Copper-catalyzed aerobic aliphatic C-H oxygenation directed by an amidine moiety

Article abstract of DOI:10.1021/ja305833a

A method for the oxygenation of tertiary C-H bonds of N-alkylamidines and N-(2-alkylaryl)amidines is described that utilizes the CuBr?SMe ₂/2,2′-bipyridine catalytic system under an O₂ atmosphere and provides dihydrooxazoles and 4H-1,3-benzoxazines. The oxygen atom is incorporated from atmospheric molecular oxygen during the present process.

Full text of DOI:10.1021/ja305833a

Communication
pubs.acs.org/JACS
Copper-Catalyzed Aerobic Aliphatic C−H Oxygenation Directed by
an Amidine Moiety
Yi-Feng Wang,† Hui Chen,† Xu Zhu, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A method for the oxygenation of tertiary
C−H bonds of N-alkylamidines and N-(2-alkylaryl)-
amidines is described that utilizes the CuBr·SMe2/2,2′-
bipyridine catalytic system under an O2 atmosphere and
provides dihydrooxazoles and 4H-1,3-benzoxazines. The
oxygen atom is incorporated from atmospheric molecular
oxygen during the present process.
liphatic C−H bonds are omnipresent functions in organic
Amolecules, and those without activation by the adjacent
functional groups (e.g., carbonyl groups) are extremely stable
and inert even under strongly acidic and basic reaction
conditions. Although various approaches for oxidative function-
alization of unactivated aliphatic C−H bonds with transition-
metal catalysts have recently been developed,1,2 exploitation of
the catalytic reaction that enables the realization of oxidative
C−H functionalization in a predictable chemo- and regiose-
lective manner is still one of the most challenging issues in
organic synthesis. Especially, catalytic systems capable of
performing selective C−H oxidation in substrates bearing
electron-rich nitrogen functional groups are extremely scarce.
Herein we report a copper-catalyzed aerobic C−H oxygenation
of aliphatic C−H bonds (resulting in C−O bond formation)
directed by an amidine moiety that is easily installed on primary
amines.3
We have been interested in copper-mediated oxidative
functionalization of carbon−carbon unsaturated bonds as well
as C−H bonds under aerobic conditions,4,5 and we recently
%) and 2,2′-bipyridine (bpy) (20 mol %) in dimethyl sulfoxide
(DMSO) at 100 °C under an O2 atmosphere, a C−H
oxygenation product, dihydrooxazole 2a, was isolated in 67%
yield (entry 1). An isotope-labeling experiment using an 18O2
atmosphere revealed that the oxygen atom in the resulting C−
O bond was derived from atmospheric O2 (see entry 11), which
is particularly rare in the literature precedents for catalytic C−H
oxygenation.8,9 This unprecedented aerobic C−H oxygenation
reaction to form dihydrooxazole 2a prompted us to optimize
the reaction conditions. Other Cu sources showed the catalytic
activity regardless of their oxidation state (either I or II)
(entries 2−5), and the highest yield was provided by
CuBr·SMe2 (entry 2). Switching the solvent to N,N-
dimethylformamide (DMF) decreased the yield of 2a (entry
reported the intramolecular [3 + 2] annulation reaction of N-
pentenylamidines to give bi- and tricyclic amidines (eq 1).4a
The reaction mechanism includes putative nitrene intermediate
B (with its resonance form C), which might be formed by
stepwise single-electron oxidation and deprotonation via 1,3-
diazaallyl radical A. Stimulated by this discovery, we then
became interested in the chemical reactivity of aliphatic C−H
bonds toward the amidine moiety under Cu-catalyzed aerobic
conditions, envisioning C−H radical abstraction (i.e., a 1,5-
hydrogen radical shift)6 via 1,3-diazaallyl radical A and C−H
amination7 via nitrene species B as possible reaction pathways
(eq 2). In fact, we have found that the reactions proceed
exclusively via the 1,5-hydrogen radical shift from 1,3-diazaallyl
radical A to give C−H oxygenation products.
