Versatile spirocyclic glycine-based nitrones and their highly stereoselective 1,3-dipolar cycloaddition

Article abstract of DOI:10.1080/00397910601033781

A convenient and efficient method for the synthesis of novel spirocyclic nitrones prepared from glycine derivatives is reported. The 1,3-cycloaddition reactions of the nitrones with alkenes lead to novel isoxazolidines in high yields and with excellent re

Full text of DOI:10.1080/00397910601033781

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Versatile Spirocyclic Glycine‐Based Nitrones
and Their Highly Stereoselective 1,3‐Dipolar
Cycloaddition
Shangli Cheng a , Huimin Wu b & Xianmin Hu b
a Chemistry Department , Wuppertal University , Wuppertal, Germany
b College of Pharmacy, Wuhan University , Wuhan, Hubei, China
Published online: 25 Jul 2007.
To cite this article: Shangli Cheng , Huimin Wu & Xianmin Hu (2007) Versatile Spirocyclic Glycine‐Based
Nitrones and Their Highly Stereoselective 1,3‐Dipolar Cycloaddition, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:2, 297-308, DOI:
10.1080/00397910601033781
To link to this article: http://dx.doi.org/10.1080/00397910601033781
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Synthetic Communicationsw, 37: 297–308, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601033781
Versatile Spirocyclic Glycine-Based
Nitrones and Their Highly Stereoselective
1,3-Dipolar Cycloaddition
Shangli Cheng
Chemistry Department, Wuppertal University, Wuppertal, Germany
Huimin Wu and Xianmin Hu
College of Pharmacy, Wuhan University, Wuhan, Hubei, China
Abstract: A convenient and efficient method for the synthesis of novel spirocyclic
nitrones prepared from glycine derivatives is reported. The 1,3-cycloaddition
reactions of the nitrones with alkenes lead to novel isoxazolidines in high yields and
with excellent regio- and stereoselectivity.
Keywords: 1,3-cycloaddition, isoxazolidines, spirocyclic nitrones, stereoselectivity
INTRODUCTION
In recent years, cycloadditions between nitrones and alkenes have attracted
increased attention. The reaction allows for easy access to isoxazolines and
isoxazolidines,[1] which, in turn, have been used in the synthesis of a wide
range of natural and synthetic products, such as nucleosides,[2] lactams,[3]
amino acids,[4] and amino sugars.[5]
In principle, the reaction of nitrones with alkenes can result in four regio-
and stereoisomers.[6] Cyclic nitrones[7,8] usually show higher selectivity than
acyclic nitrones[9,10] in 1,3-dipolar cycloadditions. In this article, we report a
convenient synthesis of novel spirocyclic glycine-based nitrones and their
regio- and stereoselective reactions with alkenes to tricyclic isoxazolidines.
Received in the U.K. March 16, 2006
Address correspondence to Shangli Cheng, Chemistry Department, Wuppertal Uni-
versity, Gaussstr. 20, 42119 Wuppertal, Germany. E-mail: cheng@uni-wuppertal.de
297

