1,3-dipolar cycloaddition of nitrones with 5-methylenehydantoins: Synthesis and transformation of new spirohydantoin derivatives

Article abstract of DOI:10.1080/00397910903097237

1,3-Dipolar cycloaddition of various acyclic nitrones with 5-methylenehydantoin derivatives afforded new chiral spiroadducts in good yields. All the spirohydantoins were obtained through a regio-and stereospecific pathway, and the spirocarbon atom was linked to the isoxazolidine oxygen atom. A representative example of the reduction of the spirohydantoin 8 with Zn/AcOH led to the substituted 1,3-aminoalcohol hydantoin 20.

Full text of DOI:10.1080/00397910903097237

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1,3-Dipolar Cycloaddition of Nitrones
with 5-Methylenehydantoins:
Synthesis and Transformation of New
Spirohydantoin Derivatives
Amira Bahy a , Yakdhane Kacem a & Béchir Ben Hassine a
a Laboratory of Asymmetric Organic Synthesis and Homogeneous
Catalysis, Faculty of Sciences , Monastir, Tunisia
Published online: 07 Apr 2010.
To cite this article: Amira Bahy , Yakdhane Kacem & Béchir Ben Hassine (2010) 1,3-Dipolar
Cycloaddition of Nitrones with 5-Methylenehydantoins: Synthesis and Transformation of New
Spirohydantoin Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:9, 1377-1390, DOI: 10.1080/00397910903097237
To link to this article: http://dx.doi.org/10.1080/00397910903097237
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Synthetic Communications1, 40: 1377–1390, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097237
1,3-DIPOLAR CYCLOADDITION OF NITRONES WITH
5-METHYLENEHYDANTOINS: SYNTHESIS AND
TRANSFORMATION OF NEW SPIROHYDANTOIN
DERIVATIVES
´
Amira Bahy, Yakdhane Kacem, and Bechir Ben Hassine
Laboratory of Asymmetric Organic Synthesis and Homogeneous Catalysis,
Faculty of Sciences, Monastir, Tunisia
1,3-Dipolar cycloaddition of various acyclic nitrones with 5-methylenehydantoin derivatives
afforded new chiral spiroadducts in good yields. All the spirohydantoins were obtained
through a regio- and stereospecific pathway, and the spirocarbon atom was linked to the
isoxazolidine oxygen atom. A representative example of the reduction of the spirohydantoin
8 with Zn/AcOH led to the substituted 1,3-aminoalcohol hydantoin 20.
Keywords: 1,3-Dipolar cycloaddition; 5-methylenehydantoins; nitrones; regioselectivity; stereoselectivity
INTRODUCTION
1,3-Dipolar cycloaddition reactions are the most important and versatile
methods to build five-membered heterocycles.[1–5] They have been applied to the
synthesis of natural products such as sugar derivatives,[6] b-lactams,[7] amino acids,[8]
and alkaloids.[9]
Several examples of naturally occurring and synthetic hydantoin[10] and
spirohydantoin derivatives[11,12] undergo 1,3-dipolar cycloaddition to give numerous
compounds that exhibit various biological activities, such as antitumor,[13] anti-
arrhythmic,[14] anticonvulsant,[15] neurotransmissive,[16] herbicidal,[17] and cytotoxic
activities,[18] and act as inhibitors of glycogen phosphorylase[19] and aldose
reductase.[20] Among these biologically active compounds are hydantocidin (I) and
its analogs,[17–20] tetrantoin (II),[15] and spiro[(dihydroimidazo-2,4-dione)-5,30-
(20,30-dihydrothieno[2,3-b]naphtho-40,90-dione)] derivatives (III)[18] (Fig. 1).
In this work, we report the synthesis of the new spirohydantoin derivatives
8–19 and their reduction with Zn=AcOH. Our synthetic strategy is based on the
use of a methylenehydantoin derivative as the starting material to prepare spirohy-
dantoins, via 1,3-dipolar cycloaddition.
Received February 7, 2009.
Address correspondence to Bechir Ben Hassine, Laboratoire de Synthese Organique Asymetrique
´
et Catalyse Homogene (O1UR1201), Faculte des Sciences, Avenue de l’environnement, 5019 Monastir,
`
´
`
Tunisia. E-mail: bechirbenhassine@yahoo.fr
´
1377

1378
A. BAHY, Y. KACEM, AND B. BEN HASSINE
Figure 1. Hydantoin derivatives exhibiting biological activities.
RESULTS AND DISCUSSION
The starting compounds 5-methylenehydantoins 4a–d were prepared from
a-bromomethylester 1 according to Scheme 1. Treatment of various primary amines
with compound 1 gives produced the corresponding a-aminomethylester derivatives
2a–d in 50 to 70% yields. Derivatives 2a–d[21] were then treated with phenylisocya-
nate in refluxing toluene to furnish the N,N0-diprotected hydantoins 3a–d[22] in 50
to 90% yields. Finally, the desired new N,N0-diprotected 5-methylenehydantoins
4a–d were prepared in good yield according to the published procedure.[23]
The initial investigation on the 1,3-dipolar cycloaddition of 5-methylenehydan-
toins 4a–d with nitrones 5–7 involved the study of the reaction of 4a with nitrone 5 at
110 ꢀC in toluene solution for 24 h; compound 8 was obtained in 20% yield. Heating
the same mixture at 80 ꢀC for 24 h generated the product 8 in only 35% yield. Finally,
the reaction of 4a with 5 in toluene at 80 ꢀC for 6 days produced 8 in 63%. Increase in
reactional time beyond 6 days (up to 10 days) has not shown a variation in the
output.
In the light of these results, we decided to perform all cycloaddition reactions
of dipolarophiles 4a–d with nitrones 5–7 at 80 ꢀC in a diluted toluene solution
(0.02 M) for 6 days (Scheme 2). Yields of 8–19 range between 50 and 74% (Table 1).
Scheme 1. Synthesis of methylenehydantoins.

