Download PDF
Synlett 2008(16): 2455-2458  
DOI: 10.1055/s-2008-1078180
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Preparation and Some Synthetic Applications of 2-Hydroxyethyl-Substituted Cyclopropylamines

Antoine Joostena, Jean-Luc Vassea, Philippe Bertus*a,b, Jan Szymoniak*a
a Institut de Chimie Moléculaire de Reims, UMR CNRS 6229, Université de Reims-Champagne-Ardenne, UFR Sciences, BP 1039, 51687 Reims Cedex 2, France
e-Mail: jan.szymoniak@univ-reims.fr.;
b CNRS and Université du Maine, UMR 6011 - UCO2M, 72085 Le Mans Cedex 9, France
e-Mail: philippe.bertus@univ-lemans.fr;
Further Information

Publication History

Received 6 June 2008
Publication Date:
10 September 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Primary cyclopropylamines bearing hydroxy side chains were obtained by Ti-mediated coupling of nitriles and homoallylic alcohols. Their usefulness as synthetic intermediates was demonstrated by the preparation of a constrained glutamic acid derivative and pyrrolizidine analogues.

Key words

amino acids - cyclopropanes - nitriles - titanium - transition metals

    References and Notes

  • 1a Fujita T. J. Med. Chem.  1973,  16:  923 
    Google Scholar
  • 1b Wise R. Andrews JM. Edwards LJ. Antimicrob. Agents Chemother.  1983,  23:  559 
    Google Scholar
  • 1c Daluge SM. Martin MT. Sickles BR. Livingston DA. Nucleosides, Nucleotides Nucleic Acids  2000,  19:  297 
    Google Scholar
  • 2 Vilsmaier E. In The Chemistry of the Cyclopropyl Group   Rappoport Z. Wiley; New York: 1987.  p.1341 
    Google Scholar
  • Some recent examples:
  • 3a Bégis G. Cladingboel D. Motherwell WB. Chem. Commun.  2003,  2656 
    Google Scholar
  • 3b Moreau B. Charette AB. J. Am. Chem. Soc.  2005,  127:  18014 
    Google Scholar
  • 3c Hohn E. Pietruszka J. Solduga G. Synlett  2006,  1531 
    Google Scholar
  • 3d Tanguy C. Bertus P. Szymoniak J. Larionov OV. de Meijere A. Synlett  2006,  3164 
    Google Scholar
  • 4a Bertus P. Szymoniak J. Chem. Commun.  2001,  1792 
    Google Scholar
  • 4b Review: Bertus P. Szymoniak J. Synlett  2007,  1346 
    Google Scholar
  • 5a Kulinkovich OG. Sviridov SV. Vasilevsky DA. Synthesis  1991,  234 
    Google Scholar
  • 5b Kulinkovich OG. Eur. J. Org. Chem.  2004,  4517 
    Google Scholar
  • 6a Chaplinski V. de Meijere A. Angew. Chem., Int. Ed. Engl.  1996,  35:  413 
    Google Scholar
  • 6b de Meijere A. Kozhushkov SI. Savchenko AI. J. Organomet. Chem.  2004,  689:  2033 
    Google Scholar
  • 7a Kulinkovich OG. Savchenko AI. Sviridov SV. Vasilevski DA. Mendeleev Commun.  1993,  230 
    Google Scholar
  • 7b Kasatkin A. Sato F. Tetrahedron Lett.  1995,  36:  6079 
    Google Scholar
  • 7c Lee J. Kang CH. Kim H. Cha JK. J. Am. Chem. Soc.  1996,  118:  291 
    Google Scholar
  • 7d Lee J. Cha JK. J. Org. Chem.  1997,  62:  1584 
    Google Scholar
  • 8 Laroche C. Bertus P. Szymoniak J. Tetrahedron Lett.  2003,  44:  2485 
    CrossrefGoogle Scholar
  • 9 Laroche C. PhD Thesis   Université de Reims; France: 2006. 
    Google Scholar
  • 10a Shevchuk TA. Kulinkovich OG. Russ. J. Org. Chem.  2000,  36:  1124 
    Google Scholar
  • 10b Quan LG. Kim S.-H. Lee JC. Cha JK. Angew. Chem. Int. Ed.  2002,  41:  2160 
    Google Scholar
  • For related Ti-mediated coupling of homoallylic alcohols, see:
  • 10c Sung MJ. Pang J.-H. Park S.-B. Cha JK. Org. Lett.  2003,  5:  2137 
    Google Scholar
  • 10d Isakov VE. Kulinkovich OG. Synlett  2003,  967 
    Google Scholar
  • 10e Reichard HA. Micalizio GC. Angew. Chem. Int. Ed.  2007,  46:  1440 
    Google Scholar
  • 11 Bobrov DN. Kim K. Cha JK. Tetrahedron Lett.  2008,  49:  4089 
    CrossrefGoogle Scholar
  • 16 For a recent review devoted to aminocyclopropane-carboxylic acid derivatives, see: Brackmann F. de Meijere A. Chem. Rev.  2007,  107:  4493 
    CrossrefPubMedGoogle Scholar
  • For preceding syntheses of 2,3-methanoglutamic acid derivatives, see:
  • 17a Wakamiya T. Oda Y. Fujita H. Shiba T. Tetrahedron Lett.  1986,  27:  2143 
    Google Scholar
  • 17b Mapelli C. Elrod EF. Holt EM. Stammer CH. Tetrahedron  1989,  45:  4377 
    Google Scholar
  • 17c Slama JT. Satsangi RK. Simmons A. Lynch V. Bolger RE. Suttie J. J. Med. Chem.  1990,  33:  824 
    Google Scholar
  • 17d Lim D. Burgess K. J. Org. Chem.  1997,  62:  9382 
    Google Scholar
  • 17e Jimenez JM. Ortuno RM. Tetrahedron: Asymmetry  1996,  7:  3203 
    Google Scholar
  • 17f Kordes M. Winsel H. de Meijere A. Eur. J. Org. Chem.  2000,  3235 
    Google Scholar
  • 17g Frick JA. Klassen JB. Rapoport H. Synthesis  2005,  1751 
    Google Scholar
  • 18 Bertus P. Szymoniak J. Synlett  2003,  265 
    Article in Thieme ConnectGoogle Scholar
  • The tricyclic framework of 7 is rare in the literature, see:
  • 20a Hanessian S. Buckle R. Bayrakdarian M. J. Org. Chem.  2002,  67:  3387 
    Google Scholar
  • 20b Beak P. Wu S. Yum EK. Jun YM. J. Org. Chem.  1994,  59:  276 
    Google Scholar
  • 21 The pyrrolizidine analogue 7 was recently obtained by Ti-mediated cyclopropanation of unsaturated imides, see: Bertus P. Szymoniak J. Org. Lett.  2007,  9:  659 
    CrossrefGoogle Scholar
12

