Asymmetric Morita-Baylis-Hillman reaction catalyzed by isophoronediamine- derived bis(thio)urea organocatalysts

Article abstract of DOI:10.1021/ol061298m

(Chemical Equation Presented) New and improved bis(thio)urea catalysts were synthesized from isophoronediamine (IPDA) and tested in the Morita-Baylis-Hillman reaction. The best results were achieved in the reaction of 2-cyclohexen-1-one with cyclohexaneca

Full text of DOI:10.1021/ol061298m

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4195-4198
Asymmetric Morita
Reaction Catalyzed by
−Baylis−Hillman
Isophoronediamine-Derived Bis(thio)urea
Organocatalysts
Albrecht Berkessel,* Katrin Roland, and Jo1rg M. Neudo1rfl
Institute for Organic Chemistry, UniVersity of Cologne, Greinstrasse 4,
50939 Cologne, Germany
berkessel@uni-koeln.de
Received May 28, 2006
ABSTRACT
New and improved bis(thio)urea catalysts were synthesized from isophoronediamine (IPDA) and tested in the Morita−Baylis−Hillman reaction.
The best results were achieved in the reaction of 2-cyclohexen-1-one with cyclohexanecarbaldehyde, using the catalyst depicted above, in
combination with a novel base (N,N,N′,N′-tetramethylisophoronediamine, TMIPDA) in toluene. The desired Morita−Baylis−Hillman product was
obtained in 75% yield and 96% ee.
The Morita-Baylis-Hillman (MBH) reaction is the addition
of electron-deficient alkenes to aldehydes, promoted by
nucleophilic bases such as DABCO.1 The products of this
versatile carbon-carbon bond forming reaction are highly
functionalized allylic alcohols which can serve as valuable
building blocks for the synthesis of complex natural prod-
ucts.2 Hence, the development of a suitable asymmetric
version of the MBH reaction has attracted considerable
interest in recent years.3 Hatakeyama et al. have described
quinidine-derived chiral bases for the reaction of acrylates
with aldehydes providing ee values up to 99%. However,
the substrate scope of the latter transformation is rather
narrow.4 It was reported by Ikegami et al. that MBH reactions
are further promoted by Brønsted acid cocatalysts.5 Schaus
et al. introduced an asymmetric Brønsted acid catalyst
derived from BINOL that, in combination with PEt3, led to
ee values of up to 96% and good to moderate yields for a
(1) For reviews see: (a) Berkessel, A.; Gro¨ger, H. Asymmetric Orga-
nocatalysis; Wiley-VCH: Weinheim, Germany, 2005. (b) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811. (c) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049. (d) Ciganek, E. In Organic
Reactions; Paquette, L. A., Ed; Wiley: New York, 1997; Vol. 51, p 201.
(2) For examples see: (a) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030. (b) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867. (c) Anand,
R. V.; Baktharaman, S.; Singh, V. K. Tetrahedron. Lett. 2002, 43, 5393.
(d) Mateus, C. R.; Coelho, F. J. Braz. Chem. Soc. 2005, 16, 386.
(3) For recent advances in the asymmetric aza-Morita-Baylis-Hillman
reaction see: (a) Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005,
347, 1701. (b) Shi, M.; Chen, L.-H. Pure Appl. Chem. 2005, 77, 2105. (c)
Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761.
(4) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219. (b) Nakano, A.; Kawahara, S.; Akamatsu,
S.; Morokuma, K.; Nakatani, M.; Iwabuchi, Y.; Takahashi, K.; Ishihara,
J.; Hatakeyama, S. Tetrahedron 2006, 62, 381.
(5) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
10.1021/ol061298m CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/16/2006

