Efficient syntheses of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3- carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate

Article abstract of DOI:10.1016/j.tetlet.2011.03.025

Ethyl 2-chloroacetoacetate and its 4-chloro isomer react with cyanoacetamide in the presence of the mild, nonnucleophilic base, triethylamine under stoichiometric conditions to give high yields of ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (4-cyano-2-hydroxy-5-oxopyrrolidin-2-yl)acetate, respectively. These, under acid-catalyzed dehydration conditions, afforded ethyl 4-cyano-5-hydroxy-2- methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2- ylidene)ethanoate, respectively. Similarly, the 4-chloro isomer reacted with ethyl cyanoacetate to give the novel product, diethyl 2-cyano-4-oxohexanedioate. The use of triethylamine enables access to a whole new library of pyrrole derivatives from easily accessible, commercially available starting materials. The reactions described in this Letter enable access to libraries of important pyrrole systems in any of the isotopically enriched forms.

Full text of DOI:10.1016/j.tetlet.2011.03.025

Tetrahedron Letters 52 (2011) 2508–2510
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient syntheses of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-
3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate
⇑
Prativa B. S. Dawadi , Johan Lugtenburg
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethyl 2-chloroacetoacetate and its 4-chloro isomer react with cyanoacetamide in the presence of the
mild, nonnucleophilic base, triethylamine under stoichiometric conditions to give high yields of ethyl
4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (4-cyano-2-hydroxy-5-oxopyrr-
olidin-2-yl)acetate, respectively. These, under acid-catalyzed dehydration conditions, afforded ethyl
4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-yli-
dene)ethanoate, respectively. Similarly, the 4-chloro isomer reacted with ethyl cyanoacetate to give
the novel product, diethyl 2-cyano-4-oxohexanedioate. The use of triethylamine enables access to a
whole new library of pyrrole derivatives from easily accessible, commercially available starting materials.
The reactions described in this Letter enable access to libraries of important pyrrole systems in any of the
isotopically enriched forms.
Received 7 January 2011
Revised 25 February 2011
Accepted 4 March 2011
Available online 12 March 2011
Keywords:
Pyrroles
Pyrrolidinones
Diethyl 2-cyano-4-oxohexanedioate
Triethylamine
Ó 2011 Elsevier Ltd. All rights reserved.
The substituted pyrrole ring system is the basic building block
of a number of important biological compounds including vitamin
role-3-carboxylate (1) and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-
ylidene)ethanoate (2), respectively.
B
12, chlorophyll, heme, etc.1–3 Similarly, substituted pyrrolidinones
A solution of ethyl 2-chloroacetoacetate (4) (1.64 g, 10 mmol),
cyanoacetamide (3) (0.84 g, 10 mmol), and triethylamine (1.01 g,
10 mmol) in acetonitrile was refluxed for 2 h. After work-up, the
product, ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-
carboxylate (5) (1.85 g, 87%) was obtained as a mixture of isomers
(Scheme 1). Subsequently, product 5 was refluxed in toluene in the
presence of p-toluenesulfonic acid to afford, after work-up, the
novel product ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-
carboxylate (1) in high yield (1.25 g, 81%).
As shown in Scheme 1, following alkylation of cyanoacetamide
(3) by ethyl 2-chloroacetoacetate (4), nucleophilic attack of the
amide function led to a stable isomeric mixture of product 5 which
easily underwent acid-catalyzed elimination of water followed by
a proton shift to give the product, ethyl 4-cyano-5-hydroxy-2-
methyl-1H-pyrrole-3-carboxylate (1). The analytical data were in
agreement with the structures of products 5 and 1.
Similarly, reaction of ethyl 4-chloroacetoacetate (6) and cyano-
acetamide (3) afforded a novel product 7 (1.90 g, 89%) as a mixture
of diastereoisomers. Mass spectrometry and other spectroscopic
data indicated that this product was ethyl (4-cyano-2-hydroxy-5-
oxopyrrolidin-2-yl)acetate (7). The product 7 was heated at reflux
in the presence of p-toluenesulfonic acid in toluene for 4 h and the
elimination of water resulted in pyrrolidone 2 as a colorless solid in
a yield of 1.35 g, (87%).
are important components in the preparation of bile pigments,4
and of several classes of bioactive natural compounds with a wide
range of activity. They are useful intermediates for the synthesis of
(+)-lactacystin,5–7 (À)-rolipram,8 etc. 4-(Aminomethyl)-1-aryl-2-
pyrrolidinones are a new class of monoamine oxidase B inactiva-
tors.9 In addition, the ability to functionalize and modify the
pyrrole or pyrrolidinone moieties could allow the preparation of
some types of natural products as well as the synthesis of
biologically active molecules.
