A new regio- and stereoselective synthesis of β-enamino ketones with 3-ethoxycyclobutanones and substituted amines

Article abstract of DOI:10.1016/j.tetlet.2011.12.040

A new method toward regio- and stereoselective synthesis of β-enamino ketones is described. Through Lewis acid-catalyzed reactions between 3-ethoxycyclobutanones and substituted amines, a variety of cis and trans β-enamino ketone derivatives were prepared

Full text of DOI:10.1016/j.tetlet.2011.12.040

Tetrahedron Letters 53 (2012) 936–939
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new regio- and stereoselective synthesis of b-enamino ketones with
3-ethoxycyclobutanones and substituted amines
Pengfei Liu a,b, Gang Shan a, Shi Chen a, Yu Rao a,
⇑
a Department of Pharmacology and Pharmaceutical Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China
b School of Life Sciences, South China Normal University, Guangzhou 510631, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method toward regio- and stereoselective synthesis of b-enamino ketones is described. Through
Lewis acid-catalyzed reactions between 3-ethoxycyclobutanones and substituted amines, a variety of
cis and trans b-enamino ketone derivatives were prepared with complete regio- and stereoselectivity
at room temperature.
Received 19 October 2011
Revised 5 December 2011
Accepted 9 December 2011
Available online 16 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Regioselectivity
Stereoselectivity
b-Enamino ketones
3-Ethoxycyclobutanones
b-Enamino ketone is an especially versatile class of intermedi-
ates for the synthesis of important heterocycles such as indole,
pyrrole, pyridine, pyrimidine, pyrimidine, pyridinones, quinolines,
oxazoles, and isoxazole derivatives, etc.1,2 It has also been widely
employed to prepare natural therapeutic molecules and biologi-
cally active analogs which include anti-inflammatory, antitumor,
antimalarial, and antibacterial agents, etc.3 1,3-Amino alcohol can
be readily synthesized via reduction of b-enamino ketone as well.4
Additionally, chiral enaminones are used as ligands for diastereo-
selective synthesis.5
Owing to such important applications of b-enamino ketones,
many efforts have been devoted to developing synthetic methods
for the preparation of these compounds.6 Among the current meth-
ods for synthesizing b-enamino ketones, three are most commonly
used (Scheme 1a,b,c). One utilizes the direct condensation of 1,3-
diketones with amines.7 Another route involves the reaction of acid
chlorides and acetylenes under Sonogashira condition followed by
an attack of primary or secondary amines.8 The third approach is
through metal-mediated reduction of isoxazoles.9 Although these
methods are suitable for certain synthetic conditions, many of these
procedures have one or more limitations which include low regi-
oselectivity, circuitously synthetic steps, long reaction time, low
yield, requirement of excess of reagents or catalysts, and harsh
reaction conditions, etc. Therefore, an efficient and complementary
method for b-enamino ketone synthesis is highly desired.
Serving as a versatile synthetic intermediate, 3-ethoxycyclobuta-
noneshavebeenusedto preparevarioustypes of compoundssuchas
bicyclobutanes, silyloxy dienes, and six-membered cyclic com-
pounds.10 In those studies, 3-ethoxycyclobutanones were applied
as a formal 1,4-dipole.11 Recently our group reported the synthesis
of pyrazoles through an annulation reaction between 3-ethoxycy-
clobutanones and substituted hydrazines.12 Our studies
O
O
R3HN
R1
O
R3NH2
(a)
(b)
(c)
(Z)
(E)
R1
R1
R2
R2
condensation
H
R1
O
R3R4NH
COR2
addition of amine
R4R3N
R2
H
R2
O
H2N
R1
O
R3
R1
R4NH2
(Z)
R2
reduction of isoxazole
N
R3
R3HN
H
O
R3NH2
R2
(Z)
R1
O
R2
H
R1
(d)
H
O
R3R4NH
OEt
R
2 (E)
this work
R3R4N
H
R1
⇑
Corresponding author. Tel.: +86 10 62782025; fax: +86 10 62783404.
E-mail addresses: yrao@mail.tsinghua.edu.cn, yrao@tsinghua.edu.cn (Y. Rao).
Scheme 1. General approaches for synthesis of b-enamino ketone.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.040

