Synlett 2009(4): 681-682  
DOI: 10.1055/s-0028-1087716
SPOTLIGHT
© Georg Thieme Verlag Stuttgart ˙ New York

Methyl Cyanoformate (Mander’s Reagent)

Alex C. Bissember*
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia.
e-Mail: alexb@rsc.anu.edu.au;

Further Information

Publication History

Publication Date:
16 February 2009 (online)

Biographical Sketches

Alex Bissember was born in London in 1983. He received a B.Sc. (Honors) in Chemistry from The Australian National University (ANU) in 2005 and is now working towards his Ph.D. under the supervision of Prof. Martin Banwell at The Research School of Chemistry (ANU). His current research is focused on the development of new methods for the synthesis of biologically active heterocycles.

Introduction

Methyl cyanoformate, Mander’s reagent (Figure  [¹] ), is most commonly employed to effect the regiocontrolled synthesis of β-keto esters through the C-acylation of preformed lithium enolates. [¹] [²] It is superior to more traditional reagents such as acyl halides, anhydrides and carbon dioxide because these can also produce variable amounts of the corresponding O-acylated products. [³] In addition to its aforementioned electrophilic behaviour, methyl cyanoformate has also been employed as a dipolarophile [4] that reacts with an α-diazo-β-imido ester and, in the presence of polyoxotungstate, as a radical cyanating agent. [5] Its ­homologue ethyl cyanoformate also behaves as a dipolarophile [6] and has been used to form substituted tetrazoles. It has also been employed in the preparation of α-keto esters. [7]

Methyl cyanoformate is a commercially available, colourless liquid that is readily prepared in small quantities (up to 30 g) by treating methyl chloroformate with potassium cyanide in the presence of a phase transfer catalyst such as 18-crown-6 [8] or tetra-n-butylammonium bromide. [9]

Figure 1 Methyl Cyanoformate

Abstracts

(A) Numerous syntheses of natural products and related compounds have featured the use of methyl cyanoformate to prepare β-keto ­esters. In the first total syntheses of (+)-lyconadin A and (-)-lyconadin B, Smith and co-workers [¹0] employed Mander’s reagent for precisely this purpose.

(B) The title reagent was used to prepare an acetylenic ester that served as an early stage intermediate in the first asymmetric total synthesis of (-)-platensimycin reported by Nicolaou and co-workers. [¹¹]

(C) Ethyl cyanoformate has been shown to engage in a copper(I)-catalyzed [3+2] dipolar cycloaddition with various organoazides, including benzylazide, to afford the corresponding 1,5-disubstituted tetrazoles. [6]

(D) Nájera and co-workers reported the one-step synthesis of various chiral cyanocarbonates from a range of aldehydes using the title reagent in the presence of chiral bifunctional catalysts such as (R)- or (S)-BINOLAM-AlCl. [¹²] [¹³] It is believed that the catalytic cycle involves enantioselective hydrocyanation promoted by BINOLAM-AlCl, followed by the turnover-limiting O-alkoxycarbonylation step.

(E) Hill and Zheng have reported that irradiation (λ > 280 nm) of mixtures of various alkanes and methyl cyanoformate in the presence of either W10O32 4- or PW12O40 ³- produces the corresponding ­nitrile or α-iminoester, respectively. [5] Such reactions can be highly selective if proper temperature controls are applied. An iminyl radical intermediate is thought to be involved in these conversions.

(F) Nishihara and co-workers have described the highly stereoselective and palladium-catalyzed addition of methyl cyanoformate across norbornene-type double bonds and so affording norbornanes bearing both cyano and ester groups. [¹4] It is believed that the complex trans-Pd(CN)(CO2Me)(Ph3P)2 is an intermediate in the catalytic cycle associated with this cyanoesterification process. [¹5]

(G) Shimizu and Murakami have effected the selective formation of α-keto esters by the rhodium-catalyzed reaction of ethyl cyanoformate with arylboronic acids. [7] The observed conversion arises through preferential addition of an intermediate rhodium(I) species to the cyano group rather than to the ester carbonyl group. This conversion stands in sharp contrast to the outcomes observed when ­ethyl cyanoformate reacts with either phenyllithium or phenyl­magnesium bromide so as to afford ethyl benzoate. [7]

