Novel 4- and 7-sulfonylated 2-substituted benzoxazoles

Article abstract of DOI:10.1055/s-0030-1258494

The efficient synthesis of sulfonylated benzoxazoles at positions C ₄ or C₇ is reported. The condensation reactions involve original anilide acetal reagents which, upon acid catalysis, allow an easy cyclization reaction with the sulfonylated o-aminophenol partners. This method circumvents the classical use of orthoesters which drawback is the limited access to aromatic reagents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258494

1974
LETTER
Novel 4- and 7-Sulfonylated 2-Substituted Benzoxazoles
Sulfonylated
B
r
enzoxaz
é
oles déric Bruyneel, Jacqueline Marchand-Brynaert*
Institute of Condensed Matter and Nanosciences (IMCN), Organic and Medicinal Chemistry (CHOM), Université catholique de Louvain,
Bâtiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)474168; E-mail: jacqueline.marchand@uclouvain.be
Received 28 April 2010
We have taken advantage of the sulfonic acid group
Abstract: The efficient synthesis of sulfonylated benzoxazoles at
present on the o-aminophenol precursors (1 and 2,
positions C4 or C7 is reported. The condensation reactions involve
Scheme 1) to catalyze intramolecularly the oxazole ring
original anilide acetal reagents which, upon acid catalysis, allow an
easy cyclization reaction with the sulfonylated o-aminophenol part-
formation by reaction with orthoesters.12 We further de-
ners. This method circumvents the classical use of orthoesters veloped anilide acetals as more versatile reagents for this
which drawback is the limited access to aromatic reagents.
Brønsted acid catalyzed heterocyclization. Lastly, we
have illustrated our method with the synthesis of sulfony-
lated analogues of the UK-1 metabolite benzoxazole core
(Figure 1, structure C with R = SO3H, SO2NH2).
Key words: acetals, condensation, cyclization, heterocycles, sub-
stituents effects
3
4
The benzoxazole framework sporadically occurs in natu-
ral compounds exhibiting a broad spectrum of activities
(Figure 1).1 Synthetic efforts toward derivatives with an
increased molecular diversity mainly focuse on the 2-aryl-
substituted family.2 The common syntheses of such ox-
azole heterocycles include the heat dehydration of o-acyl-
aminophenols,3 the Beckmann rearrangement of o-
hydroxybenzophenone oximes,4 the oxidative ring clo-
sure of o-phenolic Schiff bases,5 and the direct arylation
reactions through transition-metal C2–H functionaliza-
tion.6 An interesting one-pot procedure from 2-aminophe-
nol and carboxylic acid, via the in situ formation of acid
chloride, is also reported.2c Among those synthetic routes,
little works have been dedicated to the selective insertion
of hydrophilic groups on the benzoxazole core structure.
Yet such derivatives could offer a high potential either to
modulate pharmacological properties or to give access to
water-soluble fluorophores.1,7,8
9
N
5
OMe
2
6
O
8
1
7
O
A
O
N
HO
R
HO
N
O
N
O
B (UK-1)
C
Figure 1 The benzoxazole framework (A), its occurrence in the
UK-1 metabolite (B), and simpler analogues (C)
The efficient and regioselective syntheses of our sulfony-
lated building blocks, respectively, 3-hydroxyorthanilic
acid (1) and 2-hydroxymetanilic acid (2) were previously
described (Scheme 1).11
Sulfonylated benzoxazoles on positions C5 and C6 are
readily available through the aromatic electrophilic sub-
stitution process.9 Up to now, synthetic routes toward sul-
fonylated bezoxazoles on positions C4 and C7 have been
scarcely reported. Those involve either a Newman–
Kwart-type rearrangement or a benzyne pathway.10 Re-
cently, the drawback of poor water-solubility of the natu-
ral metabolite UK-1 from Streptomyces (Figure 1) was
markedly pointed out.7 This metabolite features two criti-
cal benzoxazole moieties which impart its cytotoxic activ-
ity. Given our recent researches involving the selective
synthesis of phenoxazine scaffolds from sulfonylated
aminophenols,11 we report here a practical and efficient
synthesis of functionalized benzoxazoles bearing free sul-
fonic acid, sulfonyl ester, or sulfonamide either on posi-
tion C4 or C7.
