Atmospheric oxidative catalyst-free cross-dehydrogenative coupling of aldehydes with N-hydroxyimides

Article abstract of DOI:10.1016/j.tetlet.2017.03.064

Cross-dehydrogenative coupling (CDC) reactions of aldehydes with N-hydroxyimidates such as N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI) under catalyst-free conditions is described. Moreover, the desired products can be obtained simply by recrystallization from ethanol. This method is also applicable to the synthesis of amides in excellent yields. A radical mechanism of the type shown in Scheme 4 is proposed based upon the inhibition of the reaction in the presence of TEMPO.

Full text of DOI:10.1016/j.tetlet.2017.03.064

Accepted Manuscript
Atmospheric Oxidative Catalyst-Free Cross-Dehydrogenative Coupling of Al-
dehydes with N-hydroxyimides
Xiaohe Xu, Pingping Li, Yingyi Huang, Chuo Tong, YiYan Yan, Yuanyuan Xie
PII:
S0040-4039(17)30364-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.064
TETL 48765
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 January 2017
14 March 2017
20 March 2017
Please cite this article as: Xu, X., Li, P., Huang, Y., Tong, C., Yan, Y., Xie, Y., Atmospheric Oxidative Catalyst-
Free Cross-Dehydrogenative Coupling of Aldehydes with N-hydroxyimides, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.03.064
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Atmospheric Oxidative Catalyst-Free Cross-
Dehydrogenative Coupling of Aldehydes
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with N-hydroxyimides
Xiaohe Xu, Pingping Li, Yingyi Huang, Chuo Tong, YiYan Yan, and Yuanyuan Xie*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Atmospheric Oxidative Catalyst-Free Cross-Dehydrogenative Coupling of Aldehydes
with N-hydroxyimides
Xiaohe Xua, Pingping Lia, Yingyi Huanga, Chuo Tonga, YiYan Yana, and Yuanyuan Xiea, b∗
a
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China
b College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Cross-dehydrogenative coupling (CDC) reactions of aldehydes with N-hydroxyimidates such as
N-hydroxysuccinimide (NHSI), N-hydroxyphthalimide (NHPI) under catalyst-free conditions is
described. Moreover, the desired products can be obtained simply by recrystallization from
ethanol. This method is also applicable to the synthesis of amides in excellent yields. A radical
mechanism of the type shown in Scheme 4 is proposed based upon the inhibition of the reaction
in the presence of TEMPO.
Received in revised form
Accepted
Available online
Keywords:
Catalyst-free
Cross-dehydrogenative coupling
Atmospheric Oxidative
Aldehydes
2017 Elsevier Ltd. All rights reserved.
N-hydroxyimidates
Introduction
environmentally benign synthetic methods are still required for
the synthesis of N-hydroxyamide ester.
Nowadays, cross-dehydrogenative coupling (CDC) has been
considered as a green method to construct C-C1 and C-O2 bonds
due to its high atom efficiency and avoidance of the
Oxygen has been used as an ideal oxidant in many chemical
processes due to its abundance and environmental friendiness.8 In
the presence of O2, NHPI could be oxidized to PINO, which
could initiate the following radical oxidative reactions.9 Herein,
we envisioned that O2 could be used as oxidant for the coupling
of aldehydes with NHPI under catalyst-free conditions.
prefunctionalization of substrates. Generally, CDC reactions
requires the use of co-oxidants such as tert-butylhydroperoxide,
H2O2, potassium persulfate (K2S2O8), 2,3-dichloro-5,6-dicyano-
para-benzoquinone (DDQ) and so on.2,3 Compared to the C-C
cross-coupling, oxidative C-O coupling reactions were much
lesser developed, especially for the aldehydes involved C-O4
coupling reaction since aldehydes are prone to side oxidation and
fragmentation reactions giving carboxylic acids or carbonyl
compounds. N-hydroxyamide ester, which is an active
intermediate, can be used to synthesize amides and esters.5
Traditionally, N-hydroxyamide ester was prepared via direct
coupling of carboxylic acids with N-hydroxyimides in the
persence of carbodiimide as an activating reagents,6 which
suffers from poor atom efficiency and difficult purification
process of product. Fortunately, a few of CDC reactions of
aldehyde with N-hydroxyimide have been developed as an
effective alternative to solve this problem. In 2012, Tan and co-
workers developed an n-Bu4NBr or n-Bu4NI catalyzed cross-
coupling reaction of aldehydes with N-hydroxyimides using tert-
butyl hydrogen peroxide (TBHP) as oxidant. Later on, Barbas III
(Scheme 1 a)7a, Maity (b)7b and Lv (c)7c groups have also
successfully achieved this transformation, respectively. However,
these methods still suffer from the use of specific oxidants and
heavy-metal catalysts. Therefore, milder and more
Scheme 1. Various apporoaches for CDC reaction of aldehydes with N-
hydroxyimides
———
∗ Corresponding author. fax: +86-571-88320878; e-mail: xyycz@zjut.edu.cn

