New pathway to pyrrolidinones and pyrrolizidinones using aryl aldehydes, 3-phenyl-5-isoxazolone and secondary amino acids

Article abstract of DOI:10.1016/j.tetlet.2013.01.078

A novel and efficient approach to pyrrolidinones and pyrrolizidinones via a one-pot multicomponent reaction of aryl aldehydes, 3-phenyl-5-isoxazolone, sarcosine and l-proline, respectively in methanol under reflux condition is reported.

Full text of DOI:10.1016/j.tetlet.2013.01.078

Tetrahedron Letters 54 (2013) 1817–1820
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Tetrahedron Letters
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New pathway to pyrrolidinones and pyrrolizidinones using aryl aldehydes,
3-phenyl-5-isoxazolone and secondary amino acids
⇑
Neelakandan Vidhya Lakshmi, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient approach to pyrrolidinones and pyrrolizidinones via a one-pot multicomponent
Received 3 November 2012
Revised 16 January 2013
Accepted 20 January 2013
Available online 26 January 2013
reaction of aryl aldehydes, 3-phenyl-5-isoxazolone, sarcosine and
under reflux condition is reported.
L-proline, respectively in methanol
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidinones
Pyrrolizidinones
Aldehydes
Amino acids
3-Phenyl-5-isoxazolone
MCRs which employ three or more reactants to furnish prod-
ucts containing structure or substructure of all starting materials
in one-pot and one set of fixed reaction conditions are such exam-
ples with powerful productivity. They also form an ideal platform
for rapid generation of both complexity and diversity in a collec-
tion of compounds with predefined functionality, for example, li-
gands for catalysis or bioactive compounds.1 Therefore, the
design of efficient MCRs to achieve our desired compounds is a
challenge in organic chemistry. Recently, our research group was
involved in various multicomponent reactions that can provide
easy access to important polyfunctionalized ring structures of
chemical and pharmaceutical interest.2
The vast majority of biologically active organic compounds are
N-heterocyclic in nature, a fact that has been heavily exploited
by the pharmaceutical industry.3 The pyrrolidin-2-one structure
is one of the most popular N-heterocycles incorporated into the
structure of many complex natural products and pharmaceutical
compounds. It is known that many pyrrolidinone-containing com-
pounds exhibit a wide spectrum of biological activities on various
drug targets, such as aspartic protease, b-amyloid cleaving enzyme
(BACE), progesterone receptor (PR), human melanocortin-4 recep-
tor, factor Xa and HIV-1 integrase.4
ing methods suffer from tedious synthetic routes, long reaction
time, drastic reaction conditions, as well as narrow substrate
scope.5 We have recently developed a new pathway for spiropyrro-
lidinone oxindoles by a multicomponent reaction of isatin, sarco-
sine, 3-phenyl-5-isoxazolone via cleavage of the 3-phenyl-5-
isoxazolone ring by sarcosine.2e During our continuous efforts on
the research towards novel multicomponent reactions,2 herein,
we wish to utilize this unusual mechanistic pathway of spiropyrro-
lidinone oxindoles as a novel route to achieve functionalized pyrro-
lidinones2e by employing aromatic and heteroaromatic aldehydes.
It is also noteworthy to mention that the exploitation of a multi-
component strategy combined with cleavage of the lactone ring
for the construction of a pyrrolidinone skeleton has not been
achieved so far. Here, the highly conjugated 4-arylidene-3-phe-
nyl-5-isoxazolone formed in situ by Knoevenagel condensation be-
tween aryl aldehyde and 3-phenyl-5-isoxazolone plays a major
role in the synthesis of pyrrolidinones.
In a prototype experiment, a three-component reaction of benz-
aldehyde 1a, 3-phenyl-5-isoxazolone 2 and sarcosine 4 in metha-
nol under reflux condition was investigated (Scheme 1). Initially,
the reaction mixture was colourless. After 10 min, the solution
turns into a yellow colour which indicates the formation of the
intermediate 4-arylidene-3-phenyl-5-isoxazolone 3a and the re-
flux was continued until the completion of the reaction as evi-
denced by TLC. The reaction mixture turns into a white colour
which infers the completion of the reaction. The reaction mixture
was cooled to room temperature in which the white solid precipi-
tated from the reaction was filtered and recrystallized from meth-
anol to furnish pyrrolidinone 5a as a single product.
The development of facile synthesis of pyrrolidinones has been
the focus of much research for several decades and continues to be
an active and rewarding research area. However, most of the exist-
⇑
Corresponding author.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.078

