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Nazarov Cyclization

(Nazarov Reaction)

Published Online: 15 SEP 2010

DOI: 10.1002/9780470638859.conrr452

Comprehensive Organic Name Reactions and Reagents

Comprehensive Organic Name Reactions and Reagents

How to Cite

2010. Nazarov Cyclization. Comprehensive Organic Name Reactions and Reagents. 452:2011–2016.

Publication History

  1. Published Online: 15 SEP 2010

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Abstract

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

Nazarov cyclization, or Nazarov reaction is an acid-promoted cationic pericyclic reaction that transforms a divinyl ketone into 2-cyclopentenone. This reaction undergoes a 4-π electrocyclic, conrotatory cyclization via a 3-oxy-pentadienylic cation and requires of strong Brønsted acid or Lewis acid. Many complicated Lewis acids have been used for this reaction. This reaction gives a thermodynamically favored cyclopentenone with more substituents. Alkoxy on a vinyl group, or the presence of a bridge-headed proton on the endocyclic intermediate facilitates the protic acid-promoted cyclization. Denmark has developed the directed Nazarov cyclization and Ichikawa has developed the other form to control the regiochemistry. The interrupted Nazarov reaction has also been developed to extend the reaction of the cationic endocyclic intermediate with carbon nucleophiles.

1 General Description of the Reaction

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

This reaction was first reported by Nazarov et al. in 1942. 1 It is an acid-promoted cationic pericyclic reaction that transforms a divinyl ketone into 2-cyclopentenone. Therefore, it is generally known as the Nazarov cyclization, 2 or Nazarov reaction. (2bb, 3) In general, this reaction requires 1 eq. of strong Brønsted acid or Lewis acid (2q, 4) and undergoes a 4-π electrocyclic, conrotatory cyclization (2q, 2u, 2v, 3m, 3n, 5) via a 3-oxy-pentadienylic cation. (2q, 5) Although this reaction gives a thermodynamically favored cyclopentenone with more substituents, (2tt, 6) the classical reaction protocol generally lacks control over the position of the endocyclic double bond (Scheme 1). 6, 7 It has been found that the presence of an electron-donating group such as alkoxy on a vinyl group, 8 or the presence of a bridge-headed proton on the endocyclic intermediate (2w) facilitates the protic acid-promoted cyclization. Besides the conventional Lewis acid catalysts, such as BF3·Et2O, (2q, 4, 9) SnCl4, (2q, 4 TiCl4, (2q, 4, 9) and AlCl3, (2q, 4) more complicated Lewis acids have also been used for this reaction, such as TMSOTf, (3s, 7a) Cu(OTf)2, (2q, 3s, 4) PdCl2(MeCN)2, 10 Sc(pybox)(OTf)3, (2u) Cu(pybox)(OTf)2, (2v) dicationic Ir(III) complex [IrMe(CO)(dppe)-(DIB)](BARF)2 (where dppe = bis(diphenylphosphino)ethane, DIB = o-diiodobenzene, and BARF = [B(3,5-C6H3(CF3)2)4]), (2q) and montmorillonite clay K10. 11 In addition, MeSO3H was found to be a superior protic acid for the Nazarov reaction. (3s)

It should be pointed out that this reaction has been carried out photochemically (2v) (i.e., the photo-Nazarov cyclization (2x, 2y, 12)), or under near-critical water conditions. (3m) More importantly, it has been improved to occur in a controllable fashion, through a directed Nazarov cyclization or an interrupted Nazarov reaction. (2zz, 3h, 3k, 3u, 3v) It is worth noting that two practically directed Nazarov cyclizations have been developed, one by Denmark by using the β-cation stabilizing effect and electrofuge of silicon (Scheme 2), (2oo, 2tt, 6, 13) and the other from Ichikawa by application of a β-cation destabilizing effect and the α-electron-donating effect of fluorine (2ii, 7) to control the regiochemistry (Scheme 3). Analogous to silicon, tin is also used to direct the Nazarov cyclization. 14 The interrupted Nazarov reaction has been developed by West et al. to extend the reaction of the cationic endocyclic intermediate with carbon nucleophiles. (3l, 9, 15) Furthermore, this reaction has been extended to imino-Nazarov cyclization of vinyl allenyl imine. 12, 16

2 General Reaction Scheme

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References
original image

Scheme 1. Classical Nazarov cyclization.

original image

Scheme 2. Silicon-directed Nazarov cyclization.

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Scheme 3. Fluorine-directed Nazarov cyclization.

4 Modification

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References

This reaction has been extensively modified by the application of different Lewis acids as catalysts.

7 Cited Experimental Examples

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References
original image

Reference 3l.

A solution of 50 mg dienone (0.19 mmol) in 19 mL CH2Cl2 was cooled to −78°C, and 94 μL BF3·OEt2 (0.76 mmol) was added. After 10 min, the reaction was allowed to warm to 0°C and was stirred for 8 h. Water (10 mL) was added, and the phases were separated. The aqueous layer was washed with Et2O (2 × 15 mL), and the organic layers were combined, dried over MgSO4, filtered, and concentrated to give a colorless oil. Silica gel radial chromatography (2 mm rotor; 9:1, hexanes/EtOAc) furnished 25 mg mixed cyclopentenone in a ratio of 10:1, in a yield of 75 %. Careful chromatography of this mixture produced pure exo-diastereomer as a colorless oil, Rf = 0.37 (hexane/EtOAc, 9:1), and endo-diastereomer, Rf = 0.34 (hexane/EtOAc, 9:1).

original image

Reference 3k.

To a solution of 147 mg 3-methoxy-1-triisopropylsilyl propyne (0.65 mmol) in 3 mL THF at −78°C was added 0.25 mL 2.5 M n-BuLi in hexanes (0.63 mmol). After 30 min, a solution of 125 mg enamide (0.54 mmol) in 1 mL THF was added dropwise via cannula. The reaction was stirred at −78°C for 1 h, quenched with 1 M HCl, and diluted with ether. The aqueous phase was extracted with Et2O three times, and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. Removal of a trace solvent was done under high vacuum for 1 h. The crude product was transferred to a 4-dram vial charged with two glass beads. To a separate 4-dram vial containing 540 mg activated silica gel (9.0 mmol) was added 90 μL triethylamine (0.65 mmol). The mixture was stirred for 10 min and then transferred to the vial that contained the crude enone. The reaction was stirred at room temperature for 3 h. Direct purification of the reaction mixture by silica gel flash column chromatography with 5 % EtOAc in hexanes gave cyclopentenone (126 mg) as a colorless oil, in a yield of 63 %, Rf = 0.33 (5 % EtOAc in hexanes).

Other references related to the Nazarov cyclization are cited in the literature. 17

References

  1. Top of page
  2. General Description of the Reaction
  3. General Reaction Scheme
  4. Proposed Mechanisms
  5. Modification
  6. Applications
  7. Related Reactions
  8. Cited Experimental Examples
  9. References