1,3-DIPOLAR CYCLOADDITION OF NITRONES
1379
Scheme 2. Reaction of methylenehydantoins with nitrones and reaction conditions.
Regiochemistry and Stereochemistry
Two possible regioisomers of the cycloadduct can be theoretically obtained: the
5,5-disubstituted isoxazolidine and=or the 4,4-disubstituted isoxazolidine (Scheme 3).
In practice, we have obtained only one product. The structure of each cycloadduct
was confirmed by NMR (1H and 13C) spectra of the crude cycloaddition reaction
mixtures. Comparison of the 13C NMR data of spiroadducts 8–19 suggests that these
compounds possess the same regiochemistry. The spirocarbon resonance of all
adducts was between 90 and 93 ppm; this value located the spiro center near the very
electronegative oxygen atom of the isoxazolidine ring.
1
In addition, the H NMR analysis clearly indicated that all spiroadducts were
5,5-disubstituted isoxazolidine regioisomers; the signal of proton 3-H appeared as a
triplet or a doublet of doublets around d ¼ 3.98–4.94 ppm. It is coupled with protons
4-H and 40-H. This excluded the presence of the inverse regioisomer (4,4-disubsti-
tuted isoxazolidine), in which the NMR spectrum would exhibit a singlet for 3-H
and an AB system for the two hydrogen atoms at the 5-position of the isoxazolidine
ring. These results also supported the literature reports.[24–27] The configuration of
the cycloadduct 15 was established by x-ray crystallography as (3R5R, 3S5S): this
Table 1. Yields of adducts
Entry
Methylenehydantoin
Nitrone
Adductsa,b
Yield (%)
1
2
4a
4a
4a
4b
4b
4b
4c
4c
4c
4d
4d
4d
5
6
7
5
6
7
5
6
7
5
6
7
8
9
63
71
55
60
58
50
70
60
60
70
52
74
3
10
11
12
13
14
15
16
17
18
19
4
5
6
7
8
9
10
11
12
aReaction in toluene at 80 ꢀC for 6 days.
bYield of pure 8–19.

1380
A. BAHY, Y. KACEM, AND B. BEN HASSINE
Scheme 3. Regiochemistry of cycloaddition.
analysis proves that we obtain only the 5,5-disubstituted regioisomer (Fig. 2), which
resulted from the endo approach of the dipole toward the hydantoin carbonyl group.
The examination of this structure revealed a cis relationship between the proton 3-H
=
and the C O group of the hydantoin ring.
The cycloaddition of 5-methylenehydantoins with nitrones led to cycloadducts
having two new chiral centers: the quaternary spiroatom and the carbon linked to
the substituted phenyl group of the isoxazolidine ring.
The formation of diastereoisomeric adducts was never caused by any Z=E
interconversion of nitrons,[26–28] the relative configuration (Z) of the dipole being
always preserved in spirocompounds. Indeed, the high-performance liquid chroma-
tographic (HPLC) analysis of the crude cycloaddition reaction shows the formation
of only one diastereoisomer for adducts 8–16. Unlike cycloaddition of chiral methyl-
enehydantoin 4d, that with nitrones proceeded stereoselectively, and HPLC analysis
shows the formation of two nonracemic diastereoisomers.
Figure 2. ORTEP view of adduct 15.

1,3-DIPOLAR CYCLOADDITION OF NITRONES
1381
Scheme 4. Reduction of spiroadduct 8.
Reduction of Spiroadduct 8
The reduction of compound 8[29] with zinc in acetic acid and water at 70 ꢀC
gave product 20, obtained by a simple opening of the isoxazolidine ring (Scheme 4).
The spectroscopic data (1H and 13C NMR) were in good agreement with the
assigned structure 20. The difference between 13C NMR spectrum of the compound
8 and that of compound 20 appears at the chemical shift of the quaternary carbon
C5. Its chemical shift appears at 91 ppm in the spiranic form and at 66 ppm after
1
the ring opening. H NMR spectrum shows the presence of two new wide signals
at 4.8 ppm corresponding to labile protons (OH and NH).
CONCLUSION
We have studied the reactivity of methylenehydantoins 4a–d toward acyclic
nitrones 5–7. All spiroadducts were formed via a very high regioselectivity pathway,
and the spirocarbon atom was linked to the isoxazolidine oxygen atom.
The continuous pharmaceutical interest in the spirohydantoin compounds[21]
may justify further exploration of these results in the pharmacological field.
EXPERIMENTAL
General
All reactions were monitored on thin-layer chromatographic (TLC) Merck
60 F-254 silica-gel plates (layer thickness 0.25 mm). Column chromatography was
performed on silica gel (70–230 mesh) using ethyl acetate and cyclohexane mixture
as eluents. Melting points were determined on an Electrothermal 9002 apparatus
and are uncorrected. The optical rotation was measured by Atago Polax-2 L polar-
imeter. NMR spectra were recorded on a Bruker AC 300 spectrometer [300 MHz
(1H) and 75 MHz (13C)]. All chemical shifts were reported as d values (ppm) relative
to internal tetramethylsilane. Infrared (IR) spectra (KBr) were recorded on a Fourier
transform (FT)–IR 8400 Shimadzu spectrophotometer. Mass spectra (MS) were
recorded on a Hewlett-Packard (HP) 5792. High-resolution mass spectroscopy
(HRMS) was carried on Micromass LCTKC420. A Jasco HPLC system provided
with a Jasco 2080 pump, an automatic injector Rheodyne (7725 I), ultraviolet
(UV) detector (Jasco 2075), and a system data processor weres used (Clarity Lite).
The chromatographic analysis was performed on a C18 column (250 mmꢁ 4.6 mm).

