An efficient, one-pot, multicomponent synthesis of β-acetamido carbonyl compounds using cyanuric chloride in an aqueous medium

Article abstract of DOI:10.1055/S-0029-1218584

A one-pot, three-component reaction between an aromatic aldehyde, an enolizable ketone or a β-keto ester, and a nitrile in the presence of acetyl chloride is accomplished efficiently using cyanuric chloride in an aqueous medium to give the corresponding β

Full text of DOI:10.1055/S-0029-1218584

PAPER
803
An Efficient, One-Pot, Multicomponent Synthesis of b-Acetamido Carbonyl
Compounds Using Cyanuric Chloride in an Aqueous Medium1
Multicomponent
i
Synthe
s
sis of
b
-A
w
cetamido Carbony
a
l
C
ompoun
nds ath Das,* Malampati Srilatha, Boyapati Veeranjaneyulu, Bethapudi Rama Rao
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received 19 October 2009; revised 28 October 2009
tron-withdrawing groups, however, those with electron-
Abstract: A one-pot, three-component reaction between an aro-
matic aldehyde, an enolizable ketone or a b-keto ester, and a nitrile
in the presence of acetyl chloride is accomplished efficiently using
cyanuric chloride in an aqueous medium to give the corresponding
b-acetamido ketone or ester in high yield.
withdrawing groups gave the products in somewhat lower
yields. The acid-sensitive aldehyde cinnamaldehyde af-
forded the desired product in high yield (entry 10,
Table 1). The present conversion was found to be general
for aromatic ketones, 1,3-diketones and b-keto esters.
Several acetophenone derivatives possessing either elec-
tron-donating or electron-withdrawing groups, and pro-
piophenone were utilized to prepare the corresponding b-
acetamido carbonyl compounds. With propiophenone and
b-keto esters the products were formed with high diaste-
reoselectivity, the anti isomer being the major product. In
1H NMR spectra of similar products, the coupling con-
stant between H-2 and H-3 for an anti isomer is generally
6–8 Hz while that for a syn isomer is typically 3–5 Hz.5a
Thus the anti/syn isomeric ratio of the products could be
Key words: b-acetamido ketone, multicomponent reaction, cyanu-
ric chloride, aqueous medium
Organic reactions that occur in water as the solvent are of
significant importance due to their economic and environ-
mental benefits. We have reported several synthetic meth-
ods that take place in an aqueous medium.2 In
continuation of this work, we have developed an efficient
synthesis of b-acetamido carbonyl compounds in an aque-
ous system using cyanuric chloride [2,4,6-trichloro-1,3,5-
triazine (TCT)]. b-Acetamido carbonyl compounds con-
tain a multifunctional skeleton which is present in various
pharmacologically useful compounds.3 They can be con-
verted into b-amino alcohols which are the structural units
of many natural nucleoside antibiotics.4 The multicompo-
nent synthesis of b-acetamido ketones, catalyzed by co-
balt(II) chloride or Montmorillonite K10 clay, was
reported by Iqbal et al.5 Subsequently, these compounds
were prepared using Lewis acid catalysts.6 We found that
the three-component reaction of an aromatic aldehyde 1,
an enolizable ketone or a b-keto ester 2, and a nitrile 3, in
the presence of acetyl chloride and cyanuric chloride un-
der aqueous conditions, occurred conveniently at room
temperature to give the corresponding b-acetamido carbo-
nyl compound 4 (Scheme 1).
1
determined from the H NMR spectra of the crude prod-
ucts, although in some cases the diastereoisomers were
separated. b-Acetamido carbonyl compounds were pre-
pared using both acetonitrile and benzonitrile. The reac-
tion times were 45 minutes to 2 hours when using
acetonitrile and 10–12 hours with benzonitrile. Several
functional groups including halide, ether, nitro and alkene
remained intact during the reaction. The products were
characterized from their spectroscopic and elemental
analysis data.
