First I2-K2CO3-promoted sequential C-N and C-O bond forming approach for one-pot synthesis of 1,4-benzoxazines

Article abstract of DOI:10.1016/j.tetlet.2013.10.092

I₂-K₂CO₃ combination has been found to be an efficient, reusable, and inexpensive catalyst system for the one-pot synthesis of 3-aryl-2H-benz[1,4]oxazine via rapid CN and C-O bond formation. No by-product formation, operat

Full text of DOI:10.1016/j.tetlet.2013.10.092

Tetrahedron Letters 54 (2013) 7132–7135
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First I2–K2CO3-promoted sequential C–N and C–O bond forming
approach for one-pot synthesis of 1,4-benzoxazines
b
b
Sunil K. Singh a, , Anil K. Bajpai , Rajesh Saini
⇑
a Department of Applied Chemistry, Institute of Technology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh 495 009, India
b Department of Chemistry, Bose Memorial Research Laboratory, Government Autonomous Science College, Jabalpur, Madhya Pradesh 482 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
I2–K2CO3 combination has been found to be an efficient, reusable, and inexpensive catalyst system for the
one-pot synthesis of 3-aryl-2H-benz[1,4]oxazine via rapid C@N and C–O bond formation. No by-product
formation, operational simplicity, ambient temperature, and high yield (85–94%) are the attractive fea-
tures of the envisaged reaction. The reported one-pot synthesis of 1,4-benzoxazine involves the applica-
tion of I2–K2CO3 catalyst system for the first time and proceeds via in situ imine formation followed by
intramolecular ring transformation cascades.
Received 25 June 2013
Revised 16 October 2013
Accepted 20 October 2013
Available online 28 October 2013
Keywords:
Iodine
Ó 2013 Elsevier Ltd. All rights reserved.
One-pot reaction
a-Haloketones
b-Aminoalcohol
1,4-Benzoxazines
Benzoxazines have been a vital part of molecular skeletons for
design of a variety of biologically active compounds.1,2 These com-
pounds are valuable building blocks for the synthesis of more com-
plex derivatives ranging from herbicides and fungicides to some
natural products.3 Several benzoxazinone derivatives have been
reported to be potassium channel openers in vascular smooth mus-
cle. Photochemical transformation and other derivatization of ben-
zoxazines to other heterocyclic structures and chiral
intermediates,4 play a lead role for the synthesis of many pharma-
ceutical compounds. For example, levofloxacin, an active antibac-
terial drug contains this structural motif.5 Therefore, their
synthesis has attracted much attention in recent years and many
versatile methodologies being the result of active studies for the
synthetic development of benzoxazines have been carried out.6–11
The Literature reports various routes to substituted benzoxa-
zines which include mainly cyclocondensation of aminophenols
with suitable dihalo derivatives,7 intramolecular copper-catalyzed
O-arylation of b-aminoalcohols,8 and epoxide opening of aminoal-
cohols followed by cyclocondensation.9 Notably, alternative
methods other than cyclocondensation include alkylation of
o-nitrophenol with haloester followed by reductive cyclization10
and epoxide opening with o-halosulfonamides followed by cycliza-
tion.11 Furthermore, Heravi et al. had disclosed recently a new
method for the synthesis of 1,4-benzoxazines by the condensa-
tion of o-aminophenols and 2-bromo-1-aryl ethanones using
HClO4-SiO2 as catalyst at reflux temperature.6c However, all of
the reported methods suffer from one or more disadvantages such
as higher reaction temperature, longer reaction time, and lower
yields. Thus, development of more convenient and green protocol
for the synthesis of benzoxazines is highly required.
In view of the above valid points, we disclose herein, the first re-
port on molecular iodine/K2CO3-catalyzed one-pot synthesis of
1,4-benzoxazines via sequential C=N and C - O bond formation.
The reported reaction for the target 1,4-benzoxazine 3 involved
the stirring of a mixture of o-aminophenol 1 and a-haloketones 2
in the presence of molecular iodine and K2CO3 as catalyst system
(Scheme 1). Herein, the molecular iodine in the presence of potas-
sium carbonate has been found to be an efficient, eco-friendly,
readily available, and cost effective catalyst-system for the synthe-
sis of target 1,4-benzoxazine. Iodine being a mild Lewis acid as well
as an oxidant has been used in many organic transformations and
in organic synthesis.
In our preliminary experimentation, we investigated the opti-
mization of reaction conditions with regard to both catalyst and
solvent. Here, o-aminophenol 1 and 2-chloro-1-phenylethanone
O
R1
NH2
OH
N
O
I2/K2CO3
R1
THF-H2O (5:1)
rt
Cl
1
2
3
⇑
Corresponding author. Tel.: +91 940 621 4262; fax: +91 775 226 0007.
E-mail address: singh.skumar@gmail.com (S.K. Singh).
Scheme 1. Synthesis of benzoxazinones 3 from o-aminophenol 1 and
2.
a-haloketone
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.092

