Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry

This journal is © The Royal Society of Chemistry 2012

H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

An unexpected formation of the novel 7-oxa-2-azabicyclo[2.2.1]hept-5-ene

skeleton during the reaction of furfurylamine with maleimides and their
bioprospection using zebrafish embryo model

Carlos E. Puerto Galvis and Vladimir V. Kouznetsov*

Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de

Santander, Cra 27 calle 9, Bucaramanga A.A. 678, Colombia. Fax/Tel: +57 76 349069
*kouznet@uis.edu.co

ELECTRONIC SUPPORTING INFORMATION

List of contents Pages

1. General SI-2
2. Reagents and catalysts SI-2
3. Preparation and characterization of benzaldehyde oximes 2a-2g SI-3
4. Preparation and characterization of N-benzylmaleimides 4a-4i SI-5
5. General procedure for the synthesis of the 7-oxa-2-azabicyclo[2.2.1]hept-5-enes 6a- SI-8
6k
6. General procedure for the synthesis of the N-(10-oxa-4-azatricyclo[5.2.1.02,6]decan- SI-15
8-ene-3,5-dione-7-ylmethyl)acetamides 7a-7c
7. In vitro acetylcholinesterase inhibitory activity essay for compounds 6a-6k and 7a-7c SI-17
8. Toxicity Assessment in Vivo using zebrafish embryos for compounds 6a-6k and 7a- SI-18
7c
9. Copies of GC, 1H NMR, 13C NMR, DEPT-135, COSY, 13C HMBC and HSQC charts SI-19
of the synthesized 7-Oxa-2-azabicycles

Puerto & Kouznetsov, Page SI-1

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

1. General

Infrared (FT-IR) spectra were recorded on Lumex Infralum FT-02 spectrometer, νmax in cm1.
Bands are characterized according to the functional group. 1H-NMR spectra were recorded on a
Bruker Avance-400 (400 MHz) spectrometer. Chemical shifts are reported in ppm with the
solvent resonance as the internal standard (CDCl3: δ 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, br =
broad, m = multiplet), coupling constants (Hz) and integration. 13C-NMR spectra were recorded
on a Bruker Avance-400 (400 MHz) spectrometer with complete proton decoupling. Chemical
shifts are reported in ppm from solvent resonance as the internal standard (CDCl3: δ 77.00 ppm).
On DEPT-135 spectra, the signals of CH3 and CH carbons are shown as positive (+) and CH2
13
carbons are shown negative (-). Quaternary carbons are not shown. COSY, C-HMBC and
HSQC experiments were recorded using standard Bruker pulse sequences. A Hewlett Packard
5890a Series II Gas Chromatograph interfaced to an HP 5972 Mass Selective Detector (MSD)
with an HP MS ChemStation Data system was used for MS identification at 70 eV using a 60 m
capillary column coated with HP-5 [5%-phenylpoly(dimethylsiloxane)]. High-resolution mass
spectrometry was performed on a Micromass Q-TOF by electrospray ionisation (ESI). Melting
points were measured on a Fisher Johns melting point apparatus and are uncorrect.

Unless otherwise noted, all reactions have been carried out with distilled and dried solvents and
under atmosphere pressure. All work-up and purification procedures were carried out with
reagent grade solvents (purchased from Aldrich and Merck) in air. Thin-layer chromatography
(TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm). Column
chromatography was performed using silicagel 60 (0,063-0,200 mm) 70-230 mesh.

2. Reagents and catalysts

Benzaldehyde: Was purchased from Merck and used as received.

4-Chlorobenzaldehyde: Was purchased from Aldrich and used as received.
4-Fluorobenzaldehyde: Was purchased from Aldrich and used as received.
4-Methylbenzaldehyde: Was purchased from Aldrich and used as received.
4-Methoxybenzaldehyde: Was purchased from Aldrich and used as received.
3,4-Methylenedioxybenzaldehyde: Was purchased from Merck and used as received.
1-Naphthaldehyde: Was purchased from Merck and used as received.
Hydroxylamine hydrochloride: Was purchased from Merck and used as received.

Puerto & Kouznetsov, Page SI-2

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Sodium carbonate: Was purchased from Merck and used as received.

Palladium on activated charcoal (10 %): Was purchased from Aldrich and used as received.
Maleic anhydride: Was purchased from Merck and used as received.
Sodium acetate anhydrous: Was purchased from Merck and dried at 100 ºC for 3 days.
Acetic anhydride: Was purchased from Merck and used as received.
(S)-(−)-α-Methylbenzylamine: Was purchased from Aldrich and used as received.
(R)-(+)-α-Methylbenzylamine: Was purchased from Aldrich and used as received.
Furfurylamine: Was purchased from Aldrich and used as received.
Boric acid: Was purchased from Aldrich and used as received.
Polyethylene glycol 400 (PEG-400): Was purchased from Merck and used as received.
Maleimide: Was purchased from Aldrich and used as received.
N-Phenylmaleimide: Was purchased from Aldrich and used as received.

3. Preparation and characterization of benzaldehyde oximes

R3 R3
R2 R2
Na2CO3
+ NH2OH⋅HCl
EtOH, r.t.
R1 R1

O NOH
1a-g 2a-g

A mixture of Na2CO3 (17 mmol) and hydroxylamine hydrochloride (17 mmol) was dissolved in
20 mL of deionized water and 4 mL of ethanol at room temperature for 5 min. To the above
mixture, small amounts of the corresponding (hetero)aromatic aldehydes 1a-g (14.13 mmol)
were added for a period of 5 min. with constant stirring. The reaction mixture was stir for
another 15 min. and at the end of the reaction (confirmed by TLC) the reaction was diluted with
water (30 mL) and the precipitated product was filtered off and dried in vacuum. In cases, where
product did not precipitate out the reaction, the mixture was extracted with ethyl acetate (3 x 10
mL). The organic extract was dried over anhydrous Na2SO4 and the solvent concentrate under
reduced pressure to yield the pure product, the substituted oximes 2a-g.

Benzaldeyde oxime (2a): Extraction with ethyl acetate afforded a white solid (1.71 g, 14.13
mmol, quantitative yield); Rf = 0.77 (2:1 hexane/EtOAc); mp. 34-36 ºC; FT-IR (KBr, cm-1):
3455 (OH), 2969 (=CHAr), 1604 (C=N), 1511 (-OH), 1419 (C-N); GC: Rt = 6.02 min.; MS (EI),

Puerto & Kouznetsov, Page SI-3

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

m/z (%): 121 (M+·, 100), 94 (38), 78 (61), 77 (60), 51 (46). Acquired data are in agreement with
the literature. 1

4-Chlorobenzaldehyde oxime (2b): Extraction with ethyl acetate afforded a white solid (1.66 g,
10.67 mmol, quantitative yield); Rf = 0.52 (2:1 hexane/EtOAc); mp. 92-94 ºC; FT-IR (KBr, cm-
1
): 3301 (OH), 1589 (C=N), 1496 (C-N), 971 (C-H), 694 (C-Cl); GC: Rt = 11.08 min.; MS (EI),
m/z (%): 155 (M+·, 99), 139 (100), 136 (82), 111 (73), 75 (70). Acquired data are in agreement
with the literature. 2

4-Fluorobenzaldehyde oxime (2c): Extraction with ethyl acetate afforded a white solid (1.66 g,
10.67 mmol, quantitative yield); Rf = 0.72 (2:1 hexane/EtOAc); mp. 85-87 ºC; FT-IR (KBr, cm-
1
): 3313 (OH), 1584 (C=N), 1502 (C-N), 970 (C-H), 703 (C-F); GC: Rt = 15.34 min.; MS (EI),
m/z (%): 139 (M+·, 95), 123 (100), 108 (58), 95 (61), 75 (70). Acquired data are in agreement
with the literature. 3

4-Methylbenzaldehyde oxime (2d): Extraction with ethyl acetate afforded a white solid (1.66 g,
10.67 mmol, quantitative yield); Rf = 0.52 (2:1 hexane/EtOAc); mp. 54-55 ºC; FT-IR (KBr, cm-
1
): 3333 (OH), 2994 (CH3), 1572 (C=N), 1497 (C-N), 1028 (C-H); GC: Rt = 10.41 min.; MS
(EI), m/z (%): 135 (M+·, 96), 119 (100), 104 (76), 91 (83), 75 (61). Acquired data are in
agreement with the literature. 4

4-Methoxybenzaldehyde oxime (2e): Extraction with ethyl acetate afforded a yellowish solid
(1.66 g, 11.01 mmol, quantitative yield); Rf = 0.54 (2:1 hexane/EtOAc); mp. 102-104 ºC; FT-IR
(KBr, cm-1): 3178 (OH), 3008 (OCH3), 1604 (C=N), 1249 (C-O-C); GC: Rt = 9.71 min.; MS
(EI), m/z (%): 151 (M+·, 53), 119 (99), 91 (100), 77 (34), 63 (20). Acquired data are in agreement
with the literature.2

3,4-Methylenedioxybenzaldehyde oxime (2f): Precipitation with water afforded a white solid

(1.65 g, 9.99 mmol, quantitative yield); Rf = 0.65 (2:1 hexane/EtOAC); mp. 110-112 ºC; FT-IR
(KBr, cm-1): 3224 (OH), 2915 (CH2), 1604 (C=N), 1249 (C-O-C); GC: Rt = 11.83 min.; MS

1
R. Joseph, T. Ravindranathan and A. Sudalai, Tetrahedron Lett., 1995, 36, 1903.
2
J-T, Li, X-L. Li and T-S. Li, Ultras. Sonochem., 2006, 13, 200.
3
B. C. Sanders, F. Friscourt, P. A. Ledin, N. E. Mbua, S. A. Arumugam, J. Guo, T. J. Boltje, V. V. Popik and
G-J. Boons, J. Am. Chem. Soc., 2011, 133, 949.
4
S. Minakata, S. Okumura, T. Nagamachi and Y. Takeda, Org. Lett., 2011, 13, 2966.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

(EI), m/z (%): 165 (M+·, 100), 122 (60), 121 (53), 65 (37), 63 (42). Acquired data are in
agreement with the literature. 5

1-Naphthylaldehyde oxime (2g): Precipitation with water affored a white solid (1.64 g, 9.61
mmol, quantitative yield); Rf = 0.74 (2:1 hexane/EtOAc); mp. 99-100 ºC; FT-IR (KBr, cm-1):
3394 (OH), 3070 (=CHAr), 1619 (C=N), 1511 (-OH), 1450 (C-N); GC: Rt = 14.30 min.; MS
(EI), m/z (%):171(M+·, 50), 154 (100), 153 (87), 127 (93), 125 (50). Acquired data are in
agreement with the literature.5

4. Preparation and characterization of N-benzylmaleimides

R3
R3 R3 O

R2 R2 1) O , Et2O, r.t. O R2
H2, 10 % Pd/C O
EtOH, r.t. R1 N R1
R1 2) Ac2O, NaOAc,
70 °C
NOH NH2 O
2a-g 3a-g 4a-g

A solution of the corresponding benzaldehyde oxime 2a-g (8.25 mmol) in ethanol (25 mL) was
hydrogenated under H2 atmosphere using 10 % Pd/C (200 mg) until the complete consumption
of the oxime was verified by TLC. The suspension was filtered through a small pad of Celite and
the filter was washed with EtOH (10 mL); the combined filtrates were concentrated in vacuo to
furnish the unstable benzylamines 3a-g, as an oils. Without further purification, the crude amine
3a-g (8.25 mmol), was dissolved in anhydrous diethyl ether (10 mL), was added dropwise into
an ice-cooled solution of maleic anhydride (8.25 mmol) in anhydrous diethyl ether (15 mL). The
solid, which precipitated out of the reaction mixture after 1 h, was filtered, washed thoroughly
with ethyl ether and mixed with acetic anhydride (1.6 mL) and sodium acetate (4.12 mmol). The
reaction mixture was then heated at 70 °C (6 h) until the complete consumption of the starting
amine was ascertained by TLC. After cooling the system at room temperature, the solution was
alkalinized with aqueous Na2CO3 2 M and the product was extracted with CH2Cl2 (3 x 10 mL)
the organic extracts were combined, dried and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel and eluted with hexane/EtOAc (1:1) to
afford the desired maleimide.

N-Benzylmaleimide (4a): Same procedure as above was followed on a 7.28 mmol scale.
Purification by silica gel flash chromatography afforded a white crystalline solid (0.94 g, 5.02
5
R. S. Ramón, J. Bosson, S. Díez-González, N. Marion, S. P. Nolan, J. Org. Chem., 2010, 7, 1197.

