Transition metals in organic synthesis, Part 105. 1 Synthesis of pyrroles by silver(I)-promoted oxidative cyclization

Condensation of aromatic aldehydes with arylamines to form Schiff bases, and subsequent addition of trimethylsilylpropargylmagnesium bromide, leads to homopropargylamines which on silver(I)-promoted oxidative cyclization affords 1,2-diarylpyrroles.


Introduction
The pyrrole ring system is a crucial structural unit which is found in many biologically active alkaloids and medicinal products. 2Thus, a wide range of methods for the synthesis of pyrroles has been reported. 3,4In 2004, we described a novel synthesis of pyrroles based on a threecomponent coupling followed by a silver(I)-promoted oxidative cyclization of the resulting homopropargylamines. 5 Our silver(I)-promoted oxidative cyclization of homopropargylamines was applied to the total synthesis of natural products containing annulated pyrroles, 6 like the indolizino [8,7-b]indole alkaloid (±)-harmicine and the pyrrolo[2,1-a]isoquinoline alkaloid (±)crispine A. 7,8 In the present paper, we report full details of the silver(I)-promoted oxidative cyclization to 1,2-diarylpyrroles.

Results and Discussion
Condensation of aromatic aldehydes 1a-c with anilines 2 provides the previously known Schiff bases 3a-c (Scheme 1, Table 1). 9,10The addition of 3-trimethylsilylpropargylmagnesium bromide (4) requires an activation of the aldimines 3. Following Nakagawa's procedure by  The silver(I)-promoted oxidative cyclization of homopropargylamines 5 to pyrroles 6 has been rationalized by the following proposed mechanism (Scheme 2).The interaction of silver(I) with terminal alkynes is known to provide silver(I)-alkyne π-complexes. 12The resulting activation of the triple bond towards nucleophilic attack can be exploited for heterocyclization reactions. 13Thus, we propose that silver(I) acetate on reaction with the homopropargylamine 5 generates initially a silver(I)-alkyne π-complex 7.An intramolecular nucleophilic attack of the nitrogen atom at the electrophilic alkyne leads to the intermediate 2-pyrroline-silver(I) complex 8, which is formed in a 5-endo-dig cyclization. 14Obviously, the intramolecular nucleophilic attack at the silver(I)-alkyne π-complex 7 obviously is faster than its transformation into a silver(I) acetylide via protodesilylation.12b,15 Protonation of the enamine moiety in intermediate 8 to the iminium ion 9 is followed by -hydride elimination to afford finally metallic silver and the pyrrylium ion 10.Aromatization by loss of a proton and protodesilylation provide the pyrrole 6. Scheme 2. Proposed mechanism for the silver(I)-promoted oxidative cyclization of homopropargylamines 5.
It has been demonstrated that using the corresponding N-tosylhomopropargylamines as substrates provide 2-pyrrolines as products of the cyclization.As silver(I) is not being reduced in the course of that process, the reaction can be performed using catalytic amounts of silver(I). 16his silver(I)-catalyzed cyclization of N-tosylhomopropargylamines has been applied to the synthesis of 2-arylpyrroles and 2,2'-bipyrroles. 16,17

Conclusions
The homopropargylamines which serve as starting materials for the silver(I)-promoted pyrrole synthesis are readily available by a simple process: condensation of an aromatic aldehyde and an aniline to the corresponding Schiff base followed by Lewis acid-promoted addition of trimethylsilylpropargylmagnesium bromide.The silver(I)-promoted oxidative cyclization of the homopropargylamines provides 1,2-disubstituted pyrroles in good to excellent yields and can be applied to the total synthesis of natural products featuring a 2-arylpyrrole structural unit.
General procedure for the synthesis of the Schiff bases 3a-c.The anilines 2 (50 mmol) and magnesium sulfate are added successively to a solution of the aldehydes 1a-c (50 mmol) in ethyl acetate.The reaction mixture is stirred until total conversion is detected by thin layer chromatography (1-2 h).Magnesium sulfate is removed by filtration and washed with ethyl acetate.Removal of the solvent provides the Schiff bases 3a-c.N-Benzylidene-4-methoxyaniline (3a).Yield: 82%.Light yellow crystals; for spectroscopic data, see ref. 9

Table 1 .
Coupling to the homopropargylamines 5 and silver(I)-promoted oxidative cyclization to 6