1382
A. BAHY, Y. KACEM, AND B. BEN HASSINE
A mobile phase of methanol=hexane [80:20] was used with a flow rate of
0.6 mL=min. Detection was performed at 254 nm.
The crystal data for C24H29N3O3 were recorded on a Nonis MACH3=CAD4
˚
˚
diffractometer: M ¼ 407.50, triclinic, P-1, a ¼ 9.976(5) A, b ¼ 10.735(5) A, c ¼
3
3
˚
˚
11.134(5) A, V ¼ 1129.1(9) A , Z ¼ 2, Dc ¼ 1.199 mg=m , x-ray source Mo Ka (radia-
˚
tion), k ¼ 0.71069 A, F(000) ¼ 436, T ¼ 293(2) K, colorless plates 0.40 ꢁ 0.30 ꢁ
0.20 mm. The structure was worked out by direct methods and refined anisotropically
using a full-matrix with least squares method based on F2 to give R1 ¼ 0.0565,
wR2 ¼ 0.1319 for 7593 independent observed reflections and 387 parameters. Crys-
tallographic data (excluding structure factors) for the structure in this article have
been deposited with the Cambridge Crystallographic Data Centre as a supplemen-
tary publication number CCDC 670177. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
Methylenehydantoins 4[23] and nitrones 5–7[30–33] were prepared according to
the literature procedures.
Synthesis of Methylenehydantoins
Preparation of the a-aminomethylester derivatives (2a–d). The primary
amine (50 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine
(30 mmol) was added. The a-bromomethylester 1 (25 mmol) was added dropwise
at 0 ꢀC. Once the addition finished, the solution was stirred overnight at room tem-
perature. The solution was acidified with HCl (2 M, 15 mL) and extracted three times
with methylene chloride (3 20 mL). The organic layers were combined, dried over
MgSO4, and concentrated under a reduced pressure. The crude residue was
purified by column chromatography [SiO2–hexane=ethyl acetate (80:20)].
N-Benzylaminoester 2a. Yellow oil (50%); 1H NMR (300 MHz, CDCl3): 1.91
(s, NH), 3.36 (s, CH2-CO), 3.66 (s, OCH3), 3.74 (s, CH2Bn), 7.19–7.27 (m, 5Harom); 13
NMR (75.5 MHz, CDCl3): 49.9 (CH2-Bn), 51.8 (CH2-CO), 53.3 (OCH3), 127.2–139.4
C
(Carom), 172.9 (COO); MS (IE): (C10H13NO2): m=z ¼ 179 [Mþ], 120, 106, 91, 65.
1
N-Isobutylaminoester 2b. Yellow oil (63%); H NMR (300 MHz, CDCl3):
0.85 (d, 2CH3-iBu, J ¼ 6.6 Hz), 1.61 (s, NH), 1.62–1.69 (m, CH-iBu), 2.34 (d,
CH2-iBu, J ¼ 6.9 Hz), 3.34 (s, CH2-CO), 3.66 (s, OCH3); 13C NMR (75.5 MHz,
CDCl3): 20.9 (2CH3-iBu), 28.8 (CH2-iBu), 51.3 (CH-iBu), 52.1 (CH2-CO), 58.0
(OCH3), 173.4 (CO-O); MS(IE): (C7H15NO2): m=z ¼ 145 [Mþ], 144, 116, 98, 86,
72, 55, 41.
1
N-Isopropylaminoester 2c. Yellow oil (55%); H NMR (300 MHz, CDCl3):
0.99 (d, 2CH3-iPr, J ¼ 6.3 Hz), 1.73 (s, NH), 2.68–2.77 (m, CH-iPr), 3.35 (s, CH2-
CO), 3.66 (s, OCH3); 13C NMR (75.5 MHz, CDCl3): 23.0 (2CH3-iPr), 48.6 (CH2-
CO), 48.8 (CH-iPr), 52.1 (OCH3), 173.4 (COO); MS (IE): (C6H13NO2): m=z ¼ 131
[Mþ], 130, 116, 91, 88, 56, 43.
17
N-[(1S)-1-Phenylethyl]aminoester 2d. Yellow oil (60%); ½aꢂD þ 0.9
1
(c ¼ 3.33, AcOEt); H NMR (300 MHz, CDCl3): 1.39 (d, CH3, J ¼ 6.6 Hz), 1.95 (s,
NH), 3.28 (d, CH2-CO, J ¼ 6.9 Hz), 3.69 (s, OCH3), 3.79 (q, CH), 2.68–2.77 (m,

