Synlett 2008(10): 1495-1499  
DOI: 10.1055/s-2008-1077792
LETTER
© Georg Thieme Verlag Stuttgart · New York

Catalytic Asymmetric Formation of Secondary Allylic Amines by Aza-Claisen Rearrangement of Trifluoroacetimidates

Zhuo-qun Xin, Daniel F. Fischer, René Peters*
Department of Chemistry and Applied Biosciences, Laboratory of Organic Chemistry, ETH Zürich, Hönggerberg HCI E 111, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
Fax: +41(44)6331226; e-Mail: peters@org.chem.ethz.ch;
Further Information

Publication History

Received 23 February 2008
Publication Date:
16 May 2008 (online)

Abstract

A catalytic asymmetric synthesis of unprotected secondary allylic amines based on the aza-Claisen rearrangement of N-aryl- and N-alkyl-substituted trifluoroacetimidates has been developed, which provides the targeted products with excellent enantioselectivity.

    References and Notes

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11

Catalyst Activation
A solution of FIP-Cl (11, 1 equiv) in dry CH2Cl2 (0.33 mL/µmol) is added into a dry pear-shaped flask equipped with a magnetic stirring bar and containing AgO2CCF3 (3.8 equiv). The flask is sealed, shielded from light, and the suspension is stirred at r.t. for 24 h. The resulting wine-red suspension is filtrated through Celite and CaH2 (ca. 1:1) under N2 atmosphere and the filter cake is washed with dry CH2Cl2. Proton-sponge solution (1 M in CH2Cl2, 3 equiv) is added to the filtrate. Catalysis
The required amount of the solution of the activated catalyst is transferred into a dry flask equipped with a magnetic stirring bar containing the corresponding imidate 9. A stream of N2 is passed through the flask until the solvent is almost removed. The septum is replaced by a plastic stopper and the mixture stirred at the indicated temperature for 72 h. Then the highly viscous residue is dissolved in CH2Cl2 (1.0 mL for 100 mg of product) and the resulting solution is suspended in pentane-EtOAc (9:1, 10 mL for 100 mg of product) and filtrated through a short plug of SiO2 [eluent: pentane-EtOAc (9:1), ca. 50 mL for 100 mg of product], followed by removal of the solvent in vacuo. Further purification is performed by column chromatography [pentane-EtOAc (9:1)]. Removal of the TFA Protecting Group
Sodium tetrahydridoborate (4 equiv) is added in one portion to a solution of allylic amide 10 in EtOH (12.5 µmol/mL) at 0 °C. The reaction mixture is then allowed to warm to r.t. and stirred for additional 4 h. Water is subsequently added and the mixture extracted three times with MTBE. The combined organic phases are dried over MgSO4 and the solvent is removed in vacuo to provide the pure allylic amine 12.

