One-Pot Synthesis of Tertiary Amides from Organic Trichlorides through Oxygen Atom Incorporation from Air by Convergent Paired Electrolysis

Article abstract of DOI:10.1021/acs.joc.1c00161

A convergent paired electrolysis catalyzed by a B12 complex for the one-pot synthesis of a tertiary amide from organic trichlorides (R-CCl3) has been developed. Various readily available organic trichlorides, such as benzotrichloride and its derivatives, chloroform, dichlorodiphenyltrichloroethane (DDT), trichloro-2,2,2-trifluoroethane (CFC-113a), and trichloroacetonitrile (CNCCl3), were converted to amides in the presence of tertiary amines through oxygen incorporation from air at room temperature. The amide formation mechanism in the paired electrolysis, which was mediated by a cobalt complex, was proposed.

Full text of DOI:10.1021/acs.joc.1c00161

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Note
One-Pot Synthesis of Tertiary Amides from Organic Trichlorides
through Oxygen Atom Incorporation from Air by Convergent Paired
Electrolysis
Zhongli Luo, Kenji Imamura, Yoshihito Shiota, Kazunari Yoshizawa, Yoshio Hisaeda,*
and Hisashi Shimakoshi*
Cite This: J. Org. Chem. 2021, 86, 5983−5990
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ABSTRACT: A convergent paired electrolysis catalyzed by a B12 complex for the
one-pot synthesis of a tertiary amide from organic trichlorides (R-CCl3) has been
developed. Various readily available organic trichlorides, such as benzotrichloride
and its derivatives, chloroform, dichlorodiphenyltrichloroethane (DDT), trichloro-
2,2,2-trifluoroethane (CFC-113a), and trichloroacetonitrile (CNCCl3), were
converted to amides in the presence of tertiary amines through oxygen
incorporation from air at room temperature. The amide formation mechanism in
the paired electrolysis, which was mediated by a cobalt complex, was proposed.
such as the oxidative amidation of alcohols or aldehydes with
uring the past decade, electroorganic synthesis has been
Drecognized as a green and sustainable process in the field amines, the carbonylation of aryl iodides and tertiary amines
using palladium catalyst, etc.6
of synthetic organic chemistry.1 The electrochemical method
serves as a straightforward and powerful technique to
electrochemically activate the substrate by an electrode
process, the so-called direct electrolysis. As an electric current
could replace the traditional chemical oxidants and reductants
in electrochemistry, electroorganic synthesis offers a mild and
efficient protocol for various molecular transformations in both
academic and industrial chemistries.2
We now describe the convergent paired electrochemical
synthesis of tertiary amides from various organic trichlorides,
including environmental pollutants, which is catalyzed by the
B12 complex heptamethyl cobyrinate (1)7 in air at room
temperature as shown in Scheme 1. The paired electrolysis
simultaneously produces products at both the cathode and the
anode and also optimizes the energy efficiency of the oxidation
and reduction processes.8 The electricity on both electrodes is
effectively utilized for the desired reactions. Among the paired
Other attention has focused on the electrochemical
elimination of organic pollutants such as organohalogen
waste since many organohalogen compounds, including
organic trichlorides (RCCl3) such as DDT or chlorofluor-
ocarbons (CFCs), are dispersed in the environment.3 There-
fore, considerable interest has focused on the electrochemical
reduction of such organic halides for both the degradation of
these substances and a fundamental understanding of their
redox behavior.4 Recently, we reported the unique trans-
formation of benzotrichloride to an ester or amide by aerobic
electrolysis using the bioinspired cobalt complex, a B12
derivative, as a mediator (indirect electrolysis).5 The electro-
chemically formed Co(I) species reacts with benzotrichloride
to form oxygen-incorporated products, i.e., an ester or amide,
in the presence of an alcohol or amine in air. Acyl chloride
could be formed as an intermediate of these reactions. This
unique molecular transformation prompted us to develop
various tertiary amide syntheses in a green electrochemical
method. As the amide is the key building block in natural
products, agrochemicals, biologically and pharmaceutically
active compounds, and functional materials, effective and
efficient methodologies for amide synthesis have been studied,
Scheme 1. Convergent Paired Electrolysis for the Amide
from Organic Trichloride with a Tertiary Amine Catalyzed
by a B12 Complex (1)
Received: January 21, 2021
Published: April 2, 2021
https://doi.org/10.1021/acs.joc.1c00161
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5983−5990
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Note
a
electrolyses, a convergent paired electrolysis produces
intermediates at the cathode and the anode, and the
subsequent reaction of the intermediates could produce the
target product without any loss of the electricity.8a,b The direct
synthesis of a tertiary amide with tertiary amines from organic
trichlorides through oxygen incorporation from air by a
convergent paired electrolysis is reported in this study.9 The
development of the substrate scope and mechanistic studies
were also conducted.
