Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-Contraction of Sulfilimines

Article abstract of DOI:10.1021/jacs.1c04835

We present a modular, synthetic entry to polysubstituted pyrroles employing readily available 2,5-dihydrothiophenes. Ring-opening of the heterocycle provides access to a panel of 1,3-dienes which undergo pyrrole formation in the presence of inexpensive chloramine-T trihydrate. The transformation is conducted in an open flask and proceeds at ambient temperatures (23 °C) in nondry solvents. A careful adjustment of the electronics and sterics of the 1,3-diene precursor allows for the isolation of key intermediates. DFT studies identified a reaction mechanism that features a 6π-electrocyclization of a sulfilimine intermediate followed by spontaneous ring-contraction to reveal the pyrrole skeleton.

Full text of DOI:10.1021/jacs.1c04835

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Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-
Contraction of Sulfilimines
̈
Franz-Lucas Haut, Niklas J. Feichtinger, Immanuel Plangger, Lukas A. Wein, Mira Muller,
Tim-Niclas Streit, Klaus Wurst, Maren Podewitz,* and Thomas Magauer*
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ABSTRACT: We present a modular, synthetic entry to polysubstituted pyrroles employing readily available 2,5-dihydrothiophenes.
Ring-opening of the heterocycle provides access to a panel of 1,3-dienes which undergo pyrrole formation in the presence of
inexpensive chloramine-T trihydrate. The transformation is conducted in an open flask and proceeds at ambient temperatures (23
°C) in nondry solvents. A careful adjustment of the electronics and sterics of the 1,3-diene precursor allows for the isolation of key
intermediates. DFT studies identified a reaction mechanism that features a 6π-electrocyclization of a sulfilimine intermediate
followed by spontaneous ring-contraction to reveal the pyrrole skeleton.
Scheme 1. Pyrroles in Medicinal Chemistry and
“Heterocycle Switches” of 2,5-Dihydrothiophenes into
Furans and Pyrroles
he efficient construction of structurally encumbered and
highly functionalized heterocycles represents one of the
T
major challenges for the development of novel pharmaceuticals
and agrochemicals.1 In particular, tetrasubstituted pyrroles
have served as valuable lead structures in medicinal chemistry
to develop the anticancer agent sunitinib (1, Sutent),2 the
cholesterin-lowering drug atorvastatin (2, Lipitor),3 and the
Ca2+-channel activator FPL 64176 (3, Scheme 1A).4 For the
assembly of these heterocycles, condensation chemistry has
dominated the field for decades5 and powerful transition-metal
based coupling strategies have only emerged later.6 Ring
formation relying on pericyclic reactions represents a concep-
tionally different strategy which has found widespread
application in all areas of heterocyclic chemistry. For instance,
with the establishment of 1,3-dipoles by Huisgen, cyclo-
addition reactions became available as a robust method to
synthesize a variety of five-membered heterocycles.7 This
includes the [3 + 2]-cycloaddition reaction of azomethine,
carbonyl, and thiocarbonyl ylide intermediates to allow for the
rapid assembly of pyrroles, furans, and thiophenes.8 On the
other hand, sigmatropic rearrangements have been extensively
used to construct, for instance, indoles.9 For the synthesis of
benzofuran derivatives, interrupted Pummerer reactions10 were
reported to initiate charge-accelerated [3,3]-sigmatropic
rearrangements.11 However, electrocyclization reactions have
remained in a niche and have mainly been applied to the
synthesis of six-membered heterocycles. For example, the 6π-
electrocyclization of azatrienes was shown to provide a broad
range of pyridines.12
During our studies to convert readily available 2,5-
dihydrothiophenes 413 into tetrasubstituted furans 6, we
found an unprecedented 6π-electrocyclic ring-opening as part
of the reaction mechanism (Scheme 1B).14 While we were able
to access a variety of furans, all efforts to prepare the
corresponding pyrroles via exchange of the carbonyl function
for an imine failed. However, we later found that the exposure
of 1,3-diene 5a to inexpensive chloramine-T effects selective
Received: May 10, 2021
Published: June 9, 2021
© 2021 The Authors. Published by
American Chemical Society
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sulfilimine formation. In contrast to a preliminary study relying
on high temperatures (130 °C, two examples),15 subsequent
6π- electrocyclization/ring-contraction/elimination16 of 7
proceeded spontaneously at 23 °C in an open flask to give
pyrrole 9 (Scheme 1C).
