Transition Metal Salts-Catalyzed Aza-Michael Reactions of Enones with Carbamates

Article abstract of DOI:10.1021/ol0256163

(Matrix Presented) Several transition metal salts were found to catalyze aza-Michael reactions of enones with carbamates efficiently. The catalytic activity was strongly dependent on the nature of the metal salts. While conventional Lewis acids such as BF

Full text of DOI:10.1021/ol0256163

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1319-1322
Transition Metal Salts-Catalyzed
Aza-Michael Reactions of Enones with
Carbamates
Shu¯ Kobayashi,* Kentaro Kakumoto, and Masaharu Sugiura
Graduate School of Pharmaceutical Science, The UniVersity of Tokyo and CREST,
Japan Science and Technology Corporation (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received January 24, 2002
ABSTRACT
Several transition metal salts were found to catalyze aza-Michael reactions of enones with carbamates efficiently. The catalytic activity was
strongly dependent on the nature of the metal salts. While conventional Lewis acids such as BF3‚OEt2, AlCl3, or TiCl4 showed lower activity,
group 7−11 transition metal salts in higher oxidation states such as ReCl5, Fe(ClO ) ‚9H O, RuCl3‚nH O, OsCl3‚3H O, RhCl3‚3H O, IrCl4‚nH O,
4 3
2
2
2
2
2
PtCl4‚5H O, or AuCl3‚2H O exhibited higher catalytic activity.
2
2
The â-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-
pounds such as 1,3-amino alcohols, â-amino ketones,
â-amino acids, and â-lactams.1 Carbon-carbon bond forma-
tion between imines and enolates (Mannich-type reaction)
is one of the powerful methods for the construction of this
functionality,1d-h and we have recently demonstrated that
certain achiral2 or chiral3 Lewis acids effectively catalyzed
Scheme 1. Construction of â-Amino Carbonyl Functionality
(1) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Cardillo, G.; Tomasini, C. Chem. Soc.
ReV. 1996, 117. (c) The Organic Chemistry of â-Lactams; Georg, G. I.,
Ed.; VCH Publishers: New York, 1993. (d) Blicke, F. F. Org. React. 1942,
1, 303. (e) Tramontini, M. Synthesis 1973, 703. (f) Tramontini, M.;
Angiolini, L. Tetrahedron 1990, 46, 1791. (g) Kleinman, E. F. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, p 893. (h) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (i) Jung, M. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 30-41 and references therein. (j)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069 and references therein.
(2) (a) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya,
I. Synlett 1995, 233. (b) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc.
1997, 119, 10049. (c) Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965.
(d) Okitsu, O.; Oyamada, H.; Furuta, T.; Kobayashi, S. Heterocycles 2000,
52, 1143.
this type of reaction (Scheme 1). On the other hand, carbon-
nitrogen bond formation between R,â-unsaturated carbonyl
compounds and nitrogen nucleophiles (aza-Michael reaction)
provides an alternative route to this functionality (Scheme
1).1i
No catalyst is generally required in aza-Michael reactions
with amines1i or lithium amides4 as nucleophiles. Meanwhile,
Lewis acidic metal catalysts have also been employed in less
reactive aza-Michael reactions. A catalytic amount of FeCl3,
LiCl, HgCl2,5 lanthanide triflates [Ln(OTf)3, Ln ) La, Sm,
(4) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung,
Y. S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274 and
references therein.
(3) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180. See also ref 1j.
10.1021/ol0256163 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

