alexa A Facile and Efficient Synthesis of Quinoxalines from Phenacyl Bromides and Ortho Phenylenediamine Promoted by Zirconium Tungstate | Open Access Journals
ISSN: 2161-0401
Organic Chemistry: Current Research
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

A Facile and Efficient Synthesis of Quinoxalines from Phenacyl Bromides and Ortho Phenylenediamine Promoted by Zirconium Tungstate

Lingaiah Nagarapu*, Jyothsna Devi Palem, Rama Krishna Reddy Aruva and Rajashaker Bantu
Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
Corresponding Author : Lingaiah Nagarapu
Organic Chemistry Division II
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007, India
Tel: +91-40-27191509/10/11
Fax: +91-40-27193382
E-mail: [email protected]
Received January 07, 2014; Accepted February 20, 2014; Published February 27, 2014
Citation: Nagarapu L, Palem JD, Reddy Aruva RK, Bantu R (2014) A Facile and Efficient Synthesis of Quinoxalines from Phenacyl Bromides and Ortho Phenylenediamine Promoted by Zirconium Tungstate. Organic Chem Current Res S4:001. doi: 10.4172/2161-0401.S4-001
Copyright: © 2014 Nagarapu L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Organic Chemistry: Current Research

Keywords
Quinoxaline; o-phenylenediamine; Zirconium tungstate
Introduction
Quinoxaline derivatives are an important class of nitrogencontaining heterocycles in medicinal chemistry [1-5]. Quinoxaline synthesis and chemistry has attracted considerable attention in the past ten years [6,7]. For example, quinoxaline is a part of various antibiotics such as echinomycin, levomycin, and actinoleutin that are known to inhibit growth of gram positive bacteria, and are active against various transplantable tumors. Some of them exhibit biological activities including anti-viral, anti-bacterial, anti-inflammatory, antiprotozoal, anti-cancer (colon cancer therapies), anti-depressant, anti-HIV, and as kinase inhibitors [8-14]. They are also used in the agricultural field as fungicides, herbicides, and insecticides [1]. In addition, quinoxaline derivatives have also found applications in dyes, efficient electron luminescent materials, organic semiconductors, chemically controllable switches, building blocks for the synthesis of anion receptors, cavitands, and dehydoannulenes [15,16]. They also serve as useful rigid subunits in macrocyclic receptors in molecular recognition.
Several kinds of synthetic routes toward quinoxalines have been developed, which involve condensation of 1,2-diamines with α-diketones [17], Bi-catalyzed oxidative coupling of epoxides with ene-1,2-diamines [18], cyclization-oxidation of phenacyl bromides [19,20]. However, many of these processes suffer from one or more limitations such as drastic reaction conditions, low product yields, the use of toxic metal salts as catalysts, and relatively expensive reagents. Moreover, these reactions are often carried out in polar solvents such as DMSO leading to tedious work-up procedures. We were interested to examine the synthesis of quinoxalines by the condensation of o-phenylenediamine and substituted phenacylbromides in the presence of a catalytic amount of 5%WO3/ZrO2 [21,22].
Experimental
Melting points were determined by using Fisher John’s melting point apparatus and are uncorrected [23,24]. IR spectra were recorded on a Thermo Nicolet Nexus 670 FT-IR spectrometer. Accurate mass measurement was performed on Q STAR mass spectrometer (Applied Biosystems USA). 1H NMR spectra and 13C NMR were recorded at 300 MHz on a Bruker Avance NMR spectrometer with TMS as an internal standard (chemical shifts in δ, ppm). For column chromatography, silica gel 60-120 mesh was used. For TLC, silica gel 60F254 (Merck) was used.
