Chemo- and Diastereoselective Synthesis of Pyrrolidines from Aroylformates and δ-Tosylamino Enones via P(NMe₂)₃-Mediated Reductive Amination/Base-Catalyzed Michael Addition Cascade

Abstract

A novel P­(NMe2)3-mediated tandem (1 + 4) annulation between aroylformates and δ-tosylamino enones has been developed that affords a facile synthesis of functionalized pyrrolidines in moderate to excellent yields with exclusive chemoselectivity and high diastereoselectivity. Mechanistic investigation reveals that the reaction proceeds through an unprecedented P­(NMe2)3-mediated reductive amination/base-catalyzed Michael addition cascade. The reaction herein also represents the first study of the reactivity patterns of the Kukhtin–Ramirez adducts toward ambiphilic nucleophile–electrophiles.

Oxyphosphonium Enolate Equilibria in a (4+1)‐Cycloaddition Approach toward Quaternary C3‐Spirooxindole Assembly

“…Consistent with our earlier observations and those by Ramirez, Radosevich, and others, employing triaryl phosphines or trialkyl phosphites in the cycloaddition of 4 a and 7 a failed to provide dihydrobenzofuran 9 a. [7,14] Interestingly, dioxyphospholenes derived from P III derivatives 8 a-8 e failed to provide dihydrobenzofuran 9 a when treated with the o-QM derived in situ from 4 a. [3f] The inability of phosphorus triamides 8 d and 8 e to promote the cycloaddition highlights the impact that subtle ligand variations can have on the reactivity of intermediates derived from the addition of PL 3 to 1,2-dicarbonyls.…”

“…[6] Emboldened by recent successes in the development of Rh II -catalyzed (4 + 1)-cycloaddition strategies for the assembly of spiropyrrolidine oxindoles, enantioselective approaches toward spirocyclopentenyl oxindoles, and inspired by the success of phosphorus mediated (n + 1) enolate cyclizations, we sought a complementary metal-free method employing an in situ generated oxyphosphonium enolate. [7] During the course of these studies, we became acutely aware of how critical the single atom component was to the success of these efforts. For example, seemingly minor architectural variations in substrate functionality led to drastically different reaction outcomes.…”

Construction of NH‐Unprotected Spiropyrrolidines and Spiroisoindolines by [4+1] Cyclizations of γ‐Azidoboronic Acids with Cyclic N‐Sulfonylhydrazones

“…[9] Forthese reasons,the development of flexible methods for the synthesis of structurally diverse spiropyrrolidines have concentrated great interest in the recent years. [10][11][12][13][14][15][16][17][18] N-Sulfonylhydrazones are very attractive derivatives of carbonyl compounds,that have been extensively employed as precursors of diazo compounds in avariety of metal-catalyzed as well as non-catalytic transformations. [19][20][21][22][23] In particular,the transition-metal free reaction between N-sulfonylhydrazones and boronic acids,f irst reported by our group, [24] is av ery useful C À Cb ond forming reaction that has found ample application in organic synthesis as am ethod to generate molecular diversity from carbonyl compounds.…”

P(NMe2)3-Mediated Umpolung Spirocyclopropanation Reaction of p-Quinone Methides: Diastereoselective Synthesis of Spirocyclopropane-Cyclohexadienones

“…As was known, the readily available α-keto carbonyl compounds could be involved in the umpolung chemistry under the reductive trivalent phosphorus derivatives, facilely enabling access to reactive Kukhtin–Ramirez adducts A and B (Scheme c). − These adducts as 1,1-dipoles so far have been elegantly applied in many α,β-cyclopropanation reactions with electron-deficient α,β-unsaturated compounds . To the best of our knowledge, however, there are few reports on a remote δ,γ-cyclopropanation of Kukhtin–Ramirez adducts.…”

“…According to the results described above and previous reports, − as shown in Scheme , stereoselective models are proposed for this spirocyclopropanation of p -QMs with Kukhtin–Ramirez adducts, wherein tandem 1,6-conjugate addition/intramolecular nucleophilic substitution is involved. The origin of the diastereoselective reversal in the current spirocyclopropanation using cyclic and acyclic α-keto carbonyls might mainly arise from the different preference for cyclic oxaphospholene species B and acyclic 1,3-zwitterionic species A of Kukhtin–Ramirez adducts (Scheme c).…”