298
S. Cheng, H. Wu, and X. Hu
RESULTS AND DISCUSSION
In the first step of our synthesis of the nitrone, glycinamide hydrochloride was
reacted with a ketone[8] to form a spirocyclic imidazolidinone. Among the
various ketones tested, cyclohexanone led to the highest yield and the
purest product. Imidazolidinone 1[11] was obtained as a colorless crystalline
material after refluxing cyclohexanone with glycinamide in methanol
(Scheme 1). The spirocyclic structure of the product was confirmed by a
signal for the quaternary carbon atom at 76.54 ppm in the 13C NMR spectrum.
The transformation of imidazolidinone 1 to nitrone 2 was carried out by
oxidation with aqueous meta-chloroperoxybenzoic acid (mCPBA, Scheme 1).
The successful conversion was confirmed by 1H and 13C NMR spectroscopy.
The proton signal for the NCH2-part of starting material 1 at 3.46 ppm disap-
peared. Instead, a new signal at 7.02 ppm revealed the presence of the N55CH-
unit. In the 13C NMR, a signal at 124 ppm confirmed the imine character. The
signal for the quaternary spirocarbon shifted from 76.54 ppm in 1 to
90.73 ppm in 2 because of the electronic effect exerted by the new nitrone
functionality. The product was obtained as colorless crystals in 95% yield.
Initial attempts to react 2 with alkenes failed. A survey of known nitrones
led to the hypothesis that the unprotected amide function in 2 might be respon-
sible for a diminished tendency to undergo 1,3-dipolar cycloadditions. An
attempted benzyl protection of 2 was found to be hardly regioselective. The
N- and O-benzylated products 3 and 4 were isolated in modest yield after
flash chromatography. However, Boc protection led selectively to product 5
in almost quantitative yield after 30 min of reaction time (Scheme 2).
The cycloaddition of nitrone 5 with alkenes proved to be successful. An
investigation of the reaction with ethyl acrylate 6a (Scheme 3) in various
solvents established that 1,1-dichloroethane (DCE) led to the best reaction
rate and an excellent yield (Table 1).
Regardless of the solvent used, only one product could be detected by
NMR spectroscopy. The exo-configuration of the tricyclic isoxazolidine 7a
was assigned by X-ray analysis (Fig. 1).[12] The stereo- and regioselectivity
of the reaction induced by spirocyclic nitrone 2 was much higher than the
one seen with acyclic nitrones.[9,10]
In an extension of our study, we used our standard procedure in DCE to
react a variety of alkenes with nitrones 3–5 (Schemes 3 and 4). Tricyclic
Scheme 1. Preparation of nitrone 2.

1,3-Dipolar Cycloaddition
299
Scheme 2. Protection of nitrone 2.
isoxazolidines 7a–7e, 8a–8c, and 9a–9c were obtained in high to excellent
yields (Table 2).
Like in the cycloaddition with ethyl acrylate 6a, excellent regio- and
stereoselectivities were observed in the reaction of 5 with alkenes 6b–6e.
The NMR-spectroscopic analysis of the reaction products showed no traces
of the endo-isomer. Similarly, the reaction of nitrones 3 and 4 with 6a–6c
showed excellent selectivity. Only the exo-products were observed.
However, the reaction rate of nitrone 5 was found to be higher (Table 2).
The exo-selectivity of the reaction was confirmed once more by the x-ray
analysis of product 7b (Fig. 2).
EXPERIMENTAL
1H NMR and 13C NMR spectra were measured at a Varian Mercury 300-MHz
spectrometer. Spectra were internally referenced to TMS. Peaks are reported
in parts per million (ppm) downfield of TMS. Multiplicities are reported as
Scheme 3. Cycloaddition in different solvents.

300
S. Cheng, H. Wu, and X. Hu
Table 1. Cycloaddition in different solventsa
Reaction
time (h)
Entry
Solvent
Product
Yieldb(%)
1
2
3
4
Toluene
Xylene
Ethanol
DCE
12
24
7
7a
7a
7a
7a
15
23
68
96
5
aAll reactions were carried out under reflux conditions.
bAll were chemical pure yields.
singlet (s), doublet (d), triplet (t), quartet (q), some combination of these,
broad (br), or multiplet (m). NMR analysis of the crude products permitted
a determination of ratio of the diastereoisomers. IR spectra were recorded
on a Perkin-Elmer 983 spectrometer. MS spectra were recorded on a
Finnigan-LCQ Advantage spectrometer (ESI). Melting points were deter-
mined on a XT-4 apparatus (uncorrected). Silica gel was used for analytical
and flash chromatography. Organic solvents were used without any
treatment unless indicated as dried. Chemicals were used as commercial
products without purification.
General Procedures
Synthesis of 1,4-Diazaspiro[4,5]decan-2-one (1)
Cyclohexanone (20.7 ml, 0.2 mol) was added to a suspension of 22.10 g
(0.2 mol) of glycinamide hydrochloride in 150 ml of dried methanol, and
then 30.0 ml of NEt3was added. The mixture was refluxed for 18 h and
cooled to room temperature. The solvent was removed in reduced pressure,
Figure 1. Perspective drawing of 7a from X-ray crystal analysis.