S. K. Singh et al. / Tetrahedron Letters 54 (2013) 7132–7135
7133
Table 1
entries 1, 7 and 8). Next, optimization of the solvent for the synthe-
sis of 3a was also investigated by employing the I2/K2CO3 catalyst
system. Different solvents (THF, CH2Cl2, CH3CN, THF–H2O and
THF–ButOH, THF–methanol) were examined and better results
were obtained using THF in combination with protic polar solvents
(Table 1, entries 1, 12 and 13) as compared to those aprotic polar
solvents (Table 1, entries 10 and 11), but the best yield was
obtained with THF–H2O solvent system (Table 1, entry 1). Thus
THF–H2O (5:1) solvent system was used throughout the reaction.
Optimization of the reaction conditions for one-pot synthesis of 1,4-benzoxazine 3aa
O
NH2
OH
N
O
catalyst
Cl
Solvent
r.t
1
2a
3a
Entry
Catalyst (mol %)
Base
Time (h)b
Solvent
Yield (%)c
Substrate scope investigations revealed that a variety of a-haloke-
1
2
3
4
5
6
7
8
I2 (10)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF–H2O
THF
92
57
59
63
68
92
71
69
77
74
71
86
81
—
tone 2 reacted smoothly with different o-aminophenol 1 to afford
the corresponding target 1,4-benzoxazines 3 in excellent yield
(Table 2) with highest yield of 94% (Table 1, entry 5). Thus, the
optimized synthesis involved by stirring a mixture of o-aminophe-
CuCl2.2H2O (10)
CeCl3 (10)
CeCl3.7H2O (10)
I2 (5)
I2 (15)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
nol 1 (1 equiv), a-haloketones 2 (1 equiv), I2 (10 mol%), and K2CO3
(3 equiv) in 5 mL of THF–H2O at room temperature for 7–8 h under
a nitrogen atmosphere affording the target compound 1,4-benzox-
azine 4 in excellent yields (Table 2).
A plausible mechanism for the formation of 1,4-benzoxazine 3
is depicted in Scheme 2. The new methodology involves Lewis acid
catalyzed ring cyclization via dehydrohalogenation. Herein, the
nitrogen of o-aminophenol attacks as nucleophile on carbonyl car-
9
10
11
12
13
14
15
CH2Cl2
CH3CN
I2 (10)
I2 (10)
I2 (10)
—
THF–ButOH
THF–MeOH
THF–H2O
THF–H2O
K2CO3
—
a
bon of
a-haloketone, followed by protonation of oxygen atom
The reaction was performed using o-aminophenol 1 (1 equiv) and 2a (1 equiv)
which leads to dehydration and in situ generation of imine 5. Fur-
thermore, nucleophilic attack of oxygen atom of o-aminophenol on
the carbon bearing leaving halogen group of the a-haloketone re-
with I2 (10 mol %) and K2CO3 (3 equiv) at rt.
b
Time taken to complete the reaction.
c
Yield of isolated pure product 3a.
sults in ring-cyclization which in turn in the target 1,4-benzox-
azine 3 via dehydrohalogenation. To our understanding, the more
nucleophilicity of nitrogen than oxygen and subsequently the sta-
bility of in situ generated imine 5 is the main driving force for the
formation of target compound 3 as the depicted reaction pathway
in Scheme 2. Presumably, iodine plays a key role in the reaction in
the imine formation and ring cyclization step by polarizing the car-
bonyl group of the substrate, thereby enhancing the electrophilic-
ity of the carbonyl carbon, which facilitates the nucleophilic attack
of nitrogen of o-aminophenol. All the reactions were clean and the
products were characterized by their IR, 1H and 13C NMR spectro-
scopic data and further confirmed by comparison of their mp, TLC,
IR, and 1H, 13C NMR data with authentic samples obtained com-
mercially or prepared by the literature methods.6,12
(2a) were chosen as model substrates for the synthesis of represen-
tative 1,4-benzoxazine 3a and the reaction was performed at room
temperature under a positive pressure of nitrogen (Table 1). Sev-
eral catalysts were tested under the present reaction condition
and I2 with K2CO3 was found to be the most efficient catalyst
among CuCl2 . 2H2O, CeCl3 and CeCl3 . 7H2O (Table 1, entries
1–4). The optimum loading for the I2 was found to be 10 mol %
together with K2CO3 (Table 1, entries 1, 5 and 6). When the amount
of I2 was decreased from 10 to 5 mol% relative to substrate 1, the
yield of the target 1,4-benzoxazine 3a reduced (Table 1, entries 1
and 5), but the use of 15 mol% of I2 did not enhance the yield
(Table 1, entries 1 and 6). The reaction did not occur in the absence
of either iodine (Table 1, entry 15) or K2CO3 (Table 1, entry 14).
Different inorganic bases were tested viz., K2CO3, Na2CO3 and
NaHCO3 and the best result was obtained by using K2CO3 (Table 1,
In summary, we have developed a novel method for the prepa-
ration of 1,4-benzoxazines catalyzed by molecular iodine in con-
junction with potassium carbonate. The present protocol involves
Table 2
One pot synthesis of 1,3-oxazines 3a
O
R1
NH2
R1
N
O
I2/K2CO3
THF-H2O (5:1)
rt
Cl
OH
1
2
3
Entry
1
Aminophenol 1
a
-Haloketone 2
Reaction time (h)b
1,4-Benzoxazine 3
Yield (%)c,d
NH2
O
N
8
92
OH
1a
Cl
2a
2b
O
3a
3b
O
F
2
1a
7
85
Cl
N
F
O
(continued on next page)

