1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted efficient and versatile aza-Michael addition

Article abstract of DOI:10.1016/j.tet.2006.11.037

A convenient and versatile method was developed for aza-Michael addition using a substoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Various nitrogen nucleophiles were efficiently introduced to α,β-unsaturated carbonyl compounds employing 0.5 equiv of DBU. Furthermore, other heteroatomic nucleophiles could also be introduced successfully under the same reaction conditions.

Full text of DOI:10.1016/j.tet.2006.11.037

Tetrahedron 63 (2007) 904–909
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted
efficient and versatile aza-Michael addition
*
Chang-Eun Yeom, Mi Jeong Kim and B. Moon Kim
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 151-747, Republic of Korea
Received 20 September 2006; revised 12 November 2006; accepted 14 November 2006
Available online 13 December 2006
Abstract—A convenient and versatile method was developed for aza-Michael addition using a substoichiometric amount of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU). Various nitrogen nucleophiles were efficiently introduced to a,b-unsaturated carbonyl compounds employing
0.5 equiv of DBU. Furthermore, other heteroatomic nucleophiles could also be introduced successfully under the same reaction conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
DBU’s excellent catalytic activity in Baylis–Hillman reac-
tion was reported in 1999 by Aggarwal and Mereu, and
DBU was found to be far superior to other tertiary amines.7
This unusual reactivity was suggested to be originated from
the stabilization of b-ammonium enolate, an intermediate
from the reaction of DBU and a Michael acceptor. In relation
to this work, progress based upon the nucleophilic nature of
DBU has been made during the past decades.8
b-Aminocarbonyl compounds have been used as building
blocks for many nitrogen-containing biologically important
compounds1 such as b-aminoalcohols, 1,2-diamines, and b-
lactams.2 Therefore, a number of efficient methods for the
preparation of this unit have been developed. For a long
time Mannich reaction3 has been mainly utilized for the con-
struction of b-aminocarbonyl compounds, however, it often
requires harsh reaction conditions, allowing for a relatively
narrow scope of substrates since it has to go through an imi-
nium intermediate. Recently, aza-Michael reaction has at-
tracted much attention as a promising alternative due to its
mildness and operational simplicity.4 It also has a prominent
advantage over the Mannich reaction covering a wide range
of nitrogen nucleophiles including amides, carbamates, and
sulfonamides, which can hardly be utilized using conven-
tional Mannich condensations. Most aza-Michael reaction
protocols often employ Lewis acidic catalysts such as tran-
sition metals or Brønsted acids, i.e., PdCl2(MeCN)2,5a
InCl3,5b CeCl3$7H2O,5c Yb(OTf)3,5d SmI2,5e Cu(OTf)2,5f
Bi(NO3),5g Bi(OTf)2,5h LiClO4,5i FeCl3$6H2O,5j TMSCl,5k
boric acid,5l acidic solids,5m and so on. However, above
methods are often associated with some drawbacks, for ex-
ample, high price and toxicity of catalysts, harsh reaction
conditions, limited scope of substrates, and unexpected
side reactions such as polymerization of Michael acceptors.
Accordingly, several other reagents have been developed as
a mild promoter of the aza-Michael reaction, i.e., fluoride,6a
ionic liquid,6b–d b-cyclodextrin,6e and sodium dodecylsul-
fate (SDS).6f
Inspired by the recent advances based upon DBU, we exam-
ined DBU as a promoter for aza-Michael reaction and were
pleased to find that with a substoichiometric amount of DBU
(0.5 equiv to amine), methyl acrylate and dibenzylamine
were condensed smoothly at room temperature, affording
methyl b-(dibenzylamino)acrylate in 95% yield (Scheme
1). This preliminary study prompted us to carry out in-depth
investigation on this novel protocol.
O
O
DBU (0.5 equiv)
CH3CN, rt
6 h
Bn2NH
1 equiv
+
Bn
OMe
1.5 equiv
N
Bn
OMe
95%
Scheme 1. DBU-promoted aza-Michael reaction.
