Eucalyptol: A Bio-Based Solvent for the Synthesis of O , S , N -Heterocycles. Application to Hiyama Coupling, Cyanation, and Multicomponent Reactions

: We report here the use of eucalyptol as a bio-based solvent for Hiyama coupling, cyanation, and multicomponent reactions on O , S , N -heterocycles. These heterocycles were chosen as targets or as starting materials given their biological potential; they play an important role in therapeutically active compounds. Once again, eucalyptol proved to be a credible and sustainable alternative to common solvents.


Introduction
The solvents used in chemistry are a fundamental element of the environmental performance of processes in industrial and academic laboratories. Their influence on costs, safety, and health cannot be neglected. Even if solvent-free reactions are possible to a certain extent, they are not applicable to a large spectrum of chemical reactions and starting materials, and they may impair overall yield and product purity. Equally important, multiphasic reactions involving solid catalysts and gaseous and/or liquid reagents, which are common practice in the petrochemical and refining industry, are not easily transposable to pharmaceutical active ingredients or fine chemical syntheses.
Solvents are the most abundant constituents of chemical transformations, so acting thereon and replacing standard solvents with safer alternatives can have a great ecological impact. Nitrogen heterocyclic compounds represent an important class of compounds in the pharmaceutical industry. Therefore, it is important to provide new methods and greener approaches for their synthesis [1][2][3][4][5][6][7].
Eucalyptol or 1,8-cineole ( Figure 2) is a saturated oxygenated terpene that is widely distributed in some plants and their essential oil fractions, and depending on the species, it is contained in up to 90% in eucalyptus' essential oils isolated from fresh foliage. Its use as a solvent is also very interesting from an environmental point of view, since in addition to the fact that this solvent is recyclable by simple distillation, it comes from the waste (leaves) of the paper and wood industry, which cultivates eucalyptus trees because of their rapid growth (7 to 10 years).  Eucalyptol or 1,8-cineole ( Figure 2) is a saturated oxygenated terpene that is widely distributed in some plants and their essential oil fractions, and depending on the species, it is contained in up to 90% in eucalyptus' essential oils isolated from fresh foliage. Its use as a solvent is also very interesting from an environmental point of view, since in addition to the fact that this solvent is recyclable by simple distillation, it comes from the waste (leaves) of the paper and wood industry, which cultivates eucalyptus trees because of their rapid growth (7 to 10 years).

Multicomponent Reaction
While the chemistry community has made significant efforts toward identifying greener processes that minimize the quantity of catalysts or using multicomponent reactions and one-pot processes, solvents remain a major portion of the environmental performance of a process and have an influence on safety and health [18][19][20][21]. One of the goals  Eucalyptol or 1,8-cineole ( Figure 2) is a saturated oxygenated terpene that is widely distributed in some plants and their essential oil fractions, and depending on the species, it is contained in up to 90% in eucalyptus' essential oils isolated from fresh foliage. Its use as a solvent is also very interesting from an environmental point of view, since in addition to the fact that this solvent is recyclable by simple distillation, it comes from the waste (leaves) of the paper and wood industry, which cultivates eucalyptus trees because of their rapid growth (7 to 10 years).

Multicomponent Reaction
While the chemistry community has made significant efforts toward identifying greener processes that minimize the quantity of catalysts or using multicomponent reactions and one-pot processes, solvents remain a major portion of the environmental performance of a process and have an influence on safety and health [18][19][20][21]. One of the goals Structure and data of Eucalyptol