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Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

mmol, 69 % yield); Rf = 0.6 (1:1 hexane/EtOAc); mp. 71-73 ºC; FT-IR (KBr, cm-1): 3101
(=CHAr), 1697 (C=O), 1403 (CH2), 694 (HC=CH); GC: Rt = 11.29 min.; MS (EI), m/z (%): 187
(M+·, 100), 130 (41), 106 (59), 105 (53), 78 (23). Acquired data are in agreement with the
literature. 6

N-(4-Chlorobenzyl)maleimide (4b): Same procedure as above was followed on a 6.16 mmol

scale. Purification by silica gel flash chromatography afforded a white crystalline solid (1.09 g,
4.93 mmol, 80 % yield); Rf = 0.58 (1:1 hexane/EtOAc); mp. 68-70 ºC; FT-IR (KBr, cm-1): 3101
(=CHAr), 1712 (C=O), 1403 (CH2), 833 (C-Cl), 694 (HC=CH); GC: Rt = 14.29 min.; MS (EI),
m/z (%):221 (M+·, 95), 186 (41), 140 (100), 137 (64), 89 (42). Acquired data are in agreement
with the literature. 7

N-(4-Fluorobenzyl)maleimide (4c): Same procedure as above was followed on a 7.99 mmol

scale. Purification by silica gel flash chromatography afforded a white crystalline solid (1.41 g,
6.87 mmol, 86 % yield); Rf = 0.66 (1:1 hexane/EtOAc); mp. 88-90 ºC; FT-IR (KBr, cm-1): 3101
(=CHAr), 1697 (C=O), 1403 (CH2) , 848 (C-F), 694 (HC=CH); GC: Rt = 11.49 min.; MS (EI),
m/z (%): 205 (M+·, 100), 148 (55), 124 (71), 122 (97), 109 (51). Acquired data are in agreement
with the literature.6

N-(4-Methylbenzyl)maleimide (4d): Same procedure as above was followed on a 8.25 mmol

scale. Purification by silica gel flash chromatography afforded a white crystalline solid (1.26 g,
6.27 mmol, 76 % yield); Rf = 0.78 (1:1 hexane/EtOAc); mp. 94-96 ºC; FT-IR (KBr, cm-1): 3101
(=CHAr), 2946 (CH3), 1712 (C=O), 1403 (CH2) , 694 (HC=CH); GC: Rt = 12.76 min.; MS (EI),
m/z (%): 201 (M+·, 100), 120 (59), 118 (47), 92 (24), 91 (25). Acquired data are in agreement
with the literature. 8

N-(4-Methoxybenzyl)maleimide (4e): Same procedure as above was followed on a 6.39 mmol

scale. Purification by silica gel flash chromatography afforded a white crystalline solid (0.73 g,
3.39 mmol, 53 % yield); Rf = 0.66 (1:1 hexane/EtOAc); mp. 101-103 ºC; FT-IR (KBr, cm-1):
3101 (=CHAr), 2946 (OCH3), 1712 (C=O), 1403 (CH2), 1249 (C-O-C), 694 (HC=CH); GC: Rt

6
X. Z. Zhao, K. Maddali, M. Metifiot, S. J. Smith, B. Christie Vu, C. Marchand, S. H. Hughes, Y. Pommier
and T. R. Burke Jr., Bioorg. Med. Chem. Lett., 2011, 21, 2986.
7
E. Schweizer, A. Hoffmann-Röder, J. A. Olsen, P. Seiler, U. Obst-Sander, B. Wagner, M. Kansy, D.
W. Banner and F. Diederich, Org. Biomol. Chem., 2006, 4, 2364.
8
A. L. Schwartz and L. M. Lerner, J. Org. Chem., 1974, 39, 21.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

= 15.51 min.; MS (EI), m/z (%): 217 (M+·, 100), 174 (62), 136 (51), 134 (45), 77 (43). Acquired
data are in agreement with the literature. 9

N-(3,4-Methylenedioxybenzyl)maleimide (4f): Same procedure as above was followed on a 5.75

mmol scale. Purification by silica gel flash chromatography afforded a white crystalline solid
(0.90 g, 3.91 mmol, 68 % yield); Rf = 0.66 (1:1 hexane/EtOAc); mp. 101-103 ºC; FT-IR (KBr,
cm-1): 3001 (=CHAr), 2915 (CH2), 1712 (C=O), 1403 (CH2), 1249 (C-O-C), 694 ν(HC=CH);
GC: Rt = 17.91 min.; MS (EI), m/z (%): 231 (M+·, 100), 150 (28), 148 (32), 135 (23), 77 (24).
Acquired data are in agreement with the literature. 10

N-(Naphthalen-1-ylmethyl)maleimide (4g): Same procedure as above was followed on a 4.18

mmol scale. Purification by silica gel flash chromatography afforded a white crystalline solid
(0.82 g, 3.43 mmol, 62 % yield); Rf = 0.73 (1:1 hexane/EtOAc); mp. 73-75 ºC; FT-IR (KBr, cm-
1
): 3070 (=CHAr), 1697 (C=O), 1403 (CH2), 1373 (C=CAr), 694 (HC=CH); GC: Rt = 24.22
min.; MS (EI), m/z (%): 237 (M+·, 100), 127 (71), 115 (67), 55 (92), 54 (68). Acquired data are
in agreement with the literature.6

S-(-)-N-(1-Feniletil)maleimide (4h): Compound 7h was obtained from commercial available α-

(S)-methyl-benzylamine 3h according to the procedure described in section 4. Purification by
silica gel flash chromatography a transparent oil (0.99 g, 5.12 mmol, 62 % yield) was obtained;
Rf = 0.66 (1:1 hexane/EtOAc); FT-IR (KBr, cm-1): 3101 (=CHAr), 2977 (CH3), 1712 (C=O),
1388 (CH3), 694 (HC=CH); GC: Rt = 11.99 min.; MS (EI), m/z (%): 201 (M+·, 100), 186 (64),
158 (67), 104 (50), 77 (59). Acquired data are in agreement with the literature. 11

R-(+)-N-(1-Feniletil)maleimide (4i): Compound 7i was obtained from commercial available α-

(R)-methyl-benzylamine 3i according to the procedure described in section 4. Purification by
silica gel flash chromatography a transparent oil (1.02 g, 4.95 mmol, 60 % yield) was obtained;
Rf = 0.65 (1:1 hexane/EtOAc); FT-IR (KBr, cm-1): 3101 (=CHAr), 2977 (CH3), 1712 (C=O),
1388 (CH3), 694 (HC=CH); GC: Rt = 12.02 min.; MS (EI), m/z (%): 201 (M+·, 100), 186 (65),
158 (39), 104 (57), 77 (72). Acquired data are in agreement with the literature.11

9
E. Awuah and A. Capretta, J. Org. Chem., 2011, 76, 3122.
10
J. R. Cashman, M. MacDonald, S. Ghirmai, K. J. Okolotowicz, E. Sergienko, B. Brown, X. Garcia, D.
Zhai, R. Dahl and J. C. Reed, Bioorg. Med. Chem. Lett., 2010, 20, 6560.
11
A. Chihab-Eddine, A. Daïch, A. Jilale, B. Decroix, Tetrahedron Lett. 2001, 42, 573.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

5. General procedure for the synthesis of the 7-oxa-2-azabicyclo[2.2.1]hept-5-enes 6a-6i

2
7O 1 NH
O 6 3
R4
R3 4
5 3' 2' O 9'
N H3BO3
R2 4' 8' 10' R
O+ (10% mol) 1' 1
5' N 7'
O PEG-400, 90ºC 6' 11'
NH2 R1 1 h, N2 O 12' R2
R4
R3
5 4a-4i 6a-4i

A solution of the corresponding maleimide 4a-4i (2.13 mmol) in 10 mL of polyethylenglycol

400 (PEG-400) was placed in a 50 mL Schlenk round-bottom flask heated at 90 °C and under
positive nitrogen pressure, then boric acid (10 % mol) was added in one portion and after 20
min, furfurylamine (2.55 mmol) were added over a few minutes in small portions. The reaction
was monitored by TLC after 60 min and the mixture was poured into 50 mL of NaHCO3
solution 1 M and extracted with dichloromethane (3 x 10 mL). The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain brown oils. The residue
was purified by column chromatography on silica gel and eluted with hexane/EtOAc (2:1) to
afford the desired products as colored oils.

4-(N-Benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6a): Purification

by silica gel column chromatography afforded pure 6a as a red oil (490 mg, 1.72 mmol, 82 %
yield). Rf = 0.43 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 3039 (=CHAr),
1712 (C=O), 1403 (CH2), 1342 (HC=CH). 1H NMR δ (400 MHz, CDCl3): 7.35 (3H, dd, J = 6.2,
1.1 Hz, HPh-9’, 11’ y H-1), 7.32 – 7.26 (3H, m, HPh-8’, 10’, 12’), 6.30 (1H, dd, J = 3.1, 1.9 Hz,
H-6), 6.19 (1H, d, J = 3.1 Hz, H-5), 4.63 (2H, s, H-CH2Ph), 3.91 (1H, d, J = 14.6 Hz, Heq-3),
3.83 (1H, d, J = 14.6 Hz, Hax-3), 3.72 (1H, dd, J = 8.2, 5.0 Hz, Heq-3’), 2.86 (1H, dd, J = 17.9,
8.3 Hz, Heq-4’), 2.46 (1H, dd, J = 17.9, 5.0 Hz, Hax-4’), 2.11 (2H, br.s., NH) ppm.13C NMR δ
(400 MHz, CDCl3): 177.4, 174.8, 152.2, 142.5 (+), 135.5, 128.9 (2xCH, +), 128.7 (2xCH, +),
128.1 (+), 110.4 (+), 108.1 (+), 55.1 (+), 44.1 (-), 42.5 (-), 36.3 (-) ppm. COSY Correlation
[δH/δH]: 7.32-7.26 [HPh-9’,11’/HPh-8’,10’,12’], 7.35/6.30[H-1/H-6],7.35/6.19 [H-1/H-5],
7.35/4.63 [HPh-9’,11’/H-CH2Ph], 7.32-7.26 /4.63 [HPh-8’,10’,12’/H-CH2Ph], 6.30/6.19 [H-6/H-
5], 6.30/3.91 [H-6/Heq-3], 6.30/3.83 [H-6/Hax-3], 6.19/3.91 [H-5/Heq-3], 6.19/3.83 [H-5/Hax-3],
4.63/2.46 [H-CH2Ph/Hax-4’], 4.63/2.86 [H-CH2Ph/Heq-4’], 3.72/2.46 [Heq-3’/Hax-4’], 3.72/2.86
[Heq-3’/Heq-4’], 2.86/2.46 [Heq-4’/ Hax-4’]. HSQC Correlation [δH/δC]: 7.35-7.26/128.1-128.9
[HPh/CPh], 7.35/142.5 [H-1/C-1], 6.30/110.4 [H-6/C-6], 6.19/108.1 [H-5/C-5], 4.63/42.5 [H-
CH2Ph/C-6’], 3.91/44.1 [Heq-3/C-3], 3.83/44.1 [Hax-3/C-3], 3.72/55.1 [Heq-3’/C-3’], 2.86/36.3

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

[Heq-4’/C-4’], 2.46/36.3 [Hax-4’/C-4’]. HMBC Correlation [δH/δC]: 7.35/42.5/128.1/128.9/135.5

[HPh-9’,11’/C-6’/C-10’/C-8’,12’/C-7’], 7.35/108.1/110.4/152.2 [H-1/C-5/C-6/C-4],7.32-7.26
/42.5/128.1-128.9/135.5 [HPh-8’,10’,12’/C-6’/C-8’,9’,10’,11’,12’/C-7’], 6.30/108.1/142.5 /152.2
[H-6/C-5/C-1/C-4], 6.19/44.1/110.4/142.5/152.2 [H-5/C-3/C-6/C-1/C-4], 4.63/128.1-128.9/
135.5/174.8/177.4 [H-CH2Ph/C-8’,9’,10’,11’,12’/C-7’/C-5’/C-2’], 3.91/55.1/108.1/110.4/
142.5/152.2 [Heq-3/C-3’/C-5/C-6/C-1,C-4], 3.83/55.1/108.1/110.4/142.5/152.2 [Hax-3/C-3’/C-
5/C-6/C-1,C-4], 3.72/36.3/44.1/174.8/177.4 [Heq-3’/C-4’/C-3/C-5’/C-2’], 2.86/55.1/174.8/177.4
[Heq-4’/C-3’/C-5’/C-2’], 2.46/55.1/174.8/177.4 [Hax-4’/C-3’/C-5’/C-2’]. GC: Rt = 22.87 min.;
MS (EI), m/z (%): 283 (M+·, 1), 267 (1), 96 (100), 91 (25), 81 (36), 53 (12). HRMS (ESI+): m/z:
calcd for C16H17N2O3 (M+H+) 285.1234, found: 285.1237; Calcd for C16H16N2O3Na (M+Na+)
307.1053, found: 307.1049.

4-(N-(4-Chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6b):
Purification by silica gel column chromatography afforded pure 6b as a yellow oil (480 mg, 1.52
mmol, 84 % yield). Rf = 0.45 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 2931
(=CHAr), 1712 (C=O), 1403 (CH2), 1342 (HC=CH), 740 (C-Cl). 1H NMR δ (400 MHz,
CDCl3): 7.36 (1H, dd, J = 1.9, 0.8 Hz, H-1), 7.31-7.24 (4H, m, HAr-8’, 9’, 11’, 12’), 6.30 (1H,
dd, J = 3.2, 1.9 Hz, H-6), 6.20 (1H, d, J = 3.2 Hz, H-5), 4.59 (2H, s, H-CH2Ar), 3.91 (1H, d, J =
14.6 Hz, Heq-3), 3.82 (1H, d, J = 14.6 Hz, Hax-3), 3.72 (1H, dd, J = 8.3, 5.0 Hz, Heq-3’), 2.86
(1H, dd, J = 18.0, 8.3 Hz, Heq-4’), 2.46 (1H,dd, J = 18.0, 5.0 Hz, Hax-4’), 2.10 (1H, br.s., NH)
ppm. 13C NMR δ (101 MHz, CDCl3): 177.4, 174.7, 152.2, 142.5 (+), 134.1, 133.9, 130.4 (2xCH,
+), 128.9 (2xCH, +), 110.4 (+), 108.1 (+), 55.0 (+), 44.1 (-), 41.8 (-), 36.3 (-) ppm. COSY
Correlation [δH/δH]: 7.36/6.20 [H-1/H-5], 7.36/6.30 [H-1/H-6], 7.31-7.24/4.59 [HAr-8’, 9’, 11’,
12’/H-CH2Ar], 6.30/6.20 [H-6/H-5], 6.20/3.82 [H-5/Hax-3], 3.72/2.46 [Heq-3’/Hax-4’], 3.72/2.86
[Heq-3’/Heq-4’], 2.86/2.46 [Heq-4’/ Hax-4’]. HSQC Correlation [δH/δC]: 7.36/142.5 [H-1/C-1],
7.31-7.24 /128.9-130.4 [HAr/CAr], 6.30/110.4 [H-6/C-6], 6.20/108.1 [H-5/C-5], 4.59/41.8 [H-
CH2Ar/C-6’], 3.91/44.1 [Heq-3/C-3], 3.82/44.1 [Hax-3/C-3], 3.72/55.0 [Heq-3’/C-3’], 2.86/36.3
[Heq-4’/C-4’], 2.46/36.3 [Hax-4’/C-4’]. HMBC Correlation [δ H/δC]: 7.36/108.1/110.4/152.2 [H-
1/C-5/C-6/C-4], 7.31-7.24/41.8/128.9-130.4/133.9/134.1 [HAr-8’,9’,11’,12’/C-8’,9’,11’,12/C-
10’/C-7’], 6.30/ 108.1/142.5/152.2 [H-6/C-5/C-1/C-4], 6.20/110.4/142.5/152.2 [H-5/C-6/C-1/C-
4], 4.59/128.9-134.1/174.7/177.4 [H-CH2Ar/C-7’,8’,9’,10’,11’,12’/C-5’/C-2’], 3.91/55.0/108.1
/152.2 [Heq-3/C-3’/C-5/C-4], 3.82/55.1/108.1/152.2[Hax-3/C-3’/C-5/C-4], 3.72/36.3/44.1/174.7
/177.4 [Heq-3’/C-4’/C-3/C-5’/C-2’], 2.86/55.0/174.7/177.4 [Heq-4’/C-3’/C-5’/C-2’], 2.46/55.0/
174.7/177.4 [Hax-4’/C-3’/C-5’/C-2’]. GC: Rt = 25.28 min.; MS (EI), m/z (%): 317 (M+·, 1), 301

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

(1), 127 (7), 125 (22), 96 (100), 81 (36), 53 (9). HRMS (ESI+): m/z: calcd for C16H16ClN2O3
(M+H+) 319.0844, found: 319.0851; Calcd for C16H15ClN2O3Na (M+Na+) 341.0663, found:
341.0667.