O
S
O
S
OR2
OH
O
O
NH2
OH
N
R1C(OR2)3
R1
O
3a,b 80%
3c 50%
1
NH2
OH
N
O
R1C(OR2)3
R1
S
S
O
OH
O
OR2
O
O
4a,b 80%
4c 50%
2
a R1 = H, R2 = i-Pr
b R1 = Me, R2 = Et
c R1 = Ph, R2 = Me
Scheme 1 Synthesis of benzoxazoles sulfonylated either in position
C4 (3a–c) or C7 (4a–c) from commercial orthoesters. Reagents and
conditions: see ref. 17 and Supporting Information.
SYNLETT 2010, No. 13, pp 1974–1978
Advanced online publication: 16.07.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258494; Art ID: G12210ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sulfonylated Benzoxazoles
1975
We first determined the optimal conditions for the acid- the formation of orthothioesters which are subsequently
catalyzed cyclization of 1 and 2 with a series of commer- submitted to methanolysis in the presence of a silver salt
cial orthoesters. Whereas the common protocol for benz- and a base.15
oxazole synthesis uses high temperatures and strong acids
An excellent (yet old) procedure was reported by Mac-
in the presence of a large excess of orthoester,12 in our
Clelland and his group. It involves the condensation of an
case the reaction proceeded well under very mild condi-
tions. Typically, the compounds 1 or 2 were mixed with 3
acyl chloride with N-methylaniline followed by the prep-
aration of benzanilide acetal by using standard amide
equivalents of orthoester dissolved in a small volume of
acetal procedure.16 The last step corresponds to the treat-
dioxane and allowed to react at 60 °C for a few hours.
ment of the previous crude acetal with alcohol and an ex-
Then, the mixture was filtered and the residual solid
cess of acid which ultimately gives the desired orthoester.
washed with dichloromethane. The filtered solution was
Yet, the yields are largely dependent on the nature of the
evaporated to give crude benzoxazoles in high purity
substituents present on the aromatic nucleus.
(from NMR analysis), collected as the corresponding sul-
We reasoned that such a simple and fast synthetic route
fonic esters.
could be of interest for our acid-catalyzed cyclization (il-
lustrated in Scheme 2). The desired benzanilide acetals 5
were synthesized in high yields and used directly in the
condensation reaction with the sulfonylated aminophe-
The compounds 3a–c and 4a–c were obtained with good
to moderate yields, that is, 80% for 3a,b and 4a,b, and
50% for 3c and 4c. The benzoxazoles 3c and 4c could be
recrystallized in ethanol–dichloromethane. The simulta-
nols 1 or 2, using the same experimental conditions as for
neous protection of the sulfonic acid with orthoesters has
orthoesters.17 The desired benzoxazoles 6 or 7 were isolat-
been previously reported.13 The lower yields obtained
ed in good yields after purification by column chromatog-
raphy. The results obtained with compounds 1 and 2 in the
with trimethylbenzoate orthoester (a small amount of
product was isolated as the free sulfonic acid) point out
the limitation of the classical condensation reaction when
an aryl substituent is required at position C2.
