Michael addition reaction catalyzed by imidazolium chloride to protect amino groups and construct medium ring heterocycles

Article abstract of DOI:10.3390/molecules24234224

An effective approach for amino protection and construction of a seven-membered ring has been developed. The method uses imidazolium chloride to carry out the Michael addition reaction at low temperatures and perform amino deprotection or construction of a seven-membered ring at high temperatures.

Full text of DOI:10.3390/molecules24234224

Article
Michael Addition Reaction Catalyzed by
Imidazolium Chloride to Protect Amino Groups
and Construct Medium Ring Heterocycles
1,†
1,†
1
1
1
1
Zeshu Dai , Qingqiang Tian , Yanwu Li , Suqin Shang , Wen Luo , Xuetong Wang ,
1
1
1
1,
Dan Li , Ying Zhang , Zhiyao Li and Jianyong Yuan *
Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University,
Chongqing 400016, China
* Correspondence: 102542@cqmu.edu.cn
†
These authors contributed equally to this work.
Received: 26 September 2019; Accepted: 30 October 2019; Published: 20 November 2019
Abstract: An effective approach for amino protection and construction of a seven-membered ring
has been developed. The method uses imidazolium chloride to carry out the Michael addition
reaction at low temperatures and perform amino deprotection or construction of a seven-membered
ring at high temperatures.
Keywords: imidazolium chloride; amino protection; Michael addition reaction; amino deprotection;
solvent-free; seven-membered ring
1. Introduction
Many pharmaceutical intermediates or active molecules often contain amino groups. However,
the amino groups are unstable and easily oxidized. The protection of amino groups is therefore often
needed in the process of drug synthesis. Methods of amino functional group protection have been
reported by related literatures or patents [1]. Traditionally, functional groups were protected via
amines reacting with CBZ-Cl [2,3], (Boc) O [4–6], Fmoc-Cl [7], TFA [8,9] and Alloc-Cl [10] in the
2
presence of inorganic bases. Furthermore, we have found that bases are mainly used as a promoter.
Recently, Jadhav et al. [11] reported the use of microwaves (300 W) for selective tert-
butoxycarbonylation of various amines. In 2015, Liguori et al. [12] reported the use of 1-butyl-3-
methylimidazolium tetrauoroborate [Bmim][BF ] as the ionic liquid medium to promote selective
4
Fmoc and Cbz-protection of various structurally amines. Among the relevant protective groups used
for amino function, it would also be necessary to mention the sulfonamido[13,14] protecting groups.
Several protocols have been developed for the protection of amino groups with substituted sulfonyl
chlorides (such as 4-toluolsulfonyl chloride) using various metal-based catalyst reaction conditions.
In 2013, Nardi et al. [15] reported a new and eco-friendly process for ferrier glycosylation of
sulfonamides and amino acids with various N-nucleophiles under erbium (III) trifluoromethane-
sulfonate as a Lewis acid catalyst. However, these catalysts present a lot of disadvantages. Most of
these reactions have limitations such as high cost, corrosiveness, and toxicity. Although methods for
the protection of various amino groups are well known and well documented in the literature, it is
still very important to study the methods of protecting amino groups. Furthermore, in recent years,
a number of researchers have focused on developing greener methods.
When we began to study the reaction of o-phenylenediamine with N,N-dimethylacrylamide
catalyzed by imidazolium chloride to construct a seven-membered ring[16–18], we found that the
Molecules 2019, 24, 4224; doi:10.3390/molecules24234224
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4224
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reactants reacted in the form of Michael addition [19,20] reaction at 120 ℃, firstly. However, when
the temperature was raised to 150 ℃, the reaction product did not contain any seven-membered ring.
After identification, it was one of the raw materials that was formed by the C-N bond cleavaging. In
the next study, we find that reaction of o-phenylenediamine with acrylamide in the presence of
imidazole hydrochloride resulted in the formation of 1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-
one. In 2012, Dabiri, M. et al. [21] reported that [Hmim]TFA catalyzed the hetero-Michael reaction of
2-aminothiophenol and acrylate to construct a seven-membered ring. However, this method only
provided a ring-closing reaction of 2-aminothiophenol and acrylate, but the ring-closing reaction of
substituted phenylenediamine and a variety of Michael acceptors is still not clear.
Michael addition was one of the most important carbon-carbon and carbon-heteroatom bond-
forming strategies in synthetic organic chemistry. In the past few years, a myriad array of metal-
centered Lewis acid catalysts have been developed, including cadmium (II) chloride[22], ammonium
nitrate(V) [23], zirconium(IV) chloride[24], silica-supported aluminum chloride[25], VO(OTf)2[26]
and lanthanum trichloride (LaCl3)[27]. Recently, green organic chemistry has begun to attract
attention in organic synthesis. For example, metal organic frameworks [28] and basic alumina[29].
Although these reactions work well, most of these catalysts were non-recyclable or transition metal
salt catalysts. In addition, in some cases, toxic solvents were required, and a long reaction time was
needed. Therefore, it was necessary to explore non-metallic catalysts in organic synthesis. We recently
reported an environmentally-friendly procedure to efficiently obtain Aza-Michael adducts using
imidazolium chloride as a green catalyst.
Based on these results, we propose using imidazolium hydrochloride to catalyze the Michael
addition reaction to protect amino groups and synthesize benzodiazepine derivatives and
benzothiazide derivatives. (Scheme 1).
Scheme 1. Amino protection catalyzed by imidazole hydrochloride.
2. Results and Discussion
2.1.Optimization of Reaction Conditions
In our initial experiments, we choose aniline with N,N-dimethylacrylamide as a model substrate
and the results for development are displayed in Table 1.

