One-Pot Tandem Protocol for the Synthesis of 1,3-Bis(β-aminoacrylate)-Substituted 2-Mercaptoimidazole Scaffolds

Article abstract of DOI:10.1002/adsc.202000789

We have developed a palladium-catalyzed cross-coupling reaction of isocyanides with α-diazoacetates to form active ketenimines and following a 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed aza-Mannich type reaction with various 2-mercaptoimidazoles for the synthesis of 1,3-bis(β-aminoacrylate)-substituted 2-mercaptoimidazole derivatives with structural diversity. In addition, the use of 1H-benzo[d]imidazol-2-ol as the reaction partner also allowed the formation of 1,3-bis(β-aminoacrylate)-substituted 2-benzimidazolinone derivatives with moderate yields (34–52percent). In the aza-Mannich reaction, the regioselective N-attack rather than S-attack or O-attack at the electrophilic central carbon of ketenimines was observed. This tandem sequence is efficient since two C=C and two C?N bonds are consecutively created in one-pot. (Figure presented.).

Full text of DOI:10.1002/adsc.202000789

Title: One-Pot Tandem Protocol for the Synthesis of 1,3-Bis(β-
aminoacrylate)-Substituted 2-Mercaptoimidazole Scaffolds
Authors: Jian Luo, guoshu chen, Shu-Jie Chen, Zhao-Dong Li, Yulei
Zhao, and Yun-Lin Liu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000789
Link to VoR: https://doi.org/10.1002/adsc.202000789

10.1002/adsc.202000789
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.2020000789
One-Pot Tandem Protocol for the Synthesis of 1,3-Bis(β-
aminoacrylate)-Substituted 2-Mercaptoimidazole Scaffolds
Jian Luo,a Guo-Shu Chen,a* Shu-Jie Chen,a Zhao-Dong Li,b Yu-Lei Zhao,c and Yun-
Lin Liua*
a
School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, 510006 (China)
Fax: (+86)-343-5507; E-mail: guoshuchen@gmail.com; ylliu@gzhu.edu.cn
Department of Applied Chemistry, College of Materials and Energy, South China Agricultural University, Guangzhou
b
510642 (China).
c
School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165 (China)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We have developed a palladium-catalyzed cross- bis(β-aminoacrylate)-substituted
coupling reaction of isocyanides with α-diazoacetates to derivatives with moderate yields (34-52%). In the aza-
form active ketenimines and following 1,4- Mannich reaction, the regioselective N-attack rather than S-
2-benzimidazolinone
a
diazabicyclo[2.2.2]octane (DABCO) catalyzed aza-Mannich attack or O-attack at the electrophilic central carbon of
type reaction with various 2-mercaptoimidazoles for the ketenimines was observed. This tandem sequence is
synthesis
of
1,3-bis(β-aminoacrylate)-substituted
2- efficient since two C=C and two C-N bonds are
mercaptoimidazole derivatives with structural diversity. In consecutively created in one-pot.
addition, the use of 1H-benzo[d]imidazol-2-ol as the reaction
partner also allowed the formation of 1,3-
Keywords: 2-Mercaptoimidazole; β-Aminoacrylate;
Isocyanides; α-Diazoacetates; Tandem Reaction
methods for the synthesis of 2-mercaptoimidazole
Introduction
motif
bearing
β-aminoacrylate
units
with
substitutional and stereochemical diversity.
