Zn(ClO4)2·6H2O as a Powerful Catalyst for the Conversion of β-Ketoesters into β-Enamino Esters

Article abstract of DOI:10.1055/s-2003-44974

Zn(ClO₄)₂·6H₂O proved to be a very powerful catalyst for the condensation of primary and secondary amines with β-ketoesters to give N-substituted β-enaminoesters.

Full text of DOI:10.1055/s-2003-44974

LETTER
239
Zn(ClO4)2·6H2O as a Powerful Catalyst for the Conversion of b-Ketoesters into
b-Enamino Esters
C
a
onversionof
b-K
i
etoeste
u
rs into
b
-Ena
s
minoEsters ppe Bartoli,*a Marcella Bosco,a Manuela Locatelli,a Enrico Marcantoni,b Paolo Melchiorre,a Letizia Sambri*a
Dipartimento di Chimica Organica ‘A. Mangini’, v.le Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: giuseppe.bartoli@unibo.it
b
Dipartimento Scienze Chimiche, Università di Camerino, via S.Agostino 1, 62032 Camerino, (Macerata), Italy
Received 8 October 2003
In order to expand the applications of zinc perchlorate, we
report here that Zn(ClO4)2·6H2O can act as a powerful
catalyst for the synthesis of N-substituted b-enamino es-
ters 1 via condensation of b-ketoesters 2 with primary and
secondary amines 3 (Scheme 1).
Abstract: Zn(ClO4)2·6H2O proved to be a very powerful catalyst
for the condensation of primary and secondary amines with b-ke-
toesters to give N-substituted b-enaminoesters.
Key words: amino acid derivatives, zinc perchlorate, condensa-
tion, amines, keto esters
Preliminary results reported in Table 1 showed that in the
condensation of t-butyl acetoacetate with aniline the cata-
lytic activity of Zn(ClO4)2·6H2O can be enhanced by the
presence of anhydrous MgSO4 (Table 1, entry 3 and 4).
On the other hand, the reaction is sluggish with MgSO4
alone (Table 1, entry 2).
b-Enamino esters represent an important class of func-
tionalized building blocks. For example, they have proved
themselves valuable intermediates for the synthesis of bi-
ologically active compounds, such as a-1 and b-amino ac-
ids,2 g-aminols,2b alkaloids,3 peptides4 and heterocyclic
derivatives.5
We found that the best reaction conditions require the
presence of a small amount of Zn(ClO4)2·6H2O (5 mol%),
dry MgSO4 (30 mol%) and 1.5 equivalents of amine with
respect to the b-ketoester at room temperature in CH2Cl2.
The catalyst is very active, stable to air-moisture and not
expensive. In addition, it can be quantitatively recovered
by filtration, reactivated by heating in an oven at 60 °C16
overnight and reused. We repeated this recovering proce-
dure several times and we never observed loss of activity.
These compounds can be obtained via addition of metallic
ester or amide enolates to nitriles,6 tosyl imines,7 and
imidoyl halides,8 and via addition of enamines9 or
ketimines10 to activated carboxylic acid derivatives.
Moreover, b-enamino esters can be successfully obtained
from direct condensation of b-keto esters with amines.11
Nevertheless, most of the approaches currently available
suffer from some limitations, such as low chemical yields
and lack of general applicability.
The methodology17 can be applied to cyclic and acyclic b-
ketoesters, giving in all cases very good results with
primary, secondary, benzylic and aromatic amines.
In the last few years, we were interested in the use of
metallic perchlorates as Lewis acid promoters in various
organic transformations, such as the LiClO4 mediated
Friedel–Crafts acylation of activated benzenes12 and the
acylation of alcohols catalyzed by Mg(ClO4)2.13 In all
cases, best results were obtained using anhydrous perchlo-
rates salts, which showed increased efficiency if warmed
under vacuum at 140 °C before use. Owing to the poten-
tial hazards connected with the heating of such salts,14 we
focused our attention to more efficient perchlorates, active
even in the presence of water. In fact, Zn(ClO4)2·6H2O
was recently found to show a catalytic activity superior to
Mg(ClO4)2 for the acylation of alcohols.15
The reaction suffers from steric hindrance, therefore with
acyclic b-ketoesters carrying a substituent different than
hydrogen in the a-position or with a bulky amine it is
necessary to carry out the reaction at reflux (40 °C).
Table 1 Condensation of t-Butyl Acetoacetate 2a with Aniline 3a
(1.5 equivalents) in CH2Cl2 under Various Reaction Conditions
Ph
O
O
NH
O
catalyst
CH2Cl2
+
Ph-NH2
Ot-Bu
Ot-Bu
3a
2a
1a
Entry Catalyst (mol%)
Time (h) Yield (%)
R4
R1
R5
1
2
3
4
5
–
115
115
80
58
98
98
96b
98
O
O
N
O
R4
R5
Zn(ClO4)2·6H2O
+
R1
OR3
N
H
MgSO4 (30)a
OR3
R2
R2
3
Zn(ClO4)2·6H2O (5)
2
1
Zn(ClO4)2·6H2O (5), MgSO4 (30)a
Zn(ClO4)2·6H2O (5), MgSO4 (30)a
48
Scheme 1
21
SYNLETT 2004, No. 2, pp 0239–0242
0
2.
0
2.
2
0
0
4
a Dried in oven at 60 °C overnight before use.
b Reaction carried out with 1 equiv of aniline.
Advanced online publication: 04.12.2003
DOI: 10.1055/s-2003-44974; Art ID: G27003ST
© Georg Thieme Verlag Stuttgart · New York

