Lawesson's reagent and microwaves: A new efficient access to benzoxazoles and benzothiazoles from carboxylic acids under solvent-free conditions

Article abstract of DOI:10.1055/s-2007-967994

Lawesson's reagent acts as an efficient promoter in the solvent-free microwave-assisted synthesis of 2-substituted benzoxazoles from carboxylic acids and 2-aminophenol, and thus, constitutes a general synthetic method for these compounds. This new application of Lawesson's reagent is valid also for benzothiazoles with very high efficiency level. A variety of aromatic, heteroaromatic and aliphatic carboxylic acids react under the conditions developed with good yields in all cases. Thiobenzoic acid is a good alternative for microwave-assisted synthesis of 2-phenylbenzoxazole and 2- phenylbenzothiazole in the absence of solvents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967994

LETTER
313
Lawesson’s Reagent and Microwaves: A New Efficient Access to Benzoxazoles
and Benzothiazoles from Carboxylic Acids under Solvent-Free Conditions
L
awesson
u
’s Reagent
a
n
l
d Micr
i
owave
o
s
in Benzoazole
s
S
A
ynthesis . Seijas,* M. Pilar Vázquez-Tato,* M. Raquel Carballido-Reboredo, José Crecente-Campo,
Lucía Romar-López
Departamento de Química Orgánica, Universidad de Santiago de Compostela, Facultad de Ciencias, Aptdo. 280, 27080 Lugo, Spain
Fax +34(982)285872; E-mail: qoseijas@lugo.usc.es; E-mail: pilarvt@lugo.usc.es
Received 10 October 2006
of the microwave approach are enhanced reaction rates,
Abstract: Lawesson’s reagent acts as an efficient promoter in the
formation of purer products in high yields and easier
solvent-free microwave-assisted synthesis of 2-substituted benzox-
manipulation. MAOS has been applied in the preparation
of benzoxazole and benzothiazole compounds. Previous
azoles from carboxylic acids and 2-aminophenol, and thus, consti-
tutes a general synthetic method for these compounds. This new
application of Lawesson’s reagent is valid also for benzothiazoles research affords many possibilities from the direct heating
with very high efficiency level. A variety of aromatic, heteroaro-
of benzoic acid with o-aminophenol or o-aminothio-
phenol,18–20 to the use of acid derivatives or another func-
matic and aliphatic carboxylic acids react under the conditions de-
veloped with good yields in all cases. Thiobenzoic acid is a good
tionalities with or without a wide variety of auxiliary
alternative for microwave-assisted synthesis of 2-phenylbenzox-
reagents. Some examples of these are condensations of o-
aminophenols with S-methylisothioamide hydroiodides
azole and 2-phenylbenzothiazole in the absence of solvents.
Key words: benzothiazoles, benzoxazoles, Lawesson’s reagent,
on silica gel,21 carboxylic acids and PPA22 or PS-PPh3,23
microwaves, thiobenzoic acid
acid chlorides,24 b-keto esters,25 and a-chlorocinnamal-
dehydes together with p-toluenesulfonic acid,26 conden-
sation of o-aminothiophenols with orthoesters in the
Benzoxazole and benzothiazole are remarkable heterocy-
presence of KFS clay,27 aldehydes in the presence of
clic ring systems, both either isolated from natural product
28
SiO2 or an ionic liquid.29 Loupy20 and Chakraborti18,19
sources or accessed by total synthesis. They show a wide
have reported direct condensation of o-aminophenol or o-
aminothiophenol with benzoic acids under microwave
range of biological activities: anticancer, gram-positive
antibacterials,1 antimicrobial, anti-HIV,2 antibiotic,3 anti-
irradiation, but in both cases the reported examples
parasitic,4 antiinflamatory,5 H2-antagonist, and elastase
present a very wide range of yields. Consequently, a more
inhibitor.6 They are also fluorescent whitening agents,7
consistent solvent-free MAOS method would be useful.
constituents of cyanine dyes,8 heat resistant fibers,9
fluorescent materials,10 optical brighteners,11 and metal-
coordinated ligands.12
In our studies on the synthesis of pharmacologically ac-
tive benzoxazoles by condensation of neat benzoic acids
and o-aminophenol or o-aminothiophenol under micro-
wave heating, the results were not satisfactory. So, we ex-
plored the possibility of replacing carboxylic acids with
their derivative thiocarboxylic acids, which are more reac-
tive. Thus, a mixture of thiobenzoic acid and 2-amino-
phenol (1:1) was irradiated for 1 minute in a monomode
microwave oven (300 W, 190 °C), yielding 2-phenyl-
benzoxazole in quantitative yield. Similarly, the reaction
of thiobenzoic acid with 2-aminobenzothiol yielded 2-
phenylbenzothiazole (Scheme 1).