General procedure for synthesis of 3a-k
To a solution of o-phenylene diamine (1a, 1.1 mmol), phenacyl bromide (2a, 1.0 mmol) was added 5%WO3/ZrO2 (0.3 mmol). The mixture was refluxed for 0.5 h in 3.0 mL of CH3CN (progress of the reaction was monitored by TLC). After completion, the reaction mass was cooled to room temperature and the solid catalyst was filtered through a Buchner funnel, washed with CH3CN (2×5 mL). The filtrate was removed under reduced pressure, and the crude product was purified by column chromatograph. The recovered 5%WO3/ZrO2 dried and reused for a number of cycles without significant loss of activity.
2-Phenyl quinoxaline (3a): Solid; Yield 98%; mp 75-78˚C; IR (KBr): νmax 2913, 2841, 1916, 1711, 1623, 1521, 1401, 952, 821, 709 cm-1 1H NMR (300 MHz, CDCl3): δ 7.52-7.61 (s, 3H,Ar-H); 7.73-7.83 (m, 2H, Ar-H); 8.13-8.22 (m, 4H, Ar-H); 9.33 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 127.3, 129.0, 129.1, 129.5, 129.6, 130.1, 130.2, 136.7, 141.5, 142.2, 143.3.; MS(ESI)+: m/z= 207 [M+H]+.
2-(4-Methylphenyl)quinoxaline (3b): Solid; Yield 96%; mp 84- 90oC; IR (KBr): νmax 2923, 2855, 1937, 1727, 1676, 1541, 1426, 954, 825, 712 cm-1 . 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H,-CH3); 7.31-7.36 (d, J=8.30 Hz, 2H, Ar-H); 8.08-8.13 (d, J=8.30 Hz, 4H); 9.29 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 21.32, 127.30, 128.96, 129.16, 129.43, 129.77, 130.07, 140.36, 141.32, 143.19.
2-(4-Methoxyphenyl) quinoxaline (3c): Solid; Yield 97%; mp 94-98oC; IR (KBr): νmax 2925, 1602, 1537, 1483, 1458, 1424, 1177, 953, 845,756 cm-1 . 1H NMR (300 MHz, CDCl3): δ 3.89 (s, 3H, OCH3); 7.01- 7.09 (d, J=9.06 Hz, 2H, Ar-H); 7.6-7.7 (m, 2H, Ar-H); 8.03-8.1 (m, 3H, Ar-H); 8.15-8.21 (d, J=8.30Hz, 2H, Ar-H); 9.26 (s, 1H,=CH); 13C NMR (75 MHz, CDCl3): δ 29.64, 55.39, 114.53, 128.90, 129.02, 129.25, 129.34, 130.01, 143.06, 161.43. MS(ESI)+: m/z= 237 [M+H]+.
2-(4-Flourophenyl)quinoxaline (3d): Solid; Yield 92%; mp 112- 118oC; IR: νmax 2924, 2855, 1598, 1543, 1419, 1311, 1227, 1118, 956, 835, 754 cm-1 . 1H NMR (300 MHz, CDCl3): δ 7.20-7.27 (m, 2H, Ar-H); 7.7- 7.8 (m,2H, Ar-H); 8.09-8.11 (m, 2H, Ar-H); 8.21-8.25 (m, 2H, Ar-H); 9.28 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 116.10, 116.39, 129.13, 129.45, 129.60, 130.41, 142.92, 162.59, 165.91.
2-(4-Chlorophenyl) quinoxaline (3e): Solid; Yield 95%; mp-128- 130oC; IR: νmax 2924, 1590, 1538, 1485, 1309, 1121, 1045, 955, 830, 753 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.5-7.53 (d, J= 7.80Hz, 2H, Ar-H); 7.7-7.79 (m, 2H, Ar-H); 8.09-8.12 (t, J= 6.34 Hz, 2H, Ar-H); 8.16-8.19 (d, J= 7.806Hz, 2H, Ar-H); 9.29 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 128.76, 129.16, 129.40, 129.57, 129.78, 130.47, 142.84, 142.2,150.55.753. MS(ESI)+: m/z= 241 [M+H]+.
2-(4-Bromophenyl) quinoxaline (3f): Solid; Yield 94.0%; mp 128- 131oC; IR: νmax 2925, 1634, 1583, 1536, 1481, 1421, 1307, 1121, 1070, 954, 827, 710 cm-1 . 1H NMR (300 MHz, CDCl3): δ 7.66-7.71 (d, J=8.49 Hz, 2H, Ar-H); 7.73-7.80 (t, J= 7.81 Hz, 2H, Ar-H); 8.06-8.14 (d, J= 8.49 Hz, 4H, Ar-H); 9.29 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 96.17,128.90, 129.481, 129.66, 129.90, 130.15, 132.22, 135.56, 142.46, 156.28. MS(ESI)+: m/z= 287 [M+H]+.
2-(Napthalen-2-yl) quinoxaline (3g): Solid; Yield 96%; mp 127- 129oC; IR: νmax 2924, 2855, 1724, 1626, 1542, 1486, 1359, 1193, 963, 859, 746 cm-1 . 1H NMR (300 MHz, CDCl3): δ 7.50-7.57 (m, 2H, Ar-H); 7.7-7.81 (m, 2H, Ar-H); 7.86-7.91 (m, 1H, Ar-H); 7.97-802 (d, J= 8.30 Hz, 2H, Ar-H); 8.10-8.19(m, 2H, Ar-H); 8.65 (s, 1H, Ar-H); 9.47( s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 124.57, 126.5, 127.39, 127.77, 128.87,129.22, 129.69, 129.98, 133.38, 134.14, 141.67, 142.87, 143.71. MS(ESI)+: m/z= 257 [M+H]+.