2
Tetrahedron Letter
Results and discussion
yield of desired coupling product (3m) was obtained. It is
noteworthy that sensitive functional group such as ester group
was well tolerated in the reaction and desired product 3n was
obtained in 88% yield (entry 14), however, other sensitive group
such as hydroxyl on the aldehyde (ortho-, meta- and para-
positions) and 3-(4-methoxyphenyl)acrylaldehyde did not
process well with NHPI. Aliphatic aldehydes turned out to be
poor substrates for this transformation (entry 15).
Initially, a model reaction between p-fluorobenzaldehyde 1a
and NHPI 2a was chosen to explore optimal reaction conditions
and the results are summarized in Table 1. Firstly, the reaction
was conducted in THF at 60 oC in open air and a trace amout of
desired coupling product 3a was detected (entry 1). However, no
product was observed when DMF, DMSO, CH2Cl2, toluene and
acetone were used as solvents (entries 2-6). When the reaction
was carried out in CH3CN, the yield of 3a was increased
dramatically to 94% (entry 7). By switching to alternative
greener solvents such as EtOAc and diethyl carbonate (DEC), the
products were obtained in moderate yields (entries 8-9).
Furthermore, lower reaction temperature led to the decrease of
yield (entry 10). Then the quantities of p-fluorobenzaldehyde was
also studied, revealed that 2.0 equiv of the 1a was sufficient to
complete the conversion (entries 11-12). It is noteworthy that the
reaction did not proceed well under N2 (entry 13), indicating that
oxygen was necessary for this transformation.
Table 2. Reaction of 2a with various aldehydesa
Entry
1
R
t. (h)
6
3
Yield (%)b
4-F
3a
3b
3c
3d
3e
3f
94
93
94
92
90
93
90
94
94
95
95
90
2
2-F
8
Table 1. Optimization of the reaction conditionsa
3
4-Cl
2-Cl
2,4-Cl
4-Br
2-Br
4-CF3
4-CH3
3-OCH3
2-OCH3
H
8
O
O
O
O
Solvent
T
4
10
10
8
+
HO
N
H
O
O
5
F
O
F
3a
1a
2a
6
7c
8
8
3g
3h
3i
Entry
1
Solvent
THF
T. (o C)
60
t. (h)
6
Yield (%)b
trace
N.R.
N.R.
N.R.
N.R.
N.R.
94
10
18
18
10
6
2
DMF
100
100
30
6
9
3
DMSO
CH2Cl2
toluene
acetone
CH3CN
EtOAc
DEC
6
10
11
12
3g
3k
3l
4
6
5
100
56
6
6
6
7
80
6
13
14
18
6
3m
3n
75
88
8
77
10
18
6
75
9
100
70
83
4-COOCH3
10
11c
12d
13e
CH3CN
CH3CN
CH3CN
CH3CN
83
80
6
50
15
24
--
N.R.
80
6
93
80
6
trace
a. Reactions were conducted with 1 (1.0 mmol) and 2a (0.5 mmol) in CH3CN
(3 mL ) at 80 oC for 6-24h under open air conditions, unless otherwise noted.
b. Isolated yields after ethanol recrystallization based on 2a.
a. Reactions were conducted with 1a (1.0 mmol) and 2a (0.5 mmol) in 3 mL
solvent under open air conditions, unless otherwise noted.
c. EtOAc was used as solvent. N.R.= no reaction
b. Isolated yields after ethanol recrystallization based on 2a.
c. 1a (0.5mmol)
Then, we continued to explore the reaction of aldehydes with
N-hydroxysuccinimide (2b, NHSI) under optimized reaction
conditions with minor modifications. Gratifyingly, the desired
coupling products were obtained when a mixed solvent of
CH3CN and DEC (CH3CN/DEC = 1/1) was used, and the results
are summarized in Table 3. Aldehydes with electron-withdrawing
substitutents like CF3, fluoro, chloro, and bromo were all good
substrates and the desired coupling products were obtained in 80-
89% yields (4a-4e). Aldehydes bearing electron-donating groups
such as methyl and methoxy gave excellent yields of
d. 1a (1.5mmol)
e. Under N2. N.R.= no reaction
With the optimized reaction conditions in hand, we then
investigated the scope of this coupling reaction between NHPI
and various aldehydes, and the results are summarized in Table 2.
The reactions of NHPI with aldehydes bearing electron-
withdrawing groups, such as CF3, F, Cl, and Br at the ortho- and
para-positions of benzene rings proceeded well under the
optimized reaction conditions and gave excellent yields (90-94%)
of coupling products (3a-3h). Aldehydes with electron-donating
groups, such as methyl and methoxy afforded desired products
(3i-3k) in better yields (94-95%). These results suggest that the
electronic effect of substituents on phenyl ring (para-, meta-, and
ortho- position) in the aldehydes did not affect the efficiency of
the coupling reactions. The optimized conditions were
successfully applied to thiophene-2-carbaldehyde and moderate
corresponding products in 90-95% yields (4f-4g).
Table 3. Reaction of 2b with various aldehydesa

