1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) catalyzed Michael reactions

Article abstract of DOI:10.1016/j.tetlet.2005.08.010

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), a bicyclic guanidine base, has been found to be an excellent catalyst for Michael and Michael-type reactions. A wide variety of Michael donors and acceptors can participate in these reactions using 10-20 mol % of

Full text of DOI:10.1016/j.tetlet.2005.08.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6875–6878
1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) catalyzed
Michael reactions
Weiping Ye, Junye Xu, Chin-Tong Tan and Choon-Hong Tan*
Department of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
Received 27 June 2005; revised 28July 2005; accepted 2 August 2005
Abstract—1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), a bicyclic guanidine base, has been found to be an excellent catalyst for
Michael and Michael-type reactions. A wide variety of Michael donors and acceptors can participate in these reactions using
10–20 mol % of TDB. These reactions are mild, fast, easy to perform, produce excellent yields and can occur in several solvents
without the need for strictly anhydrous conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Bicyclic guanidine bases1 such as 1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene (Fig. 1, TBD) and 1,3,4,6,7,8-hexa-
hydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine (Fig. 1,
7-methyl-TBD or MTBD) are known as superbases
due to their high pKa values.2 They have been shown
to promote various reactions including the Wittig reac-
tion,3 nitroaldol (Henry) reaction,4 dialkyl phosphite
addition to carbonyl compounds4 and the addition of
azoles to a,b-unsaturated nitriles and esters.5
aldol-type condensation and the Michael addition of
nitroethane onto benzylidene acetone.8a Nucleophilic
ring-opening reactions of 2,2-dialkyl-1,2,3,4-tetra-
hydro-c-carbolinium salts with thiols can also be medi-
ated by polymer-supported TBD.8b Guanidine bases
have also received intense investigations as potential
enantioselective catalysts.9
Carbon–carbon bond formation is central to organic
synthesis. Direct Michael addition and Michael-type
conjugate reactions are amongst the most simple, effi-
cient and atom-economical ways to achieve this trans-
formation. These reactions are typically performed
with stoichiometric amounts of inorganic bases such as
sodium ethoxide, potassium tert-butoxide, potassium
hydroxide, sodium metal, LDA, sodium hydride or n-
butyllithium.10 Strong basic conditions can, however,
lead to side reactions. Recently, excellent enantioselec-
tive Michael reactions have been developed using transi-
Stoichiometric amounts of MTBD have also been
shown to be moderately active in Baylis–Hillman reac-
tions.6 Immobilized MTBD, in siliceous MCM-41, can
promote the Knoevenagel condensation, epoxidation7a
and the formation of thioureas.7b Polystyryl-supported
TBD (PSTBD) can catalyze 1,2-epoxide ring-opening,
N
N
N
tion metal catalysts.11 A quaternary ammonium salt,12
a
N
Me
N
N
N
H
N
proline lithium salt,13a L-proline,13b cinchona alkaloids14
and imidazolidine15 have also been shown to exhibit cat-
alytic activity in several conjugate addition reactions. In
contrast, organobases such as DBU16a,b (Fig. 1) and
TBD8a,16c are less well documented as catalysts for
Michael reactions. In this letter, we report our survey
of the range of substrates and carbon nucleophiles that
are suitable for Michael and Michael-type reactions
using TBD as the catalyst.
TBD
MTBD
DBU
NH
N
N
N
N
H
N
TMP
DABCO
TMG
Figure 1. Various organobases.
As a reliable starting point, dimethyl malonate was used
as the Michael donor to the cyclic enone, 2-cyclopenten-
1-one (Scheme 1 and Table 1). With 10 mol % of TBD,
Keywords: TBD; Michael reaction; Organobase.
*
Corresponding author. Tel.: +65 6874 2845; fax: +65 6779 1691;
e-mail: chmtanch@nus.edu.sg
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.010

