A Domino Route toward Polysubstituted Pyrroles from 2-Imidazolines and Electron-Deficient Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c01530

The reaction of 1,2-disubstituted 2-imidazolines with electron-deficient alkynes proceeds as a pseudo-three-component process and forms imidazolidines with an N-vinylpropargylamine fragment. Heating the resulting imidazolidines in xylene on air leads to a

Full text of DOI:10.1021/acs.orglett.0c01530

pubs.acs.org/OrgLett
Letter
A Domino Route toward Polysubstituted Pyrroles from
2‑Imidazolines and Electron-Deficient Alkynes
Nikita E. Golantsov,* Alexandra S. Golubenkova, Alexey A. Festa, Alexey V. Varlamov,
and Leonid G. Voskressensky*
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ABSTRACT: The reaction of 1,2-disubstituted 2-imidazolines with electron-deficient alkynes proceeds as a pseudo-three-
component process and forms imidazolidines with an N-vinylpropargylamine fragment. Heating the resulting imidazolidines in
xylene on air leads to an effective formation of polysubstituted pyrroles through a domino sequence of aza-Claisen rearrangement/
transannular nucleophilic addition/oxidative ring opening reactions. The direct one-pot transformation of 2-imidazolines to pyrroles
has been also realized.
yrroles comprise a highly important class of heterocycles
due to their use in medicinal chemistry,1 abundance in the
of an anionic intermediate followed by tautomerization
(Scheme 1, b). As reported by Jin and co-workers, changing
the basic catalyst could efficiently switch the cyclization type of
similar precursors, generated in situ from secondary N-
propargylamines and acetylenecarboxylic esters.12 Saito dem-
onstrated that N-propargyl enaminone and enaminoesters,
bearing a tosyl protecting group at the nitrogen atom, could be
easily transformed into pyrroles via Au-catalyzed aza-Claisen
rearrangement (Scheme 1, c).13 A similar synthetic inter-
mediate derived from acetylenedicarboxylic ester was shown to
undergo divergent cyclization to two types of pyrroles with
regioselective migration of the sulfonyl group.14 Related
syntheses of pyrroles from allene derivatives were also
reported.15
P
structure of numerous natural compounds,2 and application in
materials science.3 A wide range of pyrrole syntheses have been
elaborated4,5 in addition to classical Paal−Knorr and Hantzsch
methods,6 but new strategies for accessing polysubstituted
derivatives, especially based on atom- and step-economical
domino reactions, are highly desired.
In the past several decades, propargylamines have attracted
considerable attention as versatile precursors of various types
of nitrogen heterocycles, including pyrroles.7 In particular,
various compounds possessing an N-vinylpropargylamine
fragment could be cyclized into pyrrole derivatives in different
ways.8−14 One such way was based on aza-Claisen rearrange-
ment to form an allene intermediate followed by a nucleophilic
attack of the nitrogen atom on the central carbon atom of the
allene fragment. That method for the synthesis of annulated-
[b]pyrroles under thermal activation was first described by
Cossy.8 Later, a similar combinatorial microwave-assisted
approach was reported by Bremner and Organ (Scheme 1,
a).9 Rhodium(I)-catalyzed aza-Claisen rearrangement of N-
propargylanilines was used by Saito for the synthesis of 2,3-
disubstituted indoles.10 Another way to convert the N-
vinylpropargylamine into pyrrole was realized by Cacchi in
basic media. That transformation included 5-exo-dig cyclization
Herein, we introduce a new class of synthetic intermediates
possessing the N-vinylpropargylamine fragment through an
effective pseudo-three-component process and describe its
Received: May 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01530
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Syntheses of Pyrroles from Propargylamines and
Related Compounds via Aza-Claisen Rearrangement and 5-
exo-dig Cyclization
Scheme 2. Preparation of Imidazolidines 3
thermal aerobic domino transformations into polysubstituted
pyrroles (Scheme 1). Remarkably, both discovered trans-
formations are free of transition metals and additives.
a
For the general reaction, imidazoline 1 (1.7 mmol) and alkyne 2 (3.6
b
mmol) were stirred in 8 mL of dry MeCN at rt for 4 h. The reaction
We have found that imidazolidines 3 could be easily
obtained by the reaction of 1,2-disubstituted 2-imidazolines 1
with 2 equiv of terminal alkynes 2, bearing an electron-
withdrawing group (ester or acetyl) (Scheme 2). The reaction
proceeded smoothly at room temperature in aprotic solvents
such as toluene, DCE, dioxane, and MeCN. A set of adducts 3
with aryl and alkyl groups at positions 2 and 3 was synthesized.