P. Liu et al. / Tetrahedron Letters 53 (2012) 936–939
937
with complete regioselectivity. The double bond geometry of 2 was
supported by the coupling constant between two olefinic protons
which was 8.50 Hz. Interestingly, only Z-isomer product was ob-
tained, which hints a potential hydrogen-bonding effect that may
account for the stereochemistry outcomes of primary amines.
However, as secondary amines such as TsNHPh was used as sub-
strate, exclusively E-isomer product 3 was formed. The corre-
sponding geometry of double bond of 3 was confirmed with a
significant larger coupling constant of 13.70 Hz. This result sug-
gests that more thermodynamic stable E-isomers are preferred
products in the case of secondary amines.
Encouraged by these preliminary results, we started to optimize
this reaction by screening different conditions (Table 1). In the case
of TsNH2, we found that besides TiCl4, other Lewis acids, such as
BF3.OEt2, SnCl4 can catalyze b-enamino ketone formation with
equal or higher levels of efficiency. In general, a small catalyst
amount, like 0.05 or 0.1 equiv of SnCl4 can promote the reaction
more effectively than higher catalyst loadings. It was observed that
the reaction also proceeded smoothly in various solvents, such as
DCM, DCE, CH3CN, and toluene, and gave b-enamino ketone 2 in
moderate to excellent yields. Lower temperature only has a slight
effect on yield and reaction time. Typically the reaction will pro-
ceed to completion within one hour in a fast and clean manner
at ambient temperature. Entry 6 in Table 1 was found to be the
best conditions for TsNH2. Attempts to apply these conditions to
secondary amines such as TsNHPh, were as successful as those to
TsNH2. After further screening the conditions, we discovered that
1) with TsNH2
Me
O
Me
TsHN
H
O
TsNH2
a
Me
Me
OEt
H
1
2
(Z) 40%
2) with TsNHPh
H
O
Me
O
Me
TsNHPh
a
Ph
N
Me
Me
Ts
H
3
OEt
1
(E) 19%
Condition: a) 0.50 eq. TiCl4, DCM, rt, 0.5 h
Scheme 2. Preliminary studies.
demonstrated, for the first time, 3-ethoxycyclobutanones can be
employed as 1,3-dicarbonyl synthon for useful chemical
transformations.
To date, there is no report in the literatures that 3-ethoxycy-
clobutanones could be operated as 1,3-dicarbonyl synthon to pre-
pare b-enamino ketones. Herein we report the development of a
new efficient one-step approach toward regio- and stereoselective
syntheses of b-enamino ketone through Lewis acid-catalyzed reac-
tion between 3-ethoxycyclobutanone and substituted amine
(Scheme 1d).
In comparison with intramolecular trapping the zwitterionic
intermediate resulted from activated 3-ethoxycyclobutanone by
Lewis acid to afford a new five-member ring, we envisioned that
intermolecularly approaching this in situ formed oxocarbonium
intermediate with nucleophiles such as substituted amines, a vari-
ety of hemiaminal ethers could be generated respectively. After
elimination of EtOH from hemiaminal ether intermediates, corre-
sponding b-enamino ketones could be obtained eventually
(Scheme 1d).
Table 2
Reaction scope with respect to primary amines
R1
R3HN
H
O
O
R2
R3NH2
R2
(Z-isomer)
0.05 eq.SnCl4, DCM, rt
0.5-1.0 h
H
R1
OEt
Product
Yielda
(%)
Product
Yielda
(%)
To test our hypothesis, a model study was initiated with TsNH2
which is selected as the nitrogen nucleophile and 2,2-dimethyl 3-
ethoxycyclobutanone (Scheme 2).13 As a Lewis acid promoter,
0.5 equiv of TiCl4 was added to the reaction mixture. The reaction
was very fast and went to completion in 30 min at room tempera-
ture. Delightfully the desired product 2 was obtained in a 40% yield
CbzHN
H
O
TsHN
H
O
Me
Me
Me
4
11
84
78
94
82
78
95
75
93
H
H
FmocHN
O
FmocHN
O
O
O
5
12
Me
Me
Me
75
96
71
95
78
79
H
H
H
O
H
O
Table 1
TsHN
TsHN
Optimization of the reaction conditions
6
13
15
Et
Et
H
H
Me
TsHN
H
O
O
Me
TsNH2
Conditions
H
Et
O
H
Me
Me
CbzHN
FmocHN
7
14
H
OEt
1
2
Et
Et
H
H
Yielda (%)
H
O
H
Et
Entry
Catalyst
Condition
FmocHN
O
TsHN
1
2
3
4
5
6
7
8
9
TiCl4
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.05 equiv, DCM, rt, 0.5 h
0.3 equiv, DCM, rt, 0.5 h
1.0 equiv, DCM, rt, 0.5 h
0.1 equiv, DCE, rt, 0.5 h
51
75
84
68
65
96b
68
56
81
43
45
87
BF3OEt2
SnCl4
TfOH
Et
8
Bn
H
H
H
O
Et
H
TMSOTf
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
TsHN
FmocHN
H
H
9
16
H
H
O
FmocHN
O
CbzHN
H
10
11
12
0.1 equiv, Toluene rt, 0.5 h
0.1 equiv, CH3CN, rt, 0.5 h
0.1 equiv,DCM,0 °C, 1.5 h
H
10
17
H
H
a
Conversion ratio.
Isolated yield.
b
a
Isolated yield.

