Silver-mediated direct amination of benzoxazoles: Tuning the amino group source from formamides to parent amines

Article abstract of DOI:10.1002/anie.200903957

Formamides or parent amines were used as an amino group source for the silver-mediated amination of benzoxazoles. Although reactions with formamides proceeded at high temperatures, the direct amination with amines took place under much milder conditions (

Full text of DOI:10.1002/anie.200903957

Angewandte
Chemie
DOI: 10.1002/anie.200903957
À
C N Bond Formation
Silver-Mediated Direct Amination of Benzoxazoles: Tuning the Amino
Group Source from Formamides to Parent Amines**
Seung Hwan Cho, Ji Young Kim, S. Yunmi Lee, and Sukbok Chang*
Dedicated to Professor Sunggak Kim
À
The construction of C N bonds of heteroaromatic com-
pounds is a highly important transformation in synthetic
chemistry since it can offer nitrogen-containing molecules of
great interest in biological, pharmaceutical, and materials
sciences.[1] During the past decades, remarkable progresses
À
have been made in the metal-facilitated C N bond-forming
reactions such as hydroamination[2] or oxidative amidation[3]
of double or triple bonds as well as the Buchwald–Hartwig-
type cross couplings.[4] Despite these significant advances,
direct installation of amino groups or their surrogates on aryl
Scheme 1. Decarbonylative amination of benzoxazole (1a).
À
or alkyl C H bonds is still challenging. To meet this demand,
even in the absence of the palladium catalyst and with slightly
higher yields.
a new approach involving oxidative addition of amino or
amido moieties into hydrocarbons has been extensively
studied.[5,6] In particular, site-selective amination of preor-
Encouraged by these preliminary result, we subsequently
tried to optimize the decarbonylative amination conditions
using benzoxazole (1a) in neat DMF (40 equiv),[13] as shown
in Table 1. Although no desired product was obtained in the
absence of the silver salt or the acid additives (entries 1 and
2), addition of certain types of carboxylic acids promoted the
transformation in the presence of silver salts (entries 3–8).[14]
Among various acids examined, p-anisic acid turned out to be
most effective for the amination reaction (entry 8). Catalytic
amounts of Ag2CO3 did not furnish the desired product
(entry 9), thus indicating that the use of stoichiometric
amounts of silver salts is essential for smooth conversion
under these reaction conditions.[15] In addition, other silver
sources such as Ag2O, AgOAc, AgOTf (Tf = triflate), or AgF
(entry 10) were less effective when compared to Ag2CO3.[13]
À
ganized arenes through catalytic C H bond activation was
recently developed.[6] An ortho-selective amination of naph-
thols through thermal cleavage of disubstituted hydrazines
was also reported.[7] Most recently, Mori and co-workers have
reported an oxidative amination of azoles using copper salts
at high temperature ( ꢀ 1408C).[8] Herein, we describe an
À
unprecedented silver-mediated C N bond formation of
benzoxazoles by decarbonylative coupling with formamides.
On the basis of mechanistic considerations, we have also
developed a direct amination protocol with parent amines
under very mild reaction conditions.[9]
À
In line with our recent efforts on metal-catalyzed C H
bond functionalization,[10] we wondered whether subjection of
electron-rich heteroarenes to Pd/Ag-catalytic systems in the
presence of formamides could provide amidated products
(Scheme 1).[11] To our surprise, when benzoxazole (1a) was
treated with N,N-dimethylformamide (DMF) using the Pd-
(OAc)2/Ag2CO3 system in the presence of an acetic acid
additive, 2-aminated benzoxazole 2a was obtained as a single
product, albeit in moderate yield. In contrast, no amidated
product 3a was observed under other reaction conditions
examined.[12] Subsequent studies revealed that the unex-
pected decarbonylative amination reaction also proceeded
Table 1: Optimization of reaction conditions.[a]
Entry
Silver salt
Acid additive
Yield [%][b]
1
2
3
4
5
6
7
8
none
none
none
CF3CO2H
CH3CO2H
<1
<1
<1
44
58
54
71
78
<1
30
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgF
C6H5CO2H
[*] S. H. Cho, J. Y. Kim, S. Y. Lee, Prof. Dr. S. Chang
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, 305-701 (Republic of Korea)
Fax: (+82)42-350-2810
(4-NO2)C6H4CO2H
(4-Me)C6H4CO2H
(4-MeO)C6H4CO2H
(4-MeO)C6H4CO2H
(4-MeO)C6H4CO2H
9[c]
10[d]
E-mail: sbchang@kaist.ac.kr
[**] This research was supported by a Korea Research Foundation Grant
(KRF-2008-C00024, Star Faculty Program) funded by the Korean
Government.
