Paal-knorr pyrrole synthesis in water

Article abstract of DOI:10.1080/00397911.2013.857691

Water was a suitable medium for Paal-Knorr pyrrole cyclocondensation. Hexa-2,5-dione was reacted with several aliphatic and aromatic primary amines, affording N-substituted 2,5-dimethyl pyrrole derivatives in good to excellent yields. An efficient, green method using water either as environmentally friendly solvent or catalyst was presented.

Full text of DOI:10.1080/00397911.2013.857691

This article was downloaded by: [Memorial University of Newfoundland]
On: 31 July 2014, At: 14:34
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
Paal–Knorr Pyrrole Synthesis in Water
Dilek Akbaşlar a , Onur Demirkol a & Sultan Giray a
a Department of Chemistry , Art and Science Faculty, Çukurova
University , Adana , Turkey
Accepted author version posted online: 02 Dec 2013.Published
online: 28 Mar 2014.
To cite this article: Dilek Akbaşlar , Onur Demirkol & Sultan Giray (2014) Paal–Knorr Pyrrole Synthesis
in Water, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:9, 1323-1332, DOI: 10.1080/00397911.2013.857691
To link to this article: http://dx.doi.org/10.1080/00397911.2013.857691
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 Communications®, 44: 1323–1332, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.857691
PAAL–KNORR PYRROLE SYNTHESIS INWATER
Dilek Akbas¸lar, Onur Demirkol, and Sultan Giray
Department of Chemistry, Art and Science Faculty, Çukurova University,
Adana, Turkey.
GRAPHICAL ABSTRACT
Abstract Water was a suitable medium for Paal–Knorr pyrrole cyclocondensation. Hexa-
2,5-dione was reacted with several aliphatic and aromatic primary amines, affording
N-substituted 2,5-dimethyl pyrrole derivatives in good to excellent yields. An efficient, green
method using water either as environmentally friendly solvent or catalyst was presented.
Keywords Green chemistry; hexa-2,5-dione; Paal–Knorr; pyrrole; water
INTRODUCTION
Green chemistry has become a crucial research area with the increasing interest
in developing environmentally friendly reaction conditions, in particular, atom-eco-
nomic catalytic processes or reactions without using any catalysts and organic sol-
vents.[1] The use of water as solvent in organic reactions has attracted the attention of
researchers because of the economic and environmental benefits of water, such as low
cost and the lack of flammability, explosive, mutagenic, and carcinogenic properties.
In addition, some unique properties, including high cohesive energy, large surface ten-
sion, high polarity, and high specific heat capacity, have led to use of water in many
organic reactions instead of conventional organic solvents.[2,3]
Pyrrole and its derivatives are the heterocyclic compounds that are not only
found in the structures of several drugs and natural compounds such as haem, chlo-
rophyll, and B12 vitamin but also show some important pharmacological properties
Received September 12, 2013.
Address correspondence to Elife Sultan Giray, Department of Chemistry, Art and Science Faculty,
Çukurova University, 01330 Adana, Turkey. E-mail: esgiray@cu.edu.tr
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
1323