2-Mercaptoimidazoles are an important class of
nitrogen-containing heterocycles.[1] They are widely
prevalent in a number of pharmaceuticals and
biologically active natural and non-natural products
(Figure 1).[2] The structure-activity relationship
studies revealed that substituents at the nitrogen atom
of 2-mercaptoimidazole are critical to the biological
activities.[2a-e] In addition, 2-mercaptoimidazole
derivatives are also widely used as ligands for
transition-metal catalysts.[3] As
a consequence,
Figure 1. Selected examples of pharmaceuticals and
considerable attention has been devoted to
developing expeditious and efficient approaches for
the construction and functionalization of this
heterocyclic scaffold with a high degree of structural
diversity in recent decades.[1-2] On the other hand, the
β-aminoacrylates are useful synthetic building blocks
because the conjugation of enamine and ester makes
them readily participate in a number of reactions via
different pathways.[4] In particular, β-aminoacrylates
have found their greatest utility in the construction of
β-amino acids through transition metal-catalyzed
hydrogenation.[5] The β-amino acid unit has often
been installed in nitrogen heterocycles to tune their
pharmacological properties as it constitutes a special
position in biological activity profiles.[6] Accordingly,
it is interesting and highly desirable to develop new
bioactive molecules containing 2-mercaptoimidazole unit.
Diazo compounds are highly useful building
blocks that have found widespread applications in
organic chemistry because they readily form reactive
carbenes.[7] These carbenes can participate in a
variety of transformations such as X-H (X = C, N, O,
S, Si, B, P) insertion,[8] cyclopropanation,[9] ylide-
based cycloaddition reaction[10] and Wolff
rearrangement.[11] In addition, as two formally
divalent organic species, isocyanide and carbene have
been reported to be capable of undergoing transition-
metal catalyzed cross-coupling reaction to give
ketenimines, which could be further trapped by a
series of nucleophiles to provide value-added
1
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
compounds.[12] Cai,[12g, 12m] Cheng,[12h] Zhao[12j-l] and
with α-aryl diazo ester via sequential Pd-catalysis and
Brønsted acid catalysis (Scheme 1b).[16a] In this
transformation, the possible key ketenimine
intermediate I was not stable enough to be isolated
but spontaneously and quickly be trapped by the
nucleophilic indole C3 position to furnish tricyclic
spiroindolenine II. Based on this result, along with
the consideration of the structural feature of
ketenimines, we questioned whether the replacement
of indole group with a less electron-rich aromatic ring
such as phenyl group would inhibit the intramolecular
cyclization process, thus provided the possibility to
trap ketenimine intermediates by external 2-
mercaptoimidazoles under Brønsted base catalysis to
12n]
other groups[12i,
have made significant
contributions in this research field. However, these
pioneering reports mainly employed the aldehyde-
derived
N-tosyl
hydrazine[12g-h]
and
2,2,2-
trifluorodiazothane (CF3CHN2)[12j-k] as the carbene
precursors, and the nucleophiles were limited to H2O,
alcohols, amines and activated methylene isocyanides
(Scheme 1a). In stark contrast, the potential of α-aryl
or α-alkyl-diazoacetates in the cross-coupling
reactions with isocyanides have rarely been explored,
although the resulting ketenimine[13] intermediates
could potentially function as versatile building blocks
in the synthesis of β-aminoacrylates.
form
1,3-bis(β-aminoacrylate)-substituted
2-
mercaptoimidazole derivatives (Scheme 1c). Herein,
we disclose the development of such a tandem
process.
Results and Discussion
To test the feasibility of working hypothesis
depicted in Scheme 1c, we first tried to develop an
efficient cross-coupling reaction by utilizing the
easily
accessbile
4-(2-isocyanoethyl)-1,2-
dimethoxybenzene 1a and phenyl diazoacetate 2a as
o
the model substrates at 80 C in THF for 3 h. In the
presence of Pd(PPh3)4 (5 mol%), the cross-coupling
reaction of 1a and 2a led to the formation of
ketenimine 3aa in 78% yield (Table 1, entry 1).
Encouraged by this result, we tested a series of
palladium catalysts. However, the replacement of
Pd(PPh3)4 with Pd2(dba)3, Pd(acac)2, Pd(CF3CO2)2,
Pd(OAc)2 or Pd(PPh3)2Cl2 only resulted in inferior
results by comparison with that of Pd(PPh3)4 (entries
2-6). The screening of solvents indicated that the
reaction also took place efficiently in CH3CN (entry
7), other solvents such as dioxane, CH2Cl2, toluene,
EtOAc and DMF all gave inferior yields (entries 8-
12). Furthermore, the effect of reaction temperature
was also investigated. It was found that neither
raising nor decreasing the reaction temperature could
improve the yield even with prolonged reaction time
(entries 13-15). Finally, we found that the catalyst
amount could be decreased to 2.5 mol% without
affecting the reaction efficiency (entry 16, 77% yield),
but the lower amount (1.0 mol%) was detrimental to
the reactivity (entry 17, 65% yield).
