A Homo 3+2 Dipolar Cycloaddition: The Reaction of Nitrones ... · Supporting information: Page 1 A Homo 3+2 Dipolar Cycloaddition: The Reaction of Nitrones with Cyclopropanes Ian

Supporting Information

for

Angew. Chem. Int. Ed. Z51573

© Wiley-VCH 200369451 Weinheim, Germany

Supporting information: Page 1

A Homo 3+2 Dipolar Cycloaddition: The Reaction of Nitrones with Cyclopropanes

Ian S. Young and Michael A. Kerr*

[*] Prof. Michael A. KerrDepartment of ChemistryThe University of Western OntarioLondon, Ontario N6A 5B7 CanadaFax: 519-661-3022E-mail: [email protected]

mailto:[email protected]


Experimental

General

Melting points were determined using a Gallenkamp melting point apparatus and areuncorrected. Infrared spectra were obtained as thin films on NaCl plates using a Bruker Vector33 FT-IR instrument. NMR experiments were performed on a Varian Inova 600 or Mercury 400instrument and samples were obtained in CDCl3 (referenced to 7.26 ppm for 1H and 77.0 for13C). Coupling constants (J) are in Hz. Mass spectra were obtained on a Finnigan MAT 8200spectrometer at 70 eV. Dichloromethane was distilled prior to use according to the standard procedure. All otherreagents and solvents were used as purchased from Aldrich or Lancaster. Reactions werechecked for completion by TLC (EM Science, silica gel 60 F254). Flash chromatography wasperformed using silica gel purchased from Silicycle Chemical Division Inc. (230-400 mesh)

Typical Experimental Procedure for Preparation of Adducts 3

Yb(OTf)3•xH2O (5 mol %) was added to a solution of cyclopropane 2 (0.5 mmol) and nitrone 1(0.6 mmol) in methylene chloride (4 mL) or 1,2-dichloroethane. Reactions in methylenechloride were performed at r.t., while reactions in 1,2-dichloroethane were refluxed for the timeindicated in Table 1. A few examples required higher mol % of Yb(OTf)3•xH2O to preventnitrone oligomerization, the mol % used is indicated in the physical data. The reaction mixturewas then pre-absorbed onto silica gel and pure product was obtained after flash columnchromatography on silica gel (elution with 2% EtOAc in hexanes). Samples could berecrystallized from CH2Cl2/hexanes if desired.

NO

OO

OO

Entry 1, Compound 3a

71 % yield, r.t., 18 hrs, 20% Yb(OTf)3•xH2O; colorless prisms, m.p. 117-118 oC; Rf = 0.57 (30%EtOAc in hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.56-7.53 (m 2H), 7.18-7.16 (m, 3H), 6.93(s, 4H), 5.63 (s, 1H), 4.39-4.32 (m, 3H), 4.13-4.06 (m, 1H), 3.98-3.89 (m, 1H), 3.89-3.81 (m,1H), 2.85 (ddd, J = 14.4, 5.2, 13.2 Hz, 1H), 2.42 (d, J = 14.4 Hz, 1H) 2.17 (s, 3H), 1.34 (t, J =7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H) ; 13C NMR (100 MHz, CDCl3): δ = 169.9, 168.1, 146.4,135.2, 130.9, 130.7, 129.0, 127.9, 127.7, 116.0, 67.5, 67.0, 62.1, 61.6, 58.2, 25.5, 20.5, 14.1,13.7; IR (thin film): νmax = 3027, 2981, 2922, 1738, 1610, 1508, 1450, 1367, 1229, 1192, 1108,1022, 970, 876, 779, 708; HRMS calc’d for C23H27O5N = 397.1890, found 397.1892.


