An expedient synthesis of β-acetamido- and β-benzamidocarbonyl compounds via KAL(SO4)2·12H2O-catalyzed three-component coupling reaction

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An Expedient Synthesis of β-Acetamido-
and β-Benzamidocarbonyl Compounds
via KAl(SO4)2·12H2O-catalyzed Three-
component Coupling Reaction
Aniruddha Molla a & Sahid Hussain a
a Department of Chemistry , Indian Institute of Technology Patna ,
Patna , 800 013 , India
Published online: 24 Oct 2013.
To cite this article: Aniruddha Molla & Sahid Hussain (2013) An Expedient Synthesis of β-Acetamido-
and β-Benzamidocarbonyl Compounds via KAl(SO4)2·12H2O-catalyzed Three-component Coupling
Reaction, Organic Preparations and Procedures International: The New Journal for Organic Synthesis,
45:6, 494-503, DOI: 10.1080/00304948.2013.834788
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Organic Preparations and Procedures International, 45:494–503, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.834788
An Expedient Synthesis of β-Acetamido-
and β-Benzamidocarbonyl Compounds
via KAl(SO4)2·12H2O-catalyzed
Three-component Coupling Reaction
Aniruddha Molla and Sahid Hussain
Department of Chemistry, Indian Institute of Technology Patna, Patna 800 013,
India
β-Aminocarbonyl compounds are important structural units of several biologically ac-
tive compounds such as dolastins, astins, onchidin, jasplakinolide and motuporin,1 and
useful building blocks for β-lactams2,3 and β-peptides4 that are present in a variety of
drugs.5 Traditionally, this class of compounds is prepared by the Dakin-West reaction;6–8
the condensation of α-amino acids with acetic anhydride in the presence of a base provides
the α-acetamidoketones through intermediate azalactones. In recent years, the Mannich
reaction9,10 and its variants have been used in the synthesis of several biologically and
pharmacologically important β-aminocarbonyl compounds.5 One of the interesting ways
for the synthesis of β-aminocarbonyl compounds is multi-component coupling of alde-
hyde, enolizable ketone, acetyl chloride and acetonitrile first reported by Iqbal and co-
workers11–13 and later by some other groups using catalyst such as Bi-salts,14 zeolite Hβ,15
Zn(OTf)2,16 Cu(OTf)2 and Sc(OTf)3,17 ZrOCl2·8H2O,18,19 CeCl3·7H2O,20 chiral Bro¨nsted
acid,21 sulfamic acid22, cellulose-H2SO4,23 SiO2-H2SO4,24 TMSCl,25 FeCl3,26 hetaropoly
acid,27 Zn(HSO4)2,28 and silica-supported perchloric Acid.29 Though the reported meth-
ods are worthy, they suffer from some drawbacks such as requiring air-sensitive or costly
catalysts14–21 and harsh reaction conditions (high temperatures).23–25 Therefore, the elabora-
tion of new methods for this type of multi-component reaction is still useful. In continuation
of our investigations the synthesis of β-aminocarbonyl compounds,30–32 we were prompted
to explore the use of aluminium potassium sulfate dodecahydrate (KAl(SO4)2·12H2O)33,34
a naturally occurring material, widely available, water-soluble, air-stable, relatively non-
toxic and inexpensive reagent able to activate the carbonyl group. Herein, we report an
efficient and convenient procedure for the synthesis of β-aminocarbonyl compounds using
KAl(SO4)2·12H2O as a catalyst (Scheme 1).
Received April 10, 2013; in final form June 21, 2013.
Address correspondence to Sahid Hussain, Department of Chemistry, Indian Institute of Tech-
nology Patna, Patna 800 013, India. E-mail: sahid@iitp.ac.in
494