Cyanuric chloride is an inexpensive and safe reagent. It
reacts with water to release hydrochloric acid which cata-
lyzes the reaction to furnish the b-acetamido carbonyl
compounds 4 (Scheme 2).5,7
A series of b-acetamido carbonyl compounds was pre-
pared in high yields following this method (Table 1). The
aldehyde substrates contained electron-donating or elec-
Cl
OH
N
N
N
N
+
H2O
+
HCl
Cl
N
Cl
HO
N
OH
TCT
O
R3
MeCOCl
TCT
R3
NH
O
+
O
O
O
OCOMe
Cl
+OCOMe
R1
H
N
O
R3CN
MeCOCl
H+
+
+
R1
H
R2
R1
R2
H2O
r.t.
0.75–12 h
R1
H
R1
R1
O
X
:NCR3
X
1
2
3
4
77–92%
R3
O
O
O
Scheme 1 The multicomponent synthesis of b-acetamido carbonyl
O
R3
O
R3CONH
R1
compounds
O
N
N
O
H2O
H+
R2
H+
+
R1
R1
R2
R2
SYNTHESIS 2010, No. 5, pp 0803–0806
x
x
.
x
x
.2
0
1
0
Advanced online publication: 07.12.2009
DOI: 10.1055/s-0029-1218584; Art ID: Z22209SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 The mechanism for the formation of b-acetamido carbo-
nyl compounds 4

804
B. Das et al.
PAPER
Infrared spectra were obtained using a Perkin Elmer RX1 FT-IR
spectrophotometer. 1H and 13C NMR spectra were recorded at 200
MHz and 50 MHz, respectively, using a Varian Gemini 200 MHz
spectrometer and CDCl3 as the solvent. Mass spectra (ESI-MS)
were obtained using an LC-MSD Trap SL spectrometer. Elemental
analyses were obtained using an Elementar Vario EL instrument.
Column chromatography was performed over silica gel (BDH 100–
200 mesh) and TLC was carried out using silica gel GF254 (Merck)
plates. Characterization data is provided for novel compounds.
Cyanuric chloride is easy to handle and is safe compared
to concentrated hydrochloric acid. The cyanuric acid by-
product formed during the reaction was removed by aque-
ous extraction.7Several of the Lewis acids previously em-
ployed for this conversion are costly, not readily
available, deactivated by water or require the use of harm-
ful organic solvents.
In conclusion, we have developed an efficient, one-pot,
multicomponent synthesis of b-acetamido carbonyl com-
pounds using cyanuric chloride in an aqueous medium.
The mild aqueous reaction conditions, high yields of
products, impressive diastereoselectivity, operational
simplicity and application of a cost-effective reagent (to
generate the catalyst) are notable advantages of the
present method.
