Microwave-assisted method for synthesis of 1,3-disubstituted pyrroles

Article abstract of DOI:10.1080/00397910802613647

1,3-Disubstituted pyrroles were prepared by a microwave-assisted reaction of pyrrolidine and aldehydes in toluene as well as in solvent-free conditions. Reactions were completed in a few minutes in the solvent-free condition but a long time (up to 30min)

Full text of DOI:10.1080/00397910802613647

This article was downloaded by: [The Aga Khan University]
On: 31 December 2014, At: 03:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Microwave-Assisted Method for
Synthesis of 1,3-Disubstituted
Pyrroles
Viera Poláčková a , Eva Veverková a , Štefan Toma a
& Dariusz Bogdal b
a Faculty of Natural Sciences , Department of
Organic Chemistry, Comenius University , Bratislava,
Slovak Republic
b Department of Chemistry and Technology ,
Politechnika Krakowska , Krakow, Poland
Published online: 15 Apr 2009.
To cite this article: Viera Poláčková , Eva Veverková , Štefan Toma & Dariusz Bogdal
(2009) Microwave-Assisted Method for Synthesis of 1,3-Disubstituted Pyrroles,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:10, 1871-1876, DOI: 10.1080/00397910802613647
To link to this article: http://dx.doi.org/10.1080/00397910802613647
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 39: 1871–1876, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802613647
Microwave-Assisted Method for Synthesis of
1,3-Disubstituted Pyrroles
1
Viera Polackova, Eva Veverkova, Stefan Toma, and
ꢀ 1
ꢀ 1
ˇ
Dariusz Bogdal2
ˇ
ꢀ
1Faculty of Natural Sciences, Department of Organic Chemistry,
Comenius University, Bratislava, Slovak Republic
2Department of Chemistry and Technology, Politechnika Krakowska,
Krakow, Poland
Abstract: 1,3-Disubstituted pyrroles were prepared by a microwave-assisted
reaction of pyrrolidine and aldehydes in toluene as well as in solvent-free condi-
tions. Reactions were completed in a few minutes in the solvent-free condition
but a long time (up to 30 min) was necessary to complete reactions in toluene.
Yields of products depended considerably on the aldehyde used.
Keywords: Microwave assisted, pyrroles, solvent free
INTRODUCTION
Substituted pyrroles are important substances because of their interesting
biological properties. Some of them are synthetic precursors of many
natural products.[1] Pyrrole derivatives are used also in the manufacture
of pharmaceuticals because such compounds often possess antipsychotic
or antimycobacterial properties.[2] One of described methods of pyrrole
synthesis consists of reaction of oximes derived from ketones with acety-
lene using a superbase in high temperature.[3] The second method starts
from 1-tosyl derivatives of 3-substituted pyrroles via pyrrole potassium
Received September 16, 2008.
ˇ
Address correspondence to Stefan Toma, Department of Organic Chemistry,
ꢀ
Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2,
SK-842 15 Bratislava, Slovak Republic. E-mail: toma@fns.uniba.sk
1871

ꢀˇ
V. Polackova et al.
ꢀ
1872
intermediate[4] and its akylation. The third method is a three-step
synthesis starting from acetals of 3-alkenals.[5] A nonoxidative method
for synthesis of 1,3-disubstituted pyrroles from pyrrolidine and aldehydes
was described very recently by Oda et al.[6] They reported reaction of
pyrrolidine with 2 equivalents of aldehyde, without any catalyst. To reach
good product yields, it was necessary to perform the reaction in an auto-
clave at 140–200 ꢀC. Good yields of 1,3-disubstituted pyrroles were
achieved in 12–24 h reaction time. A possible reaction mechanism was
also suggested.[6]
It is well known that dramatic reduction in reaction time and higher
product yields can be achieved when the reactions are carried out under
microwave irradiation.[7–9] Microwave irradiation has especially good
effect on reactions in solvent-free conditions.[10] A number of authors
have described success in reactions that do not occur with conventional
heating.[11,12]
EXPERIMENTAL
Microwave experiments were carried out in the Biotage Initiator reactor
(max. power 300 W). The 1H NMR and 13C NMR spectra were measured
at 300 MHz for 1H and 75 MHz for 13C on a Varian Gemini spectrometer
in CDCl3 with tetramethylsilane (TMS) as an internal standard. Gas
chromatography–Mass spectrometry (GC-MS) measurements were
performed on the gas chromatograph Trace GC 2000 Series Thermoquest
CE instrument with a flame ionization detector and the Voyager
GC-MS Thermoquest Finnigan in SCAN mode. Melting points were
determined on a Kofler hot stage apparatus. New compounds were also
characterized by microanalysis.
General Procedure
Reactions Using Microwave Irradiation
A reaction vessel charged with an appropriate aldehyde (1) (4 or 8 mmol),
pyrrolidine (2) (2 mmol), and toluene (1 ml) was sealed and irrradiated by
microwaves for the appropriate time in the microwave reactor (Table 1).
The reaction mixture was then cooled to room temperature, and the
solvent was evaporated. Products 3a–i were separated by column chro-
matography (Al2O3, 1:9 ethylacetate–hexane) and identified by spectro-
scopic analyses. Products 3a–c and 3e–g were identified by comparison
to authentic samples described inlitterature.[6,13]

