Synthesis and characterisation of 5-(6-substituted phenyl-2H-chromen-3-yl) oxazole derivatives

Article abstract of DOI:10.2174/157017812803521126

Here we demonstrate the synthesis of various derivatives of 5-(6-substituted phenyl-2H-chromen-3-yl)- oxazoles 5(a-k) by using Suzuki coupling conditions with different substituted boronic acids and obtained 23-57 % yields. We also synthesised various derivatives of the 5-(substituted 2H-chromen-3-yl)-oxazoles 3(a-j) mediated by TOSMIC as a reagent and achieved 58-70 % yield.

Full text of DOI:10.2174/157017812803521126

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Letters in Organic Chemistry, 2012, 9, 683-690
683
Synthesis and Characterisation of 5-(6-substituted phenyl -2H-chromen-3-
yl) Oxazole Derivatives
Palle Sadanandam,a Nomula Sathaiah,b Vantikommu Jyothi,b Murugulla A. Chari,*b,c Donthabak-
thuni Shobhab, Parthasarathi Das*d and Khagga Mukkanti*a
aDepartment of Chemical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University,
Kukatpally, Hyderabad-85, India
bDr. MACS Bio-Pharma Pvt. Ltd., Plot-32/A, Westren Hills, Kukatpally, Hyderabad-500085, A.P, India
cDepartment of Complexity Science and Engineering, School of Frontier Sciences, 5-1-5, Kashiwanoha, Kashiwa,
University of Tokyo, Chiba 277-8561, Japan
dAurigene Discovery Technologies Limited, Bollaram Road, Miyapur, Hyderabad 500049, India
Received November 08, 2011: Revised August 27, 2012: Accepted August 27, 2012
Abstract: Here we demonstrate the synthesis of various derivatives of 5-(6-substituted phenyl-2H-chromen-3-yl)-
oxazoles 5(a-k) by using Suzuki coupling conditions with different substituted boronic acids and obtained 23-57 % yields.
We also synthesised various derivatives of the 5-(substituted 2H-chromen-3-yl)-oxazoles 3(a-j) mediated by TOSMIC as
a reagent and achieved 58-70 % yield.
Keywords: 5-(substituted 2H-chromen-3-yl)-oxazoles, 5-(6-substituted phenyl-2H-chromen-3-yl)-oxazoles, suzuki coupling,
TOSMIC reagent.
INTRODUCTION
disorders and microbial infections [14] and show potent anti-
fungal activity [15]. Derivatives of 2H-benzopyrans, like
2,4-diphenyl-2H-benzopyran and 2,2, 4-triphenyl-2H ben-
zopyran, have been studied for their photochromic behavior
[16]. Owing to their biological and pharmaceutical impor-
tance, there has been a constant research in the development
of new methodologies for the synthesis of 2H-chromene de-
rivatives [17]. During the last twenty years, the study of the
biological activities of chromene derivatives has been the
aim of many scientists [18-27]. Fused chromenes are inter-
esting due to their significant antibacterial [28-32] and novo-
biocin [33-34] activities. In addition to the above Johnson
et al. reported [35] the structure-based design of a parallel
synthetic array directed toward the discovery of irreversible
inhibitors of human rhinovirus 3c protease. Mannhold et al.
reported [36] the 6-sulfonyl chromenes as highly potent
katp-channel openers. Mohamed Hegab et al. reported [37]
the synthesis and pharmacological activities of some con-
densed 4-chloro-2, 2-dialkyl chromene-3-carbaldehyde de-
rivatives. El-Saghier et al. reported [38] the synthesis and
antibacterial activity of some new fused chromenes. Rajitha
et al. reported [39] the synthesis and biological activity of
meso-tetrakis (2, 10-dioxo-2H, 10H-pyrano [2, 3-f]
chromene-9-yl) porphyrins. Synthesis of 3-substituted
chromenes and its derivatives were reported by Perumal et
al. [40], Kaye et al. [41], Wang et al. [42], Wu et al. [43],
Brase et al. [44], Johnson et al. [35], Min Jiang and Min Shi
et al. [45], Qian Wang and Finn M.G et al. reported [17c],
the synthesis of 2H-chromenes from salicylaldehydes by a
catalytic petasis reaction. Previous attempts to prepare 2H-
chromenes chemoselectively via the cyclisation of 2-
The chroman structural unit is found in a large number of
drugs and natural products [1]. Chroman derivatives exhibit
various useful biological activities [2], such as antioxidant
[3], antiestrogen [4], anticonvulsion [5], and neuroprotection
[6]. Many synthetic methods for chromans have been devel-
oped [2, 7]. One of the efficient pathways is based on the
transformation of 2H-chromenes, including oxidation [7a, 8],
reduction [9] and conjugate addition [10]. Coumarins (2H-
chromen-2-ones) are chemical compound (specifically, a
benzopyrone) found in many plants or natural products, and
readily recognised as the scent of newly-mown hay, and has
been used in perfumes since 1882. In view of the ubiquity of
this fragment in a variety of biologically active compounds,
the synthesis of various 2H-Chromen-2-one analogues is
important in gauging their potential as a source of che-
motherapeutics. 2H-1-Benzopyrans, commonly known as
2H-benzopyrans or 2H-chromenes, are key structural units of
a variety of biologically important compounds, many of
which are pharmaceutically significant. The 2H-benzopyran
daurichromenic acid is known to exhibit anti-HIV properties
[11], while coutareagenin possess antidiabetic activity [12].