Employing Sharpless’ conditions for the synthesis of N-tosyl
sulfilimines (chloramine-T trihydrate, acetonitrile, 23 °C),17
we observed rapid conversion of 1,3-diene 5a to pyrrole 9a in
53% yield (Scheme 2, entry 1). The 2,5-dihydropyrrole 10 was
single run. Modifications of R1 (highlighted in red) allowed for
the implementation of electronically enriched arenes and a
thiophene to give 9b−d in constantly good yields (72−79%).
The presence of a strongly electron withdrawing substituent
such as a nitro group (9e) or a trifluoromethyl group (9f) was
well tolerated (63−64%). Different aryl halides were also
shown to effectively undergo pyrrole formation to deliver
chloride 9g, fluoride 9h, and bromide 9i in high yields between
69 and 78%. In addition, tertiary amide 9j and aldehyde 9k
were accessible from the reaction (59−65%). As shown for the
synthesis of the alkyl (R1 = Me, n-Bu)- and allyl-substituted
pyrroles 9l−n (52−76%), an aryl residue was not required at
the C3 position. Only alkyne 9o and pivalate 9p were obtained
in lower yields (28−30%). Lactone 9q (42%) was also
accessible, thus expanding the synthetic utility to annelated
ring systems. When the ester was changed to amides (R2,
highlighted in blue), the primary and secondary amides 12a,b
were isolated in 56 and 81% yields, respectively. The latter
bears the 3,4-substitution pattern as found in atorvastatin (2).
Additionally, the Weinreb amide 12c was synthesized in 33%
yield. Ketones also participated in the transformation and gave
the di- and trisubstituted pyrroles 13a−c in good yields (55−
77%). The presence of nitriles was also tolerated under the
reaction conditions but required the absence of m-CPBA
during the workup process. This allowed for the isolation of
pyrrole 14a in 51% yield (18% in the presence of m-CPBA).
Consequently, we were able to prepare pyrrole 14b (42%),
which was quantitively converted to the fungicide fludioxonil
(15, Pestanal)1c,18 through N-tosyl cleavage under basic
conditions (NaOH, MeOH). Application of O-mesitylenesul-
fonyl hydroxylamine (MSH) and sodium carbonate19 allowed
for the direct conversion of 1,3-diene 5a to the unprotected
pyrrole 16 (30%), which was produced in higher yields via
deprotection of 9a (Cs2CO3, MeOH, 84%). To conclude the
synthetic scope, we explored the productivity of other
chloramines to trigger the pyrrole formation of 5a.
Commercially available chloramine-B monohydrate allowed
for the construction of pyrrole 17a in 88% yield. When its p-
nitrophenyl (chloramine-N), p-methoxyphenyl (chloramine-P)
and methyl (chloramine-M) derivatives were applied, pyrroles
17b−d were also accessible in yields up to 75%.
By changing to sterically encumbered 1,3-dienes such as 18,
we were able to isolate the reactive sulfilimine 19 (61% yield,
step A) under the standard reaction conditions (Scheme 4A).
To our delight, thermal activation (toluene, reflux) allowed for
the smooth initiation of the subsequent cascade to deliver
pyrrole 20 in decent yield (76%, step B). When this two-step
protocol was applied, trisubstituted pyrrole 21 (78% and 49%)
and tetrasubstituted pyrrole 22 (61% and 99%) were formed.