With the optimized reaction conditions in hand, we
then assessed the generality of the Pd(PPh3)4
catalyzed cross-coupling reactions of different
isocyanides 1 and α-diazo esters 2, and the results are
summarized in Table 2. With phenyl diazoacetate 2a,
a variety of linear alkyl isocyanides 1a-1i bearing
both electron-donating (MeO, Me) and electron-
withdrawing (F, Cl, CF3) groups on the aryl ring were
well tolerated under the above reaction conditions to
give the corresponding ketenimines 3aa-3ja in 66-
84% yields. Furthermore, other simple and
commercially available isocyanides such as tert-butyl
isocyanide 1k and cyclohexyl isocyanide 1l were also
Scheme 1. Previous work and present reaction design.
Owing to the versatility of reactive metal carbenes,
the merger of a metal catalyzed carbenoid reaction
with an organocatalytic reaction have recently
emerged as an attractive strategy to elaborate diazo
compounds to various valuable products in a
stereochemically controllable and operationally
simple way.[14] In this regard, tandem sequences
involving a metal-catalyzed X-H or C-H insertion and
an organocatalytic addition are extensively studied.[15]
However, the sequences which couple metal
catalyzed cross-coupling reaction of isocyanide with
carbene to produce synthetic useful ketenimine for
subsequent organocatalytic reaction are considerably
rare.[16a] As a continuation of our research interest on
isocyanide chemistry,[16] we have recently reported
the construction of polycyclic spiroindolines III
through a tandem cross-coupling/spirocyclization-
/Mannich-type reaction of 3-(2-isocyanoethyl)indole
2
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions
efficiently converted into the desired ketenimines 3ka-3la
in 78% and 74% yield, respectively. However, when aryl
isocyanides, such as isocyanobenzene 1l was employed as
the coupling partner, the reaction became very complex
and no desired product 3ma was obtained, which
constituted the limitations of this methodology. Then, the
substrate scope of α-diazo esters 2 were examined in
combination with isocyanide 1a as the coupling partner. It
was found that the transformation exhibits good tolerance
of steric hindrance as α-diazoacetates 2b-2d bearing a
CO2Et, CO2 Pr and CO2 Bu group, respectively, giving
comparable results (65-67% yield). We also tested α-diazo
ketone 2e, but it did not work under identical conditions. In
addition, as expected, other α-aryl-α-diazoacetates 2 with
ortho-, meta- or para-substituents also participated
efficiently in this cross-coupling reaction, yielding the
desired products 3af-3ao in moderate to good yields (61-
84%). Similarly, 1,1’-biphenyl substituted diazoacetate 2p
was also amenable and afforded the corresponding product
3ap in 76% yield. Finally, it should be mentioned that
attempts to use other diazoacetates such as ethyl 2-
diazoacetate and diethyl 2-diazomalonate gave no
conversion at all, indicating the α-aryl group was essential
for this reaction.
[Pd]
[mol%]
T
Yield
[%]b
Entrya
Solvent
[oC]
1
2
Pd(PPh3)4 (5)
Pd(dba)2 (5)
THF
THF
80
80
80
80
80
80
80
80
80
80
80
80
100
50
25
80
80
78
21
30
3
4
5
6
7
8
9
10
11
12
13
14c
15c
16
17
Pd(acac)2 (5)
Pd(CF3CO2)2 (5)
Pd(OAc)2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (2.5)
Pd(PPh3)4 (1.0)
THF
THF
THF
THF
CH3CN
dioxane
CH2Cl2
toluene
EtOAc
DMF
THF
i
t
35
trace
trace
75
56
58
42
54
57
62
43
38
77
65
THF
THF
THF
THF
[a]Reaction conditions: 1a (0.3 mmol), 2a (0.60 mmol) and
Pd catalyst (1-5 mol%) in solvent (2.0 mL) were stirred at
indicated temperature for 3 h. [b]Isolated yield. [c]The
reaction time is 6 h.
