Improved conditions for the proline-catalyzed aldol reaction of acetone with aliphatic aldehydes

Article abstract of DOI:10.1055/s-0033-1340919

The proline-catalyzed asymmetric aldol reaction between aliphatic aldehydes and acetone has, to date, remained underdeveloped. Challenges in controlling this reaction include avoiding undesired side reactions such as aldol condensation and self-aldolization. In recent years we have developed optimized conditions, which enable high yields and good to excellent enantioselectivities, and which are presented in this communication. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340919

932▌
LETTER
lIemtterproved Conditions for the Proline-Catalyzed Aldol Reaction of Acetone
with Aliphatic Aldehydes
Proline-Catalyzed Aldol Reaction of Acetone with Aliphatic Aldehydes
Alberto Martínez, Kristina Zumbansen, Arno Döhring, 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
Dedicated to Max Malacria on the occasion of his 65th birthday
(S)-proline
(20 mol%)
Abstract: The proline-catalyzed asymmetric aldol reaction be-
tween aliphatic aldehydes and acetone has, to date, remained under-
developed. Challenges in controlling this reaction include avoiding
undesired side reactions such as aldol condensation and self-aldol-
ization. In recent years we have developed optimized conditions,
which enable high yields and good to excellent enantioselectivities,
and which are presented in this communication.
O
O
OH
O
+
H
R
CHCl3 (1 mL)
30 °C, 3–14 d
R
1
2
3
(1 mmol)
(4 mL)
O
OH
O
OH
O
OH
Key words: aldehydes, aldol reaction, asymmetric catalysis, or-
ganocatalysis, proline
3a
3b
72%
er = 99.5:0.5
3c
76%
er = 97.5:2.5
84%
er > 99.5:0.5
O
OH
O
OH
Since the advent of modern organocatalysis, the asymmet-
ric aldol reaction of simple ketones such as acetone with
aldehydes catalyzed by proline and its derivatives has oc-
cupied a prominent position in this field.1,2 However, the
reaction of aliphatic aldehydes has remained underdevel-
oped, presumably due to the many possible side reactions
such as self aldolizations and aldol condensation reac-
tions. Most studies have focused on aromatic aldehydes or
branched aldehydes such as isobutyraldehyde, where
these undesired reactions are impossible or minimal. Pro-
line-catalyzed aldol reactions of acetone with α-un-
branched aldehydes have proven to be extremely
challenging and even those utilizing α-trisubstituted alde-
hydes have rarely been reported. Herein we present our
studies on improving the proline-catalyzed aldol reaction
of acetone with all types of aliphatic aldehydes, which
have led to, what has proven to be in our laboratories, op-
timal conditions.
O
OH
Ph
3e
62%
er = 99:1
3f
75%
3d
70%
er = 99:1
er = 95.5:4.5
Scheme 1 Enantioselective aldol reaction of α-quaternary aldehydes
1 with acetone
While the analogous reaction with α-branched aldehydes
such as isobutyraldehyde has already been highly devel-
oped and generally gives good yield and enantioselectivi-
ty, we also attempted at further optimizing the conditions
for these substrates.3 An in-depth study of possible cosol-
vents in this reaction revealed that the presence of both
CHCl3 and DMSO is beneficial for the reaction. We found
that when both cosolvents are applied simultaneously,
high chemoselectivity and stereoselectivity can be ob-
tained. We examined the generality of our new reaction
conditions for the proline-catalyzed enantioselective aldol
reaction of α-branched aldehydes (Scheme 2).
As the reactivity of aliphatic aldehydes in this reaction
varies significantly with the degree of substitution in the
α-position, we chose to study α-trisubstituted, α-branched,
and α-unbranched aldehydes separately, and to develop
optimal conditions for each substrate class.
Our protocol proved to be suitable for a number of α-
branched aldehydes with both open chain (5a and 5b) as
well as cyclic (5c–f) substituents. While the cyclopentyl-
substituted product 5c was obtained with modest enantio-
selectivity, presumably due to the low steric demand of
the cyclopentyl substituent, aldehydes bearing larger rings
led to highly enantioselective product formation.
We began our studies with the nonenolizable α-quaternary
derivatives. After optimizing the reaction conditions us-
ing pivaldehyde as the model substrate,3 we found a sol-
vent mixture of acetone and chloroform to be optimal, and
explored a series of α-trisubstituted aldehydes, which all
reacted smoothly under our newly developed conditions
and gave aldol products in excellent enantioselectivity
(Scheme 1).
Importantly, the reactions of both α-quaternary and α-ter-
tiary aldehydes could be carried out on a multigram scale.
Products 3a (250 mmol scale, 74%, er >99.5:0.5) and 5a
(256 mmol scale, 75%, er = 98.5:1.5) were obtained in
similar yields and enantioselectivities as those obtained
SYNLETT 2014, 25, 0932–0934
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-0033-1340919; Art ID: ST-2014-D0096-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Proline-Catalyzed Aldol Reaction of Acetone with Aliphatic Aldehydes
933
(S)-proline
(20 mol%)
(S)-proline
(5 mol%)
O
O
OH
O
O
O
OH
O
+
+
DMSO (16 mL)
10 °C, 20 d
H
R
R
DMSO (1 mL)
CHCl3 (1 mL)
10 °C, 3–9 d
H
R
R
6
2
7
4
2
5
(2 mmol)
(64 mL)
(1 mmol)
(3 mL)
O
OH
O
OH
O
OH
O
OH
O
OH
O
OH
7a
61%
er = 88:12
7b
50%
er = 87.5:12.5
7c
5a
89%
er = 98.5:1.5
5b
51%
er = 96.5:3.5
5c
70%
er = 91.5:8.5
44%
er = 84:16
O
OH
O
O
OH
O
OH
O
OH
O
OH
O
OH
Ph
OTBS
Ph
7d
70%
er = 86:14
7e
67%
er = 82:18
7f
70%
er = 85:15
5d
90%
er = 96:4
5e
84%
er = 94.5:5.5
5f
72%
er = 95.5:4.5
Scheme 3 Enantioselective aldol reaction of α-unbranched alde-
hydes 6 with acetone
Scheme 2 Enantioselective aldol reaction of α-branched aldehydes
4 with acetone
In summary, we have found useful and optimal conditions
for the (S)-proline-catalyzed asymmetric direct aldol reac-
tion of aliphatic aldehydes with acetone. To the best of our
knowledge the enantioselectivities and yields obtained in
this study equal or exceed many previously reported
methods, including those involving more elaborate and
expensive aminocatalysts. While the results obtained with
α-unbranched aliphatic aldehydes are not yet satisfactory,
the possibility to suppress the undesired reaction path-
ways by optimizing the reaction conditions was demon-
strated. This challenge will hopefully be addressed in the
near future by combining the results presented herein with
the application new proline-derived catalysts.
on a small scale. At the same time most of the proline used
could be reisolated.4
We were also interested in developing robust reaction
conditions for the reaction between acetone and the noto-
rious α-unbranched aliphatic aldehydes. Despite numer-
ous attempts,2b,5 this reaction has remained challenging
due to the difficulties in controlling undesired side reac-
tions such as aldol condensation6 and/or self aldolization
of the aldehyde.7
The ratio, in which these diverse possible products are
formed, is strongly dependent on factors such as solvent,
temperature, catalyst loading, and concentration, which
rendered an extensive screening of reaction conditions
necessary for this process.3 We found that conducting the
reaction with a lowered catalyst loading and under diluted
conditions and allowing for prolonged reaction times led
to the best possible reaction outcome.
(S)-Proline (0.2 mmol) was added to a solution of aldehyde 1 (1
mmol) in acetone (4 mL) and CHCl3 (1 mL) and was stirred at
30 °C. After this time the reaction mixture was extracted with Et2O
and brine (3×). The organic layer was dried over Na2SO4, filtered,
and concentrated. Hydroxy ketone 3 was isolated by column chro-
matography (silica, pentane–Et2O).
Having developed these very mild reaction conditions, we
explored the scope of this reaction with different α-
unbranched aliphatic aldehydes (Scheme 3).
Acknowledgment
While the reactions are rather slow, and full conversion
was not even achieved after 20 days, the desired products
7 could be obtained with reasonable yields and enantiose-
lectivities. The model substrate n-hexanal (6a) reacted
smoothly yielding 61% of aldol product 7a with 88:12 en-
antiomeric ratio. n-Octanal (6b) and isopentanal (6c) were
less reactive but gave similar enantioselectivity.
Generous support by the Max Planck Society is acknowledged. We
also thank the members of our HPLC and GC departments for their
analytical support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Furthermore products 7d–f, in some cases bearing oxy-
genated side chains, were obtained with similar yields and
enantioselectivities. While these reaction conditions are
obviously not perfect, especially in terms of reaction
times, it should be noted that an almost complete suppres-
sion of the undesired reaction pathways was achieved.
References and Notes
(1) Mahrwald, R. In Modern Aldol Reactions; Wiley-VCH:
Weinheim, 2004.
(2) (a) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem.
Soc. 2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386. (c) List, B.; Pojarliev, P.; Castello, C.
Org. Lett. 2001, 3, 573.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 932–934