Molecules 2019, 24, 4224
Table 1. Optimization of conditions for the reaction of the Aza-Michael addition.
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H
NH
Catalyst
Solvent
N
N
2
N
O
O
2
3
1
Temperature
(℃)
120
Entry
Cat (eq)
Solvent
Time (h)
Yield (%) c
1
2
3
4
5
6
7
8
9
10
11
12b
13b
14b
15b
-
-
-
-
-
-
-
-
-
4
4
6
4
6
4
4
4
4
4
4
6
6
4
4
trace
69
10
60
50
75
65
40
32
61
73
18
NO
63
Imidazolium chloride (0.3)
Imidazole (0.3)
120
120
120
90
120
130
140
120
120
120
100
70
120
120
HCl (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.1)
Imidazolium chloride (0.2)
Imidazolium chloride (0.5)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
Imidazolium chloride (0.3)
-
-
-
H2O
CH3CN
Toluene
Xylene
66
a Reaction conditions: Unless otherwise noted, all reactions were carried out with 1 (10.8 mmol, 1
equiv), 2 (14.0 mmol, 1.3 equiv), Imidazolium chloride (0.1–0.5 equiv); bAll solvents are 2mL; cYields
of products 3. Abbreviations: NO, no reaction.
Firstly, our investigation commenced with the reaction of aniline 1 and N, N-dimethyl
acrylamide 2 with imidazolium chloride (0.3 equiv) at 110 ℃ solvent-free. We obtained product 3
(Table 1, Entry 2) in a yield of 69%. However, only a trace product was detected in the absence of
catalysts (Table 1, Entry 1). On the other hand, when we used 0.3 equiv of HCl and imidazole as
catalysts, we obtained products 3 and 4 (Table 1, Entries 3 and 4) in yields of 60% and 10%, respectively.
Inspired by the results, the impact of varying the reaction temperature was investigated (Table 1, Entries
5−8). The best yield was obtained under solvent-free conditions at 120 ℃ (Table 1, Entry 6). When the
temperature was raised or decreased, the yields lowered (Table 1, Entries 5, 7 and 8). These experiments
demonstrated that the reaction was highly sensitive to temperature. Next, concerning the amount of
catalysts, it was observed that 0.3 eq of imidazolium chloride were sufficient to obtain a good yield.
Lowering the amount of catalyst from 30 mol% to 10 mol% resulted in a yield of 32%, indicating that the
yields were significantly decreased (Table 1, Entries 9 and 10). Increasing the amount of catalysts had little
influence on the yield (Table 1, Entry 11). Finally, we turn our target to the effect of solvents on the reaction.
We had tried various solvents such as water and acetonitrile, but unsatisfactory yields were obtained,
possibly a result from the effect of temperature on the reaction (Table 1, Entries 12 and 13). However, the
reaction was attempted in non-polar media such as toluene and Xylene, and a total yield of 63%-66% was
obtained (Table 1, Entries 14 and 15).

Molecules 2019, 24, 4224
Table 2. Optimization of reaction conditions for the deprotection of amino groupa.
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H
catalyst
solvent
NH2
N
N
O
1
3
Temperatur
e (℃)
150
Entry
Cat (eq)
Solvent
Time (h)
Yield (%) b
1
2
3
4
5
6
7
8
9
10
11c
12c
13c
-
-
-
-
-
-
-
-
-
6
6
6
6
6
6
6
6
6
6
6
6
6
Trace
Trace
8
Trace
61
63
65
23
35
65
Imidazole (0.7)
HCl (0.7)
150
150
120
150
160
180
150
150
150
100
90
150
Imidazolium chloride (0.7)
Imidazolium chloride (0.7)
Imidazolium chloride (0.7)
Imidazolium chloride (0.7)
Imidazolium chloride (0.1)
Imidazolium chloride (0.5)
Imidazolium chloride (1.0)
Imidazolium chloride (0.7)
Imidazolium chloride (0.7)
Imidazolium chloride (0.7)
-
-
H2O
benzene
xylene
NO
NO
57
a General conditions: 3 (5.2 mmol, 1 equiv), imidazolium chloride (0.1–1 equiv) under solvent-free
conditions for 6 h; b Isolated yields are given; c All solvents are 2 mL. Abbreviations: NO, no reaction.
Interestingly, our team unexpectedly discovered that imidazolium chloride could catalyze the C−N
bond-cleavaging reactions at 150 ℃. So, after the amino group was protected, we began to screen the
conditions for amino deprotection. The N, N-Dimethyl-3-phenylamino-propionamide (Table 2, 3) was
selected as the model reaction for 6 h. The results are listed in Table 2.
At the beginning of our study, we found that the reaction was performed under the conditions
of 0.7 equivalent of imidazolium chloride at 150 ℃. The expected product was detected (Table 2,
Entry 5). However, only a trace product was detected in the absence of catalysts (Table 2, Entry 1).
When 0.7 equiv of HCl was used, the yield of the product 1 (Table 2, Entry 3) was 8%. Furthermore,
the impact of varying the reaction temperature was investigated. Compared to the yield of 1 at 150
℃ (Table 2, entry 5), the yield of the reaction performed at 120 ℃ was significantly decreased (Table
2, Entry 4). However, when temperature was increased to 160 ℃ and 180 ℃ for 6h, the yields were
63% and 65%, respectively (Table 2, Entries 6 and 7). The expected product was obtained at a yield of
23% only when the amount of catalyst was decreased to 10 mol% (Table 2, Entry 8). The yield of
product 1 did not increase significantly when the reaction was carried out at the condition of 1 equiv
of catalyst (Table 2, Entry 10) compared to 0.7 equiv of catalyst (Table 2, Entries 5). When the reaction
was performed in water or benzene, no reaction occurred in the presence of catalyst (Table 2, Entries
11 and 12). The yield of the expected product was 57% when the reaction was conducted in xylene
(Table 2, Entry 13). The optimum yield was obtained when the reaction was carried out under solvent
free conditions (Table 2, Entry 5).

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Table 3. Optimization of synthesis of medium ring heterocycles a.
Entry
1
2
3
4
5
6
7
8
Cat(eq)
Imidazolium chloride(0.3)
-
Solvent
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
CH3CN
H2O
dioxane
Temp(°C)
120
120
120
120
80
Time(h)
Yield(%)b
5
5
5
5
5
5
5
5
5
9
9
9
9
45
NO
34
trace
13
25
31
75
76
15
10
27
10
HCl(0.3eq)
Imidazolium(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
100
110
140
150
70
100
100
110
9
10
11
12
13
toluene
ethylene glycol diethyl
ether
2-methoxyethanol
2-ethoxyethanol
xylene
14
Imidazolium chloride(0.3)
120
5
39
15
16
17
18
Imidazolium chloride(0.3)
Imidazolium chloride(0.3)
Imidazolium chloride(0.1)
Imidazolium chloride(0.5)
125
140
140
140
5
5
5
5
43
trace
19
xylene
49
a General conditions: 4 (4.6 mmol, 1 equiv), 5 (7.9 mmol, 1.7 equiv), imidazolium chloride (0.1–0.5
b
equiv) under solvent-free conditions for 6 h; Isolated yields are given. All solvents are 2 mL.
Abbreviations: NO, no reaction.
However, the reaction of o-phenylenediamine with acrylamide at 140 ℃ for 5 h to obtain 1,3,4,5-
tetrahydro-2H-ben-zo[b][1,4]diazepin-2-one gave a very good yield. Inspired by this result, we herein
tried to synthesize benzodiazepines and benzothiazides derivatives through the further study of
Michael addition reaction. Hence, the o-phenylenediamine (4) and acrylamide (5) were selected as
the substrates for the optimization studies. Gratifyingly, the substrates 4 and 5 could be transformed
into product 6 in a yield of 45% by heating in the presence of imidazole hydrochloride in xylene at
140 °C for 5 h (Table 3, Entry 1). Next, a variety of temperatures were explored; it was observed that
the desired yields can be obtained only at 140 °C (Table 3, Entries 5−9). Subsequently, several other
solvents such as CH3CN, toluene, and 2-ethoxyethanol were screened, among which none gave the
products in good yields (Table 3, Entries 10−16). Furthermore, yields of 19% and 49% were obtained
when 0.1 eq of imidazolium chloride and 0.5eq of imidazolium chloride were used as the catalysts,
respectively (Table 3, Entries 17 and 18).
2.2. Scope of Substituted Substrate
Table 4. Substrate scope of substituted amines and acrylamide derivatives. a.

