Lewis Acid-Catalyzed Dimerization of N-Unprotected Aziridines

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.

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

References

For recent reviews see:

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22

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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24 Hamilton WC. Ibers JA. Hydrogen Bonding in Solids   WA Benjamin Inc.; New York: 1968.  p.16 

25

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.

26

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.

27 Mikami K. Terada M. Matsuzawa H. Angew. Chem. Int. Ed.  2002,  41:  3554 ; and references therein cited

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.