Preparation and rearrangement of N-vinyl nitrones: Synthesis of spiroisoxazolines and fluorene-tethered isoxazoles

Article abstract of DOI:10.1021/ol3022885

N-Vinyl nitrones derived from fluorenone have been prepared via a copper-mediated coupling between fluorenone oxime and vinyl boronic acids. These compounds undergo subsequent rearrangement and addition reactions that are distinct from the traditional [3 + 2] cycloaddition reactivity of nitrones. Thermal rearrangements of fluorenone N-vinyl nitrones give spiroisoxazolines, while treatment with alkynes provides fluorene-tethered isoxazoles. The scope and limitations of the preparation of fluorenone N-vinyl nitrones and their subsequent rearrangement and addition reactions are discussed.

Full text of DOI:10.1021/ol3022885

Preparation and Rearrangement of N-Vinyl Nitrones: Synthesis of Spiroisoxazolines and
Fluorene-Tethered Isoxazoles
*
Dong-Liang Mo, Donald A. Wink, Laura L. Anderson
Department of Chemistry, University of Illinois, Chicago,
845 W. Taylor St., Chicago, IL 60607-7061
lauralin@uic.edu
Supporting Information:
Contents:
I.
General Experimental Information
S-2
II.
Synthesis of N-Vinyl Nitrones 3 via Copper-Mediated Coupling of S-3
Fluorenone Oxime 1 and Vinyl Boronic Acids 2 (Scheme 2)
III.
IV.
Synthesis of Spiroisoxazolines 3 via Thermal Rearrangement of Fluorenone S-10
N-Vinyl Nitrones (Table 2)
Additions and Rearrangements of N-Vinyl Nitrones: Preparation of S-15
Fluorene-Tethered Isoxazoles (Table 3)
V.
Independent Synthesis of Nitrone 3b
Mechanistic Discussion
S-19
S-21
VI.
VII
Three-Dimensional Representations of 3g and 5m as Determined by X-Ray S-22
Crystallography
VIII. References
S-23
S-24
S-69
S-98
S-124
1
1
1
1
13
IX.
X.
H, C, and DEPT Data for Fluorene N-Vinyl Nitrones 3
13
H, C, and DEPT Data for Spiroisoxazolines 5
13
XI.
XII.
H, C, and DEPT Data for 6-14
13
H, C, and DEPT Data for 4, S-1, and S-2

I. General Experimental Information.
1
13
H NMR and C NMR spectra were recorded at ambient temperature using 500 MHz spectrometers. The
data are reported as follows: chemical shift in ppm from internal tetramethylsilane on the  scale,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants
(
Hz), and integration. High resolution mass spectra were acquired on an LTQ FT spectrometer, and were
obtained by peak matching. Melting points are reported uncorrected. Analytical thin layer
chromatography was performed on 0.25 mm extra hard silica gel plates with UV254 fluorescent indicator.
Medium pressure liquid chromatography was performed using force flow of the indicated solvent system
down columns packed with 60Å (40 – 60 µm) mesh silica gel (SiO ). Unless otherwise noted, all
2
reagents and solvents were obtained from commercial sources and, where appropriate, purified prior to
use. THF, CH Cl , and toluene were dried by filtration through alumina according to the procedure of
2
2
1
Grubbs. Vinyl boronic acids were prepared according to literature procedures and used without further
2
purification.

II. Synthesis of N-Vinyl Nitrones 3 via Copper-Mediated Coupling of Fluorenone Oxime 1 and
Vinyl Boronic Acids 2 (Scheme 2).
General Procedure A. A scintillation vial was charged with 9H-fluoren-9-one oxime 1 (1 equiv), vinyl
boronic acid 2 (3 equiv), Cu(OAc) (2 equiv), and anhydrous Na SO (8-9 equiv). These solids were then
2
2
4
diluted with 1,2-dichloroethane (DCE) to form a 0.1 M solution of 9H-fluoren-9-one oxime. Pyridine (10
equiv) was added to the resulting slurry via syringe. The scintillation vial was then capped with a septum
pierced with a ventilation needle and the reaction mixture was stirred at 25 ºC for 18 h. DCE and pyridine
were then removed under reduced pressure and the crude reaction mixture was purified by medium
pressure chromatography (1:20-1:3; ethyl acetate:hexanes) to give 3 as a yellow oil or solid.
Nitrone 3a: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
(
0.059 g; 0.30 mmol), (Z)-hex-3-en-3-ylboronic acid 2a (0.115 g, 0.899 mmol), Cu(OAc) (0.108 g, 0.595
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4
afforded 3a as a yellow oil (0.051 g, 61%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.87 (d, J = 7.5 Hz, 1H), 7.70-7.68 (m, 3H),
3
7
1
.47-7.44 (m, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34-7.31 (m, 1H), 7.21-7.18 (m, 1H), 5.75 (t, J = 7.5 Hz,
H), 2.87-2.83 (m, 1H), 2.60-2.55 (m, 1H), 2.33-2.28 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H), 1.14 (t, J = 7.5
1
3
Hz, 3H); C NMR (125 MHz, CDCl ): δ 146.6, 144.0, 139.3, 138.7, 132.5, 130.9, 130.8, 129.0, 128.9,
3
1
1
2
29.8, 127.1, 124.4, 124.2, 120.3, 119.4, 21.8, 20.6, 13.0, 11.6; IR (thin film) 3053, 2966, 2926, 2872,
-
1
+
606, 1526, 1446, 1336, 1256, 1209, 773, 725 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H)
1
9
20
78.1545, found 278.1541.
Nitrone 3b: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), cyclohexenylboronic acid 2b (0.113 g, 0.897 mmol), Cu(OAc) (0.108 g, 0.595
(
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4

afforded 3b as a yellow solid (0.070 g, 84%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.85 (d, J = 8.0 Hz, 1H), 7.68-7.63 (m, 3H),
3
7
1
.46-7.43 (m, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.25-7.22 (m, 1H), 6.05-6.04 (m,
H), 2.85-2.81 (m, 1H), 2.40-2.31 (m, 3H), 1.97-1.93 (m, 2H), 1.83-1.80 (m, 2H); C NMR (125 MHz,
1
3
CDCl ): δ 145.3, 143.5, 139.2, 138.8, 132.4, 130.8, 130.6, 128.9, 128.8, 127.4, 127.0, 124.9, 123.9, 120.3,
3
1
19.4, 25.4, 24.2, 22.2, 21.2; IR (thin film) 3057, 2934, 2857, 1606, 1529, 1446, 1249, 1209, 769, 725
-
1
+
cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 276.1388, found 276.1396; mp 176-177 ºC.
19
18
Nitrone 3b (using 1.5 equiv of 2b): General procedure A was employed using the following reagents:
H-fluoren-9-one oxime 1 (0.059 g; 0.30 mmol), cyclohexenylboronic acid 2b (0.057 g, 0.45 mmol),
Cu(OAc) (0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol).
9
2
2
4
General procedure A afforded 3b as a yellow solid (0.044 g, 53%) after purification using medium
pressure chromatography (1:10; ethyl acetate: hexanes).
Nitrone 3c (using 2 equiv of 2c): General procedure A was employed using the following reagents: 9H-
fluoren-9-one oxime 1 (0.059 g; 0.30 mmol), Z-2-buten-2-yl boronic acid 2c (0.060 g, 0.60 mmol),
Cu(OAc) (0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol).
2
2
4
General procedure A afforded 3c as a yellow oil (0.045 g, 60%) after purification using medium pressure
1
chromatography (1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.84 (d, J = 7.5 Hz, 1H),
3
7
1
.67-7.65 (m, 2H), 7.49 (d, J = 7.5 Hz, 1H), 7.44-7.41 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.33-7.30 (m,
H), 7.23 (t, J = 7.5 Hz, 1H), 5.84 (q, J = 6.5 Hz, 1H), 2.22 (s, 3H), 1.86 (d, J = 6.0 Hz, 3H); C NMR
1
3
(
125 MHz, CDCl ): δ 143.2, 142.9, 139.2, 138.8, 132.4, 130.8, 130.6, 129.0, 128.8, 127.5, 127.0, 123.8,
3
1
7
23.0, 120.3, 119.5, 13.9, 12.9; IR (thin film) 3053, 2919, 2850, 1606, 1529, 1446, 1253, 1206, 696, 769,
-1
+
32 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 250.1232, found 250.1223.
17
16
Nitrone 3d: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), cyclopentenylboronic acid 2d (0.100 g, 0.893 mmol), Cu(OAc) (0.108 g, 0.595
(
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4
afforded 3d as a yellow solid (0.058 g, 74%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.86 (d, J = 7.0 Hz, 1H), 7.67-7.66 (m, 2H),
3
7
.56 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.0 Hz, 1H), 7.39-7.31 (m, 2H), 7.23 (t, J = 7.0 Hz, 1H), 6.04-6.03
1
3
(
m, 1H), 2.93-2.90 (m, 2H), 2.68-2.65 (m, 2H), 2.27-2.24 (m, 2H); C NMR (125 MHz, CDCl ): δ 147.5,
3
144.8, 139.3, 138.8, 132.2, 131.0, 130.4, 129.2, 128.8, 127.5, 127.4, 127.1, 123.6, 120.4, 119.5, 31.6,

