Condensation of 4-aryl-4-oxobutanoic acids with benzylamines: Synthetic and structural studies on 1-arylmethyl-3-[(E)-1-arylmethylidene]-5-phenyl-2,3- dihydro-1H-2-pyrrolones

Article abstract of DOI:10.1007/s10593-007-0044-7

The microwave-mediated reaction of 4-aryl-4-oxobutanoic acids with benzylamines furnished 1-arylmethyl-3-[(E)-1-arylmethylidene]-5-phenyl-2,3- dihydro-1H-pyrrolones. This result is in contract to the earlier report on this reaction conducted under neat conditions. Structures for the products were assigned on the basis of spectral data and confirmed by independent synthesis.

Full text of DOI:10.1007/s10593-007-0044-7

Chemistry of Heterocyclic Compounds, Vol. 43, No. 3, 2007
CONDENSATION OF 4-ARYL-4-OXOBUTANOIC ACIDS WITH BENZYLAMINES:
SYNTHETIC AND STRUCTURAL STUDIES ON 1-ARYLMETHYL-3-[(E)-
1-ARYLMETHYLIDENE]-5-PHENYL-2,3-DIHYDRO-1H-2-PYRROLONES
H. Surya Prakash Rao, S. Senthilkumar, K. Gopu, and Shaik Rafi
The microwave-mediated reaction of 4-aryl-4-oxobutanoic acids with benzylamines furnished
1-arylmethyl-3-[(E)-1-arylmethylidene]-5-phenyl-2,3-dihydro-1H-pyrrolones. This result is in contract
to the earlier report on this reaction conducted under neat conditions. Structures for the products were
assigned on the basis of spectral data and confirmed by independent synthesis.
Keywords: pyrrolones, domino reactions, microwave.
Multicomponent condensation reactions taking place either by design or by serendipity are attractive
routes for the preparation of complex products from simple starting materials [1, 2]. In this context, the reaction
of 4-oxo-4-phenyl-butanoic acid (1a) with amines has attracted the attention of organic chemists from the
beginning of the 20th century because of the formation of orange-colored pyrrolone derivatives through
multicomponent condensations following domino pathways [3-8]. In addition, pyrrolones with structural
diversity are attractive targets for synthesis as they are expected to show impressive biological properties [9].
We have been interested in the synthesis of different nitrogen heterocycles via microwave-mediated
multicomponent condensation reactions [10-13]. Recently we reported a facile multicomponent condensation
involving 4-oxo-4-phenylbutanoic acid esters with ammonium formate [14]. In continuation of this study, we
conducted the microwave-mediated solution-phase condensation of 4-oxo-4-phenylbutanoic acid (1a) with
benzylamine 2a with an intention to generate pyrrolidones of diverse structures. We anticipated that the reaction
would furnish pyrrolidones of the type 3 as reported by Saeed [15] (Scheme 1).
Scheme 1
Ar
O
O
N
+
COOH
Ph
NH2
Ph
Ar
N
Ph
H
O
Ph
1a,b
3a,b
2a
1, 3 a Ar = Ph, b Ar = 4-ClC6H4
__________________________________________________________________________________________
Department of Chemistry, Pondicherry University, Pondicherry 605 014, India; e-mail:
hspr@yahoo.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 368-373, March, 2007.
Original article submitted November 24, 2006.
292
0009-3122/07/4303-0292©2007 Springer Science+Business Media, Inc.

