Bismuth(III) oxychloride procatalyst based one-pot multicomponent synthesis of β′-acetamido-β-dicarbonyl compounds with special reference to pref-β′-acetamido-β-oxo esters

Article abstract of DOI:10.1055/s-2006-958955

Bismuth(III) chloride generated in situ from the procatalyst bismuth(III) oxychloride and acetyl chloride efficiently catalyzes the one-pot synthesis of β′-acetamido-β-dicarbonyl compounds from aldehydes, enolizable β-diketones, or β-oxo esters and acetyl

Full text of DOI:10.1055/s-2006-958955

190
PAPER
Bismuth(III) Oxychloride Procatalyst Based One-Pot Multicomponent
Synthesis of b¢-Acetamido-b-dicarbonyl Compounds with Special Reference
to pref-b¢-Acetamido-b-oxo Esters
S
ynthesis of b¢-A
i
c
etami
n
do-
b
-dicarbo
a
nyl Compounds Ghosh,*a Swarupananda Maiti,a Soumen Ghosh,b Alok K. Mukherjeeb
a
Department of Chemistry, Jadavpur University, Kolkata 700032, India
E-mail: ghoshrina@yahoo.com
Department of Physics, Jadavpur University, Kolkata 700032, India
b
Received 3 July 2006; revised 24 October 2006
based organic synthesis,5,6l,m we report herein, the effi-
cient application of this reagent in the one-pot synthesis,
in solution as well as under solvent-free conditions, of
b-acetamido carbonyl compounds 4 and 5 derived from
Abstract: Bismuth(III) chloride generated in situ from the procata-
lyst bismuth(III) oxychloride and acetyl chloride efficiently cata-
lyzes the one-pot synthesis of b¢-acetamido-b-dicarbonyl
compounds from aldehydes, enolizable b-diketones, or b-oxo esters
and acetyl chloride in acetonitrile solution and under solvent-free enolizable b-dicarbonyl starting materials 2 and 3, with
conditions at room temperature; in the case of the b-oxo ester de-
rived products, these are obtained with moderate to excellent dia-
stereoselectivity in favor of the pref-isomer. X-ray crystallographic
analysis of one pref-b¢-acetamido-b-oxo ester exhibits C–H···O and
N–H···O intermolecular interactions in the three-dimensional su-
pramolecular assembly.
special reference to the corresponding pref-b¢-acetamido-
b-oxo esters 4 (Table 1), which could be utilized as struc-
tural units for the generation of corresponding peptidomi-
metic library compounds.
Under optimized conditions, benzaldehyde (1a) reacted
with methyl acetoacetate (2) and acetyl chloride in aceto-
nitrile (reagent as well as solvent) in the presence of bis-
muth(III) oxychloride (20 mol%) at room temperature to
give the corresponding b¢-acetamido-b-oxo ester 4a in
96% yield and with moderate diastereoselectivity (3:1) in
favor of the pref-isomer (Table 1, entry 1). Under similar
condition, aromatic aldehydes 1c–g containing electron-
donating groups like chloro, methyl, hydroxy, bromo, or
fluoro in the aromatic ring (Table 1, entries 5, 6, 8–10) re-
acted with methyl acetoacetate (2), acetyl chloride, and
acetonitrile in acetonitrile solution producing quite effi-
ciently the corresponding products 4c–g; concomitant
acetylation of the 4-hydroxy group of 1e occurred to give
4e. The pref-selectivities of the products 4c–e,g (Table 1,
entries 5, 6, 8, and 10) were excellent, but the bromo-sub-
stituted product 4f (Table 1, entry 9) did not show any ste-
reoselectivity in solution. Although, the yields of the
products from aromatic aldehydes containing electron-
withdrawing groups like nitro or cyano in the ring 1b or
1h were good with moderate pref-selectivity of the nitro-
substituted product 4b (Table 1, entry 4), the 4-cyano-
benzaldehyde derived product 4h exhibited no stereose-
lectivity in solution (Table 1, entry 11). The reactions of
all these substrates 1a–h proceed efficiently under sol-
vent-free condition at ambient temperature with overall
excellent or exclusive pref-selectivity of most of the prod-
ucts (Table 1, entries 1, 4–6, 8–10). Although, the selec-
tivity of the 4-cyanobenzaldehyde (1h) reaction under
solvent-free conditions was moderate (1:2.7), it was only
1:1 when acetonitrile was used as the reactant and solvent
(Table 1, entry 11). It is interesting to note that the diaste-
reoselectivity of the 4-nitrobenzaldehyde (1b) reactions
changed dramatically from parf/pref 1:4 (MeCN as sol-
vent) to exclusively pref (solvent-free) and for 4-bro-
mobenzaldehyde (1f) reactions parf/pref 1:1 (MeCN as
Key words: multicomponent reaction, bismuth(III) oxychloride,
bismuth(III) chloride, catalysis, b¢-acetamido-b-dicarbonyl com-
pounds, diastereoselectivity
One-pot multicomponent synthesis has drawn the atten-
tion of many organic chemists because of the advantages
it has over conventional multistep synthesis and the poten-
tial for its application to the generation of library com-
pounds for drug development.1 b-Amino alcohols derived
from b-acetamido ketones are important structural units
common in naturally occurring nucleoside antibiotics, e.g.
