Highly Efficient Aza-Michael Reactions of Enones with Carbamates Using a Combination of Quaternary Ammonium Salts and BF3·OEt 2 as a Catalyst

Article abstract of DOI:10.1055/s-2003-43333

Aza-Michael reactions of enones with carbamates took efficiently in the presence of a catalytic amount of quaternary ammonium salts and BF ₃·OEt₂ 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:10.1055/s-2003-43333

LETTER
2337
Highly Efficient Aza-Michael Reactions of Enones with Carbamates Using a
Combination of Quaternary Ammonium Salts and BF3·OEt2 as a Catalyst
A
za-Michael Re
i
action
-
s
w
ithQ
W
uaternaryAmmonium
S
ealts and BF3
n
·
OEt2 Xu, Lyi Li, Chun-Gu Xia,* Shao-Lin Zhou, Jing-Wei Li, Xiao-Xue Hu
State Key Laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, 730000, P. R. China
Fax +86(931)8277088; E-mail: cgxia@ns.lzb.ac.cn
Received 13 October 2003
weakly nucleophilc, many catalysts are practically inef-
Abstract: Aza-Michael reactions of enones with carbamates took
fective in catalyzing a similar reaction with carbamates.
Recently, Spencer et al. demonstrated that PdCl2(MeCN)2
and copper-catalyzed intermolecular aza-Michael reac-
efficiently in the presence of a catalytic amount of quaternary am-
monium salts and BF3·OEt2 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 car- tions of enones with benzyl carbamate as nitrogen nucleo-
phile.11 And Kobayashi surveyed catalytic activity of
bamates by transition metal salts catalysts.
various transition metal salts in the aza-Michael reaction
of enones with benzyl carbamate and demonstrated that
some transition metal salts, such as platinum salts, iridium
salts, gold salts, are effective for addition reactions with
carbamates.12 However, all these catalysts were not re-
ported that could be performed in catalyzing the conjugate
addition of chalcone with carbamates. Although recent
advances have made this route more attractive, develop-
ment of cheaper, simpler, and more efficient metal cata-
lyst, especially which can be applied to chalcone, is highly
desirable.
Key words: quaternary ammonium salts, Lewis acids, Michael re-
action, carbamate, enone
The b-amino carbonyl functionality is not only a segment
of biologically important natural products but also a ver-
satile intermediate for the synthesis of nitrogen-contain-
ing compounds.1 The development of novel synthetic
methods leading to b-amino ketone, b-amino acids or
their derivatives has attracted much attention in organic
synthesis.2 Among the traditional methods for generating
-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.3 However, due to the harsh reaction con-
ditions and the long reaction times, the classic Mannich
reaction presents serious disadvantages.4 Alternatively,
aza-Michael additions can be used to create carbon-het-
eroatom bonds by reaction of a,b-unsaturated carbonyl
compounds with amines. The conjugated addition of nu-
cleophiles to a,b-unsaturated compounds usually requires
strong basic conditions or acid catalysis.5 To avoid typical
disadvantages resulting from the presence of such cata-
lyst, a large number of alternative procedures have been
developed in the past few years.6–10 However, most meth-
ods for intermolecular conjugated addition to unsaturated
carbonyl compounds reported to date describe the addi-
tion of alkyl or aryl amines. Because carbamates are
We are also interested in aza-Michael reactions of enones
with carbamates and other nitrogen-containing reagent.13
To the best of our knowledge, only we first reported a
iron-catalyzed aza-Michael reaction of chalcone in the
presence of TMSCl.13a Herein, we reported a new catalyst
system is quite effective for the aza-Michael reactions of
chalcone and other enones with carbamates.
As a special Lewis acid catalyst,14 quaternary ammonium
salt has been shown to be extraordinarily effective and
useful catalysts for alkylation,15 aldol,16 epoxidation,17
and Michael reaction.18 A systematic study of the Michael
addition of thiols to a,b-unsaturated ketones in the pres-
ence of quaternary ammonium salts and cinchona alka-
loids as a catalyst has also been reported.18,19 However, no
reports are available on a quaternary ammonium salts-cat-
alytic approach for the aza-Michael reaction. We try to ex-
plore the catalytic activities of quaternary ammonium
salts in the aza-Michael reaction, and found that the cata-
O
OEt
HN
O
O
O
Catalyst
OEt
H2N
CH2Cl2, r.t.
