Effective promotion of beirut reaction by-cyclodextrin in water

Article abstract of DOI:10.1080/00397911.2010.517371

A mild and highly efficient, environmentally friendly procedure has been developed for the conversion from benzofurazan-N-oxides to quinoxaline di-N-oxides in the presence of-cyclodextrin in water at room temperature with excellent yields. The application of cyclodextrin precludes the use of organic solvent, and the catalyst can be recovered and reused in subsequent reactions with the same catalytic activity. Herein, the Beirut reaction is carried out in the medium of water for the first time. The reaction mechanism was proposed based on the inclusion complexation of-cyclodextrin with benzofurazan-N-oxides which was confirmed by 1H NMR, ultraviolet/visible spectrum, and infrared spectroscopy. Copyright

Full text of DOI:10.1080/00397911.2010.517371

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Effective Promotion of Beirut Reaction
by β-Cyclodextrin in Water
Tao Sun a , Wen-Jing Zhao a , Ai-You Hao a & Li-Zhen Sun a
a School of Chemistry and Chemical Engineering, Shandong
University, Jinan, China
Version of record first published: 11 Jul 2011.
To cite this article: Tao Sun , Wen-Jing Zhao , Ai-You Hao & Li-Zhen Sun (2011): Effective Promotion
of Beirut Reaction by β-Cyclodextrin in Water, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 41:20, 3097-3105
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Synthetic Communications1, 41: 3097–3105, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517371
EFFECTIVE PROMOTION OF BEIRUT REACTION BY
b-CYCLODEXTRIN IN WATER
Tao Sun, Wen-Jing Zhao, Ai-You Hao, and Li-Zhen Sun
School of Chemistry and Chemical Engineering, Shandong University,
Jinan, China
GRAPHICAL ABSTRACT
Abstract A mild and highly efficient, environmentally friendly procedure has been developed
for the conversion from benzofurazan-N-oxides to quinoxaline di-N-oxides in the presence
of b-cyclodextrin in water at room temperature with excellent yields. The application of
cyclodextrin precludes the use of organic solvent, and the catalyst can be recovered and
reused in subsequent reactions with the same catalytic activity. Herein, the Beirut reaction
is carried out in the medium of water for the first time. The reaction mechanism was pro-
posed based on the inclusion complexation of b-cyclodextrin with benzofurazan-N-oxides
1
which was confirmed by H NMR, ultraviolet=visible spectrum, and infrared spectroscopy.
Keywords Benzofurazan-N-oxides; catalysis; cyclodextrin; green chemistry; quinoxaline
di-N-oxides; water
INTRODUCTION
The compounds of quinoxaline di-N-oxide (QXO) have been widely used as
important drugs for sterilization and growth-promotion of animals. QXO also has
pharmacological properties that make them usable as intermediates for producing
Received November 7, 2009.
Address correspondence to Ai-You Hao, School of Chemistry and Chemical Engineering,
Shandong University, Jinan, 250 100, China. E-mail: haoay@sdu.edu.cn
3097

