Facile and diastereoselective synthesis of β-acetamido ketones and keto esters via direct Mannich-type reaction

Article abstract of DOI:10.1016/j.tet.2008.11.071

A Mannich-type three-component reaction involving aldehydes, acetamide, and enolizable ketones or β-keto esters for the preparation of β-acetamido carbonyl compounds in the presence of TMSCl is described. This newly developed protocol is operationally convenient, widely applicable, and highly diastereoselective.

Full text of DOI:10.1016/j.tet.2008.11.071

Tetrahedron 65 (2009) 1026–1032
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile and diastereoselective synthesis of b-acetamido ketones and keto esters
via direct Mannich-type reaction
*
Hui Mao, Jieping Wan, Yuanjiang Pan
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Mannich-type three-component reaction involving aldehydes, acetamide, and enolizable ketones or
-keto esters for the preparation of -acetamido carbonyl compounds in the presence of TMSCl is de-
scribed. This newly developed protocol is operationally convenient, widely applicable, and highly
Received 24 September 2008
Received in revised form 15 November 2008
Accepted 21 November 2008
Available online 27 November 2008
b
b
diastereoselective.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ZrOCl2$8H2O,10 PCl3,11 silica sulfuric acid,12 Cu(OTf)2,13 BiOCl,14 and
SiCl2-ZnCl2.15 These compounds have been disclosed as very ef-
With their advantages of atom-efficient transformations, readily
available materials, and various products, multicomponent re-
actions (MCRs) have received significant research interest from
chemical and medicinal communities.1 As one of the mostly studied
MCRs, discovered in 1912, Mannich reaction is an aminoalkylation
reaction of aldehyde (Scheme 1)2 and is a very useful method for
fective catalysts. Recently, CeCl2$7H2O16 and FeCl3$6H2O17 were
also successfully employed to promote this reaction.
Theoretically, since amines were able to produce
tones and keto esters through Mannich reaction, acetamide could
similarly proceed to corresponding -acetamido ketones and keto
b-amino ke-
b
esters through this type of reaction. Surprisingly, the classical
Mannich reaction is not easily applicable to amides probably due to
its low reactivity character. Thus, for this study, we report an effi-
the preparation of b-amino compounds. It is also, therefore, a very
important basic reaction in organic synthesis.3
cient Mannich-type MCR to directly prepare
compounds from aldehydes, acetamide, and enolizable ketones or
b-acetamido carbonyl
NHR2O
CHO
b-keto esters in the presence of TMSCl (Scheme 2).
O
O
+
+
R2NH2
R3
R1
O
R3
R1
NHAc
O
O
CHO
Scheme 1.
O
O
TMSCl
+
+
CH3CONH2
CH3CONH2
CH3CN, reflux
R2
R2
R1
R1
b
-Acetamido carbonyl compounds can be used as the precursor
of 1,3-amino alcohols,4 -amino acids,5 and -lactams.6 They are
b
g
NHAc
O
CHO
+
the building blocks of numerous pharmaceutical and biological
compounds.7 Dakin et al. first reported the preparation of this kind
of compound by Dakin–West reaction in 1928, which is exactly the
O
TMSCl
CH3CN, reflux
Ph
+
Ph
R
R
condensation between an a-amino acid and acetic anhydride in the
presence of a base providing the acetamido ketones.8 Iqbal et al.
meanwhile, developed the cobalt-catalyzed one-pot multicompo-
nent coupling route involving ketones, aldehydes, acetonitrile as
well as AcCl to prepare this class of compound.5 Later on, a number
Scheme 2. A Mannich-type three-component reaction for the preparation of b-acet-
amido carbonyl compounds.
2. Results and disscussion
of catalyst systems were reported for the synthesis of b-acetamido
carbonyl compounds via the same reaction, including
2.1. Optimization of Mannich-type multicomponent reaction
for the synthesis of -acetamido carbonyl compounds
b
Initially, the reaction of benzaldehyde, acetamide, and acetyl-
acetone was chosen as model. We used a CH3CN solution of
* Corresponding author. Tel.: þ86 0570 8795 1264; fax: þ86 0570 8795 1629.
E-mail address: cheyjpan@zju.edu.cn (Y. Pan).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.071

H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
1027
Table 1
product was formed, and CoCl2 and (
L
)-proline did not catalyze this
Optimization of Mannich-type multicomponent reaction of benzaldehyde, acet-
amide, and acetylacetonea
reaction, either (Table 1, entries 1–3). Previously, our research
group had successfully used TMSCl to promote Biginelli-type con-
densations,18 isoindolinone synthesis,19 and multicomponent syn-
thesis of thiazines and tetrahydropyrimidones.20 The preliminary
results showed that it could also promote this reaction, but the
yield was not so satisfying (Table 1, entry 4). To test the effect of the
amount of TMSCl, 0.5 mmol TMSCl was added in the same condi-
tion, and the yield was increased to 86% (Table 1, entry 5). No sig-
nificant impact on the yield was observed when the amount of
TMSCl was added to 0.7 mmol (Table 1, entry 6). Consequently, if no
catalyst was added, the results showed that there would be no
corresponding product as well (Table 1, entry 7).
