Divergent ionic liquid supported synthesis of isolable guanidine linked
quinoxalinone and benzodiamine
Li-Hsun Chen
a, Zhan-Hui Xu
a, Chun-Chung Lin
b, Chung-Ming Sun
a,⇑a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-50, Taiwan, ROC
bDepartment of Chemistry, National Tsing Hua University, Hsinchu 300-13, Taiwan, ROC
a r t i c l e
i n f o
Article history:
Received 22 September 2012 Revised 23 October 2012 Accepted 2 November 2012 Available online 20 November 2012 Keywords:
Ionic liquid support Microwave synthesis One-Bead-Two-Compound Quinoxalinones
a b s t r a c t
Ionic liquid supported synthesis of guanidine linked piperazine, diazepane, and aminomethylpiperidine to difluoroquinoxalinones and difluoro benzodiamine was achieved by two regioisomeric products. They were isolated from one pot reduction and intramolecular cyclization to afford quinoxalinone ring system with traceless cleavage of ionic liquid support. Besides, the ionic-supported other isomer was further cleaved in methanol. All the reactions were carried out on an ionic liquid support under various condi-tions to deliver biologically relevant scaffolds with high purity and excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
Diversity oriented synthesis (DOS) has significantly revolution-ized the drug discovery process and also has an impact on material science, catalysts, polymers, and pesticides.1In recent years, the
design and synthesis of pharmacologically relevant heterocyclic molecules by DOS techniques has proven to be a promising strat-egy in the preparation of privileged-substructure-based libraries.2
Integration of advanced technologies such as microwave, ionic li-quid (IL), and polymer supported synthesis in the combinatorial synthesis of numerous multi-functionalized molecules is the key to speed up initial drug discovery.3 Microwave-assisted IL
sup-ported organic synthesis is more popular in recent years because of the advanced instrumentation to provide reproducible results in homogeneous conditions.4Focusing on the synthesis of
drug-like molecules, substituted heterocyclic compounds with a high degree of structural diversity are useful as potentially therapeutic agents.5Furthermore, compounds that contain heterocyclic
moie-ties often exhibit improved solubility and can facilitate salt forma-tion properties, which are important for oral absorpforma-tion and bioavailability.6In chemical genetics, development of synthetic
li-braries in privileged scaffolds is specifically utilized to explore bio-logical pathway in cells or organisms. The design and synthesis of small molecules with structural, substituent, and chiral diversity from easily available building block through a short and efficient approach is important to access a wide variety of structurally com-plex small molecules.7,8
Our interest is to develop the regioselective nucleophilic meth-od for IL-fluorinated nitrobenzene. We choose 2,3,4,5-tetrafluoro-nitrobenzene (TFNB) for our studies where two activated fluorine atoms (2 and 4 positions) for regioselective nucleophilic substitu-tion and two non-active fluorine atoms (3 and 5 posisubstitu-tions) could present in target compound to attempt to increase its potential pharmacodynamic utilities. In the solution phase synthesis, gener-ally nucleophilic aromatic substitution follows the sequence of C-2 C-4 > C-5 > C-3 order according to MNDO semi-empirical calculation for nucleophilic reactivity on TFNB as shown inFigure 1. Based on these differences in calculations of reactivity in activated fluoro group as well as analysis of the nature of nucleophile, we contemplate that the modification in the reaction conditions could provide the selective nucleophilic substitution. According to our assumption, we designed a synthetic route that allowed sequential nucleophilic aromatic substitution and provide the controlled syn-thetic route for multi-substituted TFNB system. For a succession of two nucleophilic substitution steps, where N1 is the first nucleo-phile and N2 is the second nucleonucleo-phile, the order of substitution presents the opportunity of obtaining heterocyclic scaffolds and was shown inFigure 1.9
Our approach based on sequential SNAr reactions on TFNB was
planned to apply for the synthesis of guanidine linked to quinoxali-none moiety by heterocyclic core such as piperazine, azepane, and aminomethylpiperidine. Quinoxalinones represent a privileged moiety in medicinal chemistry and are ubiquitous substructures in material science and pharmaceuticals.9Some of the
quinox-alinone derivatives act as psychotropic, hypnotic, cardiotonic, antihistamine agents, and possess cardiovascular activity, antiin-flammatory activity as well as are HIV-1 reverse transcriptase
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.012
⇑Corresponding author. Tel.: +886 3 513 1511; fax: +886 3 573 6007. E-mail address:[email protected](C.-M. Sun).