Derivatives of 3, 4-diphenylchromans are known to have
estrogenic activity [13]. Numerous derivatives of 2H-
benzopyrans are useful for the treatment of proliferative skin
*Address correspondence to this author at the Department of Chemical
Sciences, Institute of Science and Technology, Jawaharlal Nehru Techno-
logical University, Kukatpally, Hyderabad-85, India; Tel: +91-040-2315
8661; Fax: +91-040-23158665; E-mail: machari100@yahoo.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

684 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Sadanandam et al.
Br
Br
O
Br2/DMF
O
O
O
K2CO3
O
OH
OH
1
2
3
2-Hydroxy-benzaldehyde
5-bromo-2-hydroxy
benzaldehyde
6-bromo-2H-chromene-3-carbaldehyde
HO
OH
B
N
O
N
O
NC
S
Br
R
O
O
O
O
Suzuki Coupling
TOSMIC
MeOH
5 (a-k)
5-(6-Phenyl-2H-chromen-3-yl)-oxazole
4
5-(6-bromo-2H-chromen-3-yl)oxazole
Scheme 1. Synthesis of 6-substituted (2H-chromen-3-yl)-oxazole derivatives (5a-k).
hydroxybenzaldehyde derived Baylis–Hillman products had
proved unsuccessful affording, instead, complex mixtures of
chromene and coumarin derivatives [41, 46]. Chen et al.
reported [47] the reaction of quinoxalin-2-ones with TOS-
MIC reagent, and Krishna et al. reported [48] that the syn-
thesis of oxazole and pyrrole 3-carbethoxy/3-arylsulfonyl D
and L-2-deoxyribosides by TOSMIC addition/cyclization on
D and L-2-deoxyribo-1-carboxaldehyde and unsaturated
esters. Herr et al. [49] reported the preparation of 5-(2-
methoxy-4-nitrophenyl)-oxazole, Saikachi et al. [50] re-
ported the reaction with pyridine aldehydes to form oxa-
zoles. Wildeman et al. reported [51] the reaction with carbon
disulfide to form thiazoles. Chromene moiety is present in
some of the drugs [1] which are leucoanthocy anidin, gui-
bourtinidol, leucopelargonidin, robalzotan, catechin, non-
abine, 11-nor-9-carboxy-THC, hyperoside, proanthocyanidin
C1, brodifacoum fumarin, and difenacoum. To contribute to
this area of research, here, we are interested in developing a
methodology that provides facile access to 2H-chromene
derivatives. To contribute to this area of research, we are
interested in developing a methodology that provides facile
access to 2H-chromene derivatives. However, to the best of
our knowledge, there has been no report available on the
synthesis of 2H-chromene derivatives using the present
methodology in the open literature so far.
carbaldehyde 3 by using the acrolein. Making use of this
compound, 6-bromo-2H-chromene-3-carbaldehyde 3 can be
prepared by mixing 5-bromo-2-hydroxybenzaldehyde 2 and
acrolein. Tosyl methyl isocyanide is a useful synthon for the
preparation of the oxazoles. This is the key step in the pre-
sent scheme. To a stirred solution of 6-bromo-2H-chromene-
3-carbaldehyde 3 in methanol, tosylmethyl isocyanide
(TOSMIC) was added at room temperature under nitrogen
atmosphere and the resulting reaction mixture was refluxed
for four hours. In this way we can obtain 5-(6-bromo-2H-
chromen-3-yl) oxazole 4 as an off-white solid. By making
use of the above compound 5-(6-bromo-2H-chromen-3-yl)-
oxazole 4, we have prepared the different derivatives of 5-(6-
substituted phenyl-2H-chromen-3-yl)-oxazole compounds
5(a-k) by using suzuki coupling conditions with different
substituted boronic acids. The resulting compounds were
confirmed with the physicochemical and NMR, Mass and IR
spectroscopy. Here we described the synthesis of different
novel 5-(6-substituted phenyl-2H-chromen-3-yl)-oxazole
compounds using various reagents in the given below condi-
tions (Scheme 1).
Present our approach to synthesize substituted (2H-
chromen-3-yl)-oxazole derivatives: Tosyl methyl isocya-
nide (TOSMIC) is a useful synthon for the preparation of the
oxazoles. To a stirred solution of substituted 2H-chromene-
3-carbaldehyde 2(a-j) in methanol, tosylmethyl isocyanide
(TOSMIC) was added at room temperature under nitrogen
atmosphere and the resulting reaction mixture was refluxed
for 4 h to obtain the 5-(substituted 2H-chromen-3-yl) oxa-
zole derivatives 3 (a-j). We can prepare the substituted 2H-
chromene-3-carbaldehyde 2 (a-j) by the reaction of substi-
tuted 2-hydroxybenzaldehyde 1(a-j) with acrolein or cro-
tanaldehyde. The reaction carried out in the given below
mentioned conditions (Scheme 2) and the resulting com-
pounds are given in Table 2.
RESULTS AND DISCUSSION
The biosynthesis of coumarin in plants is via hydroxyla-
tion, glycolysis and cyclisation of cinnamic acid. Coumarin
can be prepared in a laboratory in a perkin reaction between
salicylaldehyde and acetic anhydride. Here we prepared 5-
(6-substituted phenyl-2H-chromen-3-yl)-oxazole compounds
5(a-k) and substituted (2H-chromen-3-yl)-oxazole deriva-
tives 3(a-j) and results are presented in Tables 1 and 2.
