Photocatalyst-Free Visible-Light Enabled Synthesis of Substituted Pyrroles from α-Keto Vinyl Azides

Article abstract of DOI:10.1002/adsc.202000562

An efficient photocatalyst-free visible light enabled synthesis of substituted pyrroles from α-keto vinyl azides (readily prepared via Knoevenagel condensation of phenacyl azides with 2-oxo-2H-chromene-3-carbaldehydes) was developed. The reaction proceeds

Full text of DOI:10.1002/adsc.202000562

Title: Photocatalyst-Free Visible-Light Enabled Synthesis of Substituted
Pyrroles from α-Keto Vinyl Azides
Authors: Satheesh Borra, Lodsna Borkotoky, Uma Devi Newar, Babulal
Das, and Ram Maurya
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000562
Link to VoR: https://doi.org/10.1002/adsc.202000562

10.1002/adsc.202000562
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Photocatalyst-Free Visible-Light Enabled Synthesis of
Substituted Pyrroles from α-Keto Vinyl Azides
Satheesh Borra,a, b Lodsna Borkotoky,a, b Uma Devi Newar,a, b Babulal Dasc and Ram
Awatar Mauryaa, b,*
a
Applied Organic Chemistry Group, Chemical Sciences & Technology Division, CSIR-North East Institute of Science
& Technology (NEIST), Jorhat-785006 (India)
E-mail: ram.cdri@gmail.com
Academy of Scientific and Innovative Research (AcSIR), CSIR-NEIST Jorhat-785006 (India)
b
c
Department of Chemistry, Indian Institute of Technology, Guwahati-781039 (India)
(S. Borra and L. Borkotoky equally contributed to this work.)
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
reaction set-up and sustainable perspective. This
enabled synthesis of substituted pyrroles from α-keto vinyl manuscript deals with a photocatalyst-free visible
Abstract. An efficient photocatalyst-free visible light
azides (readily prepared via Knoevenagel condensation of
phenacyl azides with 2-oxo-2H-chromene-3-
carbaldehydes) was developed. The reaction proceeds
through a denitrogenative photodecomposition of α-keto
vinyl azides, 1,3-amino group migration, and coupling of
intermediates with secondary amines.
light enabled synthesis of a library of coumarin fused
pyrroles from α-keto vinyl azides. These molecular
scaffolds are found in pharmaceutically valuable
natural products (Lamellarins I, Ningalins II) and
other synthetic molecules (III, IV, V, VI) with
unique photochemical as well as redox-switching
properties (Figure 1). They possess promising
anticancer, antitumor, and fluorescent neuroimaging
properties.[6]
Keywords: photocatalyst-free; photochemical reaction;
vinyl azides; pyrroles; 1,3-amine migration
Pyrrole is one of the most vital five membered N-
heterocycles frequently found in a plethora of natural
products, pharmaceuticals, drugs and other valuable
materials.[1] Molecular scaffolds with pyrrole as a key
structural unit possess a broad range of biological
properties such as antitumor, antipsychotic, anti-
inflammatory,
antioxidant,
antifungal,
and
antibacterial activities.[2] Therefore, chemists have
always been fascinating for developing innovative
synthetic routes to pyrrole scaffolds. It is not
surprising that a variety of newer organic reactions
for the construction of substituted pyrroles are
incessantly being discovered.[3] Apart from metal and
non-metal catalyzed reactions, many photochemical
methods to synthesize pyrrole derivatives were also
reported recently. [4]
Since the beginning, high energy ultra-violet (UV)
light was mostly utilized in photochemical organic
transformations. However, this trend has been
dramatically changed over the past few years as a
large numbers of visible light driven organic
reactions are being explored.[4,5] Visible light is often
preferred over UV irradiations because of its product
selectivity, little radiation safety requirements, simple
Figure 1. Examples of some important natural and
synthetic fused pyrrole molecules.
