Synthesis of new spiro[1,4,2-dioxazole-5,3'-indolin]-2'-ONE by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1080/00397911.2010.497595

Novel spiro[1,4,2-dioxazole-5,3'-indolin]-2'-one derivatives were synthesized by 1,3-dipolar cycloaddition reactions of the isatin derivative with aryl nitrile oxide. The cycloadducts were characterized by spectral data including ¹H NMR, ¹³C NMR, infrared, mass spectra, and elementary analysis. Copyright

Full text of DOI:10.1080/00397911.2010.497595

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Synthesis of New Spiro[1,4,2-
dioxazole-5,3′-indolin]-2′-one by 1,3-
Dipolar Cycloaddition
Rachid Bouhfid a b , Nicolas Joly a , El Mokhtar Essassi b , Vincent
Lequart a , Mohamed Massoui b & Patrick Martin a
a Unité de Catalyse et de Chimie du Solide, UMR CNRS, Béthune,
France
b Laboratoire de Chimie Organique Hétérocyclique, Pôle de
compétences Pharmacochimie Université Mohammed V-Agdal,
Rabat, Moracco
Version of record first published: 20 May 2011.
To cite this article: Rachid Bouhfid, Nicolas Joly, El Mokhtar Essassi, Vincent Lequart, Mohamed
Massoui & Patrick Martin (2011): Synthesis of New Spiro[1,4,2-dioxazole-5,3′-indolin]-2′-one by 1,3-
Dipolar Cycloaddition, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 41:14, 2096-2102
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Synthetic Communications1, 41: 2096–2102, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.497595
SYNTHESIS OF NEW SPIRO[1,4,2-DIOXAZOLE-5,3’-
INDOLIN]-2’-ONE BY 1,3-DIPOLAR CYCLOADDITION
Rachid Bouhfid,1,2 Nicolas Joly,1 El Mokhtar Essassi,2
Vincent Lequart,1 Mohamed Massoui,2 and Patrick Martin1
1
´
Unite de Catalyse et de Chimie du Solide, UMR CNRS, Bethune, France
Laboratoire de Chimie Organique Heterocyclique, Pole de competences
´
2
´ ´
ˆ
´
´
Pharmacochimie Universite Mohammed V-Agdal, Rabat, Moracco
GRAPHICAL ABSTRACT
Abstract Novel spiro[1,4,2-dioxazole-5,30-indolin]-20-one derivatives were synthesized by
1,3-dipolar cycloaddition reactions of the isatin derivative with aryl nitrile oxide. The
cycloadducts were characterized by spectral data including 1H NMR, 13C NMR, infrared,
mass spectra, and elementary analysis.
Keywords 1,4,2-Dioxazole; 1,3-dipolar cycloaddition; isatin; isoxazole; isoxazoline
INTRODUCTION
Spiroindoline derivatives are synthetic or natural products[1–4] with various
interesting properties. Their biological activities[5] are attributed to their specific
structure composed of an indoline core linked to other heterocyclic arrangements
such as isoxazoline, triazoline, or dioxazoline systems. For example, the spiro[indole-
thiazolidine] compounds are used as pharmacological agents and as mammalian cell
cycle inhibitors,[4] and possess anti-inflammatory,[5] antibacterial,[6] and anticonvul-
sant activities.[7] Spiro[indole-pyrrolidines] (Fig. 1, I) exhibit local anesthetic
activity[8] and binding affinity to glycine receptors.[9] Spiro[3H-indole-3,40-[4H]
pyran]-2(1H)-ones (Fig. 1, II) are used as anti-inflammatory agents and have central
nervous system activities.[10] Spiro[3H-indole-3,30-pyrazoline]-2-ones are used as
blood platelet aggregations.[11]
Received February 18, 2010.
Address correspondence to Nicolas Joly, Unite de Catalyse et de Chimie du Solide, UMR CNRS
´
8181, IUT de Bethune BP 819, 62408, Bethune, France. E-mail: nicolas.joly@univ-artois.fr
´
´
2096

