n-Butylsulfonated nano-titania (n-TiO 2 -NH-(CH 2 ) 4 -SO 3 H) as a highly efficient and reusable nanocatalyst was prepared by grafting 2,4-toluene diisocyanate as a bi-functional covalent linker onto a nano-titania support, followed by reduction and then ring opening-reaction of the synthesized amine with 1,4-butanesultone. Fourier transform infrared spectroscopy, X-ray diffraction, field-emission scanning electron microscopy and thermogravimetric analysis were used to characterize the catalyst. The catalytic activity of n-TiO 2 -NH-(CH 2 ) 4 -SO 3 H was evaluated in the synthesis of tetrahydrobenzo[b]pyrans, which affords high yields. Statistical experimental design was applied as an efficient and powerful method to achieve the optimal conditions for this catalytic reaction leading to high yield. Moreover, the catalyst was recovered and reused at least six times without a significant decrease in catalytic activity.