An efficient synthesis of β-aminoketone compounds through three-component Mannich reaction catalyzed by calcium chloride

Article abstract of DOI:10.1007/s00706-011-0609-0

Various β-aminoketones were synthesized in a three-component reaction of ketones, aldehydes, and amines in the presence of calcium chloride as catalyst in ethanol in high yields as compared to other synthetic methods. The advantages of this new method are a short reaction time (2 h), high yields, easy workup, convenience, low cost, and eco-friendly protocol. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0609-0

Monatsh Chem (2012) 143:625–629
DOI 10.1007/s00706-011-0609-0
ORIGINAL PAPER
An efficient synthesis of b-aminoketone compounds
through three-component Mannich reaction catalyzed
by calcium chloride
•
Pramod Kulkarni Balaji Totawar
•
Pudukulathan K. Zubaidha
Received: 7 May 2010 / Accepted: 5 August 2011 / Published online: 16 September 2011
Ó Springer-Verlag 2011
Abstract Various b-aminoketones were synthesized in a
three-component reaction of ketones, aldehydes, and
amines in the presence of calcium chloride as catalyst in
ethanol in high yields as compared to other synthetic
methods. The advantages of this new method are a short
reaction time (2 h), high yields, easy workup, convenience,
low cost, and eco-friendly protocol.
imine intermediate may be preformed, or its amine and
aldehyde precursors may be used directly (Scheme 1).
Direct Mannich reactions of aldehydes, ketones, and
aryl amines have recently been realized via organic and
mineral acids, such as proline [10–12], acetic acid [13], p-
dodecylbenzenesulfonic acid [14], and some Lewis acids
[15, 16]. However, these methods often suffer from the
drawbacks of long reaction times and harsh reaction con-
ditions, toxicity, and difficulty in product separation, which
limit their use in the synthesis of complex molecules. This
has led organic chemists to focus on developing more
convenient methods for the synthesis of b-aminoketones.
Recent achievements in the efficient construction of these
molecules include the development of various catalysts,
such as Lewis acid catalysts [17], Bronsted acid catalysts
[18, 19], and Lewis base catalysts [20], to facilitate Man-
nich reactions. For example, scandium triflate, copper
triflate, scandium tris(dodecyl sulfate), and scandium
tris(dodecanesulfonate) [21]. Cl3 [22], HBF4 [23], zirco-
nium catalyst [24], ionic liquid [25], and NbCl5 [26] have
also been used to catalyze these reactions and good yields
were obtained, but these catalysts are associated with long
reaction times, and sterically hindered b-aminoketones
could not be obtained. Lanthanide triflate in certain sol-
vents, such as dichloromethane and acetonitrile, have also
been known to catalyze the Mannnich reaction [27, 28].
Keywords b-aminoketone Á Calcium chloride Á
Mannich reaction Á Three-component reaction
Introduction
Mannich-type reactions are a class of very important
carbon–carbon bond-forming reactions in organic synthesis
and represent some of the most widely utilized chemical
transformations for the construction of nitrogenous
molecules [1–3]. In Mannich transformations, three-com-
ponents, a ketone, an aldehyde, and an amine, react to form
b-aminoketones, which in turn are important synthetic
intermediates for various pharmaceutical and natural
products [4–9]. The increasing popularity of the Mannich
reaction has been fueled by the ubiquitous nature of
nitrogen in drugs and natural products as well as by the
potential of this three-component reaction to generate
diversity. Both direct variants with unmodified ketone
donors and indirect variants utilizing preformed enolate
equivalents have been described [1–3]. In addition, the
Results and discussion
Calcium chloride is inexpensive, non-toxic to the
environment, and easily available. This salt has been used
as an efficient Lewis base in an aldol reaction of dimeth-
ylsilyl enolates in aqueous N,N-dimethylformamide [29],
the Biginelli reaction [30], and in the formation of
P. Kulkarni Á B. Totawar Á P. K. Zubaidha (&)
School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded 431 606, Maharashtra, India
e-mail: p.zubaidha@rediffmail.com
123

