Base-Catalyzed [3 + 2] Cycloaddition of N-Benzyl Ketimines to Arylacetylenes Followed by Oxidation: A One-Pot Access to Polyarylated 2 H-Pyrroles via Intermediate Pyrrolines

Article abstract of DOI:10.1021/acs.orglett.1c01009

N-Benzyl ketimines undergo [3 + 2] cycloaddition with arylacetylenes in the KOBut/DMSO solution to 2,3,5-triarylpyrrolines, which are oxidized (chloranil, DDQ) in situ to 2,3,5-triaryl-2H-pyrroles in 53-71% yields. The intermediate 1-pyrrolines can be isolated in 31-91% yields and separately oxidized to the corresponding 2H-pyrroles.

Full text of DOI:10.1021/acs.orglett.1c01009

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Letter
Base-Catalyzed [3 + 2] Cycloaddition of N-Benzyl Ketimines to
Arylacetylenes Followed by Oxidation: A One-Pot Access to
Polyarylated 2H‑Pyrroles via Intermediate Pyrrolines
Ivan A. Bidusenko, Elena Yu. Schmidt, Igor A. Ushakov, Alexander V. Vashchenko,
and Boris A. Trofimov*
Cite This: Org. Lett. 2021, 23, 4121−4126
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ABSTRACT: N-Benzyl ketimines undergo [3 + 2] cycloaddition with arylacetylenes
in the KOBut/DMSO solution to 2,3,5-triarylpyrrolines, which are oxidized (chloranil,
DDQ) in situ to 2,3,5-triaryl-2H-pyrroles in 53−71% yields. The intermediate 1-
pyrrolines can be isolated in 31−91% yields and separately oxidized to the
corresponding 2H-pyrroles.
In the light of this knowledge, when conceiving the study of
the reaction between N-benzyl ketimines and arylacetylenes,
which is here reported, we have expected to obtain either the
above azadienes or propargylamines. To our surprise, none of
these compounds were present in the reaction mixture after the
reaction of N-benzyl ketimine 1a with phenylacetylene 2a in
the KOBut/DMSO solution. Instead, 2,3,5-triphenylpyrroline
3aa and small amounts of its oxidized form, 2H-pyrrole 4aa,
were detected, meaning that we serendipitously encountered
an example of another reaction, which can be defined as [3 +
2] cycloaddition of ketimines to acetylenes (Scheme 2).
Importantly, the content of 2H-pyrrole 4aa was noticeably
increased upon aeration of the reaction mixture.
enzyl ketimines are known to be versatile building blocks
Bfor the construction of complex nitrogen-containing
heterocycles1 due to their ability of generating, under the
action of strong bases, azaallyl anions, which represent highly
active multifaceted intermediates, widely applied in organic
synthesis for various carbon−carbon and carbon−heteroatom
bond-forming processes.1
Recently,2 we have shown that N-benzyl ketimines react
with acetylene gas in the strong basic KOBut/DMSO solution
(pKa ≈ 35)3 to stereoselectively afford 1,3-diaryl-2-azapenta-
dienes (Scheme 1A). Earlier,4 we have reported that ketimines
in the same superbasic medium are added to arylacetylenes as
Csp-centered carbanions to deliver propargylamines (Scheme
1B). Arylaldimines under similar conditions are formally CH-
vinylated with arylacetylenes to 1,2,4-triaryl-1-azabutadienes
(Scheme 1C).5
Scheme 2. KOBut/DMSO-Catalyzed [3 + 2] Cycloaddition
of Ketimine 1a to Acetylene 2a
Scheme 1. Previous Works
Previously,6 the [3 + 2] cycloaddition between lithium 1,3-
diphenyl-2-azaallyl anions and 1,4-diphenylbutadiyne to form
2,5-dihydro-1H-pyrrole was reported by Vo-Quang and Vo-
Quang (Scheme 3).
This pyrroline structure differs from pyrroline 3aa probably
because of substantial differences of substrate structures and
reaction conditions.