Before the bulk electrolysis, cyclic voltammetry (CV) studies
were conducted to investigate the cathodic and anodic process
of 1 with RCCl3 and a tertiary amine as shown in Figures S1
and S2, respectively. A reversible Co(II)/Co(I) redox couple
of 1 was observed at −0.59 V vs. Ag/AgCl under N2 in
CH3CN. The addition of 50 equiv mol of benzotrichloride (2)
changed the voltammetric pattern of 1, and a new irreversible
wave was observed around −0.6 V vs. Ag/AgCl in air. The
appearance of a large catalytic current peak implies the efficient
reaction of the Co(I) species of 1 with 2, while an irreversible
anodic oxidation peak was observed for triethylamine (3) in
CN3CN in air. A tertiary amine is known to cause oxidative
dealkylation to form a dialkyl amine and an aldehyde in the
presence of H2O.10 These CV studies suggest the potential for
the desired paired electrolysis of RCCl3 and the tertiary amine
mediated by 1 in air at room temperature.
Table 1. Reaction Optimization
conversion
yield
b
a
b
entry
conditions
as shown
as shown
as shown
as shown
as shown
as shown
as shown
electrode
(%)
(%)
1
2
3
4
5
C(−)−C(+)
Pt(−)−Pt (+)
C(−)−Pt(+)
Pt(−)−C(+)
C(−)−Zn(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
C(−)−C(+)
99
64
99
55
99
99
44
trace
90
99
95
61
73
53
12
c
d
6
e
0
7
35
trace
66
20
41
8
9
10
11
no catalyst
+1.3 V vs. Ag/AgCl
dry CH3CN
f
g
as shown
60
0
92
12
13
no electricity
as shown
0
89
h
a
Conditions are as follows: [1] = 1.25 × 10−4 M, [2] = 2.5 × 10−2 M,
[3] = 1.4 × 10−1 M, [nBu4NClO4] = 1 × 10−1 M, and solvent
CH3CN at room temperature. Applied potentials were −0.6 V vs. Ag/
b
AgCl for 3 h. Conversions of 2 and the yields of the product (4)
c
were based on the initial concentration of the substrate. Electrolysis
was carried out in the glovebox (O2 < 1 ppm). Mixture of (Z)- and
(E)-1,2-dichlorostilbenes (50 and 51, respectively) were formed at
70% and 16%, respectively. Under O2. H2O < 100 ppm. An imine/
oxime-type cobalt complex (5) was used as the catalyst. Gram scale
electrolysis was carried out using 1.03 g of 2 in CH3CN containing of
0.1 M nBu4NPF6.
d
The convergent paired electrolysis of 2 with 3 was carried
out in an undivided cell equipped with a carbon felt (C) or a
Pt mesh cathode and a C, Pt, or Zn plate anode in air at room
e
f
g
h
n
temperature in 0.1 M Bu4NClO4, which contained CH3CN.
The optimization of the reaction, including the control
reaction, is summarized in Table 1. When the electrolysis
was carried out at −0.6 V vs. Ag/AgCl in air using the C(+)−
C(−) electrode pair with 0.5 mol % 1, N,N-diethylbenzamide
(4) was obtained in a 95% yield with an excellent selectivity
(Table 1, entry 1). The turnover number of catalyst 1 was 190.
During the electrolysis, a +1.2 to +1.3 V vs. Ag/AgCl potential
was charged on the noncontrolled counter anode, which
allowed the oxidation of 3.11 The electrode materials had an
influence on this reaction, and other electrode pairs afforded
only moderate 53−73% yields of 4 (Table 1, entries 2−4).
When Zn was used as the anode, the yield of 4 decreased to
12% since Zn worked as a sacrificial electrode that disturbed
the oxidation of 3 (Table 1, entry 5). When the electrolysis was
carried out under N2 (in the glovebox, O2 < 1 ppm), almost all
of 2 was consumed after 3 h of electrolysis, and dechlorinated
products, (Z)- and (E)-1,2-dichlorostilbenes (50 and 51,
respectively), were obtained instead of 4 (Table 1, entry 6). In
contrast, too much oxygen disturbed the reaction, and the
conversion of 2 was only 44% after 3 h of electrolysis because
oxygen quenched the labile Co(I) species (Table 1, entry 7).
Without a catalyst, the reaction did not proceed under the
same conditions (Table 1, entry 8). When the anodic potential
was controlled at +1.3 V vs. Ag/AgCl based on the oxidation
potential of 3 (Figure S2), 66% of 4 was obtained (Table 1,
entry 9), while the ca. −0.8 V vs. Ag/AgCl potential was
charged on the noncontrolled counter cathode during the
electrolysis. The yield of 4 decreased to 20% in dry CH3CN
(H2O < 100 ppm) since H2O is necessary for the formation of
diethyl amine by the hydrolysis of the oxidized intermediate of
3 (Table 1, entry 10).10 The imine/oxime-type cobalt complex
(5) [Co(III){(C2C3)(DO)(DOH)pn}Br2] (see Chart S1 in
the Supporting Information), which is a well-known functional
model compound of B12,12 showed a low reactivity with a 41%
yield of the product (Table 1, entry 11), probably due to its
low stability under aerobic electrolysis conditions.13 The B12
complex 1 is a tough and excellent catalyst for the reaction. No
desired product could be produced without electricity (Table
1, entry 12). Notably, the gram-scale electrolysis was easily
designed due to the simple setup of the reaction system in the
paired electrolysis, and a 20× substrate concentration with 1.03
g of 2 afforded an 89% yield of 4 using cheap C electrodes
(Table 1, entry 13).
