One-pot multicomponent synthesis of β-acetamido ketones based on BiCl3 generated in situ from the procatalyst BiOCl and acetyl chloride

Article abstract of DOI:10.1055/s-2004-836024

Aromatic aldehydes react in one pot at room temperature with enolizable ketones and acetonitrile in the presence of acetyl chloride and catalytic amount of BiOCl producing the corresponding β-acetamido ketones in very high to excellent yields. BiCl_3<

Full text of DOI:10.1055/s-2004-836024

LETTER
115
One-Pot Multicomponent Synthesis of b-Acetamido Ketones Based on BiCl3
Generated in situ from the Procatalyst BiOCl and Acetyl Chloride
O
ne-Pot Multico
i
ponen
n
t
Synthesis
o
a
f
b
-AcetamidoK
G
etones hosh,* Swarupananda Maiti, Arijit Chakraborty
Department of Chemistry, Jadavpur University, Kolkata 700032, India
E-mail: ghoshrina@yahoo.com
Received 21 August 2004
Table 1 One-Pot Synthesis of b-Acetamido Ketone from Benz-
aldehyde, Acetophenone, Acetyl Chloride and Acetonitrile in the
Presence of Different Metal Salts
Abstract: Aromatic aldehydes react in one pot at room temperature
with enolizable ketones and acetonitrile in the presence of acetyl
chloride and catalytic amount of BiOCl producing the correspond-
ing b-acetamido ketones in very high to excellent yields. BiCl3
generated in situ from BiOCl and acetyl chloride catalyzes the
multicomponent reaction.
Entry
Metal salt
Metal salt
(mol%)
Time
(h)
Yield (%)
of product
1
2
3
4
5
6
7
8
BiOCl
BiOCl
BiCl3
15
20
20
20
20
20
20
20
12
7
79
92
92
90
80
77
78
86
Key words: multicomponent reaction, BiOCl, procatalyst, BiCl3,
b-acetamido ketone
3.5
9
Because of significant advantages over conventional lin-
ear type synthesis, one-pot multicomponent reactions
have emerged as an improved synthetic strategy for tailor-
made structural scaffolds and combinatorial libraries in
drug discovery process.1 b-Acetamido- or amino ketones2
are potential intermediates for the synthesis of other im-
portant molecules like 1,3-amino alcohols,3a,b units com-
mon in natural nucleoside peptide antibiotics, e.g.,
nikkomycins or neopolyoxins.3d,e Multicomponent routes
leading to b-acetamido ketones reported by Iqbal et al. are
based on Lewis acid catalysts such as CoCl24a,b or Mont-
morillonite K10 clay.4c
Bi2(SO4)3
BiONO3
FeCl3
10
24
19
6
AlCl3
ZnCl2
from the procatalyst BiOCl and acetyl chloride. A variety
of aromatic aldehydes (1–9) reacted with enolizable ke-
tones (10–13) and acetonitrile (reactant as well as solvent)
at room temperature in the presence of 20 mol% of BiOCl
and ca. 2 equivalents of acetyl chloride (Scheme 1,
Table 1 and Table 2).9,10 Comparative experiments on the
one-pot synthesis of b-acetamido ketone (14) from benz-
aldehyde (1), acetophenone (10), acetyl chloride and
acetonitrile in the presence of different Bi(III) salts like
BiOCl, BiCl3, Bi2(SO4)3, BiO(NO3) and other metal salts
such as FeCl3, AlCl3 and ZnCl2 reveal that among all these
BiOCl is the reagent of choice in terms of yield, moisture
stability and ease of handling (Table 1). The minimum
load of BiOCl was optimized to be 20 mol% (entries 1 and
2, Table 1). Thus, in a model experiment, when benzalde-
hyde (1, ca. 1 equivalent) was reacted with acetophenone
(10, ca. 1 equivalent) and acetyl chloride (ca. 2 equiva-
lents) in the presence of BiOCl (20 mol%) in acetonitrile
(3 mL) at room temperature, the corresponding b-acet-
amido ketone (14) was formed in 7 hours in 92% yield
(entry 2, Table 1; entry 1, Table 2). Each of o-, m-, or p-
nitrobenzaldehyde (2–4) reacted separately with ace-
tophenone and other components furnishing the corre-
sponding b-acetamido ketones in very good to excellent
yields (entries 5–7, Table 2). Similarly, aromatic alde-
hydes (5–7) containing electron-donating groups also re-
acted efficiently. Thus, reaction of p-chloro-, p-methoxy-
or m-hydroxy benzaldehyde (entries 8–10, Table 2) fur-
Recently, Bi(III) salts have gained much interest in or-
ganic synthesis5 for their Lewis acidity and low toxicity
level.5b BiOCl is a readily available, moisture stable pre-
cursor of the desired Bi(III) salt. Its Lewis acidity is low,6
but it can generate BiCl3 in reaction with acetyl chloride,
which has also been established and utilized by Dubac et
al. in Friedel–Crafts acylation reaction.7 Moreover, it has
also got a very low toxicity level, LD50 rat (oral): 22g/kg.5b
Scheme 1
In continuation to our systematic scanning on the efficacy
of BiOCl-based organic reaction,8 we report herein our
interesting observations on the multicomponent synthesis
of the title compounds based on BiCl3 generated in situ
SYNLETT 2005, No. 1, pp 0115–0118
0
5.
0
1.
2
0
0
5
Advanced online publication: 12.11.2004
DOI: 10.1055/s-2004-836024; Art ID: G32904ST
© Georg Thieme Verlag Stuttgart · New York

