Direct oxidation of N-benzylamides to aldehydes or ketones by N-bromosuccinimide

Article abstract of DOI:10.1080/00397910801929697

A simple and efficient approach for the one-pot transformation of N-benzylamides to aldehydes or ketones under mild conditions was reported. All the 20 substrates gave moderate to excellent oxidative yields under the optimized conditions. Our study may provide a new approach for the one-pot synthesis of aldehydes or ketones from the corresponding amides. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801929697

This article was downloaded by: [Duke University Libraries]
On: 14 December 2012, At: 07:15
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Direct Oxidation of N‐Benzylamides to
Aldehydes or Ketones by N‐Bromosuccinimide
Guangjun Wang a b , Zhengwei Li c , Chengyong Ha a & Ke Ding c
a Key Laboratory of Cellulose and Lignocellulosics Chemistry, Guangzhou
Institute of Chemistry, Chinese Academy of Sciences, Guangzhou,
Guangdong, China
b Graduate School of the Chinese Academy of Sciences, Beijing, China
c Guangzhou Institute of Biomedicine and Health, Chinese Academy of
Sciences, Guangzhou, Guangdong, China
Version of record first published: 24 Apr 2008.
To cite this article: Guangjun Wang, Zhengwei Li, Chengyong Ha & Ke Ding (2008): Direct Oxidation of
N‐Benzylamides to Aldehydes or Ketones by N‐Bromosuccinimide, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:10, 1629-1637
To link to this article: http://dx.doi.org/10.1080/00397910801929697
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 38: 1629–1637, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929697
Direct Oxidation of N-Benzylamides to
Aldehydes or Ketones by
N-Bromosuccinimide
Guangjun Wang,1,2 Zhengwei Li,3 Chengyong Ha,1
and Ke Ding3
1Key Laboratory of Cellulose and Lignocellulosics Chemistry,
Guangzhou Institute of Chemistry, Chinese Academy of Sciences,
Guangzhou, Guangdong, China
2Graduate School of the Chinese Academy of Sciences, Beijing, China
3Guangzhou Institute of Biomedicine and Health, Chinese Academy of
Sciences, Guangzhou, Guangdong, China
Abstract: A simple and efficient approach for the one-pot transformation of
N-benzylamides to aldehydes or ketones under mild conditions was reported. All the
20 substrates gave moderate to excellent oxidative yields under the optimized
conditions. Our study may provide a new approach for the one-pot synthesis of
aldehydes or ketones from the corresponding amides.
Keywords: Aldehyde, amide, N-bromosuccinimide, ketone, oxidation
INTRODUCTION
Functional group intertransformation is one of the most important and active
research branches in organic chemistry. It has attracted a great deal of
attention from both academia and chemical or pharmaceutical companies.
For example, extensive studies have been reported on the intertransformation
between aldehyde or ketone and alcohol, amine, or carboxylic acid, etc.[1]
Received in Japan September 21, 2007
Address correspondence to Ke Ding, Guangzhou Institute of Biomedicine and
Health, Chinese Academy of Sciences, Guangzhou International Business Incubator
A-3, Guangzhou Science Park, Guangzhou 510663, Guangdong, China. E-mail:
ding_ke@gibh.ac.cn
1629

1630
G. Wang et al.
Scheme 1. Hypothesized mechanism of NBS-mediated oxidization of N-benzyl
amides.
Although a variety of methods for the preparation of amides directly from
aldehydes or ketones are available,[2–12] only a few studies of the reversed
transformation have been reported.[5,13–17] In this article, we report a con-
venient approach to prepare aldehydes or ketones from a direct oxidization
of N-benzylamide by N-bromosuccinimide (NBS).
Recently, we have reported that NBS was able to efficiently mediate
debenzylation of N-benzyl carboxamides under mild conditions, and benzal-
dehyde was one of the major by-products from the reaction.[18] We had
hypothesized that benzaldehyde was formed from a one-pot sequence of bro-
mination, dehydrobromination, and hydrolysis (Scheme 1). This result stimu-
lated us to further investigate the oxidative potential of NBS on other
substituted N-benzyl carboxamides to form aldehydes or ketones.
RESULTS AND DISCUSSION
Our previous results have clearly indicated that chloroform seemed to be the
optimal reaction media for the NBS-initiated debenzylation and benzaldehyde
formation.[18] NBS (2.5 eq) is essential for the reacting completion, which is
due to the formation of bromine. Thus we applied these optimized conditions
to the investigation of the oxidative potential of NBS on other substituted
N-benzyl carboxamides.
We first examined the oxidation of various N-substituted benzyl aceta-
mides by NBS under the optimized conditions (Scheme 2). As summarized
in Table 1, almost all the substrates examined were effectively oxidized to
Scheme 2. Direct oxidation of N-benzylamides to aldehydes by NBS.

