A new dual catalytic system for asymmetric morita-baylis-hillman reaction

Article abstract of DOI:10.1055/s-0030-1258531

High yields and enantioselectivities up to 88% were achieved in asymmetric Morita-Baylis-Hillman reactions using a combination of chiral amino acid derived guanidines and triphenylphosphane as a novel dual catalytic system.

Full text of DOI:10.1055/s-0030-1258531

LETTER
2079
A New Dual Catalytic System for Asymmetric Morita–Baylis–Hillman
Reaction
A
symmetr
a
ic Morita–B
b
aylis–Hillm
b
a
n
ar Shah, Zekarias Yacob, Alexander Bunge, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)2093755; E-mail: liebscher@chemie.hu-berlin.de
Received 14 May 2010
plexes or phosphanes and chiral Broensted acids were
successfully applied in the asymmetric MBH reac-
tion.1,5,6,10,11
Abstract: High yields and enantioselectivities up to 88% were
achieved in asymmetric Morita–Baylis–Hillman reactions using a
combination of chiral amino acid derived guanidines and triphe-
nylphosphane as a novel dual catalytic system.
Here we report on a new dual catalytic system composed
Key words: asymmetric catalysis, amino acids, addition reactions, of triphenylphosphane and chiral guanidines. Recently
stereoselective synthesis
chiral guanidines 1 (Figure 1) have been synthesized from
(S)-a-amino esters and chloroamidinium salts, which
were further alkylated to corresponding guanidinium
salts, such as 2.12 While the latter could be useful as chiral
The Morita–Baylis–Hillman (MBH) reaction is an effec-
ionic liquids, the former seem to be promising chiral orga-
nocatalysts.
tive way in establishing carbon–carbon bonds between a
Michael acceptor and an aldehyde in the presence of ter-
tiary amines (often DABCO) or phosphanes.1,2 The latter
were often found to be more effective. Although prepara-
tively straight forward BMH reactions often have limita-
tions such as very long reaction times and narrow scope.
To overcome such problems, new catalysts were devel-
oped,3 Brønsted acids such as alcohols, water, thioureas,
ureas, or formamide were used as co-catalysts1 or high
pressure was excerted. When catalysts with a basic N-
atom are applied its basicity seems to play an important
role. For example, the strongly basic tetramethylguani-
dine turned out to be advantageous over amines concern-
ing reaction rates and yields.4
i-Pr
i-Pr
CO2Me
NMe2
i-Pr
CO2Me
NMe2
N
CO2Me
N
N
I
N
N
Me2N
Me2N
1a
1b
2
Figure 1 Chiral valine-derived guanidines used in MBH reaction
With this idea in mind we tested pentasubstituted
guanidines 1 as catalysts in MBH reaction (Scheme 1).
Attempts to use them in place of the commonly used
DABCO proved disappointing because no asymmetric in-
duction could be observed, and the yields of the racemic
MBH products were modest. This was shown by the
valine-derived guanidine 1a which gave the racemate in
51% in the reaction of 4-nitrobenzaldehyde with three
equivalents methyl acrylate (see Table 1, entry 3). Grati-
fyingly, when this guanidine 1a was applied in combina-
tion with triphenylphosphane, which is usually used as a
MBH catalyst, 70% yield of product 3a with an ee of 42%
(entry 6) was obtained.
The enantioselective Morita–Baylis–Hillman reaction re-
mained an unsolved problem until recently.1,5,6 Early at-
tempts to apply optically active b-amino alcohols which
were usually derived from natural products showed mod-
est enantioselectivities. Improvements were achieved
when chiral tertiary amines1,5,7 or phosphanes8 were used,
which were equipped with a hydroxy group forming H
bonds to the aldehyde reactant. In these cases, the usual
1,4-addition of the amine or phosphane moiety to the
Michael acceptor occurs, and the OH group of the organo-
catalyst fixes the aldehyde in a rigid transition state. Bi-
functional chiral thioureas equipped with a tertiary amino
group gave excellent enantioselectivities in the synthesis
of MBH products. Again it was assumed that the tertiary
amine adds to the 4-position of the Michael system while
the thiourea forms H bonds to the oxygen atoms of the re-
actants.1,9
O
OH
Ar
catalyst
CO2Me
+
Ar
promoter
CO2Me
3a Ar = 4-O2NC6H4
Furthermore, dual catalytic systems consisting of (S)-pro-
line and an oligopeptide or 1-methylimidazole, chiral
(thio)ureas and DMAP or DABCO and chiral La com-
Scheme 1 MBH reaction of 4-nitrobenzaldehyde and methyl acry-
late performed in the presence of a N-containing catalyst and a pro-
moter
SYNLETT 2010, No. 14, pp 2079–2082
Advanced online publication: 28.07.2010
DOI: 10.1055/s-0030-1258531; Art ID: G15710ST
x
x
.x
x
.2
0
1
0
Based on these results we studied the effect of parameters
on the reaction of 4-nitrobenzaldehyde with methyl acry-
© Georg Thieme Verlag Stuttgart · New York

