L-proline/CoCl2-catalyzed highly diastereo- and enantioselective direct aldol reactions

Article abstract of DOI:10.1002/chem.201101299

The CoCl₂/L-proline (1:2) system was found to be an excellent catalyst for direct aldol reactions. Excellent yields (up to 93 %) and a significant improvement in diastereoselectivity (anti/syn up to 45:1) as well as enantioselectivity (up to mo

Full text of DOI:10.1002/chem.201101299

DOI: 10.1002/chem.201101299
l-Proline/CoCl2-Catalyzed Highly Diastereo- and Enantioselective
Direct Aldol Reactions
Ananta Karmakar, Tapan Maji, Sebastian Wittmann, and Oliver Reiser*[a]
Abstract: The CoCl2/l-proline (1:2)
as the sole catalyst were observed. This
catalyst system was successfully applied
to both cyclic and acyclic ketones in
combination with aromatic and aliphat-
system was found to be an excellent
catalyst for direct aldol reactions. Ex-
cellent yields (up to 93%) and a signif-
icant improvement in diastereoselectiv-
ity (anti/syn up to 45:1) as well as
enantioselectivity (up to more than
99% ee) compared with using proline
ic aldehydes. In situ chelation of CoCl2
and proline (1:2) is proposed to pro-
mote the reaction through a six-mem-
bered Zimmermann–Traxler type tran-
sition state involving the positioning of
proline-enamine and the aldehyde
through chelation to CoII.
Keywords: aldol reaction
· alde-
hydes · cobalt · diastereoselectivity ·
ketones
Introduction
Moreover, pioneering studies with Zn-(amino acid)2 com-
plexes by Darbre, Reymond, and co-workers for direct aldol
reactions in aqueous media were reported.[10a–e] These stud-
ies revealed that Zn-(proline)2 is the best catalyst among
other Zn-(amino acid)2 complexes, giving rise to quantita-
tive conversion and 56% ee for the reaction of 4-nitroben-
zaldehyde and acetone.[10a] Subsequently, this field of Zn-
amino acid catalyzed aldol reaction in aqueous media was
further developed by several groups either by varying the
zinc salts and/or the proline derivatives employed.[10f–k]
Kudo and co-workers developed PEG-RS resin-supported
tripeptides in combination with ZnCl2 for the direct aldol
reaction of acetone in aqueous media with up to 84% enan-
tioselectivity.[10f] Mlynarski[10g–h] and Pan[10i] described Zn/
bis(prolinamides) rather than simple Zn/l-proline com-
plexes as outstanding (d.r. up to 99:1, ee up to 98%) stereo-
selective catalysts for direct aldol reactions in the presence
of water (50 vol%). Very recently, the group of Penhoat in-
vestigated direct aldol reactions of cyclohexanone catalyzed
by proline/Lewis acid combinations.[10k] Use of proline/ZnCl2
in DMSO/H2O (4:1) in the reaction of 4-nitrobenzaldehyde
with cyclohexanone, gave excellent results (d.r. 16:1; ee
>99%), however, other aromatic aldehydes proved to be in-
ferior substrates (d.r. 3:1–9:1; ee 80–87%) under the same
reaction condition.[10h]
In the history of organic synthesis, aldol reactions are
among the most widely studied and extensively used of all
the approachs to C C bond formation, most notably for
À
rapid access to polyoxygenated compounds.[1] The first enan-
tioselective organocatalytic aldol reactions[2] were described
for the proline-catalyzed synthesis of optically active partial
structures of steroids by Wiechert and co-workers in 1971,[3]
and later by Hajos and Parrish in 1974,[4] but it attracted
more attention in synthesis after its stunning exploration as
a general organocatalyst for aldol reactions by the groups of
List and Barbas.[5]
There have been a significant number of successful at-
tempts to improve the efficiency and selectivity of the origi-
nal proline-catalyzed aldol process,[6] most prominently by
modification of the carboxylic group of proline or by intro-
ducing a bulky alkyl/aryl group at the 4-position of proline.[7]
Excellent results were also achieved by employing different
additives such as 2,4-dinitrophenol, (R)- or (S)-binol, d-cam-
phorsulfonic acid, or thiourea in combination with proline.[8]
On the other hand, metal–amino acid or metal–amine
chelation also proved to be very useful and such systems
have been broadly utilized in various kinds of organic trans-
formations, including aldol reactions.[9] So far, zinc[10] and ru-
bidium[11] have been explored in combination with proline
and other amino acids in asymmetric organic syntheses.
