Expedient synthesis of a new class of organic building blocks: N-allenylpyrrole-2-carbaldehydes

Article abstract of DOI:10.1016/j.tetlet.2020.152666

Hitherto unknown N-allenylpyrrole-2-carbaldehydes were synthesized via the formylation of readily available N-allenylpyrroles under the action of the mild formylating complex DMF/(COCl)₂. The reaction selectively proceeds in the case of pyrrole

Full text of DOI:10.1016/j.tetlet.2020.152666

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Expedient synthesis of a new class of organic building blocks: N-allenylpyr‐
role-2-carbaldehydes
Svetlana V. Martynovskaya, Victoria S. Shcherbakova, Igor A. Ushakov,
Tatyana N. Borodina, Andrey V. Ivanov
PII:
S0040-4039(20)31177-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152666
TETL 152666
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 August 2020
5 November 2020
12 November 2020
Please cite this article as: Martynovskaya, S.V., Shcherbakova, V.S., Ushakov, I.A., Borodina, T.N., Ivanov,
A.V., Expedient synthesis of a new class of organic building blocks: N-allenylpyrrole-2-carbaldehydes,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152666
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Graphical Abstract
Expedient synthesis of a new class of organic
Leave this area blank for abstract info.
building
blocks:
N-allenylpyrrole-2-
carbaldehydes
Svetlana V. Martynovskaya, Victoria S. Shcherbakova, Igor A. Ushakov, Tatyana N. Borodina and Andrey V.
Ivanov*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Expedient synthesis of a new class of organic building blocks: N-allenylpyrrole-2-
carbaldehydes
Svetlana V. Martynovskaya, Victoria S. Shcherbakova, Igor A. Ushakov, Tatyana N. Borodina and Andrey
V. Ivanov*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Hitherto unknown N-allenylpyrrole-2-carbaldehydes were synthesized via the formylation of
readily available N-allenylpyrroles under the action of the mild formylating complex
DMF/(COCl)2. The reaction selectively proceeds in the case of pyrroles with electron-
withdrawing substituents to afford the products in good to excellent yields. For pyrroles bearing
electron-donating substituents, the reaction proceeds in a cascade manner to deliver unusual
complex products, the structure of which was confirmed by X-ray diffraction analysis. The target
N-allenylpyrrole-2-carbaldehydes represent promising synthons for organic synthesis.
Available online
Keywords:
N-Allenylpyrroles
N-Allenylpyrrol-2-carbaldehydes
Formylation
2009 Elsevier Ltd. All rights reserved.
Vilsmeier–Haack reaction
* Corresponding author.
1. Introduction
E-mail address: ivanov@irioch.irk.ru
allenes thus obtained often exhibit impressive activities as enzyme
inhibitors, cytotoxic, or antiviral agents[15,16,17].
Therefore, the combination of highly reactive aldehyde and
allenyl moieties on the biologically important pyrrole core may
open up new horizons in this area of research.
Functionalized pyrroles represent an important class of
versatile building blocks for the directed synthesis of a wide
variety of compounds and materials with tailor-made properties.
For example, they have found increased applications in the design
of pharmaceuticals and congeners of natural compounds[1]. The
pyrrole core is a ubiquitous structural unit of new antibiotics,
pheromones,
toxins,
cell
fission
inhibitors,
and
2. Results and Discussion
immunomodulating agents[2,3]. Pyrrolecarbaldehydes are
intermediates and starting materials in organic synthesis, for
example, to produce valuable compounds such as carbolines,
cyanopyrroles, divinylpyrroles, and various oligopyrrolic
systems[4,5]. They are also employed in biomedical chemistry[6]
as models for the investigation of multiple sclerosis and expansion
of the genetic alphabet[7], ligands for metallocomplexes[8], and
conjugated polymers[9,10].
The most common method for the introduction of a formyl
group into the pyrrole ring is the classical Vilsmeier-Haack
reaction, which was discovered in the first half of the 20th
century[18] and has been employed for the synthesis of a wide
variety of pyrrolecarbaldehydes. However, we have previously
found that when electron-rich groups (namely, the N-vinyl moiety)
are incorporated into the initial pyrrole, the classical Vilsmeier-
Haack reaction loses its selectivity and proceeds with the
formation of various by-products that significantly reduces the
applicability of this approach[19].More intriguingly, the N-allenyl
group (see above) seems to be even less suitable for Vilsmeier-
Haack formylation, since it contains not only the sp2 carbon atom,
but also the sp carbon atom, thus being susceptible to attack of an
electrophile.
Furthermore, the allene fragment is more sensitive to acids than
the vinyl group, and it is common knowledge that the allene group
can undergo various prototropic rearrangements under the
influence of acid [20]. We believe that for this reason N-
allenylpyrroles containing an aldehyde moiety, remain under
explored.
The allene fragment, on the other hand, is a popular structural
motif in organic chemistry. Allenes possess unique features and
exhibit high reactivity that can significantly improve the biological
and
pharmacological
properties
of
allene-containing
compounds[11]. For example, the allenic prostaglandin analogue
enprostil, was reported to be a highly potent inhibitor of gastric
acid secretion[12,13]. In addition, enprostil exerts anti-
inflammatory activity[14].
Allene moieties have been systematically introduced into
pharmacologically active classes of compounds (e.g. steroids,
prostaglandins, amino acids, nucleosides). The functionalized
_______