NO

OO

OO

Entry 2, Compound 3b

94 % yield, r.t., 18 hrs, 5% Yb(OTf)3•xH2O; colorless needles, m.p. 154-155 oC; Rf = 0.53 (30%,EtOAc in hexanes); 1H-NMR (600 MHz, CDCl3): δ = 7.62 (dd, J = 1.5, 8.4 Hz, 2H), 7.59 (d, J =7.5 Hz, 2H), 7.48 (dd, J = 7.5, 7.5 Hz, 2H), 7.43-7.40 (m, 1H), 7.24-7.20 (m, 3 H), 7.03 (d, J =8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 5.78 (s, 1H), 5.07 (dd, J = 12.0, 3.0 Hz, 1H), 3.95, (s, 3H),3.49 (s, 3H), 2.91-2.80 (m, 2H), 2.20 (s, 3H); 13C NMR (150 MHz, CDCl3): δ = 170.1, 168.3,146.2, 139.5, 135.1, 130.9, 130.5, 129.0, 128.6, 128.2, 128.0, 127.9, 126.4, 116.0, 78.7, 66.0,59.5, 53.4, 52.5, 31.6, 20.5; IR (thin film): νmax = 3062, 3028, 2950, 2923, 2855, 1742, 1508,1437, 1258, 1232, 1177, 1085, 1049, 987, 952, 816, 743; HRMS calc’d for C27H27O5N =445.1890, found 445.1886. Cis conformation confirmed by X-Ray diffraction.

NO

OO

OO

Entry 3, Compound 3c

95% yield, r.t., 5 hrs, 5% Yb(OTf)3•xH2O; colorless needles, m.p. 141-142 oC; Rf = 0.36 (20%EtOAc in hexanes); 1H-NMR (600 MHz, CDCl3): δ = 7.56-7.53 (m, 2H), 7.51-7.49 (d, J = 7.2Hz, 2H), 7.37 (dd, J = 7.8, 7.8Hz, 2H), 7.31-7.28 (m, 1H), 7.20-7.18 (m, 3H), 6.98 (d, J = 8.1Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 16.2 Hz, 1H), 6.41 (dd, J = 16.2, 6.4 Hz, 1H), 5.66(s, 1H), 4.69-4.65 (m, 1H), 3.91 (s, 3H), 3.47 (s, 3H), 2.71-2.64 (m, 2H), 2.18 (s, 3H); 13C NMR(100 MHz, CDCl3): δ = 170.0, 168.3, 146.2, 136.6, 135.0, 132.5, 131.0, 130.5, 129.0, 128.6,128.0, 128.0, 127.9, 127.0, 126.6, 116.1, 77.1, 66.1, 59.1, 53.4, 52.6, 30.6, 20.5; IR (thin film):νmax = 3057, 3026, 2951, 2928, 1741, 1612, 1508, 1438, 1239, 1200, 1075, 965, 816, 747, 698;HRMS calc’d for C29H29O5N = 471.2047, found 471.2034 Cis conformation confirmed by X-Ray diffraction.


NO

OO

OO

Entry 4, Compound 3d

73% yield, r.t., 42 hrs, 5% Yb(OTf)3•xH2O; low melting solid; Rf = 0.60 (30% EtOAc inhexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.57-7.54 (m, 2H), 7.20-7.17 (m, 3H), 7.01 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.10 (ddd, J = 17.6, 10.4, 5.2 Hz, 1H), 5.68 (s, 1H), 5.53(d, J =17.6 Hz, 1H), 5.36 (d, J = 10.4 Hz, 1H), 4.58-4.52 (m, 1H), 4.44-4.34 (m, 2H), 3.98-3.91(m, 1H), 3.91-3.84 (m, 1H), 2.64-2.61 (m, 2H), 2.19 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.03 (t, J =7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 169.4, 167.8, 146.2, 136.0, 134.9, 130.8, 130.6,128.9, 127.8, 127.6, 117.0, 115.9, 77.0, 66.2, 62.1, 61.6, 58.8, 30.3, 20.4, 14.0, 13.5; IR (thinfilm): νmax = 2983, 2929, 2872, 1739, 1612, 1509, 1449, 1254, 1230, 1152, 1087, 1027, 985, 931,875, 811, 701; HRMS calc’d for C25H29O5N = 423.2047, found 423.2041

