Aroylation of Electron-Rich Pyrroles under Minisci Reaction Conditions

Article abstract of DOI:10.1021/acs.orglett.0c00041

The development of Minisci acylation on electron-rich pyrroles under silver-free neutral conditions has been reported featuring the regioselective monoacylation of (NH)-free pyrroles. Unlike conventional Minisci conditions, the avoidance of any acid that could result in the polymerization of pyrroles was the key to success. The umpolung reactivity of the nucleophilic acyl radical, generated in situ from arylglyoxylic acid, could help explain the mechanism of product formation with electron-rich pyrroles. Alternatively, the nucleophilic substitution of the acyl radical on the electron-deficient pyrrole radical cation is proposed.

Full text of DOI:10.1021/acs.orglett.0c00041

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Letter
Aroylation of Electron-Rich Pyrroles under Minisci Reaction
Conditions
Joydev K. Laha,* Mandeep Kaur Hunjan, Shalakha Hegde, and Anjali Gupta
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ABSTRACT: The development of Minisci acylation on electron-rich pyrroles under silver-free neutral conditions has been reported
featuring the regioselective monoacylation of (NH)-free pyrroles. Unlike conventional Minisci conditions, the avoidance of any acid
that could result in the polymerization of pyrroles was the key to success. The umpolung reactivity of the nucleophilic acyl radical,
generated in situ from arylglyoxylic acid, could help explain the mechanism of product formation with electron-rich pyrroles.
Alternatively, the nucleophilic substitution of the acyl radical on the electron-deficient pyrrole radical cation is proposed.
Scheme 1. Minisci Acylation of Electron-Deficient and
Electron-Rich Arenes
he decarboxylative acylation of the electron-deficient
1
Theterocycle using arylglyoxylic acid in the presence of a
silver(I) catalyst and persulfate under acidic conditions,
pioneered by Minisci,2 is commonly referred to as Minisci
acylation.3 The innate capacity of the nucleophilic acyl radical4
to react with an activated heterocycle renders the Minisci
acylation mechanistically very distinct from Friedel−Crafts
acylation5 wherein aromatic electrophilic substitution occurs.
Modern methods of acylation capitalizing on the use of
aromatic aldehydes, hydroxymethyl arenes, or even methyl
arenes as acylating agents and an oxidant, often described as
Minisci-type acylation, have been found to be quite resourceful
for acylating electron-deficient arenes.6 Perhaps most im-
portantly, Minisci acylation has never been demonstrated with
electron-rich arenes. In the current portfolio, whether Minisci
acylation could be implemented with electron-rich arenes
remains a question (Scheme 1).
Pyrrole and its substituted derivatives are important five-
membered heterocycles present in natural pigments and
pharmaceuticals such as tolmetin, atorvastatin, and ketorolac,
displaying a broad spectrum of pharmaceutical and biological
implications.7
In particular, 2-aroylpyrroles possess diverse activities
including use as building blocks, a core skeleton of simple
and complex structural organic architectures, and use in
material sciences.8
of mono- and diacylated products and often a mixture of
regioisomers, causing difficulty in isolation and a reduced yield
of 2-aroylpyrrole and the extensive polymerization of pyrroles
under acidic conditions. Remarkably, some of these limitations
have been overcome using a catalytic amount of Lewis acid
10a
AlPW12O40
and using protected pyrroles such as N-p-
With pyrrole being an electron-rich heteroarene, Friedel−
Crafts acylation happens to be a benchmark for the preparation
of 2-aroylpyrroles from pyrroles.9 Whereas the general
limitations of this method include the use of acyl halide, a
stoichiometric amount of Lewis acid, and strongly acidic
conditions, the practical difficulties may include the formation
Received: January 4, 2020
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© XXXX American Chemical Society
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A

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a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant (equiv)
additive
solvent
temperature
yield (%)
c
1
TBHP (4−8)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (2)
K2S2O8 (1)
K2S2O8 (2)
TBAI
AgNO3, H2SO4
AgNO3
DCE
90−100 °C
80 °C
80 °C
rt
80 °C
80 °C
80 °C
rt
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
00
40
85
00
91
91
60
<10
0
45
80
54
73
00
d
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
e
3
e
4
AgNO3
5
6
7
8
9
10
11
12
13
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
Na2S2O8 (2)
K2S2O8 (2)
DCE
MeOH
MeCN
MeCN
f
14
TEMPO
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), oxidant (2−8 equiv), additive (10−20 mol %), solvent (2 mL), temp/time 80 °C/6 h.
