Unexpected beneficial effect of ortho -substituents on the (s)-proline-catalyzed asymmetric aldol reaction of acetone with aromatic aldehydes

Article abstract of DOI:10.1055/s-0033-1340920

An intriguing effect of electronegative 2,6-substituents on the stereochemical outcome of (S)-proline-catalyzed aldol reactions between benzaldehyde derivatives and acetone is reported. Remarkably high enantioselectivities can be achieved with such substrates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340920

LETTER
▌961
lUettner expected Beneficial Effect of ortho-Substituents on the (S)-Proline-
Catalyzed Asymmetric Aldol Reaction of Acetone with Aromatic Aldehydes
Beneficial Effect of ortho-Substituents on Asymmetric Aldol Reaction
Alberto Martínez, Manuel van Gemmeren, Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received: 04.02.2014; Accepted: 16.02.2014
perature, water content,7 or amount of catalyst (see
Abstract: An intriguing effect of electronegative 2,6-substituents
Supporting Information for details). Under our newly de-
on the stereochemical outcome of (S)-proline-catalyzed aldol reac-
veloped conditions, the corresponding aldol product (R)-
tions between benzaldehyde derivatives and acetone is reported.
Remarkably high enantioselectivities can be achieved with such
3a8 was obtained with 76% yield and an enantiomeric ra-
substrates.
tio of 88.5:11.5. This represents a substantial improve-
ment compared to the results reported in our initial work
(62% yield, er = 80:20; Scheme 1).3a,9 The mixture of
DMSO and CHCl3 (1:1) used as cosolvent proved to be
crucial, both increasing the reaction rate and minimizing
side reactions, such as aldol condensation.
Key words: aldehyde, aldol reaction, asymmetric catalysis, or-
ganocatalysis, proline
Asymmetric aldol reactions are amongst the most useful
carbon–carbon bond-forming reactions in organic synthe-
sis.1,2 The full potential of (S)-proline as catalyst for inter-
molecular aldol reactions was realized in 2000, when we
reported the first organocatalytic enantioselective aldol
reaction between unmodified ketones and aldehydes.3
This report provided proof of principle for the rational use
of small organic molecules as stereoselective catalysts,4,5
at the same time highlighting the potential of organocatal-
ysis in natural product synthesis.6
Interestingly, when ortho-substituted aromatic aldehydes
were used as substrates, an increase of enantioselectivity
with growing substituents was observed (Cl < Br < I; Ta-
ble 1).
Table 1 Aldol Reaction of ortho-Halogenated Benzaldehyde Deriv-
atives 1 with Acetone 2a
O
X
O
OH
X
(S)-proline
(5 mol%)
O
+
H
CHCl3 (20 vol%)
DMSO (20 vol%)
0 °C, 4 d
Aromatic aldehydes have been widely studied as sub-
strates in amine-catalyzed aldol reactions. In our initial
work,3a only moderate enantioselectivities were achieved
(Scheme 1). We were interested in improving both yield
and enantioselectivity of this reaction, by further optimiz-
ing the reaction conditions, while retaining (S)-proline as
catalyst.
1
2
4
Entry
Product
Yield 4 (%) erb
O
OH Cl
2
1
3
4
Using benzaldehyde (1a) as model substrate, we exten-
sively screened different parameters such as solvent, tem-
1c
78
85:15
6
5
DMSO (80 vol%)
4a
acetone 2 (20 vol%)
O
OH Br
r.t., 4 h
60%
er = 80:20
(ref. 3a)
(S)-proline (30 mol%)
2
3
81
81
87.5:12.5
O
O
OH
CO2H
Ph
H
4b
N
H
Ph
1a
3a
O
OH
I
(S)-proline (5 mol%)
improved
conditions
76%
er = 88.5:11.5
DMSO (20 vol%)
CH3Cl (20 vol%)
acetone 2 (60 vol%)
0 °C, 4 d
91:9
4c
a Reaction conditions: aldehyde 1 (0.5 mmol), acetone 2 (0.75 mL),
CHCl3 (0.25 mL), DMSO (0.25 mL), and (S)-proline (5 mol%) were
stirred at 0 °C for 4 d.
Scheme 1 Comparison of original and newly optimized conditions
for the (S)-proline-catalyzed aldol reaction between benzaldehyde
(1a) and acetone (2)
b Determined by HPLC using a chiral stationary phase.
c Approximately 10% of the double aldol addition was observed by
1H NMR analysis of the crude reaction mixture using an internal stan-
dard.
SYNLETT 2014, 25, 0961–0964
Advanced online publication: 25.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340920; Art ID: ST-2014-D0097-L
© Georg Thieme Verlag Stuttgart · New York

