ZrOCl2·8H2O: an efficient Lewis acid catalyst for the one-pot multicomponent synthesis of β-acetamido ketones

Article abstract of DOI:10.1016/j.tet.2006.02.037

Aromatic aldehydes were reacted in one-pot with enolisable ketones, acetonitrile and acetyl chloride at ambient temperature in the presence of ZrOCl₂·8H₂O to furnish the corresponding β-acetamido ketones in very good to excellent yie

Full text of DOI:10.1016/j.tet.2006.02.037

Tetrahedron 62 (2006) 4059–4064
ZrOCl2$8H2O: an efficient Lewis acid catalyst for the one-pot
multicomponent synthesis of b-acetamido ketones
a
a
Rina Ghosh,a, Swarupananda Maiti, Arijit Chakraborty,
*
Santu Chakrabortyb and Alok K. Mukherjeeb
aDepartment of Chemistry, Jadavpur University, Kolkata 700 032, India
bDepartment of Physics, Jadavpur University, Kolkata 700 032, India
Received 6 October 2005; revised 24 January 2006; accepted 9 February 2006
Abstract—Aromatic aldehydes were reacted in one-pot with enolisable ketones, acetonitrile and acetyl chloride at ambient temperature in
the presence of ZrOCl2$8H2O to furnish the corresponding b-acetamido ketones in very good to excellent yields. X-ray crystallographic
analysis of one anti-b-acetamido ketone exhibited a two-dimensional supramolecular framework by a combination of N–H/O, C–H/O
and C–H/p (arene) hydrogen bonds.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
prompted to explore the efficacy of ZrOCl2$8H2O as an
activator for the one-pot synthesis of b-acetamido ketones
from aromatic aldehydes, enolisable ketones, acetyl
chloride and acetonitrile.
Due to several advantages over conventional multi-step
synthesis and also because of their promising applications in
pharmaceutical chemistry for the generation of structural
scaffolds and combinatorial libraries for drug development,1
one-pot multicomponent reactions have recently drawn the
attractionoforganicchemists.b-Acetamidoor-aminoketones
are potential intermediates for the generation of b-amino
alcohols2—structural units common in natural nucleoside
antibiotics such as nikkomycins or neopolyoxins.3
2. Results and discussions
2.1. Synthesis
Under the optimized reaction conditions (Table 1, Scheme 1),
benzaldehyde (1, w1 equiv) reacted at room temperature
with acetophenone (11, w1 equiv), acetyl chloride
(w2 equiv) and acetonitrile (reagent as well as solvent) in
the presence of ZrOCl2$8H2O (w20 mol%) to furnish the
corresponding b-acetamido ketone (15) in excellent yield
(90%, entry 2, Table 1 and entry 1, Table 2). Other
benzaldehyde derivatives containing electron-withdrawing
(entries 5–7, Table 2) and -donating groups (entries 8–10 and
12, Table 2) in the aromatic ring also reacted with
acetophenone (11), acetyl chloride and acetonitrile affording
the corresponding b-acetamido ketones (16–21 and 23) in
very high to excellent yields with concomitant acetylation of
The reported one-pot syntheses of the title compounds from
aldehydes, enolisable ketones, acetyl chloride and aceto-
nitrile are based on CoCl2,4a,b Montmorillonite K-10 Clay,4c
4d
SiO2–H2SO4 or BiCl3 generated in situ from BiOCl and
acetyl chloride.5 Recently, because of the easy availability
in earth crust6 and low toxicity,7 Zr(IV) compounds,
especially ZrCl4 have received considerable attention in
various organic reactions,8 but reported zirconium oxy-
chloride based reactions are only a few.9 In one of our
earlier reports we have established for the first time that
ZrOCl2$8H2O acts as an efficient Lewis acid catalyst for
acylation of alcohols, phenols, amines, thiol and thiophe-
nols.9a In further continuation to our ongoing research on
metal oxysalt-based organic reactions5,9a,10 we were
Table 1. Standardisation of reaction condition
Entry
Metal salts (mol%)
Time (h)
Yield of
product (%)
Keywords: One-pot multicomponent synthesis; ZrOCl2$8H2O; Lewis acid
catalyzed; b-Acetamido ketone.
1
2
3
ZrOCl2$8H2O (15)
ZrOCl2$8H2O (20)
ZrCl4 (20)
12
5
5
83
90
87
*
Corresponding author: Fax: 91 033 24734266; e-mail: ghoshrina@ya-
hoo.com
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.037

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R. Ghosh et al. / Tetrahedron 62 (2006) 4059–4064
anti-isomers (entries 16 and 17, Table 2). Similarly,
R3
R2
O
R3
R5
R6CN, MeCOCl
propiophenone (14) was equally a good substrate to react
separately with benzaldehyde (1), p-chloro-(5), o-nitro-
benzaldehyde (2), p-tolualdehyde (8) or vanilin (9) in the
presence of other components affording the corresponding
b-acetamido ketones (28–32, entries 18–22, Table 2) with
concomitant acetylation of the phenolic –OH groups of the
products in relevant system (entry 22, Table 2), but the
reactions were either not diastereoselective (entries 18–20) or
proceeded with poor diastereoselectivity (entries 21 and 22).
The reaction of salicylaldehyde (10) with propiophenone (14)
and other components was, however, tricky; only 31% of the
desired acetylated product (33) could be isolated (entry 23).
The preparative efficacy of this one-pot synthesis was further
checked by scaling-up (w10 folds) of the reaction of
benzaldehyde (1) with acetophenone (11) and other ingre-
dients in solvent as well as in solvent-free conditions (entries
2 and 3, Table 2), which proceeded in 92 and 93% respective
yields. The reaction also proceeded with equal efficacy (entry
4, Table 2) with the recovered and isolated ZrOCl2$8H2O. It
may be mentioned here that a mixture of benzaldehyde (1),
+
R4
R4
CHO
20 mol% ZrOCl2.8H2O, r.t.