Received: March 23, 2021
Published: May 21, 2021
https://doi.org/10.1021/acs.orglett.1c01009
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4121−4126
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Letter
Scheme 4, a number of 2H-pyrroles 4 with diverse aryl
substituents were obtained in 53−71% yield. The reaction
Scheme 3. Cycloaddition of 1,3-Diphenyl-2-azaallyl Anions
to 1,4-Diphenylbutadiyne6
a
Scheme 4. Synthesis of 2H-Pyrroles
It is relevant to emphasize that polyarylated 2H-pyrroles are
of special interest because of their unique structural
architecture and applications as precursors in heterocyclic
synthesis.7 Despite the many efforts invested to the develop-
ment of methodology for the preparation of polyarylated 2H-
pyrroles, creation of compound libraries of this class remains a
challenge.7,8 In view of steady interest in 2H-pyrroles,
especially polyarylated ones,8 we have attempted to optimize
the reaction found first in relation to the synthesis of 2H-
pyrroles. The optimization was implemented using the same
substrates pair (1a + 2a). Several selected representative results
of these experiments are collected in Table 1.
Table 1. Optimization of 2H-Pyrrole 4aa Synthesis from
a
Ketimine 1a and Acetylene 2a (Scheme 2)
1a/KOBut molar
yield of 3aa
yield of 4aa
b
b
entry
ratio
oxidant
(%)
(%)
1
2
3
4
5
6
7
8
1:1
1:0.2
1:1
1:1
1:0.2
1:1
no
71
70
36
22
68
47
traces
traces
traces
traces
14
20
traces
6
c
air
air
air
c
d
c
c
oxygen
oxygen
chloranil
e
1:0.2
1:0.2
65
66
e
DDQ
a
Conditions: 1a (1 mmol), 2a (1 mmol), KOtBu, DMSO (3 mL),
b
60°C, 15 min. Isolated yield after column chromatography (SiO2, n-
c
hexane/ethyl acetate, 20:1). Bubbling of air (oxygen) for 1 h.
d
e
Bubbling of air for 2 h. 1 mmol, 1 h.
a
Conditions: 1 (1 mmol), 2 (1 mmol), KOBut (0.2 mmol), DMSO
(3 mL), chloranil (1 mmol). Isolated yields after column
chromatography (SiO2, n-hexane/ethyl acetate, 10:1) are given.
The reaction was carried out as follows: the reactants (1a +
2a) were stirred in KOBut/DMSO solution at 60°C for 15
min. The reaction mixture turned reddish-purple right after the
reactants contacted, indicating the generation of azaallyl
anions.1b The color was gradually fading to brown during
the reaction. Next, oxidation on air (oxygen, chloranil, DDQ)
was employed, and the reaction mixture was stirred at the same
temperature for 1−2 h more. The oxidation with air allowed
2H-pyrrole 4aa to be synthesized in a yield of not higher than
20% (1 equiv of KOBut, 2 h, entry 4). With pure oxygen
passing through the reaction mixture with 0.2 equiv of the
base, the yield of pyrroline 3aa was 68%, and 2H-pyrrole was
formed in traces (entry 5), while with 1 equiv of KOBut, the
yield of 3aa dropped to 47%, and the yield of 4aa was found to
be 6% (entry 6). The application of chloranil or DDQ (entries
7, 8) as oxidants resulted in almost quantitative oxidation of
pyrroline 3aa to 2H-pyrrole 4aa for 1 h (65 and 66% yield,
respectively), which is in agreement with the literature data
concerning oxidation of pyrrolines9 and pyrrolidines10 to 2H-
pyrroles. Under the conditions studied, the possible oxidation
of dimsyl anion was not observed.
tolerates a considerable structural diversity of N-benzyl
ketimines covering substituted aromatic, heteroaromatic, and
condensed aromatic moieties. Among functionalities in the
benzene ring are Ph, CF3, F, Cl, Br, and OMe substituents.
