Facile synthesis of new functionalized 3,4-dihydro-2H-pyrroles using 2-isocyanoacetates

Article abstract of DOI:10.1016/j.tetlet.2020.151944

A one-step synthesis of novel functionalized 3,4-dihydro-2H-pyrroles from 2-isocyanoacetates and readily synthesized acrylonitriles is reported. The reaction proceeds smoothly under mild conditions with high efficiency. The structures of two representativ

Full text of DOI:10.1016/j.tetlet.2020.151944

Tetrahedron Letters 61 (2020) 151944
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of new functionalized 3,4-dihydro-2H-pyrroles
using 2-isocyanoacetates
Huijie Zhang a,b, Kaikai Lv a,b, Lanping Ma b, Yongliang Zhang b, Ting Yu b, Lin Chen b, Xin Wang b,
Jingkang Shen b, Tao Meng a,b,
⇑
a School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-step synthesis of novel functionalized 3,4-dihydro-2H-pyrroles from 2-isocyanoacetates and read-
ily synthesized acrylonitriles is reported. The reaction proceeds smoothly under mild conditions with
high efficiency. The structures of two representative structures, 3a and 3m, were confirmed by X-ray
crystallographic analysis.
Received 18 March 2020
Revised 11 April 2020
Accepted 13 April 2020
Available online 16 April 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Dihydro-2H-pyrroles
2-Isocyanoacetates
(E)-2-Styrylbenzothiazole
Acrylonitriles
Introduction
Owing to their intrinsic properties as nucleophiles and elec-
trophiles, isocyanides have been extensively applied in organic
synthesis, particularly in the synthesis of nitrogen-containing
molecules. Among them, isocyanides-based formal [4+1] annula-
tion reactions have transpired as an efficient and direct protocol
for the synthesis of various five-membered compounds [1]. We
have also been involved in the construction of novel small libraries
of N-heterocycles using Groebke-Blackburn-Bienaymé multicom-
ponent reaction [2].
We envisioned that (E)-2-styrylbenzothiazole 1a might also
undertake the [4+1] intermolecular cyclization with isocyanides,
however, no reaction occurred under the typical GBB reaction con-
dition using Sc(OTf)3 as a catalyst (route A, Scheme 1) [3]. How-
ever, we accidentally found that by using DBU as the promoter in
this reaction, a new class of 3,4-dihydro-2H-pyrroles 3a was
obtained (route B, Scheme 1), the structure of compound 3a was
confirmed by single crystal X-ray diffraction analysis [4]. And to
the best of our knowledge, this type of structure has not previously
been reported. It is well-known that pyrrole and 2H-pyrrole are the
ubiquitous cores in many natural products and small molecule
chemotherapeutics, which possess diverse pharmacological prop-
erties [5]. Therefore, they are regarded as privileged structures by
Route A
Route B
Scheme 1. Synthetic approach to 3,4-dihydro-2H-pyrrole derivative 3a.
synthetic chemists because of widespread applications in medici-
nal chemistry and materials science. As such, a lot of effort has
been spent developing practical methods for the synthesis of pyr-
role units that incorporate appropriate functionality [5c,6].
⇑
Corresponding author.
E-mail address: tmeng@simm.ac.cn (T. Meng).
https://doi.org/10.1016/j.tetlet.2020.151944
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
H. Zhang et al. / Tetrahedron Letters 61 (2020) 151944
polar or less polar solvents, such as THF, dichloromethane or
Result and discussion
DMF (entries 3, 11, 12 and 13, Table 1). In general, higher yields
of the desired products were obtained at lower temperatures, the
higher reaction temperature led to a significant decrease of reac-
tion yield (60 °C, entry 14, Table 1). To our delight, the reaction
yield was increased up to 84% when the temperature was
decreased to 0 °C (entry 15, Table 1), and in most cases, the reac-
tion was completed within several hours.
However, the reaction of 3-(4-methoxyphenyl)-2-phenylacry-
lonitrile (1l) with methyl isocyanoacetate (2a) under the same
reaction condition only generated a trisubstituted pyrrole 4 in
62% yield. The identity of 4 was determined by spectral analysis
and further confirmed by X-ray crystallographic analysis
(Scheme 2) [4]. Similar findings were reported by Bullington and
Samet as side-products in their synthesis [5d,8]. These results
suggest that the cyclic 1-azadiene moiety is essential for the
formation of 3,4-dihydro-2H-pyrrole ring. Based on the above
preliminary results, a plausible mechanism for this process is
proposed in Scheme 3. The formation of compound 4 presumably
arises from initial Michael addition undergoing a retro-Michael
with the leaving group being phenylacetonitrile (A ? B). The
resulting intermediate then reacted with isocyanoacetate again
to obtain intermediate C, followed by a subsequent prototropic
These findings prompted us to turn our attention to optimizing
the conditions for the efficient formation of this series of 3,4-dihy-
dro-2H-pyrroles. The investigation was initiated with 2-(benzoth-
iazol-2-yl)acrylonitrile (1a) and methyl isocyanoacetate (2a) as
model substrates to optimize the reaction conditions, 2-(benzoth-
iazol-2-yl)acrylonitrile (1a) and it’s analogues were synthesized
according to the method previously described [7]. The nature of
the base was found to have a pronounced impact on the process.
The reaction did not proceed in the absence of base (entry 1,
Table 1). Among the organic bases, DBU (1,8-diazabicyclo[5.4.0]un-
dec-7-ene) was shown to be more effective than DABACO and tri-
ethylamine (entries 2–5, Table 1). Moreover, among the different
inorganic bases tested, potassium carbonate was the best base
for this reaction, and the corresponding yield was enhanced up
to 55% (entry 8, Table 1). Using weaker bases, such as sodium
bicarbonate (entry 6, Table 1), or stronger bases, such as sodium
hydroxide (entry 7, Table 1), no product was formed. Lower yield
was observed when using 10% equimolar ratio of potassium car-
bonate (entry 10, Table 1), which indicated that an equimolar
amount of base was required. Moreover, the decrease of the reac-
tion yield was observed when the solvent was switched to non-
Table 1
Optimization of reaction conditions.a
Entry
Base (mol%)
Solvent
Temp/°C
Yield (%)b
1
2
3
4
5
6
7
8
–
MeOH
MeOH
THF
60
25
25
25
25
25
25
25
25
25
25
25
25
60
0
0
DBU(100)
DBU(100)
DABCO(100)
TEA(100)
42
24
38
0
0
0
55
32
23
25
15
32
6
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
CH2Cl2
DMF
MeOH
MeOH
NaHCO3(100)
NaOH(100)
K2CO3(100)
Na2CO3(100)
K2CO3(10)
K2CO3(100)
K2CO3(100)
K2CO3(100)
K2CO3(100)
K2CO3(100)
9
10
11
12
13
14
15
84
a
Reaction conditions: 1a (3.42 mmol, 1.0 equiv.), 2a (1.1 equiv.), base (mol%), solvent (20 mL), 3 h.
Isolated yield.
b
Scheme 2. Synthesis of 4.[a] [a] Reaction conditions: 1l (1.0 equiv.), 2a (1.1 equiv.), K2CO3 (1.0 equiv.), MeOH (5 mL), 0 °C, 3 h. [b] Isolated yield.

