Application of Polyphosphoric Acid-Mediated Acyl Migration for Regiospecific Synthesis of Diverse 2-Acylpyrroles from Chalcones

Article abstract of DOI:10.1002/jhet.3494

A metal-free approach for the synthesis of 2-acylpyrroles is reported in this paper. Synthesis of the target molecule started from chalcones and was carried out in two steps. Initial step involved the conversion of chalcones to corresponding 4-substituted-3-acylpyrroles by reaction with TosMIC. In the subsequent step, target molecules were obtained in modest to good yields by polyphosphoric acid-mediated acyl rearrangement of 3-acylpyrroles to their 2-acyl congeners. The crucial final step was amenable to diverse substitutions on pyrrole ring. Preliminary experiment for the determination of mechanism indicated the involvement of acylium ion.

Full text of DOI:10.1002/jhet.3494

Month 2019
Application of Polyphosphoric Acid-Mediated Acyl Migration for
Regiospecific Synthesis of Diverse 2-Acylpyrroles from Chalcones
*
Togiti Uday Kumar, Yadagiri Thigulla, Krishnan Rangan, and Anupam Bhattacharya
Department of Chemistry, Birla Institute of Technology and Science, Pilani (Hyderabad Campus), Hyderabad 500078,
India
*E-mail: anupam@hyderabad.bits-pilani.ac.in
Received September 21, 2018
DOI 10.1002/jhet.3494
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A metal-free approach for the synthesis of 2-acylpyrroles is reported in this paper. Synthesis of the target
molecule started from chalcones and was carried out in two steps. Initial step involved the conversion of
chalcones to corresponding 4-substituted-3-acylpyrroles by reaction with TosMIC. In the subsequent step,
target molecules were obtained in modest to good yields by polyphosphoric acid-mediated acyl rearrange-
ment of 3-acylpyrroles to their 2-acyl congeners. The crucial final step was amenable to diverse substitutions
on pyrrole ring. Preliminary experiment for the determination of mechanism indicated the involvement of
acylium ion.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
of diverse acyl fluoranthene compounds [8]. The reported
reactions were carried out in polyphosphoric acid (PPA)
at various temperatures and resulted in the regioselective
formation of the target molecules. Several other types of
acyl rearrangement reactions are also known, which
include base-induced Baker-Venkataraman and acid-
catalyzed Fries rearrangements. Yu et al. reported the
synthesis of multi-functionalized chromeno[2,3-c]pyrrol-
9(2H)-ones from 1,3-diaryl-1,3-diketones and amino acids
2-Acylpyrroles on their own or as part of a larger
framework are known for a multitude of biological/
biomedical properties ranging from non-steroidal anti-
inflammatory drugs, antibiotics, to anticancer compounds
[1–5]. Some important examples of this type of
compounds include tolmetin, ketorolac, pyoluteorin,
calcimycin, and diverse marinopyrroles (Fig. 1).
Acyl migrations within the molecular framework
represent an important organic transformation used in
multitude of synthetic strategies. Zamir et al. in a paper
reported acid-catalyzed acyl rearrangement on a taxane,
using
4-(dimethylamino)pyridine-catalyzed
Baker–
Venkataraman rearrangement as a key step [9]. Similar
acyl migration was used by Fougerousse et al. for the
synthesis of dibenzoylmethanes [10]. Fries rearrangement
was used by Jeon and Magnion for the synthesis of
hydroxyl aryl ketones using methanesulfonic acid and
methanesulfonic anhydride [11]. Maeda et al. reported
application of photo Fries rearrangement on pyrenyl
esters [12]. Reported reaction was amenable to the
presence of electron releasing/withdrawing groups as well
9-dihydro-13-acetylbaccatin-III
[6].
Ashfield
and
co-workers applied the chemoselective O-acyl to N-acyl
migration in the Staudinger ligation for the synthesis of
diverse amides [7]. In a paper by Arganat and co-workers,
Friedel-Crafts acyl rearrangement, which is primarily a C-
acyl to C-acyl migration, has been used for the synthesis
© 2019 Wiley Periodicals, Inc.

T. U. Kumar, Y. Thigulla, K. Rangan, and A. Bhattacharya
Vol 000
Figure 1. Examples of biologically active 2-acylpyrrole compounds.
as diverse heteroaromatic carboxylates. Base-promoted
C → N acyl migration was used by Vicario and
co-workers for the synthesis of nonproteinogenic tertiary
and quaternary N-alkyl α-amino acids [13]. In a recent
work by Kong et al., indolo[3,2-c]quinolinones were
synthesized via a Pd/Cu catalyzed 1,2-acyl migration,
starting from indole-2-carboxamides [14]. The methods
reported thus clearly demonstrate the applicability of acyl
rearrangement in diverse synthetic routes.
However, acyl rearrangement has been rarely used as a
method for the preparation of 2-acylpyrroles. One of the
very first examples of acyl rearrangement on pyrrole
systems was reported by Palmer et al. in their attempt to
cyclize various 3-(2-pyrrolyl)propanoic acids [15]. It was
noticed that in the presence of PPA, the desired compound
performed using the stoichiometric amount of AlCl3 and
dry Et2O as a solvent in modest to good yields.
Based on the previous reports, we initiated studies on
synthesis of diverse 4-substituted-2-acylpyrroles using
rarely implemented acyl rearrangement. The simplicity of
such a transformation and the possibility of introducing
acyl group by avoiding unselective Friedel-Crafts/
Vilsmeier-Haack reactions was an added attraction. A
straightforward retrosynthetic strategy was conceived to
start our investigation in this domain (Scheme 1).
