Iodine-catalyzed amination of benzoxazoles: A metal-free route to 2-aminobenzoxazoles under mild conditions

Article abstract of DOI:10.1021/jo201402a

A facile metal-free route of oxidative amination of benzoxazole by activation of C-H bonds with secondary or primary amines in the presence of catalytic iodine in aqueous tert-butyl hydroperoxide proceeds smoothly at ambient temperature (Figure presented) under neat reaction condition to furnish the high yield of the aminated product. This user-friendly method to form C-N bonds produces tertiary butanol and water as the byproduct, which are environmentally benign. The application of the methodology is demonsrated by synthesizing therapeutically active benzoxazoles.

Full text of DOI:10.1021/jo201402a

ARTICLE
pubs.acs.org/joc
Iodine-Catalyzed Amination of Benzoxazoles: A Metal-Free Route to
2-Aminobenzoxazoles under Mild Conditions
Manjunath Lamani and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S Supporting Information
b
ABSTRACT: A facile metal-free route of oxidative amination of
benzoxazole by activation of CÀH bonds with secondary or
primary amines in the presence of catalytic iodine in aqueous
tert-butyl hydroperoxide proceeds smoothly at ambient tempera-
ture under neat reaction condition to furnish the high yield of the aminated product. This user-friendly method to form CÀN bonds
produces tertiary butanol and water as the byproduct, which are environmentally benign. The application of the methodology is
demonsrated by synthesizing therapeutically active benzoxazoles.
’ INTRODUCTION
oxidant. In view of the increased attention to design environ-
mentally benign and metal-free methods for the formation of
CÀN bonds and continuation of our research on green
chemistry,10 herein we report a novel and efficient metal-free
method for the oxidative CÀH bond activation of benzoxazoles
for the formation of CÀN bond using catalytic amount of I2 and
TBHP in acetic acid under solvent-free conditions.
Transition-metal-catalyzed CÀH bond activation reactions of
arenes and heteroarenes are important in synthetic organic
chemistry,1 which have been widely used in the synthesis of
pharmacologically active organic compounds and natural products.
CÀN bond-forming reactions are traditionally accomplished by
BuchwaldÀHartwig-type amination,2 Ullmann3 and Goldberg
couplings,4 and cross-coupling reactions of boronic acids, stan-
nanes, and siloxanes with corresponding amines.5 The disadvan-
tages associated with these methods are the utility of poisonous
metals and expensive transition-metal catalysts or ligands. Addi-
tionally, heavy metal impurities in drug intermediates and harsh
reaction conditions limit the utility of such methods. Hence, the
development of environmentally benign procedures to synthesize
such compounds is highly desirable. In this direction, CÀH
amination of heteroarenes has been achieved by using copper,
silver, manganese, iron, cobalt, and other catalysts.7 Hence, there is
a huge surge in the literature to develop these methods under
environmentally benign conditions.1 However, CÀH amination of
heteroarenes under metal-free conditions are less known.8,9 In this
direction, stoichiometric amountof PIDA (phenyliodine diacetate)
under heating condition was employed for the amination of
benzoxazoles in two steps using ring-opened adduct O-hydroxy-
amidine.8a Apart from this, a recent report by Nachtsceim and
co-workers uses tetrabutylammonium iodide along with terminal
oxidant is utilized for the amination of benzoxazole.8b
’ RESULTS AND DISCUSSION
Our optimization studies began with the activation of benzox-
azole (1a) and amination with diethyl amine (2a). As seen in
Table 1, a variety of reaction conditions were employed to
achieve the optimal conditions. Initial screening of the oxidants
revealed that the oxidants such as H2O2 or sodium perborate are
not suitable for this reaction (Table 1, entries 1 and 2). Further
investigation has shown that the reaction proceeds well with
aqueous TBHP (1 equiv) at room temperature in AcOH
(1 equiv) (entries 3À8). Subsequent experiments revealed that
the coupling reaction requires 5 mol % of I2 (entries 5À8).
However, increasing the amount of I2 did not bring considerable
change in the outcome of the reaction (entries 3 and 4).
Performing the reaction in organic solvents such as dioxane,
CH3CN, or EtOAc did not enhance the yield of 3a (Table 1,
entries 3À7). The excellent yield of the product 3a was obtained
when the reaction was performed without any solvent (Table 1,
entry 8). The importance of acid additive is shown in entry 9. The
reaction of benzoxazole (1a) and diethylamine (2a) in the
absence of AcOH resulted in low yield of 3a (36%) indicating
the significance of the acid additive in the reaction (Table 1, entry 9).
TFA or TfOH as additives did not furnish the amination prod-
uct (Table 1, entries 10 and 11). Amination of benzoxazole was
not observed in the absence of either TBHP or iodine, indicating
that I2/TBHP combination is crucial for the reaction (Table 1,
entries 12 and 13). Therefore, we decided to carry out further
2-Aminobenzoxazole derivatives are generally synthesized by
transition-metal-catalyzed amination with N-chloroamines,6a
amines,6b and amides6c or O-acylated hydroxylamines.6d The
latest development for the synthesis of 2-aminobenzoxazole
includes transition-metal-catalyzed amination of formamides
and amines using stoichiometric amount of metal catalysts such
as silver carbonates,7a a substoichiometric amount of FeCl3,7b
Cu(OAc)2 H2O,7c or CuBr2 using oxygen as an oxidant.
