One-pot heterocondensation for benzoxazinone derivatives using sodium perborate as catalsyt

Article abstract of DOI:10.3987/COM-07-11046

An efficient synthesis of series of benzoxazinones, employing sodium perborate tetrahydrate (SPB) as a condensing agent is described. SPB in water and formic acid system is proved as a selective catalyst of hydration for cyanides. The rate enhancement and

Full text of DOI:10.3987/COM-07-11046

HETEROCYCLES, Vol. 71, No. 7, 2007
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HETEROCYCLES, Vol. 71, No. 7, 2007, pp. 1615 - 1622. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd March, 2007, Accepted, 23rd April, 2007, Published online, 24th April, 2007. COM-07-11046
ONE-POT
HETEROCONDENSATION
FOR
BENZOXAZINONE
DERIVATIVES USING SODIUM PERBORATE AS CATALYST
Mazaahir Kidwai,* Priya, and Kavita Singhal
*Green Chemistry Research Laboratory, Department of Chemistry, University of
Delhi, Delhi-110007, India
Telefax: 91-11-27666235; kidwai.chemistry@gmail.com
Abstract – An efficient synthesis of series of benzoxazinones, employing sodium
perborate tetrahydrate (SPB) as a condensing agent is described. SPB in water and
formic acid system is proved as a selective catalyst of hydration for cyanides. The
rate enhancement and high yield is attributed to the coupling of suitable catalyst
with this solvent system. This methodology eliminates the number of steps during
the reaction.
INTRODUCTION
Efavirenz (Sustiva), a benzoxazinone derivative, is a non-nucleoside reverse transcriptase inhibitor that was
approved by the FDA in 1998 and is presently in clinical use for the treatment of AIDS. The fight against
HIV by developing more efficacious drugs than Efavirenz has been the prime driving force for
benzoxazinone derivatization which has attained considerable attention.1-6 The derivatives of
benzoxazinone have also reported to possess progesterone receptor modulatory,7 peroxisome proliferatory
activated receptory8,9 and antimycobacterial activities.10,11
Recent years have witnessed a phenomenal growth in the reactions occurring in aqueous medium,12 safe
handling and usage of less expensive catalysts.13 SPB14 (sodium perborate), being cheap and large
industrial chemical (over 500,000 tons per annum), is used as a source of “active oxygen” in detergents,
means is alternative to various forms of chlorine for fibre bleaching. Further, few applications are found in
organic synthesis15-19 and here its potential utility examined as a selective hydrolyzing agent for organic
transformations. Moreover, it is a reagent of choice for these types of synthesis, by serving as a viable
alternative to peroxides and peroxy acids as safer reagent results in relatively innocuous side products.20,21
Keeping in view of all these above reports it was thought worthwhile to perform one-pot
heterocondensation of o-hydroxy aromatic aldehydes, hydroxylamine hydrochloride and various aromatic
or heteroaromatic aldehydes to afford 2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-4-ones.
The

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HETEROCYCLES, Vol. 71, No. 7, 2007
application of water-formic acid-SPB system in conjunction with one-pot heterocondensation provides
unique chemical processes with special attributes in context of green chemistry. Thus, this protocol should
be welcome in these environmentally conscious days.
RESULTS AND DISCUSSION
Since literature22-26 revealed that 2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-4-one synthesis were
carried out in three different steps. Firstly, o-hydroxybenzonitrile (3) was prepared consisting two
functional groups (–CN and –OH). Among these two, only the cyano group is transformed to yield
corresponding amides (–CONH2) in the presence of various oxidising agents to yield o-hydroxybenzamide
intermediate (4) in step 2. Then in final step intermediate (4) undergoes cyclization reaction with aldehydes
(5a-g) to give 2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-4-ones (6a-i) as product. To carry out such
synthesis in three steps is not only tedious with reduced yields but that requires hazardous chemicals27 like
HCl,28 secondary amines (pyrrolidine, morpholine) as base29 which contaminates final products. As
isolation of the intermediates and the re-employing it as a reactant or substrate for target moiety synthesis
led to yield losses as compared to one-pot heterocondensation synthesis. By optimizing the reaction
conditions to obtain the desired product successfully, considering the sufficient purity in lesser time, an
attempt has been made to develop new simple procedure for the preparation of heterocyclic compounds of
biological interest. We report herein, for the first time a three component condensation of
o-hydroxyaromatic aldehydes (1), hydroxylamine hydrochloride (2) and various aromatic or
heteroaromatic
aldehydes
(5a-i),
catalysed
by
SPB
to
give
final
moiety
(2,3-dihydrobenzo[e][1,3]oxazin-4-ones) as shown in Scheme 1. Various experimental trials were carried
out to standardise the reaction conditions. The key element in our approach is the novel utilization of
o-hydroxyaromatic aldehydes (1) as a bifunctional building block whose application to the construction of
various benzofused oxygen heterocycles of chemical and biological interest is investigated.
o-Hydroxy aldehyde (1) was taken with hydroxylamine hydrochloride in formic acid, where in situ formed
oxime get transformed to cyanide via the elimination of water to give o-hydroxybenzonitrile (3) without
touching the OH group. The completion of this transformation was checked by TLC which then followed
by the addition of SPB dissolved in water and aldehyde (aromatic/heteroaromatic) and the reaction
proceeds efficiently. Here, SPB specifically hydrolises the cyano group of (3) to amide, here again the
hydroxyl group remained as such and leads to o-hydroxybenzamide (4) intermediate in the reaction mixture
itself. The addition of aqueous solution of SPB makes this synthetic procedure mild and catalytic. As
shown in Table 1, both aromatic and heteroaromatic aldehydes were tolerated equally to cyclize and gave
final products (6a-i) in good to excellent yields. The best suitable solvent for the onward steps is the system
of formic acid and water (1:1, v/v). To our surprise, the addition of water to formic acid in the first step,