Present our approach to synthesize 5-(6-substituted
phenyl-2H-chromen-3-yl)-oxazole compounds 5(a-k): 5-
bromo-2-hydroxybenzaldehyde 2 (5-bromo salicilaldehyde)
can be prepared by bromination of salicylaldehyde 1 (2-
By using the above substituted 2H-chromene-3-
carbaldehyde derivatives 2(a-j), we have prepared the differ-
ent derivatives of the 5-(substituted 2H-chromen-3-yl)-
oxazoles 3(a-j) mediated by TOSMIC as a reagent, which is
a key step in the present scheme.
hydroxybenzaldehyde). By using 5-bromo-2-hydroxy
-
benzaldehyde 2, we can prepare 6-bromo-2H-chromene-3-

Synthesis and Characterisation of 5-(6-Substituted Phenyl -2H-Chromen-3-yl)
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
685
Table 1. Synthesis of 6-substituted (2H-Chromen-3-yl)-oxazole Derivatives (5a-k).
Product(5a-k)a
Yield(%)b
Boronic acid
S.No.
Reagent Used
N
N
N
Br
OH
O
O
1
34
N
B
O
OH
O
OH
B
N
H2N
OH
N
O
O
2
57
Br
O
NH2
N
OH
B
N
N
O
Br
O
3
33
23
24
O
N
OH
O
O
OH
B
N
N
O
Br
OH
O
N
O
4
5
6
O
O
O
Br
OH
B
N
H
Br
O
OH
O
O
N
Br
O
N
OH
OH
O
Br
O
O
O
B
28
O
O
N
OH
B
N
Br
O
7
8
39
37
OH
O
CN
OH
B
O
O
O
N
N
OH
Br
O
O
NC
OH
B
S
O
N
N
OH
O
Br
Br
28
34
O
N
F
S
F
9
O
OH
O
O
N
B
OH
O
O
10
F
F
O
OH
O
N
N
B
Br
OH
36
O
O
11
O
O
O
aAll products were characterised by IR, NMR, and mass spectroscopy. bYield refers to pure products after purification by column chromatography.
N
O
O
S
NC
O
O
O
R
O
R
R
O
O
OH
TOSMIC
MeOH
3 (a-j)
1 (a-j)
2 (a-j)
Substituted 2-hydroxy
benzaldehyde
5-(Substituted 2H-chromen-3-yl)
Substituted-2H-chromene-3-
oxazole
carbaldehyde
Scheme 2. Synthesis of 5-(substituted 2H-chromen-3-yl) oxazole derivatives 3 (a-j).

686 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Sadanandam et al.
Table 2. Synthesis of Substituted 2H-chromene-3-carbaldehyde Derivatives 2(a-j) and 5-(substituted 2H-chromen-3-yl)-oxazole
Derivatives 3(a-j).
Various Salicylaldehydes
(1a-1j) + Reagent
Product(3a-3j)a
S.No.
Product(2a-2j)
Yield (%)b
Yield(%)
Time (h)
N
O
Cl
Cl
Cl
H
O
O
1
75
14.5
14.0
68
OH
O
O
1a+ AcrCyllaldehyde
Cl
3a
2a
2b
Cl
O
N
O
H
O
2
3
76
73
64
66
O
O
OH
tBu
3b
tBu
1b+ Acrylaldehyde
N
O
O
H
O
15.0
O
O 2c
OH
3c
1c+ Acrylaldehyde
O
N
O
H
O
O
4
5
76
62
14.5
15.0
70
62
O
O
O
OH
1d+ Acrylaldehyde
O
2d
3d
N
H
O
OH
O
2e
3e
3f
tBu
tBu
1e+ Crotonaldehyde
O
N
H
O
O
63
15.0
68
6
O 2f
O
O
OH
1f+ Crotonaldehyde
N
O
Br
Br
Br
O
O
H
84
60
14.0
14.5
62
60
7
8
O 2g
OH
3g
1g+ Acrylaldehyde
N
H
N
2
H2N
O
H N
2
O
H
O
O
O 2h
3h
OH
1h+ Acrylaldehyde
S
S
S
N
O
O
H
O
9
88
15.0
15.0
58
62
O3i
O
OH
2i
2j
1i+ Acrylaldehyde
Br
Br
N
Br
O
O
H
10
82
O
O 3j
O
OH
1j+ Acrylaldehyde
aAll products were characterised by IR, NMR, and mass spectroscopy. bYield refers to pure products after purification by column chromatography.
