An efficient approach to the cyclotrimerisation of alkynes: solvent-free synthesis of 1,3,5-trisubstituted benzenes using p -toluenesulfonic acid monohydrate

An environmentally friendly, efficient method for transforming alkynes into substituted benzenes catalyzed by p -toluenesulfonic acid monohydrate ( p -TsOH·H 2 O) under solvent-free conditions has been developed, which conforms to the principles of “green” chemistry and overcomes the shortcomings of previous methods for the synthesis of substituted benzenes. The reaction is quite general and provides good to excellent yields.


Introduction
The development of new transformations that are not only efficient, selective, and high-yielding but that are also environmentally benign is one of the challenge chemists are facing. 1,22][3][4] "Green" chemistry aims at the total elimination or at least the minimization of generated waste and the implementation of sustainable processes through the adoption of 12 fundamental principles.An alternative strategy to reduce the E-factor of reactions and their impact on the environment is to conduct them under solvent-free conditions.3][14][15][16][17][18][19][20] However, most of these protocols suffer from the need of using precious metal catalysts, lower yields or harsh operating conditions, and mixtures of 1,3,5-and 1,2,4-trisubstituted benzenes are obtained in general.Recently, we reported that a novel indium(III)-catalyzed cyclotrimerization of alkynes in the presence of 2iodophenol gave 1,3,5-substituted benzenes with complete regioselectivity.However, the indium(III)-catalyzed cyclotrimerization was less successful with alkynylsilanes (only 15% yield of 2a) and needed to be carried out in sealed tubes. 21Meanwhile, considering their expensive nature, inadequate accessibility, toxicity of the additives often used, the generation of toxic waste and the use of organic solvent as well as harsh conditions, there is an urgent need to develop a powerful method with a high regioselectivity to meet the requirement of green chemistry.Here we describe a green approach towards the regioselective synthesis of 1,3,5-trisubstituted benzenes via the p-TsOH•H2O-catalyzed [22][23][24][25][26][27][28] trimerization of alkynes under solvent-free conditions.

Results and Discussion
In order to identify the optimal reaction conditions, 1-phenyl-2-trimethylsilylacetylene 1a was chosen as a model substrate.Firstly, the cyclotrimerization was carried out in the presence of 10 mol% TfOH under solvent-free conditions and the desired product 2a was isolated in 53% yield (Table 1, entry 1).The reaction using TFA, CAN, H2SO4, HNO3 and H3PO4 as catalysts produced 2a only in low yields (Table 1, entries 2, 3 and 10-12).Changing the catalyst to p-TsOH•H2O furnished the product 2a in 68% yield (Table 1, entry 6).Furthermore, a higher yield was obtained when the amount of p-TsOH•H2O was increased from 0.1 equiv to 0.5 equiv or 1.0 equiv (Table 1, entries 7 and 8).Other catalysts such as oxalic acid, AcOH, HCl, or Lewis acids did not promote the cyclotrimerization reaction (Table 1, entries 4, 5, 9 and 13-16).

Conclusions
In conclusion, we have developed an environmentally friendly, economical and efficient method for cyclotrimerization of alkynes under solvent-free conditions in the presence of p-TsOH•H2O.The major advantages of the method lie in the cheap catalyst, easy work-up and avoidance of the use of toxic solvents such as DMF, DMSO, CH3CN and toluene.Air-tolerant and atomeconomical characteristics of the method accord with the concept of modern green chemistry and will be appealing for industries.

Experimental Section
General.All compounds are commercially available and were used without further purification.NMR spectra were recorded on a Bruker AVANCE DPX-400 or Bruker AVANCE DRX-500 instrument with TMS as an internal reference.MS measurements were performed on Bruker Reflex III mass spectrometer (ESI).Elemental analyses were carried out with an Elementar Vario Micro Cube in the School of Chemistry & Chemical Engineering of Guangxi Normal University, China.Flash chromatography was performed with QingDao silica gel (300-400 mesh).
General procedure for the cyclotrimerization of alkynes 1.To a 10 mL flask, alkynes (0.6 mmol) and p-TsOH•H2O (1.0 equiv) were successively added.The mixture was stirred at 60 o C for 3 h and at 140 o C for the rest of the time, which was monitored periodically by TLC.After completion of the reaction, the reaction mixture was neutralized by saturated NaHCO3, and then extracted with CH2Cl2 (3 × 20 mL).The combined organic layers were dried by anhydrous MgSO4, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography (PE/EA) and gave the corresponding products.

Table 1 .
Screening of catalysts for the cyclotrimerization of 1-phenyl-2-trimethylsilylacetylene a oC for 3 h and then at 140 o C for 10 h.b Isolated yield of pure product based on 1a.