Microwave-assisted direct synthesis of 2-substituted benzoxazoles from carboxylic acids under catalyst and solvent-free conditions

Article abstract of DOI:10.1055/s-2005-868509

A direct coupling of carboxylic acids with 2-aminophenol under microwave irradiation has been achieved leading to the synthesis of 2-substituted benzoxazoles under metal and solvent-free conditions. Aliphatic, aromatic and heteroaromatic carboxylic acids provide good yields. Benzoxazole formation takes place in the presence of chloro, methoxy, phenoxy, thiophenoxy, and α,β-unsaturated functionalities. In the case of dicarboxylic acids, the reaction proceeds via the formation of the corresponding anhydride with predominant formation of the mono-benzoxazole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868509

LETTER
1401
Microwave-Assisted Direct Synthesis of 2-Substituted Benzoxazoles from
Carboxylic Acids under Catalyst and Solvent-Free Conditions
S
R
ynthesis of 2-Su
a
bstituted B
j
enzoxazoles f
K
rom Carboxylic
A
u
cids mar, C. Selvam, Gurmeet Kaur, Asit K. Chakraborti*
National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab – 160062, India
Fax +91(172)2214692; E-mail: akchakraborti@niper.ac.in
Received 26 January 2005
OH
N
OH
Y
Z
a
O
N
b
Abstract: A direct coupling of carboxylic acids with 2-aminophe-
nol under microwave irradiation has been achieved leading to the
synthesis of 2-substituted benzoxazoles under metal and solvent-
free conditions. Aliphatic, aromatic and heteroaromatic carboxylic
acids provide good yields. Benzoxazole formation takes place in the
presence of chloro, methoxy, phenoxy, thiophenoxy, and a,b-unsat-
urated functionalities. In the case of dicarboxylic acids, the reaction
proceeds via the formation of the corresponding anhydride with pre-
dominant formation of the mono-benzoxazole.
+
R
R
R
R
NH2
1
2
3
c
XO
N
H
4
X = halogen, OH, OCOR; Y = OH, Cl, F, OEt;
Z = NH, O, Se; R = aryl, alkyl
Key words: benzoxazole, carboxylic acid, 2-aminophenol, direct
coupling, microwave, metal-free
Scheme 1 Various synthetic strategies for construction of the
benzoxazole moiety
The benzoxazole moiety is an important pharmacophore These methodologies suffer from limitations in the prepa-
due to the wide spectrum of biological activity displayed ration of the starting materials (seleno esters/amides, acid
by 2-substituted benzoxazoles. These include melatonin chlorides/fluorides, 2-hydroxy/acyloxy anilides), the re-
1
2
receptor agonist, LPAAT-b and cyclooxygenase inhibi- quirement of excess reagents (PPTS/PPA, p-TsOH,
3
4
5
tory, anticancer, 5-HT receptor antagonist, antimyco- SOCl /HF, PPh -DEAD, metal catalysts/oxidizing agents,
3
2
3
6
7
8
bacterial, elastase inhibitory and VLA-4 antagonist
activities. Benzoxazoles also find applications in material tion times, and most cases are only applicable to the syn-
sciences as photochromatic agents and laser dyes.
ionic liquids, etc.), harsh reaction conditions, long reac-
9
10
thesis of 2-aryl substituted benzoxazoles. Of particular
concern is the use of HF and metal catalysts (employed in
the radical/oxidative cyclization reactions) and contami-
nation of the product with trace amounts of metallic impu-
rities is detrimental to the determination of biological
activity. Therefore, a direct coupling of 1 with carboxylic
acids (Scheme 2) should constitute an ideal methodology
for the synthesis of 2-substituted benzoxazoles. However,
as the hydroxyl group is a poor leaving group it requires
electrophilic activation of the carboxylic acid to form the
intermediate anilide 4. The poor nucleophilicity of the
phenolic hydroxyl group necessitates activation of the
amide carbonyl of 4 for cyclodehydration. Thus, the reac-
tion requires heating in the presence of a stoichiometric
amount of (i) polyphosphoric acid/ester at high tempera-
The various strategies adopted for construction of the ben-
zoxazole moiety are summarized in Scheme 1. The strat-
egy ‘a’ involves treatment of 2-aminophenol (1) with a
selenoester/amide (in EtOH at r.t. for 4 d or under reflux
in pyridine for 14 h), or with an acid fluoride/chloride.