7d
3
Recently, Chang7e and co-workers reported an elegant example
for the synthesis of 2-aminoxazoles by employing cobalt and
Received: July 6, 2011
manganese catalysts and tert-butylhydroperoxide (TBHP) as
Published: August 25, 2011
r
2011 American Chemical Society
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ARTICLE
Table 1. Optimization of Amination Reactionsa
Similarly, benzoxazole 1a reacted with ethyl 1-piperazinecar-
boxylate (2k) to furnish the amination product 3s in excellent
yield (95%, entry 18).
After successful demonstration of oxidative amination of
benzoxazoles with secondary amines, we turned our attention
to the amination of benzoxazoles with primary amines. Notably,
the oxidative amination of benzoxazoles with primary amines in
Cu-catalyzed coupling failed to furnish the coupled product.7c
In light of this observation, we continued our exploration on
oxidative amination of benzoxazoles with primary amines under
standard reaction conditions. As expected, a variety of primary
amines such as benzylamine (2l), 4-methylbenzylamine (2m),
2-phenylethylamine (2n), and propargylamine (20) underwent
a smooth coupling with 1a at room temperature to produce the
corresponding amination products 3t, 3u, 3v, or 3w in good
yields (Table 3).
Inspired by the versatility of this amination reaction, we
diverted our attention to employ this methodology to synthe-
size therapeutically active benzoxazoles. A quick survey of the
literature indicated that 5-chloro-7-methylbenzoxazole (1e)
is a good precursor to react with N-methylpiperazine and
N-methylhomopiperazine to afford the corresponding N-ami-
nated benzaxozoles, which exhibit antidiarrhetic activity11 and
are potential radioligands for PET (positron emission tomo-
graphy) imaging. Generally, these orally active benzoxazole
derivatives are prepared in a multistep reaction using O-nitro-
phenol as the precursor via benzo[d]oxazole-2-thiol derivatives.
Hence, 5-chloro-7-methylbenzoxazole 1e was subjected to an
optimized coupling reaction with cyclic diamines such as N-
methylpiperazine (2d) and N-methylhomopiperazine (2j) to
afford the corresponding amination products 3x and 3y, which
exhibit antidiarrhetic activity in excellent yield (95% and 94%,
respectively, Scheme 1). However, benzothiazole was inert for
the amination reaction with piperidine and hence did not furnish
the expected product.
Our attempts to understand the mechanism of this reaction
have not been successful. During the preparation of this
manuscript, Chang7e and co-workers reported the cyclization
of O-hydroxybenzamidine with PIDA to get 2-aminooxazoles
in good yields. In light of this observation, we synthesized
intermediate amidines 4-methyl-2-(pyrrolidin-1-ylmethyle-
neamino)phenol (I) and 4-methyl-2-(piperdin-1-ylmethyle-
neamino)phenol (II) and independently reacted them with
I2/TBHP and AcOH in EtOAc under the standard coupling
conditions. In this reaction, the amination occurred success-
fully to produce the corresponding cyclic products 4 and 3i in
excellent yields (Scheme 2).
However, the reaction of 1a with 2a under the optimized
conditions in the presence of BHT (2,6-bis(1,1-dimethylethyl)-
4-methylphenol) furnished 3a in 90%. This reaction indicates
that the reaction may not be going through the radical inter-
mediate. Contrary to the observation of Chang and co-workers,7d
the reaction of 5-methylbenzoxazole with piperidine in the
absence of AcOH did not furnish the ring-opened adduct
amidines (Scheme 3). Nevertheless, 5-methylbenzoxazole un-
derwent a smooth coupling with piperidine in the absence of
acetic acid under the standard reaction conditions to produce the
corresponding amination products 3i in 60% yield along with
starting materials in 35% (Scheme 3). However, the absence of
acetic acid in the reaction of benzoxazole (1a) with N,N-
dimethylamine (2a) has produced a lower yield of the product
3a (Table 1, 36%, entry 9).
I2
T
yieldb
(%)
entry (mol %)
oxidant
additive solvent (°C)
1
2
20
30
32
10
5
H2O2
AcOH
neat
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
nr
<5
32
90
91
88
90
39
36
nr
NaBO3 4H2O AcOH
dioxane
dioxane
dioxane
dioxane
EtOAc
CH3CN
neat
3
3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
none
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
none
4
5
6
5
7
5
8
5
9
5
neat
10
11
12
13
5
TFA
neat
5
TfOH
AcOH
AcOH
neat
nr
5
neat
nr
none
TBHP
neat
nr
a Optimal conditions: 1a (1 mmol), 2a (1 mmol), I2 (0.05 mmol),
acid additive (1.1 mmol), oxidant (1 mmol). b Isolated yield, nr =
no reaction.
reactions in the absence of the solvent. In a typical reaction,
benzoxazole (1a, 1 equiv), diethyl amine (2a, 1 equiv), AcOH
(1.1 mmol), I2 (5 mol %), and aq TBHP (70% solution in
water,1 equiv) were stirred at room temperature under neat
reaction conditions for 12 h followed by aqueous workup
furnished the amination product (3a) in 95% isolated yield.