4-(N-(4-Fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6c):
Purification by silica gel column chromatography afforded pure 6c as a yellow oil (510 mg, 1.71
mmol, 88 % yield). Rf = 0.56 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 2931
(=CHAr), 1712 (C=O), 1403 (CH2), 1342 (HC=CH), 632 (C-F). 1H NMR δ (400 MHz, CDCl3):
7.36 (1H, dd, J = 1.8, 0.6 Hz, H-1), 7.35-7.31 (2H, m, HAr-8’, 12’), 7.00-6.92 (2H, m, HAr-9’,
11’),6.30 (1H, dd, J = 3.1, 1.9 Hz, H-6), 6.19 (1H, d, J = 3.2 Hz, H-5), 4.59 (2H, s, H-CH2Ar),
3.91 (1H, d, J = 14.6 Hz, Heq-3), 3.82 (1H, d, J = 14.6 Hz, Hax-3), 3.72 (1H, dd, J = 8.2, 5.0 Hz,
Heq-3’), 2.85 (1H, dd, J = 17.9, 8.2 Hz, Heq-4’), 2.45 (1H, dd, J = 17.9, 5.0 Hz, Hax-4’), 2.07 (1H,
br.s., NH) ppm. 13C NMR δ (101 MHz, CDCl3): 177.4, 174.8, 162.5, 152.2, 142.5 (+), 131.4,
130.9 (2xCH, +), 115.6 (2xCH, +), 110.4 (+), 108.1 (+), 55.0 (+), 44.1 (-), 41.7 (-), 36.3 (-) ppm.
COSY Correlation [δH/δH]: 7.36/6.19 [H-1/H-5], 7.36/6.30 [H-1/H-6], 7.35-7.31/4.59 [HAr-
8’,12’/H-CH2Ar], 7.35-7.31/7.00-6.92 [HAr-8’,12’/HAr-9’,11’],6.30/6.19 [H-6/H-5], 6.19/3.91
[H-5/Heq-3], 6.19/3.82 [H-5/Hax-3], 3.72/2.45 [Heq-3’/Hax-4’], 3.72/2.85 [Heq-3’/Heq-4’],
2.85/2.45 [Heq-4’/Hax-4’]. HSQC Correlation [δ H/δC]: 7.36/142.5 [H-1/C-1], 7.35-7.31/130.9
[HAr-8’,12’/C-8’,12’], 7.00-6.92/115.6 [HAr-9’,11’/C-9’,11’], 6.30/110.4 [H-6/C-6], 6.19/108.1
[H-5/C-5], 4.59/41.7 [H-CH2Ar/C-6’], 3.91/44.1 [Heq-3/C-3], 3.82/44.1 [Hax-3/C-3], 3.72/55.0
[Heq-3’/C-3’], 2.85/36.3 [Heq-4’/C-4’], 2.45/36.3 [Hax-4’/C-4’]. HMBC Correlation [δH/δC]:
7.36/108.1/110.4/152.2 [H-1/C-5/C-6/C-4], 7.35-7.31/41.7/115.6/131.4/162.5[HAr-8’,12’/C-
6’/C-9’,11’/C-7’/C-10’],7.00-6.92/130.9/131.4/162.5 [HAr-9’,11’//C-8’,12’/C-7’/C-10’], 6.30/
108.1/142.5/152.2 [H-6/C-5/C-1/C-4], 6.19/110.4/142.5/152.2 [H-5/C-6/C-1/C-4], 4.59/130.9/
131.4/174.8/177.4 [H-CH2Ar/C-8’,12’/C-7’/C-5’/C-2’], 3.91/55.0/108.1/152.2 [Heq-3/C-3’/C-
5/C-4], 3.82/55.0/108.1/152.2 [Hax-3/C-3’/C-5/C-4],3.72/36.3/44.1/174.8/177.4 [Heq-3’/C-4’/C-
3/C-5’/C-2’], 2.85/55.0/174.8/177.4 [Heq-4’/C-3’/C-5’/C-2’], 2.45/55.0/174.8/177.4 [Hax-4’/C-
3’/C-5’/C-2’]. GC: Rt = 23.17 min.; MS (EI), m/z (%): 301 (M+·, 1), 285 (1), 109 (33), 97 (6), 96
(100), 81 (42). HRMS (ESI+): m/z: calcd for C16H16FN2O3 (M+H+) 303.1139, found: 303.1135;
Calcd for C16H15FN2O3Na (M+Na+) 325.0959, found: 325.0953.

4-(N-(4-Methylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6d):
Purification by silica gel column chromatography afforded pure 6d as a yellow oil (550 mg, 1.84
mmol, 93 % yield). Rf = 0.42 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 3023

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

(CH3), 2931 (=CHAr), 1712 (C=O), 1403 (CH2), 1342 (HC=CH). 1H NMR δ (400 MHz,
CDCl3): 7.38 (1H, dd, J = 1.8, 0.8 Hz, H-1), 7.28-7.26 (2H, m, HAr-8’, 12’), 7.12 (2H, d, J = 7.8
Hz, HAr-9’, 11’), 6.32 (1H, dd, J = 3.2, 1.9 Hz, H-6), 6.21 (1H, d, J = 3.2 Hz, H-5), 4.61 (2H, s,
H-CH2Ar), 3.93 (1H, d, J = 14.6 Hz, Heq-3), 3.84 (1H, d, J = 14.7 Hz, Hax-3), 3.72 (1H, dd, J =
8.3, 5.0 Hz, Heq-3’), 2.87 (1H, dd, J = 17.9, 8.3 Hz, Heq-4’), 2.47 (1H, dd, J = 17.9, 5.0 Hz, Hax-
4’), 2.32 (3H, s, CH3), 2.10 (1H, br.s., NH) ppm.13C NMR δ (101 MHz, CDCl3): 177.5, 174.9,
152.2, 142.5 (+), 137.9, 132.5, 129.4 (2xCH, +), 128.9 (2xCH, +), 110.4 (+), 108.1 (+), 55.0 (+),
44.1 (-), 42.2 (-), 36.3 (-), 21.2 (+) ppm. GC: Rt = 23.99 min.; MS (EI), m/z (%): 297 (M+·, 1),
281 (1), 97 (6), 96 (100), 81 (39), 53 (12). HRMS (ESI+): m/z: calcd for C17H19N2O3 (M+H+)
299.1390, found: 299.1387; Calcd for C17H18N2O3Na (M+Na+) 321.1210, found: 321.1206.

4-(N-(4-Methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6e):
Purification by silica gel column chromatography afforded pure 6e as a yellow oil (520 mg, 1.67
mmol, 91 % yield). Rf = 0.49 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 2931
(=CHAr), 2838 (OCH3), 1697 (C=O), 1403 (CH2), 1342 (HC=CH), 1249 (C-O-C). 1H NMR δ
(400 MHz, CDCl3): 7.36 (1H, dd, J = 1.8, 0.7 Hz, H-1), 7.33-7.27 (2H, m, HAr-8’, 12’), 6.83-
6.79 (2H, m, HAr-9’, 11’), 6.30 (1H, dd, J = 3.1, 1.9 Hz, H-6), 6.19 (1H, d, J = 3.2 Hz, H-5),
4.57 (2H, s, H-CH2Ar), 3.91 (1H, d, J = 14.6 Hz, Heq-3), 3.82 (1H, d, J = 14.6 Hz, Hax-3), 3.76
(3H, s, OCH3), 3.70 (1H, dd, J = 8.3, 5.0 Hz, Heq-3’), 2.84 (1H, dd, J = 17.9, 8.3 Hz, Heq-4’),
2.44 (1H, dd, J = 17.9, 5.0 Hz, Hax-4’), 2.09 (1H, br.s., NH) ppm. 13
C NMR δ (101 MHz,
CDCl3): 177.5, 174.9, 159.4, 152.3, 142.5 (+), 130.4 (2xCH, +), 127.8, 114.0 (2xCH, +), 110.3
(+), 108.1 (+), 55.3 (+), 55.1 (+), 44.1 (-), 41.9 (-), 36.3 (-) ppm. COSY Correlation [δ H/δH]:
7.36/6.19 [H-1/H-5], 7.36/6.30 [H-1/H-6], 7.33-7.27/4.57[HAr-8’,12’/H-CH2Ar], 7.33-7.27/6.83-
6.79 [HAr-8’,12’/HAr-9’,11’],6.30/6.19 [H-6/H-5], 6.19/3.91 [H-5/Heq-3], 6.19/3.82 [H-5/Hax-3],
3.70/2.44 [Heq-3’/Hax-4’], 3.70/2.84 [Heq-3’/Heq-4’], 2.84/2.44 [Heq-4’/ Hax-4’]. HSQC
Correlation [δH/δC]: 7.36/142.5 [H-1/C-1], 7.33-7.27/130.4 [HAr-8’, 12’/C-8’,12’], 6.83-
6.79/114.0 [HAr-9’,11’/C-9’-11’], 6.30/110.3 [H-6/C-6], 6.19/108.1 [H-5/C-5], 4.57/41.9 [H-
CH2Ar/C-6’], 3.91/44.1 [Heq-3/C-3], 3.82/44.1 [Hax-3/C-3], 3.76/55.3 [H-OCH3/C-OCH3],
3.70/55.1 [Heq-3’/C-3], 2.84/36.3 [Heq-4’/C-4’], 2.44/36.3 [Hax-4’/C-4’]. HMBC Correlation
[δH/δC]: 7.36/108.1/110.3/152.3 [H-1/C-5/C-6/C-4], 7.33-7.27/41.9/114.0/159.4 [HAr-8’,12’/H-
CH2Ar/C-9’,11’/C-10’], 6.83-6.79 /127.8/130.4/159.4 [HAr-9’,11’/C-7’/C-8’,12’/C-10’],
6.30/108.1/142.5/152.3 [H-6/C-5/C-1/C-4], 6.19/110.3/142.5/152.3 [H-5/C-6/C-1/C-4],
4.57/127.8/130.4/174.9/177.5 [H-CH2Ar/C-7/C-8’,12’/C-5’/C-2’], 3.91/55.1/108.1/152.3 [Heq-
3/C-3’/C-5/C-4], 3.82/55.1/108.1/152.3 [Hax-3/C-3’/C-5/C-4], 3.79/159.4 [H-OCH3/C-10’],

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

3.70/36.3/44.1/174.9/177.5 [Heq-3’/C-4’/C-3/C-5’/C-2’], 2.84/55.1/174.9/177.5 [Heq-4’/C-3’/C-

5’/C-2’], 2.44/55.1/174.9/177.5 [Hax-4’/C-3’/C-5’/C-2’]. GC: Rt = 25.98 min.; MS (EI), m/z (%):
314 (M+·, 1), 297 (1), 162 (6), 121 (49), 96 (100), 81 (38), 53 (8). HRMS (ESI+): m/z: calcd for
C17H19N2O4 (M+H+) 315.1339, found: 315.1344; Calcd for C17H18N2O4Na (M+Na+) 337.1159,
found: 337.1155.

