Highly efficient phosphine-catalyzed aza-Michael reactions of α,β-unsaturated compounds with carbamates in the presence of TMSCl

Article abstract of DOI:10.1016/j.tetlet.2004.04.053

Aza-Michael reactions of enones with carbamates took place efficiently in the presence of a catalytic amount of phosphine and TMSCl to afford the total products in high yields. The new catalytic system was also efficient in the aza-Michael reaction of chalcone, which was difficult to react with carbamates by transition metal salts catalysts.

Full text of DOI:10.1016/j.tetlet.2004.04.053

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4507–4510
Highly efficient phosphine-catalyzed aza-Michael reactions of
a,b-unsaturated compounds with carbamates in the presence
of TMSCl
Li-Wen Xu and Chun-Gu Xia*
State key laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, PR China
Received 4 March 2004; revised 7 April 2004; accepted 9 April 2004
Abstract—Aza-Michael reactions of enones with carbamates took place efficiently in the presence of a catalytic amount of phos-
phine and TMSCl to afford the total products in high yields. The new catalytic system was also efficient in the aza-Michael reaction
of chalcone, which was difficult to react with carbamates by transition metal salts catalysts.
Ó 2004 Elsevier Ltd. All rights reserved.
With the growing realization that some b-amino car-
bonyl compounds display significant biological activi-
ties, the development of novel synthetic methods leading
to b-amino ketone, b-amino acids or their derivatives
has attracted much attention in organic synthesis.1
Among the traditional methods for generating b-amino
carbonyl compounds, Mannich-type reaction is one of
the classical and powerful methods, the reactions of
enolates either with imines are established processes for
the synthesis of these moieties through carbon–carbon
bond formation.2 However, due to the harsh reaction
conditions and the long reaction times, the classic
Mannich reaction presents serious disadvantages.3
Alternatively, owing to simplicity and atom economy,
the more widely used method is the conjugated addition
of nitrogen nucleophiles to a,b-unsaturated enones (aza-
Michael reaction). Aza-Michael addition of a nitrogen-
centered nucleophile is a convenient way to introduce
amine-based functionality to a b-carbon attached to an
electron-withdrawing group.4 Following this strategy,
very recently various nitrogen linked functionalized
Michael adducts have been synthesized.5 The conju-
gated addition of nucleophiles to a,b-unsaturated com-
pounds usually requires basic conditions or acid
catalysis.6 To avoid typical disadvantages resulting from
the presence of such catalyst, a large number of alter-
native procedures have been developed in the past few
years.7–11 However, most methods for intermolecular
conjugated addition to unsaturated ketones reported to
date describe the addition of alkyl or aryl amines.
Because carbamates are weakly nucleophiles, many
catalysts are practically ineffective in catalyzing a similar
reaction with carbamates.4;12 Although recent advances
have made this route more attractive, development of
cheaper, simpler and more efficient catalyst, especially
which can be applied to weakly nucleophilic carbamates,
is highly desirable.
Phosphines and their derivatives were used as stoichio-
metric reagents or catalyst in organic synthesis and
organic reaction, including the Wittig reaction,13
Staudinger reaction,14 Mitsunobu reaction,15 Baylis–
Hillman16 and other well-known ‘name’ reaction.17
However, to the best of our knowledge, there has not
been reported the aza-Michael reaction of a,b-unsatu-
rated compounds catalyzed by phosphine and it’s
derivatives.
The previous works5 promoted us to investigate the aza-
Michael addition reactions of chalcone. At first, we
discovered that the phosphine ligand alone with TMSCl
was actually a more active catalyst. In the presence of
catalytic amounts of triphenylphosphine and TMSCl,
we observed that the direct addition of carbamates to
a,b-unsaturated ketones in high yield. Several phos-
phines were tested using the 2-cyclohexen-1-one as a
Keywords: Conjugate addition; Aza-Michael; Carbamates; Enones;
Phosphine.
* Corresponding author. Tel.: +86-931-8276531; fax: +86-931-82770-
88; e-mail: cgxia@ns.lzb.ac.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.053

