Lewis Acid-Catalyzed Dimerization of N-Unprotected Aziridines

Aldo Caiazzo; Shadi Dalili; Andrei K. Yudin

doi:10.1055/s-2003-42062

LETTER

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;

Abstract

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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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References

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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.

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.

<A NAME="RS08303ST-27">27</A> Mikami K. Terada M. Matsuzawa H. Angew. Chem. Int. Ed. 2002, 41: 3554 ; and references therein cited

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.

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.