nikkomycins or neopolyoxins.2 b-Acetamido esters are
readily converted into b-amino acids, which are important
synthons for the generation of structural scaffolds related
to peptidomimetic enzyme inhibitors of current interest.3
Reported Lewis acid catalyzed one-pot syntheses of b-ac-
etamido carbonyl compounds are based on cobalt(II)
chloride,4a–c poly-cobalt(II) chloride,4d montmorillonite
K10,4e silica gel–sulfuric acid,4f or bismuth(III) oxychlo-
ride.5 Methods based on cobalt(II) chloride or montmoril-
lonite K10 generate mainly the parf-b¢-acetamido-b-oxo
esters (described as anti-isomer by Iqbal4a–d) from the cor-
responding b-oxo esters. Recently, bismuth(III) salts have
gained much attention in organic synthesis.6 In an earlier
report5 we showed that bismuth(III) chloride generated in
situ from the procatalyst bismuth(III) oxychloride effi-
ciently catalyzed the one-pot synthesis of b-acetamido ke-
tones starting from the corresponding aromatic aldehyde,
an enolizable ketone, acetonitrile, and acetyl chloride. In
continuation of our research on bismuth(III) oxychloride
SYNTHESIS 2007, No. 2, pp 0190–0196
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x
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x
x
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0
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Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958955; Art ID: T09806SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of b¢-Acetamido-b-dicarbonyl Compounds
191
Table 1 Bismuth(III) Oxychloride Procatalyst Based One-Pot Synthesis of b¢-Acetamido-b-dicarbonyl Compounds
BiOCl (20 mol%)
NHCOMe
AcCl, MeCN
MeCN solvent or neat
r.t.
O
O
X
CHO
+
R1
X
1
R1
O
O
2 X = OMe
3 X = Me
4 X = OMe
5 X = Me
Entry
Aldehyde b¢-Acetamido-b-dicarbonyl compound Time (h) soln [neat] Yielda (%) soln [neat] Ratiob parf/pref solution [neat]
R
X
1
2
1a
1a
1a
1b
1c
1d
1d
1eg
1f
4a
4a
4a
4b
4c
4d
4d
4e
4f
Ph
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
6 [7]
6 [7]
96 [93]
91c [92]
90e [–d]
58 [57]
75 [76]
82 [82]
85f [–d]
61 [53]
87 [81]
87 [84]
75 [65]
91 [91]
57 [53]
90 [89]
70 [68]
89 [85]
92 [90]
61 [62]
85 [92]
1:3 [1:5.7]
Ph
1:3 [1:6.6]
3
Ph
6 [–d]
1:3 [–d]
4
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-AcOC6H4
4-BrC6H4
4-FC6H4
4-NCC6H4
Ph
12 [12]
12 [12]
5 [5]
1:4 [pref only]
5
1:27 [1:15]
6
pref only [pref only]
7
4 [–d]
1:3 [–d]
8
24 [28]
22 [27]
10 [15]
22 [28]
4 [6]
1:7.5 [1:7.5]
9
1:1 [1:11]
10
11
12
13
14
15
16
17
18
19
1g
1h
1a
1b
1c
1d
1eg
1h
1i
4g
4h
5a
5b
5c
5d
5e
5h
5i
1:6.6 [1:10]
1:1 [1:2.7]
–
–
–
–
–
–
–
–
4-O2NC6H4
4-ClC6H4
4-MeC6H4
4-AcOC6H4
4-NCC6H4
4-MeOC6H4
n-C7H15
Me
12 [12]
4 [4]
Me
Me
10 [10]
12 [12]
8 [11]
14 [14]
14 [18]
Me
Me
Me
1j
5j
Me
a Unoptimized chromatographed yields.
b By 1H NMR.
c Scale-up experiment (~ ten-fold).
d Reaction not performed.
e The reaction was performed with recovered BiOCl (~ ten-fold).
f At 50 °C.
g Starting from 1e, R = 4-HOC6H4.
solvent) to 1:11 (solvent-free); the reason for the dramatic products and finally confirmed by the X-ray crystallo-
change in selectivity in these substrates which have the graphic analysis7 of the single crystal of a model com-
opposite electron demand is not, however, clear. It is in- pound 4d (ORTEP diagram in Figure 1). Crystal packing
teresting to note that the overall diastereoselectivities of exhibited intermolecular N–H···O and C–H···O hydrogen
the b¢-acetamido-b-oxo esters 4a–h from the bismuth(III) bonds between molecules related by translation to form
2
oxychloride based one-pot reaction differed from those infinite chains of R2 (14) rings propagating along the
observed by Iqbal et al. in the cobalt(II) chloride or mont- [010] direction. Additional intermolecular C–H···O hy-
morillonite K10 catalyzed one-pot reactions,4 the latter drogen bonds in the [101] direction between molecules re-
proceeded mainly with parf-selectivity. The pref-selectiv- lated by the screw symmetry link the parallel chains into
ity of the present reactions was established by NMR of the three-dimensional supramolecular assembly (Figure 2).
Synthesis 2007, No. 2, 190–196 © Thieme Stuttgart · New York

192
R. Ghosh et al.
PAPER
showed varied selectivities in favor of the pref-diastereo-
mer.