962
A. Martínez et al.
LETTER
Table 2 Aldol Addition of ortho-Disubstituted Aromatic Aldehydes
1 with Acetonea (continued)
Yields were generally good and only traces of the corre-
sponding enone, derived from the competitive aldol con-
densation pathway, could be observed. With the highly
reactive 2-chlorobenzaldehyde, approximately 10% of the
product resulting from double aldol addition were ob-
served as side product (Table 1, entry 1).10
(S)-proline
(5 mol%)
O
O
OH
O
+
CHCl3 (20 vol%)
DMSO (20 vol%)
0 °C, 4 d
H
Ar
Ar
1
2
5
Based on this initial observation, we speculated that in-
creasing the steric bulk of the benzaldehyde derivative
could lead to an increased enantioselectivity. Based on
this hypothesis we studied a variety of ortho-substituted
benzaldehyde derivatives (Table 2).
Entry
7
Product
Yield 5 (%)
erb
O
OH Cl
87
99.5:0.5
Me
Table 2 Aldol Addition of ortho-Disubstituted Aromatic Aldehydes
1 with Acetonea
5g
(S)-proline
(5 mol%)
O
OH
O
O
OH
O
+
CHCl3 (20 vol%)
DMSO (20 vol%)
0 °C, 4 d
H
Ar
Ar
1
2
8
64
93.5:6.5
5
Entry
Product
Yield 5 (%)
erb
5h
5i
OH
F
F
O
O
O
O
OH Me
F
F
9e
51
88:12
1
84
93:7
Me
F
F
5a
OH OMe
O
OH
OH
10e
25f
98.5:1.5
2c
3c
4
73
97:3
MeO
Cl
5j
OH OH
5b
5c
O
F
F
F
11
12
86
60
66:34
60
98.5:1.5
95:5
Br
5k
O
OH
O
OH OMe
81
Me
99.5:0.5
5d
O
O
OH
5l
a Reaction conditions: aldehyde 1 (0.5 mmol), acetone 2 (0.75 mL),
CHCl3 (0.25 mL), DMSO (0.25 mL), and (S)-proline (5 mol%) were
stirred at 0 °C for 4 d.
5
82
99:1
MeO
b Determined by HPLC with a chiral stationary phase.
c Varying amounts of the double aldol product were observed by
1H NMR analysis of the crude reaction mixture.
d The reaction was performed on a 94 mmol scale.
e 30 mol% of catalyst were used.
5e
5f
OH Cl
6c
69 (82)d
99:1
Cl
f 40% of the corresponding enone were obtained.
The pentafluorobenzaldehyde-derived aldol product 5a
was obtained with high yield and 93:7 enantiomeric ratio
(Table 2, entry 1). 2-Chloro-6-fluorobenzaldehyde also
reacted smoothly with the enantioselectivity increasing to
Synlett 2014, 25, 961–964
© Georg Thieme Verlag Stuttgart · New York