1324
D. AKBAS¸LAR, O. DEMIRKOL, AND S. GIRAY
Scheme 1. Synthesis of N-substituted-2,5-dimethyl pyrrole in water.
such as antibacterial, antiviral, and antitumor activities. Because of these properties,
the synthesis of pyrrole derivatives has an important role in heterocyclic chemistry
and there is increasing interest in the synthesis of this kind of compounds.
There are several methods for the synthesis of many pyrrole derivatives.
Generally, these methods are based on the cyclocondensation reactions. Classical
methods for their preparation include Knorr, Hantzsch, and Paal–Knorr condensa-
tion reactions. In the Paal–Knorr reaction, 1,4-dicarbonyl compounds are converted
to pyrroles in the presence of ammonia or primary amines. Recently, many catalysts
have been used for this conversion such as montmorillonite KSF,[4] microwave irradia-
.
tion,[5] Bi(NO3)3 5H2O,[6] Sc(OTf)3,[7] and layered zirconium phosphate and zirconium
sulfophenyl phosphonate.[8] Some other methods for synthesis of pyrroles include con-
jugate addition reactions,[9] annulations reactions,[10,11] multicomponent reactions,[12]
and aza-Wittig reactions.[13] However, several of these methods suffer from certain
drawbacks such as prolonged reactions times, use of volatile or hazardous organic
solvents, tedious workup conditions, use of extra energy source, and toxic metals.[4,5]
In continuation of our efforts toward the development of greener methodolo-
gies,[14] we report herein a simple, clean, and environmentally friendly process for the
synthesis of N-substituted pyrrole derivatives by reaction of various aliphatic and
aromatic amines with hexa-2,5-dione for the first time in water (Scheme 1).
RESULTS AND DISCUSSION
At the onset of this work, we have investigated the optimum conditions for the
synthesis of 1-benzyl-2,5-dimethyl-1H-pyrrole as a model compound for conducting
the reactions in water at different temperatures. At room temperature, the condensa-
tion reaction between benzyl amine (10 mmol) and hexa-2,5-dione (10 mmol) in 5 mL
water in 15 min resulted in poor yields (45%). When further prolonging the reaction
time to 3h, no remarkable change was observed in yield. At 50oC, the same reac-
tion required 3h of reaction time for excellent yields (95%). When the reaction took
place at the boiling point of water, the product was also obtained in excellent yields
(96%) but in a short time (15 min). Moreover, we also studied influence of the amount
of water used on the reaction yields. We found that the yield was not dramatically
affected by adding different amounts of water (5, 10, and 15 mL). Five mL of water
was enough; an excessive amount of it did not increase the yield remarkably.
Having the established the reaction conditions, various aliphatic and aromatic
amines were reacted with hexa-2,5-dione to investigate the reaction field, and the results
are displayed in Table 1. In all cases, the Paal–Knorr reaction proceeded smoothly and
gave the corresponding N-substituted 2,5-dimethyl pyrroles in good to excellent yields.

PAAL–KNORR PYRROLE SYNTHESIS IN WATER
1325
Table 1. Synthesis of N-substituted 2,5-dimethyl pyrroles in water
Entry
Amine (1b–23b)
Product (1a–23a)
Yield (%)
1
96
95
98
2
3
4
5
94a
96a
6
97b
7
8
96
75
(Continued)

1326
D. AKBAS¸LAR, O. DEMIRKOL, AND S. GIRAY
Table 1. Continued
Entry
9
Amine (1b–23b)
Product (1a–23a)
Yield (%)
n.o.
10
90
11
88
12
13
14
96
85
95
(Continued)

PAAL–KNORR PYRROLE SYNTHESIS IN WATER
1327
Table 1. Continued
Entry
15
Amine (1b–23b)
Product (1a–23a)
Yield (%)
75a
16
17
76a
78a
18
19
n.o.
n.o.
20
21
98
n.o.
(Continued)

1328
D. AKBAS¸LAR, O. DEMIRKOL, AND S. GIRAY
Table 1. Continued
Entry
22
Amine (1b–23b)
Product (1a–23a)
Yield (%)
n.o
23
81
Note: Reaction conditions: amine (10 mmol), 2,5-hexadione (10 mmol), 5 mL water, 15 min, 100oC.
aAmine (5 mmol), 2,5-hexadione (10 mmol), 5 mL water, 15 min, 100oC.
bAmine (3.3 mmol), 2,5-hexadione (10 mmol), 5 mL water, 15 min, 100oC.
n.o., not observed.
It is well known that the reactivity of aliphatic amine is more nucleophilic or
more basic compared with that of aromatic amines.[15] Thus, it is obviously seen that
o
aliphatic amines give greater yields than aromatic amines in water medium at 100 C.
Furthermore, the electronic effect of substituent on the aromatic rings of aryl amines in
the Paal–Knorr condensation was not clear. The presence of either an electron-donating
or an electron-withdrawing group in the aromatic ring prompted the reaction, with quan-
titative conversions being achieved after 15 min (Table 1, entries 8, 10, 11, 15, and 16).
It is important to note that the less nucleophilic aromatic amines and the ones
less soluble in water were not coupled with hexan-2,5-dione in this condition (Table 1,
entries 9, 18–21). Both prolonged reaction time and increase in amount of water could
not further improve their reactivity.
With these results in hand, we subjected di- or tri-amino substrates to this meth-
odology. Two or three equivalents of hexan-2,5-dione were required to have a com-
plete conversion of di- or tri-amines. Bipyrrole or tripyrrole compounds were obtained
in good to excellent yields (Table 1, entries 4–6, 15–17). Also, aliphatic diamines gave
products in greater yields than those of aromatic diamines (Table 1, entries 4, 5, 15, 16).
The role of water was further explored for Paal–Knorr condensation by per-
forming the reactions of benzylamine and aniline with hexa-2,5-dione as model reac-
tions in various organic solvents at reflux temperatures (Tables 2 and 3).
After extensive screening, we found that the yields of both 2,5-dimethyl-
1-phenyl-1H-pyrrole and 1-benzyl-2,5-dimethyl-1H-pyrrole, respectively, in different
organic solvents were approximately the same as the ones obtained in water. Also, the
corresponding products were obtained in only poor yields (25%, 30%) in the absence
of solvent. Water is more preferable than the other solvents because it not only is an
environmentally friendly and easily available solvent but also presents a simple prod-
uct isolation procedure.