b
c
d
Isolated yield (%). Using substrates 1a, 1b, and 1c (0.5 mmol), TBHP (4 equiv), and TBAI (10 mol %). AgNO3 (15 mol %) and H2SO4 (1
e
f
equiv). AgNO3 (15 mol %). TEMPO (4 equiv).
toluenesulfonylpyrrole,10b 1,5-diazabicyclo[4.3.0]non-5-ene
(DBN) as a nucleophilic catalyst,10c ultrasonic-assisted
phosphoric-acid-modified zeolite,10d and hexafluoroisopropa-
nol (HFIP) as a solvent.10e Several other significant methods
describing the synthesis of 2-benzoylpyrroles include the
Vilsmeier−Haack aroylation of pyrroles,11a the reaction of 2-
lithio-SEM pyrrole with benzoyl halides,11b the use of N-
acylbenzotriazoles,11c carboxylic acids and trifluoroacetic
anhydride,11d and benzaldehydes11e as alternate acyl sources,
the Cu(OTf)2-catalyzed synthesis of substituted pyrroles from
α-diazoketones,11f and the palladium-catalyzed carbopallada-
tion of nitriles.11g Nevertheless, the previously reported
methods have their own identity and various degrees of
deliverability in the preparation of 2-aroylpyrroles. However, to
the best of our knowledge, no reports are available for the
acylation of pyrroles either by modern methods of oxidative
acylation or by Minisci acylation. While designing the
conditions for the Minisci acylation of pyrroles, a primary
question was how to react the nucleophilic acyl radical with the
electron-rich pyrrole. We envisaged that the umpolung
reactivity of any of these reactant partners could help facilitate
the reaction. It was pertinent to consider any reaction
parameter that could promote the reaction. Although acidic
conditions are essential for the activation of electron-deficient
heterocycles under Minisci acylation, the avoidance of acidic
conditions was necessary for the acylation of pyrroles, largely
to avoid polymerization under acidic conditions.
advancement of Minisci acylation on electron-rich heteroarene
substrates that were otherwise previously unexplored. The
distinguishable features of the protocol include regioselective
monoacylation, a broad substrate scope of pyrroles, especially
(NH)-free pyrroles, and other electron-rich heterocycles, such
as indoles, thiophene, and benzothiazole. A key to the success
of the product formation was to realize the umpolung reactivity
of the acyl radical or pyrroles.
To test the hypothesis that the nucleophilic acyl radical
would react slowly with electron-rich pyrroles in Minisci-type
acylations, an acylation of pyrroles employing acylating agents
such as benzaldehyde 1a, benzylalcohol 1b, or toluene 1c was
performed under oxidative conditions (tert-butyl hydroper-
oxide (TBHP) (4−8 equiv), tetrabutylammonium iodide
(TBAI) (10−20 mol %), 1,2-dichloroethane (DCE), 90−100
°C, 24 h). However, 2-benzoylpyrrole 3 did not form in these
reactions (Table 1, entry 1). Replacing the acylating agent with
phenylglyoxylic acid 1 and reacting with pyrrole 2 under
classical Minisci conditions in the presence of catalytic AgNO3
and H2SO4 at 80 °C gave 3, albeit in low yield (entry 2).
Eliminating H2SO4 in the reaction improved the yield of 3
significantly (entry 3). Therefore, acidic conditions may have a
deleterious effect on the reaction. However, the reaction did
not proceed when carried out at room temperature (entry 4).
Thus heating a reaction of 2 and 1 in the presence of K2S2O8
in MeCN, however, excluding catalytic AgNO3 and H2SO4,
resulted in the formation of 3 with an isolated yield 91% (entry
5). Decreasing the stoichiometric amount of oxidant from 3
equiv to 2 equiv gave a comparative yield (entry 6). However,
a further decrease to 1 equiv reduced the yield significantly
(entry 7). Reducing the temperature from 80 °C to room
temperature had a deleterious effect, suggesting that persulfate
activation is prohibited (entry 8).
