Metal-Free C-N or C-C Bond Cleavages of α-Azido Ketones: An Oxidative-Amidation Strategy for the Synthesis of α-Ketothioamides and Amides

Article abstract of DOI:10.1021/acs.joc.9b01777

A novel metal-free oxidative-amidation strategy for the synthesis of α-ketothioamides and amides from α-azido ketones was developed. The C-H bond thionation of α-azido ketones with elemental sulfur could form α-ketothioacyl azide, which was then nucleophilically attacked by amines, causing the cleavage of the C-N bond to afford α-ketothioamides, while amides could be formed with the release of nitrogen gas and cyano anion in the presence of PhI(OAc)₂ by selective C-C bond cleavage.

Full text of DOI:10.1021/acs.joc.9b01777

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Note
Metal-Free C-N or C-C Bond Cleavages of #-Azido Ketones: An Oxidative-
Amidation Strategy for the Synthesis of #-Ketothioamides and Amides
Pei Yu, Yuwei Wang, Zhigang Zeng, and Yunfeng Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01777 • Publication Date (Web): 14 Oct 2019
Downloaded from pubs.acs.org on October 14, 2019
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Metal-Free C-N or C-C Bond Cleavages of α-Azido Ketones: An
Oxidative-Amidation Strategy for the Synthesis of α-Ketothioamides and Amides
7
8
9
Pei Yu,† Yuwei Wang,† Zhigang Zeng,*,‡ and Yunfeng Chen*,†
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†School of Chemistry and Environmental Engineering, Wuhan Institute of Technology,
Wuhan 430073, China.
‡School of Nuclear Technology and Chemistry & Biology, Hubei University of
Science and Technology, Xianning 437100, China.
ABSTRACT: A novel metal-free oxidative-amidation strategy for the synthesis of
α-ketothioamides and amides from α-azido ketones was developed. The C-H bond
thionation of α-azido ketones with elemental sulfur could form α-ketothioacyl azide,
which was then nucleophilically attacked by amines causing the cleavage of C-N
bond to afford α-ketothioamides. While amides could be formed with the release of
nitrogen gas and cyano anion in the presence of PhI(OAc)2 by selective C-C bond
cleavage.
Organic azides are used as nitrogen sources, and they can not only offer three
nitrogen atoms to construct 1,2,3-triazoles,1 but also tend to undergo denitrogenation
to form open-chain nitrogen-containing compounds2 and aza-hetrocycles.3 On the
other hand, azido group can be regarded as a pseudohalide anion, which is a potential
leaving group in organic synthesis.4 Indeed, the acyl azides have been considered as
acylating agents for a long time,5 which could yield amides via nucleophilc
substitution of azide anion with different amines (Scheme 1a). Still, the azido
fragments as leaving groups in organic synthesis have not been well developed so far.
Recently, 3-azidopropanoic acid has been transformed into diverse aza-heterocycles
(Scheme 1b).6 During the reaction, the aliphatic azido group functioned as a
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pseudohalogenic leaving group in an intramolecular nucleophilic substitution with
amines and diamines, respectively. Besides, the deazidoalkoxylation of acyl geminal
diazides (which derivated from oxidative in situ diazidation with sodium azide) with
lithiated alcohols or thiophenols has been developed to construct N,O/N,S-acetals by
using azide as leaving groups.7 Furthermore, the fragment of acyl diazides can also
give acyl cyanides and acyl azides via the cleavage of C-N or C-C bonds (Scheme
1c).8 However, the formation of germinal diazido compounds needs excess sodium
azides and oxidants. Indeed, as a class of azide compounds, α-azido ketones have
played important roles in organic synthesis due to their excellent reactivity.9
Encouraged by the previous works, we envisioned whether α-azido ketones could be
cleaved directly by the oxidative activation of the methylene group, thus, the related
fragment could be captured to transform into other products. Herein, we reported a
metal-free synthesis of α-ketothioamides and amides via the reactions of α-azido
ketones with amine in the presence of elemental sulfur or PhI(OAc)2. These two
reactions exhibited wide substrate scopes, high yields and mild reaction conditions,
and the reaction processes involved the selective cleavages of C-N3 and C-C bonds.
Because amides and thioamides are important building blocks in organic synthesis
and medicinal chemistry,10 the study on the synthesis and applications of amides
(thioamides) has attracted a lot of attention in the past decades.11 Even though there
are many methods available for the synthesis of α-ketothioamides12 and amides,13 this
work offers a novel reactivity of α-azido ketones and gives an alternative strategy for
the synthesis of α-ketothioamides and amides.
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Scheme 1 Strategies about Azide Group Acting as a Pseudohalogenic Leaving
Group
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Previous work on N3- as a leaving group
-
O
O
- N3
(a)
R
N3
R
NHR
Ar
N
NH
Ar
7
8
9
O
O
N
1. DIC, TEA
or
HO
N3
2. - N3- (or azide transfer)
(b)
HN
O
R
R
R
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O
O
O
R
R
CN
N3
-
- N3
Nu
R'
Nu
R'
(c)
R
R
O
N3
N3
N3
This work
PhI(OAc)2
R1R2NH
O
R1
N
O
O
S8, R1R2NH
R1
N3
Ar
R2
Ar
N
R2
-
- N2, - CN -
Ar
- N3
S
Initially, we investigated the formation of α-ketothioamides. Phenacyl azide (1a)
and morpholine (2a) were selected as the model substrates to optimize the reaction
conditions (Table 1). The reaction was performed by using 2.0 equiv. of elemental
sulfur
in
DMF
at
room
temperature.
The
target
product
2-morpholino-1-phenyl-2-thioxoethanone (3a) was obtained with 41% isolated yield
after 3h (entry 1), and morpholino(phenyl)methanone (4a) was also obtained with
53% yield. Inspired by this result, the reaction temperature was increased to 70 °C,
but no significant improvement was observed (entry 2). Then, DMSO, NMP, toluene,
THF, CH2Cl2, CH3CN CH3OH and 1,4-dioxane were also employed as alternative
reaction media, respectively (entries 3–10). Among these reactions, the yield of 3a
was enhanced to 88% by using THF, and the formation of amide 4a was significantly
inhibited. However, other solvents were inappropriate for the model reaction, and all
of them gave only a trace amount of 3a. Subsequently, reducing the amount of
elemental sulfur was found to be negative, and consequently, a considerably low yield
of 3a was afforded (entry 11). Additionally, when Na2S•9H2O, NaSH•nH2O, and
K2S2O8 were chose as the sulfur sources respectively, the target product 3a was not
obtained yet (entries 12–14).
