Efficient synthesis of some new 2,3-dimethylquinoxaline-1-oxides using bis(acetoxy)phenyl-λ 3-iodane as an oxidant

Article abstract of DOI:10.1080/00397911.2013.832775

A series of 2-(arylimino)-3-(hydroxyimino)butanes 3a-g, easily accessed by the condensation of variously substituted anilines 1a-g with biacetyl monoxime 2, were efficiently cyclized to afford 2,3-dimethylquinoxaline-1-oxides 4a-g using bis(acetoxy)phenyl-λ ³-iodane as an oxidant. This methodology utilizes a commercially available and environmental benign oxidant to achieve the title compounds in excellent yields under mild conditions. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.832775

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Efficient Synthesis of Some New 2,3-
Dimethylquinoxaline-1-oxides Using
3
Bis(acetoxy)phenyl-λ -iodane as an
Oxidant
Ranjana Aggarwal a , Chinu Rani a & Garima Sumran a
a Department of Chemistry , Kurukshetra University , Kurukshetra ,
Haryana , India
Accepted author version posted online: 08 Nov 2013.Published
online: 24 Feb 2014.
To cite this article: Ranjana Aggarwal , Chinu Rani & Garima Sumran (2014) Efficient Synthesis of
3
Some New 2,3-Dimethylquinoxaline-1-oxides Using Bis(acetoxy)phenyl-λ -iodane as an Oxidant,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:7, 923-928, DOI: 10.1080/00397911.2013.832775
To link to this article: http://dx.doi.org/10.1080/00397911.2013.832775
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Synthetic Communications1, 44: 923–928, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.832775
EFFICIENT SYNTHESIS OF SOME NEW
2,3-DIMETHYLQUINOXALINE-1-OXIDES USING
BIS(ACETOXY)PHENYL-k3-IODANE AS AN OXIDANT
Ranjana Aggarwal, Chinu Rani, and Garima Sumran
Department of Chemistry, Kurukshetra University, Kurukshetra,
Haryana, India
GRAPHICAL ABSTRACT
Abstract A series of 2-(arylimino)-3-(hydroxyimino)butanes 3a–g, easily accessed by the
condensation of variously substituted anilines 1a–g with biacetyl monoxime 2, were
efficiently cyclized to afford 2,3-dimethylquinoxaline-1-oxides 4a–g using bis(acetoxy)
phenyl-k3-iodane as an oxidant. This methodology utilizes a commercially available and
environmental benign oxidant to achieve the title compounds in excellent yields under mild
conditions.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-(Arylimino)-3-(hydroxyimino)butanes; bis(acetoxy)phenyl-k3-iodane; 2,3-
dimethylquinoxaline-1-oxides
INTRODUCTION
Heterocycles are ubiquitous scaffolds in pharmacologically active compounds,
agrochemicals, and natural products. Quinoxaline systems, in particular, constitute a
privileged substructure and are present in a large number of compounds with diverse
biological activities such as cytotoxic agents and CB2 receptor agonists.[1] The
quinoxaline ring system represents the core skeleton of various antibiotics, for
example, triostin A, quinomycin, levomycin, and actinoleutin. Interestingly,
quinoxaline N-oxide and its derivatives also exhibit antileishmanial, antimalarial,
anti-inflammatory, trypanocidal, anticancer, antituberculosis, and antimycobacterial
Received June 18, 2013.
Address correspondence to Ranjana Aggarwal, Department of Chemistry, Kurukshetra University,
Kurukshetra 136 119, Haryana, India. E-mail: ranjanaaggarwal67@gmail.com; ranjana67in@yahoo.com
923