Spectroscopic Data of A
¹H NMR (250 MHz, C6D6): δ = 1.46 (d, J = 5.8 Hz, 18 H), 2.88 (br s, 2 H), 4.73 (br s, 5 H), 5.29 (d, J = 10.2 Hz, 1 H), 5.40 (d, J = 17.2 Hz, 1 H), 6.09-6.25 (m, 1 H). ¹³C NMR (62.9 MHz, C6D6): δ = 26.98, 38.50, 74.70, 76.94, 116.48, 136.41.

13

General Procedure for the MeTi(O i -Pr) 3 -Mediated Cyclopropanation of Homoallylic Alcohols and Nitriles
To a solution (under argon) of nitrile (1 mmol) and homoallylic alcohol (1.2 mmol) in THF (10 mL) was added dropwise MeTi(Oi-Pr)3 (1.2 mmol, 0.29 mL) and the reaction was stirred for 30 min. A solution of cyclohexyl magnesium chloride (2.4 mmol, 1.2 mL, 2 M in Et2O) was added dropwise to the mixture and was stirred for 90 min. Water (5 mL) was added followed by EtOAc (10 mL). The product was extracted with EtOAc (3 × 10 mL). The combined extracts were dried over MgSO4. After evaporation of the solvent, the product was purified by flash chromatography on SiO2 to give 3a-i or 6a-f.