However, to our surprise, in contrast to the findings of Saeed, the reaction furnished pyrrolone 4a instead
of 3a (Scheme 2). Similarly, unlike the findings of Saeed, the reaction of the acid 1c with benzylamine 2a
furnished pyrrolone 4c rather than anticipated pyrrolone 3b. We have now re-investigated this interesting
reaction in detail and report the results of this study.
Scheme 2
Ar
O
i
Ar1
N
NH2
Ar
COOH
+
Ar1
Ar1
1a–c
2a–c
O
4a–e
i: PEG-200, MW, 300 W, 2 min.
1,2 a Ar = Ar1 = Ph; b Ar = Ar1 = 4-Me-C6H4, c Ar = Ar1 = 4-ClC6H4;
4 a Ar = Ar1 = Ph, b Ar = 4-MeC6H4, Ar1 = Ph; c Ar = 4-ClC6H4, Ar1 = Ph, d Ar = Ph,
Ar1 = 4-MeC6H4, e Ar = Ph, Ar1 = 4-ClC6H4
The microwave-mediated reaction of keto acid 1a with benzylamine 2a leads to the formation of 1-
benzyl-5-phenyl-3-[(E)-1-phenylmethylidene]-2,3-di- hydro-1H-2-pyrrolone (4a) exclusively in 78% yield. The
structure of pyrrolone 4a was confirmed on the basis of spectral and analytical data. The UV spectrum of 4a
showed two λmax at 310 (logε4.24) and 410 nm (logε2.11) due to cinnamoyl-type and diphenylbutadiene
moieties present in the molecule. The IR spectrum of 4a showed a band at ν 1701 cm-1 due to the presence of
1
five-membered amide carbonyl. As anticipated from its structure, 4a displayed three singlets in the H NMR
spectrum at δ 4.79, 6.20, and 7.46 ppm assignable to N−CH2Ph, alkenic hydrogen on C(4), and methylidene
13
hydrogen, respectively. The C NMR spectrum of 4a showed eighteen signals, which included one aliphatic,
sixteen aromatic/olefinic, and one carbonyl carbons. The mass spectrum of 4a displayed m/z peak at 337 in
support of molecular formula C24H19NO. It is clear from spectral studies that the product 4a was formed by the
condensation of the two units of benzylamine 2a and one unit of 4-oxo-4-phenylbutanoic acid (1a) [16]. The
stereochemistry at the methylidene group was assigned on the basis of comparison of spectral data with
compounds of similar structure [17].
Transformation of keto acid 1a and benzylamine to 4a also took place under normal thermal conditions
at 140°C in 2 h. However, the rate of transformation was faster under microwave irradiation. Thus, as
anticipated, there was an about 100-fold increase in the rate of pyrrolidone 4a generation under the influence
of microwaves. In this context, we repeated the reaction of keto acid 1a with benzylamine 2a under the
conditions reported by Saeed by heating them together without solvent in a preheated oil bath. The reaction
furnished two products, 3a and 4a, in the ratio of 1:4, i.e., even under direct heating without any solvent,
pyrrolone 3a was the minor product. The structure for 3a was assigned on the basis of spectral data. Even though
1
most of the signals in H NMR spectrum of 3a prepared by us match the reported values, there were some
differences (see Experimental).
To test the generality of the three-component condensation involving one molecule of oxo acid 1 and
two molecules of benzylamine 2, the reaction was carried out with keto acids having electron-releasing (CH3,
1b) and electron- withdrawing (Cl, 1c) groups located on the C(4) position of the aryl ring. Thus, on reaction
with benzylamine 2a two butanoic acids 1b and 1c were smoothly transformed into corresponding pyrrolone
derivatives 4b and 4c in 67 and 83% yield, respectively (Scheme 2). Similarly, benzylamines 2b and 2c having
electron-releasing (CH3, 2b) and electron-withdrawing (Cl, 2c) groups reacted with keto acid 1a smoothly to
furnish pyrrolones 4d and 4e in 74 and 79% yield, respectively. Structures for pyrrolones 4b-e were assigned on
the basis of spectral and analytical data, which are well comparable with the parent compound 4a.
293

Scheme 3
O
O
H
i
N
Ph
+
Ph
NH2
Ph
COOH
Ph
O
5
2a
1a
ii or iii
3a or 4a
i: DCC, DCM, rt, 95%, ii: P2O5, benzene or toluene, reflux, or iii: conc. H2SO4, DCM, rt.
Saeed reported isolation of the amide 5 as a by-product in the reaction of 1a and 2a and its isolation was
taken as a mechanistic evidence for the formation of pyrrolone 3a. We have now prepared the amide 5 by an
independent route by dehydrocondensation of keto acid 1a and benzylamine 2a using DCC (Scheme 3). The
amide 5 failed to undergo cyclization to pyrrolone 3 or 4 under a variety of microwave/thermal conditions.
Scheme 4
Ph
Ph
– H2O
1a
2a
N
+
HOOC
6
Ph
Ph
N
Ph
N
– H+
+
N
Ph
Ph
Ph
O
HO
O
9
7
8
Ph
N
Ph
N
PhCH2NH2
–2H
Ph
Ph
Ph
Ph
O
O
10
4a
Based on the accumulated results, a possible mechanism for the formation of pyrrolones 4 from 4-keto
acids 1 and benzylamines 2 is given in Scheme 4. Initial dehydrocondesation of 1a with benzylamine 2a
furnished imine 6, which on cyclization led to formation of pyrrolone 8 via 7. 2-Pyrrolones of the type 8 are
highly reactive intermediates and they could exist in equilibrium between structures 8 and 9. Further reaction of
9 with benzylamine led to the formation of 10, which on oxidative dehydrogenation furnished highly conjugated
pyrrole 4a.
To further ascertain the structure and to support the mechanism for the formation of 4a the pyrrolones
4a,b were synthesized independently by a two-step sequence as shown in Scheme 5. The keto acids 1a,b were
condensed with benzaldehyde 11 under dehydrating conditions to yield lactones 12a,b [18], which on treatment
with benzylamine 2a furnished pyrrolones 4a,b in quantitative yield.
294