With the optimized reaction conditions in hand,14 the
aerobic convergent paired electrolysis for the formation of an
amide was applied to other substrates, i.e., benzotrichloride
derivatives, DDT, chloroform (CHCl3), 1,1,1-trichloroethane
(CH3CCl3), CFC-113a (CF3CCl3), trichloroacetonitrile
(CNCCl3), etc., as shown in Scheme 2A. The corresponding
diethylamides (6−20) were obtained in moderate to good
yields. When 3-methylbenzotrichloride was used as the
substrate, N,N-diethyl-3-methylbenzamide (11) was obtained
in a 90% yield as a mosquito repellent, DEET.15 From
trichloroacetonitrile (CNCCl3), cyanoformamide (20) was
obtained in a 90% yield. The tertiary amine scope was also
investigated, as shown in Scheme 2B. A variety of the tertiary
amides (4 and 21−26) were obtained from 2 with the
symmetric tertiary amines in moderate to good yields.
When the asymmetric tertiary amines (27−30) were used as
the anodic substrate, asymmetric dialkylamides (35−37,
respectively) were obtained with symmetric dialkylamides
(21 and 4) as byproducts, as shown in Scheme 3. From the
cyclic asymmetric tertiary amines (31−33), cyclic dialkyla-
mides (38−40) were obtained in moderate yields. Notably, N-
acylpiperidine (39), a more promising mosquito repellent than
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Note
a
a
Scheme 2. Reaction Scope
Scheme 3. Asymmetric Tertiary Amine Scope
a
Conditions are as follows: [1] = 1.25 × 10−4 M, [2] = 2.5 × 10−2 M,
[amine] = 1.4 × 10−1 M, and [nBu4NClO4] = 1 × 10−1 M at room
temperature. Applied potentials were −0.6 V vs. Ag/AgCl for 3 h.
b
The conversion of substrate PhCCl3 and the yield of the product
c
were based on the initial concentration of the substrate. No other
amide product was obtained. The oxidation potential (Epa) of 34 is >
d
+1.8 V vs. Ag/AgCl in CH3CN (Figure S4).
Scheme 4. Application of the Paired Electrolysis for Dual
Amidation
a
Conditions are as follows: [1] = 1.25 × 10−4 M, [R−CCl3] = 2.5 ×
10−2 M, [3] = 1.4 × 10−1 M, and [nBu4NClO4] = 1 × 10−1 M at room
temperature. Applied potentials were −0.6 V vs. Ag/AgCl for 3 h. The
yields of the product were based on the initial concentration of the
b
substrate. Applied potentials were −1.1 V vs. Ag/AgCl for 3 h.
c
Conditions are as follows: [1] = 2.5 × 10−4 M, [R−CCl3] = 5.0 ×
10−2 M, and [3] = 7 × 10−1 M. Applied potentials were −0.9 V vs.
d
e
Ag/AgCl for 3 h. Solvent DMF. The applied potential was −0.8 V
vs. Ag/AgCl.
DEET, was obtained by this method.16 It is noted that no
amide product was obtained when diethyl cyanoamine (34)
was used as the anodic substrate, since the oxidation potential
of 34 is over +1.8 V vs. Ag/AgCl in CH3CN (Figure S15) and
no desired diamine could be formed by the anodic reaction.
Moreover, the paired electrolysis was applied for the
bifunctional substrate with 1 mol % B12 catalyst, as shown in
Scheme 4. From carbon tetrachloride (41) with 3,
tetraethylurea (42) and diethylcarbamoyl chloride (43) were
obtained under optimized conditions in 52% and 12% yields,
respectively. From 1,1,1,2,2,2-hexachloroethane (44) with 3,
N,N,N′,N′-tetraethyl oxamide (45) was obtained in a 48%
yield. As ureas and oxamides are important carbonyl
compounds in organic synthesis, the one-pot synthesis of
these compounds under mild conditions should have a
significant impact in both the academic and industrial
chemistries.17
The proposed reaction mechanism is shown in Scheme 5.
The dichloromethylbenzene radical (A) should be formed
from the trichloromethylbenzene (2) by the Co(I) species of
1.5,9 The radical A may rapidly react with oxygen to form the
peroxy radical (B).18 The coupling and subsequent elimination
of oxygen may form the oxy radical D. The disproportionation
of D should form the acyl chloride as an intermediate.19 At the
same time, the tertiary amine was oxidized at the anode to give
a radical cation (E), which would decompose into the
dialkylamine (59) by hydrolysis.20 The acyl chloride species
should react with the dialkylamine to form the tertiary amides.
