A microwave assisted synthesis of benzoxazoles from carboxylic acids

Article abstract of DOI:10.1016/j.tet.2012.10.084

A series of various poly-substituted benzoxazoles were synthesized starting from readily available carboxylic acids. The method is based on TCT (cyanuric chloride)/microwave acid activation and it is characterized by mild conditions, allowing for a wide range of starting materials and functionalization of final products.

Full text of DOI:10.1016/j.tet.2012.10.084

Tetrahedron xxx (2012) 1e5
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Tetrahedron
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A microwave assisted synthesis of benzoxazoles from carboxylic acids
*
Giammario Nieddu , Giampaolo Giacomelli
ꢀ
Dipartimento di Chimica e Farmacia, Universita degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 May 2012
Received in revised form 3 October 2012
Accepted 22 October 2012
Available online xxx
A series of various poly-substituted benzoxazoles were synthesized starting from readily available car-
boxylic acids. The method is based on TCT (cyanuric chloride)/microwave acid activation and it is
characterized by mild conditions, allowing for a wide range of starting materials and functionalization of
final products.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzoxazoles
Carboxylic acids
Amino acids
Cyanuric chloride
Microwave
1. Introduction
under hydrogen transfer catalysis20 and the use of the Hantzsch
ester for reductive cyclization.21
The benzoxazole ring is a core structure found in a wide class of
natural and synthetic compounds showing biological properties,
such as natural antimycobacterials,1 non-nucleoside reserve tran-
scriptase inhibitors,2 peroxisome proliferators activated receptor
Despite the numbers of reported methods, benzoxazole syn-
thesis often suffers limitations, due to harsh reaction conditions,
the particular reagents involved or the preparation of starting
materials thus limiting functionalization of final products (often
restricted to 2-arylbenzoxazoles). Moreover, reagents, such as
PPA,15 SOCl2, p-TsOH, oxidants or metal-based reagents catalysts18
are frequently used in large amounts or excess, making product
purification difficult. The result is a series of methods mainly
addressed to 2-arylbenzoxazole syntheses, with decreasing yields
with different substrates. In this context, improvements, both in
terms of mildness and efficiency, would be of worth.
g
antagonists,3 cathepsin S inhibitors,4 cytotoxic natural products,5
5-HT3 receptor antagonists,6 estrogen receptor- agonists,7 anti-
b
cancer agents,8 and elastase inhibitors.9 Benzoxazoles also find
applications in agricultural field, as herbicides,10 and in techno-
logical fields, as whitening agents and laser dyes,11 in organic light
emitting diodes (OLEDs),12 and polymer production.13
Benzoxazoles are usually synthesized from 2-aminophenols, by
coupling with carboxylic acid derivatives or by oxidative cyclization
of a phenolic imine intermediate.14 The first route requires strongly
acidic conditions (usually polyphosphoric acid), high temperatures,
and long reaction times,15 whereas the second route requires strong
oxidants.14,16 A milder oxidative cyclization is also reported,
employing N-iodosuccinimide.17 ortho-Haloanilides are another
class of starting material often employed to give 2-substituted
benzoxazoles through metal-catalyzed cyclization.10,18 Apart from
cyclization reactions, 2-substituted benzoxazoles are prepared by
arylation, alkylation, and amination of the benzoxazole moiety, via
metal-catalyzed CeH bond activation.19 Recent examples of ben-
zoxazole synthesis include the employment of the Shvo catalyst
2. Results and discussion
We have already investigated the use of TCT (cyanuric chloride,
2,4,6-trichloro-1,3,5-triazine, 2a) derivatives to activate carboxylic
acids, as an alternative method to the use of acid chlorides.22 The
use of carboxylic acids as starting materials provides a wider range
of different building blocks for heterocycle functionalization,
compared to acid chlorides,23 and the mildness of this kind of
activation avoids the use of harsh chlorinating reagents (like SOCl2),
allowing an easy extension to amino acids and leading to the syn-
thesis of chiral 2-substituted benzoxazoles.
In order to define the conditions of the reaction, we tested the
process using benzoic acid as a representative substrate (Scheme 1).
