Three-component, one-pot synthesis of benzo[B][1,4]oxazines in ionic liquid 1-butyl-3-methylimidazolium bromide

Article abstract of DOI:10.1080/00397911.2010.540056

Benzo[b][1,4]oxazines have been synthesized in good to excellent yields in the presence of the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]Br under relatively mild conditions without any added catalyst, The method offers the advantages of good

Full text of DOI:10.1080/00397911.2010.540056

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Three-Component, One-Pot Synthesis of
Benzo[b][1,4]oxazines in Ionic Liquid 1-
Butyl-3-methylimidazolium Bromide
Ebrahim Soleimani a , Mohammad Mehdi Khodaei a & Afsaneh Taheri
Kal Koshvandi a
a Department of Chemistry, Razi University, Kermanshah, Iran
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 11 Jan 2012
To cite this article: Ebrahim Soleimani, Mohammad Mehdi Khodaei & Afsaneh Taheri Kal Koshvandi
(2012): Three-Component, One-Pot Synthesis of Benzo[b][1,4]oxazines in Ionic Liquid 1-Butyl-3-
methylimidazolium Bromide, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:9, 1367-1371
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Synthetic Communications1, 42: 1367–1371, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.540056
THREE-COMPONENT, ONE-POT SYNTHESIS
OF BENZO[b][1,4]OXAZINES IN IONIC LIQUID
1-BUTYL-3-METHYLIMIDAZOLIUM BROMIDE
Ebrahim Soleimani, Mohammad Mehdi Khodaei, and
Afsaneh Taheri Kal Koshvandi
Department of Chemistry, Razi University, Kermanshah, Iran
GRAPHICAL ABSTRACT
Abstract Benzo[b][1,4]oxazines have been synthesized in good to excellent yields in the
presence of the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]Br under rela-
tively mild conditions without any added catalyst, The method offers the advantages of good
yields and short reaction times, and the ionic liquid can be easily separated from the product
and reused.
Keywords Benzo[b][1,4]oxazines; [bmim]Br; ionic liquid; isocyanide; multicomponent
reactions
INTRODUCTION
Heterocyclic skeletons serve as ideal scaffolds on which pharmacophores can
be appended to yield potent and selective drugs.[1] This is especially true for
six-member ring heterocyclic compounds, which are core components of a large
number of substances that possess a wide range of interesting biological activities.[2]
In this respect, the utility of the benzo[b][1,4]oxazin scaffold as a privileged structure
for the generation of drug-like libraries in drug-discovery programs has been amply
demonstrated. Benzo[b][1,4]oxazin derivatives have been used as the basic frame-
work for substances of interest in numerous therapeutic areas, such as anti-Candina
albicans agents,[3] antifungals,[4] and kinase inhibitors.[5]
Multicomponent reactions (MCRs) have been frequently used by synthetic
chemists as a facile means to generate molecular diversity from bifunctional sub-
strates that react sequentially in an intramolecular fashion.[6] Devising MCRs that
achieve the formation of multiple bonds in a single operation is one of the major
Received November 10, 2010.
Address correspondence to Ebrahim Soleimani, Department of Chemistry, Razi University,
Kermanshah, Iran. E-mail: e_soleimanirazi@yahoo.com
1367

1368
E. SOLEIMANI, M. M. KHODAEI, AND A. T. K. KOSHVANDI
challenges in modern organic synthesis.[7] As such processes avoid time-consuming
and costly purification processes, as well as protection–deprotection steps, they are
inherently more environmentally benign and atom economical.[8] They provide a
powerful tool for the one-pot synthesis of diverse and complex compounds as well
as small and drug-like heterocycles.[9] MCRs that involve isocyanides are by
far the most versatile reactions in terms of scaffolds and number of accessible
compounds.[6,10]
In recent years, studies of low-waste routes and reusable reaction media for
enhanced selectivity and energy minimization are key interests of synthetic organic
chemists the world over.[11] In this context, in recent times, the use of room-
temperature ionic liquids as green solvents in organic synthetic processes has gained
considerable importance because of their solvating ability, negligible vapor pressure,
and easy recyclability.[12] We have recently shown that they can also promote and
catalyze isocyanide-based MCRs under ambient conditions without the need for
any added catalyst or ligand.[13]
RESULTS AND DISCUSSION
Proceeding along the same lines, we chose to evolve an efficient and ecofriendly
process for the preparation of benzo[b][1,4]oxazines 4 by the three-component
condensation of 2-aminophenole 1, an aldehyde 2, and isocyanide 3 in the
presence of 1-butyl-3-methylimidazolium bromide ([bmim]Br) as reaction media as
well as promoters, in the absence of any added catalyst, at ambient temperature
(Scheme 1).
As indicated in Table 1, the reaction of aldehydes with 2-aminophenole and
isocyanides afforded benzo[b][1,4]oxazines in [bmim]Br as a promoter in very good
yields.
To optimize the reaction conditions, we conducted the condensation of benzal-
dehyde (1 mmol), 2-aminophenole (1 mmol), and cyclohexyl isocyanide (1 mmol)
with stirring at room temperature in various ionic liquids (1 mmol) after 12 h.
The results showed that the efficiency and the yield of the reaction in [bmim]Br
was greater than those obtained in other ionic liquids. Also, to illustrate the need
for [bmim]Br, the reaction was studied in the absence of [bmim]Br, in which no
product was produce at room temperature after 12 h. Obviously, [bmim]Br is an
important component of the reaction (Table 2).
One of the advantages of ionic liquids is their ability to function as a recyclable
reaction medium. We were able to separate [bmim]Br from the reaction medium eas-
ily by washing with water and evaporating the solvent under vacuum, and reuse it for
subsequent reactions.
Scheme 1. Synthesis of benzo[b][1,4]oxazines.