Yb],6 or InCl37 was reported to mediate the conjugate addition
of aliphatic amines to R,â-unsaturated carbonyls in non-
aqueous or aqueous solvents. Recently, Pd(II), Rh(I), Ir(I),
and Ru(II) complexes have been reported to be effective for
addition of amines to acrylic acid derivatives.8 With O-
benzylhydroxyamine or aromatic amines as nucleophiles,
asymmetric catalysis has been attained using chiral titanium,
magnesium, and nickel compounds.9,10 An enantioselective
aluminum catalyst has also been developed for the conjugate
addition of hydrazoic acid to R,â-unsaturated imides.11
While either a base or acid catalyst is used in aza-Michael
reactions with a less nucleophilic carbamate (mostly in-
tramolecular reactions),12 Spencer et al. have quite recently
demonstrated that PdCl2(MeCN)2 catalyzed intermolecular
aza-Michael reactions of enones with benzyl carbamate as a
nitrogen nucleophile.13 It is noted that such a less nucleophilc
carbamate serves as a nitrogen nucleophile in the presence
of the palladium catalyst to react intermolecularly with
enones under mild conditions. In relation to our efforts to
develop useful asymmetric synthetic methods for â-amino
carbonyl compounds,2,3 we are interested in aza-Michael
reactions of R,â-unsaturated carbonyls with carbamates.
Herein, we report that several transition metal salts other
than palladium salts are quite effective for the aza-Michael
reactions of enones with carbamates.
First, we surveyed catalytic activity of various transition
metal salts (mostly chlorides) in the reaction of phenyl
propenyl ketone (1a) with benzyl carbamate (2a) in dichlo-
romethane at room temperature (Table 1). Among the metal
salts tested, ZrCl4 (run 13), ReCl5 (run 23), Fe(ClO4)3‚9H2O
(run 24), RuCl3‚nH2O (run 27), OsCl3‚3H2O (run 28), RhCl3‚
3H2O (run 30), IrCl4‚nH2O (run 32), PtCl4‚5H2O (run 36),
AuCl (run 39), and AuCl3‚2H2O (run 40) were found to be
effective as well as PdCl2(MeCN)213 (run 34). On the other
hand, lower yields were obtained with conventional oxophilic
Lewis acids, i.e., BF3‚OEt2, AlCl3, SnCl4, Sc(OTf)3, and TiCl4
(runs 1, 2, 5, 10, and 12). It is noteworthy that, unlike
conventional Lewis acid-catalyzed reactions, group 7-11
Table 1. Catalytic Activity of Metal Salts
run
MXn
time/h
yield/%
1
2
3
4
5
6
7
8
9
BF3‚OEt2
AlCl3
GaCl3
2
6
6
6
2
6
6
6
6
6
6
2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
2
6
6
6
2
6
6
6
2
6
6
6
20
trace
7
NRa
8
NRa
NRa
NRa
5
15
NRa
6
70
53
NRa
4
5
31
trace
9
trace
12
96
88
6
trace
78
96
NRa
94
12
qu a n t.
trace
95
NRa
82
InCl3
Sc(OTf)3
YCl3‚6H2O
LaCl3‚7H2O
SbCl3
SiCl4
SnCl4
PbCl2
TiCl4
ZrCl4
HfCl4
VCl3
NbCl5
TaCl5
Cr(ClO4)3‚6H2O
MoCl3
WCl5
Mn(ClO4)2‚8H2O
ReCl3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
ReCl5
Fe(ClO4)3‚9H2O
Fe(OTf)3
FeCl3
RuCl3‚nH2O
OsCl3‚3H2O
Co(ClO4)2‚6H2O
RhCl3‚3H2O
IrCl3‚nH2O
IrCl4‚nH2O
Ni(ClO4)2‚6H2O
PdCl2(CH3CN)2
PtCl2
(5) (a) Cabral, J.; Laszlo, P.; Mahe´, L.; Montaufier, M.-T.; Randriama-
hefa, S. L. Tetrahedron Lett. 1989, 30, 3969. (b) Pe´rez, M.; Pleixats, R.
Tetrahedron 1995, 51, 8355.
(6) (a) Matsubara, S.; Yoshioka, M.; Utimoto, K. Chem. Lett. 1994, 827.
(b) Jenner, G. Tetrahedron Lett. 1995, 36, 233.
PtCl4‚5H2O
Cu(OTf)2
AgClO4
NRa
NRa
qu a n t.
91
5
11
NRa
(7) Loh, T.-P.; Wei, L.-L. Synlett 1998, 975.
AuCl
(8) Kawatsura, M.; Hartwig, J. F. Organometallics 2001, 20, 1960.
(9) A review for enantioselective conjugate additions, see: Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033.
(10) (a) Falborg, L.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1
1996, 2823. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am.
Chem. Soc. 1998, 120, 6615. (c) Sibi, M. L.; Liu, M. Org. Lett. 2000, 2,
3393. (d) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun.
2001, 1240.
AuCl3‚2H2O
Zn(ClO4)2‚6H2O
Cd(ClO4)2‚6H2O
HgCl2
a No reaction occurred.
(11) Myers, J. K.; Jacobensen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.
(12) For base catalysts, see: (a) Hirama, M. J. Synth. Org. Chem., Jpn.
1987, 45, 346 (intramolecular). (b) Wipf, P.; Kim, Y. Tetrahedron Lett.
1992, 33, 5477 (intramolecular). (c) Wipf, P.; Kim, Y.; Goldstein, D. M. J.
Am. Chem. Soc. 1995, 117, 11106 (intramolecular). (d) Es-Sayed, M.;
Gratkowski, C.; Krass, N.; Meyers, A. I.; de Meijere, A. Synlett 1992, 962
(intermolecular). (e) de Meijere, A.; Ernst, K.; Zuck, B.; Brandl, M.;
Kozhushkov, S. I.; Tamm, M.; Yufit, D. S. Howard, J. A. K.; Labahn, T.
Eur. J. Org. Chem. 1999, 3105 (intermolecular). For acid catalyst, see: (f)
Takeuchi, Y.; Tokuda, S.; Takagi, T.; Koike, M.; Abe, H.; Harayama, T.;
Shibata, Y.; Kim, H.-s.; Wataya, Y. Heterocycles 1999, 51, 1869 (intramo-
lecular). (g) McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett. 2000,
41, 1849 (intramolecular).
transition metals in the sixth period are effective in the
present reaction and that metals in higher oxidation states,
except for AuCl, showed higher catalytic activity.14
(14) For recent examples utilizing Pr(IV), Au(III), or Ru(III) chloride
as a catalyst for cyclizations of unsaturated compounds or a Friedel-Crafts
acylation, see: (a) Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem.
1995, 60, 5567. (b) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am.
Chem. Soc. 1998, 120, 8305. (c) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am.
Chem. Soc. 2001, 123, 11863. (d) Fu¨rstner, A.; Voigtla¨nder, D.; Schrader,
(13) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25.
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Org. Lett., Vol. 4, No. 8, 2002