3
subsequently abstracts one hydrogen atom from A and forms
radical B. Further oxidation of B affords the final product 3a.
Entry
R
t. (h)
6
4
Yield (%)b
Scheme 3. Coupling of p-fluorobenzaldehyde with NHPI in the presence of
1
2
3
4
5
6
7
8
4-F
4a
4b
4c
4d
4e
4f
83
82
80
82
89
95
90
80
TEMPO.
2-F
10
10
10
8
4-Cl
4-Br
4-CF3
4-CH3
3-OCH3
H
10
12
10
4g
4h
a. Reactions were conducted with 1 (1.0 mmol) and 2b (0.5 mmol) in
CH3CN/DEC (1:1 3 mL ) at 80 oC for 6-12h under open air conditions .
b. Isolated yields after ethanol recrystallization based on 2b
N-hydroxyimide esters (3 or 4) are usually used as active
esters for amidation process. To demonstrate the practical utility
of this coupling reaction, the reaction of benzaldehyde with
NHPI was performed at an 8 mmol scale and the product 3l was
still obtained in excellent yield [Scheme 2, eq. (1)]. Next, 3l was
used as active esters to synthesize amides, providing amidation
products in excellent yields [Scheme 2, eq. (2)]. Meanwhile, one-
pot synthesis of amide directly from aldehyde, NHPI and amine
was investigated. After the oxidative coupling of benzaldehyde
and NHPI, butan-1-amine was added directly to the reaction
mixture, and the desired product 5b was obtained in 90% yield
[Scheme 2, eq. (3)].
Scheme 4 Proposed mechanism for CDC reaction of p-fluorobenzaldehyde
with NHPI
In conclusion, we have developed a novel and efficient
approach for the synthesis of N-hydroxyimide esters via cross-
dehydrogenative coupling (CDC) of aldehydes with NHPI under
oxidative catalyst-free conditions. Notably, the use of molecular
oxygen (air) as the terminal oxidant and simple purification
process make this method environmentally friendly and practical.
Moreover, this approach was successfully used for the
straightforward synthesis of various amides. Further studies on
this CDC reactions between other aromatic aldehydes and N-
hydroxyimides and its mechanism are currently underway.
Acknowkedgment
We are grateful to the National Natural Science Foundation of
China (No.21576239) for financial support. We thank Dr. Qi
Shuai for helpful discussions.
References and notes
1. Some reviews on CDC reactions: a) Li, C. J.; Li, Z. Pure Appl. Chem.,
2006, 78, 935; b) Li, C. J. Acc. Chem. Res., 2009, 42, 335; c)
Scheuermann, C. Chem.-Asian J., 2010, 5, 436; d) Yeung, C. S.; Dong,
V. M. Chem. Rev., 2011, 111, 1215; e) Cho, S. H.; Kim, J. Y.; Chang, J.
S. Chem. Soc. Rev., 2011, 40, 5068; f) Liu, C.; Zhang, H.; Shi, W.; Lei,
A. Chem. Rev., 2011, 111, 1780; g) Girard, S. A.; Knauber, T.; Li, C. J.
Angew. Chem., Int. Ed., 2014, 53, 74.
2. a) Zhang, L. B.; Hao, X. Q.; Zhang, S. K.; Liu, Z. J.; Zheng, X. X.;
Gong, J. F.; Niu, J. L.; Song M. P. Angew.Chem., Int. Ed., 2015, 54,
272; b) Li, Y.; Li, Z. S.; Xiong, T.; Zhang, Q.; Zhang, X. Y. Org. Lett.,
2012, 14, 3522; c) Pandey, G.; Pal, S.; Lah., R. Angew. Chem., Int. Ed.,
2013, 52, 5146; d) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed.,
2008, 47, 6411; e) Bhadra, S.; Matheis, C.; Katayev, D.; Goossen, L. J.
Angew. Chem., Int. Ed., 2013, 52, 9279.
Scheme 2. Synthesis of various amides.
In order to gain a good insight into the mechanism of reaction,
one control experiment of 4-fluorobenzaldehyde (1a) with NHPI
(2a) was conducted in the presence of TEMPO under the
standard reaction conditions and the desired product 3a was not
detected (Scheme 3), indicating that the reaction might proceed
in a radical way. Based on the results of this experiment and the
literature reported,7,8 a plausible reaction pathway was illustrated
in Scheme 4. Initially, in the presence of molecular oxygen and
under heating, NHPI could afford PINO radical, which
3. Alagiri, K.; Devadig, P.; Prabhu, K. R. Chem.,-Eur. J., 2012,18, 5160.
4. a) Rout,S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K. Org.
Lett., 2012, 14, 3982; b) Schulze, A.; Giannis, A. Adv. Synth. Catal.,
2004, 346, 252
5. a) Nefkens, G. H. L.; Tesser, G. I. J. Am. Chem. Soc., 1961, 83, 1263; b)
Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am. Chem. Soc.,
1964, 86, 1839; c) Cline, G. W.; Hanna, S. B. J. Am. Chem. Soc., 1987,
109, 3087.

