A concise and efficient synthesis of benzimidazo[1,2-c]quinazolines through CuI-catalyzed intramolecular N-arylations

  1. Xinlong Pang1,2,
  2. Chao Chen1,
  3. Ming Li2 and
  4. Chanjuan Xi1

1Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China, Tel: +86-10-62773684
2College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China

  1. Corresponding author email

This article is part of the Thematic Series "Copper catalysis in organic synthesis".

Guest Editor: S. R. Chemler
Beilstein J. Org. Chem. 2015, 11, 2365–2369. https://doi.org/10.3762/bjoc.11.258
Received 30 Aug 2015, Accepted 16 Nov 2015, Published 30 Nov 2015

Abstract

A series of functionalized benzimidazo[1,2-c]quinazoline derivatives was obtained in excellent yields under mild conditions through a CuI-catalyzed Ullmann N-arylation starting from easily available starting materials.

Keywords: benzimidazo[1,2-c]quinazoline; (bromophenyl)iodonium salt; copper catalyst; o-cyanoaniline; quinazolin-4(3H)-imine; Ullmann N-arylation

Introduction

Nitrogen-containing heterocycles are ubiquitous backbones in natural products, medicine and organic materials. In addition, they are also important ligands for catalytic reactions. Recently, the conjugation of different types of azaheterocycles in the same molecule has received considerable attention since the resulting ring-fused molecules often show unique organic optoelectronic properties and bioactive activities [1,2]. Among them, benzimidazo[1,2-c]quinazolines were intensively investigated and promising biological activities were observed, such as anticancer, antiviral, antimicrobial, anti-inflammatory and anticonvulsant [3-5]. Indeed, some of them are already used as antimicrobial agents and lipid peroxidation inhibitors [6]. Consequently, the development of an efficient way to prepare various benzimidazo[1,2-c]quinazoline derivatives is highly desired. Although some methods for the synthesis of benzimidazo[1,2-c]quinazoline derivatives have been reported quite recently [7-12], they often require complicated starting materials that are not readily available and need harsh conditions. Herein we report a CuI-catalyzed concise and efficient method for the synthesis of benzimidazo[1,2-c]quinazoline derivatives through the intramolecular N-arylation reaction of bromo-substituted quinazolin-4(3H)-imines that are easily prepared from o-cyanoaniline (1) and diaryliodonium salts 2 based on our previously published method [13,14] (Scheme 1).

[1860-5397-11-258-i1]

Scheme 1: CuI-catalyzed synthesis of benzimidazo[1,2-c]quinazolines 4 by intramolecular N-arylation of bromo-substituted quinazolin-4(3H)-imine derivatives 3.

Results and Discussion

During the study of the synthesis of various carbocycles or heterocycles with copper catalysts [13-17], we found an interesting tandem reaction of o-cyanoanilines 1 and diaryliodonium salts 2 to produce quinazolin-4(3H)-imine derivatives 3 with Cu(OTf)2 as the catalyst [13]. Encouraged by this finding, we initially attempted the reaction of o-cyanoaniline (1a) with di-(o-bromophenyl)iodonium salt 2. The reaction of 2 equiv of o-cyanoaniline (1a) with 2 in DCE at 110 °C for 6 h in the presence of 20 mol % Cu(OTf)2 bromo-substituted quinazolin-4(3H)-imine derivative 3a in 82% isolated yield. The subsequent treatment of 3a with CuI (0.1 equiv) and K2CO3 (1 equiv) in DMSO at room temperature for 50 min led to benzimidazo[1,2-c]quinazoline derivative 4a in 37% yield (Table 1, entry 1). To optimize the yield of the desired product 4a different conditions were screened. When the reaction temperature was increased to 60 °C, compound 4a was formed in 98% yield (96% isolated, Table 1, entry 3). On the other hand, the replacement of DMSO by other solvents led to lower yields of 4a even at elevated temperatures (Table 1, entries 5–9). Other copper salts such as Cu(OTf)2, CuBr or CuCl were also able to catalyze the reaction, but they were not as efficient as CuI as the catalyst (Table 1, entries 5–9). It is worth mentioning that the imino group (sp2) other than the amino group (sp3) in 3a reacted through the Cu-catalyzed Ullmann reaction [18-25].