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cathodic and anodic reactions are effectively utilized for the
desired organic synthesis without the need for sacrificial redox
reagents. Notably, this method can also be scaled up for the
practical synthesis of amides using cheap carbon- felt
electrodes in a simple undivided cell. Further applications of
the paired electrolysis reactions are ongoing in our laboratory.
Scheme 5. Proposed Mechanism
EXPERIMENTAL SECTION
■
Chemicals. All solvents and chemicals used in this study were of
reagent grade and used without further purification unless otherwise
noted. Dry CH3CN was purchased from Kanto Kagaku, and the water
content was measured before use of ca. 100 ppm. The heptamethyl
cobyrinate perchlorate (1) (Chart S1) was synthesized by a previously
reported method.24 The cobalt complex Co(III){(C2C3)(DO)-
(DOH)pn}Br2 (5) (Chart S1) ((C2C3)(DO)(DOH)pn is the
deprotonated form of 4,10-dipropyl-5,9-diazatrideca-4,9-diene-3,10-
dione dioxime) was prepared according to the literature.25 Authentic
samples of the amide products from the catalytic reactions were
purchased from Aldrich or Tokyo Kasei Kogyo (TCI). Other
compounds were isolated by chromatography (Silica Gel 60N,
spherical, neutral) using dichloromethane/n-hexane (1:1) as the
1
eluent and identified by GC-MS, H NMR, 13C NMR, HR-MS (EI),
The actual formation of the acyl chloride (56) was confirmed
by GC-MS during the electrolysis of 3,4-dichlorobenzotri-
chloride (55) in the absence of a tertiary amine, as shown
Scheme S1B (see Figure S17). To support this mechanism, an
ESR spin-trapping experiment was also conducted using 5,5-
dimethylpyrroline N-oxide (DMPO), and the ESR signal for
the oxygen-centered radical-trapped DMPO (58)21 (g = 2.009,
AN = 13.5 G, and AH = 7.7 G) was observed during the
electrolysis of 4-chlorobenzotrichloride (57) in air, as shown in
Scheme S1C. Under this condition, the yield of 10 decreased
to 5%. To help understand the reaction of the carbon-centered
radical A with O2 to form acyl chloride, we performed DFT
calculations using the B3LYP functional combined with the 6-
31G** basis. All the calculated energies are summarized in
Figure 1. The DFT calculations support the proposed
and IR techniques. Oxygen gas (18O2) (97.0% atom 18O) was
purchased from Shoko Co., Ltd. and used as received. 3-
Methylbenzotrichloride, the substrate for the electrochemical syn-
thesis of DEET (11), was synthesized according to the literature.26
Measurements. The elemental analyses were obtained from the
Service Center of Elementary Analysis of Organic Compounds at
Kyushu University. The NMR spectra were recorded by a Bruker
Avance 500 spectrometer and a Bruker Avance NEO 400
spectrometer at the Center of Advanced Instrumental Analysis of
Kyushu University. The ESR spectra were measured using a Bruker
EMX-Plus X-band spectrometer at room temperature. The UV−vis
absorption spectra were measured by a Hitachi U-3300 spectropho-
tometer at room temperature. The MALDI-TOF mass spectra were
obtained by a Bruker autoflex II instrument using 6-aza-2-thiothymine
as the matrix. The high resolution-mass spectra of the new
compounds (15, 35, and 36) were obtained by a JEOL JMS-700
instrument using m-nitrobenzylalcohol as the matrix. The gas
chromatography−mass spectra (GC-MS) were obtained using a
Shimadzu GCMS-QP5050A instrument equipped with a J&W
Scientific DB-1 column (length of 30m, ID of 0.25 mm, and film of
0.25 μm) and helium as the carrier gas. For the measurement, the
injector and detector temperatures were 250 °C, and the oven
temperature was initially held at 100 °C for 2 min and then increased
to 240 °C at a rate of 10 °C/min. The gas chromatography (GC) data
were obtained using a Shimadzu GC-2010 instrument equipped with
a J&W Scientific DB-1 column (length of 30m, ID of 0.25 mm, and
film of 0.25 μm) and argon as the carrier gas. For the measurement,
the injector and detector temperatures were 250 °C, and the oven
temperature was initially held at 100 °C for 2 min and then increased
to 240 °C at a rate of 10 °C/min. The IR spectra were recorded by a
JASCO FT-IR 460 plus KH spectrophotometer using KBr discs. The
cyclic voltammogram (CV) was obtained using a BAS CV 50 W
electrochemical analyzer. A three-electrode cell equipped with a 3.0
mm diameter glassy carbon (GC) rod and a 1.6 mm diameter
platinum (Pt) wire as the working and counter electrodes,
respectively, were used. An Ag/AgCl (3.0 M NaCl) electrode served
as the reference. Acetonitrile solutions containing 1 (1.0 × 10−3 M)
and nBu4NClO4 (1.0 × 10−1 M) were deaerated prior to each
measurement, and the inside of the cell was maintained under a
nitrogen atmosphere throughout each measurement. With this setup,
the E1/2 value of ferrocene/ferrocenium (Fc/Fc+) was +0.44 V vs. Ag/
AgCl. The water content in the CH3CN solvent was measured by a
Karl Fischer moisture analyzer (Metrohm 831 KF).