Herein we wish to report the cobalt(II)-proline catalyzed
direct aldol reaction (Scheme 1) of both cyclic and acyclic
[a] Dr. A. Karmakar, Dr. T. Maji, Dipl.-Chem. S. Wittmann,
Prof. Dr. O. Reiser
Institut fꢀr Organische Chemie
Universitꢁt Regensburg
Universitꢁtsstrasse 31
93053 Regensburg (Germany)
Fax : (+49)941-943-4121
E-mail: oliver.reiser@chemie.uni-regensburg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101299.
Scheme 1. l-Proline/CoCl2 (2:1) catalyzed direct aldol reaction.
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FULL PAPER
Table 2. Screening studies with different solvents in the CoCl2/proline
catalyzed aldol reaction.
ketones with aldehydes in either MeOH or DMSO that, in
general, proceeds with significantly higher efficiency com-
pared with classic proline catalyzed direct aldol reactions,
and is also superior to other metal–proline or metal–amino
acid complexes reported so far.
Entry[a]
1[e]
2
Solvent
Yield [%][b]
d.r. (anti/syn)[c]
8:1 (1.7:1[f])
1.6:1
–
10:1 (3:1)
ee [%][d]
92 (89[f])
63
–
98 (58)
Results and Discussion
DMSO
DMF
H2O
76 (89)
73
<10
91 (89)
88
25
<5
<5
<10
It has already been established that metal(II) salts chelate
amino acids in a 1:2 (metal/amino acid) fashion.[12] Conse-
quently, we screened a variety of readily available 1:2 met-
al(II) chloride/proline complexes, which were prepared in
situ, for the aldol reaction between cyclohexanone (1a) and
4-nitrobenzaldehyde (2a) in DMSO; the latter being the op-
timum solvent for this reaction with proline as catalyst.
To our delight, a wide variety of proline–metal complexes
could be used to achieve the transformation into 3a, al-
though yields and selectivities varied considerably depend-
ing on the metal ion (Table 1). Although proline was still
the best catalyst with respect to yield under the conditions
applied (Table 1, entry 1), zinc, nickel, and cobalt chloride
were found to superior in respect to diastereoselectivity
(Table 1, entries 6–8) and, in the latter case, also in enantio-
selectivity (Table 1, entry 8). Among these metal salts,
cobalt chloride (Table 1, entry 8) also showed the best reac-
tivity, rivaling the performance of proline, thus this metal
was used in all subsequent experiments.
3
4[e]
5
MeOH
EtOH
iPrOH
THF
dioxane
CH3CN
toluene
CH2Cl2
none
9:1
5:1
–
–
–
–
–
2:1
91
78
–
–
–
–
–
71
6
7
8
9
10
11
12
no reaction
no reaction
23
[a] Anhydrous CoCl2 was used. [b] Combined isolated yield of anti-3a
and syn-3a. [c] Determined from the 1H NMR spectrum of the crude re-
action mixture. [d] Determined by chiral HPLC analysis. [e] Values in
brackets were obtained with l-proline as catalyst in the absence of
CoCl2. [f] Data from Sakthivel et al.[5c]
of research groups that protic solvents are not amenable for
aldol reactions catalyzed by proline.[7c,13] In our hands, the
reaction between 1a and 2a with l-proline as catalyst alone
also proceeded with significantly lower diastereo- and enan-
tioselectivity (Table 3, entries 1 and 3).
Varying the ratio between cobalt and proline revealed a
1:2 stoichiometry was optimum, which is in agreement with
the results reported for analogous zinc complexes.[10] Inter-
estingly, a 1:4 stoichiometry was still tolerated (Table 3,
entry 2), albeit with somewhat diminished selectivity, where-
as an excess of cobalt drastically reduced the activity of the
catalyst system.
Table 1. Screening of metal(II) chlorides with proline in the direct aldol
reaction of cyclohexanone and 4-nitrobenzaldehyde.
[a]
Entry
MCl2
Yield [%][b]
d.r. (anti/syn)[c]
ee [%][d]
1
2
3
4
5
6
7
8
None
MnCl2
FeCl2
MgCl2
CuCl2
ZnCl2
NiCl2
CoCl2
89
77
73
69
21
42
44
76
1.7:1[e]
1.5:1
1.6:1
2:1
1:1
4:1
89[e]
37
63
69
75
79
81
92
Table 3. Screening studies with different concentration of CoCl2 in the
aldol reaction of 1a and 2a using 20 mol% l-proline in methanol.