938
P. Liu et al. / Tetrahedron Letters 53 (2012) 936–939
Table 3
Reaction scope with respect to secondary amines
H
O
R1
O
R2
R3NHR4
R
2 (E-isomer)
R3R4N
0.1 eq.SnCl4, DCM, rt
0.5-1.0 h
H
R1
OEt
Product
Yielda (%)
Product
Yield (%)
73
H
O
H
O
O
O
Ph
N
Me
Pr
Pr
Pr
68
3
27
28
29
N
Ts
H
Me
Cbz H
H
O
H
p-F-C6H4
Me
18
74
69
56
76
66
62
67
66
70
70
68
73
46
55
65
52
48
N
Ts
N
Ts
O
H
Me
H
H
H
H
Pr
N
Me 19
N
Ts
H
Me
Ts
H
O
H
O
O
O
Me
p-F-C6H4
N
O
N
20
30
H
Me
Ts
H
H
O
H
O
Pr
N
Et
O
21
N
O
31
Cbz
H
Et
H
H
H
O
Ph
N
p-F-C6H4
Et
22
N
32
33
Ts
O
H
Et
Cbz
H
H
H
H
O
Ph
N
Et
Et
Bn
Me
N
23
Ts
H
H
H
H
H
Et
Et
Cbz
O
O
O
H
O
O
Bn
Me
24
34
35
N
N
N
O
Cbz
H
H
H
O
O
Bn
Et
25
26
N
O
H
Ts
H
Bn
Bn
N
Ts
a
Isolated yield.
0.1 equiv of SnCl4 was the most suitable condition to form b-ena-
mino ketone product 3 with TsNHPh.
geometric b-enamino ketone derivatives in modest to good yields.
Notably, as a secondary amine substrate, oxazolidin-2-one pro-
vided corresponding products in satisfactory yields as well (Table
3, compounds 20, 31, 34, and 35). Overall, in comparison with pri-
mary amines, secondary amines gave relatively lower yields, which
may in part contribute to their more steric nature. In particular, the
consistent complete regioselectivity and stereoselectivity of the
reaction were observed. Only single isomers were obtained in all
examples.
A plausible mechanism is demonstrated in Scheme 3. Upon acti-
vation of 2,2-dimethyl 3-ethoxycyclobutanone (1) with Lewis
acids, the more substituted C2–C3 bond of 3-ethoxycyclobutanone
1 was broken down preferentially to form a zwitterionic interme-
diate II. Consequently intermolecularly approaching by either pri-
mary amine TsNH2 or secondary amine TsNHPh provided the
intermediates II or IV, respectively. Following this transforming
With the optimal conditions in hand, we set out to explore the
scope for this new reaction. As shown in Table 2, a variety of 3-eth-
oxycyclobutanones were reacted with different primary amines in
the presence of 0.05 equiv SnCl4. It was found that not only TsNH2,
but also CbzNH2 and FmocNH2 can react readily to furnish the cor-
responding (Z) geometric b-enamino ketone derivatives. Notably,
all 3-ethoxycyclobutanones with varied 2-mono- or 2,2-di-substit-
utents produced the desired Z-isomer products smoothly in good
to excellent yields (Compounds 4–17, Table 2). In all cases, only
one single product was isolated, no other regioisomer or stereoiso-
mer was obtained.
As illustrated in Table 3, the optimum reaction conditions
proved to be compatible with a variety of secondary amines which
reacted with 3-ethoxycyclobutanones to readily provide (E)