2. Result and discussion
First, we screened several tertiary amines, which all have the
potential to promote this condensation (Table 1). The result
was in agreement with Aggarwal and Mereu;7 DBU was sig-
nificantly more effective in the conjugate addition between
dibenzylamine and methyl acrylate than DABCO (entry
2), DMAP (entry 3), and slightly more effective than TMG
(entry 4). Furthermore, in a control reaction without DBU,
only 3.8% of the desired product was obtained under
Keywords: Aza-Michael; DBU; Catalytic; Nitrogen nucleophiles; Conju-
gate addition.
* Corresponding author. Tel.: +82 2 880 6644; fax: +82 2 872 7505; e-mail:
kimbm@snu.ac.kr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.037

C.-E. Yeom et al. / Tetrahedron 63 (2007) 904–909
905
Table 1. Results of screening of various amine promoters in the conjugate
addition between dibenzylamine and methyl acrylate
Study on the substrate scope of the DBU-promoted aza-
Michael reactions was carried out with a wide range of nitro-
gen nucleophiles with 1.5 equiv of methyl acrylate, and the
results are collected in Table 3. Acyclic secondary amines
were introduced at the b-position of Michael acceptor in
O
O
Amine (0.5 equiv)
Bn2NH
1 equiv
+
Bn
OMe
1.5 equiv
N
Bn
OMe
CH3CN, rt
6 h
Entry
Amine
Yielda (%)
Table 3. Results of conjugate addition of various nitrogen nucleophiles to
methyl acrylate with DBU in acetonitrile
1
2
3
4
5
DBU
95
21
9
89
3.8
O
O
DABCO
DMAP
TMG
DBU (0.5 equiv)
CH3CN, rt
Amine
+
R
OMe
1.5 equiv
N
R'
OMe
1 equiv
None
a
Yields of isolated products.
Entry
Nucleophile
Bn2NH
Product
Time Yielda
(h) (%)
O
otherwise the same reaction conditions (entry 5). This obser-
vation clearly indicates that DBU is uniquely effective for
aza-Michael addition.9
Bn
N
OMe
1
6
95
Bn
O
Bn
N
To optimize the reaction conditions in detail, solvent effect
was studied in the conjugate addition between N,N0-benzyl-
methylamine and methyl acrylate using 0.5 equiv of DBU
(Table 2, entries 1–4). Interestingly, the reaction media
showed no significant influence on the progress of the
reaction, and the reaction proceeded smoothly even under
solvent-free conditions (entry 4). Among the solvents exam-
ined, acetonitrile, in which the best yield of the products was
obtained, was chosen as an appropriate medium for our
studies.
2
BnMeNH
BnNH2
4
3
94
75
OMe
OMe
OMe
O
Bn
N
3b
H
O
N
4
5
6
Piperidine
4
4
88
90
95
O
N
O
OMe
OMe
OMe
Morpholine
To see if the action of DBU is truly catalytic, we gradually
reduced the amount of DBU from 0.5 to 0.01 equiv in the
reaction between N,N0-benzylmethylamine and methyl acryl-
ate as a model reaction (Table 2). From this study, it is evi-
dent that a low loading of DBU is still effective, although
the reactivity was decreased consequently (entries 5–8).
Even 0.01 equiv of DBU afforded the desired adduct in
52% yield after 4 h, which did not change even after 12 h
(entry 8). However, in the case of the aza-Michael addition
between less reactive nucleophiles and sterically more
hindered Michael acceptors, highly prolonged reaction time
was required to yield a satisfactory result with a small amount
of DBU. As a result, we adopted 0.5 equiv as an optimal
loading amount of DBU for the following investigations.
