High Yield Synthesis of Curcumin and Symmetric Curcuminoids: A “Click” and “Unclick” Chemistry Approach

The worldwide known and employed spice of Asian origin, turmeric, receives significant attention due to its numerous purported medicinal properties. Herein, we report an optimized synthesis of curcumin and symmetric curcuminoids of aromatic (bisdemethoxycurcumin) and heterocyclic type, with yields going from good to excellent using the cyclic difluoro-boronate derivative of acetylacetone prepared by reaction of 2,4-pentanedione with boron trifluoride in THF (ca. 95%). The subsequent cleavage of the BF2 group is of significant importance for achieving a high overall yield in this two-step procedure. Such cleavage occurs by treatment with hydrated alumina (Al2O3) or silica (SiO2) oxides, thus allowing the target heptanoids obtained in high yields as an amorphous powder to be filtered off directly from the reaction media. Furthermore, crystallization instead of chromatographic procedures provides a straightforward purification step. The ease and efficiency with which the present methodology can be applied to synthesizing the title compounds earns the terms “click” and “unclick” applied to describe particularly straightforward, efficient reactions. Furthermore, the methodology offers a simple, versatile, fast, and economical synthetic alternative for the obtention of curcumin (85% yield), bis-demethoxycurcumin (78% yield), and the symmetrical heterocyclic curcuminoids (80–92% yield), in pure form and excellent yields.

The importance of having curcumin as a pure metabolite lies in expanding its complementary studies on its pharmacokinetics, pharmacodynamics, and toxicological studies [46], which help to understand the effects of this fascinating bioactive molecule in living systems. The research in chemical synthesis has been mainly directed to the preparation of derivatives [47,48] that help overcome its physicochemical properties [49] and rapid metabolism [27,42,50] and to increase its bioavailability [11,51].
Although separations of curcumin are reported in various investigations [8,10,13,66,67], its purification is a difficult task due to the presence of two closely related curcuminoids (i.e., demethoxycurcumin and bis-demethoxycurcumin [25,26,53,68,69]) due to co-crystallization phenomena. Furthermore, obtaining high-purity curcumin from natural sources is difficult since it involves repeated chromatographic and crystallization procedures.
In the methodologies developed for synthesizing curcumin, it was early recognized that protecting the α-diketone functionality is a critical step for the subsequent condensation of two vanillin molecules at the sidechain methyl groups. Thus, the well-known secondary Knoevenagel reaction on carbon C-1 is avoided [54]. In addition, adequate protection of the b-diketone function can be achieved through boron complexes using reagents such as boron trioxide [47,57,70], boric acid [58], and, more recently, boron trifluoride [71]. The approach named "click chemistry" is applied in the obtention of compounds following simple steps of joining small modular units [72]. In the present case, the protective reaction on the b-diketo function to give the BF 2 derivative occurs with a high degree of efficiency, i.e., in a "click" fashion. Furthermore, the removal of the BF 2 group occurs under equally simple conditions and high efficiency, allowing us to propose the term "unclick" for this reaction step.
The synthetic approach used in our work is adequate for obtaining the natural symmetric curcuminoids curcumin and bisdemethoxycurcumin, with a significant reduction of expensive chromatographic and crystallization steps. However, the other essential natural asymmetric demethoxycurcumin requires a somewhat different synthetic route, which is under investigation. Nevertheless, the method demonstrated robustness for synthesizing symmetric heterocyclic curcuminoids using the corresponding aldehydes. A convenient feature altogether is the economy of reagents and laboratory steps needed.