Ketimine 1c, a derivative of benzophenone, when reacted with
phenylacetylene 2a, gave 2,2,3,5-tetraphenyl-2H-pyrrole 4ca,
thereby evidencing suitability of the reaction also for the
synthesis of tetraaryl-substituted 2H-pyrroles. 1,4-Bispyrrolyl
benzene 4ra was synthesized in 53% yield from diketimine 1r
(adduct of 1,4-diacetyl benzene and benzylamine). The
reaction proceeded well with several aryl- and hetarylacetylenes
with the donor and acceptor substituents in the benzene ring,
the yields of the corresponding 2H-pyrroles 4ac−aj being 57−
71%.
As it is clear, the synthesized 2H-pyrroles 4 are formed by
oxidation of the intermediate pyrrolines, the products of
superbase-catalyzed [3 + 2] cycloaddition of benzyl ketimines
to arylacetylenes. These intermediates, apart from their
mechanistic importance, arouse self-standing interest as a
valuable class of pyrrole compounds, promising targets for
synthetic and biochemistry. Indeed, the 1-pyrroline core is
widespread in natural products11 and living organisms,12
Next, to assess the scope of the reaction, we have transferred
the best conditions found for the synthesis of 2H-pyrrole 4aa
to other pairs of benzyl ketimines and arylacetylenes with
different combinations of the substituents. As follows from
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Letter
mainly in the form of hemes,12a chlorophylls,12 and alkaloids.13
1-Pyrrolines could be used as templates of new drugs,14 as
building blocks for construction of light-driven switches15 and
boranil fluorophores,16 and as rewarding valuable synthons
toward biologically active compounds.17 Therefore, the next
move of our investigation was focused on the formation of
these intermediates.
a
Scheme 5. Synthesis of 1-Pyrrolines
For continuation of the study, we stayed with the same
reference pair (1a + 2a), which was further employed for
optimization of the initial reaction step. A combination of alkali
metal hydroxides or alkoxides with different solvents was tried.
The selected results (Table 2) showed that the best systems
Table 2. Effect of Base/Solvent Combination on the Yields
of Pyrroline 3aa Formed from Ketimine 1a and Acetylene
a
2a
b
c
entry
base
solvent
conversion of 1a (%)
yield of 3aa (%)
1
2
3
4
5
6
7
8
9
NaOH
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
NMP
THF
THF
73
97
96
100
100
97
15
28
2
traces
48
42
74
71
LiOBut
NaOBut
KOBut
NaOBut
NaOBut
NaOBut
LDA
34
traces
traces
none
a
Conditions: 1a (1 mmol), 2a (1 mmol), base (1 mmol), solvent (3
b
1
mL), 20 °C, 1 h. According to H NMR data of the crude product
(n-dodecane was used as an internal standard). Isolated yield after
c
column chromatography (SiO2, n-hexane/ethyl acetate, 20:1). LDA =
Lithium diisopropylamide.
proved to be superbase pairs NaOBut/DMSO and KOBut/
DMSO securing 74 and 71% yields of the target pyrroline 3aa
at 20 °C for 1 h (1a/MOBut molar ratio = 1:1, entries 4, 5),
whereas other base/solvent combinations were less active or
inactive at all. Analysis of the 1H NMR spectra of pyrroline 3aa
indicated the formation of two diastereomers.
Further on using NaOBut/DMSO and KOBut/DMSO as
the best superbase pairs, we have carefully examined the effects
of their concentration, reaction temperature, and time on the
process efficiency (see the SI for details, Tables S1, S2).
Arbitrarly optimized conditions of the synthesis can be
accepted: equimolar ratio of imine 1a and acetylene 2a, 3
mL of DMSO, 0.2 mmol of KOBut per 1 mmol of 1a, 60 °C,
15 min. These conditions ensure ∼100% conversion of the
starting imine 1a and 75% yield of pyrroline 3aa. In fact, the
reaction is highly selective: no products except for the target
pyrroline 3aa are detectable in the reaction mixture (1H
NMR).