1818
N. V. Lakshmi, P. T. Perumal / Tetrahedron Letters 54 (2013) 1817–1820
O
HO2C
N
O
N
H
OH
N
Ph
O
H
methanol, reflux
4
N
Ar
ArCHO
+
N
methanol, reflux
O
O
H
Ph
Ph
Ar
1a - o
2
5a - o
3a-o
Scheme 1. Synthesis of 4-arylpyrrolidinones 5a–o.
_
O
O
O
O
N
O
O
H
OH
O
H
_
N
N
Ar
O
N
CO2H
+
..
H
N
..
4
N
Ph
Ph
CO2H
Ar
Ar
Ph
- CO2
1a - o
2
4
3a - o
O
H
N
OH
N
Ar
H
Ph
5a - o
Scheme 2. Plausible mechanism for 4-arylpyrrolidinones 5a–o.
Table 1
On the basis of the above results, a tentative mechanistic inter-
pretation to explain the formation of the product 5a is proposed
(Scheme 2). The aromatic aldehyde 1a easily undergoes Knoevena-
gel condensation with 3-phenyl-5-isoxazolone 2 to provide 4-ary-
lidene-3-phenyl-5-isoxazolone 3a as intermediate6 which was
isolated and confirmed by NMR spectroscopy.7 In 3a, the lactone
part which has two bulky moieties adjacent to the isoxazolone ring
may be cleaved8 by sarcosine 49 and the decarboxylation and sub-
sequent Michael addition could facilitate cyclization to furnish 4-
arylpyrrolidinone 5a in good yield (78%).
In order to explore the applicability of the reaction over a wide
range of compounds, various derivatives of aromatic and heteroar-
omatic aldehydes 1a–o, 3-phenyl-5-isoxazolone 2 and sarcosine 4
were subjected to same reaction conditions to achieve a library of
4-aryl pyrrolidinones 5a–o in good yields. The results are summa-
rized in Table 1.
The structures of the compounds 5a–o were characterized by
spectroscopic studies and elemental analysis. The IR spectrum of
the compound 5j showed peaks at 3218 and 1714 cmÀ1 for –OH
of the oxime group and the amide carbonyl group, respectively.
The 1H NMR spectrum of compound 5j exhibited two characteristic
singlets at d 2.85 and 11.66 ppm for –NCH3 protons and –OH pro-
ton of the oxime group (D2O exchangeable), respectively. The
amide carbonyl carbon atom of the pyrrolidinone ring displayed
a peak at d 171.5 ppm in 13C NMR spectrum. A distinguishing peak
was observed at m/z 345.0 in the mass spectrum for (M++1) ion.10
The relative stereochemistry of the products 5a–o was established
through single-crystal X-ray analysis of the compound 5k
(Fig. 1).11
Synthesis of 4-aryl pyrrolidinone derivatives 5a–o
Entry ArCHO (1a–o)
Producta
(5)
Time
(min)
Yieldb
(%)
CHO
1
5a
5b
5c
40
30
30
78
80
81
1a
CHO
2
Cl
1b
CHO
Cl
3
1c
CHO
4
5d
30
78
Br
1d
CHO
Delighted by these results, we then focused our attention to
prepare 1-aryl pyrrolizidinone derivatives 7a–o by replacing sarco-
sine
2
by
L-proline 6 under identical reaction conditions
5
5e
5f
30
40
77
78
(Scheme 3). The reaction proceeded smoothly with a series of aro-
matic and heteroaromatic aldehydes 1a–o to provide a collection
of 1-aryl pyrrolizidinone derivatives 7a–o. The results are summa-
rized in Table 2.
In IR spectrum of the compound 7a, the absorptions at frequen-
cies 3424 and 1733 cmÀ1 correspond to –OH of the oxime group
and the amide carbonyl group, respectively. In the 1H NMR spec-
Br
1e
CHO
6
1f

