Iron-catalyzed direct amination of azoles using formamides or amines as nitrogen sources in air

Article abstract of DOI:10.1039/c0cc05811d

A new iron-catalyzed, direct C-H amination of azoles at C2 has been developed by using formamides or amines as nitrogen sources. Imidazole is the only additive in the catalyst system and oxygen in air is employed during the transformation process.

Full text of DOI:10.1039/c0cc05811d

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Iron-catalyzed direct amination of azoles using formamides or amines as
nitrogen sources in airw
Jian Wang, Ji-Ting Hou, Jun Wen, Ji Zhang* and Xiao-Qi Yu*
Received 27th December 2010, Accepted 27th January 2011
DOI: 10.1039/c0cc05811d
A new iron-catalyzed, direct C–H amination of azoles at C2 has
been developed by using formamides or amines as nitrogen
sources. Imidazole is the only additive in the catalyst system
and oxygen in air is employed during the transformation process.
After the optimization of reaction conditions,12 the 2-amino
substituted product 2a could be obtained from 1 and DMF in
82% yield (Table 1) without the use of any additional oxidant.
Several substituted benzoxazoles were then applied to the
decarbonylative amination under optimized conditions. As
shown in Table 1, most of the benzoxazoles, especially with
electro-donating substituents on the phenyl group, could react
smoothly to give corresponding products with good yields (up
to 87% for 2a–2f and 2h). However, benzoxazoles with strong
electro-withdrawing substituents such as a nitro group (1g)
could not progress well, and only a trace amount of product
was obtained.
Transition metal-catalyzed C–N formation is a powerful
and efficient approach for C-amination in organic synthesis.1
Outstanding results were obtained in hydroamination,2 allylic
amination,3 palladium-catalyzed Buchwald–Hartwig coupling4
and the copper-catalyzed Ullmann and Goldberg couplings.5
Along with the increasing attention paid to C–H functionali-
zation, studies about transition metal-catalyzed direct C–H
amination have also sprung up.1,6 These direct methods
include nitrene C–H insertion7 and Pd-catalyzed amination
of sp2 C–H bonds.8
Azoles, other than benzoxazoles, with similar structures
were employed for the reaction. Unfortunately, no product
was found in the reaction involving benzothiazole, benzimidazole,
1-methylbenzimidazole, and phenyloxazoles. Nevertheless,
exciting results were obtained in the reaction using 2-phenyl-
1,3,4-oxadiazole (3a) as the substrate. As shown in
Table 2, several 2-(substituted) phenyl-1,3,4-oxadiazoles could
Amino-substituted azoles are important scaffolds in medicinal
chemistry.9 Among the various approaches to these structures,
direct C–H amination has been focused on for its atom
economy. Inspiring progress regarding this synthetic method
has occurred in past decade.10 However, these methods always
need high temperatures, a large amount of metal salts,
additional oxidants, or a nitrogen atmosphere. Thus, we
hoped to find a novel, mild and atom-economic method
toward direct azole amination catalyzed by inexpensive and
environmentally benign reagents. Some transition metal salts,
especially easily available iron(III) salts, which may act as both
Lewis acid and oxidant, have the potential to be suitable
catalysts for this kind of amination. More recently, a communi-
cation was reported by Chang during the preparation of this
manuscript. They developed the direct amination of azoles
with amines by using a catalytic amount of cobalt or manga-
nese salts.11 However, the reaction needed the presence of a
stoichiometric quantity of peroxide and an acid additive.
Herein, we wish to introduce a new and mild catalytic system,
which consists of just the iron(III) salt and imidazole under air,
for direct amination.
Table 1 The iron-catalyzed decarbonylative amination of various
benzoxazoles with DMFa
Key Laboratory of Green Chemistry and Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu, 610064, P. R. China. E-mail: xqyu@tfol.com;
Fax: (+86)28-85415886
w Electronic supplementary information (ESI) available: General and
experimental information on optimisation studies and procedures for
amination. See DOI: 10.1039/c0cc05811d
a
Conditions: 1 (0.5 mmol), DMF (2 mL), FeCl3 (0.25 equiv.),
imidazole (2.0 equiv.), 130 1C, 12 h, under air. Yields were isolated
yields.
c
3652 Chem. Commun., 2011, 47, 3652–3654
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Table 2 The iron-catalyzed decarbonylative amination of various
1,3,4-oxadiazoles with DMFa
Table 3 The iron-catalyzed decarbonylative amination of benzoxa-
zole with amidesa
a
Conditions: 3 (0.5 mmol), DMF (2 mL), FeCl3 (0.5 equiv.), imidazole
(2.0 equiv.), 130 1C, 36 h, under air. Yields were isolated yields.
a
Conditions: 1a (0.5 mmol), amides (2 mL), FeCl3 (0.25 equiv.),
imidazole (2.0 equiv.), 130 1C, 12 h, R1 = H, under air. Yields were
isolated yields. FeCl3 (0.5 equiv.), 24 h. FeCl3 (0.75 equiv.), 24 h.
b
c
successfully react with DMF to give moderate to good yields
(4a–4d, 4h). Substrates with a b-naphthyl group also gave a
comparable yield of 63% (4f). Comparing these to the
reactions employing benzoxazoles, a longer reaction time
(36 h) was needed and slightly lower yields (around 70%)
were achieved. Similar to substrate 1g, nitro-substituted
2-phenyl-1,3,4-oxadiazole 3e was also hard to process in the
reaction. The oxadiazole with an aliphatic substituent (3g)
could not react smoothly, and only a trace amount of product
was detected.
proceeded in acetonitrile in the presence of 1 equiv. of FeCl3
at 60 1C.12 As shown in Table 4, benzoxazole 1a could react
with morpholine to give product 5d in 42% yield. Piperidine
could give the related product 5c with a much higher yield
(72%). The phenyl substitution on the benzoxazole ring also
benefited the reaction, and the reaction between 1d and
morpholine resulted in product 6 in 75% yield. This is the
first example of iron-catalyzed direct C–H amination of azole-
type substrates using an amine. However, non-cyclic amines
seemed unsuitable for the reaction. Only N-methylbenzylamine
could react with benzoxazole, leading to 5l in poor yield.
Subsequently, the scope of formamides with different amino
moieties was expanded to test the generality of this synthetic
protocol, and the results are summarized in Table 3. For N,N-
disubstituted formamides, a cyclic amino moiety seemed to be
critical for good results. The formamides derived from cyclic
secondary amines, such as pyrrolidine, piperidine and morpholine,
could give much higher yields (of 5b–5d, respectively) than
that derived from linear amine (N,N-diethylformamide,
leading to 5a). This might be attributed to the smaller steric
hindrance on the N atom of the cyclic secondary amines. The
best isolated yield was up to 95% (5c) in the reaction between
benzoxazole and the piperdine-derived formamide. On the
contrary, for the N-monosubstituted formamides, it’s interesting
to find that the more bulky groups on the N atom led to a
better yield (5e–5i). Increasing the catalyst loading to
0.5 equiv., a reaction employing a formamide derived from
benzylamine could give a related product in 85% yield (5k).
Additionally, instead of DMF, N,N-dimethyl acetamide
(DMA) was first employed for the reaction, and a moderate
yield (59%) of product 2a was obtained .
Table 4 The iron-mediated direct amination of benzoxazole with
aminesa
Compared to amides, such as DMF, most amines with
higher molecular weights are suitable for direct use in the
reaction. A preliminary study was carried out for the reaction
between (phenyl)benzoxazole and several amines. After
optimization of the reaction conditions, these reactions
a
Conditions: 1 (1.5 equiv.), amine (0.5 mmol), FeCl3 (1.0 equiv.),
imidazole (2.0 equiv.), CH3CN (2 mL) , 60 1C, 12 h. Yields of isolated
product shown.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3652–3654 3653