Under optimized reaction conditions, a variety of amines
were reacted with benzoxazoles to furnish amination products
(Table 2). Benzoxazoles bearing electron-donating and elec-
tron-withdrawing functional groups underwent a smooth oxi-
dative amination to form 2-aminobenzoxazole derivatives in
good to excellent yields. Benzoxazole 1a reacted well with cyclic
amines such as morpholine (2b), piperidine (2c), and N-
methylpiperazine (2d) to furnish the corresponding amination
products 3b, 3c, and 3d in good to excellent yields (entries
1À3). Similarly, 1a reacted well with N-methylbenzylamine
(2e), tetrahydroisoquinoline (2f), 1-benzhydrylpiperazine
(2g), and dibenzylamine (2h) to provide the corresponding
products 3e, 3f, 3g, or 3h (95%, 95%, 80%, and 95%, respec-
tively, entries 4À7). Coupling of 5-methylbenzoxazole (1b)
proceeded successfully with piperidine (2c), N-methylpipera-
zine (2d), thiomorpholine (2i), and N-methylhomopiperazine
(2j) to form amination products 3i, 3j, 3k, and 3l in good to
excellent yields (entries 8À11). Similarly, 5-phenylbenzoxazole
(1c) underwent a smooth coupling with morpholine (2b),
piperidine (2c), and N-methylbenzylamine (2e) to afford
2-aminobenzoxazole derivatives 3m, 3n, or 3o in good yields
(entries 12À14). The amination of benzoxazole that contains
an electron-withdrawing group is sluggish and required heating
at 60 °C in EtOAc to afford the coupled product. Hence,
6-nitrobenzoxazole (1d) was found to react with secondary
amines such as morpholine (2b), piperidine (2c), and N-
methylbenzylamine (2e) at 60 °C in ethyl acetate (12 h) to
produce the corresponding amination products 3p, 3q, or 3r in
good yields (entries 15À17, 84%, 85%, and 80%, respectively).
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ARTICLE
Table 2. Oxidative Amination of Benzoxazoles with Secondary Aminesa
a Reaction was performed at room temperature for 12 h. b Isolated yield. c At 60 °C in EtOAC.
Table 3. Amination with Primary Aminesa
Scheme 1. Synthesis of Antidiarrhetic Agents
and an aqueous solution of TBHP or H2O2 with acetic acid
(3À5 equiv) at 80 °C in CH3CN was reported by Nachtsheim
and co-workers.8b In this paper, it was suggested that the
reaction of quaternary ammonium iodide with H2O2/AcOH
generates iodonium diacetate and further helps in generat-
ing I+ source. However, we believe in our reaction, acidifica-
tion of benzoxazole produces a species III, which reacts
further with amine to furnish IV.7e Further reaction of IV
with I2 generates V, which loses a proton to generate the
product, and the reaction cycle continues (Scheme 4). Further
a Reaction was performed at room temperature for 12 h. b Isolated yield.
Recently, a metal-free approach for oxidative amination of
benzoxazole using tetrabutylammoniumiodide (TBAI, 5 mol %)
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ARTICLE
Scheme 2. Control Experiments
application of the methodology is demonsrated by synthesizing
therapeutically active benzoxazoles.
’ EXPERIMENTAL SECTION
Typical Experimental Procedure. TBHP (70% solution in
water, 1 equiv, 1 mmol) was added to a well-stirred suspension of
benzoxazole (1a, 1 mmol, 1 equiv), AcOH (1.1 mmol, 1.1 equiv),
diethylamine (2a, 1 mmol, 1 equiv), and iodine (0.05 mmol, 0.05 equiv)
at room temperature for 12 h. The reaction mixture was extracted with
EtOAc (20 mL Â 3) and dried over Na2SO4, solvent was removed under
reduced pressure, and the product was purified by silica gel column
chromatography to afford the amination product 3a.
N,N-Diethylbenzoxazol-2-amine (3a)7d. Prepared as shown in
the general experimental procedure and purified on silica gel (EtOAc/
hexane 5:95À10:90): colorless liquid; yield 95%; Rf (10% EtOAc/
hexane) 0.20; IR (neat, cmÀ1) 2975, 2935, 1640, 1580, 1460, 1247, 740;
1H NMR (CDCl3, 400 MHz) δ 1.27 (t, J = 7.2 Hz, 6H), 3.57 (q, J = 7.2
Hz, 4H), 6.97 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.9
Hz, 1H),7.34 (d, J = 7.8, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.4,
42.9, 108.4, 115.7, 119.9, 123.7, 143.5, 148.7, 162.1; HRESI-MS (m/z)
calcd for C11H14N2O (M + H) 191.1184, found (M + H) 191.1176.
2-(4-Morpholinyl)benzoxazole (3b)7e. Prepared as shown in
the general experimental procedure and purified on silica gel (EtOAc/
hexane 20:80À30:70): pale yellow solid; yield 94%; mp 90À94 °C (lit.7e
Scheme 3. Amination of Benzoxazole in the Absence of
AcOHa
a Product 3i formed along with 35% starting materials.
mp 91À94 °C); Rf (50% EtOAc/hexane) 0.30; IR (KBr, cmÀ1
)
2867,1659, 1581, 1455, 1242, 1111, 798, 756, 743; 1H NMR (CDCl3,
400 MHz) δ 3.67 (t, J = 5 Hz, 4H), 3.80 (t, J = 4.56 Hz, 4H), 7.03 (t, J =
7.9 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 7.37 (d, J =
7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 45. 6, 66.0, 108.7, 116.3,
120.8, 123.9, 142.6, 148.6, 161.9; HRESI-MS (m/z) calcd for
C11H12N2O2 (M + H) 205.0977, found (M + H) 205.0977.
