy of O 1s consists of two peaks at 531.62 eV and 530.92 eV associated with the presence of O–P and O–H groups in hydroxyapatite, respectively. The binding energy analysis of Pd revealed two predominant distinct Pd 3d doublets (3d_5/2 and 3d_3/2) at 335.3 eV and 340.6 eV, indicative of Pd (0).³¹ Palladium nanoparticle formation has been further investigated using UV-visible spectroscopy in the 200–800 nm range. The absence of absorption peaks above 300 nm in all of the samples shows the full reduction of the initial Pd(II) ions and the formation of Pd(0) nanoparticles.

After the detailed characterization of the catalyst, Pd NPs@HAP was then tested for the synthesis of tri-substituted pyridines using ammonium acetate as the nitrogen source via an acceptorless alcohol dehydrogenation strategy. The aryl methyl ketone, primary alcohol, NH₄OAC was heated in the presence of the Pd NPs@HAP catalyst at 150 °C in a Teflon-lined pressure tube under neat conditions. Upon completion of the reaction (by TLC), the crude product is purified by column chromatography. The reaction was studied with various parameters, such as the reaction temperature, time, and catalyst to optimize the reaction conditions, and the results are summarized in Table 1.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Temperature (°C)	Time (h)	Conversion^b^,^c (%)
a Reaction condition: benzyl alcohol (0.25 mmol), acetophenone (0.6 mmol), catalyst (25 mg, Pd loading 0.6 wt%), stirred for required time using a Teflon-lined pressure tube on a preheated heating block.b Conversion was calculated from ^1H NMR using 1,4-dimethoxy benzene as the internal standard.c Nd: not detected.d Catalyst (10 mg).
1	Pd NPs@HAP	100	24	30
2	Pd NPs@HAP	130	24	42
3	Pd NPs@HAP	150	24	95
4	Pd NPs@HAP	150	12	58
5	Pd NPs@HAP	Rt	24	Nd
6	Pd NPs@HAP	150	24	30^d
7	—	150	24	Nd
8	Pd^II@HAP	150	24	15
9	PdCl2	150	24	Nd
10	Pd(PPh3)4	150	24	10
11	HAP	130	24	Nd

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It was found that the product formation was complete at 150 °C (Table 1, entry 3). The reaction was incomplete at temperatures below the optimal temperature (Table 1, entries 1 and 2) and no reaction at room temperature (Table 1, entry 5). Moreover, a minimum of 24 h reaction time was required to complete the reaction (Table 1, entry 4). As expected, in the absence of the Pd NPs@HAP catalyst, we were unable to detect any product (Table 1, entry 7). Similarly, PdCl₂ or HAP alone failed to carry out any reaction (Table 1, entries 9 and 11). The catalyst precursor Pd(II)@HAP generated only a trace amount of the product (Table 1, entry 8), which indicates the role of Pd(0) NPs in the reaction mechanism. On the other hand, Pd(PPh₃)₄ failed to generate even the marginal conversion (Table 1, entry 10). The maximum yield of the product was obtained when we carried out the reaction using Pd NPs@HAP at 150 °C (heating block temperature) in a Teflon-lined pressure tube under neat conditions for 24 h (Table 1, entry 3).

Using the optimized condition, we have synthesized several 2,4,6 tri-substituted pyridines via multicomponent dehydrogenative coupling of benzyl alcohols and aryl methyl ketones with NH₄OAc as the nitrogen source. Acetophenones bearing various functional groups performed well in this reaction (Table 2). Additionally, p-Me, p-OMe gave a similar yield as that of the unsubstituted acetophenone (Table 2, 3b and 3c) and resulted in the corresponding tri-substituted pyridine with 70–80% yield. Similarly, para-substituted halogen derivatives also gave the desired product in good yields without affecting the halogen functionality (Table 2, 3d, 3e, and 3f). Interestingly, heterocyclic moieties bearing the acetyl group also performed well (Table 2, 3h), and gave the corresponding product with 65% yield. Surprisingly, the highly electron-withdrawing 4-nitro acetophenone, as well as aliphatic methyl ketones, failed to give the desired product under this protocol.

Table 2 Substrate scope for ketones ^a,b

a Reaction condition: benzyl alcohol (0.25 mmol), acetophenone (0.6 mmol), catalyst (25 mg, Pd loading 0.6 wt%), stirred for 24 h using a Teflon-lined pressure tube on a preheated heating block at 150 °C.b Yields refer to those of pure products characterized by ¹H NMR and ¹³C NMR spectroscopic data.