2080
J. Shah et al.
LETTER
late in the presence of an N-containing catalyst and a pro- tion with 1a resulted in the stereoselective formation of 3
moter (mostly triphenylphosphane) in more detail. To but in unsatisfactory ee of 26% (Table 1, entry 4). The re-
discover if pentasubstituted guanidines alone could re- action lacked stereoselectivity when DABCO was used as
place the commonly used DABCO in a nonasymmetric promoter together with 1a as catalyst in dioxane (entry 5).
MBH reaction as shown before with tetrasubstituted Thus triphenylphosphane is more effective in this dual ca-
guanidines4 1.5 equivalents of N,N-diethyl-N¢,N¢-di(n- talysis.
propyl)-N¢¢-(n-hexyl)guanidine were added to a solution
of the reactants in methanol.
Lowering the temperature from room temperature to
10 °C improved the performance of the catalytic system
1a/triphenylphosphane affording an ee of 80% (compare
Table 1 Effect of Catalysts and Promotors on MBH Reaction of
entries 6 and 7). It was even possible to increase the ee to
88% by reducing the amount of triphenylphosphane to
one equivalent (entry 8). However, a further decrease in
the applied quantity of triphenylphosphane lowered both
the ee and yield (entries 11, 12). When the ratio of 4-ni-
trobenzaldehyde to methyl acrylate was changed to 1:1
the yield as well as the ee dropped (entries 8, 9). Eventu-
ally competing polymerization of methyl acrylate as gen-
eral side reaction caused this phenomenon. Increasing the
amount of methyl acrylate to 10 equivalents which should
increase the MBH reaction gave the MBH product in 62%
yield with an unsatisfactory enantioselectivity of 12%
(Table 1, entries 8 and 10). Obviously nonstereoselective
MBH competes to a large extent in this case. The same
was observed when the amount of chiral catalyst 1a was
reduced and the ratio of 4-nitrobenzaldehyde and methyl
acrylate was 1:3. While lowering the quantity of 1a to 10
mol% resulted in just a small decrease in the ee from 88%
to 74% (compare entries 8 and 13), 5 mol% failed to pro-
vide any stereoselectivity (entry 14). Thus, an equimolar
ratio of 4-nitrobenzaldehyde and triphenylphosphane and
3 equivalents of methyl acrylate in the presence of 20
mol% of the chiral catalyst 1a seem to be optimal. At-
tempts to use this ratio at 0 °C to further improve the ste-
reoselectivity resulted in unsatisfactory results (entry 15).
It was also apparent that the nonchiral substituents at the
guanidine moiety of a-guanidino ester 1 affect the effi-
ciency, as the imidazolidine-derived analogue 1b gave
worse results in each respect (compare entries 8 and 16).
Remarkably, the cationic and thus not basic chiral guani-
dinium salt 2 derived from 1a by methylation also induced
enantioselectivity when used as promoter together with
triphenyl phosphane, but to a lesser extent (30% ee, entry
17).
4-Nitrobenzaldehyde with Methyl Acrylate to 3a (Scheme 1)13
Entry Catalyst (mol%) Promoter Conditionsa Yield ee (%)b
(equiv)
(%)
(n-Hex)N
1
none
MeOH, r.t. 82
–
NEt2
(n-Pr)2N
(20)
2
3
none
Ph3P (1)
none
CH2Cl2, r.t. 55
CH2Cl2, r.t. 51
CH2Cl2, r.t. 48
dioxane, r.t. 63
–
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (10)
1a (5)
0
4
TiCl4
26
0
5
DABCO
Ph3P (2)
Ph3P (2)
Ph3P (1)
Ph3P (1)
Ph3P (1)
6
THF, r.t.
70
42
80
88
58
12
66
34
74
0
7
THF, 10 °C 67
THF, 10 °C 70
THF, 10 °Cc 23
THF, 10 °Cd 62
8
9
10
11
12
13
14
15
16
17
Ph3P (0.5) THF, 10 °C 59
Ph3P (0.1) THF, 10 °C 47
Ph3P (1)
Ph3P (1)
Ph3P (1)
Ph3P (1)
Ph3P (1)
THF, 10 °C 70
THF, 10 °C 55
1a (20)
1b (20)
2 (20)
THF, 0 °C
29
16
68
30
THF, 10 °C 64
THF, 10 °C 55
a Reaction time 36 h, ratio of aldehyde to methyl acrylate = 1:3.
b Determined by chiral HPLC using OD-column, configuration S as
compared with literature data.11,
c Ratio of aldehyde to methyl acrylate = 1:1.
We further investigated in how far other aromatic alde-
hydes perform in MBH reaction (Table 2) under condi-
tions which appeared to be optimal with 4-
nitrobenzaldehyde. 2-Nitrobenzaldehyde gave an unsatis-
factory ee of 10%, and also the yield dropped to 44%
(Table 2, 3b). Results were better with 4-chloro and 4-
bromobenzaldehyde giving 3c (49% yield, 58% ee) and
3d (72% yield, 76% ee), respectively, but not as good as
with 4-nitrobenzaldehyde.
d Ratio of aldehyde to methyl acrylate = 1:10.
After 36 hours at room temperature the BHM product 3a
was formed in 82% yield (Table 1, entry 1) demonstrating
that pentasubstituted guanidines are efficient catalysts.
Replacement of this guanidine by triphenylphosphane af-
forded only 55% yield (entry 2).
As mentioned above, the valine-derived pentasubstituted
guanidine 1a gave only 51% yield (entry 3), and the prod-
uct 3 was racemic. The lower yield as compared with en-
try 1 could be caused by the increased bulkiness of 1a thus
hampering the conjugate addition to methyl acrylate. The
addition of the Lewis acid TiCl4 as promoter in combina-
The combination of the chiral guanidine 1a with triphe-
nylphosphane was also applied to the MBH reaction of
cyclohexanecarbaldehyde and cyclohexenone affording
product 4 in 61% yield with an ee of 38% (Scheme 2).
Synlett 2010, No. 14, 2079–2082 © Thieme Stuttgart · New York