1,3-DIPOLAR CYCLOADDITION OF NITRONES
1383
5Harom); 13C NMR (75.5 MHz, CDCl3): 24.69 (CH3), 49.0 (CH), 52.1 (CH2-CO),
58.1 (OCH3), 127.1–144.9 (Carom), 173.4 (COO).
Preparation of hydantoins (3a–d). In a 100-mL, round-bottomed flask
fitted with a magnetic stirrer, 10 mmol of a-aminomethylester, 10 mmol of phenyl-
isocyanate, and 10 mL of anhydrous toluene were placed. The resulting mixture
was stirred and heated to reflux under an argon atmosphere until complete consump-
tion of the starting materials (TLC analysis). The reaction mixture was allowed to
cool to room temperature and concentrate. The residue obtained was purified by
column chromatography [SiO2–cyclohexane=ethyl acetate (90:10)].
1-Benzyl-3-phenylimidazolidine-2,4-dione 3a. White solid (90%); mp ¼
1
141–143 ꢀC (ethyl acetate=hexane); H NMR (300 MHz, CDCl3): 3.76 (s, CH2-Bn),
4.18 (s, CH-CO), 4.65 (s, CH-CO), 7.01–7.45 (m, 10Harom); 13C NMR (75.5 MHz,
CDCl3): 50.0 (CH2-Bn), 52.8 (CH2-CO), 120.2–139.0 (Carom), 156.3 (NCON),
171.3 (CO); MS (IE): (C16H14N2O2): m=z ¼ 266 [Mþ], 223, 175, 132, 119, 104, 91,
77, 65.
1-Isobutyl-3-phenylimidazolidine-2,4-dione 3b. White solid (50%); mp ¼
1
89–91 ꢀC (ethyl acetate=hexane); H NMR (300 MHz, CDCl3): 0.99 (d, 2CH3-iBu,
J ¼ 6.6 Hz), 1.95–2.00 (m, CH-iBu), 3.28 (d, CH2-iBu, J ¼ 7.5 Hz), 4.03 (s, CH2-
CO), 7.35–7.50 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 20.3 (2CH3-iBu), 27.6
(CH2-iBu), 50.5 (CH-iBu), 50.9 (C5), 126.4–132.1 (Carom), 156.2 (NCON), 169.3
(CO); MS (IE): (C13H16N2O2): m=z ¼ 232 [Mþ], 189, 176, 119, 91, 42.
1-Isopropyl-3-phenylimidazolidine-2,4-dione 3c. White solid (60%); mp ¼
1
69–71 ꢀC (ethyl acetate=hexane); H NMR (300 MHz, CDCl3): 1.22 (d, 2CH3-iPr,
J ¼ 6.9 Hz), 3.92 (s, CH2-CO), 4.41–4.47 (m, CH-iPr), 7.31–7.46 (m, 5Harom); 13C
NMR (75.5 MHz, CDCl3): 20.1 (2CH3-iPr), 43.6 (CH-iPr), 45.0 (C5), 126.1–131.8
(Carom), 154.8 (NCON), 169.2 (CO); MS (IE): (C12H14N2O2): m=z ¼ 218 [Mþ],
203, 119, 91, 77, 56, 41.
3-Phenyl-1-[(1 S)-1-phenylethyl]imidazolidine-2,4-dione 3d. Previously
17
1
reported.[22] Yellow oil (75%); ½aꢂD þ 0.9 (c ¼ 3.15, AcOEt); H NMR (300 MHz,
CDCl3): 1.21 (d, CH3, J ¼ 7.2 Hz), 3.66 (d, CH2-CO, J ¼ 17.4 Hz), 3.96 (d, CH2-
CO, J ¼ 17.4 Hz), 3.60 (q, CH), 7.28–7.51 (m, 10Harom); 13C NMR (75.5 MHz,
CDCl3): 17.27 (CH3), 45.9 (CH2-CO), 50.6 (CH), 126.4–139.5 (Carom), 155.5
(NCON), 169.3 (CO).
Preparation of methylenehydantoins (4a–d). Sodium hydride (60%
dispersion in mineral oil, 5.16 mmol, 1.29 eq.) and diethyl oxalate (6 mmol, 1.5
eq.) were suspended in anhydrous tetrahydrofrun (THF, 5 mL), and the mixture
was heated to 60 ꢀC under an argon atmosphere. The appropriate hydantoin
(4 mmol, 1 eq.) was added dropwise. The resulting mixture was stirred and heated
to 60 ꢀC under an argon atmosphere for 48 h, cooled, and dried under reduced press-
ure. The resulting sodium salt of the 3-ethoxalylhydantoin and paraformaldehyde
(8 mmol, 2 eq.) was then suspended in xylene (10 mL), and the heterogeneous mix-
ture was stirred to reflux for 2 h. After cooling to room temperature, the solid residue
was filtered and washed with xylene. The filtrates were evaporated under a reduced

