A convenient synthesis of p-substituted 1-arylsulfonyl-pyrrolidin-2-ones

Article abstract of DOI:10.1080/14786410802090375

A convenient and novel method of cyclisation of 4-(4-substituted- phenylsulfonamido)-butanoic acids to their corresponding p-substituted 1-arylsulfonyl-pyrrolidin-2-ones was achieved by using polyphosphate ester (PPE). The reaction times were considerably

Full text of DOI:10.1080/14786410802090375

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Natural Product Research: Formerly
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A convenient synthesis of p-substituted
1-arylsulfonyl-pyrrolidin-2-ones
Muhammad Zareef a , Rashid Iqbal b , Khalid M. Khan c , Javid H.
Zaidi b , Zia-Ullah c & Muhammad Arfan b
a Department of Chemistry , University of Gujrat , Hafiz Hayat
Campus, Gujrat, Pakistan
b Department of Chemistry , Quaid-i-Azam University , Islamabad,
Pakistan
c International Center for Chemical and Biological Sciences , HEJ
Research Institute of Chemistry, University of Karachi , Karachi,
Pakistan
Published online: 29 Oct 2009.
To cite this article: Muhammad Zareef , Rashid Iqbal , Khalid M. Khan , Javid H. Zaidi ,
Zia-Ullah & Muhammad Arfan (2009) A convenient synthesis of p-substituted 1-arylsulfonyl-
pyrrolidin-2-ones, Natural Product Research: Formerly Natural Product Letters, 23:5, 485-488, DOI:
10.1080/14786410802090375
To link to this article: http://dx.doi.org/10.1080/14786410802090375
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Natural Product Research
Vol. 23, No. 5, 20 March 2009, 485–488
A convenient synthesis of p-substituted 1-arylsulfonyl-pyrrolidin-2-ones
b
c
b
c
Muhammad Zareef a , Rashid Iqbal , Khalid M. Khan , Javid H. Zaidi , Zia-Ullah
*
and Muhammad Arfanb
aDepartment of Chemistry, University of Gujrat, Hafiz Hayat Campus, Gujrat, Pakistan;
c
bDepartment of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan; International Center
for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of Karachi,
Karachi, Pakistan
(Received 16 March 2007; final version received 5 October 2007)
A convenient and novel method of cyclisation of 4-(4-substituted-phenylsulfona-
mido)-butanoic acids to their corresponding p-substituted 1-arylsulfonyl-pyrro-
lidin-2-ones was achieved by using polyphosphate ester (PPE). The reaction times
were considerably reduced, with an increase in yields, when PPE was used in
combination with a catalytic amount of pyridine.
Keywords: p-substituted 1-arylsulfonyl-pyrrolidin-2-ones; polyphosphate ester;
dehydrative cyclisation
1. Introduction
Pyrrolidinone derivatives, including N-substituted-pyrrolidin-2-ones, have been reported
to have anti-HIV, antitumour, antifungal (Coutrot, Claudel, Didierjean, & Grison, 2006),
antiviral (Brouillette et al., 2003), channel opening (Liang, Hsin, & Cheng, 2002),
neuroprotective (Moglioni, Brousse, Larena, Moltrasio, & Ortuno, 2002) and anti-
hypertensive (Kulig, Holzgrabe, & Malawska, 2001) activities. Substituted pyrrolidin-2-
ones are of interest because of their use as intermediaries for the synthesis of ꢀ-amino acids
(Corey & Zhang, 2000) and pyrrolidines (Xia & Ganem, 2001). Though a number of
methods have been reported in the literature (Brouillette et al., 2003; Coutrot et al., 2006;
Domingos, Lima, Dias, Costa, 2001 and references cited therein; Kulig et al., 2001;
Lesniak & Pasternak, 2005; Liang et al., 2002; Moglioni et al., 2002) for the synthesis of
substituted pyrrolidin-2-ones, we want to report herewith a cost effective and convenient
method for the preparation of N-substituted pyrrolidin-2-ones (Scheme 1).
The p-substituted 1-arylsulfonyl-pyrrolidin-2-ones 3a–e were prepared from corre-
sponding 4-(4-substituted-phenylsulfonamido)-butanoic acids 2a–e in the presence of
polyphosphate ester (PPE). The reaction provided compounds 3a–e in excellent yields
(65–87%) by simple stirring at room temperature (Method A).
For the second method (Method B) to synthesise compounds 3a–e, PPE in the presence
of catalytic amounts of dry pyridine (2–3 drops) in chloroform (2 mL) were used for the
dehydrative cyclisation. It is worth noting here that the reaction time was reduced from
30 h to 17 h.
*Corresponding author. Email: mzareef71@yahoo.com
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2009 Taylor & Francis
DOI: 10.1080/14786410802090375
http://www.informaworld.com