LETTER
Asymmetric Morita–Baylis–Hillman
2081
N,N,N¢,N¢-tetramethylguanidine.4 Further reaction with
the aldehyde 6 gives the adduct 13 which eliminates the
chiral guanidine (1a) resulting in the final MBH adduct
11. This last step is initiated by deprotonation of the a-po-
sition. Since a chiral base is missing this final elimination
lacks stereodiscrimination and thus leads to a racemic
product 11. There are also other mechanisms proposed in
the literature for asymmetric MBH reaction, such as kinet-
ic resolution by chiral nucleophiles with additional H-
bond donors proposed by Aggarwal et al.,14 the addition of
chiral tertiary amine to the b-position of the Michael sys-
tem similar to path D1,5 or formation of chiral iminium
salts with chiral secondary amines. As another rationaliza-
tion, formation of hydrogen bonding or metal ion–O
bonding between the chiral catalyst and the reactants of
the MBH reaction was proposed. Furthermore, hemiacetal
intermediates were assumed in amine-catalyzed MBH re-
actions.1,3,5,15 However, all these proposals cannot explain
our results without contradictions.
Table 2 MBH Reaction of Methyl Acrylate with Other Aromatic
Aldehydes to 3a–ea
3
Ar
Yield (%)
ee (%)
88
3a
3b
3c
3d
3e
4-O2NC6H4
2-O2NC6H4
4-ClC6H4
4-BrC6H4
Ph
70
44
49
72
60
10
58
76
36
a Conditions: 1a (20 mol%), ratio of aldehyde to methyl
acrylate = 1:3, Ph3P (1 equiv), THF, 10 °C, 10 h.
O
OH
O
c-Hex
1a (20 mol%)
c-Hex
+
Ph3P(1 equiv)
THF, 10 °C, 36 h
O
4
Table 3 Application of Other Chiral N-Catalysts in MBH Reaction
of 4-Nitrobenzaldehyde with Methyl Acrylate to 3aa
yield 59%
ee 33%
Entry
Catalyst
Yield (%)
ee (%)
Scheme 2 MBH reaction of cyclohexanecarbaldehyde with cyclo-
hexanone catalyzed by the dual system 1a/Ph3P
1
74
0
N
Surprisingly, enantioselectivity was not observed when
the catalytic system was applied to the reaction of 4-
nitrobenzaldehyde with methyl vinyl ketone. The applica-
tion of the chiral guanidine 1a/triphenylphosphane did not
give any MBH product in reaction of 4-nitrobenzaldehyde
with acrylonitrile.
N
H
O
OH
2
3
81
53
0
0
N
H
O
We further checked other chiral amines derived from ami-
no acids as catalysts in combination with triphenylphos-
phane (Table 3). None of them induced any
stereoselectivity, thus demonstrating the importance of
the guanidine moiety in the chiral catalyst. On the other
hand a proline amide derived chiral guanidine lacking the
ester moiety did not exert an asymmetric induction either.
N
NH2
O
4
5
69
65
0
0
i-Pr
NH2
NH2
NH
To rationalize the stereodiscriminating effect of the dual
catalytic system Ph3P/1a in the MBH reaction the follow-
ing mechanism is proposed (Scheme 3). Ph3P undergoes
conjugate addition to the acrylate in the usual way fol-
lowed by aldol-like reaction of the resulting zwitterion 5
with the aldehyde 6 according to path A. The chiral guani-
dinium salt 1a adds to the alkoxide oxygen atom of the re-
sulting aldolate 7 (path B) and causes kinetic resolution in
the further course of regeneration of the C–C double bond
by intramolecular deprotonation of the a-position afford-
ing the Michael system 9. Final deliberation of the chiral
guanidine 1a leads to the optically active MBH product
10. Since direct formation of racemic MBH product 11
from 7 without the incorporation of the chiral guanidine
1a (path C) competes with path B the MBH protocol is not
fully enantioselective. Scheme 3 also allows explaining
the lack of stereoselectivity if the chiral catalyst 1a is ap-
plied without Ph3P (Table 1, entry 3). Here, methyl acry-
late reacts with 1a by formation of a guanidinium salt 12
(path D) similarly to the reported case with achiral
N
HN
H
NH2
a Conditions: N-catalyst (20 mol%), ratio of aldehyde to methyl
acrylate = 1:3, Ph3P (1 equiv), THF, 10 °C, 36 h.
Scheme 3 could also be used to explain the stereodifferen-
tiating effect of the chiral hexasubstituted guanidinium
salt 2 which can be assumed to form an intermediate anal-
ogous to intermediate 8 according path B but with a meth-
yl group found at the guanidine N-atom instead of the
negative charge.
In summary, a new dual catalytic system for asymmetric
MBH reaction was found consisting of a chiral a-guani-
dininoester and triphenylphosphane. This system pro-
vides good enantioselectivities in MBH reactions of
aromatic aldehydes with methyl acrylate. Other Michael
acceptors such as acrylonitrile or methyl vinyl ketone do
not seem to be useful substrates under the conditions used
Synlett 2010, No. 14, 2079–2082 © Thieme Stuttgart · New York

