Direct oxidative amination of aromatic aldehydes with amines in a continuous flow system using a metal-free catalyst

Article abstract of DOI:10.1039/c6ra16240a

A novel method for metal-free oxidative amination of aromatic aldehydes and alcohols in the presence of H₂O₂/NaBr/H⁺ within 25 min in a continuous flow system has been developed. A series of different substrates were tested and the corresponding products were obtained in good yields .

Full text of DOI:10.1039/c6ra16240a

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DOI: 10.1039/C6RA16240A
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ARTICLE
Direct oxidative amination of aromatic aldehydes with amines in
continuous flow system using metal-free catalyst
Jiajia Gu, a Zheng Fang, b Chengkou Liu, a Xin Li, a Ping Wei a and Kai Guo *, a, c
Received 00th January 20xx,
Accepted 00th January 20xx
A novel method for metal-free oxidative amination of aromatic aldehydes and alcohols in the presence of H2O2/NaBr/H+
within 25min in a continuous flow system has been developed. A series of different substrates were tested and the
corresponding products were obtained in good yields.
DOI: 10.1039/x0xx00000x
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have also been reported. However, there are still drawbacks of
these methodologies, such as the catalysts reported in
literature are either expensive or involve a multistep synthesis
and it often needs stoichiometric amounts of bases and
sensitive reagents.
Introduction
General and convenient methods for the synthesis of amide
are important in organic chemistry due to the extensive
presence of amide units in natural products, pharmaceuticals,
1
Molecular halogens and related reagents are well known
oxidizing agents due to its simple operation and low cost.
Recently, our group has researched the oxidation of alcohol to
aldehyde in a continuous flow reactor with metal-free
catalyst.15 Then we continued to explore the oxidation
amidation of alcohol to amide in a two-step continuous flow
system with metal-free catalyst.16 In the process, benzyl
alcohol was firstly oxidized to aldehyde, which continued to
react with amine under TBHP to form amide. Compared with
traditional methods, this method is good enough from the
economical and green chemistry points of view. However, it
needs two different oxidants, which may cause the waste of
material and low efficiency. The second step of the reaction
needed 2 equiv number of TBHP, which was not environment
friendly. And the system was not fit for primary amines, which
limited the substrate scope. Then we intended to explore the
more interesting and challenging oxidative amidations of
aldehydes and alcohols with amines by using the same oxidant,
which led to simple operation. The results are presented here.
and polymers. The reaction of an amine with carboxylic acid,
2
which needs either more reactive derivatives or coupling
reagents 3 are the most common methods for the synthesis of
amides. However, these methods have several common
drawbacks. For example, it is poor atom-efficiency and it uses
hazardous reagents which led to wastes that cause
environmental problems. To overcome these problems,
alternative methods for the synthesis of amide have been
developed,4 such as the name reactions like the Schmidt
reaction,5 the Beckmann rearrangement,6 and Ugi reaction.7
Other methods involve dehydrogenative amidation of alcohol 8,
9
transamidation of primary amides , and oxidative amidation
10-14
of aldehydes
have also been reported. During these
methods above, oxidative amidation of aldehydes with amine
is highly desirable since it uses cheap, abundant and less
hazardous starting materials (Scheme 1).
In 1966, Nakagawa et al. first reported the oxidative
amidation of aldehydes with amines by using nickel peroxide
as the oxidant.10 After that, several groups have reported
11
new methods for the direct synthesis of amides from
aldehydes. However, these methods require the use of
expensive transition metals as catalyst. Metal-free oxidative
amidation of aldehydes with amines was first reported by Wolf
et al. in 2007 by using TBHP as the oxidant.12 Then more
13
14
Scheme 1 Oxidative amidation of aldehyde with amine
efficient catalytic methods using KI/TBHP and NaI/TBHP
Results and Discussion
a.College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
At the beginning, optimization studies were carried out by
treating benzaldehyde with morpholine to form benzoyl
morpholine 3a in different reaction conditions. And the results
were summarized in Table 1. The reaction with NaBr and
without an oxidant did not get the product (Table 1, entry 1),
whereas the reaction with H2O2 (30wt% in water) resulted in
b.College of Pharmacy, Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816,
China.
c. State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
Email: guok@njtech.edu.cn, Tel +86 25 5813 9926, Fax +86 25 5813 9935.