Scheme 4. Tentative Reaction Mechanism
2-(Piperidin-1-yl)benzo[d]oxazole (3c)6a. Prepared as shown
in the general experimental procedure and purified on silica gel (EtOAc/
hexane 20:80À30:70): pale yellow solid; yield 94%; mp 72À75 °C (lit.6a
mp 74À75 °C); Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1
)
2867,1659, 1581, 1455, 1242, 1111, 798, 756, 743; 1H NMR (CDCl3,
400 MHz) δ 1.68 (s, 6H), 3.66 (s, 4H), 6.97 (t, J = 7.6 Hz, 1H), 7.12 (t,
J = 7.6 Hz, 1H), 7.22 (d, J = 8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 24.1, 25.2, 46.6, 108.5, 115.9, 120.3, 123.8,
143.4, 148.7, 162.4; HRESI-MS (m/z) calcd for C11H12N2O2 (M + H)
203.1184, found (M + H) 203.1184.
2-(4-Methyl-1-piperazinyl)benzoxazole (3d)11a. Prepared as
shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 5:95À15:85): white solid; yield 82%; mp 37À39 °C
(lit.11a mp 36À38 °C); Rf (20% EtOAc/hexane) 0.20; IR (KBr, cmÀ1
)
2817, 1638, 1581, 1459, 1303, 1290, 1001, 744; 1H NMR (CDCl3, 400
MHz) δ 2.40 (s, 3H), 2.60 (t, J = 4.3 Hz, 4H), 3.76 (t, J = 4.7 Hz, 4H),
7.02(t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.27À7.24 (m, 1H), 7.35
(d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 45.0, 45.9, 53.9,
108.8, 116.3, 120.8, 123.9, 142.8, 148.7, 161.9; HRESI-MS (m/z) calcd
for C12H15N3O (M + H) 218.1293, found (M + H) 218.1290.
work is underway in our laboratories to study the reaction
mechanism.
’ CONCLUSION
In conclusion, we have developed a mild and efficient metal-
free direct oxidative amination of benzoxazole via CÀH bond
activation to form a 2-aminobenzoxazole derivative under neat
reaction conditions at room temperature. A wide range of
benzoxazole derivative containing electron-donating and electron-
withdrawing groups were coupled with both primary and sec-
ondary amines. The coupling reactions were performed using a
stoichiometric amount of TBHP under solvent-free conditions.
This user-friendly method produces tertiary butanol and water as
the byproducts, which are environmentally benign. The present
methodology constitutes a user-friendly and environmentally
benign reaction for CÀN bond formation of benzoxazoles. The
N-Benzyl-N-methylbenzoxazol-2-amine (3e)12. Prepared as
shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 15:85À20:80): off-white solid; yield 95%; mp
50À54 °C (lit.12 mp 51À53 °C); Rf (25% EtOAc/hexane) 0.30; IR
1
(KBr, cmÀ1) 1646, 1580, 1460, 740; H NMR (CDCl3, 400 MHz) δ
3.08 (s, 3H), 4.71 (s, 2H), 6.99 (t, J = 7.7 Hz, 1H), 7.15 (t, J = 7.6 Hz,
1H), 7.32À7.23 (m, 6H), 7.38 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 34.9, 53.6, 108.5, 115.9, 120.2, 123.8, 127.4, 127.5, 128. 6,
136.2, 143.3, 148.8, 162.8; HRESI-MS (m/z) calcd for C15H14N2O (M + H)
239.1184, found (M + H) 239.1180.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)benzoxazole (3f)7a. Pre-
pared as shown in the general experimental procedure and purified on
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ARTICLE
silica gel (EtOAc/hexane 5:95À10:90): pale yellow solid; yield 95%; mp
85À88 °C (lit.7a mp 83À85 °C); Rf (10% EtOAc/hexane) 0.30; IR
(KBr, cmÀ1) 2843, 1658, 1581, 1460, 1399, 1372, 1261, 740; 1H NMR
(CDCl3, 400 MHz) δ 3.01 (t, J = 6.4 Hz, 2H), 3.96 (t, J = 6 Hz, 2H), 4.86
(s, 2H), 7.02 (t, J = 7.8 Hz, 1H), 7.37À7.15 (m, 6H), 7.38 (d, J = 7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 28.5, 43.1, 47.2, 108.7, 116.3, 120.5,
123.9, 126.4, 126.5, 126.8, 128.8, 132.4, 134.0, 143.2, 148.8, 162.0;
HRESI-MS (m/z) calcd for C16H14N2O (M + H) 251.1184, found (M + H)
251.1183
2-(4-Benzhydrylpiperazin-1-yl)benzoxazole (3g). Prepared
as shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 10:90À15:85): pale yellow solid; yield 80%; mp
164À168 °C; Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 2815,
1636, 1578, 1455, 1265, 1240, 1005, 742; 1H NMR (CDCl3, 400 MHz)
δ 2.51 (t, J = 5 Hz, 4H), 3.69 (t, J = 5 Hz, 4H), 4.28 (s, 1H), 7.00 (dt, J1 =
1 Hz, J2 = 7.8 Hz, 1H), 7.14 (dt, J1 = 1 Hz, J2 = 7.6 Hz, 1H), 7.35À7.18
(m, 8H), 7.44À7.42 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 45.8,
51.1, 76.0, 108.7, 116.2, 120.6, 123.9, 127.2, 127.9, 128.6, 142.1, 143.1,
148.7, 162.2. Anal. Calcd for C24H23N3O: C, 78.02; H, 6.27; N, 11.37.