We have a programme to make libraries of stable isotope-
enriched pyrrole systems accessible.10 We reasoned that the
reaction of a simple functionalized halogen compound with an
activated amide may give, in one step, a product with all the
required functional groups to form the required pyrrole or pyrro-
lidinone system. The key step requires the presence of the mild
nonnucleophilic base, trimethylamine (pKa ꢀ10) to deprotonate
the active methylene group (pKa ꢀ10), without appreciably deprot-
onating the amide function (pKa ꢀ16).11
We now report a triethylamine-catalyzed reaction of ethyl
2-chloroacetoacetate and its isomer, ethyl 4-chloroacetoacetate
with cyanoacetamide to afford C-alkylation products, followed by
an intramolecular cyclization and acid-catalyzed dehydration for
the preparation of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyr-
Analytical data confirmed the product as ethyl (2Z)-(4-cyano-5-
oxopyrrolidin-2-ylidene)ethanoate (2). Also, the 1H NMR
assignments were further confirmed by 1H–13C and 1H-correlation
⇑
Corresponding author.
E-mail address: p.b.s.dawadi@gmail.com (P.B.S. Dawadi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.025

P. B. S. Dawadi, J. Lugtenburg / Tetrahedron Letters 52 (2011) 2508–2510
2509
CN
CN
EtO2C
EtO2C
CN
CN
EtO2C
EtO2C
H3C
Cl
O
H+
4
3
+
H3C
HO
O
1
N
H
O
5
O
2
OH
H3C
N
H
H C
O
H2N
H2N
1
5
4
3
CN
CN
Cl
CN
4
3
H+
2
5
2a
O
3
O
1
O
+
2b
EtO2C
EtO2C
O
N
H
O
N
H
H2N
EtO2C
HO
EtO2C
2
7
6
1
3
CN
5
CO2Et
6
2
4
EtO2C
6
+
O
CN
CO2Et
9
8
Scheme 1.
spectroscopy methods. The pyrrolidinone structure of product 2
was established by comparing its analytical data with those of
ethyl (2Z)-(5-oxopyrrolidin-2-ylidene)ethanoate (obtained as an
intermediate in a stepwise synthesis of levulinic acid).12
Based on the effectiveness of triethylamine in this process, we
searched the literature for possible precedents. The reactions of
ethyl 2-chloroacetoacetate (4) with ethyl cyanoacetate (8) using
triethylamine and diisopropylethylamine have been described.13,14
Recently, the reaction of ethyl acetoacetate with chloroacetalde-
hyde in the presence of ammonium hydroxide was reported, the
product of which was ethyl 2-methyl-1H-pyrrole-3-carboxylate.
The reaction proceeds via initial alkylation followed by a subse-
quent Paal–Knorr reaction.15
These results motivated us to use ethyl 4-chloroacetoacetate (6)
as the alkylating agent in the reaction with ethyl cyanoacetate (8).
In this case, the new product, diethyl 2-cyano-4-oxohexanedioate
(9) was obtained in high yield (2.15 g, 89%).
Access to any isotopomer of cyanoacetamide and ethyl cyanoac-
etate has been previously reported by us.16 Similarly, access to any
isotopomer of ethyl acetoacetate and its 2-chloro derivative has
been described.17 The reagents we used in this work are commer-
cially available materials, which can easily be obtained in any sta-
ble isotope enriched form. Thus, using the chemistry described in
this Letter, many biologically important pyrrole systems are acces-
sible in any stable isotope labeled form.
(neat): 3430, 3320, 3234, 3176, 2986, 2243, 1699, 1668, 1652,
1615, 1575, 1557 cmÀ1. HRMS (calculated for C9H12N2O4) m/z
212.2026, (obtained) 212.2013.
Ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate (1):
To a solution of 5 (1.70 g, 8 mmol) in toluene (50 mL) was added
pTsOH (0.20 g, 1 mmol) and the mixture refluxed for 2 h. The sol-
vent was evaporated and the residue was dissolved in CHCl3
(50 mL)/EtOAc (25 mL). The precipitated solid was filtered and
dried under vacuum to yield 1, 1.25 g, (81%) as a colorless solid.
3
1H NMR (300 MHz, DMSO-d6): d = 1.21 (t, JH–H = 7.1 Hz, 3H, CH3),
3
2.29 (s, 3H, CH3), 4.14 (q, JH–H = 7.0 Hz, 2H, CH2), 11.52 (s, 1H,
NH), 11.65 (s, 1H, OH) ppm. 13C NMR (75 MHz, DMSO-d6):
d = 13.5 (CH3), 15.3 (CH3), 60.4 (CH2), 72.1 (C–CN), 108.5 (C-CO2Et),
117.3 (CN), 129.3 (C–CH3), 153.2 (C–OH), 164.2 (C@O) ppm. FT-IR
(neat): 3329, 3168, 2987, 2244, 1668, 1652, 1575 cmÀ1. HRMS (cal-
culated for C9H10N2O3) m/z 194.1873, (obtained) 194.1864.