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra.]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
RSC Adv., 2016, 00, 1-3 | 1
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Table 2 The oxidation amidation of aldehydes with morpholine in batch and
16% of the product (Table 1, entry 2). Under the similar
conditions 10mol% NaBr and H2O2 provided 64% of the
product (Table 1, entry 3). And when the equiv number of
NaBr decreased to 5mol%, it almost had no effect on the yield
of the product (Table 1, entries 3, 4). However, the equiv
number of H2O2 had a great influence on the yield (Table 1,
entries 4, 5 and 6).
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continuous flow systems
DOI: 10.1039/C6RA16240A
Table 1 Optimization of oxidative amidation for the synthesis of amide a
Yield (%) c
Entry
1
Aldehyde
Product
Batch a
Conti-flow b
62
96
Entry
Catalyst (mmol)
NaBr (0.1)
-
Oxidant (mmol)
-
Yield (%) b
2
3
4
58
94
93
1
2
-
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (1.5)
H2O2 (3)
16
64
62
48
64
3
NaBr (0.1)
NaBr (0.05)
NaBr (0.05)
NaBr (0.05)
NP d
4
5
6
a
NP
NP
82
Reaction conditions: benzaldehyde (1mmol), morpholine (2mmol), sulphuric
acid (1mol%), dioxane (3mL), 80 ˚C, 30h. b Isolated yield.
In In further study, both aromatic and aliphatic aldehydes
were employed (Table 2). Moderate yield of benzaldehyde
(Table 2, entry 1, "Batch" column) and 4-nitrobenzaldehyde
(Table 2, entry 2, "Batch" column) were obtained. However,
there was no product obtained of 4-methoxybenzaldehyde
(Table 2, entry 3, "Batch" column) and 4-aminobenzaldehyde
(Table 2, entry 4, "Batch" column), probably due to the
reactivity between amines/alkoxys and hypobromite
restrained the oxidation. And aliphatic aldehyde did not get
5
NP
a
Reaction conditions in batch: aldehyde (1mmol), morpholine (2mmol),
NaBr (5mol%), sulphuric acid (1mol%), hydrogen peroxide (30wt% in water,
2mmol), dioxane (3mL), 80 ºC, 30 h. Reaction conditions in continuous-
flow system: solution A: 0.33M of aldehyde, 0.67M of hydrogen peroxide
(30wt% in water), 5mol% of sodium bromide and 1mol% of sulphuric acid in
dioxane, flow rate 0.1 mL/min; solution B: 0.67M of morpholine in the
b
c
d
the amide product, too (Table 2, entry 5, "Batch" column), dioxane, flow rate 0.1 mL/min, 80ºC, 25min. Isolated yield. NP=No
Product.
which probably due to the low reactivity of aliphatic aldehyde.
To overcome these problems in the oxidation process,
continuous flow microreactors with benefits of high surface-
to-volume ratio, efficient mass transfer and heat transfer, high
selectivity was employed in this study.17 In recent years,
continuous flow technology has become increasingly popular
in organic synthesis.18 Owing to the high efficiency of heat and
mass transmission, which contributes to reactivity of reactants,
the reaction time will be shorten, and the reaction efficiency
will be improved much more.
Then we designed an assembled continuous flow system, as
shown in Figure 1. It consists of two syringe pumps, T-piece
micromixer and microreactor. And the volume of the syringe
and microreactor are 20mL, and 5mL, respectively. In the
reaction process, the mole ratio of reactants and reaction time
can be modulated by changing the flow rate of syringes. And
Figure 1 Continuous flow system
the temperature was controlled by oil bath.