We began our investigation with the copper-catalyzed
aerobic reactions of N-(2,2-diphenylethyl)benzimidamide (1a)
(Table 1). Interestingly, when 1a was treated with CuI (20 mol
Received: June 15, 2012
Published: July 12, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
a b
,
Table 1. Optimization of the Reaction Conditions
Chart 1. C−H Oxygenation of N-Alkylamidines
temp time
yield
b
entry
Cu salt
Cul
additive
solvent
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
bpy
bpy
bpy
bpy
bpy
bpy
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
10
5
3
67
CuBr·SMe2
CuCI
70
56
62
37
57
53
70
77
75
5
c
c
CuBr2
100
100
100
100
100
80
4
Cu(OAc)2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
4
2
c
DABCO DMSO
2
phen
bpy
bpy
bpy
DMSO
DMSO
DMSO
2
24
24
24
d
10
80
f
11
DMSO/
PhCF3
80
79 (76 )
e
e
g
12
CuBr·SMe2
bpy
DMSO/
PhCF3
80
40
0
a
Unless otherwise noted, the reactions were carried out using 0.3
mmol of amidine 1 with 20 mol % CuBr·SMe2 and 20 mol % 2,2′-
bipyridine in 5:1 DMSO/CF3Ph at 80 °C under an O2 atmosphere.
Isolated yields are shown. The reaction was run at 100 °C.
Optically active 1f was used for the reaction and gave racemic 2f.
a
Unless otherwise noted, the reactions were carried out using 0.3
mmol of amidine 1a in solvent (0.05 M) at 60 °C under an O2
b
c
b
c
d
atmosphere. Isolated yields. 1H NMR yield. The reaction was
d
e
f
carried out under an air atmosphere. DMSO/PhCF3 = 5:1. Yield of
2a-18O when the reaction was carried out under an 18O2 atmosphere.
g
Scheme 1. Proposed Reaction Mechanism for the C−H
Oxygenation
The reaction was carried out under a N2 atmosphere.
6). Reactions with other types of nitrogen ligands, such as 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,10-phenanthroline
(phen), also gave moderate to good yields of 2a (entries 7 and
8). It was found that lowering the reaction temperature to 80
°C increased the reaction time but resulted in a better yield of
2a (entry 9). Reduction of the oxygen partial pressure by using
an air atmosphere (PO = 0.21 atm) did not affect the product
2
yield of 2a (entry 10). It was found that the cosolvent system of
5:1 DMSO/PhCF3 delivered a slightly better yield of 2a (entry
11). Under a N2 atmosphere, no reaction was observed even
after 40 h, and 1a was completely recovered (entry 12).
Using the CuBr·SMe2/2,2′-bipyridine catalytic system in 5:1
DMSO/PhCF3 solvent (Table 1, entry 11), we examined the
generality of this C−H oxygenation of N-alkylamidines 1 for
the synthesis of dihydrooxazoles 2 (Chart 1). Variation of the
R1 substituent of 1 showed that various aromatic rings,
including bromophenyl, naphthyl, and thienyl groups (for
2b−d), were tolerated and that an isopropyl substituent could
be introduced (2e). Starting from optically active amidine 1f
bearing a chiral tertiary carbon center,10 racemic dihydroox-
azole 2f was formed in 72% yield, suggesting that the present
process indeed involves a carbon radical intermediate.11
Amidines 1g and 1h with two successive tertiary carbons at
the 5- and 6-positions (marked in red and green, respectively)
relative to the amidine nitrogen at the 1-position (marked in
blue) selectively provided the corresponding dihydrooxazoles
2g and 2h. The reaction allowed the installation of an indole
motif (2i). 5,5-Dialkyloxazoles, including several spirocyclic
compounds, could be constructed in good to moderate yields
(2j−o). Introduction of a methyl group at R4 did not affect the
reaction (2p), while oxygenation of the secondary C−H bond
resulted in a low yield (2q).
of amidine 1 by higher-oxidation-state CuII species (described
as [CuII]) generated from CuIBr with molecular oxygen12
would provide 1,3-diazaallyl radical II, which may undergo a
1,5-H radical shift to afford tertiary carbon radical III.
Subsequently, III would react with molecular oxygen to give
superoxo radical IV, further Fenton-type fragmentation of
which would deliver Cu(II) alkoxide V.13 Finally, intra-
molecular nucleophilic attack of alkoxide V onto the amidine
moiety followed by elimination of ammonia would lead to the
formation of dihydrooxazole 2.14
Next, the reactivity of N-(2-isopropylphenyl)amidines 3 for
the present C−H oxygenation was examined (Scheme 2). In
this case, 4H-1,3-benzoxazines 4 were obtained via a 1,6-H
radical shift followed by oxygenation and cyclization. Brasche
and Buchwald15 reported the reaction of N-arylamidines in the
presence of 15 mol % Cu(OAc)2 and 5 equiv of AcOH in
DMSO at 100 °C under an O2 atmosphere, which provided
benzimidazoles via aromatic C−H amination, while the present
On the basis of these results, a possible mechanism is
proposed in Scheme 1. In this scenario, one-electron oxidation
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Journal of the American Chemical Society
Communication
Scheme 2. C−H Oxygenation of N-(2-
Isopropylphenyl)amidines
Chart 2. Transformation of 2 into Amino Alcohols
system interestingly afforded 4H-1,3-benzoxazines exclusively
via sp3 C−H oxygenation.
When N-(2,6-dimethylphenyl)amidine 3f was subjected to
the present reaction conditions, quinazoline 5f was formed in
49% yield via formal C−H amination, which could be achieved
in a stepwise manner through oxygenative CO bond
formation on one of the methyl groups and successive
dehydrative cyclization of the amidine moiety with the carbonyl
group (Scheme 3).
a
Method I: the reaction was carried out by initial treatment of AlCl3 (1
equiv) in tetrahydrofuran (THF) with LiAlH4 (3 equiv) at 0 °C
Scheme 3. Formation of a Quinazoline via C−H Amination
followed by addition of dihydrooxazole 2 and stirring at room
b
temperature. Method II: unless otherwise noted, the reaction was
carried out using 5 equiv of HCl (1 M) in THF at room temperature.
c
See the Supporting Information for more details. The reaction was
carried out using method II with 10 equiv of HCl (1 M) at 65 °C. 2n
was recovered in 78% yield.
ditions has been exploited for the synthesis of dihydrooxazoles
and 4H-1,3-benzoxazines. The dihydrooxazoles could be further
converted into N-benzyl- and N-acylamino alcohols by
treatment with AlH3 and aqueous HCl, respectively. We are
currently engaged in further synthetic applications of the
amidine moiety as a potential directing group for other types of
C−H oxidation reactions.
Vicinal amino alcohol functionalities are privileged as the
structural elements in biologically active molecules as well as
ligands for transition-metal catalysts.16 Having developed a
method for the preparation of dihydrooxazoles 2 through the
present aerobic C−H oxygenation, we finally explored their
concise transformation into vicinal amino alcohols (Chart 2). It
was found that reduction of 2 by aluminum hydride (AlH3,
prepared in situ from LiAlH4 and AlCl3)4a,17 proceeded
smoothly to give N-benzylamino alcohols 6 (the reduction of
2e provided N-isobutylamino alcohol 6e). On the other hand,
acid-mediated hydrolysis18 of 2 provided N-acylamino alcohols
7, although the hydrolysis of 2n was very sluggish, probably
because of steric hindrance by the adamantyl moiety. Taking
advantage of the ready accessibility of amidines 1 from the
corresponding primary amines allows the overall trans-
formation to be summarized as β-C−H hydroxylation of
primary amines, where the amidine moiety plays the role of a
directing group for C−O bond formation as well as a potential
protecting group for the amine.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
shunsuke@ntu.edu.sg
■
Author Contributions
†Y.-F.W. and H.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University and the Singapore Ministry of
Education (Academic Research Fund Tier 2: MOE2012-T2-
1-014). We thank Dr. Yongxin Li and Dr. Rakesh Ganguly
In summary, amidine-directed C−H oxygenation of aliphatic
C−H bonds under copper-catalyzed aerobic reaction con-
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Journal of the American Chemical Society
Communication
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