The methodologies developed under strategy ‘b’ include
photochemical, oxidative, and radical cyclization of
Schiff base 3. In approach ‘c’, the benzoxazole ring annu-
lation is achieved by thermal/photochemical intramolecu-
lar aromatic nucleophilic substitution of 2-haloanilides 4
1
1
12
1
3
14
15
1
6
in a basic medium, cyclodehydration (with excess PPTS
1
3
in xylene under reflux or heating at 230 °C ) and in-
tramolecular Mitsunobu reaction of 2-hydroxyanilide 4,17
and acid catalyzed (with 2 equiv of p-TsOH in xylene un-
der reflux for 2–72 h) deacylative condensation of the 2-
acyloxyanilide 4. Other methods involve Ru-catalyzed
hydroamination of diynes with 1 and degradative cy-
4
,22
ture (ca. 200 °C) for two hours, (ii) boric acid in xylene
2
3
1
8
for 24 hours, and (iii) SnCl in dioxane at 180 °C for 30
2
2
4
1
9
hours. We thought that the need to use an acidic activa-
tor and prolonged time may be avoided in carrying out the
reaction under microwave-assisted dielectric heating
which has been reported to accelerate a number of reac-
tions. We report herein a microwave-assisted direct cou-
pling of 1 with aryl/alkyl carboxylic acids leading to the
synthesis of 2-substituted benzoxazoles under catalyst
and solvent-free conditions.
clization of the imine derived from trifluoromethylaryl
2
0
ketones and 1 under basic conditions. A recent review
provides an account of the current methods for the synthe-
sis of 2-substituted azoles that involve functionalization
2
5
of 2-H and 2-halo-substituted azoles and do not include
methodology for construction of the benzoxazole ring.21
Since there are a few literature reports10a,24,26 for synthesis
of 2-alkylsubstituted benzoxazoles, we planned to use
phenyl acetic acid (5) as a representative carboxylic acid
SYNLETT 2005, No. 9, pp 1401–1404
Advanced online publication: 27.04.2005
DOI: 10.1055/s-2005-868509; Art ID: D02205ST
0
1.
0
6.
2
0
0
5
©
Georg Thieme Verlag Stuttgart · New York

1
402
R. Kumar et al.
LETTER
OH
O
5, 6, 8 and 9, Table 2). The lesser yield obtained with
benzoic acid (entry 1, Table 2) is the result of evaporative
loss of the starting carboxylic acid due to its sublimable
nature.
OH
HO
–H2O
+
Ar(R)
Ar(R)
O
NH2
N
H
Ar(R)
1
2
4
O
2
–H O
O
OH
Ar(R)
We next planned to carry out the condensation of 1 with
dicarboxylic acids (Scheme 4). Treatment of 1 (1.5 equiv)
with succinic acid (7, 1 equiv) for 20 minutes using full
microwave power resulted in the formation of monoben-
zoxazole 8 and bis-benzoxazole 9 in 70% and 15% yields
N
N
H
Scheme 2 Direct coupling of 1 with carboxylic acids for construc-
tion of the benzoxazole moiety
(
GCMS), respectively, along with an unidentified product
(
15%). The use of three equivalents of 1, under similar
to determine the optimum reaction conditions for cou- conditions, afforded 8 and 9 in 36% and 54% yields
pling with 1 (Scheme 3). Thus, 1 (2.5 mmol) was treated (GCMS), respectively. The reaction of 1 (1.5 equiv) with
with varying amounts of 5 under different conditions in a phthalic acid (10, 1 equiv), under similar conditions, led
domestic microwave oven (Table 1). On each occasion to the formation of mono-benzoxazole 11 (93%) and
the reaction was monitored by GCMS. The best results phthalic anhydride (7%, GCMS) and no detectable
were obtained on treating 1 with 5 (1.5 equiv) for 20 min- amount of the corresponding bis-benzoxazole was
utes using full microwave power and micro mode opera- formed. An increase of the amount of 1 to 3 equivalents
tion.