In summary, we have designed and synthesised some
biologically active derivatives of chromene-oxazoles by us-
ing various reagents and different conditions. We believe
that this procedure is convenient, economic and a user-
friendly alternative process for the synthesis of these various
novel chromene-oxazole derivatives. Intially, we have pre-
pared the 6-bromo-2H-chromene-3-carbaldehyde by using
the acrolein and 5-bromosalicylaldehyde and used this alde-
hyde and tosyl methyl isocyanide (TOSMIC) which is a use-
ful synthon for the preparation of the 5-(6-bromo-2H-

Synthesis and Characterisation of 5-(6-Substituted Phenyl -2H-Chromen-3-yl)
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
687
chromen-3-yl)-oxazole, at room temperature under nitrogen
atmosphere. By making use of the above compound 5-(6-
bromo-2H-chromen-3-yl) oxazole, we have prepared the
different derivatives of 5-(6-substituted phenyl-2H-chromen-
3-yl)-oxazole compounds by using Pd(dppf)2Cl2 as catalyst,
Suzuki coupling conditions with different substituted boronic
acids. In addition to these compounds substituted 5-(2H-
chromen-3-yl)-oxazole derivatives are also synthesized by
using TOSMIC reagent with substituted-2H-chromene-3-
carbaldehydes. We have prepared the substituted-2H-
chromene-3-carbaldehydes by using the substituted salicy-
laldehydes on reaction with acrolein and TOSMIC is used as
synthon for the preparation of the 5-(substituted 2H-
chromen-3-yl)-oxazoles. This is the key step in the prepara-
tion of the 5-(2H-chromen-3-yl)-oxazole derivatives. All
compounds were characterized by physico chemical and IR,
NMR, Mass spectral data.
TOSMIC (4.08 g, 20.92 mmol) was added at room tempera-
ture under nitrogen atmosphere and the resulting reaction
mixture was refluxed for 4 h. TLC indicated that complete
consumption of starting material. Reaction mixture was
cooled to room temperature evaporated the solvent quenched
with water extracted with EtOAc (3x25 ml). Combined or-
ganic layer was washed with brine solution, dried over anhy-
drous sodium sulphate and solvent was evapourated to ob-
tain5-(6-bromo-2H-chromen-3-yl)-oxazole as off white solid
(2g, 68.8% yield).
Synthesis of 5-(6-substituted phenyl-2H-chromen-3-
yl)-oxazole(5a-k): To a stirred solution of 5-(6-bromo-2H-
chromen-3-yl)-oxazole (100 mg, 0.36 mmol) and boronic
acid (0.431 mmol) in 1, 4-Dioxane: H2O (4:1) mixture (5
ml), potassium carbonate (124 mg, 0.899 mmol) was added
at room temperature under N2 atm stirred for 5 min, then
boronic acid (0.431 mmol) followed by Pd(dppf)2Cl2 (0.05
eq) were added at room temperature and resulting reaction
mixture was degassed with argon gas for 10 min then it was
EXPERIMENTAL
o
kept in microwave at 100 C for 1 h. TLC indicated that
All chemicals and solvents were obtained from Aldrich
and Spectro Chem India Pvt. Ltd., and used without further
purification. Column chromatographic separations were car-
ried out on silica gel 60-120 mesh size. The 1H NMR spectra
of samples were recorded on a JEOL 400-MHz NMR spec-
trometer using TMS as an internal standard in DMSO-d6.
Mass spectra were recorded on a EIMS.
complete consumption of starting material. Reaction mixture
was filtered through celite pad, celite pad was washed with
EtOAc, filtrate was washed with water followed by brine
solution, dried over anhydrous sodium sulphate and solvent
was evapourated to obtain crude material, which was puri-
fied by silica gel (100-200 mesh) column chromatography
using 0-10 % EtOAc in n-Hexane as eluents.
Synthesis of 5-bromo-2-hydroxybenzaldehyde
2
Spectral data for 5a- 5k: 3-(3-Oxazol-5-yl-2H-
chromen-6-yl)-quinoline (5a): white solid; mp: 157-159 oC;
IR (KBr): 3414.11, 1492.08, 1115.80, 820.90 cm-1; 1H NMR
(400 MHz, DMSO-d6) ꢀ : 4.90 (m, 4H), 6.83 (d, 2H, J =12.0
Hz), 6.90 (s,2H), 7.34 (s, 2H), 7.44-7.51 (m, 4H) ppm; EIMS
(m/z): 327.12 (M +H)+.
(Scheme 1): To a stirred solution of salicylaldehyde 1 (2-
hydroxybenzaldehyde) (2 g, 16.3 mmol) in chloroform (30
ml) bromine (0.945 mL, 19.65 mmol) was added at 0oC and
the resulting reaction mixture was stirred for 6 h at 50oC.
Reaction progress was monitored through TLC which was
indicated that complete consumption of starting material.
Then reaction mixture was diluted with water (50 ml) ex-
tracted with chloroform (3x25 ml). Combined extracts were
washed with water (50 ml) followed by brine solution (50
ml), dried over anhydrous sodium sulfate and solvent was
removed under reduced pressure to obtain the compound as
pale yellow solid (2.5g, 75.98% yield).
4-(3-Oxazol-5-yl-2H-chromen-6-yl)-benzylamine (5b):
o
white solid; mp: 161-164 C; IR (KBr): 3435.93, 1483.67,
1
1111.39, 814.95 cm-1 ; H NMR (400 MHz, DMSO-d6) ꢀ:
5.01-5.40 (m, 4H), 6.84 (d, 2H, J =8.0 Hz), 6.99 (s, 2H),
7.32 (d, 2H, J = 8.0 Hz), 7.45-7.52 (m, 4H), 8.50 (s, 2H)
ppm; EIMS (m/z): 304.12 (M +H)+.
3-(3-Oxazol-5-yl-2H-chromen-6-yl)-pyridine (5c): white
solid; mp: 146-148 oC; IR (KBr): 3432.40, 1476.27, 1109.61,
798.00 cm-1; 1H NMR (400 MHz, DMSO-d6) ꢀ: 5.01 (s, 2H),
7.00 (d, 1H, J =7.0 Hz), 7.09 (s, 1H), 7.44-7.50 (m, 2H),
7.55 (m, 1H), 7.68 (s, 1H), 8.04 (d, 1H, J = 8.0 Hz), 8.48-
8.56 (2H, m), 8.87 (1H, s) ppm; EIMS (m/z): 277.12 (M
+H)+.