4-(N-(3,4-Methylenedioxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-
ene (6f): Purification by silica gel column chromatography afforded pure 6f as a yellow oil (460
mg, 1.40 mmol, 89 % yield). Rf = 0.43 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317
(NH), 2900 (CH2), 1697 (C=O), 1403 (CH2), 1326 (HC=CH), 1249 (C-O-C). 1H NMR δ (400
MHz, CDCl3): 7.36 (1H, dd, J = 1.9, 0.8 Hz, H-1), 6.86-6.82 (2H, m, HAr-8’, 12’), 6.70 (1H, dd,
J = 7.7, 0.6 Hz, HAr-11’), 6.30 (1H, dd, J = 3.2, 1.9 Hz, H-6), 6.19 (1H, dd, J = 3.2, 0.6 Hz, H-5),
5.91 (2H, s, -OCH2O-), 4.52 (2H, s, H-CH2Ar), 3.91 (1H, d, J = 14.6 Hz, Heq-3), 3.82 (1H, d, J =
14.6 Hz, Hax-3), 3.70 (1H, dd, J = 8.3, 5.0 Hz, Heq-3’), 2.84 (1H, dd, J = 17.9, 8.3 Hz, Heq-4’),
2.44 (1H, dd, J = 17.9, 5.0 Hz, Hax-4’), 2.22 (1H, br.s., NH) ppm. 13
C NMR δ (101 MHz,
CDCl3): 177.3, 174.7, 152.1, 147.7, 147.3, 142.4 (+), 129.2, 122.5 (+), 110.3 (+), 109.4 (+),
108.2 (+), 108.0 (+), 101.1 (-), 55.0 (+), 44.1 (-), 42.2 (-), 36.2 (-) ppm. COSY Correlation
[δH/δH]: 7.36/6.19 [H-1/H-5], 7.36/6.30 [H-1/H-6], 6.86-6.82/4.59 [HAr-8’,12’/H-CH2Ar], 6.86-
6.82/6.70 [HAr-8’,12’/HAr-11’], 6.30/6.19 [H-6/H-5], 6.19/3.91 [H-5/Heq-3], 6.19/3.82 [H-5/Hax-
3], 3.70/2.44 [Heq-3’/Hax-4’], 3.70/2.84 [Heq-3’/Heq-4’], 2.84/2.44 [Heq-4’/ Heq-4’]. HSQC
Correlation [δH/δC]: 7.36/142.4[H-1/C-1], 6.86-6.82/109.4/122.59 [HAr-8’,12’/C-8’,12’], 6.70/
108.2 [H-11’/C-11’], 6.30/110.3 [H-6/C-6], 6.19/108.0 [H-5/C-5], 5.91/101.1 [H-OCH2O/C-
OCH2O], 4.52/42.2 [H-CH2Ar/C-6’], 3.91/44.1 [Heq-3/C-3], 3.82/44.1 [Hax-3/C-3], 3.70/55.0
[Heq-3’/C-3’], 2.84/36.2 [Heq-4’/C-4’], 2.44/36.2 [Hax-4’/C-4’]. HMBC Correlation [δH/δC]:
7.36/108.0/110.3/152.1 [H-1/C-5/C-6/C-4], 6.86-6.82/42.2/108.0/109.4/147.37/147.75 [HAr-
8’,12’/C-6’/C-12’/C-8’/C-10’/C-9’], 6.70/109.4/129.2/147.3/147.75 [H-11’/C-12’/C-7’/C-10’/C-
9’], 6.30/108.0/142.4/152.1 [H-6/C-5/C-1/C-4], 6.19/110.3/142.4/152.1 [H-5/C-6/C-1/C-
4],5.91/147.3/147.7 [H-OCH2O/C-10’/C-9],4.52/109.4/122.5/129.2/174.7/177.3[H-CH2Ar/C-
12’/C-8’/C-7’/C-5’/C-2’], 3.91/55.0/108.0/152.1 [Heq-3/C-3’/C-5/C-4], 3.82/55.0/108.0/152.1
[Hax-3/C-3’/C-5/C-4], 3.70/36.2/44.1/174.7/177.3 [Heq-3’/C-4’/C-3/C-5’/C-2’], 2.84/55.0/174.7
/177.3 [Heq-4’/C-3’/C-5’/C-2’], 2.44/55.0/174.7/177.3 [Hax-4’/C-3’/C-5’/C-2’]. GC: Rt = 27.55
min.; MS (EI), m/z (%): 328 (M+·, 1), 311 (1), 135 (45), 96 (100), 81 (39), 77 (9), 53 (9). HRMS
(ESI+): m/z: calcd for C17H17N2O5 (M+H+) 329.1132, found: 329.1135; Calcd for C17H16N2O5Na
(M+Na+) 351.0951, found: 351.0945.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

4-(N-(1-Naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6g):
Purification by silica gel column chromatography afforded pure 6g as a yellow oil (530 mg, 1.60
mmol, 95 % yield). Rf = 0.56 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH), 3054
(=CArH), 1712 (C=O), 1511 (CAr=CAr), 1403 (CH2), 1342 (HC=CH). 1H NMR δ (400 MHz,
CDCl3): 8.27 (1H, d, J = 8.4 Hz, H-14’), 7.85 (1H, d, J = 8.1 Hz, H-11’), 7.80 (1H, d, J = 8.3
Hz, H-10’), 7.56 (2H, ddd, J = 7.1, 4.9, 1.4 Hz, H-8’ y 13’), 7.49 (1H, ddd, J = 8.0, 6.9, 1.1 Hz,
H-12’), 7.41 (1H, dd, J = 8.1, 7.2 Hz, H-9’), 7.36 (1H, dd, J = 1.9, 0.8 Hz, H-1), 6.29 (1H, dd, J
= 3.1, 1.9 Hz, H-6), 6.18 (1H, d, J = 3.2 Hz, H-5), 5.12 (2H, d, J = 3.9 Hz, H-CH2), 3.91 (1H, d,
J = 14.6 Hz, Heq-3), 3.82 (1H, d, J = 14.6 Hz, Hax-3), 3.71 (1H, dd, J = 8.3, 5.0 Hz, Heq-3’), 2.87
(1H, dd, J = 17.9, 8.3 Hz, Heq-4’), 2.49 (1H, dd, J = 17.9, 5.0 Hz, Hax-4’), 2.09 (1H, br.s., NH)
ppm. 13C NMR δ (101 MHz, CDCl3): 177.7, 175.0, 152.2, 142.5 (+), 133.8, 131.3, 130.5, 128.9
(+), 128.8 (+), 127.8 (+), 126.6 (+), 125.9 (+), 125.3 (+), 123.5 (+), 110.3 (+), 108.1 (+), 55.0
(+), 44.1 (-), 40.3 (-), 36.3 (-) ppm. COSY Correlation [δH/δH]: 8.27/7.56 [H-14’/H-13’],
7.85/7.49 [H-11’/H-12’], 7.80/7.41 [H-10’/H-9’], 7.56/5.12 [H-8’/H-CH2], 7.56/7.41 [H-8’/H-
9’], 7.56/7.49 [H-13’/H-12’], 7.36/6.18 [H-1/H-5], 7.36/6.29 [H-1/H-6], 6.29/6.18 [H-6/H-5],
3.91/3.82 [Heq-3/Hax-3], 3.71/2.49 [Heq-3’/Hax-4’], 3.71/2.87 [Heq-3’/Heq-4’], 2.87/2.49 [Heq-
4’/Hax-4’]. HSQC Correlation [δH/δC]: 8.27/123.5 [H-14’/C-14’], 7.85/128.8 [H-11’/C-11’],
7.80/128.9 [H-10’/C-10’], 7.56/126.6 [H-13’/C-13’], 7.56/127.8 [H-8’/C-8’], 7.49/125.9 [H-
12’/C-12’], 7.41/125.3 [H-9’/C-9’], 7.36/142.5 [H-1/C-1], 6.29/110.3 [H-6/C-6], 6.18/108.1 [H-
5/C-5], 5.12/40.3 [H-CH2/C-6’], 3.91/44.1 [Heq-3/C-3], 3.82/44.1 [Hax-3/C-3], 3.71/55.0 [Heq-
3’/C-3’], 2.87/36.3 [Heq-4’/C-4’], 2.49/36.3 [Hax-4’/C-4’]. HMBC Correlation [δH/δC]:
8.27/125.9/130.5/133.8 [H-14’/C-12’/C-7’/C-14a], 7.85/126.6/131.3/133.8 [H-11’/C-13’/C-
10 /C-14 ], 7.80/127.8/131.3/ 133.8[H-10’/C-8’/C-10 /C-14 ], 7.56/131.3 [H-8’/C-10a], 7.56/
a a a a

128.8/128.9/131.3 [H-13’/C-11’/C-10’/C-10a], 7.49/123.5/133.8 [H-12’/C-11’/C-14’/C-14a],

7.41/130.5/133.8 [H-9’/C-7’/C-14a],6.29/108.1/142.5/152.2 [H-6/C-5/C-1/C-4], 6.18/110.3/
142.5/152.2 [H-5/C-6/C-1/C-4], 5.12/127.8/130.5/175.0/177.7 [H-CH2Ar/C-8’/C-7’/C-5’/C-2’],
3.91/55.0/108.1/152.2 [Heq-3/C-3’/C-5/C-4], 3.82/55.0/108.1/152.2 [Hax-3/C-3’/C-5/C-4],
3.71/36.3/44.1/175.0/177.7 [Heq-3’/C-4’/C-3/C-5’/C-2’], 2.87/55.0/175.0/177.7 [Heq-4’/C-3’/C-
5’/C-2’], 2.49/55.0/175.0/177.7 [Hax-4’/C-3’/C-5’/C-2’]. GC: Rt = 31.01 min.; MS (EI), m/z (%):
334 (M+·, 1), 317 (1), 141 (37), 115 (11), 96 (100), 81 (37), 53 (10). HRMS (ESI+): m/z: calcd
for C20H19N2O3 (M+H+) 335.1390, found: 335.1385; Calcd for C20H18N2O3Na (M+Na+)
357.1210, found: 357.1214.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

4-(S-(-)-N-(1-Phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene
(6h): Purification by silica gel column chromatography afforded pure 6h as a yellow oil (510
mg, 1.71 mmol, 86 % yield). Rf = 0.56 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317
(NH), 2977 (CH3), 1697 (C=O), 1388 (HC=CH), 1187 (CH3). 1H NMR δ (400 MHz, CDCl3):
7.42 (2H, d, J = 7.9 Hz, HAr-8’, 12’), 7.36 (1H, d, J = 1.0 Hz, H-1), 7.33-7.23 (3H, m, HAr-9’,
10’, 11’), 6.30 (1H, dd, J = 3.1, 1.5 Hz, H-6), 6.19 (1H, d, J = 2.6 Hz, H-5), 5.43-5.35 (1H, m,
H-6’), 3.90 (1H, dd, J = 14.8, 3.3 Hz, Heq-3), 3.80 (1H, d, J = 14.5 Hz, Hax-3), 3.64 (1H, ddd, J =
16.3, 8.3, 5.3 Hz, Heq-3’), 2.80 (1H, dt, J = 17.7, 7.6 Hz, Heq-4’), 2.47-2.37 (1H, m, Hax-4’), 2.02
(1H, br.s., NH), 1.81-1.78 (3H, m, H-CH3) ppm. 13C NMR δ (101 MHz, CDCl3): 177.5, 174.9,
152.3, 142.5 (+), 139.5, 128.5 (2xCH, +), 127.9 (+), 127.6 (2xCH, +), 110.4 (+), 108.1 (+), 54.8
(+), 50.4(+), 44.2 (-), 36.3 (-), 16.6 (+) ppm. GC: Rt = 23.39 min.; MS (EI), m/z (%): 298 (M+·,
1), 281 (1), 106 (25), 96 (100), 81 (46), 77 (9), 53 (12). HRMS (ESI+): m/z: calcd for
C17H19N2O3 (M+H+) 299.1390, found: 299.1394; Calcd for C17H18N2O3Na (M+Na+) 321.1210,
found: 321.1205.

4-(R-(+)-N-(1-Phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene
(6i): Purification by silica gel column chromatography afforded pure 6i as a yellow oil (480 mg,
1.63 mmol, 82 % yield). Rf = 0.50 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3317 (NH),
2977 (CH3), 1697 (C=O), 1388 (HC=CH), 1187 (CH3). 1H NMR δ (400 MHz, CDCl3): 7.43-
7.40 (2H, m, HAr-8’, 12’), 7.36 (1H, td, J = 2.2, 0.8 Hz, H-1), 7.33-7.23 (3H, m, HAr-9’, 10’ and
11’), 6.30 (1H, dt, J = 3.4, 1.7 Hz, H-6), 6.19 (1H, d, J = 2.7 Hz, H-5), 5.39 (1H, qd, J = 7.4, 3.0
Hz, H-6’), 3.89 (1H, dd, J = 14.6, 3.2 Hz, Heq-3), 3.80 (1H, dd, J = 14.6, 1.7 Hz, Hax-3), 3.63
(1H, ddd, J = 17.7, 8.3, 5.3 Hz, Heq-3’), 2.80 (1H, ddd, J = 17.8, 8.2, 7.4 Hz, Heq-4’), 2.42 (1H,
ddd, J = 17.9, 8.3, 5.2 Hz, Hax-4’), 2.11 (1H, br.s., NH), 1.79 (3H, dd, J = 7.3, 2.7 Hz, H-CH3)
ppm. C NMR δ (101 MHz, CDCl3): 177.5, 174.8, 152.1, 142.4 (+), 139.3, 128.4 (2xCH,+),
13

127.9 (+), 127.5 (2xCH, +), 110.3 (+), 108.0 (+), 54.7 (+), 50.4 (+), 44.1 (-), 36.2 (-), 16.5 (+)
ppm. GC: Rt = 23.12 min.; MS (EI), m/z (%): 298 (M+·, 1), 281 (1), 106 (24), 98 (7), 96 (100),
81 (38), 53 (8). HRMS (ESI+): m/z: calcd for C17H19N2O3 (M+H+) 299.1390, found: 299.1386;
Calcd for C17H18N2O3Na (M+Na+) 321.1210, found: 321.1215.

