A novel highly stereoselective multi-component synthesis of N-substituted β-amino ketone derivatives using copper(II) phthalocyanine as reusable catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.04.016

Stereoselective synthesis of N-substituted β-amino ketone derivatives with substituents include one or two polar hetero atoms on benzene rings in many cases has been achieved by a one-pot multi-component process using copper(II) phthalocyanine as catalyst

Full text of DOI:10.1016/j.tetlet.2011.04.016

Tetrahedron Letters 52 (2011) 3110–3115
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Tetrahedron Letters
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A novel highly stereoselective multi-component synthesis of N-substituted
b-amino ketone derivatives using copper(II) phthalocyanine as reusable catalyst
⇑
V. S. Shinu, P. Pramitha, D. Bahulayan
Department of Chemistry, University of Calicut, Malappuram 673635, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of N-substituted b-amino ketone derivatives with substituents include one or
two polar hetero atoms on benzene rings in many cases has been achieved by a one-pot multi-component
process using copper(II) phthalocyanine as catalyst. The new process is suitable for the inclusion of a
wide variety of substrates for the construction of highly functionalized Mannich-type structural scaffolds.
The catalyst used is recycled and reused for repeating the reactions.
Received 27 January 2011
Revised 30 March 2011
Accepted 1 April 2011
Available online 9 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper(II) phthalocyanine
Stereoselectivity
Mannich-type reaction
b-Amido ketone derivative
Multi-component reaction
The b-keto amide functionality has been found in a number of
biologically important natural products such as nikkomycins and
neopolyoxins. It is also a useful building block for the synthesis of
b-amino acids, b-lactams, and b-amino alcohols.1–6 A recent devel-
opment in the synthesis of N-substituted b-amino ketone deriva-
tives is the emergence of a multi-component reaction (MCR)7–14
which involves one-pot condensation of a non-enolizable aldehyde,
an enolizable ketone and acetonitrile in the presence of acetyl chlo-
ride15–21 (Scheme 1). Several new catalysts have been reported over
the years but many of them suffer the serious drawback of poor
R2
R2
R1
R1
R3
R3
CHO
Acid catalysis
CH3COCl
O
NH
CH3
O
O
CN
Table 1
CH3
Activity of CuPc, ZnPc and AlPcCl for the multi-component synthesis of b-acrylamido
ketones
Scheme 1. Acid catalyzed stereoselective multi-component synthesis of b-acetam-
Cl
Cl
ido ketones.
CH3COCl
CHO
MPc
M= Zn, Al-Cl, Cu
O
NH
O
O
CN
2a
N
N
N
N
N
Entry Catalyst Amount of the
catalyst (mol %)
Reaction
time (h)
Yield (%)a
M
N
N
N
Reaction
at 70 °C
Reaction
at rt
1
2
3
4
5
6
7
8
ZnPc
AlPcCl
CuPc
CuPc
CuPc
CuPc
CuPc
Nil
10
10
10
7
3
3
6.0
6.0
6.0
6.0
61
63
77
76
76
77
77
0
2
4
7
6
7
6
6
0
M= Cu, Zn, Al-Cl
6.0
Figure 1. Metallopthalocyanines.
3.5
16.0
16.0
3
—
⇑
Corresponding author. Tel.: +91 9995538062; fax: +91 494 2400269.
E-mail address: bahulayan@yahoo.com (D. Bahulayan).
a
Based on the weight of the isolated pure products.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.016

V. S. Shinu et al. / Tetrahedron Letters 52 (2011) 3110–3115
3111
Table 2
stereoselectivity and substrate control (for a detailed list of refer-
ences about reported catalysts, see Supplementary data).
CuPc catalyzed formation of b-acrylamido ketones
R1
R1
R3
In continuation of our ongoing research programme for
developing highly functionalized structural scaffolds based on
N-substituted b-amino ketone derivatives, we decided to look into
the possibility of developing a new protocol that can expand
substrate scope as well as stereo control. For this we proposed to
re-examine this one-pot MCR process in the presence of different
metallopthalocyanines (MPcs).
