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Synlett 2003(14): 2198-2202  
DOI: 10.1055/s-2003-42062
LETTER
© Georg Thieme Verlag Stuttgart · New York

Lewis Acid-Catalyzed Dimerization of N-Unprotected Aziridines

Aldo Caiazzo, Shadi Dalili, Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
Fax: +1(416)9465042; e-Mail: ayudin@chem.utoronto.ca;
Further Information

Publication History

Received 24 July 2003
Publication Date:
07 October 2003 (online)

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Abstract

The dimerization of N-unprotected aziridines in the presence of catalytic amounts of Lewis acids has been investigated. When the reaction is carried out in the presence of alkyl aceto­acetates and ytterbium(III) triflate, dimeric products are obtained in high yields and selectivities.

Key words

aziridines - catalysis - dimerization - Lewis acids - ytterbium (III) triflate

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To a solution of 7-azabicyclo[4.1.0]heptane (1) [22] (200 mg, 2.06 mmol) and methyl acetoacetate (2a) (1.03 mmol%) in 4 mL of THF, 1 mol% of the acid additive was added. The resulting mixture was stirred for 16 h at r.t. The conversion and selectivity were determined through analysis of the crude reaction mixture by GC (biphenyl as internal standard) and 1H NMR.

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To a solution of 7-azabicyclo[4.1.0]heptane (1) (200 mg, 2.06 mmol) in 4 mL of CH2Cl2, Yb(OTf)3 (12.7 mg, 1 mol%) was added. The resulting mixture was stirred for 16 h at r.t. The mixture was treated with 5% NaOH and the aq layer was extracted with CH2Cl2 (3 × ). The combined organic layers were dried over Na2SO4 and the solvent and unconverted aziridine were evacuated. The residue was distilled at reduced pressure to give 30 mg (15% yield) of trans-2-(7-aza-bicyclo[4.1.0]hept-7-yl)cyclohexylamine(5) as clear oil.
1H NMR (CDCl3, 400 MHz): δ = 2.82 (t, J = 10 Hz, 1 H), 1.65-1.90 (m, 9 H), 1.50 (m, 1 H), 1.05-1.42 (m, 9 H), 0.96 (t, J = 10 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 75.2, 56.8, 39.8, 34.1, 33.5, 30.7, 25.1, 24.9, 24.7, 24.6, 20.6, 20.5. HRMS-FAB: m/z calcd for C12H22N2: 194.32016, found: 194.31995.