NEW SPIRO[1,4,2-DIOXAZOLE-5,30-INDOLIN]-20-ONE
2097
Figure 1. Examples of indolone spiro-derivatives.
They are also used as precursors in the total synthesis of natural alkaloids.[12,13]
In continuation of our previous synthetic work on isatin and its derivatives,[14,15]
we have performed the synthesis of a novel series of compounds corresponding to
isatin bearing dioxazolyl and=or oxazolidinyl heterocyclic moieties. Our synthetic
strategy for the building of such spirooxindolyl compounds consisted of a 1,3-dipolar
=
cycloaddition reaction on the 3-exocyclic position of the C O double bond of
indoline-2,3-dione derivatives. The synthetic strategy used in this rationale consisted
of the pathway described in Scheme 1. To our knowledge, there are only a few pub-
lished manuscripts in the literature dedicated to the synthesis of such compounds.[16,17]
RESULTS AND DISCUSSIONS
The initial step (Fig. 2) consisted of an alkylation of the 2,3-indolinedione 1,
conducted at room temperature under phase-transfer-catalysis (PTC) conditions, with
the individual benzyl chloride, allyl bromide, or propargyl bromide in the presence of
dry K2CO3. Dimethylformamid was used as solvent, and tetra-n-butylammonium
bromide (TBAB) was the catalyst. One resulting product (2–4) was formed for each
individual N-alkylation in a good yield. The structural assignment of products 2–4
was straightforward and relied upon the elemental analysis and spectral data,
including Fourier transform–Infrared (FT-IR), 1H NMR, 13C NMR, and mass
spectrometry.
The 1,3-dipolar cycloaddition reaction of isatin derivatives 2–4 with the nitrile
oxide product generated in situ from 4-methoxybenzaldoxime 5 and sodium
Scheme 1. Synthetic pathway followed for the synthesis of isatin derivatives.

2098
R. BOUHFID ET AL.
Figure 2. N-Alkylation of isatin in phase-transfer–catalysis conditions.
=
hypochloride was studied (Fig. 3). It was found that beside the C O participating in
the formation of the 1,4,2-dioxazole ring, the C-C alkene (allyl) or alkyne (propargyl)
bond also experienced a 1,3-dipolar cycloaddition reaction with the nitrile oxide to
form the isoxazole or isoxazoline rings linked to the indole ring via a methylene group.
The structures of the synthesized spiro[indole-dioxazoline] compounds,
containing the various substituted isatin rings, were confirmed as follows. The FT-IR
spectrum of 6–10 showed peaks around 1610 cmꢀ1 for the amide carbonyl, improving
the presence of the oxindole moitey. The 1H NMR spectrum of 7 showed the methoxy
protons as a singulet at 3.86 ppm, the methylene protons as a singulet at 4.89 ppm,
and the aromatic protons as multiplet at 6.74–7.82 ppm. The 13C NMR spectrum
exhibited the following signals attributed respectively to: methylene benzylic at
44.0 ppm, methoxy group at 55.4 ppm, C-3 spiro carbon at 105.2 ppm, and isatin
carbonyl at 169.3 ppm. Identical results were observed for the other derivatives
irrespective of the nature of the substituent present in the N1 of the isatin moiety.
The disappearance of the signal at 183 ppm due to the ketonic carbonyl confirmed
the involvement of the carbonyl group in 1,3-dipolar cycloaddition.
The respective obtainment of compounds 9 and 11 from the cycloaddition of
nitrile oxide to N-allylisatin and N-propargylisatin can be explained by the involvement
of the subsequent reaction of the dipole with the allylic and propargylic groups. The
structural elucidation of the novel series of spiro[1,4,2-dioxazole-5,30-indolin]-20-one
derivatives was accomplished as in the following section. The proton spectrum of 11
showed two singlets at 3.87 and 3.88 ppm, which were assigned to the protons of
Figure 3. 1,3-Dipolar cycloaddition reaction on N-alkylisatin.