4508
L.-W. Xu, C.-G. Xia / Tetrahedron Letters 45 (2004) 4507–4510
Table 1. Evaluation of phosphine as catalysts in aza-Michael reaction of cyclohexenone with ethyl carbamate
O
O
Cat. PR3
rt/CH2Cl2
NH2COOEt
NHCOOEt
Entrya
Phosphines
Additives
Time (h)
Yields (%)b
1
2
3
4
5
6
7
8
PPh3
PPh3
––c
24
15
8
0
95
TMSCl
TMSCl
––c
PPh3
82
0
P(n-Bu)3
P(n-Bu)3
TPPTSd
Et3N
24
15
15
24
24
TMSCl
TMSCl
TMSCl
TMSCl
Quant.
96
Trace
Trace
Pyridine
a Reactions were conducted with catalyst (10 mol %), enone (1 mmol), ethyl carbamate (1.2 mmol), Me3SiCl (1.1 mmol) in dichloromethane (4 mL) at
room temperature.
b Isolated yield.
c No addition of Me3SiCl.
d TPPTS is tris(3-sulfophenyl)phosphine.
These enones provided the corresponding b-amino
ketone in good isolated yields. In contrast to previous
transition metal catalysts, PBu3/TMSCl catalytic system
could also mediate aza-Michael addition of carbamates
to chalcone and its derivatives. Simple carbamates such
as ethyl carbamate, were suitable nucleophiles and
moderate yields were obtained with the synthetically
more useful benzyl carbamate. Although carbamates are
very weakly nucleophiles, some chalcone derivatives
were similarly effective substrates in the aza-Michael
reaction, which allows the introduction of the amide
group. However, electro-poor Br or NO2-substituted
chalcones worked unfavorably to give corresponding in
low yields (entries 7–9). In this conjugate addition
reaction, good to excellent yields of b-amino ketones
were obtained with several cyclic and acyclic enones
(entries 1, 2 and 10). Benzyl carbamate, ethyl carbamate
reacted smoothly with 2-cyclohexen-1-one, 3-penten-2-
O
O
O
R2
O
HN
O
R1
Cat. PR3
rt/CH2Cl2
O
R1
R1
or
N
R2
or
O
NHCOOR
R2
NH2COOR
R = C2H5, Benzyl
1a-h
2a-c
3
Scheme 1.
benchmark (Table 1). Tributylphosphine was more
reactive than triphenylphosphine under the same con-
ditions, and nitrogen-based catalysts were not effective
in this aza-Michael reaction. And there are no product
for this reaction in the absence of TMSCl.
Aza-Michael reactions of other various chalcone deriv-
atives with carbamates in dichloromethane at room
temperature were also investigated (Scheme 1, Table 2).
Table 2. Aza-Michael reactions of various carbamates with enones19
Entrya
Enone
Carbamate
Yield (%)b
98
O
NH2CBZ
2a
1
1a
O
NH2CBZ
2a
2
1b
92
O
3
4
1c
NH2CBZ
2a
64
68
1c
NH2COOEt
2c
O
5
1c
45
HN
O
O
6
7
1d
NH2COOEt
2c
63
38
O
1e
NH2CBZ
2a
Br

L.-W. Xu, C.-G. Xia / Tetrahedron Letters 45 (2004) 4507–4510
4509
Table 2 (continued)
Entrya
Enone
Carbamate
Yield (%)b
trace
O
O
8
1f
NH2COOEt
2c
NO2
Cl
9
1g
NH2COOEt
2c
32
98
O
10
1h
NH2CBZ
(2a)
H3C
CH3
a Reactions were conducted with catalyst (P(n-Bu)3, 10 mol %), enone (1 mmol), 1.2 mmol of ethyl carbamate or benzyl carbamate (NH2CBZ),
Me3SiCl (1.1 mmol) in dichloromethane (4 mL) at 30 °C for 24 h.
b Isolated yield.
one and 2-cyclopetenone to give corresponding aza-
Michael adducts in high yields.
chalcone and cyclic enones with carbamates. Although
the mechanism of the reaction is still unclear, asym-
metric catalysis based on the catalyst might be possible.
We are currently investigating the development of an
enantioselective catalytic process. Further study along
this line is now in progress.
Although the role of TMSCl is not completely under-
stood, it may be explained in terms of Lewis acid, which
activates the carbonyl group. A plausible mechanism for
the aza-Michael reaction was similarly to the previous
related mechanism,18 initial interaction by the TMSCl to
the a,b-unsaturated ketone 1 results in activation of
enones, and phosphinium enolate 3 was obtained by the
conjugate addition of phosphine. Then phosphinium
enolate was deprotonate an equivalent of carbamate to
form the intermediate 4, which facilitated the conjugate
addition. Proton transfer and elimination of TMS-group
from the intermediate gave the corresponding b-amino
ketone 5 and resulted in the regeneration of TMSCl and
intermediate to complete the cycle (Scheme 2).
Acknowledgements
This study was supported in part by the Natural Science
Founder of National for financial support of the work
(29933050 and 20373082).
References and notes
In conclusion, we have demonstrated that the conjugate
addition of enones especially chalcone with a less
nucleophilic carbamates can be accomplished on phos-
phine/TMSCl catalyst system under very mild condi-
tions. Apart from experimental simplicity, the
advantages of this methodology is the use of a very
cheap catalyst and the insensitivity of the reaction
mixture towards air. The catalyst systems based on the
combination of phosphine and TMSCl was found to be
a highly active catalyst for aza-Michael reaction of
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TMSCl
R1
SiMe3
R1
O
O
O
R1 TMSCl
PR3
Cl -
R3P
NH2COOR
R2
R2
R2
1
3
2
O
HCl
SiMe3
R1
O
R1
R2
ROOCHN
R2
ROOCHN
O
5
4
R1
R2
1
Scheme 2.