1,3-Dipolar Cycloaddition
301
and the residue was taken up in a two-phase system of water and ethyl acetate.
After the organic phase had been separated off, extraction was carried out
twice more with ethyl acetate, and the extract was dried over sodium
sulfate. After the solvent had been evaporated, the residue was recrystallized
from ethyl acetate/petroleum ether ¼ 3/7, affording imidazolidinone 1
(20.10 g) as a white crystal (yield 69%), mp: 120–1228C (ref. 1218C [11]).
1H NMR (CDCl3): d 1.54 (m, 10H), 1.97 (s, 1H), 3.49 (s, 2H), 8.17 (br., s,
1H). 13C NMR (CDCl3): d 22.92, 24.84, 38.18, 48.70, 76.51, 176.82.
HRMS (ESI) calculated for C8H14N2Oþ: m/z ¼ 154; found: m/z ¼ 154.
Synthesis of 1,4-Diazaspiro[4,5]decan-3-one-1-oxide (2)
Compound 1 (6.34 g, 41.2 mmol) in 180 ml of CH2Cl2 were reacted with three
portions (2.5 equiv., in total, 20.6 g) of aqueous m-CPBA in an ice bath within
3 h. The white suspension was stirred for 5 h at 08C until the conversion was
complete (monitoring by thin-layer chromatography, TLC); 50 ml of 10%
NaS2O3 solution was added for reduction of the excess m-CPBA and the
phases were mixed thoroughly by vigorous stirring for 1 hr. Saturated
NaHCO3 solution (30 ml) was added. After the suspension turned to
pellucid, the organic phase was separated off, and the aqueous phase was
extracted twice more with CH2Cl2. The combined methylene chloride
phases were washed with sat. NaHCO3 solution, water, and brine; dried
over sodium sulfate; and evaporated under reduced pressure. The crude
product was already in a pure form, and it can be crystallized from
ethyl acetate/petroleum ether to afford a white powder, yield 95%, mp:
Scheme 4. Cycloaddition reactions of protected nitrones and alkenes: a)
R2 ¼ CO2Et, R3 ¼ H; b) R2 ¼ Ph, R3 ¼ H; c) R2 ¼ CO2Me, R3 ¼ Me; d)
R2 ¼ CH2OH, R3 ¼ H, and e) R2 ¼ O-n-Bu, R3 ¼ H.

302
S. Cheng, H. Wu, and X. Hu
Table 2. Cycloaddition reactions of nitrones with alkenesa
Entry
(%)
Reaction
time (h)
Nitrone
Olefin
Product
Yieldb
1
2
3
3
3
4
4
4
5
5
5
5
5
6a
6b
6c
6a
6b
6c
6a
6b
6c
6d
6e
8
6
8a
8b
8c
9a
9b
9c
7a
7b
7c
7d
7e
96
97
82
87
97
82
96
96
83
67
73
3
12
8
4
5
8
6
16
5
7
8
5
9
12
16
12
10
11
aAll reaction were carried out under reflux condition.
bAll were chemical pure yields.
1
131–1338C. H NMR (CDCl3): d 1.32 (m, 1H), 1.65 (m, 4H), 1.83 (d, 1H,
J ¼ 8.1), 1.95 (m, 2H), 2.20 (m, 2H), 7.02 (s, 1H), 9.61 (s, 1H). 13C NMR
(CDCl3): d 22.54, 24.03, 35.41, 90.72, 123.93, 166.08. HRMS (ESI) calcu-
lated for C8H12N2Oþ2 : m/z ¼ 168; found: m/z ¼ 168.
Protection of Nitrone 2 with Benzyl Bromide to Nitrones 3 and 4
Nitrone 2 (1.68 g, 10 mmol) in 20 ml DMSO was stirred for 10 min, 1.12 g
(20 mmol) of KOH and 1.2 ml (10 mmol) of benzyl bromide were added.
The suspension was stirred for 18 h at room temperature. The resulting
solution was poured into 30 ml of steamed water and 30 ml of petroleum
ether. After the organic phase was separated off, the aqueous phase was
extracted twice with 30 ml of petroleum ether. The organic layers were
Figure 2. Perspective drawing of 7b from X-ray crystal analysis.