Synthesis of 6-bromo-2H-chromene-3-carbaldehyde
3: To a stirred solution of 5-bromo-2-hydroxybenzaldehyde
(2.5 g, 10.94 mmol) in 1, 4-dioxane (25 ml), potassium car-
bonate (3.02 g, 21.88 mmol) was added at room temperature
under nitrogen atmosphere and stirred for 15 min at room
temperature, then acrolein (1.05 g, 18.65 mmol) was added
and the resulting reaction mixture was refluxed for 15 h.
Reaction progress was monitored by TLC, reaction mixture
was cooled to room temperature, filtered through celite pad,
celite pad was washed with ethylacetate (50 ml). Filtrate was
washed with water (30 ml) followed by brine solution (30
ml), dried over anhydrous sodium sulfate and evaporated the
solvent to obtain the crude material which was purified by
silica gel (100-200 mesh) column chromatography using 0-
10% EtOAc in n-Hexane as eluents to afford the 6-bromo-
2H-chromene-3-carbaldehyde as yellow solid (2.5 g, 84.17%
yield).
4-(3-Oxazol-5-yl-2H-chromen-6-yl)-benzaldehyde
(5d): white solid; mp: 135-138 oC; IR (KBr): 3434.96,
1697.08, 1171.72, 812.58 cm-1; 1H NMR (400 MHz, DMSO-
d6) ꢀ: 5.01 (s, 2H), 7.00 (d, 1H, J = 4.0 Hz), 7.10 (s, 1H),
7.49 (s, 1H), 7.63 (d, 1H, J = 6.0 Hz), 7.72-7.76 (m, 1H),
7.85-7.93 (m, 2H), 7.97-8.01 (m, 2H), 8.5 (s, 1H), 10.01 (s,
1H) ppm; EIMS (m/z): 304.00 (M +H)+.
5-[6-(4-Bromo-phenyl)-2H-chromen-3-yl]-oxazole
(5e): white solid; mp: 131-134 oC; IR (KBr): 3435.06,
1695.02, 1175.77, 813.57 cm-1; 1H NMR (400 MHz, DMSO-
d6) ꢀ: 5.01 (s, 2H), 6.80-6.86 (m,1H), 6.94-7.02 (m, 2H),
7.29-7.36 (m, 1H), 7.45-7.52 (m, 2H), 7.58-7.66 (m, 2H),
Synthesis of 5-(6-bromo-2H-chromen-3-yl)-oxazole 4:
To
a
stirred solution of 6-bromo-2H-chromene-3-
carbaldehyde (2.5 g, 10.46 mmol) in methanol (25 ml),

688 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Sadanandam et al.
Synthesis of 5-(substituted 2H-chromen-3-yl)-oxazole
3(a-j): To a stirred solution of substituted-2H-chromene-3-
carbaldehyde (10.46 mmol) in methanol (25 mL), TOSMIC
(20.92 mmol) was added at room temperature under N2 at-
mosphere and the resulting reaction mixture was refluxed for
4 h. TLC indicated that complete consumption of starting
material. Reaction mixture cooled to room temperature
evaporated the solvent quenched with water extracted with
EtOAc (3x25 mL). Combined organic layer was washed
with brine solution, dried over anhydrous Na2SO4 and sol-
vent was evaporated to obtain 5-(substituted 2H-chromen-3-
yl)-oxazole derivatives (60- 69 % yield).
7.68-7.78 (m, 1H), 8.50 (s,1H) ppm; EIMS (m/z): 355.00 (M
+H)+.
5-(6-Furan-yl-2H-chromen-3-yl)-oxazole (5f): white
solid; mp: 128-130 oC; IR (KBr): 3432.54, 1674.74, 1107.74,
815.05 cm-1; 1H NMR (400 MHz, DMSO-d6) ꢀ: 6.84 (d, 3H,
J = 7.2 Hz), 7.00 (s, 2H), 7.30-7.36 (m, 2H), 7.46-7.52 (m,
3H), 8.50 (s, 1H) ppm; EIMS (m/z): 267.00 (M +H)+.
5-[6-(4-Ethyl-phenyl)-2H-chromen-3-yl]-oxazole (5g):
o
white solid; mp: 128-132 C; IR (KBr): 3430.71, 1613.76,
1
1238.22, 820.38 cm-1; H NMR (400 MHz, DMSO-d6) ꢀ:
1.22 (t, 3H, J = 10.0 Hz), 2.63 (q, 2H, J = 8.0 Hz), 5.15 (s,
2H), 6.92 (d, 2H, J =12.0 Hz), 6.98 (s, 1H), 7.07 (s, 1H),
7.27 (s, 2H), 7.32-7.35 (m, 1H), 7.92 (d, 1H, J =2.0 Hz),
7.47 (d, 2H, J = 12.0 Hz), 7.91 (s, 1H) ppm; EIMS (m/z):
267.00 (M +H)+.
