A metal-free oxidative amination of benzoxazoles with primary amines and ammonia

Article abstract of DOI:10.1055/s-0031-1289902

An efficient synthesis of 2-aminobenzoxazoles is described by a direct oxidative amination of unfunctionalized benzoxazoles with primary amines. The reaction could be performed in the absence of transition metals by using catalytic amounts of a quaternary ammonium iodide and tert-butylhydroperoxide as a cheap and easy-to-handle co-oxidant. In addition to primary amines, aqueous solutions of NH₃ were used to introduce a primary amine group into the heterocyclic core. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289902

LETTER
97
A Metal-Free Oxidative Amination of Benzoxazoles with Primary Amines and
Ammonia
Metal-Free
O
xidat
l
ive
A
m
r
inationo
i
f
B
enz
c
oxazoles h Kloeckner, Nicole M. Weckenmann, Boris J. Nachtsheim*
Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295897; E-mail: boris.nachtsheim@uni-tuebingen.de
Received 22 July 2011; revised 26 October 2011
HP).8,9 First mechanistic investigations led us to suggest
Abstract: An efficient synthesis of 2-aminobenzoxazoles is de-
an activation through in situ iodination of the secondary
amine and thence an electrophilic amination mechanism
(Scheme 1).
scribed by a direct oxidative amination of unfunctionalized benzox-
azoles with primary amines. The reaction could be performed in the
absence of transition metals by using catalytic amounts of a quater-
nary ammonium iodide and tert-butylhydroperoxide as a cheap and
easy-to-handle co-oxidant. In addition to primary amines, aqueous
solutions of NH3 were used to introduce a primary amine group into
the heterocyclic core.
Herein we wish to present a first systematic investigation
of TBAI-catalyzed aminations of benzoxazoles with
much less reactive primary amines. As a starting point we
studied the reaction between benzoxazole (1a) and N-bu-
tylamine (2a).10 To find the optimal reaction conditions
for this valuable transformation we chose to investigate
the reaction between benzoxazole (1a) and N-butylamine
(2a) with catalytic amounts of TBAI and acetic acid as
acid additive (Table 1). Using 5 mol% of TBAI as catalyst
and with H2O2 as co-oxidant at ambient temperature the
desired 2-aminobenzoxazole 3a could be isolated in 17%
yield (Table 1, entry 2). With TBHP as co-oxidant the
yield could be increased significantly to 31% (Table 1, en-
try 3). Raising the reaction temperature to 80 °C finally
gave 3a in a good isolated yield of 69% (Table 1, entry 6).
Key words: green chemistry, amination, homogeneous catalysis,
iodine, oxidation
Aromatic and heteroaromatic amines are widely distribut-
ed structural motifs that can be found in important classes
of organic molecules such as pharmaceuticals, agrochem-
icals, organic dyes, and conducting polymers. An efficient
way to introduce the crucial C–N functionality is the di-
rect oxidative amination of a (hetero)aryl C–H bond.1
Meanwhile a variety of transition metals such as Pd,2 Ag,3
Cu,4 Mn, Co,5 and Fe6 were described to catalyze this re-
action.7 However, catalytic metal-free oxidative amina-
tions are much less explored.
Table 1 Optimizing the Reaction Conditions
Bu
NH
O
O
N
TBAI (5 mol%)
Bu
H
+
R
H2N
O
N
R
R
I–
solvent, [O], AcOH
N
N
N
H
1a
2a
3a
R
[O]
Entry [O]a
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
DMF
Temp (°C) Time (h) Yield (%)d
H
R
R
O
N
1
2
–
r.t.
r.t.
r.t.
40
60
80
80
80
80
80
80
24
24
24
7
0
17
31
44
63
69
19
19
48
31
5
R
R
N
N
I
b
H2O2
I
3
TBHPc
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
4
O
5
3.5
N
6
3.5
2
Scheme 1 Iodide-catalyzed oxidative amination of oxazoles
7
In our attempts to develop novel iodide-catalyzed oxida-
tive C–C and C–X bond-forming reactions we have re-
cently developed a metal-free oxidative direct amination
of azoles with secondary amines by using catalytic
amounts of tetrabutylammoniumiodide (TBAI) and aque-
ous solutions of H2O2 or tert-butylhydroperoxide (TB-
8
2
9
PhMe
2
10
11
EtOH
2
AcOH
2
a Co-oxidant.
b Conditions: 30% aq solution; 3 equiv based on 1a.
SYNLETT 2012, 23, 97–100
Advanced online publication: 23.11.2011
DOI: 10.1055/s-0031-1289902; Art ID: D23611ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.
2
0
1
1
c Conditions: 70% aq solution; 1.5 equiv based on 1a were used for
entries 3–11.
d Isolated yield after column chromatography.