3098
T. SUN ET AL.
plant-protection agents.[1] Previous methods of synthesis of QXO involve the
oxidation of quinoxaline with poor yields and present great trouble in separation.[2]
To solve the problem, an efficient and straightforward synthetic path, the Beirut
reaction, from benzofurazan-N-oxides (BFO) to QXO was developed. It was gener-
ally carried out in organic solvents in the presence of amines, which were used as the
catalysts.[3] However, this method needs a long time (overnight), and the application
of organic solvent would also cause environmental problems. Also, when BFO is
mixed with reducing amine, an explosion might happen because of the high energy
of the BFO molecule.[4] These reactions were unsuccessful in water alone[5] because
of the poor solubility and inert nature of BFO. Furthermore, much by-product is
generated and therefore the yield is poor.
We have explored Beirut reactions using water as the reaction medium at room
temperature. The best choice appeared to be through supramolecular catalysis
involving cyclodextrins (CDs), with water as solvent, because such reactions do
not generate toxic waste products. Thus, an attractive procedure for the synthesis
of QXO from BFO, different from the classical approach, was developed for the first
time under supramolecular catalysis in water in the presence of b-CD at room
temperature (Scheme 1).
Because green chemistry is becoming a central issue in both academic and
industrial research in the 21st century,[6] the integration of catalysis with facile cata-
lyst separation and recycling should be a primary focus of future research activities.
The toxic and volatile nature of organic solvents widely used in organic synthesis
also has posed a serious threat to the environment. Water is considered as an ideal
solvent because it is safe, economical, and environmentally benign.[7] Room-
temperature synthesis of the target molecule is also of particular interest for the
concern of saving energy.
CDs, cyclic oligosaccharides commonly composed of six, seven, or eight
D-glucopyranosyl units connected by a-(1,4)-glycosidic linkages, have the ability
to form inclusion complexes with a wide range of substrates in aqueous solution
for their particular structures (Scheme 2). Complexation depends on the size, shape,
Scheme 1. Beirut reaction in the presence of b-cyclodextrin in water.

b-CYCLODEXTRIN PROMOTES BEIRUT REACTION
3099
Scheme 2. Structures of cyclodextrins.
and hydrophobicity of the guest molecule. This property has led to their wide
applications as enzyme mimics and catalysts.[8] They promote reactions by
supramolecular catalysis involving reversible formation of host–guest complexes
by noncovalent bonding as observed in enzymes.
In general, the reaction was carried out by the in situ formation of the b-CD
complex of BFO in water followed by the addition of the nucleophile, which was
then stirred at room temperature for a short time to give the corresponding QXO
with impressive yields (Table 1).
The reaction went smoothly at room temperature and was monitored by
thin-layer chromatography (TLC). All the products were characterized by 1H
NMR, infrared (IR), mass spectroscopy, elemental analysis, and otherwise compared
with the known compounds.[3] In the absence of b-CD, the reaction did take place
with a poor yield (less than 40%). b-CD can be recycled and reused without loss of
the catalytic activity. The complex inclusion takes place in situ during the process,
1
and the complex has been isolated and characterized by H NMR and IR studies.
During the reaction, a homogeneous solution was formed. In the absence of
b-CD, the reaction mixture was suspended in liquid. This indicates that b-CD and
BFO may form an inclusion complex. The fact that the yields were so poor in the
absence of b-CD and also that BFO is insoluble in water shows the primary role that
CD plays: the solubilization of BFO through b-CD in water. The inclusion complex
of b-CD and BFO in these b-CD-catalyzed reactions in water has been postulated
and confirmed by spectroscopic evidence as follows: Evidence to this mechanistic
1
approach was deduced from H NMR, ultraviolet=visible (UV-vis) spectrum, and
IR spectroscopy. A comparison of the 1H NMR spectra (D2O) of b-CD and
b-CD-BFO complex was undertaken (Table 2). It could be seen that there is a clear
upfield shift of H-5 (0.010 ppm) protons of b-CD in the b-CD-BFO complex as com-
pared to b-CD, indicating the formation of an inclusion complex of BFO with b-
1
CD.[9] Based on the H NMR results, it could be seen BFO and b-CD might form
some kind of complex (Fig. 1).
The complex stoichiometry of BFO=b-CD was confirmed by UV spectroscopy
using Job’s plot method. The experimental curve (Fig. 2), describing the interactions
between BFO and b-CD in the aqueous solution, goes through a maximum at a
molar fraction of 0.5, which indicates that the complex stoichiometries of BFO=
b-CD in aqueous solution are 1:1.[10] The intermolecular interactions between
=
BFO (guest) and b-CD (host) in water can be represented as follows: G þ H G ꢀ H.
Moreover, a comparison of the Fourier transform (FT)–IR spectra of BFO,
b-CD, the solid inclusion complex, and the physical mixture of BFO=b-CD was also