Figure 1. Computed energy diagrams for the acyl chloride (60)
formation step. Units are in kilocalories per mole.
mechanism of the energetically preferred acyl chloride
formation. Thus, the formed acyl chloride should react with
the dialkylamine to form the tertiary amide.22 Finally, the
incorporation of oxygen into the amide was confirmed using
18O2. In the MS analysis for the electrolysis of 2, the parent
peak was observed at m/z 177 for 4 in air, while corresponding
parent peak for 4′ (18O) observed at m/z 179 under 18O2, as
shown in Scheme S1D (see Figure S18).
General Procedure for Paired Electrolysis. The controlled-
potential electrolysis of benzotrichloride (2) was carried out in a one-
compartment cell equipped with a carbon felt cathode and anode (1 ×
3 cm2) at −0.6 V vs. Ag/AgCl in the presence of 1 at room
In summary, we have developed a convergent paired
electrolysis method for the direct synthesis of tertiary amides
from organic trichlorides under mild conditions. Both the
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n
temperature in 0.14 M triethylamine (3) and 0.1 M Bu4NClO4 that
contained 10 mL of CH3CN in air at room temperature. The applied
potential for the electrolysis between the working and reference
electrodes was kept constant using a Hokuto Denko HA BF-501A
potentiostat, and the electrical quantity was also recorded. The
concentrations of the catalyst (1) and substrate (2) were 1.25 × 10−4
and 2.5 × 10−2 M, respectively. After the electrolysis, the electrolyte
solution was passed through silica gel using a CHCl3 eluent, then
4-Chloro-N,N-diethylbenzamide (12).36 Yellow oil, 47 mg, 89%
1
yield. GC-MS m/z 211. H NMR (400 MHz, CDCl3): δ 7.39−7.36
(m, 2H), 7.33−7.31 (m, 2H), 3.53 (bs, 2H), 3.24 (bs, 2H), 1.24 (bs,
3H), 1.12 (bs, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 170.2,
135.7, 135.1, 128.7, 127.8, 43.3, 39.4, 14.2, 12.9.
N,N-Diethyl-2-oxo Butyramide (13).34 Colorless oil, 47 mg, 93%
1
yield. GC-MS m/z 173. H NMR (500 MHz, CDCl3): δ 4.36−4.31
(q, J = 7.25 Hz, 2H), 3.45−3.41 (q, J = 7.25 Hz, 2H), 3.31−3.27 (q, J
= 7.25 Hz, 2H), 1.38−1.35 (t, J = 7.25 Hz, 3H), 1.25−1.17 (m, 6H).
13C{1H} NMR (125 MHz, CDCl3): δ 163.3, 161.5, 61.8, 42.4, 39.1,
14.2, 14.0, 12.5.
analyzed by GC-MS, H NMR, and 13C NMR. All other products in
the paired electrolysis were purified by the same method.
1
Gram-Scale Paired Electrolysis. A 20× scale-up of the
electrolysis of 2 (1.03 g, 1.25 × 10−4 M) was carried out at −0.6 V
vs. Ag/AgCl in the presence of 1 (1.25 × 10−4 M) at room
temperature in 0.1 M nBu4NPF6 and 0.14 M 3 that contained 200 mL
of CH3CN with same reaction conditions as general procedure. After
electrolysis, the product was purified by silica gel chromatograph
(CHCl3 eluent), and 0.788 g (89% yield) of 4 was obtained.
ESR Spin-Trapping Experiment. The ESR spectra of the DMPO
spin-adduct were observed after 1 h of electrolysis at −0.6 V vs. Ag/
N,N-Diethyl-α-oxo-1H-pyrrole-2-acetamide (14).34 Colorless oil,
1
37 mg 76% yield. GC-MS m/z 194. H NMR (500 MHz, CDCl3): δ
9.58 (bs, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 6.35−6.33 (m, 1H), 3.54−
3.50 (q, J = 7.25 Hz, 2H), 3.36−3.32 (q, J = 7.25 Hz, 2H), 127−1.24
(t, J = 7.25, 3H), 1.21−1.18 (t, J = 7.25 Hz, 3H). 13C NMR{1H} (125
MHz, CDCl3): δ 180.0, 166.3, 129.6, 126.9, 120.4, 111.7, 42.4, 39.2,
14.3, 12.7.
α-(Acetyloxy)-N,N-diethylbenzeneacetamide (15). White solid,
n
1
AgCl in 0.1 M Bu4NClO4 that contained CH3CN in air at room
37 mg, 60% yield. GC-MS m/z 248 (M-1). H NMR (500 MHz,
temperature, where [1] = 1.25 × 10−4 M, [2] = 2 0.5 × 10−2 M, [3] =
1.4 × 10−1 M, and [DMPO] = 6.25 × 10−2 M. The settings for the
ESR measurements were as follows: a frequency of 9.78 GHz, a power
of 1.0 mW, a center field of 3515 G, a sweep width of 150 G, a
modulation amplitude of 3.0 G, a time constant of 40 ms, and a sweep
time of 20 s.