5-(6, 8-Dichloro-2H-chromen-3-yl)-oxazole (3a): Off
o
white solid; mp 162–164 C; IR (KBr): 3105.37, 1385.97,
1
1104.66 cm-1; H NMR (400 MHz, DMSO-d6): ꢀ 5.18 (s,
2H), 7.01 (s, 1H), 7.38 (d, J = 2.30 Hz, 1H), 7.45 (d, 1H, J =
2.33 Hz), 7.50 (s, 1H), 8.53 (s, 1H) ppm; EIMS (m/z): 268
(M +H)+; Anal. Calcd. for C12H7Cl2NO2: C, 53.93; H, 2.62;
N, 5.24. Found: C, 53.76; H, 2.60; N, 5.22.
4-(3-Oxazol-5-yl-2H-chromen-6-yl)-benzonitrile (5h):
o
white solid; mp: 140-142 C; IR (KBr): 3435.88, 1474.26,
1
1109.79, 800.05 cm-1; H NMR (400 MHz, CDCl3) ꢀ: 6.94-
6.99 (m, 2H), 7.30-7.33 (m, 1H), 7.35-7.39 (m, 1H), 7.54 (t,
2H, J = 6.0 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.76 (d, 1H, J =
8.1 Hz), 7.82 (s, 1H), 7.97-8.06 (m, 2H) ppm; EIMS (m/z):
301.15 (M +H)+.
5-(8-tert-Butyl-2H-chromen-3-yl)-oxazole (3b): Off
o
white solid; mp 157–159 C; IR (KBr): 3109.40, 1485.97,
1
1217.14 cm-1; H NMR(400 MHz, DMSO-d6): ꢀ 1.33 (s,
9H), 4.97(s, 2H), 6.89 (t, J =7.62 Hz, 1H), 6.97 (s, 1H), 7.12-
7.15 (m, 1H), 7.44 (s, 1H), 8.46 (s, 1H) ppm; 13C NMR (100
MHz, DMSO-d6): ꢀ 29.913, 34.450, 63.611, 119.558,
119.869, 119.934, 121.902, 123.442, 123.969, 126.238,
127.139, 137.232, 137.611, 151.943, 162.659 ppm; EIMS
(m/z): 256 (M + H)+; Anal. Calcd. for C16H17NO2: C, 75.29;
H, 6,66; N, 5.49. Found: C, 75.26; H, 6.64; N, 5.46.
5-[6-(4-Methyl
sulfanyl-phenyl)-2H-chromen-3-yl]-
oxazole (5i): white solid; mp: 151-153 oC; IR (KBr):
2922.42, 1472.90, 1018.11, 635.54 cm-1; 1H NMR (400
MHz, CDCl3) ꢀ: 2.52 (s, 3H), 5.15 (s, 2H), 6.93 (d, 1H, J =
8.0 Hz), 6.99 (s, 1H), 7.08 (s, 1H), 7.22 (d, 1H, J = 8.0 Hz),
7.28-7.34 (m, 3H), 7.39 (d, 1H, J =12.0 Hz), 7.42 (s, 1H),
7.92 (s, 1H) ppm; EIMS (m/z): 322.15 (M +H)+.
5-(8-Allyl-2H-chromen-3-yl)-oxazole (3c): Off-white
solid; mp 149–151oC; IR (KBr): 3100.37, 1480.09, 1218.12
5-[6-(2,5-Difluoro-phenyl)-2H-chromen-3-yl]-oxazole
(5j): white solid; mp: 134-136 oC; IR : (KBr): 3436.06,
1690.82, 1176.75, 814.55 cm-1; 1H NMR (400 MHz, CDCl3)
ꢀ: 5.01 (s, 2H), 6.92-7.00 (m, 3H), 7.05-7.15 (m, 3H), 7.28-
7.36 (m, 2H), 7.91 (m, 1H) ppm; EIMS (m/z): 312.15 (M
+H)+.
1
cm-1; H NMR (400 MHz, DMSO-d6): ꢀ 2.49 (s, 1H), 5.01-
5.05 (m, 4H), 5.99-6.00 (m, 2H), 6.89-6.90 (m, 1H), 6.98 (s,
1H), 7.03 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.42
(s, 1H), 8.46 (s, 1H) ppm; EIMS (m/z): 240 (M + H)+; Anal.
Calcd. for C15H13NO2: C, 75.31; H, 5.43; N, 5.85. Found: C,
75.30; H, 5.48; N, 5.83.
5-[6-(4-Methoxy-phenyl)-2H-chromen-3-yl]-oxazole
(5k): white solid; mp: 148-150 oC; IR (KBr): 3435.34,
1658.98, 1109.68, 825.05 cm-1; 1H NMR (400 MHz, CDCl3)
ꢀ: 3.82 (s, 3H), 5.15 (s, 2H), 6.91 (s, 1H), 6.95 (s, 1H), 6.98-
6.99 (m, 1H), 7.31 (s, 1H), 7.27 (d, 1H, J = 3.0 Hz, 7.43-7.45
(m, 1H), 7.46-7.48 (m, 2H), 7.5 (d, 1H, J = 9.0 Hz), 7.91 (s,
1H); EIMS (m/z): 306.15 (M +H)+.
5-(2H-Chromen-3-yl)-oxazole (3d): Off-white solid; mp
o
1
154–156 C; IR (KBr): 3105.37, 1485.97, 1217.14 cm-1; H
NMR (400 MHz, DMSO-d6): ꢀ 5.01 (s, 2H), 6.85(d, J = 8.0
Hz, 1H), 6.93 (t, J =12.0 Hz, 1H), 7.15 (d, J =7.48, 1H),
7.36 (s, 1H), 8.16 (s, 1H) ppm; EI MS (m/z): 200 (M + H)+;
Anal. Calcd. for C12H9NO2: C, 72.36; H, 4.52; N, 7.03.
