Unprecedented nucleophile-promoted 1,7-S or Se shift reactions under Pummerer reaction conditions of 4-alkenyl-3-sulfinylmethylpyrroles

A unique 1,7-S- and Se-shift reaction under Pummerer reaction conditions of 4-alkenyl-3-sulfinyl- and seleninylpyrroles was described. The usual Pummerer reaction of 4-(alkenylaminomethyl)-3-phenylsulfinylpyrroles and a successive reaction with tetrabutylammonium hydroxide (TBAH) yielded either pyrrolo[3,2-c]azepines or N-pyrrol-3-ylmethyl-N-(4-hydroxy-3-sulfanylpropyl)-p-toluenesulfonamides (diols). Seleno-Pummerer reactions of 3-selanylmethylpyrroles also proceeded via in situ generation of selenoxides, followed by a treatment with TBAH.

We further investigated the 1,7-S shift reaction from the azepinium cation 21b to the corresponding alcohol. We first predict that the intramolecular 1,7-S shift could occur via the transannular sulfonium intermediate 22b to form the S-shifted pyrroloazepine 23b because the 1,7-S shift reaction proceeded with high diastereoselectivity (11b, 12b, 11d, 12d). The calculation data also supported the intramolecular 1,7-S shift reaction as shown in Fig. S7. The speculation that the diol 17a could be formed by the base-promoted hydrolysis of bis(trifluoroacetate) 16a was ruled out by the DFT-calculation as shown in  bis(trifluoroacetoxy)pyrrole 16a with TBAH would provide the diol 17a. We also calculated the azepine formation from the sulfonium intermediate 14b (Fig. S9). The thionium ion (-sulfur-substituted carbenium ion) 18ba, which was generated from the normal Pummerer reaction, could be stabilized by the bridged intermediate 19b (estimated at −5.05 kcal/mol by the DFT calculations), easily undergo intramolecular cyclization to give 20b. The 1,5-hydride shift reaction of 20b forms the azepinium cation 21b. The final 1,7-S shift reaction have been already described above.

Experimental
General experimental methods.
Analytical thin layer chromatography (TLC) was performed using silica gel precorted glass plates and visualized by ultraviolet radiation (254 nm).
Flash column chromatography on silica gel was performed using silica gel (particle size 0.063-0.200 mm) under air pressure. Melting points were determined and uncorrected. 1 H and 13 C NMR spectra were determined with 600 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm) with respect to tetramethylsilane as an internal standard. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet. IR spectra were determined on a FT-IR infrared spectrometer and are expressed in reciprocal centimeters. EI mass spectra (MS) were obtained with direct-insertion probe at 70 eV. ESI measurements and their high resolution mass were performed using Quadrupole and TOF system.

(E)-N-Boc-N-2-butenyl-p-toluenesulfonamide
(1.08 g, 3.32 mmol) was added dropwise trifluoroacetic acid (6.0 mL) at room temperature. The reaction mixture was stirred for 0.5 h and evaporated under reduced pressure. The residue was crystallized from n-hexane and filtered off to give the titled compound 3c (0.742 g, 99%) as white powder. N-Boc-N-cinnamyl-p-toluenesulfonamide. S9 To a DMF (7.0 mL) solution of N-Boc-p-toluenesulfonamide (1.00 g, 3.69 mmol) was added 60% sodium hydride (0.22 g, 5.53 mmol) at 0 °C. The reaction mixture was stirred for 15 min at room temperature. To the mixture at 0 °C were added cinnamyl chloride (0.675 g, 4.42 mmol) and 15-crown-5-ether (0.22 g, 3.69 mmol) at 0 °C. The mixture was stirred for 12 h and poured into water (50 mL). The S19 organic layer was separated and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with H 2 O (50 mL × 2) and dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was precipitated from n-hexane and filtered off to give the titled compound (1.35 g, 95%) as white powders.  N-3-Methylbut-2-enyl-p-toluenesulfonamide (3e). S7 To a chloroform (5.0 mL) solution of
NaHCO 3 (50 mL) and then dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give  at 0 o C. The reaction mixture was further stirred for 5 min and poured into a sat.
NaHCO 3 (50 mL). The whole was vigorously stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with a sat. NaHCO 3 (50 mL) and then dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give  The whole was vigorously stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was washed with a sat. NaHCO 3 (50 mL) and then dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with  NaHCO 3 (50 mL) and then dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with
sodium hydrogen carbonate (50 mL) and then dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give Typical procedure for Pummerer reaction of 5a with TFAA and successive treatment with TBAH, synthesis of diol 9a.
The mixture was stirred for 10 h and poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give 3-Acetoxymethyl-4-(N-allyl-N-tosylaminomethyl)-1-(tosyl)pyrrole (7a), entry 1, Table 1.
The combined organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give Pummerer reaction of pyrrole 5e with TFAA and successive treatment with TBAH.
The mixture was stirred for 0.5 h and poured into water (50 mL). The organic layer was separated and the aqueous layer was extracted with CHCl 3 . The combined organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to at room temperature. The mixture was stirred for 2 h and poured into water (50 mL).
The organic layer was separated and the aqueous layer was extracted with chloroform.
The combined organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by preparative TLC on silica gel eluting with AcOEt-n-hexane (2:3) to give
To a dichloroethane (1.5 mL) solution of
To 1,2-dichloroethane (15 mL The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was dried over MgSO 4 . The solvent was removed under reduced pressure. The residue was purified by the preparative TLC on silica gel eluting with AcOEt-n-hexane (1:2) to give

X-ray crystallographic analysis
Data of sulfone derivative of 5a and pyrroloazepine 12d were taken on a Rigaku AFC5R diffractometer with graphite-monochromated Mo-K radiation ( = 0.71069 Å). The structures of sulfone derivative of 5a and 12d were solved by direct methods with SIR97.
Full-matrix least-squares refinement was employed with anisotropic thermal parameters for all non-hydrogen atoms. All calculations were performed using the Crystal Structure