-1
3
1.1, 22.4; IR (thin film) 2963, 2923, 2854, 1602, 1536, 1442, 1256, 1206, 769, 725 cm ; HRMS (ESI)
+
m/z calcd. for C H NO (M+H) 262.1232, found 262.1228; mp 123-124 ºC.
18
16
Nitrone 3e: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), (Z)-cycloheptenylboronic acid 2e (0.113 g, 0.807 mmol), Cu(OAc) (0.108 g, 0.595
(
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4
afforded 3e as a yellow solid (0.068g, 78%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.84 (d, J = 7.0 Hz, 1H), 7.73 (d, J = 8.5
3
Hz, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.39 (t, J = 7.0 Hz, 1H), 7.34 (t, J = 7.5 Hz,
1
2
1
3
H), 7.25 (t, J = 7.5 Hz, 1H), 6.15-6.12 (m, 1H), 2.81-2.78 (m, 1H), 2.68-2.63 (m, 1H), 2.36-2.33 (m,
1
3
H), 1.97-1.95 (m, 2H), 1.89-1.87 (m, 2H), 1.79-1.72 (m, 2H); C NMR (125 MHz, CDCl ): δ 149.2,
3
42.9, 139.2, 138.8, 132.6, 130.9, 130.8, 129.1, 128.9, 128.8, 127.3, 127.0, 123.9, 120.3, 119.4, 31.6,
-1
0.7, 27.3, 26.7, 26.3; IR (thin film) 3054, 2921, 2852, 1603, 1527, 1442, 1341, 1252, 768, 727 cm ;
+
HRMS (ESI) m/z calcd. for C H NO (M+H) 290.1545, found 290.1539; mp 143-144 ºC.
20
20
Nitrone 3f: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), 3,6-dihydro-2H-pyran-4-ylboronic acid 2f (0.115 g, 0.899 mmol), Cu(OAc) (0.108
(
2
g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure
2
4
A afforded 3f as a yellow solid (0.068 g, 81%) after purification using medium pressure chromatography
1
(
1:3; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.83 (d, J = 7.5 Hz, 1H), 7.71-7.67 (m, 3H),
3
7
4
1
6
.48-7.45 (m, 1H), 7.40-7.33 (m, 2H), 7.27-7.24 (m, 1H), 6.10-6.09 (m, 1H), 4.41-4.37 (m, 2H), 4.23-
1
3
.20 (m, 1H), 3.92-3.91 (m, 1H), 2.90-2.81 (m, 1H), 2.70-2.67 (m, 1H); C NMR (125 MHz, CDCl ): δ
3
44.3, 142.1, 139.3, 139.0, 132.1, 131.2, 130.3, 129.3, 128.8, 127.8, 127.0, 124.1, 123.3, 120.4, 119.5,
-1
4.3, 64.4, 25.7; IR (thin film) 3053, 2930, 2860, 1606, 1533, 1438, 1344, 1256, 1206, 769, 725 cm ;
+
HRMS (ESI) m/z calcd. for C H NO (M+H) 278.1811, found 278.1173; mp 180-181 ºC.
18
16
2

Nitrone 3g: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
(
(
0.059 g; 0.30 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid 2g (0.165 g, 0.897 mmol), Cu(OAc)2
0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General
2
4
procedure A afforded 3g as a yellow solid (0.073 g, 72%) after purification using medium pressure
1
chromatography (1:3; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.84 (d, J = 7.0 Hz, 1H),
3
7
7
2
1
.96 (d, J = 7.5 Hz, 1H), 7.66-7.64 (m, 2H), 7.45-7.42 (m, 1H), 7.38-7.35 (m, 1H), 7.33-7.30 (m, 1H),
.24-7.21 (m, 1H), 5.92-5.91 (m, 1H), 4.10-4.03 (m, 4H), 2.97-2.93 (m, 1H), 2.67-2.57 (m, 2H), 2.43-
13
.39 (m, 1H), 2.08-2.04 (m, 2H); C NMR (125 MHz, CDCl ): δ 144.5, 144.3, 139.1, 139.0, 132.3,
3
31.0, 130.6, 129.0, 128.7, 127.8, 127.0, 124.7, 122.2, 120.1, 119.5, 106.9, 64.8, 64.6, 34.7, 30.7, 24.5; IR
-1
(
thin film) 3061, 2952, 2883, 1606, 1529, 1449, 1118, 1063, 769, 732 cm ; HRMS (ESI) m/z calcd. for
+
C H NO (M+H) 334.1443, found 334.1447; mp 195-197 ºC.
2
1
20
3
Nitrone 3h: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), 4-phenylcyclohex-1-enylboronic acid 2h (0.164 g, 0.812 mmol), Cu(OAc) (0.108
(
2
g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure
2
4
A afforded 3h as a yellow solid (0.083 g, 78%) after purification using medium pressure chromatography
1:10; ethyl acetate: hexanes). Nitrone 3h was isolated as a mixture of C(vinyl)–N bond rotomers which
(
13
1
were only distinguishable by C NMR spectroscopy. H NMR (500 MHz; CDCl ): δ 8.88 (d, J = 7.0 Hz,
3
1
7
1
1
H), 7.78 (d, J = 7.0 Hz, 1H), 7.72 (t, J = 6.5 Hz, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.42-7.33 (m, 6H), 7.31-
.27 (m, 2H), 6.15-6.14 (m, 1H), 2.95-2.07 (m, 2H), 2.64-2.47 (m, 3H), 2.28-2.23 (m, 1H), 2.15-2.12 (m,
1
3
H); C NMR (125 MHz, CDCl ) rotomer A: δ 145.3, 139.4, 138.9, 132.4, 131.0, 130.6, 129.1, 128.9,
3
13
28.7, 127.5, 127.1, 126.8, 126.7, 124.6, 124.5, 124.0, 123.6, 120.4, 119.5, 39.4, 32.3, 29.6, 26.9;
C
NMR (125 MHz, CDCl ) rotomer B: δ 145.1, 139.3, 138.9, 132.4, 131.0, 130.6, 129.1, 128.9, 128.7,
3
1
3
27.5, 127.1, 126.8, 126.7, 124.6, 124.5, 124.0, 123.6, 120.4, 119.5, 38.6, 32.1, 29.4, 25.7; IR (thin film)
-1
057, 3022, 2918, 2836, 1603, 1531, 1445, 1245, 699, 679 cm ; HRMS (ESI) m/z calcd. for C H NO
2
5
22
+
(
M+H) 352.1701, found 352.1711; mp 175-176 ºC.
Nitrone 3i: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
(
(
0.059 g; 0.30 mmol), 4-tert-butylcyclohex-1-enylboronic acid 2i (0.164 g, 0.901 mmol), Cu(OAc)2
0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General
2
4
procedure A afforded 3i as a yellow solid (0.071 g, 71%) after purification using medium pressure

