The Nicholas-Type Activation of Cyclopropanes toward Reactions with ­Nitrones in the Homo-[3+2]-Dipolar Cycloaddition

Abstract

2-Ethynyl-1,1-carboethoxyclopropane, when treated with Co₂(CO)₈, results in the formation of the Co₂(CO)₆ adduct which in turn undergoes smooth cycloaddition in the presence of Sc(OTf)₃ to form the corresponding tetrahdyro-1,2-oxazines. The adducts can either be decomplexed to yield the parent acetylenes or made to undergo Pauson-Khand reactions to form 6-cyclo­pentenyltetrahydro-1,2-oxazines.

tetrahydro-1,2-oxazine - cycloaddition - cyclopropanes - Pauson-Khand

References and Notes

1 Young IS. Kerr MA. Angew. Chem. Int. Ed.  2003,  42:  3023 

2 Young IS. Kerr MA. Org. Lett.  2004,  6:  139 

3 Ganton MD. Kerr MA. J. Org. Chem.  2004,  69:  8554 

4 Sibi MP. Ma Z. Jasperse CP. J. Am. Chem. Soc.  2005,  127:  5764 

5 Young IS. Williams JL. Kerr MA. Org. Lett.  2005,  7:  953 

For excellent reviews of the chemistry of donor/acceptor cyclopropanes see:

6a Pagenkopf BL. Tetrahedron  2005,  61:  321 

6b Reissig H.-U. Zimmer R. Chem. Rev.  2003,  103:  1151 

6c Wong HNC. Hon M.-Y. Tse C.-W. Yip Y.-C. Tanko J. Hudlicky T. Chem. Rev.  1989,  89:  165 

6d Danishefsky S. Acc. Chem. Res.  1979,  12:  66 

For reviews of the Nicholas reaction see:

