One-pot synthesis of mannich bases under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2013.853191

A mild and practically convenient one-pot procedure for the Mannich reaction via condensation of amines, aldehydes and malonates, β-ketoesters, or β-dicarbonyl compounds has been carried out without using any organic solvent, metallic catalyst, or Lewis acids or bases at room temperature. The present protocol offers several advantages, such as goods yields, simple procedure with easy workup, and the absence of any volatile, hazardous organic solvents and metallic catalyst.

Full text of DOI:10.1080/00397911.2013.853191

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One-Pot Synthesis of Mannich Bases Under Solvent-Free
Conditions
Onur Demirkol a , Dilek Akbaşlar a , Sultan Giray a & B. BarışAnıl b
a Department of Chemistry, Art&Science Faculty , Çukurova University , 01330 , Adana ,
Turkey
b Department of Chemistry, Science Faculty , Ataturk University , 01330 , Adana , Turkey E-
mail:
Accepted author version posted online: 02 Dec 2013.Published online: 02 Dec 2013.
To cite this article: Synthetic Communications (2013): One-Pot Synthesis of Mannich Bases Under Solvent-Free Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2013.853191
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Sultan Giray
One-Pot Synthesis
One-Pot Synthesis of MannichBases Under Solvent-Free Conditions
OnurDemirkol1, DilekAkbaşlar1, Sultan Giray1, B. BarışAnıl2
1Department of Chemistry ,Art&Science Faculty, Çukurova University,01330 Adana,
Turkey. 2Department of Chemistry , Science Faculty, Ataturk University,01330 Adana,
Turkey. E-mail: banil@atauni.edu.tr
Corresponding authors: Sultan Giray, Department of Chemistry ,Art&Science
Faculty, Çukurova University,01330 Adana, Turkey. E-mail: esgiray@cu.edu.tr
Graphical Abstract
Abstract
A mild and practically convenient one-pot procedure for the Mannich reaction via
condensation of amines, aldehydes and malonates, β-ketoesters or β-dicarbonyl
compounds has been carried out without using any organic solvent, metallic catalyst and
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Lewis acids or bases at room temperature. The present protocol offers several advantages,
such as goods yields, simple procedure with an easy work-up and the absence of both any
volatile, hazardous organic solvents and metallic catalyst.
KEYWORDS:Mannich bases, Multicomponent reaction, One-pot synthesis, Solvent-
free synthesis, β –dicarbonyl compounds
Introduction
Mannich reaction has been one of the most important C-C bond forming reaction in
organic chemistry for the preparation of β-dicarbonyl compounds which are valuable
synthetic intermediates for various pharmaceuticals and bio-active natural products.[1]
Therefore, much consideration has been drawn to the development of this reaction and
numerous methods have been adopted to its application.[2] Recently, chemists are more
interested in the synthesis of Mannich products using one-pot multicomponent with
environmentally friendly approach that maximizes the utility of known multi-component
reactions.[3-4] Various β-dicarbonyl compounds have been synthesized using three
component reactions in the presence of ionic liquids,[5] Brønsted acids,[6-9] CeCl3.7H20,[10]
Zn(OTf)2,[7]H3PW12O4,[8] polymer supported sulphonic acid,[9]Tröger’s base,[11]
adenine,[12] CAN,[13] HClO4-SiO2,[14] NbCl5,[15] BiCl3,[16] and SnCl2.[17] However, some of
these methods suffer from many disadvantages such as high cost, a large amount of
catalysts, low yields, incompatibility with environment, prolonged reaction time, usage of
volatile, hazardous organic solvents and tedious work up conditions. In spite of the fact
that many catalysts[18-42] have been developed in promoting the Mannich reaction, it is
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still desirable to develop low-cost, efficient and powerful methods for this reaction. On
the other hand, a solvent-free reaction is of great importance in synthetic organic
chemistry as it reduces the environmental pollution, saves energy and decreases the
handling costs due to purification techniques.[43-47] Also, the solvent-free reaction not
only is experimentally simple, proceeds well without using any catalysts such as Lewis
acids and bases,[11-17]Brønsted acids[6-9] etc., but also generates virtually no by-products.