A two-steps synthetic protocol was developed consisting of activa-
tion of a carboxylic acid with a triazine derivative 2 followed by
* Corresponding author. Tel.: þ39 079 229531; fax: þ39 079 212069; e-mail
addresses: gmrnd@uniss.it, gmrndd@hotmail.com (G. Nieddu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.084
Please cite this article in press as: Nieddu, G.; Giacomelli, G., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.084

2
G. Nieddu, G. Giacomelli / Tetrahedron xxx (2012) 1e5
Cl
N
N
O
N
2a X= Cl
2a DCM, NEt3
N
b X= OMe
1)
MW (40 °C, 10 min)
O
R
O
O
N
X
X
3
R
O
N
O
O
N
O
R1
HO
R
R
1
HO
NH2
R
O
R
1
4
1
2)
R
3
5
OH
Scheme 1. Two steps synthesis of 2-substituted benzoxazoles.
R
O
N
1) 3, MW (60 °C, 30 min)
NH
R
2) solventless
O
R1
reaction of the activated acid with 2-aminophenol through forma-
tion of amide and subsequent cyclization.
MW (130 °C, 120 min)
OH
6
R1
4a-o
In the first stage we evaluated the use of both TCT (2a)24 and the
corresponding alkoxide derivative CDMT (2-chloro-4,6-dimethoxy-
1,3,5-triazine, 2b),25 aiming to an activation process as efficient as
possible, while keeping at the same time the mildness of the
method. Activation of the acid with TCT was carried out in presence
of triethylamine (1 equiv respect to acid) in dry DCM, checking the
effect of different TCT/acid ratios (1:1e1:3) and the influence of
temperature. Thus, using TCT, we carried out reactions at room
temperature and under a slight heating (both through thermal and
microwave irradiation). Activation with CDMT was instead con-
ducted in dry THF in the presence of NMM (N-methylmorpholine),
with an acid/CDMT/NMM ratio of 1:1:1 at room temperature for
1 h. The yields of the first stage could not directly evaluated as the
intermediate cannot be isolated and the efficiency of the first step
was therefore calculated taking into account the final yields of
a standard reaction. Use of TCT generally gave good results while all
tests employing CDMT led to poor yields (less than 10%).
Scheme 2. Synthetic path to 2-substituted benzoxazoles.
Table 1
Conversion to benzoxazoles (standard 2 h reaction time)29
Entry
Compound
Conversion
82%
N
O
1
4a
N
O
2
3
4
5
6
4b
4c
4d
4e
4f
Cl
68%
78%
79%
71%
74%
N
O
The effects of solvents and heating parameters were investigated to
optimize reaction conditions of second stage. Other than leading the
second stage in the starting DCM solution, we evaluate the addition of
DMF, NMP, THF, and toluene as a co-solvent.
Reports on solvent-free reactions have become increasingly
frequent and the field has developed into an important branch of
synthetic chemistry.26 Recently, much attention has focused on
microwave assisted organic reactions in the absence of solvent.27
The reaction was therefore checked under solvent-free condi-
tions, by removing the starting solvent by flushing the reaction
mixture with nitrogen after the addition of 2-aminophenol.
Warming of the reaction mixture was conducted by both thermal
heating and microwave irradiation. Temperature was tested rang-
ing from 70 to 170 ꢀC (higher temperatures were reached by mi-
crowave irradiation in closed vessel) and reaction times varied from
30 min to 2 h.
N
O
NO2
Cl
N
O
N
O
So, the carboxylic acid (1 equiv) was activated with 1/3 equiv
TCT (2a) and NEt3 in dry DCM under a slight microwave irradiation
(40 ꢀC, 20 W max, 10 min). The intermediate esters 5, formed by
substitution of all chlorine atoms by carboxylate ions on the tri-
azine ring, were not isolated but directly reacted with 2-
aminophenol. After heating reaction mixture to 60 ꢀC (50 W max
power) for 30 min, DCM was evaporated by means of a gentle
stream of nitrogen and the subsequent solvent-free reaction mix-
ture heated to 130 ꢀC for 120 min (50 W max power). Formation of
intermediate amide 6, followed by cyclization, gives 2-substituted
benzoxazoles (Scheme 2). The crude reaction mixture was extrac-
ted with a DCM/EtOAc mixture, causing the precipitation of triazine
byproducts and ammonium salts and allowing an easy chromato-
graphic purification of desired products.