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General Procedure for the Preparation of ( Z )-3-[2-(7-Aza-bicyclo[4.1.0]hept-7-yl)-cyclohexylamino]-2-butenoate ( 3) . To a solution of 7-azabicyclo[4.1.0]hep-tane(1) (200 mg, 2.06 mmol) and acetoacetate(2) (1.03 mmol) in 4 mL of CH2Cl2, Yb(OTf)3 (12.7 mg, 1 mol%) was added. The resulting mixture was stirred 16 h at r.t. Upon completion of the reaction (by GC) the solvent was eva-cuated and the crude oil was purified by column chromato-graphy (silica gel, 80:20 hexanes-EtOAc, with 5% Et3N).
3a (R = Me, R1 = H): Isolated as a white solid (86%, mp 51-53 °C). 1H NMR (CDCl3, 400 MHz): δ = 8.59 (d, J = 10.2 Hz, 1 H), 4.39 (s, 1 H), 3.61 (s, 3 H), 3.40-3.48 (m, 1 H), 2.03 (s, 3 H), 1.88 (d, J = 12.1 Hz, 2H), 1.61-1.75 (m, 7 H), 1.10-1.39 (m, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 171.0, 161.6, 80.9, 73.8, 57.7, 49.6, 40.8, 33.7, 33.6, 31.3, 25.0, 24.6, 24.4, 20.7, 20.4, 20.1. HRMS-FAB: m/z calcd for C17H28N2O2: 292.21508, found: 292.21487.
3b (R = Et, R1 = H): Isolated as a clear oil (83%). 1H NMR (CDCl3, 400 MHz): δ = 8.58 (d, J = 10 Hz, 1 H), 4.38 (s, 1 H), 4.08 (q, J = 4 Hz, 2 H), 3.42 (m, 1 H), 2.02 (s, 3 H), 1.87 (m, 2 H), 1.55-1.78 (m, 7 H), 1.06-1.39 (m, 10 H), 1.25 (t, J = 4 Hz, 3 H). 13C NMR (CDCl3, 100 MHz): δ = 170.8, 161.6, 81.3, 73.8, 58.1, 57.7, 40.9, 33.8, 33.7, 31.4, 25.0, 24.6, 24.4, 20.8, 20.4, 20.2, 14.7. HRMS-FAB: m/z calcd for C18H30N2O2: 306.44848, found: 306.44818.
3c (R = Pr, R1 = H): Isolated as a clear oil (82%). 1H NMR (CDCl3, 400 MHz): δ = 8.60 (d, J = 10 Hz, 1 H), 4.40 (s, 1 H), 3.98 (t, J = 6.8Hz, 2 H), 3.38-3.47 (m, 1 H), 2.02 (s, 3 H), 1.87 (d, J = 15 Hz, 2 H), 1.60-1.75 (m, 9 H), 1.1-1.38 (m, 10 H), 0.943 (t, J = 7.6Hz, 3 H). 13C NMR (CDCl3, 100 MHz): δ = 170.9, 161.5, 81.3, 73.9, 63.9, 57.7, 40.9, 33.8, 33.7, 31.4, 25.1, 24.6, 24.5, 22.5, 20.8, 20.5, 20.2, 10.5. HRMS-FAB: m/z: calcd for C19H32N2O2: 320.47536, found: 320.47494
3d (R = i-Pr, R1 = H): Isolated as a clear oil (70%). 1H NMR (CDCl3, 400 MHz): δ = 8.62 (d, J = 10 Hz, 1 H), 4.92-5.00 (m, 1 H), 4.36 (s, 1 H), 3.38-3.47 (m, 1 H), 2.02 (s, 3 H), 1.87 (d, J = 14 Hz, 2 H), 1.6-1.76 (m, 7 H), 1.23 (dd, J 1 = 6.4 Hz, J 2 = 6.4 Hz, 6 H), 1.1-1.4 (m, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 170.5, 161.4, 81.9, 73.9, 64.8, 57.8, 40.9, 33.8, 33.7, 31.4, 25.1, 24.7, 24.6, 24.5, 22.3, 20.8, 20.5, 20.2. HRMS-FAB: m/z calcd for C19H32N2O2: 320.47536, found: 320.47496.
3e (R = n-Bu, R1 = H): Isolated as a clear oil (85%). 1H NMR (CDCl3, 400 MHz): δ = 8.59 (d, J = 10 Hz, 1 H), 4.40 (s, 1 H), 4.03 (t, J = 6.8Hz, 2 H), 3.39-3.48 (m, 1 H), 2.02 (s, 3 H), 1.87 (d, J = 12 Hz, 2 H), 1.59-1.75 (m, 9 H), 1.10-1.44 (m, 12 H), 0.93 (t, J = 7.2 Hz, 3 H). 13C NMR (CDCl3, 100 MHz): δ = 171.0, 161.6, 81.4, 73.9, 62.2, 57.8, 41.0, 33.9, 33.8, 31.5, 31.3, 25.1, 24.7, 24.5, 20.9, 20.6, 20.3, 19.4, 13.9. HRMS-FAB: m/z calcd for C20H34N2O2: 334.50224, found: 334.50247.
3f (R = t-Bu, R1 = H): Isolated as a clear oil (82%). 1H NMR (CDCl3, 400 MHz): δ = 8.54 (d, J = 10 Hz, 1 H), 4.32 (s, 1 H), 3.36-3.44 (m, 1 H), 1.98 (s, 3 H), 1.87 (d, J = 12.8Hz, 2 H), 1.7-1.8 (m, 6 H), 1.46 (s, 9 H), 1.1-1.4 (m, 11 H). 13C NMR (CDCl3, 100 MHz): δ = 171.0, 160.9, 83.1, 77.5, 73.9, 57.9, 41.0, 34.0, 33.8, 31.6, 28.8, 25.2, 24.7, 24.68, 24.64, 20.9, 20.6, 20.2. HRMS-FAB: m/z calcd for C20H34N2O2: 334.50224, found: 334.50249.
