A metal-free amination of benzoxazoles - The first example of an iodide-catalyzed oxidative amination of heteroarenes

Article abstract of DOI:10.1021/ol201439t

An efficient transition-metal-free amination of benzoxazoles has been developed. With catalytic amounts of tetrabutylammoniumiodide (TBAI), aqueous solutions of H₂O₂ or TBHP as co-oxidant and under mild reaction conditions, highly desirable 2-aminobenzoxazoles were isolated in excellent yields of up to 93%. First mechanistic experiments indicate the in situ iodination of the secondary amine as the putative mode of activation.

Full text of DOI:10.1021/ol201439t

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3754–3757
A Metal-Free Amination of
Benzoxazoles ꢀ The First Example of an
Iodide-Catalyzed Oxidative Amination of
Heteroarenes
Tanja Froehr, Christian P. Sindlinger, Ulrich Kloeckner, Peter Finkbeiner, and
Boris J. Nachtsheim*
€
€
Institut fu€r Organische Chemie, Eberhard Karls Universitat Tubingen,
Auf der Morgenstelle 18, 72076 Tu€bingen, Germany
boris.nachtsheim@uni-tuebingen.de
Received May 27, 2011
ABSTRACT
An efficient transition-metal-free amination of benzoxazoles has been developed. With catalytic amounts of tetrabutylammoniumiodide (TBAI), aqueous
solutions of H2O2 or TBHP as co-oxidant and under mild reaction conditions, highly desirable 2-aminobenzoxazoles were isolated in excellent yields of
up to 93%. First mechanistic experiments indicate the in situ iodination of the secondary amine as the putative mode of activation.
Hypervalent iodine compounds have gained much at-
tention as mild oxidation reagents in organic synthesis. In
particular aryl-λ3-iodanes (iodine in the oxidation state
þIII) have been established as cheap and nontoxic alter-
natives to transition metals in oxidative CꢀH bond
activations.1,2 Elegant catalytic methods based on the in
situ generation of the reactive iodine(III) species from an
iodoarene precursor in combination with stoichiometric
amounts of a cheap and easy to handle co-oxidant such as
mCPBA were developed by Kita and Wirth.3
a seminal work enantiopure tetraalkylammoniumiodides
(TAAIs) could be used in a highly enantioselective oxida-
tive cycloetherification of ketophenols (Scheme 1).
Scheme 1. TAAI-Catalyzed Oxidative Cycloetherification4
Very recently, a novel class of iodine-based oxidation
catalysts was introduced by Ishihara and co-workers. In
In combination with H2O2 or tert-butyl hydroperoxide
(TBHP) as co-oxidant [O], in situ generated tetraalkyl-
ammonium(hypo)iodites were proposed as catalytically
active species. Typical aryl-λ3-iodanes showed only poor
reactivity in the same reaction.4
Inspired by this novel metal-free oxidative CꢀH activa-
tion approach we now want to present the first direct
amination of heteroaromatic CꢀH bonds catalyzed by
(1) For reviews, see: (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(c) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229. (d) Merritt,
E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. (e) Pouysegu,
L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235. (f) Duschek,
A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2011, 50, 1524. (g) Merritt, E. A.;
Olofsson, B. Synthesis 2011, 517.
(2) Recent examples for hypervalent iodine compounds in oxidative
cross-coupling reactions: (a) Dohi, T.; Ito, M.; Morimoto, K.; Iwata,
M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 1301. (b) Kita, Y.;
Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem.
Soc. 2009, 131, 1668. (c) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.;
(4) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010,
328, 1376. During the preparation of this manuscript other TBAI-
catalyzed CꢀH activations have been published: (a) Uyanik, M.; Suzuki,
D.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50, 5331.
(b) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan,
X. Chem.;Eur. J. 2011, 17, 4085. (c) Rodrıguez, A.; Moran, W. J. Org.
Lett. 2011, 13, 2220.
€
Fujioka, H.; Kita, Y. Angew. Chem., Int. Ed. 2010, 49, 3334. (d) Schafer,
S.; Wirth, T. Angew. Chem., Int. Ed. 2010, 49, 2786.
(3) For reviews, see: (a) Richardson, R. D.; Wirth, T. Angew. Chem.,
Int. Ed. 2006, 45, 4402. (b) Dohi, T.; Kita, Y. Chem. Commun. 2009,
2073.
r
10.1021/ol201439t
Published on Web 06/21/2011
2011 American Chemical Society

