Diversified facile synthesis of benzimidazoles, quinazolin-4(3H)-ones and 1,4-benzodiazepine-2,5-diones via palladium-catalyzed transfer hydrogenation/condensation cascade of nitro arenes under microwave irradiation

Kaicheng Zhu , Jian-Hong Hao, Cheng-Pan Zhang, Jiajun Zhang, Yiqing Feng* and Hua-Li Qin*
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, Hubei Province 430070, P. R. China. E-mail: fengjerry1108@yahoo.com; qinhuali@whut.edu.cn; Fax: +86 27 87749300; Tel: +86 27 87749300

Received 4th December 2014 , Accepted 6th January 2015

First published on 6th January 2015

A highly efficient diversified methodology for preparation of benzimidazole, quinazolin-4(3H)-ones and 1,4-benzodiazepine-2,5-diones is established using a palladium-catalyzed transfer hydrogenation (CTH)/condensation cascade of o-nitroaniline and o-nitrobenzamides in a triethylamine–formic acid azeotropic mixture (2[thin space (1/6-em)]:[thin space (1/6-em)]5) under microwave irradiation.

Benzimidazoles, quinazolin-4(3H)-ones and 1,4-benzodiazepine-2,5-diones comprise some of the most important core structures found in a variety of natural products and pharmacophores. Some representative therapeutic bioactivities associated with these heterocycles include antitumor,1 anticonvulsant,2 antiinflammatory,3 antibiotic4 and antianxiety.5 A variety of methodologies for construction of these heterocyclic scaffolds were reported,6 most of which either employed the corresponding o-amino substrates as starting material or proceeded through multi-step sequences. Syntheses of the title compounds under microwave irradiation have been reported in recent years,7 most of which employ corresponding o-amino aryl compounds as starting materials. Direct synthesis of the title heterocycles through reductive cyclocondensation of nitroarene derivatives has been investigated.8 The application of these methods, however, is usually limited by disadvantages associated with the use of uncommon catalysts and/or prolonged reaction times. Microwave-assisted one-pot reductive cyclocondensation of the corresponding nitro- or azo-compounds for formation of the target heterocycles mediated by Fe(0), Sn(II), on the other hand, requires a stoichiometric amount of metal reductant, which inevitably leads to large amounts of waste.9

Due to these disadvantages of the existing methods, there have been increasing demands for more efficient and environmentally-benign methodologies for the preparation of the title heterocyclic compounds. We herein report a new solvent-free method for facile and diversified construction of benzimidazole, quinazolin-4(3H)-one and 1,4-benzodiazepine-2,5-dione scaffolds, via a palladium-catalyzed transfer hydrogenation (CTH)/condensation cascade of nitro arenes in triethylamine–formic acid azeotropic mixture under microwave irradiation (Scheme 1).10

image file: c4ra15765f-s1.tif
Scheme 1 Synthesis of benzimidazoles, quinazolin-4(3H)-ones and 1,4-benzodiazepine-2,5-diones.

Our design of the new methodology hinged on an optimal reaction medium which would not only serve as the hydrogen source for the Pd-CTH reduction of nitro arene substrates, but also as the mono-carbon source that undergoes heterocycle formation with the intermediate aniline derivatives resulted from the Pd-CTH reduction. Thus, our initial focus was directed toward screening for such an optimal reaction medium.

To this end, common mono-carbon CTH reagents including formic acid, ammonium formate, formamide–ammonium formate mixture and triethylamine–formic acid azeotropic mixture (Et3N[thin space (1/6-em)]:[thin space (1/6-em)]HCO2H = 2[thin space (1/6-em)]:[thin space (1/6-em)]5, TEAF)11 were tested using o-nitrobenzamides 1a and 1b as substrates in the presence of 10% Pd/C as catalyst (Scheme 2). The reaction in formic acid afforded the reduced aniline products readily but led to inefficient formation of the desired quinazolinone heterocycles. We next examined HCO2NH4, however, the high pressure resulting from vigorous decomposition of ammonium formate under microwave irradiation forced us to abandon it due to potential safety concerns. The mixture of HCONH2–HCO2NH4 did lead to the desired quinazolinone products. But unfortunately, when N-substituted o-nitrobenzamide such as 1b was used as substrate, quinazolin-4(3H)-one (2a) was isolated as an inevitable side product (∼25%) in addition to the desired 3-isopropyl quinazolin-4-one (2b, ∼65%). This side product 2a was generated by an intramolecular transamidation from 2-formimidamidebenzamide (1b′′), a condensation product between 2-amino-N-isopropylbenzamide (1b′) and formamide.12

image file: c4ra15765f-s2.tif
Scheme 2 Screening of reaction media.