Previously, we demonstrated the intramolecular acylation of
2-arylpyridines via multiple C−H functionalizations of a 3-
methyl, hydroxymethyl, or aldehyde group as a latent acylating
agent to synthesize various substituted azafluorenones.12
Recently, we demonstrated the intramolecular Minisci
acylation of arylpyridines under silver-free neutral conditions
to the synthesis of azafluorenones.13 Herein we describe the
decarboxylative acylation of electron-rich pyrroles using
arylglyoxylic acids as acylating agents under silver-free, acid-
free neutral conditions. The protocol represents a fine
There was no product formation in the absence of K2S2O8,
explaining the importance of persulfate in the reaction (entry
9). A solvent other than MeCN exerted varied yields of the
product (entry 10−12). Changing the oxidant from K2S2O8 to
B
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Na2S2O8 resulted in a reduced yield of the product, probably
due to the low solubility of Na2S2O8 in MeCN (entry 13).
When the reaction was performed in the presence of a radical
scavenger TEMPO, the formation of product 3 was markedly
suppressed, suggesting that a free-radical intermediate was
involved in the reaction (entry 14). Unlike conventional
Minisci conditions, the optimized conditions use silver-free
neutral conditions to achieve the success.
Scheme 3. Substrate Scope for the Synthesis of Substituted
2-Aroylpyrroles
To demonstrate the general relevance of our protocol to the
synthesis of different 2-aroylpyrroles, we next investigated the
reactions of pyrrole and different arylglyoxylic acids under the
optimized conditions (Scheme 2). Whereas arylglyoxylic acid
Scheme 2. Substrate Scope for the Synthesis of 2-
Aroylpyrroles
and 48) under the optimized conditions. Various other
attempts including performing the reaction at a higher
temperature (110 °C) or the addition of a catalytic amount
of AgNO3 (20 mol %) or Cu(OAc)2 (20 mol %) under the
optimized conditions did not provide the respective aroylated
product with 33, 34, and 36. Interestingly, 4-bromo derivatives
of 2-acetylpyrrole and 2-trichloroacetylpyrrole afforded the
benzoylated products 47 and 49 in 92 and 80% yield,
respectively. This suggests that the presence of a bromo group
on 2-acetyl and 2-trichloroacetylpyrrole made these substrates
vulnerable for acylation under the optimized conditions, which
requires further investigation. Subsequent to the exploration of
various pyrroles, the other electron-rich heterocycles were
investigated. The reaction was well tolerated by 2-bromothio-
phene and benzothiazole, and the yields of the corresponding
products were good to excellent (50 and 51). Similarly, 2-
methylindole and 3-methylindole worked well under the
optimized conditions affording aroylated products 52 and 53
in 75 and 81% yield, respectively. However, furan derivatives,
such as 2-methylfuran and 2-acetylfuran used in this study
largely remained unreacted under the optimized conditions.
Whereas the formation of any aroylated product was not
observed when benzo[b]thiophene was used as the substrate, a
dimer of benzo[b]thiophene formed under the optimized
conditions. Notably, our optimized conditions feature silver
and acid-free conditions, unlike those conventionally used in
Minisci acylation.
with an electron-donating group at the o-position yielded 17 in
93% yield, arylglyoxylic acid with an electron-withdrawing
group at the o-position (e.g., Cl, Br, F, or CF3) also delivered
the products 18−21 in 76−87% yield. The arylglyoxylic acid
containing an electron-donating group at the m-position also
gave the desired product 22 in 91% yield.
Both electron-withdrawing and electron-donating substitu-
tions at the p-position of arylglyoxylic acid were also tolerated
under the optimized conditions and yielded 2-aroylpyrroles
23−28 in 80−95% yields. A disubstituted arylglyoxylic acid, 2-
(3,4-dimethoxyphenyl)-2-oxoacetic acid, was also a viable
substrate, resulting in the desired acylated product 29 in
68% yield.
