Iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes: A simple and direct synthesis of functionalized pyrroles

Article abstract of DOI:10.1021/jo902661y

Chemical Equation Represented A simple, convenient, and multicomponent coupling strategy for the synthesis of highly functionalized pyrroles catalyzed by iron(III) salts has been developed. This strategy demonstrated fourcomponent coupling reactions of 1,3-dicarbonyl compounds, amines, aromatic aldehydes, and nitroalkanes without an inert atmosphere. This methodology provides an alternative approach for easy access of highly substituted pyrroles in moderate to very good yields using four simple and readily available building blocks via one-pot tandem reaction. Notably, this method is very cheap, straightforward, and environmentally friendly compared to the existing methods.

Full text of DOI:10.1021/jo902661y

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Iron(III)-Catalyzed Four-Component Coupling Reaction of
1,3-Dicarbonyl Compounds, Amines, Aldehydes, and Nitroalkanes:
A Simple and Direct Synthesis of Functionalized Pyrroles
Sukhendu Maiti, Srijit Biswas, and Umasish Jana*
Department of Chemistry, Jadavpur University, Kolkata 700032, West Bengal, India
jumasish2004@yahoo.co.in
Received December 16, 2009
A simple, convenient, and multicomponent coupling strategy for the synthesis of highly functiona-
lized pyrroles catalyzed by iron(III) salts has been developed. This strategy demonstrated four-
component coupling reactions of 1,3-dicarbonyl compounds, amines, aromatic aldehydes, and
nitroalkanes without an inert atmosphere. This methodology provides an alternative approach for
easy access of highly substituted pyrroles in moderate to very good yields using four simple and
readily available building blocks via one-pot tandem reaction. Notably, this method is very cheap,
straightforward, and environmentally friendly compared to the existing methods.
Introduction
derivatives.5 Among the various methods for the synthesis of
pyrroles, the most frequently used methods are Hantzsch,6
Knorr,7 and Paal-Knorr8 reactions. Although these meth-
ods are very useful for the synthesis of pyrrole derivatives,
these classical reactions have significant drawbacks such as
availability of the starting materials, multisteps synthetic
operations, functional group compatibility, regiospecificity,
The pyrrole ring represents an important class of structur-
al unit frequently found in many natural products1 and bio-
logically and pharmaceutically active compounds.2 It has
been widely used as antitumor,3a anti-inflammatory,3b,c
antibacterial,3c,d antioxidant,3e and antifungal agents.3f
Furthermore, they are also extensively used in material
science.4 Consequently, many new synthetic methods have
been developed for the construction of pyrroles and their
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Published on Web 02/04/2010
DOI: 10.1021/jo902661y
r
2010 American Chemical Society

Maiti et al.
JOCArticle
and harsh reaction conditions, which limit their scope. To
overcome these limitations, various new efficient strategies
such as multicomponent coupling9,5b,10y,z and transition
metal5b,9a,g,10 catalyzed reactions have recently been devel-
oped. Among them multicomponent coupling reactions
(MCRs) offer significant advantages over classical stepwise
methods, because they offer rapid and convergent construc-
tion of complex molecules without the need of isolation and
purifications of any intermediates, resulting in substantial mini-
mization of waste, labor, time, and cost.11 Thus, such reactions
are economically and environmentally more attractive and
have become an important tool in modern organic synthesis.
In this context, four-component coupling reactions for the
synthesis of pyrroles have received much attention.9a,e,h,12
However, the use of expensive and toxic chemicals, nonavail-
ability of the substrates, and cumbersome procedures for the
product isolation limit their practical applications. Therefore,
ongoing studies for the synthesis of pyrroles in terms of effi-
ciency, minimal environmental effect, operational simplicity,
economic viability, and high selectivity in the presence of less
expensive catalyst are still highly desirable.
available for the iron-catalyzed synthesis of pyrroles. As part of
our ongoing research program at developing various iron-salts-
mediated efficient new organic transformations,15 we wish
to report here a novel FeCl3-catalyzed four-component
coupling of commercially available 1,3-dicarbonyl com-
pounds, aldehydes, amines, and nitroalkanes for the
synthesis of highly functionalized pyrroles in one pot. This
methodology represents a simple route to access of tetra-
and pentasubstituted pyrroles in moderate to good yields
under mild conditions.
Results and Discussion
According to the Grob and Cameisch reaction, it is well-
known that pyrroles can be obtained from Michael reaction
of β-enamino ketones or esters and nitroalkenes followed by
cyclization.16 However, only little has been explored in this
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JOCArticle
SCHEME 1. Strategy for the Lewis Acid Mediated One-Pot
Four-Component Coupling
TABLE 1. Four-Component Coupling Reactions under Various Cata-
lytic Conditionsa
entry
catalyst (mol %)
reaction time (h)
yield (%)b
1
2
none
FeCl3 (5)
24
7
10
40
field and reported only for aliphatic nitroalkenes.17 Moreover,
in this method it is a prerequisite to prepare nitroalkenes from
aldehyde and nitroalkanes, and β-enaminocarbonyl deriva-
tives from β-dicarbonyl and amines beforehand. Consequ-
ently, there are opportunities for further improvement of this
reaction. In our present study, we hypothesized that if we could
generate simultaneously in one pot both β-keto-enamines (A)
of 1,3-dicarbonyl compounds and nitrostyrene (B) from read-
ily available starting materials in the presence of a suitable
catalyst, and if these two component undergo Michael reac-
tion, this could represent a possible tandem synthesis of func-
tionalized pyrroles (Scheme 1).
3
4
5
6
7
8
9
10
11
12
13
14
FeCl3 (10)
FeCl3.6H2O (10)
FeBr3 (10)
Fe(acac)3 (10)
FeCl3 (10)
Fe(OTf)3 (10)
InCl3 (10)
Yb(OTf)3 (10)
PTSA (10)
7
7
48
44
40
12
16
7
16
15
10
14
9
19
56c
38
15
29
25
27
25
trace
CF3SO3H (10)
FeCl3 (10) þ CF3SO3H (10)
HCl (30)
16
12
aAll reactions were carried out using aldehyde (1 mmol), amine
(1 mmol), and active methylene compounds (1 mmol) with nitromethane
(1 mL) under reflux. bYield obtained after column chromatography.
cAmine (1.5 mmol) was used.
To achieve this goal, at first the reaction conditions were ex-
plored using four commercially available substrates such as
aromatic amine 1c, aldehyde 2d, acetylacetone 3a, and nitro-
methane 4a in the presence of various catalysts (Table 1). Keep-
ing in mind the advantages of iron, our initial investigation
focused on the development of iron-salts-catalyzed four-compo-
nent coupling reactions. In a preliminary experiment, first we
tested this reaction using the above said amine, aldehyde, and
acetylacetone in nitromethane in the presence of various
iron salts such as FeCl3, FeCl3.6H2O, FeBr3, Fe(OTf)3 and
Fe(acac)3. After great deal of screening on different parameters,
we found that aromatic amine 1c (1.5 mmol), aldehyde 2d (1
mol) and acetylacetone 3a (1 mmol) in nitromethane (1 mL)
produced pyrrole 5e in 56% yield after refluxing 7 h in the
presence of anhydrous FeCl3 (10 mol %) (Table 1, entry 7).
Next, we examined this reaction in the presence of various
other catalysts such as InCl3, Yb(OTf)3, PTSA (p-toluenesul-
fonic acid), HCl, and CF3SO3H in similar reaction conditions.
However, it was evident that anhydrous FeCl3 (10 mol %) was
the most effective catalyst for this transformation. Although
the reaction proceeded very slowly without any catalyst, the
desired product was obtained in only a small amount after
heating for more than 24 h (Table 1, entry 1). Therefore, FeCl3
dramatically accelerated this reaction and gave good yield of
the product 5a. The reaction was also studied in various
solvents such as tetrahydrofuran, dichloromethane, dichloro-
ethane, and toluene; however, the yield of the desired product
was decreased. So, in this reaction nitroalkane was used both as
a solvent and as one of the reactants as well.
reflux in the presence of anhydrous FeCl3 (10 mol %) for a
set period of time (monitored by TLC) without an inert
atmosphere. Then after removal of excess nitroalkane the pro-
duct was directly purified using column chromatography.
