Download PDF
Synthesis 2006(4): 680-686  
DOI: 10.1055/s-2006-926307
PAPER
© Georg Thieme Verlag Stuttgart · New York

Sodium Borohydride as the Only Reagent for the Efficient Reductive Alkylation­ of Malononitrile with Ketones and Aldehydes

Jason C. Dunham, Adam D. Richardson, Robert E. Sammelson*
Department of Chemistry, Ball State University, Muncie, IN 47306-0445, USA
Fax: +1(765)2856505; e-Mail: resammelson@bsu.edu;
Further Information

Publication History

Received 1 August 2005
Publication Date:
19 January 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

An efficient and convenient method for the synthesis of primary and secondary monosubstituted malononitriles has been developed. In this method, sodium borohydride in isopropanol has a catalytic effect on the initial condensation between malononitrile and aldehydes or ketones at 0 °C. The sodium borohydride also simultaneously acts as a reagent and reduces the unsaturated intermediate formed in situ by the condensation. This simple reductive alkylation method effectively consumes all malononitrile and selectively produces only monosubstituted malononitriles. Unsymmetrically disubstituted malononitriles are prepared via alkylation of these monosubstituted derivatives.

Key words

malononitrile - ketones - aldehydes - condensations - reductions

    References

  • 1a Qian F. McCusker JE. Zhang Y. Main AD. Chlebowski M. Kokka M. McElwee-White L. J. Org. Chem.  2002,  67:  4086 
    CrossrefGoogle Scholar
  • 1b Bloomfield JJ. J. Org. Chem.  1961,  26:  4112 
    CrossrefGoogle Scholar
  • 2a Wu Z.-L. Li Z.-Y. J. Org. Chem.  2003,  68:  2479 
    CrossrefGoogle Scholar
  • 2b Meguro M. Yamamoto Y. J. Org. Chem.  1999,  64:  694 
    CrossrefGoogle Scholar
  • 2c Díez-Barra E. de la Hoz A. Moreno A. Sánchez-Verdú P. J. Chem. Soc., Perkin Trans. 1  1991,  2589 
    CrossrefGoogle Scholar
  • 3a Texier-Boullet F. Foucaud A. Tetrahedron Lett.  1982,  23:  4927 
    CrossrefGoogle Scholar
  • 3b Cabello JA. Campelo JM. Garcia A. Luna D. Marinas JM. J. Org. Chem.  1984,  49:  5195 
    CrossrefGoogle Scholar
  • 3c Prout FS. J. Org. Chem.  1953,  18:  928 
    CrossrefGoogle Scholar
  • 4a Garden SJ. Guimarães CRW. Corréa MB. de Oliveira CAF. da Cunha Pinto A. de Alencastro RB. J. Org. Chem.  2003,  68:  8815 
    CrossrefGoogle Scholar
  • 4b Zhang B. Zhu X.-Q. Lu J.-Y. He J. Wang PG. Cheng J.-P. J. Org. Chem.  2003,  68:  3295 
    CrossrefGoogle Scholar
  • 4c Ranu BC. Dutta J. Guchhait SK. Org. Lett.  2001,  3:  2603 
    CrossrefGoogle Scholar
  • 4d Ranu BC. Samanta S. Tetrahedron  2003,  59:  7901 
    CrossrefGoogle Scholar
  • 5 Sammelson RE. Allen MJ. Synthesis  2005,  543 
    Article in Thieme ConnectGoogle Scholar
  • 6 Zhang Z. Gao J. Xia J.-J. Wang G.-W. Org. Biomol. Chem.  2005,  3:  1617 
    CrossrefGoogle Scholar
  • 7 Brown HC. Wheeler OH. Ichikawa K. Tetrahedron  1957,  1:  214 
    CrossrefGoogle Scholar
  • 9 Chiriac CI. Tanasa F. Onciu M. Tetrahedron Lett.  2003,  44:  3579 
    CrossrefGoogle Scholar
  • 10 Condensation of malononitrile with acetone-d 6 was observed in this lab using NMR and TLC but complete condensation without any catalyst takes more than 24 h at r.t. A solution of malononitrile and acetone in i-PrOH (0.5 M and 1.0 M, respectively; similar to our reaction conditions, but without NaBH4) only produces small amounts (ca. 20%) of condensation product after 24 h at r.t. when analyzed by TLC. For a recent report on the Knoevenagel condensation of malononitrile with aromatic aldehydes in EtOH without catalyst, see: Wang X.-S. Zeng Z.-S. Li Y.-L. Shi D.-Q. Tu S.-J. Wei X.-Y. Zong Z.-M. Synth. Commun.  2005,  35:  1915 
    CrossrefGoogle Scholar
  • 11 Desai UV. Pore DM. Mane RB. Solabannavar SB. Wadgaonkar PP. Synth. Commun.  2004,  34:  25 
    CrossrefGoogle Scholar
  • 12a For information about Meldrum’s acid pKa = 7.3 in DMSO, see: Arnett EM. Maroldo SG. Schilling SL. Harrelson JA. J. Am. Chem. Soc.  1984,  106:  6759 
    CrossrefGoogle Scholar
  • 12b For information about malononitrile pKa = 11.1 in DMSO, see: Matthews WS. Bares JE. Bartmess JE. Bordwell FG. Cornforth FJ. Drucker GE. Margolin Z. McCallum RJ. McCollum GJ. Vanier NR. J. Am. Chem. Soc.  1975,  97:  7006 
    CrossrefGoogle Scholar
  • 13a Okada S, Oohira D, and Otaka K. inventors; PCT Int. Appl. WO 2004020399,  .  ; Chem. Abstr. , 140, 235428
  • 13b Otaka T, and Ohira D. inventors; Jpn. Kokai Tokkyo Koho JP 2004099597,  .  ; Chem. Abstr. , 140, 303517
  • 13c Otaka K, Oohira D, and Suzuki M. inventors; PCT Int. Appl. WO 2002090321,  .  ; Chem. Abstr. , 137, 352788
  • 13d Otaka K, Suzuki M, and Oohira D. inventors; PCT Int. Appl. WO 2002089579,  .  ; Chem. Abstr. , 137, 369842
  • 14 Yokoyama M. Kashiwagi M. Iwasaki M. Fuhshuku K. Ohta H. Sugai T. Tetrahedron: Asymmetry  2004,  15:  2817 
    CrossrefGoogle Scholar
  • 16 Wada M. Mitsunobu O. Tetrahedron Lett.  1972,  13:  1279 
    CrossrefGoogle Scholar
  • 17 Echevarria A. Martin M. Perez C. Rozas I. Arch. Pharm. (Weinheim, Ger.)  1994,  327:  303 
    CrossrefGoogle Scholar
  • 18 Chikashita H. Nishida S. Miyazaki M. Morita Y. Itoh K. Bull. Chem. Soc. Jpn.  1987,  60:  737 
    CrossrefGoogle Scholar
  • 20 Bauer T. Thomann R. Mülhaupt R. Macromolecules  1998,  31:  7651 
    CrossrefGoogle Scholar
8

Isolated yield for the previous one-pot method (ref. 5) was 83% and the reaction time was 10 min for the condensation step. The current yield was 78% in ≤6 min for both steps.

15

The second portion of NaBH4 was added after 90 min.

19

Additional trimethylacetaldehyde was added after 60 min.

21

The second portion of NaBH4 was added after 20 min.