Synthesis of Tetrahydroazepines through Silyl Aza-Prins Cyclization Mediated by Iron(III) Salts

A new methodology for the synthesis of seven-membered unsaturated azacycles (tetrahydroazepines) was developed. It is based on the powerful aza-Prins cyclization in combination with the Peterson-type elimination reaction. In a single reaction step, a C–N, C–C bond and an endocyclic double bond are formed. Under mild reaction conditions and using iron(III) salts as sustainable catalysts, tetrahydroazepines with different degrees of substitution are obtained directly and efficiently. DFT calculations supported the proposed mechanism.

) and a small amount of DMAP. Once the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography (n-hexane/EtOAc solvent system).

General procedure for substitution of tosylate by sulfonylamide
To a solution of corresponding tosylate (1.0 equiv.) in dry DMF (0.25 M) at room temperature under inert atmosphere were added TsNH2 or MsNH2 (2.0 equiv.) and Cs2CO3 (1.5 equiv.). The reaction mixture was warmed to 80 ºC until the starting material was completely consumed. Then, it was allowed to reach room temperature and the reaction mixture was filtered through a pad of silica gel. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography (n-hexane/EtOAc solvent system).

General procedure for -alkylation of esters
Following the procedure described by Panek and coworkers, 1 to a solution of i-Pr2NH (2.0 equiv.) in dry THF (0.94 M vs i-Pr2NH) at -78 ºC under inert atmosphere was added n-BuLi (2.0 equiv.). The mixture was stirred at 0 ºC for 10 min. and then cooled to -78 ºC. Next, a solution of the ester (1.0 equiv.) in dry THF (2.35 M) was added dropwise. This mixture was stirred at -78 ºC for 30 min. and alkyl iodide (2.7 equiv.) in dry THF (4.7 M) was added. The reaction mixture was allowed to reach room temperature and stirred overnight. It was quenched with saturated aqueous NH4Cl. The phases were separated and the aqueous layer was extracted with 3 x EtOAc. The combined organic phases were dried over anhydrous MgSO4, filtrated, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (n-hexane/EtOAc solvent system).

General procedure for reduction of esters to alcohols
To a solution of ester (1.0 equiv.) in dry Et2O (0.06 M) at 0 ºC under inert atmosphere was added LiAlH4 (2.0 equiv). Then, the ice-bath was removed and the mixture was stirred at room temperature. Once the reaction was completed, saturated aqueous K2CO3 solution and water were added. The solid was filtrated and the organic phase was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (n-hexane/EtOAc solvent system).

3-(triphenylsilyl)pent-4-enoic acid (precursor of 19)
To a solution of bis-homoallylic alcohol 17 (0.250 g, 0.73 mmol, 1.0 equiv.) in 2.4 mL of dry DMF (0.3 M) at room temperature under inert atmosphere was added PDC (1.37 g, 3.65 mmol, 5.0 equiv.) and a small amount of MgSO4. The reaction mixture was stirred overnight. Then, it was filtered through a pad of Celite. Water was added and aqueous phase was extracted with 3 x EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered through a pad of silica, and concentrated under reduced pressure. This crude reaction was used in the next step without further purification.

Computational details
All the calculations reported in this paper were obtained with the Gaussian 09 suite of programs. 5 All species were optimized using the B3LYP functional 6 in conjunction with the D3 dispersion correction suggested by Grimme et al. 7 using the standard double-ζ quality def2-SVP 8 basis sets for all atoms. Solvents effects were taken into account during the geometry optimizations using the polarizable continuum model (PCM). 9 All stationary points were characterized by frequency calculations. 10 Reactants and products have positive definite Hessian matrices, whereas transition structures show only one negative eigenvalue in their diagonalized force constant matrices, and their associated eigenvectors were confirmed to correspond to the motion along the reaction coordinate under consideration using the intrinsic reaction coordinate (IRC) method. 11 Compounds involving iron(III) were computed using a high-spin (S = 5/2) configuration. Single-point energy refinements were carried out at the same DFT level the much larger triple-ζ quality def2-TZVPP basis sets. This level is denoted PCM(CH2Cl2)-B3LYP-D3/def2-TZVPP//PCM(CH2Cl2)-B3LYP-D3/def2-SVP.