NHAc
O
CHO
+
O
O
Catalyst
CH3CN, reflux
+
CH3CONH2
O
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
HCl
CoCl2
(
TMSCl
TMSClc
TMSCld
No
0
0
0
30
86
85
0
L
)-proline
a
2.2. Mannich-type multicomponent reaction of acetamide,
acetylacetone, and different aldehydes
Conditions: benzaldehyde (0.5 mmol), acetamide (0.6 mmol), acetylacetone
(0.6 mmol), CH3CN (3 ml), catalyst (0.1 mmol), 7 h.
b
Isolated yield based on aromatic aldehyde.
TMSCl (0.5 mmol).
TMSCl (0.7 mmol).
c
With the encouraging results, various aldehydes were employed
for this reaction under the established protocol (Table 2). All re-
actions proceeded smoothly to give the corresponding compounds
(Table 2, entries 1–8) in good yields, except for aldehyde containing
a nitro group at the para position. It gave the Knoevenagel con-
densation product rather than our desired product (Scheme 3).
d
benzaldehyde (0.5 mmol), acetamide (0.6 mmol), and acetylace-
tone (0.6 mmol) in the presence of diluted HCl (1 mol/l, 0.1 ml) that
was stirred at reflux for 7 h. Unfortunately, however, no target
Table 2
Mannich-type multicomponent reaction of acetamide, acetylacetone, and different aldehydesa
NHAc
O
O
CHO
O
O
TMSCl
CH3CN, reflux
+
CH3CONH2
+
R
R
Entry
1
Product
NHAcO
Yieldb (%)
86
Entry
5
Product
NHAcO
Yieldb (%)
70
1a
1b
1e
1f
O
Br
O
NHAcO
NHAcO
2
3
78
6
78
O
MeO
MeO
O
NHAcO
NHAcO
1c
84
75
7
8
1g
1h
80
81
F
O
O
NHAcO
Cl
NHAcO
4
1d
Cl
O
O
a
Conditions: aldehyde (0.5 mmol), acetamide (0.6 mmol), acetylacetone (0.6 mmol), CH3CN (3 ml), TMSCl (0.5 mmol), 5–10 h.
Isolated yield based on aromatic aldehyde.
b
NHAcO
CHO
+
O
O
O
O
O2N
O2N
TMSCl
CH3CONH2
+
O
CH3CN, reflux
O2N
Scheme 3.

1028
H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
Table 3
Mannich-type multicomponent reaction of acetamide, ethylacetoacetate, and different aldehydesa
NHAc
O
NHAc
O
CHO
+
O
O
TMSCl
+
CH3CONH2
+
CH3CN, reflux
OEt
O
OEt
O
anti
OEt
R
R
R
syn
Entry
1
Product
NHAcO
Yieldb (%)
84
syn/antic
Entry
5
Product
NHAcO
Yieldb (%)
71
syn/antic
2a
2b
4:96
2e
2f
45:55
O
OEt
Br
O
OEt
NHAcO
NHAcO
2
3
75
82
76
15:85
25:75
6:94
6
7
8
79
81
80
36:64
23:77
50:50
O
OEt
MeO
MeO
O
OEt
NHAcO
NHAcO
2c
2g
2h
F
O
OEt
O
OEt
NHAcO
Cl
NHAcO
4
2d
Cl
O
OEt
O
OEt
a
Conditions: aldehyde (0.5 mmol), acetamide (0.6 mmol), ethylacetoacetate (0.6 mmol), CH3CN (3 ml), TMSCl (0.5 mmol), 5–10 h.
Isolated yield based on aromatic aldehyde.
b
c
The ratio of syn/anti diastereomers was determined from the 1H NMR spectrum of the crude mixture.
2.3. Mannich-type multicomponent reaction of acetamide,
corresponding b-acetamido keto esters were obtained (Table 3).
ethylacetoacetate, and different aldehydes
Accompanied with moderate to good yield, good diasteroselectivity
was found with these reactions. Specifically, the de value of the
reaction with benzaldehyde was up to 92% (Table 3, entry 1).
The major products obtained were the anti isomers (Table 3, entries
To further test the scope of the reaction, ethylacetoacetate as
methylene donor was subjected to the reaction, and the
Table 4
Mannich-type multicomponent reaction of acetamide, acetophenone, and different aldehydesa
NHAc
O
CHO
COMe
TMSCl
+
CH3CONH2
+
CH3CN, reflux
R
R
Entry
1
Product
NHAc
Yieldb (%)
80
Entry
5
Product
Yieldb (%)
70
NHAcO
O
3a
3b
3e
3f
Br
NHAcO
NHAcO
NHAcO
NHAcO
NHAcO
2
3
74
6
75
MeO
MeO
3c
73
71
7
8
3g
3h
73
76
F
Cl
NHAcO
4
3d
Cl
a
Conditions: aldehyde (0.5 mmol), acetamide (0.6 mmol), acetophenone (0.6 mmol), CH3CN (3 ml), TMSCl (0.5 mmol), 5–10 h.
Isolated yield based on aromatic aldehyde.
b

H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
1029
CHO
aldehyde oxygen.23 Complex B and acetamide formed their corre-
sponding hemiaminal C via standard nucleophilic addition re-
action. Followed by loss of one molecular Me3SiOH, the reactive
intermediate D was formed. At the same time, the enolizable ke-
tone or b-keto ester nucleophilic attacked the intermediate to af-
ford the final product E.