3g (R = Allyl, R1 = H): Isolated as a clear oil (80%). 1H NMR (CDCl3, 400 MHz): δ = 8.58 (d, J = 10 Hz, 1 H), 5.91-6.00 (m, 1 H), 5.29 (dd, J 1 = 17.2 Hz, J 2 = 3.2 Hz, 1 H), 5.17 (dd, J 1 = 9.2 Hz, J 2 = 2.6 Hz, 1 H), 4.55 (dt, J 1 = 5.2 Hz, J 2 = 1.5 Hz, 2 H), 4.44 (s, 1 H), 3.92-3.48 (m, 1 H), 2.04 (s, 3 H), 1.87 (d, J = 12.8 Hz, 2 H), 1.60-1.74 (m, 7 H), 1.10-1.38 (m, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 170.3, 161.9, 133.9, 116.7, 81.0, 73.9, 63.1, 57.9, 40.9, 33.8, 33.7, 31.4, 25.1, 24.6, 24.5, 20.8, 20.5, 20.3. HRMS-FAB: m/z = calcd for C19H30N2O2: 318.45948, found: 318.45966.
3h (R = Cy, R1 = H): Isolated as a clear oil (75%). 1H NMR (CDCl3, 400 MHz): δ = 8.62 (d, J = 10.4 Hz, 1 H), 4.67-4.71 (m, 1 H), 4.38 (s, 1 H), 3.38-3.47 (m, 1 H), 2.01 (s, 3 H), 1.87 (d, J = 8.4 Hz, 4 H), 1.62-1.76 (m, 10 H), 1.07-1.41 (m, 15 H). 13C NMR (CDCl3, 100 MHz): δ = 170.6, 161.6, 81.9, 74.0, 70.4, 57.9, 50.7, 41.1, 33.9, 33.8, 32.4, 31.5, 25.7, 25.2, 24.7, 24.6, 24.3, 20.9, 20.6, 20.3. HRMS-FAB: m/z calcd for C22H36N2O2: 360.54012, found: 360.5399.
3j (R = Bn, R1 = H): Isolated as a clear oil (75%). 1H NMR (CDCl3, 400 MHz): δ = 8.59 (d, J = 10 Hz, 1 H), 7.31-7.38 (m, 3 H), 7.25-7.29 (m, 2 H), 5.10 (s, 2 H), 4.48 (s, 1 H), 3.39-3.48 (m, 1 H), 2.03 (s, 3 H), 1.86 (d, J = 12 Hz, 2 H), 1.57-1.75 (m, 7 H), 1.10-1.38 (m, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 170.5, 162.2, 137.8, 128.5, 127.8, 127.7, 81.2, 73.9, 64.2, 58.0, 41.1, 33.9, 33.8, 31.5, 25.2, 24.7, 24.6, 20.9, 20.6, 20.4. HRMS-FAB: m/z calcd for C23H32N2O2: 368.51936, found: 368.51961.
3k (R, R1 = Me): Isolated as a clear oil in 62% yield. 1H NMR (CDCl3, 400 MHz): δ = 9.39 (d, J = 9.6 Hz, 1 H), 3.69 (s, 3 H), 3.46-3.55 (m, 1 H), 2.09 (s, 3 H), 1.89 (d, J = 11.2 Hz, 2 H), 1.83 (s, 3 H), 1.71-1.77 (m, 6 H), 1.11-1.39 (m, 11 H). 13C NMR (CDCl3, 100 MHz): δ = 171.6, 159.8, 84.9, 74.1, 57.7, 50.2, 40.6, 33.9, 31.3, 25.1, 24.6, 24.5, 24.4, 20.8, 20.6, 15.9, 12.7. HRMS-FAB: m/z calcd for C18H30N2O2: 306.44848, found: 306.44908.
3m (R = Me, R1 = allyl): Isolated as a clear oil in 63% yield. 1H NMR (CDCl3, 400 MHz): δ = 9.54 (d, J = 9.6 Hz, 1 H), 5.79-5.92 (m, 1 H), 4.90-5.02 (m, 2 H), 3.68 (s, 3 H), 3.47-3.57 (m, 1 H), 3.02-3.06 (m, 2 H), 2.08 (s, 3 H), 1.91 (d, J = 12.3 Hz, 2 H), 1.72-1.80 (m, 7 H), 1.12-1.44 (m, 10 H). 13C NMR (CDCl3, 100 MHz): δ = 171.4, 160.8, 138.8, 112.8, 87.7, 73.8, 57.7, 50.3, 40.7, 34.0, 33.9, 31.3, 25.0, 24.7, 24.6, 24.4, 20.8, 20.5, 15.5. HRMS-FAB: m/z calcd for C20H32N2O2: 332.24638, found: 332.24582.
3n (R = Me, R1 = Bn): Isolated as a clear oil in 60% yield. 1H NMR (CDCl3, 400 MHz): δ = 9.69 (d, J = 9.6 Hz, 1 H), 7.14-7.30 (m, 5 H), 3.72 (s, 2 H), 3.68 (s, 3 H), 3.50-3.54 (m, 1 H), 2.05 (s, 3 H), 1.92 (d, J = 10.2 Hz, 2 H), 1.72-1.84 (m, 5 H), 1.10-1.61 (m, 12 H). 13C NMR (CDCl3, 100 MHz): δ = 171.7, 161.4, 143.2, 128.0, 127.8, 125.3, 88.9, 73.7, 57.9, 50.3, 40.7, 34.0, 33.9, 32.7, 31.4, 25.0, 24.7, 24.6, 24.4, 20.7, 20.5, 15.9. HRMS-FAB: m/z calcd for C24H34N2O2: 382.54624, found: 382.54568.