It is worthwhile to mention that the reactions of the sub-
strates 1a,b,d,f with methyl acetoacetate (2) and acetyl
chloride in acetonitrile in the presence of the Brønsted ac-
id, hydrochloric acid (20 mol%, Table 2) also produced
the corresponding b¢-acetamido-b-dicarbonyl compounds
4, but in lower yields compared to their bismuth(III)-
based Lewis acid counterparts. Like the previous cases,
the pref-selectivities of hydrochloric acid catalyzed reac-
tions in solution, except that from 4-bromobenzaldehyde
(1f), were lower in comparison with those obtained from
reactions conducted in the presence of bismuth(III) oxy-
chloride.
Figure 1 ORTEP structure of pref-4d
The pref-selectivity of the b-oxo ester derived products 4
in the present procedure can be explained by the coupling
of the intermediate (I, initially generated in situ by the re-
action of the aldehyde, acetyl chloride, and acetonitrile)
with mainly the b-oxo ester derived bismuth (E)-enolate
IIb, probably via the kinetically more favored six-mem-
bered transition state (Scheme 1, shown with bismuth(III)
oxychloride, arising out of Re-Si or Si-Re attack) in which
bismuth attains a pentagonal bipyramidal geometry. 1,3-
syn-Diaxial interactions in the other possible transition
state (Scheme 1, arising from Re-Re or Si-Si attack) make
that pathway more energy-demanding, leading to the ki-
netically less favored parf-diastereomer. This is also cor-
roborated by the decrease in pref-selectivity in the
reaction of 4-tolualdehyde (1d) (Table 1, entry 7) at high-
er temperature. It is worthwhile to mention here that the
present synthesis of b¢-acetamido-b-oxo esters 4 is highly
Figure 2 Crystal packing of pref-4d
The efficacies of the one-pot syntheses of b¢-acetamido-b-
dicarbonyl compounds from benzaldehyde (1) or its deac-
tivated or activated derivatives 1b,d,f catalyzed by other
bismuth(III) salts (20 mol% each) namely bismuth(III) tri-
flate, bismuth(III) bromide, bismuth sulfate, or bismuth
subnitrate and also by the Brönsted acid hydrochloric acid
were compared with those of the corresponding bis-
muth(III) oxychloride based reactions. The results of
these reactions are summarized in Table 2.
O
+
RCHO
1
+
+
AcCl
MeCN
X
O
BiCl3
BiOCl (20 mol%)
2 X = OMe
3 X = Me
Under standard reaction condition, the yields of the reac-
tions of the substrates, benzaldehyde (1a), 4-nitrobenz-
aldehyde (1b) or 4-tolualdehyde (1d), in acetonitrile
solution or under solvent-free conditions based on bis-
muth(III) oxychloride were better in comparison with the
reactions based on bismuth(III) triflate, bismuth(III) bro-
mide, bismuth sulfate, or bismuth subnitrate (cf. Table 1,
entries 1, 4, 7 and Table 2). The pref-selectivities of the
reactions from benzaldehyde (1a), 4-nitrobenzaldehyde
(1b), or 4-tolualdehyde (1d) in solution based on other
bismuth(III) salts were comparable in a few cases
(Table 1, entry 1, vs Table 2, entries 1, 5, 9, and 13 and
Table 1, entry 4 vs Table 2 entries 6 and 14), better on two
occasions (Table 1, entry 4 vs Table 2, entries 2 and 10)
or much lower in other reactions in solution or under neat
conditions with respect to those conducted by bis-
muth(III) oxychloride. As mentioned earlier, the 4-bro-
mobenzaldehyde (1f) derived reaction in the presence of
bismuth(III) oxychloride in solution was unselective, al-
though the reaction catalyzed by other bismuth(III) salts
Me
Ar
N
COX
IIb
+
+
O
O
O
O
O
Bi
Cl2
IIa
BiCl2
(X = Me/OMe)
I
+
+
+
+
Me
Cl
Bi
Me
R
Cl
Bi
H
Cl
Cl
..
O
O
..
..
N
XOC
..
+
XOC
+
+
O
O
N
R
H
H
H
O
O
favored transition state
NHCOMe
disfavored transition state
NHCOMe
+
COMe
R
COMe
R
COX
COX
4 X = OMe, pref-product (major)
4 X = OMe, parf-product (minor)
Scheme 1
Synthesis 2007, No. 2, 190–196 © Thieme Stuttgart · New York

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Synthesis of b¢-Acetamido-b-dicarbonyl Compounds
193
Table 2 Synthesis of b¢-Acetamido-b-dicarbonyl Compounds Catalyzed by Bismuth(III) Salts or Hydrochloric Acid (20 mol%)
Entry
Substrate
1a
Catalyst
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
BiBr3
Time (h) soln [neat] Product
Yield (%) soln [neat] Ratio parf/prefa soln [neat]
1
1 [1]
2 [3]
4a
4b
4d
4f
91 [83]
84 [77]
83 [83]
81 [72]
85 [81]
79 [69]
87 [78]
85 [76]
89 [90]
82 [78]
88 [82]
90 [83]
89 [88]
83 [76]
83 [85]
88 [92]
64 [–]
1:4.2 [1:4.5]
1:10.7 [1:9.3]
1:4.2 [1:4.2]
1:6.6 [1:4.6]
1:2.5 [1:3.1]
1:5.2 [1:10.1]
1:6.1 [1:2.4]
1:11.4 [1:3.9]
1:3.1 [1:2.1]
1:7.2 [1:5.3]
1:4.5 [1:1.3]
1:1.6 [1:5.3]
1:5.2 [1:3.0]
1:4.7 [1:3.6]
1:4.9 [1:17.4]
1:3.1 [1:9.1]
1:4.2 [–]
2
1b
1d
1f
3
3 [4]
4
4 [6]
5
1a
3 [5]
4a
4b
4d
4f
6
1b
1d
1f
BiBr3
5 [7]
7
BiBr3
6 [8]
8
BiBr3
9 [12]
2 [5]
9
1a
Bi2(SO4)3
Bi2(SO4)3
Bi2(SO4)3
Bi2(SO4)3
BiONO3
BiONO3
BiONO3
BiONO3
HCl
4a
4b
4d
4f
10
1b
1d
1f
8 [11]
8 [10]
9 [12]
5 [8]
11
12
13
1a
4a
4b
4d
4f
14
1b
1d
1f
10 [14]
5 [7]
15
16
12 [16]
72 [–]
48 [–]
24 [–]
36 [–]
17
1a
4a
4b
4d
4f
18
1b
1d
1f
HCl
51 [–]
1:2.7 [–]
19
HCl
70 [–]
1:19.6 [–]
20
HCl
38 [–]
1:6.9 [–]
a By 1H NMR.
