Novel and highly efficient synthesis of 3-(alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-dione derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.11.109

The oxidation of 3a,8a-dihydroxy-2-(alkyl/benzylthio)indeno[1,2-d]imidazol-8(3H)-ones to give the corresponding 3-(alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-dione derivatives in good to excellent yields at room temperature using two oxidants, periodic acid in aqueous ethanol and lead(IV) acetate in acetic acid, has been reported.

Full text of DOI:10.1016/j.tetlet.2016.11.109

Accepted Manuscript
Novel and Highly Efficient Synthesis of 3-(Alkyl/benzylthio)-9b-hydroxy-1H-
imidazo[5,1-a]isoindole-1,5(9bH)-dione Derivatives
Azar Jamaleddini, Mohammad Reza Mohammadizadeh
PII:
S0040-4039(16)31600-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.109
TETL 48395
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 September 2016
21 November 2016
25 November 2016
Please cite this article as: Jamaleddini, A., Reza Mohammadizadeh, M., Novel and Highly Efficient Synthesis of 3-
(Alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-dione Derivatives, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.109
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Novel and Highly Efficient Synthesis of 3-(Alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-
a]isoindole-1,5(9bH)-dione Derivatives
Azar Jamaleddini,a Mohammad Reza Mohammadizadeha,*
aDepartment of Chemistry, Faculty of sciences, Persian Gulf University, Bushehr 75169, Iran
*
Corresponding author. Tel./fax: +98 77334541494. E-mail addresses: mrmohamadizadeh@pgu.ac.ir.
Abstract: The oxidation of 3a,8a-dihydroxy-2-(alkyl/benzylthio)indeno[1,2-d]imidazol-8(3H)-
ones to give the corresponding 3-(alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-
1,5(9bH)-dione derivatives in good to excellent yields at room temperature using two oxidants,
periodic acid in aqueous ethanol and lead(IV) acetate in acetic acid, has been reported.
Keywords: 3a,8a-dihydroxyindeno[1,2-d]imidazoles, 9b-hydroxy-1H-imidazo[5,1-a]isoindole-
1,5(9bH)-diones, oxidation, periodic acid, lead(IV) acetate
The imidazolyl moiety1 has a wide-range of applications as building blocks in the
development of new drugs,2 organometallic catalysis,3 coordination chemistry,4 and asymmetric
catalysis.5 Isoindole is an important heterocyclic ring system which occurs as the core structure
in a variety of naturally occurring alkaloids and synthetic compounds,6 possessing a diverse
pharmacological profile including antimicrobial,7 anthelmintic,8a-b insecticidal,8c cyclooxygenase
isoenzyme (COX-2),9a thrombin inhibition9b and anticancer activities.9c They also have broad
applications as organic light-emitting devices (OLED)10 and as key structural moieties for the
preparation of oligoacenes11a-b and porphyrins.11c-d Among the imidazole fused isoindoles, the
synthesis and biological activity of imidazo[5,1-a]isoindole derivatives are more widely
investigated. There are several reported procedures for the preparation of these compounds,
however, the majority of these methods suffer from one or more drawbacks such as the use of
structurally complex and expensive catalysts and starting materials, harsh reaction conditions,
multi-step procedures leading to low overall yields, and low chemoselectivity.12-19
Recently we reported the oxidative cleavage of a series of vicinal cyclic diols, prepared
from the addition reactions of ninhydrin with several 1,3-binucleophiles; e.g. urea,20

