Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-ones via a Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction

Article abstract of DOI:10.1021/acscombsci.6b00038

Multicomponent reactions (MCRs) have become a powerful tool for drug discovery and development owing to their advantages of fast and efficient construction of a large library of products with complexity and diversity. However, conventional MCRs usually pr

Full text of DOI:10.1021/acscombsci.6b00038

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Article
Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-Ones via a
Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction
Sichao Zheng, Shufang Zhong, Zhipeng Chen, Wenhua Chen, and Qiuhua Zhu
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00038 • Publication Date (Web): 29 Jun 2016
Downloaded from http://pubs.acs.org on July 4, 2016
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Efficient Synthesis of a Series of Novel
Octahydroquinazoline-5-Ones via a Simple on-
Water Urea-Catalyzed Chemoselective Five-
Component Reaction
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Sichao Zheng, Shufang Zhong, Zhipeng Chen, Wenhua Chen* and Qiuhua Zhu*
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical
Sciences, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515,
China.
KEYWORDS: multiꢀcomponent reaction, octahydroquinazolineꢀ5ꢀones, water solvent,
enaminones, synthetic method
ABSTRACT: Multiꢀcomponent reactions (MCRs) have become a powerful tool for drug
discovery and development owing to their advantages of fast and efficient construction of a large
library of products with complexity and diversity. However, conventional MCRs usually proceed
in environmentꢀunfriendly organic solvents rather than in water, a green solvent used by nature
for biological chemistry. Herein, a simple and efficient onꢀwater ureaꢀcatalyzed chemoselective
fiveꢀcomponent reaction (5CR) has been developed for the synthesis of a series of novel
octahydroquinazolineꢀ5ꢀones (6), the derivatives of quinazolinones possessing diverse biological
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activities. The molecular structure of 6 was confirmed by singleꢀcrystal Xꢀray diffraction. The
5CR can proceed at room temperature under normal atmospheric pressure in good yields and
afford a large library of octahydroquinazolineꢀ5ꢀones with various aromatic and aliphatic
substituents at Nꢀ1, Cꢀ2 and Nꢀ3. In addition, a green method has been developed for the
synthesis of enaminones, important intermediates in the 5CR and in synthetic chemistry.
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INTRODUCTION
Quinazolinones are a class of important azaheterocycles possessing diverse biological
1
2,
3
4
5,
6
6
activities , such as, antiꢀcancer,
antiꢀbacterial, anticonvulsant,
antidepressant, antiꢀ
7
8
inflammatory, and antihypertension. Different substituents or the same substituent at different
positions usually show different influences on their biological activities. As shown in Figure 1,
quinazolinones with different substituents and carbonyl at different positions I to III show
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9
8
antitumor, antibiotic and antihypertensive activities, respectively. Therefore, the development
of the efficient synthetic methods for various quinazolinones has attracted great interest from
synthetic chemistry. Most of the reported methods are about the synthesis of quinazolineꢀ4ꢀ
1
0ꢀ15
16ꢀ19
ones
and quinazolineꢀ2,4ꢀ(1H,3H)ꢀdiones.
Only a twoꢀstep reaction has been reported for
8
the synthesis of quinazolineꢀ5ꢀones although octahydroquinazolineꢀ5ꢀones, for example III in
8
Figure 1, have been found to possess a high antihypertensive effect.
O
O
O
N
N
3
N
H
O
N
O
O
N
1
N
COOH
CN
2
N
O
N
R2
Cl
Ν
S
Ν
R
3
Cl
R1
O
I
II
III
6
Figure 1. Examples of quinazolinones with different biological activities and the quinazolineꢀ5ꢀ
ones with substituents at Nꢀ1, Cꢀ2 and Nꢀ3 synthesized in the work.
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The use of environmentꢀbenign substances is one of the main concerns of green
chemistry. Water is a green solvent used by nature for biological chemistry. However, organic
chemists give little consideration to water as a useful reaction solvent until the early work of
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Breslow showing how water enhances the DielsꢀAlder reactions. Many organic reactions in
water show that water exhibits unique reactivity and selectivity that cannot be attained in
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conventional organic solvents.
