DOI: 10.1002/cssc.201301064 Solid Catalysts for Multistep Reactions: One-Pot Synthesis of 2,3-Dihydro-1,5-benzothiazepines with Solid Acid and Base Catalysts Maria J. Climent,* Avelino Corma,* Sara Iborra, and Laura Martí [a] Introduction The synthesis of heterocycles that contain N and S atoms, such as benzothiazepines, are of interest in the search for new drugs because of to their wide spectrum of pharmacological properties. For instance, 1,5-benzothiazepines are used in car- diovascular treatments (diltiazem, fluorodiazepam, etc.), as muscle relaxants, as inhibitors towards HIV-integrase, as anti- convulsants, and as antibiotics. [1] It is known that 2,3-dihydro- and 3,4,5-tetrahydro-1,5-benzothiazepines are cholinesterase inhibitors that have potential as active drugs in the treatment of Alzheimer’s disease. [2] In addition, a series of benzothiaze- pines that contain fluorine and fluorophenyl groups have been found to treat cancer metastasis. [3] The general method to build the ring skeleton of 1,5-benzo- thiazepines is the reaction of 2-aminothiol, a,b-unsaturated compounds (a,b-unsaturated esters or a,b-unsaturated ke- tones), and b-haloketones in the presence of homogeneous acid or base catalysts. A secondary reaction that can limit the yield of 1,5-benzothiazepines is the competitive dimerization of 2-aminothiol, which can take place to an extent that de- pends on the catalyst and reaction conditions. Thus, a variety of Brønsted and Lewis acids, [4] such as ethanol saturated with HCl (g) , trifluoroacetic acid and glacial acetic in DMF, BF 3 ·Et 2 O, gallium triflate, and ionic liquids, have been used as catalysts with reasonable success. The preferred bases to catalyze this reaction are pyridine and piperidine. [5] For instance, on starting from chalcone and 2-aminothiophenol in the presence of pi- peridine, [6] the 1,3-diphenyl-1-(2-aminophenylsulfide)-3-propa- none intermediate is obtained in the first step (72 % yield). This is cyclized in the second step in glacial acetic acid to give the corresponding 1,5-benzothiazepine in 74 % yield after heating to reflux in methanol, which gives a 53.3 % final yield of the global process. The use of homogeneous catalysts that require a neutraliza- tion step, solvents with high boiling points (e.g., DMF), and long reaction times (which favor the formation of the corre- sponding disulfide), are the main disadvantages of the meth- ods described above. Compared with homogeneous catalysts, heterogeneous catalysts offer the advantages of easy and safe handling, they avoid neutralization steps and decrease the generation of waste. However, the number of examples report- ed in the literature of the synthesis of 1,5-benzothiazepines by using heterogeneous catalysts is low, and in most cases the main drawback is that the amount of the catalyst used with re- spect to the amount of reactants has to be very high (100 wt % or even higher) to achieve a good performance. For instance, Kodomari et al. [7] synthesized 2,4-diaryl-2,3-dihydro- 1,5-benzothiazepines from 2-aminothiophenol and chalcone in presence of silica gel (catalyst/substrate ratio 5.7:1) in 87 % yield after 3 h reaction time. Recently, Yadav et al. [8] reported the synthesis of 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine derivatives in good yields (86–93 %) by using Amberlyst 15 as the acid catalyst and ionic liquids as solvents at 60 8C. In this case, a high catalyst/substrate ratio (1.7:1 wt %) was used. Arya and Dandia [9] prepared fluorinated-2-carboxy-2,3-dihydro-1,5- benzothiazepines by the reaction of substituted 2-aminothio- phenols with 3-(4-fluoro-2-methylbenzoyl)-2-propenoic acid by using different metal-cation-exchanged Y zeolites (CeY, LaY, 1,5-Benzothiazepines derivatives were obtained first by starting from 1,3-diphenylpropenone derivatives (chalcones) and 2-ami- nothiophenol by using aluminosilicate solid catalysts. However, diffusional limitations and the strong adsorption of products on the catalyst are deleterious for catalyst activity and life. Then a structured amorphous mesoporous catalyst with large pores and mild acidity that works at higher temperatures al- lowed us to obtain high conversions (99 %) and selectivities (98 %) of the desired product. A one-pot synthesis of 1,5-ben- zothiazepines that starts from benzaldehyde, acetophenone, and 2-aminothiophenol with 95 % yield was performed by combining optimized solid base and acid catalysts in batch mode as well as in a continuous-flow reactor system. Much better conversion and selectivity as well as process intensifica- tion has been achieved with the structured mesoporous mate- rials by avoiding intermediate and final neutralization and pu- rification steps required in the synthesis reported previously that uses homogeneous catalysts. [a] Prof. Dr. M. J. Climent, Prof. Dr. A. Corma, Prof. Dr. S. Iborra, L. Martí Instituto de Tecnología Química (UPV-CSIC) Universitat PolitØcnica de Valncia Avda dels Tarongers s/n, 46022, Valencia (Spain) Fax: (+ 34) 963877809 E-mail: acorma@itq.upv.es mjcliol@qim.upv.es Supporting Information for this article is available on the WWW under http://dx.doi.org/10.1002/cssc.201301064.  2014 Wiley-VCH Verlag GmbH & Co. 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