98
U. Kloeckner et al.
LETTER
Table 2 Reaction Scope with Various Primary Amines11
(continued)
Other polar and nonpolar solvents did not improve the
yields (Table 1, entries 7–10). Running the reaction in
glacial acetic acid (Table 1, entry 11) gave 3a in trace
amounts only. Furthermore, it is important to note that
without the addition of a co-oxidant (Table 1, entry 1) or
without addition of an iodide source no reaction was ob-
served.
R
O
O
N
TBAI (5 mol%)
H
+
H2N R
NH
MeCN, aq TBHP
AcOH, 80 °C
N
1a
2
3
Entry Amine 2
Product 3
Time Yield
(h)
(%)
With our optimized reaction conditions we began to in-
vestigate the substrate scope of our oxidative amination
reaction. First we examined various primary alkyl amines
(Table 2).
H2N
O
9
2
80
NH
NH
N
2i
Table 2 Reaction Scope with Various Primary Amines11
3i
3j
R
O
N
O
N
TBAI (5 mol%)
O
N
10
4
2
28
66
H
+
H2N R
NH
H2N
MeCN, aq TBHP
AcOH, 80 °C
2j
1a
2
3
Entry Amine 2
Product 3
Time Yield
(h)
(%)
O
N
11
NH
H2N
O
H2N Bu
NH
Bu
1
3.5
69
2k
N
3k
2a
3a
3b
3c
Besides the initially chosen N-butylamine a variety of oth-
er aliphatic primary amines could be used for this reaction
such as isopropyl-, isobutyl-, and tert-butylamine
(Table 2, entries 2–4). The corresponding 2-aminobenz-
oxazoles 3b–d were isolated in up to 76% yield.
O
N
H2N
2
3.5
3.5
72
76
NH
NH
2b
O
N
3
In addition we were able to transform benzylamine (2e)
and 1-phenylethylamine (2f) to the desired products 3e
and 3f in 59% and 81% yield, respectively. Various cyclic
primary amines, such as cyclopentyl- or cyclohexylamine
(2g and 2h) as well as exo-2-aminonorbornan (2i), gave
the corresponding 2-aminobenzoxazoles 3g–i in up to
80% yield (Table 2, entries 7–9).
H2N
2c
O
N
H2N
4
2
46
59
81
NH
NH
2d
3d
3e
O
N
Allylamine 2j can be used for this oxidative amination as
well, although yielding 3j only in a moderate yield of
28%. Synthetically highly valuable alkynylamines are
also tolerated. As an example 1-ethynylcyclohexanamine
(2k) gave 3k in 66% yield. It is worth mentioning that ar-
omatic primary amines such as aniline did not react under
our optimized reaction conditions (data not shown).
Ph
5
6
1.5
1.5
H2N
Ph
Ph
2e
Ph
O
N
H2N
NH
NH
2f
3f
Subsequently, we varied the benzoxazole motif and react-
ed diverse substituted azoles with 1-phenylethylamine
(Table 3). Benzoxazoles bearing electron-donating alkyl
groups (1b–d) and a 5-methoxy group (1e) showed the
highest reactivity (Table 3, entries 1–3). The desired ami-
nated products 3l–o were isolated in excellent yields of up
to 90% after short reaction times (1–2.5 h).
O
N
H2N
7
8
1.5
73
59
2g
3g
3h
H2N
O
N
1
5-Chlorobenzoxazole (1f) gave 3p in a good yield of 71%
as well (Table 3, entry 5). However, the more electron-
poor 5-fluoro- and 6-nitro-substituted benzoxazoles 1g
and 1h showed a decreased reactivity yielding 3q and 3r,
respectively, in only 56% and 18% yield (Table 3, entries
6 and 7). Naphthoxazole 1i gave the desired product 3s in
41% yield (Table 3, entry 8).
NH
2h
Synlett 2012, 23, 97–100
© Thieme Stuttgart · New York

