A novel, convenient, and efficient procedure for the synthesis of spiroisoindoline-1,5′-oxazolidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.02.163

A novel, convenient, and practical one-pot procedure for the direct synthesis of spiroisoindoline-1,5′-oxazolidine derivatives is described via oxidative cleavage of 3a,8a-dihydroxyindeno[2,1-d]imidazole-2,8-diones with lead(IV) acetate at room temperature.

Full text of DOI:10.1016/j.tetlet.2010.02.163

Tetrahedron Letters 51 (2010) 2467–2469
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel, convenient, and efficient procedure for the synthesis
of spiroisoindoline-1,50-oxazolidine derivatives
*
Mohammad Reza Mohammadizadeh , Neda Firoozi
Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
A novel, convenient, and practical one-pot procedure for the direct synthesis of spiroisoindoline-1,50-oxa-
zolidine derivatives is described via oxidative cleavage of 3a,8a-dihydroxyindeno[2,1-d]imidazole-2,8-
diones with lead(IV) acetate at room temperature.
Article history:
Received 10 December 2009
Revised 16 February 2010
Accepted 26 February 2010
Available online 3 March 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Ninhydrin
Urea
Dihydroxyindeno[2,1-d]imidazole-
2,8-diones
Oxidative cleavage
Spiroisoindoline-1,50-oxazolidines
Developing new synthetic methods for novel nitrogen-contain-
ing molecules is an important area of organic synthesis.1 Among
these compounds, isoindoline derivatives are of particular interest
because of their diverse biological activities and clinical applica-
tions. The core ring structure is present in many heterocycles
which have been shown to elicit a wide array of biological effects
including NMDA receptor antagonism,2a modulation of estrogen2b
and dopamine D3 and D4 receptors,2c,d inhibition of selective sero-
tonin reuptake,2e and anti-bacterial activity.2f Similarly, oxazoli-
dine moieties are present in many biologically active molecules
of pharmaceutical interest. These ring systems have been exploited
successfully in medicinally valuable compounds such as the anti-
cancer prodrugs doxazolidine, doxoform, and doxaz carbamate.3
These heterocyclic units are also useful intermediates for the syn-
thesis of polymers and agricultural chemicals.4 Several substituted
oxazolidines have been investigated extensively because of their
importance as chiral auxiliaries in the synthesis of a variety of chi-
ral compounds and as chain-protecting groups for amino alcohols.5
The vast number of transformations1–4 reported over the last few
years has led to significant interest in the chemistry of these
compounds.6
reaction of ninhydrin 1 and urea (Scheme 1).7 In continuation of
this work, and as a part of our ongoing program on ninhydrin-
based reactions for the preparation of new heterocyclic deriva-
tives,8 we focused our attention on the oxidative cleavage of the
dihydroxyindeno[1,2-d]imidazole derivatives 2 for the formation
of the corresponding heterocycles.
Initially, we found that when a mixture of lead tetraacetate and
dihydroxyindeno[1,2-d]imidazole9 (2a) in ethanol was stirred for
3 h at room temperature, a solid compound was obtained, and its
structure was characterized as 2-benzylspiro[isoindoline-1,50-oxa-
zolidine]-20,3,40-trione (4a) (Scheme 2) using spectroscopic data
and CHN analysis.
For example, the 1H NMR spectrum of 4a10 exhibited two dis-
tinct doublets at d 4.54 and d 4.75 readily recognized as arising
from two diastereotopic CH2 protons along with a singlet at d
2.54 for the NH proton. Nine aromatic H-atoms are located as mul-
tiplets in the range of d 7.28–7.89. The 1H-decoupled 13C NMR
spectrum of 4a showed 15 distinct resonances in agreement with
the proposed structure. The signals at d 44.0, d 153.3, d 167.9,
and d 169.7 correlated with the benzylic CH2 and carbonyl groups,
respectively. The spiro carbon resonated at d 95.7. The structure of
product 4a was further confirmed by mass spectrometry, which
showed a molecular ion peak at 308. Finally, the structure of the
product was determined unambiguously by an X-ray diffraction
study (Fig. 1).
Recently, we introduced a new procedure for the diastereose-
lective synthesis of highly functionalized dihydrofuran derivatives
3 by the intramolecular Wittig reaction on dihydroxyindeno[1,2-
d]imidazole 2, which was easily synthesized from the addition
Next, the solvent and temperature were investigated to find the
optimum reaction conditions. After extensive screening, we found
that the reaction proceeded best in acetic acid at room tempera-
ture. Increasing the reaction temperature not only remarkably
* Corresponding author.
E-mail addresses: mrmohamadizadeh@pgu.ac.ir, mrmohamadizadeh@gmail.
com (M.R. Mohammadizadeh).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.02.163

