Efficient one-pot synthesis of substituted lactams via three-component solvent-free reaction catalyzed by ytterbium triflate

Article abstract of DOI:10.1080/00397911.2011.628774

Three-component synthesis of 1,5-dihydro-2H-pyrrol-2-one derivatives from pyruvate, aldehyde, and aniline was described. The reaction proceeds successfully under solvent-free conditions using ytterbium as a catalyst. The structures of the synthesized compounds are assigned on the basis of elemental analysis, infrared, ¹H NMR, ¹³C NMR, and mass spectral data.

Full text of DOI:10.1080/00397911.2011.628774

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Efficient One-Pot Synthesis of
Substituted Lactams via Three-
Component Solvent-Free Reaction
Catalyzed by Ytterbium Triflate
Arasampattu S. Nagarajan a & Boreddy S. R. Reddy a
a Industrial Chemistry Laboratory , Central Leather Research
Institute, Adyar , Chennai , India
Accepted author version posted online: 08 May 2012.Published
online: 21 Feb 2013.
To cite this article: Arasampattu S. Nagarajan & Boreddy S. R. Reddy (2013) Efficient One-Pot
Synthesis of Substituted Lactams via Three-Component Solvent-Free Reaction Catalyzed by Ytterbium
Triflate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 43:9, 1229-1236, DOI: 10.1080/00397911.2011.628774
To link to this article: http://dx.doi.org/10.1080/00397911.2011.628774
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Synthetic Communications1, 43: 1229–1236, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.628774
EFFICIENT ONE-POT SYNTHESIS OF SUBSTITUTED
LACTAMS VIA THREE-COMPONENT SOLVENT-FREE
REACTION CATALYZED BY YTTERBIUM TRIFLATE
Arasampattu S. Nagarajan and Boreddy S. R. Reddy
Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar,
Chennai, India
GRAPHICAL ABSTRACT
Abstract Three-component synthesis of 1,5-dihydro-2H-pyrrol-2-one derivatives from pyr-
uvate, aldehyde, and aniline was described. The reaction proceeds successfully under
solvent-free conditions using ytterbium as a catalyst. The structures of the synthesized com-
pounds are assigned on the basis of elemental analysis, infrared, 1H NMR, 13C NMR, and
mass spectral data.
Keywords Ethyl pyruvate; pyrrol-2-ones; solvent-free condition; substituted lactams;
ytterbium triflate
INTRODUCTION
Multicomponent reactions (MCRs)[1] have received great attention from the
chemical community because they permit the building of architecturally complex
molecules from relatively simple starting materials. Although significant progress
has been made in the area of MCRs, there is still a high demand for new processes
aimed at the rapid assembly of heterocyclic molecules. 1,5-Dihydro-2H-pyrrol-2-
ones, heterocyclic compounds that are found in many natural products and exhibit
promising biological properties,[2–4] have been subjected to extensive study in the
past years. Accordingly, synthetic efforts have been made toward the construction
of this class of molecules. In general, 3-aminopyrrol-2-ones were obtained by the
Received August 25, 2011.
Address correspondence to Boreddy S. R. Reddy, Industrial Chemistry Laboratory, Central
Leather Research Institute, Adyar, Chennai 600 020, India. E-mail: nagarajan12003@gmail.com
1229

1230
A. S. NAGARAJAN AND B. S. R. REDDY
Scheme 1. Synthesis of 1,5-dihydro-2H-pyrrol-2-ones.
two-component condensation of anilines with pyrrolidine-2,3-diones[3c] or b,c-
unsaturated a-oxo esters.[4a] Pyrrolidinediones and b,c-unsaturated a-oxo esters
were normally prepared from the corresponding aldehydes and pyruvate derivatives.
A one-pot, three-component coupling of aniline, aldehyde, and pyruvate would be
an ideal process for the synthesis of these targeted lactams. In this regard, a single
example of such a three-component coupling reaction in the presence of sulfuric acid
has been reported.[4b] An asymmetric, catalytic, one-pot, three-component coupling
of aniline, aldehyde, and pyruvate has been reported.[5] Recently, a simple and effec-
tive approach to the synthesis of 1,5-dihydro-2H-pyrrol-2-one derivatives via
three-component reactions by hydrogen bonding catalyst has also been reported
by Cheng et al.[6] However, both (asymmetric and hydrogen bonding catalyst) of
these reactions require cumbersome workup and purification steps. Most of these
procedures were time-consuming and produce lots of waste products.
Recently, ytterbium triflate chemistry has attracted much attention as
Yb(OTf)3 has emerged as an alternative, safe, economical, air- and moisture-tolerant
Lewis acid that has been used in various organic transformations.[7] Therefore, we
have investigated ytterbium triflate catalyst in a one-pot, simple, mild, and efficient
procedure for the rapid construction of 1,5-dihydro-2H-pyrrol-2-ones via a
three-component reaction of substituted cyclic or acyclic aldehydes 1, amines 2,
and ethyl pyruvate 3 (Scheme 1).
To the best of our knowledge, there is no report on the one-pot synthesis of
1,5-dihydro-2H-pyrrol-2-ones in the literature using ytterbium triflate as a catalyst.
Table 1. One-pot, three-component synthesis of lactam 4.5 using different Lewis
acidsa
Entry
Lewis acid
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
AlCl3
ZnCl2
TiCl4
8
5
18
07
11
02
09
84
13
17
6
BF3-OEt3
SnCl2
11
10
2
Yb(OTf)3
ZrCl4
SiO2
9
10
aReaction conditions: o-chlorobenzaldehyde (0.1 mmol), 2,4,6-trimethylaniliine
(0.2 mmol), ethyl pyruvate (0.3 mmol), catalyst (20 mol%), rt.
bYield of isolated and purified products.

