One-pot synthesis of pyrrole derivatives from (E)-1,4-diaryl-2-butene-1,4-diones

Article abstract of DOI:10.1016/S0040-4039(01)01334-X

2,5-Di- and 1,2,5-trisubstituted pyrrole derivatives can be prepared conveniently from (E)-1,4-diaryl-2-butene-1,4-diones in a one-pot operation through domino-pathways via palladium-assisted transfer hydrogenation followed by a Paal-Knorr reaction using ammonium formate and its analogs.

Full text of DOI:10.1016/S0040-4039(01)01334-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6595–6597
One-pot synthesis of pyrrole derivatives from
(E)-1,4-diaryl-2-butene-1,4-diones
H. Surya Prakash Rao* and S. Jothilingam
Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
Received 3 May 2001; revised 10 July 2001; accepted 20 July 2001
Abstract—2,5-Di- and 1,2,5-trisubstituted pyrrole derivatives can be prepared conveniently from (E)-1,4-diaryl-2-butene-1,4-
diones in a one-pot operation through domino-pathways via palladium-assisted transfer hydrogenation followed by a Paal–Knorr
reaction using ammonium formate and its analogs. © 2001 Elsevier Science Ltd. All rights reserved.
Pyrrole and its derivatives are ubiquitous among natu-
rally occurring organic compounds.1 They are commonly
found as structural motifs in bio-active molecules such
as porphyrins, alkaloids and co-enzymes.2 In view of
their importance, there is a continuing interest in devel-
oping versatile synthetic routes.3 Generally, pyrroles are
synthesized by the condensation of 1,4-dicarbonyl com-
pounds with primary amines. This condensation, known
as the Paal–Knorr reaction, has a wide scope, permitting
the synthesis of a wide variety of pyrrole derivatives.4
Recently, it was found that microwaves enhance the rate
of this reaction.5 In this communication we wish to report
a novel one-pot synthesis of 2,5-di- and 1,2,5-trisubsti-
tuted pyrrole derivatives from 2-butene-1,4-diones
through domino pathways involving the reduction of a
double bond followed by reductive amination–cycliza-
tion (Scheme 1).
was utilized for reduction of the double bond and also
as a source of ammonia for reductive amination–cycliza-
tion. When the reaction was performed in polyethyleneg-
lycol (PEG-200) in a domestic microwave oven (200 W),
the reaction time was reduced to 30 s and the yield rose
to 92%.6 Results obtained in this study are presented in
Table 1.
Even though there are several reports on the microwave-
assisted rate enhancement of organic reactions in high
dielectric constant solvents such as water and DMF, we
are reporting here for the first time the utility of PEG-200
as a solvent in such reactions. PEG-200 is miscible with
water, thereby simplifying the work-up. Furthermore, it
is inexpensive and readily available in bulk quantities.
We attempted the above reaction in PEG-400, ethylene
glycol, diethylene glycol, triethylene glycol, tetraethylene
glycol, DMF and without any solvent (Table 2). The
maximum yield of the desired product was obtained
when the reaction was performed in PEG-200 or tetra-
ethylene glycol. Surprisingly, the reaction did not take
place when PEG-400 was used as a solvent, possibly due
to low solubility of ammonium formate.
The reaction of (E)-1,4-diphenyl-2-butene-1,4-dione 1a
with ammonium formate 2a in the presence of palladium
on carbon (10%) in methanol at reflux, resulted in the
formation of known 2,5-diphenylpyrrole 3a in 87% yield
in 30 min. In this one-pot reaction, ammonium formate
Pd/C (10%), PEG-200,
microwave (200 W)
or MeOH reflux
O
Ar
RNH3 HCOO
Ar
Ar
+
N
Ar
R
O
1a-f
2a-d
3a-i
Scheme 1. 1a: Ar=C6H5, 1b: Ar=4-ClC6H4, 1c: Ar=4-BrC6H4, 1d: Ar=4-CH3C6H4, 1e: Ar=4-OCH3C6H4, 1f: Ar=4-Cl-3-
CH3C6H3; 2a: R=H, 2b: R=n-C4H9, 2c: R=C6H5, 2d: R=CH2C6H5; 3a: Ar=C6H5, R=H; 3b: Ar=4-ClC6H4, R=H; 3c:
Ar=4-BrC6H4, R=H; 3d: Ar=4-CH3C6H4, R=H; 3e: Ar=4-OCH3C6H4, R=H; 3f: Ar=4-Cl-3-CH3C6H3, R=H; 3g: Ar=
C6H5, R=n-C4H9; 3h: Ar=C6H5, R=C6H5; 3i: Ar=C6H5, R=CH2C6H5.
Keywords: substituted pyrroles; transfer hydrogenation; Paal–Knorr reaction; microwave.
* Corresponding author. E-mail: hspr@satyam.net.in
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01334-X