R3
CuPc (3 mol%)
CHO
O
NH
O
RCOCl
70 °C, 3.5 h
O
CN
Entry
Reaction components
b-Acrylamido
ketone
Yielda
(%)
Aldehyde
Ketone
Acid
chloride
MPcs (Fig. 1) have been extensively studied due to their poten-
tial applications in developing materials for advanced technolo-
gies.22–25 In the present study, we have explored the catalytic
efficiency of copper(II) phthalocyanine (CuPc), zinc phthalocyanine
(ZnPc), and aluminium phthalocyanine chloride (AlPcCl) for the
one-pot synthesis of N-substituted b-amino ketone derivatives.
In a typical experiment,26 synthesis of the b-acrylamido ketone
derivative 2a (Table 1) was carried out by heating 2-chlorobenzal-
dehyde, acetophenone, and acetyl chloride with catalytic amount
of CuPc in acrylonitrile at 70 °C. The progress of the reaction was
monitored by TLC analysis. The reaction was found to complete
in 3.5 h and analytically pure 2a was obtained We have then stud-
ied the efficiency of AlPcCl and ZnPc for this reaction. The synthetic
approach was identical to that highlighted above. As shown in
Cl
O
Cl
Cl
CHO
2a
77
O
O
O
O
NH
Br
O
Br
O
Cl
CHO
2b
2c
79
73
O
O
NH
O
O
O
Cl
CHO
NH
Cl
Cl
OH
O
O
Cl
O
CHO
O
OH
2d
77
O
O
NH
Cl
O
O
O
O
Table 3
CuPc catalyzed formation of b-acrylamido ketones from
a
-substituted ketones
Cl
Cl
Cl
Br
O
Cl
R2
R2
Cl
R1
R1
R3
CHO
R3
CuPc (3 mol%)
2e
2f
78
75
75
CHO
O
O
NH
O
NH
O
RCOCl
70 °C, 3.5 h
O
CN
Br
O
Br
Cl
Cl
Yielda Syn/
CHO
Entry
Reaction components
(%)
78
antib
O
NH
O
Aldehyde
Cl
Ketone
b-Acrylamido ketone
Cl
O
Cl
Br
Cl
Cl
CHO
2g
O
O
O
O
NH
O
CHO
3a
12:88
O
NH
O
NO2
O
NO2
Cl
Br
Br
2h
69
CHO
O
NH
O
O
CHO
3b
3c
77
76
10:90
12:88
O
Br
O
Br
NH
O
Cl
CHO
2i
2j
71
73
O
O
Cl
Cl
O
NH
O
O
CHO
O
O
O
Cl
Cl
O
NH
O
CHO
O
NH
O
Cl
O
Cl
O
O
CHO
O
3d
3e
79
73
9:91
O
2k
68
CHO
O
O
NH
O
NH
O
Cl
O
O
Cl
Cl
O
Cl
O
Cl
Cl
CHO
CHO
2l
63
65
O
O
O
O
NH
NH
O
CHO
10:90
O
O
NH
O
2m
O
a
Yield of the isolated anti-diastereomers (stereochemistry assigned based on the
coupling constant of methine protones).
a
b
Syn/anti ratio determined from 1H NMR of the crude mixture.
Based on the weight of the isolated pure products.

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V. S. Shinu et al. / Tetrahedron Letters 52 (2011) 3110–3115
Table 4
CuPc catalyzed formation of b-propionamido carbonyl derivatives
R1
R1
R3
R3
CuPc (3 mol%)
CHO
O
NH
O
CH3COCl
70 °C, 3.5 h
O
CN
Entry
Reaction components
Ketone
Yielda (%)
Aldehyde
b-Propionamide ketone
4a
O
71
CHO
O
NH
O
Cl
Cl
CHO
4b
75
77
O
O
NH
O
Br
Br
4c
CHO
O
O
NH
O
O
NO2
NO2
4d
69
CHO
O
NH
O
CHO
4e
56
72
51
NH
O
O
O
Br
OH
Br
OAc
4f
CHO
O
NH
O
O
O
CHO
4g
O
NH
O
Cl
Cl
CHO
4h
54
O
NH
O
O
a
Based on the weight of the isolated pure products.