5:1
8:1
[a] Anhydrous metal chlorides were used. [b] Combined isolated yield of
anti-3a and syn-3a. [c] Determined from the 1H NMR spectrum of the
crude reaction mixture. [d] Determined by chiral HPLC analysis.
[e] Data from Sakthivel et al.[5c]
Entry[a]
CoCl2/Proline
Yield [%][b]
d.r. (anti/syn)[c]
ee[d]
1
2
3
proline only
1:4
89
92
91
53
78
71
59
41
<10
3:1
5:1
10:1
10:1
5:1
3:1
2:1
1:1
58
89
98
96
92
88
86
74
–
1:2
1:2
1:1
1.5:1
2:1
4[e]
5
Further screening with respect to solvent (Table 2) and
cobalt/proline ratio (Table 3) was performed. Gratifyingly,
we found that the reaction of 1a with 2a was accomplished
with improved yield (91%) and selectivity (anti/syn 10:1;
98% ee) in methanol (Table 2, entry 4), which is advanta-
geous from an operational point of view compared with the
use of DMSO, which is required for aldol reactions cata-
lyzed by proline alone. It was previously noted by a number
6
7
8
9
2.5:1
5:1
–
[a] Reagent grade solvents were used without further purification.
[b] Combined isolated yield of anti-3a and syn-3a. [c] Determined from
the 1H NMR spectrum of crude reaction mixture. [d] Determined by
chiral HPLC analysis. [e] 10 mol% of l-proline was used.
Chem. Eur. J. 2011, 17, 11024 – 11029
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11025

O. Reiser et al.
To investigate the scope of the cobalt–proline catalyzed
reaction, different aldehydes in combination with cyclic ke-
tones were evaluated under the optimized conditions de-
scribed above (Table 4). Good to excellent yields and selec-
tivities were achieved with both electron-rich as well as elec-
tron-deficient aromatic aldehydes and with aliphatic alde-
hydes. In all cases, the reactions proceeded with significantly
improved diastereo- and enantioselectivities with respect to
the use of proline alone.
When acetone was used as the ketone substrate in aldol
reactions with aromatic aldehydes (Table 5), the enantiose-
lectivity was again significantly improved with the cobalt–
proline catalyst compared with proline alone. Unlike the re-
actions with cyclic ketones (Table 4), better enantioselectivi-
ties were attained in DMSO than in MeOH.
gave rise to aldol compounds 7a and 8a, resulting from the
regiospecific reaction at the methyl group of 1e and 1 f, re-
spectively.
It has been established that metal(II) ions interact with
amino acids in a 1:2 ratio,[12] moreover, a crystal structure of
ZnCl2(l-proline)2 has already been described by Lutz and
Bakker under neutral conditions.[14]
In analogy, we therefore propose that initially two mole-
cules of proline are bound through the carboxylate groups
to cobalt(II), giving rise to 10 (Scheme 2). The key catalyti-
cally active species could then function as the C2-symmetri-
cal cobalt–proline complex 11, a hypothesis that is support-
ed by Open-Shell HF-DFT (B3LYP) calculations performed
by Guillion et al.[12a] Moreover, during the aldol reaction, a
pH value of 4–6 was measured, which is in agreement with
the liberation of HCl during catalyst formation. Interesting-
ly, a mixture of only CoCl2 and proline (1:2) in MeOH re-
mains at pH 6–7; suggesting that a species such as 11 only
forms upon addition of the substrates. The course of the
aldol reaction can be explained by the organocatalyzed pro-
Likewise, the combination of proline with CoCl2 was
found to be equally effective for the aldol reaction of un-
symmetrical ketones (Table 6). Enhanced diastereo- and
enantioselectivities were observed together with good yields.