P. Liu et al. / Tetrahedron Letters 53 (2012) 936–939
939
National Natural Science Foundation of China (Grant # 21142008)
and Tsinghua University 985 Phase II funds. We thank Dr. Y. Li
(Massachusetts Institute of Technology) and Dr. M. J. Dai (Harvard
University) for helpful discussions. We also thank Mr. J. Zhao for
his help in preliminary studies.
Me
RHN
H
O
O
O
Me
2
LA
Me
Me
+
RNH2
3
1
H
OEt
Me
Me
Me
H
Supplementary data
RN
EtO
O
LA-O
Me
H
LA
Me
Me
NHR
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.040.
RNH2
OEt
LA
H
OEt
II
I
III
References and notes
Me
H
O
O
O
Me
2
3
OEt
LA
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Me
Me
+ RNHPh
RPhN
1
H
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Me
Me
Me
LA
LA-O
Me
OEt O
LA
H
Me
Me
RPhN
NPhR
RHN
OEt
H
OEt
IV
Ph
IH
V
Scheme 3. Plausible mechanism.
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step, a proton transfer generated hemiaminal ether intermediates
III or V. Finally, elimination of one molecule of EtOH from III or V
afforded corresponding Z or E geometric products.
In summary, an efficient one-step protocol has been developed
for the rapid synthesis of b-enamino ketones from easily accessible
starting materials at ambient temperature. To the best of our
knowledge, this is the first report about regio- and stereoselective
syntheses of both cis and trans b-enamino ketones by one single
method. This method has been found to be generally useful for
the preparation of a variety of b-enamino ketone derivatives some
of which are difficult to make via conventional approaches. The
reaction demonstrates excellent reactivity, complete regioselectiv-
ity and stereoselectivity, and high yields. By employing 3-eth-
oxycyclobutanones in this unique ring-opening reaction with
substituted amines, we have shown, for the first time, that this
masked 1,3-dicarbonyl synthon acts as a three-carbon synthon of
3-ethoxycyclobutanones in the preparation of b-enamino ketones.
Further studies using 3-ethoxycyclobutanones as three-carbon
components in other chemical transformations are currently in
progress.
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2009, 131, 14202.
12. Shan, G.; Liu, P.; Rao, Y. Org. Lett. 2011, 13, 1746.
13. Aromatic and alphatic primary amines such as aniline and PrNH2 failed to give
corresponding products under the same conditions.
Acknowledgments
This work was supported by the national ‘973’ grant from the
Ministry of Science and Technology (Grant # 2011CB965300),