PhIO as a powerful cyclizing reagent: Regiospeciflc [3+2]-tandem oxidative cyclization of imine toward cofacially self-aggregated low molecular mass organic materials

Article abstract of DOI:10.1021/jo8028136

The powerful cyclization and tandem oxidation property of environmentally benign PhIO is developed for the first time, which leads to regiospecific [3+2]-tandem oxidative cyclization of imine at room temperature in rapid access to a new class of compounds

Full text of DOI:10.1021/jo8028136

access to a new class of desired compounds using simple starting
material under metal-free conditions is one of the paramount
challenges in modern organic synthesis. Application of the TOC
reaction in the synthesis of low molecular mass self-aggregated
organic materials (LMSOM) is interesting in the context of
achieving the target as they have attracted growing attention in
the emerging fields of nanoscience and nanotechnology, mainly
due to their promising applications in optical and optoelectronic
nanodevices including semiconductors, fluorescence sensing
abilities, and light emitting diodes.2,3 Another important goal
of achieving the target molecule by the TOC reaction is to
address some aspects of modern criteria of synthetic efficiency4
like regioselectivity, energy, time and atom economy, and use
of nonconventional reaction media and environmentally benign
reagent to reduce impact on the environment and hazards.
Polyvalent organo iodine compounds have found immense
applications as environmentally benign, chemoselective, and
smart oxidizing agents in synthetic chemistry.5-10 Iodosoben-
zene (PhIO) has emerged as the most important family member
because of its wide synthetic application as a starting material
in the preparation of numerous iodine(III) compounds5 and also
as an oxygen donor in metal-catalyzed asymmetric epoxidation
and other oxidation reactions.6 Evolution of its oxidizing
property is not that much investigated compared to the other
hypervalent organoiodanes.5 It is believed that due to poor
solubility of polymerized iodosobenzene [(PhIO)n] in organic
PhIO as a Powerful Cyclizing Reagent:
Regiospecific [3+2]-Tandem Oxidative
Cyclization of Imine toward Cofacially
Self-Aggregated Low Molecular Mass Organic
Materials
Palash Pandit, Nirbhik Chatterjee, Samiran Halder,
Sandip K. Hota, Amarendra Patra, and Dilip K. Maiti*
Department of Chemistry, UniVersity Colleges of Science
and Technology, UniVersity of Calcutta, 92, A. P. C. Road,
Kolkata-700009, India
maitidk@yahoo.com
ReceiVed December 26, 2008
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S. Langmuir 2008, 24, 2671–2679. (c) Ajayaghosh, A.; Praveen, V. K.;
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The powerful cyclization and tandem oxidation property of
environmentally benign PhIO is developed for the first time,
which leads to regiospecific [3+2]-tandem oxidative cy-
clization of imine at room temperature in rapid access to a
new class of compounds, 1,2-functionalized 4,5-diarylimi-
dazoles, in excellent yield with synthetic efficiency. Size,
shape, and activity of the involved nanoreactors for the green
approach built up from various surfactants are investigated.
Spontaneous generation of low molecular mass self-ag-
gregated organic materials, their cofacial one-dimensional
packing, and interesting photophysical properties are reported.
(8) (a) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y. Tetrahedron Lett.
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Org. Chem. 2008, 73, 7775–7778.
Tandem oxidative cyclization (TOC) reaction is one of the
fundamental organic transformations, and this versatile and
powerful synthetic tool is capable of synthesizing complex
biomolecules and natural products in one step.1 However, most
of the TOC reactions are investigated by using metal catalysts
to maximize the regioselection. Development of the TOC
property of an environmentally benign reagent for easy and rapid
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Soc. 2006, 128, 13704–13705. (b) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-
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M. R. J. Am. Chem. Soc. 2007, 129, 11880–11881.
10.1021/jo8028136 CCC: $40.75
Published on Web 02/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2581–2584 2581