626
P. Kulkarni et al.
O
O
the reaction was then studied by substituting various
amines and aldehydes. The results are summarized in
Table 1. In general, high yields of b-aminoketones were
obtained in 2 h using CaCl2 in ethanol. Substrates
bearing various functional groups such as CH3, OCH3,
Cl, NO2, and OH all reacted to produce the corre-
sponding b-aminoketones; m- and p-substituted aromatic
amines gave good results, while o-substituted amines and
aldehydes gave a low yield due to steric hindrance.
Aromatic aldehydes gave good yields, but an electron-
withdrawing substituent on aldehydes resulted in low
yields of product. Finally, the scope of the reaction was
studied using cyclohexanone, benzaldehyde, and substi-
tuted amines (Scheme 3). Cyclohexanone was observed
to be more reactive than acetophenone and did not
require the addition of HCl to increase the catalytic
activity of CaCl2. In general, high yields of b-amino-
ketones were obtained in 2 h using CaCl2 in ethanol.
The results are summarized in Table 2.
NH2
R3
Direct
R1
H
R2
R3
O
NH
R1
R2
R3
OR(NR2)
R1
N
Indirect
H
R2
Preformed
enolate
equivalent
Preformed
imine
Scheme 1
R1
NH2
R2
CHO
O
1 eq. CaCl2
EtOH
, 2 h
O
R1
R2
N
H
Scheme 2
In conclusion, the method described here is a convenient
way to produce b-aminoketones under mild conditions and
may find widespread usage in organic synthesis.
phosphonates [31]. To the best of our knowledge, direct
Mannich-type reactions catalyzed by calcium chloride have
not been reported. Here, we report a calcium chloride-
catalyzed three-component Mannich-type reaction of
ketones, substituted aromatic aldehydes, and substituted
aromatic amines that leads to the efficient synthesis of
b-aminoketones under mild conditions. Our experiments
demonstrated that stirring acetophenone, benzaldehyde,
aniline, and 1 equivalent of calcium chloride in ethanol for
8 h led to the formation of the corresponding Mannich
product (Scheme 2). We observed that the same reaction
catalyzed with calcium chloride, in the presence of one
drop HCl in ethanol, reduced the reaction time to 2 h and
achieved a higher yield of pure product. The scope of
Experimental
All purchased chemicals were of analytical grade and used
without further purification. Melting points were determined
by the open capillary method. IR spectra were recorded on a
FT-IR 3.1 Win-BOMEM apparatus. 1H and 13C NMR
spectra were recorded on a Bruker DRX-300 Avance spec-
trometer using deuterated chloroform (CDCl3) as the solvent
and tetramethylsilane (TMS) as the internal standard.
Table 1 Three-component calcium chloride-catalyzed Mannich-type reactions with substituted amines and substituted aldehydes
Starting R1
Starting R2
Product
Time/h
2
Yielda/%
M.p./°C
86
169–170 [26]
CHO
NH2
O
N
H
2
82
170–171 [34]
CHO
NH2
O
N
H
123

An efficient synthesis of b-aminoketone compounds
Table 1 continued
627
Starting R1
Starting R2
Product
Time/h
2
Yielda/%
90
M.p./°C
172–173 [34]
131–132 [26]
130–131 [33]
185–186 [34]
139–140 [35]
163–164 [34]
107–108 [32]
CHO
NH2
Cl
O
O
O
N
H
Cl
2
2
2
2
2
2
84
91
84
84
91
40
CHO
CHO
CHO
CHO
CHO
CHO
NH2
N
H
Cl
Br
Cl
NH2
N
H
Br
NH2
NO2
O
N
H
NO2
NH2
O
N
H
NO2
NO2
NH2
OMe
O
N
H
OMe
NH2
OMe
O
N
H
OMe
123

628
P. Kulkarni et al.
Table 1 continued
Starting R1
Starting R2
Product
Time/h
2
Yielda/%
72
M.p./°C
117–118 [34]
NH2
Cl
CHO
Cl
O
O
O
N
H
2
2
2
64
61
57
105–106 [26]
149–151 [34]
158–162 [36]
CHO
NO2
NH2
NH2
NH2
NO2
N
H
CHO
OMe
OMe
N
H
CHO
NO2
O
NO2
NH
2
79
131–132 [35]
NO2
NH2
CHO
O
NO2
N
H
Reaction conditions 1 mmol aromatic aldehyde, 1 mmol acetophenone, 1 mmol aromatic amine, 1 equiv CaCl2, EtOH, heat for 2 h
a
1
Isolated yield—structures of products were confirmed by H NMR
General procedure for synthesis of b-aminoketones
R
CHO
O
NH2
1 eq. CaCl2
EtOH
O
One equivalent of CaCl2 was added to a mixture of
acetophenone or cyclohexanone (5 mmol), benzaldehyde
(5 mmol) and aniline (5 mmol) in 5 cm3 ethanol. One
drop of HCl was added when acetophenone was the
starting material. The resulting mixture was stirred at
60–80°C for 2 h. Workup with 5% NaHCO3 resulted in
the precipitation of the product as a solid, which was
filtered, washed with water, and recrystallized from EtOH.
R
N
H
, 2 h
Scheme 3
All of the products are known, and physical data were
found to be identical with those reported in the literature
(Tables 1, 2).
123