NEW SPIRO[1,4,2-DIOXAZOLE-5,30-INDOLIN]-20-ONE
2099
methoxy group and a signal at 5.08 ppm due to the methylene protons. A singlet at
6.67 ppm was also observed, corresponding to the isoxazolic proton, while its 13C
NMR spectrum contains two signals at 102.7 and 105.2 ppm, which can be respectively
assigned to C-3 spiro and CH isoxazolic, as with those corresponding to methylene,
methyl, and aromatic carbons. Mass spectrometric anþalysis was performed by electron
impact (EI) with the presence of a molecular ion Mꢁ (m=z ¼ 483), proving that two
molecules of the nitrile oxide were involved in the reaction process.
The formation of the spirodioxazole-oxindole structure in all reactions showed
that the cycloaddition proceeded with high chemoselectivity when using the nitrile
oxide, which prefers to react with C-3 carbonyl ketone, and with a high regioselec-
tivity as the oxygen of the nitrile oxide adds exclusively to either the substitued
carbon of double or to the triple bonds of 3 and 4 respectively
The formation of spirodioxazole-oxindole in all reactions shows that the
cycloaddition proceeds chemoselectively, with the nitrile oxide preferring to react
with C3 carbonyl ketone and regioselectively with the oxygen of the nitrile oxide
adding to the substituent carbon of double and triple bonds of 3 and 4 respectively.
CONCLUSION
1,3-dipolar cycloaddition reaction of isatin derivatives 1–4 with nitrile oxide
=
was studied. It was found that beside its C O (ketone) participating in formation
of 1,4,2-dioxazole ring and C-C (allyl or propargyl), it also underwent a 1,3-dipolar
cycloaddition reaction with nitrile oxide to afford isoxazole or isoxazoline rings
linked by methylene group to indole ring. The construction of spiro[indole-
dioxazole] molecules is essential to explore new medicines and agrochemical
compounds.
We evaluate the ability of these new potentially active molecules to cross the
blood brain barrier by testing them in vitro.[18] They will also be tested in the near
future for their anti-inflammatory and antitumoral properties.
EXPERIMENTAL
Melting points were determined using a capillary melting-point apparatus and
1
are uncorrected. H and 13C NMR spectra were recorded in CDCl3 solution with
tetramethylsilane (TMS) as an internal reference using a Bruker Avance 300 instru-
ment; chemical shifts are given in d ppm downfield from tetramethylsilane (TMS).
Multiplicities of 13C NMR resources were assigned by distortionless enhancement
by polarization transfer (DEPT) experiments. Mass spectra (MS) were recorded in
a Varian MAT 311A spectrometer. Elemental analyses were performed by the
´
´
´
IUT de Bethune, Departement de Chimie (Bethune, France), and infrared spec-
troscopy was performed using a FT-IR Bruker Vector 22 apparatus equipped with
a diamond reflection accessory.
Alkylation Reaction
General procedure. K2CO3 (0.02 mol, 2.76 g), 22 mmol alkyl halides, and
tetra-n-butylammonium bromide TBAB (0.001 mol, 0.321 g) was added to a solution