Compound 2 was envisaged as the substrate for the final
step leading to 3. Synthesis of compound 2 was supposed
to be carried out by reaction between easily accessible
chalcones (1) via van Leusen’s pyrrole synthesis [20–23].
4H-cyclopenta[b]pyrrole-4-ones
and
corresponding
pyrrole-6-ones were obtained. Acyl rearrangement on
pyrrole systems was also studied by Carson and Davis
[16]. In their work, rearrangement of N-alkyl-2-
acylpyrroles to corresponding N-alkyl-3-acylpyrroles was
noticed in the presence of anhydrous trifluoroacetic acid.
However, 2-acylpyrroles or 3-acylpyrroles bearing
hydrogen on nitrogen resulted in an equilibrium mixture
of both the acylated pyrroles, with their ratio dependent on
the nature of the reaction medium. Dellemagne et al. in a
separate paper has explored trifluoroacetic acid mediated
synthesis 1-phenylpyrrole-3-carboxaldehydes from their
2-isomers using dichloroethane as a solvent [17]. The final
products were obtained in good yields with very high
regioselectivity. Acyl rearrangement of 2-acylpyrroles to
their C-3 isomers was also noticed by Pina et al. in their
attempt to carryout acylation of 1-nitrophenyl pyrroles,
using acid anhydrides in the presence of catalytic amount
of orthophosphoric acid [18]. Interestingly, most of the
examples show rearrangement of 2-acyl systems to their
3-acyl congeners, and very few papers have highlighted
the reverse process. Jefford and co-workers have reported
the synthesis of 2-acylpyrroles by intramolecular delivery
of acylium ion from their N-substituted mixed anhydrides
to C-2 position of pyrroles [19]. These reactions were
RESULTS AND DISCUSSION
Our initial synthetic efforts started from chalcones,
which were converted to corresponding di-substituted
pyrroles by reaction with well-known isonitrile source
TosMIC in the presence of potassium tert-butoxide and
DMSO as solvent at 25°C for 0.5 h. After fully
characterizing the products, we embarked on a screening
program to identify the most appropriate condition for
their conversion to the target molecules (Table 1). For
this purpose, phenyl(4-phenyl-1H-pyrrol-3-yl)methanone
(2a) was chosen as the model substrate. As 1,2-acyl
shift/migration was the desired goal of this work, choice
of reaction conditions was based on Fries and other 1,2-
acyl rearrangements reported in literature [8,11,24–27].
Thus, reactions were attempted with Lewis acids such as
AlCl3, ZnCl2, and FeCl3 (Entries 1–3). While no
Scheme 1. Retrosynthetic analysis of the target molecules.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Application of Polyphosphoric Acid-Mediated Acyl Migration for Regiospecific
Synthesis of Diverse 2-Acylpyrroles from Chalcones
Table 1
Screening of reaction conditions for acyl migration.
Entry
Acid (20 mol%)
Solvent
Temp. (°C)
Yield (%)b
1
2
3
4
AlCl3
ZnCl2
FeCl3
1,2-DCB
1,2-DCB
1,2-DCB
DCM
140
140
140
40
NR
NR
66
FeCl3
20
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
THF
60
NR
NR
28
1,4-dioxane
PhNO2
Ph2O
1,2-DCE
-
110
140
140
85
120
140
140
80
140
60
60
140
110
110
48
9
FeCl3
NR
NR
NR
NR
NR
34
NR
NR
NR
73
10
11
12
13
14
15
16
17
18a
19
CH3COOH
CH3COOH
CH3COOH
H3PO4
H3PO4
CF3SO3H
HCl
1,2-DCB
THF
-
1,2-DCB
THF
THF
1,2-DCB
-
PEG-400
PPA
PPA
PPA
NR
All the reactions were carried out for 12 h.
aComplete conversion was noticed in 30 min.
bIsolated yield. NR, no reaction.
conversion was noticed in case of AlCl3 and ZnCl2, FeCl3
gave the target molecule in 66% yield. The purified
1
product was thoroughly characterized by H NMR and
13C NMR, prior to further optimization of reaction
1
conditions. H NMR of compound 3a revealed downfield
shift of NH peak to 12.25 ppm from 11.64 ppm in 2a,
which indicated the presence of an electron-withdrawing
group on the adjacent carbon. Additionally,
disappearance of C─H peak at position 2 and presence of
a proton at carbon-3 indicates rearrangement of acyl
group to the second position of pyrrole. 13C NMR further
substantiated the proof for acyl rearrangement as
carbonyl peak underwent a 6.5 ppm downfield shift to
184.2 ppm. Single crystal X-ray crystallography further
ascertained the structure of compound 3a (CCDC number
1859629) as shown in Figure 2. The pyrrole ring and
phenyl ring substituted to the pyrrole ring are almost
coplanar with dihedral angle C11-C10-C12-C13 = 0.36°
only. The phenyl ring plane, which is attached to the
carbonyl group, is deviating 40.83° from the pyrrole ring
plane. The molecules form a hydrogen-bonded dimer
with pyrrole N─H as donor and the carbonyl oxygen
atom as acceptor with N─H … O non-covalent hydrogen
Figure 2. The ORTEP diagram of compound 3a. The thermal ellipsoids
are drawn with the 50% probability level. [Color figure can be viewed
at wileyonlinelibrary.com]
bond length and D─H─A bond angle of 2.03 Å and
155.3° respectively.