Found: C, 78.24; H, 6.30; N, 11.21.
3.80À3.76 (m, 2H), 3.86À3.84 (m, 2H), 6.79 (d, J = 8.1 Hz), 7.14À7.09
(m, 2H); 13CNMR(CDCl3, 100 MHz) δ21.5, 27.1, 46.3, 46.9, 47.1, 57.3,
58.0, 107.9, 116.33 120.8, 133.5, 143.4, 146.9, 162.4; HRESI-MS (m/z)
calcd for C14H19N3O(M + Na) 268.1426, found (M + Na) 268.1425.
2-(4-Morpholinyl)-5-phenylbenzoxazole (3m)7e. Prepared
as shown in the general experimental procedure and purified on silica
gel (EtOAc/hexane 15:85À20:80): beige solid; yield 92%; mp
106À110 °C (lit.7e 105À110 °C); Rf (20% EtOAc/hexane) 0.30; IR
(KBr, cmÀ1) 2915, 2955,2969, 2856, 1638, 1579, 1465, 1446, 1425,
1385, 1357, 1303, 1274, 1258, 1207, 1191, 1069, 1058, 981, 894, 761,
699, 591, 515; 1H NMR (CDCl3, 400 MHz) δ 1.66 (s, 6H), 3.65 (s, 6H),
7.29À7.21 (m, 3H), 7.40 (t, J = 7.4 Hz, 2H), 7.58À7.55 (m, 3H); 13C
NMR (CDCl3, 100 MHz) δ 45.6, 66.0, 108.7, 115.0, 120.2, 126.8, 127.2,
128.6, 137.8, 141.4, 143.4, 148.2, 162.4; HRESI-MS (m/z) calcd for
C17H16N2O2 (M + H) 281.1290, found (M + H) 281.1299.
5-Phenyl-2-(piperidin-1-yl)benzoxazole (3n)7a. Prepared as
shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 15:85À20:80): pink solid; yield 91%; mp 117À121 °C
(lit.7a mp 118À120 °C); Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1
)
2938, 2922, 2854, 1647, 1638, 1578, 1466, 762; 1H NMR (CDCl3, 400
MHz) δ 3.67 (q, J = 2 Hz, 4H), 3.76 (q, J = 4.4 Hz, 4H), 7.32À7.23 (m,
3H), 7.41 (t, J = 7.4 Hz, 2H), 7.59À7.56 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 23.9, 25.1, 46.5, 108.4, 114.5, 119.6, 126.7, 127.1, 128.5,
128.7, 137.5, 141.5, 143.7, 148.2, 162.6; HRESI-MS (m/z) calcd for
C18H18N2O (M + H) 279.1497, found (M + H) 279.1497.
N,N-Dibenylbenzoxazol-2-amine (3h)1. Prepared as shown in
the general experimental procedure and purified on silica gel (EtOAc/
hexane 5:95À10:90): colorless liquid; yield 95%; Rf (10% EtOAc/
hexane) 0.30; IR (KBr, cmÀ1) 3027, 1640, 1577, 1456, 1401, 1241, 821,
739, 698; 1H NMR (CDCl3, 400 MHz) δ 4.69 (s, 4H), 7.03 (t, J = 8.9
Hz, 1H), 7.22À7.16 (m, 1H), 7.35À7.25 (m, 11H), 7.40 (d, J = 7.8 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 50.3, 108.8, 116.2, 120.5, 124.0,
127.7, 127.9, 128.7, 136.2, 143.4, 148.8, 163.0; HRESI-MS (m/z) calcd
for C21H18N2O (M + Na) 337.1317, found (M + Na) 337.1317.
5-Methyl-2-(piperidin-1-yl)benzoxazole (3i)7e. Prepared as
shown in general experimental procedure and purified on silica gel
(EtOAc/hexane 5:95À10:90): white solid; yield 92%; mp 98À100 °C
2-(N-Benzyl-N-methylamino)-5-phenylbenzoxazole (3o)7e.
Prepared as shown in the general experimental procedure and purified on
silica gel (EtOAc/hexane 10:90À15:85): beige solid; mp yield 93%; mp
97À100 °C (lit.7e mp 96À100 °C); Rf (20% EtOAc/hexane) 0.30; IR
(KBr, cmÀ1) 3028, 1641, 1580, 1416, 1394, 1253, 1202, 1115, 812, 758,
697; 1H NMR (CDCl3, 400 MHz) δ 3.14 (s, 2H), 4.77 (s, 2H),
7.25À7.23 (m, 1H), 7.36À7.29 (m, 7H), 7.44À7.40 (m, 2H),
7.60À7.58 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 35.2, 53.8, 108.6,
114.8, 119.8, 126.8, 127.3, 127.6, 127.7, 128.7, 128.7, 136.3, 137.7, 141.6,
144.0, 148.6, 163.4; HRESI-MS (m/z) calcd for C21H18N2O (M + H)
315.1497, found (M + H) 315.1499.