pref-selective, although the general stereoselectivity of hyde (1a), methyl acetoacetate (2), acetyl chloride, and
our earlier synthesis of b-acetamido ketones5 based on acetonitrile in the presence of bismuth(III) oxychloride
bismuth(III) oxychloride was not good.
(20 mol%) in solution and under solvent-free conditions,
which produced the corresponding b¢-acetamido-b-oxo
ester 4a in excellent yields with comparable pref-selectiv-
ity in solution and slightly increased pref-selectivity under
neat conditions (Table 1, entry 2). Recovered bismuth(III)
oxychloride5 also worked equally well (Table 1, entry 3)
in terms of yield and diastereoselectivity. It is also to be
noted here that unlike some of the reported methods4b,c the
bismuth(III) oxychloride based one-pot synthesis is not
susceptible to the presence of oxygen and the reaction
does not require several days to go to completion.
The pref-selectivity of other bismuth(III) Lewis acids and
hydrochloric acid based one-pot reactions are also ex-
plained by a similar mechanistic pathway and transition
state model as depicted for bismuth(III) oxychloride me-
diated reactions in Scheme 1. Figure 3 represents the
probable favored transition state for hydrochloric acid cat-
alyzed reactions.
The preparative efficacy of the procedure was established
through scale-up (~ ten-fold) experiments with benzalde-
The scope and limitation of the methodology mediated by
bismuth(III) oxychloride were further extended by suc-
cessful one-pot conversion of a mixture of alkyl or aro-
matic aldehyde, b-diketone, acetyl chloride, and
acetonitrile in solution as well as under solvent-free con-
ditions to the corresponding b¢-acetamido-b-dioxo com-
pounds 5 in good to excellent yields (Table 1, entries 12–
19). It is also to be noted here that for some reasons yet un-
+
+
Me
H
H
O
..
XOC
+
N
R
H
OCOMe
Figure 3 Favored transition state for hydrochloric acid catalyzed re-
actions
Synthesis 2007, No. 2, 190–196 © Thieme Stuttgart · New York

194
R. Ghosh et al.
PAPER
pref-Isomer
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 144 °C.
known to us, the reaction of 4-methoxybenzaldehyde (1i),
acetyl chloride, and acetonitrile with methyl acetoacetate
(2) in the presence of bismuth(III) oxychloride (20 mol%) IR (KBr): 3330, 2960, 1745, 1715, 1645, 1530, 1450, 1430, 1365,
1265, 1220, 1160, 1100, 1040, 1000, 905, 840, 760, 705, 620 cm–1.
in solution did not proceed even though the reaction with
1H NMR (300 MHz, CDCl3): d = 2.02 (s, 3 H), 2.14 (s, 3 H), 3.71
(s, 3 H), 4.08–4.10 (d, J = 5.5 Hz, 1 H), 5.73–5.78 (m, 1 H), 6.90–
6.93 (d, J = 8.6 Hz, 1 H), 7.24–7.35 (m, 5 H).
acetylacetone (3) proceeded to give the desired product 5i
in good yields. Salicylaldehyde was consumed in the re-
action mixture with acetyl chloride, acetonitrile, methyl
acetoacetate (2) and bismuth(III) oxychloride (20 mol%)
in solution, but the corresponding product was formed in
very poor yield because of the formation of several other
side products (not isolated).
Methyl 3-Acetamido-2-acetyl-3-(4-nitrophenyl)propanoate
(4b)4c
Yield (after chromatography): 58% (soln), 57% (solvent-free).
pref-Isomer
In summary, among a variety of bismuth(III) salts, bis-
muth(III) oxychloride procatalyst-based (bismuth(III)
chloride catalyzed) one-pot synthesis describes an effi-
cient method for the generation of pref-selective b¢-acet-
amido-b-oxo esters 4 in particular and b¢-acetamido-b-
dicarbonyl compounds 4 and 5 in general by the one-pot
reaction of various aldehydes 1 with methyl acetoacetate
(2) or acetylacetone (3), acetyl chloride, and acetonitrile at
room temperature in solution as well as under solvent-free
conditions on a milligram or gram scale.