TABLE 1. Studies of TOC Reaction in Aqueous and Organic
Media
reaction
dimension of the reaction conversion
entry media
surfactant
nanoreactor (nm) time (h)
(%)
1
2
3
4
5
6
7
CH2Cl2 no surfactant N/A
CH3CN no surfactant N/A
4
3
3
100
100
100
100
80
water
water
water
water
water
CTAB
SDS
290 (250-320)
380 (200-600)
580 (490-700)
460 (400-600)
5
tween 20
tween 80
triton CF-10 510 and 1110
20
20
48
100
20
SCHEME 1. Regiospecific [3+2]-Tandem Oxidative
Cyclization of Imine by PhIO
FIGURE 1. Optical microscope image of the nanoreactor formed by
aqueous surfactant.
solvent it is less reactive and thus activation is required to
generate the actual oxidizing monomeric species in solution.5b
Oxidation reactions of iodosobenzene have been carried out in
the presence of Lewis acids,7 catalysts,8 and transition metal
complexes5 and also with its ortho carboxylic acid derivatives.9
Only a few reactions like epoxidation of ketene,10a oxidative
decarboxylation,10b and oxidation of amine10c and alkene10d are
reported with PhIO alone as an oxidant. Recently, we have
reported the chemoselective oxidizing property of PhIO to
generate nitrile oxides from aldoximes.10e In this Note, we report
for the first time excellent [3+2]-cyclization and tandem
oxidation property of PhIO. It has transformed imines (1) in
common organic solvent and in neutral aqueous media (Table
1) at room temperature in rapid access to designed compounds,
1,2-functionalized-4,5-diaryl-imidazoles (2, Scheme 1), with
complete regiospecificity which have expectantly shown inter-
esting self-assemble and photophysical properties suitable for
designing fluorescent biosensor and optoelectronic nanodevices.2
The concept of green chemistry and its application in organic
synthesis has emerged as a major solution for the development
of cleaner and more benign chemical processes.11 Initially, we
have studied the TOC in common organic solvents (entries 1
and 2, Table 1) and the progress of the reaction is very fast
(3-4 h) with complete dissolution of PhIO. We are very keen
to develop a complete green [3+2]-TOC reaction using the
environmentally benign reagent PhIO and water as reaction
medium. After extensive studies this reaction is developed in
aqueous media by making a confined reactor12 built up from
molecular assemblies of cationic (CTAB), anionic (SDS), and
neutral amphiphilic surfactants (Table 1). The shape of the
nanoreactors is nearly spherical as is observed with an optical
microscope (Figure 1) with use of its thin film. We have
FIGURE 2. DLS size distribution data of the spherical nanoreactors
formed by aqueous SDS.
measured their dimension (290-1110 nm) by dynamic light
scattering (Figure 2 and Supporting Information). They are
sufficiently hydrophobic in nature to solubilize the organic
compounds like imine (1) and PhIO into their hydrophobic cores
and protect water labile substances from decomposition. Our
studies reveal that the reaction rate depends on the size and
population of the nanoreactors. The dimensions of the nanore-
actors formed by CTAB and SDS are optimum (300-400 nm)
for their efficiency (entries 3 and 4). However, they are very
large (350-1240 nm) and too small (ca. 10 nm) made by neutral
surfactants (entries 5-7) and thus are not effective. Kita and
co-workers have studied sulfide oxidation by PhIO8a and PhIO28b
under miceller and reverse miceller environment and found
quaternary ammonium salts as indispensable in solubilization
and activation of the hyperiodanes. They have considered
surfactants as catalysts enhancing the chemical and optical yield
of the reactions. However, our investigation with DLS and an
optical microscope has confirmed that the role of the surfactant
is not as catalyst but forming nanometer micelles (nanoreactor)
to perform the organic transformation with comparable reaction
rate studied in organic media (Table 1).
Imidazoles are ubiquitous motifs in pharmaceuticals as well
as in important natural products.13 New and straightforward
methods to access these substrates are thus highly desirable.
There are numerous accounts in the literature on the synthesis
of imidazoles mainly by using acid- and metal-catalyzed
reactions.13a Synthesis of 4,5-diarylimidazoles is not much
investigated13b although their analogues have been identified
as potential candidates for antibacterial, antirheumatoid arthritis,
anti-inflammatory, and other bioactivities.13b,c This green ap-
proach is highly efficient in synthesizing a variety of imidazoles
(Table 2) containing functional groups and a heteroatomic and
(11) (a) Anastas, P. T.; Heine, L. G.; Willimson, T. C. Green Chemical
Syntheses and Processes; Oxford University Press: New York, 2000. (b)
Lancaster, M. Handbook of Green Chemistry and Technology; Clark, J. H.,
Macquarrie, D. J., Eds.; Blackwell Publishing: Abingdon, UK, 2002. (c) Horvath,
I. T. Chem. ReV. 1995, 95, 1. (d) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem.
Res. 2002, 35, 686–694.
(12) (a) Chatterjee, A.; Maiti, D. K.; Bhattacharya, P. K. Org. Lett. 2003, 5,
3967–3969. (b) Li, C.-J. Chem. ReV. 2005, 105, 3095–3165. (c) Vriezema, D. M.;
Argones, M. C.; Elemans, J. A. A. W.; Cornelissen, J. J. L. M.; Rowan, A. E.;
Nolte, R. J. M. Chem. ReV. 2005, 105, 1445–1489. (d) Dallinger, D.; Kappe,
C. O. Chem. ReV. 2007, 107, 2563–2591.
(13) (a) Grimmet, M. R. ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., ; Rees, C., ; Scriven, E. F. V., Eds.; Pergamon Press: Elmsford, NY,
1996; Vol. 3. (b) Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski,
E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843–846. (c) Luca, L. D. Curr. Med.
Chem 2006, 13, 1–23.
2582 J. Org. Chem. Vol. 74, No. 6, 2009