large variety of aldehydes in the reaction with 2-cyclohexen-
1-one.6 The first application of (thio)urea catalysts for the
MBH reaction was reported by Connon et al., but no
asymmetric version was investigated.7 A chiral bifunctional
catalyst was disclosed by Wang et al. carrying a Brønsted
basic tertiary amine and a quasi-Lewis acidic thiourea group
attached to a chiral scaffold.8 Bis(thio)ureas derived from
chiral trans-1,2-diaminocyclohexane were also proven to be
suitable catalysts for the asymmetric MBH reaction, as
described by Nagasawa et al.9
2-cyclohexen-1-one (3) at 10 °C in the presence of 20
mol % of catalyst and base without any solvent (Table 1).
Table 1. Screening of the Bis(thio)ureas 1a-f in the Reaction
of 2-Cyclohexen-1-one (3) with Cyclohexanecarbaldehyde (2)a
Herein, we report improved bis(thio)urea catalysts derived
from isophoronediamine [3-(aminomethyl)-3,5,5-trimethyl-
cyclohexylamine, IPDA]. IPDA is a readily available 1,4-
diamine produced industrially on a multiton scale. IPDA and
its derivative isophoronediisocyanate [5-isocyanato-1-(iso-
cyanatomethyl)-1,3,3-trimethylcyclohexane, IPDI] are used
as monomers for urethane and epoxy resins.10 The large scale
optical resolution of IPDA was described recently by our
group.11
The obvious advantages of bis(thio)urea catalysts are their
facile and modular synthesis. Structurally diverse potential
catalysts are easily accessible by condensation of a chiral
diamine with 2 equiv of iso(thio)cyanate (Figure 1).
entry
catalyst
yield (%)b
ee (%)b,c
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
10
30
11
81
3
86
87
93
90
70
10
1
a The reaction was carried out with 1 equiv of 2 and 4 equiv of 3 in the
presence of 20 mol % catalyst and DABCO under neat conditions at 10 °C
for 72 h. b Yields and ee values were determined by GC on chiral stationary
phase, using an internal standard. c Enantiomeric excess was in favor of
the (R)-enantiomer. Absolute configuration was assigned by comparison
of the retention times with those reported by Nagasawa et al.9
The bis(thio)urea 1d was found to be the optimum catalyst
for this reaction, providing the product 4 in 81% yield and
90% ee after 72 h (entry 3). The corresponding urea catalyst
1b showed lower activity and selectivity (entry 1), while the
alkyl-substituted bis(thio)ureas 1e and 1f were almost
completely inactive (entries 5 and 6).
In general, the thiourea catalysts proved to be superior to
urea catalysts for this transformation (entries 3 and 4). This
is presumably due to the stronger H-bonding ability of
thioureas compared to ureas, and therefore stronger interac-
tion with the substrates.14
The nature of the nucleophilic base is known to have a
pronounced influence on the MBH reaction.15 Therefore
various tertiary amine bases were screened in combination
with catalyst 1d for the test reaction (Table 2).
Tetramethylated IPDA [(1R,3S)-TMIPDA] was found to
be the most effective base for this particular reaction,
producing the allylic alcohol 4 with 90% yield and 91% ee
(Table 2, entry 5). Under the conditions of this study, the
amount of TMIPDA could be reduced from 20 mol % to 10
mol % without loss in activity or selectivity (Table 2, entries
5 and 6).
Figure 1. Synthesis of bis(thio)urea catalysts.
When the same reaction was carried out with DABCO,
reduction of the amount of base from 20 mol % to 10
The catalytic activity of these bis(thio)ureas was tested in
the model reaction of cyclohexanecarbaldehyde (2) with
(12) X-ray crystallographic data for 1a and 1c are included in the
Supporting Information.
(13) For synthesis of the catalysts 1b and 1d see: Berkessel, A.;
Mukherjee, S.; Mu¨ller, T. N.; Cleeman, F.; Roland, K.; Brandenburg, M.;
Neudo¨rfl, J. M.; Lex, J. Submitted for publication.
(14) For recent reviews on catalysis by hydrogen-bond donors see: (a)
Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(15) For examples of base influence on the MBH reaction see: (a)
Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311. (b) Aggarwal,
V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692. (c) Luo, S.;
Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng, J.-P. Tetrahedron Lett.
2002, 43, 7369.
(6) (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094. (b) McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kliman, L.
T.; Schaus, S. E. AdV. Synth. Catal. 2004, 346, 1231.
(7) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301.
(8) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293.
(9) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron
Lett. 2004, 45, 5589.
(10) For examples see: (a) Hoenel, M.; Pfeil, A.; Budnick, T.; Schwan,
H. German patent 4344510 A1, 1995. (b) Tillack, J.; Schmalstieg, L.; Puetz,
W.; Ruttmann, G. German patent 19935329 A1, 2001.
(11) Berkessel, A.; Roland, K.; Schro¨der, M.; Neudo¨rfl, J. M.; Lex, J.
Submitted for publication.
4196
Org. Lett., Vol. 8, No. 19, 2006