Light yellow crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp
153–154 °C.
IR (KBr): 3320, 3060, 2980, 2930, 1745, 1710, 1655, 1595, 1545,
1515, 1435, 1345, 1285, 1270, 1230, 1160, 1110, 1040, 960, 910,
860, 805, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04 (s, 3 H), 2.09 (s, 3 H), 3.34
(s, 3 H), 4.30–4.32 (d, J = 4.9 Hz, 1 H), 5.89–5.93 (m, 1 H), 7.09–
7.12 (d, J = 9.0 Hz, 1 H), 7.45–7.48 (d, J = 8.6 Hz, 2 H), 8.17–8.20
(d, J = 8.8 Hz, 2 H).
Methyl 3-Acetamido-2-acetyl-3-(4-chlorophenyl)propanoate
(4c)4c
Yield (after chromatography): 75% (soln), 76% (solvent-free).
All unknown compounds were characterized by IR, NMR, MS, and
elemental analysis. NMR spectra were recorded on Bruker DPX
300 spectrometer using CDCl3 as solvent and TMS as the internal
standard. Elemental analyses were performed on a Perkin-Elmer au-
toanalyzer 2400 II from IACS, Kolkata 700032, India. MS data
were taken on GCMS-QP5000 (Shimadzu). The X-ray crystallo-
graphic data were recorded on Bruker SMART CCD area detector
using graphite monochromator.
pref-Isomer
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 145 °C.
IR (KBr): 3325, 2960, 2940, 1750, 1715, 1650, 1550, 1435, 1370,
1285, 1270, 1230, 1165, 1120, 1100, 1050, 1020, 910, 850, 725
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H), 2.15 (s, 3 H), 3.73
(s, 3 H), 4.05–4.07 (d, J = 5.4 Hz, 1 H), 5.68–5.73 (m, 1 H), 6.92–
6.95 (d, J = 8.9 Hz, 1 H), 7.21–7.31 (m, 4 H).
All reagents were of commercial grade and were used from freshly
opened containers without further purification. Organic solvents
were dried by standard methods and were distilled before use.
Progress of reactions was checked by TLC on silica gel G (Merck)
using EtOAc–petroleum ether (bp 60-80 °C) (2:1) as the mobile
phase. Silica gel (60–120 mesh) was used for column chromatogra-
phy.
Methyl 3-Acetamido-2-acetyl-3-(4-methylphenyl)propanoate
(4d)4c
Yield (after chromatography): 82% (soln), 82% (solvent-free).
pref-Isomer
b¢-Acetamido-b-dicarbonyl Compounds 4 and 5; General Pro-
cedure
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 130 °C.
In solution: To a soln of aldehyde 1 (~1 equiv) and methyl acetoac-
etate (2) or acetylacetone (3) (~1 equiv) in anhyd MeCN (4 mL) was
added BiOCl (~20 mol%). To the resulting suspension was finally
added AcCl (~2 equiv) and the mixture was stirred at r.t. When the
reaction was complete, the mixture was diluted with CH2Cl2,
washed with brine (1 × 20 mL), and the aqueous layer was then ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic extracts
were washed with NaHCO3 soln (1 × 15 mL) followed by H2O
(1 × 20 mL). The organic layer was dried (Na2SO4) and concentrat-
ed to dryness to give a crude residue that was purified by column
chromatography (silica gel, EtOAc–petroleum ether (bp 60–80 °C)
(3:2).
IR (KBr): 3330, 3030, 2950, 2920, 1740, 1720, 1645, 1525, 1430,
1370, 1290, 1265, 1220, 1160, 1115, 1090, 1040, 1005, 965, 905,
840, 810, 770, 720, 595 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H), 2.15 (s, 3 H), 2.35
(s, 3 H), 3.70 (s, 3 H), 4.06–4.08 (d, J = 5.8 Hz, 1 H), 5.69–5.75 (m,
1 H), 6.87–6.89 (d, J = 8.2 Hz, exchangeable NH), 7.10–7.18 (m, 4
H).
1H NMR (300 MHz, CDCl3, D2O-exchange): d = 1.99 (s, 3 H), 2.15
(s, 3 H), 2.3 (s, 3 H), 3.7 (s, 3 H), 4.06–4.08 (d, J = 5.9 Hz, 1 H),
5.70–5.72 (d, J = 5.8 Hz, 1 H), 7.1–7.18 (m, 4 H).
MS (EI): m/z = 277 (M+), 245, 234, 218, 192, 176, 160, 145, 132,
Under solvent-free conditions: To a mixture of aldehyde 1 (~1
equiv), methyl acetoacetate (2) or acetylacetone (3) (~1 equiv), and
anhyd MeCN (~3 equiv) was added BiOCl (~20 mol%). Finally,
AcCl (~2 equiv) was added and the mixture was stirred at r.t. When
the reaction was complete, it was diluted with CH2Cl2 (15 mL) and
then worked up as described above.
120, 105, 91, 43 (base peak).
Crystal data for C15H19NO4: Single crystals of 3d suitable for X-
ray crystallography were grown from n-hexane–EtOAc.