Table 1, CuPc was found to be slightly more efficient than other
MPcs and 3 mol % of catalyst was found to be enough for the com-
pletion of reaction. We have also carried out the reactions at room
temperature, but the yield obtained was significantly low.
strate scope, we have categorized our study in different groups
such as (a) reactions with acrylonitrile, (b) reactions with propioni-
trile, (c) reactions with aromatic and substituted aliphatic nitriles,
and (d) reactions with acetonitrile.
Control reactions were done in the absence of a catalyst at con-
ditions described for the reactions in the presence of the catalyst.
No product formation was observed in the absence of the catalyst.
Promising results obtained in our initial studies prompted us to
choose CuPc as the model catalyst for studying the reactions of
substituted aldehydes and ketones. In order to explain the sub-
Reactions of substituted aldehydes and ketones with acryloni-
trile in the presence of CuPc resulted in the formation of the de-
sired product in good yield (Table 2). The reaction is not
significantly influenced by the nature of substituent on aldehydes
or ketones, however, a slight enhancement in yield was observed
with aldehydes bearing a substituent like chlorine or bromine at

V. S. Shinu et al. / Tetrahedron Letters 52 (2011) 3110–3115
3113
Table 5
CuPc catalyzed formation of b-propionamido carbonyl derivatives from
a-substituted ketones or ketoester
R2
R2
R1
R1
R3
R3
CuPc (3 mol%)
CHO
O
NH
O
CH3COCl
70 °C, 3.5 h
O
CN
Entry
Reaction components
Ketone
Yielda (%)
Syn/antib
Aldehyde
Cl
b-Propionamide ketone
Cl
O
5a
74
12:88
8:92
CHO
O
NH
O
Cl
O
O
O
Cl
O
CHO
5b
5c
71
76
O
O
NH
O
Cl
O
Cl
O
CHO
10:90
10:90
O
O
NH
O
NO2
O
NO2
O
O
5d
5e
71
65
CHO
O
NH
O
Cl
Cl
CHO
12:88
O
O
NH
O
a
Yield of the isolated anti-diastereomers (stereochemistry assigned based on the coupling constant of methine protones).
Syn/anti ratio determined from 1H NMR of the crude mixture.
b
the ortho-position (Table 2, entries 2a and 2b). We have also con-
ducted the reactions with other acid chlorides to study the com-
patibility of different acid chlorides for this reaction. Acid
chlorides like propionyl chloride and valeroyl chloride underwent
the desired reaction to form b-amido ketone derivatives in moder-
ate to good yields (Table 2, entries 2h–2k). The effect of the cata-
lyst on diastereoselectivity was examined by conducting the
effectively transformed into the corresponding N-substituted b-
amido ketone derivatives in moderate to good yield. Here also,
the reaction of
a,b-unsaturated aldehyde like cinnamaldehyde
with benzonitrile resulted in the formation of the desired product
in 72% yield.27
We have then studied the performance of copper(II) phthalocy-
anine in the reactions of aldehydes and ketones with acetonitrile.
All the reactions resulted in the formation of 70–80% desired
products.28
The reactions were found to be very clean and the products
were isolated by aqueous work-up after filtering off the catalyst.
No column purification was required and the products obtained
were sufficiently pure for spectral analysis. Stereochemical out-
reactions with
a-substituted ketones. As shown in Table 3, all
reactions proceeded well and the substrates were transformed
effectively into the corresponding b-amido carbonyl compounds
with ꢀ90% anti-diastereoselectivity irrespective of the substituent
patterns present in aldehydes or ketones.
The reactions of propionitrile with various aldehydes and ke-
tones in the presence of CuPc resulted in the formation of
come of the reactions were studied using
a-substituted ketones
51–77% of various b-propionamido ketones (Table 4).
a
,b-unsatu-
like benzoyl acetone and ethyl methyl ketone. These reactions also
afforded excellent anti-diastereoselectivity for the desired
products.29
rated aldehydes like cinnamaldehyde also afforded corresponding
unsaturated b-amido ketones (Table 4, entries 4g and 4h). Diaste-
reoselectivity was examined by performing the reactions with
In our previous paper we have reported the use of Selectflu-
or™ for this reaction with certain substrates.21 As suggested by
one of the referees, we thought it is appropriate to compare the
catalytic activities of both the catalysts. We found that CuPc is
more efficient than Selectfluor™ for the synthesis of b-acrylamido
and b-propionamido ketones whereas the activities of both the
catalysts are almost same for the synthesis of b-acetamido
ketones. An interesting observation was obtained with the reac-
a-substituted ketones (Table 5). All the reactions resulted in the
formation of ꢀ90% anti-diastereomers of the b-propionamido ke-
tones irrespective of the nature of the substituents present in
substrates.