Table 1. Optimization of the Reaction Conditions for the Synthesis of
α-Ketothioamidesa
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Yieldb of Yieldb of
Entry
Solvent
S sources
T (℃)
3a (%)
41
4a (%)
53
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1
2
DMF
DMF
S8
r.t.
70
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
S8
40
50
3
DMSO
NMP
S8
36
47
4
S8
35
41
5
Toluene
THF
S8
trace
88
0
6
S8
trace
trace
0
7
CH2Cl2
CH3CN
CH3OH
1,4-dioxane
THF
S8
trace
trace
trace
trace
63
8
S8
S8
9
trace
0
10
11c
12
13
14
S8
S8
trace
0
THF
Na2S·9H2O
NaSH·nH2O
K2S2O8
0
THF
0
0
THF
0
0
aGeneral conditions: 1a (0.5 mmol), 2a (1.5 mmol), S8 (1.0 mmol)
in 3mL of solvent, stirred at room temperature for 3h under air
atmosphere. bIsolated yield. c0.75 mmol sulfur was used.
With the optimized conditions in hand (Table 1, entry 6), the scope of this
reaction was subsequently examined (Scheme 2). As shown in Scheme 2, all the
reactions proceeded smoothly and gave the target compounds α-ketothioamides
(3a–3z) in moderate to good yields. Initially, some common heterocyclic secondary
amines, (e.g., morpholine, piperidine and pyrrolidine) were employed to react with
α-azido ketones, respectively. As a result, the corresponding α-ketothioamides were
obtained in good yields (3a–3i, 75–91%). Both electron-donated group (-CH3) and
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halo-substituted groups (-F, -Cl) on the para-position of benzene of phenacyl azides
were well tolerated. Significantly, when tetrahydroisoquinolines were used as the
amine sources, the isomerized α-ketothioamide products 3j and 3k were obtained with
characterization by NMR. The structure of 3k was further confirmed by X-ray
crystallography. We then tested the reaction conditions by using aliphatic primary
amines including benzylamine, cyclohexylamine and cyclopentylamine. Pleasantly,
the expected secondary α-ketothioamides were formed in acceptable yields (3l–3v,
74%–87%). However, in this case, an appropriate amount of inorganic base such as
potassium carbonate must be added to promote the reaction. Besides, some
low-boiling acyclic amines such as n-butylamine and n-propylamine were also
suitable for this reaction (3w–3y, 63–68%). Finally, we further tried to utilize
aromatic amines such as aniline to accomplish the title reaction. Nevertheless,
2-oxo-N,2-diphenylethanethioamide (3z, 42%) was obtained in lower yield due to the
difficulty of separation and purification.
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Scheme 2. Scope of α-Ketothioamidesa
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R2
N
O
O
N3
R2
THF
r.t.
R3
HN
R3
+
+ S8
S
R1
R1
1
2
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O
X
O
N
N
n
S
S
R1
R1
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R1 = H, n = 1, X = O, 3a (88%)
R1 = CH3, 3j (86%)
R
1 = CH3, n = 1, X = O, 3b (90%)
R1 = F, n = 1, X = O, 3c (77%)
R
1 = F, 3k (84%)
R
R
1 = Cl, n = 1, X = O, 3d (81%)
1 = H, n = 1, X = CH2, 3e (91%)
R1 = CH3, n = 1, X = CH2, 3f (91%)
R
R
R
1 = F, n = 1, X = CH2, 3g (75%)
1 = Cl, n = 1, X = CH2, 3h (82%)
1 = H, n = 0, X = CH2, 3i (78%)
3k
R2
O
H
O
H
N
N
S
R1
n
S
R1
R1 = CH3, n = 1, 3q (78%)b
R1 = F, n = 1, 3r (74%)b
R1 = Cl, n = 1, 3s (75%)b
R1 = CH3, n = 2, 3t (80%)b
R1 = F, n = 2, 3u (79%)b
R1 = Cl, n = 2, 4v (76%)b
R1 = H, R2 = CH3, 3l (82%)b
R1 = H, R2 = OCH3, 3m (79%)b
R1 = H, R2 = Cl, 3n (87%)b
R1 = CH3, R2 = H, 3o (81%)b
R1 = Cl, R2 = H, 3p (80%)b
O
H
O
H
N
N
n
S
R1
S
R1 = H, n = 1, 3w (63%)b
R1 = H, n = 2, 3x (68%)b
R1 =Cl , n = 2, 3y (65%)b
3z (42%)b
aGeneral conditions: α-azido ketones (0.5 mmol), amines
(1.5 mmol), and sulfur (1.0 mmol) in 3 mL of THF,
stirred at room temperature monitored by TLC; Yield of
b
isolated product based on phenacyl azide. K2CO3 (0.5
mmol) was added.
During the optimization of the reaction conditions of α-ketothioamides as
mentioned, we unexpectedly found that when DMF was used as a solvent, besides of
the desired product 3a, the amide 4a was also formed. We further investigated it and
found that the reaction was accompanied by the formation of SCN- (see Supporting
Information for details). Nevertheless, many attempts to selective synthesis of amides
in the presence of S8 were failed. Therefore, we speculated that there was a certain
competition between the formation of amides and α-ketothioamides during the
reaction. There was no big difference between the pKa of HSCN (4.00) and that of
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-
HN3 (4.67), theoretically, the N3 leaves easier to some extent. It’s hard to selectively
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8
produce the amides via the cleavage of C-C bond in this sulfur reaction system
although there was an irreversible denitrogenation for the leave of SCN-. Thus, some
other oxidants were taken into consideration and the conditions for selective synthesis
of amides were screened (Table 2). The I2 and tetrabutylammonium iodide (TBAI)
did not promote the reactions (entries 1 and 2). However, the target amide 4a formed
as a single product when (diacetoxyiodo) benzene (PIDA) was introduced as an
additive to the reaction system. The subsequent changing of the PIDA loading
revealed that one equivalent of PIDA was sufficient (entries 2, 5 and 6). The reaction
was also carried out in DMSO and toluene, respectively, and the results reconfirmed
that DMF was the solvent of choice (entries 7–11).