Table 2. Aza-Michael Reactions of Various Enones 1 with Carbamates 2a
a Enone:carbamate ) 1.0:1.5, unless otherwise noted (see ref 15). b Enone:carbamate ) 2.0:1.0.
We observed that most of the effective metal salts were
partially soluble in dichloromethane and that the salts
dissolved to some extent after adding the substrates. With
an expectation to improve the catalytic activity, the use of
acetonitrile and nitromethane as solvents, in which PtCl4‚
5H2O dissolves completely, was examined. Although PtCl4‚
5H2O-catalyzed reactions of 1a and 2a in these solvents
provided comparable yields of 3a (85% and 89%, respec-
tively) to that in dichloromethane (82%, Table 1, run 36),
no significant improvement was observed. A less polar
solvent, toluene, gave an inferior result (45%), while use of
strongly coordinating solvents, DMSO, DMF, and THF,
resulted in no reaction.
W.; Giebel, D.; Reetz, M. T. Org. Lett. 2001, 3, 417. (e) Me´ndez, M.;
Mun˜oz, M. P.; Nevada, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2001, 123, 10511. (f) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.;
Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (g) Hashmi, A. S. K.;
Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3, 3769.
With several effective catalysts in hand, aza-Michael
reactions of various enones with carbamates in dichloro-
methane at room temperature were next investigated (Table
Org. Lett., Vol. 4, No. 8, 2002
1321