7-Methyl-2-phenylquinoxaline (3h): Solid; Yield 87%; mp 117- 120oC ; IR (KBr): νmax 2923, 2855, 1942, 1725, 1626, 1541, 1426, 954, 825, 712 cm-1 . 1H NMR (300 MHz, CDCl3): δ 2.44 (s, 3H,-CH3); 6.69 (d, J=8.687Hz, 2H, Ar-H); 7.66-7.7 (m, 2H); 8.1-8.4 (m, 2H), 8.19-8.26 (m, 2H) 9.30 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 21.32, 128.21, 128.92 129.11, 129.43, 130.9, 131.27, 140.36, 141.42, 143.19. MS(ESI)+: m/z= 221 [M+H]+.
2-(4-Bromophenyl)-7-methylquinoxaline (3i): Solid; Yield 78%; mp 126-129oC ; IR (KBr): νmax 2923, 2855, 1937, 1727, 1676, 1541, 1426, 954, 825, 712 cm-1 . 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H,-CH3); 6.69 (d, J=8.687Hz, 2H, Ar-H); 7.69-7.71 (m, 2H); 8.04-8.06 (m, 2H), 8.19-8.27 (m, 2H) 9.30 (s, 1H, =CH); 13C NMR (75 MHz, CDCl3): δ 21.32, 128.52, 129.34, 129.43,129.91 130.9, 131.27, 140.36, 141.64, 143.19. MS(ESI)+: m/z= 298 [M+H]+.
7-Bromo-3-(4-methylphenyl)pyrido[2,3-b]pyrazine (3j): Solid; Yield 89.0%; mp 118-120oC; IR: νmax 2928, 2855, 1785, 1587, 1432, 1365, 1123, 986, 874, 823, 753 cm-1 .; 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H, CH3); 7.34-7.39 (d, J= 8.309Hz,4H, Ar-H); 7.5-7.7 (m, 1H, Ar-H); 8.19-8.26 (d, J=8.30 Hz, 2H, Ar-H); 8.59-8.6 (d, J=2.26 Hz, 1H, Ar- H); 9.14-9.16 (d, J= 2.26Hz, 1H, Ar-H); 13C NMR (75MHz, CDCl3): δ 21.324, 124.56, 125.32,126.39, 127.89, 28.16, 129.86, 129.91, 131.26, 132.82, 133.14, 124.57, 127.77, 128.87, 129.22, 129.29, 129.69, 133.38, 134.14, 141.67, 142.37, 148, 3.71.
2-(Biphenyl-4-yl) quinoxaline (3k): Solid; Yield 95%; mp 116- 118oC; IR: νmax 2924, 1722, 1677, 1533,1417, 1303, 1127, 953, 914, 844, 722 cm-1 . 1H NMR (300 MHz, CDCl3): δ 7.36-7.39 (d, J=7.16 Hz, 1H, Ar-H); 7.42-7.49 (t, J= 7.36 Hz, 2H, Ar-H); 7.61-7.67(d, J=7.17 Hz, 2H, Ar-H); 7.7-7.79 (m,4H, Ar-H); 8.1-8.17 (t, J=10.9 Hz, 2H, Ar-H); 8.28 -8.33 (d, J=8.30 Hz, 2H, Ar-H); 9.36 (s, 1H, =CH).13C NMR (75 MHz, CDCl3): δ 124.57, 127.77, 128.87, 129.22, 129.29, 129.69, 133.38, 134.14, 141.67, 142.37, 143.
Results and Discussion
In order to optimize the reaction conditions, including solvents and temperature, and a suitable catalyst for the preparation of quinoxalines from o-phenylene diamine and α-halo-ketones, the condensation of o-phenylenediamine, with phenacyl bromide was chosen as a model reaction, and its behavior was studied in the presence of different catalysts and without catalyst in CH3CN at reflux temperature. The results are listed in Table 1. As Table 1 indicates, pTSA, PMA solid, FeCl3 gave relatively good yields of the product in long reaction times: however by using 5%WO3/ZrO2, the product was produced in excellent yield in very short reaction time. Thus, 5%WO3/ZrO2 was the catalyst of choice for all the reactions (Scheme 1).
Subsequently, we investigated on the use of different solvents for the purpose. In chlorinated solvents such as dichloromethane and chloroform the reaction was very slow and resulted in lower product yield. Similar results were obtained in coordinating solvents such as THF, diethyl and dimethyl ether. On the other hand, conducting the reaction in inert solvents such as CH3CN improved the reaction rates as well as product yields. After screening different solvents, CH3CN came out as the solvent of choice, which not only afforded the products in good yield, but also with higher reaction rates (90% yield in 0.5 hours) (Table 1). It is also noticed that the condensation using 5% WO3/ZrO2 proceeds rapidly and is superior to the different reagents with respect to reaction time, temperature and yield. This claim is justified through the representative examples, illustrated in Table 1, in which the efficiency of 5% WO3/ZrO2 has been compared with those of different Lewis/protic acid catalysts (Table 1). The formation of compound 3a was evident from the appearance of [M+H]+ peak at m/z 221 in mass spectrum (ESI), C-H stretching at 2923 cm-1, C=N stretching at 1727 cm-1 in IR and the appearance of methyl protons as singlet at δ 2.45 and the characteristic proton of quinoxalines at δ 9.29 in 1H NMR.