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With an assembled continuous-flow system, all the results were shown in Table 4. Moderate to good yields were
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reactions displayed in Table 2 were re-performed. Compared obtained with both electron-deficient anDdOeI:le10ct.1r0o3n9-/rCi6cRhAb16e2n4z0yAl
with batch condition, better reactivity and yield were realized alcohols (Table 4, 3a-3c, 3f). And heterocyclic alcohols gave the
(Table 2, entries 1, 2). What’s more, 93% of 3c and 82% of 3d corresponding products in good yields (Table 3, 3i and 3j), too.
were obtained, which was inhibited in batch conditions (Table
Table 4 The oxidation amidation of benzyl alcohols with morpholine in continuous flow
system a
2, entry 3). This proved that continuous-flow could improve
the functional group compatibility of the oxidation.
Unfortunately, reaction with aliphatic aldehyde was
unsuccessful in continuous flow system, which due to the low
reactivity (Table 2, entry 5).
Encouraged by these results, a library of amides was
synthesized from various aldehydes and amines. The results
were summarized in Table 3. Good to excellent yields were
obtained in most cases. First of all, a wide range of
arylaldehydes were used to react with morpholine. Both
electron-rich and electron-deficient arylaldehydes provided
good yield to corresponding product (Table 3, 3f-3h). Similarly,
heterocyclic aldehydes gave the corresponding benzoyl
morpholine in good yields (Table 3, 3i and 3j). Then a variety of
amines were also used to react with benzaldehyde to test the
scope of substrates. Secondly amines reacted well in this
system (Table 3, 3k
could not get the desired product in our previous study,16 also
had good reactivity (Table 3, 3o 3q).
-3n). what’s more, primary amines, which
a Reaction conditions: solution A: 0.33M of benzyl alcohols, 0.67M of morpholine
in dioxane, flow rate 0.1 mL/min; solution B: 1.67M of hydrogen peroxide (30wt%
in water), 10mol% of sodium bromide and 1mol% of sulphuric acid in the dioxane,
flow rate 0.1 mL/min, 80˚C, 25min. b Isolated yield.
-
Table 3 The oxidation amidation of aldehydes with amines in continuous flow systems a
15, 16
On the basis of previous studies,
a possible mechanism
was proposed as shown in Scheme 2. Firstly, Br- was oxidized
to form the hypobromous acid in the presence of hydrogen
peroxide and acid. The reaction between aldehyde and amine
may probably proceed through a hemiaminal intermediate,
which can be further oxidized to the product amide by the
generated hypobromous acid. And acid and Br- were
reformatted to maintain the system circularly. In the case of
direct amidation of benzyl alcohols, the reaction was expected
to go through an aldehyde intermediate. To confirm this
proposed mechanism, hydrobromic acid (40%, aq.), which was
an important intermediate in the reaction pathway, was
employed directly to replace Br- source and sulfuric acid. A
yield of 56% of amide was isolated in the model reaction,
which supported the mechanism strongly.
a
Reaction conditions: solution A: 0.33M of aldehyde, 0.67M of hydrogen
peroxide (30wt% in water), 5mol% of sodium bromide and 1mol% of sulphuric
acid in dioxane, flow rate 0.1 mL/min; solution B: 0.67M of amine in the dioxane,
flow rate 0.1 mL/min, 80˚C, 25min.
Then we have also researched the applicability of the
present catalytic system to benzyl alcohol derivatives. And the
Scheme 2 Proposed mechanism of the oxidative amination of aldehyde and alcohol
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elution with ethyl acetate in petroleum ether tVoiewobArttiaclienOntlhinee
amide product 3a.
Conclusions
DOI: 10.1039/C6RA16240A
In conclusion, we have developed a simple, general and
straightforward method for the synthesis of the amide by
oxidative coupling between an aldehyde/alcohol and an amine
in continuous flow system. Compared with our previous work
on the oxidative amination of alcohol to amide, this method is
green and simple due to the use of one oxidant. And primary
amines were also had good reactivity, which had no reactivity
in our previous work. In this strategy, no external base or
additive is required. And the reaction time is much shorter
than that in batch. Moreover, the present methodology was
metal-free. Formation of amides from alcohols, which is
difficult to some extent, was also achieved in this study.