O
N
N
N
N
14
H
N
O
N
N
N
H
7
8
9
14
14
14
95
98
97
O
O
O
O
NH
O
N
OMe
O
O
S
O
O
NH2
S
N
OMe
O
H
O
O
O
Table 2. Results of decreasing the amount of DBU and varying solvents in
the condensation between N,N0-benzylmethylamine and methyl acrylate
N
N
OMe
NH
10
20
14
92
99
O
O
O
O
DBU
Solvent, rt
4 h
+
BnMeNH
1 equiv
Bn
OMe
1.5 equiv
N
Me
OMe
O
O
11c
12
N
H
OMe
Entry
DBU (equiv)
Solvent
Yielda,b (%)
NH2
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.3
0.1
0.05
0.01
CH3CN
DMF
Toluene
None
CH3CN
CH3CN
CH3CN
CH3CN
95
85
83
89
85 (7 h)
76 (8.5 h)
63 (10 h)
52 (12 h)
48
14
24
0
N
OMe
O
H
O
O
13
O
NH2
O
N
OMe
H
a
Yields of isolated products.
Di-substituted product was isolated in 18% yield using 1.2 equiv of
methyl acrylate.
This reaction was performed at 50 ꢀC.
a
b
Yields of isolated products.
Values in parentheses indicate the time required for complete consump-
tion of the starting material.
b
c

906
C.-E. Yeom et al. / Tetrahedron 63 (2007) 904–909
excellent yields irrespective of steric bulkiness (entries 1 and
2). Unfortunately, reaction with primary amine suffered
from over-alkylation producing a low yield of the mono-
alkylated product. However, the ratio between mono- and
di-substituted products was considerably improved when a
reduced amount of methyl acrylate (1.2 equiv) was em-
ployed (entry 3). Cyclic amines such as piperidine (entry
4), morpholine (entry 5), pyrazole (entry 6), and imidazole
(entry 7) also underwent the conjugate addition successfully.
Surprisingly, relatively weak nucleophiles such as carba-
mate (entry 8), sulfonamide (entry 9), and phthalimide (en-
try 10) also gave the aza-Michael adducts in excellent yields,
though prolonged reaction time was required for complete
conversions. At this stage, we were curious of the reaction
with indole since it often leads to rather complicated re-
sults.10 Two types of reactions are possible: Michael reaction
at the NH and Friedel–Crafts alkylation at the C3 position
of the indole ring. In addition, unwanted side reactions can
be observed, e.g., dimerization and polymerization. To our
delight, using this protocol N-alkylation of indole proceeded
regioselectively giving excellent yield of the product, when
the reaction was heated slightly (entry 11). Unfortunately,
the addition of aniline was rather sluggish furnishing only
24% yield even after 2 days (entry 12). A simple carbamate
such as CbzNH2 was totally unreactive under the reaction
conditions (entry 13).
in the presence of 0.5 equiv of DBU in acetonitrile (Scheme
2). After 3.5 h, piperidine adduct (product A) was obtained
almost exclusively, in 83% yield, leaving a trace of the
aniline adduct (product B).
O
N
OMe
DBU (0.5 equiv)
CH3CN, rt
A, 83 %
+
N
H
+
NH2
1 equiv
O
1 equiv
O
OMe
N
H
OMe
B, trace
1.2 equiv
Scheme 2. Selective 1,4-addition of piperidine to methyl acrylate over
aniline.
To evaluate the scope of this method, conjugate additions
between a variety of Michael acceptors and nitrogen nucleo-
philes were screened extensively (Table 4). Unsubstituted
a,b-unsaturated compounds such as methyl vinyl ketone
and acrylonitrile gave moderate to good yields of the corre-
sponding Michael adducts with several nitrogen nucleo-
philes (entries 1–6). In the case of acrylonitrile, excess
amount (2 equiv) was required for the completion of the re-
action presumably due to the volatility of the reagent (entries
4–6). To test the steric effect, substituted a,b-unsaturated
carbonyls such as dimethyl maleate, methyl methacrylate,
and methyl crotonate were tested as Michael acceptors
(entries 7–15). Reactions of N,N0-benzylmethylamine,
piperidine, and 2-oxazolidinone with dimethyl maleate
underwent readily at room temperature (entries 7, 8, and 9,
Based upon the low reactivity of aromatic amines, we
assumed that selective addition of aliphatic over aromatic
amines would be feasible under this reaction system.