Found: C, 72.35; H, 4.50; N, 7.02.
Synthesis of substituted 2H-chromene-3-carbaldehyde
2(a-j): To a stirred solution of substituted 2-hydroxybenz-
aldehyde (10.94 mmol) in 1,4-dioxane (25 mL), K2CO3
(21.88 mmol) was added at room temperature under N2 at-
mosphere and stirred for 15 min at room temperature, then
acrolein (18.65 mmol) was added and the resulting reaction
mixture was refluxed for 15 h. Reaction progress was moni-
tored by TLC, reaction mixture was cooled to room tempera-
ture, filtered through celite pad, celite pad was washed with
EtOAc (50 mL). Filtrate was washed with water (30 mL)
followed by brine solution (30 mL), dried over anhydrous
sodium sulfate and evaporated the solvent to obtain the crude
material which was purified by silica gel (100-200 mesh)
column chromatography using 0-10 % EtOAc in n-hexane as
eluents to afford the substituted-2H-chromene-3-carbalde-
hyde (75-85 % yield).
5-(8-tert-Butyl-2-methyl-2H-chromen-3-yl)-oxazole
o
(3e): Off-white solid; mp 165–167 C; IR (KBr): 3105.30,
1
1485.91, 1217.10 cm-1; H NMR (400 MHz, DMSO-d6): ꢀ
1.26 (s, 3H), 1.35 (m, 9H), 5.49-5.51 (m, 1H), 6.85-7.21 (m,
6H) ppm; EIMS (m/z): 270 (M+ H)+; Anal. Calcd. for
C17H19NO2: C, 75.83; H, 7.06; N, 5.20. Found: C, 75.81; H,
7.04; N, 5.19.
5-(2-Methyl-2H-chromen-3-yl)-oxazole (3f): White
solid; mp 161–163 oC; IR (KBr): 3104.02, 1484.92, 1217.16
1
cm-1; H NMR (400 MHz, DMSO-d6): ꢀ 1.26 (s, 3H), 5.38
(d, J = 6.2 Hz, 1H), 6.85 (d, J =6.8 Hz, 1H), 6.93-6.94 (m,
1H), 7.18-7.26 (m, 2H), 7.45 (s, 1H), 8.45 (s, 1H) ppm;
EIMS (m/z): 214 (M + H)+; Anal. Calcd. for C13H11NO2: C,
73.23; H, 5.16; N, 6.57. Found: C, 73.23; H, 5.14; N, 6.55.

Synthesis and Characterisation of 5-(6-Substituted Phenyl -2H-Chromen-3-yl)
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
689
2000, 122(41), 9968-9976. (f) Andrianasolo, E.H.; Haramaty, L.;
Rosario-Passaper, R.; Bidle, K.; White, E.; Vetriani, C.; Falkowski,
P.; Lut, R. Ammonificins A and B, hydroxyethylamine chroman
derivatives from a cultured marine hydrothermal vent bacterium,
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Chem., 2008, 20, 518.
Kwak, J.H.; Kang, H.E.; Jung, J.K.; Kim, H.; Cho, J.; Lee, H. Syn-
thesis of 7-hydroxy-4-oxo-4H-chromene-and 7-hydroxychroman-2-
carboxylic acid N-alkyl amides and their antioxidant activities.
Arch. Pharm. Res., 2006, 29(9), 728-734.
Kanbe, Y.; Kim, M.H.; Nishimoto, M.; Ohtake, Y.; Kato, N.; Tsu-
nenari, T.; Taniguchi, K.; Ohizumi, I.; Kaiho, S.; Morikawa, K.; Jo,
J. C.; Lim, H.S.; Kim, H.Y. Discovery of thiochroman and chro-
man derivatives as pure antiestrogens and their structure–activity
relationship. Bioorg. Med. Chem., 2006, 14(14), 4803-4819.
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chromans as a novel scaffold for anticonvulsant activity. Bioorg.
Med. Chem. Lett., 2006, 16(7), 1803-1806.
5-(6-Bromo-2H-chromen-3-yl)-oxazole (3g): White
o
solid; mp 168–170 C; IR (KBr): 3421.12, 1483.79, 1112.06
1
cm-1; H NMR (400 MHz, DMSO-d6): ꢀ 5.04 (s, 2H), 6.08
(s, 1H), 6.83 (s, 1H,), 6.97 (s, 1H), 7.285 (d, J = 2.2 Hz, 1H),
7.47 (d, J =2.2 Hz, 1H), 8.48 (s, 1H) ppm; 13C NMR (100
MHz, DMSO-d6) ꢀ: 39.85, 64.34, 113.47, 117.63, 118.04,
121.08, 124.64, 129.94, 132.12, 147.17, 152.65, 152.99 ppm;
EIMS (m/z): 278 (M + H)+; Anal. Calcd. for C12H8BrNO2: C,
51.98; H, 2.88; N, 5.05. Found: C, 51.88; H, 2.85; N, 5.04.