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Table 2. Optimization on the Reaction Conditions for Amides Synthesisa
T (℃)
Entry Solvent Additives
Yieldb (%)
1
2
DMF
DMF
I2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
0
TBAI
PIDA
--
3
DMF
68
4
DMF
0
5c
6d,e
7
DMF
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
35
DMF
89
DMSO
Toluene
THF
60
8
trace
trace
0
9
10
11
CH2Cl2
CH3CN
trace
aGeneral conditions: 1a (0.5 mmol), 2 (1.0 mmol), and
additive (1.0 mmol) in 3mL of solvent, stirred at room
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b
temperature for 1h under air atmosphere. Isolated
5
6
c
d
yield. The loading of PIDA was 0.05 mmol. The
7
8
loading of PIDA was 0.5 mmol. eUnder N2 atmosphere
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Motivated by the above findings, we extended the scope of this reaction (Scheme
3). It was found that both heterocyclic secondary amine (e.g., morpholine and
piperidine, 4a–4e, 81%–89%), and aliphatic primary amine (e.g., benzylamine,
cyclohexylamine and cyclopentylamine, 4f–4r, 80%–92%) afforded good yields. It
should be noted that aniline could not participate in the reaction due to its easy
oxidization.
Scheme 3. Scope of Amidesa,b
aGeneral conditions: 1 (0.5 mmol), 2 (1.0 mmol), and
PIDA (0.5 mmol) in 3 mL of DMF, stirred at room
temperature for 1h under N2 atmosphere. bYield of
isolated product based on 1.
As mentioned above, SCN- was detected during the formation of
α-ketothioamides in DMF media, which revealed that there should be a thionation of
the methylene group. In order to gain further insights into the reaction mechanism,
some control experiments were performed (Scheme 4). Firstly, no reaction occurred
when α-azidopropiophenone (5) was chosen to react with morphine in the presence of
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elemental sulfur (Scheme 4a). Meanwhile, acetophenone (6) could not give the
corresponding products (Scheme 4b). Phenylglyoxal (7) afforded the α-ketothioamide
with 70% yield as single product by using DMF, and when using THF as solvent, both
the α-ketothioamide 3a and amide 4a were not observed (Scheme 4c), which
indicated that the phenylglyoxal intermediate was not involved in the reaction
process.
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Scheme 4. Control Experiments
On the basis of these experimental results, a possible mechanism for the dual
reaction paths is outlined in Scheme 5. Firstly, an enol tautomerization of
α-azidoacetophenone to form 2-azido-1-phenylethenol A occurs. Then, the enol A
electrophilic attacks on sulfur to form intermediate B, which undergo
desulfhydrylation to give the key intermediate α-ketothioacyl azide D. Next, the azido
group of the intermediate D leaves to form α-ketothioamide under the nucleophilic
attack of amines. However, the mechanism of the synthesis of amide may involve the
fact that PIDA first reacts with the enol A to form intermediate E. E is further
fragmented by the elimination of iodobenzene and acetate ion to generate
intermediate F, and F is then abstracted by an acetate ion to remove a hydrogen
proton. Subsequently, nitrogen gas is released to form an acyl cyanide intermediate G.
Finally, the nucleophilic attack of amine pushes the cyano group off to form the
amide.
Scheme 5. Plausible Mechanism for the Formation of α-Ketothioamides and
Amides
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CONCLUSIONS
In summary, we have developed a novel oxidative-amidation strategy for the synthesis
of α-ketothioamides and amides via metal-free C-N or C-C bond cleavages of α-azido
ketones. According to our study and the previous literature, a plausible reaction
mechanism was reasonably explained. Notably, due to the special fragmentation of
azide group, simple operation and broad substrate tolerance, the method will have a
promising application in high-efficient synthesis of α-ketothioamides and amides. The
study sheds some light on the study of the new reactivity of α-azido ketones and
selective C-C and C-N cleavages.
EXPERIMENTAL SECTION
General Information
Unless otherwise stated, all chemicals used in the experiments were obtained from
commercial sources and used directly without further treatment. TLC was performed
with detection of compounds with UV light. Flash column chromatography
purification of the products was accomplished on silica gel (200−300 mesh).
Petroleum ether (PE) (60−90 °C) and ethyl acetate (EA) were used as eluents for
silica gel chromatography. Melting points for all solid products were measured on an
X-4A melting point apparatus without correction. H and 13C NMR spectra were
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recorded at 22 °C on a Bruker AV 400 and 600 MHz spectrometer with
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6
7
8
1
13
tetramethylsilane (TMS) as an internal standard. H and C chemical shifts in NMR
spectra were referenced relative to signals of CDCl3 (δ 7.26 ppm for 1H and 77.0 ppm
for 13C). High-resolution mass spectra (HRMS) were acquired on Waters Acquity
UPLC Class I/Xevo G2Q-TOF.
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General Procedure for the Synthesis of α-Azido Ketones
The α-azido ketones were synthesized according to the literatures.14,15 Acetophenone
1a (1.2 g, 10 mmol) was dissolved in CH3CN (40 mL) in a 250 mL round-bottom
flask, and then NBS (1.87 g, 10.5 mmol), p-TSA (2 mmol) were added. After stirred
at 60 °C for 6h, the reaction mixture was extracted with EtOAc (3 × 40 mL). The
extract was washed with saturated aqueous NaHCO3, brine and dried over anhydrous
Na2SO4. The solvent was evaporated to obtain 2-bromo-1-phenylethanone. Then, the
resultant 2-bromo-1-phenylethanone (1.91 g, 10 mmol) was dissolved in aqueous
ethanol (VEtOH/VH2O = 2:1, 30 mL). Finally, sodium azide (1.30 g, 20 mmol) was
added slowly into the mixture. About 1 h later, the reaction mixture was quenched
with water, extracted with EtOAc (3 × 40 mL). The organic phase was washed with
water and saturated brine, respectively, and then was dried over anhydrous Na2SO4.
After filtered, the solvent was removed in vacuo to yield the desired product
2-azido-1-phenylethanone as pale yellow oil (1.55g, 96%). Compound
2-azido-1-phenylethanone could also be further purified by flash chromatography on
silica (petroleum ether / ethyl acetate, 40:1) as pale yellow oil.
General Procedure for the Synthesis of α-Ketothioamides
A mixture of α-azido ketones 1 (0.5 mmol), amine 2 (1.5 mmol), elemental sulfur (1
mmol) in 3mL of THF was stirred under an air atmosphere in a 10 mL tube at room
temperature. After the reaction finished (as monitored by TLC), the mixture was
quenched with water, and extracted with EtOAc (3 × 40 mL). The combined organic
layers were dried over anhydrous Na2SO4, and the solvent was evaporated in vacuo.
The resulting mixture was chromatographed on silica gel by eluting with petroleum
ether / ethyl acetate (V/V = 15:1) to provide the product as bright yellow solid or
yellow oil (which crystallized slowly at room temperature).