CDCl3): δ 7.46−7.39 (m, 5H), 6.18 (s, 1H), 3.154−3.50 (m, 1H),
1.31−3.24 (m, 2H), 319−3.14 (m, 1H), 2.16 (s, 3H), 1.12−1.09 (t, J
= 7.25 Hz, 3H), 1.05−1.02 (t, J = 7.25 Hz, 3H). 13C NMR{1H} (125
MHz, CDCl3): δ 170.7, 166.9, 134.6, 129.2, 129.0, 128.6, 73.5, 41.5,
40.6, 20.9, 13.5, 12.7. HRMS (EI) m/z: [M]+ Calcd for C14H19NO3
249.1365. Found: 249.1371.
2,2-Bis(4-chlorophenyl)-N,N-diethylacetamide (16).34 White
Theoretical Calculations. Geometry optimizations were per-
formed using the hybrid (Hartree−Fock/DFT) B3LYP functional27,28
combined with the 6-31G** basis set.29 The RB3LYP functional was
used for the closed-shell molecules. The solvent effects were estimated
for methanol using the PCM method. The Gaussian 09 program30
was used for all the calculations. After the structural optimization, the
vibration frequencies were systematically computed to ensure that the
potential-energy surface on each optimized geometry corresponded to
a local minimum with no imaginary frequencies.
1
solid, 50 mg, 60% yield. GC-MS m/z 335. H NMR (500 MHz,
CDCl3): δ 7.29−7.27 (m, 4H), 7.18−7.16 (m, 4H), 5.08 (s, 1H),
3.44−3.39 (q, J = 7.0 Hz, 2H), 3.31−3.27 (q, J = 7.0 Hz, 2H), 1.18−
1.12 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 170.0, 138.0,
133.1, 130.2, 128.8, 53.1, 42.2, 40.8, 14.7, 12.8.
N,N-Diethyl Cyanoformamide (20).37 Colorless oil, 28 mg, 90%
yield. GC-MS m/z 126. 1H NMR (500 MHz, CDCl3): δ 3.64 (q, J =
7.25 Hz, 2H), 3.46 (q, J = 7.25 Hz, 2H), 1.31(t, J = 7.25 Hz, 3H),
1.19 (t, J = 7.25 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
144.4, 110.7, 43.6, 40.0, 14.4, 12.4.
Analytical Data of the Compounds. 2-Chloro-N,N-diethylben-
zamide (6).31 Colorless oil, 48 mg, 94% yield. GC-MS m/z 211. H
1
N,N-Dipropylbenzamide (22).38 Yellow oil, 40 mg, 78% yield. GC-
NMR (400 MHz, CDCl3): δ 7.40−7.38 (m, 1H), 7.32−7.28 (m, 3H),
3.80−3.78 (m, 1H), 3.42−3.37 (m, 1H), 3.19−3.12 (m, 2H), 1.29−
1.25 (t, J = 8.0 Hz, 3H), 1.08−1.04 (t, J = 8.0 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ 167.7, 136.8, 130.3, 129.8, 129.6, 127.5,
126.9, 42.7, 38.9, 13.9, 12.6.
1
MS m/z 205. H NMR (500 MHz, CDCl3): δ 7.38−7.35 (m, 5H),
3.46 (bs, 2H), 3.16 (bs, 2H), 1.69 (bs, 2H), 1.53 (bs, 2H), 0.99−0.97
(t, J = 7.2 Hz, 3H), 0.75−0.73 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(125 MHz, CDCl3): δ 171.8, 137.4, 129.0, 128.3, 126.5, 50.7, 46.4,
21.9, 20.7, 11.3, 11.0.
2-Fluoro-N,N-diethylbenzamide (7).32 Yellow oil, 45 mg, 92%
1
N,N-Dibutylbenzamide (23).39 Colorless oil, 47 mg, 80% yield.
yield. GC-MS m/z 195. H NMR (500 MHz, CDCl3): δ 7.38−7.31
1
(m, 2H), 7.20−7.17 (m, 1H), 7.11−7.08 (m, 1H), 3.60−3.57 (m,
2H), 3.24−3.19 (q, J = 7.2 Hz, 2H), 1.18−1.15 (t, J = 7.2 Hz, 3H),
1.10−1.07 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
GC-MS m/z 233. H NMR (500 MHz, CDCl3): δ 7.38−7.33 (m,
5H), 3.49 (bs, 2H), 3.19 (bs, 2H), 1.48−1.41 (m, 4H), 1.13 (bs, 2H),
0.98−0.78 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.6,
137.5, 128.9, 128.3, 126.5, 50.7, 48.8, 44.4, 30.9, 29.7, 20.3, 19.8, 13.9,
13.6.