M = 277.32, monoclinic, space group P21/c, a = 18.198(6),
b = 5.149(2), c = 15.990(5) Å, b = 99.83(6)°, l = 0.71073,
V = 1476.6(8) Å3, z = 4, Dcalc = 1.247 mg/M3, m = 0.09 mm–1,
T = 293(2) K, refinement for data with I > 2s(I) (1640 reflections,
Rint = 0.0539) gave R1(F) = 0.0617 and wR2(F2) = 0.1498 for all
data.
Methyl 3-Acetamido-2-acetyl-3-phenylpropanoate (4a)4c
Yield (after chromatography): 96% (soln), 93% (solvent-free).
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Synthesis of b¢-Acetamido-b-dicarbonyl Compounds
195
Methyl 3-Acetamido-3-(4-acetoxyphenyl)-2-acetylpropanoate
(4e)4c
Anal. Calcd for C14H17O3N: C, 67.99; H, 6.92; N, 5.66. Found: C,
67.91; H, 7.01; N, 5.19.
Yield (after chromatography): 61% (soln), 53% (solvent-free).
N-[2-Acetyl-1-(4-nitrophenyl)-3-oxobutyl]acetamide (5b)4b
Light yellow crystals [EtOAc–petroleum ether (bp 60–80 °C)];
yield (after chromatography): 57% (soln), 53% (solvent-free); mp
179 °C.
pref-Isomer
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 170 °C.
IR (KBr): 3320, 1760, 1710, 1640, 1430, 1360, 1110, 1040, 910,
860, 840, 815, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H), 2.17 (s, 3 H), 2.28
(s, 3 H), 3.71 (s, 3 H), 4.05–4.07 (d, J = 5.6 Hz, 1 H), 5.72–5.77 (m,
1 H), 6.90–6.94 (d, J = 8.9 Hz, 1 H), 7.03–7.06 (d, J = 8.6 Hz, 2 H),
7.28–7.31 (d, J = 8.6 Hz, 2 H).
IR (KBr): 3260, 1720, 1700, 1660, 1610, 1595, 1415, 1370, 1355,
1290, 1250, 1150, 1100, 980, 855, 780, 750, 700, 600 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.05 (s, 3 H), 2.10 (s, 3 H), 2.35
(s, 3 H), 4.32–4.33 (d, J = 4.9 Hz, 1 H), 5.89–5.94 (m, 1 H), 7.09–
7.12 (d, J = 9.0 Hz, 1 H), 7.46–7.49 (d, J = 8.6 Hz, 2 H), 8.21–8.23
(d, J = 6.4 Hz, 2 H).
Methyl 3-Acetamido-2-acetyl-3-(4-bromophenyl)propanoate
(4f)4c
Yield (after chromatography): 87% (soln), 81% (solvent-free).
N-[2-Acetyl-1-(4-chlorophenyl)-3-oxobutyl]acetamide (5c)
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 90% (soln), 89% (solvent-free); mp 168 °C.
pref-Isomer
IR (KBr): 3290, 2910, 1715, 1695, 1640, 1530, 1490, 1400, 1370,
1360, 1305, 1285, 1245, 1190, 1170, 1150, 1090, 1010, 970, 830,
800, 745, 715, 685, 620, 600 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H), 2.05 (s, 3 H), 2.27
(s, 3 H), 4.23–4.25 (d, J = 5.5 Hz, 1 H), 5.77–5.82 (m, 1 H), 7.00–
7.03 (d, J = 9.0 Hz, 1 H), 7.19–7.22 (d, J = 8.5 Hz, 2 H), 7.27–7.30
(d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3, proton-decoupled): d = 23.2, 29.9,
31.1, 51.3, 70.3, 127.9, 128.9, 133.6, 137.8, 169.9, 202.2, 204.9.
MS (ES): m/z = 304.05 [M+ + Na], 306.07 [M+ + Na + 2].
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 146 °C.
IR (KBr): 3320, 1740, 1710, 1645, 1540, 1430, 1370, 1280, 1220,
1160, 1040, 1010, 845 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H), 2.16 (s, 3 H), 3.73
(s, 3 H), 4.05–4.06 (d, J = 5.4 Hz, 1 H), 5.66–5.71 (m, 1 H), 6.92–
6.95 (d, J = 8.9 Hz, 1 H), 7.15–7.18 (d, J = 8.2 Hz, 2 H), 7.43–7.46
(d, J = 8.2 Hz, 2 H).
Methyl 3-Acetamido-2-acetyl-3-(4-fluorophenyl)propanoate
(4g)4c
Yield (after chromatography): 87% (soln), 84% (solvent-free).
Anal. Calcd for C14H16ClO3N: C, 59.68; H, 5.72; N, 4.97. Found: C,
59.63; H, 5.94; N, 4.72.
pref-Isomer
N-[2-Acetyl-1-(4-methylphenyl)-3-oxobutyl]acetamide (5d)4a
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography: 70% (soln), 68% (solvent-free); mp 151 °C.
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 116 °C.
IR (KBr): 3320, 1740, 1710, 1650, 1530, 1510, 1435, 1370, 1230,
1160, 1110, 1040, 845 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H), 2.16 (s, 3 H), 3.71
(s, 3 H), 4.05–4.07 (d, J = 5.6 Hz, 1 H), 5.69–5.74 (m, 1 H), 6.91–
6.94 (d, J = 8.4 Hz, 1 H), 6.98–7.03 (t, J = 8.6 Hz, 2 H), 7.24–7.29
(t, J = 6.8 Hz, 2 H).