This methodology was successfully employed to prepare dif-
ferent aliphatic and aromatic 2-substituted benzoxazoles 4 in
moderate to good conversions (Table 1, entries 1e12). In order to
evaluate the reactivities of the different starting materials, the
cyclization process was always conducted heating to 130 ꢀC for 2 h
(50 W max power). All reactions furnished the benzoxazoles, the
other product being the unreacted amides. The synthetic protocol
N
O
7
4g
70%
O
N
8
4h
4i
74%
72%
49%
O
Ph
N
9
O
t-Bu
Cl
N
O
10
4j
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G. Nieddu, G. Giacomelli / Tetrahedron xxx (2012) 1e5
3
Table 1 (continued )
R
R
N
O
1) TCT activation
2) cyclization
Pg
Entry
Compound
Conversion
73%
HOOC
N
H
HN Pg
1
R
N
O
7
4p-u
11
4k
4l
Ph
Scheme 3. Synthesis of N-{1-(benzo[d]oxazol-2-yl)alkyl}benzamides.
N
O
12
13
14
15
16
70%
72%
71%
69%
57%
( )8
carbamate protecting groups, like N-Cbz and N-Fmoc, did not lead
to the desired products. An accurate investigation showed that the
reactions occurred until the formation of the amide, and the
drawback was found to be in the cyclization step. In fact we ob-
served degradation of carbamate protecting groups during cycli-
zation step, thus allowing side reactions.28 Finally, the choice of the
N-benzoyl protecting group was found to be correct for the syn-
thesis of 1-(benzo[d]oxazol-2-yl)alkylamines 4peu. Benzoxazole
N
O
4m
4n
4o
4p
O
N
O
O
Ph
synthesis starting from N-benzoyl a-amino acids gave satisfactory
results, leading to the final products in good yields (>60%) after
purification. In this case the cyclization step required longer re-
action times: standard 120 min reaction time always gave a mixture
of only final product and intermediate amide, and when prolonging
the reaction time, the formation of side products appeared to be
consistent. However, in this way we could prepare protected
1-(benzo[d]oxazol-2-yl)alkylamines as pure products. Previous
reports on the synthesis of 2-benzoxazoles indicated good yields
only with Z-proline,18a while in other cases, approximate yields
from 11 to 33% of not analytically pure products could only be
achieved.
O
N
O
N
Ph
N
O
Ph
O
HN
Ph
N
O
17
18
19
4q
4r
4s
71%
49%
58%
O
HN
Ph
3. Conclusion
N
O
In conclusion, here we propose a useful method for the syn-
thesis of benzoxazoles, starting directly from readily available acids.
A mild activation process allows the use of a wide range of starting
materials, so allowing the functionalization of final products, and
avoids extra steps to prepare starting materials. Furthermore,
cheap, easy-to-handle reagents, and simple workup make this
method very practical. Energetic consumption and solvent required
are low, making this method an interesting improvement also in
terms of green chemistry. Moreover it was possible to produce an
interesting class of benzoxazole starting from natural amino acids.
O
HN
Ph
S
N
O
O
HN
Ph
HN
20
21
4t
61%
4. Experimental
N
O
O
HN
4.1. General methods
Ph
All reagents and solvents employed were purchased from Sig-
maeAldrich. Reagents were used without further purification.
Solvents were dried and distilled by usual methods. Microwave
reactions were carried out using a CEM Discover instrument (CEM
Corporation), in a 10 mL glass tube (CEM designed 10 mL pressure-
rated reaction vial), under a nitrogen atmosphere. Temperature was
monitored by an infrared monitoring system. TLC analysis was
performed with Merck Kieselgel 60 F254 plates and spots visualized
using UV light at 254 nm. Flash-column chromatography was
performed on Merck Kieselgel 60 (230e400 mesh). Melting points
were determined in open capillary tubes on a Buchi apparatus and
are uncorrected. Optical rotations were measured on Jasco P1010
polarimeter. IR were recorded on Jasco FT-IR480plus spectrometer.