b-Acetamido Carbonyl Compounds; General Procedure
To a soln of aldehyde (1.0 mmol), ketone or b-keto ester (1.0 mmol)
and AcCl (2.0 mmol) in MeCN–H2O or PhCN–H2O (2:1, 5 mL)
was added TCT (20 mol%). The mixture was stirred at r.t. and the
reaction progress was monitored by TLC. After completion,
EtOAc–H2O (1:1, 10 mL) was added. The organic layer was sepa-
rated and the aq portion was extracted with EtOAc (3 × 5 mL). The
combined organic layer was washed with H2O (3 × 5 mL), dried
over anhyd Na2SO4 and then concentrated. The residue was subject-
Table 1 Synthesis of b-Acetamido Carbonyl Compounds Using Cyanuric Chloride in an Aqueous Medium
Entry
1
R1
R2
R3
X
Time (h)
Yield (%)a
87
Product (syn/anti)b
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
1.5
1.5
2
4a
2
Ph
4-ClC6H4
H
84
4b
3
Ph
4-O2NC6H4
H
77
4c
4
4-MeC6H4
3,4,5-(MeO)3C6H2
4-ClC6H4
3-Cl-4-FC6H3
3-Cl-4-FC6H3
4-O2NC6H4
cinnamyl
Ph
H
1
90
4d
5
Ph
H
0.75
1.5
2
92
4e
6
Ph
H
85
4f
7
Ph
H
82
4g
8
4-ClC6H4
Ph
H
2
80
4h
9
H
2
79
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-ClC6H4
Ph
H
1
89
4j
2-naphthyl
4-MeOC6H4
4-ClC6H4
2-naphthyl
4-HOC6H4
4-O2NC6H4
2-naphthyl
3,4,5-(MeO)3C6H2
4-O2NC6H4
3-O2NC6H4
Ph
H
1.25
1
89
4k
Ph
Me
90
4l (10:90)
4m (14:86)
4n (15:85)
4o
Ph
Me
1.5
1.5
1.5
1
87
Ph
Me
90
Me
Me
Me
Me
Me
Me
Ph
COMe
COMe
COMe
COOEt
COOEt
COOEt
H
88
89
4p
1
92
4q
1
91
4r (8:92)
4s (16:84)
4t (18:82)
4u
2
87
2
89
12
10
10
12
77
4-MeC6H4
3,4-(MeO)2C6H3
4-ClC6H4
Ph
Ph
H
80
4v
Ph
Ph
H
82
4w
Ph
Ph
H
79
4x
a Yield of isolated product after column chromatography.
b The syn/anti ratio was determined from the 1H NMR spectrum of the crude product.
Synthesis 2010, No. 5, 803–806 © Thieme Stuttgart · New York

PAPER
Multicomponent Synthesis of b-Acetamido Carbonyl Compounds
805
ed to column chromatography (silica gel, hexane–EtOAc) to afford
the pure b-acetamido carbonyl compound.
N-[1-(2-Naphthyl)-3-oxo-3-phenylpropyl]acetamide (4k)
IR (KBr): 3274, 1681, 1640, 1548, 1373, 1299 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.32 (1 H, br d, J = 8.0 Hz), 7.98–
7.35 (12 H, m), 5.60 (1 H, m), 3.66 (1 H, dd, J = 12.0, 4.0 Hz), 3.40
(1 H, dd, J = 12.0, 2.0 Hz), 1.86 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 198.6, 169.8, 139.2, 137.0, 133.6,
133.1, 132.5, 128.6, 128.4, 128.0, 127.8, 127.5, 126.1, 125.6, 125.3,
124.9, 50.0, 43.3, 23.4.
N-[3-Oxo-3-phenyl-1-(3,4,5-trimethoxyphenyl)propyl]acet-
amide (4e)
IR (KBr): 3277, 1687, 1646, 1558, 1246 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.89 (2 H, d, J = 8.0 Hz), 7.53 (1
H, t, J = 8.0 Hz), 7.41 (2 H, t, J = 8.0 Hz), 6.70 (1 H, d, J = 8.0 Hz),
6.50 (2 H, s), 5.39 (1 H, m), 3.80 (6 H, s), 3.75 (3 H, s), 3.69 (1 H,
dd, J = 12.0, 2.0 Hz), 3.31 (1 H, dd, J = 12.0, 4.0 Hz), 2.01 (3 H, s).
ESI-MS: m/z = 318 [M + H]+.
13C NMR (50 MHz, CDCl3): d = 197.2, 169.0, 153.2, 150.0, 138.5,
137.2, 136.8, 134.6, 128.1, 127.8, 103.8, 60.0, 55.3, 49.5, 44.9,
22.6.
Anal. Calcd for C21H19NO2: C, 79.50; H, 5.99; N, 4.42. Found: C,
79.41; H, 5.96; N, 4.36.
N-[2-Methyl-1-(2-naphthyl)-3-oxo-3-phenylpropyl]acetamide
(anti-4n)
ESI-MS: m/z = 358 [M + H]+.