N. V. Lakshmi, P. T. Perumal / Tetrahedron Letters 54 (2013) 1817–1820
1819
Table 1 (continued)
Entry ArCHO (1a–o)
Producta
(5)
Time
(min)
Yieldb
(%)
CHO
Br
7
5g
5h
5i
40
40
40
79
79
81
OMe
OMe
1g
CHO
8
OMe
1h
CHO
Figure 1. ORTEP diagram of compound 5k.
9
Br
O
trum, a singlet was observed at d 8.72 ppm which showed the pres-
ence of –OH proton of the oxime group (D2O exchangeable).
The amide carbonyl carbon atom of the pyrrolizidinone ring res-
onated at d 174.5 ppm in 13C NMR spectrum.
O
1i
CHO
The presence of a molecular ion peak at m/z 321.7 in the mass
spectrum further supported the formation of the product 7a.12
The relative stereochemistry of the compounds 7a–o was assigned
by analogy of the compound 5k.
In summary, we have demonstrated a simple, facile and novel
route to pyrrolidinones and pyrrolizidinones from aromatic/het-
eroaromatic aldehydes, 3-phenyl-5-isoxazolone and secondary
10
11
5j
40
40
80
80
1j
CHO
5k
amino acids such as sarcosine and L-proline, respectively. The
Knoevenagel condensation product from aldehyde and 3-phenyl-
5-isoxazolone was formed in situ and in which the lactone part
1k
CHO
12
5l
40
81
Table 2
N
Synthesis of 1-aryl pyrrolizidinone derivatives 7a–o
H
1l
Entry
ArCHO (1a–o)
Producta (7)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
70
60
60
70
80
90
80
90
90
60
60
60
60
80
80
75
81
80
77
75
75
76
75
76
78
79
82
81
79
80
CHO
13
14
15
5m
5n
5o
30
40
35
78
81
82
1m
OHC
Fe
1n
N
CHO
N
H
1o
a
a
The products were characterized by IR, NMR, mass and elemental analysis.
Isolated yield after recrystallization.
The products were characterized by spectral and elemental analysis.
Isolated yield by recrystallization.
b
b
O
N
Ph
OH
H
N
H
ArCHO
+
methanol, reflux
+
N
Ar
CO2H
O
N
H
O
H
Ph
1a - o
2
6
7a - o
Scheme 3. Synthesis of 1-aryl pyrrolizidinones 7a–o.