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After exploring various acetophenones, we then checked the performance of different alcohols for this synthesis (Table 3). Various benzylic alcohols undergo this reaction with good performance, and we isolated the corresponding tri-substituted pyridine with 70–75% yield.

Table 3 Substrate scope for alcohols^a,b

a Reaction condition: benzyl alcohol (0.25 mmol), acetophenone (0.6 mmol), catalyst (25 mg, Pd loading 0.6 wt%), stirred for 24 h using a Teflon-lined pressure tube on a preheated heating block at 150 °C.b Yields refer to those of pure products characterized by ¹H NMR and ¹³C NMR spectroscopic data.

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4-Methyl benzyl alcohol and 4-isopropyl benzyl alcohol underwent the reaction smoothly, and resulted in 79–80% yields of the desired products (Table 3, 3i and 3j). Similarly, 4-OMe substituted benzyl alcohol also resulted in 75% yield of the anticipated product (Table 3, 3k). Halogen-substituted benzyl alcohol underwent the reaction easily (Table 3, 3l and 3m). Moreover, the easily hydrolyzable 4-(allyloxy)benzyl alcohol also gave the corresponding pyridine selectively (Table 3, 3n). The 4-nitrobenzyl alcohol and aliphatic alcohols failed to give the product as in the previous case.

After exploring the substrate scope for alcohols and methyl ketones, we studied the mechanism of the reaction. To analyze the mechanism, we carried out various controlled experiments (Scheme 2). When we carried out the reaction only with benzyl alcohol in the presence of Pd NPs@HAP, we isolated benzaldehyde and detected hydrogen by gas chromatography (Scheme 2a and Fig. S6†). This confirms the formation of benzaldehyde as the intermediate. Similarly, when we performed the reaction without NH₄OAC, we confirmed the corresponding chalcone as the product (Scheme 2b). Furthermore, to confirm chalcone as the intermediate, we performed a reaction using synthesized chalcone and NH₄OAC under the same condition, which resulted in the corresponding trisubstituted pyridine in 100% conversion (Scheme 2c). Moreover, the crude ¹H NMR after the half interval of the reaction showed the formation of benzaldehyde and chalcone as the reaction intermediate (Scheme 2d).

Scheme 2 Controlled experiments (^eisolated yield, ^fconversion was calculated from ¹H NMR using a crude reaction mixture).

From all these experiments and available literature, we have proposed a suitable mechanism for the transformation. The proposed mechanism is depicted in Scheme 3. Initially, the Pd@HAP-catalyzed dehydrogenation of alcohol resulted in the formation of benzaldehyde, which is coupled with methyl ketone, and generates the corresponding α,β-unsaturated ketone. Meanwhile, the second molecule of ketone reacts with ammonium acetate, forming the corresponding imine. Further condensation of the formed imine and α,β-unsaturated ketone, followed by cyclization, produces the desired 2,4,6-tri-substituted pyridine as the final product. Moreover, there was no significant difference in the yield obtained when we carried out the reaction in the presence of metallic mercury (mercury poisoning test), ruling out the leaching of metallic Pd from the HAP support. However, during catalyst recyclability, it has been observed that the catalyst efficiency slowly decreased (Fig. S7†). Metal contamination in the final product was checked by ICP-MS, and was found to be less than 1 microgram of palladium per gram of product, which is within the acceptable limit for pharmaceutical application.³²

Scheme 3 Proposed mechanism.

Conclusion

In conclusion, we have reported on palladium nanoparticles supported on hydroxyapatite as the catalyst for the synthesis of tri-substituted pyridines using ammonium acetate as the nitrogen source via an acceptorless alcohol dehydrogenation strategy. The present methodology has wide functional group tolerance, and offers general applicability for the synthesis of a variety of tri-substituted pyridine derivatives in an environmentally benign route. This methodology offers other important advantages, such as avoiding toxic ligands and bases, use of a biocompatible material as the catalyst support, operational simplicity, among other advantages. To the best of our knowledge, this is the first report of direct tri-substituted pyridine synthesis via acceptorless alcohol dehydrogenation using NH₄OAC as the ammonia source catalyzed by a supported metal catalyst.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

R. D. acknowledges the Science and Engineering Research Board (SRG/2020/002161) India for funding. H. P. and V. M. are thankful to NIT Calicut for their fellowship.

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Footnote

† Electronic supplementary information (ESI) available: General information, experimental procedure, catalyst characterization data, ¹H NMR, and ¹³C NMR spectral data of all compounds. See DOI: https://doi.org/10.1039/d4ra00439f

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