Synthesis of β-Acetamido- and β-Benzamidocarbonyl Compounds
495
Scheme 1
KAl(SO4)2·12H2O catalyzed synthesis of β-aminocarbonyl compounds.
In order to determine the optimal reaction conditions, several experiments were carried
out with a mixture of benzaldehyde (2 mmol), acetophenone (2 mmol), acetyl chloride
(3 mmol) and acetonitrile (3 ml) at room temperature. In the absence of the catalyst, the
expected product was obtained in only 15% yield and after 24 h; a longer time was required
with 1 and 5 mol% of catalyst. However, since the use of 10 mol% catalyst furnished the
β-acetamidocarbonyl compounds in good yields, all the reactions were conducted with this
catalyst ratio (based on benzaldehyde). No product was formed in the absence of acetonitrile
and of acetyl chloride.
A variety of electron-donating and electron-withdrawing substituted aromatic alde-
hydes underwent the reaction smoothly giving the desired products in good yields (Table
1). Aromatic aldehydes bearing a nitro substituent required longer reaction times (Entries
12–16). In order to confirm product formation, the crystal structure of the product in Entry 14
was obtained. CCDC-874016 contains the supplementary crystallographic data. Reactions
carried out with benzonitirile instead of acetonitrile proceed to furnish β-benzamidoketones
in good yields. The likely mechanistic pathway is proposed for this reaction (Scheme 2).
Scheme 2
Probable mechanism of alum catalyzed reaction for the preparations of β-acetamidocarbonyl
compounds.

496
Hussain and Molla
Table 1
KAl(SO4)2·12H2O-catalyzed Condensations
Time Yield
Entry Aldehyde
01
Ketone
Products
(h)
(%)
mp (◦C)
8
88
100
(102–10426)
02
03
8
91
83
150
(153–15426)
10
110
(113–11525)
04
05
06
07
08
10
10
10
10
10
81
84
78
83
96
170
(172–17327)
105
(110–11126)
170
(172–17427)
120
(120–12228)
145
(146–14826)
(Continued on next page)

Synthesis of β-Acetamido- and β-Benzamidocarbonyl Compounds
497
Table 1
KAl(SO4)2·12H2O-catalyzed Condensations
(Continued)
Time Yield
Entry Aldehyde
09
Ketone
Products
(h)
(%)
mp (◦C)
11
91
180
(180–18226)
10
11
10
11
97
90
144
(148–15026)
170 (see
Table 2)
12
13
12
13
88
82
150
(153–15426)
140
(142–14426)
14
15
13
13
86
84
140
(139–14026)
200
(199–20018)
16
17
13
9
85
78
186
(186–18826)
125
(125–12729)
(Continued on next page)

498
Hussain and Molla
Table 1
KAl(SO4)2·12H2O-catalyzed Condensations
(Continued)
Time Yield
(h) (%)
Entry Aldehyde
18
Ketone
Products
mp (◦C)
10
12
15
79
80
77
135 (see
Table 2)
19
20
137–139
(see Table
2)
100–102
(see Table
2)
21
22
23
15
14
14
76
80
108–110
(see Table
2)
21:79a
25:75a
131
(128–13026)
74 130 (13019)
24
25
47:53a
29:71a
14
14
79
76
140
(140–14326)
130
(131–13326)
(Continued on next page)

Synthesis of β-Acetamido- and β-Benzamidocarbonyl Compounds
499
Table 1
KAl(SO4)2·12H2O-catalyzed Condensations
(Continued)
Time Yield
Entry Aldehyde
26
Ketone
Products
(h)
(%)
mp (◦C)
14
75
145 (14619)
28:72a
27
28
10
10
71
74
98
(90–9326)
110
(110–11426)
29
10
76
150
(151–15226)
30
31
3.0
3.5
82
85
198 (20023)
196 (19523)
32
33
3.5
4.0
80
79
185 (see
Table 2)
170 (see
Table 2)
asyn:anti ratio.