HETEROCYCLES, Vol. 71, No. 7, 2007
1617
leads to no product formation as the elimination of water becomes harder. Other solvents and different
solvent found systems like methanol, acetonitrile, ethyl acetate, chloroform, ethanol: water, chloroform:
water, were also tried, but found to possess poor solubility of both hydroxylamine hydrochloride and SPB
leads to very low yield (21-30%). In the course of optimization for the second step of these reaction
conditions, the reason for the low yields (21-30%) is the regeneration of the corresponding amides (in step
3) through hydrolysis. Although polar solvents deactivate the activity of catalysts to some extent, we
discovered that the reaction in the water and formic acid system is very effective in the presence of 5
equivalents of catalyst.
R1
R1
OH
CN
OH
HCO2H
Step 1
+
NH2OH HCl
R2
R2
CHO
2
1
3
NH2OH HCl
2
SPB, H2O
R3CHO (5a-i)
HCO2H
Step 2
SPB, H2O
R1
R1
R3
O
O
OH
R3CHO (5a-i)
NH
Step 3
R2
R2
CONH2
4
(6a-i)
Scheme 1
When the conversion of CN to CONH2 group completed, the intermediate o-hydroxybenzamide starts
condensing to give cyclized product with aldehydes (already present in the reaction mixture) immediately.
At such mentioned reaction conditions, it was suspected that formic acid itself could react with intermediate
(4) instead of aldehydes to give a different cyclized product, but the characterization of final products (6a-i)
ruled out the possibility of product formed by involvement of formic acid. The IR spectra of (6a-i) contain
characteristic absorption bands of stretching vibrations of C=O group at 1665-1680 cm-1. The stretching
vibrations of alkyl groups and alicyclic C–H bonds give rise to absorption in the region of 2960-2870 cm-1,
those of the C–H bonds in the aromatic ring appear at 3060-3030 cm-1. In the IR spectra of compounds 6f
the bands of the fragment C–O–C are observed in the region 1080-1200 cm-1. Also, the 1H NMR spectrum
showed the presence of singlet due to C2-H at δ 7.0-7.15, characterized the formation of product in Scheme
1
1. Apart from IR and H NMR, CHN analysis and mass spectra also supported the proposed product.
Chemical shifts of 13C NMR spectra is in accordance with the desired synthesized products and
confirmation their formation.

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HETEROCYCLES, Vol. 71, No. 7, 2007
Table 1. Reaction times and yields for the synthesis of 2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-
4-one (6a-i)
Com-
Yielda
(%)
No
1
Product
pound
R1
H
R2
H
R3
Time (h)
10-11
O
6a
CHO
85
88
NH
O
O
Cl
2
6b
6c
H
H
H
H
Cl
CHO
10.5-11.5
12.0-12.5
NH
O
1
2'
3'
5'
9
6
10
5
O
1'
4' OMe
8
7
2
MeO
CHO
3 NH
3
4
5
6
95
75
80
84
4
6'
O
HO
OH
O
6d
6e
6f
H
H
H
H
H
H
12.0-13.0
11.5-12.0
12.5-13.5
CHO
NH
O
1
5'
4'
3'
9
6
10
O
1'
8
7
2
S
3 NH
CHO
4
5
S
O
O
O
O
O
O
CHO
NH
O
NO2
3'
1
O
2'
NO2
9
6
10
1'
8
7
4'
2
CHO
7
6g
H
H
85
13.5-14.0
5
3 NH
4
6'
5'
O
OMe
O
8
9
6h
6i
OCH3
H
84
82
12.5-13.0
13.0-13.5
CHO
NH
O
CHO
O
OMe
H
Cl
NH
Cl
MeO
O
a isolated and unoptimized yields.