6876
W. Ye et al. / Tetrahedron Letters 46 (2005) 6875–6878
Table 2. TBD (10 mol %) catalyzed Michael reaction between various
carbon nucleophiles and 2-cyclopenten-1-one in toluene
O
O
catalyst
CO2Me
CO2Me
Entry Donor
Product
Time
Yielda (%)
solvent, rt
O
CO2Me
MeO2C
1
CO2Et
1
30 min
90
CO2Et
Scheme 1. Organobase catalyzed Michael reaction between 2-cyclo-
penten-1-one and dimethyl malonate.
CO2Et
2
EtO2C
O
t
Table 1. The influence of different organobases and solvents on the
reaction in Scheme 1
CO2 Bu
2
1 h
99
99
t
CO2 Bu
t
CO2 Bu
3
Entry Catalyst (mol %) Solvent
Time
5 min
Yielda (%)
95
tBuO2C
O
1
2
3
4
5
6
7
TBD (10)
TBD (5)
Toluene
Toluene
DMF
MeOH
MeCN
Et2O
30 min 95
15 min 90
15 min 90
30 min 90
30 min 90
30 min 90
COMe
TBD (10)
TBD (10)
TBD (10)
TBD (10)
TBD (10)
3
10 h
CO2Et
COMe
EtO2C
O
4
THF
8TBD (20)
Tol:H
2O (99:1) 30 min 90
COMe
9
MTBD (10)
Toluene
Toluene
Toluene
6 h
24 h
37 h
91
93
85c
4
6 h
6 h
95
10
11
DBUb (10)
TMG (10)
CONMe2
COMe
5
Me2NOC
a Isolated yield. Conversion estimated to be 100% by TLC. No side
products observed.
b DBN had a similar reaction profile as DBU.
c Reaction did not complete.
O
O
O
O
5
94b
O
6
a Isolated yield. Conversion estimated to be 100% by TLC. No side
products observed.
the reaction proceeded smoothly at room temperature
(25 °C) with toluene as the solvent. The reaction was
complete in 5 min and, after flash chromatography, gave
an excellent isolated yield of 95% (Table 1, entry 1). The
amount of catalyst could be reduced to 5 mol % (entry
2) without affecting the yield. This protocol is much
more convenient and operationally simpler to perform
than the reported methodology using sodium methoxide
to generate the same product.17
b 20 mol % of catalyst used.
role as a hydrogen bond donor in the catalytic cycle. This
type of interaction would be enhanced in non-polar sol-
vents such as toluene. The TMG catalyzed reaction (en-
try 11) was not able to reach completion. Other
organobases such as TMP, DABCO and DIPEA were
ineffective as catalysts for this reaction. No products
were observed after 56 h of reaction time. This is not
unexpected as the conjugate acids of these bases have rel-
atively low pKa values.
Under the same conditions, a variety of solvents such as
DMF (entry 3), methanol (entry 4), acetonitrile (entry
5), diethyl ether (entry 6) and THF (entry 7) were found
to be suitable solvents for this reaction. These reactions
were typically complete within 15–30 min giving isolated
yields of P90%. We also discovered that this reaction was
not sensitive to moisture. For example, the reaction in tol-
uene containing 1% water with 20 mol % of the catalyst
was complete in 30 min and the yield was 90% (entry 8).
Subsequently, we investigated the suitability of a range
of carbon nucleophiles for this reaction using 2-cyclo-
penten-1-one as the substrate. Diethyl malonate (Table
2, entry 1), di-tert-butyl malonate (entry 2), ethyl aceto-
acetate (entry 3), N,N-dimethylacetoacetamide (entry 4)
and 2-acetylcyclopentanone (entry 5) were all found to
be useful donors. The reactions of all these nucleophiles
proceeded smoothly, giving high isolated yields of the
Michael adducts. It is interesting to note that the reaction
with 2-acetylcyclopentanone generated no side products
even though it contained multiple enolizable protons (en-
try 5). This demonstrates the mildness and chemoselec-
tivity of this reaction. The quaternary carbon of the
product was identified using DEPT NMR experiments.
Next, we were keen to find out if it was a general phe-
nomenon for organobases to act as catalysts in Michael
reactions. We compared the results obtained with TBD
against a variety of organobases such as MTBD, DBU,
DBN, 1,1,3,3-tetramethylguanidine (Fig. 1, TMG),
tetramethylpiperidine (Fig. 1, TMP), DABCO and diiso-
propylethylamine (DIPEA). MTBD (entry 9), DBU (en-
try 10) and DBN were all effective catalysts for this
reaction. However, they catalyzed the reaction at a much
slower rate than TBD. It is interesting to note the differ-
ence in reaction time between TBD and MTBD (entry 9).
Such differences were greatly reduced in polar solvents
such as MeOH and MeCN. The guanidinium intermedi-
ate that is generated when TBD is protonated may play a
Using dimethyl malonate as the donor, we decided to
investigate other suitable Michael acceptors (Table 3).
We found that with 10–20 mol % of TBD, a wide range
of substrates including various b-nitrostyrenes (Table 3,
entries 1–3), various chalcones (entries 4–6), trans-1,2-

