The N azarov Cyclization

Abstract

The Nazarov cyclization is named after the eminent Russian chemist I. N. Nazarov (1900–1957). In the course of an extensive study on the formation of allyl vinyl ketones by the mercuric ion and acid‐catalyzed hydration of dienynes, Nazarov and his co‐workers discovered a secondary reaction to form 2‐cyclopentenones. Nazarov initially formulated a direct acid‐catalyzed closure of the allyl vinyl ketones and demonstrated the preparation of 2‐cyclopentenones from these precursors in dozens of cases. However in 1952, Braude and Coles suggested the intermediacy of carbocations and demonstrated that the formation of 2‐cyclopentenones actually proceeds via the α,α′‐divinyl ketones. This fact, together with further mechanistic clarification, has led to the current formulation of the Nazarov cyclization as the acid‐catalyzed closure of divinyl ketones to 2‐cyclopentenones. This process was already documented in 1903. Treatment of dibenzylideneacetone with concentrated sulfuric acid and acetic anhydride followed by mild alkaline hydrolysis afforded a ketol, the correct structure of which was finally proposed in 1955. Other examples of acid‐catalyzed cyclizations of divinyl ketones exist in the early literature, as do reactions which must have proceeded via divinyl ketones. A broader definition of the Nazarov cyclization includes a wide variety of precursors that under specific reaction conditions also produce 2‐cyclopentenones via divinyl ketones or their functional equivalents. A case in point is the formation of a cyclopentenone by treatment of either divinyl ketone or tetrahydropyrone with ethanolic hydrochloric acid. It is the structural variety of precursors that lends versatility to the Nazarov cyclization and which also serves as the organizational framework for this chapter. To facilitate presentation, the reaction is divided into six categories defined by the structure of the precursor: (1) cyclization of divinyl and allyl vinyl ketones, (2) cyclization of silylated (stannylated) divinyl ketones, (3) in situ generation/cyclization of divinyl ketones or equivalents, (4) generation/cyclization of divinyl ketone equivalents by solvolysis, (5) alkyne‐based precursors of divinyl ketones, and (6) coupling reactions to form and cyclize divinyl ketones. The logic of this sequence follows from the order of decreasing structural similarity of the precursors to divinyl ketones. This is intended to be comprehensive in the coverage of cyclizations which produce 2‐cyclopentenones. The related electrocyclic closure of less oxidized pentadienylic cations is not covered. The reaction was most recently reviewed in 1991. Prior to that, the Nazarov cyclization had been reviewed in 1983 and also in the context of pentannulation.

Stereochemical Courses and Mechanisms of Ring-opening Cyclization of Donor–Acceptor Cyclopropylcarbinols and Cyclization of 7-Benzyloxy Dibenzyl Lignan Lactones

“…4f The mechanism distinguishes the ringopening cyclization of DA cyclopropylcarbinols (formal homoNazarov cyclization 9 -type reaction) from concerted reactions or pericyclic reactions such as the original Nazarov cyclization. 10 As a similar cyclization, we investigated the Lewis acidmediated cyclization of 5a and 5b. The synthesis of these substrates was as follows (Scheme 6): i) 4h the Cu(OTf ) 2 -mediated oxy-homo-Michael reaction of bicyclic donoracceptor cyclopropanes 3, prepared via asymmetric cyclopropanation 11 using HayashiJørgensen catalyst, 12 with 1.0 equiv of BnOH gave a 1:1 mixture of lactones 4a and 4b (if 2.0 equiv of BnOH is used, lactone 4a can be obtained with high stereoselectivity), ii)…”

The Piancatelli Rearrangement: New Applications for an Intriguing Reaction

“…The mechanism shown in Scheme 2 resembles the Nazarov cyclization, in which a divinylketone, activated by Brønsted or Lewis acids, rearranges to a cyclopent-2-enone progressing through a pentadienylic cation (C) and a conrotatory ring-closure (Scheme 3) [3][4][5]. The second alternative mechanism (Scheme 5) was proposed by Yin and co-workers, while investigating the rearrangement of 2-furylcarbinols bearing an hydroxyalkyl chain at the 5 position [8].…”

“…Recently Subba Reddy's group illustrated a further application of the aza-Piancatelli reaction by a new route to 3,4-dihydro-2H-benzo[b] [1,4]oxazine and thiazine derivatives, core structures shared among several biologically and pharmacologically active compounds [61]. This new procedure is based on a domino aza-Piancatelli/hetero-Michael addition conducted by reacting 2-furylcarbinols with 2-aminophenols or 2-aminothiophenols (Scheme 21).…”

“…Preliminary experiments with 10% phosphomolybdic acid gave products in rather good yields (75%, 2.5 h), but the use of indium salts as catalysts [62][63][64][65] (10 mol% In(OTf) 3 ) in acetonitrile at room temperature allowed the optimization of the synthesis of 3,4-dihydro-2H-benzo[b] [1,4] thiazine derivative (51a) up to 86% in terms of yields, with high diastereoselectivity and shorter reaction times (2 h) [61].…”

“…Moreover 2-aminothiophenols failed to react under these conditions. Complex mixtures or no reaction were observed in the attempts of building [1,4]heterocycles different from benzoxazine, starting from building blocks such as o-phenylenediamines, pyrocatechols or 2-aminopyridin-3-ol. The introduction of an electron-withdrawing group (e.g., methanesulfonyl, tosyl) on one of the nitrogens of o-phenylenediamines proved beneficial for the isolation of the desired products (Scheme 22, 53a-d).…”