NO

OO

OO

CH3

Entry 5, Compound 3e

76 % yield, reflux C2H4Cl2, 18 hrs, 5% Yb(OTf)3•xH2O; thick yellow oil; Rf = 0.51 (30% EtOAcin hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.52-7.49 (m, 2H), 7.26-7.24 (m, 3H), 4.65 (s,1H), 4.25 (q, J = 7.2 Hz, 2H), 4.15 (m, 1H), 3.91(ddd, J = 4.8, 11.6, 11.6 Hz, 1H), 3.86-3.80 (m,1H), 3.76-3.68 (m, 1H), 2.67-2.60 (m, 1H) 2.38 (s, 3H), 2.30 (broad d, J = 14.4 Hz, 1H), 1.24 (t,J = 7.0 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 169.7, 168.2, 135.0,130.8, 127.9, 127.6, 69.0, 66.4, 61.7, 61.2, 57.6, 43.3, 25.5, 13.9, 13.5; ); IR (thin film): νmax =3060, 2983, 2913, 2878, 1738, 1449, 1389, 1367, 1251, 1189, 1159, 1102, 1061, 1042, 1023,962, 862, 756; HRMS calc’d for C17H23O5N = 321.1577, found 321.1569.


NO

OO

OO

CH3

Entry 6, Compound 3f

84 % yield, r.t., 48 hrs, 5% Yb(OTf)3•xH2O; colorless prisms, m.p. 94-96 oC; Rf = 0.43 (30%EtOAc in hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.64 (broad s, 2H), 7.51 (d, J = 7.2 Hz,2H), 7.43 (t, J = 7.4 Hz, 2 H), 7.38-7.32 (m, 4H), 4.92 (dd, J = 2.6, 11.8 Hz, 1H), 4.87 (s, 1H),3.91 (s, 3H), 3.40 (broad s, 3H), 2.79-2.64 (m, 1H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3): δ= 170.2, 168.3, 139.9, 134.5, 130.8, 128.5, 128.2, 128.03, 127.98, 126.3 77.8, 67.6, 59.2, 53.3,52.4, 43.3, 30.8; IR (thin film): νmax = 3029, 2997, 2953, 2866, 1743, 1495, 1436, 1258, 1194,1098, 1061, 952, 881, 831, 753, 700, 645, 609; HRMS calc’d for C21H23O5N = 369.1577, found369.1576; Cis conformation confirmed by X-ray diffraction.

NO

OO

OO

CH3

Entry 7, Compound 3g

74 % yield, r.t., 36 hrs, 5% Yb(OTf)3•xH2O; colorless solid, m.p. 143-144 oC; Rf = 0.41 (30 %EtOAc in hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.48 (broad s, 2H), 7.36 (d, J = 7.2 Hz,2H). 7.27-7.16 (m, 6H), 6.64 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 4.2 Hz, 1H), 4.71 (s, 1H),4.47-4.44 (m, 1H), 3.79 (s, 3H), 3.30 (broad s, 3H), 2.51-2.38 (m, 5H); 13C NMR (100 MHz,CDCl3): δ = 170.2, 168.4, 136.4, 132.2, 130.9, 128.5, 128.3, 128.2, 128.0, 127.9, 127.4, 126.5,76.2, 68.0, 58.8, 53.3, 53.4, 43.3, 29.9; IR (thin film): νmax = 3025, 2999, 2950, 2891, 1737,1434, 1338, 1261, 1182, 1158, 1096, 1071, 1021, 970, 950, 850, 774, 749; HRMS calc’d forC23H25O5N = 395.1734, found 395.1732.