6596
H. Surya Prakash Rao, S. Jothilingam / Tetrahedron Letters 42 (2001) 6595–6597
Table 1. Reaction of 1,4-diaryl-2-butene-1,4-diones 1a–f with ammonium formates 2a–d in PEG-200 under microwave
irradiation
Entry
Ene–dione
Formate derivative
Pyrrole
Time (min)a
Yield (%)b,c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1a
1a
1a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
0.5 (30)
1.0 (45)
1.0 (45)
1.5 (45)
2.0 (60)
2.0 (60)
2.0 (60)
2.0 (60)
2.0 (60)
92 (87)
80 (60)
85 (63)
85 (61)
89 (37)
84 (23)
56 (26)
63 (29)
60 (28)
a The number in parentheses is the reaction time in MeOH at reflux.
b Yield of isolated and purified product, yield in parentheses is from the reactions conducted in MeOH at reflux.
c All the products were characterized on the basis of analytical and spectral data, with the exception of 3f, the other pyrrole derivatives are known
compounds.7
Thus, we have demonstrated a simple synthesis of 2,5-
and 1,2,5-trisubstituted pyrroles in a one-pot operation
from 1,4-diaryl-2-butene-1,4-diones via enone reduction
followed by the generation of the pyrrole moiety with
ammonium formate or alkyl/aryl ammonium formates.
Furthermore, we have introduced PEG-200 as a conve-
nient solvent for microwave-assisted organic reactions,
which we hope, will find general use.
Table 2. Reaction of (E)-1,4-diphenyl-2-butene-1,4-dione
with ammonium formate in the presence of Pd/C in vari-
ous solvents under microwave irradiation for 30 s at 200
W
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
PEG-200
92
PEG-400a
No reaction
Ethylene glycol
Diethylene glycol
Triethylene glycol
Tetraethylene glycol
DMFa
50
60
82
92
10
25
Acknowledgements
Without solvent
HSPR thanks AICTE and UGC, India for research
grant.
a Ammonium formate was found to be sparingly soluble in PEG-400
and DMF.
References
To test the generality of the reaction, a variety of
(E)-1,4-diaryl-2-butene-1,4-diones 1b–f were trans-
formed to the corresponding 2,5-diarylpyrroles 3b–f
(Table 1). Even when an electron-donating methoxy
group was placed in the phenyl ring of the ene–dione
1e, the yield of the substituted pyrrole 2e was very good
under the influence of microwaves (89%). When this
reaction was performed in refluxing methanol the yield
was only 37%. Similarly, the reaction of ene–dione 1f
using microwave irradiation furnished pyrrole deriva-
tive 3f in 84% yield, whereas under thermal conditions
the yield was only 23%.
1. Boger, D. L.; Boyee, C. W.; Labrili, M. A.; Sehon, C. A.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 54.
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6. In a typical experiment, ene–dione 1f (166 mg, 0.5 mmol),
ammonium formate (34 mg, 5.0 mmol), 10% palladium on
carbon (5.0 mg) and PEG-200 (5 mL) were taken in a
conical flask and the resulting mixture was irradiated in a
domestic microwave oven (BPL-Sanyo, India; mono-
mode, multi-power; power source: 230 V, 50 Hz,
microwave frequency: 2450 MHz) at 200 W for 2 min.
After that, the mixture was cooled to room temperature,
diluted with 50 mL dichloromethane (DCM) and the
palladium/carbon was removed by Celite filter. The clear
filtrate was washed with water (2×50 mL), saturated
aqueous sodium chloride (50 mL) and dried over an-
hydrous sodium sulfate. The solvent was removed
under reduced pressure and the crude product was chro-
We extended the scope of the reaction by employing
different alkylammonium formates 2b–d as one of the
reactive species. Thus, the reaction of n-butylammo-
nium formate 2b with 1a in the presence of Pd/C under
microwave irradiation in PEG-200 furnished 1-butyl-
2,5-diphenyl-1H-pyrrole 3g in 56% yield (Table 1).
Similarly, when phenylammonium formate 2c and ben-
zylammonium formate 2d were employed, 1-phenyl-2,5-
diphenylpyrrole 3h and 1-benzyl-2,5-diphenylpyrrole 3i
were obtained in good yields (Table 1). To the best of
our knowledge, this is the first report on the utility of
alkyl/aryl ammonium formates for the reduction and
amination–cyclization sequence.

H. Surya Prakash Rao, S. Jothilingam / Tetrahedron Letters 42 (2001) 6595–6597
6597
matographed on silica using hexanes/DCM as the eluent
to yield pyrrole 3f as a white solid (134.3 mg, 85%) after
removal of the solvent. An analytically pure sample was
obtained by recrystallization from DCM/hexanes; mp
NMR (75 MHz, CDCl3): l=19.9, 108.0, 121.8, 122.2,
123.9, 125.9, 129.3, 131.2, 136.3; MS (EI) m/z=316 (M+);
Anal. calcd for C18H15Cl2N: C, 68.37; H, 4.78; N, 4.43.
Found: C, 68.25; H, 4.81; N, 4.37.
1
190°C; umax (methanol) 335 nm; wmax 3469 cm−1; H NMR
7. (a) Cortes, E. C.; Romero, E. C.; Martinez, R. Org. Mass.
Spectrom. 1990, 25, 127; (b) Periasamy, M.; Srinivas, G.;
Bharathi, P. J. Org. Chem. 1999, 64, 4204.
(300 MHz, CDCl3): l=2.41 (s, 6H), 6.53 (br s, 2H),
7.20–7.35 (m, 4H), 7.32 (br s, 2H), 8.40 (s, br, 1H); 13C