Results
Although the protection reaction of acetylacetone is commonly carried out with boron trifluoride etherate [73][74][75], its manipulation requires extreme caution [2]. A much safer alternative is found using boron trifluoride complex in THF (Scheme 1). Five advantages at least are introduced, i.e., (I) minimum release of toxic vapors from the container, (II) both high density (1.268 g/mL) and boiling point (180 • C) allows easier manipulation when measuring the required volumes; (III) the addition of the reagent to the reaction flask is carried out at room temperature; (IV): no violent reaction is observed upon addition of reagents and (V): the use of inert atmosphere does not seem critical for the reaction to proceed. The synthesis of curcuminoids-BF2 has been previously reported in a one-pot reaction [76]. In our scaled-up approach (98 mmol), it was found convenient a stepwise procedure to overcome the bulk generation of HF, which promotes the formation of quaternary ammonium salts from n-butylamine. The isolation of a powdered product renders a rather convenient material for further workup. Thus, the BF2 derivatives can be advantageously manipulated and purified as solid starting materials, favoring cleaner and higher overall yields (see Table 1). The synthesis of curcuminoids-BF 2 has been previously reported in a one-pot reaction [76]. In our scaled-up approach (98 mmol), it was found convenient a stepwise procedure to overcome the bulk generation of HF, which promotes the formation of quaternary ammonium salts from n-butylamine. The isolation of a powdered product renders a rather convenient material for further workup. Thus, the BF 2 derivatives can be advantageously manipulated and purified as solid starting materials, favoring cleaner and higher overall yields (see Table 1). The high yields obtained in the aldol condensation reaction (Scheme 2) are explained by the following two reasons: (1) the precipitation of the condensed compound consequently produces a continuous consumption of the reactants in solution [76] and (2) the protection of acac through the use of BF 3 is an approach that affords much better yields [77].
The synthesis of curcuminoids-BF2 has been previously reported in a one-pot reaction [76]. In our scaled-up approach (98 mmol), it was found convenient a stepwise procedure to overcome the bulk generation of HF, which promotes the formation of quaternary ammonium salts from n-butylamine. The isolation of a powdered product renders a rather convenient material for further workup. Thus, the BF2 derivatives can be advantageously manipulated and purified as solid starting materials, favoring cleaner and higher overall yields (see Table 1). The high yields obtained in the aldol condensation reaction (Scheme 2) are explained by the following two reasons: (1) the precipitation of the condensed compound consequently produces a continuous consumption of the reactants in solution [76] and (2) the protection of acac through the use of BF3 is an approach that affords much better yields [77]. The crude product of the aldol condensation reaction to obtain curcumin-BF2 contains residues (see Figure 1) of n-butylamine and tributyl borate, which are easily removed after washing with a mixture of distilled water and acetone (10-20% acetone), see Figure 2. The crude product of the aldol condensation reaction to obtain curcumin-BF 2 contains residues (see Figure 1) of n-butylamine and tributyl borate, which are easily removed after washing with a mixture of distilled water and acetone (10-20% acetone), see Figure 2.   One of the critical steps in the synthesis of curcuminoids (heptanoids) is the cleavage of the BF2 group to obtain 1,3-diketone form (or enol). Yields greater than 80% are reported when the BF2 group is hydrolyzed in several media (organics: MeOH/DMSO [76,78] and One of the critical steps in the synthesis of curcuminoids (heptanoids) is the cleavage of the BF 2 group to obtain 1,3-diketone form (or enol). Yields greater than 80% are reported when the BF 2 group is hydrolyzed in several media (organics: MeOH/DMSO [76,78] and MeOH/DMSO/triethylamine or inorganics: diluted NaOH [73] and sodium oxalate [79]). However, the efficiency and reproducibility of reported procedures have been considered limited [73].
The removal of boron reaction by-products has been reported using inorganic salts [80] (e.g., aluminum sulfates and sodium aluminates) or silica, but efficient removal has been reported using amorphous Al 2 O 3 [81]. This feedback has served to assay additional means that can catalyze the hydrolysis of the BF 2 group through the use of three different metalhydrated oxides (Scheme 3): SiO 2 (silica) or Na 12 [(AlO 2 ) 12 (SiO 2 ) 12 ] · xH 2 O (molecular sieves) or Al 2 O 3 xH 2 O (alumina).
Molecules 2023, 28, x FOR PEER REVIEW 5 of 14 MeOH/DMSO/triethylamine or inorganics: diluted NaOH [73] and sodium oxalate [79]). However, the efficiency and reproducibility of reported procedures have been considered limited [73]. The removal of boron reaction by-products has been reported using inorganic salts [80] (e.g., aluminum sulfates and sodium aluminates) or silica, but efficient removal has been reported using amorphous Al2O3 [81]. This feedback has served to assay additional means that can catalyze the hydrolysis of the BF2 group through the use of three different metal-hydrated oxides (Scheme 3): SiO2 (silica) or Na12[(AlO2)12(SiO2)12]·xH2O (molecular sieves) or Al2O3 xH2O (alumina). Initially, it was chosen to carry out the opening reactions catalyzed in silica using two different alcoholic solvents (ethanol and methanol). However, ethanol is more ecofriendly, and curcumin was obtained 72 h later in low yield (possibly due to the adsorption of curcumin to silica). Therefore, methanol was found more appropriate for removing the boron-difluoride moiety ( Table 2). Initially, it was chosen to carry out the opening reactions catalyzed in silica using two different alcoholic solvents (ethanol and methanol). However, ethanol is more ecofriendly, and curcumin was obtained 72 h later in low yield (possibly due to the adsorption of curcumin to silica). Therefore, methanol was found more appropriate for removing the boron-difluoride moiety ( Table 2).