Numerous synthetic methods are available for 2-aryl-
benzothiazoles and 2-arylbenzoxazoles. The most impor-
tant ones include the reaction of o-aminophenols and o-
aminothiophenols with benzoic acids or their derivatives
in a wide set of conditions such as polyphosphoric acid
(PPA),13 polyphosphate ester or a mixture of methane-
sulfonic acid and phosphorus pentoxide,14 through the for-
mation of selenoamides,15 etc.16 Most of these protocols,
however, suffer from drawbacks, namely long reaction
times and the use of corrosive acids.
Microwave-assisted organic synthesis (MAOS) is a pow-
erful technique that is being used more and more to accel-
erate thermal organic reactions. This is a consequence of
the selective absorption of microwave energy by polar
molecules or polar transition state intermediates formed
during the course of the reaction.17 Regardless of the ori-
gin of a special microwave effect, microwave-enhanced
chemistry can be extremely efficient and it is applicable to
a broad range of practical syntheses. The notable features
H2N
O
N
Z
MW
+
Ph
Ph
SH
HZ
1
2, Z = O
3, Z = S
4a, Z = O
5a, Z = S
Scheme 1
These results showed that this procedure is a very good
alternative for preparing 2-arylbenzoxazoles and 2-aryl-
benzothiazoles. However, the lack of a wide number of
commercial thiobenzoic acids makes it necessary to
prepare them beforehand from benzoic acids, using any
SYNLETT 2007, No. 2, pp 0313–0317
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967994; Art ID: G30306ST
© Georg Thieme Verlag Stuttgart · New York

314
J. A. Seijas et al.
LETTER
published method.30 Therefore, an alternative method phenylbenzoxazole (5a, Scheme 2). The optimization of
based on benzoic acids would be more suitable.
reaction conditions was carried out at different tempera-
tures (150–190 °C), reaction times and by changing the
molar percent amounts of LR (25%, 35%, 40% and 50%).
The best set of conditions (power setting 300 W for 4 min
at 190 °C, with 35% molar amount of LR) led to pure
(checked by NMR) 2-phenylbenzoxazole. Further purifi-
cation by flash chromatography of the crude of reaction
yielded 83% of 2-phenylbenzoxazole. This yield is very
high compared to 35% reported for 2-phenylbenzoxazole
obtained by microwave irradiation in absence of LR.18 It
stands out that greater amounts of LR do not lead to higher
yields. This suggests that a LR by-product can also act as
an activating agent, although this has not been previously
established. The scope of this reaction was demonstrated
by the efficient syntheses of several 2-substituted benzox-
azoles in good yields (59–90%, Table 1).41 The carboxylic
acids were chosen in order to check the compatibility of
the method with several substitution patterns of benzoic
acids, including chlorine, methyl and methoxy groups in
different positions and with a variable degree of sub-
stitution (Table 1, entries 1–7). It is noticeable that the
low yield (62%) in the reaction of 2,3-dimethoxybenzoic
to give 4c was due to a partial demethylation in the
hindered ortho-position, since 2-(2-hydroxy-3-methoxy-
Lawesson’s reagent (LR) has been recently applied in
MAOS for thionation of carbonyl compounds,31 alcohol
deoxygenation,32 synthesis of isocyanates,33 1,3,2-diaza-
phosphorines and 1,3,2-oxazaphosphorines,34 1,3,4-thia-
diazoles,35 thiophenes and 1,3-thiazoles.36 Upon heating,
its central phosphorus/sulfur four-membered ring breaks
to form two reactive dithiophosphine ylides. In fact, much
of the chemistry of LR is the chemistry of these reactive
intermediates.37 It had been used in this way to activate
carboxylic acids towards peptide bond formation37,38
through the formation of a mixed anhydride between
Lawesson’s reagent and carboxylic acid. Even more, LR
can act through the formation in situ of the thioacid as
reported by Rothenberger et al.39
LR has never been used in the synthesis of benzoxazoles
and benzothiazoles, and it would be a good choice since it
is a way to take advantage of its ability to form mixed an-
hydrides and enhance this reaction. Joined to microwave
irradiation this could lead to an effective synthetic method
for the above-mentioned heterocycles.