Like proline, use of the combination of cobalt/proline also
Table 4. Direct aldol reactions of cyclic ketones with aldehydes catalyzed by cobalt/proline (MeOH) in comparison with proline (MeOH or DMSO).[a]
Entry
Ketone/R-CHO
1a/2a
R
Aldol
3a
Solvent
t [h]
Yield [%][c,e]
d.r. (anti/syn)[d,e]
ee [%][e,f]
98 (58)
89[g]
MeOH
36
36
60
72
36
36
36
36
60
60
48
48
36
36
48
36
48
36
60
72
72
72
72
72
48
36
48
36
91 (69)
41[g]
81 (61)
43
80 (63)
58
83 (49)
65
73 (51)
45
77 (68)
46
93 (86)
88
84 (64)
39
79 (67)
70
80 (71)
57
50 (43)
98 (97)
61 (64)
90 (91)
75 (72)
53
10:1 (3:1)
1.7:1[g]
6:1 (2:1)
1:1
13:1 (7:1)
2:1
15:1 (6:1)
3:1
4:1 (2:1)
1:1
16:1 (8:1)
1.5:1
45:1 (19:1)
20:1
9:1 (4:1)
1.5:1
9:1 (3:1)
3:1
8:1 (3:1)
2:1
27:1 (9:1)
24:1 (19:1)
17:1 (11:1)
27:1 (21:1)
9:1 (4:1)
2:1
1
2
4-NO2C6H4
Ph
DMSO[b]
MeOH
90 (60)
85
95 (60)
79
94 (73)
86
92 (64)
79
94 (67)
81
98 (96)
96
95 (67)
87
98 (81)
88
1a/2b
3b
DMSO[b]
MeOH
3
1a/2c
1a/2d
1a/2e
1a/2 f
1a/2g
1a/2h
1a/2i
1a/2j
1a/2k
1a/2l
1b/2a
1c/2a
4-CF3C6H4
4-ClC6H4
3-MeOC6H4
2-ClC6H4
C6F5
3c
3d
3e
3 f
3g
3h
3i
DMSO[b]
MeOH
4
DMSO[b]
MeOH
5
DMSO[b]
MeOH
6
DMSO[b]
MeOH
7
DMSO[b]
MeOH
8
4-BrC6H4
2-NO2C6H4
2-furyl
DMSO[b]
MeOH
9
DMSO[b]
MeOH
90 (67)
73
10
11
12
13
14
3j
DMSO[b]
MeOH
89 (87)
iPr
3k
3l
DMSO[b]
MeOH
>99 (96[h]
)
85 (79)
98.5 (94)
91 (35)
87
77 (41)
84
c-C6H11
DMSO[b]
MeOH
4-NO2C6H4
4-NO2C6H4
4a
5a
DMSO[b]
MeOH
83 (67)
50
10:1 (3:1)
1.7:1
DMSO[b]
[a] Ketone (3 equiv) and aldehyde (1 equiv) were successively added to a solution of anhydrous CoCl2 (10 mol%) and l-proline (20 mol%) in MeOH
(0.1 mLmmolÀ1 of aldehyde), and the reaction was monitored by TLC until full consumption of aldehyde was observed. [b] Obtained from the reaction
1
with proline in the absence of CoCl2 under otherwise identical conditions. [c] Isolated yield of anti product only. [d] Determined from the H NMR spec-
trum of the crude mixture. [e] Results given within parenthesis were obtained from the reaction with proline in the absence of CoCl2. [f] Determined by
chiral HPLC analysis. [g] Data from Sakthivel et al.[5c] [h] Data from Bahmanyar et al.[5f]
11026
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Chem. Eur. J. 2011, 17, 11024 – 11029

Stereoselective Direct Aldol Reactions
FULL PAPER
Table 5. Reaction with CoCl2/proline compared with proline catalyzed direct aldol of
acetone with aldehydes.[a]
reaction of cyclic and acyclic ketones with aromatic
as well as aliphatic aldehydes. The efficiency of the
reaction is significantly higher compared with the
analogous classical proline-catalyzed process, as
well as with other metal–proline complexes em-
ployed previously. The protocol developed is op-
erationally straightforward, involving mixing inex-
pensive CoCl2 and proline in a 1:2 stoichiometry.
For cyclic ketones, the reaction proceeds best in
MeOH, which is a more user-friendly solvent than
DMSO, which has to be employed when proline is
used as a catalyst alone.
Entry
1
R
Aldol
Solvent
t [h]
Yield [%][b,c]
70 (68,[e] 49[f])
73 (72)
ee [%][c,d]
82 (76,[e] 72[f])
54 (21)
4-NO2
6a
DMSO
MeOH
DMSO
MeOH
DMSO
MeOH
DMSO
MeOH
DMSO
MeOH
24
36
48
48
24
30
36
36
36
36
2
3
4
5
H
6b
6c
68 (62,[e] 43[f])
62 (66)
84 (60,[e] 72[f])
60 (38)
4-CF3
4-Cl
2-Br
72 (70)
84 (74)
69 (61)
63 (41)
6d
6m
70 (76, 76[f])
75 (71)
67 (50, 75[f])
61 (47)
66 (74, 74[f])
72 (73)
82 (66, 72[f])
57 (42)
Experimental Section
[a] Aldehyde (1 equiv) was added to a solution of anhydrous CoCl2 (10 mol%) and l-
proline (20 mol%) in MeOH/acetone (4:1; 0.15 mLmmolÀ1 of aldehyde), and the re-
action (room temp.) was monitored by TLC until full consumption of the aldehyde
was observed. [b] Isolated yield. [c] Results given within parenthesis were obtained
from the reaction with proline in the absence of CoCl2 under otherwise identical con-
ditions. [d] Determined by chiral HPLC analysis. [e] Data from Sakthivel et al.[5c]
[f] Data from Zhou and Shan,[8c] reactions were carried out at 08C for 48 h.