NO

OO

OO

CH3

Entry 8, Compound 3h

52% yield, reflux C2H4Cl2 18 hrs, 5% Yb(OTf)3•xH2O; yellow oil; Rf = 0.57 (30% EtOAc inhexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.53-7.51 (m, 2H), 7.29-7.26 (m, 3H), 5.98 (ddd, J =17.6, 12.4, 5.6 Hz, 1H), 5.38 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 12.4 Hz), 4.74 (s, 1H), 4.38-4.28(m, 3H), 3.89-3.72 (m, 2H), 2.45-2.43 (m, 5H), 1.30 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.0 Hz, 3H);13C NMR (100 MHz, CDCl3): δ = 169.6, 168.0, 136.6, 134.4, 131.0, 128.0, 127.8, 76.2, 67.7,61.9, 61.4, 58.5, 43.2, 29.6, 13.9, 13.5; IR (thin film): νmax = 3088, 3062, 2984, 2884, 1739,1449, 1389, 1368, 1254, 1191, 1158, 1100, 1079, 1002, 957, 929, 862; HRMS calc’d forC19H25O5N = 347.1734, found 347.1732.

NO

OO

OO

CH3

O

O

Entry 9, Compound 3i

50% yield, r.t., 42 hrs, 5% Yb(OTf)3•xH2O; colorless prisms, m.p. 121-122 oC; Rf = 0.34 (30%EtOAc in hexanes); 1H-NMR (600 MHz, CDCl3): δ = 7.43 (d, J = 7.2 Hz, 2H), 7.33 (dd, J = 7.8,7.8 Hz, 2H), 7.27 (dd, J = 7.2, 7.2 Hz, 1H), 7.22 (broad s, 1H), 6.92 (d, J = 7.8 Hz, 1H) 6.73 (d, J= 7.8 Hz, 1H), 6.70 (d, J = 16.2, 1H), 6.29 (broad d, J = 16.2 Hz, 1H), 5.95 (dd, J =1.8, 5.1 Hz,2H), 4.70 (s, 1H), 4.50-4.47 (m, 1H), 3.86 (s, 3H), 3.46 (broad s, 3H), 2.51-2.48 (m, 5H); 13CNMR (150 MHz, CDCl3): δ = 170.2, 168.4, 147.4, 147.2, 136.4, 132.4, 128.5, 127.9, 127.4,126.6, 124.7, 111.0, 107.7, 101.0, 76.2, 67.2, 58.9, 53.3, 52.5, 43.2, 29.9; ); IR ( thin film): νmax =2997, 2953, 2923, 2887, 1741, 1490, 1445, 1250, 1197, 1173, 1122, 1093, 1073, 1038, 967, 912,803, 735; HRMS calc’d for C24H25O7N = 439.1631, found 439.1631.


NH

NO

OO

OO

Entry 10, Compound 3j

96% yield, r.t., 3 hrs, 5% Yb(OTf)3•xH2O; colorless needles, decomposes at 90 oC; Rf = 0.40(30% EtOAc in hexanes); 1H-NMR (600 MHz, CDCl3): δ = 8.05 (broad s, 1H), 7.68 (d, J = 6.6Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.46 (dd, J = 7.2, 7.2 Hz, 2H), 7.40(dd, J = 7.2, 7.2 Hz, 1H), 7.18-7.17 (m, 1H), 7.11-7.07 (m, 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.8 (d,J = 8.7 Hz, 2H), 6.26 (s, 1H), 5.11 (dd, J = 3.3, 10.8 Hz, 1H), 3.94 (s, 3H), 3.25 (s, 3H), 2.83-2.76 (m, 2H), 2.11 (s, 3H) ; 13C NMR (100 MHz, CDCl3): δ = 170.2, 168.4, 146.4, 139.4, 134.6,131.0, 129.0, 128.6, 128.2, 127.9, 126.5, 125.2, 121.6, 119.3, 118.3, 115.7, 111.0, 108.3, 78.559.1, 58.2, 53.3, 52.5, 31.2, 20.4; IR (thin film): νmax = 3412, 3058, 3028, 2950, 2924, 1737,1507, 1454, 1435, 1257, 1228, 1180, 815, 740; HRMS calc’d for C29H28O5N2 = 484.1999, found484.1994.