In addition, trisubstituted pyrrole 23 was obtained in good
yields (62%), provided that benzonitrile was employed as the
solvent.20 As exemplified by 24, we found that the absence of
an electron-withdrawing group (EWG) also allows for the
isolation of its corresponding sulfilimines (99% yield, step A)
under the standard reaction conditions. After this, thermal
activation resulted in the formation of pyrrole 24 in
quantitative yield. It is worth noting that, when sulfilimine
25 was subjected to thermal conditions (111 °C), a complete
reaction was observed within 20 min. However, the main
product was identified as the 2,5-dihydropyrrole 26 (44%)
accompanied by small quantities of its cis-fused diastereomer
(not shown, 10%) and pyrrole 27 (10%). Resubjecting 26 to
refluxing toluene led to full conversion (28 h) to 27 in
a
Scheme 2. Optimization Studies
a
Legend: (1) yield determined by 1H NMR analysis using
nitromethane as internal standard; (2) isolated yield, 0.2 mmol
scale of 5a−c. Abbreviations: Ts = p-toluenesulfonyl, DMF = N,N-
dimethylformamide, HFIP = hexafluoroisopropyl alcohol, m-CPBA =
m-chloroperbenzoic acid.
isolated as the second product together with traces of
trisubstituted pyrrole 11, which might originate from 10 via
a competing oxidation pathway. Further screening revealed
slightly lower yields for the solvents N,N-dimethylformamide,
methanol, and water (32−49%, entries 2−4). In the presence
of 1 equiv of p-toluenesulfonic acid monohydrate (p-TsOH·
H2O, entry 5), the yield was increased to 70%. The use of
hexafluoroisopropyl alcohol (HFIP) as the cosolvent allowed
for the removal of p-TsOH·H2O and further improved the
yield of 9a to 84% (entry 6). The use of 1.5 equiv of
chloramine-T trihydrate or anhydrous chloramine-T (2 equiv)
led to decreased yields (41−65%, entries 7 and 8). Dichlor-
amine-T (TsNCl2) led to rapid consumption of the substrate,
but pyrrole formation was accompanied by decomposition to
give 9a in only 23% yield. Variation of the vinyl sulfide revealed
diene 5a (R = Me) to be superior to 5b (R = Et, 68%) and 5c
(R = Ph, 59%), delivering pyrrole 9a in an 83% isolated yield.
The addition of m-chloroperbenzoic acid (m-CPBA) after full
conversion of the starting material allowed for selective sulfur
oxidation of 11 and facilitated the isolation of pure 9a.
With our optimized conditions in hand, we investigated the
robustness and compatibility of the protocol for a panel of 1,3-
dienes (Scheme 3). The scalability was demonstrated by the
rapid synthesis of more than 1.5 g (78%) of pyrrole 9a in a
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a
Scheme 3. Synthetic Scope
a
Standard conditions: substrate (0.2 mmol), chloramine-T trihydrate (2.0 equiv), MeCN/HFIP (9/1, 0.1 M), 0.5−8 h and then m-CPBA (1.0
equiv), 23 °C, 1 h. See Section 4.1 in the Supporting Information for experimental and substrate specific details. Legend: (1) no addition of m-
CPBA.
quantitative yield through the thermal release of methanethiol.
Finally, sulfilimine 25 was directly converted into pyrrole 27 in
92% yield after an extended reaction time (44 h, step B).
Having investigated the synthetic scope, we conducted
further experiments to gain insights into the mechanism of the
pyrrole formation. Thereby, chloramine-T was shown to
effectively trigger the elimination of methyl sulfide from 2,5-
dihydropyrrole 10 at ambient temperatures (23 °C, Scheme
4B). This revealed that 2 equiv of chloramine-T is required for
full conversion and to avoid formation of a mixture of pyrrole
and 2,5-dihydropyrrole (compare Scheme 2, entry 7). In
addition, 10 was obtained through a Pummerer-type activation
of sulfoxide 28 in the presence of triflic anhydride (Tf2O) and
p-toluenesulfonamide (TsNH2, Scheme 4C).21 The lack of
chloramine-T under these reaction conditions allowed for the
selective formation of the 2,5-dihydropyrrole core without
further elimination.