Ac
acetamide
acetylacetone
No reaction
TMSCl, CH3CN
reflux, 7h
Ac
TMSCl, CH3CN
reflux, 7h
O2N
NO2
CHO
Ac
acetamide
acetylacetone
No reaction
3. Conclusion
TMSCl, CH3CN
reflux, 7h
TMSCl, CH3CN
reflux, 7h
Ac
In summary, we have developed a new Mannich-type multi-
component reaction in the presence of TMSCl for the preparation of
CHO
OMe
b-acetamido ketones and keto esters. This direct method provided
acetylacetone
Ac
a facile and useful supplement for those already established routes.
(Not isolated)
TMSCl, CH3CN
reflux, 7h
Ac
MeO
4. Experimental
4.1. General
Scheme 4.
1–7). The ratio of syn/anti diastereomers was determined from the
1H NMR spectrum of the crude product compared with that
reported in the literature.21
The melting points were determined using XT-4 apparatus and
were not corrected. The NMR spectra were recorded on a Bruker
AVANCE DMX-500 spectrometry using CDCl3 as solvent and TMS as
the internal standard. Mass spectra were performed on a Bruker
Esquire 3000 mass spectrometer equipped with ESI interface and
ion trap analyzer. HRMS were obtained on a Bruker 7-tesla FT-ICR
MS equipped with an electrospray source.
2.4. Mannich-type multicomponent reaction of acetamide,
acetophenone, and different aldehydes
Finally, we focused on the reaction of acetophenone. Fortu-
nately, the expected results were obtained. Various acetophenone
4.2. General procedure for the preparation of
carbonyl compounds
b-acetamido
were found to produce the
(Table 4).
b-acetamido ketones in good yields
TMSCl(0.5 mmol)wasaddedtoasolutionofaldehyde(0.5 mmol),
acetamide (0.6 mmol), and acetylacetone or ethylacetoacetate or
acetophenone (0.6 mmol) in acetonitrile (3 ml). The reaction was
stirred at reflux temperature until the reaction was completed
(monitored by TLC). Then the mixture was extracted with ethyl ace-
tate (3ꢀ20 ml), washed with water (3ꢀ20 ml), dried over Na2SO4.
After the solvent was removed, the crude mixture was recrystallized
from ethyl acetate–hexane and the solid product was afforded.
2.5. Mechanism for Mannich-type multicomponent reaction
promoted by TMSCl
From Table 1 (entry 7), the reaction including benzaldehyde,
acetamide, and acetylacetone failed to give the correlative product
in the absence of TMSCl, which indicated that the latter plays an
important role in the reaction. To further discuss the mechanism of
this Mannich-type reaction, a variety of aromatic aldehydes con-
taining both electron withdrawing and donating group at the para
position were treated with acetylacetone under the same experi-
mental conditions. The results showed that this reaction can give
the corresponding Knoevenagel condensation product except the
aldehyde containing a electron donating group. Then, the Knoe-
venagel condensation product reacted with acetamide under the
same conditions. However, no Mannich-type product was observed
(Scheme 4).
4.2.1. N-(2-Acetyl-3-oxo-1-phenyl-butyl)-acetamide (1a)
White solid, yield 86%, mp 132–134 ꢁC. 1H NMR (500 MHz,
CDCl3):
d 7.16–7.25 (5H, m, Ph), 7.03 (1H, d, J 8.5 Hz, NH), 5.78 (1H,
dd, J 5.0 Hz, 9.3 Hz, CH), 4.23 (1H, d, J 5.5 Hz, CH), 2.17 (3H, s, COMe),
2.02 (3H, s, COMe), 1.91 (3H, s, COMe). 13C NMR (125 MHz, CDCl3):
d
205.4, 202.8, 169.9, 139.5, 129.0, 128.0, 126.6, 126.5, 70.7, 52.1, 31.2,
30.1, 23.5. MS (ESI): m/z 270 ([MþNa]þ). HRMS (ESI): ([MþNa]þ):
Calcd for C14H17NO3Na: 270.1101; Found: 270.1096.
On the basis of the results and previous related Mannich re-
action mechanistic research,22 a possible mechanism for this
Mannich-type reaction was proposed in Scheme 5. Initially, TMSCl
acted as a Lewis acid to activate aldehyde A by complexation with
4.2.2. N-(2-Acetyl-3-oxo-1-p-tolyl-butyl)-acetamide (1b)
White solid, yield 78%, mp 150–152 ꢁC. 1H NMR (500 MHz,
CDCl3): d 7.15 (2H, d, J 8.3 Hz, Ph), 7.08 (2H, d, J 8.2 Hz, Ph), 5.81 (1H,
dd, J 6.5 Hz, 2.7 Hz, CH), 4.28 (1H, d, J 6.3 Hz, CH), 2.29 (3H, s, CH3),
2.20 (3H, s, COMe), 2.10 (3H, s, COMe), 1.95 (3H, s, COMe). 13C NMR
SiMe3
+O
OSiMe3
O
O
(125 MHz, CDCl3):
d 205.3, 202.8, 169.9, 137.6, 136.6, 129.6, 126.4,
O
Si
71.0, 52.0, 31.0, 30.2, 23.4, 21.2. MS (ESI): m/z 284 ([MþNa]þ). HRMS
(ESI): ([MþNa]þ): Calcd for C15H19NO3Na: 284.1257; Found:
284.1250.