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General Procedure for the Synthesis of Amides
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A mixture of α-azido ketones 1 (0.5 mmol), amine 2 (1.0 mmol), and PIDA (0.5 mmol)
in 3mL of DMF was stirred under an N2 atmosphere in a 10 mL sealed tube at room
temperature (as monitored by TLC). Upon completion (as monitored by TLC), the
resulting suspension was extracted with ethyl acetate (3 × 40 mL), and the combined
organic phase was dried over anhydrous Na2SO4. The solution provided therein was
subjected to reduced pressure to remove the solvent. The residue was then employed
for silica gel column chromatography, and the pure product was acquired by using
petroleum ether/ethyl acetate (V/V = 8:1) as an eluent.
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A Gram Scale for the Synthesis of α-Ketothioamides 3e and Amide 4a
A mixture of 2-azido-1-phenylethanone 1a (1.13g, 7 mmol), piperidine (1.79g, 21
mmol), elemental sulfur (0.45g, 14 mmol) in 30mL of THF was stirred under an air
atmosphere in a 100 mL tube at room temperature. Refer to the general procedure
above to get 3e (1.33g, 83%) as a yellow solid.
A mixture of 2-azido-1-phenylethanone 1a (1.13g, 7 mmol), morpholine (1.22g, 14
mmol), and PIDA (2.25g, 7 mmol) in 3mL of DMF was stirred under an N2
atmosphere in a 10 mL sealed tube at room temperature. Refer to the general
procedure above to get 4a (1.15g, 86%) as a yellow oil.
Characterization data
2-azido-1-phenylethanone (1a).15a According to the reported procedure as a yellow oil
(1.55g, 96%); Purification by silica gel chromatography (eluent: PE→PE/EA = 20:1,
1
Rf = 0.35); H NMR (400 MHz, CDCl3) δ 7.81–7.79 (m, 2H), 7.55–7.51 (m, 1H),
13
7.42–7.38 (m, 2H), 4.48 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 193.0, 133.9,
133.7, 128.5, 127.4, 54.4.
2-azido-1-(p-tolyl)ethanone (1b).15a According to the reported procedure as a yellow
solid (1.65g, 94%); Purification by silica gel chromatography (eluent: PE→PE/EA =
20:1, Rf = 0.32); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.29 (d, J =
13
8.0 Hz, 2H), 4.53 (s, 2H), 2.43 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 192.8,
145.2, 131.9, 129.6, 128.0, 54.8, 21.7.
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2-azido-1-(4-fluorophenyl)ethanone (1c).15a According to the reported procedure as a
yellow solid (1.77g, 90%); Purification by silica gel chromatography (eluent: PE→
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8
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PE/EA = 20:1, Rf = 0.30); H NMR (400 MHz, CDCl3) δ 7.96–7.91 (m, 2H),
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7.19–7.14 (m, 2H), 4.53 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 166.2 (d,
J = 256.8 Hz), 130.8 (d, J = 3.2 Hz), 130.6 (d, J = 9.6 Hz), 116.2 (d, J = 22.0 Hz),
54.7.
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2-azido-1-(4-chlorophenyl)ethanone (1d).15a According to the reported procedure as a
yellow solid (1.87g, 96%); Purification by silica gel chromatography (eluent: PE→
1
PE/EA = 20:1, Rf = 0.35); H NMR (400 MHz, CDCl3) δ 7.85–7.83 (m, 2H),
7.48–7.46 (m, 2H), 4.52 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 192.1, 140.7,
132.6, 129.31, 129.30, 54.8.
2-morpholino-1-phenyl-2-thioxoethanone (3a).12d Pale yellow solid (103.5 mg, 88%);
mp 114−115 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf
1
= 0.10); H NMR (400 MHz, CDCl3) δ 7.98–7.96 (m, 2H), 7.60 (t, J = 7.2 Hz, 1H),
7.47 (t, J = 7.6 Hz, 2H), 4.32–4.29 (m, 2H), 3.89–3.87 (m, 2H), 3.68–3.65 (m, 2H),
13
3.58–3.56 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 195.5 187.8, 134.3, 133.1,
129.7, 128.8, 66.3, 66.2, 51.8, 47.0.
2-morpholino-2-thioxo-1-(p-tolyl)ethanone (3b).12d Pale yellow solid (112.2 mg, 90%);
mp 114−115 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf
= 0.10); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz,
2H), 4.33–4.31 (m, 2H), 3.91–3.88 (m, 2H), 3.69–3.67 (m, 2H), 3.59–3.57 (m, 2H),
2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.0, 187.8, 145.7, 130.7, 129.9,
129.6, 66.5, 66.3, 51.8, 47.0, 21.8.
1-(4-fluorophenyl)-2-morpholino-2-thioxoethanone (3c).12d Pale yellow solid (97.5
mg, 77%); mp 138−139 °C; Purification by silica gel chromatography (eluent: PE/EA
1
= 10:1, Rf = 0.10); H NMR (400 MHz, CDCl3) δ 8.03–7.99 (m, 2H), 7.18–7.12 (m,
2H), 4.31–4.29 (m, 2H), 3.89–3.87 (m, 2H), 3.69–3.67 (m, 2H), 3.59–3.56 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 186.2, 166.3 (d, J = 257.6 Hz), 132.5 (d, J
= 9.6 Hz), 129.6 (d, J = 2.8 Hz), 116.2 (d, J = 22.0 Hz), 66.4, 66.2, 51.8, 47.1.
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1-(4-chlorophenyl)-2-morpholino-2-thioxoethanone (3d).12d Pale yellow solid (109.2
mg, 81%); mp 158−160 °C; Purification by silica gel chromatography (eluent: PE/EA
= 10:1, Rf = 0.10); 1H NMR (400 MHz, CDCl3) δ 7.95–7.92 (m, 2H), 7.48–7.45 (m,
2H), 4.33–4.30 (m, 2H), 3.91–3.89 (m, 2H), 3.71–3.69 (m, 2H), 3.60–3.58 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 186.4, 141.0, 131.8, 131.2, 129.3, 66.5,
66.3, 51.9, 47.2.
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1-phenyl-2-(piperidin-1-yl)-2-thioxoethanone (3e).12d Pale yellow solid (106.2 mg,
91%); mp 70−71 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1,
1
Rf = 0.19); H NMR (400 MHz, CDCl3) δ 8.00–7.98 (m, 2H), 7.61–7.58 (m, 1H),
7.50–7.46 (m, 2H), 4.26–4.24 (m, 2H), 3.55–3.52 (t, J = 5.2 Hz, 2H), 1.86–1.74 (m,
4H), 1.63–1.62 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.4, 187.9, 134.1,
133.4, 129.8, 128.8, 53.0, 48.1, 26.4, 25.3, 24.1.
