A two-step continuous flow synthesis of amides from alcohol using a metal-free catalyst

Article abstract of DOI:10.1039/c5ra20838f

Metal-free oxidative amination of aromatic alcohols in the presence of TBHP provides convenient access to amides in 86-96% yield under mild reaction conditions within 15 min in a two-step continuous flow reactor system. This method avoids expensive transition metal catalysts and integrates alcohol oxidation and amide bond formation, which are usually accomplished separately, into a single operation.

Full text of DOI:10.1039/c5ra20838f

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DOI: 10.1039/C5RA20838F
A two-step continuous flow synthesis of amides from alcohol using metal-free
catalyst with good yield

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A two-step continuous flow synthesis of amides from alcohol
using metal-free catalyst
Jiajia Gu, a Zheng Fang, b Chengkou Liu, a Zhao Yang, c Xin Li, a Ping Wei a and Kai Guo *, a, d
Received 00th January 20xx,
Accepted 00th January 20xx
Metal-free oxidative amination of aromatic alcohols in the presence of TBHP provides convenient access to amides in
86−96% under mild reaction conditions within 15min in a two-step continuous flow reactor system. This method avoids
expensive transition metal catalysts and integrates alcohol oxidation and amide bond formation, which are usually
accomplished separately, into a single operation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
aldehyde in situ and then further oxidize the hemiaminal to
the desired amide via the loss of 2 equiv of H2. A common
shortcoming of these methods is that expensive transition
Introduction
The formation of amide bonds is one of the most important
organic reactions due to the abundance of this functional
group in natural products, polymers, and pharmaceuticals.
The most frequently used amide formations involve the
reaction of an amine (including ammonia) with activated
carboxylic acid derivatives
metal catalysts are required and amides are obtained in only
1, 2 moderate yields in some cases.
The coupling of an alcohol
1 with an amine 2 is expected to
proceed via oxidation of the alcohol to an aldehyde and
formation of an intermediate hemiaminal. Further oxidation of
3-7
or coupling with carboxylic acids
the hemiaminal would lead to the amide
3, while elimination
mediated by a coupling reagent. 8 These existing methods have
several common drawbacks, such as poor atom-efficiency, use
of hazardous reagents, and generation of wastes that not only
reduce process efficiency but also pose environmental
problems. More recent approach, which is quite attractive in
terms of green chemistry and economic considerations, has
considered the use of oxidative amination from aldehydes.
However, these methods require the use of expensive
transition metals as catalyst, and the use of aldehydes can be
troublesome due to their inherent reactivity.
From the recent perspective of green chemistry, the
development of efficient and practical amide formation
reactions remains a great challenge. The direct amidation of
alcohols with amines can be a potentially attractive method
since it uses cheap, abundant and stable starting materials and
has potential industrial, which can be applied in the synthesis
of water and return of hydrogen would provide amine
4
(Scheme 1). The balance between these pathways may be
expected to favor amide formation in the presence of an
oxidant or when the hemiaminal is stabilized. Generally,
hemiaminals have low stability, either reverting to carbonyl
9-16 compound and amine or undergoing dehydration. However,
there are examples of isolated hemiaminals.25, 26 From Scheme
1 we can see that alcohol oxidation and amide bond formation
are usually accomplished separately, which involves three
main consecutive steps: (1) activation-the oxidation of alcohols
to form aldehydes; (2) bond construction-the coupling of
aldehydes with amines to produce hemiaminals as reactive
intermediates; (3) dehydrogenation-subsequent oxidation of
hemiaminals to amides through H2 liberation or H transfer to a
hydrogen acceptor.
A strategy to overcome the close
“coupling” of the two oxidation steps is to design two separate
reactions to achieve the same net transformation. However,
the added complexity in multistep batch reactions, as
compared with one-pot processes, can make such
development efforts time-consuming and less efficient.
of pharmaceutical intermediates or other products such as
proline-derived amides. Recently, several groups
reported catalytic amide formation from alcohols, using
transition metal catalysts to oxidize the alcohol to the
17-24
have
a.College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
b.College of Pharmacy, Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816,
China.
c. College of Pharmacy, China School of Pharmaceutical of University, No 24.
Tongjiaxiang, Nanjing 210009, China.
d.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
Scheme 1. Oxidative amidation of alcohol with amine
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The use of continuous flow microreactors provides a improve the yield of the product, other oxidantsVwiewerAertictleesOtnelidne.
valuable platform for the development of multistep syntheses When we used TBHP (70wt% in water) aDs OoIx:i1d0a.1n0t3,9t/hC5eRyAi2e0l8d38oFf
by integrating multiple unit operations into one single network the product was improved apparently (Table 1, entry 2). H2O2
27
and eliminating the handling of intermediate species.