Our initial success with FeCl3 using 1,2-DCB as solvent
prompted us to explore reactions with different solvents
and reaction temperatures (Entries 4–9). While product
formation was observed with DCM, PhNO2, and Ph2O,
the yields obtained were lower compared with initial
attempt with FeCl3. Further screenings were carried out
with Brönsted acids (Entries 10–19). Here, reaction was
successful only with H3PO4 and PPA (neat), with
PPA-mediated reaction giving the highest yield of 73%.
Interestingly, when 1,2-DCB or PEG-400 were used as
solvents in reactions involving PPA, no product
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. U. Kumar, Y. Thigulla, K. Rangan, and A. Bhattacharya
Vol 000
formation was noticed. Based on the previous results, we
established the use of PPA (neat) at 110°C for 0.5 h as
the best condition for the formation of 2-acylpyrrole (3a)
from 3-acylpyrrole (2a).
52%, respectively) were recorded (3p–q). Applying the
established conditions on naphthalen-2-yl(4-phenyl-1H-
pyrrol-3-yl)methanone (2r) resulted in synthesis of the
corresponding 2-acyl system (3r) in 55% yield. With 2-/
3-thieno and 2-pyrido acyl systems (2s–w), rearranged
products were obtained in 15–82% yields. Interestingly,
with 3-acylthieno systems, only 2-acylpyrrole product
was obtained and possible 2-acylthieno rearranged
product was not seen. This result clearly demonstrates
suitability of the method and its regiospecificity while
generating rearranged 2-acylpyrrole product, even if
corresponding C-2 positions are available in thiophene
systems. Low yield in case of compound 3w indicates
destabilization of putative acyl carbocation, which is
likely to form in the reaction. Similar observation is also
noticed in case of compound 3p containing p-fluoro
substituent.
Based on the results obtained in the previous studies, an
experiment was also conducted to understand the
mechanism of acyl migration. Previous literature
examples from pyrrole and indole systems have
speculated formation of an acylium ion as well as internal
transfer of acyl group [15,28]. Reaction was carried out
on phenyl(4-phenyl-1H-pyrrol-3-yl)methanone in the
presence of anisole, with 1:1 ratio of both the substrates.
On completion, the reaction mixture was analyzed by ESI
mass spectroscopy, which indicated formation of
(2-methoxyphenyl)(phenyl)methanone/(4-methoxyphenyl)
(phenyl)methanone [M + H+ = 213] along with compound
3a [M + H+ = 248] (ESI). Based on this observation, a
plausible mechanism has been proposed for the reaction
With the optimized conditions in hand, assortments of
4-substituted-3-acylpyrroles were used to explore the
substrate scope of the reaction (Table 2). Reactions were
initially attempted by varying the substituents at the fourth
position of 3-benzoylpyrrole (2a–g). While all the
aforementioned substrates were compatible, comparatively
better yield was obtained with p-tolyl substituent.
Substrate 2d bearing p-nitrophenyl substituent provided
the desired product in 53% yield. With mono/di-
halogenated halogen phenyl substituents (2e–g), final
products could be obtained in modest to good yields.
Subsequent studies were conducted on 3-acylpyrroles
bearing bi-phenyl, anthracen-9-yl, and methyl as
substituents (2h–j). In these studies, an inverse
relationship was shown between the size of the substituent
and the yield of the reaction. N-Substituted systems (2k–l)
on the other hand gave modest yield, indicating steric
hindrance posed by the presence of substituent on pyrrole
nitrogen.
Further studies were carried out to ascertain the effect of
acyl groups on the feasibility/yield of the reaction (2m–w).
Substrates with diverse benzoyl substituents indicated
possible involvement of acyl carbocation in the reaction,
as relatively high yields were seen with molecules bearing
methyl and methoxy/di-methoxy groups as substituents
(3m–o). In case of p-fluoro and p-chloro substituted
benzoyl systems, comparatively low yields (25% and
Table 2
Synthesis of diverse 2-acylpyrroles.
3a R = Ph; R’ = Ph; R" = H; 73%
3m R = (p-CH3)Ph; R’ = Ph; R" = H; 64%
3b R = Ph; R’ = (p-CH3)Ph; R" = H; 74%
3c R = Ph; R’ = (p-OCH3)Ph; R" = H; 37%
3d R = Ph; R’ = (p-NO2)Ph; R" = H; 53%
3e R = Ph; R’ = (p-F)Ph; R" = H; 55%
3f R = Ph; R’ = (o, p-Cl, Cl)Ph; R" = H; 65%
3g R = Ph; R’ = (o, p-Cl, F)Ph; R" = H; 60%
3h R = Ph; R’ = (p-Ph)Ph; R" = H; 65%
3i R = Ph; R’ = anthracen-9-yl; R" = H; 22%
3j R = CH3; R’ = Ph; R" = H; 73%
3n R = (p-OCH3)Ph; R’ = Ph; R" = H; 53%
3o R = (m, p-OCH3, OCH3)Ph; R’ = Ph; R" = H; 63%
3p R = (p-F)Ph; R’ = Ph; R" = H; 25%
3q R = (p-Cl)Ph; R’ = Ph; R" = H; 52%
3r R = naphthalen-2-yl; R’ = Ph; R" = H; 55%
3s R = thiophen-2-yl; R’ = Ph; R" = H; 77%
3t R = thiophen-2-yl; R’ = (p-OCH3)Ph; R" = H; 45%
3u R = thiophen-2-yl; R’ = (o, p-Cl, Cl)Ph; R" = H; 82%
3v R = thiophen-3-yl; R’ = Ph; R" = H; 79%
3w R = pyridine-2-yl; R’ = Ph; R" = H; 15%
3k R = Ph; R’ = Ph; R" = CH3; 35%
3l R = Ph; R’ = Ph; R" = CH2Ph; 40%
All the reactions were carried out for 30 min.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Application of Polyphosphoric Acid-Mediated Acyl Migration for Regiospecific
Synthesis of Diverse 2-Acylpyrroles from Chalcones
Scheme 2. Plausible mechanism for the conversion of 3-acylpyrrole to 2-
acylpyrrole.
performed using CrysAlis PRO on a single crystal Rigaku
Oxford XtaLab Pro diffractometer.