TABLE 2. Regiospecific [3+2]-TOC Reaction of Imine by PhIO
SCHEME 3. Studies of the Reaction Path for the TOC
Reaction
entry imine
R1
R
time (h) product yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-methoxyphenyl
4-nitrophenyl
3-nitrophenyl
4-bromophenyl
4-methoxyphenyl
4-chlorophenyl
2-allyloxyphenyl
4-cyanophenyl
2-furyl
Et
Et
Et
3.0
4.0
4.0
5.0
5.0
4.0
3.5
6.0
5.0
6.0
7.0
5.0
5.0
2a
2b
2c
2d
2e
2f
2g
2h
2i
72
80
82
75
80
70
81
77
68
67
80
82
79
Et
nBu
Et
Et
tBu
Et
1j
1k
1l
3-pyridyl
2-quinyl
2-methoxyphenyl
Et
2j
2k
2l
Et
tBu
1m 3,4-dichlorophenyl Me
2m
SCHEME 2. Proposed Path for the TOC Reaction That
Occurred Inside the Surfactant Assembled Nanoreactor
organic nanomaterials.2,3 In this regard, the generation of the
submicrotube from 2,4,5-triphenylimidazole by the reprecepi-
tation method under heating and sonication is important.3a In a
bid to our continuous effort to design and synthesize new
heterocycles and to study their self-assembly properties,2a we
report herein a new class of LMSOM from 2c, 2f, and 2m (Table
2) which are easily accessible by the one-step green synthesis
protocol. Elegant approaches have been devised to achieve the
self-assembled nanostructured materials.3 However, these small
organic molecules spontaneously form tunable nanomaterials
in common organic solvents (Supporting Information). To gain
insight into the aggregation morphology of the nanomaterials
formed by compound 2c, two different solvents have been
subjected to SEM. In ether medium it forms organic material
of spherical dimension with a coral-like well-defined shape
constructed by highly self-aggregated linear nanofibers about
200 nm in width (panel a, Figure 3) whereas a flat sheet-like
nanomaterial is obtained in ethyl acetate at about 250 nm in
width (Supporting Information). Spontaneous self-aggregated
nanobelts (panel b, Figure 3), nanorods, and spiral fibrils
(Supporting Information) are generated by compound 2f, and
also stack nicely (panel c, Figure 3) by compound 2m in
different solvents. The large red shift in UV measured in the
self-aggregated solid state compared to their dilute solutions
(panel d, Figure 3) is probably due to their unidirectional π-π
stacking. Unusual fluorescent amplification is also observed from
dilute solution to its higher concentration (Supporting Informa-
tion) and it becomes extremely large in the solid state (panel e,
Figure 3). These 1D LMSOM (panel f, Figure 3) with strong
photophysical properties are important in the generation of
biosensor14 and optoelectronic nanodevices of higher sensitivity.2,3
In conclusion, we have for the first time demonstrated the
powerful [3+2]-cyclization and tandem oxidation property of
the environmentally benign reagent PhIO leading to regiospecific
TOC of imines with synthetic efficiency. The nanoreactors
formed by various surfactants in aqueous media were studied
by DLS and optical micrography. CTAB and SDS are found to
be efficient for the TOC reaction. Using this robust green
substituted aromatic nucleus essential for favorable binding
interactions with the receptors to achieve the desired biological
activities.13c
The proposed path of the TOC of imines to the corresponding
imidazoles by PhIO is shown inside the nanoreactor (Scheme
2). The nitrogen atoms of two imines are captured by PhIO to
form cyclized intermediate 2C and followed by loss of PhI
generating the oxidative cyclized intermediate 2F. Oxidative
dehydrogenation by PhIO in the final step leads to generation
of 2. We have successfully trapped the intermediate 2F
supporting the proposed path. We have investigated whether
the regiospecific formation of imidazoles (2) has progressed
through dimerization of possible nitrile ylides which may be
generated by the oxidant PhIO.10e Failure in both the attempts
for intermolecular (4, i) and intramolecular (5, ii) 1,3-DC
reactions with olefins proves that the reactions follow solely
path b toward 2 due to the strong cyclization property of the
oxidant PhIO (Scheme 3). The [3+2]-tandem oxidative cycliza-
tion ability of PhIO is so powerful that the two sterically
hindered aromatic groups have been placed side-by-side (2)
without generation of the other regioisomer (3, Scheme 1).
Design and easy access to LMSOM is now a new challenge
in organic synthesis wherein macrocyclic compounds or opti-
cally insensitive alkyl chains/steroidal groups substituted com-
pounds have usually been utilized for the fabrication of 1D
(14) (a) Toutchkine, A.; Kraynov, V.; Hahn, K. J. Am. Chem. Soc. 2003,
125, 4132–4145. (b) Camacho, C.; Matias, J. C.; Cao, R.; Matos, M.; Chico, B.;
Hernandez, J.; Longo, M. A.; Sanroman, M. A.; Villalonga, R. Langmuir 2008,
24, 7654–7657.
J. Org. Chem. Vol. 74, No. 6, 2009 2583