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a
Reaction conditions: Unless otherwise noted, 1 (5 mmol, 1 equiv), 2 (6.5 mmol, 1.3 equiv),
imidazolium chloride (0.3 equiv), solvent-free conditions, 2–9 h, at 120 ℃; b Yields after column
purification; c This reaction was performed at 100 ℃;d This reaction was performed for 0.5 h at rt.
e
This reaction was performed for 10 min at 70 ℃. Abbreviations: NR, no reaction.
With the optimized reaction conditions on hand, the scope of the Michael addition reactions was
explored using a wide range of amines and acrylamide derivatives, as shown in Table 4. Firstly,
aniline reacted with N,N-dimethylacrylamide to form the corresponding Michael addition product
in a yield of 74% (Table 4, 3a). Aromatic amine substituted with electron-donating groups (e.g.,
amino, methoxy, or phenyl) at different positions reacted very well with N, N-dimethylacrylamide,
generating the corresponding products in moderate to good yields (Table 4, 3b–3e). Similarly,
aromatic amine possessing a weak electron-withdrawing group, such as 4-bromoaniline, underwent
a smooth reaction to obtain a medium yield of the corresponding product 3 (Table 4, 3f and 3g).
However, it is worth noting that aromatic amines substituted by a strong electron withdrawing group
did not react with N,N-dimethylacrylamide (Table 4, 3h). Moreover, to further investigate the scope
of this reaction system, the reactions of different substituted amines and acrylamide derivatives (e.g.,
acrylamide N,N-dimethylacrylamide, methyl acrylate, ethyl acrylate or tert-butyl acrylate) were also
tested. Aromatic amine bearing either electron-rich or weak electron-deficient substituents all
underwent the reactions smoothly to give the expected products in yields of 33% to 88% (Table 4, 3i–
3v). However, the representative of the heterocyclic aromatic amines such as 2-aminopyridine could
be transformed into the corresponding product in a yield of 33%. The lower yield was ascribed to
lower nucleophilicity of heterocyclic aromatic amines (Table 4, 3s). The reaction of secondary amines
with acrylamide was further tested. The secondary arylamine N-methylaniline was converted into
the corresponding product in excellent yields (Table 4, 3w). Encouraged by these satisfying results,
aza-Michael addition of various aliphatic amines and acrylamide were performed.The aza-Michael
addition of pyrrolidine and 4-methylpiperidine could also proceed smoothly within shorter reaction
period, obtaining the corresponding products in good yields (Table 4, 3x and 3y). The higher yields
might be attributed to the stronger nucleophilicity of aliphatic amines.

Molecules 2019, 24, 4224
Table 5. Substrate scope of the deprotection of aromatic amino groups. a
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R1
N
0.7 equiv
NH HCl
R1
R2
N
R3
NH
R2
2-9 h 150 °C
O
3b
1
Entry
Substance
Time (h)
Product
Yieldb (%)
NH2
H
N
N
1
6
63
O
3ba
1a
H
NH2
N
N
O
2
3
4
9
NH2
82
NH2
1b
3bb
O
NH
2
HN
N
85
1c
3bc
H
NH2
N
N
4
5
5
72
40
O
N
O
O
1d
1e
3bd
H
NH2
Cl
N
O
12
Cl
3be
H
NH2
N
N
O
6
7
8
11
10
6
70
73
70
Br
Br
1f
3bf
H
NH2
N
NH
2
O
1g
3bg
H
NH2
N
NH
2
O
N
Br
Br
1h
NH
3bh
H
2
2
N
9
4
81
35
O
NH
1i
NH
2
3bi
NH2
H
N
N
10
10
O
Cl
Cl
1j
3bj
H
NH
2
N
O
11
12
13
14
9
6
6
6
72
76
72
82
O
3bk
3bl
1k
1l
H
N
NH2
O
O
H
NH2
N
O
O
1m
3bm
H
NH
2
N
O
Cl
O
Cl
1o
3bo
a Reaction conditions: Unless otherwise noted, All reactions were carried out with 3b (1.0 mmol, 1
equiv) and imidazolium chloride (0.7 mmol, 0.7 equiv), under solvent-free conditions for 4–11 h at
150 ℃; b Yields after column purification. Abbreviations: NR, no reaction.

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After the amino group was protected, substrate ranges of the deprotection of aromatic amino
groups were investigated and the results were displayed in Table 5. Heating a solution of N,N-
Dimethyl-3-phenylamino-propionamide (3aa) using 0.7 eq of imidazolium chloride at 150 ℃ without
solvent resulted in the formation of aniline in a yield of 63% (Table 5, 1a). The use of substrates with
electron-donating substituents generally resulted in higher yields than the substrates with a weak
electron-withdrawing substituent such as Cl, Br (Table 5, 1b–1f). Next, when the dimethylamino
substituent was replaced by -NH2 or diethylamino, the yields were 35-81% (Table 5, 1g–1j).
Meanwhile, R3 substituents such as ethoxy and Tert-butoxy groups were tolerable under these
optimized conditions. Compound 3bk–3bo gave the corresponding product in medium yields (Table
5, 1k–1o).
Table 6. Substrate scope of substituted 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-ones and
substituted 2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-ones. a
Entry
Substance
Time (h)
Product
Yieldb (%)
1
5
74
2
5
68
34
3c
13
4
5
0.5
4
93
90
6
7
2
2
34
31
a Reaction conditions: Unless otherwise noted, 4a (3.0 mmol, 1 eq) and 5a (5.1 mmol, 1.7 eq), imidazolium
chloride (0.3 equiv), at 140 ℃; b Yields after column purification; c This reaction was performed at 90 ℃ for 5 h
and then at 140 °C for 8 h. Abbreviations: NR, no reaction.