116
R. Ghosh et al.
LETTER
nished the respective desired products in excellent yields, with alkali and repeating experiments (5 recycles) with
although N,N-dimethylamino benzaldehyde was reluctant the regenerated and re-isolated BiOCl also proceeded
to react under the standard reaction condition. Acetonitrile with equal efficacy without any loss in the activity of the
as well as benzonitrile took part in this multicomponent regenerated procatalyst (entry 4, Table 2).
reaction. Reaction of benzaldehyde and acetophenone
To evaluate, whether the reaction proceeds via chalcone-
with benzonitrile in the presence of BiOCl and acetyl
type intermediate, chalcone was treated separately with
chloride also proceeds in dichloromethane (entry 12) or in
acetonitrile in the presence of BiOCl and acetyl chloride
neat condition (entry 13) affording the corresponding b-
but the mixture failed to give any b-acetamido ketone
benzamido ketone (22) in good yields. As reported earli-
even after 3 days (Scheme 3). Acetonitrile is probably
incorporated in the aldehyde-derived intermediate with
er,8 like acetyl chloride, benzoyl chloride was also capable
of generating BiCl3 from BiOCl (Scheme 2). Thus, reac-
subsequent acetate migration and coupling with the ke-
tion of m-nitrobenzaldehyde (3) and acetophenone (10)
tone enolate, following a pathway similar to that proposed
with acetonitrile in the presence of BiOCl (20 mol%) and
by Iqbal et al. in a CoCl2-catalyzed reaction.4b The proba-
benzoyl chloride (ca. 5 equivalents) furnished the corre-
ble catalytic cycle and the mechanistic pathway may be
depicted as shown in Scheme 4.
sponding b-acetamido ketone (16) in high yield
(Scheme 2, Table 2, entry 14). The present procedure was
equally fruitful with an a-unsubstituted ketone such as p-
methoxyacetophenone (11) leading to the corresponding
desired product (21) in excellent yield (entry 11, Table 2).
Scheme 3
Scheme 2
To explore further the scope and limitation of this meth-
odology we also examined the reaction of aromatic alde-
hydes with a-substituted enolizable ketones (12, 13).
Thus, when benzaldehyde (1) was reacted with ethyl
methyl ketone (12) and acetonitrile in the presence of
BiOCl and acetyl chloride, the b-acetamido ketone (23)
generated from the more substituted enolate was obtained
in 75% yield with moderately good diastereoselectivity
(syn/anti 1:5, entry 15, Table 2). Similarly, propiophe-
none (13) reacted separately with benzaldehyde (1, entry
16), p-chloro- or o-nitro or o-hydroxy benzaldehyde (5, 2
and 9, entries 17, 18 and 20, Table 2) and also with
Scheme 4
In summary, we have demonstrated the efficacy of BiCl3
in situ generated from the procatalyst BiOCl towards the
catalyzed one-pot multicomponent synthesis of b-aceta-
vaniline (8, entry 19, Table 2) resulting in their respective
b-acetamido ketones (25–28) with concomitant acetyl-
ation of the phenolic -OH group in relevant substrates
mido ketones from a variety of aromatic aldehydes, eno-
(entries 19 and 20) in good to excellent yields, although
lizable ketones, acetyl chloride and aceto- or benzonitrile.
in poor diastereoselectivities (dr ca. 1.3 to ca. 2). Interest-
ingly, selectivity was in favor of the anti isomer from
o-funtionalized benzaldehydes (2 and 9, entries 18 and
20, Table 2) unlike the m- or p-substituted benzaldehyde
The notable feature of the present procedure lies in the sta-
bility of BiOCl, its easy availability, low cost, very low
toxicity and recyclability without any loss of its activity.
Although the diastereoselectivity of the reaction from a-
substituted enolizable ketones were poor, but the general
high to excellent yields of the a-unsubstituted ketone-de-
rived title compounds in solvent and also in neat condi-
(5 and 3).
The preparative efficacy of the present procedure was es-
tablished by a scaling-up experiment (ca. 10 fold) with
benzaldehyde (1), acetophenone (10) and acetonitrile us-
ing BiOCl and acetyl chloride in solvent (entry 2, Table 2)
and in solvent-less condition (entry 3, Table 2), which fur-
nished the desired b-acetamido ketone (14) in excellent
tion, along with the reusability and low toxicity of the
procatalyst, make it a suitable alternative to the reported
methods particularly for the synthesis of the b-acetamido
ketones based on a-unsubstituted ketones and for their
yields in both of these cases. After the reaction BiOCl was
industrial application.
regenerated from the aqueous extract by precipitation
Synlett 2005, No. 1, 115–118 © Thieme Stuttgart · New York

