A green, facile, and practical preparation of capsaicin derivatives with thiourea structure

Capsaicin derivatives with thiourea structure (CDTS) is highly noteworthy owing to its higher analgesic potency in rodent models and higher agonism in vitro. However, the direct synthesis of CDTS remains t one or more shortcomings. In this study, we present reported a green, facile, and practical synthetic method of capsaicin derivatives with thiourea structure is developed by using an automated synthetic system, leading to a series of capsaicin derivatives with various electronic properties and functionalities in good to excellent yields.


Results and discussion
Initially, the vanilylamine hydrochloride (1) and 1-isothiocyanatoheptane (2a) were chosen as model substrates to optimize the reaction conditions, and the reaction was monitored by HPLC.The reaction of 1 and 2a was carried out in the presence of K 2 CO 3 in EtOH at r.t. for 24 h.The reaction proceeded smoothly to give the vanilylthiourea (3a) in 34% yield (Table 1, entry 1).Then, a series of solvents was evaluated for the condensation reaction (entries 2-6).The results revealed that solvent effect played a crucial role; H 2 O is the best in terms of yields.This might be attributed to the poor solubility of K 2 CO 3 in other solvents.Encouraged by this result, subsequently, different bases, including KOH, NaOH, Na 2 CO 3 , NaHCO 3 , Na 2 SiO 3 , CeCO 3 and NEt 3 , were examined (entries 7-13), giving good to excellent yields except weak base NaHCO 3 (entry 10), of which Na 2 SiO 3 offered the highest yield (entry 11).It was noteworthy that the reaction hardly occurred in absence of base (entry 14).This could be larger due to the strength of base, leading to a lower solubility (weak base) of vanilylamine hydrochloride (1) or a higher solubility (strong base) of vanilylthiourea (3a).Additional efforts at reaction optimization(base loading and reaction time)provided the similar levels of selectivity.Finally, the optimized conditions were then concluded as follows: 1 (0.2 mmol), 2a (0.22 mmol) and Na 2 SiO 3 (0.22 mmol) in H 2 O (2 mL) at r.t. for 12 h, and 3a was obtained in 99% yield.Notably, the column chromatographic separation was not required.After simple filtration, 3a were obtained in 84% yields.
With the potential application of this versatile synthetic transformation (green solvents, mild reaction conditions, and simple post processing) to the chemical enterprise, we explored the development of an automated synthetic system to further demonstrate the synthetic utility of this method.As depicted in Fig. 3   As shown in Fig. 4a, the vanilylamine hydrochloride (1) and isothiocyanatoheptane (2a) were chosen as model substrates to validate the design concept of automated synthetic system and its potential for large scale production of thioureas with high yield.The automated synthetic system is capable of fulfilling the whole process of synthesis of 3a, in which a general six-step sequential unit operation is included as follows (Fig. 4b): (i) 1a (3 mmol), 2a (3.3 mmol), and Na 2 SiO 3 (3.3mmol) were added into the reaction module.(ii) H 2 O (30 mL) was then injected into reaction module, which is predetermined by the program med method using the syringe pump and solvent selection value.(iii) The mixture was stired for 12 h at r.t.(iv) The mixture was transferred to filter module and filtered by vacuum pump.(v) EtOH was then injected into filter module, which is predetermined by the program med method using the syringe pump and solvent selection value.(vi) The mixture was stired for 5 min, and then filtered to give the desired thiourea 3a in 84% yield.
With the establishment of the optimized reaction conditions and the process of automated synthesis, a series of substrates was explored to determine the generality of this method, and the results are summarized in Fig. 5.  www.nature.com/scientificreports/ In general, the corresponding thioureas 3a-3y were obtained with good to excellent yields (69-96%), except 3 l (50% yield).The chain length of the alkyl isothiocyanates tended to slightly influenced to the yield (3a vs 3b vs 3c vs 3d).The substituents of benzyl isothiocyanates could contain both electron-withdrawing and electrondonating groups at the para position of benzene rings, for example, -F (3f., 90% yield), -Cl (3 g, 78% yield), -OMe (3 h, 94% yield).3,4-disubstituted benzyl isothiocyanate was viable substrate as well (3i, 81% yield).Under the standard conditions, product 3j was also smoothly yielded in excellent yields (92%).In contrast to phenylethyl isothiocyanate (2j), substrate 2 k bearing a strong electron withdrawing CF 3 group at the at the para position of benzene ring led to a significantly reduction in yield (3 g, 82% vs. 3 k, 50%), while weakly electron withdrawing group (F, and Cl), and electron donating goups (Me, and MeO) at the at the para position of benzene rings had little effect on the yield (3 l-3o, 69-90% yield).Moreover, The good tolerance of the halogen atom (F, and Cl)at different positions on the benzene rings demonstrated good compatibility of the protocol(3 l vs. 3p vs. 3q, and 3 m vs. 3r vs. 3 s).After that, phenylpropyl isothiocyanates were also investigated, the reaction of substrates 2t and 2u readily took place under the optimized conditions, offering the corresponding products with good yields.Finally, the isothiocyanatobenzene, benzoyl isothiocyanate, and (R)-(1-isothiocyanatopropyl)benzene were also investigated.Products 3v-3 × were smoothly yielded in 78-87% yields.
To compare the efficiency of our method with the reported methods for the synthesis of CDTS, we have tabulated the results of these methods to promote the synthesis of compounds 3a, 3b, 3 g, 3j and 3u from.The results are summarized in Table 2. Obviously, our method showed a much higher yields and green.

Conclusions
In summary, an automated synthetic system have been have been developmented and evaluated as a equipment for the synthesis of capsaicin derivatives with thiourea structures via a condensation reaction of vanilylamine hydrochloride and isothiocyanates under room temperature and green solvent (water as solvent) conditions.The notable advantages of this method are automatic reaction and post-processing, mild reaction conditions, ready availability of starting materials, high functional groups tolerance, good to excellent yields.Thus, this procedure is a better and more practical alternative for green chemistry.Moreover, the analgesic potency in rodent models of these CDTS is being tested in our group.

Methods
Automated synthesis of CDTS 3. (i) 1 (3 mmol), 2 (3.3 mmol), and Na2SiO3 (3.3 mmol) were added into the reaction moldule.(ii) H2O (30 mL) was then injected into reaction moldule, which is predetermined by the program med method using the syring pump and solvent selection value.(iii) The mixture was stired for 12 h at r.t.(iv) The mixture was transferred to filter moldule and filtered by vacuum pump.(v) EtOH was then injected into filter moldule, which is predetermined by the program med method using the syring pump and solvent selection value.(vi) The mixture was stired for 5 min, and then filtered to give the desired thiourea 3.

Figure 1 .
Figure 1.Capsaicin and its derivatives with thiourea structure.

Figure 2 .
Figure 2. Previous studies and our work.

Figure 3 .
Figure 3. Photograph (a) and schematic (b) of the automated synthetic system.

Table 2 .
Comparison of our method with the reported methods for the synthesis of CDTS.