R2
R5
O6
R1
R1
NHCR
O
Scheme 1.
the m-hydroxy benzaldehyde derived product (entry 10,
Table 2). p-Dimethylaminobenzaldehyde, however, was inert
to the present reaction conditions. Other enolisable ketones
(a-unsubstituted and -substituted, 12–14) also served as good
substrates for the present one-pot synthesis. Thus, the reaction
of benzaldehyde (1) with p-methoxyacetophenone (12),
acetyl chloride and acetonitrile in the presence of ZrOCl2$8-
H2O proceeded efficiently resulting in the desired product
(22) in 92% yield (entry 11, Table 2). a-Substituted enolisable
ketones such as ethyl methyl ketone (13) also reacted with
benzaldehyde (1) or p-tolualdehyde (8) resulting in
high yields of the title compounds (26 and 27), although,
with moderate or poor diastereoselectivity in favour of the
Table 2. ZrOCl2$8H2O catalyzed one-pot synthesis of b-acetamido ketone
R3
O
R3
R2
R5
R6CN, MeCOCl
20 mol% ZrOCl2.8H2O, r.t.
+
R4
R4
R2
CHO
R5
R1
O
R1
NHCR6
1-10
O
11, R4 = Ph, R5 = H
15-30
12, R4 = p-OMe-C6H4-, R5 = H
13, R4 = Me, R5 = Me
14, R4 = Ph, R5 = Me
Entry
Aromatic aldehyde
b-Acetamido ketone
Time (h)
Yield (%)a
syn/anti
1
2
3
4
5
6
7
8
R1ZR2ZR3ZH (1)
R1ZR2ZR3ZH (1)
R1ZR2ZR3ZH (1)
R1ZR2ZR3ZH (1)
R1ZR2ZR3ZR5ZH, R4ZPh, R6ZMe (15)
R1ZR2ZR3ZR5ZH, R4ZPh, R6ZMe (15)
R1ZR2ZR3ZR5ZH, R4ZPh, R6ZMe (15)
R1ZR2ZR3ZR5ZH, R4ZPh, R6ZMe (15)
5
5
5
5
12
6
7
8
7
4.5
4
90
92b
93c
90d
85
92
69
91
92
92
92
94
61
86e
89f
86
81
94
83
80
94
74
31
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
R1ZNO2, R2ZR3ZH (2)
R2ZNO2, R1ZR3ZH (3)
R3ZNO2, R1ZR2ZH (4)
R1ZR2ZH, R3ZCl (5)
R1ZR2ZH, R3ZOMe (6)
R1ZR3ZH, R2ZOH (7)
R1ZR2ZR3ZH (1)
R1ZNO2, R2ZR3ZR5ZH, R4ZPh, R6ZMe (16)
R2ZNO2, R1ZR3ZR5ZH, R4ZPh, R6ZMe (17)
R3ZNO2, R1ZR2ZR5ZH, R4ZPh, R6ZMe (18)
R1ZR2ZR5ZH, R3ZCl, R4ZPh, R6ZMe (19)
R1ZR2ZR5ZH, R3ZOMe, R4ZPh, R6ZMe (20)
R1ZR3ZR5ZH, R2ZOAc, R4ZPh, R6ZMe (21)
R1ZR2ZR3ZR5ZH, R4Zp-MeO–C6H4, R6ZMe (22)
R1ZR2ZR5ZH, R4ZPh, R3ZR6ZMe (23)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
R3ZMe, R1ZR2ZH (8)
R2ZNO2, R1ZR3ZH (3)
R2ZNO2, R1ZR3ZH (3)
R2ZNO2, R1ZR3ZH (3)
R1ZR2ZR3ZH (1)
4
R1ZR3ZR5ZH, R2ZNO2, R4Zp-OMe–C6H4, R6ZMe (24)
R2ZNO2, R1ZR3ZR5ZH, R4ZR6ZPh (25)
R2ZNO2, R1ZR3ZR5ZH, R4ZR6ZPh (25)
R1ZR2ZR3ZH, R4ZR5ZR6ZMe (26)
48
36
36
2
3.5
6
2
10
4
1:4.5g
1:1.6g
1.1:1h
1:1h
1.1:1h
2.2:1g
1.5:1h
1:1h
R1ZR2ZH, R3Z Me (8)
R1ZR2ZR3ZH (1)
R1ZR2ZH, R3ZR4ZR5ZR6ZMe (27)
R1ZR2ZR3ZH, R4ZPh, R5ZR6ZMe (28)
R1ZR2ZH, R3ZCl, R4ZPh, R5ZR6ZMe (29)
R1ZNO2, R2ZR3ZH, R4ZPh, R5ZR6ZMe (30)
R1ZR2ZH, R3ZR5ZR6ZMe, R4ZPh (31)
R1ZH, R2ZOMe, R3ZOAc, R4ZPh, R5ZR6ZMe (32)
R1ZOAc, R2ZR3ZH, R4ZPh, R5ZR6ZMe (33)
R1ZR2ZH, R3ZCl (5)
R1ZNO2, R2ZR3ZH (2)
R1ZR2ZH, R3ZMe (8)
R1ZH, R2ZOMe, R3ZOH (9)
R1ZOH, R2ZR3ZH (10)
12
11
a Chromatographed yield.
b Scale-up experiment (w10 fold).
c Under neat condition (w10 fold).
d
e
f
9
2
With recovered ZrOCl $8H2O.
2
Using PhCN (w2 equiv) in CH Cl2.