4510
L.-W. Xu, C.-G. Xia / Tetrahedron Letters 45 (2004) 4507–4510
2003, 2337; (h) Xu, L. W.; Xia, C. G.; Li, J. W.; Zhou, S.
L. Synlett 2003, 2246.
bined organic layers were dried over Na2SO4, filtered and
evaporated. The crude product was purified by column
chromatography (eluting solvent EtOAc/petrol ether). All
the compounds were identified by GC–MS (Agilent 6890N
GC/5973N MS, HP-5MS) and usual spectral methods.
Selected spectral data of new compounds, Table 1, entry 2:
1H NMR: d 4.96 (br s, 1H), 4.05 (m, 2H), 3.89 (m, 1H),
2.63 (m, 2H), 2.34–2.00 (m, 4H), 1.62 (m, 2H), 1.19 (d,
J ¼ 6:4, 3H); 13C NMR: d 209.4, 157.8, 61.3, 50.2, 48.1,
41.0, 31.3, 22.1, 14.7; GC–MS, m=z 185. Anal. Calcd for
C9H15NO3: C 58.38, H 8.11, N 7.57. Found: C 58.33, H
8.13, N 7.59. Table 2, entry 3: 1H NMR (400 MHZ,
CDCl3): d 7.88 (d, J ¼ 7:2 Hz, 2H), 7.54 (t, J ¼ 7:2 Hz,
1H), 7.44–7.22 (m, 12H), 5.89 (br s, 1H), 5.33 (d,
J ¼ 6:0 Hz, 1H), 5.09 (s, 2H), 3.68 (dd, J ¼ 16:7 Hz,
J ¼ 4:2 Hz, 1H), 3.45 (dd, J ¼ 16:7 Hz, J ¼ 4:8 Hz, 1H);
13C NMR (100 MHZ, CDCl3): d 197.8, 155.7, 141.2, 136.6,
136.3, 133.4, 128.6, 128.5, 128.1, 127.5, 126.3, 66.8, 51.8,
43.9. GC–MS, m=z 359. IR (Solid) mmax/cmꢀ1 ¼ 3366,
3029, 2965, 1721, 1681, 1526, 1291, 1241, 1221, 1022, 746,
699. Anal. Calcd for C23H21NO3: C 76.88, H 5.85, N 3.90.
Found: C 76.86, H 5.85, N 3.92. Entry 4: 1H NMR: d 7.88
(d, J ¼ 7:2 Hz, 2H), 7.55–7.21 (m, 8H), 5.72 (br s, 1H),
5.28 (dd, J1 ¼ 6:4 Hz, J2 ¼ 14:0 Hz, 1H), 3.67 (m, 2H),
3.40–3.46 (m, 1H), 1.21 (t, J1 ¼ 6:4 Hz, J2 ¼ 14:0 Hz, 3H);
13C NMR: d 198.2, 159.8, 156.2, 141.6, 136.8, 133.6, 128.9,
128.3, 127.7, 61.2, 51.9, 44.2, 14.8; GC–MS, m=z 297, 224,
208, 178, 134, 105, 77, 51, 29. Anal. Calcd for C18H19NO3:
C 72.73, H 6.40, N 4.71. Found: C 72.71, H 6.39, N 4.72.
Entry 5: 1H NMR: d 7.95 (d, J ¼ 7:2 Hz, 2H), 7.54 (t,
J ¼ 7:24 Hz, 1H), 7.45–7.24 (m, 7H), 5.36 (dd, J1 ¼
6:0 Hz, J2 ¼ 8:6 Hz, 1H), 4.22 (dd, J1 ¼ 1:6 Hz,
J2 ¼ 8:8 Hz, 1H), 3.57 (br s, 2H), 3.43 (dd, J1 ¼ 8:0 Hz,
J2 ¼ 16:0 Hz, 1H); 13C NMR: d 197.2, 157.9, 138.7, 136.6,
133.7, 129.1, 129.0, 128.4, 127.5, 62.2, 54.6, 43.4, 40.6;
GC–MS: m=z 295; Anal. Calcd for C18H17NO3: C 73.24, H
6. (a) Perlmutter, P. Conjugate Addition Reactions in Organic