An efficient synthesis of b-aminoketone compounds
629
Table 2 Three-component
Starting R
Product
Time/h
2
Yielda/%
84
M.p./°C
calcium chloride-catalyzed
Mannich-type reactions with
139–140 [34]
118–119 [34]
137–138 [34]
NH2
cyclohaxanone, benzaldehyde,
and various amines
O
N
H
2
82
NH2
O
N
H
Reaction conditions 1 mmol
aromatic aldehyde, 1 mmol
cyclohexanone, 1 mmol
aromatic amine, 1 equiv CaCl2,
EtOH, heated for 2 h
2
77
NH2
Cl
Cl
O
N
H
a
Isolated yield—structures of
products were confirmed by
1H NMR
18. Akiyama T, Takaya J, Kagoshima H (1999) Synlett 9:1426
19. Akiyama T, Matsuda K, Fuchibe K (2005) Synlett 2:322
20. Takahasi E, Fujisawa H, Mukaiyama T (2004) Chem Lett 33:926
21. Kobayashi S, Busujima T, Nagayama S (1999) Synlett 5:545
22. Loh TP, Wei LL (1998) Tetrahedron Lett 39:323
23. Akiyama T, Takaya J, Kagoshima H (1999) Synlett 7:1045
24. Ishitani H, Ueno M, Koyabayashi S (1997) J Am Chem Soc
119:7153
25. Sahoo S, Joseph T, Halligudi SB (2006) J Mol Catal A: Chem
244:179
26. Wang R, Li B, Huang T, Shi L, Lu X (2007) Tetrahedron Lett
48:2071
27. Manabe K, Mori Y, Kobayashi S (1999) Synlett 9:1401
28. Kobayashi S, Ishitani H, Komiyama S, Oniciu DC, Katrizky AR
(1999) Tetrahedron Lett 37:3731
29. Miura K, Nakagawa T, Hosomi A (2002) J Am Chem Soc
124:536
References
1. Kleinnmann IF (1991) In: Trost BM (ed) Comprehensive organic
synthesis, vol 2, chapter 4.1. Pergamon Press, New York. Review
2. Arend M, Westermann B, Risch N (1998) Angew Chem Int Ed
37:1044. Review
3. Blicke FF (1942) Org React 1:303. Review
4. Davis FA, Zhang Y, Anilkumar G (2003) J Org Chem 68:8061
5. Evans GB, Furneaux RH, Tyler PC, Schramm VL (2003) Org
Lett 5:3639
6. Martin SF (2002) Acc Chem Res 35:895
7. Fujita T, Nagasawa H, Uto Y, Hashimoto T, Asakawa Y, Hori H
(2004) Org Lett 6:827
8. Joshi NS, Whitaker LR, Francis MB (2004) J Am Chem Soc
126:15942
9. Abonia R, Insuasty B, Quiroga J, Nogueras M, Meier H (2004)
Mini Rev Org Chem 1:387
30. Gangadasu NP, Raju BC, Rao VJ (2006) Ind J Chem 45B:1259
31. Kaboudin Zahedi H (2008) Chem Lett 37:540
32. Thierry O, Etienne N (2004) J Org Chem 69:9292
33. Mohammad AB, Firouzeh N, Gholam HM (2007) Tetrahedron
Lett 48:6801
34. Kidwai M, Mishra NK, Bansal V, Ajeet K, Mozumdar S (2009)
Tetrahedron Lett 50:1355
35. Li Z, Ma X, Liu J, Feng X, Tian G, Zhu A (2007) J Mol Catal A:
Chem 272:132
10. List B, Pojarliev P, Biller WT, Martin HJ (2002) J Am Chem Soc
124:827
11. List B (2000) J Am Chem Soc 122:9336
12. Duthaler RO (2003) Angew Chem Int Ed 42:975
13. Mogilaiah K, Kankaiah G (2002) Ind J Heterocycl Chem 11:283
14. Manabe K, Mori Y, Kobayashi S (2001) Tetrahedron 57:2537
15. Kobayashi S, Hamada T, Manabe K (2002) J Am Chem Soc
124:5640
16. Desai P, Schildknegt K, Agrios KA, Mossman C, Milligan GL,
Aube J (2002) J Am Chem Soc 122:7226
17. Shimizu M, Itohara S (2000) Synlett 12:1828
36. Kidwai M, Bhatnagar D, Mishra NK, Bansal V (2008) Catal
Commun 9:2547
123