2100
R. BOUHFID ET AL.
of indoline-2,3-dione 1 (20 mmol, 2.92 g) in dimethylformamid 40 mL. The mixture
was stirred at room temperature for 24 h. The solution was filtered, and the solvent
was removed under reduced pressure. The residue was recrystallized from ethanol to
afford 2–4.
N-Benzylindoline-2,3-dione 2. The compound was obtained as orange
crystals in 80% yield, mp ¼ 133–135 ꢂC (ethanol); IR: nmax 1737, 1605 cmꢀ1
;
1H
NMR (CDCl3): d 4.86 (s, 2H, NCH2), 6.70–7.56 (m, 9H, HAr); 13C NMR (CDCl3):
d 44.0 (NCH2); 111.1, 123.9, 125.4, 127.8, 128.1, 129.1, 138.þ4 (CHAr); 117.6, 134.5,
ꢁ
=
=
150.7 (Cq); 158.3 (C Oamide); 183.3 (C Oketone). IE-MS: M (m=z) ¼ 237.
N-Allylindoline-2,3-dione 3. The compound was obtained as red crystals in
86% yield, mp ¼ 89–91 ꢂC (ethanol); IR: nmax 1734, 1606 cmꢀ1; H NMR (CDCl3):
1
3
4
3
d 4.24 (dd, 2H, NCH2, J ¼ 2.4 Hz, J ¼ 0.7 Hz), 5.19 (m, 2H, ¼CH2, J ¼ 2.4 Hz,
3J ¼ 1.5 Hz), 5.70 (m, 1H, ¼CH, J ¼ 1.5 Hz, J ¼ 0.7 Hz); 6.81–7.46 (m, 4H, CHAr);
3
4
13C NMR (CDCl3): d 42.4 (NCH2); 118.5 (¼CH2); 130.2 (¼ CH); 110.9, 123.8, 125.2,
þ
ꢁ
=
138.4 (CHAr); 117.4, 156.7 (Cq); 157.9 (C Oamide); 183.2 (C Oketone). IE-MS: M
=
(m=z) ¼ 187.
N-Propargylindoline-2,3-dione 4. The compound was obtained as orange
crystals in 76% yield, mp ¼ 156–158 ꢂC (ethanol); IR: nmax 1738, 1605 cmꢀ1
;
1H
4
4
NMR (CDCl3): d 2.35 (t, 1H, ꢃCH, J ¼ 2.4 Hz), 4.52 (d, 2H, NCH2, J ¼ 2.4 Hz),
7.22–7.63 (m, 4H, HAr). 13C NMR (CDCl3): d 36.8 (NCH2); 73.9 (ꢃCH); 111.7,
=
=
125.2, 126.þ2, 139.3 (CHAr); 117.4, 149.4 (Cq); 158.6 (C Oamide); 182.7 (C Oketone).
ꢁ
IE-MS: M (m=z) ¼ 185.
1,3-Dipolar Cycloaddition
General procedure. Isatin 1 (N-alkylisatin 2–4) (6.8 mmol) was dissolved in
20 mL of dichloromethane. p-Methoxybenzaldoxime 5 (10.2 mmol) was added to this
solution, and the mixture stirred at 0 ꢂC. Sodium hypochlorite (10 mL, 24%) was
added dropwise to the mixture, and stirring continued for 6 h. The organic phase
was separated off and dried with Na2SO4; and the solvent was evaporated in vacuo.
The residue was purified by column chromatography on silica gel using a 8:2 mixture
of hexane and ethyl acetate as eluent.
3-(4-Methoxyphenyl)spiro[1,4,2-dioxazoline-5,3’-indoline]-7-one 6. The
compound was obtained in 66% yield, mp ¼ 176–178 ꢂC (hexane–ethyl acetate);
1
IR: nmax 3194, 1605 cmꢀ1; H NMR (CDCl3): d 3.72 (s, 3H, OCH3); 6.92–7.84 (m,
8H, HAr). 13C NMR (CDCl3): d 54.8 (OCH3); 101.1 (Cspiro); 114.5, 131.6, 112.7,
113.8, 120.7, 123.2, 125.1, 137.9 (CHAr); 141.3, 160.4, 164.7, 168.5 Cq; IE-MS: m=z
þ
ꢁ
(%): 296 [M ], 268 (100), 264 (30), 136 (25), 32 (22). Anal. calcd. for C16H12N2O4:
C, 64.86; H, 4.08; N, 9.46. Found: C, 64.94; H, 3.98; N, 9.51%.
3-(4-Methoxyphenyl)-6-benzylspiro[1,4,2-dioxazoline-5,3’-indoline]-7-
one 7. The compound was obtained in 73% yield, mp ¼ 144–146 ꢂC (hexane–ethyl
acetate). IR: nmax 1610 cmꢀ1 1H NMR (CDCl3): d 3.86 (s, OCH3); 4.89 (s,
;
NCH2); 6.74–7.82 (m, 13HAr). 13C NMR (CDCl3): d 55.4 (OCH3); 44.0 (NCH2);
105.2 (Cspiro); 110.2, 114.3, 123.8, 125.8, 127.4, 127.9, 128.9, 129.0, 132.9 (CHAr);