Similar experiments were done with aromatic nitriles as well
as with substituted aliphatic nitriles like benzonitrile, o-tolunitri-
le, benzyl cyanide, and 3-bromopropionitrile in the presence of
CuPc. All nitriles examined were found to be efficient and
tion of an a,b- unsaturated aldehyde like cinnamaldehyde. In this

3114
V. S. Shinu et al. / Tetrahedron Letters 52 (2011) 3110–3115
x
x
x
H2
C
CH3
CH2
H
O
O
O
CuIPc
CuIIPc
CuIPc
5
x
x
CuIIPc
x
+
x
CH2
H
-Cl
O
O
COR
O
O
CuIPc
6
RCOCl
X
R1CN
-RCOO
X
H2O
X
X
O
N
O
HN
O
C
R1
R1
7
Scheme 2. Possible mechanism for the catalysis of metallopthalocyanines in the synthesis of b- amido ketones.
case, CuPc afforded 72% of the desired product whereas Selectflu-
or failed to produce the corresponding N-substituted amino
ketone.30
References and notes
1. Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094.
2. Cordova, A. Acc. Chem. Res. 2004, 37, 102–112.
The recyclability of the catalyst was examined by performing
the reactions with recovered catalyst. For this, the catalyst recov-
ered from the reaction mixture was purified by repeated washing
with acetone and subjected to vacuum drying in an air oven at
80 °C for 2 h. The performance of the purified catalyst was exam-
ined by conducting the reactions up to five cycles. The recovered
catalyst was found to be very effective for converting the sub-
strates into products. All the reactions yielded almost same
amount of the product.31 The Maldi-T of MS of the recovered and
purified catalyst is given in Supplementary data.
3. Berluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B. J. Org. Chem. 1993, 58,
5972–5975.
4. Enders, D.; Moser, M.; Geibel, G.; Laufer, M. C. Synthesis 2004, 12, 2040–2046.
5. Dahn, U.; Hagenmaier, H.; Hohne, H.; Konig, W. A.; Wolf, G.; Zahner, H. Arch.
Microbiol. 1976, 107, 143–160.
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Agric. Biol. Chem. 1980, 44, 1709–1711.
7. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley: Weinheim, 2005.
8. Bonne, D.; Coquerel, Y.; Constantieux, T.; Rodriguez, J. Tetrahedron: Asymmetry
2010, 21, 1085–1109.
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10. Dotz, K. H.; Stendel, J., Jr. Chem. Rev. 2009, 109, 3227–3274.
11. Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
A possible reaction sequence that account for the formation of
b-amido ketones is given in Scheme 2. The central metal atom of
the macrocyclic phthalocyanine initiates the reaction by activating
the enol formation. The addition of aldehyde moiety to the acti-
vated enol 5 followed by the acylation forms the b-acyloxy ketone
intermediate 6. The acyloxy group of 6 then replaced by more nule-
ophilic nitrogen of the nitrile to form a stable cation intermediate
7.21 7 on further reaction with water or other reactive intermedi-
ates like HOCl formed32 during reaction may lead to the formation
of b-amido ketone derivative. It is reasonable to assume that, the
specific geometrical arrangement of peripheral metal binding
isoindol units restrict the approach of the aldehyde carbocation
moiety from the more hindered face to enhance the formation of
the anti-diastereomer.
12. Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev. 2009, 109, 796–814.
13. Domling, A. Chem. Rev. 2006, 106, 17–89.
14. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
15. Bhatia, B.; Reddy, M. M.; Iqbal, J. J. Chem. Soc., Chem. Commun. 1994, 713–714.
16. Reddy, M. M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett. 1995, 36, 4877–4880.
17. Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett. 1997, 38, 1083–1086.
