Synlett 2009(19): 3221-3223  
DOI: 10.1055/s-0029-1218382
SPOTLIGHT
© Georg Thieme Verlag Stuttgart ˙ New York

Petasis Reagent

Carine Vaxelaire
Faculté des Sciences Pharmaceutiques et Biologiques, Avenue de l′Observatoire 4, 75270 Paris, France
e-Mail: carine.vaxelaire@univ-paris5.fr;

Further Information

Publication History

Publication Date:
13 November 2009 (online)

Biographical Sketches

Carine Vaxelaire was born in Remiremont, France, in 1982. She studied chemistry at the engineering school CPE-Lyon and at the University of Lyon, France. Currently, she is pursuing her Ph.D. ­under the supervision of Professor Janick Ardisson and Dr. Ange Pancrazi at the Paris Descartes University, France. Her research is focused on the total synthesis of a natural molecule using multistep synthesis.

Introduction

The Petasis reagent [¹] (dimethyl titanocene, Cp2TiMe2) is readily prepared by the reaction of methylmagnesium chloride [²] or methyllithium [³] with titanocene dichloride. It is used for transforming carbonyl groups to terminal al­kenes, [4] like the Tebbe reagent or Wittig reaction. Unlike the Wittig reaction, the Petasis reagent can react with a wide range of carbonyls, such as aldehydes, ketones, ­esters, and lactones including enolizable and acid-labile substrates. The Petasis reagent is also non-pyrophoric, relatively air- and water-stable, and can be used directly as a solution in toluene-THF.

The active olefinating reagent, Cp2TiCH2, can be prepared by heating the Petasis reagent in toluene or THF to 60-75 ˚C. The Petasis reaction can also be promoted by microwave irradiation.

Scheme 1

Abstracts

(A) Adehydes and ketones can be selectively methylenated in the presence of less electrophilic carbonyls groups such as esters [¹a] [5] and amides. [6]

(B) Reaction of dimethyl titanocene with heteroatom-substituted carbonyls, [¹b] such as silylesters, lactones, [7] thioesters, selenoesters, and acylsilanes gives the corresponding heteroatom-substituted al­kenes.

(C) Petasis methylenation can be accomplished in the presence of many protecting groups, like silyl ethers, [8] benzyl ethers, [9] and acetals. [¹0] The reaction in the presence of an unprotected hydroxyl group [¹¹] can also be efficient when an excess of the reagent is used.

(D) The selectivity of this reaction has been extended to unsymmetrical oxalates [¹²] and oxalate monoesters or monoamides. Improvement of the methylenation can be promoted by microwave irradiation. [¹³]

(E) The reaction of β-lactams with Cp2TiMe2 can be realized in good yields as long as the lactams are properly activated by N-protection. [¹4]

(F) Homologue dialkyltitanocene derivatives of the Petasis reagent can be prepared from titanocene dichloride and alkyllithium or Grignard reagents, [¹5] with the exception of compounds that undergo facile β-hydride elimination.

(G) The Petasis reagent has been utilized in a tandem methylen­ation-claisen rearrangement to give ring extension [¹6] or contraction. [¹7]

(H) One application of the Petasis reagent is the Petasis-Ferrier rearrangement, [¹8] which involves methylenation of a 1,3-dioxan-4-one to give an enol ether which yields in the presence of a trialkylaluminium reagent a 2,6-syn-disubstitued tetrahydropyranone. This method has been utilized as an exceptional powerful tool for the total synthesis of complex natural product. [¹9]

(I) A one-pot methylenation-RCM procedure has been developed by Nicolaou [²0] using Petasis reagent as both methylenation reagent and RCM catalyst.