Aldol reactions using cyclohexanone: Ketone (3 equiv) and
aldehyde (1 equiv) were successively added to a solution of
anhydrous CoCl2 (10 mol%) and l-proline (20 mol%) in
MeOH (0.10 mLmmolÀ1 of aldehyde) at RT (20–258C), and
the reaction was monitored by TLC until full consumption of
aldehyde was observed. The reaction was quenched with
water and extracted with ethyl acetate three times. The com-
bined organic layer was evaporated under reduced pressure
and the diastereoisomeric ratio was evaluated from 1H NMR
analysis of the crude material. The extract was purified by flash column
chromatography.
line-type transition state 12, in which cobalt takes the role
of the proton. Due to the C2 symmetry of 11, both available
coordination sites for cobalt give rise to the same stereoiso-
mer of the aldol products.
Aldol reactions using acetone: Aldehyde (1.0 equiv) was added to a solu-
tion of anhydrous CoCl2 (10 mol%) and l-proline (20 mol%) in a mix-
ture of MeOH (or DMSO) and acetone (4:1, 1.50 mLmmolÀ1 of alde-
hyde) at RT (20–258C), and the reaction was monitored by TLC until
full consumption of aldehyde was observed. The reaction was quenched
with water and extracted with ethyl acetate three times. The combined
organic layer was evaporated under reduced pressure and the crude ma-
terial was purified by flash column chromatography.
Conclusion
By merging transition-metal catalysts and organocatalysis,[15]
we have developed the CoCl2/proline catalyzed direct aldol
Aldol reactions using unsymmetrical ketones: Prepared analogously to
aldol reactions with cyclohexanone.
Table 6. CoCl2/proline catalyzed direct aldol of unsymmetrical ketones with aldehydes.[a]
Entry
1
R1
Et
R2
H
R3
Aldol
Solvent
t [h]
Yield [%][b,d]
d.r. (anti/syn)[c,d]
ee [%][d,e]
MeOH
DMSO
MeOH
DMSO
MeOH
DMSO
MeOH
DMSO
MeOH
DMSO
60
36
60
36
60
36
65
36
72
36
73 (69)
64 (74)
76 (61)
68 (70)
90 (63)
87 (83)
86 (49)
92 (92)
90 (67)
89 (90)
–
–
–
91 (64)
90 (75)
85 (43)
50 (23)
76 (58)
80 (67)
55 (37)
81 (67[f])
90 (73)
83 (71)
4-NO2
7a
2
3
4
5
Ph
H
H
H
H
4-NO2
4-CN
2-Cl
8a
9a
9 f
–
4:1 (2:1)
3:1 (1.5:1)
4:1 (2:1)
4:1 (1.5:1[f])
5:1 (1.8:1)
2:1 (1.5:1)
OH
OH
OH
2-Br
9m
[a] Ketone (3 equiv) and aldehyde (1 equiv) were successively added to a solution of anhydrous CoCl2 (10 mol%) and l-proline (20 mol%) in MeOH or
DMSO (0.1 mLmmolÀ1 of aldehyde), and the reaction was monitored by TLC until full consumption of aldehyde was observed. [b] Isolated yield; non-
separable (anti/syn) mixture for 9a, 9 f, and 9m. [c] Determined from the 1H NMR spectrum of the crude mixture. [d] Results given within parenthesis
were obtained from the reaction with proline in the absence of CoCl2 under otherwise identical conditions. [e] Determined by chiral HPLC analysis.
[f] Data from Sakthivel et al.[5c]
Chem. Eur. J. 2011, 17, 11024 – 11029
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O. Reiser et al.
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Scheme 2. Proposed transition state.
Acknowledgements
A.K. thanks Alexander von Humboldt Foundation (AvH) for a postdoc-
toral fellowship and T.M. thanks the Deutscher Akademischer Austausch
Dienst (DAAD) for a doctoral fellowship.
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Chem. Eur. J. 2011, 17, 11024 – 11029

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Received: April 28, 2011
Published online: August 17, 2011
Chem. Eur. J. 2011, 17, 11024 – 11029
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www.chemeurj.org
11029