build up the nanoreactor in aqueous media. PhIO (500 mg, 2.25
mmol) was added, and the content was allowed to attain room
temperature. The reaction was complete after 3-7 h. The postre-
action mixture was extracted with ethyl acetate (3 × 10 mL), and
the combined organic portion was washed with a brine solution (2
× 10 mL), dried on activated sodium sulfate, and concentrated in
a rotary evaporator under reduced pressure at room temperature.
The crude product was chromatographed on silica gel (60-120
mesh) and eluted with ethyl acetate-petroleum ether. Thus, the
reaction with [(4-bromobenzylidene)amino]acetic acid ethyl ester
(1d, 270 mg, 1.0 mmol) using CTAB (120 mg, 0.33 mmol) afforded
1-ethoxycarbonylmethyl-4,5-bis(4-bromophenyl)-1H-imidazole-2-
carboxylic acid ethyl ester (2d) after processing in an isolated yield
of 75% (400 mg, 0.75 mmol). Compound 2d and others (2a-m)
were characterized by 1H and 13C NMR (NDC and DEPT), FT-IR,
and mass (EI-MS and HR-MS) spectral analysis. The structure is
established by 2D NMR spectra.
Compound 2d: yellow semisolid; 1H NMR (300 MHz, CDCl3)
δ 1.10 (3H, t, J ) 7.2 Hz), 1.18 (3H, t, J ) 7.2 Hz), 4.07 (2H, q,
J ) 6.9 Hz), 4.20 (2H, q, J ) 7.2 Hz), 4.37 (2H, s), 7.22 (2H, s),
7.43 (2H, d, J ) 7.5 Hz), 7.55 (4H, d, J ) 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 13.9, 14.1, 46.8, 60.6, 62.3, 124.2, 124.5, 126.9,
127.6, 128.1, 128.5, 130.1, 130.8, 131.7, 132.0, 138.6, 147.8, 162.5,
167.4; EI-MS (m/z) 534 (M+), 504, 440, 404, 365; IR (neat, cm-1
)
1199, 1378, 1474, 1723, 2377, 2926; HR-MS (m/z) for
C22H21Br2N2O4 (M + H) calcd 536.9848, found 536.9895 (highest
ion peak).
Acknowledgement. We acknowledge the financial support
of this work by the DST (SR/S1/OC-22/2006), India and Center
for Research in Nanoscience and Nanotechnology, C.U. We
thank Prof. Anjan Dasgupta, Prof. Arup Mukherjee, and Dr.
Prabir K. Maiti of C.U. for providing optical microscope, mass
spectrometry, and SEM (TEQIP) instrumental facilities. N.C.
and S.H. thank CSIR, and P.P. thanks UGC, India for research
fellowships. We also thank P. Ghosh, S. Chatterjee, and S.
Bhowmik for running spectra of our samples.
FIGURE 3. Cofacially self-aggregated one dimensional organic na-
nomaterials and their photophysical properties.
protocol we have synthesized three UV and fluorescence active
LMSOM forming tunable cofacial 1D stacking suitable for
designing biosensor and optoelectronic nanodevices. Extension
of this strategy toward new heterocycles, novel LMSOM and
their application as biosensor and nanodevices, and DFT
calculations for geometry optimization and self-assembly is in
progress.
Supporting Information Available: General methods, ex-
perimental procedures, imaging pictures, elucidation of structure
by 2D NMR, spectroscopic data, and spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experimental Section
General Procedure for the TOC Reaction. A mixture of imine
1 (1.0 mmol), surfactant (0.33 mmol), and water (15 mL) in a round-
bottomed flask (25 mL) was stirred at 10-15 °C for 15 min to
JO8028136
2584 J. Org. Chem. Vol. 74, No. 6, 2009