Direct Oxidation of N-Benzylamides
1631
Table 1. Direct oxidation of N-benzylamides to aldehydes by NBSa
Entry
R1
R2
Yield 2 (%)b
a
b
c
d
e
f
3-CH3
4- CH3
4-t-Bu
4-MeO
3,4-O-CH2-O-
2-F
CH3
CH3
79
73
68
82c
72d
63
55
51
83
78
68
72
91
77
80
CH3
CH3
CH3
CH3
g
h
i
2-F, 6-Cl
2-F, 4-Br
4-Cl
CH3
CH3
CH3
CH3
j
3-Br
4-Cl
k
l
i-Pr
t-Bu
4-Cl
4-Cl
m
n
o
t-BuO
C6H6
2-Furan
4-Cl
4-Cl
aThe reactions were carried out at r.t. with NBS (2.5 equiv) in chloroform for 18 h.
bIsolated yields.
c3-Bromo-4-methoxybenzaldehyde was obtained.
d7-Bromo-benzo[1,3]dioxole-5-carboxaldehyde was obtained.
yield the corresponding aldehydes with moderate to excellent yields. Of note,
the unsubstituted benzylic methyl group in compounds 1a or 1b was not
affected, which indicated high selectivity of this oxidation on N-benzyl car-
boxamides. When the phenyl ring was bearing strong electron-donating
groups such as methoxyl or methenedioxyl groups (1d and 1e), oxidization
together with bromination of the phenyl ring occurred. Interestingly, when
the substrates are carrying an ortho-fluoride, relatively lower yields were
obtained (1f, 1g, 1h). The oxidation of 1f, 1g, and 1h almost gave identical
yields, which indicated that steric hindrance might not play an important
role in the NBS-mediated oxidation.
The influence of steric hindrance on the NBS-mediated oxidation was
further investigated by examination of various N-(4-chloro)-benzyl carboxa-
mides. When N-(4-chlorobenzyl)acetamide was utilized, an 83% yield was
obtained. N-(4-Chlorobenzyl)isobutyramide and N-(4-chlorobenzyl)pivala-
mide gave yields of 68% and 72% respectively. This suggested that steric
hindrance had little influence on the NBS-mediated oxidation. N-(4-
Chloro)-benzyl aromatic carboxamides 1n and 1o were also able to be
oxidized to corresponding aldehyde with excellent yields. The oxidation of
tert-butyl 4-chlorobenzylcarbamate gave a high yield of 91%, which may
be due to the cleavage of the Boc group during the reaction.
The NBS-mediated oxidation was further extended to more sterically
hindrant N-(a-substituted)benzyl carboxamides (Scheme 3). As shown in

1632
G. Wang et al.
Scheme 3. Oxidation of N-benzylamides to ketones by NBS.
Table 2, all the N-(a-substituted)benzyl carboxamides were readily oxidized
with excellent yields. Of note, the oxidation of N-(a-alkyl) benzyl carboxa-
mides did not yield only the corresponding ketones, but a-bromo or a,a-
dibromo ketones were also produced. Especially in the case of compound
3c, only a,a-dibromo ketone 4c was isolated with a yield of up to 88%. It
is also noteworthy that although the compound 3c also beared another
benzylic carbon, onlya,a-dibromo ketone 4c was formed, and no benzylic
center bromination was observed. This indicated the preference of the bromo-
nation on an a-carbon of an aldehye or ketone against that of a benzylic center.
Table 2. Oxidation of N-benzylamides to ketones by NBSa
Entry
Substrate
Product
Yield 4 (%)b
a
40c
39c
b
67
16
c
88
76
d
e
83
aThe reactions were carried out at r.t. with NBS (2.5 equiv) in chloroform for 18 h.
bIsolated yields.
cRatio 4a1:4a2 was determined by GC-MS.