[a] Reaction conditions: 1a (0.5 mmol), DMF (40 equiv), Ag salt
(2.0 equiv), acid additive (5.0 equiv) at 1308C for 12 h. [b] Yield is
based on 1H NMR spectroscopy. [c] 0.1 equivalents of Ag2CO3 were used
relative to 1a. [d] 4 equivalents of Ag salt were used.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903957.
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Under the optimized reaction conditions, we
explored the substrate scope of benzoxazoles in the
decarbonylative amination using DMF (Scheme 2).
Benzoxazoles bearing substituents with diverse elec-
tronic properties such as methoxy (2b), methyl (2c),
and phenyl groups (2d) all smoothly reacted with
DMF to provide the desired products in high yields.
No significant rate difference was observed between
these substituted substrates. Interestingly, a labile
substituent such as chloro group (2e) at the C5
position of benzoxazole was tolerated under the
present reaction conditions. However, a reaction with
5-nitrobenzoxazole (2 f) afforded the corresponding
product with a slightly lower yield.
2-Aminobenzoxazoles bearing substituents at the
C4- or C6-positions were also readily obtained with
similar efficiency (2g and 2h). Notably, when benzo-
thiazole was subjected to the reaction conditions, a
C2-aminated product (2i) was selectively obtained in
a synthetically acceptable yield, thus demonstrating
Scheme 3. Decarbonylative amination with formamides. [a] Reaction conditions:
1d (0.5 mmol), formamide (25 equiv), Ag2CO3 (2.0 equiv), p-anisic acid
(5.0 equiv) at 1308C for 12 h. Yield of isolated product shown in brackets.
[b] 40 equivalents of formamide was used. Boc=tert-butoxycarbonyl.
substrates bearing an amido or ester functional group (4h and
4i).
Meanwhile, we were pleased to observe that when an
optically active formamide, (R)-N-methyl-N-(1-phenylethyl)-
formamide, was treated with 5-phenylbenzoxazole (1d), the
corresponding product 4j was obtained in good yield without
racemization [Eq. (1)].[17] This result is significant since the
present procedure can also be utilized for the introduction of
an optically active amino group onto heteroarenes. 2-Amino-
benzoxazole derivatives are of great interest in medicinal
Scheme 2. Decarbonylative amination with heteroarenes. [a] Reaction
conditions: 1 (0.5 mmol), DMF (40 equiv), Ag2CO3 (2.0 equiv), p-anisic
acid (5.0 equiv) at 1308C for 12 h. Yield of isolated product shown in
brackets. [b] The reaction was carried out for 36 h. [c] 4-Toluic acid
(5.0 equiv) was used.
chemistry, and they have been important targets in combina-
torial approaches.[18]
Although comprehensive studies are required to elucidate
the mechanistic details of the present reaction, a tentative
proposal is presented in Scheme 4. It is envisioned that the
formamide substrates are first decarbonylated by the action
of carboxylic acid additives to afford amines (or their salts),[19]
which subsequently react with protonated benzoxazoles 5
leading to a putative 2-aminobenzoxazoline intermediate 6.
Rearomatization of 6 could be facilitated by a silver species,
presumably through a single electron transfer to afford the 2-
aminated product 7.[15,20] Kinetic isotope competition experi-
ments were carried out for the reaction of 5-methylbenzox-
azole and its 2-deuterated derivative with DMF to reveal the
intermolecular kinetic isotope effects (kH/D) to be 0.9,[13]
that the present protocol can be readily extended to other
types of heteroarenes.[16]
We next examined the scope of formamides in the silver-
mediated amination of benzoxazoles (Scheme 3). Various
types of formamides were readily employed and afforded
products bearing 2-(N,N-diethylamino) (4a), pyrrolidinyl
(4b), piperidinyl (4c), and morpholinyl (4d) groups in good
yields. High efficiency in the amination reaction was main-
tained even in the case of N-monoalkylformamide substrates.
For instance, 2-aminobenzoxazole derivatives substituted
with N-methyl (4e), tert-butyl (4 f), or cyclohexyl (4g)
groups were easily obtained, thus offering an additional
opportunity for further manipulation of the products
obtained. However, no product was afforded with formamide
À
thereby implying that a silver-mediated C H activation
pathway is less likely.