A second Pummerer-type reaction was demonstrated by the
activation of sulfilimine 19 with oxalyl chloride (COCl)2.22 On
the basis of our previous work,14 19 was rapidly converted into
a trisubstituted furan bearing an unstable benzylic chloride. By
telescoping the reaction in a one-pot fashion, the chloride was
hydrolyzed (silver nitrate, acetone/water) to deliver furan 29
(39%). Finally, we adapted the 6π-electrocyclization/ring-
contraction sequence for sulfoxide 28, resulting in the smooth
formation of the 3,4-substituted furan 30 (52%, Scheme 4D).
In a continuation of our mechanistic studies, DFT
calculations (B3LYP-D3/6-311++G(2d,2p)) in implicit aceto-
nitrile shed light on the rapid conversion of 1,3-diene 5a to
pyrrole 9a at ambient temperature (Scheme 5, highlighted in
black). Sulfilimine A is initially generated from the reaction of
5a with chloramine-T, which is supported by the isolation of
sulfilimines such as 19.23 A thermal 6π-electrocyclization via
TS-A with a barrier of ΔG⧧ = 13.5 kcal/mol results in the
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a
Scheme 4. Mechanistic Investigations
a
See Section 4.3 in the Supporting Information for experimental details. Legend: (1) benzonitrile as the solvent, 191 °C, 1 h (step B); (2) yield
1
determined by H NMR analysis using methyl phenyl sulfone as an internal standard.
formation of 2,3-dihydrothiazine B. Facile ring-contraction
through a 1,2-aza shift with a low activation energy (ΔG⧧ = 6.0
kcal/mol, TS-B) delivers the thermodynamically favored 2,5-
dihydropyrrole 10 (ΔG = −39.5 kcal/mol), which could be
isolated in the absence of chloramine-T (compare Scheme 2).
Since a second equivalent of chloramine-T was shown to
rapidly promote the final aromatization step (compare Scheme
4B), we assume an exergonic sulfilimine formation with ΔΔG
= −25.3 kcal/mol to yield C, which undergoes spontaneous
elimination to give pyrrole 9a and sulfonamide 31.24
On the basis of the isolation of several reactive intermediates
(Scheme 4A), additional calculations were carried out to
explain the kinetic hindrance. For the sterically encumbered
sulfilimine 19 (highlighted in blue), we found only a slightly
increased barrier for the 6π-electrocyclization (TS-19) in
comparison to TS-A with ΔΔG⧧ = 2.7 kcal/mol. However, the
formation of 2,3-dihydrothiazine D as well as the ring-
contraction product TS-D is energetically increased (ΔΔG =
9.8 kcal/mol and ΔΔG⧧ = 13.8 kcal/mol) due to the rigidity of
the annelated cyclohexene bearing the gem-dimethyl sub-
stitution pattern.25 Intermediate D was found to kinetically
favor the back reaction, a 6π-electrocyclic ring-opening, to
regenerate 19 instead of undergoing ring-contraction via TS-D
to 2,5-dihydropyrrole E (ΔΔG⧧ = 7.6 kcal/mol). Con-
sequently, the product formation is kinetically suppressed at
ambient temperature (23 °C), thus allowing for the isolation of
19. This is fully consistent with the thermal activation of 19
(111 °C, Scheme 4A) resulting in the formation of pyrrole 20
via intermediate E.
The lack of an EWG (highlighted in red) significantly
increases the activation energy for the 6π-electrocyclization of
sulfilimine 32 (ΔΔG⧧ = 10.1 kcal/mol, TS-32 vs TS-A).26 In
contrast to 2,3-dihydrothiazines B and D, the charge-separated
intermediate F is preferentially formed, in which heterolytic
cleavage of the S−N bond is observed. However, the ring-
contraction barrier for TS-F is comparable to that of TS-B
(ΔΔG⧧ = 1.3 kcal/mol), and the thermodynamics of 2,5-
dihydropyrrole G are equal to those of 10. The similarity of the
thermodynamic profiles (B → 10 and F → G) stands in sharp
contrast to the sterically deactivated pathway of intermediate D
to E. Alternative pathways for the formation of the 2,5-
dihydropyrroles 10, E, and G have been investigated in detail
(See Section 6 in the Supporting Information) but are
energetically less favorable.