Irradiation of a mixture of benzoic acid (6a), o-amino-
phenol (2) and LR40 in a monomode oven afforded 2-
Table 1 Synthesis of Benzoxazoles
Entry
1
Acid
6a
6b
6c
R
Product
4a42
4b20
4c
Time (min)a
Yield (%)b
83
Ph
4
4
4
4
4
4
4
4
4
4
4
4
2
2
2
2
2
2
3,4-(MeO)2C6H3
2,3-(MeO)2C6H3
2-MeOC6H4
2,4,5-(MeO)3C6H2
3-MeC6H4
4-ClC6H4
79
3
62c
78
4
6d
6e
4d43
4e
5
74
6
6f
4f44
4g45
4h44
4i46
90
7
6g
6h
6i
75
8
1-naphthyl
2-naphthyl
2-pyridinyl
2-thienyl
87
9
86
10
11
12
13
14
15
16
17
6j
4j47
4k48
4l46
71
6k
6l
80
2-phenylethenyl
Bn
59
6m
6n
6o
6p
6q
4m23
4n
90
3,4-(MeO)2C6H3CH2
C6H13
80
4o49
4p50
4q51
90
C11H23
88
C17H35
84
a Reactions were heated at 190 °C for the time indicated.41
b All yields are for isolated product with previous purification by flash chromatography.52
c Partial demethylation in the hindered ortho-position gave 2-(2-hydroxy-3-methoxyphenyl)benzoxazole in 16% yield.
Synlett 2007, No. 2, 313–317 © Thieme Stuttgart · New York

LETTER
Lawesson’s Reagent and Microwaves in Benzoazoles Synthesis
315
phenyl)benzoxazole was isolated in 16% yield. minutes of irradiation. This yield was highly improved by
Condensed polycyclic aromatic acids were successfully the use of LR (Table 2, entry 1).
transformed into the corresponding benzoxazoles
In all cases the yields for benzothiazoles from aromatic
(Table 1, entries 8 and 9). Aromatic heterocyclic acids are
and aliphatic carboxylic acids were high (Table 2).41 In
also compatible with the reaction conditions (Table 1, en-
general, the reaction times required to prepare benzothia-
tries 10 and 11), as well as a,b-unsaturated carboxylic ac-
zoles were shorter than those of their oxygen analogues.
ids like cinnamic acid; however, in this case the yield is
Some mechanistic aspects involved in this reaction are
lower (Table 1, entry 12). Alkyl carboxylic acids, such as
still under study. It is supposed that an activated carboxy-
phenylacetic acid and homoveratric acid (Table 1, entries
lic acid derivative is formed as previously described.38
13 and 14), and aliphatic carboxylic acids (Table 1, en-
When benzoic acid was heated with LR under microwave
tries 15–17) afforded the corresponding benzoxazoles in
irradiation as in benzoazole syntheses, all the starting acid
high yield, requiring shorter reaction times.
was consumed, but the formation of thiobenzoic acid was
not detected. Furthermore, under the described conditions
H2N
N
LR
2-aminophenol and 2-aminothiophenol react with LR to
R
CO2H
+
R
give 1,3,2-oxazaphospholine62 or 1,3,2-thiazaphospholine
2-sulfides, respectively. These results suggest that both
reagents can be activated by LR.
MW
Z
HZ
6a–q
2, Z = O
3, Z = S
4a–q, Z = O
5a–q, Z = S
Scheme 2
In conclusion, a new, fast, efficient and general method
for the synthesis of benzoxazoles and benzothiazoles from
carboxylic acids and o-aminophenol or o-aminothio-
phenol, respectively, is presented. This solvent-free pro-
cedure employs LR to activate the carboxylic acid,
extending the range application of LR. Our method is
competitive with previous ones, both with conventional or
microwave heating, since it leads to good yields and
The developed procedure was extended to the synthesis of
benzothiazoles. Previously reported microwave-assisted
synthesis by Chakraborti19 for 2-arylbenzothiazoles from
benzoic acids and o-aminothiophenol afforded poor to
moderate yields (12% for 2-phenylbenzothiazole) after 20
Table 2 Synthesis of Benzothiazoles
Entry
1
Acid
6a
6b
6c
R
Product
5a53
5b54
5c19
5d19
5e
Time (min)a
Yield (%)b
91
Ph
1
2
3,4-(MeO)2C6H3
2,3-(MeO)2C6H3
2-MeOC6H4
2,4,5-(MeO)3C6H2
3-MeC6H4
4-ClC6H4
1
85
3
1
81
4
6d
6e
1
81
5
1
70
6
6f
5f55
1
85
7
6g
6h
6i
5g19
5h56
5i57
1
86
8
1-naphthyl
2-naphthyl
2-pyridinyl
2-thienyl
1
88
9
1
90
10
11
12
13
14
15
16
17
6j
5j58
1
88
6k
6l
5k15
5l59
1
85
2-phenylethenyl
Bn
1
59
6m
6n
6o
6p
6q
5m19
5n
0.5
0.5
0.5
0.5
0.5
91
3,4-(MeO)2C6H3CH2
C6H13
85
5o60
5p61
5q61
90
C11H23
91
C17H35
84
a Reactions were heated at 190 °C for the time indicated.41
b All yields are for isolated product with previous purification by flash chromatography.52
Synlett 2007, No. 2, 313–317 © Thieme Stuttgart · New York