3100
T. SUN ET AL.
Table 1. Beirut reaction in the presence of b-cyclodextrin
Entry
Substrate
Producta
Time (min) Conv. (%)b Isolated yields (%)
1
2
3
4
5
CH3CH2CHO
25
35
40
45
20
99
93
95
84
82
75
62
67
71
61
CH3CH2CH2CHO
CH3CO(CH2)4CH3
CH3COCH2COCH3
aAll the products were characterized by 1H NMR, IR, or elemental analysis.
bThe product purity without isolation as detected by HPLC.
undertaken (Table 3). In the physical mixture of BFO=CD, N!O stretching absorp-
tion in the region 1429 cmꢁ1 disappeared in the solid inclusion complex, which
proved hydrogen bonding was formed to weaken the N!O bond. In the physical
Table 2. Comparison of the inclusion of CD=BFO and CD
Inclusion of CD=BFO
CD
Status: yellow-white powder
Status: white powder
1H NMR (300 MHz, D2O): d 4.954 (d, H-1),
3.835 (t, H-5), 3.734 (d, H-6), 3.549 (d, H-2),
3.510 (t, H-3), 3.454 (d, H-4)
1H NMR (300 MHz, D2O): d 4.958 (d, H-1),
3.845 (t, H-5), 3.734 (d, H-6), 3.553 (d, H-2),
3.514 (t, H-3), 3.458 (d, H-4)

b-CYCLODEXTRIN PROMOTES BEIRUT REACTION
3101
Table 3. Comparison of the inclusion of CD=BFO and the physical mixture of CD=BFO
Inclusion of CD=BFO
Physical mixture of CD=BFO
Status: yellow-white powder
Status: yellow powder
IR v max (KBr, cmꢁ1): 3410, 2927, 1618, 1590,
1539, 1487, 1414, 1334, 1244, 1156, 1080, 1030,
943, 704, 577.
IR v max (KBr, cmꢁ1): 3443, 2925, 2363, 1616,
1589, 1539, 1485, 1424, 1125, 1016, 893, 835, 750,
671, 572.
Figure 1. Job’s curve of the inclusion complex of BFO=b-CD in the aqueous solution.
mixture, stretching vibration of the hydroxyl group became much wider in the solid
inclusion complex, which might be related to the inclusion between b-CD and BFO.
We can deduce that BFO is included in the cavity of b-CD.[11] It appears that b-CD
not only solubilizes BFO but also forms a b-CD-BFO complex through H bonding,
which may weaken the rigidity of the ring of BFO. Covalence effect, just as the role
enzymes play, may happen to result in the reaction.
The fact that these yields were less in presence of a-CD as the catalyst may be
due to the unsuitable cavity of a-CD for BFO.[12] Besides, b-CD was chosen as the
preferred catalyst because it is inexpensive and easily accessible.
Figure 2. Possible mechanism of the Beirut reaction in the presence of b-cyclodextrin.