1
3
66.1, 158.1 (C−F, JC−F = 246.5 Hz), 130.6 (C−F, JC−F = 7.3 Hz),
3
2
128.5 (C−F, JC−F = 4.5 Hz), 125.5 (C−F, JC−F = 18.3 Hz), 124.4
4
2
N,N-Dihexylbenzamide (24).40 Colorless oil, 40 mg, 55% yield.
(C−F, JC−F = 3.7 Hz), 115.8 (C−F, JC−F = 21.9 Hz), 43.0, 39.2,
13.9, 12.8.
1
GC-MS m/z = 289. H NMR (500 MHz, CDCl3): δ 7.38−7.33 (m,
2,4-Dichloro-N,N-diethylbenzamide (8).33 Yellow oil, 58 mg, 94%
5H), 3.48 (bs, 2H), 3.18 (bs, 2H), 1.65−1.11 (m, 16H), 0.91−0.83
(m, 6H). 13C NMR{1H} (125 MHz, CDCl3): δ 171.6, 137.0, 128.9,
128.34, 126.5, 49.0, 44.8, 31.6, 31.3, 28.7, 27.5, 26.7, 26.2, 22.5, 13.9.
N,N-Dioctylbenzamide (25).38 Colorless oil, 52 mg, 60% yield.
1
yield. GC-MS m/z 246. H NMR (500 MHz, CDCl3): δ 7.42−7.41
(m, 1H), 7.31−7.29(m, 1H), 7.22−7.21 (m, 1H), 3.81−3.80 (m,
1H), 3.41−3.38 (m, 1H), 3.18−3.11 (m, 2H), 1.28−1.25(t, J = 7.2
Hz, 3H), 1.08−1.05 (t, J = 7.2 Hz, 3H). 13C NMR{1H} (125 MHz,
CDCl3): δ 166.8, 135.3, 135.1, 131.3, 129.6, 128.4, 127.4, 42.7, 39.1,
13.9, 12.6.
1
GC-MS m/z 345. H NMR (500 MHz, CDCl3): δ 7.38−7.33 (m,
5H), 3.47 (bs, 2H), 3.18 (bs, 2H), 1.65−1.19 (m, 24H), 6.09 (bs,
6H). 13C{1H} NMR (125 MHz, CDCl3): δ 171.6, 137.5, 128.9, 128.3,
126.5, 31.7, 29.2, 22.6, 14.0.
3,4-Dichloro-N,N-diethylbenzamide (9).34 Pale green oil, 54 mg,
1
N,N-Diphenylbenzamide (26).38 White solid, 45 mg, 60% yield.
87% yield. GC-MS m/z 246. H NMR (500 MHz, CDCl3): δ 7.49−
1
7.47 (m, 2H), 7.22−7.20(m, 1H), 3.53 (bs, 2H), 3.25 (bs, 2H),
1.24−1.13 (m, 6H). 13C NMR{1H} (125 MHz, CDCl3): δ 168.8,
137.1, 133.5, 132.9, 130.5, 128.6, 125.7, 43.3, 39.5, 14.1, 12.9.
3-Fluoro-N,N-diethylbenzamide (10).35 Yellow oil, 44 mg, 90%
GC-MS m/z 301. H NMR (500 MHz, CDCl3): δ 7.51−7.50 (m,
2H), 7.39−7.27 (m, 11H), 7.16−7.14 (m, 2H), 4.71 (bs, 2H), 4.41
(bs, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ 172.2, 137.0, 136.4,
136.2, 129.6, 128.8, 128.7, 128.5, 128.4, 128.3, 127.6, 127.0, 126.7,
51.5, 46.8.
1
yield. GC-MS m/z 195. H NMR (500 MHz, CDCl3): δ 7.39−7.36
(m, 1H), 7.14−7.07 (m, 2H), 3.54 (bs, 2H), 3.52 (bs, 2H), 1.25−
1.12 (m, 6H). 13C NMR{1H} (125 MHz, CDCl3): δ 169.8, 162.5
(C−F, 1JC−F = 248.3 Hz), 139.4 (C−F, 3JC−F = 6.2 Hz), 130.2 (C−F,
N-Ethyl-N-methylbenzamide (35). Colorless oil, 25 mg, 60% yield.
GC-MS m/z 163 (M). 1H NMR (500 MHz, CDCl3): δ 7.40 (bs, 5H),
3.62−3.58, 3.31−3.26 (q, J = 7.25 Hz, 2H), 3.08, 2.94 (s, 3H), 1.26−
123, 1.15−1.12 (t, J = 6.94 Hz). 13C{1H} NMR (125 MHz, CDCl3):
δ 171.7, 171.0, 136.8, 129.3, 128.3, 126.8, 126.4, 45.9, 42.1, 36.7, 32.2,
3JC−F = 8.2 Hz), 122.0 (C−F, JC−F = 3.7 Hz), 116.1 (C−F, JC−F
=
4
2
2
21.0 Hz), 113.7 (C−F, JC−F = 21.9 Hz), 43.2, 39.4, 14.2, 12.9.
5987
https://doi.org/10.1021/acs.joc.1c00161
J. Org. Chem. 2021, 86, 5983−5990

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
13.6, 12.1. HRMS (EI) m/z: [M]+ Calcd for C10H13NO 163.0997.