4-(1H-Pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6j): Compound 6j was

obtained from commercial available maleimide 4j according to the procedure described in
section 5. Purification by silica gel column chromatography afforded pure 6j as a yellow oil (372
mg, 1.91 mmol, 93 % yield). Rf = 0.35 (1:1 hexane/EtOAc); FT-IR (liquid film, cm-1): 3409

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

(NH-Maleimide), 3347 (NH-Bicycle), 3000 (CH2), 1619 (C=O), 1581 (C-N), 1442 (CH2), 1288
(HC=CH). 1H NMR δ (400 MHz, CDCl3): 8.81 (1H, s, 1H, br.s., NH-Maleimide), 7.38 (1H, dd,
J = 1.9, 0.8 Hz, H-1), 6.32 (1H, dd, J = 3.2, 1.9 Hz, H-6), 6.23 (1H, dd, J = 3.2, 0.7 Hz, H-5),
3.93 (1H, d, J = 14.6 Hz, Heq-3), 3.84 (1H, d, J = 14.6 Hz, Hax-3), 3.78 (1H, dd, J = 8.3, 5.3 Hz,
Heq-3’), 2.88 (1H, dd, J = 18.1, 8.3 Hz, Heq-4’), 2.53 (1H, dd, J = 18.1, 5.3 Hz, Hax-4’), 2.12 (1H,
br.s., NH-Bicycle) ppm. 13C NMR δ (101 MHz, CDCl3): 178.2, 175.5, 152.1, 142.6 (+), 110.4
(+), 108.3 (+), 56.2 (+), 44.1 (-), 37.3 (-) ppm. GC: Rt = 6.33 min.; MS (EI), m/z (%): 194 (M+·,
1), 177 (2), 122 (4), 106 (2), 96 (100), 81 (74), 69 (8), 53 (22). HRMS (ESI+): m/z: calcd for
C9H11N2O3 (M+H+) 195.0764, found: 195.0768; Calcd for C9H10N2O3Na (M+Na+) 217.0584,
found: 217.0579.

4-(N-Phenyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-azabicyclo[2.2.1]hept-5-ene (6k): Compound

6k was obtained from commercial available N-phenylmaleimide 4k according to the procedure
described in section 5. Purification by silica gel column chromatography afforded pure 6k as a
white solid (910 mg, 3.36 mmol, 91 % yield). mp. 90-92 °C. Rf = 0.39 (1:1 hexane/EtOAc); FT-
IR (KBr-disk cm-1): 3286 (NH), 2854 (C-H), 1712 (C=O), 1403 (CH2), 1187 (HC=CH). 1H
NMR δ (400 MHz, CDCl3): 7.49-7.45 (2H, m, HAr-7’ and 11’), 7.4-7.40 (1H, m, HAr-9’), 7.39
(1H, dd, J = 8.5, 6.2 Hz, H-1), 7.28-7.25 (2H, m, HAr-8’, 10’), 6.34 (1H, dd, J = 3.1, 1.9 Hz, H-
6), 6.26 (1H, d, J = 3.1 Hz, H-5), 3.98 (1H, dd, J = 14.6 Hz, Heq-3), 3.91 (1H, dd, J = 8.3, 5.2
Hz, Heq-3’), 3.90 (1H, d, J = 14.5 Hz, Hax-3), 3.04 (1H, dd, J = 18.0, 8.4 Hz, Heq-4’), 2.66 (1H,
dd, J = 18.0, 5.3 Hz, Hax-4’), 2.41 (1H, br.s., NH) ppm. 13C NMR δ (101 MHz, CDCl3): 176.8,
174.2, 152.1, 142.6 (+), 131.5, 129.3 (2xCH, +), 128.8 (+), 126.4 (2xCH, +), 110.4 (+), 108.3
(+), 55.1 (+), 44.2 (-), 36.4 (-) ppm. GC: Rt = 14.28 min.; MS (EI), m/z (%): 270 (M+·, 1), 252
(1), 192 (32), 96 (100), 81 (25), 77 (48), 53 (17). HRMS (ESI+): m/z: calcd for C15H15N2O3
(M+H+) 271.1077, found: 271.1074; Calcd for C15H14N2O3Na (M+Na+) 293.0897, found:
293.0902.

6. General procedure for the synthesis of the N-(10-oxa-4-azatricyclo[5.2.1.02,6]decan-8-ene-

3,5-dione-7-ylmethyl)acetamides 7a-7c
O
O R
O N
H3BO3
O
N R (10% mol)
+ O
PEG-400, 90ºC,
NH
O N2 HN
O
O
5b 4b, 4j, 4k 7a-7c

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

A solution of the corresponding maleimide 4b, 4j and 4k (1.95 mmol) in 10 mL of

polyethylenglycol 400 (PEG-400) was placed in a 50 mL Schlenk round-bottom flask heated at
90 °C and under positive nitrogen pressure, then boric acid (10 % mol) was added in one portion
and after 20 min, N-acetyl furfurylamine 5b (2.34 mmol) were added over a few minutes in
small portions; N-acetyl furfurylamine was easily prepared from commercial furfurylamine
according to the described procedure. 12 The reaction was monitored by TLC and after 3 hours
the mixture was diluted with 50 mL of NaHCO3 solution 1 M and the precipitated product was
filtered off, washed with distillated water and then with ethyl acetate, finally the resulting solid
was dried in vacuum to afford the desired products as stable solids.

N-(10-Oxa-1H-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-7-ylmethyl)acetamide (7a):
Compound 7a was obtained according to the procedure described above after filter, washing and
drying the resulting precipitate, obtaining 7a as a white solid (336 mg, 1.42 mmol, 84 % yield).
Rf = 0.42 (1:1 hexane/EtOAc); mp: 148-150 ºC; FT-IR (KBr disk, cm-1): 3332 (NH-Maleimide
and NH-Amide), 3023 (HC=CH), 1712 (C=O-Maleimide), 1650 (C=O-Amide), 1558 (C-N),
1430 (CH3), 1187 (C-O-C). 1H NMR δ (400 MHz, d6-DMSO): 11.26 (1H, s, NH-Maleimide),
8.00 (1H, t, J = 5.2 Hz, NH-Amide), 6.53 (1H, d, J = 4.8 Hz, H-8), 6.30 (1H, d, J = 5.4 Hz, H-9),
3.95 (1H, dd, J = 14.6, 6.3 Hz, H-1), 3.34 (2H, d, J = 5.2 Hz, H-CH2), 3.00 (1H, d, J = 6.3 Hz,
H-2), 2.88 (1H, d, J = 6.2 Hz, H-6), 1.81 (3H, s, H-CH3) ppm. 13
C NMR δ (101 MHz, d6-
DMSO): 177.7, 176.5, 169.6, 137.8 (+), 137.4 (+), 90.5, 80.2 (+), 51.6 (+), 49.5 (+), 37.8 (-),
22.5 (+). HRMS (ESI+): m/z: calcd for C11H13N2O4 (M+H+) 237.0897, found: 237.0892; Calcd
for C11H12N2O3Na (M+Na+) 259.0689, found: 259.0683.*

N-(4-(Phenyl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-7-ylmethyl)acetamide
(7b): Compound 7b was obtained according to the procedure described above after filter,
washing and drying the precipitate, obtaining 7b as a white solid (474 mg, 1.52 mmol, 78 %
yield). Rf = 0.27 (1:1 hexane/EtOAc); mp: 184-186 ºC; FT-IR (KBr disk, cm-1): 3378 (NH),
3070 (HC=CH), 1712 (C=O-Maleimide), 1663 (C=O-Amide), 1527 (C-N), 1496 (CH3), 1203
(C-O). 1H NMR δ (400 MHz, d6-DMSO): 8.08 (1H, t, J = 5.9 Hz, NH), 7.53-7.47 (2H, m, HAr-2’
and 6’), 7.45-7.40 (1H, m, HAr-4’), 7.21 (2H, dt, J = 8.6, 2.0 Hz, HAr-3’ and 5’), 6.61 (1H, dd, J
= 5.6, 1.2 Hz, H-8), 6.40 (1H, d, J = 5.7 Hz, H-9), 4.06 (1H, dd, J = 14.8, 6.7 Hz, H-1), 3.38
(2H, d, J = 5.2 Hz, CH2), 3.23 (1H, d, J = 6.5 Hz, H-6), 3.12 (1H, d, J = 6.5 Hz, H-2), 1.83 (3H,
s, H-CH3) ppm. 13C NMR δ (101 MHz, d6-DMSO): 175.5, 174.2, 169.6, 137.9 (+), 137.5 (+),

12
S. Naik, G. Bhattacharjya, B. Talukdar,; B. K. Patel, Eur. J. Org. Chem., 2004, 1254.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

132.0, 129.0 (2xCH, +), 128.5 (+), 126.8 (2xCH, +), 90.8, 80.5 (+), 50.5 (+), 48.5 (+), 37.8 (-),
22.4 (+). HRMS (ESI+): m/z: calcd for C17H17N2O4 (M+H+) 313.1183, found: 313.1187; Calcd
for C17H16N2O4Na (M+Na+) 335.1002, found: 335.1005.*13

N-(4-(4-Chlorobenzyl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-7-
ylmethyl)acetamide (7c): Compound 7c was obtained according to the procedure described
above after filter, washing and drying the precipitate, obtaining 7c as a white solid (637 mg, 1.76
mmol, 92 % yield). Rf = 0.27 (1:1 hexane/EtOAc); mp: 205-207 ºC; FT-IR (KBr disk, cm-1):
3317 (NH), 3085 (HC=CH), 1697 (C=O-Maleimide), 1650 (C=O-Amide), 1558 (C-N), 1496 (CH3),
1295 (C-O), 863 (C-Cl). 1H NMR δ (400 MHz, CDCl3): 7.28-7.21 (4H, m, HAr-2’, 3’, 5’ and 6’), 6.49
(2H, s, H-8 and H-9), 6.22 (1H, t, J = 6.0 Hz, NH), 5.21 (2H, s, H-1), 4.59 (2H, s, H-CH2Ar),
3.82 (2H, d, J = 6.2 Hz, H-CH2NH), 2.99 (1H, d, J = 6.3 Hz, H-5), 2.87 (1H, d, J = 6.3 Hz, H-2),
1.99 (3H, s, H-CH3) ppm. 13C NMR δ (101 MHz, CDCl3): 175.5, 175.0, 170.4, 138.9 (+), 137.2
(+), 133.9, 133.8, 129.6 (2xCH, +), 128.9 (2xCH, +), 90.8, 80.8 (+), 50.3 (+), 48.4 (+), 41.9 (-),
38.6 (-), 23.3 (+) ppm. HRMS (ESI+): m/z: calcd for C18H18ClN2O3 (M+H+) 361.0950, found:
361.0947; Calcd for C18H17ClN2O3Na (M+Na+) 383.0769, found: 383.0772.*

7. In vitro acetylcholinesterase inhibitory activity essay for compounds 6a-6k and 7a-7c

To assess the inhibitory activity of the compounds toward AChE, we followed the
spectrophotometric method described by Ellman 13 and adapted in our laboratory with some
modifications. 14 The colorimetric reaction was performed in a 96 well plates using purified
AChE from Electrophorus electricus (type V-S). Inhibition curves were made by preincubating
for 30 min 50 μL of a solution of each compound (twelve different concentrations were tested)
in phosphate-buffered solution (PBS), at pH 7.5, and 50 μL of a enzymatic solution containing
0.25 U/mL of AChE. After this preincubation period, 100 μL of a substrate solution (0.24 mM of
5,5’-dithiobis-2-nitrobenzoic acid (DTNB), 0.04 M of Na2HPO4 and 0.24 mM of
acetylthiocholine iodide in distilled water) were added, allowing 5 min more of incubation,
where the DTNB produces the yellow anion 5-thio-2-nitrobenzoic acid along with the enzymatic
degradation of acetylthiocholine. Changes in absorbance were detected using a multiwell
spectrophotometer (VERSAmaxTM, Molecular Devices) at 412 nm. Compounds inhibiting the
AChE ativity would reduce the color generation and it intensity; thus, IC values were calculated

* Not detected trough GC-MS due to the retro-Diels-Alder reaction in the vaporization chamber. Only the N-
13

acetyl furfurylamine and the respective maleimide were registered using this technique.
13
G. L. Ellman, K. D. Courtney, V. Jr. Andres and R. M. Feather-Stone, Biochem. Pharmacol., 1961, 7, 88.
14
V. V. Kouznetsov, L. Y. Vargas Méndez, A. Muñoz Acevedo, Lett. Drug Des. Discov., 2010, 7, 710.

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

as the concentration of compound that produces 50 % of AChE activity inhibition. Data are
expressed as the standard error of the mean (SEM) of at least three different experiments in
duplicate (Table SI1).

Compound IC50 (mM)a

6a 0.233 ± 0.003
6b 0.200 ± 0.004
6c 0.267 ± 0.008
6d 0.315 ± 0.014
6e 0.293 ± 0.004
6f 0.235 ± 0.011
6g 0.279 ± 0.015
6h 0.249 ± 0.012
6i 0.262 ± 0.012
6j 0.302 ± 0.008
6k 0.419 ± 0.026
7a 0.236 ± 0.006
7b 0.287 ± 0.009
7c 0.212 ± 0.008
Physostigmine 0.173 ± 0.009b
a
IC50 values are the mean ± SEM of at least three
different experiments in duplicate. b IC50 values are
expressed in μM.

8. Toxicity Assessment in Vivo using zebrafish embryos for compounds 6a-6k and 7a-7c

Wild-type adult zebrafish of both sexes were obtained from a pet shop and were separated in two
tanks (30 L each), according to their gender, at 26±2 °C under natural light-dark photoperiods.
The fish were feed twice daily and the water quality was recorded weekly, in order to acclimate
the animals for at least two weeks before experiments begin. For the reproduction of the adult
fishes, small breeding tanks were set up in the evening previous to experiment, each containing
three males and one female specimen. The tanks were isolated until next morning when the
lights switch on and the natural mating occurs, without any perturbation. The embryos were
collected, pooled and washed with E3 medium and examined to discarded dead, delayed,
malformed and unfertilized embryos, while the adult fish were returned to their corresponding
tank. The selected embryos were distributed in 96-well plates as appropriate to the screen, three
embryos per well (embryonic plates). Compounds 6a-6k and 7a-7c were diluted into the E3
screening medium with 2% V/V of DMSO and aliquots of 200 μL were prepared at
concentrations ranging from 200 μM to 5 μM (source plates). The surrounding medium was
carefully removed from the embryonic plates using an 8-multichannel pipette and then the
appropriate chemical aliquot of each compound (200 μL), from the source plate, were added into
the corresponding well of the embryonic plate. Eight controls wells were used peer plate, each
containing E3 medium with 2% V/V of DMSO. The embryonic plates were incubated at 28 °C

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and examined at 24, 48, 72 and 96 hours post-fertilization (hpf) by a OPTIKA zoom stereo
microscope (trinocular version of model SZM-1) Figure 1. The Ethics and Research Committee
of the Heart Institute of Bucaramanga approved the protocol under the Acta Number 050 of May
26 of 2012.