SYNTHESIS OF SUBSTITUTED LACTAMS
1231
Table 2. Effect of catalyst loading on one-pot, three-component reactiona
Entry
Yb(OTf)3 (mol%)
Time (h)
Yield (%)
1
2
3
4
5
10
15
20
2
2
2
2
56
71
74
81
ao-Chlorobenzaldehyde (0.1 mmol), 2,4,6-trimethylaniline (0.2 mmol), ethyl
pyruvate (0.3 mmol), and ytterbium triflate (5–20 mol%), rt.
Initially,
a one-pot, three-component reaction of o-chlorobenzaldehyde 1
(0.1 mmol), 2,4,6-trimethyl aniline 2 (0.2 mmol), and ethyl pyruvate 3 (0.3 mmol)
was planned (Scheme 1). Several Lewis acids were screened in our model reaction
(Table 1).
RESULTS AND DISCUSSION
Interestingly, the use of other Lewis acids such as AlCl3, SnCl4, ZnCl2, and
BF3-OEt2 were found to have lower catalytic activity and resulted in a small or trace
amount of the desired product. Only AlCl3 gave a minor amount of 1,5-dihydro-2H-
pyrrol-2-one 4 along with other side products. Yb(OTf)3 gave a high yield of 4 within
a short time. Therefore, Yb(OTf)3 alone was the most effective Lewis acid catalyst
for the one-pot, three-component synthesis of 4. Various solvents such as EtOH,
MeCN, CH2Cl2, tetrahydrofuran (THF), Et2O, and PhMe were also screened for
this reaction. The best results were observed under solvent-free conditions. In a
further investigation, a sequential one-pot reaction of aldehyde 1 (0.1 mmol), amine
(0.2), and ethyl pyruvate 3 (0.3 mmol) in the presence of ytterbium triflate (5–
20 mol%) was performed, leading to the synthesis of 1,5-dihydro-2H-pyrrol-2-one
4. The progress of the reaction was monitored by thin-layer chromatography
(TLC). After the complete consumption of aldehyde with ethyl pyruvate, amine
(2 mmol) was added to the same flask. Product 4 was obtained in 57–84% yield
within 1–2 h. Encouraged by this initial result, a one-pot, three-component reaction
was performed by mixing aldehyde, amine, and ethyl pyruvate. The catalyst loading
was optimized using different molar concentrations of ytterbium triflate under
solvent-free conditions at room temperature (Table 2). A good yield of product 4
was obtained using 20 mol% of catalyst. Prolonging the reaction time and increasing
the amount of Yb(OTf)3 catalyst to 40 mol% did not improve the yield.
On increasing the concentration of Yb(OTf)3 and not that of ethyl pyruvate,
many other side products were obtained. From these results, it was evident that
the catalyst concentration plays a crucial role in optimizing the reaction.
To explore the generality and scope of this method, a wide variety of substi-
tuted aromatic aldehydes and amines were reacted with ethyl pyruvate under the
same experimental conditions to afford the corresponding 4. Yb(OTf)3 was found
to be compatible with various substituents (electron withdrawing as well as donating
substituents) such as OMe, OH, NO2, Cl, and Me. The presence of an
electron-releasing group such as methoxy in the para position to the aldehyde and

1232
Entry
4.1
A. S. NAGARAJAN AND B. S. R. REDDY
Table 3. One-pot, three-component synthesis of 4
1
2
Product
Yield (%)
65
4.2
4.3
71
64
4.4
4.5
62
84
4.6
57
4.7
4.8
74
68
4.9
70
4.10
73
(Continued )