924
R. AGGARWAL, C. RANI, AND G. SUMRAN
activities.[2] Methyl-3-[(2-quinoxalinyl)methylene]carbazate-N,N0-dioxide, commer-
cially known as carbadox,[3] has proven to be an efficient antibacterial and
growth-promoting material. Penicillin derivatives of quinoxaline N,N0-dioxide
carboxylic acids[4] exhibit remarkable activity against Salmonella and Proteus
species.[5]
Because of the broad biological properties, a variety of approaches have been
developed for the preparation of quinoxaline-N-oxides. The most common method
for the synthesis of quinoxaline N-oxides involves the N-oxidation of quinoxaline
by using different oxidizing reagents such as hydrogen peroxide, peracetic acid,
peroxyformic acid, m-chloroperbenzoic acid, monoperphthalic acid, permaleic acid,
and peroxy sulfuric acid in sulfuric acid.[6] Even though this strategy for synthesis
of quinoxaline N-oxides has proven to be efficient and general, all of these syn-
thetic routes share several drawbacks such as drastic reaction conditions, tedious
workup, the use of toxic and corrosive reagents, long reaction times, and poor sel-
ectivity. For example, treatment of 2,3-diphenylquinoxaline with excess of aqueous
H2O2 in acetic acid gives expected 1,4-dioxide along with N,N0-dibenzoyl-o-
phenylenediamine.[7] Quinoxaline-N-oxides have been synthesized successfully by
the reaction of benzofurazan-1-oxide with enones and amines.[8] Maroulis et al.
also have reported the synthesis of some quinoxaline-N-oxides by the oxidative
cyclization of benzil-a-arylimino oximes using lead tetraacetate (LTA).[9] This reac-
tion was regioselective but the choice of reagent was inappropriate because of
highly toxic nature of LTA. To overcome these difficulties, development of a con-
venient protocol for the synthesis of quinxaline-N-oxides is still of paramount
importance.
In recent years, hypervalent iodine compounds, referred as k3-iodanes, are gain-
ing the attention of a number of organic chemists because of their mild and highly
selective oxidizing properties. These reagents have emerged as reagents of choice
for various synthetically useful transformations. The reactivity pattern of k3-iodane
reagents closely resembles with those of organometallic compounds such as salts of
Pd, Pt, Hg(II), Ni(IV), Pb(IV), and Tl(III) as oxidizing agents. k3-Iodane reagents
are commercially available and they do not have undesirable toxic, hazardous, and
harmful effects. Inspired from applications of hypervalent iodine reagents and in con-
tinuation of our previous work on the synthesis of 2,3-diphenylquinoxaline-1-
oxides,[10] we report herein the synthesis of 2-(arylimino)-3-(hydroxyimino)butanes
3 and their oxidation to some new 2,3-dimethylquinoxaline-1-oxides 4 using bis
(acetoxy)phenyl-k3-iodane.
RESULTS AND DISCUSSION
The synthetic approach, illustrated in Scheme 1, starts from the appropriately sub-
stituted anilines (1a–g), which condensed with biacetyl monoxime (2) in toluene to fur-
nish the key intermediates, 2-(arylimino)-3-(hydroxyimino)butanes (3a–g) in 70–80%
yield. Subsequently, synthesis of the title compounds, 2,3-dimethylquinoxaline-1-oxides
(4a–g), was achieved by intramolecular cyclization of 2-(arylimino)-3-(hydroxyimino)-
butanes (3a–g) using bis(acetoxy)phenyl-k3-iodane as an oxidant in dichloromethane
at room temperature (Scheme 1).

2,3-DIMETHYLQUINOXALINE-1-OXIDES
925
Scheme 1. Synthesis of 2,3-dimethylquinoxaline-1-oxides.
The structures of all the newly synthesized compounds 3c–g and 4a–g were
characterized on the basis of infrared (IR), NMR (1H and 13C) spectral data, and
elemental analyses. The known compounds 3a and 3b were identified by the compari-
son of their 1H NMR with those reported in the literature.[11] The IR spectra of com-
pounds 3c–g displayed characteristic absorption bands ranging from 3117 to
1
3142 cmꢀ1 (¼ N-OH). The H NMR spectra of 3c–g displayed two singlets of three
proton intensity each at d 2.02–2.05 ppm and d 2.18–2.21 ppm corresponding to C1
and C4 methyl groups, respectively. It may be noted that methyl adjacent to hydroxyl
imino group (¼ N-OH) is more deshielded than the other methyl group adjacent to
¼N-Ar due to high electronegativity associated with oxygen. One broad singlet of
one proton intensity has also been observed at d 7.95–8.25 ppm due to the hydroxy
imino (¼N-OH) group. The IR spectrum of 4a–g showed the disappearance of the
absorption band in the range 3117–3142 cmꢀ1 (¼N-OH), indicating the conversion
1
of 3 to 4. The H NMR spectra of 4a–g exhibited signals at d 2.69–2.71 ppm and d
2.74–2.77 ppm corresponding to C3-CH3 and C2-CH3, respectively. Protons in the
aromatic region resonated in the range d 7.36–8.75 ppm confirmed formation of
quinoxaline nucleus. Further, disappearance of broad singlet at d 7.95–8.25 ppm
(¼N-OH) also confirmed the oxidation of 2-(arylimino)-3-(hydroxyimino)butanes
(3) to 2,3-dimethylquinoxaline-1-oxides (4). The 13C NMR spectra of 3c–g and
4a–g are given in the experimental part.
A plausible mechanism for the conversion of 3 to 4 is outlined in Scheme 2. It is
assumed that generation of a new I(III) intermediate (5) in the initial step takes place
by the electrophilic attack of bis(acetoxy)phenyl-k3-iodane on the 2-aryliminoximes
(3). This is followed by reductive elimination of iodobenzene and acetic acid to give
2-nitroso-3 (phenylimino)butan-2-ylacetate (6), which undergoes entropy-favored
electrophilic cyclization to afford intermediate 7. Loss of another mole of acetic acid
and spontaneous aromatization leads to the formation of 2,3-dimethylquinoxaline-1-
oxide (4).