On the basis of the proposed mechanism, we envision that
amines (or their salts) could be directly employed in the
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was directly introduced at the 2-postion of a benzoxazole
derivative without racemization (8g). In addition, 2,2’-(1,4-
piperazinediyl)bisbenzoxazole (8h) was efficiently prepared
in one-pot by simply controlling the stoichiometry of reac-
tants, albeit under slightly more demanding conditions. It was
intriguing to observe that 6-methylbenzothiazole reacted with
an amine and gave the desired product (8i) using silver(I)
oxide in the presence of a catalytic amount of zinc(II) acetate
instead of acid additives.[21]
As an interesting application of the present reaction, the
coumarinyl piperazine derivative 9 was treated with benzox-
azole (1a) under the direct amination conditions. The
reaction proceeded smoothly and afforded the corresponding
2-aminobenzoxazole product 10, which is known to display
highly potent anti-HIV and antitumor activities [Eq. (2)].[22]
In summary, we have disclosed the first example of silver-
mediated amination of benzoxazoles using formamides or
parent amines as an amino group source. Although reactions
with formamides proceed at high temperatures, the direct
amination with amines takes place under much milder
conditions to afford 2-aminobenzoxazoles bearing a wide
range of functional groups, thereby opening a new avenue for
Scheme 4. A proposed pathway of the amination reaction.
amination of benzoxazoles. Moreover, milder reaction con-
ditions were also anticipated by the direct use of amines
because the involvement of slow decarbonylation of forma-
mides can be avoided in this case (as compared to the use of
formamides).
Indeed, we were delighted to find that when
amines were treated with benzoxazoles, 2-ami-
nated products were obtained in good yields
(Scheme 5).[13] The silver-mediated reaction of
benzoxazoles with amines proceeded smoothly
under much milder reaction conditions as com-
pared to formamides: temperatures (608C for
amines versus 130–1408C for formamides),
number of equivalents of the amine sources (0.8–
1 equiv for amines versus 40 equiv for forma-
mides), or acid additives (2 equiv for amines
versus 5 equiv for formamides). It should also be
mentioned that organic solvents could be
employed in the reaction with amines to make
the direct amination reaction more versatile (i.e.,
solid substrates can be used).
The fact that the use of carboxylic acid
additives was also important in the reaction with
amines to achieve high efficiency suggests that
Scheme 5. Direct amination using parent amines. [a] Reaction conditions: 1
(1.2 equiv), amine (0.5 mmol), Ag2CO3 (1.2 equiv), benzoic acid (2.0 equiv) in
CH3CN at 608C for 12 h. Yield of isolated product shown in brackets. [b] Enantio-
meric excess (ee) of both amine reactant and product was 96%. [c] p-Anisic acid
(2.0 equiv) was used instead of benzoic acid. [d] The reaction was carried out for
24 h. [e] 3.0 equivalents of 1a, benzoic acid, and Ag2CO3 were used relative to the
amine. [f] Reaction conditions: 1 (1.2 equiv), amine (0.5 mmol), Ag2O (2.0 equiv),
Zn(OAc)2 (0.2 equiv) in CH3CN at 808C for 12 h.
protonated benzoxazole 5 (Scheme 4) would be
involved as a key species—even in the direct
amination reaction discussed in our mechanistic
proposal. We observed that the new reaction
conditions were compatible with a wide range of
functional groups. For instance, benzoxazoles
bearing 2-amino groups such as morpholinyl-
(8a), N,N-diallyl (8b), or piperazinyl (8c) moieties
could be isolated in high yields. The tetrahydro-
quinolinyl group was readily introduced at the 2-
position of benzoxazole (8d) in good yield.
Although no aminated products were obtained
from the reaction with formamides containing
amido or ester groups (Scheme 3, 4h and 4i), the
direct use of amines resulted in high yields of the
corresponding benzoxazoles (8e and 8 f) under
mild reaction conditions. An optically active amine
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the regioselective formation of C N bonds through direct
2
À
C(sp ) H functionalization of heteroarenes.
Received: July 19, 2009
Revised: September 24, 2009
Published online: October 23, 2009
À
Keywords: amination · benzoxazoles · C N coupling ·
.
formamides · silver
[13] The same kinetic isotope effect experiments were also per-
formed using 5-methylbenzoxazole and its 2-deuterated com-
pound with morpholine to give a value of kH/D = 1.07. See the
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