LETTER
Beneficial Effect of ortho-Substituents on Asymmetric Aldol Reaction
963
97:3 enantiomeric ratio (Table 2, entry 2). As expected, an A possible rationalization of the effect exerted by ortho
even more pronounced effect was observed when a bromo substituents is depicted in Figure 1. The steric demand of
substituent was present, and product 5c was obtained with the substituent(s) is expected to result in an increasingly
very high enantioselectivity (Table 2, entry 3). Surprising- perpendicular orientation of the aromatic ring and the al-
ly, when the effect of methyl and methoxy groups was dehyde moiety. When comparing the Houk–List transi-
compared, the sterically more demanding methyl substit- tion state models leading to the major (A) and minor (B)
uent led to a less enantioselective reaction (Table 2, en- enantiomers,16 a steric clash between the ortho substitu-
tries 4 and 5). This finding suggested that apart from the ent(s) and the incoming enamine is present in B. In addi-
steric properties of the ortho substituent(s), electronic tion to this steric factor, when R contains an
properties (presence of electronegative heteroatoms in the electronegative heteroatom, the charge densities on this
ortho substituent) might also influence the reaction out- atom and on the carboxylate moiety of the catalyst will
come. When chlorine was present instead of fluorine (cf. lead to an additional electronic repulsion in the disfavored
products 5b with 5f, and 5d with 5g) higher enantioselec- transition state B. In concert, these effects lead to the sub-
tivities were obtained (Table 2, entries 6 and 7).
stantial increase of enantioselectivity reported in this
study.
In the case of 9-anthraldehyde, aldol product 5h was ob-
tained with 93.5:6.5 enantiomeric ratio and moderate
yield. In this particular case the solvent system employed
plays an important role in the reactivity and selectivity of
the process.11 Lower enantioselectivity was obtained in
the case of 2,6-dimethylbenzaldehyde (Table 2, entry 9).
When we used 2,6-dimethoxybenzaldehyde, a very elec-
tron-rich and unreactive aldehyde the desired product 5j
was isolated in 25% yield and with an enantiomeric ratio
of 98.5:1.5. In this case 30 mol% of catalyst were required
and a considerable amount of the aldol condensation prod-
uct was observed (Table 2, entry 10).
O
O
N
N
O
O
O
H
O
H
steric and electronic
repulsion
vs.
R
R
H
H
R
R
A
B
Figure 1 Rationalization of the observed effect of ortho substituents
It is important to highlight that it is possible to scale up
this process. High yield and identical enantioselectivity
were obtained when compound 5f was synthesized on a
94 mmol scale (Table 2, entry 6). Importantly most of the
proline used could be reisolated.12
In summary we have found a remarkable effect on the en-
antiocontrol of the aldol reaction between acetone and ar-
omatic aldehydes caused by ortho substituents on the
aldehyde. Using (S)-proline as catalyst ortho,ortho-disub-
stituted aromatic aldehydes react smoothly with acetone
yielding the corresponding aldol adducts with exceptional
enantioselectivities. A rationalization of the observed ef-
fect based on both the steric and electronic properties of
the substituents was provided and is in agreement with the
widely accepted stereochemical model for this type of re-
actions.
Finally we compared the behavior of two seemingly sim-
ilar substrates, 2-hydroxy- and 2-methoxynaphthalde-
hyde, under our best conditions (Table 2, entries 11 and
12). The 2-hydroxynaphthaldehyde-derived aldol adduct
5k, which is in equilibrium with its closed lactol form, has
been reported to form with poor enantioselectivity (63:37
er) when using trans-4-OH-(S)-proline as catalyst.13
Similarly we obtained a disappointing enantiomeric ratio
for 5k (66:34). In contrast, when 2-methoxynapththalde-
hyde was used, we were pleased to obtain aldol product 5l
with exceptionally high enantiomeric excess, as would be
expected considering the positive effect of ortho substitu-
ents presented herein. This pronounced difference in en-
antiocontrol can be rationalized by invoking an
intramolecular hydrogen bond in 2-hydroxynaphthalde-
hyde, which could facilitate the attack of the enamine on
the aldehyde.14 This activation stands in direct competi-
tion with the coordination of the aldehyde by the cata-
lyst’s carboxylic acid moiety, which is known to be
crucial for the stereoselectivity of the process.15 To sup-
port this proposal, we conducted the two reactions using
pyrrolidine (5 mol%) as catalyst. We found that the reac-
tion of 2-hydroxynaphthaldehyde proceeds four times
faster than that of 2-methoxynaphthaldehyde, which indi-
cates that internal activation in present in this substrate.
(S)-Proline (0.025 mmol) was added to a solution of the correspond-
ing aldehyde 1 (0.5 mmol) in acetone (0.75 mL), CHCl3 (0.25 mL),
and DMSO (0.25 mL) and was stirred at 0 °C for 4 d. After this
time, H2O was added to the reaction mixture, which was extracted
with EtOAc (3×). The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The hydroxy ketone was isolated by column chromatogra-
phy (silica, hexane–EtOAc).
Acknowledgment
Generous support by the Max Planck Society is acknowledged. We
also thank our HPLC department for their support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 961–964

964
A. Martínez et al.
LETTER
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