Direct Oxidation of N-Benzylamides
CONCLUSIONS
1633
In summary, a simple and efficient transformation directly from amides to
aldehyde or ketone was achieved under mild conditions. All 20 substrates
gave moderate to excellent oxidative yields under the optimized conditions.
The results also clearly revealed the great selectivity of this oxidation on
N-benzyl carboxamides over unsubstituted or alkyl substituted benzylic
groups. Our study may provide a new approach for the one-pot synthesis of
aldehydes or ketones from the corresponding amides.
EXPERIMENTAL
All the starting materials and chemical reagents were obtained from commer-
cial suppliers and used without further purification. The amides were prepared
using standard procedures. 1H-NMR and 13C-NMR spectra were recorded on
Bruker 400-Mz and 100-Mz spectrometers respectively using CDCl3 as
solvent and TMS as an internal standard. Chemical shifts are reported in
hertz (Hz). Splitting patterns: s, singlet; d, doublet; m, multiplet; br, broad.
Mass spectra were recorded on Agilent 1200LC-MS or Shimadzu GC-2010
spectrometers.
General Procedure for Oxidation
CHCl3 (20 mL) and NBS (5.0 mmol) were added to a solution of carboxamide
(2.0 mmol) at r.t., and the resulting mixture was stirred at rt for 18 h. The
solvent was removed in vacuo, then EtOAc (25 mL) and aq. NaOH (1 M,
10 mL) were added to the residue. The mixture was stirred for 5 min at rt,
then the organic layers were separated. The aqueous phase was extracted
with EtOAc (3 ꢀ 10 mL), and the combined organic layers were washed
with H2O (2 ꢀ 10 mL) and brine (1 ꢀ 10 mL) and dried over Na2SO4. The
solvent was removed in vacuo, and the residue was purified by chromato-
grapthy to yield the products.
Data
3-Methylbenzaldehyde (2a)
MS (EI): 119 (M-H)þ; 1H NMR (400 MHz, CDCl3): d 9.91 (s, 1H), 7.60–7.62
(m, 2H), 7.34–7.36 (m, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): d
192.3, 138.8, 136.5, 135.2, 129.9, 128.8, 127.1, 21.0.

1634
G. Wang et al.
4-Methylbenzaldehyde (2b)
1
MS (EI): 119 (M-H)þ; H NMR (400 MHz, CDCl3): d 9.91 (s, 1H), 7.75
(d, J ¼ 8.0 Hz, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 191.9, 145.5, 134.2, 129.8, 21.8.
4-tert-Butylbenzaldehyde (2c)
1
MS (EI): 163 (M þ H)þ; H NMR (400 MHz, CDCl3): d 9.97 (s, 1H), 7.81
(d, J ¼ 8.5 Hz, 2H), 7.58 (d, J ¼ 8.2 Hz, 2H), 1.35 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 191.9, 158.4, 134.1, 130.1, 129.7, 125.9, 125.4, 35.3,
31.1.
3-Bromo-4-methoxybenzaldehyde (2d)
MS (EI): 215 (Mþ); 1H NMR (400 MHz, CDCl3): d 9.78 (s, 1H), 8.02 (s, 1H),
7.77 (d, J ¼ 6.4 Hz, 1H), 6.94 (d, J ¼ 4.0 Hz, 1H), 3.96 (s, 3 H); 13C NMR
(100 MHz, CDCl3): d 189.5, 160.7, 134.6, 131.1, 130.8, 112.7, 111.6, 56.6.
7-Bromo-benzo[1,3]dioxole-5-carboxaldehyde (2e)
1
MS (EI): 229 (Mþ); H NMR (400 MHz, CDCl3): d 10.11 (s, 1H), 7.30
(s, 1H), 7.20 (s, 1H), 6.99 (s, 1H), 6.02 (s, 2H); 13C NMR (100 MHz,
CDCl3): d 189.5, 152.5, 148.2, 127.3, 120.7, 112.5, 107.4, 101.9.
2-Fluorobenzaldehyde (2f)
MS (EI): 123 (M-H)þ; 1H NMR (400 MHz, DMSO-d6): d 10.3 (s, 1H), 7.79–
7.83 (m, 1H), 7.51–7.57 (m, 1H), 7.19–7.20 (m, 1H), 7.08–7.13 (m, 1H); 13
NMR (100 MHz, CDCl3): d 186.1, 165.0, 162.4, 135.3, 127.7, 123.6, 123.2,
115.6.
C
6-Chloro-2-fluorobenzaldehyde (2g)
1
MS (EI): 157 (M-H)þ; H NMR (400 MHz, CDCl3): d 10.40 (s, 1H), 7.28–
7.45 (m, 1H), 7.22 (m, 1H), 6.99–7.01 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 184.7, 162.5, 159.9, 134.9, 133.0, 124.7, 119.7, 113.6.
4-Bromo-2-fluorobenzaldehyde (2h)
1
MS (EI): 203 (Mþ); H NMR (400 MHz, CDCl3): d 10.24 (s, 1H), 7.68
(m, 1H), 7.32–7.38 (m, 2H); 13C NMR (100 MHz, CDCl3): d 185.0, 164.5,
161.8, 129.2, 128.7, 127.4, 122.1, 119.3.