Synthesis of 1,3-Disubstituted Pyrroles
1873
Table 1. Synthesis of 1,3-disubstituted pyrroles produced under microwave
irradiation
Reaction conditions
Temp Time
Solvent (ꢀC) (min)
Yield
(%)
Product[ref.]
R or Ar
Yielda (%)
3a[6]
(CH3)2CH
Toluene
—
—
—
Toluene
—
200
200
200
200
200
200
200
200
200
180
200
180
200
200
180
200
200
200
200
200
200
200
200
200
200
30
30
10
6
66 (12 h)
8 (24 h)
—
78
92
90
77
67
88
57
66
58
32
57
12
32
30
39
58
61
23
74
75
54
33
53
22
30
—
3b[6]
3c[6]
3d
Cyclohexyl
10 76 (21 h, 180 ꢀC)
10
30
10
60
60
60
30
60
60
30
30
10
10
30
10
30
10
30
10
15
—
79 (20 h)
Ph(CH3)CH
Toluene
—
CH3CH(CH3)-CH2 Toluene
—
—
—
—
—
—
—
—
Toluene
Toluene
—
Toluene
Toluene
—
Toluene
Toluene
—
Toluene
—
Toluene
—
—
3e[13]
n-C3H7
C6H5
3f[6]
—
47 (20 h)
3g[6]
4-(Cl)C6H4
—
60 (24 h)
—
3h
3i
4-(CN)C6H4
—
—
—
—
4-(OCH3)C6H4
—
aYield of reaction performed under thermal heating (reaction time 12–20 h) as
reported in Ref. 6.
Spectral Data
Compound 3d
1H NMR (300 MHz, CDCl3): d 0.92 (d, J ¼ 6.6 Hz, 6H), 0.90 (d,
J ¼ 6.6 Hz, 6H), 1.60 (m, 6H), 2.44 (q, J ¼ 8.1, 2H), 3.80 (t, J ¼ 7.5 Hz,
2H), 5.96 (dd, J ¼ 2.2 Hz, 1.8 Hz, 1H), 6.42 (dd, J ¼ 2.4 Hz, 1.8 Hz,
1H), 6.54 (dd, J ¼ 2.4 Hz, 2.2 Hz, 1H). 13C NMR (CDCl3, 75 Hz ): d
124.5, 120.0, 117.6, 107.7, 47.7, 40.5. 40.4, 29.7, 27.8, 25.6, 22.6, 22.4.