chromatography (1:10; ethyl acetate: hexanes). Nitrone 3i was a mixture of C(vinyl)–N bond rotomers
13
1
which were only distinguishable by C NMR spectroscopy. H NMR (500 MHz; CDCl ): δ 8.84 (d, J =
3
7
7
1
1
.0 Hz, 1H), 7.68-7.76 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H),
.26-7.25 (m, 1H), 6.05-6.03 (m, 1H), 2.89-2.86 (m, 1H), 2.43-2.31 (m, 2H), 2.15-2.20 (m, 2H), 1.55-
1
3
.54 (m, 2H), 0.97 (s, 9H); C NMR (125 MHz, CDCl ) rotomer A: δ 145.3, 143.9, 139.3, 138.8, 132.4,
3
13
30.8, 128.9, 128.8, 127.5, 127.0, 125.2, 124.0, 123.6, 120.3, 119.4, 43.6, 32.4, 27.4, 27.2, 26.2, 23.8; C
NMR (125 MHz, CDCl ) rotomer B: δ 145.1, 143.3, 139.1, 138.8, 132.4, 130.7, 128.9, 128.8, 127.5,
3
1
2
3
27.0, 125.1, 124.1, 123.6, 120.3, 119.4, 42.7, 32.2, 27.4, 27.2, 25.9, 23.8; IR (thin film) 3053, 2955,
-1
+
868, 1609, 1526, 1446, 1336, 1253, 1209, 776, 728 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H)
2
3
26
32.2014, found 332.2019; mp 186-187 ºC.
Nitrone 3j: General procedure A was employed with the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), 2-phenyl-vinyl boronic acid 2j (0.120 g, 0.811 mmol), Cu(OAc) (0.108 g, 0.595
(
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4
afforded 3i as a yellow oil (0.061 g, 68%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.90 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 13.5
3
1
3
Hz, 1H), 7.90 (d, J = 13.5 Hz, 1H), 7.72-7.66 (m, 3H), 7.61-7.59 (m, 2H), 7.47-7.30 (m, 7H); C NMR
125 MHz, CDCl ): δ 145.5, 139.7, 138.8, 133.4, 133.1, 132.7, 131.6, 131.1, 130.2, 129.9, 129.4, 129.2,
(
3
1
1
29.0, 128.0, 127.8, 127.5, 125.0, 120.9, 119.7; IR (thin film) 3060, 3029, 2924, 2870, 1601, 1509, 1448,
-1
+
248, 987, 728 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 298.1232, found 298.1235.
2
1
16
Nitrone 3k: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), 1-hexenylboronic acid 2k (0.115 g, 0.899 mmol), Cu(OAc) (0.108 g, 0.595
(
2
mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2
4
afforded 3k as a yellow oil (0.072 g, 86%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.85 (d, J = 8.0 Hz, 1H), 7.71-7.59 (m, 4H),
3
7
2
1
3
.53 (t, J = 7.0 Hz, 1H), 7.38-7.35 (m, 2H), 7.31 (t, J = 7.0 Hz, 1H), 7.03-7.00 (m, 1H), 2.41-2.37 (m,
1
3
H), 1.61-1.55 (m, 2H), 1.47-1.43 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ
3
44.1, 139.5, 138.7, 134.6, 134.2, 133.1, 130.8, 130.3, 129.2, 128.9, 127.6, 127.3, 124.9, 120.7, 119.6,
-1
0.7, 29.3, 22.3, 13.8; IR (thin film) 3053, 2955, 2924, 2859, 1509, 1452, 1268, 1211, 983, 769, 722 cm ;
+
HRMS (ESI) m/z calcd. for C H NO (M+H) 278.1545, found 278.1538.
19
20
Nitrone 3k (using 1.5 equiv of 2k): General procedure A was employed using the following reagents:
H-fluoren-9-one oxime 1 (0.059 g; 0.30 mmol), 1-hexenylboronic acid 2k (0.058 g, 0.453 mmol),
9

Cu(OAc) (0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol).
2
2
4
General procedure A afforded 3b as a yellow solid (0.060 g, 72%) after purification using medium
pressure chromatography (1:10; ethyl acetate: hexanes).
Nitrone 3l: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
(
0.059 g; 0.30 mmol), (Z)-1-phenylbut-1-enylboronic acid 2l (0.158 g, 0.898 mmol), Cu(OAc) (0.108 g,
2
0
.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol). General procedure A
2 4
afforded 3l as a yellow solid (0.056 g, 57%) after purification using medium pressure chromatography
1
(
1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.91 (d, J = 7.5 Hz, 1H), 7.74-7.69 (m, 3H),
3
7
.58 (d, J = 7.5 Hz, 2H), 7.48-7.46 (m, 1H), 7.41-7.31 (m, 5H), 7.21 (t, J = 7.5 Hz, 1H), 6.10 (t, J = 7.5
1
3
Hz, 1H), 2.55-2.53 (m, 2H), 1.19 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 144.8, 139.3, 139.0,
3
1
1
32.5, 131.8, 131.4, 131.3, 131.1, 131.0, 130.7, 129.1, 128.9, 128.8, 128.7, 127.4, 127.2, 124.4, 120.3,
-1
19.5, 21.8, 13.2; IR (thin film) 3024, 2926, 2860, 1602, 1526, 1496, 1446, 1253, 1030, 728, 689 cm ;
+
HRMS (ESI) m/z calcd. for C H NO (M+H) 326.1545, found 326.1553; mp 43-44 ºC.
23
20
Nitrone 3m: General procedure A: 9H-fluoren-9-one oxime 1 (0.059 g; 0.30 mmol), (Z)-1-(4-
nitrophenyl)hex-1-enylboronic acid 2m (0.224 g, 0.899 mmol), Cu(OAc) (0.108 g, 0.595 mmol), Na SO
2
2
4
(
0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol) afforded 3m as a yellow solid (0.067 g, 56%)
1
after purification using medium pressure chromatography (1:10; ethyl acetate: hexanes). H NMR (500
MHz; CDCl ): δ 8.86 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.70 (d, J =
3
7.5 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.49-7.47 (m, 1H), 7.41-7.38 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.21
(
0
t, J = 7.5 Hz, 1H), 6.32 (t, J = 7.5 Hz, 1H), 2.54-2.48 (m, 2H), 1.59-1.55 (m, 2H), 1.44-1.40 (m, 2H),
1
.94 (t, J = 7.5 Hz, 3H) (The nitroarene is does not have a plane of symmetry according to H NMR
1
3
analysis.); C NMR (125 MHz, CDCl ): δ 147.8, 145.3, 143.1, 139.5, 139.1, 138.2, 133.5, 132.2, 131.5,
3
1
30.3, 130.2, 129.6, 129.0, 127.5, 127.3, 124.0, 123.9, 120.6, 119.7, 30.7, 28.3, 22.4, 13.8 (The nitroarene
1
3
appears to have a plane of symmetry by C NMR analysis; therefore, we assume that the unsymmetrical
resonances must be coincidental.); IR (thin film) 3057, 2959, 2923, 2857, 1598, 1522, 1446, 1348, 1249,
-1
+
769, 728 cm ; HRMS (ESI) m/z calcd. for C H N O (M+H) 399.1709, found 399.1705; mp 69-70 ºC.
25 23 2 3

