S. Wang et al. / Tetrahedron Letters 54 (2013) 6233–6236
6235
Table 4
5 mol% nBu4NI
O
O
N
Reaction between benzaldehyde and N-methylanilinea
TBHP (4 equiv)
N
Et3N
N
AcOH ( 2 equiv )
CH3CN,90°C
Me
N
H
H
6
2x
2.0 equiv
7
N
CHO
N
50% yield
nBu4NI, TBHP
1.0 equiv
O
O
EA, 90°C
1a
3a
5
4
Scheme 1. Amination of benzoxazole with tertiary triethylamine.
Entry
nBu4NI (mol %)
TBHP (equiv)
Yield of 3ab (%)
Yield of 5b (%)
1
2
3
4
5
2.5
10
20
2.5
2.5
4
4
4
2
6
65
70
59
69
47
15
27
22
20
O
OH
Ph
PhCHO
TBHP
Ph
Ph
Ph
Ph
Ph
NH
N
Ph
N
4
D
3
CH2O
OH
Trace
a
Reaction conditions: 1a (2.5 mmol), 2a (0.5 mmol), nBu4NI, TBHP, EtOAc (3 ml),
90 °C, 24 h, TBHP: tert-Butyl hydroperoxide 70% in water.
N
N
tBuO
tBuOOH
2
b
Isolated yield.
C
H2O
1/2 I2
I
Ph
amidation with benzaldehyde to yield 3r gracefully. So far, the flu-
oro group has been completely tolerated in both aldehyde and
amine. To investigate the steric effect, substituents on the different
positions of aniline or benzaldehyde were screened (3d, 3h, 3i, 3p,
3s, and 3t). The results showed an obvious yield decrease when the
substituent was moved from para-position to ortho-position.
Meanwhile, two bulky isopropyls were introduced into the ortho-
position of N,N-dimethylaniline to examine the effect of a larger
steric hindrance. Surprisingly, the desired hindered amide product
3u was isolated in 99% yield. Combining these two results, a con-
clusion is drawn that the steric hindrance impact is minor, while
the electronic effect of the functional groups attached to the arene
ring is outstanding. At last, other N-substituted amines also under-
went the reaction smoothly by oxidative dealkylation. Not only
aromatic amines but also aliphatic amines such as triethylamine
and tributylamine were used in the amidation reactions catalyzed
by nBu4NI to obtain 3x and 3y in moderate yields .
Ph
N
N
B
A
Scheme 2. Proposed reaction mechanism.
(Scheme 1). To the best of our knowledge, the nBu4NI-catalyzed di-
rect amination of benzoxazole 6 using tertiary amines as nitrogen
sources has never been reported.
A tentative mechanism for the oxidative amidation of aldehydes
with tertiary amines as nitrogen sources is proposed in Scheme 2.
Initially, a reaction between an iodide (IÀ) ion and TBHP provides a
tert-butyloxy radical and iodine (I2).12b The generated radical ab-
stracts a hydrogen atom from the C–H bond adjacent to a nitrogen
atom to afford radical A, followed by oxidation to afford iminium
ion B. Subsequently, hydrolysis of B through C affords secondary
amine 4. Theoretically, a further hydrogen abstraction and one-
electron oxidation is feasible, such as the reaction in Table 4. In
fact, once it is produced, amine 4 immediately combines with alde-
hyde which is in large excess relative to the ‘slow’-releasing amine.
Finally, the desired amide product 3 is obtained after an oxidation
process of the intermediate D.
In conclusion, we have developed a novel amidation reaction of
aromatic aldehydes with tertiary amines in the absence of metal. A
variety of aldehydes and tertiary amines could be used to obtain
the related amides in moderate to excellent yields, and only cheap
and nontoxic nBu4NI was used as the catalyst. Further investiga-
tion on the reaction is ongoing in our laboratory.
To clarify the possible reaction pathway, the reaction between
benzaldehyde and N-methylaniline was optimized. To our delight,
two kinds of products 3a and 5 were formed in good yields and this
is sufficient evidence toward the direct acylation of N–H under our
catalytic system. Logically, the minor product 5 should be obtained
by oxidative amidation of benzaldehyde 1a with phenylamine
which was generated from demethylation of N-methylaniline 4.
This does accord with Reddy’s report about oxidative amidation
of aldehydes with primary amines catalyzed by KI-TBHP in 2008.
10b
Generally, catalyst loading and the quantity of oxidant have a
significant effect on the yield of these two amides. An excellent
overall yield of 3a and 5 was achieved in the presence of 4 equiv
of TBHP by using 10% nBu4NI as catalyst (Table 4, entry 2). The ratio
between 3a and 5 was steady except entry 5 in which TBHP was
increased to 6 equiv.
Acknowledgments
This work was financially supported by the National Program
on Key Basic Research Project of China (973 Program,
2013CB328900) and the National Science Foundation of China
(Grant Nos. 21202107 and 20121001).
With the proven fact that the secondary amines generated
in situ from tertiary amines have been utilized effectively in hand,
we exploited other reactants which could combine these ‘slow’-
releasing amines. In our previous study, we have reported iron-cat-
alyzed direct amination of benzoxazole 6 using secondary amines
as nitrogen sources.18 Meanwhile, iodine- or nBu4NI-catalyzed
benzoxazole 6 C–H amination with amines was also presented by
Prabhu and Nachtsheim respectively.19 Based on these develop-
ments, we envisioned that what if the tertiary amines might sub-
stitute for secondary amines to react with benzoxazole 6.
Disappointedly, we did not isolate the desired product when benz-
oxazole 6 was mixed into N,N-dimethylaniline 2a under our opti-
mized conditions. This result was coincident with previous
reports that phenylamine was inert in the oxidative amination of
benzoxazole. However, triethylamine 2x could react smoothly with
benzoxazole 6 with a 50% yield using a slightly different condition
Supplementary data
Supplementary data associated with this article can be found, in
References and notes