Scheme 1
SYNLETT 2003, No. 15, pp 2337–2340
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-43333; Art ID: U21303ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2338
L.-W. Xu et al.
LETTER
Table 1 Evaluation of Quaternary Ammonium Salts as Catalysts in
lyst was not effective in this reaction with or without a
base (for example, NaOH, K2CO3).
Aza-Michael Reaction of Cyclohexenone with Ethyl Carbamatea
Entry Catalystsb
Enones
Products
Yield (%)c
It has reported that Me3SiCl was helpful to the conjugate
addition of organic-copper regeants20 and Michael addi-
tion reactions of chiral benzylic anions.21 Recently, we
also found that FeCl3·6H2O was an effective catalyst for
this aza-Michael reaction in the presence of TMSCl.13a
The previous studies prompted us to address the question
whether the combination of quaternary ammonium salts
and BF3·OEt2 or Me3SiCl generate the most active cata-
lysts. At this point we decided to investigate the new sys-
tem of Me3SiCl or BF3·OEt2 and quaternary ammonium
salts as a new Lewis acid catalyst in the aza-Michael reac-
tion.
1
2
3
4
TBAB
TEAC
THAB
95
88
90
23
O
O
d
–
NHCOOEt
NHCOOEt
NHCBZ
2
3
4
5
TBAB
TBAB
TBAB
TEAB
92
90
86
89
O
O
O
O
O
O
O
O
O
O
NH2COOR/TMSCl/r.t.
cat. TBAB etc.
R
R
NHCOOR
n
n
2a–d
n = 0, 1
R = H, CH3
1a–d
n = 0, 1
R = H, CH3
NHCBZ
O
Scheme 2 Conjugate addition of carbamate to a,b-unsaturated cy-
clic enone at room temperature.
N
O
Several attempts have been performed toward achieving
conjugate addition of carbamates to chalcone in the pres-
ence of Me3SiCl or BF3·OEt2. We surveyed catalytic ac-
tivity of various quaternary ammonium salts, such as
TBAB, TEAB, benzyltrimethylammonium chloride,
TEAC, in the aza-Michael reaction of chalcone with ethyl
carbamate in CH2Cl2 at room temperature (Scheme 1). In-
terestingly, all the quaternary ammonium salts were found
to be effective in the conjugate addition of chalcone with
ethyl carbamate in the presence of BF3·OEt2 (40–50% iso-
lated yields). The combination of quaternary ammonium
salts and Me3SiCl was proved to an inefficient catalyst in
the aza-Michael reaction (lower yields). And the combi-
nation of TBAB–BF3·OEt2 shows the best result in this
aza-Michael reaction. A control experiment was conduct-
ed in the absence of quaternary ammonium salt catalyst
and no desired product was observed in the Me3SiCl or
BF3·OEt2-catalyzed aza-Michael reaction. Single quater-
nary ammonium salts catalyst was also not effective in the
aza-Michael reaction without Me3SiCl or BF3·OEt2. In
this Letter, having established the remarkable catalytic ac-
tivity of TBAB–BF3·OEt2 catalytic system in the aza-
Michael reaction, we disclose the first conjugate addition
of enones with carbamates.
6
7
TBAB
TBAB
Trace
Trace
O
O
O
O
NHCOOEt
NHCOOEt
a All reactions were carried out using 10 mol% of quaternary ammo-
nium salt catalyst, cyclohexenone (1 mmol), carbamate (1.2 mmol)
and BF3·OEt2 (0.2 mmol) in CH2Cl2 at r.t. for 24 h.
b TBAB = tetrabutylammonium bromide; THAB = tetrahexylammo-
nium bromide; TEAB = tetraethylammonium bromide; TEAC = tet-
raethylammonium chloride.
c Isolated yields.
d No addition of quaternary ammonium salt.
chalcone derivatives. However, the combination of qua-
ternary ammonium salts and other Lewis acid or Brønsted
acid, such as, aqueous HBF4, TsOH, CF3COOH, was also
effective in this aza-Michael reaction but have lower
yields than the combination with BF3·OEt2.
With the effective catalyst system in hand (TBAB/
BF3·OEt2), aza-Michael reactions of various cyclic enones
with carbamates in CH2Cl2 at room temperature were in-
vestigated (Scheme 2 and Table 1). In this conjugate addi-
tion reaction, good to excellent yields of b-amino ketones
were obtained with several cyclic enones. Benzyl carbam-
ate, ethyl carbamate reacted smoothly with 2-cyclohexen-
1-one, 2-cyclopetenone and other acyclic enones to give
corresponding aza-Michael adducts in high yields.
Recently, Spencer et al reported that Brønsted acid cata-
lyst can be superior to metal ion catalyst when weak nu-
cleophiles
are
used
in
the
hetero-Michael
reaction.22Although this aza-Michael reaction of alkyl
enones were induced by Brønsted acid, for example, aque-
ous HBF4, TsOH, these Brønsted acid catalysts that are
successfully employed in aza-Michael additions with
alkyl enones have failed to produce b-amino ketone of
Synlett 2003, No. 15, 2337–2340 © Thieme Stuttgart · New York