2468
M. R. Mohammadizadeh, N. Firoozi / Tetrahedron Letters 51 (2010) 2467–2469
RO2C
HO
CO2R
O
O
O
Ph3P
OH
NH
OH
OH
urea
RO2C
r.t., 84-94%
CO2R
O
HO
NH
H2O/THF
N
N
O
O
2
1
H
H
3
Scheme 1. Our previous work7 on the diastereoselective synthesis of highly functionalized dihydrofurans 3.
O
Table 1
One-pot synthesis of spiro[isoindoline-1,50-oxazolidine]-20,3,40-trione derivatives 4a
O
NH
Entry
Urea
Product
Yieldb (%)
O
OH
NH
HO
O
Pb(OAc)4, ethanol, r.t.
4 h, 65%
O
O
N
Ph
NH
N
H2N
N
H
Ph
O
O
O
O
5a
1
84
4a
Ph
2a
N
Ph
Scheme 2. Initial study on the oxidative cleavage of dihydroxyindeno[1,2-d]imi-
dazoles 2a.
O
4a
O
O
N
N
H
N
H
O
O
5b
2
3
4
75
73
80
N
O
4b
O
O
Ph
NH
H2N
N
H
O
O
Ph
5c
N
O
4c
O
O
NH
H2N
N
H
O
O
Figure 1. X-ray crystal structure of 4a. CCDC 753345.
5d
N
accelerated the reaction rate but also increased side reactions and
by-product formation.
O
4d
a
Furthermore, using this method, we obtained the spiroisoindo-
line-1,50-oxazolidine derivatives 4a–d which could also be pre-
pared using a one-pot procedure involving the addition of lead
tetraacetate to a mixture of ninhydrin 1 and urea 5 (Scheme 3).
Using this one-pot procedure10 the separation and purification
steps involved with dihydroxyindeno[1,2-d]imidazoles 2 were
eliminated and consequently, a considerable amount of time and
solvent were saved. Some of the spiroisoindoline-1,50-oxazolidine
derivatives 4 were efficiently prepared using this optimized one-
pot procedure and their structures were deduced from spectro-
scopic data and CHN analysis.10 The results are shown in Table 1.
All reactions were performed using 1.0 mmol of ninhydrin, 1.0 mmol of urea,
and 1.5 mmol of Pb(OAc)4 in 5 mL of acetic acid at room temperature.
b
Isolated yield.
Transannular interactions and reactions among functional
groups have already been identified when the donating and
accepting functional groups are located at suitable positions in
medium-sized (8–11-membered) ring molecules.11 Consequently,
here the formation of a benzo[e][1,3]diazocine-1,3,5,6(2H,4H)-tet-
raone intermediate 6 from the oxidative cleavage of cyclic diols 2,
involving lead tetraacetate, and its subsequent intermolecular
rearrangement to the spiroisoindoline-1,50-oxazolidines 4 is pro-
posed as a reasonable mechanism (Scheme 4).
O
O
The reaction was very sensitive to the nature of the R1 substitu-
ent; it progressed effectively when R1 was a small group such as H
or methyl (Table 1, entries 1–4), but no product was obtained with
more bulky R1 substituents such as phenyl, ethyl, and propyl, even
on heating the reaction mixture for a longer time.
In summary, we have reported a novel transformation involving
oxidative cleavage of 3a,8a-dihydroxyindeno[2,1-d]imidazole-2,8-
diones in the presence of lead(IV) acetate, which affords spiroiso-
R1
N
R1HN
O
NHR2
1.
O
OH
OH
5a-d
O
R2
N
2. Pb(OAc)4, AcOH, r.t., 3 h
O
O
4 a-d
1
Scheme 3. One-pot synthesis of spiroisoindoline-1,50-oxazolidines 4a–d.