A Control 72 hpf

80 mM 60 mM

B Control 96 hpf

80 mM 60 mM
Delay development DD
134.4°

Fig. 1 A: Zebrafish embryos treated with compound 6g at 72 hpf. The embryos treated at 100,
150 and 200 μM died after chemical exposure at this time. The main visual phenotype, to
measure the development delay at this stage, was when the eggs hatch and the alevins could be
photographed. At 80 μM after 72 hpf, the eggs have not hatched at the same rate than the control
did and the digestive damage could be observed at 60 μM. B: Zebrafish embryos treated with
compound 6g at 96 hpf. Embryos treated at 80 μM finally died after 96 hpf. Head–trunk angle
(red dotted line) 134.4° (control angle: 148°) at 60 μM indicating several development delay.
The yellow dotted line, indicates that the embryos treated with 60 μM and below, did not
consume their yolk at the same rate to the control fish, putting in evidence the digestive damage
(DD) induced by the 7-oxa-2- azabicyclo[2.2.1]hept-5-ene 6g.

9. Copies of GC, 1H NMR, 13C NMR, DEPT-135, COSY, 13C HMBC and HSQC charts of the
synthesized 7-Oxa-2-azabicycles

Puerto & Kouznetsov, Page SI-19

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI1. Chromatogram of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6a.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
10'
6'
8' 9'
6a

Puerto & Kouznetsov, Page SI-20

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

1
Figure SI2. H-NMR spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-
azabicyclo[2.2.1]hept-5-ene 6a.
CP48-1

7.26 Chloroform-d
1H CP48-1

7
7.36
7.36
7.35
7.34
7.32
7.31
7.30
7.29
7.28
7.28
7.27

6.31
6.30
6.30
6.30
6.20
6.19

4.63

3.93
3.90
3.84
3.81
3.74
3.72
3.72
3.70

2.89
2.87
2.85
2.82

2.49
2.48
2.44
2.43

2.11
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
10'
6'
8' 9'
6a
HAr-9, 10, 11 (m) H-5 (d) Hax-3 (d) Hax-4' (dd)
7.29 6.19 3.83 2.46

HAr-8, 12. H-1 (dd) H-6 (dd) H-CH2Ar (s) Heq-3 (d) Heq-4' (dd) NH (br.s.)
7.35 6.30 4.63 3.91 2.86 2.11

Heq-3' (dd)
3.72
2.92
2.92

0.97
0.97

1.59

1.01
1.00
1.02

0.99

1.04

1.06
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

13
Figure SI3. C-NMR spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-
azabicyclo[2.2.1]hept-5-ene 6a.
CP48-2
77.16 Chloroform-d

13C CP48-2
177.49
174.88

152.28

142.56

135.55

128.91
128.77
128.13

110.41
108.14

55.11

44.19
42.53

36.34
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
10'
C-10' (s) 6'
128.13 9'
8'
C-5' (s) C-8', 12' (s) C-5 (s) 6a C-6' (s)
174.88 128.91 108.14 42.53

C-2' (s) C-4 (s) C-1 (s) C-7' (s) C-6 (s) C-3' (s) C-3 (s) C-4' (s)
177.49 152.28 142.56 135.55 110.41 55.11 44.19 36.34

C-9', 11' (s)

128.77

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-21

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI4. DEPT-135 spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6a.
CP48-2

142.47

128.83
128.69
128.04

110.32
108.05

55.03

44.11
42.45

36.25
DEPT135 CP48-2

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
10'
6'
8' 9'
6a

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI5. COSY spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6a.

CP48-2 2.0
COSY CP48-2

2.5

3.0

3.5

4.0

4.5
δ (ppm)

7
5.0
O 1 2
6 NH
5.5
4 3
5 3'
4' 2' 6.0
O
5' 12' 11'
N 1' 6.5
O 7'
10'
6'
7.0
8' 9'
6a 7.5

7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-22

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI6. HSQC spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6a.

CP48-2 30
HSQC CP48-2
40

50

60

70

80

90

δ (ppm)
100

7 110
O 1 2
6 NH 120

4 3 130
5 3'
4' 2' 140
O
5' 12' 11'
N 1' 150
O 7'
10'
6' 160

8' 9' 170

6a
180

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Figure SI7. HMBC spectrum of 4-(N-benzyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6a.

CP48-2 30
HMBC CP48-2
40

50

60

70

80

90
7
O 1 2 100
δ (ppm)

6 NH
110
4 3
5 3' 120
4' 2'
O
5' 130
12' 11'
N 1'
O 7'
10'
140
6'
150
8' 9'
160
6a
170

180

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-23

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI8. Chromatogram of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
Cl
6' 10'
8' 9'
6b

Puerto & Kouznetsov, Page SI-24

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI9. 1H-NMR spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.
CP61

7.26 Chloroform-d
1H CP61
7.36
7.36
7.36
7.36
7.31
7.30
7.29
7.28
7.27
7.27

7.25
7.24

6.31
6.30
6.30
6.30
6.20
6.19

4.59

3.93
3.89
3.84
3.80
3.74
3.72
3.72
3.70

2.89
2.87
2.85
2.83

2.49
2.47
2.44
2.43

2.10
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
Cl
6' 10'
8' 9'
H-1 (dd) H-5 (d) Hax-3 (d) Hax-4' (dd)
7.36 6.20 6b 3.82 2.46

HAr-8', 9', 11', 12' (m) H-6 (dd) H-CH2Ar (s) Heq-3 (d) Heq-4' (dd) NH (br.s.)
7.27 6.30 4.59 3.91 2.86 2.10

Heq-3' (dd)
3.72
1.00
4.43

1.00
1.00

2.13

1.05
1.02
1.05

1.06

1.08

1.11
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

Figure SI10. 13C-NMR spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.
CP61
77.16 Chloroform-d

13C CP61
7
O
177.40
174.79

152.21

142.59

134.12
133.98
130.42
128.95

110.42
108.18

2 55.08

44.18
41.83

36.32
1
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
Cl
6' 10'
8' 9'
C-8' y 12' (s)
128.95 6b
C-5' (s) C-7' (s) C-5 (s) C-6' (s)
174.79 133.98 108.18 41.83

C-2' (s) C-4 (s) C-1 (s) C-10' (s) C-6 (s) C-3' (s) C-3 (s) C-4' (s)
177.40 152.21 142.59 134.12 110.42 55.08 44.18 36.32

C-9' y 10' (s)

130.42

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-25

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI11. DEPT-135 spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.
CP61

142.50

130.33
128.86

110.33
108.09

54.99

44.09
41.74

36.23
DEPT135 CP61

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
Cl
6' 10'
8' 9'
6b

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI12. COSY spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.

CP61
COSY CP61 2.0

2.5

3.0

3.5

4.0

4.5
δ (ppm)

7
5.0
O 1 2
6 NH
5.5
4 3
5 3' 6.0
4' 2'
O
5' 12' 11' 6.5
N 1'
O 7'
Cl 7.0
6' 10'
8' 9'
7.5
6b

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-26

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI13. HSQC spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.

CP61 30
HSQC CP61
40

50

60

70

80

90

100

δ (ppm)
7
110
O 1 2
6 NH 120

4 3
5 3' 130
4' 2'
O 140
5' 12' 11'
N 1'
O 7' 150
Cl
6' 10'
160
8' 9'
170
6b

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Figure SI14. HMBC spectrum of 4-(N-(4-chlorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6b.

CP61
HMBC CP61
40

50

60

70

80

90
7
O 1 2 100
δ (ppm)

6 NH
110
4 3
5 3'
2' 120
4' O
5' 12' 11' 130
N 1'
O 7'
140
Cl
6' 10'
8' 9' 150

6b 160

170

180
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-27

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI15. Chromatogram of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
F
6' 10'
8' 9'
6c

Puerto & Kouznetsov, Page SI-28

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI16. 1H-NMR spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.
CP63
1H CP63

7
O 2
7.36
7.36
7.35
7.35
7.35
7.34
7.00
6.99
6.98
6.97
6.97
6.96
6.95
6.94
6.94

6.31
6.30
6.30
6.29
6.20
6.19

4.59

3.93
3.89
3.84
3.80
3.73
3.72
3.71
3.70

2.89
2.87
2.84
2.82

2.48
2.47
2.44
2.42

2.07
1
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
F
6' 10'
8' 9'
6c
HAr-8', 12' (m) H-5 (d) Heq-3 (d)
7.33 6.19 3.91

HAr-9', 11' (m) H-6 (dd) H-CH2Ar (s) Hax-3 (d) Heq-4' (dd) Hax-4' (dd) NH (br.s.)
6.97 6.30 4.59 3.82 2.85 2.45 2.07

H-1 (dd) Heq-3' (dd)

7.36 3.72
1.24
1.81

2.10

1.00
1.01

2.00

1.04
1.00
1.05

1.07

1.10

1.28
7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

Figure SI17. 13C-NMR spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.
CP71
77.16 Chloroform-d

13C CP71

7
177.44
174.84

163.80
161.34

152.23

142.58

131.43
131.40
130.94
130.86

115.75
115.54

110.41
108.17

O 55.08

44.18
41.79

36.32
1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
F
6' 10'
8' 9'
6c
C-5' (s) C-8', 12' (d) C-6 (s) C-6' (s)
174.84 130.90 110.41 41.79

C-2' (s) C-10' (d) C-4 (s) C-1 (s) C-7' (d) C-9', 11' (d) C-3' (s) C-3 (s) C-4' (s)
177.44 162.57 152.23 142.58 131.42 115.65 55.08 44.18 36.32

C-5 (s)
108.17

175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-29

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI18. DEPT-135 spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.
CP71

142.49

130.85
130.77

115.66
115.45

110.32
108.08

54.99

44.09
41.70

36.23
DEPT135 CP71 7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
F
6' 10'
8' 9'
6c

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI19. COSY spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.

CP71 2.0
COSY CP71

2.5

3.0

3.5

4.0

4.5
δ (ppm)

5.0
7
O 1 2
5.5
6 NH
4 3 6.0
5 3'
4' 2'
O 6.5
5' 12' 11'
N 1'
O 7' 7.0
F
6' 10'
9' 7.5
8'
6c
8.0

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-30

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI20. HSQC spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.

CP71 30
HSQC CP71
40

50

60

70

80

δ (ppm)
90
7
O 1 2 100
6 NH
110
4 3
5 3'
4' 2' 120
O
5' 12' 11'
N 1' 130
O 7'
F
6' 10' 140

8' 9'
150
6c

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Figure SI21. HMBC spectrum of 4-(N-(4-fluorobenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6c.

CP71 30
HMBC CP71
40

50

60

70

80

90
7
100
δ (ppm)

O 1 2
6 NH 110

4 3 120
5 3'
4' 2'
O 130
5' 12' 11'
N 1' 140
O 7'
F
6' 10' 150
8' 9'
160
6c
170

180

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-31

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI22. Chromatogram of 4-(N-(4-methylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6d.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
CH3
6' 10'
8' 9'
6d

Puerto & Kouznetsov, Page SI-32

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI23. 1H-NMR spectrum of 4-(N-(4-methylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6d.
CP2

7.26 Chloroform-d
1H CP80
7
O 1 2
7.39
7.38
7.38
7.38
7.26

7.13
7.11

6.33
6.32
6.32
6.32
6.22
6.21

4.61

3.95
3.91
3.86
3.82
3.74
3.73
3.72
3.71

2.90
2.88
2.85
2.83

2.50
2.48
2.45
2.44
2.32

2.10
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
CH3
6' 10'
8' 9'
6d
HAr-8', 12' (m) H-5 (d) Hax-3 (d) CH3-Ar (s)
7.26 6.21 3.84 2.32

H-1 (dd) H-6 (dd) H-CH2Ar (s) Heq-3 (d) Heq-4' (dd) Hax-4' (dd) NH (br.s.)
7.38 6.32 4.61 3.93 2.87 2.47 2.10

HAr-9', 11' (d) Heq-3' (dd)

7.12 3.72
1.00

2.25

2.09

1.01
1.02

2.12

1.04
1.02
1.05

1.04

1.08

3.19

1.05
7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

Figure SI24. 13C-NMR spectrum of 4-(N-(4-methylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6d.
CP2
77.16 Chloroform-d

13C CP80

7
177.53
174.93

152.23

142.57

137.91

132.58
129.42
128.92

110.40
108.16

O 2
55.07

44.18
42.27

36.31

21.24
1
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
CH3
6' 10'
C-9', 11' (s) 8' 9'
128.92
6d
C-5' (s) C-7' (s) C-5 (s) C-6' (s)
174.93 137.91 108.16 42.27

C-2' (s) C-4 (s) C-1 (s) C-10' (s) C-6 (s) C-3' (s) C-3 (s) C-4' (s) CH3-Ph (s)
177.53 152.23 142.57 132.58 110.40 55.07 44.18 36.31 21.24

C-8', 12' (s)

129.42

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-33

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI25. DEPT-135 spectrum of 4-(N-(4-methylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6d.
CP2

142.50

129.35
128.85

110.33
108.09

55.00

44.11
42.19

36.23

21.17
DEPT135 CP80

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
CH3
6' 10'
8' 9'
6d

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-34

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI26. Chromatogram of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
OMe
6' 10'
8' 9'
6e

Puerto & Kouznetsov, Page SI-35

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012

H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI27. 1H-NMR spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.
CP65

7.26 Chloroform-d
1H CP65

7
7.36
7.36
7.36
7.35
7.31
7.29
7.29
6.83
6.82
6.81
6.80
6.80
6.79

6.31
6.30
6.30
6.29
6.19
6.19

4.57

3.92
3.89
3.84
3.80
3.76
3.71
3.70
3.69
3.68

2.87
2.85
2.82
2.80

2.46
2.45
2.42
2.41

2.09
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
OMe
6' 10'
9' Heq-3' (dd)
8' 3.70
6e
HAr-8', 12' (m) H-5 (d) Heq-3 (d) NH (br.s.)
7.30 6.19 3.91 2.09

H-1 (dd) HAr-9', 11' (m) H-6 (dd) H-CH2Ar (s) Hax-3 (d) Heq-4' (dd) Hax-4' (dd)
7.36 6.81 6.30 4.57 3.82 2.84 2.44

OCH3 (s)
3.76
1.03
2.15

2.15

1.03
1.05

2.15

1.04
1.11
3.31
1.06

1.07

1.09

1.38
7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

Figure SI28. 13C-NMR spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.
CP65
77.16 Chloroform-d

13C CP65
7
O
177.52
174.92

159.44

152.30

142.54

130.44
127.86

114.08

110.39
108.11

2
55.35
55.10

44.19
41.98

36.33
1
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
OMe
6' 10'
8' 9'
6e
C-5' (s) C-4 (s) C-7' (s) C-6 (s) C-3' (s) C-6' (s)
174.92 152.30 127.86 110.39 55.10 41.98

C-2' (s) C-10' (s) C-1' (s) C-8', 12' (s) C-9', 11' (s) OCH3 (s) C-3 (s) C-4' (s)
177.52 159.44 142.54 130.44 114.08 55.35 44.19 36.33

C-5 (s)
108.11

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-36

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI29. DEPT-135 spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.
CP65

142.45

130.35

113.99

110.31
108.03

55.26
55.02

44.10
41.89

36.24
DEPT135 CP65

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7'
OMe
6' 10'
8' 9'
6e

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI30. COSY spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.