1820
N. V. Lakshmi, P. T. Perumal / Tetrahedron Letters 54 (2013) 1817–1820
9
9
5. (a) Quintás, D.; Garc
i
a, A.; Dom
i
nguez, D. Tetrahedron Lett. 2003, 44, 9291; (b)
was cleaved by the secondary amino acids serendipitously. The
simplicity of the approach makes this strategy useful for the syn-
thesis of novel pyrrolidinones and pyrrolizidinones. Further studies
to delineate the scope and limitations of the present methodology
are underway.
Gemma, S.; Campiani, G.; Butini, S.; Morelli, E.; Minetti, P.; Tinti, O.; Nacci, V.
Tetrahedron 2002, 58, 3689.
6. González, M.; Segura, J. L.; Seoane, C.; Martín, N. J. Org. Chem. 2001, 66, 8872.
7. Spectral data of compound 3j: 1H NMR (500 MHz, DMSO-d6): d 7.33–7.35 (d, 2H,
J = 8.40 Hz, –Ar–H), 7.56–7.61 (m, 3H, –Ar–H), 7.61–7.65 (m, 2H, –Ar–H), 7.72
(s, 1H, @CH), 8.25–8.27 (d, 2H, J = 8.40 Hz, –Ar–H), 8.31–8.34 (m, 3H,–Ar–H).
13C NMR (125 MHz, DMSO-d6): d 117.2, 123.2, 126.2, 126.3, 126.8, 127.9, 128.8,
129.1, 129.3, 130.1, 132.3, 134.5, 136.4, 137.1, 138.9, 140.2, 154.1, 164.5, 168.6.
8. Lee, S.; Jung, S. Carbohydr. Res. 2004, 339, 461.
Acknowledgment
9. Crich, D.; Bowers, A. A. Org. Lett. 2007, 9, 5323.
One of the authors, N.V.L. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship.
10. Typical experimental procedure for 5j:
A mixture of 2-naphthaldehyde 1j
(1.0 mmol), 3-phenyl-5-isoxazolone 2 (1.0 mmol), sarcosine 4 (1.0 mmol) in
methanol was refluxed for 40 min and cooled to room temperature. The solid
formed in the reaction mixture was filtered, dried under vacuum. The crude
solid product was purified by recrystallization in methanol to obtain the pure
product 5j in good yield (80%).
Supplementary data
Spectral data of compound 5j: (Table 1, entry 10): White solid. Mp 202–204 °C.
Rf 0.3 (50% EtOAc/petroleum ether). mmax (KBr): 3218, 2369, 1714, 1436,
695 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 2.85 (s, 3H, –NCH3), 3.51 (t, 1H,
.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.078.
J = 9.2 Hz, –NCH), 3.90 (t, 1H, J = 9.2 Hz, –NCH), 4.54–4.56 (m, 1H, –CH), 4.76–
4.78 (m, 1H, CH), 7.20–7.22 (m, 5H, –Ar–H), 7.38–7.41 (m, 1H, –Ar–H), 7.43–
7.47 (m, 2H, –Ar–H), 7.73 (d, 1H, J = 7.7 Hz, –Ar–H), 7.78 (d, 1H, J = 7.7 Hz, –Ar–
H), 7.83–7.87 (m, 2H, –Ar–H), 11.66 (br s, 1H, –OH, D2O exchangeable). 13C
NMR (125 MHz, DMSO-d6): d 30.1, 36.9, 49.1, 54.8, 123.2, 124.7, 126.2, 126.3,
126.8, 127.9, 128.8, 129.0, 129.3, 131.9, 133.9, 136.6, 137.4, 154.1, 171.5. MS
(m/z): 345.0 M++1. Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13.
Found: C, 76.78; H, 5.89; N, 8.18.
References and notes
1. (a) Sun, J.; Sun, Y.; Gong, H.; Xie, Y.-J.; Yan, C.-J. Org. Lett. 2012, 14, 5172; (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123; (c) Zhu, J.; Bienayme, H. Multicomponent Reactions;
Wiley: Weinheim, 2005; (d) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007,
36, 1095; (e) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367; (f)
Jiang, B.; Li, Q.-Y.; Tu, S.-J.; Li, G. Org. Lett. 2012, 14, 5210; (g) Zhu, Q.; Gao, L.;
Chen, Z.; Zheng, S.; Shu, H.; Li, J.; Jiang, H.; Liu, S. Eur. J. Med. Chem. 2012, 54,
232; (h) Brahmachari, G.; Das, S. Tetrahedron Lett. 2012, 53, 1479.
2. (a) Lakshmi, N. V.; Josephine, G. A. S.; Perumal, P. T. Tetrahedron Lett. 2012, 53,
1282; (b) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.; Perumal, P. T.
Eur. J. Med. Chem. 2012, 51, 79; (c) Lakshmi, N. V.; Tamilisai, R.; Perumal, P. T.
Tetrahedron Lett. 2011, 52, 5301; (d) Kiruthika, S. E.; Lakshmi, N. V.; Banu, B. R.;
Perumal, P. T. Tetrahedron Lett. 2011, 52, 6508; (e) Lakshmi, N. V.; Arun, Y.;
Perumal, P. T. Tetrahedron Lett. 2011, 52, 3437.
11. Crystallographic data for compound 5k in this Letter have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC-904110. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk.
12. Spectral data of compound 7a: (Table 2, entry 1): Green solid. Mp 220–222 °C. Rf
0.3 (50% EtOAc/petroleum ether). mmax (KBr): 3424, 1733, 1570, 1470,
1181 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 1.50 (d, 1H, J = 10.2 Hz, –CH),
.
1.71 (d, 1H, J = 13.0 Hz, –CH), 2.06–2.08 (m, 1H, –CH), 2.64–2.66 (m, 2H, –CH2),
3.18 (d, 1H, J = 9.2 Hz, –CH), 3.92–3.94 (m, 1H, –CH), 4.20–4.21 (m, 1H, –CH),
4.37 (d, 1H, J = 9.2 Hz, –CH), 6.84 (d, 1H, J = 8.4 Hz, –Ar–H), 7.07–7.10 (m, 3H, –
Ar–H), 7.30–7.33 (m, 4H, –Ar–H), 7.37–7.39 (m, 2H, –Ar–H), 8.72 (br s, 1H, –OH,
D2O exchangeable). 13C NMR (125 MHz, DMSO-d6): d 17.6, 25.8, 34.7, 39.5,
53.2, 62.1, 126.4, 126.9, 127.9, 128.7, 129.1, 129.2, 130.6, 132.2, 133.4, 140.8,
163.5, 174.5. MS (m/z): 321.7 M++1. Anal. Calcd for C20H20N2O2: C, 74.98; H,
6.29; N, 8.74. Found: C, 74.92; H, 6.34; N, 8.78.
3. (a) Moriyama, K.; Izumisawa, Y.; Togo, H. J. Org. Chem. 2012, 77, 9846; (b) Li, G.;
Ding, Z.; Xu, B. Org. Lett. 2012, 14, 5338.
4. (a) Donohoe, T. J.; Chiu, J. Y. K.; Thomas, R. E. Org. Lett. 2007, 9, 421; (b) Liu, Z.;
Nefzi, A. J. Comb. Chem. 2010, 12, 566.