Table 1. Optimizing the Reaction Conditions
Scheme 2. TAAI-Catalyzed Oxidative Amination of Heteroar-
enes
mol %
TBAI
[O]
additive
(equiv)c
t
yield
[%]d
entrya
(equiv)b
[h]
quaternary ammonium iodides under oxidative conditions
(Scheme 2).
1
20
20
20
20
10
10
5
H2O2 (2)
TBHP (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (5)
TBHP (1.5)
ꢀ
ꢀ
72
72
12
12
3
29
traces
0
2
As heteroaromatic model substrates we chose benzox-
azoles since 2-aminooxazoles and 2-aminothiooxazoles
are frequently found structural motifs in numerous
pharmacological active compounds.5 Transition-metal-
catalyzed direct aminations of azoles have been described
recently. In particular Ag(I),6 Co(II), Mn(II),7 Fe(III),8
and Cu(II)9 were found to catalyze this transformation.
However harsh reaction conditions or activated amine
derivatives (e.g., N-chloroamines or N-formamides) were
required. A metal-free version of this transformation has
not been described so far.
In first experiments we examined the reaction between
benzoxazole 1a and morpholine 2a (Table 1). With cata-
lytic amounts of simple tetrabutylammoniumiodide (TBAI)
as the precatalyst and an aqueous solution of H2O2 as the
oxidizing reagent at room temperature we were pleased to
isolate the desired 2-morpholinobenzoxazole 3a in 29%
yield (Table 1, entry 1). Withan aqueous solution of TBHP
only traces of 3a could be detected at room temperature
(Table 1, entry 2). Tetrabutylammoniumbromide and
-chloride showed no catalytic activity at all. Addition of
a base such as K2CO3 or NEt3 (Table 1, entries 3 and 4)
resulted in a complete loss of reactivity. Surprisingly, when
carboxylic acids, in particular acetic acid or benzoic acid,
were added to the reaction mixture, the yields of 3a
increased significantly to 68% and 70% respectively. With
further optimization of the reaction conditions, the
yields of 3a finally could be increased to 80%. The
necessary high excess of H2O2 (5 equiv) is most likely
the result of an undesired BrayꢀLiebhafsky reaction.10
Since this iodate-catalyzed oscillating decomposition of
H2O2 is not known for other peroxides, we thought to test
the reaction between 1a and 2a again with TBHP, now
under our optimized conditions. To our delight we found
that with only 1.5 equiv of TBHP at 80 °C and with acetic
acid as an additive, 3a can be isolated in a comparable yield
3
K2CO3 (2)
NEt3 (2)
4
0
5
HOAc (2)
PhꢀCO2H (2)
HOAc (2)
HOAc (2)
HOAc (5)
HOAc (3)
70
68
70
18
80
80
6
4
7
3
8
2
4
9
10e
5
18
1
5
a General reaction conditions: 0.336 mmol 1a and 0.672 (2 equiv) 2a
in 1 mL of acetonitrile at rt. b All experiments were performed with
aqueous solutions of H2O2 (30%) or TBHP (70%). The given equiva-
lents are related to 1a. No reaction was observed without the addition of
a co-oxidant. c The given equivalents are related to 1a. d Isolated yield
after column chromatography. e Reaction was performed at 80 °C.
of 80%. Thus we tested both co-oxidants (H2O2 and
TBHP) simultaneously in the following discussion of our
substrate scope.
With our optimized reaction conditions in hand we first
investigated the reaction between various benzoxazoles 1
and morpholine 2a (Scheme 3).
Scheme 3. Amination of Various Benzoxazoles with Morpho-
linea
(5) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49,
2282.
(6) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem., Int.
Ed. 2009, 48, 9127.
(7) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int.
Ed. 2010, 49, 9899.
(8) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Chem.
Commun. 2011, 47, 3652.
(9) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
Lett. 2009, 11, 1607. (b) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J.
Am. Chem. Soc. 2010, 132, 6900. (c) Zhao, H.; Wang, M.; Su, W.; Hong,
M. Adv. Synth. Catal. 2010, 352, 1301. (d) Guo, S.; Qian, B.; Xie, Y.; Xia,
C.; Huang, H. Org. Lett. 2011, 13, 522.
(10) (a) Bray, W. C. J. Am. Chem. Soc. 1921, 43, 1262. (b) Schmitz, G.
Phys. Chem. Chem. Phys. 2010, 12, 6605.
a General reaction conditions: Method A: 0.336 mmol of 1, 0.672
mmol of 2a, 5 equiv of H2O2 (30% aq solution), 5 equiv of HOAc, in
1 mL of acetonitrile. Method B: 0.336 mmol of 1, 0.403 mmol of 2a,
1.5 equiv of TBHP (70% aq solution), 3 equiv of AcOH in 1 mL of
acetonitrile at 80 °C.
Org. Lett., Vol. 13, No. 14, 2011
3755