Following the general reaction conditions, we next examined
the scope of this reaction with various aromatic amines, and the
results are summarized in Table 2. In general the reaction was
proceeded smoothly for various substituted and unsubstituted
aromatic amines to produce the desired substituted pyrroles in
moderate yields (47-56%). The yields were almost the same
regardless of the substituent. Electron-rich aromatic amines
such as p-toluidine (Table 2, entry 3) and p-methxoy aniline
(Table 2, entries 4-6 and 10) were reacted, and corresponding
products were afforded in moderate yields.
The weakly electron-deficient halogen-containing (-Cl, -F,
and -Br) anilines were also subjected to the reaction condi-
tions, and the desired pyrroles were obtained in moderate
yields (Table 2, entries 7-9). However, in the case of strongly
electron-withdrawing group such as -NO2, the yield of the
product was not satisfactory and the reaction was not studied
further. This observation could be explained from the low
nucleophilicity of the aromatic amine, which inhibited the
formation of corresponding β-keto enamine. Moreover, to
expand the scope of this reaction with respect to aldehyde
substrates, various aromatic aldehydes were surveyed for this
reaction. In general, the electronic properties of the susbtitu-
ents of aromatic aldehydes did not affect the reactivity. Both
electron-donating and weakly electron-withdrawing function-
alities such as methoxy, methyl, and chloro- and bromo-
groups reacted smoothly to afford the desired pyrroles. No-
tably, when the unsymmetrical 1,3-diketone 3b was used as the
substrate, the pyrrole 5j was chemoselectively formed in 50%
yield, that is, only the more activated acetyl group partici-
pated in the condensation process. The structures all of the
The experimental procedure for this reaction was very
simple and straightforward. A mixture of 1,3-dicarbonyl
compound (1 mmol), aromatic amine (1.5 mmol), aromatic
aldehyde (1 mmol), and nitro alkane (1 mL) was heated to
(17) (a) Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263.
(b) Meier, H. Liebigs Ann. Chem 1981, 1534. (c) Sanchez, A. G.; Mancera,
M.; Rosado, F. J. Chem. Soc., Perkin Trans. 1 1980, 1199.
1676 J. Org. Chem. Vol. 75, No. 5, 2010

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TABLE 2. FeCl3-Catalyzed Four-Component Coupling Synthesis of Functionalized Pyrrole with Aromatic Aminesa
entry
R1
R2
R3, R4
reaction time (h)
products
yield (%)b
1
2
3
4
5
6
7
8
9
10
Ph, 1a
1a
p-MeC6H4, 1b
p-OMeC6H4, 1c
1c
Ph, 2a
o-BrC6H4, 2b
p-OMeC6H4, 2c
2a
p-ClC6H4, 2d
2c
2c
p-MeC6H4, 2e
CH3, CH3, 3a
3a
3a
3a
3a
3a
3a
3a
14
14
16
14
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
54
48
47
53
56
52
50
51
49
50
1c
8
p-FC6H4, 1d
p-ClC6H4, 1e
p-BrC6H4, 1f
1c
13
13
14
14
2c
2d
3a
CH3, Ph, 3b
5j
aAll reactions were carried out using aldehyde (1 mmol), amine (1.5 mmol), and 1,3-dicarbonyl compounds (1 mmol) with nitromethane (1 mL) under
reflux. bYield obtained after column chromatography.
substituted pyrroles were unambiguously characterized by
1H and 13CNMR and IR and HRMS.
compounds and nitrostyrene intermediates in this reaction,
which then undergo Michael reaction followed by cycliza-
tion leading to the final pyrrole products. FeCl3 or other
Lewis acids accelerated this reaction by increasing the elec-
trophilic character of 1,3-dicarbonyl compounds and conse-
quently accelerated the formation of β-enamino carbonyl
compounds.18 The generation of nitrostyrene as an inter-
mediate in these reaction conditions, Lewis acid catalyzed
activation of Michael reaction, and subsequent ring annula-
tions leading to the final pyrrole product were finally con-
firmed by a set of reactions.19 Presumably, FeCl3 activated
more strongly compared to the other Lewis or Bronstead
acids and thus gave the better results. It is noteworthy to
mention that formation of imine is much faster compared to
the other reactions; however, we understood that during the
progress of the reaction the imine was hydrolyzed back to
aldehyde and amine under the reaction conditions as imine
formation is a reversible process, and hence the desired
product was obtained through the formation of β-enamino
carbonyl compounds and nitrostyrene.20
Encouraged by these investigations, subsequently, we inves-
tigated this tandem reaction with an array of amines, aromatic
aldehydes, activemethylene compounds, and nitroalkanes, and
the results are presented in Table 3. The reaction appeared to be
quite general with respect to the amines, 1,3-dicarbonyl com-
pounds, and aldehydes. Aliphatic amines such as n-hexyl amine
1g and cyclohexylamine 1h also reacted with acetylacetone 3a
and gave 54%, 59%, and 56% yield of 6a, 6b, and 6c,
respectively (Table 3, entries 1-3). Interestingly, the benzyl
amine 1i (Table 3, entries 4-13, 21, 22) and p-methoxybenzyl-
amine 1j (Table 3, entries 14-20) efficiently reacted under
these conditions and generated corresponding products 6d-6x
in high yields. This four-component coupling reaction can also
be successfully applied with heteroaromatic aldehydes such as
2-formylthiophene 2f and 2-formylfuran 2g (Table 3, entries 5,
6, and 20), which worked at lower temperature (80 °C) and
afforded hybrid heterocyclic compounds 6e, 6t, and 6f in 55%,
56%, and 46%, respectively. Notably, aldehydes bearing a
strong electron-withdrawing group such as -NO2 also under-
went smooth reaction and gave high yields of the products 6g,6i
and 6o, 85%, 60% and 78%, respectively (Table 3, entries 7, 9,
and 15). Likewsie, 2-naphthyladehyde 2m also reacted effi-
ciently to produce the expected pyrrole 6s in 65% yield (Table 3,
entry 19). Furthermore, aldehyde bearing a nitrile group such
as 2k (table 3, entry 10) was also compatible and underwent
smooth conversion in the present reaction conditions with β-
keto esters 3c to yield the desired compound 6j in 61%.
However, nitroethane 4b was found to be the less reactive in
this reaction and gave slightly lower yields of the desired
products (Table 3, entries 21-24) compared to nitromethane;
probably steric hindrance hampered this reaction. Finally, we
tested the efficiency of this reaction with aliphatic aldehyde
such as isobutyraldehyde (Table 3, entry 25) and n-butyralde-
hyde (Table 3, entry 26) with benzyl amine, and both of the
substrates converted smoothly to the desired product. Thus,
variations in all four components were accommodated very
comfortably in this four-component coupling reaction, gene-
rating moderate to high yields of the functionalized pyrroles.
Although the exact role of the catalyst is not known yet, we
hypothesized the in situ generation of β-enamino carbonyl
(18) During our study with activemethylene compounds we often ob-
served the formation of β-enamino carbonyl compounds from the corre-
sponding activemethylene compounds and anilines derivatives in the
presence of catalytic amount of FeCl3. FeCl3-catalyzed formation of β-
enamino carbonyl compounds has also reported by others; see: Hebbache,
H.; Hank, Z.; Boutamine, S.; Meklati, M.; Bruneau, C.; Renaud, J.-L. C. R.
Chimie 2008, 11, 612–619.
(19) Nitrostyrene 1 was prepared separately from benzaldehyde and
nitromethane, and when the following three-component coupling reaction
was performed without any catalyst, only 10% yield of the desired product
was obtained after refluxing for 24 h. However, in the presence of FeCl3 (10
mol%), 60% of the desired product obtained after 7 h of refluxing.
(20) To prove this, an imine was separately prepared from p-methxoyani-
line and benzaldehyde, and when a three-component coupling reaction was
conducted with this imine, acetylacetone, and nitromethane under anhy-
drous (argon atmosphere) conditions in the presence of FeCl3, no desired
product was obtained. However, when the reaction was carried out in the
presence of water (2 equiv), the reaction worked and gave the desired product
in comparable yield.
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TABLE 3. FeCl3-Catalyzed Four-Component Coupling Synthesis of Functionalized Pyrroles with Various Substratesa
aAll reactions were carried out using aldehyde (1 mmol), amine (1.5 mmol), and 1,3-dicarbonyl compounds (1 mmol) with nitromethane (1 mL) under
reflux. bYield obtained after column chromatography. cAldehyde (1.3 mmol), amine (1 mmol), and 1,3-dicarbonyl compounds (1 mmol) were used in
nitromethane (1 mL). dThe reactions were carried out at 80 °C. eThe reactions were carried out at 70 °C.