1384
A. BAHY, Y. KACEM, AND B. BEN HASSINE
pressure, and the corresponding residue was purified by column chromatography
[SiO2–cyclohexane=ethyl acetate (90:10)].
1-Benzyl-5-methylene-3-phenylimidazolidine-2,4-dione 4a. Previously
reported.[5] White solid (80%); mp ¼ 104–106 ꢀC; 1H NMR (300 MHz, CDCl3):
4.73 (d, CH2 ¼ C, J ¼ 2.4 Hz), 4.80 (s, CH2-Bn), 5.40 (d, CH2 ¼ C, J ¼ 2.4 Hz),
7.18–7.42 (m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 44.8 (CH2-Bn), 96.5
(CH2 ¼ C), 126.0–135.2 (Carom), 135.5 (Cq ¼ C), 153.7 (NCON), 161.7 (CO); IR
(KBr)=cmꢃ1
:
nC-N ¼ 1419, nC
¼ 1493, nC
¼ 1656, nC ¼ 1729,
=
=
=
Carom
CH2
O
nC ¼ 1777, nC-Harom ¼ 3059; MS (IE): (C17H14N2O2): m=z ¼ 278 [Mþ], 131, 119,
=
O
103, 91, 77, 65, 51.
1-Isobutyl-5-methylene-3-phenylimidazolidine-2,4-dione 4b. White solid
(50%); mp ¼ 71–73 ꢀC; 1H NMR (300 MHz, CDCl3): 0.98 (d, 2CH3-iBu, J ¼ 6.6 Hz),
2.08–2.17 (m, CH-iBu), 3.47–3.50 (d, CH2-iBu, J ¼ 7.5 Hz), 4.86 (d, CH2 ¼ C,
J ¼ 2.1 Hz), 5.52 (d, CH2 ¼ C, J ¼ 2.1 Hz), 7.35–7.50 (m, 5Harom); 13C NMR
(75.5 MHz, CDCl3): 20.1 (2CH3-iBu), 27.0 (CH-iBu), 48.1 (CH2-iBu), 95.0
(CH2 ¼ C), 125.9–131.4 (Carom), 135.9 (Cq ¼ C), 153.4 (NCON), 161.5 (CO); MS
(IE): (C14H16N2O2): m=z ¼ 244 [Mþ], 201, 188, 119, 82, 54, 41.
1-Isopropyl-5-methylene-3-phenylimidazolidine-2,4-dione 4c. White solid
1
(79%); mp ¼ 35–37 ꢀC; H NMR (300 MHz, CDCl3): 1.48 (d, 2CH3-iPr, J ¼ 7.2 Hz),
4.40–4.47 (m, CH-iPr), 4.97 (d, CH2 ¼ C, J ¼ 2.4 Hz), 5.54 (d, CH2 ¼ C, J ¼ 2.1 Hz),
7.34–7.49 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 19.8 (2CH3-iPr), 45.2
(CH-iPr), 95.5 (CH2 ¼ C), 126.0–131.4 (Carom), 134.3 (Cq ¼ C), 152.6 (NCON),
161.6 (CO).
5-Methylene-3-phenyl-1-[(1S)-1-phenylethyl]imidazolidine-2,4-dione
17
4d. Yellow solid (85%); mp ¼ 120 ꢀC;½aꢂD þ 0.26 (c ¼ 2.25, AcOEt); 1H NMR
(300 MHz, CDCl3): 1.73 (d, CH3, J ¼ 7.5 Hz), 4.52 (d, CH2 ¼ C, J ¼ 2.1 Hz), 5.30
(d, CH2 ¼ C, J ¼ 2.1 Hz), 5.60 (q, CH), 7.14–7.35 (m, 10Harom); 13C NMR
(75.5 MHz, CDCl3): 16.6 (CH3), 50.9 (CH), 97.7 (CH2 ¼ C), 126.3–139.4 (Carom),
153.6 (Cq ¼ C), 161.8 (NCON), 169.3 (CO).
Synthesis of Nitrones
N,a-Diphenylnitrone 5. White solid (80%); mp ¼ 112–114 ꢀC; 1H NMR
(300 MHz, CDCl3): 7.26–8.41 (m, 10Harom), 7.92 (s, CH N); 13C NMR
=
=
(75.5 MHz, CDCl3): 121.8–149.1 (Carom), 130.7 (CH N).
1
C-Phenyl-N-tert-butylnitrone 6. White crystals (74%); mp ¼ 70–72 ꢀC; H
NMR (300 MHz, CDCl3): 1.60 (s, 3CH3-tBu), 7.38–8.29 (m, 5Harom), 7.53 (s,
=
CH N); 13C NMR (75.5 MHz, CDCl3): 28.3 (3CH3-tBu), 70.8 (C-tBu),
=
128.4–131.0 (Carom), 129.9 (CH N).
1
C-(2-Methoxyphenyl)-N-isopropylnitrone 7. Yellow oil (70%); H NMR
(300 MHz, CDCl3): 1.43 (d, 2CH3-iPr, J ¼ 6.3 Hz), 3.78 (OCH3), 4.19 (m, CH-iPr),
6.79–9.30 (m, 4Harom), 7.88 (s, CH N); 13C NMR (75.5 MHz, CDCl3): 21.2
=
=
(2CH3-iPr), 55.8 (CH-iPr), 68.4 (OCH3), 110.0–131.2 (Carom), 131.5 (CH N),
157.1 (Cq-OCH3).