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This work was financially supported by the National
Science Foundation of China (Nos. 20972104, 20902062, and
20725206), the Program for Changjiang Scholars in China.
We also thank the Analytical & Testing Center of Sichuan
University for NMR analysis.
Notes and references
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Scheme 1 A proposed pathway of the amination reaction.
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In any case, this synthetic protocol might be a potential
method for this type of direct amination.
Although systematic studies are required to elucidate the
mechanistic details of the direct amination of benzoxazoles, a
proposed mechanism is presented in Scheme 1. It is shown that
benzoxazole was firstly attacked by a Lewis acid to form
intermediate 7. In the presence of imidazole, this formed an
amine in situ, which acted as a nucleophile that could then
attack the 2-position of benzoxazole to generate precursor 8.
Finally, oxidation of 8 led to the rearomatized product. We
speculate that in this reaction, iron(III) species acted as the
Lewis acid, which activated the C-2 position of the benz-
oxazole and oxidant, which completed the final rearomatization.
Meanwhile, oxygen might mainly act as a co-oxidant to
transfer iron(II) and regenerate the trivalent iron species. In
the absence of oxygen, only a 30% yield was obtained in the
reaction involving DMF with 0.5 equiv. of FeCl3, and the yield
increased to 74% in the presence of air (ESIw, Table S1, entries
11 and 17). Similarly, the reaction using morpholine as the
substrate could also benefit from oxygen, and the use of
an oxygen balloon could increase the yield from 42% (5d,
Table 4) to 57%, while only a 14% yield was obtained in the
absence of oxygen.w A radical scavenger effect was also
investigated to study the reaction further by using 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO).w Results indicated
that TEMPO only inhibited the decarbonylation of
formamides, and it was possible that no radical was produced
in the amination process.
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In summary, a new catalytic system for decarbonylative
coupling between azoles and formamides was developed.
Moderate to good results were achieved for a series of
substrates. In comparison with previously reported systems,
more inexpensive and accessible iron salts were used as
the catalyst, and relatively mild and easily handled reaction
conditions, without additional oxidant, were employed. More-
over, instead of amides, several amines were also found to be
beneficial for the direct amination. Further studies to elucidate
the mechanism and to expand the synthetic scope of this
reaction are currently under way.
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12 Optimization studies of the direct amination of benzoxazoles with
formamides or amines were carried out. See ESIw.
c
3654 Chem. Commun., 2011, 47, 3652–3654
This journal is The Royal Society of Chemistry 2011