General procedure for the synthesis of compounds
(3a–3w). To a 25 mL round bottom flask equipped with
a stir bar was added appropriate 3,4-disubstituted pyrrole
(0.5 mM) and PPA (2 mL). The reaction mixture was
then allowed to stir for 30 min at 110°C under nitrogen
atmosphere. It was subsequently cooled to room
temperature and stirred with water (10 mL) for 30 min.
The aqueous solution thus obtained was extracted with
ethyl acetate (3 × 10 mL), and the ensuing organic layer
was successively washed with brine and dried over
anhydrous Na2SO4. Finally, the dried organic layer was
concentrated under reduced pressure, and the residue
obtained was purified by column chromatography.
(Scheme 2). It is felt that protonation of carbon bearing the
acyl group is the first step of this rearrangement, followed
by cleavage of acyl group from pyrrole ring. Given the
natural tendency of pyrrole ring to undergo electrophilic
substitution reaction at the second position, the final step
of this mechanism involves the reaction of acylium cation
at the aforementioned position.
Phenyl(4-phenyl-1H-pyrrol-2-yl)methanone (3a).
Yield:
73%; white solid; mp 148–154°C; Rf 0.3 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3264, 1609, 1600,
1560, 1059; 1H NMR (400 MHz, DMSO-d6):
δ
7.16–7.21 (m, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.54–7.59
(m, 2H), 7.62–7.68 (m, 3H), 7.73 (dd, J = 3.1, 1.6 Hz,
1H), 7.88–7.91 (m, 2H), 12.25 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 116.1, 124.0, 125.4, 126.2,
126.4, 128.9, 129.1, 131.7, 132.2, 134.8, 138.8, 184.2;
CONCLUSION
ESI-MS (m/z): 248.0 [M + H]+.
In conclusion, we have developed a simple strategy for
the synthesis of diverse 2-acylpyrroles. Target molecules
were synthesized in two steps, starting from easily
accessible chalcones. Well-established van Leusen’s
pyrrole synthesis was used to perform the first step,
whereas the final step involved application of seldom
used acid-catalyzed acyl migration. The PPA-assisted
method developed for the final step gave the desired
products in modest to good yields and could be applied to
diverse substituted pyrrole systems. The regiospecificity
of the method towards C-2 position of pyrrole is
demonstrated even when corresponding positions were
available in activated phenyl and thiophene systems. A
preliminary mechanistic study was also performed, which
indicated involvement of acylium ion in generating the
rearranged product.
Phenyl(4-(p-tolyl)-1H-pyrrol-2-yl)methanone (3b). Yield:
74%; white solid; mp 152–158°C; Rf 0.4 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3262, 1623, 1571,
1
1146, 807; H NMR (400 MHz, DMSO-d6): δ 2.28 (s,
3H), 7.14 (dd, J = 4.8, 2.2 Hz, 3H), 7.56 (dd, J = 10.0,
7.9 Hz, 4H), 7.64 (t, J = 7.4 Hz, 1H), 7.69 (dd, J = 3.1,
1.5 Hz, 1H), 7.87–7.91 (m, 2H), 12.22 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 21.1, 115.9, 123.7, 125.3,
126.2, 128.9, 129.1, 129.7, 131.6, 131.9, 132.1, 135.4,
138.9, 184.1; ESI-MS (m/z): 262.0 [M + H]+.
4-(4-Methoxyphenyl)-1H-pyrrol-2-yl)(phenyl)methanone
(3c). Yield: 37%; white solid; mp 118–124°C; Rf = 0.4
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3269,
1
3012, 1614, 1562, 1147; H NMR (400 MHz, CDCl3): δ
3.82 (s, 3H), 6.91 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 7.36
(s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.49–7.54 (m, 2H),
7.59 (t, J = 7.4 Hz, 1H), 7.92–7.96 (m, 2H), 9.87 (s, 1H);
13C NMR (101 MHz, CDCl3): δ 55.3, 114.2, 116.1,
121.5, 126.5, 127.0, 127.2, 128.4, 128.9, 131.6, 131.9,
EXPERIMENTAL
138.3, 158.5, 184.8; ESI-MS (m/z): 278.0 [M + H]+.