aminouracil,21 enol,22a and enamine22b-c derivatives, using lead(IV) acetate or periodic acid under
various conditions. In all cases the reactions progressed via eight-membered heterocyclic
intermediates containing 1-donor-5-acceptor groups, similar to that shown in Scheme 3
(intermediate E). Depending on the employed oxidant, reaction conditions, and the nature of
substituents, these intermediates were converted to spiro20-22b or fused22c N/O-containing
heterocycles.
As a part of our ongoing program on the synthesis of novel heterocycles,23 we have
investigated the synthesis and oxidation of 3a,8a-dihydroxy-2-(alkyl/benzylthio)indeno[1,2-
d]imidazol-8(3H)-ones 4. To begin, 2-(benzylthio)-3a,8a-dihydroxy-3a,8a-dihydroindeno[1,2-
d]imidazol-8(3H)-one 4a was prepared in high yield from the one-pot, two-step reaction of
thiourea and benzylchloride in EtOH, followed by the addition of ninhydrin (Scheme 1).
Addition of benzyl chloride to thiourea gave 2-benzylisothiouronium chloride 3a which was
directly subjected to the addition reaction with ninhydrin at room temperature to give 3a,8a-
1
dihydroxyindeno[1,2-d]imidazole 4a whose structure was determined by H and 13C-NMR
spectroscopy as well as mass spectrometry.
Scheme 1. One-pot synthesis of 3a,8a-dihydroxyindeno[1,2-d]imidazole 4a
Next, with the expectation of the formation of either compound 5 or 6 (Fig. 1),20-22 we
investigated the oxidative cleavage of 3a,8a-dihydroxyindeno[1,2-d]imidazole 4a using two
oxidants; lead(IV) acetate and periodic acid under different conditions.
Figure 1. Expected products20-22 from the oxidative cleavage of 3a,8a-dihydroxyindeno[1,2-
d]imidazole 4a

After extensive screening, we found that the reaction proceeded best with periodic acid in
1
aqueous EtOH at room temperature (Scheme 2). Although, the H and 13C-NMR and mass
spectrometry data of the obtained compound was initially indicative of spiro[imidazole-4,1'-
isobenzofuran] 5 (Fig. 1), to our surprise, single crystal X-ray crystallography showed that the
reaction proceeded with the formation of 3-(benzylthio)-9b-hydroxy-1H-imidazo[5,1-
a]isoindole-1,5(9bH)-dione 7a (Fig. 2).
Scheme 2. Preparation of 3-(benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-
dione 7a
The 1H NMR spectrum of 7a exhibited an AB-quartet pattern at δ 4.60 arising from two
diastereotopic CH2 protons as well as a broad singlet at δ 8.15 for the OH proton. Nine aromatic
1
13
H-atoms were observed as multiplets in the range of δ 7.20–8.05. The H-decoupled C NMR
spectrum of 7a showed 15 distinct resonances which were in agreement with the proposed
structure. The signals at δ 36.1, δ 166.1, δ 180.9 and δ 185.1 correlated with the benzylic CH2
functional group, the S-Bz substituted carbon of the imidazole moiety and the carbonyl groups,
respectively. The quaternary carbon connected to the hydroxyl group resonated at δ 90.6. The
structure of product 7a was further confirmed by mass spectrometry, which showed a molecular
ion peak at 324.

Figure 2. Single crystal X-ray structure of 7a (CCDC 1506317).
In order to evaluate the feasibility of this new strategy for the synthesis of 3-
(alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-dione
derivatives
7,
various thioalkyl and thioaryl substituted 3a,8a-dihydroxyindeno[1,2-d]imidazoles 4 were
subjected to the oxidation reaction with periodic acid in aqueous EtOH at room temperature. All
reactions were complete in less than 20 minutes and the precipitated products 7 were purified by
recrystallization from EtOH or column chromatography (Table 1).
Table 1. Synthesis of 3-(alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-
diones 7a-p from the oxidation of 3a,8a-dihydroxyindeno[1,2-d]imidazole derivatives 4a-p

Entry
1
Product (7)
Yielda
Yieldb
Entry
9
Product (7)
Yielda Yieldb
92
93
85
95
85
90
95
90
90
84
2
3
10
11
88
90
90
85
83
91
98
77
86
80
4
5
12
13
96
90
85
93
90
80
83
77
6
7
14
15