2-(piperidin-1-yl)-2-thioxo-1-(p-tolyl)ethanone (3f).12g Pale yellow solid (112.5 mg,
91%); mp 84−86 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1,
Rf = 0.19); 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 2H), 7.27–7.25 (m, 2H),
4.24–4.21 (m, 2H), 3.52–3.50 (m, 2H), 2.41 (s, 3H), 1.84–1.72 (m, 4H), 1.60 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 194.6, 187.9, 145.2, 130.8, 129.8, 129.5, 52.9,
48.0, 26.3, 25.3, 24.0, 21.8.
1-(4-fluorophenyl)-2-(piperidin-1-yl)-2-thioxoethanone (3g). Pale yellow solid (94.2
mg, 75%); mp 68−71 °C; Purification by silica gel chromatography (eluent: PE/EA =
1
10:1, Rf = 0.19); H NMR (400 MHz, CDCl3) δ 8.04–7.99 (m, 2H), 7.17–7.12 (m,
2H), 4.25–4.22 (m, 2H), 3.53–3.51 (m, 2H), 1.85–1.74 (m, 4H), 1.61 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 193.9, 186.4, 166.2 (d, J = 257.2 Hz), 132.5 (d, J = 9.6
Hz), 129.8 (d, J = 2.8 Hz), 116.1 (d, J = 22.0 Hz), 53.0, 48.1, 26.4, 25.3, 24.0.
1-(4-chlorophenyl)-2-(piperidin-1-yl)-2-thioxoethanone (3h).12f Pale yellow solid
(109.8 mg, 82%); mp 119−121 °C; Purification by silica gel chromatography (eluent:
1
PE/EA = 10:1, Rf = 0.19); H NMR (400 MHz, CDCl3) δ 7.94–7.91 (m, 2H),
7.46–7.43 (m, 2H), 4.24–4.21 (m, 2H), 3.53–3.50 (m, 2H), 1.82–1.75 (m, 4H), 1.62 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 186.4, 140.6, 131.9, 131.1, 129.1,
53.0, 48.1, 26.4, 25.3, 24.0.
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1-phenyl-2-(pyrrolidin-1-yl)-2-thioxoethanone (3i).12b Yellow solid (99.0 mg, 78%);
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mp 45−46 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf =
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8
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0.17); H NMR (400 MHz, CDCl3) δ 7.98–7.96 (m, 2H), 7.60–7.56 (m, 1H),
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7.48–7.44 (m, 2H), 3.92 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 2.10–1.98 (m,
4H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.6, 188.7, 134.1, 132.7, 129.9, 128.7,
51.2, 51.0, 26.0, 23.7.
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2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-thioxo-1-(p-tolyl)ethanone (3j). Pale yellow
solid (127.0 mg, 86%); mp 135−137°C; Purification by silica gel chromatography
(eluent: PE/EA = 10:1, Rf = 0.23); The ratio of two conformational isomers is about
1
2:1. H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.29–7.22(m, 6H), 5.31
(s, 2H), 3.81 (t, J = 6.0 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 195.9, 187.9, 145.5, 134.3, 131.1, 130.8, 129.6, 128.4, 127.1,
126.7, 125.8, 49.3, 45.7, 29.2, 21.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H18NOS 296.11092; Found 296.1118.
2-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(4-fluorophenyl)-2-thioxoethanone (3k). Pale
yellow solid (125.7 mg, 84%); mp 94−96°C; Purification by silica gel
chromatography (eluent: PE/EA = 10:1, Rf = 0.23); The ratio of two conformational
isomers is about 2:1. 1H NMR (400 MHz, CDCl3) δ 8.07−8.02 (m, 2H), 7.31–7.26 (m,
3H), 7.19–7.15(m, 3H), 5.31 (s, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.1, 186.4, 166.3 (d, J = 256.0 Hz), 132.9,
132.7 (d, J = 10.0 Hz),131.0, 129.8 (d, J = 2.8 Hz), 128.4, 127.3, 127.2, 126.8, 116.2
(d, J = 22.0 Hz), 49.4, 49.2, 29.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H15FNOS 300.0858; Found 300.0866.
N-(4-methylbenzyl)-2-oxo-2-phenylethanethioamide (3l). Pale yellow solid (110.4 mg,
82%); mp 124−125 °C; Purification by silica gel chromatography (eluent: PE/EA =
1
10:1, Rf = 0.19); H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.03–8.01 (m, 2H),
7.59–7.56 (m, 1H), 7.45–7.41 (m, 2H), 7.29–7.26 (m, 2H), 7.21–7.19 (m, 2H), 4.88 (d,
J = 5.6 Hz, 2H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.3, 187.6, 138.2,
133.8, 133.7, 132.1, 130.7, 129.7, 128.3, 128.1, 49.1, 21.1; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C16H16NOS 270.0947; Found 270.0952.
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N-(4-methoxybenzyl)-2-oxo-2-phenylethanethioamide (3m). Pale yellow solid (112.7
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6
mg, 79%); mp 106−107 °C; Purification by silica gel chromatography (eluent: PE/EA
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8
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= 10:1, Rf = 0.11); H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.04–8.02 (m, 2H),
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7.59–7.56 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.32–7.29 (m, 2H), 6.93–6.89 (m, 2H),
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4.85 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 193.1,
187.6, 159.6, 133.8, 133.7, 130.7, 129.8, 128.1, 127.2, 114.4, 55.3, 48.9; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C16H15NO2SNa 308.0721; Found 308.0727.
N-(4-chlorobenzyl)-2-oxo-2-phenylethanethioamide (3n). Pale yellow solid (126.0 mg,
87%); mp 118−120 °C; Purification by silica gel chromatography (eluent: PE/EA =
1
10:1, Rf = 0.15); H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.01–7.99 (m, 2H),
7.60–7.56 (m, 1H), 7.44–7.41 (m, 2H), 7.36–7.30 (m, 4H), 4.91 (d, J = 5.6 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 187.6, 134.2, 133.9, 133.7, 133.6, 130.7,
129.6, 129.1, 128.2, 48.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H13ClNOS
290.0401; Found 290.0409.