afforded 11 as the sole product. The formation of phthalic
anhydride during the reaction with 10 led us to believe
that the reaction with a dicarboxylic acid may proceed via
the corresponding anhydride. Thus, we carried out the
coupling of 1 with succinic and phthalic anhydrides. Con-
densation of 1 (1.5 equiv) with succinic anhydride (1
equiv) gave 8 and 9 in 70% and 24% yields (GCMS), re-
spectively, and the corresponding products were formed
in 30% and 60%, respectively, with the use of three equiv-
OH
HO
O
MW
O
N
+
NH2
1
5
6
Scheme 3 Microwave-assisted direct coupling of 1 with 5 for the
formation of 2-phenyl benzoxazole
To establish the generality of the reaction, 1 was treated alents of 1. Reaction of phthalic anhydride with 1 (1.5
with various carboxylic acids under microwave-assisted equiv) gave 11 in 93% yield without any formation of the
dielectric heating in a domestic microwave oven using bis-benzoxazole. The lack of formation of the bis-benzox-
micro mode operation and full power for 20 minutes azole from phthalic acid is presumably due to the steric
(
Table 2). Aromatic (entries 1–3, 11 and 12, Table 2), het- hindrance of the benzoxazole moiety in 11 towards nu-
eroaromatic (entries 15 and 16, Table 2), aliphatic (entries cleophilic attack of the second molecule of 1 on the adja-
–6, 7, 13 and 14, Table 2) and a,b-unsaturated (entry 10, cent carboxylic acid. In the case of the reaction with 7, the
4
Table 2) carboxylic acids afforded the corresponding 2- steric effect of the benzoxazole moiety in 8 is less due to
substituted benzoxazoles in good yields. The reaction was the linear structure and allows further nucleophilic attack
compatible with other functional groups such as chloro, by the amino group of 1 on the pendant carboxylic acid.
methoxy, phenoxy and thiophenoxy groups (entries 2, 3,
Table 2 Microwave-Assisted Direct Coupling of 1 with Various
Carboxylic Acids for Benzoxazole Formationa
Table 1 Microwave-Assisted Direct Coupling of 1 with 5 under
a
Various Conditions
Yield (%)b–d
Entry
Carboxylic acid
Entry
5:1b
1.25
1.5
1.5
2
Powerc
Full
Time (min) Yield (%)d
OH
n
O
R
1
2
3
4
20
20
15
20
20
50
86
60
90
61
1
2
3
4
5
6
R = H, n = 0
R = 2-Cl, n = 0
R = 4-Cl, n = 0
R = H, n = 1
R = 3-OMe, n = 1
R = 4-OMe, n = 1
O
35
63
42
79
60
62
Full
Full
Full
5
1.5
60%
a
The mixture of 1 (2.5 mmol) and 5 was treated under microwave-
assisted dielectric heating using a domestic microwave oven under
micro mode operation.
b
Molar ratio.
Full power is 1.35 kHz.
GCMS yield of 6.
c
X
d
OH
7
X = CH2
63
Synlett 2005, No. 9, 1401–1404 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted Benzoxazoles from Carboxylic Acids
1403
Table 2 Microwave-Assisted Direct Coupling of 1 with Various
Carboxylic Acids for Benzoxazole Formation (continued)
We have described herein a microwave-assisted direct
synthesis of 2-substituted benzoxazoles from carboxylic
a
27
Yield (%)b–d
acids. The reaction works well with aromatic, heteroar-
omatic, a,b-unsaturated and arylalkyl carboxylic acids in
good yields and is compatible with functional groups such
as chloro, methoxy, phenoxy and thiophenoxy. The rate of
benzoxazole formation is dependent on the steric factors
surrounding the carboxylic acid. Reactions with dicarbox-
ylic acids proceed via the formation of the corresponding
anhydrides and afford predominantly the mono-benzox-
azoles. The advantages of this method include (i) avoid-
ance of the use of acid or metal catalyst, (ii) short reaction
times, and (iii) waste minimization.28
Entry
Carboxylic acid
8
9
X = O
X = S
O
60
80
OH
1
0
61
O
OH
n
Typical Procedure for the Synthesis of 2-Substituted Benzox-
azoles
A mixture of 1 (273 mg, 2.5 mmol) and phenyl acetic acid (510 mg,
1
1
1
2
n = 0
n = 1
58
61
3
.75 mmol) in a beaker (25 mL) was placed in domestic microwave
oven (BPL, Model BMC 900T, 1.35 kW, 2450 MHz) and heated
under microwave-assisted dielectric heating (micromode, full pow-
er) for 20 min. The reaction mixture was allowed to reach r.t. and
OH
n
O
was then extracted with Et O (2 × 15 mL). The combined ethereal
2
1
1
3
4
n = 0
n = 1
65
70
extracts were washed with sat. NaHCO (2 × 10 mL), brine (10
3
mL), dried (Na SO ), and concentrated under reduced pressure to
2
4
afford the crude product which on passing through a column of sil-
ica gel (60–120 mesh, 10 g) and elution with hexane–EtOAc (94:6,
1
00 mL) afforded pure 2-benzylbenzoxazole (412 mg, 79%; entry
–
1 1
OH
OH
4, Table 2). IR (neat): 3019, 1589, 1405, 1215 cm . H NMR (300
N
S
MHz, CDCl ): d = 4.25 (s, 2 H), 7.23–7.39 (m, 7 H), 7.41–7.46 (m,
3
O
O
1
3
1
1
1
H), 7.64–7.70 (m, 1 H). C NMR (300 MHz, CDCl ): d = 35.2,
10.4, 119.8, 124.1, 124.6, 127.3, 126.8, 128.9, 134.7, 141.3, 151.0,
3
1
5
6
58
82
65.1. MS (APCI): m/z = 210 [M + 1]; identical with an authentic
2
4
sample of 2-benzylbenzoxazole. The remaining reactions were
carried out following this general procedure.