(4-(4-Nitrophenyl)-1H-pyrrol-2-yl)(phenyl)methanone
(3d). Yield: 53%; yellow solid; mp 206–212°C; Rf 0.5
All the compounds and reagents required were
purchased from commercial sources and were used
without further purification. Solvents were dried and
[hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3264,
1
1
distilled using standard procedures, prior to use. H NMR
1504, 1627, 1111, 850; H NMR (400 MHz, DMSO-d6):
(300/400 MHz) and 13C NMR (75.5/101 MHz) spectra
were recorded in CDCl3 and DMSO using (CH3)4Si as
internal standard. IR spectra were recorded as KBr plates
on Jasco FT/IR-4200 instrument. Melting points were
recorded on a Biotech India melting point apparatus and
are uncorrected. Single-crystal X-ray studies were
δ 7.38 (dd, J = 2.4, 1.6 Hz, 1H), 7.58 (dd, J = 7.2,
6.1 Hz, 2H), 7.64–7.70 (m, 1H), 7.91 (t, J = 1.7 Hz, 1H),
7.92 (s, 1H), 7.95–7.98 (m, 1H), 7.99 (d, J = 2.1 Hz,
1H), 8.00 (dd, J = 3.3, 1.6 Hz, 1H), 8.17 (dd, J = 6.8,
4.7 Hz, 2H), 12.53 (s, 1H); 13C NMR (101 MHz,
DMSO-d6): δ 116.7, 124.0, 124.5, 125.8, 126.0, 129.0,
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T. U. Kumar, Y. Thigulla, K. Rangan, and A. Bhattacharya
Vol 000
129.2, 132.3, 132.4, 138.4, 142.0, 145.5, 184.4; HRMS-
(m, 4H), 7.47 (d, J = 1.6 Hz, 3H), 7.48–7.54 (m, 14H),
7.59 (ddd, J = 7.4, 3.9, 1.3 Hz, 3H), 7.93 (d, J = 1.5 Hz,
3H), 7.95 (d, J = 4.5 Hz, 6H), 7.98 (s, 3H), 8.11 (d,
J = 8.2 Hz, 6H), 8.60 (s, 3H), 12.59 (s, 3H); 13C NMR
(101 MHz, DMSO-d6): δ 121.1, 121.9, 125.7, 126.1,
126.6, 126.9, 127.8, 128.8, 128.9, 129.1, 130.5, 130.9,
131.4, 131.4, 132.2, 138.8, 184.2; HRMS-ESI (m/z):
ESI (m/z): Calcd for C17H12N2O3 [M + H]+ 293.0921
found 293.092.
(4-(4-Fluorophenyl)-1H-pyrrol-2-yl)(phenyl)methanone
(3e). Yield: 55%; white solid; mp 108–114°C; Rf 0.3
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3259,
1
1625, 1587, 1562, 1205, 1076, 896; H NMR (400 MHz,
Calcd for C25H17NO [M + H]+ 348.1383 found 348.1383.
DMSO-d6): δ 7.16 (dd, J = 11.1, 5.2 Hz, 3H), 7.56 (t,
J = 7.8 Hz, 2H), 7.64 (t, J = 6.8 Hz, 1H), 7.70 (dd,
J = 8.6, 5.1 Hz, 3H), 7.89 (d, J = 7.9 Hz, 2H), 12.25 (s,
1H); 13C NMR (101 MHz, DMSO-d6): δ 115.8, 116.1,
123.9, 125.2, 127.2, 128.9, 129.1, 131.4, 131.7, 132.2,
138.8, 161.2, 184.2; HRMS-ESI (m/z): Calcd for
C17H12FNO [M + H]+ 266.0976 found 266.0974.
(4-Methyl-1H-pyrrol-2-yl)(phenyl)methanone (3j). Yield:
73%; brown solid; white solid; mp 144–150°C; Rf 0.3
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3198,
1630, 1568, 1217, 938; 1H NMR (400 MHz,
CDCl3 + two drops of DMSO-d6): δ 2.48 (s, 3H), 7.18
(d, J = 9.6 Hz, 1H), 7.20–7.26 (m, 1H), 7.36 (dd,
J = 16.3, 8.6 Hz, 3H), 7.53 (t, J = 8.5 Hz, 2H), 10.71 (s,
1H); 13C NMR (101 MHz, CDCl3 + two drops of
DMSO-d6): δ 25.6, 113.8, 121.9, 125.2, 126.2, 126.5,
(4-(2,4-Dichlorophenyl)-1H-pyrrol-2-yl)(phenyl)methanone
(3f).
Yield: 65%; white solid; mp 92–98°C; Rf 0.4
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3264,
1736, 1626, 1561, 1294; 1H NMR (400 MHz,
DMSO-d6): δ 7.13–7.15 (m, 3H), 7.37 (dd, J = 8.4,
2.2 Hz, 3H), 7.54 (t, J = 7.4 Hz, 6H), 7.58–7.61 (m, 4H),
7.62 (d, J = 2.2 Hz, 3H), 7.66 (dd, J = 3.7, 2.1 Hz, 5H),
7.86–7.91 (m, 6H), 12.47 (s, 3H); 13C NMR (101 MHz,
DMSO-d6): δ 119.18, 121.87, 126.53, 127.94, 128.96,
129.14, 129.90, 131.03, 131.67, 131.87, 132.00, 132.34,
128.8, 132.8, 134.5, 188.1; ESI-MS (m/z): 186.0 [M + H]+.
(1-Methyl-4-phenyl-1H-pyrrol-2-yl)(phenyl)methanone
(3k).
