New N-Substituted Dipolarophiles in 1,3-Dipolar Cycloaddition of Nitrones

Abstract

(N-Vinyl)-1,3-oxazolidin-2-ones, -1,3-oxazolidine-2-thi-ones and -N′-methylimidazolidin-2-one were conveniently used as new dipolarophiles in thermal 1,3-dipolar cycloaddition involving activated nitrones, and led to new 5-N-substituted isoxazolidines in high yields. A moderate to total trans-diastereoselectivity was observed, increasing with the degree of substitution at C-4.

1,3-dipolar cycloaddition - dipolarophile - nitrone - N-vinyl-oxazolidinone - oxazolidinethione - imidazolidinone

References and Notes

1a Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, In Organic Nitro Chemistry   Vol. 20:  Torssell KBG. VCH; New York: 1988. 

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3 Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry towards Heterocycles and Natural Products   Padwa A. Pearson WH. John Wiley and Sons; Hoboken, NJ: 2003. 

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7

Optimized Experimental Procedure for Thermal 1,3-DC.
A stirred toluene solution (5 mL) of dipolarophile (0.5 mmol, 1 equiv) and nitrone (0.5 mmol, 1 equiv) was refluxed under argon. After cooling, the crude mixture was concentrated in vacuo. The product was purified by column chromatography on silica gel.
Physical data of selected isolated adducts.
Compound cis-3: pale yellow oil. IR (neat): 1738, 1194, 1028 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, 3 H, J = 7.1 Hz, Et), 2.57 (ddd, 1 H, J = 4.1, 7.6, 13.6 Hz, H-4_A), 2.87 (ddd, 1 H, J = 8.2, 9.1, 13.6 Hz, H-4_B), 3.55 (dd, 1 H, J = 7.6, 9.1 Hz, H-4′), 3.75 (dt, 1 H, J ₄ = 5.9, 9.1 Hz, H-4′), 3.84 (q, 1 H, J = 9.1 Hz), 4.00 (dd, 1 H, J = 13.5 Hz), 4.12 (m, 3 H), 4.29 (m, 2 H, H-5′), 5.92 (dd, 1 H, ³ J _5-4A = 4.1 Hz, ³ J _5-4B = 8.2 Hz, H-5), 7.28-7.37 (m, 5 H, H-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9 (Et), 36.3 (C-4), 40.8 (C-4′), 61.5, 61.6 (Bn, OEt), 62.3 (C-5′), 66.6 (C-3), 81.5 (C-5), 127.6, 128.2, 129.1, 135.8 (C-Ar), 157.6 (C-2′), 169.8 (C=O).
Compound trans-3: pale yellow oil. IR (neat): 1737, 1182, 1034 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (t, 3 H, ³ J _8-7 = 7.1 Hz, Et), 2.55 (ddd, 1 H, ³ J _4A-5 = 4.4 Hz, ³ J _4A-3 = 7.9 Hz, ² J _4A-4B = 13.3 Hz, H-4_A), 2.83 (ddd, 1 H, ³ J _4B-5 = 6.9 Hz, ³ J _4B-3 = 7.9 Hz, ² J _4B-4A = 13.3 Hz, H-4_B), 3.54 (t, 2 H, ³ J _{4 ′ -5 ′} = 7.9 Hz, H_{4 ′}), 3.74 (m, 1 H, H-3), 4.11 (m, 2 H, Bn), 4.18 (q, 2 H, ³ J _7-8 = 7.1 Hz, OEt), 4.30 (t, 2 H, ³ J _{4 ′ -5 ′} = 7.3 Hz, H_{5 ′}), 5.84 (dd, 1 H, ³ J _5-4A = 4.4 Hz, ³ J _5-4B = 7.9 Hz, H-5), 7.27-7.38 (m, 5 H, H-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (Et), 35.4 (C-4), 40.4 (C-4′), 60.3 (Bn), 61.5 (OEt), 62.1 (C-5′), 65.3 (C-3), 82.1 (C-5), 127.7, 128.3, 129.3, 135.8 (C-Ar), 157.2 (C-2′), 169.3 (C=O). HRMS (EI): m/z calcd for C₁₆H₂₀N₂O₅ [M]⁺: 320.1372; found: 320.1393.