1,3-DIPOLAR CYCLOADDITION OF NITRONES
1385
Cycloadducts 8–19: General Procedure
A solution of nitrone 5–7 (1 mmol) and methylenehydantoins 4a–d (1 mmol) in
toluene (3 mL) was stirred at 80 ꢀC under an argon atmosphere for 24 h. The solvent
was then removed, and the residue was crystallized (ethanol).
6-Benzyl-2,3,8-triphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-7,9-dione
8. White crystals (63%); mp¼ 183–185 ꢀC (ethanol); Rf 0.41 (cyclohexane=ethyl acetate
90:10); 1H NMR (300MHz, CDCl3): 2.78 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.5 Hz), 3.00 (dd,
H4’, J ¼ 6.3 Hz, J ¼ 13.5 Hz), 4.81 (dd, H3, J¼ 6.3 Hz, J ¼ 10.8 Hz), 4.85 (d, H, (CH2-
Bn), J ¼ 15.9 Hz), 5.09 (d, H, (CH2-Bn), J ¼ 15.9 Hz), 7.05–7.55 (m, 20Harom); 13C
NMR (75.5 MHz, CDCl3): 43.4 (CH2-Bn), 45.6 (C4), 71.9 (C3), 91.0 (C5), 120.4–148.2
=
(Carom); 154.9 (C7), 169.6 (C9), IR (KBr)=cm: nNO ¼ 756; nC-N ¼ 1419, nC
¼ 1493,
Carom
nC ¼ 1729, nC-H arom ¼ 3059. HRMS calcd. for C30H25N‘3O3 [Mþ H]þ: 476.1974;
=
O
found: 476.1976. Retention time (tR)¼ 6.987.
6-Benzyl-2-tert-butyl-3,8-diphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-
7,9-dione 9. White crystals (71%); mp ¼ 175–177 ꢀC (ethanol); Rf 0.55
(cyclohexane=ethyl acetate 90:10); 1H NMR (300 MHz, CDCl3): 0.92 (s, 3CH3-
tBu), 2.49 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.5 Hz), 2.72 (dd, H4’, J ¼ 6.6 Hz, J ¼ 13.5 Hz),
4.44 (dd, H3, J ¼ 6.6 Hz, J ¼ 10.8 Hz), 4.67 (d, H, (CH2-Bn), J ¼ 15.9 Hz), 4.91 (d, H,
(CH2-Bn), J ¼ 15.9 Hz), 7.15–7.38 (m, 15Harom); 13C NMR (75.5 MHz, CDCl3): 26.7
(3CH3-tBu), 43.7 (CH2-Bn), 48.2 (C4), 60.1 (C-tBu), 65.6 (C3), 91.2 (C5), 126.2–140.2
(Carom), 155.3 (C7), 170.5 (C9). HRMS calcd. for C28H29N3O3 [M þNa]þ: 478.2106;
found: 478.2101. Retention time (tR) ¼ 7.487.
6-Benzyl-2-isopropyl-3-(2-methoxyphenyl)-8-phenyl-1-oxa-2,6,8-
triazaspiro[4.4]nonane-7,9-dione 10. White crystals (55%); mp ¼ 91–93 ꢀC
1
(ethanol); Rf 0.30 (cyclohexane=ethyl acetate 90:10); H NMR (300 MHz, CDCl3):
1.13 (dd, 2CH3-iPr), 2.45 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.5 Hz), 3.05 (dd, H4’, J ¼ 6.6 Hz,
J ¼ 13.5 Hz), 3.32 (m, CH-iPr), 3.72 (OCH3), 4.49 (d, H, (CH2-Bn), J ¼ 15.9 Hz), 4.83
(d, H, (CH2-Bn), J ¼ 15.9 Hz), 4.88 (t, H3), 6.81–7.59 (m, 14Harom); 13C NMR
(75.5 MHz, CDCl3): 14.6–17.6 (2CH3-iPr), 42.7 (C4), 43.1 (CH2-Bn), 55.1 (CH-
iPr), 55.2 (OCH3), 60.8 (C3), 92.3 (C5), 110.5–137.4 (Carom), 154.8 (C7), 157.0
(C11), 170.4 (C9). HRMS calcd. for C28H29N3O4 [M þ H]þ: 472.2237; found:
472.2232. Retention time (tR) ¼ 7.098.
6-Isobutyl-2,3,8-triphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-7,9-dione
11. White crystals (60%); mp¼ 148–150 ꢀC (ethanol); Rf 0.44 (cyclohexane=ethyl acet-
ate 90:10); 1H NMR (300MHz, CDCl3): 1.10 (dd, 2CH3-iBu), 2.49 (m, CH-iBu), 2.91
(dd, H4, J ¼ 10.2 Hz, J ¼ 13.5Hz), 3.20 (dd, H4’, J ¼ 6.9 Hz, J ¼ 13.5 Hz), 3.41 (dd, H,
(CH2-iBu), J ¼ 14.1 Hz, J ¼ 6.6 Hz), 3.66 (dd, H, (CH2-iBu), J ¼ 14.1 Hz, J ¼ 9 Hz),
4.94 (dd, H3, J ¼ 6.9 Hz, J ¼ 10.2Hz), 7.07–7.54 (m, 15Harom); 13C NMR (75.5 MHz,
CDCl3): 20.7–20.9 (2CH3-iBu), 28.6 (CH-iBu), 45.8 (C4), 48.1 (CH2-iBu), 71.4 (C3),
91.6 (C5), 118.5–148.6 (Carom), 155.0 (C7), 169.9 (C9). HRMS calcd. for C27H27N3O3
[M þ Na]þ: 464.1950; found: 464.1938. Retention time (tR) ¼ 7.570.
2-Tert-butyl-6-isobutyl-3,8-diphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-
7,9-dione 12. White crystals (58%); mp¼ 144–146 ꢀC (ethanol); Rf 0.58
1
(cyclohexane=ethyl acetate 90:10); H NMR (300 MHz, CDCl3): 0.95 (s, 3CH3-tBu),