To our delight, this reaction had a wide substrate tolerance
with respect to substituents at positions 1 and 2 of the starting
imidazoline, including donor- and acceptor-substituted phenyl
groups and heteroaryl and alkyl radicals.
A fragment of propargyl(vinyl)amine could be noticed in the
structure of compounds 3. This fact gave us the idea to
perform a propargyl type of aza-Claisen rearrangement on
these molecules. To assay this synthetic opportunity, we
explored transformations of imidazolidine 3 upon heating in
different solvents (Table 1).
time was 24 h.
imidazolidine 3a was not full, and pyrrole 4a was isolated in
34% yield (Table 1, entry 1). A gradual increase in the reaction
time showed completion was achieved after reflux for 2 h,
delivering target pyrrole 4a in 73% yield (Table 1, entries 2
and 3). The use of chlorobenzene as a solvent with a higher
boiling point reduced the reaction time to 30 min (Table 1,
entry 4). In its turn, carrying out the reaction in DMSO at 130
°C gave target pyrrole 4a in 44% yield but was accompanied by
the formation of pyrrolopyrazine 5 (Table 1, entry 5). The best
yield of 78% for pyrrole 4a could be achieved in 30 min with
the use of xylene as a solvent (Table 1, entry 6). Performing
the reaction under an oxygen atmosphere instead of air did not
give any benefits (Table 1, entry 7). Further variation of time
failed to increase the yield of 4a (Table 1, entries 8 and 9).
In a search for better conditions, we continued the use of the
microwave-assisted approach to perform the [3,3]-sigmatropic
rearrangement. The solution of imidazolidine 3a in DCE was
first irradiated in a closed vessel in a microwave reactor under
argon and then exposed to air for the oxidation to occur. Those
We were pleased to find that refluxing adduct 3a in toluene
under air proceeded as a domino transformation, induced by
[3,3]-sigmatropic rearrangement and followed with an
oxidative ring opening, furnishing a pyrrole 4a. After the
mixture had been refluxed for 30 min, the conversion of
B
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With the optimized conditions in hand, we synthesized a
series of pyrroles 4b−g from N(3)-aryl-substituted adducts 3
(Scheme 3). The domino reaction tolerated both electron-
Table 1. Optimization Studies
a
Scheme 3. Synthesis of Pyrroles 4
b
yield (%)
entry
solvent
temp (°C) time (h)
oxidant
air
air
air
air
air
air
O2
air
air
air
air
O2
MCPBA
t-BuOOH
air
air
air
air
4a
5
a
1
PhMe
PhMe
PhMe
PhCl
DMSO
o-xylene
o-xylene
o-xylene
o-xylene
DCE
DCE
DCE
DCE
DCE
DCE
H2O
MeCN
CHCl3
111
111
111
132
130
144
144
144
144
110
130
130
130
130
150
130
130
130
0.5
1.0
2.0
0.5
0.5
0.5
0.5
0.25
1.0
0.5
0.5
0.5
0.5
0.5
0.25
0.5
0.5
0.5
34
66
73
70
44
78
73
64
72
45
74
57
52
72
26
29
60
−
−
−
−
15
−
−
−
−
−
−
−
−
18
48
51
14
66
a
2
a
3
a
4
a
5
a
6
c
7
a
8
a
9
d,
d,
d,
d,
d,
d,
d,
d,
d
e
e
f
10
11
12
13
14
15
16
17
18
g
h
e
e
e
−
b
a
Imidazolidine (3a) in 2 mL of solvent was heated in air. Isolated
c
d
yield. The reaction was run under an O2 atmosphere (1 atm). The
solution was irradiated in a closed vessel in a microwave reactor
a
e
For the general reaction, imidazolidine 3 (0.5 mmol) was refluxed in
(Monowave 300, Anton Paar GmbH). The solution was exposed to
air for 12 h after irradiation. The solution was purged with oxygen for
10 min after irradiation. MCPBA (1.1 equiv) was added after
f
10 mL of o-xylene for 0.5 h under vigorous stirring in air. For the one-
pot procedure, imidazoline 1 (0.5 mmol) and alkyne 2 (1.1 mmol)
were stirred in 10 mL of o-xylene until imidazoline was fully
consumed (TLC monitoring) and then refluxed for 0.5 h. The yields
for the latter procedure are indicated in parentheses. The reaction
was performed on a 2.25 mmol scale of imidazoline 1a.