1,3-Dipolar Cycloaddition
303
washed with 10 ml ꢀ 2 sat. NH4Cl solution and dried over Na2SO4, and the
solvent was removed under vacuum. The residue was purified by flash chrom-
atography on silica gel, eluting with ethyl acetate/petroleum ether ¼ 1/6 to
afford compound 3 (yield 23%) and 4 (yield 19%) as white crystals.
4-Benzyl-1,4-diazaspiro[4,5]decan-3-one-1-oxide (3)
1
Mp: 103–1048C. H NMR (CDCl3): d 1.29 (m, 1H), 1.59 (m, 3H), 1.74
(m, 2H), 1.84 (m, 2H), 2.09 (m, 2H), 4.73 (s, 2H), 7.10 (s, 1H), 7.29
(m, 5H). 13C NMR (CDCl3): d 22.96, 32.22, 35.02, 52.47, 69.40, 101.37,
128.34, 128.41, 128.43, 135.38, 164.81. HRMS (ESI): calculated for
C15H18N2Oþ2 : m/z ¼ 258; found: m/z ¼ 258.
3-Benzyl-1,4-diazaspiro[4,5]decen-3-1-oxide (4)
Mp: 92–948C. 1H NMR (CDCl3): d 1.40 (m, 2H), 1.62 (m, 1H), 1.81 (m, 3H,),
1.84 (m, 2H,), 2.05 (m, 2H), 5.17 (s, 2H), 7.02 (s, 1H), 7.22 (m, 5H). 13C NMR
(CDCl3): d 23.39, 33.60, 34.35, 58.36, 70.42, 121.13, 128.38, 128.40, 128.67,
136.82, 164.7. HRMS (ESI): calculated for C15H18N2Oþ2 : m/z ¼ 258; found:
m/z ¼ 258.
4-tert-Butyloxycarbonyl-1,4-diazaspiro[4,5]decan-3-one-1-oxide (5)
To a stirred solution of nitrone 2 (4.2 g, 25 mmol) in dried CH2Cl2, di-tert-
butyl dicarbonate [(Boc)2O, 10.9 g, 50 mmol], triethylamine (TEA) (4.2 ml,
30 mmol, 1.2 equiv.), and 4-N,N-dimethylaminopyridine (DMAP) as
catalyst were added. The mixture was stirred at room temperature until the
starting material disappeared (about 30 min). The mixture was poured into
sat. aq. NH4Cl solution and extracted with CH2Cl2. The organic phase was
dried, and the solvent was removed under vacuum. The residue was then
recrystallized from ethyl acetate/petroleum ether ¼ 1/4 to afford compound
1
7 as a white powder in quantitative yield, mp: 94–968C. H NMR (CDCl3):
d 1.32 (m, 2H), 1.58 (s, 9H), 1.81 (m, 4H), 2.17 (m, 2H), 2.70 (ddd, 2H,
J ¼ 5.1, 5.1, 5.1), 6.91 (s, 1H). 13C NMR (CDCl3): d 14.92, 23.68, 25.48,
28.51, 35.11, 89.06, 149.27, 162.33, 163.57. HRMS (ESI) calculated for
C13H20N2Oþ4 : m/z ¼ 268; found: m/z ¼ 268.
General Experimental Procedures of Cycloadditions of Nitrones
Exo-7-tert-butoxycarbonyl-3-ethoxycabonyl-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spirocyclo-hexane (7a)
A solution of nitrone 5 (0.27 g, 1 mmol) and 0.40 g (4 mmol, 4 equiv.) of ethyl
acrylate (6a) in 10 ml of ethanol was at reflux for 7 h. The reaction mixture