There are a few reports on one-pot three component Mannich reaction under solvent free
conditions.[48-52] However, in these studies some metallic compounds, Lewis acids and
bases were used to accelerate the reaction.
Pursuing our studies on the Mannich reaction of β-dicarbonyl compounds, we wished to
explore new conditions to make the synthesis simpler, to save energy and to prevent
usage of hazardous solvents in Mannich reaction. We herein report an efficient,
environmentally benign direct Mannich reaction under very mild conditions. Efficient
coupling between β-dicarbonylcomponds (1), primary amines (2) and aldehydes (3) was
performed without using any organic solvents and catalysts (Scheme 1).The desired
products were obtained in moderate to good yields.
Results and Discussion
In this paper, we describe the results of our studies on a three-component reaction
between aryl aldehydes, β-dicarbonyl compounds, β-ketoesters or malonates, aromatic
and aliphatic amines. The reaction is created by simple mixing three common reactants
without using any catalyst and solvent at room temperature.
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The preliminary reaction of three component Mannich reaction of methyl-3-
oxopentanoate (6) with benzaldehyde (5) and aniline (7) (entry 13, Table 1) under solvent
free and catalyst free condition got completed in 1,5 h at ambient temperature to afford
the corresponding β-aminodicarbonyl compound (4m) in 60% yield.
Encouraged by this result, the three component one-pot Mannich reaction of several β-
dicarbonyl compound, β-ketoesters or malonates, aromatic amines and aryl aldehydes
was investigated under identical reaction conditions to report the reaction field activity
and generality of this protocol, and the results were displayed in Table 1.
In all cases smooth reaction were observed to afford the β-aminodicarbonyl compounds
4a-4w in moderate to good yields. Various aromatic aldehydes with different substituents
such as electron releasing group (–OCH3) and electron withdrawing group (-F) show
approximately similar effect on the formation of products and in their yields ( entries
3,5,21 and 23 in Table1). So far as amines compounds were concerned, aliphatic amines
could be more favourable than aromatic amines to give β-aminodicarbonyl compounds in
terms of yields (entries 2,3,5 and 11 in Table1). Careful analysis of Table 1 reveals that
the reactions were responsive to various aromatic aldehydes and primary aliphatic,
aromatic amines using this method. Both β-ketoesters and 1,3-dicarbonyl compounds
were also gave the corresponding β-aminodicarbonylcompounds with good yields.
Furthermore, R1 and R2 groups in the β-dicarbonyl compounds have a crucial effect on
the product yields. It could be inferred that the reactivities of β-dicarbonyl compound
with bulky alkoxy group were weaker than those of β-dicarbonyl compound with less
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substituted (entries 2,4 and 12 in Table 1). Moreover, there is a remarkable decrease in
products yields.
A probable route for the formation of β-aminodicarbonyl compounds presents in Scheme
2. To find the true pathway, we conducted a series of experiments with benzaldehyde (5),
aniline (7) and methyl-3-oxopentanoate (6) at room temperature under solvent-free
condition. When the reaction mixture stirred for 30 minutes, not only some physical
changes such as solidification, color change, but also sign of the product formation on
TLC were observed. In an another experiment, a mixture of benzaldehyde (5) and
methyl-3-oxopentanoate (6) was stirred for 12 hours at room temperature which failed to
give any aldol condensation product. This rules out path-A for the product formation.
However, when pre-formed imine which is the condensation product of benzaldehyde (5)
and aniline (7) was reacted with methyl-3-oxopentanoate (6) under the reaction condition
described in scheme 1, the product β-aminodicarbonyl formed in a similar manner with
similar yield as given Table 1 (Entry 13). Taking into consideration this observation, it
can be come to a decision that path-B is operative for this new methodology.