In summary, we have demonstrated the synthetic potential
of 2,5-dihydrothiophene-derived sulfilimines to access a variety
of polysubstituted pyrroles under mild reaction conditions.
Both the experimental results and DFT calculations are fully
consistent with a mechanism that involves a 6π-electro-
cyclization/ring-contraction sequence. Despite the omnipre-
sence of pericyclic reactions in heterocyclic chemistry,
electrocyclic reactions have been largely limited to the
formation of six-membered heterocycles. The developed
methodology fills that gap and expands the unique chemical
space of electrocyclic reactions. Further studies toward related
N-heterocycles are currently ongoing in our laboratories and
will be reported in due course.
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a
Scheme 5. Computational Studies
a
Proposed reaction mechanism as calculated with B3LYP-D3/6-311++G(2d,2p) in acetonitrile treated as the implicit solvent (see Section 6 in the
Supporting Information for details). Relative Gibbs free energies at 298 K are given in kcal/mol, whereas the energies of the respective sulfilimines
A, 19, and 32 are arbitrarily set to zero. The energetically most favorable pathway for 1,3-diene 5a to pyrrole 9a is highlighted in black. For
comparison, the influences of sterics (blue, 19 → 20) and electronics (red, 32 → 24) were investigated.
0000-0003-1290-9556; Email: thomas.magauer@
uibk.ac.at
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04835.
■
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Authors
Experimental details, spectroscopic data, and details of
the calculations (PDF)
Franz-Lucas Haut − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria; orcid.org/
0000-0003-2091-6270
Niklas J. Feichtinger − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria
Immanuel Plangger − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria; orcid.org/
0000-0002-9912-5377
Lukas A. Wein − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Mira Muller − Institute of Organic Chemistry and Center for
̈
Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
Accession Codes
CCDC 2081881−2081884 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 Authors
Maren Podewitz − Institute of General, Inorganic and
Theoretical Chemistry and Center for Molecular Biosciences,
Leopold-Franzens-University Innsbruck, 6020 Innsbruck,
Austria; orcid.org/0000-0001-7256-1219;
Email: maren.podewitz@uibk.ac.at
■
Thomas Magauer − Institute of Organic Chemistry and
Center for Molecular Biosciences, Leopold-Franzens-
University Innsbruck, 6020 Innsbruck, Austria; orcid.org/
Tim-Niclas Streit − Institute of Organic Chemistry and Center
for Molecular Biosciences, Leopold-Franzens-University
Innsbruck, 6020 Innsbruck, Austria
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(b) Gassman, P. G.; Van Bergen, T. J.; Gruetzmacher, G. Use of
Halogen-Sulfide Complexes in the Synthesis of Indoles, Oxindoles,
and Alkylated Aromatic Amines. J. Am. Chem. Soc. 1973, 95, 6508−
6509.
Klaus Wurst − Institute of General, Inorganic and Theoretical
Chemistry and Center for Molecular Biosciences, Leopold-
Franzens-University Innsbruck, 6020 Innsbruck, Austria
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04835
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Austrian Science Fund FWF
(P31023-NBL to T.M., P33528 and M2005 to M.P.), the
Center for Molecular Biosciences CMBI and the Tyrolean
Science Fund TWF (UNI-0404/2340 to F.-L.H. and F.16642/
5-2019 to L.A.W.). Furthermore, we gratefully acknowledge
Dr. Kevin R. Sokol and Christoph Habiger (LFU Innsbruck)
for experimental assistance. The computational results
presented here have been achieved using the LEO HPC
infrastructure at the LFU Innsbruck.
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Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(23) Alternative strategies to selectively synthesize sulfilimine A from
1,3-diene 5a (TsN3, FeCl2 or PIDA, TsNH2) resulted in the direct
formation of pyrrole 9a (70% or 40%, respectively). See Section 4.4 in
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(25) No sulfilimine but rather exclusive pyrrole formation was
observed for the unsubstituted cyclohexene ring (13c, Scheme 3).
(26) For related studies on the influence of changes in the
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to Promote Sluggish Electrocyclization of 1,3,5-Hexatrienes by
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(c) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D.
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