An Improved Practical Route to (±)‐Epibatidine through L‐Proline Catalyzed Intramolecular Michael Addition

Abstract

This paper describes a rapid and practical synthetic route involving six‐step reactions towards the diastereoselectively synthesis of (±)‐endo‐Epibatidine, starting from 6‐chloro‐3‐pyridinecarboxaldehye. The effective Henry reaction gave precursor (E)‐6‐(6‐chloropyridin‐3‐yl)‐5‐nitrohex‐5‐en‐2‐one (3a) which could be used in the next step. Various benzoic acid derivatives were used to optimize intramolecular Michael addition of ketone to pyridinylnitroolefins to provide the key intermediate 3‐(6‐chloropyridin‐3‐yl)‐4‐nitrocyclohexanone ((±)‐7a) with high yield.

Synthesis of Functionalized Thieno[2,3-b]indoles via One-Pot Reaction of Indoline-2-thiones with Morita–Baylis–Hillman and Rauhut–Currier Adducts of Nitroalkenes

“…α-Hydrazinonitroalkenes were employed as substrates for the synthesis of functionalized triazoles and arenofurans, 23 whereas pyrazoles, furans, decalins, cycloalkanones, spirocycles, and a bridged heterobicyclic compound epibatidine were efficiently synthesized from RC-adducts. 22,24,25 Very recently, we reported an effective strategy for the synthesis of aminophenanthrenes and benzoquinolines from RC-adducts of nitroalkenes using Hauser–Kraus reaction of sulfonyl phthalide as the key step. 26 As part of our ongoing program to synthesize functionalized heterocycles, herein, we report a novel approach for the construction of indole-annulated thiophenes from MBH/RC-adducts of nitroalkenes and indoline-2-thione.…”

“…Our group has long-term interest in the Morita–Baylis–Hillman (MBH) and Rauhut–Currier (RC) reactions of nitroalkenes and their applications toward the synthesis of several carbo- and heterocycles . Specifically, α-hydrazinonitroalkenes prepared via MBH reaction of nitroalkenes with azodicarboxylates and an RC adduct of nitroalkene with MVK are well utilized as synthons for the preparation of several functionalized carbo- and heterocycles. , These are excellent Michael acceptors which participate in cascade Michael addition–cyclization sequences. − There is also the possibility of further exploitation of the reactivity of hydrazino and ketoalkyl moieties that are retained in the products. α-Hydrazinonitroalkenes were employed as substrates for the synthesis of functionalized triazoles and arenofurans, whereas pyrazoles, furans, decalins, cycloalkanones, spirocycles, and a bridged heterobicyclic compound epibatidine were efficiently synthesized from RC-adducts. ,, Very recently, we reported an effective strategy for the synthesis of aminophenanthrenes and benzoquinolines from RC-adducts of nitroalkenes using Hauser–Kraus reaction of sulfonyl phthalide as the key step .…”

Morita-Baylis-Hillman and Rauhut-Currier Reactions of Conjugated Nitroalkenes

“…Recently, Zeng et al and Reddy et al have reported intramolecular cyclization of RC adduct 38 using l-proline (10 mol%) as the catalyst (Scheme 34). [44,45] Both the authors have reported high yields and diastereoselectivities, but poor or no enantioselectivities in this reaction. Our own results after catalyst screening and considerable optimization of reaction conditions suggest that l-proline/DMSO is the combination that gives good yield and diastereoselectivity, though with poor enantioselectivity.…”

One-pot regioselective synthesis of functionalized and fused furans from Morita–Baylis–Hillman and Rauhut–Currier adducts of nitroalkenes

“…7 Despite the availability of numerous methods, development of novel and efficient diversity oriented approaches for the synthesis of functionalized and fused furans would be very valuable both from synthetic and biological perspectives. As part of the studies on the Morita-Baylis-Hillman (MBH) 8 and Rauhut-Currier (RC) 9 reactions of nitroalkenes and the applications of the products, [10][11][12][13][14][15][16][17][18][19][20] we and others have utilized the MBH acetates of nitroalkenes 1 (LG ¼ OAc) for the synthesis of several carbocycles 11 and heterocycles. 12,13 The methodology involves a cascade S N 2 0 reaction of a binucleophile with MBH acetate 1 followed by an intramolecular Michael addition taking advantage of the 1,2 or 1,3-bi-electrophilic character of 1 as outlined in Scheme 1a.…”

“…We and others have employed RC adducts of nitroalkenes for the synthesis of functionalized pyrazoles, 15 decalins, 16 cycloalkanones, 17 spirocycles 18 and bridged heterobicyclics such as epibatidine. 19 The reactivity prole of a representative RC adduct 6, derived from the imidazole/LiCl mediated RC reaction of nitroalkene with MVK, is outlined in Scheme 2a. Recently, we have reported a highly diastereoselective Michael initiated intramolecular aldol reaction involving compound 6 and cyclohexanone 7 for the synthesis of highly substituted transdecalins 8 (Scheme 2b).…”