4
Tetrahedron Letter
6. a) Grochowski, E.; Jurczak, J. Synthesis, 1977, 277; b) Ogura, H.;
Kobayashi, T.; Shimizu, K.; Kawabe, K.; Takeda, K. Tetrahedron Lett.,
1979, 20, 4745; c) Kim, S.; Ko, K. Y. J. Chem. Soc., Chem. Commun.,
1985, 473; d) Pçchlauer, P.; Hendel, W. Tetrahedron, 1998, 54, 3489; e)
Kim, M.; Han, K. J. Synth. Commun., 2009, 39, 4467.
7. a) Tan, B.; Toda, N.; Barbas III, C. F. Angew. Chem. Int. Ed., 2012, 51,
12538; b) Dinda, M.; Bose, C.; Ghosh, T.; Maity, S. RSC Adv., 2015, 5,
44928. (c) Lv, Y. H.; Sun, K.; Pu, W. Y.; Mao, Sh. K.; Li, G.; Niu, J. J.;
Chen, Q.; Wang, T. T. RSC Adv., 2016, 6, 93486.
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P. J. D.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L. Jr.; Linderman, R.
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9. a) Liang, Y. F.; Wang, X. Y.; Tang, C. H.; Shen, T.; Liu, J. Z.; Jiao, N.
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Chem. Rev., 2007, 107, 3800; f) Samanta, S.; Donthiri, R. R.; Ravi, C.;
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10. Typical experimental procedure: p-Fluorobenzaldehyde (1a) (124.0 mg,
1.0 mmol, 1.0 equiv.) and NHPI (2a) (82.0 mg, 0.5 mmol, 0.5 equiv.)
were dissolved in CH3CN (3 mL) and then stirred under reflux for 6 h
under open air conditons. After the reaction was completed (monitored
by TLC), the reaction mixture was concentrated under vacuum. The
residue was purified by ethanol recrystallization to give the product 3a
(134.7 mg, 94% yield) as a white solid, m. p. 193-195 °C (lit.7c 194-
1
195°C). H NMR (400 MHz, DMSO-d6, ppm) δ = 8.25 (dd, J = 8.8, 5.2
Hz, 2H), 8.03-8.01 (m, 2H), 7.98-7.96 (m, 2H), 7.52 (t, J = 8.8 Hz, 2H).
13C NMR (100 MHz, DMSO-d6, ppm) δ = 166.1 (1JC-F = 253.3 Hz),
161.53, 161.45, 135.4, 133.1 (3JC-F = 10.1 Hz), 127.9, 123.9, 120.6 (4JC-F
= 2.1 Hz), 116.8 (2JC-F = 22.4 Hz).

5
Highlights
1. Catalyst-Free protocol
2. Air as the terminal oxidant
3. Simple purification
4. Gram synthesis
5. One-pot synthesis amides