The possible mechanism proposed for the synthesis of β-amino dicarbonyl compounds is
shown in scheme 3. The mechanism involves a two-pathway. In the first step a carbanion
was generated from β-dicarbonyl compound by the amine. In the second step addition of
amine to the aldehyde results an imine and the nucleophilic attack of carbanion to amine
leads to the product. According to this hypothesis, amine acts as a dual role of both imine
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and carbanion formation. While it takes place in imine formation as reactant, it acts as
Lewis base in carbanion formation.
Conclusions
Solvent-free conditions are especially crucial for providing an eco-friendly system. One
of the advantages of solvent-free reaction, comparison to the reaction in solvents, is that
the products are often so pure that no further purification using chromatography is
needed. A solvent-free, environmentally clean, much milder, inexpensive and simple one-
pot multi-component method has been developed for the efficient synthesis of β-
aminodicarbonyl compound in good to high yields by one-pot three-component
condensation of various aldehyde, amine and β-ketoesters, malonates or 1,3-dicarbonyl
compounds at room temperature. The main advantages of this present protocol are the
simple work-up, no base, acid or any additional activator required, and the residue was
crystallized from diethyl ether to give the desired product without further purification
Experimental
All reagents were obtained from commercial sources and were used without
purification. IR spectra were recorded on a Perkin-Elmer 55148 spectrometer. 1H and 13C
NMR spectra were recorded on a Bruker 300 MHzUltrashield spectrometer and a
BrukerAvance III 400 MHz spectrometer, and shifts are given in ppm downfield from
TMS as an internal standard. Melting points were determined using aElectrothermal 9100
instrument. Elemental analyses were measured on a Thermo Flash 2000 Organic
Elemental Analyzer.
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General experimental procedure(4a-4w)
In a typical reaction, aldehyde (3 mmol), amine (5 mmol), and malonates or β-
dicarbonyl compounds (5 mmol) were stirred at room temperature (25 ° C) in a round-
bottomed flask. After a certain time the reaction mixture became viscous and solidified.
Reaction mixture was extracted with water and then diethyl ether (3x10 mL). The solid
was separated by filtration and the product was recrystallized from diethyl ether. The
product was identified using FT-IR and NMR spectroscopy.
Selected Data
methyl 2-((benzylamino)(phenyl)methyl)-3-oxobutanoate (4a, C19H21NO3)
white solid; mp145-147 °C; yield 0.47 g (51%);Rf= 0.19 (n-hexane/EtOAc, 4:1); υmax
(KBr) 3265, 3028, 2950, 1706, 1648, 1255, 1087, 1217 cm-1 ; δH (400 MHz, CDCl3) 7.29-
7.00 ( m, 10 H), 4.38 (s, 1H), 4.08(d, J = 10.4 Hz, 1H ), 3.43(s, 2H), 3.18(s, 3H), 2.39 (d,
J = 10.8 Hz, 1H,) 1.14 (s, 3H ); δC (100 MHz, CDCl3) 204.07, 173.07, 148.15 , 139.83,
129.13, 128.18, 127.60, 127.54, 127.47, 125.81, 67.99 , 59.21, 51.39, 49.94 ,28.71. Anal.
Calcd. for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 72.99; H, 6.87; N, 4.12.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. the
publisher’s website will be a live link
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References
1.
a) Müller, R.; Goesmann, H.; Waldmann, H. Angew. Chem. Int. Ed.1999, 38, 184;
b) Suginome, M.; Uehlin, L.; Murakami, M.; J. Am. Chem. Soc.2004, 126, 13196; c)
Notz, W.; Tanaka, F.; Watanabe, S.-I.; Chowdari, N.S.; Turner, J.M.; Thayumanvan, R.;
Barbas, C.F. J. Org.Chem.2003, 68, 9624; d) Joshi, N.S.; Whitaker, L.R.; Francis, M.B.
J.Am. Chem. Soc.2004, 126, 15942; Evans, G.B.; Furneaux, R.H.; Tyler, P.C.; Schramm,
V.L. Org. Lett. 2003, 5, 3639; Liu, M.; Sibi, M.P. Tetrahedron 2002, 58, 7991.
2.
Azend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. Engl.1998, 37,
1044.
3.