18. Prabhakaran, E. N.; Iqbal, J. J. Org. Chem. 1999, 64, 3339–3341.
19. Rao, I. N.; Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 4079–
4082.
20. Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735–5738.
21. Shinu, V. S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D. Tetrahedron Lett.
2009, 50, 4838–4843.
22. McKeown, N. B. Phthalocyanine Materials Synthesis Structure and Function;
Cambridge University Press: Cambridge, 1998.
23. de la Torre, G.; Vazquez, P.; Agullo-Lopez, F.; Torres, T. J. Mater. Chem. 1998, 8,
1671–1683.
24. de la Torre, G.; Vazquez, P.; Agullo-Lopez, F.; Torres, T. Chem. Rev. 2004, 104,
3723–3750.
25. Dini, D.; Hanack, M. J. Porphyrins Phthalocyanines 2004, 8, 915–933.
26. Typical experimental procedure for the synthesis of an N- substituted b-amino
ketone derivative: to the stirred suspension of CuPc (3 mol %) in nitrile
(5 mL),aldehyde (2.5 mmol), enolizable ketone (2.5 mmol) and acid chloride
(1 mL) were added and heated at 70 °C for 3.5 h. The reaction mixture was then
cooled to room temperature and the catalyst was filtered off. The filtrate was
then poured into crushed ice and stirred for 30 min. The organic layer was
extracted with dichloromethane (2 Â 60 mL), dried on anhydrous Na2SO4 and
concentrated under vacuum. Silica gel column chromatography of the residue
using petroleum ether-ethyl acetate (2:1) as eluent afforded N-substituted b-
amino ketone derivatives. In the case of b-acetamido ketones, the filtrate after
the removal of the catalyst was poured into ice-cold water and stirred for 1 h.
The precipitated solid was filtered and dried. The dried sample was washed
with diethyl ether (3 Â 20 mL) to afford the corresponding b-acetamido ketone
derivative. Spectral data for 2a: 1H NMR (400 MHz, DMSO-d6): d = 8.55–8.53 (d,
J = 7.20 Hz, 1H), 7.98–7.96 (t, 2H), 7.66–7.62 (t, 1H), 7.54–7.49 (m, 3H), 7.44–
7.41 (dd, 1H), 7.36–7.25 (M, 2H), 5.77 (s, 1H), 3.74–3.71 (t, 3H), 3.54–3.48 (t,
In summary, we have developed a copper(II) phthalocyanine
mediated one-pot stereoselective process for the synthesis of wide
variety of N-substituted b-amino ketone derivatives. Under the de-
scribed catalytic conditions, a diverse array of functional groups,
present in aldehydes, ketones, and nitriles are tolerated. The reus-
ability of the catalyst and increased anti-diastereoselectivity makes
it as a green alternative to the rapid generation of Mannich-type
products.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.016.

V. S. Shinu et al. / Tetrahedron Letters 52 (2011) 3110–3115
3115
1H), 2.58–2.55 (t, 2H). 13C NMR (100 MHz, DMSO-d6): d = 196.40, 168.23,
27. See Table 6 given in the Supplementary data.
28. See Table 7 given in the Supplementary data.
29. See Table 8 given in the Supplementary data.
30. See Table 9 given in the Supplementary data.
31. See Table 10 given in the Supplementary data.
32. Liu, J.; Wong, C. H. Tetrahedron Lett. 2002, 43, 4037–4039.
140.13, 136.31, 133.32, 131.58, 129.31, 128.71, 128.68, 128.58, 128.02, 127.70,
127.29, 46.40, 43.17, 40.90, 40.12, 39.91, 39.71, 39.50, 39.29, 39.08, 38.87,
38.17. FT-IR (KBr): 3292.86, 3086.51, 2970.80, 1682.59, 1647.88, 1596.77,
1552.42, 1442.49, 1404.49, 1384.64, 1356.68, 1287.25, 1231.33, 1196.61,
1119.26, 748.24, 690.39, 614.21 cmÀ1. MS: m/z = 314.1 (M+), 229.1.