Multicomponent Reaction
While the chemistry community has made significant efforts toward identifying greener processes that minimize the quantity of catalysts or using multicomponent reactions and one-pot processes, solvents remain a major portion of the environmental performance of a process and have an influence on safety and health [18][19][20][21]. One of the goals of the present study was to assess the potential of associating a multicomponent reaction with a more eco-compatible solvent. The class of molecules chosen for synthesis was highly functionalized pyridines [22]. In this specific case, to the best of our knowledge, only three teams have reported their synthesis; however, the reactions were performed using conventional solvents, namely chloroform [23], ethanol [24], and methanol [25]. After ascertaining the most widely used reaction conditions and stoichiometry, we performed the reactions using eucalyptol as solvent (Table 1). of the present study was to assess the potential of associating a multicomponent reaction with a more eco-compatible solvent. The class of molecules chosen for synthesis was highly functionalized pyridines [22]. In this specific case, to the best of our knowledge, only three teams have reported their synthesis; however, the reactions were performed using conventional solvents, namely chloroform [23], ethanol [24], and methanol [25]. After ascertaining the most widely used reaction conditions and stoichiometry, we performed the reactions using eucalyptol as solvent (Table 1). The expected compound (1) was obtained in 28 to 54% yield. Adding a catalyst to the reaction was always detrimental to the yield when compared to a catalyst-free reaction performed with the same stoichiometry and temperature. The best result was obtained without catalyst using one equivalent of benzaldehyde and two equivalents of pyrrolidine and malonitrile (Table 1, Entry 2). For the synthesis of compound 1, this solvent substitution proved to be advantageous over the above-mentioned studies that used chloroform (32%) [23] and ethanol (52%) [24]. However, our yield was lower when compared to that of the team that performed the reaction in methanol (79%) [25]. Nevertheless, it should be highlighted that the 79% yield was obtained with the addition of DMAP (20 mol%) as catalyst. To test which parameter influenced the yield, we performed the reaction in methanol without catalyst and then verified that the use of eucalyptol resulted in a higher yield when the reaction mixture was catalyst-free. With the best reaction conditions in hand, we proceeded to analyze the scope and limitations of the reaction.
The derivatives (1-6) were synthesized in 45 to 68% yield ( Figure 3). The nature of the aldehyde did not cause major disparities in the yield of the different final compounds. Then, considering the aldehyde that presented the highest yield, the potential of eucalyptol using other sources of amines (piperidine, thiomorpholine, 2,6-dimethylmorpholine, and 1-phenylpiperazine) was evaluated: the final compounds 7-10 were synthesized in moderate to good yields ( Figure 4).  The expected compound (1) was obtained in 28 to 54% yield. Adding a catalyst to the reaction was always detrimental to the yield when compared to a catalyst-free reaction performed with the same stoichiometry and temperature. The best result was obtained without catalyst using one equivalent of benzaldehyde and two equivalents of pyrrolidine and malonitrile (Table 1, Entry 2). For the synthesis of compound 1, this solvent substitution proved to be advantageous over the above-mentioned studies that used chloroform (32%) [23] and ethanol (52%) [24]. However, our yield was lower when compared to that of the team that performed the reaction in methanol (79%) [25]. Nevertheless, it should be highlighted that the 79% yield was obtained with the addition of DMAP (20 mol%) as catalyst. To test which parameter influenced the yield, we performed the reaction in methanol without catalyst and then verified that the use of eucalyptol resulted in a higher yield when the reaction mixture was catalyst-free. With the best reaction conditions in hand, we proceeded to analyze the scope and limitations of the reaction.
The derivatives (1-6) were synthesized in 45 to 68% yield ( Figure 3). The nature of the aldehyde did not cause major disparities in the yield of the different final compounds. Then, considering the aldehyde that presented the highest yield, the potential of eucalyptol using other sources of amines (piperidine, thiomorpholine, 2,6-dimethylmorpholine, and 1phenylpiperazine) was evaluated: the final compounds 7-10 were synthesized in moderate to good yields ( Figure 4).

Palladium Catalyzed Cyanation
The second reaction explored with eucalyptol as solvent was palladium-catalyzed cyanation. This reaction offers an appropriate alternative to the Rosenmund-Von Braun reaction [26][27][28][29][30], which frequently employs severe reaction conditions and sometimes needs an intensive work up. Due to all of these features and properties, efforts were made to find greener conditions. For this study, we used three compounds commonly used in our team to build molecules of interest with biological potential [15,31,32]. Each compound underwent an optimization study in order to find the ideal conditions. To the best of our knowledge, here, we present the first cyanation process of these scaffolds. After reviewing previously reported information [33][34][35][36][37][38][39] related to the cyanation of O,S,N-containing heterocycles, we performed the optimization on 4-chlorothieno [3,2- In the literature, Zn(CN) 2 is often used as cyanide source. The reaction can occur because, as the cyanide nucleophile is a strong σ-donor and can be fatal to the catalytic system, it is essential to keep its concentration low in the reaction. An unfavorable point is its limited solubility in DMF (1.8 × 10 −4 g/mL at 80 • C), which is a solvent commonly used in these reactions [40].
Another source of cyanide (non-toxic), K 4 [Fe(CN) 6 ], has also been described and can be used in a mixture with palladium catalysts to obtain aryl nitriles from their corresponding halides [41]. From this background, we tested reaction conditions using eucalyptol as solvent. Compound 11 was obtained in a yield from 7 to 56% (Table 2).