Using PhCN (w3 equiv) in neat condition.
g Ratio of methine protons of syn and anti isomers (by 1H NMR).
h Ratio of isolated yields (by preparative TLC) of syn and anti isomers.

R. Ghosh et al. / Tetrahedron 62 (2006) 4059–4064
4061
acetophenone (11), acetyl chloride and aceonitrile in the
presence of ZrCl4 (w20 mol%) also produced the corre-
sponding b-acetamido ketone (15) in excellent yield (entry 3,
Table 1), but ZrOCl2$8H2O was the catalyst of choice
because of its moisture stability, recoverability and reusability
without any loss of the catalytic activity.
a combination of N–H/O, C–H/O and C–H/p (arene)
hydrogen bonds.
3. Conclusion
The efficacy of ZrOCl2$8H2O for the one-pot generation of
b-acetamido ketones from aromatic aldehyde, enolisable
ketone, acetyl chloride and acetonitrile in solvent as well as
in solvent-free conditions has been established. The special
feature of the present procedure lies in the easy availability,
low toxicity, moisture compatibility, recoverability and
reusability of the catalyst. Although, it exhibits very low to
moderate diastereoselectivity but very high to excellent
yields of the products make this procedure a suitable
competitor with the other existing methodologies particu-
larly for the synthesis of b-acetamido ketones based on
a-unsubstituted ketones. X-ray structure analysis of one
model anti-isomer exhibits two-dimensional supramolecu-
lar assembly by a combination of N–H/O, C–H/O and
C–H/p (arene) intermolecular interactions.
Unlike our earlier report on BiOCl based one-pot synthesis
of b-acetamido ketones5 a mixture of m-nitrobenzaldehyde
(3), acetophenone (11), benzoyl chloride in the presence of
acetonitrile and ZrOCl2$8H2O failed to generate the
corresponding b-acetamido ketone even after 7 days. But,
the use of a different nitrile such as benzonitrile in solvent
(CH2Cl2) or solvent-free conditions (entries 14 and 15) in a
mixture of benzaldehyde, acetophenone and acetyl chloride
in the presence of ZrOCl2$8H2O (w20 mol%) could lead to
the expected product (25) in similar yields as with the
acetonitrile counterpart (entry 1, Table 2) although these
reactions proceeded with a much slower rate.
A mixture of chalcone (w1 equiv), acetyl chloride
(w2 equiv) and ZrOCl2$8H2O (20 mol%) in acetonitrile
failed to produce any b-acetamido ketone (15). Thus, this
reaction also follows a similar mechanistic pathway as
described in our earlier report of the one-pot synthesis based
on BiOCl.5 It is also noteworthy to mention that neither a
mixture of benzaldehyde, acetophenone, acetic anhydride
and ZrOCl2$8H2O in acetonitrile nor a mixture of
benzaldehyde acylal, acetophenone and ZrOCl2$8H2O in
acetonitrile could generate any of the corresponding
b-acetamido ketone (15) even after stirring each mixture
for a prolonged time.
4. Experimental
4.1. General
All melting points are uncorrected. IR spectra were recorded
on Perkin Elmer 297 spectrophotometer. NMR spectra were
recorded on Bruker DPX-300/Mercury 400/Unity 500
spectrometer using CDCl3 as solvent and TMS as the
internal standard. Elemental analyses were performed on a
Perkin Elmer auto analyzer 2400 II.
2.2. X-ray crystallographic study of anti-31
The structures of the anti-isomers were confirmed by the
X-ray crystallographic analysis of one model anti-isomer
(anti-31). Single crystals of anti-31 were grown by slow
crystallization from a solution of EtOAc–hexane. The
molecular view of compound anti-31 is shown in Figure 1.
The torsion angles C1–C7–C8–C10 K158.7(1)8 and
C7–C8–C10–C13 K179.0(1)8 indicate that the propyl
chain connecting the two nearby planar phenyl rings,
C1–C6 and C13–C18, is almost straight; the dihedral angles
between the two phenyl rings is 44.98(3)8. The crystal
packing of anti-31 reveals that the molecules are linked
into two-dimensional supramolecular framework by
4.2. General experimental procedure
(a) In solution. To a solution of aldehydes (w1 mmol) and
acetophenone (w1 mmol) in dry acetonitrile (4 mL) was
added ZrOCl2$8H2O (w20 mol%). To the resulting
suspension was finally added acetyl chloride (w2 mmol)
and the reaction mixture was stirred at ambient temperature.
After the completion of the reaction (checked by TLC with
EtOAc-pet.ether (60-80 8C) the mixture was diluted with
CH2Cl2 (20 mL), washed with brine solution (1!20 mL)
and the aqueous layer was then extracted with CH2Cl2 (3!
15 mL). The combined organic layer was washed with
NaHCO3 solution (1!15 mL) followed by water (1!
20 mL). The organic layer was dried over Na2SO4,
concentrated to dryness and the crude residue was purified
on silica gel column after elution with 3:2 EtOAc–pet. ether
(60-80 8C). Mixture of diastereomers were separated by
preparative TLC on silica plates using 1:2 EtOAc–pet. ether
(60-80 8C).
(b) In solvent-free conditions. To a mixture of aromatic
aldehydes (w1 mmol), acetophenone (w1 mmol) and dry
acetonitrile (w3 mmol) was added ZrOCl2$8H2O
(w20 mmol). Finally, acetyl chloride (w2 mmol) was
added and the reaction mixture was stirred at ambient
temperature. After completion of the reaction, it was diluted
with CH2Cl2 (15 mL) and then worked-up as described
in (a).
Figure 1. ORTEP diagram of single crystal of anti-31.