Discussion
The synthesis of curcumin and curcuminoids has been carried out with three simple reaction steps: (1) protection of keto-enol functionality of acetylacetone (acac) by BF 3 ·THF; (2) condensation of the corresponding aromatic aldehyde catalyzing with nbutylamine; (3) cleavage of the BF 2 group by means of hydrated metal oxides. Curcumin, bis-demethoxycurcumin itself, and two heterocyclic curcuminoids were obtained with very good yields and were fully characterized by spectroscopic techniques.
In a general description, this procedure consists of three basic yet simple general steps: (a) a protective step (reaction of the 2,4-pentanedione with boron trifluoride avoiding the Knoevenagel secondary reaction) while activating the methyl groups promoting (b) the efficient aldol condensation and (c) the deprotecting reaction step removing the BF 2 group and allowing the recovery of the original b-diketone function.
It suggested that the mechanism for the removal of the BF 2 group is due to an anion exchange phenomenon involving the reaction of boron and the basic OH-group or water in agreement with previous mechanistic proposals [81,82], which are specifically adsorbed and are present at the surfaces of hydrated metal oxides [83][84][85]. A possible reaction mechanism is depicted in Scheme 4.

Discussion
The synthesis of curcumin and curcuminoids has been carried out with three simple reaction steps: (1) protection of keto-enol functionality of acetylacetone (acac) by BF3·THF; (2) condensation of the corresponding aromatic aldehyde catalyzing with n-butylamine; (3) cleavage of the BF2 group by means of hydrated metal oxides. Curcumin, bis-demethoxycurcumin itself, and two heterocyclic curcuminoids were obtained with very good yields and were fully characterized by spectroscopic techniques.
In a general description, this procedure consists of three basic yet simple general steps: (a) a protective step (reaction of the 2,4-pentanedione with boron trifluoride avoiding the Knoevenagel secondary reaction) while activating the methyl groups promoting (b) the efficient aldol condensation and (c) the deprotecting reaction step removing the BF2 group and allowing the recovery of the original b-diketone function.
It suggested that the mechanism for the removal of the BF2 group is due to an anion exchange phenomenon involving the reaction of boron and the basic OH-group or water in agreement with previous mechanistic proposals [81,82], which are specifically adsorbed and are present at the surfaces of hydrated metal oxides [83][84][85]. A possible reaction mechanism is depicted in Scheme 4. The proposal mechanism in step I is supported by Venkata [71], and steps II, III, and IV are supported by Weiss [73]. Adsorption and removal of the B(OH − )4 species are supported by previous references [80][81][82][83][84].
The integrity of the free curcuminoid on the aluminum oxides or under the reaction medium does not lead to decomposition since it is known that the breakdown of the BF2 generates HF [73], and the curcuminoids are relatively unaffected by pH from 2 to 7 [8]. Our best yields in the obtention of curcumin were achieved using MeOH/Al 2 O 3 , probably associated with the more significant boron adsorption in acidic pH, though other authors associate boron adsorption with the presence of hydroxide ions present in alumina [86].
The 1 H-NMR spectrum of curcumin (Figure 3) confirms the assigned structure, and characteristic signals of the vinyl protons (α,β-unsaturated, system AB) are present in the form of two doublets at 7.54 and 6.75 with coupling constants ca. 16 Hz (trans). Evidence for the keto-enol tautomerism is given by the signal observed at 16.47 ppm (enol) and the signal corresponding to the methine proton (CH) at 6.06 ppm. Additionally, the DEPT-135 spectrum (see Supplementary Material) shows no (CH 2 ) methylene carbons; methines (CH) and methyl groups (CH 3 ) are observed as positive signals and fit satisfactorily with data reported in the literature [59]. Similarly, the 1 H-NMR spectra of all other symmetric curcuminoids show a consistent correlation between structure and spectral features (see Supplementary Material). The mass spectrum (MS) of curcumin shows a characteristic peak at m/z = 368, which corresponds adequately to the molecular ion of curcumin and is consistent with the chemical formula C 21 H 20 O 6 . In addition, the spectrum shows a base peak with m/z = 177 representing the expected molecular fragment. Mass spectra of bis-demethoxycurcumin (6) m/z = 308, furan-curcumin (7) m/z = 256, and thiophene-curcumin (8) m/z = 288 show a consistent peak with the chemical formulas C 19  The present synthetic route was successfully extended for the obtention of other symmetrical curcuminoids (compounds 6-8) with 4-hidroxybenzaldehyde, furfural, and thiophenecarboxaldehyde. Thus, when 4-hidroxybenzaldehyde and furfural were used in the corresponding curcuminoid synthesis using a modified Pabon s approach, the yields decreased significantly to a reported 33 and 8%, respectively [77,87].
Interestingly, the heterocyclic curcuminoid resulting from 2-thiophene carboxaldehyde (compound 4) afforded excellent yields (95%) in the aldol condensation reaction, while the cleavage of the BF 2 group on MeOH/alumina afforded (compound 8) in 92% yield. This overall high yield is even higher than the corresponding one observed for curcumin.
The term "Click Chemistry" [88] has been adopted for curcumin synthesis based on three simple concepts: (I) reactions are broad in scope and give high yields; (II) starting reagents are readily available, and simple reaction conditions are needed, and (III) no chromatographic methods are required to purify curcumin and other symmetric curcuminoids. The term "Unclick" refers to the efficient removal of the protecting/activator group, namely BF 2 , which was also achieved in high yield.
All chemicals were available commercially, and the solvents were purified with conventional methods before use [89].
Melting points were determined on an Electrothermal Engineering IA9100 digital melting point apparatus in open capillary tubes and were uncorrected [1,2]. 1 H and 13 C NMR spectra were obtained in a Bruker Fourier 400 MHz spectrometer using TMS as an internal reference and CDCl 3 or Acetone-d 6 , or DMSO-d 6 as solvents. NMR spectra were processed with MestreNova software 12.0.0 [90] and are found in the Supplementary Materials. Spectroscopic measurements. IR absorption spectra were recorded using an FT-IR Bruker Tensor 27 spectrophotometer in the range of 4000-400 cm −1 as KBr pellets [1,2] (see Supplementary Materials).