N-benzyl-2-oxo-2-(p-tolyl)ethanethioamide (3o). Pale yellow solid (109.1 mg, 81%);
mp 89−91 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf =
0.15); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.39–7.24
13
(m, 7H), 4.93 (d, J = 5.6 Hz, 2H), 2.42 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
193.8, 187.3, 145.1, 135.3, 131.1, 131.0, 129.1, 128.9, 128.4, 49.3, 21.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C16H16NOS 270.0947; Found 270.0952.
N-benzyl-2-(4-chlorophenyl)-2-oxoethanethioamide (3p). Pale yellow solid (115.9mg,
80%); mp 79−80 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1,
Rf = 0.22); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.03-8.02 (m, 1H), 8.00-7.99
13
(m, 1H), 7.42–7.36 (m, 7H), 4.92 (d, J = 5.6 Hz, 2H); C{1H} NMR (100 MHz,
CDCl3) δ 192.3, 186.0, 140.4, 135.1, 132.2, 129.1, 128.5, 128.4, 128.4, 49.4; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C15H13ClNOS 290.0401; Found 290.0409.
N-cyclopentyl-2-oxo-2-(p-tolyl)ethanethioamide (3q). Pale yellow solid (96.5 mg,
78%); mp 90−91 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1,
Rf = 0.28); 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.23
(d, J = 8.0 Hz, 2H), 4.84–4.78 (m, 1H), 2.41 (s, 3H), 2.22–2.19 (m, 2H), 1.77–1.63 (m,
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6H); C{1H} NMR (100 MHz, CDCl3) δ 193.1, 187.8, 131.2, 130.9, 128.9, 56.5,
32.2, 24.1, 21.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18NOS 248.1109;
Found 248.1112.
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N-cyclopentyl-2-(4-fluorophenyl)-2-oxoethanethioamide (3r). Pale yellow solid (93.0
mg, 74%); mp 67−69 °C; Purification by silica gel chromatography (eluent: PE/EA =
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10:1, Rf = 0.30); H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.13–8.09 (m, 2H),
7.13–7.08 (m, 2H), 4.83–4.74 (m, 1H), 2.25–2.18 (m, 2H), 1.80–1.69 (m, 4H),
1.67–1.61 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.9, 186.1, 166.1 (d, J =
256.8 Hz), 133.6 (d, J = 9.6 Hz), 130.2, 115.4 (d, J = 22.0 Hz), 56.6, 32.12, 24.1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H15FNOS 252.0858; Found 252.0862.
2-(4-chlorophenyl)-N-cyclopentyl-2-oxoethanethioamide (3s). Pale yellow solid
(100.4 mg, 75%); mp 117−118 °C; Purification by silica gel chromatography (eluent:
PE/EA = 10:1, Rf = 0.30); 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.03–7.99 (m,
2H), 7.42–7.39 (m, 2H), 4.82–4.73 (m, 1H), 2.26–2.18 (m, 2H), 1.78–1.71 (m, 4H),
13
1.67–1.61 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 191.4, 186.2, 140.3, 132.4,
132.2, 128.4, 56.7, 32.2, 24.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H15ClNOS 268.0563; Found 268.0569.
N-cyclohexyl-2-oxo-2-(p-tolyl)ethanethioamide (3t). Pale yellow solid (104.6 mg,
80%); mp 130−133 °C; Purification by silica gel chromatography (eluent: PE/EA =
10:1, Rf = 0.26); 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 8.0 Hz, 2H), 4.50–4.41 (m, 1H), 2.41 (s, 3H), 2.18–2.14 (m, 2H),
1.82–1.77 (m, 2H), 1.72– 1.67 (m, 1H), 1.49–1.25 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.7, 187.8, 144.9, 131.2, 130.8, 128.9, 53.6, 31.2, 25.4, 24.5, 21.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C15H20NOS 262.1266; Found 262.1273.
N-cyclohexyl-2-(4-fluorophenyl)-2-oxoethanethioamide (3u). Pale yellow solid (104.8
mg, 79%); mp 114−115 °C; Purification by silica gel chromatography (eluent: PE/EA
1
= 10:1, Rf = 0.26); H NMR (400 MHz, CDCl3) δ 8.14–8.09 (m, 2H), 8.12 (m, 1H),
7.13–7.09 (m, 2H), 4.49–4.39 (m, 1H), 2.18–2.14 (m, 2H), 1.83–1.78 (m, 2H),
13
1.72–1.67 (m, 1H), 1.49–1.25 (m, 5H); C{1H} NMR (100 MHz, CDCl3) δ 191.4,
186.1, 166.1 (d, J = 256.8 Hz), 133.6 (d, J = 9.6 Hz), 130.2 (d, J = 2.8 Hz), 115.4 (d, J
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= 22.0 Hz), 53.7, 31.2, 25.4, 24.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C14H17FNOS 266.1015; Found 266.1024.
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2-(4-chlorophenyl)-N-cyclohexyl-2-oxoethanethioamide (3v). Pale yellow solid (107.1
mg, 76%); mp 145−150 °C; Purification by silica gel chromatography (eluent: PE/EA
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= 10:1, Rf = 0.30); H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.97 (d, J = 8.4 Hz,
2H), 7.39 (d, J = 8.4 Hz, 2H), 4.47–4.38 (m, 1H), 2.16–2.12 (m, 2H), 1.82–1.77 (m,
13
2H), 1.71–1.67 (m, 1H), 1.50–1.25 (m, 5H); C{1H} NMR (100 MHz, CDCl3) δ
191.1, 186.3, 140.3, 132.2, 132.1, 128.4, 53.7, 31.1, 25.3, 24.5; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H17ClNOS 282.0719; Found 282.0728.
2-oxo-2-phenyl-N-propylethanethioamide (3w). Pale yellow solid (65.3 mg, 63%); mp
36−37 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf =
1
0.22); H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.05–8.02 (m, 2H), 7.59–7.56 (m,
1H), 7.43 (t, J = 7.8 Hz, 2H), 3.77–3.72 (m, 2H), 1.84–1.75 (m, 2H), 1.05 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 187.7, 133.8, 130.7, 128.1, 46.9,
21.2, 11.5.
N-butyl-2-oxo-2-phenylethanethioamide (3x).12b Pale yellow solid (75.2 mg, 68%);
mp 70−71 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf =
0.26); 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.57 (t, J
= 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 3.80–3.75 (m, 2H), 1.78–1.71 (m, 2H),
1.51–1.42 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
193.4, 187.8, 133.8, 130.7, 128.8, 128.1, 45.0, 29.8, 20.2, 13.7.