Table 1: Optimization of reaction conditions for the synthesis of benzimidazo[1,2-c]quinazoline 4a from quinazolin-4(3H)-imine derivative 3a.

[Graphic 1]
Entry Cu salt Temperature (°C) Solvent Yield (%)a
1 CuI rt DMSO 37
2 CuI 40 DMSO 72
3 CuI 60 DMSO 98 (96b)
4 CuI 110 DMSO 98
5 CuI 110 DCE 51
6 CuI 110 CH3CN 31
7 CuI 110 DCM 43
8 CuI 110 toluene 89
9 CuI 110 DCE 51
10 Cu(OTf)2 60 DMSO 82
11 CuBr 60 DMSO 86
12 CuCl 60 DMSO 91

aEstimated crude yield by NMR with trichloroethylene as internal standard. bIsolated yield.

Inspired by the successful cyclization of quinazolin-4(3H)-imine 3a, further imines were prepared and subjected to the cyclization conditions. Notably, in this protocol, after work-up, the desired bromo-substituted quinazolin-4(3H)-imine derivatives 3 were directly employed in the next step reaction without the need for chromatographic purification and the results are summarized in Table 2. Quinazolin-4(3H)-imines 3 having methyl, fluoro or chloro substituents all worked well in the reaction and provided the corresponding quinazolines 4 in high yields (Table 2, entries 2, 3 and 6). In addition changing the position of the fluoro substituent did not affect the yield of the products (Table 2, entries 3–5).

Table 2: CuI-catalyzed synthesis of benzimidazo[1,2-c]quinazolines 4 from bromo-substituted quinazolin-4(3H)-imines 3.

Entry Bromo-substituted quinazolin-4(3H)-imine 3 Benzimidazo[1,2-c]quinazoline 4 Yielda
1 [Graphic 2]
3a
[Graphic 3]
4a
96%
2 [Graphic 4]
3b
[Graphic 5]
4b
95%
3 [Graphic 6]
3c
[Graphic 7]
4c
95%
4 [Graphic 8]
3d
[Graphic 9]
4d
94%
5 [Graphic 10]
3e
[Graphic 11]
4e
93%
6 [Graphic 12]
3f
[Graphic 13]
4f
96%

aIsolated yield.

To further expand the scope of the protocol, we attempted the synthesis of imine 3g starting from two different nitriles. The reaction of o-cyanoaniline (1a), benzonitrile (1g) and di-(o-bromophenyl)iodonium salt 2 in the presence of Cu(OTf)2 gave the desired imine 3g together with imine 3a. After isolation of 3g it was further treated with 10 mol % of CuI in DMSO for 50 min to give product 4g in quantitative yield (Scheme 2).

[1860-5397-11-258-i2]

Scheme 2: Cu-catalyzed reaction of o-cyanoaniline (1a), benzonitrile (1g) and di-(o-bromophenyl)iodonium salt 2 producing imine 3g and its subsequent cyclization in the presence of CuI.

It is worth mentioning that during the course of our study, we observed that products 4 were not stable to acid. For example, treatment of 4c with aqueous HCl solution led to ring-opening product 5 (Scheme 3). The structure of 5 was confirmed by X-ray diffraction analysis (Figure 1), clearly showing the cleavage of the quinazoline ring rather than the imidazole ring [26].

[1860-5397-11-258-i3]

Scheme 3: Acid-promoted ring-opening reaction from quinazoline 4c to 5.

[1860-5397-11-258-1]

Figure 1: ORTEP drawing of 5, [C20H16F2N4O]·2Cl·H2O with 35% probability ellipsoids, showing the atomic numbering scheme.

Conclusion

We have demonstrated a CuI-catalyzed pathway to produce functionalized benzimidazo[1,2-c]quinazoline derivatives from bromo-substituted quinazolin-4(3H)-imines through a selective intramolecular N-arylation reaction. The bromo-substituted quinazolin-4(3H)-imines are easily synthesized from readily available o-cyanoanilines and di-(o-bromophenyl)iodonium salt. The extension of the reaction and the investigation of the biological activity of the new products are currently under progress in our laboratory.

Supporting Information

Supporting Information File 1: Full experimental procedures, characterization data, and NMR charts for compounds 3a–g and 4a–g.
Format: PDF Size: 1.4 MB Download

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21102080, 21372138) and Tsinghua University Initiative Scientific Research Program (2011Z02150).

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