2-Morpholino-6-nitrobenzoxazole (3p). Prepared as shown in
the general experimental procedure and purified on silica gel (EtOAc/
hexane 10:90À15:85): yellow solid; yield 84%; mp 140À144 °C; Rf
(30% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 2982, 2918, 1651, 1589,
1504, 1322, 1294, 1103, 851; 1H NMR (CDCl3, 400 MHz) δ 3.77 (t, J =
5.3 Hz, 4H), 3.85 (t, J = 4.3 Hz, 4H), 7.34 (d, J = 8.6 Hz, 1H), 8.20À8.14
(m, 2H); 13C NMR (CDCl3, 100 MHz) δ 45.7, 66.0, 105.2, 115.1, 121.5,
141.6, 147.8, 149.7, 164.5; HRESI-MS (m/z) calcd for C11H11N3O4 (M+Na)
272.0647, found (M + H) 272.0643.
6-Nitro-2-(piperidin-1-yl)benzoxazole (3q). Prepared as shown
in the general experimental procedure and purified on silica gel (EtOAc/
hexane 10:90À15:85): yellow solid; yield 85%; mp 102À106 °C; Rf (30%
EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 2947, 2863, 1651, 1587, 1506, 1449,
1369, 1332,1320, 1291, 1024, 803; 1H NMR (CDCl3, 400 MHz) δ 1.72 (s,
6H), 3.73 (s, 4H), 7.28 (d, J = 8.7 Hz, 1H), 8.17À8.09 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 23.8, 25.6, 46.7, 104.7, 114.5, 121.5, 141.1, 147.8,
150.4, 164.8; HRESI-MS (m/z) calcd for C12H13N3O3(M + Na)
270.0855, found (M + Na) 270.0854.
N-Benzyl-N-methyl-6-nitrobenzoxazol-2-amine (3r). Prepared
as shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 10:90À15:85): yellow solid; yield 80%; mp 100À104 °C;
Rf (20% EtOAc/hexane) 0.30; IR (neat, cmÀ1) 1653, 1591, 1510, 1466,
1330, 1283, 1132, 819; 1H NMR (CDCl3, 400 MHz) δ 3.19 (s, 3H), 4.80
(s, 2H), 7.39À7.31 (m, 6H), 8.19À8.13 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 35.2, 54.0, 105.0, 114.7, 121.4, 127.7, 128.1, 128.9, 135.3, 141.2,
147.9, 150.3, 165.6; HRESI-MS (m/z) calcd for C15H13N3O3(M + Na)
306.0855, found (M + Na) 306.0854.
(lit.7e mp 94À97 °C); Rf (20% EtOAc/hexane) 0.20; IR (KBr, cmÀ1
)
1
2940, 2855, 1656, 1587, 1440, 1292, 1259, 1183, 1019, 889, 792; H
NMR (CDCl3, 400 MHz) δ 1.65 (s, 6H), 2.37 (s, 3H), 3.63 (s, 4H), 6.78
(d, J = 8 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 7.13 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 21.4, 23.9, 25.1, 107.8, 116.3, 120.8, 133.3, 143.2,
146.7, 162.4; HRESI-MS (m/z) calcd for C13H16N2O (M + H)
217.1341, found (M + H) 217.1346 .
5-Methyl-2-(4-methyl-1-piperazinyl)benzoxazole (3j)11a
.
Prepared as shown in the general experimental procedure and purified
on silica gel (EtOAc/hexane 10:90À20:80): white solid; yield 82%; mp
65À67 °C (lit.11a mp 63À64 °C); Rf (20% EtOAc/hexane) 0.20; IR
(KBr, cmÀ1) 2919, 2850, 2803, 1645, 1574, 1449, 1281, 1268, 1171,
1147, 1003, 803; 1H NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.38 (s,
3H), 2.51 (t, J = 5.1 Hz, 4H), 3.71 (t, J = 5 Hz, 4H), 6.80À6.82 (m, 1H),
7.15À7.10 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 21.5, 45.5, 46.2,
54.2, 108.0, 116.7, 121.3, 133.6, 143.2, 146.9, 162.6; HRESI-MS (m/z)
calcd for C13H17N3O (M + H) 232.1450, found (M + H) 232.1454.
5-Methyl-2-thiomorpholinobenzoxazole (3k). Prepared as
shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 5:95À7:93): colorless liquid; yield 60%; Rf (10%
EtOAc/hexane) 0.40; IR (KBr, cmÀ1) 2916, 1633, 1583, 1260, 1180,
956; 1H NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 2.72 (t, J = 5 Hz, 4H),
3.98 (t, J = 5 Hz, 4H), 6.82 (d, J = 8 Hz, 1H), 7.15À7.10(m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 21.5, 26.0, 48.0, 108.0, 116.7, 121.4, 133.7,
142.9, 146.8, 161.8; HRESI-MS (m/z) calcd for C12H14N2OS (M + H)
235.0905, found (M + H) 235.0907.