After achieving an expeditious and efficient
protocol for the construction of ketenimines 3, we
next became interested in exploring whether they
could be trapped by 2-mercaptoimidazole 4a in the
absence or presence of catalysts, thus providing a
novel route toward 1,3-bis(β-aminoacrylate)-
substituted 2-mercaptoimidazole derivatives 5. The
intrinsic problem of this transformation was the
challenging regioselectivity because previous studies
Table 2. Pd-catalyzed cross-coupling reaction of
isocyanides 1 and α-diazoacetates 2.a-b
revealed
that
nucleophilic
attack
of
2-
mercaptoimidazole often took place preferentially at
the sulfur atom rather than nitrogen atom.[17]
Accordingly, the reaction of ketenimine 3aa and 2-
mercaptoimidazole 4a was examined to optimize the
conditions. As shown in Table 3, no reaction
occurred after heating the reaction mixture in THF at
o
80 C for 3 h (Table 3, entry 1). Under the otherwise
identical conditions but in the presence of Brønsted
base catalyst 1,4-diazabicyclo[2.2.2]octane (DABCO,
30 mol%), the reaction proceeded to give desired
product 5a in 18% yield (entry 2). Further parameter
screening revealed that catalyst, solvent, temperature
and catalyst amount have a significant effect on this
transformation (entries 3-15). The best reaction
conditions were found to be 30 mol% catalyst
o
DABCO, with CH3CN as the solvent at 80 C for 1.5
h (entry 6). The structure of product 5a was
determined by using NMR spectroscopy, HRMS and
X-ray crystallographic analysis (For details, see the
Supporting Information).[18] The X-ray structure of
compound 5a shows that the β-aminoacrylate group
bears a Z-configuration to form a H-bond between
their amino and ester groups, and the two β-
aminoacrylate groups are oriented in the anti
conformation presumably to avoid the large steric
repulsion.
[a]Reaction conditions: 1 (0.15 mmol), 2 (0.30 mmol) and
Pd(PPh3)4 catalyst (2.5 mol%) in THF (1.0 mL) were
stirred at 80 oC for 3-4 h. [b]Isolated yield.
3
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
Table 3. Optimization of reaction conditions
(MeO) groups on the phenyl ring resulted in excellent
yields (90-97%). Further studies revealed that 2-
mercaptothiazoles 4f and 4g worked as well, giving
products 5t and 5u with 92% and 93% yield,
respectively. Besides various 2-mercaptothiazoles,
the reactions between 1H-benzo[d]imidazol-2-ol 4h
and a series of ketenimines also proceeded smoothly
to provide the target products 5v-5z in 44-71% yields.
It should be noted that the aza-Mannich reactions
exclusively take place at the nitrogen atom in all
cases. These results clearly demonstrated the
excellent regioselectivity, good functional group
tolerance and the generality of this approach.
Catalyst
[mol%]
T
Yield
[%]b
Entrya
Solvent
[oC]
1
2
3
4
5
6
7
8
9
10
11
12c
13d
14d
15
-
THF
THF
80
80
80
80
80
80
80
80
80
80
80
80
80
50
25
0
18
20
15
31
92
82
trace
11
trace
16
DABCO (30)
DABCO (30)
DABCO (30)
DABCO (30)
DABCO (30)
Et3N (30)
dioxane
EtOAc
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Table 4. DABCO-catalyzed aza-Mannich reaction of
ketenimine 3 with 2-mercaptoimidazoles 4.
TBD (30)
DBU (30)
K2CO3 (30)
tBuOK (30)
DABCO (20)
DABCO (10)
DABCO (30)
DABCO (30)
85
71
83
NR
X-ray structure of compound 5a
[a]Reaction conditions: 3 (0.11 mmol), 4 (0.05 mmol) and
catalyst (30 mol%) in solvent (0.7 mL) were stirred at
indicated temperature for 1.5 h. [b]Isolated yield. [c]The
reaction time is 4 h. [d] The reaction time is 7 h.