    References

  • 1 Mander L. Sethi SP. Tetrahedron Lett.  1983,  24:  5425 
  • 2 Crabtree SR. Mander L. Sethi SP. Org. Synth.  1991,  70:  256 
  • 3 House HO. Modern Synthetic Reactions   Benjamin; Menlo Park: 1972.  p.760-763,   and references cited therein
  • 4 Looper R. Pizzirani D. Schreiber SL. Org. Lett.  2006,  8:  2063 
  • 5 Zheng Z. Hill CL. Chem. Commun.  1998,  2467 
  • 6 Bosch L. Vilarrasa J. Angew. Chem. Int. Ed.  2007,  46:  3926 
  • 7 Shimizu H. Murakami M. Chem. Commun.  2007,  2855 
  • 8 Childs ME. Weber WP. J. Org. Chem.  1976,  41:  3486 
  • 9 Nii Y. Okano K. Kobayashi S. Ohno M. Tetrahedron Lett.  1979,  20:  2517 
  • 10 Beshore DC. Smith AB. J. Am. Chem. Soc.  2007,  129:  4148 
  • 11 Nicolaou KC. Edmonds DJ. Li A. Tria GS. Angew. Chem. Int. Ed.  2007,  46:  3942 
  • 12 Baeza A. Casas J. Nájera C. Sansano J. J. Org. Chem.  2006,  41:  3837 
  • 13 Baeza A. Casas J. Nájera C. Sansano J. Saá JM. Eur. J. Org. Chem.  2006,  1949 
  • 14 Nishihara Y. Inoue Y. Izawa S. Miyasaka M. Tanemura K. Nakajima K. Takagi K. Tetrahedron  2006,  62:  9872 
  • 15 Nishihara Y. Inoue Y. Izawa S. Miyasaka M. Yamaguchi T. Kojima M. Takagi K. Organometallics  2007,  26:  4054 

    References

  • 1 Mander L. Sethi SP. Tetrahedron Lett.  1983,  24:  5425 
  • 2 Crabtree SR. Mander L. Sethi SP. Org. Synth.  1991,  70:  256 
  • 3 House HO. Modern Synthetic Reactions   Benjamin; Menlo Park: 1972.  p.760-763,   and references cited therein
  • 4 Looper R. Pizzirani D. Schreiber SL. Org. Lett.  2006,  8:  2063 
  • 5 Zheng Z. Hill CL. Chem. Commun.  1998,  2467 
  • 6 Bosch L. Vilarrasa J. Angew. Chem. Int. Ed.  2007,  46:  3926 
  • 7 Shimizu H. Murakami M. Chem. Commun.  2007,  2855 
  • 8 Childs ME. Weber WP. J. Org. Chem.  1976,  41:  3486 
  • 9 Nii Y. Okano K. Kobayashi S. Ohno M. Tetrahedron Lett.  1979,  20:  2517 
  • 10 Beshore DC. Smith AB. J. Am. Chem. Soc.  2007,  129:  4148 
  • 11 Nicolaou KC. Edmonds DJ. Li A. Tria GS. Angew. Chem. Int. Ed.  2007,  46:  3942 
  • 12 Baeza A. Casas J. Nájera C. Sansano J. J. Org. Chem.  2006,  41:  3837 
  • 13 Baeza A. Casas J. Nájera C. Sansano J. Saá JM. Eur. J. Org. Chem.  2006,  1949 
  • 14 Nishihara Y. Inoue Y. Izawa S. Miyasaka M. Tanemura K. Nakajima K. Takagi K. Tetrahedron  2006,  62:  9872 
  • 15 Nishihara Y. Inoue Y. Izawa S. Miyasaka M. Yamaguchi T. Kojima M. Takagi K. Organometallics  2007,  26:  4054 

Figure 1 Methyl Cyanoformate