NEW SPIRO[1,4,2-DIOXAZOLE-5,30-INDOLIN]-20-ONE
2101
þ
ꢁ
114.4, 121.6, 134.7, 143.9, 159.5, 162.5, 169.3 (Cq). IE-MS: m=z (%): 386 [M ], 358
(100), 354 (43), 296 (34), 253 (24), 91 (38). Anal. calcd. for C23H18N2O4: C, 71.49; H,
4.70; N, 7.25. Found: C, 71.54; H, 4.63; N, 7.31%.
3-(4-Methoxyphenyl)-6-prop-2-enylspiro[1,4,2-dioxazoline-5,3’-indoline]
-7-one 8. The compound was obtained in 47% yield, mp ¼ 131–133 ꢂC (hexane–
1
ethyl acetate). IR: nmax 1604 cmꢀ1; H NMR (CDCl3): d 3.32 (s, 3H, OCH3), 4.22
(m, 2H, NCH2), 5.67 (m, 1H, ¼CH), 5.18 (m, 2H, ¼CH2), 7.01–7.76 (m, 8H,
H
Ar). 13C NMR (CDCl3): d 54.9 (OCH3); 43.1 (NCH2); 119.7 (¼CH2); 131.6
(¼CH); 104.2 (Cspiro); 112.1, 115.5, 124.3, 125.5, 129.5, 137þ.2 (CHAr); 114.0, 121.2,
ꢁ
145.1, 161.5, 164.9, 169.9 (Cq). IE-MS: m=z (%): 336 [M ], 308 (100), 304 (35),
296 (44), 203 (25). Anal. calcd. for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found:
C, 67.77; H, 4.86; N, 8.35%.
3-(4-Methoxyphenyl)-6-f[3-(4-methoxyphenyl)(4,5-dihydroisoxazol-5-yl)]
methylgspiro[1,4,2-dioxazoline-5,3’-indoline]-7-one 9. The compound was
obtained in 23 % yield, mp ¼ 157–159 ꢂC (hexane–ethyl acetate). IR: nmax 1609 cmꢀ1
;
1H NMR (CDCl3): d 3.42–3.55 (s, 3H, OCH3); 4.12 (m, 2H, NCH2); 5.17 (m, 1H,
CH); 3.01 (m, 2H, CH2); 6.89–7.81 (m, 12H, HAr). 13C NMR (CDCl3): d 55.1–55.7
(OCH3); 44.4 (NCH2); 77.8 CH; 50.6 (CH2); 103.2 (Cspiro); 111.8, 115.2, 122.9,
125.3, 131.4, 138þ.2 (CHAr); 113.9, 120.5, 143.6, 161.4, 167.1, 171.1 (Cq). IE-MS:
ꢁ
(m=z, %): 485 [M ], 457 (100), 453 (34), 352 (28), 296 (37), 189 (30). Anal. calcd. for
C27H23N3O6: C, 66.80; H, 4.78; N, 8.66. Found: C, 66.74; H, 4.90; N, 8.60%.
3-(4-Methoxyphenyl)-6-prop-2-ynylspiro[1,4,2-dioxazoline-5,3’-indoline]-
7-one 10. The compound was obtained in 54% yield, mp ¼ 136–138 ꢂC (hexane–
1
4
ethyl acetate). IR: nmax 1603 cmꢀ1; H NMR (CDCl3): d 2.49 (t, 1H, ꢃCH, J ¼
4
2.4 Hz); 3.40 (s, 3H, OCH3); 3.84 (d, 2H, NCH2, J ¼ 2.4 Hz); 6.74–7.78 (m, 8H,
H
Ar). 13C NMR (CDCl3): d 42.1 (NCH2); 55.3 (OCH3); 69.6 (CH); 102.4 (Cspiro);
112.5, 115.3, 125.1, 129.0, 129.6, 131.3 (CHAr); 106.4, 116.9, 121.2, 142.8, 162.1,
þ
ꢁ
166.4, 170.0 (Cq). IE-MS: (m=z, %): 334 [M ], 304 (100), 302 (45), 296 (34), 201
(27). Anal. calcd. for C19H14N2O4: C, 68.26; H, 4.22; N, 8.38. Found: C, 68.23;
H, 4.15; N, 8.44%.
3-(4-Methoxyphenyl)-6-f[3-(4-methoxyphenyl)isoxazol-5-yl]methylg
spiro[1,4,2-dioxazoline-5,3’-indoline]-7-one 11. The compound was obtained in
1
31% yield, mp ¼ 170–172 ꢂC (hexane–ethyl acetate). IR: nmax 1606cmꢀ1; H NMR
(CDCl3): d 3.87–3.88 (s, 3H, OCH3), 5.08 (s, 2H, NCH2), 6.67 (s, 1H, Hisoxazole),
6.98–7.81 (m, 12H, HAr); 13C NMR (CDCl3): d 36.1 (NCH2); 55.8–55.9 (OCH3);
102.7 (Cspiro); 105.2 (CHisoxazole); 110.6, 114.9, 115.1, 125.5, 126.7, 127.7, 129.1, 134.1
(CHAr); 102.4, 114.0, 121.1, 130.1, 144.0, 159.7, 161.7, 162.0, 162.6, 164.9, 169.0
þ
ꢁ
(Cq). IE-MS: (m=z, %): 483 [M ], 455 (100), 451 (43), 350 (33), 296 (30), 149 (21). Anal.
calcd. for C27H21N3O6: C, 67.07; H, 4.38; N, 8.69. Found: C, 67.15; H, 4.30; N, 8.64%.
ACKNOWLEDGMENTS
The authors acknowledge the financial support provided by the Ministry
ˆ
ESRSFC of the Moroccan Government (Pole de Competences Pharmacochimie)
´
´
and IUT Bethune.

2102
R. BOUHFID ET AL.
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