g
irradiation, and the mixture was stirred for an additional 1 h under Ar.
t-BuOOH (70% aqueous solution, 1.1 equiv) was added after
irradiation, and the mixture was stirred for an additional 1 h under Ar.
h
b
experiments, performed at 110 or 130 °C, showed results
comparable to those of conventional heating in toluene or
chlorobenzene, respectively (Table 1, entry 10 or 11,
respectively). Full consumption of 3a was achieved in 30
min at 130 °C (TLC and LCMS), while exposure of the
reaction mixture to air led to the gradual formation of pyrrole
4a. The oxidation step could be accelerated significantly by
purging the reaction mixture with oxygen (Table 1, entry 12).
The use of MCPBA or t-BuOOH during the oxidation step led
to the same pyrrole 4a, but with lower yields (Table 1, entry 13
or 14, respectively).
An attempt to reduce the time of the microwave-assisted
step through the increase in the temperature to 150 °C led to
the favorable but undesired formation of a pyrrolopyrazine 5
(Table 1, entry 15). Bicyclic product 5 was also formed in a
majority with the transition to a polar protic solvent, water
(Table 1, entry 16). The reaction in acetonitrile produced
pyrrole 4a in 60% yield, while compound 5 was also present
(Table 1, entry 17). Unexpectedly, exclusive formation of
pyrrolopyrazine 5 in 66% yield could be observed in
chloroform (Table 1, entry 18). Presumably, degradation of
chloroform generated trace amounts of HCl, which could
promote the undesired pathway. In summary, the most
effective and experimentally straightforward method for
pyrrole 4a synthesis was refluxing adduct 3a in xylene on air.
donating and electron-withdrawing groups in an aryl moiety,
giving pyrroles in moderate to good yields. The structure of
compound 4a was unambiguously determined by single-crystal
X-ray diffraction study (CCDC 2000635).
It is worth noting that the imidazoline 1 to pyrrole 4
transformation could be realized in a one-pot fashion without
the isolation of adduct 3. In this case, the solution of starting
imidazoline 1 in xylene was treated with 2.1 equiv of the
alkyne. After 4 h at rt, the reaction mixture was refluxed for 30
min to give the final pyrroles, comparable to a two-step
procedure (for details, see the Supporting Information).
Remarkably, methyl-substituted adduct 3l failed to give
pyrrole 4h through the aforementioned procedure. The highly
nucleophilic secondary amine moiety was forming, capable of
intermolecular reactions with the ester groups, producing
oligomeric material. This reactivity gave us an idea to initially
introduce electrophiles into the reaction mixture to trap the
alkyl-substituted amines, thus granting an opportunity to
substantially expand the scope of pyrroles. Indeed, the
approach worked smoothly with the addition of electrophiles
such as acetic anhydride, Boc2O, isocyanates, or isothiocya-
nates. A wide scope of pyrroles 6 was synthesized (Scheme 4).
The 1-(β-aminoethyl) chain in those pyrroles could be
variously decorated with amide, carbamate, urea, or thiourea
moieties. Imidazolidines 3h−j, containing a phenyl substituent
C
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a
respectively. Moreover, thienyl-substituted imidazolidine read-
ily gave the corresponding pyrrole 6l in 63% yield. The
synthesis of 2-acetylpyrrole 6m failed. In general, the yields of
the diester-substituted pyrroles were greater than those of the
diacetyl ones.
Scheme 4. Synthesis of Pyrroles 6
As in case of pyrroles 4, synthesis of pyrroles 6 could be
performed in a one-pot fashion, starting from imidazolines 1.
The yields in such pseudo-five-component reactions were
comparable with the yields of two-step procedures but
benefited from the obvious economy of time and resources
(Scheme 4, yields in parentheses).
