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

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.

amino acids - cyclopropanes - nitriles - titanium - transition metals

References and Notes

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For related Ti-mediated coupling of homoallylic alcohols, see:

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<A NAME="RG20408ST-12">12</A>

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.

<A NAME="RG20408ST-13">13</A>

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.

<A NAME="RG20408ST-14">14</A>

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.

<A NAME="RG20408ST-15">15</A>

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

<A NAME="RG20408ST-16">16</A> For a recent review devoted to aminocyclopropane-carboxylic acid derivatives, see: Brackmann F. de Meijere A. Chem. Rev.  2007,  107:  4493 

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<A NAME="RG20408ST-19">19</A>

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.

The tricyclic framework of 7 is rare in the literature, see:

<A NAME="RG20408ST-20A">20a</A> Hanessian S. Buckle R. Bayrakdarian M. J. Org. Chem.  2002,  67:  3387 

<A NAME="RG20408ST-20B">20b</A> Beak P. Wu S. Yum EK. Jun YM. J. Org. Chem.  1994,  59:  276 

<A NAME="RG20408ST-21">21</A> The pyrrolizidine analogue 7 was recently obtained by Ti-mediated cyclopropanation of unsaturated imides, see: Bertus P. Szymoniak J. Org. Lett.  2007,  9:  659