Anal. Calcd for C20H23NO5: C, 67.23; H, 6.44; N, 3.92. Found: C,
67.12; H, 6.41; N, 3.84.
IR (KBr): 3418, 1651, 1025 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.24 (1 H, d, J = 8.0 Hz), 8.01 (2
H, d, J = 8.0 Hz), 7.80–7.74 (5 H, br s), 7.60–7.39 (5 H, m), 5.81 (1
H, t, J = 8.0 Hz), 4.06 (1 H, m), 1.66 (3 H, s), 0.88 (3 H, d, J = 7.0
Hz).
13C NMR (50 MHz, CDCl3): d = 202.2, 168.1, 138.6, 135.4, 131.5,
131.0, 128.2, 127.5, 127.2, 125.8, 125.4, 125.1, 54.9, 44.8, 21.4,
15.1.
N-[1-(3-Chloro-4-fluorophenyl)-3-oxo-3-phenylpropyl]acet-
amide (4g)
IR (KBr): 3285, 1688, 1648, 1548, 1499, 1253 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.88 (2 H, d, J = 8.0 Hz), 7.57 (1
H, t, J = 8.0 Hz), 7.42 (2 H, t, J = 8.0 Hz), 7.34 (1 H, br d, J = 8.0
Hz), 7.19 (1 H, m), 7.02 (1 H, t, J = 8.0 Hz), 6.82 (1 H, d, J = 8.0
Hz), 5.45 (1 H, m), 3.80 (1 H, dd, J = 12.0, 2.0 Hz), 3.38 (1 H, dd,
J = 12.0, 4.0 Hz), 2.02 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 199.1, 169.9, 159.5, 155.1, 139.6,
136.2, 134.8, 129.8, 129.0, 126.2, 117.1 (d, J = 10.0 Hz), 49.6,
44.3, 24.0.
ESI-MS: m/z = 332 [M + H]+.
Anal. Calcd for C22H21NO2: C, 79.76; H, 6.34; N, 4.23. Found: C,
79.82; H, 6.30; N, 4.17.
N-[2-Methyl-1-(2-naphthyl)-3-oxo-3-phenylpropyl]acetamide
(syn-4n)
ESI-MS: m/z = 320 [M + H]+.
IR (KBr): 3418, 1650, 1025 cm–1.
Anal. Calcd for C17H15ClFNO2: C, 63.85; H, 4.70; N, 4.38. Found:
C, 63.77; H, 4.67; N, 4.35.
1H NMR (200 MHz, CDCl3): d = 7.91 (2 H, d, J = 8.0 Hz), 7.75–
7.70 (4 H, m), 7.51 (1 H, t, J = 8.0 Hz), 7.46–7.38 (5 H, m), 6.19 (1
H, d, J = 6.0 Hz), 5.53 (1 H, dd, J = 6.0, 4.0 Hz), 4.12 (1 H, m), 1.95
(3 H, s), 1.19 (3 H, d, J = 7.0 Hz).
13C NMR (50 MHz, CDCl3): d = 201.8, 168.7, 149.9, 139.3, 133.2,
132.5, 128.8, 127.8, 127.6, 127.4, 126.1, 125.7, 125.4, 54.3, 45.0,
22.5, 14.5.
N-[1-(3-Chloro-4-fluorophenyl)-3-(4-chlorophenyl)-3-oxopro-
pyl]acetamide (4h)
IR (KBr): 3278, 1688, 1647, 1550, 1498, 1237 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.20 (1 H, m), 7.93 (2 H, d, J = 8.0
Hz), 7.50–7.41 (3 H, m), 7.30 (1 H, m), 7.11 (1 H, m), 5.39 (1 H,
m), 3.56 (1 H, dd, J = 12.0, 4.0 Hz), 3.29 (1 H, dd, J = 12.0, 2.0
Hz), 1.85 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 196.2, 168.8, 158.3, 154.9, 140.2,
138.6, 135.0, 130.0, 128.7, 127.5, 119.1 (d, J = 10.0 Hz), 117.4 (d,
J = 10.0 Hz), 48.0, 44.8, 22.6.