Palladium Catalyzed Cyanation
The second reaction explored with eucalyptol as solvent was palladium-catalyzed cyanation. This reaction offers an appropriate alternative to the Rosenmund-Von Braun reaction [26][27][28][29][30], which frequently employs severe reaction conditions and sometimes needs an intensive work up. Due to all of these features and properties, efforts were made to find greener conditions. For this study, we used three compounds commonly used in our team to build molecules of interest with biological potential [15,31,32]. Each compound underwent an optimization study in order to find the ideal conditions. To the best of our knowledge, here, we present the first cyanation process of these scaffolds. After reviewing previously reported information [33][34][35][36][37][38][39] related to the cyanation of O,S,N-containing heterocycles, we performed the optimization on 4-chlorothieno [3,2- In the literature, Zn(CN)2 is often used as cyanide source. The reaction can occur because, as the cyanide nucleophile is a strong σ-donor and can be fatal to the catalytic system, it is essential to keep its concentration low in the reaction. An unfavorable point is its limited solubility in DMF (1.8 × 10 −4 g/mL at 80 °C), which is a solvent commonly used in these reactions [40].
To test the versatility of conditions over bromine derivatives, we chose a molecule synthesized in a previous study reported by our team [31] (Figure 5).  The desired product 13 was obtained in good yield using eucalyptol as solvent at 140 °C for 27 h with Pd2(dba)3/dppf as catalytic system and Zn(CN)2 as cyanide source.

Hiyama Coupling
Hiyama coupling is a palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. Its particularity lies in the requirement for a fluoride ion or a base as activating agent [42,43]. This coupling was chosen in order to compare it with the results obtained and reported previously by our team [15] on the performance of Sonogashira coupling using eucalyptol as solvent on O,S,N-heterocycles.
As with the previous two reactions reported above, this work started with a literature review [43][44][45][46][47] to test the conditions for our scaffold and identify the best coupling conditions.
Optimization was achieved starting from 7-chlorothieno[3,2-b]pyridine and 1-phenyl-2-trimethylsilylacetylene and by varying the amount and type of Pd source with or without ligand as well as the type and amount of activating agent (fluoride ion or a base). Reactions with eucalyptol were conducted at 100 °C for durations summarized in Table 4.
Process optimization led to the isolation of compound 14 in a yield ranging from 30 to 80%. The best reaction conditions using eucalyptol as solvent were achieved at 100 °C for 48 h with Pd(CH3CN)2Cl2/PPh3 as a catalytic system and Cs2CO3 as a base.
To test the versatility of conditions over bromine derivatives, we chose a molecule synthesized in a previous study reported by our team [31] (Figure 5).  The desired product 13 was obtained in good yield using eucalyptol as solvent at 140 °C for 27 h with Pd2(dba)3/dppf as catalytic system and Zn(CN)2 as cyanide source.

Hiyama Coupling
Hiyama coupling is a palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. Its particularity lies in the requirement for a fluoride ion or a base as activating agent [42,43]. This coupling was chosen in order to compare it with the results obtained and reported previously by our team [15] on the performance of Sonogashira coupling using eucalyptol as solvent on O,S,N-heterocycles.
As with the previous two reactions reported above, this work started with a literature review [43][44][45][46][47] to test the conditions for our scaffold and identify the best coupling conditions. The desired product 13 was obtained in good yield using eucalyptol as solvent at 140 • C for 27 h with Pd 2 (dba) 3 /dppf as catalytic system and Zn(CN) 2 as cyanide source.