Robinson, R. J. Chem. Soc.1917, 111, 762-768.
4.
Majumbar, K. C.; Ponra, S.; Ghosh, T. RSC Adv. 2012, 2, 1144-1152.
Giray, E.S.; Chiappe, C.; Tunalı, Z.; Rajamani, S. RSC Adv.2011, 1, 761-764.
Yamasaki, S.; Lida, T.; Shibasaki, M. Tetrahedron1999, 55, 8857-8867.
Yang, Y.Y.; Shou, W.G.; Wang, Y.G. Tetrahedron2006, 62, 10079-10086.
Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079-2082.
Limura, S.; Nobutou, D.; Manabe, K.; Kobayashi, S. Chem. Commun.2003, 14,
5.
6.
7.
8.
9.
1644-1646.
10.
11.
Dai, Y.; Li, H.D.; Lu, C.X. Chin. Chem. Lett.2010, 21,31.
Wu, H.; Chen, X.; Wan, Y.; Ye, L.; Xin, H.; Xu, H.; Yue, C.; Pang, L.; Ma, R.;
Shi, D. Tetrahedron Letters2009, 50, 1062-1065.
12.
13.
Goswami, P.; Das, B. Tetrahedron Letters2009, 50, 2384-2388.
Kidwai, M.; Bhatnagar, D.; Mishra, N.K.; Bansal, V. Catal. Commun.2008, 9,
2547-2549.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
14.
6804.
15.
2073.
16.
17.
18.
19.
20.
21.
201.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Bigdeli, M.A.; Nemati, F.; Mahdavinia, G.H. Tetrahedron Letters2007, 48, 6801-
Wang, R.; Li, B.G.; Huang, L.S.; Lu, X.X. Tetrahedron Letters2007, 48, 2071-
Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965-1967.
Wang, M.; Song, Z.; Wan, X., Zhao, S. Monatsh. Chem.2009, 140, 1205.
Loh, T.P.; Liung, S.B.K.W.; Tan, K.L.; Wei, L.L. Tetrahedron2000, 56, 3227.
Akiyama, T.; Itoh, J.; Fuchibe, K. Synlett2002, 1269..
Zhang, C.X.; Dong, J.C.; Cheng, T.M.; Li, R.T. Tetrahedron Lett.2001, 42, 461
Wang, L.M.; Han, J.W.; Sheng, J.; Tian, H.; Fan, Z.Y. Catal. Commun.2005, 6,
Qian, C.T.; Gao, F.F.; Chen, R.F. Tetrahedron Lett.2001, 42, 4673.
Ranu, B.C.; Samanta, S.; Guchhait, S.K. Tetrahedron 2002, 58, 983.
Ollevier, T.; Nadeau, E. J. Org. Chem.2004, 69, 9292.
Shou, W.G.; Yang, Y.Y.; Wang, Y.G. Tetrahedron Lett.2006, 47, 1845.
Limura S.; Nobutou, D.; Manabe, K.; Kobayashi, S. Chem. Commun. 2003, 1644.
Saito, S.; Kobayashi, S. J. Am. Chem. Soc.2006, 128, 8704.
Xia, M.; Lu, Y.D. J. Fluor. Chem.2006, 127, 1119.
Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079.
Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett2006, 133.
Urbaniak, M.; Iwanek, W. Tetrahedron2006, 62, 1508.
Gonzales, A.S.; Arrayas, R.G.; Carretero, J.C. Org.Lett.1999, 1, 1965.
Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
34.
35.
36.
1878.
37.
38.
39.
40.
41.
42.
Li, Z.; Ma, X.; Liu, J. J. Mol. Catal. A: Chem.2007, 272, 132.
Gu, Y.; Ogawa, C.; Kobayashi, J.; Angew. Chem. Int.Ed.2006, 45, 7217.
Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C.F. Angew. Chem. Int. Ed.2007, 46,
Yang, J.W.; Stadler, M.; List, B. Angew. Chem. Int.Ed.2007, 46, 609.
Saruhashi, K.; Kobayashi, S. J. Am. Chem. Soc.2006, 128, 11232.
Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 10054.
Cutting, G.A.; Stainford, N.E.; Willis, M.C. J. Am.Chem. Soc. 2007, 129, 10632.
Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.Soc.2007, 129, 500.
Liu, T.Y.; Cui, H.L.; Long, J.; Li, B.J.; Wu, Y.; Ding, L.S.; Chen, Y.C. J. Am.
Chem. Soc.2007, 9, 1319.
43.
Andrews, P.C.; Deacon, G.B.; Junk, P.C.; Spiccia, N.F. Green Chem.2007, 9,
1319.
44.
Das, B.; Chowdury, N. Mol. Catal. A:Chem.2007, 263, 212.
Azizi, N.; Aryanasab, F.; Saidi, M.R. Org. Lett.2006, 8, 5275.
Shen, I.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett.2005, 46, 507.
Lin, J.; Zhang, L.F. Monatsh. Chem. 2007, 138, 77.
45.
46.
47.
48.
Yue, B.Y.; Yi, T.F.; Zhu, C.B.; Liu, G. Journal of Industrial and Engineering
Chemistry 2009, 15, 653-656.
49.
50.
51.
Chen, X.M.; Li, X.S.; Chan, A.S.C. Chinese Chemical Letters2009, 20, 407-410.
Sharifi, A.; Mirzaei, M.; Naimi-Jamal, M.R. Monatsh. Chem.2001, 132, 875-880.
Kureshy, R.I.; Agrawal, S.; Saravanan, S.; Khan, N.H.; Shah, A.K.; Sayed, H.R.;
Bajaj, H.C., Suresh, E. Tetrahedron Letters2010, 51, 487-494.
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
52.
Heravi, M.M.; Zakeri, M.; Mohammadi, N. Chinese Chemical Letters 2011, 22,
797-800.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
Table 1Mannich reaction of β-ketoesters, aldehydes and primary amines
Entry.
β-dicarbonyl Aldehydes
Amines
Time
compounds
Products and
yields % (h)
R1R2R3 R4
1 CH3
OCH3
C6H5
C6H5
C6H5CH2
8 4a 51
2 CH3
3 CH3
OCH3
CH3CH2CH24 4b82
5 4c76
CH3CH2CH2 4 4d 84
OCH3
p-OCH3C6H4 C6H5
4 CH3
OCH2CH3
OCH2CH3
CH3
C6H5
5 CH3
p-OCH3C6H4
C6H5
C6H5
5 4e74
8 4f 54
6 CH3
C6H5CH2
6 4g 60
7 CH3O tert- C6H5
C6H5
Bu
8 OCH2CH3
9 OCH3
OCH2CH3
C6H5
C6H5
6 4h 60
OCH3C6H5
OCH3
C6H5CH2
C6H5
2 4ı 64
C6H52
10 OCH3
11 CH3
4j 69
OCH2CH3
Otert-Bu
OCH3
p-OCH3C6H4 CH3CH2
C6H5
C6H5C6H51,5 4m 60
5 4k82
12 CH3
CH3CH2CH2 6 4l 52
13 CH3CH2
14 CH3CH2
OCH3
C6H5
p-
1,5 4n 56
MeC6H4CH2
15 CH3
CH3 C6H5
CH3CH2CH2 4o 83
4
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16 CH3
17 CH3
18 CH3
Otert-Bu
Otert-Bu
Otert-Bu
C6H5
C6H5
C6H5
CH3CH2CH2 6 4p 63
C6H5CH2
p-
5 4q 67
54r59
MeC6H4CH2
C6H5CH2
p-
19 CH3CH2
20 OCH3
OCH3
CH3
C6H5
C6H5
3 4s 58
2 4t 62
MeC6H4CH2
C6H5
21 CH3
22 CH3
23 CH3
OCH3
C6H5
m-F C6H4
CH3m-F4
2 4u 70
0,5 4v 74
1 4w 72
C6H4
OCH2CH3 m- F C6H4
C6H5
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Scheme. 1
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Scheme. 2
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Scheme 3
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