Ionic liquid supported synthesis of tricyclic pyrimido
[1,2-
a]benzimidazoles by a telescoped Michael/hetero
annulation strategy
†
Manikandan Selvaraju, Wei-Shuen Shiu, Manohar V. Kulkarni and Chung-Ming Sun* A telescoped sequence involves the reaction of cationic imidazolium attached 2-aminobenzimidazoles with in situ generated 1,1-dicyano-2-aryl ethylenes was explored for the regioselective synthesis of pyrimido[1,2-a]benzimidazoles. The perceived regioselectivity was presumed in terms of preferential Michael addition of 2-aminobenzimidazole followed by intramolecular annulation to the exclusive formation of 4-iminopyrimidines on an ionic liquid support. A plausible mechanistic pathway for their selective formation is discussed and fully supported by X-ray analysis. The present strategy reveals both the amine function and the ring nitrogen in substituted 2-aminobenzimidazoles are active sites for nucleophilic attack ona,b-unsaturated nitriles.
Introduction
Construction of ve/six membered nitrogen heterocycles generally requires a functionalized N–C–N moiety and 2-amino nitrogen heterocycles which are the common building blocks for this purpose. Tautomerism and competing nucleophilicities are oen found in 2-amino nitrogen heterocycle systems and presents challenging problems, especially when both of the nitrogens are able to react witha,b-unsaturated compounds. In particular, substituted 2-aminobenzimidazoles possess the hitherto structural features and reactivity proles to build up a fused pyrimidine ring.1 Pyrimido[1,2-a]benzimidazole is
non-naturally occurring nitrogen heterocycles embedded with guanidine unit in the fused tricyclic system. These are synthe-sized by the reaction of 2-aminobenzimidazoles by a variety of reagents with a three carbon fragment, which can act as a double electrophile.2 The active methylene derivative is
considered as an important intermediate for the synthesis of various heterocycles due to the presence of both nucleophilic and electrophilic sites.3 Analogs of this tricyclic system were
synthesized by three component coupling under microwave irradiation and by using thiamine hydrochloride as a catalyst in aqueous conditions.4–7Attempts have been made in recent years
to address the problem of discrimination of two regioisomeric products in the reactions of 2-aminobenzimidazoles, the origin which lies in the competing nucleophilicities of the 2-amino
group and the ring nitrogen.7 The variation on the active
methylene component with ketoesters in ionic liquid medium has been reported and Sheibani et al. demonstrated the multi-component reaction of 2-aminobenzimidazole with ethyl-a-cyanocinnamoates in the presence of various base catalyst and the outcome of the product is differ from the present endeavor.8,9
These tricyclic compounds have been employed as imaging agents for detecting neurological disorders because of their unique binding ability to tau-proteins and b-amyloid peptides.10Introduction of an amino group on the
benzimid-azole ring has resulted in molecules to act as VR1 type capsaicin receptor ligands.11 Bi-functional pyrimidines and
pyrimidobenzimidazoles with ortho-amino and cyano groups have found their ability to act as anti-inammatory and anthelmintic agents respectively12,13(Fig. 1).
In recent years, multicomponent reactions (MCR) based on telescoped/tandem procedures where the reagents added one at a time and without work up have proven to be a valuable and rapid approach in drug discovery and natural product synthesis.14 Currently ionic liquids advanced as a soluble
support and attracted considerable interest owing to their homogeneous reaction medium, simple and convenient work up protocol and conventional spectroscopic monitoring
Fig. 1 Structurally related biologically active pyrimidobenzimidazoles. Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10,
Taiwan. E-mail: [email protected]
† Electronic supplementary information (ESI) available: Spectroscopic data (1H, 13C NMR, LRMS, HRMS, FT-IR) of essential intermediates, compounds 5 and
X-ray data of compound 5i. CCDC 936241. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra42658k
Cite this: RSC Adv., 2013, 3, 22314
Received 30th May 2013 Accepted 6th September 2013 DOI: 10.1039/c3ra42658k www.rsc.org/advances
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Published on 04 October 2013. Downloaded by National Chiao Tung University on 28/04/2014 01:49:06.