304
S. Cheng, H. Wu, and X. Hu
1
was then concentrated under reduced pressure; the H NMR spectrum of the
crude product indicated there was only one diastereomeric. Recrystallization
from ethyl acetate/petroleum ether afforded 0.25 g of 7a as a white crystalline
powder, 68% yield; when used was DCE (1,2-dichloroethane) as solvent
instead, the same product was obtained, and the yield was up to 96%, mp:
1
91–928C. H NMR (CDCl3): d 1.31 (m, 4H), 1.55 (s, 9H), 1.67 (m, 2H),
1.76 (m, 3H), 1.95 (m, 1H), 2.24 (m, 2H), 2.37 (m, 1H), 2.93 (m, 2H), 3.98
(m,1H), 4.17 (m, 1H), 4.28 (m,1H), 4.53 (m, 1H). 13C NMR (CDCl3): d
14.58, 22.57, 23.63, 25.44, 28.39, 30.77, 34.35, 34.73, 61.69, 63.49, 73.83,
83.85, 86.50, 150.00, 171.61, 173.69. HRMS (ESI): calculated for
C18H28N2Oþ6 : m/z ¼ 368; found: m/z ¼ 368.
The data of X-ray analysis: Crystal data: C18H28N2O6, M ¼ 368, orthor-
3
˚
˚
hombic, a ¼ 11.6537(9), b ¼ 8.9902(7), c ¼ 37.502(3) A, U ¼ 3929.0(5) A ,
T ¼ 273(2) K, space group Pbca, Z ¼ 8, m ¼ 0.046 mm21, 24019 reflections
measured, 4505 unique (Rint ¼ 0.0337), which were used in all calculations.
The final wR(F2) was 0.1500 (all data). [CCDC 299270 contains the sup-
plementary crystallographic data for this compound. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk).]
Exo-7-tert-butoxycarbonyl-3-phenyl-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spirocyclohexane (7b)
A solution of nitrone 5 (1.34 g, 5 mmol) and 1.04 g (10 mmol, 2 equiv.), of
styrene 6b in 20 ml of DCE was stirred at reflux for 5 h. The reaction
mixture was then concentrated under reduced pressure; the 1H NMR
spectrum of the crude product indicated there was only one diastereomer.
Crystallization from ethyl acetate/petroleum ether afforded 1.78 g of 7b as
1
a white crystalline powder; 96% yield, mp: 126–1278C. H NMR (CDCl3):
d 1.28 (m, 1H), 1.57 (s, 9H), 1.61 (m, 3H), 1.80 (m, 2H), 2.31 (m, 2H),
2.55 (m, 1H), 3.19 (m, 1H), 4.12 (m, 2H), 5.08 (t, 2H, J ¼ 7.2), 7.33
(m, 5H). 13C NMR (CDCl3): d 22.87, 23.30, 25.00, 28.01, 29.96, 32.22,
34.79, 40.03, 64.78, 77.32, 83.44, 87.40, 125.60, 127.19, 127.46, 128.37,
142.00, 149.93, 173.67. HRMS (ESI): calculated for C21H28N2Oþ4 :
m/z ¼ 372; found: m/z ¼372.
The data of X-ray analysis: crystal data: C21H28 N2O4, M ¼ 372, mono-
clinic, a ¼ 10.4334 (8), b ¼ 11.3450(9), b ¼ 90.9100(10), 90 deg,
3
˚
˚
c ¼ 17.2179(14) A, U ¼ 2007.6 (3) A , T ¼ 273 (2) K, space group, P2
(1)/c, Z ¼ 4, m ¼ 0.085 mm21, 13885 reflections measured, 5269 unique
2
(Rint ¼ 0.0197), which were used in all calculations. The final wR (F ) was
0.1438 (all data). [CCDC 299269 contains the supplementary crystallographic
data for this compound. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,