926
R. AGGARWAL, C. RANI, AND G. SUMRAN
Scheme 2. Plausible mechanism for the formation of 2,3-dimethylquinoxaline-1-oxides.
EXPERIMENTAL
Melting points were determined in open capillaries in electrical apparatus and
are uncorrected. Infrared spectra were recorded on IR M-500 spectrophotometer
1
(Buck Scientific Inc, Norwalk, CT) in KBr pellets (nmax in cmꢀ1). H (300 MHz)
and 13C NMR (75 MHz) spectra were measured on a Bruker instrument (Billerica,
MA) by using CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard.
Chemical shifts are expressed as d in parts per million (ppm). Coupling constants (J)
are given in hertz (Hz). Elemental analysis was performed at CDRI and the com-
pounds gave satisfactory results (within ꢁ0.05 of the calculated values).
Commercially available variously substituted anilines (1) and biacetyl mono-
xime (2) were used without further purification.
General Procedure for the Synthesis of 2-(Arylimino)-3-
(hydroxyimino)butane 3
A solution of biacetyl monoxime 1 (10.1 g, 0.1 mol) and an appropriately
substituted aniline 2 (0.1 mol) in toluene (20 ml) was refluxed for 4–5 h. The progress
of the reaction was monitored by thin-layer chromatography (TLC). On completion
of the reaction, excess solvent was distilled off in a vaccum. The solid thus obtained
was recrystallized from ethanol to give 3.
2-(4-Methoxyphenylimino)-3-(Hydroxyimino)butane (3c)
1
Yield 82%; mp 143–144 ꢂC; H NMR (CDCl3) d: 2.05 (s, 3H, -CH3), 2.21 (s,
3H, -CH3), 3.83 (s, 3H, -OCH3), 6.72 (d, 2H, J ¼ 8.7 Hz, Ph-3, 5-H), 6.94 (d, 2H,
J ¼ 8.7 Hz, Ph-2, 6-H), 8.13 (s, 1H, OH); 13C NMR (CDCl3) d: 9.30, 15.54, 55.48,
114.25, 120.62, 143.68, 156.34, 159.04, 164.45; IR (cmꢀ1): 3117 (OH), 3086 (C-H),

2,3-DIMETHYLQUINOXALINE-1-OXIDES
927
1612, 1504. Anal. calcd. for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C,
64.11; H, 6.86; N, 13.55.
General Procedure for the Synthesis of 2,3-Dimethylquinoxaline-
1-oxide 4
Bis(acetoxy)phenyl-k3-iodane (0.354 g, 0.0011 mol) was added to a solution of
3 (0.001 mol) in dichloromethane (20 ml) in small portions over a period of 5 min at
room temperature. The reaction mixture was allowed to stir for 5 h at room tempera-
ture. The progress of the reaction was monitored by TLC. When all the starting
material had been consumed, excess solvent was distilled off in vacuo to give a
gummy residue containing the product and iodobenzene. The residue was triturated
with petroleum ether to remove iodobenzene, and a solid was obtained that was
recrystallized from aqueous ethanol to give 4.
7-Methoxy-2,3-dimethylquinoxaline-1-oxide (4c)
Yield 72%; mp 128–132 ꢂC; 1H NMR (CDCl3) d: 2.71 (s, 3H, 3-CH3), 2.74 (s, 3H,
2-CH3), 4.00 (s, 3H, 7-OCH3), 7.38 (dd, 1H, Jo ¼ 9.0 Hz, Jm ¼ 2.4 Hz, 6-H), 7.89 (s, 1H,
5-H), 7.92 (s, 1H, 8-H); 13C NMR (CDCl3) d: 13.99, 23.43, 56.10, 97.27, 123.24,
130.37, 136.31, 139.55, 151.72, 160.75; IR (cmꢀ1): 3048 (C-H), 1612, 1498. Anal. calcd.
for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.74; H, 5.94; N, 13.70.
1
Complete experimental details and H and 13C NMR spectra are given in the
Supporting Information, available online.
CONCLUSION
In conclusion, we have developed an efficient and ecofriendly method for the
synthesis of some new 2,3-dimethylquinoxaline-1-oxides from 2-(arylimino)-3-
(hydroxyimino)butanes using bis(acetoxy)phenyl-k3-iodane as an oxidant.
ACKNOWLEDGMENTS
The authors are grateful to the Council of Scientific and Industrial Research,
New Delhi, India, for providing financial assistance to Chinu Rani, in the form of
junior and senior research fellowships. Thanks are also extended to the Sophisticated
Analytical Instrument Facility, Central Drug Research Institute, Lucknow, for pro-
viding elemental analyses.
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