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R. Ghosh et al. / Tetrahedron 62 (2006) 4059–4064
4.2.1. N-(3-Oxo-1,3-diphenyl-propyl)-acetamide (15).4c
(Yield 240 mg, 90%). White crystals, (EtOAc-pet.ether,
60-80 8C) mp 104–105 8C, (lit.4c mp 102–104 8C). 1H NMR
(300 MHz, CDCl3): d 2.03 (s, 3H), 3.40–3.48 (dd, JZ6.0,
16.9 Hz, 1H), 3.72–3.79 (dd, JZ5.1, 16.9 Hz, 1H),
5.53–5.60 (m, 1H), 6.68–6.70 (br d, JZ7.5 Hz, 1H),
7.22–7.35 (m, 5H), 7.42–7.47 (m, 2H), 7.54–7.58 (m, 1H),
7.88–7.91 (m, 2H). 13C NMR (50 MHz, CDCl3): d 23.5,
43.3, 50.0, 126.6, 127.5, 128.2, 128.7, 128.8, 133.6, 136.7,
141.6, 169.6, 199.3.
(d, JZ7.2 Hz, 1H), 6.80–6.84 (m, 2H), 7.23–7.25 (d,
JZ8.8 Hz, 2H), 7.41–7.45 (t, JZ7.8 Hz, 2H), 7.53–7.57
(t, JZ7.6 Hz, 1H), 7.88–7.91 (d, JZ8 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d 23.6, 43.6, 49.8, 55.5, 114.2, 127.9,
128.3, 128.9, 133.3, 133.6, 136.9, 159.1, 169.6, 198.8.
4.2.7. N-[1-(3-Acetoxy-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (21).4c (Yield 299 mg, 92%). White crystals,
(EtOAc-pet.ether, 60-80 8C) mp 114–115 8C, (lit.4c mp
1
114–115 8C). H NMR (400 MHz, CDCl3): d 1.99 (s, 3H),
2.26 (s, 3H), 3.39–3.45 (dd, JZ5.8, 17.0 Hz, 1H), 3.68–3.74
(dd, JZ5.6, 17.2 Hz, 1H), 5.53–5.58 (m, 1H), 6.73–6.75 (br
d, JZ8.4 Hz, 1H), 6.95–6.98 (dd, JZ2.2, 7.8 Hz, 1H),
7.08–7.09 (t, JZ2.0 Hz, 1H), 7.17–7.19 (d, JZ8.0 Hz, 1H),
7.27–7.31 (t, JZ7.8 Hz, 1H), 7.42–7.46 (m, 2H), 7.53–7.57
(m, 1H), 7.88–7.89 (d, JZ7.6 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d 21.3, 23.6, 43.2, 49.7, 120.1, 120.9,
124.2, 128.3, 128.9, 129.8, 133.79, 136.8. 143.0, 151.1,
169.5, 169.7, 198.5.
4.2.2. N-[1-(2-Nitro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (16).4c (Yield 265 mg, 85%). Off white crystals,
(EtOAc-pet.ether, 60-80 8C) mp 191–192 8C, (lit.4c mp
186–188 8C). 1H NMR (200 MHz, CDCl3): d 2.02 (s,
3H), 3.60–3.69 (m, 2H), 5.96–5.99 (m, 1H), 7.09 (s, 1H),
7.37–7.50 (m, 3H), 7.56–7.59 (m, 2H), 7.71–7.74 (m, 1H),
7.93–7.96 (m, 3H). 13C NMR (50 MHz, CDCl3): d 23.4,
42.3, 47.5, 125.2, 128.4, 128.5, 128.9, 129.9, 133.6, 133.9,
136.3, 136.8, 148.5, 169.5, 198.7.
4.2.3. N-[1-(3-Nitro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (17).4c (Yield 287 mg, 92%). White crystals,
(EtOAc/pet. ether, 60:80) mp 139–140 8C, (lit.5 mp
4.2.8. N-[3-(4-Methoxy-phenyl)-3-oxo-1-phenyl-propyl]-
acetamide (22). (Yield 273 mg, 92%). White crystals,
(EtOAc-pet.ether, 60-80 8C) mp 130 8C. IR (KBr): 3260,
1
1
139–140 8C). H NMR (300 MHz, CDCl3): d 2.08 (s, 3H),
1680, 1640, 1600, 1570, 1255, 1170, 990, 700 cmK1. H
3.47–3.55 (dd, JZ5.4, 17.5 Hz, 1H), 3.77–3.84 (dd, JZ4.9,
17.5 Hz, 1H), 5.63–5.69 (m, 1H), 6.95–6.98 (d, JZ7.5 Hz,
1H), 7.44–7.51 (m, 3H), 7.57–7.62 (t, JZ7.3 Hz, 1H),
7.70–7.73 (d, JZ7.5 Hz, 1H), 7.88–7.90 (br d, JZ7.3 Hz,
2H), 8.07–8.10 (d, JZ8.1 Hz, 1H), 8.22 (br s, 1H). 13C
NMR (50 MHz, CDCl3): d 23.5, 43.0, 49.2, 121.4, 122.4,
128.2, 128.9, 129.6, 133.2, 134.1, 136.3, 143.7, 148.4,
169.9, 198.0.
NMR (300 MHz, CDCl3): d 2.00 (s, 3H), 3.31–3.39 (dd, JZ
5.9, 16.6 Hz, 1H), 3.64–3.71 (dd, JZ5.3, 16.6 Hz, 1H), 3.84
(s, 3H), 5.50–5.57 (m, 1H), 6.86 (br s, 1H), 6.89 (br d, JZ
8.8 Hz, 2H), 7.18–7.34 (m, 5H), 7.88 (br d, JZ8.8 Hz, 2H).
13C NMR (75 MHz, CDCl3): d 23.4, 42.8, 50.0, 55.5, 113.8,
126.4, 127.3, 128.5, 129.7, 130.4, 141.1, 163.8, 169.5,
197.1. Anal. Calcd for C18H19O3N: C, 72.71; H, 6.44; N,
4.71; Found: C, 72.65; H, 6.82; N, 4.67.