ꢀˇ
V. Polackova et al.
ꢀ
1874
GC-MS: 207 (40, Mþ), 164 (10), 151 (100), 106 (15), 94 (55), 80 (23), 43
(12). Anal. calcd. for C14H25N (207.35): C, 81.1; H, 12.15; N, 6.75.
Found: C, 80.21; H, 11.66; N, 6.11.
Compound 3h
1H NMR (300 MHz, CDCl3): d 3.87 (s, 2H), 5.06 (s, 2H), 6.01 (dd,
J ¼ 2.7 Hz, 2.1 Hz, 1H), 6.41 (dd, J ¼ 1.8 Hz, 2.1 Hz, 1H), 6.61 (dd,
J ¼ 1.8 Hz, 2.7 Hz, 1H), 7.15 (d, J ¼ 6.6 Hz, 2H), 7.33 (d, J ¼ 6.6 Hz,
2H), 7.57 (d, J ¼ 6.6 Hz, 2H), 7.62 (d, J ¼ 6.6 Hz, 2H). 13C NMR (CDCl3,
75 Hz): d 147.8, 143.6, 132.6, 132.1, 129.3, 127.3, 121.8, 119.4, 109.7, 52.8,
33.6. GC-MS: 297 (100, Mþ), 195 (49), 181 (47), 154 (10), 127 (12), 116
(92), 89 (20). Anal. calcd. for C20H15N3 (297.13): C, 80.78; H, 5.08; N,
14.13. Found: C, 80.12; H, 5.04; N, 14.11.
Compound 3i
1H NMR (300 MHz, CDCl3): d 3.74 (s, 2H), 3.78 (s, 3H), 3.79 (s, 3H),
4.90 (s, 2H), 5.97 (dd, J ¼ 2.7 Hz, 2.2 Hz, 1H), 6.39 (dd, J ¼ 2.2 Hz,
1.8 Hz, 1H), 6.56 (dd, J ¼ 1.8, 2.7 Hz, 1H), 6.81 (d, J ¼ 6.8 Hz, 2H),
6.84 (d, J ¼ 6.8 Hz, 2H), 7.57 (d, J ¼ 6.8 Hz, 2H), 7.62 (d, J ¼ 6.8 Hz,
2H). 13C NMR (CDCl3, 75 Hz): d 134.5, 131.5, 130.2, 129.5, 129.4,
123.4, 120.9, 118.9, 114.3, 113.6, 108.7, 55.6, 55.2, 52.7, 32.6. GC-MS:
307 (40, Mþ), 186 (8), 121 (100). Anal. calcd. for C20H21NO2 (297.13):
C, 78.15; H, 6.89; N, 4.56. Found: C, 77.89; H, 6.78; N, 4.53.
RESULTS AND DISCUSSION
We have had good experience in enhancing the reaction rates of various
reactions by microwave irradiation (MWI), and therefore we decided to
test influence of MWI on Oda’s reaction of pyrrolidine with different
aldehydes (Scheme 1).
The initial experiment was carried out with isobutyraldehyde and
pyrrolidine in a 2:1 molar ratio. After 30 min of microwave irradiation
using toluene as the solvent, we isolated pyrrol 3a in 78% yield. We
decided to test this reaction under solvent-free conditions. For the reac-
tion under solvent-free conditions, an excess of aldehyde (4:1 molar ratio)
had to be used. According to the data presented in Table 1, very good
yield of the product 3a (92%) was obtained in 30 min. Then we decided
to shorten the reaction time and found that even 10 min of MWI resulted
in 90% yield of the product, but shortening the reaction time to 6 min

Synthesis of 1,3-Disubstituted Pyrroles
1875
Scheme 1.
resulted in decreasing the yield to 77%. Optimal microwave conditions
(30 min in toluene or 10 min in solvent-free condition) were then applied
to the reaction between pyrrolidine (2) and a-branched aldehydes. We
obtained reaction products in good to very good yields (Table 1, 3b,
3c), but for b-branched aldehyde (isobutyraldehyde) it was necessary to
prolong the reaction time to 60 min. Reactions in toluene as well as in
solvent-free conditions provided preparatively interesting yields of the
product 3d. In the case of 3,3-dimethylbutyraldehyde, we observed the
product in the crude reaction mixture [1H NMR (300 MHz, CDCl3): d
0.93 (s, 9H), 0.94 (s, 9 H), 1.49 (m, 4 H), 2.44 (t, J ¼ 8.1, 2H), 3.81 (t,
J ¼ 7.5 Hz, 2H), 5.83 (dd, J ¼ 2.2 Hz, 1.8 Hz, 1H), 6.10 (dd, J ¼ 2.4 Hz,
1.8 Hz, 1H), 6.34 (dd, J ¼ 2.4 Hz, 2.2 Hz, 1H); GC-MS: 235 (21), 178
(14), 164 (100), 150 (8), 80 (7)], but it was not stable and therefore could
not be isolated in pure form and fully characterized.
Oda et al.[6] described very low yields of products in a reaction with
nonbranched aliphatic aldehydes (15% with n-hexanal). Therefore, we
were curious if MWI would have a positive effect on the reaction course
with this type of aldehydes. With n-butanal as the aldehyde, we obtained
reaction product 3e in 32% yield.
For attaining good yields in reactions with aromatic aldehydes,
Oda et al.[6] described that it was necessary to use high pressure. We
observed that substituted benzaldehydes gave preparatively useful yields
of the corresponding products in toluene (3f–i), but lower yields of pro-
ducts were achieved under solvent-free conditions, which could be caused
by the fact that such aldehydes are solid and there are problems with
mass transfer. Alternatively, this observation can be explained also by
the hypothesis that the reaction mixture did not reach the appropriate
inner pressure.
In summary, we have discovered that 1,3-disubstituted pyrroles can
be prepared in 10–30 min under controlled microwave heating both with
and without the solvent. Better yields were achieved than those described
by prolonged (12–20 h) thermal heating.