W. Ye et al. / Tetrahedron Letters 46 (2005) 6875–6878
6877
Table 3. TBD (10 mol %) catalyzed Michael reaction between dimethyl malonate and various substrates in toluene
Entry
Substrate
Product
Time (min)
Yielda (%)
MeO2C
CO2Me
NO2
NO2
NO2
1
5
96
94
7
MeO2C
O
CO2Me
NO2
8
O
2
3
5
5
MeO2C
CO2Me
NO2
NO2
93
92
Me
9
Me
MeO2C CO2Me
O
O
4
60
10
MeO2C CO2Me
O
O
O
5
6
5
98
O2N
MeO
O
11
O2N
MeO2C CO2Me
O
120
95b
12
MeO
MeO2C CO2Me
O
O
7
5
96
O
13
MeO2C
CO2Me
O
O
EtO
O
8
9
30
91c
EtO
O
OEt
OEt
14
MeO2C
NC
CO2Me
CN
93b
CN
120
NC
15
a Isolated yield. Conversion estimated to be 100% by TLC. No side product observed for all experiments.
b 20 mol % of catalyst used.
c 15 mol % of catalyst used.
dibenzoylethylene (entry 7), diethyl fumarate (entry 8)
and fumaronitrile (entry 9) were suitable substrates for
this reaction (see Supplementary data for more exam-
ples). The b-nitrostyrenes were excellent substrates for
this reaction, giving high yields within a short reaction
time. We realized that electron deficient chalcones were
more active substrates and reacted in shorter times.
However, the difference in reaction time did not affect
the yield of the reactions.
Using our methodology, we therefore focussed on
broadening the range of suitable acceptors for the donor
2-acetylcyclopentanone (Scheme 2). We tested various
activated terminal alkenes and found several suitable
acceptors; for example acrylonitrile (Table 4, entry 1),
acrylates (entries 2 and 3), phenyl vinyl sulfone (entry
4) and phenyl vinylsulfonate (entry 5). All reactions
were complete within a short reaction time, giving
moderate to excellent isolated yields of previously
unreported Michael adducts.
One-step construction of a quaternary carbon is often a
difficult task, especially under catalytic conditions and
this area has attracted the interest of many chemists.18
In conclusion, we have discovered a mild, catalytic, high
yielding and efficient methodology for Michael and

6878
W. Ye et al. / Tetrahedron Letters 46 (2005) 6875–6878
´
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O
O
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5 min
a Isolated yield. Conversion estimated to be 100% by TLC. No side
products observed.
Michael-type reactions using TBD. This reaction is easy
to perform, is usually fast and the purification protocol
is simple. No side products were observed for most reac-
tions. As this reaction is not sensitive to moisture, the
solvent used and reaction conditions need not be abso-
lutely anhydrous. This methodology can accommodate
a wide range of substrates and donors, making it a use-
ful addition to the chemistÕs toolbox. Using this proto-
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containing quaternary carbon centres that were previ-
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commercially available. We are currently actively pursu-
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Acknowledgements
This work was supported by a grant (R-143-000-196-
101) and scholarships (to W.P.Y. and J.Y.X.) from the
National University of Singapore. We thank the Medic-
inal Chemistry Program for their financial support. We
also thank Professor Teck-Peng Loh and Dr. Martin J.
Lear for helpful discussions.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2005.08.010. Experimental procedures and spectral
data of the products are presented. More examples of
suitable substrates and donors for TBD catalyzed Mi-
chael reactions are provided. Spectral data of previously
unreported products are also presented.
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