Cl
H2N
N
H
R
(A)
R
R
(C)
(B)
4.2.3. N-[2-Acetyl-1-(4-fluoro-phenyl)-3-oxo-butyl]-
acetamide (1c)
NHAc O
O
O
OH
Me3SiOH
White solid, yield 84%, mp 138–140 ꢁC. 1H NMR (500 MHz,
R1
R1
N
CDCl3):
d 7.18–7.21 (2H, m, Ph), 7.13 (2H, d, J 9.1 Hz, NH), 6.90–6.94
O
(E)
(2H, m, Ph), 5.74 (1H, dd, J 6.5 Hz, 2.7 Hz, CH), 4.21 (1H, d, J 6.4 Hz,
R
R
CH), 2.15 (3H, s, COMe), 2.04 (3H, s, COMe), 1.89 (3H, s, COMe). 13C
(D)
NMR (125 MHz, CDCl3):
128.4, 115.9, 71.0, 51.6, 30.9, 30.2, 23.6. MS (ESI): m/z 288
d 205.1, 202.5, 169.9, 163.3, 161.3, 135.4,
Scheme 5. A possible mechanism for TMSCl-promoted Mannich-type reaction for the
preparation of -acetamido carbonyl compounds.
b

1030
H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C14H16FNO3Na:
23.5, 14.1. MS (ESI): m/z 300 ([MþNa]þ). HRMS (ESI): ([MþNa]þ):
288.1006; Found: 288.1000.
Calcd for C15H19NO4Na: 300.1206; Found: 300.1202.
4.2.4. N-[2-Acetyl-1-(4-chloro-phenyl)-3-oxo-butyl]-
acetamide (1d)
4.2.10. 2-(Acetylamino-p-tolyl-methyl)-3-oxo-butyric acid ethyl
ester (2b)
White solid, yield 75%, mp 167–169 ꢁC. 1H NMR (500 MHz,
White solid, yield 75%, mp 98–101 ꢁC. Data for major isomer
CDCl3):
d
7.30 (2H, d, J 8.4 Hz, Ph), 7.22 (2H, d, J 8.4 Hz, Ph), 7.04 (2H,
(anti): 1H NMR (500 MHz, CDCl3):
d 7.10 (2H, d, J 8.5 Hz, Ph), 7.01 (2H,
d, J 8.2 Hz, NH), 5.82 (1H, dd, J 6.5 Hz, 2.7 Hz, CH), 4.26 (1H, d, J
d, J 8.5 Hz, Ph), 5.64 (1H, dd, J 6.7 Hz, 2.5 Hz, CH), 4.07 (2H, q, J 3.7 Hz,
CH2), 3.99 (1H, d, J 6.7 Hz, CH), 2.22 (3H, s, CH3), 2.10 (3H, s, COMe),
1.88 (3H, s, COMe), 1.11 (3H, t, J 7.0 Hz, CH3). 13C NMR (125 MHz,
5.6 Hz, CH), 2.28 (3H, s, COMe), 2.10 (3H, s, COMe), 2.00 (3H, s,
COMe). 13C NMR (125 MHz, CDCl3):
d 205.3, 202.5, 170.0, 138.1,
133.9, 129.2, 128.1, 70.4, 51.5, 31.4, 30.1, 23.5. MS (ESI): m/z 304
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C14H16ClNO3Na:
304.0711; Found: 304.0710.
CDCl3): d 204.0,169.9,167.4,137.6,136.4,129.5,126.2, 63.9, 62.0, 52.3,
30.6, 23.4, 21.1, 14.1. MS (ESI): m/z 300 ([MþNa]þ). HRMS (ESI):
([MþNa]þ): Calcd for C16H21NO4Na: 314.1363; Found: 314.1359.
4.2.5. N-[2-Acetyl-1-(4-bromo-phenyl)-3-oxo-butyl]-
acetamide (1e)
4.2.11. 2-[Acetylamino-(4-fluoro-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2c)
White solid, yield 70%, mp 188–190 ꢁC. 1H NMR (500 MHz,
White solid, yield 82%, mp 100–102 ꢁC. Data for major isomer
CDCl3):
d
7.37 (2H, d, J 8.4 Hz, Ph), 7.22 (2H, d, J 8.4 Hz, Ph), 7.04 (2H,
(anti): 1H NMR (500 MHz, CDCl3):
d 8.43 (1H, d, J 8.9 Hz, NH), 7.33–
d, J 13.8 Hz, NH), 5.73 (1H, dd, J 5.6 Hz, 3.6 Hz, CH), 4.18 (1H, d, J
7.38 (2H, m, Ph), 7.10–7.15 (2H, m, Ph), 5.43 (1H, dd, J 9.1 Hz, 2.4 Hz,
CH), 4.04 (1H, d, J 11.2 Hz, CH), 3.87 (2H, q, J 7.1 Hz, CH2), 2.50 (3H, s,
COMe), 1.76 (3H, s, COMe), 0.92 (3H, t, J 7.1 Hz, CH3). 13C NMR
5.6 Hz, CH), 2.20 (3H, s, COMe), 2.02 (3H, s, COMe), 1.92 (3H, s,
COMe). 13C NMR (125 MHz, CDCl3):
d 205.2, 202.5, 170.0, 138.6,
132.1, 128.4, 122.0, 70.4, 51.6, 31.4, 30.1, 23.5. MS (ESI): m/z 348
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C14H16BrNO3Na:
348.0206; Found: 348.0203.
(125 MHz, CDCl3): d 202.0,169.7,168.1,161.6,137.7,130.4,116.2, 65.7,
62.2, 52.3, 30.7, 23.7,14.7. MS (ESI): m/z 318 ([MþNa]þ). HRMS (ESI):
([MþNa]þ): Calcd for C15H18FNO4Na: 318.1112; Found: 318.1105.