Gratifyingly, we found that when o-nitrobenzamide 1a and 1b were subjected to Pd-CTH-cyclization in azeotropic triethylamine–formic acid mixture (TEAF) under microwave irradiation, the desired quinazolinone products 2a and 2b were isolated in high yields as the sole product, respectively. To our delight, TEAF served as a good CTH hydrogen source, then also as a single-carbon source for the subsequent cyclocondensation. In addition, triethylamine, formed from decomposition of TEAF, did not interfere with the N-substituted 2-nitrobenzamide (1b), and afforded 3-substituted quinazolin-4(3H)-one (2b) readily without generating any detectable 2a (vide supra). The azeotropic TEAF mixture heats up very quickly under irradiation due to its high microwave absorbance, and remains a homogeneous liquid from room temperature to 180 °C, which ensures the completion of the condensation in a short time. As an added advantage, TEAF solvates the generally insoluble nitrobenzamides well at room temperature, and is miscible with water and methanol, which leads to an easy work-up afterward. It was also found that in this TEAF medium, only 0.5 mol% Pd/C was sufficient to finish the reaction.

With TEAF in hand as the desired multi-functional medium, we went on to explore the substrate scope of this methodology through the synthesis of a series of 3-substituted quinazolin-4(3H)-ones (Table 1). Thus, 3-alkyl quinazolin-4(3H)-ones 2b–d were prepared in high yields under our cascade conditions. N-Aryl-2-nitrobenzamide underwent reductive Niementowski cyclocondensation with TEAF, affording 3-substituted quinazolin-4(3H)-ones 2f–i in good to excellent yields. The free phenol functionality was well tolerated (2i), and the electron withdrawing groups on either the N-aryl (2j) or the parent framework (2k) did not affect the cyclization. The bis-reduction-cyclocondensation cascade took place on symmetrical substrates under our condition and gave symmetric bis-quinazolinone products 2m–n in moderate yields. Interestingly, when N-2′-nitrophenyl-2-nitrobenzamide was subjected to the optimized conditions, the tetracyclic benzo[4,5]imidazo[1,2-c]quinazoline 2l was isolated as the major product.

Table 1 Synthesis of quinazolin-4(3H)-one via palladium CTH reduction–cyclocondensationa

image file: c4ra15765f-u1.tif

a Reaction conditions: o-nitrobenzamide (1.0 mmol), 10% Pd/C (0.5 mol%), TEAF (4.0 equiv.) were heated at 150 °C for 8 min under microwave irradiation. Isolated yields were reported.
image file: c4ra15765f-u2.tif

We then applied our methodology to the preparation of benzimidazole compounds, and to our delight, the desired benzimidazole products (4a–k) were generated in generally high yields under the optimized condition (Table 2). Substrates bearing either electron rich (3c–e) or electron deficient (3g–h) N-aryls gave equally good yields of the benzimidazole products. It is noteworthy that although our palladium-CTH reduction–cyclocondensation represents a typical hydrogenation condition, by lowering the reaction temperature to 100 °C, we were able to retain most (5[thin space (1/6-em)]:[thin space (1/6-em)]1, >80%) of the N-benzyl functionality in the product (4i). This one-pot transformation was also highly efficient for heterocyclic substrates, affording the 3H-imidazo[4,5-b]pyridine (4j) and 3H-imidazo[4,5-g]quinoline (4k) in good yields.

Table 2 Synthesis of benzimidazoles via palladium CTH reduction–cyclocondensationa

image file: c4ra15765f-u3.tif

a Reaction conditions: 2-nitroaniline (1.0 mmol), 10% Pd/C (0.5 mol%), TEAF (4.0 equiv.) were heated at 150 °C for 5 min under microwave irradiation. Isolated yields were reported.b Reaction was conducted under 100 °C for 12 min to avoid debenzylation, 15% of 4a was isolated.
image file: c4ra15765f-u4.tif

It is worth mentioning that most products in Tables 1 and 2 could be obtained at high purity (>95%) after filtration and a simple aqueous extraction, with no chromatography required. In addition, this one-pot condensation could be achieved on gram scale with excellent yield (>90%) under the identical condition,13 which demonstrated the potential of this protocol for both laboratory synthesis and industrial production.14

To further expand the substrate scope of our methodology, this protocol was examined with 2-nitrobenzoyl-α-amino acid methyl esters 5a–b (Scheme 3). Interestingly, these substrates, after reduction, did not cyclize with TEAF in a Niementowski fashion to give quinazoline products as expected. Instead, intramolecular aminolysis of the methyl ester dominated and afforded benzodiazepine compounds (6a–b).

image file: c4ra15765f-s3.tif
Scheme 3 Formation of 1,4-benzodiazepine-2,5-diones.

In summary, we have discovered a highly efficient and diversified one-pot method for the construction of benzimidazole, quinazolin-4(3H)-one and 1,4-benzodiazepine-2,5-dione scaffolds from nitro arenes through a palladium-CTH reduction–condensation cascade in triethylamine–formic acid azeotropic mixture (TEAF) under microwave irradiation. This method features the unprecedented application of TEAF as a multi-functional reaction medium which enabled highly efficient construction of diverse heterocyclic products. Other applications of this methodology are currently underway and will be disclosed in due course.


This work was supported in part by the Natural Sciences Foundation of Hubei Province (20141j0169) and Wuhan University of Technology.

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  12. image file: c4ra15765f-u5.tif.
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Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra15765f
These two individuals contributed equally to this work.

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