Direct amination of β-oxo esters

Article abstract of DOI:10.1016/S0040-4039(00)02200-0

The reaction of NsONHCO₂Et, in the presence of CaO, with β-oxo esters gives the corresponding aminated products in yields up to 58%. A substrate carrying the Oppolzer sultam undergoes amination with 40% diastereoselectivity.

Full text of DOI:10.1016/S0040-4039(00)02200-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1171–1173
Direct amination of b-oxo esters
Stefania Fioravanti, Alberto Morreale, Lucio Pellacani* and Paolo A. Tardella
Dipartimento di Chimica dell’Universita` di Roma ‘La Sapienza’, P. le Aldo Moro 2, I-00185 Roma, Italy
Received 18 September 2000; accepted 29 November 2000
Abstract—The reaction of NsONHCO2Et, in the presence of CaO, with b-oxo esters gives the corresponding aminated products
in yields up to 58%. A substrate carrying the Oppolzer sultam undergoes amination with 40% diastereoselectivity. © 2001 Elsevier
Science Ltd. All rights reserved.
Among the methods for formation of carbonꢀnitrogen
bonds,1 the amination of b-dicarbonyl compounds has
received little attention.2–4 An intramolecular reductive
amination of b-oxo esters,5 as well as the addition of
dialkyl azodicarboxylates to b-diketones under spe-
cialised conditions6 have been very recently reported.
We now present our results on the direct amination of
b-oxo esters by using NsONHCO2Et slowly added in
the presence of inorganic bases. Ethyl acetoacetate can
be easily aminated or bis-aminated in the a-position
(Scheme 1) at room temperature in dichloromethane
solution in 3 h, giving 17 (4%) and 2 (41%) when a
threefold excess of CaO was used.
We recently described the use of ethyl N-[(4-nitroben-
zenesulphonyl)oxy]carbamate (NsONHCO2Et) as an
aminating agent for different substrates and for b-
enamino esters, in the absence of added bases.7 Similar
reagents have recently reported by Hanessian8 to give
unexpected alkoxyaminocarbonylation of b-dicarbonyl
compounds and by others9 as electrophilic aminating
agents on amide cuprates.
In order to minimise the bis-adduct 2, an experiment
with a fivefold excess of ethyl acetoacetate and a two-
fold excess of CaO was performed; under these condi-
tions 58% of 1 and 8% of 2 were obtained. In
monoalkylated b-oxo esters (3a,b), under the same con-
ditions, the carbamate or the carbazate functional
group can be directly introduced, again in the a-posi-
Scheme 1.
Scheme 2.
Keywords: amination; keto acids and derivatives; amino acids and derivatives; carbamates.
* Corresponding author. Fax: +39 06490631; e-mail: pellacani@uniroma1.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02200-0

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S. Fiora6anti et al. / Tetrahedron Letters 42 (2001) 1171–1173
tion, giving 4a,b and 5a,b (Scheme 2)10 and the main
product depends on the relative amounts of the
reagents used (Table 1).
NsONHCO2Et with an authentic sample of 7, prepared
by a reported procedure.12
Interestingly, starting from b-oxo esters having a ring
(3c,d) the bicyclic aziridines11 6c,d were isolated
(Scheme 3), in addition to products 4c,d and 5c,d
(Table 2).
Although no mechanistic interpretation can be made at
this point, we believe that hydrogen abstraction by a
nitrene can generate small amounts of 7, that is quickly
aziridinated, as proved by the fast reaction of
A substrate carrying the Oppolzer sultam 8 underwent
amination giving a 54% yield of 9 (Scheme 4) with 40%
diastereoselectivity, a value similar to that observed in
Table 1. Amination of monoalkylated b-oxo esters
Base
Molar ratios substrate:base:NsONHCO2Et
Time (h)
Yields (%)a
4
5
3a
3b
CaO
1:6:2
5:2:1
3
1
3
5
1
42
58
14
28
5
22
4
43
1:6:6b
1:6/6:3
5:2/2:1
CaO/LiOH
5
Traces
a All compounds were separated by flash-chromatography (hexane/ethyl acetate, 70:30) and characterized by 1H, 13C NMR, IR, GC/MS
spectroscopy.
b Added in batches.
Scheme 3.
Table 2. Amination of b-oxo esters 3c,d
Molar ratios substrate:CaO:NsONHCO2Et
Time (h)
Yields (%)a
4
5
6
3c
3d
1:6:2
5:2:1
1:6:2
5:2:1
3
1
3
3
35
49
38
40
4
–
5
–
19
4
13
10
a All compounds were separated by flash-chromatography (hexane/ethyl acetate, 75:25) and characterized by 1H, 13C NMR, IR, GC/MS
spectroscopy.
Scheme 4.

S. Fiora6anti et al. / Tetrahedron Letters 42 (2001) 1171–1173
1173
the alkylation of the same substrate.13 No amination
was observed starting from the a-methyl derivative of 8.
6. Meseguer, M.; Moreno-Man˜as, M.; Vallribera, A. Tetra-
hedron Lett. 2000, 41, 4093–4095.
7. Felice, E.; Fioravanti, S.; Pellacani, L.; Tardella, P. A.
Further experiments aimed at increasing the
diastereoselectivity will be reported in due course. The
amination of other b-dicarbonyl compounds is also in
progress.
Tetrahedron Lett. 1999, 40, 4413–4416.
8. Hanessian, S.; Johnstone, S. J. Org. Chem. 1999, 64,
5896–5903.
9. Zheng, N.; Armstrong, III, J. D.; McWilliams, J. C.;
Volante, R. P. Tetrahedron Lett. 1997, 38, 2817–2820.
1
10. 4a: IR (CCl4) 3417, 1749, 1734 cm−1; H NMR (CDCl3)
l 1.12–1.38 (m, 6H, CH2CH3), 1.72 (s, 3H, CH3), 2.20 (s,
3H, CH3CO), 4.11 (q, J=7.3 Hz, 2H, OCH2), 4.24 (q,
J=7.3 Hz, 2H, OCH2), 6.10–6.35 (br, 1H, NH); 13C
NMR (CDCl3) l 14.04, 14.59, 24.26, 29.78, 61.28, 61.75,
68.63, 154.93, 169.24, 197.48; GC-MS m/z 231 (M+, <1),
189 (21), 188 (65), 158 (27), 143 (28), 142 (33), 116 (40),
115 (32), 114 (19), 88 (54), 86 (33), 70 (26), 44 (13), 43
(41), 42 (100).
Acknowledgements
We thank the Italian Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica (MURST) and the
Universita` di Roma ‘La Sapienza’ (National Project
‘Stereoselezione in Sintesi Organica. Metodologie e
Applicazioni’) and Consiglio Nazionale delle Ricerche
(CNR) for financial support.
5a: IR (CCl4) 3391, 1736 cm−1 1H NMR (CDCl3) l
;
1.15–1.40 (m, 9H, CH2CH3), 1.63 (s, 3H, CH3), 2.34 (s,
3H, CH3CO), 4.05–4.40 (m, 6H, OCH2), 6.35–6.75 (br,
1H, NH); 13C NMR (CDCl3) l 13.74, 14.54, 14.89, 19.57,
24.32, 62.22, 63.27, 63.44, 68.72, 156.64, 156.87, 169.16,
199.07; GC-MS m/z 318 (M+, <1), 231 (11), 203 (60), 188
(70), 173 (14), 157 (51), 142 (29), 131 (12), 129 (42), 116
(10), 101 (100), 90 (11), 35 (12), 83 (17), 70 (10), 57 (19),
43 (48), 42 (43).
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