Elemental analyses were performed on PerkineElmer Elemental
Analyzer 240B. 1H NMR and 13C NMR were recorded at 300 and
75.4 MHz, in CDCl3, with TMS as an internal standard and chemical
shifts are given in parts per million (multiplicity: s¼singlet,
d¼doublet, dd¼double doublet, t¼triplet, q¼quadruplet,
quint¼quintuplet, m¼multiplet). The N-benzoyl derivatives of the
N
4u
O
N
55%
Ph
O
was then applied to
a
-hydroxy and natural
a
-amino acid de-
rivatives, to include low cost chiral substituents into the 2-position
of the heterocycle (Scheme 3). Examination of the data collected
showed that only little variation of the conversions could be noted
even when the starting amide contained the substituted phenyl
group. Only in the case of the benzoxazole 4j derived from 2-
amino-5-chlorophenol (Table 1, entry 10) was the conversion
<50% after 2 h. Good results were obtained employing methoxy-
acetic and phenoxyacetic acids, also (Table 1, entries 13, 14).
Synthesis of benzoxazoles starting from natural a-amino acids
required protection of the amino group. The preliminary reactions,
carried out with N-Boc protected amino acids were unsuccessful, as
only the intermediate amides 6 were recovered and in low yields
(<15%) at the end of the overall process. Even the use of other
a
-amino acids were prepared according to literature procedures,30
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4
G. Nieddu, G. Giacomelli / Tetrahedron xxx (2012) 1e5
and identified by comparison with published data (1H and 13C NMR,
melting point, optical rotation).
(300 MHz, CDCl3)
d
7.72e7.75 (m, 1H), 7.52e7.55 (m, 1H), 7.33e7.36
162.4,
(m, 2H), 4.71 (s, 2H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
150.7, 140.7, 125.2, 124.3, 120.1, 110.6, 66.8, 59.1; Anal. Calcd for
C9H9NO2: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.17; H, 5.59; N, 8.62.
4.2. Typical procedure for the preparation of 4
In a reaction tube containing a well-stirred solution of the car-
boxylic acid (1.83 mmol) and NEt3 (0.25 mL 1.83 mmol) in dry
CH2Cl2 (3 mL), cyanuric chloride (0.11 g, 0.61 mmol) was added in
small amounts at room temperature. The sealed tube was heated by
microwave irradiation to 40 ꢀC (max power 20 W) for 10 min.
2-Aminophenol (0.18 g, 1.66 mmol) was then added, and the closed
vessel was irradiated at 60 ꢀC (max power 50 W) for 30 min. Solvent
was then removed by a gentle stream of nitrogen, giving a semi-
solid residue. The sealed tube was then irradiated at 130 ꢀC (max
power 50 W) for 120 min. The reaction mixture was then extracted
with EtOAc/DCM (1:1) and the crude products were purified by
silica gel column chromatography (EtOAc/hexane 1:9 for 4aen and
4:6 for 4oeu) to afford desired benzoxazoles.
4.2.7. {4-(Benzo[d]oxazol-2-yl)piperidin-1-yl}(phenyl)methanone
(4o). Dark green oil; IR (film)
1632, 1568, 1455, 1435, 1279, 1244, 1145, 1005, 747, 709; 1H NMR
(300 MHz, CDCl3) 7.66e7.72 (m, 1H), 7.47e7.53 (m, 1H), 7.41 (s,
5H), 7.29e7.35 (m, 2H), 4.66 (b, 1H), 3.87 (b, 1H), 3.21 (m, 3H),
2.00e2.27 (b, 4H); 13C NMR (75 MHz, CDCl3)
170.3, 167.8, 150.5,
n
(cmꢁ1) 3058, 2952, 2925, 2858,
d
d
140.9, 135.8, 129.5, 128.4, 126.7, 124.7, 124.2, 119.6, 110.3, 46.7, 35.8,
29.4; Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C,
74.52; H, 5.97; N, 9.21.
4.2.8. N-{(S)-1-(Benzo[d]oxazol-2-yl)ethyl}benzamide(4p). Colourless
solid: mp 191 ꢀC; [
a]
D
20 þ4.21 (c 0.66, DCM); IR (film)
n
(cmꢁ1) 3283,
2933, 1636, 1611, 1572, 1528, 1457, 1243, 757, 700; 1H NMR (300 MHz,
CDCl3)
7.39e7.44 (m, 2H), 7.30e7.33 (m, 2H), 7.22 (b, 1H), 5.61 (q, J 7.0 Hz,
1H), 1.73 (d, J 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
166.8, 166.6,
150.9, 140.6, 133.7, 131.8, 128.6, 127.1, 125.2, 124.5, 119.9, 110.8, 44.4,
20.1; Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C,
72.07; H, 5.35; N, 10.40.