Yield: 35%; yellow liquid; Rf 0.4 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3087, 1623, 1573,
1
1198, 723; H NMR (400 MHz, DMSO-d6): δ 4.00 (s,
3H), 7.03 (d, J = 1.9 Hz, 1H), 7.21–7.15 (m, 1H), 7.33
(t, J = 7.7 Hz, 2H), 7.55 (ddd, J = 8.1, 5.4, 1.1 Hz, 4H),
7.66–7.61 (m, 1H), 7.80 (dt, J = 3.8, 1.7 Hz, 3H); 13C
NMR (101 MHz, DMSO-d6): δ 37.5, 118.8, 123.6,
125.2, 126.4, 128.8, 129.2, 129.3, 129.9, 130.9, 132.1,
134.3, 139.7, 185.5; HRMS-ESI (m/z): Calcd for
C18H15NO [M + H]+ 262.1226 found 262.1229.
(1-Benzyl-4-phenyl-1H-pyrrol-2-yl)(phenyl)methanone
132.52, 138.65, 184.31; ESI-MS (m/z): 316.0 [M + H]+.
(4-(2-Chloro-4-fluorophenyl)-1H-pyrrol-2-yl)(phenyl)
methanone (3g). Yield: 60%; white solid; mp 106–120°C;
Rf 0.3 [hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1
:
3410, 1614, 1559, 1123, 893; 1H NMR (400 MHz,
DMSO-d6): δ 7.10 (dd, J = 2.4, 1.6 Hz, 1H), 7.23 (td,
J = 8.5, 2.7 Hz, 1H), 7.47 (dd, J = 8.9, 2.7 Hz, 1H), 7.55
(t, J = 7.4 Hz, 2H), 7.59–7.65 (m, 2H), 7.65–7.70 (m,
1H), 7.85–7.91 (m, 2H), 12.41 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 115.1, 117.5, 119.3, 122.0,
126.3, 128.9, 129.1, 130.2, 130.9, 131.8, 132.2, 132.3,
138.6, 162.8, 184.2; HRMS-ESI (m/z): Calcd for
(3l).
Yield: 40%; light yellow liquid; Rf 0.5 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3410, 1614, 1559,
1
1123, 893; H NMR (400 MHz, DMSO-d6): δ 5.69 (s,
2H), 7.10 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 9.6, 2.7 Hz,
3H), 7.25 (d, J = 7.3 Hz, 1H), 7.30–7.37 (m, 4H), 7.52
(dd, J = 10.3, 4.6 Hz, 2H), 7.58–7.64 (m, 3H), 7.74–7.79
(m, 2H), 8.00 (d, J = 1.9 Hz, 1H); 13C NMR (101 MHz,
DMSO-d6): δ 52.0, 119.7, 124.2, 125.3, 126.6, 127.2,
127.7, 128.8, 128.9, 129.2, 129.4, 129.5, 130.4, 132.2,
134.1, 139.2, 139.6, 185.5; ESI-MS (m/z): 338.0 [M + H]+.
C17H11ClFNO [M + H]+ 300.0586 found 300.0588.
(4-([1,10-Biphenyl]-4-yl)-1H-pyrrol-2-yl)(phenyl)methanone
(3h). Yield: 65%; light yellow solid; mp 198–204°C; Rf
0.5 [hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3266,
1
1611, 1565, 1287, 760; H NMR (400 MHz, DMSO-d6):
(4-Tolyl)(4-phenyl-1H-pyrrol-2-yl)methanone
(3m).
δ 7.23–7.26 (m, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.46 (t,
J = 7.7 Hz, 2H), 7.58 (t, J = 6.7 Hz, 2H), 7.62–7.67 (m,
3H), 7.67–7.71 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.81
(dd, J = 3.1, 1.5 Hz, 1H), 7.95 (m, 2H), 12.31 (s, 1H);
13C NMR (101 MHz, DMSO-d6): δ 116.1, 124.2, 125.7,
125.9, 126.8, 127.3, 127.6, 129.0, 129.2, 129.3, 131.8,
132.2, 134.0, 138.0, 138.8, 140.3, 184.2; HRMS-ESI
(m/z): Calcd for C23H7NO [M + H]+ 324.1383 found
Yield: 64%; white solid; mp 126–132°C; Rf 0.4 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3264, 3028, 1599,
1
1559, 894; H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H),
7.15 (dd, J = 2.5, 1.6 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H),
7.32 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.43
(dd, J = 3.0, 1.5 Hz, 1H), 7.53 (dd, J = 8.2, 1.1 Hz, 2H),
7.87 (d, J = 8.1 Hz, 2H), 10.07 (s, 1H); 13C NMR
(101 MHz, CDCl3): δ 21.6, 116.1, 121.9, 125.3, 126.4,
127.3, 128.8, 129.1, 129.2, 131.8, 134.4, 135.5, 142.7,
324.1389.
184.7; ESI-MS (m/z): 262.0 [M + H]+.
(4-(Anthracen-9-yl)-1H-pyrrol-2-yl)(phenyl)methanone
(3i). Yield: 22%; light yellow solid; mp 122–128°C; Rf
(4-Methoxyphenyl)(4-phenyl-1H-pyrrol-2-yl)methanone
(3n). Yield: 53%; white solid; mp 184–190°C; Rf = 0.4
0.4 [hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3278,
1608, 1572, 3038, 1122; 1H NMR (400 MHz,
DMSO-d6): δ 6.98 (dd, J = 2.4, 1.5 Hz, 3H), 7.43–7.46
[hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3198,
1
1630, 1568, 1217, 938; H NMR (400 MHz, CDCl3): δ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Application of Polyphosphoric Acid-Mediated Acyl Migration for Regiospecific
Synthesis of Diverse 2-Acylpyrroles from Chalcones
3.90 (s, 3H), 6.99–7.01 (m, 1H), 7.02–7.03 (m, 1H), 7.14
(dd, J = 2.6, 1.6 Hz, 1H), 7.21–7.25 (m, 1H), 7.34–7.39
(m, 2H), 7.41 (dd, J = 3.0, 1.5 Hz, 1H), 7.53–7.55 (m,
2H), 7.97–7.98 (m, 1H), 7.99–8.01 (m, 1H), 9.88 (s, 1H);
13C NMR (101 MHz, CDCl3): δ 55.5, 113.7, 115.5,
121.4, 125.3, 126.4, 127.2, 128.8, 130.8, 131.2, 131.8,
(4-Phenyl-1H-pyrrol-2-yl)(thiophen-2-yl)methanone (3s).
