Download PDF
Synlett 2003(2): 0265-0267
DOI: 10.1055/s-2003-36785
LETTER
© Georg Thieme Verlag Stuttgart · New York

Ti-Mediated Chemoselective Conversion of Cyanoesters and Cyanoamides into β-Aminoesters and 1-Aza-spirolactams Bearing a Cyclopropane Ring.

Philippe Bertus, Jan Szymoniak*
Réactions Sélectives et Applications, CNRS and Université de Reims, 51687 Reims Cedex 2, France
Fax: +33(326)913431; e-Mail: jan.szymoniak@univ-reims.fr;
Further Information

Publication History

Received 2 December 2002
Publication Date:
22 January 2003 (online)

    Permissions and Reprints All articles of this category

Abstract

α-Cyanoesters or tertiary α-cyanoamides react with Grignard reagents and Ti(i-PrO)4 to afford respectively β-amino esters or amides, bearing a cyclopropane ring. Starting from β- or γ-cyanoesters, spirocyclopropanelactams are formed via an in situ cyclopropanation-lactamization sequence.

Key words

cyclizations - cyclopropanes - nitriles - spiro compounds - titanium

    References

  • 1 Bertus P. Szymoniak J. Chem. Commun.  2001,  1792 
    CrossrefGoogle Scholar
  • 2 Bertus P. Szymoniak J. J. Org. Chem.  2002,  67:  3965 
    CrossrefGoogle Scholar
  • 3a Kulinkovich OG. Sviridov SV. Vasilevsky DA. Pritytskaja TS. Russ. J. Org. Chem.  1989,  25:  2027 
    Article in Thieme ConnectGoogle Scholar
  • 3b Kulinkovich OG. Sviridov SV. Vasilevsky DA. Synthesis  1991,  234 
    Article in Thieme ConnectGoogle Scholar
  • For reviews, see:
  • 4a de Meijere A. Kozhushkov SI. Savchenko AI. In Titanium and Zirconium in Organic Synthesis   Marek I. Wiley-VCH; Weinheim: 2002.  p.390 
    Google Scholar
  • 4b Kulinkovich OG. de Meijere A. Chem. Rev.  2000,  100:  2789 
    Google Scholar
  • 5 Lee J. Kim YG. Bae JG. Cha JK. J. Org. Chem.  1996,  61:  4878 
    CrossrefGoogle Scholar
  • 6a Chaplinski V. de Meijere A. Angew. Chem., Int. Ed. Engl.  1996,  35:  413 
    CrossrefGoogle Scholar
  • 6b Lee J. Cha JK. J. Org. Chem.  1997,  62:  1584 
    CrossrefGoogle Scholar
  • 7 Carboxylic esters have been demonstrated to be generally more reactive towards the cyclopropanation reaction than the corresponding amides, see: Cho SY. Lee J. Lammi RK. Cha JK. J. Org. Chem.  1997,  62:  8235 
    CrossrefGoogle Scholar
  • For recent reviews on the use and preparation of β-amino acids, see:
  • 11a Steer DA. Lew RA. Perlmutter P. Smith AI. Aguilar MI. Curr. Med. Chem.  2002,  9:  811 
    Google Scholar
  • 11b Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 
    Google Scholar
  • 13 These spirocyclopropanelactams cannot be directly prepared from cyclic imides using the same procedure (Grignard reagent and titanium isopropoxide), since the resulting titanaoxacyclopentanes do not lead to cyclopropane formation. See: Lee J. Ha JD. Cha JK. J. Am. Chem. Soc.  1997,  119:  8127 
    CrossrefGoogle Scholar
  • 14 The spirolactam 16, being a γ-aminobutyric acid (GABA) analogue, has already been prepared, in several steps. See: Kordes M. Winsel H. de Meijere A. Eur. J. Org. Chem.  2000,  3235 
    CrossrefGoogle Scholar
8

Under the same cyclopropanation conditions, the ester 2 alone or the amide 3 alone give cyclopropanol 5 (66% yield) or cyclopropylamine 6 (40%) respectively, irrespective of the addition of BF3·OEt2.

9

No cyclopropane-containing product was obtained from ethyl cyanoacetate, probably due to the presence of acidic hydrogens.

10

Typical procedure for the synthesis of 8, 10, 12 and 14: Ethyl 1′-aminobicyclopropyl-1-carboxylate 10: To a solution of nitrile 9 (139 mg, 1 mmol) and Ti(i-PrO)4 (0.33 mL, 1.1 mmol) in anhydrous Et2O (5 mL), was added dropwise at room temperature a solution of EtMgBr in Et2O (2 mmol). After the mixture was stirred for 1 h, BF3·OEt2 (0.25 mL, 2 mmol) was added. After additional stirring for 30 min, water (1 mL) was added, followed by 10% aq HCl (10 mL) and CH2Cl2 (20 mL). A 10% aq NaOH 10% solution was added to the resulting clear mixture until the pH became basic. The product was extracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were dried (Na2SO4). After evaporation of the solvent, the product was purified by flash chromatography on silica gel (Et2O, then acetone) to afford 83 mg (49%) of 10 as a pale yellow oil. IR (KBr): 3373, 1719, 1311 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.35-0.39 (m, 2 H), 0.60-0.69 (m, 4 H), 1.15-1.21 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H), 2.15 (s, 2 H), 4.15 (q, J = 7.1 Hz, 2 H). 13C NMR (126 MHz, CDCl3): δ = 13.1, 14.2, 14.7, 30.5, 34.9, 60.5, 174.8. MS (EI, 70 eV), m/z (%): 169 (4, M+),154 (18), 140 (34), 123 (60), 112 (78), 94 (100).

12

Typical procedure for the synthesis of 16, 18, 20 and 22: 4-Azaspiro[2.5]octan-5-one 18: To a solution of nitrile 17 (141 mg, 1 mmol) and Ti(i-PrO)4 (0.33 mL, 1.1 mmol) in anhydrous Et2O (5 mL), was added dropwise at room temperature a solution of EtMgBr in Et2O (2 mmol). After the mixture was stirred for 1 h, water (1 mL) was added, followed by CH2Cl2 (20 mL). The resulting precipitate was removed and washed with CH2Cl2 (2 × 10 mL). The combined organic extracts were dried (Na2SO4). After evaporation of the solvent, the product was purified by flash chromatography on silica gel (Et2O, then Et2O-MeOH, 95:5) to afford 80 mg (63%) of 18 as a white solid, mp 124-125 °C. IR (KBr): 3183, 3058, 2951, 1655, 1404 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.58-0.66 (m, 2 H), 0.69-0.76 (m, 2 H), 1.61-1.67 (m, 2 H), 1.83-1.95 (m, 2 H), 2.37 (t, J = 6.7 Hz, 2 H), 7.08 (s, 1 H). 13C NMR (63 MHz, CDCl3): δ = 12.8, 20.0, 30.9, 31.1, 35.8, 173.5. MS (EI, 70 eV), m/z (%): 125 (38, M+), 96 (48), 82 (100).