Then, we investigated the scope of substituted pyrroles with
different arylglyoxylic acids under our optimized conditions
(Scheme 3). Different arylglyoxylic acids such as 2-(furan-2-
yl)-2-oxoacetic acid and 2-oxo-2-(thiophen-2-yl)acetic acid
worked, successfully affording the desired 2-acylated pyrroles
42 and 43 in 80−91% yield. The reaction of N-methylpyrrole
with 1 delivered 2-benzoyl-N-methylpyrrole 44 in 81% yield.
When N-tosylpyrrole 33 was reacted with phenylglyoxylic acid
under the optimized conditions, no product formation was
observed. Likewise, 2-acetylpyrrole 34 and 2-trichloroacetyl-
pyrrole 36 also did not yield the corresponding products (46
The possible reaction pathways are shown in Scheme 4.
Initially, the homolytic cleavage of K2S2O8 under thermal
conditions could generate a sulfate radical anion (SO4•−),
which upon reaction with 1 could produce acyl radical 54 via
decarboxylation.13 The formation of benzoylated product 3
could occur via two pathways.
The acylium ion 5514 could form from acyl radical 54, which
upon electrophilic substitution with pyrrole 2 could form 3. In
pathway 2, the sulfate radical anion (SO4•−) can capture one
electron from pyrrole 2, resulting in pyrrole radical cation 2*,15
which on reaction with nucleophilic acyl radical 54 could
generate adduct 3*. The intermediate 3* on deprotonation
could yield 2-benzoylpyrrole 3.
C
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experiments suggest that just the generation of the acyl radical
was not the only way to the product formation. Changing the
nucleophilic acyl radical to an electron-deficient species,
acylium ion, or a similar electrophilic species could possibly
lead to the product formation.
Scheme 4. Plausible Reaction Mechanism
In pathway 2, a comparison of redox potentials of N-
methylpyrrole 32 and sulfate radical anion (SO4•−) was
considered. Whereas the oxidation potential of N-methyl-
pyrrole 32 is reported to be 1.20 V,15h the redox potential of
17
•−
•−
SO4 is 2.43 V. Therefore, SO4 can readily oxidize 32 to
N-methylpyrrole radical cation 32*, making it an electron-
deficient species, similar to that reported with other hetero-
cycles (Scheme 6, panel a).18
Scheme 6. Control Experiments in Favor of Pathway 2
To gain confidence in the mechanistic pathways, we carried
out some control experiments. From the inhibition effect of
TEMPO under the optimized conditions, it was apparent that
the reaction involved a radical as a reactive intermediate.
Furthermore, the generation of acyl radical 54 was confirmed
by trapping a TEMPO adduct 56 (Scheme 5, panel a).
Scheme 5. Control Experiments in Favor of Pathway 1
To further support the formation of 32*, we exposed 32 to
the optimized conditions in the absence of 1. A mass peak at
m/z 132.87 (see the Supporting Information) corresponding
to bipyrrole 58 was observed. In the absence of any other
reactant partner, 32* could undergo dimerization or even
polymerization.15f Thus the reaction of electron-deficient 32*
and the nucleophilic acyl radical 54 could explain the product
formation.19 However, any other pathway not discussed here is
not ruled out. On the basis of the control experiments, it is
difficult to predict whether one pathway or both pathways are
operating simultaneously. Nonetheless, the umpolung reac-
tivity of the acyl radical and the aromatic nucleophilic
substitution on pyrroles are the subjects of intensive research.
To demonstrate a translational application of our laboratory
concept, we prepared a major intermediate 59 of a marketed
NSAID drug, Tolmetin (Tolectin), by reacting N-methyl-
pyrrole 32 and 4-methylphenylglyoxylic acid 14 under the
optimized conditions, which upon subsequent functionaliza-
tion could give the drug (Scheme 7).20
In conclusion, Minisci acylation of electron-rich arenes,
which is otherwise conceptually forbidden, has successfully
been developed by exploring pyrroles and indoles as electron-
rich substrates. Unlike the Friedel−Crafts reaction largely
reported for acylations of pyrroles, the current study describing
the acylation of pyrroles using arylglyoxylic acids under silver-
free neutral conditions happens to be the first report of the
Minisci acylation of pyrroles. Whereas any comparison of the
two methods was not the objective, the motivation of this
study was to demonstrate Minisci acylation on electron-rich
Electron-deficient pyrroles such as 33, 34, and 36 were also
found to be ineffective toward the product formation (panel
b). The reactions of 2 and benzaldehyde 1a, benzylalcohol 1b,
or toluene 1c in the presence of TBHP did not give 3,
although benzil 5716 was obtained in this reaction (panel c).