2).15 Benzyl N-methyl carbamate (2b) (run 2) and 2-oxazoli-
done (2c) (run 3) reacted smoothly with phenyl propenyl
ketone (1a) to give the corresponding aza-Michael adducts
3b and 3c in high yields, while reactions of enones 1b-g
with benzyl carbamate (2a) provided adducts 3d-i in
moderate to high yields (runs 4-9). It is noteworthy that
metal salts such as PtCl4‚5H2O effectively catalyzed the
reactions of R-substituted enones 1c-f (runs 5-8) with 2a,
while the reactions proceeded sluggishly using PdCl2-
(MeCN)2 as a catalyst.16 The reaction of an R,â-unsaturated
ester such as methyl acrylate with 2a was unproductive under
these catalytic conditions as well as the palladium-catalyzed
reaction.13
observed, i.e., benzyl carbamate (2a) was formed in 45%
after 8 h. This result indicates that the reaction would be
under thermodynamic control. Finally, the profiles of the
reactions of 1a with 2a catalyzed by PtCl4‚5H2O and PdCl2-
(MeCN)2 at 10 °C are shown in Figure 1. It turned out that
To get insight into the reaction mechanism, we performed
several experiments as follows. First, the PtCl4‚5H2O-
catalyzed reaction of 1a with 2a was conducted in the
presence of a radical inhibitor, 2,6-di-tert-butyl-4-methyl-
phenol (BHT) or hydroquinone. The reactions proceeded
smoothly to give 3a in somewhat higher yields, 98% and
95%, respectively. Thus, the mechanism via the single
electron transfer is unlikely in this reaction. Second, IR
analysis of the acetonitrile solution of 2a and PtCl4‚5H2O
(a 1:1 mixture) showed no significant change of the
ν(CdO) frequency of the carbamate (1735 cm-1 to 1734
cm-1), while the acetonitrile solution of 2a and Sc(OTf)3
exhibited a large shift of the frequency (1666 cm-1). On the
other hand, 13C NMR analysis of a 1:1 mixture of PtCl4‚
5H2O and enone 1a in CD3CN showed almost no change in
the chemical shifts of 1a, while that of Sc(OTf)3 and 1a
exhibited large shift changes.17 It is suggested that the mode
of interaction of the substrates with PtCl4‚5H2O would differ
from that of conventional oxophilic Lewis acids such as
Sc(OTf)3. Third, when the isolated product 3d was treated
with a catalytic amount of PtCl4‚5H2O (10 mol %) under
the reaction conditions, the retro-aza-Michael reaction was
Figure 1. Plots of isolated yield of 3a versus time for PtCl4‚5H2O-
and PdCl2(MeCN)2-catalyzed aza-Michael reactions of 1a with 2a.
the reaction with PtCl4‚5H2O proceeded faster than that with
PdCl2(MeCN)2, giving >95% yield after 2.5 h. As already
shown in Table 2, the differences in the catalytic activity
between PtCl4‚5H2O and PdCl2(CH3CN)2 are remarkable
when R-substituted enones are used (runs 5-8). It should
be noted that this difference was observed even in the
reaction of more reactive enone 1a.
In summary, we have revealed that several transition metal
catalysts, especially group 7-11 transition metal salts in
higher oxidation states, were effective for aza-Michael
reactions of enones with carbamates. Although the mecha-
nism of the reaction is still unclear, asymmetric catalysis
based on these metal salts might be possible. Further study
along to this line is now in progress.
(15) Experimental procedure: To a metal salt (0.025 mmol, 0.1 equiv)
in dichloromethane (1 mL) was added an enone (0.250 mmol, 1 equiv) and
a carbamate (0.375 mmol, 1.5 equiv) After being stirred for 2-48 h at
room temperature, the reaction mixture was quenched with saturated aqueous
sodium hydrogen carbonate, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried over Na2SO4,
filtered, and evaporated. The crude product was purified by preparative
TLC to give a â-amino ketone.
(16) It was reported that the reaction of 3-methyl-3-penten-2-one (1c)
with 2a resluted in no reaction in the presence of PdCl2(MeCN)2 as a
catalyst; see ref 13.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Japan Society
of the Promotion of Sciences.
(17) 13C NMR (75 MHz, CD3CN) 1a: δ 191.1, 145.9, 138.9, 133.6,
129.6, 129.3, 128.3, 18.6. 1a+PtCl4‚5H2O (a 1:1 mixture): δ 191.6, 146.6,
138.7, 133.8, 129.6, 129.3, 128.2, 18.6. 1a+Sc(OTf)3 (a 1: 1 mixture): δ
198.1, 158.4, 137.1, 136.3, 131.8, 130.1, 127.8, 122.4, 19.9.
OL0256163
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Org. Lett., Vol. 4, No. 8, 2002