Oxidative cleavage of benzylic C-N bonds under metal-free conditions

Article abstract of DOI:10.1039/c4ob01633e

An interesting procedure for the oxidative cleavage of benzylic C-N bonds has been developed. Using TBAI as the catalyst and H₂O₂as the oxidant, various benzylamines were transformed into their corresponding aromatic aldehydes in moderate to good yields. Notably, this is the first example of an oxidative cleavage of benzylic C-N bonds under metal-free conditions.

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ARTICLE TYPE
Oxidative cleavage of benzylic C-N bond under metal-free conditions
a+
a+
a
a
a,b
Jin-Long Gong, Xinxin Qi, Duo Wei, Jian-Bo Feng, and Xiao-Feng Wu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
An interesting procedure for the oxidative cleavage of
examined the amount of TBHP, 4 equiv of TBHP gave better
benzylic C-N bond has been developed. By using TBAI as the 50 yield of aldehyde (Table 1, entry 2). It was noted that the yield of
catalyst and H O as the oxidant, various benzyl amines were
product was poor without TBAI (Table 1, entry 4); this result
indicated that TBAI was indispensable for the reaction. However,
the yield didn’t improve when increase the catalyst loading to 20
mol% (Table 1, entry 5). The employment of the temperatures to
80 C and 120 C made the product yield decreased (Table 1,
entries 6 and 7). Moreover, oxidants including di-tert-butyl
2
2
transformed into the corresponding aromatic aldehydes in
moderate to good yields. Notably, this is the first example on
oxidative cleavage of benzylic C-N bond under metal-free
conditions.
1
0
5
6
6
5
0
5
peroxide (DTBP) and H O were examined (entry 8-10), we were
Benzylic amine is a class of prevalent functional group in organic
chemistry, which has been used as ideal protecting group and
2
2
delighted to find that the yield of benzaldehyde had significant
change by using H O as the oxidant, especially with 8 equiv. of
1
substrates in organic synthesis. Additionally, benzyl amines are
2
2
H O , afforded the desired product in 87% yield (Table 1, entry
1
2
2
3
3
4
4
5
0
5
0
5
0
5
present in natural products, pharmaceutical and bio-active
2
2
2
1
2). Furthermore, we also investigated the efficiency of some
molecules as well. An effective and selective procedure for the
other catalysts, such as I and KI, provided the corresponding
cleavage of C-N bond offers more options to excess their
derivatives and raising the potential to find alternative core
structure with better bio-activities. On the other hand, aromatic
aldehydes represent a high value class of compounds in organic
chemistry, which could be widely used as an active formyl unit in
the synthesis of other organic compounds, such as drugs, spices,
dyes, pesticides and so on. Hence, a methodology based on
benzyl amines to aldehydes is necessary and important.
2
products in 83% and 62% yields (Table 1, entries 13 and 14). At
last, solvents screening (MeCN, DMSO, DMF, H O, 1,4-dioxane)
2
showed that DMAc is the optimal solvent for this transformation.
[a]
Table 1. Screening of reaction conditions.
th
Since the 20 century, provide ‘Green’ oxidation process has
become a hot issue in new methodology development as the
3
acceptance of ‘sustainable development’ by our community.
Thus, new reactions without the demand of expensive transition-
metal catalysts have drawn more and more attention from organic
Entry
Catalyst
mol%)
Oxidant
Temp
(C)
100
100
100
100
100
80
Yield 2a
[b]
(
(equiv)
(%)
4
chemists. For example, the combination of tetrabutylammonium
1
2
3
4
5
6
7
8
9
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (0)
TBHP (2)
TBHP (4)
TBHP (6)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
DTBP (4)
45
50
22
11
29
32
37
trace
59
70
87
83
62
iodide (TBAI) and tert-butyl hydroperoxide (TBHP) is of great
interest in oxidative transformation due to its inexpensive, high
5
efficiency and benign environmental impact. We have been
interested in developing cheap and green oxidation procedures
TBAI (20)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
6
during last two years. Oxidative procedures based on cheap
metal catalysts or without metal catalyst have been developed.
Here, we wish to report our recent results on the transition metal-
free oxidative transformation of N,N-dimethylbenzyl amines to
the corresponding aromatic aldehydes. By using TBAI as the
120
100
100
100
100
100
100
H
2
H
2
H
2
H
2
H
2
O
2
O
2
O
2
O
2
O
2
(4)
(6)
(8)
(8)
(8)
1
1
1
1
a
0
1
2
3
catalyst and H O2 as the green oxidant, benzyl amines were
2
selectively and effectively transformed into the corresponding
aldehydes in moderate to good yields.
Initially, we conducted the reaction by heating a solution of
N,N-dimethylbenzyl amine 1a in DMAc using 10 mol% TBAI
and 2 equiv of TBHP. Gratifyingly, we got benzaldehyde 2a in
I
2
(10)
KI (10)
Reaction conditions: 1a (1 mmol), catalyst, oxidant, DMAc (2 mL) for
b
2
4 h. GC yield.
70
4
5% yield (Table 1, entry 1). Encouraged by this result, we
employed N,N-dimethylbenzyl amine 1a as the model substrate to
optimize the reaction conditions (Table 1). Subsequently, we
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With the optimized reaction conditions in hand, we employed
TBAI/H O as the catalyst system to study the substrate scope of
2
2
benzyl amines. As shown in Table 2, the reactions proceeded
smoothly with a variety of functional groups on the benzene ring.
The substrates bearing chloro-, bromo- at para position were
compatible under standard conditions (Table 2, entries 2 and 3).
Furthermore, nitro- and cyano- substitutions can give the desired
aldehydes in good yields as well, especially cyano- group which
can be transformed into the corresponding primary amides in the
presence of oxidant (Table 2, entries 6 and 7). A comparable
product yield to electron-withdrawing group was observed when
the para position was substituted with electron-donating group,
such as methoxy, tert-butyl moieties (Table 2, entries 9 and 10).
However, substrates containing para-methyl group provided the
corresponding product with slightly lower yield (Table 2, entry
5
0
5
0
Scheme 1. Formation of benzaldehyde from primary and
secondary benzyl amines.
3
5
1
1
2
Based on these results, a possible reaction mechanism is
shown in Scheme 2. First, decomposition of H O by TBAI to
2
2
generate hydroxy radical, which abstracts hydrogen of benzylic
C-H bond and forms radical A. Radical A is then oxidized to
iminium ion B, followed by hydrolysis to afford the final product
40
2
.
8
). It is noteworthy that those bearing para- and meta-substituted
aryl groups worked better than ortho-substitution, probably due
to the steric hindrance (Table 2, entries 3-5 and 10-12). We also
tested the para-vinylphenyl substrate, which afforded the wished
aldehyde in 50% yield (Table 2, entry 13). Furthermore,
naphthalene and biphenyl substituents were also investigated and
resulted in 66% and 68% yields respectively (Table 2, entries 14
and 15).
Scheme 2. Proposed reaction mechanism.
[
a]
2
5
Table 2. Oxidative cleavage of benzylic C-N bond.
Conclusions
4
5
5
6
5
0
5
0
In summary, a practical metal free strategy has been achieved for
the synthesis of aromatic aldehydes using various N,N-dimethyl
benzyl amines as starting materials. The reaction was mediated
[
b]
Entry
1
Ar
Yield (%)
85
by an inexpensive and environmental friendly TBAI/H O system
2 2
and provided the benzaldehyde derivatives with moderate to good
yields. Notably, this is the first example on oxidative cleavage of
benzylic C-N bond under metal-free conditions.
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
6 5
C H
4-BrC
6
H
4
66
4-ClC
3-ClC
2-ClC
6
6
6
H
4
H
4
H
4
57
58
General reaction procedure: Under air, in a 50 mL tube, TBAI
52
(
10 mol%), and a stirring bar was added. Then DMAc (2 mL),
4-NO
4-CNC
4-MeC
4-t-BuC
2
C
6
H
4
61
H O (8 equiv.), substrate (1 mmol) were injected by syringe.
1g
1h
1i
6
H
4
62
2
2
o
Then close the tube and keep the final solution at 100 C for 24 h.
When the reaction was finished, the solvent was removed in
vacuo, and the residue was purified by flash column (petroleum
ether/ethyl acetate). All the products are commercially available.
6
H
4
40
6
H
4
66
1
1
1
1
1
1
0
1
2
3
4
5
1j
4-OMeC
3-OMeC
2-OMeC
6
6
6
H
4
H
4
H
4
63
1k
1l
59
40
Notes and references
1m
1n
1o
4-VinylC
naphthyl
biphenyl
6
H
4
50
66
a
68
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou, Zhejiang Province, People’s Republic of China,
a
2 2
Reaction conditions: 1a (1 mmol), TBAI (10 mol%), H O (8 equiv),
3
10018
o
b
DMAc (2 mL), 100 C for 24 h. Isolated yield.
6
7
5
0
E-mail: xiao-feng.wu@catalysis.de
b
+
Leibniz-Institut für Katalyse an der Universität Rostock, Albert-
Einstein-Straße 29a, 18059 Rostock (Germany)
These authors contributed equally to this work.
Furthermore, primary and secondary benzyl amines which are
represented by benzyl amine and N-methyl benzyl amine were
studied as well (Scheme 1). Only trace amount of benzaldehyde
was obtained from benzyl amine, while the reaction with N-
methylbenzyl amine could afforded benzaldehyde in 50% yield.
Acknowledgments: The authors thank the financial support from Zhejiang
Sci-Tech University (1206838-Y). We appreciate the general support
from Professor Matthias Beller in LIKAT.
† Electronic Supplementary Information (ESI) available: [Analytic datas
and NMR spectrums]. See DOI: 10.1039/b000000x/
3
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