Scheme 5
Ar
Ar
N
O
i
ii
O
O
PhCHO
+
COOH
Ph
Ph
Ar
Ph
O
11
1a–b
4a–b
12a–b
i: Ac2O/Et3N, reflux, 95%; ii: PhCH2NH2, 100%; 1,4,12 a Ar = Ph, b Ar = 4-MeC6H4
In conclusion, we have shown that both under microwave irradiation and normal thermal solution-phase
conditions, the reaction of 4-oxo-4-phenylbutanoic acids 1 with benzylamines 2 furnish pyrrolones 4.
EXPERIMENTAL
All solvents required for this study were distilled before use. Thin-layer chromatography (TLC) was
performed with silica gel-G (SRL, India) or silica gel GF-254 (E-Merck) using hexane/ethyl acetate as eluent,
and the plates were visualized with iodine vapors or UV light. Column chromatography was accomplished on
silica gel (100-200 mesh, Acme synthetic chemicals) packed by the slurry method using EtOAc-hexane as
eluent. IR spectra were recorded as KBr solutions or neat using an ABB Bomem MB 104 FT-IR spectrometer.
1H NMR and 13C NMR spectra were recorded with Brucker (300 and 75 MHz respectively) NMR spectrometers
using TMS and the center line of the chloroform-D triplet (77.0 ppm) as internal standard, respectively. Melting
points were recorded using a Gallenkamp melting point apparatus and were uncorrected. Mass spectra were
recorded on a Finnigan MAT 8230 mass spectrometer. The microwave reactions were carried out using a BPL-
Sanyo microwave oven, India; mono-mode, multipower, power source: 230 V, 50 Hz, microwave frequency:
2450 MHz. The starting materials, 4-oxo-4-phenylbutanoic acids 1, were prepared by the Friedel-Crafts
acylation of aromatic hydrocarbons with succinic anhydride according to the literature procedure [19].
Preparation of pyrrolones 4 (General procedure).
1-Benzyl-5-phenyl-3-[(E)-1-phenylmethylidene]-2,3-dihydro-1H-2-pyrrolone (4a). 4-Oxo-4-phenyl-
butanoic acid (1a) (150 mg, 0.842 mmol) and benzylamine (2a) (214 mg, 2 mmol) were taken in a 25 ml conical
flask, dissolved in 4 ml PEG-200, and allowed to keep under microwave irradiation at 300 W for 2 min. After
completion of the reaction (TLC) the reaction mixture was cooled to room temperature and diluted with ice-
cooled water (50 ml) and dichloromethane (20 ml). The organic layer was separated and washed with water
(3×10 ml), brine solution (2×10 ml), dried (Na2SO4), and concentrated under vacuo to furnish the crude product,
which was subjected to column chromatography (silica gel 100-200 mesh) using 10% EtOAc–hexane as an
eluent to give compound 4a. Yield 221 mg (78%), an orange solid, mp 140-142°C (lit. 142-143°C [5]), Rf 0.42
(10% EtOAc–hexane). UV spectrum (MeOH), λmax, nm (logε): 310 (4.66), 410 (2.27). IR spectrum, ν cm-1: 696,
1
737, 758, 1027, 1075, 1141, 1319, 1362, 1491, 1557, 1617, 1701, 3054. H NMR spectrum (300 MHz,
CDCl3–CCl4, 1:1), δ, ppm (J, Hz): 4.79 (2H, s); 6.20 (1H, s); 7.02 (2H, d, J = 6.3); 7.17-7.21 (2H, m); 7.25-
7.39 (9H, m); 7.46 (1H, s); 7.62 (2H, d, J = 8.1). 13C NMR spectrum (75 MHz, CDCl3–CCl4, 1:1), δ ppm:
44.69, 100.84, 127.22 (2C), 128.06, 128.52, 128.57, 128.85 (2C), 129.38, 129.98, 130.28, 131.61, 132.81,
136.10, 137.83, 149.59, 170.48. LRMS, m/z (I, %): 337 [M]+ (37), 246 (6), 228 (10), 202 (14), 139 (10), 119
(20), 91 (100), 77 (10), 65 (28), 51 (8). Found, %: C 85.47; H 5.71; N 4.12. C24H19NO. Calculated, %: C 85.43;
H 5.68; N 4.15.
295

