An unexpected simple synthesis of N-substituted 2-acetoxy-5-arylpyrroles and their hydrolysis to 3 and 4-pyrrolin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2004.10.136

The preparation of 2-acetoxy-5-arylpyrroles and 3-pyrrolin-2-ones, from 3-aroylpropionamides and acetyl chloride, is described. The unexpected synthesis of N-substituted 2-acetoxy-5-arylpyrroles, from the reaction of 3-aroyl-propionamides with a large excess of refluxing acetyl chloride, and their alkaline hydrolysis to 3- and 4-pyrrolin-2-ones, is described.

Full text of DOI:10.1016/j.tetlet.2004.10.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9353–9355
An unexpected simple synthesis of N-substituted
2-acetoxy-5-arylpyrroles and their hydrolysis to
3 and 4-pyrrolin-2-ones
Georgia Tsolomiti and Athanase Tsolomitis*
The Laboratory of Organic Chemistry, The School of Chemical Engineering, The National Technical University of Athens,
Athens 157 80, Greece
Received 9 August 2004; revised 15 October 2004; accepted 22 October 2004
Abstract—The unexpected synthesis of N-substituted 2-acetoxy-5-arylpyrroles, from the reaction of 3-aroyl-propionamides with a
large excess of refluxing acetyl chloride, and their alkaline hydrolysis to 3- and 4-pyrrolin-2-ones, is described.
Ó 2004 Elsevier Ltd. All rights reserved.
The importance of the pyrrole ring system has continued
to stimulate a great deal of interest in the development
of new methodologies for its synthesis. Several recent
reviews on this topic are available.1–3 Pyrroles, which
occur in porphyrins,4 pigments,5 and other natural
products6 have found applications in materials science7
and are common components in molecular recognition
and self-assembly ensembles.8–10 On the other hand, 3-
pyrrolin-2-ones are important structural units in organic
and medicinal chemistry including the synthesis of alka-
loids, nucleosides, antineoplastic agents or immunosup-
pressants.11 The a,b-unsaturated lactam moiety can be
utilized as a Michael acceptor for a variety of nucleo-
philes including stabilized carbanions,12 and nitrogen
nucleophiles.13,14 Therefore the synthesis of such build-
ing blocks is currently receiving considerable
attention.15,16
hydrolysis of 2-acetoxypyrroles 2 was shown to give a
mixture of 3- and 4-pyrrolin-2-ones 4 and 5, respec-
tively, in a ratio between 70:30 to 80:20, evidently
through the unstable21,22 2-hydroxypyrroles 3 (Scheme
1). After recrystallization of the pyrrolinone mixture,
the pure 3-pyrolin-2-ones 4a,b and 4d could be sepa-
rated.23 We have not yet used other special physical
methods for the separation of the other pyrrolinones.
It must be pointed out that the transformation of 3-
pyrrolin-2-ones 4a,b and 4d to the corresponding
acetoxypyrroles 2 was accomplished by resubjection to
acetyl chloride. This transformation was also successful
for the 3- and 4-pyrrolin-2-one mixtures. An isomeriza-
tion study between 3- and 4-pyrrolin-2-ones has been re-
ported,24 as well as the non-existence of the pure
isomers, at room temperature.
A
proposed mechanism for 2-acetoxypyrrole
formation could involve: tautomerization of the 3-aroyl-
propionamides to the corresponding 5-hydrox-
2
Here we wish to report a simple and unexpected synthe-
sis of N-substituted 2-acetoxy-5-arylpyrroles 2 from the
corresponding 3-aroylpropionamides 1, via a cyclocon-
densation–acetylation reaction, conducted with a large
excess of acetyl chloride under reflux,17 and their alka-
line hydrolysis to the corresponding 3- and 4-pyrrolin-
2-ones 4 and 5 (Scheme 1). The starting N-substituted
3-aroylpropionamides 1 were prepared from the corre-
sponding 3-aroylpropionic acids.18–20 The alkaline
1
ypyrrolidinones 6, their subsequent dehydration to the
4-pyrrolin-2-ones 5, which after acetylation of these or
their tautomers, 2-hydroxypyrroles 3, proceed to the 2-
acetoxypyrroles 2 (Scheme 2). Both the tautomerization
and dehydration routes could be acid catalyzed by traces
of hydrogen chloride present in the acetyl chloride. The
elimination of 6 to 5 could proceed via the O-acetate
of 6.