This indicates that the nucleophilic acyl radical does not react
with electron-rich pyrroles.
Finally, 1 was exposed to the optimized conditions in the
absence of 2. The mass of the reaction mixture was analyzed
after 1 and 2 h. Whereas no mass peak due to 1 was observed,
a peak at m/z 105 (M) (see the Supporting Information) was
observed, suggesting the formation of the acyl cation14 55 in
the reaction (panel d). On the basis of these limited
experiments, pathway 1 may be validated wherein the
umpolung reactivity of acyl radical is reflected. These
D
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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.0c00041.
■
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Experimental procedures, characterization data of new
compounds, and copies of H and 13C NMR spectra
1
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Joydev K. Laha − Department of Pharmaceutical Technology
(Process Chemistry), National Institute of Pharmaceutical
Education and Research, S. A. S. Nagar, Punjab 160062,
India; orcid.org/0000-0003-0481-5891; Email: jlaha@
niper.ac.in
Authors
Mandeep Kaur Hunjan − Department of Pharmaceutical
Technology (Process Chemistry), National Institute of
Pharmaceutical Education and Research, S. A. S. Nagar,
Punjab 160062, India
Shalakha Hegde − Department of Pharmaceutical Technology
(Process Chemistry), National Institute of Pharmaceutical
Education and Research, S. A. S. Nagar, Punjab 160062, India
Anjali Gupta − Department of Pharmaceutical Technology
(Process Chemistry), National Institute of Pharmaceutical
Education and Research, S. A. S. Nagar, Punjab 160062, India
(9) Sartori, G.; Maggi, R. Advances in Friedel-Crafts Acylation
Reactions: Catalytic and Green Processes; CRC Press, 2017.
(10) (a) Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Aluminum
dodecatungstophosphate (AlPW12O40) as a non-hygroscopic Lewis
acid catalyst for the efficient Friedel−Crafts acylation of aromatic
compounds under solvent-less conditions. Tetrahedron 2004, 60,
10843−10850. (b) Huffman, J. W.; Smith, V. J.; Padgett, L. W.
Acylation of N-p-toluenesulfonylpyrrole under Friedel−Crafts con-
ditions: evidence for organoaluminum intermediates. Tetrahedron
2008, 64, 2104−2112. (c) Taylor, J. E.; Jones, M. D.; Williams, J. M.;
Bull, S. D. Friedel−Crafts Acylation of Pyrroles and Indoles using 1,5-
Diazabicyclo[4.3.0]non-5-ene (DBN) as a Nucleophilic Catalyst. Org.
Lett. 2010, 12, 5740−5743. (d) Bai, G. Y.; Yang, Y. H.; Ma, Z.; Xu, J.
Z.; De Qiu, M.; He, F.; Yan, X. L.; Dou, H. Y. Friedel−Crafts
acylation of pyrrole over ultrasonic-assisted phosphoric acid-modified
Hβ zeolite. Res. Chem. Intermed. 2012, 38, 795−806. (e) Vekariya, R.
H.; Aube, J. Hexafluoro-2-propanol-promoted intermolecular Frie-
del−Crafts acylation reaction. Org. Lett. 2016, 18, 3534−3537.
(11) (a) White, J.; McGillivray, G. The Vilsmeier-Haack aroylation
of pyrroles reexamined. J. Org. Chem. 1977, 42, 4248−4251.
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly appreciate Prof. Eric M. Ferreira (University of
Georgia) for insightful suggestions to help improve the
manuscript. The generous funding from the CSIR New
Delhi is greatly acknowledged. M.K.H. thanks the NIPER S.
A. S. Nagar for a research fellowship. This manuscript is
dedicated to Prof. Ganesh Pandey on the occasion of his 65th
birthday.
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