1386
A. BAHY, Y. KACEM, AND B. BEN HASSINE
0.99 (d, 2CH3-iBu), 2.44 (m, CH-iBu), 2.60 (dd, H4, J ¼ 10.5 Hz, J ¼ 13.5 Hz), 2.85
(dd, H4’, J ¼ 6.9 Hz, J ¼ 13.5 Hz), 3.20 (dd, H, (CH2-iBu), J ¼ 14.1Hz, J ¼ 6.6 Hz),
3.52 (dd, H, (CH2-iBu), J ¼ 14.1Hz, J ¼ 9.3 Hz), 4.49 (dd, H3, J ¼ 6.9 Hz, J ¼ 10.5 Hz),
7.18–7.39 (m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 20.5–20.9 (2CH3-iBu), 26.7
(3CH3-tBu), 28.2 (CH-iBu), 47.7 (C-tBu), 47.8 (C4), 60.0 (CH2-iBu), 65.2 (C3), 90.4
(C5), 126.1–140.9 (Carom), 154.9 (C7), 170.5 (C9). HRMS calcd. for C25H31N3O3
[M þ H]þ: 422.2444; found: 422.2438. Retention time (tR) ¼ 7.743.
2-Isopropyl-6-isobutyl-3-(2-methoxyphenyl)-8-phenyl-1-oxa-2,6,8-tria-
zaspiro[4.4]nonane-7,9-dione 13. White crystals (50%); mp ¼ 135–137 ꢀC (etha-
1
nol); Rf 0.34 (cyclohexane=ethyl acetate 90:10); H NMR (300 MHz, CDCl3): 0.90
(dd, 2CH3-iBu), 1.14 (dd, 2CH3-iPr), 2.23 (m, CH-iBu), 2.56 (dd, H4, J ¼ 8.1 Hz,
0
J ¼ 13.8 Hz), 3.06–3.36 (m, H4 , CH2-iBu, CH-iPr), 3.87 (OCH3), 4.91 (t, H3),
6.90–7.65 (m, 9Harom); 13C NMR (75.5 MHz, CDCl3): 17.9–21.8 (2CH3-iPr),
20.4–20.6 (2CH3-iBu), 28.2 (CH-iBu), 43.5 (C4), 47.7 (CH2-iBu), 55.6 (CH-iPr),
55.7 (OCH3), 61.1 (C3), 92.6 (C5), 110.8–132.0 (Carom), 155.0 (C7), 157.3
(C-OCH3), 170.8 (C9). HRMS calcd. for C25H31N3O4 [M þNa]þ: 460.2212; found:
460.2225. Retention time (tR) ¼ 6.107.
6-Isopropyl-2,3,8-triphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-7,9-dione
14. White crystals (70%); mp ¼ 174–176 ꢀC (ethanol); Rf 0.34 (cyclohexane=ethyl
1
acetate 90:10); H NMR (300 MHz, CDCl3): 1.62 (dd, 2CH3-iPr), 2.86 (dd, H4,
0
J ¼ 10.5 Hz, J ¼ 13.5 Hz), 3.14 (dd, H4 , J ¼ 6.3 Hz, J ¼ 13.5 Hz), 4.25 (m, CH-iPr),
4.91 (dd, H3, J ¼ 6.3 Hz, J ¼ 10.5 Hz), 6.94–7.59 (m, 15Harom); 13C NMR
(75.5 MHz, CDCl3): 21.1 (2CH3-iPr), 45.8 (CH-iPr), 46.0 (C4), 71.3 (C3), 91.4 (C5),
120.1–137.4 (Carom), 148.6 (C7), 169.6 (C9). HRMS calcd. for C26H25N3O3 [M þ H]þ:
428.1974; found: 428.1979. Retention time (tR) ¼ 6.107.
2-Tert-butyl-6-isopropyl-3,8-diphenyl-1-oxa-2,6,8-triazaspiro[4.4]nonane-
7,9-dione 15. White crystals (60%); mp ¼ 147–149 ꢀC (ethanol); Rf 0.47
(cyclohexane=ethyl acetate 90:10); 1H NMR (300 MHz, CDCl3): 1.02 (s, 3CH3-
tBu), 1.61 (dd, 2CH3-iPr), 2.66 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.2 Hz), 2.96 (dd, H4’,
J ¼ 6.6 Hz, J ¼ 13.2 Hz), 4.30 (m, CH-iPr), 4.55 (dd, H3, J ¼ 6.6 Hz, J ¼ 10.8 Hz),
7.29–7.49 (m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 20.9–21.1 (2CH3-iPr), 26.4
(3CH3-tBu), 45.5 (CH-iPr), 48.6 (C4), 59.5 (C-tBu), 65.0 (C3), 90.1 (C5),
125.9–140.2 (Carom), 153.0 (C7), 170.1 (C9). HRMS calcd. for C24H29N3O3 [M þ H]þ:
408.2287; found: 408.2278. Retention time (tR) ¼ 7.283.
2,6-Diisopropyl-3-(2-methoxyphenyl)-8-phenyl-1-oxa-2,6,8-triazaspiro[4.4]-
nonane-7,9-dione 16. White crystals (60%); mp ¼ 129–131 ꢀC (ethanol); Rf 0.33
1
(cyclohexane=ethyl acetate 90:10); H NMR (300 MHz, CDCl3): 1.13 (dd, 2CH3-
iPr), 1.15 (dd, 2CH3-iPr), 2.50 (dd, H4, J ¼ 10.5 Hz, J ¼ 13.5 Hz), 3.11 (dd, H4’,
J ¼ 6.6 Hz, J ¼ 13.5 Hz), 3.15 (m, CH-iPr), 3.85 (OCH3), 3.98 (m, CH-iPr), 4.89 (t,
H3), 6.88–7.61 (m, 9Harom); 13C NMR (75.5 MHz, CDCl3): 16.9–21.5 (2CH3-iPr),
20.8–20.9 (2CH3-iPr), 44.1 (C4), 45.4 (CH-iPr), 54.9 (CH-iPr), 55.4 (OCH3), 60.5
(C3), 91.9 (C5), 110.5–131.4 (Carom), 153.0 (C7), 157.0 (C-OCH3), 170.3 (C9). HRMS
calcd. for C24H29N3O4 [M þ H]þ: 424.2237; found: 424.2244. Retention time
(tR ¼ 7.164).