3102
T. SUN ET AL.
In conclusion, our methodology provides a new method for Beirut reaction
from BFO to QXO using water as the medium. The reaction proceeds under mild
conditions with a good yield and can be carried out easily at room temperature with
recycling of b-CD. Since we have reported the green syntheis of BFO,[13] our
approach here may provide a new way to produce highly pure and directly used
drugs without further purification.
EXPERIMENTAL
Chemicals and solvents were either purchased or purified by standard techni-
ques. b-CD was purchased from Guangdong Yunan Chemical Reagent Co. Ltd.
and recrystallized twice from distilled water before application.
Melting points were recorded on a digital melting-point apparatus (WRS-1B)
and are uncorrected. An IR spectrum was recorded on an Avatar 370 FI-IR
1
spectrophotometer. H NMR spectra was recorded on a Bruker Avance III–300
and Bruker Avance III–400 using dimethylsulfoxide (DMSO) or D2O as the solvent
with tetramethylsilane (TMS) as an internal standard at room temperature. Chemi-
cal shifts are given in d relative to TMS; the coupling constants J are given in hertz.
UV=vis spectra were recorded at room temperature with a TU-1800 pc UV=vis
spectrophotometer. TLC analysis was performed on glass plates precoated with sil-
ica gel F254 obtained from Qingdao Haiyang Chemicals, China. High-performance
liquid chromatography (HPLC) analysis was performed on a Shimadzu LC-10AT
HPLC with a Shimadzu SPD-10A UV-vis detector (detection wavelength¼ 260 nm),
and the mobile phase was selected as a mixture of methanol and water (Vmethanol
=
VH2O ¼ 70=30) with a 1.0 ml=min flow rate.
Preparation of BFO: General Procedure
To a mixture of o-nitro aniline (10 g), 95% ethanol (50 mL), and KOH (3 g), 8%
sodium hypochlorite (25 ml) was added slowly while stirring. The mixture was stirred
at room temperature for 2.5 h. The progress of the reaction was monitored by TLC.
After completion of the reaction, water (20 ml) was added, and a great deal of
precipitation appeared. The precipitate was collected by filtration under reduced
pressure. The crude product was further purified by recrystallization (Vmethanol
1
=
VH2O ¼ 4=1) to provide the pure product in about 90% yields (characterized by H
NMR, IR, and elemental analysis).
Beirut Reaction in Presence of b-CD in Water
b-CD (1 mmol) and NaOH (1 g) was dissolved in water (50 mL) and a clear sol-
ution was formed. BFO (1 mmol) dissolved in methanol (1 mL) was added dropwise
and stirred for half an hour until the inclusion was formed. Then, the carbonyl
compound (4 mmol) was added and the mixture was stirred at temperature until
the reaction was complete (as monitored by TLC, Vethyl acetate=Vpetroleum ¼ 5=1).
The mixture was extracted with ethyl acetate (20 ml ꢂ 3), and the extract was col-
lected. The organic layer was dried over anhydrous Na2SO4, and the solvent was
removed under reduced pressure. The product was directly tested by HPLC. The