486
M. Zareef et al.
OH
ii
HN
O
O
O
S
O
O
S
OH
i
N
R
H2N
O
O
3a–e
1
2a–e
R
i) RC H SO Cl, aq. NaOH (5%), ether; ii) Polyphosphate (PPE) or PPE, pyridine
6
4
2
2a, 3a R = CH , 2b, 3b R = Cl, 2c, 3c R = OCH , 2d, 3d R = NO , 2e, 3e R = NHCOCH
3
3
3
2
Scheme 1.
The PPE (F.L. Fieser & M. Fieser, 1967 and references therein) and 4-(4-substituted-
phenylsulfonamido)-butanoic acids (Furniss, Hannaford, Rogers, Smith, & Tatchell) 2a–e
were prepared by the reported methods. The synthesised compounds were characterised by
1
elemental/HRMS, UV, IR, H NMR, 13C NMR and mass spectral data.
In conclusion, we present a novel, efficient and cost effective method for the synthesis
of p-substituted 1-arylsulfonyl-pyrrolidin-2-ones catalysed by PPE. It is worthwhile to
note that the reaction time could be reduced when PPE was used in combination with dry
pyridine (Method B), with an increase in yields.
2. Experimental
Melting points were determined on a Gallenkamp digital melting point apparatus and are
uncorrected. IR spectra were recorded in KBr discs on a FT-IR model FTS 3000 MX
spectrometer. Elemental analysis was performed on a Carlo Erba 1106 elemental analyser.
1H NMR (400 and 500 MHz) spectra were recorded on a Bruker NMR spectro-
photometer. The chemical shifts of proton signals are in parts per million (ppm) downfield
from tetramethylsilane (TMS) as an internal standard. EI-MS spectra were recorded on
MAT 312 and MAT 311A mass spectrometers. Thin layer chromatography (TLC) was
performed on pre-coated silica gel 60 F254 aluminum sheets (Merck).
2.1. General procedure for the synthesis of p-substituted 1-arylsulfonyl-pyrrolidin-2-ones
(3a–e)
Method A: A mixture of 4-(4-substitutedphenylsulfonamido)-butanoic acid (2) (1.00 mmol)
and PPE (2.5 mL) was stirred under anhydrous conditions at room temperature for
25–30 h. After completion of the reaction, the mixture was treated with a saturated
solution of aqueous sodium bicarbonate (25 mL) and extracted with chloroform
(3 ꢀ 15 mL). The combined extract was washed with brine, water and dried over sodium
sulfate (anhydrous). The solvent was removed using a rotary evaporator. The oily product
was crystallised from absolute ethanol, filtered and recrystallised from chloroform and
ethanol (1 : 5) to afford compounds 3a–e.
Method B: 4-(4-substitutedphenyl-sulfonamido)-butanoic acid (2) (1.00 mmol), PPE
(2.5 mL) and catalytic amounts of dry pyridine (2–3 drops) in dry CHCl3 (2 mL) were
stirred at room temperature for 16–17 h. The remaining method is the same as Method A.