d 7.85 (d, J 6.9 Hz, 2H), 7.66e7.69 (m, 1H), 7.47e7.52 (m, 2H),
4.2.1. 2-(4-Chloro-3-nitrophenyl)benzo[d]oxazole (4e). Colourless
solid: mp 192 ꢀC; IR (film)
n
(cmꢁ1) 2920, 2850, 1527, 1449, 1343,
d
1239,1071, 807, 749; 1H NMR (300 MHz, CDCl3)
d
7.40e7.44 (m, 2H),
8.74 (d, J 2.0 Hz, 1H), 8.38 (dd, J 2.0 Hz, 8.4 Hz, 1H), 7.79e7.82 (m,
1H), 7.72 (d, J 8.4 Hz, 1H), 7.60e7.64 (m, 1H); 13C NMR (75 MHz,
CDCl3)
d 159.7, 150.9, 148.4, 141.7, 132.7, 131.3, 129.8, 127.2, 126.2,
125.2, 124.4, 120.6, 110.9; Anal. Calcd for C13H7ClN2O3: C, 56.85; H,
2.57; N, 10.20. Found: C, 56.90; H, 2.49; N, 10.24.
4.2.9. N-{(S)-1-(Benzo[d]oxazol-2-yl)-2-phenylethyl}benzamide
(4q). Pale red solid: mp 181 ꢀC; [
a]
20 ꢁ5.32 (c 0.53, DCM); IR (film)
D
n
(cmꢁ1) 3304, 3060, 3029, 2924, 2853, 1644, 1531, 1488, 1455, 1241,
4.2.2. 2-(4-Methoxybenzyl)-5-methylbenzo[d]oxazole (4g). Orange
747, 698; 1H NMR (300 MHz, CDCl3)
d 7.76e7.79 (m, 2H), 7.63e7.66
oil; IR (film)
1034, 801; 1H NMR (300 MHz, CDCl3)
3H), 7.05 (d, J 8.2 Hz, 1H), 6.86e6.81 (m, 2H), 4.16 (s, 2H), 3.73 (s,
3H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3)
165.6, 158.6, 149.1,
n
(cmꢁ1) 2930, 2835, 1776, 1612, 1570, 1513, 1249, 1178,
(m, 1H), 7.47e7.54 (m, 2H), 7.38e7.43 (m, 2H), 7.32e7.35 (m, 2H),
7.18e7.21 (m, 3H), 7.03e7.06 (m, 3H), 5.83e5.90 (m, 1H), 3.41e3.55
d
7.45 (s, 1H), 7.30e7.25 (m,
(m, 2H); 13C NMR (75 MHz, CDCl3)
d 166.9, 165.0, 150.8, 140.5, 135.5,
d
133.7, 131.8, 129.4, 128.6, 128.5, 127.1, 125.2, 124.5, 119.9, 110.8, 49.4,
39.4; Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C,
77.25; H, 5.32; N, 8.13.
141.2, 133.8, 129.8, 126.7, 125.5, 119.4, 114.0, 109.6, 55.0, 34.2, 21.2;
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.92; H, 6.05; N, 5.51.
4.2.10. N-{(S)-1-(5-Methylbenzo[d]oxazol-2-yl)ethyl}benzamide
4.2.3. 5-Chloro-2-[(4-methylphenyl)methyl]benzo[d]oxazole
(4r). Colourless solid: mp 194e196 ꢀC; [
a
]
D
20 ꢁ1.85 (c 0.26, MeOH);
(4j). Yellow solid: mp 52e54 ꢀC; IR (film)
n
(cmꢁ1) 2923,1565, 1515,
IR (film)
n
(cmꢁ1) 3264, 2924, 1761, 1632, 1572, 1532, 1488, 1377,
1452, 1427, 1256, 1143, 1054, 805; 1H NMR (300 MHz, CDCl3)
(d, J 2.1 Hz, 1H), 7.35e7.13 (m, 6H), 4.20 (s, 2H), 2.32 (s, 3H); 13C
NMR (75 MHz, CDCl3) 166.8, 149.5, 142.4, 137.0, 131.2, 129.5, 129.5,
d
7.64
1258,1111, 800, 694; 1H NMR (300 MHz, CDCl3)
d 7.88e7.85 (m, 2H),
7.52e7.36 (m, 6H), 7.13 (br d, J 8.3 Hz,1H), 5.65e5.56 (quint, J 7.2 Hz,
1H), 2.45 (s, 3H), 1.73 (d, J 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
128.8, 124.8, 119.7, 111.0, 34.8, 21.0; Anal. Calcd for C15H12ClNO: C,
69.91; H, 4.69; N, 5.43. Found: C, 69.80; H, 4.72; N, 5.50.
