An efficient and inexpensive catalyst system for the aza-Michael reactions of enones with carbamates

Article abstract of DOI:10.1039/b307733k

A new strategy which uses very cheap FeCl₃ as an effective catalyst in the presence of Me₃SiCl has been developed for the conjugate addition of enones and chalcone with unactivated weakly nucleophilic carbamates.

Full text of DOI:10.1039/b307733k

An efficient and inexpensive catalyst system for the aza-Michael
reactions of enones with carbamates†
Li-Wen Xu, Chun-Gu Xia* and Xiao-Xue Hu
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physic,
Chinese Academy of Science, Lanzhou, 730000, P R China. E-mail: cgxia@ns.lzb.ac.cn;
Fax: 86-931-8277088
Received (in Cambridge, UK) 8th July 2003, Accepted 5th September 2003
First published as an Advance Article on the web 17th September 2003
A new strategy which uses very cheap FeCl
3
as an effective
addition of organic-copper reagents13 and Michael addition
reactions of chiral benzylic anions.14 At this point we decided to
catalyst in the presence of Me SiCl has been developed for
3
the conjugate addition of enones and chalcone with un-
activated weakly nucleophilic carbamates.
investigate the use of Me
were made toward achieving conjugate addition of carbamates
to chalcone in the presence of Me SiCl, we surveyed the
3
SiCl as an additive. Several attempts
3
The b-amino carbonyl functionality is not only a segment of
biologically important natural products but also a versatile
intermediate for the synthesis of nitrogen-containing com-
catalytic effects of various inexpensive transition metal salts in
the aza-Michael reaction of chalcone with ethyl carbamate in
CH
2
Cl
2
at room temp. (Table 1, Scheme 1). Interestingly,
·6H O and FeCl were
1
pounds. The development of novel synthetic methods leading
among the metal salts tested, only FeCl
3
2
3
to b-amino ketones, b-amino acids or their derivatives has
attracted much attention in organic synthesis. Mannich-type
reaction is one of the classical and powerful methods for the
found to be effective in the conjugate addition of chalcone with
ethyl carbamate. We also tested the effects of other Brønsted or
Lewis acids instead of Me
BF ·OEt , HCl, p-TsOH, aq. HBF
aza-Michael reaction of chalcone. Here we disclose the first
conjugate addition of enones with carbamates with Me SiCl/
FeCl ·6H O as the catalyst system.
With this effective catalyst in hand, aza-Michael reactions of
various chalones with carbamates in CH Cl at room temp.
3
SiCl, and found that acids such as
2
construction of this functionality. However, due to the harsh
3
2
4
have similar effects in the
reaction conditions and long reaction times, the classic Mannich
3
reaction presents serious disadvantages. Therefore, a variety of
3
methods have been reported for the synthesis of b-amino
carbonyl compounds. But owing to simplicity and atom
economy, the more widely used method is the conjugated
addition of nitrogen nucleophiles to a,b-unsaturated enones
3
2
2
2
were investigated (Table 2).‡ In this conjugate addition
reaction, moderate yields of b-amino ketones were obtained
with chalcone.
Aza-Michael reactions of other various cyclic enones with
carbamates in dichloromethane at room temp. were also
investigated (Table 3).‡ Benzyl carbamate, ethyl carbamate and
2-oxazolidone reacted smoothly with 2-cyclohexen-1-one and
2-cyclopentenone to give the corresponding aza-Michael ad-
ducts in high yields. Note that similar results can be achieved
with 5 mol% catalyst (entries 3, 5 and 14). Additionally, the
(
aza-Michael reaction). The conjugated addition of nucleo-
philes to a,b-unsaturated compounds usually requires basic
4
conditions or acid catalysis. To avoid typical disadvantages
resulting from the presence of such a catalyst, a large number of
alternative procedures have been developed in the past few
years.5 However, most methods for intermolecular conjugated
addition to unsaturated ketones reported to date describe the
addition of alkyl or aryl amines. Because carbamates are weak
nucleophiles, many catalysts are practically ineffective in
catalyzing a similar reaction with carbamates. Spencer et al.