H. Zhang et al. / Tetrahedron Letters 61 (2020) 151944
3
Scheme 3. The possible reaction mechanism of acrylonitriles and isocyanoacetate.
shift gives the final aromatic pyrrole ring D. Whereas the Ar group
is benzothiazole, isocyanoacetate would attack 2-
styrylbenzothiazole first in the presence of a base to generate an
intermediate E, which would undergo a rearrangement to furnish
compound F, a subsequent 1,3-H shift gives the 3,4-dihydro-2H-
pyrrole as product G.
With the optimized conditions in hand, we next examined a
series of reactions between substrates 1a–m and isocyanoacetates
to establish the scope and limitations of this process. Substrates
1a–m contain acrylonitrile moiety, since nitrile group is widely
used in medicinal chemistry and nitrile-containing compounds
comprise a substantial proportion in the therapeutic drugs [9].
The simplicity of a one-pot procedure is perfectly amenable to
automation for combinatorial synthesis. Likewise, all the syntheses
were performed on a parallel synthesizer (Radleys Discovery Tech-
nology, Carousel 12 Place Reaction Station) to give corresponding
products. We first examined the reaction of substrates benzoxa-
zole acrylonitrile (1b), N-methyl-benzimidazole acrylonitrile (1c)
and 2-(pyridin-2-yl)acrylonitrile (1d), which showed less reactive
compared with benzothiazole, gave the corresponding products
(3b–d) in moderate yields (ranging from 45 to 60%; Table 2). Sub-
sequently, reactions of various 2-styrylbenzothiazoles (1a, 1e–k)
2
Table 2
Synthesis of 3b–n under optimized conditions.a
Entry
1
Ar
R1
R2
Product, yield (%)b
Me–
3b, 51
(1b)
(1c)
(1d)
2
3
4
Me–
Me–
Me–
3c, 45
3d, 60
3e, 50
(1e)
(1f)
5
6
Me–
Me–
3f, 56
3g, 85
(1g)
(continued on next page)