4.2.6. N-[2-Acetyl-1-(4-methoxy-phenyl)-3-oxo-butyl]-
acetamide (1f)
4.2.12. 2-[Acetylamino-(4-chloro-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2d)
White solid, yield 78%, mp 147–149 ꢁC. 1H NMR (500 MHz,
White solid, yield 76%, mp 106–108 ꢁC. Data for major isomer
CDCl3):
d
7.30 (2H, d, J 8.4 Hz, Ph), 7.22 (2H, d, J 8.4 Hz, Ph), 7.04 (2H,
(anti): 1H NMR (500 MHz, CDCl3):
d 7.16–7.21 (4H, m, Ph), 5.43 (1H,
d, J 8.2 Hz, NH), 5.82 (1H, dd, J 6.5 Hz, 2.7 Hz, CH), 4.26 (1H, d, J
dd, J 6.9 Hz, 1.9 Hz, CH), 4.06 (2H, q, J 2.7 Hz, CH2), 3.98 (1H, d, J
6.7 Hz, CH), 2.11 (3H, s, COMe), 1.89 (3H, s, COMe), 1.11 (3H, t, J
5.6 Hz, CH), 3.76 (3H, s, OMe), 2.28 (3H, s, COMe), 2.10 (3H, s,
COMe), 2.00 (3H, s, COMe). 13C NMR (125 MHz, CDCl3):
d
205.3,
7.2 Hz, CH3). 13C NMR (125 MHz, CDCl3):
d 203.6, 170.0, 167.1, 138.1,
202.5, 170.0, 138.1, 133.9, 129.2, 128.1, 70.4, 51.5, 31.4, 30.1, 23.5. MS
(ESI): m/z 300 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for
C15H19NO4Na: 300.1206; Found: 300.1212.
133.7, 129.2, 127.9, 63.0, 61.8, 51.9, 30.5, 23.3, 14.1. MS (ESI): m/z 334
([MþNa]þ). HRMS (ESI): ([Mþ Na]þ): Calcd for C15H18ClNO4Na:
334.0817; Found: 334.0811.
4.2.7. N-[2-Acetyl-1-(3-methoxy-phenyl)-3-oxo-butyl]-
acetamide (1g)
4.2.13. 2-[Acetylamino-(4-bromo-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2e)
White solid, yield 80%, mp 130–131 ꢁC. 1H NMR (500 MHz,
White solid, yield 71%, mp 120–122 ꢁC. Data for major isomer
CDCl3):
d
7.27 (1H, s, Ph), 7.07 (1H, d, J 8.4 Hz, NH), 6.76–6.84 (3H, m,
(anti): 1H NMR (500 MHz, CDCl3):
d 7.14–7.25 (4H, m, Ph), 5.61 (1H,
Ph), 5.82 (1H, dd, J 6.4 Hz, 3.3 Hz, CH), 4.28 (1H, d, J 6.0 Hz, CH), 3.78
dd, J 7.1 Hz, 2.3 Hz, CH), 4.08 (2H, q, J 7.1 Hz, CH2), 3.98 (1H, d, J
4.5 Hz, CH), 2.10 (3H, s, COMe), 1.89 (3H, s, COMe), 1.11 (3H, t, J
(3H, s, OMe), 2.23 (3H, s, COMe), 2.10 (3H, s, COMe), 1.97 (3H, s,
COMe). 13C NMR (125 MHz, CDCl3):
d
205.3, 202.8, 169.9, 160.0,
1.3 Hz, CH3). 13C NMR (125 MHz, CDCl3):
d 203.6, 170.0, 169.0, 140.3,
141.1, 130.1, 118.7, 112.9, 70.7, 55.5, 52.0, 31.2, 30.1, 23.5. MS (ESI): m/
z 300 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C15H19NO4Na:
300.1206; Found: 300.1209.
132.7, 128.9, 121.3, 63.5, 61.9, 52.0, 30.6, 23.4, 14.1. MS (ESI): m/z 378
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C15H18BrNO4Na:
378.0311; Found: 378.0300.
4.2.8. N-[2-Acetyl-1-(2-chloro-phenyl)-3-oxo-butyl]-
acetamide (1h)
4.2.14. 2-[Acetylamino-(4-methoxy-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2f)
White solid, yield 81%, mp 96–98 ꢁC. 1H NMR (500 MHz, CDCl3):
White solid, yield 79%, mp 103–105 ꢁC. Data for major isomer
d
7.48 (1H, d, J 9.2 Hz, NH), 7.26–7.47 (2H, m, Ph), 7.12–7.16 (2H, m,
(anti): 1H NMR (500 MHz, CDCl3):
d 7.20 (2H, d, J 3.4 Hz, Ph), 6.8 (2H,
Ph), 6.02 (1H, dd, J 5.2 Hz, 5.1 Hz, CH), 4.41 (1H, d, J 4.2 Hz, CH), 2.29
d, J 1.5 Hz, Ph), 5.69 (1H, dd, J 6.7 Hz, 2.3 Hz, CH), 4.12 (2H, q, J 2.9 Hz,
CH2), 4.02 (1H, d, J 6.6 Hz, CH), 3.76 (3H, s, OMe), 2.17 (3H, s, COMe),
1.95 (3H, s, COMe), 1.11 (3H, t, J 7.1 Hz, CH3). 13C NMR (125 MHz,
(3H, s, COMe), 2.00 (3H, s, COMe), 1.91 (3H, s, COMe). 13C NMR
(125 MHz, CDCl3):
d 205.9, 202.9, 192.8, 169.9, 136.4, 132.5, 129.8,
127.3, 66.9, 50.0, 31.9, 29.4, 23.5. MS (ESI): m/z 304 ([MþNa]þ).