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reaction progress.15 Application of microwave (MW) as an
energy source in coupled with ionic liquid support greatly diminishes the in-pot reaction time and thus accelerates the reaction rates.16We have developed MW assisted soluble PEG
supported synthesis of 2-amino bis-benzimidazoles because of their potential binding property with DNA minor groove.17,18
Recently we reported a novel in situ 1,3-sigmatropic rearrange-ment of Povarov reaction by PEG supported 2-amino-benzimidazoles under MW irradiation leading to the formation of 4,10-dihydropyrimido[1,2-a]benzimidazoles and also the application of ionic liquid as a soluble support in designing new green chemistry route to privilegedb-carboline structures.19,20
The present paper employs n-hydroxyethylmethylimidazolium uoroborate as an ionic liquid support to explore an unique regioselective, telescoped route for the multicomponent synthesis of pyrimido[1,2-a]benzimidazoles.
Results and discussion
Methylhydroxyethyl imidazolium uoroborate (IL) readily prepared from 1-methylimidazole and 2-bromoethanol was chosen as the suitable ionic liquid support for the present investigation. The rst part of the synthetic sequence is the preparation of ionic liquid conjugated 2-aminobenzimidazoles which commenced with the formation of an ionic liquid–ester conjugate with 3-nitro-4-uorobenzoic acid which was able to directly monitor the reaction progress by proton NMR. The parent IL exhibited–OCH2protons at 4.25 ppm which
under-went a downeld shi to 4.85 ppm. Subsequent steps involved an ipso-uoro displacement by various primary amines, fol-lowed by neutral reduction of nitro group. The ring closure to
1-substituted 2-aminobenzimidazoles 1 was accomplished by cyanogen bromide as a source of one carbon and a masked amino function by [4 + 1] approach (Scheme 1). Construction of pyrimidine required a three carbon electrophile and a,b-unsaturated nitriles were thought to be ideal for this step in view of their dual roles as double electrophiles and a masked imino functional groups. We investigated the three component reaction of 2-aminobenzimidazole–IL conjugates 1 with malo-nonitrile 2 and benzaldehyde 3 with a variety of different solvents, bases and the temperature. Subsequently, the ideal reaction condition was optimized with piperidine as a base catalyst in reuxing isopropanol for 48 h. To further improve the synthetic efficiency, we took advantage of ionic liquid support for its good microwave absorption by their highly polar, ionic nature and the reaction was completed in 20 min under microwave irradiation. The synergic coupled microwave and ionic liquid support drastically reduced the in-pot reaction time from 48 h under conventional reux conditions to 20 min. The tolerance of different functionalities such as ester, nitro and uoro under this harsh condition provides a wide scope to decorate the target molecule with various substituent groups.
Irrespective of the electronic nature of the substituents, all the reactions were occurred very fast within 20 minutes followed by the exclusion of water molecule as the sole by-product. Detachment of the ionic liquid support was accomplished by treating the IL-conjugates 4 with sodium methoxide in meth-anol for 12 h at room temperature. Release of the desired compounds 5 from the support was conrmed by TLC moni-toring of the reaction (Table 1).
It is noteworthy to mention that all the crude products aer the cleavage are subjected to HPLC analysis and shows the
Scheme 1 Ionic liquid supported synthesis of pyrimidobenzimidazoles.