In conclusion, acetyl chloride is an excellent reagent for
the cyclocondensation–acetylation reaction of 3-aroyl-
propionamides to the corresponding N-substituted
Keywords: 2-Acetoxypyrroles; 3-Pyrrolin-2-ones; 3-Aroylpropion-
amides; Acetyl chloride.
*
Corresponding author. E-mail: tsolom@chemeng.ntua.gr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.136

9354
G. Tsolomiti, A. Tsolomitis / Tetrahedron Letters 45 (2004) 9353–9355
AcCl
reflux
hydrolysis
HO
ArCOCH2CH2CONHR
Ar
OAc
N
1
R
2
Ar
O
Ar
O
Ar
OH
N
N
N
R
R
R
5
4
3
2
4
Ar
R
yield(%)
Ar
(a): C6H5-
(b): p-CH3C6H4-
(d): C6H5-
R
yield(%)
(a): C6H5-
(b): p-CH3C6H 4- C6H5-
(c): p-ClC6H4-
(d): C6H5-
(e): p-CH3OC6H4- C6H5CH2-
(f): P-CH3C6H4- C6H5CH2-
(g): p-BrC6H4-
C6H5-
61
59
62
81
73
75
67
C6H5-
C6H5-
C6H5CH2- 71
66
70
C6H5-
C6H5CH2-
C6H5CH2-
Scheme 1.
HO
Ar
H2O
ArCOCH2CH2CONHR
Ar
O
O
N
N
1
6
5
R
R
AcCl
Ar
Ar
OH
OAc
N
N
R
3
R
2
Scheme 2.
7. (a) Baumgarten, M.; Tyutyulkov, N. Chem. Eur. J. 1998,
4, 987–989; (b) Deronzier, A.; Moutet, J.-C. Curr. Top.
Electrochem. 1994, 3, 159–200.
8. Gale, P. A.; Anzenbacher, P.; Sessler, J. L. Coord. Chem.
Rev. 2001, 222, 57–102.
5-aryl-2-acetoxypyrroles. The latter is likely to be a use-
ful synthon for the preparation of 3-pyrrolin-2-ones.
The application of this method to c-keto amides with
other substituents present on the functional groups
and methylene chain, as well as the separation of all
the 3-pyrrolin-2-ones and the 4-pyrrolin-2-ones, is cur-
rently being investigated.
9. Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew.
Chem., Int. Ed. 2001, 40, 2383–2426.
10. Wemmer, D. E. Biopolymers 1999, 52, 197–211.
11. Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990,
55, 5017–5025, and references cited therein.
12. Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J.
Org. Chem. 1998, 63, 220–221.
References and notes
1. Sundberg, R. J.; Nguyen, P. V. Prog. Heterocycl. Chem.
1994, 6, 110–128.
13. Langlois, N.; Calvez, O.; Radom, M.-O. Tetrahedron Lett.
1997, 38, 8037–8040.
2. Sundberg, R. J. Prog. Heterocycl. Chem. 1992, 4, 81–
94.
14. Langlois, N.; Radom, M.-O. Tetrahedron Lett. 1998, 39,
857–860.
3. Gilchrist, T. L. Contemp. Org. Synth. 1994, 1, 205–217.
4. Smith, K. M. J. Porphyr. Phthalocya. 2000, 4, 319–
324.
15. Mattern, R.-H. Tetrahedron Lett. 1996, 37, 291–294.
16. Woo, C.-K.; Jones, K. Tetrahedron Lett. 1991, 32, 6949–
6952.
5. Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507–526.
6. Christophersen, C. In The Alkaloids; Brossi, A., Ed.;
Academic: Orlando, 1985; Vol. 24, Chapter 2.
17. Typical procedure for the preparation of 2-acetoxypyr-
roles 2. A mixture of the c-keto amide 1 (20mmol) and
acetyl chloride (100–150mL) (depending on the c-keto

G. Tsolomiti, A. Tsolomitis / Tetrahedron Letters 45 (2004) 9353–9355
9355
amide solubility), was refluxed for 1–4h. The solution was
concentrated under vacuum to a residue, which proved to
be almost pure (1H NMR) compound 2. After recrystal-
lization, an analytical sample was obtained in 59–81%
yield. 2-Acetoxy-1,5-diphenylpyrrole 2a: yield 61%, mp
112–113°C. Anal. Calcd for C18H15NO2: C, 77.95; H,
5.46; N, 5.05%. Found: C, 77.99; H, 5.71; N, 5.04%. IR
21.32; N, 3.72%. IR (Nujol mull, cmÀ1): 1776, 1567, 1555,
1503 and 1493; H NMR (300MHz, CDCl3): 2.08 (s, 3H,
CH3CO), 5.01 (s, 2H, –CH2Ph), 6.02 (d, J = 4Hz, 1H, –
CH@), 6.22 (d, J = 4Hz, 1H, –CH@), 6.83–7.53 (m, 9H,
arom). 13C NMR (75.5MHz, CDCl3): 20.57, 47.00, 96.35,
107.32, 121.36, 126.12, 127,64, 128.14, 129.06, 130.41,
131.92, 132.15, 138.23, 167.90.
1
1
(Nujol mull, cmÀ1): 1770, 1603, 1565, 1515 and 1499; H
18. Chiron, R.; Graff, Y. Bull. Soc. Chim. Fr. 1970, 575–583.
19. Cromwell, N. H.; Cook, K. E. J. Am. Chem. Soc. 1958, 80,
4573–4577.
20. Codfrey, C. R. A. Eur. Pat. Appl. EP 1987, 246,735;
Codfrey, C. R. A. Chem. Abstr. 1988, 108, 150464s.
21. Atkinson, J. H.; Atkinson, R. S.; Johnson, A. W. J. Chem.
Soc. 1964, 5999–6009.
NMR (300MHz, CDCl3): d 2.07 (s, 3H, CH3CO), 6.06 (d,
J = 4Hz, 1H, –CH@), 6.42 (d, J = 4Hz, 1H, –CH@), 7.12–
7.52 (m, 10H, arom). 13C NMR (75.5MHz, CDCl3):
20.39, 96.81, 107.70, 126.40, 127.90, 128.22, 128.33,
128.42, 128.95, 129.21, 132.96, 133.74, 136.98, 170.85.
HRMS (EI) calcd for C18H15NO2: 277.3172. Found:
277.3214. 2-Acetoxy-5-(4-methylphenyl)-1-phenylpyrrole
2b: yield, 59%, mp 79–81°C. Anal. Calcd for
C19H17NO2: C, 78.33; H, 5.88; N, 4.81%. Found: C,
78.11; H, 5.76; N, 4.68%. IR (Nujol mull, cmÀ1): 1779,
1597, 1560, 1526 and 1500; 1H NMR (300MHz, CDCl3): d
2.07 (s, 3H, CH3CO), 2.28 (s, 3H, CH3Ar), 6.02 (d,
J = 4Hz, 1H, –CH@), 6.33 (d, J = 4Hz, 1H, –CH@), 6.95–
7.47 (m, 9H, arom). HRMS (EI) calcd for C19H17NO2;
291.3438. Found 291.3465. 2-Acetoxy-5-(4-chlorophenyl)-
1-phenylpyrrole 2c: yield, 62%, mp 126–128°C. Anal.