Ethyl (4-cyano-2-hydroxy-5-oxopyrrolidin-2-yl)acetate (7): To a
solution of ethyl 4-chloroacetoacetate (6) (1.64 g, 10 mmol) and
cyanoacetamide (3) (0.84 g, 10 mmol) in MeCN (50 mL) was added
Et3N (1.01 g, 10 mmol). The solution was stirred for 16 h at room
temperature. The precipitated solid was filtered and the filtrate
evaporated under reduced pressure to give crude 7. Further purifi-
cation by column chromatography (EtOAc/n-hexane, 8:2) afforded
7 as a colorless solid (1.90 g, 89%). 1H NMR (300 MHz, CD3CN/TMS)
d = 1.23 (t, 3JH–H = 7.2 Hz, 3H, CH3), 2.54–2.58 (m, 2H, CH2), 2.75 (m,
2H, CH2), 3.92 (t, 3JH–H = 9.5 Hz, 1H, CH), 4.16 (q, 3JH–H = 7.1 Hz, 2H,
CH2), 4.51 (br s, 1H, NH), 7.30 (br s, 1H, OH) ppm. 13C NMR
(75 MHz, DMSO-d6): d = 15.2 (CH3), 33.1 (CH), 39.8 (CH2), 44.8
(CH2), 61.2 (CH2), 85.2 (C–OH), 119.5 (CN), 169.1 (C@O), 170.1
(C@O) ppm. FT-IR (neat): 3470, 3314, 2974, 2932, 2254, 1714,
1702, 1438 cmÀ1. HRMS (calculated for C9H12N2O4) m/z 212.2026,
(obtained) 212.2010.
Ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxyl-
ate (5): To a solution of ethyl 2-chloroacetoacetate (4) (1.64 g,
10 mmol), cyanoacetamide (3) (0.84 g, 10 mmol) in MeCN
(50 mL) was added Et3N (1.01 g, 10 mmol). The solution was re-
fluxed for 2 h and the precipitated solid filtered and the filtrate
evaporated in vacuo to yield 1.85 g, (87%) of compound 5 as a yel-
3
low solid. 1H NMR (300 MHz, CDCl3/TMS): d = 1.33 (t, JH-
3
H = 7.1 Hz, 3H, CH3), 1.78 (s, 3H, CH3), 3.52 (d, JH-H = 10.6 Hz, 1H,
Ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate (2): To a
solution of 7 (1.70 g, 8 mmol) in toluene (50 mL) was added pTsOH
(0.20 g, 1 mmol) and the mixture refluxed for 4 h. The mixture was
filtered and the filtrate evaporated under reduced pressure to yield
a viscous substance which crystallized at room temperature to
3
3
CH), 4.14 (q, JH-H = 7.1 Hz, 2H, CH2), 4.44 (d, JH-H = 10.6 Hz, 1H,
CH), 7.28 (s, 1H, NH), 7.82 (s, 1H, OH) ppm. 13C NMR (75 MHz,
CDCl3/TMS): d = 14.1 (CH3), 26.6 (CH3), 35.3 (CH), 55.2 (CH), 62.5
(CH2), 85.6 (C), 115.8 (CN), 167.2 (C@O), 167.8 (C@O) ppm. FT-IR

2510
P. B. S. Dawadi, J. Lugtenburg / Tetrahedron Letters 52 (2011) 2508–2510
yield 1.35 g, (87%) of product 2. 1H NMR (300 MHz, CDCl3/TMS)
d = 1.28 (t, JH–H = 7.2 Hz, 3H, CH3), 3.14 (dd, JH–H = 17.5 Hz, JH–
Planck-Institute for Bioinorganic Chemistry, Muelheim, Germany)
for his valuable suggestions. The authors wish to thank C. Erkelens
and F. Lefeber for recording the NMR spectra, and H. Peeters (Free
University of Amsterdam, The Netherlands) for recording the mass
spectra.
3
2
3
2
3
H = 7.3 Hz, 1H of CH2), 3.26 (dd, JH–H = 17.5 Hz, JH–H = 9.9 Hz, 1H
3
3
of CH2), 3.76 (dd, JH–H = 9.8 Hz, JH–H = 7.3 Hz, 1H, CH), 4.20 (q, 3J
H–H = 7.3 Hz, 2H, CH2), 5.14 (s, 1H, CH), 10.16 (br s, 1H, NH) ppm.