crude purity around 67–96% which enables the atom economic and synthetic efficiency of the developed protocol. The infrared spectra of target compounds 5 shows bands around 1715, 2200 and 3300 cm1indicating the presence of ester, carbonyl and nitrile and NH groups. A signicant feature of the1H-NMR of all
the compounds is the appearance of a downeld doublet around 9.5 ppm of H2(Jmeta¼ 1–2 Hz with H6). The downeld
shi is due to the presence of azomethine group, and it is possible that H2is located inside the de-shielding zone of the
C]N p bond. This observation is highly supportive of the structure 5. The other possible isomeric structure 6 arising from the Michael addition by the ring nitrogen was not observed in
the present work. However, such isomeric compounds have both been reported in the literature as mixture of products.7It is
likely that the N-alkylation (R1) probably enhances the
nucleo-philicity of the 2-amino group, which forms the basis for the observed regioselectivity and exclusive formation of the 4-iminopyrimidine tautomer. Role of imino tautomer is also proposed in the biochemical mechanistic pathways of thiamine and its T-like structure in the understanding Hoogsteen pair-ings and stacking interactions in DNA pyrimidine bases.21–23On
the basis of the above observations, the possible mechanism for the formation of compounds 5 is proposed in Scheme 2. The malononitrile and the aldehyde arerst condensed to generate
Table 1 Synthesis of 4,10-dihydropyrimido[1,2-a]benzimidazoles 5
Entry R1NH2 R2CHO Puritya(%) Yieldb(%) Entry R1NH2 R2CHO Puritya(%) Yieldb(%)
5a 93 89 5k 86 73 5b 78 88 5l 90 74 5c 89 85 5m 85 78 5d 96 81 5n 93 69 5e 82 78 5o 90 74 5f 79 79 5p 87 79 5g 93 71 5q 88 67 5h 68 85 5r 82 84 5i 82 79 5s 80 81 5j 96 86 5t 97 72
aPurity of the crude compounds.bYields were determined on the weight of puried samples.
thea, b-unsaturated nitrile intermediate. The next step involves the preferential nucleophilic attack of the 2-amino group at the b-carbon of the nitriles in a typical Michael addition. Subse-quently, the ring nitrogen attacks the imino carbon leading to a zwitterionic intermediate, where compound 5 is obtained by proton exchange and facile oxidation. The driving force for the facile dehydrogenation is the generation of a highly conjugated pyrimidine ring system and it is pertinent to mention that the recently observed aerobic a,b-dehydrogenation of carbonyl compounds may support for this proposed autoxidation step.24
The proposed structure is unequivocally supported by X-ray analysis† and the ORTEP diagram for 5i is presented (Fig. 2). The C10–N4distance of 1.27 ˚A is the shortest among all the C–N
bond distances and clearly supports the exocyclic imine struc-ture. The cis orientation of C10–N4bond with C1–C2bond brings
the C2proton in close spatial proximity, which accounts for its
de-shielding effect on H2, consistently observed in all the
compounds 5.
Conclusion
In conclusion, we have developed a three component telescoped synthesis of novel benzimidazole iminopyrimidines with high regioselectivity. The reaction process involves Knoevenagel condensation, Michael type addition followed by intramolecular six-membered heterocyclization sequence. The selective forma-tion can be raforma-tionalized in terms of the preferential reactivity between the ylidenic double bond and the 2-amino functionality. The convenient one-pot operation, atom economic and exclusive regioselectivity are the salient features of this novel protocol. The synergic coupled microwave and ionic liquid support in the synthetic protocol drastically reduced the in-pot reaction time
Scheme 2 A proposed mechanism for the regioselective synthesis of IL-conjugated 4-iminopyrimidine fused benzimidazoles 4.
Fig. 2 ORTEP diagram and structure of compound 5i.
and accelerated the rapid generation of the functionalized 4-iminopyrimidines. Regioselective synthesis of this novel frame-work bearing benzimidazole, cyano and exocyclic azomethine functionalities may open a new avenue to discover interesting biologically active compounds.
Acknowledgements
The authors thank the National Science Council of Taiwan for the nancial assistance and the authorities of the National Chiao Tung University for providing the laboratory facilities. This paper is particularly supported by “Aim for the Top University Plan” of the National Chiao Tung University and Ministry of Education, Taiwan.
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