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Then, we investigated the functional group tolerance on a seven-membered ring. The data were
presented in Table 6. O-phenylenediamine and acrylamide derivatives reacted well, leading to the
corresponding products in moderate to good yields (Table 6, 6a−6d). It is worth noting that o-
phenylenediamine and N,N-dimethylacrylamide or tert-Butyl acrylate reactions were not observed
under these reaction conditions. The disubstituted o-phenylenediamine (such as 4,5-difluoro-2-
phenylenediamine) and acrylamide derivatives were compatible in this reaction, obtaining the
corresponding products in good yields (Table 6, 6e). We explored the reaction of 2-aminothiophenol
with acrylamide or methacrylamide under standard reaction conditions, providing the
corresponding product in yields of 34% and 31% (Table 6, 6f and 6g). These low yields might be
attributed to more by-products of the Michael addition reaction.
3. Conclusions
In conclusion, we have developed a highly efficient and environmentally friendly method for
amino protection and seven-membered ring construction. The reactions initiated by aza-Michael
reactions to protect the amino group, followed by deprotection of the amino group or transaminated.
This method has a wide scope of substrates, providing a wide range of aromatic amines and aliphatic
amines. Also, the significance of our finding can reduce the number or amount of organic solvents,
potentially toxicity, and hazardous catalysts. It is most important that we have used non-metallic
catalysts and compared them with the other metal catalysts. Moreover, the results provide further
evidence that it is possible to use this method in the synthesis of bioactive compounds. It is
noteworthy that this method is complementary to the previously reported amino protective reactions.
4. Materials and Methods
4.1. Chemicals and Materials
All reagents were purchased from Meyer Reagent Co., Ltd. (Shanghai, China), Macklin Reagent
Co., Ltd. (Shanghai, China), Chongqing Chuandong Chemical Co., Ltd. (Chongqing, China), etc., and
1
13
used without further purification. H- and C-NMR spectra were recorded on a Bruker Avancell
NMR (600 MHz) instruments. Chemical shifts were reported in ppm and coupling constants (J) in Hz.
TLC plates were visualized by exposing UV light or by iodine. Purification of crude compounds and
separation of reaction mixtures were carried out by column chromatography using silica gel (200–
300 meshes, Shanghai, China). All substrates are known compounds according to the literature.
4.2. General Procedures for Michael Addition Reaction
The 1 (5.0 mmol) and 2 (6.5 mmol) in a molar ratio of 1:1.3 reacted with stirring in the presence
of imidazolium hydrochloride (1.5 mmol, 0.3 eq). Heating was performed using an oil bath and the
reaction was followed up by TLC until completion. After completion of the reaction, the system was
cooled. The organic layer was extracted using water (15 mL) and ethyl acetate (20 mL) and dried
using anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was
subjected to column chromatography eluting with petroleum ether: ethyl acetate (7:1) mixtures.
4.2.1. Synthesis of 3-(Pyrrolidin-1-yl)propanamide(3x)
To a mixture of pyrrolidine (7.0 mmol, 1 equiv) and acrylamide (9.2 mmol, 1.3 equiv),
imidazolium hydrochloride (2.1 mmol, 0.3 eq) was added. The mixture was stirred at RT and
monitored by TLC. After the reaction completed, the reaction mixture was cooled to allow the
products crystallize (ethyl acetate/methanol (5:1)). The crystallized products were filtered and further
washed by ethyl acetate, dried, and evaluated by spectral analysis (3x).

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4.2.2. Synthesis of 3-(4-Methylpiperidin-1-yl)propanamide (3y)
To a mixture of 4-methylpiperidine (5.1 mmol, 1 equiv) and acrylamide (9.2 mmol, 1.3 equiv),
imidazolium hydrochloride (2.1 mmol, 0.3 eq) was added. The mixture was stirred at 70 ℃ and
monitored by TLC. After the reaction completed, the reaction mixture was cooled to allow the
products to crystallize (ethyl acetate/methanol (5:1)). The crystallized products were filtered, and
further washed by ethyl acetate, dried, and evaluated by spectral analysis (3y).
4.1. General Procedure for Amino Deprotection
Placed 3b (1 mmol, 1 equiv) and imidazolium chloride (0.7 mmol, 0.7 equiv) in a tube-type
schlenk flask, stirred at 150 ℃, and monitored the reaction progress by TLC. After the reaction
completed, the reaction mixture was cooled. The organic layer was extracted using water (15 mL)
and ethyl acetate (20 mL) and dried using anhydrous Na2SO4, then filtered and concentrated under
reduced pressure. The residue was subjected to column chromatography eluting with petroleum
ether: ethyl acetate (10:1) mixtures.
4.1. General Methods for Synthesis of Substituted 1,3,4,5-Tetrahydro-2H-1,5-benzodiazepine-2-ones and
Substituted 2,3-Dihydrobenzo[b][1,4]thiazepin-4(5H)-ones
To 20 mL of schlenk tube with a magnetic stir bar we successively added 4a (3.0 mmol, 1 eq), 5a
(5.1 mmol, 1.7 eq), and imidazolium hydrochloride (0.9 mmol, 0.3 eq). Then we added xylene (1 mL)
to the reaction mixture. The mixture was stirred at 140 °C. The progress of the reaction was
monitored by TLC. After the reaction completed, water (15 mL) was added to the reaction mixture.
The solution was extracted using ethyl acetate (3 × 15 mL) and dried using anhydrous Na2SO4. The
crude product was purified by flash chromatography eluting with petroleum ether: ethyl acetate (5:1)
mixtures.
4.1.1. Synthesis of 1,3,4,5-Tetrahydro-2H-benzo[b][1,4]diazepin-2-one (6c).
To 20 mL of schlenk tube with a magnetic stir bar, o-phenylenediamine (4.6 mmol, 0.5 g, 1 eq),
methyl acrylate (7.9 mmol, 0.68 g, 1.7 eq) and imidazolium hydrochloride (1.4 mmol, 0.15 g, 0.3 eq)
were successively added. Then xylene (1 mL) was added to the reaction mixture. The mixture was
stirred at 90℃for 5 h and then at 140 °C for 8 h. The progress of the reaction was monitored by TLC.
After the reaction completed, water (15 mL) was added to the reaction mixture. The solution was
extracted with ethyl acetate (3 × 15 mL) and dried using anhydrous Na2SO4. The crude product was
purified by flash chromatography using silica gel to obtain the corresponding product (6c).
N,N-Dimethyl-3-phenylamino-propionamide (3a): The product was obtained as a white solid in a yield
1
of 74% (0.34 g), MP: 103–106 ℃ [30]. HNMR (600 MHz, CDCl3) δ 7.17 (dd, J = 8.4, 7.4 Hz, 2H), 6.69 (t,
J = 7.3 Hz, 1H), 6.64 (d, J = 7.7 Hz, 2H), 4.33 (s, 1H), 3.48 (t, J = 6.0 Hz, 2H), 2.95 (d, J = 3.5 Hz, 6H), 2.59
13
(t, J = 6.0 Hz, 2H). C-NMR (151 MHz, CDCl3) δ 171.62, 147.72, 129.29, 117.57, 113.26, 39.58, 37.09,
35.28, 32.20.
3-(2-Amino-phenylamino)-N,N-dimethyl-propionamide (3b): The product was obtained as a black liquid
1
in a yield of 72% (0.39 g). H NMR (600 MHz, CDCl3) δ 6.84 – 6.75 (m, 1H), 6.75 – 6.64 (m, 3H), 3.59 (s,
13
2H), 3.46 (t, J = 6.2 Hz, 2H), 2.96 (d, J = 9.6 Hz, 6H), 2.63 (t, J = 6.1 Hz, 2H). C-NMR (151 MHz, CDCl3)
δ171.73, 136.94, 135.20, 120.21, 119.03, 116.33, 112.65, 40.06, 37.11, 35.31, 32.44.
2-Amino-N-(2-dimethylcarbamoyl-ethyl)-benzamide (3c): The product was obtained as a white solid in a
1
yield of 43% (0.23 g). MP: 134–136 ℃. H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 7.41 (d, J = 7.9 Hz,
1H), 7.34 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 5.84 (s, 2H), 3.55 (t, J = 7.3
13
Hz, 2H), 3.00 (s, 3H), 2.96 (s, 3H), 2.68 (t, J = 7.3 Hz, 2H). C NMR (151 MHz, CDCl3) δ 172.03, 171.13,
149.76, 133.62, 128.45, 114.89, 113.43, 112.02, 39.16, 37.25, 35.37, 32.86.

