Iodine as an efficient catalyst for one-pot multicomponent synthesis of β-acetamido ketones

Article abstract of DOI:10.1055/s-2006-944208

Iodine efficiently catalyzes the three-component coupling of aromatic aldehydes, enolizable ketones or keto esters, and acetonitrile in the presence of acetyl chloride to afford β-acetamido ketones in good yields at room temperature. Georg Thieme Verlag S

Full text of DOI:10.1055/s-2006-944208

1756
LETTER
Iodine as an Efficient Catalyst for One-Pot Multicomponent Synthesis of
b-Acetamido Ketones1
O
ne-Pot Multico
i
ponen
s
t
Synthes
w
is of
b
-Acetamido
a
K
etones nath Das,* K. Ravinder Reddy, R. Ramu, P. Thirupathi, B. Ravikanth
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 10 February 2006
synthesis of b-acetamido ketones. Different aromatic
Abstract: Iodine efficiently catalyzes the three-component cou-
pling of aromatic aldehydes, enolizable ketones or keto esters, and
acetonitrile in the presence of acetyl chloride to afford b-acetamido
ketones in good yields at room temperature.
aldehydes and acetophenones have been utilized for the
preparation of these compounds (Table 1). The conver-
sion was complete at room temperature within 4–6 hours
and the products were obtained in good yields.7 Both
aromatic aldehydes containing electron-donating as well
as electron-withdrawing groups underwent the conversion
smoothly. When propiophenones (instead of aceto-
phenones) were used in the reaction both anti and syn
products were formed (Table 1, entries k–n). The anti
isomers were the major products formed and diastereo-
Key words: b-acetamido ketone, iodine, multicomponent reaction
b-Acetamido ketones are important intermediates in vari-
ous organic syntheses due to their multifunctional nature,
and their skeletons are present in different medicinally
important compounds.2 They can easily be converted into
amino alcohols that are utilized for the synthesis of
several antibiotics.3 The multicomponent synthesis of
b-amido ketones, in the presence of a Lewis acid such as
CoCl24a–c and Montmorillonite K10 clay, was reported by
Iqbal et al.4d However, the CoCl2-catalyzed reaction re-
quired a longer reaction time (5 days) at room temperature
while the K10 clay catalyzed reaction required a higher
reaction temperature (70 °C).
1
selectivity was high (as evidenced from the H NMR
spectra).7 b-Acetamido ketones were also prepared from
b-keto esters by the reaction of aromatic aldehydes, aceto-
nitrile, and acetyl chloride in the presence of iodine
(Table 1, entries o–w). Aromatic aldehydes having both
electron-donating and electron-withdrawing groups were
applied. In this case also anti and syn products were
formed. The structures of the products were determined
from their spectral (1H NMR and MS) data.7 When the
conversion was carried out with keto esters (instead of
ketones) a nitrogen atmosphere was required7 to avoid the
formation of a,b-unsaturated carbonyl compounds
(Knoevenagel reaction products), which decreases the
yields of the desired b-acetamido ketones.
In recent years, iodine has emerged as an effective catalyst
for various organic transformations.5 In continuation of
our work5d,5e on the application of this catalyst for the de-
velopment of useful synthetic methodologies we have ob-