[2]
[3]
[4]
4-(3-Oxazol-5-yl-2H-chromen-6-yl)-benzylamine (3h):
White solid; mp 166-168 oC; IR (KBr): 3435.93, 1483.67,
1
814.95 cm-1; H NMR (400 MHz, DMSO-d6): ꢀ 5.01 (m,
4H), 6.83 (d, J = 8.0 Hz, 2H), 6.99 (s, 2H), 7.29-7.36 (m,
2H), 7.45-7.52 (m, 4H), 8.50 (s, 2H) ppm; EIMS (m/z):
304.12 (M + H)+; Anal. Calcd. for C19H16N2O2: C, 75.24; H,
5.28; N, 9.24. Found: C, 75.20; H, 5.26; N, 9.20.
[5]
[6]
[7]
Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M.N. Design and
synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids.
Bioorg. Med. Chem., 2009, 17(17), 6432-6441.
5-[6-(4-Methylsulfanyl-phenyl)-2H-chromen-3-yl]-
oxazole (3i): White solid; mp 164-166 oC; IR (KBr): 358.66,
a) Wang, Q.L.; She, X.G.; Ren, X.F.; Ma, J. Pan X.F. The first
asymmetric total synthesis of several 3,4-dihydroxy-2,2-dimethyl-
chroman derivatives. Tetrahedron: Asymmetry, 2004, 15(1), 29-34.
(b) Doi, F.; Ohara, T.; Ogamino, T.; Higashinakasu, K.; Hasegawa,
K.; Nishiyama, S. Synthesis of chroman derivatives by the ring ex-
pansion reaction of spirodienones, and an assessment of their plant
growth inhibition. Bull. Chem. Soc. Jpn., 2004, 77(12), 2257-2263.
(c) Hashmi, A.S.K.; Rudolph, M.; Bats, J.W.; Frey, W.; Rominger,
F.; Oeser, T. Gold-catalyzed synthesis of chroman, dihydrobenzo-
furan, dihydroindole, and tetrahydroquinoline derivatives. Chem.
Eur. J., 2008, 14(22), 6672-6678.
Lesch, B.; Brase, S. A short, atom-economical entry to tetrahy-
droxanthenones. Angew. Chem. Int. Ed., 2004, 43(1), 115-118.
a) Loiodice, F.; Longo, A.; Bianco, P.; Tortorella, V. 6-Chloro-2,3-
dihydro-4H-1-benzopyran carboxylic acids: Synthesis, optical reso-
lution and absolute configuration. Tetrahedron: Asymmetry, 1995,
6(4), 1001-1011. (b) Hatzenbuhler, N.T.; Baudy, R.; Evrard, D. A.;
Failli, A.; Harrison, B.L.; Lenicek, S.; Mewshaw, R.E.; Saab, A.;
Shah, U.; Sze, J.; Zhang, M.; Zhou, D.; Chlenov, M.; Kagan, M.;
Golembieski, J.; Hornby, G.; Lai, M.; Smith, D.L.; Sullivan, K.M.;
Schechter, L.E.; Andree, T.H. advances toward new antidepres-
sants with dual serotonin transporter and 5-HT1A receptor affinity
within a class of 3-aminochroman derivatives. Part 2. J. Med.
Chem., 2008, 51(21), 6980-7004.
1
1472.90, 1028.11 cm-1; H NMR (400 MHz, CDCl3): ꢀ 2.5
(s, 3H), 6.92-6.95 (d, 1H), 6.99 (s, 1H), 7.08 (s, 1H), 7.18-
7.24 (m, 1H), 7.31-7.35 (m, 2H), 7.36-7.40 (m, 1H), 7.43 (s,
1H), 7.45-7.52 (m, 2H), 7.64 (s, 1H), 7.93 (s, 1H) ppm;
EIMS (m/z): 322.15 (M + H)+; Anal. Calcd for C19H15NO2S:
C, 71.02; H, 4.67; N, 4.36. Found: C, 71.00; H, 4.64; N,
4.34.
5-[6-(4-Bromo-phenyl)-2H-chromen-3-yl]-oxazole
[8]
[9]
(3j): White solid; mp 162-164 oC; IR (KBr): 3436.53,
1
1633.93, 813.64 cm-1; H NMR (400 MHz, DMSO-d6): ꢀ
5.01 (s, 2H), 6.80-6.86 (m, 1H), 6.94-7.02 (m, 2H), 7.29-
7.36 (m, 1H), 7.45-7.52 (m, 2H), 7.58-7.66 (m, 2H), 7.68-
7.78 (m, 1H), 8.50 (s, 1H) ppm; EIMS (m/z): 355.00 (M +
H)+; Anal. Calcd for C18H12BrNO2: C, 61.01; H, 3.38; N,
3.95. Found: C, 61.00; H, 3.34; N, 3.93.
CONFLICT OF INTEREST
[10]
[11]
Nyerges, M.; Virányi, A.; Marth, G.; Dancsó, A.; Balaskó, G.;
Tꢁke, L. Synlett 2004, 2761. (b) Virányi, A.; Marth, G.; Dancsó,
A.; Balaskó, G.; Tꢁke, L.; Nyerges, M. 3-nitrochromene deriva-
tives as 2ꢂ components in 1,3-dipolar cycloadditions of azomethine
ylides. Tetrahedron, 2006, 62(37), 8720-8730.
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
Zhendong, J.; Ying, K. WO 2004058738, 2004. (b) Iwata, N.;
Wang, N.; Yao, X.; Kitanaka, S. Structures and histamine release
Declared none.
inhibitory
effects
of
prenylated
orcinol
derivatives
from Rhododendron dauricum. J. Nat. Prod., 2004, 67(7), 1106-
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