500
Hussain and Molla
Table 2
Spectroscopic data of New Compounds (from Table 1)
Combustion Analysis
(Found)
13C-NMR (δ)
(CDCl3+DMSO-
d6)
IR
Cmpda (cm−1
)
1H-NMR (δ) (CDCl3)
C
H
N
11b
3276,
3069,
2945,
1682,
1643,
1541,
7.82 - 7.93 (4H, m), 7.71 (1H,
d, J = 7.8 Hz), 7.42–7.61
(8H, m), 7.26–7.30 (2H,
m), 5.69–5.75 (1H, m),
3.85 (1H, dd, J = 4.8,
17.1 Hz), 3.52 (1H, dd, J =
5.7, 17.1 Hz),
64.72 4.44 3.43
(64.89) (4.50) (3.48)
18b
3298, 7.78 (2H, d, J = 8.4 Hz), 7.58 197.6, 169.5,
57.46 4.82 3.72
158.9, 135.3, (57.30) (5.01) (3.80)
132.6, 132.0,
3007,
1689,
1654,
1585
(2H, d, J = 8.4 Hz), 7.23
(2H, d, J = 8.8 Hz), 6.83
(2H, d, J = 8.4 Hz), 6.47
(1H, d, J = 7.2 Hz),
129.7, 128.8,
127.8, 114.1,
55.3, 49.7,
43.4, 23.5
5.45–5.50 (1H, m), 3.76
(3H, s), 3.72 (1H, dd, J =
5.2, 16.8 Hz), 3.36 (1H, dd,
J = 6.8, 19.2 Hz), 2.01 (3H,
s)
19b
3270, 12.26 (1H, s), 7.80–7.82 (1H, 204.1, 169.5,
68.99 6.11 4.47
3099,
1646,
1525
m), 7.44–7.48 (1H, m),
7.22–7.25 (2H, m),
6.91–6.98 (2H, m),
6.82–6.88 (1H, m), 6.38
(1H, d,
162.5, 159.0, (68.81) (6.20) (4.52)
136.8, 132.4,
130.1, 127.8,
119.4, 119.2,
118.6, 114.1,
J = 7.2 Hz), 5.45 (1H, dd, J
= 6.8, 12.8 Hz), 3.77 (3H,
s), 3.73–3.75 (1H, m),
3.39–3.45 (1H, m), 1.99
(3H, s).
55.2, 49.8,
43.2, 23.4
20c
3256, 9.88 (3H, s), 8.00–8.02 (2H,
197.3, 159.0,
77.19 6.21 3.75
3078,
1689,
1518
m), 7.51–7.87 (3H, m),
7.27–7.47 (5H, m),
6.70–6.79 (4H, m),
136.3, 135.7, (77.20) (6.39) (3.81)
133.5, 131.9,
129.4, 129.0,
5.32–5.88 (2H, m), 3.70
(3H, s), 2.06 (3H, s).
128.9, 128.7
(2C), 128.3,
127.9, 113.8,
57.7, 56.9,
55.2, 22.2.