5-Methyl-2-(4-methyl-1,4-diazepan-1-yl)benzoxazole (3l).
Prepared as shown in the general experimental procedure and purified
on silica gel (EtOAc/hexane 25:75À40:60): gray solid; yield 80%; mp
66À70 °C; Rf (50% EtOAc/hexane) 0.20; IR (KBr, cmÀ1) 2945, 2788,
1638, 1584, 1181, 791; 1H NMR (CDCl3, 400 MHz) δ 2.03À2.09 (m,
2H), 2.38 (s, 3H), 2.41 (s, 3H), 2.67À2.64 (m, 2H), 2.79À2.76 (m, 2H),
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ARTICLE
Ethyl 4-(Benzo[d]oxazol-2-yl)piperazine-1-carboxylate (3s).
Prepared as shown in the general experimental procedure and purified on
silica gel (EtOAc/hexane 5:95À10:90): pink solid; yield 95%; mp
97À100 °C; Rf (10% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 2988,
procedure and purified on silica gel (EtOAc/hexane 25:75À40:60):
white solid; yield 94%; mp 112À114 °C (lit.12 mp 116À117 °C); Rf
(50% EtOAc/hexane) 0.20; IR (neat, cmÀ1) 2940, 1644, 1626, 1572,
1459, 1172, 792; 1H NMR (CDCl3, 400 MHz) δ 2.13À2.10 (m, 2H),
2.36 (s, 3H), 2.45 (s, 3H), 2.75À2.73 (m, 2H), 2.86À2.84 (m, 2H),
3.81À3.78 (m, 2H), 3.90À3.88 (m, 2H), 6.77 (s, 1H), 7.12 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.8, 26.6, 46.0, 46.4, 46.9, 57.1, 57.7, 113.4,
119.8, 121.4, 128.7, 143.8, 146.3, 162.6; HRESI-MS (m/z) calcd for
C14H18ClN3O (M + H) 280.1217, found (M + H) 280.1215.
1
2930, 2870, 1674, 1583, 1460, 1235, 1166, 1086, 993, 761; H NMR
(CDCl3, 400 MHz) δ 1.29 (t, J = 7.08 Hz, 3H), 3.63À3.61 (m, 4H),
3.68À3.67 (m, 4H), 4.18 (q, J = 7.1 Hz, 2H), 7.04 (t, J = 7.7 Hz, 1H), 7.17
(t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 14.6, 43.0, 45.3, 61.7, 108.8, 116.4, 120.9,
124.0, 142.7, 148.6, 155.3, 161.8; HRESI-MS (m/z) calcd for
C14H17N3O3(M + Na) 298.1168, found (M + Na) 298.1167.
5-Methyl-2-(pyrrolidin-1-yl)benzoxazole (4)8a. Prepared as
shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 5:95À10:90): brown solid; yield 95%; mp 97À100 °C
N-Benzylbenzo[d]oxazol-2-amine (3t)12. Prepared as shown
in the general experimental procedure and purified on silica gel (EtOAc/
hexane 5:95À10:90): white solid; yield 80%; mp 113À115 °C (lit.12 mp
115À117 °C); Rf (5% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 1665,
1
(lit.8a mp 101 °C); Rf (20% EtOAc/hexane) 0.30; H NMR (CDCl3,
400 MHz) δ 2.03À2.00 (m, 4H), 2.38 (s, 3H), 3.64À3.61 (m, 4H), 6.77
(d, J = 7.9 Hz, 1H), 7.14À7.08 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 21.5, 25.5, 47.3, 107.8, 116.2, 120.6, 133.3, 143.5, 147.0, 161.0; HRESI-
MS (m/z) calcd for C12H14N2O (M + H) 203.1184, found (M + H)
203.1186.
1
1589, 1461, 1248; H NMR (CDCl3, 400 MHz) δ 4.66 (s,2H), 5.49
(bs,1H), 7.02 (t, J = 7.8 Hz,1H), 7.17 (t, J = 7.6 Hz,1H), 7.25 (d, J =
8.4 Hz, 1H), 7.39À7.29 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 46.9,
108.8, 116.3, 120.9, 123.9, 127.6, 127.8, 128.8, 137.7, 142.6, 148.5,
162.0; HRESI-MS (m/z) calcd for C14H12N2O (M + H) 225.1028,
found (M + H) 225.1025.
(E)-4-Methyl-2-((pyrrolidin-1-ylmethylene)amino)phenol
(I)8a. Prepared as shown in the experimental procedure and purified on
silica gel (EtOAc/hexane 15:85À40:60): gray solid; yield 92%; mp
1
100À104 °C (lit.8a mp 106 °C); Rf (50% EtOAc/hexane) 0.20; H
N-(4-Methylbenzyl)benzo[d]oxazol-2-amine (3u)14. Prepared
as shown in the general experimental procedure and purified on silica gel
(EtOAc/hexane 5:95À10:90): white solid; yield 70%; mp 148À150 °C
NMR (CDCl3, 400 MHz) δ 1.95 (s, 4H), 2.24 (s, 3H), 3.51 (s,4H),
6.79À6.69 (m, 3H), 7.96 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.9,
24.7, 25.2, 45.3, 112.8, 116.1, 123.6, 128.7, 137.2, 147.8, 149.2; HRESI-
MS (m/z) calcd for C12H16N2O(M + H) 205.1341, found (M + H)
205.1342.