b-CYCLODEXTRIN PROMOTES BEIRUT REACTION
3103
resulting product can be further purified by column chromatography using a mixture
of ethyl acetate and petroleum (Vethyl acetate=Vpetroleum ¼ 10=1) as the eluent. After
neutralization of the mixture and removal of the water under reduced pressure, b-
CD was recovered by filtration with an 85% yield and reused for five consecutive
runs in this reaction without change in the yield or purity of the product. The control
experiment was carried out at the same conditions except for the addition of b-CD.
Preparation of Inclusion of b-CD/BFO
b-CD (1.05 mmol), and KOH (3 g) was dissolved in water (25 ml), and a clear
solution formed. BFO (1 mmol) dissolved in methanol (1 mL) was added dropwise
and stirred for half an hour until precipitation appeared. The precipitate was
collected by filtration under reduced pressure, washed with water, and dried.
Detection of the Stoichiometries of BFO/b-CD Complex
Two equimolar stock solutions (10ꢁ3 mol=L), one of BFO (g) and the other of
b-CD (h), were prepared. A set of working solutions was then obtained by mixing Vg
mL of the stock BFO solution with (Vt ꢁ Vh) mL of the stock b-CD’s solution, where
Vt is a fixed total volume and Vg is a variable value (from 0 to 10 mL, 0 ꢃ Vg ꢃ Vt).
Experimental Characterization Data for the Obtained Compounds
BFO. Yellow powder; mp ¼ 66–67 ꢄC; 1H NMR (400 MHz, DMSO-d6): d 7.69
(2H, s, Ar-H), 7.46 (2H, s, Ar-H); IR n max (KBr, cmꢁ1): 3443, 2925, 2363, 1616,
1589, 1539, 1485, 1424, 1125, 1016, 893, 835, 750, 671, 572. Anal. calcd. for
C6H4N2O2: C, 52.94; H, 2.94; N, 20.59. Found: C, 52.56; H, 2.99; N, 20.52.
1
Compound 1. Yellow powder; H NMR (400 MHz, DMSO-d6): 8.80 (1H, s,
CH), 8.48–8.42 (2H, q, Ar-H), 7.98–7.89 (2H, m, Ar-H), 3.15 (3H, t, CH3). Calcd.
for C9H8N2O2: C, 61.00; H, 4.55; N, 15.81. Found: C, 60.49; H, 4.80; N, 15.51.
1
Compound 2. Yellow powder; H NMR (400 MHz, DMSO-d6): d 8.69 (1H,
s, CH), 8.49–8.42 (2H, m, Ar-H), 7.97–7.91 (2H, m, Ar-H), 2.90 (2H, q, CH2), 1.26
(3H, t, CH3); IR n max (KBr, cmꢁ1): 3437, 3072, 3021, 2973, 2941, 1636, 1605, 1537,
1501, 1453, 1433, 1367, 1338, 1267, 1241, 1172, 1119, 1096, 1068, 916, 892, 868, 837,
770, 740, 637, 612, 541. Calcd. for C10H10N2O2: C, 63.14; H, 5.30; N, 14.73. Found:
C, 62.96; H, 5.369; N, 14.65.
Compound 3. White powder; 1H NMR (400 MHz, DMSO-d6): 8.50–8.46
(2H, m, Ar-H), 7.93–7.88 (2H, m, Ar-H), 3.10–3.05 (2H, t, CH2), 2.61 (3H, s,
CH3-methy), 1.65–1.55 (2H, m, CH2), 1.49–1.40 (2H, m, CH2), 0.96–0.91 (3H, t,
CH3-butyl). Calcd. for C12H12N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.17;
H, 6.90; N, 12.01.
1
Compound 4. Yellow powder; H NMR (400 MHz, DMSO-d6): d 8.43 (2H,
d, J ¼ 3.5 Hz, Ar-H), 7.88 (2H, d, J ¼ 3.2 Hz, Ar-H), 2.93 (4H, s, CH2), 1.83 (4H, s,
CH2); IR n max (KBr, cmꢁ1): 3455, 3125, 2943, 2866, 1987, 1953, 1737, 1605, 1516,
1441, 1422, 1400, 1357, 1315, 1277, 1246, 1125, 1089, 1016, 979, 933, 904, 842, 824,

3104
T. SUN ET AL.
776, 694, 668, 640, 613, 557, 528, 436. Calcd. for C12H12N2O2: C, 66.65; H, 5.59; N,
12.96. Found: C, 66.34; H, 5.32; N, 12.90.
1
Compound 5. Yellow powder; H NMR (300 MHz, DMSO-d6): d 8.51–8.43
(2H, m, Ar-H), 8.04–7.95 (2H, m, Ar-H), 2.66 (3H, s, CH3), 2.37 (3H, s, CH3); IR n
max (KBr, cmꢁ1): 3438, 1717, 1635, 1518, 1419, 1333, 1280, 1214, 1098, 1053, 967,
830, 776, 638, 613, 513. Calcd. for C11H10N2O3: C, 60.55; H, 2.78; N, 12.84. Found:
C, 60.35; H, 2.89; N, 12.18.
All compounds were compared with the known (prepared through the formal
synthetic method[3]) by TLC (with the same Rf values) and HPLC (with the same
retention times).
ACKNOWLEDGMENTS
This work was supported by the NSFC (Grant No. 20625307), the National
Basic Research Program of China (973 Program, 2009CB930103), and the Graduate
Independent Innovation Foundation of Shandong University (GIIFSDU,
´
yzc09057). We thank Dr. Z. Yang from Universite Pierre et Marie Curie for editing
the manuscript for language corrections.
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