Yield: 77%; white solid; mp 120–126°C; Rf 0.3 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3289, 1583, 1271,
1
755, 500; H NMR (300 MHz, CDCl3): δ 7.19–7.24 (m,
1H), 7.40 (dd, J = 10.6, 4.6 Hz, 4H), 7.57 (d, J = 7.2 Hz,
2H), 7.68 (d, J = 4.1 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H),
9.65 (s, 1H); 13C NMR (101 MHz, DMSO-d6): δ 114.5,
123.8, 125.4, 126.4, 129.1, 131.1, 132.9, 133.7, 134.8,
134.4, 162.9, 183.7; ESI-MS (m/z): 278.0 [M + H]+.
(3,4-Dimethoxyphenyl)(4-phenyl-1H-pyrrol-2-yl)methanone
(3o). Yield: 63%; white solid; mp 158–164°C; Rf 0.4
143.5, 175.2; ESI-MS (m/z): 254.0 [M + H]+.
[hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3257,
(4-(4-Methoxyphenyl)-1H-pyrrol-2-yl)(thiophen-2-yl)
methanone (3t). Yield: 45%; white solid; mp 186–192; Rf
1
1598, 1233, 1138, 812; H NMR (400 MHz DMSO-d6):
0.4 [hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3275,
δ 3.86 (d, J = 7.7 Hz, 6H), 7.12 (d, J = 8.4 Hz, 1H), 7.18
(t, J = 7.4 Hz, 1H), 7.22 (d, J = 3.8 Hz, 1H), 7.34 (t,
J = 7.7 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.60 (dd,
J = 8.3, 1.9 Hz, 1H), 7.64–7.70 (m, 3H), 12.16 (s, 1H);
13C NMR (101 MHz, DMSO-d6): δ 55.9, 56.1, 111.4,
112.0, 115.4, 123.3, 123.4, 125.3, 125.9, 126.3, 129.1,
131.2, 131.8, 134.9, 148.9, 152.5, 183.0; HRMS-ESI (m/
z): Calcd for C19H7NO3 [M + H]+ 308.1281 found
1
1592, 1570, 809, 1247; H NMR (400 MHz, DMSO-d6):
δ 3.77 (s, 3H), 6.91–6.95 (m, 2H), 7.29 (dd, J = 4.9,
3.8 Hz, 1H), 7.48–7.51 (m, 1H), 7.62 (dd, J = 3.1,
1.5 Hz, 1H), 7.64 (s, 1H), 7.66 (s, 1H), 8.00 (dd, J = 5.0,
1.0 Hz, 1H), 8.13 (dd, J = 3.8, 1.0 Hz, 1H), 12.14 (s,
1H); 13C NMR (101 MHz, DMSO-d6): δ 55.5, 114.1,
114.5, 123.2, 126.3, 126.6, 127.4, 129.0, 130.9, 132.8,
133.6, 143.6, 158.2, 175.1; HRMS-ESI (m/z): Calcd for
308.1282.
C16H13NO2S [M + H]+ 284.074 found 284.0739.
4-(2,4-Dichlorophenyl)-1H-pyrrol-2-yl)(thiophen-2-yl)
(4-Fluorophenyl)(4-phenyl-1H-pyrrol-2-yl)methanone
(3p). Yield: 25%; white solid; mp 118–124°C; Rf 0.3
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3259,
methanone (3u).
Yield: 82%; white solid; mp 156–
1
162°C; Rf 0.5 [hexane: ethylacetate = 4:1]; νmax (KBr)/
1625, 1556, 1205, 896; H NMR (400 MHz, DMSO-d6):
1
cmꢀ1: 3273, 1577, 1510, 291, 1136; H NMR (400 MHz,
δ 7.18–7.21 (m, 2H), 7.36 (dt, J = 15.5, 8.4 Hz, 4H),
7.65–7.69 (m, 2H), 7.75 (dd, J = 3.1, 1.5 Hz, 1H), 7.98
(dd, J = 8.8, 5.6 Hz, 2H), 12.27 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 115.8, 116.1, 124.1, 125.4,
126.3, 129.1, 131.5, 131.9, 134.7, 135.3, 164.6, 182.7;
DMSO-d6): δ 7.28 (dd, J = 4.9, 3.8 Hz, 1H), 7.41 (dd,
J = 8.4, 2.2 Hz, 1H), 7.51 (dd, J = 2.4, 1.6 Hz, 1H), 7.62
(d, J = 2.2 Hz, 1H), 7.64 (dd, J = 3.2, 1.5 Hz, 1H), 7.71
(d, J = 8.4 Hz, 1H), 8.00 (dd, J = 5.0, 1.0 Hz, 1H), 8.08
(dd, J = 3.8, 1.0 Hz, 1H), 12.44 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 117.5, 122.0, 126.3, 127.9,
129.0, 129.9, 130.5, 131.7, 131.9, 132.1, 132.5, 133.0,
133.9, 143.2, 175.3; HRMS-ESI (m/z): Calcd for
ESI-MS (m/z): 266.0 [M + H]+.