1678 J. Org. Chem. Vol. 75, No. 5, 2010

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In general the reactions are quite simple and high-yielding and
can be performed without an inert atmosphere, and only a
catalytic amount of FeCl3 (10 mol %) is sufficient to push the
reaction forward. This reaction worked smoothly with a wide
range of substrates with respect to all of the components. The
conditions of this reaction were mild and a wide range of func-
tional groups such as -OMe, -Cl, -Br, -F, -Me, -NO2, -CN, esters,
ketones, and heteroaromatic motifs such as thiophene and furan
were compatible in the present reaction conditions. Moreover, it
is noteworthy to mention that the Grob and Cameisch reaction is
only known for aliphatic amines so far;16,17 however, in the
present iron-salt-catalyzed four-component coupling reactions
both aliphatic and aromatic amines could be used.
esis of 1-[4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-
pyrrol-3-yl]-ethanone (Table 2, Entry 5). To a stirred solution of
p-anisdine 1c (185 mg, 1.5 mmol), p-chlorobenzaldehyde 2d (140
mg, 1 mmol), and acetylacetone 3a (100 mg, 1 mmol) in
nitromethane (1 mL) was added anhydrous FeCl3 (16 mg, 0.1
mmol). The mixture was heated to reflux slowly for 7 h and
cooled down to room temperature. The excess solvent was
removed under vacuum, and the residue was directly purified
by silica gel column chromatography to afford the product 5e as
white solid (189 mg, 0.56 mmol, 56%), mp 117-119 °C. IR
(neat) 3007, 2933, 1651, 1514, 1249 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.09 (s, 3H), 2.36 (s, 3H), 3.86 (s, 3H), 6.61 (s, 1H), 6.98
(d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.26-7.36 (m, 4H)
ppm . 13C NMR (CDCl3, 75 MHz) δ 12.8, 31.0, 55.5, 114.5,
121.0, 122.1, 124.7, 127.4, 128.4, 130.5, 131.4, 132.7, 134.6,
135.9, 159.3, 197.1 ppm. HRMS: m/z calcd for C20H18ClNNaO2
362.0924; found 362.0922.
Conclusions
1-(2-Methyl-1,4-diphenyl-3-pyrrolyl)-ethanone (Table 2, En-
try 1). Acetylacetone 3a (100 mg, 1 mmol), benzaldehyde 2a
(106 mg, 1 mmol), aniline 1a (140 mg, 1.5 mmol), nitromethane
4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated
as described for 5e to obtain the white solid 5a (149 mg, 0.54
mmol, 54%), mp 105-107 °C. IR (neat) 3057, 3028, 1651, 1504,
1404, 1222 cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.09 (s, 3H),
2.42 (s, 3H), 6.68 (s, 1H), 7.31-7.43 (m, 7H), 7.45-7.50 (m, 3H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 12.8, 31.0, 120.6, 122.5,
126.2, 126.3, 126.8, 128.1, 128.2, 129.3, 129.8, 135.3, 136.0,
138.7, 197.6 ppm. HRMS: m/z calcd for C19H18NO (M þ 1)
276.1388; found 276.1389.
In summary, we have successfully developed a novel, ope-
rationally simple, economical, and environmentally friendly
one-pot four-component coupling reaction to synthesis
functionalized pyrroles by employing 1,3-dicarbonyl com-
pounds, aromatic aldehyde, amines, and nitro alkanes. To
the best of our knowledge this is first report of Grob and
Cameisch’s pyrrole synthesis catalyzed by a Lewis acid via
one-pot four component-coupling reactions. Moreover, it
has several advantages: (1) an inexpensive and environmen-
tally friendly FeCl3 (10 mol %) has been used as a catalyst,
(2) all components are readily available and inexpensive, (3)
it allows the direct introduction of carbonyl functionalities
onto the pyrrole skeleton, (4) a wide variety of functional
groups can survive, (5) it is highly selective and allows the
isolation of the desired pyrroles in moderate to high yields
(38-85%), and (6) the reactions were applicable to a combi-
nation of substrates such as aromatic and aliphatic amines,
aromatic and aliphatic aldehydes, β-diketones and β-keto-
esters and with nitroalkanes. Therefore, considering the above
advantages and experimental simplicity, this one-pot catalytic
transformation clearly represents an appealing methodology
for the synthesis of highly functionalized pyrroles both in
academia and pharmaceutical industries. Further study in this
area is going on in our laboratory to improve the yield,
mechanism, and possible applications of this reaction.
1-[4-(2-Bromophenyl)-2-methyl-1-phenyl-1H-pyrrol-3-yl]-etha-
none (Table 2, Entry 2). Acetylacetone 3a (100 mg, 1 mmol), o-
bromobenzaldehyde 2a (185 mg, 1 mmol), aniline 1a (140 mg,
1.5 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16
mg, 0.1 mmol) were treated as described for 5e to obtain the
product as brown sticky liquid 5b (170 mg, 0.48 mmol, 48%). IR
(neat) 3057, 3010, 1651, 1500, 1406, 1222 cm-1 1H NMR
.
(CDCl3, 300 MHz) δ 1.98 (s, 3H), 2.45 (s, 3H), 6.64 (s, 1H),
7.17-7.23 (m, 1H), 7.31-7.52 (m, 7H), 7.66 (d, J = 8.0 Hz, 2H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 13.1, 30.2, 121.1, 122.3,
124.6, 125.2, 126.3, 127.1, 128.1, 128.8, 129.3, 132.0, 132.7,
135.5, 137.5, 138.6, 196.4 ppm. HRMS: m/z calcd for C19H16-
BrNNaO 376.0313; found 376.0316.
1-[4-(4-Methoxyphenyl)-2-methyl-1-p-tolyl-1H-pyrrol-3-yl]-etha-
none (Table 2, Entry 3). Acetylacetone 3a (100 mg, 1 mmol), p-
anisaldehyde 2c (130 mg, 1 mmol), p-toludine 1b (161 mg, 1.5
mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg,
0.1 mmol) were treated as described for 5e to obtain the product
as brown sticky liquid 5c (150 mg, 0.47 mmol, 47%). IR (neat)
3001, 2926, 1651, 1504, 1402, 1246 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.11 (s, 3H), 2.42 (s, 3H), 2.44 (s, 3H), 3.86 (s, 3H), 6.63
Experimental Section
1
General Methods. H NMR spectra were recorded on a 300
MHz and a 500 MHz spectrometer as solutions in CDCl3.
Chemical shifts are expressed in parts per million (ppm, δ) and
are referenced to CHCl3 (δ = 7.26 ppm) as an internal standard.
All coupling constants are absolute values and are expressed in
hertz. The description of the signals include s = singlet, brs =
broad singlet, d = doublet, dd = double doublet, t = triplet,
(s, 1H), 6.94 (d, J = 6.7 Hz, 2H), 7.21-7.32 (m, 6H) ppm. 13
C
NMR (CDCl3, 75 MHz) δ 13.0, 21.1, 30.9, 55.3, 113.7, 120.6,
122.3, 125.9, 126.0, 128.4, 129.9, 130.4, 135.6, 136.2, 138.1,
158.7, 197.8 ppm. HRMS: m/z calcd for C21H21NNaO2
342.1470; found 342.1473.
q = quartet, m = multiplet, and dq = doublet of quartet. 13
C
1-[1-(4-Methoxyphenyl)-2-methyl-4-phenyl-1H-pyrrol-3-yl]-
ethanone (Table 2, Entry 4). Acetylacetone 3a (100 mg, 1 mmol),
benzaldehyde 2a (106 mg, 1 mmol), p-anisidine 1c (185 mg, 1.5
mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg,
0.1 mmol) were treated as described for 5e to obtain the product
as yellow solid 5d (162 mg, 0.53 mmol, 53%), mp 90-91 °C. IR
(neat) 3009, 2933, 1647, 1514, 1250 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.07 (s, 3H), 2.38 (s, 3H), 3.86 (s, 3H), 6.63 (s, 1H), 7.0
(d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H), 7.29-7.35 (m, 1H),
7.37-7.39 (m, 4H) ppm. 13C NMR (CDCl3, 75 MHz) δ 12.7,
31.0, 55.5, 114.4, 120.8, 122.2, 126.0, 126.7, 127.4, 128.2, 129.3,
131.6, 135.6, 136.1, 159.2, 197.6 ppm. HRMS: m/z calcd for
C20H20NO2 (M þ 1) 306.1494; found 306.1487.