7134
S. K. Singh et al. / Tetrahedron Letters 54 (2013) 7132–7135
Table 2 (continued)
Entry
Aminophenol 1
a-Haloketone 2
Reaction time (h)b
1,4-Benzoxazine 3
Yield (%)c,d
O
OMe
Me
Cl
3
4
1a
Cl
7.5
92
N
MeO
Me
2c
O
3c
O
1a
Cl
8
90
N
2d
O
3d
3e
O
Cl
N
5
6
1a
1a
7
94
92
Cl
O
2e
O
Cl
Cl
Cl
Cl
N
7.5
Cl
Cl
O
2f
3f
O
N
O
7
8
1a
1a
7.5
89
91
2g
3g
O
Me
Cl
N
O
8
Cl
Me
2h
2i
3h
O
N
9
1a
1a
8
8
90
89
l
C
Cl
Cl
O
Cl
N
3i
3j
O
10
Cl
2j
O
O
MeO
MeO
Me
11
12
1a
1a
8
8
91
89
Cl
N
O
2k
3k
3l
O
Me
Cl
N
2l
O
O
CF3
13
14
1a
1a
7.5
90
92
Cl
N
F3C
2m
2n
O
3m
3n
O
S
N
8
S
Cl
O

S. K. Singh et al. / Tetrahedron Letters 54 (2013) 7132–7135
7135
Table 2 (continued)
Entry
Aminophenol 1
a-Haloketone 2
Reaction time (h)b
1,4-Benzoxazine 3
Yield (%)c,d
NH2
OH
O
N
15
8
91
89
Cl
1b
2o
O
3o
O
OMe
N
Cl
16
1b
8
MeO
2p
O
3p
a
13
See Experimental Section for general procedure
Time required for completion of the reaction.
.
b
c
Yield of isolated and purified product.
All the compounds synthesized are known.
d
6,12
.
O
I
I
R1
OH
H
N
O
NH2
NH2 Cl
OH
I2/K2CO3
R1
R1
-I2
THF-H2O (5:1)
Cl
OH
OH
Cl
1
4
2
R1
N
R1
N
O
K2CO3
-HCl
-H2O
Cl
OH
3
5
Scheme 2. A plausible mechanism for dehydrohalogenation, C–N, and C–O bond formation to synthesize 1,4-benzoxazines.
11. Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Ind. Eng. Chem. Res. 2003, 42, 680.
12. Gao, K.; Yu, C.-B.; Wang, D.-S.; Zhou, Y.-G. Adv. Synth. Catal. 2012, 354, 483–
488.
simple operation at ambient temperature to give high yields of the
products in a one-pot procedure and would be a practical alterna-
tive to the existing procedures for the synthesis of such kind of fine
chemicals.
13. General procedure for the synthesis of 1,4-benzoxazine 3: A flame-dried round
bottom flask was charged with o-aminophenol
1 (1 equiv), 2-chloro-1-
phenylethanone (1 equiv), and I2 (0.1 mmol) in 5 mL of THF/H2O (5:1)
2
under positive pressure of nitrogen followed by addition of K2CO3 (3 equiv).
The resulting solution was stirred for 7–8 h at room temperature (Table 2).
After completion of the reaction (monitored by TLC), the reaction mixture was
quenched with satd aq Na2SO3 until the iodine color almost disappeared and
was extracted with CHCl3. The organic layer was washed with satd aq NaHCO3
and brine, and dried over Na2SO4. Then the combined organic layer was
concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel using hexane/EtOAc (10:1) as eluent to
afford analytically pure sample of 3. The structure of products was confirmed
by comparison of their mp, TLC, IR, and 1H, 13C NMR data with authentic
samples obtained commercially or prepared by the literature methods.6,12
Physical data of representative compound. Compound 3c: yellow solid, mp
130–132 °C, 92% yield. 1H NMR (400 MHz, CDCl3) d: 3.94 (s, 3H), 5.01 (s, 2H),
6.92 (d, J = 8.0 Hz, 1H), 7.09–7.15 (m, 2H), 7.19 (t, J = 5.9 Hz, 1H), 7.32–7.40 (m,
3H), 7.53 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 55.4, 73.9, 113.2, 115.4, 116.9,
122.1, 123.5, 124.7, 127.9, 128.9, 134.7, 139.8, 153.2, 161.4, 164.7. EIMS (m/z):
239 (M+). Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 6.27. Found: C, 75.00;
H, 5.80; N, 5.56. Compound 3d: yellow solid, mp 136–139 °C, 90% yield. 1H NMR
(400 MHz, CDCl3) d: 2.43 (s, 3H), 5.09 (s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 7.04 (t,
J = 7.3 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.26–7.38 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H),
7.68 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 23.2, 73.1,
115.9, 122.4, 123.6, 126.7, 128.0, 129.1, 130.2, 131.5, 133.7, 139.0, 140.1, 152.6,
164.3. EIMS (m/z): 223 (M+). Anal. Calcd for C15H13NO: C, 80.69; H, 5.87; N,
6.27. Found: C, 81.05; H, 5.56; N, 6.05. Compound 3m: yellow solid, mp 164–
166 °C, 90% yield. 1H NMR (400 MHz, CDCl3) d: 5.07 (s, 2H), 6.99 (d, J = 8.1 Hz,
1H), 7.04 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.75
(d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 73.5,
115.6, 121.9, 123.1, 124.6, 125.5, 126.9, 128.4, 129.7, 130.9, 132.7, 137.4, 139.8,
152.1, 164.1. EIMS (m/z): 277 (M+). Anal. Calcd for C15H10F3NO: C, 64.98; H,
3.64; N, 5.05. Found: C, 64.77; H, 4.00; N, 5.33. Compound 3p: yellow solid, mp
143–145 °C, 89% yield. 1H NMR (400 MHz, CDCl3) d: 1.38 (s, 9H), 5.01 (s, 2H),
6.90 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 1.9 Hz, 4H), 7.90–7.94
(m, 2H). 13C NMR (100 MHz, CDCl3) d: 30.7, 31.9, 32.8, 40.5, 73.9, 115.6, 120.4,
123.9, 127.9, 129.0, 129.9, 131.1, 132.5, 134.2, 139.0, 143.6, 149.7, 164.8. EIMS
(m/z): 265 (M+). Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C,
81.78; H, 7.48; N, 5.05.
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