HRMS (ESI): ([MþNa]þ): Calcd for C14H16ClNO3Na: 304.0711;
Found: 304.0706.
CDCl3): d 204.1,169.8,167.5,159.3,131.6,128.0,114.3, 63.5, 62.0, 55.4,
52.1, 30.6, 23.5, 14.1. MS (ESI): m/z 330 ([MþNa]þ). HRMS (ESI):
([MþNa]þ): Calcd for C16H21NO5Na: 330.1312; Found: 330.1317.
4.2.9. 2-(Acetylamino-phenyl-methyl)-3-oxo-butyric acid ethyl
ester (2a)
4.2.15. 2-[Acetylamino-(3-methoxy-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2g)
White solid, yield 84%, mp 106–109 ꢁC. Data for major isomer
White solid, yield 81%, mp 101–103 ꢁC. Data for major isomer
(anti): 1H NMR (500 MHz, CDCl3):
d
7.16–7.25 (5H, m, Ph), 7.01 (1H,
(anti): 1HNMR (500 MHz, CDCl3):
d 7.20 (1H, s, Ph), 6.84–6.98 (3H, m,
d, J 8.0 Hz, NH), 5.68 (1H, dd, J 6.3 Hz, 3.3 Hz, CH), 4.08 (2H, q, J
3.6 Hz, CH2), 4.03 (1H, d, J 6.8 Hz, CH), 2.09 (3H, s, COMe), 1.91 (3H,
s, COMe), 1.11 (3H, t, J 7.1 Hz, CH3). 13C NMR (125 MHz, CDCl3):
Ph), 5.71 (1H, dd, J 6.4 Hz, 2.8 Hz, CH), 4.12 (2H, q, J 7.1 Hz, CH2), 4.06
(1H, d, J 6.3 Hz, CH), 3.76 (3H, s, OMe), 2.16 (3H, s, COMe),1.95 (3H, s,
COMe), 1.11 (3H, t, J 7.1 Hz, CH3). 13C NMR (125 MHz, CDCl3):
d
204.1,
d
204.0, 169.7, 167.4, 139.4, 128.8, 127.9, 126.7, 63.1, 62.1, 52.6, 30.8,
169.9, 167.4, 160.0, 141.1, 129.9, 118.8, 113.1, 112.8, 63.8, 62.1, 55.4,

H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
1031
52.5, 30.8, 23.5, 14.1. MS (ESI): m/z 330 ([MþNa]þ). HRMS (ESI):
([MþNa]þ): Calcd for C16H21NO5Na: 330.1312; Found: 330.1309.
129.1, 129.0, 128.4, 128.3, 49.4, 43.0, 23.7. MS (ESI): m/z 368
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C17H16BrNO2Na:
368.0262; Found: 368.2064.
4.2.16. 2-[Acetylamino-(2-chloro-phenyl)-methyl]-3-oxo-butyric
acid ethyl ester (2h)
4.2.22. N-[1-(4-Methoxy-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (3f)
Colorless liquid, yield 80%. Data for major isomer (anti): 1H NMR
(500 MHz, CDCl3):
d
7.29–7.42 (4H, m, Ph), 5.68 (1H, dd, J 5.5 Hz,
White solid, yield 75%, mp 110–112 ꢁC. 1H NMR (500 MHz,
3.4 Hz, CH), 4.14 (2H, q, J 3.5 Hz, CH2), 3.98 (1H, d, J 7.1 Hz, CH), 2.38
CDCl3): d 7.91 (2H, d, J 7.2 Hz, Ph), 7.55 (1H, d, J 7.4 Hz, Ph), 7.45 (2H,
(3H, s, COMe), 2.01 (3H, s, COMe), 1.08 (3H, t, J 7.1 Hz, CH3). 13C NMR
t, J 7.9 Hz, Ph), 7.25 (2H, t, J 5.1 Hz, Ph), 6.8 (2H, t, J 7.4 Hz, Ph), 5.51
(1H, m, CH), 3.75 (3H, s, CH3), 3.73 (1H, dd, J 5.3 Hz, 11.5 Hz, CH2),
3.42 (1H, dd, J 6.5 Hz, 10.3 Hz, CH2), 1.99 (3H, s, COMe). 13C NMR
(125 MHz, CDCl3):
d 204.1, 169.7, 167.3, 136.4, 132.6, 131.1, 130.0,
128.9, 127.2, 62.1, 59.6, 50.4, 31.4, 23.5, 14.0. MS (ESI): m/z 334
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C15H18ClNO4Na:
334.0817; Found: 334.0809.
(125 MHz, CDCl3):
d 198.8, 169.6, 159.0, 136.8, 133.6, 133.2, 128.9,
128.3, 127.8, 114.5, 55.5, 49.8, 43.5, 23.6. MS (ESI): m/z 320
([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C18H19NO3Na:
320.1257; Found: 320.1251.