(J) A one-carbon homologation was achieved using Petasis methylenation followed by acid hydrolysis. [²¹]

    References

  • 1a Petasis NA. Bzowej EI. J. Am. Chem. Soc.  1990,  112:  6392 
  • 1b Petasis NA. Lu SP. Tetrahedron Lett.  1995,  36:  2393 
  • 2 Payack JF. Hughes DL. Cai D. Cottrell IF. Verhoeven TR. Org. Synth.  2002,  79:  19 
  • 3 Clauss K. Bestian H. Justus Liebigs Ann. Chem.  1962,  654: 
  • 4 Hartley RC. McKiernan GJ. J. Chem. Soc., Perkin Trans. 1  2002,  2763 
  • 5 Colson PJ. Hegedus LS. J. Org. Chem.  1993,  58:  5918 
  • 6 Atarashi S. Choi JK. Ha DC. Hart FJ. Kuzmich D. Lee CS. Ramesh S. Wu SC. J. Am. Chem. Soc.  1997,  119:  6226 
  • 7a Morency L. Barriault L. J. Org. Chem.  2005,  70:  8841 
  • 7b Smith ABIII. Simon V. Org. Lett.  2006,  8:  3315 
  • 8a Lambert WT. Hanson GH. Benayoud F. Burke SD. J. Org. Chem.  2005,  70:  9382 
  • 8b Gaunt MJ. Jessiman AS. Orsini P. Tanner HR. Hook DF. Ley SV. Org. Lett.  2003,  5:  4819 
  • 9 Heskamp BM. Veeneman GH. van der Marel GA. Van Boeckel CAA. Van Boom JH. Tetrahedron  1995,  51:  8397 
  • 10 Johns BA. Pan YT. Elbein AD. Johnson CR. J. Am. Chem. Soc.  1997,  119:  4856 
  • 11 Li X. Ohtake H. Takahashi H. Ikegami S. Synlett  2001,  1885 
  • 12a Chenault HK. Chafin LF. J. Org. Chem.  1994,  59:  6167 
  • 12b Chenault HK. Castro A. Chafin LF. Yang J. J. Org. Chem.  1996,  61:  5024 
  • 13 Cook MJ. Fleming DW. Gallagher T. Tetrahedron Lett.  2005,  46:  297 
  • 14 Martinez I. Howell AR. Tetrahedron Lett.  2000,  41:  5607 
  • 15a Petasis NA. Bzowej EI. J. Org. Chem.  1992,  57:  1327 
  • 15b Petasis NA. Akritopoulou I. Synlett  1992,  665 
  • 15c Petasis NA. Bzowej EI. Tetrahedron Lett.  1993,  34:  943 
  • 16a Davidson JEP. Anderson EA. Buhr W. Harrisson JR. O’Sullivan PT. Collins I. Green RH. Holmes AB. Chem. Commun.  2000,  629 
  • 16b Anderson EA. Davidson JEP. Harrison JR. O’Sullivan PT. Burton JW. Holmes AB. Tetrahedron  2002,  58:  1943 
  • 17 Petasis NA. Bzowej EI. Tetrahedron Lett.  1993,  34:  1721 
  • 18 Petasis NA. Lu S.-P. Tetrahedron Lett.  1996,  37:  141 
  • Few examples:
  • 19a Smith AB. Mesaros EF. Meyer EA. J. Am. Chem. Soc.  2006,  128:  5292 
  • 19b Smith ABIII. Simov V. Org. Lett.  2006,  8:  3315 
  • 19c Smith ABIII. Minibiole KP. Verhoest PR. Beauchamp TJ. Org. Lett.  1999,  1:  913 
  • 20 Nicolaou KC. Postema MHD. Claiborne CF. J. Am. Chem. Soc.  1996,  118:  1565 
  • 21 (a) Taber DF. Kong S. Malcolm SC. J. Org. Chem.  1998,  63:  7953 
  • 21 (b) Panda J. Ghosh S. J. Chem. Soc., Perkin Trans. 1  2001,  3013 
  • 21 (c) Donohoe TJ. Guillermin J.-B. Frampton C. Walter DS. Chem. Commun.  2000,  465 

    References

  • 1a Petasis NA. Bzowej EI. J. Am. Chem. Soc.  1990,  112:  6392 
  • 1b Petasis NA. Lu SP. Tetrahedron Lett.  1995,  36:  2393 
  • 2 Payack JF. Hughes DL. Cai D. Cottrell IF. Verhoeven TR. Org. Synth.  2002,  79:  19 
  • 3 Clauss K. Bestian H. Justus Liebigs Ann. Chem.  1962,  654: 
  • 4 Hartley RC. McKiernan GJ. J. Chem. Soc., Perkin Trans. 1  2002,  2763 
  • 5 Colson PJ. Hegedus LS. J. Org. Chem.  1993,  58:  5918 
  • 6 Atarashi S. Choi JK. Ha DC. Hart FJ. Kuzmich D. Lee CS. Ramesh S. Wu SC. J. Am. Chem. Soc.  1997,  119:  6226 
  • 7a Morency L. Barriault L. J. Org. Chem.  2005,  70:  8841 
  • 7b Smith ABIII. Simon V. Org. Lett.  2006,  8:  3315 
  • 8a Lambert WT. Hanson GH. Benayoud F. Burke SD. J. Org. Chem.  2005,  70:  9382 
  • 8b Gaunt MJ. Jessiman AS. Orsini P. Tanner HR. Hook DF. Ley SV. Org. Lett.  2003,  5:  4819 
  • 9 Heskamp BM. Veeneman GH. van der Marel GA. Van Boeckel CAA. Van Boom JH. Tetrahedron  1995,  51:  8397 
  • 10 Johns BA. Pan YT. Elbein AD. Johnson CR. J. Am. Chem. Soc.  1997,  119:  4856 
  • 11 Li X. Ohtake H. Takahashi H. Ikegami S. Synlett  2001,  1885 
  • 12a Chenault HK. Chafin LF. J. Org. Chem.  1994,  59:  6167 
  • 12b Chenault HK. Castro A. Chafin LF. Yang J. J. Org. Chem.  1996,  61:  5024 
  • 13 Cook MJ. Fleming DW. Gallagher T. Tetrahedron Lett.  2005,  46:  297 
  • 14 Martinez I. Howell AR. Tetrahedron Lett.  2000,  41:  5607 
  • 15a Petasis NA. Bzowej EI. J. Org. Chem.  1992,  57:  1327 
  • 15b Petasis NA. Akritopoulou I. Synlett  1992,  665 
  • 15c Petasis NA. Bzowej EI. Tetrahedron Lett.  1993,  34:  943 
  • 16a Davidson JEP. Anderson EA. Buhr W. Harrisson JR. O’Sullivan PT. Collins I. Green RH. Holmes AB. Chem. Commun.  2000,  629 
  • 16b Anderson EA. Davidson JEP. Harrison JR. O’Sullivan PT. Burton JW. Holmes AB. Tetrahedron  2002,  58:  1943 
  • 17 Petasis NA. Bzowej EI. Tetrahedron Lett.  1993,  34:  1721 
  • 18 Petasis NA. Lu S.-P. Tetrahedron Lett.  1996,  37:  141 
  • Few examples:
  • 19a Smith AB. Mesaros EF. Meyer EA. J. Am. Chem. Soc.  2006,  128:  5292 
  • 19b Smith ABIII. Simov V. Org. Lett.  2006,  8:  3315 
  • 19c Smith ABIII. Minibiole KP. Verhoest PR. Beauchamp TJ. Org. Lett.  1999,  1:  913 
  • 20 Nicolaou KC. Postema MHD. Claiborne CF. J. Am. Chem. Soc.  1996,  118:  1565 
  • 21 (a) Taber DF. Kong S. Malcolm SC. J. Org. Chem.  1998,  63:  7953 
  • 21 (b) Panda J. Ghosh S. J. Chem. Soc., Perkin Trans. 1  2001,  3013 
  • 21 (c) Donohoe TJ. Guillermin J.-B. Frampton C. Walter DS. Chem. Commun.  2000,  465 

Scheme 1