The physical data of new compounds are provided below.
1
2
-(2-Chlorophenyl)benzoxazole (Table 2, entry 2): mp 59–61 °C.
a
The mixture of carboxylic acid (1.5 equiv) and 1 (1 equiv) was treat-
–1 1
IR (KBr): 1589, 1567, 1533, 1469, 1450, 1432, 1020, 812 cm . H
NMR (300 MHz, CDCl ): d = 8.15–8.12 (m, 1 H), 7.86–7.83 (m, 1
H), 7.61–7.53 (m, 2 H), 7.45–7.36 (m, 4 H). C NMR (75 MHz,
CDCl ): d = 160.93, 150.56, 141.67, 133.47, 131.86, 131.80,
1
2
6
ed under microwave-assisted dielectric heating using a domestic
microwave oven under micro mode operation using full power (1.35
kW) for 20 min.
3
13
3
b
Isolated yield of the corresponding 2-substituted benzoxazole
31.36, 126.89, 126.24, 125.54, 124.62, 120.48, 110.71. MS: m/z =
obtained after chromatographic purification.
30 [M + 1]. Anal. Calcd for C H ClNO: C, 67.99; H, 3.51; N,
c
1
d
1
13
8
All the products were characterized from spectral data (IR, H NMR,
.10. Found: C, 67.97; H, 3.53; N, 6.11.
3
C NMR and MS).
All new compounds gave satisfactory elemental analyses.
2-(3-Methoxybenzyl)benzoxazole (Table 2, entry 5): IR (neat):
3
–
1
1
394, 2907, 1593, 1513, 1258, 1019 cm . H NMR (300 MHz,
CDCl ): d = 7.69–7.65 (m, 1 H), 7.44–7.40 (m, 1 H), 7.29–7.20 (m,
3
O
3
3
H), 6.96–6.91 (m, 2 H), 6.81–6.78 (m, 1 H), 4.21 (s, 2 H), 3.75 (s,
O
13
OH
H). C NMR (75 MHz, CDCl ): d = 164.92, 159.74, 150.89,
3
N
OH
MW
8
9
OH
141.18, 136.07, 129.67, 124.56, 124.04, 121.17, 119.65, 114.59,
12.61, 110.31, 55.01, 35.10. MS: m/z = 240 [M + 1]. Anal. Calcd
for C H NO : C, 75.30; H, 5.48; N, 5.85. Found: C, 75.31; H,
O
O
+
+
O
1
20 min
NH2
O
1
5
13
2
OH
N
5.46; N, 5.83.
N
1
7
2-(Phenoxymethyl)benzoxazole (Table 2, entry 8): IR (neat):
–
1
3
063, 2924, 1599, 1495, 1454, 1239, 1213, 1169, 1040, 833 cm .
OH
1
O
H NMR (300 MHz, CDCl ): d = 7.75–7.72 (m, 1 H), 7.53–7.49 (m,
1 H), 7.35–7.25 (m, 4 H), 7.05–6.95 (m, 3 H), 5.28 (s, 2 H).
3
1
3
OH
MW
20 min
C
O
O
N
+
NMR (75 MHz, CDCl ): d = 161.32, 157.74, 150.78, 140.62,
OH
3
NH2
1
29.51, 125.43, 124.47, 121.76, 120.26, 114.67, 110.75, 62.60. MS:
OH
O
m/z = 226 [M + 1]. Anal. Calcd for C H NO : C, 74.65; H, 4.92;
1
4
11
2
1
10
11
N, 6.22. Found: C, 74.64; H, 4.94; N, 6.21.
2-(Phenylsulfanylmethyl)benzoxazole (Table 2, entry 9): IR
Scheme 4 Direct condensation of 1 with dicarboxylic acids
–
1
1
(
neat): 3057, 2924, 1610, 1566, 1453, 1241, 837, 690 cm . H
Synlett 2005, No. 9, 1401–1404 © Thieme Stuttgart · New York

1
404
R. Kumar et al.
LETTER
NMR (300 MHz, CDCl ): d = 7.66–7.63 (m, 1 H), 7.45–7.39 (m, 3
H), 7.25–7.14 (m, 5 H), 4.26 (s, 2 H). C NMR (75 MHz, CDCl3):
(9) (a) Heynderickx, A.; Guglielmetti, R.; Dubest, R.; Aubard,
J.; Samat, A. Synthesis 2003, 1112. (b) Organic
3
1
3
d = 162.87, 150.84, 140.93, 134.23, 130.29, 128.94, 127.11,
Photochromes; El’tsov, A. V., Ed.; Plenum Press: New
York, 1990, 178.