PAAL–KNORR PYRROLE SYNTHESIS IN WATER
1329
Table 2. Synthesis of 2,5-dimethyl-1-phenyl-1H-pyrrole in different solvents
Temperature
(oC)
Yield (%)
for 7a
Entry
Solvent
Water
Methanol
Ethanol
Acetone
Chloroform
Ethyl acetate
THF
1
2
3
4
5
6
7
8
9
100
65
78
56
62
77
66
40
110
69
25
96
95
93
85
75
90
89
90
87
75
25
DCM
Toluene
Hexane
None
10
11
Note: Reaction conditions: Aniline (10 mmol), 2,5-hexzadione (10mmol),
solvent (5mL), 15min.
At room temperature, because of the absence of the solute-water H-bonding, the
water keeps the three-dimensional H–bonding network with increasing temperature.
The H–bonds break down, the orientational preference of water molecules decrease,
and then organic reactions take place in hot water. Water at the boiling point creates
an ideal medium for the Paal–Knorr reaction proceeding in less acidic or neutral con-
dition. A plausible mechanism is shown in Scheme 2.
Toprovethebenefitof ourmethodology,wecollectedinTable4resultsof 2,5-dimeth-
ylpyrrole synthesis under different conditions. As indicated in Table 4, this compound was
synthesized in organic solvents in the presence of various catalysts or under solvent-free
conditions using microwave irradiation with catalysts. In addition to having the general
advantages attributed to green chemistry, our present method is better or comparable with
others in terms of yields, reaction time, and environmental friendliness.
Table 3. Synthesis of 1-benzyl-2,5-dimethyl-1H-pyrrole in different solvents
Temperature
(oC)
Yield (%)
for 12a
Entry
Solvent
Water
Methanol
Ethanol
Acetone
Chloroform
Ethyl acetate
THF
1
2
3
4
5
6
7
8
9
100
65
78
56
62
77
66
40
110
69
25
96
95
94
90
81
96
94
93
91
80
30
DCM
Toluene
Hexane
None
10
11
Note: Reaction conditions: Benzylamine (10mmol), 2,5-hexzadione (10mmol),
solvent (5mL), 15min.

1330
D. AKBAS¸LAR, O. DEMIRKOL, AND S. GIRAY
Table 4. Comparison of some other methods with the present procedure for the synthesis of 2,5-dimethyl-
1-phenyl-1H-pyrrole
Entry
Catalyst/solvent
T (oC)
Time
9 h
10 h
3 h
25min
25min
25min
25min
24 h
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
I2/THF
25
25
25
30
30
30
30
60
60
89
95
96
96
77
78
34
56
88
4
4
16
7
7
7
7
8
8
Montmorillonite,KSF/CH2Cl2
Fe3-montmorillonite/CH2Cl2
Sc(OTf)3/solvent-free
Sc(OTf)3/CH2Cl2
Cu(OTf)2/solvent-free
CuCl2/solvent-free
α-Zr(KPO4)2/solvent-free
α-Zr(CH3PO3)1.2(O3PC6H4SO3H)
0.8/solvent-free
2 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
ZnCl4/solvent-free
p-TSA/CH3CN
Cationic exchange resin/H2O
[MIMBS]3PW12O40/CH3CN
γ-Fe2O3@SiO2-Sb(III)-IL/H2O
NiCl2/H2O
40
80
130
80
100
100
100
25
25
60
25
reflux
25
7 min
1 h
5 h
2 h
40 min
2 h
80 min
3 h
35 min
5 min
10 h
20 min
12 h
5 min
15min
98
83
85
93
95
62
48
96
96
98
96
92
98
100
96
17
18
18
18
19
19
19
20
21
22
6
23
24
25
Table 3
ZnBr2/H2O
[Bmim]I ionic liquid
.
UO2(NO3)2 6H2O/MeOH/.
Microwave/I2
.
Bi(NO)3 5H2O/CH2Cl2
Ps/GaCl3/CH3CN
BiCl3/SiO2/hexane
.
Bi(NO3)3 5H2O/Microwave
90
100
Noncatalyst/H2O
Scheme 2. Plausible mechanism for Paal–Knorr pyrrole cyclocondensation in water.