2
To date, only two similar compounds have been documented as
the minor products of reactions. It was reported[21] that indole-2-
carbaldehydes functionalized with an N-propargyl moiety
underwent acetylene-allene isomerization under the action of
sodium metal. The isomerization of an unsubstituted propargyl
aldehyde into the N-allenylpyrrol-2-carbaldehyde in the presence
of sodium hydride was also described[22]. The use of sodium
metal and sodium hydride makes the method impracticable and
environmentally dangerous.
It was previously shown that propargyl chloride was involved
in the N-alkylation of pyrroles with simultaneous isomerization to
the allene in the presence of a superbase medium[23]. In this case,
a wide range of α,β-substituted pyrroles available via the Trofimov
reaction (synthesis of pyrroles from ketoximes and acetylene)[24]
were employed as the starting compounds. In recent years, the
expediency of the Trofimov pyrrole synthesis has been
significantly improved due to the replacement of explosive and
O
O
N
N
N
b
29
C
C
C
N
c
d
e
85
84
88
C
O
N
N
N
H3C
H3C
C
C
C
O
H3C
H3C
N
O
O
C
flammable
dichloroethane[25,26,27].
acetylene
with
its
safer
precursor,
O
O
H3C
H3C
O
O
O
N
N
N
N
N
f
91
91
84
Earlier[28], we developed a modified version of the Vilsmeier-
Haack reaction, which allows N-vinylpyrroles to be formylated
using the milder formylating complex DMF/(COCl)2, with the
acid-labile vinyl group being preserved. In the present work, we
applied the same approach for the introduction of an aldehyde
group into N-allenylpyrroles. Consequently, the formyl group was
introduced selectively into the 2-position of the pyrrole ring of N-
allenylpyrrole while preserving the allene function. Finally,
C
C
C
C
C
Cl
Cl
g
h
N
Br
Br
substituted
N-allenylpyrrol-2-carbaldehydes
have
been
C
synthesized for the first time in 29-91% yield (Scheme 1, Table 1).
Oxalyl chloride was added dropwise to N,N-
dimethylformamide in dichloromethane, then a solution of N-
allenylpyrrole 1 in dichloromethane was added dropwise. After
stirring at room temperature, the reaction mixture was treated with
an aqueous solution of sodium acetate. Extraction with
dichloromethane gave crude product 2, which was purified by
column chromatography.
It should be noted that under these conditions, which were
previously successfully applied to the formylation of N-
vinylpyrroles, the reaction times were shorter (15 min instead of
30 min). It was shown that a prolonged process led to resinification
of the reaction mixture, and this, in turn, hindered purification of
the crude product and decreased the yields of N-allenylpyrrole-2-
carbaldehydes 2.
O
N
N
i
73
C
C
O
O
N
N
j
58
87
C
C
N
N
S
S
k
C
C
Reagents and conditions: (COCl)2 (11 mmol), DMF (11 mmol), CH2Cl2 (13
R2
R1
R2
R1
i. DMF/(COCl)2/CH2Cl2/-78 o
C
20-25 oC, 50 min
mL), 1 (10 mmol), CH3COONa (50 mmol).
ii. CH3COONa/H2O/20-25 oC, 20 min
O
As can be seen from Table 1, the selectivity of N-allenylpyrrole
formylation dramatically depends on the nature of the substituent
on the pyrrole ring. N-Allenylpyrroles 1 bearing aromatic and
heteroaromatic substituents on the pyrrole ring (2c-2i, 2k)
exclusively afforded the target N-allenylpyrrole-2-carbaldehydes
in good to excellent yields (73–91%). In the case of donor
substituents (2a, 2b), the yields were only moderate (29–48%),
and product 3 was also observed in the reaction mixture, the
structure of which was unambiguously proved by X-ray diffraction
analysis using the formylation of 1b as a representative example
(Scheme 2, Fig. 1).
N
N
C
C
2a-2k
29-91% isolated yield
Scheme 1. Synthesis N-allenylpyrroles-2-carbaldehydes 2a-k.
Table 1. Formylation of N-allenylpyrroles.
Isolated
yield (%)
Entry
N-Allenylpyrroles 1
Product 2
n-Pr
n-Pr
O
O
i. DMF/(COCl)2/CH2Cl2
n-Bu
n-Bu
N
N
20-25 oC, 50 min
-78 o
C
a
48
ii. CH3COONa/H2O/20-25 oC, 20 min
O
C
C
N
+
N
N
N
O
CH3
C
C
CH3
2b:
3b:
29%
27%
1b

3
Scheme 2. The formylation of 1b.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
The reported study was funded by RFBR, project number 19-
33-90051. Experimental work was carried out using the equipment
of the Baikal Analytical Centre for Collective Use of the Siberian
Branch of the Russian Academy of Sciences. The authors would
like to thank Dr.Sc. Rozentsveig I.B. and the employees of the
laboratory of unsaturated heteroatomic compounds of Irkutsk
Institute of Organic Chemistry SB RAS for the helpful suggestions
and fruitful discussion.
Figure 1. X-ray structure of 3b.
The formation of product 3b can be rationalized as a cascade
process catalyzed by acid (product of the partial hydrolysis of
chloroanhydride with traces of water, Scheme 3).
Supplementary Material
Supplementary data to this article can be found online at
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route to
a new class of substituted N-allenylpyrrole-2-
carbaldehydes, which are promising building blocks and reagents.

4
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Graphical Abstract
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29.
Highlights
 Hitherto unknown N-allenylpyrrole-2-
carbaldehydes have been synthesized
 Mild formylating complex DMF/(COCl)2.
 Promising synthons for fine organic
synthesis
Expedient synthesis of a new class of organic
Leave this area blank for abstract info.
building
blocks:
N-allenylpyrrole-2-
carbaldehydes
Svetlana V. Martynovskaya, Victoria S. Shcherbakova, Igor A. Ushakov, Tatyana N. Borodina and Andrey V.
Ivanov*
30.