Accordingly, a control reaction was carried out to evaluate
the selectivity; an equimolar mixture of piperidine and ani-
line was allowed to react with 1.2 equiv of methyl acrylate
Table 4. Results of conjugate addition of nitrogen nucleophiles to a,b-unsaturated compounds in the presence of 0.5 equiv of DBU in acetonitrile
Entry
Nucleophile
Acceptor
Product
Time (h)
Temperature
Yielda (%)
O
O
O
Bn
Bn
1
BnMeNH
3
rt
71
N
O
O
N
Bn
2
3
Bn2NH
6
rt
rt
79
85
O
O
O
14
O
NH
O
N
4b
5b
24
24
rt
rt
98
97
N
H
CN
CN
N
N
CN
CN
BnMeNH
Bn
N
N
N
N
6b
24
14
14
rt
rt
rt
99
93
95
CN
H
CN
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
7
BnMeNH
Bn
N
MeO2C
N
CO2Me
N
H
MeO2C
8
(continued)

C.-E. Yeom et al. / Tetrahedron 63 (2007) 904–909
907
Table 4. (continued)
Entry
Nucleophile
Acceptor
Product
Time (h)
14
Temperature
rt
Yielda (%)
O
MeO2C
CO2Me
O
O
NH
MeO2C
CO2Me
N
9
93
O
O
O
O
Bn
10
11
BnMeNH
8
8
50 ꢀC
50 ꢀC
73
81
OMe
OMe
N
N
OMe
O
OMe
N
H
N
O
O
N
N
OMe
OMe
N
H
12
13
14
14
14
50 ꢀC
50 ꢀC
94
77
N
O
O
Bn
BnMeNH
OMe
OMe
O
O
O
O
N
OMe
10
18
50 ꢀC
50 ꢀC
82
89
N
H
OMe
OMe
O
O
O
O
15
O
NH
O
N
OMe
a
Yields of isolated products.
2 equiv of acrylonitrile were added.
b
respectively), however, reactions with either a- or b-methyl
substituted acrylates proceeded significantly more slowly.
When the reaction temperature was elevated to 50 ꢀC,
reactions proceeded smoothly and good to excellent yields
of products were obtained in the reactions of methyl meth-
acrylate with N,N0-benzylmethylamine, piperidine, and
imidazole (entries 10, 11, and 12, respectively) and in the
reactions of methyl crotonate with N,N0-benzylmethylamine,
morpholine, and 2-oxazolidinone (entries 13, 14, and 15,
respectively).
As for the role of DBU for the activation in the Michael
addition of the amines to a,b-unsaturated systems, we spec-
ulate that simple basic catalysis cannot fully explain the
mechanism. More work should be done to clarify the exact
mechanism of the DBU-promoted reaction.
3. Conclusion
We developed a novel method for a mild and efficient aza-
Michael addition promoted by DBU. Primary and acyclic
and cyclic secondary amines efficiently provided Michael
adducts with unsubstituted and a- or b-methyl-substituted
acrylates and their analogs. In the case of a primary amine,
side product formation could be minimized by controlling
the amount of a Michael acceptor. Less reactive amines
such as 1,2-diazole, imidazole, 2-oxazolidinone, sulfon-
amide, phthalimide, and indole can also be applied success-
fully without additional modification of the experimental
procedure. Reaction of aniline, however, was very sluggish.
Reactions of substituted Michael acceptors such as maleate
ester and a- and b-methyl acrylates also proceeded smoothly
with all secondary amines examined, sometimes assisted by
moderate heating. This method is versatile, high yielding,
and operationally very simple; it does not require intricate
precautions such as exclusion of air and moisture.
Encouraged by the versatility and effectiveness of this
method, we attempted hetero-Michael addition reactions
with other heteroatomic nucleophiles. As representative nu-
cleophiles, a thiol and a phosphite were examined, and the
results were also good in both cases. At room temperature,
benzyl mercaptan and dimethyl phosphite were introduced
at the b-position of methyl acrylate with ease to afford the
corresponding adducts in 99 and 93% yields, respectively,
as shown in Scheme 3.