4.2.4. N-[1-(4-Nitro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (18).4c (Yield 215 mg, 69%). White amorphous
solid, (EtOAc-pet.ether, 60-80 8C) mp 154 8C, (lit.4c mp
4.2.9. N-[1-(4-Methyl-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (23). (Yield 264 mg, 94%). White crystals,
(EtOAc-pet.ether, 60-80 8C) mp 112 8C. IR (KBr): 3295,
1
148–149 8C). H NMR (300 MHz, CDCl3): d 2.08 (s, 3H),
1
1680, 1650, 1550, 1350, 1200, 810, 755, 690 cmK1. H
3.46–3.54 (dd, JZ5.4, 17.6 Hz, 1H), 3.77–3.85 (dd, JZ4.8,
17.6 Hz, 1H), 5.6–5.7 (m, 1H), 6.96–6.98 (d, JZ7.7 Hz,
1H), 7.44–7.62 (m, 5H), 7.87–7.90 (d, JZ7.3 Hz, 2H),
8.15–8.18 (d, JZ8.6 Hz, 2H). 13C NMR (50 MHz, CDCl3):
d 23.5, 42.7, 49.3, 123.9, 127.5, 128.2, 128.9, 134.1, 136.2,
147.1, 148.8, 174.2, 198.1.
NMR (CDCl3, 300 MHz): d 2.02 (s, 3H), 2.30 (s, 3H), 3.39–
3.47 (dd, JZ6.2, 16.7 Hz, 1H), 3.71–3.78 (dd, JZ5.1,
16.7 Hz, 1H), 5.49–5.56 (m, 1H), 6.61–6.63 (d, JZ7.2 Hz,
1H), 7.10–7.23 (m, 4H), 7.42–7.59 (m, 3H), 7.90–7.93 (d,
JZ7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): d 20.8, 23.2,
43.1, 49.6, 126.2, 127.9, 128.5, 129.2, 133.3, 136.5, 136.9,
137.7, 169.4, 198.4. Anal. Calcd for C18H19O2N: C, 76.84;
H, 6.80; N, 4.97; Found: C, 76.94; H, 7.18; N, 4.90.
4.2.5. N-[1-(4-Chlorophenyl)-3-oxo-3-phenyl-propyl]-
acetamide (19).4a (Yield 274 mg, 91%). White crystals,
(EtOAc-pet.ether, 60-80 8C) mp 149–150 8C, (lit.4a mp
150 8C). 1H NMR (400 MHz, CDCl3): d 2.00 (s, 3H), 3.37–
3.43 (dd, JZ5.6, 17.2 Hz, 1H), 3.69–3.74 (dd, JZ4.8,
17.1 Hz, 1H), 5.49–5.54 (m, 1H), 6.81–6.83 (d, JZ7.6 Hz,
1H), 7.27 (s, 4H), 7.42–7.46 (t, JZ7.8 Hz, 2H), 7.54–7.58
(t, JZ7.2 Hz, 1H), 7.87–7.89 (d, JZ8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d 23.6, 43.1, 49.5, 128.1, 128.3, 128.9,
129.0, 133.4, 133.9, 136.7, 139.8, 169.7, 198.6.
4.2.10. N-[3-(4-Methoxy-phenyl)-1-(3-nitro-phenyl)-3-
oxo-propyl]-acetamide (24). (Yield 209 mg, 61%). White
crystals, (EtOAc-pet.ether, 60-80 8C) mp 132 8C. IR (KBr):
3300, 3065, 2840, 1665, 1645, 1600, 1520, 1350, 1255,
1240, 1170, 1020, 990, 820, 805, 735, 660 cmK1. 1H NMR
(300 MHz, CDCl3): d 2.08 (s, 3H), 3.39–3.47 (dd, JZ5.3,
17.2 Hz, 1H), 3.70–3.78 (dd, JZ5.0, 17.2 Hz, 1H), 3.86 (s,
3H), 5.60–5.66 (m, 1H), 6.90–6.94 (d, JZ8.7 Hz, 2H),
7.05–7.07 (d, JZ7.9 Hz, 1H), 7.45–7.50 (t, JZ7.9 Hz, 1H),
7.69–7.71 (d, JZ7.6 Hz, 1H), 7.86–7.88 (d, JZ8.6 Hz, 2H),
8.07–8.09 (d, JZ8.1 Hz, 1H), 8.20 (s, 1H). 13C NMR
(75 MHz, CDCl3): d 23.3, 42.1, 49.1, 55.4, 113.8, 121.1,
122.1, 129.1, 129.3, 130.3, 132.7, 143.4, 164.0, 169.6,
192.9, 196.4. Anal. Calcd for C18H18O5N2: C, 63.15; H,
5.29; N, 8.18; Found: C; 63.27, H; 5.03, N, 7.98.
4.2.6. N-[1-(4-Methoxy-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (20).4d (Yield 273 mg, 92%). White crystals,
(EtOAc-pet.ether 60-80 8C) mp 110–112 8C. IR (KBr):
3310, 1690, 1650, 1550, 1510, 1240, 1030, 760, 690 cmK1
.