NMR spectra were recorded on a 75 MHz and a 125 MHz
spectrometer as solutions in CDCl3 with complete proton
decoupling. Chemical shifts are expressed in parts per million
(ppm, δ) and are referenced to CHCl3 (δ = 77.0 ppm) as an
internal standard. The routine monitoring of reactions was
performed with silica gel coated glass slides, which were ana-
lyzed with iodine. Solvents, reagents, and chemicals were pur-
chased. Nitromethane was dried with CaH2 prior to use. All
reactions involving moisture-sensitive reactants were executed
with oven-dried glassware.
General Procedure for FeCl3-Catalyzed One-Pot Synthesis of
Pyrroles. Representative Experimental Procedure for the Synth-
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Maiti et al.
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1-[1,4-Bis(4-methoxyphenyl)-2-methyl-1H-pyrrol-3-yl]-etha-
none (Table 2, Entry 6). Acetylacetone 3a (100 mg, 1 mmol), p-
anisaldehyde 2c (130 mg, 1 mmol), p-anisidine 1c (185 mg, 1.5
mmol), nitromethane4a(1mL), andanhydrous FeCl3 (16mg, 0.1
mmol) were treated as described for 5e to obtain the product as
brown solid 5f (174 mg, 0.52 mmol, 52%), mp 133-135 °C. IR
(neat) 3005, 2964, 1645, 1504, 1249 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.09 (s, 3H), 2.38 (s, 3H), 3.83(s, 3H), 3.86 (s, 3H), 6.59 (s,
1H), 6.91-6.99 (m, 4H), 7.22-7.30 (m, 4H) ppm. 13C NMR
(CDCl3, 75 MHz) δ 12.8, 30.9, 55.2, 55.5, 113.7, 114.4, 120.6,
122.2, 125.6, 127.4, 128.4, 130.4, 131.6, 135.5, 158.6, 159.2, 197.5
ppm. HRMS: m/z calcd for C21H21NNaO3 358.1419; found
358.1419.
p-anisaldehyde 2c (169 mg, 1.3 mmol), n-hexylamine 1g (101 mg,
1 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg,
0.1 mmol) were treated as described for 5e to obtain the product
as sticky dark reddish liquid 6a (169 mg, 0.54 mmol, 54%). IR
(neat) 2929, 2858, 1647, 1510, 1244 cm-1. 1H NMR (CDCl3, 300
MHz) δ 0.87-0.91 (m, 3H), 1.31-1.32 (m, 6H), 1.69-1.73(m,
2H), 2.01 (s, 3H), 2.48 (s, 3H), 3.78-3.81 (m, 2H), 3.83 (s, 3H),
6.44 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 11.5, 14.0, 22.5, 26.4, 30.7,
30.9, 31.4, 46.5, 55.3, 113.6, 114.7, 116.1, 119.3, 121.6, 125.2,
128.9, 130.4, 134.7, 158.6, 197.4 ppm. HRMS: m/z calcd for
C20H28NO2 (M þ 1) 314.2120; found 314.2118.
1-[4-(4-Chlorophenyl)-1-hexyl-2-methyl-1H-pyrrol-3-yl]-etha-
none (Table 3, Entry 2). Acetylacetone 3a (100 mg, 1 mmol), p-
chlorobenzaldehyde 2d (182 mg, 1.3 mmol), n- hexylamine 1g
(101 mg, 1 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 5e to
obtain the product as sticky dark reddish liquid 6b (187 mg, 0.59
mmol, 59%). IR (neat) 2929, 1649, 1510, 1417, 1182 cm-1. 1H
NMR (CDCl3, 300 MHz) δ 0.86-0.91 (m, 3H), 1.31-1.32 (m,
6H), 1.70-1.75(m, 2H), 2.01 (s, 3H), 2.46 (s, 3H), 3.81 (t, J = 7.3
Hz, 2H), 6.47 (s, 1H), 7.23 (d, J = 6.6 Hz, 2H), 7.31 (d, J = 6.6
Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ 11.6, 14.1, 22.6,
26.5, 30.9, 31.1, 31.5, 46.8, 119.7, 121.6, 124.4, 128.5, 128.7,
130.7, 132.6, 135.1, 135.2, 197.2 ppm. HRMS: m/z calcd for
C19H24ClNNaO 340.1444; found 340.1445.
1-[4-(4-Chlorophenyl)-1-cyclohexyl-2-methyl-1H-pyrrol-3-yl]-
ethanone (Table 3, Entry 3). Acetylacetone 3a (100 mg, 1 mmol),
p-chlorobenzaldehyde 2d (182 mg, 1.3 mmol), cyclohexylamine
1h (99 mg, 1 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 5e to
obtain the product as sticky off white solid 6c (155 mg, 0.56
mmol, 56%), mp 98-100 °C. IR (neat) 2933, 2856, 1649, 1508,
1413 cm-1. 1H NMR (CDCl3, 500 MHz) δ 1.21-1.26 (m, 2H),
1.39-1.47 (m, 2H), 1.56-1.64 (m, 2H), 1.76 (d, J = 13 Hz, 2H),
1.91 (d, J = 13 Hz, 2H), 2.02 (s, 3H), 2.49 (s, 3H), 3.89 (t, J = 3.5
Hz, 1H), 6.57 (s, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.31(d, J = 8.5
Hz, 2H) ppm. 13C NMR (CDCl3, 125 MHz) δ 11.4, 25.5, 25.9,
31.2, 34.1, 55.3, 116.0, 121.4, 124.5, 128.5, 130.6, 132.6, 134.6,
135.4, 197.5 ppm. HRMS: m/z calcd for C19H23ClNO (M þ 1)
316.1468, found 316.1464.
1-[1-(4-Fluorophenyl)-4-(4-methoxyphenyl)-2-methyl-1H-pyr-
rol-3-yl]-ethanone (Table 2, Entry 7). Acetylacetone 3a (100 mg,
1 mmol), p-anisaldehyde 2c (130 mg, 1 mmol), p- flouroaniline 1d
(167 mg, 1.5 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16mg, 0.1 mmol) were treated asdescribed for5e toobtain
the product as brown solid 5g (162 mg, 0.50 mmol, 50%), mp
78-80 °C. IR (neat) 3003, 1651, 1508, 1246, 1215 cm-1. 1H NMR
(CDCl3, 300 MHz) δ 2.08 (s, 3H), 2.39 (s, 3H), 3.85 (s, 3H), 6.61
(s, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.19 (t, J = 8.6 Hz, 2H),
7.28-7.34 (m, 4H) ppm. 13C NMR (CDCl3, 75 MHz) δ 12.7,
31.0, 55.2, 113.7, 116.1, 116.4, 120.4, 122.6, 125.9, 127.9, 128.0,
128.1, 130.3, 134.8, 135.2, 158.7, 160.4, 163.6, 197.6 ppm. HRMS:
m/z calcd for C20H18FNNaO2 346.1219; found 346.1217.
1-[1-(4-Chlorophenyl)-4-(4-methylphenyl)-2-methyl-1H-pyr-
rol-3-yl]-ethanone (Table 2, Entry 8). Acetylacetone 3a (100 mg,
1 mmol), p-tolualdehyde 2e (120 mg, 1 mmol), p-chloroaniline 1e
(191 mg, 1.5 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 5e to
obtain the product as off white solid 5h (165 mg, 0.51 mmol,
51%), mp 127-129 °C. IR (neat) 3020, 1651, 1494, 1415, 1222
cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.08 (s, 3H), 2.39 (s, 6H),
6.62 (s, 1H), 7.18-7.29 (m, 6H), 7.44-7.48 (m, 2H) ppm. 13C
NMR (CDCl3, 75 MHz) δ 12.8, 21.1, 31.0, 120.2, 122.8, 126.5,
127.4, 129.0, 129.1, 129.5, 132.7, 134.0, 136.6, 137.3, 197.6 ppm.
HRMS: m/z calcd for C20H18ClNNaO 346.0975; found 346.0973.