7a Teobald BJ. Tetrahedron  2002,  58:  4133 

7b Green JR. Curr. Org. Chem.  2001,  5:  809 

8 Christie SDR. Davoile RJ. Elsegood MRJ. Fryatt R. Jones RCF. Pritchard GJ. Chem. Commun.  2004,  21:  2474 

9

Typical Experimental Procedure for the Cycloaddition of Cobalt-Complexed Cyclopropanediesters. Preparation of Compound 14.
A flame-dried round-bottom flask was charged with cyclopropane 9 (100 mg, 0.202 mmol) in 5 mL of dry CH₂Cl₂ under an argon atmosphere. Nitrone 10 (44 mg, 0.222 mmol) and Sc(OTf)₃ (10 mg, 0.020 mmol) were added and the mixture was stirred until the reaction appeared complete by TLC (3 h). The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (5% EtOAc-hexanes). Tetrahydro-1,2-oxazine 14 (126 mg, 0.182 mmol, 90%) was obtained as a red crystalline solid; mp 158-159 °C; R _f = 0.57 (25% EtOAc-hexanes). ¹H NMR (600 MHz, CDCl₃): δ = 7.54-7.53 (m, 2 H), 7.18-7.14 (m, 5 H), 7.12-7.10 (m, 2 H), 6.84 (t, J = 7.2 Hz, 1 H), 6.19 (s, 1 H), 5.73 (s, 1 H), 5.10 (dd, J = 11.9, 2.9 Hz, 1 H), 4.43-4.37 (m, 2 H), 3.94-3.84 (m, 2 H), 2.81 (dd, J = 14.1, 2.9 Hz, 1 H), 2.72 (dd, J = 14.1,11.9 Hz, 1 H), 1.36 (t, J = 7.2 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 199.2, 169.4, 167.5, 148.6, 134.5, 130.6, 128.5, 128.1, 127.7, 121.9, 116.2, 91.5, 77.6, 71.3, 66.8, 62.5, 61.8, 59.4, 33.6, 14.1, 13.5. IR (thin film): ν_max = 2986, 2098, 2026, 1740, 1598, 1493, 1454, 1368, 1298, 1256, 1183, 1075, 1020, 877, 755, 700 cm^-1. HRMS (CI, isobutane): m/z calcd for C₃₀H₂₅Co₂NO₁₁: 694.0170; found: 694.0078.
Characterization data for compound 17, prepared as above: mp 164-165 °C; R _f = 0.57 (25% EtOAc-hexanes). ¹H NMR (600 MHz, CDCl₃): δ = 7.20-7.17 (m, 3 H), 7.14-7.13 (m, 2 H), 6.91-6.87 (m, 2 H) 6.80 (dd, J = 5.1, 3.3 Hz, 1 H), 6.18 (s, 1 H), 6.05 (s, 1 H), 5.09 (dd, J = 12.2, 2.4 Hz, 1 H), 4.40 (m, 2 H), 4.00 (m, 1 H), 3.96 (m, 1 H), 2.83 (dd, J = 14.0, 2.4 Hz, 1 H), 2.734 (dd, J = 14.0, 12.2 Hz, 1 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.07 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 199.3, 168.9, 167.1, 148.4, 133.5, 129.4, 128.4, 127.0, 125.2, 122.5, 116.5, 90.8, 78.3, 71.4, 65.0, 62.5, 62.0, 59.6, 33.7, 14.1, 13.7. IR (thin film): ν_max = 2985, 2098, 2029, 1749, 1597, 1454, 1369, 1295, 1267, 1246, 1202, 1074, 1023, 958, 860, 760, 704 cm^-1. HRMS (CI, isobutane): m/z calcd for C₂₈H₂₃Co₂NO₁₁S: 699.9734; found: 699.9707.
Characterization data for compound 22, prepared as above: mp 128-129 °C; R _f = 0.43 (25% EtOAc-hexanes. ¹H NMR (600 MHz, CDCl₃): δ = 8.19 (d, J = 8.1 Hz, 2 H), 7.83 (d, J = 8.1 Hz, 2 H), 7.28-7.23 (m, 3 H), 7.17 (d, J = 7.2 Hz), 6.06 (s, 1 H), 5.02 (s, 1 H), 4.98 (dd, J = 12.0, 2.4 Hz, 1 H), 4.43-4.31 (m, 2 H), 3.90-3.80 (m, 2 H), 3.82 (d, J = 12.6 Hz, 1 H), 3.61 (d, J = 12.6 Hz, 1 H), 2.74 (dd, J = 14.4, 2.4 Hz, 1 H), 2.42 (dd, J = 14.4, 12.0 Hz, 1 H), 1.33 (t, J = 7.2 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 199.0, 168.7, 167.3, 147.8, 142.5, 136.2, 132.2, 128.5, 128.2, 127.3, 122.8, 91.8, 76.6, 70.9, 65.3, 62.5, 62.0, 59.4, 59.3, 33.2, 14.1, 13.6. IR (thin film): ν_max = 2988, 2097, 2057, 2030, 1740, 1606, 1526, 1349, 1254, 1184, 1089, 1017, 859, 699 cm^-1. HRMS (CI, isobutane): m/z calcd for C₃₁H₂₆Co₂N₂O₁₃: 753.0177; found: 753.0140.

10

Typical Experimental Procedure for the Decomplexation of the Cycloadducts. Preparation of Compound 27. A solution of tetrahydro-1,2-oxazine 14 (179 mg, 0.259 mmol) in 5 mL of dry THF was cooled to 0 °C in a 50-mL round-bottom flask. A solution of I₂ (979 mg, 3.89 mmol) in 20 mL of THF was added via cannula and the mixture was stirred for 2 h. The reaction mixture was then poured into a solution of sat. NaHCO₃ and Na₂SO₃ (1:1 v/v, 100 mL). The aqueous mixture was extracted with Et₂O (3 × 100 mL), the organic layers were combined, washed with brine and dried over anhyd MgSO₄. The solvent was then evaporated to yield tetrahydro-1,2-oxazine 27 (102 mg, 0.250 mmol, 97%) as a colorless oil. R _f = 0.40 (40% EtOAc-hexanes). ¹H NMR (600 MHz, CDCl₃): δ = 7.54-7.53 (m, 2 H), 7.19-7.14 (m, 5 H), 7.07-7.05 (d, J = 8.4 Hz, 2 H), 6.84 (t, J = 7.8 Hz, 1 H), 5.64 (s, 1 H), 4.75 (d, J = 12.6, 2.4 Hz, 1 H), 4.40-4.32 (m, 2 H), 3.93-3.83 (m, 2 H), 2.90 (dd, J = 14.4, 12.6 Hz, 1 H), 2.77 (dd, J = 14.4, 2.4 Hz, 1 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.00 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 169.1, 167.3, 148.2, 130.6, 128.5, 128.5, 128.2, 127.9, 122.1, 116.2, 74.9, 67.7, 66.6, 62.5, 61.9, 58.7, 31.6, 14.1, 13.6 (one sp carbon not visible). IR (thin film): ν_max = 3285, 2983, 1739, 1597, 1494, 1454, 1390, 1368, 1229, 1186, 1152, 1075, 1020, 942, 875, 755, 700 cm^-1. HRMS (EI): m/z calcd for C₂₄H₂₅NO₅: 407.1733; found: 407.1738.