With the optimal conditions in hand, we then
explored the scope of this DABCO-catalyzed aza-
Mannich reaction with respect to ketenimines 3 and
2-mercaptoimidazoles 4. As shown in Table 4, this
protocol was able to tolerate a variety of different
substituted ketenimines. The positions and electronic
characteristics of the substituents did not affect the
reactivity significantly, as evidenced by the good to
excellent yields for the products 5a-5g and 5i-5o.
However, presumably owing to steric effect, the aza-
Mannich reaction of ketenimine 3ka with 2-
mercaptoimidazole failed to deliver any 1,3-bis(β-
[a] Reaction conditions: 3 (0.11 mmol), 4 (0.05 mmol) and
DABCO (30 mol%) in CH3CN (0.7 mL) were stirred at 80
oC for 1.5-2.0 h. [b] Isolated yield.
To improve the synthetic efficiency and simplify
the operation, we next turned our attention to merge
the Pd-catalyzed cross-coupling reaction and
DABCO-catalyzed aza-Mannich reaction into a one-
pot sequential protocol. Since CH3CN was the
optimum medium for both cross-coupling and aza-
Mannich reactions, a convenient one-pot tandem
aminoacrylate)substituted
2-mercaptoimidazole
derivative 5h. In addition, the transformation of 2-
mercaptobenzimidazoles 4b-4e with either electron-
withdrawing groups (F, Cl, NO2) or electron-donating
4
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
sequence was developed (Table 5). After the initial
Pd(PPh3)4 catalyzed reaction of isocyanides 1 and α-
diazo esters
2
finished, DABCO and 2-
mercaptoimidazoles or 1H-benzo[d]imidazol-2-ol
were added successively, and then the reaction
mixture was stirred at 80 C till completion. By this
o
simple one-pot procedure, a series of 1,3-bis(β-
aminoacrylate)-substituted 2-mercaptoimidazole and
2-benzimidazolinone derivatives 5 could be obtained
in moderate yields over two steps (34-68%, Table 5).
indicating that the remaining Pd(PPh3)4 and α-diazo
esters 2 had no severe detrimental effect on the
subsequent DABCO catalyzed aza-Mannich reaction.
These results demonstrated the power of sequential
Pd/Brønsted base catalysis in rapidly elaborating α-
diazo esters to value added compounds.
Scheme 2. Scale-up synthesis of product 5a.
On the basis of our experimental results and
relevant literature reports,[2, 12, 16a] a possible reaction
mechanism for this one-pot formation of 1,3-bis(β-
aminoacrylate)-substituted
derivatives 5 (5a as example) was proposed in
Scheme 3. First, 4-(2-isocyanoethyl)-1,2-
2-mercaptoimidazole
Table 5. One-pot synthesis of 1,3-bis(β-aminoacrylate)-
substituted 2-mercaptoimidazole derivatives 5 through
sequential Pd catalysis and Brønsted base catalysis.
dimethoxybenzene 1a coordinates with Pd(PPh3)4 to
form intermediate I, which then reacts with phenyl
diazoacetate 2a to give the Pd-carbene intermediate
II along with the release of N2. Subsequently,
intermediate II undergoes migratory insertion and
reductive elimination to give ketenimine intermediate
3aa and regenerate the palladium catalyst. After that,
ketenimine 3aa could be selectively trapped by one
of the NH groups in 2-mercaptoimidazole 4a through
the deprotonation activation under Brønsted base
catalysis, affording the mono-(β-aminoacrylate)
substituted 2-mercaptoimidazole intermediate III. It
could further react with ketenimine 3aa to finally
form the desired product 5a.