Contents lists available atSciVerse ScienceDirect
Tetrahedron Letters
inhibitor (I).10The incorporation of piperazine or related
heteroar-omatic sub-units on the quinoxalinone ring system has been the focus of much attention which has exhibited a wide range of bio-logical activities, for example, Carta et al. recently reported the synthesis and antimicrobial activities of over 150 quinoxalinones (II).11 Moreover, the synthesis of such systems bearing bioactive guanidine unit that are attached to heterocyclic systems are of much interest due to the often unusual chemical, physical, and bio-logical properties that such systems exhibit.12The introduction of a guanidyl type group improves the in vivo pharmacokinetic proper-ties of thrombin and FXa inhibitors (III)13(Fig. 2).
Here we report the efficient traceless synthesis of guanidine linked piperazinyl, azepanyl, and aminomethylpiperidinyl quinox-alinones with substitutional diversity from versatile building blocks which include chiral amino acids, secondary amine deriva-tives such as piperidines, piperazines, and homopiperazines, and their stepwise regio-selective reaction with TFNB. The method de-scribe in this Letter is a part of our continuing effort to explore traceless synthetic methodology to construct new heterocycles li-braries. An IL-supported approach gives the advantage to employ the inexpensive asymmetric scaffold TFNB for the straightforward construction of complicated, fused heterocycles.
The synthetic strategy commenced with anchoring of amino acids to IL by the esterification method developed by our group.8
Various aliphatic, aromatic, and hetero-aromatic chiral amino acids were immobilized on an ionic liquid support to produce the IL-supported amino acid conjugates 1 with built-in structural diversity. The main task of this synthetic pathway was the regioselective nucleophilic aromatic substitution reaction with tetra-fluoro-nitrobenzene (TFNB) by IL anchored chiral amino acid 1. The TFNB has two active sites (2-fluoro and 4-fluoro) for nucleophilic substitution. Previously, Hardcastle and co-workers tried the similar nucleophilic substitution with penta-fluoro-nitrobenzene and ended up with the mixture of 2-substituted and 4-substituted nitrobenzene products.9 Similarly, Ji et al also obtained the mixture of ortho and para substituted com-pounds in a similar substitution in dimethyl formamide at room temperature.
We reported here the efficient traceless synthesis of 5,7-di-fluoro-2-oxo-1,2,3,4-tetrahydro-quinoxalin-piperazines with three points of diversity. These versatile building blocks which include chiral amino acids, secondary amine derivatives such as piperi-dines, piperazines, and homopiperazines, and their regio-selective reaction appear to occur at either 2- or 4-position of 2,3,4,5-tetra-fluoronitrobenzene (TFNB) to provide two isomeric products. For the purpose of library generation, the multi-step synthesis is con-veniently carried out on the ionic liquid support to facilitate puri-fication by precipitation. The fluoro displacement reaction of 1 with an excess of TFNB inside the microwave cavity proceeds to completion in 30 min with the formation of IL-bound tri-fluoro-nitrobenzoamines 3 and 4. It takes 10 h to finish the same coupling reaction by conventional reflux heating or 1 h by sealed tube or 24 h to complete the coupling reaction at room temperature (Scheme 1).
When IL-bound amines 1 react with TFNB 2 in acetonitrile, two IL-bound region-isomers 3 and 4 are formed to display a ‘one-bead-two-compound’ feature. Just as expected, the reaction ap-pears to occur at either 2- or 4-position to provide two isomeric products from each IL support. This was theoretically predicted by the MNDO semi-empirical calculation method and other organ-ic synthesis reports.9So in a subsequent step, the displacement of
the second active fluorine at 2- or 4-position with piperazines, homopiperazines, and 4-(aminomethyl)piperidines in the presence of triethylamine was introduced to this basic structure to give the products 5 and 6, though there is a primary amine group in the 4-(aminomethyl)piperidine. Next we tried to introduce the guanidinyl group into 5 and 6 with N,N0-di-tert-butoxycarbonyl
1H-benzotriazole-1-carboxamindine derivatives 7 in ACN in the presence of TEA which took place for 18 h to give products 8 and 9. All the IL bound intermediates and final compounds are purified by precipitation with the addition of ether (Scheme 2).
Reduction mixtures of IL bound intermediates 8 and 9 with Zn/ HCOONH4gave the anticipated compounds 10 because the
tion had taken place at the same time. The reduction and cycliza-tion of 8 were operated simultaneously in situ, this is also accompanied by the cleavage of the ionic liquid support by an
H N N H O F3C N NH N H N F O CH3 O O H3C CH3
HIV-1 Reverse Trascriptase Inhibitors
N N O CH3 N NH2 NH HN
Thrombin and FXa inhibitors
I II III
Antimicrobial agent
Figure 2. Biologically active relevant heterocyclic scaffolds. NO2 F F F F 0.198 0.121 0.155 0.141 NO2 F F N1 F NO2 N1 F F F NO2 N2 F N1 F NO2 N1 F N2 F N1 N2 A B C D
N1= First nucliophile, N2= Second nucliophile mixture of products Figure 1. MNDO semi-empirical calculation for TFNB.