316
J. A. Seijas et al.
LETTER
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PGIDIT05PXIB26201PR, PR405 A 098/59-0 and for a predoctoral
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(141 mg, 0.35 mmol) was irradiated in an open vessel with
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Hz), 7.79–7.76 (m, 1 H, ArH), 7.58–7.55 (m, 1 H, ArH), 7.40
(t, 1 H, ArH, J = 7.6 Hz), 7.35–7.32 (m, 2 H, ArH), 2.45 (s,
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142.3, 139.0, 132.6, 129.1, 128.4, 127.2, 125.3, 125.0,
124.8, 120.2, 110.8, 21.6. MS (EI): m/z (%) = 209 (100)
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Lawesson’s Reagent and Microwaves in Benzoazoles Synthesis
317
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2-(2,4,5-Trimethoxyphenyl)benzothiazole (5e): mp 200–
201 °C (EtOH). 1H NMR (300 MHz, CDCl3): d = 8.07 (s, 1
H, ArH), 8.04 (d, 1 H, ArH, J = 7.9 Hz), 7.89 (d, 1 H, J = 7.9
Hz), 7.46 (ddd, 1 H, ArH, J = 8.2, 7.0, 1.2 Hz), 7.34 (dd, 1
H, ArH, J = 7.9, 0.9 Hz), 6.62 (s, 1 H, ArH), 4.04, 4.01 and
3.97 (3 s, 3 × 3 H, 3 × OCH3). 13C NMR (75 MHz, CDCl3):
d = 163.3, 153.0, 152.4, 152.3, 143.0, 136.0, 126.0, 124.4,
122.5, 121.4, 114.6, 111.5, 97.4, 56.8, 56.7, 56.3. MS (EI):
m/z (%) = 301 (100) [M+], 286 (11), 272 (30), 256 (11), 228
(11), 215 (4), 186 (5), 160 (2). Anal. Calcd for C16H15NO3S:
C, 63,77; H, 5,02; N, 4,65. Found: C, 64.05; H, 4.73; N, 4.87.
2-[(3,4-Dimethoxyphenyl)methyl]benzothiazole (5n): mp
68–69 °C (hexane). 1H NMR (300 MHz, CDCl3): d = 7.97
(dd, 1 H, ArH, J = 8.8, 0.9 Hz), 7.73 (dd, 1 H, J = 7.9, 1.3
Hz), 7.40 (td, 1 H, ArH, J = 7.9, 1.2 Hz), 7.28 (t, 1 H, ArH,
J = 7.6 Hz), 6.90–6.85 (m, 2 H, ArH), 6.80 (d, 1 H, ArH,
J = 7.9 Hz), 4.34 (s, 2 H, CH2), 3.82 and 3.81 (2 s, 2 × 3 H,
2 × OCH3). 13C NMR (75 MHz, CDCl3): d = 171.9, 153.5,
149.4, 148.6, 135.8, 129.9, 126.1, 125.0, 122.9, 121.7,
121.5, 112.6, 111.6, 56.03, 56.00, 40.4. MS (EI): m/z (%) =
285 (100) [M+], 270 (9), 242 (13), 227 (11), 199 (14), 151
(10). Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30; N,
4.91. Found: C, 67.14; H, 5.28; N, 4.85.
(51) Bywater, W. G.; Coleman, W. R.; Kamm, O.; Merritt, H. J.
Am. Chem. Soc. 1945, 67, 905.
(52) Data of Previously Undescribed Compounds.