1-Benzyl-5-(4-methylphenyl)-3-[(E)-1-phenylmethylidene]-2,3-dihydro-1H-2-pyrrolone (4b). Following
the general procedure described above, the reaction of 4-(4-methylphenyl)-4-oxobutanoic acid (1b) (161 mg,
0.842 mmol) and benzylamine (2a) (214 mg, 1.56 mmol) in 6 ml PEG-200 gave compound 4b which was
purified by column chromatography. Yield 153 mg (52%), an orange solid, mp 154-156°C, Rf 0.39 (10%
EtOAc–hexane). UV spectrum (MeOH), λmax, nm (logε): 311 (4.36), 410 (2.32). IR spectrum, ν, cm-1: 691, 737,
760, 822, 1026, 1141, 1319, 1360, 1449, 1494, 1610, 1701, 2903, 3027. 1H NMR spectrum (300 MHz, CDCl3–
CCl4, 1:1), δ, ppm (J, Hz): 2.38 (3H, s); 4.84 (2H, s); 6.22 (1H, s); 7.09 (2H, d, J = 6.6); 7.14-7.26 (8H, m);
7.33-7.44 (3H, m); 7.49 (1H, s); 7.65 (2H, d, J = 7.2). 13C NMR spectrum (75 MHz, CDCl3–CCl4, 1:1), δ
ppm: 170.99, 149.66, 139.54, 137.77, 135.91, 132.49, 130.18 (2C), 129.90, 129.39, 129.28 (2C), 128.82 (2C),
128.45 (2C), 128.32, 127.85 (2C), 127.04, 126.99 (2C), 100.34, 44.59, 21.33. LRMS, m/z (I, %): 351 [M]+
(100), 245 (6), 217 (12), 91 (56). Found, %: C 85.39; H 6.05; N 4.02. C25H21NO. Calculated, %: C 85.43;
H 6.02; N 3.99.
1-Benzyl-5-(4-chlorophenyl)-3-[(E)-1-phenylmethylidene]-2,3-dihydro-1H-2-pyrrolone (4c). Following
the general procedure described above, the reaction of 4-(4-chlorophenyl)-4-oxobutanoic acid 1c (150 mg, 0.71
mmol) and benzylamine 2a (151 mg, 1.42 mmol) in 4 ml PEG-200 gave compound 4c, which was purified by
column chromatography. Yield 199 mg (76%), an orange solid, mp 160-162°C, Rf 0.41 (10% EtOAc–hexane).
UV spectrum (MeOH), λmax, nm (logε): 310 (4.84), 410 (2.13). IR spectrum, ν, cm-1: 693, 737, 761, 836, 1091,
1141, 1317, 1361, 1451, 1488, 1617, 1702, 2902, 3024. 1H NMR spectrum (300 MHz, CDCl3–CCl4, 1:1), δ, ppm
(J, Hz): 4.79 (2H, s); 6.21 (1H, s); 7.04 (2H, d, J = 6.6); 7.18-7.26 (5H, m); 7.30-7.43 (4H, m); 7.50 (1H, s); 7.63
(2H, d, J = 6.6). 13C NMR spectrum (75 MHz, CDCl3–CCl4, 1:1), δ, ppm: 44.81, 101.26, 127.09, 127.39, 128.69,
128.96, 129.31 (2C), 129.64, 129.71, 129.97, 130.35, 133.55, 135.63, 135.96, 137.67, 148.41, 170.50. LRMS, m/z
(I, %): 373 [M+ + 2] (18), 371 [M]+ (38), 245 (10), 228 (10), 202 (14), 91 (100), 65 (12). Found, %: C 77.56; H
4.91; N 3.79. C24H18ClNO. Calculated, %: C 77.52; H 4.88; N 3.77.
1-(4-Methylbenzyl)-3-[(E)-1-(4-methylphenyl)methylidene]-5-phenyl-2,3-dihydro-1H-2-pyrrolone
(4d). Following the general procedure described above, the reaction of 4-oxo-4-phenylbutanoic acid 1a (100 mg,
0.56 mmol) and 4-methylbenzylamine 2b (121 mg, 0.99 mmol) in 6 ml PEG-200 gave compound 4d. Yield 152
mg (74%), after purification by column chromatography (silica gel 100-200 mesh; eluent 20% ethyl acetate–
hexane), an orange solid, mp 90°C, Rf 0.83 (20% ethyl acetate–hexane). UV spectrum (MeOH), λmax, nm (logε):
317 (3.7). IR spectrum, ν, cm-1: 698, 764, 812, 926, 1022, 1075, 1179, 1352, 1389, 1447, 1512, 1599, 1700,
3026. 1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 2.28 (3H, s); 2.38 (3H, s); 4.8 (2H, s); 6.24 (1H, s);
13
7.23 (2H, d, J = 7.8); 7.31 (2H, m); 7.33-7.39 (9H, m); 7.52 (1H, s); 7.64 (2H, d, J = 6.8). C NMR spectrum
(100 MHz, CDCl3), δ, ppm: 21.18, 21.65, 22.83, 29.45, 29.84, 30.17, 32.07, 44.53, 101.84, 127.25, 128.20,
128.70, 129.28, 129.42, 129.79, 130.46, 131.68, 133.20, 133.33, 134.92, 136.81, 140.15, 149.19, 171.16. Found,
%: C 85.41; H 6.36; N 3.81. C24H23NO. Calculated, %: C 85.45; H 6.34; N 3.83.
1-(4-Chlorobenzyl)-3-[(E)-1-(4-chlorophenyl)methylidene]-5-phenyl-2,3-dihydro-1H-2-pyrrolone
(4e). Following the general procedure described above, the reaction of 4-oxophenyl-4-butanoic acid 1a (100 mg,
0.56 mmol) and 4-chlorobenzylamine 2c (87 mg, 0.62 mmol) in 6 ml PEG-200 gave compound 4e after
purification by column chromatography. Yield 179 mg (79%), orange solid, mp 110°C, Rf 0.67 (20% ethyl
acetate–hexane). IR spectrum, ν, cm-1 693, 757, 758, 1029, 1141, 1318, 1362, 1491, 1555, 1617, 1701, 3053. 1H
NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 4.85 (2H, s); 6.25 (1H, s); 7.07 (2H, d, J = 6.4); 7.19-7.21
(2H, m); 7.25-7.39 (7H, m); 7.52 (1H, s); 7.64 (2H, d, J = 6.8). Found, %: C 71.01; H 4.24; N 3.91.
C24H17NOCl2. Calculated, %: C 70.95; H 4.22; N 3.95.
N-Benzyl-4-(1-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-3-pyrrolylidene)-4-phenylbutan- amide (3a).
Compound 1a (200 mg, 1.12 mmol) and benzylamine 2a (120 mg, 1.12 mmol) were taken in a 5 ml RB and heated to
reflux for 2 h in a preheated oil bath (180°C). The reaction mixture, cooled to room temperature, was diluted with
dichloromethane (20 ml). The organic solution was washed with water (2×20 ml) and brine (20 ml). The
solvent was removed after drying (Na2SO4), which was carried out under reduced pressure. The crude product
296