served that this is a very suitable catalyst for the one-pot
coupling of aldehydes, enolizable ketones or ketoesters,
and acetonitrile in the presence of acetyl chloride to form
b-acetamido ketones at room temperature (Scheme 1).
A plausible mechanism for the reaction is given below
(Scheme 2). The reaction did not afford the desired prod-
ucts in the absence of iodine even after eight hours at room
temperature; the presence of acetyl chloride was also vi-
tal. The acetyl group of the products was derived from
MeCN. This has been proven by carrying out the reaction
with PhCN instead of MeCN which yielded the expected
the product (Table 1, entry x).
R2
O
MeCN
O
R1
AcCl
R
+
R1
R
H
I2,r.t.
4–6 h
R2
HNAc
O
1
2
75–89%
3
In conclusion, iodine has been employed here as an appro-
priate catalyst for the one-pot multicomponent synthesis
of b-acetamido ketones on the basis of its (a) high effi-
ciency, (b) easy availability, (c) low cost, (d) operational
simplicity, and (e) action under mild reaction conditions.
The products were formed in good yields with short
reaction times. Thus, the present method offers a practical
approach for the synthesis of b-acetamido ketones.
Scheme 1
Multicomponent reactions have gained much importance
in synthetic organic chemistry as they afford the target
products in a single operation without isolating the inter-
mediates.6 Thus, the reaction time is reduced and both
energy and raw materials are saved. The present three-
component coupling reaction catalyzed by molecular
iodine is a very simple and convenient method for the
Acknowledgment
The authors thank UGC and CSIR, New Delhi for financial assi-
stance.
SYNLETT 2006, No. 11, pp 1756–1758
Advanced online publication: 04.07.2006
1
2
.0
7
.2
0
0
6
DOI: 10.1055/s-2006-944208; Art ID: D04206ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Multicomponent Synthesis of b-Acetamido Ketones
1757
Table 1 Iodine-Catalyzed Formation of b-Acetamido Ketones
Entry
b-Acetamido ketone 3
Time (h)
Yield (%)a
anti/synb
R2
R3
R1
R4
HNAc
O
a
b
c
d
e
f
R1 = R2 = R3 = R4 = H
4.5
5.0
4.5
4.0
4.5
4.5
5.5
4.0
5.5
5.0
85
83
85
85
80
80
75
85
80
75
–
–
–
–
–
–
–
–
–
–
R1 = OMe, R2 = R3 = R4 = H
R1 = Cl, R2 = R3 = R4 = H
R1 = NO2, R2 = R3 = R4 = H
R1 = R2 = R4 = H, R3 = Cl
R1 = R2 = R4 = H, R3 = NO2
R1 = Me, R2 = R3 = R4 = H
R2 = NO2, R1 = R3 = R4 = H
R1 = R2 = R3 = H, R4 = Br
g
h
i
j
R1 = OMe, R2 = R3 = H, R4 = NO2
R
HNAc
O
k
l
R = OMe
R = Me
R = Cl
5.5
5.0
5.0
5.0
85
80
85
85
72:28
97:3c
90:10
96:4
m
n
R = NO2
R2
R1
COOR
R3
HNAc
O
o
p
q
r
R1 = R2 = H, R3 = R = Me
5.5
5.0
6.0
5.5
5.0
5.5
4.5
6.0
6.0
6.0
80
89
80
80
75
85
84
80
80
76
52:48
55:45
74:26
62:38
50:50
65:35c
64:36
80:20
91:9c
–
R1 = NO2, R2 = H, R3 = R = Me
R1 = H, R2 = NO2, R3 = R = Me
R1 = H, R2 = Cl, R3 = R = Me
R1 = R2 = H, R3 = Me, R = Et
R1 = Cl, R2 = H, R3 = Me, R = Et
R1 = NO2, R2 = H, R3 = Me, R = Et
R1 = NO2, R2 = H, R3 = Ph, R = Et
R1 = Cl, R2 = H, R3 = Ph, R = Et
s
t
u
v
w
x
O2N
PhCONH
O
a Isolated yield of the mixture of diastereomers.
b Ratio obtained from the 1H NMR spectrum of the crude reaction mixture.
c The major anti product was obtained in pure form by crystallization from EtOAc–hexane.
Synlett 2006, No. 11, 1756–1758 © Thieme Stuttgart · New York