O
O
DBU (0.5 equiv)
SH
+
+
S
OMe
99%
CH3CN, rt
4 h
OMe
1.5 equiv
1 equiv
O
O
O
O
DBU (0.5 equiv)
CH3CN, rt
2 h
MeO
MeO
4. Experimental
4.1. General
MeO
MeO
PH
P
OMe
93%
OMe
1.5 equiv
1 equiv
All reactions were carried out under nitrogen atmosphere in
dried solvents. 1H (300 MHz) and 13C NMR (75 MHz)
Scheme 3. Results of hetero-Michael addition using a thiol or a phosphite as
nucleophiles.

908
C.-E. Yeom et al. / Tetrahedron 63 (2007) 904–909
spectra were recorded in CDCl3 on Bruker AM-300 instru-
ments. Chemical shifts were reported in parts per million (d
units) downfield of Me4Si (TMS) as the internal standards,
or residual CHCl3. High-resolution mass spectra (HRMS)
were obtained from JEOL JMS 600 mass spectrometer.
Acetonitrile (CH3CN) was purchased from Aldrich as a
reagent grade in a Sure/SealÔ bottle, and used directly
without further purification. DBU and other commercially
available materials were purchased from supplier (Aldrich,
Acros, and TCI) and used without further purification. All
reactions as well as column chromatography were moni-
tored routinely by thin layer chromatography, which is
performed with aluminum backed silica gel plates coated
with a 0.2 mm thickness of silica gel 60 F254 (Merck).
Column chromatography was performed with indicated
eluting conditions on silica gel (Merck 7734 or 9385 Kie-
selgel 60). All known Michael adducts were analyzed by
NMR analysis, and their data were in agreement with the
literature values.
4.2.12. Methyl 3-(N-phenylamino)propionate (Table 3,
entry 12). See Ref. 11h.
4.2.13. 4-(N-Benzyl-N-methylamino)butan-2-one (Table
4, entry 1). See Ref. 5c.
4.2.14. 4-(N-Dibenzylamino)butan-2-one (Table 4, entry
2). See Ref. 5c.
4.2.15. 4-(2-Oxazolidinyl)butan-2-one (Table 4, entry 3).
See Ref. 6a.
4.2.16. 3-Piperidinylpropionitrile (Table 4, entry 4). See
Ref. 12a.
4.2.17. 3-(N-Benzyl-N-methylamino)propionitrile (Table
4, entry 5). See Ref. 12b.
4.2.18. 3-Pyrazolylpropionitrile (Table 4, entry 6). See
Ref. 12c.
4.2. General procedure for the aza-Michael reaction
(Table 1, entry 1)
4.2.19. 2-(N-Benzyl-N-methylamino)succinic acid di-
methyl ester (Table 4, entry 7). Colorless oil (eluted with
n-hexane/EtOAc¼10:1). 1H NMR (300 MHz, CDCl3)
d 7.31–7.27 (m, 5H), 3.90 (dd, J¼7.9, 7.3 Hz, 1H), 3.77 (s,
3H), 3.75–3.67 (m, 2H), 3.68 (s, 3H), 2.88 (dd, J¼15.8,
7.9 Hz, 1H) 2.68 (dd, J¼15.8, 7.3 Hz, 1H), 2.25 (s, 3H);
13C NMR (75 MHz, CDCl3) d 171.8, 171.7, 139.0, 128.7,
128.3, 127.1, 62.3, 59.1, 51.8, 51.5, 37.9, 34.8; HRMS
(EI) Calcd for C14H19NO4 [M]+: 265.1314, found: 265.1313.
To a magnetically stirred solution of dibenzylamine
(1.0 mmol) and methyl acrylate (1.5 mmol) in CH3CN
(0.5 ml) was added DBU (0.5 mmol) at room temperature.
After 6 h, the mixture was concentrated through vacuum
evaporation. The resulting residue was purified by silica
gel column chromatography (n-hexane/EtOAc¼6:1), and
the pure aza-Michael adduct was isolated in 95% yield.