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N,N-Dimethyl-3-(naphthalen-1-ylamino)-propionamide (3d): The product was obtained as a colorless
1
liquid in a yield of 73% (0.52 g). H-NMR (600 MHz, CDCl3) δ 7.77 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.8
Hz, 1H), 7.39 – 7.28 (m, 2H), 7.26 (t, J = 7.8 Hz, 1H), 7.18 – 7.10 (m, 1H), 6.57 (d, J = 7.5 Hz, 1H), 5.64 –
13
4.87 (m, 1H), 3.56 (t, J = 5.8 Hz, 2H), 2.86 (d, J = 6.3 Hz, 6H), 2.62 (t, J = 5.8 Hz, 2H). C-NMR (151 MHz,
CDCl3) δ 171.86, 143.27, 134.42, 128.48, 126.53, 125.77, 124.76, 123.87, 120.40, 117.37, 104.31, 39.73,
37.15, 35.36, 31.92.
3-(4-Methoxy-phenylamino)-N,N-dimethyl-propionamide (3e): The product was obtained as a white solid
1
in a yield of 81% (0.5 g). MP: 85-87 ℃. H-NMR (600 MHz, CDCl3) δ6.78 (d, J = 8.6 Hz, 2H), 6.64 (d, J
13
= 8.6 Hz, 2H), 3.75 (s, 3H), 3.43 (t, J = 5.9 Hz, 2H), 2.96 (d, J = 6.5 Hz, 6H), 2.59 (t, J = 5.9 Hz, 2H).
C
NMR (151 MHz, CDCl3) δ 171.72, 152.41, 141.82, 114.92, 114.91, 55.80, 40.83, 37.12, 35.30, 32.18.
3-(2-Chloro-phenylamino)-N,N-dimethyl-propionamide (3f): The product was obtained as a yellow liquid
1
in a yield of 82% (0.52 g). H NMR (600 MHz, CDCl3) δ 7.24 (dd, J = 7.9, 1.5 Hz, 1H), 7.15 – 7.11 (m,
1H), 6.71 (dd, J = 8.2, 1.1 Hz, 1H), 6.61 (tt, J = 14.6, 7.3 Hz, 1H), 4.92 (s, 1H), 3.54 (t, J = 6.4 Hz, 2H), 2.96
13
(d, J = 2.3 Hz, 6H), 2.62 (t, J = 6.4 Hz, 2H). C NMR (151 MHz, CDCl3) δ 170.16, 142.73, 128.25, 126.74,
118.56, 116.21, 110.12, 38.30, 36.08, 34.30, 31.33.
3-(4-Bromo-phenylamino)-N,N-dimethyl-propionamide (3g): The product was obtained as a white solid
1
in a yield of 55% (0.47 g). MP: 110–113 ℃. H NMR (600 MHz, CDCl3) δ7.24 (d, J = 8.8 Hz, 2H), 6.52
13
(d, J = 8.8 Hz, 2H), 4.65 (s, 1H), 3.44 (t, J = 5.9 Hz, 2H), 2.96 (d, J = 8.4 Hz, 6H), 2.58 (t, J = 5.9 Hz, 2H). C
NMR (151 MHz, CDCl3) δ 171.46, 146.80, 131.97, 114.83, 109.08, 39.58, 37.11, 35.32, 31.95.
3-Phenylamino-propionamide (3i): The product was obtained as a white solid in a yield of 84% (0.39 g).
1
MP: 53–56 ℃ [31]. H NMR (600 MHz, CDCl3) δ7.18 (t, J = 7.9 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.63 (d,
13
J = 7.9 Hz, 2H), 5.91 (s, 2H), 3.44 (t, J = 6.1 Hz, 2H), 2.49 (t, J = 6.1 Hz, 2H). C NMR (151 MHz, CDCl3)
δ 174.26, 147.54, 129.38, 118.09, 113.40, 39.99, 34.91.
3-(4-Bromo-phenylamino)-propionamide (3j): The product was obtained as a white solid in a yield of 79%
1
(0.68 g). MP: 122–125 ℃. H NMR (600 MHz, CDCl3) δ7.29 – 7.28 (m, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.64
13
– 6.47 (m, 2H), 5.57 (d, 2H), 3.48 – 3.41 (m, 2H), 2.59 – 2.50 (m, 2H). C NMR (151 MHz, CDCl3) δ
173.48, 146.05, 132.10, 115.26, 110.16, 40.19, 34.28.
N,N-Diethyl-3-phenylamino-propionamide (3k)[32]: The product was obtained as a yellow liquid in a
1
yield of 83% (0.39 g). H NMR (600 MHz, CDCl3) δ 7.21 – 7.11 (m, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.64 –
6.61 (m, 2H), 4.10 (m, 1H), 3.46 (t, J = 6.2 Hz, 2H), 3.36 (q, J = 7.1 Hz, 2H), 3.23 (q, J = 7.2 Hz, 2H), 2.57
13
(t, J = 6.2 Hz, 2H), 1.10 (td, J = 7.1, 5.6 Hz, 6H). C NMR (151 MHz, CDCl3) δ170.75, 148.04, 129.25,
117.35, 113.18, 41.90, 40.13, 39.75, 32.00, 14.16, 13.11.
N,N-Diethyl-3-p-tolylamino-propionamide (3l): The product was obtained as a white solid in a yield of
1
72% (0.39 g). MP: 52–55 ℃. H NMR (600 MHz, CDCl3) δ6.98 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 8.3 Hz,
2H), 3.45 (t, J = 6.1 Hz, 2H), 3.37 (q, J = 7.1 Hz, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.58 (t, J = 6.1 Hz, 2H), 2.23
13
(s, 3H), 1.11 (td, J = 7.1, 3.1 Hz, 6H). C NMR (151 MHz, CDCl3) δ170.77, 145.45, 129.78, 126.96, 113.66,
41.87, 40.41, 40.09, 31.96, 20.41, 14.17, 13.11.
3-(2-Amino-phenylamino)-N,N-diethyl-propionamide (3m): The product was obtained as a black liquid
1
in a yield of 63% (0.34 g). H NMR (600 MHz, CDCl3) δ 6.82 – 6.77 (m, 1H), 6.75 – 6.69 (m, 3H), 3.85 (s,
2H), 3.47 (t, J = 6.2 Hz, 2H), 3.39 (q, J = 7.1 Hz, 2H), 3.29 (q, J = 7.2 Hz, 2H), 2.65 (t, J = 6.2 Hz, 2H), 1.14
13
(dt, J = 13.9, 7.1 Hz, 6H). C NMR (151 MHz, CDCl3) δ170.87, 136.52, 135.44, 120.22, 119.48, 116.43,
113.28, 41.94, 40.62, 40.17, 32.06, 14.21, 13.12.
3-(3-Chloro-phenylamino)-N,N-diethyl-propionamide (3o): The product was obtained as a white solid in
1
a yield of 76% (0.48 g). MP: 58–61 ℃. H NMR (600 MHz, CDCl3) δ 7.04 (t, J = 8.0 Hz, 1H), 6.65 – 6.61
(m, 1H), 6.59 (t, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.2, 2.2 Hz, 1H), 4.58 (m, 1H), 3.49 – 3.41 (m, 2H), 3.37 (q,
13
J = 7.1 Hz, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.57 (t, J = 6.0 Hz, 2H), 1.18 – 0.99 (m, 6H). C NMR (151 MHz,
CDCl3) δ 171.73, 136.94, 135.20, 120.21, 119.03, 116.33, 112.65, 40.06, 37.11, 35.31, 32.44.