1H NMR (400 MHz, CDCl3): d 1.98 (s, 3H), 3.36–3.42 (dd,
JZ6.4, 17.2 Hz, 1H), 3.69–3.75 (dd, JZ5.6, 17.2 Hz, 1H),
3.74 (s, 3H), 5.47–5.51 (dd, JZ6, 13.2 Hz, 1H), 6.64–6.66

R. Ghosh et al. / Tetrahedron 62 (2006) 4059–4064
4063
4.2.11. N-[1-(3-Nitro-phenyl)-oxo-3-phenyl-propyl]-
benzamide (25). (Yield 322 mg, 86%). White crystals,
(EtOAc-pet.ether, 60-80 8C) mp 194–195 8C. IR (KBr):
(d, JZ7.0 Hz, 3H), 2.12 (s, 3H), 4.05–4.08 (m, 1H), 5.31–
5.35 (m, 1H), 7.19 (s, 4H), 7.39–7.44 (t, JZ7.6 Hz, 2H),
7.53–7.58 (t, JZ7.2 Hz, 1H), 7.55 (s, 1H, exchangeable,
1
3290, 2930, 1685, 1635, 1525, 1355, 1225, 760, 730 cmK1
.
–NH), 7.74–7.77 (d, JZ7.5 Hz, 2H). H NMR (300 MHz,
1H NMR (300 MHz, CDCl3): d 3.57–3.64 (dd, JZ5.4,
17.4 Hz, 1H), 3.87–3.95 (dd, JZ4.9, 17.4 Hz, 1H), 5.83–
5.88 (m, 1H), 7.44–7.62 (m, 7H), 7.78 (br d, JZ7.8 Hz, 1H),
7.84–7.93 (m, 5H), 8.10 (br d, JZ8.1 Hz, 1H), 8.28 (s, 1H).
13C NMR (75 MHz, CDCl3): d 42.5, 49.6, 121.39, 122.5,
127.1, 128.2, 128.7, 128.9, 129.6, 131.9, 132.9, 133.7,
134.1, 136.2, 143.5, 166.9, 198.6. Anal. Calcd for
C22H18N2O4: C, 70.57; H, 4.84; N, 7.48; Found: C, 70.16;
H, 4.96; N, 7.23.
CDCl3, D2O-exchange): d 1.37–1.39 (d, JZ7.2 Hz, 3H),
2.12 (s, 3H), 4.04–4.08 (dd, JZ3.9, 7.1 Hz, 1H), 5.32–5.33
(d, JZ3.7 Hz, 1H), 7.18(s, 4H), 7.38–7.40 (m, 2H),
7.52–7.57 (t, JZ7.3 Hz, 1H), 7.74–7.76 (d, JZ7.3 Hz, 2H).
syn-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
1
164 8C. H NMR (300 MHz, CDCl3): d 1.21 1.23 (d, JZ
6.8 Hz, 3H), 2.01 (s, 3H), 4.00–4.07 (m, 1H), 5.38–5.43 (t,
JZ7.3 Hz, 1H), 6.03–6.05 (d, JZ6.0 Hz, 1H, exchange-
able, –NH), 7.28 (s, 4H), 7.42–7.62 (m, 3H), 7.89–7.92 (d,
JZ7.6 Hz, 2H).
4.2.12. N-1-[2-Methyl-3-oxo-1-phenyl-butyl]-acetamide
(26).4c (Yield 188 mg, 86%).
1H NMR (300 MHz, CDCl3, D2O-exchange): d 1.19–1.21
(d, JZ6.9 Hz, 3H), 1.98 (s, 3H), 3.99–4.04 (t, JZ7 Hz, 1H),
5.37–5.39 (d, JZ6.9 Hz, 1H), 7.25 (s, 4H), 7.44–7.49 (m,
2H), 7.55–7.60 (m, 1H), 7.87–7.89 (d, JZ7.3 Hz, 2H).
anti-Isomer: (liquid). 1H NMR (300 MHz, CDCl3): d
1.08–1.10 (d, JZ7.1 Hz, 3H), 1.98 (s, 3H), 2.07 (s, 3H),
3.00–3.07 (m, 1H), 5.34–5.39 (t, JZ6.9 Hz, 1H), 6.29–6.32
(d, JZ7.9 Hz, 1H), 7.20–7.31 (m, 5H).
4.2.16. N-[2-Methyl-1-(2-nitro-phenyl)-3-oxo-3-phenyl-
propyl]-acetamide (30).4c (Yield 261 mg, 80%).
syn-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
126 8C, (lit.4c mp 126–127 8C). 1H NMR (300 MHz,
CDCl3): d 1.19–1.22 (d, JZ7.2 Hz, 3H), 1.96 (s, 3H),
2.05 (s, 3H), 3.08–3.17 (m, 1H), 5.13–5.18 (dd, JZ8.9,
5.3 Hz, 1H), 6.91–6.94 (d, JZ7.7 Hz, 1H), 7.2–7.3 (m, 5H).
anti-Isomer: off white crystals, (EtOAc-pet.ether, 60-80 8C)
1
mp 142 8C, (lit.4c mp 122–124 8C). H NMR (300 MHz,
CDCl3): d 1.43–1.46 (d, JZ7.1 Hz, 3H), 2.09 (s, 3H),
4.13–4.40 (m, 1H), 5.78–5.82 (dd, JZ3.6, 8.0 Hz, 1H),
7.28–7.95 (m, 10H).
4.2.13. N-[2-Methyl-1-(4-methyl-phenyl)-3-oxo-butyl]-
acetamide (27).4c (Yield 189 mg, 81%).