240
G. Bartoli et al.
LETTER
Table 2 Synthesis of b-Enamino Esters 1 via Condensation of b-Keto Ester 2 (1 equivalent) with Amine 3 (1.5 equivalents) in the Presence
of Zn(ClO4)2·6H2O (5 mol%) and MgSO4 (30 mol%) at Room Temperature, Unless Otherwise Mentioned
R4
R5
O
O
N
O
R4
R5
Zn(ClO4)2·6H2O 5% mol
+
R1
OR3
N
H
R1
OR3
R2
MgSO4 30 mol%
CH2Cl2
R2
3
2
1
Entry
1
R1
R2
H
H
H
H
R3
R4
R5
H
H
H
Product
1b
1c
Time (h)
Yield (%)
71
Me
Me
Me
Me
t-Bu
t-Bu
t-Bu
t-Bu
Et
Chx
16a
7
2
n-Bu
p-OMe-Ph
-(CH2)4-
Ph
77
3
1d
1e
48
8
95
4
97b
99
5
-(CH2)3-
-(CH2)3-
-(CH2)4-
Et
H
H
H
H
H
H
H
H
1f
5
6
Et
nBu
1g
8
91
7
Et
Ph
1h
1i
24
16a
30a
26a
15a
28
95
8
Me
Me
Me
H
Et
PhCH2
PhCH2
PhCH2
PhCH2
Ph
96b
97
9
C7H15
Et
Et
1l
10
11
12
t-Bu
Et
1m
1n
1o
77
Ph
85
Me
Cl
Et
95
a Reaction carried out at reflux.
b Reaction carried out with 1 equiv of amine.
Since it has been recently reported18 that perchlorate salts
activate anhydrides forming a cyclic complex, it may be
expected that perchlorates are able to activate other 1,3-
dicarbonyl compounds, such as b-diketones, to form an
electrophilic complex, which undergoes a smooth addi-
tion from an aminic nucleophile (Table 2).
Table 3 Synthesis of b-Enamino Ketones 5 via Condensation of b-
Diketones 2 (1 equivalent) with Aniline 3a (1.5 equivalents) in the
Presence of Zn(ClO4)2·6H2O (5 mol%) and MgSO4 (30 mol%) at
Room Temperature, Unless Otherwise Mentioned
Ph
H
Zn(ClO4)2·6H2O 5% mol
O
O
N
O
Ph-NH2
+
R1
R2
R1
R2
MgSO4 30% mol
CH2Cl2
4
5
To confirm this hypothesis, we applied this methodology
to other 1,3-dicarbonyl substrates, such as b-diketones.
Preliminary data are reported in Table 3. The obtained re-
sults show that the condensation of various b-diketones 4
with aniline proceeds smoothly in high yields in all exam-
ined cases. This methodology can be applied to symmet-
rical b-diketones. In the case of unsymmetrical
compounds the regiochemistry is controlled by the more
reactive carbonyl group, which undergoes the attack of
the amine (Table 3, entry 2). However, in the case of
1,1,1-trifluoro-pentan-2, 4-dione (Table 3, entry 4), the
obtained product 5d19 derives from the addition of the
aniline to the although less reactive carbonyl bound to the
methyl group. Very likely, this anomalous result can be
ascribed to the fact that in solution the starting material is
present in over 95% as the keto-enol tautomer 6d
(Figure 1).20
Entry
R1
R2
Product
5a
Time (h) Yield (%)
1
2
3
4
5
Me
Me
Et
Me
Ph
4
95
98
89
80
78
5b
5
Et
5c
5.5
28
31a
Me
Ph
CF3
Ph
5d
5e
a Reaction carried out at reflux.
O
O
O
OH
CF3
CF3
6d
4d
Figure 1
In conclusion, Zn(ClO4)2·6H2O shows a strong catalytic
activity in promoting the condensation of amines with
1,3-dicarbonyl substrates. The present method appears to
be competitive and in some cases superior to previously
Synlett 2004, No. 2, 239–242 © Thieme Stuttgart · New York