Calcd for C18H14ClNO2: C, 69.35; H, 4.53; Cl, 11.37; N,
4.49%. Found: C, 69.49; H, 4.60; Cl, 11.57; N, 4.36%. IR
22. Plieninger, H.; Decker, M. Liebigs Ann. Chem. 1956, 598,
198–207.
23. General procedure for the preparation of 3-pyrrolin-2-
ones 4. To a refluxing solution of 2-acetoxypyrrole 2
(10mmol) in methanol (80–130mL), a solution of 0.01N
potassium hydroxide (20mL) was added dropwise. Reflux
was continued (40–75min), until reaction was complete
(TLC). The solution was then concentrated under vacuum
and the residue was recrystallized from benzene/petrol
ether, to give an analytical sample of 3-pyrrolin-2-one 4, in
66–71% yields, or a pure mixture of 3- and 4-pyrrolin-
2-ones 4 and 5, in 74–86% yields, (as proved25 from 1H
NMR and elemental analysis). 1,5-Diphenyl-3-pyrrolin-2-
one 4a: yield, 66%, mp 166–168°C, lit.26 167–168°C. IR
(Nujol mull, cmÀ1): 1686, 1598, 1503; 1H NMR (300MHz,
CDCl3): d 5.65 (t, J = 1.8Hz, 1H, C5), 6.20 (dd, J = 6Hz
and J = 1.8Hz, 1H, C4), 6.83–7.60 (m, 11H, 10 arom and
C3). 13C NMR (75.5MHz, CDCl3): 67.70, 121.71, 124.89,
126.46, 127.02, 128.76, 129.11, 129.43, 135.33, 137.64,
148.63, 171.01. 5-(4-Methylphenyl)-1-phenyl-3-pyrrolin-2-
one 4b: yield 70%, mp 127–129°C. Anal. Calcd for
C17H15NO: C, 81.90; H, 6.06; N, 5.61%. Found: C,
81.86; H, 6.13; N, 5.44%. IR (Nujol mull, cmÀ1): 1680,
1593, 1498; 1H NMR (300MHz, CDCl3): d 2.28 (s, 3H,
CH3Ar), 5.63 (t, J = 1.8Hz, 1H, C5), 6.24 (dd, J = 6Hz
and 1.8Hz, 1H, C4), 6.93–7.62 (m, 10H, 9 arom and C3).
13C NMR (75.5MHz, CDCl3): 21.18, 67.51, 121.76,
124.84, 126.35, 126.95, 129,10, 130.12, 132.19, 137.69,
138.62, 148.78, 171.04. 1-Benzyl-5-phenyl-3-pyrrolin-2-
one 4d: yield 71%, mp 125–127°C. Anal. Calcd for
C17H15NO: C, 81.90; H, 6.06; N, 5.61%. Found: C,
82.06; H, 6.25; N, 5.44%. IR (Nujol mull, cmÀ1): 1678,
1
(Nujol mull, cmÀ1): 1773, 1598, 1560, 1510 and 1500; H
NMR (300MHz, CDCl3): d 2.07 (s, 3H, CH3CO), 6.03 (d,
J = 4Hz, 1H, –CH@), 6.37 (d, J = 4Hz, 1H, –CH@), 6.87–
7.50 (m, 9H, arom). 2-Acetoxy-1-benzyl-5-phenylpyrrole
2d: yield 81%, mp 74–76°C. Anal. Calcd for C19H17NO2:
C, 78.33; H, 5.88; N, 4.81%. Found: C, 78.27; H, 5.75; N,
4.73%. IR (Nujol mull, cmÀ1). 1773, 1603, 1565, 1511 and
1497; 1H NMR (300MHz, CDCl3): d 2.05 (s, 3H,
CH3CO), 5.05 (s, 2H, –CH2Ph), 6.03 (d, J = 4Hz, 1H, –