Natural Product Research
487
2.2. p-Methylphenylsulfonyl-pyrrolidin-2-one (3a)
Method A: yield 83%; Method B: yield 85%; m.p. ¼ 145–146ꢁC. UV (ꢁmax, CH3OH, nm):
1
267, 246; IR (ꢂmax, KBr, cmꢂ1): 3059 (CH–Ar), 1729 (C¼O), 1356, 1166 (SO2); H NMR
(500 MHz, C3H6O-d6): ꢃ 2.06–2.13 (m, 2H, CH2), 2.38 (t, J ¼ 8.0 Hz, 2H, COCH2), 2.43 (s,
3H, CH3), 3.90 (t, J ¼ 7.0, 2H, NCH2), 7.42 (d, J ¼ 8.2 Hz, 2H, ArH), 7.88 (d, J ¼ 8.2 Hz,
2H, ArH); 13C NMR (75 MHz, CDCl3): ꢃ 18.2, 21.7, 32.2, 47.3, 128.0, 129.7, 135.1, 145.2,
173.4; EI MS (% rel. abundance): 241 (Mþþ2), 240 (Mþþ1), 177 (3), 176 (39), 175 (90),
174 (90), 157 (3), 156 (6), 155 (62), 139 (16), 121 (29), 120 (89), 119 (4), 118 (4), 93 (2), 92
(29), 91 (100), 89 (17), 65 (54); Anal. Calcd for C11H13NO3S: (239.2899) C, 55.21; H, 5.48;
N, 5.85; S, 13.41; Found: C, 55.54; H, 5.29; N, 5.66; S, 13.70.
2.3. p-Chlorophenylsulfonyl-pyrrolidin-2-one (3b)
Method A: yield 78%; Method B: yield 80%, m.p. ¼ 154–156ꢁC; UV (ꢁmax, CH3OH, nm):
1
266, 242. IR (ꢂmax, KBr, cmꢂ1): 3051 (CH–Ar), 1739 (C¼O), 1376, 1166 (SO2); H NMR
(250 MHz, CDCl3): ꢃ 2.33–2.02 (m, 2H, CH2), 2.40 (t, J ¼ 7.0 Hz, 2H, COCH2), 3.87
(t, J ¼ 7.0, 2H, NCH2), 7.88 (d, J ¼ 8.2 Hz, 2H, ArH), 7.97 (d, J ¼ 8.2 Hz, 2H, ArH); 13C
NMR (63 MHz, CDCl3): ꢃ 18.4, 32.4, 47.5, 128.4, 129.9, 135.2, 145.4, 173.5; EI MS (% rel.
abundance): 260 (Mþþ1), 195 (62), 175 (100), 112 (15), 111 (39), 76 (16), 75 (29); HRMS:
Calcd for C10H10NO3SCl: 259.007; Found: 259.005.
2.4. p-Methoxyphenylsulfonyl-pyrrolidin-2-one (3c)
Method A: yield 85%; Method B: yield 87%; m.p. ¼ 151–152ꢁC; UV (ꢁmax, CH3OH, nm):
1
291, 249; IR (ꢂmax, KBr, cmꢂ1): 3079 (CH–Ar), 1733 (C¼O), 1355, 1161 (SO2); H NMR
(500 MHz, acetone-d6): ꢃ 2.00–2.03 (m, 2H, CH2), 2.37 (t, J ¼ 7.0 Hz, 2H, CH2CO), 3.80
(t, J ¼ 7.0 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 7.26 (d, J ¼ 8.2 Hz, 2H, ArH), 7.86
(d, J ¼ 8.2 Hz, 2H, ArH); 13C NMR (63 MHz, CDCl3): ꢃ 18.0, 32.6, 47.2, 57.1, 128.0,
129.2, 135.0, 145.1, 173.1. EI MS (% rel. abundance): 256 (Mþþ1), 192 (54), 172 (16), 171
(100), 109 (4), 108 (4), 107 (39), 76 (29), 65 (54). Anal. Calcd for C11H13NO4S: (255.2993)
C, 51.75; H, 5.13; N, 5.49; S, 12.56. Found: C, 51.61; H, 4.97; N, 5.67; S, 12.35.
2.5. p-Nitrophenylsulfonyl-pyrrolidin-2-one (3d)
Method A: yield 65%; Method B: yield 66%; m.p. ¼ 162–163ꢁC; UV (ꢁmax, CH3OH, nm):
1
311, 249; IR (ꢂmax, KBr, cmꢂ1): 3068 (CH–Ar), 1739 (C¼O), 1375, 1166 (SO2); H NMR
(250 MHz, CDCl3): ꢃ 2.01–2.04 (m, 2H, CH2), 2.48 (t, J ¼ 7.3 Hz, 2H, COCH2), 3.94
(t, J ¼ 7.2, 2H, NCH2), 7.87 (d, J ¼ 8.2 Hz, 2H, ArH), 8.46 (d, J ¼ 8.0 Hz, 2H, ArH);
13C NMR (63 MHz, CDCl3): ꢃ 19.1, 32.5, 49.2, 128.8, 129.8, 135.7, 147.2, 176.5; HRMS
Calcd for C10H10NO5S: 270.2604; Found: 270.2646.
2.6. p-Acetamidophenylsulfonyl-pyrrolidin-2-one (3e)
Method A: yield 72%; Method B: yield 78%; m.p. ¼ 153–155ꢁC. UV (ꢁmax, CH3OH, nm):
299, 245; IR (ꢂmax, KBr, cmꢂ1): 3286 (NH), 1725 (C¼O), 1679 (C¼O), 1366, 1155 (SO2);
1H NMR (500 MHz, acetone-d6): ꢃ 2.01–2.03 (m, 2H, CH2), 2.38 (t, J ¼ 7.0 Hz, 2H,