Butler suggested that water should be high or at the top of the
list when organic and industrial chemists seek to chose a solvent for synthesis, and divided the
organic reactions using water as solvent into two typical types: pure inꢀwater reactions of soluble
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reactants and pure onꢀwater reactions of highly insoluble reactants. Interestingly, onꢀwater
reactions normally exhibit substantial rate acceleration when insoluble reactants are stirred in
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aqueous suspension. However, onꢀwater reactions have received relatively little attention from
organic synthetic chemistry. In term of catalysts, organocatalysts have become a thriving area in
synthetic chemistry for the advantages such as being stable in air and water, available from
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biological materials, inexpensive and easy to prepare, simple to use and nonꢀtoxic.
Multiꢀcomponent reaction (MCR) is an ideal reaction mode which is consistent with the
concept of green chemistry owing to its high efficiency. In addition, MCRs could be used to
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build structural diversity and complexity of compound libraries.
They have been recognized
by the synthetic community in industry and academia as a preferred method to design and
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discover biologically active compounds. Considering the MCR advantages, we are interested in
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1ꢀ35
the development of MCRs for the synthesis of novel heterocycles
and their biological
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6
properties. We recently synthesized a series of novel C6ꢀunsubstituted tetrahydropyrimidines
(
THPs) via a convenient ureaꢀcatalyzed chemoselective fiveꢀcomponent reaction (5CR) of butꢀ2ꢀ
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ynedioates, primary amines, formaldehyde and aromatic aldehydes. According to the proposed
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5
CR mechanism, we deduced that the 5CR might be developed as a 5CR for the synthesis of
octahydroquinazolineꢀ5ꢀones (6) in Figure 1. However, only trace of 6 was observed under the
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reaction conditions for the synthesis of THPs. Encouraged by Butler's suggestion about the use
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of water and a few of efficient MCRs in water,
the influence of water on the 5CR synthesis
of 6 was investigated. To our surprise, the 5CR for the synthesis of 6 proceeded smoothly in
water at room temperature in higher yields using urea as catalyst and acetic acid (AcOH) as
promoter which afford a simple and efficient method for the synthesis of a library of
quinazolineꢀ5ꢀones for investigation into their biological activities. Since some reactants or
intermediates are highly insoluble, the 5CR is belong to onꢀwater reaction.
RESULTS AND DISCUSSION
Screen of reaction conditions for the 5CR synthesis of 6{1,1,1}
The structures of the diversity reagents used are shown in Figure 2. As shown in Scheme 1, our
research
began
with
the
synthesis
of
7,7ꢀdimethylꢀ1,2,3ꢀtriphenylꢀ1,2,3,4,7,8ꢀ
hexahydroquinazolinꢀ5(6H)ꢀone (6{1,1,1}) via the 5CR of dimedone (1), aniline (2{1}),
benzaldehyde (3{1}), aniline (4{1}) and formaldehyde (5). The 5CR was firstly conducted under
37
the reaction conditions A for the synthesis of THPs and only trace of 6{1,1,1} was obtained.
However, 54% of 6{1,1,1} was obtained upon replacing 1 and 2{1} by enaminone 7{1}. These
results means the conditions A is favourable for the fourꢀcomponent reaction (4CR) of 7{1},
3
{1}, 4{1} and 5 but unfavorable for the condensation of 1 and 2{1}. The 5CR could not
4
2
proceed under the conditions (B) for the condensation of 1 and 2{1}. Since a 5CR has
advantages of less operating, manpowerꢀ and materialꢀsaving over a 4CR, the study of the 5CR
is needed for practical application.