Direct Oxidation of N-Benzylamides
1635
4-Chlorobenzaldehyde (2i)
MS (EI): 141 (Mþ); 1H NMR (400 MHz, CDCl3): d 9.99 (s, 1H), 7.84
(d, J ¼ 4 Hz, 2H), 7.54 (d, J ¼ 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 190.8, 140.9, 134.8, 130.9, 129.5.
3-Bromobenzaldehyde (2j)
MS (EI): 185 (Mþ); 1H NMR (400 MHz, CDCl3): d 9.89 (s, 1 H), 7.93 (s, 1H),
7.78 (d, J ¼ 2.0 Hz, 1H), 7.74 (d, J ¼ 1.2 Hz, 1H), 7.37 (t, J ¼ 4.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 189.7, 137.0, 136.3, 131.3, 129.5, 127.3,
122.4.
2-Bromoacetophenone and Acetophenone Mixture (4a)
LC-MS: 198 (Mþ) and 120 (Mþ); 1H NMR (400 MHz, CDCl3): d 7.86–7.89
(m, 4H), 7.45–7.52 (m, 2H), 7.35–7.42 (m, 4H), 4.37 (s, 2H), 2.51 (s, 3H).
4-Acetyltoluene (4b–1)
MS (ESI): 135 (M þ H)þ; 1H NMR (400 MHz, CDCl3): d 7.78 (d, J ¼ 8.4 Hz,
2H), 7.18 (d, J ¼ 8.0 Hz, 2 H), 2.50 (s, 2H), 2.33 (s, 2H); 13C NMR (100 MHz,
CDCl3): d 197.8, 143.8, 134.7, 129.2, 128.4, 26.5, 21.6.
4-Methyl-2-bromoacetophenone (4b–2)
1
MS (ESI): 213 (M þ H)þ; H NMR (400 MHz, CDCl3): d 7.88 (d, J ¼ 8.0,
2H), 7.28 (d, J ¼ 8.0 Hz, 2H), 4.43 (s, 2H), 2.43 (s, 2H); 13C NMR
(100 MHz, CDCl3): d 190.9, 145.2, 131.5, 129.6, 129.1, 30.9, 21.8.
2,2-Dibromo-1-indanone (4c)
1
MS (EI): 290 (Mþ), 292 (M þ 2)þ; H NMR (400 MHz, CDCl3): d 7.77
(d, J ¼ 11.2 Hz, 1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.42 (d, J ¼ 4.0 Hz,1H),
4.29 (s, 2H); 13C NMR (100 MHz, CDCl3): d 192.65, 147.0, 136.8, 129.0,
127.0, 126.6, 125.9, 56.8, 52.4.
Diphenyl Ketone (4d)
MS (ESI): 183.1 (M þ H)þ; 1H NMR (400 MHz, CDCl3): d 7.69
(d, J ¼ 3.2 Hz, 4H), 7.47 (t, J ¼ 7.2 Hz, 2H), 7.36 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 196.74, 137.63, 132.41, 130.06, 128.28.