Compound cis-8: colorless crystals; mp 185-186 °C. IR (neat): 1743, 1410, 1234, 1018 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.40 (ddd, 1 H, ³ J _4A-5 = 5.3 Hz, ³ J _4A-3 = 6.3 Hz, ² J _4A-4B = 13.4 Hz, H-4_A), 3.04 (dt, 1 H, ³ J _4B-3 = ³ J _4B-5 = 8.3 Hz, ² J _4B-4A = 13.4 Hz, H-4_B), 3.37 (dt, 1 H, ³ J _{4 ′ B-5 ′ A} = 5.3 Hz, ² J _{4 ′ B-4 ′ A} = ³ J _{4 ′ B-5 ′ B} = 8.3 Hz, H-4′_B), 3.68 (q, 1 H, ³ J _{4 ′ A-5 ′} = ² J _{4 ′ A-4 ′ B} = 8.3 Hz, H-4′_A), 4.26 (dt, 1 H, ³ J _{5 ′ B-4 ′} = 8.3 Hz, ² J _{5 ′ B-5 ′ A} = 9.1 Hz, H-5′_B), 4.34 (ddd, 1 H, ³ J _{5 ′ A-4 ′ B} = 5.3 Hz, ³ J _{5 ′ A-4 ′ A} = 8.3 Hz, ² J _{5 ′ A-5 ′ B} = 9.1 Hz, H-5′_A), 4.72 (dd, 1 H, ³ J _3-4A = 6.3 Hz, ³ J _3-4B = 8.3 Hz, H-3), 6.13 (dd, 1 H, ³ J _5-4A = 5.3 Hz, ³ J _5-4B = 8.3 Hz, H-5), 7.00 (t, 1 H, J = 7.5 Hz), 7.03 (d, 2 H, J = 7.5 Hz,), 7.24 (t, 2 H, J = 7.5 Hz,), 7.31 (t, 1 H, J = 7.5 Hz), 7.39 (t, 1 H, J = 7.5 Hz), 7.51 (d, 1 H, J = 7.5 Hz,). ¹³C NMR (100 MHz, CDCl₃): δ = 40.2 (C-4′), 41.2 (C-4), 62.3 (C-5′), 70.0 (C-3), 82.4 (C-5), 116.3, 123.2, 126.4, 127.8, 128.9, 129.0, 140.6, 150.2 (C-Ar), 157.8 (C-2′). Anal. Calcd for C₁₈H₁₈N₂O₃: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.64; H, 5.74; N, 9.18.
Compound trans-15: pale yellow oil. IR (neat): 1731, 1489, 1477, 1324, 1260, 1186 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (t, 3 H, ³ J _8-7 = 7.1 Hz, Et), 2.45 (ddd, 1 H, ³ J _4A-5 = 3.5 Hz, ³ J _4A-3 = 8.1 Hz, ² J _4A-4B = 13.9 Hz, H-4_A), 3.02 (ddd, 1 H, ³ J _4B-5 = 8.1 Hz, ³ J _4B-3 = 9.1 Hz, ² J _4B-4A = 13.9 Hz, H-4_B), 3.59-3.71 (m, 2 H, H-4′), 3.84 (br, 1 H, H₃), 4.12 (s, 2 H, Bn), 4.23 (q, 2 H, ³ J _7-8 = 7.1 Hz, OEt), 4.41-4.51 (m, 2 H, H-5′), 6.39 (dd, 1 H, ³ J _5-4A = 3.5 Hz, ³ J _5-4B = 8.1 Hz, H-5), 7.28-7.35 (m, 5 H, H-Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3 (Et), 36.7 (C-4), 43.4 (C-4′), 59.2 (Bn), 61.5 (OEt), 64.8 (C-3), 67.0 (C-5′), 84.7 (C-5), 127.8, 128.4, 129.3, 135.9 (C-Ar), 169.1 (C=O), 187.6 (C-2′). HRMS (ESI⁺): m/z calcd for C₁₆H₂₀N₂O₄SK [M + K]⁺: 375.0781; found: 375.0775.
Compound trans-19: pale yellow oil. IR (neat): 1734, 1474, 1353, 1283, 1208 cm^-1. ¹H NMR (400 MHz, CDCl₂CDCl₂, 60 °C): δ = 1.20 (t, 3 H, ³ J _7-8 = 7.1 Hz, Et), 1.22 (s, 3 H, Me), 1.30 (s, 3 H, Me), 2.80 (ddd, 1 H, ³ J _4A-5 = 6.0 Hz, ³ J _4A-3 = 8.6 Hz, ² J _4A-4B = 13.9 Hz, H-4_A), 3.08 (ddd, 1 H, ³ J _4B-3 = 6.3 Hz, ³ J _4B-5 = 7.6 Hz, ² J _4B-4A = 13.9 Hz, H-4_B), 3.97 (dd, 1 H, ³ J _3-4A = 8.6 Hz, ³ J _3-4B = 6.3 Hz, H-3), 4.01 (s, 2 H, Bn), 4.06-4.12 (m, 4 H, OEt and H-5′), 5.74 (dd, 1 H, ³ J _5-4A = 6.0 Hz, ³ J _5-4B = 7.6 Hz, H-5), 7.16-7.29 (m, 5 H, H-Ar). ¹³C NMR (100 MHz, CDCl₂CDCl₂, 60 °C): δ = 14.2 (Et), 25.4 (Me), 25.8 (Me), 37.1 (C-4), 60.4 (Bn), 61.3 (OEt), 64.2 (C-4′), 66.0 (C-3), 79.3 (C-5′), 84.6 (C-5), 127.5, 128.2, 129.5, 136.4 (C-Ar), 169.6 (C=O), 186.4 (C-2′).

