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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;
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Publikationsverlauf

Received 6 June 2008
Publikationsdatum:
10. September 2008 (online)

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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

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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.