It is noteworthy that in most cases, the mono-(β-
aminoacrylate) substituted 2-mercaptoimidazole
intermediate III could not be detected under the
catalysis of DABCO and is very susceptible to further
undergo aza-Mannich reaction with
a second
molecule of ketenimine. However, after carefully
screening the reaction conditions, we found that
intermediate III could be isolated in 42% yield when
treating ketenimine 3aa with equal molar amount of
2-mercaptoimidazole 4a (1.0 equiv) in the presence
of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 30
mol%). The intermediate III reacted smoothly with
an external ketenimine 3aa (1.2 equiv) to afford the
desired product 5a in 83% yield under standard
conditions. This result to some extend supports part
of the proposed reaction mechanism depicted in
Scheme 3.
[a] Reaction conditions: 1 (0.15 mmol), 2 (0.3 mmol) and
Pd(PPh3)4 catalyst (2.5 mol%) in CH3CN (1.0 mL) were
o
stirred at 80 C for 3-4 h. After the full consumption of 1
by TLC analysis, 4 (0.075 mmol) and DABCO (0.0225
mmol) were added. [b] Isolated yield.
Conclusion
In conclusion, we have developed a Pd-catalyzed
cross-coupling reaction of aliphatic isocyanides with
α-diazoacetates to form active ketenimines and
following a DABCO catalyzed aza-Mannich type
reaction with various 2-mercaptoimidazoles or 1H-
benzo[d]imidazol-2-ol under mild reaction conditions
to regioselectively provide 1,3-bis(β-aminoacrylate)-
Furthermore, we performed a gram-scale one-pot
sequential reaction of 4-(2-isocyanoethyl)-1,2-
dimethoxybenzene 1a (0.84 g), phenyl diazoacetate
2a (1.549 g) and 2-mercaptoimidazole 4a (0.330 g)
under the standard conditions, and product 5a was
isolated in 65% (1.186 g) total yield (Scheme 2),
which showed the potential for this synthetic protocol
as a useful tool in practical synthetic context.
substituted
2-mercaptoimidazole
and
2-
benzimidazolinone derivatives in moderate yields. In
5
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
the aza-Mannich reaction, the nucleophilic attack of
2-mercaptoimidazole or 1H-benzo[d]imidazol-2-ol to
the central carbon of ketenimines took place
exclusively at the nitrogen center. This tandem
sequence is efficient since two C=C and two C-N
bonds are created in one-pot. Considering that both 2-
mercaptoimidazole scaffold and β-aminoacrylate
group are important elements in drug discovery, the
products described in this manuscript might be
interesting and helpful for medicinal studies. Further
exploitation of new tandem sequences which couple
metal catalyzed ketenimine formation with other
organocatalytic reactions are ongoing in our lab.
Scheme 3. Control experiment and proposed reaction mechanism.
To a 10.0 mL Schlenk tube were successively added 2-
mercaptoimidazole 4a (0.05 mmol), DABCO (0.015
mmol), anhydrous CH3CN (0.8 mL) and ketenimine 3a
(0.11 mmol). The reaction mixture was stirred vigorously
Experimental Section
o
See the SI for full experimental data.
at 80 C under N2 atmosphere till full consumption of 2-
mercaptoimidazole 4a by TLC analysis. Then the reaction
mixture was directly subjected to column chromatography
using petroleum ether/ethyl acetate (from 5:1-2:1) as the
eluent to afford product 5a (white solid) in 92% yield (mp
189 oC). 1H NMR (500 MHz, CDCl3): δ 2.11-2.18 (m, 2H),
2.58-2.67 (m, 4H), 3.07-3.12 (m, 2H), 3.632 (s, 6H), 3.634
(s, 6H), 3.88 (s, 6H), 6.35-6.39 (m, 4H), 6.58 (dd, J = 8.5,
2.0 Hz, 2H), 6.75 (d, J = 8.0 Hz, 2H), 6.83-6.90 (m, 8H),
7.08 (brs, 4H), 8.99 (dd, J = 7.5, 3.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): δ 170.20, 167.81, 148.86, 148.28,
147.65, 134.39, 131.21, 130.86, 130.27, 127.04, 126.38,
123.39, 120.88, 111.75, 111.16, 109.58, 97.87, 55.93,
55.65, 51.41, 44.66, 35.42. HRMS (ESI): Exact mass calcd
for C47H48N4NaO8S [M+Na]+: 851.3085, Found: 851.3098.