N-butyl-2-(4-chlorophenyl)-2-oxoethanethioamide (3y). Pale yellow solid (83.1 mg,
65%); mp 49−50 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1,
Rf = 0.33); 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.39
(d, J = 7.6 Hz, 2H), 3.78–3.73 (m, 2H), 1.75–1.72 (m, 2H), 1.48–1.43 (m, 2H), 0.98 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.5, 186.4, 140.3, 132.2,
132.1, 128.4, 45.1, 29.7, 20.2, 13.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C12H15ClNOS 256.0563; Found 256.0575.
2-oxo-N,2-diphenylethanethioamide (3z).12d Pale yellow solid (50.7 mg, 42%); mp
87−90 °C; Purification by silica gel chromatography (eluent: PE/EA = 10:1, Rf =
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0.30); 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.09–8.07 (m, 2H), 8.00–7.98 (m,
2H), 7.62–7.58 (m, 1H), 7.49–7.44 (m, 4H), 7.35–7.32 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 189.3, 186.8, 137.8, 134.0, 133.7, 131.0, 129.2, 128.0, 127.4, 122.2.
morpholino(phenyl)methanone (4a).13d Yellow oil (85.1 mg, 89%); Purification by
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silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.11); H NMR (600 MHz,
13
CDCl3) δ 7.34–7.33 (m, 5H), 3.69–3.37 (m, 8H); C{1H} NMR (150 MHz, CDCl3) δ
170.1, 135.0, 129.6, 128.3, 126.8, 66.6, 48.0, 42.3.
morpholino(p-tolyl)methanone (4b).16a Yellow oil (90.3 mg, 88%); Purification by
silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.11); 1H NMR (400 MHz,
CDCl3) δ 7.28–7.25 (m, 2H), 7.18–7.16 (m, 2H), 3.64 ( s, 8H), 2.33 (d, J = 4.8 Hz,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 170.4, 139.9, 132.2, 129.0, 127.1, 66.7,
48.0, 42.6, 21.2.
(4-chlorophenyl)(morpholino)methanone (4c).16b Brown solid (91.4 mg, 81%); mp
71−73 °C; Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.11);
1H NMR (400 MHz, CDCl3) δ 7.38–7.32 (m, 4H), 3.67–3.46 (m, 8H); 13C{1H} NMR
(100 MHz, CDCl3) δ 169.2, 135.9, 133.5, 128.8, 128.6, 66.7, 47.4, 42.6.
piperidin-1-yl(p-tolyl)methanone (4d).16c Yellow oil (80.4 mg, 85%); Purification by
1
silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.21); H NMR (400 MHz,
CDCl3) δ 7.28–7.26 (m, 2H), 7.17 (d, J = 7.6 Hz, 2H), 3.66 (s, 2H), 3.35 (s, 2H), 2.35
(s, 3H), 1.65–1.55 ( m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 139.2, 133.4,
128.8, 126.8, 48.6, 43.1, 25.6, 24.5, 24.0, 21.2.
(4-chlorophenyl)(piperidin-1-yl)methanone (4e).16a White solid (90.6 mg, 81%); mp
71−73 °C; Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.21);
1H NMR (400 MHz, CDCl3) δ 7.35–7.28 (m, 4H), 3.65 (s, 2H), 3.29 (s, 2H),
1.64–1.49 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1 , 135.2 , 134.7 , 128.5,
128.2, 48.6, 43.1, 26.4, 25.4, 24.4.
N-benzylbenzamide (4f).9c White solid (95.1 mg, 90%); mp 104−105 °C; Purification
1
by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.14); H NMR (400 MHz,
CDCl3) δ 7.80–7.78 (m, 2H), 7.51–7.47 (m, 1H), 7.43–7.39 (m, 2H), 7.35–7.27 (m,
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5H), 6.65 (s, 1H), 4.62 (d, J = 5.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4,
138.2, 134.3, 131.5, 128.7, 128.5, 127.8, 127.5, 126.9, 44.0
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N-benzyl-4-methylbenzamide (4g).9c White solid (103.6 mg, 92%); mp 135−136 °C;
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1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.14); H NMR
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(400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.36–7.35 (m, 4H), 7.32–7.28 (m, 1H),
7.22 (d, J = 8.2 Hz, 2H), 6.43 (s, 1H), 4.63 (d, J = 5.6 Hz, 2H), 2.39 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 167.3, 142.0, 138.3 , 131.5, 129.2, 128.7, 127.9, 127.6,
126.9, 44.1, 21.4.
N-benzyl-4-fluorobenzamide (4h). White solid (97.4 mg, 85%); mp 145−147 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.17); H NMR
(400 MHz, CDCl3) δ 7.81–7.78 (m, 2H), 7.37–7.28 (m, 5H), 7.11–7.06 (m, 2H), 6.48
13
(s, 1H), 4.62–4.61 (m, 2H); C{1H} NMR (100MHz, CDCl3) δ 166.3, 164.7 (d, J =
251.9 Hz), 138.0, 130.5 (d, J = 3.2 Hz), 129.3 (d, J = 8.8 Hz), 128.8, 127.9, 127.7,
115.6 (d, J = 22.0 Hz), 44.2.
N-benzyl-4-chlorobenzamide (4i).9c White solid (105.6 mg, 86%); mp 169−171 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.25); H NMR
(400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.36–7.29 (m,
5H), 6.43 (s, 1H), 4.63 (d, J = 5.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3,
137.9, 137.8, 132.7, 128.8, 128.4, 127.9, 127.7, 44.2.
N-cyclohexylbenzamide (4j).17 White solid (87.4 mg, 86%); mp 138−140 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.26); H NMR
(600 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.8
Hz, 2H), 6.17 (s, 1H), 3.97–3.92 (m, 1H), 2.00 (d, J = 12.0 Hz, 2H), 1.73 (d, J = 13.2
13
Hz, 2H), 1.63 (d, J = 13.2 Hz, 1H), 1.42–1.36 (m, 2H), 1.26–1.14 (m, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 166.6, 135.0, 131.2, 128.4, 126.8, 48.6, 33.2, 25.5, 24.9.
N-cyclohexyl-4-methylbenzamide (4k).17 White solid (92.3 mg, 85%); mp 158−159 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.28); H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 5.97 (s, 1H),
4.01–3.93 (m, 1H), 2.38 (s, 3H), 2.04–2.00 (m, 2H), 1.77–1.72 (m, 3H), 1.46–1.37 (m,
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2H), 1.26–1.18 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 166.5, 141.6, 132.2,
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6
129.1, 126.8, 48.6, 33.2, 25.6, 24.9, 21.4.