d 166.8, 166.6, 149.1, 140.8, 134.3, 133.8, 131.7, 128.5, 127.1, 126.2,
119.7, 110.1, 44.4, 21.4, 20.0; Anal. Calcd for C17H16N2O2: C, 72.84; H,
5.75; N, 9.99. Found: C, 72.76; H, 5.82; N, 10.05.
20
4.2.4. 2-[(R)-1-Phenylpropyl]benzo[d]oxazole (4k). Orange oil; [
þ2.86 (c 0.14, MeOH); IR (film)
1566, 1455, 1242, 746, 698; 1H NMR (300 MHz, CDCl3)
a]
D
n
(cmꢁ1) 3029, 2963, 2927, 2873,
7.69e7.73
4.2.11. N-{(S)-1-(Benzo[d]oxazol-2-yl)-3-(methylthio)propyl}benza-
20
d
mide (4s). Dark yellow oil; [
a
]
ꢁ4.06 (c 0.32, MeOH); IR (film)
n
D
(m, 1H), 7.20e7.44 (m, 8H), 4.12 (t, J 7.8 Hz, 1H), 2.34e2.49 (m, 1H),
(cmꢁ1) 3062, 2918, 1758, 1642, 1531, 1483, 1454, 1241, 1104, 744,
2.07e2.21 (m, 1H), 0.97 (t, J 3.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
710, 613; 1H NMR (300 MHz, CDCl3)
d
7.87e7.90 (m, 2H), 7.68e7.71
d
168.0, 150.7, 141.2, 139.7, 128.6, 127.9, 127.2, 124.5, 124.0, 119.7,
(m, 1H), 7.51e7.56 (m, 2H), 7.33e7.48 (m, 5H), 5.71e5.78 (m, 1H),
110.4, 47.8, 27.5, 12.2; Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N,
5.90. Found: C, 80.92; H, 6.40; N, 5.95.
2.62e2.68 (m, 2H), 2.30e2.60 (m, 2H), 2.11 (s, 3H); 13C NMR
(75 MHz, CDCl3)
125.3, 124.6, 119.9, 110.8, 47.9, 33.1, 29.9, 29.6, 15.5; Anal. Calcd for
18H18N2O2S: C, 66.23; H, 5.56; N, 8.58. Found: C, 66.21; H, 5.69; N,
d 167.0,165.3,150.8,140.6,133.6,131.9, 128.6,127.2,
4.2.5. 6-Methyl-2-nonylbenzo[d]oxazole (4l). Pale yellow oil; IR
C
8.65.
(film)
n
(cmꢁ1) 2925, 2854, 1613, 1574, 1487, 1465, 1246, 1117, 941,
810; 1H NMR (300 MHz, CDCl3)
d
7.52 (d, J 8.1 Hz, 1H), 7.26 (s, 1H),
7.09 (d, J 8.1 Hz, 1H), 2.89 (t, J 7.7 Hz, 2H), 2.45 (s, 3H), 1.86 (quint, J
4.2.12. N-{(S)-1-(Benzo[d]oxazol-2-yl)-2-(1H-indol-3-yl)ethyl}ben-
7.5 Hz, 2H), 1.42e1.26 (m, 12H), 0.87 (t, J 6.7 Hz, 3H); 13C NMR
zamide (4t). Viscous yellow oil; [
a
]
20 þ14.58 (c 0.10, DCM); IR (film)
D
(75 MHz, CDCl3)
29.3, 29.2, 29.2, 29.1, 28.5, 26.7, 22.6, 21.5, 14.0; Anal. Calcd for
17H25NO: C, 78.72; H, 9.71; N, 5.40. Found: C, 78.80; H, 9.76; N,
d
166.7, 151.0, 139.1, 134.5, 125.0, 118.7, 110.3, 31.8,
n
(cmꢁ1) 3299 (br), 3057, 2924, 2852, 2359, 1646, 1521, 1487, 1455,
1241, 742, 711; 1H NMR (300 MHz, CDCl3)
d 8.07 (s, 1H), 7.70 (d, J
C
5.44.