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primary amines 2{1-5}
NH2
NH2
NH2
NH
2
NH
2
NH
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Br
2{1}
2{2}
2{3}
2{4}
2{5}
primary amines 4{1-4}
NH2
NH2
NH
2
NH2
Br
O
4{3}
4{1}
4{2}
4
{4}
aldehyde 3{1-13}
CHO
O
CHO
CHO
OH
CHO
OH
CHO
CHO
CHO
S
S
OH
O
O
O
Br
3{1}
3
{2}
3{3}
3{4}
3{5}
3{6}
3{7}
CHO
CHO
CHO
CHO
CHO
CHO
Br
NO2
CF3
CN
3{8}
3{9}
3{10}
3{11}
3{12}
3
{13}
Figure 2. Molecular structures of the diversity reagents used in the work.
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O
NH2
CHO
NH2
A
B
trace
5CR
O
O
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Η
H
O
Ν
1
2{1}
3{1}
4{1}
5
1 equiv 1 equiv 3.5 equiv 3.5 equiv 1.4 equiv
B
condensation
8%
6{1,1,1}
6{1,1,1}
O
9
4CR
3
{1}
.5 equv. 3.5 equv.
A: Urea (0.2 equiv) /AcOH (4 equiv), MeOH (methanol), rt;
B: I (0.2 equiv), MeCN (acetonitrile), rt
4{1}
5
A
54%
3
1.4 equv.
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N
H
7
{1}
1
equiv.
2
Scheme 1. 4CR and 5CR synthesis of 6{1,1,1}.
As shown in Table 1, the reaction conditions for the 5CR synthesis of 6{1,1,1} were
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optimized. Based on the conditions for the synthesis of THPs (entry 1), the influence of
solvents was firstly investigated (entries 2ꢀ6). Surprisingly, water is the most suitable solvent for
the 5CR (entry 6). By screening the amount of AcOH (entries 7ꢀ9) and urea (entries 10 and 11),
the yield of 6{1,1,1} increased to 72% (entry 10). Then, the influence of catalysts was studied
(entries 12ꢀ15). It can be seen that the yield of 6{1,1,1} decreased sharply when only AcOH or
urea was used (comparing entry 10 and 12/13) or when proline or Cu(AcO) was used as catalyst
2
(
comparing entry 10 and 14/15). These results indicate that urea is an efficient catalyst for the
5CR when AcOH was used as a promoter. The screen (entries 16ꢀ22) of the amount of reactants
{1}, 4{1} and 5 leads to the enhancement of the 5CR product yield (76%) (entry 21). The
3
suitable reaction time is 24 h (entry 24). Therefore, the optimal reaction conditions for the 5CR
synthesis of 6{1,1,1} are 1:2{1}:3{1}:4{1}:5:urea:AcOH=1:1.1:4:3:1.4:0.3:2. Under the optimal
conditions, the yield (84%) of 6{1,1,1} synthesized by the 5CR is similar to that (85%)
synthesized by the 4CR (Scheme 1). It is worth mentioning that the yield (96%) of the
condensation reaction of 1 and 2{1} promoted by AcOH in water is similar to that (98%)
4
2
43
catalyzed by I in MeCN and higher than that (60%) catalystꢀfree in water. In addition, the
2
reaction time (3 h) of the onꢀwater AcOHꢀpromoted condensation is shorter than that (24 h) of
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the onꢀwater catalystꢀfree one.