934
A. Martínez et al.
LETTER
(3) For the optimization of reaction conditions, see the
Supporting Information.
(4) Between 84–87% of the total (S)-proline was reisolated and
reused in different experiments, without loss catalytic
activity.
(5) For selected examples, see: (a) Tang, Z.; Jiang, F.; Yu, L.-T.;
Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.; Yang, Z.-
H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. J. Am. Chem. Soc. 2005, 127, 9285. (c) Maa, S.;
Zhang, S.; Duan, W.; Wang, W. Bioorg. Med. Chem. Lett.
2009, 19, 3909.
(6) (a) Zumbansen, K.; Döhring, A.; List, B. Adv. Synth. Catal.
2010, 352, 1135. (b) Abell, S.; Medina, F.; Tichit, D.; Pérez-
Ramírez, J.; Cesteros Salagre, P.; Sueiras, J. E. Chem.
Commun. 2005, 1453. (c) Yang, S.-D.; Wu, L.-Y.; Yan, Z.-
Y.; Pan, Z.-L.; Liang, Y.-M. J. Mol. Catal. A 2007, 268, 107.
(d) Chi, Y.; Scroggins, S. T.; Boz, E.; Fréchet, J. M. J. J. Am.
Chem. Soc. 2008, 130, 17287.
(7) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) Cordova, A. Tetrahedron Lett. 2004,
45, 3949.
Synlett 2014, 25, 932–934
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