–9
2 2
demonstrated PdCl (MeCN) , Brønsted acid and copper-cata-
Table 1 Catalytic activity of metal salts in aza-Michael reaction of
lyzed intermolecular aza-Michael reactions of enones with
benzyl carbamate as nitrogen nucleophile.10 Quite recently,
Kobayashi surveyed the catalytic activities of various transition
metal salts in the aza-Michael reaction of enones with benzyl
carbamate and demonstrated that salts of platinum, iridium,
chalconea
Yield (%)b
Entry
Catalyst (10 mol%)
CuI
Time/h
1
2
3
4
5
6
7
8
9
24
24
24
12
12
12
24
24
24
24
24
24
24
24
trace
c
gold, etc. are very effective for addition reactions with
Co(OAc)
Mn(OAc)
2
·4H
·4H
2
O
NR
carbamates.11 However, all these catalysts are ineffective in
2
2
O
trace
45
40
FeCl
FeCl
3
2
·6H O
catalyzing the conjugate addition of chalcone with carbamates.
To the best of our knowledge, the aza-Michael reaction of
chalcone has not been reported. Therefore, development of
more effective and inexpensive catalyst systems, especially
which can be applied to chalcone, is highly desirable.
We are interested in the aza-Michael reactions of enones with
carbamates, and the previous findings prompted us to in-
vestigate new catalysis in this aza-Michael reaction. Herein, we
report a new catalyst system is quite effective for the aza-
Michael reactions of chalcone and other enones with carba-
mates.
3
2 2
Cu(OAc) ·2H O
CuBr
trace
NR
trace
NR
NR
NR
NR
NR
NR
2 2
Ni(acac) ·2H O
NiCl ·2H O
2
2
10
11
12
Cu(OTf)2
CuCl ·2H
PdCl (MeCN)
·7H
·4H
2
2
O
d
2
2
1
1
3
4
CrCl
3
2
O
2
O
AuCl
3
a
Reactions were conducted with catalyst (10 mol%), chalcone (1 mmol),
3 2 2
ethyl carbamate (1.2 mmol), Me SiCl (1.1 mmol) in CH Cl (3 ml) at room
3 2
FeCl ·6H O is to date the most efficient catalyst for the
temp. b Isolated yield. No reaction occurred. d No addition of Me
c
12
3
SiCl.
Michael reaction of b-keto esters with vinyl ketones. Inspired
by previous reports of Michael reactions we consider
FeCl
reaction. However, we found that no reaction occurred using
FeCl ·6H O as a catalyst in this aza-Michael addition reaction.
It has been reported that Me SiCl was helpful for the conjugate
3 2
·6H O to be also an efficient catalyst for the aza-Michael
3
2
3
†
Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b3/b307733k/
Scheme 1
2
570
CHEM. COMMUN., 2003, 2570–2571
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Table 2 Aza-Michael reactions of various carbamates with b-phenyl-
the present reaction system. When the total product was treated
a
enones
with the catalyst system under the same reaction conditions, the
retro-aza-Michael reaction was not observed. So this result
indicated that the reaction is not under thermodynamic control.
UV analysis of a CH
FeCl ·6H O showed a large wavelength shift (251 nm in
CH Cl and 234 nm in CH CN), while solutions of chalcone
and FeCl ·6H O, aq. HBF and Cu(OTf) showed no significant
wavelength change (226 nm in CH CN). It is suggested that the
mode of interaction of the substrates with this catalytic system
would differ from that of conventional Brønsted acids.
2 2 3
Cl solution of chalcone, Me SiCl and
3
2
2
2
3
3
2
4
2
Entry
Enone
Carbamate
Time/h
12
Yield (%)b
3
1
2
NH
2
CBZ
CBZ
50
42
NH
2
18
Notes and references
‡
(
Representative aza-Michael addition reaction was as follows: FeCl
27 mg, 0.1 mmol) and the enones (1 mmol) were dissolved in CH
ml). Me SiCl (1.1 mmol) was added. Then carbamate (1.2 mmol) was added
3
·6H
2
O
(3
3
4
24
24
24
52
40
45
2
Cl
2
3
in one portion. The yellow solution was stirred at room temp. and
conversion was monitored by TLC. After completion of the reaction, the
mixture was quenched with 5 ml sat. aq. NaHCO
was extracted with CH Cl . The combined organic layers were dried over
Na SO , filtered, and evaporated. The crude product was purified by
column chromatography (eluting solvent EtOAc/petroleum ether).
3
, and the aqueous layer
5
NH
2
COOEt
2
2
2
2
4
a
Reactions carried out with FeCl
SiCl (1.1 mmol) in CH
Isolated yield after column chromatography.
3
·6H
2
O (10 mol%), enone (1 mmol),
carbamate (1.2 mmol), Me
3
2
Cl (3 ml) at room temp..
2
b
1
(a) G. Cardill and C. Tomasini, Chem. Soc. Rev., 1996, 117; (b)
Enantioselective Synthesis of b-Amino Acids, ed. E. Juaristi, Wiley-
VCH, New York, 1997; (c) The Organic Chemstry of b-Lactams, ed. G.