488
M. Zareef et al.
COCH2), 2.46 (s, 3H, CH3), 3.85 (t, J ¼ 6.8, 2H, NCH2), 7.73 (d, J ¼ 8.0 Hz, 2H, ArH),
7.88 (d, J ¼ 8.2 Hz, 2H, ArH); EI MS; m/z (% rel. abundance): 284 (Mþþ2), 220 (62), 198
(39), 183 (100), 155 (29), 75 (4), 65 (16); Anal. Calcd for C12H14N2O4S: (282.315) C, 51.05;
H, 5.10; N, 9.92; S, 11.36; Found: C, 51.26; H, 5.34; N, 9.78; S, 11.39.
Acknowledgement
We are thankful to the Higher Education Commission for providing the necessary funds for these
studies.
References
Brouillette, W.J., Bajpai, S.N., Ali, S.M., Velu, S.E., Atigadda, V.R., Lommer, B.S., et al. (2003).
Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: Modifications of essential
pyrrolidinone ring substituents. Bioorganic and Medicinal Chemistry, 11, 2739–2749.
Corey, E.J., & Zhang, F.Y. (2000). Enantioselective Michael addition of nitromethane to ꢄ,ꢅ-enones
catalyzed by chiral quaternary ammonium salts. A simple synthesis of (R)-baclofen. Organic
Letters, 2, 4257–4259.
Coutrot, P., Claudel, S., Didierjean, C., & Grison, C. (2006). Stereoselective synthesis and
glycosidase inhibitory activity of 3,4-dihydroxy-pyrrolidin-2-one, 3,4-dihydroxy-piperidin-
2-one and 1,2-dihydroxy-pyrrolizidin-3-one. Bioorganic and Medicinal Chemistry Letters, 16,
417–420.
Domingos, J.L.O., Lima, E.C., Dias, A.G., & Costa, R.R. (2004). Stereoselective preparation of
pyrrolidin-2-ones from a Z-enoate derived from D-(þ)-mannitol. Tetrahedron: Asymmetry, 15,
2313.
Fieser, F.L., & Fieser, M. (1967). Reagents for Organic Synthesis (p. 892). USA: John Wiley and
Sons, Inc.
Furniss, B.S., Hannaford, A.J., Rogers, V., Smith, P.W.G., & Tatchell, A.R. (1978). Vogel’s
textbook of practical organic chemistry. (4th Ed., pp. 1135–1136). London: Longman.
Kulig, K., Holzgrabe, U., & Malawska, B. (2001). Stereocontrolled synthesis of the enantiomers of
1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)-propyl]-pyrrolidin-2-one. Tetrahedron: Asymmetry,
12, 2533–2536.
Lesniak, S., & Pasternak, B. (2005). Cyclisation at very high temperature. Thermal transformations
of N-alkyl and N,N-dialkyl cinnamic amides into pyrrolidin-2-ones under FVT conditions.
Tetrahedron Letters, 46, 3093–3095.
Liang, P.H., Hsin, L.W., & Cheng, C.Y. (2002). N-Arylated pyrrolidin-2-ones and morpholin-3-ones
as potassium channel openers. Bioorganic and Medicinal Chemistry, 10, 3267–3276.
Moglioni, A.G., Brousse, B.N., Larena, A.A., Moltrasio, G.Y., & Ortuno, R.M. (2002).
Stereoselective synthesis of cyclobutyl GABA analogues and related compounds from
(ꢂ)-(S)-verbenone. Tetrahedron: Asymmetry, 13, 451–454.
Xia, Q., & Ganem, B. (2001). Asymmetric total synthesis of (-)-ꢄ -kainic acid using an
enantioselective, metal-promoted ene cyclization. Organic Letters, 3, 485–487.