1
syn-Isomer: oil, H NMR (300 MHz, CDCl3): d 1.25–1.27
(d, JZ7.0 Hz, 3H), 2.02 (s, 3H), 4.42–4.47 (m, 1H),
5.71–5.76 (t, JZ7.9 Hz, 1H), 6.64–6.66 (d, JZ6.7 Hz, 1H),
7.35–7.93 (m, 9H).
anti-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
162 8C. H NMR (300 MHz, CDCl3): d 1.19–1.22 (d, JZ
7.2 Hz, 3H), 1.97 (s, 3H), 2.05 (s, 3H), 2.59 (s, 3H),
3.11–3.16 (m, 1H), 5.12–5.17 (m, 1H), 6.18–6.25 (d, JZ
12.6 Hz, 1H), 7.21–7.97 (m, 4H).
1
4.2.17. N-[2-Methyl-1-(4-methyl-phenyl)-3-oxo-3-phenyl-
propyl]-acetamide (31). (Yield 278 mg, 94%).
syn-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
1
134 8C, (lit.4c mp 134 8C). H NMR (300 MHz, CDCl3): d
1.18–1.20 (d, JZ7.1 Hz, 3H), 2.03 (s, 3H), 2.08 (s, 3H),
2.31 (s, 3H), 3.08–3.12 (m, 1H), 5.10–5.15 (m, 1H),
6.83–6.86 (d, JZ7.9 Hz, 1H), 7.12 (s, 4H).
anti-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
170 8C. IR (KBr): 3313, 2987, 1685, 1647, 1543, 1367,
1142, 970, 702 cmK1 1H NMR (300 MHz, CDCl3): d
.
1.36–1.38 (d, JZ7.16 Hz, 3H), 2.10 (s, 3H), 2.24 (s, 3H),
4.05–4.14 (m, 1H), 5.33–5.37 (m, 1H), 7.01–7.04 (d, JZ
7.93 Hz, 2H), 7.11–7.14 (d, JZ8.01 Hz, 2H), 7.37–7.56 (m,
4H), 7.76–7.79 (d, JZ7.68 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d 16.5, 20.9, 23.3, 44.4, 55.5, 126.2, 128.2, 128.6,
129.1, 133.4, 136.4, 136.7, 137.8, 169.9, 204.9. Anal. Calcd
for C19H21O2N: C, 77.25; H, 7.16; N, 4.74; Found: C, 77.23;
H, 7.14; N, 4.48.
4.2.14. N-(2-Methyl-3-oxo-1,3-diphenyl-propyl)-acet-
amide (28).4c (Yield 264 mg, 94%).
anti-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
1
174 8C, (lit.4c mp 140 8C). H NMR (300 MHz, CDCl3): d
1.38–1.40 (d, JZ7.1 Hz, 3H), 2.13 (s, 3H), 4.07–4.16 (m,
1H), 5.37–5.41 (dd, JZ3.8, 8.9 Hz, 1H), 7.16–7.54 (m, 9H),
7.75–7.77 (d, JZ7.4 Hz, 2H).
syn-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C) mp
119 8C. IR (KBr): 3240, 3055, 1678, 1639, 1553, 1371,
syn-Isomer: white crystal. (EtOAc-pet.ether, 60-80 8C) mp
120 8C. H NMR (300 MHz, CDCl3): d 1.21–1.24 (d, JZ
1
1290, 972, 710 cmK1 1H NMR (300 MHz, CDCl3): d
.
6.9 Hz, 3H), 2.00 (br s, 3H), 4.03–4.13 (m, 1H), 5.45–5.50
(t, JZ7.7 Hz, 1H), 5.99–6.02 (d, JZ5.9 Hz, 1H), 7.23–7.60
(m, 8H), 7.90–7.93 (d, JZ7.3 Hz, 2H).
1.20–1.22 (d, JZ6.96 Hz, 3H), 1.98 (s, 3H), 2.29 (s, 3H),
4.00–4.14 (m, 1H), 5.41–5.46 (t, JZ7.64 Hz, 1H),
5.99–6.02 (d, JZ7.68 Hz, 1H), 7.08–7.11 (d, JZ7.83 Hz,
2H), 7.20–7.28 (d, JZ8.0 Hz, 2H), 7.43–7.59 (m, 3H),
7.89–7.92 (d, JZ7.38 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d 14.0, 20.9, 23.1, 45.6, 54.8, 126.8, 128.1,
128.6, 129.1, 133.0, 136.3, 136.9, 137.5, 169.7, 201.9.
Anal. Calcd for C19H21O2N: C, 77.25; H, 7.16; N, 4.74;
Found: C, 77.23; H, 6.94; N, 4.35.
4.2.15.
N-[1-(4-Chloro-phenyl)-2-methyl-3-oxo-3-
phenyl-propyl]-acetamide (29).4c (Yield 262 mg, 83%).
anti-Isomer: white crystals, (EtOAc-pet.ether, 60-80 8C)
mp 162 8C. 1H NMR (300 MHz, CDCl3): d 1.38–1.40

4064
R. Ghosh et al. / Tetrahedron 62 (2006) 4059–4064
Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363–371. (e)
4.2.18. Acetic acid 5-(1-acetylamino-2-methyl-3-oxo-3-
phenyl-propyl)-2-methoxy-phenyl ester (32).11 (Yield
273 mg, 74%).
¨
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210.
2. (a) Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.;
Olano, B. J. Org. Chem. 1993, 58, 5972–5975. (b) Enders,
D.; Moser, M.; Geibel, G.; Laufer, M. C. Synthesis 2004,
2040–2046.
anti-Isomer: white crystals, (EtOAc/pet. ether, 60:80 8C)
mp 177 8C.11 1H NMR (300 MHz, CDCl3): d 1.37–1.40 (d,
JZ7.0 Hz, 3H), 2.12 (s, 3H), 2.26 (s, 3H), 3.72 (s, 3H),
4.08–4.17 (m, 1H), 5.31–5.37 (m, 1H), 6.81–6.91 (m, 3H),
7.40–7.62 (m, 4H), 7.76–7.79 (d, JZ7.5 Hz, 2H).