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3-Benzylamino-N,N-diethyl-propionamide (3p): The product was obtained as a white solid in a yield of
1
84% (0.45 g). MP: 119–121 ℃. H NMR (600 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.68 – 7.51 (m, 2H), 7.51 –
7.37 (m, 3H), 4.26 – 4.04 (m, 2H), 3.27 (q, J = 7.1 Hz, 4H), 3.05 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H),
13
1.11 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, DMSO-d6) δ 168.78, 132.51, 130.46,
129.32, 129.12, 50.27, 43.13, 41.74, 40.38, 40.24, 40.11, 29.02, 14.40, 13.47.
3-Phenylamino-propionic acid methyl ester (3q): The product was obtained as a white solid in a yield of
1
88% (0.41 g). MP: 32–35 ℃ [33]. H NMR (600 MHz, CDCl3) δ 7.17 (t, J = 7.6 Hz, 2H), 6.71 (t, J = 7.3 Hz,
13
1H), 6.61 (d, J = 8.1 Hz, 2H), 4.02 (s, 1H), 3.68 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H).
C
NMR (151 MHz, CDCl3) δ 172.85, 147.60, 129.52, 129.35, 129.15, 117.91, 117.75, 117.54, 113.24, 113.06,
112.83, 99.99, 51.78, 39.43, 33.73.
3-p-Tolylamino-propionic acid ethyl ester (3r) [34]: The product was obtained as a yellow liquid in a yield
1
of 82% (0.44 g). H NMR (600 MHz, CDCl3) δ 7.02 – 6.91 (m, 2H), 6.58 – 6.51 (m, 2H), 4.14 (qd, J = 7.5,
2.3 Hz, 2H), 3.85 (s, 1H), 3.41 (td, J = 6.4, 1.0 Hz, 2H), 2.58 (td, J = 6.4, 0.8 Hz, 2H), 2.23 (d, J = 2.3 Hz,
13
3H), 1.25 (ddd, J = 7.1, 4.5, 1.8 Hz, 3H). C NMR (151 MHz, CDCl3) δ 172.44, 145.32, 129.96, 129.78,
126.92, 113.30, 60.56, 60.52, 39.83, 33.92, 20.37, 20.19, 14.19.
3-(Pyridin-2-ylamino)-propionic acid ethyl ester (3s): The product was obtained as a grey solid in a yield
1
of 33% (0.15 g). MP: 46–48 ℃ [35]. H NMR (600 MHz, CDCl3) δ 8.08 (dd, J = 4.8, 0.9 Hz, 1H), 7.45 –
7.31 (m, 1H), 6.56 (dd, J = 6.7, 5.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 4.96 (s, 1H), 4.15 (q, J = 7.1 Hz, 2H),
13
3.64 (d, J = 5.1 Hz, 2H), 2.63 (t, J = 6.2 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ
172.61, 158.22, 147.93, 137.37, 112.94, 107.64, 60.60, 37.36, 34.23, 14.20.
3-p-Tolylamino-propionic acid tert-butyl ester (3t): The product was obtained as a yellow liquid in a yield
1
of 82% (0.44 g). H NMR (600 MHz, CDCl3) δ6.91 (d, J = 7.9 Hz, 2H), 6.48 (d, J = 8.2 Hz, 2H), 3.83 (s,
13
1H), 3.29 (t, J = 6.3 Hz, 2H), 2.43 (t, J = 6.3 Hz, 2H), 2.16 (s, 3H), 1.37 (s, 9H). C NMR (151 MHz, CDCl3)
δ 170.79, 144.49, 128.74, 125.82, 112.29, 79.75, 39.02, 34.08, 28.67, 27.09, 26.95, 19.35.
3-Phenylamino-propionic acid tert-butyl ester (3u) [36]: The product was obtained as a yellow liquid in a
1
yield of 80% (0.37 g). H NMR (600 MHz, CDCl3) δ 7.16 (dd, J = 11.1, 4.2 Hz, 2H), 6.69 (t, J = 7.3 Hz,
13
1H), 6.60 (d, J = 7.9 Hz, 2H), 4.03 (s, 1H), 3.37 (t, J = 6.3 Hz, 2H), 2.50 (t, J = 6.3 Hz, 2H), 1.44 (s, 9H).
C
NMR (151 MHz, CDCl3) δ 171.79, 147.88, 129.33, 129.30, 117.62, 117.59, 113.10, 113.07, 80.86, 39.69,
35.17, 28.17, 28.14.
3-(4-Chloro-phenylamino)-propionic acid tert-butyl ester (3v): The product was obtained as a white solid
1
in a yield of 83% (0.53 g). MP: 33–36 ℃. H NMR (600 MHz, CDCl3) δ 7.13 (d, J = 8.7 Hz, 2H), 6.57 (d,
13
J = 8.7 Hz, 2H), 4.41 (s, 1H), 3.37 (t, J = 6.3 Hz, 2H), 2.52 (t, J = 6.3 Hz, 2H), 1.45 (s, 9H). C NMR (151
MHz, CDCl3) δ 171.60, 146.03, 129.13, 122.51, 114.40, 81.07, 39.98, 34.76, 28.11.
3-(Methyl-phenyl-amino)-propionamide (3w): The product was obtained as a white solid in a yield of
1
80% (0.43 g). MP: 88–90 ℃. H NMR (600 MHz, DMSO-d6) δ 7.38 (s, 1H), 7.21 – 7.10 (m, 2H), 6.85 (s,
1H), 6.70 (d, J = 8.0 Hz, 2H), 6.65 – 6.54 (m, 1H), 3.56 – 3.49 (m, 2H), 2.84 (s, 3H), 2.29 – 2.09 (m, 2H).
13
C NMR (151 MHz, DMSO-d6) δ 173.82, 149.12, 129.54, 116.60, 116.13, 112.78, 112.43, 48.84, 38.13,
32.50.
3-(pyrrolidin-1-yl)propanamide (3x) [37]: The product was obtained as a yellow liquid in a yield of 96%
1
(0.48 g). H NMR (600 MHz, CDCl3) δ 8.21 (s, 1H), 5.88 (s, 1H), 2.79 (s, 2H), 2.62 (s, 4H), 2.45 (s, 2H),
13
1.82 (t, J = 3.5 Hz, 4H). C NMR (151 MHz, CDCl3) δ 175.51, 53.84, 53.43, 51.62, 34.13, 23.50, 22.75.
3-(4-methylpiperidin-1-yl)propanamide (3y): The product was obtained as a white solid in a yield of 95%
1
(0.47 g). MP: 116–117 ℃ [38]. H NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 5.43 (s, 1H), 2.93 (d, J=11.7,
2H), 2.61 (td, J = 6.4, 3.8, 2H), 2.40 (t, J = 6.2, 2H), 2.00 (t, J = 11.0, 2H), 1.68–1.56 (m, 2H), 1.48–1.30 (m,