1758
B. Das et al.
LETTER
CH3
+
O
R
H
+
N
O
R
H
Cl
CH3
R
H
O
CH3COCl
I2
O
..
R
O
CH3
OCOCH3
..
NCCH3
CH3
O
CH3
O
CH3
O
O
HN
O
O
N
O
CH3
H3C
R1
N
O
CH3
R1
R
R1
R
+
R
Scheme 2
monitored by TLC. When the reaction was complete the
mixture was treated with a solution of aq Na2S2O3 and
extracted with EtOAc (3 × 10 mL). The extract was
concentrated and the residue was purified over silica gel to
obtain b-acetamido ketones.
References and Notes
(1) Part 85 in the series,‘Studies on Novel Synthetic
Methodologies’. IICT Communication No. 03336.
(2) (a) Casimir, J. R.; Turetta, C.; Ettouati, L.; Paris, J.
Tetrahedron Lett. 1995, 36, 4747. (b) Godfrey, A. G.;
Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.;
Mitchell, D. J. Org. Chem. 2003, 68, 2623.
When the reaction was carried out with ketoesters (instead of
ketones) a nitrogen atmosphere was required.
Compound 3d: 1H NMR (CDCl3, 200 MHz): d = 8.21 (d, 2
H, J = 8.9 Hz), 7.88 (d, 2 H, J = 8.9 Hz), 7.63–7.42 (m, 5 H),
7.02 (d, 1 H, J = 8.1 Hz), 5.62 (m, 1 H), 3.82 (dd, 1 H,
J = 17.0, 4.4 Hz), 3.46 (dd, 1 H, J = 17.0, 5.2 Hz), 2.06 (s, 3
H). FABMS: m/z = 313 [M + H]+.
(3) Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44, 1709.
(4) (a) Bhatia, B.; Reddy, M. M.; Iqbal, J. J. Chem. Soc., Chem.
Commun. 1994, 713. (b) Mukhopadhyay, M.; Bhatia, B.;
Iqbal, J. Tetrahedron Lett. 1997, 38, 1083. (c) Rao, I. N.;
Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003,
68, 4079. (d) Bahulayan, D.; Das, S. K.; Iqbal, J. J. Org.
Chem. 2003, 68, 5735.
(5) (a) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org.
Chem. 2001, 66, 7527. (b) Ramalinga, K.; Vijayalakshmi,
P.; Kaimal, T. N. B. Tetrahedron Lett. 2002, 43, 879.
(c) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Prasad, A.
R. Tetrahedron Lett. 2002, 43, 9703. (d) Das, B.; Banerrjee,
J.; Ramu, R.; Ravindranath, N.; Ramesh, C. Tetrahedron
Lett. 2003, 44, 5465. (e) Srinivas, K. V. N. S.; Das, B.
Synthesis 2004, 2091.
(6) (a) Eilbracht, P.; Schimdt, A. Chem. Rev. 1999, 99, 3329.
(b) Montgomery, J. Acc. Chem. Res. 2000, 33, 467.
(c) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168.
(7) General Procedure: To a mixture of an aldehyde (1 mmol),
enolizable ketone (1 mmol), and AcCl (1 mmol) in MeCN
(or PhCN) (5 mL) molecular iodine (10 mol%) was added.
The mixture was stirred at r.t. and the reaction was
Compound 3l: 1H NMR (CDCl3, 200 MHz): d = 7.82, (d, 3
H, J = 8.0 Hz), 7.45 (m, 1 H), 7.40–7.31 (m, 2 H), 7.22 (d, 2
H, J = 8.0 Hz), 6.93 (d, 2 H, J = 8.0 Hz), 5.48 (t, 1 H, J = 9.0
Hz), 4.09 (m, 1 H), 2.19 (s, 3 H), 1.92 (s, 3 H), 1.27 (d, 3 H,
J = 7.0 Hz). FABMS: m/z = 296 [M + H]+.
Compound 3t: 1H NMR (CDCl3, 200 MHz): d = 7.3–7.22,
(m, 4 H), 6.98 (d, 1 H, J = 8.9 Hz), 5.69 (dd, 1 H, J = 8.9, 5.9
Hz), 4.21 (q, 2 H, J = 7.0 Hz), 4.01 (d, 1 H, J = 5.9 Hz), 2.19
(s, 3 H), 2.04 (s, 3 H), 1.28 (t, 3 H, J = 7.0 Hz). FABMS:
m/z = 314, 312 [M + H]+.
Compound 3w: 1H NMR (CDCl3, 200 MHz): d = 8.16 (d, 2
H, J = 8.0 Hz), 7.94 (d, 2 H, J = 8.0 Hz), 7.64–7.20 (m, 5 H),
7.36 (d, 1 H, J = 9.0 Hz), 5.80 (dd, 1 H, J = 9.0, 5.2 Hz), 4.92
(d, 1 H, J = 5.2 Hz), 4.18 (q, 2 H, J = 7.0 Hz), 2.00 (s, 3 H),
1.19 (t, 3 H, J = 7.0 Hz). FABMS: m/z = 376, 374 [M + H]+.
Compound 3x: 1H NMR (CDCl3, 200 MHz): d = 8.18 (d, 2
H, J = 8.3 Hz), 7.96–7.84 (m, 5 H), 7.63–7.44 (m, 8 H), 5.82
(m, 1 H), 3.92 (dd, 1 H, J = 17.3, 4.5 Hz), 3.56 (dd, 1 H, J =
17.3, 5.3 Hz). FABMS: m/z = 375 [M + H]+.
Synlett 2006, No. 11, 1756–1758 © Thieme Stuttgart · New York