LETTER
Metal-Free Oxidative Amination of Benzoxazoles
99
Table 3 Variation of the Benzoxazole Scaffold11
aq NH3
O
N
O
N
TBAI (10 mol%)
Ph
H
NH2
NH2
R
R
MeCN, aq TBHP
AcOH, 80 °C
H2N
1
3
2f
O
O
O
Ph
O
O
N
TBAI (5 mol%)
NH2
NH2
H
NH
R
R
MeCN, aq TBHP
AcOH, 80 °C
N
3t
N
N
N
1
3
3u
2 h, 46%
3v
3 h, 54%
3 h, 73%
Entry Benzoxazole 1
Product 3
Time Yield
(h) (%)
O
N
O
N
NH2
NH2
t-Bu
Cl
O
N
O
3w
3 h, 33%
3x
NH
NH
2 h, 35%
1
2.5 86
Ph
N
Scheme 2 Oxidative amination of benzoxazoles with ammonia
1b
3l
O
N
O
Reaction of 1a with ammonia yielded 3t in 73% yield
(Scheme 2). However, yields dropped significantly for the
reaction of other substituted benzoxazoles with ammonia.
Alkyl-substituted benzoxazoles gave the desired products
3u–v in up to 54% yield. The chlorinated benzoxazole 1f
gave the desired 2-amino derivative 3x in only 35% yield.
The reasons for this significant drop in yield by changing
the substitution pattern are not clear to us at this point. A
detailed side-product analysis is part of ongoing investi-
gations.
2
1
90
Ph
N
1c
3m
O
O
NH
3
1.5 77
N
Ph
Ph
t-Bu
N
t-Bu
1d
3n
O
N
O
N
NH
4
2
1
71
71
MeO
MeO
Finally, we wanted to investigate whether chiral primary
amines keep their stereoinformation in the final reaction
product. Thus we decided to react optical pure (R)-1-phe-
nylethylamine [(R)-2f] with 1a (Scheme 3). Chiral GC
analysis indeed showed an optical purity for the reaction
product (R)-3f of 99% ee (see Supporting Information).
1e
3o
O
N
O
NH
5
Ph
Cl
N
Cl
1f
3p
O
O
Ph
NH
6
1.5 56
Ph
O
N
O
N
Bu4NI (5 mol%)
N
Ph
F
N
F
NH
+
H2N
CH3CN, aq TBHP
AcOH, 80 °C
1g
3q
O2N
1a
(R)-2f
99% ee
(R)-3f
99% ee
O
N
O2N
O
N
NH
7
8
1
18
Scheme 3 Oxidative amination of benzoxazole with (R)-1-phenyl-
Ph
ethylamine
1h
3r
In summary we have developed an efficient metal-free ox-
idative amination of benzoxazoles with primary amines
and ammonia. With lowest amounts (5–10 mol%) of the
quaternary ammonium iodide TBAI the desired 2-ami-
nobenzoxazoles could be obtained in good yields after
short reaction times. Chiral primary amines can be used in
our oxidative amination reaction without a loss of optical
purity.
O
O
N
NH
5.5 41
N
Ph
1i
3s
Next we considered whether we could introduce a primary
amine group at the 2-position of the benzoxazole scaffold.
The easiest way to achieve this goal would be a reaction
of the azole with aqueous ammonia. We were pleased to
find that benzoxazoles could be easily aminated in the
proposed way, under the same reaction conditions that we
had used previously, by using ammonia instead of prima-
ry amines. However, for this reaction, catalyst loading had
to be increased from 5 mol% to 10 mol%.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We gratefully acknowledge financial support by the Deutsche
Forschungsgemeinschaft (NA 955/1-1) and the Fonds der Che-
mischen Industrie.
© Thieme Stuttgart · New York
Synlett 2012, 23, 97–100

100
U. Kloeckner et al.
LETTER
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(11) Typical Experimental Procedure
A reaction vessel was charged with AcOH (0.061 g, 1.010
mmol, 3 equiv) and TBHP (70% solution in H2O, 0.065 g,
0.504 mmol, 1.5 equiv) in MeCN (0.2 mL). After the
addition of TBAI (0.006 g, 0.017 mmol, 5 mol%), 1-phenyl-
ethylamine (2f, 0.029 g, 0.403 mmol, 1.2 equiv), and benz-
oxazole (1a, 0.040 g, 0.336 mmol, 1 equiv) in MeCN (0.2
mL) were added. The reaction mixture was stirred until TLC
showed full conversion of benzoxazole (1.5 h). The reaction
was quenched by addition of an aq solution of Na2S2O5 (2
mL) and a sat. solution of NaHCO3 (5 mL). The mixture was
extracted with CH2Cl2 (5 × 5 mL), combined organic phases
were dried over Na2SO4, and the solvent was removed in
vacuo. The residue was purified by column chromatography
[silica gel; hexane–EtOAc = 10:1 (v/v)] to yield 3f (0.061 g,
81%) as a white amorphous solid. 1H NMR (400 MHz,
CDCl3): d = 7.43–7.41 (m, 2 H), 7.34–7.31 (m, 2 H), 7.28–
7.20 (m, 3 H), 7.12 (t, 1 H, J = 7.7 Hz), 6.99 (t, 1 H, J = 7.7
Hz), 6.88 (br s, 1 H), 5.11 (q, 1 H, J = 6.8 Hz), 1.66 (d, 3 H,
J = 6.7 Hz). 13C{1H} NMR (100 MHz, CDCl3): d = 161.6,
148.4, 143.4, 142.7, 128.7, 127.4, 125.9, 123.8, 120.6,
116.0, 108.8, 52.8, 23.1. IR (neat): 2970, 1658, 1648, 1580,
1458, 1366, 1217, 698 cm–1. HRMS (EI): m/z calcd for
C15H15N2O2 [M + H]+: 239.1179; found: 239.1178. Anal.
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C, 75.96; H, 5.56; N, 11.88. Detailed spectroscopic data as
well as 1H and 13C NMR spectra of all compounds 3a–v are
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Synlett 2012, 23, 97–100
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