LETTER
One-Pot Multicomponent Synthesis of b-Acetamido Ketones
117
Table 2 One-Pot Synthesis of b-Acetamido Ketones
Entry
Aromatic aldehyde
b-Acetamido ketone
Time Yield, %a
syn/
anti
(h)
(mp, °C)
1
2
R1 = R2 = R3 = H (1)
R1 = R2 = R3 = R5 = H, R4 = Ph, R6 = Me (14)
R1 = R2 = R3 = R5 = H, R4 = Ph, R6 = Me (14)
R1 = R2 = R3 = R5 = H, R4 = Ph, R6 = Me (14)
R1 = R2 = R3 = R5 = H, R4 = Ph, R6 = Me (14)
R1 = NO2, R2 = R3 = R5 = H, R4 = Ph, R6 = Me (15)
R2 = NO2, R1 = R3 = R5 = H, R4 = Ph, R6 = Me (16)
R3 = NO2, R1 = R2 = R5 = H, R4 = Ph, R6 = Me (17)
R1 = R2 = R5 = H, R3 = Cl, R4 = Ph, R6 = Me (18)
R1 = R2 = R5 = H, R3 = OMe, R4 = Ph, R6 = Me (19)
R1 = R3 = R5 = H, R2 = OAc, R4 = Ph, R6 = Me (20)
7
92 (104–105)
91b
–
–
–
–
–
–
–
–
–
–
–
R1 = R2 = R3 = H (1)
7
3
R1 = R2 = R3 = H (1)
7
92c
4
R1 = R2 = R3 = H (1)
7
90,d 92e
5
R1 = NO2, R2 = R3 = H (2)
R2 = NO2, R1 = R3 = H (3)
R3 = NO2, R1 = R2 = H (4)
R1 = R2 = H, R3 = Cl (5)
R1 = R2 = H, R3 = OMe (6)
R1 = R3 = H, R2 = OH (7)
R1 = R2 = R3 = H (1)
12
8
84 (191–192)
91 (139–140)
64 (154)
6
7
8
8
10
9
80 (150)
9
90 (110–112)
93 (114–115)
91 (130)
10
11
4.5
R1 = R2 = R3 = R5 = H, R4 = p-MeO-C6H4, R6 = Me
4
(21)
12
13
14
15
16
17
18
19
R1 = R2 = R3 = H (1)
R1 = R2 = R3 = R5 = H, R4 = R6 = Ph (22)
12
12
55f (194–195)
–
R1 = R2 = R3 = H (1)
R1 = R2 = R3 = R5 = H, R4 = R6 = Ph (22)
55g
68h
75
94
81
72
83
–
R2 = NO2, R1 = R3 = H (3)
R1 = R2 = R3 = H (1)
R2 = NO2, R1 = R3 = R5 = H, R4 = Ph, R6 = Me (16)
R1 = R2 = R3 = H, R4 = R5 = R6 = Me (23)
R1 = R2 = R3 = H, R4 = Ph, R5 = R6 = Me (24)
R1 = R2 = H, R3 = Cl, R4 = Ph, R5 = R6 = Me (25)
R1 = NO2, R2 = R3 = H, R4 = Ph, R5 = R6 = Me (26)
1d
–
2
8
1:5i
2:1j
1.8:1j
1:2.2j
1.6:1j
R1 = R2 = R3 = H (1)
R1 = R2 = H, R3 = Cl (5)
R1 = NO2, R2 = R3 = H (2)
2
10
11
R1 = H, R2 = OMe, R3 = OH R1 = H, R2 = OMe, R3 = OAc, R4 = Ph, R5 = R6 = Me
(8)
(27)
20
R1 = OH, R2 = R3 = H (9)
R1 = OAc, R2 = R3 = H, R4 = Ph, R5 = R6 = Me (28)
12
60
1:1.4j
a Chromatographed yield.
b Scale-up experiment (ca. 10 fold).
c Under neat condition (ca. 10 fold).
d With recovered BiOCl.
e Yield after 5 recycles using recovered BiOCl.
f Using PhCN (ca. 2 equiv) in CH2Cl2.
g Using PhCN (ca. 3 equiv) in neat condition.
h Using PhCOCl (ca. 5 equiv) instead of MeCOCl.
i Ratio of methine protons of syn and anti isomers (by 1H NMR).
j Ratio of isolated yields (by preparative TLC) of syn and anti isomers.
Synlett 2005, No. 1, 115–118 © Thieme Stuttgart · New York