CH@), 6.25 (d, J = 4Hz, 1H, –CH@), 6.87–7.50(m, 10H,
arom). 13C NMR (75.5MHz, CDCl3): 20.55, 47.03, 96.12,
106.84, 126.23, 127.30, 127.49, 128.76, 128.95, 129.00,
129.42, 139.26, 137,87, 138.51, 167.97. 2-Acetoxy-1-ben-
zyl-5-(4-methoxyphenyl)pyrrole 2e: yield, 73%, mp 78–
79°C. Anal. Calcd for C20H19NO3: C, 74.74; H, 5.96; N,
4.36%. Found: C, 74.67; H, 5.97; N, 4.32%. IR (Nujol
mull, cmÀ1): 1778, 1613, 1563 and 1521; 1H NMR
(300MHz, CDCl3): 2.02 (s, 3H, CH3CO), 3.73 (s, 3H,
CH3O), 5.00 (s, 2H, –CH2Ph), 5.94 (d, J = 4Hz, 1H, –
CH@), 6.13 (d, J = 4Hz, 1H, –CH@), 6,70–7.43 (m, 9H,
arom). 13C NMR (75.5MHz, CDCl3): 20.56, 46.90, 55.41,
95.78, 106.15, 114.14, 125.80, 126.24, 127.46, 128.94,
129.12, 130.49, 137.34, 138.62, 159.21, 168.05. 2-Acet-
oxy-1-benzyl-5-(4-methylphenyl)pyrrole 2f: yield 75%, mp
89–91°C. Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27;
N, 4.59%. Found: C, 78.51; H, 6.11; N, 4.48%. IR (Nujol
mull, cmÀ1): 1778, 1613, 1572, 1560, 1517 and 1495; 1H
NMR (300MHz, CDCl3): 2.05 (s, 3H, CH3CO), 2.35 (s,
3H, CH3Ar), 5.03 (s, 2H, –CH2Ph), 6.00 (d, J = 4Hz, 1H,
–CH@), 6.19 (d, J = 4Hz, 1H, –CH@), 6.87–7.50 (m, 9H,
arom). 13C NMR (75.5MHz, CDCl3): 20.56, 21.23, 64.99,
95.96, 106.44, 126.23, 127.45, 128.34, 128.93, 129.00,
129.46, 130.36, 137.12, 137.61, 138.62, 168.00. 2-Acet-
oxy-1-benzyl-5-(4-bromophenyl)pyrrole 2g: yield 67%, mp
113–114°C. Anal. Calcd for C19H16BrNO2: C, 61.64; H,
4.36; Br, 21.58; N, 3.78%. Found: C, 61.75; H, 4.40; Br,
1
1598, 1494; H NMR (300MHz, CDCl3): d 3.61 and 5.20
(dd, J = 15Hz, 2H, –CHaHbPh), 4.88 (t, J = 1.8Hz, 1H,
C5), 6.21 (dd, J = 6Hz and 1.8Hz, 1H, C4), 6.85–7.50 (m,
11H, 10 arom and C3). 13C NMR (75.5MHz, CDCl3):
43.59, 66.06, 126.43, 127.71, 128.51, 128.82, 129.10,
129.46, 133.57, 134.63, 137.64, 148.49, 171.72.
24. Baker, J. T.; Sifniades, S. J. Org. Chem. 1979, 44, 2798–
2800.
25. An analytical sample (mp 159–163°C, after recrystalliza-
tion), of a mixture of pyrrolinones 4a and 5a showed the 3-
pyrrolin-2-one 4a signals and of those at d 3.39 (d,
J = 2.5Hz, 1H, C3) and 5.68 (t, J = 2.5Hz, 1H, C4), which
agree24 with the 4-pyrrolin-2-one structure 5a. Analogous
sets of signals appeared in all the pyrrolinone mixtures.
26. Boyd, G. V.; Heatherington, K. J. Chem. Soc., Perkin
Trans. 1 1973, 2523–2529.