Found: 163.0988.
Authors
Zhongli Luo − Department of Chemistry and Biochemistry,
Graduate School of Engineering, Kyushu University, Fukuoka
819-0395, Japan
Kenji Imamura − Institute for Materials Chemistry and
Engineering, Kyushu University, Fukuoka 819-0395, Japan
Yoshihito Shiota − Institute for Materials Chemistry and
Engineering, Kyushu University, Fukuoka 819-0395, Japan;
orcid.org/0000-0003-2054-9845
N-Cyclohexyl-N-ethylbenzamide (36). Yellow oil, 41 mg, 70%
1
yield. GC-MS m/z 231. H NMR (500 MHz, CDCl3 at 40 °C): δ
7.39−7.37, 7.34−7.32 (bs, 5H), 3.44, 3.21 (m, 3H), 1.37−1.04 (m,
13H). 13C{1H} NMR (125 MHz, CDCl3 at 40 °C): δ 171.4, 137.9,
128.8, 128.4, 126.0, 58.8, 36.4, 31.7, 25.8, 25.3, 14.9. HRMS (EI) m/
z: [M]+ Calcd for C15H21NO 231.1623. Found: 231.1619.
N-Ethyl-N-isopropylbenzamide (37).41 Yellow oil, 34 mg, 72%
1
yield. GC-MS m/z 191. H NMR (500 MHz, CDCl3): δ 7.40−7.26
(m, 5H), 3.95 (bs, 1H), 3.42−3.23 (m, 2H), 1.29−1.15 (m, 9H).
13C{1H} NMR (125 MHz, CDCl3): δ 171.2, 137.9, 128.8, 128.4,
126.0, 50.1, 35.3, 21.0, 14.9.
Kazunari Yoshizawa − Institute for Materials Chemistry and
Engineering, Kyushu University, Fukuoka 819-0395, Japan;
orcid.org/0000-0002-6279-9722
Phenyl(pyrrolidin-1-yl)methanone (38).38 Yellow oil, 26 mg, 60%
1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00161
yield. GC-MS m/z 175. H NMR (500 MHz, CDCl3): δ 7.52−7.50
(m, 2H), 7.40−7.38 (m, 2H), 3.67−3.64 (t, J = 7.0 Hz, 2H), 3.44−
3.41 (t, J = 7.0 Hz, 2H), 1.99−1.94 (m, 2H), 1.90−1.85 (m, 2H).
13C{1H} NMR (125 MHz, CDCl3): δ 169.7, 137.4, 129.7, 128.2,
127.1, 49.5, 46.1, 26.4, 24.4.
Notes
The authors declare no competing financial interest.
4-Morpholinylphenylmethanone (40).38 Yellow oil, 24 mg, 50%
1
yield. GC-MS m/z 191. H NMR (500 MHz, CDCl3): δ 7.41−7.40
ACKNOWLEDGMENTS
■
(m, 5H), 3.77−3.46 (m, 8H). 13C{1H} NMR (125 MHz, CDCl3): δ
170.5, 135.4, 129.8, 128.5, 127.1, 66.9, 48.2, 42.8.
This study was partially supported by a Grant-in-Aid for
Scientific Research (B) (JP19H02735) from the Japan Society
for the Promotion of Science (JSPS). Part of the study was
performed under the Cooperative Research Program of
“Dynamic Alliance for Open Innovation Bridging Human,
Environment and Materials” (20203024) and a grant from the
Nippon Sheet Glass Foundation (HAKF541800).
1,1,3,3-Tetraethylurea (42).42 Yellow oil, 28 mg, 52% yield. GC-
1
MS m/z 172. H NMR (500 MHz, CDCl3): δ 3.16 (q, J = 7.13 Hz,
8H), 1.11 (t, J = 7.13 Hz, 12H). 13C{1H} NMR (125 MHz, CDCl3):
δ 164.9, 42.2, 13.2.
Diethylcarbamoyl Chloride (43).43 Yellow oil, 8 mg, 12% yield.
1
GC-MS m/z 135. H NMR (500 MHz, CDCl3): δ 3.51−3.39 (m,
4H), 1.26−1.19 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ
148.6, 45.7, 44.4, 13.7, 12.8.
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■
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00161.
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AUTHOR INFORMATION
■
Corresponding Authors
Yoshio Hisaeda − Department of Chemistry and Biochemistry,
Graduate School of Engineering, Kyushu University, Fukuoka
819-0395, Japan; orcid.org/0000-0001-9196-8006;
Email: yhisatcm@mail.cstm.kyushu-u.ac.jp
Hisashi Shimakoshi − Department of Chemistry and
Biochemistry, Graduate School of Engineering, Kyushu
University, Fukuoka 819-0395, Japan; orcid.org/0000-
0003-4644-2392; Email: shimakoshi@mail.cstm.kyushu-
u.ac.jp
5988
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The Journal of Organic Chemistry
pubs.acs.org/joc
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