PAAL–KNORR PYRROLE SYNTHESIS IN WATER
1331
CONCLUSIONS
In summary, considering the requirement of green chemistry, water was suc-
cessfully used as solvent in place of organic solvents for the Paal–Knorr reaction.
N-Substituted 2,5-dimethyl pyrrole compounds were synthesized in the conden-
sation reaction of hexan-2,5-dione with various aliphatic and aromatic primary
amines at the boiling point of water without using any catalysts or organic solvents.
The poor solubility of products in water facilitated the isolation protocol based on
extraction, filtration, or crystallization. In most cases, the crude products are pure
and do not need any further purifications. The pyrrole compounds were obtained
in good to excellent yields (75–98%) via the properties of water and they were char-
1
acterized by melting point, Fourier transform–infrared (FT-IR), H NMR, and
13CNMR techniques.
EXPERIMENTAL
1
IR spectra were recorded on a Perkin-Elmer 55148 spectrometer. H and 13C
NMR spectra were recorded on a Bruker 300-MHz Ultrashield spectrometer and
a Bruker Avance III 400-MHz spectrometer, and shifts are given in parts per mil-
lion (ppm) downfield from tetramethylsilane (TMS) as an internal standard. Melting
points were determined using an Electrothermal 9100 instrument.
General Experimental Procedure (1a–23a)
A round-bottom flask equipped with a magnetic stirrer was charged with pri-
mary aliphatic, aromatic amines (10 mmol), hexa-2,5-dione (10 mmol), and distilled
o
water (5 mL). This suspension was refluxed at 100 C for 15 min. The reaction was
monitored by thin-layer chromatography (TLC) (4:1 n-hexane/ethylacetate). After
the reaction mixture was cooled to room temperature, the product was filtered and
washed with water. It was recrystallized from methanol. The resulting product was
identified using FT-IR and NMR spectroscopy.
2,5-Dimethyl-1-propyl-1H-pyrrole (1a) (1a, C9H15N)
Yellow oil; yield 1.32 g (96 %); υmax (KBr) 3100, 2965, 2932, 2875, 1519, 1348; δH
(300 MHz, CDCl3; Me4Si) 5.85 (s, 2H), 3.77 (t, J = 7.8 Hz, 2H), 2.31 (s, 6H), 1.78–1.68
(m, 2H), 1.03 (t, J = 7.5 Hz, 3H); δC (75 MHz, CDCl3; Me4Si) 127.44, 105.00, 45.30,
24.30, 12.57, 11.44. Found: C, 78.47; H, 11.09; N, 10.44. Calcd. for C9H15N: C, 78.77;
H, 11.02; N, 10.21%.
FUNDING
The authors are thankful to the Scientific and Technical Research Council of Turkey
(Grant TUBITAK-211T146) for the financial support.