7.4 Hz, 2H), 7.60e7.62 (m,1H), 7.44e7.51 (m, 3H), 7.24e7.37 (m, 5H),
7.11 (t, J 7.6 Hz, 1H), 6.95 (t, J 7.4 Hz, 2H), 6.80 (b, 1H), 5.90e5.95 (m,
1H), 3.60e3.70 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 167.0, 165.6,
4.2.6. 2-(Methoxymethyl)benzo[d]oxazole (4m). Dark yellow oil; IR
150.8,140.6,136.0,133.6,131.7,128.4,127.7,127.1,125.0,124.4,123.0,
122.1,119.8,119.6, 118.4,111.2,110.7,109.5, 49.4, 29.3; Anal. Calcd for
(film) n
(cmꢁ1) 2917, 2850, 1781, 1731, 1455, 1101, 744, 612; 1H NMR
Please cite this article in press as: Nieddu, G.; Giacomelli, G., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.084

G. Nieddu, G. Giacomelli / Tetrahedron xxx (2012) 1e5
5
13. (a) Li, J.; Dai, L.; Wang, C. Eur. Polym. J. 2008, 44, 483e493; (b) Xie, Z.; Zhuang,
Q.; Wang, Q.; Liu, X.; Chen, Y.; Han, Z. Polymer 2011, 52, 5271e5276; (c) Chen,
W.-H.; Pang, Y. Tetrahedron Lett. 2010, 51, 1914e1918; (d) Ogura, T.; Higashihara,
T.; Ueda, M. Eur. Polym. J. 2010, 46, 1576e1581; (e) Calle, M.; Lee, Y. M. Mac-
romolecules 2011, 44, 1156e1165.
14. For reviews on benzoxazoles, see: (a) Boyd, G. V. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 6,
pp 177e223; (b) Hartner, F. W., Jr. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol.
3, pp 261e318; (c) Yeh, V.; Iyengar, R. In Comprehensive Heterocyclic Chemistry
III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2008; Vol. 4, pp 487e543.
C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C, 75.71; H, 5.11; N,
11.09.
4.2.13. {(S)-2-(Benzo[d]oxazol-2-yl)pyrrolidin-1-yl}(phenyl)meth-
20
anone (4u). Dark green oil; [
a
]
ꢁ24.45 (c 0.20, DCM); IR (film)
n
D
(cmꢁ1) 3057, 2957, 2924, 2853, 1633, 1574, 1455, 1409, 1242, 748,
702; 1H NMR (300 MHz, CDCl3)
d
7.69e7.72 (m, 1H), 7.61e7.64 (m,
2H), 7.50e7.53 (m, 1H), 7.41e7.46 (m, 3H), 7.29e7.33 (m, 2H),
5.54e5.58 (m,1H), 3.83e3.91 (m,1H), 3.61e3.69 (m,1H), 2.43e2.55
(m, 1H), 2.16e2.35 (m, 2H), 1.96e2.05 (m, 1H); 13C NMR (75 MHz,
15. (a) Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982, 484e485; (b) Hein, D.
W.; Alheim, R. J.; Leavitt, J. J. J. Am. Chem. Soc. 1957, 79, 427e429; (c) So, Y. H.;
Heeschen, J. P. J. Org. Chem. 1997, 62, 3552e3561.
CDCl3)
d 169.9, 166.4, 150.6, 141.2, 136.1, 130.3, 128.2, 127.4, 124.7,
124.2, 120.0, 110.7, 55.1, 50.1, 31.0, 25.4; Anal. Calcd for C18H16N2O2:
C, 73.95; H, 5.52; N, 9.58. Found: C, 73.89; H, 5.60; N, 9.49.
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Acknowledgements
The work was financially supported by the university of Sassari
and MIUR (Rome) within the project PRIN 2007.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.084.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
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Please cite this article in press as: Nieddu, G.; Giacomelli, G., Tetrahedron (2012), http://dx.doi.org/10.1016/j.tet.2012.10.084