For reviews of the Pauson-Khand reaction see:

11a Gibson SE. Mainolfi N. Angew. Chem. Int. Ed.  2005,  44:  3022 

11b Blanco-Urgoiti J. Anorbe L. Perez-Serrano L. Dominguez G. Perez-Castells J. Chem. Soc. Rev.  2004,  33:  32 

12

Typical Experimental Procedure for the Pauson-Khand Reactions of the Cobalt-Complexed Cycloadducts. Preparation of Compound 31.
Tetrahydro-1,2-oxazine 14 (102 mg, 0.147 mmol) was dissolved in 4 mL of CH₂Cl₂ and ethene gas was bubbled through the solution for 5 min. 4-Methylmorpholine N-oxide (103 mg, 0.882 mmol) was then added and the reaction mixture was stirred under a balloon of ethene until the reaction appeared to subside by TLC. The solvent was then evaporated and the crude reaction mixture was purified by chromatography on silica gel (5% EtOAc-hexane). Tetrahydro-1,2-oxazine 31 was obtained as a white solid (42 mg, 0.091 mmol). Alternatively, tetrahydro-1,2-oxazine 14 could be prepared according to the typical procedure for the homo-[3+2]-dipolar cycloaddition and the reagents for the Pauson-Khand reaction could be added to the reaction mixture once the cycloaddition was complete. Tetrahydro-1,2-oxazine 31 was obtained in an overall yield of 68% using this one-pot procedure. Mp 47-49 °C; R _f = 0.20 (25% EtOAc-hexane). ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (s, 1 H), 7.56-7.54 (m, 2 H), 7.18-7.12 (m, 5 H) 7.06 (d, J = 8.0 Hz, 2 H), 6.80 (t, J = 7.2 Hz, 1 H), 5.73 (s, 1 H), 4.82 (d, J = 8.0 Hz, 1 H), 4.43-4.30 (m, 2 H), 3.97-3.80 (m, 2 H), 2.80 (dd, J = 14.2, 1.8 Hz, 1 H), 2.72-2.62 (m, 3 H), 2.50-2.48 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 206.9, 169.2, 167.8, 159.0, 148.0, 144.6, 134.9, 130.6, 128.4, 128.0, 127.8, 121.5, 115.7, 72.5, 65.9, 62.3, 61.7, 58.7, 34.9, 29.9, 26.9, 14.0, 13.6. IR (thin film): ν_max = 3095, 3062, 3029, 2984, 2932, 1738, 1706, 1600, 1493, 1453, 1367, 1344, 1246, 1186, 1089, 1030, 961, 919, 876, 789, 756, 734, 702, 622 cm^-1. HRMS (EI): m/z calcd for C₂₇H₂₉NO₆: 463.1995; found: 463.1998.

13

In the case of ethylene, a balloon of the gas was placed over the reaction mixture and NMO was added.

14

It is notable that the one-pot cycloaddition/Pauson-Khand yield for adduct 31 is higher than the combined yield for the two individual processes. The reasons for this are not clear although the reaction time allowed for the Pauson-Khand in the latter case was significantly longer and was done in the presence of a Lewis acid. This is under investigation.