HETEROCYCLES, Vol. 71, No. 7, 2007
1619
CONCLUSION
Sodium perborate tetrahydrate (SPB) was found to be an excellent homogenous catalyst employed to get
the transformation of o-hydroxybenzonitrile into corresponding amides to provide wide variety of
2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-4-ones in water and formic acid system. SPB is
non-corrosive, water soluble and selective oxidising catalyst which not only extends the scope of organic
synthesis but also a viable substitute for hazardous peroxides and peroxyacids. These results also illustrate
that intermediate 4 is a useful substrate for the generation of an array of oxygen fused heterocycles with
three points of diversity and for synthesis of mentioned target moiety.
EXPERIMENTAL
The temperature of the reaction mixture was measured with a non-contact mini-Gun type IR thermometer
1
(model 8868). IR spectra were recorded on a Perkin-Elmer FTIR-1710 spectrometer using KBr pellets. H
NMR spectra were obtained on Bruker Avance spectrospin 300 (300 MHz) using TMS as internal standard
and chemical shift are in δ. Elemental analysis was performed on a Heraeus CHN-Rapid analyzer. The
melting points (uncorrected) were determined on a Thomas Hoover melting point apparatus. 13C NMR
pectra were recorded on 75.6 MHz on a Bruker Topspin spectrometer (300 MHz). Mass spectra were
recorded on a ToF MS. All reactants were purchased from Sigma-Aldrich and Lanchester and used as such
without further purification.
General procedure for the synthesis of 2-substituted-2,3-dihydrobenzo[e][1,3]oxazin-4-ones (6a-i)
A solution of o-hydroxyaromaticaldehyde (0.01 mol) and NH2OH·HCl (0.013 mol) taken in 99% HCO2H
(5-10 mL) is refluxed for 1-2 h and then added SPB (8.3g, 5 eq.) dissolved in water (5-10 mL) and the
reaction mixture was stirred at 80 °C. The progress of reaction was monitored through TLC (Merck TLC:
mean particle size 10-12 µm; particle size distribution 5-20 µm; layer thickness 250 µm; plate height 30
mm). After 8-10 h, aldehyde (0.01 mol) was added. Upon completion, allow the reaction mixture to cool
and then filter it. The reaction mixture is diluted with water (50-60 mL) neutralized under ice cooling with
5% aqueous NaOH and extracted with Et2O (2 x 30 mL). The ethereal extracted is dried with Na2SO4 and
concentrated using a rotary evaporator to give final product (6a-i) which is further purified by column
chromatography [column of silica gel, elution with n-hexane: AcOEt 9:1 (v/v)].
2-Phenyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6a). Mp 166-168 °C (lit.,29 168 °C). IR νmax (KBr,
cm-1): 3160, 3060, 1675. 1H NMR (300 MHz, CDCl3) δ: 7.07 (s, 1H), 7.31-8.22 (m, 9H, Ar-H), 10.69 (s,
1H, NH). HRMS: M+ 225.0 Anal. Calcd for C14H11NO2: C, 74.66; H, 4.88; N, 6.22. Found: C, 74.65; H,
4.86; N, 6.23.
2-(4-Chlorophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6b). Mp 204-206 °C (lit.,27 205-206 °C). IR
ν
max (KBr, cm-1); 3165, 3060, 1680. 1H NMR (300 MHz, CDCl3) δ: 7.12 (s, 1H), 7.24 (d, 2H, Ar-H), 7.42 (d,

