Nazarov-type cyclization reactions

Subsequent investigations by Denmark have shown that vinylsilanes can direct the course of Nazarov-type cyclization reactions. Once again the regiochemical outcome is controlled by the -effect as substitution takes place at the carbon bearing the silyl group (Scheme 7). This clever modification provided a solution to the serious problem of double bond isomerization that is frequently observed in the classical Nazarov reaction. Treatment of the enone (11) with commercially available anhydrous iron(III) chloride (FeCb) promoted cyclization to give one double bond isomer of the m-hydrindinone (12) in excellent yield. Table 2 summarizes a representative collection of cyclization reactions catalyzed by FeCb. 

Nazarov-type cyclization of x,x-dienones. The cyclization of a,a -dienones of type 1 to annelated cyclopentenones (2) is effected in yields of 10-20% with the usual Lewis acid catalysts SnCl4, CF3COOH, or BF3 etherate. However, reaction of 1 with 2 equiv. of ISi(CH3)3 effects this cyclization in 48% yield. However SnCl4 is more satisfactory for cyclization to ring-fused cyclopentenoid systems such as 4. 

Cyclopentenone annelation (cf. 10,444). The reagent undergoes a Nazarov-type cyclization with an a,/S-unsaturated acid chloride to give an annelated 3-phenylthio-cyclopentenone. This reaction was used to prepare the bicyclic cyclopentenone 3, a useful intermediate in synthesis of cyclopentenoid natural products, such as hirsutene (4).3... 

Finally, there has been speculation and recent experimental support for the involvement of a Nazarov-type cyclization in the biosynthesis of c/ s-jasmonic acid ° and marine-derived prostanoids. Radiolabel tracer studies have demonstrated Ae intermediacy of 8-HPETE (104) in the biosynthesis of prostanoid intermediate preclavulone A (lO ). This remarkable conversion was proposed to proceed by formation of allene oxide (105) followed by isomerization to (107) via the 2-oxidocyclopentadienyl cation (106 Scheme 41). To demonstrate the chemical feasibility of this proposal, Corey reported the transformation of epoxysilane (108) to, inter alia, the cyclopentenone (111 Scheme 42). The reaction is presumed to involve formation of the allene oxide (109) followed by isomerization to the 2-oxi-dopentadienylic cation (110). Conrotatory closure of (110) is expected to produce the cis isomer of (111) as observed. 

However, the first of these, (154), is predominant and temperature dependence studies were used to substantiate that the preferred reaction path affords (154). This product arise by a Nazarov-type cyclization. Deuterium labelling experiments were used to show that there was an intramolecular hydrogen abstraction process leading to (154). The last compound, (156), is formed by an intramolecular dipolar addition. While the naphthyl substituted enone reacts efficiently the phenyl analogue... 

An Inspired variant in the preparation of divinyl ketones, which then undergo Nazarov-type cyclizations to cyclopentenones, is shown in Scheme 7. The reaction involves the treatment of a tetrahydro-... 

Scheme 10.61. A representation of a Nazarov-type cyclization occurring as a result of the addition of trimethylsilylethene (vinyltrimethylsUane [CH2=CHSi(CH3)3]) to cyclopen-tenoyl chloride in the presence of tin(IV) chloride. It is important to note that the putative primary carbocation is presumed to be stabilized by overlap of the empty p- type orbital on carbon with the bond between the sihcon and the carbon to which it is directly attached, that is, the P-effect as well as partial bonding to SnCU". (see Habermas, K. L. Denmark, S. E. Jones, T. K. The Nazarov cyclization, in Paquette, L. A. (ed.). Organic Reactions, Vol. 45, Wiley, Hoboken, NJ, 1994 Magnus, R Quagliato, D. /. Org. Chem., 15>85,50,1621).

A similar type of chiraUty transfer was exploited by Tius in the total synthesis of roseophilin (69) (Scheme 3.15) [18]. A key intermediate in the synthetic pathway consisted of a substituted cyclopentanone, constructed via a Nazarov-type cyclization. The asymmetric cyclopentannulation reaction was initiated by generating the cyclopentenyl intermediate in situ using the lithioallene 64 and the amide 65. The chiral substituent on the delocahzed carbocation 66 induced... 

In the presence of (la) or Me3Si[B(OTf)4], the intramolecular Friedel-Crafts-type reaction of P,p-difluoro-a-enones with arenes proceeds smoothly to give 4-fluoro-1,2-dihydronaphthalenes in good yield [113]. The stabilizing effect of fluorine on a-carbenium ions enhances the reactivity to enable the rapid, efficient reaction at 0 °C (Scheme 9.44). The directing effect has also been utilized for a Nazarov-type cyclization [114]. 

Alkynylaziridines carrying an aryl group have been reported to give spiro [isochroman-4,2 -pyrrolines] with gold salts as catalysts and involve a Friedel-Crafts-type intramolecular reaction followed by cyclization of the aminoaUene intermediate, both initiated by the dual a and n Lewis acidities of gold. Tandem Au(in)-catalysed heterocyclization/Nazarov cyclizations leading to substituted carbocycle fused fiirans have been reported and computational studies support the function of solvent (Scheme 114). ° ... 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

Acid-catalyzed cyclization of divinyl ketone 56-57 occurs by conrotatory cyclization of 3-hydroxy pentadienyl cation [31]. This type of cyclization reaction is known as Nazarov cyclization reaction [31]. 

Nazarov-type Reactions. It has been shown that the highly Lewis acidic Sc(OTf)3 and Yb(OTf)3 can catalyze the Nazarov cyclization. Recently, Dy(OTf)3 has been err5>loyed to catalyze the rearrangement of furfural and furylcarbinol reagents. These rearrangements are proposed to terminate in Nazarov-type 47T electrocyclizations. A Dy(OTf)3-catalyzed formation of trans-4,5-diamino-2-cyclopenten- 1-ones fromfurfural and nitrogen nucleophiles has been disclosed (eq 5). ... 

The synthetically most useful reaction of this type is the Nazarov cyclization, in which a cross-conjugated dienone like 4.89 forms a cyclopentenone 4.92 when treated with acid, in this case a Lewis acid. 

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