despite the oxidizing reaction conditions. In addition to
cyclic amines, secondary aliphatic amines can be used in
this transformation (3pꢀ3s). In addition to simple dialkyl-
amines, synthetically more useful diallylamine and
dibenzylamine are tolerated. Undesired oxidations or ha-
logenations of the double bonds, the aromatic ring, or the
methylene units have not been observed. Furthermore we
were pleased to find that with TBHP even a primary amine
such as butyl amine could be used in our amination
procedure to yield 3t in a good yield of 69%.
Scheme 4. Amination of Benzoxazole with Various Aminesa
These promising results prompted us to investigate
our novel method toward the synthesis of the coumarin
derivative 5. 5 is known for its potent anti-HIV and
antitumor activity, and an efficient late stage arylation of
the piperazyl moiety of the potential precursor 4 would
give an easy access to various N-aryl derivatives.12 To our
delight our standard reaction protocol using aq H2O2
yielded 5 in a good yield of 59% under mild reaction
conditions (Scheme 5).
Scheme 5. TAAI-Mediated Synthesis of the Anti-HIV
Reagent 5a
a General reaction conditions: Method A: 0.336 mmol of 1a, 0.672
mmol of 2, 5 equiv of H2O2 (30% aq solution), 5 equiv of HOAc in 1 mL
of acetonitrile. Method B: 0.336 of mmol 1a, 0.403 mmol of 2, 1.5 equiv
of TBHP (70% aq solution), 3 equiv of AcOH in 1 mL of acetonitrile
at 80 °C.
Alkyl- and halogen-substituted benzoxazoles could be
aminated in perfect regioselectivity to yield the desired
2-(morpholino)benzoxazoles 3aꢀ3f in up to 86% yield.
Reaction of naphtho[1,2-d]oxazole with morpholine
yielded 2-aminonaphthooxazole 3e in an excellent yield
of 93%. Even the electron-poor 6-nitrobenzoxazole could
be derivatized to 3g, however with decreased yields. Here a
significant difference in yields (18% and 52%) was recog-
nized between the two oxidation reagents. Even though
yields were comparable when using H2O2 or TBHP as co-
oxidants, in the latter case a full conversion was observed
after 1 h for all substrates.
Next we discovered the reaction between various
linear and cyclic secondary amines and benzoxazole 1a
(Scheme 4). In addition to morpholine we could efficiently
use pyrrolidine, piperidine, and azepane for our oxidative
amination procedure. The desired products 3jꢀ3l were
obtained in 57ꢀ62% yield. Furthermore we could syn-
thesize 2-piperazylbenzoxazoles 3m and 3n in excellent
yields starting from N-methyl and N-acylpiperazine.
2-(N-alkylpiperazyl)benzoxazoles of this type were already
described as potent 5-HT3-receptor agonists.11 To our
surprise an unprotected hydroxyl group attached to the
N-alkyl residue of piperazine is tolerated as well (3o),
a Reaction conditions: Method A: 0.336 mmol of 1a, 2 equiv of 4, 5
equiv of H2O2 (30% aq solution), 5 equiv of HOAc, 1 mL of acetonitrile.
Method B: 0.336 mmol of 1a, 0.336 mmol (1.0 equiv) of 4, 1.5 equiv of
TBHP (70% aq solution) in 1 mL of acetonitrile at 80 °C.
After we examined a satisfying substrate scope we
performed several synthetic experiments to unravel the
underlying reaction mechanism. Addition of the radical
scavenger TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl)
had only a slight impact on the yield of 3a (58%).
Furthermore no TEMPO-bound intermediate could be
observed. Thus a radical mechanism can be ruled out.
Since catalytic amounts of I2 (without co-oxidant) did not
yield 3a, the in situ generation of I2 and its subsequent
function as a mild Lewis acid is also excluded.
Next we tried to examine the reactivity of iodine in the
oxidation state þ1 (Scheme 6). Stoichiometric amounts of
ICl, a potent source for iodonium ions (IR2þ), yielded 3a in
65% yield. Thusa mechanismthatpassesthroughIþ seems
plausible. Subsequently we wanted to verify whether in
(12) Al-Soud, Y. A.; Al-Sa’doni, H. H.; Amajaour, H. A. S.; Salih,
K. S. M.; Mubarak, M. S.; Al-Masoudi, N. A.; Jaber, I. H. Z.
Naturforsch. 2008, 63b, 83.
(ꢀ13) The potential in situ generation of ammonium(hypo)iodites
(IO /IO2ꢀ) as catalytically active species cannot be ruled out at this
point and is part of further investigations.
(14) Urbansky, E. T.; Cooper, B. T.; Margerum, D. W. Inorg. Chem.
1997, 36, 1338.
(11) (a) Yoshida, S.; Shiokawa, S.; Kawano, K.-I.; Ito, T.;
Murakami, H.; Suzuki, H.; Sato, Y. J. Med. Chem. 2005, 48, 7075.
(b) Sato, Y.; Imai, M.; Amano, K.; Iwamatsu, K.; Konno, F.; Kurata,
Y.; Sakakibara, S.; Hachisu, M.; Izumi, M.; Matsuki, N.; Saito, H. Biol.
Pharm. Bull. 1997, 20, 752.
3756
Org. Lett., Vol. 13, No. 14, 2011