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11

Complete complexation was ascertained by ¹H NMR.

The rearranged nitrone was identified by the low-field signal of the ortho aromatic protons in ¹H NMR. For seminal work on the Behrend rearrangement and further studies, see:

12a Behrend R. Konig E. Justus Liebigs Ann. Chem.  1891,  238 

12b Behrend R. Konig E. Justus Liebigs Ann. Chem.  1891,  355 

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14

Under our standard conditions, similar levels of trans-selectivity were observed in the reaction of 1 with ethyl vinyl ether (4:1) and tert-butyl vinyl ether (3:1).

For preparation of dipolarophiles, see:

15a Gaulon C. Gizecki P. Dhal R. Dujardin G. Synlett  2002,  952 

15b Gaulon C. Dhal R. Dujardin G. Synthesis  2003,  2269 

15c Chery F. Desroses M. Tatibouët A. De Lucchi O. Rollin P. Tetrahedron  2003,  59:  4563 

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16 Such diastereomeric separation was seldom reported for adducts deriving from alkyl vinyl ethers. For a successful case, see: Fischer R. Dugovi B. Wiesenganger T. Fisera L. Hametner C. Prónayová N. Heterocycles  2005,  65:  591 

17 For previous use of chiral N-vinyl-1,3-oxazolidin-2-ones in [4+2] asymmetric reactions, see: Gaulon C. Dhal R. Chapin T. Maisonneuve V. Dujardin G. J. Org. Chem.  2004,  69:  952 

18 For recent use of chiral N-vinyl-1,3-oxazolidine-2-thiones in [4+2] asymmetric reactions, see: Tardy S. Tatibouët A. Rollin P. Dujardin G. Synlett  2006,  1425