presence of several benzanilide acetals 5 are reported in
Table 1.18 The synthesis of reagents 516 is given as Sup-
porting Information and the access to one particular re-
In addition, the relative difficulty to synthesize aromatic agent (FG = o-OBn) is described in the Scheme 3. Table 1
orthoesters bearing diverse functional groups does not shows that three 4-sulfonic benzoxazoles (6a–c) and one
bode well for a general synthetic route. For instance, aro-
matic orthoesters are not readily synthesized using the Table 1 Condensation Reactions with Benzanilide Acetals
classical Pinner reaction.14 An alternative route includes
Entry Substrates FG of 5a Productsb Yield (%) Notec,d
OR
Ph
4 steps
Aryl-COX
1
2
3
4
1
1
1
1
2-MeO
3-MeO
2-O2N
2-BnO
6a
6b
–
70
60
Aryl
N
(X = Cl, OH)
Me
OR
5
>80% of 5¢
–
–
SO3
SO3
6c
60
65
+ 20% ester
of 6c
NH2
OH
OH
or
5
6
7
2
2
2
2-MeO
3-MeO
2-O2N
7a
–
NH2
1 or 2
>50% 5¢
>80% 5¢
RO
H+
N
+
Aryl
Ph
–
RO
Me
a Crude acetals 5 were prepared from the corresponding benzoic ac-
ids, purity of the reagent was verified by 1H and 13C NMR (Figure 2).
–
–
SO3
SO3
OH
NH2
OR
+
OR
O
Aryl
or
+
+
PhNHMe
N(Me)Ph
N(Me)Ph
NH2
OH
OR
OR
FG
FG
5
5'
SO3H
FG = functional group
R = Me, Et
N
N
O
Aryl
Aryl
or
Figure 2
O
SO3H
7
b Except for 6c for which a part of the benzoxazole was isolated as a
sulfonate ester, all of the benzoxazoles gave free sulfonic acid deriv-
atives.
6
Scheme 2 Synthesis of benzoxazoles sulfonated either in position
C4 (3a-c) or C7 (4a-c) from benzanilide acetals. Reagents and condi-
tions: see ref. 17 and Supporting Information.
c The nature of the side product was confirmed by NMR.
d Benzanilide 5¢ results from hydrolysis of 5.
Synlett 2010, No. 13, 1974–1978 © Thieme Stuttgart · New York

1976
F. Bruyneel, J. Marchand-Brynaert
LETTER
7-sulfonic benzoxazole (7a) were readily accessible, This acid was converted into acyl chloride and substituted
while three condensations failed (entries 3, 6, and 7) and with N-methylaniline to give the required benzanilide 8¢.
the hydrolyzed reagent 5¢ was recovered.
O-Alkylation with ethyl triflate gave the imidatonium salt
which was reacted with freshly made sodium ethoxide to
produce the desired benzanilide acetal 8 in an overall
yield of 80% for seven steps.
Increasing the amount of acetal 5 (3–10 equiv), and heat-
ing at higher temperatures (60–80 °C) for a long time (17–
48 h) did not help. The reaction most probably proceeds
via an acid–base equilibrium as the first step, giving the The condensation of 8 with the substrate 1, as previously
intermediate aryl(bisalkoxy)carbenium ion. The forma- described, gave the desired heterocyclic scaffold 6c. The
tion of this reactive species (Scheme 2) should be favored benzyl ether of the benzoxazole 6c, bearing the free sul-
by electron-donating substituents on the aryl moiety (i.e., fonic acid group, was quantitatively cleaved under usual
FG = 2-OMe and 2-OBn) and disfavored by electron- hydrogenation conditions20 to afford the target compound.
withdrawing substituents (i.e., FG = 2-NO2 and 3-OMe This benzoxazole 9 is quite water-soluble (≥10–4 M) and
with a lesser importance). The difference of reactivity be- features interesting fluorescence properties with blue
tween the substrates 1 and 2 vs. the 3-OMe reagent 5 (en- emission from sunlight irradiation, like the well known 2¢-
tries 2 and 6) also suggests that the intramolecular acid hydroxy-2-phenylbenzoxazole dye, an intercalating agent
catalysis for assisting the condensation–cyclization is into DNA duplex.21
more efficient when the sulfonic acid group is next to the
aniline function. It is worthy of note that a similar, but in-
The robustness of benzoxazole sulfonic acids 6 under
standard experimental conditions has been further illus-
trated with the transformation of 6a into primary sulfon-
amide 10 (Scheme 4). The free acid was converted into
termolecular assistance by methanesulfonic acid (3 equiv)
is known.2c
The problem of chemoselective deprotection of a O-meth- the corresponding sulfonyl chloride with PCl5/OPCl3 and
yl ether function on benzoxazole derivatives has been pre- then substituted by ammonia in a biphasic medium to give
viously reported in the literature.1a Accordingly, we the derivative 10 with an overall yield of 90%.