93
81
80
89
8
16
b
aIsolated yield using the H5IO6/H2O/EtOH system; Isolated yield using the Pb(OAc)4/AcOH
system
As shown in Table 1, the procedure worked well for both alkyl and benzyl substituted
diols 4. The oxidation reaction of diols 4a-p proceeded rapidly, however, the benzyl substituted
products 7a-l were more conveniently precipitated from the reaction mixture. Therefore, benzyl
substituted products 7a-l were obtained in relatively higher yields than the corresponding alkyl
substituted products 7m-p.
Notably, the oxidation of 3a,8a-dihydroxyindeno[1,2-d]imidazole derivatives 4a-p with
lead(IV) acetate in acetic acid at room temperature also progressed efficiently to give the
corresponding 9b-hydroxy-1H-imidazo[5,1-a]isoindole-1,5(9bH)-diones 7a-p in good to
excellent yields. Although, from an eco-friendly point of view, the aqueous periodic acid system
is preferred.
A proposed mechanism is shown in Scheme 3. Benzo[e][1,3]diazocine-1,5,6(2H)-trione
E resulting from the oxidation of diols 4 with periodic acid or lead(IV) acetate proceeds via
intermediates C and D, respectively. Due to the suitable positioning of electron-donating (N-2)
and electron-withdrawing (C-6) atoms, strong transannular interactions between N-2 and C-6 are
predominant in benzodiazocine cycle E. Unlike our previous studies20-23,25 where this type of
transannular interaction caused ring cleavage at the C(1)-N(2) bond, in the case of
benzodiazocine E, this interaction led to cyclization.

Scheme 3. Proposed mechanism for the preparation of imidazo[5,1-a]isoindoles 7 via oxidation
of dihydroxyindenoimidazolones 4
In summary we have studied the oxidation of dihydroxyindeno[1,2-d]imidazolones using
periodic acid in aqueous ethanol and lead(IV) acetate in acetic acid. Using these oxidation
systems we have introduced two highly efficient procedures for the synthesis of 9b-hydroxy-1H-
imidazo[5,1-a]isoindole-1,5(9bH)-dione derivatives.
Acknowledgements
The authors thank the Research Council of the Persian Gulf University of Bushehr for financial
support of this work.
References and notes
1.
(a) Xi, N.; Huang, Q.; Liu, L. in: Comprehensive heterocyclic chemistry III, Vol. 4,
(Eds.: Katrirzky, A. R.; Rees, C. W.), Elsevier, Amsterdam 2008, pp 143–364. (b)
Revuelta, J.; Machetti, F.; Cicchi, S. in: Modern heterocyclic chemistry, Vol. 2, (Eds.:
ßlvarez-Builla, J.; Vaquero, J. J.; Barluenga, J.), Wiley-VCH, Weinheim, 2011, pp 809–
923.
2.
(a) Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409. (b) Lipshutz, B. H.
Chem. Rev. 1986, 86, 795.
3.
4.
5.
6.
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
Nieto, I.; Cervantes-Lee, F.; Smith, J. M. Chem. Commun. 2005, 3811.
Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619.
(a) Speck, K.; Magauer, T. Beilstein J. Org. Chem. 2013, 9, 2048. (b) Sović, I.;
Karminski-Zamola, G. Chem. Ind.: J. Chemists Chem. Engin. 2014, 63, 173. (c)
Heugebaert, T. S. A.; Romana, B. I.; Stevens, C. V. Chem. Soc. Rev. 2012, 41, 5626. (d)
Meng, X.-B.; Han, D.; Zhang, S.-N.; Guo, W.; Cui, J.-R.; Li, Z.-J. Carbohydr. Res. 2007,
342, 1169.

