Pyrroline aldol reactions

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

Condensation of A pyrroline with pyrrole readily affords a stable compound, 2-(2-pyrrolidyl)pyrrole.97 The pyrrole trimer345> 848 and indole dimer347 are formed by analogous aldol reactions. The dimerizations of some derivatives and analogs of J1-pyrroline and Zl -piperideine, e.g. J1-pyrroline-2-carboxylic acid and 4-thia-J1-piperideine-2-carboxylic acid, take a similar course.348... 

Birch reductions of acylpyrroles have been studied in some detail <07MI1888 07OL421>. A Birch reductive aldol reaction of 72 in the presence of acetaldehyde gave 3-pyrroline 73, a useful intermediate for the production of pyrrolidinone-based building block 74 <07OL421>. 

Aldol-type condensations are useful for making the c connection in 3-pyrroHn-2-ones, hence it makes sense to combine an aldol reaction with an amidation to form a straightforward intermolecular-type ac approach to 3-pyrrolin-2-ones. It turns out that not many aldol-lactamiza-tion approaches have been reported for making (non-tetramic acid) 3-pyr-rohn-2-ones. One example, reported by Yao and coworkers, involves the synthesis of lactam-terminated polyketides (Scheme 63 2007BMCL3426). 1,3,5-Trisubstituted 3-pyrrolin-2-ones 257 were prepared by treating esters... 

Anionic/oxidative reaction sequences have been developed in addition to the domino anionic/reductive processes. For example, with regard to the synthesis of novel diaryl heterocycles as COX-2 inhibitors [500], including rofecoxib (Vioxx) 2-972 [501] (which has recently been withdrawn from the market) or the pyrrolin-2-one derivative 2-973 [494], Pal and coworkers reported on a so-far unique domino aldol condensation/oxidation sequence (Scheme 2.218) [503]. 

Reversing the position of the aldol electrophile, Enders and coworkers developed a type ce approach to complex 3-pyrrolin-2-ones that involved a quadruple cascade process (Scheme 91 2014S1539). Treatment of cinnamaldehyde (353) and the a-ketoamide 354 with pyrrolidine catalyst 355 and NaOAc gives the fused 3-pyrrolin-2-one 357. The mechanism of the reaction includes a Michael addition by the amide followed by aldol condensation to generate the 3-pyrrolin-2-one intermediate 356 subsequent Michael and aldol transformations with a second equivalent of 353 then gives the fused cyclopentene ring. 

Yavari and Bayat used similar fiinctionahty and replaced the aldol condensation with a Wittig reaction to prepare 3-ethoxy-3-pyrrolin-2-ones in a type ce fashion (Scheme 92 2002SC2527). Treatment of... 

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