synthesized the water-soluble sulfonylated analogue of
Given the structural similarity of sulfonamide 10 to
UK-1 scaffold using the benzyl ether as the protecting
known carbonic anhydrase (CA) inhibitors,22 we tested
group7b (Scheme 3).
our compound against the human CA-I enzyme; 10 was
found active only at high concentrations (>200 mM).
OH
OBn
OH
CO2H
CO2Me
CO2Me
O
O
(b)
(a)
(c)
OH
NH2
S
S
O
OMe
O
OMe
i) PCl5, OPCl3,
CH2Cl2
N
N
ii) NH3 (aq)
CH2Cl2
O
O
OEt
O
OBn
EtO
6a
10 (90%)
COCl
(d)
N
(e)
N
Scheme 4 Conversion into primary sulfonamide. Reagents and
conditions: see Supporting Information.
Me
O
Bn
Me
O
Bn
In conclusion, we have disclosed two routes allowing the
preparation of 4- or 7-sulfonylated benzoxazoles under
very mild conditions. The compounds present various
substitutions at position C2 (H, alkyl, aryl) and an in-
creased water-solubility. Further derivatizations have
been illustrated with the synthesis of an analogue of UK-
1 metabolite and a sulfonamide related to CA inhibitors.
Works are in progress for similarly preparing phosphory-
lated benzoxazoles23 and exploiting their metal-chelating
properties.
8'
Bn
8 (~80%)
O
OH
O
S
OH
O
O
S
O
HO
N
(f)
(g)
N
O
2'
1'
6'
3'
+ 1
4'
O
5'
6c (60%)
9 (95%)
Scheme 3 Synthesis of 2-(2¢-hydroxy-phenyl)-benzoxazole-4-sul-
fonic acid. Reagents and conditions: (a) THF, DBU, MeI; (b) BnBr,
K2CO3, CH2Cl2–MeOH; (c) i. 1.4 N NaOH, dioxane, reflux; ii. oxalyl
chloride, CH2Cl2, DMF; (d) N-Me aniline, Et3N; (e) EtOSO2CF3 (2
equiv) in CH2Cl2, then EtONa; (f) dioxane, D, overnight; (g) Pd/C, H2,
EtOH, 6 h.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
The required acetal 8 was synthesized from salicylic acid.
First the acid protection was realized using DBU and
methyl iodide in acetonitrile.19 Next, benzylation of phe-
nol with benzyl bromide and K2CO3, followed by saponi-
fication gave the crude acid in excellent yield >90%.20
Acknowledgment
This research was supported in part by the European Commission,
Sixth Framework Program (NMP2-CT2004-505899, SOPHIED)
and in part by the Concerted Research Programme ARC 08/13-009
Synlett 2010, No. 13, 1974–1978 © Thieme Stuttgart · New York

LETTER
Sulfonylated Benzoxazoles
1977
(UCL, Belgium). J. Marchand-Brynaert is senior research associate
of FRS (FNRS, Belgium).
purified by column chromatography (silica gel,
cyclohexane–EtOAc).