IR (KBr): 3290, 1715, 1690, 1635, 1540, 1370, 1355, 1305, 1290,
1245, 1145, 1085, 965, 810, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.09 (s, 3 H), 2.25
(s, 3 H), 2.30 (s, 3 H), 4.26–4.28 (d, J = 5.9 Hz, 1 H), 5.79–5.84 (m,
1 H), 6.90–6.93 (d, J = 8.9 Hz, 1 H), 7.10–7.16 (m, 4 H).
Methyl 3-Acetamido-2-acetyl-3-(4-cyanophenyl)propanoate
(4h)4c
Yield (after chromatography): 75% (soln), 65% (solvent-free).
N-[1-(4-Acetoxyphenyl)-2-acetyl-3-oxobutyl]acetamide (5e)4b
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 89% (soln), 85% (solvent-free); mp 145 °C.
pref-Isomer
IR (KBr): 3600, 3280, 1755, 1730, 1700, 1650, 1550, 1370, 1200,
1170, 1140, 1110, 960, 910, 880, 850, 660, 620 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H), 2.10 (s, 3 H), 2.29
(s, 6 H), 4.25–4.27 (d, J = 5.6 Hz, 1 H), 5.82–5.87 (m, 1 H), 7.00–
7.07 (m, 3 H), 7.27–7.29 (d, J = 8.7 Hz, 2 H).
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; mp 140 °C.
IR (KBr): 3325, 2230, 1716, 1655, 1537, 1366, 1230, 1040, 851,
596, 567 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.07 (s, 3 H), 2.16 (s, 3 H), 3.75
(s, 3 H), 4.09–4.11 (d, J = 5.0 Hz, 1 H), 5.73–5.78 (m, 1 H), 7.01–
7.04 (d, J = 8.7 Hz, 1 H), 7.40–7.43 (d, J = 8.7 Hz, 2 H), 7.61–7.64
(d, J = 8.2 Hz, 2 H).
N-[2-Acetyl-1-(4-cyanophenyl)-3-oxobutyl]acetamide (5h)
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 92% (soln), 90% (solvent-free); mp 165 °C.
N-[2-Acetyl-3-oxo-1-phenylbutyl]acetamide (5a)
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 91% (soln), 91% (solvent-free); mp 132–133 °C.
IR (KBr): 3265, 3000, 2960, 2240, 1720, 1700, 1660, 1610, 1550–
1470, 1420, 1370, 1420, 1370, 1360, 1310, 1290, 1250, 1210, 1170,
1155, 1100, 1080, 975, 890, 830, 770, 625, 600 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.03 (s, 3 H), 2.09 (s, 3 H), 2.33
(s, 3 H), 4.28–4.29 (d, J = 4.9 Hz, 1 H), 5.84–5.89 (m, 1 H), 7.06–
7.09 (d, J = 8.9 Hz, 1 H), 7.39–7.42 (d, J = 8.1 Hz, 2 H), 7.62–7.65
(d, J = 8.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3, proton-decoupled): d = 23.2, 29.8,
31.3, 51.3, 69.4, 111.7, 118.3, 127.2, 132.6, 144.7, 169.9, 201.9,
204.8.
IR (KBr): 3360, 2970, 1700, 1650, 1530, 1455, 1360, 1300, 1270,
1200, 1160, 1105, 955, 890, 760, 710, 620 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 (s, 3 H), 2.09 (s, 3 H), 2.27
(s, 3 H), 4.30–4.32 (d, J = 5.6 Hz, 1 H), 5.82–5.87 (m, 1 H), 7.10–
7.13 (d, J = 7.9 Hz, 1 H), 7.25–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3, proton decoupled): d = 23.2, 29.9, 31.0,
51.9, 70.4, 126.3, 127.8, 128.8, 139.2, 169.7, 202.6, 205.2.
MS (TOF): m/z = 270.01 [M+ + Na].
MS (TOF): m/z = 295.10 [M+ + Na].
Synthesis 2007, No. 2, 190–196 © Thieme Stuttgart · New York

196
R. Ghosh et al.
PAPER
(2) (a) Dähn, U.; Hagenmaier, H.; Höhne, H.; König, W. A.;
Wolf, G.; Zähner, H. Arch. Microbiol. 1976, 107, 249.
(b) Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44, 1709.
(3) (a) Aube, J. In Advances in Amino Acid Mimetics and
Peptidomimetics, Vol. 1; Abell, A., Ed.; JAI Press:
Greenwich CT, 1997. (b) Leung, D.; Abbenante, G.; Fairlie,
D. P. J. Med. Chem. 2000, 43, 305.
Anal. Calcd for C15H16O3N2: C, 66.16; H, 5.92; N, 10.28. Found: C,
65.99; H, 5.94; N, 10.04.
N-[2-Acetyl-1-(4-methoxyphenyl)-3-oxobutyl]acetamide (5i)4b
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 61% (soln), 62% (solvent-free); mp 150 °C.