Synthon Preparation
In a 250 mL round flask, 10 mL of 2,4-pentanodione (acac, 98 mmol) was dissolved in 30 mL of dichloromethane; subsequently, 11 mL of boron trifluoride tetrahydrofuran complex (BF 3 ·THF, 98 mmol) was added to the solution, and the reaction was left overnight with magnetic stirring at room temperature. After, the organic phase was concentrated in vacuo affording the resulting product, which can be directly used for the following reaction step.

General Methodology
Mixture 1. In a 100 mL Erlenmeyer flask, 7.5 g of vanillin (49 mmol) was dissolved in 25 mL of EtOAc, 6.3 mL of tributyl borate (24.5 mmol) was added, and this mixture was heated until homogenization was achieved.
Mixture 2. In a 250 mL round flask, 4 g of synthon (1.1 eq, 27 mmol) was dissolved in 25 mL of EtOAc, and then the homogenous product 1 was added to the solution; then, 2.7 mL of N-butylamine (27 mmol, in 10 mL of EtOAc) was added dropwise. The reaction was left overnight with magnetic stirring at room temperature. Finally, a solid red precipitate was filtered-off and washed with a mixture of 50 mL water/acetone 90::10. This same methodology (same molar amounts) was carried out to synthesize the symmetrical curcuminoids-BF 2 .

Reaction Conditions for "Unclick" Removal of the BF 2 Group
In a 500 mL round flask, 10 g of curcuminoid-BF 2 was dissolved in 400 mL of methanol (MeOH), 20% weight of metal oxide (catalyst) was added to the solution, and the mixture was left overnight under magnetic stirring at reflux. The reaction was quenched by filtration using a sintered glass funnel packed with celite. MeOH was evaporated in vacuo, and reaction crude was extracted with 150 mL of EtOAc (ethyl acetate) and water (3 × 100 mL). The organic phase was dried with Na 2 SO 4 and concentrated in vacuo to afford the curcuminoid product, which was purified by recrystallization using EtOAc and hexane. The yields obtained for the synthesis of curcumin with several catalyzers were as follows: silica (70%), molecular sieves (80%) and alumina (85%). This same methodology (same amounts) was carried out for the synthesis of symmetrical curcuminoids (compounds 6-8).

Conclusions
Using simple high-yield steps, we contribute with a laboratory-scale strategy to obtain curcumin and symmetric curcuminoids. As a result, it can provide significant quantities of these compounds for physicochemical, analytical, and biological assay studies. This synthetic route is appropriate for using different aldehydes to obtain the corresponding symmetric curcuminoids. Due to the accessibility of this simple three-step synthetic approach, the method offers excellent potential for making available curcumin and symmetric curcuminoids on a large scale. The benefits of the present synthesis widen the perspectives for expanding the scientific studies concerning the fascinating molecular structures of curcuminoids and their widely recognized biological effects.

Patents
An application for a patent is underway in the country of the authors.