Nazarov-type cyclization

A Nazarov-type cyclization was exploited to prepare annelated pyrroles <06OL163>. Acylation of iV-tosylpyrrole 65 with carboxylic acid 66 promoted by trifluoroacetic anhydride gave intermediate 2-ketopyrrole 67 which underwent a Nazarov-type cyclization to give cyclopenta[fc> pyrrolc 68. Another route to cyclopenta[fc]pyrroles involved a novel cyclization involving pyrrole-substituted enones and isocyanides <06OL3975>. 

Cyclopentenones from Nazarov and Nazarov-type cyclizations Ferric chloride, 133 Organotin reagents, 211 Trifluoroacetic anhydride-2,6-Luti-dine, 177... 

The related transformation of 1-phenyl-2-propen-1-ones 81 (a Nazarov-type cyclization) [Eq. (5.121)] has also been studied by Shudo and co-workers.316 The acidity dependence (Table 5.25) and, in particular, the linear relationship between rates and acidity values strongly suggest the involvement of (9,0-diprotonated... 

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... 

A synthesis of cyclopentenones somewhat related to those shown earlier was found from conjugated 1,3-enynes (equation 19) Cyclopentenones are obtained by the hydrolysis of the enol acetates. This transformation involves a 1,3-migration of the acetate to form pentadienyl cation and the formation of the gold carbene after a Nazarov-type cyclization. DFT calculations support this mechanism and provide interesting insight into the mechanism of the final stages of the process. 

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. 

The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation-dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product (Scheme 70) <2005TL6847>. 

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. 

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... 

A synthesis of cross-conjugated 2-cyclopenten-l-ones from dialkenyl ketones is readily induced by TMSOTf (eq 73). A strong fluorine-directing effect has been observed for such Nazarov-type cycUzation, as mixtures of products have been observed for nonfluorinated dialkenyl ketones. The addition of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a cosolvent dramatically accelerates the cyclization. Other acids such as BF3-OEt2, FeCls, polyphosphoric acid, or TiOH are less effective while neither TMSI nor TMSOMe promote this cyclization at all in CH2CI2. 3-Ethoxycarbonyltetrahydro-)/-pyrones also undergo such Nazarov-type cyclization. ... 

The presence of /3-heteroatom substituents offers various synthetically attractive possibilities. For example, silyl-substituted dienynes can undergo Si-assisted Nazarov-type cyclization, as exemplified in Scheme 14. 

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).

The a-(carboethoxy)vinyl cuprate (84), generated by conjugate addition of lithium cyanomethylcuprate to ethyl propiolate, reacts with a,jS-unsaturated acid chlorides to form divinyl ketones. Subsequent Nazarov-type cyclization, now shown to be promoted by trimethylsilyl iodide, yields highly substituted cyclopentenones (Scheme 43)." ... 

Trimethylsilyl iodide has been shown to be another efficient reagent for the preparation of cyclopentenones via Nazarov-type cyclizations. ... 

A full report has been published on the annulation of the -keto-ester (83) by the cyclopropylphosphonium salt (84) leading to (85) hydrolysis of the intermediate vinyl sulphide was effected by an iodolactonization procedure, as standard methods failed. An alternative annulation method (Scheme 8) involves the acylation of vinyl cuprates by unsaturated acid chlorides followed by Nazarov cyclization MeaSil can sometimes serve as a good reagent for this step. Nazarov-type cyclizations using acetylenic acetals have also been employed in... 

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]. 

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