CP65
COSY CP65 2.0

2.5

3.0

3.5

4.0

4.5
δ (ppm)

7
5.0
O 1 2
6 NH
5.5
4 3
5 3'
4' 2' 6.0
O
5' 12' 11'
N 1' 6.5
O 7'
OMe
6' 10'
7.0
8' 9'
6e 7.5

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-37

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI31. HSQC spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.

CP65
HSQC CP65 30

40

50

60

70

80

90

100

δ (ppm)
7 110
O 1 2
NH 120
6
3 130
4
5 3'
4' 2' 140
O
5' 12' 11' 150
N 1'
O 7'
OMe 160
6' 10'
9' 170
8'
6e 180

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Figure SI32. HMBC spectrum of 4-(N-(4-methoxylbenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6e.

CP65
HMBC CP65
40

50

60

70

80

90

7 100
δ (ppm)

O 1 2
NH 110
6
3 120
4
5 3'
4' 2' 130
O
5' 12' 11'
N 1' 140
O 7'
OMe 150
6' 10'
8' 9'
160
6e
170

180
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-38

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI33. Chromatogram of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-

2-azabicyclo[2.2.1]hept-5-ene 6f.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7' 10'
6' O
8' 9'
O
6f

Puerto & Kouznetsov, Page SI-39

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI34. 1H-NMR spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-

oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.
CP70

7.26 Chloroform-d
1H CP70
7
O 1 2
NH
7.36
7.36
7.36
7.35

6.85
6.83
6.83
6.71
6.71
6.69
6.69

6.31
6.30
6.30
6.29
6.20
6.20
6.19
6.19

5.91

4.52

3.93
3.89
3.84
3.80
3.72
3.71
3.70
3.69

2.88
2.86
2.83
2.81

2.47
2.46
2.43
2.41

2.22
6

4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7' 10'
6' O
8' 9'
O
6f
HAr-11' (dd) H-5 (dd) Hax-3 (d) NH (br.s)
6.70 6.19 3.82 2.22

H-1 (dd) HAr-8', 12' (m) H-6 (dd) -OCH2O- (s) H-CH2Ar (s) Heq-3 (d) Heq-4' (dd) Hax-4' (dd)
7.36 6.84 6.30 5.91 4.52 3.91 2.84 2.44

Heq-3' (dd)
3.70
1.00

2.11

1.05

1.04

1.04

2.13

2.04

1.05
1.05
1.06

1.05

1.11

0.89
7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2
δ (ppm)

Figure SI35. 13C-NMR spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-

oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.
CP63
177.38
174.78

152.19

147.75
147.37

142.47

129.24

122.59

110.31
109.45
108.28
108.04

101.11

77.07

55.00

44.10
42.22

36.24
13C CP63

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7' 10'
6' O
C-5 (s)
108.04 8' 9'
O
C-5' (s) C-9' (s) C-8' (s) C-12' (s) 6f C-6' (s)
174.78 147.75 122.59 109.45 42.22

C-2' (s) C-4 (s) C-1 (s) C-8' (s) C-6 (s) -OCH2O- (s) C-3' (s) C-3 (s) C-4' (s)
177.38 152.19 142.47 129.24 110.31 101.11 55.00 44.10 36.24

C-10' (s) C-11' (s)

147.37 108.28

175 165 155 145 135 125 115 105 95 90 85 80 75 70 65 60 55 50 45 40 35 30

δ (ppm)

Puerto & Kouznetsov, Page SI-40

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI36. DEPT-135 spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-

7-oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.
CP63

142.47

122.59

110.31
109.45
108.28
108.04

101.11

55.00

44.10
42.22

36.24
DEPT135CP63

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 7' 10'
6' O
8' 9'
O
6f

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI37. COSY spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-

oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.

CP63
COSY CP63
2.5

3.0

3.5

4.0

4.5
δ (ppm)

7 5.0
O 1 2
6 NH 5.5

4 3
5 3' 6.0
4' 2'
O
5' 12' 11'
N 1' 6.5
O 7' 10'
6' O
7.0
8' 9'
O
6f 7.5

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
δ (ppm)

Puerto & Kouznetsov, Page SI-41

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI38. HSQC spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-

oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.

CP63
HSQC CP63 40

50

60

70

80

90

100

δ (ppm)
7 110
O 1 2
NH 120
6
130
4 3
5 3'
4' 2' 140
O
5' 12' 11' 150
N 1'
O 7' 10'
O 160
6'
8' 9' 170
O
6f 180

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
δ (ppm)

Figure SI39. HMBC spectrum of 4-(N-(3,4-methylenedioxybenzyl)-pyrrolidin-3-yl-2,5-dione)-7-

oxa-2-azabicyclo[2.2.1]hept-5-ene 6f.

CP63
40
HMBC CP63

50

60

70

80

90
7
O 1 2 100
NH
δ (ppm)

6
110
4 3
5 3' 120
4' 2'
O
5' 12' 11' 130
N 1'
O 7' 10' 140
6' O
8' 150
9'
O
6f 160

170

180

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
δ (ppm)

Puerto & Kouznetsov, Page SI-42

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI40. Chromatogram of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 14' 13'
N 1'
O 7'
12'
6'

6g 8' 11'

9' 10'

Puerto & Kouznetsov, Page SI-43

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI41. 1H-NMR spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.
CP70
1H CP70

7
O
8.28
8.26

7.86
7.84
7.81
7.79

7.56
7.56
7.55
7.54
7.54
7.54
7.51
7.49
7.43
7.41
7.41
7.36
7.36
7.36
7.35
6.30
6.30
6.29
6.29
6.19
6.18

5.16
5.12
5.11
5.08

3.93
3.89
3.83
3.80
3.73
3.72
3.71
3.70

2.90
2.88
2.85
2.83

2.52
2.51
2.48
2.46

2.09
1 2
6 NH
4 3
5 3'
4' 2'
O
5' 14' 13'
N 1'
O 7'
12'
6'
H-12' (ddd)
7.49 6g 8' 11'
H-10' (d) H-1 (dd) H-5 (d) Hax-3 (d) Heq-4' (dd) NH (br.s.)
7.80 7.36 6.18 9' 10' 3.82 2.87 2.09

H-14' (d) H-11' (d) H-9' (dd) H-6 (dd) H-CH2Ar (s) Hax-3' (dd) Hax-4' (dd)
8.27 7.85 7.41 6.29 5.12 3.71 2.49

H-8' y 13' (ddd) Heq-3 (d)

7.56 3.91
1.01

1.04
1.05

2.05
1.01
1.03
1.01

1.00
1.02

1.95

1.02
1.07
1.03

1.02

1.02

1.33
8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
δ (ppm)

Figure SI42. 13C-NMR spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.
CP70
177.66
174.97

152.20

142.47

133.78
131.25
130.46
128.86
128.75
127.82
126.61
125.88
125.24
123.51

110.32
108.05

54.95

44.08

40.25

36.25
13C CP70
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
C-12' (s) 5' 14' 13'
125.88 N 1'
O 7'
12'
C-8' (s)
127.82 6'

C-10' (s) 6g 8' 11'

128.86

C-5' (s) C-14a' (s) C-9' (s) C-5 (s)

9' 10' C-6' (s)
174.97 133.78 125.24 108.05 40.25

C-2' (s) C-4 (s) C-1 (s) C-10a' (s) C-6 (s) C-3' (s) C-3 (s) C-4' (s)
177.66 152.20 142.47 131.25 110.32 54.95 44.08 36.25

C-7' (s)
130.46

C-11' (s)
128.75

C-13' (s)
126.61

C-14' (s)
123.51

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-44

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI43. DEPT-135 spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.
CP70

142.47

128.86
128.75
127.82
126.61
125.88
125.24
123.51

110.32
108.05

54.95

44.08

40.25

36.25
DEPT135 CP70
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 14' 13'
N 1'
O 7'
12'
6'

6g 8' 11'

9' 10'

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI44. COSY spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.

CP70
COSY CP70 2.0

2.5

3.0

3.5

4.0

4.5
δ (ppm)

5.0
7
O 1 2 5.5
6 NH
6.0
4 3
5 3'
4' 2' 6.5
O
5' 14' 13'
N 1' 7.0
O 7'
12'
6' 7.5

6g 8' 11' 8.0

9' 10' 8.5

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-45

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI45. HSQC spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.

CP70 30
HSQC CP70
40

50

60

70

80

90

100

δ (ppm)
7
O 1 2
110
6 NH
120
4 3
5 3'
2' 130
4' O
5' 14' 13' 140
N 1'
O 7'
12' 150
6'
160
6g 8' 11'
170
9' 10'
180

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Figure SI46. HMBC spectrum of 4-(N-(1-naphthyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6g.

CP70
HMBC CP70
40

50

60

70

80

7 90
O 1 2
100
NH
δ (ppm)

6
110
4 3
5 3'
4' 2' 120
O
5' 14' 13' 130
N 1'
O 7'
12' 140
6'
150
6g 8' 11'
160
9' 10'
170

180

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-46

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI47. Chromatogram of 4-(S-(-)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6h.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
6h

Puerto & Kouznetsov, Page SI-47

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI48. 1H-NMR spectrum of 4-(S-(-)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6h.
CP72

7.26 Chloroform-d
1H CP72
7.43
7.41
7.36
7.36
7.33
7.31
7.29
7.27

6.31
6.31
6.30
6.30
6.20
6.19

5.42
5.40
5.40
5.39
5.38
5.37

3.92
3.91
3.88
3.87
3.82
3.79
3.68
3.67
3.66
3.65
3.64
3.63
3.62
3.61

2.85
2.83
2.81
2.80
2.78
2.76

2.46
2.45
2.44
2.44
2.43
2.41
2.40
2.02
1.80
1.80
1.80
1.79
1.78
1.78
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H-1 (d) H-5 (d) H3C Hax-3 (d) Hax-4' (m) NH (br.s.)
7.36 6.19 8' 9' 3.80 2.42 2.02

HAr-8', 12' (d) H-6 (dd) H-6' (m)

6h Heq-3' (ddd) Heq-4' (dt) H-CH3 (m)
7.42 6.30 5.39 3.64 2.80 1.79

HAr-9', 10', 11' (m) Heq-3 (dd)

7.29 3.90
2.00
0.99
3.35

0.99
1.00

1.02
2.14

1.03
1.07

1.00

1.03

1.09

1.58

3.06
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6
δ (ppm)

Figure SI49. 13C-NMR spectrum of 4-(S-(-)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6h.
CP72
77.16 Chloroform-d

13C CP72
177.59
174.92

152.31

142.56
139.52

128.58
127.99
127.66

110.40
108.11

54.86

50.47

44.21

36.31

16.67
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
C-5' (s) C-7' (s) C-10' (s) C-5 (s) 6h C-3 (s)
174.92 139.52 127.99 108.11 44.21

C-2' (s) C-4 (s) C-1 (s) C-8', 12' (s) C-6 (s) C-3' (s) C-4' (s) C-CH3 (s)
177.59 152.31 142.56 128.58 110.40 54.86 36.31 16.67

C-9', 11' (s) C-6' (s)

127.66 50.47

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-48

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI50. DEPT-135 spectrum of 4-(S-(-)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-

2-azabicyclo[2.2.1]hept-5-ene 6h.
CP72

142.46

128.48
127.89
127.55

110.30
108.01

54.74

50.50

44.11

36.27

16.57
DEPT135 CP72
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
6h

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

δ (ppm)

Puerto & Kouznetsov, Page SI-49

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI51. Chromatogram of 4-(R-(+)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6i.