Nitrone 3n: General procedure A: 9H-fluoren-9-one oxime 1 (0.059 g; 0.30 mmol), (Z)-1-(4-
fluorophenyl)hex-1-enylboronic acid 2n (0.200 g, 0.901 mmol), Cu(OAc) (0.108 g, 0.595 mmol),
2
Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol) afforded 3n as a yellow oil (0.069 g,
2
4
1
6
1%) after purification using medium pressure chromatography (1:10; ethyl acetate: hexanes). H NMR
(
500 MHz; CDCl ): δ 8.88 (d, J = 7.5 Hz, 1H), 7.70-7.67 (m, 3H), 7.57-7.55 (m, 2H), 7.48-7.45 (m, 1H),
3
7
.40-7.37 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.21-7.18 (m, 1H), 7.10 (t, J = 8.5 Hz, 2H), 6.12 (t, J = 7.5
1
3
Hz, 1H), 2.47-2.41 (m, 2H), 1.53-1.52 (m, 2H), 1.42-1.38 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H); C NMR
125 MHz, CDCl ): δ 163.9 (d, J = 248 Hz), 144.7, 144.0, 139.4, 139.0, 132.4, 131.2, 130.7 (d, J = 9.0
(
3
Hz), 130.6, 130.2, 129.3, 128.9, 127.9, 127.4, 127.2, 124.2, 120.4, 119.6, 116.0 (d, J = 22 Hz), 30.9, 28.1,
-1
2
2.5, 13.8; IR (thin film) 3061. 2955, 2926, 2857, 1602, 1529, 1508, 1249, 769, 728 cm ; HRMS (ESI)
+
m/z calcd. for C H FNO (M+H) 372.1764, found 372.1760.
25
23
Nitrone 3o: General procedure A was employed using the following reagents: 9H-fluoren-9-one oxime 1
0.059 g; 0.30 mmol), (Z)-1-(4-(trifluoromethyl)phenyl)hex-1-enylboronic acid 2o (0.244 g, 0.897 mmol),
Cu(OAc) (0.108 g, 0.595 mmol), Na SO (0.360 g, 2.53 mmol), and pyridine (0.240 mL, 2.97 mmol).
(
2
2
4
General procedure A afforded 3o as a yellow solid (0.069 g, 54%) after purification using medium
1
pressure chromatography (1:10; ethyl acetate: hexanes). H NMR (500 MHz; CDCl ): δ 8.87 (d, J = 7.5
3
Hz, 1H), 7.71-7.65 (m, 7H), 7.50-7.47 (m, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.20 (t, J
=
7.5 Hz, 1H), 6.24 (t, J = 7.5 Hz, 1H), 2.52-2.48 (m, 2H), 1.58-1.54 (m, 2H), 1.43-1.39 (m, 2H), 0.94 (t,
13
J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 145.1, 143.7, 139.5, 139.0, 135.4, 132.4 (d, J = 29 Hz),
3
132.0, 131.3, 130.5, 129.4, 129.1, 129.0, 128.6, 127.5, 127.3, 125.8 (q, J = 3.8 Hz), 124.9 (d, J = 270 Hz),
1
24.1, 120.5, 119.6, 30.8, 28.2, 22.5, 13.8; IR (thin film) 3057, 2959, 2926, 2864, 1606, 1529, 1321,
-1
+
1245, 1129, 1067, 728 cm ; HRMS (ESI) m/z calcd. for C H NOF (M+H) 422.1732, found 422.1723;
26 23 3
mp 60-61 ºC.

III. Synthesis of Spiroisoxazolines 3 via Thermal Rearrangement of Fluorenone N-Vinyl Nitrones
Table 2).
(
General procedure B: A Teflon-sealed reaction flask was charged with a 0.1 M solution of 3 (1.0 equiv)
in toluene. The reaction mixture was heated to 140 ºC for 12-36 h. Toluene was removed from the
reaction mixture under vacuum and the crude reaction mixture was purified by medium pressure
chromatography (1:10-1:3; ethyl acetate:hexanes) to give 5 as a yellow oil or white solid.
Spiroisoxazoline 5a: Spiroisoxazoline 5a was prepared using general procedure B. Nitrone 3a (0.083 g;
0.30 mmol) was dissolved in toluene (3 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5a as a colorless oil (0.067 g,
1
8
1
1
3
1
2
1%). H NMR (500 MHz; CDCl ): δ 7.63-7.59 (m, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.0 Hz,
3
H), 7.38-7.36 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 3.63 (dd, J = 10.0 Hz, 5.0 Hz,
H), 2.58-2.55 (m, 1H), 2.43-2.39 (m, 1H), 1.70-1.67 (m, 1H), 1.46-1.43 (m, 1H), 1.35 (t, J = 7.5 Hz,
H), 0.42 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 164.0, 146.6, 142.9, 140.4, 140.3, 129.5,
13
3
29.4, 128.1, 127.5, 125.3, 123.7, 120.2, 120.0, 94.5, 58.5, 20.8, 20.7, 11.7, 10.8; IR (thin film) 2968,
-1
934, 2874, 1609, 1445, 1381, 1296, 1211, 863, 762, 730 cm ; HRMS (ESI) m/z calcd. for C H NO
19
20
+
(
M+H) 278.1545, found 278.1537.
Spiroisoxazoline 5b: Spiroisoxazoline 5b was prepared using general procedure B. Nitrone 3b (0.055 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 36 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5b as a colorless oil (0.038 g,
0
1
7
1
1
1
1
0%). H NMR (500 MHz; CDCl ): δ 7.62-7.59 (m, 2H), 7.51 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 6.5 Hz,
3
H), 7.37-7.35 (m, 2H), 7.32-7.30 (m, 1H), 7.25-7.24 (m, 1H), 3.53-3.50 (m, 1H), 2.99 (d, J = 14.5 Hz,
H), 2.34-2.29 (m, 1H), 2.10-2.04 (m, 1H), 1.83 (d, J = 13.0 Hz, 1H), 1.51-1.44 (m, 3H), 1.34-1.2 (m,
H); C NMR (125 MHz, CDCl ): δ 160.8, 147.3, 143.5, 140.2, 140.0, 129.3, 129.2, 128.2, 127.3, 126.0,
1
3
3
23.4, 120.2, 119.8, 93.5, 56.5, 28.0, 25.8, 25.4, 24.3; IR (thin film) 3057, 2938, 2860, 1635, 1453, 1303,

-1
+
1
1
206, 845, 757, 732 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 276.1388, found 276.1389; mp
19 18
76-177 ºC.
Spiroisoxazoline 5c: Spiroisoxazoline 5c was prepared using general procedure B. Nitrone 3c (0.050 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5c as a colorless oil (0.034 g,
0
1
6
7
9%). H NMR (500 MHz; CDCl ): δ 7.62-7.59 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 3H),
3
.31 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 3.72 (q, J = 7.0 Hz, 1H), 2.12 (s, 3H), 0.95 (d, J = 7.5
Hz, 3H); C NMR (125 MHz, CDCl ): δ 160.5, 146.2, 142.9, 140.4, 140.2, 129.6, 129.5, 128.2, 127.5,
1
3
3
1
1
2
25.6, 123.5, 120.2, 119.9, 95.0, 52.9, 12.3, 12.0; IR (thin film) 3043, 2977, 2915, 1602, 1449, 1383,
-1
+
315, 1267, 858, 761, 728 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 250.1232, found
1
7
16
50.1240.
Spiroisoxazoline 5e: Spiroisoxazoline 5e was prepared using general procedure B. Nitrone 3e (0.043 g;
.15 mmol) was dissolved in toluene (2 mL) and heated for 36 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5e as a colorless oil (0.032 g,
0
1
7
3
1
6%). H NMR (500 MHz; CDCl ): δ 7.61 (d, J = 7.5 Hz, 3H), 7.45 (d, J = 7.5 Hz, 1H), 7.40-7.30 (m,
3
H), 7.24 (t, J = 7.5 Hz, 1H), 3.75 (d, J = 11.5 Hz, 1H), 3.05 (dd, J = 17 Hz, 5.0 Hz, 1H), 2.57-2.51 (m,
H), 1.98-1.96 (m, 2H), 1.81-1.78 (m, 1H), 1.59-1.56 (m, 1H), 1.41-1.33 (m, 2H), 1.26-1.14 (m, 2H); C
13
NMR (125 MHz, CDCl ): δ 165.4, 145.3, 143.3, 140.8, 140.0, 129.6, 129.5, 128.1, 127.5, 125.2, 123.8,
3
1
1
20.1, 119.9, 95.5, 60.0, 31.1, 29.7, 28.3, 27.3, 25.3; IR (thin film) 3061, 2925, 2852, 1606, 1445, 1312,
-1
+
214, 753, 730 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 290.1545, found 290.1544.
2
0
20
Spiroisoxazoline 5f: Spiroisoxazoline 5f was prepared using general procedure B. Nitrone 3f (0.055 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 36 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5f as a white solid (0.041 g,
0
1
7
1
5%). H NMR (500 MHz; CDCl ): δ 7.63-7.60 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz,
3
H), 7.41-7.37 (m, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.26-7.24 (m, 1H), 4.28 (dd, J = 11.0 Hz, 7.0 Hz, 1H),