With the provisionally optimum conditions established, we
have investigated the substrate scope for the synthesis of
pyrrolines 3 via [3 + 2] cycloaddition of imines 1 to acetylenes
2. As follows from Scheme 5, the synthesis was successfully
extended over a number of ketimines derived from aryl alkyl
ketones (including condensed aromatic and heteroaromatic
ones) and benzylamines to produce pyrrolines 3aa−ra in good
yields. The process tolerated also diketimine 1r (derived from
1,4-diacetyl benzene and benzylamine), with bispyrrolenyl
a
Conditions: 1 (2 mmol), 2 (2 mmol), KOBut (0.4 mmol), DMSO
(6 mL). Isolated yields after column chromatography [SiO2, n-
hexane/ethyl acetate = 10:1 (for 3aa−3ah); n-hexane/ethyl acetate =
1:1 (for 3ai, 3aj)] are given.
benzene 3ra being obtained in 31% isolated yield. Ketimine 1c
reacted with phenylacetylene 2a to form two regioisomers in a
7:1 ratio. The minor 4-Ph-regioisomer is likely formed via the
addition of the more hindered site of the 2-azaallyl anion to
phenylacetylene.1
The experiments have demonstrated that the reaction is
applicable to a series of aryl- and hetarylacetylenes 2a−j, the
yields of the corresponding pyrrolines 3ab−aj reaching 91%
(Scheme 4). The reaction of N-benzyl ketimine 1a with
internal acetylene (diphenylacetylene) did not take place under
the standard conditions.
The diastereomeric ratio of the products 3 ranged from 3:1
to 2:1 with the predominance of the (2R*,3R*)-isomer. In all
cases, the diastereomers were separated by column chromatog-
raphy and fully characterized.
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The structure and stereochemistry of pyrrolines 3 were
established by NMR spectroscopy (1H, 13C, 15N) including 2D
techniques (NOESY, COSY, HSQC, HMBC) and were also
confirmed by single-crystal X-ray analysis of (2R*,3R*)-3ka
and (2R*,3S*)-3af (Figure 1).
equiv of KOBut. The incorporation of deuterium (1H NMR) in
the positions 3 and 4 of pyrroline 3aa was quantitative.
Scheme 8. Deuterium Exchange in Pyrroline 3aa
The concerted [3 + 2] cycloaddition seems to be also
probable, though in such case less sterically hindered 4-Ph
regioisomers might be formed, but experimentally, the latter
were not observed.
To check electron-transfer/radical pathways as a possible
channel in the reaction mechanism, the reaction of ketimine 1n
with phenylacetylene 2a in the presence of TEMPO (20 mol
%), a typical radical scavenger, was carried out under the
standard conditions. As a result, pyrroline 3na was isolated in
69% yield (without TEMPO, the yield was 74%, Scheme 4),
i.e., the process proceeds efficiently in both cases. Thus, the
free radical mechanism does not contribute to the overall
process. This also agrees with the absence of dimers of azaallyl
anions, which might be expected if the single-electron transfer
process takes place.18
Figure 1. X-ray structures (from ethyl ether; CCDC 2070913,
2070914).
Expectedly, pure pyrrolines, e.g., 3aa−aj, are readily oxidized
to afford the 2H-pyrroles 4aa−aj in high yields (Scheme 6),
which implies the effective conversion of all synthesized
pyrrolines to the corresponding 2H-pyrroles.
Scheme 6. Oxidation of Pyrrolines 3 to 2H-Pyrroles 4
In summary, we have developed a superbase-catalyzed [3 +
2] cycloaddition reaction between N-benzyl ketimines and
arylacetylenes followed by the intermediate oxidation to afford
eagerly sought polyarylated 2H-pyrroles and their precursors,
the corresponding 1-pyrrolines, which are of importance for
heterocyclic synthesis, pharmaceutics, and materials science.
This methodology has several attractive features: a facile
procedure, available starting materials, simple catalytic systems,
mild reaction conditions, and a wide structural variety of the
products.
Thus, a general mechanistic picture for the synthesis of 2H-
pyrroles 4 via pyrrolines 3 by superbase-catalyzed [3 + 2]
cycloaddition of N-benzyl ketimines 1 to arylacetylenes 2 can
be represented as follows. The reaction includes the addition of
deprotonated N-benzyl ketimines (azaallyl anions A) to the
triple bond followed by isomerization of carbanions B into the
conjugated carbanions C and their cyclization to pyrrolines 3.