General procedure for the synthesis of products 3
[Methyl 3-((3,4-dimethoxyphenethyl)imino)-2-phenyl-
acrylate (3aa) as example].
To a 10.0 mL Schlenk tube were successively added
[Pd(PPh3)4] (2.5 mol%), isonitrile 1a (0.15 mmol),
anhydrous THF (1.0 mL) and phenyl diazoacetate 2a (0.3
mmol). The reaction mixture was stirred vigorously at 80
oC under N2 atmosphere till full consumption of isonitrile
1a by TLC analysis. Then the reaction mixture was
directly subjected to column chromatography using
petroleum ether/ethyl acetate (from 20:1-3:1) as the eluent
1
to afford product 3aa (pale-yellow oil) in 77% yield. H
NMR (500 MHz, CDCl3): δ 3.03 (t, J = 7.0 Hz, 2H), 3.74
(s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 4.01 (t, J = 7.0 Hz, 2H),
6.73 (s, 1H), 6.74-6.77 (m, 2H), 7.12-7.15 (m, 1H), 7.24-
7.28 (m, 2H), 7.32-7.34 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 172.24, 168.87, 149.00, 147.97, 130.79, 129.89,
128.32, 126.86, 125.64, 120.82, 111.92, 111.32, 67.03,
55.84, 55.78, 52.08, 51.40, 36.09. HRMS (ESI): Exact
mass calcd for C20H21NNaO4 [M+Na]+: 362.1363, Found:
362.1352.
General procedure for the one-pot synthesis of
products 5 [(Z)-methyl 3-((3,4-dimethoxyphenethyl)-
amino)-3-(3-(Z)-1-((3,4-dimethoxyphenethyl)amino)-2-
phenylprop-1-en-1-yl)-2-thioxo-2,3-dihydro-1H-benzo-
[d]imidazol-1-yl)-2-phenylacrylate (5a) as example].
To a 10.0 mL Schlenk tube were successively added
[Pd(PPh3)4] (2.5 mol%), isonitrile 1a (0.15 mmol),
anhydrous CH3CN (1.0 mL) and phenyl diazoacetate 2a
(0.3 mmol). The reaction mixture was stirred vigorously at
General procedure for the synthesis of products 5 [(Z)-
methyl 3-((3,4-dimethoxyphenethyl)amino)-3-(3-(Z)-1-
((3,4-dimethoxyphenethyl)amino)-2-phenylprop-1-en-1-
yl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-
phenylacrylate (5a) as example].
o
80 C under N2 atmosphere. After the full consumption of
isonitrile 1a by TLC analysis, 2-mercaptoimidazole 4a
(0.075 mmol) and DABCO (0.0225 mmol) were added
successively, and then the reaction mixture was stirred at
6
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10.1002/adsc.202000789
Advanced Synthesis & Catalysis
o
80 C till completion. The reaction mixture was directly
Grabowski, R. D. Tillyer, F. Spindler, C. Malan, J. Am.
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subjected to column chromatography using petroleum
ether/ethyl acetate (from 5:1-2:1) as the eluent to afford the
product 5a in 65% total yield. The NMR data was the same
as described above.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21801050), the Scientific Research Project of
Guangzhou Municipal Colleges and Universities (No.
201831816), the Start-up Grant from Guangzhou University (No.
2700050378) and the Natural Science Foundation of Shandong
Province (No. ZR2018BB026) for the financial support.
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8
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FULL PAPER
One-Pot Tandem Protocol for the Synthesis of 1,3-
Bis(β-aminoacrylate)- Substituted 2-
Mercaptoimidazole Scaffolds
Adv. Synth. Catal. Year, Volume, Page – Page
Jian Luo,a Guo-Shu Chen,a* Shu-Jie Chen,a Zhao-
Dong Li,b Yu-Lei Zhao,c and Yun-Lin Liua*
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