28

Compound 3a (200 mg, 0.685 mmol) and benzenethiol (6) (94 mg, 0.854 mmol) were dissolved in 6 mL of degassed CH3CN. The reaction mixture was stirred at r.t. for 16 h. The crude 1H NMR of the reaction mixture showed completion of the reaction and presence of the ring opening compound in two diastereomeric forms (7a and 8a; 10% de). The solvent was then removed in vacuo and the residue was eluted on silica (CH2Cl2-MeOH, 98:2) to provide compounds 7a and 8a as clear oils in an inseparable mixture (60% yield), from which 1H NMR were taken.
1H NMR (CDCl3, 400 MHz): δ = 8.71 (d, J = 9.9 Hz, 1 H), 8.63 (d, J = 9.9 Hz, 1 H), 7.45-7.38 (m, 2 × 2 H), 7.33-7.19 (m, 2 × 3 H), 4.48 (s, 1 H), 4.44 (s, 1 H), 3.65 (s, 3 H), 3.60 (s, 3 H), 3.22 (m, 2 × 1 H), 2.97 (m, 2 × 1 H), 2.57 (m, 2 × 1 H), 2.49 (m, 2 × 1 H), 2.17-1.86 (m, 2 × 5 H), 1.99 (s, 3 H), 1.97 (s, 3 H), 1.82-1.59 (m, 2 × 4 H), 1.52-1.06 (m, 2 × 8 H). HRMS-FAB: m/z calcd for C23H34N2O2S: 403.24192, found: 403.24125.

29

Compounds 10a and 11a were prepared from 2-methyl-aziridine (9) using standard procedure (see ref. [26] ). Upon completion of the reaction (16 h by GC) the solvent was evacuated and the crude oil was purified by column chromatography (silica gel, 90:10 hexanes-EtOAc, with 5% Et3N). Combined yield: 64% (oils, 8% de).
A: 1H NMR (CDCl3, 300 MHz): δ = 8.49 (d, J = 7.8 Hz, 1 H), 4.43 (s, 1 H), 3.77 (m, 1 H), 3.61 (s, 3 H), 2.35 (m, 1 H), 2.21 (m, 1 H), 1.98 (s, 3 H), 1.49 (d, J = 3 Hz, 1 H), 1.35 (m, 1 H), 1.25 (m, 4 H), 1.17 (d, J = 5.4 Hz, 3 H). 13C NMR (CDCl3, 75 MHz): δ = 170.9, 161.3, 81.8, 67.5, 49.8, 49.5, 34.7, 34.6, 20.4, 19.6, 18.1. HRMS-FAB: m/z calcd for C11H20N2O2: 212.29324, found: 212.29277.
B: 1H NMR (CDCl3, 300 MHz): δ = 8.56 (d, J = 8.4 Hz, 1 H), 4.43 (s, 1 H), 3.81 (m, 1 H), 3.62 (s, 3 H), 2.63 (dd, J = 12 Hz, 5.3 Hz, 1 H), 2.00 (s, 3 H), 1.96 (dd, J = 12 Hz, 5.3 Hz, 1 H), 1.44 (m, 2 H), 1.20 (m, 4 H), 1.12 (d, J = 5.4 Hz). 13C NMR (CDCl3, 75 MHz): δ = 171.0, 161.3, 81.6, 67.7, 49.8, 49.6, 35.9, 33.8, 20.6, 19.7, 18.1. HRMS-FAB: m/z calcd for C11H20N2O2: 212.29324, found: 212.29295.