3
.78-3.70 (m, 2H), 3.56-3.52 (m, 1H), 3.47-3.45 (m, 1H), 2.91 (d, J = 14.0 Hz, 1H), 2.75-2.60 (m, 1H);
1
3
C NMR (125 MHz, CDCl ): δ 157.2, 146.4, 142.2, 140.1, 139.9, 129.8, 129.7, 128.5, 127.5, 125.6,
3
1
1
2
23.6, 120.5, 120.3, 91.9, 68.8, 67.0, 54.5, 27.0; IR (thin film) 3068, 2966, 2919, 2857, 1606, 1453, 1278,
-1
+
220, 1089, 845, 761, 732 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 278.1181, found
1
8
16
2
78.1188; mp 183-184 ºC.
Spiroisoxazoline 5g: Spiroisoxazoline 5g was prepared using general procedure B. Nitrone 3g (0.066 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 36 h. Solvent removal and purification by
medium pressure chromatography (1:3; ethyl acetate: hexanes) afforded 5g as a white solid (0.032 g,
0
1
4
1
1
9%). H NMR (500 MHz; CDCl ): δ 7.62-7.58 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.5 Hz,
3
H), 7.38-7.36 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.25-7.21 (m, 1H), 4.05-3.81 (m, 5H), 2.98-2.94 (m,
H), 2.69-2.63 (m, 1H), 1.99-1.97 (m, 1H), 1.86-1.81 (m, 2H), 1.49-1.45 (m, 1H); C NMR (125 MHz,
1
3
CDCl ): δ 159.2, 146.8, 143.0, 140.1, 139.9, 129.6, 129.5, 128.3, 127.6, 125.7, 123.7, 120.3, 119.8, 108.3,
3
9
3.7, 64.7, 64.6, 54.3, 35.8, 33.4, 22.3; IR (thin film) 3051, 2963, 2884, 1442, 1274, 1116, 1072, 1044,
-1
+
758, 730 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 334.1443, found 334.1442; mp 169-170
21 20 3
ºC.
Spiroisoxazoline 5l: Spiroisoxazoline 5l was prepared using general procedure B. Nitrone 3l (0.065 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5l as a white solid (0.049 g,
0
1
7
1
8%). H NMR (500 MHz; CDCl ): δ 7.73-7.72 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.0 Hz,
3
H), 7.61 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49-7.44 (m, 3H), 7.43-7.37 (m, 2H), 7.31-7.27
(
m, 2H), 3.96 (dd, J = 10.0 Hz, 3.0 Hz, 1H), 1.88-1.81 (m, 1H), 1.80-1.73 (m, 1H), 0.46 (t, J = 7.5 Hz,
1
3
3
1
2
3
H); C NMR (125 MHz, CDCl ): δ 161.8, 148.3, 141.7, 140.9, 139.2, 130.0, 129.8, 129.7, 129.5, 128.9,
3
28.5, 127.6, 127.4, 126.2, 123.3, 120.2, 120.0, 95.5, 56.9, 22.4, 12.1; IR (thin film) 3050, 2966, 2934,
-1
+
872, 1591, 1449, 1350, 1260, 874, 757, 696 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H)
2
3
20
26.1545, found 326.1540; mp 84-86 ºC.

Spiroisoxazoline 5m: Spiroisoxazoline 5m was prepared using general procedure B. Nitrone 3m (0.079
g; 0.20 mmol) was dissolved in toluene (2 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5m as a white solid (0.048 g,
1
6
1%). H NMR (500 MHz; CDCl ): δ 8.34 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.5
3
Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.46-7.39 (m, 3H), 7.31-7.29 (m, 2H), 4.04
(
dd, J = 10.5 Hz, 3.0 Hz, 1H), 1.81-1.66 (m, 2H), 1.03-0.98 (m, 1H), 0.96-0.90 (m, 1H), 0.87-0.82 (m,
1
3
1
1
5
H), 0.60-0.57 (m, 1H), 0.56 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 160.0, 148.4, 147.7,
3
41.2, 140.9, 139.2, 135.8, 130.1, 129.8, 128.6, 128.1, 127.6, 126.0, 124.2, 123.1, 120.4, 120.2, 96.5,
4.7, 29.2, 28.6, 22.1, 13.4; IR (thin film) 3053, 2952, 2923, 2864, 1602, 1522, 1446, 1245, 860, 769, 725
-
1
+
cm ; HRMS (ESI) m/z calcd. for C H N O (M+H) 399.1709, found 399.1711; mp 110-112 ºC.
25
23
2
3
Spiroisoxazoline 5n: Spiroisoxazoline 5n was prepared using general procedure B. Nitrone 3n (0.074 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5n as a white solid (0.046 g,
0
1
6
1
2%). H NMR (500 MHz; CDCl ): δ 7.72-7.70 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.0 Hz,
3
H), 7.58 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.44-7.37 (m, 2H), 7.30-7.26 (m, 2H), 7.19-7.15
(
0
m, 2H), 3.97 (dd, J = 10.0 Hz, 3.0 Hz, 1H), 1.77-1.71 (m, 2H), 1.03-0.98 (m, 1H), 0.96-0.89 (m, 1H),
1
3
.86-0.81 (m, 1H), 0.60-0.59 (m, 1H), 0.56 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 164.7 (d,
3
J = 250 Hz), 160.8, 148.2, 141.7, 140.9, 139.2, 134.7, 129.8, 129.5, 129.3 (d, J = 7.4 Hz), 128.5, 127.5,
26.1, 125.9 (d, J = 3.6 Hz), 123.2, 120.2, 116.2 (d, J = 22 Hz), 95.6, 55.3, 29.3, 28.7, 22.1, 13.4; IR (thin
1
-
1
film) 3065, 2952, 2934, 2864, 1606, 1511, 1453, 1336, 1231, 1159, 835, 757, 728 cm ; HRMS (ESI) m/z
calcd. for C H NOF (M+H) 372.1764, found 372.1773; mp 83-84 ºC.
+
2
5
23

Spiroisoxazoline 5o: Spiroisoxazoline 5o was prepared using general procedure B. Nitrone 3o (0.084 g;
.20 mmol) was dissolved in toluene (2 mL) and heated for 12 h. Solvent removal and purification by
medium pressure chromatography (1:5; ethyl acetate: hexanes) afforded 5o as a white solid (0.057 g,
0
1
6
8%). H NMR (500 MHz; CDCl ): δ 7.85 (d, J = 7.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.0
3
Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.57 (d, J = 7.0 Hz, 1H), 7.48-7.38 (m, 3H), 7.29-7.26 (m, 2H), 4.02-
4
0
1
.00 (d, J = 8.5 Hz, 1H), 1.78-1.72 (m, 2H), 1.01-0.99 (m, 1H), 0.94-0.90 (m, 1H), 0.84-0.81 (m, 1H),
1
3
.62-0.59 (m, 1H), 0.56 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 160.6, 147.7, 141.5, 140.9,
3
39.2, 133.8, 131.8 (d, J = 33.0 Hz), 129.9, 129.7, 128.5, 127.6, 127.5, 126.1, 125.9 (q, J = 4.0 Hz), 124.9
(
2
(
d, J = 264.0 Hz), 123.1, 120.3, 120.1, 96.0, 54.9, 29.3, 28.6, 22.1, 13.4; IR (thin film) 3057, 2959, 2930,
-1
864, 1446, 1321, 1165, 1122, 1071, 845, 757, 732 cm ; HRMS (ESI) m/z calcd. for C H NOF
26 23 3
+
M+H) 422.1732, found 422.1743; mp 100-102 ºC.