To establish the generality and scope of our method, various phenacyl bromides have been reacted with o-phenylenediamine. The results are displayed in Figure 1. As seen, the reaction proceeds efficiently and the respective quinoxalines were obtained in good to excellent yields and shorter reaction times.
In continuation of our studies [25-30] towards the synthesis of novel compounds as useful biologically active compounds, we report in this communication an efficient synthesis of quinoxalines derivatives. To the best of our knowledge, in the literature there appear no reports for the synthesis and screening of quinoxalines derivatives using ZrO2/ WO3. This fact has prompted us to investigate in depth the utility of 5% WO3/ZrO2 for the synthesis of quinoxalines.
The effect of electron releasing and electron with drawing substituent on the aromatic ring of phenacyl bromides on the reaction was investigated. As Figure 1 demonstrates, electron releasing groups and electron withdrawing groups did not affect significantly on the yields and the reaction times (Figure 1, entries 2, 3 and 4, 5, 6). Using 1,2-diamines possessing electron-withdrawing substituent needed longer reaction times and the yields were lower (Table 2, entry 10).
Ease of recycling of the catalyst is one of the most advantages of our method. For the reaction of o-phenylenediamine,with phenacyl bromide no significant loss of the product yield was observed when 5%WO3/ZrO2 was used after four times recycling (Table 2) (Scheme 2).
Conclusion
In conclusion, we have successfully synthesized and characterized derivatives of substituted quinoxalines using a catalytic amount of 5%WO3/ZrO2. This simple procedure is efficient and can be applied to a wide variety of phenacyl bromides. Shorter reaction times and excellent product yields make this catalytic system an alternative method for the synthesis of substituted quinoxaline derivatives. Further application to explore this simple catalytic system for construction of biological molecules is under progress. The remarkable catalytic activity of 5%WO3/ZrO2 exhibited is convincingly superior to the recently reported other catalytic methods with respect to reaction time, amount of catalyst used. Easy workup and ready availability of the catalyst makes the procedure superior over the existing methods. Environmental acceptability, low cost, high yields and recyclability of the 5%WO3/ZrO2 are the important features of this protocol. Furthermore the present protocol is readily amenable to parallel synthesis and generation of combinatorial substituted quinoxaline libraries.
Acknowledgements
The authors are gratefully acknowledged to the DST-SERB/EMEQ-078/2013 for the financial support.
References

Tables and Figures at a glance

 

Table icon Table icon
Table 1 Table 2

 

Figures at a glance

 

Figure Figure Figure
Figure 1 Scheme 1 Scheme 2
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Article Usage

  • Total views: 11560
  • [From(publication date):
    May-2014 - Oct 18, 2017]
  • Breakdown by view type
  • HTML page views : 7774
  • PDF downloads :3786
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords