Peroxidation of C-H bonds adjacent to an amide nitrogen atom under mild conditions

Article abstract of DOI:10.1021/ol5012168

Under mild conditions, the oxidative functionalization of C-H bonds adjacent to an amide nitrogen atom was achieved. tert-Butylperoxyamido acetal was obtained in high yields and could be further converted into α-substituted amides by treatment with Grigna

Full text of DOI:10.1021/ol5012168

Letter
pubs.acs.org/OrgLett
Peroxidation of C−H Bonds Adjacent to an Amide Nitrogen Atom
under Mild Conditions
Hui Yu* and Jie Shen
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai, 200092, P. R. China
Key Laboratory of Yangtze River Water Environment, Ministry of Education, Siping Road 1239, Shanghai, 200092, P. R. China
S
* Supporting Information
ABSTRACT: Under mild conditions, the oxidative function-
alization of C−H bonds adjacent to an amide nitrogen atom
was achieved. tert-Butylperoxyamido acetal was obtained in
high yields and could be further converted into α-substituted
amides by treatment with Grignard reagents.
n recent decades, catalytic functionalization reactions of C−
IH bonds adjacent to a nitrogen atom have received
considerable attention with noticeable progress having been
made.1 These reactions provide novel methods for the synthesis
of nitrogen containing compounds in an economically favorable
way by using environmentally benign processes. N-Aryl
substituted amines are appropriate substrates for the inves-
tigation of such reactions, such as N,N-dialkylanilines,2 N-aryl
tetrahydroisoquinolines (THIQ),3 glycine derivatives,4 and
aminoketones.5 Most of these reactions are believed to proceed
with the in situ generated iminium ion or imine as the
intermediate, which is subsquently attacked by a nucleophile to
form C−C, C−N, and C−P bonds. Although reasonable
amounts of synthetically meaningful compounds have been
prepared under mild conditions by such a strategy, one
drawback still exists in that it is difficult to remove the aryl
group from the obtained products, which has limited the
application of this methodology in organic synthesis.
However, these methods commonly require air- and moisture-
sensitive transition metal reagents, expensive oxidants, or a high
temperature.10 To the best of our knowledge, the preparation
of tert-butyloperoxyamido acetals directly from secondary
amides has not been reported on before. Herein, we describe
our work on the C−H bond peroxidation of amides under mild
conditions and its application in organic synthesis.
Initially, N-benzylbenzamide 1a was chosen as the model
substrate to optimize reaction conditions including the catalyst
type, solvent, and temperature. As shown in Table 1, the
reaction of 1a with 3.0 equiv of TBHP (70% solution in water)
was examined in CH3CN with copper salts (50 mol %) as the
catalyst at room temperature, and no reaction occurred (Table
1, entries 1−2). When I2 or NIS was used as the catalyst, the
Table 1. Screening of Reaction Conditions
Compared with the aryl group, the acyl group is a more
commonly used protective group for the synthesis of amine
derivatives for the convenient preparation and cleavage of
amides. Thus, functionalization of a C−H bond adjacent to the
nitrogen atom of an amide is of great importance in organic
synthesis and has attracted much interest in recent years.
Various methods for the direct functionalization of a C−H
bond adjacent to the nitrogen atom of an amide have been
reported on including (a) Mannich-type reactions of N-
acylglycine derivatives with aldimine or ketimine as inter-
mediates,4a,6 (b) Friedel−Crafts type arylation of amides in the
presence of a metal catalyst such as Fe or Cu,7 and (c) direct
sp3 C−H bond activation of amides using an Ir(I) complex as
the catalyst.8 A developed indirect strategy that differs from
these direct functionalization processes is to convert amides to
tert-butyloperoxyamido acetals, which could be isolated and
reacted with nucleophiles to provide final products, while
avoiding byproducts in a one-pot reaction.9 N-Acyl tetrahydro-
isoquinoline (THIQ) derivatives are familiar models for these
peroxidation processes, and corresponding tert-butylperoxy-
amido acetals have been prepared under different conditions.
a
entry
catalyst (0.5 equiv)
solvent (2 mL)
yield (%)
1
CuBr
Cul
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
N.R.
N.R.
trace
8
2
3
l2
4
NIS
5
Nal
32
6
Kl
25
7
Csl
37
8
NH4l
nBu4Nl
nBu4Nl
nBu4Nl
11
b
9
68 (85 )
c
d
10
11
12
43 (60 )
38
62
nBu4Nl
CH2Cl2
a
b
c
Isolated yield. 6.0 equiv of TBHP were used. Reaction carried out
d
at 40 °C. Reaction carried out at 0 °C.
Received: April 28, 2014
© XXXX American Chemical Society
A
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desired product tert-butyloperixyamido acetal 3a was isolated in
low yield (Table 1, entries 3−4). Other iodine sources
including metal iodides and NH4I resulted in the formation
of 3a in moderate yields (Table 1, entries 5−8). When n-
Bu4NI11 was used as the catalyst, 3a could be obtained in 68%
yield together with 20% 1a recovered. To promote the reaction,
an additional portion of 3.0 equiv of TBHP was added to the
reaction mixture after being stirred for 6 h. All the starting
material was consumed, and the yield of 3a was increased to
85% (Table 1, entry 9). Increasing the reaction temperature to
40 °C resulted in a low yield, and decreasing the reaction
temperature to 0 °C led to long reaction times and the
increased consumption of TBHP (9.0 equiv) (Table 1, entry
10). Changing the solvent to EtOAc or CH2Cl2 resulted in the
formation of 2a in lower yields (Table 1, entries 11−12). On
the basis of these results, entry 9 represents the best conditions.
Once the optimized reaction conditions were established, the
effect of the substrate was examined, with the results
summarized in Table 2. N-Benzyl amides of substituted benzoic
acid were investigated first, and the corresponding peroxides
were obtained in good yields regardless of the electron-
donating or -withdrawing groups on the benzene ring (Table 2,
2b−e). N-Benzylnaphthoylamides also gave the desired
product in 79% yield for the optimized reaction. Heterocyclic
substrate N-benzylthiophene-2-carboxamide underwent a
smooth reaction to give the product in excellent yields
(Table 2, 2g). Aliphatic substrates such as N-benzyl-
cinnamamide and N-benzylisobutyramide could also be
converted into the corresponding products in good yields
(Table 2, 2h−i). Carbamates including benzyl benzylcarbamate
and tert-butyl benzylcarbamate were also tested using the
optimized reaction, but no desired products were found (Table
2, 2j).
Table 2. Peroxidation of Amides 1
For substrates with methyloxyl substituted at different
positions on the benzyl group of N-benzylbenzamide, no
significant steric hindrance was observed, and the substrate with
the MeO group in the ortho-position afforded the desired
product in 94% yield (Table 2, 2k−m). When the substituted
groups were located in the para-position, substrates with
electron-donating groups gave higher yields than those with
electron-withdrawing groups (Table 2, 2m−p). The hetero-
cyclic substrate N-(pyridin-2-ylmethyl)benzamide also gave a
good yield (Table 2, 2q). N-Allylbenzamide is also a suitable
substrate for the reaction, and the corresponding product was
obtained in 65% yield (Table 2, 2r). N-Butylbenzamide was
also tested, but no reaction occurred and all the starting
materials remained untouched (Table 2, 2s).
a
Isolated yield.
Scheme 1. Plausible Reaction Mechanisms
Although the detailed reaction mechanism still remains to be
clarified, a radical reaction pathway is proposed as shown in
Scheme 1a. The tert-butoxyl and tert-butylperoxy radicals were
generated from the n-Bu4NI−TBHP system. The H atom
adjacent to the nitrogen atom of the amide was abstracted by
the tert-butoxyl radical to form radical A, which was trapped by
the tert-butylperoxy radical to give the product.11b,j A control
experiment was carried out to elucidate the mechanism. When
1.0 equiv of TEMPO was added to the reaction, the yield of 2a
decreased significantly to 35%, which suggests the possibility of
a radical pathway. An alternative plausible pathway is the
nucleophilic addition of TBHP to an acylimine intermediate
3,12 which was generated by dehydrogenation of 1. This
pathway could be ruled out, because when the reaction was
carried out using t-BuOH as the solvent, 2a was obtained in
80% yield as the only product and no t-BuOH addition product
could be found.13
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The acetal structure of the resultant compounds 2 allows it
to serve as a versatile intermediate for organic synthesis.14
When 2a was treated with 3.0 equiv of PhMgBr in Et2O, N-
benzhydrylbenzamide15 4a was obtained in 86% yield within 15
min at room temperature. Under the same conditions, α-
substituted amides 4b−4n were prepared in high yields up to
95%. One exception is that when 2q was reacted with 3.0 equiv
of PhMgBr, no product was found and all the starting material
decomposed. Treatment of 2a with 3.0 equiv of 2-MePhMgBr
also gave the corresponding product in good yield (Table 3,
4p). BuMgBr and BnMgBr also gave the desired products in
65% and 90% yield respectively (Table 3, 4q−4r).
Scheme 2. Peroxidation of α-Substituted N-
Benzylbenzamides and N-Benzyl-N-methylbenzamide
Table 3. Reaction of 2 with Grignard Reagents
In conclusion, we have developed an efficient and practical
method for the synthesis of tert-butylperoxyamido acetal by
simple oxidative functionalization of N-benzylbenzamides. The
reaction was carried out under mild conditions using TBHP as
the oxidant and n-Bu4NI as the catalyst. By treating tert-
butylperoxyamido acetals with Grignard reagents, α-substituted
amides could be prepared in high yields. Attempts to convert
the obtained tert-butylperoxyamido acetals into other amide
derivatives using different nucleophiles are still in progress in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, and copies
1
of the H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail:yuhui@tongji.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Tongji University (20123231) is
gratefully acknowledged.
■
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