2082
J. Shah et al.
LETTER
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OMe
OMe
O
OMe
O
Ph3P
O
O
H
O
R
R
6
5
PPh3
Ph3P
7
path A
path C
1a
1a
path D
path B
OMe
PPh3
i-Pr
NMe2
N
O
OH OMe
Me2N
Me2N
CO2Me
Me2N
12
N
R
O
O
OMe
11
i-Pr
H
MeO2C
O
O
R
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Kliman, L. T.; Schaus, S. E. Adv. Synth. Catal. 2004, 346,
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8
R
Ph3P
6
1a
O
N
OMe
rate-
determining,
kinetic
R
O
H
Me2N
resolution
Me2N
MeO2C
13
i-Pr
i-Pr
NMe2
CO2Me
Me2N
R
NH
OH OMe
O
O
OMe
O
R
(11) Yang, K. S.; Lee, W. D.; Pan, J. F.; Chen, K. M. J. Org.
Chem. 2003, 68, 915.
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2008, 917.
1a
10
9
Scheme 3 Proposed mechanism for asymmetric MBH reaction
catalyzed by the dual catalytic system 1a/Ph3P
(13) Typical Procedure of the MBH Reaction of Methyl
Acrylate with Aldehydes
Triphenylphosphine (262 mg, 1 mmol) was added to a
solution of the aldehyde (1.0 mmol), methyl acrylate (300
mg, 3.0 mmol), and catalyst (0.2 mmol) in THF (1 mL) at
10 °C. The reaction mixture was stirred for about 36 h. After
completion of the reaction (TLC check) the reaction mixture
was partitioned with EtOAc (2 × 25 mL) and H2O (2 × 25
mL). The organic phase was washed with brine (2 × 25mL),
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography
(n-hexane–EtOAc = 4:1).
so far. Presently, further structural variants, in particular
other a-guanidino carboxylic acid derivatives are investi-
gated as chiral catalysts for MBH reactions in our labora-
tories.
Acknowledgment
Financial support by Bundesministerium für Bildung und For-
schung (BMBF) is gratefully acknowledged. We thank Prof. Dr.
Kantlehner for providing N,N-diethyl-N¢,N¢-dipropyl-N¢¢-hexylgua-
nidine as well as Saltigo GmbH, Bayer Services GmbH & Co.
OHG, BASF AG, and Sasol GmbH for the donation of chemicals.
(14) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem. Int. Ed. 2005, 44, 1706.
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D. T. J. Org. Chem. 2005, 70, 3980. (b) Price, K. E.;
Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett.
2005, 7, 147.
References and Notes
(1) Menozzi, C.; Dalko, P. I. In Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007, 151.
Synlett 2010, No. 14, 2079–2082 © Thieme Stuttgart · New York