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a
Table 1. Optimization of conditions for the 5CR synthesis of 6{1,1,1}
catalysts
1
2{1}
3{1}
4{1}
5
6{1,1,1}
solvents, rt
1
equiv 1.1 equiv
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b
entry solvent 3{1} 4{1} 5
catalyst
AcOH t
yield
/
equiv
/h /%
1
MeOH 3.5
EtOH 3.5
MeCN 3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.2
1.4 urea/0.3
1.4 urea/0.4
1.4
4
4
4
4
4
4
3
2
1
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
trace
trace
trace
trace
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2
3
4
DMF
DCM
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3
5
6
H O
2
60
7
H O
2
62
8
H O
2
68
9
H O
2
54
10
11
12
H O
2
72
H O
2
70
H O
2
45
13
14
15
16
17
18
19
20
21
H O
2
1.4 urea/0.3
1.4 proline/0.4
39
H O
2
4
38
H O
2
1.4 Cu(AcO) /0.1 4
50
2
H O
2
1.4 urea/0.3
1.4 urea/0.3
1.2 urea/0.3
1.6 urea/0.3
1.4 urea/0.3
1.4 urea/0.3
2
2
2
2
2
2
72
H O
2
2
60
H O
2
3
68
H O
2
3
71
H O
2
3
68
H O
2
4
3
76
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H O
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3
1.4 urea/0.3
1.4 urea/0.3
1.4 urea/0.3
1.4 urea/0.3
2
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5
75
2
H O
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12 79
c
H O
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24 84/85
48 82
H O
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a
Reaction was carried out with 1 (0.5 mmol), 2{1} (0.55 mmol), AcOH in 2 mL solvents at
room temperature for 3 h, followed by adding 4{1}, 38% 5, 3{1} and different catalysts
sequentially and then kept stirring for desired time. Isolated yield. 4CR yield. MeOH:
methanol; EtOH: ethanol; MeCN: acetonitrile; DMF: dimethylformide; DCM: dichloromethane.
b
c
Scope of the urea-catalyzed 5CR for the synthesis of 6
With the optimized conditions (entry 24 in Table 1), the scope of the 5CR synthesis of 6 was
investigated. As shown in Table 2, the scope of the ureaꢀcatalyzed 5CR is wide, that is, both
aliphatic and aromatic amines could be used as reactants 2 and 4, and both aliphatic and aromatic
aldehydes could be used as reactant 3, which lead to easy construction of a large library of 6 with
1
2
3
different aliphatic and aromatic substituents R , R and R . Using aromatic aldehydes with
different substituents, including strong electronꢀdonating (entry 2ꢀ5) and ꢀwithdrawing (entries
1
0 and 11) substituents, as reactant 3, the 5CR proceeded smoothly in medium to good yields
(
entries 1ꢀ11). When aliphatic aldehydes, such as nꢀvaleraldehyde and isoꢀbutyraldehyde, were
used as reactant 3, similar product yields were obtained (comparing entries 12/13 and 1). These
results indicate that aldehydes show no significant influence on the 5CR. The case is similar for
aniline (entry 1), aromatic amines with electronꢀdonating, weak electronꢀwithdrawing and largerꢀ
size substituents (entries 14ꢀ18) and aliphatic benzylamine (entries 19 and 20) as reactants 2 and
4. However, when aromatic amine with strong electronꢀwithdrawing substituent, such as nitro,
was used as reactant 2 or 4, no target product could be produced. The molecular structure of
6
{1,1,12} was confirmed by singleꢀcrystal Xꢀray diffraction (Figure 3).
a
Table 2. Scope of the 5CR synthesis of quinazolinones 6
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O
O
0
2
.3 equiv urea
equiv AcOH
R2
O
Ν
1
3
2
R NH
R CHO
R NH
2
2
O
Η
H
H
2
O
R3
Ν
R
rt, 24h
1
1 equiv
1.1 equiv
4 equiv
3 equiv
4{1-4}
1
.4 equiv
1
2{1-5}
3{1-13}
5
6
10
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2
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yield
Entry
R
R
R
6
b
(%)
1
2
2{1}
2{1}
4{1}
4{1}
3{1}
6{1,1,1} 84
6{1,1,2} 68
3
#
{Balamurugan,
201}
3
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
3{3}
3{4}
3{5}
3{6}
3{7}
3{8}
3{9}
3{10}
3{11}
3{12}
3{13}
6{1,1,3} 71
6{1,1,4} 83
6{1,1,5} 61
6{1,1,6} 80
6{1,1,7} 83
6{1,1,8} 73
6{1,1,9} 84
6{1,1,10} 74
6{1,1,11} 65
6{1,1,12} 85
6{1,1,13} 83
4
5
6
7
8
9
10
11
12
13
4
#
{Balamurugan,
201}
14
2{1}
3{1}
3{8}
6{1,2,1} 82
6{2,2,8} 66
2
#
{Balamurugan,
201}
4{Balamurugan,
#201}
15
16
17
18
19
20
2{1}
2{3}
2{4}
2{1}
2{5}
4{3}
4{1}
4{1}
4{4}
4{4}
3{1}
3{1}
3{1}
3{1}
3{1}
6{1,3,1} 80
6{3,1,1} 74
6{4,1,1} 70
6{1,4,1} 72
6{5,4,1} 67
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a
Reaction was carried out with 1 (1 mmol), 2 (1.1 mmol), AcOH (2 mmol) in 4 mL water at
room temperature for 3 h, followed by adding 4 (3 mmol), 38% 5 (1.4 mmol)，3 (4 mmol) and
urea (0.3 mmol) sequentially and then kept stirring for 24 h. Isolated yield.