SYNTHESIS OF SUBSTITUTED LACTAMS
1233
Table 3. Continued
Entry
4.11
1
2
Product
Yield (%)
69
4.12
4.13
71
62
Notes. Reaction time 2 h, Yb (OTf)3, 20 mol%.
the para position to amine enhances the product formation as indicated by greater
yield (Table 3, entries 4.1 and 4. 2). Similarly, the presence of electron-withdrawing
group (halogen=nitro) in the para position to the aldehyde and ortho and para
groups to the amine reduces the product formation as indicated by lower yield
(Table 3, entries 4.3 and 4.4). For a strong electron-withdrawing group such as
nitro or fluro in the para position to the aldehyde group and bromo in ortho
and para to amine requires longer reaction time and lower yield (Table 3, entries
4.6). An aliphatic group reaction proceeds smoothly to gives greater yield
(Table 3, entries 4.12 and 4.13). The resultant products were obtained in good
to excellent yields in short reaction times (Table 3). All the products obtained were
1
fully characterized by spectroscopic methods including IR, H NMR, 13C NMR,
and mass spectroscopy. The spectral data were also compared with the reported
values.
CONCLUSION
In summary, this method provides an efficient multicomponent approach for
the synthesis of 1,5-dihydro-2H-pyrrol-2-ones. The reaction is versatile and also
offers several advantages such as good yields, shorter reaction times, cleaner reaction
profiles, and simple experimental and workup procedures.
EXPERIMENTAL
Ethyl pyruvate 3 (0.3 mmol) and ytterbium triflate (20 mol%) were added suc-
cessively to a stirred mixture of aldehyde 1 (0.1 mmol) and amine 2 (0.2 mmol) at

1234
A. S. NAGARAJAN AND B. S. R. REDDY
room temperature with vigorous stirring for 1–2 h. The precipitated solid was filtered
and washed with a mixture of ethyl acetate=hexane (20:80 v=v). The product
obtained was pure as found by TLC and 1H and 13C NMR spectroscopy. However,
the products were further purified by recrystallization from ethyl acetate and ethanol
(70:30 v=v).
1-(3,4-Diflurophenyl)-5-(4-methoxyphenyl)-3-[(3,4-diflurophenyl)
amino]-4H-pyrrol-2(5H)one, 4a
ꢀ1
.
1H NMR (300 MHz, CDCl3):
=
IR (KBr): 3357 (N–H), 1677 (C O) cm
d ¼ 3.75 (s, 3H), 5.72 (d, J ¼ 2.74 Hz, 1 H), 6.04 (d, J ¼ 2.74 Hz, 1 H), 6.72 (s, 1
H), 6.94 (d, J ¼ 9.06 Hz, 2 H), 7.17–7.19 (m, 2 H), 7.25–7.30 (m, 2H), 7.35–7.39
(m, 3 H); 13C NMR (75 MHz, CDCl3): d ¼ 54.7, 64.13, 108.5, 113.4, 118.5, 118.8,
122.5, 126.6, 128.9, 129.5, 131.7, 131.6, 132.4, 136.1, 136.8, 140.9, 54.1, 156.6,
158.1, 159.3, 166.99 ppm; LCQ–MS (ESI) m=z 428.1. Anal. calcd. for C23H16 F4
N2O2: C, 64.49; H, 3.76; N, 6.54. Found C, 64.41; H, 3.69; N, 6.48.
1-(4-Methoxyphenyl)-5-(cyclohexyl)-3-[(4-methoxy phenyl)amino]-
4H-pyrrol-2(5H)-one, 4b
1
IR (KBr): n max ¼ 3327 (s, N–H enamine), 1674 (s, C O amide) cmꢀ1. H
=
NMR (300 MHz, CDCl3): d ¼ 1.97–2.24 (m, 10H), 3.74 (s, 3 H), 3.77 (s, 3 H), 5.96
(d, J ¼ 2.74 Hz, 1 H), 6.07 (d, J ¼ 2.47 Hz, 1 H), 6.33 (s, 1 H), 6.44 (t, J ¼ 2.47 Hz,
2 H,), 6.81–6.86 (m, 2H), 7.03 (d, J ¼ 9.33 Hz, 2 H), 7.48 (d, J ¼ 9.33 Hz, 2 H); 13C
NMR (75 MHz, CDCl3): d ¼ 15.7, 19.3, 21.9, 25.7, 26.6, 27.5, 55.9, 64.2, 98.5,
104.7, 106.8, 117.9, 118.2, 122.2, 127.4, 135.7, 154.1, 159.1, 166.7 ppm; MS (EIþ):
LCQ–MS (ESI) m=z 392.2. Anal. calcd. for C24H28N2O3: C, 73.44; H, 7.19; N,
7.14. Found C, 73.37; H, 7.23; N, 7.21.
ACKNOWLEDGMENT
A. S. Nagarajan thanks the Council of Scientific and Industrial Research,
New Delhi, for financial assistance.
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