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HETEROCYCLES, Vol. 71, No. 7, 2007
2H, Ar-H), 7.55-8.21 (m, 4H, Ar-H), 10.72 (s, 1H, NH). HRMS: M+ 259.8. Anal. Calcd for C14H10NO2Cl:
C, 64.73; H, 3.85; N, 5.39. Found: C, 64.75; H, 3.85; N, 5.36.
2-(4-Methoxyphenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6c). Mp 165-166 °C (lit.,27 166-167 °C ).
IR νmax (KBr, cm-1); 3175, 3065, 1675. 1H NMR (300 MHz, CDCl3) δ: 3.84 (S, 3H, OCH3), 7.01 (s, 1H),
7.21 (d, 2H, Ar-H), 7.39 (d, 2H, Ar-H), 7.47-8.12 (m, 4H, Ar-H), 10.70 (s, 1H, NH). HRMS: M+ 255.3.
Anal. Calcd for C15H13NO3: C, 70.58; H, 5.09; N, 5.49. Found: C, 70.56; H, 5.07; N, 5.51. 13C NMR (75.6
MHz, CDCl3) δ: C2-98.97, C4-161.49, C5-119.22, C6-129.56, C7-120.27, C8-132.83, C9-114.38, C10-158.56,
C1'-134.62, C2'-126.98, C3'-112.46, C4'-159.07, C5'-112.46, C6'-126.98, C(-OCH3)-55.59.
2-(2-Hydroxyphenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6d). Mp 172 °C. IR νmax (KBr, cm-1);
3350, 3160, 3065, 1670. 1H NMR (300 MHz, CDCl3) δ: 7.13 (s, 1H), 7.24-8.12 (m, 8H, Ar-H), 10.76 (s, 1H,
NH). HRMS: M+ 241.0. Anal. Calcd for C14H11NO3: C, 69.70; H, 4.56; N, 5.80. Found: C, 69.66; H, 4.59;
N, 5.84.
2-Thiophen-2-yl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6e). Mp 174 °C. IR νmax (KBr, cm-1): 3160,
3060, 1675. 1H NMR (300 MHz, CDCl3) δ: 6.76-6.81 (m, 1H, thienyl H), 7.00 (d, 2H, thienyl H), 7.11 (s,
1H), 7.49-8.22 (m, 4H, Ar-H), 10.77 (s, 1H, NH). HRMS: M+ 231.3. Anal. Calcd for C12H9NO2S: C, 62.33;
H, 3.89; N, 6.06; S, 13.85. Found: C, 62.33; H, 3.88; N, 6.06; S, 13.86. 13C NMR (75.6 MHz, CDCl3) δ:
C2-99.07, C4-161.57, C5-119.26, C6-129.62, C7-120.32, C8-132.87, C9-114.41, C10-158.59, C1'-146.32,
C3'-124.79, C4'-125.88, C5'-123.45.
2-Benzo[1,3]dioxol-5-yl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6f). Mp 198-199 °C (lit.,29 199-200 °C).
IR νmax (KBr, cm-1): 3165, 3060, 1670. 1H NMR (300 MHz, CDCl3) δ: 5.92 (s, 2H, OCH2O), 6.72 (d, 2H,
Ar-H), 7.11 (s, 1H), 7.14-7.89 (m, 5H, Ar-H), 10.77 (s, 1H, NH). HRMS: M+ 268.90. Anal. Calcd for
C15H11NO4: C, 66.91; H, 4.08; N, 5.20. Found: C, 66.92; H, 4.07; N, 5.19.
2-(3-Nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-ones (6g). Mp 217-218 °C (lit.,27 218-219 °C). IR
ν
max (KBr, cm-1): 3170, 3055, 1680. 1H NMR (300 MHz, CDCl3) δ: 7.14 (s, 1H), 7.55-8.31 (m, 7H, Ar-H),
8.23 (s, 1H, Ar-H), 10.75 (s, 1H, NH). HRMS: M+ 270.4. Anal. Calcd for C14H10N2O4: C, 62.22; H, 3.70; N,
10.37. Found: C, 62.21; H, 3.69; N, 10.37. 13C NMR (75.6 MHz, CDCl3) δ: C2-99.09, C4-161.59, C5-119.27,
C6-129.61, C7-120.33, C8-132.89, C9-114.44, C10-158.59, C1'-143.49, C2'-122.27, C3'-149.28, C4'-121.67,
C5'-129.67, C6'-134.07.
9-Methoxy-2-phenyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6h). Mp 188 °C. IR νmax (KBr, cm-1): 3175,
3060, 1665. 1H NMR (300 MHz, CDCl3) δ: 7.07 (s, 1H), 7.31-8.22 (m, 8H, Ar-H), 10.69 (s, 1H, NH), 3.84
(s, 3H, OCH3). HRMS: M+ 255.0. Anal. Calcd for C15H13NO3: C, 70.58; H, 5.09; N, 5.49. Found: C, 70.59;
H, 5.08; N, 5.47.
7-Chloro-2-(4-methoxyphenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (6i). Mp 176 °C. IR νmax (KBr,

HETEROCYCLES, Vol. 71, No. 7, 2007
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1
cm-1); 3170, 3065, 1675. H NMR (300 MHz, CDCl3) δ: 3.84 (s, 3H, OCH3), 7.01 (s, 1H), 7.21 (d, 2H,
Ar-H), 7.39 (d, 2H, Ar-H), 7.47-8.12 (m, 3H, Ar-H), 10.70 (s, 1H, NH). HRMS: M+ 299. Anal. Calcd for
C15H12NO3Cl: C, 62.17; H, 4.14; N, 4.83. Found C, 62.14; H, 4.15; N, 4.85.
ACKNOWLEDGEMENTS
The authors are thankful to CSIR, New Delhi, for their financial assistance.
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