Hiyama Coupling
Hiyama coupling is a palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. Its particularity lies in the requirement for a fluoride ion or a base as activating agent [42,43]. This coupling was chosen in order to compare it with the results obtained and reported previously by our team [15] on the performance of Sonogashira coupling using eucalyptol as solvent on O,S,N-heterocycles.
As with the previous two reactions reported above, this work started with a literature review [43][44][45][46][47] to test the conditions for our scaffold and identify the best coupling conditions.
Optimization was achieved starting from 7-chlorothieno[3,2-b]pyridine and 1-phenyl-2-trimethylsilylacetylene and by varying the amount and type of Pd source with or without ligand as well as the type and amount of activating agent (fluoride ion or a base). Reactions with eucalyptol were conducted at 100 • C for durations summarized in Table 4.  Based on our results (Table 4, Entry 11), the scope and limitations of the Hiyama coupling on 7-chlorothieno[3,2-b]pyridine were assessed using several silylacetylenes (Table 4).
Compounds 14-19 substituted in position 7 were synthesized in moderate to good yield, demonstrating the generalizability of this method using eucalyptol as solvent (Figure 6).
From these results, we explored the same conditions on 4-chlorofuro[3,2-c]pyridine. Two examples (20)(21) were synthesized in low yield by Hiyama coupling (Figure 7). This scaffold showed lower reactivity. This aspect had already been observed when we synthesized the same products by Sonogashira coupling using eucalyptol [15].

Entry
Pd (eq.) Lig (eq.) CN (eq.) T ( • C) t (h) Yield a (%) Process optimization led to the isolation of compound 14 in a yield ranging from 30 to 80%. The best reaction conditions using eucalyptol as solvent were achieved at 100 • C for 48 h with Pd(CH 3 CN) 2 Cl 2 /PPh 3 as a catalytic system and Cs 2 CO 3 as a base.
Compounds 14-19 substituted in position 7 were synthesized in moderate to good yield, demonstrating the generalizability of this method using eucalyptol as solvent ( Figure 6).  Based on our results (Table 4, Entry 11), the scope and limitations of the Hiyama coupling on 7-chlorothieno[3,2-b]pyridine were assessed using several silylacetylenes (Table 4).
Compounds 14-19 substituted in position 7 were synthesized in moderate to good yield, demonstrating the generalizability of this method using eucalyptol as solvent (Figure 6).
From these results, we explored the same conditions on 4-chlorofuro[3,2-c]pyridine. Two examples (20)(21) were synthesized in low yield by Hiyama coupling (Figure 7). This scaffold showed lower reactivity. This aspect had already been observed when we synthesized the same products by Sonogashira coupling using eucalyptol [15]. From these results, we explored the same conditions on 4-chlorofuro [3,2-c]pyridine. Two examples (20)(21) were synthesized in low yield by Hiyama coupling (Figure 7). This scaffold showed lower reactivity. This aspect had already been observed when we synthesized the same products by Sonogashira coupling using eucalyptol [15].

Recyclability of the Solvent
As the reusability of the solvent is essential from an economic and environmental perspective, we have already shown its feasibility in Pd-mediated cross-coupling reactions in our previous work [15][16][17], wherein an average 70% solvent recovery (using a rotary evaporator system) was observed for each reaction series without noticeable loss of properties. Although the boiling point of eucalyptol is relatively high, it is possible to evaporate it, in a few minutes, with a normal pump and recirculating chiller in a classical rotary evaporator system.

Multicomponent Reaction: General Procedure for Synthesis of Compounds 1-10
A mixture of aldehyde (50 mg; 1 eq.), amino derivative (2 eq.), malonitrile (2 eq.) in Eucalyptol (2 mL) was stirred at 100 °C for 24 h. The reaction was followed by TLC. After completion, the reaction was cooled to room temperature and the mixture was concentrated under vacuum. The solid obtained was purified by flash chromatography using a mixture of AcOEt/petroleum ether.

Recyclability of the Solvent
As the reusability of the solvent is essential from an economic and environmental perspective, we have already shown its feasibility in Pd-mediated cross-coupling reactions in our previous work [15][16][17], wherein an average 70% solvent recovery (using a rotary evaporator system) was observed for each reaction series without noticeable loss of properties. Although the boiling point of eucalyptol is relatively high, it is possible to evaporate it, in a few minutes, with a normal pump and recirculating chiller in a classical rotary evaporator system.

Multicomponent Reaction: General Procedure for Synthesis of Compounds 1-10
A mixture of aldehyde (50 mg; 1 eq.), amino derivative (2 eq.), malonitrile (2 eq.) in Eucalyptol (2 mL) was stirred at 100 • C for 24 h. The reaction was followed by TLC. After completion, the reaction was cooled to room temperature and the mixture was concentrated under vacuum. The solid obtained was purified by flash chromatography using a mixture of AcOEt/petroleum ether.