The latter, after addition of an oxidant (chloranil, DDQ), are
transformed to the corresponding 2H-pyrroles 4 likely via
carbanion D (Scheme 7).
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01009.
Experimental procedures, compound characterizations,
NMR spectra, and crystallographic data (PDF)
Accession Codes
Scheme 7. Tentative Mechanism
CCDC 2070913−2070914 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Boris A. Trofimov − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences,
664033 Irkutsk, Russia; orcid.org/0000-0002-0430-
3215; Email: boris_trofimov@irioch.irk.ru
If, according to ref 5, the reaction starts with the addition of
acetylide anions to the C=N bond, then another regioisomeric
pyrroline (with R4 in the position 4) would be formed.
The formation of intermediate carbanions D and E is
supported by exchange of protons in the positions 3 and 4 of
pyrroline 3aa for deuterium (Scheme 8) in DMSO-d6 with 1
Authors
Ivan A. Bidusenko − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences,
664033 Irkutsk, Russia; orcid.org/0000-0003-0783-
6233
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Letter
2010. (c) Sammes, M. P.; Katritzky, A. R. The 2H- and 3H-Pyrroles.
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̈
Fröhlich, R.; Wurthwein, E.-U. 2H-Pyrrole Derivatives from an Aza-
Elena Yu. Schmidt − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences,
664033 Irkutsk, Russia
Nazarov Reaction Cascade Involving Indole as the Neutral Leaving
Group. Eur. J. Org. Chem. 2008, 2008, 3656−3667. (e) Koetzner, L.;
Leutzsch, M.; Sievers, S.; Patil, S.; Waldmann, H.; Zheng, Y.; Thiel,
W.; List, B. The Organocatalytic Approach to Enantiopure 2H- and
3H-Pyrroles: Inhibitors of the Hedgehog Signaling Pathway. Angew.
Chem., Int. Ed. 2016, 55, 7693−7697. (f) Polák, P.; Tobrman, T.
Dearomatization Strategy for the Synthesis of Arylated 2H-Pyrroles
and 2,3,5-Trisubstituted 1H-Pyrroles. Org. Lett. 2017, 19, 4608−4611.
(g) Yamaguchi, M.; Fujiwara, S.; Manabe, K. Synthesis of 2,2,5-
Trisubstituted 2H-Pyrroles and 2,3,5-Trisubstituted 1H-Pyrroles by
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Direct C3-Arylation. Org. Lett. 2019, 21, 6972−6977.
Igor A. Ushakov − A. E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch, Russian Academy of Sciences,
664033 Irkutsk, Russia
Alexander V. Vashchenko − A. E. Favorsky Irkutsk Institute
of Chemistry, Siberian Branch, Russian Academy of Sciences,
664033 Irkutsk, Russia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01009
Notes
The authors declare no competing financial interest.
(9) (a) Sammes, M. P.; Chung, M. W. L.; Katritzky, A. R. The
synthesis and chemistry of azolenines. Part 4. Preparation and
Rearrangement of Some 3,5-Diaryl-2H-pyrrole-2,2-dicarboxylic Es-
ters. J. Chem. Soc., Perkin Trans. 1 1985, 1773−1779. (b) Soret, A.;
ACKNOWLEDGMENTS
■
This work was financially supported by a grant from the
Russian Science Foundation (project no. 19-13-00052). The
authors thank the Baikal Analytical Centre of collective use for
the equipment.
Muller, C.; Guillot, R.; Blanco, L.; Deloisy, S. Short and Efficient
̈
Synthesis of 2H-Pyrroles from 7-Oxanorbornadiene Derivatives.
Tetrahedron 2011, 67, 698−705.
(10) Cheruku, S. R.; Padmanilayam, M. P.; Vennerstrom, J. L.
Synthesis of 2H-Pyrroles by Treatment of Pyrrolidines with DDQ.
Tetrahedron Lett. 2003, 44, 3701−3703.
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