LETTER
Highly Efficient Aza-Michael Reactions of Enones with Carbamates
2339
Table 2 Aza-Michael Reactions of Various Carbamates with Chal-
catalyst and the insensitivity of the reaction mixture to-
wards air. The catalyst systems based on the combination
of quaternary ammonium salts and BF3·OEt2 was found to
be highly active catalyst for aza-Michael reaction of chal-
cone and cyclic enones with carbamates. Although the
mechanism of the reaction is still unclear, asymmetric ca-
talysis based on the catalyst might be possible. We are
currently investigating the development of an enantiose-
lective catalytic process. Further study along to this line is
now in progress.
cone Derivativesa
4
a
b
c
d
e
f
R1
R2
R
Yield (%)b
H
Ph
Ph
Ph
CH3
Ph
Ph
NH2CBZ
NH2COOEt
NH2CBZ
NH2CBZ
NH2COOEt
O
50
41
47
42
50
42
p-Br
p-CH3
H
p-CH3
H
Acknowledgment
This study was supported in part by the Natural Science Founder of
National for financial support of the work (29933050).
HN
O
g
h
i
o-Cl
H
Ph
Ph
Ph
Ph
Ph
NH2COOEt
NH2COOEt
NH2CBZ
NH2COOEt
O
40
43
42
29
41
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R1
R1
4a–l
3a–g
Scheme 3
Aza-Michael reactions of other various chalcone deriva-
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were also investigated (Scheme 3, Table 2)23. In contrast
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conditions. Apart from experimental simplicity, the ad-
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Synlett 2003, No. 15, 2337–2340 © Thieme Stuttgart · New York

2340
L.-W. Xu et al.
LETTER
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combined organic layers were dried over Na2SO4, filtered,
and evaporated. The crude product was purified by column
chromatography (eluting solvent: EtOAc–petroleum 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. 4a:
IR(solid): 3366, 3029, 2965, 1721, 1681, 1526, 1291, 1241,
1221, 1022, 746, 699 cm–1.1H NMR (400 MHz, CDCl3): d =
7.88 (d, J = 7.2 Hz, 2 H), 7.54 (t, J = 7.2 Hz, 1 H), 7.44–7.22
(m, 12 H), 5.89 (br s, 1 H), 5.33 (d, J = 6.0 Hz, 1 H), 5.09 (s,
2 H), 3.68 (dd, J = 16.7 Hz, J = 4.2 Hz, 1 H), 3.45 (dd, J =
16.7 Hz, J = 4.8 Hz, 1 H). 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. 4f:
1H NMR: d = 7.95 (d, J = 7.2 Hz, 2 H), 7.54 (t, J = 7.2 Hz, 1
H), 7.45–7.24 (m, 7 H), 5.36 (dd, J1 = 6.0 Hz, J2 = 8.6 Hz, 1
H), 4.22 (dd, J1 = 1.6 Hz, J2 = 8.8 Hz, 1 H), 3.57 (br s, 2 H),
3.43 (dd, J1 = 8.0Hz, J2 = 16.0 Hz, 1 H): 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. 4g: 1H NMR: d = 7.88 (d, J = 7.2 Hz, 2 H),
7.57 (m, 1 H), 7.41 (m, 2 H),7.24 (m, 2 H), 6.81 (m, 2 H),
5.63 (br s, 1 H), 5.22 (dd, J1 = 6.4 Hz, J2 = 14.0 Hz, 1 H),
4.07 (dd, J1 = 6.8 Hz, J2 = 14.0 Hz, 2 H), 3.64–3.74 (m, 2 H),
3.37–3.43 (m, 1 H), 1.20 (t, J1 = 6.4 Hz, J2 = 15.2 Hz, 3 H).
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. 4h:
1H NMR: d = 7.88 (d, J = 7.2 Hz, 2 H), 7.55–7.21 (m, 8 H),
5.72 (br s, 1 H), 5.28 (dd, J1 = 6.4 Hz, J2 = 14.0 Hz, 1 H),
3.67 (m, 2 H), 3.40–3.46 (m, 1 H), 1.21 (t, J1 = 6.4 Hz, J2 =
14.0 Hz, 3 H). 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. 4i:
1H NMR: d = 7.85 (d, J = 7.2 Hz, 2 H), 7.57–7.20 (m, 12 H),
6.00 (br s, 1 H), 5.26 (dd, J1 = 6.0 Hz, J2 = 13.2 Hz, 1 H),
4.77 (br s, 2 H), 3.65 (m, 1 H), 3.40 (dd, J = 5.2 Hz, J = 16.8
Hz, 1 H). 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.
(22) (a) Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Synlett 2003,
1070. (b) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003, 5,
2141.
(23) Representative Experimental Procedure:
TBAB (0.1 mmol) and the enones (1 mmol) were dissolved
in CH2Cl2 (3 mL). BF3·OEt2 (0.2 mmol) was added. Then
carbamate (1.2 mmol) was added in one portion. The
mixture solution was stirred at r.t. and conversion was
monitored by TLC (for 24 h). After completion of the
reaction, the mixture was quenched with sat. aq NaHCO3 (5
Synlett 2003, No. 15, 2337–2340 © Thieme Stuttgart · New York