OH =
Et3N, ACN r.t. 24hr or reflux 18hr or seal tube 1h or MW 30 min O O NH2 R1 N OH N BF4 F F F F NO2 OH HO O NH2 R1 1 2 3 4 F F NO2 F H N O R1 O NO2 F H N F R1 O O F room temperature reflux seal tube micro wave condition compound 3 : 4 2 : 1 3 : 1 4 : 1 1 : 1 IL IL IL IL IL
Scheme 1. Regioselective SNAr reaction at ortho-position of TFNB.
+ 3 4 5 6 Et3N/ACN rt 8h + N N N Et3N, ACN, rt, 18h 8 9 7 NH HN NH N F F NH O2N R1 O O HN N F O2N F N O R1 O H + N N F F NH O2N R1 O O N N F O2N F N O R1 O H NBoc NBoc H BocN BocN H BocN NBoc H + 5 6 HN NH HN NH HN NH2 NH HN IL IL IL IL Scheme 2. Second SNAr reaction to incorporate heterocyclic unit and guanidinylation.
Zn/NH4COOH MeOH, rt
+
11 10 KCN MeOH, rt 12 8 + 9 N N F F N N R1 O NBoc NBoc H H N N F H2N F BocN BocHN N O R1 O H N N F H2N F N O R1 O H BocN BocN H ILintra-molecular nucleophilic attack on the IL attached site and no more cleavage step is required. Traceless cleavage compounds 10 and IL-supported compounds 11 are separated easily by addition of ether to precipitate 11 selectively. Acyclic aniline 11 will need further to split in the presence of KCN to give trans-esterified moi-ety 12 (Scheme 3).14
We successfully acquired the drug-like skeletons difluoroben-zodiamines 12 and difluoro-2-quinoxalinones 10, upon completion of the reduction of 8, subsequent intra-molecular cyclization reac-tion to give traceless compounds 10 and IL immobilized 9 was ob-tained through filtration after precipitation in ether. The versatility of sequential regioselective nucleophilic reaction was determined
Table 1 Scope of methodology 10 12 N N F F N N R1 O NBoc NBoc H H N N F H2N F BocN BocHN N O R1 O H
Entry Amino acids Diamines Yieldsa
(10/12) a HO NH2 O Ph N N H H 86(2/1) b HO NH2 O Ph N H2N H 82(4/1) c HO NH 2 O N N H H 80(2/1) d HO NH2 O N N H H 83(1:1) e HO NH 2 O N H2N H 92(4:1) f HO NH2 O N N H H 85(3/1) g HO NH2 O N H2N H 86(1/1) h HO NH2 O N N H H 88(3/1) i HO NH2 O N H2N H 86(4/1) j HO NH2 O N H N N H H 88(1/1) k HO NH2 O N H N H2N H 90(1/1) a
by employing various aliphatic, aromatic, and hetero-aromatic amino acids. In all the amino acids the regioselectivity was achieved in nucleophilic substitution reaction. The chiral elements were introduced into the difluorobenzodiamines 12 by using the chiral amino acids. Furthermore the different diamino-heterocy-cles namely piperazine, diazepine, and 4-aminomethylpiperidines were used in combination with the above amino acid to construct the scaffold diversity. All the substrates reacted efficiently to deli-ver the final cyclized products with no substantial difference in the yields.Table 1describes the scope of developed methodology and the diversity elements of the scaffold.
We have successfully developed a rapid and efficient solution synthesis of benzimidazole linked pyrrolo[1,2-a]benzimidazol-ones, pyrido[1,2-a]benzimidazolpyrrolo[1,2-a]benzimidazol-ones, and isoindo[1,2-a]benzimi-dazoles with three sets of diversity on ionic liquid support. A cascade reaction was systematically applied to furnish diverse het-erocyclic molecular libraries with IL-supported synthesis from an IL-fluoro scaffold (TFNB) moiety which was indispensable for the method in view of its double reactive sites. Guanidine linked di-fluoro-2-quinoxalinones 10 were directly obtained by concomitant intramolecular cyclization after reduction, whereas the stable difluorobenzodiamines 12 was further released from the ionic li-quid support after precipitation.
This approach provides a high speed path for the rapid synthesis of bis-heterocyclic libraries with a high degree of structural diver-sity. The powerful potential of multidisciplinary synthetic ap-proach, integrating ionic liquid support, and microwave synthesis with multistep synthesis has great potential to produce biologi-cally interesting molecules for drug discovery.