(lit.14 mp 148À150 °C); Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1
)
1
1665, 1589, 1461, 1248; H NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H),
4.60 (s, 2H), 6.45 (br, 1H), 7.00 (t, J = 8 Hz, 1H), 7.14À7.10 (m, 3H),
7.27À7.18 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ 21.0, 46.7, 108.7,
116.1, 120.7, 123.8, 127.6, 129.4, 134.7, 137.4, 142.7, 148.4,162.1; HRESI-
MS (m/z) calcd for C15H14N2O(M + Na) 261.1004, found (M + Na)
261.1003.
4-Methyl-2-((piperidin-1-ylmethylene)amino)phenol (II)8a.
Prepared as shown in the general experimental procedure and purified
on silica gel (EtOAc/hexane 15:85À40:60): white solid; yield 89%;
mp 100À104 °C (lit.8a mp 101 °C); Rf (50% EtOAc/hexane) 0.20;
1H NMR (CDCl3, 400 MHz) δ 1.58À1.54 (m, 4H), 1.64À1.61 (m,
2H), 2.22 (s, 3H), 3.55À3.28 (br, 4H), 6.75 (d, J = 7.8 Hz, 1H),
6.69À6.67 (m, 2H), 7.62 (s, 1H), 13C NMR (CDCl3, 100 MHz) δ 20.7,
21.2, 24.4, 26.4, 42.9, 50.2, 112.6, 116.1, 123.4, 128.5, 136.8, 147.7,151.3;
HRESI-MS (m/z) calcd for C12H18N2O (M + H) 219.1497, found
(M + H) 219.1495.
N-Phenethylbenzo[d]oxazol-2-amine (3v)12. Prepared as shown
in the general experimental procedure and purified on silica gel (EtOAc/
hexane 5:95À10:90): white solid; yield 65%; mp 80À83 °C (lit.12
82À84 °C); Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 3178, 3057,
2929, 1672, 1654, 1647, 1586, 1462, 1249, 741; 1H NMR (CDCl3, 400
MHz) δ 2.98 (t, J = 6.8 Hz, 2H), 3.74 (t, J = 6.2 Hz, 2H), 5.21 (br, 1H),
7.02 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.25À7.21 (m, 4H),
7.37À7.29 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 35.7, 44.1, 108.7,
116.3, 120.8, 123.9, 126.7, 128.7, 128.8, 138.3, 142.9, 148.4, 161.8;
HRESI-MS (m/z) calcd for C15H14N2O (M + H) 239.1184, found (M + H)
239.1185.
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data are avail-
b
able (including 1H and 13C NMR spectra) for all products. This
material is available free of charge via the Internet at http://pubs.
acs.org.
2-(Propargylamino)benzoxazole (3w)13. Prepared as shown
in the general experimental procedure and purified on silica gel (EtOAc/
hexane 5:95À10:90): white solid; yield 63%; mp 120À124 °C (lit.13 mp
118À120 °C); Rf (20% EtOAc/hexane) 0.30; IR (KBr, cmÀ1) 3406,
3275, 1685, 1666, 1588, 1338, 1246, 741, 648; 1H NMR (CDCl3, 400
MHz) δ 2.32 (s, 1H), 4.28 (s, 2H), 5.80 (br, 1H), 7.06 (t, J = 7.8 Hz,
1H), 7.18 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 8 Hz, 7.42 (d, J = 7.8 Hz);
13C NMR (CDCl3, 100 MHz) δ 32.8, 72.3, 79.2, 108.9, 116.8, 121.3, 124.0,
142.5, 148.7, 161.2; HRESI-MS (m/z) calcd for C10H8N2O (M + H)
173.0715, found (M + H) 173.0715.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +91-80-22932887. Fax: +91-80-23600529. E-mail: prabhu@
orgchem.iisc.ernet.in.
5-Chloro-7-methyl-2-(4-methyl-1-piperazinyl)benzoxazole
(3x)11a. Prepared as shown in the general experimental procedure and
purified on silica gel (EtOAc/hexane 25:75À35:65): yellow solid; yield
95%; mp 64À66 °C (lit.11a mp 62À64 °C); Rf (30% EtOAc/hexane)
’ ACKNOWLEDGMENT
We thank the Indian Institute of Science and CSIR for
financial support of this investigation, Dr. A. R. Ramesha for
useful discussions, and Prof. S. Chandrasekhar for encourage-
ment. M.L. thanks CSIR for a fellowship.
1
0.20; IR (KBr, cmÀ1) 1645, 1627, 1574, 1452, 1302, 895; H NMR
(CDCl3, 400 MHz) δ 2.36 (s, 3H), 2.39 (s, 3H), 2.58 (t, J = 5.2 Hz, 4H),
3.75 (t, J = 5.2 Hz, 4H), 6.80 (s, 1H), 7.12 (s, 1H), 13C NMR (CDCl3, 100
MHz) δ 45.0, 45.9, 53.9, 113.7, 119.9, 121.9, 128.8, 143.6, 146.2, 162.4;
HRESI-MS (m/z) calcd for C13H16ClN3O (M + H) 266.1060, found
(M + H) 266.1072.
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7943
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ARTICLE
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