14

Selected Data of 2-[(1 R *,2 S *)-2-amino-2-benzyl-cyclopropyl] Ethanol (3a)
¹H NMR (250 MHz, MeOD): δ = 0.41 (t, J = 5.5 Hz, 1 H), 0.77 (dd, J = 9.2, 5.0 Hz, 1 H), 0.91-1.02 (m, 1 H), 1.62 (ddd, J = 14, 9.5, 5.8 Hz, 1 H), 1.68-1.90 (m, 1 H), 2.45 (br s, 3 H), 2.70 (dd, J = 18.0, 14.1 Hz, 2 H), 3.58 (t, J = 5.7 Hz, 2 H), 7.27 (m, 5 H). ¹³C NMR (62.9 MHz, MeOD): δ = 18.0, 22.9, 30.6, 37.6, 47.5, 61.9, 126.7, 128.7, 129.4, 139.3. IR (neat): 3417, 2922, 1641, 1495, 1452, 1047 cm-¹. HRMS (ES): m/z calcd for C12H18NO [M + H]+: 192.1388; found: 192.1383.

15

In contrast, similar cyclopropanation of substituted homoallylic alcohols and carboxylic esters occurs with good 1,3-diastereoselection, see ref. 10b.

19

Selected Data of 1-[2-Hydroxy-2-(2-methoxyphenyl)-ethyl]-4-azaspiro[2.4]heptan-5-one (6f)
Minor diastereomer: ¹H NMR (250 MHz, MeOD): δ = 0.49 (t, J = 6.0 Hz, 1 H), 0.76 (dd, J = 9.6, 6.0 Hz, 1 H), 1.00 (ddd, J = 9.5, 6.6, 4.4 Hz, 1 H), 1.62 (ddd, J = 14.0, 9.5, 5.8 Hz, 1 H), 1.81-1.85 (m, 1 H), 1.93 (ddd, J = 14.0, 7.6, 4.4 Hz, 1 H), 2.15-2.24 (m, 3 H), 3.84 (s, 3 H), 5.04 (dd, J = 7.6, 5.8 Hz, 1 H), 6.88-6.96 (m, 2 H), 7.21 (td, J = 7.5, 1.4 Hz, 1 H), 7.38 (dd, J = 7.5, 1.4 Hz, 1 H). ¹³C NMR (62.9 MHz, MeOD): δ = 15.5, 21.4, 31.5, 31.7, 38.0, 44.7, 55.8, 69.7, 111.3, 121.5, 127.6, 129.2, 133.9, 157.6, 180.4. IR (KBr): 3420, 2523, 2076, 1651, 1457, 1117 cm-¹.
Major diastereomer: ¹H NMR (250 MHz, MeOD): δ = 0.41 (t, J = 6 Hz, 1 H), 0.70 (dd, J = 9.5, 6.0 Hz, 1 H), 0.89-0.95 (m, 1 H), 1.64-1.68 (m, 1 H), 1.83 (ddd, J = 14.3, 8.8, 5.5 Hz, 1 H), 1.89-1.98 (m, 2 H), 2.05-2.12 (m, 2 H), 3.83 (s, 3 H), 5.15 (t, J = 5.1 Hz, 1 H), 6.89 (dd, J = 7.5, 0.6 Hz, 1 H), 6.94 (td, J = 7.5, 0.6 Hz, 1 H), 7.22 (td, J = 7.5, 1.5 Hz, 1 H), 7.46 (dd, J = 7.5, 1.5 Hz, 1 H). ¹³C NMR (62.9 MHz, MeOD): δ = 15.4, 20.7, 31.2, 31.4, 36.6, 44.9, 55.7, 68.4, 111.3, 121.3, 127.4, 129.1, 133.7, 157.4, 180.5. IR (KBr): 3405, 2505, 2075, 1658, 1462, 1118 cm-¹. HRMS (ES): m/z calcd for C15H20NO3 [M + H]+: 192.1443; found: 192.1442.