Synthesis of β-Acetamido- and β-Benzamidocarbonyl Compounds
501
Table 2
Spectroscopic data of New Compounds (from Table 1) (Continued)
Combustion Analysis
(Found)
13C-NMR (δ)
(CDCl3+DMSO-
d6)
IR
Cmpda (cm−1
)
1H-NMR (δ) (CDCl3)
C
H
N
21c
3312, 8.41 (1H, t, J = 8.8 Hz), 8.02 201.7, 168.4,
76.84 6.81 4.98
140.9, 136.2, (76.91) (6.89) (4.92)
133.8, 128.2,
2972,
1688,
1653,
1554
(1H, d, J = 7.6 Hz), 7.78
(1H, d, J = 7.6 Hz),
7.08–7.63 (7H, m),
127.9, 127.8,
5.16–5.27 (1H, m), 4.88
(1H, brs), 4.01–4.10 (1H,
m), 1.94 (3H, s), 1.19 (3H,
d, J = 6.8 Hz).
127.6, 127.3,
54.9, 45.1,
22.4, 15.4
32 c
3356, 11.22 (1H, s), 8.22 (1H, d, J
195.9, 168.6,
61.33 5.49 4.77
2952,
1616,
1491
= 6.4 Hz), 7.18–7.26 (4H,
m), 6.31 (1H, d, J =
7.6 Hz), 2.52 (2H, m), 2.31
(2H, m), 2.07 (3H, s), 1.91
(2H, m).
141.1, 128.5, (61.26) (5.68) (4.82)
127.5, 115.5,
45.8, 36.4,
30.7, 26.3, 20.2
33 c
3356, 11.21 (1H, s), 8.15 (1H, d, J
195.7, 169.3,
66.42 6.62 4.84
2954,
1617,
1512
= 6.0 Hz), 7.25 (2H, d, J =
7.6 Hz), 6.78 (2H, d, J =
7.2 Hz), 6.31 (1H, d, J =
7.6 Hz), 2.56 (2H, m), 2.32
(2H, m), 2.05 (3H, s), 1.92
(2H, m).
157.8, 134.4, (66.44) (6.75) (4.91)
126.8, 112.6,
55.6, 45.7,
37.1, 29.6,
22.9, 20.2
aRefers to entry number of Table 1. bLight yellow solid. cWhite solid.
To extend the scope of the condensation, a variety of aromatic aldehydes (Entries
22–26) were treated with methyl acetoacetate and acetyl chloride in the presence of 10 mol%
of catalyst at room temperature and the corresponding β-acetamidoketo esters were ob-
tained in good yields and moderate-to-good diastereoselectivities. The reaction with (ortho,
meta, para) NO2-substituted aldehydes with methyl acetoacetates gave only Knoevenagel
condensation products instead of the expected product (Entries 27–29). Treatment of aro-
matic aldehydes (Entries 30–33) with cyclic 1,3-diketones under the same conditions
proceeded quite rapidly to give the products in good yields whereas the reactions with
aliphatic non-cyclic ketones did not work.
In conclusion, we have developed a simple, efficient and ‘greener’ protocol for the
preparation of β-acetamido- and β-benzamidocarbonyl compounds using alum as rela-
tively non-toxic and inexpensive catalyst. The salient features of this protocol include

502
Hussain and Molla
operational simplicity, high yields of the products, avoidance of column chromatography,
ready availability, relatively low toxicity, and moisture compatibility of the catalyst.
Experimental Section
All reagents were purchased either from Sigma or Merck. Solvents were dried and purified
using standard techniques. Melting points were determined on a SRS-EZ-Melt melting point
apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a Shimadzu IR
1
Afinity I. H NMR spectra and 13C NMR spectra were obtained on a Bruker 300 MHz,
500 MHz and Jeol 400 MHz spectrometer in CDCl3 or DMSO-d6 using TMS as an
internal reference and chemicals shifts are in δ (ppm). GC-MS data were determined in
Thermo Scientific ITQ 1100 spectrometer. The crystal structure data were acquired using
Bruker SMART APEX-II CCD difractometer. CCDC-874016 contains the supplementary
crystallographic data for this paper. The data can be extracted free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
General Procedure for the Preparation of β-Acetamido- and β-Benzamidoketones
or β-Keto Esters
To a stirred solution of aldehyde (2 mmol, 0.212 g) and acetophenone (2 mmol, 0.24 g) or
methyl acetoacetate (2 mmol, 0.232 g) in acetonitrile (3 ml) [or benzonitrile (3 ml)] were
added acetyl chloride (3 mmol, 0.236 g) and KAl(SO4)2·12H2O (0.2 mmol, 0.094 g) at room
temperature for the time noted in the Table 1. After completion of the reaction (monitored
by TLC using silica and ethyl acetate-hexane as solvent), crushed ice was added to the
reaction mixture which was stirred thoroughly. The solids formed were collected and dried
to give the corresponding products which were recrystallized from ethyl acetate-hexane
and fully characterized by recording IR, NMR and other analysis.
Acknowledgments
A. Molla is thankful to IIT Patna for a research fellowship and the authors are thankful to
IIT Guwahati for providing single crystal XRD facility and SAIF (CDRI Lucknow, Panjab
University, Chandigrah and IIT Chennai) for NMR facility.
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