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13
1H), 1.21 (ddd, J = 15.6, 12.5, 3.7, 2H), 0.88 (d, J = 6.5, 3H). C NMR (151 MHz, CDCl3) δ 174.94, 53.92,
53.27, 42.62, 37.18, 33.88, 31.92, 30.49, 21.63.
1
Phenylamine (1a)[39]: The product was obtained as a colorless liquid in a yield of 63% (0.12 g). H NMR
(600 MHz, CDCl3) δ 7.11 (dd, J = 8.4, 7.4 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.58 (dd, J = 8.5, 1.0 Hz, 2H),
13
3.49 (s, 2H). C NMR (151 MHz, CDCl3) δ 146.69, 129.47, 118.61, 115.29.
o-phenylenediamine (1b): The product was obtained as a colorless solid in a yield of 82% (0.17 g). MP:
1
13
100–102 ℃ [40]. H NMR (600 MHz, CDCl3) δ 6.87 – 6.50 (m, 4H), 3.35 (s, 4H). C NMR (151 MHz,
CDCl3) δ 134.71, 120.22, 116.70.
1-Aminonaphthalene (1c): The product was obtained as a white solid in a yield of 85% (0.2 g). MP: 45–
1
48 ℃ [41]. H NMR (600 MHz, CDCl3) δ 7.79 (tt, J = 7.0, 4.2 Hz, 2H), 7.51 – 7.37 (m, 2H), 7.37 – 7.24 (m,
13
2H), 6.76 (dd, J = 7.1, 1.2 Hz, 1H), 4.12 (s, 2H). C NMR (151 MHz, CDCl3) δ 142.10, 134.43, 128.59,
126.38, 125.89, 124.90, 123.69, 120.83, 119.02, 109.72.
4-Methoxy-phenylamine (1d): The product was obtained as a brown solid in a yield of 72% (0.16g). MP:
1
56–59 °C [42]. H NMR (600 MHz, CDCl3) δ 6.86 – 6.68 (m, 2H), 6.68 – 6.57 (m, 2H), 3.85 – 3.61 (m, 3H),
13
3.39 (s, 2H). C NMR (151 MHz, CDCl3) δ 152.78, 139.92, 116.41, 114.79, 55.72.
2-Chloro-phenylamine (1e) [43]: The product was obtained as a colorless liquid in a yield of 40% (0.09
1
g). H NMR (600 MHz, CDCl3) δ 7.31 – 7.19 (m, 1H), 7.04 (dd, J = 10.2, 4.2 Hz, 1H), 6.68 (dd, J = 16.0,
13
6.6 Hz, 2H), 4.00 (s, 2H). C NMR (151 MHz, CDCl3) δ 143.12, 129.53, 127.82, 119.32, 119.12, 116.06.
4-Bromo-phenylamine (1f): The product was obtained as a grey solid in a yield of 70% (0.19 g). MP: 59–
1
62 ℃ [44]. H NMR (600 MHz, CDCl3) δ 7.29 – 7.09 (m, 2H), 6.61 – 6.42 (m, 2H), 3.66 (d, J = 36.7 Hz,
13
2H). C NMR (151 MHz, CDCl3) δ 145.41, 131.95, 116.68, 110.09.
1
Phenylamine (1g): The product was obtained as a colorless liquid in a yield of 73% (0.12 g). H NMR
(600 MHz, CDCl3) δ7.11 (dd, J = 8.4, 7.4 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.58 (dd, J = 8.5, 1.0 Hz, 2H),
13
3.49 (s, 2H). C NMR (151 MHz, CDCl3) δ 146.69, 129.47, 118.61, 115.29.
4-Bromo-phenylamine (1h): The product was obtained as a grey solid in a yield of 70% (0.17 g). MP: 59–
1
–62 ℃. H NMR (600 MHz, CDCl3) δ 7.29 – 7.09 (m, 2H), 6.61 – 6.42 (m, 2H), 3.66 (d, J = 36.7 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ 145.41, 131.95, 116.68, 110.09.
o-phenylenediamine (1i): The product was obtained as a colorless solid in a yield of 81% (0.19 g). MP:
1
13
100–102 ℃. H NMR (600 MHz, CDCl3) δ 6.87 – 6.50 (m, 4H), 3.35 (s, 4H). C NMR (151 MHz, CDCl3)
δ 134.71, 120.22, 116.70.
3-Chloro-phenylamine (1j) [45]: The product was obtained as a colorless liquid in a yield of 35% (0.09
1
g). H NMR (600 MHz, CDCl3) δ 7.01 (t, J = 8.0 Hz, 1H), 6.69 (dd, J = 7.9, 1.1 Hz, 1H), 6.59 (t, J = 2.1 Hz,
13
1H), 6.47 (dd, J = 8.1, 2.2 Hz, 1H), 3.65 (s, 2H). C NMR (151 MHz, CDCl3) δ 147.85, 134.82, 130.47,
118.42, 114.97, 113.36.
p-Tolylamine (1k): The product was obtained as a colorless solid in a yield of 72% (0.17 g). MP: 43–45
1
℃ [46]. H NMR (600 MHz, CDCl3) δ 7.07 – 6.83 (m, 2H), 6.58 (d, J = 8.0 Hz, 2H), 3.46 (s, 2H), 2.23 (s,
13
3H). C NMR (151 MHz, CDCl3) δ 143.91, 129.82, 127.80, 115.32, 20.52.
p-Tolylamine (1l): The product was obtained as a colorless solid in a yield of 76% (0.18 g). MP: 43–45
1
℃. H NMR (600 MHz, CDCl3) δ 7.07 – 6.83 (m, 2H), 6.58 (d, J = 8.0 Hz, 2H), 3.46 (s, 2H), 2.23 (s, 3H).
13
C NMR (151 MHz, CDCl3) δ 143.91, 129.82, 127.80, 115.32, 20.52.
1
Phenylamine (1m): The product was obtained as a colorless liquid in a yield of 72% (0.16 g). H NMR
(600 MHz, CDCl3) δ7.11 (dd, J = 8.4, 7.4 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.58 (dd, J = 8.5, 1.0 Hz, 2H),
13
3.49 (s, 2H). C NMR (151 MHz, CDCl3) δ 146.69, 129.47, 118.61, 115.29.