Benzoyl morpholine (3a). White solid; 1.24g, 96% yield;
1
m.p.=72-74
°
C; H NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 5H),
3.80–3.28 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 170.1, 169.4,
134.3, 128.9, 127.5, 126.1, 65.9, 59.4, 20.0, 13.2; HRMS (ESI)
m/z calcd for C11H13NO2 [M+H]+ 192.1019, found 192.1040.
N-(4-Nitrobenzoyl)morpholine (3b). Light yellow solid; 1.43g,
1
94% yield; m.p.=101-102°C; H NMR (400 MHz, CDCl3) δ 8.32–
8.27 (m, 2H), 7.61–7.56 (m, 2H), 3.72 (d, J = 67.2 Hz, 6H), 3.39
(s, 2H); 13C NMR (101 MHz, CDCl3) δ 167.0, 147.5, 140.4, 127.1,
123.0, 65.7; HRMS (ESI) m/z calcd for C11H11N2O4 [M+H]+
237.0831, found 237.0857.
N-(4-Methoxybenzoyl)morpholine (3c). Yellow oil; 1.37g, 93%
yield; 1H NMR (400 MHz, CDCl3) δ 7.41–7.36 (m, 2H), 6.94–6.89
(m, 2H), 3.84 (d, J = 3.2 Hz, 3H), 3.76–3.54 (m, 8H); 13C NMR
(101 MHz, CDCl3) δ 169.4, 159.9, 128.2, 126.3, 112.8, 65.9,
54.3; HRMS (ESI) m/z calcd for C12H15NO3 [M+H]+ 222.1085,
found 222.1094.
Experimental
General details
Reaction solvents were obtained commercially, and used
without further purification. Commercial reagents were used
as received. Reaction were monitored by thin-layer
chromatography (TLC) on 0.25mm precoated Merck Silica Gel
N-(4-Aminobenzoyl)morpholine (3d). White solid; 1.12g, 82%
1
yield; m.p.=131-132°C; H NMR (400 MHz, CDCl3) δ 7.26–7.21
(m, 2H), 6.65–6.59 (m, 2H), 3.93 (s, 2H), 3.73–3.56 (m, 8H); 13
C
NMR (101 MHz, CDCl3) δ 169.9, 147.4, 128.4, 123.4, 113.2,
65.9, 59.4, 52.4, 20.0, 13.2; HRMS (ESI) m/z calcd for
C11H14N2O2 [M+H]+ 207.1089, found 207.1096.
1
60 F254, visualizing with ultraviolet light. H/13C NMR spectra
were recorded on 400’54 ascend purchased from Bruker
Biospin AG, operating at 400/100 MHz, respectively. Chemical
shifts (δ) are reported in parts per million (ppm) downfield
from tetramethylsilane (TMS), which was used as internal
standard. Flash column chromatography was performed on
Merck Silica Gel 60 (200-300mesh) using petroleum ether and
ethyl acetate.
N-(4-Methybenzoyl)morpholine (3f). Light yellow oil; 1.24g,
1
91% yield; H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.1 Hz, 2H),
7.20 (d, J = 8.0 Hz, 2H), 3.69 (s, 8H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 169.6, 139.1, 131.3, 128.1, 126.2, 65.9, 29.3,
20.4; HRMS (ESI) m/z calcd for C12H15NO2 [M+H]+ 206.1136,
found 206.1147.
General procedure for synthesis of compound 3a by
benzaldehyde with morpholine: 0.01mol of benzaldehyde,
H2O2 (30wt% in water, 0.02mol, 2eq), NaBr (5 mol%) and
H2SO4 (1 mol%) were dissolved in 30mL dioxane, which was in
syringe A. Morpholine (0.02mol, 2eq) was dissolves in 30mL
dioxane, which was in syringe B. The flow rate of syringe A and
B were both 0.1mL/min. And the temperature of the oil bath
was set in 80˚C. The reaction liquid was collected, and
dissolved in ethyl acetate, washed with H2O. The organic layer
was dried over anhydrous sodium sulfate and solvent was
removed under vacuum. And the crude product was purified
by flash chromatography on silica gel by gradient elution with
ethyl acetate in petroleum ether to obtain the amide product
N-(4-Chlorobenzoyl)morpholine (3g). White solid; 1.38g, 92%
1
yield; m.p.=75-77
°
C; H NMR (400 MHz, CDCl3) δ 7.38 (q, J =
8.5 Hz, 4H), 3.92–3.32 (m, 8H); 13C NMR (101 MHz, CDCl3) δ
168.4, 135.0, 132.6, 127.9, 127.6, 99.9, 65.8; HRMS (ESI) m/z
calcd for C11H12ClNO2 [M+H]+ 226.6720, found 226.6724.