ESI-MS: m/z = 332 [M + H]+.
Anal. Calcd for C22H21NO2: C, 79.76; H, 6.34; N, 4.23. Found: C,
79.65; H, 6.28; N, 4.16.
N-[2-Acetyl-1-(2-naphthyl)-3-oxobutyl]acetamide (4q)
IR (KBr): 3286, 1722, 1646, 1544, 1366 cm–1.
ESI-MS: m/z = 354 (35Cl/35Cl [M + H]+), 356 (35Cl/37Cl [M + H]+),
1H NMR (200 MHz, CDCl3): d = 8.17 (1 H, d, J = 8.0 Hz), 7.86–
7.64 (4 H, m), 7.58 (1 H, d, J = 8.0 Hz), 7.48–7.41 (2 H, m), 5.82 (1
H, t, J = 8.0 Hz), 4.48 (1 H, d, J = 8.0 Hz), 2.22 (3 H, s), 1.98 (3 H,
s), 1.86 (3 H, s).
358 (37Cl/37Cl [M + H]+).
Anal. Calcd for C17H14Cl2FNO2: C, 57.63; H, 3.96; N, 3.96. Found:
C, 57.55; H, 3.94; N, 3.92.
13C NMR (50 MHz, CDCl3): d = 201.3, 200.9, 169.0, 137.4, 133.4,
132.8, 129.2, 129.0, 127.9, 126.0, 125.4, 125.2, 125.0, 72.1, 51.5,
30.2, 29.5, 22.0.
N-{(2E)-1-[2-(4-Chlorophenyl)-2-oxoethyl]-3-phenylprop-2-en-
1-yl}acetamide (4j)
IR (KBr): 3284, 1684, 1643, 1367, 1295 cm–1.
ESI-MS: m/z = 298 [M + H]+.
1H NMR (200 MHz, CDCl3): d = 7.91 (2 H, d, J = 8.0 Hz), 7.45 (2
H, d, J = 8.0 Hz), 7.32–7.12 (5 H, m), 6.55 (1 H, d, J = 14.0 Hz),
6.48 (1 H, d, J = 8.0 Hz), 6.31 (1 H, dd, J = 12.0, 7.0 Hz), 5.02 (1
H, m), 3.51 (1 H, dd, J = 12.0, 2.0 Hz), 3.29 (1 H, dd, J = 12.0, 4.0
Hz), 2.03 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 198.2, 169.8, 140.1, 137.4, 135.5,
132.4, 129.9, 129.5, 129.2, 129.0, 128.6, 128.1, 127.3, 48.0, 42.5,
22.8.
Anal. Calcd for C18H19NO3: C, 72.73; H, 6.40; N, 4.71. Found: C,
72.58; H, 6.38; N, 4.66.
Ethyl 2-[(Acetylamino)(3,4,5-trimethoxyphenyl)methyl]-
3-oxobutanoate (anti-4r)
IR (KBr): 3296, 1719, 1651, 1593, 1463 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.20 (1 H, d, J = 8.0 Hz), 6.62 (2
H, s), 5.57 (1 H, t, J = 8.0 Hz), 4.00 (2 H, q, J = 7.0 Hz), 3.95 (1 H,
d, J = 8.0 Hz), 3.84 (6 H, s), 3.70 (3 H, s), 2.26 (3 H, s), 1.82 (3 H,
s), 1.20 (3 H, t, J = 7.0 Hz).
ESI-MS: m/z = 328 (35Cl [M + H]+), 330 (37Cl [M + H]+).
Anal. Calcd for C19H18ClNO2: C, 69.62; H, 5.50; N, 4.28. Found: C,
69.55; H, 5.48; N, 4.26.