1332
D. AKBAS¸LAR, O. DEMIRKOL, AND S. GIRAY
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. (a) Horvath, I. T. Green Chem. 2008, 10, 1024; (b) Lancester, M. Green Chemistry: An
Introductory Text; Royal Society of Chemistry: Cambridge, 2002; (c) Matlack, A. S.
Introduction to Green Chemistry; Marcel Dekker: New York, 2001; (d) Anastas, P. T.;
Warner, J. C. Green Chemistry: Theory and Practice; Oxford University, New York, 1988.
2. (a) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239–1240; (b) Breslow, R.; Maitra,
U.; Rideout, D. Tetrahedron Lett. 1983, 24, 1901–1904; (c) Rideout, D. C.; Breslow, R. J.
Am. Chem. Soc. 1980, 102, 7816–7817.
3. (a) Muldoon, S. J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2005, 44, 3275–3279; (b) Jung, Y. S.; Marcus, R. A. J. Am. Chem. Soc. 2007, 129,
5492–5502.
4. Banik, B. K.; Samajdar, S.; Banik, I. J. Org. Chem. 2004, 69, 213–216.
5. Rao, H. S. P.; Jothilingam, S.; Scheeren, H. W. Tetrahedron 2004, 60, 1625–1630.
6. Banik, K. B.; Banik, I.; Dasgupta, K. S. Tetrahedron Lett. 2005, 46, 2643–2645.
7. Chen, J.; Wu, H.; Zhang, X.; Su, W. Tetrahedron Lett. 2006, 47, 5383–5387.
8. Curini, M.; Montanari, F.; Margarita, R. Tetrahedron Lett. 2003, 44, 3923–3925.
9. Dieter, R. K.; Yu, H. Organic Lett. 2000, 2, 2283–2286.
10. Arcadi, A.; Rossi, E. Tetrahedron 1998, 5, 15253–15272.
11. Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Thseng, J. C.; Luh, T. Y. J. Am. Chem. Soc.
2000, 122, 4992–4993.
12. Bharadwaj, A. R.; Scheidt, K. A. Organic Lett. 2004, 6, 2397–2399.
13. Katritzky, A.; Jiang, J.; Steel, P. J. J. Org. Chem. 1994, 59, 4551–4555.
14. (a) Dog˘an, A.; Giray, E. S. Proceedings of 12th European Meeting on Supercritical
Fluids, Austria, 2010; (b) s¸irin, Ö.; Giray, E. S. Proceedings of 12th European Meeting
on Supercritical Fluids, Austria, 2010; (c) Koldas¸, S.; Giray, E. S. Proceedings of 12th
˙
European Meeting on Supercritical Fluids, Austria, 2010; (d) S¸ims¸ek, I.; Giray, E. S.
Proceedings of 9th International Symposium on Super critical Fluids, France, 2009; (e)
Alpman, S. F.; Koldas¸, S.; Giray, E. S. Proceedings of 9th International Symposium on
Supercritical Fluids, France, 2009.
15. (a) Sreekumar, R.; Padmakumar, R. Synth. Commun. 1998, 28(9), 1661; (b) Texier-Boullent,
F.; Klein, B.; Hamlein, J. Synthesis 1986, 409.
16. Song, G.; Wang, B.; Wang, G.; Kang, Y.; Yang, T.; Yang, L. Synth. Commun. 2005, 35(8),
1051–1057.
17. Zhang, Z.; Li, J.; Li, T. Ultrason. Sonochem. 2008, 15, 673–676.
18. Gao, L.; Bing, L.; Zhang, Z.; Deng, K. J. Organomet. Chem. 2013, 735, 26–31.
19. Ma, F. P.; Li, B. L.; Mo, L. B.; Liu, N.; Kang, H. J.; Liu, Y. N.; Zhang, Z. H. Appl. Catal.A
2013, 457, 34–41.
20. Wang, B.; Gu, Y.; Suo, J. Tetrahedron Lett. 2004, 45, 3417–3419.
21. Sivakumar, A.; Satyanarayana, V. S. V. Ultrason. Sonochem. 2011, 18, 917–922.
22. Bandyopadhyay, D.; Mukherjee, S.; Banik, B. Molecules 2010, 15, 2520–2525.
23. Rahmatpour, A. J. Organomet. Chem. 2012, 712, 15–19.
24. Aghapoor, K.; Ebadi-Nia, L.; Mohsenzadeh, F.; Morad, M. M.; Balavar, Y.; Darabi, H. R.
J. Organomet. Chem. 2012, 708–709, 25–30.
25. Rivera, S.; Bandyopadhyay, D.; Banik, B. Tetrahedron Lett. 2009, 50, 5445–5448.