12

Analytical Data for the Secondary Amines
Compound 12a: 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, J = 6.9 Hz, 3 H), 1.38-1.49 (m, 2 H), 1.53 (m, 2 H), 3.66 (br, 1 H), 3.75 (d, J = 6.0 Hz, 1 H), 5.09-5.20 (m, 2 H), 5.70 (ddd, J 1 = 6.0 Hz, J 2 = 10.2 Hz, J 3 = 16.8 Hz, 1 H), 6.38 (dt, J 1 = 2.6 Hz, J 2 = 5.7 Hz, 2 H), 7.38 (dt, J 1 = 2.6 Hz, J 2 = 5.7 Hz, 2 H). 13C NMR (75 MHz, C6D6): δ = 14.1, 19.3, 37.9, 55.4, 77.7, 114.6, 115.7, 137.8, 139.5, 147.2. MS (EI): m/z (%) = 258 (100), 301 (31) [M+]. HRMS (EI): m/z calcd for C12H16IN [M]+: 301.0322; found: 301.0326. [α]D 28.6 +8.1 (c 0.407, CHCl3); ee determination: Chiralcel AD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 250 nm, t R = 12.4 min (R), 13.8 min (S).
Compound 12b: 1H NMR (300 MHz, CDCl3): δ = 0.96 (t, J = 7.2 Hz, 3 H), 1.38-1.61 (m, 4 H), 3.51 (br, 1 H), 3.74 (q, J = 6.3 Hz, 2 H), 5.12 (dt, J 1 = 1.2 Hz, J 2 = 10.2 Hz, 1 H), 5.19 (dt, J 1 = 1.5 Hz, J 2 = 17.1 Hz, 1 H), 5.71 (ddd, J 1 = 6.0 Hz, J 2 = 10.2 Hz, J 3 = 17.1 Hz, 1 H), 6.51-6.55 (m, 2 H), 6.84-6.89 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 19.2, 38.1, 56.5, 113.9, 114.1, 115.0, 115.2, 115.5, 140.0, 143.8, 153.8, 156.9. MS (EI): m/z (%) = 150 (100), 193 (15) [M+]. HRMS (EI): m/z calcd for C12H16FN [M]+: 193.1261; found: 193.1262. [α]D 28.4 -4.4 (c 0.120, CHCl3); ee determination: Chiralcel AD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 250 nm, t R = 9.0 min (R), 9.8 min (S).
Compound 12c: 1H NMR (300 MHz, CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3 H), 1.45-1.56 (m, 2 H), 1.73 (dt, J 1 = 6.8 Hz, J 2 = 14.4 Hz, 2 H), 4.01 (dt, J 1 = 6.4 Hz, J 2 = 6.4 Hz, 1 H), 4.38 (br, 1 H), 5.15-5.35 (m, 2 H), 5.83 (ddd, J 1 = 6.0 Hz, J 2 = 10.0 Hz, J 3 = 17.2 Hz, 1 H), 6.63 (d, J = 6.4 Hz, 1 H), 7.20-7.24 (m, 1 H), 7.31 (dd, J 1 = 7.6 Hz, J 2 = 8.0 Hz, 1 H), 7.41-7.46 (m, 2 H), 7.76-7.84 (m, 2 H). HRMS (EI): m/z calcd for C16H19N [M]+: 225.1512; found: 225.1512. [α]D 27.9 -5.6 (c 0.242, CHCl3). Additional data are consistent with those reported in the literature for a racemic sample, see ref. 13; ee determination: Chiralcel OD-H, n-hexane-i-PrOH (98.0:2.0), 0.8 mL/min, 250 nm, t R = 11.4 min (S), 14.3 min (R).
Compound 12d: 1H NMR (300 MHz, CD2Cl2): δ = 1.04 (br, 1 H), 1.10 (d, J = 6.6 Hz, 3 H), 2.72-2.89 (m, 4 H), 3.13-3.22 (m, 1 H), 4.98-5.10 (m, 2 H), 5.59-5.71 (m, 1 H), 7.16-7.31 (m, 5 H). 13C NMR (75 MHz, CD2Cl2): δ = 21.9, 37.0, 49.1, 56.9, 114.1, 126.4, 128.7, 129.1, 141.1, 143.6. MS (EI): m/z (%) = 84 (100), 175 (1) [M+]. HRMS (EI): m/z calcd for C12H17N [M]+: 175.1356; found: 175.1356. [α]D 27.8 -21.1 (c 0.085, CHCl3); ee determination (on the stage of 10d): Chiralcel OD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, t R = 12.1 min (R), 13.0 min (S).
Compound 12e: 1H NMR (300 MHz, CD2Cl2): δ = 0.83 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H), 1.03 (br, 1 H), 1.56-1.65 (m, 1 H), 2.65-2.78 (m, 4 H), 2.83-2.90 (m, 1 H), 5.01-5.12 (m, 2 H), 5.56 (ddd, J 1 = 8.4 Hz, J 2 = 10.2 Hz, J 3 = 17.1 Hz, 1 H), 7.16-7.31 (m, 5 H). 13C NMR (75 MHz, CD2Cl2): δ = 18.5, 19.6, 32.7, 36.9, 49.3, 68.0, 116.3, 126.3, 128.7, 129.2, 140.0, 141.2. MS (EI): m/z (%) = 160 (100), 188 (1) [M - CH3]+. HRMS (EI): m/z calcd for C13H18N [M - CH3]+: 188.1434; found: 188.1432. [α]D 26.9 -13.5 (c 0.075, CHCl3); ee determination (on the stage of 10e): Chiralcel AD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm,
t R = 7.5 min (R), 9.4 min (S).
Compound 12f: 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.19-1.65 (m, 10 H), 1.65-1.89 (m, 2 H), 2.41-2.50 (m, 1 H), 2.45-2.73 (m, 2 H), 2.97-3.04 (m, 1 H), 5.08-5.17 (m, 2 H), 5.62 (ddd, J 1 = 8.1 Hz, J 2 = 10.2 Hz, J 3 = 17.1 Hz, 1 H), 7.15-7.30 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.7, 27.2, 30.3, 31.9, 32.3, 37.3, 47.4, 61.6, 116.0, 125.6, 128.2, 128.3, 141.3, 142.1. MS (EI): m/z (%) = 140 (100), 245 (2) [M+]. HRMS (EI): m/z calcd for C17H27N [M]+: 245.2138; found: 245.2137. [α]D 27.9 -2.0 (c 0.322, CHCl3); ee determination: Chiralcel OD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, t R = 9.8 min (S), 11.1 min (R).