1
24.96, 124.23, 119.84, 110.40, 31.54. MS: m/z = 242 [M + 1].
Anal. Calcd for C H NOS: C, 69.68; H, 4.59; N, 5.80, S, 13.29.
Found: C, 69.66; H, 4.61; N, 5.81, S, 13.28.
(10) (a) Heathcock, C. H. In Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M.; Flemming, I., Eds.; Pergamon Press:
New York, 1991. (b) Reser, A.; Leyshon, L. J.; Saunders,
D.; Mijovic, M. V.; Bright, A.; Bogie, J. J. Am. Chem. Soc.
1
4
11
2
-(1-Naphthalenylmethyl)benzoxazole (Table 2, entry 12): IR
–
1 1
(neat): 3049, 2923, 1613, 1567, 1455, 1241, 1143, 801 cm . H
1972, 94, 2414.
NMR (300 MHz, CDCl ): d = 8.16–8.13 (m, 1 H), 7.83–7.76 (m, 2
3
(
11) (a) Cohen, V. I.; Pourabass, S. J. Heterocycl. Chem. 1977,
14, 1321. (b) Cohen, V. I. J. Heterocycl. Chem. 1979, 16, 13.
12) (a) Chen, C.; Chen, Y.-J. Tetrahedron Lett. 2004, 45, 113.
H), 7.68–7.64 (m, 1 H), 7.52–7.35 (m, 5 H), 7.25–7.16 (m, 2 H),
.66 (s, 2 H). 1 C NMR (75 MHz, CDCl ): d = 165.03, 150.84,
41.23, 133.79, 131.77, 130.84, 128.66, 128.24, 127.66, 126.44,
25.77, 125.46, 125.15, 124.05, 123.63, 119.68, 110.35, 32.86. MS:
3
4
1
1
3
(
(
b) Nadaf, R. N.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J. Mol. Catal. A: Chem. 2004, 214, 155.
c) Pottorf, R. S.; Chadha, N. K.; Katevics, M.; Ozola, V.;
m/z = 260 [M + 1]. Anal. Calcd for C H NO: C, 83.37; H, 5.05; N,
1
8
13
(
5
.40. Found: C, 83.35; H, 5.04; N, 5.38.
Suna, E.; Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron
Lett. 2003, 44, 175.
2
-(2-Naphthalenylmethyl)benzoxazole (Table 2, entry 14): IR
–
1
(
neat): 3054, 2924, 1614, 1568, 1455, 1241, 1142, 837, 817 cm .
(13) Tauer, E.; Grellmann, K. H. J. Org. Chem. 1981, 46, 4252.
1
H NMR (300 MHz, CDCl ): d = 7.78–7.74 (m, 4 H), 7.70–7.68 (m,
3
(14) (a) Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi,
M. Org. Lett. 2003, 5, 3713; and references therein.
1
3
1
H), 7.47–7.39 (m, 4 H), 7.25–7.21 (m, 2 H), 4.37 (s, 2 H). C
NMR (75 MHz, CDCl ): d = 165.00, 150.90, 141.23, 133.36,
3
(b) Wilfred, C. D.; Taylor, R. K. J. Synlett 2004, 1628.
1
1
32.40, 132.06, 128.41, 127.59, 126.81, 126.12, 125.79, 124.58,
24.07, 119.70, 110.31, 35.24. MS: m/z = 260 [M + 1)]. Anal. Calcd
(
1
c) Bougrin, K.; Loupy, A.; Soufiaoudi, M. Tetrahedron
998, 54, 8055.
for C H NO: C, 83.37; H, 5.05; N, 5.40. Found: C, 83.35; H, 5.03;
1
8
13
(15) Park, M. S.; Jun, K.; Shin, S. R.; Oh, S. W.; Park, K. H. J.
Heterocycl. Chem. 2002, 39, 1279; and references therein.
N, 5.43.
(
16) (a) El-Sheikh, M. I.; Marks, A.; Biehl, E. R. J. Org. Chem.
981, 46, 3256. (b) Park, Y.-T.; Jung, C.-H.; Kim, K.-W. J.
1
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(
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Synlett 2005, No. 9, 1401–1404 © Thieme Stuttgart · New York