1,3-DIPOLAR CYCLOADDITION OF NITRONES
1387
2,3,8-Triphenyl-6-[(1 s)-1-phenylethyl]-1-oxa-2,6,8-triazaspiro[4.4]nonane-
17
7,9-dione 17. White crystals (70%); mp ¼ 168–170 ꢀC (ethanol); ½aꢂD ꢃ 0.3 (c ¼ 0.83,
1
AcOEt); Rf 0.47 (cyclohexane=ethyl acetate 90:10); H NMR (300 MHz, CDCl3):
0
1.98 (t, CH3), 2.70 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.5 Hz), 2.90 (dd, H4 , J ¼ 6.3 Hz,
J ¼ 13.5 Hz), 4.60 (dd, H3, J ¼ 6.3 Hz, J ¼ 10.8 Hz), 5.45 (quin, CH), 7.23–7.71 (m,
20Harom); 13C NMR (75.5 MHz, CDCl3): 26.4 (CH3), 48.3 (C4), 52.8 (CH), 65.2
(C3), 90.5 (C5), 125.8–141.9 (Carom), 153.3 (C7), 169.8 (C9). HRMS calcd. for
C31H27N3O3 [M þ H]þ: 490.2131; found: 490.2138. Retention times tR1 ¼ 7.790,
tR2 ¼ 8.970.
2-Tert-butyl-3,8-diphenyl-6-[(1 s)-1-phenylethyl]-1-oxa-2,6,8-triazaspiro[4.4]
17
nonane-7,9-dione 18. White crystals (52%); mp ¼ 178–180 ꢀC (ethanol);½aꢂD ꢃ 0.17
1
(c ¼ 1.68, AcOEt); Rf 0.44 (cyclohexane=ethyl acetate 90:10); H NMR (300 MHz,
CDCl3): 0.96 (s, 3CH3-tBu), 1.92 (d, CH3), 2.64 (dd, H4, J ¼ 10.8 Hz, J ¼ 13.5 Hz),
0
2.81 (dd, H4 , J ¼ 6.3 Hz, J ¼ 13.5 Hz), 4.50 (dd, H3, J ¼ 6.3 Hz, J ¼ 10.8 Hz), 5.25
(quin, CH), 7.18–8.23 (m, 15Harom); 13C NMR (75.5 MHz, CDCl3): 26.8 (CH3),
28.7 (3CH3-tBu), 48.7 (C4), 53.1 (CH), 60.1 (C3), 65.6 (C-tBu), 90.9 (C5),
126.1–142.2 (Carom), 153.8 (C7), 170.1 (C9). HRMS calcd. for C29H31N3O3 [M þ H]þ:
470.2444; found: 470.2450. Retention times tR1 ¼ 7.720, tR2 ¼ 8.977.
2-Isopropyl-3-(2-methoxyphenyl)-8-phenyl-6-[(1 s)-1-phenylethyl]-1-oxa-
2,6,8-triazaspiro[4.4]nonane-7,9-dione 19. Yellow solid (74%); mp ¼ 140 ꢀC
17
(ethanol); ½aꢂD ꢃ 0.15 (c ¼ 0.83, AcOEt); Rf 0.36 (cyclohexane=ethyl acetate 90:10);
1H NMR (300 MHz, CDCl3): 1.41 (d, 2CH3-iPr), 1.80 (d, CH3-CH, J ¼ 6.6 Hz),
2.45 (dd, H4, J ¼ 8.1 Hz, J ¼ 13.5 Hz), 3.05 (dd, H4’, J ¼ 8.1 Hz, J ¼ 13.5 Hz), 3.20
(m, CH-iPr), 3.77 (OCH3), 4.15 (q, CH-CH3), 4.88 (t, H3), 6.78–7.41 (m, 14Harom);
13C NMR (75.5 MHz, CDCl3): 21.6 (2CH3-iPr), 42.5 (C4), 55.9 (CH-iPr), 56.0
(OCH3), 68.5 (C3), 93.5 (C5), 110.1–131.7 (Carom), 158.8 (C7), 170.1 (C-OCH3),
171.2 (C9). HRMS calcd. for C29H31N3O4 [M þNa]þ: 508.2212; found: 508.2224.
Retention times tR1 ¼ 7.591, tR2 ¼ 8.807.
Reduction of Compound 8
To a suspension of 0.4 mmol of pure spirohydantoin 8 in 9 mL of acetic acid=
water (1:2), 1.6 mmol of zinc were added. The reaction mixture was heated at 70 ꢀC
for 48 h. The solution was cooled to room temperature. Zinc salts were filtered off,
and the filtrate was concentrated. The residue was partitioned between 10%
ammonium hydroxide=methylene chloride. The aqueous layer was extracted with
CH2Cl2, and the combined organic fractions were dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by column chromatography
[SiO2–cyclohexane=ethyl acetate (80:20)] to give the compounds 20.
(2-Anilino-2-phenylethyl)-1-benzyl-5-hydroxy-3-phenylimidazolidine-
2,4-dione 20. Yellow solid (49%); mp ¼ 164–166 ꢀC; Rf 0.38 (cyclohexane=ethyl
1
acetate 90:10); H NMR (300 MHz, DMSO-d6): 2.12 (d, H4, J ¼ 15 Hz), 2.50 (t,
0
H4 , J ¼ 13.5 Hz), 3.84 (dd, H3, J ¼ 13.5 Hz, J ¼ 2.7 Hz), 3.96 (d, H10, J ¼ 16.5 Hz),
4.75 (2 s, NH and OH), 5.17 (d, H10’, J ¼ 16.5 Hz), 6.64–7.40 (m, 20Harom);
13C NMR (75.5 MHz, DMSO-d6): 43.2 (C4), 45.6 (C10), 52.8 (C3), 66.0 (C5),

1388
A. BAHY, Y. KACEM, AND B. BEN HASSINE
116.9–143.6 (Carom), 156.2 (C7), 174.3 (C9); IR (KBr)=cmꢃ1: nC-N ¼ 1410, nC
C30H27N3O3 [M þ H]þ: 478.2131; found: 478.2129.
¼
=
Carom
=
1494, nC ¼ 1721, nC-Harom ¼ 2924; nN-H&O-H ¼ 3437. HRMS calcd. for
O
ACKNOWLEDGMENT
´ ´
The authors are grateful to DGRSRT (Direction Generale de la Recherche
´
Scientifique et de la Renovation Technologique) of the Tunisian Ministry of Higher
Education, Scientific Research, and Technology for the financial support.
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