7.
8.
9.
(a) El-Gohary, N.; Shaaban, M. I. Arch. Pharm. Chem. Life Sci. 2015, 348, 666. (b) El-
Tamany, El-S. H.; Sowellim, S. Z.; Hamed, A. A.; Radwan, A. S. Res. Chem. Intermed.
2015, 41, 2675.
(a) Sena, V. L. M.; Srivastava, R. M.; Silva, R. O.; Lima, V. L. M. Farmaco 2003, 58,
1283. (b) Bamnela, R.; Shrivastava, S. P. Indian J. Chem. 2014, 53B, 1128. (c) Hall, I.
H.; Voorstad, P. J.; Chapman, J. M.; Cocolas, G. H. J. Pharm. Sci. 1983, 72, 845.
(a) Portevin, B.; Tordjman, C.; Pastoureau, P.; Bonnet, J.; Nanteuil G. D. J. Med. Chem.
2000, 43, 4582. (b) Masic, L. P.; Mlinsek, G.; Solmajer, T.; Bakija, A. T.; Stegnard, M.;
Kikelj, D. Bioorg. Med. Chem. Lett. 2003, 13, 789. (c) Kashinath, K.; Jadhava, P. D.;
Reddy, D. S. Org. Biomol. Chem. 2014, 12, 4098. (d) Pongprom, N.; Bachitsch, H.;
Bauchinger, A.; Ettefagh, H.; Haider, T.; Hofer, M.; Knafl, H.; Slanz , R.; Waismeyer,
M.; Wieser, F.; Spreitzer, H. Monatshefte Chemie Chem. Month. 2010, 14, 53.
(a) Gauvina, S.; Santerrea, F.; Dodeleta, J. P.; Dingb, Y.; Hlilb, A. R.; Hayb, A. S.;
Andersonc, J.; Armstrongc, N. R.; Gorjancd, T. C.; D'Ioriod, M. Thin Solid Films 1999,
353, 218. (b) Mi, B.-X.; Wang, P.-F.; Liu, M.-W.; Kwong, H.-L.; Wong, N.-B.; Lee, C.-
S.; Lee, S.-T. Chem. Mater. 2003, 15, 3148.
10.
11.
(a) Chen, Y.-L.; Lee, M. H.; Wong, W.-Y.; Lee, A. W. M. Synlett 2006, 2510. (b) Chen,
Z.; Müller, P.; Swager, T. M. Org. Lett. 2006, 8, 273. (c) Ito, S.; Murashima, T.; Uno, H.;
Ono, N. Chem. Commun. 1998, 1661. (d) Ito, S.; Ochi, N.; Uno, H.; Murashima, T.; Ono,
N. Chem. Commun. 2000, 893.
12.
13.
14.
Xu, X.; Zhao, L.; Li, Y.; Soul, J.-F.; Doucet, H. Adv. Synth. Catal. 2015, 357, 2869.
Hosseinkhani, B.; Islami, M. R.; Hosseinkhani, S. Synlett 2015, 26, 2277.
(a) Yasmin, N.; Ray, J. K. Synlett 2010, 924. (b)Csende, F.; Miklós, F.; Stájer, G. Current
Org. Chem. 2012, 16, 1005.
15.
16.
17.
18.
19.
20.
21.
Laha, J K.; Dayal, N.; Singh, S.; Bhimpuria, R. Eur. J. Org. Chem. 2014, 5469.
Byun, Y.-S.; Jung, C.-H.; Park, Y.-T. J. Heterocyclic Chem. 1995, 32, 1835.
Das, S.; Fro1hlich, R.; Pramanik, A. Org. Lett. 2006, 8, 4263.
Aldabbagh, F.; Clyne, M. A. Lett. Org. Chem. 2006, 3, 510.
Arai, N.; Takahashi, M.; Mitani, M.; Mori, A. Synlett 2006, 3170.
Mohammadizadeh, M. R.; Firoozi, N.; Tetrahedron Lett. 2010, 51, 2467.
Mohammadizadeh, M. R.; Bahramzadeh, M.; Taghavi, S. Z.; Tetrahedron Lett. 2010, 51,
5807.
22.
(a) Mohammadizadeh, M. R.; Saberi, D.; Taghavi, S. Z. Tetrahedron Lett. 2016, 57, 264.
(b) Mahdavinia, G. H.; Mohammadizadeh, M. R.; Ariapour, N.; Alborz, M. Tetrahedron
Lett. 2014, 55, 1967. (c) Mohammadizadeh, M. R.; Firoozi, N.; Aradeh, R. Helv. Chim.
Acta 2011, 94, 410.
23.
24.
25.
Saberi, D.; Mohammadizadeh, M. R.; Esmaeili, R. Helv. Chim. Acta 2015, 98, 1411.
Qiu, K.; Wang, R. Synthesis 2015, 47, 3186.
Mohammadizadeh, M. R.; Basti, F. J. Iran. Chem. Soc. 2015, 12, 1171.

Novel and Highly Efficient Synthesis of 3-(Alkyl/benzylthio)-9b-hydroxy-1H-imidazo[5,1-
a]isoindole-1,5(9bH)-dione Derivatives
Azar Jamaleddini, Mohammad Reza Mohammadizadeh*
Department of Chemistry, Faculty of sciences, Persian Gulf University, Bushehr 75169, Iran
*Corresponding author. Tel./fax: +98 77334541494; mrmohamadizadeh@pgu.ac.ir.

*Simple method for the synthesis of structurally complex compounds
*Procedures are fast and highly efficient
*The starting materials are simple and commercially available