4.2.1. Methyl 3-(N-benzylamino)propionate (Table 3,
entry 1). See Ref. 11a.
4.2.20. 2-Piperidinylsuccinic acid dimethyl ester (Table 4,
entry 8). See Ref. 12d.
4.2.2. Methyl 3-(N,N-dibenzylamino)propionate (Table 3,
entry 2). See Ref. 5c.
4.2.21. 2-(2-Oxazolidinyl)succinic acid dimethyl ester
(Table 4, entry 9). Colorless oil (eluted with EtOAc). H
1
NMR (300 MHz, CDCl3) d 4.83 (m, 1H), 4.37 (m, 2H),
3.77 (s, 3H), 3.72 (s, 3H), 3.64 (t, J¼7.6 Hz, 2H), 2.97
(dd, J¼16.5, 7.8 Hz, 1H) 2.75 (dd, J¼16.5, 7.4 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 170.6, 169.2, 158.2, 62.5,
52.9, 52.9, 52.3, 42.9, 34.4; HRMS (CI) Calcd for
C9H14NO6 [M+H]+: 232.0821, found: 232.0821.
4.2.3. Methyl 3-(N-benzyl-N-methylamino)propionate
(Table 3, entry 3). See Ref. 11b.
4.2.4. Methyl 3-piperidinylpropionate (Table 3, entry 4).
See Ref. 11a.
4.2.5. Methyl 3-morpholinylpropionate (Table 3, entry
5). See Ref. 5m.
4.2.22. Methyl 3-(N-benzyl-N-methylamino)-2-methyl-
propionate (Table 4, entry 10). See Ref. 12e.
4.2.6. Methyl 3-pyrazolylpropionate (Table 3, entry 6).
See Ref. 11c.
4.2.23. Methyl 3-piperidinyl-2-methylpropionate (Table
4, entry 11). See Ref. 12a.
4.2.7. Methyl 3-imidazolylpropionate (Table 3, entry 7).
See Ref. 11d.
4.2.24. Methyl 3-imidazolyl-2-methylpropionate (Table
4, entry 12). Colorless oil (eluted with EtOAc). H NMR
1
(300 MHz, CDCl3) d 7.46 (s, 1H), 7.04 (s, 1H), 6.89 (s,
1H), 4.25 (dd, J¼14.0, 7.7 Hz, 1H), 4.00 (dd, J¼14.0,
6.2 Hz, 1H), 3.68 (s, 3H), 2.88 (m, 1H), 1.19 (d, J¼7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 174.1, 137.6, 129.6,
119.1, 52.1, 49.2, 41.4, 14.9; HRMS (CI) Calcd for
C8H13N2O2 [M+H]+: 169.0977, found: 169.0978.
4.2.8. Methyl 3-(2-oxazolidinyl)propionate (Table 3,
entry 8). See Ref. 6a.
4.2.9. Methyl 3-(4-toluenesulfonylamino)propionate
(Table 3, entry 9). See Ref. 11e.
4.2.10. N,N-Phthaloyl-b-alanine methyl ester (Table 3,
entry 10). See Ref. 11f.
4.2.25. Methyl 3-(N-benzyl-N-methylamino)-3-methyl-
propionate (Table 4, entry 13). See Ref. 12f.
4.2.11. Methyl 3-(1-indolyl)propionate (Table 3, entry
11). See Ref. 11g.
4.2.26. Methyl 3-methyl-3-morpholinylpropionate
(Table 4, entry 14). See Ref. 5m.

C.-E. Yeom et al. / Tetrahedron 63 (2007) 904–909
909
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4.2.27. Methyl 3-methyl-3-(2-oxazolidinyl)propionate
(Table 4, entry 15). See Ref. 12g.
4.2.28. Methyl 3-benzylsulfanyl-propionate (Scheme 3).
See Ref. 13a.
4.2.29. Methyl 3-dimethoxyphosphorylpropionate
(Scheme 3). See Ref. 13b.
Acknowledgements
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