1-[1-(4-Bromophenyl)-4-(4-methoxyphenyl)-2-methyl-1H-pyr-
rol-3-yl]-ethanone (Table 2, Entry 9). Acetylacetone 3a (100 mg,
1 mmol), p-anisaldehyde 2c (130 mg, 1 mmol), p-bromoaniline
1f (258 mg, 1.5 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 5e to
obtain the product as red solid 5i (188 mg, 0.49 mmol, 49%), mp
1-[1-Benzyl-4-(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl]-etha-
none (Table 3, Entry 4). Acetylacetone 3a (100 mg, 1 mmol), p-
chlorobenzaldehyde 2d (140 mg, 1 mmol), benzylamine 1i (161
mg, 1.5 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3
(16 mg, 0.1 mmol) were treated as described for 5e to obtain the
product as orange yellow sticky liquid 6d (258 mg, 0.80 mmol
1
119-121 °C. IR (neat) 3007, 1649, 1492, 1406, 1246 cm-1. H
NMR (CDCl3, 300 MHz) δ 2.07 (s, 3H), 2.39 (s, 3H), 3.84 (s,
3H), 6.60 (s, 1H), 6.93 (d, J = 8.5 Hz, 2H), 7.20-7.29 (m, 4H),
7.61 (d, J = 8.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ
12.8, 31.0, 55.2, 113.7, 114.9, 120.1, 121.9, 122.9, 126.2, 127.7,
128.0, 130.3, 131.1, 132.5, 135.0, 137.7, 158.8, 197.6 ppm.
HRMS: m/z calcd for C20H19BrNO2 (M þ 1) 384.0599; found
384.0592.
1
80%). IR (neat) 3030, 1651, 1508, 1417, 1180 cm-1. H NMR
(CDCl3, 300 MHz) δ 2.05 (s, 3H), 2.40 (s, 3H), 5.06 (s, 2H), 6.54
(s, 1H), 7.09 (d, J = 7.7 Hz, 2H), 7.24-7.35 (m, 7H) ppm. 13
C
NMR (CDCl3, 75 MHz) δ 11.5, 31.1, 50.3, 120.2, 122.0, 124.6,
126.6, 127.9, 128.3, 128.9, 130.5, 132.6, 134.7, 135.3, 136.4, 197.1
ppm. HRMS: m/z calcd for C20H19ClNO (M þ 1) 324.1155;
found 324.1151.
[5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-2-methylcyclopenta-
1,4-dienyl]phenyl-methanone (Table 2, Entry 10). Benzoylaceto-
phenone 3b (162 mg, 1 mmol), p-chlorobenjaldehyde 2d (140
mg, 1 mmol), p-anisidine 1c (185 mg, 1.5 mmol), nitromethane
4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated
as described for 5e to obtain the product as orange red sticky
liquid 5j (200 mg, 0.50 mmol, 50%). IR (neat) 3005, 1635, 1514,
1249 cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.24 (s, 3H), 3.88 (s,
3H), 6.80 (s, 1H), 7.00-7.06 (m, 5H), 7.20-7.36 (m, 6H), 7.73 (d,
J = 8.1 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ 12.4, 55.6,
114.5, 120.3, 120.4, 125.1, 127.4, 127.9, 128.0, 128.3, 128.6,
128.8, 129.2, 129.5, 129.8, 131.5, 131.7, 132.0, 133.5, 135.7,
139.4, 159.3, 194.0 ppm. HRMS: m/z calcd for C25H21ClNO2
(M þ 1) 402.1261; found 402.1252.
1-[1-Benzyl-2-methyl-4-(thiophen-2-yl)-1H-pyrrol-3-yl]-etha-
none (Table 3, Entry 5). To a stirred solution of acetylacetone 3a
(100 mg, 1 mmol), 2-thiophenylaldehyde 2f (112 mg, 1 mmol),
and benzylamine 1i (161 mg, 1.5 mmol) in nitromethane 4a
(1 mL) was added anhydrous FeCl3 (16 mg, 0.1 mmol). The
mixture was heated at 80 °C for a set period of time and cooled to
room temperature. The excess solvent was removed under
vacuum, and the residue was directly purified by silica gel
column chromatography to afford the product as gray solid 6e
(162 mg, 0.55 mmol, 55%), mp 136-138 °C. IR (neat) 3086,
1
2928, 1647, 1413, 1352 cm-1. H NMR (CDCl3, 300 MHz) δ
2.15 (s, 3H), 2.44 (s, 3H), 5.05 (s, 2H), 6.64 (s, 1H), 6.96 (d, J =
3.4 Hz, 1H), 7.02-7.05 (m, 1H), 7.08-7.10 (m, 2H), 7.26 (d,
J = 4.7 Hz, 1H), 7.30-7.38 (m, 3H) ppm. 13C NMR (CDCl3,
1-[1-Hexyl-4-(4-methoxyphenyl)-2-methyl-1H-pyrrol-3-yl]-etha-
none (Table 3, Entry 1). Acetylacetone 3a (100 mg, 1 mmol),
1680 J. Org. Chem. Vol. 75, No. 5, 2010

Maiti et al.
JOCArticle
75 MHz) δ 11.6, 30.5, 50.3, 117.2, 121.5, 122.5, 124.8, 126.6, 126.9,
127.1, 127.9, 128.1, 128.9, 129.3, 135.5, 136.2, 137.1, 197.0 ppm.
HRMS: m/z calcd for C18H17NNaOS 318.0929, found 318.0929.
1-[1-Benzyl-4-(furan-2-yl)-2-methyl-1H-pyrrol-3-yl]-ethanone
(Table 3, Entry 6). Acetylacetone 3a (100 mg, 1 mmol), 2-
furfuraldehyde 2g (96 mg, 1 mmol), benzylamine 1i (161 mg,
1.5 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16
mg, 0.1 mmol) were treated as described for 6e to obtain the
product as off-white solid 6f (128 mg, 0.46 mmol, 46%), mp
liquid 6j (201 mg, 0.61 mmol, 61%). IR (neat) 3020, 2947, 2224,
1699, 1606, 1286 cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.50 (s,
3H), 3.71 (s, 3H), 5.10 (s, 2H), 6.67 (s, 1H), 7.09 (d, J = 6.6 Hz,
2H), 7.34-7.38 (m, 3H), 7.48 (d, J = 6.6 Hz, 2H), 7.61 (d, J =
6.7 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ 11.6, 50.6, 50.7,
109.4, 110.6, 119.4, 121.2, 124.6, 126.5, 128.0, 129.0, 129.6,
131.4, 136.2, 137.4, 140.7, 165.7 ppm. HRMS: m/z calcd for
C21H19N2O2 (M þ 1) 331.1447; found 331.1445.
Methyl 1-Benzyl-4-(4-chlorophenyl)-2-methyl-1H-pyrrole-3-
carboxylate (Table 3, Entry 11). Methylacetoacetate 3c (116
mg, 1 mmol), p-chlorobenzaldehyde 2d (131 mg, 1 mmol),
benzylamine 1i (161 mg, 1.5 mmol), nitromethane 4a (1 mL),
and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as
described for 5e to obtain the product as off-white solid 6k
(271 mg, 0.80 mmol, 80%), mp 79-80 °C. IR (neat) 3012, 1685,
1523, 1280, 1195 cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.49 (s,
3H), 3.70 (s, 3H), 5.08 (s, 2H), 6.59 (s, 1H), 7.09 (d, J = 6.5 Hz,
2H), 7.28-7.37 (m, 7H) ppm. 13C NMR (CDCl3, 75 MHz) δ
11.6, 50.5, 50.5, 110.7, 120.6, 125.0, 126.5, 127.7, 127.9, 128.9,
130.4, 132.0, 134.3, 136.6, 136.8, 166.0 ppm. HRMS: m/z calcd
for C20H19ClNO2 (M þ 1) 340.1104; found 340.1096.
1
109-111 °C. IR (neat) 3030, 1651, 1556, 1413, 1180 cm-1. H
NMR (CDCl3, 300 MHz) δ 2.20 (s, 3H), 2.46 (s, 3H), 5.07 (s,
2H), 6.39 (d, J = 3.0 Hz, 1H), 6.44-6.46 (m, 1H), 6.74 (s, 1H),
7.09 (d, J = 6.7 Hz, 2H), 7.31-7.39 (m, 3H), 7.47 (bs, 1H) ppm.
13C NMR (CDCl3, 75 MHz) δ 11.9, 30.0, 50.6, 107.9, 111.2,
114.9, 121.5, 126.8, 128.1, 128.3, 129.1, 135.8, 136.4, 141.7,
149.2, 196.7 ppm. HRMS: m/z calcd for C18H18NO2 (M þ 1)
280.1338; found 280.1332.