(18) Spectroscopic Data for Selected Compounds
2-(2¢-Methoxyphenyl)benzoxazole-4-sulfonic Acid (6a)
White solid. Yield 70%. Mp <225 °C (slow decomp.). IR:
2923, 2352, 1647, 1548, 1419, 1240, 1105, 1049, 750 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.90 (s, 3 H, OCH3),
7.23 (ddd, 1 H, J = 0.8, 2.6 Hz, 8.3 Hz, H3¢), 7.37 (br t, 1 H,
J = 7.9 Hz, H5¢), 7.56 (br t, 1 H, J = 8.0 Hz, H6), 7.68 (dd, 1
H, J = 1.0, 7.8 Hz, H7), 7.71 (m, 1 H, H4¢), 7.77 (dd, 1 H,
References and Notes
(1) (a) Reynolds, M. B.; DeLuca, M. R.; Kerwin, S. M. Bioorg.
Chem. 1999, 27, 326. (b) Tipparaju, S.; Joyasamal, S.;
Pieroni, M.; Kaiser, M.; Brun, R.; Kozikowski, A. P. J. Med.
Chem. 2008, 51, 7344.
(2) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
12404. (b) Kantam, M. L.; Venkanna, G. T.; Kumar,
K. B. S.; Balasubrahmanyam, V.; Bhargava, S. Synlett 2009,
1753. (c) Kumar, D.; Rudrawar, S.; Chakraborti, A. K. Aust.
J. Chem. 2008, 61, 881.
J = 1.0, 8.2 Hz, H6¢), 7.82 (dd, 1 H, J = 1.0, 7.8 Hz, H5). 13
C
NMR (75 MHz, DMSO-d6): d = 56.3 (OCH3), 112.2 (C3¢),
112.6 (C7), 119.0 (C5¢), 120.6 (C1¢), 123.6 (C4¢), 125.2 (C6¢),
128.7 (C5), 131.4 (C6), 138.6 (C4), 140.3 (C9), 151.4 (C8),
160.5 (C2), 162.4 (C2¢). ESI-MS: m/z (%) = 304.13 (100) [M
– H]–, 289.07 (25), 198.05 (10). ESI-HRMS: m/z [M – H]–
calcd for C14H10NO5S: 304.0280; found: 304.0267.
(3) (a) Huxley, A. Synlett 2006, 2658. (b) Kumar, R.; Selvam,
C.; Kaur, G.; Chakraborti, A. K. Synlett 2005, 1401.
(4) Sardarian, A. R.; Shahsavari-Fard, Z. Synlett 2008, 1391.
(5) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951.
(6) (a) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665.
(b) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272.
(7) (a) Wang, B. B.; Maghami, N.; Goodlin, V. L.; Smith, P. J.
Bioorg. Med. Chem. Lett. 2004, 14, 3221. (b) McKee,
M. L.; Kerwin, S. Bioorg. Med. Chem. 2008, 16, 1775.
(8) Tian, Y.; Chen, C. I.; Yang, C. C.; Young, A. C.; Jang, S. H.;
Chen, W. C.; Jen, A. K.-Y. Chem. Mater. 2008, 20, 1977.
(9) Crocetti, L.; Maresca, A.; Temperini, C.; Hall, R. A.;
Scozzafava, A.; Mühlschlegel, F. A.; Supuran, C. T. Bioorg.
Med. Chem. Lett. 2009, 19, 1371.
(10) (a) Zonta, C.; DeLucchi, O.; Volpicelli, R.; Cotarca, L. Top.
Curr. Chem. 2007, 275, 131. (b) Brett, A. D.; Rabinowitz,
M.; Rosen, M. D.; Woods, C. R. WO2008124524, 2008.
(11) (a) Bruyneel, F.; Enaud, E.; Billottet, L.; Vanhulle, S.;
Marchand-Brynaert, J. Eur. J. Org. Chem. 2008, 72.
(b) Bruyneel, F.; Payen, O.; Rescigno, A.; Tinant, B.;
Marchand-Brynaert, J. Chem. Eur. J. 2009, 8283.
(12) (a) So, Y.-H.; Heeschen, J. P. J. Org. Chem. 1997, 62, 3552.
(b) Khajavi, M. S.; Mohammadi, A. A. J. Chem. Res., Synop.
2002, 136.