IV. Additions and Rearrangements of N-Vinyl Nitrones: Preparation of Fluorene-Tethered
Isoxazoles (Table 3).
General procedure C: A Teflon-sealed reaction flask was charged with a 0.1 M toluene solution of 3
(
1.0 equiv) and an alkyne (3 equiv). The reaction mixture was heated to 140 ºC for 12-36 h. Toluene was
removed from the reaction mixture under vacuum and the crude reaction mixture was purified by medium
pressure chromatography (1:10-1:3; ethyl acetate:hexanes) to give 6-15 as oils or solids.
Isoxazole-tethered fluorene 6: Isoxazole-tethered fluorene 6 was prepared using general procedure C.
Nitrone 3b (0.055 g; 0.20 mmol) and methyl propiolate (0.053 g, 0.63 mmol) were dissolved in toluene (2
mL) and heated for 36 h. Solvent removal and purification by medium pressure chromatography (1:20-
1
1
:3; ethyl acetate: hexanes) afforded 6b as a light yellow oil (0.043 g, 60%). H NMR (500 MHz; CDCl ):
3
δ 8.14 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.65 (d, J = 7.0
Hz, 1H), 7.38-7.32 (m, 1H), 7.31-7.28 (m, 3H), 6.71 (t, J = 7.0 Hz, 1H), 3.90 (s, 3H), 2.92-2.86 (m, 4H),
1
3
2
1
2
.01-1.98 (m, 2H), 1.79-1.76 (m, 2H); C NMR (125 MHz, CDCl ): δ 165.8, 161.7, 143.7, 140.9, 139.2,
3
38.6, 137.4, 135.9, 133.2, 129.8, 127.9, 127.8, 127.6, 126.9, 124.9, 119.8, 119.7, 119.5, 52.1, 28.9, 28.8,
7.9, 26.7; IR (thin film) 3050, 2930, 2857, 1719, 1584, 1438, 1194, 1107, 769, 728 cm ; HRMS (ESI)
m/z calcd. for C H NO (M+H) 360.1600, found 360.1609.
-1
+
23
22
3
Isoxazole-tethered fluorene 7: Isoxazole-tethered fluorene 7 was prepared using general procedure C.
Nitrone 3b (0.055 g; 0.20 mmol) and ethyl but-2-ynoate (0.076 g, 0.68 mmol) were dissolved in toluene
(
(
2 mL) and heated for 12 h. Solvent removal and purification by medium pressure chromatography
1:20-1:3; ethyl acetate: hexanes) afforded 7b as an amorphous solid (0.039 g, 50%). H NMR (500 MHz;
1
CDCl ): δ 7.82 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz,
3
1
1
1
H), 7.36-7.28 (m, 4H), 6.70 (t, J = 7.5 Hz, 1H), 4.49 (q, J = 7.0 Hz, 2H), 2.88-2.82 (m, 4H), 2.56 (s, 3H),
1
3
.97-1.94 (m, 2H), 1.78-1.76 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 162.6,
3
62.5, 156.0, 140.8, 139.2, 138.6, 137.4, 135.8, 130.0, 127.7, 127.5, 127.4, 127.0, 126.9, 124.9, 119.8,

1
1
19.7, 119.5, 60.8, 29.0, 28.8, 27.9, 26.8, 14.4, 11.9; IR (thin film) 3057, 2931, 2861, 1710, 1613, 1448,
-1
+
337, 1183, 1094, 736 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 388.1913, found 388.1902.
2
5
26
3
Isoxazole-tethered fluorene 8: Isoxazole-tethered fluorene 8 was prepared using general procedure C.
Nitrone 3e (0.070 g; 0.24 mmol) and methyl propiolate (0.053 g, 0.63 mmol) were dissolved in toluene (2
mL) and heated for 36 h. Solvent removal and purification by medium pressure chromatography (1:20-
1
1
8
:3; ethyl acetate: hexanes) afforded 8 as a yellow oil (0.049 g, 54%). H NMR (500 MHz; CDCl ): δ
3
.13 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5
Hz, 1H), 7.38-7.28 (m, 4H), 6.72 (t, J = 7.5 Hz, 1H), 3.90 (s, 3H), 2.86-2.84 (m, 4H), 1.90-1.85 (m, 2H),
1
3
1
1
2
7
.75 (t, J = 7.5 Hz, 2H), 1.58-1.52 (m, 2H); C NMR (125 MHz, CDCl ): δ 165.8, 161.8, 143.7,140.8,
3
39.3, 138.5, 137.5, 135.6, 133.1, 130.5, 127.7, 127.4, 126.9, 126.8, 124.9, 119.8, 119.6, 119.4, 52.1,
9.2, 29.1, 28.9, 28.0, 26.7; IR (thin film) 3057, 2931, 2855, 1710, 1584, 1442, 1274, 1198, 1151, 1109,
30 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 374.1756, found 374.1761.
-1
+
24
24
3
Isoxazole-tethered fluorene 10: Isoxazole-tethered fluorene 9 was prepared using general procedure C.
Nitrone 3i (0.065 g; 0.20 mmol) and methyl propiolate (0.053 g, 0.63 mmol) were dissolved in toluene (2
mL) and heated for 36 h. Solvent removal and purification by medium pressure chromatography (1:20-
1
1
8
:3; ethyl acetate: hexanes) afforded 9 as a yellow oil (0.038 g, 47%). H NMR (500 MHz; CDCl ): δ
3
.02 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.65 (d, J = 7.5
Hz, 1H), 7.39-7.27 (m, 4H), 6.71 (t, J = 7.0 Hz, 1H), 3.87 (s, 3H), 3.05-3.00 (m, 1H), 2.94-2.90 (m, 1H),
1
3
2
.89-2.77 (m, 2H), 2.14-2.11 (m, 1H), 1.79-1.75 (m, 1H), 1.53-1.52 (m, 1H), 1.00 (s, 9H); C NMR (125
MHz, CDCl ): δ 165.7, 161.7, 143.7, 140.9, 139.3, 138.5, 137.4, 135.2, 133.0, 131.1, 127.7, 127.4, 127.0,
3
1
1
4
26.9, 124.9, 119.9, 119.7, 119.5, 52.0, 49.2, 34.2, 30.8, 28.2, 28.1, 27.8; IR (thin film) 3054, 2953, 2864,
-1
+
720, 1584, 1445, 1321, 1195, 1113, 1005, 733 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H)
2
7
30
3
16.2226, found 416.2225.
Fluorene 11 and Isoxazole 12: Fluorene 10 and isoxazole 11 were prepared using general procedure C.
Nitrone 3a (0.059 g; 0.21 mmol) and methyl propiolate (0.053 g, 0.63 mmol) were dissolved in toluene (2