4.2.17. N-(3-Oxo-1,3-diphenyl-propyl)-acetamide (3a)
White solid, yield 80%, mp 103–105 ꢁC. 1H NMR (500 MHz,
CDCl3):
d
7.81 (2H, d, J 7.4 Hz, Ph), 7.46 (1H, d, J 7.4 Hz, Ph), 7.35 (2H,
4.2.23. N-[1-(3-Methoxy-phenyl)-3-oxo-3-phenyl-propyl]-
t, J 7.8 Hz, Ph), 7.13–7.25 (5H, m, Ph), 6.75 (1H, d, J 7.5 Hz, NH), 5.48
(1H, m, CH), 3.66 (1H, dd, J 5.3 Hz, 11.5 Hz, CH2), 3.35 (1H, dd, J
6.1 Hz, 10.7 Hz, CH2), 1.91 (3H, s, COMe). 13C NMR (125 MHz, CDCl3):
acetamide (3g)
Colorless liquid, yield 73%. 1H NMR (500 MHz, CDCl3):
d 7.91 (2H,
d, J 7.3 Hz, Ph), 7.55 (1H, d, J 7.4 Hz, Ph), 7.45 (2H, t, J 7.8 Hz, Ph), 7.22
(1H, t, J 7.9 Hz, Ph), 6.76–6.92 (4H, m, Ph), 5.54 (1H, m, CH), 3.77 (3H,
s, CH3), 3.74 (1H, dd, J 5.3 Hz, 12.1 Hz, CH2), 3.42 (1H, dd, J 6.1 Hz,
d
198.7, 169.7, 141.1, 136.8, 133.8, 128.9, 128.3, 127.7, 126.6, 50.1, 43.5,
23.6. MS (ESI): m/z 290 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd
for C17H17NO2Na: 290.1151; Found: 290.1147.
10.7 Hz, CH2), 2.02 (3H, s, COMe).13C NMR (125 MHz, CDCl3):
d 198.8,
169.7, 160.0, 142.8, 136.8, 133.7, 129.9, 128.9, 118.9, 112.7, 55.5, 49.8,
43.4, 23.7. MS (ESI): m/z 320 ([MþNa]þ). HRMS (ESI): ([MþNa]þ):
Calcd for C18H19NO3Na: 320.1257; Found: 320.1252.
4.2.18. N-(3-Oxo-3-phenyl-1-p-tolyl-propyl)-acetamide (3b)
White solid, yield 74%, mp 112–114 ꢁC. 1H NMR (500 MHz,
CDCl3): d 7.92 (2H, t, J 7.2 Hz, Ph), 7.56 (1H, t, J 7.4 Hz, Ph), 7.44 (2H, t,
J 7.9 Hz, Ph), 7.22 (2H, d, J 8.1 Hz, Ph), 7.11 (2H, d, J 8.4 Hz, Ph), 6.74
(1H, d, J 7.4 Hz, NH), 5.51 (1H, m, CH), 3.74 (1H, dd, J 5.3 Hz, 11.5 Hz,
CH2), 3.44 (1H, dd, J 6.3 Hz,10.5 Hz, CH2), 2.29 (3H, s, CH3), 2.00 (3H,
4.2.24. N-[1-(2-Chloro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (3h)
White solid, yield 76%, mp 135–137 ꢁC. 1H NMR (500 MHz,
s, COMe). 13C NMR (125 MHz, CDCl3):
d
198.7, 169.7, 138.1, 137.3,
CDCl3): d 7.89 (2H, d, J 7.3 Hz, Ph), 7.33–7.56 (5H, m, Ph), 7.16–7.22
136.8, 133.6, 129.5, 128.9, 128.3, 126.6, 50.0, 43.5, 23.6, 21.2. MS
(ESI): m/z 290 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for
C18H19NO2Na: 304.1308; Found: 304.1303.
(2H, m, Ph), 6.98 (1H, d, J 7.3 Hz, NH), 5.83 (1H, m, CH), 3.75 (1H, dd,
J 6.0 Hz, 10.9 Hz, CH2), 3.45 (1H, dd, J 5.5 Hz, 10.5 Hz, CH2), 2.04 (3H,
s, COMe). 13C NMR (125 MHz, CDCl3):
d 199.1, 169.5, 138.4, 136.7,
133.9, 132.7, 130.1, 128.9, 128.6, 127.2, 48.3, 41.6, 23.6. MS (ESI): m/z
324 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for C17H16ClNO2Na:
324.0762; Found: 324.0758.
4.2.19. N-[1-(4-Fluoro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (3c)
White solid, yield 73%, mp 109–111 ꢁC. 1H NMR (500 MHz,
CDCl3):
d
7.90 (2H, d, J 7.3 Hz, Ph), 7.58 (1H, t, J 7.3 Hz, Ph), 7.46 (2H,
Acknowledgements
t, J 8.2 Hz, Ph), 7.29–7.44 (2H, m, Ph), 6.96–7.01 (2H, m, Ph), 6.74
(1H, d, J 7.5 Hz, NH), 5.55 (1H, m, CH), 3.74 (1H, dd, J 5.0 Hz, 12.0 Hz,
CH2), 3.44 (1H, dd, J 6.0 Hz,10.9 Hz, CH2), 2.05 (3H, s, CH3), 2.00 (3H,
This work was supported by the National Natural Science
Foundation of China (No. 20775069).
s, COMe). 13C NMR (125 MHz, CDCl3):
d 198.8, 169.7, 163.2, 161.2,
137.0,136.8,133.9,129.0,128.4,115.8, 49.5, 43.3, 29.9, 23.7. MS (ESI):
m/z 308 ([MþNa]þ). HRMS (ESI): ([MþNa]þ): Calcd for
C17H16FNO2Na: 308.1057; Found: 308.1052.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.11.071.