2-(2¢-Benzyloxyphenyl)benzoxazole-4-sulfonic Acid (6c)
Yellow powder. Yield 60%. Mp 180–185 °C. IR: 2923,
1549, 1450, 1419, 1249, 1197, 1051, 752 cm–1. 1H NMR
(300 MHz, CD3OD/CDCl3): d = 5.21 (s, 2 H, CH2Ph), 6.64
(d, 1 H, J = 7.4 Hz, H3¢), 6.74 (t, 1 H, J = 7.4 Hz, H5¢), 6.90–
7.05 (m, 6 H, Ph and H4¢), 7.29 (t, 1 H, J = 7.8 Hz, H6), 7.39
(d, 1 H, J = 7.9 Hz, H7), 7.55 (d, 1 H, J = 7.4 Hz, H6¢), 7.75
(d, 1 H, J = 7.7 Hz, H5). 13C NMR (75 MHz, CD3OD/
CDCl3): d = 72.2 (CH2Ph), 112.8 (C3¢), 115.6 (C7), 115.7
(C1¢), 121.8 (C5¢), 123.2 (C4¢), 125.1 (C6¢), 127.7 (Ph), 127.8
(Ph), 128.1 (Ph), 130.5 (C5), 133.1 (C6), 135.1 (C4), 136.3
(C9), 150.0 (C8), 155.7 (C2), 162.6 (C2¢). ESI-MS: m/z
(%) = 380.07 (95) [M – H]–, 289.36 (100). ESI-HRMS: m/z
[M – H]– calcd for C20H14NO5S: 380.0588; found: 380.0593.
2-(2¢-Methoxyphenyl)benzoxazole-7-sulfonic Acid (7a)
Red solid. Yield 65%. Mp <210 °C (slow decomp.). IR:
2923, 1602, 1552, 1480, 1419, 1220, 1199, 817, 794 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.89 (s, 3 H, OCH3),
7.24 (dd, 1 H, J = 2.5, 7.9 Hz, H3¢), 7.35 (t, 1 H, J = 7.8 Hz,
H4¢), 7.55–7.62 (m, 2 H, H5 and H5¢), 7.69 (m, 1 H, H6¢), 7.78
(m, 2 H, H6 and H4). 13C NMR (75 MHz, DMSO-d6): d =
56.3 (OCH3), 112.9 (C3¢), 118.8 (C9), 121.2 (C5¢), 124.4 (C4¢),
124.9 (C4 and C6¢), 128.5 (C6), 131.5 (C5), 133.1 (C1¢), 143.0
(C7), 146.7 (C8), 160.5 (C2), 163.1 (C2¢). ESI-MS: m/z
(%) = 304.17 (100) [M – H]–, 289.30 (70), 261.36 (30). ESI-
HRMS: m/z [M – H]– calcd for C14H10NO5S: 304.0280;
found: 304.0269.
2-(2¢-Hydroxyphenyl)benzoxazole-4-sulfonic Acid (9)
Brown solid. Yield 95%. Mp 197–200 °C. IR: 3174, 2921,
1631, 1548, 1454, 1421, 1247, 1054, 746 cm–1. 1H NMR
(300 MHz, CD3OD): d = 7.02–7.07 (m, 2 H, H3¢ and H4¢),
7.41–7.48 (m, 3 H, H6, H5¢, OH), 7.81 (d, 1 H, J = 8.2 Hz,
H7), 7.87 (d, 1 H, J = 7.7 Hz, H6¢), 8.06 (d, 1 H, J = 7.9 Hz,
H5). 13C NMR (75 MHz, CD3OD): d = 112.8 (C3¢), 115.3
(C7), 119.9 (C5¢), 125.8 (C1¢), 127.3 (C4¢), 130.0 (C6¢), 133.8
(C5), 136.5 (C6), 137.8 (C4), 139.3 (C9), 152.5 (C8 and C2),
166.0 (C2¢). ESI-MS: m/z (%) = 289.87 (100) [M – H]–. ESI-
HRMS: m/z [M – H]– calcd for C13H8NO5S: 290.0234;
found: 290.0123.