BENZO[b][1,4]OXAZINES
1369
Table 1. Synthesis of benzo[b][1,4]oxazines in [bmim]Br
Product
R1
R2
Yield (%)
4a
4b
4c
4d
4e
4f
Ph
4-ClC6H4
Cyclohexyl
Cyclohexyl
Cyclohexyl
94a
98a
97a
99a
96a
95a
95a
91a
94a
91a
98b
3-NO2C6H4
4-NO2C6H4
4-CH3C6H4
4-CH3OC6H4
4-HOC6H4
Ph
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
4g
4 h
4i
tert-Butyl
tert-Butyl
4-NO2C6H4
4-CH3OC6H4
4-NO2C6H4
4j
4k
tert-Butyl
1,1,3,3-Tetramethyl-butyl
aKnown compound.
bNew compound.
Table 2. Synthesis of benzo[b][1,4]oxazines in the presence of various ionic liquids
Ionic liquid Yield (%)
Tetrabutylammonium bromide 50
Tetrabutylphosphonium bromide
Tetrabutylphosphonium chloride
benzyltributylammonium chloride
1-Butyl-3-methylimidazolium bromide ([bmim]Br)
Without ionic liquid
60
75
Trace
99
Trace
CONCLUSION
In conclusion, we have introduced an efficient and environmentally friendly
approach for the synthesis of benzo[b][1,4]oxazines via condensation of an aldehyde,
2-aminophenole, and an isocyanide using [bmim]Br in good to excellent yields at
room temperature. The method offers easy experimental workup procedure and
reuse of ionic liquid.
EXPERIMENTAL
All purchased solvents and chemicals were of analytical grade and used with-
out further purification. Melting points and infrared (IR) spectra of all compounds
were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spec-
trometer, respectively. The 1H and 13C NMR spectra were obtained on a Bruker-200
Avance instrument using CDCl3 as solvent and tetramethylsilane (TMS) as internal
standard at 200 and 50 MHz, respectively. The mass spectra were recorded on a
Finnigan-MAT 8430 instrument.
All products (except 4k) are known compounds, which were characterized by
1
IR and H NMR spectral data, and their melting points were compared with litera-
ture reports.[14]

1370
E. SOLEIMANI, M. M. KHODAEI, AND A. T. K. KOSHVANDI
General Procedure
[bmim]Br (1.4 mmol) was added to a solution of 2-aminophenole (1 mmol),
aldehyde (1.1 mmol), and isocyanide (1.1 mmol). The resulting mixture was stirred
for 12 h at room temperature. After completion of the reaction, as indicated by
thin-layer chromatography (ethyl acetate=n-hexane, 2:1), the reaction mixture was
washed with water (10 cm3) and the solid residue was crystallized from ethanol to
give the pure product.
N-(2,4,4-Trimethylpentan-2-yl)-3-(4-nitrophenyl)-4H-benzo[b][1,4]oxazin-
2-amine (4k). Yellow crystals; yield 0.37 g (98%); mp 185–187 ꢀC; IR (KBr) (nmax
,
cmꢁ1): 3165, 3155;1H NMR (200 MHz, CDCl3): dH ¼ 1.01 [s, C(CH3)3], 1.41 [s,
C(CH3)2], 1.71 (s, CH2), 5.50 (brs, 2NH), 6.96–8.87 (8H, m, H-Ar) ppm. 13C
NMR (75 MHz, CDCl3): dC ¼ 31.1 [C(CH3)2], 31.4 (CH2), 53.3 [C(CH3)3], 53.2
[C(CH3)2], 118.2, 124.3, 125.8, 127.8, 128.4, 130.3, 131.0, 132.4, 141.7, 147.9,
þ
=
149.5, 159.1 (C-Ar and NH-C C-NH) ppm; MS (70 eV): m=z (%) ¼ 381 (M , 25),
268 (100), 253 (40), 57 (50). Anal. calcd. for C22H27N3O3: C, 69.27; H, 7.13; N,
11.02;. Found: C, 69.50; H, 7.23; N, 11.00.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of
Razi University.
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