was subjected to column chromatography on SiO2 and eluted with increasing amounts of ethyl acetate in hexane
(1:9 to 2:8). Pooling of fractions having a clear product led to isolation of amide 3a, yield 100 mg (18%) and
compound 4a, yield 272 mg (72%). The spectral data of 3a generated in this experiment almost matched with
previously prepared sample 3a [15], orange solid, mp 160–162°C. IR spectrum, ν, cm–1: 782, 1493, 1600, 1684,
1
1807, 1887, 1953, 2924, 3061, 3322. H NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 2.48 (2H, t, J = 7.8);
3.64 (2H, t, J = 7.8); 4.42 (2H, d, J = 6.0); 4.71 (2H, s); 5.68 (1H, s); 7.03 (2H, d, J = 8.1); 7.19-7.40 (18H, m). 13C
NMR spectrum (75 MHz, CDCl3), δ, ppm: 29.3, 35.81, 43.36, 44.53, 102.97, 126.92 (2C), 127.02, 127.12, 127.67
(2C), 127.94 (2C), 128.44 (6C), 128.87, 128.95, 129.06, 131.22, 137.67, 138.79, 140.00, 145.00, 153.87, 169.50,
171.80.
HSPR thanks University Grants Commission, India, for the Special Assistance Program (SAP-DRS), the
Council of Scientific Industrial Research, India, and the Department of Science and Technology, India, for
financial assistance. S. Rafi thanks CSIR for the Junior Research Fellowship awarded in the major research
project awarded to HSPR. We thank Prof. A. Srikrishna, Sophisticated Instrumentation Facility and
Sophisticated Analytical Instrumentation Center, for generously recording NMR spectra.
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