Although DBU is usually classified as a nonnucleophilic
base, it is known to be very active in the MBH reaction.15a
Unfortunately, in this case, the high activity of DBU led to
lower selectivity and the formation of a significant amount
of the aldol addition product of 2-cyclohexen-1-one (3) and
cyclohexanecarbaldehyde (2) (Table 2, entry 4). Alkaloids
were not particularly efficient in this reaction (Table 2, entries
8, 9, and 10). Nevertheless, the pseudoenantiomeric com-
pounds quinine and quinidine provided the same product
enantiomer, which shows that in this case, the chirality of
the base has no significant influence on the enantioselectivity.
The MBH reaction of 3 and 2 was usually carried out
under neat conditions in an excess of 2-cylohexen-1-one (3).
For further optimization, the influence of a solvent on the
reaction was investigated (Table 3). The concentration of
Table 2. Optimization of the Base in the Reaction of
2-Cyclohexen-1-one (3) with Cyclohexanecarbaldehyde (2)a
entry
base
yield (%)b
ee (%)b
1
2
3
4
5
6
7
8
9
DABCO
DABCOc
DMAP
81
48
30
56
90
90
67
12
12
2
90
90
48
59
91
90
82
91
90
72
DBU
TMIPDA
TMIPDAc
quinuclidine
quinine
quinidine
brucine
NEt3
10
11
Table 3. Solvent Effects on the MBH Reaction of
2-Cyclohexen-1-one (3) with Cyclohexanecarbaldehyde (2)a
3
a Unless stated otherwise, the reaction was carried out with 1 equiv of
2 and 4 equiv of 3 in the presence of 20 mol % catalyst 1d and base under
neat conditions at 10 °C for 72 h. b See footnote b in Table 1. c 10 mol %
of base.
mol % resulted in an approximately proportional reduction
of the reaction rate (Table 2, entries 1 and 2). IPDA
derivatives have a strong tendency to adopt the e,e rather
than the a,a conformation of the cyclohexyl backbone,
resulting in a large distance between the two nitrogen atoms
(Scheme 1).11 Compared to the rather compact structure of
entry
solvent
yield (%)b
ee (%)b
1
2c
3
toluene
toluene
DMF
70
75
14
55
96
96
25
95
4
DCM
a The reaction was carried out with 1 equiv of 2 (2.00 M in solvent) and
2 equiv of 3 in the presence of 20 mol % catalyst 1d and DABCO at 10 °C
for 72 h. b See footnote b in Table 1. c Result after 65 h with TMIPDA as
base.
Scheme 1
the aldehyde was kept constant, and only 2 equiv of 3 was
added in these experiments. Toluene emerged as the best
solvent for this reaction, affording the product 4 in 70% yield
and 96% ee, which corresponds to the best result reported
to date by Schaus et al.6
When TMIPDA was used as a base instead of DABCO,
the reaction rate was slightly increased without loss in
selectivity (Table 3, entry 2). In DCM, comparable asym-
metric induction was achieved, although the reaction was
significantly slower (Table 3, entry 4).
DABCO, steric hindrance will be much less in TMIPDA,
allowing both tertiary amine moieties to act as base
simultaneously. This hypothesis is further underlined by the
X-ray crystal structure of 1a (Figure 2). The N-N distance
Polar solvents such as MeOH, DMF (Table 3, entry 3),
THF, dioxane, and their mixtures with water were found to
inactivate the catalyst, presumably by strong coordination
to the thiourea moieties.17
The use of nonpolar solvents provided enhanced selectivi-
ties, albeit at the expense of somewhat reduced reaction rates
(16) Wada, T.; Kishida, E.; Tomiie, Y.; Suga, H.; Seki, S.; Nitta, I. Bull.
Chem. Soc. Jpn. 1960, 33, 1317.
Figure 2. X-ray structure of catalyst 1a.
(17) Polar solvents are assumed to catalyze the MBH reaction by a proton
transfer mechanism. The same mechanism presumably underlies the
frequently observed autocatalysis by the product. (a) Aggarwal, V. K.;
Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1734.
(b) Buskens, P.; Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2005,
127, 16762.
of the backbone NH moieties in 1a is 6.25 Å, compared to
a N-N distance of 2.53 Å for DABCO.16
Org. Lett., Vol. 8, No. 19, 2006
4197