Next, it is necessary to discuss the mechanisms of the
discovered transformations (Scheme 5). The Michael addition
Scheme 5. Proposed Mechanism of Imidazolidine
Formation and Their Transformation to Pyrroles 4 and 6
of imidazoline 1 to the first molecule of electron-deficient
alkyne 2 leads to a zwitterion A, which deprotonates the
second molecule of alkyne. The resulting acetylenide ion
attacks C(2) of the imidazolinium ion, leading to an adduct 3.
The domino transformation of adduct 3 into pyrrole 4 starts
with the thermal [3,3]-sigmatropic propargyl aza-Claisen
rearrangement,16 which leads to the labile nine-membered
allene B. This intermediate immediately undergoes a trans-
annular nucleophilic addition of the nitrogen atom onto the
central atom of the allene system with the formation of bicyclic
zwitterion C. Then, a non-aromatic pyrrolopyrazine 7 is
formed due to a proton transfer. The autoxidation17 of this
intermediate, containing a strongly electron-rich double bond
in the six-membered ring, probably proceeds through the initial
formation of a radical 8, which then turns into a hydroperoxide
D. The interaction of pyrrolopyrazine 7 with hydroperoxide D
gives two molecules of cyclic aminal E, which undergoes a ring
opening reaction, delivering either pyrrole 4 or, in the presence
of an acylating reagent, pyrrole 6.
a
For the general reaction, an acylating agent (0.55 mmol) was added
to a solution of imidazolidine 3 (0.5 mmol) in 10 mL of o-xylene and
the mixture was refluxed for 0.5 h under vigorous stirring in a reaction
flask protected with a CaCl2 tube in the air. For the one-pot
procedure, imidazoline 1 (0.5 mmol) and alkyne 2 (1.1 mmol) were
stirred in 10 mL of o-xylene for 4 h, an acylating agent (0.55 mmol)
was added, and the mixture was refluxed for 0.5 h. The yields for the
b
latter procedure are indicated in parentheses. The reaction was
performed on a 2.25 mmol scale of imidazoline 1g.
We succeeded in detecting a labile non-aromatic inter-
mediate 7 by NMR and mass spectrometry, while performing
the rearrangement of adduct 3a in a C6D6 solution under argon
at C(2) with both electron-donating or electron-withdrawing
groups, could be effectively transformed into pyrroles 6i−k,
D
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(for details, see the Supporting Information). Keeping the
solution of compound 7 on air led to pyrrole 4, proving the
viability of the intermediate for the reaction pathway. In its
turn, treatment of the solution of 7 with t-BuOK caused
tautomerization into the corresponding aromatic pyrrolopyr-
azine 5. A similar result was obtained by adding TFA to the
solution, followed by neutralization with NaHCO3. Refluxing
the imidazolidine 3a in o-xylene under argon also led to
compound 5 in moderate yield along with tar formation. These
observations are consistent with the results, obtained earlier
under microwave irradiation in various solvents, and explain
the formation of pyrrolopyrazine 5 in more polar solvents upon
the promotion of tautomerization. It should be noted that
pyrrolopyrazine 5 does not transform into pyrrole 4 under
heating on air.
Thus, we have developed a convenient and preparative
method for the conversion of synthetically readily available 2-
imidazolines to polysubstituted pyrroles. The approach
comprises a novel pseudo-three-component reaction of
imidazoline with electron-deficient alkynes (2 equiv) to
produce imidazolidines and a domino aza-Claisen/trans-
annular nucleophilic addition/oxidative ring cleavage/acylation
sequence of the latter.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01530
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been funded by the Russian Science Foundation
(Project No 18-73-00017).
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01530.
■
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Experimental procedures, analytical data, and copies of
1H and 13C spectra (PDF)
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free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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Authors
Alexandra S. Golubenkova − Organic Chemistry Department,
Science Faculty, Peoples’ Friendship University of Russia
(RUDN University), Moscow 117198, Russia
Alexey A. Festa − Organic Chemistry Department, Science
Faculty, Peoples’ Friendship University of Russia (RUDN
University), Moscow 117198, Russia; orcid.org/0000-
0002-5113-1938
Alexey V. Varlamov − Organic Chemistry Department, Science
Faculty, Peoples’ Friendship University of Russia (RUDN
University), Moscow 117198, Russia
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