b
O1
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N2
N1
Figure 3. Molecular structure of 6{1,1,12} in a single crystal (CCDC 995978).
Possible mechanism of the 5CR synthesis of 6
According to the obtained experimental results, the possible mechanism of the 5CR synthesis
of 6 was proposed. As depicted in Scheme 2, under AcOH catalysis the condensation reaction of
dimedone 1 with primary amine 2 leads to the formation of intermediate 7' that transforms to
enaminone 7 via ketoꢀenol tautomerization. Intermediate 9 is expected to be produced via an azaꢀ
33, 44
45
eneꢀtype reaction
rather than via a Mannichꢀtype reaction because Mannichꢀtype reaction
product could not be observed if the primary amine 2 was replaced by secondary amine Nꢀ
2
4, 37, 46, 47
methyl aniline. Reactant 3 is activated by urea
and converts to an active form 3' that
reacts with 9 and hence forms intermediate 10. Finally, target product 6 is generated via the
intramolecular cyclization of 10. The proposed 5CR mechanism includes four elementary steps:
condensation, azaꢀeneꢀtype reaction, nucleophilic addition and intramolecular cyclization.
According to the proposed mechanism, aromatic amines with electronꢀdonating substituents are
favorable for the 5CR but those with electronꢀwithdrawing substituent are not favorable. As for
the influence of the substituents of reactant aldehydes on the 5CR, the opposite is the case. The
5
CR reactivity mainly depends on the nucleophilicity of reactants amines because the reactants
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aldehydes are activated by urea and AcOH. These well explain the substituent influence of
aromatic amines and aldehydes on the 5CR for the synthesis of 6.
O
O
O
1
R
2
NH2
R CHO AcOH/urea
3
3
R2
R NH
2
Η
H
Ν
10
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2
4
5
R3
O
Ν
R
1
1
urea
AcOH
6
AcOH
-H O
2
condensation
N
intramolecular
cyclization
AcOH
-H
O
R2
O
8
O
2
HN
H
NH
H
N
R1
7
'
O
tautomerization
O
3'
tautomerization
R3
R2
R2
8
O
O
N
H
O
O
N
aza-ene-type
reaction
NH nucleophilic
addition
OH
2
R
R3
H
N
R1
N
R1
N
9
10
7
R1
Scheme 2. Possible mechanism of the ureaꢀcatalyzed chemoselective 5CR for the synthesis of 6.
CONCLUSION
We have developed an efficient and simple ureaꢀcatalyzed chemoselective 5CR for the
synthesis of a series of novel octahydroquinazolineꢀ5ꢀones 6. The 5CR can proceed in water at
8
room temperature in good yields. The reported octahydroquinazolineꢀ5ꢀones only have aromatic
substituents at Nꢀ1 and Nꢀ3 positions and were synthesized via a twoꢀstep reaction: the
condensation of 1 and 2 in toluene under reflux and the threeꢀcomponent reaction (3CR) of 7, 4
and 5 in EtOH under reflux in 65ꢀ85% (only 3CR yield). Compared with the reported method for
the synthesis of the quinazolineꢀ5ꢀones, the 5CR for the synthesis of 6 possesses advantages of
green solvent (water), powerꢀsaving (rt), less operating procedures (oneꢀpot reaction), higher
overall yield and more diverse products (the substituents are not only at Nꢀ1 and Nꢀ3 but also at
Cꢀ2 at which the substitution is very difficult via conventional synthetic methods owing to steric
hindrance, moreover, these substituents are not only aryl but also alkyl). Therefore, the simple
and efficient 5CR affords easy access to construction of a large library of octahydroquinazolineꢀ
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5
ꢀones for investigation into their biological activities. In addition, we have developed a new
greener synthetic method for the synthesis enaminones 7 that are important synthetic
4
8ꢀ50
intermediates and have attracted great interest in synthetic chemistry.
