Brønsted Acid‐Promoted Cascade Alkylation/Cyclization of Pyrroles with N,N‐Dimethylaminomethyleneglutaconic Acid Dinitrile: A Concise Route to Cyclopenta[b]pyrroles

Abstract

AB r ønsted acid (p-TsOH·H 2 O) promoted alkylation/cyclization cascade reactiono fp yrroles with N,N-dimethylaminomethyleneglutaconic acid dinitrile was efficiently realized to afford functionalized cyclopenta [b]pyrroles with excellent diastereoselectivity.D eamination of the corresponding ammonium saltso ft he cyclopenta [b]pyrroles with methyl iodide led to dihydrocyclopenta[c]pyrroles. Thec ascade reactionp athway was confirmed by isolation and transformation of the reactioni ntermediate,i .e., the 2-alkylated pyrrole.Keywords: Brønsted acid;c yclization; cyclopenta [b]pyrroles; N,N-dimethylaminomethyleneglutaconic acid dinitrile;pyrroles Fused heterocyclic compoundsc ontainingacyclopenta [b]pyrrole motif are present in many biologically active natural products andm edicinallyi mportant compounds, [1] such as,k rill fluorescent substance F [2] which is ac omponent of the phorbine chromophore presenti na ll types of chlorophylls,r oseophilin, [1c,3] and an inhibitor of d-amino oxidase [4] (Figure 1). Consequently,m uch effort has recentlyb een devoted to the synthesis of cyclopenta [b]pyrrole derivatives.T he acid-mediated Nazarov cyclization is au seful method for the constructiono ff ive-membered carbocycles, [5] which has usuallyb een employed as as traightforward route to access cyclopentenone-fused pyrroles.[6] Tr ansition metal-catalyzed cyclization/ring expansion of functionalized alkynes, [7] hydroformylation of 1,4-dienes followed by condensation with primary amines, [8] and other reactions [9] have also been applied for the synthesis of cyclopenta[b]pyrrole derivatives.Brønsted or Lewis acid-promoted Friedel-Crafts cyclization has been considereda sapowerful method to prepare heterocyclic compounds.[10] Ap yrrole ring can thusb eu sed as the "template"-like structure to establish another ring onto it for the construction of polycyclic compounds, [11] in which annulation of prefunctionalized alkynes or olefins to ap yrrole core is usuallyi nvolved. After screening of the relevant known synthetic methods, we reasonedt hat ad iene might be utilized to replace the pre-functionalized alkyneso ro lefins for the same purpose.T he polarized diene, N,N-dimethylaminomethyleneglutaconic acid dinitrile, [12] which is structurally endowedw ith an electron-donating NMe 2 moiety andt wo electronwithdrawing cyano groups attacheda ti ts two C=C bonds,h as been useda saC 3 building block to synthesize carbocyclic compounds.[13] Recently,w ef ound that Brønsted acids could promote Friedel-Crafts alkylationo fi ndoles with N,N-dimethylaminomethy-