Vinyl azides have long been known to decompose
into nitrenes and/or 2H-azirines under thermal as well
UV light exposure, and it has been widely utilized to
synthesize various N-heterocycles.[7] However,
visible light enabled synthetically useful reactions of
vinyl azides were unexplored until Yoon and co-
workers reported a photosensitized decomposition of
vinyl azides to access pyrroles (Scheme 1a).[8a] In the
same year, Xiao and co-workers also reported a
visible light enabled coupling of vinyl azides and 2H-
1
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10.1002/adsc.202000562
Advanced Synthesis & Catalysis
azirines with alkynes to yield pyrroles (Scheme
1b).[8b] Recently, Meggers and co-workers reported a
visible light triggered [2+3]cycloaddition of alkenes
and vinyl azides to synthesize pyrrolines in high
enantiomeric excess (Scheme 1c).[8c] In continuation
to our interest over the development of visible light
enabled synthesis of N-heterocycles,[9] we intended to
study the photochemical reactions of α-keto vinyl
azides (VII & VIII)to access pyrroles (IX) (Scheme
1d).
these solvents interfere with substrate or reaction
intermediates leading to the formation of multiple
products.
Table 1. Optimization studies of the decomposition of
vinyl azide 1a.[a]
Entry
Energy source
Solvent
Time
(h)
Yield
(%)[b]
1
7 W blue LED
8 W CFL
DCE
24
24
12
85
65
41
2
DCE
3
4 [c]
heating (60 °C)
7 W blue LED
7 W blue LED
7 W blue LED
7 W blue LED
DCE
DCE
24
24
24
24
85
82
NI
NI
5
DCM
MeOH
CH3CN
6
7
[a] Reaction condition: Conc. of 1a in solvent: 0.1 M, blue LED
light (7 W kept in close contact with the reaction vessel),
open air atmosphere.
[b] Isolated yields.
[c] Under nitrogen atmosphere.
NI = Not isolated (complex mixture).
Scheme 1: Visible light enabled synthesis of pyrroles from
vinyl azides.
With optimized reaction conditions in hand, we
tried to study the scope of the reaction by
synthesizing a series of substituted pyrroles (Figure
2). Several vinyl azides having electron donating
(OMe, Me, Ph), electron withdrawing (CN), and
halogen (Cl) in their aroyl residue got smoothly
converted into corresponding pyrroles in high yields
(80-85%).
To start with, vinyl azide 1a was prepared by a
Knoevenagel condensation reaction of 2-oxo-4-
(piperidin-1-yl)-2H-chromene-3-carbaldehyde
2a
with 2-azido-1-(4-methoxyphenyl)ethanone 3a using
piperidinium acetate as an additive in
dichloromethane (DCM). UV-Visible spectrum of
compound 1a showed strong absorption of light in
280-440 nm range with absorption maxima at 303
and 380 nm. Therefore, we envisioned that a
photocatalyst might not be required and planned to
study its photodecomposition using a blue LED light
(Table 1). Irradiation of 0.1 M solution of the model
substrate 1a in DCE with a blue LED (7 W) light led
to the formation of a clear yellow spot on TLC, which
was isolated, and its chemical structure was assigned
1
as 4a by analysing its H/13C NMR, IR, MS/HRMS
spectral data (Table 1, entry 1). The yield of
compound 4a was same whether the reaction was
carried out under inert (N2) or open air atmosphere
(Table 1, entries 1 & 4). It indicated that atmospheric
oxygen did not interfere with reaction intermediates.
Irradiation of 1a with a 8 W compact fluorescent
lamp (CFL) or heating at 60 °C in DCE also led to its
complete decomposition, however 4a was obtained in
lower yields (Table 1, entries
2
&
3).
Photodecomposition of 1a in DCM gave good yield
of 4a whereas complex reaction mixtures were
observed using MeOH and CH3CN as the reaction
solvents (Table 1, entries 5-7). It indicated that both
Figure 2. Scope of the photodecomposition of vinyl azides
1 to access substituted pyrroles 4
2
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10.1002/adsc.202000562
Advanced Synthesis & Catalysis
Piperidine, diethylamine, morpholine and 1,2,3,4-
presented in Scheme 3. Upon absorption of light, the
vinyl azide 1 expels a molecule of nitrogen from its
excited state to form a 2H-azirine 5. Being in
conjugation with the 2H-azirine, the amino group
drives its ring opening to give intermediate 6 which
subsequently undergoes an intramolecular cyclization
to yield 7. Next, an intermediate 9 is formed via two
successive [1,5] sigmatropic shift of the amine group.