1636
G. Wang et al.
2-(Bromoacetyl)naphthalene (4e)
1
MS (EI): 248 (Mþ); H NMR (400 MHz, CDCl3): d 8.51 (s, 1H), 7.97–8.04
(m, 2H), 7.88–7.93 (m, 2 H), 7.56–7.65 (m, 2H), 4.58 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 191.31, 135.91, 132.43, 131.33, 130.97, 129.72,
129.06, 128.84, 127.87, 127.09, 124.18, 30.92.
ACKNOWLEDGMENTS
The authors are grateful for the financial support from the Chinese Academy
of Sciences (KSCX2-YW-R-27) and seed funding from the Guangzhou
Institute of Biomedicine and Health (GIBH). Prof. Dawei Ma from the
Shanghai Institute of Organic Chemistry (CAS) is gratefully acknowledged
for the helpful discussions and advice.
REFERENCES
1. Katritzky, A. R. T.; Taylor, R. J. K. Comprehensive Organic Functional Group
Transformations, 1st edn.; Elsevier: Amsterdam, Netherlands, 2005.
2. Ishihara, K. Y.T. Synthesis of carboxamides by LDA-catalyzed Haller–Bauer and
Cannizzaro reactions. Org. Lett. 2004, 6, 1983–1986.
3. Nemchik, A.; Badescu, V.; Phanstiel, O. N-(Benzoyloxy)amines: An investigation
of their thermal stability, synthesis, and incorporation into novel peptide con-
structs. Tetrahedron 2003, 59, 4315–4325.
4. Padmanabhan, S. L.; Thakkar, R. C.; Paresh, M.; Durant, G. J. A general procedure
for the synthesis of acylguanidines derived from aliphatic and aromatic amines.
Synth. Commun. 2001, 3, 2491–2497.
5. Newman, M. S. C.; Edward, G. Effect of surfaces on the McFadyen–Stevens
aldehyde synthesis: An improved procedure. J. Am. Chem. Soc. 1958, 80,
862–864.
6. Doyle, M. P. D.; Donnelly, D. J.; Kooistra, S. J.; Odubela, D. A.; Abayomi, A.;
West, C. T.; Zonnebelt, S. M. Silane reductions in acidic media, III: Reductions
of aldehydes and ketones to alcohols and alcohol derivatives: General syntheses
of alcohols, symmetrical ethers, carboxylate esters and acetamides. J. Org.
Chem. 1974, 39, 2740–2747.
7. Minisci, F. P. C.; Recupero, F.; Fontana, F.; Pedulli, G. F. Aerobic oxidation of
N-alkylamides catalyzed by N-hydroxyphthalimide under mild conditions: Polar
and ethalpic effects. J. Org. Chem. 2002, 67, 2671–2676.
8. Miura, K.; Ootsuka, K.; Suda, S.; Nishikori, H.; Hosomi, A. Lewis acid–catalyzed
reductive amination of carbonyl compounds with aminohydrosilanes. Synlett.
2001, 1617–1619.
9. Pan, S. C.; List, B. Catalytic one-pot, three-component Acyl–Strecker reaction.
Synlett. 2007, 318–320.
10. Brown, E. G. N.; John, M. Alkylation of Rink’s amide linker on polystyrene resin:
A reductive amination approach to modified amine-linkers for the solid phase

Direct Oxidation of N-Benzylamides
1637
synthesis of N-substituted amide derivatives. Tetrahedron Lett. 1997, 38,
8457–8460.
11. Dube, D. S.; Andrew, A. Reductive N-alkylation of amides, carbamates and ureas.
Tetrahedron Lett. 1999, 40, 2295–2298.
12. Elmorsy, S. S. B.; Doria, S.; Nour, M. A.; Kandeel, E. M. The direct synthesis of
secondary amides from aldehydes: A novel general redox procedure mediated by
iodotrichlorosilane (ITCS). Zeitschrift fuer Naturforschung, B: Chem. Sci. 1994,
49, 417–421.
´
13. Hans-Rene Bjørsvik, F. F.; Liguoric, L. A.; Minisci, F. A bromine-catalysed free-
radical oxidation of acetamides from primary and secondary alkylamines by H2O2.
Chem. Commun. 2001, 6, 523–524.
14. Jaisankar, P. P.; Bikash, G.; Venkatachalam, S. Microwave assisted McFadyen–
Stevens and Huang–Minlon reactions. Synth. Commun. 2002, 32, 2569–2573.
15. Thomas, C. W. L.; Routley, H. A. Thermolysis of benzhydrazones in the presence
of copper. Tetrahedron Lett. 1988, 29, 811–812.
16. Wang, J.-R.; Lei, L.; Wang, Y.-F.; Zhang, Y.; Deng, W.; Guo, Q.-X. Aerobic
oxidation with N-hydroxyphthalimide catalysts in ionic liquid. Tetrahedron Lett.
2005, 46, 4647–4651.
17. Gopinathan, M. B.; Vivekananda, B. M. A new general method for the introduction
of the aldehyde function in aromatic compounds. Tehtrahedron Lett. 1979, 20,
3875–3876.
18. Kuang, L. P.; Zhou, J.; Chen, S.; Ding, K. Room-temperature debenzylation of
N-benzylcarboxamides by N-bromosuccinimide. Synthesis 2007, 20, 3129–3134.