M. R. Mohammadizadeh, N. Firoozi / Tetrahedron Letters 51 (2010) 2467–2469
2469
O
C
O
R1
N
O
O
R1
O
R1
O
O
O
N
R1
O
O
OH
N
OH
OH
HN
HN
R1
O
O
R2
Pb(OAc)4
N
HO
O
N
4
+
N
O
R2
oxidative cleavage
N
N
R2
O
O
R2
R2
O
1
5
2
6
Scheme 4. Proposed mechanism for the formation of spiro[isoindoline-1,50-oxazolidine]-20,3,40-triones 4.
indoline-1,50-oxazolidine derivatives. The combination of high
yields, short reaction times, and mild conditions makes this meth-
od highly efficient.
9. Dihydroxyindeno[1,2-d]imidazoles 2a–d were obtained quantitatively from
the reaction of ninhydrin 1 and urea derivatives 5 in water (or ethanol).
10. General procedure for the one-pot preparation of spiroisoindoline-1,50-oxazolidines
4a–d: A mixture of ninhydrin 1 (1 mmol), urea 5 (1 mmol), and ethanol (1 mL)
was stirred at room temperature for 0.5 h. Pb(OAc)4 (1.2 mmol) and acetic acid
(2 mL) were added and the mixture was stirred for 2.5 h. Products 4a–d
precipitated and were easily separated from the reaction mixture by filtration.
Pure product 4d was obtained by evaporation of the solvent at room
temperature and recrystallization of the crude product from n-hexane. 2-
Benzylspiro[isoindoline-1,50-oxazolidine]-20,3,40-trione (4a): mp 215–217 °C; IR
ꢀ
Acknowledgments
The authors thank the Research Council of the Persian Gulf Uni-
versity of Bushehr for financial support of this work. We also thank
Dr. M. Helliwell at the University of Manchester, UK for X-ray data.
(KBr):
m
3100–2924 (w), 1832 (s), 1762 (s), 1701 (s); 1H NMR (500 MHz,
CDCl3): d 2.54 (s, 1H, NH), 4.54 (d, 1H, J = 15.8 Hz, CH2), 4.75 (d, 1H, J = 15.8 Hz,
CH2), 7.28–7.32 (m, 5H, arom), 7.74–7.80 (m, 3H, arom), 7.87–7.89 (m, 1H,
arom); 13C NMR (125 MHz, CDCl3): d 44.0, 95.7, 122.3, 124.6, 128.4, 128.7,
128.9, 131.3, 132.0, 133.7, 135.5, 139.2, 153.3, 167.9, 169.7; Anal. Calcd for
C17H12N2O4: C, 66.23; H, 3.92; N, 9.09. Found: C, 66.32; H, 3.84; N, 8.95. m/z
308 (M+, 23%), 219 (38), 208 (34), 160 (73), 106 (100), 91 (96). 2,30-
Dimethylspiro[isoindoline-1,50-oxazolidine]-20,3,40-trione (4b): mp 190–191 °C;
1838 (s), 1760 (s), 1695 (s); 1H NMR (500 MHz, CDCl3): d 2.67 (s, 3H,
ꢀ
m
References and notes
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IR (KBr):
CH3), 3.18 (s, 3H, CH3), 7.33–7.36 (m, 1H, arom), 7.55–7.76 (m, 2H, arom),
7.94–8.02 (m, 1H, arom); 13C NMR (125 MHz, CDCl3): d 25.4, 26.0, 92.8, 122.8,
126.9, 128.1, 132.6, 135.8, 141.1, 155.9, 166.9, 167.4; Anal. Calcd for
C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C, 58.61; H, 4.00; N, 11.29.
m/z 246 (M+, 8%), 202 (100), 161 (27), 104 (45). 2-Phenylspiro[isoindoline-1,50-
ꢀ
m 3050–2930 (w), 1835
oxazolidine]-20,3,40-trione (4c): mp >300 °C; IR (KBr):
(s), 1760 (s), 1695 (s); 1H NMR (500 MHz, CDCl3): d 7.36–7.48 (m, 5H, arom),
7.52 (d, 1H, J = 6.6 Hz, arom), 7.70–7.75 (m, 2 H, arom), 7.99 (d, 1H, J = 6.5 Hz,
arom), 8.68 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3): d 96.7, 125.0, 125.6,
128.6, 129.5, 130.0, 131.1, 132.1, 132.7, 133.8, 137.7, 151.3, 167.0, 167.6; Anal.
Calcd for C16H10N2O4: C, 65.31; H, 3.43; N, 9.52. Found: C, 65.37 H, 3.49; N,
9.46. m/z 294 (M+, 100%), 224 (92), 179 (77), 76 (37). 2-Methylspiro[isoindoline-
ꢀ
1,50-oxazolidine]-20,3,40-trione (4d): mp >300 °C; IR (KBr):
m 3090–2935 (w),
1845 (s), 1766 (s), 1702 (s); 1H NMR (500 MHz, DMSO-d6): d 2.89 (s, 3H, CH3),
7.67–7.94 (m, 4H, arom); 13C NMR (125 MHz, DMSO-d6): d 25.2, 95.7, 124.0,
124.3, 131.4, 132.8, 134.4, 139.1, 154.5, 167.4, 170.9; Anal. Calcd for
C11H8N2O4: C, 56.90; H, 3.47; N, 12.06. Found: C, 57.05; H, 3.40; N, 12.01. m/
z 232 (M+, 63%), 162 (100), 117 (95), 104 (48), 76 (55).
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