mL) and heated for 12 h. Solvent removal and purification by medium pressure chromatography (1:20-
:3; ethyl acetate: hexanes) afforded 10 (0.027 g, 62%) as a white solid and 11 as a clear, colorless oil
0.020 g, 61%).
1
(
3,4 1
Fluorene 10: H NMR (500 MHz; CDCl ): δ 7.87 (d, J = 7.0 Hz 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.72 (d,
3
J = 7.0 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.38-7.27 (m, 4H), 6.75 (t, J = 7.5 Hz, 1H), 2.89-2.85 (m, 2H),
13
1
.32 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 140.8, 139.4, 138.6, 137.5, 135.0, 132.6, 127.6,
3
1
27.3, 126.9, 126.8, 124.9, 119.8, 119.6, 119.4, 22.7, 14.0; IR (thin film) 3053, 2966, 2930, 2868, 1645,
-1
+
1442, 1165, 776, 728 cm ; HRMS (EI) m/z calcd. for C H (M ) 206.1096, found 206.1090; mp 46-48
16 14
ºC.
1
Isoxazole 11: H NMR (500 MHz; CDCl ): δ 8.15 (s, 1H), 3.90 (s, 3H), 2.85 (q, J = 7.5 Hz, 2H), 1.37 (t,
3
13
J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl ): δ 166.8, 161.8, 143.7, 133.1, 52.1, 21.7, 11.1; IR (thin
film) 2950, 2877, 1724, 1584, 1438, 1198, 1109, 1002, 762 cm ; HRMS (ESI) m/z calcd. for C H NO
3
M+H) 156.0661, found 156.0657.
3
-1
7
10
+
(
Fluorene 10 and Isoxazole 12: Fluorene 10 and isoxazole 12 were prepared using general procedure C.
Nitrone 3a (0.059 g; 0.21 mmol) and ethyl but-2-ynoate (0.076 g, 0.68 mmol) were dissolved in toluene
(
(
2 mL) and heated for 12 h. Solvent removal and purification by medium pressure chromatography
1:20-1:3; ethyl acetate: hexanes) afforded 10 (0.021 g, 48%) as a white solid and 12 as a clear, colorless
oil (0.018 g, 46%).
5
1
Isoxazole 12: H NMR (500 MHz; CDCl ): δ 4.38 (q, J = 7.0 Hz, 2H), 2.79 (q, J = 7.0 Hz, 2H), 2.58 (s,
3
1
3
3
H), 1.39 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 163.7, 162.6,
3

1
7
55.9, 127.3, 60.8, 21.5, 14.4, 11.9, 11.2; IR (thin film) 2975, 2934, 2874, 1710, 1622, 1448,1341, 1094,
-1
+
36 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 184.0974, found 184.0972.
9
14
3
Fluorene 10 and Isoxazole 13: Fluorene 10 and isoxazole 13 were prepared using general procedure C.
Nitrone 3a (0.059 g; 0.21 mmol) and ethyl 3-phenylpropiolate (0.100 g, 0.574 mmol) were dissolved in
toluene (2 mL) and heated for 12 h. Solvent removal and purification by medium pressure
chromatography (1:20-1:3; ethyl acetate: hexanes) afforded 10 (0.025 g, 58%) as a white solid and 13 as a
clear, colorless oil (0.030 g, 59%).
6
1
Isoxazole 13: H NMR (500 MHz; CDCl ): δ 8.03-8.02 (m, 2H), 7.46-7.42 (m, 3H), 4.42 (q, J = 7.0 Hz,
3
1
3
2
1
1
2
H), 2.89 (q, J = 7.0 Hz, 2H), 1.41-1.38 (m, 6H); C NMR (125 MHz, CDCl ): δ 164.1, 162.3, 155.1,
30.0, 128.3, 127.2, 126.8, 126.5, 61.3, 21.6, 14.3, 11.2; IR (thin film) 3061, 2975, 2923, 1714, 1590,
448, 1369, 1183, 1087, 765, 686 cm ; HRMS (ESI) m/z calcd. for C H NO (M+H) 246.1130, found
3
-1
+
1
4
16
3
46.1130.
Fluorene 10 and Isoxazole 14: Fluorene 10 and isoxazole 14 were prepared using general procedure C.
Nitrone 3l (0.065 g; 0.20 mmol) and methyl propiolate (0.053 g, 0.63 mmol) were dissolved in toluene (2
mL) and heated for 12 h. Solvent removal and purification by medium pressure chromatography (1:20-
1
6
:3; ethyl acetate: hexanes) afforded 10 (0.026 g, 63%) as a white solid and 14 as a white solid (0.025 g,
2%).
7
1
Isoxazole 14: H NMR (500 MHz; CDCl ): δ 8.28 (s, 1H), 8.11-8.10 (m, 2H), 7.47-7.46 (m, 3H), 3.94
3
1
3
(
(
s, 3H); C NMR (125 MHz, CDCl ): δ 162.5, 161.8, 143.8, 134.4, 131.2, 128.8, 126.9, 126.4, 52.2; IR
3
thin film) 3065, 2955, 1722, 1559, 1453, 1321, 1249, 1147, 1114, 997, 776, 714, 693 cm ; HRMS (ESI)
m/z calcd. for C H NO (M+H) 204.0661, found 204.0669; mp 60-62 ºC.
-1
+
1
1
10
3

V. Independent Synthesis of Nitrone 3b.
8
Compound S1: Diphenyl diselenide (2.34 g, 7.5 mmol) was suspended in EtOH (40 mL) in a round-
bottom flask equipped with a septum and N inlet. A solution of NaBH (0.756 g, 20 mmol) in EtOH (40
2
4
mL) was added dropwise via syringe to the bright yellow reaction mixture over 20 min. The addition was
halted (after 35 mL had been added) when all of the yellow color disappeared to give a colorless solution.
The reaction mixture was then cooled to 0°C (ice/H O bath) for 5 min and glacial acetic acid (2.28 mL,
2
40 mmol) was added dropwise via syringe. Next, 1-nitrocyclohexene (1.2 mL, 10 mmol) was added as a
solution in EtOH (4 mL) via syringe and the reaction mixture was allowed to stir for 5 min at 0°C before
the ice bath was removed and the reaction mixture was allowed to warm to 25 ºC and stir overnight. The
reaction mixture was then poured into H O (200 mL) and extracted with Et O (100 mL). The organic
2
2
layer was washed with H O (100 mL) and the combined aqueous washes were back extracted with Et O
2
2
(
100 mL). The combined organic layers were then washed with brine (100 mL), dried with MgSO , and
4
concentrated to give the crude product which was purified by silica gel column chromatography (hexane
1
to hexane/EA= 20/1) to give S-1 as a colorless liquid (1.30g, 46%). H NMR (500 MHz; CDCl ): δ 7.61
3
(
(
1
8
d, J = 7.0 Hz, 2H), 7.38-7.37 (m, 1H), 7.32 (t, J = 7.0 Hz, 2H), 4.42 (dt, J = 11.0 Hz, 4.0 Hz, 1H), 3.40
dt, J = 11.0 Hz, 4.0 Hz, 1H), 2.32-2.25 (m, 2H), 1.94-1.89 (m, 1H), 1.80-1.78 (m, 1H), 1.70-1.68 (m,
1
3
H), 1.41-1.39 (m, 2H), 1.26-1.21 (m, 1H). C NMR (125 MHz, CDCl ): δ 137.1, 129.1, 128.8, 125.5,
3
9.5, 42.1, 32.5, 32.4, 25.8, 23.6.
9
Compound S-2: Compound S-1 (0.200 g, 0.7 mmol) was dissolved in EtOH (7 mL) and dilute HCl (8
mL, 10%/wt) was added via syringe at 25 ºC. Zn dust (1.8 g, 28 mmol) was then added in small portions
and the reaction mixture was stirred at 25 ºC overnight. When the reaction was completed, Na CO (aq)
2
3
was added to the mixture until pH=9. The reaction mixture was extracted with ethylacetate (3 x 50 mL),
dried with MgSO , concentrated, and purified by silica gel column chromatography (hexane/EA/NEt =
4
3
1
5
2
/1/1) to give S-2 as a colorless liquid (0.091 g, 51%). H NMR (500 MHz; CDCl ): δ 7.58 (d, J = 7.0 Hz,
3
H), 7.28-7.23 (m, 3H), 2.80-2.76 (m, 1H), 2.59 (dt, J = 10.5 Hz, 3.5 Hz, 1H), 2.14-2.12 (m, 1H), 1.99-