I. George, VCH, New York, 1993; (d) E. Juaristi and H. Lopez-Ruiz,
Curr. Med. Chem., 1999, 6, 983; (e) D. Seebach and J. L. Matthews,
Chem. Commun., 1997, 2015; (f) W. J. Drury, D. Ferraris, C. Cox, B.
Young and T. Leckta, J. Am. Chem. Soc, 1998, 120, 11006; (g) E.
Hagiwara, A. Fujii and M. Sodeoka, J. Am. Chem. Soc., 1998, 120,
Table 3 Aza-Michael reactions of various carbamates with cyclic enones
2
474; (h) J. K. Myers and Jacobsen, J. Am. Chem. Soc., 1999, 121, 8959;
(i) S. Abele and D. Seebach, Eur. J. Org. Chem., 2000, 6, 1.
2
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T. Furuta and S. Kobayashi, Heterocycles, 2000, 52, 1143; (e) H.
Ishitani, M. Ueno and S. Kobayashi, J. Am. Chem. Soc., 2000, 122,
8180.
TMS
(equiv.)
a
Yield (%)b
Entry
Enone
Carbamate
Time/h
1
2
24
18
—
Tracec
88
1.1
3
4
M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed., 1998,
37, 1044.
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Tsukada, K. Yazawa, Y. S. Gyoung and Y. Yamamoto, J. Org. Chem.,
3
4
18
12
1.1d
1.1
82
90
5
NH
2
COOEt
12
1.1d
1.1
89
1
997, 62, 6274 and refs. therein (d) S. D. Bull, S. G. Davies, S. Delgado-
6
7
8
9
12
10
12
12
92
93
66
30
Ballester, G. Fenton, P. M. Kelly and A. D. Smith, Synlett, 2000, 1257;
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0.5
0.25e
0.05
0.5
5
6
1
0
NH
NH
2
CBZ
CBZ
12
81
1
1
1
2
12
12
0.05
1.1
46
85
7 (a) M. Kawatsura and J. F. Hartiwig, Organometallics, 2001, 20, 1960;
(b) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033; (c) W.
Zhuang, R. G. Hazell and K. A. Jørgensen, Chem. Commun., 2001,
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J. J. Shay, M. Liu and C. P. Jasperse, J. Am. Chem. Soc., 1998, 120,
6615.
1
3
2
12
0.5
83
1
1
a
4
5
12
12
1.1d
1.1
74
87
8 G. Bartoli, M. Bosco, E. Marcantoni, M. Pertrini, L. Sambri and E.
Torregiani, J. Org. Chem., 2001, 66, 9052.
Reactions carried out with cyclic enone (1 mmol), carbamate (1.2 mmol),
in CH
2
Cl
2
(3 ml) at room temp. using FeCl
3
·6H
2
O (10 mol%) and Me
3
SiCl.
SiCl.
9 N. Srivastava and B. K. Banik, J. Org. Chem., 2003, 68, 2109.
10 (a) M. J. Gaunt and J. B. Spencer, Org. Lett., 2001, 3, 25; (b) T. C.
Wabnitz and J. B. Spencer, Tetrahedron Lett., 2002, 43, 3891; (c) T. C.
Wabnitz, J. Q. Yu and J. B. Spencer, Synlett, 2003, 1070; (d) T. C.
Wabnitz and J. B. Spencer, Org. Lett., 2003, 5, 2141.
b
c
Isolated yield after column chromatography. No addition of Me
3
d
e
3 2 3 2
Addition of 5 mol% FeCl ·6H O. Addition of 1 mol% FeCl ·6H O.
1
1 S. Kobayashi, K. Kakumoto and M. Sugiura, Org. Lett, 2002, 4,
319.
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Commun., 1997, 943.
reaction can be performed with 50 mol% Me
3
SiCl without
1
sacrificing yield (entries 7, 10 and 13).
1
The reaction was performed with FeCl
addition of Me SiCl in CH Cl
3
·6H O without
2
3
2
2
or acetonitrile, but Michael
adducts were not obtained. On the other hand, Me SiCl was also
3
1
3 E. Nakamura, S. Aoki, K. Sekiya, H. Oshino and I. Kuwajima, J. Am.
Chem. Soc., 1987, 109, 8056.
ineffective in aza-Michael reactions with these less nucleophilic
carbamates. To get insight into the reaction mechanism, we
performed several experiments to confirm the possibilities in
14 R. E. J. Beckwith, N. Heron and N. S. Simpkins, J. Organomet. Chem.,
2002, 658, 21.
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