4.2.20. N-[1-(4-Chloro-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (3d)
References and notes
White solid, yield 71%, mp 146–148 ꢁC. 1H NMR (500 MHz,
1. For general review, see: (a) Alexander, D.; Ivar, U. Angew. Chem., Int. Ed. 2000,
39, 3168; (b) Diego, J. R.; Miguel, Y. Angew. Chem., Int. Ed. 2005, 44, 1602; (c)
Armstrong, R. W.; Combs, A. P. Acc. Chem. Res. 1996, 29, 123.
CDCl3): d 7.81 (2H, d, J 7.3 Hz, Ph), 7.50 (1H, t, J 6.5 Hz, Ph), 7.38 (2H,
t, J 8.0 Hz, Ph), 7.18–7.20 (4H, m, Ph), 6.71 (1H, d, J 7.2 Hz, NH), 5.46
(1H, m, CH), 3.67 (1H, dd, J 5.0 Hz, 12.2 Hz, CH2), 3.37 (1H, dd, J
6.4 Hz, 11.3 Hz, CH2), 1.96 (3H, s, COMe). 13C NMR (125 MHz, CDCl3):
2. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647.
3. Michael, A.; Bernhard, W.; Nikolaus, R. Angew. Chem., Int. Ed. 1998, 37, 1400.
4. Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S. J. Org. Chem. 1993, 58, 5972.
5. Mukhopadhyay, M.; Bhatia, B.; Iqbal, J. Tetrahedron Lett. 1997, 38, 1083.
6. Rao, I. N.; Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J. Org. Chem. 2003, 68, 4079.
7. Casimir, J. R.; Turetta, C.; Ettouati, L.; Paris, J. Tetrahedron Lett. 1995, 36, 4797.
8. DaKin, H. D.; West, R. J. J. Biol. Chem. 1928, 91, 745.
d
198.7, 169.7, 139.7, 136.7, 134.0, 133.4, 129.1, 129.0, 128.3, 128.1,
49.5, 43.0, 23.7. MS (ESI): m/z 324 ([MþNa]þ). HRMS (ESI):
([MþNa]þ): Calcd for C17H16ClNO2Na: 324.0762; Found: 324.0755.
10. Ghosh, R.; Maiti, S.; Chakraborty, A.; Chakraborty, S. Tetrahedron Lett. 2006, 47,
8137.
11. Mohammad, A.; Azimeh, S. Synth. Commun. 2008, 38, 354.
12. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron 2005, 46, 2105.
13. Pandey, G.; Singh, R. P.; Singh, V. K. Tetrahedron Lett. 2005, 46, 2137.
14. Ghosh, R.; Maiti, S.; Chakraborty, A. Synlett 2005, 115.
4.2.21. N-[1-(4-Bromo-phenyl)-3-oxo-3-phenyl-propyl]-
acetamide (3e)
White solid, yield 70%, mp 147–149 ꢁC. 1H NMR (500 MHz,
CDCl3): d 7.84 (2H, d, J 7.2 Hz, Ph), 7.54 (1H, t, J 7.3 Hz, Ph), 7.44 (2H,
15. Tarek, A. S.; Saad, S. E.; Mohamed, A. I. Tetrahedron Lett. 2007, 48, 6199.
16. Kan, A. T.; Choudhury, L. H.; Parvin, T.; Ali, M. A. Tetrahedron Lett. 2006, 47, 8137.
17. Kan, A. T.; Parvin, T.; Choudhury, L. H. Tetrahedron 2007, 63, 5593.
18. Zhu, Y.; Huang, S.; Pan, Y. Eur. J. Org. Chem. 2005, 11, 2354.
19. Wan, J.; Wu, B.; Pan, Y. Tetrahedron 2007, 63, 9338.
t, J 8.0 Hz, Ph), 7.39 (2H, d, J 8.3 Hz, Ph), 7.20 (2H, d, J 8.4 Hz, Ph), 6.72
(1H, d, J 7.0 Hz, NH), 5.50 (1H, m, CH), 3.72 (1H, dd, J 5.3 Hz, 16.0 Hz,
CH2), 3.41 (1H, dd, J 6.2 Hz, 16.8 Hz, CH2), 2.01 (3H, s, COMe). 13C
NMR (125 MHz, CDCl3):
d 196.5, 166.7, 140.0, 136.4, 134.0, 131.8,

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H. Mao et al. / Tetrahedron 65 (2009) 1026–1032
20. Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y. Org. Lett. 2006, 8, 2599.
21. (a) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292; (b) Guanti, G.; Narisano,
E.; Banfi, L. Tetrahedron Lett. 1987, 2, 4331; (c) Hui, W.; Yang, S.; Yu, W.; Pu, Z.
Tetrahedron 2007, 63, 2404.
22. (a) Michael Arend, A.; Bernhard, W.; Nikolaus, R. Angew. Chem., Int. Ed. 1998, 37,
1044; (b) Scott, K. B.; Stephen, F. M. Tetrahedron 2001, 57, 3221; (c) Armando, C.
Acc. Chem. Res. 2004, 37, 102.
23. Doug, E.; Daniel, A. J. Am. Chem. Soc. 2000, 122, 3288.