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S. G.; Delgado-Ballester, S.; Fenton, G.; Kelly, P. M.;
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1
5.76, N 4.75. Found: 73.21, H 5.75, N 4.79. Entry 6: H
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NMR: d 7.88 (d, J ¼ 7:2 Hz, 2H), 7.53 (d, J ¼ 7:6 Hz, 1H),
7.41 (d, J ¼ 7:6 Hz, 2H), 7.22 (m, 2H), 7.09 (m, 2H), 5.64
(br s, 1H), 5.23 (dd, J1 ¼ 6:4 Hz, J2 ¼ 12.0 Hz, 1H), 4.08
(dd, J1 ¼ 6:8 Hz, J2 ¼ 14:0 Hz, 2H), 3.65 (m, 1H), 3.40 (dd,
J1 ¼ 6:0 Hz, J2 ¼ 16:4 Hz, 1H), 2.27 (s, 3H); 1.20 (t,
J1 ¼ 6:4 Hz, J2 ¼ 15:2 Hz, 3H); 13C NMR:
d 197.9,
155.9, 138.4, 137.1, 136.6, 133.3, 129.3, 128.6, 128.1,
126.3, 60.9, 51.4, 44.1, 31.5, 14.2; GC–MS, m=z 311. Anal.
Calcd for C19H21NO3: C 73.31, H 6.75, N 4.50. Found: C
73.26, H 6.72, N 4.54. Entry 7: 1H NMR: d 7.85 (d,
J ¼ 7:2 Hz, 2H), 7.57–7.20 (m, 12H), 6.00 (br s, 1H), 5.26
(dd, J1 ¼ 6:0 Hz, J2 ¼ 13:2 Hz, 1H), 4.77 (br s, 2H), 3.65
(m, 1H), 3.40 (dd, J ¼ 5:2 Hz, J ¼ 16:8 Hz, 1H); 13C
NMR: d 197.9, 157.0, 156.0, 140.7, 136.6, 136.5, 133.9,
132.0, 129.0, 128.7, 128.5, 128.3, 127.9, 121.5, 67.1, 51.4,
43.8. Anal. Calcd for C23H20NO3Br: C 63.01, H 45.66, N
3.20. Found: C 62.99, H 45.65, N 3.25. Entry 9: 1H NMR:
d 7.88 (d, J ¼ 7:2 Hz, 2H), 7.57 (m, 1H), 7.41 (m, 2H),7.24
(m, 2H), 6.81 (m, 2H), 5.63 (br s, 1H), 5.22 (dd,
J1 ¼ 6:4 Hz, J2 ¼ 14:0 Hz, 1H), 4.07 (dd, J1 ¼ 6:8 Hz,
J2 ¼ 14:0 Hz, 2H), 3.64–3.74 (m, 2H), 3.37–3.43 (m, 1H),
1.20 (t, J1 ¼ 6:4 Hz, J2 ¼ 15:2 Hz, 3H); 13C NMR: d 198.2,
159.0, 156.1, 136.9, 133.7, 133.6, 128.9, 128.3, 127.8, 114.2,
61.1, 55.5, 51.5, 44.3, 14.8. Anal. Calcd for C18H18NO3Cl:
C 65.16, H 5.43, N 4.22. Found: C 65.12, H 5.41, N
4.25.
17. (a) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119,
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19. General procedure for conjugate addition of carbamate to
enone: Phopshine (0.1 mmol), carbamate (1.2 mmol) and
the enones (1 mmol) were dissolved in dichloromethane
(3 mL). Then TMSCl (1.1 mmol) was added in one
portion. The mixture solution was stirred at 30 °C and
was monitored by TLC (general for 24 h). After comple-
tion of the reaction, the mixture was quenched with 5 mL
saturated aqueous sodium hydrogen carbonate, and the
aqueous layer was extracted with chloroform. The com-