1,3-Dipolar Cycloaddition
305
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.
ac.uk).]
Exo-7-tert-butoxycarbonyl-3-methoxycarbonyl-3-methyl-6-oxo-2-oxa-
1,7-diazabicyclo[3,3,0]octan-8-spirocyclohexane (7c)
Methyl methacrylate (4 equiv.), 12 h, 83%, crystalline powder Mp: 150–
1
1518C. H NMR (CDCl3): d 1.25 (m, 2H), 1.54 (s, 9H), 1.56 (s, 3H), 1.72
(m, 6H), 2.40 (m, 2H), 2.48 (m, 1H), 3.13 (d, 1H, J ¼ 13.2), 3.71 (s, 3H),
3.99 (d, 1H, J ¼ 8.4). 13C NMR (CDCl3): d 23.00, 23.63, 24.63, 25.37,
28.41, 30.16, 34.95, 42.03, 52.96, 64.48, 81.42, 83.63, 87.27, 149.99,
172.61, 173.18. HRMS (ESI): calculated for C18H28N2Oþ6 : m/z ¼ 368;
found: m/z ¼ 368.
Exo-7-tert-butoxycarbonyl-3-hydroxymethyl-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spiro-cyclohexane (7d)
Allyl alcohol (3 equiv.), 16 h, 67%, crystalline powder. Mp: 124–1258C. 1H
NMR (CDCl3): d 1.50 (m, 18H), 1.93 (m, 1H), 2.43 (m, 1H), 2.59 (m, 1H),
2.72 (m, 1H), 3.36 (m, 1H), 4.18 (d, 1H, J ¼ 11.7), 4.32 (m, 2H). 13C NMR
(CDCl3): d 21.64, 21.72, 25.38, 27.96, 29.62, 35.25, 36.27, 60.75, 64.85,
75.72, 82.40, 89.97, 149.28, 171.25. HRMS (ESI): calculated for
C16H26N2Oþ5 : m/z ¼ 326; found: m/z ¼ 326.
Exo-7-tert-butoxycarbonyl-3-butoxy-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spirocyclohexane (7e)
Vinyl butyl ether (3 equiv.), 12 h, 73%, crystalline powder. 1H NMR (CDCl3):
d 0.93 (t, 3H, J ¼ 7.2), 1.24 (m, 1H), 1.39 (m, 2H), 1.54 (s, 9H), 1.75 (m, 3H),
1.88 (m, 2H), 2.26 (dd, 4H, J ¼ 12.6, 10.2), 2.47 (dd, 2H, J ¼ 9.0, 22.5), 2.69
(m, 1H), 2.93 (dd, 1H, J ¼ 13.5, 6.6), 3.41 (dd, 1H, J ¼ 12.9, 6.6), 3.72 (dd,
1H, 12.9, 6.6), 4.01 (d, 1H, 6.0), 5.07 (d, 1H, J ¼ 6.0). 13C NMR (CDCl3): d
14.06, 19.55, 22.69, 23.39, 25.31, 28.26, 30.51, 31.80, 34.55, 38.99, 63.34,
67.92, 83.70, 86.64, 99.86, 150.17, 174.44. HRMS (ESI): calculated for
C19H32N2Oþ5 : m/z ¼ 368; found: m/z ¼ 368.
Exo-7-benzyl-3-ethoxycarbonyl-3-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spirocyclohexane (8a)
1
Ethyl acrylate (4 equiv.), 8 h, 96%. H NMR (CDCl3): d 1.07 (m, 1H), 1.29
(t, 3H, J ¼ 7.2), 1.56 (m, 10H), 2.33 (d, 1H, J ¼ 12.3), 2.89 (dd, 1H,
J ¼ 3.9, 3.0), 4.10 (m, 1H), 4.19 (q, 2H, J ¼ 7.2), 4.45 (m, 2H), 7.29
(m, 5H). 13C NMR (CDCl3): d 14.42, 22.11, 23.33, 25.25, 31.80, 34.19,
35.59, 43.79, 61.57, 63.51, 74.31, 84.86, 126.48, 127.57, 128.74, 138.04,