1-[1-Benzyl-2-methyl-4-(30-nitrobiphenyl-2-yl)-1H-pyrrol-3-yl]-
ethanone (Table 3, Entry 7). Acetylacetone 3a (100 mg, 1 mmol),
m-nitrobiphenylaldehyde 2h (227 mg, 1 mmol), benzylamine 1i
(161 mg, 1.5 mmol), nitromethane 4a (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 6e to
obtain the product as orange yellow sticky liquid 6g (349 mg,
Ethyl
1-Benzyl-4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-
carboxylate (Table 3, Entry 12). Ethylacetoacetate 3d (130
mg, 1 mmol), p-flourobenzaldehyde 2l (124 mg, 1 mmol),
benzylamine 1i (161 mg, 1.5 mmol), nitromethane 4a (1 mL),
and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as
described for 5e to obtain the product as orange yellow sticky
liquid 6l (270 mg, 0.80 mmol 80%). IR (neat) 3032, 2980, 1693,
1529, 1282 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.15 (t, J = 7.1
Hz, 3H), 2.48 (s, 3H), 4.16 (q, J = 7.1 Hz, 2H), 5.07 (s, 2H), 6.56
(s, 1H), 6.97-7.09 (m, 4H), 7.29-7.38 (m, 5H) ppm. 13C NMR
(CDCl3, 75 MHz) δ 11.5, 14.0, 50.5, 59.3, 111.0, 114.0, 114.3,
120.3, 125.2, 126.5, 127.8, 128.9, 130.7, 130.8, 131.8, 131.8,
136.5, 136.6, 160.0, 163.3, 165.7 ppm. HRMS: m/z calcd for
C21H21FNO2 (M þ 1) 338.1556; found 338.1551.
0.85 mmol, 85%). IR (neat) 3012, 2926, 1645, 1529, 1350 cm-1
.
1H NMR (CDCl3, 300 MHz) δ 1.92 (s, 3H), 2.33 (s, 3H), 4.98 (s,
2H), 6.32 (s, 1H), 6.88-6.90 (m, 2H), 7.26-7.31 (m, 4H),
7.42-7.44 (m, 6H), 7.57-7.59 (m, 1H), 8.09-8.10 (m, 2H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 11.6, 30.3, 50.1, 121.3,
121.5, 122.4, 123.4, 124.4, 126.2, 127.8, 128.2, 128.7, 128.9,
129.7, 131.8, 134.9, 135.4, 135.4, 136.3, 139.0, 143.2, 147.7,
195.7 ppm. HRMS: m/z calcd for C26H23N2O3 (M þ 1)
411.1709; found 411.1705.
[1-Benzyl-4-(3-bromophenyl)-2-methyl-1H-pyrrol-3-yl](phenyl)-
methanone (Table 3, Entry 8). Benzoylacetophenone 3b (162 mg,
1 mmol), m-bromobenzaldehyde 2i (185 mg, 1 mmol), benzyl-
amine 1i (161 mg, 1.5 mmol), nitromethane 4a (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described
for 5e to obtain the product as orange yellow sticky liquid 6h
(326 mg, 0.76 mmol, 76%). IR (neat) 3028, 1631, 1595, 1427,
1209 cm-1. 1H NMR (CDCl3, 500 MHz) δ 2.35 (s, 3H), 5.13 (s,
2H), 6.74 (s, 1H), 6.90 (t, J = 8.0 Hz, 1H), 7.0 (d, J = 8.0 Hz,
1H), 7.12 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H), 7.21 (t,
J = 7.5 Hz, 2H), 7.29 (t, J = 1.5 Hz, 1H), 7.33 (q, J = 7.5 Hz,
2H), 7.39 (t, J = 7.5 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H) ppm. 13C
NMR (CDCl3, 125 MHz) δ 11.4, 50.7 119.8, 120.2, 121.9, 124.8,
126.8, 127.1, 127.8, 128.0, 128.5, 129.1, 129.3, 129.7, 131.2,
131.8, 135.6, 136.6, 137.3, 139.7, 193.9 ppm. HRMS: m/z calcd
for C25H21BrNO (M þ 1) 430.0807; found 430.0802.
Ethyl 1-Benzyl-4-(4-chlorophenyl)-2-phenyl-1H-pyrrole-3-car-
boxylate (Table 3, Entry 13). Ethylbenzoylacetate 3e (192 mg,
1 mmol), p-chlorobenzaldehyde 2l (140 mg, 1 mmol), benzyl-
amine 1i (161 mg, 1.5 mmol), nitromethane 4a (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described
for 5e to obtain the product as black sticky liquid 6m (241 mg,
0.58 mmol, 58%). IR (neat) 3030, 2980, 1699, 1487, 1286 cm-1
.
1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J = 7.1 Hz, 3H), 3.97 (q,
J = 7.1 Hz, 2H), 4.92 (s, 2H), 6.71 (s, 1H), 6.99-7.01 (m, 2H),
7.26-7.40 (m, 12H) ppm. 13C NMR (CDCl3, 75 MHz) δ 13.8,
50.9, 59.6, 120.9, 127.1, 127.8, 127.9, 128.0, 128.1, 128.5, 128.6,
128.8, 128.9, 129.2, 130.6, 130.8, 130.8, 132.0, 132.3, 133.9,
137.2, 139.7, 165.1 ppm. HRMS: m/z calcd for C26H23ClNO2
(M þ 1) 416.1417; found 416.1412.
1-[1-Benzyl-2-methyl-4-(4-nitrophenyl)-1H-pyrrol-3-yl]-etha-
none (Table 3, Entry 9). Acetylacetone 3a (100 mg, 1 mmol), p-
nitrobenzaldehyde 2j (151 mg, 1 mmol), benzylamine 1i (161 mg,
1.5 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16
mg, 0.1 mmol) were treated as described for 5e to obtain the
product as deep red sticky liquid 6i (200 mg, 0.60 mmol 60%). IR
(neat) 3030, 1647, 1597, 1516, 1348 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.13 (s, 3H), 2.44 (s, 3H), 5.10 (s, 2H), 6.66 (s, 1H), 7.10
(d, J = 6.9 Hz, 2H), 7.27-7.40 (m, 3H), 7.47 (d, J = 8.5 Hz, 2H),
8.21 (d, J = 8.5 Hz, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ
11.8, 31.4, 50.8, 121.4, 122.3, 123.7, 123.8, 124.3, 126.8, 127.1,
128.3, 129.2, 129.6, 136.1, 136.2, 143.4, 146.6, 196.9 ppm.
HRMS: m/z calcd for C20H19N2O3 (M þ 1) 335.1396; found
335.1393
Methyl 1-Benzyl-4-(4-cyanophenyl)-2-methyl-1H-pyrrole-3-
carboxylate (Table 3, Entry 10). Methylacetoacetate 3c (116
mg, 1 mmol), p-cyanobenzaldehyde 2k (131 mg, 1 mmol),
benzylamine 1i (161 mg, 1.5 mmol), nitromethane 4a (1 mL),
and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as
described for 5e to obtain the product as orange yellow sticky
1-[4-(3-Bromophenyl)-1-(4-methoxybenzyl)-2-methyl-1H-pyr-
rol-3-yl]-ethanone (Table 3, Entry 14). Acetylacetone 3a (100 mg,
1 mmol), m-bromobenzaldehyde 2i (185 mg, 1 mmol), p-methoxy-
benzylamine 1j (206 mg, 1.5 mmol), nitromethane 4a (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described for
5e to obtain the product as orange yellow sticky liquid 6n (299 mg,
0.75 mmol, 75%). IR (neat) 3007, 1647, 1512, 1419, 1249 cm-1. 1H
NMR (CDCl3, 300 MHz) δ 2.08 (s, 3H), 2.46 (s, 3H), 3.82 (s, 3H),
5.00 (s, 2H), 6.53 (s, 1H), 6.90 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7
Hz, 2H), 7.22-7.28 (m, 2H), 7.42-7.50 (m, 1H), 7.51 (bs, 1H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 11.6, 31.0, 49.9, 55.3, 114.3,
120.2, 121.8, 122.2, 124.2, 128.0, 128.2, 129.5, 129.6, 131.9, 135.4,
138.4, 159.3, 197.1 ppm. HRMS: m/z calcd for C21H20BrNNaO2
420.0575; found 420.0577.