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
6i

Puerto & Kouznetsov, Page SI-50

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI52. 1H-NMR spectrum of 4-(R-(+)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6i.
CP1

7.26 Chloroform-d
1H CP73
7.43
7.42
7.41
7.36
7.36
7.36
7.36
7.35
7.31
7.30
7.29
7.27
7.27

7.26
6.31
6.30
6.30
6.30
6.29
6.19
6.19

5.42
5.41
5.40
5.39
5.38
5.37
5.36
5.36

3.91
3.90
3.88
3.87
3.82
3.81
3.78
3.78
3.67
3.66
3.65
3.64
3.63
3.62
3.61
3.59
2.84
2.82
2.82
2.80
2.80
2.78
2.78
2.76

2.45
2.44
2.43
2.42
2.41
2.40
2.11

1.80
1.79
1.78
1.78
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
H-1 (td) H-5 (d) Hax-3 (dd) Hax-4' (ddd) H-CH3 (dd)
7.36 6.19 6i 3.80 2.42 1.79

HAr-8', 12' (m) H-6 (dt) H-6' (qd) Heq-3 (dd) Heq-4' (ddd) NH (br.s.)
7.42 6.30 5.39 3.89 2.80 2.11

HAr-9', 10', 11' (m) Heq-3' (ddd)

7.27 3.63
2.03
1.01
3.16

0.98
0.99

0.89

1.01
1.00

1.02

1.01

1.02

1.27

3.05
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6
δ (ppm)

Figure SI53. 13C-NMR spectrum of 4-(R-(+)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6i.
CP1
177.53
174.88

152.17

142.49
139.39

128.49
127.90
127.52

110.33
108.07

54.73

50.48

44.10

36.25

16.57
13C CP73
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
6i
C-5' (s) C-7' (s) C-10' (s) C-5 (s) C-6' (s) C-4' (s)
174.88 139.39 127.90 108.07 50.48 36.25

C-2' (s) C-4' (s) C-1 (s) C-8', 12' (s) C-6 (s) C-3' (s) C-3 (s) C-CH3 (s)
177.53 152.17 142.49 128.49 110.33 54.73 44.10 16.57

C-9', 11' (s)

127.52

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

δ (ppm)

Puerto & Kouznetsov, Page SI-51

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI54. DEPT-135 spectrum of 4-(R-(+)-N-(1-phenylethyl)-pyrrolidin-3-yl-2,5-dione)-7-oxa-

2-azabicyclo[2.2.1]hept-5-ene 6i.
CP1

142.50

128.49
127.92
127.52

110.33
108.07

54.71

50.48

44.10

36.25

16.56
DEPT135 CP73

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5' 12' 11'
N 1'
O 6'
7' 10'

H3C
8' 9'
6i

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

1
Figure SI55. H-NMR spectrum of 4-(1H-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-
azabicyclo[2.2.1]hept-5-ene 6j.
CP20
7.26 Chloroform-d

1H CP 92
8.81

7.38
7.38
7.38
7.38

6.33
6.32
6.32
6.31
6.24
6.23
6.23
6.23

3.95
3.91
3.86
3.82
3.80
3.79
3.78
3.77

2.92
2.90
2.87
2.85
2.56
2.54
2.51
2.50

2.12
7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
NH
O 1'
6j

H-5 (dd) Hax-3 (d) Hax-4’ (dd)

6.23 3.84 2.53

NH-Maleimide (s) H-1 (dd) H-6 (dd) Heq-3 (d) Heq-4’ (dd) NH-Bicycle (s)
8.81 7.38 6.32 3.93 2.88 2.12

Heq-3’ (dd)
3.78
0.82

0.96

1.01
0.97

1.07
1.04
1.05

1.10

1.06

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
δ (ppm)

Puerto & Kouznetsov, Page SI-52

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

13
Figure SI56. C-NMR spectrum of 4-(1H-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-
azabicyclo[2.2.1]hept-5-ene 6j.
CP20

77.16 Chloroform-d
13C CP 92
178.24
175.53

152.11

142.67

110.47
108.32
7

56.25

44.13

37.34
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
NH
O 1'
6j

C-5' (s) C-5 (s) C-4' (s)

175.53 108.32 37.34

C-2' (s) C-4 (s) C-1 (s) C-6 (s) C-3' (s) C-3 (s)
178.24 152.11 142.67 110.47 56.25 44.13

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI57. DEPT-135 spectrum of 4-(1H-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6j.
CP20
142.57

110.37
108.22

56.15

44.03

37.24
DEPT135 CP 92

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
NH
O 1'
6j

180 175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-53

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

1
Figure SI58. H-NMR spectrum of 4-(N-phenyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-
azabicyclo[2.2.1]hept-5-ene 6k.
CP12

7.26 Chloroform-d
1H CP 139

7
7.49
7.48
7.47
7.47
7.45
7.41
7.41
7.41
7.40
7.40
7.39
7.39
7.38
7.28
7.27
7.27
7.26

7.26
6.35
6.34
6.34
6.34
6.27
6.26

4.00
3.96
3.93
3.92
3.91
3.91
3.89
3.89

3.07
3.05
3.02
3.00

2.69
2.68
2.64
2.63

2.41
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
N 1'
O 11'
6'
H-1 (dd) 7' 10'
7.39
8' 9'
HAr-8' and 10' (m) H-5 (d) Hax-3 (d) Hax-4' (dd)
7.27 6.26 6k 3.90 2.66

HAr-9' (m) H-6 (dd) Heq-3' (dd) Heq-4' (dd) NH (br. s)

7.41 6.34 3.98 3.04 2.41

HAr-7' and 11' (m) Heq-3' (dd)

7.47 3.91
2.44
2.35
2.61

1.19
1.18

1.24
2.40

1.22

1.23

1.00
7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2
δ (ppm)

Figure SI59. 13C-NMR spectrum of 4-(N-phenyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6k.
CP12
77.16 Chloroform-d

13C CP 139

7
176.81
174.28

152.17

142.67

131.57
129.33
128.89
126.42

110.47
108.31

55.16

44.23

36.45
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
N 1'
O 11'
6'
7' 10'
C-8' and 10' (s)
126.42
8' 9'
C-2' (s) C-7' and 11' (s) C-5 (s) 6k
176.81 129.33 108.31

C-5' (s) C-4 (s) C-1 (s) C-6' (s) C-6 (s) C-3' (s) C-3 (s) C-4' (s)
174.28 152.17 142.67 131.57 110.47 55.16 44.23 36.45

C-9' (s)
128.89

175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Puerto & Kouznetsov, Page SI-54

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI60. DEPT-135 spectrum of 4-(N-phenyl-pyrrolidin-3-yl-2,5-dione)-7-oxa-2-

azabicyclo[2.2.1]hept-5-ene 6k.
CP12

142.61

129.27
128.83
126.35

110.41
108.25

55.10

44.16

36.39
DEPT135 CP 139

7
O 1 2
6 NH
4 3
5 3'
4' 2'
O
5'
N 1'
O 11'
6'
7' 10'

8' 9'
6k

175 170 165 160 155 150 145 140 135 130 125 120 115 110 105 100 95 90 85 80 75 70 65 60 55 50 45 40 35
δ (ppm)

Figure SI61. 1H-NMR spectrum of N-(10-oxa-1H-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-7-

ylmethyl)acetamide 7a.
CP10

2.50 Dimethyl Sulfoxide-d6

1H CP 93

10 O
O 3 4
11.26

1
8.01
8.00
7.99

6.54
6.52
6.31
6.30

3.97
3.96
3.94
3.92

3.35
3.33
3.01
3.00
2.89
2.87

1.81
9
2 NH
7
8 6 5 O
11
HN12
13 O

14
7a
H-9 (d) H-2 (d)
6.30 3.00

NH-Maleimide (s) NH-Amide (t) H-8 (d) H-1 (dd) H-6 (d) H-CH3 (s)
11.26 8.00 6.53 3.95 2.88 1.81

H-CH2 (d)
3.34
1.02

0.98

0.97

0.93

1.00

2.08

0.92
0.91

3.00

11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
δ (ppm)

Puerto & Kouznetsov, Page SI-55

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI62. 13C-NMR spectrum N-(10-oxa-1H-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-7-

ylmethyl)acetamide 7a.
CP10

39.52 Dimethyl Sulfoxide-d6

13C CP 93
177.75
176.50

169.64

137.84
137.47

90.59

80.21

51.60
49.59

37.80

22.54
10 O
O 3 4
1
9
2 NH
7
8 6 5 O
11
HN12
13 O

C-3 (s) C-9 (s) 14 C-2 (s)

176.50 137.47 7a 49.59

C-5 (s) C-8 (s) C-7 (s) C-1 (s) C-6 (s) C-11 (s) C-14 (s)
177.75 137.84 90.59 80.21 51.60 37.80 22.54

C-13 (s)
169.64

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Figure SI63. DEPT-135 spectrum of N-(10-oxa-1H-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-dione-

7-ylmethyl)acetamide 7a.
CP10
138.22
137.85

80.59

51.98
49.96

38.18

22.92
DEPT135 CP 93

10 O
O 3 4
1
9
2 NH
7
8 6 5 O
11
HN12
13 O

14
7a

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-56

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H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI64. 1H-NMR spectrum of N-(10-oxa-4-phenyl-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-

dione-7-ylmethyl)acetamide 7b.
CP21

2.50 Dimethyl Sulfoxide-d6

1H CP 140

3'
10 O 2' 4'
8.09
8.08
8.06

7.52
7.50
7.50
7.49
7.48
7.45
7.44
7.43
7.22
7.22
7.21
7.20
7.20
7.19

6.62
6.61
6.60
6.60
6.40
6.39

4.09
4.08
4.05
4.04

3.39
3.38
3.24
3.23
3.13
3.11

1.83
O 3 4 1'
1 5'
9
2 N
6'
7
8 6 5 O
11
HN12
13 O

14
HAr-4' (m) H-8 (dd) 7b H-6 (d)
7.43 6.61 3.12

NH (t) HAr-2' and 6' (m) H-9 (d) H-1 (dd) H-2 (d) H-CH3 (s)
8.08 7.50 6.40 4.06 3.23 1.83

HAr-3' and 5' (dt) H-CH2 (d)

7.21 3.38
1.00

2.13
1.08

2.07

1.01

1.09

0.98

1.99

1.04
1.12

3.10
8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8
δ (ppm)

Figure SI65. 13C-NMR spectrum of N-(10-oxa-4-phenyl-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-

dione-7-ylmethyl)acetamide 7b.
CP21

39.52 Dimethyl Sulfoxide-d6

13C CP 140 3'
10 O 2' 4'
O 3 4 1'
1 5'
9
2 N
6'
175.56
174.22

169.66

137.98
137.53

132.04
129.04
128.52
126.84

7
90.87

80.57

50.50
48.56

37.81

22.47
8 6 5 O
11
HN12
13 O

14
7b
C-2' and 6' (s)
129.04

C-3 (s) C-9 (s) C-3' and 5' (s) C-2 (s)
174.22 137.53 126.84 48.56

C-5 (s) C-8 (s) C-4' (s) C-7 (s) C-1 (s) C-6 (s) C-11 (s) C-14 (s)
175.56 137.98 128.52 90.87 80.57 50.50 37.81 22.47

C-13 (s) C-1' (s)

169.66 132.04

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-57

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012

H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI66. DEPT-135 spectrum of N-(10-oxa-4-phenyl-4-azatricyclo[5.2.1.02,6]decan-8-ene-3,5-

dione-7-ylmethyl)acetamide 7b.
CP21

138.42
137.97

129.48
128.96
127.29

81.02

50.95
49.00

38.25

22.92
DEPT135 CP 140

3'
10 O 2' 4'
O 3 4 1'
1 5'
9
2 N
6'
7
8 6 5 O
11
HN12
13 O

14
7b

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Figure SI67. 1H-NMR spectrum of N-(4-(4-chlorobenzyl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-8-

ene-3,5-dione-7-ylmethyl)acetamide 7c.
CP7
7.26 Chloroform-d

1H CP 82
7.25
7.24
7.22

6.49

6.24
6.22
6.21

5.21

4.59

3.83
3.81

3.00
2.98
2.88
2.86

1.99
10 O
O 3 4 7' 2'
1 1'
2 N 3'
9
7 4'
5 6' Cl
8 6 O
11 5'
HN12
13 O

14
H-8 and H-9 (s) H-6 (d)
6.49 7c 2.87

HAr-2',3',5' and 6' (m) NH (t) H-1 (s) H-CH2Ar (s) H-CH2NH (d) H-2 (d) H-CH3 (s)
7.24 6.22 5.21 4.59 3.82 2.99 1.99
4.52

2.09

1.00

1.01

2.03

2.12

1.04

1.05

3.01

7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8
δ (ppm)

Puerto & Kouznetsov, Page SI-58

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is © The Royal Society of Chemistry 2012

H3BO3-Catalyzed the Unexpected Synthesis of 7-Oxa-2-azabicycles Electr. Supporting Information

Figure SI68. 13C-NMR spectrum of N-(4-(4-chlorobenzyl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-8-

ene-3,5-dione-7-ylmethyl)acetamide 7c.
CP7

77.16 Chloroform-d
13C CP 82
175.56
175.06

170.46

138.92
137.20
133.92
133.84

129.68
128.97

90.89

80.84

50.39
48.40

41.93

38.63

23.34
10 O
O 3 4 7' 2'
1 1'
2 N 3'
9
7 4'
5 6' Cl
8 6 O
11 5'
C-3' and 5' (s)
128.97 HN12
13 O
C-1' (s)
133.84
14
C-3 (s) C-9 (s) 7c C-2 (s) C-13 (s)
175.06 137.20 48.40 38.63

C-5 (s) C-8 (s) C-7 (s) C-1 (s) C-6 (s) C-7' (s) C-14 (s)
175.56 138.92 90.89 80.84 50.39 41.93 23.34

C-13 (s) C-4' (s)

170.46 133.92

C-2' and 6' (s)

129.68

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Figure SI69. DEPT-135 spectrum of N-(4-(4-chlorobenzyl)-10-oxa-4-azatricyclo[5.2.1.02,6]decan-

8-ene-3,5-dione-7-ylmethyl)acetamide 7c.
CP7
138.85
137.13

129.61
128.90

80.77

50.32
48.33

41.86

38.56

23.27
DEPT135 CP 82

10 O
O 3 4 7' 2'
1 1'
2 N 3'
9
7 4'
5 6' Cl
8 6 O
11 5'
HN12
13 O

14
7c

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

δ (ppm)

Puerto & Kouznetsov, Page SI-59