13C NMR (75 MHz, CDCl3/TMS): d = 14.1 (CH3), 30.5 (CH), 30.7
(CH2), 60.4 (CH2), 92.9 (CH), 115.5 (CN), 151.7 (@C), 167.4 (C@O),
167.9 (C@O) ppm. FT-IR (neat): 3326, 2984, 2913, 2257, 1752,
1679, 1641, 1471 cmÀ1. HRMS (calculated for C9H10N2O3) m/z
194.1873, (obtained) 194.1864.
References and notes
1. Acheson, R. M. An Introduction to the Chemistry of Heterocyclic Compounds; John
Wiley & Sons: New York, 1976.
2. Badger, G. M. The Chemistry of Heterocyclic Compounds; Academic Press: New
York, 1961.
3. Jackson, A. H. Pyrroles. In Comprehensive Organic Chemistry-The Synthesis and
Reactions of Organic Compounds; Barton, D., Ollis, W. D., Eds.; Pergamon Press:
Oxford, 1979; pp 275–320. Chapter 17.1, vol. 4.
4. Brower, J.; Lightner, D. A.; McDonagh, A. F. Tetrahedron 2001, 57, 7813–7827.
5. Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114, 10677.
6. Uno, H.; Baldwin, J. E.; Russel, A. T. J. Am. Chem. Soc. 1999, 116, 2139–2140.
7. Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka, H.;
Sasaki, Y. J. Antibiot. 1991, 44, 113–116.
Diethyl 2-cyano-4-oxohexanedioate (9): To a solution of ethyl 4-
chloroacetoacetate (6) (1.64 g, 10 mmol) and ethyl cyanoacetate
(8) (1.13 g, 10 mmol) in MeCN (50 mL) was added Et3N (1.01 g,
10 mmol). The solution was refluxed for 1 h. The precipitated solid
was filtered and the filtrate evaporated under reduced pressure to
give the product. Further purification by column chromatography
(EtOAc/n-hexane, 8:2) afforded 9 as a yellow oil (2.15 g, 89%). 1H
3
8. Meyers, A. I.; Snyder, L. J. Org. Chem. 1993, 58, 36–42.
NMR (300 MHz, CDCl3/TMS) d = 1.24 (t, JH–H = 7.3 Hz, 3H, CH3),
9. Ding, C. Z.; Silverman, R. B. J. Enzyme Inhib. Med. Chem. 1992, 6, 223–231.
10. Dawadi, P. B. S.; Lugtenburg, L. In Targets in Heterocyclic Systems. Chemistry and
Properties. Reviews and Accounts on Heterocyclic Chemistry; Attanasi, O. A.,
Spinelli, D., Eds., 2008. 12, 1–30.
11. Henrdrickson, J. B.; Cram, D. J.; Hammond, G. S. Organic Chemistry, third ed.;
McGraw Hill: New York, 1959.
3
2
3
1.34 (t, JH–H = 7.3 Hz, 3H, CH3), 3.18 (dd, JH–H = 18.5 Hz, JH–
2
3
H = 5.7 Hz, 1H of CH2), 3.31 (dd, JH–H = 18.5 Hz, JH–H = 6.5 Hz, 1H
3
of CH2), 3.56 (s, 2H, CH2), 4.01 (t, JH–H = 6.2 Hz, 1H, CH), 4.23 (q,
3JH–H = 7.3 Hz, 2H, CH2), 4.28 (q, JH–H = 7.3 Hz, 2H, CH2) ppm. 13C
3
NMR (75 MHz, CDCl3/TMS): d = 13.5 (CH3), 13.6 (CH3), 31.3 (CH),
41.1 (CH2), 48.3 (CH2), 61.3 (CH2), 62.9 (CH2), 115.7 (CN), 164.8
(C@O), 166.1 (C@O), 197.7 (C@O) ppm. FT-IR (neat): 2259, 1738,
1721 cmÀ1. HRMS (calculated for C11H15NO5) m/z 241.2405, (ob-
tained) 241.2395.
12. Dawadi, P. B. S.; Lugtenburg, L. Eur. J. Org. Chem. 2003, 4654–4663.
13. Hu, Y. G.; Li, G. H.; Ding, M. W. ARKIVOC 2008, 151–158. xiii.
14. Bakavoli, M.; Feizyzadeh, B.; Rahimizadeh, M. Tetrahedron Lett. 2006, 47, 8965–
8968.
15. Skaddan, M. B. J. Labelled Compd. Radiopharm. 2010, 53, 73–77.
16. Dawadi, P. B. S.; Lugtenburg, L. Eur. J. Org. Chem. 2007, 1294–1300.
17. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324–6334.
Acknowledgments
This work was supported by grants from Volkswagen Stiftung
(I/79979). We are very grateful to Professor Dr. W. Gaertner (Max