1-[1-(4-Methoxybenzyl)-2-methyl-4-(30-nitrobiphenyl-2-yl)-
1H-pyrrol-3-yl]-ethanone (Table 3, Entry 15). Acetylacetone 3a
(100 mg, 1 mmol), m-nitrobiphenylaldehyde 2h (227 mg, 1
mmol), p-methoxy benzylamine 1j (205 mg, 1.5 mmol), nitro-
methane 4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol)
J. Org. Chem. Vol. 75, No. 5, 2010 1681

Maiti et al.
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were treated as described for 6d to obtain the product as dark red
sticky liquid 6o (343 mg, 0.78 mmol, 78%). IR (neat) 3005, 1647,
133.6, 136.6, 159.2, 165.9 ppm. HRMS: m/z calcd for
C26H25NNaO3 422.1732; found 422.1731.
1
1527, 1514, 1350, 1247 cm-1. H NMR (CDCl3, 300 MHz) δ
1-[1-(4-Methoxybenzyl)-2-methyl-4-(thiophen-2-yl)-1H-pyr-
rol-3-yl]-ethanone (Table 3, Entry 20). Acetylacetone 3a (100
mg, 1 mmol), 2-thiophenylaldehyde 2f (112 mg, 1 mmol),
p-methoxybenzylamine 1j (206 mg, 1.5 mmol), nitromethane
4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated
as described for 6e to obtain the product as off white solid 6t
(182 mg, 0.56 mmol, 56%), mp 80-82 °C. IR (neat) 3009, 1649,
2.08 (s, 3H), 2.49 (s, 3H), 3.90 (s, 3H), 5.00 (s, 2H), 6.39 (s, 1H),
6.89-7.01 (m, 4H), 7.48-7.60 (m, 4H), 7.67 (d, J = 7.7 Hz, 2H),
8.17-8.19 (m, 2H) ppm. 13C NMR (CDCl3, 75 MHz) δ 11.8,
30.4, 49.8, 55.4, 114.3, 121.2, 121.6, 122.4, 123.4, 124.6, 127.8,
127.9, 128.3, 128.8, 129.8, 131.9, 135.0, 135.4, 135.5, 139.0,
143.3, 147.8, 159.3, 195.9 ppm. HRMS: m/z calcd for
C27H24N2NaO4 463.1634; found 463.1631.
1
1514, 1413, 1249 cm-1. H NMR (CDCl3, 300 MHz) δ 2.14
Methyl
4-(4-Fluorophenyl)-1-(4-methoxybenzyl)-2-methyl-
(s, 3H), 2.45 (s, 3H), 3.78 (s, 3H), 4.97 (s, 2H), 6.60 (s, 1H), 6.87
(d, J = 6.6 Hz, 2H), 6.94-6.95 (m, 1H), 7.01-7.06 (m, 3H),
7.25(dd, J = 1.0 Hz, 5.2 Hz, 1H) ppm. 13C NMR (CDCl3, 75
MHz) δ 11.9, 30.5 50.0, 55.4, 114.5, 117.3, 121.6, 122.5, 125.0,
127.1, 127.3, 128.3, 128.4, 135.8, 137.3, 159.4, 197.4 ppm.
HRMS: m/z calcd for C19H20NO2S (M þ 1) 326.1215; found
326.1207.
1H-pyrrole-3-carboxylate (Table 3, Entry 16). Methylacetoace-
tate 3c (116 mg, 1 mmol), p-flourobenzaldehyde 2l (124 mg, 1
mmol), p-methoxybenzylamine 1j (206 mg, 1.5 mmol), nitro-
methane 4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol)
were treated as described for 5e to obtain the product as off-white
solid 6p (289.8 mg, 0.70 mmol, 70%), mp 70-72 °C. IR (neat)
3012, 2947, 1695, 1514, 1284 cm-1. 1H NMR (CDCl3, 300 MHz)
δ 2.29 (s, 3H), 3.48 (s, 3H), 3.60 (s, 3H), 4.79 (s, 2H), 6.33 (s, 1H),
6.68 (d, J = 6.7 Hz, 2H), 6.78-6.84 (m, 4H), 7.10-7.13 (m, 2H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 11.6, 50.0, 50.5, 55.3, 110.6,
114.2, 114.3, 114.5, 120.2, 125.1, 128.0, 128.5, 130.5, 130.6, 131.8,
131.8, 136.5, 159.2, 160.0, 163.3, 166.1 ppm. HRMS:m/z calcd for
C21H21FNO3 (M þ 1) 354.1505; found 354.1503.
1-[1-Benzyl-4-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-
ethanone (Table 3, Entry 21). Acetylacetone 3a (100 mg, 1
mmol), p-chlorobenzaldehyde 2d (140 mg, 1 mmol), benzyl-
amine 1i (161 mg, 1.5 mmol), nitroethane 4b (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described
for 5e to obtain the product as orange yellow sticky liquid 6u
(158 mg, 0.47 mmol 47%). IR (neat) 3005, 2920, 1645, 1514,
1408 cm-1. 1H NMR (CDCl3, 500 MHz) δ 1.95 (s, 3H), 2.01 (s,
3H), 2.46 (s, 3H), 5.13 (s, 2H), 6.99 (d, J = 7.5 Hz, 2H), 7.23 (d,
J = 7.5 Hz, 2H), 7.29-7.33 (m, 1H), 7.35-7.38 (m, 4H) ppm.
13C NMR (CDCl3, 125 MHz) δ 10.3, 11.8, 31.1, 47.0, 121.2,
121.6, 125.6, 125.7, 126.3, 126.4, 127.6, 128.2, 128.4, 128.7,
129.0, 131.9, 132.6, 134.5, 135.7, 136.7, 196.8 ppm. HRMS: m/z
calcd for C21H21ClNO (M þ 1) 338.1312; found 338.1305.
1-[1-Benzyl-4-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-
ethanone (Table 3, Entry 22). Acetylacetone 3a (100 mg, 1
mmol), p-flourobenzaldehyde 2l (124 mg, 1 mmol), benzylamine
1i (161 mg, 1.5 mmol), nitroethane 4b (1 mL), and anhydrous
FeCl3 (16 mg, 0.1 mmol) were treated as described for 5e to
obtain the product as yellow solid 6v (122 mg, 0.38 mmol, 38%),
Methyl 4-(3-Bromophenyl)-1-(4-methoxybenzyl)-2-methyl-
1H-pyrrole-3-carboxylate (Table 3, Entry 17). Methylacetoace-
tate 3c (116 mg, 1 mmol), m-bromobenzaldehyde 2i (185 mg,
1 mmol), p- methoxybenzylamine 1j (206 mg, 1.5 mmol),
nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1
mmol) were treated as described for 5e to obtain the product
as orange yellow sticky liquid 6q (290 mg, 0.70 mmol, 70%). IR
(neat) 2947, 1699, 1514, 1438, 1249 cm-1. 1H NMR (CDCl3, 300
MHz) δ 2.48 (s, 3H), 3.68 (s, 3H), 3.80 (s, 3H), 4.99 (s, 2H), 6.56
(s, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 7.17 (t,
J = 7.8 Hz, 1H), 7.26-7.31 (m, 1H), 7.35-7.37 (m, 1H), 7.51
(bs, 1H) ppm. 13C NMR (CDCl3, 75 MHz) δ 11.5, 50.1, 50.6,
55.3, 110.6, 114.4, 120.6, 121.6, 124.6, 127.9, 128.1, 128.4, 129.0,
131.9, 136.8, 138.0, 159.3, 166.0 ppm. HRMS: m/z calcd for
C21H20BrNNaO3 436.0524; found 436.0508.
Ethyl 4-(4-Chlorophenyl)-1-(4-methoxybenzyl)-2-methyl-1H-
pyrrole-3-carboxylate (Table 3, Entry 18). Ethylacetoacetate
3d (130 mg, 1 mmol), p-chlorobenzaldehyde 2d (140 mg, 1
mmol), p- methoxybenzylamine 1j (206 mg, 1.5 mmol), nitro-
methane 4a (1 mL), and anhydrous FeCl3 (16 mg, 0.1 mmol)
were treated as described for 5e to obtain the product as orange
yellow liquid 6r (291 mg, 0.76 mmol 76%). IR (neat) 2980, 2837,
1693, 1514, 1249 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.09 (t,
J = 7.1 Hz, 3H), 2.42 (s, 3H), 3.73 (s, 3H), 4.09 (q, J = 7.1 Hz,
2H), 4.92 (s, 2H), 6.47 (s, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.96 (d,
J = 8.5 Hz, 2H) 7.18-7.25 (m, 4H) ppm. 13C NMR (CDCl3, 75
MHz) δ 11.5, 14.1, 50.0, 55.3, 59.4, 110.8, 114.3, 120.2, 124.9,
127.5, 128.0, 128.5, 130.5, 131.9, 134.4, 136.5, 159.2, 165.6 ppm.