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Chloro-phenylamine (1o): The product was obtained as a white solid in a yield of 82% (0.21 g). MP: 65–
1
67 ℃ [47]. H NMR (600 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 3.64 (s, 2H).
13
C NMR (151 MHz, CDCl3) δ 144.97, 129.14, 123.16, 116.25.
2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (6a, 6b and 6c): The products were obtained as a tan solid
1
in yields of 74% (0.24 g), 68% (0.22 g) and 34% (0.17 g), respectively. MP: 138–140 ℃ [48,49]. H NMR
(600 MHz, CDCl3) δ 8.36 (s, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H),
13
6.74 (d, J = 7.9 Hz, 1H), 3.70 – 3.63 (m, 2H), 2.80 – 2.69 (m, 2H). C NMR (151 MHz, CDCl3) δ 174.06,
138.75, 126.36, 125.36, 122.19, 120.57, 119.89, 45.55, 36.19.
4-Methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (6d): The product was obtained as a white
1
solid in a yield of 93% (0.30 g). MP: 182–184 ℃ [50,51]. H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 7.01
– 6.97 (m, 1H), 6.95 (dd, J = 7.7, 1.0, 1H), 6.88 (t, J = 7.5, 1H), 6.78 (d, J = 7.8, 1H), 4.03 (dt, 1H), 3.55 (s,
13
1H), 2.64 (dd, J = 13.6, 4.0, 1H), 2.45 (dd, J = 13.7, 7.9, 1H), 1.33 (d, J = 6.3, 3H). C NMR (151 MHz,
CDCl3) δ 173.07, 138.25, 128.00, 125.64, 122.19, 121.41, 121.00, 54.14, 41.44, 23.62.
7,8-difluoro-2-methyl-1,2,3,5-tetrahydro-1,5-benzodiazepin-4-one (6e): The product was obtained as a
1
white solid in a yield of 90% (0.29 g). MP: 193.5–195 ℃. H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 6.82
(dd, J = 10.6, 7.9, 1H), 6.64 (dd, J = 11.0, 7.5, 1H), 4.05 (dd, J = 12.1, 6.3, 1H), 3.38 (s, 1H), 2.63 (dd, J=13.5,
13
4.5, 1H), 2.40 (dd, J = 13.5, 7.6, 1H), 1.72 (s, 1H), 1.33 (d, J = 6.3, 3H). C NMR (151 MHz, CDCl3) δ =
172.99, 148.33, 148.24, 146.69, 146.60, 145.90, 145.84, 144.30, 144.21, 134.80, 124.80, 111.04, 110.91,
109.69, 109.56, 55.07, 40.76, 23.43.
2,3-dihydro-1,5-benzothiazepine-4(5H)-one (6f): The product was obtained as a brown solid in a yield of
1
34% (0.11 g). Mp: 215–216℃[52]. H NMR (600 MHz, CDCl3) δ 8.55 (s, 1H), 7.61 (d, J = 7.7, 1H), 7.37
13
(td, J = 7.7, 1.2, 1H), 7.17 (t, J = 7.6, 1H), 7.14 (d, J = 7.8, 1H), 3.46 (t, J = 6.9, 2H), 2.65 (t, J = 6.9, 2H). C
NMR (151 MHz, CDCl3) δ 173.71, 141.41, 135.51, 129.83, 126.97, 126.49, 123.30, 34.29, 33.54.
3-Methyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (6g): The product was obtained as a white solid
1
in a yield of 31% (0.10 g). Mp: 176–178 ℃ [53]. H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.60 (d, J =
7.6, 1H), 7.36 (t, J = 6.9, 1H), 7.17 (t, J = 8.2, 1H), 7.13 (d, J = 7.8, 1H), 3.49 (dd, J = 11.3, 6.0, 1H), 3.05 –
13
2.98 (m, 1H), 2.79 (dt, J = 12.6, 6.3, 1H), 1.19 (d, J = 6.6, 3H). C NMR (151 MHz, CDCl3) δ 175.74, 141.12,
135.15, 129.72, 127.72, 126.46, 123.47, 41.51, 36.33, 15.47.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1.
Author Contributions: conceptualization, Z.D., Q.T. and Y.L.; methodology, Z.D., Q.T.; software, S.S; validation,
W.L. and X.W.; formal analysis, D.L.; investigation, Y.Z.; resources, Z.L.; data curation, Q.T.; writing—original
draft preparation, Z.D.; writing—review and editing, Y.L.; visualization, Y.L.; supervision, Z.L.; project
administration, Q.T.; funding acquisition, J.Y.
Funding: This research was funded by Chongqing Science and Technology Commission Project of china, grant
number “cstc2018jscx-msybx0294”.
Conflicts of Interest: The authors declare that there is no conflict of interest.
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