LETTER
Conversion of b-Ketoesters into b-Enamino Esters
241
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Acknowledgment
All work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica. Metodologie e Applicazioni’
supported by MIUR, Rome, and by the University of Bologna, in
the framework of ‘Progetto di Finanziamento Pluriennale, Ateneo
di Bologna’.
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(16) These conditions are sufficient to reactivate the catalyst,
without any decomposition process. Zn(ClO4)2·6H2O in fact
decomposes under vacuum at temperatures higher than
140 °C.
(17) Representative Experimental Procedure: Synthesis of
tert-butyl-3-anilino-2-butenoate (1a). To a round-bottom
flask Zn(ClO4)2·6H2O (24 mg, 0.063 mmol), MgSO4 (46 mg,
0.38 mmol), t-butyl acetoacetate (0.21 mL, 1.26 mmol),
CH2Cl2 (0.5 mL) and aniline (0.17 mL, 1.90 mmol) were
added. The reaction mixture was stirred at r.t. for 21 h. After
addition of 5 mL of CH2Cl2, the catalyst was filtered off and
the solution was concentrated at reduced pressure. The crude
product was purified by filtration on a short silica gel column
pre-treated with Et3N. The filtered catalyst was reactivated
by heating in a oven at 60 °C overnight and reused.
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4.60 (bs, 1 H, CH), 7.05–7.20 (m, 3 H, Ph), 7.25–7.35 (m, 2
H, Ph), 10.40 (bs, 1 H, NH). 13C NMR (75 MHz, CDCl3):
d = 20.2 (CH3), 28.6 (CH3), 78.5 (C), 87.8 (CH), 124.2 (CH),
124.6 (CH), 128.9 (CH), 139.5 (C), 158.0 (C), 170.3 (C). IR
(nujol): nNH = 3272 cm–1. MS (EI): m/z (%) = 233(6) [M+],
17 7(16), 118 (41), 77 (30), 59 (100).
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JHH = 7.2 Hz), 1.27 (t, 3 H, CH3, JHH = 7.2 Hz), 1.35–1.40
(m, 2 H, CH2), 1.45–1.60 (m, 2 H, CH2), 1.80–1.90 (m, 2 H,
CH2), 2.45–2.60 (m, 4 H, 2 × CH2), 3.15–3.25 (m, 2 H,
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Synlett 2004, No. 2, 239–242 © Thieme Stuttgart · New York

242
G. Bartoli et al.
LETTER
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(CH2), 58.2 (CH2), 91.9 (C), 164.8 (C), 168.4 (C). IR (neat):
n
NH = 3320 cm–1. MS (EI): m/z (%) = 211 (43) [M+], 182 (9),
166 (28), 122 (100).
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Synlett 2004, No. 2, 239–242 © Thieme Stuttgart · New York