Scheme 6. Reactivity of N-Iodomorpholine Hydroiodide 6 HIa
Scheme 7. A Putative Reaction Mechanism
3
a Reaction conditions are given in the Supporting Information.
situ generation of an activated N-iodamine is likely. Thus
N-iodomorpholine hydroiodide (6 HI) was synthesized
3
elimination of iodide the desired reaction product 3a can
be observed.
and further investigated. The reaction of 6 HI with ben-
3
zoxazole gave 3a in 33% yield (Scheme 6b). A 2-fold excess
of 6 HI did not increase the yield. However, when catalytic
amounts of 6 HI (10 mol %) were used, 3a was isolated in
In conclusion we described the first TBAI-catalyzed
direct amination of heteroarenes. This is the first example
of a metal-free synthesis of highly desirable 2-aminoben-
zoxazoles starting from unfunctionalized amines and ben-
zoxazoles. The mild reaction conditions, lowest amounts
ofcheap and nontoxic TBAIascatalyst, and easytohandle
co-oxidants such as H2O2 and TBHP make this novel
amination protocol highly viable for future applications.
In the near future we would like to establish TAAIs in
oxidative CꢀN bond forming reactions as cheap and
nontoxic alternatives for noble metals. Furthermore more
experiments are needed for a deeper mechanistic under-
standing of TAAI-catalyzed amination reactions.
3
3
92% yield. As a consequence the activation of the amine
via in situ formation of a highly reactive NꢀI bond from
TBAI and the co-oxidant seems plausible.13 This result in
addition to the fact that carboxylic acids, in particular
acetic acid, have a positive influence made us think about a
first mechanistic proposal for our newly found oxidative
amination procedure (Scheme 7). In the presence of an
excess of acetic acid, TBAI is oxidized to iodoniumdiace-
tate A and subsequently liberates acetylhypoiodite B. B is a
highly potent Iþ source which generates 6 from morpho-
line in the next step.14
Caused by the slightly acidic reaction conditions,
only small amounts of the secondary amine remain in a
neutral and reactive state and thus concentrations of 6
can be kept low. This prevents an undesired compropor-
tionation reaction between R2NꢀI and Iꢀ to form I2 that
might cause the low yields observed when using stoichio-
metric amounts of 6 (Scheme 6b). In the next step
addition of 6 to benzoxazole yields 2-aminobenzoxazo-
lidine D through transition state C. After base-induced
Acknowledgment. We gratefully acknowledge financial
support by the Deutsche Forschungsgemeinschaft (NA
955/1-1).
Supporting Information Available. Experimental pro-
cedures, analytical data, 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
3757