The and m-CPBA led to poor yield (Table 1, entry 3, 4). In the
streamlined operation renders continuous scanning of reaction absence of oxidant, the product was obtained only in trace
parameters and therefore enables fast screening of catalysts (Table 1, entry 5). Next, the temperature was investigated and
and rapid optimization of reaction conditions. At the same we observed that whether increasing the temperature to
time, the modular nature of multistep syntheses in flow allows 100˚C or reducing it to 50˚C, it led to a significant decrease in
for the reaction parameters to be individually adjusted for the amount of product 3aa. Thus, 80˚C was regarded as the
each step and makes it possible to access a substantially larger optimum temperature (Table 1, entry 2, 6, 7). The reaction
28
operating space. In 2013, Jensen and co-workers
utilizing time (Table 1, entry 2, 8, 9) and equiv number of oxidant
oxygen and urea hydrogen peroxide as oxidant to oxidize (Table 1, entry 2, 10, 11) were also investigated, which led to
alcohol to amide in continuous flow reactor. However, the best reaction conditions.
catalyst they used was Ru/Al2O3, and the reactor was complex.
Here we report a two-step continuous flow reactor to
integrate these two steps into a single operation, which are
difficult to do this in batch.
Table 1. Selected results for screening the optimized reaction conditions a
Our group has researched the oxidation of alcohol to
aldehyde in a continuous flow reactor with metal-free catalyst.
29
In the process, we used H2O2/NaBr/H+ system as oxidant to
oxidize benzyl alcohol to aldehyde, which could react with
amines to form amides in the presence of an oxidant. Then we
designed a two-step continuous flow reactor system, as shown
in Figure 1. It consists of three syringe pumps, two T-piece
micromixers and two microreactors. The volume of the syringe
and two microreactors are 20mL, 1.96mL and 13.08mL,
respectively. The mole ratio of reactants and reaction time can
be modulated by changing the flow rate of syringes. And the
temperature was controlled by oil bath.
T1
(˚C)
T2
(˚C)
t1
t2
Yield(%)
Entry
Oxidant
(min) (min)
of 3aa b
1
2
H2O2/NaBr/H+
TBHP
70
70
70
70
70
70
70
70
70
70
70
80
80
80
80
80
100
50
80
80
80
80
3
3
3
3
3
3
3
3
3
3
3
10
10
56
94
3
H2O2
10
34
4
m-CPBA
-
10
16
5
10
trace
76
6
TBHP
10
7
TBHP
10
62
8c
9d
10e
11f
TBHP
6.7
13.3
10
82
TBHP
93
TBHP
87
TBHP
10
91
a
Reaction conditions: solution A: 0.667M of 1a in dioxane, flow rate 0.327
mL/min; solution B: 1.334M of H2O2, 2 mol% of NaBr and 1 mol% of H2SO4 in
dioxane, flow rate 0.327mL/min; solution C: 0.667M of 2a, 0.667M of oxidant in
b
c
d
e
f
dioxane, flow rate 0.654mL/min, unless otherwise noted. Isolated yield.
Figure 1. A two-step continuous flow reactor system
solution C: 0.334M of 2a, 0.334M of TBHP in dioxane, flow rate 1.308mL/min.
solution C: 1.334M of 2a, 1.334M of TBHP in dioxane, flow rate 0.327mL/min.
solution C: 0.667M of 2a, 0.5M of TBHP in dioxane, flow rate 0.654mL/min.
solution C: 0.667M of 2a, 1.0M of TBHP in dioxane, flow rate 0.654mL/min.
Results and Discussion
At the outset, a model reaction of benzyl alcohol 1a and
morpholine 2a to form benzoyl morpholine 3aa was chosen to
identify the reaction system. As we had achieved the
Optimized reaction conditions for a two-step continuous
flow synthesis of benzoyl morpholine from benzyl alcohol had
been obtained. Then we used the similar conditions to test the
same reaction in batch. The yield of the product reached to
76%, which was lower than that in continuous flow system.