Compound 12g: 1H NMR (300 MHz, CDCl3): δ = 0.89 (d, J = 6.3 Hz, 6 H), 1.29-1.39 (m, 2 H), 1.54-1.90 (m, 3 H), 2.43-2.51 (m, 1 H), 2.55-2.73 (m, 3 H), 2.98-3.05 (dt, J 1 = 5.4 Hz, J 2 = 7.8 Hz, 1 H), 5.09-5.17 (m, 2 H), 5.63 (ddd, J 1 = 8.4 Hz, J 2 = 10.2 Hz, J 3 = 17.1 Hz, 1 H), 7.15-7.30 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 22.6, 22.7, 26.1, 32.2, 37.2, 39.3, 45.3, 61.6, 116.0, 125.6, 128.2, 128.3, 141.2, 142.2. MS (EI): m/z (%) = 126 (100), 231 (3) [M+]. HRMS (EI): m/z calcd for C16H25N [M]+: 231.1982; found: 231.1981. [α]D 27.9 -2.7 (c 0.382, CHCl3); ee determination: Chiralcel AD-H, n-hexane-i-PrOH (95.0:5.0), 0.8 mL/min, 210 nm, t R = 5.0 min (R), 5.3 min (S).
Compound 12h: 1H NMR (300 MHz, CDCl3): δ = 1.06 (d, J = 8.1 Hz, 21 H), 1.63 (br, 1 H), 1.68-1.90 (m, 2 H), 2.57-2.81 (m, 4 H), 3.01-3.08 (m, 1 H), 3.74-3.84 (m, 2 H), 5.10-5.17 (m, 2 H), 5.60-5.72 (m, 1 H), 7.15-7.30 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 12.0, 18.0, 32.2, 37.4, 49.4, 61.2, 62.6, 115.9, 125.5, 128.1, 128.2, 141.1, 142.0. MS (EI): m/z (%) = 256 (100), 361 (6) [M+]. HRMS (EI): m/z calcd for C22H39NOSi [M]+: 361.2795; found: 361.2796. [α]D 24.5 -2.6 (c 0.435, CHCl3); ee determination (on the stage of 10h): Chiralcel OD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, t R = 7.5 min (S), 9.2 min (R).
Compound 12i: 1H NMR (300 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H), 1.41 (br , 1 H), 1.65-1.87 (m, 2 H), 2.45-2.50 (m, 2 H), 2.55-2.78 (m, 3 H), 2.86-2.95 (m, 1 H), 3.01 (q, J = 6.6 Hz, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.10-5.17 (m, 2 H), 5.62 (ddd, J 1 = 8.1 Hz, J 2 = 10.2 Hz, J 3 = 17.1 Hz, 1 H), 7.17-7.30 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 14.3, 32.2, 34.9, 37.3, 42.5, 60.4, 61.2, 116.3, 125.8, 128.4, 128.4, 141.0, 142.2, 172.9. MS (EI): m/z (%) = 156 (100), 261 (2) [M+]. HRMS (EI): m/z calcd for C16H23NO2 [M]+: 261.1723; found: 261.1725. [α]D 27.2 -3.6 (c 0.250, CHCl3); ee determination (on the stage of 10i): Chiralcel OD-H, n-hexane-i-PrOH (95.0:5.0), 0.8 mL/min, 210 nm,
t R = 12.8 min (S), 15.6 min (R).
Compound 12j: 1H NMR (300 MHz, CDCl3): δ = 0.002 (s, 3 H), 0.006 (s, 3 H), 0.83 (s, 9 H), 1.76 (br, 1 H), 2.70-2.98 (m, 4 H), 3.17 (dt, J 1 = 3.9 Hz, J 2 = 8.1 Hz, 1 H), 3.46 (dd, J 1 = 8.4 Hz, J 2 = 9.9 Hz, 1 H), 3.57 (dd, J 1 = 4.5 Hz, J 2 = 9.9 Hz, 1 H), 5.12-5.24 (m, 2 H), 5.55-5.67 (m, 1 H), 7.16-7.31 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = -5.5, -5.4, 18.3, 25.9, 36.4, 48.7, 63.6, 66.2, 117.5, 126.1, 128.5, 128.7, 138.1, 140.2. MS (EI): m/z (%) = 160 (100), 305 (1) [M+]. HRMS (EI): m/z calcd for C18H31NOSi [M]+: 305.2170; found: 305.2173. [α]D 25.7 -20.4 (c 0.31, CHCl3); ee determination (on the stage of 10j): Chiralcel OD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, t R = 6.2 min (R), 8.0 min (S).
Compound 12k: 1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.6 Hz, 3 H), 1.06 (br, 1 H), 1.21 (s, 3 H), 1.26-1.35 (m, 6 H), 1.37-1.47 (m, 2 H), 1.75 (dt, J 1 = 3.0 Hz, J 2 = 8.7 Hz, 2 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.58 (dd, J 1 = 6.6 Hz, J 2 = 10.8 Hz, 2 H), 5.04-5.15 (m, 2 H), 5.77 (dd, J 1 = 10.8 Hz, J 2 = 17.4 Hz, 1 H), 7.15-7.31 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 14.1, 22.7, 23.6, 27.3, 30.4, 31.0, 31.9, 42.1, 42.5, 56.8, 112.9, 125.7, 128.3, 128.4, 142.9, 146.4. MS (EI): m/z (%) = 154 (100), 244 (7) [M - CH3]+. HRMS (EI): m/z calcd for C17H26N [M - CH3]+: 244.2060; found: 244.2059. [α]D 26.5 -18.0 (c 0.125, CHCl3); ee determination (on the stage of 10k): Chiralcel OD-H, n-hexane-i-PrOH (99.5:0.5), 0.8 mL/min, 210 nm, t R = 7.5 min (S), 8.9 min (R).