4
H. Zhang et al. / Tetrahedron Letters 61 (2020) 151944
Table 2 (continued)
Entry
7
Ar
R1
R2
Product, yield (%)b
Me–
3h, 50
(1h)
8
9
Me–
Me–
3i, 70
3j, 51
(1i)
(1j)
10
11
Me–
Et–
3k, 52
3l, 77
(1k)
(1a)
12
13
Me–
Me–
3m, 78
3n, 64
(1m)
(1n)
a
Reaction conditions: 1a–n (1.0 equiv.), 2a–b (1.1 equiv.), K2CO3 (1.0 equiv.), MeOH, 0 °C, 3 h.
b
Isolated yields.
Scheme 4. Synthesis of 3o–p.[a] [a] Reaction conditions: 1a (1.0 equiv.), 2a (1.1 equiv.), K2CO3 (1.0 equiv.), 30% CH3NH2 or (CH3)2NH alcohol solution, 0 °C, 3 h.
with methyl isocyanoacetate (2a) and ethyl isocyanoacetate (2b)
were investigated (Table 2, entries 4–11). All reactions worked
well to produce the expected products 3e–l in moderate to good
yield (50–85% yields). While measuring the 1H NMR, we observed
that compounds bearing the aliphatic substituents as R1 group
(3m–n) showed different NMR spectral profile. The core structure
of compound 3m turned out to be 3,4-dihydro-2H-pyrrole-4-car-
bonitrile identified by X-ray crystallographic analysis [4], which
is the valence-bond isomer of the aryl substituted series (3a–l).
Possible reason is that aliphatic substituents stabilized the inter-
mediate F which does not undergo further 1,3-H shift process
(Scheme 3).
Moreover, we were pleased to find that under the same reaction
condition, the use of 30% methylamine or dimethylamine alcohol
solution as the solvent for in situ ammonolysis of methyl iso-
cyanoacetate 2a, the amide products 3o and 3p was obtained with
decent yields (Scheme 4).
this method. Meanwhile, biological activities of this rarely
described class of compounds are currently under investigation.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Science & Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Pro-
gram”, China (grant no.: 2014ZX09508001), the National Natural
Science Foundation of China (grant nos.: 81473130, 81473092).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151944.
Conclusion
In summary, we have developed an efficient method for the
sequential synthesis of new functionalized 3,4-dihydro-2H-pyrrole
derivatives, which were characterized by means of 1H NMR, 13C
NMR, HRMS and X-ray. Easily accessible starting materials, metal
catalyst-free conditions, good yields are the main advantages of
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