The investigation into
0
1
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6
7
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0
the biological activities and optical properties of 6 is underway in our group.
EXPERIMENTAL
General procedure for the synthesis of octahydroquinazoline-5-ones 6 in Table 2
All reactions were run with the following steps: (a) dimedone 1 (1 mmol, 140 mg), primary
amine 2 (1.1 mmol) and AcOH (2 mmol, 120 ꢁL) were added in a tube with 4 mL distilled water
and kept stirring for 3 h; (b) amine 4 (3 mmol), 38% formaldehyde 5 (1.4 mmol, 112 ꢁL),
aldehyde 3 (4 mmol) and urea (0.3 mmol, 18 mg) were successively added into the above
mixture and kept stirring at room temperature for 24 h. After the reactions were completed, the
product mixtures were extracted with dichloromethane three times. The organic phase was dried
with anhydrous Na SO , filtered and evaporated under reduced pressure, then purified by
2
4
preparative TLC with petroleum etherꢀethyl acetate (6:1−1:1) as eluent to afford the desired
products 6 in 61−85% yields.
1,2,3,4,7,8-hexahydro-7,7-dimethyl-1,2,3-triphenylquinazolin-5(6H)-one 6{1,1,1}. White
solid, 84% yield; Mp: 167–168℃; IR νmax (KBr) 3059, 2955, 2926, 1625, 1587, 1572, 1492,
:
ꢀ1 1
1450, 1388, 1293, 1258, 1193, 1174, 1154, 1122, 1077, 1031, 1010, 931, 758, 740, 698 cm ; H
NMR (400 MHz, CDCl ) δ = 7.50 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.40 – 7.35 (m,
3
1H), 7.33 – 7.22 (m, 5H), 7.05 (d, J = 8.3 Hz, 2H), 6.94 (m, 3H), 6.20 (s, 1H), 4.40 (d, J = 17.0
Hz, 1H), 3.63 (d, J = 17.0 Hz, 1H), 2.38 (d, J = 16.5 Hz, 1H), 2.28 (s, 2H), 2.17 (d, J = 16.5 Hz,
13
1
H), 1.05 (d, J = 9.0 Hz, 6H) ppm; C NMR (101 MHz, CDCl ) δ = 193.96, 155.83, 149.40,
3
143.75, 138.73, 129.43, 129.22, 128.73, 128.33, 126.92, 126.81, 126.57, 120.95, 118.54, 106.14,
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1.44, 50.13, 41.65, 40.13, 33.02, 28.83, 28.01 ppm; MS (ESI): m/z 409 (M + H , 100); Anal.
Calcd for C H N O: C, 82.32; H, 6.91; N, 6.86. Found: C, 81.85; H, 6.84; N, 6.64.
28 28
2
ASSOCIATED CONTENT
Supporting Information
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General experimental procedures, characterization data, the H NMR and C NMR spectra of
octahydroquinazolineꢀ5ꢀones 6. This information is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: zhuqh@smu.edu.cn
*Eꢀmail: whchen@smu.edu.cn
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Foundation of China (21272111). We thank
Chen Junguo for his help on the preparation of products.
ABBREVIATIONS
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6
MCR, Multiꢀcomponent reaction; 5CR, fiveꢀcomponent reaction; THPs, tetrahydropyrimidines;
4CR, fourꢀcomponent reaction; rt: room temperature; AcOH, acetic acid; MeOH: methanol;
EtOH: ethanol; MeCN: acetonitrile; DMF: dimethylformide; DCM: dichloromethane; TLC, thin
layer chromatography.
0
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