And the reaction time in batch was 30h, which was much
longer than 15min. Most importantly, the reaction in batch
was much more troublesome. The two oxidation steps needed
to accomplished separately, morpholine and TBHP in dioxane
were added to the reaction liquid when benzyl alcohol was
29
optimized conditions of benzyl alcohol to aldehyde, which
was the first step in this study, we would mainly optimize the
second step according to the first step of this reaction. And the
results of the optimization of the reaction conditions were
summarized in Table 1. First of all, we continued to use the
H2O2/NaBr/H+ system as oxidant, and the corresponding
product was obtained in 56% yield (Table 1, entry 1). To
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oxidized to benzaldehyde completely, which led to time- to form the hypobromite intermediate, whichViyewieAlrdtieclde Ontlhinee
consuming and less efficient. From these results we can see corresponding carbonyl compoundsDOI:v10ia.1039α/C-h5RyAd2r0o8g3e8nF
that the continuous flow system was fit for the multistep elimination. BrØnsted acid and Br- were reformatted to
reaction.
maintain the system circularly. Then the carbonyl compounds
Then we used a wide range of benzyl alcohols to test the reacted with amine to form an intermediate hemiaminal. And
substrate scope of this reaction. The results obtained are further oxidation of the hemiaminal leaded to the product
summarized in Table 2. Good to excellent yields were obtained amide.
in most cases. The TBHP-promoted oxidative amination
provided convenient access to both electron-deficient and
Table 3. Scope of amine a
electron-rich arylamides
alcohols 1k and 1l gave the corresponding benzoyl morpholine
in good yields (3ka 3la).
(3aa-3ja). Similarly, heterocyclic
,
Table 2. Scope of benzyl alcohol a
a
Reaction conditions: solution A: 0.667M of 1a in dioxane, flow rate 0.327
mL/min; solution B: 1.334M of H2O2, 2 mol% of NaBr and 1 mol% of H2SO4 in
dioxane, flow rate 0.327mL/min, T1 =70˚C; solution C: 0.667M of 2a, 0.667M of
oxidant in dioxane, flow rate 0.654mL/min, T2 =80˚C.
a
Reaction conditions: solution A: 0.667M of 1a in dioxane, flow rate 0.327
mL/min; solution B: 1.334M of H2O2, 2 mol% of NaBr and 1 mol% of H2SO4 in
dioxane, flow rate 0.327mL/min, T1 =70˚C; solution C: 0.667M of 2a, 0.667M of
oxidant in dioxane, flow rate 0.654mL/min, T2 =80˚C.
Scheme 2. Proposed mechanism of the oxidative amination of alcohol
A wide range of secondary amines had also been used to
test the substrate scope of the reaction, and the results were
shown in Table 3. The formation of several benzamides
Conclusions
occurred with excellent yields (3aa-3ah). However, only low
In summary, we have developed an efficient and direct
synthesis of amides from alcohols in continuous flow system.
yields (42%) were obtained when diethylamine was used (3ai).
Importantly, proline-derived amides can be prepared in
excellent yields (3af). And when primary amine was used, it
could not get the amide product.
The mechanism of oxidative amidation of alcohol with
amine can be divided into two steps (Scheme 2). 29 Initially, Br-
was oxidized to form the hypobromous acid in the presence of
acid and hydrogen peroxide. The generated hypobromous acid
subsequently reacted with the corresponding hydroxyl group
This transition-metal-free strategy provides
a practical
synthesis of various amides and integrates alcohol oxidation
and amide bond formation, which are usually accomplished
separately, into a single operation. It also clearly shows the
major advantage of continuous multistep systems to allow
chemical or reaction parameters to be independently
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adjusted, hence providing a larger design space for developing 3.86–3.31 (m, 8H); 13C NMR (101 MHz, CDClV3i)ewδArti1cl6e8O.n3lin8e,
DOI: 10.1039/C5RA20838F
chemical reactions or systems.
133.08, 130.82, 127.83, 123.25, 65.81.
1
N-(3-Methybenzoyl)morpholine (3ga).32 Light yellow oil. H
NMR (400 MHz, CDCl3) δ 7.23–7.18 (m, 1H), 7.14 (dt, J = 10.8,
5.5 Hz, 2H), 7.09 (d, J = 7.4 Hz, 1H), 3.87–3.19 (m, 8H), 2.28 (d,
J = 8.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.59, 137.47,
134.28, 129.54, 127.34, 126.67, 122.95, 65.87, 47.15, 41.44,
20.34.
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
60 F254, visualizing with ultraviolet light. 1H/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.
1
N-(2-Methybenzoyl)morpholine (3ha).32 Light yellow oil. H
NMR (400 MHz, CDCl3) δ 7.23–7.17 (m, 1H), 7.17–7.10 (m, 2H),
7.08 (d, J = 7.2 Hz, 1H), 3.79–3.65 (m, 4H), 3.49 (s, 2H), 3.16 (d,
J = 4.5 Hz, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
169.07, 134.61, 133.15, 129.48, 128.03, 124.98, 124.80, 65.94,
46.23, 40.88, 25.88, 17.99.