The net result of the process is an apparent 1,3-amino
tetrahydroisoquinoline units of the vinyl azides 1
migrated smoothly during the reaction to yield
pyrroles 4. The reaction was equally successful when
a halogen (Br) substituent was taken in the coumarin
residue of the vinyl azide (1c). Vinyl azides I having
primary or secondary amino group could not be
prepared using our standard protocol, therefore such
photodecompositions could not be studied. All the
synthesized compounds were fully characterized by
group migration. Finally the intermediate
9
1
their H/13C NMR, IR, MS/HRMS spectral data. X-
isomerises to the pyrrole 4.
ray crystallography studies for compound 4b were
also executed to give an unambiguous proof of its
structural assignment.
Next, we thought of further exploring the scope of
pyrrole synthesis by attempting a similar 1,3-
migration of an alkoxy group of vinyl azide VIII
(Scheme 1d) under similar reaction conditions. We,
therefore, prepared vinyl azide 1l via Knoevenagel
condensation reaction of 2-azido-1-(p-tolyl)ethanone
3c with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde
2f. The UV-Visible absorption spectrum of vinyl
azide 1l showed strong absorption of light in 287-430
nm with absorption maxima at 339 nm. The
photodecomposition of 1l was studied under various
conditions including blue LED light, CFL light,
heating, and exposure of light in the presence
catalytic Ru(bpy)3(PF6)2 (For details, see electronic
supporting information). However, in all the cases we
ended up with a reaction mixture with multiple spots
on TLC which could not be purified using silica-gel
column chromatography. To our surprise, when 1l
was exposed to blue LED light in the presence of
piperidine, the reaction gave a prominent spot on
TLC with very little side products. After work-up and
purification, compound 4d was isolated in 78% yield
(Scheme 4).
We were curious to know whether the 1,3-amino
group migration during the formation of pyrrole 4
from vinyl azide
1
was intramoleculer or
intermolecular process. Therefore, we planned a
couple of control experiments. In the first experiment,
photodecomposition of vinyl azide 1b was performed
in the presence of morpholine (Scheme 2a). In the
second one, equimolar mixtures of vinyl azides 1d
and 1h were irradiated with blue LED light in DCE
(Scheme 2b). In none of the cases, a crossover
product was obtained thereby suggesting the
intramolecular nature of the 1,3-amino group
migration.
Scheme 2. Control experiments.
Scheme 4. Photochemical coupling of 1l with piperidine to
yield pyrrole 4d.
Mechanistic rationalization for the smooth
formation of 4d from the coupling of piperidine and
vinyl azide 1l is depicted in Scheme 4. After
absorption of light, the vinyl azide 1l undergoes
denitrogenative decomposition into a 2H-azirine
followed by its ring opening and annulations to
intermediate 10, in a similar fashion depicted in
Scheme 3. The methoxy group of the intermediate 10
is not as good nucleophile as the amino group of the
intermediate 7. Therefore, it does not lead to the
anticipated 1,3- methoxy group migration. The
intermediate 10 is attacked by piperidine to give
intermediate 11, which after elimination of a
Scheme 3. Mechanistic hypotheses for the conversion of
vinyl azides 1 into pyrroles 4.
A
mechanistic
rationalisation
of
the
photodecomposition of vinyl azide 1 to pyrrole 4 is
3
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10.1002/adsc.202000562
Advanced Synthesis & Catalysis
molecule of methanol and isomerisation yields
pyrrole 4d.
In order to explore the scope of the reaction and
study the similar migration of a carbon substituent
(aryl), vinyl azide 12 was prepared and its
photodecomposition was studied. Vinyl azide 12
remained un-decomposed when its solution in DCE
(0.1 M) was irradiated with a blue LED light (7W)
for a period of 12 h. Therefore, a photosensitized
decomposition of vinyl azide 12 was performed using
Ru(bpy)3(PF6)2 (1 mol%) as a photocatalyst (Scheme
6). Vinyl azide 12 was completely decomposed in 24
h giving multiple spots on TLC. The major product of
the reaction was characterized as 2H-azirine 13.