2-(2,3-Dimethoxyphenyl)benzoxazole (4c): mp 75–76 °C
(hexane). 1H NMR (300 MHz, CDCl3): d = 7.83–7.77 (m,
1 H, ArH), 7.69 (dd, 1 H, ArH, J = 7.9, 1.5 Hz), 7.60–7.53
(m, 1 H, ArH), 7.35–7.29 (m, 2 H, ArH), 7.14 (t, 1 H, ArH,
J = 8.0 Hz), 7.03 (dd, 1 H, ArH, J = 8.2, 1.4 Hz), 3.99 (s, 3
H, OCH3), 3.87 (s, 3 H, OCH3). 13C NMR (75 MHz, CDCl3):
d = 161.7, 154.0, 150.9, 149.0, 142.2, 125.3, 124.6, 124.5,
122.6, 122.0, 120.4, 115.6, 110.8, 61.7, 56.3. MS (EI): m/z
(%) = 255 (100) [M+], 240 (18), 226 (56), 212 (10), 197 (13),
169 (2). Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N,
5.49. Found: C, 70.41; H, 5.09; N, 5.38.
2-(2,4,5-Trimethoxyphenyl)benzoxazole (4e): mp 146–148
°C (hexane). 1H NMR (300 MHz, CDCl3): d = 7.72–7.69 (m,
1 H, ArH), 7.59 (s, 1 H, ArH), 7.50–7.46 (m, 1 H, ArH),
7.26–7.21 (m, 2 H, ArH), 6.53 (s, 1 H, ArH), 3.91, 3.87 and
3.86 (3 s, 3 × 3 H, 3 × OCH3). 13C NMR (75 MHz, CDCl3):
d = 163.3, 155.2, 154.2, 149.1, 143.0, 140.5, 125.0, 124.9,
118.9, 110.5, 108.3, 101.5, 100.9, 56.7, 56.2. MS (EI): m/z
(%) = 285 (100) [M+], 271 (29), 256 (76), 242 (19), 240 (17),
227 (7), 212 (13). Anal. Calcd for C16H15NO4: C, 67.36; H,
5.30; N, 4.91. Found: C, 67.66; H, 4.96; N, 5.11.
(53) Osuka, A.; Uno, Y.; Horiuchi, H.; Suzuki, H. Synthesis
1984, 145.
(54) Mortimer, C. G.; Wells, G.; Crochard, J.-P.; Stone, E. L.;
Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med.
Chem. 2006, 49, 179.
(55) Ulrich, H. In Science of Synthesis, Vol. 11; Schaumann, E.,
Ed.; Thieme: Stuttgart, 2001, 835–912.
(56) Deligeorgiev, T. C. Dyes Pigm. 1990, 12, 243.
(57) Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles
2004, 63, 2769.
2-[(3,4-Dimethoxyphenyl)methyl]benzoxazole (4n): mp
66–68 °C (hexane). 1H NMR (300 MHz, CDCl3): d = 7.68–
7.64 (m, 1 H, ArH), 7.43–7.40 (1 H, m, ArH), 7.27–7.22 (m,
2 H, ArH), 6.91–6.87 (m, 2 H), 6.80 (d, 1 H, ArH, 8.0 Hz),
4.17 (s, 2 H, CH2), 3.83 and 3.81 (2 s, 2 × 3 H, 2 × OCH3).
13C NMR (75 MHz, CDCl3): d = 165.7, 151.2, 149.4, 148.6,
141.6, 127.4, 124.9, 124.4, 121.4, 120.0, 112.4, 111.7,
110.6, 56.1, 35.0. MS (EI): m/z (%) = 269 (100) [M+], 254
(42), 226 (7), 183 (5), 151 (20). Anal. Calcd for C16H15NO3:
C, 71.36; H, 5.61; N, 5.20. Found: C, 71.05; H, 5.73; N, 5.16.
(58) Tzanopoulou, S.; Pirmettis, I. C.; Patsis, G.; Raptopoulou,
C.; Terzis, A.; Papadopoulos, M.; Pelecanou, M. Inorg.
Chem. 2006, 45, 902.
(59) Boger, D. L. J. Org. Chem. 1978, 43, 2296.
(60) Elderfield, R. C.; McClenachan, E. C. J. Am. Chem. Soc.
1960, 82, 1982.
(61) DuBrow, P. L.; Hoerr, C. W.; Harwood, H. J. J. Am. Chem.
Soc. 1952, 74, 6241.
(62) Shabana, R.; Atrees, S. S. Phosphorus, Sulfur Silicon Relat.
Elem. 1995, 105, 57.
Synlett 2007, No. 2, 313–317 © Thieme Stuttgart · New York

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