ꢀˇ
V. Polackova et al.
ꢀ
1876
ACKNOWLEDGMENTS
1
We thank Dr. B. Horvath and his staff for H and 13C NMR analyses
and Dr. R. Kubinec and his staff for GC-MS analyses, both from the
Institute of Chemistry of Faculty of Natural Sciences, Comenius Univer-
sity. The financial support of the Ministry of Education of the Slovak
Republic is acknowledged. This work was carried out as a part of the
COST D32=0010=2002 project.
REFERENCES
1. Nelson, D. L.; Cox, M. M. Lehninger Principles of Biochemistry, 3rd ed.
Worth Publishing: New York, 2000.
2. Van Wijngaarden, I.; Kruse, C.; Van Hes, R.; Van der Heyden, J. Preparation
of pyrrolidinylpyrroles and analogs as antipsychotic agents. US Patent
4,791,132, 1988; Chem. Abstr. 109, 92773z.
3. Schmidtt, E. Y.; Mikhaleva, A. I.; Vasil’tsov, A. M.; Zaitsev, A. M.; Zorina,
N. V. A straightforward synthesis of pyrroles from ketones and acetylene: A
one-pot version of the Trofimov reaction. Arkivoc 2005, 7, 11–17.
4. Vorob’eva, S. L.; Magedov, I. V.; Traven, V. F. A convenient method of
synthesis of 1,3-disubstituted pyrroles. Chem. Heterocycl. Comp. 1991, 27,
504–505.
5. Kulinkovitsch, O. G.; Sorokin, V. L.; Azzuz, A.; Sviridinov, S. V.; Masalov,
N. V. A convenient method for the preparation of 1-substituted and 1,3-
disubstituted pyrroles from acetals of 3-alkenals. Synthesis 1993, 1059–1060.
6. Oda, M.; Fukuchi, Y.; Ito, S.; Thanh, N. C. H.; Kuroda, S. A facile non-
oxidative method for synthesizing 1,3-disubstituted pyrroles from pyrrolidine
and aldehydes. Tetrahedron Lett. 2007, 48, 9159–9162.
7. Loupy, A. (Ed.). Microwaves in Organic Synthesis, 2nd ed., Wiley-VCH:
Weinheim, Germany, 2006; vols 1 and 2.
8. Kappe, C. O.; Stadler, A. (Eds.). Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, Germany, 2005.
}
9. Tierney, J. P.; Lindstrom, P. (Eds.); Microwave Assisted Organic Synthesis;
Blackwell Publishing Ltd., Oxford, 2005.
´
10. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boulett, F.; Jacquault, P.; Mathe, D.
New solvent free organic synthesis using focused microwaves. Synthesis 1998,
1–22.
11. Alonso, F.; Beletskaya, I. P.; Yus, M. Non-conventional methodologies
for transition-metal-catalysed carbon–carbon coupling: A critical overview:
Part 1: The Heck reaction. Tetrahedron 2005, 61, 11771–11835.
12. Alonso, F.; Beletskaya, I. P.; Yus, M. Non-conventional methodologies for
transition-metal-catalysed carbon–carbon coupling: A critical overview:
Part 2: The Suzuki reaction. Tetahedron 2008, 64, 3047–3101.
13. Holm, T. Homolysis in the reaction of Grignard reagents, II: The reaction of
pyridazine. Acta Chim. Scand. 1990, 44, 279–283.