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N-cyclohexyl-4-fluorobenzamide (4l).17 White solid (88.5 mg, 80%); mp 151−152 °C;
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1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.32); H NMR
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(400 MHz, CDCl3) δ 7.77–7.74 (m, 2H), 7.11–7.06 (m, 2H), 5.92 (s, 1H), 3.99–3.91
(m, 1H), 2.04–2.00 (m, 2H), 1.78–1.73 (m, 2H), 1.67–1.63 (m, 1H), 1.48–1.37 (m,
13
2H), 1.28–1.15 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 165.6, 164.6 (d, J =
250.0 Hz), 131.2, 129.1 (d, J = 8.8 Hz), 115.5 (d, J =22.0 Hz), 48.8, 33.2, 25.5, 24.9.
4-chloro-N-cyclohexylbenzamide (4m).17 White solid (99.8 mg, 84%); mp
193−196 °C; Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf =
1
0.39); H NMR (400 MHz, CDCl3) δ 7.70–7.67 (m, 2H), 7.41–7.37 (m, 2H), 5.93 (s,
1H), 4.00–3.91 (m, 1H), 2.05–2.01 (m, 2H), 1.79–1.74 (m, 2H), 1.68–1.64 (m, 1H),
13
1.49–1.38 (m, 2H), 1.29–1.16 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 166.5,
137.4, 133.4, 128.7, 128.3, 48.8, 33.2, 25.5, 24.9.
N-cyclopentylbenzamide (4n).18b White solid (80.4 mg, 85%); mp 159−160 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.26); H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.48–7.45 (m, 1H), 7.41–7.38 (m, 2H),
6.18 (s, 1H), 4.43–4.34 (m, 1H), 2.11–2.05 (m, 2H), 1.75–1.59 (m, 4H), 1.52–1.46 (m,
13
2H); C{1H} NMR (100 MHz, CDCl3) δ 167.1, 134.9, 131.2, 128.4, 126.8, 51.6,
33.1, 23.8.
N-cyclopentyl-4-methylbenzamide (4o). White solid (87.4 mg, 86%); mp 139−140 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.25); H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.07 (s, 1H),
4.41–4.36 (m, 1H), 2.38 (s, 3H), 2.11–2.04 (m, 2H), 1.74–1.62 (m, 4H), 1.52–1.44 (m,
13
2H); C{1H} NMR (100 MHz, CDCl3) δ 167.1, 141.6, 132.0, 129.1, 126.8, 51.6,
33.2, 23.8, 21.4.
N-cyclopentyl-4-fluorobenzamide (4p).18a White solid (87.0 mg, 84%); mp
138−139 °C; Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf =
1
0.32); H NMR (400 MHz, CDCl3) δ 7.76–7.73 (m, 2H), 7.09–7.05 (m, 2H), 6.11 (s,
1H), 4.41–4.32 (m, 1H), 2.11–2.04 (m, 2H), 1.76–1.60 (m, 4H), 1.52–1.44 (m, 2H);
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13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 164.5 (d, J = 252.0 Hz), 131.0, 129.1 (d, J
= 8.8 Hz), 115.4 (d, J = 22.0 Hz), 51.8, 33.2, 23.8.
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4-chloro-N-cyclopentylbenzamide (4q). White solid (97.3 mg, 87%); mp 169−171 °C;
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1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.32); H NMR
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(400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.41–7.38 (m, 2H), 6.00 (s, 1H),
4.43–4.34 (m, 1H), 2.13–2.06 (m, 2H), 1.77–1.63 (m, 4H), 1.52–1.44 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.1, 137.5, 133.3, 128.8, 128.3, 51.8, 33.2,
23.8.
N-butyl-4-chlorobenzamide (4r).19 White solid (85.7 mg, 81%); mp 81−82 °C;
1
Purification by silica gel chromatography (eluent: PE/EA = 5:1, Rf = 0.25); H NMR
(400 MHz, CDCl3) δ 7.77–7.67 (m, 2H), 7.38–7.36 (m, 2H), 6.26 (s, 1H), 3.45–3.40
13
(m, 2H), 1.62–1.54 (m, 2H), 1.44–1.34 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 166.5, 137.5, 133.2, 128.7, 128.3, 39.9, 31.6, 20.1, 13.7.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications
website at DOI:
Crystallographic data for 3k (CIF) and copies of the 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: yfchen@wit.edu.cn.
*E-mail: zzgang2012@hotmail.com
ORCID
Yunfeng Chen: 0000-0002-6220-5015
Zhigang Zeng: 0000-0002-1048-1499
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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We are grateful to the National Natural Science Foundation of China (31601675),
the PhD Start-up Fund of Hubei University of Science and Technology (BK201821),
the Science and Technology Program of Xianning (Xnkj-04), China, and the 10th
Graduate's Innovation of Wuhan Institute of Techonology (CX2018146).
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Advances in Multicomponent Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles. Adv.
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Copper-Catalyzed
Oxidative
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9198–9203; (c) Chen, Y.; Nie, G.; Zhang, Q.; Ma, S.; Li, H.; Hu, Q. Copper-Catalyzed
[3+2] Cycloaddition/Oxidation Reactions between Nitro-olefins and Organic Azides:
Highly Regioselective Synthesis of NO2-Substituted 1,2,3-Triazoles. Org. Lett. 2015,
17, 1118–1121; (d) Hein, J. E.; Fokin, V. V. Copper-Catalyzed Azide-Alkyne
Cycloaddition (CuAAC) and Beyond: New Reactivity of Copper(I) Acetylides. Chem.
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Synthesis of Triazoles from Nonactivated Terminal Alkynes via the Three-Component
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(2) (a) Liu, J. B.; Sheng, X. H.; Sun, C. Z.; Huang, F.; Chen, D. Z. A Computational
Mechanistic Study of Amidation of Quinoline N-Oxide: The Relative Stability of
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2452–2461; (b) Miura, T.; Funakoshi, Y.; Morimoto, M.; Biyajima, T.; Murakami, M.
Synthesis of Enaminones by Rhodium-Catalyzed Denitrogenative Rearrangement of
1-(N-Sulfonyl-1,2,3-triazol-4-yl)alkanols. J. Am. Chem. Soc. 2012, 134,
17440–17443.
(3) For some examples, see: (a) Xu, M. M.; Cao, W. B.; Xu, X. P.; Ji, S. J. Efficient
Synthesis of 2-Arylquinazolin-4-Amines via a Copper-Catalyzed Diazidation and
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Ring Expansion Cascade of 2-Arylindoles. Chem. Commun. 2018, 54, 12602–12605;
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