Synthesis 2010, No. 5, 803–806 © Thieme Stuttgart · New York

806
B. Das et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 200.4, 169.2, 165.8, 157.2, 150.0,
135.0, 104.9, 65.3, 60.1, 55.2, 52.4, 27.0, 22.2, 12.5.
References
(1) Part 198 in the series ‘Studies on novel synthetic
methodologies’.
ESI-MS: m/z = 368 [M + H]+.
(2) (a) Das, B.; Banerji, J.; Mahender, G.; Majhi, A. Org. Lett.
2004, 6, 3349. (b) Das, B.; Holla, H.; Venkateswarlu, K.;
Majhi, A. Tetrahedron Lett. 2005, 46, 8895. (c) Das, B.;
Venkateswarlu, K.; Krishnaiah, M. Helv. Chim. Acta. 2007,
90, 149. (d) Das, B.; Satyalakshmi, G.; Suneel, K.
Tetrahedron Lett. 2009, 50, 2770.
Anal. Calcd for C18H25NO7: C, 58.86; H, 6.81; N, 3.82. Found: C,
58.72; H, 6.77; N, 3.74.
N-[1-(3,4-Dimethoxyphenyl)-3-oxo-3-phenylpropyl]benzamide
(4w)
IR (KBr): 3348, 1681, 1640, 1497, 1221 cm–1.
(3) (a) Casimir, J. R.; Turetta, C.; Ettouati, L.; Paris, J.
Tetrahedron Lett. 1995, 36, 4797. (b) Godfrey, A. G.;
Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.;
Mitchell, D. J. Org. Chem. 2003, 68, 2623.
(4) Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44, 1709.
(5) (a) Rao, I. N.; Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J. Org.
Chem. 2003, 68, 4079. (b) Bahulayan, D.; Das, S. K.; Iqbal,
J. J. Org. Chem. 2003, 68, 5735.
(6) (a) Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K.
Tetrahedron Lett. 2005, 46, 2137. (b) Ghosh, R.; Maiti, S.;
Chakraborty, A. Synlett 2005, 115. (c) Khan, A. T.;
Choudhary, L. A.; Parvin, T.; Ali, M. A. Tetrahedron Lett.
2006, 47, 8137. (d) Salama, T. A.; Elmorsy, S. S.; Khalil,
A.-G. M.; Ismail, M. A. Tetrahedron Lett. 2007, 48, 6199.
(7) Bigdeli, M. A.; Mahdavinia, G. H.; Jafari, S.; Hazarkhani, H.
Catal. Commun. 2007, 8, 2229.
1H NMR (200 MHz, CDCl3): d = 7.92 (2 H, d, J = 8.0 Hz), 7.81 (2
H, d, J = 8.0 Hz), 7.71 (1 H, d, J = 8.0 Hz), 7.56–7.40 (6 H, m), 6.85
(1 H, d, J = 2.0 Hz), 6.78 (1 H, d, J = 8.0 Hz), 6.67 (1 H, dd,
J = 8.0, 2.0 Hz), 5.83 (1 H, m), 3.90 (3 H, s), 3.71 (3 H, s), 3.67 (1
H, dd, J = 12.0, 2.0 Hz), 3.45 (1 H, dd, J = 12.0, 4.0 Hz).
13C NMR (50 MHz, CDCl3): d = 199.3, 167.4, 153.8, 150.6, 137.0,
134.9, 133.7, 131.4, 129.9, 129.0, 128.7, 127.2, 115.0, 113.1, 111.8,
55.6, 55.4, 46.1, 42.5.
ESI-MS: m/z = 390 [M + H]+.
Anal. Calcd for C24H23NO4: C, 74.04; H, 5.91; N, 3.60. Found: C,
73.92; H, 5.86; N, 3.56.
Acknowledgment
The authors thank CSIR and UGC, New Delhi for financial assis-
tance.
Synthesis 2010, No. 5, 803–806 © Thieme Stuttgart · New York