Direct construction of benzimidazo[l,2-c]quinazolin-6-ones via metal-free oxidative C–C bond cleavage

Ping-Gui Liab, Cheng Yana, Shuai Zhua, Shu-Hui Liua and Liang-Hua Zou*a
aSchool of Pharmaceutical Science, The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Lihu Avenue 1800, Wuxi, 214122, P. R. China. E-mail:
bState Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Xianlin Avenue 163, Nanjing 210093, China

Received 26th September 2018 , Accepted 23rd October 2018

First published on 25th October 2018

A highly regioselective C–C bond cleavage/amination of isatins has been developed for the synthesis of benzimidazo[1,2-c]quinazolin-6-ones by reacting with o-phenylene diamines. This practical transition-metal-free method is operationally simple, enabling the C–C bond cleavage and triple C–N bond formation, wherein molecular oxygen is the sole required oxidant.

Over the past few years, research on indoles and their derivatives has gained extensive interest due to their broad range of biological activities.1 In particular, isatins (1H-indole-2,3-diones), a subclass of the indole family, widely exist in the natural world and exhibit a wide range of biological and medicinal activities.2 To date, considerable efforts have been made to synthesize complex heterocyclic skeletons for the discovery of biological scaffolds or anti-cancer medicines using isatins and their derivatives as starting materials. Common methods for the construction of polycyclic compounds (Scheme 1) based on isatins and their derivatives include the following: (a) ring-formation through the C3 site, which is a well-established strategy, such as in the synthesis of three-membered ring,3 four-membered ring,4 five-membered ring5 and six-membered ring.6 (b) Ring-formation through the cleavage of the C2–N bond. For example, Barba et al. reported the electrosynthesis of tryptanthrins via this route.7 Subsequently, other groups have also developed the synthesis of such compounds starting from isatins.8 (c) Ring-formation through the insertion of heteroatoms into the C2–C3 bond, which has rarely been reported in the construction of heterocyclic compounds.9
image file: c8qo01039k-s1.tif
Scheme 1 Strategies for the construction of polycylic compounds based on isatins and their derivatives.

Imidazo[l,2-c]quinazolin-6-ones represent a class of important heterocycles with enriched biological profiles. For example, compounds A and B serve as potent antihypertensive agents that selectively antagonize the α1-adrenoceptor (Scheme 2).10 Several methods are known for the synthesis of such heterocycles: (a) a tandem aza-Wittig reaction/heterocumulene-mediated annulation reaction (Scheme 3, eqn (a));11 (b) the reductive cyclization of 2-(2-nitrophenyl)benzoimidazoles with isocyanates promoted by a low-valent titanium reagent (Scheme 3, eqn (b));12 (c) the reaction of 2-(2-aminophenyl) benzoimidazoles with ethyl chloroformate in pyridine (Scheme 3, eqn (c));13 and (d) amidinyl radical formation through anodic N–H bond cleavage (Scheme 3, eqn (d)).14 Despite these advances, most of these approaches still suffer from several limitations, such as the requirement of multistep synthesis of the precursors and expensive reagents and/or noble catalysts. Consequently, there is still great demand to explore new methodologies to synthesize such heterocycles. The construction of new chemical bonds through oxidative C–C bond cleavage using dioxygen as the sole oxidant, especially without the use of a transition-metal catalyst, has attracted increasing interest in organic synthesis as a green protocol.

image file: c8qo01039k-s2.tif
Scheme 2 Representative imidazo[l,2-c]quinazolin-6-ones.

image file: c8qo01039k-s3.tif
Scheme 3 Traditional methods for the synthesis of benzimidazo[l,2-c]quinazolin-6-ones.

Recently, the auto-oxidation strategy based on dioxygen (O2) has attracted much attention to address numerous challenges due to the fact that it is environmentally benign and sustainable as an oxidant.15 In the course of our investigation of the functionalization of indoles,16 we have recently observed that the benzimidazo[l,2-c]quinazolin-6-ones could be generated via the reactions of isatins and o-phenylene diamines under metal-free conditions in the presence of molecular oxygen (Scheme 3, eqn (e)).17 In the present study, a new and green method for the synthesis of benzimidazo[l,2-c]quinazolin-6-ones is reported.

The initial screening and optimization of the reaction conditions were conducted with compounds 1a and 2a as the substrates (on 0.25 mmol scale) and CH3CN as the solvent, and product 3a was obtained in 45% yield by heating at 130 °C (Table 1, entry 1). Next the use of other solvents was attempted, such as DMSO, toluene, DMF and dioxane, and DMSO proved to be the most efficient solvent for this reaction, affording product 3a in 88% yield (Table 1, entries 2–5). An attempt to employ Ag2CO3 as an oxidant or additive led to a lower yield (Table 1, entry 6). When performing the reaction at a lower or higher temperature, the yields dropped significantly (Table 1, entries 7 and 8). Instead of oxygen, an air or argon atmosphere afforded 3a in lower yield or did not work (Table 1, entries 9 and 10).