306
S. Cheng, H. Wu, and X. Hu
171.81, 173.41. HRMS (ESI): calculated for C20H26N2Oþ4 : m/z ¼ 358; found:
m/z ¼ 358.
Exo-7-benzyl-3-phenyl-6-oxo-2-oxa-1,7-diazabicyclo[3,3,0]octan-8-
spirocyclohexane (8b)
1
Styrene (2 equiv.), 6 h, 97%, crystalline powder. Mp: 123–1248C. H NMR
(CDCl3): d 1.17 (m, 1H), 1.46 (m, 2H), 1.64 (m, 5H), 1.82 (m, 1H), 2.16
(m, 1H), 2.55 (m, 1H), 3.17 (dd, 1H, J ¼ 6.6, 12.3), 4.23 (d, 1H, J ¼ 8.1),
5.04 (t, 1H, J ¼ 7.2), 5.27 (s, 2H), 7.31 (m, 10H). 13C NMR (CDCl3): d
22.30, 22.85, 24.73, 31.28, 35.45, 40.14, 43.64, 64.91, 77.83, 85.97, 125.71,
127.12, 127.24, 127.47, 128.20, 128.32, 137.86, 140.60, 173.10. HRMS
(ESI): calculated for C23H26N2Oþ2 : m/z ¼ 362; found: m/z ¼ 362.
Exo-7-benzyl-3-methoxycarbonyl-3-methyl-6-oxo-2-oxa-1,7-
diazabicyclo[3,3,0]octan-8-spirocyclo-hexane (8c)
1
Methyl methacrylate (4 equiv.), 12 h, 82%, crystalline powder. H NMR
(CDCl3): d 1.47 (m, 1H), 1.54 (s, 3H), 1.76 (m, 9H), 2.43 (d, 1H, J ¼ 9.0),
2.95 (d, 1H, J ¼ 13.2), 3.85 (d, 1H, J ¼ 9.0), 4.25 (d, 1H, J ¼ 15.6), 4.63
(m, 3H), 5.23 (s, 1H), 7.32 (m, 5H). 13C NMR (CDCl3): d 17.31, 22.03,
23.27, 25.14, 34.32, 35.67, 43.92, 50.07, 53.65, 61.76, 67.62, 84.48, 127.57,
128.74, 129.00, 136.64, 172.75, 176.03. HRMS (ESI): calculated for
C20H26N2Oþ4 : m/z ¼ 358; found: m/z ¼ 358.
Exo-6-benzyl-3-ethoxycarbonyl-2-oxa-1,7-diazabicyclo[3,3,0]-6-
octen-8-spirocyclohexane (9a)
1
Ethyl acrylate (4 equiv.), 8 h, 87%. H NMR (CDCl3): d 1.47 (m, 1H), 1.59
(t, 3H, J ¼ 7.2), 1.76 (m, 10H), 2.41 (d, 1H, J ¼ 12.3), 2.92 (dd, 1H,
J ¼ 3.9, 3.0), 4.10 (m, 1H), 4.25 (q, 2H, J ¼ 7.2), 4.63 (m, 2H), 7.32
(m, 5H). 13C NMR (CDCl3): d 14.31, 22.03, 23.27, 25.14, 31.87, 34.32,
35.67, 43.92, 61.76, 63.62, 74.48, 83.75, 126.32, 127.15, 128.21, 136.64,
169.45, 170.12. HRMS (ESI): calculated for C20H26N2Oþ4 : m/z ¼ 358;
found: m/z ¼ 358.
Exo-7-benzyl-3-phenyl-2-oxa-1,7-diazabicyclo[3,3,0]-6-octen-8-
spirocyclohexane (9b)
1
Styrene (2 equiv.), 8 h, 97%, crystalline powder. Mp: 85–868C. H NMR
(CDCl3): d 1.65 (m, 9H), 2.12 (m, 1H), 2.40 (m, 1H), 2.61 (dd, 1H,
J ¼ 12.0, 4.5), 4.50 (d, 1H, J ¼ 7.5), 4.60 (dd, 1H, J ¼ 15.3, 4.5), 5.25
(m, 2H), 7.31 (m, 10H). 13C NMR (CDCl3): d 23.45, 23.65, 25.66, 32.71,
39.41, 40.35, 68.23, 71.05, 78.94, 95.00, 126.84, 128.33, 128.37, 128.54,

1,3-Dipolar Cycloaddition
307
128.66, 128.75, 136.28, 138.61, 167.10. HRMS (ESI): calculated for
C23H26N2Oþ2 : m/z ¼ 362; found: m/z ¼ 362.
Exo-7-benzyl-3-methoxycarbonyl-3-methyl-2-oxa-1,7-
diazabicyclo[3,3,0]-6-octen-8-spirocyclo-hexane (9c)
1
Methyl methacrylate (4 equiv.), 16 h, 82%, crystalline powder. H NMR
(CDCl3): d 1.45 (m, 1H), 1.58 (s, 3H), 1.72 (m, 9H), 2.51 (d, 1H, J ¼ 9.0),
3.02 (d, 1H, J ¼ 13.2), 3.93 (d, 1H, J ¼ 9.0), 4.36 (d, 1H, J ¼ 15.6), 4.72
(m, 3H), 5.29 (s, 1H), 7.36 (m, 5H). 13C NMR (CDCl3): d 18.27, 21.82,
23.03, 24.97, 31.92, 32.27, 44.25, 51.28, 63.20, 64.83, 75.61, 79.36, 127.59,
128.76, 129.03, 138.23, 169.63, 170.58. HRMS (ESI): calculated for
C20H26N2Oþ4 : m/z ¼ 358; found: m/z ¼ 358.
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