N-(3-Chlorobenzoyl)morpholine (3ia).30 Colourless oil. 1H
NMR (400 MHz, CDCl3) δ 7.35–7.24 (m, 3H), 7.23–7.17 (m, 1H),
3.83–3.23 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 167.77,
136.02, 133.64, 129.00, 128.97, 126.26, 124.14, 65.77, 46.99,
41.45, 25.88.
1
N-(2-Chlorobenzoyl)morpholine (3ja).30 Light yellow solid. H
General procedure for synthesis of compound 3: 0.02mol of
benzyl alcohol 1 was dissolved in 30mL dioxane, which was in
syringe A. And H2O2 (30wt% in water, 0.04mol, 2eq), NaBr (2
mol%) and H2SO4 (1 mol%) were dissolved in 30mL dioxane,
NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 1H), 7.37–7.27 (m, 3H),
3.89 (ddd, J = 16.6, 11.3, 5.6 Hz, 1H), 3.83–3.73 (m, 3H), 3.73–
3.65 (m, 1H), 3.63–3.55 (m, 1H), 3.34–3.16 (m, 2H); 13C NMR
which was in syringe B. Secondary amine 2 (0.02mol, 2eq) and (101 MHz, CDCl3) δ 165.95, 134.37, 129.35, 129.32, 128.68,
126.83, 126.28, 65.80, 65.71, 46.10, 41.05.
TBHP (70wt% in water, 0.02mol, 2eq) were dissolves in 30mL
dioxane, which was in syringe C. The flow rate of syringe A, B
and C were 0.327mL/min, 0.327mL/min, and 0.654mL/min,
respectively. And the temperature of the two oil baths was set
in 70˚C and 80˚C, respectively. 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
4-Morpholinyl-2-thienylmethanone (3ka).32 Light yellow oil.
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 162.63, 135.57, 127.94,
127.85, 125.75, 65.82, 59.36, 20.03, 13.18.
2-Furanyl-4-morpholinylmethanone (3la).23 Yellow oil. 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 158.11,
146.76, 142.76, 115.81, 110.38, 65.96, 29.30.
obtain the amide product 3.
Benzoylpiperidine (3ab).23 Colourless oil. H NMR(400 MHz,
1
Benzoyl morpholine (3aa).23 White solid, H NMR(400 MHz,
CDCl3) δ 7.38–7.31 (m, 5H), 3.80–3.28 (m, 8H). HRMS (ESI) m/z
calcd for C11H13NO2 [M+H]+ 192.1019, found 192.1040.
1
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 169.29, 135.51, 128.32,
127.37, 125.76, 47.75, 42.11, 25.44, 24.61, 23.57.
N-(4-Methybenzoyl)morpholine (3ba).23 Light yellow oil. H
1
Benzoylpyrrolidine (3ac).23 Colourless oil. H NMR(400 MHz,
1
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
169.64, 139.08, 131.31, 128.13, 126.21, 65.90, 29.30, 20.37.
CDCl3) δ 7.51–7.26 (m, 5H), 3.56 (s, 2H), 3.36 (s, 2H), 1.84 (s,
4H); 13C NMR (101 MHz, CDCl3) δ 168.74, 136.17, 128.76,
127.22, 126.05, 48.57, 45.16, 25.36, 23.51.
(
3ad).33 Yellow oil. 1H
N-(4-Methoxybenzoyl)morpholine
(
3ca).23 Yellow oil. 1H
1-Benzoyl-4-methylpiperazine
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 169.43, 159.90, 128.19, 126.32, 112.78, 65.92, 54.35.
NMR(400 MHz, CDCl3) δ 7.59–7.27 (m, 5H), 3.74 (s, 2H), 3.58–
3.24 (m, 2H), 2.65–2.12(m, 7H); 13C NMR (101 MHz, CDCl3) δ
173.36, 169.33, 134.73, 128.68, 127.46, 126.01, 54.16, 53.62,
46.50, 44.89, 40.92, 20.48.
1
N-(4-Nitrobenzoyl)morpholine (3da).10 Light yellow solid. H
1-Benzoyl-4-Bocpiperazine (3ae).33 White solid. H NMR(400
1
NMR(400 MHz, CDCl3) δ 8.34–8.26 (m, 2H), 7.62–7.55 (m, 2H),
3.87–3.31 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 167.04,
147.49, 140.41, 127.13, 122.96, 65.73.
MHz, CDCl3) δ 7.46–7.34 (m, 5H), 3.73 (s, 2H), 3.41 (s, 6H), 1.46
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.60, 153.55, 134.47,
128.90, 127.58, 126.02, 79.34, 46.34, 42.85, 27.35.