Table 1 Optimization of reaction conditions for the synthesis of 3aa

image file: c8qo01039k-u1.tif

Entry Solvent Yieldb [%]
a Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), solvent (2 mL), oxygen atmosphere, 24 h, 130 °C.b Yield after column chromatography.c Use of Ag2CO3 as the additive.d 100 °C.e 120 °C.f 140 °C.g 150 °C.h Under an air atmosphere.i Under an argon atmosphere.
1 CH3CN 45
2 DMSO 88
3 Toluene 51
4 DMF 46
5 Dioxane 36
6 DMSO 65c
7 DMSO 55d, 79e
8 DMSO 78f, 60g
9 DMSO 20h
10 DMSO 0i

With the optimized reaction conditions in hand (entry 2, Table 1), the scope of the synthesis was investigated and the results are summarized in Scheme 4. Substrates with various electron-donating or electron-withdrawing substituents were applied to the reaction system to provide a series of benzimidazo[l,2-c]quinazolin-6-ones. For example, the reaction of substrates bearing electron-donating substituents such as methyl and methoxyl groups afforded the corresponding products 3b–d in good yields ranging from 40% to 92%. In addition, substrates with electron-withdrawing groups such as –F, –Cl and –Br also worked well in the procedure, furnishing the desired products 3e–k in moderate to excellent yields. The substrate functionalized with a strong electron-withdrawing group –OCF3 was also tested, providing the corresponding product 3l in a good yield of 77%. It appeared that various electron-donating and electron-withdrawing substituents were well tolerated in the reaction and there was no straightforward correlation between the electronic properties of the substituents and reaction efficiency. However, the steric and electronic properties of the substrates apparently played an important role in the reaction efficiency (40% yield of 3b vs. 92% yield of 3c; 91% yield of 3g vs. 37% yield of 3i). Furthermore, the reaction of one substrate with a methyl group on the nitrogen as the protecting group also proceeded well, yielding product 3m in a good yield of 70%.

image file: c8qo01039k-s4.tif
Scheme 4 The scope of the reaction of isatins (1) with o-phenylene diamine (2a). Reaction conditions: 1 (0.25 mmol), 2a (0.25 mmol), DMSO (2 mL), oxygen atmosphere, 130 °C.

In order to further explore the scope of the reaction, several o-phenylene diamines bearing various substituents were investigated and the results are summarized in Scheme 5. The reactions of the substrates bearing the methyl group with compound 1a exhibited good regioselectivities, providing products 3n and 3o in 72% and 67% yields, respectively. When a substrate containing two methyl groups was chosen the reaction proceeded well with three isatins bearing electron-donating or electron-withdrawing substituents, giving the corresponding products 3p–r in yields ranging from 33% to 70%. Subsequently 2,3-naphthalenediamine was also employed in the procedure to afford product 3s in 30% yield. Furthermore, the reaction of substrates with the electron-withdrawing group –Cl worked well, giving product 3t in 71% yield. Finally, a substrate with two –Cl groups was also examined in the reaction, which provided the desired product 3u in 67% yield. A simple alkyl diamine (ethylenediamine) was tested under the optimized conditions, albeit no product was obtained.

image file: c8qo01039k-s5.tif
Scheme 5 The scope of the reaction of 1,2-diaminobenzenes 2 with isatins 1. Reaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), DMSO (2 mL), oxygen atmosphere, 24 h, 130 °C.

In order to elucidate the mechanism, several control experiments were conducted. Initially, it was assumed that the reaction might proceed via a reaction of 2a and an intermediate 4. The control reaction indeed afforded the desired product 3a in 85% yield (Scheme 6, eqn (a)).18 Next, the role of dioxygen in the reaction was investigated. Under the optimized reaction conditions, isatoic anhydride was not observed by GC-MS when compound 2a was absent, showing that isatoic anhydride might not be stable at high temperature (Scheme 6, eqn (b)). In order to further demonstrate the possible isatoic anhydride intermediate implied by the aforementioned three control experiments, piperidine served as the stronger electrophile to trap the possible isatoic anhydride generated in situ, wherein compound 6 was observed by GC-MS under the standard conditions (Scheme 6, eqn (c)).9b However, merely trace amounts of product 3a were formed when isatoic anhydride was reacted with compound 2a under an argon atmosphere, instead of a dioxygen atmosphere, indicating that O2 is not only responsible for the transformation of isatin to isatoic anhydride, but also promotes the subsequent reaction process (Scheme 6, eqn (a)). On the other hand, both radical scavengers TEMPO (2,2,6,6-tetramethylpiperidinooxy) and BHT (2,6-di-tert-butyl-4-hydroxytoluene) did not obviously influence this reaction, which indicates that a radical pathway might not be involved in this reaction (Scheme 6, eqn (d)). In order to test the scalability of the new protocol, we performed the reaction on a gram scale under the optimized conditions and product 3a was obtained in a good yield of 75% (see the ESI).

image file: c8qo01039k-s6.tif
Scheme 6 Control reactions.

Based on these results, a possible mechanism for this reaction was proposed. Taking the synthesis of 3a for example (Scheme 7), isatoic anhydride (4) is first formed through the oxidation of 1a under a dioxygen atmosphere.19 Then a condensation reaction between 4 and 2a proceeds to give intermediate II or II′ through two different pathways. According to the results observed by GC-MS, the reaction through path b is unfavorable. Subsequently, an intramolecular attack of the nitrogen atom to ketone provides intermediate III or III′, which gives intermediate IV or IV′ with the aid of a hydrogen ion. The third attack of the nitrogen atom to ketone provides intermediate V or V′, which transforms to the final product 3a or 3a′ through intramolecular condensation, according to the GC-MS analysis (Scheme 6, eqn (e)).

image file: c8qo01039k-s7.tif
Scheme 7 Proposed pathway for the synthesis of 3a.

In summary, an efficient and practical method was developed for the construction of benzimidazo[l,2-c]quinazolin-6-ones under an oxygen atmosphere via the reaction of simple isatins and o-phenylene diamines. This practical transition-metal-free reaction is operationally simple with C–C bond cleavage and triple C–N bond formation. A series of substituents were well-tolerated, providing the corresponding products in good to excellent yields.

Conflicts of interest

There are no conflicts to declare.


This work was financially supported by the NSF of Jiangsu Province (BK20150129), and the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (No. PPZY2015B146).

Notes and references

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Electronic supplementary information (ESI) available. CCDC 1858811. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8qo01039k
These authors contributed equally to this work.

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