The successful coupling of vinyl azide 1l with
piperidine prompted us to explore the scope of the
reaction. Several vinyl azides 1j-u were prepared and
coupled with amines to yield pyrroles under same
reaction conditions (Scheme 5). Vinyl azides (1j-u)
bearing electron withdrawing groups (CN, NO2),
electron donating groups (OMe, Me, 4-Phenyl, 2-
Naphthyl) and halogens (Br and Cl) in their aroyl
residue were coupled efficiently with piperidine to
afford fused pyrrole (4a-b, 4d-f, 4j-n) in good yields
(75-80%). The photochemical coupling reaction was
successfully generalized with piperidine, morpholine,
pyrrolidine,
N,N-diethylamine,
and
1,2,3,4-
tetrahydroisoquinoline. In all these cases, good yield
of desired pyrrole derivatives (4a-w) were obtained.
The coupling of vinyl azide with primary amines
(methylamine and 4-toludine) gave inseparable
multiple spots on TLC which were not purified. In
another experiment, a photochemiocal coupling of
vinyl azide 1j with a secondary aromatic amine (N-
methylaniline) was attempted. Analysis of the
reaction mixture revealed the formation of desired
pyrrole among with the several by-products (for
details, see the electronic supporting information).
Next, we investigated the possibility of a thermal
coupling of vinyl azide 1j with piperidine. In an
experiment that was performed at ambient
temperature in dark, both the starting materials (vinyl
azide 1j and piperidine) remained un-reacted even
after 12 h. Further heating the same reaction mixture
at 60 °C led to complete decomposition of the vinyl
azide with the formation of many spots on TLC. The
desired pyrrole 4a could not be isolated from the
thermal coupling of vinyl azide 1j with piperidine.
These results clearly demonstrate the superiority of
photochemical coupling of the vinyl azides with
secondary amines (Scheme 5).
Scheme 6. Photosensitized decomposition of vinyl azide
12 into 2H-azirine 13.
In conclusion, a novel visible light enabled
photocatalyst-free synthetic method to construct
pyrroles from α-keto vinyl azides was developed.
Vinyl azides having amino group in conjugation with
the
azide
underwent
denitrogenative
photodecomposition and 1,3-amino group migration
to yield pyrroles. On the other hand, vinyl azides
having methoxy group in conjugation with the azide
were smoothly coupled with secondary amines to
give pyrroles in good yields. Several control
experiments were carried out to get mechanistic
insight of the reaction. As this photochemical
transformation does not require external photocatalyst
or additive, it reduces chemical wastes and the
manufacturing costs. The reaction opens up the
possibility of studying further photochemical
rearrangements and coupling of nucleophiles with
vinyl azides to construct complex molecular scaffolds.
Experimental Section
General procedure for decomposition of vinyl azides
(1a-i) in the presence of blue LEDs to yield substituted
pyrroles 4a-i: In a 25 mL round bottom flask, the
corresponding vinyl azide (0.5 mmol) was taken in DCE (5
mL). Next, the reaction mixture was stirred and irradiated
with a 7W blue LED light placed in close contact to the
reaction vessel till completion (24 h). Next, the reaction
mixture was concentrated to obtain a crude product which
was purified by silica-gel (100-200 mesh) column
chromatography using ethyl acetate
/ n-hexane in
increasing polarity to yield compounds 4a-i.
Acknowledgements
The authors thank Council of Scientific and Industrial Research
New Delhi (OLP 2038) and Department of Science & Technology
(DST) New Delhi (GPP0351) for financial support. S. B., L.B.
and U. D. N. thank University Grants Commission New Delhi
and DST India for their fellowships.
Scheme 5. Photochemical coupling of vinyl azides 1 with
secondary amines to yield pyrroles 4.
4
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10.1002/adsc.202000562
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.202000562
Advanced Synthesis & Catalysis
COMMUNICATION
Photocatalyst-Free Visible-Light Enabled
Synthesis of Substituted Pyrroles from α-Keto
Vinyl Azides
Adv. Synth. Catal.Year, Volume, Page – Page
Satheesh Borra, Lodsna Borkotoky, Uma Devi
Newar, Babulal Das and Ram Awatar Maurya*
6
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