tion of 2-cyclohexen-1-one (3) and consequently the sup-
pression of the unselective background reaction catalyzed
by DABCO. Unfortunately, for other substrates, in particular
benzaldehyde, the decrease in rate was even more pro-
nounced. Therefore, the general substrate scope of the
reaction was studied under neat conditions with 4 equiv of
2-cyclohexen-1-one (3) (Table 4). We furthermore found that,
with the exception of cyclohexanecarbaldehyde (2) as
substrate (see Table 2), DABCO provides superior yields
and ee values compared to TMIPDA.
Table 4. MBH Reaction of Enones and Acrylates with
Aldehydes Catalyzed by IPDA-Derived Bis(thio)ureasa
Benzaldehyde is still one of the most challenging substrates
for the MBH reaction with 2-cyclohexen-1-one (3). Catalyst
1a effected this transformation with 65% yield and 77% ee
(Table 4, entry 2). To the best of our knowledge, this is the
best result for this pair of substrates reported so far. In
general, aliphatic aldehydes gave better enantioselectivity
compared to aromatic ones in the MBH with 2-cyclohexen-
1-one (3). The same trend was observed for the reactions
with 2-cyclopenten-1-one (Table 4, entries 7 and 8) and
methyl acrylate (Table 4, entries 9 and 10).
In conclusion, we have found very active and enantio-
selective bis(thio)urea catalysts, derived in one step from the
readily available 1,4-diamine IPDA. Good to excellent yields
and enantiomeric excesses were obtained in the MBH
reaction of a variety of aldehydes with 2-cyclohexen-1-one
(3). Furthermore, it was shown for the first time that bis-
(thio)ureas are capable of activating Michael-acceptors
besides 2-cyclohexen-1-one (3). Future investigations will
include further probing of the substrate scope. Extensive
kinetic and spectroscopic studies aiming at a mechanistic
model for enantioselectivity are underway and will be
published in due course.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie. We thank the BASF AG for a
donation of IPDA. TMIPDA was kindly provided by Stefan
Schnippering (this research group).
a The reaction was carried out with 1 equiv of aldehyde and 4 equiv of
enone or acrylate in the presence of 20 mol % catalyst and DABCO at 10
°C for 72 h. b The reaction was carried out in toluene with 2 equiv of enone
and 20 mol % TMIPDA as base. c GC yield. d Isolated yield. e ee determined
by GC. f ee determined by HPLC.
Supporting Information Available: Experimental pro-
cedures for the preparation of catalysts 1a, 1c, 1e, and 1f
and analytical data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(Table 2, entry 1 and Table 3, entry 1). The increase in
enantioselectivity can be explained by the lower concentra-
OL061298M
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Org. Lett., Vol. 8, No. 19, 2006