N-(4-Bromobenzoyl)morpholine
(3h). Light yellow solid;
1
1.58g, 88% yield; H NMR (400 MHz, CDCl3) δ 7.58–7.54 (m,
2H), 7.31–7.27 (m, 2H), 3.86–3.31 (m, 8H); 13C NMR (101 MHz,
CDCl3) δ 168.4, 133.1, 130.8, 127.8, 123.2, 65.8; HRMS (ESI)
m/z calcd for C11H12BrNO2 [M+H]+ 271.1260, found 271.1284.
2-Furanyl-4-morpholinylmethanone (3i). Yellow oil; 1.12g, 93%
yield; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 1.7, 0.8 Hz, 1H),
7.03 (dd, J = 3.5, 0.7 Hz, 1H), 6.49 (dd, J = 3.5, 1.8 Hz, 1H), 3.82
(s, 4H), 3.77–3.72 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 158.1,
146.7, 142.7, 115.8, 110.4, 65.9, 29.3; HRMS (ESI) m/z calcd for
C9H11NO3 [M+H]+ 182.0772, found 182.0783.
3a
.
General procedure for synthesis of compound 3a by benzyl
alcohol with morpholine: 0.01mol of benzyl alcohol,
morpholine (0.02mol, 2eq) were dissolved in 30mL dioxane,
which was in syringe A. And H2O2 (30wt% in water, 0.05mol,
5eq), NaBr (10 mol%) and H2SO4 (1 mol%) were dissolves in
30mL dioxane, which was in syringe B. The flow rates of
syringe A and B were both 0.1mL/min. And the temperature of
the oil bath was set at 80˚C. The reaction liquid was collected,
and dissolved in ethyl acetate, washed with H2O. The organic
layer was dried over anhydrous sodium sulfate and solvent
was removed under vacuum. And the crude product was
purified by flash chromatography on silica gel by gradient
4-Morpholinyl-2-thienylmethanone (3j). Light yellow oil;
1.23g, 94% yield; 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 5.0,
1.0 Hz, 1H), 7.22 (dd, J = 3.6, 1.0 Hz, 1H), 6.97 (dd, J = 5.0, 3.7
Hz, 1H), 3.71–3.63 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 162.6,
135.6, 127.9, 127.8, 125.7, 65.8, 59.4, 20.0, 13.2; HRMS (ESI)
m/z calcd for C9H11NO2S [M+H]+ 198.0544, found 198.0568.
Benzoylpiperidine (3k). Colourless oil; 1.14g, 91% yield; 1H
NMR(400 MHz, CDCl3) δ 7.31(s, 5H), 3.63 (s, 2H), 3.27 (s, 2H),
1.70–1.35 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 169.3, 135.5,
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Org. Lett., 2004,
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, 3675. (c) Black, D. A.; Arndtsen, B. A. Org.
128.3, 127.4, 125.7, 47.7, 42.1, 25.4, 24.6, 23.6; HRMS (ESI)
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, 1991. (d) Katritzky, A. R.; Cai, C.;VSieiwngAhrti,clSe.OKn.linJe.
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1
Benzoylpyrrolidine (3l). Colourless oil; 1.05g, 90% yield; H
NMR (400 MHz, CDCl3) δ 7.43 (dt, J = 8.5, 3.7 Hz, 2H), 7.35–
7.28 (m, 3H), 3.46 (d, J = 81.7 Hz, 4H), 1.84 (s, 4H); 13C NMR
(101 MHz, CDCl3) δ 168.7, 136.2, 128.7, 127.2, 126.0, 48.6,
45.2, 25.4, 23.5; HRMS (ESI) m/z calcd for C11H13NO [M+H]+
176.1031, found 176.1045.
3
4
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron, 2005, 61,
10827.
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3405. (c) Cheng, C.; Hong, S. H. Org. Biomol. Chem., 2011,
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20.
1-Benzoyl-4-methylpiperazine (3m). Yellow oil; 1.21g, 89%
5
6
(a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem., 1996,
61, 4196. (b) Tang, P. Org. Synth., 2005, 81, 262. (c) Charville,
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1
yield; H NMR (400 MHz, CDCl3) δ 7.40–7.28 (m, 5H), 3.74 (s,
2H), 3.34 (s, 2H), 2.55–2.27 (m, 4H), 2.25 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 173.4, 169.3, 134.7, 128.7, 127.5, 126.0, 54.2,
53.6, 46.5, 44.9, 40.9, 20.5; HRMS (ESI) m/z calcd for C12H16N2O
[M+H]+ 205.1296, found 205.1305.
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N,N-Dibenzylbenzamide (3n). White solid; 1.80g, 90% yield;
m.p.=113-114°
C; 1H NMR (400 MHz, CDCl3) δ 7.51–7.11 (m,
15H), 4.70 (s, 2H), 4.40 (s, 2H); 13C NMR (101 MHz, CDCl3) δ
172.3, 136.9, 136.4, 136.2, 129.7, 128.8, 128.6, 128.4, 127.6,
127.0, 126.7, 51.6, 46.9; HRMS (ESI) m/z calcd for C21H19NO
[M+H]+ 302.1500, found 302.1509.
ACS Catal., 2015, 5, 4143.
7
(a) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.;
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Ed., 2009, 48, 4114. (c) Dang, T. T.; Zhu, Y.; Ghosh, S. C.; Chen,
N-Benzylbenzamide (3o). White solid; 1.16g, 83% yield;
m.p.=104-106
°
C; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz,
A.; Chai, C. L. L.; Seayad, A. M. Chem. Commun., 2012, 48
1805.
,
2H), 7.53–7.20 (m, 8H), 6.48 (s, 1H), 4.64 (d, J = 5.5 Hz, 2H); 13
C
NMR (101 MHz, CDCl3) δ 167.4, 138.2, 134.4, 131.5, 128.8,
128.6, 127.9, 127.6, 127.0, 44.2; HRMS (ESI) m/z calcd for
C14H13NO [M+H]+ 212.1031, found 212.1084.
8
9
(a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc., 2005,
127, 16046. (b) Chen, Z.-W.; Jiang, H.-F.; Pan, X.-Y.; He, Z.-J.
Tetrahedron, 2011, 67, 5920.
(a) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am.
Chem. Soc., 2003, 125, 3422. (b) Allen, C. L.; A. Atkinson, B.
N.; Williams, J. M. J. Angew. Chem., Int. Ed., 2012, 51, 1383.
(c) Tamura, M.; Tonomura, T.; Shimizu, K.-I.; Stasuma, A.
Green Chem., 2012, 14, 717. (d) Zhang, M.; Imm, S.; Bahn, S.;
Neubert, L.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.,
2012, 51, 3905.
N-Butylbenzamide (3p). White solid; 1.01g, 86% yield;
1
m.p.=41-43
°
C; H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 93.1,
13.0 Hz, 2H), 7.48–7.09 (m, 3H), 6.22 (d, J = 75.4 Hz, 1H), 3.53–
3.11 (m, 2H), 1.58 (dt, J = 14.0, 7.0 Hz, 2H), 1.39 (dd, J = 14.5,
7.2 Hz, 2H), 0.94 (dd, J = 9.2, 5.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 167.6, 134.9, 131.2, 128.5, 126.8, 39.8, 31.7, 20.2,
13.8; HRMS (ESI) m/z calcd for C11H15NO [M+H]+ 178.1187,
found 178.1189.
10 (a) Nakagawa, K.; Inoue, H.; Minami, K. Chem. Commun.,
1966, 17. (b) Nakagawa, K.; Mineo, S.; Kawamura, S.;
Horikawa, M.; Tokumoto, T.; Mori, O. Synth. Commun., 1979,
N-Cyclopentylbenzamide (3q). White solid; 1.05g, 84% yield;
9
, 529.