NO

OO

OO

I

Compound 4

77% yield, 9:7 (A:B) mixture of rotamers, r.t., 42 hrs, 10% Yb(OTf)3•xH2O; m.p. 120-128 oC; Rf= 0.54 (30% EtOAc in hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.78 (dt, J = 1.6, 8.0 Hz, 2H,rotamer B), 7.48 (dd, J = 1.6, 6.8 Hz, 2H, rotamer A), 7.31-7.29 (dd, J = 1.6, 8.0 Hz, 2H,rotamer B), 7.25-7.19 (m, 3H, rotamer A), 7.13 (ddd, J = 1.6, 8.4, 8.4 Hz, 1H, rotamer A), 7.09-7.04 (m, 3H, 2 H rotamer A, 1H rotamer B), 6.95 (ddd, J = 1.4, 8.4, 8.4 Hz, 1H, rotamer A),6.77-6.96 (m, 4H, rotamer B), 6.06 (ddd, J = 5.2, 10.4, 16.8, 1H, rotamer A), 5.81 (ddd, J = 6.4,10.8, 16.8, 1H, rotamer B), 5.68-5.63 (m, 1H, rotamer B), 5.50-5.44 (m, 1H rotamer A, 1Hrotamer B), 5.41-5.36 (m, 1H rotamer A, 1H rotamer B), 5.31 (ddd, J = 1.4, 1.4, 9.2 Hz, 1H,rotamer A), 5.22 (ddd, J = 1.4, 1.4, 9.2 Hz, 1H, rotamer B), 4.97-4.92 (m, 1H, rotamer A), 3.92(s, 3H, rotamer A), 3.72 (s, 3H, rotamer B), 3.44 (s, 3H, rotamer B), 3.41 (s, 3H, rotamer A),2.71-2.53 (m, 1H, rotamer B, 2H, rotamer A), 2.00 (dd, J = 13.6, 10.0 Hz, 1H, rotamer B); IR(thin film): νmax = 3058, 3023, 2949, 2901, 1736, 1579, 1464, 1436, 1255, 1147, 1084, 1021,989, 933, 766, 720; HRMS calc’d for C22H22O5NI = 507.0543, found 507.0542


Heck Coupling

To a solution of the iodocycloadduct 4 (0.4 mmol) in CH3CN (5 mL) was added triethylamine(1.2 mmol) and Pd(PPh3)4 (20 mol %). The reaction mixture was heated at reflux under anatmosphere of argon for 18 hours, after which TLC indicated complete consumption of thestarting material. The reaction mixture was cooled to room temperature and directly absorbedonto silica gel. Pure product was obtained after flash column chromatography on silica gel(EtOAc and hexanes).

NO

O

O

OO

Compound 5

73% yield, reflux CH3CN, 18 hrs, 20% Pd(PPh3)4; yellow solid; decomposes at 60 oC; Rf = 0.47(30% EtOAc in hexanes); 1H-NMR (400 MHz, CDCl3): δ = 7.71-7.68 (m, 2H), 7.65 (dd, J = 1.6,8.0 Hz, 1H), 7.38-7.31 (m, 3H), 7.27-7.25 (m, 1H), 7.12-7.08 (m, 1H), 7.01 (dd, J = 1.2, 8.0 Hz,1H), 5.74 (d, J = 0.8 Hz, 1H), 5.31 (s, 1H), 5.06 (d, J = 0.8 Hz, 1H), 5.05-5.02 (m, 1H), 3.34 (s,3H), 3.32-3.27 (m, 4H), 2.54 (ddd, J = 0.8, 2.8, 14.4 Hz, 1H); 13C NMR (150 MHz, CDCl3): δ =169.9, 168.9, 146.6, 139.0, 138.3, 129.1, 128.7, 128.2, 128.0, 124.8, 123.1, 122.8, 121.7, 107.5,71.6, 68.3, 52.9, 52.5, 52.1, 30.9; IR (thin film): νmax = 3060, 3027, 2948, 2927, 2922, 1737,1627, 1601, 1482, 1436, 1251, 1202, 1073, 1024, 953, 910, 759; HRMS calc’d for C22H21O5N =379.1420, found 379.1421.














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A Homo 3+2 Dipolar Cycloaddition: The Reaction of Nitrones ... · Supporting information: Page 1 A Homo 3+2 Dipolar Cycloaddition: The Reaction of Nitrones with Cyclopropanes Ian