IR (KBr): 3300, 3060, 2960, 2840, 1720, 1700, 1650, 1585, 1530,
1510, 1360, 1305, 1290, 1250, 1180, 1150, 1090, 1030, 970, 830,
735, 600 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H), 2.10 (s, 3 H), 2.23
(s, 3 H), 3.77 (s, 3 H), 4.24–4.26 (d, J = 6.1 Hz, 1 H), 5.76–5.81 (m,
1 H), 6.82–6.85 (d, J = 8.7 Hz, 2 H), 6.88–6.91 (d, J = 9.3 Hz, 1 H),
7.16–7.19 (d, J = 8.7 Hz, 2 H).
(4) (a) Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron
Lett. 1997, 38, 1083. (b) Reddy, M. M.; Bhatia, B.; Iqbal, J.
Tetrahedron Lett. 1995, 36, 4877. (c) Rao, I. N.;
Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003,
68, 4079. (d) Prabhakaran, E. N.; Iqbal, J. J. Org. Chem.
1999, 64, 3339. (e) Bahulayan, D.; Das, S. K.; Iqbal, J. J.
Org. Chem. 2003, 68, 5735. (f) Khodaei, M. M.;
Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005,
46, 2105. (g) Rao, N.; Prabhakaran, E. N.; Das, K. S.; Iqbal,
J. J. Org. Chem. 2003, 68, 4079.
N-[1-(1-Acetyl-2-oxopropyl)octyl]acetamide (5j)
White crystals [EtOAc–petroleum ether (bp 60–80 °C)]; yield (after
chromatography): 85% (soln), 92% (solvent-free); mp 118 °C.
(5) Ghosh, R.; Maiti, S.; Chakraborty, A. Synlett 2005, 115.
(6) (a) Leonard, N. M.; Wieland, L. C.; Mohan, R. S.
Tetrahedron 2002, 58, 8373. (b) Suzuki, H. In
IR (KBr): 3287, 2920, 2856, 1716, 1699, 1651, 1553, 1361, 1284,
1149, 1138 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.85–0.89 (t, J = 6.5 Hz, 3 H),
1.25–1.67 (m, 12 H), 1.93 (s, 3 H), 2.17 (s, 3 H), 2.29 (s, 3 H), 3.89–
3.91 (d, J = 4.0 Hz, 1 H), 4.60–4.67 (m, 1 H), 6.38–6.41 (d, J = 9.6
Hz, 1 H).
13C NMR (75 MHz, CDCl3, proton-decoupled): d = 14.0, 22.5,
23.2, 26.5, 29.1, 29.2, 29.8, 31.3, 31.7, 33.8, 48.6, 68.5, 169.9,
204.0, 205.8.
Organobismuth Chemistry; Suzuki, H.; Matano, Y., Eds.;
Elsevier: Amsterdam, 2001, Chap. 1, 18–20. (c) Huang,
Y.-Z.; Zhou, Z.-L. In Comprehensive Organometallic
Chemistry, Vol. 11; Abel, E. W.; Stone, F. G. A.; Wilkinson,
G., Eds.; Pergamon: Oxford, 1995, 502–513. (d) Suzuki,
H.; Ikegami, T.; Matano, Y. Synthesis 1997, 249.
(e) Marshall, J. A. Chemtracts 1997, 10, 1064. (f) Vidal, S.
Synlett 2001, 1194. (g) Komatsu, N. In Organobismuth
Chemistry; Suzuki, H.; Matano, Y., Eds.; Elsevier:
Armsterdam, 2001, Chap. 5, 371–440. (h) Orita, A.;
Tanahashi, C.; Kakuda, A.; Otera, J. Angew. Chem. Int. Ed.
2000, 39, 2877. (i) Orita, A.; Tanahashi, C.; Kakuda, A.;
Otera, J. J. Org. Chem. 2001, 66, 8926. (j) Le Roux, C.;
Dubac, J. Synlett 2002, 181. (k) Chakraborti, A. K.;
Gulhane, R.; Shivani Synlett 2003, 1805. (l) Ghosh, R.;
Maiti, S.; Chakraborty, A. Tetrahedron Lett. 2004, 45,
6775. (m) Ghosh, R.; Chakraborty, A.; Maiti, S.
MS (TOF): m/z = 292.18 [M+ + Na].
Anal. Calcd for C15H27NO3: C, 66.88; H, 10.10; N, 5.19. Found: C,
67.08; H, 10.08; N, 4.83.
Acknowledgment
The financial assistance from CSIR, New Delhi (Scheme Nos. 01/
1672/00/EMR-II and 01/1951/04/EMR-II) to R.G. and Senior Re-
search Fellowship to S.M. are gratefully acknowledged. The au-
thors are also thankful to FIST-DST (India) for supporting the
Department of Chemistry, Jadavpur University with NMR faci-
lities.
Tetrahedron Lett. 2004, 45, 9631.
(7) Crystallographic data of the compound pref-16 has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 601470.
Copies of the data can be obtained free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(1223)336033 or e-mail:
References
(1) (a) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R.
J.; Steele, J. Tetrahedron 1995, 51, 8135. (b) Armstrong, R.
W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T.
A. Acc. Chem. Res. 1996, 29, 123. (c) Thomson, L. A.;
Ellman, J. A. Chem. Rev. 1996, 96, 555. (d) Tietze, L. F.;
Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363.
deposit@ccdc.cam.ac.uk].
(e) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (f) Multicomponent Reactions; Zhu, J.; Bienaymé, H.,
Eds.; Wiley-VCH: Weinheim, 2005.
Synthesis 2007, No. 2, 190–196 © Thieme Stuttgart · New York