(13) Wrobel, J.; Rogers, J.; Green, D.; Kao, K. Synth. Commun.
2002, 32, 2695.
(14) DeWolfe, R. H. Carboxylic Ortho Acid Derivatives;
Academic Press: New York, 1970.
(15) Breslow, R.; Pandey, P. S. J. Org. Chem. 1980, 45, 741.
(16) McClelland, R. A.; Patel, G.; Lam, P. J. Org. Chem. 1981,
46, 1011.
(17) Synthesis of Benzanilide Acetals – General Procedure
Benzanilide (1 equiv, 10 mmol) and (m)ethyl trifluoro-
methanesulfonate (1.2 equiv)were stirred in dry CH2Cl2 (6
mL) overnight. Dry Et2O (40 mL) was added at 0 °C, and the
mixture was left 1 h until all the imidatonium salt had
precipitated. This salt was separated from the solvent,
dissolved into CH2Cl2 (6 mL) and added dropwise over a
period of 30 min to a cooled (0 °C) stirred solution of NaOEt
freshly made by addition of Na (0.5 g) to EtOH (20 mL). The
solvents were removed by rotary evaporation and hexane (40
mL) was added. This dissolved the crude anilide acetal, and
the excess of salt was filtered off. Evaporation gave the
crude acetal.
2-(2¢-Methoxyphenyl)benzoxazole-4-sulfonamide (10)
White powder. Yield 90%. Mp <210 °C (slow decomp.). IR:
2918, 1544, 1423, 1328, 1251, 1157, 1139, 754 cm–1. 1H
NMR (300 M Hz, DMSO-d6): d = 3.91 (s, 3 H, OCH3), 7.27
(ddd, 1 H, J = 0.8, 2.6, 8.3 Hz, H3¢), 7.55–7.60 (m, 4 H,
SO2NH2, H7 and H4¢), 7.79–7.85 (m, 2 H, H5¢ and H6), 7.91
(dd, 1 H, J = 1.2, 6.6 Hz, H6¢), 8.07 (dd, 1 H, J = 0.8, 8.2 Hz,
H5). 13C NMR (75 MHz, DMSO-d6): d = 55.9 (OCH3), 113.0
(C3¢), 115.2 (C7), 119.2 (C5¢), 120.7 (C1¢), 122.9 (C4¢), 125.5
(C6¢), 127.4 (C5), 131.0 (C6), 134.7 (C4), 138.0 (C9), 151.3
(C8), 160.1 (C2), 163.8 (C2¢). ESI-MS: m/z (%) = 304.90
Cyclization into Benzoxazole – General Procedure
Sulfonylated aminophenols (1 equiv, 1 mmol) and orthoester
(3 equiv) or benzanilide acetal (3 equiv) were added to
dioxane (3 mL), and the mixture was heated at 60 °C
overnight. The crude reaction mixture was filtered directly,
and the residual solid was triturated twice with CH2Cl2 and
filtered again. The filtered solutions were pooled together
and concentrated under vacuum. The residue was either
recrystallized in a mixture of CH2Cl2–EtOH (8:2 v/v) or
Synlett 2010, No. 13, 1974–1978 © Thieme Stuttgart · New York

1978
F. Bruyneel, J. Marchand-Brynaert
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(100) [M + H]+, 242.09 (20). HRMS (CI): m/z [M + H]+
(21) (a) Abou-Zied, O. K. Chem. Phys. 2007, 337, 1.
calcd for C14H12N2O4S: 305.05960; found: 305.05976.
(b) Mazzitelli, C. L.; Rodriguez, M.; Kerwin, S. M.;
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(23) Bruyneel, F.; D’Auria, L.; Payen, O.; Courtoy, P. J.;
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Synlett 2010, No. 13, 1974–1978 © Thieme Stuttgart · New York

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