118
R. Ghosh et al.
LETTER
(6) Chakraborti, A. K.; Gulhane, R.; Shivani Synlett 2003,
Acknowledgment
1805.
The financial assistances from CSIR, New Delhi (Scheme No. 01/
1672/00/EMR-II) to RG and from UGC, New Delhi to AC (SRF)
are gratefully acknowledged.
(7) Répichet, S.; Le Roux, C.; Roques, N.; Dubac, J.
Tetrahedron Lett. 2003, 44, 2037; and references cited
therein.
(8) Ghosh, R.; Maiti, S.; Chakraborty, A. Tetrahedron Lett.
2004, 45, 6775.
References
(9) General Experimental Procedure: To a solution of
aldehyde (1 mmol), enolizable ketone (1 mmol) and BiOCl
(20 mol%) in dry MeCN (4 mL) MeCOCl (2 mmol) was
added and the reaction mixture was stirred at r.t. After
completion of the reaction (checked by TLC, Table 1) the
mixture was diluted with CH2Cl2 and washed with brine
solution (10 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 5 mL), the pooled organic layer was then
washed subsequently with H2O (1 × 6 mL), NaHCO3 (1 × 6
mL) and finally with H2O (1 × 6 mL). The organic layer was
dried over Na2SO4, concentrated and the residue was
purified by column filtration on silica gel.
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and/or elemental analysis and by comparing the physical
data with those in the literature.4 The following spectral data
are representative:
Compound 21: White crystals [EtOAc–petroleum ether (60–
80 °C)]; mp 130 °C. IR (KBr): 3270, 1675, 1640, 1598,
1570, 1525, 1420, 1365, 1250, 1205, 1170, 1020, 990, 830,
800, 700 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3
H), 3.31–3.39 (dd, 1 H, J = 5.95, 16.59 Hz), 3.64–3.71 (dd,
1 H, J = 5.28, 16.57 Hz), 3.84 (s, 3 H), 5.53 (m, 1 H), 6.86
(br s, 1 H), 6.89 (br d, 2 H, J = 8.82 Hz), 7.18–7.34 (m, 5 H),
7.88 (br d, 2 H, J = 8.81 Hz). 13C NMR (75 MHz, CDCl3):
d = 23.37, 42.76, 50.02, 55.46, 113.80, 126.41, 127.30,
128.55, 129.66, 130.45, 141.07, 163.77, 169.49, 197.08.
Anal. Calcd for C18H19O3N: C, 72.71; H, 6.44; N, 4.71.
Found: C, 72.65; H, 6.82; N, 4.67.
Compound 22: White crystals [EtOAc–petroleum ether (60–
80 °C)]; mp 194–195 °C. IR (KBr): 3285, 1685, 1635, 1545,
1525, 1400, 1350, 1310, 1290, 1225, 1200, 755, 735, 700,
690 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.57–3.64 (dd, 1
H, J = 5.38 Hz, 17.45 Hz), 3.87–3.95 (dd, 1 H, J = 4.94,
17.45 Hz), 5.85 (m, 1 H), 7.44–7.62 (m, 7 H), 7.78 (br d, 1
H, J = 7.8 Hz), 7.84–7.93 (m, 5 H), 8.10 (br d, 1 H, J = 8.11
Hz), 8.28 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 42.55,
49.63, 121.39, 122.48, 127.11, 128.16, 128.74, 128.89,
129.64, 131.98, 132.89, 133.67, 134.09, 136.21, 143.47,
166.89, 198.63. Anal. Calcd for C22H18N2O4: C, 70.57; H,
4.84; N, 7.48. Found: C, 70.16; H, 4.96; N, 7.23.
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G., Eds.; Pergamon: New York, 1995, 502–513. (d)Suzuki,
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Synlett 2005, No. 1, 115–118 © Thieme Stuttgart · New York