HRMS: m/z calcd for C22H23ClNO3 (M þ 1) 384.1366; found
384.1365.
Ethyl 1-(4-Methoxybenzyl)-2-methyl-4-(naphthalen-2-yl)-1H-
pyrrole-3-carboxylate (Table 3, Entry 19). Ethylacetoacetate 3d
(130 mg, 1 mmol), 2-Napthyldehyde 2m (156 mg, 1 mmol), p-
methoxybenzylamine 1j (206 mg, 1.5 mmol), nitromethane 4a (1
mL), and anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as
described for 5e to obtain the product as yellow orange liquid 6s
(259 mg, 0.65 mmol, 65%). IR (neat) 3012, 2837, 1691, 1514,
1247 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.09 (t, J = 7.1 Hz,
3H), 2.53 (s, 3H), 3.81 (s, 3H), 4.16 (q, J = 7.1 Hz, 2H), 5.03 (s,
2H), 6.67 (s, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.5 Hz,
2H), 7.44 (t, J = 3.8 Hz, 2H), 7.55 (d, J = 8.5 Hz, 1H),
7.77-7.84 (m, 4H) ppm. 13C NMR (CDCl3, 75 MHz) δ 11.5,
14.1, 50.0, 55.3, 59.3, 111.1, 114.3, 120.5, 125.1, 125.6, 126.0,
126.5, 126.8, 127.5, 127.7, 128.0, 128.6, 128.7, 132.1, 133.2,
mp 102-104 °C. IR (neat) 3032, 1649, 1514, 1408, 1220 cm-1
.
1H NMR (CDCl3, 300 MHz) δ 1.95 (s, 3H), 1.98 (s, 3H), 2.47 (s,
3H), 5.11 (s, 2H), 6.96 (d, J = 6.8 Hz, 2H), 7.08 (t, J = 8.8 Hz,
2H), 7.21-7.34 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz) δ
10.4, 12.0, 31.1, 47.1, 115.1, 115.4, 125.8, 126.5, 127.7, 128.4,
129.1, 132.2, 132.3, 133.1, 136.8, 160.4, 163.6, 197.2 ppm.
HRMS: m/z calcd for C21H20FNNaO 344.1427; found
344.1427.
1-[4-(4-Chlorophenyl)-1-(4-methoxybenzyl)-2,5-dimethyl-1H-
pyrrol-3-yl]-ethanone (Table 3, entry 23). Acetylacetone 3a (100
mg, 1 mmol), p-tolualdehyde 2e (120 mg, 1 mmol), p-methoxy-
benzylamine 1j (206 mg, 1.5 mmol), nitroethane 4b (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described
for 5e to obtain the product as yellow solid 6w (162 mg, 0.44
mmol, 44%), mp 117-119 °C. IR (neat) 3005, 1645, 1514, 1408,
1249 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.72 (s, 3H), 1.79 (s,
3H), 2.27 (s, 3H), 3.59 (s, 3H), 4.84 (s, 2H), 6.67-6.68 (m, 4H),
7.00 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H) ppm. 13C
NMR (CDCl3, 75 MHz) δ 10.2, 11.7, 31.1, 46.4, 55.2, 114.3,
121.0, 121.4, 126.2, 126.8, 127.8, 128.3, 128.5, 131.8, 132.5,
134.5, 135.6, 158.9, 196.8 ppm. HRMS: m/z calcd for
C22H22ClNNaO2 390.1237; found 390.1232.
1-[1-(4-Methoxybenzyl)-2,5-dimethyl-4-p-tolyl-1H-pyrrol-3-
yl]-ethanone (Table 3, Entry 24). Acetylacetone 3a (100 mg, 1
mmol), p-chlorobenzaldehyde 2d (140 mg, 1 mmol), p-methoxy-
benzylamine 1j (206 mg, 1.5 mmol), nitroethane 4b (1 mL), and
anhydrous FeCl3 (16 mg, 0.1 mmol) were treated as described
for 5e to obtain the product as orange yellow sticky liquid 6x
(156 mg, 0.45 mmol, 45%). IR (neat) 2920, 1645, 1514, 1408,
1249 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.92 (s, 3H), 2.00 (s,
3H), 2.39 (s, 3H), 2.48 (s, 3H), 3.79 (s, 3H), 5.04 (s, 2H),
1682 J. Org. Chem. Vol. 75, No. 5, 2010

Maiti et al.
JOCArticle
6.85-6.92 (m, 4H), 7.14-7.21 (m, 4H) ppm. 13C NMR (CDCl3,
75 MHz) δ 10.3, 11.8, 21.1, 30.9, 46.4, 55.2, 114.3, 121.5, 122.3,
126.0, 126.9, 127.9, 128.7, 128.8, 130.4, 133.9, 134.3, 136.1,
158.9, 197.5 ppm. HRMS: m/z calcd for C23H26NO2 (M þ 1)
348.1964; found 348.1955.
1-(1-Benzyl-4-isopropyl-2-methyl-1H-pyrrol-3-yl)-ethanone
(Table 3, Entry 25). Acetylacetone 3a (100 mg, 1 mmol), iso-
buteraldehyde 2n (72 mg, 1 mmol), benzylamine 1i (161 mg, 1.5
mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg,
0.1 mmol) were treated as described for 6e, the reaction was done
at 70 °C to obtain the product as dark red liquid 6y (200 mg, 0.72
mmol, 72%). IR (neat) 2960, 1641, 1496, 1417 cm-1. 1H NMR
(CDCl3, 300 MHz) δ 1.21 (d, J = 3.7 Hz, 6H), 2.37 (s, 3H), 2.47
(s, 3H), 3.34 (q, J = 6.7 Hz, 1H), 5.01 (s, 2H), 6.40 (s, 1H), 7.00
(d, J = 6.8 Hz, 2H), 7.31-7.33 (m, 3H) ppm. 13C NMR (CDCl3,
75 MHz) δ 12.4, 24.1, 25.7, 31.1, 50.4, 117.7, 121.6, 126.2, 127.6,
128.8, 132.4, 135.0, 137.1, 195.8 ppm. HRMS: m/z calcd for
C17H21NNaO 278.1521; found 278.1524.
0.1 mmol) were treated as described for 6e, with the reaction
performed at 70 °C to obtain the product as dark red liquid 6z
(115 mg, 0.45 mmol, 45%). IR (neat) 2956, 1643, 1496, 1417 cm-1
.
1H NMR (CDCl3, 300 MHz) δ 0.99 (t, J = 7.3 Hz, 3H), 1.58-1.65
(m, 2H), 2.40 (s, 3H), 2.45 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 5.00 (s,
2H), 6.37 (s, 1H), 7.00 (d, J = 7.2 Hz, 2H), 7.27-7.35 (m, 3H)
ppm. 13C NMR (CDCl3, 75 MHz) δ 12.3, 14.1, 23.4, 29.7, 30.9,
50.1, 119.5, 121.7, 124.7, 126.3, 127.6, 128.8, 135.6, 137.0, 195.7
ppm. HRMS: m/z calcd for C17H21NNaO 278.1521; found
278.1526.
Acknowledgment. We gratefully acknowledge the finan-
cial and infrastructural support from the UGC-CAS
programme of the Department of Chemistry, Jadavpur
University. S.M. and S.B. also are thankful to the University
Grants Commission (UGC), Jadavpur University and New
Delhi, India, respectively, for their fellowships.
1-(1-Benzyl-2-methyl-4-propyl-1H-pyrrol-3-yl)-ethanone
(Table 3, Entry 26). Acetylacetone 3a (100 mg, 1 mmol),
buteraldehyde 2o (72 mg, 1 mmol), benzylamine 1i (161 mg,
1.5 mmol), nitromethane 4a (1 mL), and anhydrous FeCl3 (16 mg,
Supporting Information Available: Copies of NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1683