N-(4-Chlorobenzoyl)morpholine (3ea).30 White solid. 1H 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 168.37, 135.03, 132.61, 127.86,
127.65, 99.96, 65.83.
(S)-tert-Butyl-N-benzoylprolinate (3af).34 White solid. 1H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2H), 7.31 (dd, J =
15.5, 6.6 Hz, 5H), 4.48 (dd, J = 8.0, 5.6 Hz, 1H), 3.72 (t, J = 6.5
Hz, 1H), 3.55 (dt, J = 13.8, 7.0 Hz, 1H), 3.43 (dd, J = 13.1, 8.7 Hz,
1H), 1.99–1.87 (m, 4H), 1.43 (s, 9H), 1.33–1.13 (m, 18H); 13C
N-(4-Bromobenzoyl)morpholine (3fa).31 Light yellow solid. 1H
NMR (400 MHz, CDCl3) δ 7.58–7.54 (m, 2H), 7.31–7.27 (m, 2H),
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17 Gunanathan, C.; Ben-David, Y.; Milstein, D. SVciieewnAcretic,le2O0n0lin7e,
NMR (101 MHz, CDCl3) δ 170.44, 168.52, 138.26, 135.51,
129.01,128.66, 127.29, 127.21, 126.19, 125.77, 113.05, 80.29,
61.02, 58.93, 48.93, 45.65, 32.81, 30.91, 29.12, 28.68, 28.43,
28.34, 27.01, 26.73, 24.36, 21.67, 21.67, 13.10.
317, 790.
DOI: 10.1039/C5RA20838F
18 Zweifel, T.; Naubron, J.-V.; Grützmacher, H. Angew. Chem.,
Int. Ed., 2008, 48, 559.
19 Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.,
2008, 130, 17672.
20 Andrew J. A. Watson, Aoife C. Maxwell, and Jonathan M. J.
Williams. Org. Lett., 2009, 11, 2667.
21 De Sarkar, S.; Studer, A. Org. Lett., 2010, 12, 1992.
22 Xu, K.; Hu, Y.; Zhang, S.; Zha, Zh.; Wang, Zh. Chem. Eur. J.,
2012, 18, 9793.
23 Jiang L., Zh., Yan Zh., Feng Sh., You Q. D. Tetrahedron Lett.,
2012, 53, 3178.
24 Kobra Azizi, Meghdad Karimi, Fatemeh Nikbakht, Akbar
Heydari. Applied Catalysis A: General, 2014, 482, 336.
25 Heine, A.; DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C. H.;
Wilson, I. A. Science, 2001, 294, 369.
N-Benzyl-N-methylbenzamide (3ag).33 Colourless oil. 1H NMR
(400 MHz, CDCl3) δ 7.42–7.00 (m, 10H), 4.67 (s, 1H), 4.42 (s,
1H), 2.85 (d, J = 69.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
170.91, 136.02, 135.58, 135.21, 128.58, 127.72, 127.40,
127.14, 126.53, 125.86, 54.13, 49.75, 35.97, 32.14, 28.65.
N-Methyl-N-phenylbenzamide
(
3ah).35 Colourless oil. 1H
NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 7.9, 6.6 Hz, 2H), 7.16–
7.02 (m, 6H), 6.95 (d, J = 7.6 Hz, 2H), 3.42 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 169.64, 143.88, 134.90, 128.55, 128.10, 127.67,
126.68, 125.87, 125.45, 37.36.
N,N-Diethylbenzamide (3ai).35 Colourless oil. 1H NMR(400
MHz, CDCl3) δ 7.60–7.30 (m, 5H), 3.54 (s, 2H), 3.25 (s, 2H),
1.27–0.98 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 170.32,
136.24, 128.08, 127.37, 125.26, 42.26, 38.25, 30.49, 29.12,
13.18, 11.89.
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29 Ch. K. Liu; Zh. Fang; Zh. Yang; Q. W. Li; Sh. Y. Guo; K. Zhang
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Acknowledgements
The research has been supported by National Key Basic
Research Program of China (973 Program) 2012CB725204; the 30 Pilo, M.; Porcheddu, A.; De Luca, L. Org. Biomol. Chem.,
2013, 11, 8241.
National High Technology Research and Development Program
of China (863 Program) 2014AA022101; the National Natural
Science Foundation of China (Grant No.U1463201, 81302632
and 21402240); the youth in Jiangsu Province Natural Science
Fund (Grant No.13KJA150002, BK20130913 and BY2014005-
03); a Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
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