¨ ¨ ¨
3. (a) Dahn, U.; Hagenmaier, H.; Hohne, H.; Konig, W. A.;
¨
Wolf, G.; Zahner, H. Arch. Microbiol. 1976, 107, 249–256. (b)
Kobinata, K.; Uramoto, M.; Nishii, M.; Kusakabe, H.;
Nakamura, G.; Isono, K. Agric. Biol. Chem. 1980, 44,
1709–1711.
1
syn-Isomer: oil, H NMR (300 MHz, CDCl3): d 1.27–1.29
(d, JZ6.6 Hz, 3H), 2.02 (s, 3H), 2.28 (s, 3H), 3.77 (s, 3H),
4.04–4.10 (m, 1H), 5.43–5.49 (t, JZ7.6 Hz, 1H), 6.17–6.19
(d, JZ6.8 Hz, 1H), 6.80–6.95 (m, 3H), 7.40–7.60 (m, 3H),
7.87–7.90 (d, JZ7.4 Hz, 2H).
4. (a) Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett.
1997, 38, 1083–1086. (b) Bhatia, B.; Reddy, M. M.; Iqbal, J.
J. Chem. Soc., Chem. Commun. 1994, 713–714. (c) Bahulayan,
D.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 5735–5738.
(d) Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P.
Tetrahedron Lett. 2005, 46, 2105–2108.
4.2.19. Acetic acid 3-(1-acetylamino-2-methyl-3-oxo-3-
phenyl-propyl)-phenyl ester (33).4c (Yield 105 mg, 31%).
5. Ghosh, R.; Maity, S.; Chakraborty, A. Synlett 2005, 115–118.
6. Riley, J. P.; Chester, R. Introduction to Marine Chemistry;
Academic: NY, 1971.
anti-Isomer: white crystals, (EtOAc/pet. ether, 60:80) mp
1
162 8C, (lit.4c mp 142 8C). H NMR (300 MHz, CDCl3): d
1.32–1.35 (d, JZ7.1 Hz, 3H), 2.08, (s, 3H), 2.41 (s, 3H),
3.96–4.04 (m, 1H), 5.50–5.54 (dd, JZ3.6, 8.4 Hz, 1H),
7.03–7.08 (m, 2H), 7.17–7.22 (t, JZ7.1 Hz, 2H), 7.37–7.55
(m, 4H), 7.75–7.78 (d, JZ7.4 Hz, 2H).
7. Farnworth, F.; Jones, S. L.; McAlpine, I. Speciality Inorganic
Chemicals; Royal Society of Chemistry: London, 1980;
Special publication No. 40.
8. (a) Spotlight: Bora, U. Synlett 2003, 1073–1074. (b) Heine,
H. W.; Cottle, D. L.; van Mater, H. L. J. Am. Chem. Soc. 1946,
68, 524. (c) Poll, T.; Helmchen, G.; Bauer, B. Tetrahedron
Lett. 1984, 25, 2191–2194. (d) Evans, D. A.; Chapman, K. T.;
Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238–1256. (e)
Frank-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lett.
1990, 31, 5027–5030. (f) Denmark, S. E.; Weber, E. J.;
Wilson, T. M.; Wilson, T. M. Tetrahedron 1989, 45,
1053–1065. (g) (i) Itsuno, S.; Sakurai, Y.; Ito, K. Synthesis
1988, 995–996. (ii) Itsuno, S.; Sakurai, Y.; Shimizu, K.;
Ito, K. M. J. Chem. Soc., Perkin Trans. 1 1990, 1859–1863.
(iii) Chary, K. P.; Thomas, R. M.; Iyengar, D. S. Indian
J. Chem., Sect. B 2000, 39, 57–59. (iv) Chary, K. P.; Raja Ram,
S.; Iyengar, D. S. Synlett 2000, 683–685. (h) Harrowven,
D. C.; Dainty, R. F. Tetrahedron Lett. 1996, 37, 7659–7660. (i)
Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999,
319–320. (j) Karimi, B.; Seradj, H. Synlett 2000, 805–806.
(k) Yadav, J. S.; Reddy, B. V. S.; Ray, K. S.; Reddy, K. B.;
Prasad, A. R. Synthesis 2001, 2277–2280. (l) Smitha, S.;
Reddy, Ch. S. Synthesis 2004, 834–836.
1
syn-Isomer: oil, H NMR (300 MHz, CDCl3): d 1.29–1.31
(d, JZ6.1 Hz, 3H), 1.97 (s, 3H), 2.39 (s, 3H), 4.08 (br s,
1H), 5.74–5.76 (m, 1H), 5.87 (s, 1H), 7.06–7.60 (m, 7H),
7.90–7.92 (d, JZ7.5 Hz, 2H).
Crystallographic data of the compound anti-31 has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 285299. Copies
of the data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: C44
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
CSIR, New Delhi (Scheme Nos. 01/1672/00/EMR-II and
01/1951/04/EMR-II, for research funding to R.G. and
fellowship to S.M.) and UGC (SRF to A.C. and S.C.) are
gratefully acknowledged for the financial assistances.
9. (a) Ghosh, R.; Maiti, S.; Chakraborty, A. Tetrahedron Lett.
2005, 46, 147–151. (b) Easwaramurthy, M.; Ravikumar, R.;
Lakshmanan, A. J.; Raju, G. J. Indian J. Chem., Sect. B 2005,
44, 635–637. (c) Yakaiah, T.; Reddy, G. V.; Lingaiah, B. P. V.;
Rao, P. S.; Narsaiah, B. Indian J. Chem., Sect. B 2005, 44,
1301–1303.
References and notes
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