Acknowledgments
The authors thank the National Science Council of Taiwan for the financial assistance. This work is particularly supported by ‘Center for Bioinformatics Research of Aiming for the Top Univer-sity Program’ of the National Chiao Tung UniverUniver-sity and Ministry of Education, Taiwan, ROC.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 11.012.
References and notes
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14. General procedure for the synthesis of 10 and 12: IL-supported compound 1 (1 g) was added to a 50 ml flask with 0.11 g of TFNB 2 (3 equiv, 0.59 mmol) and TEA 0.16 mL (6 equiv, 1.15 mmol) in 10 ml acetonitrile. The reaction mixture was heated for 30 min under microwave in open vessel condition. After the completion of reaction, ether was added to the reaction mixture to precipitate the two isomers of the IL-supported compounds 3 and 4 and washed with ether (30 mL 2). IL-supported compounds 3 and 4 dissolved in acetonitrile (10 mL), piperazine or homopiperazine or aminomethylpiperidine (3 equiv, 0.57 mmol), and 0.18 ml TEA (6 equiv, 1.18 mmol) were stirred at room temperature for 8 h, then ether was added to the reaction mixture to precipitate the IL-supported compounds 5 and 6. IL-supported compounds 5 and 6 dissolved in acetonitrile (10 mL) with 0.20 g of N,N0
-di-tert-butoxycarbonyl-1H-benzotriazole-1-carbox-amidine 7 (3 equiv, 0.56 mmol) and 0.16 ml TEA (6 equiv, 1.15 mmol) were stirred at room temperature for 18 h. The ether (50 mL) was added after the reaction was completed. The precipitation was filtered, and dried under high vacuum to give guanidinyl compounds 8 and 9. IL-supported compounds 8 and 9 dissolved in methanol (10 mL) with 233 mg of powder Zn and 112 mg of NH4COOH (10 equiv,
1.79 mmol) were stirred at room temperature for 1 h. Monitoring the reaction progress by TLC showed that compound 10 was released from ionic liquid support. The filtrate was concentrated after precipitation, dried well and submitted to spectrum analysis. Further purification by column chromatography furnished the pure guanidinyl heterocyclic linked quinaxolinones 10 as a liquid. Compound 10a:1
H NMR (300 MHz, CDCl3) d 10.18 (s, –NH), 8.95 (s, 1H), 7.39–7.35 (m, 2H), 7.32–7.30 (m, 1H), 7.20–7.17 (m, 2H), 6.40 (d, J = 11.2 Hz, 1H), 4.05–3.91 (m, 2H), 3.71 (m, 4H), 3.19 (m, 4H), 2.86–2.78 (dd, J = 13.3, 10.8 Hz, 1H), 1.50 (s, 18H);13 C NMR (75 MHz, CDCl3) d 168.5, 164.7, 160.4, 159.2, 155.9, 152.8, 149.3, 136.1, 135.9, 129.2, 128.9, 128.6, 127.1, 126.7, 120.2, 118.0, 99.9, 97.8, 50.8, 44.5, 39.9, 31.1, 29.6, 28.0; IR (cm1 , neat): 3275, 2924, 2852, 1678; MS (ESI-MS) m/z: 601 [M+H]+ ; HRMS Calcd for C30H38F2N6O5: m/z 600.2872; Found 601.2948 [M+H]+. The IL-supported
compound 11 was cleaved in methanol (10 mL) and 26 mg KCN (3 equiv, 0.40 mmol) for 18 h. Ether (50 mL) was added to precipitate IL-1 and the filtrate was concentrated to give compounds 12 as a liquid. Compound 12a:1
H NMR (300 MHz, CDCl3) d 7.31–7.22 (m, 3H), 7.17–7.15 (m, 2H), 6.25–6.20 (dd, J = 12.3, 2.0 Hz, 1H), 4.31 (t, J = 6.1 Hz, 1H), 3.63 (s, 3H), 3.38–3.20 (m, 4H), 3.07 (d, J = 6.5 Hz, 2H), 2.81–2.76 (m, 4H), 1.50 (s, 18H);13C NMR (75 MHz, CDCl 3) d 173.7, 167.7, 148.9, 145.6, 143.8, 142.6, 136.4, 132.4, 128.7, 128.4, 126.8, 114.8, 114.5, 110.2, 97.5, 83.3, 52.8, 51.8, 49.9, 46.2, 38.6; IR (cm1, neat): 2871, 1737;
MS (ESI-MS) m/z: 633 [M+H+]; HRMS Calcd for C
31H42F2N6O6: m/z 632.3134;