11 (a) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc., 2006, 128, 13064. (b)
Kekeli E.-K.; Christian Wolf. Org. Lett., 2007, , 3429. (c) Gao,
m.p.=133-134°
C; 1H NMR (400 MHz, CDCl3) δ 7.80–7.70 (m,
9
2H), 7.51–7.35 (m, 3H), 6.11 (s, 1H), 4.45–4.34 (m, 1H), 2.08 (td,
J = 11.4, 6.1 Hz, 2H), 1.78–1.59 (m, 4H), 1.49 (td, J = 12.5, 6.1
Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 167.2, 135.0, 131.2, 128.5,
126.8, 51.7, 33.2, 23.8; HRMS (ESI) m/z calcd for C12H15NO
[M+H]+ 190.1187, found 190.1192.
J.; Wang, G.-U. J. Org. Chem., 2008, 73, 2955. (c) Qian, C.;
Zhang, X.; Li, J.; Xu, F.; Zhang, Y.; Shen, Q. Organometallics,
2009, 28, 3856. (d) Li, J. M.; Xu, F.; Zhang, Y.; Shen, Q. J. Org.
Chem., 2009, 74, 2575. (e) Sarkar, S. D.; Studer, A. Org. Lett.,
2010,12,1992. (f) Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.;
Seayad, A. M.; Tuan, D. T.; Chen, A. Adv. Synth. Catal., 2012,
354, 1407. (g) Subhash C. G.; Joyce S. Y. Ngiam; Abdul M. S.;
Dang T. T.; Christina L. L. Chai; and Anqi Chen. J. Org. Chem.,
2012, 77, 8007.
Acknowledgements
12 Kekeli E.-K.; C. Wolf. Org. Lett., 2007, 9, 3429.
13 K. R. Reddy; C. U. Maheswari; M. Venkateshwar; M. L.
Kantam. Eur. J. Org. Chem., 2008, 14, 3619.
14 M. Karimi; D. Saberi; K. Azizi; M. Arefi; A. Heydari.
Tetrahedron Lett., 2014, 55, 5351.
The research has been supported by the National Natural
Science Foundation of China (Grant No.21522604, U1463201
and 21402240); the youth in Jiangsu Province Natural Science
Fund (Grant No.BK20150031, BK20130913 and BY2014005-03);
a
Project Funded by the Priority Academic Program 15 C. K. Liu; Z. Fang; Z. Yang; Q. W. Li; S. Y. Guo; K. Zhang; K. Guo.
Tetrahedron Lett., 2015, 56, 5973.
Development of Jiangsu Higher Education Institutions (PAPD).
16 J. J. Gu; Z. Fang; C. K. Liu; Z. Yang; X. Li; P. Wei; K. Guo. RSC
Adv., 2015, 5, 95014
17 (a) Park, C. P.; Kim, D.-P. J. Am. Chem. Soc., 2010, 132, 10102.
(b) McMullen, J. P.; Stone, M. T.; Buchwald, S. L.; Jensen, K. F.
Angew. Chem. Int. Ed., 2010, 49, 7076.
18 For reviews of microreactor, see: (a) B. P. Mason; K. E. Price;
J. L. Steinbacher; A. R. Bogdan and D. T. McQuade, Chem.
Rev., 2007, 107, 2300. (b) J.-I. Yoshida; A. Nagaki and T.
Notes and references
1
Humphrey, J. M.; Chamberlin, A. R. Chem. Rev., 1997, 97,
2243.
2
(a)Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett.,
2004, 6, 3477. (b) Shendage, D. M.; Froehlich, R.; Haufe, G.
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Yamada, Chem. Eur. J., 2008, 14, 7450. (c) Charlotte Wiles
and Paul Watts, Chem. Commun., 2011, 47, 6512.
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DOI: 10.1039/C6RA16240A
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DOI: 10.1039/C6RA16240A
Metal-free oxidative amination of aromatic aldehydes with amines in continuous
flow system under mild reaction conditions
.