1
3
1
1
.96 (m, 1H), 1.71-1.62 (m, 3H), 1.46-1.43 (m, 1H), 1.24-1.14 (m, 2H). C NMR (125 MHz, CDCl ): δ
35.8, 128.9, 127.8, 127.7, 54.4, 54.2, 35.8, 34.3, 27.2, 25.1.
3
Compound 4: 9-Fluorenone (0.468 g, 2.6 mmol), amine S-2 (0.652 g, 2.6 mmol), TsOH (0.020 g), 4 Å
molecular sieves (3.0 g) and toluene (5 mL) were placed into a three neck, round bottom flask connected
to a condenser and an N inlet. The reaction mixture was then heated to 120°C for 24 h. The molecular
2
sieves were then removed by filtration and the mixture was concentrated to give the crude imine.
1
Recrystallization of the crude material from hexane gave 4 as a yellow solid (0.324 g, 29%). H NMR
(
500 MHz; CDCl ): δ 7.76 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.58-7.56 (m, 3H), 7.51-7.45 (m,
3
1
2
1
1
H), 7.44-7.38 (m, 1H), 7.30-7.24 (m, 3H), 7.22-7.15 (m, 3H), 4.53-4.51 (m, 1H), 3.67-3.63 (m, 1H),
.37-2.33 (m, 1H), 2.09-2.06 (m, 1H), 1.93-1.90 (m, 1H), 1.84-1.83 (m, 1H), 1.74-1.64 (m, 2H), 1.54-
13
.47 (m, 2H); C NMR (125 MHz, CDCl ): δ 161.2, 144.4, 143.8, 140.7, 138.6, 135.7, 134.7, 131.0,
3
30.7, 129.1, 128.7, 128.0, 127.3, 124.3, 123.0, 120.3, 119.1, 64.6, 50.4, 33.1, 33.0, 26.6, 24.4; IR (thin
-1
film) 3053, 2924, 2853, 1716, 1611, 1452, 1295, 1190, 918, 728 cm ; HRMS (ESI) m/z calcd. for
C H NSe (M+H) 418.1074, found 418.1077.
+
2
5
24
Nitrone 3b: Imine 4 (0.208 g, 0.5 mmol) was dissolved in CH Cl (4 mL) and the solution was cooled to
2
2
-
78 ºC for 10 min. A solution of m-CPBA (0.157 g, 0.6 mmol) in CH Cl (4 mL) was added dropwise
2 2
over 5 min. The reaction mixture was then stirred for 5 min at 25 ºC and then cooled to 0 ºC with an
ice/water bath. A second portion of m-CPBA (0.157 mg, 0.6 mmol) was added to the reaction mixture as
a CH Cl (4 mL) solution and allowed to stir for 10 min. The reaction mixture was then cooled to -78 ºC,
2
2
and i-Pr NH (0.17 mL, 0.6 mmol) was added before warming to 25 ºC and stirring overnight. The
2
reaction mixture was then poured into H O (10 mL) and extracted with CH Cl (3 x 10 mL). The
2
2
2
combined organic layers were then washed with brine (100 mL), dried with MgSO and concentrated to
4
give the crude product, which was purified by silica gel column chromatography (hexane/EA= 3/1) to
1
give 3b as a yellow solid (0.015 g , 10%). H NMR (500 MHz; CDCl ): δ 8.85 (d, J = 8.0 Hz, 1H), 7.68-
3
7
6
.63 (m, 3H), 7.46-7.43 (m, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.25-7.22 (m, 1H),
13
.05-6.04 (m, 1H), 2.85-2.81 (m, 1H), 2.40-2.31 (m, 3H), 1.97-1.93 (m, 2H), 1.83-1.80 (m, 2H);
C
NMR (125 MHz, CDCl ): δ 145.3, 143.5, 139.2, 138.8, 132.4, 130.8, 130.6, 128.9, 128.8, 127.4, 127.0,
3
124.9, 123.9, 120.3, 119.4, 25.4, 24.2, 22.2, 21.2.

VI. Mechanistic Discussion.
Proposed mechanisms for the conversion of N-vinyl nitrones to spiroisoxazolines and fluorene-tethered
isoxazoles via nitrile oxide intermediates are illustrated below in Scheme S-1.
Scheme S-1.
Although the intermediacy of a nitrile oxide is consistent with the final products observed for these
transformations, two additional pieces of mechanistic data suggest that the conversion of N-vinyl nitrones
to fluorene-tethered isoxazoles (or a mixture of substituted fluorenes and isoxazoles) in the presence of
propiolates may not be proceeding via the same intermediates as spiroisoxazoline formation: 1)
spiroisoxazolines do not form mixtures of substituted fluorenes and isoxazoles when heated in the
presence of propiolates, and 2) spiroisoxazoline formation is not observed below 100 ºC, while mixtures
of substituted fluorenes and isoxazoles can be isolated when N-vinyl nitrones are heated in the presence of
propiolates at 80 ºC. The first experiment shows that spiroisoxazolines do not cyclorevert at elevated
temperature to give nitrile oxides and do not function as intermediates on the reaction pathway to the
formation of fluorene-tethered isoxazoles or mixtures of substituted fluorenes and isoxazoles. The
reaction temperature data indicates that spiroisoxazoline formation requires a higher energy reactive
intermediate than the formation of mixtures of substituted fluorenes and isoxazoles. Therefore, we have
proposed an alternative mechanism for the preparation of tethered-isoxazoles or mixtures of fluorenes and
isoxazoles which involves an initial interaction between the electron-deficient alkyne and the N-vinyl
nitrone prior to cycloreversion (Scheme S-2). This reaction pathway could be further energetically
favored by resonance stabilization of the build-up of partial positive charge at the quaternary carbon
center of the tricyclic intermediate.
Scheme S-2.

VII. Three-Dimensional Representations of 3g and 5m.
Compound 3g
Compound 5m
Two inequivalent molecules are observed in the unit cell due to distortion of the n-Bu group.

VIII. References.
1. A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen, F. J. Timmers, Organometallics 1996,
15, 1518.
2. Patil, A. S., Mo, D.-L., Wang, H.-Y., Mueller, D. S. and Anderson, L. L. Angew. Chem. Int. Ed. 2012,
51, 7799.
3
4
5
6
7
8
9
. Wawzonek, S.; Dufek, E. J. Am. Chem. Soc. 1956, 78, 3530.
. Wolf, J.; Brandt, L.; Fries, A.; Werner, H. Angew. Chem. 1990, 102, 584.
. McMurry, J. E. Org. Synth. 1973, 53, 59.
. Ward, F. E.; Buckler, R. T. J. Org. Chem. 1980, 45, 4608.
. Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y. Org. Lett. 2011, 13, 2966.
. Hayama, T.; Tomoda, S.; Takeuchi, Y.; Nomura, Y. Tetrahedron Lett. 1982, 23, 4733.
. Denis, J. N.; Vicens, J.; Krief, A. Tetrahedron Lett. 1979, 2697.

3a
5.86
2.93
1.94
1
.0 10 .05
0.98
0.90
0.90 0.95
1
.001.06
9
8
7
6
5
4
3
2
1
PPM

3a
200
150
100
50
PPM

3a
200
150
100
50
PPM

3b
3.04
2.96
2.14
2.06
2.20
0.95
0.93
0.98
1.04
0.96
9
8
7
6
5
4
3
2
1
0PPM

3b
180
160
140
120
100
80
60
40
20
PPM

3b
200
150
100
50
0 PPM

3c
3.04
3.07
1.97
1
.0 31 .01
0
.95
0.99
0.99
1
.08
1
.00
8
6
4
2
PPM