(4-Chlorophenyl)(4-phenyl-1H-pyrrol-2-yl)methanone
(3q). Yield: 52%; white solid; mp 150–156°C; Rf 0.4
[hexane: ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3270,
1
C15H9Cl2NOS [M + H]+ 321.9855 found 321.9855.
(4-Phenyl-1H-pyrrol-2-yl)(thiophen-3-yl)methanone (3v).
2359, 1610, 1589, 757; H NMR (400 MHz DMSO-d6):
δ 7.19 (ddd, J = 8.4, 4.6, 1.3 Hz, 2H), 7.34 (t,
J = 7.7 Hz, 2H), 7.60–7.65 (m, 2H), 7.67 (dd, J = 8.2,
1.1 Hz, 2H), 7.76 (dd, J = 3.1, 1.5 Hz, 1H), 7.88–7.95
(m, 2H), 12.30 (s, 1H); 13C NMR (101 MHz, DMSO-d6):
δ 116.4, 124.4, 125.4, 126.3, 126.4, 129.0, 129.1, 131.0,
131.4, 134.7, 137.0, 137.4, 182.8; ESI-MS (m/z): 282.0
Yield: 79%; white solid; mp 178–184°C; Rf 0.3 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3271, 1583, 1416,
1
1387, 819; H NMR (400 MHz, DMSO-d6): δ 7.20 (t,
J = 7.4 Hz, 1H), 7.30 (dd, J = 4.9, 3.8 Hz, 1H), 7.36 (t,
J = 7.7 Hz, 2H), 7.58 (dd, J = 2.4, 1.6 Hz, 1H), 7.73 (dd,
J = 9.4, 2.2 Hz, 3H), 8.15 (dd, J = 3.8, 1.0 Hz, 1H), 8.01
(dd, J = 5.0, 1.0 Hz, 1H), 12.24 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 114.5, 123.8, 125.4, 126.3,
126.4, 129.0, 129.1, 131.1, 132.9, 133.7, 134.8, 175.2;
HRMS-ESI (m/z): Calcd for C15H11NOS [M + H]+
[M + H]+.
Naphthalen-2-yl(4-phenyl-1H-pyrrol-2-yl)methanone (3r).
Yield: 55%; light yellow solid; mp 180–186°C; Rf 0.4
[hexane: ethylacetate = 4:1]; νmax (KBr)/cmꢀ1: 3275,
1
1600, 1561, 1391, 899; H NMR (400 MHz, DMSO-d6):
δ 7.19 (t, J = 7.4 Hz, 1H), 7.30–7.32 (m, 1H), 7.34 (t,
J = 7.7 Hz, 2H), 7.61–7.71 (m, 4H), 7.77 (dd, J = 3.1,
1.5 Hz, 1H), 7.94 (dd, J = 8.5, 1.7 Hz, 1H), 8.04 (d,
J = 7.9 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.20 (d,
J = 7.8 Hz, 1H), 8.56 (s, 1H), 12.31 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 116.4, 124.0, 125.4, 125.6,
126.3, 126.4, 127.2, 128.1, 128.5, 128.6, 129.1, 129.9,
130.0, 131.9, 132.6, 134.8, 134.9, 136.1, 184.2; HRMS-
ESI (m/z): Calcd for C21H15NO [M + H]+ 298.1226
found 298.1230.
254.0634 found 254.063.
(4-Phenyl-1H-pyrrol-2-yl)(pyridin-2-yl)methanone (3w).
Yield: 15%; white solid; mp 158–164°C; Rf 0.5 [hexane:
ethylacetate = 9:1]; νmax (KBr)/cmꢀ1: 3267, 1636, 1502,
1
1133, 888; H NMR (400 MHz, DMSO-d6): δ 3.75 (s,
3H), 6.86 (d, J = 8.8 Hz, 2H), 7.02 (t, J = 2.2 Hz, 1H),
7.21 (dd, J = 5.0, 3.7 Hz, 1H), 7.26–7.34 (m, 2H), 7.50
(dd, J = 3.1, 2.0 Hz, 1H), 7.72 (dd, J = 3.7, 1.1 Hz, 1H),
7.93 (dd, J = 5.0, 1.1 Hz, 1H), 11.61 (s, 1H); 13C NMR
(101 MHz, DMSO-d6): δ 122.2, 123.4, 126.7, 127.6,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. U. Kumar, Y. Thigulla, K. Rangan, and A. Bhattacharya
Vol 000
[13] Ugarriza, I.; Uria, U.; Carrillo, L.; Vicario, J. L.; Reyes, E.
Chem A Eur J 2014, 20, 11650.
[14] Kong, J.; Zheng, Z.; Tang, R.; Wang, M.; Sun, Y.; Li, Y. Org
Lett 2018, 20, 5696.
128.1, 130.3, 130.7, 132.6, 133.0, 135.9, 137.8, 148.8,
155.9, 186.9, 189.0; HRMS-ESI (m/z): Calcd for
C16H12N2O [M + H]+ 249.1022 found 249.1024.
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Chem Heterocycl Compd 1989, 25, 268.
Acknowledgments. TUK acknowledge BITS-Pilani for
providing Ph.D. fellowship. Authors gratefully acknowledge
support from the Department of Science and Technology, India,
for the FIST grant SR/FST/CSI-240/2012.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet